PMID- 26765955 TI - Fluorescent asymmetric bis-ureas for pyrophosphate recognition in pure water. AB - Three fluorescent asymmetric bis-urea receptors (L1-L3) have been synthesised. The binding properties of L1-L3 towards different anions (fluoride, acetate, hydrogencarbonate, dihydrogen phosphate, and hydrogen pyrophosphate HPpi(3-)) have been studied by means of (1)H-NMR, UV-Vis and fluorescence spectroscopy, single crystal X-ray diffraction, and theoretical calculations. In particular, a remarkable affinity for HPpi(3-) has been observed in the case L1 (DMSO-d6/0.5% H2O) which also acts as a fluorimetric chemosensor for this anion. Interestingly, when L1 is included in cetyltrimethylammonium (CTAB) micelles, hydrogen pyrophosphate recognition can also be achieved in pure water. PMID- 26765956 TI - Hip fracture and the influence of dementia on health outcomes and access to hospital-based rehabilitation for older individuals. AB - BACKGROUND: For older individuals who sustain a hip fracture, the presence of dementia can influence their access to hospital-based rehabilitation. PURPOSE: This study compares the characteristics and health outcomes of individuals with and without dementia following a hip fracture; and access to, and outcomes following, hospital-based rehabilitation in a population-based cohort. METHOD: An examination of hip fractures involving individuals aged 65 years and older with and without dementia using linked hospitalisation, rehabilitation and mortality records during 2009-2013. RESULTS: There were 8785 individuals with and 23 520 individuals without dementia who sustained a hip fracture. Individuals with dementia had a higher age-adjusted 30-d mortality rate compared to individuals without dementia (11.7% versus 5.7%), a lower proportion of age-adjusted 28-d re admission (17.3% versus 24.4%) and a longer age-adjusted mean length of stay (22.2 versus 21.9 d). Compared to individuals without dementia, individuals with dementia had 4.3 times (95% CI: 3.90-4.78) lower odds of receiving hospital-based rehabilitation. However, when they did receive rehabilitation they achieved significant motor functional gain at discharge compared to admission using the Functional Independence Measure, but to a lesser extent than individuals without dementia. CONCLUSION: Within a population-based cohort, older individuals with dementia can benefit from access to, and participation in, rehabilitation activities following a hip fracture. This will ensure that they have the best chance of returning to their pre-fracture physical function and mobility. Implications for Rehabilitation Older individuals with dementia can benefit from rehabilitation activities following a hip fracture. Early mobilisation of individuals post-hip fracture surgery, where possible, is advised. Further work is needed on how best to work with individuals with dementia after a hip fracture in residential aged care to maximise any potential functional gains. PMID- 26765957 TI - The Eyes Absent Proteins in Developmental and Pathological Angiogenesis. AB - Management of neoangiogenesis remains a high-value therapeutic goal. A recently uncovered association between the DNA damage repair pathway and pathological angiogenesis could open previously unexplored possibilities for intervention. An attractive and novel target is the Eyes absent (EYA) tyrosine phosphatase, which plays a critical role in the repair versus apoptosis decision after DNA damage. This study examines the role of EYA in the postnatal development of the retinal vasculature and under conditions of ischemia-reperfusion encountered in proliferative retinopathies. We find that the ability of the EYA proteins to promote endothelial cell (EC) migration contributes to a delay in postnatal development of the retinal vasculature when Eya3 is deleted specifically in ECs. By using genetic and chemical biology tools, we show that EYA contributes to pathological angiogenesis in a model of oxygen-induced retinopathy. Both in vivo and in vitro, loss of EYA tyrosine phosphatase activity leads to defective assembly of gamma-H2AX foci and thus to DNA damage repair in ECs under oxidative stress. These data reveal the potential utility of EYA tyrosine phosphatase inhibitors as therapeutic agents in inhibiting pathological neovascularization with a range of clinical applications. PMID- 26765959 TI - Enhanced Photocatalytic Activity of Bismuth Precursor by Rapid Phase and Surface Transformation Using Structure-Guided Combustion Waves. AB - The development of an efficient method for manipulating phase and surface transformations would facilitate the improvement of catalytic materials for use in a diverse range of applications. Herein, we present the first instance of a submicrosecond time frame direct phase and surface transformation of Bi(NO3)3 rods to nanoporous beta-Bi2O3 rods via structure-guided combustion waves. Hybrid composites of the prepared Bi(NO3)3.H2O rods and organic fuel were fabricated by a facile preparation method. The anisotropic propagation of combustion waves along the interfacial boundaries of Bi(NO3)3.H2O rods induced direct phase transformation to beta-Bi2O3 rods in the original structure due to the rapid pyrolysis, while the release of gas molecules enabled the formation of nanoporous structures on the surfaces of rods. The developed beta-Bi2O3 rods showed improved photocatalytic activity for the photodegradation of rhodamine B in comparison with Bi(NO3)3.H2O rods and alpha-Bi2O3 rods due to the more suitable interdistance and the large contact areas of the porous surfaces. This new method of using structure-guided combustion waves for phase and surface transformation may contribute to the development of new catalysts as well as the precise manipulation of diverse micronanostructured materials. PMID- 26765958 TI - Altered Expression of Bone Morphogenetic Protein Accessory Proteins in Murine and Human Pulmonary Fibrosis. AB - Idiopathic pulmonary fibrosis is a chronic, progressive fibrotic disease with a poor prognosis. The balance between transforming growth factor beta1 and bone morphogenetic protein (BMP) signaling plays an important role in tissue homeostasis, and alterations can result in pulmonary fibrosis. We hypothesized that multiple BMP accessory proteins may be responsible for maintaining this balance in the lung. Using the bleomycin mouse model for fibrosis, we examined an array of BMP accessory proteins for changes in mRNA expression. We report significant increases in mRNA expression of gremlin 1, noggin, follistatin, and follistatin-like 1 (Fstl1), and significant decreases in mRNA expression of chordin, kielin/chordin-like protein, nephroblastoma overexpressed gene, and BMP and activin membrane-bound inhibitor (BAMBI). Protein expression studies demonstrated increased levels of noggin, BAMBI, and FSTL1 in the lungs of bleomycin-treated mice and in the lungs of idiopathic pulmonary fibrosis patients. Furthermore, we demonstrated that transforming growth factor beta stimulation resulted in increased expression of noggin, BAMBI, and FSTL1 in human small airway epithelial cells. These results provide the first evidence that multiple BMP accessory proteins are altered in fibrosis and may play a role in promoting fibrotic injury. PMID- 26765960 TI - Superoxide dismutases in chronic gastritis. AB - Human gastric diseases have shown significant changes in the activity and expression of superoxide dismutase (SOD) isoforms. The aim of this study was to detect Mn-SOD activity and expression in the tissue of gastric mucosa, primarily in chronic gastritis (immunohistochemical Helicobacter pylori-negative gastritis, without other pathohistological changes) and to evaluate their possible connection with pathohistological diagnosis. We examined 51 consecutive outpatients undergoing endoscopy for upper gastrointestinal symptoms. Patients were classified based on their histopathological examinations and divided into three groups: 51 patients (archive samples between 2004-2009) with chronic immunohistochemical Helicobacter pylori-negative gastritis (mononuclear cells infiltration were graded as absent, moderate, severe) divided into three groups. Severity of gastritis was graded according to the updated Sydney system. Gastric tissue samples were used to determine the expression of Mn-SOD with anti-Mn-SOD Ab immunohistochemically. The Mn-SOD expression was more frequently present in specimens with severe and moderate inflammation of gastric mucosa than in those with normal mucosa. In patients with normal histological finding, positive immunoreactivity of Mn-SOD was not found. Our results determine the changes in Mn SOD expression occurring in the normal gastric mucosa that had undergone changes in the intensity of chronic inflammatory infiltrates in the lamina propria. PMID- 26765961 TI - I148M variant of PNPLA3 increases the susceptibility to non-alcoholic fatty liver disease caused by obesity and metabolic disorders. AB - BACKGROUND: The patatin-like phospholipase 3 (PNPLA3) rs738409 gene polymorphism is an important genetic determinant of non-alcoholic fatty liver disease (NAFLD). However, the associations between liver fat and metabolic traits in rs738409 G allele carriers and the allelic influence on this association have not been fully studied. AIM: To investigate the influence of the PNPLA3 gene polymorphism on the association of liver fat with serum metabolic factors and carotid atherosclerosis. METHODS: Liver fat was measured by quantitative ultrasound in 4300 subjects in the Shanghai Changfeng community and analysed for its association with obesity and metabolic factors in individuals with the PNPLA3 CC, CG and GG genotypes. RESULTS: Non-alcoholic fatty liver disease occurred in 37.9% and 28.8% of the subjects with the GG and CC genotypes respectively (P < 0.001). Liver fat was significantly associated with body mass index, waist circumference, serum triglycerides, high-density lipoprotein cholesterol, fasting blood glucose and insulin in the PNPLA3 rs738409 G allele carriers (P < 0.001). Compared with the CC homozygotes, the GG homozygotes presented higher liver fat and liver fibrosis scores despite their better metabolic status (comparison of regression line slopes, P < 0.05). An increase in liver fat was accompanied by a significant increase in the average and maximum carotid intima-media thickness in subjects with the PNPLA3 CC genotype but not in those with the GG genotype. CONCLUSIONS: PNPLA3 rs738409 G allele carriers were found to be more susceptible to the metabolic-related hepatic steatosis, and developed NAFLD and liver fibrosis despite presenting relatively better metabolic statuses and lower risks for carotid atherosclerosis. PMID- 26765962 TI - Clinical Outcomes of Endoscopic Ultrasonography-Guided Pancreatic Cyst Ablation. AB - OBJECTIVES: Endoscopic ultrasonography-guided ethanol ablation therapy for pancreatic cystic lesions is a minimally invasive treatment but still is an experimental therapy. The aims were to investigate the safety and efficacy of endoscopic ultrasonography-guided ethanol ablation therapy. METHODS: The inclusion criteria were the following: clinically indeterminate pancreatic cystic lesions in radiologic imaging studies, 2 to 5 cm unilocular or oligolocular cysts without communication to main pancreatic duct, and patients with high-risk operation. RESULTS: There were 91 study patients with median follow-up of 40 months. The response rate was as follows: complete resolution, 41 (45%); partial resolution, 37; and persistent cysts, 13. Pancreatic cystic lesions were categorized based on cystic fluid analysis: 9 intraductal papillary mucinous neoplasms (IPMNs), 12 mucinous cystic neoplasms, 33 serous cystic neoplasms, and 28 uncategorized cysts. The success rate was significantly different according to cystic fluid analysis (serous cystic neoplasm, 58%; mucinous cystic neoplasm, 50%; IPMN, 11%; uncategorized cysts, 39%; P < 0.0001). There were 3 patients with mild pancreatitis after the treatment. CONCLUSIONS: Endoscopic ultrasonography guided ethanol ablation therapy seems to be a safe treatment modality. However, it was only effective in 11% of IPMNs. Therefore, the clinical application should be very limited for certain patients who could not tolerate the surgical treatment. PMID- 26765963 TI - Monocarboxylate Transporters MCT1 and MCT4 Regulate Migration and Invasion of Pancreatic Ductal Adenocarcinoma Cells. AB - OBJECTIVES: Novel treatments for pancreatic ductal adenocarcinoma (PDAC) are severely needed. The aim of this work was to explore the roles of H-lactate monocarboxylate transporters 1 and 4 (MCT1 and MCT4) in PDAC cell migration and invasiveness. METHODS: Monocarboxylate transporter expression, localization, activity, and function were explored in human PDAC cells (MIAPaCa-2, Panc-1, BxPC 3, AsPC-1) and normal human pancreatic ductal epithelial (HPDE) cells, by quantitative polymerase chain reaction, immunoblotting, immunocytochemistry, lactate flux, migration, and invasion assays. RESULTS: MCT1 and MCT4 (messenger RNA, protein) were robustly expressed in all PDAC lines, localizing to the plasma membrane. Lactate influx capacity was highest in AsPC-1 cells and lowest in HPDE cells and was inhibited by the MCT inhibitor alpha-cyano-4-hydroxycinnamate (4 CIN), MCT1/MCT2 inhibitor AR-C155858, or knockdown of MCT1 or MCT4. PDAC cell migration was largely unaffected by MCT1/MCT2 inhibition or MCT1 knockdown but was reduced by 4-CIN and by MCT4 knockdown (BxPC-3). Invasion measured in Boyden chamber (BxPC-3, Panc-1) and spheroid outgrowth (BxPC-3) assays was attenuated by 4-CIN and AR-C155858 and by MCT1 or MCT4 knockdown. CONCLUSIONS: Human PDAC cells exhibit robust MCT1 and MCT4 expression and partially MCT1- and MCT4-dependent lactate flux. PDAC cell migration is partially dependent on MCT4; and invasion, on MCT1 and MCT4. Inhibition of MCT1 and MCT4 may have clinical relevance in PDAC. PMID- 26765964 TI - Prognostic Validity of the American Joint Committee on Cancer and the European Neuroendocrine Tumors Staging Classifications for Pancreatic Neuroendocrine Tumors: A Retrospective Nationwide Multicenter Study in South Korea. AB - OBJECTIVES: Pancreatic neuroendocrine tumors (pNETs) are diverse diseases with different prognosis. The American Joint Committee on Cancer (AJCC) and the European Neuroendocrine Tumor Society (ENETS) introduced 2 different tumor node metastasis (TNM) stages, and the World Health Organization (WHO) proposed WHO 2010 grading system for pNETs. Therefore, we aimed to validate the prognostic relevance of these 3 systems for pNETs in South Korea. METHODS: The Korean Society of Gastrointestinal Cancer created a retrospective registry of pNETs in 153 patients from 15 hospitals between 2002 and 2012. RESULTS: On the basis of the WHO 2010 grade, 2-year progression-free-survival (PFS) rates for G1, G2, and G3 were 92%, 62%, and 25% (P < 0.01). According to ENETS and AJCC staging, 2-year PFS rates for stages I through IV were 94%, 87%, 49%, 20%, and 92%, 61%, 60%, 20%, respectively (P < 0.01). A Cox multivariate regression analysis revealed that the only statistically significant prognostic factor was the TNM classification of either the AJCC or the ENETS stage (P < 0.01). In addition, the kappa value between the AJCC and the ENETS stages was 0.46 indicating a "moderate" agreement (P < 0.01). CONCLUSIONS: The AJCC and ENETS TNM classifications for pNETs are prognostic for PFS and can be adopted in clinical practice in South Korea. PMID- 26765965 TI - Pancreatic Adenocarcinoma in the Finistere Area, France, Between 2002 and 2011 (1002 Cases): Population Characteristics, Treatment and Survival. AB - OBJECTIVES: The aims of the study were (a) to describe the characteristics of all incident cases of pancreatic adenocarcinoma diagnosed in the population of the Finistere area between 2002 and 2011, (b) to report on their therapeutic management, and (c) to analyze survival and prognostic factors. METHODS: All residents of the administrative region of Finistere who were diagnosed with pancreatic adenocarcinoma between January 2002 and December 2011 were registered in the digestive cancer registry. Survival data were analyzed using the Kaplan Meier method and were compared using log-rank tests. Multivariate analysis was performed using a binary logistic regression model to identify prognostic factors. RESULTS: A total of 1002 patients with a pancreatic adenocarcinoma were registered, of whom 60% had metastases at diagnosis. Only 10% of patients underwent a potentially curative negative margin resection (R0); their median survival was 22.0 months. The median survival of the overall population was 4.1 months. The stages of the disease and the patient's age were independent prognostic factors in multivariate analysis. CONCLUSIONS: Our study confirms the dramatic prognosis of this cancer. Because the tumor stage is the main prognostic factor in pancreatic adenocarcinoma, efforts should focus on the earlier diagnosis of pancreatic cancer. PMID- 26765966 TI - Large-scale distribution of microbial and viral populations in the South Atlantic Ocean. AB - Viruses are abundant, diverse and dynamic components of the marine environments and play a significant role in the ocean biogeochemical cycles. To assess potential variations in the relation between viruses and microbes in different geographic regions and depths, viral and microbial abundance and production were determined throughout the water column along a latitudinal transect in the South Atlantic Ocean. Path analysis was used to examine the relationships between several abiotic and biotic parameters and the different microbial and viral populations distinguished by flow cytometry. The depth-integrated contribution of microbial and viral abundance to the total microbial and viral biomass differed significantly among the different provinces. Additionally, the virus-to-microbe ratio increased with depth and decreased laterally towards the more productive regions. Our data revealed that the abundance of phytoplankton and microbes is the main controlling factor of the viral populations in the euphotic and mesopelagic layers, whereas in the bathypelagic realm, viral abundance was only weakly related to the biotic and abiotic variables. The relative contribution of the three viral populations distinguished by flow cytometry showed a clear geographical pattern throughout the water column, suggesting that these populations are composed of distinct taxa able to infect specific hosts. Overall, our data indicate the presence of distinct microbial patterns along the latitudinal transect. This variability is not limited to the euphotic layer but also detectable in the meso- and bathypelagic layers. PMID- 26765967 TI - Molecular characterization of Botrytis ourmia-like virus, a mycovirus close to the plant pathogenic genus Ourmiavirus. AB - The molecular characterization of a novel single-stranded RNA virus, obtained by next generation sequencing using Illumina platform, in a field grapevine isolate of the plant pathogenic fungus Botrytis, is reported in this work. The sequence comparison of this virus against the NCBI database showed a strong identity with RNA dependent RNA polymerases (RdRps) of plant pathogenic viruses belonging to the genus Ourmiavirus, therefore, this novel virus was named Botrytis ourmia-like virus (BOLV). BOLV has one open reading frame of 2169 nucleotides, which encodes a protein of 722 amino acids showing conserved domains of plant RNA viruses RdRps such as the most conserved GDD active domain. Our analyses showed that BOLV is phylogenetically closer to the fungal Narnavirus and the plant Ourmiavirus than to Mitovirus of the family Narnaviridae. Hence, we proposed that BOLV might represent the link between fungal viruses of the family Narnaviridae and the plant ourmiaviruses. PMID- 26765968 TI - A novel rabies vaccine based-on toll-like receptor 3 (TLR3) agonist PIKA adjuvant exhibiting excellent safety and efficacy in animal studies. AB - Vaccination alone is not sufficiently effective to protect human from post exposure rabies virus infection due to delayed generation of rabies virus neutralizing antibodies and weak cellular immunity. Therefore, it is vital to develop safer and more efficacious vaccine against rabies. PIKA, a stabilized chemical analog of double-stranded RNA that interacts with TLR3, was employed as adjuvant of rabies vaccine. The efficacy and safety of PIKA rabies vaccine were evaluated. The results showed that PIKA rabies vaccine enhanced both humoral and cellular immunity. After viral challenge, PIKA rabies vaccine protected 70-80% of animals, while the survival rate of non-adjuvant vaccine group (control) was 20 30%. According to the results of toxicity tests, PIKA and PIKA rabies vaccine are shown to be well tolerated in mice. Thus, this study indicates that PIKA rabies vaccine is an effective and safe vaccine which has the potential to develop next generation rabies vaccine and encourage the start of clinical studies. PMID- 26765969 TI - Antagonism or synergism between papaya ringspot virus and papaya mosaic virus in Carica papaya is determined by their order of infection. AB - Antagonism between unrelated plant viruses has not been thoroughly described. Our studies show that two unrelated viruses, papaya ringspot virus (PRSV) and papaya mosaic virus (PapMV) produce different symptomatic outcomes during mixed infection depending on the inoculation order. Synergism occurs in plants infected first with PRSV or in plants infected simultaneously with PRSV and PapMV, and antagonism occurs in plants infected first with PapMV and later inoculated with PRSV. During antagonism, elevated pathogenesis-related (PR-1) gene expression and increased reactive oxygen species production indicated the establishment of a host defense resulting in the reduction in PRSV titers. Polyribosomal fractioning showed that PRSV affects translation of cellular eEF1alpha, PR-1, beta-tubulin, and PapMV RNAs in planta, suggesting that its infection could be related to an imbalance in the translation machinery. Our data suggest that primary PapMV infection activates a defense response against PRSV and establishes a protective relationship with the papaya host. PMID- 26765970 TI - Influence of RNA Strand Rigidity on Polyion Complex Formation with Block Catiomers. AB - Polyion complexes (b-PICs) are prepared by mixing single- or double-stranded oligo RNA (aniomer) with poly(ethylene glycol)-b-poly(L-lysine) (PEG-PLL) (block catiomer) to clarify the effect of aniomer chain rigidity on association behaviors at varying concentrations. Here, a 21-mer single-stranded RNA (ssRNA) (persistence length: 1.0 nm) and a 21-mer double-stranded RNA (small interfering RNA, siRNA) (persistence length: 62 nm) are compared. Both oligo RNAs form a minimal charge-neutralized ionomer pair with a single PEG-PLL chain, termed unit b-PIC (uPIC), at low concentrations (<~ 0.01 mg mL(-1)). Above the critical association concentration (~ 0.01 mg mL(-1)), ssRNA b-PICs form secondary associates, PIC micelles, with sizes up to 30-70 nm, while no such multimolecular assembly is observed for siRNA b-PICs. The entropy gain associated with the formation of a segregated PIC phase in the multimolecular PIC micelles may not be large enough for rigid siRNA strands to compensate with appreciably high steric repulsion derived from PEG chains. Chain rigidity appears to be a critical parameter in polyion complex association. PMID- 26765972 TI - Two-dimensional infrared spectroscopy of neat ice Ih. AB - The assignment of the distinct peaks observed in the OH stretch lineshape of ice Ih is controversial. Recent two-dimensional infrared spectroscopic measurements provided new data. The spectra are, however, challenging to interpret and here we provide simulations that help overcome experimental issues as thermal signals and finite pulse duration. We find good agreement with experiment and the difference between H2O and D2O ices is well accounted for. The overall dynamics is demonstrated to be faster than observed for the corresponding liquid water. We find that excitonic cross peaks exist between the dominant exciton peaks. This leads us to conclude that the cross peaks arise due to the formation of delocalized exciton states, which have essentially no directional correlation between their transition dipoles as opposed to what is commonly seen, for example, in isolated water, where the transition dipoles of the eigenstates are perpendicular to each other. PMID- 26765971 TI - Maternal behavior as a predictor of sibling interactions during mealtimes. AB - Children who frequently experience encouragement or pressure to eat are more likely to exhibit less favorable eating behaviors and dietary outcomes. Siblings can encourage or pressure each other to eat during mealtimes, but the role of mothers in shaping sibling mealtime interactions is not understood. The objective of this study was to examine the association between the behavior of mothers and siblings during mealtimes. The associations of maternal presence and maternal engagement with children during mealtimes with encouragements to eat delivered by the child to his/her sibling were examined. Children aged 4-8years (n=73) were videotaped while eating a routine evening meal at home with one sibling present. Encouragement to eat delivered by the index child to the sibling, maternal presence, and non-food-related and food-related maternal engagement were coded from the videotapes. Poisson regression showed that maternal presence was associated with fewer encouragements to eat from the index child to the sibling (rate ratio (RR): 0.40, 95% confidence interval (CI): 0.26, 0.62). Each type of maternal engagement was independently associated with the number of encouragements to eat from the index child to the sibling: maternal engagement that was not food-related was associated with fewer encouragements to eat (RR: 0.62, 95% CI: 0.53, 0.73), while maternal engagement that was food-related was associated with more encouragements to eat (RR: 1.49, 95% CI: 1.22, 1.81). Future studies may explore how sibling interactions may mediate links between maternal behavior during mealtimes and children's health-related outcomes. PMID- 26765973 TI - Progressively Earlier Initiation of Renal Replacement Therapy for Acute Kidney Injury Is Unwarranted and Potentially Harmful. AB - BACKGROUND: The optimal timing of renal replacement therapy (RRT) initiation for acute kidney injury (AKI) is unknown. There is debate as to whether starting RRT earlier for AKI is superior to starting it only after 'conventional', life threatening indications are present. SUMMARY: In recent years, there has been an ongoing trend in clinical practice to initiate RRT for AKI long before indications appear. Observational studies show many patients now begin RRT for AKI in the absence of 'conventional' indications. While this shift may have been prompted by observational studies suggesting improved outcomes with earlier RRT, there was not sufficient justification for a change in clinical practice: many recent, observational studies suggest that early RRT may not beneficial or may be even harmful. Moreover, none of 3 underpowered RCTs reported to date found 'early' RRT initiation beneficial. Lowering the threshold for RRT initiation inevitably leads to more patients receiving unnecessary treatment and this is a matter of concern, considering the fact that complications are potentially fatal and RRT is very costly. While we await definitive studies, calls to shift clinical practice back toward the initiation of RRT for 'conventional', life threatening indications only, should be heeded. KEY MESSAGES: 'Earlier' initiation of RRT for AKI is already occurring in clinical practice but is not justified on the basis of the studies to date. Lowering the threshold for initiation leads to more patients receiving unnecessary RRT. RRT has potentially fatal complications and is expensive. While we await definitive trials, RRT should be started only after 'conventional', life-threatening indications occur and not earlier. PMID- 26765974 TI - Copper-Catalyzed Denitrogenative Transannulation Reaction of Pyridotriazoles: Synthesis of Imidazo[1,5-a]pyridines with Amines and Amino Acids. AB - The copper-catalyzed aerobic oxidative synthesis of imidazo[1,5-a]pyridines via cascade denitrogenative transannulation reaction of pyridotriazoles with benzylamines with good functional group tolerance is developed. The present methodology is also applicable to amino acids to obtain imidazo[1,5-a]pyridines via decarboxylative oxidative cyclization. PMID- 26765976 TI - Synergistic gold and enamine catalysis: intermolecular alpha-alkylation of aldehydes with allenamides. AB - Aldehydes can be alpha-alkylated with allenamides by the combined action of an organocatalyst and a gold complex. The reaction requires the simultaneous generation of an enamine and a gold-activated allenamide. Importantly, by using a chiral amine as organocatalyst it is possible to obtain aldehyde products featuring all-carbon quaternary stereocenter at their alpha-position, with moderate to good levels of enantioselectivity. PMID- 26765975 TI - Modeling complete removal of risk assessment questions in the USA predicts the risk of HIV exposure in blood recipients could increase despite the use of nucleic acid testing. AB - BACKGROUND AND OBJECTIVES: The safety of the blood supply in a number of countries is achieved by interventions that include behaviour-based time-limited or indefinite deferrals and screening of donated units for transfusion transmitted infections. The relatively high sensitivity of nucleic acid testing (NAT) used in blood donor screening has raised the question of whether such time based deferrals can be eliminated in favour of individual risk assessment. MATERIALS AND METHODS: Data on the annual number of incident human immunodeficiency virus (HIV) infections associated with various behaviours and on the performance characteristics of NAT applied to donor screening were used to model the number of potentially infected units that might escape detection in the worst-case scenario in which individual risk assessment was implemented, but was not effective as a screening tool, and donors did not otherwise self-select for lower risk. RESULTS: In the absence of effective individual risk-based screening or donor self-selection, the model predicts that in the United States, an additional 39 (95% CI 35-43) HIV-infected units would escape detection by nucleic acid testing, potentially capable of exposing approximately 68 (95% CI 61-75) individuals to the risk of HIV infection through the administration of prepared blood components. CONCLUSION: Despite some inherent uncertainty, the worst-case scenario of completely ineffective individual risk assessment, absence of donor self-selection and increased reliance on NAT for blood screening is estimated to be associated with an approximately fourfold increase in the risk of HIV exposure through transfusion in the United States. PMID- 26765977 TI - Does Helicobacter pylori play a role in the pathogenesis of non-cystic fibrosis bronchiectasis? AB - BACKGROUND: The aim of this study was to investigate whether Helicobacter pylori plays a role in the pathogenesis and severity of non-cystic fibrosis bronchiectasis, and its relationship with gastroesophageal reflux (GER). METHODS: Forty-one patients and 16 controls between 5 and 18 years of age were enrolled. H. pylori was investigated on polymerase chain reaction and culture in gastric juice (GJ) and bronchoalveolar lavage fluid (BALF). Urea breath test (UBT) was also used for defining H. pylori infection. GER was detected on 24 h pH monitoring or scintigraphy. Computed tomography (CT) scoring was used to quantify the severity and extent of bronchiectasis. RESULTS: Nine patients (22%) in the bronchiectasis group (BG) and three patients (18.8%) in the control group (CG) had H. pylori-positive BALF. Sixteen BG patients (39%) and seven CG patients (43.8%) had H. pylori-positive GJ. UBT was positive in 11 BG patients (26.8%) and in three CG patients (18.8%). H. pylori positivity in BALF, GJ and UBT was not significantly different between the two groups (P > 0.05). Six patients with GER and five patients without GER in BG had H. pylori-positive BALF and GJ (P = 0.827). No association was found between BALF H. pylori positivity and forced expiratory volume in 1 s (FEV1 ) in BG. CT score was significantly higher in BG patients with H. pylori-positive compared with H. pylori-negative BALF (P < 0.05). CONCLUSIONS: Helicobacter pylori is not associated with the pathogenesis of bronchiectasis but it may be responsible for the severity of the disease. PMID- 26765978 TI - Infection control in the operating room: is it more than a clean dish? AB - PURPOSE OF REVIEW: Healthcare-associated infections (HCAIs) are driven by a complex interplay between host defenses, pathogen traits, and pathogen transmission. A better understanding of each of these factors is required to extend infection control beyond antibiotic therapy to improvements in basic preventive measures that can achieve sustained HCAI reductions. The purpose of this article is to review recent advancements in our understanding of these issues for the operating room environment. RECENT FINDINGS: The importance and implications of intraoperative bacterial transmission have been solidified, and hyper transmissible, virulent, and antibiotic resistant bacterial strains have been characterized. As a result, a best practice for improved intraoperative infection control has been delineated. Little advancement has been made in our understanding of the efficacy of higher inspired oxygen concentrations, improved postoperative glucose control, perioperative normothermia, and prophylactic antibiotic selection, timing, and dose for HCAI prevention. SUMMARY: Recent work has led to the development of evidence-based hand hygiene, environmental cleaning, patient decolonization, and intravascular catheter design and handling improvement strategies. Evidence suggests that a best practice for postoperative infection control is a multimodal program that utilizes these interventions to target patient, provider, and environmental reservoirs in parallel. The development of novel diagnostic tools for targeted attenuation of hyper virulent, transmissible and resistant strains/strain characteristics is indicated to improve patient decolonization efforts. PMID- 26765979 TI - Individualized antibiotic strategies. AB - PURPOSE OF REVIEW: Infections are common complications in critically ill patients and are frequently treated with antibiotics. Unfortunately, delivery of optimal therapy is complicated because efficacy of antimicrobials is influenced by the timing of treatment initiation, the use of combination therapy, and the optimization of drug dosing. RECENT FINDINGS: Early diagnosis of infection is mandatory to provide a rapid and appropriate antibiotic therapy. The presence of less susceptible strains, in particular for hospital-acquired infections, or patients with severe disease, such as the presence of septic shock, may need combination antibiotic therapy. Antibiotic pharmacokinetics, notably volume of distribution and total body clearance, are significantly altered in these critically ill patients and can influence the attainment of adequate circulating levels when standard dosage regimens are administered. Higher dosing should be considered in such patients, although in case of renal impairment and reduced clearance, drug accumulation could also result in some side-effects. Nebulized antibiotics may provide a better clinical response than systemic antibiotics in ventilator-associated pneumonia because of multidrug-resistant pathogens. SUMMARY: The optimal use of antibiotics in the management of severe infections is an important challenge for ICU physicians. Antimicrobial therapy needs to be individualized according to specific patient characteristics, infecting organisms, and susceptibility patterns. PMID- 26765980 TI - A MULTIVARIATE MODEL OF SYNESTHESIA. AB - Synesthesia is defined in this paper as a sensory phenomenon in which a stimulus in one sense mode is interpreted in terms appropriate to some other sense mode. The paper deals explicitly with auditory-visual synesthesia or chromesthesia. The model proposes two cognitive spaces for the two sense modes, differing from each other only in terms of what is called a modal axis. Two separate sub-populations of individuals are hypothesized, one made up of persons who can collapse their cognitive space along the modal axis. These people are assumed to be those who regularly experience synesthesia. Persons who do not regularly experience synesthesia axe assumed either (a) to be unable to collapse their cognitive space, or (b) to do so in a different way. Subjeats in the study rated colors and adjectives as to their appropriate- ness in describing musical selections. Estimates of color and adjective spaces were computed by cluster analyses based upon the ratings. The color space closely resembled the three-dimensional color solid, and fit well with the adjective space. Subsamples selected as extreme groups on the basis of synesthesia experience showed identical adjective spaces but different color spaces, as would be predicted from the model. PMID- 26765981 TI - PREDICTIVE EFFICIENCY AS A FUNCTION OF AMOUNT OF INFORMATION. AB - The effect of changing the amount of information on judges' predictive efficiency in a clinical prediction task was studied. Thirty judges predicted 30 students' average achievement scores on the basis of different amount of test data. One group of judges had information about the intercorrelations among the tests and the ecologkal validity of the tests. Another group of judges had only informahion about which tests were used. The predictive efficiency was not a monotonically increasing function of amount of test data. The most marked result was that the relative predictive efficiency decreased from four to six tests in both groups. PMID- 26765982 TI - A FACTOR ANALYSIS OF SELECTED MARKERS FOR OBJECTIVE PERSONALITY FACTORS. AB - A large scale (60 variables, 569 subjects), attempted replication of Cattell's factors U.I. 16, 17, 19, 20, 21, 23, 24, 32 is reported, plus an evaluation of his universal index series. Factoring was carried out on marker variables, with both orthogonal and oblique rotation, at both primary and sec- ondary factor levels. Seven factors were identifiable a t the primary level and four at the secondary level. At neither level were the factors other than partly similar, and then only in certain cases, to Cattell's factors. An examination of Cattell's data both in general and in a specific case and a discussion of necessary criteria to assess replication show why this might occur. Contrary to prior kpectation what actually emerged from this group of carefully selected Cattell markers were factors which more closely resembled those of Eysenck, especially at the second order level. PMID- 26765983 TI - TOWARD THE INTERPRETATION OF CANONICAL DIMENSIONS. AB - Since canonical correlations (Rc) reflect the relationships between linear combinations of two sets of items, variance shared by both sets may or may not be high. This paper examines a procedure providing needed clarification in the interpretation of Rc. Three canonical solutions disclosed that highly sig- nificant Rcs may actually represent very little overlapping variance. A redundancy index proved to be an invaluable aid for placing the Rc in proper perspective. The efficiency for extracting shared variance was found to decrease steadily with each successive canonical variate. PMID- 26765984 TI - A METHOD FOR IDENTIFYING HOMOGENEOUS CLASSES. AB - The problem of selecting a method for identifying homogeneous classes within a heterogeneous sample was considered. It was suggested that a definition of a class was needed to provide the basis for such a method of analysis. Thus a method was proposed which was explicitly derived from a definition. The defiition required the objects in a class to be different from objects not in the class as well as similar to each other. A comparison of the results from various samples indicated the necessity for classification methods to recognize the error in natural observations. As the size of a sample increases, so does the probability of a deviant or erroneous comparison among objects. Thus an allowance was made for 6% of the comparisons involving any object to be deviant. PMID- 26765985 TI - THE SELECTION OF INDEPENDENT VARIABLES AND PRIOR PROBABILITIES AS A FACTOR INFLUENCING THE ACCURACY OF CLASSIFYING INDIVIDUALS TO EXISTING GROUPS. AB - This paper first examines some of the suggestions made by Lohnes and Gribbons (1970) for improving the hit rate of multiple discriminant classification analysis. Alternative to their ideas are advanced and the effect upon hit rate is determined. It is found that an improvement, over their best hit rate, of greater than 26% can be achieved by adopting the ideas proposed by this paper. These involve a more careful selection of the variables and the prior probabilities used in the discriminant function. PMID- 26765986 TI - FOUR METHODS OF ANALYZING BETWEEN VARIATION FOR THE K-GROUP MANOVA PROBLEM. AB - Four methods of analyzing between variation in the k-group MANOVA problem are considered. Specifically, they are (1) discriminant analysis, (2) stepdown analysis, (3) contrasts on the classification variable and (4) a two group breakdown. These methods are discussed briefly, with certain basic com- puting equations being given. Then a sample problem is used to illustrate how the methods may be applied and interpreted. The univariate h2 (squared correlation ratio) is related t o a corresponding multivariate measure. Also, a variant of h2 is introduced to indicate the proportion of variance in each of the dependent variables which is accounted for by the classification variable. PMID- 26765987 TI - MULTIVARIATE INDICES OF STRENGTH OF ASSOCIATION. AB - Multivariate extensions of univariate measures of association that are employed in comparative experiments are reviewed. Two of these are generalizations of the correlation ratio, and the third is a generalization of Hays' omega. The numerical values of these three indices are empirically compared along with a fourth index, the proportion of correct classifications, using two sets of data and various numbers of predictor variables. As in the univariate case, the values of the correlational indices are nearly the same in all situations investigated. The use of a correlational index versus the proportion of correct classifications depends upon the intent of the researcher. PMID- 26765989 TI - Buffy coat smear or Knott's test: which to choose for canine microfilaria screening in field studies? AB - BACKGROUND: In recent years, an increasing number of cases of canine dirofilariasis have been reported worldwide. However, the rate of infection in dogs is largely unknown in many remote areas, and the importance of field studies for determination of the prevalence of canine dirofilariasis in such areas is well recognized. The detection of microfilariae by the modified Knott's test (MKT) is a recommended screening method for canine dirofilariasis. OBJECTIVES: The purposes of this study were to compare the diagnostic sensitivity of the MKT with the buffy coat smear method (BCS), and to evaluate the utility of these 2 methods under field study conditions. METHODS: One hundred and fifty dogs of the Maio Island of Republic of Cabo Verde, were screened for microfilariae using MKT and BCS. The results of the 2 methods were generated in a blinded manner and statistically compared. RESULTS: The detection rate was 4.67% with the MKT and 5.33% with BCS, which is statistically not different. The latter allowed a morphologic identification of Dirofilaria repens (later confirmed by molecular biology methods) and an estimation of parasite load, which varied from 15 to 185 microfilariae/mL. CONCLUSIONS: The methods MKT and BCS were comparable in terms of diagnostic sensitivity. However, the BCS was technically less demanding and produced permanent preparations, in which co-infection with other hematologic pathogens can easily be assessed. Overall, this method is well suited to assess microfilariae in a large number of animals, and it could replace the MKT in studies devoted to dirofilariasis. PMID- 26765990 TI - Outcomes of Implementing an Evidence-Based Hypertension Clinical Guideline in an Academic Nurse Managed Health Center. AB - This column shares the best evidence-based strategies and innovative ideas on how to facilitate the learning and implementation of EBP principles and processes by clinicians as well as nursing and interprofessional students. Guidelines for submission are available at http://onlinelibrary.wiley.com/journal/10.1111/(ISSN)1741-6787. PMID- 26765991 TI - Different NT-proBNP circulating levels for different types of cardiac amyloidosis. AB - AIM: Several studies suggest that the N-terminal fragment of pro-brain natriuretic peptide levels are quite different in wild-type transthyretin (TTR) related amyloidosis (ATTRwt) and mutated TTR-related amyloidosis (ATTRm) compared with immunoglobulin light-chain cardiac amyloidosis. Our aim was to test this hypothesis in a cohort of patients with different types of cardiac amyloidosis. PATIENTS AND METHODS: Seventy patients with ATTRwt, ATTRm, and light-chain cardiac amyloidosis matched for left ventricular (LV) mass index were studied by standard echocardiography, tissue Doppler imaging, and plasmatic cardiac biomarkers. RESULTS: Despite similar LV mass and renal function, patients with ATTR cardiac amyloidosis showed lower levels of N-terminal fragment of pro-brain natriuretic peptide than do light-chain amyloidosis ones, especially when expressed as a function of LV mass index. CONCLUSION: Amyloidogenic light-chain derived fibrils induce more severe myocardial dysfunction in light-chain amyloidosis than in ATTR, despite similar myocardial infiltration. Thus, the degree of cardiac dysfunction may be related not only to the amount of amyloid deposited, but also to qualitative differences among fibrils. PMID- 26765992 TI - Pregnancy in women with cardiovascular disease in the guidelines era: an Italian single-center experience. AB - AIMS: The aim of the present study is to determine pregnancy outcome with regard to the risk class and the modality way of referral to our joint Cardiac Obstetric Clinic. METHODS: This is a prospective observational study. Patients referred to our clinic between 2011 and 2014 were included. Reason and timing for referral were recorded. Two groups were identified: women who were known to have cardiac disease before referral (group I) and women who were not (group II). Pregnancies were managed as recommended by the ESC Guidelines. Cardiac events were defined as death, heart failure requiring treatment, documented tachyarrhythmias, thromboembolic events and need for urgent endovascular procedures or surgery. RESULTS: Of the 110 pregnancies, 51 (47%) were in group I and 57 (53%) in group II. Congenital (44%) and valvular (27%) diseases were the most frequent diagnosis. Thirty-two percent of patients were in WHO risk classes III-IV. Thirty percent were referred for symptoms, 70% for risk assessment. Women in group II were evaluated later in pregnancy than those in group I (25.6 +/- 9 vs. 21.4 +/- 9; P < 0.01). Cardiovascular events occurred in 15 (13.6%) pregnancies and were more common in WHO risk classes III-IV (11, P < 0.001), in group II (12, P= 0.02) and in patients referred for symptoms (11, P < 0.001). Stillbirths occurred only in classes III-IV (three pregnant, 2.7%). CONCLUSION: There was no maternal or neonatal mortality and an overall acceptable incidence of cardiovascular events but a relevant percentage of pregnant were first referred late and/or for the onset of symptoms. Events were more frequent in these patients. Further efforts are needed to optimize referral to specialized centers. PMID- 26765993 TI - Variations in voice level and fundamental frequency with changing background noise level and talker-to-listener distance while wearing hearing protectors: A pilot study. AB - OBJECTIVE: Speech production in noise with varying talker-to-listener distance has been well studied for the open ear condition. However, occluding the ear canal can affect the auditory feedback and cause deviations from the models presented for the open-ear condition. Communication is a main concern for people wearing hearing protection devices (HPD). Although practical, radio communication is cumbersome, as it does not distinguish designated receivers. A smarter radio communication protocol must be developed to alleviate this problem. Thus, it is necessary to model speech production in noise while wearing HPDs. Such a model opens the door to radio communication systems that distinguish receivers and offer more efficient communication between persons wearing HPDs. DESIGN: This paper presents the results of a pilot study aimed to investigate the effects of occluding the ear on changes in voice level and fundamental frequency in noise and with varying talker-to-listener distance. STUDY SAMPLE: Twelve participants with a mean age of 28 participated in this study. RESULTS: Compared to existing data, results show a trend similar to the open ear condition with the exception of the occluded quiet condition. CONCLUSIONS: This implies that a model can be developed to better understand speech production for the occluded ear. PMID- 26765996 TI - Up-regulated fractalkine (FKN) and its receptor CX3CR1 are involved in fructose induced neuroinflammation: Suppression by curcumin. AB - Recent studies suggest that diet-induced fractalkine (FKN) stimulates neuroinflammation in animal models of obesity, yet how it occurs is unclear. This study investigated the role of FKN and it receptor, CX3CR1, in fructose-induced neuroinflammation, and examined curcumin's beneficial effect. Fructose feeding was found to induce hippocampal microglia activation with neuroinflammation through the activation of the Toll-like receptor 4 (TLR4)/nuclear transcription factor kappaB (NF-kappaB) signaling, resulting in the reduction of neurogenesis in the dentate gyrus (DG) of mice. Serum FKN levels, as well as hypothalamic FKN and CX3CR1 gene expression, were significantly increased in fructose-fed mice with hypothalamic microglia activation. Hippocampal gene expression of FKN and CX3CR1 was also up-regulated at 14d and normalized at 56d in mice fed with fructose, which were consistent with the change of GFAP. Furthermore, immunostaining showed that GFAP and FKN expression was increased in cornu amonis 1, but decreased in DG in fructose-fed mice. In vitro studies showed that GFAP and FKN expression was stimulated in astrocytes, and suppressed in mixed glial cells exposed to 48h-fructose, with the continual increase of pro-inflammatory cytokines. Thus, increased FKN and CX3CR1 may cause a cross-talk between activated glial cells and neurons, playing an important role in the development of neuroinflammation in fructose-fed mice. Curcumin protected against neuronal damage in hippocampal DG of fructose-fed mice by inhibiting microglia activation and suppressed FKN/CX3CR1 up-regulation in the neuronal network. These results suggest a new therapeutic approach to protect against neuronal damage associated with dietary obesity-associated neuroinflammation. PMID- 26765997 TI - Suppressor of cytokine signaling 2 modulates the immune response profile and development of experimental cerebral malaria. AB - Plasmodium falciparum infection results in severe malaria in humans, affecting various organs, including the liver, spleen and brain, and resulting in high morbidity and mortality. The Plasmodium berghei ANKA (PbA) infection in mice closely recapitulates many aspects of human cerebral malaria (CM); thus, this model has been used to investigate the pathogenesis of CM. Suppressor of cytokine signaling 2 (SOCS2), an intracellular protein induced by cytokines and hormones, modulates the immune response, neural development, neurogenesis and neurotrophic pathways. However, the role of SOCS2 during CM remains unknown. SOCS2 knockout (SOCS2(-/-)) mice infected with PbA show an initial resistance to infection with reduced parasitemia and production of TNF, TGF-beta, IL-12 and IL-17 in the brain. Interestingly, in the late phase of infection, SOCS2(-/-) mice display increased parasitemia and reduced Treg cell infiltration, associated with enhanced levels of Th1 and Th17 cells and related cytokines IL-17, IL-6, and TGF beta in the brain. A significant reduction in protective neurotrophic factors, such as glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF), was also observed. Moreover, the molecular alterations in the brain of infected SOCS2(-/-) mice were associated with anxiety related behaviors and cognition impairment. Mechanistically, these results revealed enhanced nitric oxide (NO) production in PbA-infected SOCS2(-/-) mice, and the inhibition of NO synthesis through l-NAME led to a marked decrease in survival, the disruption of parasitemia control and more pronounced anxiety-like behavior. Treatment with l-NAME also shifted the levels of Th1, Th7 and Treg cells in the brains of infected SOCS2(-/-) mice to the background levels observed in infected WT, with remarkable exception of increased CD8(+)IFN(+) T cells and inflammatory monocytes. These results indicate that SOCS2 plays a dual role during PbA infection, being detrimental in the control of the parasite replication but crucial in the regulation of the immune response and production of neurotrophic factors. Here, we provided strong evidence of a critical relationship between SOCS2 and NO in the orchestration of the immune response and development of CM during PbA infection. PMID- 26765998 TI - Characterization of the full-length btuB riboswitch from Klebsiella pneumoniae. AB - Riboswitches are cis-regulatory RNA elements on the mRNA level that control the expression of the downstream coding region. The interaction of the riboswitch with its specific metabolite, which is related to the function of the controlled gene, induces a structural change of the RNA architecture. Consequently, gene regulation is induced by un/masking of the ribosome binding site (RBS). In the genome of Klebsiella pneumoniae a sequence was identified by bioinformatics and proposed to be a B12 riboswitch regulated by coenzyme B12. Here we study this new coenzyme B12-dependent riboswitch system by in-line probing and ITC. The riboswitch sequence includes the whole expression platform as well as RBS. In line probing experiments were performed to investigate the structural rearrangement of this 243-nt long RNA sequence while Isothermal Titration Calorimetry (ITC) yielded the thermodynamic parameters of the interaction between the riboswitch and its metabolite. The interaction of coenzyme B12 with the butB riboswitch of K. pneumoniae is an exothermic process with a 1:1 binding stoichiometry and binding affinities of log KA=6.73+/-0.02 at 15 degrees C and log KA=6.00+/-0.09 at 30 degrees C. PMID- 26765999 TI - New antibacterial, non-genotoxic materials, derived from the functionalization of the anti-thyroid drug methimazole with silver ions. AB - The new silver(I) compound {[AgBr(MU2-S-MMI)(TPP))]2} (1) and the known one [AgCl(TPP)2(MMI)] (2) were obtained by refluxing toluene solutions of silver(I) halide with triphenylphosphine (TPP) and the anti-thyroid drug 2-mercapto-1 methyl-imidazole or methimazole (MMI). The complexes were characterized by m.p., vibrational spectroscopy (mid-FT-IR), (1)H, (31)P-NMR, UV-Vis spectroscopic techniques and X-ray crystallography. The antibacterial effect of 1 and 2 against the bacterial species Pseudomonas aeruginosa (PAO) and Escherichia coli was evaluated. Compound 1 exhibits comparable activity to the corresponding one of the silver nitrate which is an antibacterial drug in use. The in vivo genotoxicity of 1-2 by the mean of Allium cepa test shows no alterations in the mitotic index values due to the absence of chromosomal aberrations. The mechanism of action of the title compounds is evaluated. The DNA binding tests indicate the ability of the complexes 1-2 to modify the activity of the bacteria. The binding constants of 1-2 towards CT-DNA indicate interaction through opening of the hydrogen bonds of DNA. Docking studies on DNA-complexes interactions confirm the binding of both complexes 1-2 in the major groove of the CT-DNA. In conclusion the silver complex 1 is an anti-bacterial and non-genotoxic material, which can be applied to antibacterial drug in the future. PMID- 26766000 TI - Evaluation of employing poly-lysine tags versus poly-histidine tags for purification and characterization of recombinant copper-binding proteins. AB - Quantitative characterization of metalloproteins at molecular and atomic levels generally requires tens of milligrams of highly purified samples, a situation frequently challenged by problems in generating unmodified native forms. A variety of affinity tags, such as the popular poly-histidine tag, have been developed to facilitate purification but they generally rely on expensive affinity resins and their presence may interfere with protein characterization. This paper documents that addition of a poly-lysine tag to the C-terminus enables, for the copper-binding proteins examined, ready purification in large scale via cost-effective cation-exchange chromatography. The tag may be removed readily by the enzyme carboxypeptidase B to generate the native protein with no extra residues. However, this cleavage step is normally not necessary since the poly-lysine tag is shown to have no detectable affinity for either Cu(I) or Cu(II) and imposes no interference to the copper binding properties of the target proteins. In contrast, the poly-histidine tag possesses a sub-picomolar affinity for Cu(I) and -nanomolar affinity for Cu(II) and may need to be removed for reliable characterization of the target proteins. These conclusions may be extended to the study of other metallo-proteins and metallo-enzymes. PMID- 26766001 TI - The inhibition of glycerol permeation through aquaglyceroporin-3 induced by mercury(II): A molecular dynamics study. AB - Mercurial compounds are known to inhibit water permeation through aquaporins (AQPs). Although in the last years some hypotheses were proposed, the exact mechanism of inhibition is still an open question and even less is known about the inhibition of the glycerol permeation through aquaglyceroporins. Molecular dynamics (MD) simulations of human aquaporin-3 (AQP3) have been performed up to 200ns in the presence of Hg(2+) ions. For the first time, we have observed the unbiased passage of a glycerol molecule from the extracellular to cytosolic side. Moreover, the presence of Hg(2+) ions covalently bound to Cys40 leads to a collapse of the aromatic/arginine selectivity filter (ar/R SF), blocking the passage of both glycerol and water. Interestingly, the local conformational changes of the protein follow mercury coordination by water and by aminoacidic donor atoms. Overall, the obtained results are important to improve the design of selective AQP inhibitors for future therapeutic and imaging applications. PMID- 26766017 TI - Linkage to and retention in care following healthcare transition from pediatric to adult HIV care. AB - Outcomes following healthcare transition (HCT) from pediatric to adult HIV care are not well described. We sought to describe clinical outcomes following HCT within our institution among young adults with behavioral-acquired (N = 31) and perinatally-acquired (N = 19) HIV. We conducted a retrospective cohort study among HIV-infected adults who attempted transition from pediatric to adult HIV care within our institution. The primary end point was retention in care, defined as the completion of at least two visits over 12 months following linkage to adult care. Additional end points include time to linkage to adult care, and changes in CD4 + T cell count and HIV RNA across time. Outcomes were compared between perinatal and behavioral HIV cohorts. Binary data were analyzed using the Fisher exact test and continuous data were analyzed using the Mann-Whitney test. Forty-three (86%) of 50 patients were successfully linked to adult care. The median time to linkage was 98 days. Fifty percent of patients achieved full retention in care at 12 months post-linkage. Though those with behavioral acquired HIV attempted transfer at an older age, the groups did not differ in rates of linkage and retention in adult care. CD4 + T cell counts and rates of viral suppression did not differ between pre- and post-HCT periods. Despite high rates of successful linkage to adult care in our study population, rates of retention in adult HIV care following HCT were low. These results imply that challenges remain in the adult HIV care setting toward improving the HCT process. PMID- 26766018 TI - Chain-Length-Dependent Exciton Dynamics in Linear Oligothiophenes Probed Using Ensemble and Single-Molecule Spectroscopy. AB - Exciton dynamics in pi-conjugated molecular systems is highly susceptible to conformational disorder. Using time-resolved and single-molecule spectroscopic techniques, the effect of chain length on the exciton dynamics in a series of linear oligothiophenes, for which the conformational disorder increased with increasing chain length, was investigated. As a result, extraordinary features of the exciton dynamics in longer-chain oligothiophene were revealed. Ultrafast fluorescence depolarization processes were observed due to exciton self-trapping in longer and bent chains. Increase in exciton delocalization during dynamic planarization processes was also observed in the linear oligothiophenes via time resolved fluorescence spectra but was restricted in L-10T because of its considerable conformational disorder. Exciton delocalization was also unexpectedly observed in a bent chain using single-molecule fluorescence spectroscopy. Such delocalization modulates the fluorescence spectral shape by attenuating the 0-0 peak intensity. Collectively, these results provide significant insights into the exciton dynamics in conjugated polymers. PMID- 26766020 TI - Giant Energy Density and Improved Discharge Efficiency of Solution-Processed Polymer Nanocomposites for Dielectric Energy Storage. AB - Large-aspect-ratio composite nanofibers with interior hierarchical interfaces are employed to break the adverse coupling of electric displacement and breakdown strength in flexible poly(vinylidene fluoride-hexafluoropropylene) nanocomposite films, a small loading of 3 vol% BaTiO3@TiO2 nanofibers gives rise to the highestenergy density (~31.2 J cm(-3)) ever achieved in polymer nanocomposites dielectrics. PMID- 26766021 TI - Effect of nitrate enrichment and diatoms on the bioavailability of Fe(III) oxyhydroxide colloids in seawater. AB - The photoconversion of colloidal iron oxyhydroxides was a significant source of bioavailable iron in coastal systems. Diatoms dominate phytoplankton communities in coastal and upwelling regions. Diatoms are often exposed to eutrophication. We investigated the effects of different species of diatom, cell density, illumination period, and nitrate additions on the bioavailability of Fe(III) oxy hydroxide colloids in seawaters. With the increase of illumination period from 1 to 4 h, the ratios of concentrations of total dissolved Fe (DFe) to colloidal iron oxyhydroxides and Fe(II) to DFe increased up to 24.3% and 23.9% for seawater without coastal diatoms, 45.6% and 30.2% for Skeletonema costatum, 44.3% and 29.7% for Thalassiosira weissflogii, respectively. The photochemical activity of coastal diatoms themselves (excluding the dissolved organic matter secreted by algae) on the species transformation of iron in seawater (including the light induced dissolution of Fe(III) oxyhydroxide colloids and the photo-reduction of Fe(III) into Fe(II)) was confirmed for the first time. There was no significant difference of the ability of S. costatum and Thalassiosira weissflogii on the photoconversion of colloidal iron oxyhydroxides. The photoproduction of dissolved Fe(II) and DFe in the seawater with or without diatoms could be depressed by the nitrate addition. PMID- 26766022 TI - Photolytic fate and genotoxicity of benzophenone-derived compounds and their photodegradation mixtures in the aqueous environment. AB - This study investigates the environmental fate of eight benzophenone derivatives (the pharmaceutical ketoprofen, its phototransformation products 3 ethylbenzophenone and 3-acetylbenzophenone, and five benzophenone-type UV filters) by evaluating their photolytic behaviour. In addition, the genotoxicity of these compounds and the produced photodegradation mixtures was studied. Laboratory-scale irradiation experiments using a medium pressure UV lamp revealed that photodegradation of benzophenones follows pseudo-first-order kinetics. Ketoprofen was the most photolabile (t1/2 = 0.8 min), while UV filters were more resistant to UV light with t1/2 between 17 and 99 h. The compounds were also exposed to irradiation by natural sunlight and showed similar photostability as predicted under laboratory conditions. Solar photodegradation experiments were performed in distilled water, lake and seawater, and revealed that photosensitizers present in natural waters significantly affect the photolytic behaviour of the investigated compounds. In this case, the presence of lake water resulted in accelerated photodecomposition, while seawater showed different effects on photodegradation, depending on a compound. Further, it was shown that the transformation products of ketoprofen 3-ethylbenzophenone and 3 acetylbenzophenone were formed under environmental conditions when ketoprofen was exposed to natural sunlight. Genotoxicity testing of parent benzophenone compounds using the SOS/umuC assay revealed that UV filters exhibited weak genotoxic activity in the presence of a metabolic activation system, however the concentrations tested were much higher than found in the environment (>=125 MUg mL(-1)). After irradiation of benzophenones, the produced photodegradation mixtures showed that, with the exception of benzophenone that exhibited weak genotoxic activity, all the other compounds tested did not elicit any activity when exposed to UV light. PMID- 26766023 TI - Photodecomposition of tetrabromobisphenol A in aqueous humic acid suspension by irradiation with light of various wavelengths. AB - The reactive species generated in aqueous 3,3',5,5'-tetrabromobisphenol A (TBBPA)/humic acid (HA) suspensions above the TBBPA pKa (~7.4), under various light-irradiation conditions, namely ambient and ultraviolet light, were investigated using electron paramagnetic resonance (EPR) spectroscopy and liquid chromatography-mass spectrometry (LC-MS). We confirmed that singlet oxygen and OH radicals are the key reactive oxygen species generated at wavelengths greater than 400 and 300 nm, respectively. The amount of 2,6-dibromo-p-benzosemiquinone anion radicals (2,6-DBSQ(*-)) formed under irradiation at 400 nm increased linearly with respect to irradiation time; the initial reaction rate was 7.03 * 10(-9) mol g(-1) HA s(-1). The rate increased with increasing pH and light intensity. LC-MS and EPR spectroscopy showed that tribromohydroxybisphenol A was formed under irradiation at 300 nm via reaction of OH radicals with TBBPA. This study, for the first time, shows that the main byproducts formed during irradiation at wavelengths above 300 nm are 2,6-DBSQ(*-) and tribromohydroxybisphenol A, generated from singlet oxygen ((1)O2) and OH radicals, respectively. Photodecomposition of TBBPA in the environment may occur by formation of (1)O2 and OH radicals. PMID- 26766024 TI - Effect of arsenate As (V) on the biomarkers of Myriophyllum alterniflorum in oligotrophic and eutrophic conditions. AB - Alternate watermilfoil, Myriophyllum alterniflorum is an aquatic macrophyte found in the Limousin rivers (France) whose potential for biomonitoring of metal pollution has been demonstrated. The objective of the present study carried out in vitro was to identify biomarkers for an early detection of the pollution by a metalloid As (V) in eutrophic and oligotrophic conditions. A synthetic medium of similar composition to the waters of the River Vienne was prepared. The morphological development of watermilfoil was monitored for 30 days, with or without contamination by 100 MUg L(-1) As (V). In addition, the mineralization of plants and the analysis of biomarkers (chlorophylls, photosynthetic and respiratory intensities ...) were investigated after 21 days. Our results indicated that eutrophic medium, induced a decrease in chlorophyll pigments, in growth and an increase in H2O2 compared to the oligotrophic medium. While, the presence of As (V), led to a decrease in the osmotic potential, pigment content, photosynthesis and respiration rates and an inhibition of shoot branching of plants in both conditions. However, a significant increase in H2O2 content was noted in the eutrophic medium. Finally, As (V) was found to be more accumulated in roots than shoots in both conditions but was more accumulated in oligotrophic one. Therefore, we can conclude that the water trophic level modifies the response of M. alterniflorum in presence of arsenate. Thus, M. alterniflorum shows a great promise in water-quality biomonitoring. PMID- 26766025 TI - The protective effect of vitamin E against changes in fatty acid composition of phospholipid subclasses in gill tissue of Oreochromis niloticus exposed to deltamethrin. AB - The effects of deltamethrin on the fatty acid composition of phospholipid subclasses (phosphatidylchlonine (PC), phosphatidylethanolamine (PE), phosphatidylinositole (PI) and phosphatidylserine (PS)) in gill tissue of Oreochromis niloticus (Perciformes: Cichlidae) and the possible protective effect of vitamin E against deltamethrin were determined by gas chromatography. The changes in the fatty acid profile were analysed after 14 d of exposure. Treatments included Group I (fed with basal diet only), Group II (fed with vitamin E-supplemented diet), Group III (fed with basal diet and exposed to deltamethrin) and Group IV (fed with vitamin E-supplemented diet and exposed to deltamethrin). The effects of deltamethrin on PI, PE and PS were valid for the total saturated fatty acids (SFAs), monounsaturated fatty acids (MUFAs) and polyunsaturated fatty acids (PUFAs). The effect on PC was detected in total SFAs and total PUFAs. The vitamin E-supplemented diet did not show complete protective effect on fatty acid composition of the fish exposed to deltamethrin. However, the protective effect was observed in total SFAs, total MUFAs and total PUFAs in PC. In PI, protective effect was only recorded on total PUFAs. There was no protective effect in PS and PE. The results of the present study demonstrated that deltametrin exposure had harmful effects on cell membrane and treatment with vitamin E could only partially protect fish gills. PMID- 26766026 TI - Evolutionary Footprints of Short Tandem Repeats in Avian Promoters. AB - Short tandem repeats (STRs) or microsatellites are well-known sequence elements that may change the spacing between transcription factor binding sites (TFBSs) in promoter regions by expansion or contraction of repetitive units. Some of these mutations have the potential to contribute to phenotypic diversity by altering patterns of gene expression. To explore how repetitive sequence motifs within promoters have evolved in avian lineages under mutation-selection balance, more than 400 evolutionary conserved STRs (ecSTRs) were identified in this study by comparing the 2 kb upstream promoter sequences of chicken against those of other birds (turkey, duck, zebra finch, and flycatcher). The rate of conservation was significantly higher in AG dinucleotide repeats than in AC or AT repeats, with the expansion of AG motifs being noticeably constrained in passerines. Analysis of the relative distance between ecSTRs and TFBSs revealed a significantly higher rate of conserved TFBSs in the vicinity of ecSTRs in both chicken-duck and chicken-passerine comparisons. Our comparative study provides a novel insight into which intrinsic factors have influenced the degree of constraint on repeat expansion/contraction during avian promoter evolution. PMID- 26766027 TI - Vascular response to everolimus- and biolimus-eluting coronary stents versus everolimus-eluting bioresorbable scaffolds--an optical coherence tomography substudy of the EVERBIO II trial. AB - QUESTIONS UNDER STUDY: Head-to-head optical coherence tomography (OCT) data comparing metallic stents with bioresorbable vascular scaffolds (BVS) are lacking. This study assessed vascular healing at 9-month follow-up after implantation of everolimus- and biolimus-eluting stents (EES; BES) and everolimus eluting BVS. METHODS: OCT was performed in 74 patients enrolled in the EVERBIO II (NCT01711931) trial (23 with EES: 26 lesions, 7 625 struts; 23 with BES: 26 lesions, 6 140 struts; 28 with BVS: 33 lesions, 10 891 struts). OCT images were acquired using the pullback and nonocclusive flushing technique and analysed offline. RESULTS: BVS demonstrated fewer uncovered struts per patient (12 +/- 27 [3.8 +/- 8.4%] vs 59 +/- 55 [21.8 +/- 13.7%] in the EES&BES group, p <0.001), and thicker neointimal hyperplasia (BVS 102 +/- 44 um vs EES&BES 66 +/- 36 um, p <0.01). There was no significant difference with regard to malapposed struts (2.1 +/- 2.7% in the BVS vs 4.4 +/- 8.8% in the EES&BES group, p = 0.41). In a predefined signal intensity scale, quantitative analysis of the "key component" (black) revealed lower intensity in BVS than EES&BES (14 +/- 23% vs 13 +/- 12%, p = 0.007). Intensity was lower in polylactide-containing stents (BVS&BES) than in EES (15 +/- 19% vs 10 +/- 10%, p <0.001). CONCLUSIONS: BVS has fewer uncovered struts and presents with a thicker neointimal coverage compared with EES&BES. It is not known whether this improved capping correlates with superior vascular healing. Polylactide-containing stents (BVS and BES) demonstrate lower peristrut intensity compared with EES. PMID- 26766028 TI - Health-Related Quality of Life in End-Stage Renal Disease Patients: How Often Should We Ask and What Do We Do with the Answer? AB - BACKGROUND: End-stage renal disease (ESRD) patients have poor health-related quality of life (HRQOL) comparing to general population and comparable HRQOL to patients with other major chronic diseases. Poor HRQOL is associated with shorter survival. There is a limited threshold to which dialysis dose and parameters management can improve HRQOL in ESRD patients. Numerous studies have sought to find interventions to improve HRQOL. This article is to review the symptoms associated with poor HRQOL and how frequent the quality of life (QOL) should be evaluated to improve the outcome. SUMMARY: It is required by the Center for Medicare and Medicaid Services to evaluate HRQOL of dialysis patients annually. KDIGO recommends the symptoms to be assessed regularly and the treatment is redirected toward a patient-centered care model. Studies have shown that measuring patient-reported outcomes frequently, from 4 times a day to every 3-6 months, without intervention did not improve the HRQOL significantly. Appropriate intervention of the symptoms may improve the quality of life (QOL). Studies in oncology have also showed a similar result. The commonly used tools to evaluate the HRQOL in dialysis patients take up to 30 min for completion. Therefore, frequent assessment of all the symptoms can provide more burden than benefit to the patients. In addition to the annual HRQOL measurements, more frequent evaluation of targeted symptoms can be helpful. For appropriate intervention of the symptoms, effective communication between providers, as well as a multidisciplinary approach, is essential to improve HRQOL and outcomes in dialysis patients. KEY MESSAGES: Measurement of patient-reported outcomes may provide an opportunity to improve outcomes in ESRD. The frequent measurement of symptoms and QOL may be burdensome. Consider targeted measurement of symptoms to complement HRQOL measurement. Improved communication and the use of a multidisciplinary team provide mechanisms to improve HRQOL in ESRD. PMID- 26766029 TI - Development and validation of a risk prediction algorithm for the recurrence of suicidal ideation among general population with low mood. AB - BACKGROUND: Suicidal ideation is one of the strongest predictors of recent and future suicide attempt. This study aimed to develop and validate a risk prediction algorithm for the recurrence of suicidal ideation among population with low mood METHODS: 3035 participants from U.S National Epidemiologic Survey on Alcohol and Related Conditions with suicidal ideation at their lowest mood at baseline were included. The Alcohol Use Disorder and Associated Disabilities Interview Schedule, based on the DSM-IV criteria was used. Logistic regression modeling was conducted to derive the algorithm. Discrimination and calibration were assessed in the development and validation cohorts. RESULTS: In the development data, the proportion of recurrent suicidal ideation over 3 years was 19.5 (95% CI: 17.7, 21.5). The developed algorithm consisted of 6 predictors: age, feelings of emptiness, sudden mood changes, self-harm history, depressed mood in the past 4 weeks, interference with social activities in the past 4 weeks because of physical health or emotional problems and emptiness was the most important risk factor. The model had good discriminative power (C statistic=0.8273, 95% CI: 0.8027, 0.8520). The C statistic was 0.8091 (95% CI: 0.7786, 0.8395) in the external validation dataset and was 0.8193 (95% CI: 0.8001, 0.8385) in the combined dataset. LIMITATIONS: This study does not apply to people with suicidal ideation who are not depressed. CONCLUSIONS: The developed risk algorithm for predicting the recurrence of suicidal ideation has good discrimination and excellent calibration. Clinicians can use this algorithm to stratify the risk of recurrence in patients and thus improve personalized treatment approaches, make advice and further intensive monitoring. PMID- 26766030 TI - Effects of smoking on perinatal depression and anxiety in mothers and fathers: A prospective cohort study. AB - INTRODUCTION: Considerable concern persists on tobacco use during perinatal periods. No study has simultaneously investigated the longitudinal association of paternal smoking with maternal and paternal depressive and anxiety symptoms during perinatal periods. METHODS: In this prospective study, 533 couples (pregnant women and their husbands) completed 5 self-report instruments from early pregnancy until 6 months postpartum. Generalized estimating equations were used for the analyses. RESULTS: We found that fathers who smoked in the mother's presence had higher depressive (regression coefficient=1.0, 95% confidence interval (CI) 0.3-1.8) and anxiety symptoms (3.0, 95% CI=1.2-4.7) during perinatal periods compared with nonsmoking fathers. Paternal smoking in the mother's presence also increased maternal disturbances, especially for depression during pregnancy (1.2, 95% CI=0.1-2.3) and anxiety during the postpartum period (3.4, 95% CI=0.6-6.3). No significant association was found between paternal smoking but not in the mother's presence and maternal emotional disturbances. Paternal smoking but not in the mother's presence affected only paternal anxiety, especially in the postpartum period (regression coefficient 2.7, 95% CI 0.7-4.7) compared with nonsmokers. LIMITATIONS: Self-report measures were used. The effects of maternal smoking could not be estimated because of the small sample of pregnant women who disclosed their smoking status. CONCLUSIONS: These findings imply a necessity to combine strategies for smoking cessation with interventions for affective disturbances in fathers. We also stress the importance of at least restricting the father's smoking in the presence of the pregnant wife during perinatal periods if smoking cessation is tentatively unattainable. PMID- 26766031 TI - Meta-analysis indicates that SNP rs9939609 within FTO is not associated with major depressive disorder (MDD) in Asian population. AB - BACKGROUND: Major depressive disorder (MDD) is one of the most prevalent psychiatric illnesses with heritability of up to 38%. The fat mass- and obesity associated (FTO) gene, in particular the single nucleotide polymorphism (SNP) rs9939609, has been identified as a genetic risk loci associated with MDD. However, most prior studies have involved European and American populations. Whether rs9939609 is an true risk SNP for MDD in Asian populations remains inconclusive. METHODS: In the present study, we conducted a meta-analysis of the association between rs9939609 and MDD in Asian populations by combining 5 available case-control samples totaling 6531 cases and 12,359 controls. RESULTS: Our meta-analysis suggests that rs9939609 is not a risk SNP for MDD in Asian populations by fixed effect model (Z=1.04, P=0.30, OR=0.96, 95% CI=0.90-1.03). LIMITATIONS: The age distribution and gender ratios were not matched well in the combined samples of cases and controls. Publication bias might be also considered with only a relatively small number of association studies of FTO rs9939609 with MDD in Asian populations. CONCLUSIONS: The absence of association of rs9939609 with MDD in our Asian populations suggests a potential genetic heterogeneity in the susceptibility of MDD on this locus. PMID- 26766032 TI - Patterns of microstructural white matter abnormalities and their impact on cognitive dysfunction in the various phases of type I bipolar disorder. AB - BACKGROUND: In recent years, diffusion tensor imaging (DTI) studies have detected subtle microstructural abnormalities of white matter (WM) in type I bipolar disorder (BD). However, WM alterations in the different phases of BD remain to be explored. The aims of this study is to investigate the WM alterations in the various phases of illness and their correlations with clinical and neurocognitive features. METHODS: We investigated the DTI-derived fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD) and axial diffusivity (AD) in patients with type I BD (n=61) subdivided in manic (n=21), depressive (n=20) and euthymic phases (n=20) vs. healthy controls (n=42), using a tract-based spatial statistics (TBSS) approach. Then, we investigated whether the subgroups of patients in the various phases of illness present different patterns of WM abnormalities. Finally we studied the correlations between WM alterations and clinical-cognitive parameters. RESULTS: We found a widespread alteration in WM microstructure (decrease in FA and increase in MD and RD) in BD when compared to controls. The various subgroups of BD showed different spatial patterns of WM alterations. A gradient of increasing WM abnormalities from the euthymic (low degree and localized WM alterations mainly in the midline structures) to the manic (more diffuse WM alterations affecting both midline and lateral structures) and, finally, to the depressive phase (high degree and widespread WM alterations), was found. Furthermore, the WM diffuse alterations correlated with cognitive deficits in BD, such as decreased fluency prompted by letter and decreased hits and increased omission errors at the continuous performance test. LIMITATIONS: Patients under treatment. CONCLUSIONS: The WM alterations in type I BD showed different spatial patterns in the various phases of illness, mainly affecting the active phases, and correlated with some cognitive deficits. This suggests a complex trait- and state-dependent pathogenesis of WM abnormalities in BD. PMID- 26766033 TI - Availability of prescription drugs for bipolar disorder at online pharmacies. AB - BACKGROUND: There is increasing use of online pharmacies to purchase prescription drugs. While some online pharmacies are legitimate and safe, there are many unsafe and illegal so-called "rogue" online pharmacies. This study investigated the availability of psychotropic drugs online to consumers in the US, using 5 commonly prescribed drugs for bipolar disorder. METHODS: Using the search term "buy [drug name]" in the Google, Yahoo and Bing search engines, the characteristics of the online pharmacies found on the first two pages of search results were investigated. The availability of the requested dosage and formulations of two brand (Seroquel XR, Abilify) and three generic drugs (lamotrigine, lithium carbonate and bupropion SR) were determined. RESULTS: Of 30 online pharmacies found, 17 (57%) were rated as rogue by LegitScript. Of the 30 pharmacies, 15 (50%) require a prescription, 21 (70%) claim to be from Canada, with 20 of these having a Canadian International Pharmacy association (CIPA) seal on the website. Only 13 of the 20 sites with a CIPA seal were active CIPA members. There were about the same number of trust verification seals on the rogue and legitimate pharmacy sites. Some rogue pharmacies are professional in appearance, and may be difficult for consumers to recognize as rogue. All five brand and generic drugs were offered for sale online, with or without a prescription. However, many substitutions were presented such as different strengths and formulations including products not approved by the FDA. LIMITATIONS: No evaluation of product quality, packaging or purchasing. CONCLUSIONS: Psychotropic medications are available online with or without a prescription. The majority of online pharmacy websites were rogue. Physicians should ask about the use of online pharmacies. For those who choose to use online pharmacies, two measures to detect rogue pharmacies are recommended: (1) only purchase drugs from pharmacies that require a prescription, and (2) check all pharmacy verification seals directly on the website of the certifying organization, every time, before purchase. PMID- 26766034 TI - Life adversity in depressed and non-depressed older adults: A cross-sectional comparison of the brief LTE-Q questionnaire and life events and difficulties interview as part of the CASPER study. AB - BACKGROUND: There is a paucity of research on the nature of life adversity in depressed and non-depressed older adults. Early life events work used in-depth interviews; however, larger epidemiological trials investigate life adversity using brief questionnaires. This study investigates the type of life adversity experienced in later life and its association with depression and compares adversity captured using a brief (LTE-Q) and in-depth (LEDS) measure. METHODS: 960 participants over 65 years were recruited in UK primary care to complete the PHQ-9 and LTE-Q. A sub-sample (n=19) completed the LEDS and a question exploring the subjective experience of the LTE-Q and LEDS. RESULTS: Important life adversity was reported on the LTE-Q in 48% of the sample. In the LTE-Q sample the prevalence of depression (PHQ-9>=10) was 12%. Exposure to recent adversity was associated with doubling of the odds of depression. The LTE-Q only captured a proportion of adversity measured by the LEDS (42% vs 84%). Both measures showed health, bereavement and relationship events were most common. LIMITATIONS: The cross-sectional design limits the extent to which inferences can be drawn around the direction of causality between adversity and depression. Recall in older adults is questionable. CONCLUSIONS: UK older adults face adversity in areas of health, bereavement and relationships which are associated with depression. This has clinical relevance for psychological interventions for older adults to consider social context and social support. It helps identify the strengths and weaknesses of a brief adversity measure in large scale research. Further research is needed to explore the mechanisms of onset and direction of causality. PMID- 26766035 TI - Clinical predictor and circulating microRNA profile expression in patients with early onset post-stroke depression. AB - OBJECTIVE: We aim to explore the clinical factors and blood biomarker for predicting the early-onset post-stroke depression (PSD). METHODS: 251 acute ischemic stroke patients were divided into PSD group and non-PSD group by Hamilton depression scale in 2 weeks after stroke. The clinical data, the severity, etiology and location of stroke were recorded. The analysis of inflammatory mediator, glycose and lipid metabolism was performed on the day of admission. The association between clinical factors and early onset PSD was studied by logistic regression analysis. In addition, the differentially expressed miRNAs in plasma between the two groups were screened by gene chip and the bio-information was further investigated by GO and KEEG analysis. RESULTS: Among 251 patients, 45 (17.93%) were diagnosed as early onset PSD. NIHSS score (>3) and carotid stenosis were independent relative factors with early-onset PSD (OR 3.479 and 2.617, p=0.000 and 0.009, respectively). Moreover, lower LDL trended toward association with early onset PSD in minor stroke subgroup (p=0.084). MiRNA profile demonstrated 25 differential expressed circulating miRNAs with FC>=2 and P<=0.05 between the two groups. The target genes of these miRNAs were enriched in pathways of cancer and MAPK signaling. LIMITATIONS: The sample of the study was small. The results should be further confirmed in large cohort patients. CONCLUSIONS: Early onset PSD was more likely in patients with severe neurological deficits and carotid artery stenosis, also note the possible association between lower LDL and depression in minor stroke. Blood miRNAs may be served as a potential biomarker for PSD diagnosis. PMID- 26766036 TI - Validity and reliability of the Brief version of Quality of Life in Bipolar Disorder" (Bref QoL.BD) among Chinese bipolar patients. AB - BACKGROUND: Previous literatures on quality of life (QoL) in bipolar disorder (BD) strongly suggested that a disease-specific QoL measure for patients with BD should be developed to evaluate QoL more specifically and reliably. To our knowledge, "Quality of Life in Bipolar Disorder" (QoL.BD) is the first and only questionnaire produced to specifically measure QoL in people with BD. In China, there is no disease-targeted measure available to specifically measure QoL in Chinese patients with BD. OBJECTIVE: The aim of the study is to revise and validate the brief version of the QoL.BD (Bref QoL.BD ) into Chinese version. METHODS: All the items of the Bref QoL.BD was translated into Chinese language, using the Brislin translation mode. The questionnaire was administered to a total sample of 231 subjects, including 101 BD patients and 130 healthy controls, to test the psychometric properties of Bref QoL.BD (e.g. internal consistency, retest reliability, content validity, item analysis, confirmatory factor analysis, criterion validity, convergent validity, discriminative validity and feasibility). RESULTS: The Chinese version of the Bref QoL.BD had very high internal consistency (Cronbach's alpha=0.815) and retest reliability (intraclass correlation coefficient (ICC )=0.808). Confirmatory factor analysis (CFA) validated the original one-factor structure. The direction and magnitude of correlations with 36-item Short-Form Health Survey (SF-36; rs= 0.313, P<0.001) and 17-Hamilton Depression Rating Scale(HAMD; rs=-0.328, P <0.001) suggesting the criterion validity and convergent validity, respectively. The scores of Bref QoL.BD in subsyndromic BD group (HDRS>=4 and BRMS>=3), asymptomatic BD group (HDRS<=3 and BRMS<=2) and the control group significantly decreased successively, suggesting a discriminative validity of the instrument. LIMITATIONS: Cross sectional design and a small sample size from only one tertiary care center. And BD patients enrolled were euthymic, excluding the acute BD patients. CONCLUSIONS: The Chinese version of the Bref QoL.BD is a feasible, reliable and valid tool for the assessment of QoL for Chinese BD patients. PMID- 26766037 TI - Fast-neutron multiplicity analysis based on liquid scintillation. AB - In this study, according to the establishment of the classical neutron multiplicity measurement equation, a fast-neutron multiplicity analysis and measurement equation is established, considering the influence of neutron scattering cross-talk, by means of theoretical analysis and computer simulation. Moreover, the fission rate F, multiplication M, and (alpha, n) reaction rate alpha in the established equation were solved. A new measurement method of scattering cross-talk was established and the established equation was validated using Geant4 simulation. The fast-neutron multiplicity counting equation has only a smaller deviation from the fast-neutron multiplicity counting system based on liquid scintillation detector, and it has a wider application prospect. PMID- 26766038 TI - Intracranial Transplantation of Hypoxia-Preconditioned iPSC-Derived Neural Progenitor Cells Alleviates Neuropsychiatric Defects After Traumatic Brain Injury in Juvenile Rats. AB - Traumatic brain injury (TBI) is a common cause of mortality and long-term morbidity in children and adolescents. Posttraumatic stress disorder (PTSD) frequently develops in these patients, leading to a variety of neuropsychiatric syndromes. Currently, few therapeutic strategies are available to treat juveniles with PTSD and other developmental neuropsychiatric disorders. In the present investigation, postnatal day 14 (P14) Wistar rats were subjected to TBI induced by a controlled cortical impact (CCI) (velocity = 3 m/s, depth = 2.0 mm, contact time = 150 ms). This TBI injury resulted in not only cortical damages, but also posttrauma social behavior deficits. Three days after TBI, rats were treated with intracranial transplantation of either mouse iPSC-derived neural progenitor cells under normal culture conditions (N-iPSC-NPCs) or mouse iPSC-derived neural progenitor cells pretreated with hypoxic preconditioning (HP-iPSC-NPCs). Compared to TBI animals that received N-iPSC-NPCs or vehicle treatment, HP-iPSC-NPC transplanted animals showed a unique benefit of improved performance in social interaction, social novelty, and social transmission of food preference tests. Western blotting showed that HP-iPSC-NPCs expressed significantly higher levels of the social behavior-related genes oxytocin and the oxytocin receptor. Overall, HP-iPSC-NPC transplantation exhibits a great potential as a regenerative therapy to improve neuropsychiatric outcomes after juvenile TBI. PMID- 26766039 TI - Insulin Signaling in Liver and Adipose Tissues in Periparturient Dairy Cows Supplemented with Dietary Nicotinic Acid. AB - The glucose homeostasis in dairy cattle is very well controlled, in line with the metabolic adaptation during the periparturient period. Former studies showed that nicotinic acid (NA) lowered plasma non-esterified fatty acids (NEFA) concentrations and increased insulin sensitivity in dairy cows. Thus, the purpose of this study was to investigate whether the expression of proteins involved in hepatic and adipose insulin signaling and protein expression of hepatic glucose transporter 2 (GLUT2) were affected by dietary NA and dietary concentrate intake in periparturient dairy cows. Twenty pluriparous German Holstein cows were fed with the same diet from about 21 days before the expected calving date (d-21) to calving. After calving, cows were randomly assigned in 4 groups and fed with diets different in concentrate proportion ("HC" with 60:40% or "LC" with 30:70% concentrate-to-roughage ratio) and supplemented with NA (24 g/day) (NA) or without (CON) until d21. Biopsy samples were taken from the liver, subcutaneous (SCAT) and retroperitoneal (RPAT) adipose tissues at d-21 and d21. Protein expression of insulin signaling molecules (insulin receptor (INSR), phosphatidylinositol-3-kinase (PI3K), protein kinase Czeta (PKCzeta)) and hepatic GLUT2 was measured by Western Blotting. The ratio of protein expression at d21/at d-21 was calculated and statistically evaluated for the effects of time and diet. Cows in HC had significantly higher dietary energy intake than cows in LC. In RPAT a decrease in PI3K and PKCzeta expression was found in all groups, irrespectively of diet. In the liver, the GLUT2 expression was significantly lower in cows in NA compared with cows in CON. In conclusion, insulin signaling might be decreased in RPAT over time without any effect of diet. NA was able to modulate hepatic GLUT2 expression, but its physiological role is unclear. PMID- 26766040 TI - Hepatitis B Virus HBx Activates Notch Signaling via Delta-Like 4/Notch1 in Hepatocellular Carcinoma. AB - Hepatitis virus B (HBV) infection is one of the major causes of hepatocellular carcinomas (HCC). HBx protein encoded in HBV genome is one of the key viral factors leading to malignant transformation of infected cells. HBx functions by interfering with cellular functions, causing aberration in cellular behaviour and transformation. Notch signalling is a well-conserved pathway involved in cellular differentiation, cell survival and cell death operating in various types of cells. Aberration in the Notch signalling pathways is linked to various tumors, including HCC. The role of HBx on the Notch signalling in HCC, however, is still controversial. In this study, we reported that HBV genome-containing HCC cell line HepG2 (HepG2.2.15) expressed higher Notch1 and Delta-like 4 (Dll4), compared to the control HepG2 without HBV genome. This upregulation coincided with increased appearance of the cleavage of Notch1, indicating constitutively activated Notch signalling. Silencing of HBx specifically reduced the level of Dll4 and cleaved Notch1. The increase in Dll4 level was confirmed in clinical specimens of HCC lesion, in comparison with non-tumor lesions. Using specific signalling pathway inhibitors, we found that MEK1/2, PI3K/AKT and NF-kappaB pathways are critical for HBx-mediated Dll4 upregulation. Silencing of HBx clearly decreased the level of phosphorylation of Akt and Erk1/2. Upon silencing of Dll4 in HepG2.2.15, decreased cleaved Notch1, increased apoptosis and cell cycle arrest were observed, suggesting a critical role of HBx-Dll4-Notch1 axis in regulating cell survival in HCC. Furthermore, clonogenic assay confirmed the important role of Dll4 in regulating cell survival of HBV-genome containing HCC cell line. Taken together, we reported a link between HBx and the Notch signalling in HCC that affects cell survival of HCC, which can be a potential target for therapy. PMID- 26766042 TI - Thank You, Edward. Merci, Louis. PMID- 26766041 TI - Protective Role of False Tendon in Subjects with Left Bundle Branch Block: A Virtual Population Study. AB - False tendons (FTs) are fibrous or fibromuscular bands that can be found in both the normal and abnormal human heart in various anatomical forms depending on their attachment points, tissue types, and geometrical properties. While FTs are widely considered to affect the function of the heart, their specific roles remain largely unclear and unexplored. In this paper, we present an in silico study of the ventricular activation time of the human heart in the presence of FTs. This study presents the first computational model of the human heart that includes a FT, Purkinje network, and papillary muscles. Based on this model, we perform simulations to investigate the effect of different types of FTs on hearts with the electrical conduction abnormality of a left bundle branch block (LBBB). We employ a virtual population of 70 human hearts derived from a statistical atlas, and run a total of 560 simulations to assess ventricular activation time with different FT configurations. The obtained results indicate that, in the presence of a LBBB, the FT reduces the total activation time that is abnormally augmented due to a branch block, to such an extent that surgical implant of cardiac resynchronisation devices might not be recommended by international guidelines. Specifically, the simulation results show that FTs reduce the QRS duration at least 10 ms in 80% of hearts, and up to 45 ms for FTs connecting to the ventricular free wall, suggesting a significant reduction of cardiovascular mortality risk. In further simulation studies we show the reduction in the QRS duration is more sensitive to the shape of the heart then the size of the heart or the exact location of the FT. Finally, the model suggests that FTs may contribute to reducing the activation time difference between the left and right ventricles from 12 ms to 4 ms. We conclude that FTs may provide an alternative conduction pathway that compensates for the propagation delay caused by the LBBB. Further investigation is needed to quantify the clinical impact of FTs on cardiovascular mortality risk. PMID- 26766068 TI - A Loop-Mediated Isothermal Amplification Assay and Sample Preparation Procedure for Sensitive Detection of Xanthomonas fragariae in Strawberry. AB - Xanthomonas fragariae is a bacterium that causes angular leaf spot of strawberry. Asymptomatic infection is common and contributes to the difficulties in disease management. The aim of this study was to develop a loop-mediated isothermal amplification (LAMP) assay as an efficient method for detection of asymptomatic infections of X. fragariae. In addition, a new method of sample preparation was developed that allows sampling of a larger amount of plant tissue, hence increasing the detection rate in real-life samples. The sample preparation procedure includes an overnight incubation of strawberry tissues in phosphate buffered saline (PBS), followed by a quick sample concentration and a boiling step to extract DNA for amplification. The detection limit of the LAMP assay was approximately 2*10(3) CFU/mL for pure bacteria culture and 300 CFU/mL for bacteria spiked strawberry leaf and petiole samples. LAMP provided a 2-3 fold lower detection limit than the standard qPCR assay but was faster, and more user friendly. The LAMP assay should serve as a rapid, sensitive and cost-effective tool for detecting asymptomatic infections of X. fragariae in strawberry nursery stock and contribute to improved disease management. PMID- 26766070 TI - Evolution and function of anterior cervical vertebral fusion in tetrapods. AB - The evolution of vertebral fusion is a poorly understood phenomenon that results in the loss of mobility between sequential vertebrae. Non-pathological fusion of the anterior cervical vertebrae has evolved independently in numerous extant and extinct mammals and reptiles, suggesting that the formation of a 'syncervical' is an adaptation that arose to confer biomechanical advantage(s) in these lineages. We review syncervical anatomy and evolution in a broad phylogenetic context for the first time and provide a comprehensive summary of proposed adaptive hypotheses. The syncervical generally consists of two vertebrae (e.g. hornbills, porcupines, dolphins) but can include fusion of seven cervical vertebrae in some cetaceans. Based on the ecologies of taxa with this trait, cervical fusion most often occurs in fossorial and pelagic taxa. In fossorial taxa, the syncervical likely increases the out-lever force during head-lift digging. In cetaceans and ricochetal rodents, the syncervical may stabilize the head and neck during locomotion, although considerable variation exists in its composition without apparent variability in locomotion. Alternatively, the highly reduced cervical vertebral centra may require fusion to prevent mechanical failure of the vertebrae. In birds, the syncervical of hornbills may have evolved in response to their unique casque-butting behaviour, or due to increased head mass. The general correlation between ecological traits and the presence of a syncervical in extant taxa allows more accurate interpretation of extinct animals that also exhibit this unique trait. For example, syncervicals evolved independently in several groups of marine reptiles and may have functioned to stabilize the head at the craniocervical joint during pelagic locomotion, as in cetaceans. Overall, the origin and function of fused cervical vertebrae is poorly understood, emphasizing the need for future comparative biomechanical studies interpreted in an evolutionary context. PMID- 26766069 TI - Statin Use and Incident Cataract Surgery: A Case-Control Study. AB - PURPOSE: To determine the association between statin use and incident cataract surgery. METHODS: Using the resources of the Rochester Epidemiology Project, a retrospective population-based, case-control study was performed. Cases included 6024 county residents aged 50 years and older who had first-eye cataract surgery between 1 January 2004 and 31 December 2011. Controls included residents who had never had cataract surgery and were matched to cases by age, sex, and index date within 1 month of surgery. Statin medications continuously prescribed for at least 1 year before the surgery date (cases) or index date (controls) were examined. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using logistic regression models. RESULTS: There were 2557 (42%) statin users among cases having cataract surgery compared to 2038 (34%) statin users among controls never having had cataract surgery (p < 0.0001). Incident cataract surgery was significantly associated with increased odds of statin use (OR 1.29, 95% CI 1.19-1.55) after adjusting for age, sex, diabetes, cardiovascular disease, cerebrovascular disease, peripheral vascular disease, renal disease, oral and inhaled steroid use, and selective serotonin reuptake inhibitor use. The association was consistent in both subgroups of women (OR 1.34, 95%CI 1.22-1.49) and men (OR 1.17, 95% CI 1.05-1.30). CONCLUSIONS: Incident cataract surgery was associated with increased odds of statin use, and underscores the possibility that increasing statin use could be contributing to rising rates of cataract surgery. PMID- 26766071 TI - MSClique: Multiple Structure Discovery through the Maximum Weighted Clique Problem. AB - We present a novel approach for feature correspondence and multiple structure discovery in computer vision. In contrast to existing methods, we exploit the fact that point-sets on the same structure usually lie close to each other, thus forming clusters in the image. Given a pair of input images, we initially extract points of interest and extract hierarchical representations by agglomerative clustering. We use the maximum weighted clique problem to find the set of corresponding clusters with maximum number of inliers representing the multiple structures at the correct scales. Our method is parameter-free and only needs two sets of points along with their tentative correspondences, thus being extremely easy to use. We demonstrate the effectiveness of our method in multiple-structure fitting experiments in both publicly available and in-house datasets. As shown in the experiments, our approach finds a higher number of structures containing fewer outliers compared to state-of-the-art methods. PMID- 26766072 TI - Direct Simulation of the Self-Assembly of a Small DNA Origami. AB - By using oxDNA, a coarse-grained nucleotide-level model of DNA, we are able to directly simulate the self-assembly of a small 384-base-pair origami from single stranded scaffold and staple strands in solution. In general, we see attachment of new staple strands occurring in parallel, but with cooperativity evident for the binding of the second domain of a staple if the adjacent junction is already partially formed. For a system with exactly one copy of each staple strand, we observe a complete assembly pathway in an intermediate temperature window; at low temperatures successful assembly is prevented by misbonding while at higher temperature the free-energy barriers to assembly become too large for assembly on our simulation time scales. For high-concentration systems involving a large staple strand excess, we never see complete assembly because there are invariably instances where two copies of the same staple both bind to the scaffold, creating a kinetic trap that prevents the complete binding of either staple. This mutual staple blocking could also lead to aggregates of partially formed origamis in real systems, and helps to rationalize certain successful origami design strategies. PMID- 26766109 TI - Using the Medication Error Prioritization System To Improve Patient Safety. AB - Coupled with administration support of an action plan that promotes quality of care and a culture of safety, the Medication Error Prioritization System (which automates parts of error review) has led to improvements for an integrated health care system. PMID- 26766110 TI - Therapy with low-dose azacitidine for MDS in children and young adults: a retrospective analysis of the EWOG-MDS study group. AB - Low-dose azacitidine is efficient and safe in the therapy of malignant myeloid disorders in adults but data in children are lacking. We present a retrospective analysis of 24 children and young adults with myelodysplastic syndrome (MDS) who received azacitidine at the time of first diagnosis or relapse after allotransplant (2 children were treated with azacitidine both initially and for relapse). Diagnoses were refractory cytopenia of childhood (N = 4), advanced primary MDS (N = 9) and secondary MDS (N = 11). The median duration of treatment was four cycles. Azacitidine was well tolerated, but cytopenias led to dose reduction in five cases. Treatment was discontinued in one child because of impaired renal function. Sixteen MDS patients were treated with azacitidine at first diagnosis. One complete clinical remission was observed and one child showed complete marrow remission; six children experienced stable disease with haematological improvement. Ten children received azacitidine for relapsed MDS after transplant: of these, seven experienced stable disease for 2-30 cycles (median 3), including one patient with haematological improvement for seven cycles. In summary, azacitidine is effective in some children with MDS and appears to be a non-toxic option in palliative situations to prolong survival. PMID- 26766111 TI - Ameloblastin, an Extracellular Matrix Protein, Affects Long Bone Growth and Mineralization. AB - Matrix molecules such as the enamel-related calcium-binding phosphoprotein ameloblastin (AMBN) are expressed in multiple tissues, including teeth, bones, and cartilage. Here we have asked whether AMBN is of functional importance for timely long bone development and, if so, how it exerts its function related to osteogenesis. Adolescent AMBN-deficient mice (AMBN(Delta5-6) ) suffered from a 33% to 38% reduction in femur length and an 8.4% shorter trunk spinal column when compared with WT controls, whereas there was no difference between adult animals. On a cellular level, AMBN truncation resulted in a shortened growth plate and a 41% to 49% reduction in the number of proliferating tibia chondrocytes and osteoblasts. Bone marrow stromal cells (BMSCs) isolated from AMBN mutant mice displayed defects in proliferation and differentiation potential as well as cytoskeleton organization. Osteogenesis-related growth factors, such as insulin like growth factor 1 (IGF1) and BMP7, were also significantly (46% to 73%) reduced in AMBN-deficient BMSCs. Addition of exogenous AMBN restored cytoskeleton structures in AMBN mutant BMSCs and resulted in a dramatic 400% to 600% increase in BMP2, BMP7, and Col1A expression. Block of RhoA diminished the effect of AMBN on osteogenic growth factor and matrix protein gene expression. Addition of exogenous BMP7 and IGF1 rescued the proliferation and differentiation potential of AMBN-deficient BMSCs. Confirming the effects of AMBN on long bone growth, back crossing of mutant mice with full-length AMBN overexpressors resulted in a complete rescue of AMBN(Delta5-6) bone defects. Together, these data indicate that AMBN affects extracellular matrix production and cell adhesion properties in the long bone growth plate, resulting in altered cytoskeletal dynamics, increased osteogenesis-related gene expression, as well as osteoblast and chondrocyte proliferation. We propose that AMBN facilitates rapid long bone growth and an important growth spurt during the skeletogenesis of adolescent tooth-bearing vertebrates. (c) 2016 American Society for Bone and Mineral Research. PMID- 26766112 TI - Women selectively guard their (desirable) mates from ovulating women. AB - For women, forming close, cooperative relationships with other women at once poses important opportunities and possible threats-including to mate retention. To maximize the benefits and minimize the costs of same-sex social relationships, we propose that women's mate guarding is functionally flexible and that women are sensitive to both interpersonal and contextual cues indicating whether other women might be likely and effective mate poachers. Here, we assess one such cue: other women's fertility. Because ovulating (i.e., high-fertility) women are both more attractive to men and also more attracted to (desirable) men, ovulating women may be perceived to pose heightened threats to other women's romantic relationships. Across 4 experiments, partnered women were exposed to photographs of other women taken during either their ovulatory or nonovulatory menstrual cycle phases, and consistently reported intentions to socially avoid ovulating (but not nonovulating) women-but only when their own partners were highly desirable. Exposure to ovulating women also increased women's sexual desires for their (highly desirable) partners. These findings suggest that women can be sensitive to subtle cues of other women's fertility and respond (e.g., via social exclusion, enhanced sexual attention to own mate) in ways that may facilitate their mate retention goals while not thwarting their affiliative goals. PMID- 26766113 TI - Selective Multiamination of C70 Leading to Curved pi Systems with 60, 58, 56, and 50 pi Electrons. AB - Secondary aliphatic amines add to a pole pentagon of [70]fullerene in the presence of N-fluorobenzenesulfonimide to form cyclopentadienyl-type adducts, C70(NSO2 Ph)(NR(1)R(2))4 (1), which can be converted into analogous C70 derivatives such as C70 (NHSO2 Ph)(NHTol)5 (2). Further addition reactions of either 1 or 2 take place selectively at the opposite pole pentagon of the C70 cage, thus forming curved pi systems with a reduced number of pi electrons, and the products include a dodecakis-adduct with a Vogtle belt motif. PMID- 26766114 TI - Transcriptome-wide interrogation of RNA secondary structure in living cells with icSHAPE. AB - icSHAPE (in vivo click selective 2-hydroxyl acylation and profiling experiment) captures RNA secondary structure at a transcriptome-wide level by measuring nucleotide flexibility at base resolution. Living cells are treated with the icSHAPE chemical NAI-N3 followed by selective chemical enrichment of NAI-N3 modified RNA, which provides an improved signal-to-noise ratio compared with similar methods leveraging deep sequencing. Purified RNA is then reverse transcribed to produce cDNA, with SHAPE-modified bases leading to truncated cDNA. After deep sequencing of cDNA, computational analysis yields flexibility scores for every base across the starting RNA population. The entire experimental procedure can be completed in ~5 d, and the sequencing and bioinformatics data analysis take an additional 4-5 d with no extensive computational skills required. Comparing in vivo and in vitro icSHAPE measurements can reveal in vivo RNA-binding protein imprints or facilitate the dissection of RNA post transcriptional modifications. icSHAPE reactivities can additionally be used to constrain and improve RNA secondary structure prediction models. PMID- 26766115 TI - Isolation of ubiquitinated substrates by tandem affinity purification of E3 ligase-polyubiquitin-binding domain fusions (ligase traps). AB - Ubiquitination is an essential protein modification that influences eukaryotic processes ranging from substrate degradation to nonproteolytic pathway alterations, including DNA repair and endocytosis. Previous attempts to analyze substrates via physical association with their respective ubiquitin ligases have had some success. However, because of the transient nature of enzyme-substrate interactions and rapid protein degradation, detection of substrates remains a challenge. Ligase trapping is an affinity purification approach in which ubiquitin ligases are fused to a polyubiquitin-binding domain, which allows the isolation of ubiquitinated substrates. Immunoprecipitation is first used to enrich for proteins that are bound to the ligase trap. Subsequently, affinity purification is used under denaturing conditions to capture proteins conjugated with hexahistidine-tagged ubiquitin. By using this protocol, ubiquitinated substrates that are specific for a given ligase can be isolated for mass spectrometry or western blot analysis. After cells have been collected, the described protocol can be completed in 2-3 d. PMID- 26766116 TI - Optimization of drug combinations using Feedback System Control. AB - We describe a protocol for the discovery of synergistic drug combinations for the treatment of disease. Synergistic drug combinations lead to the use of drugs at lower doses, which reduces side effects and can potentially lead to reduced drug resistance, while being clinically more effective than the individual drugs. To cope with the extremely large search space for these combinations, we developed an efficient combinatorial drug screening method called the Feedback System Control (FSC) technique. Starting with a broad selection of drugs, the method follows an iterative approach of experimental testing in a relevant bioassay and analysis of the results by FSC. First, the protocol uses a cell viability assay to generate broad dose-response curves to assess the efficacy of individual compounds. These curves are then used to guide the dosage input of each drug to be tested in combination. Data from applied drug combinations are input into the differential evolution (DE) algorithm, which predicts new combinations to be tested in vitro. This process identifies optimal drug-dose combinations, while saving orders of magnitude in experimental effort. The complete optimization process is estimated to take ~4 weeks. FSC does not require insight into the disease mechanism, and it has therefore been applied to find combination therapies for many different pathologies, including cancer and infectious diseases, and it has also been used in organ transplantation. PMID- 26766117 TI - Consciousness isn't all-or-none: Evidence for partial awareness during the attentional blink. AB - Alternative views of the nature of consciousness posit that awareness of an object is either an all-or-none phenomenon or that awareness can be partial, occurring independently for different levels of representation. The all-or-none hypothesis predicts that when one feature of an object is identified, all other features should be consciously accessible. The partial awareness hypothesis predicts that one feature may reach consciousness while others do not. These competing predictions were tested in two experiments that presented two targets within a central stream of letters. We used the attentional blink evoked by the first target to assess consciousness for two different features of the second target. The results provide evidence that there can be a severe impairment in conscious access to one feature even when another feature is accurately reported. This behavioral evidence supports the partial awareness hypothesis, showing that consciousness of different features of the same object can be dissociated. PMID- 26766118 TI - Historical Aspects of Endemic Trachoma in Peru: 1895-2000. PMID- 26766120 TI - Cyclin D1 and p16 Expression in Blue Nevi and Malignant Melanoma. AB - BACKGROUND: Differentiating benign blue nevi from blue nevus-like melanoma can be diagnostically challenging. We aimed to determine the utility of immunohistochemical staining for p16 and cyclin D1 in distinguishing benign blue nevi and malignant melanoma. MATERIALS AND METHODS: Thirty-two biopsy specimens taken between 2007 and 2015 were obtained from the Department of Pathology at the Queen's Medical Center in Honolulu, HI. These included 9 common blue nevi, 8 cellular blue nevi (2 with atypical features), and 15 malignant melanomas (3 blue nevus-like melanoma). The primary outcome was the difference in p16 and cyclin D1 staining between benign blue nevi and malignant melanoma. Staining of specimens for p16 and cyclin D1 was graded on the strength of staining, and the percent of tumor that stained positive. A specimen was deemed positive if it showed 2+ staining in >=50% of the tumor. RESULTS: The majority (82%) of blue nevi stained negative for p16. There was not a significant difference between p16 staining in benign blue nevi and melanoma (P=0.06). Eleven (73%) melanomas stained positive for cyclin D1 with a sensitivity of 0.73 and positive predictive value of 1.0. All blue nevi were negative for cyclin D1, making its specificity 1.0 and its negative predictive value 0.8. This difference in cyclin D1 staining in blue nevi and melanoma was significant (P=0.0001). CONCLUSIONS: Cyclin D1 may be useful in differentiating benign blue nevi from melanoma. PMID- 26766121 TI - Rapid and Specific Diagnosis of Extrapulmonary Tuberculosis by Immunostaining of Tissues and Aspirates With Anti-MPT64. AB - BACKGROUND: Extrapulmonary tuberculosis (EPTB) constitutes about 15% to 20% of all cases of tuberculosis (TB). The confirmation of EPTB has always been a challenge to laboratory personnel. We aim to evaluate the diagnostic potential of immunostaining with anti-MPT64 in various EPTB specimens. MATERIALS AND METHODS: We studied a total of 51 TB cases and 38 non-TB control specimens comprising of fine-needle aspirates and formalin-fixed biopsies. These were investigated using a combination of the Ziehl-Neelsen method, the Lowenstein-Jensen culture, immunostaining with anti-MPT64 and anti-BCG, and nested-polymerase chain reaction (PCR) for IS6110. Results of all the tests were compared using nested-PCR as the gold standard. RESULTS: Diagnostic validation of immunostaining for anti-MPT64 was performed using nested-PCR as the gold standard. The overall sensitivity, specificity, and positive and negative predictive values for immunostaining with anti-MPT64 were 100%, 97%, 97%, and 100%, respectively. CONCLUSIONS: Immunostaining using anti-MPT64 is a rapid and sensitive method for establishing an early and specific diagnosis of Mycobacterium tuberculosis infection. The technique is simple to be incorporated into routine pathology laboratories. PMID- 26766119 TI - Acute stress alters autonomic modulation during sleep in women approaching menopause. AB - Hot flashes, hormones, and psychosocial factors contribute to insomnia risk in the context of the menopausal transition. Stress is a well-recognized factor implicated in the pathophysiology of insomnia; however the impact of stress on sleep and sleep-related processes in perimenopausal women remains largely unknown. We investigated the effect of an acute experimental stress (impending Trier Social Stress Task in the morning) on pre-sleep measures of cortisol and autonomic arousal in perimenopausal women with and without insomnia that developed in the context of the menopausal transition. In addition, we assessed the macro- and micro-structure of sleep and autonomic functioning during sleep. Following adaptation to the laboratory, twenty two women with (age: 50.4 +/- 3.2 years) and eighteen women without (age: 48.5 +/- 2.3 years) insomnia had two randomized in-lab overnight recordings: baseline and stress nights. Anticipation of the task resulted in higher pre-sleep salivary cortisol levels and perceived tension, faster heart rate and lower vagal activity, based on heart rate variability measures, in both groups of women. The effect of the stress manipulation on the autonomic nervous system extended into the first 4 h of the night in both groups. However, vagal tone recovered 4-6 h into the stress night in controls but not in the insomnia group. Sleep macrostructure was largely unaltered by the stress, apart from a delayed latency to REM sleep in both groups. Quantitative analysis of non-rapid eye movement sleep microstructure revealed greater electroencephalographic (EEG) power in the beta1 range (15-<=23 Hz), reflecting greater EEG arousal during sleep, on the stress night compared to baseline, in the insomnia group. Hot flash frequency remained similar on both nights for both groups. These results show that pre-sleep stress impacts autonomic nervous system functioning before and during sleep in perimenopausal women with and without insomnia. Findings also indicate that women with insomnia had increased EEG arousal and lacked recovery in vagal activity across the stress night suggesting a greater sensitivity to stress in this group. PMID- 26766122 TI - Comparison of Dual-ISH (DISH) With Fluorescence In Situ Hybridization (FISH) and Correlation With Immunohistochemical Findings for HER2/Neu Status in Breast Carcinoma. AB - INTRODUCTION: The most widely used methods for determination of HER2/neu status in breast carcinoma are immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). Both techniques are associated with technical and interpretive difficulties. Alternative methods exist including quantitative PCR and the newly developed chromogenic dual in situ hybridization (DISH). METHODS: We evaluated HER2 DISH as an alternative to FISH and report our findings from 101 cases. In addition, we correlated HER2 DISH and FISH results with HercepTest and 4B5 immunohistochemistry. RESULTS: Eight cases failed FISH analysis and none failed DISH analysis. A 95% (88/93) concordance was found between DISH and FISH for all cases in the series. When only 2+ IHC cases were evaluated, the concordance was 94% for DISH and FISH. Using the 2013 ASCO/CAP recommendations, none of the tested cases were equivocal by FISH or DISH despite 66% of cases being 2+ by HercepTest and 32% by the 4B5 antibody. COMMENT: Our study, which utilizes a majority of IHC equivocal cases, demonstrates that HER2 FISH and DISH are concordant methodologies. HER2 DISH is therefore an acceptable alternative to FISH. PMID- 26766123 TI - Distribution of Pancreatic Polypeptide-secreting Endocrine Cells in Nondiabetic and Diabetic Cases. AB - The aim of the study was to demonstrate the effects of cigarette smoking and ongoing inflammation in chronic pancreatitis on the functioning of pancreatic polypeptide (PP)-secreting cells and to determine the relationship between the occurrence of an increased number of PP cells in the pancreas, the change in their location, and the intensity of their inflammatory changes in the course of pancreatitis and diabetes. Samples of tissues from healthy persons and from patients were verified histopathologically, and then PP was localized by immunohistochemical staining using the monoclonal anti-human PP antibody. The histopathologic evaluation of the hormone expression intensity in tissue sections was carried out using the semiquantitative method and was calculated with digital image analysis. The present study showed a very strong PP expression in the pancreatic tissue (especially in the head of the pancreas) derived from smoking patients with diabetes. The increase in the percentage of cells in the PP islets, between the acinar cells in smoking patients with diabetes and a statistically significant increase in the expression of PP, indicates a pancreatic endocrine dysfunction and suggests that cigarette smoking has a negative impact on the organ's efficiency. Because of its properties, the PP appears to be a useful marker of the endocrine insufficiency of the pancreas and a specific prognostic parameter of developing diabetes due to chronic pancreatitis. PMID- 26766124 TI - An Androgen Receptor-positive Carcinoma of the Lacrimal Drainage System Resembling Salivary Duct Carcinoma: Case Report and Review of the Literature. AB - Carcinomas of the lacrimal drainage apparatus are rare and due to their aggressive behavior, they usually require extensive surgical treatment. We report a unique case of a 60-year-old man presenting with proptosis found to have a mass in the lacrimal drainage system on magnetic resonance imaging. Histology revealed a high-grade carcinoma with morphologic features of salivary gland duct carcinoma. Immunohistochemistry showed an extensive positive staining to androgen receptor. This is the first report of salivary gland-like duct carcinoma of the lacrimal drainage apparatus. Androgen receptor should be included in the immunohistochemical panel for the diagnostic work-up of lacrimal drainage system carcinomas, which resemble salivary gland duct carcinoma. This finding could have important diagnostic and therapeutic implications. PMID- 26766125 TI - Intratumoral Heterogeneity for Ki-67 Index in Invasive Breast Carcinoma: A Study on 131 Consecutive Cases. AB - INTRODUCTION: In addition to conventional histopathologic parameters, the assessment of proliferation is a major factor in treatment decision in breast carcinoma patients. The aim of this study was to assess whether Ki-67 heterogeneity in invasive breast carcinomas could have an impact over treatment decision. MATERIALS AND METHODS: Immunohistochemistry for Ki-67 was evaluated in resection specimens of 131 consecutive invasive breast carcinomas. Heterogeneity was defined as the presence of a low (<17%) and high (>35%) proliferative activity within the same tumor in the same histologic section. The rest of the cases were defined as homogenous. Clinical-pathologic features were also analyzed. RESULTS: A total of 107 (81.67%) of the cases were homogenous and 24 of 131 cases (18.32%) showed heterogeneity as defined above. Among these, 10 (41.6%) cases showed a gradient of increasing staining toward the tumor edge and 14 (58.4%) cases showed hot spots. In general, the proliferative activity varied from 1% to 90% in different areas of the tumor. A higher incidence of breast carcinoma was observed after menopause in both groups (83.33% in heterogeneous cases and 79.43% in homogeneous cases) (P=0.783). These groups were similar as far as the most frequent histologic types were concerned: no special type (95.83% vs. 56.07%) (P=0.0001). Tumor histologic grade, T and N stage were similar in both groups. We noted a higher proportion of stage N3 cases in the heterogeneous tumor group (54.16% vs. 34.57%) (P=0.14). Prognostic markers analysis in the heterogeneous cases revealed 100% positivity for hormone receptors (compared with 94.65%) and a much higher proportion of HER2-negative cases (87.5% vs. 73.83%) (P=0.19). CONCLUSION: As Ki-67 heterogeneity can be encountered in breast carcinomas and Ki-67 value could have an impact on clinical decisions, it is mandatory to evaluate the whole specimen and not only the core biopsy specimen and to correlate it with mitotic count. PMID- 26766126 TI - IMP3 Immunoreactivity is More Sensitive Than AMACR in Detecting Dysplastic Epithelium and Early Adenocarcinoma in Barrett Esophagus. AB - CONTEXT: alpha-methylacyl coenzyme A racemase (AMACR) and insulin-like growth factor-II mRNA-binding protein 3 (IMP3) are 2 markers helpful in detecting difficult cases of dysplasia in Barrett esophagus (BE). However, no comparison studies have been performed to assess their performance in the same patient population. OBJECTIVES: The aim of our study was to compare the immunohistochemical expression of IMP3 and AMACR in dysplastic lesions and early adenocarcinoma (EAC) arising in BE and evaluate their sensitivity and specificity. DESIGN: A total of 98 cases [BE negative for dysplasia, n=24; indefinite for dysplasia (BE-IND), n=18; low-grade dysplasia (LGD), n=24; high grade dysplasia (HGD), n=16; and EAC, n=16] were immunostained for AMACR and IMP3 and evaluated for the degree, the extent, and the intensity of staining. RESULTS: No immunoreactivity for AMACR or IMP3 was observed in all 24 cases of BE negative for dyplasia. One of 18 (5.5%) cases of BE-IND was positive for IMP3, but all were negative for AMACR. AMACR and IMP3 were positive in 16.7% versus 41.7 % of the cases with BE-LGD, 25% versus 62.5% of BE-HGD, and 62.5% versus 93.7% of EAC, respectively. The sensitivity of AMACR and IMP3 for the detection of dysplasia in BE is 16.7% and 41.7% for LGD, 25% and 62.5% for HGD, and 62.5% and 93.7% in EAC, respectively. The specificity is 100% for both markers. In addition, a comparison of the intensity of reactivity shows a better result with IMP3 (36/98, 36.7%) than with AMACR (18/98, 18.4%) (P<0.001). CONCLUSIONS: IMP3 has a similar specificity, but a better sensitivity, intensity, and extent of reactivity in comparison with AMACR, and may be used as an alternative to AMACR, in support of the diagnosis of BE-dysplasia and EAC. PMID- 26766127 TI - Immunohistochemical Expression of Progesterone Receptors in Nonmeningothelial Central Nervous System Tumors. AB - INTRODUCTION: Immunostaining of progesterone receptors (PRs) has been described as a prognostic factor related to recurrences in meningiomas. However, its expression in other primary intracranial tumors has been poorly studied. In this paper, we compare the pattern of expression of the receptor in meningiomas with that of nonmeningothelial intracranial tumors to evaluate its value in the diagnosis of the former. MATERIALS AND METHODS: A total of 42 nonmeningothelial intracranial tumors (21 glioblastomas, 4 anaplastic oligodendrogliomas, 4 oligodendrogliomas, 1 pilomyxoid astrocytoma, 3 ependymomas, 8 schwannomas, 1 chordoid chordoma) and 32 meningiomas (1 rhabdoid, 1 papillary, 5 atypical, 7 with histologic features of more aggressive behavior, 1 microcyst, 8 meningothelial, 7 transitional, 2 fibroblastic) were studied for PR by immunohistochemistry. RESULTS: About 73.8% of the nonmeningothelial tumors and 100% of the meningiomas were positive for the receptor, the difference being statistically significant (P=0.0017). The mean percentage of positive tumor cells per high-power field was frequently higher than 30% in meningiomas and lower than 10% in nonmeningothelial tumors (P=0.0001). CONCLUSIONS: Although we detected that immunostaining for the PR is more frequently observed in meningiomas, we confirmed its expression in diverse nonmeningothelial primary intracranial tumors. Immunohistochemistry for PR would be useful in the diagnosis of meningioma only when its positivity shows a mean higher than 30% of the positive tumor cells per high-power field. PMID- 26766128 TI - Embedded Fin-Like Metal/CNT Hybrid Structures for Flexible and Transparent Conductors. AB - In this paper, an embedded fin-like metal-coated carbon nanotube (Fin-M/CNT) structure is demonstrated for flexible and transparent conductor wire applications. Embedded in a polydimethylsiloxane polymeric substrate, Fin-M/CNT wires with a minimum width of 5 MUm and a minimum pitch of 10 MUm have been achieved. Direct current resistances of single Fin-M/CNT wires, where the supporting CNT structures have been covered by Ti/Al/Au metal coatings of different thicknesses, have been measured. The high aspect ratio of the fin-like structures not only improves the adhesion between the wires and the polymeric substrate, but also yields a low resistance at a small surface footprint. In addition, transparent Fin-M/CNT grid lines with hexagonal patterns, with a sheet resistance of as low as 45 Omega sq(-1) , have been achieved at an optical transmittance of 88%. The robustness of the Fin-M/CNT structures has been demonstrated in bending tests up to 500 cycles and no significant changes in wire resistances are observed. PMID- 26766130 TI - The natural product content of the selected Cabernet Franc wine samples originating from Serbia: a case study of phenolics. AB - This work aimed to evaluate the content of selected phenolic natural products in the wine samples made of three new Serbian Cabernet Franc clones (Nos. 02, 010 and 012, respectively) and mother vine (used as the relevant standard) during the period 2008-2012. Compared with all other wine samples, the Cabernet Franc wine of the clone No. 010 was found to have the highest total content of polyphenolics (1.85 +/- 0.02 g/L) and anthocyanins (178.55 +/- 3.75 mg/L). In addition, its Folin-Ciocalteu index (36.86 +/- 0.12) stood out among the examined samples. Finally, the same wine was enriched with ellagic and gallic acids (3.44 +/- 0.29 and 27.46 +/- 0.21 mg/L, respectively), catechin (135.16 +/- 6.47 mg/L) and epicatechin (51.33 +/- 2.33 mg/L), the natural products known to exert significant lipid-lowering effects. Taken all together, the clone No. 010 developed in Serbia may offer new Cabernet Franc wine with geographical indication. PMID- 26766131 TI - Identification of epitope-based peptide vaccine candidates against enterotoxigenic Escherichia coli: a comparative genomics and immunoinformatics approach. AB - Enterotoxigenic Escherichia coli (ETEC) associated diarrhea remains a global killer with an estimated annual incidence rate of 840 million infections and 3 800 000 deaths worldwide. There are no vaccines available for ETEC and the traditional vaccine development approach is arduous and time consuming. Thus, alternative in silico approaches for epitope prediction have engrossed the interest of researchers to reduce resources and time of vaccine development. Computational approaches are playing a crucial role in fighting against rapidly growing infectious organisms. In this study we employed an integrated comparative genomics and immunoinformatics approach for proteome scale identification of peptide vaccine candidates. The proteins shared between both ETEC E24377A and H10407 strains, but lacking in commensal E. coli SE11, were subjected to immunoinformatics analysis. For a protein pool shared between different pathogenic ETEC strains, we investigated varied physicochemical and immunogenic properties to prioritize potential vaccine candidates. Epitopes were further tested using docking studies to bind in the MHC-I binding cleft. Predicted epitopes provided more than a 95% population coverage in diarrhea endemic regions presented by major MHC-I supertypes, and bind efficiently to a MHC molecule. We conclude by accentuating that the epitopes predicted in this study are believed to accelerate the development of successful vaccines to control or prevent ETEC infections, albeit the results require experimental validation using model organisms. This study underscores that in silico approaches, together with omics data, hold great potential to be utilized for rapid and reliable genome-wide screening for identification of vaccine candidates against devastating infectious diseases. PMID- 26766132 TI - Anger Assessment in Clinical and Nonclinical Populations: Further Validation of the State-Trait Anger Expression Inventory-2. AB - OBJECTIVE: The most commonly used instrument for measuring anger is the State Trait Anger Expression Inventory-2 (STAXI-2; Spielberger, 1999). This study further examines the validity of the STAXI-2 and compares anger scores between several clinical and nonclinical samples. METHOD: Reliability, concurrent, and construct validity were investigated in Dutch undergraduate students (N = 764), a general population sample (N = 1211), and psychiatric outpatients (N = 226). RESULTS: The results support the reliability and validity of the STAXI-2. Concurrent validity was strong, with meaningful correlations between the STAXI-2 scales and anger-related constructs in both clinical and nonclinical samples. Importantly, patients showed higher experience and expression of anger than the general population sample. Additionally, forensic outpatients with addiction problems reported higher Anger Expression-Out than general psychiatric outpatients. CONCLUSION: Our conclusion is that the STAXI-2 is a suitable instrument to measure both the experience and the expression of anger in both general and clinical populations. PMID- 26766133 TI - Characteristics of a Dysphonic Population Referred for Voice Assessment and/or Voice Therapy. AB - OBJECTIVE: The aim of this study was to define patient characteristics of a dysphonic population in terms of voice disorder, gender, age, and subjective and objective vocal parameters and to explore the relevant characteristics of the most frequent groups of voice disorders. PATIENTS AND METHODS: Patient records from 4,447 subjects referred for voice assessment and/or voice therapy were analyzed. RESULTS: Significantly more cases of dysphonia were structural as compared to nonstructural. This significant difference was found in almost all age groups. Significantly more women were diagnosed with dysphonia than men. The most common symptom was light-to-moderate hoarseness. The average voice handicap index was 31 and the average dysphonia severity index was -0.6. Vocal fold nodules (VFN), functional voice disorders (FVD) and vocal fold paralysis (VFP) were the three most frequently diagnosed vocal pathologies and were analyzed in detail. Women were found to be significantly more vulnerable to FVD, VFN and cysts, whereas men were significantly more often diagnosed with carcinoma, hyperkeratosis, laryngitis, papillomatosis, presbyphonia, puberphonia and VFP. CONCLUSIONS: The results of this study allow a better estimation of the clinical needs and costs for a specific dysphonic population looking for help and highlight the gender-related risks of specific voice disorders. PMID- 26766134 TI - Enhanced Sphingomyelinase Activity Contributes to the Apoptotic Capacity of Electronegative Low-Density Lipoprotein. AB - Sphingomyelinase (SMase) catalyzes the degradation of sphingomyelin to ceramide. In patients with metabolic syndrome or diabetes, circulating plasma ceramide levels are significantly higher than in normal individuals. Our data indicate that electronegative low-density lipoprotein (LDL) shows SMase activity, which leads to increased ceramide levels that can produce pro-inflammatory effects and susceptibility to aggregation. According to sequence alignment and protein structure predictions, the putative catalytic site of SMase activity is in the alpha2 region of apoB-100. To identify specific post-translational modifications of apoB100 near the catalytic region, we performed data-independent, parallel fragmentation liquid chromatography/mass spectrometry (LC/MS(E)), followed by data analysis with ProteinLynx GlobalServer v2.4. Results showed that the serine of apoB100 in electronegative LDL was highly O-glycosylated, including S(1732), S(1959), S(2378), S(2408), and S(2429). These findings may support the changing of the alpha-helix/beta-pleated sheets ratio in protein structure analysis. Further study is necessary to confirm the activation of SMase activity by electronegative LDL. PMID- 26766135 TI - Enzymatic Acylation of Anthocyanin Isolated from Black Rice with Methyl Aromatic Acid Ester as Donor: Stability of the Acylated Derivatives. AB - The enzymatic acylation of anthocyanin from black rice with aromatic acid methyl esters as acyl donors and Candida antarctica lipase B was carried out under reduced pressure. The highest conversion of 91% was obtained with benzoic acid methyl ester as acyl donor; cyanidin 3-(6"-benzoyl)-glucoside, cyanidin 3-(6" salicyloyl)-glucoside, and cyanidin 3-(6"-cinnamoyl)-glucoside were successfully synthesized. This is the first report on the enzymatic acylation of anthocyanin from black rice with methyl aromatic esters as acyl donors and lipase as biocatalyst. Furthermore, the acylation with aromatic carboxylic acids enhanced both the thermostability and light resistivity of anthocyanin. In particular, cyanidin 3-(6"-cinnamoyl)-glucoside was the most stable among the three acylated anthocyanins synthesized. PMID- 26766136 TI - The Role of Rac1 in the Growth Cone Dynamics and Force Generation of DRG Neurons. AB - We used optical tweezers, video imaging, immunocytochemistry and a variety of inhibitors to analyze the role of Rac1 in the motility and force generation of lamellipodia and filopodia from developing growth cones of isolated Dorsal Root Ganglia neurons. When the activity of Rac1 was inhibited by the drug EHop-016, the period of lamellipodia protrusion/retraction cycles increased and the lamellipodia retrograde flow rate decreased; moreover, the axial force exerted by lamellipodia was reduced dramatically. Inhibition of Arp2/3 by a moderate amount of the drug CK-548 caused a transient retraction of lamellipodia followed by a complete recovery of their usual motility. This recovery was abolished by the concomitant inhibition of Rac1. The filopodia length increased upon inhibition of both Rac1 and Arp2/3, but the speed of filopodia protrusion increased when Rac1 was inhibited and decreased instead when Arp2/3 was inhibited. These results suggest that Rac1 acts as a switch that activates upon inhibition of Arp2/3. Rac1 also controls the filopodia dynamics necessary to explore the environment. PMID- 26766137 TI - TEMPO-functionalized zinc phthalocyanine: synthesis, magnetic properties, and its utility for electrochemical sensing of ascorbic acid. AB - Zinc(ii) phthalocyanine (TEMPO-ZnPc), peripherally functionalized with 2,2,6,6 tetramethyl-1-piperidinyloxy (TEMPO) radicals is synthesized and its magneto structural and electrochemical behaviors are investigated. TEMPO-ZnPc shows multi electron ring based reduction reactions and a TEMPO based oxidation reaction. Spectroelectrochemical measurements support these peak assignments. TEMPO-ZnPc is tested as a homogeneous and heterogeneous ascorbic acid (AA) sensor. Disappearance of TEMPO-ZnPc based reduction processes and the observation of new waves at around 0 and 1.20 V with respect to increasing AA concentration indicate the interaction of TEMPO-ZnPc with AA and usability of the complex as an electrochemical AA sensor. For practical usage as heterogeneous electrocatalysts for AA sensing, a glassy carbon electrode (GCE) is coated with TEMPO-ZnPc (GCE/TEMPO-ZnPc) and this modified electrode is tested as a heterogeneous AA sensor. The redox peak of GCE/TEMPO-ZnPc at 0.81 V decreases the peak current while a new wave is observed at 0.65 V during the titration of the electrolyte with AA. GCE/TEMPO-ZnPc sense AA with 1.75 * 10(-6) mol dm(-3) LOD with a sensitivity of 1.89 * 10(3) A cm mol(-1). PMID- 26766138 TI - How do older people with sight loss manage their general health? A qualitative study. AB - PURPOSE: Older people with sight loss experience a number of barriers to managing their health. The purpose of this qualitative study was to explore how older people with sight loss manage their general health and explore the techniques used and strategies employed for health management. METHODS: Semi-structured face to-face interviews were conducted with 30 participants. Interviews were audio recorded, transcribed verbatim and analysed using thematic analysis. RESULTS: Health management challenges experienced included: managing multiple health conditions; accessing information; engaging in health behaviours and maintaining wellbeing. Positive strategies included: joining support groups, clubs and societies; using low vision aids; seeking support from family and friends and accessing support through health and social care services. CONCLUSION: Healthcare professionals need to be more aware of the challenges faced by older people with sight loss. Improved promotion of group support and charity services which are best placed to share information, provide fora to learn about coping techniques and strategies, and give older people social support to prevent isolation is needed. Rehabilitation and support services and equipment can only be beneficial if patients know what is available and how to access them. Over-reliance on self advocacy in current healthcare systems is not conducive to patient-centred care. Implications for Rehabilitation Sight loss in older people can impact on many factors including health management. This study identifies challenges to health management and highlights strategies used by older people with sight loss to manage their health. Access to support often relies on patients seeking information for themselves. However, self-advocacy is challenging due to information accessibility barriers. Informal groups and charities play an important role in educating patients about their condition and advising on available support to facilitate health management. PMID- 26766139 TI - 3D Printing of Biocompatible Supramolecular Polymers and their Composites. AB - A series of polymers capable of self-assembling into infinite networks via supramolecular interactions have been designed, synthesized, and characterized for use in 3D printing applications. The biocompatible polymers and their composites with silica nanoparticles were successfully utilized to deposit both simple cubic structures, as well as a more complex twisted pyramidal feature. The polymers were found to be not toxic to a chondrogenic cell line, according to ISO 10993-5 and 10993-12 standard tests and the cells attached to the supramolecular polymers as demonstrated by confocal microscopy. Silica nanoparticles were then dispersed within the polymer matrix, yielding a composite material which was optimized for inkjet printing. The hybrid material showed promise in preliminary tests to facilitate the 3D deposition of a more complex structure. PMID- 26766140 TI - Incidental finding of multiple well-differentiated papillary mesotheliomas in peritoneum. AB - We present a case of multiple well-differentiated papillary mesotheliomas (WDPM) in the peritoneum found incidentally in a 63-year-old man with urothelial carcinoma of the bladder. When multiple tumors are seen, malignant mesothelioma should be excluded by histopathological examination as this may have a similar focal appearance to WDPM. True stromal invasion is by far the most reliable criterion of mesothelial malignancy. In doubtful cases, a conservative diagnostic approach has been recommended. Compared to malignant mesotheliomas, WDPMs are rare and have a relatively indolent clinical course with a good prognosis. Great care is needed when diagnosing mesothelial proliferations, given the crucial nature of a benign vs malignant diagnosis. No standardized treatment has yet been established. PMID- 26766141 TI - Impact of patient characteristics on the clinical efficacy of mongersen (GED 0301), an oral Smad7 antisense oligonucleotide, in active Crohn's disease. AB - BACKGROUND: In a phase 2 study, mongersen, an oral antisense oligonucleotide targeting Smad7, was effective in inducing clinical remission in approximately 60% of patients with active Crohn's disease (CD). AIM: In a post hoc analysis to evaluate those patient disease characteristics that may have influenced the efficacy and safety of mongersen therapy. METHODS: Patients with steroid dependent/resistant, active CD were randomised to mongersen 10, 40 or 160 mg/day or placebo for 2 weeks; patients were followed for 10 weeks. Clinical remission [Crohn's Disease Activity Index (CDAI) score <150] and clinical response (CDAI score reduction >=100 points) were assessed at weeks 2, 4 and 12 for these subgroups: disease duration <5/>=5 years, human serum C-reactive protein (hsCRP) <3/>=3 mg/L, and CDAI at baseline <=260/>260. Additional patient baseline and disease characteristics were explored. RESULTS: Clinical remission and response rates were significantly higher in patients receiving mongersen 40 and 160 mg/day but not 10 mg/day vs. placebo and independent of disease duration and hsCRP. Patients with baseline CDAI <=260 had significantly higher remission rates with 40 and 160 mg/day. In patients with baseline CDAI >260, remission rates were statistically greater with 160 mg/day and numerically better with 40 mg/day vs. placebo. Adverse event rates were similar across treatment groups. Mongersen was safe and well tolerated. CONCLUSIONS: Patients with higher CDAI scores achieved clinical remission most frequently with the highest mongersen dose. Disease duration and baseline human serum C-reactive protein did not appear to significantly impact efficacy of mongersen in this study (EudraCT Number: 2011 002640-27.). PMID- 26766142 TI - Extracellular vesicles concentration is a promising and important parameter for industrial bioprocess monitoring. AB - Extracellular vesicles (EVs) are membrane vesicles that are produced by cells to be released into their microenvironment. In this study, we present the EV concentration as a new factor for optimization of industrial bioprocess control. The release of EVs depends on many cell properties, including cell activation and stress status, and cell death. Therefore, the EV concentration might provide a readout for identification of the cell state and the conditions during a bioprocess. Our data show that the EV concentration increased during the bioprocess, which indicated deteriorating conditions in the bioreactor. This increase in EV concentration in the fermentation broth was the consequence of two different processes: cell activation, and cell death. However, the release of EVs from activated living cells had a much weaker impact on EV concentration in the bioreactor than those released during cell death. EVs and cells in the bioprocess environment were quantified by flow cytometry. The most accurate data were obtained directly from unprocessed samples, making the monitoring of the EV concentration a rapid, easy, and cheap method. These EV concentrations reflect the conditions in the bioreactor and provide new information regarding the state of the bioprocess. Therefore, we suggest EV concentration as a new and important parameter for the monitoring of industrial bioprocesses. PMID- 26766143 TI - Variation in Current Management of Term and Late-preterm Neonates at Risk for Early-onset Sepsis: An International Survey and Review of Guidelines. AB - BACKGROUND: Uncertainty about the presence of infection results in unnecessary and prolonged empiric antibiotic treatment of newborns at risk for early-onset sepsis (EOS). This study evaluates the impact of this uncertainty on the diversity in management. METHODS: A web-based survey with questions addressing management of infection risk-adjusted scenarios was performed in Europe, North America, and Australia. Published national guidelines (n = 5) were reviewed and compared with the results of the survey. RESULTS: 439 Clinicians (68% were neonatologists) from 16 countries completed the survey. In the low-risk scenario, 29% would start antibiotic therapy and 26% would not, both groups without laboratory investigations; 45% would start if laboratory markers were abnormal. In the high-risk scenario, 99% would start antibiotic therapy. In the low-risk scenario, 89% would discontinue antibiotic therapy before 72 hours. In the high risk scenario, 35% would discontinue therapy before 72 hours, 56% would continue therapy for 5-7 days, and 9% for more than 7 days. Laboratory investigations were used in 31% of scenarios for the decision to start, and in 72% for the decision to discontinue antibiotic treatment. National guidelines differ considerably regarding the decision to start in low-risk and regarding the decision to continue therapy in higher risk situations. CONCLUSIONS: There is a broad diversity of clinical practice in management of EOS and a lack of agreement between current guidelines. The results of the survey reflect the diversity of national guidelines. Prospective studies regarding management of neonates at risk of EOS with safety endpoints are needed. PMID- 26766144 TI - Determining Persistence of Bocavirus DNA in the Respiratory Tract of Children by Pyrosequencing. AB - BACKGROUND: Although human bocavirus type 1 (HBoV1) is a respiratory pathogen, presence of HBoV-DNA in secretions of asymptomatic children raised the question on the significance of HBoV-positive results. METHODS: Archived specimens from a prospective, longitudinal study were tested for HBoV. A total of 94 children (aged 6-36 months) were HBoV(+) during 172 upper respiratory tract infection (URI) and/or acute otitis media (AOM) episodes. We used pyrosequencing of NP1, VP1 and VP2 genes to type HBoV and subtype HBoV1 in these specimens. RESULTS: Of the specimens tested, HBoV-DNA were successfully sequenced in 128 (74%) samples from 70 children; all were HBoV type 1. Subtypes identified (n = 108) were LWK/TW (63%), LWK/BJ (20%), Bonn/BJ (16%) and LWK/KU3 (1%). Of 46 children for whom shedding pattern could be determined, viral clearance within 30 days (13-29 days) occurred in 28%; another 22% of children had no recurrence after 32-267 days. Prolonged virus presence of >30 days (34-181 days+) occurred in 22%; intermittent detection (61+ to 170+ days) in 20%. Infection with the same HBoV1 subtype after 4-5 negative samples (244 and 265 days interval) occurred in 4%. Infection with 2 different HBoV1 subtypes (29 and 87 days apart) occurred in only 4%. Newly acquired HBoV1-URI resulted in AOM in 53% of cases. CONCLUSIONS: Children with HBoV1 infection commonly shed for a prolonged period leading to repeated viral DNA detection. Recurrence after 8-9 months suggests possible persistence and reactivation. Infections with 2 different HBoV1 subtypes within 1-year period are uncommon. Newly acquired HBoV1-URI is often complicated by AOM. PMID- 26766145 TI - Risk Factors for Pertussis Among Hispanic Infants: Metropolitan Portland, Oregon, 2010-2012. AB - BACKGROUND: In 2012, Oregon observed its highest numbers of reported pertussis cases since 1953. The greatest morbidity occurred among infants <6 months of age, with higher rates among Hispanics than non-Hispanics. To explain this disparity, we analyzed pertussis surveillance data. METHODS: An analysis was conducted among infants <6 months of age in the Portland metropolitan area during 2010-2012. Characteristics examined were ethnicity (Hispanic or non-Hispanic), household size (>4 or <=4 persons), pertussis vaccination status (upto-date or not up-to date for age), child care center attendance (yes or no), infant birth weight (<2500 or >=2500 g) and maternal age (<20 or >=20 years). RESULTS: Eighty-two infants <6 months of age with pertussis were identified. Twenty-eight case infants (34%) were Hispanic, and 54 (66%) were non-Hispanic. By ethnicity, infants with pertussis were similar in illness confirmation method, sex, age, hospitalization status, vaccination status, child care center attendance, infant birth weight and maternal age. Hispanic infants were more likely than non Hispanic infants to live in households with >4 persons. Univariate analysis showed Hispanic infants had approximately 2.3 times the risk for pertussis, compared with non-Hispanic infants, and infants living in households >4 persons had approximately 2.4 times the risk for illness, compared with those in households with <4 persons; stratified risk ratios did not differ between Hispanic (2.4; confidence interval: 1.0-5.7]) and non-Hispanic infants (2.0; confidence interval: 1.2-3.5). CONCLUSIONS: A household size of >4 persons is a potential risk factor for pertussis; the magnitude of this risk is similar for Hispanic and non-Hispanic infants. PMID- 26766146 TI - Bloodstream Infections in Hospitalized Children: Epidemiology and Antimicrobial Susceptibilities. AB - BACKGROUND: Bloodstream infection is a major cause of morbidity and mortality. Much of our understanding of the epidemiology and resistance patterns of bloodstream infections comes from studies of hospitalized adults. METHODS: We evaluated the epidemiology and antimicrobial resistance of bloodstream infections occurring during an 11-year period in a large, tertiary care children's hospital in the US. All positive blood cultures were identified retrospectively from clinical microbiology laboratory records. We excluded repeat positive cultures with the same organism from the same patient within 30 days and polymicrobial infections. RESULTS: We identified 8196 unique episodes of monomicrobial bacteremia in 5508 patients. Overall, 46% were community onset, 72% were Gram positive bacteria, 22% Gram-negative bacteria and 5% Candida spp. Coagulase negative Staphylococcus was the most common isolated organism. ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter spp.) accounted for 20% of episodes. No S. aureus isolate was resistant to vancomycin or linezolid, and no increase in vancomycin minimum inhibitory concentration among methicillin-resistant S. aureus was observed during the study period. Clinically significant increases in vancomycin-resistant Enterococcus, ceftazidime-resistant P. aeruginosa or carbapenem-resistant Enterobacteriaceae were not observed during the study period; however, rates of methicillin-resistant S. aureus increased over time (P < 0.01). CONCLUSIONS: Gram-positive and ESKAPE organisms are leading causes of bacteremia in hospitalized children. Although antimicrobial resistance patterns were favorable compared with prior reports of hospitalized adults, multicenter studies with continuous surveillance are needed to identify trends in the emergence of antimicrobial resistance in this setting. PMID- 26766147 TI - Diagnosis and Management of Pediatric Transplant-associated Viral Infections. PMID- 26766148 TI - A molecular theory of nematic-nematic phase transitions in mesogenic dimers. AB - We study theoretically the molecular origins of the fascinating, and still debated, nematic-nematic phase transition exhibited by symmetric, statistically achiral, mesogenic dimers. A simple molecular model that mimics the key features and symmetry (C2V) of this class of mesogens is presented. In the mean-field approximation, the model yields up to three positionally disordered phases, one isotropic and two nematic. The low temperature nematic phase (NX) has a local two fold symmetry axis, which is also a direction of molecular polar ordering and is tightly twisted about a macroscopic phase axis. The onset of polar ordering generates spontaneous chiral symmetry breaking and the formation of chiral domains of opposite handedness, manifested primarily by the twisting of the polar director. Within these domains the statistical balance between the enantiomer conformations is slightly shifted and the principal axes of the ordering tensors of the molecular segments twist at constant tilt angles with the helical axis. Key experimental results on the NX phase of liquid crystalline dimers are discussed in the light of the theoretical predictions of the model, which are also contrasted with the predictions of the twist-bend nematic model. PMID- 26766149 TI - Hybrid Procedure (Endo/Epicardial) versus Standard Manual Ablation in Patients Undergoing Ablation of Longstanding Persistent Atrial Fibrillation: Results from a Single Center. AB - INTRODUCTION: Ablation of longstanding persistent atrial fibrillation (LSPAF) is the most challenging procedure in the treatment of AF, either by surgical or by percutaneous approach. OBJECTIVE: We investigated the difference in success and complication rates between combined surgical epicardial and endocardial catheter ablation procedure and our standard endocardial ablation procedure. METHODS AND RESULTS: Twenty-four consecutive patients (group 1) with LSPAF and enlarged left atrium (>4.5 cm) underwent a combined procedure, consisting of surgical, closed chest, epicardial, radiofrequency ablation (nContact, NC, USA) via pericardial access, and concomitant endocardial ablation (hybrid procedure). Procedural complications and long-term outcomes were compared to those of 35 consecutive patients who refused the hybrid procedure and underwent standard endocardial only ablation (group 2). Baseline characteristics were comparable. In group 1, 1 patient (4.2%) developed post-procedural cardio-embolic stroke and 3 (12.5%) died (1 atrio-esophageal fistula, 1 fatal stroke, 1 of unknown cause in early follow up), while no strokes or deaths occurred in group 2. Overall complication rates were higher for group 1 (P = 0.036). At 24-month follow-up, 4 (19%) patients in group 1 and 19 (54.3%) in group 2 were arrhythmia-free after a single procedure, on or off antiarrhythmic drugs (P<0.001). Total procedural time (276.9 +/- 63.5 vs. 203.15 +/- 67.3 minutes) and length of hospital stay (5 [IQR 3-8] vs. 1 [IQR 1-3] days were significantly shorter for group 2 (P <0.001). CONCLUSIONS: In patients with LSPAF and enlarged left atrium, a concomitant combined surgical/endocardial ablation approach increases complication rate and does not improve outcomes when compared to extensive endocardial ablation only. PMID- 26766150 TI - Self-reported social skills impairment explains elevated autistic traits in individuals with generalized social anxiety disorder. AB - Screening for autism in individuals with generalized social anxiety disorder (GSAD) is complicated by symptom overlap between GSAD and autism spectrum disorder (ASD). We examined the prevalence of self-reported autistic traits within a sample of participants with a diagnosis of GSAD (n=37) compared to individuals without a GSAD diagnosis (NOSAD; n=26). Of the GSAD sample participants, 70.84% self-reported autistic traits above a cut-off of 65 on the Autism Quotient-Short (AQ-S) and reported significantly more autistic traits on 3 of 5 AQ-S subscales compared to the NOSAD group. Diagnosis uniquely predicted variation in the social skills subscale above and beyond the other subscales and other predictors. Furthermore, variation in the social skills subscale largely explained group differences on the other subscales. Our results suggest caution in utilizing measures like the AQ-S with clinical populations characterized by social difficulties such as individuals with a GSAD diagnosis. PMID- 26766151 TI - [Hepatic pseudolesions adjacent to the falciform ligament]. AB - INTRODUCTION: Accurate detection of hepatic pseudolesions using multi-detector CT and MRI examinations is crucial for the differentiation of benign alterations from primary and secondary malignant lesions in hepatic parenchyma. METHOD: The authors conducted a systematic literature review in PubMed. "Liver" and "pseudolesion" were used as keywords in English and Czech, and papers/articles published from 2000 to 2014 were retrieved. RESULTS: The authors presented a literature review. In addition, the authors performed a retrospective evaluation of a group of patients treated for liver disease at University Hospital Ostrava where this anomaly was encountered in 7 cases.In 3 of the patients, diagnostic laparoscopy was done, with visual examination of the lesion accompanied by intraoperative ultrasound exam (IOUS) and partial excision, to establish the diagnosis. Subsequent histological assessment of the specimens confirmed the diagnosis of a steatotic lesion in each of these 3 patients. Additional 2 of the 7 patients underwent liver surgery for concurrent metastatic lesions of colorectal cancer and an open-access revision of the suspected lesions was performed. Visual inspection and intraoperative ultrasound (IOUS) was followed by excisional biopsy. The histology revealed macro- and micro-vesicular steatosis and excluded malignant changes. The last 2 patients still continue to be followed up regularly on a 6-month routine check-up basis at our hepatology unit. CONCLUSION: The authors presented their own experience gained through inter disciplinary cooperation at Multidisciplinary conferences. A literature overview of this unusual subject is also included. Particularly in oncologic patients, correct interpretation of these pseudolesions may help to avoid unnecessary biopsies, further imaging examinations and diagnostic laparoscopies and/or explorative laparotomies. PMID- 26766152 TI - [Management of groin wound infection after arterial surgery using negative pressure wound therapy]. AB - INTRODUCTION: Infection is a serious complication in vascular reconstructive surgery. When the entire graft is infected, its excision and subsequent replacement is the only option of treatment. In case of localised graft infection in the groin, the vascular reconstruction can be saved using negative-pressure wound therapy (NPWT). METHODS: Retrospective study design was used to evaluate the efficiency of NPWT in the treatment of infected inguinal wounds following arterial reconstructive surgery. The assessments included demographic patient characteristics, causative agents, type of reconstruction and NPWT outcome. Wound infection was graded based on the Szilagyi classification. Patients were followed up for 12 months after the therapy. Complete wound healing, retained graft patency, and no clinical signs or laboratory evidence of infection were regarded as successful results of treatment. RESULTS: Between 2009 and 2012, 20 patients with deep groin infection (Szilagyi II and III) following arterial reconstructive surgery were treated by NPWT. The patient group included 12 men and 8 women; mean age was 68.1 years. Nine patients underwent aorto-femoral arterial reconstructions (with vascular prosthesis in 8 cases), and surgery below the inguinal ligament was done in 11 patients (with vascular prosthesis in 7 cases). Of the 20 patients, early infection within 30 days of surgery was recorded in 17 (85%) patients; Szilagyi grade III groin infection with exposed prosthetic graft was found in 5 (25 %) patients (infection: early, 4; late, 1). The causative agents isolated from the wound included Staphylococcus aureus (n=8), Pseudomonas aeruginosa (n=5) and Escherichia coli (n=5). Mean NPWT duration was 12.7 days. Wound healing was achieved in 17 patients (success rate, 85 %). Patients with early Szilagyi II infection showed the best outcomes (92.3%). CONCLUSION: Localised wound infection in the groin after arterial surgery is a serious complication of arterial reconstruction procedures. In eligible patients, such an infection can be treated conservatively using NPWT. The method is most efficient in the management of early infections. Wounds infected with P. aeruginosa or those with suture line exposure require special treatment. Long-term follow-up is necessary due to the risk of recurrent infection. PMID- 26766153 TI - [Our experience with the measurement of transcutaneous oxygen tension for evaluation of blood circulation in peripheral arteries in patients with critical ischemic disease of lower limbs]. AB - INTRODUCTION: The measurement of transcutaneous oxygen pressure (TcpO2) is a non invasive method to quantify skin oxygenation at capillary level and their nutritive ability needed to heal the ischemic defect. TcpO2 pressure values below 30 mm Hg are specific for critical limb ischemia and predict complicated healing. The purpose of this study was to verify the cut-off pressure in patient unable to undergo vascular reconstruction, and to verify the possibility of using this method to evaluate the effectiveness of vascular reconstructive surgery. METHODS: The group included 52 patients (35 men and 17 women). The mean age of patients in the group was 66.5 years (max. 85, min. 44). RESULTS: In our group of patients we confirmed that the TcpO2 values of successfully healed ischemic wounds were equal or greater than 30 mm Hg (mean TcpO2 value at the dorsum of the foot was 37.0 mm Hg +/- 9.5 mm Hg), compared to the group of unsuccessfully healed patients whose values were lower (mean TcpO2 value at the dorsum of the foot was 9.0 mm Hg +/- 5.3 mm Hg). CONCLUSION: TcpO2 is a suitable method in predicting the healing of ischemic defects and any possible need for surgical or endovascular revascularization. Thanks to its non-invasive nature and undemanding measurement, it surely helps to make better decisions in choosing the therapeutic procedure needed to heal the defect. PMID- 26766154 TI - [Determination of CEA, EGFR and hTERT expression in peritoneal lavage in patients with pancreatic adenocarcinoma using RT - PCR method]. AB - INTRODUCTION: The aim of this study is to assess the significance of CEA, EGFR and hTERT as markers of occult tumor cells for predicting treatment outcomes in pancreatic cancers, as well as determining the cut-off values of these markers individually in peritoneal lavage. METHOD: The study compared 87 patients undergoing palliative operations (bypass surgery, biological sampling for subsequent oncological treatment) for either stage III or IV (UICC) pancreatic ductal adenocarcinomas with a control group of 24 healthy patients. Abdominal cavity lavage was performed at the beginning of the surgery in both groups, using 100 ml of physiological solution (phosphate buffered saline, pH 7.2). The samples were transported in bottles containing 1.5 ml 0.5 M EDTA and 10 ml of fetal bovine serum. Total RNA samples were all processed and purified by reverse transcription. Occult tumor cells in the peritoneal lavage were detected by the real-time RT-PCR method using CEA, EGFR and hTERT as markers of tumor cells. Another aim was to calculate the cut-off values of these markers. Statistical analysis was done using software R (www.r-project.org) and Statistica (StatSoft, Inc. USA). RESULTS: Mean expression of CEA, EGFR and hTERT in peritoneal lavage in the control group was 2501, 716749 and 104 copies of mRNA / mg RNA. Threshold, cut-off values were determined as the "mean + 2 times standard deviation". Absolute expression values were further normalized to expression of the house keeping gene glyceraldehyde-3-phosphate dehydrogenase (GAPDH). After normalization, cut-off values of the tested markers were 4.89, 115.88 and 0.02 copies of mRNA/GAPDH mRNA. As regards absolute expression of the markers tested, only hTERT was able to statistically significantly (p<0.001) distinguish the analysed groups, where patients with advanced pancreatic adenocarcinoma had a higher expression of hTERT. Absolute expression of CEA or EGFR was not able to discriminate between the two groups. The more accurate normalized expression values of the test markers demonstrated a statistically significantly higher expression of hTERT (p<0.005) and CEA (p<0.001) in patients with advanced adenocarcinoma compared to the control group. CONCLUSION: Absolute hTERT expression in peritoneal lavage of patients with advanced pancreatic cancer was significantly higher compared to the control group. PMID- 26766155 TI - [Surgical therapy of pancreatic cancer - 5 years survival]. AB - INTRODUCTION: The purpose was to identify 5-year survivors among a group of radically resected patients with pancreatic cancer and analyse the characteristics and factors associated with their 5-year survival. Single tertiary centre experience. METHOD: A prospectively maintained database of 155 pancreatic resections from January 2006 to June 2010 was scanned to identify patients after curative radical resections for pancreatic ductal adenocarcinoma. The clinical and pathological data was analysed retrospectively. The outcomes of the PDAC group were evaluated using Kaplan-Meier analysis (survival) with the Log rank test and Cox regression analysis (evaluation of prognostic factors). Characteristics of the survivors were discussed. Significance level of 0.05 was used. Those factors were used as independent variables for Cox regression analysis whose significant effect on survival was shown based on Kaplan-Meier analysis. RESULTS: Among 155 patients undergoing a curative pancreatic resection, 73 had a pancreatic ductal adenocarcinoma. Fifteen patients (20.5%) after radical surgery survived over 5 years, 13 of whom are still alive. In the group of the survivors, the mean overall survival was 77.1 months (60110) and the median survival was 74 months. The mean relapse-free interval in the group of the survivors was 63.3 months (14110) with the median of 65 months. Factors associated with a longer survival included the absence of lymph node infiltration (p=0.031), uncomplicated postoperative course (p=0.025), absence of vascular invasion (p=0.017), no blood transfusions (p=0.015) and the use of postoperative therapy - predominantly chemotherapy (p=0.009). Significant independent predictors of survival included vascular invasion HR=2.239 (95%CI: 1.0934.590; p=0.028), postoperative chemotherapy HR=2.587 (95%CI: 1.3015.145; p=0.007) and blood transfusion HR=2.080 (95%CI: 1.0274.212; p=0.042). The risk of death was increased 2.2 times in patients with vascular invasion, 2.1 times in patients with transfusions, and finally 2.6 times in those with no chemotherapy. CONCLUSION: Factors associated with an improved overall survival included: the absence of lymph node infiltration, an uncomplicated postoperative course, absence of vascular invasion, no need of blood transfusions, and finally the use of postoperative chemotherapy. Vascular invasion, use of blood transfusions and postoperative adjuvant chemotherapy were significant independent prognostic factors of survival. PMID- 26766156 TI - Perigraft seroma as a rare angiosurgical complication. AB - Perigraft seroma is quite a rare complication that may occur after implantation of Dacron or expanded polytetrafluoroethylene (ePTFE) vascular grafts. We report a case of a 54-year-old patient with perigraft seroma around an axillofemoral bypass (ePTFE graft). Definitive treatment involved the explantation of this extraanatomic bypass with perigraft seroma and the implantation of an aortobiiliac bypass using vascular prosthesis made of a different material. Based on published studies, therapeutic options for this complication are discussed. No guidelines or recommendations are available. In conclusion, the approach to perigraft seroma treatment remains strictly individual. Vascular graft replacement using grafts made of different material seems to be the best option in the case of recurring perigraft seroma, where less invasive procedures were not successful. PMID- 26766157 TI - [Vascular dialysis access with transposed superficial femoral vein]. AB - The authors describe the case report of a 63 years old female patient with chronic renal failure in systemic lupus erythematosus. Vascular dialysis access in upper limbs could no more be used. The condition was approached by constructing an arteriovenous (AV) fistula in the thigh with transposed superficial femoral vein as the first procedure in the Czech Republic. PMID- 26766158 TI - Volatile fatty acids (VFAs) production from swine manure through short-term dry anaerobic digestion and its separation from nitrogen and phosphorus resources in the digestate. AB - The sustainability of an agricultural system depends highly upon the recycling of all useful substances from agricultural wastes. This study explored the feasibility of comprehensive utilization of C, N and P resources in swine manure (SM) through short-term dry anaerobic digestion (AD) followed by dry ammonia stripping, aiming at achieving (1) effective total volatile fatty acids (VFAs) production and separation; (2) ammonia recovery from the digestate; and (3) preservation of high P bioavailability in the solid residue for further applications. Specifically, two ammonia stripping strategies were applied and compared in this work: (I) ammonia stripping was directly performed with the digestate from dry AD of SM (i.e. dry ammonia stripping); and (II) wet ammonia stripping was conducted by using the resultant filtrate from solid-liquid separation of the mixture of digestate and added water. Results showed that dry AD of the tested SM at 55 degrees C, 20% TS and unadjusted initial pH (8.6) for 8 days produced relatively high concentrations of total VFAs (94.4 mg-COD/g-VS) and ammonia-N (20.0 mg/g-VS) with high potentially bioavailable P (10.6 mg/g-TS) remained in the digestate, which was considered optimal in this study. In addition, high ammonia removal efficiencies of 96.2% and 99.7% were achieved through 3 h' dry and wet stripping (at 55 degrees C and initial pH 11.0), respectively, while the total VFAs concentration in the digestate/filtrate remained favorably unchanged. All experimental data from the two stripping processes well fitted to the pseudo first-order kinetic model (R(2) = 0.9916 0.9997) with comparable theoretical maximum ammonia removal efficiencies (Aeq, >90%) being obtained under the tested dry and wet stripping conditions, implying that the former was more advantageous due to its much higher volumetric total ammonia-N removal rate thus much smaller reactor volume, less energy/chemicals consumption and no foaming problems. After 8 days' dry AD and 3 h' dry ammonia stripping, the separated liquid containing VFAs and the recovered ammonia were both marketable products, and the solid residues with averagely higher C/N ratios of 25.7 than those of raw SM (18.0) meanwhile maintaining a relatively high bioavailable P content of 8.1 mg/g-TS can serve as better feedstock for methane fermentation. PMID- 26766159 TI - Design of a fixed-bed ion-exchange process for the treatment of rinse waters generated in the galvanization process using Laminaria hyperborea as natural cation exchanger. AB - In this study, the removal of zinc from galvanization wastewaters was performed in a fixed bed column packed with brown macro-algae Laminaria hyperborea, acting as a natural cation exchanger (resin). The rinse wastewater presents a zinc concentration between 9 and 22 mg/L, a high concentration of light metals (mainly Na and Ca), a high conductivity (0.5-1.5 mS/cm) and a low organic content (DOC = 7-15 mg C/L). The zinc speciation diagram showed that approximately 80% of zinc is in the form of Zn(2+) and ?20% as ZnSO4, considering the effluent matrix. From all operational conditions tested for zinc uptake (17 < bed height<27 cm, 4.5 < flow rate<18.2 BV/h, 0.8 < particle equivalent diameter<2.0 mm), the highest useful capacity (7.1 mg Zn/g algae) was obtained for D/dp = 31, L/D = 11, 9.1 BV/h, tau = 6.4 min, corresponding to a service capacity of 124 BV (endpoint of 2 mg Zn/L). Elution was faster and near to 100% effective using 10 BV of HCl (1 M, 3.0%, 363 g HCl/L of resin), for flow rates higher than 4.5 BV/h. Calcium chloride solution (0.1 M) was selected as the best regenerant, allowing the reuse of the natural resin for more than 3 saturation/elution/regeneration cycles. The best operation conditions were scaled-up and tested in a pre-pilot plant. The scale-up design of the cation exchange process was proposed for the treatment of 2.4 m(3)/day of galvanization wastewater, resulting in an estimated reactants cost of 2.44 ?/m(3). PMID- 26766160 TI - Effects of dissolved oxygen on performance and microbial community structure in a micro-aerobic hydrolysis sludge in situ reduction process. AB - A sludge process reduction activated sludge (SPRAS), with a sludge process reduction module composed of a micro-aerobic tank and a settler positioned before conventional activated sludge process, showed good performance of pollutant removal and sludge reduction. Two SPRAS systems were operated to investigate effects of micro-aeration on sludge reduction performance and microbial community structure. When dissolved oxygen (DO) concentration in the micro-aerobic tank decreased from 2.5 (SPH) to 0.5 (SPL) mg/L, the sludge reduction efficiency increased from 42.9% to 68.3%. Compared to SPH, activated sludge in SPL showed higher contents of extracellular polymeric substances and dissolved organic matter. Destabilization of floc structure in the settler, and cell lysis in the sludge process reduction module were two major reasons for sludge reduction. Illumina-MiSeq sequencing showed that microbial diversity decreased under high DO concentration. Proteobacteria, Bacteroidetes and Chloroflexi were the most abundant phyla in the SPRAS. Specific comparisons down to the class and genus level showed that fermentative, predatory and slow-growing bacteria in SPL community were more abundant than in SPH. The results revealed that micro aeration in the SPRAS improved hydrolysis efficiency and enriched fermentative and predatory bacteria responsible for sludge reduction. PMID- 26766161 TI - Interaction of a conjugated polyaromatic molecule with a single dangling bond quantum dot on a hydrogenated semiconductor. AB - Controlling the strength of the coupling between organic molecules and single atoms provides a powerful tool for tuning electronic properties of single molecule devices. Here, using scanning tunneling microscopy and spectroscopy (STM/STS) supported by theoretical modeling, we study the interaction of a planar organic molecule (trinaphthylene) with a hydrogen-passivated Ge(001):H substrate and a single dangling bond quantum dot on that surface. The electronic structure of the molecule adsorbed on the hydrogen-passivated surface is similar to the gas phase structure and the measurements show that HOMO and LUMO states contribute to the STM filled and empty state images, respectively. Furthermore, we show that the electronic properties are not significantly affected when the molecule is attached to the single dangling bond, which is in contrast with the strong interaction of the molecule with a dangling bond dimer. Our results show that the dangling bond quantum dots could stabilize organic molecules on a hydrogenated semiconductor without affecting their originally designed gas phase electronic properties. Together with the ability to laterally manipulate the molecules on the surface, this will be advantageous in the construction of single-molecule devices, where the coupling and positioning of the molecules on the substrate could be tuned by a proper design of the surface quantum dot arrays, comprising both single and dimerized dangling bonds. PMID- 26766163 TI - Heart failure and sleep-disordered breathing. AB - PURPOSE OF REVIEW: Sleep-disordered breathing, which includes both obstructive and central sleep apnoea (OSA and CSA, respectively), is highly prevalent in patients with heart failure. In this review, we outline our current understanding of the bidirectional relationship between these disorders and heart failure. We also explore the role of recent advances in therapeutics. RECENT FINDINGS: Although early studies suggest promise of adaptive servoventilation in treating sleep-disordered breathing, particularly CSA with associated Cheyne-Stokes respiration, the recent clinical trial in the heart failure patient population has demonstrated worse cardiovascular outcome in symptomatic patients. SUMMARY: Both OSA and CSA are highly prevalent in patients with heart failure. Effective treatment of OSA with continuous positive airway pressure can improve cardiovascular outcome in these patients. However, recent evidence suggests that adaptive servoventilation cannot be safely recommended as a therapy for CSA in the context of heart failure, as a result of increased risk of cardiovascular mortality. PMID- 26766162 TI - Pathogen-reduced Ebola virus convalescent plasma: first steps towards standardization of manufacturing and quality control including assessment of Ebola-specific neutralizing antibodies. AB - BACKGROUND: Ebola virus disease is a public health emergency of international concern, and enormous efforts are being made in the development of vaccines and therapies. Ebola virus convalescent plasma is a promising anti-infective treatment of Ebola virus disease. Therefore, we developed and implemented a pathogen-reduced Ebola virus convalescent plasma concept in accordance with national, European and global regulatory framework. MATERIALS AND METHODS: Ebola virus convalescent plasma manufacture and distribution was managed by a collection centre, two medical centres and an expert group from the European Blood Alliance. Ebola virus convalescent plasma was collected twice with an interval of 61 days from a donor recovering from Ebola virus disease in Germany. After pathogen reduction, the plasma was analysed for Ebola virus-specific immunoglobulin G (IgG) antibodies and its Ebola virus neutralizing activity. RESULTS: Convalescent plasma could be collected without adverse events. Anti Ebola virus IgG titres and Ebola-specific neutralizing antibodies in convalescent plasma were only slightly reduced after pathogen reduction treatment with S59 amotosalen/UVA. A patient in Italy with Ebola virus disease was treated with convalescent plasma without apparent adverse effects. DISCUSSION: As proof of principle, we describe a concept and practical implementation of pathogen-reduced Ebola virus convalescent plasma manufacture, quality control and its clinical application to an Ebola virus disease patient. PMID- 26766164 TI - Advances in aortic disease management: a year in review. AB - PURPOSE OF REVIEW: The medical and surgical management of aortic disease is continually changing in search for improved outcomes. Our objective is to highlight recent advances in a few select areas pertaining to aortic disease and aortic surgery: the genetics of aortopathy, medical therapy of aortic aneurysms, advances in cardiac imaging, and operative strategies for the aortic arch. RECENT FINDINGS: As our understanding of the genetic basis for aortopathy continues to improve, routine genetic testing may be of value in assessing patients with genetically triggered forms of aortic disease. With regard to medical advances, treating patients with Marfan syndrome with either losartan or atenolol at an earlier stage in their disease course improves outcomes. In addition, novel imaging indices such as wall shear stress and aortic stiffness assessed by MRI may become useful markers of aortopathy and warrant further study. With regard to the optimal technique for cerebral perfusion in aortic arch surgery, high-quality data are still lacking. Finally, in patients with complex, multilevel aortic disease, the frozen elephant trunk is a viable single-stage option compared with the conventional elephant trunk, although with an increased risk for spinal cord injury. SUMMARY: Based on recent advances, continued studies in genetics, cardiac imaging, and surgical trials will further elucidate the etiology of aortopathy and ultimately guide management, both medically and surgically. PMID- 26766165 TI - Musculoskeletal abnormalities in congenital diaphragmatic hernia survivors: Patterns and risk factors: Report of a Japanese multicenter follow-up survey. AB - BACKGROUND: The aim of this study was to investigate the natural history and associated predictors of musculoskeletal deformities in congenital diaphragmatic hernia (CDH) survivors. METHODS: A multicenter retrospective survey was conducted among CDH patients between January 2006 and December 2010 in Japan, and a follow up survey was performed between September 2013 and October 2013. One hundred and eighty-two (79.8%) of the 228 patients were alive. An orthopedic survey of 159 survivors without severe coexisting congenital anomalies was subsequently carried out, and the rates of pectus excavatum (PE), scoliosis and chest asymmetry were evaluated. RESULTS: Scoliosis, PE and chest asymmetry were found in 20 (12.6%), 19 (11.9%) and 12 (7.5%) patients, respectively. In total, 44 patients (27.7%) developed orthopedic abnormalities. Reduction in the oxygenation index within 24 h after birth (P = 0.044), large diaphragmatic defects (P = 0.047) and patch repair (P = 0.014) were predictive for scoliosis. In addition, Apgar score at 5 min was significantly lower in the patients who developed PE (P = 0.034); and stomach herniation (P = 0.004) and liver herniation (P = 0.013) at prenatal diagnosis and large diaphragmatic defects (P = 0.036) were predictive of chest asymmetry. CONCLUSIONS: Approximately one-quarter of the survivors developed musculoskeletal abnormalities in the present survey of CDH patients. These data suggest that each musculoskeletal abnormality has its own specific predictors. PMID- 26766166 TI - Age, weight and decompression sickness in rats. AB - OBJECTIVE: The aim of this study was to determine if, after controlling for weight, age is associated with decompression sickness (DCS) in rats. METHODS: Following compression-decompression, male rats aged 11 weeks were observed for DCS. After two weeks recovery, surviving rats were re-dived using the same compression-decompression profile. RESULTS: In this experiment, there was a clear difference between DCS outcome at ages 11 or 13 weeks in matched rats (p = 0.002). DISCUSSION: Even with weight included in the model, age was significantly associated with DCS (p = 0.01), yet after removal of weight the association was much stronger (p = 0.002). CONCLUSION: We believe that age is likely to be found associated with the probability of DCS in a larger dataset with a wider range of parameters, after accounting for the effect of weight. PMID- 26766168 TI - Management of Hypertension in Diabetic Nephropathy: How Low Should We Go? AB - Hypertension is a frequent comorbidity often following the development of diabetic nephropathy among individuals with type 1 diabetes and affecting most patients with type 2 diabetes at the time of diagnosis. Multiple prospective randomized placebo-controlled trials demonstrate that tight blood pressure control among patients with diabetic nephropathy reduces the rates of macrovascular and microvascular complications. While randomized trials exist and support a blood pressure goal of <140/90 mm Hg for patients with nondiabetic kidney disease, there are no prospective data regarding a specific blood pressure goal on progression of diabetic nephropathy. Retrospective data analyses from trials show a linear relationship between either baseline or achieved study blood pressure and progression of nephropathy. Very high albuminuria is a hallmark of diabetic nephropathy with reductions by either angiotensin converting enzyme inhibitors (ACEi) or angiotensin receptor blocker (ARB) monotherapy associated with slowed nephropathy progression. However, combination antihypertensive therapy, while decreasing proteinuria, augments the risk of hyperkalemia, hypotension, and kidney dysfunction. Given the lack of trial data for a BP goal among patients with diabetic nephropathy, prospective trials are needed to define the optimal blood pressure necessary to preserve kidney function. At present, guideline blood pressure goals of less than 140/90 mm Hg and the use of ACEi or ARB therapy for those with more than 300 mg of albuminuria are mandated. PMID- 26766169 TI - Prognostic value of human mature adrenomedullin in patients with acute myocardial infarction. AB - Adrenomedullin (ADM) correlates with adverse cardiovascular outcomes in patients with acute myocardial infarction (AMI) and in patients with heart failure. Measurement of human mature ADM (mADM) has been difficult, and recent studies have used its surrogate - the mid-regional pro-ADM (MRproADM). Our objective was to determine whether mADM measured by a novel sandwich immunoassay, using the anti-C-terminal and an anti-mid-regional monoclonal antibody, was prognostic of 30-day, 90-day, 1-year, and 2-year major adverse cardiovascular events (MACEs) in 1111 consecutive patients who have suffered an AMI. We also compared it with the effect of MRproADM in the same patient population. A total of 311 (27.0%) patients experienced the primary endpoint at 2 years follow-up. The median (inter quartile range) of mADM was significantly higher in patients who experienced a 2 year MACE [60.90 (44.00-86.97)] pg/ml, compared to event-free survivors [49.59 (36.20-68.15)] pg/ml (P < 0.001). mADM, taken as 1 SD of the continuous variable, was predictive of MACEs in multivariate analysis, with hazard ratios [95% confidence intervals (CIs)] at 90 days [1.28 (1.01-1.62)], 1 year [1.31 (1.08 1.59)], and 2 years [1.42 (1.07-1.64)]. It was also independently predictive of death at 1-year [1.52 (1.12-2.05)] and 2-year [1.42 (1.07-1.89)] follow-up. mADM was a better predictor of these outcomes than MRproADM, apart from death at 90 days, and combined death and heart failure hospitalization at 1 and 2 years, respectively. Human mADM can be reliably measured and predicts MACE events at medium-term follow-up, and confirms the paradigm of risk stratification using MRproADM - a surrogate for the active hormone. The relationship between mADM and MACE appears to be a continuum. PMID- 26766170 TI - Power of the Name. PMID- 26766171 TI - The Appraising Evidence Game. AB - This column shares the best evidence-based strategies and innovative ideas on how to facilitate the learning of EBP principles and processes by clinicians as well as nursing and interprofessional students. Guidelines for submission are available at http://onlinelibrary.wiley.com/journal/10.1111/(ISSN)1741-6787. PMID- 26766175 TI - A Review of Pediatric Chronic Kidney Disease. AB - Chronic kidney disease is complex in both adults and children, but the disease is far from the same between these populations. Here we review the marked differences in etiology, comorbidities, impact of disease on growth and quality of life, issues unique to adolescents and transitions to adult care, and special considerations of congenital kidney and urinary tract anomalies for transplantation. PMID- 26766172 TI - Effects of interventions on use of hearing protectors among farm operators: A randomized controlled trial. AB - OBJECTIVE: The purpose of this study was to compare the effectiveness of three interventions designed to promote hearing protector device (HPD) use. DESIGN: Randomized controlled trial. STUDY SAMPLE: Farm operators (n = 491) were randomly assigned to one of five intervention groups: (1) interactive web-based information with mailed assortment of HPDs; (2) Interactive web-based information only; (3) static web-based information with mailed assortment of HPDs; (4) Static web-based information only; or (5) mailed assortment of HPDs only. Data were analysed using a mixed model approach. RESULTS: HPD use increased among all participants, and increased more among participants receiving the mailed HPDs (with or without information) compared to participants receiving other interventions. Participants receiving the interactive web-based information had comparable increased use of HPDs to those receiving the static web-based information. Participants receiving the mailed HPDs had more positive situational influences scale scores than other participants. Program satisfaction was highest among mailed and web-based information groups. CONCLUSIONS: A mailed assortment of hearing protectors was more effective than information. Interactive and static information delivered via web were similarly effective. Programs interested in increasing HPD use among farmers should consider making hearing protectors more available to farmers. PMID- 26766176 TI - Recombinant carp IL-4/13B stimulates in vitro proliferation of carp IgM(+) B cells. AB - Teleost IL-4/13B is a cytokine related to mammalian IL-4 and IL-13, of which hitherto the function had not been studied at the protein level. We identified an IL-4/13B gene in common carp (Cyprinus carpio) and expressed the recombinant protein (rcIL-4/13B). RcIL-4/13B was shown to stimulate proliferation of IgM(+) B cells, because after four days of stimulation the IgM(+) fraction of carp kidney and spleen leukocytes had formed many cell colonies, whereas such colonies were not found in the absence of rcIL-4/13B stimulation. After nine days of incubation with rcIL-4/13B these cells had proliferated to more than 3-to-7-fold higher numbers when compared to untreated cells. The proliferating cells contained a majority of IgM(+) cells but also other cells, as indicated by FACS and RT-PCR analyses. The important conclusion is that in fish not only IL-4/13A has B cell stimulating properties, as a previous publication has shown, but also IL-4/13B. PMID- 26766177 TI - Effects of dietary supplementation of Lactobacillus rhamnosus or/and Lactococcus lactis on the growth, gut microbiota and immune responses of red sea bream, Pagrus major. AB - Pagrus major fingerlings (3.29 +/- 0.02 g) were fed with basal diet (control) supplemented with Lactobacillus rhamnosus (LR), Lactococcus lactis (LL), and L. rhamnosus + L. lactis (LR + LL) at 10(6) cell g(-1) feed for 56 days. Feeding a mixture of LR and LL significantly increased feed utilization (FER and PER), intestine lactic acid bacteria (LAB) count, plasma total protein, alternative complement pathway (ACP), peroxidase, and mucus secretion compared with the other groups (P < 0.05). Serum lysozyme activity (LZY) significantly increased in LR + LL when compared with the control group. Additionally, fish fed the LR + LL diet showed a higher growth performance (Fn wt, WG, and SGR) and protein digestibility than the groups fed an individual LR or the control diet. Superoxide dismutase (SOD) significantly increased in LR and LR + LL groups when compared with the other groups. Moreover, the fish fed LR or LL had better improvement (P < 0.05) in growth, feed utilization, body protein and lipid contents, digestibility coefficients (dry matter, protein, and lipid), protease activity, total intestine and LAB counts, hematocrit, total plasma protein, biological antioxidant potential, ACP, serum and mucus LZY and bactericidal activities, peroxidase, SOD, and mucus secretion than the control group. Interestingly, fish fed diets with LR + LL showed significantly lower total cholesterol and triglycerides when compared with the other groups (P < 0.05). These data strongly suggest that a mixture of LR and LL probiotics may serve as a healthy immunostimulating feed additive in red sea bream aquaculture. PMID- 26766178 TI - Roles of dopamine receptors in mediating acute modulation of immunological responses in Macrobrachium rosenbergii. AB - Dopamine (DA) was found to influence the immunological responses and resistance to pathogen infection in invertebrates. To clarify the possible modulation of DA through dopamine receptors (DAR) against acute environmental stress, the levels of DA, glucose and lactate in the haemolymph of Macrobrachium rosenbergii under hypo- and hyperthermal stresses were measured. The changes in immune parameters such as total haemocyte count (THC), differential haemocyte count (DHC), phenoloxidase (PO) activity, respiratory bursts (RBs), superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities and phagocytic activity (PA) were evaluated in prawns which received DAR antagonists (SCH23390, SCH, D1 antagonist; domperidone, DOM, D2 antagonist; chlorpromazine, CH, D1+2 antagonist) followed by hypo- (15 degrees C) and hyperthermal (34 degrees C) stresses. In addition, pharmacological analysis of the effect DA modulation was studied in haemocytes incubated with DA and DAR antagonists. The results revealed a significant increase in haemolymph DA accompanied with upregulated levels of glucose and lactate in prawns exposed to both hypo- and hyperthermal stresses in 2 h. In addition, a significant decrease in RBs per haemocyte was noted in prawns which received DAR antagonists when they exposed to hyperthermal stress for 30 min. In in vitro test, antagonism on RBs, SOD and GPx activity of haemocytes were further evidenced through D1, D1, D1+D2 DARs, respectively, in the meantime, no significant difference in PO activity and PA was observed among the treatment groups. These results suggest that the upregulation of DA, glucose and lactate in haemolymph might be the response to acute thermal stress for the demand of energy, and the DAR occupied by its antagonistic action impart no effect on immunological responses except RBs in vivo even though the modulation mediated through D1 DAR was further evidenced in RBs, SOD and GPx activities in vitro. It is therefore concluded that thermal stress mediate stress responses not only through DAR but also via diverse pathways, and DA might modulate the levels of RBs, SOD and GPx activities mainly through D1 DAR. PMID- 26766179 TI - Effect of salinity on regulation mechanism of neuroendocrine-immunoregulatory network in Litopenaeus vannamei. AB - The effects of low salinity (transferred from 310/00 to 260/00, 210/00, and 160/00) on the regulation pathways of neuroendocrine-immunoregulatory network were investigated in Litopenaeus vannamei. The results showed that the hormones (corticotrophin-releasing hormone, adrenocorticotropic hormone) and biogenic amines (dopamine, noradrenaline, 5-hydroxytryptamine) concentrations in lower salinity groups increased significantly within 12 h. The gene expression of biogenic amine receptors showed that dopamine receptor D4 and alpha2 adrenergic receptor in lower salinity groups decreased significantly within 12 h, whereas the 5-HT7 receptor significantly increased within 1d. The second messenger synthetases (adenylyl cyclase, phospholipase C) and the second messengers (cyclic adenosine monophosphate, cyclic guanosine monophosphate) of lower salinity groups shared a similar trend in which adenylyl cyclase and cyclic adenosine monophosphate reached the maximum at 12 h, whereas phospholipase C and cyclic guanosine monophosphate reached the minimum. The immune parameters (total hemocyte count, phenoloxidase activity, phagocytic activity, crustin expression, antibacterial activity, C-type lectin expression, hemagglutinating activity) in lower salinity groups decreased significantly within 12 h. Except for the total hemocyte count, all the parameters recovered to the control levels afterwards. Therefore, it may be concluded that the neuroendocrine-immunoregulatory network plays a principal role in adapting to salinity changes as the main center for sensing the stress and causes immune response in L. vannamei. PMID- 26766180 TI - Comparative proteomic analysis of Litopenaeus vannamei gills after vaccination with two WSSV structural proteins. AB - White spot syndrome virus (WSSV) is one of the most devastating viral pathogens of cultured shrimp worldwide. Recently published papers show the ability of WSSV structural protein VP28 to vaccinate shrimp and raise protection against the virus. This study attempted to identify the joining proteins of the aforementioned shrimp quasi-immune response by proteomic analysis. The other envelope protein, VP36B, was used as the non-protective subunit vaccine control. Shrimp were intramuscularly injected with rVPs or PBS on day 1 and day 4 and then on day 7 their gill tissues were sampled. The two-dimensional electrophoresis (2 DE) patterns of gill proteins between vaccinated and PBS groups were compared and 20 differentially expressed proteins identified by mass spectrometry, some of which were validated in gill and hemocyte tissues using real-time quantitative RT PCR. Many of identified proteins and their expression levels also linked with the shrimp response during WSSV infection. The list of up-regulated protein spots found exclusively in rVP28-vaccinated shrimp include calreticulin and heat shock protein 70 with chaperone properties, ubiquitin, and others. The two serine proteases, chymotrypsin and trypsin, were significantly increased in shrimp of both vaccinated groups compared to PBS controls. The information presented here should be useful for gaining insight into invertebrate immunity. PMID- 26766181 TI - Yersinia ruckeri lipopolysaccharide is necessary and sufficient for eliciting a protective immune response in rainbow trout (Oncorhynchus mykiss, Walbaum). AB - Enteric redmouth disease (ERM), caused by Yersinia ruckeri, has been controlled successfully using immersion-applied bacterin vaccines for several decades. While the host response to vaccination and the mechanism of protection of this vaccine have been elucidated, the bacterial components eliciting protection have remained unclear. Here we show that highly purified serotype O1 Y. ruckeri lipopolysaccharide (LPS) is sufficient to induce a protective response to experimental challenge in rainbow trout (Oncorhynchus mykiss). Dose response experiments demonstrated that Y. ruckeri LPS at doses of 1 ng/fish and above resulted in essentially complete protection and doses as low as 0.01 ng/fish (1.38 ng/kg) resulted in significant protection, thus demonstrating the extremely high potency of this immunogen. Analysis of the Y. ruckeri genome identified a cluster of putative O-antigen biosynthetic genes specific to serotype O1 strains. This cluster primarily consisted of genes encoding proteins predicted to function in the biosynthesis of legionamic acid, a nonulosonic acid known to be part of the O-polysaccharide repeat of O1 Y. ruckeri. Mutation of the nab2 gene, a nonulosonic acid biosynthesis gene (nab gene), resulted in production of severely truncated forms of LPS. Vaccination with bacterin vaccines derived from the nab2 mutant and its wild type parent strain demonstrated that LPS is a required component of the whole-cell bacterin vaccine and suggests that LPS is the only cellular component contributing to the protective response elicited by this vaccine. We speculate that the exceptionally high potency of Y. ruckeri LPS accounts for the unusual success of this vaccine when delivered by immersion. PMID- 26766182 TI - Ferritin from the Pacific abalone Haliotis discus hannai: Analysis of cDNA sequence, expression, and activity. AB - Ferritin plays an important role in iron homeostasis due to its ability to bind and sequester large amounts of iron. In this study, the gene encoding a ferritin (HdhFer2) was cloned from Pacific abalone (Haliotis discus hannai). The full length cDNA of HdhFer2 contains a 5'-UTR of 121 bp, an ORF of 516 bp, and a 3' UTR of 252 bp with a polyadenylation signal sequence of AATAAA and a poly(A) tail. It also contains a 31 bp iron-responsive element (IRE) in the 5'-UTR position, which is conserved in many ferritins. HdhFer2 consists of 171 amino acid residues with a predicted molecular weight (MW) ~19.8 kDa and a theoretical isoelectric point (PI) of 4.84. The deduced amino acid sequence of HdhFer2 contains two ferritin iron-binding region signatures (IBRSs). HdhFer2 mRNA was detected in a wide range of tissues and was dominantly expressed in the gill. Infection with the bacterial pathogen Vibrio anguillarum significantly upregulated HdhFer2 expression in a time-dependent manner. Recombinant HdhFer2 (rHdhFer2) purified from Escherichia coli was able to bind ferrous iron in a concentration-dependent manner. In summary, these results suggest that HdhFer2 is a crucial protein in the iron-withholding defense system, and plays an important role in the innate immune response of abalone. PMID- 26766183 TI - Autism and Overcoming Job Barriers: Comparing Job-Related Barriers and Possible Solutions in and outside of Autism-Specific Employment. AB - The aim of this study was to discover how individuals with autism succeed in entering the job market. We therefore sought to identify expected and occurred barriers, keeping them from taking up and staying in employment as well as to identify the solutions used to overcome these barriers. Sixty-six employed individuals with autism--17 of them with autism-specific employment--participated in an online survey. Results showed a variety of possible barriers. Individuals in autism-specific employment named formality problems--problems with organizational and practical process-related aspects of the job entry--most frequently while individuals in non-autism-specific employment mentioned social problems--obstacles concerning communication and human interaction--most. In terms of solutions, both groups used their own resources as much as external help, but differed in their specific strategies. In addition, correlations of an autism-specific employment with general and occupational self-efficacy as well as life and job satisfaction were examined. Possible implications of the results are discussed with regard to problem solving behavior and the use of strengths. PMID- 26766186 TI - Grief following pet and human loss: Closeness is key. AB - The authors compared grief severity and its predictors in two equivalent college student samples who had experienced the death of a pet (n = 211) or a person (n = 146) within the past 2 years. The human death sample reported higher grief severity, p < .01, but effect sizes were small (ds = .28-.30). For both samples, closeness to the deceased was overwhelmingly the strongest predictor of grief severity; other predictors generally dropped out with closeness added to the model. Results highlight the importance of including closeness to deceased in grief research, and its centrality in understanding grief counseling clients. PMID- 26766184 TI - Validation of Walking Trails for the Urban TrainingTM of Chronic Obstructive Pulmonary Disease Patients. AB - PURPOSE: Accessible interventions to train patients with chronic obstructive pulmonary disease (COPD) are needed. We designed urban trails of different intensities (low, moderate and high) in different types of public spaces (boulevard, beach and park). We aimed to validate the trails' design by assessing the physiological response to unsupervised walking trails of: (1) different intensities in COPD patients, and (2) same intensity from different public spaces in healthy adults. METHODS: On different days and under standardized conditions, 10 COPD patients walked the three intensity trails designed in a boulevard space, and 10 healthy subjects walked the three intensity trails in three different spaces. We measured physiological response and energy expenditure using a gas analyzer. We compared outcomes across trails intensity and/or spaces using mixed effects linear regression. RESULTS: In COPD patients, physiological response and energy expenditure increased significantly according to the trails intensity: mean (SD) peak VO2 15.9 (3.5), 17.4 (4.7), and 17.7 (4.4) mL/min/kg (p-trend = 0.02), and MET-min 60 (23), 64 (26), 72 (31) (p-trend<0.01) in low, moderate and high intensity trails, respectively. In healthy subjects there were no differences in physiological response to walking trails of the same intensity across different spaces. CONCLUSIONS: We validated the trails design for the training of COPD patients by showing that the physiological response to and energy expenditure on unsupervised walking these trails increased according to the predefined trails' intensity and did not change across trails of the same intensity in different public space. Walkable public spaces allow the design of trails that could be used for the training of COPD patients in the community. PMID- 26766187 TI - Sleep Duration, Quality of Sleep, and Use of Sleep Medication, by Sex and Family Type, 2013-2014. AB - KEY FINDINGS: Data from the National Health Interview Survey, 2013-2014. Single parents, especially women, were more likely than adults in other types of families to have short sleep duration, frequently have trouble falling asleep and staying asleep, and frequently wake up feeling not well-rested. Within family types, women were more likely than men to frequently have trouble falling asleep and staying asleep, and to frequently wake up feeling not well-rested. Overall, adults in two-parent families were less likely than adults in other types of families to have taken sleep medication four times or more in the past week. PMID- 26766185 TI - Early Cellular Changes in the Ascending Aorta and Myocardium in a Swine Model of Metabolic Syndrome. AB - BACKGROUND: Metabolic syndrome is associated with pathological remodeling of the heart and adjacent vessels. The early biochemical and cellular changes underlying the vascular damage are not fully understood. In this study, we sought to establish the nature, extent, and initial timeline of cytochemical derangements underlying reduced ventriculo-arterial compliance in a swine model of metabolic syndrome. METHODS: Yorkshire swine (n = 8 per group) were fed a normal diet (ND) or a high-cholesterol (HCD) for 12 weeks. Myocardial function and blood flow was assessed before harvesting the heart. Immuno-blotting and immuno-histochemical staining were used to assess the cellular changes in the myocardium, ascending aorta and left anterior descending artery (LAD). RESULTS: There was significant increase in body mass index, blood glucose and mean arterial pressures (p = 0.002, p = 0.001 and p = 0.024 respectively) in HCD group. At the cellular level there was significant increase in anti-apoptotic factors p-Akt (p = 0.007 and p = 0.002) and Bcl-xL (p = 0.05 and p = 0.01) in the HCD aorta and myocardium, respectively. Pro-fibrotic markers TGF-beta (p = 0.01), pSmad1/5 (p = 0.03) and MMP-9 (p = 0.005) were significantly increased in the HCD aorta. The levels of pro-apoptotic p38MAPK, Apaf-1 and cleaved Caspase3 were significantly increased in aorta of HCD (p = 0.03, p = 0.04 and p = 0.007 respectively). Similar changes in coronary arteries were not observed in either group. Functionally, the high cholesterol diet resulted in significant increase in ventricular end systolic pressure and-dp/dt (p = 0.05 and p = 0.007 respectively) in the HCD group. CONCLUSION: Preclinical metabolic syndrome initiates pro-apoptosis and pro fibrosis pathways in the heart and ascending aorta, while sparing coronary arteries at this early stage of dietary modification. PMID- 26766204 TI - A Persistent Interest in Viruses. PMID- 26766205 TI - Observing Single Molecules Complexing with Cucurbit[7]uril through Nanogap Surface-Enhanced Raman Spectroscopy. AB - In recent years, single-molecule sensitivity achievable by surface-enhanced Raman spectroscopy (SERS) has been widely reported. We use this to investigate supramolecular host-guest chemistry with the macrocyclic host cucurbit[7]uril, on a few-to-single-molecule level. A nanogap geometry, comprising individual gold nanoparticles on a planar gold surface spaced by a single layer of molecules, gives intense SERS signals. Plasmonic coupling between the particle and the surface leads to strongly enhanced optical fields in the gap between them, with single-molecule sensitivity established using a modification of the well-known bianalyte method. Changes in the Raman modes of the host molecule are observed when single guests included inside its cavity internally stretch it. Anisotropic intermolecular interactions with the guest are found which show additional distinct features in the Raman modes of the host molecule. PMID- 26766207 TI - A self-calibrating approach for the segmentation of retinal vessels by template matching and contour reconstruction. AB - The automated processing of retinal images is a widely researched area in medical image analysis. Screening systems based on the automated and accurate recognition of retinopathies enable the earlier diagnosis of diseases like diabetic retinopathy, hypertension and their complications. The segmentation of the vascular system is a crucial task in the field: on the one hand, the accurate extraction of the vessel pixels aids the detection of other anatomical parts (like the optic disc Hoover and Goldbaum, 2003) and lesions (like microaneurysms Sopharak et al., 2013); on the other hand, the geometrical features of the vascular system and their temporal changes are shown to be related to diseases, like the vessel tortuosity to Fabry disease Sodi et al., 2013 and the arteriolar to-venus (A/V) ratio to hypertension (Pakter et al., 2005). In this study, a novel technique based on template matching and contour reconstruction is proposed for the segmentation of the vasculature. In the template matching step generalized Gabor function based templates are used to extract the center lines of vessels. Then, the intensity characteristics of vessel contours measured in training databases are reconstructed. The method was trained and tested on two publicly available databases, DRIVE and STARE; and reached an average accuracy of 0.9494 and 0.9610, respectively. We have also carried out cross-database tests and found that the accuracy scores are higher than that of any previous technique trained and tested on the same database. PMID- 26766206 TI - Shape analysis of hypertrophic and hypertensive heart disease using MRI-based 3D surface models of left ventricular geometry. AB - The focus of this study was to develop advanced mathematical tools to construct high-resolution 3D models of left-ventricular (LV) geometry to evaluate focal geometric differences between patients with hypertrophic cardiomyopathy (HCM) and hypertensive heart disease (HHD) using cardiac magnetic resonance (MR) cross sectional images. A limiting factor in 3D analysis of cardiac MR cross-sections is the low out-of-plane resolution of the acquired images. To overcome this problem, we have developed a mathematical framework to construct a population based high-resolution 3D LV triangulated surface (template) in which an iterative matching algorithm maps a surface mesh of a normal heart to a set of cross sectional contours that were extracted from short-axis cine cardiac MR images of patients who were diagnosed with either HCM or HHD. A statistical analysis was conducted on deformations that were estimated at each surface node to identify shape differences at end-diastole (ED), end-systole (ES), and motion-related shape variation from ED to ES. Some significant shape difference in radial thickness was detected at ES. Differences of LV 3D surface geometry were identified focally on the basal anterior septum wall. Further research is needed to relate these findings to the HCM morphological substrate and to design a classifier to discriminate among different etiologies of LV hypertrophy. PMID- 26766208 TI - Mapping of Low-Frequency Raman Modes in CVD-Grown Transition Metal Dichalcogenides: Layer Number, Stacking Orientation and Resonant Effects. AB - Layered inorganic materials, such as the transition metal dichalcogenides (TMDs), have attracted much attention due to their exceptional electronic and optical properties. Reliable synthesis and characterization of these materials must be developed if these properties are to be exploited. Herein, we present low frequency Raman analysis of MoS2, MoSe2, WSe2 and WS2 grown by chemical vapour deposition (CVD). Raman spectra are acquired over large areas allowing changes in the position and intensity of the shear and layer-breathing modes to be visualized in maps. This allows detailed characterization of mono- and few layered TMDs which is complementary to well-established (high-frequency) Raman and photoluminescence spectroscopy. This study presents a major stepping stone in fundamental understanding of layered materials as mapping the low-frequency modes allows the quality, symmetry, stacking configuration and layer number of 2D materials to be probed over large areas. In addition, we report on anomalous resonance effects in the low-frequency region of the WS2 Raman spectrum. PMID- 26766210 TI - Facet-Mediated Growth of High-Quality Monolayer Graphene on Arbitrarily Rough Copper Surfaces. AB - A synthetic approach for high-quality graphene on rough Cu surfaces via chemical vapor deposition is proposed. High-quality graphene is synthesized on rough Cu surfaces by inducing surface faceting of Cu surfaces prior to graphene growth. The electron mobility of synthesized graphene on the rough Cu surfaces is enhanced to 10 335 cm(2) V(-1) s(-1). PMID- 26766209 TI - De Novo Transcriptome Assembly of the Chinese Swamp Buffalo by RNA Sequencing and SSR Marker Discovery. AB - The Chinese swamp buffalo (Bubalis bubalis) is vital to the lives of small farmers and has tremendous economic importance. However, a lack of genomic information has hampered research on augmenting marker assisted breeding programs in this species. Thus, a high-throughput transcriptomic sequencing of B. bubalis was conducted to generate transcriptomic sequence dataset for gene discovery and molecular marker development. Illumina paired-end sequencing generated a total of 54,109,173 raw reads. After trimming, de novo assembly was performed, which yielded 86,017 unigenes, with an average length of 972.41 bp, an N50 of 1,505 bp, and an average GC content of 49.92%. A total of 62,337 unigenes were successfully annotated. Among the annotated unigenes, 27,025 (43.35%) and 23,232 (37.27%) unigenes showed significant similarity to known proteins in NCBI non-redundant protein and Swiss-Prot databases (E-value < 1.0E-5), respectively. Of these annotated unigenes, 14,439 and 15,813 unigenes were assigned to the Gene Ontology (GO) categories and EuKaryotic Ortholog Group (KOG) cluster, respectively. In addition, a total of 14,167 unigenes were assigned to 331 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Furthermore, 17,401 simple sequence repeats (SSRs) were identified as potential molecular markers. One hundred and fifteen primer pairs were randomly selected for amplification to detect polymorphisms. The results revealed that 110 primer pairs (95.65%) yielded PCR amplicons and 69 primer pairs (60.00%) presented polymorphisms in 35 individual buffaloes. A phylogenetic analysis showed that the five swamp buffalo populations were clustered together, whereas two river buffalo breeds clustered separately. In the present study, the Illumina RNA-seq technology was utilized to perform transcriptome analysis and SSR marker discovery in the swamp buffalo without using a reference genome. Our findings will enrich the current SSR markers resources and help spearhead molecular genetic research studies on the swamp buffalo. PMID- 26766211 TI - Deafness gene mutations in newborns in Beijing. AB - OBJECTIVE: To determine the incidence of congenital hearing loss (HL) in newborns by the rate of deafness-related genetic mutations. DESIGN: Clinical study of consecutive newborns in Beijing using allele-specific polymerase chain reaction based universal array. STUDY SAMPLE: This study tested 37 573 newborns within 3 days after birth, including nine sites in four genes: GJB2 (35 del G, 176 del 16, 235 del C, 299 del AT), SLC26A4 (IVS7-2 A > G, 2168 A > G), MTRNR1 (1555 A > G, 1494 C > T), and GJB3 (538 C > T). The birth condition of infants was also recorded. RESULTS: Of 37 573 newborns, 1810 carried pathogenic mutations, or 4.817%. The carrier rates of GJB2 (35 del G, 176 del 16, 235 del C, 299 del AT), GJB3 (538 C > T), SLC26A4 (IVS7-2 A > G, 2168 A > G), and MTRNR1 (1555 A > G, 1494 C > T) mutations were 0.005%, 0.104%, 1.924%, 0.551%, 0.295%, 0.253%, 1.387%, 0.024%, and 0.274%, respectively. Logistic regression analysis indicated no statistically significant relationship between mutations and infant sex, premature delivery, twin status, or birth weight. CONCLUSIONS: The 235delC GJB2 mutation was the most frequent deafness-related mutation in the Chinese population. Genetic screening for the deafness gene will help detect more cases of newborn congenital HL than current screening practices. PMID- 26766212 TI - The Practice of Anal Dilations following Anorectal Reconstruction in Patients with Anorectal Malformations: An International Survey. AB - Purpose The objective of this study was to investigate the current practices of anal dilations after anorectal reconstruction for anorectal malformations (ARMs) in different centers. Materials and Methods An online survey, consisting of 27 questions about the practice of anal dilations, was launched in March 2015 among 54 pediatric surgeons with expertise in colorectal surgery. The survey was divided into three sections. The first section included questions regarding the country of origin, the role in the department, the average number of ARM cases treated per year, and the surgical approach used to repair ARMs. The second section was accessible only for surgeons who perform anal dilations and enquired about their modality of performing anal dilations-their attitude toward complications such as rectal prolapse, bleeding, or perineal dehiscence occurring during dilations-and about the incidence of rectal prolapse and/or anal stenosis, which required surgical repair, in their series of patients with ARMs. The third section was accessible only for surgeons who do not perform anal dilations and enquired the incidence of rectal prolapse and/or anal stenosis that required surgical repair in their series of patients with ARMs. Results A total of 36 pediatric surgeons from 20 countries completed the survey. All participants performed anal dilations. Twenty-five (70%) surgeons performed the first dilation 14 days after anorectal reconstruction; 30 (83%) surgeons performed it in the outpatient clinic; 34 (94%) surgeons used metal dilators and 30 (83%) surgeons lubricated the dilator with an anesthetic/steroid-free ointment; 21 (59%) surgeons tailored the first dilator size to the specific anatomical features of each patient; 27 (75%) surgeons used 1-mm-diameter increments in the dilator size and 22 (61%) surgeons increased the size weekly; 16 (45%) surgeons followed up with the patients weekly until the proper dilator size was reached. This was determined according to Pena's protocol by 25 (70%) surgeons: 23(64%) surgeons initially performed dilations twice daily; 24(66%) surgeons tapered the frequency of dilations once the desired caliber was reached. No general agreement exists in the management of complications such as rectal prolapse, bleeding, or perineal dehiscence occurring during dilations. Incidence of rectal prolapse and anal stenosis was reported less than 5%, respectively, by 25(70%) and 29(81%) respondents. Conclusion Anal dilations for ARM are performed worldwide according to different modalities. Prospective and randomized clinical trials could be useful to establish a standardized protocol. PMID- 26766213 TI - In Vitro Developmental Toxicology Screens: A Report on the Progress of the Methodology and Future Applications. AB - There has been increasing focus on generation and assessment of in vitro developmental toxicology models for assessing teratogenic liability of chemicals. The driver for this focus has been to find reliable in vitro assays that will reduce or replace the use of in vivo tests for assessing teratogenicity. Such efforts may be eventually applied in testing pharmaceutical agents where a developmental toxicology assay or battery of assays may be incorporated into regulatory testing to replace one of the two species currently used in teratogenic assessment. Such assays may be eventually applied in testing a broader spectrum of chemicals, supporting efforts aligned with Tox21 strategies and responding to REACH legislation. This review describes the developmental toxicology assays that are of focus in these assessments: rodent whole embryo culture, zebrafish embryo assays, and embryonic stem cell assays. Progress on assay development as well as future directions of how these assays are envisioned to be applied for broader safety testing of chemicals are discussed. Altogether, the developmental model systems described in this review provide rich biological systems that can be utilized in better understanding teratogenic mechanisms of action of chemotypes and are promising in providing proactive safety assessment related to developmental toxicity. Continual advancements in refining/optimizing these in vitro assays are anticipated to provide a robust data set to provide thoughtful assessment of how whole animal teratogenicity evaluations can be reduced/refined in the future. PMID- 26766215 TI - Magnetic resonance spectroscopic imaging at superresolution: Overview and perspectives. AB - The notion of non-invasive, high-resolution spatial mapping of metabolite concentrations has long enticed the medical community. While magnetic resonance spectroscopic imaging (MRSI) is capable of achieving the requisite spatio spectral localization, it has traditionally been encumbered by significant resolution constraints that have thus far undermined its clinical utility. To surpass these obstacles, research efforts have primarily focused on hardware enhancements or the development of accelerated acquisition strategies to improve the experimental sensitivity per unit time. Concomitantly, a number of innovative reconstruction techniques have emerged as alternatives to the standard inverse discrete Fourier transform (DFT). While perhaps lesser known, these latter methods strive to effect commensurate resolution gains by exploiting known properties of the underlying MRSI signal in concert with advanced image and signal processing techniques. This review article aims to aggregate and provide an overview of the past few decades of so-called "superresolution" MRSI reconstruction methodologies, and to introduce readers to current state-of-the art approaches. A number of perspectives are then offered as to the future of high-resolution MRSI, with a particular focus on translation into clinical settings. PMID- 26766216 TI - Parametric Regression on the Grassmannian. AB - We address the problem of fitting parametric curves on the Grassmann manifold for the purpose of intrinsic parametric regression. We start from the energy minimization formulation of linear least-squares in Euclidean space and generalize this concept to general nonflat Riemannian manifolds, following an optimal-control point of view. We then specialize this idea to the Grassmann manifold and demonstrate that it yields a simple, extensible and easy-to implement solution to the parametric regression problem. In fact, it allows us to extend the basic geodesic model to (1) a "time-warped" variant and (2) cubic splines. We demonstrate the utility of the proposed solution on different vision problems, such as shape regression as a function of age, traffic-speed estimation and crowd-counting from surveillance video clips. Most notably, these problems can be conveniently solved within the same framework without any specifically tailored steps along the processing pipeline. PMID- 26766214 TI - Probing the Folding-Unfolding Transition of a Thermophilic Protein, MTH1880. AB - The folding mechanism of typical proteins has been studied widely, while our understanding of the origin of the high stability of thermophilic proteins is still elusive. Of particular interest is how an atypical thermophilic protein with a novel fold maintains its structure and stability under extreme conditions. Folding-unfolding transitions of MTH1880, a thermophilic protein from Methanobacterium thermoautotrophicum, induced by heat, urea, and GdnHCl, were investigated using spectroscopic techniques including circular dichorism, fluorescence, NMR combined with molecular dynamics (MD) simulations. Our results suggest that MTH1880 undergoes a two-state N to D transition and it is extremely stable against temperature and denaturants. The reversibility of refolding was confirmed by spectroscopic methods and size exclusion chromatography. We found that the hyper-stability of the thermophilic MTH1880 protein originates from an extensive network of both electrostatic and hydrophobic interactions coordinated by the central beta-sheet. Spectroscopic measurements, in combination with computational simulations, have helped to clarify the thermodynamic and structural basis for hyper-stability of the novel thermophilic protein MTH1880. PMID- 26766217 TI - A Novel Performance Evaluation Methodology for Single-Target Trackers. AB - This paper addresses the problem of single-target tracker performance evaluation. We consider the performance measures, the dataset and the evaluation system to be the most important components of tracker evaluation and propose requirements for each of them. The requirements are the basis of a new evaluation methodology that aims at a simple and easily interpretable tracker comparison. The ranking-based methodology addresses tracker equivalence in terms of statistical significance and practical differences. A fully-annotated dataset with per-frame annotations with several visual attributes is introduced. The diversity of its visual properties is maximized in a novel way by clustering a large number of videos according to their visual attributes. This makes it the most sophistically constructed and annotated dataset to date. A multi-platform evaluation system allowing easy integration of third-party trackers is presented as well. The proposed evaluation methodology was tested on the VOT2014 challenge on the new dataset and 38 trackers, making it the largest benchmark to date. Most of the tested trackers are indeed state-of-the-art since they outperform the standard baselines, resulting in a highly-challenging benchmark. An exhaustive analysis of the dataset from the perspective of tracking difficulty is carried out. To facilitate tracker comparison a new performance visualization technique is proposed. PMID- 26766218 TI - Fast Rotation Search with Stereographic Projections for 3D Registration. AB - Registering two 3D point clouds involves estimating the rigid transform that brings the two point clouds into alignment. Recently there has been a surge of interest in using branch-and-bound (BnB) optimisation for point cloud registration. While BnB guarantees globally optimal solutions, it is usually too slow to be practical. A fundamental source of difficulty lies in the search for the rotational parameters. In this work, first by assuming that the translation is known, we focus on constructing a fast rotation search algorithm. With respect to an inherently robust geometric matching criterion, we propose a novel bounding function for BnB that is provably tighter than previously proposed bounds. Further, we also propose a fast algorithm to evaluate our bounding function. Our idea is based on using stereographic projections to precompute and index all possible point matches in spatial R-trees for rapid evaluations. The result is a fast and globally optimal rotation search algorithm. To conduct full 3D registration, we co-optimise the translation by embedding our rotation search kernel in a nested BnB algorithm. Since the inner rotation search is very efficient, the overall 6DOF optimisation is speeded up significantly without losing global optimality. On various challenging point clouds, including those taken out of lab settings, our approach demonstrates superior efficiency. PMID- 26766222 TI - Practice Pattern Variation in the Care of Children With Acute Asthma. AB - OBJECTIVES: Pediatric asthma is a highly prevalent disease, affecting over 7 million U.S. children and accounting for 750,000 annual emergency department (ED) visits. Guidelines from the National Asthma Education and Prevention Program recommend limited use of chest radiography (CXR), complete blood counts (CBCs), and antibiotics when managing acute exacerbations of asthma. However, studies suggest frequent overutilization of these resources. The objective was to evaluate differences between pediatric and general EDs in rates of CXRs, CBCs, and use of antibiotics for pediatric asthma exacerbations. METHODS: This was a repeated cross-sectional analysis of data from the National Hospital Ambulatory Medical Care Survey from 2000 through 2010 of CXR, CBCs, and antibiotics during ED visits for pediatric acute asthma exacerbations. Multivariable logistic regression was performed to identify differences in asthma management by ED type (pediatric vs. general) after adjusting for demographic covariates. RESULTS: There were 3,313 observations, representing an estimated 10.9 million (95% confidence interval [CI] = 9.7 to 12.1 million) ED visits for acute asthma without bacterial coinfection. Of these, 17.4% occurred in pediatric EDs. Multivariable logistic regression revealed that visits to pediatric EDs were less likely to include CXRs (adjusted odds ratio [AOR] = 0.39; 95% CI = 0.25 to 0.60), CBCs (AOR = 0.42; 95% CI = 0.22 to 0.80), and antibiotics (AOR = 0.50; 95% CI = 0.31 to 0.82) after adjustment for race/ethnicity, triage level, academic ED, metropolitan statistical area, and geographic region. CONCLUSIONS: There are substantial differences in diagnostic testing and antibiotic usage for management of acute exacerbations of asthma by ED type, suggesting potential resource overuse in general EDs. Future studies should focus on evaluating the effect of quality improvement efforts for ED asthma management. PMID- 26766223 TI - African Pygmies. AB - Paul Verdu introduces the anthropology and genetics of African populations often summarised under the label 'Pygmy'. PMID- 26766224 TI - Antimicrobial peptides. AB - Antimicrobial peptides and proteins (AMPs) are a diverse class of naturally occurring molecules that are produced as a first line of defense by all multicellular organisms. These proteins can have broad activity to directly kill bacteria, yeasts, fungi, viruses and even cancer cells. Insects and plants primarily deploy AMPs as an antibiotic to protect against potential pathogenic microbes, but microbes also produce AMPs to defend their environmental niche. In higher eukaryotic organisms, AMPs can also be referred to as 'host defense peptides', emphasizing their additional immunomodulatory activities. These activities are diverse, specific to the type of AMP, and include a variety of cytokine and growth factor-like effects that are relevant to normal immune homeostasis. In some instances, the inappropriate expression of AMPs can also induce autoimmune diseases, thus further highlighting the importance of understanding these molecules and their complex activities. This Primer will provide an update of our current understanding of AMPs. PMID- 26766225 TI - Task-specific transfer of perceptual learning across sensory modalities. AB - It is now widely accepted that primary cortical areas of the brain that were once thought to be sensory-specific undergo significant functional reorganisation following sensory deprivation. For instance, loss of vision or audition leads to the brain areas normally associated with these senses being recruited by the remaining sensory modalities [1]. Despite this, little is known about the rules governing crossmodal plasticity in people who experience typical sensory development, or the potential behavioural consequences. Here, we used a novel perceptual learning paradigm to assess whether the benefits associated with training on a task in one sense transfer to another sense. Participants were randomly assigned to a spatial or temporal task that could be performed visually or aurally, which they practiced for five days; before and after training, we measured discrimination thresholds on all four conditions and calculated the extent of transfer between them. Our results show a clear transfer of learning between sensory modalities; however, generalisation was limited to particular conditions. Specifically, learned improvements on the spatial task transferred from the visual domain to the auditory domain, but not vice versa. Conversely, benefits derived from training on the temporal task transferred from the auditory domain to visual domain, but not vice versa. These results suggest a unidirectional transfer of perceptual learning from dominant to non-dominant sensory modalities and place important constraints on models of multisensory processing and plasticity. PMID- 26766226 TI - Molecular Evolution: The Perplexing Diversity of Mitochondrial RNA Editing Systems. AB - New analysis of rapidly evolving mitochondrial genomes in calcaronean sponges has demonstrated that accurate gene expression requires systematic nucleotide insertion throughout RNA transcripts, altering previous views that RNA editing systems are difficult to maintain in genomes with high mutation rates. PMID- 26766227 TI - Sensory Plasticity: When Eye Movements Change Visual Appearance. AB - When we look straight at an object, it appears the same as when it is seen from the corner of our eye; however, this stability of visual appearance can collapse if inconspicuous object changes are introduced during eye movements. PMID- 26766228 TI - Land Plant Evolution: Listen to Your Elders. AB - The genetic and molecular basis of the developmental programs underlying adaptive morphological changes is largely unknown. A new study reveals an ancient gene that has been instrumental for the generation of morphological diversity and adaptation in land plants. PMID- 26766229 TI - Evolution: One Penis After All. AB - Amniote penises come in many shapes but are missing from the basal tuatara. This has been taken as evidence for multiple evolutionary origins of the penis. Now, genital swellings have been found in tuatara embryos, arguing for a single origin. PMID- 26766230 TI - Ecology: Electrical Cable Bacteria Save Marine Life. AB - Animals at the bottom of the sea survive oxygen depletion surprisingly often, and a new study identifies cable bacteria in the sediment as the saviors. The bacterial electrical activity creates an iron 'carpet', trapping toxic hydrogen sulfide. PMID- 26766232 TI - Sensory Development: Childhood Changes in Visual Cortical Function. AB - A new study reveals that the integration of multiple visual depth cues in visual cortex develops surprisingly late in human childhood. PMID- 26766233 TI - Plant Signaling: Ubiquitin Pulls the Trigger on Chloroplast Degradation. AB - Diverse proteolytic pathways regulate chloroplasts. Recent work has revealed significant new roles for chloroplast ubiquitination in stress adaptation, involving targeted protein removal through the ubiquitin-proteasome system, or selective, whole-chloroplast degradation. PMID- 26766231 TI - Neuroscience: A Distributed Neural Network Controls REM Sleep. AB - How does the brain control dreams? New science shows that a small node of cells in the medulla - the most primitive part of the brain - may function to control REM sleep, the brain state that underlies dreaming. PMID- 26766235 TI - The evolution of dance. AB - Evidence from multiple sources reveals a surprising link between imitation and dance. As in the classical correspondence problem central to imitation research, dance requires mapping across sensory modalities and the integration of visual and auditory inputs with motor outputs. Recent research in comparative psychology supports this association, in that entrainment to a musical beat is almost exclusively observed in animals capable of vocal or motor imitation. Dance has representational properties that rely on the dancers' ability to imitate particular people, animals or events, as well as the audience's ability to recognize these correspondences. Imitation also plays a central role in learning to dance and the acquisition of the long sequences of choreographed movements are dependent on social learning. These and other lines of evidence suggest that dancing may only be possible for humans because its performance exploits existing neural circuitry employed in imitation. PMID- 26766234 TI - Genes and Odors Underlying the Recent Evolution of Mosquito Preference for Humans. AB - Mosquito species that specialize in biting humans are few but dangerous. They include the African malaria vectors Anopheles gambiae and Anopheles coluzzii, as well as Aedes aegypti, the cosmopolitan vector of dengue, chikungunya, and yellow fever. These mosquitoes have evolved a remarkable innate preference for human odor that helps them find and bite us. Here I review what is known about this important evolutionary adaptation, from its historical documentation to its chemical and molecular basis. PMID- 26766236 TI - Hybrid Vesicles with Alterable Fully Covered Armors of Nanoparticles: Fabrication, Catalysis, and Surface-Enhanced Raman Scattering. AB - This work reports on the facile preparation of hybrid polymer vesicles with alterable armors of metal nanoparticles by using a novel hyperbranched polymer vesicle as the templates. The vesicles were prepared through the aqueous self assembly of a hyperbranched multiarm copolymers with many tertiary amino groups on the surface, which can electrostatically complexed or coordinated with metal ions like AuCl4(-), PtCl6(2-), and Ag(+) ions. Subsequently, the vesicles coated with metal ions can be in situ reduced into metal nanoparticles, through which a series of surface-engineered vesicles (Au@vesicles, Ag@vesicles, Pt@vesicles) with an advantage of fully covered metal nanoparticles on the surface could be readily prepared. The morphologies, structures, and formation mechanism of the as prepared hybrid vesicles were carefully characterized, and the obtained hybrid vesicles also showed great potentials in catalysis and surface-enhanced Raman scattering (SERS) applications. PMID- 26766237 TI - Atomically Thin Mesoporous Nanomesh of Graphitic C3N4 for High-Efficiency Photocatalytic Hydrogen Evolution. AB - Delamination of layer materials into two-dimensional single-atom sheets has induced exceptional physical properties, including large surface area, ultrahigh intrinsic carrier mobility, pronounced changes in the energy band structure, and other properties. Here, atomically thin mesoporous nanomesh of graphitic carbon nitride (g-C3N4) is fabricated by solvothermal exfoliation of mesoporous g-C3N4 bulk made from thermal polymerization of freeze-drying assembled Dicyandiamide nanostructure precursor. With the unique structural advantages for aligned energy levels, electron transfer, light harvesting, and the richly available reaction sites, the as-prepared monolayer of mesoporous g-C3N4 nanomesh exhibits a superior photocatalytic hydrogen evolution rate of 8510 MUmol h(-1) g(-1) under lambda > 420 nm and an apparent quantum efficiency of 5.1% at 420 nm, the highest of all the metal-free g-C3N4 nanosheets photocatalysts. PMID- 26766238 TI - An early Oligocene fossil demonstrates treeshrews are slowly evolving "living fossils". AB - Treeshrews are widely considered a "living model" of an ancestral primate, and have long been called "living fossils". Actual fossils of treeshrews, however, are extremely rare. We report a new fossil species of Ptilocercus treeshrew recovered from the early Oligocene (~34 Ma) of China that represents the oldest definitive fossil record of the crown group of treeshrews and nearly doubles the temporal length of their fossil record. The fossil species is strikingly similar to the living Ptilocercus lowii, a species generally recognized as the most plesiomorphic extant treeshrew. It demonstrates that Ptilocercus treeshrews have undergone little evolutionary change in their morphology since the early Oligocene. Morphological comparisons and phylogenetic analysis support the long standing idea that Ptilocercus treeshrews are morphologically conservative and have probably retained many characters present in the common stock that gave rise to archontans, which include primates, flying lemurs, plesiadapiforms and treeshrews. This discovery provides an exceptional example of slow morphological evolution in a mammalian group over a period of 34 million years. The persistent and stable tropical environment in Southeast Asia through the Cenozoic likely played a critical role in the survival of such a morphologically conservative lineage. PMID- 26766239 TI - Unified Total Synthesis of 3-epi-Ryanodol, Cinnzeylanol, Cinncassiols A and B, and Structural Revision of Natural Ryanodol and Cinnacasol. AB - Ryanodane diterpenoids structurally share an extremely complex fused ring system, but differ in the substitution patterns of the hydroxy groups. Since these congeners exhibit various biologically important functions, their efficient chemical constructions have been greatly anticipated. We previously accomplished the total synthesis of ryanodine (1) using pentacycle 8 as the advanced intermediate. Here, we report the unified total syntheses of four distinct diterpenoids, 3-epi-ryanodol (3), cinnzeylanol (4), cinncassiols B (5), and A (6), from 8, all within 10 steps. A series of highly optimized chemo- and stereoselective reactions and protecting-group manipulations enabled assembly of the densely oxygenated structures of 3-6. Furthermore, the present synthetic studies established the C13S stereochemisty of 5-7 and revised the proposed structures of natural ryanodol (2) and cinnacasol (7) to be those of 3 and 6, respectively. PMID- 26766286 TI - Cord blood transplant for acute myeloid leukaemia. AB - Umbilical cord blood is a haematopoietic progenitor cell source for patients with acute myeloid leukaemia (AML), other haematological malignancies and metabolic diseases who can be cured by allogeneic haematopoietic cell transplantation, but who do not have a human leucocyte antigen compatible related or unrelated donor. Although the first cord blood transplants were done in children, there are currently more cord blood transplants performed in adults. In this review, we explore the history of umbilical cord blood transplantation, paediatric and adult outcome results, and novel trends to improve engraftment and reduce infection. Umbilical cord blood transplantation cures approximately 30-40% of adults and 60 70% of children with AML. Controversial issues, including the use of double versus single cord blood units for transplantation, optimal cord blood unit selection, infection prophylaxis, conditioning regimens and graft versus host disease prophylaxis, will be reviewed. Finally, comparison to other graft sources, cost, access to care, and the ideal graft source are discussed. PMID- 26766287 TI - Accuracy of Coverage Survey Recall following an Integrated Mass Drug Administration for Lymphatic Filariasis, Schistosomiasis, and Soil-Transmitted Helminthiasis. AB - BACKGROUND: Achieving target coverage levels for mass drug administration (MDA) is essential to elimination and control efforts for several neglected tropical diseases (NTD). To ensure program goals are met, coverage reported by drug distributors may be validated through household coverage surveys that rely on respondent recall. This is the first study to assess accuracy in such surveys. METHODOLOGY/PRINCIPAL FINDINGS: Recall accuracy was tested in a series of coverage surveys conducted at 1, 6, and 12 months after an integrated MDA in Togo during which three drugs (albendazole, ivermectin, and praziquantel) were distributed. Drug distribution was observed during the MDA to ensure accurate recording of persons treated during the MDA. Information was obtained for 506, 1131, and 947 persons surveyed at 1, 6, and 12 months, respectively. Coverage (defined as the percentage of persons taking at least one of the MDA medications) within these groups was respectively 88.3%, 87.4%, and 80.0%, according to the treatment registers; it was 87.9%, 91.4% and 89.4%, according to survey responses. Concordance between respondents and registers on swallowing at least one pill was >95% at 1 month and >86% at 12 months; the lower concordance at 12 months was more likely due to difficulty matching survey respondents with the year-old treatment register rather than inaccurate responses. Respondents generally distinguished between pills similar in appearance; concordance for recall of which pills were taken was over 80% in each survey. SIGNIFICANCE: In this population, coverage surveys provided remarkably consistent coverage estimates for up to one year following an integrated MDA. It is not clear if similar consistency will be seen in other settings, however, these data suggest that in some settings coverage surveys might be conducted as much as one year following an MDA without compromising results. This might enable integration of post-MDA coverage measurement into large, multipurpose, periodic surveys, thereby conserving resources. PMID- 26766288 TI - Photodynamic detection of canine mammary gland tumours after oral administration of 5-aminolevulinic acid. AB - 5-Aminolevulinic acid (5-ALA) is widely used in photodynamic detection (PDD) and therapy. We evaluated the pharmacokinetics of 5-ALA-induced porphyrins and its effectiveness in PDD in dogs with mammary gland tumours (MGTs) following oral administration. Healthy dogs and those with MGTs (nine each) were orally administered 4 mg kg-1 5-ALA. Protoporphyrin IX (PpIX) was not detected in the plasma of healthy dogs but it peaked in dogs with MGT at 2 h after 5-ALA administration. In the PDD study, 16 dogs with MGT were orally administered 40 mg kg-1 5-ALA, and MGT but not normal tissue showed red fluorescence after 2-4 h. Photon counts were 6635-63 890 and 59-4011 (median, 19 943 and 919) for MGT and non-tumour tissues, respectively. Cell density strongly correlated with PpIX photon counts of MGT tissue of the dogs (R = 0.743, P = 0.0009). We suggest that 5-ALA-PDD might be an effective diagnostic tool for MGTs. PMID- 26766289 TI - Quantification and compensation of the influence of pulse transients on symmetry based recoupling sequences. AB - Deviations of amplitude and phase of radio-frequency pulses from the desired values, can have a severe impact on the performance of multiple-pulse sequences in NMR spectroscopy. A particular problem are pulse transients that appear every time there is a discontinuity in amplitude or phase. Based on a Floquet description using pulses with arbitrarily shaped amplitudes and phases we present a systematic study of the influence of pulse transients on symmetry-based pulse sequences in solid-state NMR under magic-angle spinning. This treatment explains the dependence of the experimentally observed transfer efficiency on the details of experimental setups. In addition, three approaches are compared which have the aim to re-establish highly efficient recoupling. We demonstrate that the application of transient-compensated pulses as basic elements of symmetry-based sequences leads to a significantly improved robustness of the experiments with respect to variations in the experimental setup. PMID- 26766290 TI - The potential for a protective vaccine for rhinovirus infections. PMID- 26766291 TI - Influence of Morbid Obesity on the Clinical Pharmacokinetics of Various Anti Infective Drugs: Reappraisal Using Recent Case Studies-Issues, Dosing Implications, and Considerations. AB - Owing to availability of scanty pharmacokinetic data, dosing decisions in morbid obesity is increasingly challenging in the field of anti-infective drugs. However, in recent years data are emerging that describe the pharmacokinetics of anti-infective drugs in morbidly obese subjects. The objectives of the present work were: (1) to collate the recent reports pertaining to the pharmacokinetics in morbidly obese subjects for several anti-infective drugs and provide an overview of the pharmacokinetic data along with the applicable pharmacodynamics and/or clinical outcome; (2) to perform regression analysis on limited dataset for a few drugs to verify the existence of relationships between Cmax/Ctrough versus steady-state volume of distribution (Vss)/clearance to enable data prediction in morbid obesity subjects; (3) to provide a general discussion on issues and dosing implications. The key findings of this review were: (a) drugs such as vancomycin, ethambutol, and fluconazole, where the VSS is substantially greater in morbidly obese patients, need a dosing strategy with the appropriate body mass descriptors; (b) other drugs such as moxifloxacin, linezolid, doripenem, meropenem, voriconazole, oseltamivir, tigecycline, levofloxacin may not ordinarily need dosing adjustments; PMID- 26766292 TI - Therapeutic Role of Resveratrol and Quercetin on Aortic Fibroblasts of Psammomys obesus After Oxidative Stress by Hydrogen Peroxide. AB - In our study, we propose to analyze the effects of resveratrol (RES) and quercetin (QRC) on proliferation markers, oxidative stress, apoptosis, and inflammation of aortic fibroblasts of Psammomys obesus after induced oxidative stress by hydrogen peroxide (H2O2). Fibroblasts were incubated in RES 375 MUM and QRC 0.083 MUM for 24 hours after exposure to H2O2 1.2 mM for 6 hours. We performed the proliferation rate, cells viability, morphological analyses, cytochrome c, Akt, ERK1/2, and p38 MAPK quantification. The redox status was achieved by proportioning of malondialdehyde, nitric monoxide, advanced oxidation protein products, carbonyl proteins, catalase, and superoxide dismutase activity. The inflammation was measured by TNFalpha, MCP1, and NF-kB assay. The extracellular matrix (ECM) remodeling was performed by SDS-PAGE. Stressed fibroblasts showed a decrease of cell proliferation and viability, hypertrophy and oncosis, chromatin hypercondensation and increase of cytochrome c release characteristic of apoptosis, activation of ERK1/2 and Akt pathway, and decreases in p38 MAPK pathways marking the cellular resistance. The redox state was disrupted by increased malondialdehyde, nitric monoxide, advanced oxidation protein products, carbonyl protein production, catalase and superoxide dismutase activity, and a decreased production of proteins including collagens. Inflammation state was marked by MCP-1, TNFalpha, and NF-kB increase. Treatment of fibroblasts stressed by RES and QRC inverted the oxidative stress situation decreasing apoptosis and inflammation, and improving the altered redox status and rearrangement of disorders observed in extracellular matrix. H2O2 induced biochemical and morphological alterations leading to apoptosis. An improved general condition is observed after treatment with RES and QRC; this explains the antioxidant and antiapoptotic effects of polyphenols. PMID- 26766293 TI - Statistical Primer on Biosimilar Clinical Development. AB - A biosimilar is highly similar to a licensed biological product and has no clinically meaningful differences between the biological product and the reference (originator) product in terms of safety, purity, and potency and is approved under specific regulatory approval processes. Because both the originator and the potential biosimilar are large and structurally complex proteins, biosimilars are not generic equivalents of the originator. Thus, the regulatory approach for a small-molecule generic is not appropriate for a potential biosimilar. As a result, different study designs and statistical approaches are used in the assessment of a potential biosimilar. This review covers concepts and terminology used in statistical analyses in the clinical development of biosimilars so that clinicians can understand how similarity is evaluated. This should allow the clinician to understand the statistical considerations in biosimilar clinical trials and make informed prescribing decisions when an approved biosimilar is available. PMID- 26766295 TI - Life stress versus traumatic stress: The impact of life events on psychological functioning in children with and without serious illness. AB - OBJECTIVE: To determine the differential impact of potentially traumatic events (PTEs) and other stressful life events on psychological functioning in 2 groups of children: those with cancer and those without history of serious illness. METHOD: Children with cancer age 8-17 (n = 254) and age-, sex-, and race/ethnicity-matched controls (n = 142) completed self-report measures of stressful life events and psychological functioning. Stressful life events included those that may meet Diagnostic and Statistical Manual of Mental Disorders (4th ed.; DSM-IV; American Psychiatric Association, 2000) A1 criteria (PTEs; 9 events) and others that would likely not (other events; 21 events). RESULTS: Children with cancer endorsed significantly more PTEs than control children. There were no differences between groups in number of other events experienced. Hierarchical regression analyses revealed that number of other events accounted for significant variance in psychological functioning, above and beyond group status, demographic factors (age and socioeconomic status), and number of PTEs. DISCUSSION: The number of cumulative other events experienced is a significant predictor of psychological functioning in both youth with serious illness and controls. In contrast, cumulative PTEs appear to have a minor (albeit significant) impact on children's psychological functioning. Assessment of psychological functioning would benefit from a thorough history of stressful life events, regardless of their potential traumatic impact. PMID- 26766296 TI - Excess glycogen does not resolve high ultimate pH of oxidative muscle. AB - Skeletal muscle glycogen content can impact the extent of postmortem pH decline. Compared to glycolytic muscles, oxidative muscles contain lower glycogen levels antemortem which may contribute to the higher ultimate pH. In an effort to explore further the participation of glycogen in postmortem metabolism, we postulated that increasing the availability of glycogen would drive additional pH decline in oxidative muscles to equivalent pH values similar to the ultimate pH of glycolytic muscles. Glycolysis and pH declines were compared in porcine longissimus lumborum (glycolytic) and masseter (oxidative) muscles using an in vitro system in the presence of excess glycogen. The ultimate pH of the system containing longissimus lumborum reached a value similar to that observed in intact muscle. The pH decline of the system containing masseter samples stopped prematurely resulting in a higher ultimate pH which was similar to that of intact masseter muscle. To investigate further, we titrated powdered longissimus lumborum and masseter samples in the reaction buffer. As the percentage of glycolytic sample increased, the ultimate pH decreased. These data show that oxidative muscle produces meat with a high ultimate pH regardless of glycogen content and suggest that inherent muscle factors associated with glycolytic muscle control the extent of pH decline in pig muscles. PMID- 26766294 TI - Overview of CDK9 as a target in cancer research. AB - CDK9 is a protein in constant development in cancer therapy. Herein we present an overview of the enzyme as a target for cancer therapy. We provide data on its characteristics and mechanism of action. In recent years, CDK9 inhibitors that have been designed with molecular modeling have demonstrated good antitumoral activity in vitro. Clinical studies of the drugs flavopiridol, dinaciclib, seliciclib, SNS-032 and RGB-286638 used as CDK9 inhibitors are also reviewed, with their additional targets and their relative IC50 values. Unfortunately, treatment with these drugs remains unsuccessful and involves many adverse effects. We could conclude that there are many small molecules that bind to CDK9, but their lack of selectivity against other CDKs do not allow them to get to the clinical use. However, drug designers currently have the tools needed to improve the selectivity of CDK9 inhibitors and to make successful treatment available to patients. PMID- 26766297 TI - Development and Characterization of Edible Films Based on Fruit and Vegetable Residues. AB - Edible films were developed from the solid residue of the processing of whole fruits and vegetables. The solid residue, processed into flour (FVR flour) was chemically and structurally characterized by microstructure, elemental composition, structural links, and moisture sorption isotherm. Films were prepared by casting using aqueous extracts of 8% and 10% of flour (w/w) and characterized in terms of thickness, water solubility, mechanical properties, water vapor permeability, and Fourier transform infrared (FTIR). The analysis of microstructure and elemental composition, performed on flour (mean particle size 350 MUm), showed an essentially granular aspect, with the presence of fibrous particles having potassium as one of the most abundant elements. FTIR results showed similarity between the characteristic bands of other raw materials used in edible films. The sorption isotherm of FVR flour showed a typical profile of foods rich in soluble components, such as sugars. Dried films presented an average thickness of 0.263 +/- 0.003 mm, a homogenous aspect, bright yellow color, pronounced fruit flavor, and high water solubility. The FTIR spectra of the edible films revealed that addition of potato skin flour did not change the molecular conformation. Moreover, the films presented low tensile strength at break when compared with fruit starch-based films. PMID- 26766298 TI - Foreword. PMID- 26766299 TI - Editorial. PMID- 26766300 TI - Remote Magnetomechanical Nanoactuation. AB - A novel approach to nanoactuation that relies on magnetomechanics instead of the conventional electromechanics utilized in micro and nanoactuated mechanical systems is devised and demonstrated. Namely, nanoactuated magnetomechanical devices that can change shape on command using a remote magnetic external stimulus, with a control at the subnanometer scale are designed and fabricated. In contrast to micro and nanoactuated electromechanical systems, nanoactuated magnetomechanical remote activation does not require physical contacts. Remote activation and control have a tremendous potential in bringing vast technological capabilities to more diverse environments, such as liquids or even inside living organisms, opening a clear path to applications in biotechnology and the emerging field of nanorobotics. PMID- 26766301 TI - Red Wine Tannin Structure-Activity Relationships during Fermentation and Maceration. AB - The correlation between tannin structure and corresponding activity was investigated by measuring the thermodynamics of interaction between tannins isolated from commercial red wine fermentations and a polystyrene divinylbenzene HPLC column. Must and/or wine samples were collected throughout fermentation/maceration from five Napa Valley wineries. By varying winery, fruit source, maceration time, and cap management practice, it was considered that a reasonably large variation in commercially relevant tannin structure would result. Tannins were isolated from samples collected using low pressure chromatography and were then characterized by gel permeation chromatography and acid-catalyzed cleavage in the presence of excess phloroglucinol (phloroglucinolysis). Corresponding tannin activity was determined using HPLC by measuring the thermodynamics of interaction between isolated tannin and a polystyrene divinylbenzene HPLC column. This measurement approach was designed to determine the ability of tannins to hydrophobically interact with a hydrophobic surface. The results of this study indicate that tannin activity is primarily driven by molecular size. Compositionally, tannin activity was positively associated with seed tannins and negatively associated with skin and pigmented tannins. Although measured indirectly, the extent of tannin oxidation as determined by phloroglucinolysis conversion yield suggests that tannin oxidation at this stage of production reduces tannin activity. Based upon maceration time, this study indicates that observed increases in perceived astringency quality, if related to tannin chemistry, are driven by tannin molecular mass as opposed to pigmented tannin formation or oxidation. Overall, the results of this study give new insight into tannin structure-activity relationships which dominate during extraction. PMID- 26766302 TI - Synthesis and spectroscopic behaviour of metal complexes of meso-alkylidenyl carbaporphyrinoids and their expanded analogues. AB - Treatment of meso-malonylidene-(m-benzi)porphyrin and meso-malonylidene-(m benzi)pentaphyrin with Pd(ii), Au(iii), Ni(ii) and Ag(i) afforded the corresponding metal complexes. The synthesized metal complexes were characterized by spectroscopy including single crystal X-ray, NMR and mass spectrometry. Most metal complexes were stable in solution. The metal complexes showed strong absorption in the near IR region. PMID- 26766303 TI - Polysaccharide-based micro/nanocarriers for oral colon-targeted drug delivery. AB - Oral colon-targeted drug delivery has attracted many researchers because of its distinct advantages of increasing the bioavailability of the drug at the target site and reducing the side effects. Polysaccharides that are precisely activated by the physiological environment of the colon hold greater promise for colon targeting. Considerable research efforts have been directed towards developing polysaccharide-based micro/nanocarriers. Types of polysaccharides for colon targeting and in vitro/in vivo assessments of polysaccharide-based carriers for oral colon-targeted drug delivery are summarised. Polysaccharide-based microspheres have gained increased importance not just for the delivery of the drugs for the treatment of local diseases associated with the colon (colon cancer, inflammatory bowel disease (IBD), amoebiasis and irritable bowel syndrome (IBS)), but also for it's potential for the delivery of anti-rheumatoid arthritis and anti-chronic stable angina drugs. Besides, Polysaccharide-based micro/nanocarriers such as microbeads, microcapsules, microparticles, nanoparticles, nanogels and nanospheres are also introduced in this review. PMID- 26766304 TI - Rituximab in the Treatment of Refractory Noninfectious Scleritis. AB - PURPOSE: To describe the outcomes of the use of rituximab in the treatment of refractory noninfectious scleritis. DESIGN: Retrospective case series. METHODS: Review of the medical charts of patients with noninfectious scleritis refractory to conventional immunomodulatory therapy who were seen at the Massachusetts Eye Research and Surgery Institution between 2005 and 2015. The primary outcome measure in this study was steroid-free remission. Secondary outcomes were favorable response (decrease in scleritis activity score) and decrease in steroid dependence. RESULTS: There were 15 patients, with a mean follow-up duration of 34 months. Fourteen patients (93.3%) showed a clinical improvement, with 13 (86.6%) achieving a scleritis activity score of zero at 6 months. To date, 2 patients continue to enjoy durable drug-free remission (28 and 32 months follow-up). There was only 1 adverse effect recorded (infusion hypotension) requiring cessation of rituximab. CONCLUSION: Rituximab can be an effective treatment modality for recalcitrant noninfectious scleritis and, in some, can result in long-term durable drug-free remission. PMID- 26766305 TI - Influence of Demographic Variables on Metalinguistic Skills. AB - BACKGROUND/AIMS: The existing literature reports no clear patterns for the influence of extralinguistic variables on MSs because they vary across languages. Therefore, the current study addresses this issue by analyzing the development of MSs at the beginning of formal schooling and by determining the extent to which demographic variables affect metalinguistic development in normally developing European-Portuguese (EP) children. METHODS: The sample included 80 EP first graders aged 6;00-6;11 years who presented a normal linguistic development. The Language Test - Preschool Language Assessment (TL-ALPE) was used to assess MSs in the domains of semantic, structural, and phonological awareness. RESULTS: At the beginning of formal schooling, only one phonological awareness task involving syllables was considered to be acquired and established among all metalinguistic tasks elicited. Significant group differences were not found for the demographic variables of gender, socioeconomic status, and ecological setting. CONCLUSION: These findings contribute to the increasing literature on MSs. The reference information provided is important for accurately identifying school-aged children with language impairment. PMID- 26766306 TI - Accuracy of Inferior Vena Cava Ultrasound for Predicting Dehydration in Children with Acute Diarrhea in Resource-Limited Settings. AB - INTRODUCTION: Although dehydration from diarrhea is a leading cause of morbidity and mortality in children under five, existing methods of assessing dehydration status in children have limited accuracy. OBJECTIVE: To assess the accuracy of point-of-care ultrasound measurement of the aorta-to-IVC ratio as a predictor of dehydration in children. METHODS: A prospective cohort study of children under five years with acute diarrhea was conducted in the rehydration unit of the International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b). Ultrasound measurements of aorta-to-IVC ratio and dehydrated weight were obtained on patient arrival. Percent weight change was monitored during rehydration to classify children as having "some dehydration" with weight change 3-9% or "severe dehydration" with weight change > 9%. Logistic regression analysis and Receiver Operator Characteristic (ROC) curves were used to evaluate the accuracy of aorta to-IVC ratio as a predictor of dehydration severity. RESULTS: 850 children were enrolled, of which 771 were included in the final analysis. Aorta to IVC ratio was a significant predictor of the percent dehydration in children with acute diarrhea, with each 1-point increase in the aorta to IVC ratio predicting a 1.1% increase in the percent dehydration of the child. However, the area under the ROC curve (0.60), sensitivity (67%), and specificity (49%), for predicting severe dehydration were all poor. CONCLUSIONS: Point-of-care ultrasound of the aorta-to IVC ratio was statistically associated with volume status, but was not accurate enough to be used as an independent screening tool for dehydration in children under five years presenting with acute diarrhea in a resource-limited setting. PMID- 26766307 TI - Pre-birth cohort study of atopic dermatitis and severe bronchiolitis during infancy. AB - BACKGROUND: Infants hospitalized for bronchiolitis (i.e. severe bronchiolitis) are at increased risk of childhood asthma. There are many known risk factors for severe bronchiolitis, including cardiac and pulmonary diseases. Less is known about the association between atopic diseases and risk of severe bronchiolitis. We sought to further examine risk factors for severe bronchiolitis, focusing on atopic dermatitis (AD). METHODS: We conducted a nested cohort study within the Massachusetts General Hospital Obstetric Maternal Study (MOMS), a prospective cohort of pregnant women enrolled during 1998-2006. Children of mothers enrolled in MOMS were included in the analysis if they received care within our health system (n = 5407). Potential risk factors for bronchiolitis and hospitalization data were extracted from the children's electronic health records; we also examined pregnancy and perinatal risk factors collected from the underlying MOMS data. RESULTS: During the first year of life, 125 infants (2.3%) had severe bronchiolitis. Eighteen of these patients had AD; 11 (61%) were diagnosed with AD prior to bronchiolitis hospitalization. In unadjusted analyses, AD was associated with severe bronchiolitis (chi(2) 14.6; p < 0.001). In multivariable analyses adjusting for nine known risk factors for severe bronchiolitis, including demographics, birth season, disposition at birth, cardiac disease, maternal parity, and delivery mode, AD was associated with increased odds of severe bronchiolitis (odds ratio 2.72, 95% confidence interval 1.60-4.63). CONCLUSIONS: Atopic dermatitis is significantly associated with severe bronchiolitis in infancy. The mechanism of the AD-bronchiolitis association is unclear and merits further study; this research may shed light on the pathogenesis of asthma. PMID- 26766308 TI - A comprehensive review of the published assays for the quantitation of the immunosuppressant drug mycophenolic acid and its glucuronidated metabolites in biological fluids. AB - Therapeutic use of mycophenolic acid (MPA) is steadily on the rise in combination with other immunosuppressant drugs in transplantation patients. The biotransformation of MPA resulted in the formation of glucuronide metabolites, MPAG and AcMPAG. There are a plethora of assays validated for the analysis of MPA alone or with MPAG/AcMPAG in various biological specimens including plasma/serum, urine, ultrafiltrate, saliva, PBMC, dried blood spots, tissue extract, tumor biopsies and vitreous humor. Based on the need for experimental work, a proper choice of the assay and internal standard may be made using the choices in the literature. While the chemical methods involving high-performance liquid chromatography (HPLC) or LC coupled with triple quadrupole mass spectrometry (LC MS/MS) are popular, enzymatic assays, in spite of their higher bias, have been used for the routine drug monitoring of MPA. The objectives of the present review are: (a) to provide a focused systematic compilation of the HPLC or LC-MS/MS methods for MPA, MPAG and/or AcMPAG published in the last decade (2005 to current) to enable visual comparison of the methods; (b) to compare and contrast a few enzymatic assays with those of the chemical methods; and (c) to discuss relevant issues/limitations and perspectives on select assays under various subheadings. PMID- 26766310 TI - Initial Experience With Robotic Pancreatic Surgery: Technical Feasibility and Oncological Implications. AB - Robotic surgery has been introduced in the field of minimally invasive surgery to improve the handling of high-demanding procedures with encouraging results. We aimed to evaluate the clinical safety and the oncological adequacy of robot assisted pancreatic surgery by analyzing a consecutive series in terms of surgical and oncological outcomes. A total of 53 consecutive cases including 36 pancreatoduodenectomies (PD) and 14 distal pancreatectomies (DP) were evaluated. The overall postoperative morbidity and mortality were 32% and 3.8%, respectively. Radical resection was achieved in 93.7% of PD and 100% of DP, with a mean number of harvested lymph nodes of 29.8 for PD and 20.5 for DP. The 3-year cumulative overall survival was 44.2% and 73.9% for patient with pancreatic ductal adenocarcinoma and nonductal malignancy, respectively. Robotic technology may be useful to reproduce conventional open pancreatic surgery with a minimally invasive approach, overcoming some of the intrinsic limitations of conventional laparoscopy. PMID- 26766309 TI - Human pluripotent stem cell culture density modulates YAP signaling. AB - Human pluripotent stem cell (hPSC) density is an important factor in self-renewal and differentiation fates; however, the mechanisms through which hPSCs sense cell density and process this information in making cell fate decisions remain to be fully understood. One particular pathway that may prove important in density dependent signaling in hPSCs is the Hippo pathway, which is regulated by cell cell contact and mechanosensing through the cytoskeleton and has been linked to the maintenance of stem cell pluripotency. To probe regulation of Hippo pathway activity in hPSCs, we assessed whether Hippo pathway transcriptional activator YAP was differentially modulated by cell density. At higher cell densities, YAP phosphorylation and localization to the cytoplasm increased, which led to decreased YAP-mediated transcriptional activity. Furthermore, total YAP protein levels diminished at high cell density due to the phosphorylation-targeted degradation of YAP. Inducible shRNA knockdown of YAP reduced expression of YAP target genes and pluripotency genes. Finally, the density-dependent increase of neuroepithelial cell differentiation was mitigated by shRNA knockdown of YAP. Our results suggest a pivotal role of YAP in cell density-mediated fate decisions in hPSCs. PMID- 26766311 TI - Comparison of Modified Retroperitoneal Adrenalectomy With the Gold Standard for Benign Adrenal Tumors. AB - OBJECTIVES: To compare our modified retroperitoneoscopic adrenalectomy with the standard procedure. METHODS: A total of 68 patients underwent modified retroperitoneoscopic adrenalectomy. Simultaneously, another 23 patients were treated using the standard procedure. The demographic data and perioperative outcomes of the patients were obtained for statistical analysis. RESULTS: No significant differences in age, evaluated blood loss, oral intake, and hospital stay were observed. The mean operation time in the modified group was shorter than that in the standard group (58.3+/-16.4 vs. 79.5+/-23.6 min, P<0.05). The median total length of incision was shorter in the modified group than in the standard group (4.5+/-0.8 vs. 6.4+/-1.1 cm, P<0.05). The modified group also showed significantly better pain control (3 vs. 6 diclofenac sodium use, P<0.05) and cosmetic outcome (score, 9.1+/-1.8 vs. 8.2+/-2.1, P<0.05) than the standard group. CONCLUSIONS: Our modified retroperitoneoscopic adrenalectomy is a safe and alternative procedure for adrenal tumors. This procedure offers superior cosmetic outcome, better pain control, and shorter operation time compared with the standard retroperitoneal adrenalectomy. PMID- 26766312 TI - Ergonomics in Laparoscopic Surgery--A Survey of Symptoms and Contributing Factors. AB - PURPOSE: We aimed to investigate physical/cognitive symptoms experienced by clinicians undertaking laparoscopic surgery (LS) in relation to demographics, operating factors, and instruments. METHODS: Fifty trainees/consultants practicing LS in Southeast England completed a 17-question survey. Results were analyzed using nonparametric tests of metric, ordinal, and binomial data. RESULTS: Forty-five percent of respondents reported moderate/severe symptoms during long cases (>2 h). Worse neck/shoulder (N=45, P=0.01), back (N=44, P=0.002), and fatigue/irritability (N=42, P=0.02) symptoms were reported for long (vs. short) cases. Assistants reported worse back symptoms than principle operators (N=43, P=0.02, long cases). Females (vs. males), glove size <=6.5 (vs. >=7.0), and experience <=5years (vs. 5 to 10, >10 y) reported worse symptoms relating to handle dimensions (N=45, P=0.004, 0.001, 0.01, respectively). Ninety six percent believe ergonomics should be incorporated into LS courses. CONCLUSIONS: Principle and assistant surgeons experience adverse symptoms during LS; ergonomics training and handles dimensions, accommodating female surgeons, and smaller glove sizes may reduce this. PMID- 26766313 TI - Endoscopic Management of Bariatric Surgery Complications. AB - Obesity is a global epidemic that has significant impact on morbidity, mortality, and rising health care costs. In morbidly obese patients with body mass index >40 kg/m2, bariatric surgery is a grade A recommendation and is associated with up to 40% reduction in premature death. Increasingly, endoscopy is seen as a safer and more cost-effective approach to the management of weight loss surgery complications including gastrointestinal bleeding, development of anastomotic ulcers, staple-line leaks and fistulas, strictures, weight regain, bezoars, choledocholithiasis, and gastric band erosion and slippage. Many endoscopic interventions currently rely on a combination of specialized equipment, such as stents, suture systems, clips, and balloon dilators to successfully treat these issues. This article will present common postoperative complications in bariatric surgery, discuss the latest evidence for their endoscopic management, and offer future directions in the endoluminal therapy of obese patients. PMID- 26766314 TI - Usefulness of Laparoscopy in Gangrenous Cholecystitis. AB - BACKGROUND: Gangrenous cholecystitis (GC) is a rare and severe condition requiring immediate cholecystectomy. The aim of this study was to compare outcomes of laparoscopic cholecystectomy with open cholecystectomy in patients with GC. MATERIALS AND METHODS: The records of 278 patients with GC who underwent cholecystectomy, for acute cholecystitis were compared with those of 531 patients with nongangrenous cholecystitis. In patients with GC, the outcomes of laparoscopic cholecystectomy were also compared with the outcomes of open cholecystectomy. RESULTS: Multivariate analysis demonstrated an independent association of diabetes mellitus, temperature, muscle rigidity on examination, white cell blood count, gallbladder wall thickening, gallbladder wall interruption, detection of pericholecystic exudate on ultrasonography, with the development of acute GC. The rate of conversions in the GC group was higher than in nongangrenous cholecystitis group. In patients with GC morbidity did not differ between patients operated using laparoscopic technique or open technique. Total and postoperative hospital stays were shorter in patients operated using laparoscopic technique. CONCLUSIONS: Laparoscopic cholecystectomy is a safe procedure in patients with GC. Although the conversion rate to open surgery was elevated, the number of other complications was comparable to open surgery. Laparoscopic cholecystectomy significantly reduced total hospital stays and medical costs. PMID- 26766315 TI - Two Decades of Laparoscopic Adrenalectomy: 326 Procedures in a Single-Center Experience. AB - AIM: Aim of this study is to evaluate the results of 20-year single-center laparoscopic adrenalectomy (LA), with different transperitoneal techniques. MATERIALS AND METHODS: Three hundred twenty-six adrenalectomies were performed from 1993 to 2013 using a transperitoneal approach through anterior access, flank access, and anterior submesocolic access (adopted by the author for left LA since 2004). RESULTS: Overall 142 men and 184 women (mean age 59.3 y) underwent 196 right, 113 left, and 17 bilateral adrenalectomies. There was 1 fatal outcome (0.30%) due to sepsis. Conversion to open surgery was required in 7 patients (2.14%) for intraoperative bleeding (n=5), paroxysmal hypertension during pheochromocytoma removal (n=1), and tearing of the colon during bilateral adrenalectomy in a patient with Cushing hyperplasia (n=1).There were 15 postoperative complications (4.60%) managed conservatively. CONCLUSIONS: Transperitoneal LA is a safe, minimally invasive procedure ensuring early recovery. The submesocolic access is faster and minimizes surgical dissection. PMID- 26766316 TI - Limited Evidence for Robot-assisted Surgery: A Systematic Review and Meta Analysis of Randomized Controlled Trials. AB - PURPOSE: To evaluate available evidence on robot-assisted surgery compared with open and laparoscopic surgery. METHOD: The databases Medline, Embase, and Cochrane Library were systematically searched for randomized controlled trials comparing robot-assisted surgery with open and laparoscopic surgery regardless of surgical procedure. Meta-analyses were performed on each outcome with appropriate data material available. Cochrane Collaboration's tool for assessing risk of bias was used to evaluate risk of bias on a study level. The GRADE approach was used to evaluate the quality of evidence of the meta-analyses. RESULTS: This review included 20 studies comprising 981 patients. The meta-analyses found no significant differences between robot-assisted and laparoscopic surgery regarding blood loss, complication rates, and hospital stay. A significantly longer operative time was found for robot-assisted surgery. Open versus robot-assisted surgery was investigated in 3 studies. A lower blood loss and a longer operative time were found after robot-assisted surgery. No other difference was detected. CONCLUSIONS: At this point there is not enough evidence to support the significantly higher costs with the implementation of robot-assisted surgery. PMID- 26766317 TI - Comments on "Transabdominal Preperitoneal (TAPP) Versus Totally Extraperitoneal (TEP) for Laparoscopic Hernia Repair: A Meta-Analysis". PMID- 26766318 TI - Laparoscopy for Occult Left-sided Diaphragm Injury Following Penetrating Thoracoabdominal Trauma is Both Diagnostic and Therapeutic. AB - INTRODUCTION: The diagnosis of occult traumatic diaphragm injury (TDI) has posed a dilemma to trauma surgeons. No imaging modality can accurately and conclusively identify small defects in the integrity of the diaphragm following penetrating trauma. Diagnostic laparoscopy (DL) offers a minimally invasive method of evaluating the integrity of the diaphragm. METHODS: An Electronic Surgical Registry (ESR) and a Hybrid Electronic Medical Record (HEMR) system have been maintained within the Pietermaritzburg Metropolitan Trauma Service since January 1, 2012. The study was conducted between 2 hospitals located in Pietermaritzburg, KwaZulu Natal, South Africa, namely, Greys (tertiary) and Edendale (regional). Patient data were entered into the registries at the end of patient care (discharge, interhospital transfer, or death). The registries were interrogated to retrieve all cases of DL performed for left-sided penetrating thoracoabdominal trauma. RESULTS: A total of 96 patients underwent semielective DL following penetrating left-sided thoracoabdominal trauma. This included 94 stab wounds and 2 gunshot wounds. The mean patient age was 29 years (range, 15 to 68 y, SD=8.8). The majority (59/96) of patients were male. Twenty-two (23% incidence) cases of TDI were identified at DL. Eighteen (82%) were repaired laparoscopically, and the remaining 4 required conversion to laparotomy and open repair. CONCLUSIONS: TDI presents in a spectrum from the obvious to the occult. Our results validate the utilization of DL as a minimally invasive intervention for both the diagnosis and repair of TDI in selected patients presenting with penetrating left-sided thoracoabdominal trauma. PMID- 26766319 TI - Primary Closure Versus Biliary Drainage After Laparoscopic Choledocotomy: Results of a Comparative Study. AB - INTRODUCTION: To evaluate the feasibility, safety, and short-term outcomes of primary closure (PC) and biliary drainage (BD), after the laparoscopic treatment of common bile duct (CBD) stones by choledocotomy. PATIENTS AND METHODS: Between January 2009 and December 2014, 102 patients underwent laparoscopy for lithiasis of the CBD. Intraoperative cholangiography was systematically performed, followed by choledocoscopy, depending on the size of the CBD. RESULTS: Eighty (78.4%) of the 102 patients underwent laparoscopic stone extraction by choledocotomy, and were assigned to 2 groups: PC (group A, n=25), and BD (group B, n=55). Groups A and B were comparable in terms of age (62.3+/-26.1 vs. 66.0+/-19.3 y; P=0.53), the percentage of women (72.0% vs. 76.4%; P=0.68), body mass index (25.9+/-6.1 vs. 26.9+/-4.4 kg/m; P=0.52), and CBD diameter (11.6+/-3.1 vs. 12.1+/-3.8 mm; P=0.59). The mean durations of surgery and of hospital stay were significantly shorter in group A: 179+/-38 versus 211+/-57 minutes (P=0.02) and 5.4+/-2.0 versus 8.4+/-3.2 days (P<0.001). Groups A and B were comparable in terms of serious postoperative morbidity (Clavien-Dindo scores of 3, 4, and 5): 2 versus 4 (P=1). In group B, bile drain removal was complicated by choleperitoneum in 3 cases. CONCLUSIONS: With shorter durations of surgery and hospital stay, equivalent postoperative morbi-mortality, and an absence of the specific morbidity due to bile drainage, PC may be considered a safe and feasible option for the laparoscopic management of CBD stones by choledocotomy. PMID- 26766320 TI - Can a Fully Covered Self-Expandable Metallic Stent be Used Temporarily for the Management of Duodenal Retroperitoneal Perforation During ERCP as a Part of Conservative Therapy? AB - PURPOSE: There are no reports comparing the results of conservative/nonsurgical management with the addition of fully covered self-expandable metallic stents (FCSEMS) with the conservative approach in endoscopic retrograde cholangiopancreatography (ERCP)-related duodenal retroperitoneal (type II) perforations. The aim of this study was to evaluate whether the addition of FCSEMS to conventional treatment provides further benefits in the course of type II perforations. METHODS: A total of 7471 ERCP with sphincterotomy performed between 2007 and 2014 were evaluated, and a total of 25 type II perforations (0.33%) were identified. About 20 patients who were detected during ERCP and biliary cannulation was accomplished were included in the study. Patients were divided into 2 groups: the conservative treatment group (10 patients) and the FCSEMS group (10 patients). Groups were compared for clinical findings, results of serial white blood cell (WBC) counts, the length of hospital stay, the need for surgery, and death, retrospectively. RESULTS: Five patients in the conservative treatment group and none of the patients in the FCSEMS group had pain requiring narcotic and/or nonsteroidal anti-inflammatory analgesics during the follow-up period (P=0.005). On post-ERCP day 1, in the conservative and the FCSEMS groups, mean WBC counts were 13,218+/-4410*10 and 8714+/-3270*10, respectively (P=0.029). The perforation-related length of hospital stay was 15.77+/-5.21 days in the conservative group and 11.7+/-3.19 days in the FCSEMS group (P=0.053). Excluding the patient with severe pancreatitis in the conservative group, there were no deaths or need for surgery. CONCLUSIONS: Compared with conservative treatment alone, the addition of FCSEMS provides further benefits in terms of a painless course, lower WBC counts, and a short hospital stay. FCSEMS can be used as an additional treatment modality in type II perforation. PMID- 26766321 TI - Hemobilia After Laparoscopic Cholecystectomy: Imaging Features and Management of an Unusual Complication. AB - PURPOSE: To assess the imaging features and the management of hemobilia after laparoscopic cholecystectomy (LC). MATERIALS AND METHODS: A total of 12 patients who were treated for hemobilia after LC were included in the study. Selective arteriography was performed to find the bleeding artery. Coils or microcoils were deployed superselectively to occlude the bleeding branch. The clinical course, imaging findings, the embolic effect, complications, and follow-up were evaluated. RESULTS: Risk factors for hemobilia included a variant ductal anatomy, a variant cystic artery, and intraoperative adhesion. Abdominal computed tomography (CT) could provide the diagnostic signs as follows: a hematocele in the abdominal cavity, the gallbladder fossa, and the bile duct, biliary dilation, pseudoaneurysm of the right hepatic artery, and contrast extravasations on contrast-enhanced CT. No rebleeding occurred after the transcatheter arterial embolization in all patients without immediate procedural complications. CONCLUSIONS: Gallbladder triangle anatomic variation and intraoperative adhesion were the risk factors for hemobilia after LC. Abdominal CT is a useful examination for the diagnosis. Transcatheter arterial embolization is the therapeutic option of choice. PMID- 26766322 TI - Hepatic Vein Injuries During Laparoscopic Hepatectomy. AB - BACKGROUND: Laparoscopic hepatectomy (LH) has now been widely performed in experienced centers. However, hepatic vein injury (HVI) during LH is especially dangerous, because it may cause conversion, air embolization, fatal hemorrhaging, or even death. MATERIALS AND METHODS: Perioperative characteristics of 4 patients who underwent LH suffering HVI were recorded, including 2 for right HVIs, 1 for middle HVI, and 1 for left HVI. Ultrasonic shears was used for liver mobilization. Linear stapler was adopted to cut off hepatic vein. A 4-0 prolene was used to repair HVI. RESULTS: In case 1 laparoscopic right hemihepatectomy was performed for hepatic hemangioma. The root of right hepatic vein was injured. Repairing time was about 10 minutes and hemorrhaging was about 150 mL. In case 2 laparoscopic segmentectomy for S7 and S8 was performed for hepatic hemangioma. The right hepatic vein was injured. Repairing time was about 8 minutes and hemorrhaging was about 220 mL. In case 3 laparoscopic trisegmentectomy for S2 S4+S5, S8 was performed for hepatic echinococcosis. The middle hepatic vein was injured. Repairing time was about 8 minutes and hemorrhaging was about 110 mL. In case 4 laparoscopic left lateral segmentectomy was performed for hepatocellular carcinoma. The left hepatic vein was injured. Repairing time was about 7 minutes and hemorrhaging was about 80 mL. All the HVIs were successfully repaired by a 4 0 #20 prolene. No complications were observed. CONCLUSIONS: Skillful stitching, experienced surgeons, and smooth cooperation can effectively handle HVI. However, conversion to laparotomy should be performed timely if uncontrolled hemorrhaging occurs, to ensure patients' safety. PMID- 26766323 TI - Intraoperative Assessment of Esophagogastric Junction Distensibility During Laparoscopic Heller Myotomy. AB - We sought to characterize the changes in esophagogastric junction (EGJ) distensibility during Heller Myotomy with Dor fundoplication using the EndoFLIP device. Intraoperative distensibility measurements on 14 patients undergoing Heller myotomy with Dor fundoplication were conducted over an 18-month period. Minimum esophageal diameter, cross-sectional areas, and distensibility index were measured at 30 and 40 mL catheter volumes before myotomy, postmyotomy, and following Dor fundoplication. Distensibility index is defined as the narrowest cross-sectional area divided by the corresponding pressure expressed in mm/mm Hg. Heller myotomy was found to lead to significant changes in the distensibility characteristics of the EGJ. Minimum esophageal diameter and EGJ distensibility increased significantly with Heller myotomy. PMID- 26766325 TI - Correction: Copper-mediated cyanation of indoles and electron-rich arenes using DMF as a single surrogate. AB - Correction for 'Copper-mediated cyanation of indoles and electron-rich arenes using DMF as a single surrogate' by Lianpeng Zhang et al., Org. Biomol. Chem., 2015, 13, 8322-8329. PMID- 26766326 TI - Dynamic recrystallization behavior of a biomedical Ti-13Nb-13Zr alloy. AB - The dynamic recrystallization (DRX) behavior of a biomedical titanium Ti-13Nb 13Zr alloy has been investigated using the high temperature compression tests under wide range of strain rates (0.001-1/s) and temperatures 900-1050 degrees C. A constitutive equation represented as a function of temperature, strain rate and true strain is developed and the hot deformation apparent activation energy is calculated about 534kJ/mol. By considering the exponential relationship between work-hardening rate (theta) and stress, a new mathematical model was proposed for predicting flow stress up to the critical strain during hot deformation. The mathematical model for predicting flow stress up to the critical strain exhibits better consistency and accuracy. The DRX kinetic equation of Ti-13Nb-13Zr alloy is described as XDRX=1-exp[-0.32(E-EcE(*))(2.3)] . The DRX kinetic model was validated by microstructure observation. It was also found that the process of DRX was promoted by decreasing strain rate and increasing deformation temperature. Eventually, the continuous dynamic recrystallization (CDRX) was identified to be the DRX mechanism using transmission electron microscope (TEM). PMID- 26766327 TI - Mechanical and in vitro evaluation of an experimental canine patent ductus arteriosus occlusion device. AB - Patent ductus arteriosus (PDA) is a congenital cardiovascular malformation in which a fetal connection between the aorta and pulmonary artery remains patent after birth. This defect commonly results in clinical complications, even death, necessitating closure. Surgical ligation is the most common treatment but requires a thoracotomy and is therefore invasive. A minimally invasive option is preferable. A prototype device for PDA occlusion which utilizes shape memory polymer foams has been developed and evaluated using mechanical and in vitro experiments. Removal force and radial pressure measurements show that the prototype device exhibited a lower removal force and radial pressure than a commercially available device. The in vitro experiments conducted within simplified and physiological PDA models showed that the prototype does not migrate out of position into the pulmonary artery at either physiological or elevated pressures in multiple model configurations. While the radial pressure and removal force were lower than commercial devices, the device performed acceptably in the in vitro benchtop experiments warranting further prototype development. PMID- 26766328 TI - Experimental and computational assessment of F-actin influence in regulating cellular stiffness and relaxation behaviour of fibroblasts. AB - In biomechanics, a complete understanding of the structures and mechanisms that regulate cellular stiffness at a molecular level remain elusive. In this paper, we have elucidated the role of filamentous actin (F-actin) in regulating elastic and viscous properties of the cytoplasm and the nucleus. Specifically, we performed colloidal-probe atomic force microscopy (AFM) on BjhTERT fibroblast cells incubated with Latrunculin B (LatB), which results in depolymerisation of F actin, or DMSO control. We found that the treatment with LatB not only reduced cellular stiffness, but also greatly increased the relaxation rate for the cytoplasm in the peripheral region and in the vicinity of the nucleus. We thus conclude that F-actin is a major determinant in not only providing elastic stiffness to the cell, but also in regulating its viscous behaviour. To further investigate the interdependence of different cytoskeletal networks and cell shape, we provided a computational model in a finite element framework. The computational model is based on a split strain energy function of separate cellular constituents, here assumed to be cytoskeletal components, for which a composite strain energy function was defined. We found a significant influence of cell geometry on the predicted mechanical response. Importantly, the relaxation behaviour of the cell can be characterised by a material model with two time constants that have previously been found to predict mechanical behaviour of actin and intermediate filament networks. By merely tuning two effective stiffness parameters, the model predicts experimental results in cells with a partly depolymerised actin cytoskeleton as well as in untreated control. This indicates that actin and intermediate filament networks are instrumental in providing elastic stiffness in response to applied forces, as well as governing the relaxation behaviour over shorter and longer time-scales, respectively. PMID- 26766329 TI - Assessment of mechanical properties of porcine aortas under physiological loading conditions using vascular elastography. AB - Non-invasive assessment of the elastic properties of the arterial wall is often performed with ultrasound (US) imaging. The purpose of this study is to estimate mechanical properties of the vascular wall using in vitro inflation testing on biological tissue and two-dimensional (2-D) US elastography, and investigate the performance of the proposed methodology for physiological conditions. An inflation experiment was performed on 12 porcine aortas for (a) a large pressure range (0-140mmHg); and (b) physiological pressures (70-130mmHg) to mimic in vivo hemodynamic conditions. Two-dimensional radiofrequency (RF) data were acquired for one longitudinal and two transverse cross-sections for both experiments, and were analyzed to obtain the geometry and diameter-time behavior. The shear modulus (G) was estimated from these data for each pressure range applied. In addition, an incremental study based on the static data was performed to (1) investigate the changes in G for increasing mean arterial pressure (MAP) for a certain pressure difference (30, 40, 50 and 60mmHg); (2) compare the results with those from the dynamic experiment, for the same pressure range. The resulting stress-strain curves and shear moduli G (94+/-16kPa) for the static experimentare in agreement with literature and previous work. A linear dependency on MAP was found for G, yet the effect of the pulse pressure difference was negligible. The dynamic data revealed a G of 250+/-20kPa, whereas the incremental shear modulus (Ginc) was 240+/-39kPa. For all experiments, no significant differences in the values of G were found between different image planes. This study shows that 2-D US elastography of aortas during inflation testing is feasible and reproducible under controlled and physiological circumstances. In future studies, the in vivo, dynamic experiment should be repeated for a range of MAPs, and pathological vessels should be examined. PMID- 26766330 TI - Biomedical research in the USA: at the dawn of a golden age? PMID- 26766331 TI - Rights of refugees--collaboration is key. PMID- 26766332 TI - Care of the dying adult: a time for hope. PMID- 26766335 TI - What does Pfizer's merger mean for drug development? PMID- 26766333 TI - Italy, the Land of Holy Miracles--revisited. PMID- 26766336 TI - Nepal's silent epidemic of suicide. PMID- 26766337 TI - Magdi Yacoub: a lifelong affair with the heart. PMID- 26766338 TI - Coca-Cola's multifaceted threat to global public health. PMID- 26766339 TI - Everyone counts--so count everyone in England and Wales. PMID- 26766340 TI - Uncounted causes of death. PMID- 26766341 TI - HIV treatment: time to lean forward. PMID- 26766342 TI - Iran, sanctions, and research collaborations. PMID- 26766343 TI - Safe water, sanitation, hygiene, and a cholera vaccine. PMID- 26766344 TI - Iran's health-care system in transition. PMID- 26766345 TI - Suicide in Iran. PMID- 26766346 TI - Vitamin A deficiency--an unexpected cause of visual loss. PMID- 26766347 TI - Vitamin A deficiency in adolescents: rare or underdiagnosed? PMID- 26766348 TI - Narrow QRS Tachycardia With RR Alternans and 2:1 VA Relation. PMID- 26766349 TI - Theoretical studies on binding modes of copper-based nucleases with DNA. AB - In the present work, molecular simulations were performed for the purpose of predicting the binding modes of four types of copper nucleases (a total 33 compounds) with DNA. Our docking results accurately predicted the groove binding and electrostatic interaction for some copper nucleases with B-DNA. The intercalation modes were also reproduced by "gap DNA". The obtained results demonstrated that the ligand size, length, functional groups and chelate ring size bound to the copper center could influence the binding affinities of copper nucleases. The binding affinities obtained from the docking calculations herein also replicated results found using MM-PBSA approach. The predicted DNA binding modes of copper nucleases with DNA will ultimately help us to better understand the interaction of copper compounds with DNA. PMID- 26766350 TI - Potential for leaching of heavy metals in open-burning bottom ash and soil from a non-engineered solid waste landfill. AB - Bottom ash from open-burning of municipal waste practised in developing countries poses a risk of heavy metal leaching into groundwater. Compared to incineration ash, there is limited information on heavy metal leaching from open-burning ash and soil from non-engineered landfills. Batch and column experiments were conducted to address three specific objectives; (1) to determine aqua regia extractable concentrations of heavy metals in fresh ash, old ash and soil from beneath the landfill, (2) to determine the relationship between heavy metal leaching, initial and final pH of leaching solution, and aqua regia extractable concentrations, and (3) to determine the breakthrough curves of heavy metals in ashes and soil. Aqua regia extractable concentrations of Cd, Zn, Mn, Cu, Ni and Pb were significantly higher (p < 0.05) in fresh and old ashes than soil beneath landfill and uncontaminated soil (control). Increasing initial solution pH from 5 and 7 to 9 significantly reduced the mobility of Pb, Zn and Cu but not Cd whose mobility peaked at pH 7 and 9. Concentrations of desorbed heavy metals were not correlated with aqua regia extractable concentrations. Final pH of leachate rebounded to close to original pH of the material, suggesting a putative high buffering capacity for all materials. Both batch and column leaching showed that concentrations of leached heavy metals were disproportionately lower (<5%) than aqua regia extractable concentrations in most cases. The retardation of heavy metals was further evidenced by sigmoidal breakthrough curves. Heavy metal retention was attributed to precipitation, pH-dependent adsorption and formation of insoluble organo-metallic complexes at near-neutral to alkaline pH. Overall, the risk of heavy metal leaching from ash and soil from the waste dump into groundwater was low. The high pH and the presence of Zn, Fe, Mn and Cu make ash an ideal low-cost liming material and source of micronutrients particularly on acidic soils prevalent in sub-Saharan Africa. PMID- 26766351 TI - A sequential extraction procedure to evaluate the mobilization behavior of rare earth elements in soils and tailings materials. AB - A novel sequential extraction method for evaluation of the mobilization behavior of rare earth elements in soils and mine tailings materials is presented. The sequence consists of the following four steps: 0.05 mol L(-1) calcium nitrate (easily soluble and ion exchange fraction), 0.1 mol L(-1) citric acid (fraction mobilized by complexation and carbonate bound), 0.05 mol L(-1) hydroxylamine hydrochloride (pH = 2) (reducible fraction), 1.4 mol L(-1) nitric acid (acid soluble fraction). The procedure was optimized with a certified soil material and a mine tailings material and was applied to eight samples of a soil profile. The different results obtained by using either the developed method or the widespread used BCR-Method for comparison are discussed. There were clear advantages using the newly created sequential extraction procedure in getting more detailed information about the bioavailable fraction and a fraction addressing REE phosphates. PMID- 26766352 TI - Decomposition and heavy metal variations of the typical halophyte litters in coastal marshes of the Yellow River estuary, China. AB - The concentrations of C, Pb, Cr, Cu, Zn, Ni and Mn were determined in decomposing litters of Phragmites australis, Suaeda salsa and Suaeda glauca in three plots of the Yellow River estuary to investigate the variations of metal stocks. Results showed that the decomposition rates significantly differed among species (p < 0.05), in the order of S. glauca (0.002010 d(-1)) > S. salsa (0.000814 d(-1)) > P. australis (0.000766 d(-1)). The concentrations of Cu and Zn in the three litters (particularly S. glauca) generally showed increasing tendency, while those of Pb, Cr, Ni and Mn exhibited different temporal variations. Compared to P. australis and S. salsa, the key mechanisms affecting the variation of metals in S. glauca might be more complex. In most periods, Pb stocks in P. australis, S. salsa and S. glauca, Zn stocks in S. salsa and S. glauca, and Cr, Ni and Mn stocks in P. australis and S. glauca were lower than the initial ones, implying that release exceeded incorporation. Comparatively, Zn stocks in P. australis, Cr, Ni and Mn stocks in S. salsa and in particular Cu stocks in the three litters were generally positive, evidencing incorporation of these metals in most sampling times. The three halophytes were particular efficient in binding Cu and releasing Pb, indicating that the potential eco-toxic risk of Pb exposure might be serious. This study emphasized the strong influences of key biotic (litter types, carbon/metal ratios and activities of microbial organisms) and abiotic variables (salinity, sediment resuspension induced by tidal inundation and passive sorption onto recalcitrant organic fractions) on metal cycling in coastal marshes of the Yellow River estuary. PMID- 26766353 TI - Using mercury isotopes to understand the bioaccumulation of Hg in the subtropical Pearl River Estuary, South China. AB - Coastal and estuarine regions are important areas of mercury pollution. Therefore, it is important to properly characterize the sources and bioaccumulation processes of mercury in these regions. Here, we present mercury stable isotopic compositions in 18 species of wild marine fish collected from the Pearl River Estuary (PRE), south China. Our results showed variations in mass independent fractionation (Delta(199)Hg: +0.05 +/- 0.100/00 to +0.59 +/- 0.300/00) with a Delta(199)Hg/Delta(201)Hg of ~1.26, suggesting that aqueous MeHg underwent photo-degradation prior to incorporation into the food chain. For the results, we discovered small but significant differences of Delta(199)Hg values among herbivorous, demersal, and carnivorous fish, indicating that different feeding guilds of fish may have incorporated MeHg with various degrees of photo demethylation. The consistent mercury isotope compositions between fish feeding habitat and mercury sources in the estuary provide potentially important findings on the transformation and bioaccumulation of this toxic metal in subtropical coastal environments. PMID- 26766354 TI - Acute effects of air pollution on influenza-like illness in Nanjing, China: A population-based study. AB - Influenza-like illness causes substantial morbidity and mortality. Air pollution has already been linked to many health issues, and increasing evidence in recent years supports an association between air pollution and respiratory infections. It is a pioneer study in China to quantify the effects of air pollution on influenza-like illness. This study used wavelet coherence analysis and generalized additive models to explore the potential association between air pollution (including particulate matter with aerodynamic diameter ?2.5 MUm (PM2.5), particulate matter with aerodynamic diameter ?10 MUm (PM10) and nitrogen dioxide (NO2)) and influenza-like illness (a total of 59860 cases) in Nanjing, China from January 1, 2013 to December 31, 2013. The average concentrations of PM2.5, PM10 and NO2 were 77.37 MUg/m(3), 135.20 MUg/m(3) and 55.80 MUg/m(3). An interquartile range increase in PM2.5 concentration was associated with a 2.99% (95% confidence interval (CI): 1.64%, 4.36%) increase in daily influenza-like cases on the same day, while the corresponding increase in NO2 was associated with a 3.77% (95% CI: 2.01%, 5.56%) increase in daily cases. People aged 0-4 were proved to be significantly susceptible to PM10 and NO2; 5-14 ages were significantly susceptible to PM2.5 and PM10; and 15-24 ages were significantly susceptible to all the analyzed air pollutants. Air pollution effects tended to be null or negative for patients aged over 25, which might be due to the small number of influenza-like cases in this age group. This study can be useful for understanding the adverse health effects of air pollution and the cause of influenza-like illness. PMID- 26766355 TI - Waterborne exposure to bisphenol F causes thyroid endocrine disruption in zebrafish larvae. AB - While bisphenol F (BPF) has been frequently detected in various environmental compartments, limited information is available on its effect on thyroid endocrine system. In the present study, zebrafish (Danio rerio) embryos were exposed to 0.2, 2, 20, and 200 MUg/L of BPF from 2 h post-fertilization (hpf) to 144 hpf. The whole-body content of thyroid hormones, thyroid-stimulating hormone (TSH), and transcription of genes belonging to the hypothalamic-pituitary-thyroid (HPT) axis were investigated. BPF exposure resulted in alterations of both T3 and T4 contents, increased the ratios of T3/T4, demonstrating thyroid endocrine disruption. Moreover, TSH content was significantly induced in a concentration dependent manner after exposure to BPF. The increased gene transcription of dio2 might assist to degrade increased T3 contents. Treatment with BPF also significantly increased transcription of genes involved in thyroid hormone regulation (crh) and synthesis (nis and tg) as a compensatory mechanism for the decrease of T4 contents. However, the gene encoding protein involved in TH transport (ttr) was transcriptionally significantly down-regulated after exposure to BPF. Taken together, these results suggest that BPF alters the transcription of genes involved in the HPT axis as well as changes whole-body contents of thyroid hormones and TSH in zebrafish embryos/larvae, thus causing an endocrine disruption of the thyroid system. PMID- 26766356 TI - Different responses of soil microbial metabolic activity to silver and iron oxide nanoparticles. AB - The knowledge regarding the effects of metal or metal oxide nanoparticles on soil microbial metabolic activity and key ecological functions is limited, relative to the information about their species diversity. For this reason, the responses of soil microbial metabolic activity to silver (AgNPs) and iron oxide (FeONPs) nanoparticles, along concentration gradients of each, were evaluated by microcalorimetry and soil nitrification potential. The changes in abundances of bacteria, eukaryotes and ammonia-oxidizing bacteria were measured by real time quantitative PCR. It was found that AgNP (at 0.1, 1 and 10 mg kg(-1) soil) amendments decreased soil microbial metabolic activity, nitrification potential and the abundances of bacteria and ammonia-oxidizing bacteria; on the contrary, FeONPs had the positive effects on soil microbial metabolic activity (at 1 and 10 mg kg(-1) soil) and soil nitrification potential (at 0.1 and 1 mg kg(-1) soil). Specific microbial metabolic activity and specific nitrification potential further revealed that metal or metal oxide nanoparticles could change the C and N cycles of the agricultural soil through influencing soil microbial metabolism. These findings could deepen the understanding of the influence of NPs on soil microorganisms and their driven soil ecology process. PMID- 26766357 TI - Effects of HRT and water temperature on nitrogen removal in autotrophic gravel filter. AB - Organic Carbon added to low ratio of carbon to nitrogen (C/N ratio) wastewater to enhance heterotrophic denitrification performance might lead to higher operating costs and secondary pollution. In this study, sodium thiosulfate (Na2S2O3) was applied as an electron donor for a gravel filter (one kind of constructed wetland) to investigate effects of hydraulic retention time (HRT) and water temperature on the nitrate removal efficiency. The results show that with an HRT of 12 h, the average total nitrogen (TN) removal efficiencies were 91% at 15-20 degrees C and 18% at 3-6 degrees C, respectively. When HRT increased to 24 h, the average TN removal increased accordingly to 41% at 3-6 degrees C, suggesting denitrification performance was improved by extended HRT at low water temperatures. Due to denitrification, 96% of added nitrate nitrogen (NO3(-)-N) was converted to nitrogen gas, with a mean flux of nitrous oxide (N2O) was 0.0268 0.1500 ug m(-2) h(-1), while 98.86% of thiosulfate was gradually converted to sulfate throughout the system. Thus, our results show that the sulfur driven autotrophic denitrification constructed wetland demonstrated an excellent removal efficiency of nitrate for wastewater treatment. The HRT and water temperature proved to be two influencing factors in this constructed wetland treatment system. PMID- 26766358 TI - The occurrence of Dechlorane Plus and related norbornene-based flame retardants in Baltic wild salmon (Salmo salar). AB - Twenty five Baltic wild salmon (Salmo salar) specimens were analysed for the content of Dechlorane-related compounds (DRCs). Out of the ten analysed DRCs, seven compounds were detected in the muscle tissues of salmon, including Dechlorane (Dec) 602, Dec 603, syn- and anti-stereoisomers of Dechlorane Plus (DP), Dechlorane Plus monoadduct (1,3-DPMA), hexachlorocyclopentadienyl dibromocyclooctane (DBHCTD), and Mirex. The concentrations of Dec 604 and two DP dechlorinated compounds - decachloropentacyclooctadecadiene (Cl10DP) and undecachloropentacyclooctadecadiene (Cl11DP) - were below the limit of detection in all samples. The aggregated concentrations of DRCs (SigmaDRC) were in the range of 551-3339 pg g(-1) fresh weight (f.w.) with 1,3-DPMA being the predominant DRC component contributing up to 70% to the SigmaDRC. The fractional abundance of syn- and anti-DP stereoisomers showed a pronounced enrichment of anti-DP and was close to the composition of OxyChem((r)) DP commercial product. The obtained concentrations of DRCs were substantially lower than those reported in previous studies of biotic samples (among them fish, mollusks, white stork and peregrine falcon eggs) from inland freshwater reservoirs in more industrialised areas throughout Europe and North America. A statistically significant relationships between the concentrations of Dec 602 and the concentrations of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs), polychlorinated biphenyls (PCBs), and polybrominated diphenyl ethers (PBDEs) was observed. PMID- 26766359 TI - Characterization and distribution of metal and nonmetal elements in the Alberta oil sands region of Canada. AB - This review covers the characterization and distribution of metals and nonmetals in the Alberta oil sands region (AOSR) of Canada. The development of the oil sands industry has resulted in the release of organic, metal and nonmetal contaminants via air and water to the AOSR. For air, studies have found that atmospheric deposition of metals in the AOSR decreased exponentially with distance from the industrial emission sources. For water, toxic metal concentrations often exceeded safe levels leading to the potential for negative impacts to the receiving aquatic environments. Interestingly, although atmospheric deposition, surface waters, fish tissues, and aquatic bird eggs exhibited increasing level of metals in the AOSR, reported results from river sediments showed no increases over time. This could be attributed to physical and/or chemical dynamics of the river system to transport metals to downstream. The monitoring of the airborne emissions of relevant nonmetals (nitrogen and sulphur species) was also considered over the AOSR. These species were found to be increasing along with the oil sands developments with the resultant depositions contributing to nitrogen and sulphur accumulations resulting in ecosystem acidification and eutrophication impacts. In addition to direct monitoring of metals/nonmetals, tracing of air emissions using isotopes was also discussed. Further investigation and characterization of metals/nonmetals emissions in the AOSR are needed to determine their impacts to the ecosystem and to assess the need for further treatment measures to limit their continued output into the receiving environments. PMID- 26766360 TI - Influences of metal ions on microcystin-LR degradation capacity and dynamics in microbial distribution of biofilm collected from water treatment plant nearby Kasumigaura Lake. AB - Microcystins-LR (MC-LR) which is a kind of potent hepatotoxin for humans and wildlife can be biodegraded by microbial community. In this study, the capacity of biofilm in degrading MC-LR was investigated with and without additional metal ions (Mn(2+), Zn(2+) and Cu(2+)) at the concentration of 1 mg L(-1). The results indicated that the degradation rate of MC-LR by biofilm was inhibited by introduced Mn(2+) and Cu(2+) during the whole culture period. MC-LR cannot be degraded until a period of culture time passed both in the cases with Zn(2+) and Cu(2+) (2 and 8 days for Zn(2+) and Cu(2+), respectively). The results of mlrA gene analysis showed that the abundance of MC-LR degradation bacteria (MCLDB) in the microbial community under Mn(2+) condition was generally lower than that under no additional metal ion condition. Meanwhile, a two days lag phase for the proliferation of MCLDB occurred after introducing Zn(2+). And a dynamic change of MCLDB from Cu(2+) inhibited species to Cu(2+) promoted species was observed under Cu(2+) condition. The maximum ratio of MCLDB to overall bacteria under various conditions during culture process was found to follow the tendency as: Cu(2+) > Zn(2+) ~ no additional metal ion (Control) > Mn(2+), suggesting the adverse effect of Mn(2+), no obvious effect of Zn(2+) and positive effect of Cu(2+) on the distribution ratio of MCLDB over the biofilm. PMID- 26766361 TI - The effects of co-contaminants and native wetland sediments on the activity and dominant transformation mechanisms of a 1,1,2,2-tetrachloroethane (TeCA) degrading enrichment culture. AB - Bioremediation strategies, including bioaugmentation with chlorinated ethene degrading enrichment cultures, have been successfully applied in the cleanup of subsurface environments contaminated with tetrachloroethene (PCE) and/or trichloroethene (TCE). However, these compounds are frequently found in the environment as components of mixtures that may also contain chlorinated ethanes and methanes. Under these conditions, the implementation of bioremediation may be complicated by inhibition effects, particularly when multiple dehalorespirers are present. We investigated the ability of the 1,1,2,2-tetrachloroethane (TeCA) dechlorinating culture WBC-2 to biotransform TeCA alone, or a mixture of TeCA plus PCE and carbon tetrachloride (CT), in microcosms. The microcosms contained electron donors provided to biostimulate the added culture and sediment collected from a wetland where numerous "hotspots" of contamination with chlorinated solvent mixtures exist. The dominant TeCA biodegradation mechanism mediated by the WBC-2 culture in the microcosms was different in the presence of these wetland sediments than in the sediment-free enrichment culture or in previous WBC 2 bioaugmented microcosms and column tests conducted with wetland sediment collected at nearby sites. The co-contaminants and their daughter products also inhibited TeCA biodegradation by WBC-2. These results highlight the need to conduct biodegradability assays at new sites, particularly when multiple contaminants and dehalorespiring populations are present. PMID- 26766362 TI - Degradation of extracellular polymeric substances (EPS) extracted from activated sludge by low-concentration ozonation. AB - Reaction mechanisms between ozone and extracellular polymeric substances (EPS) can be the key of understanding the improvements in microbial aggregates properties by low-concentration ozonation. In this study, EPS are extracted from activated sludge and treated continuously by ozone gas at 270 +/- 41 ppm. The reaction between ozone and EPS was investigated by observation of EPS component concentrations, functional groups and molecular weight distributions using UV-Vis spectrometry, excitation-emission matrix fluorescence spectroscopy (EEM), high performance size-exclusion chromatography (HPSEC) and gas chromatography-mass spectrometry (GC-MS). In a 12-hour-ozonation experiment, significant ozone consumption was observed in the first 4 h and protein concentration in EPS solution was reduced by 30 +/- 12%. However, the polysaccharides concentration only had a slightly decrease at the end of the ozonation process. UV-Vis spectra and EEM spectra results suggest that ozone removed protein and fluorescent matters (SMP and tryptophan-like aromatic protein) rapidly by attacking specific amino acid residues on polypeptide chain. After ozonation, the molecular weight of polysaccharide and protein dropped by 4 orders of magnitude according to HPSEC results. TOC concentration of EPS solution was reduced by 13 +/- 2% after ozonation. The loss in TOC could be explained by the observation of volatile organic compounds such as carboxylic acids, aldehydes and ketones in the off-gas detected by GC-MS. The results in this study can provide a better understanding towards the mechanisms of improvements in activated sludge properties by ozonation. PMID- 26766363 TI - Source regional contributions to PM2.5 in a megacity in China using an advanced source regional apportionment method. AB - To quantify contributions of individual source categories from diverse regions to PM2.5, PM2.5 samples were collected in a megacity in China and analyzed through a newly developed source regional apportionment (SRA) method. Levels, compositions and seasonal variations of speciated PM2.5 dataset were investigated. Sources were determined by Multilinear Engine 2 (ME2) model, and results showed that the PM2.5 in Tianjin was mainly influenced by secondary sulphate & secondary organic carbon SOC (percent contribution of 26.2%), coal combustion (24.6%), crustal dust & cement dust (20.3%), secondary nitrate (14.9%) and traffic emissions (14.0%). The SRA method showed that northwest region R2 was the highest regional contributor to secondary sources, with percent contributions to PM2.5 being 9.7% for secondary sulphate & SOC and 6.0% for secondary nitrates; the highest coal combustion was from local region R1 (6.2%) and northwest R2 (8.0%); the maximum contributing region to crustal & cement dust was southeast region R4 (5.0%); and contributions of traffic emissions were relatively spatial homogeneous. The seasonal variation of regional source contributions was observed: in spring, the crustal and cement dust contributed a higher percentage and the R4 was an important contributor; the secondary process attributed an increase fraction in summer; the mixed coal combustion from southwest R5 enhanced in autumn. PMID- 26766365 TI - Sorption and coprecipitation of copper to ferrihydrite and humic acid organomineral complexes and controls on copper availability. AB - Coprecipitation of Fe oxide and organic matter in redox dynamic sediments controls the net retention and form of Cu in the solid precipitates. In this study, coprecipitation and sorption of Cu with organomineral precipitation solids formed at different Fe:organic carbon (OC) ratios were compared for net Cu removal and extractability. As more humic acid was present during precipitation of Fe, TEM images indicated smaller Fe oxide particles formed within an organic matrix as expected. In coprecipitation reactions, as the ratio of Fe:OC decreased, more Cu was removed from solution at pH 5.5 and below. However, in sorption reactions, there was an inhibition of Cu removal at low OC concentrations. As the pH increased from 5.5 to 7 and as solution phase OC concentration increased, more Cu remained dissolved in both coprecipitation and sorption reactions. The addition of Ca(2+), glycine, histidine and citric acid or lowering the pH resulted in more extractable Cu from the coprecipitation compared with the sorption reactions. The variations in Cu extraction were likely due to a combination of a more amorphous structure in CPT products, and the relative abundance of available Fe oxide or OC binding sites. This has implications for the assumption of additivity in binding phases and for researchers conducting binding or exposure experiments. PMID- 26766364 TI - Evaluating the effects of allelochemical ferulic acid on Microcystis aeruginosa by pulse-amplitude-modulated (PAM) fluorometry and flow cytometry. AB - We investigated the effects of allelochemical ferulic acid (FA) on a series of physiological and biochemical processes of blue-green algae Microcystis aeruginosa, in order to find sensitive diagnostic variables for allelopathic effects. Algal cell density was significantly suppressed by FA (0.31-5.17 mM) only after 48 h exposure. Inhibitions of photosynthetic parameters (F(v)/F(m) and F(v)'/F(m)') occurred more rapidly than cell growth, and the stimulation of non photochemical quenching was observed as a feed-back mechanisms induced by photosystem II blockage, determining by PAM fluorometry. Inhibitions on esterase activity, membrane potential and integrity, as well as disturbance on cell size, were all detected by flow cytometry with specific fluorescent markers, although exhibiting varied sensitivities. Membrane potential and esterase activity were identified as the most sensitive parameters (with relatively lower EC50 values), and responded more rapidly (significantly inhibited only after 8 h exposure) than photosynthetic parameters and cell growth, thus may be the primary responses of cyanobacteria to FA exposure. The use of PAM fluorometry and flow cytometry for rapid assessment of those sensitive variables may contribute to future mechanistic studies of allolepathic effects on phytoplankton. PMID- 26766366 TI - EDTA addition enhances bacterial respiration activities and hydrocarbon degradation in bioaugmented and non-bioaugmented oil-contaminated desert soils. AB - The low number and activity of hydrocarbon-degrading bacteria and the low solubility and availability of hydrocarbons hamper bioremediation of oil contaminated soils in arid deserts, thus bioremediation treatments that circumvent these limitations are required. We tested the effect of Ethylenediaminetetraacetic acid (EDTA) addition, at different concentrations (i.e. 0.1, 1 and 10 mM), on bacterial respiration and biodegradation of Arabian light oil in bioaugmented (i.e. with the addition of exogenous alkane-degrading consortium) and non-bioaugmented oil-contaminated desert soils. Post-treatment shifts in the soils' bacterial community structure were monitored using MiSeq sequencing. Bacterial respiration, indicated by the amount of evolved CO2, was highest at 10 mM EDTA in bioaugmented and non-bioaugmented soils, reaching an amount of 2.2 +/- 0.08 and 1.6 +/- 0.02 mg-CO2 g(-1) after 14 days of incubation, respectively. GC-MS revealed that 91.5% of the C14-C30 alkanes were degraded after 42 days when 10 mM EDTA and the bacterial consortium were added together. MiSeq sequencing showed that 78-91% of retrieved sequences in the original soil belonged to Deinococci, Alphaproteobacteria, Gammaproteobacteia and Bacilli. The same bacterial classes were detected in the 10 mM EDTA-treated soils, however with slight differences in their relative abundances. In the bioaugmented soils, only Alcanivorax sp. MH3 and Parvibaculum sp. MH21 from the exogenous bacterial consortium could survive until the end of the experiment. We conclude that the addition of EDTA at appropriate concentrations could facilitate biodegradation processes by increasing hydrocarbon availability to microbes. The addition of exogenous oil-degrading bacteria along with EDTA could serve as an ideal solution for the decontamination of oil-contaminated desert soils. PMID- 26766367 TI - Degradation properties and identification of metabolites of 6-Cl-PMNI in soil and water. AB - In order to provide the scientific basis for the environmental risk assessment of cycloxaprid and 6-Cl-PMNI (intermediate of cycloxaprid), the degradation properties of 6-Cl-PMNI in aerobic, anaerobic and/or sterile soil, as well as in water with different pH values at different temperature were explored under laboratory conditions using HPLC for its kinetics study and UPLC-MS/MS for the identification of its metabolites/degradation products. Fortification study showed that the recoveries of 71.4-100.5% with the maximum coefficient variation (CV) of 7.47% were obtained. The linear range was 0.1-10 mg/L with the good linearity of R(2) = 0.9990. For standard, the method LOD (limit of detection) and LOQ (limit of quantification) was 0.03 mg/L and 0.1 mg/L, respectively. Results demonstrated the good performance of the developed method. Kinetics study indicated that the degradation half-lives (t0.5) in pH 3-pH 10 buffers varied from 111.8 d to 288.8 d at 25 degrees C but rapidly shortened to 1.6-25.7 d at 70 degrees C. Good negative linear ships (R(2) >= 0.8423) between half life and temperature were found. 6-Cl-PMNI could be readily degraded in non-sterile soil (t0.5 0.8-7.5 d) while slowly degraded in sterile soil (t0.5 64.8-91.2 d). Three hydrolytic products and one metabolite of 6-Cl-PMNI in aerobic soil were identified. The CC olefinic bond reacted with H2O by Markovnikov Additive Reaction and the split of C-Cl were mainly proposed as the possible reaction pathway for 6-Cl-PMNI degradation in water and in soil, respectively. PMID- 26766368 TI - Biotransformation of inorganic arsenic in a marine herbivorous fish Siganus fuscescens after dietborne exposure. AB - Arsenic (As) is well known to be biodiminished along marine food chains. The marine herbivorous fish at a lower trophic level are expected to accumulate more As. However, little is known about how marine herbivorous fish biotransform the potential high As bioaccumulation. Therefore, the present study quantified the biotransformation of two inorganic As species (As(III) and As(V)) in a marine herbivorous fish Siganus fuscescens following dietborne exposure. The fish were fed on As contaminated artificial diets at nominal concentrations of 400 and 1500 MUg As(III) or As(V) g(-1) (dry weight) for 21 d and 42 d. After exposure, As concentrations in intestine, liver, and muscle tissues of rabbitfish increased significantly and were proportional to the inorganic As exposure concentrations. The present study demonstrated that both inorganic As(III) and As(V) in the dietborne phases were able to be biotransformed to the less toxic arsenobetaine (AsB) (63.3-91.3% in liver; 79.0%-95.2% in muscle). The processes of As biotransformation in rabbitfish could include oxidation of As(III) to As(V), reduction of As(V) to As(III), methylation to monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA), and subsequent conversion to AsB. These results also demonstrated that AsB synthesis processes were diverse facing different inorganic As species in different tissues. In summary, the present study elucidated that marine herbivorous fish had high ability to biotransform inorganic As to the organic forms (mainly AsB), resulting in high As bioaccumulation. Therefore, marine herbivorous fish could detoxify inorganic As in the natural environment. PMID- 26766369 TI - Insights into photolytic mechanism of sulfapyridine induced by triplet-excited dissolved organic matter. AB - The ubiquity of sulfonamide antibiotics (SAs) in natural waters urges insights into their fate for ecological risk assessment in the aqueous euphotic zone. In this study, we investigated the effect of dissolved organic matter (DOM) on the photolysis of SAs with sulfapyridine as a reprentative. Results show that excited triplet state DOM ((3)DOM(*)) is largely responsible for the photodegradation of sulfapyridine. The reaction of (3)DOM(*) with a substructure model compound of SAs confirmed that sulfapyridine has one reaction site (aniline-N). Density functional theory (DFT) calculation was performed, which indicates that the anionic sulfapyridine has higher (3)DOM(*) reactivity than that of the neutral form, which was also confirmed by steady state photolytic experiments. In the reaction, electrons of the aniline-N transfer to the carbonyl oxygen atom of (3)DOM(*) moiety, followed by proton transfer, and leading to the formation of sulfapyridine radicals. The photolytic mechansim of sulfapyridine initiated by (3)DOM(*) is helpful in understanding the photochemical fate and assessing the ecological risks of SAs in the aquatic environment. PMID- 26766370 TI - The impact of humic acid on chromium phytoextraction by aquatic macrophyte Lemna minor. AB - Studies assessing chromium phytoextration from natural waters rarely consider potential implications of chromium speciation in the presence of ubiquitous humic substances. Therefore, the present study investigated the influence of environmentally relevant concentration of humic acid (TOC = 10 mg L(-1)) on chromium speciation (Cr = 0.15 mg L(-1)) and consequently on phytoextraction by aquatic macrophyte duckweed Lemna minor. In absence of humic acid, only hexavalent chromium was present in water samples and easily taken up by L. minor. Chromium uptake resulted in a significant reduction of growth rate by 22% and decrease of chlorophyll a and chlorophyll b contents by 48% and 43%, respectively. On the other hand, presence of humic acid significantly reduced chromium bioavailability (57% Cr uptake decrease) and consequently it did not cause any measurable effect to duckweed. Such effect was related to abiotic reduction of hexavalent chromium species to trivalent. Hence, findings of our study suggest that presence of humic acid and chromium speciation cannot be neglected during phytoextraction studies. PMID- 26766371 TI - Pulmonary Fissure Detection in CT Images Using a Derivative of Stick Filter. AB - Pulmonary fissures are important landmarks for recognition of lung anatomy. In CT images, automatic detection of fissures is complicated by factors like intensity variability, pathological deformation and imaging noise. To circumvent this problem, we propose a derivative of stick (DoS) filter for fissure enhancement and a post-processing pipeline for subsequent segmentation. Considering a typical thin curvilinear shape of fissure profiles inside 2D cross-sections, the DoS filter is presented by first defining nonlinear derivatives along a triple stick kernel in varying directions. Then, to accommodate pathological abnormality and orientational deviation, a [Formula: see text] cascading and multiple plane integration scheme is adopted to form a shape-tuned likelihood for 3D surface patches discrimination. During the post-processing stage, our main contribution is to isolate the fissure patches from adhering clutters by introducing a branch point removal algorithm, and a multi-threshold merging framework is employed to compensate for local intensity inhomogeneity. The performance of our method was validated in experiments with two clinical CT data sets including 55 publicly available LOLA11 scans as well as separate left and right lung images from 23 GLUCOLD scans of COPD patients. Compared with manually delineating interlobar boundary references, our method obtained a high segmentation accuracy with median F1-scores of 0.833, 0.885, and 0.856 for the LOLA11, left and right lung images respectively, whereas the corresponding indices for a conventional Wiemker filtering method were 0.687, 0.853, and 0.841. The good performance of our proposed method was also verified by visual inspection and demonstration on abnormal and pathological cases, where typical deformations were robustly detected together with normal fissures. PMID- 26766372 TI - An Intrinsically Switchable Ladder-Type Ferroelectric BST-on-Si Composite FBAR Filter. AB - This paper presents a ladder-type bulk acoustic wave (BAW) intrinsically switchable filter based on ferroelectric thin-film bulk acoustic resonators (FBARs). The switchable filter can be turned on and off by the application of an external bias voltage due to the electrostrictive effect in thin-film ferroelectrics. In this paper, Barium Strontium Titanate (BST) is used as the ferroelectric material. A systematic design approach for switchable ladder-type ferroelectric filters is provided based on required filter specifications. A switchable filter is implemented in the form of a BST-on-Si composite structure to control the effective electromechanical coupling coefficient of FBARs. As an experimental verification, a 2.5-stage intrinsically switchable BST-on-Si composite FBAR filter is designed, fabricated, and measured. Measurement results for a typical BST-on-Si composite FBAR show a resonator mechanical quality factor (Q(m)) of 971, as well as a (Q(m)) * f of 2423 GHz. The filter presented here provides a measured insertion loss of 7.8 dB, out-of-band rejection of 26 dB, and fractional bandwidth of 0.33% at 2.5827 GHz when the filter is in the on state at a dc bias of 40 V. In its off state, the filter exhibits an isolation of 31 dB. PMID- 26766373 TI - BeiDou Time Transfer With the Standard CGGTTS. AB - The R2CGGTTS software tool developed at the Royal Observatory of Belgium (ROB) to provide clock solutions in the standard Common GNSS Generic Time Transfer Standard (CGGTTS) has been extended to BeiDou Navigation Satellite System (BDS). The BDS includes satellites in three different orbits: 1) Medium Earth Orbit (MEO); 2) Inclined Geosynchronous Satellite Orbit (IGSO); and 3) Geostationary Earth Orbit (GEO). This paper presents first results obtained with this upgraded software, and a comparison between common view (CV) time transfer solutions obtained with either BDS, or GPS or Galileo. These preliminary results indicate that the BeiDou MEO satellites give time transfer results with a higher noise than the GPS results. This additional noise is shown to be due to some elevation dependent delay in the BDS code measurements. Some biases were furthermore pointed out between the CV results obtained with the different BeiDou MEO satellites when the receivers used in the two stations are of different make. These biases may reach some nanoseconds, and find most probably their origin in the receiver hardware or firmware. It is shown additionally that using the BeiDou IGSO satellites and the GEO satellites, although increasing the number of observations, especially in the Asia-Pacific region, introduces a significant time transfer noise in the CV results. PMID- 26766374 TI - LSDT: Latent Sparse Domain Transfer Learning for Visual Adaptation. AB - We propose a novel reconstruction-based transfer learning method called latent sparse domain transfer (LSDT) for domain adaptation and visual categorization of heterogeneous data. For handling cross-domain distribution mismatch, we advocate reconstructing the target domain data with the combined source and target domain data points based on l1-norm sparse coding. Furthermore, we propose a joint learning model for simultaneous optimization of the sparse coding and the optimal subspace representation. In addition, we generalize the proposed LSDT model into a kernel-based linear/nonlinear basis transformation learning framework for tackling nonlinear subspace shifts in reproduced kernel Hilbert space. The proposed methods have three advantages: 1) the latent space and the reconstruction are jointly learned for pursuit of an optimal subspace transfer; 2) with the theory of sparse subspace clustering, a few valuable source and target data points are formulated to reconstruct the target data with noise (outliers) from source domain removed during domain adaptation, such that the robustness is guaranteed; and 3) a nonlinear projection of some latent space with kernel is easily generalized for dealing with highly nonlinear domain shift (e.g., face poses). Extensive experiments on several benchmark vision data sets demonstrate that the proposed approaches outperform other state-of-the-art representation-based domain adaptation methods. PMID- 26766375 TI - A Retinal Mechanism Inspired Color Constancy Model. AB - In this paper, we propose a novel model for the computational color constancy, inspired by the amazing ability of the human vision system (HVS) to perceive the color of objects largely constant as the light source color changes. The proposed model imitates the color processing mechanisms in the specific level of the retina, the first stage of the HVS, from the adaptation emerging in the layers of cone photoreceptors and horizontal cells (HCs) to the color-opponent mechanism and disinhibition effect of the non-classical receptive field in the layer of retinal ganglion cells (RGCs). In particular, HC modulation provides a global color correction with cone-specific lateral gain control, and the following RGCs refine the processing with iterative adaptation until all the three opponent channels reach their stable states (i.e., obtain stable outputs). Instead of explicitly estimating the scene illuminant(s), such as most existing algorithms, our model directly removes the effect of scene illuminant. Evaluations on four commonly used color constancy data sets show that the proposed model produces competitive results in comparison with the state-of-the-art methods for the scenes under either single or multiple illuminants. The results indicate that single opponency, especially the disinhibitory effect emerging in the receptive field's subunit-structured surround of RGCs, plays an important role in removing scene illuminant(s) by inherently distinguishing the spatial structures of surfaces from extensive illuminant(s). PMID- 26766376 TI - Compressed Coverage Masks for Path Rendering on Mobile GPUs. AB - We present an algorithm to accelerate resolution independent curve rendering on mobile GPUs. Recent trends in graphics hardware have created a plethora of compressed texture formats specific to GPU manufacturers. However, certain implementations of platform independent path rendering require generating grayscale textures on the CPU containing the extent that each pixel is covered by the curve. In this paper, we demonstrate that generating a compressed grayscale texture prior to uploading it to the GPU creates faster rendering times in addition to the memory savings. We implement a real-time compression technique for coverage masks and compare our results against the GPU-based implementation of the highly optimized Skia rendering library. We also analyze the worst case properties of our compression algorithms. We observe up to a 2 * speed improvement over the existing GPU-based methods in addition to up to a 9:1 improvement in GPU memory gains. We demonstrate the performance on multiple mobile platforms. PMID- 26766377 TI - Objective Quality Prediction of Image Retargeting Algorithms. AB - Quality assessment of image retargeting results is useful when comparing different methods. However, performing the necessary user studies is a long, cumbersome process. In this paper, we propose a simple yet efficient objective quality assessment method based on five key factors: i) preservation of salient regions; ii) analysis of the influence of artifacts; iii) preservation of the global structure of the image; iv) compliance with well-established aesthetics rules; and v) preservation of symmetry. Experiments on the RetargetMe benchmark, as well as a comprehensive additional user study, demonstrate that our proposed objective quality assessment method outperforms other existing metrics, while correlating better with human judgements. This makes our metric a good predictor of subjective preference. PMID- 26766378 TI - Epileptic Pattern Recognition and Discovery of the Local Field Potential in Amygdala Kindling Process. AB - Epileptogenesis, which occurs in an epileptic brain, is an important focus for epilepsy. The spectral analysis has been popularly applied to study the electrophysiological activities. However, the resolution is dominated by the window function of the algorithm used and the sample size. In this report, a temporal waveform analysis method is proposed to investigate the relationship of electrophysiological discharges and motor outcomes with a kindling process. Wistar rats were subjected to electrical amygdala kindling to induce temporal lobe epilepsy. During the kindling process, different morphologies of afterdischarges (ADs) were found and a recognition method, using template matching techniques combined with morphological comparators, was developed to automatically detect the epileptic patterns. The recognition results were compared to manually labeled results, and 79%-91% sensitivity was found. In addition, the initial ADs (the first 10 s) of different seizure stages were specifically utilized for recognition, and an average of 85% sensitivity was achieved. Our study provides an alternative viewpoint away from frequency analysis and time-frequency analysis to investigate epileptogenesis in an epileptic brain. The recognition method can be utilized as a preliminary inspection tool to identify remarkable changes in a patient's electrophysiological activities for clinical use. Moreover, we demonstrate the feasibility of predicting behavioral seizure stages from the early epileptiform discharges. PMID- 26766379 TI - Movement Strategy Discovery during Training via Haptic Guidance. AB - Haptic guidance has previously been investigated to facilitate motor skill training, whereupon a robotic device assists a trainee in executing the desired movement. However, many studies have reported a null or even detrimental effect of haptic guidance on training compared to unassisted practice. While prior studies have focused on using haptic guidance to refine a movement strategy, our study explores its effect on the discovery of a new strategy. Subjects learned to manipulate a virtual under-actuated system via a haptic device either with or without haptic guidance (and without haptic feedback of system dynamics). The guidance enabled subjects to experience a range of successful movements, rather than strictly enforcing one trajectory. Subjects who trained with guidance adopted a strategy that involved faster reaches, required greater control of the system's degrees of freedom, and increased the potential for faster task completion. However, overall improvement of task performance was limited with the new strategy. PMID- 26766380 TI - Character Reading via Stylus Reproducing Normal Handwriting Motion. AB - In this paper, we report a method of intuitively transmitting symbolic information to untrained users via only their hands, without using any visual or auditory cues. In this simple concept, three-dimensional letter trajectories are presented to the user's hand via a stylus which is mechanically manipulated. In experiments, participants were able to read 14 mm-high lower-case letters displayed at a rate of one letter per second with an accuracy rate of 71.9 percent in their first trials, which improved to 91.3 percent after a 5-minute training period. These results showed small individual differences among participants (standard deviation of 12.7 percent in the first trials and 6.7 percent after training). We also found that this accuracy was still retained to a high level (85.1 percent, with SD of 8.2 percent) even when the letters were reduced to a height of 7 mm. Thus, we revealed that sighted adults potentially possess the ability to read small letters accurately at normal writing speed using their hands. PMID- 26766381 TI - Closed-Loop Modulation of the Pathological Disorders of the Basal Ganglia Network. AB - A generalized predictive closed-loop control strategy to improve the basal ganglia activity patterns in Parkinson's disease (PD) is explored in this paper. Based on system identification, an input-output model is established to reveal the relationship between external stimulation and neuronal responses. The model contributes to the implementation of the generalized predictive control (GPC) algorithm that generates the optimal stimulation waveform to modulate the activities of neuronal nuclei. By analyzing the roles of two critical control parameters within the GPC law, optimal closed-loop control that has the capability of restoring the normal relay reliability of the thalamus with the least stimulation energy expenditure can be achieved. In comparison with open loop deep brain stimulation and traditional static control schemes, the generalized predictive closed-loop control strategy can optimize the stimulation waveform without requiring any particular knowledge of the physiological properties of the system. This type of closed-loop control strategy generates an adaptive stimulation waveform with low energy expenditure with the potential to improve the treatments for PD. PMID- 26766382 TI - Image Super-Resolution via Adaptive Regularization and Sparse Representation. AB - Previous studies have shown that image patches can be well represented as a sparse linear combination of elements from an appropriately selected over complete dictionary. Recently, single-image super-resolution (SISR) via sparse representation using blurred and downsampled low-resolution images has attracted increasing interest, where the aim is to obtain the coefficients for sparse representation by solving an l0 or l1 norm optimization problem. The l0 optimization is a nonconvex and NP-hard problem, while the l1 optimization usually requires many more measurements and presents new challenges even when the image is the usual size, so we propose a new approach for SISR recovery based on regularization nonconvex optimization. The proposed approach is potentially a powerful method for recovering SISR via sparse representations, and it can yield a sparser solution than the l1 regularization method. We also consider the best choice for lp regularization with all p in (0, 1), where we propose a scheme that adaptively selects the norm value for each image patch. In addition, we provide a method for estimating the best value of the regularization parameter lambda adaptively, and we discuss an alternate iteration method for selecting p and lambda . We perform experiments, which demonstrates that the proposed regularization nonconvex optimization method can outperform the convex optimization method and generate higher quality images. PMID- 26766383 TI - A Novel Twin Support-Vector Machine With Pinball Loss. AB - Twin support-vector machine (TSVM), which generates two nonparallel hyperplanes by solving a pair of smaller-sized quadratic programming problems (QPPs) instead of a single larger-sized QPP, works faster than the standard SVM, especially for the large-scale data sets. However, the traditional TSVM adopts hinge loss which easily leads to its sensitivity of the noise and instability for resampling. To enhance the performance of the TSVM, we present a novel TSVM with the pinball loss (Pin-TSVM) which deals with the quantile distance and is less sensitive to noise points. We further investigate its properties, including the noise insensitivity, between-class distance maximization, and within-class scatter minimization. In addition, we compare our Pin-TSVM with the twin parametric margin SVM and the SVM with the pinball loss in theory. Numerical experiments on a synthetic data set and 14 benchmark data sets with different noises demonstrate the feasibility and validity of our proposed method. PMID- 26766384 TI - Privacy Protection for Telecare Medicine Information Systems Using a Chaotic Map Based Three-Factor Authenticated Key Agreement Scheme. AB - Telecare medicine information systems (TMIS) provide flexible and convenient e health care. However, the medical records transmitted in TMIS are exposed to unsecured public networks, so TMIS are more vulnerable to various types of security threats and attacks. To provide privacy protection for TMIS, a secure and efficient authenticated key agreement scheme is urgently needed to protect the sensitive medical data. Recently, Mishra et al. proposed a biometrics-based authenticated key agreement scheme for TMIS by using hash function and nonce, they claimed that their scheme could eliminate the security weaknesses of Yan et al.'s scheme and provide dynamic identity protection and user anonymity. In this paper, however, we demonstrate that Mishra et al.'s scheme suffers from replay attacks, man-in-the-middle attacks and fails to provide perfect forward secrecy. To overcome the weaknesses of Mishra et al.'s scheme, we then propose a three factor authenticated key agreement scheme to enable the patient to enjoy the remote healthcare services via TMIS with privacy protection. The chaotic map based cryptography is employed in the proposed scheme to achieve a delicate balance of security and performance. Security analysis demonstrates that the proposed scheme resists various attacks and provides several attractive security properties. Performance evaluation shows that the proposed scheme increases efficiency in comparison with other related schemes. PMID- 26766385 TI - Recent Development in Big Data Analytics for Business Operations and Risk Management. AB - "Big data" is an emerging topic and has attracted the attention of many researchers and practitioners in industrial systems engineering and cybernetics. Big data analytics would definitely lead to valuable knowledge for many organizations. Business operations and risk management can be a beneficiary as there are many data collection channels in the related industrial systems (e.g., wireless sensor networks, Internet-based systems, etc.). Big data research, however, is still in its infancy. Its focus is rather unclear and related studies are not well amalgamated. This paper aims to present the challenges and opportunities of big data analytics in this unique application domain. Technological development and advances for industrial-based business systems, reliability and security of industrial systems, and their operational risk management are examined. Important areas for future research are also discussed and revealed. PMID- 26766386 TI - Cooperative Output Regulation of Heterogeneous Linear Multi-Agent Systems by Event-Triggered Control. AB - In this paper, we consider the cooperative output regulation problem of heterogeneous linear multi-agent systems (MASs) by event-triggered control. We first develop an event-triggering mechanism for leader-following consensus of homogeneous MASs. Then by proposing an internal reference model for each agent, a novel distributed event-triggered control scheme is developed to solve the cooperative output regulation problem of heterogeneous MASs. Furthermore, a novel self-triggered control scheme is also proposed, such that continuous monitoring of measurement errors can be avoided. The feasibility of both proposed control schemes is studied by excluding Zeno behavior for each agent. An example is finally provided to demonstrate the effectiveness of the control schemes. PMID- 26766387 TI - Evolutionary Dynamic Multiobjective Optimization: Benchmarks and Algorithm Comparisons. AB - Dynamic multiobjective optimization (DMO) has received growing research interest in recent years since many real-world optimization problems appear to not only have multiple objectives that conflict with each other but also change over time. The time-varying characteristics of these DMO problems (DMOPs) pose new challenges to evolutionary algorithms. Considering the importance of a representative and diverse set of benchmark functions for DMO, in this paper, we propose a new benchmark generator that is able to tune a number of challenging characteristics, including mixed Pareto-optimal front (convexity-concavity), nonmonotonic and time-varying variable-linkages, mixed types of changes, and randomness in type change, which have rarely or not been considered or tested in the literature. A test suite of ten instances with different dynamic features is produced from the generator in this paper. Additionally, a few new performance measures are proposed to evaluate algorithms for DMOPs with different characteristics. Six representative multiobjective evolutionary algorithms from the literature are investigated based on the proposed DMO test suite and performance measures. The experimental results facilitate a better understanding of strengths and weaknesses of these compared algorithms for DMOPs. PMID- 26766388 TI - Do adolescents with attention-deficit/hyperactivity disorder show risk seeking? Disentangling probabilistic decision making by equalizing the favorability of alternatives. AB - The clinical literature provides evidence for increased risk taking by individuals with attention-deficit/hyperactivity disorder (ADHD). Most of the experimental tasks used to measure risk taking, confounded risky and disadvantageous alternatives, and therefore did not disentangle increased risk seeking from suboptimal decision making. The aim of the study was to examine whether adolescents with ADHD show risk seeking by equalizing the expected value of both certain and risky alternatives. In 3 different samples, adolescents with and without ADHD performed gambling tasks, in which they had to choose between certain and risky alternatives. Notably, the expected values of both alternatives were equal. Various personal and contextual intervening factors were controlled for. The rate of risky choices was compared across groups. In addition, participants reported on risk taking in real-life. We found that adolescents with ADHD did not choose the risky alternative more often than controls, but reported higher engagement in real-life risky behavior. These findings suggest that risky behavior shown by people with ADHD in daily life and on some experimental tasks may not be accounted for by increased risk seeking, but rather may reflect suboptimal decision making. PMID- 26766389 TI - High-performance lithium storage in an ultrafine manganese fluoride nanorod anode with enhanced electrochemical activation based on conversion reaction. AB - A facile, one-step solvothermal reaction route for the preparation of manganese fluoride nanorods is successfully developed using manganese(II) chloride tetrahydrate (MnCl2.4H2O) as the manganese source and the ionic liquid 1-butyl-3 methylimidazolium tetrafluoroborate (BmimBF4) as the fluorine source. X-ray diffraction, field-emission scanning electron microscopy and high-resolution transmission electron microscopy (HRTEM) are conducted to characterize the structural and microstructural properties of the synthesized MnF2. The pure-phase tetragonal MnF2 displays nanorod-like morphology with a diameter of about 20 nm and a length of several hundreds of nanometers. The electrochemical performance of the MnF2 nanorod anode for rechargeable lithium batteries is investigated. A reversible discharge capacity as high as 443 mA h g(-1) at 0.1 C is obtained for the lithium uptake reaction with an initial discharge plateau around 0.7 V. The striking enhancement in electrochemical Li storage performance in ultrafine MnF2 nanorods can be attributed to the small diameters of the nanorods and efficient one-dimensional electron transport pathways. Long cycle performance for 2000 cycles at 10 C with a stabilized capacity of about 430 mA h g(-1) after activation is also achieved. Furthermore, lithiated and delithiated MnF2 anodes are analyzed with HRTEM to elucidate the conversion mechanism for the electrochemical reaction of MnF2 nanorods with Li at a microscopic level. PMID- 26766390 TI - Long-term exposure to fluoxetine reduces growth and reproductive potential in the dominant rocky intertidal mussel, Mytilus californianus. AB - Environmental stressors shape community composition and ecosystem functioning. Contaminants such as pharmaceuticals are of increasing concern as an environmental stressor due to their persistence in surface waters worldwide. Limited attention has been paid to the effects of pharmaceuticals on marine life, despite widespread detection of these contaminants in the marine environment. Of the existing studies, the majority assess the negative effects of pharmaceuticals over an exposure period of 30 days or less and focus on cellular and subcellular biomarkers. Longer studies are required to determine if chronic contaminant exposure poses risks to marine life at environmentally relevant concentrations; and examination of whole organism effects are necessary to identify potential community-level consequences in estuarine and marine ecosystems. We conducted a long-term exposure study (107 days) with the anti-depressant pharmaceutical, fluoxetine (the active constituent in Prozac(r)) to determine whether minimal concentrations affected whole organism metrics in the California mussel, Mytilus californianus. We measured algal clearance rates, mussel growth, and the gonadosomatic index, a measure of reproductive health. We found that fluoxetine negatively affects all measured characteristics, however many effects were mediated by length of exposure. Our results fill an important data gap, highlighting organism-level effects of chronic exposure periods; such data more explicitly identify the overall impacts of pharmaceuticals and other contaminants on marine communities and ecosystems. PMID- 26766391 TI - The fate of organic micropollutants during long-term/long-distance river bank filtration. AB - The fate of organic micropollutants during long-term/long-distance river bank filtration (RBF) at a temporal scale of several years was investigated along a row of monitoring wells perpendicular to the Lek River (the Netherlands). Out of 247 compounds, which were irregularly analyzed in the period 1999-2013, only 15 were detected in both the river and river bank observation wells. Out of these, 10 compounds (1,4-dioxan, 1,5-naphthalene disulfonate (1,5-NDS), 2-amino-1,5-NDS, 3-amino-1,5-NDS, AOX, carbamazepine, EDTA, MTBE, toluene and triphenylphosphine oxide) showed fully persistent behavior (showing no concentration decrease at all), even after 3.6 years transit time. The remaining 5 compounds (1,3,5 naphthalene trisulfonate (1,3,5-NTS), 1,3,6-NTS, diglyme, iopamidol, triglyme) were partially removed. Their reactive transport parameters (removal rate constants/half-lives, retardation coefficients) were inferred from numerical modeling. In addition, maximum half-lives for 14 of the fully removed compounds, for which the data availability was sufficient to deduce 100% removal during sub surface passage, were approximated based on travel times to the nearest well. The study is one of very few reporting on the long-term field-scale behavior of organic micropollutants. It highlights the efficiency of RBF for water quality improvement as a pre-treatment step for drinking water production. However, it also shows the very persistent behavior of various compounds in groundwater. PMID- 26766392 TI - Selective decontamination of the digestive tract and oropharynx: after 30 years of debate is the definitive answer in sight? AB - PURPOSE OF REVIEW: Selective digestive or oropharyngeal decontamination has been being used as a means to prevent infections and death in intensive care patients for the past 30 years. It remains controversial and its use is limited. In this review, we summarize the recently published data on efficacy of selective decontamination and effects on antibiotic resistances. RECENT FINDINGS: The most recent meta-analysis shows a reduced mortality when selective digestive or oropharyngeal decontamination are compared with either standard care or oropharyngeal chlorhexidine. Selective decontamination is associated with reduced bacteraemia, and although this effect is greater with selective digestive decontamination compared with selective oropharyngeal decontamination, there is not a mortality difference between these two interventions. Reanalysis of infection data suggests, however, that selective decontamination may also have effects on concurrent control groups. Current evidence generally shows that antibiotic resistance is decreased although much of these data come from the Netherlands (an area with low endemic antibiotic resistance rates). There are currently two huge cluster randomized clinical trials, one in early recruitment, one in development, which will hopefully provide definitive answers in the years to come. SUMMARY: Current evidence suggests that selective decontamination reduces mortality without increasing antibiotic resistances; this will be tested again in two huge international trials. PMID- 26766394 TI - Permafrost thaw and intense thermokarst activity decreases abundance of stream benthic macroinvertebrates. AB - Intensification of permafrost thaw has increased the frequency and magnitude of large permafrost slope disturbances (mega slumps) in glaciated terrain of northwestern Canada. Individual thermokarst disturbances up to 40 ha in area have made large volumes of previously frozen sediments available for leaching and transport to adjacent streams, significantly increasing sediment and solute loads in these systems. To test the effects of this climate-sensitive disturbance regime on the ecology of Arctic streams, we explored the relationship between physical and chemical variables and benthic macroinvertebrate communities in disturbed and undisturbed stream reaches in the Peel Plateau, Northwest Territories, Canada. Highly disturbed and undisturbed stream reaches differed with respect to taxonomic composition and invertebrate abundance. Minimally disturbed reaches were not differentiated by these variables but rather were distributed along a disturbance gradient between highly disturbed and undisturbed sites. In particular, there was evidence of a strong negative relationship between macroinvertebrate abundance and total suspended solids, and a positive relationship between abundance and the distance from the disturbance. Increases in both sediments and nutrients appear to be the proximate cause of community differences in highly disturbed streams. Declines in macroinvertebrate abundance in response to slump activity have implications for the food webs of these systems, potentially leading to negative impacts on higher trophic levels, such as fish. Furthermore, the disturbance impacts on stream health can be expected to intensify as climate change increases the frequency and magnitude of thermokarst. PMID- 26766395 TI - Analysis of Riboflavin Compounds in the Rabbit Cornea In Vivo. AB - PURPOSE: To investigate the composition and concentration of individual riboflavin compounds in the corneal stroma in vivo after soaking with various commercially available riboflavin formulations. METHODS: Experiments were performed in 26 rabbit corneas in vivo: 24 corneas were soaked with riboflavin formulations for 30 minutes or with 0.9% NaCl for control (n = 2). After treatment, corneas were excised and prepared for ultra-high-pressure liquid chromatography (UHPLC) analysis. Additionally, computational chemical analysis of riboflavin compounds and keratan sulfate were performed. RESULTS: The amount of riboflavin and riboflavin phosphate isomers in cornea decreased by a factor of 10 to 100, when compared to the amount in riboflavin formulations. In particular, we found an inverse relationship in the ratio of riboflavin to riboflavin phosphate isomer concentration between formulations and cornea. The electronegativity and ionization potential of riboflavin and phosphate isomers are different. CONCLUSIONS: The inverse relationship observed might be explained by a stronger electronegativity of the phosphate isomers, leading to a stronger repulsion by corneal proteoglycans. Indicating the individual concentration of riboflavin compounds in formulations is more representative than the total riboflavin concentration. Riboflavin formulations and CXL protocols might be improved considering the differences in diffusion and ionization potentials of the different riboflavin compounds. PMID- 26766396 TI - Acute Gastroenteritis on Cruise Ships - United States, 2008-2014. AB - From 1990 to 2004, the reported rates of diarrheal disease (three or more loose stools or a greater than normal frequency in a 24-hour period) on cruise ships decreased 2.4%, from 29.2 cases per 100,000 travel days to 28.5 cases (1,2). Increased rates of acute gastroenteritis illness (diarrhea or vomiting that is associated with loose stools, bloody stools, abdominal cramps, headache, muscle aches, or fever) occurred in years that novel strains of norovirus, the most common etiologic agent in cruise ship outbreaks, emerged (3). To determine recent rates of acute gastroenteritis on cruise ships, CDC analyzed combined data for the period 2008-2014 that were submitted by cruise ships sailing in U.S. jurisdiction (defined as passenger vessels carrying >=13 passengers and within 15 days of arriving in the United States) (4). CDC also reviewed laboratory data to ascertain the causes of acute gastroenteritis outbreaks and examined trends over time. During the study period, the rates of acute gastroenteritis per 100,000 travel days decreased among passengers from 27.2 cases in 2008 to 22.3 in 2014. Rates for crew members remained essentially unchanged (21.3 cases in 2008 and 21.6 in 2014). However, the rate of acute gastroenteritis was significantly higher in 2012 than in 2011 or 2013 for both passengers and crew members, likely related to the emergence of a novel strain of norovirus, GII.4 Sydney (5). During 2008-2014, a total of 133 cruise ship acute gastroenteritis outbreaks were reported, 95 (71%) of which had specimens available for testing. Among these, 92 (97%) were caused by norovirus, and among 80 norovirus specimens for which a genotype was identified, 59 (73.8%) were GII.4 strains. Cruise ship travelers experiencing diarrhea or vomiting should report to the ship medical center promptly so that symptoms can be assessed, proper treatment provided, and control measures implemented. PMID- 26766397 TI - Color Reflectivity Discretization Analysis of OCT Images in the Detection of Glaucomatous Nerve Fiber Layer Defects. AB - PURPOSE: To compare the ability of Cirrus retinal nerve fiber layer (RNFL) thickness and the Color Reflectivity Discretization Analysis (CORDA), a novel optical coherence tomography (OCT) analysis method, to differentiate between normal subjects, glaucoma suspects, and glaucoma patients. PATIENTS AND METHODS: Analysis of peripapillary OCT images using Cirrus SD-OCT (optic nerve head cube 200 * 200 protocol) and postacquisition CORDA analysis of peripapillary RNFL B scan images was performed. In total, 291 eyes of 148 subjects (94 normal eyes, 100 primary open-angle glaucoma suspect eyes, and 97 eyes with primary open-angle glaucoma) were included. Area under the receiver operating characteristic curve was estimated for each region and method (Cirrus vs. CORDA) for differentiating eyes with glaucoma, and those that are glaucoma suspect, from normal eyes. RESULTS: CORDA HR1 parameter discriminated glaucoma patients from normal subjects more accurately than Cirrus RNFL thickness in nasal (P = 0.003) and temporal (P = 0.001) regions. HR1 showed greater area under the receiver operating characteristic curve than Cirrus RNFL thickness when discriminating glaucoma suspects from normal subjects in the superior (P = 0.02), nasal (P = 0.003), and temporal (P = 0.001) regions. Both were similar for mean and the inferior regions. CONCLUSIONS: In this study, the novel CORDA HR1 differentiated between normal subjects and glaucoma suspects more accurately than Cirrus RNFL, and in temporal and nasal regions when discriminating between normal and glaucomatous eyes. CORDA analysis may improve the diagnostic accuracy of Cirrus OCT for glaucoma and glaucoma suspects. PMID- 26766393 TI - Choosing words: left hemisphere, right hemisphere, or both? Perspective on the lateralization of word retrieval. AB - Language is considered to be one of the most lateralized human brain functions. Left hemisphere dominance for language has been consistently confirmed in clinical and experimental settings and constitutes one of the main axioms of neurology and neuroscience. However, functional neuroimaging studies are finding that the right hemisphere also plays a role in diverse language functions. Critically, the right hemisphere may also compensate for the loss or degradation of language functions following extensive stroke-induced damage to the left hemisphere. Here, we review studies that focus on our ability to choose words as we speak. Although fluidly performed in individuals with intact language, this process is routinely compromised in aphasic patients. We suggest that parceling word retrieval into its subprocesses-lexical activation and lexical selection-and examining which of these can be compensated for after left hemisphere stroke can advance the understanding of the lateralization of word retrieval in speech production. In particular, the domain-general nature of the brain regions associated with each process may be a helpful indicator of the right hemisphere's propensity for compensation. PMID- 26766398 TI - Intraoperative Optical Coherence Tomography Enables Noncontact Imaging During Canaloplasty. AB - PURPOSE: Here we describe intraoperative optical coherence tomography (iOCT) as a novel noncontact imaging tool for intraoperative monitoring and procedure evaluation during canaloplasty, as a nonpenetrating surgical technique to treat primary open angle glaucoma. MATERIALS AND METHODS: Retrospective case report of a patient (63 y, female), who underwent traditional canaloplasty, using a commercially available 840 nm OCT device, mounted to an operating microscope (Rescan 700). Main outcome measures were the intraoperative visibility of chamber angle structures and the ability to conduct surveillance of the surgical procedure through the prepared Descemet window, especially correct suture positioning and visible changes of the Schlemm canal after suture tensioning. RESULTS: iOCT delivered high-resolution images during canaloplasty after deep sclerectomy through the prepared Descemet window. All structures of the chamber angle, including the Schlemm canal were visible. Moreover iOCT enabled intraoperative noncontact procedure monitoring and a direct control of the correct localization and changes of the Schlemm canal after suture positioning and tensioning. CONCLUSIONS: iOCT seems to be a helpful intraoperative imaging tool during canaloplasty. iOCT allows for noncontact online evaluation of Schlemm canal localization and noncontact evaluation of suture tension. Shadowing of scleral tissue can be avoided by imaging through the routinely prepared Descemet window to visualize chamber angle structures including the implanted suture. PMID- 26766399 TI - Needle Revision With 5-fluorouracil for the Treatment of Ahmed Glaucoma Valve Filtering Blebs: 5-Fluoruracil Needling Revision can be a Useful and Safe Tool in the Management of Failing Ahmed Glaucoma Valve Filtering Blebs. AB - PURPOSE: To determine the outcome of needling with adjunctive 5-fluorouracil (5 FU) in patients with a failing Ahmed glaucoma valve (AGV) implant, and to identify predictors of long-term intraocular pressure (IOP) control. METHODS: A prospective observational study was performed on consecutive patients with medically uncontrolled primary open-angle glaucoma (POAG) with AGV encapsulation or fibrosis and inadequate IOP control. Bleb needling with 5-FU injection (0.1 mL of 50 mg/mL) was performed at the slit-lamp. Patients were examined 1 week following the needling, and then at months 1, 3, and 6. Subsequent follow-up visits were scheduled at 6-month intervals for at least 2 years. Needling with 5 FU was repeated no more than twice during the first 3 months of the follow-up. Procedure outcome was determined on the basis of the recorded IOP levels. RESULTS: Thirty-six patients with an encapsulated or fibrotic AGV underwent 67procedures (mean 1.86 +/- 0.83). Complete success, defined as IOP <= 18 mm Hg without medications, was obtained in 25% at 24 months of observation. The cumulative proportion of cases achieving either qualified (ie, IOP <= 18 mm Hg with medications) or complete success at 24 months of observation was 72.2%. In a univariate Cox proportional hazards model, age was the only variable that independently influenced the risk of failing 5-FU needling revision. Fourteen eyes (38.8%) had a documented complication. CONCLUSIONS: Needling over the plate of an AGV supplemented with 5-FU is an effective and safe choice in a significant proportion of POAG patients with elevated IOP due to encapsulation or fibrosis. PMID- 26766400 TI - Three-Year Follow-up of a Novel Aqueous Humor MicroShunt. AB - AIMS: An observational study to determine the safety and efficacy of filtering surgery employing a microlumen aqueous drainage device (InnFocus MicroShunt), used intraoperatively with Mitomycin C, implanted alone or in combination with phacoemulsification. MATERIALS AND METHODS: Single-site, prospective, nonrandomized study of 23 eyes that had failed maximum tolerated glaucoma medication, followed for 3 years. A MicroShunt was implanted ab externo through a needle tract under the limbus, draining aqueous from the anterior chamber to the scleral surface. Prespecified outcome measures include: intraocular pressure (IOP) control, with and without supplemental medication, success rate, medication use, and adverse events. RESULTS: Fourteen patients received the MicroShunt alone and 9 with cataract surgery. At 1 (n=23), 2 (n=22), and 3 (n=22) years of follow up; the qualified success rate (IOP <= 14 mm Hg and IOP reduction >= 20%) was 100%, 91%, and 95%; mean medicated IOP was reduced from 23.8 +/- 5.3 to 10.7 +/- 2.8, 11.9 +/- 3.7, and 10.7 +/- 3.5 mm Hg, and the mean number of glaucoma medications/patient was reduced from 2.4 +/- 0.9 to 0.3 +/- 0.8, 0.4 +/- 1.0, and 0.7 +/- 1.1, respectively. The most common complications were transient hypotony (13%, 3/23) and transient choroidal effusion (8.7%, 2/23), all resolved spontaneously. There were no leaks, infections, migrations, erosions, persistent corneal edema, or serious long-term adverse events. CONCLUSION: Surgery with the InnFocus MicroShunt transscleral aqueous drainage tube with Mitomycin C achieved IOP control in the low teens in most subjects up to 3 years of follow-up with only transient adverse events occurring within the first 3 months after surgery. PMID- 26766401 TI - The Relationship Between Vision-related Quality of Life and Visual Function in Glaucoma Patients. AB - PURPOSE: To evaluate the relationship between vision-related quality of life (QOL) as measured by the short-form 11-item Japanese version of the Visual Function Questionnaire (VFQ-J11) and the severity of visual field (VF) defects in patients with glaucoma. METHODS: The study included 134 glaucoma patients and 30 normal subjects. VF testing using the Humphrey Field Analyzer was performed to obtain both the VF index (VFI) and MD in both eyes of each glaucoma patient. Binocular integrated VF was constructed for each patient by merging corresponding sensitivity values from monocular VFs, and the correlation between visual function and vision-related QOL was then assessed. RESULTS: A significant relationship was found between QOL and VF in 6 of 7 subscales on the VFQ-J11, and between the composite scores in both the better eye and the worse eye in glaucoma patients. The relationship was stronger in the worse eye than in the better eye. Overall, correlation coefficients of the VFI were higher than those of MD and slightly higher than those of integrated VF in the worse eye. CONCLUSIONS: The VFI showed a marginally better correlation than MD. Assessment of VFI in the worse eye may provide useful information regarding vision-related QOL in glaucoma patients. PMID- 26766402 TI - Relationship Between Body Mass Index and Intraocular Pressure in Men and Women: A Population-based Study. AB - PURPOSE: To assess the possibility of a relationship between body mass index (BMI) and intraocular pressure (IOP) in both men and women. MATERIALS AND METHODS: A retrospective cross-sectional analysis of a database from a screening center in Israel which assessed 18,575 subjects, within an age range 20 to 80 years. RESULTS: The mean (+/-SD) age of the study sample was 46 (+/-10) years, 68% were men. A positive linear correlation was found between BMI and IOP for both men and women (r=0.166, P<0.0001 in men and r=0.202, P<0.0001 in women). Mean (95% confidence interval) IOP in subjects with BMI<25 kg/m(2) was 12.8 mm Hg (range, 12.7 to 12.9 mm Hg) and increased significantly to 13.4 (range, 13.3 to 13.5 mm Hg); 13.9 mm Hg (range, 13.8 to14.0 mm Hg), and 14.3 mm Hg (range, 14.1 to 14.5 mm Hg) for BMI subcategories 25 to 29.9, 30 to 35, and >35 kg/m(2), respectively (P<0.0001). These differences remained significant after multivariate adjustment for age, hypertension, and diabetes mellitus (P<0.0001). Similar multivariate adjustments showed that the coefficient factors for BMI (95% confidence interval) affecting IOP were 0.087 (range, 0.076 to 0.098) P<0.0001 and 0.070 (range, 0.058 to 0.082) P<0.0001 for men and women respectively, indicating that in men and women, the changes in IOP associated with a 10 kg/m(2) increase in BMI were 0.9 and 0.7 mm Hg, respectively. Subjects with abnormal BMI compared with subjects with normal BMI had increased odds ratio of having IOP>=18 mm Hg after adjusting for confounding factors (P<0.001). CONCLUSIONS: This study shows that obesity is an independent risk factor for increasing IOP in both men and women. We consider this finding particularly pertinent in the context of the current obesity epidemic. PMID- 26766403 TI - Same-Day Bilateral Glaucoma Laser Treatments in Ontario: 2000 to 2013. AB - OBJECTIVE: To analyze trends in bilateral, same-day laser iridotomies, and trabeculoplasties in Ontario over the last decade. METHODS: Ontario Health Insurance Plan billing service claims between 2000 and 2013 were analyzed for the yearly number of glaucoma laser procedures. The annual number of Ontarians with primary open-angle glaucoma (POAG) was estimated by applying composite prevalence curves to published population data and the yearly number of procedures per 1000 Ontarians with POAG was calculated. RESULTS: The volume of same-day bilateral trabeculoplasties increased from 15.3 per 1000 with POAG in 2000 to 74.7 in 2013 (4.9-fold). The proportion that were same-day bilateral procedures increased from 22.7% in 2000 to 40.2% in 2004 (76.9% increase) and remained stable from 2009 to 2013, reaching 38.5% in 2013. The number of same-day bilateral laser iridotomies increased from 3126 in 2000 to 11,716 in 2013 (3.75-fold). The proportion of iridotomies that were bilateral increased from 39% in 2000 to 54.6% in 2006 (40% increase) and remained stable from 2006 to 2013, reaching 56.7% in 2013. CONCLUSIONS: The increase in same-day bilateral trabeculoplasties coincided with the introduction of selective laser trabeculoplasty. The proportion of this practice remained constant for the last 3 years of the study period. In 2013, 56.7% of iridotomies and 38.5% of trabeculoplasties were performed as same-day bilateral procedures. We recommend comparison studies between same-day and sequential laser therapies to assess complication rates and patient satisfaction to provide an evidence-based treatment approach, as there are limited data to support this practice. PMID- 26766404 TI - An Urgent Call to Action for Nurse Leaders to Establish Sustainable Evidence Based Practice Cultures and Implement Evidence-Based Interventions to Improve Healthcare Quality. PMID- 26766405 TI - Patterns and the mediating role of avoidant coping style and illness perception on anxiety and depression in patients with chronic heart failure. AB - INTRODUCTION: Emotional distress in patients with chronic heart failure (CHF) predicts mortality, hospital readmission and quality of life. The patient's avoidant coping style and beliefs about the disease have been linked to emotional distress in CHF. However, the pattern and transmitting effects of these variables are indefinite. AIM: This study aimed to examine the links between and the potential mediating role of illness perceptions and avoidant coping style on depression and anxiety in patients with CHF. METHOD: Self-assessment data from 103 patients with CHF were subjected to path analysis in two hypothesised models. The outcome measures were coping styles, illness perception, anxiety and depression. RESULTS: Avoidant coping had a direct adverse effect on anxiety and depression. The perception of symptom burden and personal control, significantly mediated the effect between avoidant coping and anxiety and depression. CONCLUSIONS: Avoidant coping style appears to influence not only emotional distress, but also a malignant symptom perception and low sense of control over the illness. PMID- 26766406 TI - Neuroimaging studies in people with gender incongruence. AB - The current review gives an overview of brain studies in transgender people. First, we describe studies into the aetiology of feelings of gender incongruence, primarily addressing the sexual differentiation hypothesis: does the brain of transgender individuals resemble that of their natal sex, or that of their experienced gender? Findings from neuroimaging studies focusing on brain structure suggest that the brain phenotypes of trans women (MtF) and trans men (FtM) differ in various ways from control men and women with feminine, masculine, demasculinized and defeminized features. The brain phenotypes of people with feelings of gender incongruence may help us to figure out whether sex differentiation of the brain is atypical in these individuals, and shed light on gender identity development. Task-related imaging studies may show whether brain activation and task performance in transgender people is sex-atypical. Second, we review studies that evaluate the effects of cross-sex hormone treatment on the brain. This type of research provides knowledge on how changes in sex hormone levels may affect brain structure and function. PMID- 26766407 TI - Constructing the dead: Retrospective sensemaking in eulogies. AB - Eulogies serve a sensemaking function of identity construction--both for the deceased and for the survivors. This work examines the communicative construction of identity in eulogies and shows how eulogia discourse affirms and reconstructs our relational identity through communication. The article extends scholarship on eulogies by using relational communication theories to investigate how eulogic discourse functions as identity construction, considering eulogies of ordinary people, and exploring the gendered nature of eulogies. We discuss how eulogies are specific ritualized forms of communication in which the bereaved focus on self-identity as they articulate their experience of grief. PMID- 26766408 TI - Pediatric Asthma and Viral Infection. AB - Respiratory viral infections, particularly respiratory syncytial virus (RSV) and rhinovirus, are the most importance risk factors for the onset of wheezing in infants and small children. Bronchiolitis is the most common acute respiratory infection in children under 1year of age, and the most common cause of hospitalization in this age group. RSV accounts for approximately 70% of all these cases, followed by rhinovirus, adenovirus, metapneumovirus and bocavirus. The association between bronchiolitis caused by RSV and the development of recurrent wheezing and/or asthma was first described more than 40years ago, but it is still unclear whether bronchiolitis causes chronic respiratory symptoms, or if it is a marker for children with a genetic predisposition for developing asthma in the medium or long term. In any case, sufficient evidence is available to corroborate the existence of this association, which is particularly strong when the causative agent of bronchiolitis is rhinovirus. The pathogenic role of respiratory viruses as triggers for exacerbations in asthmatic patients has not been fully characterized. However, it is clear that respiratory viruses, and in particular rhinovirus, are the most common causes of exacerbation in children, and some type of respiratory virus has been identified in over 90% of children hospitalized for an episode of wheezing. Changes in the immune response to viral infections in genetically predisposed individuals are very likely to be the main factors involved in the association between viral infection and asthma. PMID- 26766410 TI - Sexual Behavior, Sexual Attraction, and Sexual Orientation Among Adults Aged 18 44 in the United States: Data From the 2011-2013 National Survey of Family Growth. AB - OBJECTIVE: This report provides national estimates of sexual behavior, sexual attraction, and sexual orientation among women and men aged 18-44 in the United States, based on the 2011-2013 National Survey of Family Growth (NSFG). METHODS: Data for the 2011-2013 NSFG were collected through in-person interviews with 10,416 women and men aged 15-44 in the household population in the United States. In this report, data are shown only for 9,175 adults aged 18-44. The data presented in this report were primarily collected using audio computer-assisted self-interviewing, in which the respondent enters his or her answers into the computer without telling them to an interviewer. The overall response rate for the 2011-2013 NSFG was 72.8%. RESULTS: Regarding opposite-sex sexual behavior, 94.2% of women and 92.0% of men aged 18-44 had ever had vaginal intercourse; 86.2% of women and 87.4% of men had ever had oral sex; and 35.9% of women and 42.3% of men had ever had anal sex. Almost three times as many women (17.4%) reported any same-sex contact in their lifetime compared with men (6.2%) aged 18 44. Feelings of attraction "only to the opposite sex" were more common for men (92.1%) compared with women (81.0%) aged 18-44. Among those aged 18-44, 92.3% of women and 95.1% of men said they were "heterosexual or straight"; 1.3% of women and 1.9% of men said they were "homosexual, gay, or lesbian"; 5.5% of women and 2.0% of men said they were bisexual; and 0.9% of women and 1.0% of men said "don't know" or "refused" (i.e., "did not report") on sexual orientation. Sexual attraction and sexual orientation correlate closely but not completely with reports of sexual behavior. Sexual behavior, sexual attraction, and sexual orientation vary by age, marital or cohabiting status, education, and race and Hispanic origin. PMID- 26766409 TI - Mesoamerican Nephropathy or Global Warming Nephropathy? AB - BACKGROUND: An epidemic of chronic kidney disease (CKD) of unknown cause has emerged along the Pacific Coast of Central America. The disease primarily affects men working manually outdoors, and the major group affected is sugarcane workers. The disease presents with an asymptomatic rise in serum creatinine that progresses to end-stage renal disease over several years. Renal biopsies show chronic tubulointerstitial disease. While the cause remains unknown, recent studies suggest that it is driven by recurrent dehydration in the hot climate. Potential mechanisms include the development of hyperosmolarity with the activation of the aldose reductase-fructokinase pathway in the proximal tubule leading to local injury and inflammation, and the possibility that renal injury may be the consequence of repeated uricosuria and urate crystal formation as a consequence of both increased generation and urinary concentration, similar to a chronic tumor lysis syndrome. The epidemic is postulated to be increasing due to the effects of global warming. SUMMARY: An epidemic of CKD has led to the death of more than 20,000 lives in Central America. The cause is unknown, but appears to be due to recurrent dehydration. Potential mechanisms for injury are renal damage as a consequence of recurrent hyperosmolarity and/or injury to the tubules from repeated episodes of uricosuria. KEY MESSAGES: The epidemic of CKD in Mesoamerica may be due to chronic recurrent dehydration as a consequence of global warming and working conditions. This entity may be one of the first major diseases attributed to climate change and the greenhouse effect. PMID- 26766411 TI - IREN, a novel EF-hand motif-containing nuclease, functions in the degradation of nuclear DNA during the hypersensitive response cell death in rice. AB - The hypersensitive response (HR), a type of programmed cell death that is accompanied by DNA degradation and loss of plasma membrane integrity, is a common feature of plant immune responses. We previously reported that transcription of IREN which encodes a novel EF-hand containing plant nuclease is controlled by OsNAC4, a key positive regulator of HR cell death. Transient overexpression of IREN in rice protoplasts also led to rapid DNA fragmentation, while suppression of IREN using RNA interference showed remarkable decrease of DNA fragmentation during HR cell death. Maximum DNA degradation associated with the recombinant IREN was observed in the presence of Ca(2+) and Mg(2+) or Ca(2+) and Mn(2+). Interestingly, DNA degradation mediated by the recombinant IREN was completely abolished by Zn(2+), even when Ca(2+), Mg(2+), or Mn(2+) were present in the reaction buffer. These data indicate that IREN functions in the degradation of nuclear DNA during HR cell death. PMID- 26766412 TI - Pathways for the OH + Br2 -> HOBr + Br and HOBr + Br -> HBr + BrO Reactions. AB - The OH radical reaction with Br2 and the subsequent reaction HOBr + Br are of exceptional importance to atmospheric chemistry and environmental chemistry. The entrance complex, transition state, and exit complex for both reactions have been determined using the coupled-cluster method with single, double, and perturbative triple excitations CCSD(T) with correlation consistent basis sets up to size cc pV5Z and cc-pV5Z-PP. Coupled cluster effects with full triples (CCSDT) and full quadruples (CCSDTQ) are explicitly investigated. Scalar relativistic effects, spin-orbit coupling, and zero-point vibrational energy corrections are evaluated. The results from the all-electron basis sets are compared with those from the effective core potential (ECP) pseudopotential (PP) basis sets. The results are consistent. The OH + Br2 reaction is predicted to be exothermic 4.1 +/- 0.5 kcal/mol, compared to experiment, 3.9 +/- 0.2 kcal/mol. The entrance complex HO...BrBr is bound by 2.2 +/- 0.2 kcal/mol. The transition state lies similarly well below the reactants OH + Br2. The exit complex HOBr...Br is bound by 2.7 +/- 0.6 kcal/mol relative to separated HOBr + Br. The endothermicity of the reaction HOBr + Br -> HBr + BrO is 9.6 +/- 0.7 kcal/mol, compared with experiment 8.7 +/- 0.3 kcal/mol. For the more important reverse (exothermic) HBr + BrO reaction, the entrance complex BrO...HBr is bound by 1.8 +/- 0.6 kcal/mol. The barrier for the HBr + BrO reaction is 6.8 +/- 0.9 kcal/mol. The exit complex (Br...HOBr) for the HBr + BrO reaction is bound by 1.9 +/- 0.2 kcal/mol with respect to the products HOBr + Br. PMID- 26766417 TI - Preface--Advances in CKD 2016. PMID- 26766416 TI - Single-Cell Electrical Phenotyping Enabling the Classification of Mouse Tumor Samples. AB - Single-cell electrical phenotyping (e.g., specific membrane capacitance (Cm) and cytoplasm conductivity (sigmap)) has long been regarded as potential label-free biophysical markers in tumor status evaluation. However, previous studies only reported the differentiation of tumor cell lines without classifying real tumor samples using cellular electrical properties. In this study, two types of mouse tumor models were constructed by injecting two types of tumor cell lines (A549 and H1299), respectively. Then tumor portions were retrieved for immunohistochemistry studies and single-cell electrical phenotyping based on home developed microfluidic platforms. Immunohistochemistry results of tumor samples confirmed the adenocarcinoma and large-cell carcinoma characteristics for A549 and H1299 based tumor samples, respectively. Meanwhile, cellular Cm and sigmap were characterized as 2.25 +/- 0.50 MUF/cm(2) and 0.96 +/- 0.20 S/m for A549 based tumor samples (ncell = 1336, Mouse I, II, III) and 1.76 +/- 0.54 MUF/cm(2) and 1.35 +/- 0.28 S/m for H1299 based tumor samples (ncell = 1442, Mouse IV, V, VI). Significant differences in Cm and sigmap were observed between these two types of tumor samples, validating the feasibility of using Cm and sigmap for mouse tumor classification. PMID- 26766415 TI - Bloodstream infections after solid-organ transplantation. AB - Solid-organ transplantation (SOT) has become the preferred strategy to treat a number of end-stage organ disease, because a continuous improvement in survival and quality of life. While preventive strategies has decreased the risk for classical opportunistic infections (such as viral, fungal and parasite infections), bacterial infections, and particularly bloodstream infections (BSIs) remain the most common and life-threatening complications in SOT recipients. The source of BSI after transplant depends on the type of transplantation, being urinary tract infection, pneumonia, and intraabdominal infections the most common infections occurring after kidney, lung and liver transplantation, respectively. The risk for candidemia is higher in abdominal-organ than in thoracic-organ transplantation. Currently, the increasing prevalence of multi-drug resistant (MDR) Gram-negative pathogens, such as extended-spectrum betalactamase-producing Enterobacteriaciae and carbapenem-resistant Klebsiella pneumoniae, is causing particular concerns in SOT recipients, a population which presents several risk factors for developing infections due to MDR organisms. The application of strict preventive policies to reduce the incidence of post transplant BSIs and to control the spread of MDR organisms, including the implementation of specific stewardship programs to avoid the overuse of antibiotics and antifungal drugs, are essential steps to reduce the impact of post transplant infections on allograft and patient outcomes. PMID- 26766418 TI - High-Throughput Determination of Statistical Structure Information for Horizontal Carbon Nanotube Arrays by Optical Imaging. AB - Optical multicolor imaging is used as a high-throughput statistical tool to determine the structure information of horizontally aligned carbon nanotube arrays on various substrates and in diverse environments. This high-throughput ability is achieved through the direct use of optical image information and an over 10-fold enhancement of the optical contrast by polarization manipulation. PMID- 26766419 TI - Haemodynamic Responses to Selective Vagal Nerve Stimulation under Enalapril Medication in Rats. AB - Selective vagal nerve stimulation (sVNS) has been demonstrated to lower blood pressure (BP) in rats without causing major side effects. This method might be adapted for the treatment of therapy-resistant hypertension in patients. Converting enzyme inhibitors (CEIs) are among the first drugs that are administered for arterial hypertension and prominently reduce BP primarily by interacting with the renin-angiotensin system of the kidneys. Beyond the reduction of BP, CEI have a positive effect on the survival rate after myocardial infarction; they reduce the rates of stroke and improve the neurohormonal status in heart-failure patients. If sVNS might be introduced as a therapy against resistant hypertension, patients will at least partially stay on their CEI medication. It is therefore the aim of this study to investigate the influence of the CEI enalapril on the haemodynamic and respiratory effects of sVNS. In 10 male Wistar rats, a polyimide-based multichannel-cuff-electrode was placed around the vagal nerve bundle to selectively stimulate the aortic depressor nerve fibres. Stimulation parameters were adapted to the thresholds of the individual animals and included repetition frequencies between 30 and 50 Hz, amplitudes of 0.5 to 1.5 mA and pulse widths between 0.4 ms and 1.0 ms. BP responses were detected with a microtip transducer in the left carotid artery, and electrocardiography was recorded with subcutaneous electrodes. After intravenous administration of enalapril (2 mg/kg bodyweight), the animals' mean arterial blood pressures (MAPs) decreased significantly, while the heart rates (HRs) were not significantly influenced. The effects of sVNS on BP and HR were attenuated by enalapril but were still present. We conclude that sVNS can lower the MAP during enalapril treatment without relevant side effects. PMID- 26766421 TI - Expression of MAGE-A1, -A9, -A11 in laryngeal squamous cell carcinoma and their prognostic significance: a retrospective clinical study. AB - CONCLUSION: The melanoma-associated antigens A1, -A9, -A11 (MAGE-A1, -A9, -A11) are relatively tumor-specific in laryngeal squamous cell carcinoma (LSCC), and could be ideal antigens for LSCC immunotherapy. In addition, MAGE-A9 probably is a poor prognostic marker for LSCC patients. OBJECTIVE: The MAGE-A family belongs to Cancer/testis antigens (CTA). However, the expression pattern of MAGE-A1, MAGE A9, and MAGE-A11 in LSCC is still unclear. This study aims to evaluate the expression and possible prognostic role of MAGE-A1, MAGE-A9, and MAGE-A11 in LSCC patients. METHODS: The expression of MAGE-A1, MAGE-A9, and MAGE-A11 in LSCC specimens was investigated by immunohistochemistry, and the association of their expression and the clinical parameters and the survival of LSCC patients were analyzed by chi-square test, Kaplan-Meier survival and Cox regression analysis. RESULTS: The expression rates of MAGE-A1, MAGE-A9, and MAGE-A11 in LSCC were 54.7%, 46.2%, and 51.9%, respectively. The expression of MAGE-A1, MAGE-A9, and MAGE-A11 in LSCC was correlated with clinical stage, lymph node metastasis, and tumor size. The overall survival of LSCC patients with positive MAGE-A1, MAGE-A9, or MAGE-A11 expression was lower than the patients without MAGE-A1, MAGE-A9, or MAGE-A11 expression. Cox's multivariable analysis showed that MAGE-A9 expression was an independently poor prognostic factor for LSCC patients. PMID- 26766422 TI - Evolution of Head and Neck Microvascular Reconstructive Strategy at an Academic Centre: An 18-Year Review. AB - Background A remarkable development through the evolution of free flap techniques has led to the modern reconstructive head and neck surgery. This study aimed to review experiences from head and neck free-flap reconstructions performed at our institution over an 18-year period. Methods Between 1995 and 2012, 594 free-flap operations were performed on 541 head and neck patients at the Department of Plastic Surgery, Helsinki University Hospital, Finland. We retrospectively recorded hospital chart data regarding patient demographics, tumor characteristics, surgical treatment, and outcome. Results The mean age of patients increased from 53 years (1995-2000) to 56 (2007-2012), while the gender distribution remained constant (60% males). The most commonly used flap type between 1995 and 2000 was radial forearm flap (50%), while during the periods of 2001 through 2006 and 2007 through 2012 the anterolateral thigh flap was the most common method (42 and 36%, respectively). The number of different flap types and flap combinations increased during these periods (15 flap types during 1995 through 2000; 17 flap types during 2001 through 2006; and 24 flap types during 2007 through 2012). Despite a wider range of flap options used during the period 2001 through 2012, the overall flap survival rate (97%) remained constant. The prevalence of surgical complications decreased from 26% (2001 through 2006) to 21% (2007 through 2012). Conclusions During the study period, the number of flap types increased and reconstructions became more individualized. The overall surgical complication rate decreased although the mean age of patients increased. PMID- 26766423 TI - Characterization of Gas-Phase Organics Using Proton Transfer Reaction Time-of Flight Mass Spectrometry: Cooking Emissions. AB - Cooking processes produce gaseous and particle emissions that are potentially deleterious to human health. Using a highly controlled experimental setup involving a proton-transfer-reaction time-of-flight mass spectrometer (PTR-ToF MS), we investigate the emission factors and the detailed chemical composition of gas phase emissions from a broad variety of cooking styles and techniques. A total of 95 experiments were conducted to characterize nonmethane organic gas (NMOG) emissions from boiling, charbroiling, shallow frying, and deep frying of various vegetables and meats, as well as emissions from vegetable oils heated to different temperatures. Emissions from boiling vegetables are dominated by methanol. Significant amounts of dimethyl sulfide are emitted from cruciferous vegetables. Emissions from shallow frying, deep frying and charbroiling are dominated by aldehydes of differing relative composition depending on the oil used. We show that the emission factors of some aldehydes are particularly large which may result in considerable negative impacts on human health in indoor environments. The suitability of some of the aldehydes as tracers for the identification of cooking emissions in ambient air is discussed. PMID- 26766424 TI - Exhaled CO2 Parameters as a Tool to Assess Ventilation-Perfusion Mismatching during Neonatal Resuscitation in a Swine Model of Neonatal Asphyxia. AB - BACKGROUND: End-tidal CO2 (ETCO2), partial pressure of exhaled CO2 (PECO2), and volume of expired CO2 (VCO2) can be continuously monitored non-invasively to reflect pulmonary ventilation and perfusion status. Although ETCO2 >=14 mmHg has been shown to be associated with return of an adequate heart rate in neonatal resuscitation and quantifying the PECO2 has the potential to serve as an indicator of resuscitation quality, there is little information regarding capnometric measurement of PECO2 and ETCO2 in detecting return of spontaneous circulation (ROSC) and survivability in asphyxiated neonates receiving cardiopulmonary resuscitation (CPR). METHODS: Seventeen newborn piglets were anesthetized, intubated, instrumented, and exposed to 45-minute normocapnic hypoxia followed by apnea to induce asphyxia. Protocolized resuscitation was initiated when heart rate decreased to 25% of baseline. Respiratory and hemodynamic parameters including ETCO2, PECO2, VCO2, heart rate, cardiac output, and carotid artery flow were continuously measured and analyzed. RESULTS: There were no differences in respiratory and hemodynamic parameters between surviving and non-surviving piglets prior to CPR. Surviving piglets had significantly higher ETCO2, PECO2, VCO2, cardiac index, and carotid artery flow values during CPR compared to non-surviving piglets. CONCLUSION: Surviving piglets had significantly better respiratory and hemodynamic parameters during resuscitation compared to non-surviving piglets. In addition to optimizing resuscitation efforts, capnometry can assist by predicting outcomes of newborns requiring chest compressions. PMID- 26766425 TI - Analyzing Clustered Data: Why and How to Account for Multiple Observations Nested within a Study Participant? AB - A conventional study design among medical and biological experimentalists involves collecting multiple measurements from a study subject. For example, experiments utilizing mouse models in neuroscience often involve collecting multiple neuron measurements per mouse to increase the number of observations without requiring a large number of mice. This leads to a form of statistical dependence referred to as clustering. Inappropriate analyses of clustered data have resulted in several recent critiques of neuroscience research that suggest the bar for statistical analyses within the field is set too low. We compare naive analytical approaches to marginal, fixed-effect, and mixed-effect models and provide guidelines for when each of these models is most appropriate based on study design. We demonstrate the influence of clustering on a between-mouse treatment effect, a within-mouse treatment effect, and an interaction effect between the two. Our analyses demonstrate that these statistical approaches can give substantially different results, primarily when the analyses include a between-mouse treatment effect. In a novel analysis from a neuroscience perspective, we also refine the mixed-effect approach through the inclusion of an aggregate mouse-level counterpart to a within-mouse (neuron level) treatment as an additional predictor by adapting an advanced modeling technique that has been used in social science research and show that this yields more informative results. Based on these findings, we emphasize the importance of appropriate analyses of clustered data, and we aim for this work to serve as a resource for when one is deciding which approach will work best for a given study. PMID- 26766426 TI - Effects of antenatal testing laws on infant mortality. AB - Even though syphilis can be prevented effectively and treated inexpensively, it has remained a global public health problem. Untreated congenital syphilis results in neonatal death, stillbirth, preterm birth, or congenital deformities. Many developing countries have recently instituted syphilis prevention programs in antenatal care, but there has not been a systematic study of the effects of such programs. This paper is the first to study antenatal testing laws initiated in the U.S. in 1938-1947 which mandated physicians and other persons permitted by law to attend to a pregnant woman to test her for syphilis. We use the variation in the timing of state antenatal testing laws to estimate the laws' effect on neonatal mortality rates and deaths due to preterm birth. Using 1931-1947 Vital Statistics data, we find that these laws decreased neonatal mortality rates of nonwhites by 3.15 per 1000 live births (a 8.6% reduction) while having no discernible impact on whites. The laws contributed to an 18% narrowing of the white-nonwhite neonatal mortality gap by 1947. Using 1950 U.S. Census data, we find that mandatory antenatal testing led to a 7% increase in the cohort size of nonwhite poor, which is consistent with the neonatal mortality results. We find universal antenatal testing to be very cost-effective, with an estimated $7600 cost (in 2013 dollars) per life-year saved. PMID- 26766427 TI - Graphene Oxides Decorated with Carnosine as an Adjuvant To Modulate Innate Immune and Improve Adaptive Immunity in Vivo. AB - Current studies have revealed the immune effects of graphene oxide (GO) and have utilized them as vaccine carriers and adjuvants. However, GO easily induces strong oxidative stress and inflammatory reaction at the site of injection. It is very necessary to develop an alternative adjuvant based on graphene oxide derivatives for improving immune responses and decreasing side effects. Carnosine (Car) is an outstanding and safe antioxidant. Herein, the feasibility and efficiency of ultrasmall graphene oxide decorated with carnosine as an alternative immune adjuvant were explored. OVA@GO-Car was prepared by simply mixing ovalbumin (OVA, a model antigen) with ultrasmall GO covalently modified with carnosine (GO-Car). We investigated the immunological properties of the GO Car adjuvant in model mice. Results show that OVA@GO-Car can promote robust and durable OVA-specific antibody response, increase lymphocyte proliferation efficiency, and enhance CD4(+) T and CD8(+) T cell activation. The presence of Car in GO also probably contributes to enhancing the antigen-specific adaptive immune response through modulating the expression of some cytokines, including IL 6, CXCL1, CCL2, and CSF3. In addition, the safety of GO-Car as an adjuvant was evaluated comprehensively. No symptoms such as allergic response, inflammatory redness swelling, raised surface temperatures, physiological anomalies of blood, and remarkable weight changes were observed. Besides, after modification with carnosine, histological damages caused by GO-Car in lung, muscle, kidney, and spleen became weaken significantly. This study sufficiently suggest that GO-Car as a safe adjuvant can effectively enhance humoral and innate immune responses against antigens in vivo. PMID- 26766428 TI - Antifouling and Antibacterial Multifunctional Polyzwitterion/Enzyme Coating on Silicone Catheter Material Prepared by Electrostatic Layer-by-Layer Assembly. AB - The formation of bacterial biofilms on indwelling medical devices generally causes high risks for adverse complications such as catheter-associated urinary tract infections. In this work, a strategy for synthesizing innovative coatings of poly(dimethylsiloxane) (PDMS) catheter material, using layer-by-layer assembly with three novel functional polymeric building blocks, is reported, i.e., an antifouling copolymer with zwitterionic and quaternary ammonium side groups, a contact biocidal derivative of that polymer with octyl groups, and the antibacterial hydrogen peroxide (H2O2) producing enzyme cellobiose dehydrogenase (CDH). CDH oxidizes oligosaccharides by transferring electrons to oxygen, resulting in the production of H2O2. The design and synthesis of random copolymers which combine segments that have antifouling properties by zwitterionic groups and can be used for electrostatically driven layer-by-layer (LbL) assembly at the same time were based on the atom-transfer radical polymerization of dimethylaminoethyl methacrylate and subsequent partial sulfobetainization with 1,3-propane sultone followed by quaternization with methyl iodide only or octyl bromide and thereafter methyl iodide. The alternating multilayer systems were formed by consecutive adsorption of the novel polycations with up to 50% zwitterionic groups and of poly(styrenesulfonate) as the polyanion. Due to its negative charge, enzyme CDH was also firmly embedded as a polyanionic layer in the multilayer system. This LbL coating procedure was first performed on prefunctionalized silicon wafers and studied in detail with ellipsometry as well as contact angle (CA) and zetapotential (ZP) measurements before it was transferred to prefunctionalized PDMS and analyzed by CA and ZP measurements as well as atomic force microscopy. The coatings comprising six layers were stable and yielded a more neutral and hydrophilic surface than did PDMS, the polycation with 50% zwitterionic groups having the largest effect. Enzyme activity was found to be dependent on the depth of embedment in the multilayer coating. Depending on the used polymeric building block, up to a 60% reduction in the amount of adhering bacteria and clear evidence for killed bacteria due to the antimicrobial functionality of the coating could be confirmed. Overall, this work demonstrates the feasibility of an easy to perform and shape-independent method for preparing an antifouling and antimicrobial coating for the significant reduction of biofilm formation and thus reducing the risk of acquiring infections by using urinary catheters. PMID- 26766429 TI - Generalizability and Effectiveness of Butterfly Phlebotomy in Reducing Hemolysis. AB - OBJECTIVES: The objective was to test the hypothesis that exclusive use of butterfly needles for phlebotomy, compared with sample collection via intravenous (IV) catheter, will reduce rates of sample hemolysis. METHODS: This was an observational study of hemolysis rates before and after implementation of a "butterfly-only" phlebotomy protocol. Weekly hemolysis rates, generated by the central laboratory, were collected and the proportion of hemolyzed specimens before and after protocol implementation were compared. RESULTS: Prior to institution of the butterfly-only protocol, 11.3% of specimens sent from the emergency department were reported as hemolyzed. During the postintervention period, only 4.3% of specimens were hemolyzed for a proportionate decrease of 62% and an absolute decrease of 7.0% (95% confidence interval = 6.6% to 7.3%). CONCLUSIONS: Use of a butterfly-only phlebotomy protocol cuts hemolysis rates by more than half when compared with IV catheter phlebotomy. PMID- 26766436 TI - Tug of War in Spindle Orientation. AB - The evolutionarily conserved Galphai-LGN-NuMA protein complex is a key regulator of spindle orientation, but how its spatiotemporal localization is achieved remains elusive. Chiu et al. (2016) show that SAPCD2 negatively regulates LGN cortical localization by competing with NuMA for LGN binding in both epithelial cells and mouse retinal progenitor cells. PMID- 26766430 TI - PCB pollution continues to impact populations of orcas and other dolphins in European waters. AB - Organochlorine (OC) pesticides and the more persistent polychlorinated biphenyls (PCBs) have well-established dose-dependent toxicities to birds, fish and mammals in experimental studies, but the actual impact of OC pollutants on European marine top predators remains unknown. Here we show that several cetacean species have very high mean blubber PCB concentrations likely to cause population declines and suppress population recovery. In a large pan-European meta-analysis of stranded (n = 929) or biopsied (n = 152) cetaceans, three out of four species: striped dolphins (SDs), bottlenose dolphins (BNDs) and killer whales (KWs) had mean PCB levels that markedly exceeded all known marine mammal PCB toxicity thresholds. Some locations (e.g. western Mediterranean Sea, south-west Iberian Peninsula) are global PCB "hotspots" for marine mammals. Blubber PCB concentrations initially declined following a mid-1980s EU ban, but have since stabilised in UK harbour porpoises and SDs in the western Mediterranean Sea. Some small or declining populations of BNDs and KWs in the NE Atlantic were associated with low recruitment, consistent with PCB-induced reproductive toxicity. Despite regulations and mitigation measures to reduce PCB pollution, their biomagnification in marine food webs continues to cause severe impacts among cetacean top predators in European seas. PMID- 26766437 TI - Cybernetics, Redux: An Outside-In Strategy for Unraveling Cellular Function. AB - A new paper in Science reveals how repetitive stimulation can identify and help to repair fragilities within a signaling network, while using linear mathematical models inspired by engineering, thereby suggesting how cybernetic methods can be integrated into systems and synthetic biology. PMID- 26766438 TI - When Less Is Better: ER Stress and Beta Cell Proliferation. AB - Pancreatic beta cells synthesize and secrete insulin to increase anabolic metabolism in an organism, and insulin synthesis has long been suspected to inhibit beta cell replication. Recently in Cell Metabolism, Szabat et al. (2015) present evidence that deletion of Insulin genes alleviates ER stress and promotes mature beta cell replication. PMID- 26766439 TI - Developing Epithelia: What the Eye Cannot Grasp. AB - In this issue of Developmental Cell, Heller et al. (2016) introduce EpiTools, a new open-source image analysis toolkit that provides user-friendly graphical interfaces to perform automatic cell-based measurements from fluorescence microscopy time-lapse images of growing epithelia. PMID- 26766440 TI - Dynamic Control of Enhancer Repertoires Drives Lineage and Stage-Specific Transcription during Hematopoiesis. AB - Enhancers are the primary determinants of cell identity, but the regulatory components controlling enhancer turnover during lineage commitment remain largely unknown. Here we compare the enhancer landscape, transcriptional factor occupancy, and transcriptomic changes in human fetal and adult hematopoietic stem/progenitor cells and committed erythroid progenitors. We find that enhancers are modulated pervasively and direct lineage- and stage-specific transcription. GATA2-to-GATA1 switch is prevalent at dynamic enhancers and drives erythroid enhancer commissioning. Examination of lineage-specific enhancers identifies transcription factors and their combinatorial patterns in enhancer turnover. Importantly, by CRISPR/Cas9-mediated genomic editing, we uncover functional hierarchy of constituent enhancers within the SLC25A37 super-enhancer. Despite indistinguishable chromatin features, we reveal through genomic editing the functional diversity of several GATA switch enhancers in which enhancers with opposing functions cooperate to coordinate transcription. Thus, genome-wide enhancer profiling coupled with in situ enhancer editing provide critical insights into the functional complexity of enhancers during development. PMID- 26766441 TI - Emergence of an Apical Epithelial Cell Surface In Vivo. AB - Epithelial sheets are crucial components of all metazoan animals, enclosing organs and protecting the animal from its environment. Epithelial homeostasis poses unique challenges, as addition of new cells and loss of old cells must be achieved without disrupting the fluid-tight barrier and apicobasal polarity of the epithelium. Several studies have identified cell biological mechanisms underlying extrusion of cells from epithelia, but far less is known of the converse mechanism by which new cells are added. Here, we combine molecular, pharmacological, and laser-dissection experiments with theoretical modeling to characterize forces driving emergence of an apical surface as single nascent cells are added to a vertebrate epithelium in vivo. We find that this process involves the interplay between cell-autonomous actin-generated pushing forces in the emerging cell and mechanical properties of neighboring cells. Our findings define the forces driving this cell behavior, contributing to a more comprehensive understanding of epithelial homeostasis. PMID- 26766442 TI - SAPCD2 Controls Spindle Orientation and Asymmetric Divisions by Negatively Regulating the Galphai-LGN-NuMA Ternary Complex. AB - Control of cell-division orientation is integral to epithelial morphogenesis and asymmetric cell division. Proper spatiotemporal localization of the evolutionarily conserved Galphai-LGN-NuMA protein complex is critical for mitotic spindle orientation, but how this is achieved remains unclear. Here we identify Suppressor APC domain containing 2 (SAPCD2) as a previously unreported LGN interacting protein. We show that SAPCD2 is essential to instruct planar mitotic spindle orientation in both epithelial cell cultures and mouse retinal progenitor cells in vivo. Loss of SAPCD2 randomizes spindle orientation, which in turn disrupts cyst morphogenesis in three-dimensional cultures, and triples the number of terminal asymmetric cell divisions in the developing retina. Mechanistically, we show that SAPCD2 negatively regulates the localization of LGN at the cell cortex, likely by competing with NuMA for its binding. These results uncover SAPCD2 as a key regulator of the ternary complex controlling spindle orientation during morphogenesis and asymmetric cell divisions. PMID- 26766444 TI - Endothelial RSPO3 Controls Vascular Stability and Pruning through Non-canonical WNT/Ca(2+)/NFAT Signaling. AB - The WNT signaling enhancer R-spondin3 (RSPO3) is prominently expressed in the vasculature. Correspondingly, embryonic lethality of Rspo3-deficient mice is caused by vessel remodeling defects. Yet the mechanisms underlying vascular RSPO3 function remain elusive. Inducible endothelial Rspo3 deletion (Rspo3-iECKO) resulted in perturbed developmental and tumor vascular remodeling. Endothelial cell apoptosis and vascular pruning led to reduced microvessel density in Rspo3 iECKO mice. Rspo3-iECKO mice strikingly phenocopied the non-canonical WNT signaling-induced vascular defects of mice deleted for the WNT secretion factor Evi/Wls. An endothelial screen for RSPO3 and EVI/WLS co-regulated genes identified Rnf213, Usp18, and Trim30alpha. RNF213 targets filamin A and NFAT1 for proteasomal degradation attenuating non-canonical WNT/Ca(2+) signaling. Likewise, USP18 and TRIM5alpha inhibited NFAT1 activation. Consequently, NFAT protein levels were decreased in endothelial cells of Rspo3-iECKO mice and pharmacological NFAT inhibition phenocopied Rspo3-iECKO mice. The data identify endothelial RSPO3-driven non-canonical WNT/Ca(2+)/NFAT signaling as a critical maintenance pathway of the remodeling vasculature. PMID- 26766443 TI - Ubiquitin Receptor Protein UBASH3B Drives Aurora B Recruitment to Mitotic Microtubules. AB - Mitosis ensures equal segregation of the genome and is controlled by a variety of ubiquitylation signals on substrate proteins. However, it remains unexplored how the versatile ubiquitin code is read out during mitotic progression. Here, we identify the ubiquitin receptor protein UBASH3B as an important regulator of mitosis. UBASH3B interacts with ubiquitylated Aurora B, one of the main kinases regulating chromosome segregation, and controls its subcellular localization but not protein levels. UBASH3B is a limiting factor in this pathway and is sufficient to localize Aurora B to microtubules prior to anaphase. Importantly, targeting Aurora B to microtubules by UBASH3B is necessary for the timing and fidelity of chromosome segregation in human cells. Our findings uncover an important mechanism defining how ubiquitin attachment to a substrate protein is decoded during mitosis. PMID- 26766445 TI - RETRACTED: The Anaphase-Promoting Complex/Cyclosome Is Essential for Entry into Meiotic M-Phase. AB - Vertebrate immature oocytes are arrested at prophase of meiosis I (MI). Hormonal stimulation breaks this prophase-I arrest and induces re-entry into MI. The mechanism underlying meiotic resumption remains largely elusive. Here, we demonstrate that the anaphase-promoting complex/cyclosome (APC/C) in complex with Cdh1 has an unexpected function in meiosis in that it is essential for meiotic resumption. We identify the catalytic subunit of protein phosphatase 6 (PP6c) as the critical substrate whose APC/C(Cdh1)-mediated destruction is a prerequisite for the re-entry of immature Xenopus laevis oocytes into MI. Preventing PP6c destruction impairs activating autophosphorylation of Aurora A, a cell-cycle kinase critical for meiotic translation. Restoring meiotic translation rescues the meiotic resumption defect of Cdh1-depleted oocytes. Thus, our studies discover that the essential function of the APC/C in triggering cell-cycle transitions is not limited to M-phase exit but also applies to entry into meiotic M-phase, and identify a crucial APC/C-PP6c-Aurora A axis in the resumption of female meiosis. PMID- 26766446 TI - EpiTools: An Open-Source Image Analysis Toolkit for Quantifying Epithelial Growth Dynamics. AB - Epithelia grow and undergo extensive rearrangements to achieve their final size and shape. Imaging the dynamics of tissue growth and morphogenesis is now possible with advances in time-lapse microscopy, but a true understanding of their complexities is limited by automated image analysis tools to extract quantitative data. To overcome such limitations, we have designed a new open source image analysis toolkit called EpiTools. It provides user-friendly graphical user interfaces for accurately segmenting and tracking the contours of cell membrane signals obtained from 4D confocal imaging. It is designed for a broad audience, especially biologists with no computer-science background. Quantitative data extraction is integrated into a larger bioimaging platform, Icy, to increase the visibility and usability of our tools. We demonstrate the usefulness of EpiTools by analyzing Drosophila wing imaginal disc growth, revealing previously overlooked properties of this dynamic tissue, such as the patterns of cellular rearrangements. PMID- 26766447 TI - Reversible Optogenetic Control of Subcellular Protein Localization in a Live Vertebrate Embryo. AB - We demonstrate the utility of the phytochrome system to rapidly and reversibly recruit proteins to specific subcellular regions within specific cells in a living vertebrate embryo. Light-induced heterodimerization using the phytochrome system has previously been used as a powerful tool to dissect signaling pathways for single cells in culture but has not previously been used to reversibly manipulate the precise subcellular location of proteins in multicellular organisms. Here we report the experimental conditions necessary to use this system to manipulate proteins in vivo. As proof of principle, we demonstrate that we can manipulate the localization of the apical polarity protein Pard3 with high temporal and spatial precision in both the neural tube and the embryo's enveloping layer epithelium. Our optimizations of optogenetic component expression and chromophore purification and delivery should significantly lower the barrier for establishing this powerful optogenetic system in other multicellular organisms. PMID- 26766490 TI - High amyloid-beta deposition related to depressive symptoms in older individuals with normal cognition: a pilot study. AB - OBJECTIVE: Previous studies have reported depressive symptoms in the preclinical stages of Alzheimer's disease (AD). The objective of this study was to determine whether depressive symptoms are associated with cortical amyloid burden. In order to do this, we measured cortical amyloid via (11) C-labeled Pittsburgh Compound B ([(11) C]PIB) uptake using positron emission tomography (PET) in cognitively normal subjects. METHODS: We performed [(11) C]PIB-PET in 29 cognitively normal, older participants. Depressive symptoms were assessed using the 15-item Geriatric Depression Scale (GDS). Abeta deposition was quantified by binding potential (BPND ), and the association between cortical mean BPND values and GDS scores was evaluated. Analysis of parametric BPND images was performed to examine the relationship between regional BPND and GDS scores. RESULTS: We found a positive correlation between depressive symptoms and mean cortical PIB-BPND in groups of subjects with middle to high PIB-BPND . There was little change in GDS-depression score between subjects with low and middle PIB-BPND levels, while an increase in GDS was shown in the high PIB-BPND group. The main BPND increase was localized to the precuneus/posterior cingulate cortex (PCu/PCC) in subjects with high PIB-BPND , and we found a significant positive relationship between PIB-BPND in this area and depressive symptoms. CONCLUSIONS: Emotional dysregulation because of Abeta neuropathology in the PCu/PCC may relate to depressive symptoms. More specifically, we found that older, cognitively normal patients with depressive episodes were more likely to have underlying AD pathology. Thus, depressive symptoms may increase the predictive ability of the identification of future AD cases. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26766491 TI - Ganglioside GD1a inhibits LPS-induced inflammation in types of cells. PMID- 26766493 TI - Simotinib as a modulator of P-glycoprotein: substrate, inhibitor, or inducer? AB - As a new antitumor drug, simotinib hydrochloride is prescribed for prolonged periods, often to patients with comorbidities. Therefore, the risk for developing drug resistance and drug-drug interactions between simotinib and other agents has to be taken into consideration. As P-glycoprotein (P-gp) is an efflux transporter, which plays a significant role in drug resistance and influences the pharmacological properties and toxicities of the drugs it interacts with, the interactions between simotinib and P-gp were investigated. Cytotoxicity was measured using the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide assay. Intracellular drug concentrations were detected by high performance liquid chromatography, fluorescence-activated cell sorting and using a fluorescence reader. P-gp ATPase activity was measured using the Pgp-Glo assay, and intracellular pH was assessed using the fluorescent probe 2',7'-bis(2 carboxyethyl)-5(6)-carboxyfluorescein acetoxymethyl. The expression and transcription of P-gp were detected by western blotting and the luciferase assay. Simotinib has no cross-resistance to P-gp substrates, and its efflux rate was independent of either the P-gp expression or the coadministered P-gp substrate. Simotinib reversed chemotherapeutic agent resistance in a short time by increasing the intracellular concentration of the chemotherapeutic agent and blocked rhodamine 123 efflux. Further studies demonstrated that simotinib inhibited P-gp activity by modulating its ATPase activity and the intracellular pH. Although simotinib induced P-gp expression after extended treatment, the induced expression of P-gp had little impact on drug resistance. Simotinib is not a substrate of P-gp. As a modulator, it functions mainly as an inhibitor of P-gp by modulating the intracellular pH and ATPase activity, although it also induces P-gp expression after extended treatment. PMID- 26766492 TI - RNF4 regulates DNA double-strand break repair in a cell cycle-dependent manner. AB - Both RNF4 and KAP1 play critical roles in the response to DNA double-strand breaks (DSBs), but the functional interplay of RNF4 and KAP1 in regulating DNA damage response remains unclear. We have previously demonstrated the recruitment and degradation of KAP1 by RNF4 require the phosphorylation of Ser824 (pS824) and SUMOylation of KAP1. In this report, we show the retention of DSB-induced pS824 KAP1 foci and RNF4 abundance are inversely correlated as cell cycle progresses. Following irradiation, pS824-KAP1 foci predominantly appear in the cyclin A (-) cells, whereas RNF4 level is suppressed in the G0-/G1-phases and then accumulates during S-/G2-phases. Notably, 53BP1 foci, but not BRCA1 foci, co-exist with pS824 KAP1 foci. Depletion of KAP1 yields opposite effect on the dynamics of 53BP1 and BRCA1 loading, favoring homologous recombination repair. In addition, we identify p97 is present in the RNF4-KAP1 interacting complex and the inhibition of p97 renders MCF7 breast cancer cells relatively more sensitive to DNA damage. Collectively, these findings suggest that combined effect of dynamic recruitment of RNF4 to KAP1 regulates the relative occupancy of 53BP1 and BRCA1 at DSB sites to direct DSB repair in a cell cycle-dependent manner. PMID- 26766494 TI - Tandem Allylboration-Prins Reaction for the Rapid Construction of Substituted Tetrahydropyrans: Application to the Total Synthesis of (-)-Clavosolide A. AB - Tetrahydropyrans are common motifs in natural products and have now been constructed with high stereocontrol through a three-component allylboration-Prins reaction sequence. This methodology has been applied to a concise (13 steps) and efficient (14 % overall yield) synthesis of the macrolide (-)-clavosolide A. The synthesis also features an early stage glycosidation reaction to introduce the xylose moiety and a lithiation-borylation reaction to attach the cyclopropyl containing side chain. PMID- 26766495 TI - Subnanometer Cobalt-Hydroxide-Anchored N-Doped Carbon Nanotube Forest for Bifunctional Oxygen Catalyst. AB - Electrochemical oxygen redox reactions are the crucial elements for energy conversion and storage including fuel cells and metal air batteries. Despite tremendous research efforts, developing high-efficient, low-cost, and durable bifunctional oxygen catalysts remains a major challenge. We report a new class of hybrid material consisting of subnanometer thick amorphous cobalt hydroxide anchored on NCNT as a durable ORR/OER bifunctional catalyst. Although amorphous cobalt species-based catalysts are known as good OER catalysts, hybridizing with NCNT successfully enhanced ORR activity by promoting a 4e reduction pathway. Abundant charge carriers in amorphous cobalt hydroxide are found to trigger the superior OER activity with high current density and low Tafel slope as low as 36 mV/decade. A remarkably high OER turnover frequency (TOF) of 2.3 s(-1) at an overpotential of 300 mV was obtained, one of the highest values reported so far. Moreover, the catalytic activity was maintained over 120 h of cycling. The unique subnanometer scale morphology of amorphous hydroxide cobalt species along with intimate cobalt species-NCNT interaction minimizes the deactivation of catalyst during prolonged repeated cycles. PMID- 26766496 TI - Emerging therapeutic targets and strategies in Crohn's disease. AB - Crohn's disease (CD) is an immune-mediated inflammatory bowel disease, in which inflammation is driven by a complex interaction between the microbiota, immune cells, genes and mediators. New mechanisms of action and several cytokines have been identified as factors involved in the inflammatory process in CD, and many new molecules have been developed to treat this complex disease. New agents have been developed that target leukocyte trafficking, block or adhesion molecules for example, as well as the development of antibodies against classic inflammatory cytokines or therapies directed against IL-12/23 and Janus kinases. The development of selective mechanisms of action and targeting of different cytokines or inflammatory mediators for each patient presents the biggest challenge for the future in CD therapy. Such agents are currently at different phases of development. We aim to review the current literature data on a targeted approach in CD, which could be promising alternative approach for CD patients in the near future. PMID- 26766497 TI - Effect of Modified Wheat Gluten on Boiling Resistance Capacity of Pork Meatballs. AB - The effect of the modified wheat gluten (MWG) extender, prepared by alcalase based hydrolysis and transglutaminase cross-linking, on meatballs was analyzed in this study. Here, we studied the effect of MWG addition on the boiling resistance capacity of pork meatballs (MB-MWG) at high temperature (100 degrees C) and increasing cooking time; meatballs with added soy protein isolates (MB-SPI) and raw wheat gluten (MB-WG) were used as references. The cooking loss, water-holding capacity (WHC), and textural properties of meatballs were investigated. The results revealed that MB-MWG showed lower cooking loss, which decreased by 49.16% compared to meatballs without added extenders when treated for 30 min. The WHC of MB-MWG significantly increased from 80.68% to 95.42%. The hardness, springiness, and chewiness (textural properties) of MB-MWG were also significantly increased by 97.05%, 6.68%, and 121.96%, respectively. The addition of MWG increased the cross-linking in meatballs during the cooking process, as indicated by the higher G'. SDS-PAGE indicated an obvious decrease in myosin heavy chain in MB-MWG cooked for 30 min at 100 degrees C, which was attributed to the interaction of myofibrillar proteins in pork meat with MWG. The nuclear magnetic resonance T2 relaxation time patterns indicated that MWG addition caused an increase in the bound water content, and decrease in the free water content, of meatballs. An analysis of the microstructures revealed that the MB-MWG formed the most regular and compact network. Therefore, MWG could be used as an ingredient to facilitate the processing of meat products. PMID- 26766498 TI - Evaluation of the dual retention properties of stationary phases based on silica hydride: Perfluorinated bonded material. AB - The synthesis of a new perfluorinated stationary phase based on silica hydride using a hydrosilation reaction was investigated. The material was characterized by elemental analysis, diffuse reflectance infrared Fourier transform spectroscopy and (13) C cross-polarization magic-angle spinning NMR spectroscopy. The retention properties of this new material were tested in the reversed-phase and normal-phase mode. Variable buffer strength experiments at two pH conditions for selected polar compounds were used to compare the new phase to hydrophilic interaction liquid chromatography retention. These results and previous data reported in the literature were used to postulate differences in the retention mechanism between hydrophilic interaction liquid chromatography and silica hydride-based stationary phases. PMID- 26766499 TI - Implicit Theories Of Personality: An Individual Differences Approach. AB - Twenty ratees were described on 20 bipolar personality trait adjectives by 51 raters in an own-control design in which both complete strangers and close friends were judged. The trait factor structures were extremely similar for both friend descriptions and stranger descriptions. Although the ratees were not distinguished in terms of acquaintanceship (friends vs, strangers), they were differentiated along physiognomic and personality dimensions reminiscent of Sheldon's typology. Individual differences among the raters were largely due to different fraternity membership and associated personality characteristics. A three mode factor analysis indicated an interaction among rater, ratee and trait dimensions. PMID- 26766500 TI - Generalizability Of Free-Recall Measurements. AB - This study investigated the generalizability of free-recall measurements. Subjects were 55 fifth-grade pupils, who completed ten trials of recalling familiar nouns plus two summary trials. The observation conditions included two list lengths (20 and 30 words), two rates of presentation (1 1/2 and 2 1/4 seconds per word), and two occasions (two weeks apart). Alpha factor analysis indicated that (1) the measurement procedures may be conceived of as derived from a single domain; (2) the homogeneity of the domain is estimated to be .64 for experienced subjects; (3) generalizability is greater with experienced subjects; and (4) the use of a summary trial is a simple way to increase the generalizability of a particular measurement procedure. The generalizability achieved by totaling performance over selected number of trials is estimated separately for naive and for experienced subjects. PMID- 26766501 TI - Comparisons Among Multidimensional Structures Of Interpersonal Relations. AB - Eighty-seven subjects made three kinds of judgments about each of 25 kinds of interpersonal relations (for example, "between supervisor and employee"): (1) direct ratings of similarity between pairs of relations; (2) repeated selections of subsets of relations having some characteristic in common; and (3) ratings of the relations on numerous bipolar scales, "INDSCAL" analyses of data from each of the judgmental tasks indicated that the conceptual space for the interpersonal relations is four-dimensional. The unrotated dimensions were interpreted as "cooperative and friendly vs. competitive and hostile," "equal vs. unequal," "socioemotional and informal vs. task-oriented and formal," and "intense vs. superficial." Different subgroups varied in terms of the weights they implicitly gave to these four dimensions. PMID- 26766502 TI - An Application Of Inferential Statistics To The Factorial Invariance Problem. AB - Attention has been drawn to the lack of standards for evaluating the degree of goodness of fit of patterns resulting from a principal components analysis of two data sets. An empirical sampling distribution of the statistic average trace (E'E), as E is obtained in the orthogonal Procrustes problem for various orders of A matrices was developed through a Monte Carlo approach. A method is presented which can be used as a guideline in determining whether factor is structures obtained from two data sets are congruent. PMID- 26766503 TI - Measuring The Cognitive Structures Of Pre-School Children: A Multidimensional Scaling Analysis Of Classification Performance And Similarity Estimation. AB - The purpose of the research was to measure the cognitive structures of five and six-year old children using a sorting task commonly employed by Piaget and also using a similarity estimation task. Multidimensional scaling techniques were used to analyze both sets of data. The similarity analysis revealed that 92% of the children had stable, organized cognitive structures for the experimental stimuli while an analysis of the sorting data (for the same students) indicated that only 30% of these children had stable structures. The study strongly suggests that the demand characteristics of sorting tasks make them relatively poor techniques for evaluating cognitive structures in children as compared with similarity tasks. PMID- 26766504 TI - The Invalidity Of Partitioned-U Tests In Canonical Correlation And Multivariate Analysis Of Variance. AB - The nearly universal practice of testing the statistical significance of individual discriminant functions and coefficients of canonical correlation by treating the residuals after successive terms of Wilks' lambda = U = -M Sigma[SUP9,SUBi=1]. In (1-r[SUBi,SUP2]) have been subtracted as if the individual components were independently chi-square distributed is shown to be logically and statistically invalid. Two suggestions for valid, but conservative, alternative procedures are considered. PMID- 26766505 TI - Queer Pedagogies Out of Place and Time: Redrawing the Boundaries of Youth, Sexual and Gender Difference, and Education. AB - For this contribution to the "Cartographies" section of the special issue on "Mapping Queer Bioethics," the author focuses on the concept of spatialized time as made material in the location of historical places, in particular as it relates to a reconsideration of approaches to Australian queer/LGBT youth education. Accordingly, the author employs historical maps as illustrative examples of spatialized time, reflecting on the relationships between historical knowledge and queer youth education. PMID- 26766506 TI - Electrically robust silver nanowire patterns transferrable onto various substrates. AB - We report a facile technique for patterning and transferring silver nanowires (AgNWs) onto various substrates. By employing only UV/O3 and vapor treatment of hexamethyldisilazane (HMDS), we are able to accurately manipulate the surface energy via alternating the terminal groups of a polydimethylsiloxane (PDMS) substrate, so as to assist selective formation and exfoliation of AgNW films. A simple UV/O3 treatment on PDMS enables uniform, well-defined, and highly conductive patterns of AgNWs after spin-coating. A vapor treatment of HMDS lowers the surface energy of the oxidized PDMS so that the patterned AgNWs embedded in an epoxy resin (EPR) are cleanly transferred from the PDMS to the target substrate. It is found that the AgNW-EPR composite on polyethylene glycol terephthalate (PET) exhibits remarkable durability under the bending test, tape test, ultrasonic treatment in water, and immersion of chemical solvents. In addition, we demonstrate that the AgNW-EPR composite work well as conductive patterns on the oxidized PDMS, polyvinyl alcohol (PVA), paper, and curved glass. The facile technique extends the applicability of AgNWs in the field of electronics, and it is potentially applicable to other nanomaterials. PMID- 26766507 TI - Impact of Bacterial and Human Genetic Variation on Staphylococcus aureus Infections. PMID- 26766508 TI - Functional transformation series and the evolutionary origin of novel forms: evidence from a remarkable termite defensive organ. AB - The origins of evolutionary novelties are often deeply puzzling. They are generally associated with new functions that were absent in ancestors. The new functional configuration should arise via intermediate stages without any loss of function or impediment to the whole organism during the transitions. Therefore, understanding of the functional configurations of transitional states can shed light on how novel forms arise. Here we infer the evolutionary origin of a highly specialized termite defensive organ "nasus" where different functions overlap in different structural configurations at intermediate evolutionary stages to ensure that each phase is functional. Soldiers of a nasutitermitine termite use reconfigured mandibular muscles to squirt a viscous secretion from a nozzle-like head projection (the nasus). This contrasts sharply with the primitive defensive strategy where mandibles are used to bite. MicroCT observations of soldiers of Nasutitermes takasagoensis and of species with the ancestral state (Hodotermopsis sjostedti, Embiratermes neotenicus) revealed three different yet fully functional configurations in the transition from ancestral to novel state: (i) elevated hydrostatic pressure induced by contraction of mandibular muscles when biting gently oozes secretion from a gland; (ii) direct pressure on an enlarged gland arises from expansion of the mandibular muscles when biting; (iii) squirting in a piston-like manner by an inflated gland enveloped by highly modified mandibular muscles. Even a structure as exotic as the nasus therefore appears to have evolved with no loss of function at any stage. Such a functional approach, holds much promise for understanding the evolutionary origin of seemingly preposterous novel forms. PMID- 26766509 TI - Not quite so blind: Semantic processing despite inattentional blindness. AB - We often fail to detect clearly visible, yet unexpected objects when our attention is otherwise engaged, a phenomenon widely known as inattentional blindness. The potentially devastating consequences and the mediators of such failures of awareness have been studied extensively. Surprisingly, however, hardly anything is known about whether and how we process the objects that go unnoticed during inattentional blindness. In 2 experiments, we demonstrate that the meaning of objects undetected due to inattentional blindness interferes with the classification of attended stimuli. Responses were significantly slower when the semantic content of an undetected stimulus contradicted that of the attended, to-be-judged object. We thus clarify the depth of the "blindness" caused by inattention, as we provide compelling evidence that failing to detect the unexpected does not preclude its processing, even at postperceptual stages. Despite inattentional blindness, our mind obviously still has access to something as refined as meaning. (PsycINFO Database Record PMID- 26766510 TI - Using task dynamics to quantify the affordances of throwing for long distance and accuracy. AB - In 2 experiments, the current study explored how affordances structure throwing for long distance and accuracy. In Experiment 1, 10 expert throwers (from baseball, softball, and cricket) threw regulation tennis balls to hit a vertically oriented 4 ft * 4 ft target placed at each of 9 locations (3 distances * 3 heights). We measured their release parameters (angle, speed, and height) and showed that they scaled their throws in response to changes in the target's location. We then simulated the projectile motion of the ball and identified a continuous subspace of release parameters that produce hits to each target location. Each subspace describes the affordance of our target to be hit by a tennis ball moving in a projectile motion to the relevant location. The simulated affordance spaces showed how the release parameter combinations required for hits changed with changes in the target location. The experts tracked these changes in their performance and were successful in hitting the targets. We next tested unusual (horizontal) targets that generated correspondingly different affordance subspaces to determine whether the experts would track the affordance to generate successful hits. Do the experts perceive the affordance? They do. In Experiment 2, 5 cricketers threw to hit either vertically or horizontally oriented targets and successfully hit both, exhibiting release parameters located within the requisite affordance subspaces. We advocate a task dynamical approach to the study of affordances as properties of objects and events in the context of tasks as the future of research in this area. (PsycINFO Database Record PMID- 26766511 TI - Poorer resolution for audiotactile than for audiovisual synchrony detection in cluttered displays. AB - The brain integrates signals from multiple modalities to provide a reliable estimate of environmental events. A temporally cluttered environment presents a challenge for sensory integration because of the risk of misbinding, yet it also provides scope for cross-modal binding to greatly enhance performance by highlighting multimodal events. We present a tactile search task in which fingertips received pulsed vibrations and participants identified which finger was stimulated in synchrony with an auditory signal. Results showed that performance for identifying the target finger was impaired when other fingers were stimulated, even though all fingers were stimulated sequentially. When the number of fingers vibrated was fixed, we found that both spatial and temporal factors constrained performance, because events occurring close to the target vibration in either space or time reduced accuracy. When tactile search was compared with visual search, we found overall performance was lower in touch than in vision, although the cost of reducing temporal separation between stimuli or increasing the presentation rate was similar for both target modalities. Audiotactile performance benefitted from increasing spatial separation between target and distractors, with a particularly strong benefit for locating the target on a different hand to the distractors, whereas the spatial manipulations did not affect audiovisual performance. The similar trends in performance for temporal manipulations across vision and touch suggest a common supramodal binding mechanism that, when combining audition and touch, is limited by the poor resolution of the underlying unisensory representation of touch in cluttered settings. (PsycINFO Database Record PMID- 26766512 TI - Dietary Strategies To Reduce the Bioaccessibility of Arsenic from Food Matrices. AB - The main route of exposure to arsenic (As) is the consumption of water and foods, in which the forms with greatest toxicity are inorganic As and dimethylarsinic acid, DMA(V). The objective of this study was to search for dietary components that reduce the bioaccessibility of As from food and water, in order to reduce the amount of As available for absorption. For this purpose, 35 compounds were assayed by use of a static in vitro model of gastrointestinal digestion. Sulfates of Fe(II) and Fe(III) reduced the solubility of inorganic As (86-99%) and DMA(V) in aqueous solution (40-66%). This reduction was also observed in rice (100%) and seaweed (60%). Aluminum, titanium, and tannic acid also reduced the bioaccessibility of As from food (42-70%). These data show that the use of dietary components may be a good strategy to reduce the entry of As into systemic circulation. PMID- 26766513 TI - Exploring the effects of landscape structure on aerosol optical depth (AOD) patterns using GIS and HJ-1B images. AB - A GIS approach and HJ-1B images were employed to determine the effect of landscape structure on aerosol optical depth (AOD) patterns. Landscape metrics, fractal analysis and contribution analysis were proposed to quantitatively illustrate the impact of land use on AOD patterns. The high correlation between the mean AOD and landscape metrics indicates that both the landscape composition and spatial structure affect the AOD pattern. Additionally, the fractal analysis demonstrated that the densities of built-up areas and bare land decreased from the high AOD centers to the outer boundary, but those of water and forest increased. These results reveal that the built-up area is the main positive contributor to air pollution, followed by bare land. Although bare land had a high AOD, it made a limited contribution to regional air pollution due to its small spatial extent. The contribution analysis further elucidated that built-up areas and bare land can increase air pollution more strongly in spring than in autumn, whereas forest and water have a completely opposite effect. Based on fractal and contribution analyses, the different effects of cropland are ascribed to the greater vegetation coverage from farming activity in spring than in autumn. The opposite effect of cropland on air pollution reveals that green coverage and human activity also influence AOD patterns. Given that serious concerns have been raised regarding the effects of built-up areas, bare land and agricultural air pollutant emissions, this study will add fundamental knowledge of the understanding of the key factors influencing urban air quality. PMID- 26766514 TI - Can cloud-based tools accelerate Alzheimer's disease drug discovery? PMID- 26766518 TI - Force Field Development for Lipid Membrane Simulations. AB - With the rapid development of computer power and wide availability of modelling software computer simulations of realistic models of lipid membranes, including their interactions with various molecular species, polypeptides and membrane proteins have become feasible for many research groups. The crucial issue of the reliability of such simulations is the quality of the force field, and many efforts, especially in the latest several years, have been devoted to parametrization and optimization of the force fields for biomembrane modelling. In this review, we give account of the recent development in this area, covering different classes of force fields, principles of the force field parametrization, comparison of the force fields, and their experimental validation. This article is part of a Special Issue entitled: Biosimulations edited by Ilpo Vattulainen and Tomasz Rog. PMID- 26766519 TI - Photoinduced Processes of Supramolecular Nanoarrays Composed of Porphyrin and Benzo[ghi]perylenetriimide Units through Triple Hydrogen Bonds with One Dimensional Columnar Phases. AB - One-dimensional supramolecular columnar phases composed of porphyrins (electron donor: D) and benzo[ghi]perylenetriimides (electron acceptor: A) through triple hydrogen bonds have been successfully constructed to perform sequential light harvesting and electron-transfer processes. A series of benzo[ghi]peryleneimide derivatives have been synthesized to examine the substituent effects such as imide and nitrile groups on the spectroscopic and electrochemical properties. Then, formation of the 1:1 supramolecular complex between zinc porphyrin and benzo[ghi]perylenetriimide derivatives through triple hydrogen bonds was confirmed by Job's plot of (1) H NMR titration. Next, the one-dimensional supramolecular nanoarrays were successfully prepared in a mixed solvent. X-ray diffraction (XRD) measurement suggested that these nanoarrays contained one dimensional columnar phases composed of stacked donor and acceptor layers. Finally, femtosecond transient absorption and electron spin resonance (ESR) measurements clearly indicated that photoinduced electron transfer occurred via the singlet excited states in the supramolecular columns. PMID- 26766520 TI - Age, sex and the association between skin test responses and IgE titres with asthma. AB - BACKGROUND: Skin prick tests (SPTs) and allergen-specific serum IgE (sIgE) measurements are the main diagnostic tools for confirming atopic sensitization. Results are usually reported as 'positive' or 'negative', using the same arbitrary cut-offs (SPT>3 mm, sIgE>0.35 kUA /l) across different ages and sexes. We investigated the influence of age and sex on the interpretation of allergy test in the context of childhood asthma. METHODS: In a population-based birth cohort (n = 1051), we ascertained the information on asthma/wheeze (validated questionnaires) and performed SPTs and sIgE measurement to inhalant allergens (dust mite, cat, dog) at follow-ups between ages three and 11 years. We investigated the association between quantitative sensitization (sum of SPT mean wheal diameters [MWD] and sIgE titres to the three allergens) and current wheeze and asthma across ages and sexes. RESULTS: We observed a significant association between the SPT MWD and sIgE titres and wheeze/asthma at most ages and for both sexes. However, the strength of this association was age- and sex-dependent. For SPTs, the strength of the association between MWD and asthma increased with increasing age; we observed the opposite pattern for sIgE titre. For any given SPT MWD/sIgE titre, boys were significantly more likely to express clinical symptoms, particularly in early life; this difference between males and females diminished with age and was no longer significant by age 11 years. CONCLUSIONS: Age and sex should be taken into account when interpreting the results of skin tests and sIgE measurement, and age- and sex-specific normative data are needed for these allergy tests. PMID- 26766521 TI - Determination of metoprolol enantiomers in human plasma and saliva samples utilizing microextraction by packed sorbent and liquid chromatography-tandem mass spectrometry. AB - A sensitive, accurate and reliable bioanalytical method for the enantioselective determination of metoprolol in plasma and saliva samples utilizing liquid chromatography-electrospray ionization tandem mass spectrometry was developed and validated. Human plasma and saliva samples were pretreated by microextraction by packed sorbent (MEPS) prior to analysis. A new MEPS syringe form with two inputs was used. Metoprolol enantiomers and internal standard pentycaine (IS) were eluted from MEPS sorbent using isopropanol after removal of matrix interferences using aliquots of 5% methanol in water. Complete separation of metoprolol enantiomers was achieved on a Cellulose-SB column (150 * 4.6 mm, 5 MUm) using isocratic elution with mobile phase 0.1% ammonium hydroxide in hexane-isopropanol (80:20, v/v) with a flow rate of 0.8 mL/min. A post-column solvent-assisted ionization was applied to enhance metoprolol ionization signal in positive mode monitoring (+ES) using 0.5% formic acid in isopropanol at a flow rate of 0.2 mL/min. The total chromatographic run time was 10 min for each injection. The detection of metoprolol in plasma and saliva samples was performed using triple quadrupole tandem mass spectrometer in +ES under the following mass transitions: m/z 268.08 -> 72.09 for metoprolol and m/z 303.3 -> 154.3 for IS. The linearity range was 2.5-500 ng/mL for both R- and S-metoprolol in plasma and saliva. The limits of detection and quantitation for both enantiomers were 0.5 and 2.5 ng/mL respectively, in both matrices (plasma and saliva). The intra- and inter-day precisions were presented in terms of RSD values for replicate analysis of quality control samples and were <5%; the accuracy of determinations varied from 96 to 99%. The method was able to determine the therapeutic levels of metoprolol enantiomers in both human plasma and saliva samples successfully, which can aid in therapeutic drug monitoring in clinical laboratories. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26766517 TI - Molecular dynamics simulations of biological membranes and membrane proteins using enhanced conformational sampling algorithms. AB - This paper reviews various enhanced conformational sampling methods and explicit/implicit solvent/membrane models, as well as their recent applications to the exploration of the structure and dynamics of membranes and membrane proteins. Molecular dynamics simulations have become an essential tool to investigate biological problems, and their success relies on proper molecular models together with efficient conformational sampling methods. The implicit representation of solvent/membrane environments is reasonable approximation to the explicit all-atom models, considering the balance between computational cost and simulation accuracy. Implicit models can be easily combined with replica exchange molecular dynamics methods to explore a wider conformational space of a protein. Other molecular models and enhanced conformational sampling methods are also briefly discussed. As application examples, we introduce recent simulation studies of glycophorin A, phospholamban, amyloid precursor protein, and mixed lipid bilayers and discuss the accuracy and efficiency of each simulation model and method. This article is part of a Special Issue entitled: Membrane Proteins edited by J.C. Gumbart and Sergei Noskov. PMID- 26766522 TI - Condom Use as a Function of Number of Coital Events in New Relationships. AB - STUDY OBJECTIVE: To assess condom use as a function of number of coital events in newly formed sexual relationships. METHODS: Participants who reported at least one new partner during the 12-week study interval (n = 115; ages 18-29 years; 48% women; 90% African American) completed weekly sexually transmitted infections testing and 3 times daily electronic diary collection assessing individual and partner-specific affect, daily activities, sexual behavior, and condom use. We analyzed event-level condom use percentage and participant-level behavior response effects. generalized additive mixed models were used to estimate condom use probability accounting for within-partner and within-participant correlations via random effects. RESULTS: The average condom use probability at the first coital event in new relationships was 55% for men and 36% for women. Analyses showed that smooth shapes of estimated condom use probabilities were similar for both sexes and were fitted using generalized additive mixed models. Relatively higher condom use percentage was followed by a sharp decline during the first 9 coital events decreasing to 16% for men and 8% for women. More rapid decline in condom use among women was highly associated with higher levels of relationship and sexual satisfaction. CONCLUSIONS: The likelihood of condom use declines sharply for both men and women after the early accrual experience with a partner. Relationship and sexual satisfaction also influence declines in condom use, especially among women. PMID- 26766523 TI - A One-Size-Fits-All HIV Prevention and Education Approach?: Interpreting Divergent HIV Risk Perceptions Between African American and East African Immigrant Women in Washington, DC Using the Proximate-Determinants Conceptual Framework. AB - BACKGROUND: To date, there are very few comparative US studies and none in DC that distinguish between US-born and foreign-born black women to examine and compare their perceptions of HIV risk. This qualitative study, therefore, analyzes African American and East African women's perceptions of HIV risk in the Washington DC Metropolitan area, which has the highest AIDS rate in the United States. METHODS: Forty in-depth, semistructured interviews and 10 cognitive interviews were conducted among a sample of 25 African American women and 25 East African born women between October 2012 and March 2013 to examine perceptions regarding HIV risk. The in-depth semistructured interviews were preceded by the cognitive interviews and accompanying survey. Study protocol was reviewed and approved by the American University Institutional Review Board. RESULTS: Adopting Boerma and Weir's Proximate Determinants conceptual framework to interpret the data, the results of the study demonstrate that African American and East African immigrant women have divergent perceptions of HIV risk. Although African American women ascribe HIV risk to individual-level behaviors and choices such as unprotected sex, East African women attribute HIV risk to conditions of poverty and survival. CONCLUSIONS: Study findings suggest that addressing HIV prevention and education among black women in DC will require distinct and targeted strategies that are culturally and community-centered to resonate with these different audiences. PMID- 26766525 TI - Measures of Attitudes Toward and Communication about Condom Use: Their Relationships With Sexual Risk Behavior Among Young Black Men Who Have Sex With Men. AB - OBJECTIVE: The aim of this study was to construct and test measures of psychosocial mediators that could be used in intervention studies seeking to promote safer sex behavior among young black men who have sex with men (YBMSM). METHODS: A total of 400 YBMSM, ages 18 to 29 years, were recruited from a clinic for sexually transmitted infection in the southern United States. All men had engaged in penile-anal sex with a man as a "top" in the past 6 months. The men completed an audio-computer-assisted self-interview and provided specimens used for nucleic acid amplification testing to detect Chlamydia and gonorrhea. Four measures were constructed and tested for criterion validity (Safer Sex Communication, Condom Turn-Offs, Condom Pleasure Scale, and a single item assessing frequency of condom use discussions before sexual arousal). RESULTS: With the exception of Safer Sex Communication, all of the measures showed criterion validity for both unprotected anal insertive and unprotected anal receptive sex. With the exception of the Condom Turn-Offs, the 3 other measures were supported by criterion validity for oral sex. Both the Condom Turn-Offs and Condom Pleasure Scale were significantly related to whether or not the men reported multiple partners as a top, but only the Condom Pleasure Scale was associated with reports of multiple partners as a "bottom." Only the Condom Turn Offs Scale was positively associated with having been diagnosed with either Chlamydia or gonorrhea. CONCLUSION: Findings provide 3 brief scales and a single item that can be used in intervention studies targeting YBMSM. Perceptions about condoms being a turnoff and about condoms enhancing pleasure showed strong association with sexual risk behaviors. PMID- 26766524 TI - Estimating the Prevalence and Predictors of Incorrect Condom Use Among Sexually Active Adults in Kenya: Results From a Nationally Representative Survey. AB - BACKGROUND: Condom use continues to be an important primary prevention tool to reduce the acquisition and transmission of HIV and other sexually transmitted infections. However, incorrect use of condoms can reduce their effectiveness. METHODS: Using data from a 2012 nationally representative cross-sectional household survey conducted in Kenya, we analyzed a subpopulation of sexually active adults and estimated the percent that used condoms incorrectly during sex, and the type of condom errors. We used multivariable logistic regression to determine variables to be independently associated with incorrect condom use. RESULTS: Among 13,720 adolescents and adults, 8014 were sexually active in the previous 3 months (60.3%; 95% confidence interval [CI], 59.0-61.7). Among those who used a condom with a sex partner, 20% (95% CI, 17.4-22.6) experienced at least one instance of incorrect condom use in the previous 3 months. Of incorrect condom users, condom breakage or leakage was the most common error (52%; 95% CI, 44.5-59.6). Factors found to be associated with incorrect condom use were multiple sexual partnerships in the past 12 months (2 partners: adjusted odds ratio [aOR], 1.5; 95% CI, 1.0-2.0; P = 0.03; >=3: aOR, 2.3; 95% CI, 1.5-3.5; P < 0.01) and reporting symptoms of a sexually transmitted infection (aOR, 2.8; 95% CI, 1.8-4.3; P < 0.01). CONCLUSIONS: Incorrect condom use is frequent among sexually active Kenyans and this may translate into substantial HIV transmission. Further understanding of the dynamics of condom use and misuse, in the broader context of other prevention strategies, will aid program planners in the delivery of appropriate interventions aimed at limiting such errors. PMID- 26766526 TI - Is Group Sex a Higher-Risk Setting for HIV and Other Sexually Transmitted Infections Compared With Dyadic Sex Among Men Who Have Sex With Men? AB - BACKGROUND: Group sex has been suggested as a potential high-risk setting for HIV and other sexually transmitted infections (STIs) among men who have sex with men (MSM). We investigated whether group sex is associated with lower condom use during anal sex and higher proportions of STIs compared with dyadic sex among HIV negative MSM between 2009 and 2012. METHODS: Cross-sectional data from 7 data waves of the Amsterdam Cohort Studies were used. The sample consisted of 465 MSM who either reported both group and dyadic sex (at n = 706 visits) or dyadic sex only (at n = 1339 visits) in the preceding 6 months. Logistic regression with generalized estimating equations was used to investigate the association between sexual setting (group vs. dyadic sex), condomless anal sex, and STI. RESULTS: Group sex was reported at 35% (706/2045) of visits. Condomless sex was more often reported during dyadic than group sex (odds ratio, 3.64 95% confidence interval, 2.57-5.16). Men who had group sex were more likely diagnosed as having gonorrhea compared with men with dyadic sex (odds ratio, 1.71; 95% confidence interval, 1.08-2.97), but this effect was not retained in the multivariate model. CONCLUSIONS: Results demonstrate within-person differences in sexual behavior during group and dyadic sex among MSM. Men were more likely to use condoms during group sex than during dyadic sex. Thus, for some, group sex may not necessarily be risky for HIV infection compared with dyadic sex. However, group sex may be a higher-risk setting for acquiring STIs other than HIV, such as gonorrhea. Group sex encounters should be recognized as distinct sexual settings with specific risk characteristics that need to be addressed accordingly. PMID- 26766528 TI - A Luetic Cauda Equina Meningoradiculitis Mimicking a Central Nervous System Lymphoma. AB - We report a case of peculiar neurosyphilis, initially misinterpreted as a lymphoproliferative disorder. This is also the first report to evaluate the utility of positron emission tomography-computed tomography in spinal cord syphilis. Cauda equina radiculitis is a rare manifestation of neurosyphilis whose diagnosis can be supported by the typical syphilitic exanthema. PMID- 26766527 TI - Patterns of Extragenital Chlamydia and Gonorrhea in Women and Men Who Have Sex With Men Reporting a History of Receptive Anal Intercourse. AB - BACKGROUND: Screening for Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (GC) in men who have sex with men is risk based. Despite high frequencies of oral and receptive anal intercourse (RAI) among women, extragenital screening is not recommended. METHODS: Women (n = 175) and men who have sex with men (n = 224) primarily recruited from a sexually transmitted infection clinic reporting a lifetime history of RAI completed a structured questionnaire and clinician collected swab samples from the rectum, pharynx, vagina (women), and urine (men). CT and GC were detected using 2 commercial nucleic acid amplification tests (Aptima Combo 2; Hologic, Inc, Bedford, MA; Xpert CT/NG, Cepheid Innovation, Sunnyvale, CA). RESULTS: The median age of the population was 26 years, 62% were white, and 88% were enrolled from a sexually transmitted disease clinic. Men were more likely than women to have GC (22.8% vs. 3.4%) and CT (21.9% vs. 12.6%). In men versus women, GC was detected in 16.5% versus 2.3% of pharyngeal swabs, 11.6% versus 2.3% of rectal swabs, and 5.4% versus 2.9% of urine samples or vaginal swabs. C. trachomatis was detected in 2.2% versus 1.7% of pharyngeal swabs, 17.4% versus 11.4% of rectal swabs, and 4.5% versus 10.3% for urogenital sites in men versus women. Overall 79.6% of CT and 76.5% of GC in men and 18.2% of CT and 16.7% of GC in women were detected only in the pharynx or rectum. CONCLUSION: Reliance on urogenital screening alone misses most of GC and CT in men and more than 15% of infections in women reporting RAI. PMID- 26766529 TI - The Value of Experiential Sexually Transmitted Disease Clinical Training in the Digital Age. AB - BACKGROUND: The translation of evidence-based guidelines for sexually transmitted disease (STD) care into clinical practice is crucial for the prevention and control of STDs. METHODS: Participants in a hands-on, multifaceted, small-group STD Clinical Intensive Course from 2006 to 2013 were asked to complete a survey regarding course content and value compared with other continuing education courses. Survey respondents with demographic and professional information were compared with all other course participants. chi Statistics were used to test for differences in proportions; the Cochran-Armitage trend test was used to evaluate for trends in response rate by year of training. RESULTS: Of 113 respondents (35.9% response rate), 92.9% felt that clinical knowledge stayed longer, 84.1% changed clinical practice more, and 90.3% recommended the course more, compared with other continuing education programs in which they had participated previously. Respondents' average suggested registration fee should the course no longer be free was $188.90. Physician assistants and advanced practice nurses were overrepresented among respondents (69.4% vs. 58.1%, P = 0.04); more recent course participants were more likely to respond (P < 0.01). CONCLUSIONS: These findings suggest that this STD experiential clinical training program is still relevant to participants in the digital age and is valued more highly than other continuing education experiences. A significant disconnect was identified between what participants are willing/able to pay versus actual course costs, indicating that cost is likely to become a barrier to participation should the course no longer be free. PMID- 26766530 TI - Morphologic Characteristics of Choroid in the Major Choroidal Thickening Diseases, Studied by Optical Coherence Tomography. AB - We investigated morphologic features of choroid in the choroidal thickening diseases, including central serous chorioretinopathy (CSC), polypoidal choroidal vasculopathy (PCV), and Vogt-Koyanagi-Harada disease (VKH), by a novel tomographic classification system of the choroid. This cross-sectional study involved 30 patients with active CSC, 30 patients with active PCV, and 27 patients with active VKH, and 30 normal controls. Utilizing enhanced depth imaging optical coherence tomography, we classified the morphology of the choroid into five categories: 1) Standard (S), 2) Dilated outer layer and Attenuated inner layer (DA), 3) Darkened (D), 4) Marbled (M), and 5) Pauci-Vascular (PV) types. Additional tomographic characteristics of the choroid such as choroidal vascular dilation, convolution, scleral invisibility, and choroidal hyper- or hypo-thickening were identified as well. The distribution of five choroidal tomographic morphology and additional tomographic characteristics in each group were analyzed. The DA type was observed in the CSC group more frequently than in the normal control group (53.3% vs 3.3%, P < 0.001). Additional tomographic characteristics, such as choroidal vascular dilation (76.7%), and choroidal hyper thickening (36.7%), were more prevalent in the CSC group than in the control group. The PCV group showed higher prevalence of DA type (33.3% vs. 3.3%, P = 0.006) than the control group. The VKH group showed a significantly higher frequency of the D type (63.0%), convolution (40.7%), and scleral invisibility (70.4%) than controls (0% for all three findings). In conclusion, CSC and PCV shared common morphologic characteristics of choroid, including dilated outer vascular layer and focally attenuated innermost layer. Dense hypo-reflectivity and convolution of choroid were the specific tomographic markers for acute VKH. A new tomographic classification system of choroid may provide discrimination ability and insight into major pachychoroidopathies. PMID- 26766533 TI - Perfluorocarbon attenuates inflammatory cytokines, oxidative stress and histopathologic changes in paraquat-induced acute lung injury in rats. AB - The effects of perfluorocarbon (PFC) on paraquat (PQ) induced acute lung injury (ALI) was evaluated among rats. Twenty four Wistar rats were divided into 4 groups: control group injected by saline physiologic 0.9%, PFC group injected by Perfluorocarbon, PQ group injected by PQ and PQ+PFC group injected by PFC one hour after receiving paraquat. Bronchoalveular fluid content, inflammatory cytokines, oxidative and histopathologic changes were measured after 72 h. The levels of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha) and transforming growth factor-beta1(TGF-beta1) in the PQ group were increased compared to either control or PFC groups, but their levels decreased in PQ+PFC group significantly (p<0.05). Also, histopathologic evaluation revealed an increase in malondialdehyde (MDA) and hydroxyproline (HP) in the PQ group but a decrease in PQ+PFC group significantly (p<0.01). PFC emulsion by its anti inflammatory, anti-oxidative and anti-fibrotic properties can reduce the inflammatory and fibrotic alterations, pulmonary oedema, and pulmonary histopathologic changes created by PQ. PMID- 26766534 TI - Effects of riverine suspended particulate matter on the post-dredging increase in internal phosphorus loading across the sediment-water interface. AB - Dredging is frequently used in the river mouths of eutrophic lakes to reduce internal phosphorus (P) loading from the sediment. However, the accumulation of P adsorbed suspended particulate matter (SPM) from the inflowing rivers negatively affects the post-dredging sediment-water interface and ultimately increases internal P loading. Here, a 360-d experiment was carried out to investigate the influence of riverine SPM on the efficacy of dredging in reducing internal P loading. SPM was added to dredged and undredged sediments collected from the confluence area of Lake Chaohu. Several parameters related to internal P loading, including oxygen profile, soluble reactive P, and ferrous iron across the sediment-water interface, organic matter, alkaline phosphatase activity, and P fractions, were measured throughout the experimental period. The results showed that the P content (especially mobile P) in the sediment increased to the pre dredging level with the accumulation of SPM in the dredged sediment. In addition, the P flux across the sediment-water interface increased with the accumulation of SPM. Several characteristics of SPM, including high organic matter content, mobile P, high activity of alkaline phosphatase, and high biological activity, were considered correlated with the post-dredging increase in internal P loading. Overall, this study showed that the heavily contaminated riverine SPM regulates the long-term efficacy of dredging as a nutrient management option in the confluence area. Management is needed to avoid or reduce this phenomenon during dredging projects of this nature. PMID- 26766535 TI - Semen phthalate metabolites, semen quality parameters and serum reproductive hormones: A cross-sectional study in China. AB - Exposure to phthalates has been found to have adverse effects on male reproductive function in animals. However, the findings from human studies are inconsistent. Here we examined the associations of phthalate exposure with semen quality and reproductive hormones in a Chinese population using phthalate metabolite concentrations measured in semen as biomarkers. Semen (n = 687) and blood samples (n = 342) were collected from the male partners of sub-fertile couples who presented to the Reproductive Center of Tongji Hospital in Wuhan, China. Semen quality parameters and serum reproductive hormone levels were determined. Semen concentrations of 8 phthalate metabolites were assessed using high-performance liquid chromatography and tandem mass spectrometry. Associations of the semen phthalate metabolites with semen quality parameters and serum reproductive hormones were assessed using confounder-adjusted linear and logistic regression models. Semen phthalate metabolites were significantly associated with decreases in semen volume [mono-n-butyl phthalate (MBP), mono-(2-ethylhexyl) phthalate (MEHP), mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), mono(2-ethyl-5 oxohexyl) phthalate (MEOHP)], sperm curvilinear velocity [monobenzyl phthalate (MBzP), MEHP, the percentage of di-(2-ethylhexyl)-phthalate metabolites excreted as MEHP (%MEHP)], and straight-line velocity (MBzP, MEHP, %MEHP), and also associated with an increased percentage of abnormal heads and tails (MBzP) (all p for trend <0.05). These associations remained suggestive or significant after adjustment for multiple testing. There were no significant associations between semen phthalate metabolites and serum reproductive hormones. Our findings suggest that environmental exposure to phthalates may impair human semen quality. PMID- 26766536 TI - Energetic endpoints provide early indicators of life history effects in a freshwater gastropod exposed to the fungicide, pyraclostrobin. AB - Organismal energetics provide important insights into the effects of environmental toxicants. We aimed to determine the effects of pyraclostrobin on Lymnaea stagnalis by examining energy allocation patterns and life history traits. Juvenile snails exposed to pyraclostrobin decreased feeding rate and increased apparent avoidance behaviors at environmentally relevant concentrations. In adults, we found that sublethal concentrations of pyraclostrobin did not affect reproductive output, however, there were significant effects on developmental endpoints with longer time to hatch and decreased hatching success in pyraclostrobin-exposed egg masses. Further, there were apparent differences in developmental effects depending on whether mothers were also exposed to pyraclostrobin suggesting this chemical can exert intergenerational effects. Pyraclostrobin also affected protein and carbohydrate content of eggs in mothers that were exposed to pyraclostrobin. Significant effects on macronutrient content of eggs occurred at lower concentrations than effects on gross endpoints such as hatching success and time to hatch suggesting potential value for these endpoints as early indicators of ecologically relevant stress. These results provide important insight into the effects of a common fungicide on important endpoints for organismal energetics and life history. PMID- 26766538 TI - Should acute myeloid leukemia patients with actionable targets be offered investigational treatment after failing one cycle of standard induction therapy? AB - PURPOSE OF REVIEW: Therapeutic failure in acute myeloid leukemia remains common. It may be advantageous to identify patients with suboptimal treatment responses early as they may benefit from timely care strategy changes. Here, responses portending failure of standard induction therapy are reviewed and therapeutic options examined, including use of investigational, targeted agents for suitable patients. RECENT FINDINGS: Patients entering complete remission without minimal residual disease early, that is, with one cycle of standard induction chemotherapy, have a lower relapse risk and live longer than other similarly treated patients, supporting the proposition of early complete remission without minimal residual disease as a criterion for induction therapy success. Investigational small molecule drugs are appealing for patients who fail standard therapies, but complete remission rates as a single agent are typically modest. SUMMARY: The relative value of different treatment strategies if a first standard induction therapy cycle fails to produce complete remission is unknown. However, retreatment with the same therapy often leads to complete remission and provides a benchmark against which other approaches should be compared. Addition of investigational small molecule drugs to standard reinduction therapy in patients with actionable targets could offer an attractive therapeutic strategy in this situation that might improve outcomes and facilitate clinical drug testing. PMID- 26766537 TI - Red cell receptors as access points for malaria infection. AB - PURPOSE OF REVIEW: Red cell receptors provide unique entry points for Plasmodium parasites to initiate blood-stage malaria infection. Parasites encode distinct ligands that bind specifically to both highly abundant and low-copy receptors. Recent advances in the understanding of molecular and structural mechanisms of these interactions provide fundamental insights into receptor-ligand biology and molecular targets for intervention. RECENT FINDINGS: The review focuses on the requirements for known interactions, insight derived from complex structures, and mechanisms of receptor/ligand engagement. Further, novel roles for established red cell membrane proteins, parasite ligands and associated interacting partners have recently been established in red cell invasion. SUMMARY: The new knowledge underlines the intricacies involved in invasion by a eukaryotic parasite into a eukaryotic host cell demonstrated by expanded parasite ligand families, redundancy in red cell receptor engagement, multitiered temporal binding, and the breadth of receptors engaged. PMID- 26766539 TI - Revisiting maintenance therapy in acute myeloid leukemia with novel agents. AB - PURPOSE OF REVIEW: High relapse rates and therapy-related toxicity contribute to suboptimal outcomes in acute myeloid leukemia (AML) patients attaining a remission following initial induction therapy and postallogeneic stem cell transplant. Maintenance therapy holds the potential for a prolonged remission interval analogue to that seen in other hematologic malignancies. Herein we present and analyze the current data in the field. RECENT FINDINGS: Maintenance treatment approaches utilizing conventional chemotherapy, immunomodulation, hypomethylating agents, targeted small molecules, and tyrosine kinase inhibitors have been explored in this setting. The published data have not yet demonstrated convincing efficacy to merit establishment of this approach as standard of care. The role of hypomethylating agents and novel tyrosine kinase inhibitors is being actively studied in phase II/III trials and may improve patient outcome. SUMMARY: Maintenance therapy has not been shown to improve patient outcome in AML. The results of ongoing and future studies with novel agents may facilitate incorporation of this approach to standard care of AML. PMID- 26766540 TI - High temperature oxidation of iron-iron oxide core-shell nanowires composed of iron nanoparticles. AB - This work describes an oxidation process of iron-iron oxide core-shell nanowires at temperatures between 100 degrees C and 800 degrees C. The studied nanomaterial was synthesized through a simple chemical reduction of iron trichloride in an external magnetic field under a constant flow of argon. The electron microscopy investigations allowed determining that the as-prepared nanowires were composed of self-assembled iron nanoparticles which were covered by a 3 nm thick oxide shell and separated from each other by a thin interface layer. Both these layers exhibited an amorphous or highly-disordered character which was traced by means of transmission electron microscopy and Mossbauer spectroscopy. The thermal oxidation was carried out under a constant flow of argon which contained the traces of oxygen. The first stage of process was related to slow transformations of amorphous Fe and amorphous iron oxides into crystalline phases and disappearance of interfaces between iron nanoparticles forming the studied nanomaterial (range: 25-300 degrees C). After that, the crystalline iron core and iron oxide shell became oxidized and signals for different compositions of iron oxide sheath were observed (range: 300-800 degrees C) using X-ray diffraction, Raman spectroscopy and Mossbauer spectroscopy. According to the thermal gravimetric analysis, the nanowires heated up to 800 degrees C under argon atmosphere gained 37% of mass with respect to their initial weight. The structure of the studied nanomaterial oxidized at 800 degrees C was mainly composed of alpha-Fe2O3 (~ 93%). Moreover, iron nanowires treated above 600 degrees C lost their wire-like shape due to their shrinkage and collapse caused by the void coalescence. PMID- 26766541 TI - Apixaban versus Warfarin for the Prevention of Periprocedural Cerebral Thromboembolism in Atrial Fibrillation Ablation: Multicenter Prospective Randomized Study. AB - INTRODUCTION: Stroke can be a life-threatening complication of atrial fibrillation (AF) catheter ablation. Uninterrupted warfarin treatment contributes to minimizing the risk of stroke complications. METHODS AND RESULTS: This was a prospective, open-label, randomized, multicenter study assessing the safety and efficacy of apixaban for the prevention of cerebral thromboembolism complicating AF catheter ablation. Two hundred patients with drug-resistant AF were equally assigned to take either apixaban (5 mg or 2.5 mg twice daily) or warfarin (target international normalized ratio, 2-3) for at least 1 month before AF ablation. Neither drug regimen was interrupted throughout the operative period. Diffusion weighted magnetic resonance imaging was performed for all patients to detect silent cerebral infarction (SCI) after the ablation. Primary outcomes were defined as the occurrence of stroke, transient ischemic attack, SCI, or major bleeding that required intervention. The secondary outcome was minor bleeding. The groups did not statistically differ in patients' backgrounds or procedural parameters. During AF ablation, the apixaban group required administration of more heparin to maintain an activated clotting time > 300 seconds than the warfarin group (apixaban, 14,000 +/- 4,000 units; warfarin, 9,000 +/- 3,000 units). Three primary outcome events occurred in each group (apixaban, 2 SCI and 1 major bleed; warfarin, 3 SCI, P = 1.00), and 3 and 4 secondary outcome events occurred in the apixaban and warfarin groups (P = 0.70), respectively. CONCLUSION: Apixaban has similar safety and effectiveness to warfarin for the prevention of cerebral thromboembolism during the periprocedural period of AF ablation. PMID- 26766542 TI - Higher stimulus control is associated with less cigarette intake in daily smokers. AB - It is well established that environmental stimuli influence smoking in light, and to a lesser degree, heavy smokers. A 2-factor model of dependence suggests that the influence of stimulus control is masked among heavier smokers who primarily smoke for nicotine maintenance. The current study aimed to assess the influence of stimulus control across a range of moderate to heavy daily smokers. Furthermore, as local tobacco control policies may change the role of stimulus control, the study aimed to replicate previous U.S. findings on stimulus control in an Australian setting marked by strong tobacco control policies. In 2 Ecological Momentary Assessment studies, 420 participants monitored antecedents of smoking and nonsmoking situations. In a set of idiographic logistic regression analyses, situational antecedents were used to predict smoking occasions within each individual's data. Linear regression analysis was used to test for the association between stimulus control and smoking rate, and to test for differences between the 2 samples. Daily smokers' smoking was under considerable stimulus control, which was weaker at higher smoking rates. Overall, there was greater stimulus control in the Australian sample. Daily smokers also experience a degree of stimulus control, which is less influential in heavier smokers. PMID- 26766543 TI - Association of comorbid psychopathology with the duration of cannabis use disorders. AB - Risk factors for the development of cannabis use disorders (CUDs) have been well researched. Comparatively little is known, however, about factors associated with the persistence of CUDs over time. This research explored whether the temporal sequencing of comorbid psychiatric disorders in relation to the onset of the index CUD episode were associated with the length of this episode. Four comprehensive diagnostic assessments were conducted between ages 16 and 30 with a large and regionally representative community sample (n = 816), among which 173 persons were diagnosed with a lifetime CUD. In separate unadjusted analyses, any internalizing disorder and any mood disorder with onset prior to that of the index CUD episode were each significantly and negatively associated with CUD duration. These effects, however, were reduced to trend level in adjusted analyses that controlled for putative confounders. Following the onset of the index CUD episode, the subsequent occurrence of any Axis I disorder, internalizing disorder, externalizing disorder, or other substance use disorder during the index CUD episode was significantly and positively associated with the duration of that episode in both unadjusted and adjusted analyses. These findings collectively suggest that the presence of internalizing-spectrum disorders prior to the onset of the index CUD episode affords some modest protection against protracted episodes, whereas the emergence of broad-spectrum psychopathology within the index CUD episode, most notably noncannabis substance use disorders, is associated with greater disorder persistence. The relevance of these findings for various motivational models of cannabis addiction is discussed. PMID- 26766545 TI - France: Health System Review. AB - This analysis of the French health system reviews recent developments in organization and governance, health financing, health care provision, health reforms and health system performance. The French population has a good level of health, with the second highest life expectancy in the world for women. It has a high level of choice of providers, and a high level of satisfaction with the health system. However, unhealthy habits such as smoking and harmful alcohol consumption remain significant causes of avoidable mortality. Combined with the significant burden of chronic diseases, this has underscored the need for prevention and integration of services, although these have not historically been strengths of the French system. Although the French health care system is a social insurance system, it has historically had a stronger role for the state than other Bismarckian social insurance systems. Public financing of health care expenditure is among the highest in Europe and out-of-pocket spending among the lowest. Public insurance is compulsory and covers the resident population; it is financed by employee and employer contributions as well as increasingly through taxation. Complementary insurance plays a significant role in ensuring equity in access. Provision is mixed; providers of outpatient care are largely private, and hospital beds are predominantly public or private non-profit-making. Despite health outcomes being among the best in the European Union, social and geographical health inequities remain. Inequality in the distribution of health care professionals is a considerable barrier to equity. The rising cost of health care and the increasing demand for long-term care are also of concern. Reforms are ongoing to address these issues, while striving for equity in financial access; a long-term care reform including public coverage of long-term care is still pending. PMID- 26766546 TI - Fetal health locus of control: Scale properties and applications in preconception health programs. AB - Preconception health programs have resulted in improved health behaviors among participants and have shown promise in reducing adverse birth outcomes. However, the role of health beliefs in preconception health program outcomes has been overlooked but warrants attention due to reported positive associations between women's views of control over fetal health and health behavior in pregnancy. Towards an ultimate aim of improving preconception health program reach and effectiveness, we examined properties of a fetal health locus of control (FHLC; Labs & Wurtele, 1986) measure in nulliparous, childbearing aged university women and men. Students (n=1467) completed an online survey that included the FHLC subscales maternal, powerful others', and chance control over fetal health. Factor analyses and correlations with related scales supported the soundness of FHLC constructs in both women and men. All participants rated maternal control in fetal health nearly twice as highly as powerful others' and chance. We therefore recommend that FHLC be integrated into preconception health program evaluation as personal agency in fetal health likely has an important role in women's and men's preconception health behavior and health behavior change. PMID- 26766544 TI - Mutation Detection in Patients with Retinal Dystrophies Using Targeted Next Generation Sequencing. AB - Retinal dystrophies (RD) constitute a group of blinding diseases that are characterized by clinical variability and pronounced genetic heterogeneity. The different nonsyndromic and syndromic forms of RD can be attributed to mutations in more than 200 genes. Consequently, next generation sequencing (NGS) technologies are among the most promising approaches to identify mutations in RD. We screened a large cohort of patients comprising 89 independent cases and families with various subforms of RD applying different NGS platforms. While mutation screening in 50 cases was performed using a RD gene capture panel, 47 cases were analyzed using whole exome sequencing. One family was analyzed using whole genome sequencing. A detection rate of 61% was achieved including mutations in 34 known and two novel RD genes. A total of 69 distinct mutations were identified, including 39 novel mutations. Notably, genetic findings in several families were not consistent with the initial clinical diagnosis. Clinical reassessment resulted in refinement of the clinical diagnosis in some of these families and confirmed the broad clinical spectrum associated with mutations in RD genes. PMID- 26766547 TI - Can ketones compensate for deteriorating brain glucose uptake during aging? Implications for the risk and treatment of Alzheimer's disease. AB - Brain glucose uptake is impaired in Alzheimer's disease (AD). A key question is whether cognitive decline can be delayed if this brain energy defect is at least partly corrected or bypassed early in the disease. The principal ketones (also called ketone bodies), beta-hydroxybutyrate and acetoacetate, are the brain's main physiological alternative fuel to glucose. Three studies in mild-to-moderate AD have shown that, unlike with glucose, brain ketone uptake is not different from that in healthy age-matched controls. Published clinical trials demonstrate that increasing ketone availability to the brain via moderate nutritional ketosis has a modest beneficial effect on cognitive outcomes in mild-to-moderate AD and in mild cognitive impairment. Nutritional ketosis can be safely achieved by a high-fat ketogenic diet, by supplements providing 20-70 g/day of medium-chain triglycerides containing the eight- and ten-carbon fatty acids octanoate and decanoate, or by ketone esters. Given the acute dependence of the brain on its energy supply, it seems reasonable that the development of therapeutic strategies aimed at AD mandates consideration of how the underlying problem of deteriorating brain fuel supply can be corrected or delayed. PMID- 26766549 TI - Reading in Autism Spectrum Disorders: A Literature Review. AB - OBJECTIVE: To review what the literature says about reading abilities of children on the autism spectrum (autism spectrum disorders, ASD) as well as to assess the results of intervention proposals. The broad ASD diagnosis used in the last decades and the resulting changes in the prevalence of these disorders have led to a relevant increase in the number of children diagnosed with ASD in the school system. The purpose of this review is to identify the different profiles of reading abilities shown by children with ASD described in the recent literature and the results of reported intervention methods. METHODS: A review of the literature was conducted in the Web of Sciences and PubMed databases with the keywords 'autism' AND 'read*' and the filter 2010-2015. All articles published in the last 5 years focusing on description of and intervention for reading abilities in individuals with ASD were included. Review articles were excluded. RESULTS: The selected 58 articles were divided into those that described reading abilities in individuals with ASD (n = 27) and those that reported intervention procedures for reading development (n = 31). CONCLUSIONS: Direct comparisons and associations were prevented due to different inclusion criteria and lack of detailed information about intervention processes. We propose tentative conclusions that should be confirmed by further studies. PMID- 26766548 TI - Population Genetics of Plasmodium vivax in the Peruvian Amazon. AB - BACKGROUND: Characterizing the parasite dynamics and population structure provides useful information to understand the dynamic of transmission and to better target control interventions. Despite considerable efforts for its control, vivax malaria remains a major health problem in Peru. In this study, we have explored the population genetics of Plasmodium vivax isolates from Iquitos, the main city in the Peruvian Amazon, and 25 neighbouring peri-urban as well as rural villages along the Iquitos-Nauta Road. METHODOLOGY/ RESULTS: From April to December 2008, 292 P. vivax isolates were collected and successfully genotyped using 14 neutral microsatellites. Analysis of the molecular data revealed a similar proportion of monoclonal and polyclonal infections in urban areas, while in rural areas monoclonal infections were predominant (p = 0.002). Multiplicity of infection was higher in urban (MOI = 1.5-2) compared to rural areas (MOI = 1) (p = 0.003). The level of genetic diversity was similar in all areas (He = 0.66 0.76, p = 0.32) though genetic differentiation between areas was substantial (PHIPT = 0.17, p<0.0001). Principal coordinate analysis showed a marked differentiation between parasites from urban and rural areas. Linkage disequilibrium was detected in all the areas ([Formula: see text] = 0.08-0.49, for all p<0.0001). Gene flow among the areas was stablished through Bayesian analysis of migration models. Recent bottleneck events were detected in 4 areas and a recent parasite expansion in one of the isolated areas. In total, 87 unique haplotypes grouped in 2 or 3 genetic clusters described a sub-structured parasite population. CONCLUSION/SIGNIFICANCE: Our study shows a sub-structured parasite population with clonal propagation, with most of its components recently affected by bottleneck events. Iquitos city is the main source of parasite spreading for all the peripheral study areas. The routes of transmission and gene flow and the reduction of the parasite population described are important from the public health perspective as well for the formulation of future control policies. PMID- 26766550 TI - Mediastinal Germ Cell Tumors in Pediatric Patients: A Report From the Italian Association of Pediatric Hematology and Oncology. AB - BACKGROUND: Primary mediastinal germ cell tumors (GCTs) are rare in children and still represent a challenge for both adult and pediatric oncologists because of their worse outcome compared to their gonadal counterpart. PROCEDURE: Prospectively collected data concerning patients enrolled in the Italian Association of Pediatric Haematology and Oncology study on malignant GCTs (AIEOP TCGM 2004) protocol for the treatment of GCTs were analyzed. Patients with malignant mediastinal primary GCTs were included in this study. Data regarding patients with newly diagnosed mediastinal teratoma were also collected. RESULTS: From 2005 to 2013, 20 children diagnosed with mediastinal GCTs were registered in AIEOP TCGM 2004 protocol. With a median follow-up of 89 months (range 35-123), the overall survival (OS) and event free survival (EFS) rates were 100% for teratoma and 90% for malignant GCTs. CONCLUSIONS: We confirm the favorable outcome of children affected by mediastinal teratoma and malignant GCTs. For malignant tumors, further studies on the clinical characteristics and genetic signatures on tumor samples might be necessary to better understand differences observed in high-risk patients and to assist the development of more effective treatment for this subgroup. PMID- 26766551 TI - Fixation Biases towards the Index Finger in Almost-Natural Grasping. AB - We use visual information to guide our grasping movements. When grasping an object with a precision grip, the two digits need to reach two different positions more or less simultaneously, but the eyes can only be directed to one position at a time. Several studies that have examined eye movements in grasping have found that people tend to direct their gaze near where their index finger will contact the object. Here we aimed at better understanding why people do so by asking participants to lift an object off a horizontal surface. They were to grasp the object with a precision grip while movements of their hand, eye and head were recorded. We confirmed that people tend to look closer to positions that a digit needs to reach more accurately. Moreover, we show that where they look as they reach for the object depends on where they were looking before, presumably because they try to minimize the time during which the eyes are moving so fast that no new visual information is acquired. Most importantly, we confirmed that people have a bias to direct gaze towards the index finger's contact point rather than towards that of the thumb. In our study, this cannot be explained by the index finger contacting the object before the thumb. Instead, it appears to be because the index finger moves to a position that is hidden behind the object that is grasped, probably making this the place at which one is most likely to encounter unexpected problems that would benefit from visual guidance. However, this cannot explain the bias that was found in previous studies, where neither contact point was hidden, so it cannot be the only explanation for the bias. PMID- 26766552 TI - Evaluation of pharmacist-based compared to doctor-based anticoagulation management in Qatar. AB - RATIONALE, AIMS AND OBJECTIVES: For over 60 years, warfarin has been the mainstay anticoagulant used in the outpatient setting for the prevention and treatment of a wide variety of thromboembolic clinical conditions. Guidelines recommend that health care providers managing oral anticoagulation therapy should do so in a systematic and coordinated fashion. Studies have shown that, when compared to traditional doctor-based anticoagulation management, pharmacist-managed anticoagulation services can improve patient outcomes. The first pharmacist-based anticoagulation clinic in Qatar was launched in 2013 at Alwakra Hospital. The primary objective of this research was to evaluate the impact of pharmacist versus doctor-based anticoagulation management on the percentage time under therapeutic INR (International Normalized Ratio; TTR), INR within therapeutic range and the extreme out of range INRs. METHOD: A retrospective cohort study was designed to compare the anticoagulation control of pharmacist-based warfarin clinic to the usual doctor-care. RESULTS: Data from 278 patients taking warfarin (78 managed at pharmacist and 200 at doctor-based clinic) were evaluated. Subjects followed at the pharmacist-based clinic had a superior TTR compared to those managed at the doctor-based clinic (81.8% vs. 69.8%, P < 0.001). Additionally, the percentage of visits within therapeutic range were significantly higher in the pharmacist's group compared to doctor's group (76.5% vs. 71.2%, P = 0.011). At the same time, percentage of visits with extreme subtherapeutic INR was reduced in the pharmacist-managed clinic (5.17% vs. 7.05%, P = 0.007) CONCLUSIONS: Our study indicates that pharmacist-based anticoagulation has better INR control when compared to the traditional anticoagulation management. Pharmacist-managed anticoagulation clinics should be considered and supported for warfarin management. PMID- 26766553 TI - Rates, factors, reasons, and economic impact associated with switching in rheumatoid arthritis patients newly initiated on biologic disease modifying anti rheumatic drugs in an integrated healthcare system. AB - Objectives To identify how many RA patients newly-initiated on bDMARD therapy switch to another bDMARD during the first year of treatment; to evaluate the factors and reasons associated with bDMARD switching; and to compare the RA related healthcare resource utilization (HCRU) and costs between switchers vs non switchers during the post-index period. Methods A retrospective cohort study was conducted in RA patients using the Kaiser Permanente Southern California (KPSC) database with the study time period of January 1, 2007 to December 31, 2012. The index date was defined as the date of the first bDMARD prescription. Patients had to have continuous membership eligibility with drug benefit and no prior history of bDMARD during the 24 months prior to the index date. bDMARD switching was defined as a different bDMARD claim during post-index. A multivariable logistic regression model was used to evaluate factors associated with switchers vs non switchers. Chart notes were reviewed to evaluate reasons for switching from index bDMARD. RA-related HCRU use and costs were evaluated using a generalized linear model (GLM) with gamma distribution and log link function. Results Two hundred and fifty-one patients (12%) switched from their index bDMARD to a different bDMARD during the post-index period. bDMARD switchers were more likely to be female, of Asian/Pacific race, younger than <=65 years of age, overweight, CCI score <=2, initiating etanercept or adalimumab, and have a commercial insurance plan compared to non-switchers. Reasons for switching were related mostly to lack or loss of efficacy (~51%); bDMARD switchers had overall mean adjusted RA related total costs that were 25% higher (p = 0.04) compared to non-switchers. Conclusion It is important for RA patients to receive appropriate therapy and consider bDMARD with different mechanisms of action to decrease subsequent switching, and decrease overall RA related costs as shown in this study. PMID- 26766556 TI - Sunlight Has Cardiovascular Benefits Independently of Vitamin D. AB - BACKGROUND: High blood pressure (BP) is the leading risk factor for disability adjusted life years lost globally. Epidemiological data show a correlation between increased sun exposure and reduced population BP and cardiovascular mortality. Individuals with high serum vitamin D levels are at reduced risk of hypertension, cardiovascular disease and metabolic syndrome, yet multiple trial data show that oral vitamin D supplementation has no effect on these endpoints. Sunlight is a risk factor for skin cancers, but no link has been shown with increased all-cause mortality. Cohort studies from Scandinavia show a dose dependent fall in mortality with increased sun-seeking behaviour. Skin contains significant stores of nitrogen oxides, which can be converted to NO by UV radiation and exported to the systemic circulation. Human studies show that this pathway can cause arterial vasodilatation and reduced BP. Murine studies suggest the same mechanism may reduce metabolic syndrome. SUMMARY: Sunlight has beneficial effects on cardiovascular risk factors independently of vitamin D. KEY MESSAGES: All-cause mortality should be the primary determinant of public health messages. Sunlight is a risk factor for skin cancer, but sun avoidance may carry more of a cost than benefit for overall good health. PMID- 26766557 TI - Nurse Practitioners' Use of Communication Techniques: Results of a Maryland Oral Health Literacy Survey. AB - OBJECTIVES: We examined nurse practitioners' use and opinions of recommended communication techniques for the promotion of oral health as part of a Maryland state-wide oral health literacy assessment. Use of recommended health-literate and patient-centered communication techniques have demonstrated improved health outcomes. METHODS: A 27-item self-report survey, containing 17 communication technique items, across 5 domains, was mailed to 1,410 licensed nurse practitioners (NPs) in Maryland in 2010. Use of communication techniques and opinions about their effectiveness were analyzed using descriptive statistics. General linear models explored provider and practice characteristics to predict differences in the total number and the mean number of communication techniques routinely used in a week. RESULTS: More than 80% of NPs (N = 194) routinely used 3 of the 7 basic communication techniques: simple language, limiting teaching to 2-3 concepts, and speaking slowly. More than 75% of respondents believed that 6 of the 7 basic communication techniques are effective. Sociodemographic provider characteristics and practice characteristics were not significant predictors of the mean number or the total number of communication techniques routinely used by NPs in a week. Potential predictors for using more of the 7 basic communication techniques, demonstrating significance in one general linear model each, were: assessing the office for user-friendliness and ever taking a communication course in addition to nursing school. CONCLUSIONS: NPs in Maryland self-reported routinely using some recommended health-literate communication techniques, with belief in their effectiveness. Our findings suggest that NPs who had assessed the office for patient-friendliness or who had taken a communication course beyond their initial education may be predictors for using more of the 7 basic communication techniques. These self-reported findings should be validated with observational studies. Graduate and continuing education for NPs should increase emphasis on health-literate and patient-centered communication techniques to increase patient understanding of dental caries prevention. Non-dental healthcare providers, such as NPs, are uniquely positioned to contribute to preventing early childhood dental caries through health-literate and patient-centered communication. PMID- 26766558 TI - Sudden Deaths Among Oil and Gas Extraction Workers Resulting from Oxygen Deficiency and Inhalation of Hydrocarbon Gases and Vapors - United States, January 2010-March 2015. AB - In 2013, an occupational medicine physician from the University of California, San Francisco, contacted CDC's National Institute for Occupational Safety and Health (NIOSH), and the Occupational Safety and Health Administration (OSHA) about two oil and gas extraction worker deaths in the western United States. The suspected cause of these deaths was exposure to hydrocarbon gases and vapors (HGVs) and oxygen (O2)-deficient atmospheres after opening the hatches of hydrocarbon storage tanks. The physician and experts from NIOSH and OSHA reviewed available fatality reports from January 2010 to March 2015, and identified seven additional deaths with similar characteristics (nine total deaths). Recommendations were made to industry and regulators regarding the hazards associated with opening hatches of tanks, and controls to reduce or eliminate the potential for HGV exposure were proposed. Health care professionals who treat or evaluate oil and gas workers need to be aware that workers might report symptoms of exposure to high concentrations of HGVs and possible O2 deficiency; employers and workers need to be aware of this hazard and know how to limit exposure. Medical examiners investigating the death of oil and gas workers who open tank hatches should consider the contribution of O2 deficiency and HGV exposure. PMID- 26766555 TI - Incident Subjective Cognitive Decline Does Not Predict Mortality in the Elderly- Results from the Longitudinal German Study on Ageing, Cognition, and Dementia (AgeCoDe). AB - OBJECTIVE: Subjective cognitive decline (SCD) might represent the first symptomatic representation of Alzheimer's disease (AD), which is associated with increased mortality. Only few studies, however, have analyzed the association of SCD and mortality, and if so, based on prevalent cases. Thus, we investigated incident SCD in memory and mortality. METHODS: Data were derived from the German AgeCoDe study, a prospective longitudinal study on the epidemiology of mild cognitive impairment (MCI) and dementia in primary care patients over 75 years covering an observation period of 7.5 years. We used univariate and multivariate Cox regression analyses to examine the relationship of SCD and mortality. Further, we estimated survival times by the Kaplan Meier method and case-fatality rates with regard to SCD. RESULTS: Among 971 individuals without objective cognitive impairment, 233 (24.0%) incidentally expressed SCD at follow-up I. Incident SCD was not significantly associated with increased mortality in the univariate (HR = 1.0, 95% confidence interval = 0.8-1.3, p = .90) as well as in the multivariate analysis (HR = 0.9, 95% confidence interval = 0.7-1.2, p = .40). The same applied for SCD in relation to concerns. Mean survival time with SCD was 8.0 years (SD = 0.1) after onset. CONCLUSION: Incident SCD in memory in individuals with unimpaired cognitive performance does not predict mortality. The main reason might be that SCD does not ultimately lead into future cognitive decline in any case. However, as prevalence studies suggest, subjectively perceived decline in non-memory cognitive domains might be associated with increased mortality. Future studies may address mortality in such other cognitive domains of SCD in incident cases. PMID- 26766559 TI - Plasmonic properties of Ag nanoparticles embedded in GeO2-SiO2 matrix by atom beam sputtering. AB - Nanocomposite thin films containing Ag nanoparticles embedded in the GeO2-SiO2 matrix were synthesized by the atom beam co-sputtering technique. The structural, optical and plasmonic properties and the chemical composition of the nanocomposite thin films were studied by transmission electron microscopy (TEM) with energy dispersive X-ray spectroscopy (EDX), UV-visible absorption spectroscopy and X-ray photoelectron spectroscopy (XPS). UV-visible absorption studies on Ag-SiO2 nanocomposites revealed the presence of a strong localized surface plasmon resonance (LSPR) peak characteristic of Ag nanoparticles at 413 nm, which showed a blue shift of 26 nm (413 to 387 nm) along with a significant broadening and drastic decrease in intensity with the incorporation of 16 at% of Ge into the SiO2 matrix. TEM studies on Ag-GeO2-SiO2 nanocomposite thin films confirmed the presence of Ag nanoparticles with an average size of 3.8 nm in addition to their aggregates with an average size of 16.2 nm. Thermal annealing in air resulted in strong enhancement in the intensity of the LSPR peak, which showed a regular red shift of 51 nm (from 387 to 438 nm) with the increase in annealing temperature up to 500 degrees C. XPS studies showed that annealing in air resulted in oxidation of excess Ge atoms in the nanocomposite into GeO2. Our work demonstrates the possibility of controllably tuning the LSPR of Ag nanoparticles embedded in the GeO2-SiO2 matrix by single-step thermal annealing, which is interesting for optical applications. PMID- 26766560 TI - Vicenin-2 and scolymoside inhibit high-glucose-induced vascular inflammation in vitro and in vivo. AB - The vascular inflammatory process has been suggested to play a key role in the initiation and progression of atherosclerosis, a major complication of diabetes mellitus. Thus, in this study, we attempted to determine whether 2 structurally related flavonoids found in Cyclopia subternata, vicenin-2 and scolymoside, can suppress high-glucose (HG)-induced vascular inflammatory processes in human umbilical vein endothelial cells (HUVECs) and mice. The effects of vicenin-2 and scolymoside on HG-induced vascular inflammation were determined by measuring vascular permeability, leukocyte adhesion and migration, cell adhesion molecule (CAM) expression levels, and reactive oxygen species (ROS) formation. In addition, the anti-inflammation mechanism was investigated using immunofluorescence staining and Western blotting. The data showed that HG markedly increased vascular permeability, monocyte adhesion, expression of CAMs, formation of reactive oxygen species (ROS), and activation of nuclear factor (NF) kappaB. Remarkably, pretreatment with vicenin-2 and scolymoside attenuated all of the above-mentioned vascular inflammatory effects of HG. HG-induced vascular inflammatory responses are critical events underlying the development of various diabetic complications; therefore, our results suggest that vicenin-2 and scolymoside have significant therapeutic benefits against diabetic complications and atherosclerosis. PMID- 26766561 TI - Straylight and Visual Quality on Early Nuclear and Posterior Subcapsular Cataracts. AB - PURPOSE: To measure log(s) and OSI parameters, both related to forward light scattering in the eye, in subjects with different kinds of early cataracts nuclear or posterior subcapsular-and corrected visual acuity (CVA). METHODS: 34 eyes of 19 patients ranged between 50 and 75 years old with diagnosed nuclear (14 eyes) or posterior subcapsular cataract (20 eyes) were recruited. Only NO1, NO2, P1, and P2 opacity scores according to LOCS III were included. Observer examination included visual acuity, contrast threshold (Ct), and measurements performed by straylightmeter (straylight parameter log(s)) and double-pass instrument (objective scatter index (OSI)). RESULTS: OSI and log(s) were correlated with LOCSIII in nuclear opacities (p = 0.015 and 0.004, respectively) and in the whole data (p = 0.027 and 0.019, respectively) but did not for posterior subcapsular opacities alone. OSI was strongly correlated with log(s) in nuclear (r = 0.885 and p < 0.001) but not in posterior subcapsular cases (r = 0.382 and p = 0.097). Ct was correlated with log(s) for both cataract types (p = 0.043 for nuclear and p= 0.005 for posterior subcapsular cataract) but not with OSI (p = 0.093 for nuclear and p = 0.064 for posterior subcapsular cataract). CONCLUSIONS: OSI and log(s) discriminate early stages of nuclear cataracts when taking LOCS III as reference, so these opacities could be graded by any of those parameters. LOCSIII does not represent the visual condition for posterior subcapsular cataract. Straylightmeter measurements express the loss in contrast sensitivity caused by nuclear and posterior subcapsular opacities. Studies of lens opacities must be separated according to the type of opacity present in eyes. PMID- 26766562 TI - When the safe place does not protect: reports of victimisation and adverse experiences in psychiatric institutions. AB - Psychiatric patients report higher levels of victimisation and are at risk for further victimisation in different contexts, such as psychiatric institutions. Studies in this field tend to focus on hospital staff as victims, experiencing classic forms of victimisation (e.g. physical assault, threats, verbal abuse), through qualitative studies. This is a quantitative retrospective study that aims to know the occurrence of psychiatric victimisation and other adverse experiences in Portuguese psychiatric patients. Ninety-five psychiatric patients, between 20 and 79 years old (M - 45.18, SD - 13.06), with a history of psychiatric hospitalisation answered the Experiences in Psychiatric Institution Inventory. Participants were recruited in four psychiatric hospitals. Inpatients were approached during their hospitalisation; outpatients were approached in scheduled appointment days. Only 23 (24.2%) participants reported no victimisation. Total Experiences of Self varied from 0 to 7 (M - 1.75, SD - 1.72), Total Witnessed Experiences varied from 0 to 7 (M - 1.17, SD - 1.64), and Total Global Experiences varied from 0 to 14 (M - 2.92, SD - 3.01). These results show that victimisation and adverse experiences in psychiatric contexts are frequent and go beyond classic forms of victimisation. A deeper knowledge of these experiences and their impact in the mental health of psychiatric patients may promote quality of care provided and lead to more effective treatments, thus reducing the number and length of hospitalisations, and the financial burden for public health services. PMID- 26766563 TI - Psychiatric comorbidities in patients with hypertension--a study of registered diagnoses 2009-2013 in the total population in Stockholm County, Sweden. AB - OBJECTIVE: The objective of this study was to investigate the prevalence of concomitant hypertension and psychiatric disorders in the general population, using administrative healthcare data in Stockholm County. DESIGN AND METHOD: The study population, included all living persons who resided in Stockholm County 1 January 2011 (N = 2 ,058 ,408). Individuals with a diagnosis of hypertension were identified with data from all consultations in primary care, specialized outpatient care, and inpatient care 2009-2013. As outcome, data were obtained on all consultations because of certain psychiatric diagnoses between 2011 and 2013, including specifically depression, anxiety disorders, bipolar disorder, and schizophrenia. Age-adjusted odd ratios (ORs) with 95% confidence intervals (95% CI) were calculated for men and women with and without hypertension, with individuals without hypertension as referents. RESULTS: The age-adjusted ORs for depression in persons with hypertension were 1.293 (95% CI 1.256-1.331,) for men and 1.036 (95% CI 1.013-1.058) for women. The age-adjusted ORs for anxiety in persons with hypertension were 1.279 (95% CI 1.238-1.322) for men and 1.050 (95% CI 1.024-1.076) for women. The OR for bipolar disease were 0.904 (95% CI 0.826 0.990) for men and 0.709 (95% CI 0.656-0.767) for women. For schizophrenia, the ORs were 0.568 (95% CI 0.511-0.632) for men and 0.537 (95% CI 0.478-0.603) for women. CONCLUSION: Increased awareness of the risk of depression and anxiety among hypertensive patients is needed to combat hypertension, its complications, and psychiatric suffering in the population. Hypertension is probably underdiagnosed and neglected in individuals with severe psychiatric disorders. We warrant efforts to integrate psychiatric and hypertensive care. PMID- 26766564 TI - Effects of azilsartan medoxomil compared with olmesartan and valsartan on ambulatory and clinic blood pressure in patients with type 2 diabetes and prediabetes. AB - BACKGROUND: Angiotensin receptor blockers (ARBs) are preferred antihypertensive therapies in patients with type 2 diabetes mellitus (T2DM). Azilsartan medoxomil (AZL-M) is a potent ARB for the treatment of stages 1-2 hypertension. We compared the efficacy, safety, and metabolic effects of AZL-M to both valsartan (VAL) and olmesartan (OLM), separately in patients with impaired fasting glucose (prediabetes mellitus) and T2DM. METHODS: A pooled analysis of 3821 patients from three separate randomized placebo-controlled trials comparing the effects of AZL M (40 and 80 mg), OLM (40 mg), VAL (320 mg), and placebo on changes in ambulatory and clinic blood pressure (BP) among patients with hypertension and prediabetes mellitus or T2DM was performed. Two analysis pools were created to facilitate comparisons: Pool A included patients who received placebo, AZL-M or OLM and Pool B included those who received AZL-M or VAL. Within each pool, patients were stratified by glycemic subgroups (normoglycemic, prediabetes mellitus, or T2DM) based on hemoglobin A1c values. Changes from baseline in both 24-h and clinic SBP were the primary efficacy assessments. RESULTS: Baseline 24-h mean SBPs were approximately 145 and 146 mmHg in the prediabetes mellitus and T2DM subgroups, respectively; corresponding clinic SBPs were approximately 158 and 159 mmHg. Baseline hemoglobin A1c values for each subgroup (both pools) were normoglycemic, 5.3%; prediabetes mellitus, 6.0%; and T2DM, 6.9%. Changes from baseline in 24-h or clinic SBP were significantly greater with AZL-M, 80 mg compared with either OLM 40 mg or VAL 320 mg in all subgroups in each pool. Safety and tolerability were similar among the active treatment and placebo subgroups. CONCLUSION: These analyses indicate that AZL-M, 80 mg/day lowers SBP by a greater magnitude than OLM or VAL at maximally approved doses in patients with prediabetes mellitus and T2DM. These findings have important clinical implications for this high-risk patient group. PMID- 26766565 TI - Human Papillomavirus Infection and Vaccination: Awareness and Knowledge of HPV and Acceptability of HPV Vaccine among Mothers of Teenage Daughters in Weihai, Shandong, China. AB - In preparation for the introduction of human papillomavirus (HPV) vaccine, we investigated awareness and knowledge of HPV/HPV vaccine and potential acceptability to HPV vaccine among mothers with a teenage daughter in Weihai, Shandong, China. A cross-sectional survey was conducted in 2013 with a sample of 1850 mothers who had a daughter (aged 9-17 years) attending primary, junior and senior high schools. In the final sample (N = 1578, response rate 85.30%), awareness of HPV was reported by 305 (19.32%) mothers. Awareness varied significantly by daughter's age (P<0.01), mother's education level (P<0.01), mother's occupation (P<0.01), household income (P<0.01) and residence type (P<0.01). Knowledge about HPV/HPV vaccine was poor with a mean total score of 3.56 (SD = 2.40) out of a possible score of 13. Mothers with a higher education level reported higher levels of knowledge (P = 0.02). Slightly more than one fourth (26.49%) of mothers expressed their potential acceptability of HPV vaccine for their daughters. Acceptability increased along with increased daughters' age (P<0.01), household income (P<0.01) and knowledge level (P<0.01). House wives and unemployed mothers had the highest acceptability (P<0.01). The most common reasons for not accepting HPV vaccination were "My daughter is too young to have risk of cervical cancer (30.95%)", "The vaccine has not been widely used, and the decision will be made after it is widely used (24.91%)", "Worry about the safety of the vaccine (22.85%)". Awareness and knowledge of HPV/HPV vaccines are poor and HPV vaccine acceptability is low among these Chinese mothers. These results may help inform appropriate health education programs in this population. PMID- 26766568 TI - Mixed Quantum-Classical Simulations of Transient Absorption Pump-Probe Signals for a Photo-Induced Electron Transfer Reaction Coupled to an Inner-Sphere Vibrational Mode. AB - In a previous study (Martinez, F.; Hanna, G. Chem. Phys. Lett. 2013, 573, 77-83), we demonstrated the ability of two approximate solutions of the quantum-classical Liouville equation (QCLE) for qualitatively capturing the electronic dynamics in the pump-probe transient absorption (TA) signal of a model of a condensed phase photoinduced electron transfer reaction whose ground and excited donor states have the same equilibrium geometry. However, the question remained as to the ability of these solutions to treat the more complex situation in which the electronic states are coupled to a low-frequency inner-sphere harmonic vibrational mode (representing an intramolecular mode of the donor-acceptor complex) that shifts their equilibrium geometries with respect to each other and thereby gives rise to signatures of vibrational dynamics in the TA signal. Thus, in this study, we investigated this situation by treating the vibrational mode both quantum mechanically and classically within the context of the approximate Poisson bracket mapping equation (PBME) and forward-backward trajectory solutions (FBTS) of the QCLE. Depending on the definition of the quantum subsystem, both PBME and FBTS are capable of qualitatively capturing several of the main features in the exact TA signal and quantitatively capturing the characteristic time scale of the vibrational dynamics, despite the moderately strong subsystem-bath coupling in this model. Particularly, we found that treating the vibrational mode quantum mechanically using either PBME or FBTS better captures the signatures of the vibrational dynamics, while treating it classically using FBTS better captures the decay in the signal. These findings underscore the utility of the PBME and FBTS approaches for efficiently modeling and interpreting TA signals. PMID- 26766567 TI - Hepatic Lesions Detected after Mastectomy, in Breast Cancer Patients with Hepatitis Background May Need to Undergo Liver Biopsy to Rule Out Second Primary Hepatocellular Carcinoma. AB - PURPOSE: Liver metastasis is a common phenomenon in breast cancer patients. Hepatic lesions detected in breast cancer patients may be easily misdiagnosed as metastatic sites, rather than being treated as primary foci. This descriptive study aims to investigate the clinicopathological characteristics of second primary hepatocellular carcinoma in breast cancer patients and to infer in which circumstances liver biopsy is needed. METHODS: Eighty-one consecutive breast cancer patients with hepatic lesions admitted to our department were retrospectively studied and analyzed from January 2009 to March 2014 according to Warren and Gates' criteria for second primary cancers. RESULTS: Second primary hepatocellular carcinoma was observed in sixteen of seventy eight patients with breast cancer. There was a significant difference in HBV status between the second HCC group and liver metastases group (P<0.0001). There was no significant difference in age (P = 0.2254) and family history (P = 0.1160) between second primary HCC and metastases group. Two of these patients had synchronous second primary hepatocellular carcinoma and the remaining fourteen patients had metachronous second primary HCC. All sixteen patients were infected with hepatitis, including hepatitis virus B and C, or resolved HBV infection. CONCLUSIONS: Breast cancer patients with either HBV infection or resolved HBV infection, regardless of an elevated AFP level, may receive liver biopsy to avoid unnecessary and inappropriate treatments for metastasis. Awareness of second primary HCC in breast cancer patients needs to be emphasized. PMID- 26766566 TI - TNF Drives Monocyte Dysfunction with Age and Results in Impaired Anti pneumococcal Immunity. AB - Monocyte phenotype and output changes with age, but why this occurs and how it impacts anti-bacterial immunity are not clear. We found that, in both humans and mice, circulating monocyte phenotype and function was altered with age due to increasing levels of TNF in the circulation that occur as part of the aging process. Ly6C+ monocytes from old (18-22 mo) mice and CD14+CD16+ intermediate/inflammatory monocytes from older adults also contributed to this "age-associated inflammation" as they produced more of the inflammatory cytokines IL6 and TNF in the steady state and when stimulated with bacterial products. Using an aged mouse model of pneumococcal colonization we found that chronic exposure to TNF with age altered the maturity of circulating monocytes, as measured by F4/80 expression, and this decrease in monocyte maturation was directly linked to susceptibility to infection. Ly6C+ monocytes from old mice had higher levels of CCR2 expression, which promoted premature egress from the bone marrow when challenged with Streptococcus pneumoniae. Although Ly6C+ monocyte recruitment and TNF levels in the blood and nasopharnyx were higher in old mice during S. pneumoniae colonization, bacterial clearance was impaired. Counterintuitively, elevated TNF and excessive monocyte recruitment in old mice contributed to impaired anti-pneumococcal immunity since bacterial clearance was improved upon pharmacological reduction of TNF or Ly6C+ monocytes, which were the major producers of TNF. Thus, with age TNF impairs inflammatory monocyte development, function and promotes premature egress, which contribute to systemic inflammation and is ultimately detrimental to anti-pneumococcal immunity. PMID- 26766569 TI - Nephrotoxicity of Natural Products. AB - BACKGROUND: The manufacture and sale of natural products constitute a multi billion dollar industry. Nearly a third of the American population admit to using some form of complementary or alternative medicine, with many using them in addition to prescription medications. Most patients fail to inform their healthcare providers of their natural product use and physicians rarely inquire. Annually, thousands of natural product-induced adverse events are reported to Poison Control Centers nationwide. Natural product manufacturers are not responsible for proving safety and efficacy, as the FDA does not regulate them. However, concerns exist surrounding the safety of natural products. SUMMARY: This review provides details on natural products that have been associated with renal dysfunction. We have focused on products that have been associated with direct renal injury, immune-mediated nephrotoxicity, nephrolithiasis, rhabdomyolysis with acute renal injury, hepatorenal syndrome, and common adulterants or contaminants that are associated with renal dysfunction. KEY MESSAGES: The potential for natural products to cause renal dysfunction is justifiable. It is imperative that natural product use be monitored closely in all patients. Healthcare practitioners must play an active role in identifying patients using natural products and provide appropriate patient education. PMID- 26766570 TI - Serotonin Improves High Fat Diet Induced Obesity in Mice. AB - There are two independent serotonin (5-HT) systems of organization: one in the central nervous system and the other in the periphery. 5-HT affects feeding behavior and obesity in the central nervous system. On the other hand, peripheral 5-HT also may play an important role in obesity, as it has been reported that 5 HT regulates glucose and lipid metabolism. Here we show that the intraperitoneal injection of 5-HT to mice inhibits weight gain, hyperglycemia and insulin resistance and completely prevented the enlargement of intra-abdominal adipocytes without having any effect on food intake when on a high fat diet, but not on a chow diet. 5-HT increased energy expenditure, O2 consumption and CO2 production. This novel metabolic effect of peripheral 5-HT is critically related to a shift in the profile of muscle fiber type from fast/glycolytic to slow/oxidative in soleus muscle. Additionally, 5-HT dramatically induced an increase in the mRNA expression of peroxisome proliferator-activated receptor coactivator 1alpha (PGC 1alpha)-b and PGC-1alpha-c in soleus muscle. The elevation of these gene mRNA expressions by 5-HT injection was inhibited by treatment with 5-HT receptor (5HTR) 2A or 7 antagonists. Our results demonstrate that peripheral 5-HT may play an important role in the relief of obesity and other metabolic disorders by accelerating energy consumption in skeletal muscle. PMID- 26766574 TI - Comparative Effectiveness of Emergency Resuscitative Thoracotomy versus Closed Chest Compressions among Patients with Critical Blunt Trauma: A Nationwide Cohort Study in Japan. AB - BACKGROUND: Although emergency resuscitative thoracotomy is performed as a salvage maneuver for critical blunt trauma patients, evidence supporting superior effectiveness of emergency resuscitative thoracotomy compared to conventional closed-chest compressions remains insufficient. The objective of this study was to investigate whether emergency resuscitative thoracotomy at the emergency department or in the operating room was associated with favourable outcomes after blunt trauma and to compare its effectiveness with that of closed-chest compressions. METHODS: This was a retrospective nationwide cohort study. Data were obtained from the Japan Trauma Data Bank for the period between 2004 and 2012. The primary and secondary outcomes were patient survival rates 24 h and 28 d after emergency department arrival. Statistical analyses were performed using multivariable generalized mixed-effects regression analysis. We adjusted for the effects of different hospitals by introducing random intercepts in regression analysis to account for the differential quality of emergency resuscitative thoracotomy at hospitals where patients in cardiac arrest were treated. Sensitivity analyses were performed using propensity score matching. RESULTS: In total, 1,377 consecutive, critical blunt trauma patients who received cardiopulmonary resuscitation in the emergency department or operating room were included in the study. Of these patients, 484 (35.1%) underwent emergency resuscitative thoracotomy and 893 (64.9%) received closed-chest compressions. Compared to closed-chest compressions, emergency resuscitative thoracotomy was associated with lower survival rate 24 h after emergency department arrival (4.5% vs. 17.5%, respectively, P < 0.001) and 28 d after arrival (1.2% vs. 6.0%, respectively, P < 0.001). Multivariable generalized mixed-effects regression analysis with and without a propensity score-matched dataset revealed that the odds ratio for an unfavorable survival rate after 24 h was lower for emergency resuscitative thoracotomy than for closed-chest compressions (P < 0.001). CONCLUSIONS: Emergency resuscitative thoracotomy was independently associated with decreased odds of a favorable survival rate compared to closed-chest compressions. PMID- 26766575 TI - Transcription Factors Exhibit Differential Conservation in Bacteria with Reduced Genomes. AB - The description of transcriptional regulatory networks has been pivotal in the understanding of operating principles under which organisms respond and adapt to varying conditions. While the study of the topology and dynamics of these networks has been the subject of considerable work, the investigation of the evolution of their topology, as a result of the adaptation of organisms to different environmental conditions, has received little attention. In this work, we study the evolution of transcriptional regulatory networks in bacteria from a genome reduction perspective, which manifests itself as the loss of genes at different degrees. We used the transcriptional regulatory network of Escherichia coli as a reference to compare 113 smaller, phylogenetically-related gamma proteobacteria, including 19 genomes of symbionts. We found that the type of regulatory action exerted by transcription factors, as genomes get progressively smaller, correlates well with their degree of conservation, with dual regulators being more conserved than repressors and activators in conditions of extreme reduction. In addition, we found that the preponderant conservation of dual regulators might be due to their role as both global regulators and nucleoid associated proteins. We summarize our results in a conceptual model of how each TF type is gradually lost as genomes become smaller and give a rationale for the order in which this phenomenon occurs. PMID- 26766577 TI - What Is Citizen Science?--A Scientometric Meta-Analysis. AB - CONTEXT: The concept of citizen science (CS) is currently referred to by many actors inside and outside science and research. Several descriptions of this purportedly new approach of science are often heard in connection with large datasets and the possibilities of mobilizing crowds outside science to assists with observations and classifications. However, other accounts refer to CS as a way of democratizing science, aiding concerned communities in creating data to influence policy and as a way of promoting political decision processes involving environment and health. OBJECTIVE: In this study we analyse two datasets (N = 1935, N = 633) retrieved from the Web of Science (WoS) with the aim of giving a scientometric description of what the concept of CS entails. We account for its development over time, and what strands of research that has adopted CS and give an assessment of what scientific output has been achieved in CS-related projects. To attain this, scientometric methods have been combined with qualitative approaches to render more precise search terms. RESULTS: Results indicate that there are three main focal points of CS. The largest is composed of research on biology, conservation and ecology, and utilizes CS mainly as a methodology of collecting and classifying data. A second strand of research has emerged through geographic information research, where citizens participate in the collection of geographic data. Thirdly, there is a line of research relating to the social sciences and epidemiology, which studies and facilitates public participation in relation to environmental issues and health. In terms of scientific output, the largest body of articles are to be found in biology and conservation research. In absolute numbers, the amount of publications generated by CS is low (N = 1935), but over the past decade a new and very productive line of CS based on digital platforms has emerged for the collection and classification of data. PMID- 26766579 TI - Abstracts of Presentations at the 2015 North Central Division Meeting. PMID- 26766580 TI - Diquat associated with copper sources for algae control: Efficacy and ecotoxicology. AB - The aims of this research were to evaluate the efficacy of copper oxychloride (CuCl2.3Cu(OH)2), copper hydroxide (Cu(OH)2) and diquat (1.1'-ethylene-2.2' bipyridyldiylium dibromide), isolated and in association with 0.1% of both copper sources, in the control of the unicellular algae Ankistrodesmus gracilis and the filamentous algae Pithophora kewesis, and to determine the acute toxicity of the tested chemicals in Hyphressobrycon eques, Pomacea canaliculata, Lemna minor and Azolla caroliniana. The efficacy was estimated by the methods of chlorophyll a and pheophytin a readings, changed into growth inhibition percentage. Both algae were exposed to the following concentrations: 0.2; 0.4; 0.8; 1.2 mg L(-1) of diquat and its association with the copper sources; and 0.1; 0.3; 0.5; 0.7; 1.0 and 1.5 mg L(-1) in the isolated applications of copper hydroxide and copper oxychloride. An untreated control was kept. The acute toxicity was estimatedby 50% lethal concentration (LC50). The copper sources were effective for A. gracilis control, at rates as high as 0.1 mg L(-1) (>95% efficacy). Isolated diquat and its association with copper hydroxide were both effective at rates as high as 0.4 mg L(-1), with 95 and 88% control efficacy, respectively. The copper oxychloride was effective at 0.2 mg L(-1), with 93% efficacy. None of the tested chemicals and associations was effective on P. kewesis control. The most sensitive non target organism to the tested chemicals was L. minor; the less sensitive was H. eques. PMID- 26766581 TI - Polyoxometalate-Driven Self-Assembly of Short Peptides into Multivalent Nanofibers with Enhanced Antibacterial Activity. AB - Multivalent peptide nanofibers have attracted intense attention as promising platforms, but the fabrication of those nanofibers is mainly dependent on the spontaneous assembly of beta-sheet peptides. Herein we report an alternative approach to the creation of nanofibers: the polyoxometalate-driven self-assembly of short peptides. The resultant nanofibers with concentrated positive charges are excellent multivalent ligands for binding with bacterial cells and thus lead to a salient improvement in bioactivity. PMID- 26766582 TI - Molecular modelling, synthesis and biological evaluation of peptide inhibitors as anti-angiogenic agent targeting neuropilin-1 for anticancer application. AB - Vascular endothelial growth factor (VEGF) and its co-receptor neuropilin-1 (NRP 1) are important targets of many pro-angiogenic factors. In this study, nine peptides were synthesized and evaluated for their molecular interaction with NRP 1 and compared to our previous peptide ATWLPPR. Docking study showed that the investigated peptides shared the same binding region as shown by tuftsin known to bind selectively to NRP-1. Four pentapeptides (DKPPR, DKPRR, TKPPR and TKPRR) and a hexapeptide CDKPRR demonstrated good inhibitory activity against NRP-1. In contrast, peptides having arginine residue at sites other than the C-terminus exhibited low activity towards NRP-1 and this is confirmed by their inability to displace the VEGF165 binding to NRP-1. Docking study also revealed that replacement of carboxyl to amide group at the C-terminal arginine of the peptide did not affect significantly the binding interaction to NRP-1. However, the molecular affinity study showed that these peptides have marked reduction in the activity against NRP-1. Pentapeptides having C-terminal arginine showed strong interaction and good inhibitory activity with NRP thus may be a good template for anti-angiogenic targeting agent. PMID- 26766578 TI - Broadly Neutralizing Antibody Responses in a Large Longitudinal Sub-Saharan HIV Primary Infection Cohort. AB - Broadly neutralizing antibodies (bnAbs) are thought to be a critical component of a protective HIV vaccine. However, designing vaccines immunogens able to elicit bnAbs has proven unsuccessful to date. Understanding the correlates and immunological mechanisms leading to the development of bnAb responses during natural HIV infection is thus critical to the design of a protective vaccine. The IAVI Protocol C program investigates a large longitudinal cohort of primary HIV-1 infection in Eastern and South Africa. Development of neutralization was evaluated in 439 donors using a 6 cross-clade pseudo-virus panel predictive of neutralization breadth on larger panels. About 15% of individuals developed bnAb responses, essentially between year 2 and year 4 of infection. Statistical analyses revealed no influence of gender, age or geographical origin on the development of neutralization breadth. However, cross-clade neutralization strongly correlated with high viral load as well as with low CD4 T cell counts, subtype-C infection and HLA-A*03(-) genotype. A correlation with high overall plasma IgG levels and anti-Env IgG binding titers was also found. The latter appeared not associated with higher affinity, suggesting a greater diversity of the anti-Env responses in broad neutralizers. Broadly neutralizing activity targeting glycan-dependent epitopes, largely the N332-glycan epitope region, was detected in nearly half of the broad neutralizers while CD4bs and gp41-MPER bnAb responses were only detected in very few individuals. Together the findings suggest that both viral and host factors are critical for the development of bnAbs and that the HIV Env N332-glycan supersite may be a favorable target for vaccine design. PMID- 26766583 TI - Activation Energy of the Low-pH-Induced Lamellar to Bicontinuous Cubic Phase Transition in Dioleoylphosphatidylserine/Monoolein. AB - Electrostatic interaction is an important factor for phase transitions between lamellar liquid-crystalline (Lalpha) and inverse bicontinuous cubic (QII) phases. We investigated the effect of temperature on the low-pH-induced Lalpha to double diamond cubic (QII(D)) phase transition in dioleoylphosphatidylserine (DOPS)/monoolein (MO) using time-resolved small-angle X-ray scattering with a stopped-flow apparatus. Under all conditions of temperature and pH, the Lalpha phase was directly transformed into an intermediate inverse hexagonal (HII) phase, and subsequently the HII phase slowly converted to the QII(D) phase. We obtained the rate constants of the initial step (i.e., the Lalpha to HII phase transition) and of the second step (i.e., the HII to QII(D) phase transition) using the non-negative matrix factorization method. The rate constant of the initial step increased with temperature. By analyzing this result, we obtained the values of its apparent activation energy, Ea (Lalpha -> HII), which did not change with temperature but increased with an increase in pH. In contrast, the rate constant of the second step decreased with temperature at pH 2.6, although it increased with temperature at pH 2.7 and 2.8. These results indicate that the value of Ea (HII -> QII(D)) at pH 2.6 increased with temperature, but the values of Ea (HII -> QII(D)) at pH 2.7 and 2.8 were constant with temperature. The values of Ea (HII -> QII(D)) were smaller than those of Ea (Lalpha -> HII) at the same pH. We analyzed these results using a modified quantitative theory on the activation energy of phase transitions of lipid membranes proposed initially by Squires et al. (Squires, A. M.; Conn, C. E.; Seddon, J. M.; Templer, R. H. Soft Matter 2009, 5, 4773). On the basis of these results, we discuss the mechanism of this phase transition. PMID- 26766584 TI - Quantifying Health Across Populations. AB - In this article, I argue that as a theoretical matter, a population's health level is best quantified via averagism. Averagism asserts that the health of a population is the average of members' health-levels. This model is better because it does not fall prey to a number of objections, including the repugnant conclusion, and because it is not arbitrary. I also argue that as a practical matter, population health-levels are best quantified via totalism. Totalism asserts that the health of a population is the sum of members' health-levels. Totalism is better here because it fits better with cost-benefit analysis and such an analysis is the best practical way to value healthcare outcomes. The two results are compatible because the theoretical and practical need not always align, whether in general or in the context of population health. PMID- 26766585 TI - Parsing Myc Paralogs in Oncogenesis. AB - Myc and its paralog MycN are thought to be functionally redundant, but Myc- and MycN-driven medulloblastomas exhibit distinct phenotypes. In this issue of Cancer Cell, Vo and colleagues (2016) show that this phenotypic difference stems from the preferential ability of Myc, relative to MycN, to bind Miz1 and repress transcription. PMID- 26766586 TI - Venetoclax Adds a New Arrow Targeting Relapsed CLL to the Quiver. AB - Inhibitors of B cell receptor signaling substantially changed the treatment of chronic lymphocytic leukemia as the first targeted agents to enter routine clinical practice. A recent paper by Roberts and colleagues describes an additional therapeutic target by reporting encouraging clinical results with venetoclax, an inhibitor of the antiapoptotic protein BCL2. PMID- 26766588 TI - Polycomb Repressive Complex 2 Is a Barrier to KRAS-Driven Inflammation and Epithelial-Mesenchymal Transition in Non-Small-Cell Lung Cancer. AB - Polycomb repressive complexes (PRC) are frequently implicated in human cancer, acting either as oncogenes or tumor suppressors. Here, we show that PRC2 is a critical regulator of KRAS-driven non-small cell lung cancer progression. Modulation of PRC2 by either Ezh2 overexpression or Eed deletion enhances KRAS driven adenomagenesis and inflammation, respectively. Eed-loss-driven inflammation leads to massive macrophage recruitment and marked decline in tissue function. Additional Trp53 inactivation activates a cell-autonomous epithelial-to mesenchymal transition program leading to an invasive mucinous adenocarcinoma. A switch between methylated/acetylated chromatin underlies the tumor phenotypic evolution, prominently involving genes controlled by Hippo/Wnt signaling. Our observations in the mouse models were conserved in human cells. Importantly, PRC2 inactivation results in context-dependent phenotypic alterations, with implications for its therapeutic application. PMID- 26766587 TI - The Interaction of Myc with Miz1 Defines Medulloblastoma Subgroup Identity. AB - Four distinct subgroups of cerebellar medulloblastomas (MBs) differ in their histopathology, molecular profiles, and prognosis. c-Myc (Myc) or MycN overexpression in granule neuron progenitors (GNPs) induces Group 3 (G3) or Sonic Hedgehog (SHH) MBs, respectively. Differences in Myc and MycN transcriptional profiles depend, in part, on their interaction with Miz1, which binds strongly to Myc but not MycN, to target sites on chromatin. Myc suppresses ciliogenesis and reprograms the transcriptome of SHH-dependent GNPs through Miz1-dependent gene repression to maintain stemness. Genetic disruption of the Myc/Miz1 interaction inhibited G3 MB development. Target genes of Myc/Miz1 are repressed in human G3 MBs but not in other subgroups. Therefore, the Myc/Miz1 interaction is a defining hallmark of G3 MB development. PMID- 26766589 TI - Targeting Aberrant Epigenetic Networks Mediated by PRMT1 and KDM4C in Acute Myeloid Leukemia. AB - Transcriptional deregulation plays a major role in acute myeloid leukemia, and therefore identification of epigenetic modifying enzymes essential for the maintenance of oncogenic transcription programs holds the key to better understanding of the biology and designing effective therapeutic strategies for the disease. Here we provide experimental evidence for the functional involvement and therapeutic potential of targeting PRMT1, an H4R3 methyltransferase, in various MLL and non-MLL leukemias. PRMT1 is necessary but not sufficient for leukemic transformation, which requires co-recruitment of KDM4C, an H3K9 demethylase, by chimeric transcription factors to mediate epigenetic reprogramming. Pharmacological inhibition of KDM4C/PRMT1 suppresses transcription and transformation ability of MLL fusions and MOZ-TIF2, revealing a tractable aberrant epigenetic circuitry mediated by KDM4C and PRMT1 in acute leukemia. PMID- 26766590 TI - MiR-215 Is Induced Post-transcriptionally via HIF-Drosha Complex and Mediates Glioma-Initiating Cell Adaptation to Hypoxia by Targeting KDM1B. AB - The hypoxic tumor microenvironment serves as a niche for maintaining the glioma initiating cells (GICs) that are critical for glioblastoma (GBM) occurrence and recurrence. Here, we report that hypoxia-induced miR-215 is vital for reprograming GICs to fit the hypoxic microenvironment via suppressing the expression of an epigenetic regulator KDM1B and modulating activities of multiple pathways. Interestingly, biogenesis of miR-215 and several miRNAs is accelerated post-transcriptionally by hypoxia-inducible factors (HIFs) through HIF-Drosha interaction. Moreover, miR-215 expression correlates inversely with KDM1B while correlating positively with HIF1alpha and GBM progression in patients. These findings reveal a direct role of HIF in regulating miRNA biogenesis and consequently activating the miR-215-KDM1B-mediated signaling required for GIC adaptation to hypoxia. PMID- 26766591 TI - GSK3 Deficiencies in Hematopoietic Stem Cells Initiate Pre-neoplastic State that Is Predictive of Clinical Outcomes of Human Acute Leukemia. AB - Initial pathway alternations required for pathogenesis of human acute myeloid leukemia (AML) are poorly understood. Here we reveal that removal of glycogen synthase kinase-3alpha (GSK-3alpha) and GSK-3beta dependency leads to aggressive AML. Although GSK-3alpha deletion alone has no effect, GSK-3beta deletion in hematopoietic stem cells (HSCs) resulted in a pre-neoplastic state consistent with human myelodysplastic syndromes (MDSs). Transcriptome and functional studies reveal that each GSK-3beta and GSK-3alpha uniquely contributes to AML by affecting Wnt/Akt/mTOR signaling and metabolism, respectively. The molecular signature of HSCs deleted for GSK-3beta provided a prognostic tool for disease progression and survival of MDS patients. Our study reveals that GSK-3alpha- and GSK-3beta-regulated pathways can be responsible for stepwise transition to MDS and subsequent AML, thereby providing potential therapeutic targets of disease evolution. PMID- 26766596 TI - Treatment of Premenstrual Dysphoric Disorder: Therapeutic Challenges. PMID- 26766592 TI - An Integrated Metabolic Atlas of Clear Cell Renal Cell Carcinoma. AB - Dysregulated metabolism is a hallmark of cancer, manifested through alterations in metabolites. We performed metabolomic profiling on 138 matched clear cell renal cell carcinoma (ccRCC)/normal tissue pairs and found that ccRCC is characterized by broad shifts in central carbon metabolism, one-carbon metabolism, and antioxidant response. Tumor progression and metastasis were associated with metabolite increases in glutathione and cysteine/methionine metabolism pathways. We develop an analytic pipeline and visualization tool (metabolograms) to bridge the gap between TCGA transcriptomic profiling and our metabolomic data, which enables us to assemble an integrated pathway-level metabolic atlas and to demonstrate discordance between transcriptome and metabolome. Lastly, expression profiling was performed on a high-glutathione cluster, which corresponds to a poor-survival subgroup in the ccRCC TCGA cohort. PMID- 26766593 TI - A Biparatopic HER2-Targeting Antibody-Drug Conjugate Induces Tumor Regression in Primary Models Refractory to or Ineligible for HER2-Targeted Therapy. AB - Antibody-drug conjugate (ADC) which delivers cytotoxic drugs specifically into targeted cells through internalization and lysosomal trafficking has emerged as an effective cancer therapy. We show that a bivalent biparatopic antibody targeting two non-overlapping epitopes on HER2 can induce HER2 receptor clustering, which in turn promotes robust internalization, lysosomal trafficking, and degradation. When conjugated with a tubulysin-based microtubule inhibitor, the biparatopic ADC demonstrates superior anti-tumor activity over ado trastuzumab emtansine (T-DM1) in tumor models representing various patient subpopulations, including T-DM1 eligible, T-DM1 ineligible, and T-DM1 relapsed/refractory. Our findings indicate that this biparatopic ADC has promising potential as an effective therapy for metastatic breast cancer and a broader patient population may benefit from this unique HER2-targeting ADC. PMID- 26766594 TI - Electrochemical Capacitors with High Output Voltages that Mimic Electric Eels. AB - A new family of energy-storage devices is created by mimicking the electric eel to obtain a high output voltage. These novel energy-storage devices are flexible, stretchable, and weavable fibers, which satisfies the needs of next-generation portable and wearable electronics. The devices are fabricated via a continuous fabrication technology to effectively power electronic watches and light-emitting diodes as two examples. PMID- 26766597 TI - Procrastination and suicide proneness: A moderated-mediation model for cognitive schemas and gender. AB - This study examined the direct and indirect paths between procrastination and suicide proneness while considering gender differences. Participants included 547 undergraduates from a southeastern university. Procrastination was positively related to suicide proneness for both genders, although this relation was stronger for women. Moderated-mediation analyses with bootstrapping highlighted insufficient self-control schemas as a mediator in the relation between procrastination and suicide proneness. However, indirect pathways did not vary by gender. Results represent an extension of the Procrastination-Health Model by highlighting the contribution of cognitive factors in explaining the relation between procrastination and suicide proneness. PMID- 26766598 TI - Design, synthesis and applications of core-shell, hollow core, and nanorattle multifunctional nanostructures. AB - With the evolution of nanoscience and nanotechnology, studies have been focused on manipulating nanoparticle properties through the control of their size, composition, and morphology. As nanomaterial research has progressed, the foremost focus has gradually shifted from synthesis, morphology control, and characterization of properties to the investigation of function and the utility of integrating these materials and chemical sciences with the physical, biological, and medical fields, which therefore necessitates the development of novel materials that are capable of performing multiple tasks and functions. The construction of multifunctional nanomaterials that integrate two or more functions into a single geometry has been achieved through the surface-coating technique, which created a new class of substances designated as core-shell nanoparticles. Core-shell materials have growing and expanding applications due to the multifunctionality that is achieved through the formation of multiple shells as well as the manipulation of core/shell materials. Moreover, core removal from core-shell-based structures offers excellent opportunities to construct multifunctional hollow core architectures that possess huge storage capacities, low densities, and tunable optical properties. Furthermore, the fabrication of nanomaterials that have the combined properties of a core-shell structure with that of a hollow one has resulted in the creation of a new and important class of substances, known as the rattle core-shell nanoparticles, or nanorattles. The design strategies of these new multifunctional nanostructures (core-shell, hollow core, and nanorattle) are discussed in the first part of this review. In the second part, different synthesis and fabrication approaches for multifunctional core-shell, hollow core-shell and rattle core-shell architectures are highlighted. Finally, in the last part of the article, the versatile and diverse applications of these nanoarchitectures in catalysis, energy storage, sensing, and biomedicine are presented. PMID- 26766599 TI - Connect MM(r) - the Multiple Myeloma Disease Registry: incidence of second primary malignancies in patients treated with lenalidomide. PMID- 26766600 TI - Automated Outcome Classification of Computed Tomography Imaging Reports for Pediatric Traumatic Brain Injury. AB - BACKGROUND: The authors have previously demonstrated highly reliable automated classification of free-text computed tomography (CT) imaging reports using a hybrid system that pairs linguistic (natural language processing) and statistical (machine learning) techniques. Previously performed for identifying the outcome of orbital fracture in unprocessed radiology reports from a clinical data repository, the performance has not been replicated for more complex outcomes. OBJECTIVES: To validate automated outcome classification performance of a hybrid natural language processing (NLP) and machine learning system for brain CT imaging reports. The hypothesis was that our system has performance characteristics for identifying pediatric traumatic brain injury (TBI). METHODS: This was a secondary analysis of a subset of 2,121 CT reports from the Pediatric Emergency Care Applied Research Network (PECARN) TBI study. For that project, radiologists dictated CT reports as free text, which were then deidentified and scanned as PDF documents. Trained data abstractors manually coded each report for TBI outcome. Text was extracted from the PDF files using optical character recognition. The data set was randomly split evenly for training and testing. Training patient reports were used as input to the Medical Language Extraction and Encoding (MedLEE) NLP tool to create structured output containing standardized medical terms and modifiers for negation, certainty, and temporal status. A random subset stratified by site was analyzed using descriptive quantitative content analysis to confirm identification of TBI findings based on the National Institute of Neurological Disorders and Stroke (NINDS) Common Data Elements project. Findings were coded for presence or absence, weighted by frequency of mentions, and past/future/indication modifiers were filtered. After combining with the manual reference standard, a decision tree classifier was created using data mining tools WEKA 3.7.5 and Salford Predictive Miner 7.0. Performance of the decision tree classifier was evaluated on the test patient reports. RESULTS: The prevalence of TBI in the sampled population was 159 of 2,217 (7.2%). The automated classification for pediatric TBI is comparable to our prior results, with the notable exception of lower positive predictive value. Manual review of misclassified reports, 95.5% of which were false-positives, revealed that a sizable number of false-positive errors were due to differing outcome definitions between NINDS TBI findings and PECARN clinical important TBI findings and report ambiguity not meeting definition criteria. CONCLUSIONS: A hybrid NLP and machine learning automated classification system continues to show promise in coding free-text electronic clinical data. For complex outcomes, it can reliably identify negative reports, but manual review of positive reports may be required. As such, it can still streamline data collection for clinical research and performance improvement. PMID- 26766601 TI - Macroscopic Anatomy of the Saimaa Ringed Seal (Phoca hispida saimensis) Lower Respiratory Tract. AB - We studied the macroscopic anatomy of the lower respiratory tract of the endangered Saimaa ringed seal (Phoca hispida saimensis). Examination of one adult and one young individual found dead showed that trachea had 85 and 86 complete cartilage rings. The adjacent cartilages exhibited very few random anastomoses. There was variation in the confirmation of the trachea between the cranial and caudal part of the trachea. The right lung was divided by partly incomplete inter lobar fissures into cranial, middle, caudal, and accessory lobes. The left lung consisted of cranial, middle, and caudal lobes. The lungs were characterized by a high amount of interlobular connective tissue. Silicone casts were prepared of the two specimens to visualize the tracheobronchial branching which was similar to that of marine ringed seals but in the Saimaa ringed seal the right middle lobar bronchus originated at the same level as the accessory lobar bronchus. PMID- 26766603 TI - Assessment of glomerular filtration rate in the neonate: is creatinine the best tool? AB - PURPOSE OF REVIEW: This article answers the question of whether creatinine is the best biomarker for monitoring neonatal glomerular filtration rate (GFR) in view of recent advances in measuring neonatal renal function. RECENT FINDINGS: We rely largely on serum creatinine for the estimation of GFR in the newborn, even though creatinine is freely exchanged through the placenta. During the first few days of life, the serum creatinine reflects maternal renal function or the maternal creatinine. Back filtration of creatinine in preterm newborns is also a serious limitation. This review summarizes current knowledge on the prenatal and postnatal handling of creatinine as well as that of other, more novel biomarkers of GFR, such as cystatin C (CysC) and beta-trace protein (BTP). Only small amounts of CysC cross the placenta, whereas BTP does not cross the placenta at all. However, BTP measurements are not widely available. Recent studies on renal volumetry are also discussed. SUMMARY: Currently, CysC may be the most suitable marker of neonatal renal function, but its availability is still limited, it is more costly, and the best method of reporting acute kidney injury and neonatal estimated GFR remains to be established. PMID- 26766604 TI - Optical properties of hydroxyethyl cellulose film treated with nitrogen plasma. AB - Hydroxyethyl cellulose (HEC) film has been prepared by casting technique. The prepared sample has been treated with nitrogen plasma at different exposure times. The optical absorption was recorded at room temperature in the wavelength range of 200-800 nm. Absorbance fitting procedure curves revealed a direct allowed transition with optical band gap, Eopt, of 4.9 eV for pristine film, and this value decreases to 4.30 eV for 20 min plasma treatment time. The band tail values (Ee) were found to be increased under plasma time treatment from 1.74 eV in case of the pristine film to 2.20 eV for 20 min. The dispersion of refractive index and complex dielectric constants under plasma treatment was also studied. Variation of color parameters under effect of the plasma treatment is analyzed in the framework of CIE L*U*V* color space. PMID- 26766602 TI - Defining neonatal sepsis. AB - PURPOSE OF REVIEW: Although infection rates have modestly decreased in the neonatal intensive care unit (NICU) as a result of ongoing quality improvement measures, neonatal sepsis remains a frequent and devastating problem among hospitalized preterm neonates. Despite multiple attempts to address this unmet need, there have been minimal advances in clinical management, outcomes, and accuracy of diagnostic testing options over the last 3 decades. One strong contributor to a lack of medical progress is a variable case definition of disease. The inability to agree on a precise definition greatly reduces the likelihood of aligning findings from epidemiologists, clinicians, and researchers, which, in turn, severely hinders progress toward improving outcomes. RECENT FINDINGS: Pediatric consensus definitions for sepsis are not accurate in term infants and are not appropriate for preterm infants. In contrast to the defined multistage criteria for other devastating diseases encountered in the NICU (e.g., bronchopulmonary dysplasia), there is significant variability in the criteria used by investigators to substantiate the diagnosis of neonatal sepsis. SUMMARY: The lack of an accepted consensus definition for neonatal sepsis impedes our efforts toward improved diagnostic and prognostic options, and accurate outcomes information for this vulnerable population. PMID- 26766605 TI - Perceptual and conceptual priming of cue encoding in task switching. AB - Transition effects in task-cuing experiments can be partitioned into task switching and cue repetition effects by using multiple cues per task. In the present study, the author shows that cue repetition effects can be partitioned into perceptual and conceptual priming effects. In 2 experiments, letters or numbers in their uppercase/lowercase or word/numeral forms, respectively, served as cues for perceptual categorization tasks (e.g., the letters B, b, E, and e were cues for a color judgment and the letters D, d, G, and g were cues for a shape judgment). Some cues represented the same concept but had different percepts, allowing nominal repetitions to occur across trials (e.g., d followed by D). Conceptual priming effects were measured by comparing relational repetitions (e.g., G followed by D) with nominal repetitions, whereas perceptual priming effects were measured by comparing nominal repetitions with physical repetitions (e.g., D followed by D). Large conceptual and perceptual priming effects on response time were observed. Implications of the results for understanding cue encoding in task switching situations are discussed. (PsycINFO Database Record PMID- 26766606 TI - Evidence in support of a scalar implicature account of plurality. AB - There is increasing evidence that the plural is semantically unmarked for number such that a plural can be interpreted as meaning "at least one." The 2 experiments reported here used a picture matching paradigm to investigate the conceptual representations built during the comprehension of sentences with plural definite descriptions (e.g., leaves). In Experiment 1, participants read sentences that specified that the objects in the plural were spatially distributed (scattered leaves), spatially grouped (a pile of leaves), or neutral with respect to spatial distribution. After reading the sentence, participants saw a picture that either contained multiple spatially distributed objects, multiple spatially grouped objects, or a single object. In Experiment 2, the sentential context specified a large, uncountable set size, a small set size, or was neutral with respect to set size. The picture that followed either depicted a large set size, a small set size, or a single object. Participants read each sentence and then judged whether the picture was of an object that was in the sentence. Both experiments provided evidence that even when comprehenders build detailed conceptual representations for plural definite descriptions, they have still activated the singular interpretation of the plural. These data are consistent with an account of the plural in which the plural is semantically unmarked for number and the plural meaning is derived via a scalar implicature. (PsycINFO Database Record PMID- 26766607 TI - Injectable silica-permanganate gel as a slow-release MnO4(-) source for groundwater remediation: rheological properties and release dynamics. AB - Injectable slow-release permanganate gels (ISRPGs), formed by mixing aqueous KMnO4 solution with fumed silica powders, may have potential applications in remediating chlorinated solvent plumes in groundwater. A series of batch, column, and two-dimensional (2-D) flow cell experiments has been completed to characterize the ISRPG and study the release of permanganate (MnO4(-)) under a variety of conditions. The experiments have provided information on ISRPG rheology, MnO4(-) release dynamics and distribution in porous media, and trichloroethene (TCE) destruction by the ISRPG-released oxidant. The gel possesses shear thinning characteristics, resulting in a relatively low viscosity during mixing, and facilitating subsurface injection and distribution. Batch tests clearly showed that MnO4(-) diffused out from the ISRPG into water. During this process, the gel did not dissolve or disperse into water, but rather maintained its initial shape. Column experiments demonstrated that MnO4(-) release from the ISRPG lasted considerably longer than that from an aqueous solution. In addition, due to the longer release duration, TCE destruction by ISRPG-released MnO4(-) was considerably more effective than that when MnO4(-) was delivered using aqueous solution injection. In the 2-D flow cell experiments, it was demonstrated that ISRPGs released a long-lasting, low-concentration MnO4(-) plume potentially sufficient for sustainable remediation in aquifers. PMID- 26766613 TI - Assessing family resources: validation of the Swedish version of the Family Hardiness Index. AB - All families face normative transitions. Some are perceived as stressful and calls for family resources to maintain or restore family well-being. In times of illness, families also need to develop strengths and capabilities to enhance family well-being. The way these are developed is related to family hardiness. Family hardiness is thus seen as a family resource, and the Family Hardiness Index (FHI) was developed to measure family stress resistance and adaptation resources. The index was not available in Swedish and no extensive international psychometric evaluation was found. Therefore, the aim was to translate and validate the Swedish version of the FHI. The study was approved by a Regional Ethical Review Board. Data from 174 Swedish participants, family members to persons with cognitive dysfunctions (n = 95) and nursing students (n = 79) were included. Family members were enrolled in outpatient clinics in primary care and rehabilitation, and nursing students at a nursing school. Psychometric properties were evaluated through calculations of missing data, distributions of item and scale scores, item correlations, Cronbach's alpha, confirmatory factor analyses and correlations with theoretically related constructs. Sample scores had acceptable data quality, internal consistency for the FHI total scale was satisfactory (alpha = 0.86), and construct validity was supported. Our findings cast some doubt on the intended interpretation since confirmatory factor analyses showed that a modified four-subscale version, excluding one subscale, showed best fit. The Control subscale lacked important psychometric properties in terms of homogeneity, internal consistency and construct validity. The sample size was probably sufficiently large for the factor analyses, but the subgroup analyses should be treated with caution. The conclusion is that the Swedish version of the FHI is a promising scale for assessing family hardiness, but more solid evidence for the factor structure in various Swedish and international samples is needed. PMID- 26766615 TI - Fluorescent and colorimetric sensors for the detection of humidity or water content. AB - In this tutorial review, we describe the current state of the art in water sensors and provide an overview of the major advances made in this field post 2000. The field is currently still in its early development stages and subject to continuous improvements, and the current work provides a structured approach describing different sensing mechanisms and potential future applications associated with each of these. With these developments and their potential implications for the diverse scientific fields requiring tight control over the water content, we strongly believe the discipline is potentially at the threshold of translation into more widespread application and we hope the current review might allow for an expedited process thereof. PMID- 26766616 TI - Implicit Theory Of Psychopathology. AB - Inferential relationships of psychopathological traits were mapped by applying multidimensional scaling to judgments of the probability of joint endorsement of pairs of personality items from the Differential Personality Inventory. Three bipolar dimensions of inference, identified as uncontrolled impulse expression vs. inhibition and withdrawal, cognitive dysfunctioning vs. overcontrol and denial, and resignation vs. interpersonal conflict, were obtained. The correspondence between the inferential configuration obtained in the multidimensional scaling and the empirical structure derived from a factor analysis of the inventory's scales, administered with standard self-report instructions to an independent sample, was interpreted as indicating that implicit theory regarding psychopathology possessed some validity. PMID- 26766617 TI - The Structural Analysis Of Multivariate Data: A Sketch Of A General Theory. AB - It is shown that two major principles and two minor principles serve to generate a large number of multivariate models. A general treatment based on asymptotic properties of the likelihood ratio yields solutions to problems of local identifiability, estimation, and hypothesis-testing. PMID- 26766618 TI - Prose Representation: A Multidimensional Scaling Approach. AB - Multidimensional scaling was employed to study the comprehension of prose. Subjects rated the similarity between pairs of 20 nouns before reading. After reading a passage containing the nouns, the subjects re-rated the words with respect to similarity within the passage. Subjects then recalled the passage. The similarity ratings were analyzed by multidimensional scaling. The results indicated that the scaling analysis provided an effective, valid indicator of prose representation. The multidimensional structural characteristics of dimension interpretation, clustering, and centrality were interpreted in terms of the theme, episodes, and central organizing feature of the story, respectively. Theoretically, the analysis indicated that comprehension was a function of the passage organization mapping onto the existing memory structure superimposed upon and suppressing the prior conceptual structure. PMID- 26766614 TI - Enzyme replacement for GM1-gangliosidosis: Uptake, lysosomal activation, and cellular disease correction using a novel beta-galactosidase:RTB lectin fusion. AB - New enzyme delivery technologies are required for treatment of lysosomal storage disorders with significant pathologies associated with the so-called "hard-to treat" tissues and organs. Genetic deficiencies in the GLB1 gene encoding acid beta-galactosidase lead to GM1-gangliosidosis or Morquio B, lysosomal diseases with predominant disease manifestation associated with the central nervous system or skeletal system, respectively. Current lysosomal ERTs are delivered into cells based on receptor-mediated endocytosis and do not effectively address several hard-to-treat organs including those critical for GM1-gangliosidosis patients. Lectins provide alternative cell-uptake mechanisms based on adsorptive-mediated endocytosis and thus may provide unique biodistribution for lysosomal disease therapeutics. In the current study, genetic fusions of the plant galactose/galactosamine-binding lectin, RTB, and the human acid beta galactosidase enzyme were produced using a plant-based bioproduction platform. beta-gal:RTB and RTB:beta-gal fusion products retained both lectin activity and beta-galactosidase activity. Purified proteins representing both fusion orientations were efficiently taken up into GM1 patient fibroblasts and mediated the reduction of GM1 ganglioside substrate with activities matching mammalian cell-derived beta-galactosidase. In contrast, plant-derived beta-gal alone was enzymatically active but did not mediate uptake or correction indicating the need for either lectin-based (plant product) or mannose-6-phosphate-based (mammalian product) delivery. Native beta-galactosidase undergoes catalytic activation (cleavage within the C-terminal region) in lysosomes and is stabilized by association with protective protein/cathepsin A. Enzymatic activity and lysosomal protein processing of the RTB fusions were assessed following internalization into GM1 fibroblasts. Within 1-4h, both beta-gal:RTB and RTB:beta-gal were processed to the ~64kDa "activated" beta-gal form; the RTB lectin was cleaved and rapidly degraded. The activated beta-gal was still detected at 48h suggesting interactions with protective protein/cathepsin A. Uptake-saturation analyses indicated that the RTB adsorptive-mediated mechanisms of beta-gal:RTB supported significantly greater accumulation of beta-galactose activity in fibroblasts compared to the receptor-mediated mechanisms of the mammalian cell-derived beta gal. These data demonstrate that plant-made beta-gal:RTB functions as an effective replacement enzyme for GM1-gangliosidosis - delivering enzyme into cells, enabling essential lysosomal processing, and mediating disease substrate clearance at the cellular level. RTB provides novel uptake behaviors and thus may provide new receptor-independent strategies that could broadly impact lysosomal disease treatments. PMID- 26766619 TI - Hierarchical Cluster Analysis And The Internal Structure Of Tests. AB - Hierachical cluster analysis is shown to be an effective method for forming scales from sets of items. The number of scales to form from a particular item pool is found by testing the psychometric adequacy of each potential scale. Higher-order scales are formed when they are more adequate than their component sub-scales. It is suggested that a scale's adequacy should be assessed by a new measure of internal consistency reliability, coefficient beta, which is defined as the worst split-half reliability of the test. Comparisons with other procedures show that hierarchical clustering algorithms using this psychometrically based decisions rule can be more useful for scale construction using large item pools than are conventional factor analytic techniques. PMID- 26766620 TI - The Common Item In Measurement: Effects On Structure. AB - Procedures for analyzing common item effects on the inference of personality structure were reviewed and a study using smallest space analysis of the CPI reported. Solutions to three matrices -- intercorrelation matrix of the original CPI scales, of reduced scales (with common items removed), and of the number of common items -- were compared visually, and by interpoint distance correlations and configurational similarity analyses. Marked similarity among the original structure, the item-overlap-free structure and the built-in structure was observed. It was concluded that common items magnify an intrinsic structure already existing among scales and that the common-item problem is not likely a serious on in personality measurement. PMID- 26766621 TI - Applications Of A Theorem On The Traces Of Certain Matrix Products. AB - Two applications of Kristof's theorem on traces of matrix products are presented. One is a simplified demonstration of the method for finding a set of derived orthogonal variables maximally correlated with the original set, and the other one is a demonstration of rotational equivalence of least squares factor analyses of a given rank. The solutions are derived algebraically, without calculus, employing the Eckart-Young decomposition. PMID- 26766622 TI - On The Nonintuitive Nature Of The Correlation Coefficient: Subjective Estimation Of Three-Variable Relations. AB - The misleading character of the correlation coefficient was investigated in two studies of intuitive statistical behaviour: subjective estimation of partial correlation and subjective estimation of the minimum possible correlation between two variables given their equal correlation with a third. Fourteen Psychology Department faculty and graduate students provided estimates of partial correlations, r[SUBxy.z'] for varying positive values of rxy and rxy = ryz. Mean estimated rxy.z values were uniformly lower than theoretical (actual) values. Twenty-four statistics students and sixteen Statistics Department faculty and graduate students furnished estimates of minimum possible correlations, min rxy' for varying positive values of rxz = ryz. For both samples mean estimated min rxy was higher than the theoretical (actual) min rxy. Thus, in both studies, subjective overestimated the degree of influence on the correlation between two variables, X and Y, of a third, constraining variable, Z. The Hazards of intuitive statistical inference in the interpretation of correlational data are are discussed. PMID- 26766623 TI - Reply: T-Cell Acute Lymphoblastic Leukemia, Minimal Residual Disease, and Lymphocyte Recovery. PMID- 26766624 TI - Profile. PMID- 26766625 TI - Insights into the protective role of solid lipid nanoparticles on rosmarinic acid bioactivity during exposure to simulated gastrointestinal conditions. AB - The evaluation of the digestion effects on bioactive solid lipid nanoparticles (SLN) was performed. For this purpose, witepsol and carnauba SLN loaded with rosmarinic acid (RA) were exposed to the simulated gastrointestinal tract (GIT) conditions prevailing in stomach and small intestine. The simulation of intestinal epithelium was made with a dialysis bag and intestinal cell culture lines. Changes on SLN physical properties, RA release and absorption profiles were followed at each step. Combination of digestion pH and enzymes showed a significant effect upon SLN physical properties. Zeta potential values increased at stomach conditions and decreased at small intestine simulation. Also, at intestine, SLN increased their sizes and released 40-60% of RA, maintaining its initial antioxidant activity values. Sustained release of 40% of RA from SLN was also observed in dialysis tube. At CaCo-2 cell line, both types of SLN showed similar absorbed RA % (ca. 30%). Nevertheless, in CaCo-2/HT29x mix cell lines, for carnauba SLN a lower adsorption RA % was observed than for witepsol SLN. Solid lipid nanoparticles protected RA bioactivity (in terms of antioxidant activity) until reaching the intestine. A controlled release of RA from SLN was achieved and a significant absorption was observed at intestinal cells. Overall, SLN produced with witepsol showed a higher stability than carnauba SLN. PMID- 26766626 TI - Switzerland: Health System Review. AB - This analysis of the Swiss health system reviews recent developments in organization and governance, health financing, health care provision, health reforms and health system performance. The Swiss health system is highly complex, combining aspects of managed competition and corporatism (the integration of interest groups in the policy process) in a decentralized regulatory framework shaped by the influences of direct democracy. The health system performs very well with regard to a broad range of indicators. Life expectancy in Switzerland (82.8 years) is the highest in Europe after Iceland, and healthy life expectancy is several years above the European Union (EU) average. Coverage is ensured through mandatory health insurance (MHI), with subsidies for people on low incomes. The system offers a high degree of choice and direct access to all levels of care with virtually no waiting times, though managed care type insurance plans that include gatekeeping restrictions are becoming increasingly important. Public satisfaction with the system is high and quality is generally viewed to be good or very good. Reforms since the year 2000 have improved the MHI system, changed the financing of hospitals, strengthened regulations in the area of pharmaceuticals and the control of epidemics, and harmonized regulation of human resources across the country. In addition, there has been a slow (and not always linear) process towards more centralization of national health policy making. Nevertheless, a number of challenges remain. The costs of the health care system are well above the EU average, in particular in absolute terms but also as a percentage of gross domestic product (GDP) (11.5%). MHI premiums have increased more quickly than incomes since 2003. By European standards, the share of out-of pocket payments is exceptionally high at 26% of total health expenditure (compared to the EU average of 16%). Low and middle-income households contribute a greater share of their income to the financing of the health system than higher income households. Flawed financial incentives exist at different levels of the health system, potentially distorting the allocation of resources to different providers. Furthermore, the system remains highly fragmented as regards both organization and planning as well as health care provision. PMID- 26766627 TI - First record of Talaromyces udagawae in soil related to decomposing human remains in Argentina. AB - The morphologic features of Talaromyces udagawae Stolk and Samson are here described and illustrated. This teleomorphic Ascomycota fungus was isolated from soil obtained in Buenos Aires province (Argentina) from beneath a human cadaver in an advanced state of decomposition. After washing and serial dilution of the soil along with moist-chamber techniques for fungal cultivation, T. udagawae formed very restricted colonies of bright yellow color on different growth media with 8-ascospored asci. The ascospores were ellipsoidal and ornamented. The anamorphic state was not observed. Molecular-genetic techniques identified the species. The present record is the first of the species in Argentina, pointing it as a tool to identify soils where cadaver decomposition occurs. PMID- 26766628 TI - Enhancement of Curcumin Solubility by Phase Change from Crystalline to Amorphous in Cur-TPGS Nanosuspension. AB - Nanosuspensions (NSs) were fabricated to enhance water solubility, dissolution rate, and oral adsorption of water insoluble curcumin using sonoprecipitation method. As a good stabilizer, d-alpha-Tocopherol polyethylene glycol 1000 succinate (TPGS) was used to improve the stability of curcumin-TPGS NSs (Cur-TPGS NSs). Ultrasonic homogenization (UH) could effectively enhance the solubility of curcumin and to produce homogeneous NSs with small particle sizes. Water solubility of curcumin was significantly improved from 0.6 MUg/mL in pure water to 260 MUg/mL in the mixture of curcumin and TPGS (1:10) with UH treatment. The mean particle size of Cur-TPGS NSs was decreased significantly after UH and maintained between 208 and 246 nm. Lyophilized powder of Cur-TPGS NSs was dissolved about 91.08% whereas the pristine curcumin powder was dissolved only 6.5% at pH 7.4. This study showed a great potential of Cur-TPGS NSs as a good nano-formulation of curcumin with enhanced solubility and improved oral adsorption. PMID- 26766629 TI - Brief, Ultrabrief, and Intermediate--or Simply Milliseconds. PMID- 26766630 TI - Time-Course of Depression Improvement With Ketamine Adjunction in Electroconvulsive Therapy. PMID- 26766631 TI - Changes in Problem-Solving Capacity After a Single Electroconvulsive Treatment. PMID- 26766632 TI - Fabrication and characterization of Eri silk fibers-based sponges for biomedical application. AB - Cocoon-derived semi-domesticated Eri silk fibers still lack exploitation for tissue engineering applications due to their poor solubility using conventional methods. The present work explores the ability to process cocoon fibers of non mulberry Eri silk (Samia/Philosamia ricini) into sponges through a green approach using ionic liquid (IL)--1-buthyl-imidazolium acetate as a solvent. The formation of beta-sheet structures during Eri silk/IL gelation was acquired by exposing the Eri silk/IL gels to a saturated atmosphere composed of two different solvents: (i) isopropanol/ethanol (physical stabilization) and (ii) genipin, a natural crosslinker, dissolved in ethanol (chemical crosslinking). The sponges were then obtained by freeze-drying. This approach promotes the formation of both stable and ordered non-crosslinked Eri silk fibroin matrices. Moreover, genipin crosslinked silk fibroin sponges presenting high height recovery capacity after compression, high swelling degree and suitable mechanical properties for tissue engineering applications were produced. The incorporation of a model drug- ibuprofen--and the corresponding release study from the loaded sponges demonstrated the potential of using these matrices as effective drug delivery systems. The assessment of the biological performance of ATDC5 chondrocyte-like cells in contact with the developed sponges showed the promotion of cell adhesion and proliferation, as well as extracellular matrix production within 2 weeks of culture. Sponges' intrinsic properties and biological findings open up their potential use for biomedical applications. STATEMENT OF SIGNIFICANCE: This work addresses the preparation and characterization of non-mulberry cocoon-derived Eri silk sponges. The insolubility of cocoons-derived non-mulberry silkworms impairs their processability and applications in the healthcare field. We used a green approach with ionic liquids to overcome the lack solubility of such silk fibers. The formation of beta-sheet structures into Eri-based sponges was physically and chemically induced. The sponges were obtained by freeze-drying. The developed structures exhibited flexibility to adapt and recover their shapes upon application and subsequent removal of load, high swelling degree, ability to load an anti-inflammatory drug and to promote its sustained release. They promoted in vitro cellular adhesion, proliferation and extracellular matrix production of a chondrocyte-like cell line, opening up their potential application for biomedical applications. PMID- 26766633 TI - In situ longitudinal pre-stretch in the human femoropopliteal artery. AB - In situ longitudinal (axial) pre-stretch (LPS) plays a fundamental role in the mechanics of the femoropopliteal artery (FPA). It conserves energy during pulsation and prevents buckling of the artery during limb movement. We investigated how LPS is affected by demographics and risk factors, and how these patient characteristics associate with the structural and physiologic features of the FPA. LPS was measured in n=148 fresh human FPAs (14-80 years old). Mechanical properties were characterized with biaxial extension and histopathological characteristics were quantified with Verhoeff-Van Gieson Staining. Constitutive modeling was used to calculate physiological stresses and stretches which were then analyzed in the context of demographics, risk factors and structural characteristics. Age had the strongest negative effect (r=-0.812, p<0.01) on LPS and could alone explain 66% of LPS variability. Male gender, higher body mass index, hypertension, diabetes, coronary artery disease, dyslipidemia and tobacco use had negative effects on LPS, but only the effect of tobacco was not associated with aging. FPAs with less pre-stretch had thicker medial layers, but thinner intramural elastic fibers with less dense and more fragmented external elastic laminae. Elastin degradation was associated with decreased physiological tethering force and longitudinal stress, while circumferential stress remained constant. FPA wall pathology was negatively associated with LPS (r=-0.553, p<0.01), but the effect was due primarily to aging. LPS in the FPA may serve as an energy reserve for adaptive remodeling. Reduction of LPS due to degradation and fragmentation of intramural longitudinal elastin during aging can be accelerated in tobacco users. STATEMENT OF SIGNIFICANCE: This work studies in situ longitudinal pre-stretch (LPS) in the human femoropopliteal artery. LPS has a fundamental role in arterial mechanics, but is rather poorly studied due to lack of direct in vivo measurement method. We have investigated LPS in the n=148 human femoropopliteal arteries in the context of subject demographics and risk factors, and structural and physiologic characteristics of the artery. Our results demonstrate that LPS reduces with age due to degradation and fragmentation of intramural elastin. LPS may serve as an energy reserve for adaptive remodeling, and reduction of LPS can be accelerated in tobacco users. PMID- 26766634 TI - Interactions between N-Ethylmaleimide-sensitive factor and GluA2 contribute to effects of glucocorticoid hormones on AMPA receptor function in the rodent hippocampus. AB - Glucocorticoid hormones, via activation of their receptors, promote memory consolidation, but the exact underlying mechanisms remain elusive. We examined how corticosterone regulates AMPA receptor (AMPAR) availability in the synapse, which is important for synaptic plasticity and memory formation. Peptides which specifically block the interaction between N-Ethylmaleimide-Sensitive Factor (NSF) and the AMPAR-subunit GluA2 prevented the increase in synaptic transmission and surface expression of AMPARs known to occur after corticosterone application to hippocampal neurons. Combining a live imaging Fluorescence Recovery After Photobleaching (FRAP) approach with the use of the pH-sensitive GFP-AMPAR tagging revealed that this NSF/GluA2 interaction was also essential for the increase of the mobile fraction and reduction of the diffusion of AMPARs after treating hippocampal neurons with corticosterone. We conclude that the interaction between NSF and GluA2 contributes to the effects of corticosterone on AMPAR function. (c) 2016 Wiley Periodicals, Inc. PMID- 26766635 TI - Programmed Switching of Single Polymer Conformation on DNA Origami. AB - DNA nanotechnology offers precise geometrical control of the positioning of materials, and it is increasingly also being used in the development of nanomechanical devices. Here we describe the development of a nanomechanical device that allows switching of the position of a single-molecule conjugated polymer. The polymer is functionalized with short single-stranded (ss) DNA strands that extend from the backbone of the polymer and serve as handles. The DNA polymer conjugate can be aligned on DNA origami in three well-defined geometries (straight line, left-turned, and right-turned pattern) by DNA hybridization directed by single-stranded guiding strands and ssDNA tracks extending from the origami surface and polymer handle. We demonstrate switching of a conjugated organic polymer conformation between left- and right-turned conformations of the polymer on DNA origami based on toehold-mediated strand displacement. The switching is observed by atomic force microscopy and by Forster resonance energy transfer between the polymer and two different organic dyes positioned in close proximity to the respective patterns. Using this method, the polymer conformation can be switched six times successively. This controlled nanomechanical switching of conjugated organic polymer conformation demonstrates unique control of the shape of a single polymer molecule, and it may constitute a new component for the development of reconfigurable nanophotonic and nanoelectronic devices. PMID- 26766637 TI - Comparing Different Decontamination Procedures in Harvesting Human Donor Cornea. AB - PURPOSE: To evaluate the effects of current hygiene standards for the enucleation of postmortem eyes by investigating the number of microorganisms during subsequent steps of decontamination and tissue processing. MATERIALS AND METHODS: This prospective, non-randomized cohort study includes 184 postmortem eyes of 92 human donors. Enucleation was performed, according to an ophthalmic surgical procedure. Two groups were generated as follows: right eyes were allocated to group A, left eyes were allocated to group B. In group A, a mucosal disinfectant was used accessorily. Conjunctival smears were taken to examine germ load in both groups before any intervention, in group A after mucosal disinfection, in both groups after transportation of the whole globes in transport fluid, and in both groups after a bath in 0.75% povidone iodine solution for at least 3 minutes just before preparation of the corneoscleral disc. Smears were sent to the local microbiologic laboratory in an aseptic package for testing. RESULTS: All smears showed multiple contaminations (n = 184/184 eyes) before treatment with povidone iodine solution. Contamination was in both groups significantly prevented using the treatment strategy of an at least 3-minute bath in 0.75% povidone iodine solution (n = 1/184 eyes; p < 0.01) As a side effect, almost every eye of group A and none of group B showed brown iodine staining corresponding to corneal epithelial erosion. CONCLUSIONS: An aseptic setting for donor enucleation similar to a surgical procedure seems not to influence the outcome of germ colonization. The most effective step to decontaminate donor eyes is to use 0.75% povidone iodine solution for at least 3 minutes. PMID- 26766666 TI - Amphiphilic Copolymers Shuttle Drugs Across the Blood-Brain Barrier. AB - Medical treatment of diseases of the central nervous system requires transport of drugs across the blood-brain barrier (BBB). Here, it is extended previously in vitro experiments with a model compound to show that the non-water-soluble and brain-impermeable drug domperidone (DOM) itself can be enriched in the brain by use of an amphiphilic copolymer as a carrier. This carrier consists of poly(N-(2 hydroxypropyl)-methacrylamide), statistically copolymerized with 10 mol% hydrophobic lauryl methacrylate, into whose micellar aggregates DOM is noncovalently absorbed. As tested in a BBB model efficient transport of DOM across, the BBB is achievable over a wide range of formulations, containing 0.8 to 35.5 wt% domperidone per copolymer. In neither case, the polymer itself is translocated across the BBB model. In vivo experiments in mice show that already 10 min after intraperitoneal injection of the polymer/domperidone (PolyDOM) formulation, domperidone can be detected in blood and in the brain. Highest serum and brain levels of domperidone are detected 40 min after injection. At that time point serum domperidone is increased 48-fold. Most importantly, domperidone is exclusively detectable in high amounts in the brain of PolyDOM injected mice and not in mice injected with bare domperidone. PMID- 26766667 TI - The effect of junction modes between backbones and side chains of polyimides on the stability of liquid crystal vertical alignment. AB - Polyimides (PI-N9 and PI-N12) were synthesized from two kinds of functional diamines, whose junction modes between backbones and side chains were different. Side chains of PI-N9 were linked to the backbones with an ether bond spacer; and side chains of PI-N12 were directly linked to the backbones without any spacer. The PI alignment layer surfaces were investigated by atomic force microscopy, surface free energy measurements, X-ray photo-electron spectroscopy and polarized attenuated total reflection Fourier transformed infrared spectroscopy. It was found that PI-N9 lost the vertical alignment capability after high-strength rubbing, while PI-N12 could still induce liquid crystals (LCs) to align vertically under the same condition. The mechanism of the macroscopic molecular orientation of the PI surface is proposed. During the high-strength rubbing process, the side chain could rotate around the flexible ether bond which existed between the side chain and the main chain of PI-N9 and then fell over. Therefore, PI-N9 could not induce the vertical alignment of LCs anymore. But PI-N12 could keep LCs aligning vertically all the time, which proved that the stability of LC alignment induced by PI-N12 was better. PMID- 26766636 TI - New Amniotic Membrane Based Biocomposite for Future Application in Reconstructive Urology. AB - OBJECTIVE: Due to the capacity of the amniotic membrane (Am) to support re epithelisation and inhibit scar formation, Am has a potential to become a considerable asset for reconstructive urology i.e., reconstruction of ureters and urethrae. The application of Am in reconstructive urology is limited due to a poor mechanical characteristic. Am reinforcement with electrospun nanofibers offers a new strategy to improve Am mechanical resistance, without affecting its unique bioactivity profile. This study evaluated biocomposite material composed of Am and nanofibers as a graft for urinary bladder augmentation in a rat model. MATERIAL AND METHODS: Sandwich-structured biocomposite material was constructed from frozen Am and covered on both sides with two-layered membranes prepared from electrospun poly-(L-lactide-co-E-caprolactone) (PLCL). Wistar rats underwent hemicystectomy and bladder augmentation with the biocomposite material. RESULTS: Immunohistohemical analysis (hematoxylin and eosin [H&E], anti-smoothelin and Masson's trichrome staining [TRI]) revealed effective regeneration of the urothelial and smooth muscle layers. Anti-smoothelin staining confirmed the presence of contractile smooth muscle within a new bladder wall. Sandwich structured biocomposite graft material was designed to regenerate the urinary bladder wall, fulfilling the requirements for normal bladder tension, contraction, elasticity and compliance. Mechanical evaluation of regenerated bladder wall conducted based on Young's elastic modulus reflected changes in the histological remodeling of the augmented part of the bladder. The structure of the biocomposite material made it possible to deliver an intact Am to the area for regeneration. An unmodified Am surface supported regeneration of the urinary bladder wall and the PLCL membranes did not disturb the regeneration process. CONCLUSIONS: Am reinforcement with electrospun nanofibers offers a new strategy to improve Am mechanical resistance without affecting its unique bioactivity profile. PMID- 26766668 TI - [Evaluation and Utilization - Quality Management in a Paediatric University Outpatient Department]. AB - BACKGROUND: Based on an increasing number of outpatient treatments, an extensive demand planning is necessary to ensure the quality of medical care. University outpatient clinics are special parts of this sector and therefore it is necessary that a research demonstrates the nearly uninvestigated position of a paediatric outpatient clinic. PATIENTS: The research at the university hospital for children and adolescents in Leipzig started in 2009 to survey 2283 of in total 9391 patients and the physicians. METHODS: Sociodemographic data as well as economic and medical facts were determined by using questionnaires. In each case a questionnaire was answered by the children or their accompanying persons and a separate one was completed by the respective doctor. RESULTS: The results created a foundation, on the basis of patient volume per day and per daytime. Less than 20% of the children admitted to consult the clinic for their first time. The majority of patients visit them because of a letter of referral. Most of the patients (58%) were younger than 6 years old. Approximately 35% of patients did not come from the city region of Leipzig. CONCLUSION: The investigation evidenced the necessity of a day and night operating institution for children in the region of Leipzig as well as the high specialisation of the outpatient clinic. In need of further investigation is the cooperation between several physicians to find out if this lots of medical examination are necessary or if there took place overlapping. PMID- 26766669 TI - [Significance of Thoracic Surgery for Treatment of Pleural Empyema in Childhood and Adolescence]. AB - BACKGROUND: There still is controversy about surgical treatment of pleural empyema in children. PATIENTS AND METHODS: Retrospective analysis of treatment strategy, focussing on indication for surgery and outcome of children treated in 2 centres for pleural complications due to primary pneumonia from January 1(st) 2008 to December 31(st) 2012. RESULTS were compared to studies published within the last 10 years. RESULTS: 1 451 children with pneumonia were treated during the 5 year period. 187 (average age 6.1 years, sex: 86/101 f/m) developed a pleural effusion. THERAPY: pleural punction in 22 children, chest tube in 78 and operation in 37 children. In 9 cases microorganisms were identified. 34 children were operated for empyema stage II, only 3 for stage III. 3 children were operated due to septicaemia not responding to antibiotics. Time from admission to operation (including referring hospital):14.5 days. Time from operation to discharge: 12,5 days. All children but one were operated by thoracoscopy. COMPLICATIONS: 1 bronchopleural fistula, 1 delayed healing of the wound. All children survived and fully recovered mean (observation period 28 months postoperatively). SUMMARY: In experienced hands thoracic surgery yields excellent results for children suffering from pleural empyema stage II and III. Recent randomised prospective trials comparing fibrinolysis with VATS do not convince regarding the treatment protocols of their surgical arms. Fibrinolysis is nevertheless a valuable treatment in early stage II empyema, especially if thoracic surgical experience is not available. However, the further advanced the empyema presents, the sooner surgical experience should be gathered. PMID- 26766670 TI - What are Palliative Care Physicians for Adults Taught on Palliative Care for Children? Paediatric Aspects in Palliative Care Curricula for Adults. AB - BACKGROUND: Children suffering from life limiting diseases are frequently cared for by adult palliative care teams due to missing paediatric structures in that field. However it is questionable whether palliative care curricula for physicians comprehensively cover issues of paediatric palliative care (PaedPC). AIM: To identify all PaedPC issues included in inter-professional or medical palliative care curricula (PCC) and to evaluate the breadth and quality of PaedPC issues covered in these curricula. DESIGN: Inter-professional or medical palliative care curricula (PCC) were identified by an extensive literature review in German and English using the search-engines Google as well as Medline, MedPilot and Pubmed. RESULTS: Worldwide 30 PCC were identified, with only 15 curricula mentioning any PaedPC issues. Of those 15 curricula, up to 22 PaedPC topics were highlighted in each. In 10 or more PaedPC following topics were highlighted: grief and bereavement in family, parents and siblings; communication with children; paediatric malignancies; pain management in PPC and pharmacology. In the majority of PCC curricula where PaedPC issues were identified the following topics were mentioned- grief and bereavement in the family, parents and siblings, communication with children, paediatric malignancies, paediatric pain management and pharmacology. CONCLUSIONS: The variability of inclusion of PaedPC issues and the lack of depth and standardisation of knowledge, skills and attitudes in PaedPC issues included in PCC curricula is not sufficient to guide adult palliative care physicians in their clinical work with children suffering from life limiting diseases. PMID- 26766671 TI - [In Process Citation]. PMID- 26766672 TI - Sourceless optical fiber high temperature sensor. AB - A sourceless sapphire fiber extrinsic Fabry-Perot interferometer for ultrahigh temperature sensing is developed. A sapphire wafer is mounted on the tip of a sapphire fiber as the Fabry-Perot cavity. The interference signal is generated by the thermal radiation that transmits through the wafer and is guided to a spectrometer by a sapphire and then a silica fiber. The entire sensor system is compact and low cost. The sensor was experimentally tested up to 1593 degrees C, and a resolution around 1 degrees C was achieved. PMID- 26766673 TI - Frequency-doubled triangular-shaped waveform generation based on spectrum manipulation. AB - In this approach, spectrum manipulation is employed in triangular-shaped waveform generation. By aligning the power of five primary modulation sidebands, optical intensity with expression corresponding to the first two-term Fourier expansion of triangular-shaped waveform can be obtained. It is found that the modulation index in this Letter is no longer a fixed one, but should be within a proper range (2-3). Triangular-shaped waveform signals can be generated by using a single-drive Mach-Zehnder modulator, a standard optical interleaver, and a grating. The principle is illustrated by theory, simulation, and experiment. A 20 GHz triangular-shaped waveform signal is experimentally generated by using a 10 GHz sinusoid signal, which agrees well with the theoretical prediction and shows great potential in generating a high-quality intensity profile. PMID- 26766674 TI - Fabrication of ultrafast laser written low-loss waveguides in flexible As2S3 chalcogenide glass tape. AB - As2S3 glass has a unique combination of optical properties, such as wide transparency in the infrared region and a high nonlinear coefficient. Recently, intense research has been conducted to improve photonic devices using thin materials. In this Letter, highly uniform rectangular single-index and 2 dB/m loss step-index optical tapes have been drawn by the crucible technique. Low-loss (<0.15 dB/cm) single-mode waveguides in chalcogenide glass tapes have been fabricated using femtosecond laser writing. Optical backscatter reflectometry has been used to study the origin of the optical losses. A detailed study of the laser writing process in thin glass is also presented to facilitate a repeatable waveguide inscription recipe. PMID- 26766675 TI - Compensation of spatial dispersion of an acousto-optic deflector with a special Keplerian telescope. AB - Compensation of spatial dispersion caused by the acousto-optic deflector (AOD) when using a femtosecond laser is difficult across the whole scanning range of the system, and this is a significant impediment to its use. In conventional methods, the dispersion of the AOD was compensated only when it was at a particular position, while at other positions, the quality of the light beam was reduced. We developed a novel method for compensating the spatial dispersion within the entire scanning range using a special Keplerian telescope. Our experimental results show that the residual dispersion of the AOD is compensated sufficiently, and the focal spots of the laser reach the diffraction limit within a 40-MHz ultrasound bandwidth. PMID- 26766676 TI - Rotation of millimeter-sized objects using ordinary light. AB - The ability to optically rotate bodies offers new degrees of control of micro objects with applications in various domains, including microelectromechanical systems (MEMS), biomanipulations, or optofluidics. Here we demonstrate the optically-induced rotation of simple asymmetric two-dimensional objects using plane waves originating either from ordinary laser sources or from black body radiation. The objects are floating on an air/water interface. We observe a steady-state rotation depending on the light intensity and on the asymmetry of the object. We interpret this rotation in terms of light diffraction by the edges of the object. Such systems could be easily implemented in optofluidic devices to induce liquid flow without the need for special light sources. PMID- 26766677 TI - Ultra-wide wavelength tuning of a cascaded Raman random fiber laser. AB - An ultra-broadband tunable cascaded Raman random fiber laser pumped by a tunable (1020-1080 nm) ytterbium-doped fiber laser is investigated. By continuously adjusting the pump laser wavelength, the Raman random laser tunes accordingly due to the Raman gain competition. By increasing the pump power, up to the 5th order Raman random laser is achieved. As a result, 300 nm of continuous wavelength tuning from 1070 to 1370 nm is achieved by adjusting the pump wavelength and power altogether. The highest output power is 1.8 W at 1360 nm with an optical efficiency of 15% from 1080 nm. To the best of our knowledge, this is the widest wavelength tuning range reported for a random fiber laser so far. PMID- 26766678 TI - General approach for modeling partial coherence in spectroscopic Mueller matrix polarimetry. AB - We present a general formalism for modeling partial coherence in spectroscopic Mueller matrix measurements of stratified media. The approach is based on the statistical definition of a Mueller matrix, as well as, on the fundamental representation of the measurement process as the convolution of the sample response with a specific instrumental function. The formalism is readily extended to describe other measurement imperfections occurring jointly with partial coherence and resulting in depolarizing experimental Mueller matrices. PMID- 26766679 TI - Tunable squeezing using coupled ring resonators on a silicon nitride chip. AB - We demonstrate continuous tuning of the squeezing-level generated in a double ring optical parametric oscillator by externally controlling the coupling condition using electrically controlled integrated microheaters. We accomplish this by utilizing the avoided crossing exhibited by a pair of coupled silicon nitride microring resonators. We directly detect a change in the squeezing level from 0.5 dB in the undercoupled regime to 2 dB in the overcoupled regime, which corresponds to a change in the generated on-chip squeezing factor from 0.9 to 3.9 dB. Such wide tunability in the squeezing level can be harnessed for on-chip quantum-enhanced sensing protocols that require an optimal degree of squeezing. PMID- 26766680 TI - Compact and low-loss asymmetrical multimode interference splitter for power monitoring applications. AB - This Letter presents a compact and low-loss 1*2 asymmetrical multimode interference (A-MMI) splitter in rib geometry for on-chip power monitoring at 1.55 MUm, where a given alteration of the component cavity determines arbitrary values of the output power splitting ratios. The device shows reduced losses (~0.4-0.8 dB) and robustness across a 40 nm optical bandwidth (1540-1580 nm). PMID- 26766681 TI - Neutral particles pushed or pulled by laser pulses. AB - Acceleration of neutral particles is of great importance in many areas, such as controlled chemical reactions, atomic nanofabrication, and atom optics. Recent experimental studies have shown that pulsed lasers can be used to push neutral Rydberg atoms forward [Nature 461, 1261 (2009)10.1038/nature08481; Nat. Photonics 6, 386 (2012)10.1038/nphoton.2012.87]. Our simulation shows that pulsed lasers can also be used to pull Rydberg atoms back toward a light source. In particular, we proposed a method of using two laser pulses on a neutral atom, then selective operations on the neutral atom (pushing or pulling) can be performed by adjusting the delay time between the two laser pulses. PMID- 26766682 TI - Coherent combination of femtosecond pulses via non-collinear cross-correlation and far-field distribution. AB - We propose and demonstrate a method for active parallel coherent combinations of ultra-short laser pulses. The relative synchronization error, piston, and tilt between combined beams are controlled based on the non-collinear cross correlation and the far-field distribution. In a proof-of-principle experiment, two 29.8 fs pulses are coherently combined with the combining efficiency as high as 99%. This study opens up a way to further scale the peak intensity and provides support for the next-generation ultra-intense laser systems. PMID- 26766683 TI - All-optical short pulse translation through cross-phase modulation in a VO2 thin film. AB - VO2 is a promising material for reconfigurable photonic devices due to the ultrafast changes in electronic and optical properties associated with its dielectric-to-metal phase transition. Based on a fiber-optic, pump-probe setup at 1550 nm wavelength window, and by varying the pump-pulse duration, we show that the material phase transition is primarily caused by the pump-pulse energy. For the first time, we demonstrate that the instantaneous optical phase modulation of probe during pump leading edge can be utilized to create short optical pulses at probe wavelength, through optical frequency discrimination. This circumvents the impact of long recovery time well known for the phase transition of VO2. PMID- 26766684 TI - Enhanced nonresonant light transmission through subwavelength slits in metal. AB - We analytically describe light transmission through a single subwavelength slit in a thin perfect electric conductor screen for the incident polarization being perpendicular to the slit, and derive simple, yet accurate, expressions for the average electric field in the slit and the transmission efficiency. The analytic results are consistent with full-wave numerical calculations and demonstrate that slits of widths ~100 nm in real metals may feature nonresonant (i.e., broadband) field enhancements of ~100 and transmission efficiency of ~10 at infrared or terahertz frequencies, with the associated metasurface-like array of slits becoming transparent to the incident light. PMID- 26766685 TI - 615 fs pulses with 17 mJ energy generated by an Yb:thin-disk amplifier at 3 kHz repetition rate. AB - A combination of Er/Yb:fiber and Yb:thin-disk technology produces 615 fs pulses at 1030 nm with an average output power of 72 W. The regenerative amplifier allows variation of the repetition rate between 3 and 5 kHz with pulse energies from 13 to 17 mJ. A broadband and intense seed provided by the compact and versatile fiber front-end minimizes gain narrowing. The resulting sub-ps performance is ideal for nonlinear frequency conversion and pulse compression. Operating in the upper branch of a bifurcated pulse train, the system exhibits exceptional noise performance and stability. PMID- 26766687 TI - Diode-pumped tape casting planar waveguide YAG/Tm:YAG/YAG ceramic laser at 2013.76 nm. AB - We demonstrated the efficient guided laser action in a diode-pumped YAG/Tm:YAG/YAG ceramic planar waveguide fabricated by nonaqueous tape casting and solid-state reactive sintering technology for the first time, to the best of our knowledge. In the experiment, a maximum output power of 173 mW at a center wavelength of 2013.76 nm was obtained under an incident pump power of 10.3 W, corresponding to a slope efficiency of 3.0%. The beam quality M2=1.5 in a horizontal direction was measured at the highest output power. PMID- 26766686 TI - Optimal operational conditions for supercontinuum-based ultrahigh-resolution endoscopic OCT imaging. AB - We investigated the optimal operational conditions for utilizing a broadband supercontinuum (SC) source in a portable 800 nm spectral-domain (SD) endoscopic OCT system to enable high resolution, high-sensitivity, and high-speed imaging in vivo. A SC source with a 3-dB bandwidth of ~246 nm was employed to obtain an axial resolution of ~2.7 MUm (in air) and an optimal detection sensitivity of ~ 107 dB with an imaging speed up to 35 frames/s (at 70 k A-scans/s). The performance of the SC-based SD-OCT endoscopy system was demonstrated by imaging guinea pig esophagus in vivo, achieving image quality comparable to that acquired with a broadband home-built Ti:sapphire laser. PMID- 26766688 TI - Single-cell gap polymer-stabilized fringe-field switching transflective liquid crystal display. AB - Transflective liquid crystal displays are highly desired for mobile devices because they can be operated either in transmissive mode, illuminated by backlight in dark ambient light conditions, or reflective mode, illuminated by ambient light in bright ambient light conditions. We developed a single-cell gap transflective display based on fringe-field switching. The display consists of transmissive and reflective subpixels whose operations are synchronized through polymer stabilization. This display has a high contrast ratio because the transmittance-voltage dependences of the two subpixels are similar (they are both in dark state at 0 V and in bright state at an applied voltage) and do not interfere with each other. It has the advantages of single-cell gap and no in cell retarder and its manufacturing process is simple. PMID- 26766689 TI - Generation of a controllable multifocal array from a modulated azimuthally polarized beam. AB - In this Letter, the focal spot areas of an azimuthally polarized beam modulated with a vortex-0-2pi-phase plate or a pi-phase-step plate are numerically found to be smaller than a radially polarized beam for three pupil functions with uniform, Gaussian, and Bessel-Gauss profiles. Several types of multizone phase plates are theoretically designed and numerically simulated for generating tight multifocal arrays from the azimuthally polarized beams for what we believe is the first time. The positions and polarization states of the multifocal arrays can be controlled simply by varying the pattern of the multizone plates. The produced multifocal array with controllable position and polarization is beneficial to parallel optical recording and parallel optical imaging. PMID- 26766691 TI - Bright single-mode random laser from a concentrated solution of pi-conjugated polymers. AB - Using thin stripe excitation of a 10 ns pulsed laser, we observed robust and bright random laser (RL) emission in high concentrated solutions of poly[2 methoxy-5-(2-ethylhexyloxy)-1,4-phenylenevinylene] (MEH-PPV) and poly[2,6-(4,4 bis-(2-ethylhexyl)-4H-cyclopenta[2,1-b;3,4-b']-dithiophene)-alt-4,7-(2,1,3 benzothiadiazole)] (PCPDTBT). In particular, within the proper excitation intensity range, single line RL emission is observed in both solutions, with full width at half-maximum of 0.17 nm and 0.4 nm for MEH-PPV and PCPDTBT, respectively. The reason for the random laser is that the refractive index fluctuation due to the aggregation in concentrated solution results in spatially extended random lasing modes, which are amplified through traveling light along the interface between solution and cuvette. Our work provides a simple but effective method to achieve bright single-mode RLs, with conversion efficiency on the order of 10%. PMID- 26766690 TI - Simultaneous spatial frequency modulation imaging and micromachining with a femtosecond laser. AB - A Ti:Al2O3 chirped-pulse amplification system is used to simultaneously image and machine. By combining simultaneous spatial and temporal focusing (SSTF) with spatial frequency modulation for imaging (SPIFI), we are able to decouple the imaging and cutting beams to attain a resolution and a field-of-view that is independent of the cutting beam, while maintaining single-element detection. This setup allows for real-time feedback with the potential for simultaneous nonlinear imaging and imaging through scattering media. The novel SSTF machining platform uses refractive optics that, in general, are prohibitive for energetic, amplified pulses that might otherwise compromise the integrity of the focus as a result of nonlinear effects. PMID- 26766692 TI - Microwave photonic integrator based on a multichannel fiber Bragg grating. AB - We propose and experimentally demonstrate a microwave photonic integrator based on a multichannel fiber Bragg grating (FBG) working in conjunction with a dispersion compensating fiber (DCF) to provide a step group delay response with no in-channel dispersion-related distortion. The multichannel FBG is designed based on the spectral Talbot effect, which provides a large group delay dispersion (GDD) within each channel. A step group delay response can then be achieved by cascading the multichannel FBG with a DCF having a GDD opposite the in-channel GDD. An optical comb, with each comb line located at the center of each channel of the FBG, is modulated by a microwave signal to be integrated. At the output of the DCF, multiple time-delayed replicas of the optical signal, with equal time delay spacing are obtained and are detected and summed at a photodetector (PD). The entire operation is equivalent to the integration of the input microwave signal. For a multichannel FBG with an in-channel GDD of 730 ps/nm and a DCF with an opposite GDD, an integrator with a bandwidth of 2.9 GHz and an integration time of 7 ns is demonstrated. PMID- 26766693 TI - Measurement of microresonator frequency comb coherence by spectral interferometry. AB - We experimentally investigate the spectral coherence of microresonator optical frequency combs. Specifically, we use a spectral interference method, typically used in the context of supercontinuum generation, to explore the variation of the magnitude of the complex degree of first-order coherence across the full comb bandwidth. We measure the coherence of two different frequency combs and observe wholly different coherence characteristics. In particular, we find that the observed dynamical regimes are similar to the stable and unstable modulation instability regimes reported in previous theoretical studies. Results from numerical simulations are found to be in good agreement with experimental observations. In addition to demonstrating a new technique to assess comb stability, our results provide strong experimental support for previous theoretical analyses. PMID- 26766694 TI - Fabrication and characterization of high-efficiency double-sided blazed x-ray optics. AB - The focusing efficiency of conventional diffractive x-ray lenses is fundamentally limited due to their symmetric binary structures and the corresponding symmetry of their focusing and defocusing diffraction orders. Fresnel zone plates with asymmetric structure profiles can break this limitation; yet existing implementations compromise either on resolution, ease of use, or stability. We present a new way for the fabrication of such blazed lenses by patterning two complementary binary Fresnel zone plates on the front and back sides of the same membrane chip to provide a compact, inherently stable, single-chip device. The presented blazed double-sided zone plates with 200 nm smallest half-pitch provide up to 54.7% focusing efficiency at 6.2 keV, which is clearly beyond the value obtainable by their binary counterparts. PMID- 26766695 TI - Mid-infrared photodetectors operating over an extended wavelength range up to 90 K. AB - We report a wavelength threshold extension, from the designed value of 3.1 to 8.9 MUm, in a p-type heterostructure photodetector. This is associated with the use of a graded barrier and barrier offset, and arises from hole-hole interactions in the detector absorber. Experiments show that using long-pass filters to tune the energies of incident photons gives rise to changes in the intensity of the response. This demonstrates an alternative approach to achieving tuning of the photodetector response without the need to adjust the characteristic energy that is determined by the band structure. PMID- 26766696 TI - Slow-light effect in a silicon photonic crystal waveguide as a sub-bandgap photodiode. AB - We demonstrate a Si sub-bandgap photodiode in a photonic crystal slow-light waveguide that operates at telecom wavelengths and can be fabricated using a Ge free, standard Si-photonics CMOS process. In photodiodes based on absorption via mid-bandgap states, the slow-light enhancement enables performance that is well balanced among high responsivity, low dark current, high speed, wide working spectrum, and CMOS-process compatibility, all of which are otherwise difficult to achieve simultaneously. Owing to the slow-light effect and supplemental gain at a high reverse bias, the photodiode shows a responsivity of 0.15 A/W with a low dark current of 40 nA, which is attributed to no particular processes such as ion implantation and excess exposure of the Si surface. The maximum responsivity was 0.36 A/W. The modest gain allows for sufficient frequency bandwidth to observe an eye opening at up to 30 Gb/s. PMID- 26766697 TI - Absorption-induced transparency metamaterials in the terahertz regime. AB - Contrary to what might be expected, when an organic dye is sputtered onto an opaque holey metal film, transmission bands can be observed at the absorption energies of the molecules. This phenomenon, known as absorption-induced transparency, is aided by a strong modification of the propagation properties of light inside the holes when filled by the molecules. Despite having been initially observed in metallic structures in the optical regime, new routes for investigation and applications at different spectral regimes can be devised. Here, to illustrate the potential use of absorption-induced transparency at terahertz, a method for molecular detection is presented and supported by a theoretical analysis. PMID- 26766698 TI - Augmented reality three-dimensional object visualization and recognition with axially distributed sensing. AB - An augmented reality (AR) smartglass display combines real-world scenes with digital information enabling the rapid growth of AR-based applications. We present an augmented reality-based approach for three-dimensional (3D) optical visualization and object recognition using axially distributed sensing (ADS). For object recognition, the 3D scene is reconstructed, and feature extraction is performed by calculating the histogram of oriented gradients (HOG) of a sliding window. A support vector machine (SVM) is then used for classification. Once an object has been identified, the 3D reconstructed scene with the detected object is optically displayed in the smartglasses allowing the user to see the object, remove partial occlusions of the object, and provide critical information about the object such as 3D coordinates, which are not possible with conventional AR devices. To the best of our knowledge, this is the first report on combining axially distributed sensing with 3D object visualization and recognition for applications to augmented reality. The proposed approach can have benefits for many applications, including medical, military, transportation, and manufacturing. PMID- 26766699 TI - Light coupling in a Scotch tape waveguide via an integrated metal diffraction grating. AB - We report on the first demonstration of a flexible optical waveguide interconnecting device made of a general purpose pressure-sensitive adhesive (PSA) tape embedding nanopatterned Al thin film diffractive grating couplers. The diffractive elements allow selected broadband light to be perpendicularly coupled/decoupled into/from a PSA tape waveguide in which they are integrated. Waveguide losses and coupling efficiency are evaluated. The versatility and low cost of the used materials make the presented configuration very promising for cost-effective, ready-to-use short-distance optical interconnections. PMID- 26766700 TI - Investigations of the polarization behavior of quantum cascade lasers by Stokes parameters. AB - We experimentally investigate the full polarization behavior of mid-infrared emitting quantum cascade lasers (QCLs) in terms of measuring the complete Stokes parameters, instead of only projecting them on a linear polarization basis. We demonstrate that besides the pre-dominant linear TM polarization of the emitted light as governed by the selection rules of the intersubband transition, small non-TM contributions, e.g., circularly polarized light, are present reflecting the birefringent behavior of the semiconductor quantum well waveguide. Surprisingly unique is the persistence of these polarization properties well below laser threshold. These investigations give further insight into understanding, manipulating, and exploiting the polarization properties of QCLs, both from a laser point of view and with respect toward applications. PMID- 26766701 TI - Reflection-induced bias error in an air-core photonic bandgap fiber optic gyroscope. AB - Analysis of the bias error induced by reflections in an air-core photonic bandgap fiber gyroscope is performed by both simulation and experiment. The bias error is sinusoidally periodic under modulation, and its intensity is related to the relative positions of the reflection points. A simple and effective method for the suppression of the error is proposed, and it has been verified experimentally. PMID- 26766702 TI - Radio-frequency unbalanced M-Z interferometer for wavelength interrogation of fiber Bragg grating sensors. AB - The optical unbalanced Mach-Zehnder interferometer (UMZI) has attracted significant interests for interrogation of FBG sensors owing to its excellent advantages in sensitivity, resolution, and demodulation speed. But this method is still limited to dynamic measurements due to its poor stability and reliability when used for quasi-static detections. Here, we propose for the first time, to the best of our knowledge, a radio-frequency unbalanced M-Z interferometer (RF UMZI) for interrogation of FBG sensors, which, owing to its operation in an incoherent rather than a coherent regime, provides an ideal solution for the existing stability problem of the conventional UMZI, with remarkable features of adjustable resolution and potentially extremely high sensitivity. A dispersion compensation fiber (DCF) and single-mode fiber (SMF) with a small length difference are served as the two unbalanced arms of the RF interferometer. The induced differential chromatic dispersion transfers the wavelength shift of the FBG to the change of the RF phase difference between the two interferometric carriers, which ultimately leads to the variation of the RF signal intensity. An interrogation of a strain-turned FBG was accomplished and a maximum sensitivity of 0.00835 a.u./MUepsilon was obtained, which can easily be further improved by more than two orders of magnitude through various fiber dispersion components. Finally, the stability of the interrogation was tested. PMID- 26766703 TI - Third-order susceptibility of gold for ultrathin layers. AB - This Letter presents an experimental study of nonlinear plasmonic effects in gold stripe waveguides. The optical characterization is performed by a picosecond laser and reveals two nonlinear effects related to propagation of long-range surface plasmon polaritons: nonlinear power transmission of plasmonic modes and spectral broadening of plasmonic modes. The experimental values of the third order susceptibility of the gold layers are extracted. They exhibit a clear dependence on layer thickness. PMID- 26766704 TI - Maximum a posteriori estimator for high-contrast image composition of optical coherence tomography. AB - A quantitative signal amplitude estimator for optical coherence tomography (OCT) is presented. It is based on a statistical model of OCT signal and noise, using a Bayesian maximum a posteriori (MAP) estimation framework. Multiple OCT images are used for estimation, similar to the widely utilized intensity averaging method. The estimator is less biased especially at low-intensity regions, where intensity averaging approaches the noise power and hence is biased. The estimator is applied to posterior ocular OCT images and provides high-contrast visualization of pathologies. In addition, histogram analysis objectively shows the superior performance of the estimator compared with intensity averaging. PMID- 26766705 TI - Extreme-sensitivity terahertz polarizer inspired by an anisotropic cut-through metamaterial. AB - Submilliradian accuracy utilizing terahertz waves is used to often discover and observe novel physical phenomena. However, conventional terahertz polarizers cannot simultaneously realize a high extinction ratio, which restricts the sensitivity of the polarization angle, and a high transmission power across a broad frequency band due to the wires involved. Here, inspired by metamaterials, we demonstrate an anisotropic cut-through metal-slit array for an ideal terahertz polarizer with a high extinction ratio and transmission power. Measurements confirm extinction ratios below approximately -50 dB and average transverse magnetic-mode transmission powers of over 80% from 0.3 to 2.2 THz. The extremely sensitive mechanism can shed light on a variety of path-breaking applications such as single-photon detection and quantum information and communication at lower frequencies. PMID- 26766706 TI - Energy-efficient space-time modulation for indoor MISO visible light communications. AB - We consider an indoor multi-input single-output (MISO) visible light communication (VLC) system without channel state information at the transmitter. For such a system, an energy-efficient time-collaborative modulation (TCM) constellation is first designed by minimizing a total optical power subject to a fixed minimum Euclidean distance. Then, a new space-time transmission scheme is proposed. Comprehensive computer simulations indicate that our proposed design always has better average error performance within illumination coverage area than the currently available schemes for this application. PMID- 26766707 TI - Light controlled phase shifter for optofluidics. AB - We report the light-induced control of optical phase shift by a liquid crystal cell made with LiNbO3:Fe crystals as substrates. We show that a phase shift of a few pis can be easily reached for two orthogonal polarizations due to liquid crystal reorientation driven by the photovoltaic electric field originated in the substrates. This effect is exploited to get all-optical switching with a contrast of about 80%, by 2 s pump pulse. PMID- 26766708 TI - Compartmentalized liquid crystal alignment induced by sparse polymer ribbons with surface relief gratings. AB - We report on the liquid crystal (LC) alignment induced by sparse polymer ribbons fabricated by the two-photon polymerization-based direct laser writing method. Each ribbon is fabricated by a single scan of the laser through the photoresist and possesses surface relief gratings on both sides. The relief gratings are caused by the optical interference between the incident and reflected laser beams. With the aid of these relief gratings, LC molecules can be well aligned along the selected direction of the ribbons. LC cells with the Z-shaped and checkerboard-type microstructures are constructed based on the sparse out-of plane polymeric ribbons. Our results show that with such polymer ribbons a compartmentalized LC alignment in the arbitrary microstructures can be realized. PMID- 26766709 TI - On the generality of the Talbot condition for inducing self-imaging effects on periodic objects. AB - Integer and fractional self-imaging effects can be induced on periodic waveforms across the time, frequency, space, or angular frequency domains by imposing a quadratic phase profile along the corresponding Fourier dual domain. This phase must satisfy the well-known "Talbot condition." The resulting period-divided fractional self-images exhibit deterministic pulse-to-pulse phase variations that arise from the solution of a Gauss sum. In turn, these self-images can be regarded as inducing a Talbot effect in the Fourier dual domain. This suggests the possibility of observing self-imaging effects by imposing phase profiles that are not defined by the Talbot condition. In this Letter, we show otherwise that the phase profiles retrieved from a Gauss sum also satisfy the Talbot condition, which implies that this condition may encompass all possible quadratic phase patterns for inducing self-imaging effects. We establish here the precise relationships between the solutions of Gauss sums and the corresponding Talbot phases, and derive additional properties of Talbot phase patterns of fundamental and practical interest. PMID- 26766710 TI - Talbot multi-focal holographic fluorescence endoscopy for optically sectioned imaging. AB - A wide-field multi-plane endoscopic system incorporating multiplexed volume holographic gratings and Talbot illumination to simultaneously acquire optically sectioned fluorescence images of tissue structures from different depths is presented. The proposed endoscopic system is configured such that multiple Talbot illumination planes occur inside a volumetric sample and serve as the input focal planes for the subsequent multiplexed volume holographic imaging gratings. We describe the design, implementation, and experimental data demonstrating this endoscopic system's ability to obtain optically sectioned multi-plane fluorescent images of tissue samples in wide-field fashion without scanning in lateral and axial directions. PMID- 26766711 TI - Negative reflection from metal/graphene plasmonic gratings. AB - We propose a scheme of metal/graphene plasmonic gratings for negative reflection. The existence of graphene ribbons, introducing abrupt discontinuity on tangential components of magnetic fields for scattering waves across a graphene interface, substantially alters the dispersion of surface states on plasmonic gratings such that negative reflection that is robust against the incidence angle and can be tuned in a wide frequency range as a function of Fermi energy of graphene. Circularly polarized incidence waves are reflected and split along specular and negative directions, with respective to transverse magnetic and electric polarization. Our findings are potentially helpful for light steering in integrated optical circuits. PMID- 26766712 TI - Imaging deformation of adherent cells due to shear stress using quantitative phase imaging. AB - We present a platform for detecting cellular deformations from mechanical stimuli, such as fluid shear stress, using rapid quantitative phase imaging. Rapid quantitative phase imaging was used to analyze changes in the optical path length of adherent skin cancer cells during mechanical displacement. Both the whole-cell phase displacement and the resultant shift of the cellular center of mass were calculated over the duration of the stimulus. Whole-cell phase displacement images were found to match expectation. Furthermore, center-of-mass shifts of adherent cells were found to resemble that of a one-dimensional Kelvin Voigt (KV) viscoelastic solid. Cellular steady-state displacements from step fluid shear stimuli were found to be linearly related to the shear stress. Shear stiffness constants for cells exposed to a cytoskeletal disrupting toxin were found to be significantly lower than unexposed cells. This novel technique allows for elastographic analysis of whole-cell effective shear stiffness without the use of an exogenous force applicator, a specialized culture substrate, or tracking net perimeter movement of the cell. PMID- 26766713 TI - Ultra-compact polarization beam splitter utilizing a graphene-based asymmetrical directional coupler. AB - A novel ultra-compact polarization beam splitter (PBS) utilizing an asymmetrical directional coupler with a combination of a silicon waveguide (SW) and a graphene multilayer embedded silicon waveguide (GMESW) has been proposed and investigated. The modal characteristics of the GMESW for the TM mode varies significantly, whereas that for the TE mode changes slightly with respect to the SW, inducing the launched TM mode to directly pass through the SW with little influence from the GMESW, while the TE mode undergoes a strong coupling and is transferred to the GMESW. A designed PBS with an 8.3 MUm-long coupler and 200 nm-wide gap separation offers high extinction ratios (18.2 and 21.2 dB) and low insertion losses (0.16 and 0.36 dB) for the thru and cross ports, respectively. The presented PBS also presents the ability to work with variable splitting ratio power for the TM mode by varying the chemical potential of graphene, implying various applications in signal processing on a chip. PMID- 26766714 TI - All-fiber passively mode-locked laser based on a chiral fiber grating. AB - A novel passively mode-locked all-fiber laser using a chiral fiber grating as a polarization-selective element is demonstrated for the first time, to the best of our knowledge. The chiral fiber grating serves as a key component to form an artificial saturable absorber to realize mode locking through nonlinear polarization rotation in the cavity. The laser generates stable short pulses with energy of 0.34 nJ, a fundamental repetition rate of 3.27 MHz, and an FWHM bandwidth of 28 nm. We also show that harmonic mode-locked pulse trains of different orders can be obtained by increasing the pump power. PMID- 26766715 TI - High efficiency in mode-selective frequency conversion. AB - Frequency conversion (FC) is an enabling process in many quantum information protocols. Recently, it has been observed that upconversion efficiencies in single-photon, mode-selective FC are limited to around 80%. In this Letter, we argue that these limits can be understood as time-ordering corrections (TOCs) that modify the joint conversion amplitude of the process. Furthermore, using a simple scaling argument, we show that recently proposed cascaded FC protocols that overcome the aforementioned limitations act as "attenuators" of the TOCs. This observation allows us to argue that very similar cascaded architectures can be used to attenuate TOCs in photon generation via spontaneous parametric downconversion. Finally, by using the Magnus expansion, we argue that the TOCs, which are usually considered detrimental for FC efficiency, can also be used to increase the efficiency of conversion in partially mode-selective FC. PMID- 26766716 TI - Low-redundancy linear arrays in mirrored interferometric aperture synthesis. AB - Mirrored interferometric aperture synthesis (MIAS) is a novel interferometry that can improve spatial resolution compared with that of conventional IAS. In one dimensional (1-D) MIAS, antenna array with low redundancy has the potential to achieve a high spatial resolution. This Letter presents a technique for the direct construction of low-redundancy linear arrays (LRLAs) in MIAS and derives two regular analytical patterns that can yield various LRLAs in short computation time. Moreover, for a better estimation of the observed scene, a bi-measurement method is proposed to handle the rank defect associated with the transmatrix of those LRLAs. The results of imaging simulation demonstrate the effectiveness of the proposed method. PMID- 26766717 TI - Optical revivals in nonuniform supersymmetric photonic arrays. AB - We investigate the problem of wavepacket revivals in coupled nonuniform linear optical structures. Starting from the photonic Bloch lattices and J(x) arrays, whose propagators are fully periodic, we use cascaded discrete supersymmetric transformations to generate a family of nonuniform isospectral lattices. These new structures exhibit perfect imaging for any initial condition despite the apparent lack of order in their physical parameters. We note, however. that the SUSY-induced disordered coefficients are not random but, rather, inherit some of the features associated with the original array. PMID- 26766718 TI - Efficient carrier-envelope offset frequency stabilization through gain modulation via stimulated emission. AB - A novel scheme for intracavity control of the carrier-envelope offset (CEO) frequency of a 100 MHz mode-locked Er:Yb:glass diode-pumped solid-state laser (DPSSL) based on the modulation of the laser gain via stimulated emission of the excited Er(3+) ions is demonstrated. This method allows us to bypass the ytterbium system few-kHz low-pass filter in the f(CEO) stabilization loop and thus to push the phase lock bandwidth up to a limit close to the relaxation oscillations frequency of the erbium system. A phase lock bandwidth above 70 kHz has been achieved with the fully stabilized laser, leading to an integrated phase noise [1 Hz-1 MHz] of 120 mrad. PMID- 26766719 TI - Temperature- and strain-insensitive curvature sensor based on ring-core modes in dual-concentric-core fiber. AB - We report on a high-performance curvature sensor based on a long-period grating (LPG) in a dual-concentric-core fiber (DCCF). The LPG is inscribed to couple light from the fundamental mode of the central core to the ring-core modes, resulting in the generation of a series of resonant dips. Two adjacent dips shift toward each other when the LPG is bent. By monitoring the variation of the wavelength interval between these two dips, this LPG can be applied in curvature measurement with a sensitivity as high as -9.046 nm/m(-1). More importantly, such a wavelength interval is almost immune to the cross impacts of temperature and axial strain, since the sensitivities to temperature and axial strain are only 2.6 pm/ degrees C and 0.083 pm/MUepsilon, respectively. PMID- 26766720 TI - 50.4% slope efficiency thulium-doped large-mode-area fiber laser fabricated by powder technology. AB - We report on a triple clad large-mode-area Tm-doped fiber laser with 18 MUm core diameter manufactured for the first time by an alternative manufacturing process named REPUSIL. This reactive powder sinter material enables similar properties compared to conventional CVD-made fiber lasers, while offering the potential of producing larger and more uniform material. The fiber characterization in a laser configuration provides a slope efficiency of 47.7% at 20 degrees C, and 50.4% at 0 degrees C with 8 W output power, with a laser peak emission at 1970 nm. Finally, a beam quality near the diffraction-limit (M(x,y)2<1.1) is proved. PMID- 26766721 TI - Optical ultrafast random number generation at 1 Tb/s using a turbulent semiconductor ring cavity laser. AB - A simple method of high-speed random bit generation is presented that utilizes the turbulent output of a fiber ring cavity semiconductor laser. Random bits are generated by multi-bit sampling of the chaotic optical waveform passed through a simple post-processing procedure, leading to generation rates up to and potentially exceeding 1 Tb/s. The resulting random bit streams are tested statistically using a software package designed to test random number generators, the NIST statistical test suite. The bit streams pass each of these test sets, indicating their suitability for use in random number generation applications. This novel technique allows the generation of random bits from less complex experimental conditions than previously reported, while improving upon recent previous studies in terms of bit rate and quality of bits. PMID- 26766722 TI - Coherent mid-infrared supercontinuum generation in all-solid chalcogenide microstructured fibers with all-normal dispersion. AB - We report the coherent mid-infrared supercontinuum generation in an all-solid chalcogenide microstructured fiber with all-normal dispersion. The chalcogenide microstructured fiber is a four-hole structure with core material of AsSe2 and air holes that are replaced by As2S5 glass rods. Coherent mid-infrared supercontinuum light extended to 3.3 MUm is generated in a 2 cm long chalcogenide microstructured fiber pumped by a 2.7 MUm laser. PMID- 26766723 TI - Plasmonically induced magnetic field in graphene-coated nanowires. AB - In this Letter, we investigate a magnetic field induced by guiding plasmonic modes in graphene-coated nanowire via an inverse Faraday effect. Magnetic field distribution for different plasmonic modes has been calculated. It has been shown that a magnetic field has a vortex-like distribution for some plasmonic modes. The possibility of producing magnetic field distribution that rotates along the nanowire axis and periodically depends on azimuthal angle has been demonstrated. PMID- 26766724 TI - Phase-mismatched localized fields in A-PPLN waveguide devices. AB - Highly phase-mismatched nonlinear interactions can generate spatially localized optical fields that can affect the performance of nonlinear optical devices. We present a theoretical description of the generation of such spatially localized optical fields by ultrafast pulses. The effects of temporal walk-off and pump depletion are discussed, along with methods for suppression of the localized field while maintaining the performance of the nonlinear device. The model is validated by the measurement of the spatial profile of the localized field in a quasi-phase-matched (QPM) aperiodically poled lithium niobate (A-PPLN) waveguide. Finally, we fabricate and characterize A-PPLN devices with a 33% duty cycle to reduce the locally generated field by 90%. PMID- 26766725 TI - Focal-length-tunable elastomer-based liquid-filled plano-convex mini lens. AB - A liquid plano-convex lens with focal length tuning is proposed, which is formed by sinking an oil droplet onto the bottom of an elastomer. A simple and low-cost fabrication method is presented. The lens aperture and initial focal length can be controlled during the fabrication. Furthermore, focal length tuning is demonstrated. The lens made of a 40 mg oil droplet can achieve the tuning range from 12 to 17 mm. The effective aperture of the lens is about 2.8 mm. In the demonstration of an imaging system, the lens assists in focusing and a clear image can be observed. PMID- 26766726 TI - Cooperative nonlinear grating sensitive to light intensity and photon correlation. AB - Utilizing dipole blockade of Rydberg excitations, we study an ensemble of stationary atoms driven into the four-level N configuration for achieving a new kind of electromagnetically induced grating in the presence of a traveling-wave and a standing-wave classical control fields. This grating shows cooperative optical nonlinearities as manifested by the sensitivity of output diffraction patterns to input light intensities (photon correlations) of a quantum probe field, promising then an essential opportunity for distinguishing weaker and stronger (bunched and anti-bunched) light fields. PMID- 26766727 TI - Direct dark modes excitation in bi-layered enantiomeric atoms-based metasurface through symmetry matching. AB - We provide evidence for the mechanism of direct dark mode excitation in a metasurface composed of bi-layered Z-shaped enantiomeric meta-atoms. The electromagnetic behavior of the structure is investigated through both numerical simulations and experimental measurements in the microwave domain. We demonstrate direct field coupling excitation of second higher order electric mode under normal incidence based only on symmetry matching conditions. The proposed approach provides a better flexibility in engineering dark mode resonances that do not rely on hybridization mechanism and presents important advantages for multi-spectral sensor applications. PMID- 26766728 TI - Theoretical demonstration of Brillouin lasing effect in racetrack resonators based on germanium waveguides in the mid-infrared. AB - In this Letter, we present a theoretical investigation of integrated racetrack Brillouin lasers based on germanium waveguides that are buried in silicon nitride and operate at a wavelength of 4 MUm. General design equations in a steady-state regime have been carried out to determine the threshold power and the emitted Stokes power as a function of the resonance mismatch and coupling factor. The pulling effect as induced by the Brillouin gain dispersion and the pushing effects originated by SPM and XPM effects have been accurately investigated to predict the lasing frequency. PMID- 26766729 TI - Nanoslit cavity plasmonic modes and built-in fields enhance the CW THz radiation in an unbiased antennaless photomixers array. AB - A new generation unbiased antennaless CW terahertz (THz) photomixer emitters array made of asymmetric metal-semiconductor-metal (MSM) gratings with a subwavelength pitch, operating in the optical near-field regime, is proposed. We take advantage of size effects in near-field optics and electrostatics to demonstrate the possibility of enhancing the THz power by 4 orders of magnitude, compared to a similar unbiased antennaless array of the same size that operates in the far-field regime. We show that, with the appropriate choice of grating parameters in such THz sources, the first plasmonic resonant cavity mode in the nanoslit between two adjacent MSMs can enhance the optical near-field absorption and, hence, the generation of photocarriers under the slit in the active medium. These photocarriers, on the other hand, are accelerated by the large built-in electric field sustained under the nanoslits by two dissimilar Schottky barriers to create the desired large THz power that is mainly radiated downward. The proposed structure can be tuned in a broadband frequency range of 0.1-3 THz, with output power increasing with frequency. PMID- 26766730 TI - Cavity-based linear polarizer immune to the polarization direction of an incident plane wave. AB - We herein report a linear polarizer based on a 2D array of substrate integrated waveguide cavities, which can convert an arbitrary linearly polarized (LP) incident wave into an outgoing LP wave in a specified polarization direction with constant transmittance. Two orthogonal slots etched on the front surface of the cavity are utilized to couple a wave of arbitrary polarization into the cavity, while another slot on the back side helps to couple the field out along a desired polarization direction. Microwave experiments are performed as a proof of concept. The proposed polarizer exhibits very good performance with stable transmittance as 50% and a polarization extinction ratio over 45 dB. The new polarizer is potentially useful in novel polarization-selective devices that are immune to the polarization direction of an incident plane wave. PMID- 26766731 TI - Estimating stochastic noise using in situ measurements from a linear wavefront slope sensor. AB - It is shown how the solenoidal component of noise from the measurements of a wavefront slope sensor can be utilized to estimate the total noise: specifically, the ensemble noise variance. It is well known that solenoidal noise is orthogonal to the reconstruction of the wavefront under conditions of low scintillation (absence of wavefront vortices). Therefore, it can be retrieved even with a nonzero slope signal present. By explicitly estimating the solenoidal noise from an ensemble of slopes, it can be retrieved for any wavefront sensor configuration. Furthermore, the ensemble variance is demonstrated to be related to the total noise variance via a straightforward relationship. This relationship is revealed via the method of the explicit estimation: it consists of a small, heuristic set of four constants that do not depend on the underlying statistics of the incoming wavefront. These constants seem to apply to all situations-data from a laboratory experiment as well as many configurations of numerical simulation-so the method is concluded to be generic. PMID- 26766732 TI - Diffractive optical devices produced by light-assisted trapping of nanoparticles. AB - One- and two-dimensional diffractive optical devices have been fabricated by light-assisted trapping and patterning of nanoparticles. The method is based on the dielectrophoretic forces appearing in the vicinity of a photovoltaic crystal, such as Fe:LiNbO3, during or after illumination. By illumination with the appropriate light distribution, the nanoparticles are organized along patterns designed at will. One- and two-dimensional diffractive components have been achieved on X- and Z-cut Fe:LiNbO3 crystals, with their polar axes parallel and perpendicular to the crystal surface, respectively. Diffraction gratings with periods down to around a few micrometers have been produced using metal (Al, Ag) nanoparticles with radii in the range of 70-100 nm. Moreover, several 2D devices, such as Fresnel zone plates, have been also produced showing the potential of the method. The diffractive particle patterns remain stable when light is removed. A method to transfer the diffractive patterns to other nonphotovoltaic substrates, such as silica glass, has been also reported. PMID- 26766733 TI - Factors associated with completion of bowel cancer screening and the potential effects of simplifying the screening test algorithm. AB - BACKGROUND: The primary colorectal cancer screening test in England is a guaiac faecal occult blood test (gFOBt). The NHS Bowel Cancer Screening Programme (BCSP) interprets tests on six samples on up to three test kits to determine a definitive positive or negative result. However, the test algorithm fails to achieve a definitive result for a significant number of participants because they do not comply with the programme requirements. This study identifies factors associated with failed compliance and modifications to the screening algorithm that will improve the clinical effectiveness of the screening programme. METHODS: The BCSP Southern Hub data for screening episodes started in 2006-2012 were analysed for participants aged 60-69 years. The variables included age, sex, level of deprivation, gFOBt results and clinical outcome. RESULTS: The data set included 1,409,335 screening episodes; 95.08% of participants had a definitively normal result on kit 1 (no positive spots). Among participants asked to complete a second or third gFOBt, 5.10% and 4.65%, respectively, failed to return a valid kit. Among participants referred for follow up, 13.80% did not comply. Older age was associated with compliance at repeat testing, but non-compliance at follow up. Increasing levels of deprivation were associated with non-compliance at repeat testing and follow up. Modelling a reduction in the threshold for immediate referral led to a small increase in completion of the screening pathway. CONCLUSIONS: Reducing the number of positive spots required on the first gFOBt kit for referral for follow-up and targeted measures to improve compliance with follow-up may improve completion of the screening pathway. PMID- 26766734 TI - Oncolytic viruses: finally delivering. AB - Oncolytic viruses can be found at the confluence of virology, genetic engineering and pharmacology where versatile platforms for molecularly targeted anticancer agents can be designed and optimised. Oncolytic viruses offer several important advantages over traditional approaches, including the following. (1) Amplification of the active agent (infectious virus particles) within the tumour. This avoids unnecessary exposure to normal tissues experienced during delivery of traditional stoichiometric chemotherapy and maximises the therapeutic index. (2) The active cell-killing mechanisms, often independent of programmed death mechanisms, should decrease the emergence of acquired drug resistance. (3) Lytic death of cancer cells provides a pro-inflammatory microenvironment and the potential for induction of an anticancer vaccine response. (4) Tumour-selective expression and secretion of encoded anticancer biologics, providing a new realm of potent and cost-effective-targeted therapeutics. PMID- 26766735 TI - Tumour budding with and without admixed inflammation: two different sides of the same coin? AB - BACKGROUND: Tumour budding is an adverse prognostic indicator in colorectal cancer (CRC). Marked overall peritumoural inflammation has been associated with favourable outcome and may lead to the presence of isolated cancer cells due to destruction of invading cancer cell islets. METHODS: We assessed the prognostic significance of tumour budding and peritumoural inflammation in a cohort of 381 patients with CRC applying univariate and multivariate analyses. RESULTS: Patients with high-grade budding and marked inflammation had a significantly better outcome compared with patients with high-grade budding and only mild inflammation. Outcome in these cases, however, was still worse compared with cases with low-grade budding, in which the extent of peritumoural inflammation had no further prognostic effect. CONCLUSIONS: Tumour budding proved to be a powerful prognostic variable in patients with CRC. Scattering of invading cancer cell islets by marked overall peritumoural inflammation seems to have a minor role. PMID- 26766736 TI - A large microRNA cluster on chromosome 19 is a transcriptional hallmark of WHO type A and AB thymomas. AB - BACKGROUND: Thymomas are one of the most rarely diagnosed malignancies. To better understand its biology and to identify therapeutic targets, we performed next generation RNA sequencing. METHODS: The RNA was sequenced from 13 thymic malignancies and 3 normal thymus glands. Validation of microRNA expression was performed on a separate set of 35 thymic malignancies. For cell-based studies, a thymoma cell line was used. RESULTS: Hierarchical clustering revealed 100% concordance between gene expression clusters and WHO subtype. A substantial differentiator was a large microRNA cluster on chr19q13.42 that was significantly overexpressed in all A and AB tumours and whose expression was virtually absent in the other thymomas and normal tissues. Overexpression of this microRNA cluster activates the PI3K/AKT/mTOR pathway. Treatment of a thymoma AB cell line with a panel of PI3K/AKT/mTOR inhibitors resulted in marked reduction of cell viability. CONCLUSIONS: A large microRNA cluster on chr19q13.42 is a transcriptional hallmark of type A and AB thymomas. Furthermore, this cluster activates the PI3K pathway, suggesting the possible exploration of PI3K inhibitors in patients with these subtypes of tumour. This work has led to the initiation of a phase II clinical trial of PI3K inhibition in relapsed or refractory thymomas (http://clinicaltrials.gov/ct2/show/NCT02220855). PMID- 26766737 TI - Effects of a lifestyle intervention on endothelial function in men on long-term androgen deprivation therapy for prostate cancer. AB - BACKGROUND: Treatment of prostate cancer with androgen deprivation therapy (ADT) is associated with metabolic changes that have been linked to an increase in cardiovascular risk. METHODS: This randomised controlled trial investigated the effects of a 12-week lifestyle intervention that included supervised exercise training and dietary advice on markers of cardiovascular risk in 50 men on long term ADT recruited to an on-going study investigating the effects of such a lifestyle intervention on quality of life. Participants were randomly allocated to receive the intervention or usual care. Cardiovascular outcomes included endothelial function (flow-mediated dilatation (FMD) of the brachial artery), blood pressure, body composition and serum lipids. Additional outcomes included treadmill walk time and exercise and dietary behaviours. Outcomes were assessed before randomisation (baseline), and 6, 12 and 24 weeks after randomisation. RESULTS: At 12 weeks, the difference in mean relative FMD was 2.2% (95% confidence interval (CI) 0.1-4.3, P=0.04) with an effect size of 0.60 (95% CI <0.01-1.18) favouring the intervention group. Improvements in skeletal muscle mass, treadmill walk time and exercise behaviour also occurred in the intervention group over that duration (P<0.05). At 24 weeks, only the difference in treadmill walk time was maintained. CONCLUSIONS: This study demonstrates that lifestyle changes can improve endothelial function in men on long-term ADT for prostate cancer. The implications for cardiovascular health need further investigation in larger studies over longer duration. PMID- 26766738 TI - Phase II study of necitumumab plus modified FOLFOX6 as first-line treatment in patients with locally advanced or metastatic colorectal cancer. AB - BACKGROUND: This single-arm phase II study investigated the EGFR monoclonal antibody necitumumab plus modified FOLFOX6 (mFOLFOX6) in first-line treatment of locally advanced or metastatic colorectal cancer (mCRC). METHODS: Patients received 800-mg intravenous necitumumab (day 1; 2-week cycles), followed by oxaliplatin 85 mg m(-2), folinic acid 400 mg m(-2), and 5-fluorouracil (400 mg m( 2) bolus then 2400 mg m(-2) over 46 h). Radiographic evaluation was performed every 8 weeks until progression. Primary endpoint was objective response rate. RESULTS: Forty-four patients were enrolled and treated. Objective response rate was 63.6% (95% confidence interval 47.8-77.6); complete response was observed in four patients; median duration of response was 10.0 months (7.0-16.0). Median overall survival (OS) and progression-free survival (PFS) were 22.5 (11.0-30.0) and 10.0 months (7.0-12.0), respectively. Clinical outcome was better in patients with KRAS exon 2 wild type (median OS 30.0 months (23.0-NA); median PFS 12.0 (8.0 20.0)), compared with KRAS exon 2 mutant tumours (median OS 7.0 months (5.0 37.0); median PFS 7.0 (4.0-18.0)). The most common grade ?3 adverse events were neutropenia (29.5%), asthenia (27.3%), and rash (20.5%). CONCLUSION: First-line necitumumab+mFOLFOX6 was active with manageable toxicity in locally advanced or mCRC; additional evaluation of the impact of tumour RAS mutation status is warranted. PMID- 26766739 TI - Bone marrow micrometastases in early breast cancer-30-year outcome. AB - BACKGROUND: Micrometastases in bone marrow of women with early breast cancer were first identified immunocytochemically in the 1980s. We report on the original cohort of women with a median follow-up of 30 years. PATIENTS AND METHODS: In total, 350 women with primary breast cancer had eight bone marrow aspirates examined with antibody to epithelial membrane antigen. Data on long-term mortality were obtained via record linkage to death certification. RESULTS: At a 30-year median follow-up, 79 out of 89 (89%) patients with micrometastases have died compared with 202 out of 261 (77%) without (hazard ratio=1.46 (95% CI 1.12 1.90), P=0.0043). Most marked effect of micrometastases on overall survival (OS) was seen in patients aged ? 50 at surgery (N=97, P=0.012), and on all patients within 10 years of diagnosis. In multivariable analyses, the presence of micrometastases was no longer a statistically significant prognostic factor. CONCLUSIONS: Bone marrow micrometastases are predictive for OS, particularly in the first decade and in younger patients. PMID- 26766740 TI - Hepatocyte growth factor inhibition: a novel therapeutic approach in pancreatic cancer. AB - BACKGROUND: Pancreatic stellate cells (PSCs, which produce the stroma of pancreatic cancer (PC)) interact with cancer cells to facilitate PC growth. A candidate growth factor pathway that may mediate this interaction is the HGF-c MET pathway. METHODS: Effects of HGF inhibition (using a neutralising antibody AMG102) alone or in combination with gemcitabine were assessed (i) in vivo using an orthotopic model of PC, and (ii) in vitro using cultured PC cells (AsPC-1) and human PSCs. RESULTS: We have shown that human PSCs (hPSCs) secrete HGF but do not express the receptor c-MET, which is present predominantly on cancer cells. HGF inhibition was as effective as standard chemotherapy in inhibiting local tumour growth but was significantly more effective than gemcitabine in reducing tumour angiogenesis and metastasis. HGF inhibition has resulted in reduced metastasis; however, interestingly this antimetastatic effect was lost when combined with gemcitabine. This suggests that gemcitabine treatment selects out a subpopulation of cancer cells with increased epithelial-mesenchymal transition (EMT) and stem cell characteristics, as supported by our findings of increased expression of EMT and stem-cell markers in tumour sections from our animal model. In vitro studies showed that hPSC secretions induced proliferation and migration, but inhibited apoptosis, of cancer cells. These effects were countered by pretreatment of hPSC secretions with a HGF-neutralising antibody but not by gemcitabine, indicating a key role for HGF in PSC-PC interactions. CONCLUSIONS: Our studies suggest that targeted therapy to inhibit stromal-tumour interactions mediated by the HGF-c-MET pathway may represent a novel therapeutic approach in PC that will require careful modelling for optimal integration with existing treatment modalities. PMID- 26766741 TI - Trends in UK regional cancer mortality 1991-2007. AB - BACKGROUND: Until 1990, there was an upward trend in mortality from breast, lung, prostate, and colon cancers in the United Kingdom. With improvements in cancer treatment there has, in general, been a fall in mortality over the last 20 years. We evaluate regional cancer mortality trends in the United Kingdom between 1991 and 2007. METHODS: We analysed mortality trends for breast, lung, prostate, and colon cancers using data obtained from the EUREG cancer database. We have described changes in age-standardised rates (using European standard population) per 100,000 for cancer mortality and generated trends in mortality for the 11 regions using Joinpoint regression. RESULTS: Across all regions in the United Kingdom there was a downward trend in mortality for the four most common cancers in males and females. Overall, deaths from colon cancer decreased most rapidly and deaths from prostate cancer decreased at the slowest rate. Similar downward trends in mortality were observed across all regions of the United Kingdom with the data for lung cancer exhibiting the greatest variation. CONCLUSIONS: Mortality from the four most common cancers decreased across all regions of the United Kingdom; however, the rate of decline varied between cancer type and in some instances by region. PMID- 26766743 TI - Eric Davidson (1937-2015) and the past, present and future of EvoDevo. PMID- 26766744 TI - Drug crystallization - implications for topical and transdermal delivery. AB - INTRODUCTION: Crystallization of actives in skin following topical application was suggested by studies in the 1950s and 1960s but is poorly understood. In contrast, the problem of crystallization of actives on skin and in transdermal formulations has been known for many years. AREAS COVERED: With respect to crystallization in skin, this review describes early reports of a skin 'reservoir' and possible reasons underlying its genesis. Techniques to study crystallization on and in skin and in transdermal patches are outlined. The role of the vehicle in skin delivery is emphasised. Studies which have investigated permeation from crystalline particles are described. Approaches to limit crystallization of actives are discussed. Using supersaturation and antinuclean polymers, control of crystal size is possible; controlled release from crystals is also employed in transdermal patches. EXPERT OPINION: Drug crystallization has significant implications for topical and transdermal delivery. Approaches have been developed to counteract the issue for transdermal patches but crystallization in and on the skin for other formulations remains unresolved. Greater knowledge of residence time of excipients and their interaction with skin at the molecular level is critical in order to address the problem. This will lay the foundations for better design of topical/transdermal formulations. PMID- 26766746 TI - Jeroen S. Dickschat. AB - If I were not a scientist, I would be bored. My motto is "Keep it short!" PMID- 26766747 TI - Antimicrobial potential of commercial silver nanoparticles and the characterization of their physical properties toward probiotic bacteria isolated from fermented milk products. AB - The application of nanotechnology in the agriculture and food sector is relatively recent compared to its usage in drug delivery or pharmaceuticals. Therefore, this paper presents a study of the effect of silver nanoparticles on probiotic bacteria based on the example of Lactobacillus acidophilus LA-5, Bifidobacterium animalis subsp. lactis BB-12 and Streptococcus thermophilus ST Y31 isolated from fermented milk products. Probiotic bacteria are one of the most crucial groups of bacteria for the food industry, because of their claimed health promoting properties. Studies have shown that the type and concentration of silver nanoparticle solutions have a significant impact on the tested probiotic bacteria which are profitable for the digestive system. In the presence of all tested silver nanoparticles, St. thermophilus ST-Y31 growth was inhibited significantly by the dilution method as opposed to the disk-diffusion method. Both the disk-diffusion and the dilution methods showed no significant differences between L. acidophilus LA-5 and B. animalis subsp. lactis BB-12. The concentrations 2 MUg mL(-1) and 0.25 MUg mL(-1) had the highest antibacterial activity and statistically significant impacts on the tested probiotic strains. To our knowledge, this is the first report on potential antimicrobial effect of nanosilver against the health-promoting probiotic bacteria L. acidophilus LA-5, B. animalis subsp. lactis BB-12 and St. thermophilus ST-Y31 isolated from fermented milk products. PMID- 26766745 TI - Endogenous IL-6 of mesenchymal stem cell improves behavioral outcome of hypoxic ischemic brain damage neonatal rats by supressing apoptosis in astrocyte. AB - Mesenchymal stem cell (MSC) transplantation reduces the neurological impairment caused by hypoxic-ischemic brain damage (HIBD) via immunomodulation. In the current study, we found that MSC transplantation improved learning and memory function and enhanced long-term potentiation in neonatal rats subjected to HIBD and the amount of IL-6 released from MSCs was far greater than that of other cytokines. However, the neuroprotective effect of MSCs infected with siIL-6 transduced recombinant lentivirus (siIL-6 MSCs) was significantly weakened in the behavioural tests and electrophysiological analysis. Meanwhile, the hippocampal IL-6 levels were decreased following siIL-6 MSC transplantation. In vitro, the levels of IL-6 release and the levels of IL-6R and STAT3 expression were increased in both primary neurons and astrocytes subjected to oxygen and glucose deprivation (OGD) following MSCs co-culture. The anti-apoptotic protein Bcl-2 was upregulated and the pro-apoptotic protein Bax was downregulated in OGD-injured astrocytes co-cultured with MSCs. However, the siIL-6 MSCs suppressed ratio of Bcl-2/Bax in the injured astrocytes and induced apoptosis number of the injured astrocytes. Taken together, these data suggest that the neuroprotective effect of MSC transplantation in neonatal HIBD rats is partly mediated by IL-6 to enhance anti-apoptosis of injured astrocytes via the IL-6/STAT3 signaling pathway. PMID- 26766748 TI - Concentration Monitoring of Plasma Ribavirin: Validation of a Liquid Chromatography-Mass Spectrometric Method and Clinical Sample Collection. AB - BACKGROUND: A liquid chromatography-tandem mass spectrometric (LC-MS/MS) method was developed for routine measurement of ribavirin concentrations in EDTA anticoagulated plasma. METHODS: After protein precipitation, we used a bridged ethylene hybrid (hydrophilic interaction) chromatography column, 0.1 mmol/L ammonium formate pH 3.0, and a gradient of 85%-96% acetonitrile to achieve baseline separation of ribavirin from isobaric uridine. Quantitation was assured using both primary (m/z 245.3 > 113.0) and secondary transitions (m/z 245.3 > 96.0) of the protonated species. Chromatographic separation and column washing also negated interference from major phospholipid species. RESULTS: There was a linear relationship between concentration and response to 10 mg/L, with a minimum detectable level and a minimum level of quantitation both of 0.1 mg/L. Imprecision within the assay was <10% at 0.1 mg/L and <6% between assays for concentrations >0.4 mg/L. Bias was <4%. In clinical samples (n = 12), there was no difference in ribavirin concentrations obtained by an established liquid chromatographic assay with ultraviolet detection. Ribavirin concentrations were stable in plasma stored at room temperature for 3 days but then decreased significantly on day 7. Plasma concentrations were stable for 15 weeks at -20 degrees C. Concentrations in plasma separated from whole blood at room temperature fell by a median of 19.4% at 4 hours and then rose substantially (median 251% by 3 days). Dose-normalized ribavirin concentrations reached a steady state after a mean of >6 weeks treatment in 76 patients with hepatitis C. CONCLUSIONS: A hydrophilic interaction liquid chromatography-tandem mass spectrometric method to measure ribavirin in plasma was developed. Samples for ribavirin estimation should be kept at 4 degrees C, separated within 2 hours of collection and stored at 4 degrees C before analysis, with long-term storage at 20 degrees C. This method was applied to a study of the ribavirin therapeutic monitoring in patients with hepatitis C. PMID- 26766742 TI - CYP24A1 variant modifies the association between use of oestrogen plus progestogen therapy and colorectal cancer risk. AB - BACKGROUND: Menopausal hormone therapy (MHT) use has been consistently associated with a decreased risk of colorectal cancer (CRC) in women. Our aim was to use a genome-wide gene-environment interaction analysis to identify genetic modifiers of CRC risk associated with use of MHT. METHODS: We included 10 835 postmenopausal women (5419 cases and 5416 controls) from 10 studies. We evaluated use of any MHT, oestrogen-only (E-only) and combined oestrogen-progestogen (E+P) hormone preparations. To test for multiplicative interactions, we applied the empirical Bayes (EB) test as well as the Wald test in conventional case-control logistic regression as primary tests. The Cocktail test was used as secondary test. RESULTS: The EB test identified a significant interaction between rs964293 at 20q13.2/CYP24A1 and E+P (interaction OR (95% CIs)=0.61 (0.52-0.72), P=4.8 * 10(-9)). The secondary analysis also identified this interaction (Cocktail test OR=0.64 (0.52-0.78), P=1.2 * 10(-5) (alpha threshold=3.1 * 10(-4)). The ORs for association between E+P and CRC risk by rs964293 genotype were as follows: C/C, 0.96 (0.61-1.50); A/C, 0.61 (0.39-0.95) and A/A, 0.40 (0.22-0.73), respectively. CONCLUSIONS: Our results indicate that rs964293 modifies the association between E+P and CRC risk. The variant is located near CYP24A1, which encodes an enzyme involved in vitamin D metabolism. This novel finding offers additional insight into downstream pathways of CRC etiopathogenesis. PMID- 26766749 TI - Compliance With Enoxaparin Dosing and Monitoring Guidelines and the Impact on Patient Length of Stay: A Pilot Study. AB - BACKGROUND: To investigate the compliance of prescribers with the state-wide Queensland Health (QH) guidelines for dosing and monitoring of enoxaparin, and to examine the effect that compliance has on the patients' length of stay (LOS) in hospital. METHODS: A 4-week retrospective study of consecutive inpatients who were administered enoxaparin for the treatment of an embolic disease. Data collected included influential patient demographics such as weight, renal function; details of antifactor Xa (aXa) monitoring, and patient LOS. All dosing and monitoring for each patient was compared to the current QH guidelines for enoxaparin usage; a multidisciplinary consensus document. The reasons for noncompliance were quantified and explored. RESULTS: A total of 67 inpatients were recruited. The median (range) age, weight, and creatinine clearance of patients were 66 years (18-92), 78.5 kg (47.6-182), and 64 mL/min (16-180), respectively. Only 20 (30%) patients received enoxaparin in compliance with QH guidelines, leaving 47 (70%) noncompliant. The median (range) LOS was 7 (2-58) days for the compliant group versus 15 days (2-101) for the noncompliant (P = 0.06, Mann-Whitney U test). A total of 10 (15%) patients were monitored for aXa; none of whom were monitored correctly. Twenty-eight patients did not receive monitoring when indicated (moderate or severe renal impairment, weight >105 kg, or extended duration of therapy). In these patients, the median (range) LOS was 16.5 days (2-101). CONCLUSIONS: Current prescribing of enoxaparin does not match state guidelines. Although not significant, there was a trend toward noncompliant patients having a greater LOS in hospital. The quality of aXa monitoring is suboptimal and barriers need to be explored. Larger studies are warranted. PMID- 26766750 TI - Insights into the structural perturbations of spliced variants of CD44: a modeling and simulation approach. AB - Transient interactions between cancer stem cells and components of the tumor microenvironment initiate various signaling pathways crucial for carcinogenesis. Predominant hyaluronan (HA) receptor, CD44 is structurally and functionally one of the most variable cell surface receptors having the potential to generate a diverse repertory of CD44 isoforms by alternative splicing of variant exons and post-translational modifications. A structurally distinctive variant of CD44, CD44v10, has an inevitable role in malignant progression, invasion, and metastasis. This can be attributed to the binding of HA with CD44v10, which demonstrates a completely different behavioral pattern as compared to the other spliced variants of CD44 molecule. Absence of a comprehensively predicted crystal structure of human CD44s and CD44v10 is an impediment in understanding the resultant structural alterations caused by the binding of HA. Thus, in this study, we aim to predict the CD44s and CD44v10 structures to their closest native confirmation and study the HA binding-induced structural perturbations using homology modeling, molecular docking, and MD simulation approach. The results depicted that modeled 3D structures of CD44s and CD44v10 isoforms were found to be stable throughout MD simulations; however, a substantial decrease was observed in the binding affinity of HA with CD44v10 (-5.355 kcal/mol) as compared to CD44s. Furthermore, loss and gain of several H-bonds and hydrophobic interactions in CD44v10-HA complex during the simulation process not only elucidated the reason for decreased binding affinity for HA but also prompted toward the plausible role of HA-induced structural perturbations in occurrence and progression of carcinogenesis. PMID- 26766751 TI - Early Detection, Intervention and Prevention of Psychosis Program: Community Outreach and Early Identification at Six U.S. Sites. AB - OBJECTIVE: This study assessed the effects of a community outreach and education model implemented as part of the Early Detection, Intervention and Prevention of Psychosis Program (EDIPPP), a national multisite study in six U.S. regions. METHODS: EDIPPP's model was designed to generate rapid referrals of youths at clinical high risk of psychosis by creating a network of professionals and community members trained to identify signs of early psychosis. Qualitative and quantitative data were gathered through an evaluation of outreach efforts at five sites over a two-year period and through interviews with staff at all six sites. All outreach activities to groups (educational, medical, and mental health professionals; community groups; media; youth and parent groups; and multicultural communities) were counted for the six sites to determine correlations with total referrals and enrollments. RESULTS: During the study period (May 2007-May 2010), 848 formal presentations were made to 22,840 attendees and 145 informal presentations were made to 11,528 attendees at all six sites. These presentations led to 1,652 phone referrals. A total of 520 (31%) of these individuals were offered in-person orientation, and 392 (75%) of those were assessed for eligibility. A total of 337 individuals (86% of those assessed) met criteria for assignment to the EDIPPP study. CONCLUSIONS: EDIPPP's outreach and education model demonstrated the effectiveness of following a protocol-defined outreach strategy combined with flexibility to reach culturally diverse audiences or initially inaccessible systems. All EDIPPP sites yielded appropriate referrals of youths at risk of psychosis. PMID- 26766752 TI - Veterans' Service Utilization Patterns After Alcohol and Opioid Detoxification in VHA Care. AB - OBJECTIVE: This study aimed to examine detoxification-related service utilization in the Veterans Health Administration (VHA). METHODS: VHA data for 266,908 patients were used to examine rates and predictors of receiving detoxification, attending post-detoxification appointments, and entering specialty treatment. Multilevel, mixed-effects logistic regressions were used to examine associations between patient and facility characteristics and service utilization. RESULTS: Nationally, 8.0% of VHA patients with alcohol or opiate dependence received detoxification in fiscal year 2013 (facility range=.1%-20.4%); 43.1% of detoxified patients received follow-up (11.1%-76.4%), and 49.9% entered specialty treatment (13.0%-77.2%). In adjusted analyses, detoxification was more likely among male, younger, white, and homeless patients with documented alcohol or opiate disorders and comorbid general medical conditions but without previous addiction treatment. Detoxification was also more likely in facilities with fewer vacant addiction therapist positions. Follow-up and specialty treatments were more likely among younger, healthier homeless patients with previous addiction treatment and a documented alcohol use disorder. CONCLUSIONS: Detoxification related service utilization was highly variable across the VHA. Interventions are needed to optimize use. PMID- 26766753 TI - Mental Health Service Use Across the Life Course Among Adults With Psychiatric Disorders and Prior Suicidal Behavior. AB - OBJECTIVE: Little is known about mental health service use by adults with prior suicidal behavior and current mood or anxiety disorders. This study determined nationally representative prevalence estimates of current mental health service use by these adults, examining racial-ethnic, age, and gender differences. METHODS: Service use across the life course was examined with Collaborative Psychiatric Epidemiology Survey data from 1,139 adults with a history of suicidal behavior and current mood or anxiety disorders. RESULTS: Overall service use was 47.3%. Across the life course, African Americans showed increasing service use that paralleled use by non-Hispanic whites, Hispanics, and others, whereas use by these three groups decreased in the latter half of the life course (p interaction=.01). CONCLUSIONS: Adults with prior suicidal behavior and current mood or anxiety disorders have low mental health service use. Findings of racial ethnic disparities in use can help identify those in need of care. PMID- 26766754 TI - "Recovery Speaks": A Photovoice Intervention to Reduce Stigma Among Primary Care Providers. AB - OBJECTIVE: Preliminary findings are reported from a photovoice intervention, "Recovery Speaks," to reduce primary care provider stigma in regard to people with mental illness and addiction. METHODS: Twenty-seven primary care providers were recruited through a practice-based research network. Participants were randomly assigned to the intervention-attending a one-hour performance followed by discussion-or to no intervention. Provider stigma was evaluated by using established measures of stigma and recovery and qualitative responses. Linear mixed models controlling for baseline differences compared changes in provider stigma across time and groups. RESULTS: Providers who attended Recovery Speaks demonstrated significantly decreased negative stereotypes, attribution of dangerousness, fear, desire to coerce people into treatment, desire to segregate people from the community, and desire for avoidance. More desire to help and more hope for recovery were also found. CONCLUSIONS: Witnessing people's unique recovery stories and how they contribute to their communities may reduce provider stigma. PMID- 26766755 TI - The Concentration of Opioid Prescriptions by Providers and Among Patients in the Oregon Medicaid Program. AB - OBJECTIVE: This study examined the distribution of opioid prescribing across providers and patients and the extent to which concentrated distribution predicts opioid misuse. METHODS: Using 2013 Oregon Medicaid claims and the National Provider Identifier Registry, this study identified patients who filled at least one opioid prescription and providers who prescribed opioids for those patients (N=61,477 Medicaid beneficiaries). This study examined the distribution of opioid prescriptions by provider and patient, the extent to which high-volume opioid use was associated with potential opioid misuse, and how this association changed when patients received opioids from providers in the top decile of morphine equivalent doses (MEQ) prescribed in 2013. This study used four indicators of opioid misuse: doctor and pharmacy shopping for opioid prescriptions, opioid prescription overlap, and opioid and benzodiazepine prescription overlap. RESULTS: Opioid use and prescriptions were heavily concentrated among the top 10% of opioid users and prescribers. Those high-volume opioid users and prescribers accounted for, respectively, 83.2% and 80.8% in MEQ of entire opioids prescribed. Patients' increasing use of opioids (by MEQ) was associated with most measures of opioid misuse. Patients receiving opioids from high-volume prescribers had a higher probability of opioid prescription overlap and opioid and benzodiazepine prescription overlap compared with other patients, but the difference was significant only among patients who received high doses of opioids, and the size of the difference was modest. CONCLUSIONS: Whereas current policies emphasize reducing opioid prescriptions across all patients and providers, study results suggest that focusing policies on high-volume opioid users and prescribers may be more beneficial. PMID- 26766756 TI - Psychosis, Lack of Job Skills, and Criminal History: Associations With Employment in Two Samples of Homeless Men. AB - OBJECTIVE: This study examined factors associated with employment among homeless men with mental illness, particularly history of criminal justice involvement. METHODS: Data from 569 homeless men in the 11-site Collaborative Initiative to Help End Chronic Homelessness (2004-2009) and 1,101 homeless male veterans in the U.S. Department of Housing and Urban Development-Veterans Affairs Supportive Housing program at 19 sites (1992-2003) were analyzed. RESULTS: In neither sample was criminal or incarceration history significantly associated with job attainment or earnings for either black or white participants. In contrast, psychotic disorders and public-support income were negatively associated with job attainment and earnings. The majority of homeless veterans reported lifetime occupations as skilled or unskilled manual workers. CONCLUSIONS: These findings highlight the high rate of nonemployment among homeless men and suggest that employment among homeless men is not significantly impeded by a criminal record but by psychiatric problems and reliance on public-support income. PMID- 26766757 TI - Does Suicidal Ideation as Measured by the PHQ-9 Predict Suicide Among VA Patients? AB - OBJECTIVE: Frequency of suicidal ideation in the past two weeks, assessed by item 9 of the nine-item Patient Health Questionnaire (PHQ-9), has been positively associated with suicide mortality among patients in a setting other than the Veterans Health Administration (VHA). To inform suicide prevention activities at the VHA, it is important to evaluate whether item 9 is associated with suicide risk among patients in the VHA system. METHODS: PHQ-9 assessments (N=447,245) conducted by the VHA between October 1, 2009, and September 30, 2010, were collected. National Death Index data were used to ascertain suicide mortality from the date of PHQ-9 assessment through September 30, 2011. Multivariable proportional hazards regressions were used to evaluate associations between responses to item 9 and suicide mortality. RESULTS: After the analyses adjusted for covariates, a response of "several days" for item 9 was associated with a 75% increased risk of suicide (hazard ratio [HR]=1.75, 95% confidence interval [CI]=1.24-2.46), a response of "more than half the days" was associated with a 115% increased risk of suicide (HR=2.15, CI=1.32-3.51), and a response of "nearly every day" was associated with a 185% increased risk of suicide (HR=2.85, CI=1.81 4.47), compared with a response of "not at all." However, 71.6% of suicides during the study period occurred among patients who responded "not at all" to item 9 from their most recent PHQ-9. CONCLUSIONS: Higher levels of suicidal ideation, indicated by item 9 of the PHQ-9, were associated with increased risk of suicide among patients in the VHA system. PMID- 26766758 TI - Expanding the Role of Psychiatric Mental Health Nurse Practitioners in a State Psychiatric System: The New Hampshire Experience. AB - Psychiatric mental health nurse practitioners (PMHNPs) are assuming increasing clinical responsibilities in the treatment of individuals with mental illness as the shortage of psychiatrists and their maldistribution continues to persist in the United States. States vary widely in their statutes and administrative rules delineating PMHNP's scope of practice. This column describes the legislative process of incremental changes in New Hampshire statute and rules changes over the past 15 years that have significantly expanded PMHNP's ability to treat individuals with mental illnesses in the state mental health system. PMHNPs have worked closely with physician leaders and policy makers to allow this to occur. PMID- 26766759 TI - Use of Peer Staff in a Critical Time Intervention for Frequent Users of a Psychiatric Emergency Room. AB - Project Connect, a clinical demonstration program developed in consultation with the New York State Office of Mental Health, adapted critical time intervention for frequent users of a large urban psychiatric emergency room (ER). Peer staff provided frequent users with time-limited care coordination. Participants increased their use of outpatient services over 12 months, compared with a similar group not enrolled in the program. For persons with significant general medical, psychiatric, and social needs, provision of this intervention alone is unlikely to reduce reliance on ERs, especially among homeless individuals. PMID- 26766760 TI - Aortic Hemostasis and Resuscitation: Preliminary Experiments Using Selective Aortic Arch Perfusion With Oxygenated Blood and Intra-aortic Calcium Coadministration in a Model of Hemorrhage-induced Traumatic Cardiac Arrest. AB - OBJECTIVES: Selective aortic arch perfusion (SAAP) uses a thoracic aortic balloon occlusion catheter for heart and brain perfusion in cardiac arrest to achieve return of spontaneous circulation (ROSC). SAAP with oxygenated stored blood was studied in a model of hemorrhage-induced cardiac arrest. The study hypothesis was that intra-aortic calcium coadministration would be required to maintain normal aortic arch blood ionized calcium during SAAP and to achieve ROSC. METHODS: Twelve anesthetized, domestic swine underwent severe hemorrhage and liver injury resulting in cardiac arrest. Whole blood and packed red blood cells (RBCs) stored in citrate anticoagulant served as perfusates for SAAP. Experiments were performed with four combinations of SAAP with oxygenated stored blood and intra aortic calcium gluconate infusion: 1) whole blood without calcium, 2) whole blood with calcium, 3) lactated Ringers-diluted packed RBCs with calcium, and 4) normal saline-diluted packed RBCs with calcium. Aortic arch blood ionized calcium was monitored. Occurrence of ventricular dysrhythmias, success rate for ROSC, and the need for simultaneous intra-aortic calcium infusion were assessed. RESULTS: Selective aortic arch perfusion using whole blood without intra-aortic calcium (n = 2) resulted in severe aortic blood ionized hypocalcemia, refractory ventricular fibrillation, and no ROSC. SAAP using whole blood with intra-aortic calcium (n = 4) resulted in ROSC in all four animals. Two of four developed ventricular fibrillation that was successfully defibrillated. SAAP using packed RBCs with intra-aortic calcium resulted in ROSC in all six animals, but the intra-aortic calcium dose needed to maintain normal aortic arch blood ionized calcium levels was one-third of that needed for SAAP with whole blood. Dilution of packed RBCs with lactated Ringers (n = 2) resulted in formation of small clots in the perfusion circuit which were not seen with packed RBCs diluted with normal saline (n = 4). CONCLUSIONS: Selective aortic arch perfusion with stored whole blood or packed RBCs requires simultaneous intra-aortic calcium infusion to overcome citrate anticoagulant calcium binding, avoid refractory ventricular fibrillation, and allow for ROSC. PMID- 26766761 TI - Opening editorial 2016: Changes in scope and structure. AB - This issue of American Psychologist (AP) marks historic changes in the editorial structure and leadership of AP and related shifts in the refinement of the mission of AP and the types of papers AP will publish. As the new editor-in-chief (EIC) of AP, I am enthusiastic about psychology and the many ways that psychological knowledge can improve our lives and the societies in which we live. AP will continue to reflect the whole of psychology and welcomes the input and involvement of individuals from all areas of the field. In this editorial, I offer readers a brief overview of current journal activities and procedures for the flagship journal of the American Psychological Association (APA). (PsycINFO Database Record PMID- 26766762 TI - Developing a science of clinical utility in diagnostic classification systems field study strategies for ICD-11 mental and behavioral disorders. AB - The World Health Organization (WHO) Department of Mental Health and Substance Abuse has developed a systematic program of field studies to evaluate and improve the clinical utility of the proposed diagnostic guidelines for mental and behavioral disorders in the Eleventh Revision of the International Classification of Diseases and Related Health Problems (ICD-11). The clinical utility of a diagnostic classification is critical to its function as the interface between health encounters and health information, and to making the ICD-11 be a more effective tool for helping the WHO's 194 member countries, including the United States, reduce the global disease burden of mental disorders. This article describes the WHO's efforts to develop a science of clinical utility in regard to one of the two major classification systems for mental disorders. We present the rationale and methodologies for an integrated and complementary set of field study strategies, including large international surveys, formative field studies of the structure of clinicians' conceptualization of mental disorders, case controlled field studies using experimental methodologies to evaluate the impact of proposed changes to the diagnostic guidelines on clinicians' diagnostic decision making, and ecological implementation field studies of clinical utility in the global settings in which the guidelines will ultimately be implemented. The results of these studies have already been used in making decisions about the structure and content of ICD-11. If clinical utility is indeed among the highest aims of diagnostic systems for mental disorders, as their developers routinely claim, future revision efforts should continue to build on these efforts. (PsycINFO Database Record PMID- 26766763 TI - Youth violence: What we know and what we need to know. AB - School shootings tear the fabric of society. In the wake of a school shooting, parents, pediatricians, policymakers, politicians, and the public search for "the" cause of the shooting. But there is no single cause. The causes of school shootings are extremely complex. After the Sandy Hook Elementary School rampage shooting in Newtown, Connecticut, we wrote a report for the National Science Foundation on what is known and not known about youth violence. This article summarizes and updates that report. After distinguishing violent behavior from aggressive behavior, we describe the prevalence of gun violence in the United States and age-related risks for violence. We delineate important differences between violence in the context of rare rampage school shootings, and much more common urban street violence. Acts of violence are influenced by multiple factors, often acting together. We summarize evidence on some major risk factors and protective factors for youth violence, highlighting individual and contextual factors, which often interact. We consider new quantitative "data mining" procedures that can be used to predict youth violence perpetrated by groups and individuals, recognizing critical issues of privacy and ethical concerns that arise in the prediction of violence. We also discuss implications of the current evidence for reducing youth violence, and we offer suggestions for future research. We conclude by arguing that the prevention of youth violence should be a national priority. (PsycINFO Database Record PMID- 26766764 TI - On becoming multicultural in a monocultural research world: A conceptual approach to studying ethnocultural diversity. AB - Race, culture, and ethnicity are critical components of the human experience, yet they are often treated as nuisance variables or as post hoc explanations for poorly predicted results. Mandates to pay attention to ethnocultural diversity in research have largely been ignored. Here, we affirm some basic principles of multicultural psychology in conceptually grounded research. We first identify the importance of clear and conceptually guided ethnocultural research, and describe multiple perspectives in the field. The first perspective, a generalizability approach, seeks to find similarities and universalities across diverse groups. The second perspective, a group differences approach, attempts to determine the generalizability and limits to generalizability across different groups that are assumed to represent different cultures. The third perspective, multicultural psychology, involves specifying and measuring the mechanisms of cultural influences on behavior in ethnocultural groups underrepresented in research. In contrast to conventional approaches to culture that apply existing models to other groups, we propose an "inside-out" model that prizes the perspectives of those in ethnocultural communities that are underrepresented in research and places a secondary emphasis on generalizability. We follow with examples and new directions for multicultural psychology research. This approach has the potential to enhance researchers' ability to answer conceptually derived research questions and in combination with the other approaches promises to enhance the advancement of psychological science generally. (PsycINFO Database Record PMID- 26766765 TI - The role of neuroscience within psychology: A call for inclusiveness over exclusiveness. AB - In the present article, we appraise the increasingly prominent role of neuroscience within psychology and offer cautions and recommendations regarding the future of psychology as a field. We contend that the conflict between eliminative reductionism (the belief that the neural level of analysis will eventually render the psychological level of analysis superfluous) and emergent properties (the assumption that higher-order mental functions are not directly reducible to neural processes) is critical if we are to identify the optimal role for neuroscience within psychology. We argue for an interdisciplinary future for psychology in which the considerable strengths of neuroscience complement and extend the strengths of other subfields of psychology. For this goal to be achieved, a balance must be struck between an increasing focus on neuroscience and the continued importance of other areas of psychology. We discuss the implications of the growing prominence of neuroscience for the broader profession of psychology, especially with respect to funding agency priorities, hiring practices in psychology departments, methodological rigor, and the training of future generations of students. We conclude with recommendations for advancing psychology as both a social science and a natural science. (PsycINFO Database Record PMID- 26766766 TI - Translating psychological science: Highlighting the media's contribution to contagion in mass shootings: Comment on Kaslow (2015). AB - In her presidential address, N. J. Kaslow (see record 2015-33530-002) argued that psychologists have a responsibility to translate psychological science to the public and identifies various platforms for doing so. In this comment on her article, I advocate that psychology as a field immediately heed her call in the area of psychological science highlighting the media's contribution to contagion in mass shootings. I point out the psychological science documenting media contagion for suicide and mass shootings, the World Health Organization's (2008) guidelines for media in reporting suicide deaths to prevent that contagion, and discuss ways-based on Dr. Kaslow's suggestions-that psychologists can disseminate psychological science to prevent similar tragedies in the future. (PsycINFO Database Record PMID- 26766767 TI - Janet Taylor Spence (1923-2015). AB - The long and remarkable life of Janet Taylor Spence, the sixth woman to serve as president of the American Psychological Association (APA), ended on March 16, 2015, after a short illness. Janet's 1978 book, Masculinity & Femininity, coauthored with Robert Helmreich, was a major contribution to our understanding of the complex relationships between personal attributes, self-esteem, and attitudes toward women, as well their links to both achievement motivation and parental characteristics. Janet's interest in achievement motivation was an extension of her gender work, as she attempted to learn more about the ways in which presumed differences in achievement motivation might be related to the key dimensions of instrumentality and expressiveness. Janet's election to the presidency of the APA was the culmination of a long and broad involvement in the organization. She served on the Board of Directors from 1976 to 1978, and again in 1983 to 1984 during her presidential term. Earlier she served on the Board of Scientific Affairs and edited Contemporary Psychology in the 1970s. Janet was a fellow in four divisions (3, 8, 12, and 35), and in 2004 she received the APA Gold Medal Award for Life Achievement in the Science of Psychology. PMID- 26766768 TI - Ethel Tobach (1921-2015). AB - With the passing of Ethel Tobach, the world of psychology has lost one of its few remaining giants. While her death brings to an end an important era in 20th century comparative psychology, her contributions went beyond her research specialty into leadership and advocacy roles where she also had a substantial impact. Ethel's professional work and societal work were well recognized and often intertwined. Her many awards included the Kurt Lewin Award (1993) from Division 9 of the American Psychological Association (APA; Society for the Psychological Study of Social Issues), for "outstanding contributions to the development and integration of psychological research and social action." She served as president of APA Division 6 (1984 -1985, Comparative and Physiological Psychology) and APA's Division 48, (2004, the Society for the Study of Peace, Conflict, and Violence). Her professional contributions were acknowledged by being awarded the APA's Gold Medal Award for Lifetime Achievement in Psychology in the Public Interest (2003). In addition to a corpus of research publications and essays on various aspects of psychology, she is known for coediting several important books. PMID- 26766769 TI - Franz Samelson (1923-2015). AB - Franz Samelson, social psychologist and historian of psychology, died in Manhattan, Kansas, on March 16, 2015. Franz joined the Psychology Department at Kansas State University (KSU) in 1957 and rose through the ranks to retire as Professor in 1990. At KSU he taught social psychology informed by his dislike of narrow empiricism and a growing interest in historical topics. The history of social psychology, Franz believed, was distorted by post-World War II desires for value-free empiricism. Gordon Allport, he showed, created an origin myth for the field that suited his values, obscuring the ideological diversity of his predecessors. Turning to intelligence and intelligence testing, Franz's research again altered the scholarly landscape. Although it was long believed that psychologists' testing in World War I demonstrated the usefulness of their young science, Franz revealed this to be another disciplinary myth. Next, Franz showed that a popular history of IQ testing (Stephen Jay Gould's Mismeasure of Man) was distorted by the author's liberal enthusiasm-again showing his willingness to take on the political left as well as the right. PMID- 26766770 TI - Naomi Weisstein (1939-2015). AB - This article memorializes Naomi Weisstein, who passed away on March 26, 2015 at Mount Sinai Hospital in New York City. In Chicago, Illinois, Weisstein began what would become a defining feature of her career and legacy-combining feminist political activism with both her academic and personal life pursuits. By the time she began her first faculty position at Loyola University in Chicago in 1966, Weisstein was an outspoken feminist. In 1968, she published her now classic article "Kirche, Kuche, Kinder as Scientific Law: Psychology Constructs the Female" (PCF; New England Free Press), wherein she criticized the field of psychology for failing to understand women because of its overreliance on essentialism and biologically based theories, while ignoring the importance of social context. Her critique laid the groundwork for others to explore the social construction of gender, and for second-wave feminism to take hold within the discipline of psychology. Despite all of her varied contributions, it is PCF that helped to define Weisstein's legacy in psychology. The article has been cited as a defining moment in second-wave feminism, and several psychologists have remembered the piece as a catalyst for their feminist awakening. PMID- 26766772 TI - Correlation of Capture Efficiency with the Geometry, Transport, and Reaction Parameters in Heterogeneous Immunosensors. AB - Higher capture efficiency of biomarkers in heterogeneous immunosensors would enable early detection of diseases. Several strategies are used to improve the capture efficiency of these immunosensors including the geometry of the system along with the transport and reaction parameters. Having a prior knowledge of the behavior of the above parameters would facilitate the design of an efficient immunosensor. While the contributions of the transport and reaction parameters toward understanding of the mechanism involved in capture have been well studied in the literature, their effect in combination with the geometry of the sensors has not been explored until now. In this work, we have experimentally demonstrated that the capture efficiency of the antigen-antibody systems is inversely related to the size of the sensor patch. The experimental system was simulated in order to get an in-depth understanding of the mechanism behind the experimental observation. Further, the extent of heterogeneity in the system was analyzed using the Sips isotherm to obtain the heterogeneity index (alpha) and the reaction rate constant (K(D)) as fitted parameters for a sensor patch of 1.5 mm radius. The experimental kinetic data obtained for the same sensor patch matched reasonably with the simulation results by considering K(D) as the global affinity constant, which indicated that our system can be considered to be homogeneous. Our simulation results associated with the size dependency of the capture efficiency were in agreement with the trends obtained in our experimental observations where an inverse relation was observed owing to the fact that the mass-transfer limitation decreases with the decrease in the size of the sensor patch. The possible underlying mechanism associated with size dependency of capture efficiency was discussed based on the time-dependent radial variation of captured antigens obtained from our simulation results. A study on the parametric variation was further conducted for the nonmixed and mixed systems on the transport (Deff), reaction (K(D)), and geometric parameters (R). Two different correlations were established for the nonmixed and mixed systems between the capture efficiency (f) and a nondimensional number (t(D)/t(R)) consisting of the above-mentioned parameters. Such unified relations will be useful in designing heterogeneous immunosensors and can be extended to microfluidic immunosensors. PMID- 26766771 TI - Marked elevation in plasma osteoprotegerin constitutes an early and consistent feature of cerebral malaria. AB - Adherence of infected erythrocytes to vascular endothelium causes acute endothelial cell (EC) activation during Plasmodium falciparum infection. Consequently, proteins stored in Weibel-Palade (WP) bodies within EC are secreted into the plasma. Osteoprotegerin (OPG) binds to VWF and consequently is stored within WP bodies. Given the critical role of EC activation in the pathogenesis of severe malaria, we investigated plasma OPG levels in children with P. falciparum malaria. At presentation, plasma OPG levels were significantly elevated in children with cerebral malaria (CM) compared to healthy controls (means 16.0 vs 0.8 ng/ml; p< 0.01). Importantly, OPG levels were also significantly higher in children with CM who had a fatal outcome, compared to children with CM who survived. Finally, in children with CM, plasma OPG levels correlated with other established prognostic indices (including plasma lactate levels and peripheral parasite density). To further investigate the relationship between severe malaria and OPG, we utilised a murine model of experimental CM in which C57BL/6J mice were infected with P. berghei ANKA. Interestingly, plasma OPG levels were increased 4.6 fold within 24 hours following P. berghei inoculation. This early marked elevation in OPG levels was observed before any objective clinical signs were apparent, and preceded the development of peripheral blood parasitaemia. As the mice became increasingly unwell, plasma OPG levels progressively increased. Collectively, these data suggest that OPG constitutes a novel biomarker with prognostic significance in patients with severe malaria. In addition, further studies are required to determine whether OPG plays a role in modulating malaria pathogenesis. PMID- 26766773 TI - The influence of carer fear and self-blame when supporting a loved one with an eating disorder. AB - Carers often feel disempowered and engage in behaviours that inadvertently enable their loved one's ED symptoms and yet little is known regarding these processes. This study examined the relationships among fear, self-blame, self-efficacy, and accommodating and enabling behaviours in 137 carers of adolescents and adults with ED. The results revealed that fear and self-blame predicted low carer self efficacy in supporting their loved one's recovery as well as the extent to which carers reported engaging in recovery-interfering behaviours. The relevance of these findings are discussed in the context of family-oriented ED therapies and highlight the importance for clinicians to attend to and help to process strong emotions in carers, in order to improve their supportive efforts and, ultimately, ED outcomes. PMID- 26766774 TI - Pharmacometric Approaches to Personalize Use of Primarily Renally Eliminated Antibiotics in Preterm and Term Neonates. AB - Sepsis remains a major cause of mortality and morbidity in neonates, and, as a consequence, antibiotics are the most frequently prescribed drugs in this vulnerable patient population. Growth and dynamic maturation processes during the first weeks of life result in large inter- and intrasubject variability in the pharmacokinetics (PK) and pharmacodynamics (PD) of antibiotics. In this review we (1) summarize the available population PK data and models for primarily renally eliminated antibiotics, (2) discuss quantitative approaches to account for effects of growth and maturation processes on drug exposure and response, (3) evaluate current dose recommendations, and (4) identify opportunities to further optimize and personalize dosing strategies of these antibiotics in preterm and term neonates. Although population PK models have been developed for several of these drugs, exposure-response relationships of primarily renally eliminated antibiotics in these fragile infants are not well understood, monitoring strategies remain inconsistent, and consensus on optimal, personalized dosing of these drugs in these patients is absent. Tailored PK/PD studies and models are useful to better understand relationships between drug exposures and microbiological or clinical outcomes. Pharmacometric modeling and simulation approaches facilitate quantitative evaluation and optimization of treatment strategies. National and international collaborations and platforms are essential to standardize and harmonize not only studies and models but also monitoring and dosing strategies. Simple bedside decision tools assist clinical pharmacologists and neonatologists in their efforts to fine-tune and personalize the use of primarily renally eliminated antibiotics in term and preterm neonates. PMID- 26766775 TI - Using patient serum to epitope map soybean glycinins reveals common epitopes shared with many legumes and tree nuts. AB - Soybean consumption is increasing in many Western diets; however, recent reviews suggest that the prevalence of soy allergy can be as high as 0.5% for the general population and up to 13% for children. The immunoglobulin-E (IgE) binding of sera from six soy-sensitive adult human subjects to soybean proteins separated by 2D gel electrophoresis was studied. Synthetic peptide sets spanning the mature glycinin subunit A2 and A3 primary sequences were used to map the IgE-binding regions. Putative epitopes identified in this study were also localized on glycinin hexamer models using bioinformatics software. We identified linear IgE binding epitopes of the major storage protein Gly m 6 by screening individual soy sensitive patient sera. These epitopes were then further analysed by 3D in silico model localization and compared to other plant storage protein epitopes. Web based software applications were also used to study the ability to accurately predict epitopes with mixed results. A total of nine putative IgE-binding epitopes were identified in the glycinin A3 (A3.1-A3.3) and A2 (A2.1-A2.6) subunits. Most patients' sera IgE bound to only one or two epitopes, except for one patient's serum which bound to four different A2 epitopes. Two epitopes (A3.2 and A2.4) overlapped with a previously identified epitope hot spot of 11S globulins from other plant species. Most epitopes were predicted to be exposed on the surface of the 3D model of the glycinin hexamer. Amino acid sequence alignments of soybean acidic glycinins and other plant globulins revealed one dominant epitope hot spot among the four reported hot spots. This study may be helpful for future development of soy allergy immunotherapy and diagnosis. PMID- 26766784 TI - Improvement of ethanol production by recombinant expression of pyruvate decarboxylase in the white-rot fungus Phanerochaete sordida YK-624. AB - To improve ethanol production by Phanerochaete sordida YK-624, the pyruvate decarboxylase (PDC) gene was cloned from and reintroduced into this hyper lignin degrading fungus; the gene encodes a key enzyme in alcoholic fermentation. We screened 16 transformant P. sordida YK-624 strains that each expressed a second, recombinant PDC gene (pdc) and then identified the transformant strain (designated GP7) with the highest ethanol production. Direct ethanol production from hardwood was 1.41 higher with GP7 than with wild-type P. sordida YK-624. RT PCR analysis indicated that the increased PDC activity was caused by elevated recombinant pdc expression. Taken together, these results suggested that ethanol production by P. sordida YK-624 can be improved by the stable expression of an additional, recombinant pdc. PMID- 26766786 TI - Surrogate analyte approach for quantitation of endogenous NAD(+) in human acidified blood samples using liquid chromatography coupled with electrospray ionization tandem mass spectrometry. AB - A high-performance liquid chromatography tandem mass spectrometry (LC-MS/MS) assay for the quantitative determination of NAD(+) in human whole blood using a surrogate analyte approach was developed and validated. Human whole blood was acidified using 0.5N perchloric acid at a ratio of 1:3 (v:v, blood:perchloric acid) during sample collection. 25MUL of acidified blood was extracted using a protein precipitation method and the resulting extracts were analyzed using reverse-phase chromatography and positive electrospray ionization mass spectrometry. (13)C5-NAD(+) was used as the surrogate analyte for authentic analyte, NAD(+). The standard curve ranging from 0.250 to 25.0MUg/mL in acidified human blood for (13)C5-NAD(+) was fitted to a 1/x(2) weighted linear regression model. The LC-MS/MS response between surrogate analyte and authentic analyte at the same concentration was obtained before and after the batch run. This response factor was not applied when determining the NAD(+) concentration from the (13)C5 NAD(+) standard curve since the percent difference was less than 5%. The precision and accuracy of the LC-MS/MS assay based on the five analytical QC levels were well within the acceptance criteria from both FDA and EMA guidance for bioanalytical method validation. Average extraction recovery of (13)C5-NAD(+) was 94.6% across the curve range. Matrix factor was 0.99 for both high and low QC indicating minimal ion suppression or enhancement. The validated assay was used to measure the baseline level of NAD(+) in 29 male and 21 female human subjects. This assay was also used to study the circadian effect of endogenous level of NAD(+) in 10 human subjects. PMID- 26766785 TI - SSB binds to the RecG and PriA helicases in vivo in the absence of DNA. AB - The E. coli single-stranded DNA-binding protein (SSB) binds to the fork DNA helicases RecG and PriA in vitro. Typically for binding to occur, 1.3 m ammonium sulfate must be present, bringing into question the validity of these results as these are nonphysiological conditions. To determine whether SSB can bind to these helicases, we examined binding in vivo. First, using fluorescence microscopy, we show that SSB localizes PriA and RecG to the vicinity of the inner membrane in the absence of DNA damage. Localization requires that SSB be in excess over the DNA helicases and the SSB C-terminus and both PriA and RecG be present. Second, using the purification of tagged complexes, our results show that SSB binds to PriA and RecG in vivo, in the absence of DNA. We propose that this may be the 'storage form' of RecG and PriA. We further propose that when forks stall, RecG and PriA are targeted to the fork by SSB, which, by virtue of its high affinity for single-stranded DNA, allows these helicases to outcompete other proteins. This ensures their actions in the early stages of the rescue of stalled replication forks. PMID- 26766787 TI - Comment on: The UK Experience of a Treatment Strategy for Pediatric Metastatic Medulloblastoma Comprising Intensive Induction Chemotherapy, Hyperfractionated Accelerated Radiotherapy, and Response Directed High-Dose Myeloablative Chemotherapy or Maintenance Chemotherapy (Milan Strategy). PMID- 26766788 TI - Racial and ethnic differences in cognitive function among older adults in the USA. AB - OBJECTIVE: Examine differences in cognition between Hispanic, non-Hispanic black (NHB), and non-Hispanic white (NHW) older adults in the United States. DATA/METHODS: The final sample includes 18 982 participants aged 51 or older who received a modified version of the Telephone Interview for Cognitive Status during the 2010 Health and Retirement Study follow-up. Ordinary least squares will be used to examine differences in overall cognition according to race/ethnicity. RESULTS: Hispanics and NHB had lower cognition than NHW for all age groups (51-59, 60-69, 70-79, 80+). Hispanics had higher cognition than NHB for all age groups but these differences were all within one point. The lower cognition among NHB compared to NHW remained significant after controlling for age, gender, and education, whereas the differences in cognition between Hispanics and NHW were no longer significant after controlling for these covariates. Cognitive scores increased with greater educational attainment for all race/ethnic groups, but Hispanics exhibited the least benefit. DISCUSSION: Our results highlight the role of education in race/ethnic differences in cognitive function during old age. Education seems beneficial for cognition in old age for all race/ethnic groups, but Hispanics appear to receive a lower benefit compared to other race/ethnic groups. Further research is needed on the racial and ethnic differences in the pathways of the benefits of educational attainment for late-life cognitive function. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26766790 TI - Association of Ulcerative Colitis with FUT2 and FUT3 Polymorphisms in Patients from Southeast China. AB - OBJECTIVES: Dysbiosis of intestinal microbiota has been implicated in ulcerative colitis (UC). Fucosyltransferase (FUT) 2 and FUT3 determine expression of histo blood group antigens in the gut and may affect the intestinal microbiota. We investigated the association between FUT2 and FUT3 polymorphisms and UC in Chinese patients. METHODS: We genotyped FUT2 (rs281377, rs1047781 and rs601338) and FUT3 (rs28362459, rs3745635 and rs3894326) in 485 UC patients and 580 healthy controls using SNaPshot. We also evaluated expression of Lewis a and b antigens in the sigmoid colon of 7 UC patients and 7 patients with benign colonic polyps. RESULTS: The frequencies of mutant allele (A) and genotype (GA+AA) in FUT3 (rs3745635) were higher in UC patients than controls (P = 0.016, 95%CI: 1.339 1.699; P = 0.038, 95%CI: 1.330-1.742, respectively). Stratified analyses revealed that the frequencies of mutant allele (G) and genotype (TG+GG) of FUT3 (rs28362459) were significantly lower in patients with extensive colitis than those with distal colitis (P<0.001, 95%CI: 0.503-0.742; P = 0.001, 95%CI: 0.567 0.786, respectively). Similar conclusions were drawn for the mutant allele (A) and genotype (GA+AA) of FUT3 (rs3745635) in patients with extensive colitis compared to those with distal colitis (P = 0.006, 95%CI: 0.553-0.845; P = 0.011, 95%CI: 0.621-0.900, respectively). Although expression of Lewis b antigen in the sigmoid colon did not differ between UC patients and controls, Lewis a antigen expression was higher in the cryptic epithelium of both inflammatory and non inflammatory sigmoid colon of UC patients than controls (P = 0.028). CONCLUSIONS: Our findings indicated that polymorphisms in FUT3 and its intestinal expression might be associated with UC pathogenesis. PMID- 26766791 TI - Ubiquitination is absolutely required for the degradation of hypoxia-inducible factor--1 alpha protein in hypoxic conditions. AB - The hypoxia-inducible factor (HIF) is recognized as the master regulator of hypoxia response. HIF-alpha subunits expression are tightly regulated. In this study, our data show that ts20 cells still expressed detectable E1 protein even at 39.5 degrees C for 12 h, and complete depletion of E1 protein expression at 39.5 degrees C by siRNA enhanced HIF-1alpha and P53 protein expression. Further inhibition of E1 at 39.5 degrees C by siRNA, or E1 inhibitor Ube1-41 completely blocked HIF-1alpha degradation. Moreover, immunoprecipitations of co-transfection of HA-ubiquitin and FLAG-HIF-1alpha plasmids directly confirmed the involvement of ubiquitin in the hypoxic degradation of HIF-1alpha. Additionally, hypoxic HIF 1 alpha degradation is independent of HAF, RACK1, sumoylation or nuclear/cytoplasmic localization. Taken together, our data suggest that constitutive HIF-1alpha protein degradation in hypoxia is absolutely ubiquitination-dependent, and unidentified E3 ligase may exist for this degradation pathway. PMID- 26766792 TI - Obesity-related abnormalities couple environmental triggers with genetic susceptibility in adult-onset T1D. AB - The incidence of adult-onset T1D in low-risk non-HLA type has increased several folds, whereas the contemporaneous incidence in high-risk HLA-type remains stable. Various factors behind this selective increase in T1D in young adults remain unclear. Obesity and its associated abnormalities appear to be an important determinant; however, the underlying mechanism involved is not understood. Recently, we have developed two novel transgenic obese mice models, Mito-Ob and m-Mito-Ob, by expressing a pleiotropic protein prohibitin (PHB) and a phospho mutant form of PHB (Y114F-PHB or m-PHB) from the aP2 gene promoter, respectively. Both mice models develop obesity in a sex-neutral manner, independent of diet; but obesity associated chronic low-grade inflammation and insulin resistance in a male sex-specific manner. Interestingly, on a high fat diet (HFD) only male m-Mito-Ob mice displayed marked mononuclear cell infiltration in pancreas and developed insulitis that mimic adult-onset T1D. Male Mito-Ob mice that share the metabolic phenotype of male m-Mito-Ob mice, and female m-Mito-Ob that harbor m-PHB similar to male m-Mito-Ob mice, did not develop insulitis. Thus, insulitis development in male m-Mito-Ob in response to HFD requires both, obesity-related abnormalities and m-PHB. Collectively, this data provides a proof-of-concept that obesity-associated abnormalities couple environmental triggers with genetic susceptibility in adult-onset T1D and reveals PHB as a potential susceptibility gene for T1D. PMID- 26766793 TI - Luteolin inhibits recruitment of monocytes and migration of Lewis lung carcinoma cells by suppressing chemokine (C-C motif) ligand 2 expression in tumor associated macrophage. AB - Tumor-associated macrophages (TAMs) play pivotal roles in the progression of cancer. In order to investigate a novel candidate that inhibits the tumor supporting M2-like phenotype of TAMs, a murine macrophage cell line RAW 264.7 cells were treated with interleukin (IL)-4. Luteolin inhibited phosphorylation of signal transducer and activator of transcription 6 (STAT6), a main downstream signal of IL-4, and reduced the expression of the M2-associated genes. In addition, Luminex multiplex analysis for secreted cytokines revealed that IL-4 enhanced secretion of chemokine (C-C motif) ligand 2 (CCL2) was reduced by luteolin treatment. IL-4-stimulated migration of monocyte, THP-1 cells, was inhibited by luteolin treatment and recovered by recombinant CCL2 supplement. Moreover, luteolin decreased migration of Lewis lung carcinoma cells in a CCL2 dependent manner. Given the important role of the TAM phenotype in the tumor microenvironment, inhibitory effect of luteolin on the monocyte recruitment and cancer migration via suppression of the TAM-secreted CCL2 may suggest a novel therapeutic approach to treat malignant tumors. PMID- 26766794 TI - Phytoliths reveal the earliest fine reedy textile in China at the Tianluoshan site. AB - Textiles are among the longest and most widespread technologies in human history, although poor preservation of perishable artifacts in Paleolithic and Neolithic contexts makes them difficult to unearth and has hampered study of their production and use. Here we report evidence of a plain-woven mat from the Tianluoshan site, Zhejiang, Eastern China. Phytolith and AMS dating from the mat and modern reference collections shown that the mat was made of reeds (Phragmites australis (Cav.)) and dated to 6775-6645 cal. yr. BP. This is the earliest directly dated fiber artifact so far known in China, over at least one thousand years earlier than any established dates for woven remains elsewhere. The evidence of the mat and other related remains suggest that textile products might occur earlier than 7000-8000 years ago and are significant for understanding the history of textiles, as well as production and human adaptation in Neolithic China. PMID- 26766795 TI - The comparative evaluation of apoptosis produced by leuprolide or orchiectomy on rat prostate tissue. AB - INTRODUCTION: Organisms are constantly in a balance meaning that while new cells are produced, some of the older ones die which takes place in 2 ways: necrosis or apoptosis. Apoptosis is the programmed cellular death triggered by intrinsic or extrinsic stimuli. In this study we have evaluated the apoptosis of prostate tissue generated by surgical or medical orchiectomy. MATERIAL AND METHOD: In this experimental study, we used 36 adult male rats that were evaluated in 3 groups. The first group (Group 1) consisted of 12 rats that had bilateral orchiectomy; the second group (Group 2) included 12 rats that were given leuprolide acetate and the third group (Group 3) consisted of 12 control rats. Immunohistochemical staining of the prostate of all rats was performed and the presence of glandular atrophy and apoptosis were evaluated in the three groups. The statistical differences between the two groups were evaluated by the Fisher exact test. RESULTS: Glandular atrophy was not determined in any rat of the control group, and the apoptotic staining was in the normal limits in all the control rats. In Leuprolide group, glandular atrophy was mild in 7 cases, and moderate in 3 rats. In 2 rats of the Leuprolide group, atrophy was not demonstrated. In surgical orchiectomy group, glandular atrophy was present in all cases. Atrophy was observed as cystic atrophy. Statistical analysis with the Fisher exact test revealed that glandular atrophy was statistically significantly more common in surgical orchiectomy group compared with Leuprolide group (p = 0,012). CONCLUSION: If the aim of treatment in androgen dependent prostatic adenocarcinoma or benign prostate hypertrophy is the construction of a robust apoptosis, bilateral orchiectomy generates a more powerful apoptosis compared with Leuprolide. PMID- 26766789 TI - Cancer statistics for Asian Americans, Native Hawaiians, and Pacific Islanders, 2016: Converging incidence in males and females. AB - Cancer is the leading cause of death among Asian Americans, Native Hawaiians, and Pacific Islanders (AANHPIs). In this report, the American Cancer Society presents AANHPI cancer incidence data from the National Cancer Institute, the Centers for Disease Control and Prevention, and the North American Association of Central Cancer Registries and mortality data from the National Center for Health Statistics. Among AANHPIs in 2016, there will be an estimated 57,740 new cancer cases and 16,910 cancer deaths. While AANHPIs have 30% to 40% lower incidence and mortality rates than non-Hispanic whites for all cancers combined, risk of stomach and liver cancers is double. The male-to-female incidence rate ratio among AANHPIs declined from 1.43 (95% confidence interval, 1.36-1.49) in 1992 to 1.04 (95% confidence interval, 1.01-1.07) in 2012 because of declining prostate and lung cancer rates in males and increasing breast cancer rates in females. The diversity within the AANHPI population is reflected in the disparate cancer risk by subgroup. For example, the overall incidence rate in Samoan men (526.5 per 100,000) is more than twice that in Asian Indian/Pakistani men (216.8). Variations in cancer rates in AANHPIs are related to differences in behavioral risk factors, use of screening and preventive services, and exposure to cancer causing infections. Cancer-control strategies include improved use of vaccination and screening; interventions to increase physical activity and reduce excess body weight, tobacco use, and alcohol consumption; and subgroup-level research on burden and risk factors. CA Cancer J Clin 2016;66:182-202. (c) 2016 American Cancer Society. PMID- 26766796 TI - The factors predicting biochemical recurrence in patients with radical prostatectomy. AB - OBJECTIVE: The main objective of this study was to evaluate the factors predicting recurrence in patients who underwent radical prostatectomy (RP) for localized prostate cancer. MATERIALS AND METHODS: A total of 275 patients who underwent RP between 2000 and 2012 years in our clinic were evaluated retrospectively and 238 patients who met our criteria were included in the study. The effect of PSA values at diagnosis in addition the histopathological variables on the risk of recurrence was evaluated. Biochemical recurrence (BCR) is defined as "an increase of > 0.2 ng/ml or more in the serum total PSA count". The statistical analysis of this study was done using SPSS for Windows Version 15.0 package program. Values below p < 0.05 are accepted as statistically significant. RESULTS: The mean follow up, age and PSA of patients were 37,2 months, 66,01 +/- 6,85 years and 11,12 ng/ml, respectively. BCR rate was 28% (68/238). Univariate analysis revealed that PSA levels during initial diagnosis (p < 0.0001), Gleason score (GS) (p < 0.0001), prostatic capsule involvement (p < 0.005), extracapsular extension (p = 0.0001), seminal vesicle involvement (p < 0.003) and surgical margin positivity (p < 0.014) were significant factors in predicting recurrence, while multivariate analysis showed that PSA at initial diagnosis (p = 0.002) and GS (p = 0.003) were independent prognostic factors. PSA > 10 ng/ml and Gleason score > 7 are considered as the risk factors for BCR. CONCLUSION: Our study results showed that PSA value during initial diagnosis as well as Gleason score were independent factors in predicting BCR following radical prostatectomy. PMID- 26766797 TI - Comparison of efficacy of laser lithotripter with ultrasonic lithotripter in mini percutaneous nephrolithotomy. AB - OBJECTIVE: The aim of the study was to compare the efficacy of the laser lithotripter with the ultrasonic lithotripter in mini percutaneous nephrolithotomy (miniperc). MATERIAL AND METHODS: From June 2013 to January 2014; medical records of 77 consecutive patients who underwent miniperc operation were retrospectively evaluated. Ultrasonic lithotripter was used in 22 patients (Group 1), while laser was used in 55 patients. In the laser group, 22 patients were randomly selected who had same characteristics compared to group 1 (Group 2). Success rate, total operative time, complications according to modified Clavien classification, fluoroscopy time, haemoglobin drop, hospital stays and cost analysis were assessed. Success rates were evaluated on the second postoperative day and after the first month. RESULTS: Total operative time (p = 0.635) and fluoroscopy time (p = 0.248) were not significantly different between the two groups. In the laser group, the success rate (81.8%) was notably more than in the ultrasonic lithotripter group (68.2%) but there was no statistically significance (p = 0.296). Ten reusable ultrasonic probe were used for 22 patients, due to thinness and sensitiveness of the probe. Conversely, one single laser fiber (550 micron) was used for 22 patients. When the cost analysis of lithotripsy was considered, the cost per case was 190 dollar in group 1 and 124 dollar in group 2. (p = 0.154) Complication rate, hospital stay and haemoglobin drop were similar in both groups. CONCLUSION: Laser lithotripsy seems to be more cost effective than ultrasonic lithotripsy for miniperc but larger number of patients are required to confirm this estimation. PMID- 26766798 TI - Current approach for urinary system stone disease in pregnant women. AB - Urinary system stones can be classified according to size, location, X-ray characteristics, aetiology of formation, composition, and risk of recurrence. Especially urolithiasis during pregnancy is a diagnostic and therapeutic challenge. In most cases, it becomes symptomatic in the second or third trimester. Diagnostic options in pregnant women are limited due to the possible teratogenic, carcinogenic, and mutagenic risk of foetal radiation exposure. Clinical management of a pregnant urolithiasis patient is complex and demands close collaboration between patient, obstetrician and urologist. We would like to review current diagnosis and treatment modalities of stone disease of pregnant woman. PMID- 26766799 TI - A new approach in ureteral access sheath locating in retrograde intrarenal surgery (RIRS) by endovisional technique. AB - OBJECTIVE: To compare the results of patients who underwent retrograde intrarenal surgery (RIRS) using endovisional technique for ureteral sheat locating with control group in which endovisional technique was not applied. MATERIAL AND METHODS: Of the 41 patients who underwent RIRS treatment for kidney stone, between March 2014- August 2015, 19 patients treated with endovisional technique formed the study group and remaining 22 patients formed the control group. Patients were evaluated for age and gender, baseline and post procedural creatinine level, duration of operation, fluoroscopy and hospitalization time, size and localization of the stone, presence of multiple stones, previous shock wave lithotripsy (SWL) procedure, double J catheter requirement, complication rate, residual stone rate and absence of stone ratio. RESULTS: There was no statistically significant difference between age, gender, location of the stone, previous SWL procedure, presence of multiple stones, baseline and postprocedural creatinine level, absence of stone ratio, double J catheter requirement and hospitalization duration between the groups. The duration of operation and fluoroscopy of the patients were significantly shorter than the control group (p = 0.036 and p < 0.001, respectively). The complication rates of the endovisional technique group was significantly lower than that of the control group (p = 0.032). CONCLUSION: Endovisional technique is considered to be an appropriate and useful technique in order to locate the sheath safely in patients who has difficulty in ureteral access sheath locating and to decrease the duration of operation and fluoroscopy. PMID- 26766800 TI - Incidence of bacterial colonisation after indwelling of double-J ureteral stent. AB - OBJECTIVE: To determine the bacterial colonisation after double-J stent use and the risk factors for bacteriuria linked to the stent. MATERIALS AND METHODS: A total of 102 patients (61 men and 41 women, mean age 47.5 +/- 14.16) were examined. The stents were removed under aseptic conditions, and a urine culture was obtained before the removal of the stents. After the stents were removed, the upper, central and lower sections were separated, and washing water was sent through the stent. RESULTS: Bacterial colonisation was found in 29.4% (30 of 102) of the stents. The most frequently observed microorganisms were determined as staphylococcus, coagulase negative (8 of 30) and E. coli (5 of 30). The washing fluid used to clean the interior of the catheter produced pathogens in 8 patients (7.8%), and these pathogens were observed to be the same microorganisms that colonised the outside of the stent. There was no statistical difference between the patients with colonisation and those without in terms of age, gender, duration of stenting and reason for stent insertion. CONCLUSIONS: Though stent colonisation does not always entail symptomatic urinary tract infections, as shown in our study, the pathogens in the urine culture are the same as those colonising the stent, confirming the reality that colonisation is the main factor in these events. Additionally, according to our study, significant colonisation may be found in the first 3 weeks, contrary to the literature, causing us to consider that urinary tract infections may develop even in the early period. PMID- 26766801 TI - The effectiveness of local steroid injection after internal urethrotomy to avoid recurrence. AB - OBJECTIVE: Local steroid injection to the stricture region after internal urethrotomy (IU) is a promising technique to avoid the recurrence, although the effectiveness and safety of this technique is still controversial. We aimed to determine the efficacy and safety of local steroids as applied with the IU procedure. MATERIAL-METHOD: A total of 83 patients data with urethral stricture in men were examined retrospectively. Patients classified in two groups who had steroid injection with internal urethrotomy or not. Metil prednisolone 40 mg was injected with transurethral injection needle in the stricture region at the 5, 7 and 12 o'clock sites at the same session with internal urethrotomy. Procedure was considered successful if patient did not report any voiding difficulty and maximum flow rate > 15 mL/second for a voided volume of at least 150 mL after removal of the catheter. Patient's age, time to recurrence, previous recurrences were evaluated. RESULTS: The mean age was 56.4 (18-83) years. Of those patients 33/83 had recurrent stenosis. Nineteen out of these 33 recurrent stenosis patients were treated with local steroid injection and 14/33 had no injection. Only two patients of the steroid treated group had recurrence. Despite that 12 patients had recurrence in the steroid non-treated group. Also the primary stenosis patients showed no recurrence at the steroid+ IU group. CONCLUSIONS: The use of local steroids with IU seems to decrease the high stricture recurrence rate following IU. When local steroids were administered with complementary intention, the disease control outcomes are encouraging. Further robust comparative effectiveness studies are now required. PMID- 26766802 TI - Male sexual dysfunction in patients with chronic end-stage renal insufficiency and in renal transplant recipients. AB - MATERIALS AND METHODS: The study was conducted from December 2011 to December 2012 on 95 patients between the ages of 20 and 65 years: 44 of which had been undergoing dialysis for over a year and 51 of whom had undergone kidney transplants more than 6 months before. Comorbidities were carefully recorded, erectile function was evaluated the with IIEF5 questionnaire and serum levels of total testosterone / free and prolactin were tested at early morning (7 AM). To assess the relationship between erectile dysfunction (ED) and clinical laboratory tests, Student's t-test statistical (quantitative variables), chi-square (qualitative variables), the uni and multivariate analysis were used. RESULTS: In patients undergoing dialysis and in recently transplanted patients a higher instance of ED was found (70% and 65% of cases respectively). Amongst dialyzed patients, patients aged over 50 suffer from ED more frequently. Patients aged over 50s represent 61% of the total number of patients suffering from ED, and just 31% of patients not suffering from ED, (p = 0.006); Hyperprolactinemia was found in 23% and 20% of both groups respectively. Fifty nine % of the dialyzed patients presented values of testosterone serum levels of less than 250 ng/dl with a significant difference between those who were suffering from ED and those who were not (65% of ED patients vs. 46%,of patients not affected from ED p = 0.019). This was found in only 37% of transplanted patients and there does not appear to be a statistically significant correlation with the onset of ED (p = 0.12). In patients over the age of 50, diabetes and a condition of hypotestosteronemia were significantly correlated with ED at univariate and multivariate analyses. CONCLUSIONS: The ED in patients with end stage chronic kidney failure (CKF) continues to have a strong prevalence, either in the patients who are undergoing dialysis or in those who have received transplants. In literature this issue is not sufficiently considered if not at all. Hypotestosteronemia is a risk factor for the onset of ED in end stage CKF patients. A significantly lower prevalence of hypogonadism among dialyzed patents and transplant recipients suggests that renal transplantation may be protective for the sexual capabilities of these patients. PMID- 26766803 TI - Sexuality and erectile function after implantation of an Adjustable Transobturator Male System (ATOMS) for urinary stress incontinence. A multi institutional prospective study. AB - OBJECTIVES: To investigate erectile function and sexuality before/after implantation of the ATOMS device including continence outcome, pain perception and co-morbidities. MATERIALS AND METHODS: We collected data from 34 patients (2010-2014) who were provided with an ATOMS implant due to mild or moderate stress urinary incontinence (SUI) after radical prostatectomy (RPE), transurethral resection (TURP) or radiotherapy. Previous failed implants were no contraindication. Sexuality was evaluated with the International Index of Erectile Function (IIEF-5). The Visual Analog Scale (VAS) and Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) were used to analyse pain perception. Results regarding continence, influence of co-morbidities and drug intake were interpreted. RESULTS: IIEF-5 score increased 6 months after ATOMS implantation with a mean difference of 2.18 (Cl: 1.22, 3.14), p < 0,001). Non-sexually active patients had the greatest benefit. However, 50% of patients achieved a mean IIEF 5 of 10.1 and 38% of patients reported a new onset of sexual activity at follow up (mean IIEF-5 score of 12.9). This is in accordance with reduced SUI and absence of persistent pain syndrome. Overall success rate regarding 24h pad-use was 88% (no pad rate 38%). Previous failed implants did not influence results but diabetes, obesity and drug intake (beta-blockers, antidepressants) led to poorer outcomes. CONCLUSION: Sexuality and erectile function improves significantly 6 months after ATOMS implantation. We postulate that reduced SUI (also during sexual activity) and absence of chronic pain are the improving factors. ATOMS should be offered to men with mild to moderate SUI who are interested in regaining their erectile function and sexual activity. PMID- 26766804 TI - Comments concerning the real risk of sexual adverse events secondary to the use of 5-ARIs. AB - Treatment-induced sexual dysfunctions (SD) are a recurrent and controversial topic in recent literature on the adverse events related to the use of 5-alpha reductase inhibitors (5ARIs) (1, 2). In order to deal adequately with the various aspects of this topic, it is necessary to first cover some of the steps that allow a better definition and understanding of the subject. PMID- 26766805 TI - Ultrasound evaluation of the striated urethral sphincter as a predictive parameter of urinary continence after radical prostatectomy. AB - OBJECTIVES: The purpose of this study was to evaluate preoperatively the results of transrectal ultrasound (TRUS) in the detection of morphological, vascularization status of urethral rhabdosphincter (RS) and evaluate the correlation with urinary continence after radical prostatectomy (RP). METHODS: 211 patients who underwent RP were prospectively studied using TRUS scan of the RS thickness. At the end of the examination a study was performed with the use of colour-Doppler for the assessment of the RS vascularity pattern. The level of continence was graded on a 5 point scale as: 1 = complete continence, 2 = 1 pad daily, 3 = 2-3 pads daily, 4 = 4 or more pads daily, and 5 = complete incontinence. RESULTS: It was possible to visualize the rhabdosphincter and its vascularity in all patients. Patients with normal continence (level 1 and 2) showed a sphincter-muscle thickness of 3.5 mm (+/- 0.4) and a hypoechoic ultrasound pattern. With respect to the other levels 3, 4 and 5 of urinary incontinence RS thickness was 2.8 mm (+/- 0.5), 2.1 mm (+/- 0.6), 1.7 (+/- 0.7) respectively. Incontinence after RP (>= 3 level) was associated with urethral sphincter deficiency in the great majority of patients. Statistical significant differences were observed in the vascularity between continent and incontinent men in all measured vascularity variables (p < 0.005). CONCLUSIONS: This study suggests that RS integrity is a good predictor of urinary continence after RP and this information can be important during the preoperative phase as part of the informed consent. PMID- 26766806 TI - Penile prosthesis implant for erectile dysfunction: A new minimally invasive infrapubic surgical technique. AB - Erectile dysfunction, the most common male sexual disorder after premature ejaculation, with its important impact on man and partner's sexuality and quality of life is a persistent inability to obtain and maintain an erection sufficient to permit satisfactory sexual performance. Non-surgical treatments with controversial results are usually applyed before surgical treatment that has reached high levels of satisfaction. We describe a new surgical technique to implant three-pieces penile prosthesis in patients suffering from erectile dysfunction (ED) not responding to conventional medical therapy or reporting side effects with such a therapy. Implantation of an inflatable prosthesis, for treatment of ED, is a safe and efficacious approach with high satisfaction reported by patients and partners. Surgical technique should be minimally invasive and latest technology equipment should be implanted in order to decrease common complications and to obtain a better aesthetic result. PMID- 26766807 TI - Robot-assisted excision of seminal vesicle cyst associated with ipsilateral renal agenesis. AB - Seminal vesicle cysts (SVCs) associated with other genitourologic abnormalities are rare. Often associated with ipsilateral renal agenesis in a symptomatic patient. In symptomatic patients open surgical excision is the treatment of choice. The laparoscopic approach is a less invasive option. Recently robot assisted management has gained a primary role for the treatment of this condition. PMID- 26766808 TI - Intraoperative presentation of Bochdalek's hernia in an adult during robotic assisted partial nephrectomy: An uncommon situation and literature review. AB - Bochdalek's diaphragmatic hernia (BDH) is a congenital defect of the diaphragm that usually present during the neonatal period and rarely remain silent until adulthood. We present a 45-year-old-female case with diagnosis of double left kidney tumor prepared for robot-assisted partial nephrectomy (RPN). During the preoperative procedure she had a reduction of inspiratory volumes and increased pulmonary pressures: the robotic camera revealed the incidental presence of the left diaphragmatic defect. We report a simultaneous nephron sparing surgery (NSS) and left posterolateral BDH correction done by the da Vinci Surgical Robot (Intuitive Surgical, Sunnyvale, CA). PMID- 26766809 TI - Renal cell carcinoma in patient with crossed fused renal ectopia. AB - Primary renal cell carcinomas have rarely been reported in patients with crossed fused renal ectopia. We presented a patient with right to left crossed fused kidney harbouring renal tumor. The most frequent tumor encountered in crossed fused renal ectopia is renal cell carcinoma. In this case, partial nephrectomy was performed which pave way to preservation of the uninvolved both renal units. Due to unpredictable anatomy, careful preoperative planning and meticulous delineation of renal vasculature is essential for preservation of the uninvolved renal units. PMID- 26766810 TI - Primary testicular lymphoma: Two case reports and review of the literature. AB - Primary testicular lymphoma, is a rare testis tumor that accounts for only less than 9% of all testis tumors. In the preoperative period, it is extremely difficult to distinguish this tumor from other testis tumors. Its diagnosis is done by histological analysis. Most commonly encountered histological type is diffuse large Bcell lymphoma. Adjuvant radiotheraphy and/or chemotheraphy is given after orchiectomy. Prognosis is worse than other testis tumors. Non metastatic tumors indicates good prognosis within one year. Ongoing research in patients with primary testicular lymphoma, are on efficacy of adjuvant theraphies and preventive and cure effect on extranodal extension to central nervous system which is the most common site for recurrency. There are conflicting results because of the small number of patient size. Here we present two cases with primary testicular lymphoma at the ages 71 and 82. PMID- 26766811 TI - Accuracy of pelvic multiparametric MRI in diagnosing local recurrence following radical prostatectomy. Case report and revision of the literature. AB - A Caucasian man (73 years old) six years from radical prostatectomy for prostate cancer (PCa) showed biochemical recurrence (BCR); the follow up based on PSA evaluated every 6 months was negative (0.1 ng/ml) for 5 years, but in the last year PSA increased to 0.3 vs 0.5 ng/ml. The patient was asymptomatic and underwent 3.0 Tesla mpMRI equipped with surface 16 channels phased-array coil placed around the pelvic area; multiplanar turbo spin-echo T2-weighted (T2W), axial diffusion weighted imaging (DWI), axial dynamic contrast enhanced (DCE) and spectroscopy were performed. Pelvic mpMRI demonstrated the presence of a nodular tissue with a diameter of 10 mm. located on the left of the prostatic fossa near the rectum that was higly sospicious for local PCa recurrence. The patient underwent salvage RT (64 Gy); one year from RT PSA was 0.1 ng/ml suggesting that the patient was free from recurrence. In conclusion, mpMRI could be combined with PSA kinetics in the evaluation of men with BRC also in the presence of PSA values < 1 ng/ml. PMID- 26766812 TI - Penile prosthesis implant with bi-triangular excision and graft for surgical therapy of Peyronie's disease: A case report. AB - We present a case of a 65-year-old man, who presented with moderate erectile dysfunction and a dorsal penile deviation of 60 degrees caused by Peyronie's disease. The patient underwent bi-triangularshaped plaque excision, followed by grafting and implantation of inflatable penile prosthesis. Complete penile straightening, without mechanical or geometric abnormalities, was achieved using bi-triangular excision and grafting. Postoperatively, the patient reported high satisfaction with the results and could perform sexual intercourse naturally. This novel technique corrects any degree of penile curvature, permits malleable and semi-rigid penile prosthesis implantation, avoids penile length loss, and eliminates additional incisions. To our knowledge, this case is the first in the literature in which the bi-triangular technique was successfully used for penile prosthesis implantation secondary to Peyronie's disease. This new technique appears to be a good solution to correct penile curvature during penile prosthesis implantation for the treatment of Peyronie's disease associated with erectile dysfunction. PMID- 26766813 TI - Three-component hydraulic penile prosthesis malfunction due to penile fibrolipoma secondary to augmentative phalloplasty: A case report. AB - Fibrolipomas are an infrequent type of lipomas. We describe a case of a man suffering from subcutaneous penile fibrolipoma, who twelve months earlier has been submitted to augmentative phalloplasty due to aesthetic dysmorphophobia. The same patient three years earlier has been submitted to three-component hydraulic penile prostheses implantation due to erectile dysfunction. After six months from removing of the mass, the penile elongation and penile enlargement were stable, the prostheses were correctly functioning and the patient was satisfied with his sexual intercourse and life. The diagnostics and surgical characteristics of this case are reported. PMID- 26766814 TI - Duality of Iron Oxide Nanoparticles in Cancer Therapy: Amplification of Heating Efficiency by Magnetic Hyperthermia and Photothermal Bimodal Treatment. AB - The pursuit of innovative, multifunctional, more efficient, and safer treatments is a major challenge in preclinical nanoparticle-mediated thermotherapeutic research. Here, we report that iron oxide nanoparticles have the dual capacity to act as both magnetic and photothermal agents. We further explore every key aspect of this magnetophotothermal approach, choosing iron oxide nanocubes for their high efficiency for the magnetic hyperthermia modality itself. In aqueous suspension, the nanocubes' exposure to both: an alternating magnetic field and near-infrared laser irradiation (808 nm), defined as the DUAL-mode, amplifies the heating effect 2- to 5-fold by comparison with magnetic stimulation alone, yielding unprecedented heating powers (specific loss powers) up to 5000 W/g. In cancer cells, the laser excitation restores the optimal efficiency of magnetic hyperthermia, otherwise inhibited by intracellular confinement, resulting in a remarkable heating efficiency in the DUAL-mode (up to 15-fold amplification), with respect to the magnetophotothermal mode. As a consequence, the dual action yielded complete apoptosis-mediated cell death. In solid tumors in vivo, single mode treatments (magnetic or laser hyperthermia) reduced tumor growth, while DUAL mode treatment resulted in complete tumor regression, mediated by heat-induced tumoral cell apoptosis and massive denaturation of the collagen fibers, and a long-lasting thermal efficiency over repeated treatments. PMID- 26766815 TI - Body Mass Index May Positively Correlate with Bone Mineral Density of Lumbar Vertebra and Femoral Neck in Postmenopausal Females. AB - BACKGROUND: Our study aimed to explore the relationship between body mass index (BMI) and bone mineral density (BMD) of lumbar vertebra and femoral neck in postmenopausal females. MATERIAL/METHODS: From September 2012 to September 2014, 236 healthy postmenopausal females who underwent physical examinations at the Women & Children's Health Care Hospital of Linyi were enrolled into our study. These subjects were divided into 3 groups: underweight group, normal weight group, and overweight group. In addition, there were 2 age stratifications: <60 years old and >=60 years old. DPX-L type dual-energy X-ray bone densitometry (American Lunar Company) was used to measure the BMD of lumbar vertebra and femoral neck in the recruited subjects. Pearson test was used for correlation analysis. RESULTS: BMDs and T-scores of lumbar vertebra (L1-L4), femoral neck, proximal femur, and Ward's triangle region among the groups were ranked as follows: underweight group < normal weight group < overweight group. There were significant differences in body weight and BMI among the underweight, normal weight, and overweight groups (P<0.05). The T-scores of all examined anatomic locations showed significant differences between the underweight group and normal weight group, as well as between the underweight group and overweight group (both P<0.05). Only the T-scores of lumbar vertebra L2-L4 had significant differences between the normal weight group and overweight group (P<0.05). The BMDs of all anatomic components under study showed statistical differences in both age stratifications between the overweight group and underweight group, as well as between the overweight group and normal weight group (both P<0.05). When stratified above 60 years old, the BMDs of lumbar vertebra (L1, L2 and L4) showed statistical differences between the normal weight group and underweight group (P<0.05). Various factors could be ranked according to the absolute values of correlation coefficients as below: body weight, BMI, height, and age. Body weight, BMI, and height were positively correlated with the BMDs of all examined anatomic locations (P<0.05). However, age was negatively correlated with the various components of the body (lumbar vertebra L1, L2 and L4, femoral neck, proximal femur, Ward's triangle region: P<0.05; lumbar vertebra L3: P>0.05). CONCLUSIONS: Our study provides evidence that body weight and BMI are important factors affecting BMD. Postmenopausal females with low BMI are more likely to have osteopenia, and are likely to develop osteoporosis. BMI can be used as an important index to prevent osteoporosis. PMID- 26766846 TI - Public Health and Rare Diseases: Oxymoron No More. PMID- 26766847 TI - Asthma Prevention and Management for Aboriginal People: Lessons From Mi'kmaq Communities, Unama'ki, Canada, 2012. AB - BACKGROUND: Asthma affects at least 10% of Aboriginal children (aged 11 or younger) in Canada, making it the second most common chronic disease suffered by this demographic group; yet asthma support strategies specific to Aboriginal peoples have only begun to be identified. COMMUNITY CONTEXT: This research builds on earlier phases of a recent study focused on identifying the support needs and intervention preferences of Aboriginal children with asthma and their parents or caregivers. Here, we seek to identify the implications of our initial findings for asthma programs, policies, and practices in an Aboriginal context and to determine strategies for implementing prevention programs in Aboriginal communities. METHODS: Five focus groups were conducted with 22 recruited community health care professionals and school personnel in 5 Mi'kmaq communities in Unama'ki (Cape Breton), Nova Scotia, Canada, through a community-based participatory research design. Each focus group was first introduced to findings from a local "social support for asthma" intervention, and then the groups explored issues associated with implementing social support from their respective professional positions. OUTCOME: Thematic analysis revealed 3 key areas of opportunity and challenges for implementing asthma prevention and management initiatives in Mi'kmaq communities in terms of 1) professional awareness, 2) local school issues, and 3) community health centers. INTERPRETATION: Culturally relevant support initiatives are feasible and effective community-driven ways of improving asthma support in Mi'kmaq communities; however, ongoing assistance from the local leadership (ie, chief and council), community health directors, and school administrators, in addition to partnerships with respiratory health service organizations, is needed. PMID- 26766848 TI - A Qualitative Approach to Understanding Real-World Electronic Cigarette Use: Implications for Measurement and Regulation. AB - INTRODUCTION: An understanding of the real-world use of electronic cigarettes (e cigarettes) is needed to inform surveillance efforts and future state and federal regulation. This study investigates the behavioral aspects of e-cigarette use. METHODS: We used qualitative methods to examine salient characteristics of e cigarette use. The lead investigator (M.C.) conducted in-depth, semistructured individual interviews to explore patterns and behaviors associated with e cigarette use among a purposive sample of 50 current adult users. Thematic content analysis was used to analyze qualitative data and document themes. RESULTS: Several important themes emerged. Although most users started with "closed system" products, the majority switched from that type of e-cigarette to "open system" devices. Responses were diverse on preferred flavors, although mixing flavors was a common practice. Many users had difficulty estimating the total amount of e-liquid they used within a given period and described an iterative process in which they experimented with different nicotine levels to determine their preferred concentration. Reported frequency of use and puffing behaviors varied greatly between users and also differed from the way traditional cigarettes are smoked. CONCLUSION: Results from this study have implications for developing appropriate survey metrics for e-cigarette surveillance, the regulation of flavorings, and reporting of e-cigarette product constituents. PMID- 26766849 TI - Cigarette Smoking Among Socioeconomically Disadvantaged Young Adults in Association With Food Insecurity and Other Factors. AB - INTRODUCTION: Low socioeconomic status is associated with high rates of cigarette smoking, and socioeconomic differences in cigarette smoking tend to emerge during young adulthood. To further our understanding of socioeconomic differences in smoking among young adults, we examined correlates of smoking, with attention to multiple socioeconomic indicators that have not been examined in this population. METHODS: We analyzed data from the 2011-2012 California Health Interview Survey. The analytic sample consisted of young adults aged 18-30 years who were considered socioeconomically disadvantaged as measured by education and poverty. Logistic regression analyses were conducted to examine factors associated with smoking status in this group, and multinomial logistic regression analyses were conducted to examine correlates of smoking frequency. RESULTS: In this sample (N = 1,511; 48% female, 66% Hispanic/Latino, 18% non-Hispanic white), 39.7% reported experiencing food insecurity in the past year. Smoking prevalence was significantly higher among young adults who reported being food insecure (26.9%) than among those who reported being food secure (16.4%). Past-year food insecurity was significantly associated with current smoking, independent of sociodemographic characteristics and alcohol use. Specifically, food insecurity was significantly associated with daily but not nondaily smoking. CONCLUSION: Socioeconomically disadvantaged young adults with food insecurity may be considered a high-risk group with respect to cigarette smoking. Efforts to reduce tobacco-related health disparities should address diverse sources of socioeconomic influences, including experiences of food insecurity. PMID- 26766850 TI - Screening for cognitive dysfunction in Huntington's disease with the clock drawing test. AB - BACKGROUND: The aim of the study is to investigate the performance of the clock drawing test as a screening tool for cognitive impairment in Huntington's disease (HD) mutation carriers. METHODS: The performance of the clock drawing test was assessed in 65 mutation carriers using the Shulman and the Freund scoring systems. The mini-mental state examination, the Symbol Digit Modalities Test, the Verbal Fluency Test, and the Stroop tests were used as comparisons for the evaluation of cognitive functioning. Correlations of the clock drawing test with various cognitive tests (convergent validity), neuropsychiatric characteristics (divergent validity) and clinical characteristics were analysed using the Spearman's rank correlation coefficient. Receiver-operator characteristic analyses were performed for the clock drawing test against both the mini-mental state examination and against a composite variable for executive cognitive functioning to assess optimal cut-off scores. RESULTS: Inter-rater reliability was high for both the Shulman and Freund scoring systems (ICC = 0.95 and ICC = 0.90 respectively). The clock drawing tests showed moderate to high correlations with the composite variable for executive cognitive functioning (mean rho = 0.75) and weaker correlations with the mini-mental state examination (mean rho = 0.62). Mean sensitivity of the clock drawing tests was 0.82 and mean specificity was 0.79, whereas the mean positive predictive value was 0.66 and the mean negative predictive value was 0.87. CONCLUSION: The clock drawing test is a suitable screening instrument for cognitive dysfunction in HD, because it was shown to be accurate, particularly so with respect to executive cognitive functioning, and is easy and quick to use. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26766851 TI - Making the Case: What Is the Evidence of Impact of Applying Human Rights-Based Approaches to Health? PMID- 26766852 TI - Assessing the Impact of a Human Rights-Based Approach across a Spectrum of Change for Women's, Children's, and Adolescents' Health. AB - Global momentum around women's, children's, and adolescents' health, coupled with the ambitious and equalizing agenda of the Sustainable Development Goals (SDGs), has exposed a tension between the need for comprehensive, multi-actor, rights based approaches that seek to "close the gaps" and a growing economic and political imperative to demonstrate efficiency, effectiveness, and returns on specific investments. To address this challenge, this paper proposes a framework to measure "results" in a way that offers a more nuanced understanding of the impact of human rights-based approaches and their complexity, as well as their contextual, multi-sectoral, and evolving nature. We argue that the impact of human rights-based approaches is best measured across a spectrum of change-at the individual, programmatic, structural, and societal levels. Such an analysis would allow for more accurate assessments of the cumulative effect of these changes. The paper also underscores the long-overdue need to better define the parameters of a human rights-based approach to health. This is an important part of the research agenda on human rights and health in the context of the SDGs and the Global Strategy for Women's, Children's and Adolescents' Health, and amid calls for better measurement and greater accountability for resources, results, and rights at all levels. While this paper focuses on women's, children's, and adolescents' health, the proposed framework can apply as readily to other areas of health and provides a new frame of reference for assessing the impact of human rights-based approaches. PMID- 26766853 TI - A Review of the Impact of the Human Rights in Healthcare Programme in England and Wales. AB - This article provides the background to an analysis of the Human Rights in Healthcare Programme in England and Wales. Using evidence from source materials, summary publications, and official reports, it charts a small but important change in the relationship between health and human rights and shows how a small number of National Health Service organizations used a human rights-based approach (HRBA) to develop resources aimed at improving the quality of health services and health outcomes. Through a case study of one participating organization, it examines the development of approaches to measuring the outcomes and impacts of HRBAs. The article argues that because of the way the Programme was set up, it is not likely to provide the level of evidence of impact required to bring about a profound change in the relationship between human rights and health care. There is a need for a different approach that considers the big human rights questions that need to be asked. PMID- 26766854 TI - Rights-Based Citizen Monitoring in Peru: Evidence of Impact from the Field. AB - This paper discusses a human rights-based initiative developed in Puno, Peru, in which indigenous women seek to address problems with access and quality of care by monitoring their government-run health facilities. The evidence of impact presented here is based on a qualitative study of the rights-based monitoring initiative (53 key informant interviews in 2010-2011), corroborated by findings from a review of previous qualitative and quantitative assessments of the initiative. The research findings show that the citizen monitors are able to identify, document, and act on a set of persistent "everyday injustices" experienced by health care users. These can include illegal financial charges, abusive or dismissive treatment, extended wait times, and culturally insensitive care. These results suggest that citizen monitoring can lead to important changes at the health facility level, as well as in the lives of the volunteer monitors. It can also provide key information that can be used to put previously neglected concerns onto local and national health policy agendas. However, as this article explores, the citizen monitoring initiative faces several of its own challenges. PMID- 26766855 TI - Using Technology to Claim Rights to Free Maternal Health Care: Lessons about Impact from the My Health, My Voice Pilot Project in India. AB - My Health, My Voice is a human rights-based project that pilots the use of technology to monitor and display online data regarding informal payments for maternal health care in two districts of Uttar Pradesh, India. SAHAYOG, an organization based in Uttar Pradesh, partnered with a grassroots women's forum to inform women about their entitlements, to publicize the project, and to implement a toll-free hotline where women could report health providers' demands for informal payments. Between January 2012 and May 2013, the hotline recorded 873 reports of informal payment demands. Monitoring and evaluation revealed that the project enhanced women's knowledge of their entitlements, as well as their confidence to claim their rights. Anecdotal evidence suggests that health providers' demands for informal payments were reduced in response to the project, although hospital and district officials did not regularly consult the data. The use of technology accorded greater legitimacy among governmental stakeholders. Future research should examine the sustainability of changes, as well as the mechanisms driving health sector responsiveness. PMID- 26766856 TI - Evaluating a Human Rights-Based Advocacy Approach to Expanding Access to Pain Medicines and Palliative Care: Global Advocacy and Case Studies from India, Kenya, and Ukraine. AB - Palliative care has been defined as care that is person-centered and attentive to physical symptoms and psychological, social, and existential distress in patients with severe or life-threatening illness. The identification of access to palliative care and pain treatment as a human rights issue first emerged among palliative care advocates, physicians, and lawyers in the 1990s, with a basis in the right to health and the right to be free from cruel, inhuman, and degrading treatment. Using a case study approach, we evaluate the results of a human rights based advocacy approach on access to pain medicine and palliative care in India, Kenya, and Ukraine. In each country, human rights advocacy helped raise awareness of the issue, identify structural barriers to care, define government obligations, and contribute to the reform of laws, policies, and practices impeding the availability of palliative care services. In addition, advocacy efforts stimulated civil society engagement and high-level political leadership that fostered the implementation of human rights-based palliative care programs. Globally, access to palliative care was increasingly recognized by human rights bodies and within global health and drug policy organizations as a government obligation central to the right to health. PMID- 26766858 TI - Germany's Experience in Supporting and Implementing Human Rights-Based Approaches to Health, plus Challenges and Successes in Demonstrating Impact on Health Outcomes. PMID- 26766857 TI - The Universal Periodic Review: A Platform for Dialogue, Accountability, and Change on Sexual and Reproductive Health and Rights. AB - This paper argues that the Universal Periodic Review (UPR) of the United Nations Human Rights Council can be a critical avenue for promoting a human rights-based approach to sexual and reproductive health and well-being due to its reliance on the principles of participation and accountability. Drawing on evidence from the UPR process since its inception in 2008, the paper analyzes the impact of the UPR in advancing sexual and reproductive health and rights. The evidence collected speaks to the political opportunity represented by the UPR at the country level to enhance government accountability and national dialogue on sexual and reproductive health and rights among key stakeholders. However, the UPR should not be seen in isolation from other human rights mechanisms. Countries' implementation of UPR recommendations should be done conjointly with the guidance provided by other human rights mechanisms, including the expert views of United Nations treaty monitoring bodies and Special Procedures, and alongside strong national human rights protection systems. PMID- 26766860 TI - Interview With Francisco Songane: Evidence of Impact of Human Rights-Based Approaches to Health. PMID- 26766859 TI - Ethical and Human Rights Foundations of Health Policy: Lessons from Comprehensive Reform in Mexico. AB - This paper discusses the use of an explicit ethical and human rights framework to guide a reform intended to provide universal and comprehensive social protection in health for all Mexicans, independently of their socio-economic status or labor market condition. This reform was designed, implemented, and evaluated by making use of what Michael Reich has identified as the three pillars of public policy: technical, political, and ethical. The use of evidence and political strategies in the design and negotiation of the Mexican health reform is briefly discussed in the first part of this paper. The second part examines the ethical component of the reform, including the guiding concept and values, as well as the specific entitlements that gave operational meaning to the right to health care that was enshrined in Mexico's 1983 Constitution. The impact of this rights-based health reform, measured through an external evaluation, is discussed in the final section. The main message of this paper is that a clear ethical framework, combined with technical excellence and political skill, can deliver major policy results. PMID- 26766861 TI - What Constitutes Evidence in Human Rights-Based Approaches to Health? Learning from Lived Experiences of Maternal and Sexual Reproductive Health. AB - The impact of human rights interventions on health outcomes is complex, multiple, and difficult to ascertain in the conventional sense of cause and effect. Existing approaches based on probable (experimental and statistical) conclusions from evidence are limited in their ability to capture the impact of rights-based transformations in health. This paper argues that a focus on plausible conclusions from evidence enables policy makers and researchers to take into account the effects of a co-occurrence of multiple factors connected with human rights, including the significant role of "context" and power. Drawing on a subject-near and interpretive (in other words, with regard to meaning) perspective that focuses on the lived experiences of human rights-based interventions, the paper suggests that policy makers and researchers are best served by evidence arrived at through plausible, observational modes of ascertaining impact. Through an examination of what human rights-based interventions mean, based on the experience of their operationalization on the ground in culturally specific maternal and reproductive health care contexts, this paper contributes to an emerging scholarship that seeks to pluralize the concept of evidence and to address the methodological challenges posed by heterogeneous forms of evidence in the context of human rights as applied to health. PMID- 26766862 TI - Looking for Evidence of the Impact of Introducing a Human Rights-Based Approach in Health: The SaluDerecho Experience. AB - This paper summarizes the background, methodology, results, and lessons learned from SaluDerecho, the Initiative on Priority Setting, Equity and Constitutional Mandates in Health. Originally facilitated by the capacity-building arm of the World Bank in 2010, it was implemented in Latin American countries and later expanded to other regions of the world. Segmentation, decentralization, and lack of coordination in health systems; weak information systems; stratified societies; and hierarchical power relations in participating countries are some of the characteristics that inhibit a human rights-based approach to health. Hence, deliberate interventions like SaluDerecho are vital. Facilitating the participation of multiple stakeholders in a more informed and transparent dialogue creates a "safe" working environment to co-create policy solutions to improve transparency and accountability. The proposed evaluation methodology involves several steps that begin with an assessment of behavioral changes in actors (including policy makers, citizens, payers, and health care providers) that reshape relationships and, over time, change the functioning of health systems. Despite certain limitations, SaluDerecho has provided evidence of positive change among participating countries. PMID- 26766863 TI - Empowerment for the Right to Health: The Use of the "Most Significant Change" Methodology in Monitoring. AB - Quantitative evaluations might be insufficient for measuring the impact of interventions promoting the right to health, particularly in their ability to contribute to a greater understanding of processes at the individual, community, and larger population level through which certain results are obtained. This paper discusses the application of a qualitative approach, the "most significant change" (MSC) methodology, in the Philippines, Palestine, the Democratic Republic of the Congo, and El Salvador between 2010 and 2013 by Third World Health Aid and its partner organizations. MSC is based on storytelling through which the central question--what changes occurred?--is developed in terms of, "who did what, when, why, and why was it important?" The approach focuses on personal stories that reflect on experiences of change for individuals over time. MSC implementation over several years allowed the organizations to observe significant change, as well as evolving types of change. Participants shifted their stories from "how the programs helped them" and "what they could do to help others benefit from the programs" to "what they could do to help their organizations." The MSC technique is useful as a complement to quantitative methods, as it is a slow, participatory, and intensive endeavor that builds capacity while being applied. This makes MSC a useful monitoring tool for programs with participatory and empowering objectives. PMID- 26766864 TI - The Impact of Human Rights on Universalizing Health Care in Vermont, USA. AB - In 2010, Vermont adopted a new law embracing human rights principles as guidelines for health care reform, and in 2011, Vermont was the first state in the US to enact framework legislation to establish a universal health care system for all its residents. This article reports on the Vermont Workers' Center's human rights-based approach to universal health care and the extent to which this approach influenced decision makers. We found the following: (1) by learning about the human right to health care and sharing experiences, Vermonters were motivated to demand universal health care; (2) mobilizing Vermonters around a unified message on the right to health care made universal health care politically important; (3) using the human rights framework to assess new proposals enabled the Vermont Workers' Center to respond quickly to new policy proposals; (4) framing health care as a human right provided an alternative to the dominant economics-based discourse; and (5) while economics continues to dominate discussions among Vermont leaders, both legislative committees on health care use the human rights principles as guiding norms for health care reform. Importantly, the principles have empowered Vermonters by giving them more voice in policymaking and have been internalized by legislators as democratic principles of governance. PMID- 26766865 TI - Measuring the Impact of the Human Rights on Health in Global Health Financing. AB - In response to new scientific developments, UNAIDS, WHO, and global health financing institutions have joined together to promote a "fast-track" global scale-up of testing and treatment programs. They have set ambitious targets toward the goal of ending the three diseases by 2030. These numerical indicators, based on infectious disease modeling, can assist in measuring countries' progressive realization of the right to health. However, they only nominally reference the catastrophic impact that human rights abuses have on access to health services; they also do not measure the positive impact provided by law reform, legal aid, and other health-related human rights programs. Drawing on experience at the Global Fund to Fight AIDS, Tuberculosis and Malaria, which has incorporated expanded stakeholder consultation and human rights programming into its grants, the article argues that addressing human rights barriers to access is often an ad hoc activity occurring on the sidelines of a health grantmaking process that has focused on the scale-up of biomedical programs to meet global health indicators. To ensure that these biomedical programs have impact, UN agencies and health financing mechanisms must begin to more systematically and proactively integrate human rights policy and practice into their modeling and measurement tools. PMID- 26766866 TI - Effect of novel blend nanofibrous scaffolds on diabetic wounds healing. AB - Chitosan-poly (vinyl alcohol) (Cs: PVA) (2:3) and poly (caprolactone)-chitosan poly (vinyl alcohol) (PCL: Cs: PVA) (2:1:1.5) nanofibrous blend scaffolds were fabricated using the electrospinning technique in the authors' previous studies. The results of the previous studies confirmed the high biological properties of the scaffolds and their ability in healing of burn and excision wounds on rat model. In the present study, the biological scaffolds were applied on diabetic dorsum skin wounds and diabetic foot wound on rat models (n = 16). Macroscopic and microscopic investigations were carried out using digital images and haematoxylin and eosin (H&E) staining respectively, to measure the wound areas and to track wound healing rate. It was found that at all time points the areas of wounds treated with nanofibrous scaffolds were smaller compared with the controls. Pathological results showed much better healing efficacy for the test samples compared with the control ones. Pathological investigations proved the presence of more pronounced granulation tissues in the scaffold-treated wounds compared with the control ones. At 20 days post excision, the scaffold-treated groups achieved complete repair. The results indicated that Cs: PVA and PCL: Cs: PVA nanofibrous webs could be considered to be promising materials for burn, excision and diabetic wounds healing. PMID- 26766867 TI - Polymeric pH nanosensor with extended measurement range bearing octaarginine as cell penetrating peptide. AB - A synthetic peptide octaarginine which mimics human immunodeficiency virus-1, Tat protein is used as cell penetrating moiety for new pH nanosensors which demonstrate enhanced cellular uptake and expanded measurement range from pH 3.9 to pH 7.3 by simultaneously incorporating two complemental pH-sensitive fluorophores in a same nanoparticle. The authors believe that this triple fluorescent pH sensor provides a new tool to pH measurements that can have application in cellular uptake mechanism study and new nanomedicine design. PMID- 26766868 TI - Antibacterial activity of hybrid chitosan-cupric oxide nanoparticles on cotton fabric. AB - In this study, cupric oxide (CuO) nanoparticles were prepared using sonochemical method. The prepared nanoparticles were studied using X-ray diffraction (XRD) pattern, Fourier transform infrared (FTIR) spectroscopy, scanning electron microscopy (SEM), and transmission electron microscopy (TEM) methods. The colloidal chitosan (CS) solution was prepared using ultrasound irradiation method and simultaneously mixed with CuO nanoparticles. The coatings of colloidal solution with and without CuO nanoparticles were studied through TEM images. The cotton fabrics were separately soaked in the prepared nanoparticle-containing (hybrid) solutions by sonication method followed by pad-dry-cure method. The structural, functional, and morphological analyses of the coated and uncoated fabrics were performed using XRD, FTIR-attenuated total reflectance, and SEM analyses, respectively. The hybrid-coated cotton fabrics showed better antibacterial activity against Staphylococcus aureus and Escherichia coli. The bioactivity performance of the coated fabrics was in the order of CuO-coated fabric > CS-coated fabric. PMID- 26766869 TI - Signal amplification strategy using gold/N-trimethyl chitosan/iron oxide magnetic composite nanoparticles as a tracer tag for high-sensitive electrochemical detection. AB - This study presents a novel signal amplification method for high-sensitive electrochemical immunosensing. Gold (Au)/N-trimethyl chitosan (TMC)/iron oxide (Fe3O4) (shell/shell/core) nanocomposite was used as a tracing tag to label antibody. The tag was shown to be capable of amplifying the recognition signal by high-density assembly of Au nanoparticles (NPs) on TMC/Fe3O4 particles. The remarkable conductivity of AuNPs provides a feasible pathway for electron transfer. The method was found to be simple, reliable and capable of high sensitive detection of human serum albumin as a model, down to 0.2 pg/ml in the range of 0.25-1000 pg/ml. Findings of the present study would create new opportunities for sensitive and rapid detection of various analytes. PMID- 26766870 TI - Enhanced antimicrobial activity of silver nanoparticles-Lonicera Japonica Thunb combo. AB - Silver metals have long been known to possess antimicrobial properties. Recently, even the nanoparticle version of silver (AgNPs) has also been established as antimicrobials. In this study AgNPs were combined with extracts of the medicinal plant Chinese honeysuckle, Lonicera japonica Thunb. The antimicrobial activity of the AgNPs-herb was tested against pathogenic Escherichia coli CMCC44113. Using different AgNPs or herb (honeysuckle water extract or HWE) ratios in the presence of a fixed concentration of E. coli CMCC44113, potencies were found to be proportional with concentrations. The antimicrobial activities of AgNPs-HWE combo were significant enhanced, when compared with solely AgNPs or HWE. Thus, atomic force microscopic and propidium monoazide-PCR were used to probe the damages caused by AgNPs-HWE combo on the cell morphology and cell membrane integrity of E. coli. The mechanism of AgNPs-HWE combo against E. coli may attribute to AgNPs leads to cell wall lysis and damages cell membrane integrity, and thus increases the penetration of HWE into the bacterium, which results in more serious damage to bacterial cells. These findings indicated that AgNPs-herb was more potent than the AgNPs alone and holds promise for the development of nanoparticle enhanced herbal pharmaceuticals. PMID- 26766871 TI - Extracellular synthesis gold nanotriangles using biomass of Streptomyces microflavus. AB - Applications of nanotechnology and nano-science have ever-expanding breakthroughs in medicine, agriculture and industries in recent years; therefore, synthesis of metals nanoparticle (NP) has special significance. Synthesis of NPs by chemical methods are long, costly and hazardous for environment so biosynthesis has been developing interest for researchers. In this regard, the extracellular biosynthesis of gold nanotriangles (AuNTs) performed by use of the soil Streptomycetes. Streptomycetes isolated from rice fields of Guilan Province, Iran, showed biosynthetic activity for producing AuNTs via in vitro experiments. Among all 15 Streptomyces spp. isolates, isolate No. 5 showed high biosynthesis activity. To determine the bacterium taxonomical identity at genus level, its colonies characterised morphologically by use of scanning electron microscope. The polymerase chain reaction (PCR) molecular analysis of active isolate represented its identity partially. In this regard, 16S rRNA gene of the isolate was amplified using universal bacterial primers FD1 and RP2. The PCR products were purified and sequenced. Sequence analysis of 16S rDNA was then conducted using National Center for Biotechnology Information Basic Local Alignment Search Tool method. The AuNTs obtained were characterised by ultraviolet-visible spectroscopy, atomic force microscopy, transmission electron microscopy and energy dispersive X-ray spectroscopy, Fourier transform infrared spectroscopy (FTIR) and X-ray diffraction spectroscopy analyses. The authors results indicated that Streptomyces microflavus isolate 5 bio-synthesises extracellular AuNTs in the range of 10-100 nm. Synthesised SNPs size ranged from 10 to 100 nm. In comparison with chemical methods for synthesis of metal NPs, the biosynthesis of AuNTs by Streptomyces source is a fast, simple and eco-friendly method. The isolate is a good candidate for further investigations to optimise its production efficacy for further industrial goals in biosynthesis of AuNTs. PMID- 26766872 TI - Excitonic spin-splitting in quantum wells with a tilted magnetic field. AB - This work aims to investigate the effects of magnetic field strength and direction on the electronic properties and optical response of GaAs/AlGaAs-based heterostructures. An investigation of the excitonic spin-splitting of a disordered multiple quantum well embedded in a wide parabolic quantum well is presented. The results for polarization-resolved photoluminescence show that the magnetic field dependencies of the excitonic spin-splitting and photoluminescence linewidth are crucially sensitive to magnetic field orientation. Our experimental results are in good agreement with the calculated Zeeman splitting obtained by the Luttinger model, which predicts a hybridization of the spin character of states in the valence band under tilted magnetic fields. PMID- 26766873 TI - Exchange interactions and Curie temperatures of the tetrametal nitrides Cr4N, Mn4N, Fe4N, Co4N, and Ni4N. AB - The exchange interactions of Cr4N, Mn4N, Fe4N, Co4N, and Ni4N compounds with perovskite structure were calculated to obtain the Curie temperatures for these compounds from Monte Carlo calculations. Contrary to naive expectation, the exchange interactions vary markedly among these five compounds. In Fe4N, the intra-sublattice interaction of the Fe 3c atoms is strongly negative, leading to a significant reduction of the Curie temperature. The calculated Curie temperatures are 291 K (Cr4N), 710 K (Mn4N), 668 K (Fe4N), 827 K (Co4N), and 121 K (Ni4N), in good agreement with experimental observations where available. The much lower Curie temperature of Ni4N compared to fcc Ni is explained on the basis of the exchange interactions. PMID- 26766874 TI - Synthesis and thermo-physical properties of deep eutectic solvent-based graphene nanofluids. AB - This study introduces a new class of heat transfer fluids by dispersing functionalised graphene oxide nanoparticles (GNPs) in ammonium and phosphonium based deep eutectic solvents (DESs) without the aid of a surfactant. Different molar ratios of salts and hydrogen bond donors (HBD) were used to synthesise DESs for the preparation of different concentrations of graphene nanofluids (GNFs). The concentrations of GNPs were 0.01 wt%, 0.02 wt% and 0.05 wt %. Homogeneous and stable suspensions of nanofluids were obtained by high speed homogenisation and an ultrasonication process. The stability of the GNFs was determined through visual observation for 4 weeks followed by a centrifugal process (5000-20,000 rpm) for 30 min in addition to zeta potential studies. Dispersion of the GNPs in DES was observed using an optical microscope. The synthesised DES-based GNFs showed no particle agglomeration and formation of sediments in the nanofluids. Thermo-physical properties such as thermal conductivity and specific heat of the nanofluids were also investigated in this research. The highest thermal conductivity enhancement of 177% was observed. The findings of this research provide a new class of engineered fluid for heat transfer applications as a function of temperature, type and composition DESs as well as the GNPs concentration. PMID- 26766875 TI - The Gender Context of HIV Risk and Pregnancy Goals in Western Kenya. AB - BACKGROUND: Intentional childbearing may place heterosexual couples at risk of HIV infection in resource-limited settings with high HIV prevalence areas where society places great value on having children. OBJECTIVE: To explore cognitive, cultural, and spatial mapping of sexual and reproductive health domains and services in western Kenya among men and women. DESIGN: Community-based formative qualitative study design. SETTING: Five administrative/geographical divisions of Nyando District, western Kenya. SUBJECTS: Adult men 18 years and older and women who were of reproductive-potential ages (15 to 49 years for females) (n=90). RESULTS: Men and women have disparate goals for number of children and engage in gendered patterns of protective method use (contraceptives used by women often in secret, condoms by men but rarely). CONCLUSION: HIV infection was still seen as stigmatizing. These study results are relevant to design of effective integrated delivery for reproductive and HIV services in high-burden sub-Saharan African countries. PMID- 26766876 TI - Direct speciation analysis of thallium based on solid phase extraction and specific retention of a Tl(III) complex on alumina coated with sodium dodecyl sulfate. AB - Alumina (Al2O3) with an average particle size of 63 MUm was modified with the anionic surfactant sodium dodecyl sulfate (SDS) and then applied to (i) solid phase extraction and separation of both thallium(I) and thallium(III), and (ii) preconcentration of Tl(III) from waste water samples. Only Tl(III), in the form of its complex with diethylenetriaminepentaacetate (DTPA), was retained on the sorbent, from where it can be eluted with 40 % nitric acid. Thallium species were then quantified by ICP MS. The method was characterized by a LOD of 25 pg of Tl(I) and 160 pg of Tl(III) in 10 mL samples. A large excesses of Tl(I) over Tl(III) was tolerated, and relatively high levels of other metal ions, such as a 500-fold excess of Pb(II) and Cd(II), and a 2000-fold excess of Zn(II), respectively, do not interfere. The sorbent was easily prepared and possesses a high loading capacity, and these properties make it an attractive material for rapid and efficient extraction and speciation of Tl. Graphical abstract:Schematic of the SPE procedure for separation (with preconcentration) of Tl(III) from Tl(I) was developed and applied to direct speciation analysis of thallium in wastewater. Self-made columns packed with alumina coated with SDS were used. The method is resistant to interferences from Pb, Cd, Zn and tolerates a large excess of Tl(I) over Tl(III). PMID- 26766877 TI - Preconcentration of Fe(III), Co(II), Ni(II), Cu(II), Zn(II) and Pb(II) with ethylenediamine-modified graphene oxide. AB - We describe a novel solid phase sorbent that was synthesized by coupling graphene oxide (GO) to ethylenediamine (EDA). This nanomaterial (referred to as GO-EDA) is capable of adsorbing the ions of iron, cobalt, nickel, copper, zinc and lead. The ethylenediamine-modified graphene oxide was characterized by X-ray photoelectron spectroscopy, scanning electron microscopy and Fourier transform infrared spectroscopy. The analytical procedure relies on (a) sorption of metal ions on GO EDA dispersed in aqueous samples; (b) filtering, and (c) direct submission of the filter paper to energy-dispersive X-ray fluorescence spectrometry. This kind of dispersive micro-solid phase extraction was optimized with respect to pH values, concentration of GO-EDA, contact time, and the effects of interfering ions and humic acid on recovery of determined elements. Under optimized conditions, the recoveries of spiked samples range from 90 to 98 %. The detection limits are 0.07, 0.10, 0.07, 0.08, 0.06 and 0.10 ng mL-1 for Fe(III), Co(II), Ni(II), Cu(II), Zn(II) and Pb(II), respectively. The method has a relative standard deviation of <6 %, and its accuracy was verified by analysis of two standard reference materials [LGC6016 (estuarine water) and BCR-610 (groundwater)]. It was successfully applied to the determination of trace amounts of these metal ions in water samples. Graphical AbstractGraphene oxide was coupled to ethylenediamine in order to obtain an effective sorbent (GO-EDA) for preconcentration of Fe(III), Co(II), Ni(II), Cu(II), Zn(II) and Pb(II) from environmental water samples. PMID- 26766878 TI - Credit Card Blues: The Middle Class and the Hidden Costs of Easy Credit. AB - In an era of increased access to credit, it becomes increasingly important to understand the consequences of taking on unsecured consumer debt. We argue that credit can have both positive and negative consequences resulting from its ability to smooth life transitions and difficulties but that this occurs simultaneously with increased financial risks and stress resulting from carrying unsecured debt. We find that those in the middle of the income distribution suffer the greatest disruptions to mental health from carrying debt. Affluent borrowers are relatively unmoved by debt, suggesting the use of short-term debt as a convenience strategy for the financially well-heeled. The least advantaged borrowers are also suffer emotionally less from debt, possibly because securing spendable funds for necessities remains their most pressing concern. The onset of the Great Recession, however, produced increased emotional distress for all classes. PMID- 26766879 TI - From quarks and gluons to baryon form factors. AB - I briefly summarize recent results for nucleon and [Formula: see text] electromagnetic, axial and transition form factors in the Dyson-Schwinger approach. The calculation of the current diagrams from the quark-gluon level enables a transparent discussion of common features such as: the implications of dynamical chiral symmetry breaking and quark orbital angular momentum, the timelike structure of the form factors, and their interpretation in terms of missing pion-cloud effects. PMID- 26766881 TI - Field quantification of wetting-drying cycles to predict temporal changes of soil pore size distribution. AB - Wetting-drying (WD) cycles substantially influence structure related soil properties and processes. Most studies on WD effects are based on controlled cycles under laboratory conditions. Our objective was the quantification of WD cycles from field water content measurements and the analysis of their relation to the temporal drift in the soil pore size distribution. Parameters of the Kosugi hydraulic property model (rm,Kosugi, sigmaKosugi) were derived by inverse optimization from tension infiltrometer measurements. Spectral analysis was used to calculate WD cycle intensity, number and duration from water content time series. WD cycle intensity was the best predictor (r2 = 0.53-0.57) for the temporal drift in median pore radius (rm,Kosugi) and pore radius standard deviation (sigmaKosugi). At lower soil moisture conditions the effect of cycle intensity was reduced. A bivariate regression model was derived with WD intensity and a meteorological indicator for drying periods (ET0, climatic water balance deficit) as predictor variables. This model showed that WD enhanced macroporosity (higher rm,Kosugi) while decreasing pore heterogeneity (lower sigmaKosugi). A drying period with high cumulative values of ET0 or a strong climatic water balance deficit on the contrary reduced rm,Kosugi while slightly increasing sigmaKosugi due to higher frequency at small pore radius classes. The two parameter regression model was applied to predict the time course of soil pore size distribution parameters. The observed system dynamics was captured substantially better by the calculated values compared to a static representation with averaged hydraulic parameters. The study showed that spectral analysis is an adequate approach for the quantification of field WD pattern and that WD intensity is a key factor for the temporal dynamics of the soil pore size distribution. PMID- 26766880 TI - Intelligence in youth and health at age 50. AB - BACKGROUND: The link between intelligence in youth and all-cause mortality in later-life is well established. To better understand this relationship, the current study examines the links between pre-morbid intelligence and a number of specific health outcomes at age 50 using the NLSY-1979 cohort. METHODS: Participants were the 5793 participants in the NLSY-79 who responded to questions about health outcomes at age 50. Sixteen health outcomes were examined: two were summary measures (physical health and functional limitation), 9 were diagnosed illness conditions, 4 were self-reported conditions, and one was a measure of general health status. Linear and logistic regressions were used, as appropriate, to examine the relationship between intelligence in youth and the health outcomes. Age, sex and both childhood and adult SES, and its sub-components - income, education, & occupational prestige - are all adjusted for separately. RESULTS & CONCLUSION: Higher pre-morbid intelligence is linked with better physical health at age 50, and a lower risk for a number of chronic health conditions. For example, a 1 SD higher score in IQ was significantly associated with increased odds of having good, very good, or excellent health, with an odds ratio of 1.70 (C.I. 1.55-1.86). Thirteen of the illness outcomes were significantly and negatively associated with IQ in youth; the odds ratios ranged from 0.85 for diabetes/high blood sugar to 0.65 for stroke, per one standard deviation higher score in IQ. Adjustment for childhood SES led to little attenuation but adult SES partially mediated the relationship for a number of conditions. Mediation by adult SES was not consistently explained by any one of its components-income, education, and occupation status. The current findings contribute to our understanding of lower intelligence as a risk factor for poor health and how this may contribute to health inequalities. PMID- 26766882 TI - Biocompatible oil core nanocapsules as potential co-carriers of paclitaxel and fluorescent markers: preparation, characterization, and bioimaging. AB - The present work is focused on the long-term stability and in vitro cellular internalization of newly designed biocompatible polyester nanocapsules prepared via nanoprecipitation approach with mean diameter <165 nm and narrow size distribution, dedicated to theranostic applications. We monitored the optical, morphological, and biological properties of the nanocarriers loaded by multifunctional cargo, i.e., paclitaxel (PTX) and a fluorescent marker: coumarin 6 (CR-6) or Nile Red (NR), by fluorescence and UV-vis spectroscopy (encapsulation efficiency), dynamic light scattering (average size expressed as hydrodynamic diameter, DH), zeta potential (zeta, colloidal stability), atomic force microscopy (AFM, imaging), and confocal laser scanning microscopy (CLSM, nanocapsule visualization, and cellular internalization in vitro by human breast cancer MCF-7/WT cells). The fabricated nanocapsules with optimal composition of oleic phase, i.e., coconut oil, palm oil, and Capmul MCM, as well as polymeric shell, i.e., polylactic acid (PLA), poly (epsilon-caprolactone) (PCL), and poly (lactide-co-glycolide) (PLGA), showed high loading capacity, long-term stability, and improved localization of the active cargo in studied tumor cells. Therefore, our results prove that the studied polyester oil core nanocapsules provide lifelong and biocompatible nanocarriers suitable for in vivo administration and for diagnostic applications. PMID- 26766883 TI - Geographic variation in breeding system and environment predicts melanin-based plumage ornamentation of male and female Kentish plovers. AB - Sexual selection determines the elaboration of morphological and behavioural traits and thus drives the evolution of phenotypes. Sexual selection on males and females can differ between populations, especially when populations exhibit different breeding systems. A substantial body of literature describes how breeding systems shape ornamentation across species, with a strong emphasis on male ornamentation and female preference. However, whether breeding system predicts ornamentation within species and whether similar mechanisms as in males also shape the phenotype of females remains unclear. Here, we investigate how different breeding systems are associated with male and female ornamentation in five geographically distinct populations of Kentish plovers Charadrius alexandrinus. We predicted that polygamous populations would exhibit more elaborate ornaments and stronger sexual dimorphism than monogamous populations. By estimating the size and intensity of male (n = 162) and female (n = 174) melanin-based plumage ornaments, i.e. breast bands and ear coverts, we show that plumage ornamentation is predicted by breeding system in both sexes. A difference in especially male ornamentation between polygamous (darker and smaller ornaments) and monogamous (lighter and larger) populations causes the greatest sexual dimorphism to be associated with polygamy. The non-social environment, however, may also influence the degree of ornamentation, for instance through availability of food. We found that, in addition to breeding system, a key environmental parameter, rainfall, predicted a seasonal change of ornamentation in a sex-specific manner. Our results emphasise that to understand the phenotype of animals, it is important to consider both natural and sexual selection acting on both males and females. PMID- 26766884 TI - Why patterns of assortative mating are key to study sexual selection and how to measure them. AB - The study of sexual selection is being revolutionised by the realisation that most populations exhibit some degree of polyandry, i.e. females mating with multiple males. Polyandry can drastically change the operation of sexual selection on males as it reduces the reproductive success that males derive by mating with different females, by forcing their ejaculates to compete for fertilisation after copulation (sperm competition). Variation in polyandry within a population means that the impact of polyandry can differ drastically across males, depending on the polyandry of their own mating partners. Because the patterns through which males share mates within a population may have strong repercussions for variation in male reproductive success, measuring such patterns is critical to study the operation of sexual selection. Several methods have been proposed to measure the pattern of mate sharing at the population level. Here, we develop a new method (sperm competition intensity correlation, SCIC) and compare its performance against two established methods (Newman's assortativity and nestedness), using both idealised model populations and random simulated populations, across a range of biologically relevant population parameters: (i) population size, (ii) sex ratio and (iii) the 'mating density' of the population. We conclude that SCIC may be the most promising approach, as it is both internally consistent and robust across the parameter range. We discuss some important caveats and provide advice regarding the choice of method for future studies of sexual selection. PMID- 26766886 TI - Conflicting Opinions Flood FDA on Its Proposal for Biosimilar Naming. AB - FDA deluged with opinions on biosimilar naming plans. PMID- 26766885 TI - Survey Results: Community Liaison Programs to Cut Hospital Readmissions. AB - Community liaison programs to cut hospital readmissions. PMID- 26766887 TI - Pharmaceutical Approval Update. AB - Elotuzumab (Empliciti) and ixazomib (Ninlaro) for some multiple myeloma patients; Fluad (influenza vaccine, adjuvanted) for immunization of persons 65 years of age and older; and osimertinib (Tagrisso) for certain non-small-cell lung cancers. PMID- 26766888 TI - Alirocumab (Praluent): First in the New Class of PCSK9 Inhibitors. AB - Alirocumab (Praluent): first in the new class of PCSK9 inhibitors. PMID- 26766889 TI - 340B Program Puts Manufacturers At Risk of Duplicate Drug Discounts. PMID- 26766890 TI - Health Plans and Drug Companies Dip Their Toes Into Value-Based Pricing: The Pressure Is on P&T Committees to Monitor Utilization. AB - The agreement between Harvard Pilgrim and Amgen on a "pay for performance" deal involving evolocumab could encourage other manufacturers, health plans, and policy-makers to press for value-based pricing as drug costs continue to escalate. PMID- 26766891 TI - American College of Rheumatology 2015 Annual Meeting. AB - Key sessions at the meeting covered the effects and relationships of early remission, weight, corticosteroids, and anti-tumor necrosis factor agents in rheumatic diseases. PMID- 26766892 TI - Multiple Myeloma Market Will Expand With Launch of Monoclonal Antibodies. AB - Analysts foresee substantial growth in the multiple myeloma market in the next decade, driven mainly by the monoclonal antibodies elotuzumab and daratumumab. PMID- 26766893 TI - The STEADI Tool Kit: A Fall Prevention Resource for Health Care Providers. PMID- 26766894 TI - A critical evaluation of material safety data sheets (MSDSs) for engineered nanomaterials. AB - Material safety data sheets (MSDSs) provide employers, employees, emergency responders, and the general public with basic information about the hazards associated with chemicals that are used in the workplace and are a part of every day commerce. They are a primary information resource used by health, safety, and environmental professionals in communicating the hazards of chemicals and in making risk management decisions. Engineered nanomaterials represent a growing class of materials being manufactured and introduced into multiple business sectors. MSDSs were obtained from a total of 44 manufacturers using Internet search engines, and a simple ranking scheme was developed to evaluate the content of the data sheets. The MSDSs were reviewed using the ranking scheme, and categorized on the quality and completeness of information as it pertains to hazard identification, exposure controls, personal protective equipment (PPE), and toxicological information being communicated about the engineered nanomaterial. The ranking scheme used to evaluate the MSDSs for engineered nanomaterials was based on the determination that the data sheet should include information on specific physical properties, including particle size or particle size distribution, and physical form; specific toxicological and health effects; and protective measures that can be taken to control potential exposures. The first MSDSs for nanomaterials began to appear around 2006, so these were collected in the time period of 2007-2008. Comparison of MSDSs and changes over time were evaluated as MSDSs were obtained again in 2010-2011. The majority (67%) of the MSDSs obtained in 2010-2011 still provided insufficient data for communicating the potential hazards of engineered nanomaterials. PMID- 26766895 TI - Sustained cooperation by running away from bad behavior. AB - For cooperation to evolve, some mechanism must limit the rate at which cooperators are exposed to defectors. Only then can the advantages of mutual cooperation outweigh the costs of being exploited. Although researchers widely agree on this, they disagree intensely about which evolutionary mechanisms can explain the extraordinary cooperation exhibited by humans. Much of the controversy follows from disagreements about the informational regularity that allows cooperators to avoid defectors. Reliable information can allow cooperative individuals to avoid exploitation, but which mechanisms can sustain such a situation is a matter of considerable dispute. We conducted a behavioral experiment to see if cooperators could avoid defectors when provided with limited amounts of explicit information. We gave each participant the simple option to move away from her current neighborhood at any time. Participants were not identifiable as individuals, and they could not track each other's tendency to behave more or less cooperatively. More broadly, a participant had no information about the behavior she was likely to encounter if she moved, and so information about the risk of exploitation was extremely limited. Nonetheless, our results show that simply providing the option to move allowed cooperation to persist for a long period of time. Our results further show that movement, even though it involved considerable uncertainty, allowed would-be cooperators to assort positively and eliminate on average any individual payoff disadvantage associated with cooperation. This suggests that choosing to move, even under limited information, can completely reorganize the mix of selective forces relevant for the evolution of cooperation. PMID- 26766896 TI - 2-Ethylhexanol Derivatives as Nonionic Surfactants: Synthesis and Properties. AB - The synthesis and basic properties of 2-ethylhexanol based innovative nonionic surfactants are described in this paper. 2-Ethylhexanol as an available and relatively inexpensive raw material was used as the hydrophobe source modified by propoxylation and followed by polyethoxylation. As the result, six series of 2 ethylhexyl alcohol polyalkoxylates (EHP m E n ) were obtained with three steps of propoxylation, each followed by polyethoxylation and two series only with polyethoxylation (EHE n ). Two different catalysts were used, a dimetalcyanide and KOH. Values of average conversion rates and chemical content of the obtained products (GC, TG and GPC techniques) were compared. The influence of the applied catalyst and polyaddition degree on the homologue distribution, reactant conversion and amount of byproducts is discussed. The basic physicochemical parameters including refractive index, solubility in polar media, foaming properties and wettability were investigated and compared. Furthermore, surface activity parameters, i.e. surface tension (gammaCMC) and critical micelle concentrations were determined. Results are compared to C12-14 alcohol ethoxylates (LaE n ). Accordingly, it was found that the studied 2-ethylhexyl alcohol based compounds are effective, low foaming nonionic surfactants. PMID- 26766897 TI - Elucidation of Softening Mechanism in Rinse Cycle Fabric Softeners. Part 1: Effect of Hydrogen Bonding. AB - Most softening agents, such as rinse cycle fabric softeners, used by consumers at home contain cationic surfactants that have two long alkyl chains as their main component. The softening mechanism on fibers, especially cotton, has not yet been scientifically established, despite the market prevalence of fabric softeners for decades. One explanation for the softening effect is that the friction between fibers is reduced. According to this explanation, the fiber surfaces are coated by layers of alkyl chains. Because of the low coefficient of friction between alkyl chain layers of low surface energy, the fibers easily slide against one another yielding softer cotton clothing. However, no direct scientific evidence exists to prove the validity of this explanation. The softening mechanism of cotton yarn is discussed in this paper. Bending force values of cotton yarn treated with several concentrations of softener are measured by bend testing, and cotton and polyester yarns are compared. Results indicate that increases in cotton yarn hardness after natural drying are caused by cross-linking among inner fibers aided by bound water. This type of bound water has been known to exist even after 2 days of drying at 25 degrees C and 60 % relative humidity. Yarn dried in vacuo is soft, similar to that treated with softener. Thus, some of the softening effect caused by fabric softeners on cotton can be attributed to the prevention of cross-linking by bound water between cotton fibers. PMID- 26766898 TI - Making the diagnosis of Sjogren's syndrome in patients with dry eye. AB - Sjogren's syndrome (SS) is a chronic and progressive systemic autoimmune disease that often presents initially with symptoms of dry eye and dry mouth. Symptoms are often nonspecific and develop gradually, making diagnosis difficult. Patients with dry eye complaints warrant a step-wise evaluation for possible SS. Initial evaluation requires establishment of a dry eye diagnosis using a combination of patient questionnaires and objective ocular tests, including inflammatory biomarker testing. Additional work-up using the Schirmer test and tear film break up time can differentiate between aqueous-deficient dry eye (ADDE) and evaporative dry eye. The presence of ADDE should trigger further work-up to differentiate between SS-ADDE and non-SS-ADDE. There are numerous non-ocular manifestations of SS, and monitoring for SS-related comorbid findings can aid in diagnosis, ideally in collaboration with a rheumatologist. The clinical work-up of SS can involve a variety of tests, including tear function tests, serological tests for autoantibody biomarkers, minor salivary gland and lacrimal gland biopsies. Examination of classic SS biomarkers (SS-A/Ro, SS-B/La, antinuclear antibody, and rheumatoid factor) is a convenient and non-invasive way of evaluating patients for the presence of SS, even years prior to confirmed diagnosis, although not all SS patients will test positive, particularly those with early disease. Recently, newer biomarkers have been identified, including autoantibodies to salivary gland protein-1, parotid secretory protein, and carbonic anhydrase VI, and may allow for earlier diagnosis of SS. A diagnostic test kit is commercially available (Sjo((r))), incorporating these new biomarkers along with the classic autoantibodies. This advanced test has been shown to identify SS patients who previously tested negative against traditional biomarkers only. All patients with clinically significant ADDE should be considered for serological assessment for SS, given the availability of new serological diagnostic tests and the potentially serious consequences of missing the diagnosis. PMID- 26766899 TI - Anxiety and depression in patients with advanced macular degeneration: current perspectives. AB - Age-related macular degeneration (AMD) - despite advances in prevention and medical treatment options - remains prevalent among older adults, often resulting in functional losses that negatively affect the mental health of older adults. In particular, the prevalence of both anxiety and depression in patients with AMD is high. Along with medical treatment options, low vision rehabilitation and AMD specific behavioral and self-management programs have been developed and have demonstrated effectiveness in improving the mental health of AMD patients. This article reviews the prevalence of anxiety and depression in patients with advanced AMD, discusses potential mechanisms accounting for the development of depression and anxiety in AMD patients, presents the state-of the-art of available interventions for addressing anxiety and depression in AMD patients, and delineates recommendations for eye care professionals regarding how to screen for these two prevalent mental health problems and how to facilitate appropriate treatment for patients with AMD. PMID- 26766900 TI - Effect of milrinone on cardiac functions in patients undergoing coronary artery bypass graft: a meta-analysis of randomized clinical trials. AB - BACKGROUND AND AIM: Inotropes are commonly used to treat myocardial dysfunction, which is the major complication after coronary artery bypass graft (CABG). Milrinone, a phosphodiesterase 3 inhibitor, is one of these inotropes. Recently, a number of clinical studies have been carried out to evaluate the effects of milrinone on cardiac function in patients with low ventricular ejection fraction undergoing CABG. However, it has been inconclusive because of the inconsistent results. In addition, some studies found that milrinone increased the incidence of postoperative atrial arrhythmias and did not show any long-term beneficial effects on survival. Therefore, it is very important to perform a meta-analysis to summarize the results so as to determine the clinical efficacy and safety of milrinone. METHOD: Several databases and websites for clinical trials were searched until October 2015 for prospective clinical studies comparing milrinone versus placebo on cardiac functions in patients undergoing CAGB. RESULTS: Four articles were identified by our search strategy. 1) Milrinone decreased incidence of myocardial ischemia and myocardial infarction (15.6% versus 44.4%; 4.7% versus 18% in milrinone and control group, respectively). 2) Milrinone decreased duration of inotropic support (95% confidence interval [CI]: -6.52 to -1.68; P=0.0009) and mechanical ventilation (h) support (95% CI -5.00 to -0.69; P=0.010), but did not decrease the requirement for intra-aortic balloon pump or inotropic support (P>0.05). 3) Milrinone did not decrease the overall mortality or morbidity, intensive care unit stay (P>0.05). CONCLUSION: Perioperative continuous infusion of milrinone is effective to lower incidence of myocardial ischemia and myocardial infarction in patients post-CABG, but it was unable to improve the overall morbidity and mortality or decreased duration of intensive care unit stay. The available sample size is small; therefore, future studies should be directed toward a better understanding of the benefit of milrinone to CABG patients. PMID- 26766901 TI - BCc1, the novel antineoplastic nanocomplex, showed potent anticancer effects in vitro and in vivo. AB - PURPOSE: In spite of all the efforts and researches on anticancer therapeutics, an absolute treatment is still a myth. Therefore, it is necessary to utilize novel technologies in order to synthesize smart multifunctional structures. In this study, for the first time, we have evaluated the anticancer effects of BCc1 nanocomplex by vitro and in vivo studies, which is designed based on the novel nanochelating technology. METHODS: Human breast adenocarcinoma cell line (MCF-7) and mouse embryonic fibroblasts were used for the in vitro study. Antioxidant potential, cell toxicity, apoptosis induction, and CD44 and CD24 protein expression were evaluated after treatment of cells with different concentrations of BCc1 nanocomplex. For the in vivo study, mammary tumor-bearing female Balb/c mice were treated with different doses of BCc1 and their effects on tumor growth rate and survival were evaluated. RESULTS: BCc1 decreased CD44 protein expression and increased CD24 protein expression. It induced MCF-7 cell apoptosis but at the same concentrations did not have negative effects on mouse embryonic fibroblasts viability and protected them against oxidative stress. Treatment with nanocomplex increased survival and reduced the tumor size growth in breast cancer-bearing balb/c mice. CONCLUSION: These results demonstrate that BCc1 has the capacity to be assessed as a new anticancer agent in complementary studies. PMID- 26766902 TI - MicroRNA-125a-5p modulates human cervical carcinoma proliferation and migration by targeting ABL2. AB - BACKGROUND: In this study, we intended to understand the regulatory mechanisms of microRNA-125a-5p (miR-125a-5p) in human cervical carcinoma. METHODS: The gene expressions of miR-125a-5p in seven cervical carcinoma cell lines and 12 human cervical carcinoma samples were evaluated by quantitative real-time reverse transcription polymerase chain reaction. Ca-Ski and HeLa cells were transduced with lentivirus carrying miR-125a-5p mimics, and the effects of lentivirus induced miR-125a-5p upregulation on cervical carcinoma proliferation and migration were examined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and transwell assays, respectively. In additional, HeLa cells were inoculated into null mice to evaluate the effect of miR-125a-5p upregulation on in vivo cervical carcinoma growth. The direct regulation of miR-125a-5p on its target gene, ABL proto-oncogene 2 (ABL2), in cervical carcinoma was evaluated by quantitative real-time reverse transcription polymerase chain reaction, Western blotting and luciferase reporter assays, respectively. ABL2 was then downregulated by small interfering RNA to examine its effect on cervical carcinoma proliferation and migration. RESULTS: miR-125a-5p was downregulated in both cervical carcinoma cell lines and human cervical carcinomas. In Ca-Ski and HeLa cells, lentivirus-mediated miR-125a-5p upregulation inhibited cancer proliferation and migration in vitro and cervical carcinoma transplantation in vivo. ABL2 was shown to be directly targeted by miR-125a-5p. In cervical carcinoma, ABL2 gene and protein levels were both downregulated by miR-125a-5p. Small interfering RNA-mediated ABL2 downregulation also had tumor-suppressive effects on cervical carcinoma proliferation and migration. CONCLUSION: The molecular pathway of miR-125a-5p/ABL2 plays an important role in human cervical carcinoma. Targeting miR-125a-5p/ABL2 pathway may provide a new treatment strategy for patients with cervical carcinoma. PMID- 26766903 TI - Promoting effect of small molecules in cardiomyogenic and neurogenic differentiation of rat bone marrow-derived mesenchymal stem cells. AB - Small molecules, growth factors, and cytokines have been used to induce differentiation of stem cells into different lineages. Similarly, demethylating agents can trigger differentiation in adult stem cells. Here, we investigated the in vitro differentiation of rat bone marrow mesenchymal stem cells (MSCs) into cardiomyocytes by a demethylating agent, zebularine, as well as neuronal-like cells by beta-mercaptoethanol in a growth factor or cytokines-free media. Isolated bone marrow-derived MSCs cultured in Dulbecco's Modified Eagle's Medium exhibited a fibroblast-like morphology. These cells expressed positive markers for CD29, CD44, and CD117 and were negative for CD34 and CD45. After treatment with 1 MUM zebularine for 24 hours, the MSCs formed myotube-like structures after 10 days in culture. Expression of cardiac-specific genes showed that treated MSCs expressed significantly higher levels of cardiac troponin-T, Nkx2.5, and GATA-4 compared with untreated cells. Immunocytochemical analysis showed that differentiated cells also expressed cardiac proteins, GATA-4, Nkx 2.5, and cardiac troponin-T. For neuronal differentiation, MSCs were treated with 1 and 10 mM beta-mercaptoethanol overnight for 3 hours in complete and serum-free Dulbecco's Modified Eagle's Medium, respectively. Following overnight treatment, neuron-like cells with axonal and dendritic-like projections originating from the cell body toward the neighboring cells were observed in the culture. The mRNA expression of neuronal-specific markers, Map2, Nefl, Tau, and Nestin, was significantly higher, indicating that the treated cells differentiated into neuronal-like cells. Immunostaining showed that differentiated cells were positive for the neuronal markers Flk, Nef, Nestin, and beta-tubulin. PMID- 26766904 TI - The gastroprotective effects of hydroalcoholic extract of Monolluma quadrangula against ethanol-induced gastric mucosal injuries in Sprague Dawley rats. AB - Monolluma quadrangula (Forssk.) Plowes is used in Saudi traditional medicines to treat gastric ulcers. The hydroalcoholic extract of M. quadrangula (MHAE) was used in an in vivo model to investigate its gastroprotective effects against ethanol-induced acute gastric lesions in rats. Five groups of Sprague Dawley rats were used. The first group was treated with 10% Tween 20 as a control. The other four groups included rats treated with absolute ethanol (5 mL/kg) to induce an ulcer, rats treated with 20 mg/kg omeprazole as a reference drug, and rats treated with 150 or 300 mg/kg MHAE. One hour later, the rats were administered absolute ethanol (5 mL/kg) orally. Animals fed with MHAE exhibited a significantly increased pH, gastric wall mucus, and flattening of the gastric mucosa, as well as a decreased area of gastric mucosal damage. Histology confirmed the results; extensive destruction of the gastric mucosa was observed in the ulcer control group, and the lesions penetrated deep into the gastric mucosa with leukocyte infiltration of the submucosal layer and edema. However, gastric protection was observed in the rats pre-fed with plant extracts. Periodic acid-Schiff staining of the gastric wall revealed a remarkably intensive uptake of magenta color in the experimental rats pretreated with MHAE compared to the ulcer control group. Immunohistochemistry staining revealed an upregulation of the Hsp70 protein and a downregulation of the Bax protein in rats pretreated with MHAE compared with the control rats. Gastric homogenate showed significantly increased catalase and superoxide dismutase, and the level of malondialdehyde (MDA) was reduced in the rats pretreated with MHAE compared to the control group. In conclusion, MHAE exhibited a gastroprotective effect against ethanol-induced gastric mucosal injury in rats. The mechanism of this gastroprotection included an increase in pH and gastric wall mucus, an increase in endogenous enzymes, and a decrease in the level of MDA. Furthermore, protection was given through the upregulation of Hsp70 and the downregulation of Bax proteins. PMID- 26766905 TI - Effects of momentum-based dumbbell training on cognitive function in older adults with mild cognitive impairment: a pilot randomized controlled trial. AB - PURPOSE: The purpose of this study was to explore the effects of an innovative momentum-based dumbbell-training intervention on cognitive function in older adults with mild cognitive impairment (MCI). SUBJECTS AND METHODS: A total of 45 community-dwelling older adults with MCI were randomly assigned to either a dumbbell-training group (DTG; n=22) or a control group (CG; n=23). Participants in the DTG participated in exercise sessions three times weekly for 12 weeks. The primary outcome measures were cognitive function, including the Alzheimer's Disease Assessment Scale (ADAS) - Cognitive subscale, Trail Making Test part B, Digit Span Test (DST) - forward, and DST - backward, with secondary outcome measures being Timed Up and Go, functional reach, and the Activities-Specific Balance Confidence Scale. RESULTS: In an intent-to-treat analysis, participants in the DTG had significantly improved ADAS - Cognitive subscale scores compared to those in the CG (5.02 points, P=0.012). There was a significant within-group change (improvement) in Trail Making Test part B (33.32 seconds, P<0.001) and DST - backward (0.41 points, P=0.025) scores. No change was observed for the DST - forward measure. Participants in the DTG also improved their functional mobility compared to those in the CG (Timed Up and Go, 0.81 seconds; P=0.043). CONCLUSION: There is preliminary evidence showing the potential benefit of momentum-based dumbbell training for improving cognitive function in older adults with MCI. PMID- 26766906 TI - Impact of chronic obstructive pulmonary disease on postoperative recurrence in patients with resected non-small-cell lung cancer. AB - PURPOSE: This study aimed to determine whether the severity of chronic obstructive pulmonary disease (COPD) affects recurrence-free survival in non small-cell lung cancer (NSCLC) patients after surgical resection. PATIENTS AND METHODS: A retrospective study was performed on 421 consecutive patients who had undergone lobectomy for NSCLC from January 2008 to June 2011. Classification of COPD severity was based on guidelines of the Global Initiative for Chronic Obstructive Lung Disease (GOLD). Characteristics among the three subgroups were compared and recurrence-free survivals were analyzed. RESULTS: A total of 172 patients were diagnosed with COPD (124 as GOLD-1, 46 as GOLD-2, and two as GOLD 3). The frequencies of recurrence were significantly higher in patients with higher COPD grades (P<0.001). Recurrence-free survival at 5 years was 78.1%, 70.4%, and 46.4% in non-COPD, mild COPD, and moderate/severe COPD groups, respectively (P<0.001). By univariate analysis, the age, sex, smoking history, COPD severity, tumor size, histology, and pathological stage were associated with recurrence-free survival. Multivariate analysis showed that older age, male, moderate/severe COPD, and advanced stage were independent risk factors associated with recurrence-free survival. CONCLUSION: NSCLC patients with COPD are at high risk for postoperative recurrence, and moderate/severe COPD is an independent unfavorable prognostic factor. PMID- 26766907 TI - Age-related annual decline of lung function in patients with COPD. AB - BACKGROUND: According to the Fletcher-Peto curve, rate of decline in forced expiratory volume in 1-second (FEV1) accelerates as age increases. However, recent studies have not demonstrated that the rate of FEV1 decline accelerates with age among COPD patients. The objective of the study is to evaluate annual rate of FEV1 decline as age increases among COPD patients. METHODS: In this retrospective cohort study, we enrolled COPD patients who were followed up at two tertiary care university hospitals from January 2000 to August 2013. COPD was defined as post-bronchodilator (BD) FEV1/forced vital capacity (FVC) of <0.7. All participants had more than two spirometries, including BD response. Age groups were categorized as follows: below versus above median age or four quartiles. RESULTS: A total of 518 participants (94.2% male; median age, 67 years; range, 42 90 years) were included. Mean absolute and predictive values of post-BD FEV1 were 1.57+/-0.62 L and 52.53%+/-18.29%, respectively. Distribution of Global initiative for Chronic Obstructive Lung Disease groups did not show statistical differences between age groups categorized by two different criteria. After grouping the population by age quartiles, the rate of FEV1 decline was faster among older patients than younger ones whether expressed as absolute value ( 10.60+/-5.57 mL/year, -15.84+/-6.01 mL/year, -18.63+/-5.53 mL/year, 32.94+/-6.01 mL/year, respectively; P=0.048) or predicted value (-0.34%+/-0.19%/year, -0.53%+/ 0.21%/year, -0.62%+/-0.19%/year, -1.26%+/-0.21%/year, respectively, P=0.010). CONCLUSION: As suggested conceptually by the Fletcher-Peto curve, annual FEV1 decline among COPD patients is accelerated among older patients than younger ones. PMID- 26766908 TI - Tumor vascular-targeted co-delivery of anti-angiogenesis and chemotherapeutic agents by mesoporous silica nanoparticle-based drug delivery system for synergetic therapy of tumor. AB - To overcome the drawback of drug non-selectivity in traditional chemotherapy, the construction of multifunctional targeting drug delivery systems is one of the most effective and prevailing approaches. The intratumoral anti-angiogenesis and the tumor cell-killing are two basic approaches in fighting tumors. Herein we report a novel tumor vascular-targeting multidrug delivery system using mesoporous silica nanoparticles as carrier to co-load an antiangiogenic agent (combretastatin A4) and a chemotherapeutic drug (doxorubicin) and conjugate with targeting molecules (iRGD peptide) for combined anti-angiogenesis and chemotherapy. Such a dual-loaded drug delivery system is capable of delivering the two agents at tumor vasculature and then within tumors through a differentiated drug release strategy, which consequently results in greatly improved antitumor efficacy at a very low doxorubicin dose of 1.5 mg/kg. The fast release of the antiangiogenic agent at tumor vasculatures led to the disruption of vascular structure and had a synergetic effect with the chemotherapeutic drug slowly released in the following delivery of chemotherapeutic drug into tumors. PMID- 26766910 TI - Use of antidepressants in the treatment of major depressive disorder in primary care during a period of economic crisis. AB - OBJECTIVE: To describe antidepressant (AD) use in the treatment of major depressive disorder during a period of economic crisis. PATIENTS AND METHODS: This was a retrospective, observational study using population-based databases. Two periods were considered: 1) 2008-2009, precrisis, and 2) 2012-2013, economic crisis. Certain inclusion/exclusion criteria were taken into account for the study (initiation of AD treatment). Patients were followed up for 12 months. The main measures were use (defined daily doses), epidemiologic measures, strategies used and treatment persistence, referrals, and use of resources. Statistical significance was set at P<0.05. RESULTS: In the precrisis period, 3,662 patients were enrolled, and 5,722 were enrolled in the period of economic crisis. Average age was 58.8 years and 65.4% were women. Comparing the two periods, major depressive disorder prevalence was 5.4% vs 8.1%, P<0.001. During the period of economic crisis, AD use rose by 35.2% and drug expenditures decreased by 38.7%. Defined daily dose per patient per day was 10.0 mg vs 13.5 mg, respectively, P<0.001. At 12-month follow-up, the majority of patients (60.8%) discontinued the treatment or continued on the same medication as before, and in 23.3% a change of AD was made. CONCLUSION: Primary health care professionals are highly involved in the management of the illness; in addition, during the period of economic crisis, patients with major depressive disorder showed higher rates of prevalence of the illness, with increased use of AD drugs. PMID- 26766909 TI - Improving cytotoxicity against cancer cells by chemo-photodynamic combined modalities using silver-graphene quantum dots nanocomposites. AB - The combination of chemotherapy and photodynamic therapy has emerged as a promising strategy for cancer therapy due to its synergistic effects. In this work, PEGylated silver nanoparticles decorated with graphene quantum dots (Ag GQDs) were tested as a platform to deliver a chemotherapy drug and a photosensitizer, simultaneously, in chemo-photodynamic therapy against HeLa and DU145 cancer cells in vitro. Ag-GQDs have displayed high efficiency in delivering doxorubicin as a model chemotherapy drug to both cancer cells. The Ag-GQDs exhibited a strong antitumor activity by inducing apoptosis in cancer cells without affecting the viability of normal cells. Moreover, the Ag-GQDs exhibited a cytotoxic effect due to the generation of the reactive singlet oxygen upon 425 nm irradiation, indicating their applicability in photodynamic therapy. In comparison with chemo or photodynamic treatment alone, the combined treatment of Ag-GQDs conjugated with doxorubicin under irradiation with a 425 nm lamp significantly increased the death in DU145 and HeLa. This study suggests Ag-GQDs as a multifunctional and efficient therapeutic system for chemo-photodynamic modalities in cancer therapy. PMID- 26766911 TI - Computer task performance by subjects with Duchenne muscular dystrophy. AB - AIMS: Two specific objectives were established to quantify computer task performance among people with Duchenne muscular dystrophy (DMD). First, we compared simple computational task performance between subjects with DMD and age matched typically developing (TD) subjects. Second, we examined correlations between the ability of subjects with DMD to learn the computational task and their motor functionality, age, and initial task performance. METHOD: The study included 84 individuals (42 with DMD, mean age of 18+/-5.5 years, and 42 age matched controls). They executed a computer maze task; all participants performed the acquisition (20 attempts) and retention (five attempts) phases, repeating the same maze. A different maze was used to verify transfer performance (five attempts). The Motor Function Measure Scale was applied, and the results were compared with maze task performance. RESULTS: In the acquisition phase, a significant decrease was found in movement time (MT) between the first and last acquisition block, but only for the DMD group. For the DMD group, MT during transfer was shorter than during the first acquisition block, indicating improvement from the first acquisition block to transfer. In addition, the TD group showed shorter MT than the DMD group across the study. CONCLUSION: DMD participants improved their performance after practicing a computational task; however, the difference in MT was present in all attempts among DMD and control subjects. Computational task improvement was positively influenced by the initial performance of individuals with DMD. In turn, the initial performance was influenced by their distal functionality but not their age or overall functionality. PMID- 26766912 TI - Risk factors for hearing loss in infants under universal hearing screening program in Northern Thailand. AB - OBJECTIVE: To define the risk factors for hearing loss in infants (aged 3 months) under universal hearing screening program. MATERIALS AND METHODS: A total of 3,120 infants (aged 3 months) who underwent hearing screening using a universal hearing screening program using automated otoacoustic emission test between November 1, 2010 and May 31, 2012 in Uttaradit Hospital, Buddhachinaraj Hospital, and Sawanpracharuk Hospital (tertiary hospitals) located in Northern Thailand were included in this prospective cohort study. RESULTS: Of the 3,120 infants, 135 (4.3%) were confirmed to have hearing loss with the conventional otoacoustic emission test. Five of these 135 infants (3.7%) with hearing loss showed test results consistent with auditory brainstem responses. From the univariable analysis, there were eleven potential risk factors associated with hearing deterioration. On multivariable analysis, the risk factors independently associated with hearing loss at 3 months were birth weight 1,500-2,500 g (risk ratio [RR] 1.6, 95% confidence interval [CI] 1.1-2.6), APGAR score <6 at 5 minutes (RR 2.2, 95% CI 1.1-4.4), craniofacial anomalies (RR 2.5, 95% CI 1.6 4.2), sepsis (RR 1.8, 95% CI 1.0-3.2), and ototoxic exposure (RR 4.1, 95% CI 1.9 8.6). CONCLUSION: This study concluded that low birth weight, APGAR score <6 at 5 minutes, craniofacial anomalies, sepsis, and ototoxic exposure are the risk factors for bilateral hearing loss in infants (aged 3 months) and proper tests should be performed to identify these risk factors. As an outcome, under the present circumstances, it is suggested that infirmary/physicians/general practitioners/health action centers/polyclinics should carry out universal hearing screening in all infants before 36 weeks. The public health policy of Thailand regarding a universal hearing screening program is important for the prevention of disability and to enhance people's quality of life. PMID- 26766913 TI - Trends in Dengue Cases Imported into the United States from Pan America 2001 2012. AB - The objective of this study was to improve risk assessments of travel on dengue (DEN) virus (DENV) distribution. We investigated the exposure risk of US citizens traveling to DEN-endemic Pan American countries. The number of DEN cases reported in 51 Pan American countries from 2001 to 2012 was compared to the population of the same countries. The number of US travelers visiting the Pan American countries was categorized by region, and travel-related DEN infections were analyzed. US residents visiting the Dominican Republic exhibited the highest traveler-related DEN incidence. Brazil showed the most DEN cases in its residents (>1 million reported cases in 2010). The number of DEN cases continues to rise as does international travel and the geographic range of potential DENV vectors. DENV risk assessments may be improved by analyzing the possible routes of entry. Underreporting remains an issue for calculating DENV transmission risk by country and region. PMID- 26766914 TI - Association between promoter polymorphisms of OPN gene and cancer risk: a meta analysis. AB - BACKGROUND: Results of the association between polymorphisms of osteopontin (OPN) gene promoter region and risk of cancer were inconclusive. The aim of this meta analysis was to elucidate whether OPN promoter polymorphisms were associated with cancer risk. METHODS: Electronic databases including PubMed, Web of Science, and Chinese National Knowledge Infrastructure were systematically searched. Odd ratios (ORs) and their 95% confidential interval (CI) were used to assess the strength of association between OPN promoter polymorphisms and cancer risks. RESULTS: Nine studies were finally included in this meta-analysis. For OPN rs17524488 polymorphism, carriers of GG or -/G genotype were significantly associated with increased cancer risk compared with wild-type -/- carriers, respectively (GG vs -/-: OR =1.40, 95% CI =1.03-1.91, P=0.033; -/G vs -/-: OR =1.22, 95% CI =1.07-1.40, P=0.002). Additionally, G allele was significantly associated with increased cancer risk compared with (-) allele (OR =1.21, 95% CI =1.04-1.40, P=0.016). However, no significant association was observed of OPN rs11730582 polymorphism and cancer risk (CC vs TT: OR =0.98, 95% CI =0.49-1.97, P=0.964; CT vs TT: OR =0.88, 95% CI =0.54-1.43, P=0.610). CONCLUSION: Carriers of GG or -/G genotype of OPN promoter rs17524488 (-156-/G) polymorphism might be associated with increased risk of cancer compared with wild-type -/- carriers, respectively. However, no significant association was observed between OPN promoter rs11730582 (-443C/T) polymorphism and risk of cancer. PMID- 26766915 TI - MiR-29c inhibits cell growth, invasion, and migration of pancreatic cancer by targeting ITGB1. AB - MiR-29c is frequently dysregulated in many cancers; however, the roles of miR-29c in pancreatic cancer (PC) and underlying mechanisms remain poorly understood. In this study, we investigated the role of miR-29c in PC. Using quantitative real time polymerase chain reaction, we demonstrated that miR-29c was frequently downregulated in clinical PC tissues and cell lines. Overexpression of miR-29c significantly inhibited the proliferation, migration, and invasion of PC cells in vitro, which demonstrated that miR-29c acts as a tumor suppressor in PC cells. Further analysis revealed that ITGB1 is one of the functional target genes of miR 29c, and knockdown of ITGB1 inhibited the proliferation, migration, and invasion of PC cells, which was similar to the effects of overexpression of miR-29c. Taken together, our results highlight the significance of miR-29c-ITGB1 interaction in the development and progression of PC. PMID- 26766916 TI - Dairy consumption and lung cancer risk: a meta-analysis of prospective cohort studies. AB - BACKGROUND: Lung cancer risk is the leading cause of cancer-related deaths worldwide. We conducted a meta-analysis to evaluate the relationship between dairy consumption and lung cancer risk. METHODS: The databases included EMBASE, Medline (PubMed), and Web of Science. The relationship between dairy consumption and lung cancer risk was analyzed by relative risk or odds ratio estimates with 95% confidence intervals (CIs). We identified eight prospective cohort studies, which amounted to 10,344 cases and 61,901 participants. RESULTS: For milk intake, relative risk was 0.95 (95% CI: 0.76-1.15); heterogeneity was 70.2% (P=0.003). For total dairy product intake, relative risk was 0.96 (95% CI: 0.89-1.03), heterogeneity was 68.4% (P=0.004). CONCLUSION: There was no significant association between dairy consumption and lung cancer risk. PMID- 26766917 TI - High-dose nimotuzumab improves the survival rate of esophageal cancer patients who underwent radiotherapy. AB - Nimotuzumab (h-R3) is a humanized monoclonal antibody that is safe to use against epidermal growth factor receptor (EGFR). However, the available information is insufficient about the dose effect of monoclonal antibody against epidermal growth factor receptor for the treatment of esophageal squamous cell carcinoma (ESCC). We retrospectively recruited 66 patients with ESCC who were treated with h-R3 and chemoradiotherapy/radiotherapy. Patients who received more than 1,200 mg of h-R3 were classified as the high-dose group, and the remaining patients were classified as the low-dose group. The endpoint for efficacy was the overall survival. Differences in survival between the groups were analyzed using the log rank test. The Cox proportional hazards model was used in multivariate analysis to identify independent prognostic factors. The low-dose and high-dose groups comprised 55 and eleven patients, respectively. The median follow-up time in the final analysis was 46 months. The high-dose group showed no increased incidence of toxicities compared to the low-dose group. The 1-, 2-, and 5-year overall survival rates in the low-dose and high-dose groups were 66.9%, 50.0%, 31.5% and 90.0%, 80.0%, 66.7%, respectively (P=0.04). Multivariate analyses showed that the high-dose group had better survival than the low-dose group (hazard ratio 0.28, 95% confidence interval 0.09-0.94, P=0.039). Taken together, high-dose h-R3 showed limited toxicity and improved survival in patients with ESCC. PMID- 26766918 TI - Radiesse((r)): a novel rejuvenation treatment for the upper arms. AB - Nonsurgical esthetic improvement of the upper arms is a desirable goal for many individuals. Radiesse((r)) (calcium hydroxylapatite) is an effective dermal filler for a number of indications because of its volumizing effect and the ability to stimulate neocollagenesis. No studies have reported on its safety and effectiveness for the treatment of the upper arm. In a prospective, open-label study, 30 subjects seeking improvement in the esthetic appearance of their upper arms received injections with Radiesse((r)) (1.5 mL/arm) at two separate visits, 1 month apart. Subjects returned for a follow-up visit 4 months after the second treatment. The primary endpoint was the degree of overall subject and evaluator (investigators and study nurses) satisfaction assessed using the 5-point Global Satisfaction Scale (ranging from "1" very dissatisfied to "5" very satisfied). Secondary endpoints included assessments of skin quality (flaccidity and volume distribution) using a new Visual Analog Scale for upper arms and overall assessment of treatment using the Global Aesthetic Improvement Scale. All (100%) of both subjects and evaluators were "satisfied" or "very satisfied" with treatment. The mean Global Satisfaction Score for investigators and study nurses was 4.60 and for subjects 4.53 (satisfied to very satisfied). Assessments of flaccidity and volume improved significantly compared with baseline at the post treatment visit and also between visits. Compared with baseline, 77% of subjects were rated as considerably improved (good or great improvement) by the investigator and study nurse; 73% of subjects rated themselves as considerably improved and 43% of these rated a "great improvement." All stated they would repeat the treatment and recommend it to others. No adverse events were reported. Radiesse((r)) is an effective minimally invasive treatment option for improving upper arm contours and was associated with a 100% satisfaction rate for both subjects and evaluators. PMID- 26766920 TI - Novel drugs in the management of acute mountain sickness and high altitude pulmonary edema. PMID- 26766921 TI - Disclosure of conflicts of interest and credibility for the medical profession. PMID- 26766919 TI - HIV and smoking: associated risks and prevention strategies. AB - High rates of smoking among persons living with HIV (PLWH) may reduce the effectiveness of HIV treatment and contribute to significant morbidity and mortality. Factors associated with smoking in PLWH include mental health comorbidity, alcohol and drug use, health-related quality of life, smoking among social networks and supports, and lack of access to care. PLWH smokers are at a higher risk of numerous HIV-associated infections and non-HIV related morbidity, including a decreased response to antiretroviral treatment, impaired immune functioning, reduced cognitive functioning, decreased lung functioning, and cardiovascular disease. Seventeen smoking cessation interventions were identified, of which seven were randomized controlled trials. The most effective studies combined behavioral and pharmacotherapy treatments that incorporated comprehensive assessments, multiple sessions, and cognitive-behavioral and motivational strategies. Smoking cessation interventions that are tailored to the unique needs of diverse samples and incorporate strategies to reduce the risk of relapse are essential to advancing health outcomes in PLWH. PMID- 26766923 TI - Functional self-assembled lipidic systems derived from renewable resources. AB - Self-assembled lipidic amphiphile systems can create a variety of multi functional soft materials with value-added properties. When employing natural reagents and following biocatalytic syntheses, self-assembling monomers may be inherently designed for degradation, making them potential alternatives to conventional and persistent polymers. By using non-covalent forces, self assembled amphiphiles can form nanotubes, fibers, and other stimuli responsive architectures prime for further applied research and incorporation into commercial products. By viewing these lipid derivatives under a lens of green principles, there is the hope that in developing a structure-function relationship and functional smart materials that research may remain safe, economic, and efficient. PMID- 26766924 TI - Geographies of generation: age restrictions in international adoption. AB - International adoption relocates minors, and only minors, from one country to another. The centrality of age to adoptive migration may prevent us from seeing the significance of generation: the prospective parent's age is also examined and evaluated for its relationship to the child's age and what this relationship will mean for the creation of a family. Because international adoption results in children crossing borders to enter new kinship formations, the assumptions under which it operate require closer geographical analysis. Generation, or the age range that separates dependents and their caretakers, is a significant but unstated motivator of international adoption policies and practices. This article argues that a normative and biologised sense of intergenerational difference is embedded in international adoption. The presence of generational ideology in national laws and international norms regarding international adoption demonstrate a broader sense in which policies situate more privileged families as acceptable and others as inadequate. I draw material for this analysis from both legal documents and documents which aim to provide interpretation of those laws, with reference to international adoptions from Peru. PMID- 26766922 TI - Beyond the CMSSM without an accelerator: proton decay and direct dark matter detection. AB - We consider two potential non-accelerator signatures of generalizations of the well-studied constrained minimal supersymmetric standard model (CMSSM). In one generalization, the universality constraints on soft supersymmetry-breaking parameters are applied at some input scale [Formula: see text]below the grand unification (GUT) scale [Formula: see text], a scenario referred to as 'sub-GUT'. The other generalization we consider is to retain GUT-scale universality for the squark and slepton masses, but to relax universality for the soft supersymmetry breaking contributions to the masses of the Higgs doublets. As with other CMSSM like models, the measured Higgs mass requires supersymmetric particle masses near or beyond the TeV scale. Because of these rather heavy sparticle masses, the embedding of these CMSSM-like models in a minimal SU(5) model of grand unification can yield a proton lifetime consistent with current experimental limits, and may be accessible in existing and future proton decay experiments. Another possible signature of these CMSSM-like models is direct detection of supersymmetric dark matter. The direct dark matter scattering rate is typically below the reach of the LUX-ZEPLIN (LZ) experiment if [Formula: see text] is close to [Formula: see text], but it may lie within its reach if [Formula: see text] GeV. Likewise, generalizing the CMSSM to allow non-universal supersymmetry breaking contributions to the Higgs offers extensive possibilities for models within reach of the LZ experiment that have long proton lifetimes. PMID- 26766925 TI - Predictors of disease complications and treatment outcome among patients with chronic suppurative otitis media attending a tertiary hospital, Mwanza Tanzania. AB - BACKGROUND: Chronic suppurative otitis media (CSOM) is a major health problem in developing countries causing hearing loss and life threatening complications. Early and effective treatment based on the knowledge of causative micro-organisms and predictors of outcome are crucial in preventing these associated complications. This study was conducted to determine the predictors of CSOM complications, treatment outcome and antimicrobial susceptibility of pathogens, thus providing essential evidence to formulate a policy for management of CSOM. METHODS: This was a prospective hospital based cross sectional study involving 301 patients attending Ear Nose and Throat (ENT) clinics at Bugando Medical Centre (BMC) between October 2013 and March 2014. A standardized data collection tool was used to collect demographics and clinical characteristics of patients with CSOM. Ear swabs were collected using sterile cotton swabs and transported to the laboratory for culture and antibiotic susceptibility testing. RESULTS: Out of 301 patients with CSOM; 187 (62.1 %) had positive aerobic culture within 48 h of incubation. Disease complications and poor treatment outcome were observed in 114 (37.8 %, 95 % CI; 32.2-43.3) and 46 (15.3 %, 95 % CI; 11.2-19.3) respectively. On multivariate logistic regression analysis factors found independently to predict both disease complications and poor treatment outcome were otalgia, being infected by multi drug resistant bacteria and being HIV positive. Prolonged illness duration before seeking medical attention was also found to be associated with disease complications (OR 1.029, 95 % CI 1.007-1.05, p = 0.01). A total of 116 (61 %) of gram negative bacteria were isolated. Of 34 Staphylococcus aureus, 14 (41 %) were found to be methicillin resistant Staphylococcus aureus (MRSA) while of 116 g negative enteric bacteria, 49 (42 %) were extended spectrum beta lactamases producers (ESBL). CONCLUSIONS: Findings of this study suggest that positive HIV status, infection due to multidrug resistant pathogens and otalgia are significantly associated with disease complications and poor treatment outcome. Of great importance this study confirms that prolonged illness duration without seeking medical attention significantly predicts disease complications. Urgent preventive measures and laboratory guided early treatment are necessary to reduce complications associated with CSOM. PMID- 26766926 TI - Confirming mental health care in acute psychiatric wards, as narrated by persons experiencing psychotic illness: an interview study. AB - BACKGROUND: It is important that mental health nurses meet the safety, security and care needs of persons suffering from psychotic illness to enhance these persons' likelihood of feeling better during their time in acute psychiatric wards. Certain persons in care describe nurses' mental health care as positive, whereas others report negative experiences and express a desire for improvements. There is limited research on how persons with psychotic illness experience nurses' mental health care acts and how such acts help these persons feel better. Therefore, the aim of this study was to explore, describe and understand how the mental health nurses in acute psychiatric wards provide care that helps persons who experienced psychotic illness to feel better, as narrated by these persons. METHOD: This study had a qualitative design; 12 persons participated in qualitative interviews. The interviews were transcribed, content analysed and interpreted using Martin Buber's concept of confirmation. RESULTS: The results of this study show three categories of confirming mental health care that describe what helped the participants to feel better step-by-step: first, being confirmed as a person experiencing psychotic illness in need of endurance; second, being confirmed as a person experiencing psychotic illness in need of decreased psychotic symptoms; and third, being confirmed as a person experiencing psychotic illness in need of support in daily life. The underlying meaning of the categories and of subcategories were interpreted and formulated as the theme; confirming mental health care to persons experiencing psychotic illness. CONCLUSION: Confirming mental health care acts seem to help persons to feel better in a step-wise manner during psychotic illness. Nurses' openness and sensitivity to the changing care needs of persons who suffer from psychotic illness create moments of confirmation within caring acts that concretely help the persons to feel better and that may enhance their health. The results show the importance of taking the experiential knowledge of persons who have experienced psychotic illness seriously to develop and increase the quality of mental health care in acute psychiatric wards. PMID- 26766928 TI - JBT Special Issue on Core Management. PMID- 26766927 TI - Lipase catalysis in organic solvents: advantages and applications. AB - Lipases are industrial biocatalysts, which are involved in several novel reactions, occurring in aqueous medium as well as non-aqueous medium. Furthermore, they are well-known for their remarkable ability to carry out a wide variety of chemo-, regio- and enantio-selective transformations. Lipases have been gained attention worldwide by organic chemists due to their general ease of handling, broad substrate tolerance, high stability towards temperatures and solvents and convenient commercial availability. Most of the synthetic reactions on industrial scale are carried out in organic solvents because of the easy solubility of non-polar compounds. The effect of organic system on their stability and activity may determine the biocatalysis pace. Because of worldwide use of lipases, there is a need to understand the mechanisms behind the lipase catalyzed reactions in organic solvents. The unique interfacial activation of lipases has always fascinated enzymologists and recently, biophysicists and crystallographers have made progress in understanding the structure-function relationships of these enzymes. The present review describes the advantages of lipase-catalyzed reactions in organic solvents and various effects of organic solvents on their activity. PMID- 26766929 TI - CONSTRUCTING SURROGATE MODELS OF COMPLEX SYSTEMS WITH ENHANCED SPARSITY: QUANTIFYING THE INFLUENCE OF CONFORMATIONAL UNCERTAINTY IN BIOMOLECULAR SOLVATION. AB - Biomolecules exhibit conformational fluctuations near equilibrium states, inducing uncertainty in various biological properties in a dynamic way. We have developed a general method to quantify the uncertainty of target properties induced by conformational fluctuations. Using a generalized polynomial chaos (gPC) expansion, we construct a surrogate model of the target property with respect to varying conformational states. To alleviate the high-dimensionality of the corresponding stochastic space, we propose a method to increase the sparsity of the gPC expansion by defining a set of conformational "active space" random variables. With the increased sparsity, we employ the compressive sensing method to accurately construct the surrogate model. We demonstrate the performance of the surrogate model by evaluating fluctuation-induced uncertainty in solvent accessible surface area for the bovine trypsin inhibitor protein system and show that the new approach offers more accurate statistical information than standard Monte Carlo approaches. Furthermore, the constructed surrogate model also enables us to directly evaluate the target property under various conformational states, yielding a more accurate response surface than standard sparse grid collocation methods. In particular, the new method provides higher accuracy in high dimensional systems, such as biomolecules, where sparse grid performance is limited by the accuracy of the computed quantity of interest. Our new framework is generalizable and can be used to investigate the uncertainty of a wide variety of target properties in biomolecular systems. PMID- 26766931 TI - Bivalirudin as an Alternative to Heparin for Anticoagulation in Infants and Children. AB - Bivalirudin, a direct thrombin inhibitor, is a useful alternative to heparin for anticoagulation in infants and children. It has been found to be effective in patients requiring treatment of thrombosis, as well as those needing anticoagulation during cardiopulmonary bypass, extracorporeal life support, or with a ventricular assist device. While it has traditionally been used in patients who were unresponsive to heparin or who developed heparin-induced thrombocytopenia, it has recently been studied as a first-line agent. Bivalirudin, unlike heparin, does not require antithrombin to be effective, and as a result, has the potential to provide a more consistent anticoagulation. The case reports and clinical studies currently available suggest that bivalirudin is as effective as heparin at reaching target activated clotting times or activated partial thromboplastin times, with equivalent or the lower rates of bleeding or thromboembolic complications. It is more expensive than heparin, but the cost may be offset by reductions in the costs associated with heparin use, including anti factor Xa testing and the need for administration of antithrombin. The most significant disadvantage of bivalirudin remains the lack of larger prospective studies demonstrating its efficacy and safety in the pediatric population. PMID- 26766930 TI - Safety of TeaCrine(r), a non-habituating, naturally-occurring purine alkaloid over eight weeks of continuous use. AB - BACKGROUND: Theacrine (1,3,7,9-tetramethyluric acid) is a purine alkaloid found in certain coffee (Coffea) species, fruits (Cupuacu [Theobroma grandiflorum]), and tea (Camellia assamica, var. kucha) that has anti-inflammatory, analgesic, and neuro-locomotor properties. Recent preliminary research has also reported increased feelings of energy, reduced fatigue, and strong effects on improving focus, concentration, and motivation to exercise. The purpose of this study was to examine the safety and non-habituating effects of TeaCrine(r), a nature identical, chemically equivalent bioactive version of theacrine. METHODS: Sixty healthy men (mean +/- SD age, height, weight: 22.9 +/- 4.7 years, 183.5 +/- 9.2 cm, 86.5 +/- 13.7 kg) and women (22.3 +/- 4.5 years, 165.2 +/- 12.3 cm, 69.0 +/- 17.4 kg) were placed into one of three groups: placebo (PLA, n = 20), 200 mg TeaCrine(r) (LD, n = 19) or 300 mg Teacrine(r) (HD, n = 21) and ingested their respective supplement once daily for 8 weeks. Primary outcomes were fasting clinical safety markers (heart rate, blood pressure, lipid profiles, hematologic blood counts, biomarkers of liver/kidney/immune function) and energy, focus, concentration, anxiety, motivation to exercise, and POMS measured prior to daily dosing to ascertain potential tachyphylactic responses and habituation effects. Data were analyzed via two-way (group * time) ANOVAs and statistical significance was accepted at p < 0.05. RESULTS: All values for clinical safety markers fell within normal limits and no group * time interactions were noted. No evidence of habituation was noted as baseline values for energy, focus, concentration, anxiety, motivation to exercise, and POMS remained stable in all groups across the 8-week study protocol. CONCLUSIONS: These findings support the clinical safety and non-habituating neuro-energetic effects of TeaCrine(r) supplementation over 8 weeks of daily use (up to 300 mg/day). Moreover, there was no evidence of a tachyphylactic response that is typical of neuroactive agents such as caffeine and other stimulants. PMID- 26766932 TI - Non-Intravenous Sedatives and Analgesics for Procedural Sedation for Imaging Procedures in Pediatric Patients. AB - OBJECTIVES: The purpose of this study was to describe the method of delivery, dosage regimens, and outcomes of sedatives administered by extravascular route for imaging procedures in children. METHODS: Medline, Embase, International Pharmaceutical Abstracts, and Cochrane Database of Systematic Reviews were searched using keywords "child", "midazolam", "ketamine", dexmedetomidine", "fentanyl", "nitrous oxide", and "imaging." Articles evaluating the use of extravascular sedation in children for imaging procedures published in English between 1946 and March 2015 were included. Two authors independently screened each article for inclusion. Reports were excluded if they did not contain sufficient details on dosage regimens and outcomes. RESULTS: Twenty reports representing 1,412 patients ranging in age from 0.33 to 19 years of age were included for analysis. Due to discrepancies in doses and types of analyses, statistical analyses were not performed. Oral midazolam was the most common agent evaluated; other agents included intranasal (IN) ketamine, IN midazolam, IN fentanyl, IN and transmucosal dexmedetomidine, and N2O. Most agents were considered efficacious compared with placebo. CONCLUSIONS: Most agents showed efficacy for sedation during imaging when delivered through an extra-vascular route. Selection of agents should be based on onset time, duration, patient acceptability, recovery time, and adverse events. More robust studies are necessary to determine the optimal agent and route to utilize for imaging procedures when sedation is needed. PMID- 26766933 TI - Tailored Assays for Pharmacokinetic and Pharmacodynamic Investigations of Aliskiren and Enalapril in Children: An Application in Serum, Urine, and Saliva. AB - OBJECTIVES: Drugs that are effectively used to treat hypertension in adults (e.g., enalapril) have not been sufficiently investigated in children. Studies required for pediatric approval require special consideration regarding ethics, study design, and conduct and are also associated with special demands for the bioanalytic method. Pediatric-appropriate assays can overcome these burdens and enable systematic investigations of pharmacokinetics and pharmacodynamic in all pediatric age groups. METHODS: Tailored assays were developed for pharmacokinetic investigation of a drug in 100 MUL of serum, saliva, and urine. All assays were applied in a proof-of-concept study to 22 healthy volunteers who had been given 300 mg aliskiren hemifumarate or 20 mg enalapril maleate and allowed for dense sampling. Changes in humoral parameters of the renin-angiotensin-aldosterone system were also evaluated with 6 parameters in 2.1 mL blood per time point. RESULTS: The pharmacokinetic results of aliskiren and enalapril obtained by low volume assays in serum and urine were comparable to that noted in the literature. The dense sampling enabled very detailed concentration-time profiles that showed high intersubject variability and biphasic absorption behavior of aliskiren. The replacement of invasive sampling by saliva collection appears inappropriate for both drugs because the correlations of drug concentrations in both fluids were low. A low-volume assay was also used to determine values for in the renin angiotensin-aldosterone system and to compare those results with the published literature. CONCLUSION: These results support both the use of low-volume assays in pediatric research and the systematic investigation of their use in neonates and infants. Use of this assay methodology will increase information about drug pharmacokinetics and pharmacodynamics in this vulnerable population and might contribute to safe and effective use of pharmacotherapy. PMID- 26766934 TI - Impact of a Drug Shortage on Medication Errors and Clinical Outcomes in the Pediatric Intensive Care Unit. AB - OBJECTIVES: The purpose of this study was to assess the rate of prescribing errors, resulting adverse events, and patient outcomes associated with sedation and analgesia in the pediatric intensive care unit (PICU) before and during a national shortage of fentanyl and injectable benzodiazepines. METHODS: A retrospective chart review was performed of patients admitted to the PICU with at least 1 prescribed order for a sedative or analgesic agent during the time periods of January to February of 2011 and 2012. Initial orders for sedative and analgesic agents were identified and investigated for appropriateness of dose and were assessed for error-associated adverse events. Orders were stratified by timing in regard to clinical pharmacist on-site availability. Demographic and outcome information, including unintended extubations, ventilator days, and PICU length of stay, were gathered. RESULTS: One hundred sixty-nine orders representing 72 patients and 179 orders representing 75 patients in 2011 and 2012, respectively, were included in analysis. No differences were found in the rate of prescribing errors in 2011 and 2012 (33 errors in 169 orders vs. 39 errors in 179 orders, respectively, p=0.603). No differences were found in rates of prescribing errors in regard to clinical pharmacist on-site availability. A significant increase was seen in unintended extubations per 100 ventilator days, with 0.15 in 2011 vs. 1.13 in 2012, respectively (p<0.001). A significant decrease was seen in ventilator days per patient (p<0.001) and PICU length of stay per patient (p=0.019). CONCLUSIONS: There were no differences in rates of prescribing errors before versus during the fentanyl and benzodiazepine shortage. PMID- 26766935 TI - Characterization of Dronabinol Usage in a Pediatric Oncology Population. AB - OBJECTIVES: Chemotherapy-induced nausea and vomiting (CINV) remains an important side effect associated with administration of chemotherapy in pediatrics. The aim of this study was to retrospectively review dronabinol use in a pediatric cancer center, with the intent of characterizing its use and identifying trends such as age, sex, diagnosis, and chemotherapy that describe where dronabinol is best used as an adjuvant antiemetic. METHODS: Patients receiving dronabinol at Riley Hospital for Children between 2000 and 2010 were identified. Patients eligible for inclusion were those with malignancy <=18 years old, who received at least 1 dose of dronabinol for CINV during admission. RESULTS: Ninety-five percent of patients received moderate or highly emetogenic chemotherapy. When dronabinol doses were analyzed, 95% of patients received doses that were lower than reference guidelines, 55% received dronabinol as a scheduled medication, and 19% received dronabinol 1 to 3 hours before chemotherapy. Overall, 60% of patients had a defined positive response to dronabinol. Sixty-five percent of patients received repeat courses of dronabinol, and 62% received outpatient prescriptions for dronabinol. CONCLUSIONS: Dronabinol appears to be a viable option as an adjuvant antiemetic in pediatric CINV, but a prospective trial using patients as their own controls is necessary to truly define dronabinol's place in therapy. PMID- 26766936 TI - An Academic Multihealth System PGY2 Pediatric Pharmacy Residency Program. AB - We describe a novel multihealth system pediatric pharmacy residency program through the Ernest Mario School of Pharmacy at Rutgers University. Pediatric clinical pharmacy is a growing field that has seen an increase in demand for practitioners. Practice sites include freestanding children's hospitals, children's hospitals within adult hospitals, and pediatric units within adult hospitals. To accommodate a residency program in a region with no freestanding children's hospital, the pediatric faculty members at the Ernest Mario School of Pharmacy at Rutgers University developed a multihealth system postgraduate year 2 (PGY2) pediatric pharmacy residency program with 6 pediatric faculty members functioning as preceptors at their 5 respective practice sites. The multihealth system setup of the program provides the resident exposure to a multitude of patient populations, pediatric specialties, and pediatric pharmacy practices. In addition, the affiliation with Rutgers University allows an emphasis on academia with opportunities for the resident to lecture in small and large classrooms, facilitate discussion periods, assist with clinical laboratory classes, and precept pharmacy students. The resident has the unique opportunity to develop a research project with a large and diverse patient population owing to the multihealth system rotation sites. A multihealth system PGY2 residency in pediatric pharmacy provides the resident a well-rounded experience in pediatric clinical practice, research, and academia that will enhance the resident's ability to build his or her own pediatric pharmacy practice. PMID- 26766937 TI - Ceftaroline Fosamil Use in 2 Pediatric Patients With Invasive Methicillin Resistant Staphylococcus aureus Infections. AB - Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) is one of the most common pathogens causing pediatric infections including skin and soft tissue infections, pyogenic arthritis, osteomyelitis, and septic shock. For decades, patients were treated with antibiotics such as vancomycin and clindamycin, but there is an increasing incidence of resistance to these traditional therapies. We describe 2 cases of patients with CA-MRSA invasive infections with bacteremia who experienced vancomycin therapy failure but who were successfully treated with ceftaroline fosamil. Case 1 involves an 8-year-old Hispanic male who was diagnosed with CA-MRSA bacteremia, thigh abscess, and osteomyelitis. The patient was admitted to the pediatric intensive care unit in septic shock. Case 2 involves an 8-year-old Caucasian male who was diagnosed with CA-MRSA sepsis, right arm abscess, and osteomyelitis. We were able to successfully treat both patients with CA-MRSA sepsis and invasive infection-who failed vancomycin therapy-with ceftaroline fosamil with no adverse efiects. Despite the positive outcome in both pediatric patients, clinical trials with ceftaroline fosamil are needed to further support its use in pediatric patients. PMID- 26766938 TI - Minimum Requirements for Core Competency in Pediatric Pharmacy Practice. AB - Colleges of pharmacy provide varying amounts of didactic and clinical hours in pediatrics resulting in variability in the knowledge, skills, and perceptions of new graduates toward pediatric pharmaceutical care. The Pediatric Pharmacy Advocacy Group (PPAG) endorses the application of a minimum set of core competencies for all pharmacists involved in the care of hospitalized children. PMID- 26766939 TI - Quantitative target analysis and kinetic profiling of acyl-CoAs reveal the rate limiting step in cyanobacterial 1-butanol production. AB - Cyanobacterial 1-butanol production is an important model system for direct conversion of CO2 to fuels and chemicals. Metabolically-engineered cyanobacteria introduced with a heterologous Coenzyme A (CoA)-dependent pathway modified from Clostridium species can convert atmospheric CO2 into 1-butanol. Efforts to optimize the 1-butanol pathway in Synechococcus elongatus PCC 7942 have focused on the improvement of the CoA-dependent pathway thus, probing the in vivo metabolic state of the CoA-dependent pathway is essential for identifying its limiting steps. In this study, we performed quantitative target analysis and kinetic profiling of acyl-CoAs in the CoA-dependent pathway by reversed phase ion pair liquid chromatography-triple quadrupole mass spectrometry. Using 13C labelled cyanobacterial cell extract as internal standard, measurement of the intracellular concentration of acyl-CoAs revealed that the reductive reaction of butanoyl-CoA to butanal is a possible rate-limiting step. In addition, improvement of the butanoyl-CoA to butanal reaction resulted in an increased rate of acetyl-CoA synthesis by possibly compensating for the limitation of free CoA species. We inferred that the efficient recycling of free CoA played a key role in enhancing the conversion of pyruvate to acetyl-CoA. PMID- 26766940 TI - FabAV antivenin use after copperhead snakebite: clinically indicated or knee-jerk reaction? AB - BACKGROUND: Crotalidae Polyvalent Immune Fab (Ovine) (FabAV) antivenin is commonly recommended after pit viper snakebites. Because copperhead envenomations are usually self-limited, some physicians are reluctant to use this costly treatment routinely, while others follow a more liberal approach. We hypothesized that, in practice, only patients with evidence of significant (moderate or severe) copperhead envenomation [those with snakebite severity score (SSS) > 3] receive FabAV and examined a large cohort to determine the relationship between clinical findings and FabAV administration. METHODS: All data from patients evaluated for copperhead snakebite at a rural tertiary referral center from 5/2002 to 10/2013 were compiled. Demographics, transfer status, antivenin use, and clinical findings were collected; SSS was calculated. The relationships among FabAV use, clinical findings, and SSS were analyzed using t-test, chi-square, and Pearson's coefficient (p < 0.05 was significant). RESULTS: During the study period, 318 patients were treated for copperhead snakebite; 44 (13.8 %) received antivenin. Median dose was four vials (range: 1-10; IQR: 4,6). There were no deaths. Most patients receiving FabAV (63.6 %) were admitted. With regard to demographics and symptoms, only the degree of swelling (moderate vs. none/mild; p < 0.01) and bite location (hand/arm vs. leg: p < 0.0001) were associated with FabAV use. A SSS > 3, indicating moderate or severe envenomation, was only very weakly correlated with antivenin use (r = 0.217; p < 0.0001). The majority of patients with SSS > 3 (65.8 %) did not receive antivenin while most patients who did receive antivenin (70.5 %) had SSS <= 3 (indicating mild envenomation). CONCLUSIONS: Considerable variation occurs in antivenin administration after copperhead snakebite. Use of FabAV appears poorly correlated with patients' symptoms. This practice may expose patients to the risks of antivenin and increasing costs of medical care without improving outcomes. Guidelines used for treating other pit viper strikes, such as rattlesnake or cottonmouth snakebite may be too liberal for copperhead envenomations. Our data suggests that most patients with mild or moderate envenomation appear to do well independent of FabAV use. We suggest, for patients with copperhead snakebite, that consideration be given to withholding FabAV for those without clinical evidence of severe envenomation until prospective randomized data are available. PMID- 26766941 TI - Three Large-Scale Functional Brain Networks from Resting-State Functional MRI in Subjects with Different Levels of Cognitive Impairment. AB - Normal aging and to a greater degree degenerative brain diseases such as Alzheimer's disease (AD), cause changes in the brain's structure and function. Degenerative changes in brain structure and decline in its function are associated with declines in cognitive ability. Early detection of AD is a key priority in dementia services and research. However, depending on the disease progression, neurodegenerative manifestations, such as cerebral atrophy, are detected late in course of AD. Functional changes in the brain may be an indirect indicator of trans-synaptic activity and they usually appear prior to structural changes in AD. Resting-state functional magnetic resonance imaging (RS-fMRI) has recently been highlighted as a new technique for interrogating intrinsic functional connectivity networks. Among the majority of RS-fMRI studies, the default mode network (DMN), salience network (SN), and central executive network (CEN) gained particular focus because alterations to their functional connectivity were observed in subjects who had AD, who had mild cognitive impairment (MCI), or who were at high risk for AD. Herein, we present a review of the current research on changes in functional connectivity, as measured by RS fMRI. We focus on the DMN, SN, and CEN to describe RS-fMRI results from three groups: normal healthy aging, MCI and AD. PMID- 26766942 TI - Induced Pluripotent Stem Cells as a Novel Tool in Psychiatric Research. AB - Reprogramming of somatic cells into induced pluripotent stem cells (iPSCs) provides a valuable opportunity to study neurodevelopmental and neurodegenerative psychiatric diseases by offering an unlimited source for patient-specific neuronal and glial cells. The present review focuses on the recent advancements in modeling psychiatric disorders such as Phelan-McDermid syndrome, Timothy syndrome, Rett syndrome, schizophrenia, bipolar disorder, and dementia. The treatment effects identified in studies on iPSCs using known therapeutic compounds are also summarized in this review. Here we discuss validation of cellular models and explore iPSCs as a novel drug screening tool. Although there are several limitations associated with the current methods used to study mental disorders, using iPSCs as a model system provides the advantage of rewinding and reviewing the development and degeneration of human neural cells. PMID- 26766943 TI - Bipolar Disorder: Role of Inflammation and the Development of Disease Biomarkers. AB - Bipolar disorder is a severe and enduring psychiatric condition which in many cases starts during early adulthood and follows a relapsing and remitting course throughout life. In many patients the disease follows a progressive path with brief periods of inter-episode recovery, sub-threshold symptoms, treatment resistance and increasing functional impairment in the biopsychosocial domains. Knowledge about the neurobiology of bipolar disorder is increasing steadily and evidence from several lines of research implicates immuno-inflammatory mechanisms in the brain and periphery in the etiopathogenesis of this illness and its comorbidities. The main findings are an increase in the levels of proinflammatory cytokines during acute episodes with a decrease in neurotrophic support. Related to these factors are glial cell dysfunction, neuro-endocrine abnormalities and neurotransmitter aberrations which together cause plastic changes in the mood regulating areas of the brain and neuroprogression of the bipolar diathesis. Research in the above mentioned areas is providing an opportunity to discover novel biomarkers for the disease and the field is reaching a point where major breakthroughs can be expected in the not too distant future. It is hoped that with new discoveries fresh avenues will be found to better treat an otherwise recalcitrant disease. PMID- 26766945 TI - Factors Associated with Caregiver Burden in Dementia: 1-Year Follow-Up Study. AB - OBJECTIVE: Dementia symptoms (cognitive function, daily-living function, and neuropsychiatric symptoms) become more serious over time, which is likely to increase caregiver burden. The aim of this study is to investigate which dementia related symptoms, and how the progression of these symptoms, have influenced caregiver burden during a 1-year follow-up assessment. METHODS: A total of 110 patients with dementia were assessed for their cognitive function, daily-living function, and neuropsychiatric symptoms. Caregivers were assessed for their caregiver burden. Bivariate analyses were conducted between caregiver burden and dementia patients' symptoms, in order to examine which particular symptoms were significantly associated with caregiver burden at the baseline. A multiple regression analysis was then conducted with each significantly associated variable with a view to identifying determinants, influencing caregiver burden. Additionally, bivariate analyses were conducted between the changes in caregiver burden and the changes in patients' symptoms, to investigate which patient variable could best describe caregiver burden from baseline to the 1-year follow up. A multiple regression analysis was conducted with each significantly associated change in symptom, in order to identify determinants that influence a change in caregiver burden. RESULTS: Neuropsychiatric symptoms, such as irritability, aberrant motor-behavior, delusions and disinhibition were found to be significant predictors of caregiver burden at baseline, according to multiple regression analysis. In addition, changes in neuropsychiatric symptoms, such as delusions, agitation and memory-related functioning in daily-living significantly predict a change in caregiver burden. CONCLUSION: Our results demonstrate that neuropsychiatric symptoms and memory impairment in daily-living functions are significant predictors of an increase in caregiver burden. PMID- 26766944 TI - Impaired Empathic Abilities among Patients with Complex Regional Pain Syndrome (Type I). AB - OBJECTIVE: The aims of this study were to evaluate differences in empathic abilities between patients with complex regional pain syndrome (CRPS) Type I and healthy control subjects (HCs) and to assess correlations between empathic abilities and multidimensional aspects of pain. METHODS: Empathic ability was measured in 32 patients with CRPS Type I and in 36 HCs using the Interpersonal Reactivity Index (IRI). A comprehensive assessment of pain was conducted in the patient group using the West Haven-Yale Multidimensional Pain Inventory (WHYMPI). Psychiatric symptoms were assessed using the Beck Depression and Anxiety Inventories (BDI and BAI), and quality of life was evaluated using the WHO Quality of Life (WHOQOL-BREF) questionnaire. RESULTS: Patients with CRPS showed impaired cognitive and emotional empathic abilities compared with HCs. Significantly lower levels of perspective taking and empathic concern and higher levels of personal distress on the IRI were exhibited by the patient group. Perspective taking and personal distress were associated with affective distress and poor quality of life in social contexts (BDI, BAI, and WHOQOL). However, empathic concern was positively correlated with pain severity and social support from others (WHYMPI). CONCLUSION: A tendency toward self-oriented distress in social cognition was exhibited among patients with CRPS Type I. Impaired empathic ability was shown to have potentially negative effects on subjective emotional outcomes and social performance in the lives of patients. Interventions to improve emotional awareness and theory of mind would be beneficial for enhancing social functioning in patients with CRPS Type I. PMID- 26766946 TI - Perspectives on the Happiness of Community-Dwelling Elderly in Korea. AB - OBJECTIVE: A community survey was performed to investigate the factors and perspectives associated with happiness among the elderly in Korea (>=60 years). METHODS: Eight hundred volunteers selected from participants in the Ansan Geriatric study (AGE study) were enrolled, and 706 completed the survey. The Happiness Questionnaire (HQ), which asks four questions about happiness, was administered. To explore the relationship between happiness and depression, the Geriatric Depression Scale (GDS) and the Beck Depression Inventory (BDI) also were administered. RESULTS: The participants' average level of happiness, determined using a 100-mm visual analogue scale (VAS) of the HQ, was 64.7+/-26.0. The happiest situations for most people were "getting together with family" (23.8%) and "living in peace with family members (well-being)" (13.2%). Frequent reasons for not being happy were "worsened health condition" (28.7% of the not happy group), "economic problems of their own" (16.5%), and "economic problems of their children" (14.8%). The participants' choices regarding the essential conditions for happiness were "good health" (65.3%) and "being with family" (20.5%). The BDI and GDS scores were negatively related to the happiness score. A preliminary scale [Happy (Haeng-Bok, ) aging scale] based on the HQ for measuring the happiness level of the Korean elderly was suggested for follow-up studies. CONCLUSION: The most important factors determining the happiness of the community dwelling elderly in Korea were good family relationships, economic stability, and good health. A higher depression score negatively impacted happiness among Korean elders. Further studies on the factors in their happiness are required. PMID- 26766947 TI - Characteristics and Psychiatric Symptoms of Internet Gaming Disorder among Adults Using Self-Reported DSM-5 Criteria. AB - OBJECTIVE: The Section III of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) proposed nine diagnostic criteria and five cut point criteria for Internet Gaming Disorder (IGD). We aimed to examine the efficacy of such criteria. METHODS: Adults (n=3041, men: 1824, women: 1217) who engaged in internet gaming within last 6 months completed a self-report online survey using the suggested wordings of the criteria in DSM-5. Major characteristics, gaming behavior, and psychiatric symptoms of IGD were analyzed using ANOVA, chi-square, and correlation analyses. RESULTS: The sociodemographic variables were not statistically significant between the healthy controls and the risk group. Among the participants, 419 (13.8%) were identified and labeled as the IGD risk group. The IGD risk group scored significantly higher on all motivation subscales (p<0.001). The IGD risk group showed significantly higher scores than healthy controls in all nine psychiatric symptom dimensions, i.e., somatization, obsession-compulsion, interpersonal sensitivity, depression, anxiety, hostility, phobic anxiety, paranoid ideation, and psychoticism (p<0.001). CONCLUSION: The IGD risk group showed differential psychopathological manifestations according to DSM-5 IGD diagnostic criteria. Further studies are needed to evaluate the reliability and validity of the specific criteria, especially for developing screening instruments. PMID- 26766948 TI - Insomnia in North Korean Refugees: Association with Depression and Post-Traumatic Stress Symptoms. AB - OBJECTIVE: We investigated the prevalence of insomnia and its clinical characteristics in North Korean refugees. METHODS: North Korean refugees living in South Korea (48 males, 129 females; mean age 38.22+/-12.24 years) and South Koreans (112 males, 203 females; mean age 39.48+/-10.32 years) completed the following questionnaires: the Self-reported Questionnaire on Insomnia, Center for Epidemiological Studies-Depression Scale (CES-D), Trauma Exposure Check List for North Korean Refugees, and the Impact of Event Scale-Revised (IES-R). RESULTS: North Korean refugees had insomnia more often than South Koreans did (38.42% vs. 8.89%). Depression combined with insomnia was also more prevalent in North Korean refugees (28.25% vs. 3.17%). Compared with South Koreans with insomnia, North Korean refugees with insomnia showed higher CES-D scores. The North Korean refugees with insomnia had experienced a larger number of traumatic events, and had higher CES-D and IES-R scores compared to North Korean refugees without insomnia. Insomnia in North Korean refugees was also associated with the presence of significant depressive and post-traumatic stress disorder (PTSD) symptoms. CONCLUSION: Insomnia was common in North Korean refugees and was closely associated with depressive and PTSD symptoms. Our study suggests that complaints of insomnia may indicate more severe psychopathology, especially in refugees. PMID- 26766949 TI - Copycat Suicide Induced by Entertainment Celebrity Suicides in South Korea. AB - OBJECTIVE: Throughout the past several years, there have been a number of entertainment celebrity suicides in South Korea. The aim of this study was to investigate the clustering of suicides following celebrities' suicides in South Korea from 2005 to 2008, particularly according to certain characteristics. METHODS: Seven celebrity suicides were examined and defined using the Korean Integrated Newspaper Database System (KINDS) and from these, we considered four affected periods occurring 28 days after each celebrity's suicide. A Poisson time series autoregression model was used to estimate the relative risk of the total suicide number for each affected period from 2005 to 2008. Logistic regression analysis was performed to investigate whether there were specific increases in the numbers of suicides in subgroups matching each celebrity. RESULTS: There were significant increases in the risk of suicide during the affected periods. Remarkable increases were found in the subgroups matching each celebrity, especially in the group in which all factors (sex, age, and method) were similar. CONCLUSION: This study provides confirmation that a significant copycat effect was induced by these celebrities' suicides, especially among people who identified more with the celebrities. This implies that countermeasures for upright media coverage of celebrity suicides should be discussed and practiced properly in South Korea. PMID- 26766950 TI - The Hyperactivity of Efferent Auditory System in Patients with Schizophrenia: A Transient Evoked Otoacoustic Emissions Study. AB - OBJECTIVE: Electrophysiological studies, which are mostly focused on afferent pathway, have proven that auditory processing deficits exist in patients with schizophrenia. Nevertheless, reports on the suppressive effect of efferent auditory pathway on cochlear outer hair cells among schizophrenia patients are limited. The present, case-control, study examined the contralateral suppression of transient evoked otoacoustic emissions (TEOAEs) in patients with schizophrenia. METHODS: Participants were twenty-three healthy controls and sixteen schizophrenia patients with normal hearing, middle ear and cochlear outer hair cells function. Absolute non-linear and linear TEOAEs were measured in both ears by delivering clicks stimuli at 80 dB SPL and 60 dB SPL respectively. Subsequently, contralateral suppression was determined by subtracting the absolute TEOAEs response obtained at 60 dBpe SPL during the absence and presence of contralateral white noise delivered at 65 dB HL. No attention tasks were conducted during measurements. RESULTS: We found no significant difference in absolute TEOAEs responses at 80 dB SPL, in either diagnosis or ear groups (p>0.05). However, the overall contralateral suppression was significantly larger in schizophrenia patients (p<0.05). Specifically, patients with schizophrenia demonstrated significantly increased right ear contralateral suppression compared to healthy control (p<0.05). CONCLUSION: The present findings suggest increased inhibitory effect of efferent auditory pathway especially on the right cochlear outer hair cells. Further studies to investigate increased suppressive effects are crucial to expand the current understanding of auditory hallucination mechanisms in schizophrenia patients. PMID- 26766951 TI - Parameters of Calcium Metabolism Fluctuated during Initiation or Changing of Antipsychotic Drugs. AB - OBJECTIVE: Serum parameters of calcium homeostasis were measured based on previously published evidence linking osteoporotic fractures and/or bone/mineral loss with antipsychotics. METHODS: Prospective, four-week, time-series trial was conducted and study population consisted of patients of both genders, aged 35-85 years, admitted within the routine practice, with acute psychotic symptoms, to whom an antipsychotic drug was either introduced or substituted. Serial measurements of serum calcium, phosphorous, magnesium, 25(OH)D, parathyroid hormone, calcitonin, osteocalcin and C-telopeptide were made from patient venous blood samples. RESULTS: Calcium serum concentrations significantly decreased from baseline to the fourth week (2.42+/-0.12 vs. 2.33+/-0.16 mmol/L, p=0.022, n=25). The mean of all calcemia changes from the baseline was -2.6+/-5.7% (-24.1 to 7.7) with more decreases than increases (78 vs. 49, p=0.010) and more patents having negative sum of calcemia changes from baseline (n=28) than positive ones (n=10) (p=0.004). There were simultaneous falls of calcium and magnesium from baseline (63/15 vs. 23/26, p<0.001; OR=4.75, 95% CI 2.14-10.51), phosphorous (45/33 vs. 9/40, p<0.001; 6.06, 2.59-14.20) and 25(OH)D concentrations (57/21 vs. 13/35, p<0.001; 7.31, 3.25-16.42), respectively. Calcemia positively correlated with magnesemia, phosphatemia and 25(OH)D values. Parathyroid hormone and C telopeptide showed only subtle oscillations of their absolute concentrations or changes from baseline; calcitonin and osteocalcin did not change. Adjustment of final calcemia trend (depletion/accumulation) for relevant risk factors, generally, did not change the results. CONCLUSION: In patients with psychotic disorders and several risks for bone metabolism disturbances antipsychotic treatment was associated with the decrease of calcemia and changes in levels of the associated ions. PMID- 26766952 TI - Affective Flattening in Patients with Schizophrenia: Differential Association with Amygdala Response to Threat-Related Facial Expression under Automatic and Controlled Processing Conditions. AB - OBJECTIVE: Early neuroimaging studies have demonstrated amygdala hypoactivation in schizophrenia but more recent research based on paradigms with minimal cognitive loads or examining automatic processing has observed amygdala hyperactivation. Hyperactivation was found to be related to affective flattening. In this study, amygdala responsivity to threat-related facial expression was investigated in patients as a function of automatic versus controlled processing and patients' flat affect. METHODS: Functional magnetic resonance imaging was used to measure amygdala activation in 36 patients with schizophrenia and 42 healthy controls. During scanning, a viewing task with masked and unmasked fearful and neutral faces was presented. RESULTS: Patients exhibited increased amygdala response to unmasked fearful faces. With respect to masked fearful faces, no between-group differences emerged for the sample as a whole but a subsample of patients with flat affect showed heightened amygdala activation. The amygdala response to masked fearful faces was positively correlated with the degree of flat affect. Conversely, amygdala response to unmasked fearful faces was negatively correlated to the severity of affective flattening. In patients, amygdala responses to masked and unmasked fearful faces showed an inverse correlation. CONCLUSION: Our findings suggest that amygdala hyperresponsivity to unmasked fearful faces might be a functional characteristic of schizophrenia. Amygdala hyperresponsivity to masked fearful faces might be a specific characteristic of patients with affective flattening. A model of flat affect as a response mechanism to emotional overload is proposed. PMID- 26766953 TI - Distribution of Active and Resting Periods in the Motor Activity of Patients with Depression and Schizophrenia. AB - OBJECTIVE: Alterations of activity are prominent features of the major functional psychiatric disorders. Motor activity patterns are characterized by bursts of activity separated by periods with inactivity. The purpose of the present study has been to analyze such active and inactive periods in patients with depression and schizophrenia. METHODS: Actigraph registrations for 12 days from 24 patients with schizophrenia, 23 with depression and 29 healthy controls. RESULTS: Patients with schizophrenia and depression have distinctly different profiles with regard to the characterization and distribution of active and inactive periods. The mean duration of active periods is lowest in the depressed patients, and the duration of inactive periods is highest in the patients with schizophrenia. For active periods the cumulative probability distribution, using lengths from 1 to 35 min, follows a straight line on a log-log plot, suggestive of a power law function, and a similar relationship is found for inactive periods, using lengths from 1 to 20 min. For both active and inactive periods the scaling exponent is higher in the depressed compared to the schizophrenic patients. CONCLUSION: The present findings add to previously published results, with other mathematical methods, suggesting there are important differences in control systems regulating motor behavior in these two major groups of psychiatric disorders. PMID- 26766954 TI - Increased Neutrophil/Lymphocyte Ratio in Patients with Depression is Correlated with the Severity of Depression and Cardiovascular Risk Factors. AB - OBJECTIVE: Chronic inflammation is associated with cardiovascular (CV) risk factors and psychiatric disorders. The neutrophil to lymphocyte ratio (NLR) has been investigated as a new biomarker for systemic inflammatory response. The aim of the study is to investigate the relation of NLR with severity of depression and CV risk factors. METHODS: The study population consisted of 256 patients with depressive disorder. Patients were evaluated with the Hamilton Rating Scale for Depression (HAM-D). Patients were classified into four groups according to their HAM-D score such as mild, moderate, severe, and very severe depression. Patients were also evaluated in terms of CV risk factors. RESULTS: Patients with higher HAM-D score had significantly higher NLR levels compared to patients with lower HAM-D score. Correlation analysis revealed that severity of depression was associated with NLR in depressive patients (r=0.333, p<0.001). Patients with one or more CV risk factors have significantly higher NLR levels. Correlation analysis revealed that CV risk factors were associated with NLR in depressive patients (r=0.132, p=0.034). In logistic regression analyses, NLR levels were an independent predictor of severe or very severe depression (odds ratio: 3.02, 95% confidence interval: 1.867-4.884, p<0.001). A NLR of 1.57 or higher predicted severe or very severe depression with a sensitivity of 61.4% and specificity of 61.2%. CONCLUSION: Higher HAM-D scores are associated with higher NLR levels in depressive patients. NLR more than 1.57 was an independent predictor of severe or very severe depression. A simple, cheap white blood cell count may give an idea about the severity of depression. PMID- 26766955 TI - Overexpression of Cell Cycle Proteins of Peripheral Lymphocytes in Patients with Alzheimer's Disease. AB - OBJECTIVE: Biological markers for Alzheimer's disease (AD) will help clinicians make objective diagnoses early during the course of dementia. Previous studies have suggested that cell cycle dysregulation begins earlier than the onset of clinical manifestations in AD. METHODS: We examined the lymphocyte expression of cell cycle proteins in AD patients, dementia controls (DC), and normal controls (NC). One-hundred seventeen subjects (36 AD, 31 DC, and 50 NC) were recruited. The cell cycle proteins CDK2, CDK4, CDK6, cyclin B, and cyclin D were measured in peripheral lymphocytes. Cell cycle protein expression in the three groups was compared after adjusting for age and sex. RESULTS: The levels of cell cycle proteins CDK2, CDK4, CDK6, cyclin B, and cyclin D were significantly higher in AD patients than in the NC subjects. The DC group manifested intermediate levels of cell cycle proteins compared with the AD patients and the NC subjects. The present study indicates that cell cycle proteins are upregulated in the peripheral lymphocytes of AD patients. CONCLUSION: Cell cycle dysregulation in peripheral lymphocytes may present a promising starting point for identifying peripheral biomarkers of AD. PMID- 26766957 TI - Frontoparietal Cortical Thinning in Respiratory-Type Panic Disorder: A Preliminary Report. AB - OBJECTIVE: Many evidences raise the possibility that the panic disorder (PD) patients with respiratory subtype (RS) may have characteristic structural abnormalities. We aimed to explore the structural differences between PD patients with and without the respiratory symptoms. METHODS: Patients with PD were recruited from the Department of Psychiatry at Korea University Anam Hospital. Respiratory subtype (RS) was diagnosed when at least 4 out of 5 of the following respiratory symptoms were present during the panic attack: fear of dying, chest pain/discomfort, shortness of breath, paresthesias, and a choking sensation. We acquired high-resolution MRI scans and used FreeSurfer to obtain a measure of cortical thickness for each patient. RESULTS: Cluster based analysis revealed significantly decreased cortical thickness in the left hemisphere in the caudal middle-frontal, superior frontal, and posterior parietal areas in the RS group. No significant difference was observed in any of the limbic areas. CONCLUSION: Respiratory symptoms of panic disorder were associated with a reduction in cortical thickness in the left frontal and parietal areas. This finding leads to the assumption that the frontoparietal network is the crucial component in a larger cortical network underlying the perception of dyspnea in RS. PMID- 26766958 TI - Brain Activation Patterns Associated with the Effects of Emotional Distracters during Working Memory Maintenance in Patients with Generalized Anxiety Disorder. AB - Few studies have assessed the neural mechanisms of the effects of emotion on cognition in generalized anxiety disorder (GAD) patients. In this functional MRI (fMRI), we investigated the effects of emotional interference on working memory (WM) maintenance in GAD patients. Fifteen patients with GAD participated in this study. Event-related fMRI data were obtained while the participants performed a WM task (face recognition) with neutral and anxiety-provoking distracters. The GAD patients showed impaired performance in WM task during emotional distracters and showed greater activation on brain regions such as DLPFC, VLPFC, amygdala, hippocampus which are responsible for the active maintenance of goal relevant information in WM and emotional processing. Although our results are not conclusive, our finding cautiously suggests the cognitive-affective interaction in GAD patients which shown interfering effect of emotional distracters on WM maintenance. PMID- 26766956 TI - Construction and Validation of Brain MRI Templates from a Korean Normal Elderly Population. AB - OBJECTIVE: This study aimed to construct a Korean normal elderly brain template (KNE96) using Korean elderly individuals for use in brain MRI studies and to validate it. METHODS: We used high-resolution 3.0T T1 structural MR images from 96 Korean normal elderly individuals (M/F=48/48), aged 60 years or older (M=69.5+/-6.2 years, F=70.1+/-7.0 years), for constructing the KNE96 template. The KNE96 template was validated by comparing the registration-induced deformations between the KNE96 and ICBM152 templates using different MR images from 48 Korean normal elderly individuals (M/F=24/24), aged 60 years or older (M=71.5+/-5.9 years, F=72.8+/-5.1 years). We used the magnitude of displacement vectors (mag-displacement) and log of Jacobian determinants (log-Jacobian) to quantify the deformation produced during registration process to templates. RESULTS: The mag-displacement and log-Jacobian of the registration were much smaller using the KNE96 template than with the ICBM152 template in most brain regions. There was a prominent difference in the significant averaged differences (SADs) of the mag-displacement and log-Jacobian between the KNE96 and ICBM152 at the superior, medial, and middle frontal gyrus, the lingual, inferior, middle, and superior occipital gyrus, and the caudate and thalamus. CONCLUSION: This study suggests that templates constructed from Asian populations, such as the KNE96, may be more desirable than those from Caucasian populations, like the ICBM152, in computational neuroimaging studies that measure and compare anatomical features of the frontal and occipital lobe, thalamus and caudate. PMID- 26766959 TI - Associations between Serotonergic Genes and Escitalopram Treatment Responses in Patients with Depressive Disorder and Acute Coronary Syndrome: The EsDEPACS Study. AB - Genes related to serotonin are associated with responses to treatment for depression. We examined associations between the serotonin transporter (5-HTT) and serotonin 2a receptor (5-HTR2a) genes and responses to treatment for depressive disorders in acute coronary syndrome (ACS). A total of 255 patients who met the DSM-IV major or minor depressive disorder and recently developed ACS were randomly assigned to the escitalopram (n=127) or placebo (n=128) group in this 24-week double-blind trial (ClinicalTrial.gov identifier: NCT00419471). Remission was defined as a Hamilton Rating Scale for Depression (HAMD) score <=7. Assays were performed for the 5-HTTLPR, STin2 VNTR, 5-HTR2a 102T/C, and 5-HTR2a 1438A/G genotypes. Escitalopram was superior to placebo for treating depressive disorder with ACS but there were no significant associations between serotonergic genes and treatment responses even when considering ACS severity. The effect of escitalopram was independent of 5-HTT and 5-HTR2a polymorphisms. PMID- 26766960 TI - Desensitization of Triggers and Urge Reduction for Paruresis: A Case Report. AB - Paruresis is a special type of non-generalized social phobia that involves fear and avoidance of urination in public restrooms. We administered eight 60-minute sessions of desensitization of triggers and urge reduction (DeTUR), an addiction protocol of eye movement desensitization and reprocessing (EMDR) therapy, to a 29 year old man with paruresis of 10 year duration. Because phobic avoidance is the hallmark of any anxiety disorder, we applied DeTUR targeting the urge to avoid each anxiety-provoking situation in succession. After treatment, the participant no longer met the requirements for a diagnosis of social anxiety disorder, and the self-reported symptoms of social anxiety had decreased to non-clinical levels; furthermore, these treatment gains were maintained at the one-year follow up. Further clinical studies are needed to generalize this finding. PMID- 26766961 TI - Baseline insulin sensitivity affects response to high-amylose maize resistant starch in women: a randomized, controlled trial. AB - BACKGROUND: Resistant starch (RS) is a type of dietary fiber that can improve glucose metabolism, but its effects may be modulated by sex or baseline insulin sensitivity. This study was designed to examine the effect of high-amylose maize resistant starch (HAM-RS2) on insulin sensitivity (SI) in women, and to determine if SI status affects the response to RS. METHODS: This was a randomized, placebo controlled, double-blind, cross-over study. Participants were 40 healthy, non diabetic women aged 22-67 years in the normal-weight to obese BMI range (20.6 47.4 kg/m(2)). Two doses of HAM-RS2 were tested, 15 and 30 g per day, administered in the form of cookies. Participants were randomized to the order in which they received the experimental and placebo product. Each arm was 4 weeks, with a 4-week wash-out period in between. SI was assessed at the end of each 4 week arm of product consumption by frequently-sampled, insulin-modified, intravenous glucose tolerance test and minimal modeling. Participants were categorized as being insulin resistant (IR; SI < 7.8) or insulin sensitive (IS; SI >= 7.8) based on Gaussian analysis. The effect of treatment arm on SI was examined by mixed-model analysis within IR and IS sub-groups, using all available data. In addition, SI was examined by ANOVA among just those women who completed all three arms of the study with valid SI results. RESULTS: Among IR participants, SI was on average ~16 % higher after the 30 g arm when compared to the control arm by mixed-model analysis (n = 40, P < 0.05), and tended to be 23 % higher by ANOVA among women who completed all arms (n = 23, P = 0.06). HAM-RS2 did not affect SI in IS women. CONCLUSION: Consumption of HAM-RS2 at 30 g/day in the form of a snack food item was associated with improved insulin sensitivity in women with insulin resistance. CLINICAL TRIALS REGISTRY NUMBER: NCT0152806. PMID- 26766962 TI - Diagnostic accuracy of oblique chest radiograph for occult pneumothorax: comparison with ultrasonography. AB - BACKGRAOUND: An occult pneumothorax is a pneumothorax that is not seen on a supine chest X-ray but is detected by computed tomography scanning. However, critical patients are difficult to transport to the computed tomography suite. We previously reported a method to detect occult pneumothorax using oblique chest radiography (OXR). Several authors have also reported that ultrasonography is an effective technique for detecting occult pneumothorax. The aim of this study was to evaluate the usefulness of OXR in the diagnosis of the occult pneumothorax and to compare OXR with ultrasonography. METHODS: All consecutive blunt chest trauma patients with clinically suspected pneumothorax on arrival at the emergency department were prospectively included at our tertiary-care center. The patients underwent OXR and ultrasonography, and underwent computed tomography scans as the gold standard. Occult pneumothorax size on computed tomography was classified as minuscule, anterior, or anterolateral. RESULTS: One hundred and fifty-nine patients were enrolled. Of the 70 occult pneumothoraces found in the 318 thoraces, 19 were minuscule, 32 were anterior, and 19 were anterolateral. The sensitivity and specificity of OXR for detecting occult pneumothorax was 61.4 % and 99.2 %, respectively. The sensitivity and specificity of lung ultrasonography was 62.9 % and 98.8 %, respectively. Among 27 occult pneumothoraces that could not be detected by OXR, 16 were minuscule and 21 could be conservatively managed without thoracostomy. CONCLUSION: OXR appears to be as good method as lung ultrasonography in the detection of large occult pneumothorax. In trauma patients who are difficult to transfer to computed tomography scan, OXR may be effective at detecting occult pneumothorax with a risk of progression. PMID- 26766963 TI - Molecular diagnosis and phylogenetic analysis of human papillomavirus type-16 from suspected patients in Pakistan. AB - BACKGROUND: Human Papillomavirus (HPV) is well known pathogen that can cause benign and malignant tumors in humans, yet there is very little information regarding HPV types prevalent in Pakistan. METHODS: A total of 92 cervical secretions were collected from suspected married female patients and used for DNA isolation using a novel isolation method. The samples were tested through Polymerase Chain Reaction (PCR) using already reported primers MY09/MY11, GP5/GP6, GP5+/GP6+, CP65/CP70, CP66/CP69 and SPF1/SPF2 and with those developed in this study including HRT1 and HRT2 primer sets for typing HPV types and HACTB primer set for human beta actin gene as internal positive control. Sequencing and phylogenetic analyses were performed for two isolates to determine circulating HPV types. RESULTS: PCR with HRT1 and HRT2 indicated 2 (2.17 %) patients were positive for HPV type- 16 while 1 (1.08 %) with HPV type 18. Sequencing and phylogenetic analysis of isolates confirmed HPV type-16 in genus alpha 9 which have 99 % homology with already reported HPV from Japan and Costa Rica. CONCLUSION: This is the first report of HPV type-16 genus alpha 9 in Pakistan and the reported assay and sequence data will serve as valuable tools in further epidemiological studies for HPV surveillance to improve public health, especially of females in Pakistan. PMID- 26766964 TI - Transcriptional profiling reveals molecular basis and novel genetic targets for improved resistance to multiple fermentation inhibitors in Saccharomyces cerevisiae. AB - BACKGROUND: Lignocellulosic biomass is a promising source of renewable biofuels. However, pretreatment of lignocellulosic biomass generates fermentation inhibitors that adversely affect the growth of industrial microorganisms such as Saccharomyces cerevisiae and prevent economic production of lignocellulosic biofuels. A critical challenge on developing S. cerevisiae with improved inhibitor resistance lies in incomplete understanding of molecular basis for inhibitor stress response and limited information on effective genetic targets for increasing yeast resistance to mixed fermentation inhibitors. In this study, we applied comparative transcriptomic analysis to determine the molecular basis for acetic acid and/or furfural resistance in S. cerevisiae. RESULTS: We recently developed a yeast strain YC1 with superior resistance to acetic acid, furfural, and their mixture through inverse metabolic engineering. In this study, we first determined transcriptional changes through RNA sequencing in YC1 versus the wild type strain S-C1 under three different inhibitor conditions, including acetic acid alone, furfural alone, and mixture of acetic acid and furfural. The genes associated with stress responses of S. cerevisiae to single and mixed inhibitors were revealed. Specifically, we identified 184 consensus genes that were differentially regulated in response to the distinct inhibitor resistance between YC1 and S-C1. Bioinformatic analysis next revealed key transcription factors (TFs) that regulate these consensus genes. The top TFs identified, Sfp1p and Ace2p, were experimentally tested as overexpression targets for strain optimization. Overexpression of the SFP1 gene improved specific ethanol productivity by nearly four times, while overexpression of the ACE2 gene enhanced the rate by three times in the presence of acetic acid and furfural. Overexpression of SFP1 gene in the resistant strain YC1 further resulted in 42 % increase in ethanol productivity in the presence of acetic acid and furfural, suggesting the effect of Sfp1p in optimizing the yeast strain for improved tolerance to mixed fermentation inhibitor. CONCLUSIONS: Transcriptional regulation underlying yeast resistance to acetic acid and furfural was determined. Two transcription factors, Sfp1p and Ace2p, were uncovered for the first time for their functions in improving yeast resistance to mixed fermentation inhibitors. The study demonstrated an omics-guided metabolic engineering framework, which could be developed as a promising strategy to improve complex microbial phenotypes. PMID- 26766965 TI - Safety hazards in abdominal surgery related to communication between surgical and anesthesia unit personnel found in a Swedish nationwide survey. AB - BACKGROUND: Many adverse events occur due to poor communication between surgical and anesthesia unit personnel. The aim of this study was to identify strategies to reduce risks unveiled by a national survey on patient safety. METHODS: During 2011-2015, specially trained survey teams visited the surgery departments at Swedish hospitals and documented routines concerning safety in abdominal surgery. The reports from the first seventeen visits were reviewed by an independent group in order to extract findings related to routines in communication between anesthesia and surgical unit personnel. RESULTS: In general, routines regarding preoperative risk assessment were safe and well- coordinated. On the other hand, routines regarding medication prior to surgery, reporting between the different units, and systems for reporting and providing feedback on adverse events were poor or missing. Strategies with highest priority include: 1. a uniform national health declaration form; 2. consistent use of admission notes; 3. systems for documenting all important medical information, that is accessible to everyone; 4. a multidisciplinary forum for the evaluation of high-risk patients; 5. weekly and daily scheduling of surgical programs; 6. application of the WHO check list; 7. open dialog during surgery; 8. reporting based on SBAR; 9. oral and written reports from the surgeon to the postoperative unit; and 10. combined mortality and morbidity conferences. CONCLUSION: One repeatedly occurring hazard endangering patient safety was related to communication between surgical and anesthesia unit personnel. Strategies to reduce this hazard are suggested, but further research is required to test their effectiveness. PMID- 26766967 TI - Increased hepcidin expression in non-small cell lung cancer tissue and serum is associated with clinical stage. AB - BACKGROUND: Hepcidin is a small secreted peptide that plays a key role in iron metabolism. A high level of hepcidin expression may be implicated in colorectal cancer; however, the relationship between hepcidin and lung cancer has not yet been studied. METHODS: Serum hepcidin-25, bone morphogenetic protein (BMP)-2, and interleukin (IL)-6 concentration in 53 patients and 16 non-cancerous individuals was measured by enzyme-linked immune sorbent assay. Reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) was utilized to study the expression of hepcidin mRNA in paired tumor and non-tumor lung tissues in surgical specimens from 65 patients with non small cell lung cancer (NSCLC), as well as in six types of lung cancer cell lines and human bronchial epithelial (HBE) cells. Hepcidin protein expression and cellular localization in NSCLC was determined by immunohistochemistry. RESULTS: The serum hepcidin-25 concentration was higher in patients with NSCLC than in non-cancerous individuals, and was positively correlated with serum BMP2 concentration, but negatively with serum IL 6 levels. Serum hepcidin was also correlated with lymph node metastasis and clinical stage. Hepcidin mRNA expression was higher in cancerous tissues of NSCLC than in normal pulmonary tissues (P = 0.001). Hepcidin mRNA levels in four lung carcinoma cell lines were higher than in HBE cells. Immunohistochemistry showed that hepcidin protein was increased in cancerous tissues of NSCLC. CONCLUSIONS: The level of hepcidin expression increased in NSCLC tissue and serum. Serum hepcidin-25 level was associated with lymph node metastasis and tumor clinical stage in patients with NSCLC. PMID- 26766968 TI - Characteristics and prognostic factors of synchronous multiple primary esophageal carcinoma: A report of 52 cases. AB - BACKGROUND: To retrospectively analyze the clinical characteristics and prognostic factors of 52 cases of synchronous multiple primary esophageal carcinoma (SMPEC), in order to provide a reference for treatment strategy. METHODS: Clinical and survival data of 52 patients with SMPEC were analyzed retrospectively. The rates of overall survival (OS), depending on the different factors, were calculated using Kaplan-Meier analysis. A log-rank test was used for univariate survival analysis and Cox's proportional hazards regression model was used for multivariate survival analysis. RESULTS: Clinical and survival data of 52 patients with SMPEC, hospitalized from 1 January 2003 to 31 October 2011, were analyzed. Twelve patients underwent surgical resection, five received adjuvant radiotherapy and one received adjuvant radiochemotherapy. Thirty-seven of the 40 non-operative patients received external beam radiation therapy and 20 of them received platinum-based chemotherapy. Another three non-operative patients were given platinum-based chemotherapy alone. The one, three, and five year OS and the median survival time (MST) were 65.4%, 17.3%, 7.7%, respectively, and 15.0 months for the whole cohort. Tumor length and M stage were independent prognostic factors for the whole cohort by multivariate survival analysis (P = 0.010 and 0.047, respectively). For the radiotherapy subgroup, multivariate analysis of prognostic factors identified that shorter tumor length, M0 stage, and chemotherapy were the predominant independent predictors of long-term survival (P = 0.039, 0.022 and 0.010, respectively). CONCLUSIONS: SMPEC is a relatively rare and aggressive tumor. Combined radiotherapy with chemotherapy seemed to bring a survival benefit and may be a better management choice for unresectable and non-operative SMPEC. PMID- 26766966 TI - From "awake" to "monitored anesthesia care" thoracic surgery: A 15 year evolution. AB - Although general anesthesia still represents the standard when performing thoracic surgery, the interest toward alternative methods is increasing. These have evolved from the employ of just local or regional analgesia techniques in completely alert patients (awake thoracic surgery), to more complex protocols entailing conscious sedation and spontaneous ventilation. The main rationale of these methods is to prevent serious complications related to general anesthesia and selective ventilation, such as tracheobronchial injury, acute lung injury, and cardiovascular events. Trends toward shorter hospitalization and reduced overall costs have also been indicated in preliminary reports. Monitored anesthesia care in thoracic surgery can be successfully employed to manage diverse oncologic conditions, such as malignant pleural effusion, peripheral lung nodules, and mediastinal tumors. Main non-oncologic indications include pneumothorax, emphysema, pleural infections, and interstitial lung disease. Furthermore, as the familiarity with this surgical practice has increased, major operations are now being performed this way. Despite the absence of randomized controlled trials, there is preliminary evidence that monitored anesthesia care protocols in thoracic surgery may be beneficial in high-risk patients, with non inferior efficacy when compared to standard operations under general anesthesia. Monitored anesthesia care in thoracic surgery should enter the armamentarium of modern thoracic surgeons, and adequate training should be scheduled in accredited residency programs. PMID- 26766969 TI - Correlation study and significance of the EGFR expression in serum, lymph nodes and tumor tissue of NSCLC. AB - BACKGROUND: This study was designed to detect the protein expression of epidermal growth factor receptor (EGFR) among serum, lymph node, and tumor tissues, and to discuss their relationship and clinical significance. We investigated whether EGFR levels in serum and lymph nodes could be used as an effective method for non small cell lung cancer (NSCLC) to diagnose and assess clinical stage. METHODS: In 56 patients with NSCLC and 10 individuals with nonmalignant thoracic disease, we measured EGFR levels in serum using an enzyme immunoassay, and EGFR mRNA levels in lymph node and NSCLC tissues by quantitative real-time-polymerase chain reaction. We examined the correlation between them and with the clinical parameters. RESULTS: Serum EGFR levels substantially decreased after surgical treatment (P < 0.001). Serum EGFR levels were correlated with smoking, surgery, and pathological type after surgery (all P < 0.05). EGFR mRNA levels in lymph node and tumor tissues were correlated more closely with lymph node metastasis (P = 0.015. EGFR mRNA in tissues was higher than that of benign pulmonary diseases (P = 0.020). There was an obvious positive correlation among EGFR levels of serum and lymph node tissues (r = 0.764; P < 0.001), serum and tumor tissues (r = 0.616; P < 0.001), and lymph node and tumor tissues (r = 0.904; P < 0.001) in NSCLCs. CONCLUSION: The data suggest that detecting EGFR levels in serum and lymph node tissues could be a simple and effective method to diagnose and assess the clinical stage in patients with NSCLC. PMID- 26766970 TI - Recurrent response to advanced lung adenocarcinoma with erlotinib developing leptomeningeal metastases during gefitinib therapy and two case reports. AB - BACKGROUND: Epidermal growth factor-tyrosine kinase inhibitors (EGFR-TKIs) are one of the effective medicines in advanced lung adenocarcinoma leptomeningeal metastasis (LM) treatment in recent years. METHODS: This paper reports two cases of advanced lung adenocarcinoma with exon-EGFR19 mutation. LM occurred during gefitinib treatment with an extracranial condition under control. Later, erlotinib was adopted with a recurrent response. RESULTS: The progression free survival of both patients was over six months and their LM was under control for six and a half and nine months, respectively. LM may be sensitive on different levels to different EGFR-TKIs. CONCLUSION: Erlotinib can be used to replace gefitinib if intracranial tumor progress occurs during gefitinib treatment. However, our conclusion still needs to be proven by further clinical research. PMID- 26766971 TI - Impact of smoking on mortality of patients with non-small cell lung cancer. AB - BACKGROUND: Cigarette smoking is one of the major causes of lung cancer. However, the correlation between smoking status and the survival of patients with lung cancer is uncertain. The present study aimed to evaluate the impact of smoking status on the mortality of patients with non-small cell lung cancer (NSCLC). METHODS: The medical records of 313 patients newly diagnosed with NSCLC between January 2005 and January 2006 were reviewed. Eligible patients were divided into ever-smokers (221 patients) and never-smokers (92 patients), and the overall survival and clinical characteristics of the two groups were compared. Predictors of survival were analyzed using Cox's proportional hazards regression. RESULTS: In ever-smokers, the mean age was higher, and male gender and squamous histology were predominant compared to never-smokers. The median survival time was longer in never-smokers (21.1 vs. 41.9 months, ever-smokers vs. never-smokers, respectively; P = 0.027). Overall survival estimates at 12, 24, and 60 months were 62.9 versus 82.6%, 43.4 versus 65.2%, and 31.2 versus 42.4%, in each group. Advanced age, advanced disease stage (stages III and IV), and coexistence of interstitial lung disease were analyzed as independent risk factors for shorter survival. Although ever-smoking was not an independent risk factor, current smoking was a risk factor for higher mortality. CONCLUSIONS: The overall mortality of ever-smokers was higher than that of never-smokers in patients with newly diagnosed NSCLC, and current smoking was an independent risk factor for a poorer prognosis. PMID- 26766972 TI - Pemetrexed plus carboplatin as adjuvant chemotherapy in patients with curative resected non-squamous non-small cell lung cancer. AB - BACKGROUND: Cisplatin-based adjuvant chemotherapy provided a significant advantage in the overall survival (OS) of patients with stage II and III non small cell lung cancer (NSCLC). However, the compliance and toxicity in cisplatin based treatment were not always satisfactory. Pemetrexed plus carboplatin (PC) had better chemotherapy compliance and efficiency in advanced non-squamous NSCLC patients. The aim of our study was to investigate the feasibility and efficacy of PC as adjuvant chemotherapy in patients with completely resected non-squamous NSCLC. METHODS: Eighty-two eligible non-squamous NSCLC patients operated on with pathological stage II or IIIA were enrolled in this trial. Adjuvant chemotherapy was initiated between one and four weeks after surgery, and consisted of four cycles of pemetrexed (500 mg/m2) plus carboplatin (AUC = 5) every three weeks. The primary endpoint was the compliance of the regimen and the second endpoint was disease-free survival (DFS). RESULTS: Patient demographics were median age 58 years (range 32 to 78) and gender ratio 68.3% male/31.7% female. Forty-eight (58.5%) of the patients were at stage II, and the other thirty-four (41.5%) patients were at stage IIIA. Seventy patients (85.4%) received four cycles of therapy over a 12-week period. Reasons for discontinuing therapy included: patient's refusal (n = 10); severe adverse events (n = 1); and surgical complications (n = 1). The primary grade 3 to 4 adverse reaction was hematologic toxicity: neutropenia (13.4%); leucopenia (7.3%); anemia (3.7%); and thrombocytopenia (2.4%). Non-hematological adverse events were mild. No treatment related deaths were observed. Median DFS for stage II and IIIA patients were 38.0 months (95% confidence interval (CI): 28.1 to 47.9 months) and 21.0 months (95%CI: 13.7 to 28.3 months), respectively. CONCLUSION: Adjuvant PC chemotherapy was an acceptable regimen in resected non-squamous NSCLC patients. PMID- 26766973 TI - Combined small-cell lung carcinoma: An institutional experience. AB - BACKGROUND: The purpose of this study is to determine prognostic factors and survival in patients who present with combined small-cell lung cancer (SCLC). METHODS: A retrospective review of combined SCLC histology in patients treated between1995-2010 was undertaken. Demographics, diagnostic information, disease characteristics, treatment modality, and survival were captured. Survival estimates were performed using Kaplan Meier analysis. Statistical significance was defined as P < 0.05. RESULTS: Forty-one patients were identified, and 35 records were available for analysis. Median age at diagnosis was 68 (range 50 85). The study included 20 (57%) women and 15 (43%) men; and 94% had a current or former history of smoking. Histology was SCLC/large cell carcinoma not otherwise specified in 28 (80%), and SCLC/adenocarcinoma or SCLC/squamous cell carcinoma in seven (20%). Cardiac or pulmonary comorbidities were present in 80% of patients, and 24 patients had metastatic disease at presentation. Twenty-eight patients received treatment of chemotherapy (n = 24), cranial radiotherapy (n = 5), or thoracic radiotherapy (n = 7). Staging was as follows: stage I-III (n = 11), stage IV (n = 24). Median survival was 15.4 months (range <1-53 months) and 3.4 months (range <1-21.9 months) for American Joint Committee on Cancer (AJCC) stage I-III and stage IV, respectively. Estimated overall six and 12 month survival was 82%, 55%, 37%, and 17% for stage I-III and stage IV, respectively. An improved overall survival rate was found for patients with an Eastern Cooperative Oncology Group performance status of <2, and no weight loss (P < 0.05). CONCLUSION: Akin to SCLC, advanced stage combined SCLC portends a poor prognosis. Perhaps novel chemotherapeutic drugs or targeted agents may improve outcomes for future patient populations. PMID- 26766974 TI - Lack of epidermal growth factor receptor gene mutations in exons 19 and 21 in primary lymphoepithelioma-like carcinoma of the lung. AB - BACKGROUND: Primary lymphoepithelioma-like carcinoma (LELC) of the lung is uncommon in non-small cell lung cancer (NSCLC). Epidermal growth factor receptor (EGFR) targeted therapy has been applied in advanced common NSCLC. Whether EGFR targeted therapy is also suitable for LELC of the lung remains unclear. As we know, EGFR gene mutation is a predictive factor. Therefore, EGFR gene mutations in exons 19 and 21 in Chinese patients with LELC of the lung were investigated. METHODS: Clinicopathological information was obtained by a retrospective review of the medical history recorded in the patients' charts. EGFR gene mutations in exons 19 and 21 were analyzed in 32 samples of LELC of the lung by TaqMan real time polymerase chain reaction (RT-PCR). RESULTS: Eleven (34.4%) of the patients were male and 21 (65.6%) patients female. The mean age at diagnosis was 50.9 years (range, 25-71 years). Seven (21.9%) of the patients were smokers. In situ hybridization for Epstein-Barr virus-encoded small RNAs (EBERs) showed positive signals in all 32 patients. None of the tumors had mutations in exons 19 and 21. EGFR-targeted therapy was used in three patients with advanced disease and one patient with distant recurrence. However, no obvious therapeutic effect was found. CONCLUSION: These data showed that LELC of the lung, a special histological type of lung cancer, lacked EGFR gene mutations in exons 19 and 21, which suggested that there was no opportunity for EGFR-targeted therapy for patients with LELC of the lung. PMID- 26766975 TI - Radiotherapy dose calculation on KV cone-beam CT image for lung tumor using the CIRS calibration. AB - On-board kilovoltage (KV) cone-beam computed tomography (CBCT) images are used predominantly for the setup of patients' positioning. The image data can also potentially be used for dose calculation with the precise calibration of Hounsfield units (HU) to electron density (HU-density). CBCT calibration was analyzed in this study. A clinical treatment planning system was employed for CT and KV CBCT image to dose calculations and subsequent comparisons. Two HU-density tables were generated using the Computerized Imaging Reference Systems (CIRS) phantom. The results showed that a maximum ~4% dose discrepancy was observed for inserts. The single field isodose curves were very close. The lung clinical patient study indicated that the volume of lung tumor that achieved the prescribed dose in CBCT was lower than in the CT plan. Our study showed that the dosimetric accuracy of CBCT-based dose calculation for lung tumor is acceptable only for the purpose of dosimetric checks with calibration applied. KV CBCT images cannot replace traditional CT images for dose calculation accuracy. PMID- 26766976 TI - Localized biphasic type malignant mesothelioma arising in the peritoneum: Report of a case. AB - This report describes a rare case of localized malignant biphasic (mixed epithelioid and sarcomatoid) mesothelioma arising in the peritoneum. A 69-year old male with a history of asbestos exposure, complaining of a painful mass in the left chest wall, was found via computed tomography (CT) to have a tumor in the left peritoneum. The resected tumor was histologically and immunohistochemically consistent with a malignant mesothelioma with mixed epithelioid and sarcomatoid type and no distant metastasis. The diagnosis of localized malignant biphasic mesothelioma arising in the peritoneum was appropriate because there was no evidence of any other primary tumor. PMID- 26766977 TI - Primary anaplastic large cell lymphoma of the lung presenting with acute atelectasis. AB - Non-Hodgkin lymphoma only rarely occurs as a primary lung mass. We report a very rare case of primary pulmonary anaplastic large cell lymphoma presenting with acute atelectasis in a 55-year-old man. Chest computed tomography revealed a consolidated central mass in the left lung with obstructive pneumonia that had developed into total atelectasis. After a bronchoscopic examination failed to yield a definite diagnosis, supraclavicular lymph node biopsy was performed, revealing an anaplastic large cell lymphoma. This case illustrates the need for rapidly locating a possible biopsy site, other than the primary lung mass itself, and the value of empirical steroid treatment for avoiding devastating exacerbation when aggressive pulmonary lymphoma is suspected. PMID- 26766978 TI - Lung papillary adenocarcinoma complicated with paraneoplastic autoimmune hemolytic anemia: A case report. AB - A middle-aged woman presented at our facility and was diagnosed after surgery with lung papillary adenocarcinoma. Seven years earlier, she had suffered from autoimmune hemolytic anemia (AIHA), which was refractory. Following lung surgery, the AIHA was cured. PMID- 26766979 TI - Primary malignant achromic melanoma of the lung. AB - Currently, less than thirty cases of primary malignant melanoma of the lung have been reported in the literature. Thus, strict criteria for diagnosis have been published and include: malignant melanoma associated with bronchial epithelial changes; a solitary lung tumor; no prior history of skin, mucous membrane, intestinal or ocular melanoma; and absence of any other detectable tumor at the time of diagnosis. In this article we present a case of melanoma of the lung without evidence of extra-pulmonary disease. PMID- 26766980 TI - Pleomorphic adenoma presenting with a mediastinal mass. AB - Pleomorphic adenoma is the most common type of salivary gland tumor. Although it rarely affects the trachea and bronchus, it usually grows in the airway and presents as an endobronchial mass. We recently experienced a case of pleomorphic adenoma originating in the bronchus and growing outward into the mediastinum. We present this case with review of the computed tomography (CT) scan of the patient's chest, the endoscopic ultrasound (EUS), and the histopathology report. PMID- 26766981 TI - Primary extranodal NK/T-cell lymphoma of the lung: Mimicking bronchogenic carcinoma. AB - Primary extranodal natural killer/T- cell lymphoma, nasal type (NK/TCL) in the lung is extremely rare and associated with Epstein-Barr virus (EBV) infection. An 80-year-old male presented with hemoptysis, which had lasted three days. Physical examination revealed inspiratory crackles at the left lung base and massive splenomegaly. Chest radiograph shows a mass-like lesion in the left lower lung but no active lesion six months earlier. Computed tomography demonstrated a soft tissue mass (size: 6.6 * 5.1 cm) with increased ground-glass opacities in the left lower lobe, several pulmonary nodules, and mediastinal lymphadenopathy. Transthoracic needle biopsy of the left-lower-lobe lung mass was performed. The pathology revealed atypical lymphoid cell infiltration, which is immunoreactive for cytoplasmic CD3, CD30 and CD56, but not reactive for CK and CD20. EBV-encoded RNA (EBER) was also detected in these atypical lymphoid cells. The serum EBV DNA level was 7.03 * 10(6) copies/mL and subtype 1 EBV was identified. No evidence of lymphoma involvement was found in the extrathoracic site. Primary pulmonary lymphoma showing nasal-type NK/T-cell subtype was diagnosed. Chemotherapy with cyclophosphamide and prednisolone was initiated immediately but the patient deteriorated and died three weeks later. In conclusion, patients presenting with rapidly growing lung mass and massive splenomegaly raise the possibility of aggressive pulmonary lymphoma. Extranodal NK/T-cell lymphoma with high baseline plasma EBV DNA levels signifies poor prognosis. Identifying young high-risk patients may have benefits for early aggressive and successful treatment. PMID- 26766982 TI - Multidisciplinary approach to fetal adenocarcinoma of the lung: A case report. AB - This paper reports a case of high-grade fetal lung adenocarcinoma with particularly aggressive clinical and biological features in a 57-year-old man. Our patient first underwent neoadjuvant chemotherapy followed by surgery, and was then treated with adjuvant chemotherapy. Next, he had radiotherapy on the mediastinal region and prophylactic whole brain radiation therapy (WBRT). Following radiotherapy treatment, the patient started maintenance therapy with a somatostatin analogue. After 58 months of follow-up he is asymptomatic and disease free. PMID- 26766983 TI - Squamous cell carcinoma of the lung with simultaneous metastases to peritoneum and skeletal muscle. AB - Skeletal muscle and peritoneum are rare sites of metastases from lung cancer. We report a case of squamous cell lung cancer with concurrent metastases to skeletal muscle and peritoneum. A 71-year-old man was diagnosed with squamous cell carcinoma of the right lower lobe with metastasis to the right hilar lymph node at clinical stage T3N1M0. Because of poor performance status and comorbidity, he only received radiation therapy. Positron emission tomography-computed tomography for mid-assessment of response showed two abnormal hypermetabolic lesions in the peritoneum of the left upper quadrant area and the left thigh muscle. We performed a needle-approach biopsy in each lesion and found both of the lesions were metastases from lung cancer. The patient died after two months. PMID- 26766984 TI - Primary pulmonary peripheral T-cell lymphoma: A case report and review of the literature. AB - Primary pulmonary T-cell lymphoma is a rare condition characterized by fever, cough, dyspnea, and bilateral pulmonary nodules, usually diagnosed by transbronchial biopsy or computed tomography (CT) guided needle biopsy and pathology. In view of its poor prognosis, it is critical to distinguish and diagnose this disease as early as possible. We report here a case of a 39-year old man who presented with fever, cough, expectoration with multiple nodules, and patch shadow in both lungs by chest CT. Tissue samples were taken by CT guided needle biopsy. The histological sample and immunohistochemistry showed peripheral T-cell lymphoma-not otherwise specified (PTCL-NOS). After the patient was treated by chemotherapy for two courses, his condition deteriorated rapidly and he died 2.3 months after the onset of the disease. PMID- 26766985 TI - Giant solitary fibrous tumor of the pleura requiring left pneumonectomy. PMID- 26766986 TI - Diabetes mellitus increases postoperative mortality in non-small cell lung cancer. PMID- 26766987 TI - New basic approach to treat non-small cell lung cancer based on RNA-interference. AB - BACKGROUND: To date the therapy for non-small cell lung cancer (NSCLC) is associated with severe side effects, frustrating outcomes, and does not consider different tumor characteristics. The RNA-interference (RNAi) pathway represents a potential new approach to treat NSCLC. With small interfering ribonucleic acids (siRNAs), it is possible to reduce the expression of proliferation-dependent proteins in tumor cells, leading to their apoptosis. We propose that siRNAs could be adapted to the tumor type and may cause fewer side effects than current therapy. METHODS: Four NSCLC cell lines were cultured under standard conditions and transfected with three different concentrations of siRNAs targeted against the hypoxia-inducible factors 1alpha and 2alpha (HIF1alpha and HIF2alpha) and signal transducer and activator of transcription 3 (STAT3). The expression was observed by quantitative real-time polymerase chain reaction and western blots. For the analysis of cell growth three days after transfection, the cell number was detected using a CASY cell counter system. RESULTS: The results of the silencing of the analyzed factors differ in each cell line. Cell growth was significantly reduced in all cell lines after transfection with HIF1alpha- and STAT3-siRNA. The silencing of HIF2alpha resulted in a significant effect on cell growth in squamous, and large-cell lung cancer. CONCLUSIONS: This study shows that the knockdown and viability to siRNA transfection differ in each tumor type according to the used siRNA. This implies that the tumor types differ among themselves and should be treated differently. Therefore, the authors suggest a possible approach to a more personalized treatment of NSCLC. PMID- 26766988 TI - Differences in the efficacy of S-1 monotherapy according to histological type in pretreated patients with advanced non-small cell lung cancer. AB - BACKGROUND: S-1 is a novel antimetabolic agent that inhibits thymidylate synthase. The expression of thymidylate synthase is higher in squamous (Sq) non small cell lung cancer (NSCLC) than in non-Sq NSCLC. The aim of this retrospective study was to assess the efficacy of S-1 monotherapy for advanced NSCLC according to the histological subtype. METHODS: We reviewed the clinical records of patients with advanced NSCLC treated with S-1 monotherapy as second- or third-line therapy between May 2005 and July 2012 at the Shizuoka Cancer Center. RESULTS: A total of 71 patients were included in this retrospective study. Patient characteristics were similar in the Sq NSCLC (n = 15) and non-Sq NSCLC (n = 56) groups, except with regard to gender and smoking status. The overall response rates were 0% (95% confidence interval [CI] 0-17%) for Sq NSCLC and 11% (95% CI 3-19%) for non-Sq NSCLC (P = 0.33). For Sq NSCLC and non-Sq NSCLC, the median progression-free survival times were 2.1 and 2.8 months (P = 0.02), respectively, and the median overall survival times were 6.1 and 10.1 months (P = 0.01), respectively. CONCLUSION: S-1 monotherapy may be more effective in patients with non-Sq NSCLC than in those with Sq NSCLC. PMID- 26766989 TI - Patients harboring epidermal growth factor receptor (EGFR) double mutations had a lower objective response rate than those with a single mutation in non-small cell lung cancer when treated with EGFR-tyrosine kinase inhibitors. AB - BACKGROUND: Multiple prospective studies have demonstrated that epidermal growth factor receptor (EGFR) exon 19 and exon 21 mutations are the most powerful predictive biomarkers of response to EGFR tyrosine kinase inhibitors (TKIs) in advanced non-small-cell lung cancer (NSCLC). However, there are few studies focused on patients with double mutations compared with a single mutation. METHODS: We retrospectively screened 1,525 samples of Chinese patients with advanced NSCLC who underwent EGFR mutation detections in tumor tissues at Peking University Cancer Hospital between February 2006 and March 2011. Thirty-two cases harboring double mutations were included in this study. The Kaplan-Meier univariate analysis for prognostic factors of survival was applied. RESULTS: Patients with double mutations accounted for 2.1% (32/1525) of the overall tested samples. Double mutations were more common in female, adenocarcinoma, non smokers, Eastern Cooperative Oncology Group (ECOG0)-1 and stage IV patients. Twenty-one patients with double mutations were treated with EGFR-TKIs. The objective response rate (ORR) was 23.8%, and the disease control rate (DCR) was 76.2%. In the first-line therapy, the ORR was 16.7%, and the DCR was 66.7%. In univariate analysis, gender, smoking-status, TKI type and TKI response were correlated with progression-free survival, and patients with ECOG 0-1 had longer overall survival. CONCLUSIONS: Patients with double mutations had a low objective response rate when treated with EGFR-TKIs compared with single EGFR exon 19 or exon 21 mutations. PMID- 26766991 TI - Role of E2F-1 and its involving pathway in esophageal squamous cell carcinoma. AB - BACKGROUND: Esophageal cancer is a lethal disease and the optimal therapy remains unclear. Neoadjuvant chemotherapy provides an increased chance of survival; therefore, we attempted to identify potential molecular markers that might improve evaluations of individual responses to therapy. METHODS: We recruited 109 patients with resectable esophageal squamous cell carcinoma. The patients underwent radical esophagectomy and did not receive any other perioperative treatment. Expression of E2F-1 and molecules involved in its targeted pathways, pERK, Bim, pRb, epidermal growth factor receptor, EZH2 and pAKT, was investigated immunohistochemically. RESULTS: Correlations were observed between E2F-1 and pRb expression; EZH2 expression was significantly correlated with the degree of carcinoma differentiation (P = 0.01). Stage III patients were found to have longer survival if they did not express pERK than if they did (23 months vs. 11 months, P = 0.01). Patients with E2F-1 not expressing pRb were found to have longer survival times than those with E2F-1 who expressed pRb (18.8 months vs. 8.6 months, P = 0.021). Similarly, stage III patients with E2F-1 but not expressing pERK also survived longer than those expressing pERK (23.5 months vs. 3.9 months, P < 0.001). CONCLUSIONS: A high expression of pERK was significantly associated with poor survival in patients with locally advanced esophageal cancer. Expression of a combination of molecules, rather than of individual molecules, was more predictive of disease prognosis. E2F-1 and molecules of its targeted pathways may be candidate proteins as markers of chemosensitivity in esophageal cancer patients. PMID- 26766990 TI - Outcome of active anti-cancer treatment in elderly patients with advanced non small cell lung cancer: A single center experience. AB - BACKGROUND: This study aimed to evaluate the characteristics of active anti cancer treatment (AAT) compared with best supportive care (BSC) in elderly patients with advanced non-small cell lung cancer (NSCLC). METHODS: A retrospective analysis of 144 patients, aged 70 or older, with stage IIIb/IV NSCLC from 672 patients with confirmed lung cancer, was conducted. RESULTS: Median age at diagnosis was 77 years and median survival time was five months. On multivariate analysis, AAT independently contributed to a decreased hazard ratio of death (P = 0.04), whereas male gender (P = 0.004), a body mass index of less than 18.5 (P = 0.004), and a poor performance score were associated with an increased risk of death (P < 0.001). The 52 subjects receiving AAT experienced longer survival than the 92 subjects receiving BSC (median seven months [AAT] versus three months [BSC]; P < 0.001). When sub-classified into five-year age intervals, AAT was a significant advantage in overall survival (OS) to patients aged 70-74, but not to those >=75 years old. CONCLUSIONS: AAT for patients >=70 years old with advanced NSCLC extended OS. However, care should be taken in decisions on active anti-cancer treatments for patients over 75 years old. A prospective multicenter trial is required in the near future. PMID- 26766992 TI - Phase II trial of paclitaxel-carboplatin with intercalated gefitinib for untreated, epidermal growth factor receptor gene mutation status unknown non small cell lung cancer. AB - BACKGROUND: This study was conducted to evaluate the efficacy and safety of paclitaxel-carboplatin combined with intercalated gefitinib in patients with advanced, untreated, nonsquamous non-small cell lung cancer. METHODS: A total of 29 patients were enrolled in the study. All patients were Chinese, with a histology type of adenocarcinoma, without a smoking history, and as a result of the limited tissue sample, an epidermal growth factor receptor (EGFR) mutation test could not be performed. All patients received chemotherapy of paclitaxel carboplatin every 21 days for four cycles, and gefitinib (250 mg/day) was administered on days eight to 17 of the chemotherapy cycle. If the patient responded to chemotherapy, maintenance therapy of 250mg of gefitinib could be administered daily. RESULTS: All of the 29 patients received at least one cycle of chemotherapy and gefitinib, and 25 patients received four cycles of therapy. Eighteen patients selected maintenance therapy with gefitinib. The objective response rate was 74.1% (95% confidence interval, 53.7% to 88.9%). No complete response was achieved. The median progression-free survival was 16 months, however, the median overall survival was not available by the conclusion of the study. The major adverse event was hematologic toxicity. CONCLUSIONS: The regimen of paclitaxel-carboplatin combined with intercalated gefitinib showed a high response rate and a favorable safety profile. Gefitinib maintenance therapy was proven to be beneficial. This study proposes a good pattern of chemotherapy combined with EGFR tyrosine kinase inhibitors. PMID- 26766993 TI - Feasibility of computed tomography-guided core needle biopsy in producing state of-the-art clinical management in Chinese lung cancer. AB - BACKGROUND: A satisfactory biopsy determines the state-of-the-art management of lung cancer in this era of personalized medicine. This study aimed to investigate the suitability and efficacy of computed tomography (CT)-guided core needle biopsy in clinical management. METHODS: A cohort of 353 patients with clinically suspected lung cancer was enrolled in the study. Patient factors and biopsy variables were recorded. Epidermal growth factor receptor (EGFR) gene mutations and echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) rearrangement were detected in tumor specimens. Adequacy of biopsic obtainment for clinical trial screening and tissue bank establishment were reviewed. RESULTS: Overall diagnostic accuracy of malignancy achieved 98.5%. The median biopsy time of the cohort was 20 minutes. In patients with non-small cell lung cancer (NSCLC), 99.3% (287/289) were diagnosed as specific histologic subtypes, and two patients (0.7%) were determined as NSCLC not otherwise specified (NOS). EGFR mutations were analyzed in 81.7% (236/289) of patients with NSCLC, and 98.7% (233/236) showed conclusive results. EML4-ALK gene fusion was tested in 43.9% (127/289) of NSCLC patients, and 98.4% (125/127) showed conclusive results: 6.4% (8/125) of those had gene fusion. Ninety-six NSCLC patients participated in clinical trial screening and provided mandatory tumor slides for molecular profiling. Pathological evaluation was fulfilled in 90 patients (93.8%); 99.4% (320/322) of patients with malignancy provided extra tissue for the establishment of a tumor bank. CONCLUSIONS: CT-guided core needle biopsy provided optimal clinical management in this era of translational medicine. The biopsic modality should be prioritized in selected lung cancer patients. PMID- 26766994 TI - Development and validation of clinical diagnostic models for the probability of malignancy in solitary pulmonary nodules. AB - BACKGROUND: It is critical to develop a non-invasive and accurate method for differentiating between malignant and benign solitary pulmonary nodules. In large sample studies, the effectiveness of the diagnostic prediction model as a tool of assessment of the probability of malignancy is still unclear. The establishment of a diagnostic model based on large samples is needed. METHODS: In this study, 3358 patients diagnosed with a solitary pulmonary nodule between January 2005 and March 2013, were enrolled. All patients received surgery for pulmonary nodule resection. Clinical characters, preoperative biomarker results, and computed tomography scan findings were collected. All patients were randomly separated into a training set (n = 1679) and a test set (n = 1679); we used training sets to build a diagnostic model for the malignancy probability of pulmonary nodules, and applied the test set to validate our model, as well as other published diagnostic models. RESULT: Logistic regression analysis identified 11 clinical characteristics as independent predictors of malignancy in patients with a solitary pulmonary nodule. The goodness-of-fit statistic for the model indicated that the observed proportion of malignancies did not differ from the predicted proportion (P = 0.571). The area under the curves of the receiver operator characteristic curve for our model in the training set was 0.935. CONCLUSION: As the accuracy of the model was high, we suggest that the diagnostic model can be used as a tool to help guiding clinical decisions, when the clinician cannot make a definitive diagnosis of a solitary pulmonary nodule. PMID- 26766995 TI - Docetaxel-based chemotherapy as second-line regimen for advanced thymic carcinoma. AB - Thymic carcinoma is an uncommon neoplasm. The efficacy of second-line treatment with docetaxel in advanced thymic carcinoma has not been well studied. Therefore, we conducted a review of the efficacy of docetaxel-based chemotherapy as a second line regimen for advanced thymic carcinoma. Fifteen patients with advanced thymic carcinoma who received second-line chemotherapy with docetaxel singlet or docetaxel/platinum combination chemotherapy regimens were retrospectively reviewed. There were 11 males and four females, with a median age of 53 years. Squamous cell carcinoma was most common (n = 10), followed by undifferentiated carcinoma (n = 4), and small cell carcinoma (n = 1). Eight patients received docetaxel/platinum combination chemotherapy and seven docetaxel mono-therapy. Four patients showed partial responses, representing a response rate of 26.7%. The median progression-free survival and overall survival in the 15 patients were 4.0 (2.8-5.2) and 22.0 (14.6-29.4) months, respectively. There was no difference in progression-free survival between the docetaxel singlet or docetaxel/platinum combination chemotherapy (3.5 months vs. 4.0 months, P = 0.889). A docetaxel based regimen could be a potential therapeutic option as a second-line chemotherapy for advanced thymic carcinoma. PMID- 26766996 TI - Diagnostic concordance rate between histologic and cytologic specimens of endobronchial ultrasound-guided transbronchial needle aspiration in lung cancer: A single institution experience. AB - BACKGROUND: The aspirates from endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) were examined using the tissue core and cytology. We assessed that the tissue core was a more reliable specimen and attempted to analyze how many discrepancies were found between the two specimens. We investigated diagnostic concordance rate between histology and cytology. METHODS: From January 2011 to December 2011, a total of 267 consecutive patients with lung cancer, who underwent EBUS-TBNA, were included in this retrospective study. RESULTS: Of the 267 lung cancer patients, 207 (77.5%) were men. The median age was 65 years old. The most common pathologic type was adenocarcinoma (120, 44.9%), followed by squamous cell carcinoma (79, 29.6%). Among the 267 patients, 579 mediastinal and hilar lymph nodes were punctured. The right lower paratracheal (204, 35.2%) and subcarinal (172, 29.7%) lymph nodes were the most common nodal stations. Among the 579 lymph nodes, malignant cells were observed in 267 (46.1%) nodes, in either the histologic, cytologic or both slides: 209 in both histology and cytology, 37 in histology only, and 21 in cytology only slides. The diagnostic concordance rate between the tissue core and cytology was 90.0% (95% confidence interval CI, 87.1-92.2) (kappa = 0.79). CONCLUSIONS: The diagnostic concordance rate between the histology and cytology of EBUS-TBNA in lung cancer was 90.0% (95% CI, 87.1-92.2) (kappa = 0.79). PMID- 26766997 TI - Case of invasive mucinous adenocarcinoma mimicking chronic eosinophilic pneumonia. AB - Invasive mucinous carcinoma is difficult to distinguish from other lung diseases; therefore, confirmation of the diagnosis may be delayed. A 64-year-old woman was admitted with a six-month history of cough, febrile sensation, and shortness of breath, with worsening symptoms. A computed tomography scan of the chest revealed bilateral homogenous ground-glass opacities and consolidation with subpleural predominance. The percentage of eosinophils in the serum and induced sputum was elevated and a diagnosis of chronic eosinophilic pneumonia was established. Despite administration of a systemic steroid, she did not rapidly respond. We performed a percutaneous needle biopsy and finally confirmed invasive mucinous adenocarcinoma. PMID- 26766998 TI - Timely diagnosis of pulmonary artery tumor embolism by ultrasound-guided transbronchial needle aspiration. AB - Pulmonary artery tumor embolism (PATE) is a rare disease without an established diagnostic method. In an autopsy series, however, the incidence of PATE was relatively high, between 3% and 26% in patients with a solid tumor. Here we report a case of a patient with a massive PATE from hepatocellular carcinoma diagnosed safely and promptly by endobronchial ultrasound-guided transbronchial needle aspiration. PMID- 26766999 TI - Simultaneous pneumonectomy and esophagectomy in an elderly patient. AB - Reports of simultaneous pneumonectomy and esophagectomy for synchronous lung and esophageal carcinoma are extremely rare. We report on a 64-year-old male patient with lung adenocarcinoma who was originally scheduled to undergo a left pneumonectomy. During the operation, an esophageal squamous cell carcinoma was discovered in the mid-thoracic esophagus. Thus, a simultaneous left pneumonectomy and esophagectomy was performed, and part of the pericardium was sutured to the tunica adventitia of the descending aorta using a "net-making" method for prevention postoperative dilatation of the stomach. PMID- 26767000 TI - Esophagogastric reconstruction using remnant stomach with a single vessel pedicel: Technique and outcomes. AB - Esophageal cancer with a history of distal gastrectomy is a clinical problem. To our knowledge there have been no reports of remnant stomach fed from the left gastroepiploic artery being used in esophageal reconstruction. We, herein, report four cases of esophagogastric reconstruction using remnant stomach with a single left gastroepiploic vascular pedicel. It is more functional to use the remnant stomach than other replacements. Meanwhile, the gastric conduit fed from the left gastroepiploic artery showed sufficient vascularity and stable gastroesophageal anastomosis. The technique and outcomes in follow-up have proven feasible and save time. PMID- 26767001 TI - Demonstration program of population-based lung cancer screening in China: Rationale and study design. AB - BACKGROUND: Lung cancer is the leading cause of cancer-related death and has become an enormous economic burden in China. Low-dose spiral computed tomography (LDCT) screening could reduce lung cancer mortality. The feasibility of conducting a population-based lung cancer screening with LDCT in China is uncertain. METHODS: In 2010, a demonstration program of lung cancer screening was initiated in China. High-risk individuals were enrolled in a cluster sampling design in different centers. Participants received baseline and annual screening with spiral CT and follow-up information was collected. The objective of this program is to evaluate the feasibility of conducting population-based LDCT lung cancer screening in the Chinese context. The rates of detection, early diagnosis and treatment are defined as indicators of program performance. The optimal management strategies for nodules are explored in the Chinese context based on experiences in other studies overseas. RESULTS: A demonstration program of ongoing prospective, multi-center, population-based lung cancer screening is being performed in China. CONCLUSIONS: This demonstration program will provide opportunities to explore the feasibility of LDCT lung cancer screening in the Chinese setting. PMID- 26767002 TI - Prognosis of esophageal squamous cell carcinoma patients with preoperative radiotherapy: Comparison of different cancer staging systems. AB - BACKGROUND: The 7th edition American Joint Committee on Cancer tumor-node metastasis (AJCC TNM) staging system was published in 2010. Here we evaluate its predictive ability and compare the 6th and 7th editions of the AJCC TNM staging systems in esophageal squamous cell cancer (ESCC) with preoperative radiotherapy. METHODS: A total of 296 esophageal squamous cell carcinoma patients receiving preoperative radiotherapy between 1980 and 2007 were included. Patients were staged using the 6th and 7th edition staging systems. Survival analyses were performed using Cox regression models. The homogeneity, discriminatory ability, and monotonicity of gradients of the two staging systems were compared using linear trend chi(2), likelihood ratio statistics, and Akaike information criterion calculation. RESULTS: The overall five-year survival rate for the entire cohort was 27.1%. Female gender, length, "T," and "N," classifications according to the 7th edition staging system were the prognostic factors in univariate analyses. However, tumor histological grade and cancer location did not significantly influence patient survival. The 7th edition staging system has the highest linear trend chi(2)and likelihood ratio chi(2)scores. Compared to the 6th edition, the 7th edition staging system also has a smaller Akaike information criterion value, which represents the optimum prognostic stratification. CONCLUSIONS: The strength of the 7th edition AJCC TNM staging system lies in the new descriptors for "T" and "N" classifications. However, we did not find cancer location to be a significant prognostic factor in our cohort. Overall, the 7th edition AJCC TNM staging system performed better than the previous edition. PMID- 26767003 TI - Identification of mutant genes with high-frequency, high-risk, and high expression in lung adenocarcinoma. AB - BACKGROUND: To identify mutant genes with high-frequency-risk-expression between lung adenocarcinoma and normal samples. METHODS: The ribonucleic acid RNA-Seq data GSE34914 and GSE37765 were downloaded from the Gene Expression Omnibus database, including 12 lung adenocarcinoma samples and six controls. All RNA-Seq reads were processed and the gene-expression level was calculated. Single nucleotide variation (SNV) was analyzed and the locations of mutant sites were recorded. In addition, the frequency and risk-level of mutant genes were calculated. Gene Ontology (GO) functional analysis was performed. The reported cancer genes were searched in tumor suppressor genes, Cancer Genes, and the Catalogue of Somatic Mutations in Cancer (COSMIC) database. RESULTS: The SNV annotations of somatic mutation sites showed that 70% of mutation sites in the exon region occurred in the coding sequence (CDS). Thyroid hormone receptor interactor (TRIP)12 was identified with the highest frequency. A total of 118 mutant genes with high frequency and high-risk were selected and significantly enriched into several GO terms. No base mutation of cyclin C (CCNC) or RAB11A was recorded. At fragments per kilobase per million reads (FPKM) >= 56.5, reported tumor suppressor genes catenin (cadherin-associated protein), delta (CTNND)1, dual specificity phosphatase (DUSP)6, malate dehydrogenase (MDH)1 and RNA binding motif protein (RBM)5, were identified. Notably, signal transducer and activator of transcription 2 (STAT2) was the only transcription factor (TF) with high-risk mutation and its expression was detected. CONCLUSION: For the mutant genes with high-frequency-risk-expression, CTNND1, DUSP6, MDH1 and RBM5 were identified. TRIP12 might be a potential cancer-related gene, and expression of TF STAT2 with high-risk was detected. These mutant gene candidates might promote the development of lung adenocarcinoma and provide new diagnostic potential targets for treatment. PMID- 26767004 TI - Video-assisted thoracoscopic lobectomy with a single utility port is feasible in the treatment of elderly patients with peripheral lung cancer. AB - BACKGROUND: Video-assisted thoracoscopic (VATS) lobectomy with a single utility port has emerged as a new technology in recent years. The aim of this study is to review the technology in the treatment of elderly patients with peripheral lung cancer. METHODS: We retrospectively analyzed the clinical data of 21 elderly patients with peripheral lung cancer who underwent single utility port VATS lobectomy from February 2011 to February 2013 in the First Affiliated Hospital of Soochow University (VATS group). The clinical outcomes and postoperative complications were then compared to data from 32 elderly patients who underwent lobectomy by thoracotomy (TL group). RESULTS: No mortality occurred during the postoperative period in either group. There was no statistical difference in surgery duration, the quantity of lymph node dissection or intraoperative blood loss between the VATS and TL groups. However, significant differences existed in the postoperative hospital stay (6.19 +/- 1.69 days vs. 8.22 +/- 2.55 days), time to first activity out of bed (20.57 +/- 7.72 hours vs. 26.81 +/- 9.27 hours), chest drainage duration (4.24 +/- 1.04 days vs. 5.22 +/- 1.29 days), and total postoperative drainage volume (642.86 +/- 158.18 mL vs. 787.81 +/- 211.55 mL) between the VATS and TL groups (P <0.05). The percentage of patients with no complications in the VATS group (85.71%) is significantly higher when compared with the TL group (56.25%, P <0.05). CONCLUSION: VATS lobectomy with a single utility port is a safe and feasible surgical procedure for selected elderly patients with peripheral lung cancer. PMID- 26767005 TI - Detection of c-kit mutational status in small-cell lung cancer in a Chinese cohort. AB - BACKGROUND: Overexpression of KIT (CD117), a tyrosine kinase receptor, and its natural ligand, stem cell factor, are found in small-cell lung cancer (SCLC). Somatic mutations of the proto-oncogene c-kit constitutively activate KIT expression in a ligand-independent way. To explore the clinical value of the c kit mutation as a potential target for therapy with tyrosine kinase inhibitors, the c-kit mutational status and KIT expression in tumors from Chinese patients with SCLC were analyzed. METHODS: Using 107 paraffin-embedded SCLC tumor specimens, c-kit exons 9, 11, 13, and 17 were analyzed for mutations by polymerase chain reaction and direct sequencing. RESULTS: There were no activating mutations in exons 9, 11, 13, or 17. However, a point mutation in intron 16 (81240 G>A) was found in 11 out of the 107 samples (10.3%), of which the majority were limited-stage SCLC (10/11, 90.9%). Immunohistochemical staining of tumors harboring the c-kit point mutation using the anti-CD117 antibody showed that the mutation status was not associated with the expression of KIT. CONCLUSION: These findings indicate that the incidence and the types of c-kit mutations in SCLC tumors found in Chinese are different from those of the Caucasian population. Nevertheless, c-kit mutations are similarly rare in both groups, implying that they may not be suitable targets for c-kit-based tyrosine kinase inhibitors. PMID- 26767007 TI - Efficacy of Icotinib treatment in patients with stage IIIb/IV non-small cell lung cancer. AB - BACKGROUND: To evaluate the efficacy and safety of Icotinib - an orally administered, highly potent selective inhibitor of epidermal growth factor receptor (EGFR) and its active mutations, in the treatment of patients with advanced non-small cell lung cancer (NSCLC). METHODS: A total of 101 patients with stage IIIb/IV NSCLC were treated with 125 mg Icotinib three times a day until disease progression or intolerable toxicity. Response rate was evaluated using response evaluation criteria in solid tumors and progression-free survival (PFS) was collected. RESULTS: The overall response rate (ORR) and disease control rate (DCR) were 37.6% (38/101) and 79.2% (80/101), respectively. The median PFS was 6.5 months. Multivariate analysis showed that female gender (P= 0.048, 95% confidence interval [CI] 1.010-6.016) and occurrence of rash (P= 0.002, 95% CI 1.667-9.809) were the independent predictive factors for ORR, while a performance status (PS) score of 0-1 (P= 0.001, 95% CI 0.024-0.402) and rash (P= 0.042, 95% CI 1.089-76.557) were the independent predictive factors for DCR. In addition, PS scores of 0-1 (P <0.001, 95% CI 0.135-0.509), and non-smoking (P= 0.017, 95% CI 0.342-0.900) were found to be independent influencing factors for PFS. Moreover, patients with EGFR mutations had better PFS than patients with wild type EGFR, while patients with EGFR exon 19 deletion had better survival than those with EGFR exon 21 mutation. The most common adverse effects of Icotinib were rash (35.6%) and diarrhea (17.8%), which was tolerable. CONCLUSION: Treatment of stage IIIb/IV NSCLC patients with Icotinib was effective and tolerable, specifically in patients with EGFR mutation. PMID- 26767006 TI - Polymorphisms in DNA repair genes of XRCC1, XPA, XPC, XPD and associations with lung cancer risk in Chinese people. AB - BACKGROUND: The carcinogenic chemicals and reactive oxygen species in tobacco can result in DNA damage. DNA repair genes play an important role in maintaining genome integrity. Genetic polymorphisms of DNA repair genes and smoking may contribute to susceptibility of lung cancer. METHODS: In this hospital-based case control study, we investigated the relationship between 13 tagging single nucleotide polymorphisms (SNPs) in base excision repair pathway and nucleotide excision repair pathway genes, smoking, and lung cancer susceptibility. Thirteen tag SNPs were genotyped in 265 lung cancer patients and 301 healthy controls. Logistic regression and multifactor dimensionality reduction method were applied to explore the association and high-order gene-gene and gene-smoking interaction. RESULTS: In single tag SNP analysis, XPA rs2808668, XPC rs2733533, and XPD rs1799787 were significantly associated with lung cancer susceptibility. Joint effects analysis of XPA rs2808668, XPC rs2733533 and XPD rs1799787 showed that there was an increased risk of lung cancer with increasing numbers of risk alleles. Haplotype analysis showed that XRCC1 (rs25487, rs1799782, rs3213334) GCC had a positive association with lung cancer. Analysis of gene-gene and gene smoking interaction by multifactor dimensionality reduction showed that a positive interaction existed between the four genes and smoking. The two-factor model, including XPC rs2755333 and smoking, had the best prediction ability for lung cancer. Compared with the C/C genotype of XPC rs2733533 and no smoking, the combination of genotype A carriers with XPC rs2733533 and heavy smokers (>=30 pack-year) had a 13.32-fold risk of lung cancer. CONCLUSION: Our results suggest multiple genetic variants in multiple DNA repair genes may jointly contribute to lung cancer risk through gene-gene and gene-smoking interactions. PMID- 26767008 TI - Surgical treatment for pulmonary pleomorphic carcinoma: A retrospective study of 60 patients. AB - BACKGROUND: Pleomorphic carcinoma is a rare epithelial malignant tumor. Because the clinical characteristics and behavior of the disease remain unclear, we investigated the clinicopathological findings and prognosis of 60 patients with pleomorphic carcinoma. METHODS: The clinicopathological characteristics of 60 cases of pulmonary pleomorphic carcinoma identified between 1999 and 2011 were studied. Of these, 55 patients had peripheral disease and five had central disease. The tumor size in all patients was 1-9.5 cm (mean, 5.8 +/- 4.5 cm), while 30 had lesions with a diameter larger than 5 cm. All patients underwent pulmonary resection. RESULTS: There were no in-hospital deaths. The three and five year survival rates of all patients were 47.2% and 25.6%, respectively. The three and five year survival rates were 57.3% and 32.5% for N0 patients, and 25.4% and 17.1% for N1-2 patients, respectively. Overall survival was significantly different between the radical resection and incomplete resection groups. Multivariate Cox regression analyses of overall survival for all 60 patients indicated that radical resection (P= 0.041), tumor node metastasis (TNM) stage (P= 0.044), and nodal status (P= 0.029) were significant independent prognostic factors. CONCLUSION: Pleomorphic carcinoma is a rare type of lung cancer. In our study, pleomorphic carcinoma of the lung was often found as a peripherally located large mass and was associated with a poor prognosis. Radical resection, TNM stage and nodal status were significant independent prognostic factors. PMID- 26767009 TI - Analysis of clinicopathological features of the echinoderm microtubule-associated protein-like-4-anaplastic lymphoma kinase fusion gene in Chinese patients with advanced non-small-cell lung cancer. AB - BACKGROUND: The echinoderm microtubule-associated protein-like-4-anaplastic lymphoma kinase (EML4-ALK) fusion gene defines a novel molecular subset of non small-cell lung cancer (NSCLC). However, the clinicopathological features of patients with the EML4-ALK fusion gene have not been defined completely. METHODS: Clinicopathological data of 200 Chinese patients with advanced NSCLC were analyzed retrospectively to explore their possible correlations with EML4-ALK fusions. RESULTS: The EML4-ALK fusion gene was detected in 56 (28.0%) of the 200 NSCLC patients, and undetected in 22 (11.0%) patients because of an insufficient amount of pathological tissue. The median age of the patients with positive and negative EML4-ALK was 48 and 55 years, respectively. Patients with the EML4-ALK fusion gene were significantly younger (P< 0.001). The detection rate of the EML4 ALK fusion gene in patients who received primary tumor or metastatic lymph node resection was significantly higher than in patients who received fine-needle biopsy (P= 0.003). The detection rate of the EML4-ALK fusion gene in patients with a time lag from obtainment of the pathological tissue to EML4-ALK fusion gene detection <=48 months was significantly higher than in patients >48 months (P= 0.020). The occurrence of the EML4-ALK fusion gene in patients with wild-type epidermal growth factor receptor (EGFR) was significantly higher than in patients with mutant-type EGFR (42.5% [37/87] vs. 6.3% [1/16], P= 0.005). CONCLUSIONS: Younger age and wild-type EGFR were identified as clinicopathological characteristics of patients with advanced NSCLC who harbored the EML4-ALK fusion gene. The optimal time lag from the obtainment of the pathological tissue to the time of EML4-ALK fusion gene detection is <=48 months. PMID- 26767010 TI - Giant solitary fibrous tumor of the lung: A case report. AB - A solitary fibrous tumor arising from the lung parenchyma is rarely described. Here, we present the clinical, imaging, and histological features of a case of a 54-year-old woman with an incidental lung mass of the right lower lobe on a chest radiograph. PMID- 26767012 TI - Pulmonary inflammatory myofibroblastic tumor mimics lung cancer. PMID- 26767011 TI - Primary mediastinal pleomorphic liposarcoma involving the superior vena cava. AB - Primary mediastinal liposarcomas are extremely rare. They are primarily diseases of adults; however, they may be encountered in children. They are characterized by their large size and variable histologic subtypes, which correlate with clinical behavior and prognosis. Although the overall prognosis is poor, it is dependent upon the histologic subtype and completeness of surgical excision. Herein we present a case of a primary mediastinal pleomorphic liposarcoma in a 49 year-old male who received an en-bloc resection and superior vena cava replacement with Gortex graft. The patient has been disease-free after surgery for over 14 months. PMID- 26767013 TI - Expression and significance of squalene epoxidase in squamous lung cancerous tissues and pericarcinoma tissues. AB - BACKGROUND: A high expression of squalene epoxidase (SQLE) is related to tumor occurrence, development, and prognosis in a variety of cancers. In this study, the expression and significance of SQLE was analyzed in patients with squamous lung cancer and pericarcinoma tissues. METHODS: The SQLE mRNA and protein expression were separately examined by semi-quantitative reverse transcription polymerase chain reaction, fluorescence quantitative polymerase chain reaction and Western blot in 65 cases of squamous cell lung carcinoma tissues and adjacent non-cancerous lung tissues. RESULTS: The expression of SQLE mRNA and protein in lung squamous cancerous tissues was significantly higher than in pericarcinoma tissues (63.07% vs. 44.61%, P = 0.0348; 67.69% vs. 38.46%, P = 0.0008). The positive expression rate of SQLE mRNA was not associated with gender, age, smoking, or tumor size (P > 0.05). The expression of SQLE mRNA was closely correlated with poor differentiation, clinical stages, and lymphatic metastasis (P < 0.05). The expression of SQLE mRNA was negatively associated with overall survival rate (P < 0.05). CONCLUSION: A high expression of SQLE was found in squamous lung cancer tissues. The high expression of the SQLE gene may be closely related to the occurrence and development of squamous cell lung carcinoma. SQLE expression predicts a poor prognosis and may serve as a novel lung carcinoma molecule marker. PMID- 26767014 TI - Three-dimensional conformal reirradiation for locoregionally recurrent lung cancer previously treated with radiation therapy. AB - BACKGROUND: To evaluate the efficacy and toxicity of reirradiation using three dimensional conformal radiotherapy (3D-CRT) in symptomatic patients with locoregionally recurrent lung cancer. METHODS: Between 2005 and 2012, 15 patients with locoregionally recurrent lung cancer were retreated with 3D-CRT after previously receiving thoracic radiotherapy. The median interval between the initial irradiation and reirradiation was 12 months (range, five to 41 months). The median initial radiotherapy dose was 63 Gy (range, 45-70 Gy), and reirradiation doses ranged from 25.2 to 45.2 Gy (median, 36 Gy), with daily fractions of 1.8-4 Gy (median, 2 Gy). RESULTS: After reirradiation, 80% of the patients experienced resolved or diminished symptoms for one or more of their symptoms, with an 83% improvement in a total of 24 symptoms. The overall tumor response rate to reirradiation was 46.7%, with progressive disease occurring in only one patient. The median overall survival (OS) time was 11 months (range, one to 27 months), and the one-year OS rate was 47%. The progression-free survival time ranged from one to 10 months (median, five months). In univariate analysis, the use of combined chemotherapy and a higher reirradiation dose showed a trend toward improved survival after reirradiation. Treatment-induced toxicity included grade 2 radiation pneumonitis in only one patient, and there were no other complications, such as radiation esophagitis or myelopathy. CONCLUSIONS: Reirradiation using 3D-CRT with moderate doses for locoregionally recurrent lung cancer can provide palliative benefits without severe complications to the majority of selected patients with symptoms as a result of a regrowing tumor. PMID- 26767015 TI - Prospective phase II study of cisplatin plus pemetrexed with maintenance of pemetrexed for advanced non-squamous cell non-small cell lung cancer in Japan. AB - BACKGROUND: A previous study showed a survival benefit with maintenance therapy with pemetrexed in patients with advanced non-small cell lung cancer (NSCLC). However, it remains unclear whether continuation maintenance therapy with pemetrexed is beneficial in Japanese patients. Here, we present our phase II study that assessed the efficacy and safety of cisplatin plus pemetrexed as induction chemotherapy, followed by maintenance therapy with pemetrexed in advanced NSCLC patients in Japan. METHODS: Chemotherapy-naive patients received 500 mg/m(2) pemetrexed and 75 mg/m(2) cisplatin on day one every three weeks for four cycles. In patients who responded to therapy or achieved stable disease, pemetrexed was continued until disease progression. The primary endpoint of this study was the progression-free survival rate at six months (PFS-6). RESULTS: Of the 35 patients initially enrolled in the study, 18 (51%) received maintenance chemotherapy with pemetrexed. The median PFS was 6.7 months, and the PFS-6 was 60% (95% confidence interval [CI], 42-76%). Median overall survival (OS) was 15.5 months (95% CI, 8.3-22.7 months). The median PFS and OS in patients who received maintenance chemotherapy with pemetrexed were 9.5 months and 25.3 months, respectively. The most frequently noted severe toxicity during induction chemotherapy was neutropenia, which occurred in seven patients. Two patients discontinued maintenance therapy owing to prolonged grade 2 edema in one patient and grade 3 neutropenia in another. CONCLUSION: Continuation maintenance chemotherapy with pemetrexed is associated with a survival benefit in patients who have completed induction chemotherapy for non-squamous NSCLC. PMID- 26767016 TI - Positron emission tomography-computed tomography on predicting the efficacy of targeted therapy for lung adenocarcinoma. AB - BACKGROUND: In this study, positron emission tomography-computed tomography (PET CT) was used to monitor the maximal standard uptake value (SUVmax) in advanced lung adenocarcinoma patients with epithermal growth factor receptor (EGFR) mutation to prove its role in predicting the prognosis of targeted therapy. METHODS: A total of 46 patients with advanced lung adenocarcinoma (IIIb-IV stage) were enrolled in the current study. They were positive for EGFR mutation. All patients received gefitinib (250 mg per day, administered orally). PET-CT was conducted prior to (at baseline) and six months after gefitinib administration for the lesion size and SUVmax. The recommendations of the European Organization for Research and Treatment of Cancer criteria were chosen for PET assessment. Metabolic response (SUV decline < -25%) was compared with morphologic response evaluated by CT scan and overall survival. RESULT: Compared to patients with ?SUV% >= 25% (progressive metabolic disease), the survival time was significantly prolonged in ?SUV% < -25% (including complete metabolic response and progressive metabolic disease) (10.6/18.4, P = 0.000), but was not in -25% <= ?SUV% < 25% (stable metabolic disease) (10.6/10.7, P = 0.088). Patients who achieved ?SUV% < 25% after treatment were associated with a longer median survival, higher control rate, and better prognosis. There was a strong correlation between SUV changes (?SUV%) and CT size change (?lesion size%) (R(2) = 0.891, P = 0.000). CONCLUSION: Changes in the SUV could be used to predict the prognosis of targeted therapy in advanced lung adenocarcinoma. PMID- 26767017 TI - beta-elemene reverses the drug resistance of A549/DDP lung cancer cells by activating intracellular redox system, decreasing mitochondrial membrane potential and P-glycoprotein expression, and inducing apoptosis. AB - BACKGROUND: beta-elemene (beta-ELE) injection is a new anticancer drug extracted from Curcuma zedoaria Roscoe that has been widely used to treat malignant tumors. Recent studies show that beta-ELE reverses the drug resistance of tumor cells. To explore the possible mechanisms of beta-ELE, we investigated its effects on cisplatin (DDP)-resistant human lung adenocarcinoma A549/DDP cells. METHODS: The effects of beta-ELE on the growth of A549/DDP cells in vitro were determined by MTT assay. Apoptosis was assessed by fluorescence microscopy with Hoechst 33258 staining, flow cytometry with Annexin V-FITC/propium iodide double staining; mitochondrial membrane potential using JC-1 fluorescence probe and laser confocal scanning microscopy, and intracellular reactive oxygen species levels were measured by 2',7'-dichlorfluorescein-diacetate staining and flow cytometry; and contents of cytosolic glutathione were determined by glutathione assay kits. Intracellular Rhodamine-123 fluorescence intensity was detected by flow cytometry, and the expression of P-glycoprotein (P-gp) was detected by Western blotting. RESULTS: beta-ELE inhibited the proliferation of A549/DDP cells in a time- and dose-dependent manner. Furthermore, beta-ELE enhanced the sensitivity of A549/DDP cells to cisplatin and reversed the drug resistance of A549/DDP cells. Consistent with a role in activating apoptosis, beta-ELE decreased mitochondrial membrane potential, increased intracellular reactive oxygen species concentration and intracellular accumulation of Rhodamine-123, decreased the cytoplasmic glutathione levels and the expression of P-gp in a time- and dose dependent manner. CONCLUSIONS: These results define a pathway of beta-ELE function that involves decreased mitochondrial membrane potential and P-gp expression activated intracellular redox system, and induced apoptosis leading to reverse drug resistance. PMID- 26767018 TI - Vascular endothelial growth factor C is an indicator of lymph node metastasis in thoracic esophageal squamous cellcarcinomas and its role in long-term survival after surgery. AB - BACKGROUND: To define the role of vascular endothelial growth factor C (VEGF-C) on lymph node (LN) metastasis of human esophageal squamous cell carcinoma (ESCC), and to investigate its impact on overall survival. METHODS: Real-time polymerase chain reaction was introduced to quantify the expression of VEGF-CmRNA. One hundred and eight samples (59 tumor tissue and 59 paired normal tissue) were analyzed. RESULTS: VEGF-CmRNA expression was significantly higher in tumor tissues than in normal mucosa (P = 0.02). VEGF-CmRNA expression was significantly higher in LN (+) patients than in LN (-) patients (P = 0.04). VEGF-CmRNA expression was related to a positive LN number (P = 0.06) and a positive LN station number (P = 0.04). VEGF-CmRNA expression was significantly higher in stage III and IV patients than in stage I and II patients (P = 0.03). A logistic regression model showed that VEGF-CmRNA and T status were independent risk factors for LN metastasis(P < 0.05). In univariate analysis, survival tended to be poorer in the VEGF-CmRNA high expression group (22.0 months vs. 44.0 months, P = 0.08). A Cox regression model revealed that a positive LN station number was the only independent risk factor for overall survival (P < 0.01). CONCLUSION: VEGF-C was a useful indicator for LN metastasis in human ESCC, and it might have some influence on long-term survival by affecting LN metastasis. PMID- 26767019 TI - Prognostic factors for patients with advanced non-small cell lung cancer treated with gemcitabine-platinum as first-line therapy in an observational setting in China. AB - BACKGROUND: This study examined the prognostic factors associated with survival in advanced non-small cell lung cancer (NSCLC) patients receiving gemcitabine platinum regimens as first-line therapy in real-world clinical settings in China. METHODS: Data was analyzed from a multinational, prospective, non-interventional, observational study of individuals receiving gemcitabine-platinum regimens as first-line therapy for NSCLC, focusing on 300 patients from mainland China. A Cox regression model was used to determine the association of 38 prognostic factors, including patient smoking characteristics, with overall survival. RESULTS: In these 300 patients, the mean age was 58.9 (+/-10.8) years, with males comprising 71% of the population. Thirty percent of patients had an Eastern Cooperative Oncology Group performance status (PS) of 0 and 70% had a PS of 1. The majority of patients had NSCLC of adenocarcinoma origin (57%). Multivariate Cox regression analyses adjusted for baseline factors revealed that gender, tumor (T) staging, metastasis (M) staging, liver metastases, serum albumin, and superior vena cava obstruction were significant prognostic factors. Smoking during therapy was not significantly associated with survival, although numbers were small for this variable (n = 16). Weight loss of >10% was a significant prognostic factor for adverse events. CONCLUSIONS: Gender, T staging, M staging, liver metastases, superior vena cava obstruction, and serum albumin are prognostic factors affecting overall survival in mainland Chinese patients receiving first-line gemcitabine-platinum regimens for advanced NSCLC. These negative prognostic factors may warrant further investigation in clinical trials. PMID- 26767020 TI - Experience with the "da Vinci" robotic system for early-stage thymomas: Report of 23 cases. AB - BACKGROUND: The aim of this study was to report a single referral center experience in robotic extended thymectomy for clinical early stage thymomas, evaluating its safety, feasibility and efficacy, with special regard to oncological outcomes. METHODS: Between January 2009 and December 2012, we retrospectively selected patients who underwent robotic extended thymectomy for clinical early stage thymomas. Operative time, morbidity, mortality, duration of hospitalization, and overall and disease-free survival were analyzed. RESULTS: There were 23 patients (15 males, eight females) with a mean age of 49.3 years (range 20-66). There were no intra-operative complications, and no mortality. The mean operative time was 85.2 minutes (range 60-180). No patient underwent conversion to open surgery. All post-operative complications (4.3%) were conservatively treated. The mean post-operative stay was 3.6 days (range two to nine). The pathological analysis revealed Masaoka stage I (21 cases) and II (two cases). No disease recurrence occurred at a mean follow-up of 24.8 months. CONCLUSIONS: Robotic thymectomy is a safe and feasible technique, with a short operative time and low morbidity. Even on a small series with short follow-up, robotic extended thymectomy for thymoma appeared to be an effective treatment for early-stage thymomas. PMID- 26767021 TI - Response to first-line chemotherapy of docetaxel combined with platinum predicting the prognosis and subsequent treatment of patients with non-small cell lung cancer. AB - BACKGROUND: The aim of this study was to confirm the association between the response to docetaxel combined with platinum as first-line chemotherapy and prognosis and subsequent treatment for patients with non-small cell lung cancer (NSCLC). METHODS: This study enrolled 224 patients with NSCLC diagnosed at our institution between January 2001 and August 2012. All patients received more than two cycles of docetaxel combined with platinum as first-line chemotherapy and were reassessed after two cycles. The association between the response to first line treatment and prognosis and subsequent treatment were statistically analyzed. RESULTS: Among the 224 patients, 70 (31.25%) achieved partial response (PR), 90 (40.18%) stable disease (SD), and 64 (28.57%) progressive disease (PD). The overall survival (OS) of NSCLC patients with PR, SD and PR+SD was significantly longer than those with PD (P = 0.043; P = 0.000; P = 0.001). However, no significant difference was observed in OS between patients with PR and SD (P = 0.174). Cox regression analysis found treatment response was an independent prognostic factor (hazard ratio = 1.615, 95% confidence interval: 1.121-2.327). Two independent non-parametric sample tests showed that patients with a good response to first-line treatment had received further treatment cycles and treatment lines (P = 0.000; P = 0.000). CONCLUSIONS: Our study demonstrated that the response to docetaxel in combination with platinum as a first-line chemotherapy was an independent prognostic factor for patients with NSCLC. In addition, patients with a good response to first-line treatment had received further treatment cycles and treatment lines. PMID- 26767022 TI - Esophageal cancer incidence and mortality in China, 2010. AB - BACKGROUND: The National Central Cancer Registry of China (NCCR) is responsible for cancer surveillance. Local cancer registries in each province submit data for annual publication.. The incidence and mortality of esophageal cancer in China in 2010 by age, gender, and area is reported in this article. METHODS: There were data from 145 out of 219 qualified cancer registries. Esophageal cancer cases and deaths (ICD 10 code as C15) were stratified by location, gender, age, and cancer site. The 2000 Chinese census and Segi's population were used for age standardized incidence/mortality rates. The rank in all cancer types and cumulative rate were also calculated. RESULTS: It was estimated that 287 632 new cases were diagnosed and 208 473 patients died from esophageal cancer in 2010 in China. Esophageal cancer incidence ranked fifth of all cancer types with a rate of 21.88/100 000. Age-standardized rates by Chinese population (CASR) and World population (WASR) for incidence and mortality were 16.71/100 000 and 16.97/100 000, respectively. The mortality of esophageal cancer ranked fourth in all cancer types with a rate of 15.85/100 000. The CASR and WASR for mortality were 11.95/100 000 and 12.02/100 000, respectively. For both incidence and mortality, the rates of esophageal cancer were much higher in men than that in women, in rural areas than in urban areas, and peaked at age 80-84. CONCLUSIONS: Esophageal cancer is still a major cancer type in rural areas of China. Effective prevention and control should be emphasized, including health education, chemoprevention, and early detection in high-risk groups. PMID- 26767024 TI - Numerous osteoclast-like giant cells in metastases from lung adenocarcinoma, but absent from primary tumor. AB - We report a rare case of lung adenocarcinoma in a 54-year-old man, in whom osteoclast-like giant cells (OCGCs) were found only in metastases. Autopsy revealed that metastases involving the tongue, gallbladder, stomach, intestines, right adrenal gland, and bones contained numerous OCGCs. Some metastases to the lungs and liver also contained OCGCs, but the primary tumor and metastases to the right atrium, spleen, left adrenal gland, and lymph nodes did not. Primary lung carcinoma cells were positive for cytokeratin 7 (CK7), epithelial membrane antigen (EMA), thyroid transcription factor 1 (TTF-1), and Napsin A, but were negative for vimentin and CD68. Frequently poorly cohesive metastatic carcinoma cells admixtured with OCGCs showed weak CK7/EMA positivity, no TTF-1/Napsin A staining, and newly expressed vimentin. OCGCs were positive only for CD68 and vimentin, implying reactive cells. OCGCs can develop only in metastatic lesions, possibly associated with their anaplastic changes or epithelial mesenchymal transition. PMID- 26767023 TI - Long-term survival for 93 months of limited-stage small cell lung cancer: A case report and literature review. AB - A 49-year-old man was diagnosed with small cell lung cancer in May 2005. Chemotherapy was started with 60 mg/day cisplatin iv drip (from days one to three), 2 mg topotecan (TP) hydrochloride iv drip (from days one to four), and traditional Chinese medicine (TCM) AiDi injection for anti-tumor. After four cycles, he underwent conformal radiotherapy with 56Gy/28 fractions in October 2005. In April 2006, a mass on the right supraclavicular area was found. Therefore, he underwent another course of radiotherapy. The fields included the right supraclavicular area and the radiation dose was 50Gy/25 fractions. After completion of chemoradiotherapy, the patient achieved complete remission. Subsequently, the patient received prophylactic cranial irradiation (PCI). Until April of 2012, he had been followed up regularly. Since the SCLC diagnosis, he had received TCM for seven years. In April 2012, the patient complained of coughing again. Subsequently, the patient was given five cycles of an etoposide carboplatin regimen. A computed tomography (CT) scan was performed for review, which showed no obvious change. The patient underwent a second-line chemotherapy irinotecan cisplatin three times. However, the symptoms and CT of this patient showed no significant improvement. We changed the chemotherapy regimen to TP (topotecan 1.2 mg iv drip, days one to five; carboplatin 100 mg iv drip, days one to five). After two TP regimens, the patient died in his sleep on 3 March 2013. In this case, the standardized sequential chemotherapy and radiotherapy treatment, PCI, TCM, and good compliance may have contributed to the patient's longer survival. PMID- 26767025 TI - Favorable response to icotinib in a lung cancer patient with a special mutation at exon 19 of epidermal growth factor receptor. AB - Many studies have illustrated that two types of mutation - deletions in exon 19 and a point mutation in exon 21 (L858R) - have been reported to comprise up to 90% of all activating epidermal growth factor receptor (EGFR) mutations. A point mutation at exon 19 is a rare mutation, and to date there have been no reports investigating the sensitivities of EGFR-tyrosine kinase inhibitors (TKIs) to the mutation. In this case report, we have demonstrated a special mutation, a point mutation at c.2279T>C (p.L760P) in exon 19 of EGFR, which has responded favorably to icotinib in a lung adenocarcinoma patient with brain metastasis. Icotinib is a new type of oral EGFR-TKI developed in China and is the first EGFR-TKI in Asia. Icotinib has the potential to improve the prognosis of lung adenocarcinoma patients and with less toxic-effect. PMID- 26767026 TI - Mucosa-associated lymphoid tissue lymphoma presenting as ground glass nodule. AB - Pulmonary mucosa-associated lymphoid tissue (MALT) lymphoma rarely occurs. It is difficult to distinguish MALT lymphomas and pre-invasive lesions according to radiological findings. We report a case of 60-year-old woman who was found to have a rapidly growing ground glass nodule (GGN) on her left lower lobe, discovered on follow-up chest computed tomography. The radiological image was pure GGN, which was compatible with a pre-invasive lesion, such as non-mucinous adenocarcinoma in situ. Wedge resection was performed and the final diagnosis was stage I MALT lymphoma. After surgery, she was doing well with no evidence of recurrence one year later. We believe a lung biopsy for rapidly growing GGN is recommended in order to confirm the pathological diagnosis. PMID- 26767027 TI - Tumor response and clinical toxicity associated with second-line chemotherapy regimens for advanced non-squamous non-small cell lung cancer: A retrospective cohort study. AB - BACKGROUND: Previously reported superior tumor response of pemetrexed in the second-line setting for advanced non-squamous non-small cell lung cancer (advNS NSCLC) has never been confirmed in real-world studies. Platinum-based doublet is frequently used in the second-line setting for advanced NSCLC in China. METHODS: A retrospective cohort study was conducted including patients receiving pemetrexed or docetaxel-based chemotherapy in the second-line setting for advNS NSCLC in four Chinese tertiary care hospitals. Propensity score matched treatment groups were created for head-to-head comparisons on best tumor response and clinical toxicity. Multiple regression analyses were performed to rank the impact of the four regimens on the risks of tumor progression and hematological adverse events. RESULTS: Three hundred and eighty-four patients were included for creating matched treatment groups for pemetrexed versus platinum/pemetrexed (33 pairs), docetaxel (17 pairs), and platinum/docetaxel (29 pairs), respectively. No significant differences were identified for best tumor response between pemetrexed and the other three regimens. However, pemetrexed was associated with significantly fewer patients experiencing anemia (39.4% vs. 69.7%, P = 0.004) and neutropenia (6.1% vs. 30.3%, P = 0.021) than platinum/pemetrexed. Multiple regression analyses indicated that pemetrexed was associated with significantly slower tumor progression (hazard ratio 0.628, P = 0.040) and a significantly lower risk of neutropenia (odds ratio 0.132, P = 0.019) than docetaxel. CONCLUSIONS: Pemetrexed was associated with significantly postponed tumor progression and significantly less hematological toxicity than docetaxel in the real-world second-line setting for advNS-NSCLC in Chinese patients. Pemetrexed monotherapy had comparable tumor response, but significantly less hematological toxicity than pemetrexed-based doublet. PMID- 26767028 TI - Diagnosis and surgical treatment of esophageal carcinoma with coexistent intrathoracic vascular malformations. AB - BACKGROUND: The anomaly of intrathoracic large vessels might not only compress the esophagus resulting in dysphagia, but also hinder esophagectomy, even leading to uncontrolled massive hemorrhaging. This paper reviews our experience of seven patients with this diagnosis and their treatment. METHODS: From January 2007 through January 2012, among patients admitted with esophageal carcinoma, there were seven patients confirmed to have coexisted intrathoracic vascular anomalies. They were six men and one woman, aged 52 to 63 (mean 58.42). The vascular anomalies included aberrant right subclavian artery (ARSA) in three cases, post aortic left innominate vein (PALIV) in two cases, and one case each of right aortic arch (RAA) and pseudoaneurysm of aortic isthmus (PAAI). Their diagnosis, surgical strategy, and outcome were reviewed. RESULTS: The vascular anomalies were missed by esophagography and endoscopy, but all identified by enhanced chest computed tomography (CT). Surgery was planned according to the anatomic features of the anomalies. ARSA did not need special management. RAA underwent left thoracotomy in order to dissect the aortopulmonary arterial ligament and to facilitate the mobilization of the esophagus. PAAI had preoperative aortic stenting to prevent unexpected aortic rupture. Prophylactic ligation of thoracic duct was performed on all patients and no postoperative chylothorax was documented. CONCLUSIONS: The coexistence of intrathoracic vascular malformations with esophageal carcinoma is rare, but easily missed in routine X-ray and endoscopy. Enhanced chest CT must be performed to confirm. Surgery should be designed individually in consideration of the anatomic features of the vascular anomalies. A routine prophylactic ligation of the thoracic duct is recommended. PMID- 26767029 TI - Decreased maspin combined with elevated vascular endothelial growth factor C is associated with poor prognosis in non-small cell lung cancer. AB - BACKGROUND: This study aimed to investigate the clinical significance of the combination of maspin and vascular endothelial growth factor (VEGF)-C expression in the prognosis of non-small cell lung cancer (NSCLC). METHODS: Immunohistochemistry was performed to assay the expression of maspin and VEGF-C in primary tumor tissues, metastatic, and non-metastatic lymph nodes in 98 NSCLC patients. Survival analysis was determined by Kaplan-Meier curves. RESULTS: The positive expression rate of maspin was 26.5% (26/98) in NSCLC primary tumor tissues, significantly associated with histological type (P = 0.005) and the absence of nodal metastasis (P < 0.001). The expression of maspin in primary tumor tissues was stronger than metastatic lymph nodes of the N1 group (P = 0.048), while the metastatic lymph nodes of the N1 group had a stronger maspin expression than the N2 group (P = 0.008). In survival analysis, a positive expression of maspin of the N1 lymph node was also found to be an independent positive prognostic factor in overall survival (P = 0.003). We also found that decreased maspin combined with elevated VEGF-C is associated with a poor prognosis for disease-free survival (P = 0.019). CONCLUSION: Our results suggest that positive expression of maspin might significantly inhibit nodal metastasis in NSCLC. Decreased maspin combined with elevated VEGF-C might be associated with a poor prognosis in NSCLC. PMID- 26767030 TI - Chyle leakage patterns and management after oncologic esophagectomy: A retrospective cohort study. AB - BACKGROUND: This study aims to evaluate the incidence and characteristics of chyle leakage after curative oncologic esophagectomy, and the effectiveness of thoracic duct ligation. METHODS: This is a retrospective cohort study using the medical records of 1514 patients who underwent curative esophagectomy for esophageal cancer between September 1994 and December 2010. Patients whose pleural fluid analysis corresponded to chyle were included, and drainage patterns by different management groups were examined with multilevel models. The chyle leakage patterns during the time before and after duct ligation were also evaluated, adjusting for demographics, clinical characteristics, and treatment. RESULTS: The prevalence of chyle leakage after esophagectomy was 3.8%. The three management groups were as follows: (i) conservative-controlled only with conservative management; (ii) surgical I-duct ligation during the esophagectomy; and (iii) surgical II-duct ligation after the esophagectomy. Pattern analysis determined that drainage of the conservative group was ~400 mL/day (maximum on postoperative days [POD] = 9.2); drainage of surgical II was ~1000 mL/day (maximum on POD = 18.1). On average, thoracic duct ligation was performed 18.7 days after the esophagectomy, and drainage significantly decreased after duct ligation (P-value <0.001). CONCLUSIONS: There was a clear pattern of lower chyle leakage with the patients requiring conservative management compared with those requiring surgical management. Active and prompt surgical management needs to be considered in the early postoperative phase for patients with high-output (over 1000 mL/day) chyle leakage after esophagectomy. PMID- 26767031 TI - Retrospective study of surgery versus non-surgical management in limited-disease small cell lung cancer. AB - BACKGROUND: The role of surgery in limited small cell lung cancer (SCLC) is still controversial. To assess the role of surgery in SCLC we performed a retrospective analysis of survival in a group of limited stage patients, who were managed with trimodal therapy including surgery, or with chemotherapy and radiotherapy. METHODS: We performed a retrospective survival analysis in a series of 153 limited stage SCLC patients treated between 1995 and 2013. Kaplan-Meier survival analysis and Cox regression analysis were used to calculate the overall survival of the surgical and non-surgical groups. RESULTS: Median survival in all patients was 21.5 months. Median survival for surgical and non-surgical patients was 30.5 months and 16.9 months, respectively. The survival curves for the two arms are significantly different (P < 0.01). In multivariate analysis, the benefit of surgical treatment and thoracic radiotherapy varied in a time-dependent fashion. CONCLUSIONS: Our results suggest that surgery added to chemotherapy and radiotherapy may be associated with a therapeutic benefit in limited SCLC. PMID- 26767032 TI - Echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase rearrangement and epidermal growth factor receptor mutation coexisting in Chinese patients with lung adenocarcinoma. AB - BACKGROUND: The echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) rearrangement is almost in mutual exclusion to epidermal growth factor receptor (EGFR) and v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations, with rare exceptions. This study aimed to search for the coexisting gene alterations in Chinese patients with lung adenocarcinoma (LAC). METHODS: We detected mutations in the EGFR, KRAS, and ALK gene rearrangements in samples from 131 Chinese patients with LAC. ALK rearrangements were identified by fluorescent in situ hybridization. Mutations in EGFR (exons 19 to 21) and KRAS (codons 12 and 13) were determined by real time polymerase chain reaction. RESULTS: All patients were classified into four distinct genotype groups: EGFR mutations (n = 63; 48.1%), ALK rearrangements (n = 9; 6.9%), KRAS mutations (n = 8; 6.1%), and the wild-type (unmutated) genotype of all three genes (WT/WT/WT) (n = 53; 40.5%). Interestingly, two never-smoking women (2/131, 1.5%) harbored coexisting ALK rearrangement and EGFR mutation. ALK rearrangement occurred more frequently in young patients (8/9) (P = 0.687), non smokers (8/9) (P = 0.077), and those who had no family history of LAC (8/9) (P = 1.000); all KRAS mutations occurred in the EGFR wild type (P = 0.007). KRAS mutations were generally detected in young patients (6/8) (P = 0.658) and in those who had no family history (7/8) (P = 1.000); EGFR mutations correlated with gender (P = 0.001), and smoking status (P < 0.001). CONCLUSIONS: Two patients harboring both EGFR mutation and EML4-ALK rearrangement were detected in this study. Our data was apparently inconsistent with the traditional view that the EML4-ALK fusion gene in patients is resistant to EGFR-TKIs. PMID- 26767033 TI - New orthotopic implantation model of human esophageal squamous cell carcinoma in athymic nude mice. AB - BACKGROUND: Subcutaneous xenograft is a common method to establish animal models of human esophageal squamous cell carcinoma (ESCC). However, the growth microenvironment of transplanted tumors is different from primary tumors. Orthotopic implantation models can provide more biologically relevant context in which to study the disease. So far, an orthotopic implantation model of ESCC has rarely been reported. METHODS: The human ESCC cell line KYSE30 was transfected with pLVX-Luciferase plasmids. KYSE30-Luciferase cells were isolated and injected into the flanks of nude mice to develop a subcutaneous tumor. An orthotopic implantation model was established using the fragments derived from the subcutaneous tumor. Fluorescence imaging was used to observe the development of the orthotopic implanted tumor. Hematoxylin and eosin staining was performed to evaluate the invasion and metastasis of the tumor. RESULTS: KYSE30 cells were successfully transfected with pLVX-Luciferase plasmids. A primary tumor was developed in all mice. The mice experienced body weight loss. The implanted tumor infiltrated into the esophageal muscularis propria. However, neither distant organ nor lymph node metastasis was found. The progression of the primary tumor was monitored by in vivo fluorescence imaging. CONCLUSION: The orthotopic implantation model can be established by sewing the fragments of human ESCC to the abdominal esophagus of a nude mouse. The progression of an orthotopic implantation tumor can be monitored in real time by in vivo fluorescence imaging. PMID- 26767034 TI - Diagnostic value of serum glutathione peroxidase 3 levels in patients with lung cancer. AB - BACKGROUND: We selected glutathione peroxidase 3 (GPx3) as a specific candidate that is down regulated in patients with lung cancer. In this study, we examined the diagnostic value of serum GPx3, which is an extracellular protein and readily detectable in blood. METHODS: We collected serum samples from 342 patients with lung cancer and 126 controls (normal healthy people and patients with benign diseases or other malignancies). We measured serum GPx3 levels using the enzyme linked immunosorbent assay. RESULTS: Mean serum GPx3 levels were significantly lower in the patient group compared with the control group (10.1 +/- 5.0 MUg/mL vs. 13.0 +/- 5.8 MUg/mL, P < 0.001). In addition, mean serum GPx3 levels tended to be lower in the patients without metastasis compared with those with metastasis (9.6 +/- 4.5 MUg/mL vs. 10.7 +/- 5.7 MUg/mL, P = 0.051). Furthermore, mean serum GPx3 levels had a significant difference according to initial treatments (P < 0.001). In other words, mean serum GPx3 levels were significantly lower in the surgery group (8.2 +/- 4.1 MUg/mL) compared with the concurrent chemoradiotherapy (11.5 +/- 4.6 MUg/mL, P < 0.001), chemotherapy (10.7 +/- 5.6 MUg/mL, P < 0.001), and supportive care groups (10.9 +/- 4.8 MUg/mL, P = 0.002). CONCLUSION: Our results showed that serum GPx3 levels were significantly lower in the patients who underwent surgery, which indicates that the serum may have diagnostic value in patients at an operable stage of lung cancer, rather than those at a locally advanced or metastatic stage. PMID- 26767035 TI - Role of systemic inflammation scores in pulmonary metastasectomy for colorectal cancer. AB - BACKGROUND: Patients with pulmonary metastases from colorectal cancer can benefit from surgical removal. However, the biological determinants of postsurgical outcome are not completely elucidated. We evaluated the role of host systemic inflammation status in this setting. METHODS: The modified Glasgow prognostic score (based on serum C-reactive protein and albumin levels) and the neutrophil to-lymphocyte (NTL) ratio were obtained from 44 patients who received curative intent metastasectomy, and were used as indicators of systemic inflammation status. We tested the impact of both of these parameters on overall survival (OS) and progression-free survival (PFS), as well as their correlation with other well known prognosticators. RESULTS: Five-year PFS and OS rates were 18% and 49%, respectively. At univariate analysis, multiple metastases, disease-free interval <36 months, and a Glasgow score of 2 (P = 0.031) were significantly associated to a worse PFS rate. A NTL ratio >3 predicted disease progression in the short-term (P = 0.036), but the effect on late events was weaker (P = 0.079). Factors associated with worse OS were multiple metastasis (P = 0.002), elevated carcinoembryonic antigen (P = 0.009), a Glasgow score of 2 (P = 0.029), and a faster metastasis growth (P = 0.008). At Cox regression analysis, neither a Glasgow score of 2, nor elevated NTL ratio showed an independent effect on survival rates. CONCLUSIONS: Systemic inflammation scores did not perform well as independent survival prognosticators in patients undergoing curative-intent pulmonary metastasectomy. Further investigation is warranted to evaluate whether these measurements could still be useful when restricting the analysis to specific patient subcategories or to diverse postoperative phases. PMID- 26767036 TI - Incidence and clinical implication of tumor cavitation in patients with advanced non-small cell lung cancer induced by Endostar, an angiogenesis inhibitor. AB - BACKGROUND: Antiangiogenesis plays a key role in the treatment of non-small lung cancer (NSCLC). We observed the cavitation of lesions in patients with stage IIIB/IV NSCLC treated with Endostar and vinorelbine-cisplatin (NP) chemotherapy, and evaluated the imaging characteristics and clinical outcome of patients who developed tumor cavitation. METHODS: Our study included 105 untreated NSCLC patients who received Endostar in combination with NP chemotherapy at the Tianjin Lung Cancer Center. Chest computed tomography (CT) was performed to evaluate the efficacy every two cycles. The number of activated circulating endothelial cells (aCECs) was measured by flow cytometry. Rates of tumor cavitation were documented and their clinical CT imaging data were analyzed. RESULTS: Tumor cavitation occurred in 11 of the 105 (10.5%) patients treated with Endostar and NP. The response rates were 37.2% (35/94) in patients without cavitation, 27.3% (3/11) evaluated by Response Evaluation Criteria in Solid Tumors, and 100.0% (11/11) if evaluated by an alternate method in patients who developed cavitation. Three of the 11 cases with cavitation had a centrally located tumor. No patients had hemoptysis or any other severe side effects. Compared with patients not developing cavitation, cavity formation resulted in a longer median survival time (13.6 vs. 11.8 months, P = 0.011) and an increase in the number of aCECs (244.4/10(5) vs. 23.3/10(5), P = 0.000). CONCLUSIONS: Intratumoral cavitation induced by Endostar is common in NSCLC patients, and is not correlated with squamous histology, tumor location or pulmonary hemorrhage. Cavitation might have a significant effect on the number of aCECs and overall prognosis. PMID- 26767037 TI - Histological subtypes of lung cancer in Chinese women from 2000 to 2012. AB - BACKGROUND: The aim of the study was to characterize the histological and epidemiological features of lung cancer in Chinese women. METHODS: Demographic and histological information on female lung cancer cases identified during 1 January 2000 through 31 December 2012 from the Cancer Hospital of the Chinese Academy of Medical Sciences were collected. The International Classification of Diseases for Oncology system was used to classify the histological subtypes. Relative frequencies (RF) were estimated for major histological subtypes and compared by the years of diagnosis and birth, and among residential areas. Statistical differences were tested for RFs in the time periods with a trend test and with Pearson Chi square tests for distribution. RESULTS: Of 7070 female Chinese lung cancer cases, the major histological subtypes were adenocarcinoma (ADC) 65.79%; squamous cell carcinoma (SCC) 10.21%; small cell cancer 8.12%; large cell carcinoma, 2.79%; and adeno-squamous carcinoma (ASC), 2.19%. ADC increased, with RFs from 46.72% in the cases identified in 2000-2002 to 76.49% in 2011-2012 (Z = 16.998, P < 0.0001); SCC decreased from 15.69% to 5.97% (Z = 8.750, P < 0.0001). Compared to the cases identified in 2000-2006, the age adjusted RFs of ADC in 2007-2012 consistently increased in all study areas. CONCLUSION: The significant increase of ADC of the lung in Chinese women suggests that a persistently strong exposure to potential carcinogens in the Chinese population should be further and fully investigated. PMID- 26767038 TI - ROS1 mutation and treatment with crizotinib in a 30-year old Caucasian woman with stage IV non-small cell lung cancer/adenocarcinoma and complete remission. AB - In this case report we describe a 30 year-old Caucasian woman with a histopathological diagnosis of pulmonary adenocarcinoma in both lungs with lipidic and micropapillary growth pattern and ROS1 (C-ros oncogene 1, receptor tyrosine kinase) rearrangement. There is evidence that crizotinib can be used for molecular target therapy in these patients. We enrolled the patient in an off label program for the treatment of ROS1 rearranged adenocarcinomas with the EML4/anaplastic lymphoma kinase inhibitor crizotinib. After a follow-up of eight weeks we saw a complete remission in both lungs without any signs of metabolic tumor activity. This report shows the importance of testing young patients with adenocarcinomas of the lung for rare oncogenic driver mutations, such as ROS1, with possible molecular treatment options. PMID- 26767039 TI - Primary choriocarcinoma in mediastinum with multiple lung metastases in a male patient: A case report and a review of the literature. AB - Primary choriocarcinoma is a rare malignant tumor, particularly in men. The tumor, mostly found in the gastrointestinal system and mediastinum, often metastasizes early with poor therapeutic effects and prognosis. Herein, we present a male patient with primary mediastinum choriocarcinoma and widespread lung metastases. The disease progressed rapidly with little therapeutic effect from chemotherapy. The patient died of this disease 75 days after initial symptom presentations. Literature review found only 41 cases of primary choriocarcinoma reported in the mediastinum. This case highlights the importance of keeping primary choriocarcinoma in the differentials for mediastinum tumors in young men. Sex hormone testing is helpful to confirm diagnosis. Early biopsy should be performed to confirm pathologic diagnose, and early surgery and chemotherapy should be considered to improve the cure rate of this disease. PMID- 26767040 TI - Esophageal cancer complicated by esophagopulmonary fistula and lung abscess formation: A surgical approach. PMID- 26767042 TI - Overview of fundamental study of pazopanib in cancer. AB - Angiogenesis is an indispensible process for tumor growth and metastasis. Anti angiogenesis based therapy is one of the most promising treatments for inhibiting cancer progression. Through the exploration of inhibitors of vascular endothelial growth factor receptor (VEGFR)-2, deemed as the major angiogenesis pathway, pazopanib was found as a small molecular pan-VEGFR and pan-platelet-derived growth factor receptor (PDGFR) inhibitor, with suitable pharmacodynamic and pharmacokinetic parameters to be an oral drug. In an vitro study, pazopanib exerted anti-tumor effect through mechanisms including the Raf-MAPK/ERK (MEK) extracellular signal-regulated kinase (ERK) pathway, and directly targeted on v raf murine sarcoma viral oncogene homolog B (B-raf) as well. It inhibited the proliferation of cell lines, such as DU-145 and HRC-45 in hepatocellular carcinoma, through mechanisms like "cell cycle arrest." In vivo xenograft studies and phase I/II clinical trials revealed a series of plasma cytokine and angiogenic factors, such as interleukin (IL)-6, IL-12, hepatocyte growth factor (HGF), and soluble VEGFR2, which have significant association with clinical curative effect. Pazopanib has been shown to be effective in solid tumors and some hematological malignancies. Future studies should focus on the exploration of biomarkers to screen sensitive patients and concomitant or metronomic dosage with other kinds of medicines. PMID- 26767043 TI - Comparison of short and long-term results between sleeve resection and pneumonectomy in lung cancer patients over 70 years old: 10 years experience from a single institution in China. AB - BACKGROUND: The aim of this study was to compare the short and long-term results between sleeve resection (SR) and pneumonectomy (PN) in lung cancer patients over 70 years of age. METHODS: We retrospectively reviewed 105 lung cancer patients over 70 years of age who had undergone SR or PN at Shanghai Chest Hospital from January 2003 to December 2012. RESULTS: The SR group showed a higher frequency of airway clearance via bronchoscopy (48.6% vs. 25.7%, P = 0.04), longer surgical time (162.7 vs. 140.9 minutes, P = 0.01), and shorter postoperative stay (13.7 vs. 18.1 days, P = 0.02) than the PN group. There was no difference in hospital mortality (P = 1.00) or morbidity (P = 0.40) between the two groups. A logistic regression model showed that preoperative predicted forced expiratory volume in 1 second was the only independent risk factor for overall morbidity (P = 0.04). In survival analysis, SR showed better prognosis than PN (median 50.0 vs. 20.0 months, P < 0.01). In subgroup analysis, SR showed better survival in N0 (P = 0.03) and N1 (P < 0.01) cases, but not in N2 cases (P = 0.36). It also showed better survival in stage I + II patients (P = 0.03), but not in stage III patients (P = 0.10). CONCLUSIONS: Although PN could be carried out as safely as SR in patients over 70 years of age with a good pulmonary reservoir, SR is still recommended as a less traumatic procedure, sparing lung parenchyma with better long-term results. PMID- 26767044 TI - Apolipoprotein C1 (APOC1) as a novel diagnostic and prognostic biomarker for lung cancer: A marker phase I trial. AB - BACKGROUND: Tumor cells continuously evolve over time in response to host pressures. However, explanations as to how tumor cells are influenced by the inflammatory tumor microenvironment over time are, to date, poorly defined. We hypothesized that prognostic biomarkers could be obtained by exploring the expression of inflammation-associated genes between early and late stage lung cancer tumor samples. METHODS: Candidate inflammation-associated genes, apolipoprotein C-1 (APOC1), MMP1, KMO)1, CXCL5, CXCL)7, IL-1alpha, IL-1beta, TNF alpha and IL-6 were verified by real-time quantitative polymerase chain reaction. Gene expression profiles and immunofluorescence staining of 30 lung cancer tissues were compared. RESULTS: Expressions of APOC1 and IL-6 mRNA on tumor tissues in late stage disease were significantly higher than in early stage lung cancer samples. Immunofluorescence staining of tumor samples showed that the expression of APOC1 gradually increased from early to late stage in lung cancer patients. The expression levels of IL-6 and APOC1 in tumor samples were positively correlated; however, no prognostic value of APOC1 can be identified in serum samples. CONCLUSIONS: We found that the level of tumor APOC1 was highly expressed in late stage lung cancer. Further research is warranted to determine the molecular mechanisms underlying the cross talk of APOC1 and IL-6 in tumor progression. An expanded sample size marker phase II study may lead to the discovery of new lung cancer therapeutics targeting APOC1. PMID- 26767045 TI - Analysis of BIM (BCL-2 like 11 gene) deletion polymorphism in Chinese non-small cell lung cancer patients. AB - BACKGROUND: Drug resistance significantly weakens the efficacy of cancer treatment, and the BIM (also known as the BCL2L11 gene) deletion polymorphism has been identified as a potential biomarker for drug resistance. In this retrospective study, we included a total of 290 patients with advanced non-small cell lung cancer (NSCLC) who received treatment with epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) and chemotherapy. METHODS: The BIM deletion polymorphism of each patient was detected by polymerase chain reaction. EGFR mutations were detected by denaturing high-performance liquid chromatography methods and the amplification refractory mutation system. RESULTS: The BIM deletion polymorphism was detected in 45/290 (15.5%) Chinese NSCLC patients. No associations were observed between the BIM deletion and clinic pathologic characteristics of patients. The BIM deletion polymorphism was predictive of shorter progression-free survival in Chinese patients with EGFR mutant adenocarcinoma and who were treated with EGFR-TKIs (7.30 vs. 9.53 months, P = 0.034). Additionally, we found that the BIM deletion polymorphism was an effective predictor of short progression-free survival in individuals with EGFR mutant NSCLC and treated with chemotherapy containing pemetrexed (3.32 vs. 5.30, P = 0.012) or second-/beyond-line chemotherapy containing taxanes (1.53 vs. 2.61 months, P = 0.025). The BIM deletion was not correlated with overall survival. CONCLUSION: The BIM deletion polymorphism occurs in 15.5% of Chinese NSCLC patients, and is a biomarker for resistance to TKIs and chemotherapy. However, BIM deletion was not a decisive factor in overall survival. PMID- 26767041 TI - Targeting the Notch signaling pathway in cancer therapeutics. AB - Despite advances in surgery, imaging, chemotherapy, and radiotherapy, the poor overall cancer-related death rate remains unacceptable. Novel therapeutic strategies are desperately needed. Nowadays, targeted therapy has become the most promising therapy and a welcome asset to the cancer therapeutic arena. There is a large body of evidence demonstrating that the Notch signaling pathway is critically involved in the pathobiology of a variety of malignancies. In this review, we provide an overview of emerging data, highlight the mechanism of the Notch signaling pathway in the development of a wide range of cancers, and summarize recent progress in therapeutic targeting of the Notch signaling pathway. PMID- 26767046 TI - Tumor MET expression profile predicts the outcome of non-small cell lung cancer patients receiving epidermal growth factor receptor tyrosine kinase inhibitors. AB - BACKGROUND: This study assesses whether MET expression in tumor tissue is associated with an increased sensitivity to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) in non-small-cell lung cancer (NSCLC) patients. METHODS: This retrospective study included 69 NSCLC participants with available tumor tissue and data on treatment response and survival. MET and hepatocyte growth factor expression in tumor tissue were evaluated by immunohistochemistry. RESULTS: Positive tMET expression correlated with a shorter progression-free survival (PFS; P = 0.003) and overall survival (OS; P = 0.05). Positive pY1234/1235 expression was significantly associated with a longer PFS (P = 0.031) and OS (P = 0.012). In multivariable analyses, tMET and pY1234/1235 expression were independent factors for PFS and OS, respectively. (tMET, PFS; P = 0.02, OS; P = 0.0007 and pY1234/1234, PFS; P = 0.01, OS; P = 0.004). CONCLUSIONS: This study suggests that total and phosphorylated MET expression in tumor tissue is potentially useful for the selection of NSCLC patients who are likely to benefit from EGFR-TKIs, irrespective of their EGFR status. PMID- 26767047 TI - Efficacy and safety of docetaxel plus oxaliplatin as a first-line chemotherapy in patients with advanced or metastatic non-small cell lung cancer. AB - BACKGROUND: Platinum doublets are standard first-line treatment for stage IV non small cell lung cancer (NSCLC) without targetable driver mutations. Oxaliplatin is more potent than cisplatin, requiring fewer DNA adducts to provide equivalent cytotoxicity. The objective of this study was to evaluate the efficacy and safety of oxaliplatin combined with docetaxel as a first-line treatment for stage IV NSCLC. METHODS: This was a prospective, single-center, phase II trial. Patients with chemotherapy-naive NSCLC received 60 mg/m(2) docetaxel (day 1) and 70 mg/m(2) oxaliplatin (day 2) every three weeks for up to six cycles. The primary endpoint was objective response rate (ORR), and the secondary endpoints were progression-free survival (PFS), overall survival (OS), and safety. Treatment response was evaluated according to Response Evaluation Criteria in Solid Tumors version 1.1. RESULTS: Thirty-three patients were enrolled and a response evaluation was available in 31 patients. There were 11 patients with a partial response, 15 with stable disease, and five with progressive disease. Two patients ceased further treatment after the first cycle of chemotherapy. Thus, the ORR was 33.3% in the 33 patients of the intention-to-treat population. Median PFS was 3.6 months (95% confidence interval [CI], 2.8-4.5), and median OS was 10.9 months (95% CI, 8.2-13.6). The most common hematologic toxicity was neutropenia. Grade 3 4 neutropenia occurred in 51.5% of patients. CONCLUSION: The results suggest that the combination of oxaliplatin and docetaxel is effective in patients with NSCLC with reasonable toxicity. PMID- 26767048 TI - Cost-effectiveness of chemotherapy combined with thoracic radiotherapy versus chemotherapy alone for limited stage small cell lung cancer: A population-based propensity-score matched analysis. AB - BACKGROUND: The addition of thoracic radiotherapy improves the outcome of limited stage small cell lung cancer (LS-SCLC), however, the cost-effectiveness of this process has never been reported. We aimed to estimate the short-term cost effectiveness of chemotherapy combined with thoracic radiotherapy (C-TRT) versus chemotherapy alone (C/T) for LS-SCLC patients from the payer's perspective (Taiwan National Health Insurance). METHODS: We identified LS-SCLC patients diagnosed within 2007-2009 through a comprehensive population-based database containing cancer and death registries, and reimbursement data. The duration of interest was one year within diagnosis. We included potential confounding covariables through literature searching and our own experience, and used a propensity score to construct a 1:1 population for adjustment. We used a net benefit (NB) approach to evaluate the cost-effectiveness at various willingness to-pay (WTP) levels. Sensitivity analysis regarding potential unmeasured confounder(s) was performed. RESULTS: Our study population constituted 74 patients. The mean cost (2013 USD) and survival (year) was higher for C-TRT (42 439 vs. 28 357; 0.94 vs. 0.88). At the common WTP level (50 000 USD/life-year), C TRT was not cost effective (incremental NB - 11 082) and the probability for C TRT to be cost effective (i.e. positive net benefit) was 0.005. The result was moderately sensitive to potential unmeasured confounder(s) in sensitivity analysis. CONCLUSIONS: We provide evidence that when compared to C/T, C-TRT is effective in improving survival, but is not cost-effective in the short-term at a common WTP level from a payer's perspective. This information should be considered by clinicians when discussing thoracic radiotherapy with their LS-SCLC patients. PMID- 26767049 TI - How does four-dimensional computed tomography spare normal tissues in non-small cell lung cancer radiotherapy by defining internal target volume? AB - BACKGROUND: To investigate how the four-dimensional computed tomography (4DCT) technique spares normal tissues in non-small cell lung cancer (NSCLC) radiotherapy by defining individualized internal target volume (ITV). MATERIALS AND METHODS: Gross tumor volume (GTV) and clinical target volume (CTV) were contoured on all 10 respiratory phases of 4DCT scans in 10 patients with peripheral NSCLC. Both 3D and 4D treatment plans were performed for each patient using planning target volume (PTV)3D (derived from a single CTV plus conventional margins) and PTV4D (derived from 4D internal target volume, which included all 10 CTVs plus setup margins). Dose volume histogram and normal tissue complication probability (NTCP) values were compared for the lung, heart, and spinal cord between 3D and 4D treatment plans. RESULTS: The average PTV of the 4D (127.56 +/- 70.79) was less than the 3D plans (147.65 +/- 76.89). The 4D spared more surrounding normal tissues than the 3D plans, especially in the lung. Compared with 3D plans, V5, V10, V20 and V30 of the total lung decreased from 41.25%, 37.75%, 24.25%, 17.00% to 38.13%, 33.00%, 21.25%, 15.13%, respectively. Without increasing the NTCP of the lung significantly, the 4D plans allowed us to increase the average prescription dose from 60 Gy to 66.00 +/- 4.62 Gy. CONCLUSIONS: 4DCT based plans can reduce the target volumes, spare more normal tissues, and allow dose escalation compared with 3D plans in NSCLC radiotherapy. PMID- 26767050 TI - Bioinformatics analysis and expression study of fumarate hydratase in lung cancer. AB - BACKGROUND: As its etiology and pathogenesis is obscure, illustrating the molecular mechanism of lung cancer has become a serious and urgent task. Studies have shown that fumarate hydratase (FH) is a tumor suppressor related to tumorigenesis, development, and invasion. Our aim was to analyze the biological information of FH, and detect the messenger ribonucleic acid (mRNA) and protein expression of FH in lung cancer cells to explore its role in tumorigenesis and in the development of lung cancer. METHOD: We analyzed the biological characteristics of FH, then utilized reverse transcription-polymerase chain reaction (RT-PCR) to study FH mRNA expression in A549 and 16 human bronchial epithelial (HBE) cell lines. The protein expression of FH was detected in 57 cases of human lung cancer tissues and 19 cases of normal lung tissues by immunohistochemistry. RESULTS: 1. Bioinformatic analysis: FH mainly exist in the mitochondria; the common structural elements of FH are mainly alpha-helix, random coil, beta-turn, and extended strand; there are five possible transmembrane domains in the entire polypeptide chain; FH is a hydrophilic and soluble protein. 2. RT-PCR result: FH mRNA expression was downregulated in A549 cells compared with 16HBE cells. 3. Immunohistochemistry: FH protein expression was significantly lower in lung cancer cells than in normal lung tissues (P < 0.05), but was not correlated with the patients' age, gender, tumor size, pathological type, or lymph node, distant, or tumor node metastasis stage. CONCLUSION: FH was under-expressed in lung cancer, suggesting that it may be an indicator of tumorigenesis and could be a potential target for therapies against lung cancer in the future. PMID- 26767051 TI - Sentinel lymph node biopsy does not apply to all axillary lymph node-positive breast cancer patients after neoadjuvant chemotherapy. AB - BACKGROUND: The aim of this study was to investigate the feasibility of sentinel lymph node biopsy (SLNB) after neoadjuant chemotherapy (NAC) in breast cancer patients with confirmed axillary nodal metastases. METHODS: We enrolled 51 patients with breast cancer who received NAC. All patients were proven to have axillary nodal metastases by histopathology biopsy prior to NAC. They all underwent SLNB before breast surgery, and complete axillary lymph node dissection immediately followed. RESULTS: The identification rate for SLNB was 87.5% (84/96); the false negative rate was 24.5% (12/49). The clinicopathological factors were not significantly correlated with the identification and false negative rate of the SLNB. Lymphatic mapping, blue dye or radionuclide methods tended to decrease the identification rate of SLNB (P = 0.073). Clinical nodal status before NAC has a trend to increase the false-negative rates of the SLNB (P = 0.059). For patients with N1 clinical axillary lymph nodal status, the identification rate was 93.9%, and the false negative rate was 5.9%, compared with N2-3 patients with 73.9% and 38.9%, respectively. CONCLUSIONS: SLNB is feasible for the patients whose axillary lymph nodal status before NAC is N1. However, for N2-3 patients, SLNB cannot be used as an infallible indicator of non SLN status. PMID- 26767052 TI - Network analysis in the identification of special mechanisms between small cell lung cancer and non-small cell lung cancer. AB - BACKGROUND: To explore the similar and different pathogenesis between non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). METHODS: This study used bioinformatics methods, including functional enrichment analysis, compared the topological features of SCLC and NSCLC in the human protein interaction network in a system aspect, and analyzed the highly intense modules from an integrated network. RESULTS: This study included 5082 and 2781 significantly different expression genes for NSCLC and SCLC, respectively. The differently expressed genes of NSCLC are mainly distributed in the extracellular region and synapse. By contrast, the genes of SCLC are located in the organelle, macromolecular complex, membrane-enclosed lumen, cell part, envelope, and synapse. Compared with SCLC, the differently expressed genes of NSCLC act in the biological regulation, multicellular organismal process, and viral reproduction and locomotion, which show that NSCLC is more likely to cause a wide range of cancer cell proliferation and virus infection than SCLC. The network topological properties of SCLC and NSCLC are similar, except the average shortest path length, which indicates that most of the genes of the two lung cancers play a similar function in the entire body. The commonly expressed genes show that all of the genes in the module may also cause NSCLC and SCLC, simultaneously. CONCLUSIONS: The proteins in module will involve the same or similar biological functions and the interactions among them induce the occurrence of lung cancer. Moreover, a potential biomarker of SCLC is the interaction between APIP and apoptotic protease activating factor (APAF)1, which share a common module. PMID- 26767053 TI - Infrequent chemoradiation-induced acute esophagitis in the Asian population: A meta-analysis of published clinical trials for unresectable stage III non-small cell lung cancer. AB - Severe (grade 3 or higher) esophagitis is one of the major toxicities for chemoradiation in the treatment of stage III non-small cell lung cancer (NSCLC). The difference among ethnic groups has never been investigated in detail. Prospective trials with concurrent platinum-containing chemoradiation in unresectable disease were investigated, and a total of 116 treatment arms with 7520 patients were identified. Univariate analysis demonstrated that treatment arms conducted in Asia had significantly lower incidence of severe esophagitis (170/2534, 6.7%, odds ratio 0.289) than in other nations (1025/4986, 20.6%). In the multivariable model, Asian/non-Asian ethnicity, multi-/single-agent, and split are jointly significant predictors after adjusting for all possible factors. This study suggests that severe esophagitis occurs less frequently in the Asian population compared to the non-Asian population. PMID- 26767054 TI - Log odds of positive lymph nodes are superior to other measures for evaluating the prognosis of non-small cell lung cancer. AB - BACKGROUND: To evaluate the ability of the log odds of positive lymph nodes to predict prognosis in patients with non-small cell lung cancer (NSCLC). METHODS: Correlations between the log odds of positive lymph nodes, numbers of dissected lymph nodes, dissected lymph node stations, positive lymph nodes, positive lymph node ratio, and positive lymph node stations were retrospectively evaluated using Pearson correlation coefficients (r), survival analysis by Kaplan-Meier, Cox hazard ratio model, and log-rank tests. RESULTS: The numbers of dissected lymph nodes, positive lymph nodes, dissected lymph node stations and positive lymph node stations significantly correlated with the log odds of positive lymph nodes (P < 0.001, P < 0.001, P = 0.002 and P < 0.001, respectively). The five-year survival ratio of postoperative patients with the log odds of positive lymph nodes <11.412 and >-1.412 were 63.9% and 32.5%, respectively (P < 0.001). According to multivariate analysis, age and log odds of positive lymph nodes are independent risk factors for overall survival (hazard ratio = 2.660, 95% confidence interval 2.114-3.346, P < 0.001). A new staging system featuring a combination of log odds of positive lymph nodes and a tumor node metastasis (TNM) staging system was established for predicting survival. CONCLUSION: The log odds of positive lymph nodes are superior to the positive lymph node ratio and p-N stage for predicting prognosis of NSCLC. A new staging system that combines log odds of positive lymph nodes and the current TNM staging system predicts prognosis more accurately than the TNM system alone. PMID- 26767055 TI - Intrapulmonary unicentric Castleman disease mimicking peripheral pulmonary malignancy. AB - Castleman disease, also known as angiofollicular lymph node hyperplasia, can manifest as a unicentric or multicentric disorder. Intrapulmonary Castleman disease is very rare. Here, we present a patient with intrapulmonary Castleman disease who underwent left upper pulmonary lobectomy for suspected early lung cancer. The histopathologic diagnosis of the lobar mass was hyaline-type Castleman disease. The patient has remained well after surgery, showing no local recurrence or distant disease during a two-year follow-up period. Although unicentric Castleman disease originating in the lung is rare, it should be considered in the differential diagnosis of primary pulmonary malignant tumors. PMID- 26767056 TI - Skin involvement in diffuse large B-cell lymphoma detected using positron emission tomography. PMID- 26767057 TI - Histone acetylation and histone acetyltransferases show significant alterations in human abdominal aortic aneurysm. AB - BACKGROUND: Epigenetic modifications may play a relevant role in the pathogenesis of human abdominal aortic aneurysm (AAA). The aim of the study was therefore to investigate histone acetylation and expression of corresponding lysine [K] histone acetyltransferases (KATs) in AAA. RESULTS: A comparative study of AAA tissue samples (n = 37, open surgical intervention) and healthy aortae (n = 12, trauma surgery) was performed using quantitative PCR, immunohistochemistry (IHC), and Western blot. Expression of the KAT families GNAT (KAT2A, KAT2B), p300/CBP (KAT3A, KAT3B), and MYST (KAT5, KAT6A, KAT6B, KAT7, KAT8) was significantly higher in AAA than in controls (P <= 0.019). Highest expression was observed for KAT2B, KAT3A, KAT3B, and KAT6B (P <= 0.007). Expression of KAT2B significantly correlated with KAT3A, KAT3B, and KAT6B (r = 0.705, 0.564, and 0.528, respectively, P < 0.001), and KAT6B with KAT3A, KAT3B, and KAT6A (r = 0.407, 0.500, and 0.531, respectively, P < 0.05). Localization of highly expressed KAT2B, KAT3B, and KAT6B was further characterized by immunostaining. Significant correlations were observed between KAT2B with endothelial cells (ECs) (r = 0.486, P < 0.01), KAT3B with T cells and macrophages, (r = 0.421 and r = 0.351, respectively, P < 0.05), KAT6A with intramural ECs (r = 0.541, P < 0.001) and with a contractile phenotype of smooth muscle cells (SMCs) (r = 0.425, P < 0.01), and KAT6B with T cells (r = 0.553, P < 0.001). Furthermore, KAT2B was associated with AAA diameter (r = 0.382, P < 0.05), and KAT3B, KAT6A, and KAT6B correlated negatively with blood urea nitrogen (r = -0.403, -0.408, -0.478, P < 0.05). In addtion, acetylation of the histone substrates H3K9, H3K18 and H3K14 was increased in AAA compared to control aortae. CONCLUSIONS: Our results demonstrate that aberrant epigenetic modifications such as changes in the expression of KATs and acetylation of corresponding histones are present in AAA. These findings may provide new insight in the pathomechanism of AAA. PMID- 26767058 TI - Quality Outcomes in the Surgical Intensive Care Unit after Electronic Health Record Implementation. AB - BACKGROUND: The electronic health record (EHR) is increasingly viewed as a means to provide more coordinated, patient-centered care. Few studies consider the impact of EHRs on quality of care in the intensive care unit (ICU) setting. OBJECTIVES: To evaluate key quality measures of a surgical intensive care unit (SICU) following implementation of the Epic EHR system in a tertiary hospital. METHODS: A retrospective chart review was undertaken to record quality indicators for all patients admitted to the SICU two years before and two years after EHR implementation. Data from the twelve-month period of transition to EHR was excluded. We collected length of stay, mortality, central line associated blood stream infection (CLABSI) rates, Clostridium difficile (C. diff.) colitis rates, readmission rates, and number of coded diagnoses. To control for variation in the patient population over time, the case mix indexes (CMIs) and APACHE II scores were also analyzed. RESULTS: There was no significant difference in length of stay, C. diff. colitis, readmission rates, or case mix index before and after EHR. After EHR implementation, the rate of central line blood stream infection (CLABSI) per 1 000 catheter days was 85% lower (2.16 vs 0.39; RR, 0.18; 95% CI, 0.05 to 0.61, p < .005), and SICU mortality was 28% lower (12.2 vs 8.8; RR, 1.35; 95% CI, 1.06 to 1.71, p < .01). Moreover, after EHR there was a significant increase in the average number of coded diagnoses from 17.8 to 20.8 (p < .000). CONCLUSIONS: EHR implementation was statistically associated with reductions in CLABSI rates and SICU mortality. The EHR had an integral role in ongoing quality improvement endeavors which may explain the changes in CLABSI and mortality, and this invites further study of the impact of EHRs on quality of care in the ICU. PMID- 26767059 TI - Use of an Expedited Review Tool to Screen for Prior Diagnostic Error in Emergency Department Patients. AB - OBJECTIVE: Missed diagnoses are an important area of care quality resulting in significant morbidity and mortality. Determination of rates and causes has been limited by difficulties in screening, including the effort of manual chart review. We developed and tested a semi- automated review tool to expedite screening for diagnostic errors in an electronic health record (EHR). METHODS: We retrospectively reviewed patients seen in the emergency department (ED) of a teaching hospital over 31 days, using an automated screen to identify those with a prior in-system visit during the 14 days preceding their ED visit. We collected prior and subsequent notes from the institution's EHR for these cases, then populated a specially designed relational database enabling rapid comparison of prior visit records to the sentinel ED visit. Each case was assessed for potential missed or delayed diagnosis, and rated by likelihood as "definite, probable, possible, unlikely or none." RESULTS: A total of 5 066 patient encounters were screened by a clinician using the tool, of which 1 498 (30%) had a clinical encounter within the preceding 14 days. Of these, 37 encounters (2.6% of those reviewed) were "definite" or "probable" missed diagnoses. The rapid review tool took a mean of 1.9 minutes per case for primary review, compared with 11.2 minutes per case for reviews without the automated tool. CONCLUSIONS: Diagnostic errors were present in a significant number of cases presenting to the ED after recent healthcare visits. An innovative review tool enabled a substantially increased efficiency in screening for diagnostic errors. PMID- 26767060 TI - Using Visual Analytics to Determine the Utilization of Preoperative Anesthesia Assessments. AB - BACKGROUND: Preoperative assessments are a required and essential element of anesthetic care, yet little is known about the utilization of these documents by clinicians who are not part of the anesthesia care team. As part of perioperative workflow restructuring, we implemented a data visualization technique of electronic medical record audit log data to understand the utilization of preoperative anesthesia assessments by non-anesthesia personnel. METHODS: An audit log cache containing 140 days of data was queried for all accesses of preoperative anesthesia assessment documents for any patient who had a preoperative anesthesia assessment that was accessed during that period. User roles were aggregated into categories. Descriptive statistics and data visualization were generated using R (R Software Foundation, Vienna, Austria). Comparisons were performed with the Wilcoxon signed rank test with continuity correction. RESULTS: During the study period, 73 802 (0.015%) of the 485 062 902 audit log accesses were preoperative anesthesia assessments representing 412 departments, 302 user roles, and 3 916 distinct users who accessed preoperative anesthesia assessments from 14 235 surgical cases. Each assessment was accessed 2.9 times on average. Assessments performed in the preoperative anesthesia assessment clinic were accessed more frequently than those created on the day of surgery in the preoperative holding room (3.58 +/- 5.18 v. 1.98 +/- 1.76 average views; p<0.0001). We observed accesses of these documents by pathology and general surgery researchers, as well as orthopedics attending physicians accessing documents that were two years old. CONCLUSIONS: This approach revealed patterns of utilization that had not been previously identified, including usage by surgical residents, surgical faculty, and pathology researchers both before and after the surgical event for which the documents are generated. Knowledge of these dependencies directly informed perioperative workflow restructuring efforts. This visual analytic approach could be broadly utilized to understand documentation dependencies in a variety of clinical contexts. PMID- 26767061 TI - Safe Implementation of Computerized Provider Order Entry for Adult Oncology. AB - BACKGROUND: Oncology has lagged in CPOE adoption due to the narrow therapeutic index of chemotherapy drugs, individualized dosing based on weight and height, regimen complexity, and workflows that include hard stops where safety checks are performed and documented. OBJECTIVES: We sought to establish CPOE for chemotherapy ordering and administration in an academic teaching institution using a commercially available CPOE system. METHODS: A commercially available CPOE system was implemented throughout the hospital. A multidisciplinary team identified key safety gaps that required the development of a customized complex order display and a verification documentation workflow. Staff reported safety events were monitored for two years and compared to the year prior to go live. RESULTS: A workflow was enabled to capture real-time provider verification status during the time from ordering to the administration of chemotherapy. A customized display system was embedded in the EMR to provide a single screen view of the relevant parameters of chemotherapy doses including current and previous patient measurements of height and weight, dose adjustments, provider verifications, prior chemotherapy regimens, and a synopsis of the standard regimen for reference. Our system went live with 127 chemotherapy plans and has been expanded to 189. Staff reported safety events decreased following implementation, particularly in the area of prescribing and transcribing by the second year of use. CONCLUSIONS: We observed reduced staff reported safety events following implementation of CPOE for inpatient chemotherapy using an electronic verification workflow and an embedded custom clinical decision support page. This implementation demonstrates that CPOE can be safely used for inpatient chemotherapy, even in an extremely complex environment. PMID- 26767062 TI - Does an Electronic Health Record Improve Completeness of Prenatal Studies? AB - OBJECTIVE: To determine whether implementation of an electronic health record (EHR) would increase the rate of prenatal Human Immunodeficiency Virus (HIV) and purified protein derivative (PPD) testing. METHODS: Eligible participants received prenatal care and delivered at term at a single academic institution in March-April 2011, March-April 2012, and March-April 2013. As part of routine prenatal care, all women were tested for HIV and tuberculosis (via a PPD test) during each pregnancy. The 2011 cohort was charted on paper. The 2012 and 2013 cohorts were charted via EHR. To appear in the prenatal labs display in EHR, PPD results must be manually documented, while HIV results are uploaded automatically. Documentation of PPD and HIV tests were analyzed. RESULTS: The 2011, 2012, and 2013 cohorts had 249, 208, and 190 patients, respectively. Complete PPD and HIV results were less likely to be charted in the 2012 EHR cohort compared to the paper chart cohort (72.1% vs. 80.1%; p=0.03). This was driven by fewer documented completed PPD tests (2011 83.9% vs. 2012 72.6%; p=0.003). PPD test documentation improved non-significantly to 86.2% in the 2013 EHR cohort (p=0.5). HIV documentation rates increased from 95.2% in the paper chart cohort to 98.6% in the 2012 EHR cohort (p=0.04), and to 98.9% in the 2013 EHR cohort (p=0.03). CONCLUSIONS: EHR implementation corresponded with a marked decrease in documentation of PPD test completion. HIV documentation rates improved. PPD results were likely charted incorrectly in provider notes due to training deficiencies and lack of standardization, which did not improve significantly after retraining. PMID- 26767063 TI - A Mobile, Collaborative, Real Time Task List for Inpatient Environments. AB - BACKGROUND: Inpatient teams commonly track their tasks using paper checklists that are not shared between team members. Team members frequently communicate redundantly in order to prevent errors. METHODS: We created a mobile, collaborative, real-time task list application on the iOS platform. The application listed tasks for each patient, allowed users to check them off as completed, and transmitted that information to all other team members. In this report, we qualitatively describe our experience designing and piloting the application with an inpatient pediatric ward team at an academic pediatric hospital. RESULTS: We successfully created the tasklist application, however team members showed limited usage. CONCLUSION: Physicians described that they preferred the immediacy and familiarity of paper, and did not experience an efficiency benefit when using the electronic tasklist. PMID- 26767064 TI - Uncovering Hospitalists' Information Needs from Outside Healthcare Facilities in the Context of Health Information Exchange Using Association Rule Learning. AB - BACKGROUND: Important barriers to health information exchange (HIE) adoption are clinical workflow disruptions and troubles with the system interface. Prior research suggests that HIE interfaces providing faster access to useful information may stimulate use and reduce barriers for adoption; however, little is known about informational needs of hospitalists. OBJECTIVE: To study the association between patient health problems and the type of information requested from outside healthcare providers by hospitalists of a tertiary care hospital. METHODS: We searched operational data associated with fax-based exchange of patient information (previous HIE implementation) between hospitalists of an internal medicine department in a large urban tertiary care hospital in Florida, and any other affiliated and unaffiliated healthcare provider. All hospitalizations from October 2011 to March 2014 were included in the search. Strong association rules between health problems and types of information requested during each hospitalization were discovered using Apriori algorithm, which were then validated by a team of hospitalists of the same department. RESULTS: Only 13.7% (2 089 out of 15 230) of the hospitalizations generated at least one request of patient information to other providers. The transactional data showed 20 strong association rules between specific health problems and types of information exist. Among the 20 rules, for example, abdominal pain, chest pain, and anaemia patients are highly likely to have medical records and outside imaging results requested. Other health conditions, prone to have records requested, were lower urinary tract infection and back pain patients. CONCLUSIONS: The presented list of strong co-occurrence of health problems and types of information requested by hospitalists from outside healthcare providers not only informs the implementation and design of HIE, but also helps to target future research on the impact of having access to outside information for specific patient cohorts. Our data-driven approach helps to reduce the typical biases of qualitative research. PMID- 26767065 TI - Successful Implementation of Clinical Information Technology: Seven Key Lessons from CPOE. AB - OBJECTIVES: To identify and describe the most critical strategic and operational contributors to the successful implementation of clinical information technologies, as deployed within a moderate sized system of U.S. community hospitals. BACKGROUND AND SETTING: CHRISTUS Health is a multi-state system comprised of more than 350 services and 60 hospitals with over 9 000 physicians. The Santa Rosa region of CHRISTUS Health, located in greater San Antonio, Texas is comprised of three adult community hospital facilities and one Children's hospital each with bed capacities of 142-180. Computerized Patient Order Entry (CPOE) was first implemented in 2012 within a complex market environment. The Santa Rosa region has 2 417 credentialed physicians and 263 mid-level allied health professionals. METHODS: This report focuses on the seven most valuable strategies deployed by the Health Informatics team in a large four hospital CHRISTUS region to achieve strong CPOE adoption and critical success lessons learned. The findings are placed within the context of the literature describing best practices in health information technology implementation. RESULTS: While the elements described involved discrete de novo process generation to support implementation and operations, collectively they represent the creation of a new customer-centric service culture in our Health Informatics team, which has served as a foundation for ensuring strong clinical information technology adoption beyond CPOE. CONCLUSION: The seven success factors described are not limited in their value to and impact on CPOE adoption, but generalize to - and can advance success in - varied other clinical information technology implementations across diverse hospitals. A number of these factors are supported by reports in the literature of other institutions' successful implementations of CPOE and other clinical information technologies, and while not prescriptive to other settings, may be adapted to yield value elsewhere. PMID- 26767066 TI - The Efficacy of Patients' Wristband Bar-code on Prevention of Medical Errors: A Meta-analysis Study. AB - BACKGROUND: Patient misidentification, as a major patient safety issue, occurs in any healthcare setting and leads to inappropriate medical procedures, diagnosis or treatment, with serious outcomes. OBJECTIVES: The study aimed to investigate the effectiveness of wristband bar-code medication scanning to reduce medical errors (ME). METHODS: A meta-analysis study was conducted. The relevant studies were searched in PubMed, Embase, Cochrane Library, Web of Science and Scopus from 1990 to March 2015. Thereafter, the studies retrieved were screened based on predefined inclusion and exclusion criteria. Data were extracted, and the quality of the included studies was evaluated using the STROBE checklist. RESULTS: In total, 14 articles involving 483 cases were included. The meta-analysis indicated that the use of wristband bar-code medication scanning can reduce the ME around 57.5% (OR=0.425, 95% CI: 0.28-0.65, P<0.001). The study results showed a marked heterogeneity in the subgroup analysis (I-squared=98%). This was I(2)=70.35, P value=0.018 for the type of samples and I(2)=99%, P-value<0.001 for years and countries. CONCLUSION: Wristband bar-code medication scanning can decrease the ME in hospital setting. Since the patient's safety is the main goal of the World Health Organization, it is recommended that a unique patient identification barcode should be used with name, medical record number, and bar-coded financial number. PMID- 26767067 TI - Improving Bridging from Informatics Theory to Practice. AB - BACKGROUND: In 1962, Methods of Information in Medicine (MIM) began to publish papers on the methodology and scientific fundamentals of managing data, information, and knowledge in biomedicine and health care. Meeting an increasing demand for research about practical implementation of health information systems, the journal Applied Clinical Informatics (ACI) was launched in 2009. Both journals are official journals of the International Medical Informatics Association (IMIA). OBJECTIVES: Based on prior analyses, we aimed to describe major topics published in MIM during 2014 and to explore whether theory of MIM influenced practice of ACI. Our objectives were further to describe lessons learned and to discuss possible editorial policies to improve bridging from theory to practice. METHODS: We conducted a retrospective, observational study reviewing MIM articles published during 2014 (N=61) and analyzing reference lists of ACI articles from 2014 (N=70). Lessons learned and opinions about MIM editorial policies were developed in consensus by the two authors. These have been influenced by discussions with the journal's associate editors and editorial board members. RESULTS: The publication topics of MIM in 2014 were broad, covering biomedical and health informatics, medical biometry and epidemiology. Important topics discussed were biosignal interpretation, boosting methodologies, citation analysis, health-enabling and ambient assistive technologies, health record banking, safety, and standards. Nine ACI practice articles from 2014 cited eighteen MIM theory papers from any year. These nine ACI articles covered mainly the areas of clinical documentation and medication-related decision support. The methodological basis they cited from was almost exclusively related to evaluation. We could show some direct links where theory impacted practice. These links are however few in relation to the total amount of papers published. CONCLUSIONS: Editorial policies such as publishing systematic methodological reviews and clarification of possible practical impact of theory-focused articles may improve bridging. PMID- 26767068 TI - A Framework for (Tele-) Monitoring of the Rehabilitation Progress in Stroke Patients: eHealth 2015 Special Issue. AB - BACKGROUND: Preservation of mobility in conjunction with an independent life style is one of the major goals of rehabilitation after stroke. OBJECTIVES: The Rehab@Home framework shall support the continuation of rehabilitation at home. METHODS: The framework consists of instrumented insoles, connected wirelessly to a 3G ready tablet PC, a server, and a web-interface for medical experts. The rehabilitation progress is estimated via automated analysis of movement data from standardized assessment tests which are designed according to the needs of stroke patients and executed via the tablet PC application. RESULTS: The Rehab@Home framework's implementation is finished and ready for the field trial (at five patients' homes). Initial testing of the automated evaluation of the standardized mobility tests shows reproducible results. CONCLUSIONS: Therefore it is assumed that the Rehab@Home framework is applicable as monitoring tool for the gait rehabilitation progress in stroke patients. PMID- 26767069 TI - Clinical Decision Support and Palivizumab: A Means to Protect from Respiratory Syncytial Virus. AB - BACKGROUND AND OBJECTIVES: Palivizumab can reduce hospitalizations due to respiratory syncytial virus (RSV), but many eligible infants fail to receive the full 5-dose series. The efficacy of clinical decision support (CDS) in fostering palivizumab receipt has not been studied. We sought a comprehensive solution for identifying eligible patients and addressing barriers to palivizumab administration. METHODS: We developed workflow and CDS tools targeting patient identification and palivizumab administration. We randomized 10 practices to receive palivizumab-focused CDS and 10 to receive comprehensive CDS for premature infants in a 3-year longitudinal cluster-randomized trial with 2 baseline and 1 intervention RSV seasons. RESULTS: There were 356 children eligible to receive palivizumab, with 194 in the palivizumab-focused group and 162 in the comprehensive CDS group. The proportion of doses administered to children in the palivizumab-focused intervention group increased from 68.4% and 65.5% in the two baseline seasons to 84.7% in the intervention season. In the comprehensive intervention group, proportions of doses administered declined during the baseline seasons (from 71.9% to 62.4%) with partial recovery to 67.9% during the intervention season. The palivizumab-focused group improved by 19.2 percentage points in the intervention season compared to the prior baseline season (p < 0.001), while the comprehensive intervention group only improved 5.5 percentage points (p = 0.288). The difference in change between study groups was significant (p = 0.05). CONCLUSIONS: Workflow and CDS tools integrated in an EHR may increase the administration of palivizumab. The support focused on palivizumab, rather than comprehensive intervention, was more effective at improving palivizumab administration. PMID- 26767070 TI - Word Detection in Sung and Spoken Sentences in Children With Typical Language Development or With Specific Language Impairment. AB - BACKGROUND: Previous studies have reported that children score better in language tasks using sung rather than spoken stimuli. We examined word detection ease in sung and spoken sentences that were equated for phoneme duration and pitch variations in children aged 7 to 12 years with typical language development (TLD) as well as in children with specific language impairment (SLI ), and hypothesized that the facilitation effect would vary with language abilities. METHOD: In Experiment 1, 69 children with TLD (7-10 years old) detected words in sentences that were spoken, sung on pitches extracted from speech, and sung on original scores. In Experiment 2, we added a natural speech rate condition and tested 68 children with TLD (7-12 years old). In Experiment 3, 16 children with SLI and 16 age-matched children with TLD were tested in all four conditions. RESULTS: In both TLD groups, older children scored better than the younger ones. The matched TLD group scored higher than the SLI group who scored at the level of the younger children with TLD . None of the experiments showed a facilitation effect of sung over spoken stimuli. CONCLUSIONS: Word detection abilities improved with age in both TLD and SLI groups. Our findings are compatible with the hypothesis of delayed language abilities in children with SLI , and are discussed in light of the role of durational prosodic cues in words detection. PMID- 26767071 TI - Magnetic Resonance Imaging Findings in Childhood Period Nasopharynx Cancer. AB - BACKGROUND: Nasopharyngeal carcinoma is a rarely seen tumor in childhood. It is mostly detected late as the clinical features are similar to other childhood tumors which affect the nasopharynx and adenoidal hypertrophy. Therefore, the radiological features of childhood tumors of the nasopharynx must be well known. The aim of this study was to investigate the contribution of MR imaging features of childhood nasopharynx cancer. MATERIAL/METHODS: The study included 10 nasopharyngeal carcinoma patients under the age of 18 years who presented at hospital between February 2008 and March 2014 and who had tissue diagnosis and MRI of the nasopharynx region. The MRI scans were evaluated by two radiologists. Loco-regional spread, asymmetry, signal intensity of the tumors, and lymph nodes were evaluated. RESULTS: In all the patients there was a mass which narrowed the nasopharynx. In all cases, unilateral mastoid opacification was observed. In 9 cases (90%), parapharyngeal extension was found. In 8 cases (80%), the mass showed an extension into the nasal cavity or oropharynx. In 5 cases (50%), there was an involvement of the skull base. In 3 patients (30%), an extension to the masticator space and pterygopalatine fossa was found. There were enlarged cervical lymph nodes bilaterally in 10 cases (100%). In 4 cases (40%), a lateral retropharyngeal lymph node was detected. CONCLUSIONS: Childhood nasopharyngeal cancers are often diagnosed at an advanced stage. MR imaging can be helpful in diagnosis and differential diagnosis of childhood nasopharynx cancer from other diseases of the nasopharynx. PMID- 26767072 TI - Comparison Between Prospectively Electrocardiogram-Gated High-Pitch Mode and Retrospectively Electrocardiogram-Gated Mode for Dual-Source CT Coronary Angiography. AB - BACKGROUND: We aimed to report the image quality, relationship between heart rate and image quality, amount of contrast agent given to the patients and radiation doses in coronary CT angiography (CTA) obtained by using high-pitch prospectively ECG-gated "Flash Spiral" technique (method A) or retrospectively ECG-gated technique (method B) using 128*2-slice dual-source CT. MATERIAL/METHODS: A total of 110 patients who were evaluated with method A and method B technique with a 128*2-detector dual-source CT device were included in the study. Patients were divided into three groups based on their heart rates during the procedure, and a relationship between heart rate and image quality were evaluated. The relationship between heart rate, gender and radiation dose received by the patients was compared. RESULTS: A total of 1760 segments were evaluated in terms of image quality. Comparison of the relationship between heart rate and image quality revealed a significant difference between heart rate <60 beats/min group and >75 beats/min group whereas <60 beats/min and 60-75 beats/min groups did not differ significantly. The average effective dose for coronary CTA was calculated as 1.11 mSv (0.47-2.01 mSv) for method A and 8.22 mSv (2.19-12.88 mSv) for method B. CONCLUSIONS: Method A provided high quality images with doses as low as <1 mSv in selected patients who have low heart rates with a high negative predictive value to rule out coronary artery disease. Although method B increases the amount of effective dose, it provides high diagnostic quality images for patients who have a high heart rate and arrhythmia which makes it is difficult to obtain images. PMID- 26767074 TI - Morphological and Morphometrical Study of the Human Ossicular Chain: A Review of the Literature and a Meta-Analysis of Experience Over 50 Years. AB - The ossicular chain has been known for 500 years and yet there are a small number of morphometrical studies. We reviewed the whole literature that is available online regarding the human ossicular chain from an anatomist perspective and correlated the data from all the papers that showed any relevance. Inclusion and exclusion criteria were developed a priori. A thorough description of all ossicular differences has been made and we present their variations in dimensions trying to associate measurements obtained with race. This research included papers spreading on a horizon of over 50 years of worldwide experience. Statistical analysis revealed that there is a great difference in measurements and the results cannot be sufficiently associated. The explanation of this variation in the measurements obtained might be due to errors in the procedure. We conclude that ossicular chain reveals a great variety, and propose that a measurement protocol for auditory ossicles must be widely performed. PMID- 26767073 TI - Novel Drugs and Combination Therapies for the Treatment of Metastatic Melanoma. AB - Metastatic melanoma (MM) still remains as one of the most worrisome cancer known to mankind. In last two decades, treatment of melanoma took a dramatic turn with the discovery of targeted therapy which targets the mutations in mitogen activated protein kinase (MAPK) pathway and immune checkpoint inhibitors. These new findings have led to emergence of many novel drugs that have been approved by FDA. Targeted therapy drugs such as vemurafenib, trametinib and dabrafenib target the MAPK pathway whereas immunotherapies such as ipilimumab, nivolumab and pembrolizumab block immune checkpoint receptors on T lymphocytes. All these drugs have shown to improve the overall survival in MM. Despite these recent discoveries, treatment of MM remains challenging because of rapid development of resistance to targeted therapy. This review will discuss recently approved drugs and their adverse effects and also shed light on combination therapy in treatment of melanoma. PMID- 26767075 TI - Impact of Starting an Emergency Medicine Residency Program on Overall Mortality Rate in a Regional Trauma Center. AB - BACKGROUND: CHRISTUS Spohn Hospital Corpus Christi - Memorial began an Emergency Medicine Residency Program in March 2007. During each of the three years of their residency, residents are required to complete a trauma surgery rotation. These emergency medicine residents are the only residents participating on this rotation as there is no surgical residency. The Department of Acute Care Surgery, Trauma and Surgical Critical Care analyzed the impact of the residents on trauma patient care outcomes with the hypothesis that there were no differences. METHODS: Data including length of stay in the hospital, length of stay in the intensive care unit, time spent in the emergency department (ED), morbidities and mortalities were compiled from the trauma registry for patients from the year before the residents began (March 1, 2006 to February 28, 2007) and compared with patients from the first year the residents began their trauma rotations (March 1, 2007 to February 29, 2008). T-tests and Mann-Whitney U tests were used to compare continuous variables and a Chi-square test was used to analyze the categorical variable (mortality). Linear and logistic regression analyses were also performed in order to adjust for potential confounding factors. RESULTS: Trauma patient admission rates were 1,316 before and 1,391 after the residents began. No statistically significant differences were found among all of the outcome variables during the two time periods except for time spent in the ED (P = 0.00), which increased during the year the residents began (236.83 +/- 4.53 minutes in 2006 compared to 297.40 +/- 5.55 minutes in 2007). Linear and logistic regression analyses confirmed these results with the exception of a statistically significant decrease in mortality with the residents on the trauma service (2.8% in 2006 and 2.1% in 2007, P = 0.00) after adjustment for multiple confounding factors. CONCLUSION: The addition of emergency medicine residents to the trauma care service did increase ED length of stay, but did not increase overall hospital or intensive care unit length of stay. There was a statistically significant decrease in adjusted morbidity and mortality, thus supporting our hypothesis that the residency program did not negatively impact the trauma service and its goals of high quality patient care. PMID- 26767076 TI - Necrotizing Fasciitis Among Patients With Liver Cirrhosis in Texas, 2001 - 2010: A Population-Based Cohort Study. AB - BACKGROUND: Liver cirrhosis is a risk factor for necrotizing fasciitis (NF), and is associated with markedly worse outcomes than for NF among non-cirrhosis patients. Only limited, mostly single-center, data were reported to date on the epidemiology, clinical features, resource utilization and outcomes of NF among patients with cirrhosis. METHODS: We studied a population-based cohort of adult hospitalizations associated with cirrhosis, who had a diagnosis of NF during the years 2001 - 2010, using the Texas Inpatient Public Use Data File. The annual volume of NF hospitalizations was benchmarked against all annual hospitalizations with a diagnosis of cirrhosis. The patterns of demographics, chronic comorbidities, evolving organ failure, resource utilization and outcomes were examined. RESULTS: There were 371,745 hospitalizations associated with liver cirrhosis, with 381 NF hospitalizations during study period. The annual volume of NF hospitalizations rose 7.9%/year (P = 0.0287), while its incidence among cirrhosis-associated hospitalizations remained unchanged (P = 0.2955). Non cirrhosis comorbidities were reported in 69.6% and ICU care was required in 67.2% of NF hospitalization. The key changes noted between 2001 - 2003 and 2008 - 2010 among NF hospitalizations included rising mean (SD) Deyo-Charlson index 2.4 (1.5) vs. 3.9 (2.4) (P < 0.0001), development of >= 3 organ failures in 9.1% vs. 39.8% (P < 0.0001), and discharge to long-term care facilities 7.8% vs. 21.1% (P = 0.0204). Hospital mortality was unchanged (26% vs. 33.1%; P = 0.3659). Inflation adjusted total hospital charges did not change (P = 0.1025) during study period. CONCLUSIONS: The present cohort of NF associated with liver cirrhosis is the largest reported to date. A rising annual volume of NF events matched a corresponding increase in cirrhosis-associated hospitalizations. There was increasing burden of chronic comorbidity and rising severity of illness, with a majority of patients requiring ICU care. Case fatality was high and there has been increasing residual morbidity among hospital survivors. The observed findings warrant further study in other populations. PMID- 26767077 TI - Recent Patient Characteristics and Medications at Admission and Discharge in Hospitalized Patients With Heart Failure. AB - BACKGROUND: To improve the clinical outcome of heart failure (HF), it is important to evaluate the etiology and comorbidities of HF. We previously reported the baseline clinical characteristics and medications in hospitalized patients with HF in years 2000 - 2002 (group 2000) and 2007 - 2009 (group 2008). METHODS: We conducted a retrospective study of 158 patients who were hospitalized due to HF between 2012 and 2014 (group 2013) in the Department of Cardiology, Fukuoka University Hospital. We analyzed the clinical characteristics and medications at admission and discharge, and compared the findings in group 2013 to those in group 2000 and group 2008. RESULTS: The major causes of HF were ischemic heart disease, hypertensive cardiomyopathy, valvular heart disease, and dilated cardiomyopathy. The New York Heart Association classification in group 2013 was significantly higher than those in group 2000 and group 2008. There was no difference in the level of brain natriuretic peptide at admission between group 2008 and group 2013. Tolvaptan began to be administered in group 2013. The median dose of furosemide just before the use of tolvaptan was 40 mg/day. At discharge, group 2013 showed higher rates of beta-blocker and aldosterone antagonist. There was no difference in the frequency of loop diuretics. The dose of carvedilol at discharge was only 6.2 +/- 4.0 mg/day. Antiarrhythmic drugs and beta-blocker were used more frequently in HF with reduced ejection fraction (EF) than in HF with preserved EF. CONCLUSIONS: We may be able to improve the clinical outcome of HF by examining the differences in the clinical characteristics and medications at admission and discharge in hospitalized patients with HF. PMID- 26767078 TI - Influence of Body Composition on Lung Function and Respiratory Muscle Strength in Children With Obesity. AB - BACKGROUND: Obesity affects lung function and respiratory muscle strength. The aim of the present study was to assess lung function and respiratory muscle strength in children with obesity and determine the influence of body composition on these variables. METHODS: A cross-sectional study was conducted involving 75 children (40 with obesity and 35 within the ideal weight range) aged 6 - 10 years. Body mass index, z score, waist circumference, body composition (tetrapolar bioimpedance), respiratory muscle strength and lung function (spirometry) were evaluated. RESULTS: Children with obesity exhibited larger quantities of both lean and fat mass in comparison to those in the ideal weight range. No significant differences were found between groups regarding the respective reference values for respiratory muscle strength. Male children with obesity demonstrated significantly lower lung function values (forced expiratory volume in the first second % (FEV1%) and FEV1/forced vital capacity % (FVC%) : 93.76 +/- 9.78 and 92.29 +/- 3.8, respectively) in comparison to males in the ideal weight range (99.87 +/- 9.72 and 96.31 +/- 4.82, respectively). The regression models demonstrated that the spirometric variables were influenced by all body composition variables. CONCLUSION: Children with obesity demonstrated a reduction in lung volume and capacity. Thus, anthropometric and body composition characteristics may be predictive factors for altered lung function. PMID- 26767079 TI - Impact of Chest Pain Protocol Targeting Intermediate Cardiac Risk Patients in an Observation Unit of an Academic Tertiary Care Center. AB - BACKGROUND: Chest pain (CP) is a frequent cause of emergency room visits in United States and adds a huge financial burden to our healthcare cost. With the addition of observation units, standard CP protocols have shown to decrease length of stay (LOS) and cost per discharge (CPD). We report our experience with the development and implementation of "CP protocol for intermediate cardiac risk patients" and its impact on healthcare resource utilization at our medical center. METHODS AND RESULTS: We retrospectively analyzed 30 patients who presented to Advocate Christ Medical Center (ACMC) with CP and were considered to be at intermediate risk for acute coronary syndrome after obtaining IRB approval. Patients were treated with our standardized CP protocol and labeled as "protocol patients". Our control group consisted of patients with similar demographics and diagnosis but not treated with our CP protocol admitted in the same time period and under our own faculty. This helped remove the bias of different treating attending. Our protocol algorithm consisted of medications, an electrocardiogram (EKG), cardiac troponin I level, and a stress test if indicated. Primary clinical endpoints for this study were LOS in hours and CPD for patients in our protocol group compared to control group. LOS in the protocol group was lower compared to the control but the difference was not statistically significant (P = 0.74). The average CPD in the control group (mean = $13,446) was almost $830 more than the protocol group (mean = $14,276, P = 0.827). CONCLUSION: Implementation of standardized protocols for patients with CP has proven to be a cost effective strategy at several institutions across the country. Our study showed a reduction in CPD although not statistically significant. LOS was also reduced but did not meet statistical significance mainly due to our small sample size. Previous studies had demonstrated much larger savings between a protocol-driven group and a non-protocol-driven group. On further analysis of our data, our protocol group contained five patients who underwent invasive diagnostic tests including computed tomography for pulmonary embolism scans which were not present in the control group. This accounted for the small reduction in costs for the protocol group. PMID- 26767081 TI - Predictors of Outcome of Rectovaginal Fistula Surgery in Women With Crohn's Disease. AB - BACKGROUND: Despite measures taken to control traditional risk factors like increased rectal disease activity, anorectal stenosis, and, to a lesser extent, obesity, rates of poor outcomes after rectovaginal fistula (RVF) surgery in women with Crohn's disease (CD) are still high and require further elucidation. To bridge the gap, we sought to identify risk factors beyond the aforementioned determinants that may be associated with poor outcomes in these patients. METHODS: We designed a retrospective, unmatched, case-control study to test our hypothesis. The population comprised women with CD who underwent RVF surgery between the years of 2000 and 2013. Cases were defined as surgeries with an unsuccessful outcome at 4 weeks post-surgery, and controls represented those with a successful outcome at 4 weeks post-surgery. With multivariable logistic regression models, we sought to identify pertinent risk factors for poor outcomes after RVF surgery in these women. RESULTS: Of the 108 women with CD who were referred to our institution for evaluation of RVFs between 2000 and 2013, 39 underwent a total of 63 surgeries, of which 16 were cases and 47 were controls. There were no significant differences between them with regard to medications and clinical or mucosal disease severity, but a significantly higher proportion of poor outcomes arose from the group of women who underwent a mucosal flap procedure (88%) compared to those who had a seton placed (13%; P = 0.0004). The final adjusted logistic regression model demonstrated that women who underwent a mucosal flap procedure instead of a seton placement were 17.5 times more likely to have a poor surgical outcome (odds ratio (OR): 17.51; 95% confidence interval (CI): 3.12 - 98.43; P = 0.0012). Moreover, it was seen that women with active colonic mucosal disease, independent of rectal disease activity, were 4.4 times more likely to have a poor outcome (OR: 4.40; 95% CI: 1.06 - 18.26). CONCLUSION: Mucosal flap procedures, representing the second, or definitive, stage in surgical treatment of RVF are associated with much worse outcomes and therefore should be preceded by aggressive medical optimization of the patient. PMID- 26767080 TI - Efficacy and Safety of Ipragliflozin in Japanese Patients With Type 2 Diabetes: Interim Outcome of the ASSIGN-K Study. AB - BACKGROUND: Ipragliflozin is a sodium-glucose co-transporter 2 inhibitor that can improve glycemic control and reduce body weight and blood pressure in patients with type 2 diabetes mellitus (T2DM). We evaluated the efficacy and safety of ipragliflozin in the real-world clinical setting, with a focus on the changes of body composition up to 3 months of treatment. METHODS: This was a prospective multicenter interventional trial. We investigated changes of the blood pressure, body composition, blood glucose, hemoglobin A1c (HbA1c), ketone bodies, lipids, and insulin after treatment with ipragliflozin (50 - 100 mg/day) for 12 weeks in Japanese patients with T2DM who showed poor glycemic control despite receiving diet and exercise therapy with or without oral antidiabetic drugs for more than 12 weeks. RESULTS: Two hundred and fifty-seven subjects were included in the efficacy analysis up to 12 weeks of treatment and 301 subjects were included in the safety analysis. From baseline to 12 weeks, HbA1c showed a change of -0.68% (95% confidence interval (CI): -0.83, -0.53) and fasting blood glucose showed a change of -23.9 mg/dL (95% CI: -30.5, -17.2), with both parameters displaying a significant reduction (P < 0.001). The difference of body weight from baseline was -1.82 kg (95% CI: -2.14, -1.50), and it also showed significant reduction (P < 0.001). Analysis of body composition revealed that body fat changed by -1.46 kg (95% CI: -1.79, -1.14, P < 0.001) and body water changed by -0.37 kg (95% CI: 0.60, -0.14, P < 0.01). Laboratory tests demonstrated improvement of liver function and the lipid profile. Adverse events (AEs) occurred in 22.6% of the subjects, with frequent events being vulvovaginal candidiasis in 2.7% and cystitis in 2.0%. Serious AEs occurred in three subjects. CONCLUSIONS: In patients with T2DM, ipragliflozin improved glycemic control after 1 month of treatment and caused weight loss by reducing body fat more than body water. PMID- 26767082 TI - Efficacy and Safety of Alogliptin in Patients With Type 2 Diabetes: Analysis of the ATTAK-J Study. AB - BACKGROUND: Dipeptidyl peptidase-4 (DPP-4) inhibitors have been shown to reduce hemoglobin A1c (HbA1c) in patients with type 2 diabetes, but the reduction varies between patients and adequate glycemic control may not be achieved. We evaluated the efficacy and safety of the DPP-4 inhibitor alogliptin in the real clinical setting, and analyzed factors associated with the improvement of HbA1c by alogliptin treatment. METHODS: A retrospective observational study was performed in patients with type 2 diabetes attending hospitals or clinics belonging to the Kanagawa Physicians Association who received treatment with alogliptin for 1 year or longer. Patients using insulin were excluded from the study. The efficacy endpoints were HbA1c (National Glycohemoglobin Standardization Program value), blood glucose (fasting/postprandial), body weight, blood pressure (systolic/diastolic), liver function (glutamate oxaloacetate transaminase, glutamate pyruvate transaminase, and gamma-glutamyl transpeptidase), kidney function (serum creatinine and estimated glomerular filtration rate), serum lipids (total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides), and serum amylase. Adverse events were compiled to assess safety. RESULTS: Of 330 patients whose case records were collected, 27 patients were excluded for protocol violations, leaving 303 patients to form the full analysis set. Compared with baseline, HbA1c showed a decrease by 0.54+/-1.22% (mean +/- standard deviation) after 12 months of alogliptin treatment. Factor analysis demonstrated that the change of HbA1c after 12 months was significantly influenced by the baseline HbA1c level, duration of diabetes, concomitant use of sulfonylureas, and compliance with diet therapy. In addition, there was a significant reduction of total cholesterol, low-density lipoprotein cholesterol, and the estimated glomerular filtration rate after 12 months of alogliptin treatment, as well as a significant increase in serum creatinine. No significant changes of body weight, blood pressure, or liver function were observed. Symptoms of hypoglycemia occurred in two patients (0.6%). CONCLUSIONS: Alogliptin displayed a significant hypoglycemic effect and excellent safety in routine clinical use. Factors influencing the change of HbA1c with alogliptin therapy may include the HbA1c at the start of treatment, the duration of diabetes, use of sulfonylureas, and compliance with diet therapy. PMID- 26767083 TI - Are the Dysnatremias a Permanent Threat to the Critically Ill Patients? AB - BACKGROUD: The dysnatremias (hyponatremia and hypernatremia) are relatively common findings on admission of intensive care unit (ICU) patients and may represent a major risk. The aim of the study was to assess the ability of serum sodium levels and the Acute Physiology and Chronic Health Evaluation II (APACHE II) to predict mortality of surgical critically ill patients. METHODS: One hundred and ninety-five surgical patients (62% males and 38% females; mean age of 51.8 +/- 17.3 years) admitted to the ICU in the postoperative phase were retrospectively studied. The patients were divided into survivors (n = 152) and non-survivors (n = 43). APACHE II, and serum sodium levels at admission, 48 h and discharge were analyzed by generation of receiver operating characteristic (ROC) curves. RESULTS: The mean APACHE II was 16.3 +/- 8.3 (13.6 +/- 6.1 for survivors and 25.5 +/- 8.5 for non-survivors). The area under the ROC curve for APACHE II was 0.841 (0.782 - 0.889) and 0.721 (0.653 - 0.783), 0.754 (0.653 - 0.783) and 0.720 (0.687 - 0.812) for serum sodium level at admission, 48 h and discharge, respectively. CONCLUSION: Even though APACHE II scoring system was the most effective index to predict mortality in the surgical critically ill patients, the serum sodium levels on admission may also be used as an independent predictor of outcome. PMID- 26767084 TI - The Association Between Body Mass Index and Dental Caries: Cross-Sectional Study. AB - BACKGROUND: Obesity is a growing health-related problem worldwide. Both obesity and dental caries are important health issues with multifactorial aspects. Some studies have shown an association between body mass index (BMI) and caries in childhood/adolescence but limited data about such an association are available in adults. The primary goal of this study was to assess the prevalence of dental caries and its relationship to BMI. METHODS: We conducted a cross-sectional study at Taif University Outpatient Clinic, for adults who had a visit to the dental clinic. Baseline characteristics were obtained by the participating physician. The decayed, missing, and filled teeth (DMFT) index was used to determine the prevalence of dental caries. Information about healthy eating, smoking, exercise, sleep patterns, media consumption, and brushing habits were collected. RESULTS: A total of 385 patients were enrolled with a mean age of 28.39 years, 72.8% were male, mean DMFT index score was 6.55, and 85.5% reported brushing their teeth at least once daily. Of the participants, 55.3% were either overweight or obese, and 42.2% demonstrated a high prevalence of dental caries with no significant difference in BMI when compared to the low dental caries group. CONCLUSIONS: A high prevalence of overweight/obesity and dental caries was observed among the participants. After controlling for potential confounders like smoking and brushing habits, significant positive correlation between BMI and DMFT was observed. PMID- 26767085 TI - Clinical Relevance of Anticoagulation and Dual Antiplatelet Therapy to the Outcomes of Patients With Atrial Fibrillation and Recent Percutaneous Coronary Intervention With Stent. AB - BACKGROUND: Chronic atrial fibrillation (AF), coexisting with a history of recent coronary angioplasty with stent (PCI-S), represents an encoded indication for oral anticoagulation (OAC) with warfarin plus dual antiplatelet therapy (DAPT). METHODS: Using a retrospective cohort study, we determined the respective impacts on cardiovascular outcomes of three different pharmacologic regimens, i.e., triple therapy (TT) with warfarin + clopidogrel and aspirin, dual therapy (DT) with warfarin + clopidogrel or aspirin, and DAPT with clopidogrel + aspirin. Outcomes of interest were all-cause mortality, ischemic cardiac events, ischemic cerebral events, and bleeding events. The inclusion criterion was the coexistence of an indication for OAC (e.g., chronic AF) with an indication for DAPT due to recent PCI-S. RESULTS: Among the 98 patients enrolled, 48 (49%), 31 (31.6%), and 19 (19.4%) patients were prescribed TT, DT, and DAPT, respectively. Throughout a mean follow-up of 378 +/- 15.7 days, there were no significant differences between the three regimens for all abovementioned outcomes. In particular, the total frequency of major bleeding was similar in the three groups: five cases (10.4%) in TT, one case (3.22%) in DT and no case in DAPT groups (Chi-square test, P = 0.1987). CONCLUSIONS: TT, DT and DAPT displayed similar efficacy and safety. Although the superiority of OAC vs. DAPT for stroke prevention in AF patients has been demonstrated by previous randomized trials, a smaller frequency of high thromboembolic risks' features in DAPT group of the present study may have prevented the observation of a higher incidence of ischemic stroke in this group. PMID- 26767086 TI - Rapid Extensive Recurrence of Triple Negative Breast Cancer: Are Both Therapy and Cancer Biology the Culprit? AB - Triple negative breast cancer (TNBC) comprises 17-20% of all breast cancers and is one of the most common breast cancers. The lack of therapy and failure of existing therapy has been a challenge for clinicians. Doxorubicin (DOX) is the first-line therapy, however, it has significant limitations. Rapid extensive recurrence with metastasis in any cancer has been a challenge for surgeons and medical oncologists. The challenge can be due to failure of therapy, drug resistance, or epigenetic changes. Here, we are discussing a stage I breast cancer patient, operated and treated with appropriate chemotherapy with complete response, which recurred in less than 8 months and metastasized to bone, liver and other organs. We are also presenting lab data of the IL-6 secretions on exposure to DOX in one of the most commonly used TNBC cell lines MDA-MB-231. Breast cancer cell line MDA-MB-231 upon exposure to DOX shows an increase in IL-6 levels more than the already elevated IL-6 levels. This might be a reason for early recurrence. We concluded that patients with TNBC might benefit from a standard DOX treatment regimen with an inflammation-blocking agent. PMID- 26767087 TI - Clostridium septicum Aortitis of the Infrarenal Abdominal Aorta. AB - Clostridium septicum aortitis is a rare infection that has a strong association with occult colonic malignancy. There is also emerging evidence to support the combination of medical and surgical management over medical management alone. To the best of our knowledge, we report the 40th known case of C. septicum aortitis. PMID- 26767088 TI - In Search for Equilibrium: Immunosuppression Versus Opportunistic Infection. AB - Post-transplant immunosuppression is necessary to prevent organ rejection. Immunosuppression itself can introduce complications arising from opportunistic infections. We present a case of disseminated blastomycosis manifested only as a skin lesion in an asymptomatic patient post-orthotopic heart transplantation. A 64-year-old female who had recently undergone orthotopic heart transplant for end stage ischemic cardiomyopathy presented for a scheduled routine cardiac biopsy. The patient had no current complaints other than a crusted plaque noticed at her nasal tip. It initially manifested 6 months after surgery as a pimple that she repeatedly tried to manipulate resulting in redness and crust formation. Her immunosuppressive and prophylactic medications included: mycophenolate, tacrolimus, prednisone, bactrim, acyclovir, valganciclovir, pyrimethamine/sulfadiazine, and fluconazole. On physical examination, she was flushed, with a large and exquisitely tender crusted necrotic lesion involving almost the entire half of the nose anteriorly, the left forehead and right side of the neck. She had decreased air entry over the right lung field as well. A computed tomography (CT) image of the chest was ordered to investigate this concerning physical exam finding in the post-transplant state of this patient on immunosuppressive therapy. Chest CT revealed bilateral nodular pulmonary infiltrates with confluence in the posterior right upper lobe. Blood cultures for aerobic and anerobic organisms were negative. Both excisional biopsy of the nasal cutaneous ulcer and bronchial biopsy demonstrated numerous fungal yeast forms morphologically consistent with Blastomyces. Cultures of both specimens grew Blastomyces dermatitidis, with methicillin-resistant Staphylococcus aureus (MRSA) superinfection of the nose. She received 14 days of intravenous (IV) amphotericin B for disseminated blastomycosis and 7 days of IV vancomycin for MRSA. Her symptoms and cutaneous lesions improved and she received maintenance itraconazole treatment for 1 year. This case illustrates a delicate balance that must be struck between suppressing the immune response to prevent graft rejection and avoiding over-immunosuppression that can lead to susceptibility to infection. Thus, in any post-transplant patient, a vigorous history and physical must be performed given that infections may present without symptoms and cause grave consequences. PMID- 26767089 TI - Interhemispheric Acute Subdural Hematoma: A Distinct Entity of Subdural Hematoma. PMID- 26767090 TI - Permanent draft genome sequence of Desulfurococcus mobilis type strain DSM 2161, a thermoacidophilic sulfur-reducing crenarchaeon isolated from acidic hot springs of Hveravellir, Iceland. AB - This report presents the permanent draft genome sequence of Desulfurococcus mobilis type strain DSM 2161, an obligate anaerobic hyperthermophilic crenarchaeon that was isolated from acidic hot springs in Hveravellir, Iceland. D. mobilis utilizes peptides as carbon and energy sources and reduces elemental sulfur to H2S. A metabolic construction derived from the draft genome identified putative pathways for peptide degradation and sulfur respiration in this archaeon. Existence of several hydrogenase genes in the genome supported previous findings that H2 is produced during the growth of D. mobilis in the absence of sulfur. Interestingly, genes encoding glucose transport and utilization systems also exist in the D. mobilis genome though this archaeon does not utilize carbohydrate for growth. The draft genome of D. mobilis provides an additional mean for comparative genomic analysis of desulfurococci. In addition, our analysis on the Average Nucleotide Identity between D. mobilis and Desulfurococcus mucosus suggested that these two desulfurococci are two different strains of the same species. PMID- 26767091 TI - High quality permanent draft genome sequence of Phaseolibacter flectens ATCC 12775(T), a plant pathogen of French bean pods. AB - Phaseolibacter flectens strain ATCC 12775(T) (Halpern et al., Int J Syst Evol Microbiol 63:268-273, 2013) is a Gram-negative, rod shaped, motile, aerobic, chemoorganotroph bacterium. Ph. flectens is as a plant-pathogenic bacterium on pods of French bean and was first identified by Johnson (1956) as Pseudomonas flectens. After its phylogenetic position was reexamined, Pseudomonas flectens was transferred to the family Enterobacteriaceae as Phaseolibacter flectens gen. nov., comb. nov. Here we describe the features of this organism, together with the draft genome sequence and annotation. The DNA GC content is 44.34 mol%. The chromosome length is 2,748,442 bp. It encodes 2,437 proteins and 89 RNA genes. Ph. flectens genome is part of the Genomic Encyclopedia of Type Strains, Phase I: the one thousand microbial genomes study. PMID- 26767092 TI - Draft Genome Sequence of the Biocontrol and Plant Growth-Promoting Rhizobacterium Pseudomonas fluorescens strain UM270. AB - The Pseudomonas fluorescens strain UM270 was isolated form the rhizosphere of wild Medicago spp. A previous work has shown that this pseudomonad isolate was able to produce diverse diffusible and volatile compounds involved in plant protection and growth promotion. Here, we present the draft genome sequence of the rhizobacterium P. fluorescens strain UM270. The sequence covers 6,047,974 bp of a single chromosome, with 62.66 % G + C content and no plasmids. Genome annotations predicted 5,509 genes, 5,396 coding genes, 59 RNA genes and 110 pseudogenes. Genome sequence analysis revealed the presence of genes involved in biological control and plant-growth promoting activities. We anticipate that the P. fluorescens strain UM270 genome will contribute insights about bacterial plant protection and beneficial properties through genomic comparisons among fluorescent pseudomonads. PMID- 26767093 TI - Dairy proteins and soy proteins in infant foods nitrogen-to-protein conversion factors. AB - Protein content of any source is classically determined through the analysis of its nitrogen content done for more 100 years by the Kjeldahl method, and the obtained result is multiplied by a number named nitrogen conversion factor (NCF). The value of NCF is related to the amino acid composition of the protein source and to the eventual presence of side groups covalently bound to some amino acids of the protein chain. Consequently, the value of NCF cannot be identical for all sources of food proteins. The aim of this paper is to review the available knowledge on the two allowed protein sources for infant food formulas, milk and soybean, in order to bring the right scientific basis which should be used for the revision of both European legislation and Codex Standard for Infant Formulas. PMID- 26767094 TI - Quality assessment of clinical education services in teaching hospitals located in Kerman, Iran. AB - INTRODUCTION: Clinical education is one of the most important components of the resource generation function of health systems, and it has a very important role in graduates' competency with respect to effective, practical education. This study aimed to assess the quality of clinical services in Kerman's teaching hospitals located in southeastern Iran. METHODS: This cross-sectional study was conducted in 2011 on 303 medical students at different levels of medical education at Kerman's teaching hospitals. A modified SERVQUAL instrument was used to collect the data after its validity and reliability were checked. The data were analyzed by SPSS 18.0 using the paired t-test, Kruskal-Wallis, and post hoc tests, when appropriate. RESULTS: In all five dimensions of quality, gaps were observed between students' perceptions and expectations as follows: Assurance (mean = -1.18), Responsiveness (-1.56), Empathy (-1.4), Reliability (-1.27), and Tangibles (-1.21). There was a significant difference between the quality perceptions and expectations of the medical students (p < 0.001). A significant difference was observed between three educational levels, including externships, internships, and assistantships regarding the dimensions of the quality gaps (p < 0.001). CONCLUSION: The clinical services provided by teaching hospitals in the study did not meet the students' expectations at any of the three educational levels. As we precisely assessed the dimensions and items that had the higher quality gaps, it was apparent that, for most part, clinical education officials could improve the quality by designing interventions, which would not be very difficult to do. PMID- 26767095 TI - Effect of different gingival margin restorations of class II cavities on microleakage: an in-vitro study. AB - INTRODUCTION: Microleakage is one of the important contributing factors in the failure of resin restorations. The aim of this study was to determine the effect of the location of the gingival margin (enamel, dentin, or cementum) on nanohybrid composite resin on the microleakage of Class II posterior restoration. METHODS: This was an in vitro study done at Al-Farabi College of Dentistry and Nursing in Jeddah (Saudi Arabia). Eighty-one previously extracted human molars were taken from clinics at Al-Farabi College and divided into three main groups (27 each) according to the location of the gingival margin. Group 1: the location of the gingival margin was in the enamel. Group 2: at the cemento-enamel junction. Group 3: in the cementum. Each main group was divided into three subgroups (9 each) according to storage time. Subgroup A: storage time was 24 hours. Subgroup B: storage time was one month. Subgroup C: storage time was three months. Class II cavity was prepared in one proximal surface for each molar following the general principles of cavity preparation. All samples were restored by nanohybridresin composite (TetricEvoCeram). The specimens were stored in distilled water at 37 degrees C and a humidity of 100% in an incubator for one day, one month, and three months, respectively, according to the subgroups. After sealing, the samples were stained with 2.5% methylene blue dye. Each sample was examined microscopically by a stereomicroscope using a computerized image analyzing system. Statistical analysis was done by two-way ANOVA test comparing dye penetration mean values (MUm). RESULTS: The value of dye penetration increased remarkably from enamel, Cemento-enamel junction [CEJ] to cementum, and this was statistically significant (p < 0.001). CONCLUSION: None of the materials tested was able to completely eliminate marginal microleakage at different gingival margins. The least dye penetration was detected at the enamel gingival margin followed by CEJ and then cementum. The least microleakage was observed at the gingival margin located in the enamel. PMID- 26767096 TI - Investigating the key factors in designing a communication skills program for medical students: A qualitative study. AB - INTRODUCTION: Medical students have a serious need to acquire communication skills with others. In many medical schools, special curriculums are developed to improve such skills. Effective training of communication skills requires expert curriculum design. The aim of this study was to explore the experiences and views of experts and stakeholders in order to design a suitable training program in communication skills for medical students. METHODS: The content analysis approach was used in this qualitative study. Forty-three participants were selected from the faculty, nurses, physicians, residents, and medical students at Mashhad University of Medical Sciences using purposive sampling. The data were collected through focus group discussions and semi-structured interviews. To ensure the accuracy of the data, the criteria of credibility, transferability, dependability, and conformability were met. The data were analyzed by MAXQDA software using the Graneheim & Lundman model. RESULTS: The findings of this study consisted of two main themes, i.e., "The vast nature of the present communication skills training" and "administrative requirements of the training program regarding communication skills." The first theme included the educational needs of students, the problems associated with training people to have good communication skills, the importance of good communication skills in performing professional duties, communication skills and job requirements, the learning environment of communication skills, and the status of existing training programs for communication skills. Strategies and suitable methods for teaching communication skills and methods of evaluating the students in this regard also were obtained. CONCLUSION: The findings of this study were the elements required to design a proper and local model to teach communication skills to medical students through analyzing the concepts of effective communication. The results of this study can be useful for medical faculties in designing a proper program for teaching medical students how to communicate effectively with patients and colleagues. PMID- 26767097 TI - Cognitive emotional consequences of male infertility in their female partners: a qualitative content analysis. AB - INTRODUCTION: Infertility, as a global phenomenon and one of the most important issues of reproductive health, affects women more often than men, even when the infertility is due to a male factor. The purpose of this study was to explore the cognitive emotional experiences of women faced with male infertility. METHODS: This qualitative study was conducted in 2014-2015 in Mashhad, Iran. The perceptions and experiences of healthy women whose husbands were diagnosed with primary male factor infertility were investigated using a qualitative content analysis approach. Participants were selected through purposeful sampling, and data collection was conducted using in-depth semistructured interviews. Data were analyzed using conventional content analysis with MAXqda software. Study rigor was verified via criteria proposed by Lincoln and Guba. RESULTS: One main theme emerged through analysis entitled "cognitive emotional reactions confronting infertility diagnosis" with sub-themes of cognitive emotional reactions when confronted with male infertility diagnosis with subthemes of disbelief and denial, fear and apprehension, suffering and emotional distress, disappointment, frustration, confusion, and joy. CONCLUSION: The diagnosis of male infertility was associated with important emotional cognitive consequences for their female partners. Emotional support, providing new insights into how to treat the issue, and trying to shorten the process of diagnosis are necessary for these women. This kind of support could reduce the psychological effects of confrontation with the diagnosis of male infertility, including social insecurity for women. PMID- 26767098 TI - Competing Risk Analyses of Patients with End-Stage Renal Disease. AB - INTRODUCTION: Chronic kidney disease (CKD) is an important health problem that gradually leads to end-stage renal disease (ESRD). In ESRD patients, death due to other diseases or some events, such as renal transplantation (known as competing risks), would change the probability of observing the event of interest. The aim of this study was to estimate the survival of ESRD patients using competing risk analyses. METHODS: In this retrospective longitudinal study, 307 ESRD patients who were older than 20 were recruited from the dialysis and kidney transplant Centers in Kerman City, Iran, from2007 to 2011. To assess the impacts of the investigated factors on the outcome, a cause-specific hazard model and competing risk models were fitted. Also, the cumulative incidence (CI) approach and sensitivity analysis were implemented. All of the analyses were performed using Stata software, V.12. RESULTS: The results of competing risk models showed that age and type of dialysis were associated with death (hazard ratio (HR)=1.03, p<0.001 and HR=1.65, p=0.011, respectively). In cause specific hazard model each year increase in age was associated with a 2% increase in the risk of death. Also, the types of dialysis were associated significantly with death (HR=1.93), and the effect of the type of dialysis was estimated as HR=1.51 (p=0.04) when we assumed that all patients who had experienced transplantation survived for the longest survival time. For those for whom receiving the transplantation was considered as death, the HR for the type of dialysis as well as the corresponding p-values were 1.82 and 0.001, respectively. CONCLUSION: Ignoring the competing risks of death due to ESRD, such as renal transplantation, in estimating the survival of these patients might lead to overestimation of the results. PMID- 26767099 TI - Self-reported risk behaviors among offender motorcyclists in Ahvaz City. AB - INTRODUCTION: Road traffic accidents are among the most critical public health issues. Many people die on the roads each day and tens of millions sustain nonfatal injuries. The aim of this study is to describe the high-risk behaviors of motorcyclists in which police had to confiscate their motorcycles. METHODS: This cross-sectional study was carried out on 240 motorcyclists in Iran from December 2010 to February 2011. A researcher-created questionnaire was used to collect data on self-reported high-risk behaviors, including passing the crossroads without considering the traffic light, refusing to wear a helmet, performing stunts in the street, and driving in the opposite direction. The collected data was descriptively analyzed. RESULTS: The mean age of motorcyclists was 29.3 years (SD=8.26). Twenty-six percent (n=62) of the participants did not have a motorcycle driver's license. The analysis of risk behaviors showed that 60.8% (n=146) of the motorcycle drivers usually passed crossroads without considering the traffic light and 20.8% (n=50) performed stunts in the street. CONCLUSIONS: This study indicates that the prevalence of high-risk behaviors among motorcyclists is significant. Health education interventions may inhibit these behaviors, thus reducing the risk of injuries. PMID- 26767100 TI - Determinants of pharmaceutical expenditures of urban households: A time series study in Kermanshah province (Iran). AB - INTRODUCTION: In recent decades, the development of medical and pharmaceutical science has led to a heavy financial burden on the government, insurance companies, and the general population. Due to the increasing the cost of pharmaceutical products in the Kermanshah Province, policy makers have tried to identify the factors that resulted in the increases. The aim of this study was to determine the main factors that affect the expenditures for pharmaceutical products by urban households in Kermanshah Province, Iran. METHODS: This analytical-descriptive study was conducted using time series method. The study population was urban households of Kermanshah Province from 1991 to 2013. The explanatory variables of the log-log model were drug price index (LnDPI), the average income of urban households (LnINC), the number of physicians per 1,000 people (LnPH), and the number of hospital beds per 1,000 people (LnBE).The required data were acquired from the Statistical Center of the Ministry of Health and Medical Education. The unit root was evaluated by the Dickey-Fuller test. Stata v.11 software was used for the statistical analysis. RESULTS: Coefficients of LnDPI and LnPH were 0.97 and 0.77, respectively, and they were statistically significant (p < 0.05). Also, the coefficients of D. LnINC (first difference of LnINC) and LnBE were 0.34 and 1.8, respectively, and both of them were statistically insignificant (p > 0.05). CONCLUSION: The results showed that drugs are non-elastic and essential for households. It should be noted that the health policy makers in Iran should conduct appropriate planning to ensure both the physical and financial accessibility to drugs by urban households. The development of basic and supplementary health insurance coverage, especially for poor populations and urban areas where there are patients with chronic diseases, can be a suitable solution to reduce barriers to acquiring the required drugs. PMID- 26767101 TI - Exploring Barriers of the Health System to Rehabilitation Services for People with Disabilities in Iran: A Qualitative Study. AB - INTRODUCTION: The United Nations (UN) identified health as a basic human right, but, unfortunately, the evidence shows that people with disabilities (PWD) often have lower levels of health than the general population. This can be associated with problems in access to the services and programs. The aim of this study was to explore barriers of the health system to rehabilitation services for PWD in Iran. METHODS: This was a qualitative study conducted on 21 participants using semi-structured, in-depth interviews and content analysis from June 2014 to July 2015. Data analysis was performed by MAXQDA version 10. RESULTS: "Barriers" were the most prominent challenge of people with disabilities that needed access to rehabilitation services. These barriers were categorized into eight concepts of deficiency in the system that provides rehabilitation services, defect of education, deficiency in detecting and screening of people with disability, defect of stewardship in rehabilitation, ignoring socio-cultural factors, accessibility hardships, lack of identification, and financial hardships in rehabilitation. CONCLUSIONS: An efficient rehabilitation plan requires a common understanding, considering the long-term complications involved in addressing the barriers. Understanding the barriers of the health system to rehabilitation services requires comprehensive management that first should be familiar with all of PWD, providers, policy makers, and other beneficiaries. It also is necessary for policy makers to consider rehabilitation services as a main part of the health plan; especially, they must change their oversight of rehabilitation services and programs. Thus, policy makers should have need comprehensive management and recommended further research. PMID- 26767102 TI - Design and development of a scale of perceived barriers to self-care in patients with type 2 diabetes mellitus: an exploratory factor analysis. AB - INTRODUCTION: Despite the importance of perceived barriers against self-care in diabetic patients, the role of this factor is rarely addressed in the improvement of self-care behaviors of Iranian patients. The lack of appropriate instruments that fit demographic properties of Iranian society is one reason. The aim of this study was to develop and validate the scale of perceived barriers to self-care in patients with type 2 diabetes mellitus. METHODS: This cross-sectional study conducted on 400 patients with type 2 diabetes who were covered by the health centers in Isfahan (Iran) in 2015. A 22-item, researcher-made instrument was designed; the face and content validities of the instrument were examined through obtaining the opinions of an expert panel before administering the instrument in the study. Also, the exploratory factor analysis was used to investigate the instrument's validity. Cronbach's alpha was employed to measure its internal consistency (reliability). To examine the validity of the final scale, the mean scores of perceived barriers in patients with appropriate and inappropriate self care behaviors were compared. RESULTS: The research sample was comprised of 240 women (60%) and 160 men (40%). The mean value of the content validity index was 0.84. The results of factor analysis confirmed the validity of the 11 items and 3 factors of the developed scale. The factor loading ranged from 0.46 to 0.78. These three factors together explained 40.28% of the total variance. The overall reliability coefficient of the instrument was 0.79, ranging from 0.82 to 0.93 for three factors. CONCLUSION: According to the results, the developed scale was a valid and reliable instrument for examining the barriers perceived by the patients. The findings of this research can help health policy makers in planning to facilitate the self-care behaviors as the most vital factor in diabetes control. PMID- 26767103 TI - Assessment of neonatal mortality in the Neonatal Intensive Care Unit in Sabzevar City for the period of 2006-2013. AB - INTRODUCTION: The neonatal mortality rate (NMR) is an essential index in the assessment of community health. With the rapid advancement of neonatal care, the causes of death in this group and the overall mortality rate have changed. For these reasons, the aim of this study was to determine the current NMR and its causes in Sabzevar City's Neonatal Intensive Care Unit (NICU). METHODS: This cross-sectional study was conducted in the NICU at Sabzevar Hospital from 2006 through 2013. Based on previous studies, the sample size was determined to be 365 neonates who were admitted to the NICU and died before they were discharged. The study tool was a researcher-developed checklist related to deceased neonates in the NICU. The checklist was confirmed based on the validity of its content and its inter-rater reliability. We used chi-squared, the Mann-Whitney U test, and the Spearman correlation to analyze the data. RESULTS: The NMR in Sabzevar's NICU was 6.44 per 1000 during the seven-year period; this rate included the following cases per 1000 live births: very early mortality (2.16), early mortality (3.33), and late mortality (0.96). Among 58,270 live births, 3,667 of the neonates were admitted to the NICU during the seven-year period, which was equivalent to 62.93 admissions per 1000 live births. Of the 3,667 neonates admitted to the NICU, 375 (10.23%) died before they were discharged. The most recurrent diagnoses were respiratory distress syndrome (46%), followed by sepsis (12%). The one-sample chi squared test as a goodness-of-fit test (95% CI) showed that the mortality rates were significantly different based on gender (p = 0.004), birth weight (p < 0.001), gestational age (p < 0.001), different causes of death (p < 0.001), and different years of death (2006-2013) (p < 0.001). There also was a significant difference between the duration of survival (very early mortality, early mortality, and late mortality) (p < 0.001). CONCLUSION: Neonatal mortality in the present study was comparable with that reported in similar studies in Iran and in other countries. The strong association between the mortality rate in the NICU with premature birth and low birth weight indicates the necessity of prenatal care aimed at preventing pre-term labor. Comprehensive programs from antenatal care and care at and after birth are recommended, including the investigation of the risks for neonatal death and offering preventive strategies. PMID- 26767104 TI - Study of Educational Hospital Employees' Satisfaction with the Administration of the Health Reform Plan in Ghazvin, 2015. AB - INTRODUCTION: Employee satisfaction is considered to be an important component in the promotion of service quality and increased efficiency and effectiveness in the reform plan for a healthcare system. Neglecting this issue could result in a lack of success in achieving the healthcare system's objectives. The healthcare reform plan is being implemented to achieve the objectives of the healthcare system. Thus, given the key role of hospital employees in implementing the reform plan, the aim of this study was to determine the levels of hospital employees' satisfaction with their jobs. METHODS: This was a qualitative study in 2015 that included thematic analysis, and 138 employees of the Kosar, Rajaii, and Ghods Hospitals participated. Data were collected using semi-structured interviews, and the data were analyzed using content analysis. RESULTS: After analyzing the data collected by interviewing the employees, 132 codes were identified. The codes were classified into five general concepts including opinions about 1) the reform plan and its administrative barriers, 2) changes in visits, 3) changes in working conditions, 4) changes in salaries and 5) General satisfaction of personnel. CONCLUSION: Increasing workloads, stagnant salaries, and the shortage of personnel were the main factors that reduced the satisfaction of the hospitals' employees with the administration of the healthcare reform plan. PMID- 26767105 TI - Diagnostic Value of the Risk of Malignancy Index (RMI) for Detection of Pelvic Malignancies Compared with Pathology. AB - INTRODUCTION: Pelvic masses are among most the common causes of patient admission into gynecology clinics and one of the most common reasons for referral to gynecologic oncology departments due to the risk of uterine or ovarian malignancies. The aim of this study is to compare the four indices of the risk of malignancy index (RMI 1-4), as a combination of menstrual status, radiological findings, and serum CA125 concentration, for discrimination of benign from malignant pelvic masses. METHODS: This retrospective descriptive and analytic study was conducted on 200 patients with pelvic mass, post-surgery, and who were referred to the oncology department in Shahid Sadoughi hospital of Yazd (Iran) between June 2007 and September 2011. Data regarding demographics, pathology reports, paraclinical and clinical tests were analyzed. The four RMI indices were separately used for determination of benign vs. malignant masses using the optimized cutoff points, ROC curve, sensitivity, specificity, predictive value of positive and negative, and accuracy. Finally, p value for each index was calculated, and a final discrimination power was measured by using SPSS version 17 software. RESULTS: The calculated p values in the four RMI indices in ultrasound findings indicated statistical significance, and the RMI 2 showed the highest level of accuracy or diagnostic performance. RMI 2 had a cutoff point of 90, an under-chart area 86.7, 79.36% sensitivity, 78.95% specificity, 58.44%, positive predictive value, 90.08% negative predictive value, and 78.93% accuracy, and a p value of 0.004. However, this relationship was found not to be meaningful using CT scan images. CONCLUSIONS: Using RMI 2 for differentiation of malignant from benign pelvic masses is a reliable method with ultrasound findings. PMID- 26767106 TI - Value of Computed Tomography for Predicting the Outcome After Percutaneous Nephrolithotomy. AB - INTRODUCTION: Computerized tomography of the urinary tract (CT-UT) has been established as the diagnostic procedure of choice for urinary stones. This study aimed to evaluate its role in predicting the outcome of percutaneous nephrolithotomy (PCNL) in terms of stone free rate and residual fragments. METHOD: This prospective cohort study was conducted on 34 patients in the Urology Department of Theodor Bilharz Research Institute from January 2013 to March 2014. The patients who had large and/or multiple renal stones, including staghorn stones, in 19 renal units scheduled for PCNL were included in this study. All had a pre-operative CT-UT to determine the stones' characteristics and renal anatomy. CT-UT, together with a kidney-Ureter-Bladder (KUB) film, was taken on the first post-operative day. The data were analyzed by SPSS version 17 using independent samples t-test and the chi-squared test. RESULTS: CT-UT showed a statistical significant sensitivity in detecting residual fragments over standard KUB, yet this significance was lost when corrected to significant residual. Stone size and density were independent factors for the presence of residual stones. CONCLUSION: CT-UT post PCNL was sensitive to detect residual fragments, yet it showed no superiority over standard KUB in detecting significant residual. PMID- 26767107 TI - Use of Artificial Neural Networks (ANNs) for the Analysis and Modeling of Factors That Affect Occupational Injuries in Large Construction Industries. AB - INTRODUCTION: Occupational injuries as a workforce's health problem are very important in large-scale workplaces. Analysis and modeling the health-threatening factors are good ways to promote the workforce's health and a fundamental step in developing health programs. The purpose of this study was ANN modeling of the severity of occupational injuries to determine the health-threatening factors and to introduce a model to predict the severity of occupational injuries. METHODS: This analytical chain study was conducted in 10 large construction industries during a 10-year period (2005-2014). Nine hundred sixty occupational injuries were analyzed and modeled based on feature weighting by the rough set theory and artificial neural networks (ANNs). Two analytical software programs, i.e., RSES and MATLAB 2014 were used in the study. RESULTS: The severity of occupational injuries was calculated as 557.47 +/- 397.87 days. The findings of both models showed that the injuries' severity as a health problem resulted in various factors, including individual, organizational, health and safety (H&S) training, and risk management factors, which could be considered as causal and predictive factors of accident severity rate (ASR). CONCLUSION: The results indicated that ANNs were a reliable tool that can be used to analyze and model the severity of occupational injuries as one of the important health problems in large-scale workplaces. Additionally, the combination of rough set and ANNs is a good and proper chain approach to modeling the factors that threaten the health of workforces and other H&S problems. PMID- 26767108 TI - Nutritional and Therapeutic Characteristics of Camel Milk in Children: A Systematic Review. AB - INTRODUCTION: Camel milk is the closest to a human mother's milk. Camel milk is different from other milks, however, having low sugar and cholesterol, high minerals (sodium, potassium, iron, copper, zinc and magnesium, and vitamin C). The milk is considered have medicinal characteristics as well. This systematic review is aimed at determining and reporting nutritional values and medicinal characteristics of camel milk in children. METHODS: The search strategy of the current review is "(camel AND milk) AND (autism OR food allergy OR milk allergy OR children OR diarrhea." The search was conducted via PubMed, Scopus, and Google scholar. Also two Persian scientific databases (SID and Iranmedex) and international congresses were investigated. Full-text papers and abstracts on the topic of camel milk, evaluating nutritional value and medicinal properties, were included in this systematic review. RESULTS: Out of the 472 records found in the resources, 35 related studies were included in the final analysis. The result showed that camel milk is highly nutritious and is safe for consumption by children. CONCLUSION: It seems that many researchers did not follow a specific guideline for reporting and confirming the therapeutic properties of camel milk in children, but there is evidence denoting the importance, trials, and investigations of its usability and benefits. Camel milk as a supplemental treatment seems less invasive and costly than specialist care, medications, alternative treatments, and behavioral interventions. Based on our findings, camel milk is safer for children, effective in the treatment of autism, improves general well-being, promotes body natural defenses, is a good nutritional source, and can helps the daily nutritional needs of humans. PMID- 26767109 TI - Seasonal Distribution of Fungi in Soil Found in Two Hospitals in Bandar Abbas, Iran. AB - INTRODUCTION: Fungal contamination in hospitals has been a major health concern, especially in immunosuppressed patients. Construction programs increase the risk of fungal contaminations in hospitals. This study aimed to monitor and compare fungal contamination in two hospitals in Bandar Abbas, Iran, one of which was undergoing construction. Furthermore, the study determined the seasonal variations in the prevalence of fungi identified in the two hospitals. METHODS: This study was conducted during April-December 2014 on 146 soil samples collected from the Shahid Mohammadi Hospital that was under construction and the Shariati Hospital that was not involved in any construction program. The soil samples were collected in the morning from the dust on the ground. Statistical analysis was performed using the chi-squared test. RESULTS: Among the fungal cultures, 83.56% were found to be positive. We identified 122 fungal isolates, representing 16 genera, 13 of the genera were isolated from Shahid Mohammadi Hospital and 14 were isolated from Shariati Hospital. Aspergillus was the dominant fungus in both hospitals. In Shariati Hospital, 100% of Aspergiluss niger were isolated in the summer. In the spring, Mocur was dominant in both hospitals, and, in the winter, Rhizopus spp. was the dominant fungus in Shahid Mohammadi Hospital (55.5%); however, this fungus was dominant in spring in Shariati Hospital (66.7%). In Shariati Hospital, Scopulariopsis, Drechslera, Penicillium spp., and Yeasts were present only in the fall, whereas yeast was the dominant fungus in summer (100%) in Shahid Mohammadi Hospital. There were not significant differences between two hospitals, with the exception of Fusarium spp., which was more frequent in Shariati Hospital, where no renovation was taking place (p = 0.008). CONCLUSION: Our results indicated that specific ecological niches existed in the two general hospitals in Bandar Abbas. Special attention should be paid to environmental control programs. It is recommended that soil exposure be considered in patients' histories in addition to the current focus on infections related to food and water. PMID- 26767110 TI - The effect of casein phosphopeptide amorphous calcium phosphate fluoride paste (CPP-ACPF) on oral and salivary conditions of patients undergoing chemotherapy: A randomized controlled clinical trial. AB - BACKGROUND: Oral and saliva conditions of patients undergoing chemotherapy is often affected by the medication they receive. Up to now, no appropriate medication that possesses the positive effects of chemotherapy without presenting oral complications has been introduced. OBJECTIVE: The aim of this study was to assess the clinical effects of CPP-ACPF paste on the oral and salivary status of patients undergoing chemotherapy. METHODS: From October 2013 to April 2014, 20 patients in chemotherapy treatment plans and who met the inclusion criteria enrolled in this randomized parallel single-blind controlled clinical trial in Shohada-e-Tajrish Hospital in Tehran, Iran. Patients were divided into two groups: 1) patients received their daily medication of cancer therapy center (group 1, control); 2) patients applied CPP-ACPF Creme (MI paste plus, GC USA) twice a day as instructed (group 2). The baseline status of oral conditions of patients (mucositis, dry mouth, infection, diminished tasting sense, difficulty in food intake, burning sensation of mucosa, saliva and dental plaque pH, rest and stimulated saliva, buffering capacity of saliva) were recorded and reevaluated after 21 and 42 days. The data were analyzed with a Mann-Whitney U test. RESULTS: A total of 20 patients were allocated randomly to groups 1 and 2. The Mann-Whitney U-test showed that application of CPP-ACPF paste twice daily did not cause any significant difference in oral complication of the subject group compared with the control group (p>0.05). Among salivary signs, resting and stimulated saliva rates and saliva buffering capacity had significantly altered in the CPP-ACPF group in day 21 and 42 in comparison with those of the control group (p<0.05). CONCLUSION: Application of CPP-ACPF paste before and during chemotherapy can improve the salivary status of patients undergoing this treatment. PMID- 26767111 TI - Comparison of Pap Smear and Colposcopy in Screening for Cervical Cancer in Patients with Secondary Immunodeficiency. AB - INTRODUCTION: Cervical cancer is the second most common cancer among women worldwide. The sensitivity of conventional Pap smear in detecting cervical lesions before cervical cancer is 51%, which means the false negative value is 49%. The aim of this study was to compare two methods for screening for cervical cancer in patients with secondary immunodeficiency, i.e., the conventional Pap smear and colposcopy. METHODS: This cross-sectional study was conducted on 101 immunodeficient patients who were referred to the Gynecologic Clinic at Shahid Sadughi Hospital in Yazd from March 2011 to August 2012. All patients underwent the Pap test, a colposcopy, and a cervical biopsy, with the latter being considered as the gold-standard test. RESULTS: The most frequency of immunodeficiency was noted among patients with rheumatoid arthritis (53.3%), and this was followed by patients who were undergoing chemotherapy (30.7%), patients with lupus erythematosus (12.9%), and patients with AIDS (3%). The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of the Pap smear were 18.2, 98.5, 85.5, 71.3, and 72.2%, respectively. The respective values for colposcopy were 66.7, 98.94, 80, 97.9, and 97%, respectively. CONCLUSION: In this study the accuracy, sensitivity, specificity, and negative predictive values of colposcopy were higher than those for the Pap smear in detecting high-grade, cervical, pre-malignant lesions (cervical intraepithelial neoplasia: CIN >= 2). Therefore, an annual colposcopy is advised for secondary immunodeficient patients instead of a Pap smear. PMID- 26767112 TI - Development and implementation of Persian test of Elderly for Assessment of Cognition and Executive function (PEACE). AB - INTRODUCTION: A considerable segment of the elderly population in Iran is illiterate, and it seems the existing neuropsychological screening tests are not very useful for detecting dementia in illiterate participants. The purpose of this study was to develop and validate a tool called Persian test of Elderly for Assessment of Cognition and Executive function (PEACE) for detecting dementia in both illiterate and literate participants. METHODS: First, in order to design some of the cognitive aspects of the PEACE assay, we considered other prevalent neuropsychological instruments, such as the General Practitioner assessment of Cognition (GPCOG), Functional Assessment Staging (FAST), Mini Mental State Examination (MMSE), and Wechsler Memory scale. The other domains of PEACE were designed according to our clinical proficiencies and the culture of the society. In the next step, the participants were classified into three distinct groups, i.e., the control group (n=33), the Mild Cognitive Impairment (MCI) group (n=30), and the Alzheimer's group (n=38). All of the participants in each group were divided according to their educational level, i.e., illiterate, semi-literate, and literate. RESULTS: We developed PEACE consisting of 14 items, each of which represents a specific cognitive function, with a maximum score of 91. The 14 items are Orientation, Praxis, Attention and Concentration, Attention and Calculation, Memory, Similarity, Abstract Thinking, General Information, Language, Judgment, Gnosis, Planning (Sequencing), Problem Solving, and Animal Naming. PEACE scores are highly correlated with those of the MMSE (r=0.78). The optimal cut-off point of PEACE chosen for diagnosis of Alzheimer's disease was 67.5 (sensitivity: 75.8%, specificity: 97.4%). The PEACE scores showed a significant difference between Participants with Alzheimer's disease and the control group (p=0.0000) and the MCI group (p=0.003). In addition, there was no significant difference between illiterate and literate participants in the Alzheimer's group. However, the PEACE scores differed significantly (p=0.0000) between illiterate and literate participants in the control group. CONCLUSION: The PEACE addresses the limitations of existing tests and is appropriate for use in countries that have high rates of illiteracy. It is a valid screening mechanism for the detection of dementia in both illiterate and literate participants. PMID- 26767113 TI - Evidence of Energy Transfer from Tryptophan to BSA/HSA Protected Gold Nanoclusters. AB - This work reports on the chromophores interactions within protein-protected gold nanoclusters. We conducted spectroscopic studies of fluorescence emissions originated from gold nanoclusters and intrinsic tryptophan (Trp) in BSA or HSA proteins. Both, steady state fluorescence and lifetime measurements show a significant Forster resonance energy transfer (FRET) from Trp to the gold nanocluster. Tryptophan lifetimes in the case of protein-protected gold nanoclusters are 2.6ns and 2.3ns for BSA and HSA Au clusters while 5.8ns for native BSA and 5.6 for native HSA. The apparent distances from Trp to gold nanocluster emission center, we estimated as 24.75A0 for BSA and 23.80A0 for HSA. We also studied a potassium iodide (KI) quenching of protein-protected gold nanoclusters and compared with the quenching of BSA and HAS alone. The rates of Trp quenching were smaller in BSA-Au and HSA-Au nanoclusters than in the case of free proteins, which is consistent with shorter lifetime of quenched Trp(s) and lower accessibility for KI. While Trp residues were quenched by KI, the emissions originated from nanoclusters were practically unquenched. In summary, for BSA and HSA Au clusters, we found 55% and 59% energy transfer efficiency respectively from tryoptophan to gold clusters. We believe this interaction can be used to our advantage in terms of developing resonance energy transfer based sensing applications. PMID- 26767114 TI - Testosterone replacement in 49,XXXXY syndrome: andrological, metabolic and neurological aspects. AB - We report the case of a 19-year-old boy, presenting several congenital malformations (facial dysmorphisms, cardiac and musculoskeletal abnormalities), mental retardation, recurrent respiratory infections during growth and delayed puberty. Although previously hospitalised in other medical centres, only psychological support had been recommended for this patient. In our department, genetic, biochemical/hormonal and ultrasound examinations were undertaken. The karyotype was 49,XXXXY, a rare aneuploidy with an incidence of 1/85 000-100 000, characterised by the presence of three extra X chromosomes in phenotypically male subjects. The hormonal/biochemical profile showed hypergonadotropic hypogonadism, insulin resistance and vitamin D deficiency. The patient was then treated with testosterone replacement therapy. After 12 months of treatment, we observed the normalisation of testosterone levels. There was also an increase in pubic hair growth, testicular volume and penis size, weight loss, homeostatic model assessment index reduction and the normalisation of vitamin D values. Moreover, the patient showed greater interaction with the social environment and context. LEARNING POINTS: In cases of plurimalformative syndrome, cognitive impairment, recurrent infections during growth and, primarily, delayed puberty, it is necessary to ascertain as soon as possible whether the patient is suffering from hypogonadism or metabolic disorders due to genetic causes. In our case, the diagnosis of hypogonadism, and then of 49,XXXXY syndrome, was unfortunately made only at the age of 19 years.The testosterone replacement treatment, even though delayed, induced positive effects on: i) development of the reproductive system, ii) regulation of the metabolic profile and iii) interaction with the social environment and context.However, earlier and timely hormonal replacement treatment could probably have improved the quality of life of this subject and his family. PMID- 26767115 TI - Association between urinary 3-phenoxybenzoic acid and body mass index in Korean adults: 1(st) Korean National Environmental Health Survey. AB - BACKGROUND: According to US-EPA report, the use of pyrethrins and pyrethroids has increased during the past decade, and their area of use included not only in agricultural settings, but in commerce, and individual household. It is known that urinary 3-PBA, major metabolite of pyrethroid, have some associations with health effect in nervous and endocrine system, however, there's no known evidence that urinary 3-PBA have associations with obesity. METHOD: We used data of 3671 participants aged above 19 from the Korean National Environmental Health Survey in 2009-2011. In our analysis, multivariate piece-wise regression and logistic regression analysis were used to investigate the association between urinary 3 PBA (3-Phenoxybenzoic Acid) and BMI. RESULT: Log-transformed level of urinary 3 PBA had significantly positive association with BMI at the low-level range of exposure (p < 0.0001), and opposite associations were observed at the high level exposure (p = 0.04) after adjusting covariates. In piece-wise regression analysis, the flexion point that changes direction of the associations was at around 4 ug/g creatinine of urinary 3-PBA. As quintiles based on concentration of urinary 3-PBA increased to Q4, the ORs for prevalence of overweight (BMI >= 23 kg/m(2)) were increased, and the OR of Q5 was lower than that of Q4 (OR = 1.810 for Q4; OR = 1.483 for Q5). In the analysis using obesity (BMI >= 25 kg/m(2)) as outcome variable, significant associations were observed between obesity and quintiles of 3-PBA, however, there were no differences between the OR of Q5 and that of Q4 (OR = 1.659 for Q4; OR = 1.666 for Q5). CONCLUSION: Our analysis suggested that low-level of pyrethroid exposure has positive association with BMI, however, there is an inverse relationship above the urinary 3-PBA level at 4 ug/g creatinine. PMID- 26767116 TI - Pedal edema and jugular venous pressure for volume overload in peritoneal dialysis patients. AB - BACKGROUND: The diagnostic strength of the jugular venous pressure (JVP) and pedal edema as physical examination tools for the assessment of volume status has been minimally studied. METHODS: We conducted a prospective observational study in an outpatient peritoneal dialysis clinic in Saskatoon, Canada. Patients were adult (age 18 or older) peritoneal dialysis outpatients without any history of cardiac dysfunction, a central line, and current arteriovenous fistula. JVP was assessed by both a resident and a staff nephrologist, while the presence of edema was assessed by the resident only. Likelihood ratios were calculated for the absence or presence of pedal edema as well as the JVP at multiple cutoffs. The criterion standard for volume overload was defined as an overhydration to extracellular water ratio of greater than or equal to 7 % as determined by bioimpedance (Body Composition Monitor-Fresnius Medical Care). RESULTS: Twenty five separate patient encounters were assessed. Twelve patients were found to be volume overloaded while 13 were euvolemic. The presence and absence of edema were both significant signs for the presence (+likelihood ratio (LR) 16, 95 % confidence interval (CI) 1.02-260) or absence (-LR 0.44, 95 % CI 0.23-0.83) of volume overload, respectively. The JVP failed to reach statistical significance for the presence or absence of volume overload at any height above the sternal angle, although precision was poor for the positive likelihood ratio at cutoffs above 3 cm and the negative likelihood ratio at the 0 cm cutoff. CONCLUSIONS: The presence of pedal edema is a good indicator of volume overload in peritoneal dialysis patients without cardiac dysfunction, although its absence cannot definitively rule out significant water excess. A JVP of 1 to 3 cm was found to be not a clinically significant sign. We are unable to comment on the diagnostic strength of a low (0 cm) or high (JVP >3 cm) due to poor precision. PMID- 26767117 TI - Health literacy predicts participant understanding of orally-presented informed consent information. AB - Informed consent for participation in studies with human subjects is a critically important aspect of clinical research, but research has shown that many potential subjects do not understand information relevant to their participation. A better understanding of factors related to participant understanding of study-related information is thus important. As part of a study to develop a new measure of health literacy, participants viewed a 50 second video in their preferred language (Spanish or English) of a clinician presenting informed consent information. They then responded to six questions about it. In progressively more complicated regression models, we evaluated the relation of demographic variables, general cognitive ability, and health literacy to participants' recall of the information. In a model that only included demographic variables, Spanish language, black race and older age were associated with poorer performance. In a model that included the effects of general cognitive ability and health literacy as well as demographics, education and health literacy were related to performance. Informed consent interventions that take potential research subjects' levels of health literacy into account may result in better understanding of research-related information that can inform their decision to participate. PMID- 26767118 TI - Impact of scaling and root planing with adjunct essential-oil-based mouthwash usage on whole salivary IgG levels in patients with periodontal inflammation. AB - OBJECTIVE: The aim was to assess the effect of scaling and root planing (SRP) with and without adjunct use of an essential-oil-based-mouthwash (EOBM) on whole salivary immunoglobulin G (IgG) levels in patients with periodontal inflammation. METHODS: Fifty patients with periodontal inflammation were included. Treatment wise, these patients were randomly divided into two groups. In group 1, patients underwent SRP and were instructed to rinse with 10 mL of an EOBM twice daily for 30 days, whereas those in group 2 underwent SRP and were instructed to rinse with 10 mL of water twice daily for 30 days. Whole saliva samples were collected at baseline and after 40 days of treatment. P-values < 0.05 were considered statistically significant. RESULTS: At baseline, whole salivary IgG levels were comparable among patients in groups 1 (60.5 +/- 5.5 mg/dL) and 2 (57.3 +/- 2.4 mg/dL). After 40 days of follow-up, there is a significant decrease in whole salivary IgG levels among patients in group 1 (7.2 +/- 2.4 mg/dL) as compared to those in group 2 (26.6 +/- 4.6 mg/dL) (P < 0.001). CONCLUSIONS: SRP, when performed with adjunct use of an EOBM, is more effective in reducing whole salivary IgG levels as compared to when SRP is performed without adjunct use of an EOBM. PMID- 26767119 TI - CRP at early follicular phase of menstrual cycle can cause misinterpretation for cardiovascular risk assessment. AB - OBJECTIVE: C-reactive protein (CRP) is a well-known marker of inflammation and infection in clinical practice. This study is designed to evaluate CRP levels in different phases of menstrual cycle, which might end up with misleading conclusions especially when used for cardiovascular risk assessment. METHODS: Twenty-seven women were eligible for the cross-sectional study. Venous blood samples from each participant were collected twice during the menstrual cycle. The first sampling was held at 2nd to 5th days of the menstrual cycle for FSH, estradiol, CRP, and sedimentation, and the second was done at 21st to 24th days of the menstrual cycle for measurement of progesterone, CRP, and sedimentation values. RESULTS: CRP values were significantly higher in the early follicular phase compared to luteal phase (1.8 mg/L [0.3-7.67] vs. 0.7 mg/L [0.1-8.3], p < 0.001, respectively). In both phases of the menstrual cycle, sedimentation rate was similar (12.1 +/- 6.7 vs. 12.3 +/- 7.7; p = 0.717, respectively). CONCLUSIONS: CRP levels in early follicular phase of the menstrual cycle (menstruation) are significantly higher than CRP levels in luteal phase of the same cycle. In reproductive age women, detection of CRP for cardiovascular risk assessment during menstruation might not be appropriate. PMID- 26767121 TI - Comparative and evolutionary insights into CD4 gene across mammalian and avian taxa. AB - The present day genetic architecture of a species bears much significance to its closely related species which is due to species-specific differences, shaped by different evolutionary forces across time scale. With the availability of whole genome sequence of several closely related species, it is now possible to infer evolutionary patterns of genes and genomes in specific lineages. To this respect, CD4 gene, primarily responsible for defensive mechanism in human, is conserved across a few taxa, and thus, comparative genomic studies could be useful for better understanding of host-pathogen biology. Comparative and evolutionary analyses were performed in eleven taxa (10 mammalian and avian) with different statistical algorithms. Phylogenetic inferences revealed recent divergence of human and chimpanzee, and pig was found to be diverged from rest of the taxa significantly. Additionally, gene length, microsatellites, and secondary structures were observed across taxa. The genetic architecture of CD4 gene and its evolutionary history in different mammalian taxa provide crucial evidence in support of the fact that this gene might have been evolving at a similar rate to other human immune system genes. Future population-based study and structural modeling would unravel the differential ability to interact with HIV virus and influence immune system in humans. PMID- 26767120 TI - Effect of yogurt and pH equivalent lemon juice on salivary flow rate in healthy volunteers - An experimental crossover study. AB - BACKGROUND: Xerostomia is a common clinical problem, and different medications have been tried in its management. In the present study, routine dietary products are used to assess their effect on salivary flow. AIM: To assess the efficacy of yogurt and lemon juice on increase in salivation and its comparison with that of unstimulated saliva. MATERIALS AND METHODS: A total of 40 volunteers (aged 19-48) were selected. The pH of yogurt was calculated, and equivalent pH lemon juice was prepared. First, normal resting saliva was collected as baseline followed by every 1 min for 5 min. Patients were given lemon juice or yogurt and then crossed over to the other group to assess the impact of the stimulants on salivary flow from 1 to 5 min. RESULTS: The results were analyzed statistically. Comparisons between baseline saliva secretion and that by yogurt and lemon juice (using the ANOVA test) showed that there was a significant increase after treatment at the end of the experiment for both yogurt and lemon juice. However, yogurt showed a significant increase in saliva secretion compared to baseline than lemon juice. CONCLUSIONS: Our findings suggest that yogurt is a potential candidate for the treatment of dry mouth. PMID- 26767122 TI - Pregnancy management of women with kidney transplantation. AB - Women with renal disease, besides many dysfunctions, face increasing infertility and high-risk pregnancy due to uremia and changes of the hormonal functions. After renal transplantation, sexual dysfunction improves, providing the possibility of successful pregnancy for women of childbearing age. However, kidney transplanted patients are high-risk pregnant patients with increased maternal and fetal risks, and the graft also may be compromised during pregnancy; most studies report on several successive deliveries due to multidisciplinary team management. In clinical practice, the graft is rarely affected during the period of gestation. Fetal development disorders are also rare although preterm delivery and intrauterine growth retardation are common. For now, several studies and clinical investigations proved that, under multidisciplinary control, kidney transplanted female patients are also possible to have safe pregnancy and successful delivery. There are conflicting data in the literature about the prevention of complications and the timing of pregnancy. Herein, we would like to present some experience of our centre. A total of 847 kidney transplantations have been performed between June 1993 and December 2013 with 163 childbearing aged females (18-45 years) in our center. We report on three kidney transplanted patients who have given birth to healthy newborns. In our practice, severe complications have not been observed. PMID- 26767123 TI - Acute TIPS occlusion due to iatrogenic arteriovenous shunt in a cirrhotic patient with total portal vein thrombosis. AB - A 69-year-old man with portal hypertension was admitted with decompensated alcoholic cirrhosis and diuretic resistant ascites. Ultrasound revealed partial portal thrombosis. Due to diuretic intolerance, transjugular intrahepatic portosystemic shunt (TIPS) was decided during which a hepatic arterial branch was inadvertently catheterized. Finally, TIPS was created, but the patient continued gaining weight. Color-Doppler ultrasonography (CDUS) showed upper stent part patency with absence of flow in lower stent portion. Twenty-five days later, the patient presented melena. Endoscopy revealed blood emerging from the Vater papilla. Hepatic angiography revealed arteriovenous shunt between a hepatic arterial branch and the proximal part of the TIPS shunt. Covered stent placement restored sufficient TIPS flow. The patient deteriorated and died 1 month later. We found out that our major technical drawback was that we did not inject a small amount of contrast after puncturing the supposed portal vein, in order to confirm correct position of the needle. PMID- 26767124 TI - Percutaneous rheolytic mechanical thrombectomy in thrombosed direct intrahepatic portosystemic shunt: Report of two cases. AB - We report two patients with Budd-Chiari syndrome, who underwent direct intrahepatic portosystemic shunt complicated by shunt thrombosis. Percutaneous AngioJet mechanical thrombectomy in combination with manual catheter aspiration and balloon disruption of the residual clot was successful, restoring patency of the thrombosed shunt. PMID- 26767125 TI - Responding to Typhoon Haiyan in the Philippines. PMID- 26767126 TI - Is the response over? The transition from response to recovery in the health sector post-Haiyan. PMID- 26767127 TI - Can you help me write my story? The institutional affiliations of authors of international journal articles on post-disaster health response. PMID- 26767128 TI - Guidelines and training for maternal and newborn care post-Haiyan. PMID- 26767129 TI - Use of the WHO Package of Essential Noncommunicable Disease Interventions after Typhoon Haiyan. PMID- 26767130 TI - Surveillance for and issues relating to noncommunicable diseases post-Haiyan in Region 8. PMID- 26767131 TI - Managing surge staff and resources at the WHO Representative Office in the Philippines after Typhoon Haiyan. PMID- 26767132 TI - Is registration of foreign medical teams needed for disaster response? Findings from the response to Typhoon Haiyan. PMID- 26767133 TI - An assessment of disaster-related mortality post-Haiyan in Tacloban City. AB - INTRODUCTION: Tacloban City was seriously affected by Typhoon Haiyan with 2321 deaths distributed across its 138 villages and subvillages. In January 2014, a team from the Department of Health conducted a mortality assessment to identify risk factors for deaths that occurred during Typhoon Haiyan. METHODS: A retrospective case-control study was conducted in the four coastal villages in Tacloban City with the highest numbers of typhoon-associated deaths. A case was defined as a person who died in Tacloban City during Typhoon Haiyan and whose body was recovered and identified. Controls were selected from surviving family members of cases. Information about typhoon-related knowledge, attitudes and practices of the cases was collected using a standardized questionnaire. RESULTS: There were 100 cases and 100 controls included in the study. The cause of death for all cases was drowning, and all bodies were found inside or near their house. Multivariate analysis identified that the significant risk factors for mortality due to Haiyan were not evacuating before the storm hit (odds ratio [OR] = 10.0; 95% confidence interval [CI]: 3.8-29.1) and exiting their house during the storm (OR = 3.6; 95% CI: 1.9-7.1). Proxies reported that all cases had heard about the coming typhoon, but that 88% did not understand the message about the storm surge. Ninety-five per cent of cases did not evacuate because they did not expect the magnitude of storm. CONCLUSION: Warning messages delivered before and during emergencies should be conveyed in terms understood by the population at risk. We recommend that the results from this study be used to develop more effective messages to be used before future disasters. PMID- 26767134 TI - Rapid health assessments of evacuation centres in areas affected by Typhoon Haiyan. AB - INTRODUCTION: Typhoon Haiyan caused thousands of deaths and catastrophic destruction, leaving many homeless in Region 8 of the Philippines. A team from the Philippine Field Epidemiology Training Program conducted a rapid health assessment survey of evacuation centres severely affected by Haiyan. METHODS: A descriptive study was conducted whereby a convenience sample of evacuation centres were assessed on the number of toilets per evacuee, sanitation, drinking water, food supply source and medical services. RESULTS: Of the 20 evacuation centres assessed, none had a designated manager. Most were located in schools (70%) with the estimated number of evacuees ranging from 15 to 5000 per centre. Only four (20%) met the World Health Organization standard for number of toilets per evacuee; none of the large evacuation centres had even half the recommended number of toilets. All of the evacuation centres had available drinking-water. None of the evacuation centres had garbage collection, vector control activities or standby medical teams. Fourteen (70%) evacuation centres had onsite vaccination activities for measles, tetanus and polio virus. Many evacuation centres were overcrowded. CONCLUSION: Evacuation centres are needed in almost every disaster. They should be safely located and equipped with the required amenities. In disaster-prone areas such as the Philippines, schools and community centres should not be designated as evacuation centres unless they are equipped with adequate sanitation services. PMID- 26767135 TI - Management of the dead in Tacloban City after Typhoon Haiyan. AB - INTRODUCTION: The post-disaster management of the dead involves a series of steps including on-site identification, transfer, storage and examination of bodies and delivery to families for burial. Two weeks after Typhoon Haiyan, a team from the Department of Health (DOH) was tasked with identifying the dead in Tacloban City. METHODS: A suitable site for the collection of bodies was identified and an algorithm and standard data collection form developed. The retrieval of bodies was coordinated with the Bureau of Fire Protection personnel. Upon receipt of a body, two team members conducted a systematic external examination. Findings were documented, photos were taken and each body was assigned a unique number. RESULTS: The DOH team examined 128 bodies. Of these, the majority (86%) were complete bodies; 95% were decomposed and two were skeletonized. Two thirds (66%) were adults, sex was identifiable for 92%, and the male to female ratio was 1:1.4. The majority of adults were females. Only 11% were presumptively identified from documents in clothing; 89% remained unidentified. CONCLUSION: From the limited setting of this study, we describe the process of rapid body processing post-Haiyan. We prioritized rapid processing over more technically complicated means of identification, including DNA testing. Our protocol showed a dignified and efficient way of identifying corpses. As local and regional laboratory capacity increases in the Philippines, the collection of DNA specimens may become part of the identification algorithm. PMID- 26767136 TI - An assessment of drinking-water quality post-Haiyan. AB - INTRODUCTION: Access to safe drinking-water is one of the most important public health concerns in an emergency setting. This descriptive study reports on an assessment of water quality in drinking-water supply systems in areas affected by Typhoon Haiyan immediately following and 10 months after the typhoon. METHODS: Water quality testing and risk assessments of the drinking-water systems were conducted three weeks and 10 months post-Haiyan. Portable test kits were used to determine the presence of Escherichia coli and the level of residual chlorine in water samples. The level of risk was fed back to the water operators for their action. RESULTS: Of the 121 water samples collected three weeks post-Haiyan, 44% were contaminated, while 65% (244/373) of samples were found positive for E. coli 10 months post-Haiyan. For the three components of drinking-water systems - source, storage and distribution - the proportions of contaminated systems were 70%, 67% and 57%, respectively, 10 months after Haiyan. DISCUSSION: Vulnerability to faecal contamination was attributed to weak water safety programmes in the drinking-water supply systems. Poor water quality can be prevented or reduced by developing and implementing a water safety plan for the systems. This, in turn, will help prevent waterborne disease outbreaks caused by contaminated water post disaster. PMID- 26767137 TI - Responding to the health and rehabilitation needs of people with disabilities post-Haiyan. AB - INTRODUCTION: It is estimated that 15% of the world's population has a disability, and disasters increase their risk and vulnerability. Rehabilitation services were limited in the area of the Philippines that was affected by Typhoon Haiyan. This study describes the initial rehabilitation needs assessment and activities to increase rehabilitation services conducted in Leyte province of Region 8 after Haiyan. METHOD: A rehabilitation needs assessment for people with disabilities and injuries needing physical and functional rehabilitation care and assistive devices was conducted in health facilities, evacuation centres and selected municipalities in Leyte province between 9 November 2013 and 30 April 2014 by a consortium of agencies. Improvements to service delivery and referrals were documented. RESULTS: Rehabilitation services were reduced immediately after Haiyan, but they increased in the following months and peaked four months after Haiyan. There were 2998 individuals needing medicine and rehabilitation management, functional care and assistive devices. These included persons with pre-existing disabilities whose situations had worsened and people who had sustained injuries in the typhoon. Additional improvements included rehabilitation services with provision of assistive devices at the regional hospital, development of a directory of disability services in the region and advocacy through community-based rehabilitation. DISCUSSION: Information services and community knowledge for people with disabilities improved in Region 8 after Typhoon Haiyan, demonstrating that strengthening rehabilitation systems is a realistic goal after disasters. PMID- 26767138 TI - The prevention and control of dengue after Typhoon Haiyan. AB - OBJECTIVE: Many of the areas in the Philippines affected by Typhoon Haiyan are endemic for dengue; therefore, dengue prevention was a priority in the initial post-disaster risk assessment. We describe the dengue prevention and response strategies applied after Haiyan. METHODS: The dengue response was implemented by a wide range of national and international stakeholders. Priorities included the rapid re-establishment of an effective surveillance system to quickly identify new dengue cases, monitor trends and determine the geographical distribution of cases. Dengue rapid diagnostic tests (RDTs) were distributed to sentinel health facilities, and comprehensive vector control activities and entomological surveys were implemented. Several training sessions for key stakeholders and awareness campaigns for communities were organized. RESULTS: There were RDT-positive dengue cases reported from urban and semi-urban areas where entomological surveys also confirmed a high density of Aedes aegypti mosquitoes. Although there was an increase in dengue cases in January 2014, the number of cases remained below the epidemic threshold throughout the remaining months of 2014. DISCUSSION: There was no large outbreak of dengue after Haiyan, possibly due to the targeted, multifaceted and rapid response for dengue after Haiyan. However, surveillance differed after Typhoon Haiyan, making comparisons with previous years difficult. Multiple players contributed to the response that was also facilitated by close communication and coordination within the Health Cluster. PMID- 26767139 TI - Which surveillance systems were operational after Typhoon Haiyan? AB - INTRODUCTION: Effective disease surveillance is vital for a successful disaster response. This study assessed the functionality of the three disease surveillance systems used post-Haiyan: Philippine Integrated Disease Surveillance and Response (PIDSR), Event-based Surveillance and Response (ESR) and Surveillance in Post Extreme Emergencies and Disasters (SPEED). METHODS: A survey of 45 government health officers from affected areas was conducted in March 2014. The survey documented when each of the systems was operational and included questions that ranked the functionality of the three surveillance systems and whether they complemented each other. RESULTS: Two of 11 (18%) surveillance units had an operational SPEED system pre-event. PIDSR and ESR remained operational in five of 11 (45%) surveillance units without interruption of reporting. Ten surveillance units (91%) rated PIDSR as functional post-Typhoon; eight (72.7%) considered ESR functional. SPEED was rated as functional by three (27%) surveillance units. Seven of 11 (63.6%) surveillance units rated the three systems as being complementary to each other. DISCUSSION: In most of the areas affected by Typhoon Haiyan, the routine surveillance systems (PIDSR and ESR) were not disrupted; although, in Leyte it took seven weeks for these to be operational. Although SPEED is recommended for activation within 48 hours after a disaster, this did not occur in most of the surveyed areas. Most of the surveillance units rated PIDSR, ESR and SPEED to be complementary to each other. PMID- 26767140 TI - An assessment of the case notification system 16 months after Typhoon Haiyan in Region 8, the Philippines. AB - INTRODUCTION: The Philippines Department of Health uses the Philippine Integrated Disease Surveillance and Response (PIDSR) system to monitor 25 diseases and syndromes that have the potential to cause outbreaks. The focus of this system is to strengthen the capacity of local government units for early detection and response to outbreaks. After Typhoon Haiyan, routine disease surveillance activities were suspended at the Epidemiology and Surveillance Units (ESUs) at the city and provincial levels, as well as laboratory services; surveillance resumed as soon as local conditions allowed. METHOD: We conducted an assessment of PIDSR in March 2015, 16 months post-Haiyan, in Region 8, the most heavily affected region. We used key informant interviews and a review of data from the system to assess the core surveillance and support functions. RESULTS: All ESUs reported they were performing all surveillance core functions, although laboratory confirmation needed to be strengthened at the regional reference laboratory. Access to working communication equipment also needed improvement as did timeliness and completeness of reporting. DISCUSSION: Assessment of surveillance activities, resources and quality should be conducted post-disaster. The strength and operations of the disease surveillance system usually requires support from the local, regional and national governments, especially if there are legal mandates and legislation that includes the system in disaster planning. Regular monitoring of the system is recommended to ensure stability, system development, increased outbreak detection and fewer morbidities and fatalities. PMID- 26767141 TI - A snapshot of catastrophic post-disaster health expenses after Typhoon Haiyan. AB - INTRODUCTION: This paper provides a snapshot of the health-care costs, out-of pocket expenditures and available safety nets post-Typhoon Haiyan. METHODS: This descriptive study used a survey and document review to report direct and indirect health-care costs and existing financial protection mechanisms used by households in two municipalities in the Philippines at one week and at seven months post Haiyan. RESULTS: Reported out-of-pocket health-care expenses were high immediately after the disaster and increased after seven months. The mean reported out-of-pocket expenses were higher than the reported average household income (US$ 24 to US$ 59). DISCUSSION: The existing local and national mechanisms for health financing were promising and should be strengthened to reduce out-of pocket expenses and protect people from catastrophic expenditures. Longer-term mechanisms are needed to ensure financial protection, especially among the poorest, beyond three months when most free services and medicines have ended. Preparedness should include prior registration of households that would ensure protection when a disaster comes. PMID- 26767142 TI - Medicines management in the Philippine public sector during the response to Haiyan. AB - INTRODUCTION: Health service delivery in the Philippines is constantly challenged by disasters and emergencies. This descriptive study documented existing policies for medicines management in the Philippines and then assessed these in the public sector response post-Haiyan. METHOD: We used desk a review of existing laws, regulations and related issuances and a series of interviews of key informants from various national and local health agencies. RESULTS: We found that while numerous national policies covered critical aspects of medicines management, implementation post-Haiyan was problematic at all levels of the decentralized health-care system. We identified issues of quantification, warehousing, distribution, utilization monitoring and disposal. Donated medicines also added additional burden for storage and disposal, especially for expired and unwanted medicines. DISCUSSION: While the process of managing medicines during disasters did not differ greatly from non-emergency situations, the Haiyan experience highlighted the system's weaknesses. With the current gaps in implementation, as well as the logistical obstacles brought about by disasters, there is a need to have integrated mechanisms for medicines management in the Philippines. This assessment provided an important opportunity to review the medicines management policies at national and local levels. PMID- 26767143 TI - Social media as a risk communication tool following Typhoon Haiyan. AB - PROBLEM: In the aftermath of Typhoon Haiyan, the World Health Organization (WHO) Representative Office in the Philippines had no social media presence to share timely, relevant public health information. CONTEXT: Risk communication is essential to emergency management for public health message dissemination. As social media sites, such as Facebook, are popular in the Philippines, these were adopted for risk communication during the response to Haiyan. ACTION AND OUTCOME: The WHO Representative Office in the Philippines established Facebook, Twitter and Instagram accounts. Thirty days after these social medial channels were established, a gradual increase in followers was observed. Facebook saw the largest increase in followers which occurred as posted content gradually evolved from general public health information to more pro-active public health intervention and preparedness messaging. This included information on key health interventions encouraging followers to adopt protective behaviours to mitigate public health threats that frequently occur after a disaster. LESSONS LEARNT: During the response to Haiyan, creating a social media presence, raising a follower base and developing meaningful messages and content was possible. This event underscored the importance of building a social media strategy in non emergency times and supported the value of developing public health messages and content that both educates and interests the general public. PMID- 26767144 TI - Restarting the tuberculosis programme post-Haiyan. AB - PROBLEM: Typhoon Haiyan damaged or destroyed health infrastructure, equipment and services essential to the Philippine National Tuberculosis Programme (NTP), and it had to be re-established in the affected areas in Regions 6, 7 and 8. Continuing treatment and restoring diagnostic capacity were also challenging. CONTEXT: The Philippines has one of the highest tuberculosis (TB) burdens in the world. At the time of Typhoon Haiyan, there were an estimated 26 ,00 TB cases on treatment at directly observed treatment, short-course (DOTS) centres and 356 multidrug-resistant TB cases registered at programmatic management of drug resistant TB (PMDT) sites. As TB was not included in the Philippines early warning post-disaster surveillance system, tracking TB patients was difficult after Haiyan. ACTIONS AND OUTCOMES: Immediately following Haiyan, each aspect of the NTP was assessed to determine the extent of damage. TB patients were traced and services restored. We created maps showing the location of temporary TB diagnostic and treatment services, which hastened referrals. We provided new laboratory equipment, training and rapid testing capabilities in the affected regions. All TB services in the affected areas (473 DOTS, 490 TB microscopy and six PMDT facilities) were restored just two months after Haiyan. LESSONS LEARNT: Key lessons learnt from the NTP experience following Tyhoon Haiyan were: (1) the importance of having an electronic TB registry (database); (2) the need to include TB in the post-disaster surveillance system; (3) clear guidelines for TB control in disasters; and (4) the importance of coordination with all partners. PMID- 26767145 TI - Is my drinking a problem? A community-based alcohol intervention programme post Haiyan in Tacloban City. AB - PROBLEM: Evidence on alcohol use following disasters is scarce. After Typhoon Haiyan in the Philippines we wanted to determine whether there were alcohol related problems among the disaster survivors and to strengthen the appropriate local health service support in Tacloban City. CONTEXT: Tacloban City is a highly urbanized city that was one of the areas worst hit by Typhoon Haiyan. Prior to Haiyan there was very little support for people with alcohol problems, and the rehabilitation facility was located about 40 km away. ACTION: A pilot community based alcohol intervention programme was conducted that included: assessment of the extent of alcohol problems in the community and health-care workers baseline knowledge and skills; training of health-care workers on primary care alcohol intervention provision; and community outreach with post-training supervision. OUTCOME: The alcohol screening found 26 (22%) of those attending health care facilities would benefit from some form of alcohol intervention. Health-care workers knowledge on basic alcohol intervention was low. This was strengthened during the training, and at outreach clinics the trained health-care workers were able to identify people with alcohol problems and provide them with treatment plans. LESSONS LEARNT: We learnt that there was a problem with alcohol in Tacloban City and that it was possible to run an alcohol intervention programme in the community using minimal resources. Addressing alcohol-related issues in the community is an important public health intervention. While there is a need for policies and guidelines at the national level, a community-based intervention is possible to establish with referral mechanism to specialized care. Training modules for such programs can be further developed and institutionalized. PMID- 26767147 TI - Teacher-Mediated Interventions to Support Child Mental Health Following a Disaster: A Systematic Review. AB - OBJECTIVES: This review sought to identify, describe and assess the effectiveness of teacher-mediated interventions that aim to support child and adolescent recovery after a natural or man-made disaster. We also aimed to assess intervention applicability to rural and remote Australian school settings. METHOD: A systematic search of the academic literature was undertaken utilising six electronic databases (EBSCO, Medline, PsycINFO, Embase, ERIC and CINAHL) using terms that relate to: teacher-mediated and school-based interventions; children and adolescents; mental health and wellbeing; natural disasters and man made disasters. This was supplemented by a grey literature search. RESULTS: A total of 20 articles reporting on 18 separate interventions were identified. Nine separate interventions had been evaluated using methodologically adequate research designs, with findings suggesting at least short-term improvement in student wellbeing outcomes and academic performance. CONCLUSIONS: Although none of the identified studies reported on Australian-based interventions, international interventions could be adapted to the Australian rural and remote context using existing psychosocial programs and resources available online to Australian schools. Future research should investigate the acceptability, feasibility and effectiveness of implementing interventions modelled on the identified studies in Australian schools settings. PMID- 26767146 TI - Factors Associated With Smoking Status among HIV-Positive Patients in Routine Clinical Care. AB - BACKGROUND: Treatment-related reductions in morbidity and mortality among human immunodeficiency virus (HIV)-positive patients have been attenuated by cigarette smoking, which increases risk of cardiovascular, respiratory, and neoplastic diseases. This study investigated factors associated with smoking status among HIV-positive patients. METHODS: This cross-sectional study included 2,464 HIV positive patients attending the HIV Clinic at the University of Alabama at Birmingham between April 2008 and December 2013. Smoking status (current, former, never), psychosocial factors, and clinical characteristics were assessed. Multinomial logistic regression was used to obtain unadjusted and adjusted odds ratios (OR) and 95% confidence intervals (CI) for the association of the various factors with smoking status. RESULTS: Among HIV-positive patients (mean age 45 years, 75% male, 55% African-American), the majority reported a history of smoking (39% current and 22% former smokers). In adjusted models, patient characteristics associated with increased odds of current smoking were male gender (OR for heterosexual men, 1.8 [95% CI: 1.3-2.6]; for men who have sex with men, 1.5 [1.1-1.9]), history of respiratory diseases (1.5 [1.2-1.9]), unsuppressed HIV viral load (>50 copies/mL) (1.5 [1.1-1.9]), depression (1.6 [1.3 2.0]), anxiety (1.6 [1.2-2.1]), and prior and current substance abuse (4.7 [3.6 6.1] and 8.3 [5.3-13.3] respectively). Male gender, anxiety, and substance abuse were also associated with being a former smoker. CONCLUSIONS: Smoking was common among HIV-positive patients, with several psychosocial factors associated with current and former smoking. This suggests smoking cessation programs in HIV clinic settings may achieve greater impact by integrating interventions that also address illicit substance abuse and mental health. PMID- 26767148 TI - Demographic Determinants of Disaster Preparedness Behaviors Amongst Tehran Inhabitants, Iran. AB - BACKGROUND: Tehran is vulnerable to natural hazards, especially earthquakes. Disaster preparedness behaviors (DPB) are measures that can mitigate the adverse consequences of disasters. Demographic factors affect DPB, however, the role of some of these factors is not still clear. By understanding these effects, disaster specialists could design interventions toward specific demographics. In the present study, we aimed to investigate demographic determinants of DPB. METHODS: This cross-sectional survey was conducted in August 2014. The target population included inhabitants of Tehran who were 18 years or older. A total of 1250 participants were selected randomly and interviewed using a standardized questionnaire. RESULTS: Results of our study showed that monthly income level, previous disaster experience, residential district and occupation are demographic factors that influence DPB significantly. However, disaster preparedness was not affected by gender, educational level, number of household members, home type, home ownership and being the head of household. CONCLUSION: To promote DPB in Tehran, disaster specialists should focus on improving DPB in low-income and unemployed people, and individuals who live in high risk districts, especially in those who have not experienced disasters. KEY WORDS: Disaster, Preparedness behavior, Demographic determinants. PMID- 26767149 TI - Knowledge, Attitudes, and Experiences of HIV Pre-Exposure Prophylaxis (PrEP) Trial Participants in Botswana. AB - Recent clinical trials have shown that a daily dose of oral TDF/FTC pre-exposure prophylaxis (PrEP) is effective in reducing human immunodeficiency (HIV) risk. Understanding trial participants' perspectives about retention and PrEP adherence is critical to inform future PrEP trials and the scale-up and implementation of PrEP programs. We analyzed 53 in-depth interviews conducted in April 2010 with participants in the TDF2 study, a Phase 3, randomized, double-blind, placebo controlled clinical trial of daily oral TDF/FTC with heterosexual men and women in Francistown and Gaborone, Botswana. We examined participants' knowledge, attitudes, and experiences of the trial, identified facilitators and barriers to enrollment and retention, and compared participant responses by study site, sex, and study drug adherence. Our findings point to several factors to consider for participant retention and adherence in PrEP trials and programs, including conducting pre-enrollment education and myth reduction counseling, providing accurate estimates of participant obligations and side effect symptoms, ensuring participant understanding of the effects of non-adherence, gauging personal commitment and interest in study outcomes, and developing a strong external social support network for participants. PMID- 26767152 TI - Anterior Cervical Corpectomy with free vascularized fibular graft versus multilevel discectomy and grafting for Cervical Spondylotic Myelopathy. AB - PURPOSE: A retrospective study to compare the radiologic and clinical outcomes of 2 different anterior approaches, multilevel anterior cervical discectomy with fusion (ACDF) using autologus ticortical bone graft versus anterior cervical corpectomy with fusion (ACCF) using free vascularized fibular graft (FVFG) for the management of cervical spondylotic myelopathy(CSM). METHODS: A total of 15 patients who underwent ACDF or ACCF using FVFG for multilevel CSM were divided into two groups. Group A (n = 7) underwent ACDF and group B (n = 8) ACCF. Clinical outcomes using Japanese Orthopaedic Association (JOA) score, perioperative parameters including operation time and hospital stay, radiological parameters including fusion rate and cervical lordosis, and complications were compared. RESULTS: Both group A and group B demonstrated significant increases in JOA scores. Patients who underwent ACDF experienced significantly shorter operation times and hospital stay. Both groups showed significant increases in postoperative cervical lordosis and achieved the same fusion rate (100 %). No major complications were encountered in both groups. CONCLUSION: Both ACDF and ACCF using FVFG provide satisfactory clinical outcomes and fusion rates for multilevel CSM. However, multilevel ACDF is associated with better radiologic parameters, shorter hospital stay and shorter operative times. PMID- 26767151 TI - The Impact of Gastrointestinal Symptoms and Dermatological Injuries on Nutritional Intake and Hydration Status During Ultramarathon Events. AB - BACKGROUND: Debilitating gastrointestinal symptoms (GIS) and dermatological injuries (DI) are common during and after endurance events and have been linked to performance decrements, event withdrawal, and issues requiring medical attention. The study aimed to determine whether GIS and DI affect food and fluid intake, and nutritional and hydration status, of ultramarathon runners during multi-stage (MSUM) and 24-h continuous (24 h) ultramarathons. METHODS: Ad libitum food and fluid intakes of ultramarathon runners (MSUM n = 54; 24 h n = 22) were recorded throughout both events and analysed by dietary analysis software. Body mass and urinary ketones were determined, and blood samples were taken, before and immediately after running. A medical log was used to monitor symptoms and injuries throughout both events. RESULTS: GIS were reported by 85 and 73 % of ultramarathon runners throughout MSUM and 24 h, respectively. GIS during MSUM were associated with reduced total daily, during, and post-stage energy and macronutrient intakes (p < 0.05), whereas GIS during 24 h did not alter nutritional variables. Throughout the MSUM 89 % of ultramarathon runners reported DI. DI during MSUM were associated with reduced carbohydrate (p < 0.05) intake during running and protein intake post-stage (p < 0.05). DI during 24 h were low; thus, comparative analyses were not possible. Daily, during running, and post stage energy, macronutrient and water intake variables were observed to be lower with severity of GIS and DI (p < 0.05) throughout the MSUM only. CONCLUSIONS: GIS during the MSUM, but not the 24 h, compromised nutritional intake. DI presence and severity also compromised nutrient intake during running and recovery in the MSUM. PMID- 26767153 TI - Restoration of Cervical Alignment is Associated with Improved Clinical Outcome after One and Two Level Anterior Cervical Discectomy and Fusion. AB - BACKGROUND: Anterior cervical discectomy and fusion (ACDF) remains the standard of care for patients with cervical radiculopathy who are unresponsive to conservative care. However, the maintenance and restoration of cervical alignment as a predictive factor for outcome has not yet been fully evaluated. The purpose of this study was to evaluate the impact of maintaining or restoring cervical alignment on one and two level ACDF patients' outcome. METHODS: Data were collected from 104 patients who underwent one and two level ACDF. Cervical alignment was measured preoperatively and at follow-up visits. The patients were classified into three groups based on the postoperative change of their cervical alignment. Neck pain, arm pain, and Neck Disability Index (NDI) scores were obtained preoperatively and at the latest follow-up visit. Incidences of adjacent segment degeneration (ASD) and reoperations because of ASD were recorded. RESULTS: There were 64 patients in the Maintained group, 17 patients in the Restored group and 23 patients in the Kyphotic group. Pre-operatively, the neck pain scores, arm pain scores and NDI scores were not statistically different among the three groups (p>0.05). On average at 12 months follow-up, the neck pain scores improved by 2.7, 4.2, and 2.7 points respectively in the three groups (p>0.05). The patients' arm pain scores improved by 2.1, 2.4, and 2.8 points respectively (p>0.05). NDI scores improved by 12, 31 and 13.7 points respectively (p<0.05). The incidences of ASD and reoperations because of ASD were 16%, 12% and 35% respectively (p>0.05). CONCLUSIONS: The patients with restored cervical alignment had significantly greater NDI improvement and relatively better neck pain improvement. There was a trend for patients who had unchanged cervical kyphosis to have a higher incidence of ASD. Our study suggests that restoration of cervical alignment will contribute to improved clinical outcome in the patients who have one and two level ACDF surgeries. LEVEL OF EVIDENCE: This is a level III study. PMID- 26767155 TI - Mortality Prediction in a Vertebral Compression Fracture Population: the ASA Physical Status Score versus the Charlson Comorbidity Index. AB - BACKGROUND: Morbidity and mortality scores are useful to control for medical comorbidities in study populations where either effects of an illness or benefits of a treatment are examined. Our study examined if a direct relationship existed between the American Society of Anesthesiologists Physical Status (ASA) score and the Charlson Comorbidity Index (CCI) in an osteoporosis population where patients had sustained a vertebral compression fracture. METHODS: A retrospective chart review of patients with osteoporotic compression fractures treated by the same orthopedic surgeon between June 2000 and June 2004 was performed. The primary endpoint was death by the close of the study period (September 2006). A board certified Anesthesiologist blindly assigned all of the ASA scores as well as the Charlson Scores independently in a blinded manner. All patients were assumed to be undergoing surgery as they were assigned. A statistical relationship was examined between ASA and CCI scores through a cross table analysis with chi squared testing as both scoring systems were considered categorical. A Pearson correlation was completed to examine the quality of a linear relationship between the categorical variable ASA compared to the continuous variable Charlson. A value of p < 0.05 was considered significant. RESULTS: Ninety patients elected conservative therapy with oral analgesics and an orthosis, while 94 patients elected for kyphoplasty. The CCI by log rank testing was not significant (p= 0.2027) for the surgery population; however, the test resulted in a highly significant value (p = 0.0161) in non-operative population. The ASA Score was correlated with significance to mortality (p= 0.0150) for the surgery population, while the test was not significant (p = 0.1439) in non-operative population. Treating both ASA and CCI scores as categorical variables, a relationship between them was examined and found to be highly significant (p= 0.000001) meaning patients with low ASA scores were likely to have low CCI scores. CONCLUSION: The ASA score was predictive of mortality in a surgical population, while CCI was highly predictive of mortality in a non-surgical population. There is great agreement between the CCI score and the ASA score, reflecting that anesthesiologists subjectively consider the same elements of the patient's medical history when assigning ASA scores as the CCI objectively uses. This was a Level III Study. PMID- 26767154 TI - Systematic Review of Thigh Symptoms after Lateral Transpsoas Interbody Fusion for Adult Patients with Degenerative Lumbar Spine Disease. AB - BACKGROUND: Lateral transpsoas interbody fusion (LTIF) is a minimally invasive technique for achieving lumbar spinal fusion. While it has many advantages over open techniques it carries with it a distinct set of risks, most commonly post operative ipsilateral thigh pain, weakness and sensory disturbances. It is vital for both the surgeon and patient to understand the risks for and outcomes of injury associated with this procedure. We conducted a systematic review of the literature to evaluate the incidence, risks, and long-term clinical outcomes of post-operative thigh symptoms in patients treated with LTIF. METHODS: We conducted a search of MEDLINE, EMBASE, CINAHL, Scopus, Web of Science and the Cochrane Collaboration Library, using keywords and MeSH terms, for English language literature published through September 2014, as well as reference lists from key articles. Studies were then manually filtered to retrieve articles that met inclusion criteria. We were interested in studies that reported postoperative lower extremity symptoms after LTIF, such as pain, weakness and changes in sensation. The strength of evidence was determined based on precepts outlined by the Grades of Recommendation Assessment, Development and Evaluation Working Group (GRADE). RESULTS: A total of 392 articles were initially retrieved, with 24 ultimately meeting criteria for inclusion. The incidence of any post-operative thigh symptom varied, ranging as high as 60.7%, with 9.3% of patients experiencing a motor deficit related to direct nerve injury. Several studies reported cases of persistent symptoms at 6 months follow up. Additionally, inclusion of the L4-5 disc space and a longer duration of surgery were both identified as risks for developing postoperative thigh symptoms. CONCLUSION: The risk of postoperative thigh symptoms after LTIF is high. Thigh pain, paresthesias and weakness were the most commonly reported symptoms. While most patients' symptoms resolved by 6 months follow up, several studies reported patients with symptoms persistent as far as 12 months removed from surgery. Surgery at the L4-5 disc space and longer surgical duration place the patient at greater risk for developing postoperative and long-term thigh symptoms. PMID- 26767156 TI - Sacroiliac Joint Fusion Minimally Affects Adjacent Lumbar Segment Motion: A Finite Element Study. AB - BACKGROUND: Adjacent segment disease is a recognized consequence of fusion in the spinal column. Fusion of the sacroiliac joint is an effective method of pain reduction. Although effective, the consequences of sacroiliac joint fusion and the potential for adjacent segment disease for the adjacent lumbar spinal levels is unknown. The objective of this study was to quantify the change in range of motion of the sacroiliac joint and the adjacent lumbar spinal motion segments due to sacroiliac joint fusion and compare these changes to previous literature to assess the potential for adjacent segment disease in the lumbar spine. METHODS: An experimentally validated finite element model of the lumbar spine and pelvis was used to simulate a fusion of the sacroiliac joint using three laterally placed triangular implants (iFuse Implant System, SI-BONE, Inc., San Jose, CA). The range of motion of the sacroiliac joint and the adjacent lumbar spinal motion segments were calculated using a hybrid loading protocol and compared with the intact range of motion in flexion, extension, lateral bending, and axial rotation. RESULTS: The range of motions of the treated sacroiliac joints were reduced in flexion, extension, lateral bending, and axial rotation, by 56.6%, 59.5%, 27.8%, and 53.3%, respectively when compared with the intact condition. The stiffening of the sacroiliac joint resulted in increases at the adjacent lumbar motion segment (L5-S1) for flexion, extension, lateral bending, and axial rotation, of 3.0%, 3.7%, 1.1%, and 4.6%, respectively. CONCLUSIONS: Fusion of the sacroiliac joint resulted in substantial (> 50%) reductions in flexion, extension, and axial rotation of the sacroiliac joint with minimal (< 5%) increases in range of motion in the lumbar spine. Although the predicted increases in lumbar range of motion are minimal after sacroiliac joint fusion, the long-term clinical results remain to be investigated. PMID- 26767157 TI - A Comparison of Two Different Dosing Protocols for Tranexamic Acid in Posterior Spinal Fusion for Spinal Deformity: A Prospective, Randomized Trial. AB - BACKGROUND: Multilevel spinal fusions have typically been associated with significant blood loss. Previous studies have shown a reduction in blood loss with antifibrinolytics in both adolescent and adult spinal deformity patients. While this has been mirrored in other subspecialties as well, the dosing of TXA remains highly variable. To date, there remains a paucity of data guiding dosing for TXA in spine surgery and orthopedic surgery as a whole. METHODS/DESIGN: One hundred and fifty patients from 3 institutions (50 each site) will be consecutively enrolled and randomized to either a high dose of TXA (50mg/kg loading followed by 20mg/kg hourly) or a lose dose (10mg/kg, then 1mg/kg hourly). Both surgeons and patients will be blinded to the treatment group. Primary outcomes will be perioperative blood loss, drain output, and transfusion rate. Secondary outcomes will be length of stay, complications, and overall cost. DISCUSSION: The primary goal of this study is to provide level-1 comparative data for two TXA dosing regimens in adult spinal deformity surgery. Management of blood loss remains a critical factor in reducing complications during spinal deformity surgery. The null hypothesis is that there is no difference between high- and low-dose TXA with respect to any of the primary or secondary outcomes. PMID- 26767158 TI - Iatrogenic Baastrup's Syndrome: A Potential Complication Following Anterior Interbody Lumbar Spinal Surgery. AB - BACKGROUND: Baastrup's Syndrome is a condition that occurs when there is abnormal contact between two adjacent spinous processes resulting in back pain. An alteration in lumbar spinal alignment and/or adjacent segment compensatory motion is thought to be potential causative factors. The objective of this study was to present a case series of what appears to be iatrogenic Baastrup's Syndrome as a mid-to-late term complication following anterior lumbar interbody surgery. METHODS: A retrospective chart review was performed of all patients undergoing anterior lumbar surgery for either fusion or disc replacement to determine the prevalence of Baastrup's Syndrome. RESULTS: Over a 12-year period, 855 patients who had undergone an anterior approach for lumbar spine surgery were identified. Of them 8 patients with evidence of Baastrup's Syndrome were found; this demonstrated a prevalence of 0.9%. Diagnostic injection was a helpful clinical tool in confirming the diagnosis of iatrogenic Baastrup's Syndrome. The partial removal of the impinging spinous processes resulted in excellent clinical relief. CONCLUSIONS: Iatrogenic Baastrup's Syndrome may be an iatrogenic result of anterior lumbar surgery in small group of patients. Spinous process excision is a suggested treatment option. Further studies are necessary to explore the above phenomenon. This study is a Level 3 retrospective case series. PMID- 26767159 TI - Thoracic epidural spinal angiolipoma with coexisting lumbar spinal stenosis: Case report and review of the literature. AB - BACKGROUND: Spinal angiolipomas (SALs) are uncommon benign lesions that may present insidiously with back pain or acutely with weakness due to tumor bleeding/thrombosis. Given their rarity, these lesions are often overlooked in the differential diagnosis of epidural masses. The purpose of this article is to report the case of an epidural SAL and to conduct a literature review on the topic. METHODS: A case report and review of the literature using the PubMed/Medline databases. All case reports and case series were reviewed up to June 2015. RESULTS: A 65-year old female presented with neurogenic claudication and magnetic resonance imaging (MRI) revealed lumbar spinal stenosis. Following decompressive surgery, she experienced symptom resolution, but three months postoperatively she presented to the emergency department with acute paraparesis. A thoracic MRI revealed a lesion located between T8 and T10 causing severe spinal cord compression. Following emergent laminectomy and en bloc resection, the patient regained function and the lesion was diagnosed as SAL. Our literature review revealed 178 reported cases, with a female and thoracic predominance. The majority of patients underwent surgical treatment, achieving a gross total resection in most cases. Similarly, complete symptom resolution was the most common outcome. CONCLUSION: Spinal angiolipomas are uncommon spinal tumors. However, they may be treated as any other space-occupying lesion, and surgical resection allows for complete symptom recovery in most patients. PMID- 26767162 TI - Developing expertise in bioinformatics for biomedical research in Africa. AB - Research in bioinformatics has a central role in helping to advance biomedical research. However, its introduction to Africa has been met with some challenges (such as inadequate infrastructure, training opportunities, research funding, human resources, biorepositories and databases) that have contributed to the slow pace of development in this field across the continent. Fortunately, recent improvements in areas such as research funding, infrastructural support and capacity building are helping to develop bioinformatics into an important discipline in Africa. These contributions are leading to the establishment of world-class research facilities, biorepositories, training programmes, scientific networks and funding schemes to improve studies into disease and health in Africa. With increased contribution from all stakeholders, these developments could be further enhanced. Here, we discuss how the recent developments are contributing to the advancement of bioinformatics in Africa. PMID- 26767160 TI - Quantitative evaluation of the lumbosacral sagittal alignment in degenerative lumbar spinal stenosis. AB - GOAL OF THE STUDY: This study intends to develop a method of quantitative sagittal balance parameters assessment, based on a geometrical model of lumbar spine and sacrum. METHODS: One hundred eight patients were divided into 2 groups. In the experimental group have been included 59 patients with lumbar spinal stenosis on L1-5 level. Forty-nine healthy volunteers without history of any lumbar spine pathlogy were included in the control group. All patients have been examined with supine MRI. Lumbar lordosis has been adopted as circular arc and described either anatomical (lumbar lordosis angle), or geometrical (chord length, circle segment height, the central angle, circle radius) parameters. Moreover, 2 sacral parameters have been assessed for all patients: sacral slope and sacral deviation angle. Both parameters characterize sacrum disposition in horizontal and vertical axis respectively. RESULTS: Significant correlation was observed between anatomical and geometrical lumbo-sacral parameters. Significant differences between stenosis group and control group were observed in the value of the "central angle" and "sacral deviation" parameters. We propose additional parameters: lumbar coefficient, as ratio of the lordosis angle to the segmental angle (Kl); sacral coefficient, as ratio of the sacral tilt (ST) to the sacral deviation (SD) angle (Ks); and assessment modulus of the mathematical difference between sacral and lumbar coefficients has been used for determining lumbosacral balance (LSB). Statistically significant differences between main and control group have been obtained for all described coefficients (p = 0.006, p = 0.0001, p = 0.0001, accordingly). Median of LSB value of was 0.18 and 0.34 for stenosis and control groups, accordingly. CONCLUSION: Based on these results we believe that that spinal stenosis is associated with an acquired deformity that is measureable by the described parameters. It's possible that spinal stenosis occurs in patients with an LSB of 0.2 or less, so this value can be predictable for its development. It may suggest that spinal stenosis is more likely to occur in patients with the spinal curvature of this type because of abnormal distribution of the spine loads. This fact may have prognostic significance for develop vertebral column disease and evaluation of treatment results. PMID- 26767161 TI - Outcome Measures of an Intracanal, Endoscopic Transforaminal Decompression Technique: Initial Findings from the MIS Prospective Registry. AB - BACKGROUND: Minimally invasive transforaminal endoscopic procedures can achieve spinal decompression through either direct or indirect techniques. Subtle variations in trajectory of the surgical corridor can dictate access to the pathologic tissue. Two general strategies exist: the intradiscal "inside-out" technique and the extradiscal, intracanal (IC) technique. The IC technique utilizes a more lateral transforaminal approach than the intradiscal technique, which allows for a more direct decompression of the spinal canal. OBJECTIVE: This study is an assessment of IC patient outcome data obtained through analysis of a previously validated MIS Prospective Registry. METHODS: Post-hoc analysis was performed on the MIS Prospective Registry database containing 1032 patients. A subgroup of patients treated with the endoscopic IC technique was identified. Patient outcome measures after treatment of symptomatic disk herniation and neuroforaminal stenosis were evaluated. RESULTS: A total of 86 IC patients were analyzed. Overall, there was significant improvement in employment and walking tolerance as soon as 6 weeks post-op as well as significant one year VAS and ODI score improvement. Subanalysis of IC patients with two distinct primary diagnoses was performed. Group IC-1 (disc herniation) showed improvement in ODI and VAS back and leg outcomes at 1 year post-op. Group IC-2 (foraminal stenosis) showed VAS back and leg score improvement at one year post-op but did not demonstrate significant improvement in overall ODI outcome at any time point. The one year re operation rate was 2% (1/40) for group IC-1 and 28% (5/18) for group IC-2. CONCLUSIONS: The initial results of the MIS Registry IC subgroup show a significant clinical improvement when the technique is employed to treat patients with lumbar disc herniation. The treatment of foraminal stenosis can lead to improved short-term clinical outcome but is associated with a high re-operation rate at 1 year post-op. PMID- 26767163 TI - Widening participation would be key in enhancing bioinformatics and genomics research in Africa. AB - Bioinformatics and genome science (BGS) are gradually gaining roots in Africa, contributing to studies that are leading to improved understanding of health, disease, agriculture and food security. While a few African countries have established foundations for research and training in these areas, BGS appear to be limited to only a few institutions in specific African countries. However, improving the disciplines in Africa will require pragmatic efforts to expand training and research partnerships to scientists in yet-unreached institutions. Here, we discuss the need to expand BGS programmes in Africa, and propose mechanisms to do so. PMID- 26767164 TI - Temporal stability of parasite distribution and genetic variability values of Contracaecum osculatum sp. D and C. osculatum sp. E (Nematoda: Anisakidae) from fish of the Ross Sea (Antarctica). AB - The Ross Sea, Eastern Antarctica, is considered a "pristine ecosystem" and a biodiversity "hotspot" scarcely impacted by humans. The sibling species Contracaecum osculatum sp. D and C. osculatum sp. E are anisakid parasites embedded in the natural Antarctic marine ecosystem. Aims of this study were to: identify the larvae of C. osculatum (s.l.) recovered in fish hosts during the XXVII Italian Expedition to Antarctica (2011-2012); perform a comparative analysis of the contemporary parasitic load and genetic variability estimates of C. osculatum sp. D and C. osculatum sp. E with respect to samples collected during the expedition of 1993-1994; to provide ecological data on these parasites. 200 fish specimens (Chionodraco hamatus, Trematomus bernacchii, Trematomus hansoni, Trematomus newnesi) were analysed for Contracaecum sp. larvae, identified at species level by allozyme diagnostic markers and sequences analysis of the mtDNA cox2 gene. Statistically significant differences were found between the occurrence of C. osculatum sp. D and C. osculatum sp. E in different fish species. C. osculatum sp. E was more prevalent in T. bernacchii; while, a higher percentage of C. osculatum sp. D occurred in Ch. hamatus and T. hansoni. The two species also showed differences in the host infection site: C. osculatum sp. D showed higher percentage of infection in the fish liver. High genetic variability values at both nuclear and mitochondrial level were found in the two species in both sampling periods. The parasitic infection levels by C. osculatum sp. D and sp. E and their estimates of genetic variability showed no statistically significant variation over a temporal scale (2012 versus 1994). This suggests that the low habitat disturbance of the Antarctic region permits the maintenance of stable ecosystem trophic webs, which contributes to the maintenance of a large populations of anisakid nematodes with high genetic variability. PMID- 26767165 TI - Field and experimental evidence of a new caiman trypanosome species closely phylogenetically related to fish trypanosomes and transmitted by leeches. AB - Trypanosoma terena and Trypanosoma ralphi are known species of the South American crocodilians Caiman crocodilus, Caiman yacare and Melanosuchus niger and are phylogenetically related to the tsetse-transmitted Trypanosoma grayi of the African Crocodylus niloticus. These trypanosomes form the Crocodilian clade of the terrestrial clade of the genus Trypanosoma. A PCR-survey for trypanosomes in caiman blood samples and in leeches taken from caimans revealed unknown trypanosome diversity and frequent mixed infections. Phylogenies based on SSU (small subunit) of rRNA and gGAPDH (glycosomal Glyceraldehyde Phosphate Dehydrogenase) gene sequences revealed a new trypanosome species clustering with T. terena and T. ralphi in the crocodilian clade and an additional new species nesting in the distant Aquatic clade of trypanosomes, which is herein named Trypanosoma clandestinus n. sp. This new species was found in Caiman yacare, Caiman crocodilus and M. niger from the Pantanal and Amazonian biomes in Brazil. Large numbers of dividing epimastigotes and unique thin and long trypomastigotes were found in the guts of leeches (Haementeria sp.) removed from the mouths of caimans. The trypanosomes recovered from the leeches had sequences identical to those of T. clandestinus of caiman blood samples. Experimental infestation of young caimans (Caiman yacare) with infected leeches resulted in long-lasting T. clandestinus infections that permitted us to delineate its life cycle. In contrast to T. terena, T. ralphi and T. grayi, which are detectable by hemoculturing, microscopy and standard PCR of caiman blood, T. clandestinus passes undetected by these methods due to very low parasitemia and could be detected solely by the more sensitive nested PCR method. T. clandestinus n. sp. is the first crocodilian trypanosome known to be transmitted by leeches and positioned in the aquatic clade closest to fish trypanosomes. Our data show that caimans can host trypanosomes of the aquatic or terrestrial clade, sometimes simultaneously. PMID- 26767167 TI - Sarcocystosis in Cervus elaphus: Comparison of diagnostic methods. AB - Red deer (Cervus elaphus) from a National Wildlife Reserve near Toledo in central Spain were surveyed for Sarcocystis infection. A total of 61 deer were examined. Tissue compression and histology were used to examine samples from diaphragm and heart from each animal included in the study, and results from the two techniques and the two tissues were compared to determine the tissue and technique that provide the most accurate measure of prevalence and intensity. Prevalence and intensity were then compared between calves, yearlings and adults. Sarcocystis was detected in 59 (97%) of the 61 deer. Comparison between tissues showed that (a) prevalence based on histology was similar for heart and diaphragm, (b) prevalence based on compression was significantly higher for heart than for diaphragm and (c) intensity was significantly higher for heart than for diaphragm, regardless of the technique used. Comparison between techniques showed that (a) both techniques rendered similar prevalences and intensities of Sarcocystis infection with heart samples and (b) both techniques were not comparable with diaphragm samples (compression rendered lower prevalence but higher intensity than histology). Together these data suggest that heart is the preferable tissue for estimating prevalence and intensity, regardless of the technique used. A preliminary species identification of isolated cysts from three animals showed two morph types, corresponding to Sarcocystis cervicanis (syn. S. cf. grueneri; S. wapiti) in the heart and diaphragm of three animals and S. hjorti, only in the diaphragm of two animals. Given the different location of those morph types, both heart and diaphragm should be sampled and preferably assessed using histology to most reliably detect infection. Based on histology of heart, prevalence and intensity of Sarcocystis were significantly lower in calves than in yearlings or adults. PMID- 26767166 TI - Hemoparasites in a wild primate: Infection patterns suggest interaction of Plasmodium and Babesia in a lemur species. AB - Hemoparasites can cause serious morbidity in humans and animals and often involve wildlife reservoirs. Understanding patterns of hemoparasite infections in natural populations can therefore inform about emerging disease risks, especially in the light of climate change and human disruption of natural ecosystems. We investigated the effects of host age, sex, host group size and season on infection patterns of Plasmodium sp., Babesia sp. and filarial nematodes in a population of wild Malagasy primates, Verreaux's sifakas (Propithecus verreauxi), as well as the effects of these infections on hematological variables. We tested 45 blood samples from 36 individuals and identified two species of Plasmodium, one species of Babesia and two species of filarial nematodes. Plasmodium spp. and Babesia sp. infections showed opposite patterns of age-dependency, with babesiosis being prevalent among young animals, while older animals were infected with Plasmodium sp. In addition, Babesia sp. infection was a statistically significant negative predictor of Plasmodium sp. infection. These results suggest that Plasmodium and Babesia parasites may interact within the host, either through cross-immunity or via resource competition, so that Plasmodium infections can only establish after babesiosis has resolved. We found no effects of host sex, host group size and season on hemoparasite infections. Infections showed high prevalences and did not influence hematological variables. This preliminary evidence supports the impression that the hosts and parasites considered in this study appear to be well-adapted to each other, resulting in persistent infections with low pathogenic and probably low zoonotic potential. Our results illustrate the crucial role of biodiversity in host-parasite relationships, specifically how within-host pathogen diversity may regulate the abundance of parasites. PMID- 26767169 TI - Connecting patient care to global health trends by health app analytics. PMID- 26767168 TI - Seasonal variation in the abundance and distribution of ticks that parasitize Microcebus griseorufus at the Beza Mahafaly Special Reserve, Madagascar. AB - At Beza Mahafaly Special Reserve (BMSR), Madagascar, mouse lemurs (Microcebus griseorufus) are parasitized by multiple species of haemaphysaline ticks. At present we know little about the role ticks play in wild lemur populations and how they can alter interspecies relationships within communities or impact host fitness. In order to better understand these dynamics at BMSR, we examined parasite-host interactions as well as the ecology of mouse lemurs and their infesting ticks, Haemaphysalis lemuris and H. sp. cf. simplex. We show that season, host sex, and habitat influence the relative abundance of ticks on mouse lemurs. Specifically, infestations occur only during the dry season (May October), are higher in males, and are higher at the study site with the most ground cover and with greater density of large-bodied hosts. Microcebus likely experience decreased susceptibility to tick infestations during the wet season because at that time they rarely if ever descend to the ground. Similarly, male mouse lemurs have higher infestation rates than females because of the greater time they spend traveling and foraging on the ground. During the dry season, Microcebus likely serve as hosts for the tenrec tick, H. sp. cf. simplex, when tenrecs hibernate. In turn, during the wet season when mouse lemurs rarely descend to the ground, other small mammals at the reserve may serve as maintenance hosts for populations of immature ticks. The synchronous development of larvae and nymphs could present high risk for vector-borne disease in Microcebus. This study also provides a preliminary description of the ecology and life cycle of the most common lemur tick, H. lemuris. PMID- 26767170 TI - Service integration to reduce HIV-associated TB mortality. PMID- 26767171 TI - Medecins Sans Frontieres' Clinical Guidance mobile application: analysis of a new electronic health tool. AB - Many health care workers lack access to clinical support tools in rural and resource-limited settings. To address this gap, the Medecins Sans Frontieres (MSF) Clinical Guidelines manual was converted into a static mobile health reference application (app) entitled MSF Guidance. The app's utility and growth was examined, and within 6 months of its launch 150 countries had downloaded the app, with demonstrated retention among new and existing users. With over 3500 downloads and 36 000 sessions amounting to 250 000 screen views, MSF Guidance is a new mobile health platform with widely demonstrated utility, including potential use as an epidemiological tool, where clinical conditions investigated by app users were found to correlate with geographical outbreaks. These findings show that mobile apps can be used to disseminate health information effectively. PMID- 26767172 TI - One-stop TB-HIV services evaluation in Rwanda: comparison of the 2001-2005 and 2006-2010 cohorts. AB - BACKGROUND: Tuberculosis (TB) and human immunodeficiency virus (HIV) co-infection remains high in Rwanda. Since one-stop TB-HIV services were implemented to manage TB-HIV co-infection, their functioning and impact on TB treatment outcomes have not been assessed. OBJECTIVE: To evaluate one-stop TB-HIV services in Rwanda by comparing the TB treatment outcomes before and after their implementation in Kicukiro and Rulindo districts. METHODS: This descriptive retrospective study used a quantitative questionnaire to determine the functioning of Rwanda's one stop TB-HIV services. In-depth interviews and focus group discussions with health care providers, heads of facilities and co-infected patients were held to seek their opinion about the functioning of the services. RESULTS: The one-stop TB-HIV services at all 12 health facilities visited were functioning according to the approved criteria. However, TB treatment outcomes after the intervention were not statistically different from those before the intervention. Qualitative data showed a positive impact on the quality of service, particularly a reduction in waiting times and appointments that were better respected as a result of the efficient functioning of the services. CONCLUSION: One-stop TB-HIV services have improved the quality of service in Kicukiro and Rulindo districts. However, the services need to be strengthened programmatically to improve TB treatment outcomes. PMID- 26767173 TI - Effect of increased ART-CPT uptake on tuberculosis outcomes and associated factors, Burundi, 2009-2013. AB - We retrospectively examined 3579 records of human immunodeficiency virus infected tuberculosis (TB) patients diagnosed from January 2009 to June 2013 in 55 TB treatment facilities in Burundi, to demonstrate whether improvement of combined cotrimoxazole preventive therapy and antiretroviral therapy (ART) uptake was accompanied by improvement of treatment outcomes, and to describe associated factors. Treatment success rates increased from 71% to 80% (P < 0.001). While loss to follow-up and transfer-out rates declined significantly, death rates decreased modestly, and remained high, at 14%. ART uptake was worse in suburban areas and private for-profit institutions. World Health Organization targets could be achieved if peripheral health facilities were prioritised. PMID- 26767174 TI - Are HIV-positive presumptive tuberculosis patients without tuberculosis getting the care they need in Zimbabwe? AB - SETTING: Emakhandeni Clinic provides decentralised and integrated tuberculosis (TB) and human immunodeficiency virus (HIV) care in Bulawayo, Zimbabwe. OBJECTIVES: To compare HIV care for presumptive TB patients with and without TB registered in 2013. DESIGN: Retrospective cohort study using routine programme data. RESULTS: Of 422 registered presumptive TB patients, 26% were already known to be HIV-positive. Among the remaining 315 patients, 255 (81%) were tested for HIV, of whom 190 (75%) tested HIV-positive. Of these, 26% were diagnosed with TB and 71% without TB (3% had no TB result recorded). For the 134 patients without TB, antiretroviral treatment (ART) eligibility data were recorded for 42 (31%); 95% of these were ART eligible. Initiation of cotrimoxazole preventive therapy (CPT) and ART was recorded for respectively 88% and 90% of HIV-positive patients with TB compared with respectively 40% and 38% of HIV-positive patients without TB (P < 0.001). CONCLUSION: Presumptive TB patients without TB had a high HIV positivity rate and, for those with available data, most were ART eligible. Unlike HIV-positive patients diagnosed with TB, CPT and ART uptake for these patients was poor. A 'test and treat' approach and better service linkages could be life-saving for these patients, especially in southern Africa, where there are high burdens of HIV and TB. PMID- 26767175 TI - Setting priorities for a research agenda to combat drug-resistant tuberculosis in children. AB - SETTING: Numerous knowledge gaps hamper the prevention and treatment of childhood drug-resistant tuberculosis (TB). Identifying research priorities is vital to inform and develop strategies to address this neglected problem. OBJECTIVE: To systematically identify and rank research priorities in childhood drug-resistant TB. DESIGN: Adapting the Child Health and Nutrition Research Initiative (CHNRI) methodology, we compiled 53 research questions in four research areas, then classified the questions into three research types. We invited experts in childhood drug-resistant TB to score these questions through an online survey. RESULTS: A total of 81 respondents participated in the survey. The top-ranked research question was to identify the best combination of existing diagnostic tools for early diagnosis. Highly ranked treatment-related questions centred on the reasons for and interventions to improve treatment outcomes, adverse effects of drugs and optimal treatment duration. The prevalence of drug-resistant TB was the highest-ranked question in the epidemiology area. The development type questions that ranked highest focused on interventions for optimal diagnosis, treatment and modalities for treatment delivery. CONCLUSION: This is the first effort to identify and rank research priorities for childhood drug-resistant TB. The result is a resource to guide research to improve prevention and treatment of drug-resistant TB in children. PMID- 26767176 TI - Treatment referral system for tuberculosis patients in Dhaka, Bangladesh. AB - OBJECTIVE: To evaluate the referral system in an urban DOTS-based programme in Dhaka, Bangladesh, including the peri-urban area, and to identify opportunities to strengthen the system. DESIGN: This was a retrospective cohort study in which diagnosed tuberculosis (TB) patients and health providers from DOTS centres were interviewed. Research tools included pre-tested structured questionnaires and the TB patients' referral records. RESULTS: Of 4974 TB patients who were referred to the different treatment centres, only 1756 (35%) of the counterfoils of the referral slips were returned. Of 250 patients randomly selected for interview, 165 reported to a DOTS centre, 69 did not and 16 could not be traced. Variations in educational qualification, residence and the identification of DOTS centres after counselling were statistically significant (P < 0.05). Lower monthly income (RR = 7.84, RR = 5.03), distance from the centre (RR = 36.21) and those receiving treatment from pharmacies (RR = 3) or non-governmental organisations (RR = 28.48) have more risk of irregular treatment. CONCLUSION: A high proportion of referred patients were registered and initiated treatment, but many did not report to the referral treatment centre. Proper counselling and taking into account the patients' preferences during referral are essential to address access barriers to treatment adherence and improved treatment outcome. PMID- 26767177 TI - Screening difficult-to-reach populations for tuberculosis using a mobile medical unit, Punjab India. AB - BACKGROUND: In India, the National Health Mission has provided one mobile medical unit (MMU) per district in the state of Punjab to provide primary health care services for difficult-to-reach populations. OBJECTIVES: To determine the number of patients with presumptive tuberculosis (TB) and the number of TB cases detected and treated among patients who used the MMU services from May to December 2012 in Mohali district, Punjab, India. METHODS: A cross-sectional study was conducted and registers of the out-patient, laboratory, radiology, and TB departments of the MMU were reviewed to determine the number of persons presumed to have TB and the number of persons diagnosed with TB. RESULTS: Of 8346 patients who attended the MMUs, 663 (8%) had symptoms suggestive of TB. Among those with TB symptoms, 540 (81%) were evaluated for pulmonary TB using sputum examination or chest X-ray. In total, 58 (11%) patients had clinical or laboratory evidence of pulmonary TB, of whom 21 (36%) started anti-tuberculosis treatment. CONCLUSION: As MMUs are an integral part of the general public health system, these units have the potential to detect TB cases among difficult-to-reach populations. Additional research is required to optimise the diagnosis of TB at MMUs and to increase rates of TB treatment initiation. PMID- 26767178 TI - Intensified tuberculosis case finding amongst vulnerable communities in southern India. AB - India mainly uses passive case finding to detect tuberculosis (TB) patients through the Revised National Tuberculosis Control Programme (RNTCP). An intensified case finding (ICF) intervention was conducted among vulnerable communities in two districts of Karnataka during July-December 2013; 658 sputum smear-positive TB cases were detected. The number of smear-positive cases detected increased by 8.8% relative to the pre-intervention period (July-December 2012) in intervention communities as compared to an 8.6% decrease in communities without the ICF intervention. ICF activities brought TB services closer to vulnerable communities, moderately increasing TB case detection rates. PMID- 26767179 TI - Screening for pulmonary tuberculosis in a Tanzanian prison and computer-aided interpretation of chest X-rays. AB - SETTING: Tanzania is a high-burden country for tuberculosis (TB), and prisoners are a high-risk group that should be screened actively, as recommended by the World Health Organization. Screening algorithms, starting with chest X-rays (CXRs), can detect asymptomatic cases, but depend on experienced readers, who are scarce in the penitentiary setting. Recent studies with patients seeking health care for TB-related symptoms showed good diagnostic performance of the computer software CAD4TB. OBJECTIVE: To assess the potential of computer-assisted screening using CAD4TB in a predominantly asymptomatic prison population. DESIGN: Cross-sectional study. RESULTS: CAD4TB and seven health care professionals reading CXRs in local tuberculosis wards evaluated a set of 511 CXRs from the Ukonga prison in Dar es Salaam. Performance was compared using a radiological reference. Two readers performed significantly better than CAD4TB, three were comparable, and two performed significantly worse (area under the curve 0.75 in receiver operating characteristics analysis). On a superset of 1321 CXRs, CAD4TB successfully interpreted >99%, with a predictably short time to detection, while 160 (12.2%) reports were delayed by over 24 h with conventional CXR reading. CONCLUSION: CAD4TB reliably evaluates CXRs from a mostly asymptomatic prison population, with a diagnostic performance inferior to that of expert readers but comparable to local readers. PMID- 26767180 TI - Compliance with infection control practices in sputum microscopy centres: a study from Kerala, India. AB - BACKGROUND: One of the strategies of the Revised National Tuberculosis Control Programme in India to achieve tuberculosis control is by increasing case detection through a nationwide network of designated microscopy centres (DMC). Practice of standard precautions for infection control in these DMCs is very important to prevent transmission of infection not only to the laboratory personnel, but also to the general population. However, in India this has not been evaluated by an external agency. METHOD: A cross-sectional study was carried out to assess knowledge, facilities and compliance regarding infection control practices (ICP) in all 38 DMCs in Kannur district, Kerala, India, in 2015. Using observations and interviews, the investigators collected data in a structured format. RESULTS: Overall knowledge about infection control was found to be satisfactory among 29% of laboratory technicians. Overall facilities for infection control were satisfactory in 61% of the DMCs, while adherence to ICP was satisfactory in 45% of the DMCs. Knowledge regarding ICP was better in government DMCs, whereas facilities for ICP and adherence to biomedical waste management guidelines were better in private DMCs. CONCLUSION: Given the higher risk of infection among laboratory technicians, there is an urgent need to address the shortcomings in infection control practices. PMID- 26767181 TI - Short EpiData course: do participants use the data entry tool two years post training? AB - SETTING: Training courses on data entry are few and far between compared to analysis. To address this gap, we conducted a short 2-day course on quality assured data capture using EpiData for public health professionals in Bangalore and Puducherry, India, in 2013. OBJECTIVE: To determine the proportion of participants who used EpiData and taught the software to others during the 2 years after training and explore the reasons for doing/not doing so. DESIGN: Cross-sectional study with self-administered, semi-structured questionnaire developed using web-based Google Forms. We performed a manual thematic analysis to identify the major reasons for using/not using EpiData. RESULTS: Of 46 participants, 38 (83%) responded. Of 31 participants involved in research, 17 (55%) had used EpiData, of whom 6 (35%) had performed double entry and validation. Of the 14 who did not use EpiData, 11 had used MS Excel or SPSS/Epi Info for data entry. Of the 38 respondents, 29 (76%) had taught EpiData to other colleagues and students. Reasons for using EpiData included its user friendliness, its being open access and the ease in preventing data entry errors. Reasons for not performing double entry included lack of time and manpower. CONCLUSION: The short course on EpiData was effective in knowledge transfer and provides a scalable model for incorporation into the teaching curricula of medical schools and research institutions. PMID- 26767182 TI - Research output after participants complete a Structured Operational Research and Training (SORT IT) course. AB - Eighteen months after successfully completing one of six Structured Operational Research and Training Initiative (SORT IT) courses, e-mail questionnaires assessing post-course research output were returned by 63 participants (100% response rate). Thirty-two (51%) participants had completed new research projects, 24 (38%) had published papers, 28 (44%) had presented abstracts at conferences, 15 (24%) had facilitated at further OR courses, and 21 (33%) had reviewed scientific papers. Seven (11%) had secured further research funding and 22 (35%) stated that their institutions were involved in implementation or capacity building in operational research. Significant research output continues beyond course completion, further endorsing the value of the SORT IT model. PMID- 26767183 TI - Mainstreaming tuberculosis case detection and reporting in medical colleges in India: early lesson learnt. PMID- 26767184 TI - Involved site radiation therapy for the treatment of early-stage Hodgkin lymphoma in adolescents and young adults. AB - Radiation therapy technology has permitted the development of new treatment planning techniques. Involved field, involved node, and involved site radiotherapy fields are discussed and compared. Indications for and implications of combined modality therapy are examined, particularly as pertinent to the adolescent and young adult population. PMID- 26767186 TI - Radiographic study of the distribution of maxillary intraosseous vascular canal in Koreans. AB - BACKGROUND: This study aimed to investigate the distribution and prevalence of intraosseous loop (anastomosis between posterior superior alveolar artery and infraorbital artery) in Koreans detected on computed tomography (CT) images taken prior to sinus augmentation surgery. METHODS: From the 177 patients who underwent sinus augmentation with lateral approach at Ewha Womans University Department of Implant Dentistry, 284 CT scans were evaluated. The canal height (CH), ridge height (RH), and canal height from the sinus floor (CHS) were measured on para axial views at the first premolar, first molar, and second molar. The horizontal positions of the bony canals in the lateral wall were also classified. One-way analysis of variance (ANOVA) and t test were used to estimate the statistical differences (p < 0.05). RESULTS: The intraosseous loops were detected in 92 CT scans (32 %). The mean vertical height of the bony canals from the alveolar crest (CH) was 23.45 +/- 2.81, 15.92 +/- 2.65, and 16.61 +/- 2.92 mm at the second premolar, first molar, and second molar, respectively. In the horizontal positions of the bony canals, intraosseous type was the most predominant. The canal heights more than 15 mm and less than 17 mm were most prevalent (33.7 %) and those under 13 mm were 12.0 %. CONCLUSIONS: The radiographic findings in this study could be used to decide the lateral osteotomy line avoiding potential vascular complication. However, only one third of the canals could be detected in CT scans; a precaution should be taken for the possibility of severe bleeding during lateral osteotomy. PMID- 26767185 TI - Neural correlates of eating disorders: translational potential. AB - Eating disorders are complex and serious psychiatric illnesses whose etiology includes psychological, biological, and social factors. Treatment of eating disorders is challenging as there are few evidence-based treatments and limited understanding of the mechanisms that result in sustained recovery. In the last 20 years, we have begun to identify neural pathways that are altered in eating disorders. Consideration of how these pathways may contribute to an eating disorder can provide an understanding of expected responses to treatments. Eating disorder behaviors include restrictive eating, compulsive overeating, and purging behaviors after eating. Eating disorders are associated with changes in many neural systems. In this targeted review, we focus on three cognitive processes associated with neurocircuitry differences in subjects with eating disorders such as reward, decision-making, and social behavior. We briefly examine how each of these systems function in healthy people, using Neurosynth meta-analysis to identify key regions commonly implicated in these circuits. We review the evidence for disruptions of these regions and systems in eating disorders. Finally, we describe psychiatric and psychological treatments that are likely to function by impacting these regions. PMID- 26767188 TI - Dimethyl fumarate treatment alters circulating T helper cell subsets in multiple sclerosis. AB - OBJECTIVE: To evaluate the effect of dimethyl fumarate (DMF; Tecfidera, Biogen, Weston, MA) on CD4(+) and CD8(+) T cell subsets in patients with multiple sclerosis (MS). METHODS: Peripheral lymphocyte subsets, including CD4(+) and CD8(+) memory cells and T helper (TH) cells TH1, TH2, TH17, and peripheral regulatory T cell (pTreg) subpopulations were analyzed before and 6 months after onset of DMF treatment. RESULTS: CD4(+) and CD8(+) memory T cells were preferentially decreased compared to naive CD4(+) and CD8(+) T cell populations. Within the CD4(+) memory T cell population, frequencies of TH1 cells were decreased, whereas those of TH2 cells were increased and those of TH17 cells remained unaltered. Accordingly, we observed decreased production of interferon gamma, granulocyte-macrophage colony-stimulating factor, tumor necrosis factor alpha, and interleukin (IL)-22 by CD4(+) T cells under DMF treatment, whereas the frequency of IL-4- and IL-17A-producing CD4(+) T cells remained unchanged. With regard to regulatory T cells, proportions of pTreg increased following DMF treatment. CONCLUSION: Our data demonstrate that DMF treatment of patients with MS affects predominantly memory T cells accompanied by a shift in TH cell populations, resulting in a shift toward anti-inflammatory responses. These findings indicate that monitoring of memory subsets might enhance vigilance of impaired antiviral immunity and that patients with TH1-driven disease might preferentially benefit from DMF treatment. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that DMF might preferentially reduce CD4(+) and CD8(+) memory T cells in MS. PMID- 26767187 TI - Computer-aided design/computer-aided manufacturing of hydroxyapatite scaffolds for bone reconstruction in jawbone atrophy: a systematic review and case report. AB - BACKGROUND: We reviewed the biological and mechanical properties of porous hydroxyapatite (HA) compared to other synthetic materials. Computer-aided design/computer-aided manufacturing (CAD/CAM) was also evaluated to estimate its efficacy with clinical and radiological assessments. METHOD: A systematic search of the electronic literature database of the National Library of Medicine (PubMed MEDLINE) was performed for articles published in English between January 1985 and September 2013. The inclusion criteria were (1) histological evaluation of the biocompatibility and osteoconductivity of porous HA in vivo and in vitro, (2) evaluation of the mechanical properties of HA in relation to its porosity, (3) comparison of the biological and mechanical properties between several biomaterials, and (4) clinical and radiological evaluation of the precision of CAD/CAM techniques. RESULTS: HA had excellent osteoconductivity and biocompatibility in vitro and in vivo compared to other biomaterials. HA grafts are suitable for milling and finishing, depending on the design. In computed tomography, porous HA is a more resorbable and more osteoconductive material than dense HA; however, its strength decreases exponentially with an increase in porosity. CONCLUSIONS: Mechanical tests showed that HA scaffolds with pore diameters ranging from 400 to 1200 MUm had compressive moduli and strength within the range of the human craniofacial trabecular bone. In conclusion, using CAD/CAM techniques for preparing HA scaffolds may increase graft stability and reduce surgical operating time. PMID- 26767189 TI - Sandfly virus seroconversion associated with neurologic presentation. AB - OBJECTIVE: To describe the clinical presentation and unique neurologic manifestations of sandfly viruses (SFVs) in the Jerusalem area. METHODS: We identified all patients with acute seroconversion to SFV at the Hadassah-Hebrew University Medical Centers during the years 2008-2013 and retrospectively collected and analyzed the clinical and imaging data. RESULTS: Nine patients (ranging from 1.5 to 85 years old) were identified. Presentation included acute neurologic disease, mostly with fever, change in consciousness and behavior, seizures, headache, meningitis, limb paresis, or myelitis. Eight patients had clinical signs of meningitis, meningoencephalitis, or encephalitis alone. Four patients had myelitis. MRI identified pathologic symmetrical changes in the basal ganglia, thalami, and other deep structures in 5 patients, and additional myelitis of the spine was noted on imaging in 3 patients. Seven patients had long term follow-up: 4 completely recovered and 3 had remaining neurologic sequelae, among them 1 with permanent severe brain damage. CONCLUSION: Neurologic involvement associated with acute SFV infections is considered to be benign. However, in this series, all 9 patients presented with significant neurologic pathology associated with a unique finding of myelitis and symmetrical basal ganglia, thalami, or white matter involvement. Thus, acute SFV infection should be included in the differential diagnosis in febrile onset of neurologic manifestations and neuroradiologic changes. PMID- 26767190 TI - Lockjaw in stiff-person syndrome with autoantibodies against glycine receptors. PMID- 26767192 TI - Patient-Centered Outcomes Following Thoracentesis. AB - BACKGROUND: Pleural effusions impact over 1.5 million people annually in the United States and cause significant morbidity. Although therapeutic thoracentesis is associated with improvement in respiratory parameters, unanswered questions remain regarding its impact. OBJECTIVE: The purpose of this study was to investigate patient-centered outcomes, the need for additional pleural interventions, and mortality in the 30 days following thoracentesis. METHODS: This prospective observational cohort study was performed in a tertiary care academic medical center between December 2010 and December 2011. Adult patients referred for thoracentesis were offered enrollment. The following characteristics were evaluated both before and at 30 days postprocedure: dyspnea using modified BORG (mBORG), physical and mental quality of life (QoL) using the short form 12, and basic activities of daily living (BADLs). The primary outcomes included changes in these parameters 30 days after thoracentesis. Secondary outcomes included the need for additional pleural procedures and mortality within 30 days of the thoracentesis. Multivariable logistic regression was used for analysis. RESULTS: Of the 284 patients who underwent thoracentesis, 80 (28.2%) died within 30 days of the procedure. Of the 163 patients comprising the analytical cohort, 35 (21.5%) patients required an additional pleural intervention within 30 days of the index procedure. Patients who survived more than 30 days following thoracentesis had a sustained improvement in dyspnea and mental QoL, but a minority had improvement in physical QoL or BADLs. Surviving patients demonstrated no significant associations between bilateral and unilateral thoracentesis, volume of fluid removed, or the etiology of the effusion (malignant vs nonmalignant) and improvement in QoL, dyspnea, and BADLs. Relative to nonmalignant etiology, the presence of a malignant effusion was strongly associated with the need for an additional intervention, yielding an odds ratio (95% confidence interval [95% CI]) of 16.92 (5.47-52.37). Patients with hepatic hydrothorax and infectious etiologies of their effusion were also likely to require additional pleural interventions. CONCLUSION: The majority of patients in this cohort demonstrated sustained improvement in dyspnea and the mental aspect of QoL 30 days following thoracentesis, independent of the etiology and regardless of the volume of pleural fluid removed. A minority experienced sustained improvements in the physical aspect of QoL and BADLs. Although 28.2% of patients died within 30 days, nearly 1 in 5 survivors required an additional pleural intervention. These results emphasize the significant clinical impact, morbidity, and mortality experienced by patients who undergo thoracentesis for pleural effusions. PMID- 26767191 TI - Preclinical toxicology of oncolytic adenovirus-mediated cytotoxic and interleukin 12 gene therapy for prostate cancer. AB - The purpose of this study was to examine the toxicity of combining oncolytic adenovirus-mediated cytotoxic and interleukin 12 (IL-12) gene therapy in a preclinical model to support future phase 1 trials. One hundred and twenty C57BL/6 male mice received an intraprostatic injection of saline (n = 24) or an oncolytic adenovirus (Ad5-yCD/mutTKSR39rep-mIL12) expressing two suicide genes and mouse IL-12 (n = 96). The adenovirus was administered at three dose levels (1.3 * 106, 1.3 * 107, 1.3 * 108 vp/kg) followed by 2 weeks of 5-flurocytosine (5 FC) and gancliclovir (GCV) prodrug therapy. There were no premature deaths. Daily observations of animals did not reveal any obvious clinical problems throughout the 78-day in-life phase of the study. Animals in the highest adenovirus dose group exhibited lymphopenia and transaminitis on day 3, both of which resolved by day 17. Except for mild inflammation of the prostate and seminal vesicles, histopathology of major organs was largely unremarkable. IL-12 and interferon gamma levels in prostate and serum peaked on day 3 and were either undetectable or returned to baseline levels by day 17. No adenoviral DNA was detected in serum in any group at any time point. The results demonstrate that local administration of an oncolytic adenovirus expressing two suicide genes and IL-12 is well tolerated and support moving this investigational approach into human trials. PMID- 26767193 TI - Precise stellar surface gravities from the time scales of convectively driven brightness variations. AB - A significant part of the intrinsic brightness variations in cool stars of low and intermediate mass arises from surface convection (seen as granulation) and acoustic oscillations (p-mode pulsations). The characteristics of these phenomena are largely determined by the stars' surface gravity (g). Detailed photometric measurements of either signal can yield an accurate value of g. However, even with ultraprecise photometry from NASA's Kepler mission, many stars are too faint for current methods or only moderate accuracy can be achieved in a limited range of stellar evolutionary stages. This means that many of the stars in the Kepler sample, including exoplanet hosts, are not sufficiently characterized to fully describe the sample and exoplanet properties. We present a novel way to measure surface gravities with accuracies of about 4%. Our technique exploits the tight relation between g and the characteristic time scale of the combined granulation and p-mode oscillation signal. It is applicable to all stars with a convective envelope, including active stars. It can measure g in stars for which no other analysis is now possible. Because it depends on the time scale (and no other properties) of the signal, our technique is largely independent of the type of measurement (for example, photometry or radial velocity measurements) and the calibration of the instrumentation used. However, the oscillation signal must be temporally resolved; thus, it cannot be applied to dwarf stars observed by Kepler in its long-cadence mode. PMID- 26767194 TI - Direct observation of intersystem crossing in a thermally activated delayed fluorescence copper complex in the solid state. AB - Intersystem crossing in thermally activated delayed fluorescence (TADF) materials is an important process that controls the rate at which singlet states convert to triplets; however, measuring this directly in TADF materials is difficult. TADF is a significant emerging technology that enables the harvesting of triplets as well as singlet excited states for emission in organic light emitting diodes. We have observed the picosecond time-resolved photoluminescence of a highly luminescent, neutral copper(I) complex in the solid state that shows TADF. The time constant of intersystem crossing is measured to be 27 picoseconds. Subsequent overall reverse intersystem crossing is slow, leading to population equilibration and TADF with an average lifetime of 11.5 microseconds. These first measurements of intersystem crossing in the solid state in this class of mononuclear copper(I) complexes give a better understanding of the excited-state processes and mechanisms that ensure efficient TADF. PMID- 26767195 TI - Hybrid bilayer plasmonic metasurface efficiently manipulates visible light. AB - Metasurfaces operating in the cross-polarization scheme have shown an interesting degree of control over the wavefront of transmitted light. Nevertheless, their inherently low efficiency in visible light raises certain concerns for practical applications. Without sacrificing the ultrathin flat design, we propose a bilayer plasmonic metasurface operating at visible frequencies, obtained by coupling a nanoantenna-based metasurface with its complementary Babinet-inverted copy. By breaking the radiation symmetry because of the finite, yet small, thickness of the proposed structure and benefitting from properly tailored intra- and interlayer couplings, such coupled bilayer metasurface experimentally yields a conversion efficiency of 17%, significantly larger than that of earlier single layer designs, as well as an extinction ratio larger than 0 dB, meaning that anomalous refraction dominates the transmission response. Our finding shows that metallic metasurface can counterintuitively manipulate the visible light as efficiently as dielectric metasurface (~20% in conversion efficiency in Lin et al.'s study), although the metal's ohmic loss is much higher than dielectrics. Our hybrid bilayer design, still being ultrathin (~lambda/6), is found to obey generalized Snell's law even in the presence of strong couplings. It is capable of efficiently manipulating visible light over a broad bandwidth and can be realized with a facile one-step nanofabrication process. PMID- 26767197 TI - Correcting Susceptibility-Induced Distortion in Diffusion-Weighted MRI using Constrained Nonrigid Registration. AB - Echo Planar Imaging (EPI) is the standard pulse sequence used in fast diffusion weighted magnetic resonance imaging (MRI), but is sensitive to susceptibility induced inhomogeneities in the main B0 magnetic field. In diffusion MRI of the human head, this leads to geometric distortion of the brain in reconstructed diffusion images, and a lack of correspondence with undistorted high-resolution MRI scans that are used to define the subject anatomy. In this study, we have tested an approach to estimate and correct this distortion of using a non-linear registration framework based on mutual-information. We use the commonly acquired anatomical image as the registration-template and constrain the registration using spatial regularization and physics-based information about the characteristics of the distortion, but without requiring any additional data collection. Results are shown for simulated and experimental data. PMID- 26767199 TI - Poor drug history documentation in admission medical notes: clerking prompts and junior doctor education alone do not significantly reduce errors. AB - INTRODUCTION: Poor drug history documentation on admission may lead to medication errors; a leading cause of avoidable harm. AIMS: To assess the quality of drug histories in the notes of patients admitted to an emergency assessment unit and impact of interventions to improve documentation. METHODS: Data were collected on the accuracy of documentation in 281 drug histories including errors of omission, frequency and dose. RESULTS: The mean error rate was high at more than five per drug history. Omitted drugs included warfarin and long-term steroids, the consequences of which were potentially serious. Clerking prompts and education alone did not improve errors significantly. CONCLUSION: The error rate in drug histories is unacceptably high. More research is needed to explore factors involved in such documentation errors. PMID- 26767198 TI - The Team at Work--The Society for Acute Medicine's Benchmarking Audit 2014 (SAMBA'14). AB - BACKGROUND: The Society for Acute Medicine's Benchmarking Audit (SAMBA) serves as a tool for Acute Medical Units to compare and improve their quality of care. AIM: To audit the performance of Acute Medical Units against clinical quality indicators, standards by the Royal College of Physicians and Specialist Societies relevant to the practice of Acute Medicine. METHODS: An online survey of unit profiles and staffing levels on the audit day was followed by a 24-hour data collection on Thursday the 19th of June 2014 for all patients seen by the local Acute Medicine teams as part of the general medical take. Patients were followed up for 72 hours. We reviewed the impact of staffing levels on performance indicators. RESULTS: 66 Acute Medical Units admitted 2333 patients during the 24 hour period. Compliance with the quality standards of SAM was as follows: 84% of patients had an early warning score recorded within 30 minutes of admission, 81% of patients had been seen by a competent decision maker within four hours and 73% of patients were seen by a consultant physician within the appropriate period of time. Only 56% of patients received a standard of care compatible with all three quality standards. We found no relation between unit characteristics, staffing and performance indicator. CONCLUSION: There remains a gap between the standard described by the quality indicators and the performance of Acute Medical Units during a one-day audit. PMID- 26767200 TI - HaNDL with care. AB - Headache with neurological deficit and cerebrospinal fluid (CSF) lymphocytosis (HaNDL) syndrome is an important diagnosis to consider in patients presenting with the relevant features to acute medicine. Investigations should aim to exclude more serious differential diagnoses such as infectious, inflammatory and neoplastic causes prior to making a formal diagnosis of HaNDL. Increased awareness and early consideration of HaNDL would help to avoid unnecessary prolonged courses of antimicrobial therapy and invasive investigations such as cerebral angiography. PMID- 26767196 TI - Efficient luminescent solar cells based on tailored mixed-cation perovskites. AB - We report on a new metal halide perovskite photovoltaic cell that exhibits both very high solar-to-electric power-conversion efficiency and intense electroluminescence. We produce the perovskite films in a single step from a solution containing a mixture of FAI, PbI2, MABr, and PbBr2 (where FA stands for formamidinium cations and MA stands for methylammonium cations). Using mesoporous TiO2 and Spiro-OMeTAD as electron- and hole-specific contacts, respectively, we fabricate perovskite solar cells that achieve a maximum power-conversion efficiency of 20.8% for a PbI2/FAI molar ratio of 1.05 in the precursor solution. Rietveld analysis of x-ray diffraction data reveals that the excess PbI2 content incorporated into such a film is about 3 weight percent. Time-resolved photoluminescence decay measurements show that the small excess of PbI2 suppresses nonradiative charge carrier recombination. This in turn augments the external electroluminescence quantum efficiency to values of about 0.5%, a record for perovskite photovoltaics approaching that of the best silicon solar cells. Correspondingly, the open-circuit photovoltage reaches 1.18 V under AM 1.5 sunlight. PMID- 26767201 TI - Acquired haemophilia: an easy diagnosis to miss in a patient taking warfarin. AB - Acquired Haemophilia (AH) is an autoimmune bleeding disorder, which despite being rare, can be fatal. It occurs in patients with previously normal haemostasis who spontaneously develop IgG autoantibodies against factor VIII. Unlike congenital haemophilia, it manifests as spontaneous bleeding into skin and soft tissues. The presentation can be masked in patients who are receiving warfarin where the bleeding is often attributed to warfarin therapy, as in the case described in this report. Consideration of AH is important in patients taking anticoagulants, when coagulopathy and bleeding fails to correct with usual measures. PMID- 26767202 TI - Can Ambulatory Emergency Care have a positive impact on acute services? AB - Ambulatory Emergency Care is a key component of the service for many Acute Medical units across the United Kingdom. A well-functioning ambulatory care unit facilitiates early senior review by a consultant and may reduce the need for hospital admission by managing patients along alternative safe clinical pathways. In this article, we present 12 months of data (January 2014-January 2015) from our Ambulatory Unit at Wrightington, Wigan and Leigh NHS Foundation Trust (WWL NHSFT), which demonstrates how many different conditions can be safely managed along ambulatory care pathways and how this can significantly contribute to postive patient satisfaction survey results and meeting the A&E 4 hour target for a medium-sized Acute Trust such as WWL NHSFT. We also emphasise that the key factors of co-location of ambulatory care with the Emergency Department along with dedicated medical and nursing staff are essential to the success of this model of care. PMID- 26767203 TI - Acute General Practice--the 7 year itch. AB - The Acute GP Service has operated in Plymouth for the last 7 years. We have a mandate to improve patient care through supporting community GPs and their patients at the point of need for urgent medical assessment. I outline our service design and delivery and make the argument for the use of primary care physicians to help manage the interface between primary and secondary care. PMID- 26767204 TI - Problem based review: The patient with hypercalcaemia. AB - Hypercalcaemia is a common problem which may present to the Acute Medical Unit. Primary hyperparathyroidism (PHPT) and malignancy are the commonest causes of hypercalcaemia, accounting for over 90% of cases. Assessment of parathyroid hormone (PTH) levels is key to determining whether hypercalcaemia is parathyroid mediated. Initial systematic assessment and adequate rehydration are important to help make the underlying diagnosis and determine longer-term management. The medical management of primary hyperparathyroidism not requiring surgery, with Cinacalcet is highlighted. PMID- 26767205 TI - Wavenumber selection based analysis in Raman spectroscopy improves skin cancer diagnostic specificity. AB - Real-time Raman spectroscopy can be used to assist in assessing skin lesions suspicious for cancer. Most of the diagnostic algorithms are based on full band of the Raman spectra, either in the fingerprint region or the high wavenumber region. In this paper we explored wavenumber selection based analysis in Raman spectroscopy for skin cancer diagnosis. Wavenumber selection was implemented using windows of wavenumber and leave-one-out cross-validated stepwise regression or least and shrinkage selection operator (LASSO). The diagnostic algorithms were then generated from the selected windows of wavenumber using multivariate statistical analyses, including principal component and general discriminate analysis (PC-GDA) and partial least squares (PLS). In total a combined cohort of 645 confirmed lesions from 573 patients encompassing skin cancers, precancers and benign skin lesions were included, which were divided into training cohort (n = 518) and testing cohort (n = 127) according to the measurement time. It was found that the area under the receiver operating characteristic curve (ROC) was improved from 0.861-0.891 to 0.891-0.911 and the diagnostic specificity for fixed sensitivity 0.99-0.90 was improved from 0.17-0.65 to 0.20-0.75 with wavenumber selection based analysis. PMID- 26767206 TI - [EFFECTIVENESS COMPARISON OF DIFFERENT OPERATIVE METHODS IN TREATMENT OF CLOSED FRACTURE OF TIBIAL SHAFT]. AB - OBJECTIVE: To explore the effectiveness of three different operative methods in the treatment of closed fracture of the tibial shaft. METHODS: Between January 2012 and May 2014, 94 patients with closed fracture of the tibial shaft were treated, and the clinical data were retrospectively analyzed. Fracture was fixed with locking plate (external fixation) in 25 cases (group A), with intramedullary nail in 34 cases (group B), and with minimally invasive locking plate in 35 cases (group C). There was no significant difference in gender, age, reasons of injury, fracture types, and time from injury to operation among groups (P>0.05). The operation time, intraoperative blood loss, fluoroscopy frequency during operation, fracture union time, and complications were recorded. The effectiveness was evaluated according to Johner-Wruhs criteria. RESULTS: The operation time and fluoroscopy frequency during operation in groups A and C were significantly less than those in group B (P<0.05), but there was no significant difference between groups A and C (P>0.05). The intraoperative blood loss in groups A and C was significantly less than that in group B (P<0.05), and the blood loss in group A was significantly less than that in group C (P<0.05). All patients were followed up 15.61 months on average (range, 12-41 months). There was no significant difference in fracture union time among 3 groups (F=1.712, P=0.186). The excellent and good rates of groups A, B, and C were 92.00%, 88.24%, and 91.43% respectively according to Johner-Wruhs criteria at 12 months after operation, showing no significant difference (X2=0.301, P=0.860). At 12 months after operation, the complication incidences of groups A (12.00%, 3/25), and C (15.55%, 5/35) were significantly lower than that of group B (44.12%, 15/34) (P<0.017), but no significant difference was found between groups A and C (P>0.017). CONCLUSION: Using locking plate as external fixation and minimally invasive locking plate internal fixation are better than intramedullary nail fixation in treating closed fracture of tibial shaft because of less injury and lower complication incidence, and locking plate as external fixation is better than minimally invasive locking plate internal fixation because of less injury. PMID- 26767207 TI - The Neuropathology of Huntington's disease: classical findings, recent developments and correlation to functional neuroanatomy. AB - Huntington's disease (HD) is a severe, autosomal dominantly inherited, gradually worsening neurological disorder, the clinical features of which were first described in 1863 by Irving W. Lyon and with additional details, in 1872, by George Huntington. Progress in molecular biological research has shown that HD is caused by meiotically unstable CAG-repeats in the mutated HD gene (the so-called IT 15 gene) on chromosome 4p16.3, which encodes the mutated protein huntingtin (Htt). This monograph provides a survey of the stepwise progress in neuropathological HD research made during a time period of more than hundred years, the currently known neuropathological hallmarks of HD, as well as their pathogenic and clinical relevance. Starting with the initial descriptions of the progressive degeneration of the neostriatum (i.e., caudate nucleus and putamen) as one of the key events in HD, the worldwide practiced Vonsattel HD grading system of striatal neurodegeneration will be outlined. Correlating qualitative and quantitative neuropathological data with characteristics pertaining to the functional neuroanatomy of the human brain, subsequent chapters will highlight the latest neuropathological HD findings: the area- and layer-specifi c neuronal loss in the cerebral neo- and allocortex, the neurodegeneration of select thalamic nuclei, the affection of the cerebellar cortex and the deep cerebellar nuclei, the involvement of distinct brainstem nuclei, and the pathophysiological relevance of these pathologies for the clinical phenotype of HD. Finally, the potential pathophysiological role of axonal transport deficit PMID- 26767209 TI - Pediatrics. PMID- 26767210 TI - Diagnostic radiology. PMID- 26767211 TI - Developmental-behavioral pediatrics. PMID- 26767212 TI - Geriatric medicine. PMID- 26767213 TI - Clinical psychology. PMID- 26767214 TI - Anesthesiologist assistants. PMID- 26767215 TI - Addressing ongoing diversity concerns. PMID- 26767216 TI - Frustrations with flawed focus. PMID- 26767217 TI - Freshwater harmful algal blooms and cyanotoxin poisoning in domestic dogs. PMID- 26767218 TI - Family Medicine. PMID- 26767219 TI - Summit to explore student debt-related issues, solutions. PMID- 26767220 TI - AVMA panel to scrutinize telemedicine. PMID- 26767221 TI - Physician assistant. PMID- 26767222 TI - Veterinary wellness roundtable happening next year. PMID- 26767223 TI - AVMA supports surgeon general's call to action on walking. PMID- 26767224 TI - Medical physicist. PMID- 26767226 TI - Eradicating goat plague. PMID- 26767225 TI - U.S. could use hyperthermia, asphyxia to fight bird flu. PMID- 26767227 TI - FDA to require more illness prevention from food makers. PMID- 26767228 TI - Pathologists' assistants. PMID- 26767229 TI - Setting the Scene for 2016: From opioid addiction to fantasy sports, state lawmakers will have plenty on their plates this year--no matter who occupies the White House. PMID- 26767230 TI - Anesthesia-related neurotoxicity and the developing brain:--do not overreact. A commentary. PMID- 26767231 TI - Anesthesia and neurotoxicity in the developing brain: A non-systematic review. AB - In recent years, increasing experimental evidence has suggested an association between exposure to anesthesia in early life and subsequent poor neurodevelopmental outcome. Retrospective and follow-up studies have also suggested anesthesia-related neurotoxicity in the developing human brain. The present non-systematic review summarizes the available evidence, depicts the current knowledge on the potentially harmful effects of anesthesia and will discuss whether this knowledge urges us to implement changes in clinical practice. PMID- 26767232 TI - A comparative evaluation of the Airtraq and King Vision video laryngoscope as an intubating aid in adult patients. AB - Airtraq has been shown to improve ease of intubation in patients with normal and difficult airway. King Vision video laryngoscope is a newly introduced intubating device with an attached monitor. We here hypothesized that the King Vision video laryngoscope with channeled blade performs better during intubation as compared to Airtraq. In this study, we performed a comparison between the King Vision video laryngoscope and the Airtraq with regard to time needed for intubation, number of attempts required to intubate, and complications. Fifty ASA grade I and II adult patients posted for a routine surgical procedure were randomly divided into two groups of 25 patients each. All patients were anesthetized using similar techniques. The time required to intubate patients was significantly shorter when the King Vision video laryngoscope with channeled blade was used as compared to the Airtraq (p < 0.05). The number of attempts to successfully intubate patients was also significantly lower (p < 0.05) for the King Vision video laryngoscope than for the Airtraq. The use of the Kings Vision video laryngoscope with channeled blade should be encouraged in difficult intubation situations in adult patients with a mouth opening of more than 18 mm. PMID- 26767233 TI - A novel method of intubation and orogastric tube insertion using a C-MAC-D-blade videolaryngoscope-bougie technique. AB - INTRODUCTION: Expertise in airway management is a fundamental aspect of anesthesia practice. Fortunately 'can't intubate, can't ventilate' scenarios are extremely rare. In particular, patients with tumors on the right side of the oropharynx and larynx can be very problematic to intubate. METHODS: We present an alternative intubation technique, whereby a C-MAC D-blade videolaryngoscope is loaded with a Frova catheter in the narrow, curving channel within the blade's infero-posterior aspect on the left side of the blade. This technique can be a successful alternative in patients with difficult airways. RESULTS: The proposed technique was successfully demonstrated in a case whereby a 47-year old male with premetrics of a difficult airway, presented with a large mass in the right supraglottis and hypopharynx with through-and-through thyroid cartilage infiltration, obstructing completely the view of the glottis with direct laryngoscopy. The referral hospital considered the patient unintubatable and sent the patient to our academic center for treatment. Endotracheal intubation with the new technique was successful at the first attempt. CONCLUSIONS: The C-MAC D Blade videolaryngoscope-bougie technique provides an alternative method to intubate patients with difficult airways, even in exceptional situations such as in patients with a large right-sided oropharynx-larynx tumor. PMID- 26767234 TI - Phrenic nerve palsy following interscalene brachial plexus block; a long lasting serious complication. AB - Interscalene brachial plexus block (ISBPB) offers good analgesia for painful surgical procedures on the shoulder. We here describe two cases of long-term phrenic palsy following ISBPB that occurred in our practice in a relative short time period and both clearly illustrate the devastating impact of this complication for the patient. We will discuss the benefit of ISBPB in the context of the incidence and significant disability of hemi diaphragm paresis. Anesthesiologists must be aware of this complication and carefully weigh the advantages of ISPBP against the risks of this complication. When ISPBP is considered, the fact that the incidence of prolonged phrenic nerve palsy may be higher than previously expected should be taken into account carefully. A reevaluation on the indication and patient selection of ISBPB may even be warranted. PMID- 26767235 TI - Comparison of conventional infrainguinal versus modified proximal suprainguinal approach of Fascia Iliaca Compartment Block for postoperative analgesia in Total Hip Arthroplasty. A prospective randomized study. AB - Fascia Iliaca Compartment Block (FICB) has been widely used as a postoperative analgesic adjunct to opioids for total hip arthroplasty (THA), either by the conventional infrainguinal approach or the modified proximal suprainguinal approach irrespective of any specific advantage of one over the other. This study was conducted to compare the analgesic efficacy of the two techniques of FICB for postoperative analgesia. The 40 patients scheduled for THA were recruited for Intervention (s) and randomized to receive FICB either by suprainguinal approach (group S) or infrainguinal approach (group I) for postoperative analgesia with 40 ml of 0.2% bupivacaine, in addition to postoperative patient controlled analgesia (PCA) with morphine. Visual analogue scale (VAS) and PCA morphine consumption was used to assess the postoperative pain at 3, 6, 12 and 24 hours. The primary outcome was cumulative PCA morphine consumption in 24 hours. The pain intensity as measured by VAS scores showed significant reduction of intensity at 6 hours post block in group S as compared to group I (median [IQR]; 2[0-3]; 3[2.25-3]; p = 0.001) but, there was no significant difference in VAS at 12 and 24 hours. Postoperatively, there was significant difference in time to first PCA morphine demand (356.28 +/- 33.32 vs 291.48 +/- 37.17, p = < 0.001, respectively) in-group S vs. group I. The postoperative morphine consumption was also significantly less in group S compared to group I at 6, 12 and 24 hours and the cumulative morphine consumption in 24 hours (6.95 +/- 2.14 vs 10.50 +/- 2.24, p = < 0.001 respectively) was also less. In conclusion, in THA, suprainguinal approach of FICB has a superior postoperative analgesic efficacy compared to infrainguinal approach of FICB along with significantly less morphine consumption in first 24 hours. PMID- 26767236 TI - Heart rate correction should be kept in mind during measurements of ventricular repolarization parameters. PMID- 26767237 TI - Replacing Amalgam Restorations: A Standardized Protocol Based on Analyzing Tissue Physicochemical Modifications. AB - Almost 60% of operative dentistry is devoted to replacing restorations. When practitioners have to replace an amalgam restoration, they tend to opt for an adhesive restoration, as it is conservative of tooth tissues and mimics the natural appearance of teeth. Based on a literature review, the aim of this article is to determine the best tissue approach when replacing an old amalgam by a new adhesive restoration. After analyzing and understanding tissue alterations due to the amalgam corrosion process, the authors propose an analytical approach to managing the situation. Both tissue orientated and specific mechanical approaches are developed and should be implemented to carry out the optimal clinical procedure and achieve the most conservative and durable treatment. PMID- 26767238 TI - Evaluation of Chlorine Dioxide Irrigation Solution on the Microhardness and Surface Roughness of Root Canal Dentin. AB - The aim of this study was to evaluate the effect of chlorine dioxide and various other more common irrigation solutions on the microhardness and surface roughness of root canal dentin. Fifty human maxillary central incisors were sectioned longitudinally and treated for 1 minute with 5 ml of the following aqueous solutions (v/v%): Group 1: 13.8% chlorine dioxide, Group 2: 17% ethylene diamine tetraacetic acid (EDTA). Group 3: 7% maleic acid, Group 4: 2.5% sodium hypochlorite (5 ml/min), Group 5: Saline (control). Specimens were subjected to microhardness and surface roughness testing. Chlorine dioxide and sodium hypochlorite reduced the microhardness more than other test agents. The highest surface roughness was produced with maleic acid. Chlorine dioxide should be used cautiously during chemomechanical preparation of the root canal system in order to prevent untoward damage to the teeth. PMID- 26767239 TI - In Vitro Effects of 2.5% Titanium Tetrafluoride on Streptococcus Mutans and Lactobacillus Casei in Dentin Followed by Self-Etching Adhesive Systems. AB - The aim was to evaluate the effect of a 2.5% titanium tetrafluoride (TiF4) solution followed by self-etching adhesives against Streptococcus mutans/Sm and Lactobacillus casei/Lc. Four cylindrical-shaped cavities were performed on each dentin surface of 40 third molars and contaminated with Sm or Lc. Each one of the four cavities received one of the following treatments (n = 10): 1) control; 2) TiF4; 3) Clearfil SE Bond/CSE or Adper EasyOne/AEO; 4) TiF4 followed by CSE or AED. ANOVA was applied to data. The TiF4 solution showed an antimicrobial effect, although the TiF4 used for dentin pretreatment before CSE or AEO showed no influence on antimicrobial effect. PMID- 26767240 TI - Effectiveness of Disposable (Single-use) Tips for Dental Air-water Syringes. AB - BACKGROUND: Single-use dental syringe (SUS) tips eliminate cross-infection risks. Many dental materials are moisture sensitive; therefore bonding could be affected by remaining moisture from SUS tips. METHODS: An air-water syringe was calibrated to 50 PSI and the air pressure measured. SUS tips were then attached and pressure re-measured. Seven tips were tested; moisture content and spray pattern were investigated. Ethical approval was granted. Twenty third molar teeth were sectioned, stored in phosphate buffered saline and randomly allocated into groups with a SUS tip. They were mounted in acrylic and polished. Specimens were dried with a tip under standardised conditions, treated using a 3-step etch-prime-bond technique, then had a post bonded perpendicular to the dentine surface. The force to detach them was measured. Data were analysed using one-way analysis of variance (ANOVA) and Chi-squared tests. RESULTS: The difference in output pressure between groups proved significant (p < 0.001). Tensile force at failure was significantly different between groups (p = 0.19). CONCLUSIONS: The pressure output of the syringe and bond strength are influenced by the SUS tip. PMID- 26767241 TI - The Effect of Disinfection Techniques on the Flexural Strength of Thermopolymerisable Acrylic Resins With or Without Pigment Addition. AB - OBJECTIVES: The aim of this study was to assess the flexural strength of two brands of thermopolymerisable acrylic resins (Onda Cryl, Artigos Odontologicos Classico Ltda, Sao Paulo, SP, Brazil; and Lucitone 550, Dentsply, York, PA, USA) with varying concentrations of pigment (Poli-Cor, Artigos Odontologicos Classico Ltda, Sao Paulo, SP, Brazil) under the influence of thermocycling, storage and disinfection. MATERIAL AND METHODS: A total of 210 samples were manufactured (105 for each acrylic resin brand), with dimensions of 64 x 10 x 3.3 mm. The samples were divided into 30 subgroups (n = 7) according to the proportion of pigment used (without pigment, 3% and 7%), the assessment period (initial or thermocycling for 2000 cycles) and disinfection method (immersion in 1% sodium hypochlorite, (Apothicario, Aracatuba, SP, Brazil), microwave energy or immersion in alkaline peroxide (Efferdent, Pfizer, Morris Plains, NJ, USA). The samples were submitted to the flexural strength test before and after thermocycling, and after storage with disinfection. The disinfection process was performed every 3 days, for 60 days. Data were submitted to analysis of variance (ANOVA) and Tukey test (p < 0.05). RESULTS: The factors that provided statistical alteration in flexural strength values were resin type and assessment period. The Onda Cryl resin and the period after disinfection (126 +/- 25 MPa) exhibited the higher values of flexural strength. CONCLUSION: Following disinfection, Onda-Cryl resin exhibited the highest values of flexural strength. All the samples obtained are considered clinically acceptable. PMID- 26767242 TI - Prevalence of Peri-implant Diseases: Analyses of Associated Factors. AB - AIM. Identify the relationship between specific factors (age, sex, smoking, time of prosthesis in function, implant location, and width of peri-implant keratinized mucosa) and peri-implant diseases in patients from the Center of Research and Continuing Education in Implant Dentistry (CEPID) at the Federal University of Santa Catarina (UFSC), Brazil. MATERIALS AND METHODS: A cross sectional study was conducted in 193 patients that had received 725 external hexed cylindrical implants supporting functional prosthesis for at least 1 year (range from 1-9 years). Clinical examination included probing depths, bleeding on probing and/or suppuration. Radiographic exam was conducted to measure peri implant bone levels. RESULTS: There was no statistically significance in the association between prevalence of peri-implant diseases and age, sex, time with prostheses in function and implant location variables independently. There was a statistically significant association between the independent variables of smoking and the width of keratinized peri-implant mucosa less than 2mm, and the presence of peri-implant diseases. When all the categories were evaluated together in relation with the peri-implant diseases, the prostheses in function for 5 years and more had association with presence of both, peri-implant mucositis an peri-implantitis. Peri-implantitis prevalence was higher for males with the prostheses in use for 5 years or more. Peri-implant mucositis was more associated with the participants over 57 years of age, with systemic disease and with the prostheses in function for more than 5 years. CONCLUSIONS: Smoking habits and the width of peri-implant keratinized mucosa as independent variables were associated with the prevalence of peri-implant diseases. PMID- 26767243 TI - The Modified Semidirect Onlay Technique With Articulated Elastic Model. AB - The modified semidirect onlay technique with articulated elastic model involves the fabrication of a stone model that is quickly mounted on an articulator and it includes an elastic part that enables the fabrication of a restoration with proper occlusal anatomy. The technique overcomes the disadvantages of the direct technique such as polymerization shrinkage stress and difficulty in achieving proper contours and, compared to the indirect technique, treatment is completed in a single appointment, without laboratory cost. The novelty of the technique is that, since the restoration is fabricated on an articulated model it eliminates time for occlusal adjustments. PMID- 26767244 TI - Cast Titanium for Obturator Framework Construction in Maxillofacial Prosthodontics. AB - A 37 year old male presented with the complaint of a loose and bulky acrylic obturator prosthesis. He had previously tried to using a different acrylic obturator prostheses as well as both cobalt chromium and titanium framework obturators. The most successful previous prosthesis was a titanium based obturator which had performed well prior to a fractured clasp. Accordingly, following an exploration of the available surgical and prosthodontic treatment options, a further tooth borne partial maxillary obturator was provided successfully. The case highlights the relative merits and limitations of the use of cast titanium as a denture base material in partial denture and obturator construction. PMID- 26767245 TI - Can we turn the table on vascular access in 2016? PMID- 26767246 TI - Policy, politics, and payment in 2015. PMID- 26767247 TI - The state of the industry in 2015. PMID- 26767248 TI - How staff-assisted HHD can improve outcomes--and still meet your bottom line. PMID- 26767249 TI - Medicare Advantage associated with lower mortality for incident dialysis patients. AB - Physicians across the care continuum are increasingly aligned around the belief that coordinated care can improve patient outcomes. As the principal caregivers for one of the most medically fragile patient groups in healthcare, nephrologists are especially attuned to the potential value of integrated care. Medicare Advantage (MA) offers one way to test this hypothesis. By law, end-stage renal disease patients currently cannot enroll into an MA plan, but if they develop ESRD while in such a plan, they may continue to be enrolled. The contrast between these patients and their counterparts who carry Medicare fee for service (MFFS) thereby represents a natural experiment that affords an opportunity to examine whether enrollment in a coordinated care system may improve outcomes. In order to promote (unbiased) comparison of patients in a non-randomized context, we propensity score-matched incident dialysis patients enrolled in MA versus those in MFFS. The data demonstrate that patients who were enrolled in an MA plan upon initiation of dialysis had a 9% lower mortality rate than their MFFS counterparts. This beneficial association of MA enrollment was found to be sustained over the first two years of dialysis treatment. PMID- 26767250 TI - Emergency communication during a disaster. PMID- 26767251 TI - RRI meeting to focus on innovation, technology. PMID- 26767252 TI - [Evaluation on molluscicidal effect of chlorosalicylicamide on Oncomelania hupensis in schistosomiaisis endemic areas of eight provinces in China]. AB - OBJECTIVE: To evaluate the effects of a novel molluscicide, the salt quinoid-2', 5-dichloro-4'-nitrosalicylanilide from niclosamide (LDS), with 10% wettable powder, in main schistosomiasis epidemic areas of China, including Hunan, Jiangxi, Hubei, Anhui, Jiangsu, Sichuan, Yunnan and Zhejiang Province. METHODS: In the immersion test, 6 effective concentrations of 10% LDS were tested respectively: 0.1, 0.2, 0.4, 0.6, 0.8, 1.0 g/m3 in the field; at the same time, 50% wettable powder of niclosamide ethanolamine salt (WPN) with effective concentrations of 1.0 g/m was used as the molluscicide control, and the fresh water as the blank control, then the mortality rates of 0. hupensis snails were recorded at 24 h, 48 h and 72 h after the immersion. In the spraying test and powder-spraying test, 5 effective dosages of 10% LDS were tested respectively: 0.2, 0.4, 0.6, 0.8, 1.0 g/m2, while 50% WPN 1.0 g/m2 was used as the molluscicide control, and the fresh water as the blank control in the field for 1 d, 3 d and 7 d, then the mortality rates of O. hupensis snails were recorded at 1 d, 3 d and 7 d after the spraying and powder-spraying. RESULTS: The snail mortality rates of LDS using the immersion test for 72 h were more than 95% in the field of eight provinces (0.1 g/m in Sichuan, Jiangxi, Jiangsu and Zhejiang provinces, 0.2 g/m3 in Yunnan, Hunan and Hubei provinces, and 0.4 g/min Anhui Province); the snail mortality rates of LDS using the spraying test for 7 d were more than 85% (0.2 g/m2 in Hunan, Hubei, Jiangxi and Zhejiang provinces, 0.4 g/m2 in Sichuan and Anhui provinces, 0.6 g/m2 in Yunnan and Jiangsu provinces). The snail mortality rates of LDS the powder-spraying test for 7 d were more than 85% (0.6 g/m2 in Yunnan, Sichuan, Hubei, Jiangxi, Anhui, Jiangsu and Zhejiang provinces). According to the standards of "Efficacy test methods and evaluation of molluscicide for pesticide registration (NY/T 1617-2008)", LDS is a qualified molluscicide. CONCLUSIONS: LDS has good molluscicidal effects through the immersion, spraying and powder-spraying test in the fields. It is suitable for a variety of environments to control O. hupensis snails of schistosomiasis endemic areas in China. The recommended dosages of LDS are 0.1-0.2 g/m3 by the immersion method, 0.2-0.4 g/m2 by the spraying method, and 0.4-0.6 g/m2 by the powder spraying method in the fields. PMID- 26767253 TI - [Integration and demonstration of key techniques in the surveillance and forecast of schistosomiasis in Jiangsu Province II Molluscicidal effect of 5% niclosamide ethanolamine granules in large-scale settings]. AB - OBJECTIVE: To evaluate the field molluscicidal effect of 5% niclosamide ethanolamine granules, so as to provide a novel Oncomelania hupensis snail control approach for emergency treatment of high-risk settings. METHODS: Snail control tests with spraying of 5% niclosamide ethanolamine granules were conducted in two settings of 2 counties, and the dose-, time- and setting specific field molluscicidal effects were tested. RESULTS: In the small-scale setting, spraying of 5% niclosamide ethanolamine granules at doses of 30, 40 and 50 g/m2 resulted in 54.55%, 68.41% and 73.45% 1-day snail mortality, 57.27%, 68.59% and 80.28% 3-day snail mortality, and 63.49%, 77.58% and 85.55% 7-day snail mortality, respectively, and no significant differences were detected in 1- and 3-day snail mortality caused by spraying of 5% niclosamide ethanolamine granules at doses of 30 and 40 g/m2 (all P > 0.05), while significant difference was found in the 7-day snail mortality (chi2 = 4.549, P < 0.05). In addition, spraying of 5% niclosamide ethanolamine granules at doses of 40 and 50 g/m2 resulted in comparable 1-, 3- and 7-day snail mortality (all P > 0.05). In the large-scale setting, spraying of 5% niclosamide ethanolamine granules at a dose of 40 g/m2 resulted in 85.29% and 87.70% 3-day snail mortality, 83.89% and 91.02% 7-day snail mortality, and 83.41% and 91.84% 15-day snail mortality in the environment-cleaning group and non-cleaning group, respectively. The overall snail mortality was 90.02% in the environment-cleaning group 3 to 15 days after spraying, which was significantly higher than that (84.28%) in the non-cleaning group (chi2 = 9.950, P < 0.05). After 15 days of spraying with 5% niclosamide ethanolamine granules at a dose of 40 g/m2, the densities of living snails reduced from 19.90 and 19.83 snails/0.1 m2 to 0.60 and 2.60 snails/0.1 m2 in the environment-cleaning group and non-cleaning group, with 96.98% and 86.89% reductions, respectively. CONCLUSION: The appropriate dose of 5% niclosamide ethanolamine granules is 40 g/m2 for snail control in the field, and environment cleaning of vegetation with a height of more than 50 cm may improve the molluscicidal efficacy. PMID- 26767254 TI - [Current situation and effect of non-hazardous treatment of excrement of sanitary latrines in rural schistosomiasis endemic areas of Eryuan County, Yunnan Province]. AB - OBJECTIVE: To understand the condition of the construction and management of sanitary latrines, and assess the effect of disposal of the excrement in rural schistosomiasis endemic areas in Yunnan Province. METHODS: Three villages with schistosomiasis endemic were selected from Eryuan County and 30 households per village were sampled randomly for the field survey. The stool samples were sampled and tested according to the national standard. RESULTS: Totally 90 latrines were surveyed. The popularity rates of sanitary latrines in Yongle, Qiandian and Xinzhuang villages were 83.19%, 83.12% and 81.63% respectively. In the 90 household latrines, only 32.22% located inside the courtyard, and 91.67% of sanitary latrines and 70.00% of non-sanitary latrines had integrated buildings. Maggots or pupae or adult flies were found in 33.33% of sanitary latrines and all of non-sanitary latrines with the average amounts of 1.05 and 3.40 per latrine respectively. The removal rate of fecal coliform, the sedimentation rate of parasitic eggs and the mortality rate of Ascaris eggs were 90.00%, 80.61% and 95.20% on average respectively. The qualified rate of the fecal coliform of the outlet of the sanitary latrines was 41.67%, and the qualified rate of the mortality rate of Ascaris eggs was 78.13%. No living schistosome eggs were found at the outlets of latrines. For the effect of non hazardous treatment, there was a statistically significant difference between the sanitary latrines and non-sanitary latrines. CONCLUSIONS: The latrine improvement has a good effect on non-hazardous treatment of the excrement in Yunnan Province, but the construction, application and management of sanitary latrines still need to be strengthened. PMID- 26767255 TI - [Research of freely grazing and wild feces behaviors in schistosomiasis endemic areas of plateau mountain area in Yunnan Province]. AB - OBJECTIVE: To understand the situation of the freely grazing and wild feces behaviors of residents in plateau mountain area of schistosomiasis endemic areas in Yunnan Province. METHODS: Two villages of Xidian and Moguang in Heqing County, Yunnan Province were selected as the study area and the questionnaire surveys were performed to the randomly selected villagers aged 6 to 65 years with the sampling ratio of 30%. Then the respondents were tested for the infection of schistosomiasis by indirect hemagglutination assay (IHA). RESULTS: Totally 412 residents were surveyed. In all the responds, the ratios of "captive breed", "freely grazing "unknown" and "no response" were 55.34%, 4.85%, 26.94% and 12.86% respectively; and the ratios of "no grazing", "less than 5/week" and "no less than 5/week" were 75.49%, 16.02% and 8.50% respectively; and the ratios of "no wild feces", "less than 5/week", "no less than 5/week" and "no answer" were 68.45%, 27.67%, 2.91% and 0.97% respectively. CONCLUSIONS: Freely grazing and wild feces behaviors of residents in schistosomiasis endemic area of Heqing County are widespread, could heavily affect the control of schistosomiasis in Heqing County. The further work is to strengthen the management of human and animal feces and grazing and consolidate the results of the prevention and control of schistosomiasis and finally achieve the aim of the transmission interruption. PMID- 26767256 TI - [Laboratory analysis and diagnosis of one transfusion-transmitted quartan malaria case in Shanghai City]. AB - OBJECTIVE: To diagnose a case of quartan malaria with unknown origin by laboratory detection. METHODS: The clinical data of the case were collected and the epidemiological survey was conducted. The blood samples of the patient and the blood donor were detected by microscopy, rapid diagnostic test (RDT) and nested PCR, and the positive results were sequenced. RESULTS: The patient did not visit malaria endemic areas and have no history of malaria infection, but have history of massive blood transfusion in surgical operation. The patient was confirmed as quartan malaria by microscopy with peripheral blood smears. The patient was transfused from three donors whose peripheral blood was none of malaria infection by microscopy, RDT and nested PCR. But sequence analysis showed that the amplified band of one donor was 100% homology to the patient' s with the improved nest-multi PCR examination. CONCLUSION: This patient is confirmed of Plasmodium malariae infection via blood transfusion. Laboratory analysis and diagnosis of undefined malaria cases require multiple methods, and the improved nest-multi PCR could effectively detect the low parasitized malaria infection. PMID- 26767257 TI - [Study on immunologic function of thioredoxin glutathione reductase from Schistosoma japonicum]. AB - OBJECTIVE: To study the immunogenicity and the immuno-protection of thioredoxin glutathione reductase from Schistosomajaponicum (SjTGR) against schistosome infection in mice. METHODS: Seventy-five mice were randomly divided into 5 groups, namely, blank group, PBS group, CpG2 immunized group, TGR immunized group and TGR + CpG2 co-immunized group. Each mouse was immunized for 3 times. The mice were tail bled before the first immunization and 2 weeks after the third immunization. The serum antibody levels of total IgG, IgG1 and IgG2a against SjTGR were assayed by ELISA. Two weeks after the third immunization, each mouse was infected with 40 +/- 2 S. japonicum cercariae by abdominal skin penetration. Forty-two days later, all the mice were sacrificed to collect schistosome adult worms and liver eggs. The worm and egg reduction rates were calculated respectively. The single splenocyte of mouse was collected 2 weeks after the third immunization, and the expressions of CD44high, CD4+CD44high or CD8+CD44high on splenocytes of mice were examined by flow cytometry. After 72 h incubation with recombinant SjTGR, the levels of IL-2, IL-4, IL-10, and IFN-gamma in the single-cell supernatant were determined by using ELISA kit. RESULTS: Two weeks after the third immunization, the titers of serum IgG against SjTGR in mice immunized with SjTGR and co-immunized with SjTGR and CpG2 were higher than 1:200 000. The IgG2a: IgG1 ratio (IgG2a/IgG1) increased slowly with time in both TGR immunized group and TGR + CpG2 co-immunized group. There were obviously higher levels of IFN-gamma and IL-2 in the cell supernatant in the TGR immunized group and TGR + CpG2 co-immunized group compared to the blank, PBS and CpG2 groups (P < 0.05). The increased subpopulations of CD44high, CD8+CD44high and CD4+ CD44high cells in the splenocytes from mice immunized by SjTGR and co-immunized by SjTGR and CpG2 were found comparing to the blank, PBS and CpG2 groups (P < 0.05). The TGR immunization and TGR + CpG2 co- immunization caused 9.4% and 10.5% reductions in the number of adult worms and 9.2% and 32.8% reductions in the number of eggs, respectively. CONCLUSIONS: SjTGR displays strong immunogenicity inducing Th1 type immune response in mice. However, it could not produce protective efficacy against S. japonicum infection. CpG2 ODN may be a broadly effective Th1 adjuvant. PMID- 26767258 TI - [Effect of ICOS signaling on CD154/CD40 expressions in mice infected with Schistosoma japonicum]. AB - OBJECTIVE: To explore the effect of ICOS signaling on the CD154/CD40 expressions and immunopathology in mice infected with Schistosoma japonicum. METHODS: ICOS transgenic (ICOS-Tg) mice and wildtype FVB/NJ mice were used as experimental schistosomiasis models. The expressions of CD154 and CD40 on splenocytes and on inflammatory cells around granulomatous infiltration of the liver in the mice infected with S. japonicuin were detected by flow cytometry and im- munohistochemical staining. HE staining was applied to observe the changes on the granulomatous of the mice liver. RESULTS: Compared with the wildtype FVB/NJ mice, the expressions of CD154 on CD4 T splenocytes and of CD40 on CD19' B splenocytes in the ICOS-Tg mice significantly increased in 12 and 16 weeks post-infection (all P < 0.05). Moreover, the expressions of CD40 and CD154 on inflammatory cells around granulomatous infiltration in the liver of the ICOS-Tg mice were significantly higher than those of the wildtype FVB/NJ mice in 7, 12, 16 and 20 weeks post-infection (all P < 0.05). The volumes of liver egg granulomas of the ICOS-Tg mice were significantly bigger than those of the wildtype mice (P < 0.05 or P < 0.01). CONCLUSIONS: In ICOS-Tg mice infected with S. japonicum, the ICOS signaling has a regulatory effect on CD154/CD40 expressions, and may play an important role in the hepatic egg granuloma formation of schistosomiasis. PMID- 26767259 TI - [Cloning, expression and bioinformatics analysis of pyruvate dehydrogenase of Echinococcus granulosus]. AB - OBJECTIVE: To clone and express Echinococcus granulosus pyruvate dehydrogenase (EgPDH) gene and analyze EgPDH protein with bioinformatics tools and online database. METHODS: The total RNAs of E. granulosus was extracted and reversely transcribed into cDNA. The EgPDH gene was cloned into pET28b to construct the recombinant vector and expressed in E. coli BL21 (DE3) system subsequently. The signal peptide, transmembrane helices and subcellular location in EgPDH sequence were analyzed by the online software SignalP4.1, TMHMM sever v.2.0 and TargetP1.1, respectively. Subsequently, the structure of EgPDH was predicted by SMART. Finally, the homologue sequence and conserved sites were aligned by using BLASTP and GeneDoc among the homologous sequences of EgPDH. Based on the alignment of PDH sequence, an evolutionary tree of E. granulosus and other species were constructed by the neighbor joining method of MEGA6 software. RESULTS: The EgPDH gene was successfully amplified from cDNA of E. granulosus and expressed in the soluble fractions. The bioinformatics analysis revealed that EgPDH was a classical secreted protein and contained transketolase domain. The homology analysis revealed that the amino acid sequence of EgPDH was highly conserved in catalytic sites Glu57, Leu72, Ile86 and Phe114. The phylogenetic tree analysis of PDH proteins showed the closest relationship between E. granulosus and E. multilocularis. CONCLUSION: An EgPDH gene is cloned and expressed successfully, and the recombinant protein is analyzed by the bioinformatics approaches and structure predication. The study provides useful information for further functional study of the EgPDH protein. PMID- 26767260 TI - [Surveillance results of paragonimiasis endemic in regular surveillance sites in Sichuan Province from 2011 to 2013]. AB - OBJECTIVE: To understand the endemic situation and impact factors of paragonimiasis in Sichuan Province, so as to provide the evidence for its control work. METHODS: Four administrative villages from Xuanhan County, Kaijiang County, Pengzhou City and Yucheng District of Ya'an City were selected as regular surveillance sites. In the surveillance sites, ELISA was applied to test the infection situation of residents, questionnaire surveys were performed simultaneously; and water crabs were collected to detect the metacercariae of Paragonimus. RESULTS: From 2011 to 2013, totally 3 666 residents were tested by serum test and 104 of them were positive with a positive rate of 2.8%. Totally 3 671 residents underwent the questionnaire survey and 24.8% of them had heard about paragonimiasis, 36.3% had eaten undercooked water crabs, 56.4% had played with water crabs, and 84.6% had drunk stream water. Totally 2 463 water crabs were dissected, and metacercariae of Paragonimus were found in 620 of them with the infection rate of 25.2% and infectiosity of 4.53 per crab, respectively. CONCLUSIONS: The endemic situation of paragonimiasis in natural environments is serious in Sichuan Province. The residents in endemic area practice unhealthy diet behavior, and there is an urgent risk of the breakout of paragonimiasis. PMID- 26767261 TI - [Effect of Bacillus thuringiensis var. israelensis (Bti) on detoxification enzyme activity of larvae of Culex pipiens pallens and Aedes aegypti]. AB - OBJECTIVE: To investigate the effect of Bacillus thuringiensis var. israelensis (Bti) on the activities of three detoxification enzymes of Culex pipiens pallens and Aedes aegypti larvae. METHODS: The activities of glutathione transferase, acetyl cholinesterase and carboxyl esterase, were detected after two kinds of mosquito larvae were treated by Bti at different time and concentrations. RESULTS: The activities of three detoxification enzymes of the two kinds of mosquito larvae were influenced by Bti treatment. The activity of glutathione transferase was increased after the Bti treatment, but declined significantly and inhibited at a low level sustainably. The activity of carboxyl esterase was increased after the Bti treatment, but recovered to normal level quickly. Acetyl cholinesterase was affected slightly by the Bti treatment, shortly inhibited in the first time and then recovered. The active effects of the three detoxification enzymes were positively related to the concentration of Bti. CONCLUSION: The enzyme activities of glutathione transferase, acetyl cholinesterase and carboxyl esterase could be affected by Bti significantly. PMID- 26767262 TI - [Investigation on endemic situation of schistosomiasis in infection-controlled regions in Anhui Province]. AB - OBJECTIVE: To understand the epidemic situation of schistosomiasis in 27 counties (cities, districts) that reached the criteria of schistosomiasis infection controlled in Anhui Province. METHODS: According to the requirement of The National Assessment Scheme of Schistosomiasis, 81 administrative villages where the schistosomiasis epidemic situation was relatively heaver in above-mentioned 27 counties (1 village per town, 3 towns per county) were sampled and investigated. RESULTS: From 2012 to 2014, 81 villages were investigated, and 34,293 residents received the serum examinations, and 1,086 were positive with a positive rate of 3.17% (0.65%-9.58%), and the positives received stool examinations and the average stool positive rate was 0.37% (0-4.0%). The calculated prevalence of human infection was 0.01%. A total of 3 057 domestic animals were investigated including 438 cattle, 2,550 sheep, and 69 other animals, and no infections were detected. A total of 11,261 living Oncomelania hupensis snails were collected and detected, but no schistosome infected snails were found. Before this investigation, no infected snails were detected for more than 2 years [average 2.3 (2-6) years], and no acute schistosome infection cases were found for more than 2 years [average 4.9 (2-9) years]. CONCLUSION: The infection rates of schistosomiasis in residents and domestic animals are relatively low, and no schistosome infected snails are found in the regions. PMID- 26767263 TI - [Survey of infection situation of intestinal parasites of rural residents in plain area of Shandong Province]. AB - OBJECTIVE: To understand the current situation of infections of intestinal parasites of rural residents in four cities namely Dongying, Weifang, Jining and Heze of Shandong Province. METHODS: Twenty-four villages were randomly selected as study areas. The Kato-Katz technique was applied to test the stool samples of adult residents and the cellophane tape anus method was applied to test the infection of Enterobius vermicularis of children aged 12 years or below. Fifty families were randomly selected from each village and surveyed with questionnaires for the general situation of the family, and the knowledge of prevention and control of parasites, and healthy behaviors of the family members. RESULTS: Totally 8,227 adult residents and 1,313 children were investigated and the total infection rate of intestinal parasites was 0.55% (45 cases). The infection rates of Ascaris lumbricoides, hookworm, Trichuris trichura, E. vermicularis and Clonorchis sinensis were 0.15% (12 cases), 0.06% (5 cases), 0.09% (7 cases), 1.37% (18 cases) and 0.04% (3 cases), respectively. Totally 3,767 residents were surveyed with questionnaires, and the awareness rate of the knowledge of prevention and control of parasites was 28.72% (1,082 cases), the formation rates of washing hands before meal, washing hands after toilet, washing fruit and vegetables before eating, and never drinking unboiled water were 60.66% (2,285 cases), 50.17% (1,890 cases), 48.71% (1,835 cases), and 87.07% (3,280 cases), respectively. CONCLUSION: In the plain area of Shandong Province, the infection rates of A. lumbricoides, hookworm, T. trichura and C. sinensis are low but the infection rate of E. vermicularis of children is relatively high; the awareness rates of the knowledge of parasites as well as the formation rates of healthy behaviors are low. Therefore, the health education and promotion should be strengthened. PMID- 26767264 TI - [Epidemiological investigation on fascioliasis and its risk factors in population of Binchuan County, Yunnan Province]. AB - OBJECTIVE: To understand the infection status of Fasciola and related risk factors in population of Binchuan County, Yunnan Province. METHODS: In February and March, 2014, 6 natural villages from 2 administrative villages in Zhoucheng Town were selected as investigated sites, and the permanent residents aged >= 5 years were examined by ELISA for the serum antibody detection, and then the positive ones were examined by Kato-Katz technique and the hatching method for Fasciola egg detection. Meanwhile, the fascioliasis cases that checked out by the above methods were further surveyed, and the residents who with the same gender, similar age and negative results in the blood examination were selected as the controls, then the risk factors were explored through a case control study. RESULTS: Totally 1 207 people were included in the blood examination, and 36 positives were found with a positive rate of 2.98%. Though the differences between the positive rates of the serum antibody in people with different genders and age were not statistically significant (chi2 = 1.686, 7.106, both P > 0.05) , those between the rates of people in different administrative villages and natural villages were statistically significant (chi2 = 4.103, 13.181, both P < 0.05). Two cases were determined as positives in fecal examinations with a positive rate of 6.45% (2/31), among which, 1 case was newly discovered. The case control study showed that OR values of eating out- purchased cold dish (4.30), raw mint (1.22) , raw leek (4.30) and drinking unboiled-water (3.75) were relatively higher, but all of them were not statistically significant (chi2 = 0.524, 0.046, 0.524, 1.571, all P > 0.05). CONCLUSIONS: There is still sporadic Fasciola infection in Binchuan County. Eating raw vegetables and drinking unboiled water which are contaminated by Fasciola metacercariae may be the infection routes of local people, and to find out the exact entrance way is the key points for the infection control. PMID- 26767265 TI - [Effect of strategy of control and prevention of intestinal nematodiasis in Dongtai City, Jiangsu Province]. AB - OBJECTIVE: To explore the strategy of intestinal nematodiasis control in Dongtai City, Jiangsu Province. METHODS: The strategy of mass drug administration assisted with health education was applied in Dongtai City, which was a high endemic area of intestinal nematodiasis, and then the health education and promotion assisted with drug administration of focus population and other integrated control measures, such as the improvement of drinking water, lavatories, and environment, was applied to consolidate the achievement. RESULTS: The infection rate of intestinal nematodes reduced from 79.97% in 1989 to 6.30% in 1999, and the infection rates of hookworm, Ascaris lumgricoides and Trichuris trichura reduced to 3.31%, 0.60% and 2.57%, respectively, achieving the standard of intestinal nematodiasis control. In 2002, the infection rate of intestinal nematodes reduced to 3.73%, and the infection rates of hookworm, Ascaris lumgricoides and Trichuris trichura reduced to 2.46%, 0.20% and 1.08%, respectively, achieving the standard of effective intestinal nematodiasis control. The infection rate of intestinal nematodes was kept less than 1% after 2004. CONCLUSION: The integrated strategy of intestinal nematodiasis control in Dongtai City is effective and valuable for promotion in high endemic areas of intestinal nematodiasis. PMID- 26767266 TI - [Oncomelania hupensis snail situation in wetlands surrounding reservoirs in hilly areas in Danling County]. AB - OBJECTIVE: To master the Oncomelania hupensis snail situation in wetlands surrounding reservoirs in hilly areas in Danling County, Sichuan Province, so as to provide the reference for improving the snail control in these areas. METHODS: A medium-sized reservoir (Meiwan Reservoir) and a small-sized reservoir (Zhulinkan Reservoir) were chosen respectively , and the snail situation of the environments surrounding the reservoirs were investigated , the indexes such as the occurrence rate of frames with snails and the density of living snails at the upstream and downstream of the reservoirs as well as the surrounding environments were calculated and compared. Meanwhile , the data of the snail situation of the adjacent villages in the irrigation district at the downstream of the reservoirs year by year were collected to analyze the variation trend. RESULTS: The Meiwan Reservoir was located in the deep hill, the occurrence rate of frames with snails was 4.29%, the highest and average densities of living snails were 28.00 snails/0.1 m2 and 0.38 snails/0.1 m2, respectively. There was a statistically significant difference between the occurrence rates of frames with snails at the upstream and downstream, which were 0.17% and 22.16%, respectively (chi2 = 1,267.40, P < 0.05), and the rate of spillway was the highest (51.69%). The highest and average densities of living snails in the downstream were 7.00 and 656.10 times higher than those in the upstream respectively. The Zhulinkan Reservoir was located in the shallow hill, the occurrence rate of frames with snails was 17.29%, and the highest and average densities of the living snails were 38.00 snails/0.1 m2 and 0.61 snails/0.1 in 2, respectively. There was a statistically significant difference between the occurrence rates of frames with snails at the upstream and the downstream, which were 12.95% and 50.92% respectively (chi2 = 194.68, P < 0.05), and the rate of spillway was the highest (65.74%). The highest and average densities of living snails in the downstream were 5.43 and 10.00 times higher than those in the upstream respectively. After the construction of the two reservoirs, the snail area in the irrigation districts of the adjacent villages at the downstream was 57.26% of that before and after the construction (398,030 m2/695 160 m2). The snail area showed a down ward tendency with repeatedly rebound since the 1990s. CONCLUSIONS: The wetland surrounding the reservoir in hilly region is suitable for snail breeding, and the snail situation in the shallow hill is more serious than that in the deep hill. There exists a risk for the repeatability of snail situation in this type of area where the snails can easily diffuse. PMID- 26767267 TI - [Investigation on knowledge, attitude and practice (KAP) of college students on food-borne parasitic diseases]. AB - OBJECTIVE: To understand the status of knowledge, attitude, practice (KAP) on food-borne parasitic diseases of college students, so as to provide the basis for the development of strategies on health education. METHODS: A total of 1,114 college students in Yangzhou Polytechnic College were selected through the randomly stratified cluster sampling method, and then were investigated by questionnaires to understand their KAP on food-borne parasitic diseases. RESULTS: The awareness rates on food-borne parasitic diseases and their harms were 42.2% and 41.7% respectively in these investigated students. The awareness rates of the students with different genders, ages, regions (in Jiangsu Province) and majors were significantly different (all P < 0.01), and those of the male, 17 to 19 years age group, being born in south Jiangsu and students with mechanical engineering major were relatively low. Except the 3 items namely not keeping pets at home (32.0%), cutting raw and cooked food separately (28.6%), and washing hands before meals (67.1%), the formation rates of health behaviors of the other 9 items were all >= 80.0%. In the formation rates of not eating drunken shrimps and crabs, not eating barbecued foods, not eating half-cooked food, not prefer seeking novelty, there were statistically significant differences among the students with different genders, ages, regions and majors (all P < 0.05), and the rates of the male, 21 to 23 years age group, being born in south Jiangsu and students with mechanical engineering were relatively low. The formation rate of right attitude of the students were >= 84.8%, and in the rates of right attitude on "would not eat the foods that might be infected with the food-borne parasites", "would suggest others not to eat the foods that might be infected with the food-borne parasites", and "would give up special preferences or bad habits", there were statistically significant differences among the students with different genders and majors (all P < 0.01), and the rates of the male and students with mechanical engineering major were relatively low. CONCLUSIONS: The awareness rate of food-borne parasitic diseases of college students is relatively low , while the formation rates of health behaviors and right attitude are relatively high. So, the targeted, differentiated health education should be taken to improve their awareness of disease prevention and self-protection. PMID- 26767268 TI - [Morphology observation of Histiostoma feroniarum hypopus]. AB - OBJECTIVE: To observe the external morphology of Histiostoma feroniarum hypopus under light microscope. METHODS: The samples were collected in a mushroom cultivation base, and the Histiostoma feroniarum hypopus was isolated and purified. The slide samples were prepared and observed under an optical microscope. RESULTS: The back body of the Histiostoma feroniarum hypopus was flat with tiny bristles, the epidermis was of significant ossification, the ventral had four pairs of slender feet stretched, the sucker plate was prosperous in the end of the body, and the sucker plate had eight suckers. The gnathosoma was thin, long and highly specialized. CONCLUSION: The light microscopy shows the morphological characteristics of Histiostomaferoniarum hypopus, providing the basis for identifying the hypopus. PMID- 26767269 TI - [Surveillance of schistosomiasis epidemic situation after its transmission in- terrupted in Lufeng County, Yunnan Province]. AB - OBJECTIVE: To investigate the schistosomiasis epidemic situation changes after its transmission interrupted in Lufeng County in 1986, so as to provide the evidence for formulating the interventions for schistosomiasis elimination. METHODS: The surveillance of Oncomelania hupensis snail was performed by the systematic sampling, environmental sampling and special environmental comprehensive survey methods. The surveillance of human population was carried out by the sero logical screening method, and the positives were re-examined with the stool hatching method. The surveillance of livestock was performed by the plastic cup of pipe jacking hatching method. RESULTS: The living snails were detected in Lufeng County from 1987 to 2007 except in 1988 and 1994. The two import buffalo infected with schistosomes were detected in 2001 and ni local infected livestock were found. Since 2004, the comprehensive measures, including the social control strategy and surviv al snail elimination, were carried out, and no snails were detected and no schistosome infected persons or livestock were found for 7 consecutive years since 2008. CONCLUSIONS: The achievement of schistosomiasis transmission interrupted ha been consolidated in Lufeng County, but most of the historical snail environments have not been modified and there are stil snail breeding conditions. Therefore, we should continue to carry out the snail surveillance. PMID- 26767270 TI - [Epidemiological analysis of malaria situation in Shuyang County, Jiangsu Province from 2004 to 2013]. AB - OBJECTIVE: To understand the epidemic situation and prevalent characteristics of malaria in Shuyang County, Jiangsu Province from 2004 to 2013, so as to provide the references for formulating effective strategies and measures of malaria control. METHODS: The reported epidemic situation and epidemiological data of malaria were collected and analyzed in Shuyang County from 2004 to 2013. RESULTS: Totally 31 malaria cases were reported with an incidence rate of 0.18/100 000 in Shuyang County, from 2004 to 2013, of which 22 were local cases and 9 were imported cases. The peak season of local infection cases were during August and October. The infectors were mainly men and the sex ratio was 2.87:1. The age group from 10 to 39 years had the highest incidence. CONCLUSION: The focus of infection situation of malaria in Shuyang County is changing from local cases to imported cases. The management of floating population and training and publicity concerned with imported malaria should be strengthened. PMID- 26767271 TI - [Effect of schistosomiasis control in Jingzhou City from 2009 to 2013]. AB - OBJECTIVE: To evaluate the effect of schistosomiasis control in Jingzhou City of Hubei Province from 2009 to 2013, so as to provide the reference for the establishment of control strategy in the future. METHODS: The annual reports on schistosomiasis control from 2009 to 2013 in nine counties (cities, districts) in Jingzhou City were collected and analyzed sta- tistically. RESULTS: The estimated number of schistosomiasis patients in Jingzhou City dropped from 78 903 in 2009 to 28 034 in 2013, with a reduction rate of 63.37%. The schistosome infection rate of residents dropped from 2.21% in 2009 to 0.65% in 2013, which showed an exponential decline trend (y = 3.196e(-0.317x)). The number of cattle with schistosomiasis decreased from 2 132 in 2009 to 0 in 2013, and the infection rate of cattle dropped from 1.87% in 2009 to 0% in 2013. Only 2 cases with acute infection of schistosome were found in 2009, and no schistosome infected snails were found out in 2 consecutive years, 2012 and 2013. CONCLUSIONS: The endemic level of schistosomiasis in Jingzhou City has decreased significantly. In order to consolidate the achievement of control, the comprehensive strategy including infection source control, snail control with mol- luscicides and snail surveillance should be implemented. PMID- 26767272 TI - [Treatment and assistance for advanced schistosomiasis patients in Changshu City from 2006 to 2014]. AB - OBJECTIVE: To understand the status of treatment and assistance for advanced schistosomiasis patients in Changshu City from 2006 to 2014. METHODS: According to The Parasitic Disease Prevention Information Management System, the data of treatment and assistance for advanced schistosomiasis patients were collected and analyzed statistically in Changshu City from 2006 to 2014. RESULTS: A total of 269 advanced schistosomiasis patients were assisted. The sex ratio of men: women was 0.56: 1 with an average age of 71.71 years. The ascites-type patients accounted for 78.25%, splenomegaly-type 21.20%, and colon proliferation-type 0.55%. The clinical cure rate was 12.29%, improvement rate 62.81%, and no-change 8.67%, and the total effective rate was 75.10%. CONCLUSION: The treatment and assistance for advanced schistosomiasis patients has achieved the basic target of improving the symptoms, relieving pains and improving the living quality. PMID- 26767273 TI - [Effectiveness of integrated schistosomiasis control strategy in marshlands of Qixia District, Nanjing City]. AB - OBJECTIVE: To evaluate the effectiveness of integrated schistosomiasis control strategy in marshlands of Qixia District from 2004 to 2013. METHODS: The endemic situation and integrated control data of schistosomiasis in Qixia District from 2004 to 2013 were collected, and the morbidity and Oncomelania hupensis snail status before and after the implementa- tion of integrated schistosomiasis control strategy were compared. RESULTS: Following 10-year integrated schistosomiasis control, the human schistosome infection rate gradually decreased in Qixia District, and no infection was detected since 2007. A gradual reduction was observed in the infection rate of domestic animals, and all bovine was eliminated from the regions along the Yangtze River since 2006. In addition, the snail area and the density of living snails in 2013 reduced by 42.25% and 82.56% as compared to those in 2004, and no infected snails were found since 2009. In 2010, the district achieved schistoso- miasis transmission control. CONCLUSION: The integrated schistosomiasis control strategy is effective to accelerate schistoso- miasis control process and achieve the criteria of schistosomiasis transmission control rapidly. PMID- 26767274 TI - [Research progress in soil-transmitted helminth infection control among children at home and abroad]. AB - Children are the vulnerable group for soil-transmitted helminth (STH) infections. Being infected with STHs for long term would affect the children' s nutritious status, health development and cognitive ability. This paper reviews the prevalence and influencing factors of the infections of STHs (Ascaris lumbricoides, Trichuris trichuria and hookworm) for children at home and abroad, as well as the impact of STH infections on children's health, cognitive ability and school performance, and the related interventions and their effects. PMID- 26767275 TI - [Epidemic characteristics and security implications of Africa schistosomiasis on people who go to Africa]. AB - With the economic globalization, and the economic and trade cooperation and cultural communication between China and African countries, more and more Chinese people go to Africa for work or travel. However, there is a quick increase of imported schistosomiasis patients who return from Africa. This paper analyzes the security implications of epidemic characteristics of Africa schistosomiasis on the people who go to Africa, and put forward several suggestions to help them to prevent from schistosomiasis. PMID- 26767276 TI - [Progress of pattern recognition receptors of molluscs]. AB - Molluscs have established complete innate immunity to defense against pathogens. The pattern recognition receptors (PRRs) are the sensory receptors of molluscs to resist outside invaders, as the first reactor to initiate the innate immune response. Some PRRs have been identified in several molluscs, including Toll-like receptors (TLRs) , C-type lectins, galectins, lipopolysaccharide-beta-1,3-glucan binding protein (LGBP), Clq domain-containing protein (ClqDC), and peptidoglycan recognition protein (PGRP). PRRs have various biological activities and play important roles in the defense system of molluscs. This paper reviews the research progress of PRRs in molluscs. PMID- 26767277 TI - [A case of neonatal congenital malaria accompanied with severe thrombocytopenia]. AB - This article reports the process of diagnosis and treatment of one case of neonatal congenital malaria accompanied with severe thrombocytopenia. PMID- 26767278 TI - [Effects of Different Planting Direction and Layer Combination on Gastrodia elata f. elata in Bionic Wild Cultivation]. AB - OBJECTIVE: Combination of different planting direction and layer were set to choose the best technology of cultivation of Gastrodia elata f. elata. METHODS: To improve the yield and quality of Gastrodia elata f. elata, randomized block design experiments were carried out to investigate the yield and quality, and to analyze their economic effectiveness in bionic wild cultivation. RESULTS: Length, width, thickness and weight of southern direction's Gastrodia elata f. elata developed better than the northeast direction. The three planting layer levels on growth effect of Gastrodia elata f. elata was the 3rd layer > the 2nd layer > the 1st layer. In six treatments, combination of southern direction-the 3rd layer was the best technology of cultivation of Gastrodia elata f. elata, which had the best growth condition, the highest yield significantly higher than other treatments, and the best economic benefits. CONCLUSION: Southern direction associated with the 3rd layer is the best combination to planting Gastrodia elata f. elata in bionic wild cultivation. The planting ways not only improve the yield and quality, but also save land. PMID- 26767279 TI - [Effect of Crop Rotation and Biological Manure on Quality and Yield of "Chuju" Chrysanthemum morifolium and Continuous Cropping Soil Enzyme Activities]. AB - OBJECTIVE: To investigate the effects of chrysanthemum-wheat rotation system and biological manure on continuous cropping soil enzyme activities and quality and yield of Chrysanthemum morifolium. METHODS: Field experiments were conducted at the research base of Anhui Jutai Chuju Chrysanthemum morifolium Herbal Technology Co. , Ltd. ,in Shiji Town, Nanqiao Country, Anhui Province. Samples were collected from treatments under chrysanthemum-wheat rotation system receiving bio organic manure application of 200 kg/667 m2, conventional chrysanthemum-wheat rotation system and chrysanthemum continuous cropping system. RESULTS: Chrysanthemum-wheat rotation system and biological manure obviously influenced the quality and yield of Chrysanthemum morifolium and continuous cropping soil enzyme activities. Compared with chrysanthemum continuous cropping system, total flavonoids, chlorogenic acid, soluble sugar and free amino acid contents, quantitative of ray floret, inflorescence diameter, diameter of tubular floret, number of branch, number of flower and yield of Chrysanthemum morifolium and the activities of urease, acid phosphatase, invertase and protease in soil were increased to 42.59 mg/g, 2.52 mg/g, 4.04 mg/g, 73.33 mg/100 g, 179.56, 5.57 cm, 1.43 cm, 36.10, 330.00 and 400.09 kg/667 m2, respectively, while hydrogen peroxidase of soil under chrysanthemum-wheat rotation system was decreased. CONCLUSION: Bio-organic manure application of 200 kg/667 m2 is benefit to soil environment establishment of chrysanthemum-wheat rotation system and enhancement of quality and yield of Chrysanthemum morifolium while reducing the obstacles of continuous cropping. PMID- 26767280 TI - [Identification of Active Composition and Quality Evaluation of Paris Herbs Artificially Cultivated in Different Locations of Three Gorges Reservoir]. AB - OBJECTIVE: In order to apply the thesis basis for screening the Paris varieties which was suitable for the environments, the quality of Paris herbs of different varieties cultivated in different locations of Three Gorges Reservoir was evaluated based on the identification of active compositions. METHODS: The content of saponins in Paris herbs was measured by HPLC method; The total content of saponins, the total content of flavonoids and the total content of polysaccharides were evaluated using ultraviolet-visible spectrophotometry; Then the contents of active chemical compositions were used for comparison of the Paris herbs of different varieties in different locations. RESULTS: Types and the contents of saponin I, saponin II, saponin VI and saponin VII were all various in different Paris varieties located in different locations; with the analyses of the total content of saponins, the total content of flavonoids and the total content of polysaccharides, it was suggested that the chemical compositions existed obvious differences in different cultivars. CONCLUSION: It is proved that Paris polyphylla var. yunnanensis and Paris polyphylla var. chinensis could be cultivated on a large scale, but the techniques in artificial cultivation should be studied further. At the same time,Paris bashanensis and Paris polyphylla var. pseudothibetica are good cultivars for planting. PMID- 26767281 TI - [Preliminary Study of Lonicera hypoglauca on Germination Conditions of Sand Culture Seeds and Sterilization Method of Sand Culture Seedling Sterilization]. AB - OBJECTIVE: To explore the germination conditions of Lonicera hypoglauca sand culture seeds and the effects of sand culture seedlings sterilization. METHODS: 0.1% HgCl2 with different sterilization time, different illumination time and temperature culture condition were adopted to study the germination conditions of sand culture seeds. Different sterilization treatments and different hardening seedling days were used to test the sterilization effect of sand culture seedlings. RESULTS: The sterilization effect of the combination of 75% ethanol 30 s + 0.1% HgCl2 5 min on Lonicera hypoglauca seeds was the optimum,with the average pollution rate of 15.56%, and the average germination rate reached 51.11%. The combination of varied temperature-room temperature under light for 12 h/d was the best, with the average germination rate peaked at 75.49%, and the average germination potential reached 68.36%. The treatment of detergent liquor scrub-tap water wash on the part above the hypocotyl, which was sand cultured under the opening condition and had no root, showed the best sterilization effect, with the average pollution rate was zero, and the average survival rate peaked at 100.00%. The sterilization effect of sand culture seedlings, which was disinfected after cleaning by detergent liquor scrub-tap water wash after hardening-seeding for 30 days, was the best, with the average pollution rate of 50.00%, and the average survival rate of 100.00%. CONCLUSION: The best sterilization effect is the combination of 75% ethanol 30 s + 0.1% HgCl2 5 min; Lighting for 12 h/d of varied temperature-room temperature is regarded as the optimum culture condition. The treatment of detergent liquor scrub-tap water wash treatment on the part above the hypocotyl,which is sand cultured under the opening condition and had no root, shows the best sterilization effect. For the sand culture seedlings, before inoculated in subculture medium, should be hardening-seedling for some days and sterilized after detergent liquor scrub-tap water wash. PMID- 26767282 TI - [Optimization of Extraction Technology for Sericin from Silkworm Cocoon with Orthogonal Design]. AB - OBJECTIVE: To optimize the appropriate extracting technology for sericin from Silkworm cocoon. METHODS: Using sericin extraction rates and sericin content as the indices. The single and orthogonal experiments were used to determine the best conditions. RESULTS: The optimal extraction technology for sericin from Silkworm cocoon was as follows: 1: 30 for the ratio of solid to liquid, 3 h reflux for 2 times of extraction and water temperature at 100 degrees C. The extraction rate of sericin from Silkworm cocoon was 27.1%. CONCLUSION: The optimal extraction technology is stable, feasible, and can provide reference for further pharmacological study on cocoon sericin. PMID- 26767283 TI - [Dynamic Changes of Nucleosides and Nucleobases in Different Harvest Periods of Polygoni Multiflori Radix by UPLC-QTRAP-MS/MS]. AB - OBJECTIVE: To analyze the dynamic changes of nucleosides and nucleobases in Polygoni Multiflori Radix harvested in different periods. METHODS: UPLC-QTRAP MS/MS method was applied for the analysis of nine kinds of nucleosides and nucleobases in Polygoni Multiflori Radix. RESULTS: The content of uridine, adenine, guanosine and cytidine was higher in Polygoni Multiflori Radix harvested in different periods and assumed some difference. The trends of nucleosides and nucleobases from Polygoni Multiflori Radix according to the peak valley shape changed. The highest contents of them were in December. CONCLUSION: The accumulation of nucleosides and nucleobases in Polygoni Multiflori Radix is closely related to its growth cycle. It is found to be basically the same as that obtained when the herb is collected during the conventional collecting time. PMID- 26767284 TI - [Study on Stability of Human Intestinal Bacterial Biotransformation Model]. AB - Objective: To investigate the stability of human intestinal bacterial biotransformation model using isoquercetin as the substrate of transformation. METHODs: The in vitro transformation model was established using the intestinal bacteria form different volunteers, or different passages of the same volunteer in accordance with the "biotransformation model of human intestinal bacteria and its standard operating procedures" to transform isoquercetin. RESULTS: Within 24 hours, all models established with the intestinal bacteria from different volunteers could transform isoquercetin to quercetin and the transformation efficiency was inclined to increase with the increase of the number of culture passages. CONCLUSION: The intestinal bacterial model established in accordance with the "standard operating procedures" is stable and the results obtained with this model are reproducible, which demonstrats the suitability of this model for the investigation of the chemical constituents of Chinese medicinal materials. PMID- 26767285 TI - [HPLC-PDA-CAD Fingerprints of Salt Anemarrhenae Rhizoma]. AB - OBJECTIVE: To establish the HPLC-PDA-CAD fingerprints and to determine its seven main constituents so as to provide a reliable evidence for the scientific evaluation and quality control of salt Anemarrhenae Rhizoma. METHODS: The chromatographic fingerprint was obtained with Thermo Hypersil C18 column (250 mm x 4.6 mm, 5 MUm) and gradient eluted with acetonitrile and water; The CAD parameters were pressure of 241. 3 kPa, filter of high and range of 200 pA. The detection wavelength of PDA was set at 258 nm. RESULTS: The common mode of HPLC PDA-CAD fingerprint of salt Anemarrhenae Rhizoma was set up. There were 5 PDA and 12 CAD common peaks in the fingerprints. Timosaponin B II, anemarsaponin E, timosaponin B III, timosaponin A III, neomangiferin, mangiferin and baohuoside I were identified in fingerprints and determined. CONCLUSION: The established HPLC PDA-CAD fingerprint method is accurate, reliable, and has a good reproducibility and precision, which can be used for the quality control of salt Anemarrhenae Rhizoma. PMID- 26767286 TI - [Influence of Steam Killenzyme Torrefaction on Quality of Camellia nitidissima Based on Multi-index Evaluation]. AB - OBJECTIVE: To explore the influence of steam killenzyme torrefaction on the quality of Camellia nitidissima. METHODS: Based on the quality evaluation index, Camellia nitidissima was processed by steam killenzyme torrefaction and sun dried. The contents of functional ingredients such as flavonoids, saponins, tea polyphenols, polysaccharides, amino acids, tea extracts, catechin and epicatechin were determined by HPLC and UV. Meanwhile, the antioxidant activity was determined by ABTS method, DPPH x assay, pyrogallol method and phenanthroline. RESULTS: Compared with the sun-dried sample, the total flavonoids, saponins and epicatechin content were decreased in varying degrees, catechin was not detected. CONCLUSION: The water soluble components content of Camellia nitidissima is increased, and antioxidant capacity is enhanced by processed using steam killenzyme torrefaction. By contrast, the alcohol soluble components and antioxidant capacity are decreased. PMID- 26767287 TI - [Determination of Nucleosides and HPLC Fingerprints of Cordyceps]. AB - OBJECTIVE: To establish the HPLC fingerprints method of Cordyceps and to determine the contents of uridine, inosine, guanosine and adenosine. METHODS: The HPLC separation was performed on a Grace Prevail C18 column( 150 mm x 4.6 mm, 5 MUm) in a gradient elution mode with a mixture consisting of water and methanol at a flow rate of 1.0 mL/min, the detection wavelength was set at 260 nm, the column temperature was 25 degrees C. RESULTS: The contents of four nucleosides were determined in Cordyceps from different habitats, and the HPLC fingerprint of Cordyceps was set up with 13 common peaks. Among of them, uridine, inosine, guanosine and adenosine were identified. The similarities of ten fingerprints were greater than 0.95 with good separation of each chromatographic peak, and met the requirement of the fingerprints. There were similar results in cluster analysis and principal component analysis of the major nucleosides and the fingerprints of 10 batches of Cordyceps. The results of sample classification in principal component analysis showed a good similarity with cluster analysis. CONCLUSION: This method showed the information of chemical composition in Cordyceps, with good repeatability and similarity between samples, indicating that the stable chemical distribution and proportion of the major nucleosides in the medical materials. Fingerprints, principal component analysis and cluster analysis, which are applied to identify the different sources of Cordyceps, provide an experimental basis for establishing the characteristics evaluation methodology of medicinal materials. PMID- 26767288 TI - [HPLC Fingerprint of Anisodus tanguticus Root]. AB - OBJECTIVE: To establish an HPLC fingerprint of Anisodus tanguticus root for its quality control. METHODS: The analysis was carried out on a Ultimate AQ C18 (250 mm x 4.6 mm, 5 MUm) column with the gradient elution of acetonitrile and KH2PO4 buffer soution, whose pH was adjusted to 3.0 with phosphoric acid. The flow rate, column temperature, detection wavelength and injection volume was 1.0 mL/min, 30 degrees C, 210 nm and 10 MUL separately. The similarity evaluation and principal component analysis were used to analyze HPLC fingerprint of Anisodus tanguticus root. RESULTS: HPLC fingerprint of Anisodus tanguticus root was established with 15 common peaks by determining 18 batches of Anisodus tanguticus root samples. Four characteristic peaks, anisodine, scopolamine, anisodamine and anisodamine, were confirmed by comparing their retention time and UV spectrum with standard reference substances. The simiarities of 18 batches of Anisodus tanguticus root were between -0.891 and 0.987. Comprehensive evaluation scores of 18 batches of Anisodus tanguticus root were between -0.85 and 0.89 by principal component analysis. CONCLUSION: The established HPLC fingerprint has good precision, repeatability and stability, which can provide more comprehensive information for identification and quality control of Anisodus tanguticus root. PMID- 26767289 TI - [Chemical Constitutes from Root of Artocarpus styracifolius]. AB - OBJECTIVE: To study the chemical constituents from root of Artocarpus styracifolius. METHODS: Tne constituents were isolated from the root of Artocarpus styracifolius by column chromatography over silica gel, RP-18 silica gel, MCI GEL CHP-20P, macroporous resin HP-20, Sephadex LH-20, Toyopearl HW-40C and by preparative HPLC. Their structures were elucidated by analysis of physical and chemical properties and spectral data. RESULTS: Nine compounds were isolated and their structures were identified as p-hydroxy benzoic acid (1), syringic acid (2), 2,4-dihydroxy benzaldehyde (3), (+)-lyoniresinol (4), 5,5' dimethoxysecoisolariciresinol (5), (+)- syringaresinol (6), scopoletin (7), xylarolide (8) and trans-oxyresveratrol (9). CONCLUSION: Compounds 2, 5, 6 and 8 are isolated from Moraceae for the first time. Compounds 1, 4 and 7 are firstly characterized in the genus Artocarpus, compounds 3 and 9 are characterized in Artocarpus styracifolius for the first time. PMID- 26767291 TI - [Chemical Constituents of Eucommia ulmoides in Guizhou Province]. AB - OBJECTIVE: To study the chemical constituents of Eucommia ulmoides in Guizhou Province. METHODS: Silica gel, Sephadex LH-20, RP-18, MCI and semi-preparative HPLC were used to study the chemical constituents of Eucommia ulmoides, and the chemical structures were elucidated by application of spectral data. RESULTS: 16 compounds were isolated from the bark of Eucommia ulmoides. Their structures were identified as beta-sitosterol (1), cycloeucalenol (2), betulinic acid (3), 24 methylenecycloartenone (4), cycloeucalenone (5), salicifoliol (6), pinoresinol (7), genipin (8) , alternariol (9), balanophonin (10), eucommidiol (11), pinoresinol-4'-O-beta-D-glucopyranoside (12), eucommiol (13), deoxyeucommiol (14), 8-hydroxypinoresinol (15), and dehydrodiconiferyl alcohol -gamma'-O-beta-D glucopyranoside (16). CONCLUSION: Seven compounds, including compounds 2,4 - 6,9, 10 and 15 are isolated from Eucommia ulmoides for the first time, and compound 14 is isolated from the bark of Eucommia ulmoides for the first time. PMID- 26767290 TI - [Chemical Constituents from Leaves of Hibiscus syriacus and Their alpha Glucosidase Inhibitory Activities]. AB - OBJECTIVE: To study the chemical constituents from Hibiscus syriacus leaves and their alpha-glucosidase inhibitory activities. METHODS: Column chromatography including macroporous resins, silica gel and Sephadex LH-20 were used for the isolation and purification of all compounds. Spectroscopic methods including physical and chemical properties, 1H-NMR and 13C-NMR were used for the identification of structures. Their alpha-glucosidase inhibitory activities were detected by a 96-well microplate. RESULTS: 15 compounds were isolated and identified as beta-sitosterol(1), beta-daucostero (2), beta-amyrin (3), oleanolic acid (4), stigmast-4-en-3-one (5), friedelin (6), syriacusin A (7), kaempferol (8), isovitexin (9), vitexin (10), apigenin (11), apigenin-7-O-beta-D glucopyranoside (12), luteolin-7-O-beta-D-glucopyranoside (13), vitexin-7-O-beta D-glucopyranoside (14) and rutin (15). CONCLUSION: All the compounds are isolated from the leaves of Hibiscus syriacus for the first time. Taking acarbose as positive control, the alpha-glucosidase inhibitory activities of 15 compounds were evaluated. Compounds 7 and 9 have shown strong alpha-glucosidase inhibitory activities with IC50 of 39.03 +/- 0.38 and 32.12 +/- 0.62 mg/L, inhibition ratio of 94.95% and 97.15%, respectively. PMID- 26767292 TI - [Chemical Constitutes from Seeds of Plantago asiatica]. AB - OBJECTIVE: To study the chemical constituents of Plantago asiatica seeds. METHODS: The constituents were isolated from the seeds of Plantago asiatica by column chromatography over silica gel, MCI gel, macroporous resin HP-20, Sephadex LH-20, Polyamide and by preparative HPLC. Their structures were elucidated by analysis of physical and chemical properties and spectral data. RESULTS: Five compounds were isolated and their structures were identified as acteoside (1), isoacteoside (2), decaffeoylacteoside (3), tetradecanoic acid (4), and bis (2 ethythexyl) benzene-1,2-dicarboxylate (5). CONCLUSION: Compound 5 is isolated from Plantaginaceae for the first time. Compounds 3 and 4 are firstly characterized in Plantago asiatica. PMID- 26767293 TI - [Chemical Constituents from Processed Products of Aconitum Vilmoriniani Radix]. AB - OBJECTIVE: To investigate the chemical constituents of the processed products of Aconitum Vilmorinian Radix. METHODS: The constituents were isolated by repeated column chromatography over silica gel, alumina and RP-C18 as well as recrystallization. The structures were elucidated on the basis of spectral analysis and physicochemical properties. RESULTS: Ten compounds were obtained from the methanol extract, and they were identified as yunaconitine (1), 8 deacetyl-yunaconitine (2), geniculatine C (3), vilmorrianine B (4), vilmorrianine C(5), vilmorrianine D (6), talatisamine (7), beta-sitosterol (8), beta daucosterol (9) and beta-sitosterol acetate (10). CONCLUSION: All compounds are obtained from the processed products of Aconitum Vilmoriniani Radix for the first time. PMID- 26767294 TI - [Analysis of Volatile Components of Polypodium hastatum by GC-MS]. AB - OBJECTIVE: To further reveal the chemical constituents of Polypodium hastatum, volatile components from this plant were investigated. METHODS: The volatile components were extracted under reflux from the whole plant of Polypodium hastatum, and then analyzed qualitatively and quantitatively by GC-MS. RESULTS: 60 volatile components were detected and of all components detected, the structures and relative contents of 34 volatile compounds were elucidated. CONCLUSION: In the volatile components identified, most are fatty acid esters, especially methyl and ethyl esters, which compose the major volatile chemical constituents of Polypodium hastatum. PMID- 26767295 TI - [Study on Effective Parts of Ficus microcarpa Leaves by Serum HPLC Fingerprint]. AB - OBJECTIVE: To study the relevance between the drug effects and serum HPLC fingerprint of chemical constituents in blood from Ficus microcarpa leaves. METHODS: Fingerprints of the preparation and drug-containing serum of rats were established by HPLC. Based on the fingerprints, chemical constituents in blood were investigated. RESULTS: There were seven common peaks in the HPLC fingerprints of drug-containing serum of rats. Polarity fraction of the chemical constituents in blood existed in the ethyl acetate extract, and five fingerprint peaks of serum HPLC fingerprint existed in n-butanol extract. CONCLUSION: Determination of the component groups in blood provides some data on material basis study in vivo for Ficus microcarpa leaves. PMID- 26767296 TI - [Effect of Acanthopanax senticosus Polysaccharides on Cardiac Endogenous Metabolism in Rats Based on Metabolomics]. AB - OBJECTIVE: Using metabolomics method to study the influence of Acanthopanax senticosus polysaccharides on cardiac endogenous metabolism in rats, in order to find potential biomarkers and analyze the metabolic pathways which can explore the pharmacological effects and mechanisms of action. METHODS: 20 SD rats were randomly divided into two groups, the blank and Acanthopanax senticosus polysaccharides treatment groups, which were treated with saline and Acanthopanax senticosus polysaccharide for 20 days. On the 21th day,heart tissue were collected and each sample extract was analyzed by UPLC-Q-TOF/MS. RESULTS: 20 potential biomarkers and 6 major metabolic pathways related to cardiovascular and cerebrovascular diseases were identified. CONCLUSION: Acanthopanax senticosus polysaccharides has a certain pharmacological effects on cardio-cerebro vascular diseases, cancer and other diseases. Its mechanism may be related to the metabolic process of amino acids, fatty acid and folate. PMID- 26767297 TI - [Computational Pharmacological Study on Clopidogrel Metabolism Enzymes Influenced by Fufang Danshen Dripping Pill]. AB - OBJECTIVE: To investigate the effect of Fufang Danshen Dripping Pill on Clopidogrel metabolism enzymes target such as human liver carboxylesterasel (CES1), cytochrome P450 3A4, CYP450 2C19, CYP450 1A2, and CYP450 2B6, and to interpret the interaction effects. METHODS: The CES1, cytochrome P450 3A4, CYP450 2C19, CYP450 1A2 and CYP450 2B6 which involved in Clopidogrel metabolism were selected at first, the chemical ligand database were created then, and finally the interaction effects between the ligand database and Clopidogrel metabolism target were explored. RESULT: 1 MX1 (CES1), 3NXU (CYP450 3A4), 4GQS (CYP450 2C19), 2HI4 (CYP450 1A2) and 3IBD(CYP450 2B6) as well as THA, RIT, OXU, Chlorzoxazone and CPZ were used as receptors and cutoff for each target respectively. The number of hits with potentially positive activities with metabolism enzymes target from the bioactive compounds in the preparation was 29, 8, 31, 51 and 44, respectively. These computational pharmacological docking studies were in accordance with the referenced cocktail experiment results. CONCLUSION: It is suggested that Fufang Danshen Dripping Pill has inhibitory effects on Clopidogrel metabolism enzymes target such as CES1, Cytochrome P450 3A4, CYP450 2C19, CYP450 1A2 and CYP450 2B6. PMID- 26767298 TI - [Effect of Serum Containing Sesamin on Angiotensin II-Induced Apoptosis in Rat Cardiomyocytes]. AB - OBJECTIVE: To investigate the effect of serum containing sesamin on angiotension II (Ang II)-induced apoptosis in rat cardiomyocytes and the possible mechanisms. METHODS: H9c2 rat cardiomyocytes were preincubated with serum containing sesamin or blank serum for 12 h, followed by incubation with Ang II for 24 h. Cell viability was assessed by MTT assay and cell apoptosis was evaluated by flow cytometric analysis. Protein expression of BCL-2, BAX, Caspase-3, p47phox and superoxide dismutase (SOD) was determined by Western blot analysis. Levels of intracellular reactive oxygen species (ROS), total antioxidant capacity (T-AOC) and malondialdehyde (MDA) were measured colorimetrically. RESULTS: Preincubation with serum containing sesamin significantly improved cell viability and suppressed cell apoptosis in H9c2 rat cardiomyocytes exposed to Ang II (P < 0.05 or P < 0.01), with the expression of BAX, Caspase-3 and p47phox protein down regulated and BCL-2 and SOD protein up-regulated markedly (P < 0.05 or P < 0.01). The levels of T-AOC were effectively increased in serum containing sesamin groups, while the levels of intracellular ROS and MDA contents were decreased significantly (P < 0.05 or P < 0.01). Control serum had no influence on the above mentioned measurements. CONCLUSION: Sesamin is capable of suppressing Ang II induced apoptosis in H9c2 rat cardiomyocytes, which might be derived, at least partly, from amelioration of oxidative stress, regulation of BAX/BCL-2 protein expression and suppression of Caspase-3 protein expression. PMID- 26767299 TI - [Effects of Total Ginsenosides and Volatile Oil of Acorus tatarinowii Co Administration on Ability of Learning and Memory and Apoptosis in Alzheimer's Disease Mice Model Induced By D-Galactose and Aluminium Chloride]. AB - OBJECTIVE: To observe the effects of the co-administration of total ginsenosides and volatile oil of Acorus tatarinowii on the ability of learning and memory and apoptosis in Alzheimer's disease (AD) mice model induced by D-galactose and aluminium chloride. METHODS: 50 Kunming (KM) mice were randomly divided into normal group, model group, Aricept group (1 mg/kg), Ding Zhi Wan group (10 g/kg) and co-administration of total ginsenosides and volatile oil of Acorus tatarinowii group (co-administered group, the doses of volatile oil of Acorus tatarinowii and total ginsenosides were 30 mg/kg and 150 mg/kg, respectively). In addition to normal group, mice in other groups were given D-galactose 150 mg/ (kg x d), ip, and aluminium chloride 5 mg/kg, ig, once daily for 40 days. At the same time, mice in the treated groups were administrated with the corresponding drug from the 20th day after the modeling, once daily for 40 days. Water maze and avoiding darkness experiments were used to test learning and memory abilities; Abeta1-42 and BCL-2 content in cortex and hippocampus were detected by ELISA; the vitalities of acetyl cholinesterase ( AChE) and acetylcholine transferase (ChAT) were detected by ultraviolet spectrophotometry. Superoxide dismutase (SOD) vitalities were detected by a water-soluble tetrazolium salt (WST-1) method; the content of malondialdehyde ( MDA) in cortex and hippocampus were detected by the thiobarbituric acid (TBA) method; senile plaque on Abeta1-42 precipitation were observed by immunohistochemistry; brain tissues were observed by hematoxylin eosin staining (HE). RESULTS: As compared with model group, in the co administered group, the time of AD mice swimming, the numbers of blind area and electric shock reduced significantly (P < 0.05), and the latent period was prolonged (P < 0.05); AChE activity and levels of Abeta1-42 and MDA in cortex and hippocampus were decreased significantly (P < 0.05 or P < 0.01); ChAT and SOD activities as well as BCL-2 content were increased significantly (P < 0.05 or P < 0.01) the formation of senile plaque was decreased and brain tissue morphology was improved. CONCLUSION: Total ginsenosides and volatile oil of Acorus tatarinowii co-administration has an effect on improving the ability of learning and memory and inhibiting apoptosis. PMID- 26767300 TI - [Pattern Recognition Analysis for Quality Control of Jia Ga Song Tang by GC-MS]. AB - OBJECTIVE: To establish a scientific method for identitication and evaluation of the Tibetan prescription Jia Ga Song Tang. METHODS: Volatile oil was extracted by water steam distillation and analyzed by GC-MS. Principal component analysis (PCA) and hierarchical cluster analysis (HCA) were applied to the samples for chemical fingerprint pattern recognition research. RESULTS: 16 samples according to hierarchical cluster analysis (HCA) and principal component analysis (PCA) were divided into two classes, and results from two recognition analysis methods had good consistency. CONCLUSION: GC-MS-pattern recognition method was a kind of scientific, accurate and effective method for the quality evaluation of Jia Ga Song Tang. PMID- 26767301 TI - [Mass Transfer Kinetics Model of Ultrasonic Extraction of Pomegranate Peel Polyphenols]. AB - OBJECTIVE: The dynamic mathematical model of ultrasonic extraction of polyphenols from pomegranate peel was constructed with the Fick's second law as the theoretical basis. METHODS: The spherical model was selected, with mass concentrations of pomegranate peel polyphenols as the index, 50% ethanol as the extraction solvent and ultrasonic extraction as the extraction method. In different test conditions including the liquid ratio, extraction temperature and extraction time, a series of kinetic parameters were solved, such as the extraction process (k), relative raffinate rate, surface diffusion coefficient(D(S)), half life (t1/2) and the apparent activation energy (E(a)). RESULTS: With the extraction temperature increasing, k and D(S) were gradually increased with t1/2 decreasing,which indicated that the elevated temperature was favorable to the extraction of pomegranate peel polyphenols. The exponential equation of relative raffinate rate showed that the established numerical dynamics model fitted the extraction of pomegranate peel polyphenols, and the relationship between the reaction conditions and pomegranate peel polyphenols concentration was well reflected by the model. CONCLUSION: Based on the experimental results, a feasible and reliable kinetic model for ultrasonic extraction of polyphenols from pomegranate peel is established, which can be used for the optimization control of engineering magnifying production. PMID- 26767302 TI - [Correlation of HPLC Characteristic Spectra of Vinegar Corydalis Rhizoma Decoction Pieces, Water Decoction and Formula Granules]. AB - OBJECTIVE: To study the correlation of characteristic spectra of Vinegar Corydalis Rhizoma decoction pieces, water decoction and formula granules by HPLC, and to investigate the transfer of the main chemical constituents between three different forms. METHODS: The analysis was carried out by a Phenomenex Gemini C18 column (250 mm x 4.6 mm,5 MUm) with acetonitrile-1% acetic acid and ammonium acetate buffer solution (pH 6.0) as the mobile phase in a gradient elution mode. The detection wavelength was 280 nm with a flow rate of 0.8 mL /min. The column temperature was 30 degrees C. The characteristic spectra from 11 batches of Vinegar Corydalis Rhizoma decoction pieces, 11 batches of water decoction and 11 batches of formula granules were established respectively. RESULTS: Ten peaks in the HPLC characteristic spectra from 11 batches of formula granules could be tracked in the water decoction, nine peaks in the HPLC characteristic spectra could be tracked in the decoction pieces. In the ten common peaks, four components such as protopine, palnatine chloride, berberine hydrochloride and tetrahydropalmatine were verified. CONCLUSION: The main chemical components of Vinegar Corydalis Rhizoma decoction pieces, water decoction and formula granules are basically the same, the common component contents have similar proportion. PMID- 26767304 TI - ST-analysis in electronic foetal monitoring is cost-effective from both the maternal and neonatal perspective. AB - OBJECTIVE: Electronic foetal monitoring (EFM) together with non-invasive ST analysis (STAN) has been suggested as a superior technique to EFM alone for foetal surveillance to prevent metabolic acidosis. This study aims to compare the cost-effectiveness of these two techniques from both maternal (short term) as neonatal (long term) perspective to guide clinical decision-making. METHODS: We created two models: a maternal model, focused on the difference in mode of delivery as most important outcome, and a neonatal Markov model focused on the differences in metabolic acidosis - and its relationship to cerebral palsy (CP) - as the most relevant outcome to estimate the long-term cost-effectiveness. The cost to prevent one instrumental delivery was estimated in the maternal model. The costs to prevent one metabolic acidosis and the costs per quality adjusted life years were calculated in the neonatal model. RESULTS: The average costs of STAN are only ?34 higher when compared to EFM alone. From maternal perspective the cost of preventing one instrumental delivery was estimated at ?2602. From neonatal perspective the cost to prevent one case of metabolic acidosis was ?14 509. Over the long term, STAN becomes a dominant (cost saving) strategy if >1% of the patients exposed to metabolic acidosis acquire CP. CONCLUSIONS: Our study suggests that STAN, when compared to EFM alone, can be a cost-effective strategy from both a maternal and neonatal perspective. PMID- 26767303 TI - Ultra-high sensitivity analysis of estrogens for special populations in serum and plasma by liquid chromatography-mass spectrometry: Assay considerations and suggested practices. AB - Estrogen measurements play an important role in the clinical evaluation of many endocrine disorders as well as in research on the role of hormones in human biology and disease. It remains an analytical challenge to quantify estrogens and their metabolites in specimens from special populations including older men, children, postmenopausal women and women receiving aromatase inhibitors. Historically, immunoassays have been used for measuring estrogens and their metabolites in biological samples for risk assessment. However, the lack of specificity and accuracy of immunoassay-based methods has caused significant problems when interpreting data generated from epidemiological studies and across different laboratories. Stable isotope dilution (SID) methodology coupled with liquid chromatography-selected reaction monitoring-mass spectrometry (LC-SRM/MS) is now accepted as the 'gold-standard' to quantify estrogens and their metabolites in serum and plasma due to improved specificity, high accuracy, and the ability to monitor multiple estrogens when compared with immunoassays. Ultra high sensitivity can be obtained with pre-ionized derivatives when using triple quadruple mass spectrometers in the selected reaction monitoring (SRM) mode coupled with nanoflow LC. In this review, we have examined the special issues related to utilizing ultra-high sensitivity SID LC-SRM/MS-based methodology to accurately quantify estrogens and their metabolites in the serum and plasma from populations with low estrogen levels. The major issues that are discussed include: sample preparation for both unconjugated and conjugated estrogens, derivatization, chromatographic separation, matrix effects, and assay validation. PMID- 26767305 TI - Smart Cancer Cell Targeting Imaging and Drug Delivery System by Systematically Engineering Periodic Mesoporous Organosilica Nanoparticles. AB - The integration of diagnosis and therapy into one nanoplatform, known as theranostics, has attracted increasing attention in the biomedical areas. Herein, we first present a cancer cell targeting imaging and drug delivery system based on engineered thioether-bridged periodic mesoporous organosilica nanoparticles (PMOs). The PMOs are stably and selectively conjugated with near-infrared fluorescence (NIRF) dye Cyanine 5.5 (Cy5.5) and anti-Her2 affibody on the outer surfaces to endow them with excellent NIRF imaging and cancer targeting properties. Also, taking the advantage of the thioether-group-incorporated mesopores, the release of chemotherapy drug doxorubicin (DOX) loaded in the PMOs is responsive to the tumor-related molecule glutathione (GSH). The drug release percentage reaches 84.8% in 10 mM of GSH solution within 24 h, which is more than 2-fold higher than that without GSH. In addition, the drug release also exhibits pH-responsive, which reaches 53.6% at pH 5 and 31.7% at pH 7.4 within 24 h. Confocal laser scanning microscopy and flow cytometry analysis demonstrate that the PMOs-based theranostic platforms can efficiently target to and enter Her2 positive tumor cells. Thus, the smart imaging and drug delivery nanoplatforms induce high tumor cell growth inhibition. Meanwhile, the Cy5.5 conjugated PMOs perform great NIRF imaging ability, which could monitor the intracellular distribution, delivery and release of the chemotherapy drug. In addition, cell viability and histological assessments show the engineered PMOs have good biocompatibility, further encouraging the following biomedical applications. Over all, the systemically engineered PMOs can serve as a novel cancer cell targeting imaging and drug delivery platform with NIRF imaging, GSH and pH dual-responsive drug release, and high tumor cell targeting ability. PMID- 26767306 TI - Coverage and accuracy of myeloproliferative and myelodysplastic neoplasms in the Finnish Cancer Registry. AB - Background Registration of haematological malignancies presents specific challenges, and a wide range of data is required to ensure case ascertainment and proper classification of these diseases. We studied the data quality of myeloproliferative and myelodysplastic neoplasms in the Finnish Cancer Registry (FCR), comparing information with hospital discharges. Material and methods Hospital discharges (HILMO) in 2007-2013 including diagnostic codes of myeloproliferative and myelodysplastic neoplasms were extracted. Patients were individually linked to the FCR database for all haematological malignancies registered in 1953-2013. Coverage and accuracy of the FCR and agreement between registers was estimated. Results In total 5289 individuals were retrieved from two registers. Of these, 1406 were common, 1080 only found in the FCR and 2803 only in the HILMO. Coverage of myeloproliferative and myelodysplastic neoplasms in the FCR was 47.0% (95% CI 45.7-48.4%). Almost one quarter of the registrations in the FCR was based on a death certificate only. The accuracy of diagnosis was 51.4% (95% CI 49.4-53.3%), but it varied substantially by disease category. Kappa statistic for agreement between registers was excellent (0.83, 95% CI 0.80-0.85) for common cases. 7.6% of cases in the HILMO was registered as leukaemias in the FCR. Conclusions More than half of the patients found in the HILMO were entirely missing from the FCR. However, some of the diagnoses in HILMO may be preliminary and this represents the maximal number of missing cases. Cancer registers benefit from supplementary data sources, such as hospital discharges, to increase coverage and accuracy of register data on haematological malignancies. PMID- 26767307 TI - Massive hematoma after fine-needle aspiration of the thyroid. PMID- 26767308 TI - Biliopancreatic limb plays an important role in metabolic improvement after duodenal-jejunal bypass in a rat model of diabetes. AB - BACKGROUND AND AIMS: Roux-en-Y gastric bypass improves glucose metabolism in clinical practice, and duodenal-jejunal bypass (DJB), an experimental bypass procedure, also improves metabolism in animals. However, the mechanism remains controversial; especially, the role of the biliopancreatic limb (BP-limb) remains unclear. Our aim was to examine the importance of the function of the BP-limb after DJB using a novel operative model. METHODS: Otsuka Long-Evans Tokushima Fatty rats with diabetes were divided into the following groups: DJB with a short alimentary limb (A-limb) and long BP-limb (B-DJB group), DJB with jejunectomy (J DJB group) in which the entire length of the jejunum used for the BP-limb of the B-DJB group was excised; and a sham operation group. Glucose tolerance, plasma bile acid levels, and the gut microbiota were assessed postoperatively. RESULTS: Glucose tolerance was improved and weight gain was suppressed after surgery in the B-DJB group. In contrast, these effects were cancelled in the J-DJB group. The plasma levels of bile acids in the B-DJB group were greater than those in other groups. The analysis of gut microbiota showed distinct differences between the B-DJB and other groups; especially, the relative abundance of genus Bifidobacterium was much higher in the B-DJB group. CONCLUSION: The BP-limb played an important role in the control of weight gain, glucose tolerance, and increased plasma bile acid levels after DJB in this rat model of type 2 diabetes mellitus. Plasma bile acids and gut microbiota may be involved in these processes. PMID- 26767309 TI - Intestinal derotation procedure for facilitating pancreatoduodenectomy. AB - BACKGROUND: In pancreatoduodenectomy (PD), mesopancreas excision with division of the inferior pancreatoduodenal artery (IPDA) is technically difficult because of the complex anatomy resulting from intestinal rotation occurring during embryological development. We have developed an intestinal derotation procedure for facilitating mesopancreas excision. The perioperative factors of PD were retrospectively compared between our derotation and the conventional procedure. METHODS: The entire small intestine and right colon are mobilized from the retroperitoneum, and intestinal rotation is reduced. This procedure simplifies the anatomic situation, in which (1) the mesopancreas stretches from the right side of the superior mesenteric artery (SMA) in a horizontal plane, (2) the IPDA arises from the right wall of the SMA, and (3) the SMA is situated at the right posterior side of the superior mesenteric vein. In 232 cases undergoing PD, perioperative factors were compared retrospectively between the derotation (n = 117) and conventional (n = 115) procedure groups. RESULTS: The derotation procedure significantly decreased operative time (434 vs 516 minutes) and blood loss (521 vs 908 mL), and tended to increase the rate of R0 resection (90% vs 78%), compared with the conventional procedure. The derotation group had a significantly higher incidence of early, that is, before division of the drainage vein, IPDA division. Postoperative complication rates did not differ, between the 2 groups. CONCLUSION: The derotation procedure is a simple but useful technique that facilitates mesopancreas excision and early IPDA division during PD. PMID- 26767310 TI - Long-term impact of adhesions on bowel obstruction. AB - BACKGROUND: The incidence of reoperation for adhesive bowel obstruction after general abdominal surgery is 2.5% and carries a considerable risk of mortality and morbidity. Adhesions account for 56% of all cases of bowel obstruction. Most epidemiologic knowledge regarding adhesive bowel obstruction is derived from data of national registries and retrospective cohorts of elective abdominal surgery. Because of the design of these studies, it remains unknown whether specific operative factors impact the occurrence of bowel obstruction. We aimed to comprehensively assess risk factors for the incidence of adhesive bowel obstruction with emphasis on intraoperative surgical factors. METHODS: Follow-up study of the prospective LAPAD study (LAParotomy or LAParoscopy and Adhesions study; clinicaltrials.gov registration number: NCT01236625) that included patients undergoing all types of elective open or laparoscopic abdominal surgery. The primary endpoint of this study was (suspected) adhesive bowel obstruction. Univariable and multivariable logistic regression analysis were used to assess risk factors. RESULTS: A total of 604 (88%) of 715 patients were included; 38 (6%) patients experienced an episode of adhesive bowel obstruction. Surgery on the lower gastrointestinal tract (odds ratio 4.57, P < .01) and the severity of adhesions in the operative area (odds ratio 2.37, P = .04) independently increased the risk for adhesive small bowel obstruction. CONCLUSION: Patients undergoing surgery on the lower gastrointestinal tract and patients with more severe adhesions present at surgery have an increased risk for adhesive bowel obstruction. PMID- 26767311 TI - Diffuse cirrhosis-like recurrence of hepatocellular carcinoma after curative resection. PMID- 26767312 TI - The Potential for Treatment of Potential Celiac Disease. PMID- 26767314 TI - Heavy menstrual bleeding. PMID- 26767313 TI - Use of an Abdominal Compression Device in Colonoscopy: A Randomized, Sham Controlled Trial. AB - BACKGROUND & AIMS: Looping is a common problem during colonoscopy that prolongs procedure time. We aimed to determine the efficacy and safety of ColoWrap, an external abdominal compression device, with respect to insertion time and other procedural outcomes. METHODS: We performed a prospective study of outpatients undergoing elective colonoscopy (40-80 years old; mean age, 60.5 years) at endoscopy facilities in the University of North Carolina Hospitals from April 2013 through March 2014. Subjects were randomly assigned to groups that received either ColoWrap (n = 175) or a sham device (control, n = 175) during colonoscopy. Colonoscopists and staff were blinded to the application. The primary outcome was cecal intubation time (CIT). Secondary outcomes included use of manual pressure and position change. RESULTS: The mean CIT was similar for the control and ColoWrap groups (6.69 vs 6.67 minutes; P = .98). There were no statistical differences in the frequency of manual pressure (45% for controls vs 37% for ColoWrap group, P = .13) or position changes (4% for controls vs 2% for ColoWrap group, P = .36). Among patients with body mass index between 30 and 40 kg/m(2) (n = 78), CIT was significantly lower for patients in the ColoWrap group (4.69 minutes) than controls (6.10 minutes) (P = .03). Adverse events were similar between groups. CONCLUSIONS: In patients undergoing elective colonoscopy, application of an external abdominal compression device did not improve CIT or affect the frequency of ancillary maneuvers. A possible benefit was observed in patients with body mass index between 30 and 40 kg/m(2), but further studies are needed. ClinicalTrials.gov number: NCT02025504. PMID- 26767316 TI - Assessing the quality of proton PBS treatment delivery using machine log files: comprehensive analysis of clinical treatments delivered at PSI Gantry 2. AB - Pencil beam scanning (PBS) proton therapy requires the delivery of many thousand proton beams, each modulated for position, energy and monitor units, to provide a highly conformal patient treatment. The quality of the treatment is dependent on the delivery accuracy of each beam and at each fraction. In this work we describe the use of treatment log files, which are a record of the machine parameters for a given field delivery on a given fraction, to investigate the integrity of treatment delivery compared to the nominal planned dose. The dosimetry-relevant log file parameters are used to reconstruct the 3D dose distribution on the patient anatomy, using a TPS-independent dose calculation system. The analysis was performed for patients treated at Paul Scherrer Institute on Gantry 2, both for individual fields and per series (or plan), and delivery quality was assessed by determining the percentage of voxels in the log file dose distribution within +/- 1% of the nominal dose. It was seen that, for all series delivered, the mean pass rate is 96.4%. Furthermore, this work establishes a correlation between the delivery quality of a field and the beam position accuracy. This correlation is evident for all delivered fields regardless of individual patient or plan characteristics. We have also detailed further usefulness of log file analysis within our clinical workflow. In summary, we have highlighted that the integrity of PBS treatment delivery is dependent on daily machine performance and is specifically highly correlated with the accuracy of beam position. We believe this information will be useful for driving machine performance improvements in the PBS field. PMID- 26767317 TI - Non-pharmacological treatments for stuttering in children and adults: a systematic review and evaluation of clinical effectiveness, and exploration of barriers to successful outcomes. AB - BACKGROUND: Despite many years of research, there is no certainty regarding the cause of stuttering. Although numerous interventions have been developed, a broad based systematic review across all forms of intervention for adults and children was needed including views and perceptions of people who stutter. OBJECTIVE: The aims of the study were to report the clinical effectiveness of interventions for people who stutter (or clutter), to examine evidence regarding the views of people who stutter and the views of professionals regarding interventions. DATA SOURCES: A systematic review of quantitative and qualitative literature was carried out between August 2013 and April 2014. The following electronic databases were searched: (1) MEDLINE, (2) EMBASE, (3) The Cochrane Library (including The Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, Database of Abstracts of Reviews of Effects, Health Technology Assessment Database and NHS Economic Evaluations Database), (4) PsycINFO, (5) Science Citation Index, (6) Social Science Citation Index, (7) Cumulative Index to Nursing and Allied Health Literature, (8) ASSIA, (9) Linguistics and Language Behavior Abstracts, (10) Sociological Abstracts and (11) the EPPI Centre. Reference lists of included papers and other reviews were screened and also key journals in the subject area were hand-searched. REVIEW METHODS: The searches aimed to identify (1) evidence of clinical effectiveness in populations of pre-school children, school-aged children, adolescents and adults, and (2) data relating to perceptions of barriers and facilitators to intervention clinical effectiveness among staff and people who stutter. A metasynthesis of the two linked elements via development of a conceptual model was also carried out to provide further interpretation of the review findings. RESULTS: A systematic search of the literature identified a large number of potentially relevant studies. Of these, 111 studies examining the clinical effectiveness of interventions, 25 qualitative papers and one mixed-methods paper met the criteria for inclusion in this review. Review of the effectiveness literature indicated evidence of positive outcomes across all types of interventions. Virtually all evidence we identified reported at least some positive effect for some participants. However, there was evidence of considerable individual variation in outcome for study participants. The qualitative literature highlighted the need for programmes to be tailored to individual need with variation at the levels of the intervention, the individual and interpersonal/social elements. Metasynthesis of the data highlighted the complexity of elements that need to be considered in evaluation of long-term impacts following stuttering interventions. LIMITATIONS: Around two-thirds of the studies were considered to be at higher risk of bias. The heterogeneous nature and variability in outcomes meant that we were unable to complete a meta-analysis. CONCLUSIONS: Although much of the evidence we identified was from studies at risk of bias, it is suggested that most available interventions for stuttering may be of benefit to at least some people who stutter. There is a requirement for greater clarity regarding what the core outcomes following stuttering intervention should be and also enhanced understanding of the process whereby interventions effect change. Further analysis of those for whom interventions have not produced a significant benefit may provide additional insights into the complex intervention-outcomes pathway. STUDY REGISTRATION: This study is registered as PROSPERO CRD42013004861. PMID- 26767315 TI - Adjuvant treatment for older women with invasive breast cancer. AB - Older women experience a large share of breast cancer incidence and death. With the projected rise in the number of older cancer patients, adjuvant chemo-, radiation and endocrine therapy management will become a key component of breast cancer treatment in older women. Many factors influence adjuvant treatment decisions including patient preferences, life expectancy and tumor biology. Geriatric assessment predicts important outcomes, identifies key deficits, and can aid in the decision making process. This review utilizes clinical vignettes to illustrate core principles in adjuvant management of breast cancer in older women and suggests an approach incorporating life expectancy and geriatric assessment. PMID- 26767318 TI - The American Thyroid Association Guidelines on Voice Assessment-Have We Done Enough? PMID- 26767319 TI - Filling the gap between the quantum and classical worlds of nanoscale magnetism: giant molecular aggregates based on paramagnetic 3d metal ions. AB - In this review, aspects of the syntheses, structures and magnetic properties of giant 3d and 3d/4f paramagnetic metal clusters in moderate oxidation states are discussed. The term "giant clusters" is used herein to denote metal clusters with nuclearity of 30 or greater. Many synthetic strategies towards such species have been developed and are discussed in this paper. Attempts are made to categorize some of the most successful methods to giant clusters, but it will be pointed out that the characteristics of the crystal structures of such compounds including nuclearity, shape, architecture, etc. are unpredictable depending on the specific structural features of the included organic ligands, reaction conditions and other factors. The majority of the described compounds in this review are of special interest not only for their fascinating nanosized structures but also because they sometimes display interesting magnetic phenomena, such as ferromagnetic exchange interactions, large ground state spin values, single molecule magnetism behaviour or impressively large magnetocaloric effects. In addition, they often possess the properties of both the quantum and the classical world, and thus their systematic study offers the potential for the discovery of new physical phenomena, as well as a better understanding of the existing ones. The research field of giant clusters is under continuous evolution and their intriguing structural characteristics and magnetism properties that attract the interest of synthetic Inorganic Chemists promise a brilliant future for this class of compounds. PMID- 26767320 TI - Combining chitinase C and N-acetylhexosaminidase from Streptomyces coelicolor A3(2) provides an efficient way to synthesize N-acetylglucosamine from crystalline chitin. AB - The enzymatic bioconversion of chitin is of considerable interest for the natural production of bioactive compounds such as chitooligosaccharides and N-acetyl-d glucosamine (GlcNAc). Key enzymes are involved in the natural processing of chitin, hydrolyzing this abundant biopolymer to yield chitooligosaccharides with substantial value to the medicinal and biotechnological fields. In this study, chitinase C (ScChiC) from the soil bacterium and chitin decomposer Streptomyces coelicolor A3(2) was expressed, purified and characterized. We also optimized a Streptomyces lividans system generating ScChiC expression yields nearly 500-fold higher than the previously reported heterologous expression in Escherichia coli. The purified enzyme was found to be stable below 55 degrees C for a broad range of pH values (pH 3.5-9) and exhibited high activity against chitin and chitooligosaccharides to form chitobiose (C2) as main product. Crab shell chitin hydrolysis profiles also revealed that ScChiC catalyzes the bioconversion of chitopolysaccharides through an endo-nonprocessive mode of action. When combining ScChiC with an N-acetylhexosaminidase from S. coelicolor A3(2) (ScHEX) in an assay using crude extracts and crystalline chitin as substrate, GlcNAc was generated as final product with a yield over 90% after 8h incubation. This chitin hydrolysis yield represents one of the most efficient enzyme bioconversion of chitopolysaccharides to GlcNAc characterized to date, making the S. coelicolor ScChiC-ScHEX pair a potentially suitable contender for the viable industrial production of this important bioactive compound. PMID- 26767321 TI - A formulated double-stranded RNA diet for reducing Penaeus monodon densovirus infection in black tiger shrimp. AB - Penaeus monodon densovirus (PmDNV) is one of the major causes of stunted shrimp in the aquaculture industry in Thailand. Significant reductions in levels of PmDNV as assessed by PCR analysis of shrimp hepatopancreas were seen in both prophylactic and curative experiments after feeding shrimp with a formulated diet containing mixed inactivated bacteria harboring dsRNAs corresponding to the PmDNV ns1 and vp genes. Significant reductions of approximately 88% (prophylactic) and 64% (curative) of PmDNV were observed, suggesting that this diet has a high potential for application in commercial aquaculture for reducing PmDNV associated stunted growth of shrimp. PMID- 26767322 TI - Genome-wide association studies based on sequence-derived genotypes reveal new QTL associated with conformation and performance traits in the Franches-Montagnes horse breed. AB - To identify novel quantitative trait loci (QTL) within horses, we performed genome-wide association studies (GWAS) based on sequence-level genotypes for conformation and performance traits in the Franches-Montagnes (FM) horse breed. Sequence-level genotypes of FM horses were derived by re-sequencing 30 key founders and imputing 50K data of genotyped horses. In total, we included 1077 FM horses genotyped for ~4 million SNPs and their respective de-regressed breeding values of the traits in the analysis. Based on this dataset, we identified a total of 14 QTL associated with 18 conformation traits and one performance trait. Therefore, our results suggest that the application of sequence-derived genotypes increases the power to identify novel QTL which were not identified previously based on 50K SNP chip data. PMID- 26767324 TI - Prosthetic Mesh for Obliteration of the Nephrosplenic Space in Horses: 26 Clinical Cases. AB - OBJECTIVE: To report surgical complications, occurrence of post-obliteration colic, long term outcome, and return to previous function for horses treated with prosthetic mesh obliteration of the nephrosplenic space. STUDY DESIGN: Retrospective study. ANIMALS: Horses (n = 26) having nephrosplenic space obliteration using prosthetic mesh. METHODS: Horses undergoing mesh obliteration between January 2006 and May 2013 were included. A ProxplastTM mesh was secured to the nephrosplenic space with titanium helical coils in standing horses using laparoscopic technique. Perioperative data were obtained from the medical record and by telephone followup. Tests of proportion were used to compare the study population to the hospital colic population. Occurrence of colic within 1 year of obliteration was compared between horses where the diagnosis was confirmed at laparotomy and those diagnosed by abdominal palpation per rectum using a Fisher's exact test. RESULTS: All 26 horses undergoing mesh obliteration during the study period survived to discharge. Long term followup was available for 25 horses, with 23 returning to their previous level of function, and 21 alive at the time of followup. Cause of death was not associated with the surgical procedure in any case. Geldings and Warmbloods were overrepresented compared to the hospital colic population. Ten horses (38%) demonstrated colic after mesh obliteration. All 10 horses were examined by a veterinarian and none were diagnosed with recurrence of nephrosplenic entrapment. CONCLUSION: Mesh obliteration of the nephrosplenic space is an effective alternative to suture closure for preventing nephrosplenic entrapment of the large colon in horses. No complications related to mesh obliteration were reported in our study population. PMID- 26767323 TI - Older adults have an altered chylomicron response to a high-fat meal. AB - Ageing is associated with a prolonged and exaggerated postprandial lipaemia. This study aimed to examine the contribution of alterations in chylomicron synthesis, size and lipid composition to increased lipaemia. Healthy older (60-75 years; n 15) and younger (20-25 years; n 15) subjects consumed a high-fat breakfast. Chylomicron dynamics and fatty acid composition were analysed for 5 h in the postprandial state. Plasma TAG levels were elevated following the meal in the older subjects, relative to younger subjects (P<0.01). For older subjects compared with younger subjects, circulating chylomicron particle size was smaller (P<0.05), with greater apoB content (P<0.05) at all postprandial time points. However, total chylomicron TAG concentration between the groups was unaltered post-meal. Compared with younger subjects, the older subjects exhibited a greater proportion of oleic acid in the TAG and phospholipid (PL) fraction (P<0.05), plus lower proportions of linoleic acid in the TAG fraction of the chylomicrons (P<0.01). Thus, following the ingestion of a high-fat meal, older individuals demonstrate both smaller, more numerous chylomicrons, with a greater total MUFA and lower PUFA contents. These data suggest that the increased postprandial lipaemia of ageing cannot be attributed to increased chylomicron TAG. Rather, ageing is associated with changes in chylomicron particle size, apoB content and fatty acid composition of the chylomicron TAG and PL fractions. PMID- 26767328 TI - Objective assessment of sleep status and its correlates in hospitalized children with cancer: Exploratory study. AB - BACKGROUND: Children with cancer are known to have sleep problems. Although hospitalization and psychosocial factors are considered to be the factors affecting children's sleep, few studies have confirmed these effects. The aims of this study were to describe the sleep status of hospitalized children with cancer and to explore the correlates. METHODS: The sleep status of 11 hospitalized children (aged 2-12 years) with cancer was measured using actigraph and sleep diary during hospitalization and a short home stay. Possible correlates were assessed using a questionnaire. RESULTS: The participants had significantly longer sleep onset latency, earlier bedtime, and poorer self-evaluated sleep quality during hospitalization than the short home stay. They had shorter total sleep time, longer wake time after sleep onset, and less sleep efficiency at home, compared with healthy historical controls. Children's age, symptoms, hospitalization period, Cognitive Fatigue, Procedural Anxiety, Treatment Anxiety, Social Anxiety, and Separation Anxiety, as well as caregiver anxiety, Receptive and Focused Attitude, and Regimented Attitude were significantly correlated with sleep variables. CONCLUSIONS: Hospitalization decreased self-evaluated sleep quality, and difficulty falling asleep. The sleep of the participants at home was disturbed compared with that of healthy children. Hospitalization, patient characteristics, disease-related, and some psychosocial factors were associated with sleep variables. Medical professionals should develop a favorable environment for falling asleep in hospital for individual children. Children with cancer in the early period of hospitalization need increased care to facilitate good sleep. PMID- 26767330 TI - Multifunctional Logic in a Photosensitizer with Triple-Mode Fluorescent and Photodynamic Activity. AB - Herein we describe a photosensitizer (PS) with the capacity to perform multiple logic operations based on a pyrene-containing phthalocyanine (Pc) derivative. The system presents three output signals (fluorescence at 377 and 683 nm, and singlet oxygen ((1)O2) production), which are dependent on three inputs: two chemical (concentration of dithiothreitol (DTT) and acidic pH) and one physical (visible light above 530 nm for (1)O2 sensitization). The multi-input/multioutput nature of this PS leads to single-, double-, and triple-mode activation pathways of its fluorescent and photodynamic functions, through the interplay of various interrelated AND, ID, and INHIBIT gates. Dual fluorescence emissions are potentially useful for orthogonal optical imaging protocols while (1)O2 is the main reactive species in photodynamic therapy (PDT). We thus expect that this kind of PS logic system will be of great interest for multimodal cellular imaging and therapeutic applications. PMID- 26767331 TI - Taming Tin(IV) Polyazides. AB - The first charge-neutral Lewis base adducts of tin(IV) tetraazide, [Sn(N3)4(bpy)], [Sn(N3)4(phen)] and [Sn(N3)4(py)2], and the salt bis{bis(triphenylphosphine)iminium} hexa(azido)stannate [(PPN)2Sn(N3)6] (bpy = 2,2'-bipyridine; phen = 1,10-phenanthroline; py = pyridine; PPN = N(PPh3)2) have been prepared using covalent or ionic azide-transfer reagents and ligand-exchange reactions. The azides were isolated on the 0.3 to 1 g scale and characterized by IR and NMR spectroscopies, microanalytical and thermal methods and their molecular structures determined by single-crystal XRD. All complexes have a distorted octahedral Sn[N]6 coordination geometry and possess greater thermal stability than their Si and Ge homologues. The nitrogen content of the adducts of up to 44% exceed any Sn(IV) compound known hitherto. PMID- 26767332 TI - Ag2Mo3O10 Nanorods Decorated with Ag2S Nanoparticles: Visible-Light Photocatalytic Activity, Photostability, and Charge Transfer. AB - Ag2Mo3O10 nanorods decorated with Ag2 S nanoparticles have been synthesized by an anion-exchange route. With thiourea as the sulfur source, sulfur ions replace [Mo3O10](2-) units of active sites on the surface of Ag2Mo3O10 nanorods, forming Ag2Mo3O10 nanorods decorated with Ag2S nanoparticles. This induces enhanced absorption in the visible-light region. Ag2 S nanoparticles decorate the surface of Ag2Mo3O10 nanorods uniformly with a suitable amount of thiourea. The Ag2S/Ag2Mo3O10 nanoheterostructure enhances the photocatalytic activity on the degradations of Rhodamine B and glyphosate under visible light. This enhancement is attributed to the improved absorption of visible light and effective separation of charge carriers in the nanoheterostructure. Meanwhile, the Ag2S/Ag2Mo3O10 nanoheterostructure displays good photocatalytic stability based on cyclic photocatalytic experiments. PMID- 26767335 TI - A modified and cost-effective method for hair cortisol analysis. AB - Hair cortisol may hold potential as a biomarker for assessment of chronic psychological stress. We report a modified and cost-effective method to prepare hair samples for cortisol assay. Hair samples were ground using an inexpensive ball grinder - ULTRA-TURRAX tube drive. Cortisol was extracted from the powder under various defined conditions. The data showed that the optimal conditions for this method include cortisol extraction at room temperature and evaporation using a stream of room air. These findings should allow more widespread research using economical technology to validate the utility of hair cortisol as a biomarker for assessing chronic stress status. PMID- 26767336 TI - Commentary on Rossow et al. (2016): Early days yet in the cycle from peer to parent drinking as influences on adolescent alcohol involvement. PMID- 26767337 TI - Commentary on Guydish et al. (2016): The continuing deadly threat of tobacco use in addiction treatment. PMID- 26767338 TI - Commentary on Maier et al. (2016): Language matters--a call for caution regarding research on non-medical use of prescription drugs. PMID- 26767339 TI - Commentary on Pierce et al. (2016): Raising the bar of addiction treatment--first do no harm. PMID- 26767343 TI - Erratum. PMID- 26767340 TI - Enhancing Quit & Win contests to improve cessation among college smokers: a randomized clinical trial. AB - BACKGROUND AND AIMS: Quit & Win contests (in which smokers pledge to quit smoking for a defined period in exchange for the chance to win a prize) may be well suited for college smokers. We tested the effectiveness of multiple versus single Quit & Win contests and that of added counseling versus no counseling in smoking cessation. DESIGN: A two-by-two, randomized controlled trial with 6-month follow up. SETTING: Nineteen institutions in Minnesota, Texas, Ohio and Wisconsin. PARTICIPANTS: College student smokers (n = 1217) were randomized within site to four conditions: single (n = 306), multiple contests alone (n = 309), single contest plus counseling (n = 296) or multiple contests with counseling (n = 306). INTERVENTION: Participants in the standard contest condition (T1 and T2) were asked to abstain from all tobacco products for a 30-day period; those with confirmed abstinence were eligible for a lottery-based prize. Participants assigned to the multiple contest conditions (T3 and T4) participated in the 30 day contest and were enrolled automatically into two additional contest periods with an escalating prize structure. Participants randomized into the counseling conditions (T2 and T4) received up to six telephone-administered Motivation and Problem Solving (MAPS) counseling sessions over the 12-week treatment period. MEASURES: The primary outcome was biochemically verified 30-day point prevalence (PP) abstinence rate at 6 months. Secondary outcomes were the same abstinence at end of treatment (4 months) and a proxy measure of 6-month verified continuous abstinence rate. Outcomes were based on all participants randomized. FINDINGS: We found no evidence of an interaction between number of contests and counseling. Abstinence rates for multiple (13.5%) and single (11.7%) contests were not significantly different at 6 months [odds ratio (OR) = 1.18, 95% confidence interval (CI) = 0.84-1.66]. The addition of counseling did not improve 6-month abstinence significantly (13.7 versus 11.6%, OR = 1.21, 95% CI = 0.86-1.70). Multiple contests increased abstinence at 4 months (19.3 versus 10.3%, OR = 2.09, 95% CI = 1.50-2.91) and continuous abstinence at 6 months (7.8 versus 3.8%, OR = 2.14, 95% CI = 1.28-3.56). CONCLUSION: Multiple Quit & Win contests may increase smoking abstinence rates in college students more than single contests, but it is not clear whether adding counseling to these interventions produces any additional benefit. PMID- 26767344 TI - Mortality in eating disorders - results of a large prospective clinical longitudinal study. AB - OBJECTIVE: To report on long-term mortality in anorexia nervosa (AN), bulimia nervosa (BN), binge eating disorder (BED), and eating disorder not otherwise specified (ED-NOS), causes of death, and predictors of early death. METHOD: A large sample of consecutively admitted inpatients (N = 5,839) was followed-up on vital status through the German civil registry office. Of these patients 1,639 were treated for AN, 1,930 for BN, 363 for BED, and 1,907 for ED-NOS. Data from the main inpatient hospital treatment were applied to bivariate and multivariate Cox regression analyses on survival time from onset of eating disorder to death or end of observation. Standardized mortality ratios (SMR) were computed matched for age, gender, and person-years. RESULTS: SMR were 5.35 for AN, 1.49 for BN, 1.50 for BED, 2.39 for narrowly defined ED-NOS, and 1.70 for widely defined ED NOS. Patients with AN died earlier than patients with BN, BED, or ED-NOS who did not differ. A diagnosis of AN, chronicity, later age of onset, not living in a relationship, and an irregular type of discharge from index inpatient treatment were major predictors of a shorter time to death. Suicidality was a univariate predictor of a shorter time to death in BN only. AN patients mostly died from natural causes related to their eating disorder. DISCUSSION: Mortality in AN is excessive and considerably higher than in BN, BED, and ED-NOS. PMID- 26767346 TI - Global Proteome Analyses of Lysine Acetylation and Succinylation Reveal the Widespread Involvement of both Modification in Metabolism in the Embryo of Germinating Rice Seed. AB - Regulation of rice seed germination has been shown to mainly occur at post transcriptional levels, of which the changes on proteome status is a major one. Lysine acetylation and succinylation are two prevalent protein post-translational modifications (PTMs) involved in multiple biological processes, especially for metabolism regulation. To investigate the potential mechanism controlling metabolism regulation in rice seed germination, we performed the lysine acetylation and succinylation analyses simultaneously. Using high-accuracy nano LC-MS/MS in combination with the enrichment of lysine acetylated or succinylated peptides from digested embryonic proteins of 24 h after imbibition (HAI) rice seed, a total of 699 acetylated sites from 389 proteins and 665 succinylated sites from 261 proteins were identified. Among these modified lysine sites, 133 sites on 78 proteins were commonly modified by two PTMs. The overlapped PTM sites were more likely to be in polar acidic/basic amino acid regions and exposed on the protein surface. Both of the acetylated and succinylated proteins cover nearly all aspects of cellular functions. Ribosome complex and glycolysis/gluconeogenesis-related proteins were significantly enriched in both acetylated and succinylated protein profiles through KEGG enrichment and protein protein interaction network analyses. The acetyl-CoA and succinyl-CoA metabolism related enzymes were found to be extensively modified by both modifications, implying the functional interaction between the two PTMs. This study provides a rich resource to examine the modulation of the two PTMs on the metabolism pathway and other biological processes in germinating rice seed. PMID- 26767347 TI - The relationship between parental attitudes and behaviours in the context of paediatric chronic pain. AB - BACKGROUND: Within the context of paediatric chronic pain, parental attitudes are of particular importance given that they have the potential to impact on how parents respond to their child. The current study was designed to assess whether parental attitudes, such as parental confidence and beliefs in their child's ability to function in spite of pain, and parental catastrophising about their child's pain, are associated with parental pain-related behaviours known to be associated with poor child outcomes, such as protectiveness and high levels of monitoring. METHODS: Participants were 138 child-parent dyads recruited from a tertiary chronic pain clinic. Patients were aged 8- to 17-years. Prior to the initial clinic appointment, parents completed validated measures of parental pain catastrophising and parental responses to their child's pain. Patients completed measures of functional disability and pain intensity. RESULTS: Parents who reported lower confidence in their child's ability to cope with the pain engaged in significantly more protective, monitoring and distracting behaviours, even when controlling for the child's recent level of functioning. They also took more days off work due to their child's pain. Parents who catastrophised more about their child's pain engaged in significantly more protective and monitoring behaviours, even when controlling for the child's recent level of functioning. CONCLUSIONS: Parental behaviours in response to their child's pain are significantly related to parental confidence in their child's coping and parental pain-related catastrophising. Clinical interventions may benefit from addressing parental attitudes, especially their confidence in their child's ability to function. PMID- 26767348 TI - Entangled lives: Implications of the developmental origins of health and disease hypothesis for bioarchaeology and the life course. AB - Epidemiological research since the 1980s has highlighted the consequences of early life adversity, particularly during gestation and early infancy, for adult health (the "Barker hypothesis"). The fast-evolving field of molecular epigenetics is providing explanatory mechanisms concerning phenotypic plasticity in response to developmental stressors and the accumulation of disease risk throughout life. In addition, there is now evidence for the heritability of poor health across generations via epigenetic modifications. This research has the potential to invoke a paradigmatic shift in how we interpret factors such as growth insults and immune response in past skeletal remains. It demonstrates that health cannot be understood in terms of immediate environmental circumstances alone. Furthermore, it requires both a theoretical and practical re-evaluation of disease biographies and the life course more generally. Individual life courses can no longer be regarded as discrete, bounded, life histories, with clearly defined beginning and end points. If socioeconomic circumstances can have intergenerational effects, including disease susceptibility and growth stunting, then individual biographies should be viewed as nested or "embedded" within the lives of others. This commingling of life courses may prove problematic to unravel; nevertheless, this review aims to consider the potential consequences for bioarchaeological interpretations. These include a greater consideration of: the temporal power of human skeletons and a life course approach to past health; infant health and the implications for maternal well-being; and the impact of non proximate stressors (e.g., early life and ancestral environments) on the presence of health indicators. PMID- 26767349 TI - Technical note: An in vitro study of dental microwear formation using the BITE Master II chewing machine. AB - Dental microwear has been used for decades to reconstruct the diets of fossil hominins and bioarchaeological populations. The basic theory has been that hard brittle foods (e.g., nuts, bone) require crushing and leave pits as they are pressed between opposing cheek-tooth surfaces, whereas soft-tough foods (e.g., grass blades, meat) require shearing and leave scratches as they are dragged along opposing surfaces that slide past one another. However, recent studies have called into question the efficacy of microwear as an indicator of diet. One issue has been the limited number of in vitro studies providing empirical evidence for associations between microwear pattern and chewing behavior. We here describe a new study using a chewing simulator, the BITE Master II, to examine the effects of angle of approach between opposing teeth and food consistency on microwear surface texture. Results indicate that opposing teeth that approach one another: 1) perpendicular to the occlusal plane (crushing) result in pits; 2) parallel to the occlusal plane (shearing) result in striations in the direction of movement; and 3) oblique to the occlusal plane (45 degrees ) result in both striations and pits. Results further suggest that different food types and abrasive loads affect the propensity to accumulate microwear features independent of feature shapes. PMID- 26767353 TI - Introduction from Allan Tasman. PMID- 26767350 TI - Posterior hippocampal regional cerebral blood flow predicts abstinence: a replication study. AB - The posterior hippocampus (pHp) plays a major role in the processing and storage of drug-related cues and is linked to striatal-limbic brain circuits involved with craving and drug salience. We have recently reported that increased basal regional cerebral blood flow (rCBF) in a pHp loci, as measured by pseudo continuous arterial spin labeling magnetic resonance imaging, predicted days to cocaine relapse following residential treatment. In this secondary analysis, we explored whether rCBF in this same pHp region would successfully predict 30-day point prevalence abstinence 60 days following residential treatment in an independent group of previously studied participants with cocaine dependence. rCBF was assessed with single photon emission computerized tomography during a saline infusion in 21 cocaine dependence and 22 healthy control participants. pHp rCBF was significantly higher in those endorsing substance use (n = 10) relative to both abstinent (n = 11) (p < 0.001) and control (p < 0.05) participants. There were no significant differences in measured demographic or clinical variables between the actively using and non-using participants. This replicative finding suggests that heightened pHp activation is a significant predictor of substance use in cocaine-dependent individuals, possibly reflecting a neural susceptibility to continued drug cues. PMID- 26767354 TI - Post-tsunami mental health: A cross-sectional survey of the predictors of common mental disorders in South India 9-11 months after the 2004 Tsunami. AB - INTRODUCTION: The Asian earthquake and subsequent tsunami of December 2004, one of the largest natural disasters in history, resulted in the deaths of over 250,000 people and massive destruction in eight countries. The mental health consequences of the disaster remain relatively poorly explored. This study sought to go beyond the dose-response paradigm to examine the effect of pre-disaster socio-cultural variables on common mental disorders (CMD) after the tsunami. METHODS: A cross-sectional survey was conducted 9-11 months after the 2004 tsunami in a low-income setting in South India to assess the association between CMD, disaster-related losses and pre-disaster socio-cultural variables in a convenience adult sample of tsunami survivors. RESULTS: Sixty-four percent (339) of the 532 individuals sampled and included in the analysis screened positive for CMD. Multivariate analysis showed that female gender, older age, poor quality marital life before the disaster and death of a primary family member due to the tsunami were associated with CMD. DISCUSSION: A large majority of the sample in an area of South India screened positive for CMD 9-11 months after the tsunami. These data served as an impetus in planning a long-term, five-year post-disaster intervention. Accurate longitudinal data about risk and protective factors after a disaster are needed to plan medium- and long-term interventions. PMID- 26767355 TI - Mental health literacy: A cross-cultural study from Britain, Hong Kong and Malaysia. AB - INTRODUCTION: A cross-cultural study was conducted on the identification of psychiatric problems comparing British, Hong Kong and Malaysian participants. AIMS: To investigate the ability to correctly identify different psychiatric problems and recommend strategies for treatment. METHODS: A total of 440 participants were shown vignettes of schizophrenia, obsessive compulsive disorder (OCD), social phobia, depression, bipolar disorder, stress, child attention deficit hyperactivity disorder (ADHD), child depression and child "daily troubles". In each they were asked to say what they thought the person's problem was and how they could be helped as well as give their confidence ratings on both judgments. RESULTS: The British were the most adept at correctly identifying the cases of mental disorders in the vignettes followed by the Hong Kong Chinese and Malaysians. Overall, the depression cases were the best identified and social phobia was the least identified. In terms of help recommendation, a higher percentage of British participants endorsed professional help as useful for the person in the vignette compared to Hong Kong and Malaysian participants. DISCUSSION: The findings were discussed along with suggestions on how to improve mental health literacy. The ethnocentric nature of applying Western concepts in the East was acknowledged. PMID- 26767356 TI - Polymorphism of the serotonin transporter gene (5-HTTLPR) in major depressive disorder patients in Malaysia. AB - INTRODUCTION: The serotonin transporter promoter (5-HTTLPR) is a potential susceptibility locus in the pathogenesis of major depressive disorder. However, data from Malaysia is lacking. The present study aimed to determine the association between the homozygous short variant of the serotonin transporter promoter gene (5-HTTLPR) with major depressive disorder. METHODS: This is a candidate gene case-control association study. The sample consists of 55 major depressive disorder probands and 66 controls. They were Malaysian descents and were unrelated. The Axis I diagnosis was determined using Mini International Neuropsychiatric Interview (M.I.N.I.). The control group comprised healthy volunteers without personal psychiatric history and family history of mood disorders. Participants' blood was sent to the Institute Medical Research for genotyping. RESULTS: The present study failed to detect an association between 5 HTTLPR ss genotype with major depressive disorder (chi(2) = 3.67, d.f. = 1, P = 0.055, odds ratio 0.25, 95% confidence interval = 0.07-1.94). Sub-analysis revealed that the frequency of l allele in healthy controls was higher (78.0%) than that of Caucasian and East Asian population. However, in view of the small sample size this study may be prone to type II error (and type I error). DISCUSSION: This preliminary study suggests that the homozygous short variant of the 5-HTTLPR did not appear to be a risk factor for increasing susceptibility to major depressive disorder. PMID- 26767357 TI - Two-phase survey to determine social anxiety and gender differences in Omani adolescents. AB - INTRODUCTION: There is a lack of studies examining the effectiveness of some of the commonly used instruments to elicit the presence of social anxiety disorder (SAD) in Arab-speaking populations, such as those in Oman. The aim of this study was to establish the influence of social anxiety and the role of gender among Omani adolescents. METHODS: A two-phase protocol was used, entailing the psychometric properties of the Arabic version of the Liebowitz Social Anxiety Scale (LSAS) against the gold standard, the Diagnostic and Statistical Manual of Mental Disorders (DSM). RESULTS: According to DSM and LSAS, the prevalence of social phobia among Omani students was generally higher compared to what has been reported in other parts of the world and the crosstabs analysis showed a significant correlation between gender and SAD. DISCUSSION: The Arabic version of LSAS proved to be an effective tool for assessing and quantifying the presence of SAD. This study discusses the sociocultural factors affecting social phobia in Omani society. PMID- 26767358 TI - Ethical issues in researching interventions for behavioral disturbance in psychotic disorders. PMID- 26767359 TI - Prevalence of postpartum depression in a hospital setting among Malaysian mothers. AB - INTRODUCTION: Postpartum depression (PPD) is a disorder that affects not only mothers, but also can lead to family, social, economic and vocational breakdown. The objective of this study was to determine the prevalence and factors associated with postpartum depression among mothers in an urban hospital setting in Malaysia. METHODS: In this cross-sectional study, mothers attending routine visits at six to eight weeks postpartum at a postnatal clinic were assessed on socio-demographic data, obstetric history, social support, breastfeeding status and psychiatric history. Mini International Neuropsychiatric Interview (M.I.N.I.) was administered to establish a diagnosis of postpartum depression. RESULTS: A total of 411 subjects participated in the study. The prevalence rate of postpartum depression was 6.8%. Univariate analysis found that being a housewife, having a cesarian section, low social support, family history of depression, previous history of depression and non-exclusive breastfeeding were significantly associated with postpartum depression. Predictors for postpartum depression were non-exclusive breastfeeding (P < 0.01, OR = 23.7, 95% CI 3.1-179.7) and previous history of depression (P < 0.05, OR = 82.3, 95% CI 1.2-5897.6). DISCUSSION: The prevalence rate of postpartum depression in urban Malaysian mothers was comparable to the rates in other countries. Mothers who did no exclusively breast feeding their babies appeared to have more risk for postpartum depression. Therefore, screening for depression should become a routine during postpartum period and mothers must be encouraged to exclusively breastfeed their babies. PMID- 26767360 TI - Mental health services in the Solomon Islands. AB - The Solomon Islands comprise an archipelago of nearly 1,000 islands and coral atolls and have an estimated population of 549,574 people. Formal mental health services date back to 1950 when an asylum was established. Since then the process of mental health service development has been largely one of incremental change, with a major boost to community services in the last two decades. During the 1990s a mental health outpatient clinic was established in Honiara, together with attempts to recruit nursing staff as psychiatric coordinators in the provinces. In 1996, the Ministry commenced sending registered nurses for psychiatric training in Papua New Guinea. By 2010, there were 13 psychiatric nurses and one psychiatrist, with a second psychiatrist in training. A National Mental Health Policy was drafted in 2009 but is yet to be endorsed by Cabinet. A significant portion of the population still turns to traditional healers or church leaders for purposes of healing, seeking help from Western medicine only after all other alternatives in the community have been exhausted. There is still a long way to go before mental health services are available, affordable and accessible to the whole population, including people living in geographically remote areas. Realization of this vision requires increased resourcing for mental health services; improved communication and collaboration between the centrally-based, national mental health services and the provincial health services; and closer, ongoing relationships between all stakeholders and partners, both locally and internationally. PMID- 26767361 TI - Developing primary care psychiatry in the Asia-Pacific. PMID- 26767362 TI - Adolescents who engage exclusively in healthy weight control behaviors: Who are they? AB - BACKGROUND: Little is known about the exclusive adoption of healthy weight control behaviors in the absence of unhealthy weight control behaviors among adolescents. The current study aimed to determine (i) the prevalence of the exclusive adoption of healthy weight control behaviors, (ii) the pattern of eating behaviors and physical activity reported by those engaging exclusively in healthy weight control behaviors, and (iii) the socio-demographic and psychosocial factors associated with the exclusive use of healthy weight control behaviors among adolescents. METHODS: In a large and diverse population-based sample of US adolescents (N = 2793) who participated in EAT 2010 (Eating and Activity in Teens) the current study examined the exclusive use of healthy weight control behaviors, which included healthy eating behaviors (eating more fruits and vegetables, eating less high-fat foods, eating less sweets, drinking less soda, and being aware of portion sizes) and engaging in physical activity for the purpose of weight management. Data were analyzed using multinomial logistic regression in STATA. RESULTS: Overall, 24.0% of girls and 29.2% of boys exclusively used healthy weight control behaviors in the absence of unhealthy weight control behaviors. The exclusive use of healthy weight control behaviors was more prevalent among girls who were not overweight (27.5%) as compared to girls who were overweight (21.0%) or obese (17.5%), controlling for age, socio economic status, and ethnicity/race. In addition, the exclusive use of healthy weight control behaviors was more prevalent among girls and boys who had lower body dissatisfaction, higher self-esteem and lower depressive symptoms. CONCLUSION: Findings indicate that psychosocial health and body satisfaction may be important targets for promoting the exclusive use of healthy weight control behaviors among adolescents. PMID- 26767363 TI - Evidence of shared bovine viral diarrhea infections between red deer and extensively raised cattle in south-central Spain. AB - BACKGROUND: Bovine viral diarrhea virus (BVDV) is a pestivirus that affects cattle production worldwide and that can infect other ungulates such as cervids and even wild boar (Sus scrofa). It is believed that domestic livestock can become infected through contact with wild animals, though it is known that infection can spread among wild animals in the absence of contact with livestock. Little is known about the sharing of BVDV infection between wild and domestic animals in the same habitat, which is important for designing eradication campaigns and preventing outbreaks, especially on hunting estates with high animal densities. RESULTS: We assessed the sharing of BVDV infections among hunted red deer, wild boar and cattle in south-central Spain. Sampled red deer (Cervus elaphus; n = 267) and wild boar (n = 52) were located on 19 hunting estates, and cattle (n = 180) were located on 18 nearby farms. We used ELISA kits for the serological screening, Taqman RT-PCR assay for the virus determination, and subsequent phylogenetic analysis for 17 RT-PCR positive sample amplicons. Fifty-two red deer (19.5%) and 82 cattle (45.6%) samples tested positive by ELISA. A high apparent prevalence (22.47%) was obtained for red deer, while only five cattle farms tested positive by RT-PCR. Conversely, no wild boar tested positive by both ELISA or RT-PCR. Eleven red deer (4.1%) tested positive by both ELISA and RT-PCR; these animals may have been sampled during the last phase of viremia, or they may represent previously exposed individuals infected by a different BVDV strain. The amplicons shared 92.7-100% identity and fell within the BVDV subgroup 1b, although nine of these (from four red deer and five cattle pools) formed a separate branch. This suggests that there might be a common BVDV infecting both cattle and red deer. Higher red deer abundance was significantly associated with greater risk that extensively raised cattle would test positive for BVDV by ELISA. CONCLUSIONS: Our findings suggest that BVDV is circulating between cattle and red deer populations in proximity, but further work is required to determine whether they share the same strain(s). These results suggest the potential of BVDV to serve as a surveillance marker in these shared habitats. High seroprevalence of BVDV in red deer from our study area suggests that although BVDV infection is common, animals usually survive the infection. Further research is needed to verify and investigate the role of red deer as a BVDV reservoir. PMID- 26767364 TI - Progression of lumbar disc herniations over an eight-year period in a group of adult Danes from the general population--a longitudinal MRI study using quantitative measures. AB - BACKGROUND: A lumbar disc herniation (LDH) is a localised displacement of disc material, which may initiate changes in the disc and adjacent structures such as the nerve root and the spinal canal. Knowledge about how morphological changes in the disc relate to changes in other spinal structures might give the clinician a better understanding of the natural history and consequences of lumbar disc herniations. However, few longitudinal studies have investigated this process using reliable measures from magnetic resonance imaging (MRI). The objectives of this study were to examine changes in and associations between the size of lumbar disc herniations, dural sac area and disc height over an eight-year period using MRI at three time-points. METHODS: Individuals from a population-based cohort, the 'Backs on Funen Cohort', had MRIs taken at age 41 years and again at 45 and 49 years. Only disc levels with MRI-confirmed disc herniations at 41 or 45 years were included. Cross-sectional areas (mm(2)) of the LDH, dural sac and disc height were calculated from measurements performed on sagittal T2-weighted images using a previously validated method. Changes over time for the three MRI findings were defined as "unchanged", "increased ", "decreased", or "fluctuating". Only changes beyond 95% limits of agreement of the same measurements were regarded as valid. Associations between the three types of measures were examined cross sectionally and longitudinally. RESULTS: One hundred and forty disc levels, from 106 people (48 women and 58 men), were included. Over eight years, 65% of the herniations remained unchanged, 17.5% decreased, 12.5% increased, and 5% had a fluctuating pattern. Increased herniation size was associated with decreased dural sac area (beta-0.25[-0.52;0.01]) and increased disc height (beta 0.35[0.14;0.56]). Moreover, larger herniation size predicted a statistically significant reduction in both dural sac area (beta-0.35[-0.58;-0.13]) and disc height (beta-0.50[-0.81;-0.20]). CONCLUSIONS: On average, most LDHs do not change over a four- to eight-year period. However, larger herniation size predicts a reduction in both dural sac area and disc height. Further research should be done to determine the correlations between the progression of LDH and resolution of patient symptoms. PMID- 26767365 TI - Guidelines for reporting embedded recruitment trials. AB - BACKGROUND: Recruitment to clinical trials is difficult with many trials failing to recruit to target and within time. Embedding trials of recruitment interventions within host trials may provide a successful way to improve this. There are no guidelines for reporting such embedded methodology trials. As part of the Medical Research Council funded Systematic Techniques for Assisting Recruitment to Trials (MRC START) programme designed to test interventions to improve recruitment to trials, we developed guidelines for reporting embedded trials. METHODS: We followed a three-phase guideline development process: (1) pre meeting literature review to generate items for the reporting guidelines; (2) face-to-face consensus meetings to draft the reporting guidelines; and (3) post meeting feedback review, and pilot testing, followed by finalisation of the reporting guidelines. RESULTS: We developed a reporting checklist based on the Consolidated Standards for Reporting Trials (CONSORT) statement 2010. Embedded trials evaluating recruitment interventions should follow the CONSORT statement 2010 and report all items listed as essential. We used a number of examples to illustrate key issues that arise in embedded trials and how best to report them, including (a) how to deal with description of the host trial; (b) the importance of describing items that may differ in the host and embedded trials (such as the setting and the eligible population); and (c) the importance of identifying clearly the point at which the recruitment interventions were embedded in the host trial. CONCLUSIONS: Implementation of these guidelines will improve the quality of reports of embedded recruitment trials while advancing the science, design and conduct of embedded trials as a whole. PMID- 26767367 TI - Statistical points and pitfalls. PMID- 26767366 TI - Urtica dioica modulates hippocampal insulin signaling and recognition memory deficit in streptozotocin induced diabetic mice. AB - Diabetes mellitus has been associated with functional abnormalities in the hippocampus and performance of cognitive function. Urtica dioica (UD) has been used in the treatment of diabetes. In our previous report we observed that UD extract attenuate diabetes mediated associative and spatial memory dysfunction. The present study aimed to evaluate the effect of UD extract on mouse model of diabetes-induced recognition memory deficit and explore the possible mechanism behind it. Streptozotocin (STZ) (50 mg/kg, i.p. consecutively for 5 days) was used to induce diabetes followed by UD extract (50 mg/kg, oral) or rosiglitazone (ROSI) (5 mg/kg, oral) administration for 8 weeks. STZ induced diabetic mice showed significant decrease in hippocampal insulin signaling and translocation of glucose transporter type 4 (GLUT4) to neuronal membrane resulting in cognitive dysfunction and hypolocomotion. UD treatment effectively improved hippocampal insulin signaling, glucose tolerance and recognition memory performance in diabetic mice, which was comparable to ROSI. Further, diabetes mediated oxidative stress and inflammation was reversed by chronic UD or ROSI administration. UD leaves extract acts via insulin signaling pathway and might prove to be effective for the diabetes mediated central nervous system complications. PMID- 26767368 TI - Endovascular management of hemosuccus pancreaticus, a rare case report of gastrointestinal bleeding. AB - BACKGROUND: Hemorrhage from the pancreatic duct, or hemosuccus pancreaticus (HP), is an unusual cause of intermittent gastrointestinal bleeding. HP is most often diagnosed in patients with chronic pancreatitis, and is usually due to the rupture of an aneurysm in the splenic artery. The traditional treatment for HP is surgery, although most cases can be managed by angioembolization. CASE PRESENTATION: We present a case of HP in a patient with no history or evidence of chronic pancreatitis. Repeated endoscopy revealed fresh bleeding from the papilla of Vater. Angiography revealed an aneurysm of the splenic artery, which was the suspected cause of the intermittent bleeding from the pancreatic duct. Angiography demonstrated extravasation of contrast from the aneurysm. A peripheral Jostent stent-graft was hand-mounted on an angioplasty balloon and then inserted into the aneurysm. Arteriography revealed successful occlusion of the aneurysm with the stent-graft. No recurrent gastrointestinal bleeding was observed during the five years follow-up periods. CONCLUSION: HP should be included in the differential diagnosis of intermittent gastrointestinal bleeding in patients with histories of chronic alcoholism, even when they do not have a history of chronic pancreatitis. We recommend an interventional procedure with a metal stent for the initial treatment of HP. PMID- 26767369 TI - Chronic Arsenic Exposure-Induced Oxidative Stress is Mediated by Decreased Mitochondrial Biogenesis in Rat Liver. AB - The present study was executed to study the effect of chronic arsenic exposure on generation of mitochondrial oxidative stress and biogenesis in rat liver. Chronic sodium arsenite treatment (25 ppm for 12 weeks) decreased mitochondrial complexes activity in rat liver. There was a decrease in mitochondrial superoxide dismutase (MnSOD) activity in arsenic-treated rats that might be responsible for increased protein and lipid oxidation as observed in our study. The messenger RNA (mRNA) expression of mitochondrial and nuclear-encoded subunits of complexes I (ND1 and ND2) and IV (COX I and COX IV) was downregulated in arsenic-treated rats only. The protein and mRNA expression of MnSOD was reduced suggesting increased mitochondrial oxidative damage after arsenic treatment. There was activation of Bax and caspase-3 followed by release of cytochrome c from mitochondria suggesting induction of apoptotic pathway under oxidative stress. The entire phenomenon was associated with decrease in mitochondrial biogenesis as evident by decreased protein and mRNA expression of nuclear respiratory factor 1 (NRF-1), nuclear respiratory factor 2 (NRF-2), peroxisome proliferator activator receptor gamma-coactivator 1alpha (PGC-1alpha), and mitochondrial transcription factor A (Tfam) in arsenic-treated rat liver. The results of the present study indicate that arsenic-induced mitochondrial oxidative stress is associated with decreased mitochondrial biogenesis in rat liver that may present one of the mechanisms for arsenic-induced hepatotoxicity. PMID- 26767370 TI - Gamma-Glutamyl Cysteine Attenuates Tissue Damage and Enhances Tissue Regeneration in a rat Model of Lead-Induced Nephrotoxicity. AB - Lead is a biohazardous metal that is commonly involved in human illness including renal injury. Although it is a non-redox reactive metal, lead-induced renal injury is largely based on oxidative stress. The current work aimed at exploring the possible protective effect of gamma-glutamyl cysteine (gammaGC) against lead induced renal injury. Rats were allocated to normal and gammaGC control groups, lead-treated group, and lead and gammaGC-treated group. gammaGC alleviated lead induced renal injury as evidenced by attenuation of histopathological aberration, amelioration of oxidative injury as demonstrated by significant reduction in lipid and protein oxidation, elevation of total antioxidant capacity, and glutathione level. The activity of antioxidant enzymes superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) was significantly elevated. gammaGC significantly decreased levels of the proinflammatory cytokines tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-6, and IL-1beta and the activity of the apoptotic marker caspase-3. In addition, gammaGC reduced kidney lead content, enhanced weight gain, and improved renal function as demonstrated by reduced serum levels of urea and creatinine. Importantly, gammaGC upregulated proliferating cell nuclear antigen (PCNA) expression, denoting enhanced renal regenerative capacity. Together, our findings highlight evidence for alleviating effects of gammaGC against lead-induced renal injury that is potentially mediated through diminution of oxidative tissue injury, reduction of inflammatory response, attenuation of apoptosis, and enhancement of renal regenerative capacity. PMID- 26767371 TI - Rapid acidolysis of benzyl group as a suitable approach for syntheses of peptides naturally produced by oxidative stress and containing 3-nitrotyrosine. AB - 3-Nitrotyrosine (Nit) belongs to products of oxidative stress and could probably influence conformation of neurodegenerative proteins. Syntheses of peptides require availability of suitable synthon for introduction of Nit residue. Common phenolic protection groups are more acid labile, when they are attached to Nit residue. We have found that Fmoc-Nit(Bn)-OH is a good building block for syntheses of Nit containing peptides by Fmoc/tBu strategy. Interestingly, the peptides containing multiple Nit residues can be available solely by use of Fmoc Nit(Bn)-OH synthon. Bn is removed rapidly with ca 80 % trifluoroacetic acid in dark. The cleavage of Bn from Fmoc-Nit(Bn)-OH proceeds via pseudo-first order mechanism with activation barrier 32 kcal mol(-1) and rate k = 15.3 s(-1) at 20 degrees C. This rate is more than 2,000,000 times faster than that for cleavage of benzyl from Tyr(Bn). PMID- 26767372 TI - Application of the novel bioluminescent ligand-receptor binding assay to relaxin RXFP1 system for interaction studies. AB - Relaxin is a prototype of the relaxin family peptide hormones and plays important biological functions by binding and activating the G protein-coupled receptor RXFP1. To study their interactions, in the present work, we applied the newly developed bioluminescent ligand-receptor binding assay to the relaxin-RXFP1 system. First, a fully active easily labeled relaxin, in which three Lys residues of human relaxin-2 were replaced by Arg, was prepared through overexpression of a single-chain precursor in Pichia pastoris and in vitro enzymatic maturation. Thereafter, the B-chain N-terminus of the easily labeled relaxin was chemically cross-linked with a C-terminal cysteine residue of an engineered NanoLuc through a disulfide linkage. Receptor-binding assays demonstrated that the NanoLuc conjugated relaxin retained high binding affinity with the receptor RXFP1 (K d = 1.11 +/- 0.08 nM, n = 3) and was able to sensitively monitor binding of a variety of ligands with RXFP1. Using the novel bioluminescent binding assay, we demonstrated that three highly conserved B-chain Arg residues of relaxin-3 had distinct contributions to binding of the receptor RXFP1. In summary, our present work provides a novel bioluminescent ligand-receptor binding assay for the relaxin-RXFP1 system to facilitate their interaction studies, such as characterization of relaxin analogues or screening novel agonists or antagonists of RXFP1. PMID- 26767373 TI - Serotonergic modulation of resting state default mode network connectivity in healthy women. AB - The default mode network (DMN) plays a central role in intrinsic thought processes. Altered DMN connectivity has been linked to diminished cerebral serotonin synthesis. Diminished brain serotonin synthesis is further associated with a lack of impulse control and various psychiatric disorders. Here, we investigated the serotonergic modulation of intrinsic functional connectivity (FC) within the DMN in healthy adult females, controlling for the menstrual cycle phase. Eighteen healthy women in the follicular phase (aged 20-31 years) participated in a double-blind controlled cross-over study of serotonin depletion. Acute tryptophan depletion (ATD) and a balanced amino acid load (BAL), used as the control condition, were applied on two separate days of assessment. Neural resting state data using functional magnetic resonance imaging (fMRI) and individual trait impulsivity scores were obtained. ATD compared with BAL significantly reduced FC with the DMN in the precuneus (associated with self referential thinking) and enhanced FC with the DMN in the frontal cortex (associated with cognitive reasoning). Connectivity differences with the DMN between BAL and ATD in the precentral gyrus were significantly correlated with the magnitude of serotonin depletion. Right medial frontal gyrus and left superior frontal gyrus connectivity differences with the DMN were inversely correlated with trait impulsivity. These findings partially deviate from previous findings obtained in males and underline the importance of gender-specific studies and controlling for menstrual cycle to further elucidate the mechanism of ATD-induced changes within intrinsic thought processes. PMID- 26767374 TI - Alterations of amino acid metabolism in osteoarthritis: its implications for nutrition and health. AB - Osteoarthritis (OA) is a common form of arthritis in humans. It has long been regarded as a non-inflammatory disease, but a degree of inflammation is now recognized as being a vital inducer of subpopulation of OA. Besides inflammation, the establishment and development of OA are associated with alterations in metabolism and profiles of amino acids (AA), including glutamate- and arginine family AA as well as their related metabolites (e.g., creatinine, hydroxyproline, gamma-aminobutyrate, dimethylarginines and homoarginine). Functional AA (e.g., glutamine, arginine, glutamate, glycine, proline, and tryptophan) have various benefits (i.e., anti-inflammation and anti-oxidation) in treatment of inflammation-associated diseases, including OA. Thus, these AA have potential as immunomodulatory nutrients for patients with inflammation-induced OA. PMID- 26767375 TI - Expression and identification of the ADF-linker-3-1E gene of Eimeria acervulina of chicken. AB - Coccidiosis is a widely distributed disease with higher mortality and morbidity, which is caused by several species of protozoan parasites belonging to the genus Eimeria and recognized as a serious challenge for the poultry industry. This research was conducted to construct the recombinant plasmid pET32a(+)-ADF-linker 3-1E of Eimeria acervulina (E. acervulina) of the chicken and test the bioactivity of the ADF-linker-3-1E protein. The ADF-linker-3-1E gene of E. acervulina of the chicken was cloned by splicing by overlap extension by the polymerase chain reaction (SOE-PCR) and then inserted into the pET32a(+) to construct the recombinant plasmid pET32a(+)-ADF-linker-3-1E. The recombinant plasmid was transformed into Escherichia coli Rosetta (DE3) competent cells and then induced by IPTG (0.6 mmol/L). The expressed product in the culture medium was identified by the sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). The bioactivity of the ADF-linker-3-1E protein was tested by Western blotting. The result showed that the amplified ADF-linker-3-1E gene was about 1346 bp. The PCR amplification with the recombinant plasmid pET-32a(+)-ADF-linker 3-1E as a template resulted in a special band of 1346 bp. The digested products resulted in two fragments of 1346 bp target fragment and 5.9 kb pET-32a(+)-vector fragment. The results indicated that the ADF-linker3-1E gene was successfully inserted into the pET-32a(+)-vector. The expressed products in the culture medium resulted in a single band of approximately 54.8 kDa by SDS-PAGE. Western blotting analysis indicated that the recombinant protein could be reacted specifically with His-Tag(2A8) Mouse mAb. This study indicated that the ADF-linker-3-1E protein with good bioactivity was successfully obtained, which laid a foundation for the exploitation of the nuclear vaccine by using the ADF-linker-3-1E protein. PMID- 26767376 TI - The relationship of nitric oxide synthesis capacity, oxidative stress, and albumin-to-creatinine ratio in black and white men: the SABPA study. AB - Inadequate substrate availability and increased nitric oxide synthase inhibitor levels attenuate nitric oxide (NO) synthesis, whereas increased vascular oxidative stress may lead to inactivation of NO. We compared markers of NO synthesis capacity and oxidative stress in a bi-ethnic male population. Inter relationships of ambulatory blood pressure and urinary albumin-to-creatinine ratio with NO synthesis capacity and oxidative stress markers were investigated. NO synthesis capacity markers (L-arginine, asymmetric dimethylarginine (ADMA), and symmetric dimethylarginine (SDMA)) and oxidative stress markers (serum peroxides, total glutathione, glutathione peroxidase (GPx), glutathione reductase (GR), superoxide dismutase (SOD), and catalase) were measured. Black men displayed higher blood pressure and albumin-to-creatinine ratio (all p < 0.001), while NO synthesis capacity was more favorable (higher L-arginine and lower ADMA (p <= 0.003)). Antioxidant enzyme activities were similar except for the redox status markers (GR activity and GR/GPx ratio), which were upregulated in black men (p < 0.001). In black men, ADMA was inversely related to GPx activity (R (2) = 0.15; beta = -0.20; p = 0.050) and GPx/SOD ratio (R (2) = 0.24; beta = -0.37; p < 0.001), but none of these markers related to blood pressure or albumin-to creatinine ratio. In white men, albumin-to-creatinine ratio was positively associated with ADMA (R (2) = 0.18; beta = 0.39; p < 0.001) while ADMA was inversely related to GR activity (R (2) = 0.26; beta = -0.29; p = 0.002) and GR/GPx ratio (R (2) = 0.25; beta = -0.28; p = 0.003). Black men with elevated blood pressure and albumin-to-creatinine ratio displayed a favorable NO synthesis capacity. This may be counteracted by increased inactivation of NO, although it was not linked to vascular or renal phenotypes. In white men, reduced NO synthesis capacity may lower NO bio-availability, thereby influencing the albumin to-creatinine ratio. PMID- 26767377 TI - Heterogeneity in resistance training-induced muscle strength and mass responses in men and women of different ages. AB - Physical activity recommendations for public health include typically muscle strengthening activities for a minimum of 2 days a week. The range of inter individual variation in responses to resistance training (RT) aiming to improve health and well-being requires to be investigated. The purpose of this study was to quantify high and low responders for RT-induced changes in muscle size and strength and to examine possible effects of age and sex on these responses. Previously collected data of untrained healthy men and women (age 19 to 78 years, n = 287 with 72 controls) were pooled for the present study. Muscle size and strength changed during RT are 4.8 +/- 6.1 % (range from -11 to 30 %) and 21.1 +/ 11.5 % (range from -8 to 60 %) compared to pre-RT, respectively. Age and sex did not affect to the RT responses. Fourteen percent and 12 % of the subjects were defined as high responders (>1 standard deviation (SD) from the group mean) for the RT-induced changes in muscle size and strength, respectively. When taking into account the results of non-training controls (upper 95 % CI), 29 and 7 % of the subjects were defined as low responders for the RT-induced changes in muscle size and strength, respectively. The muscle size and strength responses varied extensively between the subjects regardless of subject's age and sex. Whether these changes are associated with, e.g., functional capacity and metabolic health improvements due to RT requires further studies. PMID- 26767378 TI - Association between magnetic resonance imaging patterns and baseline disease features in multiple myeloma: analyzing surrogates of tumour mass and biology. AB - OBJECTIVE: To assess associations between bone marrow infiltration patterns and localization in magnetic resonance imaging (MRI) and baseline clinical/prognostic parameters in multiple myeloma (MM). METHODS: We compared baseline MM parameters, MRI patterns and localization of focal lesions to the mineralized bone in 206 newly diagnosed MM patients. RESULTS: A high tumour mass (represented by International Staging System stage III) was significantly associated with severe diffuse infiltration (p = 0.015) and a higher number of focal lesions (p = 0.006). Elevated creatinine (p = 0.003), anaemia (p < 0.001) and high LDH (p = 0.001) correlated with severe diffuse infiltration. A salt and pepper diffuse pattern had a favourable prognosis. A higher degree of destruction of mineralized bone (assessed by X-ray or computed tomography) was associated with an increasing number of focal lesions on MRI (p < 0.001). Adverse cytogenetics (del17p/gain1q21/t(4;14)) were associated with diffuse infiltration (p = 0.008). The presence of intraosseous focal lesions exceeding the mineralized bone had a borderline significant impact on prognosis. CONCLUSIONS: Diffuse bone marrow infiltration on MRI correlates with adverse cytogenetics, lowered haemoglobin values and high tumour burden in newly diagnosed MM whereas an increasing number of focal lesions correlates with a higher degree of bone destruction. Focal lesions exceeding the cortical bone did not adversely affect the prognosis. KEY POINTS: * Diffuse MRI correlates with adverse cytogenetics, lowered haemoglobin and high tumour burden. * Higher numbers of MRI focal lesions correlate with increasing degree of bone destruction. * Focal lesions exceeding the cortical bone borderline significantly influence survival. * Moderate/severe diffuse infiltration and more than 23 focal lesions adversely affect survival. PMID- 26767379 TI - GNBP domain of Anopheles darlingi: are polymorphic inversions and gene variation related to adaptive evolution? AB - Anopheles darlingi is the main malaria vector in humans in South America. In the Amazon basin, it lives along the banks of rivers and lakes, which responds to the annual hydrological cycle (dry season and rainy season). In these breeding sites, the larvae of this mosquito feed on decomposing organic and microorganisms, which can be pathogenic and trigger the activation of innate immune system pathways, such as proteins Gram-negative binding protein (GNBP). Such environmental changes affect the occurrence of polymorphic inversions especially at the heterozygote frequency, which confer adaptative advantage compared to homozygous inversions. We mapped the GNBP probe to the An. darlingi 2Rd inversion by fluorescent in situ hybridization (FISH), which was a good indicator of the GNBP immune response related to the chromosomal polymorphic inversions and adaptative evolution. To better understand the evolutionary relations and time of divergence of the GNBP of An. darlingi, we compared it with nine other mosquito GNBPs. The results of the phylogenetic analysis of the GNBP sequence between the species of mosquitoes demonstrated three clades. Clade I and II included the GNBPB5 sequence, and clade III the sequence of GNBPB1. Most of these sequences of GNBP analyzed were homologous with that of subfamily B, including that of An. gambiae (87 %), therefore suggesting that GNBP of An. darling belongs to subfamily B. This work helps us understand the role of inversion polymorphism in evolution of An. darlingi. PMID- 26767381 TI - [Fatal hyperpyrexia in an adolescent patient with severe burns after a traffic accident]. AB - After a motorcycle accident a 16-year-old patient suffered severe burns to 40.5 % of the total body surface area (TBSA) of which 37 % were deep subdermal burns. After tangential and partly epifascial necrosectomy, Integra(r) was used as a temporary dermis replacement material for the lower extremities, combined with extensive negative pressure wound therapy (NPWT). In the further course of the treatment the patient developed uncontrollable hyperpyrexia with a fatal outcome. Possible influencing factors, such as the dermis replacement material combined with NPWT over large areas as well as the differential diagnoses propofol infusion syndrome, heatstroke and malignant hyperthermia are discussed. PMID- 26767382 TI - [Influencing factors and complications in open treatment of acute anterior glenoid rim fractures]. AB - BACKGROUND: The aim of this comparative study was to evaluate the clinical radiological outcome after open treatment of acute anterior glenoid rim fractures and to analyze the influencing factors and complications. PATIENTS AND METHODS: The study included 26 patients with an average age of 51.6 years (range 27-71 years) at surgery. The mean period of follow-up was 5.1 years (range 2.0-11.1 years). The average extent of glenoid fracture involvement was 25.5 % (range 18 35%) and three fixation techniques were applied: 1) bioresorbable pins (n = 16), 2) small fragment screws (n = 5) and 3) bioresorbable suture anchors (n = 5). RESULTS: The mean score values were 80.3 points for the absolute Constant score, 87.6 points for the normalized Constant score, 88.7 points for the Rowe score, 17.4 points for the Oxford shoulder score, 10.3 points for the simple shoulder test, 13.0 points for the shoulder pain and disability index and 81.5 % for the subjective shoulder value. The fixation technique did not show a significant influence; however, multi-fragment fractures were associated with a significantly inferior absolute (73 vs. 87 points, p = 0.022) and normalized Constant scores (81 vs. 94 points, p = 0.019). Subscapularis insufficiency with internal rotation deficit was found in 10 (39 %) patients and posttraumatic osteoarthritis occurred in 6 (23 %) patients. CONCLUSION: Open fixation yielded good or excellent shoulder function in 20 out of the 26 (77 %) patients and the clinical outcome primarily depended on the underlying type of fracture. Significantly inferior outcomes should be expected in patients with multi-fragment fractures. The main complications were subscapularis insufficiency and posttraumatic osteoarthritis. PMID- 26767383 TI - Acute Cellular Rejection and C4d Positivity in Heart Transplantation : A Manifestation of Asymptomatic Antibody-Mediated Rejection? AB - OBJECTIVES: The role of routine C4d staining in endomyocardial biopsy specimens is uncertain. The implications of a diagnosis of acute cellular rejection (ACR) with a positive C4d with or without any evidence of antibody-mediated rejection (AMR) are unclear. This study sought to evaluate a distinct phenotype of ACR+/C4d+ in AMR- patients. METHODS: Data on C4d, ACR, and AMR were collected. Donor-specific antibody (DSA), panel-reactive antibody (PRA), flow crossmatch, and data on ACR and AMR episodes were also reviewed. RESULTS: Thirty-five patients were followed. Group I with C4d+ biopsy specimens was compared with group II with C4d- biopsy specimens. ACR greater than 1R was higher in group I compared with group II (50% vs 7.4%; P = .01). Clinical suspicion of AMR, positive retrospective crossmatches, and detection of de novo DSA were also higher in group I. CONCLUSIONS: Our result indicate that C4d and ACR positivity in posttransplant patients may be a harbinger of a subclinical form of asymptomatic AMR. PMID- 26767380 TI - CT angiography and CT perfusion improve prediction of infarct volume in patients with anterior circulation stroke. AB - INTRODUCTION: We investigated whether baseline CT angiography (CTA) and CT perfusion (CTP) in acute ischemic stroke could improve prediction of infarct presence and infarct volume on follow-up imaging. METHODS: We analyzed 906 patients with suspected anterior circulation stroke from the prospective multicenter Dutch acute stroke study (DUST). All patients underwent baseline non contrast CT, CTA, and CTP and follow-up non-contrast CT/MRI after 3 days. Multivariable regression models were developed including patient characteristics and non-contrast CT, and subsequently, CTA and CTP measures were added. The increase in area under the curve (AUC) and R (2) was assessed to determine the additional value of CTA and CTP. RESULTS: At follow-up, 612 patients (67.5%) had a detectable infarct on CT/MRI; median infarct volume was 14.8 mL (interquartile range (IQR) 2.8-69.6). Regarding infarct presence, the AUC of 0.82 (95% confidence interval (CI) 0.79-0.85) for patient characteristics and non-contrast CT was improved with addition of CTA measures (AUC 0.85 (95% CI 0.82-0.87); p < 0.001) and was even higher after addition of CTP measures (AUC 0.89 (95% CI 0.87 0.91); p < 0.001) and combined CTA/CTP measures (AUC 0.89 (95% CI 0.87-0.91); p < 0.001). For infarct volume, adding combined CTA/CTP measures (R (2) = 0.58) was superior to patient characteristics and non-contrast CT alone (R (2) = 0.44) and to addition of CTA alone (R (2) = 0.55) or CTP alone (R (2) = 0.54; all p < 0.001). CONCLUSION: In the acute stage, CTA and CTP have additional value over patient characteristics and non-contrast CT for predicting infarct presence and infarct volume on follow-up imaging. These findings could be applied for patient selection in future trials on ischemic stroke treatment. PMID- 26767386 TI - Case Report: Escherichia fergusonnii - Pathogen in Urinary Tract Infection. AB - Urinary tract infections are one of the leading cause of morbidity in admitted patients. Most commonly caused by Escherichia coli, but there are some variants which are commonly reported in urinary tract infection. This study was about to speciate such isolate like E.fergusonnii and find out its antibiogram. PMID- 26767384 TI - Nerve growth factor improves visual loss in childhood optic gliomas: a randomized, double-blind, phase II clinical trial. AB - Paediatric optic pathway gliomas are low-grade brain tumours characterized by slow progression and invalidating visual loss. Presently there is no strategy to prevent visual loss in this kind of tumour. This study evaluated the effects of nerve growth factor administration in protecting visual function in patients with optic pathway glioma-related visual impairment. A prospective randomized double blind phase II clinical trial was conducted in 18 optic pathway glioma patients, aged from 2 to 23 years, with stable disease and severe visual loss. Ten patients were randomly assigned to receive a single 10-day course of 0.5 mg murine nerve growth factor as eye drops, while eight patients received placebo. All patients were evaluated before and after treatment, testing visual acuity, visual field, visual-evoked potentials, optic coherence tomography, electroretinographic photopic negative response, and magnetic resonance imaging. Post-treatment evaluations were repeated at 15, 30, 90, and 180 days Brain magnetic resonance imaging was performed at baseline and at 180 days. Treatment with nerve growth factor led to statistically significant improvements in objective electrophysiological parameters (electroretinographic photopic negative response amplitude at 180 days and visual-evoked potentials at 30 days), which were not observed in placebo-treated patients. Furthermore, in patients in whom visual fields could still be measured, visual field worsening was only observed in placebo-treated cases, while three of four nerve growth factor-treated subjects showed significant visual field enlargement. This corresponded to improved visually guided behaviour, as reported by the patients and/or the caregivers. There was no evidence of side effects related to nerve growth factor treatment. Nerve growth factor eye drop administration appears a safe, easy and effective strategy for the treatment of visual loss associated with optic pathway gliomas. PMID- 26767385 TI - Detection of Coxiella burnetii in acute undifferentiated febrile illnesses (AUFIs) in Iran. AB - There are limited data on the aetiology of acute undifferentiated febrile illnesses (AUFIs) in Iran. Moreover, Coxiella burnetii has not previously been detected in clinical samples in this country. Previous studies have highlighted the importance of considering C. burnetii as a cause of AUFI. In this retrospective study, in 92 cases of AUFI where Q fever was suspected, C. burnetii DNA was detected in seven samples (7.36%). This is the first molecular confirmation of C. burnetii from clinical samples from Iran. PMID- 26767387 TI - World invests too little and is underprepared for disease outbreaks, report warns. PMID- 26767388 TI - Imported cholera with acute renal failure after a short business-trip to the Philippines, Germany, October 2015. AB - A German businessman developed acute watery diarrhoea after a three-day trip to the Philippines. He was admitted with severe hypotension and acute renal failure, but recovered with rapid rehydration. Vibrio cholerae O1 serotype Ogawa was isolated. Physicians need to be aware of endemic cholera in Asia including the Philippines and consider this in their pre-travel advice. PMID- 26767389 TI - Performance of a cylindrical diode array for use in a 1.5 T MR-linac. AB - At the UMC Utrecht, a linear accelerator with integrated magnetic resonance imaging (MRI) has been developed, the MR-linac. Patient-specific quality assurance (QA) of treatment plans for MRI-based image guided radiotherapy requires QA equipment compatible with this 1.5 T magnetic field. The purpose of this study was to examine the performance characteristics of the ArcCHECK-MR in a transverse 1.5 T magnetic field. To this end, the short-term reproducibility, dose linearity, dose rate dependence, field size dependence, dose per pulse dependence and inter-diode dose response variation of the ArcCHECK-MR diode array were evaluated on a conventional linac and on the MR-linac. The ArcCHECK-MR diode array performed well for all tests on both linacs, no significant differences in performance characteristics were observed. Differences in the maximum dose deviations between both linacs were less than 1.5%. Therefore, we conclude that the ArcCHECK-MR can be used in a transverse 1.5 T magnetic field. PMID- 26767390 TI - Is treatment-resistant depression a useful concept? AB - The term treatment-resistant depression (TRD) is widely used in the context of managing mood disorders, but defining it, both conceptually and in practice, has proven difficult. Most definitions have focused on pharmacotherapy but even these have struggled to capture the complexity of varying response and duration of treatment. Both clinically and for research studies a meaningful definition of TRD is necessary because it may lead to the development of 'therapy-defined depressive subtypes' and the discovery of novel antidepressants. This brief perspective critically reviews the concept of treatment resistance and how it can be more clearly defined so as to achieve a better understanding of depression and facilitate clinical treatment trials. PMID- 26767391 TI - A negative randomised sham-controlled trial of ventral capsule/ventral striatum stimulation in treatment-resistant depression: an unsuccessful trial or treatment? PMID- 26767392 TI - Vitamin D in schizophrenia: a clinical review. AB - Vitamin D (vitD) is known for its essential role in calcium homeostasis and bone health. VitD is made endogenously in the skin from UVB radiation from sunlight. VitD is now considered as a potent neurosteroid hormone, critical to brain development and normal brain function, and is known for its anti-inflammatory property affecting various aspects of human health. VitD ligand-receptor, a receptor that mediates much of vitD's biological actions, has been found throughout the body including the central nervous system. VitD deficiency is common in patients with severe mental illness such as schizophrenia. Schizophrenia is a debilitating chronic mental illness characterised by positive symptoms, such as hallucinations and delusions, and negative symptoms including flat affect and lack of motivation. Several environmental risk factors for schizophrenia, such as season of birth, latitude and migration, have been linked to vitD deficiency. Recent studies have suggested a potential role of vitD in the development of schizophrenia. For example, neonatal vitD status is associated with the risk of developing schizophrenia in later life obesity, insulin resistance, diabetes, hyperlipidaemia and cardiovascular disease, which are commonly seen in patients with schizophrenia. It has been well established that vitD deficiency is related to these metabolic problems. The biological mechanism is most likely related to vitD's action on the regulation of inflammatory and immunological processes, consequently affecting the manifestation of clinical symptoms and treatment response of schizophrenia. Potential benefits of vitD supplementation to improve schizophrenia symptoms as well as physical health in patients with schizophrenia should be further explored in future studies. PMID- 26767393 TI - Synthesis, characterization, and biocompatible properties of alanine-grafted chitosan copolymers. AB - In order to overcome major problems regarding the lack of affinity to solvents and limited reactivity of the free amines of chitosan, introduction of appropriate spacer arms having terminal amine function is considered of interest. L-Alanine-N-carboxyanhydride was grafted onto chitosan via anionic ring-opening polymerization. The chemical and structural characterizations of L-alanine grafted chitosan (Ala-g-Cts) were confirmed through Fourier transform infrared spectroscopy and proton nuclear magnetic resonance spectroscopy ((1)H NMR). In addition, the viscoelastic properties of Ala-g-Cts were examined by means of a rotational viscometer, and thermal analysis was carried out with a thermogravimetric analyzer and differential scanning calorimetry. Morphological changes in the chitosan L-alanine moiety were determined by x-ray diffraction. To determine the feasibility of using these films as biomedical materials, we investigated the effects of their L-alanine content on physical and mechanical properties. The biodegradation results of crosslinked Ala-g-Cts films were evaluated in phosphate-buffered solution containing lysozyme at 37C. Proliferation of MC3T3-E1 cells on crosslinked Ala-g-Cts films was also investigated with use of the CCK-8 assay. PMID- 26767394 TI - Towards functional 3D-stacked electrospun composite scaffolds of PHBV, silk fibroin and nanohydroxyapatite: Mechanical properties and surface osteogenic differentiation. AB - Bone tissue engineering scaffolds have two challenging functional tasks to fulfil: to encourage cell proliferation, differentiation and matrix synthesis and to provide suitable mechanical stability upon implantation. Composites of biopolymers and bioceramics combine the advantages of both types of materials, resulting in better processability and enhanced mechanical and biological properties through matrix reinforcement. In the present study, novel thick bone composite scaffolds were successfully fabricated using electrospun flat sheets of polyhydroxybutyrate-polyhydroxyvalerate/nanohydroxyapatite/silk fibroin essence (2% nanohydroxyapatite - 2% silk fibroin essence and 5% nanohydroxyapatite - 5% silk fibroin essence, respectively). Their potential asin vitrobone regeneration scaffolds was evaluated using mouse calvarian osteoblast cells (MC3T3-E1), in terms of morphology (scanning electron microscope), cell attachment, cell proliferation, Col type I, osteopontin and bone alkaline phosphatase activity (Quantitative Real Time Polymerase Chain Reaction [qRT-PCR], enzyme-linked immunosorbent assay, immunocytochemistry). Electrospun polyhydroxybutyrate polyhydroxyvalerate scaffolds were used as reference constructs. The results showed that the compressive and tensile mechanical properties of the scaffolds are dependent on the change in their composition, and the treatment these underwent. Furthermore, methanol-treated and autoclaved (MA) P2 (2% nanohydroxyapatite, 2% silk fibroin essence) samples appeared to exhibit more promising tensile properties. Additionally, the compressive tests results confirmed that the methanol pre-treatment and the autoclaving step lead to an increase in the P2 secant modulus when compared to the non-methanol-treated ones, P2 and P5 (5% nanohydroxyapatite, 5% silk fibroin essence), respectively.Both formulations of polyhydroxybutyrate-polyhydroxyvalerate/nanohydroxyapatite/silk fibroin essence composite promoted greater cell adhesion and proliferation than the corresponding polyhydroxybutyrate-polyhydroxyvalerate control ones. Cells seeded on the composite fibrous scaffolds were extensively expanded and elongated on the fibre surface after one day in culture, whereas those seeded on the polyhydroxybutyrate-polyhydroxyvalerate scaffolds were not completely elongated. In addition, cells grown on P2 and P5 scaffolds had higher alkaline phosphatase activity when compared to those containing no nanohydroxyapatite/silk fibroin essence. PMID- 26767395 TI - Hydrophilic surface modification of acrylate-based biomaterials. AB - Acrylic polymers have proved to be excellent with regard to cell adhesion, colonization and survival, in vitro and in vivo. Highly ordered and regular pore structures thereof can be produced with the help of polyamide templates, which are removed with nitric acid. This treatment converts a fraction of the ethyl acrylate side groups into acrylic acid, turning poly(ethyl acrylate) scaffolds into a more hydrophilic and pH-sensitive substrate, while its good biological performance remains intact. To quantify the extent of such a modification, and be able to characterize the degree of hydrophilicity of poly(ethyl acrylate), poly(ethyl acrylate) was treated with acid for different times (four, nine and 17 days), and compared with poly(acrylic acid) and a 90/10%wt. EA/AAc copolymer (P(EA-co-AAc)). The biological performance was also assessed for samples immersed in acid up to four days and the copolymer, and it was found that the incorporation of acidic units on the material surface was not prejudicial for cells. This surface modification of 3D porous hydrophobic scaffolds makes easier the wetting with culture medium and aqueous solutions in general, and thus represents an advantage in the manageability of the scaffolds. PMID- 26767396 TI - Preparation and bioactive properties of nano bioactive glass and segmented polyurethane composites. AB - Composites of glutamine-based segmented polyurethanes with 5 to 25 wt.% bioactive glass nanoparticles were prepared, characterized, and their mineralization potential was evaluated in simulated body fluid. Biocompatibility with dental pulp stem cells was assessed by MTS to an extended range of compositions (1 to 25 wt.% of bioactive glass nanoparticles). Physicochemical characterization showed that composites retained many of the matrix properties, i.e. those corresponding to semicrystalline elastomeric polymers as they exhibited a glass transition temperature (Tg) between -41 and -36C and a melting temperature (Tm) between 46 and 49C in agreement with X-ray reflections at 23.6 degrees and 21.3 degrees . However, with bioactive glass nanoparticles addition, tensile strength and strain were reduced from 22.2 to 12.2 MPa and 667.2 to 457.8%, respectively with 25 wt.% of bioactive glass nanoparticles. Although Fourier transform infrared spectroscopy did not show evidence of mineralization after conditioning of these composites in simulated body fluid, X-ray diffraction, scanning electron microscopy, and energy dispersive X-ray microanalysis showed the formation of an apatite layer on the surface which increased with higher bioactive glass concentrations and longer conditioning time. Dental pulp stem cells proliferation at day 5 was improved in bioactive glass nanoparticles composites containing lower amounts of the filler (1-2.5 wt.%) but it was compromised at day 9 in composites containing high contents of nBG (5, 15, 25 wt.%). However, Runx2 gene expression was particularly upregulated for the dental pulp stem cells cultured with composites loaded with 15 and 25 wt.% of bioactive glass nanoparticles. In conclusion, low content bioactive glass nanoparticles and segmented polyurethanes composites deserve further investigation for applications such as guided bone regeneration membranes, where osteoconductivity is desirable but not a demanding mechanical performance. PMID- 26767397 TI - Trends in cancer of the liver, gall bladder, bile duct, and pancreas in elderly in Denmark, 1980-2012. AB - BACKGROUND: Cancers of the liver, bile duct, gall bladder and pancreas (HPB-c) are a heterogeneous group, united almost exclusively by a poor prognosis. As the number of elderly in the Western world continues to rise and HPB-c are associated with age, we wanted to examine changes in incidence, mortality, prevalence and relative survival for these cancers. MATERIALS AND METHODS: HBP-c was defined as ICD-10 codes C22 (liver), C23-24 (gall bladder), and C25 (pancreas). Data derived from the NORDCAN database with comparable data on cancer incidence, mortality, prevalence and relative survival in the Nordic countries, where the Danish data were delivered from the Danish Cancer Registry and the Danish Cause of Death Registry with follow-up for death or emigration until the end of 2013. RESULTS: The incidence and mortality rates of cancer of the liver and pancreas increased over time while the rates of cancer of the gall bladder and bile duct decreased. All HBP-c were more frequent in persons over the age of 70 than in younger persons. The relative one- and five-year survival rose in most HPB-c, but mainly occurring in the younger population of 0-69 years with only small to no gains in the 80 + group. CONCLUSION: As the number of persons aged 80 years or more will increase dramatically in the following years, and our results show a gap in relative survival, it is important to continue to study this population in order to improve management and outcome. PMID- 26767402 TI - Use of the Right Lobe Graft With Double Hepatic Arteries in Living-Donor Liver Transplant. AB - OBJECTIVES: We aimed to examine management of double hepatic artery reconstruction in patients under going living-donor liver transplant. MATERIALS AND METHODS: Between January 2002 and June 2014, one thousand thirty-six living donor liver transplants were performed at the Liver Transplant Institute of Malatya Inonu University. Living liver grafts with a single hepatic artery were used in 983 living-donor liver transplants, while grafts with double hepatic artery branches were used in 53 living-donor liver transplants. All of the liver grafts with double hepatic artery branches were right lobe grafts. Hepatic artery anastomosis technique and the other medical data of recipients who used grafts with double hepatic arteries were analyzed retrospectively. RESULTS: A double hepatic artery anastomosis was created in 43 recipients, while a single anastomosis was created in the remaining 10 because of ligation of the nondominant hepatic artery branch. In 40 recipients, double hepatic artery branches in the graft were anastomosed with the recipient's right and left hepatic artery. In the remaining 3 recipients, double hepatic artery branches in the graft were anastomosed with the recipient's right hepatic artery and large segment 4 hepatic arteries. Postoperative complications related with hepatic artery anas-tomoses developed in 3 recipients: hepatic artery thrombosis (n = 1), hepatic artery aneurysm (n = 1), and hepatic artery stenosis (n = 1). A recipient with hepatic artery aneurysm immediately underwent a retransplant. A recipient with a hepatic artery thrombosis relapsed and required retransplant, which was treated with thrombectomy on postoperative day 10. A recipient with hepatic artery stenosis was followed conservatively. In our series, the incidence of complications related with double hepatic artery anastomosis was found to be 6.9%. CONCLUSIONS: According to our experiences, a double hepatic artery anastomosis does not increase the risk of hepatic artery thrombosis and can be performed safely by surgeons who are experienced with hepatic vascular reconstructions in a living-donor liver transplant recipient. PMID- 26767401 TI - The real-life value of ST2 monitoring during heart failure decompensation: impact on long-term readmission and mortality. AB - CONTEXT: Prognostic value of ST2 levels and dynamics has not been investigated in acute heart failure (AHF) using prospective real-life measurements. OBJECTIVE: The objective of this study is to investigate the prognostic value of ST2 in AHF. METHODS: ST2 levels were determined at admission (n = 182) and discharge (n = 85). Primary endpoint was the composite of all-cause death and HF rehospitalisation at one year. RESULTS: Discharge ST2 (HR 2.42 [95% CI 1.46-4], p = 0.001) and DeltaST2 (HR 2.32 [95% CI 1.21-4.57], p = 0.01) but not admission ST2, remained independently prognostic for the primary endpoint after comprehensive multivariable adjustment. ST2 significantly improved prognosis stratification on top of clinical variables and NTproBNP. CONCLUSIONS: Routine clinical use of discharge ST2 and ST2 dynamics provide independent prognostic information. PMID- 26767403 TI - Identification of a Novel Function of Adipocyte Plasma Membrane-Associated Protein (APMAP) in Gestational Diabetes Mellitus by Proteomic Analysis of Omental Adipose Tissue. AB - Gestational diabetes mellitus (GDM) is considered as an early stage of type 2 diabetes mellitus. In this study, we compared demographic and clinical data between six GDM subjects and six normal glucose tolerance (NGT; healthy controls) subjects and found that homeostasis model of assessment for insulin resistance index (HOMA-IR) increased in GDM. Many previous studies demonstrated that omental adipose tissue dysfunction could induce insulin resistance. Thus, to investigate the cause of insulin resistance in GDM, we used label-free proteomics to identify differentially expressed proteins in omental adipose tissues from GDM and NGT subjects (data are available via ProteomeXchange with identifier PXD003095). A total of 3528 proteins were identified, including 66 significantly changed proteins. Adipocyte plasma membrane-associated protein (APMAP, a.k.a. C20orf3), one of the differentially expressed proteins, was down-regulated in GDM omental adipose tissues. Furthermore, mature 3T3-L1 adipocytes were used to simulate omental adipocytes. The inhibition of APMAP expression by RNAi impaired insulin signaling and activated NFkappaB signaling in these adipocytes. Our study revealed that the down-regulation of APMAP in omental adipose tissue may play an important role in insulin resistance in the pathophysiology of GDM. PMID- 26767404 TI - Adult and adolescent exposure to tobacco and alcohol content in contemporary YouTube music videos in Great Britain: a population estimate. AB - BACKGROUND: We estimate exposure of British adults and adolescents to tobacco and alcohol content from a sample of popular YouTube music videos. METHODS: British viewing figures were generated from 2 representative online national surveys of adult and adolescent viewing of the 32 most popular videos containing content. 2068 adolescents aged 11-18 years (1010 boys, 1058 girls), and 2232 adults aged 19+years (1052 male, 1180 female) completed the surveys. We used the number of 10 s intervals in the 32 most popular videos containing content to estimate the number of impressions. We extrapolated gross and per capita impressions for the British population from census data and estimated numbers of adults and adolescents who had ever watched the sampled videos. RESULTS: From video release to the point of survey, the videos delivered an estimated 1006 million gross impressions of alcohol (95% CI 748 to 1264 million), and 203 million of tobacco (95% CI 151 to 255 million), to the British population. Per capita exposure was around 5 times higher for alcohol than for tobacco, and nearly 4 times higher in adolescents, who were exposed to an average of 52.1 (95% CI 43.4 to 60.9) and 10.5 (95% CI 8.8 to 12.3) alcohol and tobacco impressions, respectively, than in adults (14.1 (95% CI 10.2 to 18.1) and 2.9 (95% CI 2.1 to 3.6)). Exposure rates were higher in girls than in boys. CONCLUSIONS: YouTube music videos deliver millions of gross impressions of alcohol and tobacco content. Adolescents are exposed much more than adults. Music videos are a major global medium of exposure to such content. PMID- 26767405 TI - Systematic review of risk prediction models for falls after stroke. AB - BACKGROUND: Falls are a significant cause of morbidity after stroke. The aim of this review was to identify, critically appraise and summarise risk prediction models for the occurrence of falling after stroke. METHODS: A systematic literature search was conducted in December 2014 and repeated in June 2015. Studies that used multivariable analysis to build risk prediction models for falls early after stroke were included. 2 reviewers independently assessed methodological quality. Data relating to model calibration, discrimination (C statistic) and clinical utility (sensitivity and specificity) were extracted. A narrative review of models was conducted. PROSPERO reference: CRD42014015612. RESULTS: The 12 included articles presented 18 risk prediction models. 7 studies predicted falls among inpatients only and 5 recorded falls in the community. Methodological quality was variable. A C-statistic was reported for 7 models and values ranged from 0.62 to 0.87. Models for use in the inpatient setting most frequently included measures of hemi-inattention, while those predicting community events included falls (or near-falls) history and balance measures most commonly. Only 2 studies reported any form of validation, and none presented a validated model with acceptable performance. CONCLUSIONS: A number of falls-risk prediction models have been developed for use in the acute and subacute stages of stroke. Future research should focus on validating and improving existing models, with reference to the Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis (TRIPOD) guidelines to ensure quality reporting and expedite clinical implementation. PMID- 26767406 TI - Tobacco and epidemiology in Korea: old tricks, new answers? PMID- 26767407 TI - Structural and functional aspects of social support as predictors of mental and physical health trajectories: Whitehall II cohort study. AB - BACKGROUND: Social support is associated with better health. However, only a limited number of studies have examined the association of social support with health from the adult life course perspective and whether this association is bidirectional. METHODS: Participants (n=6797; 30% women; age range from 40 to 77 years) who were followed from 1989 (phase 2) to 2006 (phase 8) were selected from the ongoing Whitehall II Study. Structural and functional social support was measured at follow-up phases 2, 5 and 7. Mental and physical health was measured at five consecutive follow-up phases (3-8). RESULTS: Social support predicted better mental health, and certain functional aspects of social support, such as higher practical support and higher levels of negative aspects in social relationships, predicted poorer physical health. The association between negative aspects of close relationships and physical health was found to strengthen over the adult life course. In women, the association between marital status and mental health weakened until the age of approximately 60 years. Better mental and physical health was associated with higher future social support. CONCLUSIONS: The strength of the association between social support and health may vary over the adult life course. The association with health seems to be bidirectional. PMID- 26767409 TI - School education, physical performance in late midlife and allostatic load: a retrospective cohort study. AB - BACKGROUND: The mechanisms underlying the social gradient in physical functioning are not fully understood. Cumulative physiological stress may be a pathway. The present study aimed to investigate the association between highest attained school education and physical performance in late midlife, and to determine to what extent cumulative physiological stress mediated these associations. METHODS: The study is based on data from the Copenhagen Aging and Midlife Biobank (CAMB; n=5467 participants, aged 48-62 years, 31.5% women). School education was measured as highest examination passed in primary or secondary school (3 categories). Cumulative stress was operationalised as allostatic load (AL), and measured as the number of biological parameters (out of 14) in which participants scored in the poorest quartile. Physical performance included dynamic muscle performance (chair rise ability, postural balance, sagittal flexibility) and muscle strength (jump height, trunk extension and flexion, and handgrip strength). RESULTS: Among women, higher school education was associated with better performance in all physical performance tests. Among men, higher school education was associated with better performance only in chair rise and jump height. AL partially mediated the association between school education and physical performance, and accounted only for 2-30% of the total effect among women. Similar results were observed among men for chair rise and jump height. CONCLUSIONS: These results might indicate that AL plays a minor role in the association between school education and late midlife dynamic muscle performance in both men and women, and in muscle strength among women. PMID- 26767408 TI - Dyspnoea as a predictor of cause-specific heart/lung disease mortality in Bangladesh: a prospective cohort study. AB - BACKGROUND: The spectrum of mortality outcomes by cause in populations with/without dyspnoea has not been determined. The study aimed to evaluate whether dyspnoea, a symptom, predicts cause-specific mortality differences between groups. The hypothesis was that diseases that result in chronic dyspnoea, those originating from the heart and lungs, would preferentially result in heart and lung disease mortality in those with baseline dyspnoea (relative to no dyspnoea) when followed over time. METHODS: A population-based sample of 11 533 Bangladeshis was recruited and followed for 11-12 years and cause-specific mortality evaluated in those with and without baseline dyspnoea. Dyspnoea was ascertained by trained physicians. The cause of death was determined by verbal autopsy. Kaplan-Meier survival curves, the Fine-Gray competing risk hazards model and logistic regression models were used to determine group differences in cause specific mortality. RESULTS: Compared to those not reporting dyspnoea at baseline, the adjusted HRs were 6.4 (3.8 to 10.7), 9.3 (3.9 to 22.3), 1.8 (1.2 to 2.8), 2.2 (1.0 to 5.1) and 2.8 (1.3 to 6.2) for greater risk of dying from chronic obstructive pulmonary disease (COPD), asthma, heart disease, tuberculosis and lung cancer, respectively. In contrast, there was a similar risk of dying from stroke, cancer (excluding lung), liver disease, accidents and other (miscellaneous causes) between the dyspnoeic and non-dyspnoeic groups. In addition, the HR was 2.1 (1.7 to 2.5) for greater all-cause mortality in those with baseline dyspnoea versus no dyspnoea. CONCLUSIONS: Dyspnoea, ascertained by a single question with binary response, predicts heart and lung disease mortality. Individuals reporting dyspnoea were twofold to ninefold more likely to die of diseases that involve the heart and/or lungs relative to the non-dyspnoeic individuals. Therefore, in those with chronic dyspnoea, workup to look for the five common dyspnoeic diseases resulting in increased mortality (COPD, asthma, heart disease, tuberculosis and lung cancer), all treatable, should reduce mortality and improve the public health. PMID- 26767410 TI - Are fetal growth impairment and preterm birth causally related to child attention problems and ADHD? Evidence from a comparison between high-income and middle income cohorts. AB - BACKGROUND: Cross-cohort comparison is an established method for improving causal inference. This study compared 2 cohorts, 1 from a high-income country and another from a middle-income country, to (1) establish whether birth exposures may play a causal role in the development of childhood attention problems; and (2) identify whether confounding structures play a different role in parent reported attention difficulties compared with attention deficit hyperactivity disorder (ADHD) diagnoses. METHODS: Birth exposures included low birth weight (LBW), small-for-gestational age (SGA), small head circumference (HC) and preterm birth (PTB)). Outcomes of interest were attention difficulties (Strengths and Difficulties Questionnaire, SDQ) and ADHD (Development and Well-Being Assessment, DAWBA). Associations between exposures and outcomes were compared between 7-year old children from the Avon Longitudinal Study of Parents and Children (ALSPAC) in the UK (N=6849) and the 2004 Pelotas cohort in Brazil (N=3509). RESULTS: For attention difficulties (SDQ), the pattern of association with birth exposures was similar between cohorts: following adjustment, attention difficulties were associated with SGA (OR=1.59, 95% CI 1.20 to 2.19) and small HC (OR=1.64, 95% CI 1.11 to 2.41) in ALSPAC and SGA (OR=1.35, 95% CI 1.04 to 1.75) in Pelotas. For ADHD, however, the pattern of association following adjustment differed markedly between cohorts. In ALSPAC, ADHD was associated with LBW (OR=2.29, 95% CI 1.09 to 4.80) and PTB (OR=2.33, 95% CI 1.23 to 4.42). In the Pelotas cohort, however, ADHD was associated with SGA (OR=1.69, 95% CI 1.02 to 2.82). CONCLUSIONS: The findings suggest that fetal growth impairment may play a causal role in the development of attention difficulties in childhood, as similar associations were identified across both cohorts. Confounding structures, however, appear to play a greater role in determining whether a child meets the full diagnostic criteria for ADHD. PMID- 26767411 TI - Reducing the risk of fetal distress with sildenafil study (RIDSTRESS): a double blind randomised control trial. AB - BACKGROUND: Labour is perhaps the most hazardous time in pregnancy. As many as 20 % of cerebral palsy cases in term infants result from intrapartum events and up to 63 % of babies who develop intrapartum compromise have no prior risk factors. Sildenafil citrate (SC), a phosphodiesterase 5 inhibitor, improves uterine blood supply through vasodilatation and potentially could improve placental perfusion and hence reduce the risk of intrapartum fetal hypoxia. The aim of this study is to evaluate the efficacy of SC to reduce the risk of intrapartum fetal compromise and the need for emergency operative delivery. METHODS/DESIGN: This is a single centre, double-blind, randomised, phase II clinical trial of SC or placebo given during labour to women (18-50 years of age) with a single, appropriately grown, non-anomalous baby at term (37-42 weeks gestation). Those with cardiovascular, renal, hepatic, ocular or hypertensive disease or contraindication to SC will be excluded. Participants will be randomised to either SC 50 mg or placebo capsules eight hourly (SC maximum 150 mg) to commence when admitted to birth suite for management of labour. Within 3 h of the first dose, a repeat ultrasound scan will be performed to measure any changes in uteroplacental and fetal Doppler indices. Labour will continue otherwise in accordance with hospital clinical guidelines. The primary outcome is emergency caesarean section for intrapartum fetal compromise. Secondary outcomes include the effect of SC on fetal and uteroplacental blood flow, meconium liquor, fetal heart rate abnormalities and neonatal outcomes (admission to neonatal intensive care, Apgar <7 at 5 min, cord pH <7.1 or lactate >4.0 mmol/L, neonatal encephalopathy, death). CONCLUSION: This is the first reported study evaluating the efficacy of SC on reducing the risk intrapartum fetal compromise. TRIAL REGISTRATION: Australian New Zealand Clinical Trial Registry ACTRN12615000319572. PMID- 26767412 TI - Whiplash(-like) injury diagnoses and co-morbidities--both before and after the injury: A national registry-based study. AB - BACKGROUND: Previous studies suggest that a greater proportion of neck injury patients, whose injuries were sustained through whiplash accidents, become chronic due to a component of sickness-focusing. However, it is also possible that some of those with neck injuries were already more frail prior to the injury, resulting in more consequences from a certain intensity of injury. The objective of this study was to compare co-morbidity and mortality in people with a registered neck injury diagnosis, evaluated prior to and after the neck injury, to people without a registered neck injury evaluated at the same time-points. METHODS: From a hospital patient registry over a 12-year period, we identified those with the diagnosis 'cervical-column distortion' and matched four controls for each of them on sex, age, marital status and county of residence. For calculations of co-morbidity, those with an injury at year 1, who thus had no prior data, and for those at year 12 who did not have post data, were not included. The same applied to their individually matched controls. Health data for up to 3 years prior to and up to 3 years after the year of injury were recorded. RESULTS: We identified 94,224 cases and 373,341 controls. Those with registered neck injuries had 1.2-2.0 times more co-morbidities than controls after the injury, but had already had about the same (1.3-1.8 more co morbidities) number of co-morbidities prior to the injury. Mortality up to 12 years was approximately the same in the two groups. CONCLUSIONS: Those people having a registered neck injury had more co-morbidity diagnoses both before and after the injury than those without a registered neck injury. This suggests that the co-morbidities observed after the injury may be partly related to already existing general high health care-seeking and/or a low health status, rather than being entirely the consequence of the injury. PMID- 26767413 TI - Simple steps to develop trial follow-up procedures. AB - BACKGROUND: Loss to follow-up in randomised controlled trials reduces statistical power and increases the potential for bias. Almost half of all trials fail to achieve their follow-up target. Statistical methods have been described for handling losses to follow-up and systematic reviews have identified interventions that increase follow-up. However, there is little guidance on how to develop practical follow-up procedures. This paper describes the development of follow-up procedures in a pilot randomised controlled trial of a sexual health intervention that required participants to provide and return questionnaires and chlamydia test samples in the post. We identified effective methods to increase follow-up from systematic reviews. We developed and tested prototype procedures to identify barriers to follow-up completion. We asked trial participants about their views on our follow-up procedures and revised the methods accordingly. RESULTS: We identified 17 strategies to increase follow-up and employed all but five. We found that some postal test kits do not fit through letterboxes and that that the test instructions were complicated. After identifying the appropriate sized test kit and simplifying the instructions, we obtained user opinions. Users wanted kits to be sent in coloured envelopes (so that they could identify them easily), with simple instructions and questionnaires and wanted to be notified before we sent the kits. We achieved 92 % (183/200) overall follow-up for the postal questionnaire at 1 month and 82 % (163/200) at 12 months. We achieved 86 % (171/200) overall follow-up for the postal chlamydia test at 3 months and 80 % (160/200) at 12 months. CONCLUSIONS: By using established methods to increase follow-up, testing prototype procedures and seeking user opinions, we achieved higher follow-up than previous sexual health trials. However, it is not possible to determine if the increase in response was due to our follow-up procedures. TRIAL REGISTRATION: Current Controlled Trials ISRCTN02304709 Date of registration: 27 March 2013. PMID- 26767414 TI - Implications and issues related to familial pancreatic cancer: a cohort study of hospitalized patients. AB - BACKGROUND: The surveillance of subjects at risk of pancreatic cancer is restricted to clinical research; the incidence of familial pancreatic cancer needs to be better established. Thus, we aimed to evaluate the frequency of familial pancreatic cancer in a population of hospitalized patients with pancreatic cancer. METHODS: A retrospective study based on the hospital charts of patients discharged with a diagnosis of pancreatic cancer. One hundred and eighty seven patients or their relatives were called for a phone interview. RESULTS: There were 97 males (51.9 %) and 90 (48.1 %) females. The overall mean +/- SD age was 67.3 +/- 11.8 years; the age of males was similar to that of females (P = 0140). The mean size of the tumors found was 36.3 +/- 17.4 mm (range of 5-110 mm); it was related to gender but was not related to the site of the tumor or the age of the patient. Regarding genetic diseases, three females (1.6 %) had familial adenomatous polyposis; three patients (1 male and two females) (1.6 %) had at least one relative with pancreatic cancer whereas only one 80-year old male patient (0.5 %) had two relatives affected by pancreatic cancer (the mother had died at the 65 years of age and the brother had died at 75 years of age). CONCLUSIONS: The frequency of familial pancreatic ductal adenocarcinoma is small, but its importance, from the point of view of early diagnosis, is not negligible and patients with a risk of familial cancer merit an appropriate clinical follow up. PMID- 26767415 TI - Cardiometabolic risks related to obesity severity in children and adolescents: a commentary. PMID- 26767416 TI - Caffeine and REM sleep deprivation: Effect on basal levels of signaling molecules in area CA1. AB - We have investigated the neuroprotective effect of chronic caffeine treatment on basal levels of memory-related signaling molecules in area CA1 of sleep-deprived rats. Animals in the caffeine groups were treated with caffeine in drinking water (0.3g/l) for four weeks before they were REM sleep-deprived for 24h in the Modified Multiple Platforms paradigm. Western blot analysis of basal protein levels of plasticity- and memory-related signaling molecules in hippocampal area CA1 showed significant down regulation of the basal levels of phosphorylated- and total-CaMKII, phosphorylated- and total-CREB as well as those of BDNF and CaMKIV in sleep deprived rats. All these changes were completely prevented in rats that chronically consumed caffeine. The present findings suggest an important neuroprotective property of caffeine in sleep deprivation. PMID- 26767417 TI - Kif5 regulates mitochondrial movement, morphology, function and neuronal survival. AB - Due to the unique architecture of neurons, trafficking of mitochondria throughout processes to regions of high energetic demand is critical to sustain neuronal health. It has been suggested that compromised mitochondrial trafficking may play a role in neurodegenerative diseases. We evaluated the consequences of disrupted kif5c-mediated mitochondrial trafficking on mitochondrial form and function in primary rat cortical neurons. Morphological changes in mitochondria appeared to be due to remodelling, a phenomenon distinct from mitochondrial fission, which resulted in punctate-shaped mitochondria. We also demonstrated that neurons displaying punctate mitochondria exhibited relatively decreased ROS and increased cellular ATP levels using ROS-sensitive GFP and ATP FRET probes, respectively. Somewhat unexpectedly, neurons overexpressing the dominant negative form of kif5c exhibited enhanced survival following excitotoxicity, suggesting that the impairment of mitochondrial trafficking conferred some form of neuroprotection. However, when neurons were exposed to H2O2, disruption of kif5c exacerbated cell death indicating that the effect on cell viability was dependent on the mode of toxicity. Our results suggest a novel role of kif5c. In addition to mediating mitochondrial transport, kif5c plays a role in the mechanism of regulating mitochondrial morphology. Our results also suggest that kif5c mediated mitochondrial dynamics may play an important role in regulating mitochondrial function and in turn cellular health. Moreover, our studies demonstrate an interesting interplay between the regulation of mitochondrial motility and morphology. PMID- 26767418 TI - [Emergency department consultations due to foreign body ingestion]. AB - INTRODUCTION: Foreign body (FB) ingestion is an uncommon reason for going to the Paediatric Emergency Department (PED). The aim of this study was to assess the clinical and epidemiological characteristics of foreign body ingestion and the management of these patients. PATIENTS AND METHODS: Retrospective study, including children under 14 years old with suspected foreign body ingestion seen in the PED between 2010 and 2013. An analysis was made of the circumstances of the FB ingestion, its management in the PED, and patient outcomes. RESULTS: Of the 226,666 presentations recorded, 1,608 (0.7%) were for a FB, 970 corresponding to ingestion of mainly fish bones (367, 38.7%) and coins (181, 18.7%), except in children under 1 year (plastic objects). The median age was 4.7 years, with boys being more common in those older than 4 years (58.5%). A total of 557 patients (57.3%) reported some symptom, and complementary tests were performed in 414 (42.7%). Another specialist was called in 315 (32.4%) cases, mainly from Ear, Nose and Throat (fish bones) or Surgery (coins). The FB was removed in 305 (31.4%) cases, which were mostly fish bones or sunflower seeds. Seventy-one patients (7.3%) were admitted, especially ingestion of fish bones or coins. No patient died. DISCUSSION: Ingestion of fish bones or coins by young children is a relatively common presentation in the PED, and it is associated with frequent medical interventions. Although the overall prognosis is good, and improving the health education of the population should be considered to reduce the frequency of these episodes. PMID- 26767419 TI - Levels of infection with the lungworm Angiostrongylus cantonensis in terrestrial snails from Thailand, with Cryptozona siamensis as a new intermediate host. AB - Angiostrongylus cantonensis is primarily considered an emerging infectious agent of eosinophilic meningitis or meningoencephalitis with a worldwide distribution. Rodents and snails are important invasive hosts for transmission and expansion of A. cantonensis. The objective of this study was to investigate infection levels of A. cantonensis in snails, the most important natural intermediate host. Our study location was Mueang Kamphaeng Phet district, Kamphaeng Phet Province, and was undertaken between October and December 2012. A total of 2228 freshwater and terrestrial snails were collected, comprising 1119 Filopaludina spp., 409 Pomacea caniculata, 275 Achatina fulica and 425 Cryptozona siamensis. Angiostrongylus larvae were isolated by artificial digestion methods following Baermann's techniques. A low prevalence and intensity of A. cantonensis were observed in A. fulica, while higher numbers were found in C. siamensis. None of the Filopaludina spp. and Pomacea caniculata were infected with A. cantonensis. Molecular characterization was performed by analysing the 264 bp of cytochrome c oxidase subunit I (COI). Three COI sequences of Angiostrongylus were identical to A. cantonensis with 91-99% identity. Cryptozona siamensis has not previously been recorded as an intermediate host for A. cantonensis in Thailand. The infection of A. cantonensis identified in the natural intermediate hosts is new and important information to assist in the prevention and control of human angiostrongyliasis. PMID- 26767420 TI - The importance of bilingual experience in assessing bilingual advantages in executive functions. PMID- 26767421 TI - Sex steroid receptors and apoptosis-related proteins are differentially expressed in polycystic ovaries of adult dogs. AB - In Polycystic Ovaries (PCOs), the dynamics of sex hormone receptors and follicle related apoptotic signaling remain unknown. In this study, we investigated the expression of androgen receptors (AR), estrogen receptors (ERalpha and ERbeta), and apoptosis-related molecules (BAX, active caspase-3, Bcl-2 and Survivin) on different follicular stages of PCOs in adult dogs. Clinical evidences of high estradiol and testosterone levels, persistent estrus and vaginal discharge were observed. Inhibin B immunolabeling was increased in primary and 2 to 5-mm follicles, and a marked epithelial hyperplasia was common in the ovarian surface. Ovarian epithelia and primary follicles showed low expression of AR, ERalpha, and ERbeta, whereas a moderate immunoexpression of AR was found in theca cells of secondary follicles and cysts. In PCOs, growing follicles displayed ERalpha expression, and secondary follicles exhibited higher ERbeta expression. In addition, while few ERalpha-positive cells were found in the cysts, ERbeta was moderately expressed in growing follicles and cysts. BAX was upregulated in the ovarian epithelium, primary follicles, and in the wall of follicular cysts. Active caspase-3 was significantly downregulated in the epithelium, primary follicles, and follicular cysts, whereas growing follicles had a strong immunoexpression in the granulosa cells. Bcl-2 and survivin were increased in the epithelium and primary follicles, and only survivin was upregulated in secondary and growing follicles. While Bcl-2 had a diffuse immunexpression in the follicular cysts, survivin was overexpressed by these cells. We concluded that sex steroid receptors and apoptotic proteins are differentially expressed in the follicles of adult dogs with PCOs. PMID- 26767422 TI - Evaluation of subcutaneous ICD early performance in hypertrophic cardiomyopathy from the pooled EFFORTLESS and IDE cohorts. AB - BACKGROUND: The subcutaneous implantable cardioverter-defibrillator (S-ICD) is a potential alternative to transvenous systems in hypertrophic cardiomyopathy (HCM) where lead complications are a significant issue. OBJECTIVES: To compare the S ICD efficacy of defibrillation threshold (DFT) testing, arrhythmia therapy, and complications in HCM versus non-HCM patients. METHODS: Outcomes of patients with HCM implanted with S-ICD were compared to non-HCM S-ICD recipients using pooled data from a total of 872 subjects enrolled in the EFFORTLESS Registry and US IDE study. RESULTS: The cohort included 99 HCM (75% male) and 773 non-HCM (72% male) patients with a median follow-up of 637 days. The HCM cohort was younger and more likely to receive a primary-prevention S-ICD (88.5% vs 67.5%, P < .0001). During implant testing, successful defibrillation at <=80 J was achieved in 98.9% of HCM and 98.5% of non-HCM patients. One year postoperative complication-free rates were similar: 92.7% in HCM (with no lead complications) versus 89.5% in non-HCM. There were 3 appropriate shocks for ventricular tachycardia in 3 HCM patients that were all converted by the first shock. Overall final shock conversion efficacy was 100% in HCM versus 98% in non-HCM (P = ns). Inappropriate shocks occurred in 12.5% of HCM patients and 10.3% of non-HCM patients (P = ns), being reduced by 47% using dual-zone programming. CONCLUSION: These initial data indicate the S-ICD is safe and effective in patients with HCM who are at high risk of ventricular arrhythmias and pass preimplantation electrocardiogram screening. Inappropriate shocks were mainly due to T-wave oversensing, but there were no lead complications requiring reintervention. PMID- 26767423 TI - Tetanizing prepulse: A novel strategy to mitigate implantable cardioverter defibrillator shock-related pain. AB - BACKGROUND: Skeletal muscle activation has been implicated as the source of pain associated with implantable cardioverter-defibrillator shocks. We hypothesized that the skeletal muscle response to defibrillatory shocks could be attenuated with a tetanizing prepulse immediately before biphasic shock delivery. OBJECTIVE: The purpose of this study was to test the ability of tetanizing prepulses to reduce the skeletal muscle activation associated with defibrillation. METHODS: Seven adult pigs were studied. A left ventricular coil and subcutaneous dummy can in the right thorax were used to deliver either pure biphasic waveforms or test waveforms consisting of a tetanizing pulse of high-frequency alternating current (HFAC) ramped to an amplitude of 5-100 V over 0.25-1 second, immediately followed by a biphasic shock of approximately 9 J (ramped HFAC and biphasic [rHFAC+B]). We used limb acceleration and rate of force development as surrogate measures of pain. Test and control waveforms were delivered in sinus rhythm and induced ventricular fibrillation to test defibrillation efficacy. RESULTS: Defibrillation threshold energy was indistinguishable between rHFAC+B and pure biphasic shocks. Peak acceleration and rate of force development were reduced by 72% +/- 7% and 71% +/- 22%, respectively, with a 25-V, 1-second rHFAC+B waveform compared with pure biphasic shocks. Notably, rHFAC+B with a 9-J biphasic shock produced significantly less skeletal muscle activation than a 0.1-J pure biphasic shock. CONCLUSION: A putative source of implantable cardioverter-defibrillator shock related pain can be mitigated using a tetanizing prepulse followed by biphasic shock. Human studies will be required to assess true pain reduction with this approach. PMID- 26767424 TI - Bradycardia with cooling and cryo: A reminder of the autonomic effects of cold stimuli on the heart. PMID- 26767425 TI - ECG denoising and fiducial point extraction using an extended Kalman filtering framework with linear and nonlinear phase observations. AB - In this paper we propose an efficient method for denoising and extracting fiducial point (FP) of ECG signals. The method is based on a nonlinear dynamic model which uses Gaussian functions to model ECG waveforms. For estimating the model parameters, we use an extended Kalman filter (EKF). In this framework called EKF25, all the parameters of Gaussian functions as well as the ECG waveforms (P-wave, QRS complex and T-wave) in the ECG dynamical model, are considered as state variables. In this paper, the dynamic time warping method is used to estimate the nonlinear ECG phase observation. We compare this new approach with linear phase observation models. Using linear and nonlinear EKF25 for ECG denoising and nonlinear EKF25 for fiducial point extraction and ECG interval analysis are the main contributions of this paper. Performance comparison with other EKF-based techniques shows that the proposed method results in higher output SNR with an average SNR improvement of 12 dB for an input SNR of -8 dB. To evaluate the FP extraction performance, we compare the proposed method with a method based on partially collapsed Gibbs sampler and an established EKF based method. The mean absolute error and the root mean square error of all FPs, across all databases are 14 ms and 22 ms, respectively, for our proposed method, with an advantage when using a nonlinear phase observation. These errors are significantly smaller than errors obtained with other methods. For ECG interval analysis, with an absolute mean error and a root mean square error of about 22 ms and 29 ms, the proposed method achieves better accuracy and smaller variability with respect to other methods. PMID- 26767426 TI - MALT1 Protease Activity Controls the Expression of Inflammatory Genes in Keratinocytes upon Zymosan Stimulation. AB - The protease activity of the paracaspase mucosa-associated lymphoid tissue lymphoma translocation gene 1 (MALT1) plays an important role in antigen receptor mediated lymphocyte activation by controlling the activity of the transcription factor nuclear factor-kappaB and is thus essential for the expression of inflammatory target genes. MALT1 is not only present in cells of the hematopoietic lineage, but is ubiquitously expressed. Here we report that stimulation with zymosan or Staphylococcus aureus induced MALT1 protease activity in human primary keratinocytes. Inhibition of the Src family of kinases or novel protein kinase C isoforms as well as silencing of CARMA2 or BCL10 interfered with activation of MALT1 protease. Silencing or inhibition of MALT1 protease strongly decreased the expression of important inflammatory genes such as TNFalpha, IL 17C, CXCL8 and HBD-2. MALT1-inhibited cells were unable to mount an antimicrobial response upon zymosan stimulation or phorbolester/ionomycin treatment, demonstrating a central role of MALT1 protease activity in keratinocyte immunity and suggesting MALT1 as a potential target in inflammatory skin diseases. PMID- 26767427 TI - Evidence for a permanent presence of schistosomiasis in Corsica, France, 2015. AB - We present a case of acute schistosomiasis acquired in Corsica after bathing in the Cavu River during the summer of 2015. The diagnosis was made following epidemiological, laboratory and serological assessments. After a previous outbreak of urogenital schistosomiasis during the summer of 2013, when more than 120 infections were diagnosed, this further case indicates transmission was still effective in 2015, thus suggesting a permanent presence of schistosomiasis in Corsica. PMID- 26767428 TI - The Structure-Activity Relationship of Glycosaminoglycans and Their Analogues with beta-Amyloid Peptide. AB - Alzheimer's disease (AD) is a serious neurodegenerative disorder. beta-amyloid peptide (Abeta) aggregation is believed to be the major cause of the disease. The process of Abeta aggregation can be enhanced by sulfated glycosaminoglycans. However, cell experiments have shown that sulfated glycosaminoglycan oligosaccharides or analogues may have significant neuroprotective properties and could inhibit the aggregation by competitive inhibition. The length and species of oligosaccharides or analogues can inhibit the toxicity of Abeta by inducing conformational changes of proteins in different manners. This review presents the conformational changes of Abeta in the presence of glycosaminoglycan, glycosaminoglycan oligosaccharides and analogues. The review might be helpful to comprehend the mechanism of beta-amyloid fibrillations and the aggregation process. PMID- 26767429 TI - Selection of Single Chain Antibody Fragments for Targeting Prostate Specific Membrane Antigen: A Comparison Between Cell-based and Antigen-based Approach. AB - Prostate cancer (PCa) is the most frequently diagnosed cancer and the second most common cause of cancer related mortality in United States male population. ScFv fragments have different usefulness. For example they have small size, high perfusion rate, high yield of production and are non-immunogenic, thus they can be used for therapeutic purposes. In this project we used a synthetic human ScFv library for isolation of ScFv monoclonal antibodies against prostate specific membrane antigen. For this purpose, after five rounds of cell-panning, and also five rounds of antigen-panning with rPSMA specific anti- PSMA ScFv-phage particles were isolated. Phages with high affinity toward PSMA were selected and used for further analysis. Specificity and affinity of both ScFv to PSMA and LnCaP cell line examined by ELISA. Recombinant ScFv antibody isolated from cell panning had higher specificity and affinity for both the antigen and LNCaP cell line. Our result demonstrated that ScFv antibody obtained by cell-panning can target PSMA antigen and cell lines. PMID- 26767430 TI - Facilities for small-molecule crystallography at synchrotron sources. AB - Although macromolecular crystallography is a widely supported technique at synchrotron radiation facilities throughout the world, there are, in comparison, only very few beamlines dedicated to small-molecule crystallography. This limited provision is despite the increasing demand for beamtime from the chemical crystallography community and the ever greater overlap between systems that can be classed as either small macromolecules or large small molecules. In this article, a very brief overview of beamlines that support small-molecule single crystal diffraction techniques will be given along with a more detailed description of beamline I19, a dedicated facility for small-molecule crystallography at Diamond Light Source. PMID- 26767431 TI - Assessment of job burnout by standard questionnaire survey for Chinese correctional officers. PMID- 26767432 TI - Enlarging Multiple Neoplastic Skin Growths. PMID- 26767433 TI - A Fast Chromatographic Method for Estimating Lipophilicity and Ionization in Nonpolar Membrane-Like Environment. AB - This study describes the design and implementation of a new chromatographic descriptor called log k'80 PLRP-S that provides information about the lipophilicity of drug molecules in the nonpolar environment, both in their neutral and ionized form. The log k'80 PLRP-S obtained on a polymeric column with acetonitrile/water mobile phase is shown to closely relate to log Ptoluene (toluene dielectric constant epsilon ~ 2). The main intermolecular interactions governing log k'80 PLRP-S were deconvoluted using the Block Relevance (BR) analysis. The information provided by this descriptor was compared to ElogD and calclog Ptol, and the differences are highlighted. The "charge-flush" concept is introduced to describe the sensitivity of log k'80 PLRP-S to the ionization state of compounds in the pH range 2 to 12. The ability of log k'80 PLRP-S to indicate the propensity of neutral molecules and monoanions to form Intramolecular Hydrogen Bonds (IMHBs) is proven through a number of examples. PMID- 26767434 TI - Spatially resolved, diffuse reflectance imaging for subsurface pattern visualization toward development of a lensless imaging platform: phantom experiments. PMID- 26767435 TI - Published GMO studies find no evidence of harm when corrected for multiple comparisons. AB - A number of widely debated research articles claiming possible technology-related health concerns have influenced the public opinion on genetically modified food safety. We performed a statistical reanalysis and review of experimental data presented in some of these studies and found that quite often in contradiction with the authors' conclusions the data actually provides weak evidence of harm that cannot be differentiated from chance. In our opinion the problem of statistically unaccounted multiple comparisons has led to some of the most cited anti-genetically modified organism health claims in history. We hope this analysis puts the original results of these studies into proper context. PMID- 26767436 TI - Long and short term impacts of CuO, Ag and CeO2 nanoparticles on anaerobic digestion of municipal waste activated sludge. AB - In this study, long and short term inhibition impacts of Ag, CuO and CeO2 nanoparticles (NPs) on anaerobic digestion (AD) of waste activated sludge (WAS) were investigated. CuO NPs were detected as the most toxic NPs on AD. As the CuO NP concentration increased from 5 to 1000 mg per gTS, an increase in the inhibition of AD from 5.8 to 84.0% was observed. EC50 values of short and long term inhibitions were calculated as 224.2 mgCuO per gTS and 215.1 mgCuO per gTS, respectively. Ag and CeO2 NPs did not cause drastic impacts on AD as compared to CuO NPs. In the long term test, Ag NPs created 12.1% decrease and CeO2 NPs caused 9.2% increase in the methane production from WAS at the highest dosage. FISH imaging also revealed that the abundance of Archaea in raw WAS was similar in short and long term tests carried out with WAS containing Ag and CeO2 NPs. On the other hand, CuO NPs caused inhibition of Archaea in the long term test. Digestion kinetics of WAS containing Ag, CeO2, CuO NPs were also evaluated with Gompertz, Logistic, Transference and First Order models. The hydrolysis rate constant (kH) for each concentration of Ag and CeO2 NPs and the raw WAS was 0.027745 d(-1) while the kH of WAS containing high concentrations of CuO NPs was found to be 0.001610 d(-1). PMID- 26767437 TI - Asymptomatic Pulmonary Allograft Kaposi Sarcoma: A Case Report. AB - Solid-organ transplant recipients are at high risk of developing malignancies. A greater risk of Kaposi sarcoma has been reported in lung recipients in our country, particularly in those from Southern Italy, probably due to the high prevalence of Human herpes virus 8 infection. Kaposi sarcoma affecting only the lung allograft is extremely rare. We describe a case of a lung recipient who developed Kaposi sarcoma only in the graft, 22 months after transplant. The patient, a 65-year-old man from Southern Italy, underwent bilateral lung transplant for idiopathic pulmonary fibrosis in January 2009. He developed mild/moderate acute cellular rejection (>=A2) in 4 of 6 scheduled transbronchial biopsies thus was treated with increased immunosuppressive therapy, shifting from cyclosporine to tacrolimus and mycophenolate mofetil. In July 2010, a high resolution computed tomography scan showed small bilateral lung nodules, despite a generally good condition. After 2 months, his condition worsened with a severe weight loss. A positron emission tomography scan showed mild metabolic activity in the lesions with no other localizations. In October 2010, a lung biopsy was performed, with results showing typical histologic and immunohistochemical features of Kaposi sarcoma. Molecular tissue evaluations and serologic analyses were positive for Human herpes virus 8. The patient's immunosuppressive therapy was suspended, and he started liposomal doxorubicin treatment; however, after the first cycle, he developed severe respiratory dysfunction. The patient died 27 months after lung transplant for neoplasm. Our report highlights the importance of considering Kaposi sarcoma in the differential diagnosis for lung nodules in lung transplant recipients, even in the absence of any initial specific symptom or cutaneous lesion. PMID- 26767438 TI - Genome-wide association reveals the locus responsible for four-horned ruminant. AB - Phenotypic variability in horn characteristics, such as their size, number and shape, offers the opportunity to elucidate the molecular basis of horn development. The objective of this study was to map the genetic determinant controlling the production of four horns in two breeds, Jacob sheep and Navajo Churro, and examine whether an eyelid abnormality occurring in the same populations is related. Genome-wide association mapping was performed using 125 animals from the two breeds that contain two- and four-horned individuals. A case control design analysis of 570 712 SNPs genotyped with the ovine HD SNP Beadchip revealed a strong association signal on sheep chromosome 2. The 10 most strongly associated SNPs were all located in a region spanning Mb positions 131.9-132.6, indicating the genetic architecture underpinning the production of four horns is likely to involve a single gene. The closest genes to the most strongly associated marker (OAR2_132568092) were MTX2 and the HOXD cluster, located approximately 93 Kb and 251 Kb upstream respectively. The occurrence of an eyelid malformation across both breeds was restricted to polled animals and those carrying more than two horns. This suggests the eyelid abnormality may be associated with departures from the normal developmental production of two-horned animals and that the two conditions are developmentally linked. This study demonstrated the presence of separate loci responsible for the polled and four horned phenotypes in sheep and advanced our understanding of the complexity that underpins horn morphology in ruminants. PMID- 26767439 TI - The Effects of Interlocking a Universal Hip Cementless Stem on Implant Subsidence and Mechanical Properties of Cadaveric Canine Femora. AB - OBJECTIVE: To determine if an interlocking bolt would limit subsidence of the biological fixation universal hip (BFX((r))) femoral stem under cyclic loading and enhance construct stiffness, yield, and failure properties. STUDY DESIGN: Ex vivo biomechanical study. ANIMALS: Cadaveric canine femora (10 pairs). METHODS: Paired femora implanted with a traditional stem or an interlocking stem (constructs) were cyclically loaded at walk, trot, and gallop loads while implant and bone motions were captured using kinematic markers and high-speed video. Constructs were then loaded to failure to evaluate failure mechanical properties. RESULTS: Implant subsidence was greater (P = .037) for the traditional implant (4.19 mm) than the interlocking implant (0.78 mm) only after gallop cyclic loading, and cumulatively after walk, trot, and gallop cyclic loads (5.20 mm vs. 1.28 mm, P = .038). Yield and failure loads were greater (P = .029 and .002, respectively) for the interlocking stem construct (1155 N and 2337 N) than the traditional stem construct (816 N and 1405 N). Version angle change after cyclic loading was greater (P = .020) for the traditional implant (3.89 degrees) than for the interlocking implant (0.16 degrees), whereas stem varus displacement at failure was greater (P = .008) for the interlocking implant (1.5 degrees) than the traditional implant (0.17 degrees). CONCLUSION: Addition of a stabilizing bolt enhanced construct stability and limited subsidence of a BFX((r)) femoral stem. Use of the interlocking implant may decrease postoperative subsidence. However, in vivo effects of the interlocking bolt on osseointegration, bone remodeling, and stress shielding are unknown. PMID- 26767440 TI - Apology for discrimination, bullying and sexual harassment by the President of the Royal Australasian College of Surgeons. PMID- 26767441 TI - Gender equity in surgery: dream delusion or nightmare. PMID- 26767442 TI - Gender perceptions in surgery: is it really a level playing field? PMID- 26767443 TI - Response to Re: Biologic mesh versus synthetic mesh in open inguinal hernia repair: system review and meta-analysis. PMID- 26767444 TI - Re: Biologic mesh versus synthetic mesh in open inguinal hernia repair: system review and meta-analysis. PMID- 26767445 TI - Response to Re: Index cholecystectomy in grade II and III acute calculous cholecystitis is feasible and safe. PMID- 26767446 TI - Re: Index cholecystectomy in grade II and III acute calculous cholecystitis is feasible and safe. PMID- 26767449 TI - Erratum: Suicidal ideation and suicide attempts in five groups with different severities of gambling: Findings from the National Epidemiologic Survey on Alcohol and Related Conditions by Jacquelene F. Moghaddam, Gihyun Yoon, Daniel L. Dickerson, Suck Won Kim, and Joseph Westermeyer DOI: 10.1111/ajad.12197. AB - In Ref.[1], the following error was published under the Declaration of Interest. The article erroneously acknowledged the receipt of a funding source #1R01AA022066-01. We apologize for this error. PMID- 26767451 TI - Erratum: Davis G, Surratt H, Levin F, et al. Antiretroviral medication: an emerging category of prescription drug misuse. Am J Addict. 2013. doi: 10.1111/j.1521-0391.2013.12107.x. . AB - Page 2 states the following:"Whoonga, as it is locally known, is thought to be a mixture of the NNRTI efavirenz with various quantities of cannabis, cocaine, or heroin, and it is reportedly being smoked by children as young as 14 years old" supported by the reference Sparks C. Addictive drug threatens the future of South African youth. March 15, 2011; http://mediaglobal.org/2011/03/15/addictive-drug threatens-the-future-of-south-african-youth/. (Accessed October 25, 2011). The phrase "as young as 14 years old" is correctly supported by the following reference:Mdluli, A., Ward, B, 2010. Whoonga drug spreads rapidly. The Mercury (http://www.highbeam.com/doc/1G1-229534982.html). PMID- 26767456 TI - Erratum. PMID- 26767457 TI - Erratum. PMID- 26767459 TI - Signatures of functional constraint at Fgfr1a Genes in schizothoracine fishes (Pisces: Cypriniformes): The dermal skeleton variation adapted to high-altitude environments. AB - Fishes harbor a huge resource of phenotypic diversity and are useful for understanding the genetic basis of morphological variation. However, it is difficult to transfer classical genetic mapping to most non-model species. In this study, we performed a comparative sequence analysis of Fgfr1a to first interpret the evolution of this candidate scale-loss gene in 15 schizothoracine fishes with various scale phenotypes. While considerable amino acid (AA) substitutions were observed, molecular evolution analysis indicates that the overall coding regions were subject to functional constraint. We also identified extra copies of Fgfr1a in 4 scale-loss fishes and detected accelerated evolution in one AA substitution specific to these duplicates. We speculate that Fgfr1a had accumulated mutations in the ancestral lineage of scale-loss schizothoracine fishes before experiencing duplication events, which was further followed by the diversification of species. In silico mutation analysis predicted deleterious effects of the mutations while no disruptive molecular mechanism was detected. Collectively, our results highlight the important role of Fgfr1a gene in the adaptive evolution of schizothoracine fishes during their radiation in the Qinghai-Tibetan Plateau. PMID- 26767463 TI - Corrigendum: Luminescent Metal-Organic Frameworks (MOFs) as a Chemopalette: Tuning the Thermochromic Behavior of Dual-Emissive Phosphorescence by Adjusting the Supramolecular Microenvironments. PMID- 26767468 TI - Myeloma impairs mature osteoblast function but causes early expansion of osteo progenitors: temporal changes in bone physiology and gene expression in the KMS12BM model. AB - Myeloma bone disease results from an uncoupling of osteoclastic resorption and osteoblastic bone formation, but early changes in osteogenic function remain poorly defined. We used the KMS12BM xenograft model to investigate cellular and molecular events at early and late stages of disease. Lytic lesions and changes in osteoblast and osteoclast numbers occur late (8 weeks), however, micro computed tomography of femora revealed significant reduction in bone volume at earlier disease stages (3 weeks) when tumour burden is low. Calcein labelling demonstrated reduced mineralization and bone formation at 3 weeks, suggesting functional impairment despite preserved osteoblast numbers. Osteo-progenitors from compact bone increased early (1 week), but fell at 3 weeks and were profoundly suppressed by 8 weeks. Exposure of osteoblast progenitors to multiple myeloma (MM) cells in vitro induced cell cycling, suggesting a mechanistic basis for early expansion of osteo-progenitors. We observed temporal changes in chemokine, osteogenic and osteoclastogenic genes in the stromal compartment. Notably, an early rise in CCL3 may underlie functional changes in mature osteoblasts at 3 weeks. Our data indicate that MM has distinct effects on mature osteoblasts and immature osteo-progenitors. Our findings argue for early clinical intervention to prevent bone changes that ultimately lead to the development of osteolytic disease. PMID- 26767470 TI - Corrigendum. PMID- 26767469 TI - Corrigendum. PMID- 26767471 TI - INTRODUCTION: From the Right to Know to the Right Not to Know. PMID- 26767472 TI - Defining the Scope of Public Engagement: Examining the "Right Not to Know" in Public Health Genomics. AB - In this article, we explore the concept of a "right not to know" on a population rather than individual level. We argue that a population level "right not to know" is a useful concept for helping to define the appropriate boundaries of public engagement initiatives in the emerging public health genomics context. PMID- 26767473 TI - Is There a Right Time to Know? The Right Not to Know and Genetic Testing in Children. AB - The increasing implementation of next-generation sequencing technologies in the clinical context and the expanding commercial offer of genetic tests directly toconsumers has increased the availability of previously inaccessible genetic information. A particular concern in both situations is how the volume of novel information will affect the processing of genetic and genomic information from minors. For minors, it is argued that in the provision of genetic testing, their "right not to know" should be respected as much as possible. Testing a minor early in life eliminates the possibility for the minor to make use of his or her "right not to know." The article discusses the theoretical underpinnings of the right not know, analyzes reasons why various direct-to-consumer companies process samples from minors, and discusses the right not to know in relation to common complex disorders in a pediatric population. PMID- 26767474 TI - Autonomy, the Right Not to Know, and the Right to Know Personal Research Results: What Rights Are There, and Who Should Decide about Exceptions? AB - This paper defends the right not to know personal health information, while it discards the right of research participants to receive individual research results. Disagreement regarding the right not to know stems from two different conceptions of autonomy, leading to opposing normative conclusions. Researchers occasionally have good reason to inform research participants about incidental findings in spite of the absence of a right to know such information. Such decisions have to be made by health care personnel and researchers on a case by case basis, although external support for the decisions may be available. PMID- 26767475 TI - The Right Not to Know and the Duty to Tell: The Case of Relatives. AB - Obtaining and sharing genetic information when there is a potential conflict of interest between patients and their relatives give rise to two questions. Do we have a duty to find out our genetic predispositions for disease for the sake of our relatives, or do we have a right to remain ignorant? Do we have a duty to disclose our known genetic predispositions for disease to our relatives? I argue that the answer to both questions is yes, but to a lesser extent than sometimes claimed. PMID- 26767476 TI - Recognizing the Right Not to Know: Conceptual, Professional, and Legal Implications. AB - This article argues for the importance of conceptual clarity in the debate about the so-called right not to know. This is vital both at the theoretical and the practical level. It is suggested that, unlike many formulations and attempts to give effect to this right, what is at stake is not merely an aspect of personal autonomy and therefore cannot and should not be reduced only to a question of individual choice. Rather, it is argued that the core interests that can be protected by the right not to know are better conceived of as privacy interests rather than autonomy interests. This not only helps us to understand what is in play but also informs regulatory, professional, and legal responses to handling information and taking decisions about whether or not to disclose information to persons about themselves. The practical implications of this conceptualization are explored in the context of feedback policies in health-related research. PMID- 26767477 TI - The Public Health Workforce and Willingness to Respond to Emergencies: A 50-State Analysis of Potentially Influential Laws. AB - Law plays a critical role in all stages of a public health emergency, providing an infrastructure for planning, response, and recovery efforts. A growing body of research has underscored the potential for certain types of state laws, such as those granting liability protections to responders, to influence the public health workforce's participation in emergency responses. It is therefore especially important to focus on particular state-level laws that may be associated with individuals' increased or decreased willingness to respond. We conducted a systematic identification and analysis of specific state emergency preparedness laws that may affect individuals' willingness to respond and offer recommendations for policymakers seeking to promote more effective responses to public health emergencies. PMID- 26767478 TI - Nonbinding Legal Instruments in Governance for Global Health: Lessons from the Global AIDS Reporting Mechanism. AB - Recent debate over World Health Organization reform has included unprecedented attention to international lawmaking as a future priority function of the Organization. However, the debate is largely focused on the codification of new binding legal instruments. Drawing upon lessons from the success of the Global AIDS Reporting Mechanism, established pursuant to the United Nations' Declaration of Commitment on HIV/AIDS, we argue that effective global health governance requires consideration of a broad range of instruments, both binding and nonbinding. A detailed examination of the Global AIDS Reporting Mechanism reveals that the choice of the nonbinding format makes an important contribution to its effectiveness. For instance, the flexibility and adaptability of the nonbinding format have allowed the global community to: (1) undertake commitments in a timely manner; (2) adapt and experiment in the face of a dynamic pandemic; and (3) grant civil society an unparalleled role in monitoring and reporting on state implementation of global commitments. UNAIDS' institutional support has also played a vital role in ensuring the continuing effectiveness of the Global AIDS Reporting Mechanism. Overall, the experience of the Global AIDS Reporting Mechanism evidences that, at times, nimbler nonbinding instruments can offer benefits over slower, more rigid binding legal approaches to governance, but depend critically, like all instruments, on the perceived legitimacy thereof. PMID- 26767479 TI - The "Permanent" Patient Problem. AB - Patients who enter the health care system for acute care may become "permanent" patients of the hospital when a lack of resources precludes discharge to the next level of post-acute care. Legal, professional, and ethical norms prohibit physician and acute care hospital "dumping" of these patients. However, limitless use of hospital resources for indefinite stays is untenable. In the absence of hospital policy addressing this specific issue, the availability of financial support will be determined by health care professionals' willingness to advocate for the patient and negotiate with hospital administrators and the ability and willingness of administrators to authorize the use of hospital resources. We propose five mid-level ethical principles to guide advocacy and administrative decision-making about provision of financial support for post-acute care for those patients who cannot afford it. We use two actual, de-identified cases to illustrate how these principles can be used to make reasoned, consistent decisions about the provision of post-acute financial support. PMID- 26767480 TI - Care Coordination and the Expansion of Nursing Scopes of Practice. AB - Nurse practitioners can ease increased pressure on primary care shortage while providing a cost-effective and high-quality alternative to certain physician services. However, scope-of-practice laws are restrictive and their modification remains a source of controversy. Clearly, there is a need for new thinking around the scope of practice debate. This article conducted a review of literature and laws concerning the nursing scope of practice, as well as the outcomes of nurse led care coordination models. It also examined different manifestations of the controversy that arises in scope of practice debates. We argue that improved care coordination is necessary to improve outcomes and "bend the cost curve downward." Allowing nurse practitioners and other providers to practice to the full extent of their licenses will result in improved care coordination. This can be accomplished by expanding nursing and other providers' scopes of practice. But any health care reform strategy, particularly with respect to chronic care management, must also serve to activate the patient herself as the keystone in the coordinated care process. Focusing first on the patient's need for coordinated care may be what is necessary to move beyond the existing impasse between physicians and nurses on scope of practice expansion. PMID- 26767481 TI - Tarasoff Duties after Newtown. PMID- 26767482 TI - A Proposed Ban on the Sale to and Possession of Caloric Sweetened Beverages by Minors in Public. PMID- 26767484 TI - Occupation of nucleotide in the binding pocket is critical to the stability of Rab11A. AB - The Ras superfamily of small G proteins is a family of guanosine triphosphatases (GTPases) and each GTPase has conserved amino acid sequences in the enzymatic active site that are responsible for specific interactions with GDP and GTP molecules. Rab GTPases, which belong to the Ras superfamily, are key regulators of intracellular vesicle trafficking via the recruitment of effector molecules. Here, we purified wild type, active mutant and inactive mutant of Rab11A. In this process, we found that the inactive mutant (Rab11A S25N) had low stability compared with wild type and other mutants. Further analysis revealed that the stability of Rab11A S25N is dependent on the occupation of GDP in the nucleotide binding pocket of the protein. We found that the stability of Rab11A S25N is affected by the presence of GDP, not other nucleotides, and is independent of pH or salt in FPLC buffer. Our results provide a better understanding of how GTPase can be stable under in vitro conditions without effector proteins and how proper substrate/cofactor coordination is crucial to the stability of Rab11A. Successful purification and proposed purification methods will provide a valuable guide for investigation of other small GTPase proteins. PMID- 26767485 TI - Are we ready to reliably assess transition readiness? PMID- 26767486 TI - Combined liver and kidney transplantation: Who and when? PMID- 26767487 TI - Pushing the envelope and making every organ count: Small pediatric grafts for adult recipients. PMID- 26767488 TI - Food allergies developing after solid organ transplant. AB - The development of food allergy is an increasingly recognized form of morbidity after solid organ transplant. It occurs more commonly in liver transplant recipients, although it has also been reported in heart, lung, kidney, and intestinal transplants. Pediatric transplant recipients are more likely to develop symptoms compared to adults, and reports of frequency vary widely from 5% to 38% in pediatric liver transplant recipients. Multiple mechanisms have been proposed in the literature, although no single mechanism can yet account for all reported observations. As food allergy can have at worst potentially fatal consequences, and at best require lifestyle adjustment through food avoidance, it is important for recipients to be aware of the donor's food allergies and particularly in pediatrics, the possibility of completely de novo allergies. This review explores the recent reports surrounding food allergy after solid organ transplant, including epidemiology, proposed mechanisms, and implications for practice. PMID- 26767491 TI - Autophagy and Asthma. PMID- 26767492 TI - Blood cytotoxic/inflammatory mediators in non-eosinophilic asthma. AB - BACKGROUND: Non-eosinophilic asthma (NEA) is a distinct, often corticosteroid resistant inflammatory asthma phenotype. NK and NKT-like cells are effector lymphocytes that we have shown, like CD28null T cells, to be relatively resistant to steroids and major sources of pro-inflammatory/cytotoxic mediators. We hypothesized that these cells and mediators would be increased in peripheral blood in NEA. METHODS: Adults with severe asthma and variable airflow obstruction, poorly controlled despite maintenance therapy with inhaled glucocorticosteroids and long-acting bronchodilators, were recruited. Blood was assessed in those with eosinophilic asthma (n = 12), NEA (n = 25) and healthy non smoking controls (n = 30). We applied flow cytometry to measure T, CD28null, NK and NKT-like cells and their expression of granzyme B, perforin, and killer inhibitory/activating receptors CD94(Kp43), CD158b and CD107A. Intracellular pro inflammatory cytokine production (IFN-gamma and TNF-alpha) was assessed in 18 controls and 10 patients with asthma/group. RESULTS: In NEA, there was increased expression of granzyme B by CD8+ T cells vs. CONTROLS: There was increased expression of granzyme B and CD158 and decreased CD94 on NK cells, vs. healthy controls and those with eosinophilic asthma. IFN-gamma production by NK cells and TNF-alpha production by NKT-like cells in NEA were significantly increased vs. CONTROLS: In both eosinophilic and NEA phenotypes, there were significant increases in CD4+28null T cells (72% and 81% increases, respectively, vs. controls) and their expression of pro-inflammatory cytokines. Significant correlations were noted between blood CD4+28null T cells and neutrophil numbers in induced sputum, and between corticosteroid dose and blood NKT-like cells, and their production of granzyme B and TNF-alpha and NK IFN-gamma. CONCLUSION AND CLINICAL RELEVANCE: In poorly controlled asthma, altered expression of cytotoxic/pro-inflammatory mediators can be seen on a variety of lymphocyte subsets in the peripheral blood; these changes are most apparent in NEA. Whether this pattern of expression is a marker of treatment responsiveness and future risk of exacerbations remains to be determined. PMID- 26767493 TI - General anaesthesia-induced anaphylaxis: impact of allergy testing on subsequent anaesthesia. AB - BACKGROUND: Immunoglobulin E-mediated allergy to drugs and substances used during general anaesthesia as well as non-allergic drug hypersensitivity reactions may account for anaesthesia-induced anaphylaxis. As IgE-mediated anaphylaxis is a potentially life-threatening reaction, identification of the culprit allergen is essential to avoid anaphylaxis recurrence during subsequent general anaesthesia. OBJECTIVE: To study whether preventive recommendations derived from allergy testing after intraoperative anaphylaxis were followed in subsequent general anaesthesia. METHODS: Results of standardized allergy testing after anaesthesia induced anaphylaxis and outcome of subsequent general anaesthesia were analysed retrospectively. RESULTS: Fifty-three of 107 patients were diagnosed with IgE mediated allergy to a drug or substance used during general anaesthesia, and 54 patients were test negative. Twenty-eight of 29 allergy patients tolerated subsequent general anaesthesia uneventfully. One patient with cefazolin allergy suffered from anaphylaxis recurrence due to accidental reapplication of cefazolin. Twenty-two of 24 test-negative patients tolerated subsequent general anaesthesia, whereas two patients again developed anaphylaxis despite pre medication regimens. CONCLUSION AND CLINICAL RELEVANCE: Our results confirm the practical impact of allergy testing in general anaesthesia-induced anaphylaxis. By identification of the allergen, it is possible to avoid allergic anaphylaxis during subsequent anaesthesia. In most cases, recommended pre-medication seems to prevent the recurrence of non-allergic drug hypersensitivity reactions. PMID- 26767494 TI - Bone marrow tryptase as a possible diagnostic criterion for adult systemic mastocytosis. AB - BACKGROUND: Mastocytosis is difficult to diagnose, especially when systemic mast cell activation symptoms are not present or involve only one extracutaneous organ. OBJECTIVE: The main objective was to evaluate the accuracy of the bone marrow tryptase level in the diagnosis of systemic mastocytosis in patients with a clinical suspicion of mastocytosis. METHODS: We included all adult patients evaluated in our centre between December 2009 and 2013 for suspected mastocytosis as part of a standardized procedure and who had a bone marrow and serum tryptase assay on the same day. The diagnosis of systemic mastocytosis was established on the basis of the World Health Organization criteria as the gold standard. The accuracy of the bone marrow tryptase level in the diagnosis of systemic mastocytosis was assessed by a receiver operating characteristics curve analysis. The different sensitivity and specificity values, corresponding to the set of possible bone marrow tryptase level cut-off values, were estimated with 95% confidence intervals. RESULTS: Seventy-three patients were included. The diagnosis of systemic mastocytosis was established in 43 patients (58.9%). The median bone marrow tryptase level was 423 MUg/L [95% CI: 217-868] in the systemic mastocytosis group and 7.5 MUg/L [95% CI: 4.6-17.1] in the non-systemic mastocytosis group (P < 0.001). A cut-off value of 50 MUg/L for bone marrow tryptase identified systemic mastocytosis with a sensitivity of 93.0% [95% CI: 80.9-98.5%] and a specificity of 90.0% [95% CI: 73.5-97.9%]. CONCLUSION AND CLINICAL RELEVANCE: The bone marrow tryptase level appears to be a valuable diagnostic criterion for confirming systemic mastocytosis. If this diagnosis can reliably be excluded by evaluation of the bone marrow tryptase level, there would be no need to perform a bone marrow biopsy. PMID- 26767497 TI - Interpreting adult stature in industrial London. AB - OBJECTIVES: This study examines adult stature and its association with risk of mortality in two skeletal collections from industrializing London, taking sex and socioeconomic status into account as potential sources of heterogeneity in frailty. METHODS: Mean femur and tibia lengths and the distributions of short femora and tibiae were examined in adult skeletons from the cemeteries at Lower Saint Bride's (low status) and Chelsea Old Church (high status). Cox proportional hazards models were used to determine if stature was associated with risk of mortality and how that relationship varied with sex and socioeconomic status. RESULTS: High-status females had significantly longer femora, but not tibiae, on average, than low-status females. There were no status-based differences in mean element lengths among males. There were sex and status based differences in the distribution of short femora and tibiae, and there was a significant negative association between tibia length and risk of mortality in high-status females. DISCUSSION: The results may be explained by differences in subadult mortality, potentially due to variation in infant feeding practices. Low-status infants were more likely to live in pathogenic environments and less likely to be breastfed, leading to both stature and immunological deficits, thus minimizing the association between adult stature and mortality, as the shortest individuals did not survive into adulthood. The ways in which migration and repeated epidemics of plague may have shaped stature variation during industrialization are also discussed, highlighting the importance of context in understanding the association between stature and mortality. PMID- 26767498 TI - Revisiting the Phenice technique sex classification results reported by MacLaughlin and Bruce (1990). AB - Phenice (Am J Phys Anthropol 30 (1969):297-301) reported a success rate of 96% for his method of sex determination based on three morphological features of the pelvis. Numerous studies have tested and evaluated the method with affirmative results. The results of the study by MacLaughlin and Bruce (J Forensic Sci 35 (1990):1384-1392) were inconsistent with other studies, reporting far lower rates of accuracy and a greater degree of interobserver error. The authors believe that this may be the result of the inclusion of an "ambiguous" classification category. Revised modelling using forced classification of sex provides much higher classification rates with the implication that the poor results reported by MacLaughlin and Bruce were due to methodological error for the most part. PMID- 26767499 TI - Translational research-the need of a new bioethics approach. AB - Translational research tries to apply findings from basic science to enhance human health and well-being. Many phases of the translational research may include non-medical tasks (information technology, engineering, nanotechnology, biochemistry, animal research, economy, sociology, psychology, politics, and so on). Using common bioethics principles to these areas might sometimes be not feasible, or even impossible. However, the whole process must respect some fundamental, moral principles. The purpose of this paper is to argument the need for a different approach to the morality in translational bioethics, and to suggest some directions that might be followed when constructing such a bioethics. We will show that a new approach is needed and present a few ethical issues that are specific to the translational research. PMID- 26767502 TI - The role of geminates in infants' early word production and word-form recognition. AB - Infants learning languages with long consonants, or geminates, have been found to 'overselect' and 'overproduce' these consonants in early words and also to commonly omit the word-initial consonant. A production study with thirty Italian children recorded at 1;3 and 1;9 strongly confirmed both of these tendencies. To test the hypothesis that it is the salience of the medial geminate that detracts attention from the initial consonant we conducted three experiments with 11-month old Italian infants. We first established baseline word-form recognition for untrained familiar trochaic disyllables and then tested for word-form recognition, separately for words with geminates and singletons, after changing the initial consonant to create nonwords from both familiar and rare forms. Familiar words with geminates were recognized despite the change, words with singletons were not. The findings indicate that a feature occurring later in the word affects initial consonant production and perception, which supports the whole-word phonology model. PMID- 26767500 TI - Interleukin-30 (IL27p28) alleviates experimental sepsis by modulating cytokine profile in NKT cells. AB - BACKGROUND & AIMS: Sepsis is an acute systemic inflammatory response to infection associated with high patient mortality (28-40%). We hypothesized that interleukin (IL)-30, a novel cytokine protecting mice against liver injury resulting from inflammation, would generate a protective effect against systemic inflammation and sepsis-induced death. METHODS: Sepsis was induced by lipopolysaccharide (LPS) or cecal ligation and puncture (CLP). The inhibitory effects of IL-30 on septic inflammation and associated therapeutic effects were determined in wild-type, IL30 (p28)(-/-), IL10(-/-), and CD1d(-/-) mice. RESULTS: Mice treated with pIL30 gene therapy or recombinant IL-30 protein (rIL30) were protected from LPS-induced septic shock or CLP-induced polymicrobial sepsis and showed markedly less liver damage and lymphocyte apoptosis than control septic mice. The resulting reduction in mortality was mediated through attenuation of the systemic pro-inflammatory response and augmentation of bacterial clearance. Mice lacking IL-30 were more sensitive to LPS-induced sepsis. Natural killer-like T cells (NKT) produced much higher levels of IL-10 and lower levels of interferon-gamma and tumor necrosis factor-alpha in IL-30-treated septic mice than in control septic mice. Likewise, deficiency in IL-10 or NKT cells abolished the protective role of IL-30 against sepsis. Furthermore, IL-30 induced IL-10 production in purified and LPS stimulated NKT cells. Blocking IL-6R or gp130 inhibited IL-30 mediated IL-10 production. CONCLUSIONS: IL-30 is important in modulating production of NKT cytokines and subsequent NKT cell-mediated immune regulation of other cells. Therefore, IL-30 has a role in prevention and treatment of sepsis via modulation of cytokine production by NKT. PMID- 26767503 TI - Change in knee structure and change in tibiofemoral joint space width: a five year longitudinal population-based study. AB - BACKGROUND: Change in knee cartilage volume is frequently used as a proxy for change in knee joint space width over time, but longitudinal data on these associations is limited. We aimed to determine whether change in knee cartilage volume, new or worsening meniscal extrusion (ME), meniscal tears and cartilage defects over 2.4 years correlated with change in joint space width (JSW) over 5 years in older community dwelling adults. METHODS: Participants (n = 153) had their right knee imaged using MR imaging and x-ray at baseline, and after 2.4 years (MRI) and 5 years (x-ray). Cartilage volume, cartilage defects, meniscal extrusions and meniscal tears were assessed on sagittal T1-weighted fat suppressed MRI. JSW was assessed using standard fixed semi-flexed view radiographs, and scored on those with adequate alignment. RESULTS: Participants were 51-79 (mean 62) years old; 48% were female. Cartilage volume reduced over time (medial -134 +/- 202 MUL/year, lateral -106 +/- 165 MUL/year, p < 0.001), as did JSW (medial -0.05 +/- 0.16 mm/year, lateral -0.12 +/- 0.24 mm/year, p < 0.001). In multivariable analysis, the only consistent predictor of change in JSW was new or worsening ME (medial tibia R(2) 3.1%, p = 0.031; medial femur R(2) 3.2%, p = 0.024); change in cartilage volume correlated with change in JSW laterally (R(2) 4.8%, p = 0.007) and was borderline medially (R(2) 2.2%, p = 0.064); there was no association for meniscal tears or cartilage defects. The magnitude of these associations were similar albeit somewhat greater for ME in participants with radiographic OA (R(2) 6.2%, p = 0.017). CONCLUSION: Change in ME and cartilage volume weakly predict change in JSW, but the vast majority of the variation remains unexplained. Since MRI examines cartilage directly while radiographs examine it indirectly, these results cast doubt on the validity of using JSW as a proxy measure of cartilage loss. PMID- 26767504 TI - YC-1 induces lipid droplet formation in RAW 264.7 macrophages. AB - BACKGROUND: 3-(5'-Hydroxymethyl-2'-furyl)-1-benzylindazole (YC-1) is a potential anticancer drug that may activate soluble guanylyl cyclase (sGC) and increase the level of cyclic guanosine monophosphate (cGMP). The aim of this study was to explore the effects of YC-1 on lipid droplet accumulation and foam cell formation in macrophages. RESULTS: Human-oxidized low density lipoprotein (ox-LDL) was used to induce accumulation of lipid droplets in a murine macrophage cell line, RAW 264.7. Oil red O staining showed that treatment with 20 MUM YC-1 for 24 h increased the area of intracellular lipid droplets in macrophages. The results of high content screening (HCS) with the AdipoRedTM assay further revealed that YC-1 enhanced ox-LDL-induced foam cell formation. This was evidenced by an increase in the total area of lipid droplets and the mean fluorescence intensity per cell. Inhibition of cGMP-dependent protein kinase (PKG) using KT5823 significantly reduced YC-1-enhanced lipid droplet formation in ox-LDL-induced macrophage foam cells. CONCLUSION: YC-1 induces lipid droplet formation in macrophages, possibly through the sGC/cGMP/PKG signaling pathway. This chemical should be tested with caution in future clinical trials. PMID- 26767507 TI - Skull base osteomyelitis missed in mastoidectomy for cholesteatoma. AB - Conclusions A high suspicion of skull base involvement should be warranted, even if radiological findings are not atypical, in cases of chronic otitis media (COM) with cholesteatoma. Objective To investigate some clues indicating the development of skull base osteomyelitis (SBO) in patients who received mastoidectomy, through reviewing pre-operative temporal bone computed tomography (TBCT). Method Retrospective review of patients with SBO after mastoidectomy for COM. A total of five patients with SBO after mastoidectomy with available pre operative TBCTs were enrolled in this study. Results All patients were diagnosed as COM with cholesteatoma and open cavity mastoidectomy was performed. After surgery, SBO were occurred. The recovery in these five patients was complicated by lower cranial nerve palsy, and one patient had a stroke due to lateral thrombophlebitis. Through re-interpretation of pre-operative TBCT, the bony destruction around the skull base missed at the initial diagnosis was observed in all cases. PMID- 26767506 TI - Hypnosis can reduce pain in hospitalized older patients: a randomized controlled study. AB - BACKGROUND: Chronic pain is a common and serious health problem in older patients. Treatment often includes non pharmacological approaches despite a relatively modest evidence base in this population. Hypnosis has been used in younger adults with positive results. The main objective of this study was to measure the feasibility and efficacy of hypnosis (including self hypnosis) in the management of chronic pain in older hospitalized patients. METHODS: A single center randomized controlled trial using a two arm parallel group design (hypnosis versus massage). Inclusion criteria were chronic pain for more than 3 months with impact on daily life activities, intensity of > 4; adapted analgesic treatment; no cognitive impairment. Brief pain inventory was completed. RESULTS: Fifty-three patients were included (mean age: 80.6 +/- 8.2--14 men; 26 hypnosis; 27 massage. Pain intensity decreased significantly in both groups after each session. Average pain measured by the brief pain index sustained a greater decrease in the hypnosis group compared to the massage group during the hospitalisation. This was confirmed by the measure of intensity of the pain before each session that decreased only in the hypnosis group over time (P = 0.008). Depression scores improved significantly over the time only in the hypnosis group (P = 0.049). There was no effect in either group 3 months post hospitals discharge. DISCUSSIONS AND CONCLUSION: Hypnosis represents a safe and valuable tool in chronic pain management of hospitalized older patients. In hospital interventions did not provide long term post discharge relief. TRIAL REGISTRATION: ISRCTN15615614; registered 2/1/2015. PMID- 26767505 TI - Dipeptidyl peptidase-4 inhibition and narrow-band ultraviolet-B light in psoriasis (DINUP): study protocol for a randomised controlled trial. AB - BACKGROUND: Moderate to severe psoriasis is a systemic inflammatory disease associated with insulin resistance, obesity and type 2 diabetes (T2DM). Sitagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor that improves glycaemia and has a marketing authorisation for the treatment of T2DM. Non immunosuppressive therapies that are effective for psoriasis and its associated comorbidities would be a significant advance in the treatment of this chronic disease. METHODS/DESIGN: This is a single centre, 39-week, prospective, randomised, open label, clinical trial of oral sitagliptin (Januvia((r))) in psoriasis patients who are due to undergo a course of narrow-band ultraviolet-B (NB-UVB) phototherapy. We plan to enrol 120 participants and allocate participants on a random and 1:1 basis to receive sitagliptin 100 mg daily for 24 weeks combined with NB-UVB or NB-UVB monotherapy. Participants will be followed up for 12 weeks after sitagliptin therapy is discontinued. The primary endpoint is the change in Psoriasis Area and Severity Index (PASI) 24 weeks after treatment initiation. Secondary endpoints include cumulative NB-UVB dose, number of NB-UVB treatments required to clear psoriasis, proportions of participants who achieve PASI-50 (50 % reduction in PASI from baseline), PASI-75, PASI-90 and the proportion of participants who relapse in each group. We will also analyse changes in cardiovascular disease risk factors, serum cytokine and hormone levels and peripheral blood mononuclear expression of immune proteins at 24 and 36 weeks. A subgroup of participants will have skin biopsies taken and analysed for skin levels and expression of immune cells, receptors, hormones and immune proteins. The genetic or epigenetic profile that predicts best response to DPP-4 inhibitor therapy will be analysed. The safety endpoints include the rate and severity of adverse events. DISCUSSION: This is the first randomised clinical trial assessing dipeptidyl peptidase-4 inhibition therapy in psoriasis. We hypothesise that sitagliptin therapy in combination with NB-UVB improves psoriasis severity compared to NB-UVB monotherapy. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT02347501 (Date of registration: 27 January 2015). PMID- 26767509 TI - Is late adolescence a real risk factor for an adverse outcome of pregnancy? AB - OBJECTIVE: To compare the obstetrical and neonatal outcomes of late adolescent (LA) and adult pregnancies. METHODS: Between January 2012 and December 2012, a total of 313 late adolescent pregnant aged between 16 and 19 years and 418 adult pregnant women aged between 20 and 35 years having given birth in our maternity service were enrolled into this case-control study. The demographic and clinical data were reviewed from hospital database and patients' medical records. RESULTS: The incidence of preterm birth (PB) in the LA group was significantly higher than in the adult group (p = 0.001), while the incidence of gestational diabetes mellitus was significantly lower (p = 0.001). The mean birth weight and the rate of delivered macrosomic fetuses in the study group were lower than in the control group (p = 0.03). The LA group had significantly higher rate of vaginal delivery when compared to the adult group (p = 0.001). Both the rate of pregnancy induced hypertensive disorders and postpartum hemorrhage were not statistically different between the two groups (p = 0.31; p = 0.38, respectively). The LA group had lower rate of stillbirth when compared to the adult group; however, the difference was statistically insignificant (0.3% versus 1.2%) (p = 0.24). CONCLUSIONS: The LA pregnancy should be closely followed up during their antenatal care period due to the significantly higher rate of PB. PMID- 26767508 TI - Maintenance of Increased Childhood Influenza Vaccination Rates 1 Year After an Intervention in Primary Care Practices. AB - OBJECTIVE: Influenza vaccination rates among some groups of children remain below the Healthy People 2020 goal of 70%. Multistrategy interventions to increase childhood influenza vaccination have not been evaluated recently. METHODS: Twenty pediatric and family medicine practices were randomly assigned to receive the intervention in either year 1 or year 2. This study focuses on influenza vaccine uptake in the 10 year 1 intervention sites during intervention and the following maintenance year. The intervention included the 4 Pillars Immunization Toolkit-a practice improvement toolkit, early delivery of donated vaccine for disadvantaged children, staff education, and feedback on progress. During the maintenance year, practices were not assisted or contacted, except to complete follow-up surveys. Student's t tests assessed vaccine uptake of children aged 6 months to 18 years, and multilevel regression modeling in repeated measures determined variables related to the likelihood of vaccination. RESULTS: Influenza vaccine uptake increased 12.4 percentage points (PP; P < .01) during active intervention and uptake was sustained (+0.4 PP; P > .05) during maintenance, for an average change of 12.7 PP over all sites, increasing from 42.2% at baseline to 54.9% (P < .001) during maintenance. In regression modeling that controlled for age, race, and insurance, likelihood of vaccination was greater during intervention than baseline (odds ratio 1.47; 95% confidence interval 1.44-1.50; P < .001) and greater during maintenance than baseline (odds ratio 1.50; 95% confidence interval 1.47-1.54; P < .001). CONCLUSIONS: In primary care practices, a multistrategy intervention that included the 4 Pillars Immunization Toolkit, early delivery of vaccine, and feedback was associated with significant improvements in childhood influenza vaccination rates that were maintained 1 year after active intervention. PMID- 26767510 TI - Enumeration of extracellular vesicles by a new improved flow cytometric method is comparable to fluorescence mode nanoparticle tracking analysis. AB - Extracellular vesicles (EVs) play a role in a variety of physiological and pathological processes. However, use of EVs as biomarkers has been hampered by limitations of current detection and enumeration methods. We compared fluorescence-threshold flow cytometry (FT-FC) to nanoparticle tracking analysis (NTA) for enumeration of cell culture-derived EVs. FT-FC and NTA utilising fluorescence mode (F-NTA) enumerated similar numbers of EVs stained with a membrane dye PKH67. Both methods were sufficiently sensitive to detect cell derived EVs above the background of culture medium. Light scatter NTA (LS-NTA) detected 10-100* more particles than either fluorescence-based method but demonstrated poor specificity. F-NTA appeared to have better sensitivity for <100nm vesicles, however, the FT-FC method combined direct enumeration of EVs with high sensitivity and specificity in the >100nm range. Due to wider availability and higher degree of automation and standardisation, FT-FC is a reasonable surrogate to F-NTA for quantification of EVs. FROM THE CLINICAL EDITOR: Extracellular vesicles are small particles, which can act as tools for intercellular communication. One recent area of interest in EVs is their potentials as biomarkers. In this article, the authors investigated and compared fluorescence-threshold flow cytometry (FT-FC) to nanoparticle tracking analysis (NTA) for the detection of EVs and showed that FT- FC method could be more advantageous. This technique should provide a new alternative for the future. PMID- 26767511 TI - Enrichment of immunoregulatory proteins in the biomolecular corona of nanoparticles within human respiratory tract lining fluid. AB - When inhaled nanoparticles deposit in the lungs, they transit through respiratory tract lining fluid (RTLF) acquiring a biomolecular corona reflecting the interaction of the RTLF with the nanomaterial surface. Label-free snapshot proteomics was used to generate semi-quantitative profiles of corona proteins formed around silica (SiO2) and poly(vinyl) acetate (PVAc) nanoparticles in RTLF, the latter employed as an archetype drug delivery vehicle. The evolved PVAc corona was significantly enriched compared to that observed on SiO2 nanoparticles (698 vs. 429 proteins identified); however both coronas contained a substantial contribution from innate immunity proteins, including surfactant protein A, napsin A and complement (C1q and C3) proteins. Functional protein classification supports the hypothesis that corona formation in RTLF constitutes opsonisation, preparing particles for phagocytosis and clearance from the lungs. These data highlight how an understanding of the evolved corona is necessary for the design of inhaled nanomedicines with acceptable safety and tailored clearance profiles. FROM THE CLINICAL EDITOR: Inhaled nanoparticles often acquire a layer of protein corona while they go through the respiratory tract. Here, the authors investigated the identity of these proteins. The proper identification would improve the understanding of the use of inhaled nanoparticles in future therapeutics. PMID- 26767512 TI - Comparison of complement activation-related pseudoallergy in miniature and domestic pigs: foundation of a validatable immune toxicity model. AB - Complement activation-related pseudoallergy (CARPA) is an acute adverse immune reaction caused by many nanomedicines. There is a regulatory need for a sensitive and standardizable in vivo predictive assay. While domestic pigs are a sensitive animal model, miniature pigs are favored in toxicological studies yet their utility as a CARPA model has not yet been explored. Herein, we used liposomal doxorubicin and amphotericin B (Doxil/Caelyx and AmBisome), Cremophor EL and zymosan as CARPA triggers to induce reactions in miniature and domestic pigs, and compared the hemodynamic, hematological, biochemical, and skin alterations. The changes observed after administration of the test agents were very similar in both pig strains, suggesting that miniature pigs are a sensitive, reproducible, and, hence, validatable animal model for CARPA regulatory testing. FROM THE CLINICAL EDITOR: With the advances in nanomedicine research, many new agents are now tested for use in clinical setting. Nonetheless, complement activation related pseudoallergy (CARPA) is a well known phenomenon which can be caused by nanoparticles. In this study, the authors looked at and compared the use of domestic pigs versus miniature pigs as experimental animals for toxicological studies. Their findings confirmed the possible use of miniature pigs for regulatory testing. PMID- 26767513 TI - In vitro and in vivo anti-tumor efficacy of 10-hydroxycamptothecin polymorphic nanoparticle dispersions: shape- and polymorph-dependent cytotoxicity and delivery of 10-hydroxycamptothecin to cancer cells. AB - Nanotechnology associated with a crystal engineering approach was proposed for improving the solubility and efficacy of hydrophobic drugs in this study. 10 hydroxycamptothecin polymorphic nanoparticle dispersions (HCPT-PNDs) were prepared using the supercritical anti-solvent technique coupled with the high pressure homogenization method. Shape- and polymorph-dependent tumor suppression was observed in both in vitro and in vivo models, where needle-shaped HCPT-PND exhibited dramatic improvement of antitumor efficacy. A benefit of controllable size and a large surface-to-volume ratio of needle-shaped nanoparticles is the improvement of dissolution properties, which facilitates enhancing pharmacokinetic and pharmaco-dynamic properties. The needle-shaped HCPT-PND, which with longer blood retention time and more effective cellular uptake, makes it possible to accumulate drug in tumor tissues and exhibit higher cytotoxicity. No severe systemic toxicity was observed due to sustained-dissolution and the low dose of drug in normal tissues. The results suggest that the needle-shaped HCPT PND is an interesting nano-formulation of HCPT. FROM THE CLINICAL EDITOR: Nanotechnology has enabled the production of novel therapeutics drugs against cancer. Here, the authors investigated the use of a crystal engineering approach for the modification of camptothecin in order to improve its water solubility. Physicochemical and biological properties were studied. The results would suggest the applicability of this approach for nano-formulation. PMID- 26767514 TI - Intranasal brain delivery of cationic nanoemulsion-encapsulated TNFalpha siRNA in prevention of experimental neuroinflammation. AB - Neuroinflammation is a hallmark of acute and chronic neurodegenerative disorders. The main aim of this study was to evaluate the therapeutic efficacy of intranasal cationic nanoemulsion encapsulating an anti-TNFalpha siRNA, for potential anti inflammatory therapy. TNFalpha siRNA nanoemulsions were prepared and characterized for particle size, surface charge, morphology, and stability and encapsulation efficiency. Qualitative and quantitative intracellular uptake studies by confocal imaging and flow cytometry, respectively, showed higher uptake compared to Lipofectamine(r) transfected siRNA. Nanoemulsion significantly lowered TNFalpha levels in LPS-stimulated cells. Upon intranasal delivery of cationic nanoemulsions almost 5 fold higher uptake was observed in the rat brain compared to non-encapsulated siRNA. More importantly, intranasal delivery of TNFalpha siRNA nanoemulsions in vivo markedly reduced the unregulated levels of TNFalpha in an LPS-induced model of neuroinflammation. These results indicate that intranasal delivery of cationic nanoemulsions encapsulating TNFalpha siRNA offered an efficient means of gene knockdown and this approach has significant potential in prevention of neuroinflammation. FROM THE CLINICAL EDITOR: Neuroinflammation is often seen in patients with neurodegenerative disorders and tumor necrosis factor-alpha (TNFalpha) plays a significant role in contributing to neuronal dysfunction. As a result, inhibition of TNFalpha may alleviate disease severity. In this article, the authors investigated using a cationic nanoemulsion system carrying TNFalpha siRNA intra-nasally to protect against neuroinflammation. This new method may provide a future approach in this clinical setting. PMID- 26767515 TI - Superparamagnetic iron-oxide nanoparticles mPEG350- and mPEG2000-coated: cell uptake and biocompatibility evaluation. AB - Superparamagnetic iron oxide nanoparticles (SPIONS) were synthesized by thermal decomposition of an organometallic precursor at high temperature and coated with a bi-layer composed of oleic acid and methoxy-polyethylene glycol-phospholipid. The formulations were named SPION-PEG350 and SPION-PEG2000. Transmission electron microscopy, X-ray diffraction and magnetic measurements show that the SPIONs are near-spherical, well-crystalline, and have high saturation magnetization and susceptibility. FTIR spectroscopy identifies the presence of oleic acid and of the conjugates mPEG for each sample. In vitro biocompatibility of SPIONS was investigated using three cell lines; up to 100MUg/ml SPION-PEG350 showed non toxicity, while SPION-PEG2000 showed no signal of toxicity even up to 200MUg/ml. The uptake of SPIONS was detected using magnetization measurement, confocal and atomic force microscopy. SPION-PEG2000 presented the highest internalization capacity, which should be correlated with the mPEG chain size. The in vivo results suggested that SPION-PEG2000 administration in mice triggered liver and kidney injury. FROM THE CLINICAL EDITOR: The potential use of superparamagnetic iron oxide nanoparticles (SPIONS) in the clinical setting have been studied by many researchers. The authors synthesized two types of SPIONS here and investigated the physical properties and biological compatibility. The findings should provide more data on the design of SPIONS for clinical application in the future. PMID- 26767516 TI - Nanoparticle-mediated drug delivery to high-grade gliomas. AB - High grade gliomas (HGGs) are fatal brain tumors due to their infiltration capacity and the presence of resistant cell populations. Further, the brain is naturally protected from many exogenous molecules by the brain blood barrier (BBB), which limits or cancels passage of cytotoxic drugs to the tumor sites. In order to cope with the latter problem, nanoparticle (NP)-based carriers are intensively investigated, due to multiple possibilities to drive them across the BBB to the tumor sites and drop cytotoxic molecules there. The current status of research on NP for drug delivery to HGGs has been analyzed. The results indicate gold, lipids and proteins as three main materials featuring NP formulations for HGG treatment. Albeit specific drug targeting to HGG cells may have not been so far significantly improved, NP may help drugs crossing the BBB and enter the brain thus potentially fixing at least one part of the problem. FROM THE CLINICAL EDITOR: High grade gliomas (HGG) are very aggressive tumours and current therapy remains unsatisfactory. The advance in nanomedicine has allowed the development of novel treatment modalities. In this review article, the authors outlined the current status in using nanoparticle (NP)-based carriers for drug delivery to HGG. This should help readers to understand and develop ideas for further drug carrier designs. PMID- 26767517 TI - Nanoparticulate mediated transcutaneous immunization: Myth or reality. AB - Transcutaneous immunization (TCI) is a promising route of vaccine delivery through skin due to many well documented advantages. The main obstacle in TCI is the skin's top dead layer i.e. stratum corneum which is difficult to penetrate. Efficiently delivery of antigen to the immune competent cells of epidermis or dermis in TCI might elicit an effective immune response. In this review, skin immunology with a particular focus on potential of immunological active receptors in influencing adaptive immune responses is highlighted. The challenges with TCI and methods to improve it using different adjuvants, chemical and physical approaches, delivery systems, and combination of above methods to further improve immune response following skin application of antigen are elaborately discussed. Nanoparticulate vaccine delivery systems with reference to their applications in TCI are classified according to their chronological development. Conclusively, clinical translations of above methods are also briefly reviewed. FROM THE CLINICAL EDITOR: Transcutaneous immunization has been investigated by many as a promising route of vaccination. In this comprehensive review article, the authors described and discussed the existing knowledge and difficulties in this approach. Furthermore, ways of improving transcutaneous delivery were also reviewed. PMID- 26767518 TI - Impact of heart disease and calibration interval on accuracy of pulse transit time-based blood pressure estimation. AB - Continuous blood pressure (BP) measurement without a cuff is advantageous for the early detection and prevention of hypertension. The pulse transit time (PTT) method has proven to be promising for continuous cuffless BP measurement. However, the problem of accuracy is one of the most challenging aspects before the large-scale clinical application of this method. Since PTT-based BP estimation relies primarily on the relationship between PTT and BP under certain assumptions, estimation accuracy will be affected by cardiovascular disorders that impair this relationship and by the calibration frequency, which may violate these assumptions. This study sought to examine the impact of heart disease and the calibration interval on the accuracy of PTT-based BP estimation. The accuracy of a PTT-BP algorithm was investigated in 37 healthy subjects and 48 patients with heart disease at different calibration intervals, namely 15 min, 2 weeks, and 1 month after initial calibration. The results showed that the overall accuracy of systolic BP estimation was significantly lower in subjects with heart disease than in healthy subjects, but diastolic BP estimation was more accurate in patients than in healthy subjects. The accuracy of systolic and diastolic BP estimation becomes less reliable with longer calibration intervals. These findings demonstrate that both heart disease and the calibration interval can influence the accuracy of PTT-based BP estimation and should be taken into consideration to improve estimation accuracy. PMID- 26767520 TI - IGF-1 as an Important Endogenous Growth Factor for Recovery from Impaired Urethral Continence Function in Rats with Simulated Childbirth Injury. AB - PURPOSE: We examined the functional role of endogenous IGF-1 (insulin-like growth factor-1) in the recovery phase of stress urinary incontinence induced by simulated childbirth trauma using an IGF-1 receptor inhibitor. MATERIALS AND METHODS: Simulated birth trauma was induced by vaginal distension in female Sprague Dawley(r) rats. The IGF-1 receptor antagonist JB-1 (10 and 100 MUg/kg per day) or vehicle was continuously delivered from 1 day before vaginal distension for 7 days using subcutaneous osmotic pumps. Seven, 14 and 21 days after vaginal distension the effect of JB-1 treatment was examined by functional analyses, including leak point and urethral baseline pressure, and urethral responses during passive increments in intravesical pressure, as well as molecular analyses in urethral tissues, including phosphorylation of Akt, apoptotic changes and peripheral nerve density using Western blot and immunohistochemistry. RESULTS: On functional analyses vehicle treated rats with vaginal distension had significantly decreased leak point and urethral baseline pressure, and urethral responses at 7 days, which recovered to the normal level 14 and 21 days after vaginal distension. In the JB-1 treated vaginal distension group leak point and urethral baseline pressure, and urethral responses were still significantly reduced 21 days after vaginal distension. On molecular analyses JB-1 treatment increased apoptotic cells, induced a significant decrease in phosphorylated Akt and prolonged the decrease of peripheral nerve density in urethral tissues. CONCLUSIONS: Suppression of endogenous IGF-1 activity delayed recovery from stress urinary incontinence induced by simulated childbirth trauma in rats. Thus, IGF-1 is likely to be an important endogenous mediator for functional recovery from childbirth related stress urinary incontinence. This suggests that IGF-1 could be an effective target for treating stress urinary incontinence in women. PMID- 26767519 TI - Limitations of Elastography Based Prostate Biopsy. AB - PURPOSE: The role of elastography in patients initially and at repeat prostate biopsy is still indeterminate. The existing literature is sparse and controversial. MATERIALS AND METHODS: We studied patients who underwent elastography based and systematic biopsy between October 2009 and February 2015 at Braunschweig Prostate Cancer Center. Patients were separated according to first vs repeat biopsy setting. Each prostate sextant was considered an individual case. The sensitivity, specificity, positive and negative predictive values, and accuracy of elastography to predict biopsy results were analyzed. The 95% CIs were determined by bootstrapping analysis of 2,000 samples. RESULTS: Overall 679 men and a total of 4,074 sextants were identified. Of the 679 men 160 (23.6%) underwent first biopsy and 519 (76.4%) underwent repeat biopsy. In the 160 men at first biopsy sensitivity was 18.0% (95% CI 14.5-21.3), specificity was 87.7% (95% CI 85.3-89.9), positive predictive value was 36.6% (95% CI 28.4-45.4), negative predictive value was 73.0% (95% CI 67.5-77.9) and accuracy was 67.9% (95% CI 63.4-72.2). Results in 519 men (76.4%) at repeat biopsy were 19.8% (95% CI 16.0-23.7), 90.9% (95% CI 89.9-91.9), 20.1% (95% CI 15.8-24.8), 90.7% (95% CI 89.0-92.3) and 83.5% (95% CI 81.6-85.2), respectively. CONCLUSIONS: We found limited reliability of elastography prediction at prostate biopsy in patients at first and repeat biopsies. Based on our analyses we cannot recommend a variation of well established systematic biopsy patterns or a decrease in biopsy cores based on elastography. PMID- 26767521 TI - Urinary concentrations of pyrethroid metabolites and its association with lung function in a Canadian general population. AB - OBJECTIVES: While there is increasing concern about the health impact of pyrethroid insecticides, little is known about their effect on lung function. In this cross-sectional study, urinary concentrations of pyrethroid (PYR) metabolites and their associations with lung function were examined among a Canadian general population using data from the Canadian Health Measures Survey (CHMS). METHODS: Urinary concentrations of 5 pyrethroid metabolites (3-PBA, 4-F-3 PBA, cis-DCCA, trans-DCCA and cis-DBCA) were available for 5436 CHMS participants aged 6-79 years. Lung function parameters considered were forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), FEV1/FVC ratio and forced expiratory flow between 25% and 75% of FVC. Multiple linear regression analyses were used to examine associations between PYR concentrations and lung function in children (6-11 years), adolescents (12-19 years) and adults (20-79 years), respectively. RESULTS: Almost all CHMS participants (99.8%) had PYR metabolites detectable in urine. In multiple linear regression analyses, 1 unit increase in log transformed urinary concentration (nmol/g creatinine) of total pyrethorid metabolites (SigmaPYR) was associated with a 17.4 mL reduction in FEV1 (p=0.045) in children, a 37.1 mL reduction in FVC (p=0.05) in adolescents and a 0.3% (p=0.01) increase in FEV1/FVC ratio in adults. CONCLUSIONS: These results show evidence of widespread exposures to pyrethroid insecticides among the Canadian general population. Pyrethroid exposures were associated with lower FEV1 in children, lower FVC in adolescents and relatively higher FEV1/FVC ratio in adults. Further research is necessary to confirm the potential effect of pyrethroid insecticides on lung function reported in this study. PMID- 26767523 TI - Erratum to: Short-term glucagon stimulation test of C-peptide effect on glucose utilization in patients with type 1 diabetes mellitus. PMID- 26767522 TI - [Functional brain imaging]. AB - METHOD: Functional magnetic resonance imaging (fMRI) is a non-invasive method that has become one of the major tools for understanding human brain function and in recent years has also been developed for clinical applications. PERFORMANCE: Changes in hemodynamic signals correspond to changes in neuronal activity with good spatial and temporal resolution in fMRI. Using high-field MR systems and increasingly dedicated statistics and postprocessing, activated brain areas can be detected and superimposed on anatomical images. Currently, fMRI data are often combined in multimodal imaging, e. g. with diffusion tensor imaging (DTI) sequences. This method is helping to further understand the physiology of cognitive brain processes and is also being used in a number of clinical applications. In addition to the blood oxygenation level-dependent (BOLD) signals, this article deals with the construction of fMRI investigations, selection of paradigms and evaluation in the clinical routine. Clinically, this method is mainly used in the planning of brain surgery, analyzing the location of brain tumors in relation to eloquent brain areas and the lateralization of language processing. PRACTICAL RECOMMENDATIONS: As the BOLD signal is dependent on the strength of the magnetic field as well as other limitations, an overview of recent developments is given. Increases of magnetic field strength (7 T), available head coils and advances in MRI analytical methods have led to constant improvement in fMRI signals and experimental design. Especially the depiction of eloquent brain regions can be done easily and quickly and has become an essential part of presurgical planning. PMID- 26767524 TI - Genome-wide identification, classification and expression analysis in fungal plant interactions of cutinase gene family and functional analysis of a putative ClCUT7 in Curvularia lunata. AB - Cutinase is described as playing various roles in fungal-plant pathogen interactions, such as eliciting host-derived signals, fungal spore attachment and carbon acquisition during saprophytic growth. However, the characteristics of the cutinase genes, their expression in compatible interactions and their roles in pathogenesis have not been reported in Curvularia lunata, an important leaf spot pathogen of maize in China. Therefore, a cutinase gene family analysis could have profound significance. In this study, we identified 13 cutinase genes (ClCUT1 to ClCUT13) in the C. lunata genome. Multiple sequence alignment showed that most fungal cutinase proteins had one highly conserved GYSQG motif and a similar DxVCxG[ST]-[LIVMF](3)-x(3)H motif. Gene structure analyses of the cutinases revealed a complex intron-exon pattern with differences in the position and number of introns and exons. Based on phylogenetic relationship analysis, C. lunata cutinases and 78 known cutinase proteins from other fungi were classified into four groups with subgroups, but the C. lunata cutinases clustered in only three of the four groups. Motif analyses showed that each group of cutinases from C. lunata had a common motif. Real-time PCR indicated that transcript levels of the cutinase genes in a compatible interaction between pathogen and host had varied expression patterns. Interestingly, the transcript levels of ClCUT7 gradually increased during early pathogenesis with the most significant up regulation at 3 h post-inoculation. When ClCUT7 was deleted, pathogenicity of the mutant decreased on unwounded maize (Zea mays) leaves. On wounded maize leaves, however, the mutant caused symptoms similar to the wild-type strain. Moreover, the ClCUT7 mutant had an approximately 10 % reduction in growth rate when cutin was the sole carbon source. In conclusion, we identified and characterized the cutinase family genes of C. lunata, analyzed their expression patterns in a compatible host-pathogen interaction, and explored the role of ClCUT7 in pathogenicity. This work will increase our understanding of cutinase genes in other fungal-plant pathogens. PMID- 26767525 TI - Abuse Potential of Pregabalin: A Systematic Review. AB - BACKGROUND: Several case reports and epidemiological studies have raised concern about the abuse potential of pregabalin, the use of which has increased substantially over the last decade. Pregabalin is, in some cases, used for recreational purposes and it has incurred attention among drug abusers for causing euphoric and dissociative effects when taken in doses exceeding normal therapeutic dosages or used by alternative routes of administration, such as nasal insufflation or venous injection. The magnitude of the abuse potential and the mechanism behind it are not fully known. OBJECTIVE: The aim of this study was to present a systematic review of the data concerning the abuse potential of pregabalin. METHODS: We performed a systematic literature search and reviewed the preclinical, clinical and epidemiological data on the abuse potential of pregabalin. RESULTS: We included preclinical (n = 17), clinical (n = 19) and epidemiological (n = 13) studies addressing the abuse potential of pregabalin. We also reviewed case reports (n = 9) concerning abuse of pregabalin. The preclinical studies indicated that pregabalin possesses modulatory effects on the GABA and glutamate systems, leaving room for an abuse potential. Further, clinical studies reported euphoria as a frequent side effect in patients treated with pregabalin. The majority of case reports concerning abuse of pregabalin involved patients with a history of substance abuse and, similarly, epidemiological studies found evidence of abuse, especially among opiate abusers. CONCLUSIONS: Overall, the available literature suggests an important clinical abuse potential of pregabalin and prescribers should pay attention to signs of abuse, especially in patients with a history of substance abuse. PMID- 26767526 TI - Modern Therapies for Idiopathic Inflammatory Myopathies (IIMs): Role of Biologics. AB - Despite the lack of placebo-controlled trials, glucocorticoids are considered the mainstay of initial treatment for idiopathic inflammatory myopathy (IIMs) and myositis-associated ILD (MA-ILD). Glucocorticoid-sparing agents are often given concomitantly with other immunosuppressive agents, particularly in patients with moderate or severe disease. As treatment of refractory cases of idiopathic inflammatory myopathies has been challenging, there is growing interest in evaluating newer therapies including biologics that target various pathways involved in the pathogenesis of IIMs. In a large clinical trial of rituximab in adult and juvenile myositis, the primary outcome was not met, but the definition of improvement was met by most of this refractory group of myositis patients. Rituximab use was also associated with a significant glucocorticoid-sparing effect. Intravenous immune globulin (IVIg) can be used for refractory IIMs or those with severe dysphagia or concomitant infections. Anti-tumor necrosis factor (anti-TNF) utility in IIMs is generally limited by previous negative studies along with recent reports suggesting their potential for inducing myositis. Further research is required to assess the role of new therapies such as tocilizumab (anti-IL6), ACTH gel, sifalimumab (anti-IFNalpha), and abatacept (inhibition of T cell co-stimulation) given their biological plausibility and encouraging small case series results. Other potential novel therapies include alemtuzumab (a humanized monoclonal antibody which binds CD52 on B and T lymphocytes), fingolimod (a sphingosine 1-phosphate receptor modulator that traps T lymphocytes in the lymphoid organs), eculizumab, and basiliximab. The future investigations in IIMs will depend on well-designed controlled clinical trials using validated consensus core set measures and improvements in myositis classification schemes based on serologic and histopathologic features. PMID- 26767527 TI - Woven Endobridge (WEB) device for endovascular treatment of complex unruptured aneurysms-a single center experience. AB - INTRODUCTION: The introduction of the Woven Endobridge (WEB) device increases the feasibility of endovascular treatment of wide-neck bifurcation aneurysms with limitations given by currently available sizes and shapes of the device. Parallel to other studies, we used the new device for selected patients who were no optimal candidates for established techniques like neurosurgical clipping or endovascular coiling. We aimed to report the angiographic and clinical results of WEB implantations or combinations between WEB and coiling or intracranial stents. METHODS: We reviewed the records of n = 23 interventions in 22 patients with unruptured wide-neck aneurysms (UIA) who were assigned for aneurysm treatment with the use of the WEB or adjunctive techniques. Interventional procedures and clinical and angiographic outcomes are reported for the periprocedural phase and in mid-term FU. RESULTS: Of the included 22 patients, six patients needed additional coiling, intracranial stenting, or implantation of a flow diverter. WEB implantation was technically feasible in 22 out of the 23 interventions. Follow-up angiographic imaging proved total or subtotal occlusion of the aneurysm in 19 of 22 cases. Two minor recurrences remained stable during a period of 15 months. One patient with a partially thrombosed giant MCA aneurysm had a major recurrence and was retreated with a second WEB in combination with coiling. CONCLUSION: Despite of unfavorable anatomic conditions, broad-based and large UIA endovascular treatment with the WEB and adjunctive techniques was feasible with a low risk of complications and promising occlusion rates in mid-term follow-up. PMID- 26767529 TI - Is speckle tracking actually helpful for cardiac resynchronization therapy? AB - What is the specific role of echocardiography in cardiac resynchronization therapy (CRT)? CRT has proven to be highly effective for improving symptoms and survival of patients with advanced heart failure (HF) and wide QRS. However, a significant minority of patients do not respond favorably to CRT on the basis of standard clinical selection criteria, including the electrocardiographic QRS width. Subsequently, echocardiographic assessment of left ventricular (LV) dyssynchrony has been considered useful for CRT for selected responders, but findings by multicenter studies suggest that its predictive value was not sufficiently robust to replace routine selection criteria for CRT. A more recent approach, however, using speckle-tracking echocardiography yields more accurate quantification of regional wall contraction. Speckle-tracking approaches have therefore generated a great deal of interest about their clinical applications for CRT. Although reports on speckle tracking have not been included in any recommendations as to whether patients should undergo CRT based on the current guidelines, speckle tracking can play an important supplementary part in CRT on the basis of a case-by-case clinical decision for challenging cases. Here, we review the strengths of speckle-tracking methods, and their current potential for clinical use in CRT. PMID- 26767528 TI - Optimal differentiation of high- and low-grade glioma and metastasis: a meta analysis of perfusion, diffusion, and spectroscopy metrics. AB - INTRODUCTION: To perform a meta-analysis of advanced magnetic resonance imaging (MRI) metrics, including relative cerebral blood volume (rCBV), normalized apparent diffusion coefficient (nADC), and spectroscopy ratios choline/creatine (Cho/Cr) and choline/N-acetyl aspartate (Cho/NAA), for the differentiation of high- and low-grade gliomas (HGG, LGG) and metastases (MTS). METHODS: For systematic review, 83 articles (dated 2000-2013) were selected from the NCBI database. Twenty-four, twenty-two, and eight articles were included respectively for spectroscopy, rCBV, and nADC meta-analysis. In the meta-analysis, we calculated overall means for rCBV, nADC, Cho/Cr (short TE-from 20 to 35 ms, medium-from 135 to 144 ms), and Cho/NAA for the HGG, LGG, and MTS groups. We used random effects model to obtain weighted averages and select thresholds. RESULTS: Overall means (with 95% CI) for rCBV, nADC, Cho/Cr (short and medium echo time, TE), and Cho/NAA were: for HGG 5.47 (4.78-6.15), 1.38 (1.16-1.60), 2.40 (1.67 3.13), 3.27 (2.78-3.77), and 4.71 (3.24-6.19); for LGG 2.00 (1.71-2.28), 1.61 (1.36-1.87), 1.46 (1.20-1.72), 1.71 (1.49-1.93), and 2.36 (1.50-3.23); for MTS 5.06 (3.85-6.27), 1.35 (1.06-1.64), 1.89 (1.72-2.06), 3.14 (1.57-4.72), (Cho/NAA was not available). LGG had significantly lower rCBV, Cho/Cr, and Cho/NAA values than HGG or MTS. No significant differences were found for nADC. CONCLUSIONS: Best differentiation between HGG and LGG is obtained from rCBV, Cho/Cr, and Cho/NAA metrics. MTS could not be reliably distinguished from HGG by the methods investigated. PMID- 26767531 TI - Single- versus dual-console robotic surgery: dual improves the educational experience for trainees. PMID- 26767530 TI - Infant birthweight in the US: the role of preconception stressful life events and substance use. AB - The purpose of this study was to determine the relationships among preconception stressful life events (PSLEs), women's alcohol and tobacco use before and during pregnancy, and infant birthweight. Data were from the Early Childhood Longitudinal Study-Birth Cohort (n = 9,350). Data were collected in 2001. Exposure to PSLEs was defined by indications of death of a parent, spouse, or previous live born child; divorce or marital separation; or fertility problems prior to conception. Survey data determined alcohol and tobacco usage during the 3 months prior to and in the final 3 months of pregnancy. We used staged multivariable logistic regression to estimate the effects of women's substance use and PSLEs on the risk of having a very low (<1,500 g, VLBW) or low (1,500 2,499 g, LBW) birthweight infant, adjusting for confounders. Women who experienced any PSLE were more likely to give birth to VLBW infants (adjusted odds ratio [AOR] = 1.35; 95 % confidence interval [CI] = 1.10-1.66) than women who did not experience any PSLE. Compared to women who never smoked, women who smoked prior to conception (AOR = 1.31; 95 % CI = 1.04-1.66) or during their last trimester (AOR = 1.98; 95 % CI = 1.56-2.52) were more likely to give birth to LBW infants. PSLEs and women's tobacco use before and during pregnancy are independent risk factors for having a lower birthweight baby. Interventions to improve birth outcomes may need to address women's health and health behaviors in the preconception period. PMID- 26767532 TI - Nonadherence as 4-day Antiretroviral Therapy Interruptions: Do Depression and Race/Ethnicity Matter as Much in the Modern Antiretroviral Therapy Era? AB - HIV + White, Latino, and African Americans (N = 1131) completed a survey advertised on social media to re-examine the effect of depressive symptoms (via the Patient Health Questionnaire; PHQ-9) and race/ethnicity on antiretroviral therapy nonadherence (defined as past 3-month, 4-day treatment interruption). An adjusted logistic regression showed a 15 % increase in odds for a treatment interruption per 1-unit increase on the PHQ-9. The effect of depressive symptoms on nonadherence was greater for Latinos (OR = 1.80, p < 0.05), but not for African Americans, compared to Whites. The benefits of modern ART (e.g., simpler, forgiving to minor lapses) may not circumvent the effect of depressive symptomatology. PMID- 26767533 TI - Sexual Orientation, Gender Identity and Perceived Source of Infection Among Men Who Have Sex with Men (MSM) and Transgender Women (TW) Recently Diagnosed with HIV and/or STI in Lima, Peru. AB - Risk perception and health behaviors result from individual-level factors influenced by specific partnership contexts. We explored individual- and partner level factors associated with partner-specific perceptions of HIV/STI risk among 372 HIV/STI-positive MSM and transgender women (TW) in Lima, Peru. Generalized estimating equations explored participants' perception of their three most recent partner(s) as a likely source of their HIV/STI diagnosis. Homosexual/gay (PR = 2.07; 95 % CI 1.19-3.61) or transgender (PR = 2.84; 95 % CI 1.48-5.44) partners were more likely to be considered a source of infection than heterosexual partners. Compared to heterosexual respondents, gay and TW respondents were less likely to associate their partner with HIV/STI infection, suggesting a cultural link between gay or TW identity and perceived HIV/STI risk. Our findings demonstrate a need for health promotion messages tailored to high-risk MSM partnerships addressing how perceived HIV/STI risk aligns or conflicts with actual transmission risks in sexual partnerships and networks. PMID- 26767534 TI - Barriers and Facilitators of HIV Care Engagement: Results of a Qualitative Study in St. Petersburg, Russia. AB - Russia has a large HIV epidemic, but medical care engagement is low. Eighty HIV positive persons in St. Petersburg completed in-depth interviews to identify barriers and facilitators of medical HIV care engagement. The most commonly reported barriers involved difficulties accessing care providers, dissatisfaction with the quality of services, and negative attitudes of provider staff. Other barriers included not having illness symptoms, life stresses, low value placed on health, internalized stigma and wanting to hide one's HIV status, fears of learning about one's true health status, and substance abuse. Care facilitators were feeling responsible for one's health and one's family, care-related support from other HIV-positive persons, and the onset of health decline and fear of death. Substance use remission facilitated care engagement, as did good communication from providers and trust in one's doctor. Interventions are needed in Russia to address HIV care infrastructural barriers and integrate HIV, substance abuse, care, and psychosocial services. PMID- 26767535 TI - A Livelihood Intervention to Reduce the Stigma of HIV in Rural Kenya: Longitudinal Qualitative Study. AB - The scale-up of effective treatment has partially reduced the stigma attached to HIV, but HIV still remains highly stigmatized throughout sub-Saharan Africa. Most studies of anti-HIV stigma interventions have employed psycho-educational strategies such as information provision, counseling, and testimonials, but these have had varying degrees of success. Theory suggests that livelihood interventions could potentially reduce stigma by weakening the instrumental and symbolic associations between HIV and premature morbidity, economic incapacity, and death, but this hypothesis has not been directly examined. We conducted a longitudinal qualitative study among 54 persons with HIV participating in a 12 month randomized controlled trial of a livelihood intervention in rural Kenya. Our study design permitted assessment of changes over time in the perspectives of treatment-arm participants (N = 45), as well as an understanding of the experiences of control arm participants (N = 9, interviewed only at follow-up). Initially, participants felt ashamed of their seropositivity and were socially isolated (internalized stigma). They also described how others in the community discriminated against them, labeled them as being "already dead," and deemed them useless and unworthy of social investment (perceived and enacted stigma). At follow-up, participants in the treatment arm described less stigma and voiced positive changes in confidence and self-esteem. Concurrently, they observed that other community members perceived them as active, economically productive, and contributing citizens. None of these changes were noted by participants in the control arm, who described ongoing and continued stigma. In summary, our findings suggest a theory of stigma reduction: livelihood interventions may reduce internalized stigma among persons with HIV and also, by targeting core drivers of negative attitudes toward persons with HIV, positively change attitudes toward persons with HIV held by others. Further research is needed to formally test these hypotheses, assess the extent to which these changes endure over the long term, and determine whether this class of interventions can be implemented at scale. PMID- 26767536 TI - How Different are Men Who Do Not Know Their HIV Status from Those Who Do? Results from an U.S. Online Study of Gay and Bisexual Men. AB - We compared self-described HIV-positive (31.6 %, n = 445), HIV-negative (56.8 %, n = 801), and HIV-unknown (11.6 %, n = 164) gay and bisexual men on sociodemographic and behavioral characteristics. Participants from across the U.S. were enrolled via a popular sexual networking website to complete an online survey. In total, 44.8 % of HIV-negative and HIV-unknown men said they had not been tested for HIV in the CDC-recommended last 6 months. HIV-unknown men significantly differed from HIV-negative and HIV-positive men in sexual behavior and HIV status disclosure patterns. HIV-unknown men were more willing than HIV negative men to take PrEP; however, HIV-unknown men were significantly less likely than others to have health insurance or a primary care provider. Given the observed differences, researchers should consider analyzing men who are HIV unknown distinctly from HIV-negative and HIV-positive men. PMID- 26767538 TI - HIV Serostatus Disclosure to Sexual Partners Among Sexually Active People Living with HIV in South Africa: Results from the 2012 National Population-Based Household Survey. AB - This paper explores the prevalence and correlates of HIV seropositive status disclosure to sexual partners by people living with HIV (PLHIV) in South Africa. Secondary analysis of the 2012 South African National HIV Prevalence, Incidence and Behaviour Survey was conducted on data obtained from 934 sexually active PLHIV aged 15 years and older who responded to the question about HIV seropositive status disclosure. Overall, a large majority of respondents (77.1 %) reported disclosing their HIV-positive status to all their current sex partners. Multiple regression analysis, after adjustments for sex, marital status and locality type, revealed that those who were living together, going steady, and those who were single were all 60 % [adjusted odds ratio (AOR) = 0.4, 95 % CIs 0.20-0.78; AOR = 0.4, 95 % CIs 0.24-0.77; and AOR = 0.4, 95 % CIs 0.19-1.00, all ps < 0.05] less likely to disclose their HIV positive status to their partners compared to those who were married. Those who lived in rural formal areas were 70 % less likely to disclose their HIV status to their partners compared to those who stayed in urban formal areas (AOR = 0.3, 95 % CI 0.17-0.69, p < 0.001). Those who had correct HIV knowledge and rejection of myths were 2.0 times more likely to disclose their HIV status to their partners compared to those who did not have correct HIV knowledge and rejection of myths (AOR = 2.0, 95 % CI 1.04-3.68, p < 0.05). In conclusion, intervention programmes which help improve HIV seropositive status disclosure are needed by PLHIV who are not married, live in rural formal areas, and have incorrect HIV knowledge and rejection of myths. PMID- 26767537 TI - Sociodemographic Factors, Sexual Behaviors, and Alcohol and Recreational Drug Use Associated with HIV Among Men Who Have Sex with Men in Southern Vietnam. AB - A total of 2768 MSM participated in a survey in southern Vietnam. Univariate and multivariate logistic regression analyses were performed to determine predictors of HIV infection. The prevalence of HIV among MSM was 2.6 %. HIV infection was more likely in MSM who were older, had a religion, had engaged in anal sex with a foreigner in the past 12 months, previously or currently used recreational drugs, perceived themselves as likely or very likely to be infected with HIV, and/or were syphilis seropositive. MSM who had ever married, were exclusively or frequently receptive, sometimes consumed alcohol before sex, and/or frequently used condoms during anal sex in the past 3 months were less likely to be infected with HIV. Recreational drug use is strongly associated with HIV infection among MSM in southern Vietnam. HIV interventions among MSM should incorporate health promotion, condom promotion, harm reduction, sexually transmitted infection treatment, and address risk behaviors. PMID- 26767539 TI - The Experience of Antiretroviral Treatment for Black West African Women who are HIV Positive and Living in London: An Interpretative Phenomenological Analysis. AB - Antiretroviral therapy (ART) offers a powerful intervention in HIV but effectiveness can be compromised by inadequate adherence. This paper is a detailed examination of the experience of medication in a purposively selected group of people living with HIV. In-depth interviews were conducted with 10 HIV positive, West African women of black heritage living in London, UK. This group was of interest since it is the second largest group affected by HIV in the UK. Interviews were subjected to interpretative phenomenological analysis, an idiographic, experiential, qualitative approach. The paper details the women's negative experience of treatment. ART can be considered difficult and unrelenting and may be disconnected from the women's sense of health or illness. Participants' social context often exacerbated the difficulties. Some reported an improvement in their feelings about the medication over time. These findings point to some intrinsic and social motivators which could act as spurs to adherence. PMID- 26767541 TI - The postsurgical spine. AB - Failed back surgery syndrome is the persistence or reappearance of pain after surgery on the spine. This term encompasses both mechanical and nonmechanical causes. Imaging techniques are essential in postoperative follow-up and in the evaluation of potential complications responsible for failed back surgery syndrome. This review aims to familiarize radiologists with normal postoperative changes and to help them identify the pathological imaging findings that reflect failed back surgery syndrome. To interpret the imaging findings, it is necessary to know the type of surgery performed in each case and the time elapsed since the intervention. In techniques used to fuse the vertebrae, it is essential to evaluate the degree of bone fusion, the material used (both its position and its integrity), the bone over which it lies, the interface between the implant and bone, and the vertebral segments that are adjacent to metal implants. In decompressive techniques it is important to know what changes can be expected after the intervention and to be able to distinguish them from peridural fibrosis and the recurrence of a hernia. It is also crucial to know the imaging findings for postoperative infections. Other complications are also reviewed, including arachnoiditis, postoperative fluid collections, and changes in the soft tissues adjacent to the surgical site. PMID- 26767540 TI - Effectiveness of seasonal influenza vaccine in preventing influenza primary care visits and hospitalisation in Auckland, New Zealand in 2015: interim estimates. AB - Preliminary results for influenza vaccine effectiveness (VE) against acute respiratory illness with circulating laboratory-confirmed influenza viruses in New Zealand from 27 April to 26 September 2015, using a case test-negative design were 36% (95% confidence interval (CI): 11-54) for general practice encounters and 50% (95% CI: 20-68) for hospitalisations. VE against hospitalised influenza A(H3N2) illnesses was moderate at 53% (95% CI: 6-76) but improved compared with previous seasons. PMID- 26767542 TI - Bone marrow invasion in multiple myeloma and metastatic disease. AB - Magnetic resonance imaging (MRI) of the spine is the imaging study of choice for the management of bone marrow disease. MRI sequences enable us to integrate structural and functional information for detecting, staging, and monitoring the response the treatment of multiple myeloma and bone metastases in the spine. Whole-body MRI has been incorporated into different guidelines as the technique of choice for managing multiple myeloma and metastatic bone disease. Normal physiological changes in the yellow and red bone marrow represent a challenge in analyses to differentiate clinically significant findings from those that are not clinically significant. This article describes the findings for normal bone marrow, variants, and invasive processes in multiple myeloma and bone metastases. PMID- 26767543 TI - Proliferative Hypertensive Retinopathy. PMID- 26767544 TI - Imaging yield from 133 consecutive patients with prostate cancer and low trigger PSA from a single institution. AB - AIM: To investigate the yield of imaging in patients with relapsed prostate cancer (PC) with a low trigger prostate-specific antigen (PSA). MATERIALS AND METHODS: This institutional review board (IRB)-approved, Health Insurance Portability and Accountability Act (HIPAA)-compliant retrospective study included all 133 patients (mean age 68 years; range 45-88; median 69 months since original diagnosis; interquartile range [IQR]: 32-139) with hormone-sensitive PC (HSPC, n=28) or castration-resistant PC (CRPC, n=105) and trigger PSA <4 ng/ml, who underwent same-day bone scintigraphy and computed tomography (CT; total 224 time points) at Dana-Farber Cancer Institute from January to December 2013. Clinical and pathological data were obtained by manual review of the electronic medical records. All the included bone scintigraphs and CT images were reviewed by a fellowship-trained oncoradiologist to record the metastatic pattern and any clinically significant non-metastatic findings. RESULTS: Ninety-four of the 133 (71%) patients had metastatic disease (18/28 [64%] with HSPC, 76/105 [72%] with CRPC). Forty-one of the 133 (31%) patients developed new metastatic disease and 23/133 (17%) developed new clinically significant non-metastatic findings. The incidence of osseous, nodal, and visceral metastases, and clinically significant non-metastatic findings was similar across the HSPC and CRPC groups (p>0.05 for all). Fifty-seven of the 133 (43%) patients had findings seen only at CT, of which 37 had new extra-osseous findings. Only 2/133 (2%) had findings at bone scintigraphy not seen at CT, both in areas not covered on CT. CONCLUSION: Imaging frequently demonstrated new metastatic and non-metastatic findings in patients with a low trigger PSA. CT is valuable in these patients because extra-osseous findings not visible at bone scintigraphy are frequently seen. PMID- 26767545 TI - Hypertension in Type 2 Diabetes Mellitus: Do We Need to Redefine the Role of Sulfonylureas? AB - BACKGROUND: Within a few years of diagnosis, patients with Type 2 Diabetes Mellitus (T2DM) develop hypertension. It has been hypothesized that both are part of metabolic syndrome. However, studies on diabetic patients have been undertaken while they are on treatment for diabetes. Thus, the results of these studies and inference drawn thereon may not be due to the diabetic process per se but may also be due to the medications. METHODS: A comprehensive literature search was carried out on PubMed, EMBASE and Cochrane databases and articles published between January 1970 to June 2015 were reviewed. RESULTS: Sulfonylureas due to their action on SUR1 in pituitary gland may release growth hormone and anti diuretic hormone; action on SUR2B acting upon smooth muscle may interfere with vasodilatation, thereby causing hypertension. CONCLUSIONS: Sulfonylureas may cause hypertension by their extra-pancreatic effects, further studies are needed to validate this hypothesis. PMID- 26767546 TI - Combination of Vasopressin -Epinephrine as a Novel Candidate in Patients with Cardiac Arrest. AB - OBJECTIVES: Out-hospital Cardiac arrest is considered as a global disease, which causes high rate of morbidity and mortality. Although, the return of spontaneous circulation occurs in 10 to 60 percent of cases in OHCA, with variety of treatment, the most patients faced with multiple organ failure and ultimately death. The investigations demonstrated that endogenous vasopressin levels in patients with successful resuscitation is more than died patients. Therefore, it seems the administration of vasopressin during cardiopulmonary resuscitation could be useful. The current study aimed to investigate the administration of vasopressin and epinephrine on neurological surviving of cardiac-respiratory arrest via evaluation of S100b serum factor. METHODS: For this reasons, after collecting of sera from two vasopressin-epinephrine and epinephrine receiving patients, sera were subjected for ELISA to evaluate S100b. RESULTS: The findings demonstrated that the great reductions of S100b in sera of patients that receiving vasopressinepinephrine in comparison with those patients that only got the epinephrine. Although no significant difference was observed between two groups, but survival rates after hospital discharge in group that receiving vasopressin-epinephrine was significantly higher than those patients that only got only epinephrine. CONCLUSION: Today, no advantages of vasopressin over epinephrine have been observed in clinical trials and more studies needed to improve the OHAC patient's surveillance. But, The combination vasopressin epinephrine in the current study demonstrated that efficacy of this combination should be noted. PMID- 26767547 TI - Flow cytometry: basic principles and applications. AB - Flow cytometry is a sophisticated instrument measuring multiple physical characteristics of a single cell such as size and granularity simultaneously as the cell flows in suspension through a measuring device. Its working depends on the light scattering features of the cells under investigation, which may be derived from dyes or monoclonal antibodies targeting either extracellular molecules located on the surface or intracellular molecules inside the cell. This approach makes flow cytometry a powerful tool for detailed analysis of complex populations in a short period of time. This review covers the general principles and selected applications of flow cytometry such as immunophenotyping of peripheral blood cells, analysis of apoptosis and detection of cytokines. Additionally, this report provides a basic understanding of flow cytometry technology essential for all users as well as the methods used to analyze and interpret the data. Moreover, recent progresses in flow cytometry have been discussed in order to give an opinion about the future importance of this technology. PMID- 26767548 TI - Engaging clinicians in motivational interviewing: Comparing online with face-to face post-training consolidation. AB - Motivational interviewing (MI) is an evidence-based intervention that has been widely recommended in clinical settings where consumer behaviour change is a goal of treatment. Training clinicians in MI, as with other translational endeavours, does not always result in changes to clinical practice. The present study compares two post-training approaches to consolidate MI skills following a training workshop. We randomly assigned 63 clinicians working in mental health or drug and alcohol services to receive either face-to-face group consolidation sessions or to access a series of online consolidation resources. We compared clinician engagement and devised a new instrument to measure clinician outcomes. Participants who completed follow-up consolidation retained knowledge, attitudes, and practices, regardless of consolidation method. Face-to-face consolidation sessions were superior to online materials in engaging participants (mean sessions attended was 2.1 (maximum possible = 3) compared to a mean of 1.38 sessions, respectively (t(61) = -2.73, P = 0.008, d = 0.72, 95% confidence interval: 0.19-1.25). Engagement to the completion of consolidation sessions was also influenced by previous training in MI. For every additional hour of previous MI training, there was a 10% increase in the odds that the participant would complete the final consolidation session. PMID- 26767549 TI - Effect of Arthroscopic Lavage on Systemic and Synovial Fluid Serum Amyloid A in Healthy Horses. AB - OBJECTIVE: To evaluate the effect of arthroscopic lavage on systemic serum amyloid A (SAA) and SAA, total protein, nucleated cell count, and percentage of neutrophils in synovial fluid in healthy horses. STUDY DESIGN: Prospective experimental study. ANIMALS: Healthy adult horses (n = 6). METHODS: Middle carpal joints were randomly assigned to 1 of 2 treatments: arthrocentesis (controls) or arthroscopic lavage, with 30 day washout period between treatments. Synovial fluid and blood samples were collected at 0, 24, 48, 72, 96, and 120 hours. Measurements included systemic and synovial fluid SAA, as well as total protein, nucleated cell count, and percentages of neutrophils in synovial fluid. Data were analyzed by median quantile regression and Wilcoxon signed-rank test and significance level set at P < .05. RESULTS: Systemic and synovial fluid SAA did not increase from baseline (except systemic SAA at 24 hours for both treatments) and were not significantly different between treatments. Total protein values were significantly increased after arthroscopic lavage (except at 96 hours) but not in controls at all time points. With both treatments, nucleated cell counts significantly increased from baseline values at all time points. Percentages of neutrophils were significantly increased after arthroscopic lavage at all time points, but only at 24 hours in controls. CONCLUSION: Total protein, nucleated cell count, and percentage of neutrophils in synovial fluid were significantly increased after arthroscopic lavage; however, synovial fluid SAA was not affected by this procedure. Further research is warranted to validate synovial fluid SAA as a monitoring tool during treatment of septic arthritis. PMID- 26767550 TI - Framework for the assessment of interaction between CO2 geological storage and other sedimentary basin resources. AB - Sedimentary basins around the world considered suitable for carbon storage usually contain other natural resources such as petroleum, coal, geothermal energy and groundwater. Storing carbon dioxide in geological formations in the basins adds to the competition for access to the subsurface and the use of pore space where other resource-based industries also operate. Managing potential impacts that industrial-scale injection of carbon dioxide may have on other resource development must be focused to prevent potential conflicts and enhance synergies where possible. Such a sustainable coexistence of various resource developments can be accomplished by implementing a Framework for Basin Resource Management strategy (FBRM). The FBRM strategy utilizes the concept of an Area of Review (AOR) for guiding development and regulation of CO2 geological storage projects and for assessing their potential impact on other resources. The AOR is determined by the expected physical distribution of the CO2 plume in the subsurface and the modelled extent of reservoir pressure increase resulting from the injection of the CO2. This information is used to define the region to be characterised and monitored for a CO2 injection project. The geological characterisation and risk- and performance-based monitoring will be most comprehensive within the region of the reservoir containing the carbon dioxide plume and should consider geological features and wells continuously above the plume through to its surface projection; this region defines where increases in reservoir pressure will be greatest and where potential for unplanned migration of carbon dioxide is highest. Beyond the expanse of the carbon dioxide plume, geological characterisation and monitoring should focus only on identified features that could be a potential migration conduit for either formation water or carbon dioxide. PMID- 26767552 TI - Neoepitopes and CD3-Positive and CD8-Positive Cells in Polymerase e-Mutated and Microsatellite-Instable Endometrial Cancers. PMID- 26767553 TI - Neoepitopes and CD3-Positive and CD8-Positive Cells in Polymerase e-Mutated and Microsatellite-Instable Endometrial Cancers--Reply. PMID- 26767554 TI - Evaluating Chemotherapy at the End of Life. PMID- 26767555 TI - Evaluating Chemotherapy at the End of Life. PMID- 26767556 TI - Evaluating Chemotherapy at the End of Life. PMID- 26767558 TI - Factors in Association Between Parkinson Disease and Risk of Cancer in Taiwan. PMID- 26767559 TI - Evaluating Chemotherapy at the End of Life--Reply. PMID- 26767561 TI - Error in Figure Presentation. PMID- 26767560 TI - Factors in Association Between Parkinson Disease and Risk of Cancer in Taiwan- Reply. PMID- 26767562 TI - Error in Abstract Results. PMID- 26767564 TI - The importance of context: what are our assumptions about childhood disability? PMID- 26767563 TI - Polyceraty (multi-horns) in Damara sheep maps to ovine chromosome 2. AB - Polyceraty (presence of multiple horns) is rare in modern day ungulates. Although not found in wild sheep, polyceraty does occur in a small number of domestic sheep breeds covering a wide geographical region. Damara are fat-tailed hair sheep, from the south-western region of Africa, which display polyceraty, with horn number ranging from zero to four. We conducted a genome-wide association study for horn number with 43 Damara genotyped with 606 006 SNP markers. The analysis revealed a region with multiple significant SNPs on ovine chromosome 2, in a location different from the mutation for polled in sheep on chromosome 10. The causal mutation for polyceraty was not identified; however, the region associated with polyceraty spans nine HOXD genes, which are critical in embryonic development of appendages. Mutations in HOXD genes are implicated in polydactly phenotypes in mice and humans. There was no evidence for epistatic interactions contributing to polyceraty. This is the first report on the genetic mechanisms underlying polyceraty in the under-studied Damara. PMID- 26767565 TI - Surgical Treatment of Pulmonary Artery Aneurysm with Coronary Artery Compression. PMID- 26767566 TI - Stability in care and stability in the journal. PMID- 26767567 TI - Corrigendum. Danish Diabetes Academy Workshop and Workshop Speakers. Latent autoimmune diabetes of the adult: current knowledge and uncertainty. PMID- 26767568 TI - Red Blood Cell Distribution Width Increases During Infection in Renal and Liver Graft Recipients. AB - OBJECTIVES: Organ transplant is an effective treatment for patients with end stage renal and hepatic failure. Increased use has introduced more emergency department admissions of infectious origin after transplant. Because infections usually manifest with simple complaints and fever, emergency physicians need laboratory tests and radiologic imaging procedures to quickly detect the presence and source of infection. Our aim was to analyze fever-related emergency admissions of renal and hepatic graft recipients and determine whether admitted patients had increased red blood cell distribution width and mean platelet volume levels. MATERIALS AND METHODS: We reviewed the medical records of renal and hepatic graft patients who presented to our emergency department with fever during a 4-year period. Our analyses included 150 patients in which complete blood count and C-reactive protein results were available and the source of infection was determined. We compared results with a control group of 150 transplant patients without any infectious findings. RESULTS: In the 150 solid organ graft recipients who presented to our emergency department with fever, significant differences were observed versus control patients with respect to white blood cell count, neutrophil-to-lymphocyte ratio, red blood cell distribution width, mean platelet volume, and C-reactive protein levels (P < .05). We determined that C-reactive protein levels, red blood cell distribution width, mean platelet volume, and lymphocyte count were independent indicators of infection on multiple logistic regression analyses. We also determined that red blood cell distribution width had a specificity of 94% and a sensitivity of 26%. CONCLUSIONS: We found a significantly higher red blood cell distribution width in emergency admissions of infectious origin of renal and hepatic graft recipients than in the control group (P < .001), suggesting that this measurement is a suitable marker of infection for the emergency setting by virtue of rapid availability of test results and lack of extra costs. PMID- 26767569 TI - Alzheimer's disease or Alzheimer's syndrome?: a longitudinal computed tomography neuroradiological follow-up study of 56 cases diagnosed clinically as Alzheimer's disease. AB - BACKGROUND: Some 200 patients, including those with Alzheimer's disease and other types of dementia, stay year-round in Yokohama - Houyuu Hospital. They undergo computed tomography (CT) neuroradiological examination at least once or twice a year. For this study, the accumulative data, including clinical and neuroradiological, were analyzed. METHODS: Differential diagnoses of Alzheimer's disease were performed in accordance with the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association criteria. The 56 patients (15 men, 41 women) included in this study underwent in-hospital observation on average for 4.4 years (range: 1 10 years). The patients were classified into four groups according to the age of disease onset. The CT findings were summarized for each group and then compared among the groups to determine if there were any differences related to age of onset and, if so, to identify and analyze them. RESULTS: (1) The duration of deceased cases' total clinical course (in years) compared among the four groups. In general, the degree of dementia was more severe among those with earlier disease onset. (2) In cases admitted within 2 years from onset (n =14), the suspected initiating focus of cortical atrophy occurred in the frontal lobe (n = 6), the temporal lobe (n = 6), or the fronto-temporal lobes (n = 2). (3) Although CT findings generally showed that the more severe cases had earlier onset, serial CT examinations in each case showed widely different pathologies in degree, nature and manner of progression, regardless of group classification. (4) The earliest sites of brain atrophy, sites of its severest involvement within the brain, and neuroradiological development of the cerebral cortex pathology in combination with hemispheric white matter, lateral ventricles, and third ventricles varied among the four groups and between case within each group. Alzheimer's disease could not be subclassified simply by the age of clinical onset. CONCLUSION: Cases of so-called Alzheimer's disease, as observed through continued clinical follow-up and serial CT examinations, appear so diverse in symptomatology and radiological pathomorphology that it is difficult to consider them a single nosological entity. The pathology of Alzheimer's disease has to be reconsidered in accordance with the variety observed in the sequential development of neuroradiological findings. The pathology must be reconstructed in terms of topographical dimensions and chronological developments. The diagnosis of Alzheimer's disease appears to be not so simple based on any conventional diagnostic operational standards. PMID- 26767571 TI - Response to 'The management of hepatocellular adenoma in obese patients: issues to consider'. PMID- 26767570 TI - Normobaric hyperoxia markedly reduces brain damage and sensorimotor deficits following brief focal ischaemia. AB - 'True' transient ischaemic attacks are characterized not only clinically, but also radiologically by a lack of corresponding changes on magnetic resonance imaging. During a transient ischaemic attack it is assumed that the affected tissue is penumbral but rescued by early spontaneous reperfusion. There is, however, evidence from rodent studies that even brief focal ischaemia not resulting in tissue infarction can cause extensive selective neuronal loss associated with long-lasting sensorimotor impairment but normal magnetic resonance imaging. Selective neuronal loss might therefore contribute to the increasingly recognized cognitive impairment occurring in patients with transient ischaemic attacks. It is therefore relevant to consider treatments to reduce brain damage occurring with transient ischaemic attacks. As penumbral neurons are threatened by markedly constrained oxygen delivery, improving the latter by increasing arterial O2 content would seem logical. Despite only small increases in arterial O2 content, normobaric oxygen therapy experimentally induces significant increases in penumbral O2 pressure and by such may maintain the penumbra alive until reperfusion. Nevertheless, the effects of normobaric oxygen therapy on infarct volume in rodent models have been conflicting, although duration of occlusion appeared an important factor. Likewise, in the single randomized trial published to date, early-administered normobaric oxygen therapy had no significant effect on clinical outcome despite reduced diffusion-weighted imaging lesion growth during therapy. Here we tested the hypothesis that normobaric oxygen therapy prevents both selective neuronal loss and sensorimotor deficits in a rodent model mimicking true transient ischaemic attack. Normobaric oxygen therapy was applied from the onset and until completion of 15 min distal middle cerebral artery occlusion in spontaneously hypertensive rats, a strain representative of the transient ischaemic attack-prone population. Whereas normoxic controls showed normal magnetic resonance imaging but extensive cortical selective neuronal loss associated with microglial activation (present both at Day 14 in vivo and at Day 28 post-mortem) and marked and long-lasting sensorimotor deficits, normobaric oxygen therapy completely prevented sensorimotor deficit (P < 0.02) and near-completely Day 28 selective neuronal loss (P < 0.005). Microglial activation was substantially reduced at Day 14 and completely prevented at Day 28 (P = 0.002). Our findings document that normobaric oxygen therapy administered during ischaemia nearly completely prevents the neuronal death, microglial inflammation and sensorimotor impairment that characterize this rodent true transient ischaemic attack model. Taken together with the available literature, normobaric oxygen therapy appears a promising therapy for short-lasting ischaemia, and is attractive clinically as it could be started at home in at-risk patients or in the ambulance in subjects suspected of transient ischaemic attack/early stroke. It may also be a straightforward adjunct to reperfusion therapies, and help prevent subtle brain damage potentially contributing to long-term cognitive and sensorimotor impairment in at-risk populations. PMID- 26767572 TI - Manufacturers failed to report infections from duodenoscopes, US investigation finds. PMID- 26767573 TI - Single Crossover-Mediated Markerless Genome Engineering in Clostridium acetobutylicum. AB - A novel genome-engineering tool in Clostridium acetobutylicum was developed based on singlecrossover homologous recombination. A small-sized non-replicable plasmid, pHKO1, was designed for efficient integration into the C. acetobutylicum genome. The integrated pHKO1 plasmid backbone, which included an antibiotic resistance gene, can be excised in vivo by Flp recombinase, leaving a single flippase recognition target sequence in the middle of the targeted gene. Since the pSHL-FLP plasmid, the carrier of the Flp recombinase gene, employed the segregationally unstable pAMbeta1 replicon, the plasmid was rapidly cured from the mutant C. acetobutylicum. Consequently, our method makes it easier to engineer C. acetobutylicum. PMID- 26767574 TI - Fumarate Reductase-Producing Enterococci Reduce Methane Production in Rumen Fermentation In Vitro. AB - Biotic agents such as fumarate-reducing bacteria can be used for controlling methane (CH4) production in the rumen. Fumarate-reducing bacteria convert fumarate to succinate by fumarate reductase, ultimately leading to the production of propionate. Fumarate-reducing bacteria in the genus Enterococcus were isolated from rumen fluid samples from slaughtered Korean native goats. The enterococci were identified as Enterococcus faecalis SROD5 and E. faecium SROD by phylogenetic analyses of 16S rRNA gene sequences. The fumarate reductase activities of the SROD5 and SROD strains were 42.13 and 37.05 mM NADH oxidized/min/mg of cellular nitrogen (N), respectively. Supplementation of rumen fermentation in vitro with the SROD5 and SROD strains produced significantly higher propionate, butyrate, and total volatile fatty acid (VFA) concentrations than controls at 12 h; VFA concentrations tended to increase after 24 h of incubation. The generated CH4 concentration was significantly lower in the SROD5 and SROD treatment groups after 24 h of incubation. These findings indicate that E. faecium SROD has potential as a direct-fed microbial additive for increasing total VFAs while decreasing CH4 production in rumen fermentation in vitro. PMID- 26767575 TI - Protective Effect of 4-(3,4-Dihydroxyphenyl)-3-Buten-2-One from Phellinus linteus on Naproxen-Induced Gastric Antral Ulcers in Rats. AB - The present study investigated the protective effect of naturally purified 4-(3,4 dihydroxyphenyl)-3-buten-2-one (DHP) from Phellinus linteus against naproxen induced gastric antral ulcers in rats. To verify the protective effect of DHP on naproxen-induced gastric antral ulcers, various doses (1, 5, and 10 MUg/kg) of DHP were pretreated for 3 days, and then gastric damage was caused by 80 mg/kg naproxen applied for 3 days. DHP prevented naproxen-induced gastric antral ulcers in a dose-dependent manner. In particular, 10 MUg/kg DHP showed the best protective effect against naproxen-induced gastric antral ulcers. Moreover, DHP significantly attenuated the naproxen-induced lipid peroxide level in gastric mucosa and increased the activities of radical scavenging enzymes, such as superoxide dismutase, catalase, and glutathione peroxidase, in a dose-dependent manner. A histological examination clearly demonstrated that the gastric antral ulcer induced by naproxen nearly disappeared after the pretreatment of DHP. These results suggest that DHP can inhibit naproxen-induced gastric antral ulcers through prevention of lipid peroxidation and activation of radical scavenging enzymes. PMID- 26767576 TI - A Leaf-Inhabiting Endophytic Bacterium, Rhodococcus sp. KB6, Enhances Sweet Potato Resistance to Black Rot Disease Caused by Ceratocystis fimbriata. AB - Rhodococcus species have become increasingly important owing to their ability to degrade a wide range of toxic chemicals and produce bioactive compounds. Here, we report isolation of the Rhodococcus sp. KB6, which is a new leaf-inhabiting endophytic bacterium that suppresses black rot disease in sweet potato leaves. We determined the 7.0 Mb draft genome sequence of KB6 and have predicted 19 biosynthetic gene clusters for secondary metabolites, including heterobactins, which are a new class of siderophores. Notably, we showed the first internal colonization of host plants with Rhodococcus sp. KB6 and discuss its potential as a biocontrol agent for sustainable agriculture. PMID- 26767577 TI - Comparison of Anodic Community in Microbial Fuel Cells with Iron Oxide-Reducing Community. AB - The group of Fe(III) oxide-reducing bacteria includes exoelectrogenic bacteria, and they possess similar properties of transferring electrons to extracellular insoluble-electron acceptors. The exoelectrogenic bacteria can use the anode in microbial fuel cells (MFCs) as the terminal electron acceptor in anaerobic acetate oxidation. In the present study, the anodic community was compared with the community using Fe(III) oxide (ferrihydrite) as the electron acceptor coupled with acetate oxidation. To precisely analyze the structures, the community was established by enrichment cultures using the same inoculum used for the MFCs. High-throughput sequencing of the 16S rRNA gene revealed considerable differences between the structure of the anodic communities and that of the Fe(III) oxide reducing community. Geobacter species were predominantly detected (>46%) in the anodic communities. In contrast, Pseudomonas (70%) and Desulfosporosinus (16%) were predominant in the Fe(III) oxide-reducing community. These results demonstrated that Geobacter species are the most specialized among Fe(III) reducing bacteria for electron transfer to the anode in MFCs. In addition, the present study indicates the presence of a novel lineage of bacteria in the genus Pseudomonas that highly prefers ferrihydrite as the terminal electron acceptor in acetate oxidation. PMID- 26767581 TI - Isolation and characterization of a Neisseria sp. from the captive wild goose (Anser anser). AB - The present study investigated 15 dead cases of captive wild goslings (Anser anser), which were bred in a small poultry farm in Shandong Province, China. The examined cases presented diverse clinical signs accompanied with neurological manifestations and fatal outcomes. Bacterial culture identified the gram-negative Neisseria sp. from the brain homogenate of most examined cases (10/15, 66.7%). The isolated bacteria were identified based on morphologic characteristics, biochemical tests and 16S rDNA typing. Results proved that 1 identical bacterial strain (BNO09-3) was isolated from the positive cases. The phylogeny based on the 16S rDNA gene sequences indicated that this isolate has a close relationship with various strains of genus Neisseria sp. isolated from liver and feces of duck. This is the first report of Neisseria sp. causing fatality in captive wild geese in China. PMID- 26767580 TI - Improved long-term outcome after transient cerebral ischemia in aquaporin-4 knockout mice. AB - A hallmark of stroke is water accumulation (edema) resulting from dysregulation of osmotic homeostasis. Brain edema contributes to tissue demise and may lead to increased intracranial pressure and lethal herniation. Currently, there are only limited treatments to prevent edema formation following stroke. Aquaporin 4 (AQP4), a brain water channel, has become a focus of interest for therapeutic approaches targeting edema. At present, there are no pharmacological tools to block AQP4. The role of AQP4 in edema after brain injury remains unclear with conflicting results from studies using AQP4-/- mice and of AQP4 expression following stroke. Here, we studied AQP4 and its role in edema formation by testing AQP4-/- mice in a model of middle cerebral artery occlusion using novel quantitative MRI water content measurements, histology and behavioral changes as outcome measures. Absence of AQP4 was associated with decreased mortality and increased motor recovery 3 to 14 days after stroke. Behavioral improvement was associated with decreased lesion volume, neuronal cell death and neuroinflammation in AQP4-/- compared to wild type mice. Our data suggest that the lack of AQP4 confers an overall beneficial role at long term with improved neuronal survival and reduced neuroinflammation, but without a direct effect on edema formation. PMID- 26767583 TI - Estimation of population iodine intake from iodized salt consumed through bouillon seasoning in Senegal. AB - Universal salt iodization (USI) is the main global strategy to eliminate iodine deficiency. Regulation of USI programs often omits salt used in processed foods, despite their increasing contribution to salt intake. In West Africa, bouillon seasoning is a widely consumed source of salt and is therefore relevant to USI effectiveness. To develop program guidance around iodine in bouillon, iodine retention in 13 bouillon brands commercially available in Senegal was measured over 6 months. Iodine content was measured in broth using various water volumes and cooking times, as well as in rice cooked in the broth. Average iodine loss in bouillon over 6 months in 95% humidity at 40-40.5 degrees C was 4.5% (13.6% for cubes and 0.8% for powder sachets). Iodine was retained in broth with cooking times of up to an hour and in rice cooked in broth. Modeling of contribution to iodine intake revealed that bouillon is an important source of dietary iodine in Senegal. Results may inform salt iodization standards and regulation in Senegal and countries with similar bouillon consumption levels. PMID- 26767587 TI - Accessing N-Stereogenicity through a Double Aza-Michael Reaction: Mechanistic Insights. AB - Further development of the chemistry and applications of chiral compounds that possess configurationally stable stereogenic nitrogen atoms is hampered by the lack of efficient strategies to access such compounds in an enantiomerically pure form. Esters of propiolic acid and chiral alcohols were evaluated as cheap and readily available Michael acceptors in a diastereoselective synthesis of N stereogenic compounds by means of a double aza-Michael conjugate addition. Diastereomeric ratios of up to 74:26 and high yields were achieved with (-) menthyl propiolate as a substrate. Furthermore, a detailed mechanistic investigation was undertaken to shed some light on the course of this domino transformation. Kinetic studies revealed that the protic-solvent additive acts as a Bronsted acid and activates the ester toward the initial attack of the tetrahydrodiazocine partner. Conversely, acidic conditions proved unfavorable during the final cyclization step that provides the product. PMID- 26767586 TI - Rapid Non-Crosslinking Aggregation of DNA-Functionalized Gold Nanorods and Nanotriangles for Colorimetric Single-Nucleotide Discrimination. AB - Gold nanoparticles modified with DNA duplexes are rapidly and spontaneously aggregated at high ionic strength. In contrast, this aggregation is greatly suppressed when the DNA duplex has a single-base mismatch or a single-nucleotide overhang located at the outermost surface of the particle. These colloidal features emerge irrespective of the size and composition of the particle core; however, the effects of the shape remain unexplored. Using gold nanorods and nanotriangles (nanoplatelets), we show herein that both remarkable rapidity in colloidal aggregation and extreme susceptibility to DNA structural perturbations are preserved, regardless of the shape and aspect ratio of the core. It is also demonstrated that the DNA-modified gold nanorods and nanotriangles are applicable to naked-eye detection of a single-base difference in a gene model. The current study corroborates the generality of the unique colloidal properties of DNA functionalized nanoparticles, and thus enhances the feasibility of their practical use. PMID- 26767590 TI - CORRIGENDUM. PMID- 26767592 TI - The macromolecular architecture of platelet-derived microparticles. AB - Platelets are essential for hemostasis and wound healing. They are involved in fundamental processes of vascular biology such as angiogenesis, tissue regeneration, and tumor metastasis. Upon activation, platelets shed small plasma membrane vesicles termed platelet-derived microparticles (PMPs). PMPs include functional cell adhesion machinery that comprises transmembrane receptors (most abundant are the alphaIIbbeta3 integrins), cytoskeletal systems and a large variety of adapter and signaling molecules. Glanzmann thrombasthenia (GT) is a condition characterized by platelets that are deficient of the integrin alphaIIbbeta3 heterodimer. Here, we use cryo-electron tomography (cryo-ET) to study the structural organization of PMPs (in both healthy and GT patients), especially the cytoskeleton organization and receptor architecture. PMPs purified from GT patients show a significantly altered cytoskeletal organization, characterized by a reduced number of filaments present, compared to the healthy control. Furthermore, our results show that incubating healthy PMPs with manganese ions (Mn(2+)), in the presence of fibrinogen, induces a major conformational change of integrin receptors, whereas thrombin activation yields a moderate response. These results provide the first insights into the native molecular organization of PMPs. PMID- 26767593 TI - Preeclampsia is Associated with Decreased Methylation of the GNA12 Promoter. AB - Preeclampsia, characterized by high blood pressure, albuminuria and other systemic disorders, is a serious complication during pregnancy. It has been reported that GNA12 is overexpressed during preeclampsia. In this study, we investigated the potential association between the methylation of the GNA12 promoter and preeclampsia. The methylation level at eight CpG sites of the GNA12 promoter was analyzed by MassARRAY in placenta and peripheral blood DNA samples from 50 preeclampsia patients and 50 normal pregnant women. In the placenta DNA samples, the methylation level at three CpG sites of the GNA12 promoter was significantly lower in the preeclampsia patients than in the controls. The difference was also significant at two of the three CpG sites in the peripheral blood DNA samples. The mRNA expression level of GNA12 in placenta was analyzed by real-time quantitative PCR in 20 cases and 20 controls. Consistent with the decreased methylation level, the mRNA expression level of GNA12 was higher in preeclampsia patients than in controls. Our results showed that preeclampsia is associated with decreased methylation of the GNA12 promoter, which can be detected in both the placenta and the peripheral blood of the pregnant women. PMID- 26767594 TI - Penetrating nose and maxillary sinus injury with a metal part of a military gun. AB - Foreign bodies (FBs) in the paranasal sinuses are rare, whether iatrogenic or traumatic. One of the most common causes of such traumatic injuries is gunshot wounds from the bullets. Removing FBs from the paranasal sinuses usually needs endoscopic or open surgery. We present the case of a 22-year-old male soldier who sustained a penetrating injury of his nose and maxillary sinus with an iron rod that was a part of his gun, which was removed without either endoscopic or open paranasal sinus surgery. PMID- 26767595 TI - Pulmonary embolism in a British soldier: could this have been prevented? AB - A 31-year-old soldier presented to the medical centre with acute onset pleuritic chest pain and shortness of breath. He had previously presented to combat medical technicians (CMTs) on two occasions over 2 weeks with right calf pain following a long-distance drive. On both occasions, he was managed as a musculoskeletal disorder without referral to a medical officer (MO). Following this presentation, he presented 4 days later to an MO who referred to secondary care where he was diagnosed with a pulmonary embolism (PE) and deep vein thrombosis (DVT). The CMT treatment protocol does not include the differential diagnosis, history or exam of DVT for lower leg pain. The soldier was subsequently diagnosed with antiphospholipid antibodies and high Factor VIII thrombophilia. A discussion about review and amendment of CMT protocols to include risk stratifying for DVT/ venous thromboembolism (VTE) is required. PMID- 26767596 TI - Ethics surrounding the medical evacuation of catastrophically injured individuals from an operational theatre of war. AB - Although prolonging life is usually in the best interests of patients, the British Medical Association states that it is not appropriate to prolong life with no regard to its quality. Medical advances both on the battlefield and within the field hospitals have resulted in the unexpected survival of a number of British personnel, and in some cases, soldiers are being repatriated with injuries categorised as 'catastrophic'. This paper considers medical ethics based on the Beauchamp and Childress Four Principles framework with regard to whether catastrophically injured individuals should be repatriated without any prior advanced directive and without evaluation of future quality of life. PMID- 26767598 TI - Is it time for a unified two-tier reporting system for cervical cytology and histology in the cervical screening programmes? PMID- 26767599 TI - Bethesda 2014: improving on a paradigm shift. AB - The third iteration of the Bethesda System terminology manual was recently published. This update included changes in the reporting of benign endometrial cells, and guidance for special adequacy situations and for cases in which low grade squamous intraepithelial lesions are accompanied by some cells suggesting that a high grade lesion might also be present. In addition, the manual was increased in size to include more illustrations with special studies and comparisons to histology, a greatly increased reference list, and a new chapter devoted to the modern practice of risk-based management. The third edition of the Bethesda manual is meant to serve as a primary reference for the practice of gynecologic cytology designed to provide a uniform system of reporting Worldwide for clinical, teaching, and research purposes. PMID- 26767600 TI - The LAST Project and the diagnostic bottom line. AB - The LAST Project's consensus recommendations for terminology and biomarker use to improve the accuracy and reproducibility of histopathological diagnoses for HPV associated squamous intraepithelial lesions of the lower anogenital tract are reviewed. PMID- 26767601 TI - The terminology of pre-invasive cervical lesions in the UK cervical screening programme. AB - The terminology of non-invasive epithelial abnormalities associated with an elevated risk of having or developing invasive cervical carcinoma (pre-invasive lesions) has been modified frequently over time as understanding of the underlying biology, and approaches to disease management, have changed. The arguments are now converging on the conclusion that the most appropriate terminology for cervical squamous intraepithelial abnormalities should be two tier rather than three-tier. Given the findings of the Lower Anogenital Squamous Terminology (LAST) project in the USA, which have recently been endorsed by the World Health Organisation classification of tumours of female reproductive organs, the recommended terms are low-grade and high-grade squamous intraepithelial lesion (SIL), with the option of including the relevant cervical intraepithelial neoplasia (CIN) grade in parentheses. Although, at first sight, this appears to represent only a small change, there is a fundamental conceptual difference between the systems. The CIN system requires, first, the identification of a CIN lesion and, second, the determination of its grade on a continuum, with subsequent division into three grades. The SIL system is based on the existence of two different forms of human papillomavirus (HPV) infection, with productive infection leading to low-grade SIL and transforming infection leading to high-grade SIL. PMID- 26767602 TI - Two-grade Bethesda system of reporting in cervical screening: colposcopist's view. PMID- 26767604 TI - Commentary on Paper: "Controlling the misuse of cobalt in horses". PMID- 26767605 TI - Bilateral extracranial internal carotid artery aneurysms: Case report and review of literature. AB - This is a report of a 62-year-old male with bilateral extracranial internal carotid artery aneurysms, treated with resection, and interposition bypass. Bilateral presentation of carotid aneurysms is an uncommon finding in an already rare disease. We review the etiology, natural history, and treatment options. PMID- 26767606 TI - Long-term results of simplified frozen elephant trunk technique in complicated acute type A aortic dissection: A case-control study. AB - AIM: To describe the long-term experience of a simplified frozen elephant trunk technique (sFETT) used in complicated acute type A aortic dissection (AAAD) treatment. METHODS AND RESULTS: Between January 2001 and December 2012, 34 patients (mean age 59.9 +/- 11.0 years) with complicated AAAD (DeBakey I) underwent an emergency surgery including sFETT. sFETT consisted in gluing the dissected aortic arch wall layers with gelatine-resorcinol adhesive and video assisted antegrade open arch aortic stent-graft deployment in the arch or proximal descending aorta. In addition to sFETT, the aortic root was addressed with standard techniques. A 30-day mortality was 14.7% (five patients) due to bleeding (1), multiple organ failure (2), and colon ischemia (2). Postoperative morbidity included neurological (2), renal (1) and cardio-pulmonary complications (4), as well as wound infection (1). Mean follow-up was 74.4 +/- 45.0 months. Actual survival rates were 73.5% at 1 year, 70.2% at 5 years, and 58.5% at 13 years of follow-up. Six patients died during long-term follow-up from heart failure (1) and unknown reasons (5). Five patients required reoperation for aortic arch (3) or aorto-iliac (2) progression of aneurysm during the mid- and long-term follow-up. The remaining patients showed favorable evolution of the dissected aorta with false lumen occlusion in most cases and stable aortic diameters. CONCLUSIONS: In AAAD patients, sFETT as used in our series is an easy and safe technique to repair the aortic arch. Long-term results after sFETT showed false lumen occlusion and stable aortic diameter in up to 13 years of follow-up. PMID- 26767607 TI - The path to personalized vascular therapy - We are closer than we think. AB - The terms "personalized" or "precision" medicine are being used commonly in some branches of medicine but have yet to be widely adopted in vascular surgery. Despite this, personalized vascular therapy occurs on a daily basis in every vascular specialist's office as we strive to make informed recommendations at the individual patient level. The following is a description of several of the areas where advances in personalized vascular care have been achieved, including custom devices, personalized predictions, pharmacogenetics and surgicogenetics. PMID- 26767608 TI - Communication and support from healthcare professionals is essential for living kidney donors. PMID- 26767609 TI - Health values change over time in people with type 2 diabetes. PMID- 26767611 TI - Postcardiac Injury Syndrome: A Rare Complication of Elective Coronary Angioplasty. PMID- 26767610 TI - Microvascular ischemia in hypertrophic cardiomyopathy: new insights from high resolution combined quantification of perfusion and late gadolinium enhancement. AB - BACKGROUND: Microvascular ischemia is one of the hallmarks of hypertrophic cardiomyopathy (HCM) and has been associated with poor outcome. However, myocardial fibrosis, seen on cardiovascular magnetic resonance (CMR) as late gadolinium enhancement (LGE), can be responsible for rest perfusion defects in up to 30% of patients with HCM, potentially leading to an overestimation of the ischemic burden. We investigated the effect of left ventricle (LV) scar on the total LV ischemic burden using novel high-resolution perfusion analysis techniques in conjunction with LGE quantification. METHODS: 30 patients with HCM and unobstructed epicardial coronary arteries underwent CMR with Fermi constrained quantitative perfusion analysis on segmental and high-resolution data. The latter were corrected for the presence of fibrosis on a pixel-by-pixel basis. RESULTS: High-resolution quantification proved more sensitive for the detection of microvascular ischemia in comparison to segmental analysis. Areas of LGE were associated with significant reduction of myocardial perfusion reserve (MPR) leading to an overestimation of the total ischemic burden on non-corrected perfusion maps. Using a threshold MPR of 1.5, the presence of LGE caused an overestimation of the ischemic burden of 28%. The ischemic burden was more severe in patients with fibrosis, also after correction of the perfusion maps, in keeping with more severe disease in this subgroup. CONCLUSIONS: LGE is an important confounder in the assessment of the ischemic burden in patients with HCM. High-resolution quantitative analysis with LGE correction enables the independent evaluation of microvascular ischemia and fibrosis and should be used when evaluating patients with HCM. PMID- 26767612 TI - What is eaten when all of the foods at a meal are served in large portions? AB - Portion size affects intake, but when all foods are served in large portions, it is unclear whether every food will be consumed in greater amounts. We varied the portion size (PS) of all foods at a meal to investigate the influence of food energy density (ED) on the PS effect as well as that of palatability and subject characteristics. In a crossover design, 48 women ate lunch in the laboratory on four occasions. The meal had three medium-ED foods (pasta, bread, cake) and three low-ED foods (broccoli, tomatoes, grapes), which were simultaneously varied in PS across meals (100%, 133%, 167%, or 200% of baseline amounts). The results showed that the effect of PS on the weight of food consumed did not differ between medium-ED and low-ED foods (p < 0.0001). Energy intake, however, was substantially affected by food ED across all portions served, with medium-ED foods contributing 86% of energy. Doubling the portions of all foods increased meal energy intake by a mean (+/-SEM) of 900 +/- 117 kJ (215 +/- 28 kcal; 34%). As portions were increased, subjects consumed a smaller proportion of the amount served; this response was characterized by a quadratic curve. The strongest predictor of the weight of food consumed was the weight of food served, both for the entire meal (p < 0.0001) and for individual foods (p = 0.014); subject characteristics explained less variability. Intake in response to larger portions was greater for foods that subjects ranked higher in taste (p < 0.0001); rankings were not related to food ED. This study demonstrates the complexity of the PS effect. While the response to PS can vary between individuals, the effect depends primarily on the amounts of foods offered and their palatability compared to other available foods. PMID- 26767613 TI - Psychological mindsets affect consumption: How different mindsets help (hurt) portion control. AB - The present work discusses how psychological mindsets-orientations that affect how consumers encode, interpret, and respond to information- can help, as well as hurt, portion control. To this end, the current article first provides an overview of the general idea of psychological mindsets. Subsequently, evidence from three distinct areas of mindset research is reviewed: power and powerlessness; fixed and growth; promotion and prevention. For each literature, the relevant mindsets are discussed, and their implications for consumer behavior generally and portion control specifically are illuminated. The paper also provides a discussion of gaps in mindset research with consideration given to how to bridge the theoretical development on mindsets to practical applications. PMID- 26767614 TI - A call for research exploring social media influences on mothers' child feeding practices and childhood obesity risk. AB - There is increasing interest in leveraging social media to prevent childhood obesity, however, the evidence base for how social media currently influences related behaviors and how interventions could be developed for these platforms is lacking. This commentary calls for research on the extent to which mothers use social media to learn about child feeding practices and the mechanisms through which social media influences their child feeding practices. Such formative research could be applied to the development and dissemination of evidence-based childhood obesity prevention programs that utilize social media. Mothers are identified as a uniquely important target audience for social media-based interventions because of their proximal influence on children's eating behavior and their high engagement with social media platforms. Understanding mothers' current behaviors, interests, and needs as they relate to their social media use and child feeding practices is an integral first step in the development of interventions that aim to engage mothers for obesity prevention. This commentary highlights the importance of mothers for childhood obesity prevention; discusses theoretical and analytic frameworks that can inform research on social media and mothers' child feeding practices; provides evidence that social media is an emerging context for social influences on mothers' attitudes and behaviors in which food is a salient topic; and suggests directions for future research. PMID- 26767615 TI - "When I go to bed hungry and sleep, I'm not hungry": Children and parents' experiences of food insecurity. AB - Evidence demonstrates food insecurity has a detrimental impact on a range of outcomes for children, but little research has been conducted in the UK, and children have rarely been asked to describe their experiences directly. We examined the experiences of food insecure families living in South London. Our mixed-methods approach comprised a survey of parents (n = 72) and one-to-one semi structured interviews with children aged 5-11 years (n = 19). The majority of parents (86%) described their food security during the preceding year as very low. Most reported they had often or sometimes had insufficient food, and almost all had worried about running out of food. Two thirds of parents had gone hungry. Most parents reported they had been unable to afford a nutritionally balanced diet for their children, and just under half reported that their children had gone hungry. Four themes emerged from the interviews with children: sources of food; security of food, nutritional quality of food, and experiences of hunger. Children's descriptions of insufficient food being available indicate that parents are not always able to shield them from the impact of food insecurity. The lack of school-meals and after-school clubs serving food made weekends particularly problematic for some children. A notable consequence of food insecurity appears to be reliance on low-cost takeaway food, likely to be nutritionally poor. PMID- 26767616 TI - Group size, survival and surprisingly short lifespan in socially foraging bats. AB - BACKGROUND: The relationships between group size, survival, and longevity vary greatly among social species. Depending on demographic and ecological circumstances, there are both positive and negative effects of group size variation on individual survival and longevity. For socially foraging species in particular there may be an optimal group size that predicts maximum individual survival that is directly related to the potential for information transfer, social coordination, and costs of conspecific interference. Our aim was to investigate this central aspect of evolutionary ecology by focusing on a socially foraging bat, Molossus molossus. This species optimizes foraging success by eavesdropping on the echolocation calls of group members to locate ephemeral food patches. We expected to find the highest survival and longest lifespans in small groups as a consequence of a trade-off between benefits of information transfer on ephemeral resources and costs of conspecific interference. RESULTS: In a mark recapture study of 14 mixed-sex M. molossus social groups in Gamboa, Panama, spanning several years we found the expected relatively small and intermediate, but stable groups, with a mean size of 9.6 +/- 6.7 adults and juveniles. We estimated survival proxies using Cox proportional hazard models and multistate mark recapture models generated with recapture data as well as automated monitoring of roost entrances in a subset of the groups. Median survival of females was very short with 1.8 years and a maximum estimated longevity of 5.6 years. Contrary to our expectations, we found no relationship between variation in group size and survival, a result similar to few other studies. CONCLUSIONS: Strong selection towards small group size may result from psychoacoustic and cognitive constraints related to acoustic interference in social foraging and the complexity of coordinated flight. The short lifespans were unexpected and may result from life at the energetic edge due to a highly specialized diet. The absence of a relationship between group size and survival may reflect a similar but optimized survival within the selected range of group sizes. We expect the pattern of small group sizes will be consistent in future research on species dependent on social information transfer about ephemeral resources. PMID- 26767618 TI - [Not Available]. AB - In France, few studies have investigated the experience of home caregivers with elderly people suffering from Alzheimer's disease or alcoholic behavior. The aim of this study was to describe caregivers' understanding of these disorders to identify their difficulties and satisfactions in relation to their role. Seventeen social care workers were interviewed and the content was analysed using a general inductive approach. Regarding misuse or abuse of alcohol, they expressed a feeling of helplessness, and put forth their experience and skills to communicate with the receiver of care. Concerning Alzheimer's disease, they expressed worries regarding its progression They identified themselves with the elder's anxiety, which induced fears regarding their own old age. All of them were satisfied by the care they provided and by the possibility of acquiring experience. Results could be of use in supporting clinical preventive actions for professional home caregivers dealing with these two disorders that can occur in the course of the ageing process. PMID- 26767617 TI - Reversing methanogenesis to capture methane for liquid biofuel precursors. AB - BACKGROUND: Energy from remote methane reserves is transformative; however, unintended release of this potent greenhouse gas makes it imperative to convert methane efficiently into more readily transported biofuels. No pure microbial culture that grows on methane anaerobically has been isolated, despite that methane capture through anaerobic processes is more efficient than aerobic ones. RESULTS: Here we engineered the archaeal methanogen Methanosarcina acetivorans to grow anaerobically on methane as a pure culture and to convert methane into the biofuel precursor acetate. To capture methane, we cloned the enzyme methyl coenzyme M reductase (Mcr) from an unculturable organism, anaerobic methanotrophic archaeal population 1 (ANME-1) from a Black Sea mat, into M. acetivorans to effectively run methanogenesis in reverse. Starting with low density inocula, M. acetivorans cells producing ANME-1 Mcr consumed up to 9 +/- 1 % of methane (corresponding to 109 +/- 12 umol of methane) after 6 weeks of anaerobic growth on methane and utilized 10 mM FeCl3 as an electron acceptor. Accordingly, increases in cell density and total protein were observed as cells grew on methane in a biofilm on solid FeCl3. When incubated on methane for 5 days, high-densities of ANME-1 Mcr-producing M. acetivorans cells consumed 15 +/- 2 % methane (corresponding to 143 +/- 16 umol of methane), and produced 10.3 +/- 0.8 mM acetate (corresponding to 52 +/- 4 umol of acetate). We further confirmed the growth on methane and acetate production using (13)C isotopic labeling of methane and bicarbonate coupled with nuclear magnetic resonance and gas chromatography/mass spectroscopy, as well as RNA sequencing. CONCLUSIONS: We anticipate that our metabolically-engineered strain will provide insights into how methane is cycled in the environment by Archaea as well as will possibly be utilized to convert remote sources of methane into more easily transported biofuels via acetate. PMID- 26767620 TI - Promoting justified risk-based decisions in contaminated land management. AB - Decision making and regulatory policies on contaminated land management (CLM) are commonly governed by risk assessment. Risk assessment, thus, has to comply with legislation, but also provide valid information in terms of actual risks to correctly focus the potentially required measures and allocate the available resources. Hence, reliable risk assessment is a prerequisite for justified and sustainable risk management. This paper gives an introduction to the Finnish risk based regulatory framework, outlines the challenges within the policies and the practice and provides an overview of the new guidance document to promote risk based and sustainable CLM. We argue that the current risk assessment approaches in the policy frameworks are not necessarily efficient enough in supporting justified risk-based decisions. One of the main reasons for this is the excessive emphasis put on conservative risk assessments and on generic guideline values without contributing to their appropriate application. This paper presents how some of the challenges in risk-based decision making have been tackled in the Finnish regulatory framework on contaminated land. We believe that our study will also stimulate interest with regard to policy frameworks in other countries. PMID- 26767619 TI - Barricades and brickwalls--a qualitative study exploring perceptions of medication use and deprescribing in long-term care. AB - BACKGROUND: The co-administration of multiple drugs (polypharmacy) is the single most common cause of adverse drug events in the older population, and residents of long-term care facilities (LTCFs) are at particularly high risk of medication harm. 'Deprescribing'--the withdrawal of an inappropriate medication with goal of managing polypharmacy and improving outcomes--may improve the quality of life of LTCF residents. The RELEASE study sought to explore perceptions of medication use and the concept of deprescribing in LTCFs. METHODS: Focus groups and interviews were conducted with General Practitioners (GPs), pharmacists, nursing staff, residents and their relatives within three LTCFs in the Illawarra-Shoalhaven region of NSW, Australia. Audiotapes were transcribed verbatim and, using the Integrative Model of Behaviour Prediction as a framework, thematic analysis of transcripts was conducted using QSR NVivo 10. RESULTS: Participants acknowledged the burden of too many medications (time to administer, physical discomfort, cost), yet displayed passivity towards medication reduction. Residents and relatives lacked understanding of medicine indications or potential harms. Willingness to initiate and accept medication change was dependent on the GP, who emerged as a central trusted figure. GPs preferred 'the path of least resistance', signalling systems barriers (poor uniformity of LTCF medical records, limited trained LTCF personnel); time constraints (resident consultations, follow-up with specialists and family); and the organisation of care (collaborating with LTCF staff, pharmacists and prescribing specialists) as obstacles to deprescribing. CONCLUSIONS: Targeted engagement is required to raise awareness of the risks of polypharmacy in LTCFs and encourage acceptance of deprescribing amongst residents and their relatives. GPs are integral to the success of deprescribing initiatives within this sector. PMID- 26767621 TI - RAPPER: A new method for rapid assessment of macroalgae as a complement to diatom based assessments of ecological status. AB - Most methods for ecological assessment developed since the onset of the Water Framework Directive require substantial effort by skilled analysts and are therefore expensive to use. RAPPER ("Rapid Assessment of PeriPhyton Ecology in Rivers") is a high level ecological "triage" method that enables rapid screening of sites within a water body to enable managers to identify areas subject to nutrient pressures. The method involves a survey of macroscopic algae within 10m lengths of watercourses, taking samples for subsequent identification, and assessing cover. Genus-level identification is used to ensure rapid assessment and comparability, and that the method can be used by a wide range of users. Genera of alga that form conspicuous growths recognisable with the naked eye are designated as either "stress-tolerant" ("S-taxa") or "competitive" taxa ("C taxa"), depending on their preference for locations with low or high nutrient concentrations. Genera whose representatives span a wide range of nutrient conditions, or for which few data are available, are placed in a third class, "unclassified". The presence of S-taxa and the relative cover of C-taxa are then used to determine whether a site is at risk from eutrophication. Field trials in Scotland demonstrated that the method discriminates between sites with low and high nutrient concentrations. Significant differences were also observed in values of the Trophic Diatom Index between RAPPER classification categories. RAPPER can be used alone (allowing greater spatial or temporal coverage within water bodies at lower cost than conventional assessment methods) or to increase confidence in assessments of the condition of the phytobenthos by incorporating algae other than diatoms. The outcomes also relate directly to the experiences of non-technical stakeholders, and will have benefits for communicating ecosystem health concepts to the wider public, for example through "citizen science". PMID- 26767623 TI - In-house development of a dedicated data acquisition and monitoring system for intracranial pressure, patient posture and patient symptoms in a regional neurosciences centre. AB - Management of traumatic brain injury and cerebrospinal fluid (CSF) flow disorders can be aided by measurement and monitoring of intracranial pressure (ICP). In addition to pressure measurement, knowledge of patient symptoms and posture during monitoring are also valuable, particularly in the management of CSF flow disorders. ICP monitoring systems have been developed in this centre to meet clinical needs in the absence of commercially available solutions. An early system (mark I) was developed and the technical challenges in its design are described, along with limitations to this system that motivated the development of a new mark II system. The mark II system is then described. PMID- 26767622 TI - Proposed definition of the vaginal cuff and paracolpium clinical target volume in postoperative uterine cervical cancer. AB - PURPOSE: The aim of this study was to develop an appropriate definition for vaginal cuff and paracolpium clinical target volume (CTV) for postoperative intensity modulated radiation therapy in patients with uterine cervical cancer. METHODS AND MATERIALS: A working subgroup was organized within the Radiation Therapy Study Group of the Japan Clinical Oncology Group to develop a definition for the postoperative vaginal cuff and paracolpium CTV in December 2013. The group consisted of 5 radiation oncologists who specialized in gynecologic oncology and a gynecologic oncologist. A comprehensive literature review that included anatomy, surgery, and imaging fields was performed and was followed by multiple discreet face-to-face discussions and e-mail messages before a final consensus was reached. RESULTS: Definitions for the landmark structures in all directions that demarcate the vaginal cuff and paracolpium CTV were decided by consensus agreement of the working group. A table was created that showed boundary structures of the vaginal cuff and paracolpium CTV in each direction. CONCLUSIONS: A definition of the postoperative cervical cancer vaginal cuff and paracolpium CTV was developed. It is expected that this definition guideline will serve as a template for future radiation therapy clinical trial protocols, especially protocols involving intensity modulated radiation therapy. PMID- 26767624 TI - On being a Luddite in the new world of technological nursing care. PMID- 26767625 TI - Brave new world. PMID- 26767627 TI - Down-regulation of GRalpha expression and inhibition of its nuclear translocation by hypoxia. AB - AIMS: Glucocorticoids are the most effective anti-inflammatory agent in treating pulmonary diseases typically accompanied by hypoxia. Our previous study has demonstrated that glucocorticoid receptor alpha (GRalpha) expression is reduced in hypoxia but the underlying mechanism remains elusive. In this study we aim to identify the signaling pathway involved in hypoxia-induced down-regulation of GRalpha, and whether hypoxia affects nuclear translocation of GRalpha. MAIN METHODS: Female C57BL/6 mice were sensitized with saline or ovalbumin (OVA) as the in vivo model. Mice were divided into control and OVA groups, and their lung histology and the expression of hypoxia inducible factor (HIF-1) and GRalpha were examined. A549 cells were exposed to chemical hypoxia as the in vitro model, where mitogen-activated protein kinases (MAPKs) were inhibited specifically by SB203580. Next, under normal or hypoxic conditions, the expression of GRalpha, MAPKs and HIF-1 signal protein were determined by Western blot analysis, and GRalpha translocation were observed through live-cell imaging. KEY FINDINGS: In OVA challenged mice the expression of GRalpha was down-regulated whereas HIF-1 was up-regulated. Hypoxia caused a time-dependent decrease of GRalpha expression, and activated multiple signaling pathways including MAPKs and HIF-1. Moreover, GRalpha expression increased with MAPK inhibition. Interestingly, only MAPK inhibitor SB203580, but not JNK inhibitor SP600125 or ERK inhibitor U0126 improved the expression of GRalpha under hypoxic condition. GRalpha nuclear translocation was also significantly inhibited by hypoxia. SIGNIFICANCE: Hypoxia down-regulated the expression of GRalpha through p38 signaling pathway, as well as inhibited GRalpha nuclear translocation significantly. PMID- 26767628 TI - Sentinel lymph node biopsy staging for cutaneous malignant melanoma of the head and neck. AB - Conclusion Sentinel lymph node biopsies (SLNBs) can be performed safely and with reasonable accuracy in HNM patients. The outcome provides important prognostic information concerning DFS and further treatment. However, one must recognize that SLNB is a multidisciplinary procedure with a learning curve for all. Objectives To evaluate efficacy of performing SLNBs in a series of consecutive patients with cutaneous head and neck melanoma (HNM) >= T1b from introduction of the procedure and 10 years onward. Method End-points comprised of SLNB outcome, disease-free survival (DFS), and overall survival (OS). Results SNs were harvested in 128 of 160 patients (median Breslow = 2.0 mm, 29% ulcerated); success rate = 80.0%, or 92.1% if excluding patients where SLNBs were omitted due to non-localization on pre-operative imaging or because of SN-location in the parotid basin. Ten patients (7.8%) had positive SLNBs and were offered early completion neck dissections. Of the 146 patients available for follow-up (median = 27 months), 15.8% had recurrent disease. The risk of a regional nodal recurrence after a negative SLNB was 7.5%. SN-negative patients had improved DFS c.f. SN-positive patients (p < 0.001). A positive SLNB was the most important prognostic predictor of decreased DFS (hazard ratio = 5.70; p < 0.005), but had no significant impact on OS. PMID- 26767626 TI - Lupeol inhibits LPS-induced NF-kappa B signaling in intestinal epithelial cells and macrophages, and attenuates acute and chronic murine colitis. AB - AIMS: Lupeol, a natural pentacyclic triterpene, exhibits anti-inflammatory effects. However, its role in colitis has not been investigated. In the present study, we evaluated the effect of lupeol on the NF-kappaB signaling pathway and experimental colitis in mice. MAIN METHODS: The human intestinal epithelial cells (IECs) COLO 205 and the murine macrophages RAW 264.7 were pretreated with lupeol and then stimulated with lipopolysaccharide (LPS). The production of inflammatory cytokines (IL-8 from COLO 205; IL-6, IL-12 and TNF-alpha from RAW 264.7) was determined by ELISA. The effect of lupeol on NF-kappaB pathway was examined by Western blot analysis of IkappaBalpha phosphorylation/degradation and an electrophoretic mobility shift assay (EMSA). For in vivo studies, dextran sulfate sodium (DSS)-induced acute colitis model and chronic colitis model in IL-10(-/-) mice were used. Colitis was quantified by disease activity index, colon length and histologic evaluation. KEY FINDINGS: Lupeol strongly suppressed pro inflammatory cytokine production in IECs and murine macrophages. It also inhibited LPS-induced IkappaBalpha phosphorylation/degradation and the DNA binding activity of NF-kappaB. The oral administration of lupeol significantly reduced the colitis activity and histologic scores in both acute and chronic murine colitis models. Furthermore, the up-regulation of IkappaBalpha phosphorylation in the colonic mucosa was attenuated in lupeol-treated mice. SIGNIFICANCE: Lupeol blocks the NF-kappaB signaling in IECs and murine macrophages, and attenuate experimental murine colitis. These findings suggest that lupeol is a potential therapeutic agent for inflammatory bowel disease. PMID- 26767631 TI - Mobile Spectroscopic Instrumentation in Archaeometry Research. AB - Mobile instrumentation is of growing importance to archaeometry research. Equipment is utilized in the field or at museums, thus avoiding transportation or risk of damage to valuable artifacts. Many spectroscopic techniques are nondestructive and micro-destructive in nature, which preserves the cultural heritage objects themselves. This review includes over 160 references pertaining to the use of mobile spectroscopy for archaeometry. Following a discussion of terminology related to mobile instrumental methods, results of a literature survey on their applications for cultural heritage objects is presented. Sections devoted to specific techniques are then provided: Raman spectroscopy, X-ray fluorescence spectrometry, Fourier transform infrared spectroscopy, laser-induced breakdown spectroscopy, and less frequently used techniques. The review closes with a discussion of combined instrumental approaches. PMID- 26767632 TI - Using Nondestructive Portable X-ray Fluorescence Spectrometers on Stone, Ceramics, Metals, and Other Materials in Museums: Advantages and Limitations. AB - Elemental analysis is a fundamental method of analysis on archaeological materials to address their overall composition or identify the source of their geological components, yet having access to instrumentation, its often destructive nature, and the time and cost of analyses have limited the number and/or size of archaeological artifacts tested. The development of portable X-ray fluorescence (pXRF) instruments over the past decade, however, has allowed nondestructive analyses to be conducted in museums around the world, on virtually any size artifact, producing data for up to several hundred samples per day. Major issues have been raised, however, about the sensitivity, precision, and accuracy of these devices, and the limitation of performing surface analysis on potentially heterogeneous objects. The advantages and limitations of pXRF are discussed here regarding archaeological studies of obsidian, ceramics, metals, bone, and painted materials. PMID- 26767629 TI - Baseline characteristics of participants in the VITamin D and OmegA-3 TriaL (VITAL). AB - Evidence for a role of supplemental vitamin D and marine omega-3 fatty acids in preventing cancer and cardiovascular disease (CVD) remains inconclusive and insufficient to inform nutritional recommendations for primary prevention. The VITamin D and Omega-A 3 TriaL (VITAL) is an ongoing nationwide, randomized, double-blind, placebo-controlled clinical trial designed to fill this knowledge gap. The study population consists of 25,874 U.S. adults without cancer or CVD at baseline, who were selected only on age (men aged >=50 and women aged >=55), with an oversampling of African Americans (n=5,107). In a 2 * 2 factorial design, participants were randomized to one of four supplement groups: [1] active vitamin D3 (cholecalciferol; 2000 IU/d) and active marine omega-3 fatty acids (Omacor(r) fish oil, eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA], 1g/d); [2] active vitamin D and omega-3 placebo; [3] vitamin D placebo and active marine omega-3 fatty acids; or [4] vitamin D placebo and omega-3 placebo. The mean length of the randomized treatment period will be 5 years. The randomization was successful, as evidenced by similar distributions of baseline demographic, health, and behavioral characteristics across treatment groups. The similar distribution of known potential confounders across treatment groups strongly suggests that unmeasured or unknown potential confounders are also equally distributed. VITAL is expected to provide important information on the benefit risk balance of vitamin D and omega-3 fatty acid supplementation when taken for the primary prevention of cancer and CVD. PMID- 26767633 TI - Exploring a Hidden Painting Below the Surface of Rene Magritte's Le Portrait. AB - Two state-of-the-art methods for non-invasive visualization of subsurface (or overpainted) pictorial layers present in painted works of art are employed to study Le portrait, painted by Belgian artist Rene Magritte in 1935. X-ray radiography, a commonly used method for the nondestructive inspection of paintings, had revealed the presence of an underlying figurative composition, part of an earlier Magritte painting entitled La pose enchantee (1927) which originally depicted two full length nude female figures with exaggerated facial features. On the one hand, macroscopic X-ray fluorescence analysis (MA-XRF), a method capable of providing information on the distribution of the key chemical elements present in many artists' pigments, was employed. The ability of the X rays to penetrate the upper layer of paint enabled the imaging of the facial features of the female figure and provided information on Magritte's palette for both surface and hidden composition. On the other hand, visible and near infrared hyperspectral imaging spectroscopies in transmission mode were also used, especially in the area of the table cloth in order to look through the upper representation and reveal the pictorial layer(s) below. MA-XRF provided elemental information on the pigment distributions in both the final painting and the prior whereas the transmission mode provided information related to preparatory sketches as well as revealing differences between the paints used in both compositions. These results illustrate very well the manner in which the two imaging methods complement each other, both in the sense of providing different types of information on the nature and presence of paint components/pigments and in the sense of being optimally suited to easily penetrate through different types of overpaint. PMID- 26767634 TI - Tortoiseshell or Polymer? Spectroscopic Analysis to Redefine a Purported Tortoiseshell Box with Gold Decorations as a Plastic Box with Brass. AB - The study and preservation of museum collections requires complete knowledge and understanding of constituent materials that can be natural, synthetic, or semi synthetic polymers. In former times, objects were incorporated in museum collections and classified solely by their appearance. New studies, prompted by severe degradation processes or conservation-restoration actions, help shed light on the materiality of objects that can contradict the original information or assumptions. The selected case study presented here is of a box dating from the beginning of the 20th century that belongs to the Portuguese National Ancient Art Museum. Museum curators classified it as a tortoiseshell box decorated with gold applications solely on the basis of visual inspection and the information provided by the donor. This box has visible signs of degradation with white veils, initially assumed to be the result of biological degradation of a proteinaceous matrix. This paper presents the methodological rationale behind this study and proposes a totally non-invasive methodology for the identification of polymeric materials in museum artifacts. The analysis of surface leachates using (1)H and (13)C nuclear magnetic resonance (NMR) complemented by in situ attenuated total reflection infrared spectroscopy (ATR FT-IR) allowed for full characterization of the object s substratum. The NMR technique unequivocally identified a great number of additives and ATR FT-IR provided information about the polymer structure and while also confirming the presence of additives. The pressure applied during ATR FT-IR spectroscopy did not cause any physical change in the structure of the material at the level of the surface (e.g., color, texture, brightness, etc.). In this study, variable pressure scanning electron microscopy (VP-SEM-EDS) was also used to obtain the elemental composition of the metallic decorations. Additionally, microbiologic and enzymatic assays were performed in order to identify the possible biofilm composition and understand the role of microorganisms in the biodeterioration process. Using these methodologies, the box was correctly identified as being made of cellulose acetate plastic with brass decorations and the white film was identified as being composed mainly of polymer exudates, namely sulphonamides and triphenyl phosphate. PMID- 26767635 TI - Combined Spectroscopic Analysis of Beads from the Tombs of Kindoki, Lower Congo Province (Democratic Republic of the Congo). AB - Raman spectroscopy and X-ray fluorescence (XRF) analysis are commonly applied to archaeological objects as a fast and nondestructive way to characterize the materials. Here, micro-Raman spectroscopy and chemometrics on handheld XRF results were used to completely characterize beads found during archaeological excavations in the Congo. Metallic objects, organogenic materials, and glass beads were studied. Special attention was paid to the glassy materials, as they seem to be of European production. The matrix family and crystalline phases assemblage, as well as the results from principal components analysis on the elemental data, were used to define groups of beads of similar composition, and therefore probably of similar origin. This research project establishes the feasibility of this approach to archaeological glasses, and can be used to confirm and support the bead typologies used by archaeologists. PMID- 26767636 TI - Quantitative Chemical Analysis of Archaeological Slag Material Using Handheld X ray Fluorescence Spectrometry. AB - Handheld X-ray fluorescence spectrometry (XRF) has seen a dramatic increase in use for archaeological projects. The attraction of the technique is its portable and nondestructive nature. In many cases, the archaeological artefacts in question cannot be destructively sampled, or the piece itself cannot be sent to an analytical laboratory. One of the current research interests associated with the Sagalassos project is the study of the Roman iron industry. Previously exported iron slag and ore from the site and the surrounding area was subjected to laboratory chemical analyses. These indicated that different ores were being utilized in the production of iron in different periods. In order to further the project the slag material still in the site depot needed to be analyzed. However, recent legislative changes mean that materials can only be analyzed on-site. Since samples could not be taken and destructive chemical analysis was no longer feasible, a portable, nondestructive technique was required. Handheld XRF can easily provide qualitative data, but these data are only comparable to other handheld XRF qualitative data, from the same device. Quantitative data gathering is possible, but can be more problematic, particularly when the material in question is heterogeneous in nature. A calibration file was created using the manufacturer's software and "in-house" standards made from the pre-quantified samples of iron slag available in the laboratory. In order to make the calibration as robust as possible, the composition of the standards was analyzed statistically to determine which of these created bias and leverage for specific elements. These standards were then omitted from the calibration for that element. The calibration was tested in the laboratory using samples of iron slag previously analyzed with wet chemistry, and the results indicated that most sample analyses showed <30% error. Results with a >30% error were found in samples which contained very low or very high quantities of the analyzed element, i.e., outside the limits of the calibration. The handheld XRF and the associated calibration file were then used to provide a semi-quantified chemical characterization of the samples in the field depot. PMID- 26767637 TI - Characterization of Archaeological Sediments Using Fourier Transform Infrared (FT IR) and Portable X-ray Fluorescence (pXRF): An Application to Formative Period Pyro-Industrial Sites in Pacific Coastal Southern Chiapas, Mexico. AB - Archaeological sediments from mounds within the mangrove zone of far-southern Pacific coastal Chiapas, Mexico, are characterized in order to test the hypothesis that specialized pyro-technological activities of the region's prehistoric inhabitants (salt and ceramic production) created the accumulations visible today. Fourier transform infrared spectroscopy (FT-IR) is used to characterize sediment mineralogy, while portable X-ray fluorescence (pXRF) is used to determine elemental concentrations. Elemental characterization of natural sediments by both instrumental neutron activation analysis (INAA) and pXRF also contribute to understanding of processes that created the archaeological deposits. Radiocarbon dates combined with typological analysis of ceramics indicate that pyro-industrial activity in the mangrove zone peaked during the Late Formative and Terminal Formative periods, when population and monumental activity on the coastal plain and piedmont were also at their peaks. PMID- 26767638 TI - Attenuated Total Reflection Fourier Transform Infrared (ATR FT-IR) Spectroscopy as a Forensic Method to Determine the Composition of Inks Used to Print the United States One-cent Blue Benjamin Franklin Postage Stamps of the 19th Century. AB - Through the combined use of infrared (IR) absorption spectroscopy and attenuated total reflectance (ATR) sampling, the composition of inks used to print the many different types of one-cent Benjamin Franklin stamps of the 19th century has been established. This information permits a historical evaluation of the formulations used at various times, and also facilitates the differentiation of the various stamps from each other. In two instances, the ink composition permits the unambiguous identification of stamps whose appearance is identical, and which (until now) have only been differentiated through estimates of the degree of hardness or softness of the stamp paper, or through the presence or absence of a watermark in the paper. In these instances, the use of ATR Fourier transform infrared spectroscopy (FT-IR) spectroscopy effectively renders irrelevant two 100 year-old practices of stamp identification. Furthermore, since the use of ATR sampling makes it possible to obtain the spectrum of a stamp still attached to its cover, it is no longer necessary to identify these blue Franklin stamps using their cancellation dates. PMID- 26767640 TI - Accurate Measurements of Spectral Reflectance in Picasso's Guernica Painting. AB - The use of non-invasive spectral measurements to control the conservation status is a part of the preventive conservation of artworks which nowadays is becoming increasingly interesting. This paper describes how to use a spectral measuring device and an illumination system specifically designed for such a task in a very large dimension artwork painting (7.8 m wide * 3.5 m high). The system, controlled by a Cartesian robot, allows spectral measurements in a spectral range of 400-780 nm. The measured data array has a total of 2201 circular regions with 5.5 mm spot diameter placed on a square grid. Colorimetric calculations performed from these spectral measurements may be used to characterize color shifts related to reflectance changes in specific areas of the paint. A color shifting from the expected gray has been shown. PMID- 26767639 TI - Portable Raman, DRIFTS, and XRF Analysis to Diagnose the Conservation State of Two Wall Painting Panels from Pompeii Deposited in the Naples National Archaeological Museum (Italy). AB - This work presents a methodology that combines spectroscopic speciation, performed through portable Raman spectroscopy, diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS), and energy dispersive X-ray fluorescence spectrometry (ED-XRF) working in situ, and thermodynamic speciation to diagnose the environmental impacts, induced by past and current events, on two wall painting panels (Nos. 9103 and 9255) extracted more than 150 years ago from the walls of a Pompeian house (Marcus Lucretius House, Regio IX, Insula 3, House 5/24) and deposited in the Naples National Archaeological Museum (MANN). The results show a severe chemical attack of the acid gases that can be explained only by the action of H2S during and just after the eruption of the Vesuvius volcano, that expelled a high concentration of sulfur gases. This fact can be considered as the most important process impacting the wall painting panels deposited in the museum, while the rain-wash processes and the colonization of microorganisms have not been observed in contrast to the impacts shown by the wall paintings left outside in the archaeological site of Pompeii. Moreover, the systematic presence of lead traces and strontium in both wall paintings suggests their presence as impurities of the calcite mortars (intonacco) or calcite binder of these particular fresco Pompeian murals. PMID- 26767641 TI - Analytical Capability of Defocused u-SORS in the Chemical Interrogation of Thin Turbid Painted Layers. AB - A recently developed micrometer-scale spatially offset Raman spectroscopy (MU SORS) method provides a new analytical capability for investigating non destructively the chemical composition of sub-surface, micrometer-scale thickness, diffusely scattering layers at depths beyond the reach of conventional confocal Raman microscopy. Here, we demonstrate experimentally, for the first time, the capability of MU-SORS to determine whether two detected chemical components originate from two separate layers or whether the two components are mixed together in a single layer. Such information is important in a number of areas, including conservation of cultural heritage objects, and is not available, for highly turbid media, from conventional Raman microscopy, where axial (confocal) scanning is not possible due to an inability to facilitate direct imaging within the highly scattering sample. This application constitutes an additional capability for MU-SORS in addition to its basic capacity to determine the overall chemical make-up of layers in a turbid system. PMID- 26767642 TI - Nondestructive Determination of the Age of 20th-Century Oil-Binder Ink Prints Using Attenuated Total Reflection Fourier Transform Infrared Spectroscopy (ATR FT IR): A Case Study with Postage Stamps from the Lodz Ghetto. AB - The ability to determine the production date for a painting or print would be of great benefit in the forensic detection of fakes and forgeries as well as in art history and conservation. Changes in the pigments used at different times have been invaluable in detecting incongruities that suggest fraud, but relatively little work has been published that uses the chemical changes in oil binders as they dry to determine when an ink print or an oil painting was made. Using attenuated total reflectance-Fourier transform infrared (ATR FT-IR) spectroscopy and samples with known dates, we calibrate the drying of oil binders in inks and paints and cross-validate the paints with pyrolysis-gas chromatography-mass spectrometry (Py-GC-MS). We apply the ink calibration to a case study involving the age determination of possible philatelic counterfeits from a World War II Jewish Ghetto in Occupied Poland, obtaining a date of 1946 +/- 6 (1 s, n = 9) for the genuine stamps, and 1963 +/- 16 (1 s, n = 19) for the various reproductions. PMID- 26767643 TI - Painted Fiberglass-Reinforced Contemporary Sculpture: Investigating Composite Materials, Techniques and Conservation Using a Multi-Analytical Approach. AB - A multi-analytical approach was used to study the constituent materials, manufacturing technique, and state of conservation of a contemporary sculpture. This sculpture, entitled Nuredduna, was created by Aligi Sassu in 1995 and is located in the "Bellariva garden" in Florence (Italy). Fourier transform infrared spectroscopy (FT-IR), optical and electronic microscopy (OM and SEM-EDS), X-ray diffraction (XRD), and portable X-ray fluorescence (XRF) highlighted the multi layered structure of the statue: fiberglass and an overlay of different layers (gel coat) applied with an unsaturated polyester resin added with aggregate materials and bromine compounds. A top-coat in acrylic black varnish, used as a finish, was also found. The combination of these materials with their different compositions, environmental impact, and even vandalism have negatively affected the state of conservation of Nuredduna, causing the loss of strata in its lower parts (legs and feet). PMID- 26767644 TI - The Colors of Keith Haring: A Spectroscopic Study on the Materials of the Mural Painting Tuttomondo and on Reference Contemporary Outdoor Paints. AB - To date, little attention has been given to the scientific investigation of modern and contemporary mural paintings. This paper reports on: (1) the in situ spectroscopic analyses of the mural Tuttomondo (1989) painted by Keith Haring (1958-1990) in Pisa (Italy); and (2) the laboratory characterization of acrylic paints produced by Caparol Italy GmbH & Co., the original supplier of paint materials to the artist for the mural. Ultraviolet (UV), visible (Vis), and near infrared (NIR) fiber optic reflectance spectroscopy (FORS) measurements were carried out in situ. The Caparol paint samples were characterized using benchtop instrumentation including both dispersive and Fourier transform Raman spectroscopy, Fourier transform infrared spectroscopy (FT-IR; with sample pre treatment to remove filler interference in the fingerprint region), and UV-Vis NIR FORS. This combined analytical approach confirmed that the materials used by Haring for the mural Tuttomondo have the same composition of the new Caparol acrylic paints, except for the case of the yellow pigment. This information offers valuable documentation for the materials history and for the conservation of a mural painting that is considered the last great public work by Haring. PMID- 26767645 TI - Spectroscopic Studies on the Characterization of a Persian Playing Card. AB - This paper presents the results of our investigations on a playing card preserved at The Muzih-i Aynih va Rushanai in Yazd, Iran. Conducting micro X-ray fluorescence spectrometry (MU-XRF), micro-Raman spectroscopy (MU-Raman), infrared reflectography (IRR), ultraviolet fluorescence photography, radiography, and optical microscopy, various paints applied on the playing card were identified. According to our analytical studies, red, green, blue, black, and gold-like metallic paints were identified to be a red monoazo pigment (beta-naphthol PR 53:1), chrome green, artificial ultramarine blue, carbon black, and brass powder (Dutch metal powder), respectively, dating the playing card to 1895 onward based on the manufacturing date of the red monoazo pigment. Barite was also shown to be mixed with the pigments as an extender. On the other hand, the portrait's face of the playing card was peculiarly blackened. Our analytical approach toward characterizing the blackened face showed that the black paint was achieved by carbon black and, in other words, the face was not blackened due to the darkening of Pb-bearing pigments. Moreover, it was shown that there was no underdrawing under the black face and the black paint was most probably executed in the same time with the other paints. Considering the possible use of the playing card, it was suggested not to remove the blackened face in the cleaning process since the black paint was a part of the integrity of the playing card. PMID- 26767646 TI - A Review of Energy Dispersive X-Ray Fluorescence (EDXRF) as an Analytical Tool in Numismatic Studies. AB - Energy dispersive X-ray fluorescence spectrometry (EDXRF) as an analytical technique in studies of ancient coins is summarized and reviewed. Specific EDXRF applications in historical studies, in studies of the corrosion of coins, and in studies of the optimal working conditions of some laser-based treatment for the cleaning of coins are described. PMID- 26767648 TI - [Update 2016 - Immunotherapy for urothelial carcinoma]. AB - Advanced urothelial carcinoma of the bladder is an aggressive tumor with a poor prognosis. Besides surgical therapy, classical chemotherapy with platinum compounds is the mainstay of advanced bladder cancer treatment. In recent years, immune modulating therapies have come into the focus of clinical trials. This review provides an overview of the biological mechanisms and immuno-oncological drugs that are currently being analyzed in clinical trials as well as established standard therapies. PMID- 26767647 TI - Extracellular signal-regulated kinase 1 and 2 in cancer therapy: a focus on hepatocellular carcinoma. AB - Extracellular signal-regulated kinases (ERK) pathway plays a crucial role in cancer cell survival and proliferation. This signaling pathway has been related to epithelial to mesenchymal transition and drug resistance in hepatocellular carcinoma (HCC) cells, which is a common challenge in chemotherapy. Consequently, mediators of this pathway have recently been considered as novel therapeutic targets in HCC. In this review the impact of ERK1 and ERK2 as major components of ERK signaling pathway, in HCC biology and drug resistance will be highlighted and discussed. PMID- 26767649 TI - [Operative interventions of urologic traumata in severe injured patients in the acute phase]. AB - INTRODUCTION: The frequency of urological traumata and the need for interventions in severely injured patients in Germany are unknown. The aim of this study was to determine the frequency of urological traumata in about 90,000 severely injured patients (Injury Severity Score, ISS >= 16). MATERIALS AND METHODS: Data of 90,000 patients from the TraumaRegister DGU(r) were retrospectively analyzed. All patients with an ISS of >= 16 were included. The kind of urological traumata and the need for urological intervention within 24 hours were assessed, as well as the kind of accident, additional traumata and the clinical course. RESULTS: 48,797 patients fulfilled the inclusion criteria. Urological trauma was existent in 7.1 %, especially in men (78 %). Kidneys were affected most frequently (4.8 %) compared to ureters (0.2 %), urinary bladder (1.2 %), urethra (0.5 %) and genitals (0.4 %). Traffic accidents and falls from higher levels represented the main cause for urological traumata (> 90 %). It was associated with additional pelvis, thorax and abdomen traumata (each 7.1 %) and showed a distinct increase dependent on the abbreviated injury scale (AIS). Ureter (10.6%) and urethra (6.3%) trauma was deferred diagnosed most, this was associated with a higher rate of urological operations. The general duration of hospital stay and that in the intensive care unit were prolonged by urological traumata. DISCUSSION: The data showed the prevalence of urological trauma in severely injured patients analyzed in a huge patient cohort of the TraumaRegister DGU(r). For the first time the number, degree and medical care in the reality of urological traumata in severely injured patients were available. PMID- 26767650 TI - Nicotinamide phosphoribosyltransferase leukocyte overexpression in Graves' opthalmopathy. AB - To investigate the role of NAMPT/visfatin in euthyroid patients with Graves' disease without (GD) and with Graves' ophthalmopathy (GO), we analyzed NAMPT leukocyte expression and its serum concentration. This was a single-center, cross sectional study with consecutive enrollment. In total, 149 patients diagnosed with Graves' disease were enrolled in the study. We excluded subjects with hyper- or hypothyroidism, diabetes mellitus, other autoimmune disorders, active neoplastic disease, and infection. The control group was recruited among healthy volunteers adjusted for age, sex, and BMI with normal thyroid function and negative thyroid antibodies. Serum levels of visfatin, TSH, FT4, FT3, antibodies against TSH receptor (TRAb), antithyroperoxidase antibodies, antithyroglobulin antibodies, fasting glucose, and insulin were measured. NAMPT mRNA leukocyte expression was assessed using RT-qPCR. NAMPT/visfatin serum concentration was higher in GD (n = 44) and GO (n = 49) patients than in the control group (n = 40) (p = 0.0275). NAMPT leukocyte expression was higher in patients with GO (n = 30) than in GD patients (n = 27) and the control group (n = 29) (p < 0.0001). Simple linear regression analysis revealed that NAMPT/visfatin serum concentration was significantly associated with GD (beta = 1.5723; p = 0.021). When NAMPT leukocyte expression was used as a dependent variable, simple regression analysis found association with TRAb, fasting insulin level, HOMA-IR, GD, and GO. In the stepwise multiple regression analysis, we confirmed the association between higher serum NAMPT/visfatin level and GD (coefficient = 1.5723; p = 0.0212), and between NAMPT leukocyte expression and GO (coefficient = 2.4619; p = 0.0001) and TRAb (coefficient = 0.08742; p = 0.006). Increased NAMPT leukocyte expression in patients with GO might suggest a presently undefined role in the pathogenesis of GO. PMID- 26767651 TI - Skeletal health in adult growth hormone deficiency. PMID- 26767653 TI - Cardiovascular risk factors in growth hormone deficiency: is vitamin D a new kid on the block? PMID- 26767652 TI - Increase in endogenous estradiol in the progeny of obese rats is associated with precocious puberty and altered follicular development in adulthood. AB - Maternal obesity during pregnancy has been related with several pathological states in offspring. However, the impact of maternal obesity on reproductive system on the progeny is beginning to be elucidated. In this work, we characterize the effect of maternal obesity on puberty onset and follicular development in adult offspring in rats. We also propose that alterations in ovarian physiology observed in offspring of obese mothers are due to increased levels of estradiol during early development. Offspring of control dams and offspring of dams exposed to a high-fat diet (HF) were studied at postnatal days (PND) 1, 7, 14, 30, 60, and 120. Body weight and onset of puberty were measured. Counting of ovarian follicles was performed at PND 60 and 120. Serum estradiol, estriol, androstenedione, FSH, LH, and insulin levels were measured by ELISA. Hepatic CYP3A2 expression was determined by Western blot. HF rats had a higher weight than controls at all ages and they also had a precocious puberty. Estradiol levels were increased while CYP3A2 expression was reduced from PND 1 until PND 60 in HF rats compared to controls. Estriol was decreased at PND60 in HF rats. Ovaries from HF rats had a decrease in antral follicles at PND60 and PND120 and an increase in follicular cysts at PND60 and PND120. In this work, we demonstrated that maternal obesity in rats alters follicular development and induces follicular cysts generation in the adult offspring. We observed that maternal obesity produces an endocrine disruption through increasing endogenous estradiol in early life. A programmed failure in hepatic metabolism of estradiol is probably the cause of its increase. PMID- 26767654 TI - In Praise of Error. AB - The methodological status of origin-of-life research as an experimental science, predicated on deductive logic, is assessed and illustrated by recent examples. PMID- 26767655 TI - Outcomes of different concentrations of human amniotic fluid in a keratoconjunctivitis sicca-induced mouse model. AB - To compare the effects of different concentrations of topical human amniotic fluid (HAF) in a mouse model of dry eye, forty C57BL/6 mice were divided into 4 treatment groups: 20 % HAF, 50 % HAF, 100 % HAF, and isotonic salt solution (control). Dry eye was induced by an injection of botulinum toxin B into the lacrimal gland. Tear production, ocular surface fluorescein staining, and blink rate were evaluated in each mouse at 5 time points during a 4-week period. Goblet cell density was assessed in stained histological sections. Regarding tear production, 20, 50, and 100 % HAF groups were all different from the control group (P < 0.001) at week 1. However, there were no statistically significant differences between the 20, 50, and 100 % HAF groups. At week 2, 20, 50, and 100 % HAF groups had significant improvement in staining score and were significantly different from the control group (P = 0.047, P = 0.005, and P = 0.001, respectively). No difference in spontaneous blink rate was observed between groups, at any time point. Goblet cell density was significantly decreased in the control group compared to the HAF treatment groups. All tested concentrations of topical HAF were effective and superior than the control in this keratoconjunctivitis sicca-induced mouse model. Further studies are needed to evaluate the effects of HAF on the human ocular surface. PMID- 26767657 TI - A retrospective review of pediatric difficult airways: once easy, not always easy. PMID- 26767656 TI - New insights in diagnosis and treatment for Retinopathy of Prematurity. AB - The purpose of this study was to review current perspectives on diagnosis and treatment of Retinopathy of Prematurity (ROP). We performed a systematic review of how much has been produced in research published online and on print regarding ROP in different settings around the world. Early Treatment for ROP (ETROP) classification is the currently accepted classification of ROP. Fluorescein angiography and spectral domain optical coherence tomography (SD-OCT) may eventually lead to changes in the definition of ROP, and as a consequence, they will serve as a guide for treatment. Intravitreal anti-VEGF therapy has proven to be more effective in terms of lowering recurrence, allowing growth of the peripheral retina, and diminishing the incidence of retinal detachment when proliferative ROP is diagnosed. Whether anti-VEGF plus laser are better than any of these therapies separately remains a subject of discussion. Telemedicine is evolving everyday to allow access to remote areas that do not count with a retina specialist for treatment. A management algorithm is proposed according to our reference center experience. ROP is an evolving subject, with a vulnerable population of study that, once treated with good results, leads to a reduction in visual disability and in consequence, in a lifetime improvement. PMID- 26767658 TI - Spectral absorption of visual pigments in stomatopod larval photoreceptors. AB - Larval stomatopod eyes appear to be much simpler versions of adult compound eyes, lacking most of the visual pigment diversity and photoreceptor specializations. Our understanding of the visual pigment diversity of larval stomatopods, however, is based on four species, which severely limits our understanding of stomatopod eye ontogeny. To investigate several poorly understood aspects of stomatopod larval eye function, we tested two hypotheses surrounding the spectral absorption of larval visual pigments. First, we examined a broad range of species to determine if stomatopod larvae generally express a single, spectral class of photoreceptor. Using microspectrophotometry (MSP) on larvae captured in the field, we found data which further support this long-standing hypothesis. MSP was also used to test whether larval species from the same geographical region express visual pigments with similar absorption spectra. Interestingly, despite occupation of the same geographical location, we did not find evidence to support our second hypothesis. Rather, there was significant variation in visual pigment absorption spectra among sympatric species. These data are important to further our understanding of larval photoreceptor spectral diversity, which is beneficial to ongoing investigations into the ontogeny, physiology, and molecular evolution of stomatopod eyes. PMID- 26767660 TI - Beyond localizing neurology and psychology. PMID- 26767659 TI - Streptosporangium lutulentum sp. nov., Streptosporangium fenghuangense sp. nov. and Streptosporangium corydalis sp. nov., three novel actinobacterial species isolated from National Forest Park of Fenghuang Mountain. AB - Three novel actinobacteria, designated strains NEAU-FSHN1(T), NEAU-hd-3(T) and NEAU-Y6(T), were isolated from a stream base, soil adjacent to the stream and a root of Corydalis yanhusuo L, respectively, collected from Wuchang, Heilongjiang Province, China. A polyphasic study was carried out to establish the taxonomic positions of these strains. The three strains were observed to form scant aerial hyphae that differentiated into spherical spore vesicles. The phylogenetic analysis based on the 16S rRNA gene sequences of strains NEAU-FHSN1(T), NEAU-hd 3(T) and NEAU-Y6(T) showed that the three novel isolates exhibit 99.2 % (NEAU FHSN1(T)/NEAU-hd-3(T)), 99.2 % (NEAU-FHSN1(T)/NEAU-Y6(T)) and 99.7 % (NEAU-hd 3(T)/NEAU-Y6(T)) 16S rRNA gene sequence similarities with each other and that they are closely related to strains Streptosporangium shengliense NEAU-GH7(T) (sequence similarities 98.72, 98.85, 98.99 %), Streptosporangium roseum DSM 43021(T) (98.65, 98.51, 98.58 %) and Streptosporangium album DSM 43023(T) (98.41, 98.96, 98.89 %). However, the DNA-DNA hybridization values between strains NEAU FSHN1(T), NEAU-hd-3(T) and NEAU-Y6(T) were 61.2 % (NEAU-FSHN1(T)/NEAU-hd-3(T)), 63.5 % (NEAU-FHSN1(T)/NEAU-Y6(T)) and 65.8 % (NEAU-hd-3(T)/NEAU-Y6(T)), and the values between the three strains and their close phylogenetic relatives were also below 70 %. With reference to phenotypic characteristics, phylogenetic data and DNA-DNA hybridization results, the three strains can be distinguished from each other and their close phylogenetic relatives. Thus, strains NEAU-FHSN1(T), NEAU hd-3(T) and NEAU-Y6(T) are concluded to represent three novel species of the genus Streptosporangium, for which the names Streptosporangium lutulentum sp. nov., Streptosporangium fenghuangense sp. nov. and Streptosporangium corydalis sp. nov. are proposed. The type strains are NEAU-FHSN1(T) (=CGMCC 4.7141(T) = DSM 46740(T)), NEAU-Y6(T) (=CGMCC 4.7150(T) = DSM 46722(T)) and NEAU-hd3(T) (CGMCC 4.7212(T) = JCM 30058(T)), respectively. PMID- 26767661 TI - Dissecting etiologies of posterior circulation stroke. PMID- 26767662 TI - Consensus classifications of gross motor, manual ability, and communication function classification systems between therapists and parents of children with cerebral palsy. PMID- 26767664 TI - Rare Genetic Variants Associated With Development of Age-Related Macular Degeneration. AB - IMPORTANCE: Rare variants in the complement genes CFH, CFI, C9, and C3 have been found to be highly associated with age-related macular degeneration (AMD); however, the effect on clinical characteristics and familial segregation by these variants is lacking. OBJECTIVES: To determine the contribution of rare CFH Arg1210Cys, CFI Gly119Arg, C9 Pro167Ser, and C3 Lys155Gln variants in the development of AMD in 22 multiplex families and to describe clinical differences in carriers vs noncarriers in these families and a large case-control cohort. DESIGN, SETTING, AND PARTICIPANTS: This retrospective case-control study included 114 affected and 60 unaffected members of 22 multiplex families with AMD as well as 1589 unrelated patients with AMD and 1386 unrelated control individuals enrolled in the European Genetic Database (EUGENDA). Patients were recruited from March 29, 2006, to April 26, 2013, and data were collected from April 20, 2012, to May 7, 2014. All participants underwent an extensive ophthalmic examination and completed a questionnaire. Venous blood samples were obtained from all participants for genetic analysis, including whole-exome sequencing and measurements of complement activation. Data were analyzed from September 23, 2014, to November 4, 2015. MAIN OUTCOMES AND MEASURES: Differences between carriers and noncarriers of rare variants in age at onset of symptoms, the family history of AMD, complement activation levels (C3d:C3 ratio), the presence of reticular pseudodrusen, and AMD phenotype. RESULTS: Among the 114 affected and 60 unaffected members of 22 multiplex families with AMD and the 1598 unrelated patients with AMD and 1386 controls in the EUGENDA cohort who underwent analysis, the presence of the CFI Gly119Arg, C9 Pro167Ser, or C3 Lys155Gln variant was confirmed in 18 individuals in 5 families but did not completely segregate with the disease. In the case-control cohort, the 91 affected carriers of these variants were younger at symptom onset (mean [SD] age, 67.4 [8.5] vs 71.3 [8.9] years; P = .01) and more often reported a positive family history (35 of 79 [44.3%] vs 367 of 1201 [30.6%]; P = .008) compared with the 1498 noncarriers. Patients with advanced atrophic AMD carried these rare variants more frequently than patients with neovascular AMD (11 of 93 [11.8%] vs 40 of 835 [4.8%]; P = .04). CONCLUSIONS AND RELEVANCE: Previously reported rare variants do not completely segregate within families with AMD. However, patients carrying these rare variants differ clinically from noncarriers by an earlier age at symptom onset, higher prevalence of a positive family history, and AMD phenotype. These results suggest that genetic tests for AMD might be designed to detect common and rare genetic variants, especially in families, because rare variants contribute to the age at onset and progression of the disease. PMID- 26767699 TI - Ultrasensitive Characterization of Mechanical Oscillations and Plasmon Energy Shift in Gold Nanorods. AB - Mechanical vibrational resonances in metal nanoparticles are intensively studied because they provide insight into nanoscale elasticity and for their potential application to ultrasensitive mass detection. In this paper, we use broadband femtosecond pump-probe spectroscopy to study the longitudinal acoustic phonons of arrays of gold nanorods with different aspect ratios, fabricated by electron beam lithography with very high size uniformity. We follow in real time the impulsively excited extensional oscillations of the nanorods by measuring the transient shift of the localized surface plasmon band. Broadband and high sensitivity detection of the time-dependent extinction spectra enables one to develop a model that quantitatively describes the periodic variation of the plasmon extinction coefficient starting from the steady-state spectrum with only one additional free parameter. This model allows us to retrieve the time dependent elongation of the nanorods with an ultrahigh sensitivity and to measure oscillation amplitudes of just a few picometers and plasmon energy shifts on the order of 10(-2) meV. PMID- 26767700 TI - The old and the new. PMID- 26767701 TI - Corrigendum. PMID- 26767704 TI - Genotype by environment interaction for tick resistance of Hereford and Braford beef cattle using reaction norm models. AB - BACKGROUND: The cattle tick is a parasite that adversely affects livestock performance in tropical areas. Although countries such as Australia and Brazil have developed genetic evaluations for tick resistance, these evaluations have not considered genotype by environment (G*E) interactions. Genetic gains could be adversely affected, since breedstock comparisons are environmentally dependent on the presence of G*E interactions, particularly if residual variability is also heterogeneous across environments. The objective of this study was to infer upon the existence of G*E interactions for tick resistance of cattle based on various models with different assumptions of genetic and residual variability. METHODS: Data were collected by the Delta G Connection Improvement program and included 10,673 records of tick counts on 4363 animals. Twelve models, including three traditional animal models (AM) and nine different hierarchical Bayesian reaction norm models (HBRNM), were investigated. One-step models that jointly estimate environmental covariates and reaction norms and two-step models based on previously estimated environmental covariates were used to infer upon G*E interactions. Model choice was based on the deviance criterion information. RESULTS: The best-fitting model specified heterogeneous residual variances across 10 subclasses that were bounded by every decile of the contemporary group (CG) estimates of tick count effects. One-step models generally had the highest estimated genetic variances. Heritability estimates were normally higher for HBRNM than for AM. One-step models based on heterogeneous residual variances also usually led to higher heritability estimates. Estimates of repeatability varied along the environmental gradient (ranging from 0.18 to 0.45), which implies that the relative importance of additive and permanent environmental effects for tick resistance is influenced by the environment. Estimated genetic correlations decreased as the tick infestation level increased, with negative correlations between extreme environmental levels, i.e., between more favorable (low infestation) and harsh environments (high infestation). CONCLUSIONS: HBRNM can be used to describe the presence of G*E interactions for tick resistance in Hereford and Braford beef cattle. The preferred model for the genetic evaluation of this population for tick counts in Brazilian climates was a one-step model that considered heteroscedastic residual variance. Reaction norm models are a powerful tool to identify and quantify G*E interactions and represent a promising alternative for genetic evaluation of tick resistance, since they are expected to lead to greater selection efficiency and genetic progress. PMID- 26767705 TI - Evolution of Hemodynamic and Functional Human Kidney Graft Dose Response to Dopamine Using an Implantable Doppler Device. AB - OBJECTIVES: The relation between dopamine infusion and renal hemodynamics and function has not been studied in renal allografts during early recovery. We analyzed the dose response of dopamine infusion on renal blood flow and function in human kidney transplant recipients at reperfusion and during early graft recovery. MATERIALS AND METHODS: Phasic and mean renal blood flow was measured by the pulsed Doppler technique using implantable Doppler microprobes in contact with the graft artery. Systemic and renal parameters were recorded on dopamine infusion (0, 3, 5, and 10 MUg.kg-1.min-1) immediately after transplant (day 0) in 13 patients and at day 6 in 7/13 patients with early graft recovery. Results are expressed as median and interquartile range between the 25th and 75th percentiles. RESULTS: RESULTS: At day 0, 3 MUg.kg-1.min-1) dopamine did not increase mean renal blood flow over baseline (580 mL/min [219-663 mL/min] vs 542 mL/min [207-686 mL/min]; P = .84). There was an absence of effect with higher dopamine doses, whereas cardiac output, heart rate, and systolic and mean arterial pressure were significantly increased. Urinary sodium excretion, creatinine clearance, and urine output increased dose dependently, with a positive correlation between the increase in urine output and mean arterial pressure (r = 0.48, P < .001). At day 6, 3 MUg.kg-1.min-1 dopamine increased mean renal blood flow over baseline (318 mL/min [234-897 mL/min] vs 191 mL/min [173 706 mL/min]; P = .016), with no further increase at higher doses. CONCLUSIONS: Immediately after transplant, kidney grafts with ischemic-reperfusion injury are fully dilated and do not respond to dopamine. The specific renal effects observed are due to systemic hemodynamic status. Vascular responsiveness to a "renal dopamine dose" returns on graft recovery. PMID- 26767706 TI - Re: The Benefits of High Relaxivity for Brain Tumor Imaging: Results of a Multicenter Intraindividual Crossover Comparison of Gadobenate Dimeglumine with Gadoterate Meglumine (The BENEFIT Study). PMID- 26767707 TI - Current Evaluation of the Safety and Efficacy of Aneurysm Treatment with the WEB Device. PMID- 26767708 TI - Abnormal Amygdala Resting-State Functional Connectivity in Irritable Bowel Syndrome. AB - BACKGROUND AND PURPOSE: Functional neuroimaging studies in irritable bowel syndrome have revealed abnormalities in the corticolimbic regions, specifically, hyperactivity of the amygdala during visceral and somatic stimulation. This study investigated changes in the neural circuitry of the amygdala in patients with irritable bowel syndrome based on resting-state functional connectivity. MATERIALS AND METHODS: Functional MR imaging data were acquired from 31 patients with irritable bowel syndrome and 32 healthy controls (matched for age, sex, and educational level) during rest, and the resting-state functional connectivity of bilateral amygdalae was compared. Multiple regression was performed to investigate the relationship between clinical indices of patients with irritable bowel syndrome and resting-state functional connectivity. RESULTS: Compared with healthy controls, patients with irritable bowel syndrome had higher positive resting-state functional connectivity between the amygdala and insula, midbrain, parahippocampal gyrus, pre- and postcentral gyri, and supplementary motor area. The inclusion of anxiety and depression as covariates did not alter amygdala resting-state functional connectivity differences between the study groups. Multiple covariate regression results showed that the pain intensity in patients with irritable bowel syndrome positively correlated with resting-state functional connectivity between the amygdala and supplementary motor area, pre- and postcentral gyri, and insula, while the Irritable Bowel Syndrome-Symptom Severity Score positively correlated with resting-state functional connectivity between the amygdala and insula and midbrain. CONCLUSIONS: Patients with irritable bowel syndrome showed disturbed amygdala resting-state functional connectivity with the corticolimbic regions, which could partly account for the enhanced emotional arousal and visceral information processing associated with irritable bowel syndrome. PMID- 26767709 TI - Pipeline Embolization Device with or without Adjunctive Coil Embolization: Analysis of Complications from the IntrePED Registry. AB - Flow diversion to treat cerebral aneurysms has revolutionized neurointerventional surgery. Because the addition of coils potentially increases the time and complexity of endovascular procedures, we sought to determine whether adjunctive coil use is associated with an increase in complications. Patients in the International Retrospective Study of Pipeline Embolization Device registry were divided into those treated with the Pipeline Embolization Device alone (n = 689 patients; n = 797 aneurysms; mean aneurysm size, 10.3 +/- 7.6 mm) versus those treated with the Pipeline Embolization Device and concurrent coil embolization (n = 104 patients; n = 109 aneurysms; mean aneurysm size, 13.6 +/- 7.8 mm). Patient demographics and aneurysm characteristics were examined. Rates of neurologic morbidity and mortality were compared between groups. The Pipeline Embolization Device with versus without coiling required a significantly longer procedure time (135.8 +/- 63.9 versus 96.7 +/- 46.2 min; P < .0001) and resulted in higher neurological morbidity (12.5% versus 7.8%; P = .13). These data suggest that either strategy represents an acceptable risk profile in the treatment of complex cerebral aneurysms and warrants further investigation. PMID- 26767710 TI - Cerebral Reorganization after Hemispherectomy: A DTI Study. AB - BACKGROUND AND PURPOSE: Hemispherectomy is a neurosurgical procedure to treat children with intractable seizures. Postsurgical improvement of cognitive and behavioral functions is observed in children after hemispherectomy suggesting plastic reorganization of the brain. Our aim was to characterize changes in DTI scalars in WM tracts of the remaining hemisphere in children after hemispherectomy, assess the associations between WM DTI scalars and age at the operation and time since the operation, and evaluate the changes in GM fractional anisotropy values in patients compared with controls. MATERIALS AND METHODS: Patients with congenital or acquired neurologic diseases who required hemispherectomy and had high-quality postsurgical DTI data available were included in this study. Atlas- and voxel-based analyses of DTI raw data of the remaining hemisphere were performed. Fractional anisotropy and mean, axial, and radial diffusivity values were calculated for WM and GM regions. A linear regression model was used for correlation between DTI scalars and age at and time since the operation. RESULTS: Nineteen patients after hemispherectomy and 21 controls were included. In patients, a decrease in fractional anisotropy and axial diffusivity values and an increase in mean diffusivity and radial diffusivity values of WM regions were observed compared with controls (P < .05, corrected for multiple comparisons). In patients with acquired pathologies, time since the operation had a significant positive correlation with white matter fractional anisotropy values. In all patients, an increase in cortical GM fractional anisotropy values was found compared with controls (P < .05). CONCLUSIONS: Changes in DTI metrics likely reflect Wallerian and/or transneuronal degeneration of the WM tracts within the remaining hemisphere. In patients with acquired pathologies, postsurgical fractional anisotropy values correlated positively with elapsed time since the operation, suggesting a higher ability to recover compared with patients with congenital pathologies leading to hemispherectomy. PMID- 26767711 TI - Outcomes Are Not Different between Patients with Intermediate and High DWI ASPECTS after Stent-Retriever Embolectomy for Acute Anterior Circulation Stroke. AB - BACKGROUND AND PURPOSE: Questions remain as to what benefits embolectomy provides to patients presented with considerable early ischemic changes on baseline imaging studies. This study aimed to investigate the impact of the Alberta Stroke Program Early CT Score applied to DWI on treatment outcomes in patients with acute stroke undergoing stent-retriever embolectomy. MATERIALS AND METHODS: We retrospectively analyzed the clinical and DWI data from 171 patients with acute anterior circulation stroke who were treated with stent-retriever embolectomy within 6 hours of symptom onset. DWI-ASPECTS scores were analyzed with the full scale or were dichotomized (4-6 versus 7-10). Patients with DWI-ASPECTS <=3 were excluded from the study. Associations between outcome and clinical and radiologic factors were determined with a multivariate logistic regression analysis. A good outcome was defined as a modified Rankin Scale score of 0-2 at 3 months. RESULTS: The median DWI-ASPECTS was 7 (interquartile range, 6-8). The rates of good outcome, symptomatic hemorrhage, and mortality were not different between high DWI-ASPECTS (scores of 7-10) and intermediate DWI-ASPECTS (scores of 4-6) groups. In patients with an intermediate DWI-ASPECTS, good outcome was achieved in 46.5% (20/43) of patients with successful revascularization, whereas no patients without successful revascularization had a good outcome (P = .016). In multivariate logistic regression analysis, independent predictors of good outcome were age and successful revascularization. CONCLUSIONS: Our study suggested that there were no differences in outcomes between patients with a high DWI-ASPECTS and those with an intermediate DWI-ASPECTS who underwent stent-retriever embolectomy for acute anterior circulation stroke. Thus, patients with an intermediate DWI-ASPECTS otherwise eligible for endovascular therapy may not be excluded from stent-retriever embolectomy or stroke trials. PMID- 26767712 TI - Reply. PMID- 26767714 TI - Can admission serum cystatin C level be an early marker subclinical acute kidney injury in critical care patients? AB - BACKGROUND: In critical care patients, the diagnosis of subclinical acute kidney injury (AKI) might be difficult with measurements of serum creatinine and estimated glomerular filtration rate (eGFR). Their 'sensitive kidneys' can easily be affected from sepsis, underlying diseases, medications and volume status and if they can be detected earlier, some preventive measures might be taken. In this study we aimed to determine whether admission serum cystatin C (sCys-C) and other clinical parameters can identify subclinical AKI in medical intensive care unit (ICU) patients with normal creatinine-based eGFR at admission. METHODS: A prospective cohort study, performed in an adult ICU of a university hospital between January 2008 and March 2013. The blood samples were obtained within the first 24-48 hours of admission and sCys-C levels were analyzed with particle enhanced immunonephelometric assay. AKI development was assessed according to RIFLE criteria. The cutoff value of sCys-C for the prediction of AKI was determined with receiver operating characteristic (ROC) curve analysis. RESULTS: A total of 72 patients were included in the study and 19 (26%) of them developed AKI. Among the patients with AKI admission sCys-C levels were significantly higher when compared with non-AKI patients (1.06 +/- 0.29 vs. 0.89 +/- 0.28 respectively, p = 0.026). With ROC curve analysis, the threshold level for sCys-C was 0.94 mg/L with 63% sensitivity and 66% specificity [AUC: 0.67, p = 0.026]. With logistic regression analysis 'high sCys-C levels at admission' (OR = 4.73; 95%CI 1.03-21.5, p = 0.044) was found as one of the independent variables for the prediction of AKI development, in addition to 'being intubated before ICU admission' (OR = 10.2; 95%CI 1.72-60.4, p = 0.01) and 'hypotension during ICU follow-up' (OR = 12.3; 95%CI 2.5-60.1, p = 0.002). CONCLUSION: In this cohort of patients, a high sCys-C level at admission was found to be a predictor of subclinical AKI arising during their ICU stay. If supported with further studies, it might be used to provide more accurate and earlier knowledge about renal dysfunction and to take appropriate preventive measures. PMID- 26767715 TI - Evaluation of undergraduate nursing students' clinical confidence following a mental health recovery camp. AB - In the present study, we evaluate the impact of participation in a mental health recovery camp on the clinical confidence of undergraduate nursing students in dealing with individuals with mental illness. Twenty undergraduate nursing students who participated in the recovery camp completed the Mental Health Nursing Clinical Confidence Scale both before and directly after attending the camp. Data were analysed using descriptive and inferential statistics. Participation in the recovery camp was associated with a statistically significant increase in students' level of overall confidence between the pretest and post-test data (P < 0.005). The results also demonstrated that students over the age of 25 years and who do not have a family history of mental illness are more likely to self-report a higher level of confidence in both the pre- and post results. The clinical confidence of undergraduate nursing students improved through participation in an immersive clinical experience within the recovery camp. PMID- 26767717 TI - Doctors are prejudiced against transgender patients, MPs say. PMID- 26767716 TI - Alternating or continuous exposure to cafeteria diet leads to similar shifts in gut microbiota compared to chow diet. AB - SCOPE: Overconsumption of energy-rich food is a major contributor to the obesity epidemic. The eating habits of many people are characterized by the cycling between overconsumption of energy-rich foods and dieting, the effects of which on the microbiota are currently unknown. METHODS AND RESULTS: We compared the fecal microbiota of rats either continuously fed chow or palatable cafeteria diet to a "cycled" group switched between the two diets (chow for 4, cafeteria for 3 days/wk, n = 12/group) over 16 wk. Enriched bacterial metabolic pathways were predicted, and a range of metabolic parameters was correlated to microbial taxa and pathways. Cycled rats showed large excursions in food intake on each diet switch. When switched from chow to cafeteria, they overconsumed, and when switched back to chow they underconsumed relative to those maintained on the two diets. Metabolic parameters of cycled rats were intermediate between those of the other diet groups (p < 0.05). The microbiota of cycled rats was nearly indistinguishable from rats under constant cafeteria diet, and both groups were significantly different to the chow group. Correlation analyses identified microbial metabolic pathways associated with an obese phenotype. CONCLUSION: These data suggest that continuous or intermittent exposure to palatable foods have similar effects on the gut microbiota. PMID- 26767718 TI - Will the year 2016 augur well for better patient safety and health of residents in Korea according to the enactment of the Act for improving the resident training environment and enhancing resident's status? PMID- 26767719 TI - Licensing of medical biochemists and specialists in laboratory medicine, Croatian academic educated professionals in health care. PMID- 26767721 TI - 'A Theory of the Allocation of Time' Turns Fifty: Its Impact on the Field of Health Economics. AB - The year 2015 is the 50th anniversary of the publication of 'A Theory of the Allocation of Time,' by Gary S. Becker in the 1965 volume of The Economic Journal. To mark that occasion, this editorial focuses on the importance of that paper in the history and evolution of the field of health economics. PMID- 26767720 TI - Is there an agreement among the items of the Korean physical therapist licensing examination, learning objectives of class subjects, and physical therapists' job descriptions? AB - PURPOSE: To determine the agreement among the items of the Korean physical therapist licensing examination, learning objectives of class subjects, and physical therapists' job descriptions. METHODS: The main tasks of physical therapists were classified, and university courses related to the main tasks were also classified. Frequency analysis was used to determine the proportions of credits for the classified courses out of the total credits of major subjects, exam items related to the classified courses out of the total number of exam items, and universities that offer courses related to the Korean physical therapist licensing examination among the surveyed universities. RESULTS: The proportions of credits for clinical decision making and physical therapy diagnosis-related courses out of the total number credits for major subjects at universities were relatively low (2.06% and 2.58%, respectively). Although the main tasks of physical therapists are related to diagnosis and evaluation, the proportion of physiotherapy intervention-related items (35%) was higher than that of examination and evaluation-related items (25%) on the Korean physical therapist licensing examination. The percentages of universities that offer physical therapy diagnosis and clinical decision making-related courses were 58.62% and 68.97%, respectively. CONCLUSION: Both the proportion of physiotherapy diagnosis and evaluation-related items on the Korean physical therapist licensing examination, and the number of subjects related to clinical decision making and physical therapy diagnosis in the physical therapy curriculum, should be increased to ensure that the examination items and physical therapy curriculum reflect the practical tasks of physical therapists. PMID- 26767723 TI - Corrigendum. PMID- 26767725 TI - The Campylobacter jejuni CprRS two-component regulatory system regulates aspects of the cell envelope. PMID- 26767726 TI - Assessment of asthma control using CARAT in patients with and without Allergic Rhinitis: A pilot study in primary care. AB - BACKGROUND: Asthma and Allergic Rhinitis (AR) are two chronic inflammatory diseases that are often concomitant. The Control of Allergic Rhinitis and Asthma Test (CARAT) was developed to evaluate the control of these diseases from the patients' perspective. Its performance in asthma patients without AR has not been previously studied. AIM: To test the hypothesis that CARAT can be used to assess asthma control in patients with asthma and without AR. METHODS: A cross-sectional study was conducted in 3 primary healthcare centres in Northern Portugal. Adult patients identified in the Electronic Patient Record with a diagnosis of asthma were invited to participate. CARAT was used to assess asthma control and Asthma Control Test (ACT) as a comparator. The associations between asthma patients without AR (AsAR) and with AR (AwAR) were analyzed with Spearman correlation. Additionally, Receiver Operating Characteristic (ROC) curve analysis, summarized by Area Under the Curve (AUC), was used to assess performance of CARAT for screening asthma that was not well-controlled. RESULTS: A total of 103 asthma patients completed the study, 64 (62%) had AwAR and in 87 (85%) asthma was not well-controlled. We observed a strong correlation between CARAT and ACT scores (r=0.734) in all asthma patients and in both groups: AsAR (r=0.737) and AwAR (r=0.843). ROC curve demonstrated CARAT as having a good discriminative power for both AsAR and AwAR groups (AUC=0.894 and 0.946, respectively). CONCLUSION: These initial results suggest that CARAT has a good discriminative performance, similar to other asthma control assessment tools, for asthma patients with and without AR. PMID- 26767727 TI - The Effects of a Crosslinked, Modified Hyaluronic Acid (xCMHA-S) Gel on Equine Tendon Healing. AB - OBJECTIVE: To assess the effects of a crosslinked, modified hyaluronic acid (xCMHA-S) gel on equine tendon healing using an in vivo surgical model. STUDY DESIGN: In vivo experimental study. ANIMALS: Adult horses (n = 5). METHODS: Full thickness bilateral forelimb window tenectomies were surgically created in both forelimb superficial digital flexor tendons and xCMHA-S gel was implanted intraoperatively into the right forelimb lesion of each horse whereas the left forelimb served as the untreated control. Healing was monitored by serial ultrasound examinations every 14 days over the course of the 84 day study. In addition, gross pathology, scanning electron microscopy for fiber diameter, and histological scoring were completed on tendon samples harvested after euthanasia at 84 days. RESULTS: Ultrasound assessment demonstrated a significant decrease in mean lesion size of treated (0%) compared to control (30%) tendons at 84 days. Mean (+/-SD) cumulative histologic tendon scores for control tendons (17.7 +/- 2.7) were significantly higher than treated tendons (13.6 +/- 1.9), indicating less advanced healing in the control group. Tendon cell density was increased and neovascularization, intensity of inflammation, and uniformity of fiber diameter were increased in control compared to treated tendons. There were no differences in fibroblast shape, levels of intralesional hemorrhage, linearity of collagen fibers, or collagen fiber diameter or distribution between treated and control tendons. CONCLUSION: Tendons treated with xCMHA-S gel at the time of model induction had superior histologic healing scores and sonographically smaller lesions compared to controls, suggesting that xCMHA-S gel may aid the natural healing process. PMID- 26767728 TI - Evolutionary shifts in the melanin-based color system of birds. AB - Melanin pigments contained in organelles (melanosomes) impart earthy colors to feathers. Such melanin-based colors are distributed across birds and thought to be the ancestral color-producing mechanism in birds. However, we have had limited data on melanin-based color and melanosome diversity in Palaeognathae, which includes the flighted tinamous and large-bodied, flightless ratites and is the sister taxon to all other extant birds. Here, we use scanning electron microscopy and spectrophotometry to assess melanosome morphology and quantify reflected color for 19 species within this clade. We find that brown colors in ratites are uniquely associated with elongated melanosomes nearly identical in shape to those associated with black colors. Melanosome and color diversity in large-bodied ratites is limited relative to other birds (including flightless penguins) and smaller bodied basal maniraptoran dinosaur outgroups of Aves, whereas tinamous show a wider range of melanosome forms similar to neognaths. The repeated occurrence of novel melanosome forms in the nonmonophyletic ratites suggests that melanin-based color tracks changes in body size, physiology, or other life history traits associated with flight loss, but not feather morphology. We further anticipate these findings will be useful for future color reconstructions in extinct species, as variation in melanosome shape may potentially be linked to a more nuanced palette of melanin-based colors. PMID- 26767731 TI - Amelanotic Conjunctival Melanoma. PMID- 26767732 TI - Bilateral Iris Prolapse Secondary to Eye Rubbing Following Cataract Surgery. PMID- 26767734 TI - Bilateral Extraocular Muscle Metastases From a Gastrointestinal Carcinoid Tumor. PMID- 26767733 TI - An Innocuous Adverse Effect of Routine Fundus Fluorescein Angiography. PMID- 26767737 TI - Regenerative Medicine in the 21st Century: Advances in Engineering, Chemistry, Biology and Medicine Revolutionize Healthcare. PMID- 26767738 TI - Advances in Functional Assemblies for Regenerative Medicine. AB - The ability to synthesise bioresponsive systems and selectively active biochemistries using polymer-based materials with supramolecular features has led to a surge in research interest directed towards their development as next generation biomaterials for drug delivery, medical device design and tissue engineering. PMID- 26767741 TI - Fullerene-based inhibitors of HIV-1 protease. AB - A series of Fmoc-Phe(4-aza-C60)-OH of fullerene amino acid derived peptides have been prepared by solid phase peptide synthesis, in which the terminal amino acid, Phe(4-aza-C60)-OH, is derived from the dipolar addition to C60 of the Fmoc-Nalpha protected azido amino acids derived from phenylalanine: Fmoc-Phe(4-aza-C60)-Lys3 OH (1), Fmoc-Phe(4-aza-C60)-Pro-Hyp-Lys-OH (2), and Fmoc-Phe(4-aza-C60)-Hyp-Hyp Lys-OH (3). The inhibition constant of our fullerene aspartic protease PRIs utilized FRET-based assay to evaluate the enzyme kinetics of HIV-1 PR at various concentrations of inhibitors. Simulation of the docking of the peptide Fmoc-Phe Pro-Hyp-Lys-OH overestimated the inhibition, while the amino acid PRIs were well estimated. The experimental results show that C60-based amino acids are a good base structure in the design of protease inhibitors and that their inhibition can be improved upon by the addition of designer peptide sequences. PMID- 26767742 TI - Solvent-tunable morphology and emission of pyrene-dipeptide organogels. AB - Two pyrene based organogelators in which the pyrene moiety has been linked to the diphenylalanine dipeptide have been synthesized. We show how the solvent can tune both the morphology and the optical properties of the organogels: spherical aggregates with quenched emission were obtained in acetonitrile, whereas an entangled fibrillar network with enhanced emission was formed in o dichlorobenzene. Fourier transform infrared spectroscopy, circular dichroism and nuclear magnetic resonance spectroscopy experiments suggest that both pi-pi stacking and hydrogen bonding contribute to the formation of the supramolecular networks. Ultraviolet-visible and steady state emission studies demonstrated the formation of I-aggregates in acetonitrile. In contrast, in o-dichlorobenzene, the formation of J-type aggregates leads to assemblies with enhanced emission. These results give some insight into the important role of the gelling solvent in the morphology of the supramolecular gels and may help in the design of new soft materials. PMID- 26767743 TI - Synthesis of rigid tryptophan mimetics by the diastereoselective Pictet-Spengler reaction of beta3-homo-tryptophan derivatives with chiral alpha-amino aldehydes. AB - The Pictet-Spengler (PS) cyclizations of beta(3)-hTrp derivatives as arylethylamine substrates were performed with L-alpha-amino and D-alpha-amino aldehydes as carbonyl components. During the PS reaction, a new stereogenic center was created, and the mixture of cis/trans 1,3-disubstituted 1,2,3,4 tetrahydro-beta-carbolines was obtained. The ratio of cis/trans diastereomers depends on the stereogenic centre of used amino aldehyde and the size of substituents. It was confirmed by 1H and 2D NMR (ROESY) spectra. The conformations of cyclic products were studied by 2D NMR ROESY spectra. Products of the PS condensation after removal of protecting group(s) can be incorporated into a peptide chain as tryptophan mimetics with the possibility of the beta-turn induction. PMID- 26767745 TI - Editorial comment: introducing new BJS Special Sections. PMID- 26767744 TI - Fluorescently labeled adrenomedullin allows real-time monitoring of adrenomedullin receptor trafficking in living cells. AB - The human adrenomedullin (ADM) is a 52 amino acid peptide hormone belonging to the calcitonin family of peptides, which plays a major role in the development and regulation of cardiovascular and lymphatic systems. For potential use in clinical applications, we aimed to investigate the fate of the peptide ligand after binding and activation of the adrenomedullin receptor (AM1), a heterodimer consisting of the calcitonin receptor-like receptor (CLR), a G protein-coupled receptor, associated with the receptor activity-modifying protein 2 (RAMP2). Full length and N-terminally shortened ADM peptides were synthesized using Fmoc/tBu solid phase peptide synthesis and site-specifically labeled with the fluorophore carboxytetramethylrhodamine (Tam) either by amide bond formation or copper(I) catalyzed azide alkyne cycloaddition. For the first time, Tam-labeled ligands allowed the observation of co-internalization of the whole ligand-receptor complex in living cells co-transfected with fluorescent fusion proteins of CLR and RAMP2. Application of a fluorescent probe to track lysosomal compartments revealed that ADM together with the CLR/RAMP2-complex is routed to the degradative pathway. Moreover, we found that the N-terminus of ADM is not a crucial component of the peptide sequence in terms of AM1 internalization behavior. PMID- 26767746 TI - Galectins in channel catfish, Ictalurus punctatus: Characterization and expression profiling in mucosal tissues. AB - Galectins, a family of beta-galactoside-binding lectins with conserved CRDs, which can recognize the glycans on the surface of viruses, bacteria and protozoan parasites, are emerging as key players in many important pathological processes, including acute and chronic inflammatory diseases, autoimmunity and apoptosis. Although galectins have attracted great interest in mammals, they are still poorly-characterized in teleost. Previously, several studies have reported their high expression levels in mucosal tissues before and post infection. Given the important roles for galectins in mucosal immunity, therefore, we characterized the galectin gene family and profiled family member expression after challenge with two different Gram-negative bacterial pathogens. Here, twelve galectins genes were captured in channel catfish (Ictalurus punctatus), and phylogenetic analysis showed the strongest relationship to zebrafish and salmon, which is consistent with their phylogenetic relationships. Furthermore, the galectin genes were widely expressed in catfish tissues, while most of the galectin genes were strongly expressed in mucosal tissues (skin, gill and intestine). In addition, the expression profiles of galectins after bacterial infection varied depending on both pathogen and tissue type, suggesting that galectins may exert disparate functions or exhibit distinct tissue-selective roles in the host immune response to bacterial pathogens. Further studies are needed, however, to expand functional characterization and examine whether galectins may also play additional physiological roles in catfish immunity. PMID- 26767747 TI - Differential immune response of vitellogenin gene to Vibrio anguillarum in noble scallop Chlamys nobilis and its correlation with total carotenoid content. AB - Vitellogenin (Vg), an egg yolk precursor protein, not only functions as a source of nutrients and a nonpolar molecular carrier that combine and transfer lipids, proteins, vitamin and carotenoids to oocytes during the oogenesis. but also links with the immune defense in many oviparous animals. To investigate whether Vg plays a immune defensive role in noble scallop Chlamys nobilis, an acute Vibrio anguillarum infection experiment was conducted in orange and brown scallops with different carotenoids content. qRT-PCR result showed that Vg transcripts were significantly up-regulated after challenge with V. anguillarum in orange and brown shell scallops compared to the control group and Vg expression reached the highest spot at 6 h, indicated that Vg possessed an immune function in the noble scallop. Interestingly, a significantly positive correlation between Vg transcript levels and total carotenoids content in the ovary was observed, indicating that Vg gene expression was up regulated by carotenoids. The results suggest that Vg is a potent immune protector and carotenoid may linked with Vg plays an important role in host immune system against pathogens in noble scallop C. nobilis. PMID- 26767748 TI - Brevis plant1, a putative inositol polyphosphate 5-phosphatase, is required for internode elongation in maize. AB - In maize (Zea mays L.), as in other grass species, stem elongation occurs during growth and most noticeably upon the transition to flowering. Genes that reduce stem elongation have been important to reduce stem breakage, or lodging. Stem elongation has been mediated by dwarf and brachytic/brevis plant mutants that affect giberellic acid and auxin pathways, respectively. Maize brevis plant1 (bv1) mutants, first identified over 80 years ago, strongly resemble brachytic2 mutants that have shortened internodes, short internode cells, and are deficient in auxin transport. Here, we characterized two novel bv1 maize mutants. We found that an inositol polyphosphate 5-phosphatase orthologue of the rice gene dwarf50 was the molecular basis for the bv1 phenotype, implicating auxin-mediated inositol polyphosphate and/or phosphoinositide signalling in stem elongation. We suggest that auxin-mediated internode elongation involves processes that also contribute to stem gravitropism. Genes misregulated in bv1 mutants included genes important for cell wall synthesis, transmembrane transport, and cytoskeletal function. Mutant and wild-type plants were indistinguishable early in development, responded similarly to changes in light quality, had unaltered flowering times, and had normal flower development. These attributes suggest that breeding could utilize bv1 alleles to increase crop grain yields. PMID- 26767749 TI - OsWOX3A is involved in negative feedback regulation of the gibberellic acid biosynthetic pathway in rice (Oryza sativa). AB - The plant-specific WUSCHEL-related homeobox (WOX) nuclear proteins have important roles in the transcriptional regulation of many developmental processes. Among the rice (Oryza sativa) WOX proteins, a loss of OsWOX3A function in narrow leaf2 (nal2) nal3 double mutants (termed nal2/3) causes pleiotropic effects, such as narrow and curly leaves, opened spikelets, narrow grains, more tillers, and fewer lateral roots, but almost normal plant height. To examine OsWOX3A function in more detail, transgenic rice overexpressing OsWOX3A (OsWOX3A-OX) were generated; unexpectedly, all of them consistently exhibited severe dwarfism with very short and wide leaves, a phenotype that resembles that of gibberellic acid (GA) deficient or GA-insensitive mutants. Exogenous GA3 treatment fully rescued the developmental defects of OsWOX3A-OX plants, suggesting that constitutive overexpression of OsWOX3A downregulates GA biosynthesis. Quantitative analysis of GA intermediates revealed significantly reduced levels of GA20 and bioactive GA1 in OsWOX3A-OX, possibly due to downregulation of the expression of KAO, which encodes ent-kaurenoic acid oxidase, a GA biosynthetic enzyme. Yeast one-hybrid and electrophoretic mobility shift assays revealed that OsWOX3A directly interacts with the KAO promoter. OsWOX3A expression is drastically and temporarily upregulated by GA3 and downregulated by paclobutrazol, a blocker of GA biosynthesis. These data indicate that OsWOX3A is a GA-responsive gene and functions in the negative feedback regulation of the GA biosynthetic pathway for GA homeostasis to maintain the threshold levels of endogenous GA intermediates throughout development. PMID- 26767751 TI - Comments on 'Use of composite endpoints in clinical trials' by Abdul J. Sankoh, Haihong Li and Ralph B. D'Agostino, Sr. PMID- 26767752 TI - Use of composite endpoints in clinical trials. PMID- 26767750 TI - The dual function of flavodiiron proteins: oxygen and/or nitric oxide reductases. AB - Flavodiiron proteins have emerged in the last two decades as a newly discovered family of oxygen and/or nitric oxide reductases widespread in the three life domains, and present in both aerobic and anaerobic organisms. Herein we present the main features of these fascinating enzymes, with a particular emphasis on the metal sites, as more appropriate for this special issue in memory of the exceptional bioinorganic scientist R. J. P. Williams who pioneered the notion of (metal) element availability-driven evolution. We also compare the flavodiiron proteins with the other oxygen and nitric oxide reductases known until now, highlighting how throughout evolution Nature arrived at different solutions for similar functions, in some cases adding extra features, such as energy conservation. These enzymes are an example of the (bioinorganic) unpredictable diversity of the living world. PMID- 26767753 TI - GvHD prophylaxis in non-haploidentical allogeneic peripheral blood stem cell transplantation: beyond the standard to prevent relapse in patients with high risk chronic lymphoproliferative diseases? PMID- 26767754 TI - Immigrants' adaptation to different cultural settings: A contextual perspective on acculturation: Introduction for the special section on immigration. AB - In modern multicultural societies more and more individuals deal with 2 or more cultures due to the unprecedented increase in international migration. This special section brings together research about immigrants' adaptation to various life domains, about the demands of dealing with different cultural scripts and about how immigrants can successfully bridge different cultural demands. This introduction to the special section provides a broader theoretical framework that links the different studies of the special section and demonstrates areas for further research. It also clearly illustrates the growing necessity for research in increasingly diverse societies. PMID- 26767755 TI - The Development of Entrepreneurship: Person x Context Interactions: Special Section in the International Journal of Psychology. PMID- 26767756 TI - Post-herpetic acneiform eruption: report of two cases with dermoscopic observations. PMID- 26767757 TI - Neonatal tinea corporis due to a novel strain of Trichophyton rubrum. PMID- 26767758 TI - Allergic contact dermatitis following epoxy resin exposure to a paint in a recreational setting. PMID- 26767759 TI - Discoid lupus Erythematosus-Associated Koebnerization at the Site of Healed Herpes Zoster. PMID- 26767760 TI - Dermoscopy in immunocompromised cutaneous district. PMID- 26767761 TI - Lichenoid keratosis as a cause of localised alopecia areata. PMID- 26767767 TI - Desmoplastic fibroma of the distal radius: an interesting case and a review of the literature and therapeutic implications. AB - Desmoplastic fibromas are rare, benign, locally aggressive bone tumors, which arise primarily in patients younger than 30 years old. Historically, even with greater functional loss, en bloc or wide resection of the tumors to prevent local recurrence has been the method of choice in treatment. This article discusses the presentation of a 10-year-old male who presented with a mass in the distal forearm, after reporting difficulty in pronation and supination. The patient was ultimately treated with wide resection and allo-arthrodesis with allograft. Post operatively, the patient has exhibited excellent recovery, including normal range of motion at the shoulder and elbow, and ability to perform all activities of daily livings despite reduced grip strength compared with the contralateral side. PMID- 26767769 TI - Green prison programmes, recidivism and mental health: A primer. PMID- 26767768 TI - Who cares about a delinquency prevention experiment of Boston boys born in the 1920s and 1930s? The need for long-term follow-ups in criminology. PMID- 26767770 TI - Enamel Surface with Pit and Fissure Sealant Containing 45S5 Bioactive Glass. AB - Enamel demineralization adjacent to pit and fissure sealants leads to the formation of marginal caries, which can necessitate the replacement of existing sealants. Dental materials with bioactive glass, which releases ions that inhibit dental caries, have been studied. The purpose of this study was to evaluate the enamel surface adjacent to sealants containing 45S5 bioactive glass (BAG) under simulated microleakage between the material and the tooth in a cariogenic environment. Sealants containing 45S5BAG filler were prepared as follows: 0% 45S5BAG + 50.0% glass (BAG0 group), 12.5% 45S5BAG + 37.5% glass (BAG12.5 group), 25.0% 45S5BAG + 25.0% glass (BAG25.0 group), 37.5% 45S5BAG + 12.5% glass (BAG37.5 group), and 50.0% 45S5BAG + 0% glass (BAG50.0 group). A cured sealant disk was placed over a flat bovine enamel disk, separated by a 60-um gap, and immersed in lactic acid solution (pH 4.0) at 37 degrees C for 15, 30, and 45 d. After the storage period, each enamel disk was separated from the cured sealant disk, and the enamel surface was examined with optical 3-dimensional surface profilometer, microhardness tester, and scanning electron microscopy. The results showed a significant increase in roughness and a decrease in microhardness of the enamel surface as the proportion of 45S5BAG decreased (P< 0.05). In the scanning electron microscopy images, enamel surfaces with BAG50.0 showed a smooth surface, similar to those in the control group with distilled water, even after prolonged acid storage. Additionally, an etched pattern was observed on the surface of the demineralized enamel with a decreasing proportion of 45S5BAG. Increasing the 45S5BAG filler contents of the sealants had a significant impact in preventing the demineralization of the enamel surface within microgaps between the material and the tooth when exposed to a cariogenic environment. Therefore, despite some marginal leakage, these novel sealants may be effective preventive dental materials for inhibiting secondary caries at the margins. PMID- 26767771 TI - Mechanoresponsive Properties of the Periodontal Ligament. AB - The periodontal ligament (PDL) functions as an enthesis, a connective tissue attachment that dissipates strains created by mechanical loading. Entheses are mechanoresponsive structures that rapidly adapt to changes in their mechanical loading; here we asked which features of the PDL are sensitive to such in vivo loading. We evaluated the PDL in 4 physiologically relevant mechanical environments, focusing on mitotic activity, cell density, collagen content, osteogenic protein expression, and organization of the tissue. In addition to examining PDLs that supported teeth under masticatory loading and eruptive forces, 2 additional mechanical conditions were created and analyzed: hypoloading and experimental tooth movement. Collectively, these data revealed that the adult PDL is a remarkably quiescent tissue and that only when it is subjected to increased loads--such as those associated with mastication, eruption, and orthodontic tooth movement-does the tissue increase its rate of cell proliferation and collagen production. These data have relevance in clinical scenarios where PDL acclimatization can be exploited to optimize tooth movement. PMID- 26767772 TI - Letter to the Editor, "Wnt Signaling and Its Contribution to Craniofacial Tissue Homeostasis". PMID- 26767774 TI - Annual banned-substance review: analytical approaches in human sports drug testing. AB - The aim of improving anti-doping efforts is predicated on several different pillars, including, amongst others, optimized analytical methods. These commonly result from exploiting most recent developments in analytical instrumentation as well as research data on elite athletes' physiology in general, and pharmacology, metabolism, elimination, and downstream effects of prohibited substances and methods of doping, in particular. The need for frequent and adequate adaptations of sports drug testing procedures has been incessant, largely due to the uninterrupted emergence of new chemical entities but also due to the apparent use of established or even obsolete drugs for reasons other than therapeutic means, such as assumed beneficial effects on endurance, strength, and regeneration capacities. Continuing the series of annual banned-substance reviews, literature concerning human sports drug testing published between October 2014 and September 2015 is summarized and reviewed in reference to the content of the 2015 Prohibited List as issued by the World Anti-Doping Agency (WADA), with particular emphasis on analytical approaches and their contribution to enhanced doping controls. PMID- 26767773 TI - Response to Letter to the Editor, "Wnt Signaling and Its Contribution to Craniofacial Tissue Homeostasis". PMID- 26767776 TI - Grandma. PMID- 26767775 TI - Veterans Aging. PMID- 26767777 TI - From Nine to Ninety. PMID- 26767783 TI - Article metrics: measuring the impact and importance of papers. PMID- 26767784 TI - Identification and spontaneous immune targeting of an endogenous retrovirus K envelope protein in the Indian rhesus macaque model of human disease. AB - BACKGROUND: Endogenous retroviruses (ERVs) are remnants of ancient retroviral infections that have invaded the germ line of both humans and non-human primates. Most ERVs are functionally crippled by deletions, mutations, and hypermethylation, leading to the view that they are inert genomic fossils. However, some ERVs can produce mRNA transcripts, functional viral proteins, and even non-infectious virus particles during certain developmental and pathological processes. While there have been reports of ERV-specific immunity associated with ERV activity in humans, adaptive immune responses to ERV-encoded gene products remain poorly defined and have not been investigated in the physiologically relevant non-human primate model of human disease. FINDINGS: Here, we identified the rhesus macaque equivalent of the biologically active human ERV-K (HML-2), simian ERV-K (SERV-K1), which retains intact open reading frames for both Gag and Env on chromosome 12 in the macaque genome. From macaque cells we isolated a spliced mRNA product encoding SERV-K1 Env, which possesses all the structural features of a canonical, functional retroviral Envelope protein. Furthermore, we identified rare, but robust T cell responses as well as frequent antibody responses targeting SERV-K1 Env in rhesus macaques. CONCLUSIONS: These data demonstrate that SERV-K1 retains biological activity sufficient to induce cellular and humoral immune responses in rhesus macaques. As ERV-K is the youngest and most active ERV family in the human genome, the identification and characterization of the simian orthologue in rhesus macaques provides a highly relevant animal model in which to study the role of ERV-K in developmental and disease states. PMID- 26767785 TI - Correlation between patient quality of life in palliative care and burden of their family caregivers: a prospective observational cohort study. AB - BACKGROUND: Family caregivers play a key role in palliative care at home, and understanding the interdependencies in the constellation of patient, family caregivers and service providers is important. As few longitudinal studies have examined the influence of patient quality of life (QoL) in palliative care on burden of family caregivers, the aim of this study was to identify correlations between changing patient QoL and changing burden of family caregivers that need consideration in patient management. METHODS: Palliative patients with cancer in primary care evaluated their QoL (Quality of Life Questionnaire Core 15 Palliative Care, QLQ-C15-PAL). They were assessed monthly for an interval of 6 months or until death of the patient. Family caregivers reported the burden they perceived while supporting the patient (Short form of the Burden Scale for Family Caregivers, BSFC). Longitudinal data were analysed for all patients with at least 3 available assessments, considering the most recent data for participants with more than 3 assessments. Changes in patient QoL were analysed using the Friedman test. In a stepwise regression analysis, influences of change in patient QoL on changing caregiver burden were investigated. RESULTS: One hundred patients (63 men, 37 women; average age: 68 years) were enrolled in the study. The most common primary diagnoses were colon, lung or breast cancer. In 58 cases, assessments were available from both patients and caregivers. Patients reported overall quality of life increasing towards end of life, although reporting that physical functioning deteriorated. Symptoms of pain and fatigue bothered patients most. Caregiver burden was moderate and on average did not change over time. In a stepwise regression model, the difference in emotional functioning and the difference in dyspnoea showed an influence on the development of caregiver burden (explained variance of 19.3%). CONCLUSIONS: Patients' dyspnoea, feelings of depression and anxiety impacted on the perceived burden of family caregivers, but are manageable symptoms. Our results corroborate the need of regular assessment of patients' needs taking into account caregiver burden. In this way, general practice teams can intervene early and may more likely meet patients' needs in the end of life care process. TRIAL REGISTRATION: Current Controlled Trials ISRCTN78021852, assigned on 04/04/2007. PMID- 26767786 TI - Chiral self-assembly of helical particles. AB - The shape of the building blocks plays a crucial role in directing self-assembly towards desired architectures. Out of the many different shapes, the helix has a unique position. Helical structures are ubiquitous in nature and a helical shape is exhibited by the most important biopolymers like polynucleotides, polypeptides and polysaccharides as well as by cellular organelles like flagella. Helical particles can self-assemble into chiral superstructures, which may have a variety of applications, e.g. as photonic (meta)materials. However, a clear and definite understanding of these structures has not been entirely achieved yet. We have recently undertaken an extensive investigation on the phase behaviour of hard helical particles, using numerical simulations and classical density functional theory. Here we present a detailed study of the phase diagram of hard helices as a function of their morphology. This includes a variety of liquid-crystal phases, with different degrees of orientational and positional ordering. We show how, by tuning the helix parameters, it is possible to control the organization of the system. Starting from slender helices, whose phase behaviour is similar to that of rodlike particles, an increase in curliness leads to the onset of azimuthal correlations between the particles and the formation of phases specific to helices. These phases feature a new kind of screw order, of which there is experimental evidence in colloidal suspensions of helical flagella. PMID- 26767787 TI - Development of a high-copy plasmid for enhanced production of recombinant proteins in Leuconostoc citreum. AB - BACKGROUND: Leuconostoc is a hetero-fermentative lactic acid bacteria, and its importance is widely recognized in the dairy industry. However, due to limited genetic tools including plasmids for Leuconostoc, there has not been much extensive research on the genetics and engineering of Leuconostoc yet. Thus, there is a big demand for high-copy-number plasmids for useful gene manipulation and overproduction of recombinant proteins in Leuconostoc. RESULTS: Using an existing low-copy plasmid, the copy number of plasmid was increased by random mutagenesis followed by FACS-based high-throughput screening. First, a random library of plasmids was constructed by randomizing the region responsible for replication in Leuconostoc citreum; additionally, a superfolder green fluorescent protein (sfGFP) was used as a reporter protein. With a high-speed FACS sorter, highly fluorescent cells were enriched, and after two rounds of sorting, single clone exhibiting the highest level of sfGFP was isolated. The copy number of the isolated plasmid (pCB4270) was determined by quantitative PCR (qPCR). It was found that the isolated plasmid has approximately a 30-fold higher copy number (approx. 70 copies per cell) than that of the original plasmid. From the sequence analysis, a single mutation (C->T) at position 4690 was found, and we confirmed that this single mutation was responsible for the increased plasmid copy number. The effectiveness of the isolated high-copy-number plasmid for the overproduction of recombinant proteins was successfully demonstrated with two protein models Glutathione-S-transferase (GST) and alpha-amylase. CONCLUSIONS: The high-copy number plasmid was successfully isolated by FACS-based high-throughput screening of a plasmid library in L. citreum. The isolated plasmid could be a useful genetic tool for high-level gene expression in Leuconostoc, and for extending the applications of this useful bacteria to various areas in the dairy and pharmaceutical industries. PMID- 26767788 TI - Effect of landscape features on the relationship between Ixodes ricinus ticks and their small mammal hosts. AB - BACKGROUND: The consequences of land use changes are among the most cited causes of emerging infectious diseases because they can modify the ecology and transmission of pathogens. This is particularly true for vector-borne diseases which depend on abiotic (e.g. climate) and biotic conditions (i.e. hosts and vectors). In this study, we investigated how landscape features affect the abundances of small mammals and Ixodes ricinus ticks, and how they influence their relationship. METHODS: From 2012 to 2014, small mammals and questing I. ricinus ticks were sampled in spring and autumn in 24 sites located in agricultural and forest landscapes in Brittany, France. We tested the effects of landscape features (composition and configuration) on the abundances of small mammal species and immature ticks and their relationship. Additionally, we quantified the larval tick burden of small mammals in 2012 to better describe this relationship. RESULTS: The nymph abundance was positively influenced by the larval occurrence and the wood mouse Apodemus sylvaticus abundance the previous spring because they hosted tenfold more larvae than the bank vole Myodes glareolus. The bank vole abundance in spring and autumn had a negative and positive effect, respectively, on the nymph abundance. In agricultural landscapes, wood mice were positively influenced by woodland cover and woodland/hedgerow-grassland ecotone, whereas bank voles showed the opposite or non-significant responses to these landscape variables. The woodland cover had a positive effect on immature ticks. CONCLUSION: The landscape configuration, likely by affecting the landscape connectivity, influences the small mammal communities in permanent habitats. Our study showed that the wood mouse, due to its dominance and to its tolerance to ticks, feeds a substantial proportion of larvae. The acquired resistance to ticks in the bank vole can reduce its role as a trophic resource over time. The nymph abundance seems indirectly influenced by landscape features via their effects on the small mammal community. To enhance our understanding of the epidemiology of tick-borne diseases within landscapes, further studies will integrate data on pathogen prevalence and investigate explicitly the effect of landscape connectivity on host-vector-pathogen systems. PMID- 26767789 TI - How the perspectives of nursing assistants and frail elderly residents on their daily interaction in nursing homes affect their interaction: a qualitative study. AB - BACKGROUND: Good support from and positive relations with institutional staff can enhance the psychosocial wellbeing of residents admitted to a nursing home. Nursing assistants (NAs) interact most frequently with residents and play an important role in developing good rapport with them. Most studies have described the daily interactions between NAs and residents as task oriented. Only few have attempted to explore the perspectives of NAs and residents on their daily interactions. Therefore, the aim of this study was to identify the types of daily interactions perceived by NAs and residents. We also investigated those intentions/beliefs held by NAs and residents that might direct their interactive behaviors. METHODS: A descriptive, exploratory, qualitative approach was used to explore the perspectives of 18 NAs (mean age: 51) and 15 residents (mean age: 84.4) on their daily interactions. Unstructured in-depth interviews were used to collect data. All of the interviews were conducted from July to December 2013. The collected data were transcribed verbatim and analyzed by content analysis. RESULTS: Three types of interactions were found that described the NAs' and residents' perspectives on their daily interactions: (1) physiologically-oriented daily interactions; (2) cordial interactions intended to maintain a harmonious atmosphere; and (3) reciprocal social interactions intended to develop closer rapport. One or more themes reflecting the participants' intentions or beliefs were identified from each group to support each type of interaction. CONCLUSIONS: An over-emphasis on the formal caring relationship and over-concern about maintaining a harmonious atmosphere contributed to a superficial and distant relationship between the two parties. Building close rapport takes time and involves repeated reciprocal social interactions. The findings showed that with good intentions to establish closer rapport, both NAs and residents did favors for each other. All of those favors were easily integrated in the care provided to the residents without increasing the workload of the NAs. Modifying the training given to NAs and adjusting institutional policies are crucial to raising the competence of the NAs in building good relationships with residents. Positive interactions improve the psychosocial wellbeing of the residents and encourage them to cooperate during the delivery of care, thereby improving their overall health and contributing to the NAs' job satisfaction. PMID- 26767791 TI - Pharmacokinetics and placental transfer of magnesium sulfate in pregnant women. AB - BACKGROUND: Magnesium sulfate is one of the most commonly prescribed intravenous medications in obstetrics. Despite its widespread use, there are limited data about magnesium pharmacokinetics, and magnesium is prescribed empirically without dose adjustment for different indications. OBJECTIVE: The aim of this study was to characterize the pharmacokinetics and placental transfer of magnesium sulfate in pregnant women and to determine key covariates that impact the pharmacokinetics. STUDY DESIGN: This is a prospective pharmacokinetic cohort study of pregnant women who were prescribed magnesium sulfate for preeclampsia, preterm labor, or extreme prematurity. Women received a 4-g loading dose and 2 g/h maintenance dose as clinically indicated. Maternal blood samples were obtained before and at multiple time points during and after magnesium administration. Cord blood also was sampled at delivery. A population pharmacokinetic approach that used a nonlinear mixed-effects modeling was used to characterize magnesium disposition. RESULTS: Pharmacokinetic profiles of 111 pregnant women were analyzed. Magnesium clearance was 3.98 L/h in preeclamptic women and 5.88 L/h non-preeclamptic women. Steady-state concentration of magnesium was 7.2 mg/dL in preeclamptic women compared with 5.1 mg/dL in non preeclamptic women. Maternal weight significantly impacted time to steady state. The ratio of the mean umbilical vein magnesium level to the mean maternal serum magnesium level at the time of delivery was 0.94 +/- 0.15. CONCLUSIONS: The study accurately characterizes the pharmacokinetics of magnesium administered to pregnant women. Preeclamptic status and maternal weight significantly impact serum magnesium levels. This pharmacokinetic model could be applied to larger cohorts to help tailor magnesium treatment and account for these covariates. PMID- 26767790 TI - In regard to: "Why is it appropriate to recommend human papillomavirus vaccination as cervical cancer prevention?". PMID- 26767792 TI - Increased anti-Mullerian hormone levels and ovarian size in a subgroup of women with functional hypothalamic amenorrhea: further identification of the link between polycystic ovary syndrome and functional hypothalamic amenorrhea. AB - BACKGROUND: Functional hypothalamic amenorrhea is a disorder characterized by cessation of menstrual cycles in the absence of organic disease. In most patients, it occurs in adult life after a stressful event and may be related to a condition of mild chronic energy deprivation. The endocrine pattern is characterized by low estrogen levels with an absent response to a progestogen challenge test and low-normal gonadotropin levels. A few studies have shown that some of these women may have some features of polycystic ovary syndrome; these features include an increased androgen response to gonadotropins, increased anti Mullerian hormone levels, and altered ovarian morphology or increased ovarian size. These findings suggest a link between these 2 completely different disorders: functional hypothalamic amenorrhea and polycystic ovary syndrome. The importance of the possible coexistence of these disorders in some women is important for follow-up of these women and in their treatment if they desire to become pregnant. OBJECTIVE: To determine whether a subgroup of well-characterized women with functional hypothalamic amenorrhea may have the coexistence of polycystic ovary syndrome. STUDY DESIGN: Retrospective analysis of women with functional hypothalamic amenorrhea. Forty consecutive patients and 28 normal age matched control patients were studied. Blood was obtained for serum anti Mullerian hormone, androgens, and other hormone levels and all women had ovarian ultrasonographic measurements. RESULTS: In the entire group of women with functional hypothalamic amenorrhea, anti-Mullerian hormone and ovarian volume were greater than in control patients. In 13 patients (32.5%), anti-Mullerian hormone was elevated (>4.7 ng/mL, levels consistent with polycystic ovary syndrome) and in this group, ovarian volume was significantly greater than in the remaining patients with functional hypothalamic amenorrhea. Four of the 13 women with functional hypothalamic amenorrhea who had elevated anti-Mullerian hormone levels (10%), also had ovarian volume >=10 cc (consistent with polycystic ovarian syndrome). In these patients all studied androgens were in the upper normal range or slightly elevated despite low-normal gonadotropins; mean total testosterone was significantly greater than in the other patients with increased anti Mullerian hormone values with normal ovarian size (P<.05.) Six other women with functional hypothalamic amenorrhea who had increased anti-Mullerian hormone also had isolated elevations of some androgen levels, but mean testosterone and ovarian size were normal. CONCLUSIONS: As many as 10% of women with functional hypothalamic amenorrhea may have the coexistence of polycystic ovary syndrome. Because no signs or symptoms of this disorder were reported by these women before the appearance of the amenorrhea, it does not seem to be a coincidental relationship. The possibility that functional hypothalamic amenorrhea favors the appearance of polycystic ovary syndrome or more likely, that a mild (ovulatory) phenotype of polycystic ovary syndrome predisposes to the development of functional hypothalamic amenorrhea should be considered. Possible mechanisms are unclear and need to be investigated but may involve common vulnerabilities such as psychologic and mood disturbances. PMID- 26767793 TI - Reply. PMID- 26767794 TI - The impact of fetal growth restriction on latency in the setting of expectant management of preeclampsia. AB - BACKGROUND: Fetal growth restriction is a common complication of preeclampsia. Expectant management for qualifying patients has been found to have acceptable maternal safety while improving neonatal outcomes. Whether fetal growth restriction influences the duration of latency during expectant management of preeclampsia is unknown. OBJECTIVE: The objective of the study was to determine whether fetal growth restriction is associated with a reduced interval to delivery in women with preeclampsia being expectantly managed prior to 34 weeks. STUDY DESIGN: We performed a retrospective cohort of singleton, live-born, nonanomalous deliveries at the University of Cincinnati Medical Center between 2008 and 2013. Patients were included in our analysis if they were diagnosed with preeclampsia prior to 34 completed weeks and if the initial management plan was to pursue expectant management beyond administration of steroids for fetal lung maturity. Two study groups were determined based on the presence or absence of fetal growth restriction. Patients were delivered when they developed persistent neurological symptoms, severe hypertension refractory to medical therapy, renal insufficiency, nonreassuring fetal status, pulmonary edema, or hemolysis elevated liver low platelet syndrome or when they reached 37 weeks if they remained stable without any other indication for delivery. Our primary outcome was the interval from diagnosis of preeclampsia to delivery, measured in days. Secondary outcomes included indications for delivery, rates of induction and cesarean delivery, development of severe morbidities of preeclampsia, and select neonatal outcomes. We performed a multivariate logistic regression analysis comparing those with fetal growth restriction with those with normally grown fetuses to determine whether there is an association between fetal growth restriction and a shortened interval to delivery, neonatal intensive care unit admission, prolonged neonatal stay, and neonatal mortality. RESULTS: A total of 851 patients met the criteria for preeclampsia, of which 199 met inclusion criteria, 139 (69%) with normal growth, and 60 (31%) with fetal growth restriction. Interval to delivery was significantly shorter in women with fetal growth restriction, median (interquartile range) of 3 (1.6) days vs normal growth, 5 (2.12) days, P < .001. The association between fetal growth restriction and latency less than 7 days remained significant, even after post hoc analysis controlling for confounding variables (adjusted odds ratio, 1.66 [95% confidence interval, 1.12-2.47]). There were no differences in the development of severe disease (85.9 vs 91.7%, P = .26), need for intravenous antihypertensive medications (47.1 vs 46.7%, P = .96), and the development of severe complications of preeclampsia (51.1 vs 42.9%, P = .30) in normally grown and growth-restricted fetuses, respectively. Fewer women with fetal growth restriction attained their scheduled delivery date, 3 of 60 (5.0%), compared with normally grown fetuses,12 of 139 (15.7%), P = .03. Admission to the neonatal intensive care unit, neonatal length of stay, and neonatal mortality were higher when there was fetal growth restriction; however, after a logistic regression analysis, these associations were no longer significant. CONCLUSION: Fetal growth restriction is associated with a shortened interval to delivery in women undergoing expectant management of preeclampsia when disease is diagnosed prior to 34 weeks. These data may be helpful in counseling patients regarding the expected duration of pregnancy, guiding decision making regarding administration of steroids and determining the need for maternal transport. PMID- 26767796 TI - Malpractice and obstetric practice: the correlation of malpractice premiums to rates of vaginal and cesarean delivery. PMID- 26767795 TI - Does Denonvilliers' fascia exist in women? PMID- 26767797 TI - Human amniotic fluid: a source of stem cells for possible therapeutic use. AB - Stem cells are undifferentiated cells with the capacity for differentiation. Amniotic fluid cells have emerged only recently as a possible source of stem cells for clinical purposes. There are no ethical or sampling constraints for the use of amniocentesis as a standard clinical procedure for obtaining an abundant supply of amniotic fluid cells. Amniotic fluid cells of human origin proliferate rapidly and are multipotent with the potential for expansion in vitro to multiple cell lines. Tissue engineering technologies that use amniotic fluid cells are being explored. Amniotic fluid cells may be of clinical benefit for fetal therapies, degenerative disease, and regenerative medicine applications. We present a comprehensive review of the evolution of human amniotic fluid cells as a possible modality for therapeutic use. PMID- 26767798 TI - Plasma levels of intermedin (adrenomedullin-2) in healthy human volunteers and patients with heart failure. AB - Intermedin/adrenomedullin-2 (IMD) is a member of the adrenomedullin/CGRP peptide family. Less is known about the distribution of IMD than for other family members within the mammalian cardiovascular system, particularly in humans. The aim was to evaluate plasma IMD levels in healthy subjects and patients with chronic heart failure. IMD and its precursor fragments, preproIMD(25-56) and preproIMD(57-92), were measured by radioimmunoassay in 75 healthy subjects and levels of IMD were also compared to those of adrenomedullin (AM) and mid-region proadrenomedullin(45 92) (MRproAM(45-92)) in 19 patients with systolic heart failure (LVEF<45%). In healthy subjects, plasma levels (mean+SE) of IMD (6.3+0.6 pg ml(-1)) were lower than, but correlated with those of AM (25.8+1.8 pg ml(-1); r=0.49, p<0.001). Plasma preproIMD(25-56) (39.6+3.1 pg ml(-1)), preproIMD(57-92) (25.9+3.8 pg ml( 1)) and MRproAM(45-92) (200.2+6.7 pg ml(-1)) were greater than their respective bioactive peptides. IMD levels correlated positively with BMI but not age, and were elevated in heart failure (9.8+1.3 pg ml(-1), p<0.05), similarly to MRproAM(45-92) (329.5+41.9 pg ml(-1), p<0.001) and AM (56.8+10.9 pg ml(-1), p<0.01). IMD levels were greater in heart failure patients with concomitant renal impairment (11.3+1.8 pg ml(-1)) than those without (6.5+1.0 pg ml(-1); p<0.05). IMD and AM were greater in patients receiving submaximal compared with maximal heart failure drug therapy and were decreased after 6 months of cardiac resynchronization therapy. In conclusion, IMD is present in the plasma of healthy subjects less abundantly than AM, but is similarly correlated weakly with BMI. IMD levels are elevated in heart failure, especially with concomitant renal impairment, and tend to be reduced by high intensity drug or pacing therapy. PMID- 26767799 TI - Exposure pattern influences the degree of drug-seeking behaviour after withdrawal. AB - OBJECTIVES: The occurrence of a relapse during abstinence is an important issue that must be addressed during treatment for drug addiction. We investigated the influence of drug exposure pattern on morphine-seeking behaviour following withdrawal. We also studied the role of the hippocampus in this process to confirm its involvement in drug relapse. METHODS: Male Sprague-Dawley rats that were trained to self-administer morphine (1.0 mg/kg) using 2, 4, 6, 8, or 10 h daily sessions underwent withdrawal in their home cages and were re-exposed to the operant chamber to evaluate morphine-seeking behaviour. During the relapse session, rats were intravenously injected with morphine (0.25 mg/kg) or saline before re-exposure to the chamber. In the second experiment, rats were administered a microinjection of saline or cobalt chloride (CoCl2, 1 mM), a synaptic blocker, into the CA1 of the hippocampus prior to the relapse test. RESULTS: In the first experiment, more morphine-seeking behaviour was observed in the 2 h group (animals trained to self-administer morphine during a 2 h daily session spread over 21 days) during the relapse session, despite all groups being exposed to similar amounts of morphine during the training period before withdrawal. In the second experiment, pretreatment with CoCl2 markedly reduced morphine-seeking behaviour in the 2 h group. CONCLUSIONS: The present findings suggest that the exposure pattern influences the degree of relapse and that control of memorisation is important for prevention of relapse. PMID- 26767800 TI - Optimal clustering of MGs based on droop controller for improving reliability using a hybrid of harmony search and genetic algorithms. AB - This paper proposes a novel method to address reliability and technical problems of microgrids (MGs) based on designing a number of self-adequate autonomous sub MGs via adopting MGs clustering thinking. In doing so, a multi-objective optimization problem is developed where power losses reduction, voltage profile improvement and reliability enhancement are considered as the objective functions. To solve the optimization problem a hybrid algorithm, named HS-GA, is provided, based on genetic and harmony search algorithms, and a load flow method is given to model different types of DGs as droop controller. The performance of the proposed method is evaluated in two case studies. The results provide support for the performance of the proposed method. PMID- 26767801 TI - Biological control via "ecological" damping: An approach that attenuates non target effects. AB - In this work we develop and analyze a mathematical model of biological control to prevent or attenuate the explosive increase of an invasive species population, that functions as a top predator, in a three-species food chain. We allow for finite time blow-up in the model as a mathematical construct to mimic the explosive increase in population, enabling the species to reach "disastrous", and uncontrollable population levels, in a finite time. We next improve the mathematical model and incorporate controls that are shown to drive down the invasive population growth and, in certain cases, eliminate blow-up. Hence, the population does not reach an uncontrollable level. The controls avoid chemical treatments and/or natural enemy introduction, thus eliminating various non-target effects associated with such classical methods. We refer to these new controls as "ecological damping", as their inclusion dampens the invasive species population growth. Further, we improve prior results on the regularity and Turing instability of the three-species model that were derived in Parshad et al. (2014). Lastly, we confirm the existence of spatiotemporal chaos. PMID- 26767802 TI - Comparison of Endovenous Laser and Radiofrequency Ablation in Treating Varicose Veins in the Same Patient. AB - PURPOSE: To compare endovenous laser ablation (EVLA) and radiofrequency venous ablation (RFA) in different legs in the same patients with venous insufficiency. METHODS: Sixty patients with bilateral saphenous vein insufficiency were included. Endovenous laser ablation or RFA was applied to one of the patient's legs and the remaining procedure, RFA or EVLA, to the other leg. RESULTS: Minor complications in EVLA and RFA were hyperemia at 20.7% and 31.0%, ecchymosis at 31.0% and 51.7% and edema at 27.6% and 65.5%, respectively. The rate of recanalization was 6.8% in the RFA group. No recanalization was observed in the EVLA group. The level of patients satisfied with EVLA was 51.7%, compared to 31.0% for RFA, while 17.2% of patients were satisfied with both the procedures. Times to return to daily activity were 0.9 days in the EVLA group and 1.3 days in the RFA group. CONCLUSION: The EVLA procedure may be superior to RFA in certain respects. PMID- 26767803 TI - A Meta-Analysis of Total Arch Replacement With Frozen Elephant Trunk in Acute Type A Aortic Dissection. AB - OBJECTIVES: To assess the safety and efficacy, we performed a meta-analysis of total arch replacement with frozen elephant trunk in exclusive acute type A (neither chronic nor type B) aortic dissection. METHODS: Databases including MEDLINE and EMBASE were searched through March 2015 using Web-based search engines (PubMed and OVID). Eligible studies were case series of frozen elephant trunk enrolling patients with acute type A (neither chronic nor type B) aortic dissection reporting at least early (in-hospital or 30-day) all-cause mortality. Study-specific estimates were combined in both fixed- and random-effect models. RESULTS: Fifteen studies enrolling 1279 patients were identified and included. Pooled analyses demonstrated the cardiopulmonary bypass time of 207.1 (95% confidence interval [CI], 186.1-228.1) minutes, aortic cross-clamp time of 123.3 (95% CI, 113.1-133.5) minutes, selective antegrade cerebral perfusion time of 49.3 (95% CI, 37.6-61.0) minutes, hypothermic circulatory arrest time of 39.0 (95% CI, 30.7-47.2) minutes, early mortality of 9.2% (95% CI, 7.7-11.0%), stroke of 4.8% (95% CI, 2.5-9.0%), spinal cord injury of 3.5% (95% CI, 1.9-6.6%), mid- to long-term (>=1-year) overall mortality of 13.0% (95% CI, 10.4-16.0%), reintervention of 9.6% (95% CI, 5.6-15.8%), and false lumen thrombosis of 96.8% (95% CI, 90.7-98.9%). CONCLUSIONS: Total arch replacement with frozen elephant trunk provides a safe alternative to that with conventional elephant trunk in patients with acute type A aortic dissection, with acceptable early mortality and morbidity. The rates of mid- to long-term reintervention and false lumen non thrombosis may be lower in patients undergoing the frozen than conventional elephant trunk procedure. PMID- 26767804 TI - What's in this Issue? PMID- 26767805 TI - Family support group: a tool for nurses. PMID- 26767806 TI - Communication issues within critical care - emergency department perspectives. PMID- 26767807 TI - London Calling 2015.... PMID- 26767808 TI - Meet Your Region - Ann Price Southern Region Chair. PMID- 26767809 TI - Central South: Free BACCN Conference Place Awarded at Central South's 'SOS Simulation' Study Event. PMID- 26767810 TI - What's in a name: 'significant' results? PMID- 26767811 TI - The effects of pharmacist prescribing on patient outcomes in the hospital setting: a systematic review protocol. PMID- 26767812 TI - Predicting risk and outcomes for frail older adults: a protocol for an umbrella review of available frailty screening tools. PMID- 26767814 TI - Men's perceptions of the impact of the physical consequences of radical prostatectomy on their quality of life: a qualitative systematic review protocol. PMID- 26767813 TI - An evaluation of instruments for identifying acute pain among hospitalized pediatric patients: a systematic review protocol. PMID- 26767815 TI - What keeps you strong? How primary healthcare and aged care services can support the wellbeing of older Indigenous peoples: a systematic literature review protocol. PMID- 26767816 TI - Perceived barriers to and facilitators of labor market engagement for individuals with chronic physical illness in their experience with disability policy: a systematic review of qualitative evidence protocol. PMID- 26767817 TI - Perspectives of pharmacy students, pharmacy academics and practicing pharmacists on interprofessional education and collaborative practice: a comprehensive systematic review protocol. PMID- 26767818 TI - Effectiveness of Child Advocacy Centers and the multidisciplinary team approach on prosecution rates of alleged sex offenders and satisfaction of non-offending caregivers with allegations of child sexual abuse: a systematic review. AB - BACKGROUND: Child sexual abuse is a multifaceted issue that negatively affects the lives of millions of children worldwide. These children suffer numerous medical and psychological long-term adverse effects both in childhood and adulthood. It is imperative to implement evidence- based interventions for the investigation of this crime. The use of Child Advocacy Centers and the multidisciplinary team approach may improve the investigation of child sexual abuse. OBJECTIVE: To evaluate the effectiveness of Child Advocacy Centers and the multidisciplinary team approach on prosecution rates of alleged sex offenders and satisfaction of non-offending caregivers of children less than 18 years of age, with allegations of child sexual abuse. INCLUSION CRITERIA: TYPES OF PARTICIPANTS: Children under 18 years, of any race, ethnicity or gender with allegations of child sexual abuse. Other participants included in this review are non-offending caregivers of children with allegations of child sexual abuse, and alleged sex offenders. Type of intervention : The use of Child Advocacy Centers and the multidisciplinary team approach on child sexual abuse investigations. Types of outcomes : Prosecution rates of alleged sex offenders and the satisfaction of non-offending caregivers of children with allegations of child sexual abuse. Types of studies: This review includes quasi-experimental and descriptive studies. SEARCH STRATEGY: The search strategy aimed to find published and unpublished articles in the English language published from 1985 through April 2015 for inclusion. The databases searched include: PubMed, CINAHL, EMBASE, PsycINFO, Cochrane Central Register of Controlled Trials (CENTRAL), Health Source: Nursing/Academic Edition, Criminal Justice Periodicals, ProQuest Dissertations & Theses and Criminal Justice Collections. An additional grey literature search was conducted. METHODOLOGICAL QUALITY: Two reviewers evaluated the included studies for methodological quality using standardized critical appraisal instruments from the Joanna Briggs Institute. DATA EXTRACTION: Data were extracted using standardized data extraction instruments from the Joanna Briggs Institute. DATA SYNTHESIS: Due to heterogeneity between the included studies, statistical meta-analysis was not possible. Results are presented in a narrative form. CONCLUSIONS: The use of Child Advocacy Centers and the multidisciplinary team approach in child sexual abuse investigation may have positive benefits in increasing non-offending caregivers' satisfaction and prosecution rates of alleged sex offenders. IMPLICATIONS FOR PRACTICE: Utilization of Child Advocacy Centers and the multidisciplinary team approach for child sexual abuse investigations may be beneficial in improving prosecution rates and the experiences of families involved. The use of satisfaction surveys for non-offending caregivers may be an effective tool to evaluate the satisfaction with services rendered by Child Advocacy Centers. Findings from this review may help to guide reforms. It is hoped that client satisfaction may lead to or improve utilization of services important for the healing process of victims of abuse. Child Advocacy Center multidisciplinary team interventions may improve prosecution rates and satisfaction of non-offending caregiver' in children less than 18 years of age with allegations of child sexual abuse (Grade B). When available, children with allegations of child sexual abuse should be referred to Child Advocacy Centers for evaluation (Grade B). The use of non offending caregiver satisfaction survey is recommended to evaluate the ongoing effectiveness of the Child Advocacy Centers multidisciplinary team approach. The quality improvement process will help measure the quality of care rendered by a Child Advocacy Centers and identify areas in need of improvement so a Child Advocacy Centers can continue to provide optimal care in the investigation of child sexual abuse while improving the utilization of services important for the healing process for victims of abuse (Grade B). IMPLICATIONS FOR RESEARCH: Future studies may consider interventions that include greater sample size and more diverse ethnic groups to promote generalizability of findings. PMID- 26767819 TI - The views and experiences of nurses and midwives in the provision and management of provider-initiated HIV testing and counseling: a systematic review of qualitative evidence. AB - BACKGROUND: Global progress towards HIV prevention and care is contingent upon increasing the number of those aware of their status through HIV testing. Provider-initiated HIV testing and counseling is recommended globally as a strategy to enhance uptake of HIV testing and is primarily conducted by nurses and midwives. Research shows that provider-initiated HIV testing and counseling implementation is sub-optimal. The reasons for this are unclear. OBJECTIVES: The review aimed to explore nurses' and midwives' views and experiences of the provision and management of provider-initiated HIV testing and counseling. INCLUSION CRITERIA: TYPES OF PARTICIPANTS: All cadres of nurses and midwives were considered, including those who undertake routine HIV testing as part of a diverse role and those who are specifically trained as HIV counselors. Types of phenomenon of interest: The review sought to understand the views and experiences of the provision and management of provider-initiated HIV testing and counseling (including perceptions, opinions, beliefs, practices and strategies related to HIV testing and its implementation in practice). CONTEXT: The review included only provider-initiated HIV testing and counseling. It excluded all other models of HIV testing. The review included all countries and all healthcare settings. Types of studies: This review considered all forms of qualitative study design and methodology. Qualitative elements of a mixed method study were included if they were presented separately within the publication. SEARCH STRATEGY: A three step search strategy was utilized. Eight databases were searched for papers published from 1996 to October 2014, followed by hand searching of reference lists. Only studies published in the English language were considered. METHODOLOGICAL QUALITY: Methodological quality was assessed using the Qualitative Assessment and Review Instrument developed by the Joanna Briggs Institute. DATA EXTRACTION: Qualitative findings were extracted using the Joanna Briggs Institute Qualitative Assessment and Review Instrument. DATA SYNTHESIS: Qualitative research findings were pooled using a pragmatic meta-aggregative approach and the Joanna Briggs Institute Qualitative Assessment and Review Instrument software. RESULTS: This review included 21 publications from 18 research studies, representing a wide range of countries and healthcare settings. There were 245 findings which were aggregated into 12 categories and five synthesized findings. 1. Nurses/midwives are supportive of provider-initiated HIV testing and counseling if it is perceived to enhance patient care and to align with perceived professional roles. 2. Nurses'/midwives' ability to perform provider-initiated HIV testing and counseling well requires an appropriate infrastructure and adequate human and material resources. 3. At the organizational level, nurses'/midwives' engagement with provider-initiated HIV testing and counseling is facilitated by an inclusive management structure, alongside the provision of ongoing training and clinical supervision. Provider-initiated HIV testing and counseling is hindered by difficulties in fitting it into existing workloads and routines. 4. Nurses/midwives perceive that good quality care in provider initiated HIV testing and counseling involves finding a balance between public health needs and individual patient needs. Good care requires time and the ability to apply a patient centred approach. 5. The emotional work involved in provider-initiated HIV testing and counseling can be stressful. Nurses/Midwives may require support to deal with complex moral and ethical issues. CONCLUSIONS: This review shows that provider-initiated HIV testing and counseling is supported by nurses/midwives who strive to implement it according to principles of good care and a patient centered approach. Nurses/midwives face multiple operational, infra-structural, resource and ethical challenges in the implementation of provider-initiated HIV testing and counseling. IMPLICATIONS FOR PRACTICE: The implementation process for provider-initiated HIV testing and counseling would benefit from using a quality improvement framework. Nurses/midwives undertaking provider-initiated HIV testing and counseling require management support, ongoing training and adequate infrastructure/resources. Additional guidance is required on legal/ethical issues in testing of children and in third party disclosure. IMPLICATIONS FOR RESEARCH: Operational research is required to determine an optimal skill mix and optimal methods of integrating provider-initiated HIV testing and counseling into existing work routines. PMID- 26767820 TI - Effectiveness of dexmedetomidine use in general anesthesia to prevent postoperative shivering: a systematic review. AB - BACKGROUND: Postanesthetic shivering remains a significant source of distress following general anesthesia. Despite numerous studies investigating pharmacologic prophylaxis for postanesthetic shivering, no gold standard medication has been identified. Prophylactic dexmedetomidine administration has been examined as a possible preventative treatment modality for postanesthetic shivering; however its effectiveness has not been established. OBJECTIVES: The objective of this review was to evaluate the effectiveness of intravenous prophylactic dexmedetomidine for reduction of postanesthetic shivering during the first two hours after general anesthesia. INCLUSION CRITERIA: TYPES OF PARTICIPANTS: The participants included in this study were adults between 18 and 68 years of age receiving general anesthesia for any surgical procedure. Only participants with American Society of Anesthesiologist physical status I or II were included. Types of intervention(s): This review evaluated the effectiveness of intravenous dexmedetomidine in preventing postanesthetic shivering. Studies that compared preoperative or intraoperative administration of dexmedetomidine to placebo were included. Types of studies: The studies included in this review were all randomized controlled trials. Types of outcomes: This review assessed all studies that included the following outcome measure: presence of postanesthetic shivering observed in the post-anesthesia care unit during the first two hours after the completion of surgery. SEARCH STRATEGY: A three-step search strategy was utilized in this review to find published and unpublished studies. Only studies published in English between 1999 and 2015 were included in this review. METHODOLOGICAL QUALITY: Quantitative papers selected for retrieval were assessed by two independent reviewers for methodological validity prior to inclusion in the review using standardized critical appraisal instruments from the Joanna Briggs Institute Meta-Analysis of Statistics Assessment and Review Instrument. DATA EXTRACTION: Data was extracted from papers included in the review using the standardized data extraction tool from Joanna Briggs Institute Meta-Analysis of Statistics Assessment and Review Instrument. The data extracted included specific details about the interventions, populations, study methods and outcomes of significance to the review question and specific objectives. DATA SYNTHESIS: Quantitative data was pooled in statistical meta-analysis using Joanna Briggs Institute Meta-Analysis of Statistics Assessment and Review Instrument. All results were subject to double data entry. Effect sizes were expressed as odds ratio and the 95% confidence intervals were calculated for analysis. Heterogeneity was assessed statistically using the standard Chi-square test. RESULTS: This review included eight randomized controlled trials with 625 participants. The results of the meta-analysis revealed a statistically significant decrease in postanesthetic shivering for the dexmedetomidine group. The Mantel-Haenszel overall relative risk ratio was 0.27 in favor of the dexmedetomidine group [relative risk 0.27, at 95% confidence interval 0.19, 0.36, P < 0.0001]. A relative risk reduction value was calculated as 0.73. CONCLUSIONS: The prophylactic administration of intravenous dexmedetomidine reduces the incidence of postanesthetic shivering in patients undergoing general anesthesia. PMID- 26767821 TI - Alcohol withdrawal management in adult patients in a high acuity medical surgical transitional care unit: a best practice implementation project. AB - BACKGROUND: Excessive alcohol consumption, a major health problem worldwide, affects about 6% of the United States population. Caring for patients with alcohol withdrawal syndrome in a hospital ward presents complex physiologic and psycho-social challenges which are best met with evidence-based practices. An academic medical center in the United States has been experiencing an increase in patients with alcohol withdrawal syndrome. However, gaps in clinician knowledge and infrastructure supporting the management of these patients still existed. OBJECTIVES: The aim of this project was to improve the continuity of care of patients undergoing alcohol withdrawal in a medical surgical high acuity transitional care unit by incorporating evidence-based practices, and thereby to positively impact on patient outcomes. Specific objectives were related to standardized assessments and pharmacologic management strategies. METHODS: The project used the Joanna Briggs Institute's Practical Application of Clinical Evidence System and Getting Research into Practice audit tool for promoting change in health practice. A baseline clinical audit was conducted to assess compliance with best practices for managing alcohol withdrawal syndrome, which was followed by several interventions targeted at nurses and providers. A follow up audit was conducted to assess compliance with the implemented strategies. The follow-up audit used the same evidence-based audit criteria as those used for the baseline audit. A non-probabilistic, convenience sampling approach was used. A sample size of 15 patients was used for both the baseline and follow-up audits. RESULTS: The baseline audit revealed a high compliance rate for four of the five audit criteria concerning risk assessment and pharmacologic strategies. There was sub-optimal compliance (53%) with the criterion regarding use of the Clinical Institute Withdrawal Assessment of Alcohol Scale (revised) (CIWA-Ar) scale to assess patients with alcohol withdrawal. After the interventions were implemented this criterion recorded an improvement to 100% compliance. None of the patients in the pilot were transferred to the intensive care unit (ICU) for reasons relating to alcohol withdrawal. CONCLUSIONS: The outcomes of this project demonstrated alcohol withdrawal management can be safely undertaken outside the ICU when the patients are appropriately assessed and treated for the severity of their withdrawal symptoms. This new clinical program significantly impacted on continuity of care. Challenges were resolved using an interdisciplinary team approach. The project resulted in plans for further areas of work concerning alcohol withdrawal management, including adoption of similar approaches by other acute and transitional care units. PMID- 26767822 TI - Errata: The implementation of best practice in medication administration across a health network: a multisite evidence-based audit and feedback project. PMID- 26767823 TI - A 20 years of progress and future of quantitative magnetic resonance imaging (qMRI) of cartilage and articular tissues-personal perspective. AB - OBJECTIVE: In 1994, the first article on quantitative magnetic resonance imaging (qMRI) of articular cartilage was published, and tremendous progress in image acquisition, image analysis, and applications has since been made. The objective of this personal perspective is to highlight milestones in the field of qMRI of cartilage and other articular tissues over these past 20 years. METHODS: Based on a Pubmed search of original articles, the authors selected 30 articles which they deemed to be among the first to provide an important technological step forward in qMRI of cartilage, provided a first application in a particular context, or provided mechanistic insight into articular cartilage physiology, pathology, or treatment. RESULTS: This personal perspective summarizes results from these 30 articles. Further, the authors provide examples of how qMRI of cartilage has translated to quantitative analysis approaches of other articular tissues, including bone, meniscus, and synovium/edema. Eventually, the report provides a summary of how the lessons learned might be applied to future clinical trials and clinical practice. CONCLUSIONS: Over the past 20 years, quantitative imaging of articular tissues has emerged from a method to a dynamic field of research by its own. Continuing the qMRI biomarker qualification process will be crucial in convincing regulatory agencies to accept these as primary outcomes in phase 3 intervention trials. Once successful structural intervention will actually become available in OA, qMRI biomarkers may play an essential role in monitoring response to therapy in the clinic, and in stratifying disease phenotypes that respond differently to treatment. PMID- 26767824 TI - Sentinel Node Mapping Using Indocyanine Green and Near-infrared Fluorescence Imaging Technology for Uterine Malignancies: Preliminary Experience With the Da Vinci Xi System. AB - STUDY OBJECTIVE: Sentinel lymph node (SLN) mapping has emerged as the new frontier for the surgical staging of apparently early-stage cervical and endometrial cancer. Different colorimetric and radioactive tracers, alone and in combination, have been proposed with encouraging results. Fluorometric mapping using indocyanine green (ICG) appears to be a suitable and attractive alternative to provide reliable staging [1-4]. DESIGN: In this video, we present the technique of SLN mapping in 2 cases (1 endometrial and 1 cervical cancer, respectively) using ICG and the near-infrared technology provided by the newest Da Vinci Xi robotic system (Intuitive Surgical Inc., Sunnyvale, CA). Together we report the results of our preliminary experience on the first 20 cases performed. The new robotic Da Vinci Xi system was available at our institution since May 2015. INTERVENTION: Upon institutional review board/ethical committee approval, all consecutive patients with early-stage endometrial and cervical cancer who were judged suitable for robotic surgery have been enrolled for SLN mapping with ICG. We adopted the Memorial Sloan Kettering Cancer Center SLN algorithm; the tracer was delivered into the cervix in all cases. Four milliliters (1.25 mg/mL) of ICG was injected divided into the 3- and 9-o'clock positions of the cervix alone, with 1 mL deep into the stroma and 1 mL submucosally at the skin incision. Sentinel lymph nodes were examined with a protocol including both ultrastaging with immunohistochemistry [3] and 1-step nucleic acid amplification assay [5,6] under a parallel protocol of study. During the study period, 20 cases were managed; 14 and 6 patients had endometrial and cervical cancer, respectively. SLN was detected in all cases (20/20, 100%). Bilateral SLNs were detected in 17 of 20 (85.0%) cases. Based on preoperative and intraoperative findings, 13 (65.0%) patients received systematic pelvic lymphadenectomy after SLN mapping. Three (15.0%) patients had microscopic nodal metastases on SLN. No patients had positive regional nodes other than SLN. No perioperative complications were recorded. CONCLUSION: SLN mapping has been acknowledged by the National Comprehensive Cancer Network guidelines as a viable option for the management of selected uterine malignancies [7,8]. Currently, the near-infrared technology built in the Da Vinci Xi system provides an enhanced real-time imaging system that improves the advantages given by ICG. Together with our experience, these conditions indicate that SLN mapping is an effective and safe procedure with high overall detection and low false-negative rates. PMID- 26767825 TI - Laparoscopic Vaginal-Assisted Hysterectomy With Complete Vaginectomy for Female To-Male Genital Reassignment Surgery. AB - STUDY OBJECTIVE: Total hysterectomy with bilateral salpingo-oophorectomy and vaginectomy for genital reassignment surgery is a complex procedure that is usually performed with a combined vaginal and abdominal approach. The aim of this study was to describe the feasibility of laparoscopic vaginectomy in sex reassignment surgery. METHODS: We reviewed the relevant medical history, intra/postoperative complications, and surgical results of all patients diagnosed with gender dysphoria and submitted to totally laparoscopic gender confirmation surgery in our department between January 2007 and March 2015. In total, 23 patients underwent total hysterectomy with bilateral salpingo-oophorectomy and vaginectomy in a single intervention. The vaginal mucosa was conserved to be used for the penile neourethra during the subsequent phalloplasty. MEASUREMENTS AND MAIN RESULTS: The surgeries had an average operating time of 155 +/- 42 minutes. No intraoperative complications were registered. In all patients, the vagina was totally removed, and, in most cases (n = 20), we were able to remove laparoscopically more than 50% of the vagina. Three patients had postoperative complications. One patient presented with hemoperitoneum on the second postoperative day; another presented with prolonged urinary retention, and a third patient developed a perineal hematoma 1 month after surgery. Patients were discharged less than 72 hours after surgery, except the patient who developed a postoperative hemoperitoneum. For all patients, we obtained an adequate specimen of vaginal mucosa to reconstruct the penile neourethra for the subsequent phalloplasty. CONCLUSION: This study suggests the feasibility of laparoscopic vaginectomy in genital reassignment surgery. The procedure can be executed as a continuation of the hysterectomy with the potential advantage of the laparoscopy providing better exposure of the anatomic structures with low blood losses (less than 500 mL) and few complications. Furthermore, using this approach, adequate sized vaginal mucosa flaps were obtained for the urethral reconstruction. PMID- 26767826 TI - Feasibility and Acceptability of Office-Based Polypectomy With a 16F Mini Resectoscope: A Multicenter Clinical Study. AB - STUDY OBJECTIVE: To investigate the feasibility and acceptability of office hysteroscopic polypectomy using a novel continuous-flow operative 16F mini resectoscope. DESIGN: Multicenter prospective case series (Canadian Task Force classification III). SETTING: "SS Antonio e Biagio" Hospital, Alessandria, and University "Federico II" of Naples. PATIENTS: One hundred eighty-two patients with endometrial polyps. INTERVENTIONS: Hysteroscopic polypectomy performed with 16F mini-resectoscope in an office setting, without analgesia and/or anesthesia. MEASUREMENTS AND MAIN RESULTS: Polypectomy was successfully performed in 175 patients in a single surgical step (96.15%), with only 1 patient (.54%) requiring a second office surgical step to complete the surgery. Seven patients (3.84%) were excluded from the analysis of operative parameters because of severe pelvic pain during the office procedure, which required a second inpatient surgical step. No major complications were recorded. CONCLUSION: Our findings demonstrate that removal of endometrial polyps using the 16F mini-resectoscope in an office setting is a feasible and safe surgical option. Outpatient see-and-treat polypectomy is an acceptable and effective alternative to inpatient resectoscopic polypectomy. PMID- 26767827 TI - Calprotectin (S100A8/A9) and S100A12 are associated with measures of disease activity in a longitudinal study of patients with rheumatoid arthritis treated with infliximab. AB - OBJECTIVES: The pro-inflammatory proteins calprotectin (a heterocomplex of S100A8/A9) and S100A12 have been associated with disease activity in rheumatoid arthritis (RA). The aim of this study was to compare their potential as biomarkers in a prospective study of RA patients starting with infliximab as their first biological disease-modifying anti-rheumatic drug (DMARD). METHOD: Thirty-nine RA patients were examined and serum samples collected when starting with infliximab and after 3, 6, and 12 months. Calprotectin and S100A12 were analysed by enzyme-linked immunosorbent assays (ELISAs) and, together with C reactive protein (CRP) and erythrocyte sedimentation rate (ESR), measured at all time points. A disease activity score of 28 joints (DAS28) was calculated. Radiographs of the hands, wrists, and feet were taken at baseline and after 3 years, and assessed according to the modified Sharp/van der Heijde (SvH) score. Responsiveness was evaluated according to the European League of Associations for Rheumatology (EULAR) response criteria based on 28 joints. RESULTS: Both S100 proteins were significantly higher in seropositive than in seronegative patients (p = 0.01). Calprotectin correlated significantly with CRP (rho = 0.51-0.75), ESR (rho = 0.32-0.52), and DAS28 (rho = 0.32-0.62). S100A12 correlated with calprotectin (rho = 0.62-0.77) and CRP (rho = 0.32-0.63). The S100 proteins, and especially calprotectin (rho = 0.23-0.39), showed weak associations with radiographic progression, unlike CRP/ESR. None of the S100 proteins could predict responsiveness. CONCLUSIONS: Calprotectin showed the strongest correlation with measures of disease activity and may be better than S100A12 when evaluating disease activity in RA patients. More extensive studies are needed to further compare the predictive value of the S100 proteins relative to radiographic progression. PMID- 26767828 TI - Is palinopsia in migraineurs an enhanced physiological phenomenon? AB - Background We report the occurrence of palinopsia in patients with migraine and its correlation with migraine characteristics, triggers and allodynia. Methods This study included 153 consecutive patients with migraine and recorded their clinical details, including allodynia and migraine triggers and characteristics. Palinopsia was evaluated in migraineurs and 101 controls by using a questionnaire and a novel method. Results According to the questionnaire assessment, 9.8% migraineurs had palinopsia. According to the novel method, 57.5% of migraineurs and 12% of controls had palinopsia. Migraineurs most frequently had palinopsia to red color (51.6%), followed by yellow (49.7%), blue (47.7%), green (46.4%) and the least to white (30.7%). A similar pattern with a lesser frequency was noted in controls. The duration of palinopsia was longer in migraineurs than in controls (32.68 +/- 20.24 vs. 5.92 +/- 4.55 seconds; p < 0.001). Migraineurs with palinopsia differed from those without in terms of noise as a migraine trigger ( p < 0.001) and allodynia as a migraine-associated phenomenon ( p = 0.03). In multivariable analysis, predictors of palinopsia were the frequency ( p = 0.003) and severity ( p = 0.04) of headache and the presence of headache during examination ( p = 0.0001). Conclusion Migraineurs had a pattern of palinopsia to different colors that was similar to the controls, but the palinopsia of migraineurs was more frequent and of longer duration, especially during headaches. PMID- 26767829 TI - A fatal outcome of pica. PMID- 26767830 TI - Development of sandwich ELISAs that can distinguish different types of coxsackievirus A16 viral particles. AB - Coxsackievirus A16 (CA16) is one of the major causative agents of hand, foot, and mouth disease (HFMD). No CA16 vaccine candidates have progressed to clinical trials so far. Immunogenicity studies indicated that different CA16 particles have much influence on the efficacy of a candidate vaccine. However, there are still no relevant reports on the methods of detecting different CA16 particles. In this study, we screened several monoclonal antibodies (mAbs) specific for different CA16 particles, and several sandwich enzyme-linked immunoassays (ELISAs) were developed to measure the different types of CA16 viral particles. The mAbs that could only bind denatured or empty capsids could not neutralize CA16. In contrast, the mAbs that could bind mature full particles or all types of particles showed obvious neutralizing activity. The thermal stability of different CA16 particles was evaluated using these sandwich ELISAs. The mature full particles were found to be more thermolabile than the other types of particles and could be stabilized by high concentrations of cations. These methods can be used to assist in the potency control of CA16 vaccines and will promote the development of a CA16 vaccine. PMID- 26767831 TI - A genome-wide association study of pulmonary tuberculosis in Morocco. AB - Although epidemiological evidence suggests a human genetic basis of pulmonary tuberculosis (PTB) susceptibility, the identification of specific genes and alleles influencing PTB risk has proven to be difficult. Previous genome-wide association (GWA) studies have identified only three novel loci with modest effect sizes in sub-Saharan African and Russian populations. We performed a GWA study of 550,352 autosomal SNPs in a family-based discovery Moroccan sample (on the full population and on the subset with PTB diagnosis at <25 years), which identified 143 SNPs with p < 1 * 10(-4). The replication study in an independent case/control sample identified four SNPs displaying a p < 0.01 implicating the same risk allele. In the combined sample including 556 PTB subjects and 650 controls these four SNPs showed suggestive association (2 * 10(-6) < p < 4 * 10( 5)): rs358793 and rs17590261 were intergenic, while rs6786408 and rs916943 were located in introns of FOXP1 and AGMO, respectively. Both genes are involved in the function of macrophages, which are the site of latency and reactivation of Mycobacterium tuberculosis. The most significant finding (p = 2 * 10(-6)) was obtained for the AGMO SNP in an early (<25 years) age-at-onset subset, confirming the importance of considering age-at-onset to decipher the genetic basis of PTB. Although only suggestive, these findings highlight several avenues for future research in the human genetics of PTB. PMID- 26767832 TI - Single Mother Parenting and Adolescent Psychopathology. AB - Children raised in single-mother families are at increased risk for psychopathology, but the mechanisms that help explain this relationship are understudied. In a community sample of diverse adolescents (N = 385, 52 % female, 48 % Caucasian) and their mothers, we hypothesized that single mothers would be more likely than cohabitating mothers to engage in negative parenting behaviors, which would predict adolescent psychopathology prospectively. Single mothers were more likely to engage in psychologically controlling behaviors, which predicted to their adolescent offspring experiencing higher rates of depressive symptoms and externalizing disorders. Girls were more susceptible to depressive symptoms via psychologically controlling parenting than boys in single-mother families. Further, single mothers were more likely to engage in rejecting parenting behaviors, which predicted to a higher prevalence of adolescent externalizing disorders. Surprisingly, rejection in single-mother families predicted to less severe anxiety symptoms in adolescents relative to two-parent families. It is likely that single mothers are not inherently inferior parents relative to cohabitating mothers; rather, their parenting practices are often compromised by a myriad of demands and stressors. Consistent with this postulate, low socioeconomic status was associated with single motherhood and negative parenting behaviors. Clinical implications and study limitations are discussed. PMID- 26767833 TI - Sexual Risk Behaviors in the Adolescent Offspring of Parents with Bipolar Disorder: Prospective Associations with Parents' Personality and Externalizing Behavior in Childhood. AB - We recently reported that adolescent and young adult offspring of parents with bipolar disorder (OBD), relative to control offspring, were more likely to engage in sexual risk behaviors (SRBs). The present prospective study aimed to determine the contribution of parents' personality and offspring behaviour problems in middle childhood to offspring SRBs 10 years later. We hypothesized that offspring externalizing problems in childhood would mediate the relationship between parents' personality traits of neuroticism and agreeableness and adolescent SRBs. Furthermore, we expected these associations to be more robust among the OBD than controls. At baseline, 102 offspring (52 OBD and 50 controls) aged between 4 and 14 years were assessed along with their parents, who completed a self-report personality measure and child behavior rating. Behaviour ratings were also obtained from the children's teachers. Ten years later the offspring completed an interview assessing SRBs. Mediation analyses using bootstrapping revealed that, after controlling for age and presence of an affective disorder, externalizing behaviors served as a pathway through which high parental neuroticism, low parental agreeableness, and low parental extraversion were related to SRBs in offspring. Moderated mediation analyses revealed that the relationship between parental neuroticism and childhood externalizing problems was stronger for OBD than controls. These findings add to our previous results showing parents' personality contributes to intergenerational risk transfer through behavioral problems in middle childhood. These results carry implications for optimal timing of preventative interventions in the OBD. PMID- 26767834 TI - A 9-Month-Old Girl from Iran with Extensive Erythematous Plaques Due to Trichophyton simii, a Zoophilic Dermatophyte. AB - The incidence of dermatophytosis due to Trichophyton simii is generally considered to be limited to endemic areas, particularly one area of India. However, the high similarity between the morphological features of atypical T. simii isolates and those of other dermatophytes such as Trichophyton interdigitale and Arthroderma benhamiae may lead to misidentification of the cause of dermatophytosis in many instances. We investigated a rare case of tinea corporis in a 9-month-old female with extensive erythematous lesions. Morphological features of the recovered isolate from the culture resulted in the identification of Trichophyton interdigitale. For accurate identification, the internal transcribed spacer regions (ITS1 and ITS2) of the ribosomal DNA (rDNA) gene were sequenced and the isolate was ultimately identified as T. simii. In conclusion, T. simii, which has been formerly known to be restricted to specific endemic regions, appears to be not infrequent in non-endemic areas but instead simply less well-known and consequently underestimated. To determine its actual prevalence of infection, the application of DNA-based molecular methodologies is required. PMID- 26767835 TI - A tripartite approach identifies the major sunflower seed albumins. AB - KEY MESSAGE: We have used a combination of genomic, transcriptomic, and proteomic approaches to identify the napin-type albumin genes in sunflower and define their contributions to the seed albumin pool. Seed protein content is determined by the expression of what are typically large gene families. A major class of seed storage proteins is the napin-type, water soluble albumins. In this work we provide a comprehensive analysis of the napin-type albumin content of the common sunflower (Helianthus annuus) by analyzing a draft genome, a transcriptome and performing a proteomic analysis of the seed albumin fraction. We show that although sunflower contains at least 26 genes for napin-type albumins, only 15 of these are present at the mRNA level. We found protein evidence for 11 of these but the albumin content of mature seeds is dominated by the encoded products of just three genes. So despite high genetic redundancy for albumins, only a small sub-set of this gene family contributes to total seed albumin content. The three genes identified as producing the majority of sunflower seed albumin are potential future candidates for manipulation through genetics and breeding. PMID- 26767836 TI - Tobacco nitrosamines as culprits in disease: mechanisms reviewed. AB - The link between tobacco abuse and cancer is well-established. However, emerging data indicate that toxins in tobacco smoke cause cellular injury due to enhanced toxic/metabolic effects of metabolites, disruption of intracellular signaling mechanisms, and formation of DNA, protein, and lipid adducts that impair function and promote oxidative stress and inflammation. These effects of smoking, which are largely non-carcinogenic, can be produced by tobacco-specific nitrosamines and their metabolites. These factors could account for the increased rates of neurodegeneration and insulin resistance diseases among smokers. Herein, we review nicotine and tobacco-specific nitrosamine metabolism, mechanisms of adduct formation, DNA damage, mutagenesis, and potential mechanisms of disease. PMID- 26767837 TI - Return to Play After Hamstring Injuries: A Qualitative Systematic Review of Definitions and Criteria. AB - BACKGROUND: More than half of the recurrent hamstring injuries occur within the first month after return-to-play (RTP). Although there are numerous studies on RTP, comparisons are hampered by the numerous definitions of RTP used. Moreover, there is no consensus on the criteria used to determine when a person can start playing again. These criteria need to be critically evaluated, in an attempt to reduce recurrence rates and optimize RTP. OBJECTIVE: To carry out a systematic review of the literature on (1) definitions of RTP used in hamstring research and (2) criteria for RTP after hamstring injuries. STUDY DESIGN: Systematic review. METHODS: Seven databases (PubMed, EMBASE/MEDLINE, CINAHL, PEDro, Cochrane, SPORTDiscus, Scopus) were searched for articles that provided a definition of, or criteria for, RTP after hamstring injury. There were no limitations on the methodological design or quality of articles. Content analysis was used to record and analyze definitions and criteria for RTP after hamstring injury. RESULTS: Twenty-five papers fulfilled inclusion criteria, of which 13 provided a definition of RTP and 23 described criteria to support the RTP decision. "Reaching the athlete's pre-injury level" and "being able to perform full sport activities" were the primary content categories used to define RTP. "Absence of pain", "similar strength", "similar flexibility", "medical staff clearance", and "functional performance" were core themes to describe criteria to support the RTP decision after hamstring injury. CONCLUSION: Only half of the included studies provided some definition of RTP after hamstring injury, of which reaching the athlete's pre-injury level and being able to perform full sport activities were the most important. A wide variety of criteria are used to support the RTP decision, none of which have been validated. More research is needed to reach a consensus on the definition of RTP and to provide validated RTP criteria to facilitate hamstring injury management and reduce hamstring injury recurrence. PROSPERO systematic review registration number: CRD42015016510. PMID- 26767838 TI - GH3-Mediated Auxin Conjugation Can Result in Either Transient or Oscillatory Transcriptional Auxin Responses. AB - The conjugation of the phytohormone auxin to amino acids via members of the gene family GH3 is an important component in the auxin-degradation pathway in the model plant species Arabidopsis thaliana, as well as many other plant species. Since the GH3 genes are themselves up-regulated in response to auxin, providing a negative feedback on intracellular auxin levels, it is hypothesised that the GH3s have a role in auxin homoeostasis. To investigate this, we develop a mathematical model of auxin signalling and response that includes the auxin-inducible negative feedback from GH3 on the rate of auxin degradation. In addition, we include a positive feedback on the rate of auxin input via the auxin influx transporter LAX3, shown previously to be expressed in response to auxin and to have an important role during lateral root emergence. In the absence of the LAX3 positive feedback, we show that the GH3 negative feedback suffices to generate a transient transcriptional response to auxin in the shape of damped oscillations of the model system. When LAX3 positive feedback is present, sustained oscillations of the system are possible. Using steady-state analyses, we identify and discuss key parameters affecting the oscillatory behaviour of the model. The transient peak of auxin and subsequent transcriptional response caused by the up-regulation of GH3 represents a possible protective homoeostasis mechanism that may be used by plant cells in response to excess auxin. PMID- 26767839 TI - Holoprosencephaly: antenatal and postnatal diagnosis and outcome. AB - OBJECTIVES: The objectives of this study are to ascertain the clinical outcome and overall survival of holoprosencephaly (HPE) patients diagnosed antenatally and postnatally, to determine the accuracy of antenatal diagnosis and to determine the role of neurosurgical intervention in HPE. DESIGN: This is a retrospective review over a 10-year period. PATIENTS: Sixty-three patients were included in the study, 45 were diagnosed by antenatal radiological imaging and 18 were diagnosed by postnatal radiological imaging. Patient data was drawn from Temple Street Children's University Hospital (the national paediatric neurosurgery centre), the National Maternity Hospital in Holle's Street, Dublin, and Our Lady of Sick Children Hospital, Dublin. METHODS: The study was carried out through a review of antenatal and postnatal radiological imaging and reports, clinical charts, GP letters from patient follow-up and telephone conversations with parents of HPE patients. RESULTS: Four patients in the antenatal diagnosis group had follow-up foetal MRI confirming HPE. Twelve in this group had radiological follow-up postnatally, and in five of these, HPE was confirmed. The remaining seven were identified as false positive. Alobar HPE constituted 55 % (21/38) of patients with 95 % mortality. Fifty-one percent had a normal karyotype. The overall survival in the antenatal diagnosis group was 13 %. In the postnatal group, 18 patients were identified, 67 % (12/18) lobar and 33 % (6/18) semilobar. Normal karyotype was found in 72 % (13/18), with an overall survival rate of 56 % (10/18). Neurosurgical intervention in both groups mainly consisted of CSF diversion in the form of ventriculoperitoneal (VP) or cystoperitoneal shunt (CP) (13/67). CONCLUSION: Foetal MRI should be routinely performed in suspected cases of HPE, and reliance on ultrasound alone in the antenatal period may not be sufficient. In our study, there is a high early mortality noted in severe cases of HPE, while milder forms of HPE in children tend to survive beyond infancy albeit with associated complications that required neurosurgical intervention and medical management for other associated systemic anomalies. PMID- 26767840 TI - Cerebrospinal fluid collections in sagittal suture synostosis. AB - PURPOSE: The premature fusion of the sagittal suture (scaphocephaly) may be associated with intracranial cerebrospinal fluid (CSF) dynamics alterations resulting in pericerebral effusion (PE) and/or ventriculomegaly. However, the etiology and development of such collections are not fully elucidated. The aims of this study are to clarify the characteristics of intracranial CSF collection in scaphocephaly, consider the role of surgery, and analyze the prognostic factor on CSF dynamics. METHOD: The pre- and postoperative cerebral imaging of 63 children (48 boys, 15 girls) with scaphocephaly who underwent craniotomy with decompression of the superior sagittal sinus (SSS) before 6 months of age between 2008 and 2015 were retrospectively studied. The PE was compared to the estimated value corrected for age (normal control). Evans' index (EI) was calculated. Correlations among these values and indices were analyzed. RESULT: Preoperatively, 36 of 63 patients (57 %) had larger PE than expected, and 36 of 63 patients (57 %) had pathological EI (EI > 0.3), and among them, 26 (46 %) had both. Patients with large PE tended to have pathological EI (p = 0.005). The PE and the EI were significantly decreased postoperatively (p < 0.001). The PE decreased faster than the expected natural course in 59 of 63 patients (92 %) postoperatively. CONCLUSION: The precise comparison with estimated PE prevalence corrected for age showed that PE can be found in more than half of the children with scaphocephaly, associated with ventriculomegaly. Surgery has a significant efficacious role in decreasing those CSF collections. The long-term significance of such CSF collections in scaphocephaly is still to be elucidated. PMID- 26767841 TI - Long term effect of vagus nerve stimulation in pediatric intractable epilepsy: an extended follow-up. AB - PURPOSE: Over the past two decades, vagus nerve stimulation (VNS) has become an accepted and viable treatment modality for intractable epilepsy both in children and adults. Earlier studies have demonstrated short-term seizure outcomes, usually for up to 5 years; so far, none have reported an extended outcome in children. We aimed to assess long term seizure outcome in children with intractable epilepsy for more than 5 years. METHODS: We identified patients who had VNS implantation for treatment of intractable epilepsy from March 2000 to March 2015 at our Epilepsy Center and collected data including demographic, age at epilepsy onset and VNS implantation, duration of epilepsy, seizure type, number of antiepilepsy drugs (AEDs), and monthly seizure frequency before VNS implantation and at the last clinic visit. Phone surveys were conducted with patients without recent clinic follow-up. RESULTS: Fifty-six patients (aged 4-17 at the time of implant) are the subjects of the study. Seizure reduction of >50 % was achieved in 9.8 % (6th month), 24 % (2nd year), 46.4 % (3rd year), and 54 %(5th year), and overall 35 (62.5 %) of the 56 subjects had a greater than 50 % reduction in seizure frequency at the last follow-up. Eleven patients became seizure free. The results, once obtained, were maintained steadily or even improved over time without any loss of efficacy during the follow-up. The only parameter, significantly related with clinical response, was age at seizure onset. The most frequent adverse events were hoarseness, cough, sore throat, and anorexia, experienced by 13 patients. Two patients had local wound infections and lead to the removal of the stimulator. An improvement in alertness, attention, and psychomotor activity, independent of the efficacy of vagal nerve stimulation, was observed in 8 patients. CONCLUSION: To our knowledge, this is the first pediatric study evaluating seizure outcome over more than 5 years of follow-up, and demonstrates a favorable seizure outcome of >50 % seizure frequency in 62.5 % of patients and seizure freedom in 11 patients. It is well tolerated over an extended period of time. PMID- 26767842 TI - Evaluating extent of resection in pediatric glioblastoma: a multiple propensity score-adjusted population-based analysis. AB - PURPOSE: The benefit of radical resections for glioblastoma patients remains a source of contention in the literature. Few studies have been conducted in pediatric patients, and it is becoming increasingly evident that data regarding adult glioblastoma (GB) patients cannot be generalized to pediatric patients affected by this neoplasm. A comparative effectiveness study is performed for different extent of resection (EOR) groups in the largest cohort of pediatric GB (pGB) patients. METHODS: The Surveillance, Epidemiology, and End Results (SEER) cancer registry was used to identify pGB patients from 1988 through 2009. Multivariate- and multiple propensity score (mPS)-adjusted analyses were used to determine the effect of gross total resection (GTR), partial resection (PR), and biopsy (Bx) on overall survival. Survival prospects were summarized using direct adjusted survival curves. RESULTS: A total of 342 pGB patients were identified, and 35.4 % of patients received a GTR, 28.8 % PR, 17.3 % Bx, and 17.0 % did not undergo surgery. In our cohort, a median overall survival of 12 months was observed with 1-, 2-, and 5-year survival rates of 51.7, 28.3, and 15.7 %, respectively. EOR was a predictor of survival in both the multivariate- (P < 0.001) and mPS-adjusted model (P < 0.001). Compared to the GTR group, a higher mortality rate was observed in patients who underwent a PR (HR 1.50; 95 % CI, 1.02-2.21) or Bx (HR 1.87; 95 % CI, 1.18-2.98). There were no significant differences in (adjusted) mortality risk between the PR and Bx groups. CONCLUSION: Our study suggests that GTR is independently associated with improved survival for pediatric patients with glioblastoma. PMID- 26767843 TI - Primary sporadic Burkitt lymphoma of the orbit, clinical characteristics, management, and outcomes: a case study. AB - BACKGROUND: Involvement of the orbit with Burkitt's lymphoma is a very rare presentation of extra-nodal lymphoma. ILLUSTRATIVE CASE: We report a case of a 2 year-old female presented an unusual location of sporadic Burkitt's lymphoma arising in the orbital region. Diagnostic magnetic resonance imagining identified an oval-shaped mass on the lateral rectus of the right orbit that caused dislocation of eyeball, for which she underwent a biopsy from the periorbital swellings. The mass was histologically confirmed as Burkitt's lymphoma, and postoperative aggressive chemotherapy was initiated. We describe clinical diagnosis, histological aspects, radiological features, and current management of this rapidly growing malignant tumor. CONCLUSION: Because of the rapid progression of Burkitt lymphoma, and considering that it responds well to treatment, early recognition and appropriate management are important factors for survival and to preserve visual function. PMID- 26767844 TI - The cerebral venous system and the postural regulation of intracranial pressure: implications in the management of patients with cerebrospinal fluid diversion. AB - Loss of cerebrospinal fluid (CSF) occurs commonly in daily neurosurgical practice. Understanding the altered physiology following CSF loss is important for optimization of patient care and avoidance of complications. There is overwhelming evidence now that the cerebral venous system plays a major role in intracranial pressure (ICP) dynamics especially when one takes into account the effects of postural changes, atmospheric pressure, and gravity on the craniospinal axis as a whole. The CSF and cerebral venous compartments are tightly coupled in two important ways. CSF is resorbed into the venous system, and there is also an evolved mechanism that prevents overdrainage of venous blood with upright positioning known as the Starling resistor. With loss of CSF pressure, this protective mechanism could become nonfunctional which may result in posture-related venous overdrainage through the cranial venous outflow tracts leading to pathologic states. This review article summarizes the relevant anatomic and physiologic basis of the relationship between the craniospinal venous and CSF compartments in the setting of CSF diversion. It is hoped that this article improves our understanding of ICP dynamics after CSF loss, adds a new dimension to our therapeutic methods, stimulates further research into this field, and ultimately improves our care of these patients. PMID- 26767845 TI - Enhanced autophagy reveals vulnerability of P-gp mediated epirubicin resistance in triple negative breast cancer cells. AB - Epirubicin (EPI) is widely used for triple negative breast cancer (TNBC), but a substantial number of patients develop EPI resistance that is associated with poor outcome. The underlying mechanism for EPI resistance remains poorly understood. We have developed and characterized an EPI-resistant (EPI-R) cell line from parental MDA-MB-231 cells. These EPI-R cells reached stable growth in the medium containing 8 MUg/ml of EPI. They overexpressed P-glycoprotein (P-gp) and contained numerous autophagic vacuoles. The suppression of P-gp overexpression and/or autophagy restored the sensitivity of these EPI-R cells to EPI. We further show that autophagy conferred resistance to EPI on MDA cells by blocking the nuclear factor kappa-light-chain-enhancer of activated B cells (NF kappaB)-mediated pro-apoptotic signals. Together, these results reveal a synergistic role of P-gp, autophagy, and NF-kappaB pathways in the development of EPI resistance in TNBC cells. They also suggest that blocking the P-gp overexpression and autophagy may be an effective means of reducing EPI resistance. PMID- 26767847 TI - Duodenal Penetration by the Ringed Expanded Polytetrafluoroethylene Graft for Middle Hepatic Vein Reconstruction During Living-Donor Liver Transplant: A Case Report. AB - Expanded polytetrafluoroethylene grafts are widely used for middle hepatic vein reconstruction during living-donor liver transplant because they have comparable patency to autologous or cryopreserved vessels. Mechanical complications like gastric or duodenal penetration by expanded polytetrafluoroethylene grafts have been infrequently reported. We recently experienced a case of duodenal penetration by the expanded polytetrafluoroethylene graft. The patient was a 57 year-old man who had undergone a living-donor liver transplant for cryptogenic liver cirrhosis. At an annual follow-up computed tomography scan performed 3 years after transplant, the expanded polytetrafluoroethylene graft appeared to have penetrated into the first to the second portion of the duodenum, and abnormal air shadow and partial thrombus were identified within the expanded polytetrafluoroethylene graft. The patient underwent exploratory laparotomy, the expanded polytetrafluoroethylene graft was removed, and the perforated duodenum was repaired. Pyloric exclusion with gastrojejunostomy and feeding jejunostomy was additionally performed because of a wide defect in the duodenum. Adjacent organ injuries such as duodenal or gastric penetration by the expanded polytetrafluoroethylene graft after living-donor liver transplant is rare but not uncommon. Because the use of expanded polytetrafluoroethylene grafts is essential when an adequate vessel allograft is unavailable, we can consider transposition of the omental flap between the expanded polytetrafluoroethylene graft and the stomach or duodenum to reduce this unexpected complication. PMID- 26767846 TI - Predicting the functions of a protein from its ability to associate with other molecules. AB - BACKGROUND: All proteins associate with other molecules. These associated molecules are highly predictive of the potential functions of proteins. The association of a protein and a molecule can be determined from their co occurrences in biomedical abstracts. Extensive semantically related co occurrences of a protein's name and a molecule's name in the sentences of biomedical abstracts can be considered as indicative of the association between the protein and the molecule. Dependency parsers extract textual relations from a text by determining the grammatical relations between words in a sentence. They can be used for determining the textual relations between proteins and molecules. Despite their success, they may extract textual relations with low precision. This is because they do not consider the semantic relationships between terms in a sentence (i.e., they consider only the structural relationships between the terms). Moreover, they may not be well suited for complex sentences and for long distance textual relations. RESULTS: We introduce an information extraction system called PPFBM that predicts the functions of unannotated proteins from the molecules that associate with these proteins. PPFBM represents each protein by the other molecules that associate with it in the abstracts referenced in the protein's entries in reliable biological databases. It automatically extracts each co-occurrence of a protein-molecule pair that represents semantic relationship between the pair. Towards this, we present novel semantic rules that identify the semantic relationship between each co-occurrence of a protein molecule pair using the syntactic structures of sentences and linguistics theories. PPFBM determines the functions of an un-annotated protein p as follows. First, it determines the set S r of annotated proteins that is semantically similar to p by matching the molecules representing p and the annotated proteins. Then, it assigns p the functional category FC if the significance of the frequency of occurrences of S r in abstracts associated with proteins annotated with FC is statistically significantly different than the significance of the frequency of occurrences of S r in abstracts associated with proteins annotated with all other functional categories. We evaluated the quality of PPFBM by comparing it experimentally with two other systems. Results showed marked improvement. CONCLUSIONS: The experimental results demonstrated that PPFBM outperforms other systems that predict protein function from the textual information found within biomedical abstracts. This is because these system do not consider the semantic relationships between terms in a sentence (i.e., they consider only the structural relationships between the terms). PPFBM's performance over these system increases steadily as the number of training protein increases. That is, PPFBM's prediction performance becomes more accurate constantly, as the size of training proteins gets larger. This is because every time a new set of test proteins is added to the current set of training proteins. A demo of PPFBM that annotates each input Yeast protein (SGD (Saccharomyces Genome Database). Available at: http://www.yeastgenome.org/download data/curation) with the functions of Gene Ontology terms is available at: (see Appendix for more details about the demo) http://ecesrvr.kustar.ac.ae:8080/PPFBM/. PMID- 26767848 TI - [Emile Clement Jungfleisch, pharmacist and chemist (1839-1916)]. PMID- 26767849 TI - Tobacco smoking and oxidative stress to DNA: a meta-analysis of studies using chromatographic and immunological methods. AB - Oxidative stress to DNA from smoking was investigated in one randomized smoking cessation study and in 36 cohort studies from excretion of urinary 8-oxo-7 hydrodeoxyguanosine (8-oxodG). Meta-analysis of the 36 cohort studies showed smoking associated with a 15.7% (95% CL 11.0:20.3, p < 0.0001) increased oxidative stress to DNA, in agreement with the reduction of oxidative stress to DNA found in the smoking cessation study. Meta-analysis of the 22 studies that used chromatography methodology on 1709 persons showed a significant 29.3% increase in smokers (95% CL 17.3;41.3), but meta-analysis of 14 studies on 3668 persons using ELISA methodology showed a non-significant effect of 8.7% [95% CL 1.2;18.6]. Tobacco smoke induces oxidative damage to DNA; however, this is not detected with ELISA methodology. Currently, the use of existing ELISA methodology to measure urinary excretion of 8-oxo-7-hydrodeoxyguanosine cannot be recommended. PMID- 26767850 TI - Identification of host genes that affect acquisition of an integrative and conjugative element in Bacillus subtilis. PMID- 26767851 TI - Editorial. PMID- 26767852 TI - Breakthrough in heart failure with preserved ejection fraction: are we there yet? AB - Heart failure with preserved ejection fraction (HFPEF) is a global health problem of considerable socioeconomic burden. It is projected to worsen with the aging population worldwide. The lack of effective therapies underscores our incomplete understanding of this complex heterogeneous syndrome. A novel paradigm has recently emerged, in which central roles are ascribed to systemic inflammation and generalized endothelial dysfunction in the pathophysiology of HFPEF. In this review, we discuss the role of the endothelium in cardiovascular homeostasis and how deranged endothelial-related signaling pathways contribute to the development of HFPEF. We also review the novel therapies in various stages of research and development that target different components of this signaling pathway. PMID- 26767853 TI - Emerging strategies for the treatment of pulmonary tuberculosis: promise and limitations? AB - A worsening scenario of drug-resistant tuberculosis has increased the need for new treatment strategies to tackle this worldwide emergency. There is a pressing need to simplify and shorten the current 6-month treatment regimen for drug susceptible tuberculosis. Rifamycins and fluoroquinolones, as well as several new drugs, are potential candidates under evaluation. At the same time, treatment outcomes of patients with drug-resistant tuberculosis should be improved through optimizing the use of fluoroquinolones, repurposed agents and newly developed drugs. In this context, the safety and tolerance of new therapeutic approaches must be addressed. PMID- 26767854 TI - The antibacterial effect of fatty acids on Helicobacter pylori infection. AB - Eradication of Helicobacter pylori is recommended for the management of various gastric diseases, including peptic ulcers and mucosa-associated lymphoid tissue lymphoma. Because of the increasing prevalence of antibiotic resistance, the eradication rates of antibiotic-based therapies have decreased. Therefore, alternative treatments should be considered. The antibacterial properties of fatty acids (FAs) have been investigated in various organisms, including H. pylori. Some FAs, particularly polyunsaturated FAs, have been shown to have bactericidal activity against H. pylori in vitro; however, their antibacterial effects in vivo remain controversial. Poor solubility and delivery of FAs may be important reasons for this discrepancy. Recently, a series of studies demonstrated the antibacterial effects of a liposomal formulation of linolenic acid against H. pylori, both in vitro and in vivo. Further research is needed to improve the bioavailability of FAs and apply them in clinical use. PMID- 26767855 TI - Can a high-flow nasal cannula substitute for noninvasive positive pressure ventilation in post-extubation respiratory failure? PMID- 26767856 TI - New monoclonal antibody-based test for Helicobacter pylori urease in gastric tissue. AB - BACKGROUND/AIMS: To evaluate a new monoclonal antibody for Helicobacter pylori urease in gastric tissue. METHODS: A total of 107 volunteers were enrolled. All subjects underwent a (13)C-urea breath test and esophagogastroduodenoscopy. Gastric aspirates were analyzed for pH and ammonia. Six biopsy specimens in the gastric antrum and body were obtained for a rapid urease test and histology. The new monoclonal antibody-based H. pylori urease test (HPU) was performed to rapidly and qualitatively detect urease in two biopsy specimens. RESULTS: H. pylori infection was diagnosed in 73 subjects. The sensitivity and specificity of the HPU was 89% and 74%, respectively. The subjects were divided into two groups: one with true-positive and true-negative HPU results (n = 90) and the other with false-positive and false-negative HPU results (n = 17). Across all subjects, ammonia levels were 900.5 +/- 646.7 and 604.3 +/- 594.3 MUmol/L (p > 0.05), and pH was 3.37 +/- 1.64 and 2.82 +/- 1.51 (p > 0.05). Sensitivity was higher in the presence of atrophic gastritis or intestinal metaplasia. CONCLUSIONS: HPU detected H. pylori in approximately 10 min. Gastric aspirate ammonia and pH levels did not affect the test results. Sensitivity was good in the presence of atrophic gastritis or intestinal metaplasia. PMID- 26767857 TI - Feasibility of alpha-fetoprotein as a diagnostic tool for hepatocellular carcinoma in Korea. AB - BACKGROUND/AIMS: The aim of this study was to evaluate the feasibility of alpha fetoprotein (AFP) as a diagnostic tool for hepatocellular carcinoma (HCC) in Korean patients. METHODS: We retrospectively reviewed the medical records of HCC and cirrhosis patients at three hospitals. For each HCC patient, a cirrhosis patient matched for age, sex, etiology, and Child-Pugh classification was selected by simple random sampling. The performance of AFP in the diagnosis of HCC was determined using receiver operating characteristic curve analysis. RESULTS: A total of 732 patients with HCC or cirrhosis were selected for each case and the control groups. The mean age was 54 years, and 72.4% of patients were male. The mean serum AFP levels in the HCC group and cirrhosis group were 3,315.6 and 117.2 ng/mL, respectively (p < 0.001). The area under the receiver operating characteristic curve for all HCC patients was 0.757. The sensitivity, specificity, and positive predictive value of AFP was 50.55%, 87.70%, and 80.43%, respectively, at a cut-off of 20 ng/mL; 37.70%, 95.90%, and 90.20%, respectively, at a cut-off of 100 ng/mL, and 30.05%, 97.27%, and 91.67%, respectively, at a cut off of 200 ng/mL. A cut-off of 100 ng/mL was more sensitive than one of 200 ng/mL with equivalent specificity and positive predictive value. CONCLUSIONS: The cut off AFP value for early-stage HCC was 17.4 ng/mL. Our study cautiously suggests that AFP has a role in the diagnosis of HCC, and that the appropriate value of AFP for the diagnosis of HCC may be 100 ng/mL rather than 200 ng/mL. PMID- 26767858 TI - Predictive factors of mortality within 30 days in patients with nonvariceal upper gastrointestinal bleeding. AB - BACKGROUND/AIMS: Nonvariceal upper gastrointestinal bleeding (NVUGIB) is a common medical emergency that can be life threatening. This study evaluated predictive factors of 30-day mortality in patients with this condition. METHODS: A prospective observational study was conducted at a single hospital between April 2010 and November 2012, and 336 patients with symptoms and signs of gastrointestinal bleeding were consecutively enrolled. Clinical characteristics and endoscopic findings were reviewed to identify potential factors associated with 30-day mortality. RESULTS: Overall, 184 patients were included in the study (men, 79.3%; mean age, 59.81 years), and 16 patients died within 30 days (8.7%). Multivariate analyses revealed that comorbidity of diabetes mellitus (DM) or metastatic malignancy, age >= 65 years, and hypotension (systolic pressure < 90 mmHg) during hospitalization were significant predictive factors of 30-day mortality. CONCLUSIONS: Comorbidity of DM or metastatic malignancy, age >= 65 years, and hemodynamic instability during hospitalization were predictors of 30 day mortality in patients with NVUGIB. These results will help guide the management of patients with this condition. PMID- 26767859 TI - Early monitoring for detection of antituberculous drug-induced hepatotoxicity. AB - BACKGROUND/AIMS: We investigated the time of onset of antituberculous drug induced hepatotoxicity (ADIH) and related characteristics. METHODS: Adult patients (n = 1,031) treated with first-line antituberculous drugs between February 2009 and January 2013 were enrolled. RESULTS: Of the 1,031 patients, 108 patients (10.5%) developed ADIH a mean of 39.6 +/- 43.7 days after treatment initiation. Twenty-eight patients (25.9%) developed ADIH within 7 days, 73 (67.6%) within 30 days, and the rest after 30 days. The <= 30-day group was characterized by higher peak alanine aminotransferase (ALT) level and a high proportion of patients with maintenance of first-line antituberculous drugs compared to the > 30-day group. In subgroup analysis, the <= 7-day group was characterized by higher baseline aspartate aminotransferase and ALT, high proportion of patients with maintenance of first-line antituberculous drugs, and high proportion of patients with extrapulmonary tuberculosis compared to patients with ADIH that developed beyond 7 days. In multivariate analysis, serum ALT > 40 IU/L (odds ratio [OR], 2.995; 95% confidence interval [CI], 1.580 to 5.680; p = 0.001) and presence of anti-hepatitis C virus (OR, 4.204; 95% CI, 1.822 to 9.700, p = 0.001) were independent risk factors for development of ADIH. CONCLUSIONS: Approximately 70% of the cases of ADIH occurred in the first month of antituberculous treatment, and were associated with continuation of the first line drug regimen. PMID- 26767860 TI - Predictive value of CHADS2 score for cardiovascular events in patients with acute coronary syndrome and documented coronary artery disease. AB - BACKGROUND/AIMS: The CHADS2 score, used to predict the risk of ischemic stroke in atrial fibrillation (AF) patients, has been reported recently to predict ischemic stroke in patients with coronary heart disease, regardless of the presence of AF. However, little data are available regarding the relationship between the CHADS2 score and cardiovascular outcomes. METHODS: This was a retrospective study on 104 patients admitted for acute coronary syndrome (ACS) who underwent coronary angiography, carotid ultrasound, and transthoracic echocardiography. RESULTS: The mean age of the subjects was 60.1 +/- 12.6 years. The CHADS2 score was as follows: 0 in 46 patients (44.2%), 1 in 31 (29.8%), 2 in 18 (17.3%), and >= 3 in 9 patients (8.7%). The left atrial volume index (LAVi) showed a positive correlation with the CHADS2 score (20.8 +/- 5.9 for 0; 23.2 +/- 6.7 for 1; 26.6 +/- 10.8 for 2; and 30.3 +/- 8.3 mL/m(2) for >=3; p = 0.001). The average carotid total plaque area was significantly increased with CHADS2 scores >= 2 (4.97 +/- 7.17 mm(2) vs. 15.52 +/- 14.61 mm(2); p = 0.002). Eight patients experienced cardiovascular or cerebrovascular (CCV) events during a mean evaluation period of 662 days. A CHADS2 score >= 3 was related to an increase in the risk of CCV events (hazard ratio, 14.31; 95% confidence interval, 3.53 to 58.06). Furthermore, LAVi and the severity of coronary artery obstructive disease were also associated with an increased risk of CCV events. CONCLUSIONS: The CHADS2 score may be a useful prognostic tool for predicting CCV events in ACS patients with documented coronary artery disease. PMID- 26767861 TI - Clinical efficacy of high-flow nasal cannula compared to noninvasive ventilation in patients with post-extubation respiratory failure. AB - BACKGROUND/AIMS: Post-extubation respiratory failure (PERF) is associated with poor clinica l outcomes. High-f low nasa l cannula (HF NC) ox ygen therapy has been used in patients with respiratory failure, but the clinical benefit in patients with PERF remains unclear. The aim of this study was to evaluate the clinical efficacy of HFNC compared to noninvasive ventilation (NIV) in patients with PERF. METHODS: A historic retrospective cohort analysis was performed in 28 beds in the medical Intensive Care Unit (ICU) at a single medical center in South Korea. In total, 73 patients with PERF were enrolled: 39 patients who underwent NIV from April 2007 to March 2009 and 34 patients who received HFNC from April 2009 to May 2011. RESULTS: The rate of avoidance of reintubation was not different between the HFNC group (79.4%) and NIV group (66.7%, p = 0.22). All patients with HFNC tolerated the device, whereas five of those with NIV did not tolerate treatment (p = 0.057). The mean duration of ICU stay was significantly shorter in the HFNC group than in the NIV group (13.4 days vs. 20.6 days, p = 0.015). There was no difference in ICU or in-hospital mortality rate. CONCLUSIONS: HFNC is likely to be as effective as, and better tolerated than, NIV for treatment of PERF. PMID- 26767862 TI - Effect of intranasal rosiglitazone on airway inflammation and remodeling in a murine model of chronic asthma. AB - BACKGROUND/AIMS: Asthma is characterized by airway hyperresponsiveness, inflammation, and remodeling. Peroxisome proliferator-activated receptors have been reported to regulate inflammatory responses in many cells. In this study, we examined the effects of intranasal rosiglitazone on airway remodeling in a chronic asthma model. METHODS: We developed a mouse model of airway remodeling, including smooth muscle thickening, in which ovalbumin (OVA)-sensitized mice were repeatedly exposed to intranasal OVA administration twice per week for 3 months. Mice were treated intranasally with rosiglitazone with or without an antagonist during OVA challenge. We determined airway inflammation and the degree of airway remodeling by smooth muscle actin area and collagen deposition. RESULTS: Mice chronically exposed to OVA developed sustained eosinophilic airway inflammation, compared with control mice. Additionally, the mice developed features of airway remodeling, including thickening of the peribronchial smooth muscle layer. Administration of rosiglitazone intranasally inhibited the eosinophilic inflammation significantly, and, importantly, airway smooth muscle remodeling in mice chronically exposed to OVA. Expression of Toll-like receptor (TLR)-4 and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) was increased in the OVA group and decreased in the rosiglitazone group. Co-treatment with GW9660 (a rosiglitazone antagonist) and rosiglitazone increased the expression of TLR-4 and NF-kappaB. CONCLUSIONS: These results suggest that intranasal administration of rosiglitazone can prevent not only air way inf lammation but also air way remodeling associated with chronic allergen challenge. This beneficial effect is mediated by inhibition of TLR-4 and NF-kappaB pathways. PMID- 26767863 TI - Relationship between metabolic syndrome and thyroid nodules in healthy Koreans. AB - BACKGROUND/AIMS: This study evaluated the relationship between thyroid nodules and metabolic syndrome (MS) and its components in apparently healthy Koreans. METHODS: We reviewed the records of 3,298 subjects with no noticeable symptoms who underwent thyroid ultrasound imaging as part of a routine check-up between July 2009 and June 2010; of these, 1,308 were excluded based upon predefined criteria. Among the remaining 1,990 patients, we examined the association between MS and its components and the incidence of thyroid nodules. RESULTS: Of the 1,990 subjects included in this study, 38.4% (n = 764) had thyroid nodules and 12.7% (n = 253) had MS. Female sex, older age, higher body mass index, larger waist circumference, higher glycated hemoglobin level, lower thyroid stimulating hormone level, and presence of MS were all closely related with the presence of thyroid nodules (all p < 0.05). Furthermore, the relevant number of MS components showed a positive linear correlation with the occurrence of thyroid nodules (p < 0.001). Evidence of MS alone was not independently associated with thyroid nodules after adjusting for sex and age in a multivariate binary logistic regression analysis; however, glycated hemoglobin for females and waist circumference for males, as well as both age and thyroid stimulating hormone for all patients, were identified as independent predictors for the existence of thyroid nodules (all p < 0.05). CONCLUSIONS: This study suggests a positive relationship between the components of MS and thyroid nodules in an ostensibly healthy Korean population. Our data support the idea that the recent increase in thyroid nodules is partly due to increases in both MS and obesity. PMID- 26767864 TI - Impact of dialysis modality on technique survival in end-stage renal disease patients. AB - BACKGROUND/AIMS: This study analyzed the risk factors for technique survival in dialysis patients and compared technique survival rates between hemodialysis (HD) and peritoneal dialysis (PD) in a prospective cohort of Korean patients. METHODS: A total of 1,042 patients undergoing dialysis from September 2008 to June 2011 were analyzed. The dialysis modality was defined as that used 90 days after commencing dialysis. Technique survival was compared between the two dialysis modalities, and the predictive risk factors were evaluated. RESULTS: The dialysis modality was an independent risk factor predictive of technique survival. PD had a higher risk for technique failure than HD (hazard ratio [HR], 10.8; 95% confidence interval [CI], 1.9 to 62.0; p = 0.008) during a median follow-up of 11.0 months. In the PD group, a high body mass index (BMI) was an independent risk factor for technique failure (HR, 1.3; 95% CI, 1.0 to 1.8; p = 0.036). Peritonitis was the most common cause of PD technique failure. The difference in technique survival between PD and HD was more prominent in diabetic patients with a good nutritional status and in non-diabetic patients with a poor nutritional status. CONCLUSIONS: In a prospective cohort of Korean patients with end-stage renal disease, PD was associated with a higher risk of technique failure than HD. Diabetic patients with a good nutritional status and non-diabetic patients with a poor nutritional status, as well as patients with a higher BMI, had an inferior technique survival rate with PD compared to HD. PMID- 26767865 TI - Angiotensin III increases monocyte chemoattractant protein-1 expression in cultured human proximal tubular epithelial cells. AB - BACKGROUND/AIMS: We investigated whether angiotensin III (Ang III) is involved in monocyte recruitment through regulation of the chemokine monocyte chemoattractant protein-1 (MCP-1) in cultured human proximal tubular epithelial cells (HK-2 cells). METHODS: We measured MCP-1 levels in HK-2 cells that had been treated with various concentrations of Ang III and Ang II type-1 (AT1) receptor antagonists at various time points. The phosphorylation states of p38, c-Jun N terminal kinases (JNK), and extracellular-signal-regulated kinases were measured in Ang III-treated cells to explore the mitogen-activated protein kinase (MAPK) pathway. MCP-1 levels in HK-2 cell-conditioned media were measured after pre treatment with the transcription factor inhibitors curcumin or pyrrolidine dithiocarbamate. RESULTS: Ang III increased MCP-1 protein production in dose- and time-dependent manners in HK-2 cells, which was inhibited by the AT1 receptor blocker losartan. p38 MAPK activity increased significantly in HK-2 cells exposed to Ang III for 30 minutes, and was sustained at higher levels after 60 minutes (p < 0.05). Total phosphorylated JNK protein levels tended to increase 20 minutes after stimulation with Ang III. Pre-treatment with a p38 inhibitor, a JNK inhibitor, or curcumin significantly inhibited Ang III-induced MCP-1 production. CONCLUSIONS: Ang III increases MCP-1 synthesis via stimulation of intracellular p38 and JNK MAPK signaling activity and subsequent activated protein-1 transcriptional activity in HK-2 cells. PMID- 26767866 TI - Advanced chronic kidney disease: a strong risk factor for Clostridium difficile infection. AB - BACKGROUND/AIMS: It has been suggested that chronic kidney disease (CKD) is a risk factor for Clostridium difficile infection (CDI) and is associated with increased mortality among patients infected with C. difficile. However, recent studies of the clinical impact of CKD on CDI in Asians are still insufficient. We sought to determine the relationship between CKD and CDI in a Korean population. METHODS: This was a single-center, retrospective case-control study. In total, 171 patients with CDI were included as cases and 342 age- and gender-matched patients without CDI were used as controls. We compared the prevalence of CKD in the study sample and identified independent risk factors that could predict the development or prognosis of CDI. RESULTS: Independent risk factors for CDI included stage IV to V CKD not requiring dialysis (odds ratio [OR], 2.90) and end stage renal disease requiring dialysis (OR, 3.34). Patients with more advanced CKD (estimated glomerular filtration rate < 30) and CDI showed higher in-hospital mortality and poorer responses to the initial metronidazole therapy. CONCLUSIONS: More advanced CKD is an independent risk factor for CDI and is associated with higher in-hospital mortality and poor treatment responses in CDI patients. Thus, in CKD patients, careful attention should be paid to the occurrence of CDI and its management to improve the outcome of CDI. PMID- 26767867 TI - Evaluation of treatment response and tissue necrosis as prognostic indicators following neoadjuvant chemoradiotherapy in rectal cancer patients. AB - BACKGROUND/AIMS: The objective of this study was to assess the prognostic roles of treatment response and tissue necrosis after chemoradiotherapy (CRT) in locally advanced rectal cancer. METHODS: A total of 243 patients with locally advanced rectal cancer who underwent neoadjuvant CRT were included. Three treatment response groups were classified by their pathological stage results: complete treatment response (CTR), intermediate treatment response (ITR), and poor treatment response (PTR). Three tissue necrosis groups were classified based on tissue pathological results: complete necrosis response (CNR), intermediate necrosis response (INR), and poor necrosis response (PNR). RESULTS: Overall survival (OS) and recurrence-free survival (RFS) rate at three years were 74.5% and 61.3%, respectively. The 3-year OS rates of the CTR, ITR, and PTR groups were 83.7%, 75.9%, and 69.7%, respectively (p < 0.001); the 3-year RFS rates were 76.7%, 69.0%, and 52.1%, respectively (p < 0.001). The 3-year OS rates of the CNR, INR, and PNR groups were 83.7%, 80.6%, and 61.8%, respectively (p < 0.001); the 3-year RFS rates were 76.7%, 68.9%, and 44.3%, respectively (p < 0.001). When compared to CTR/CNR, PTR/PNR was strongly related to an increased risk of recurrence (hazard ratio [HR], 5.53; 95% confidence interval [CI], 2.01 to 15.23 vs. HR, 6.37; 95% CI, 2.29 to 17.74, respectively) in univariate Cox regression. Both PTR and PNR were strongly associated with shorter RFS and OS when compared with CTR and CNR in the multivariate Cox regression. CONCLUSIONS: Tissue necrosis is an equally important prognostic marker as treatment response for oncologic outcomes in locally advanced rectal cancer. PMID- 26767868 TI - Use of cefuroxime for women with community-onset acute pyelonephritis caused by cefuroxime-susceptible or -resistant Escherichia coli. AB - BACKGROUND/AIMS: Efforts to decrease the use of extended-spectrum cephalosporins are required to prevent the selection and transmission of multi-drug resistant pathogens, such as extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae. The objectives of this study were to assess the clinical efficacy of intravenous cefuroxime as an empirical antibiotic for the treatment of hospitalized women with acute pyelonephritis (APN) caused by Escherichia coli. METHODS: We analyzed the clinical and microbiologic database of 328 hospitalized women with community-onset APN. RESULTS: Of 328 women with APN, 22 patients had cefuroxime-resistant E. coli APN, and 306 patients had cefuroxime-susceptible E. coli APN. The early clinical success rates were significantly higher (p = 0.001) in the cefuroxime-susceptible group (90.8%, 278/306) than in the cefuroxime resistant group (68.2%, 15/22) at 72 hours. The clinical cure rates at 4 to 14 days after completing antimicrobial therapy were not significantly different in the cefuroxime-resistant or -susceptible groups, with 88.2% (15/17) and 97.8% (223/228; p = 0.078), respectively. The microbiological cure rates were not significantly different and were 90.9% (10/11) and 93.4% (128/137), respectively (p = 0.550). The median duration of hospitalization in the cefuroxime-resistant and -susceptible groups was 10 days (interquartile range [IQR], 8 to 13) and 10 days (IQR, 8 to 14), respectively (p =0.319). CONCLUSIONS: Cefuroxime, a second generation cephalosporin, can be used for the initial empirical therapy of community-onset APN if tailored according to uropathogen identification and susceptibility results, especially in areas where the prevalence rate of ESBL producing uropathogens is low. PMID- 26767869 TI - Amikacin therapy for urinary tract infections caused by extended-spectrum beta lactamase-producing Escherichia coli. AB - BACKGROUND/AIMS: The number of urinary tract infections (UTIs) caused by extended spectrum beta-lactamase-producing Escherichia coli (ESBL-EC) is increasing. In an outpatient setting, there are limited therapeutic options to treat ESBL-producing pathogens. We evaluated the outcomes of amikacin outpatient parenteral antibiotic therapy (OPAT) for UTIs caused by ESBL-EC in patients not pre-treated with carbapenem. METHODS: We retrospectively evaluated the outcomes of amikacin OPAT for UTIs caused by ESBL-EC. RESULTS: From November 2011 to October 2012, eight females, who could not be hospitalized for carbapenem treatment, were treated with amikacin OPAT for nine episodes of non-bacteremic ESBL-EC UTIs. Seven of the eight patients had one or more comorbidities. Of the nine UTI cases, three had symptomatic lower UTIs and six had non-bacteremic upper UTIs. In all of the cases, symptomatic and laboratory improvements were observed following amikacin OPAT. One patient showed a delayed relapse with bilateral microabscesses 3 weeks after treatment cessation; however, a clinical and microbiological cure was eventually reached. All of the patients were able to tolerate amikacin OPAT without any significant nephrotoxicity or ototoxicity. CONCLUSIONS: Amikacin OPAT represents a feasible therapeutic option for non-bacteremic UTIs caused by ESBL EC in settings with limited resources. PMID- 26767870 TI - Risk factors and etiology of surgical site infection after radical neck dissection in patients with head and neck cancer. AB - BACKGROUND/AIMS: Surgical site infection (SSI) is a major complication after radical neck dissection (RND) in patients with head and neck cancer (HNC). We investigated the incidence, risk factors, and etiology of SSI among patients who underwent RND. METHODS: A retrospective cohort study was performed on HNC patients, excluding those with thyroid cancer, who underwent first RND at a teaching hospital between January 2006 and June 2010. Medical records were collected and analyzed to evaluate the risk factors and microbiological etiologies. RESULTS: A total of 370 patients underwent first RND. The overall incidence of SSI was 19.7% (73/370). Multivariate analysis showed that male sex (odds ratio [OR], 4.281; p = 0.004), cardiovascular diseases (OR, 1.941; p = 0.020), large amount of blood loss during surgery (OR, 4.213; p = 0.001), and surgery lasting longer than 6 hours (OR, 4.213; p = 0.002) were significantly associated with SSI. The most common causative pathogen was Staphylococcus aureus (32.6%), and 93.2% of S. aureus isolates were methicillin-resistant. Klebsiella pneumoniae (13/92, 14.1%), Pseudomonas aeruginosa (11/92, 12.0%), and Enterococcus species (11/92, 12.0%) were also frequently detected. CONCLUSIONS: Based on our results, we predict that certain groups of patients are at high risk for SSIs after major HNC surgery. Preventive measures or close monitoring in these patients may be required to reduce the likelihood of postoperative SSIs. Furthermore, even though additional research is required, we would consider changing the prophylactic antibiotic regimens according to the causative organisms. PMID- 26767871 TI - Validation and reliability of a Behcet's Syndrome Activity Scale in Korea. AB - BACKGROUND/AIMS: We prepared a cross-cultural adaptation of the Behcet's Syndrome Activity Scale (BSAS) and evaluated its reliability and validity in Korea. METHODS: Fifty patients with Behcet's disease (BD) who attended the Rheumatology Clinic of Gachon University Gil Medical Center were included in this study. The first BSAS questionnaire was administered at each clinic visit, and the second questionnaire was completed at home within 24 hours of the visit. A Behcet's Disease Current Activity Form (BDCAF) and a Behcet's Disease Quality of Life (BDQOL) form were also given to patients. The test-retest reliability was analyzed by intraclass correlation coefficients (ICC). To assess the validity, the total BSAS score was compared with the BDCAF score, the patient/physician global assessment, and the BDQOL by Spearman rank correlation. RESULTS: Twelve males and 38 females were enrolled. The mean age was 48.5 years and the mean disease duration was 6.7 years. Thirty-eight patients (76.0%) returned the questionnaire by mail. For the test-retest reliability, the two assessments were significantly correlated on all 10 items of the BSAS questionnaire (p < 0.05) and the total BSAS score (ICC, 0.925; p < 0.001). The total BSAS score was statistically correlated with the BDQOL, BDCAF, and patient/physician global assessment (p < 0.01). CONCLUSIONS: The Korean version of BSAS is a reliable and valid instrument to measure BD activity. PMID- 26767872 TI - Successful transcatheter closure of an inferior sinus venosus atrial septal defect. PMID- 26767873 TI - Churg-Strauss syndrome that presented with mediastinal lymphadenopathy and calculous cholecystitis. PMID- 26767874 TI - Diagnosis of cyclic Cushing syndrome using the morning urine free cortisol to creatinine ratio. PMID- 26767875 TI - First Korean case of Emberger syndrome (primary lymphedema with myelodysplasia) with a novel GATA2 gene mutation. PMID- 26767876 TI - Epithelioid sarcoma with spontaneous pneumothorax and massive pleural effusion. PMID- 26767877 TI - Co-existing proteinase 3-antineutrophil cytoplasmic antibody-associated vasculitis with immunoglobulin A nephropathy. PMID- 26767878 TI - Daughter cysts in a cyst of the liver: hepatic echinococcosis. PMID- 26767880 TI - Seven day opening of GP surgeries may not work everywhere, minister tells MPs. PMID- 26767879 TI - A hundred years after the first article, a recollection: Cabot ring. PMID- 26767883 TI - Beetroot juice supplementation reduces the oxygen cost of exercise without improving mitochondrial efficiency: but how? PMID- 26767884 TI - Why we need to understand the mechanics of developing cardiac sarcomeres in humans. PMID- 26767881 TI - Association of Dietary Nitrate Intake With Primary Open-Angle Glaucoma: A Prospective Analysis From the Nurses' Health Study and Health Professionals Follow-up Study. AB - IMPORTANCE: Nitric oxide signaling alterations in outflow facility and retinal blood flow autoregulation are implicated in primary open-angle glaucoma (POAG). Nitric oxide donation has emerged as a POAG therapeutic target. An exogenous source of nitric oxide is dietary nitrates. OBJECTIVE: To evaluate the association between dietary nitrate intake, derived mainly from green leafy vegetables, and POAG. DESIGN, SETTING, AND PARTICIPANTS: We followed up participants biennially in the prospective cohorts of the Nurses' Health Study (63 893 women; 1984-2012) and the Health Professionals Follow-up Study (41 094 men; 1986-2012) at each 2-year risk period. Eligible participants were 40 years or older, were free of POAG, and reported eye examinations. EXPOSURES: The primary exposure was dietary nitrate intake. Information on diet and potential confounders was updated with validated questionnaires. MAIN OUTCOMES AND MEASURES: The main outcome was the incidence of POAG and POAG subtypes; 1483 cases were confirmed with medical records and classified into subtypes defined by intraocular pressure (IOP) (>=22 or <22 mm Hg) or by visual field (VF) loss pattern at diagnosis (peripheral loss only or early paracentral loss). Cohort specific and pooled multivariable rate ratios (MVRRs) and 95% CIs were estimated. RESULTS: During 1 678 713 person-years of follow-up, 1483 incident cases of POAG were identified. The mean (SD) age for the 1483 cases was 66.8 (8.3). Compared with the lowest quintile of dietary nitrate intake (quintile 1: approximately 80 mg/d), the pooled MVRR for the highest quintile (quintile 5: approximately 240 mg/d) was 0.79 (95% CI, 0.66-0.93; P for trend = .02). The dose response was stronger (P for heterogeneity = .01) for POAG with early paracentral VF loss (433 cases; quintile 5 vs quintile 1 MVRR = 0.56; 95% CI, 0.40-0.79; P for trend < .001) than for POAG with peripheral VF loss only (835 cases; quintile 5 vs quintile 1 MVRR = 0.85; 95% CI, 0.68-1.06; P for trend = .50). The association did not differ (P for heterogeneity = .75) by POAG subtypes defined by IOP (997 case patients with IOP >=22 mm Hg: quintile 5 vs quintile 1 MVRR = 0.82; 95% CI, 0.67-1.01; P for trend = .11; 486 case patients with IOP <22 mm Hg: quintile 5 vs quintile 1 MVRR = 0.71; 95% CI, 0.53-0.96; P for trend = .12). Green leafy vegetables accounted for 56.7% of nitrate intake variation. Compared with consuming 0.31 servings per day, the MVRR for consuming 1.45 or more servings per day was 0.82 for all POAG (95% CI, 0.69-0.97; P for trend = .02) and 0.52 for POAG with paracentral VF loss (95% CI, 0.29-0.96; P for trend < .001). CONCLUSIONS AND RELEVANCE: Higher dietary nitrate and green leafy vegetable intake was associated with a lower POAG risk, particularly POAG with early paracentral VF loss at diagnosis. PMID- 26767885 TI - Blockade of calcium entry provides a therapeutic window in acute pancreatitis. PMID- 26767886 TI - The human element: moving beyond animal models to study the neuronal regulation of intestinal electrolyte transport. PMID- 26767887 TI - Considerations for determining human ex vivo submaximal skeletal muscle mitochondrial function. PMID- 26767888 TI - 'Engineering physiology' to understand the post-exercise biochemical milieu: mixing it up with anabolic hormones. PMID- 26767889 TI - Age-dependent effects of bed rest in human skeletal muscle: exercise to the rescue. PMID- 26767890 TI - Velocity and doubling time of prostate-specific antigen: mathematics can matter. AB - Changes in prostate-specific antigen (PSA) values are often reported as velocity or doubling time. We compared the association of these two calculations-at the time of PSA failure after primary treatment for prostate cancer-with prostate cancer mortality. From a source population of 1313 US Veterans with prostate cancer, including 623 treated with curative intent, the study population included 242 men experiencing biochemical failure, 81 after surgery and 161 after radiation therapy. Clinically relevant calculations of PSA velocity (linear slope) and PSA doubling time (logarithmic slope) were assessed for their association with 11-16 years of mortality from prostate cancer. Death due to prostate cancer occurred in 52/242 (21.5%) men. Among men receiving surgery, PSA velocity >=1.0 ng/mL/year was associated with increased prostate cancer mortality (HR=4.2, p value=0.037), whereas doubling time <=12 months did not confer risk (HR=1.0, p value=0.95). Conversely, among patients receiving radiation therapy, doubling time <=12 months was associated with increased prostate cancer mortality (HR=2.4, p value=0.049), but velocity did not confer a statistically significant risk (HR=3.8, p value=0.19). When assessing risk of prostate cancer mortality, PSA velocity can be more predictive after surgery and PSA doubling time can be more predictive after radiation therapy. PMID- 26767891 TI - Fast Assembly of Gold Nanoparticles in Large-Area 2D Nanogrids Using a One-Step, Near-Infrared Radiation-Assisted Evaporation Process. AB - When fabricating photonic crystals from suspensions in volatile liquids using the horizontal deposition method, the conventional approach is to evaporate slowly to increase the time for particles to settle in an ordered, periodic close-packed structure. Here, we show that the greatest ordering of 10 nm aqueous gold nanoparticles (AuNPs) in a template of larger spherical polymer particles (mean diameter of 338 nm) is achieved with very fast water evaporation rates obtained with near-infrared radiative heating. Fabrication of arrays over areas of a few cm(2) takes only 7 min. The assembly process requires that the evaporation rate is fast relative to the particles' Brownian diffusion. Then a two-dimensional colloidal crystal forms at the falling surface, which acts as a sieve through which the AuNPs pass, according to our Langevin dynamics computer simulations. With sufficiently fast evaporation rates, we create a hybrid structure consisting of a two-dimensional AuNP nanoarray (or "nanogrid") on top of a three-dimensional polymer opal. The process is simple, fast, and one-step. The interplay between the optical response of the plasmonic Au nanoarray and the microstructuring of the photonic opal results in unusual optical spectra with two extinction peaks, which are analyzed via finite-difference time-domain method simulations. Comparison between experimental and modeling results reveals a strong interplay of plasmonic modes and collective photonic effects, including the formation of a high-order stopband and slow-light-enhanced plasmonic absorption. The structures, and hence their optical signatures, are tuned by adjusting the evaporation rate via the infrared power density. PMID- 26767892 TI - Accurate determination of screw position in treating fifth metatarsal base fractures to shorten radiation exposure time. AB - INTRODUCTION: Anatomical markers can help to guide lag screw placement during surgery for internal fixation of fifth metatarsal base fractures. This study aimed to identify the optimal anatomical markers and thus reduce radiation exposure. METHODS: A total of 50 patients in Huashan Hospital, Shanghai, China, who underwent oblique foot radiography in the lateral position were randomly selected. The angles between the fifth metatarsal axis and cuboid articular surface were measured to determine the optimal lag screw placement relative to anatomical markers. RESULTS: The line connecting the styloid process of the fifth metatarsal base with the second metatarsophalangeal (MTP) joint intersected with the fifth metatarsal base fracture line at an angle of 86.85 degrees +/- 5.44 degrees . The line connecting the fifth metatarsal base styloid with the third and fourth MTP joints intersected with the fracture line at angles of 93.28 degrees +/- 5.24 degrees and 100.95 degrees +/- 5.00 degrees , respectively. The proximal articular surface of the fifth metatarsal base intersected with the line connecting the styloid process of the fifth metatarsal base with the second, third and fourth MTP joints at angles of 24.02 degrees +/- 4.77 degrees , 30.79 degrees +/- 4.53 degrees and 38.08 degrees +/- 4.54 degrees , respectively. CONCLUSION: The fifth metatarsal base styloid and third MTP joint can be used as anatomical markers for lag screw placement in fractures involving the fifth tarsometatarsal joint. The connection line, which is normally perpendicular to the fracture line, provides sufficient mechanical stability to facilitate accurate screw placement. The use of these anatomical markers could help to reduce unnecessary radiation exposure for patients and medical staff. PMID- 26767896 TI - One-Pot Synthesis of Multifunctional Polymers by Light-Controlled Radical Polymerization and Enzymatic Catalysis with Candida antarctica Lipase B. PMID- 26767893 TI - Benefits of early enteral nutrition in extremely low birth weight infants. AB - INTRODUCTION: Extremely low birth weight (ELBW) infants (i.e. preterm infants weighing < 1,000 g) often present with morphofunctional multiple organ immaturity. This study aimed to determine whether early enteral feeding improves digestive tolerance, and whether there is a difference in growth between ELBW infants who were fed with formula and those who were fed with breast milk. METHODS: This study was conducted from 2012-2013 and involved 34 ELBW infants from the Preterm Neonatology Clinic of the 'Louis Turcanu' Clinical Children's Hospital Timisoara, Romania. Early enteral nutrition was introduced for all the infants - Group I was fed with formula, while Group II was fed with breast milk. Infants in each group were given their designated type of milk (formula/breast milk), using the same feeding method and the same volume rate advancement. They were monitored for any evidence of digestive intolerance (i.e. clinical signs of infection and necrotising enterocolitis [NEC]). Their growth curves and signs of infection were also monitored. RESULTS: The average weight gained per week was greater among the infants in Group II than in Group I (120.83 g vs 97.27 g). The incidence of infection was 100% in Group I and 66.6% in Group II. Two of the infants in Group I developed NEC. CONCLUSION: Early enteral feeding helped to improve the weight of ELBW infants. Breast milk was more effective than formula at improving the weight of these infants. Feeding with formula increased the incidence of NEC, invasive infection and morbidity among ELBW infants. PMID- 26767899 TI - Malignant tumours of the duodenum. AB - No comprehensive knowledge of duodenal tumours exists in the current literature; individual types of malignant tumours may be described within malignancies of the small bowel, sets of case reports, or individual cases. Ampullary carcinomas are the exception and they are detailed in the current WHO histological classification of tumours of digestive system. Neither national nor international literature sources provide a comprehensive review of their therapy. The situation is similar when searching for surgical procedures. Resection procedures on the duodenum should thus be performed in specialized centres with sufficient experience with hepato-pancreato-biliary surgery. PMID- 26767900 TI - [Irreversible electroporation in the treatment of locally advanced pancreatic cancer]. AB - INTRODUCTION: Irreversible electroporation (IRE) is a quite novel method of tissue ablation. Its mechanism of action that does not use thermal energy is the most important feature of the method. Current experience with IRE in animal studies and in clinical practice are summarized in the paper. In particular, the paper is focused on using IRE in locally advanced pancreatic carcinoma. METHOD: The basic principle of IRE is that it causes micropores in the phospholipid membrane of cells. This leads to an impairment of cellular homeostasis and programmed cell death - apoptosis. Because of absence of protein denaturation this method spares tubular structures like vessels and ducts. This is the key feature that allows to use IRE in the pancreas where common thermic ablative procedures cannot be used for difficult anatomic circumstances and resulting injury of surrounding structures. PRE-CLINICAL AND CLINICAL STUDIES: The ability to spare vascular structures and ducts was confirmed in many animal studies. Subsequently, IRE was safely utilized also in human liver, pancreas, lung and kidneys. IRE in the treatment of advanced pancreatic cancer: Most experience with IRE ablation has been gathered for locally advanced pancreatic carcinoma where clinical studies published in the recent 5 years have provided encouraging results. CONCLUSION: Irreversible electroporation is a safe method used to decrease tumour mass in pancreatic cancer. Further studies are needed to determine its therapeutic efficiency. PMID- 26767901 TI - [Surgery of the hiatal hernia and gastroesophageal reflux dinase, Nissen or Toupet?]. AB - INTRODUCTION: In 2016 60 years will have elapsed from the first publication by Nissen about his surgical method of 360 degrees fundoplication around distal esophagus and its final effect. Nissens fundoplication is currently the most common surgical method for the gastroesophageal reflux (GER) and hiatal hernia (HH) probably. Incidence of HH ranges between 25-50% in the western population. Current prevalence of GER ranges between 4-10% in Europe and 5-7% in North America, but some studies report even 10-20%. METHODS: From 2010 to 2015, 157 laparoscopic procedures for HH or gastroesophageal reflux disease (GERD) were done at the Department of Surgery, the Second Faculty of Medicine, Charles University and Central Military Hospital in Prague. Most of the patients were operated because of symptomatic HH with/without GERD. Only very few patients were operated only for GERD without HH. The group of the patients included 73 men and 84 women with the mean age 53.9 years in the range 20-88 years. 11 patients of the group were operated because of the upside-down stomach syndrome. 109 (69.4%) patients underwent Nissens 360 degrees fundoplication (NFP) and 48 (30.6%) patients underwent Toupets 270 degrees fundoplication (TFP). The patients were followed after 3 month, 6 month, 12 month and then once a year after the surgery. Symptoms such as heartburn, dysphagia, belching, bloating or recurrence of HH or GERD were collected prospectively and analyzed retrospectively. Methods of descriptive statistics and explorative unidirectional analysis were used. RESULTS: From 2010 to 2015, 157 laparoscopic procedures were done for HH or GERD. No death occurred in the group of the patients in connection with the surgery. Similar rates of considerable improvement or resolution of the symptoms such as the reflux, heartburn, and epigastric pain were observed after three months from the surgery among patients after NFP or TFP. Postoperative dysphagia resolved in 4-7 weeks in the group after NFP, and in 3-5 weeks in the group after TFP. Disease recurrence was observed in 36 (22.9%) patients in 2 to 5 years after the surgery. Recurrence of only the gastroesophageal reflux without HH was observed in 22 patients (14 after NFP; 8 after TFP), shown by endoscopy or x-ray assessment, with a satisfactory response to PPI medication. Laparoscopic rehiatoplasty and refundoplication according to Nissen were performed in 14 patients with HH recurrence with/without the reflux (8 after NFP; 6 after TFP). CONCLUSION: Laparoscopic antireflux surgery of GERD and HH is safe and is associated with very low perioperative morbidity and minimal morbidity. Both NFP and TFP have a similar effect on restoration of the mechanical gastroesophageal barrier against gastric reflux, with significant effect on resolution of GERD and HH symptoms and with a marked improvement of the patients quality of life. As regards morbid obese patients, weight reduction is needed before the surgery. Hiatoplasty done at the same time with the bariatric procedure is recommended in morbid obese patients with HH indicated for the bariatric-metabolic surgery. PMID- 26767902 TI - [Bile leakage after liver resection: A retrospective cohort study]. AB - INTRODUCTION: Many previous reports have focused on bile leakage after liver resection. Despite the improvements in surgical techniques and perioperative care the incidence of this complication rather keeps increasing. A number of predictive factors have been analyzed. There is still no consensus regarding their influence on the formation of bile leakage. The objective of our analysis was to evaluate the incidence of bile leakage, its impact on mortality and duration of hospitalization at our department. At the same time, we conducted an analysis of known predictive factors. METHOD: The authors present a retrospective review of the set of 146 patients who underwent liver resection at the Department of Surgery of the 2nd Faculty of Medicine of the Charles University and Central Military Hospital Prague, performed between 20102013. We used the current ISGLS (International Study Group of Liver Surgery) classification to evaluate the bile leakage. The severity of this complication was determined according to the Clavien-Dindo classification system. Statistical significance of the predictive factors was determined using Fishers exact test and Students t-test. RESULTS: The incidence of bile leakage was 21%. According to ISGLS classification the A, B, and C rates were 6.5%, 61.2%, and 32.3%, respectively. The severity of bile leakage according to the Clavien-Dindo classification system - I-II, IIIa, IIIb, IV and V rates were 19.3%, 42%, 9.7%, 9.7%, and 19.3%, respectively. We determined the following predictive factors as statistically significant: surgery for malignancy (p<0.001), major hepatic resection (p=0.001), operative time (p<0.001), high intraoperative blood loss (p=0.02), construction of HJA (p=0.005), portal venous embolization/two-stage surgery (p=0.009) and ASA score (p=0.02). Bile leakage significantly prolonged hospitalization time (p<0.001). In the group of patients with bile leakage the perioperative mortality was 23 times higher (p<0.001) than in the group with no leakage. CONCLUSION: Bile leakage is one of the most serious complications of liver surgery. Most of the risk factors are not easily controllable and there is no clear consensus on their influence. Intraoperative leak tests could probably reduce the incidence of bile leakage. In the future, further studies will be required to improve the perioperative management and techniques to prevent such serious complications. Multidisciplinary approach is essential in the treatment. PMID- 26767903 TI - ["Liver fist approach" in the management of synchronous liver metastases from colorectal cancer: Preliminary non-randomized study results]. AB - INTRODUCTION: Liver metastases are diagnosed in 60% of patients with colorectal cancer, both at the time of diagnosis or later in the course of their management. Surgical treatment is the sole potentially curable method with 5-year overall survival of approximately 50%. However, only less than 20% of patients underwent liver resection. A joint effort of medical oncologists and surgeons is to increase the numbers of resected patients. The "liver first approach" (LFA) is one of approaches aimed at increasing resecability. The authors present their preliminary results using this method. METHODS: 102 patients were included in the multicentre study supported by the grant IGA NT 13660 Evaluation of quality of multimodal treatment for patients with colorectal cancer liver metastases - conducted at the Central Military Hospital between September 2012 and January 2015. We used LFA in 12 patients (12%). Patients were indicated for liver resection based on good response to neoadjuvant systemic therapy. Multiple bilobar liver involvement (>4 metastases) was present in 11 cases and one large solitary metastasis in the right liver lobe in one case. The primary tumor was located in the rectum in 9 patients, in the rectosigmoid in 3 patients; 3 patients had a colostomy. Others showed no signs of bowel obstruction. RESULTS: We have performed R0 resections in 11 cases, and two-stage hepatectomy with portal vein embolisation was indicated 3 times (in one case we did not finish the second stage due to quick progression after PVE). We performed major resections 7 times, along with sever extraanatomic resections, incl. 11 RFA (6 times in combination with major resections). Perioperative mortality was 0%, morbidity 33% (Dindo-Clavien >2). Ten patients underwent adjuvant chemotherapy, in 7 cases including radiotherapy of the small pelvis due to a local advanced primary tumor. Resection of the primary tumor was done in 7 patients (58%). Two patients died recently because of disease progression (17%); progression was observed in 6 patients (50%). CONCLUSION: We deem the LFA suitable especially for patients with metastatic rectal tumors where adjuvant systemic therapy can be combined with radiotherapy. The timing of the resection of the primary tumor still remains a question: it is necessary to rule out potential recurrence of liver metastases, which affected more than 50% of the patients. The benefit of LFA must be confimed by randomised studies. PMID- 26767904 TI - [Da Vinci assisted surgery for rectal cancer - preliminary results of nonrandomized trial]. AB - INTRODUCTION: The incidence of colorectal cancer (CRC) in the Czech Republic is reported to be one of the highest on the global scale. Radical tumor removal has been observed to be the most effective part in the context of current multimodal therapy. The authors present their preliminary results of robotic assisted treatment of rectal carcinoma (RC). METHOD: The observed group includes 61 patients who underwent robotic assisted treatment for rectal cancer. The data were collected prospectively in the last 31 patients. Analyses were conducted on epidemiological data, perioperative outcomes, complications and oncological results. RESULTS: Robotic assisted treatment of RC was performed in 61 patients: 34 men and 27 women, mean age of 62 years (33-80). Neoadjuvant oncological treatment was indicated in 46% of the patients. Average blood loss was 187 ml, transfusions were administered in three cases. Conversion to open procedure was performed 6 times, and 16 patients had postoperative complications. Anastomotic leak was observed in 10% of the patients, and 4 patients undewent surgical treatment. No patient died. Local recurrence of the cancer was diagnosed in 3 (5%) patients. The quality of mesorectal excision (ME) and the circumferential resection margin [(y)pCRM] have been determined in 27 patients since 2013. Positive (y)pCRM was recorded in two cases and incomplete ME was observed in 25.8% of the patients. CONCLUSION: Surgical treatment for RC is pivotal in multimodal therapy. Our preliminary results are similar to the conclusions in other published studies. The da Vinci robotic system is a safe manipulator in the treatment of RC and provides indisputable benefits to the surgeon when operating in the narrow pelvic space. However, the benefits of robotic treatment in abdominal surgery are yet to be evaluated in patients (with respect to long-term results, sufficient number of patients or a high EBM level of evidence). The high purchase price of the robotic device, individual instruments with equipment and non-systemic compensation constitute a significant hindrance that prevents wider use of the robotic system in the treatment of RC and other abdominal malignancies in the Czech Republic. PMID- 26767905 TI - [Urgent surgical treatment of gastric volvulus related to upside-down stomach syndrome]. AB - Upside-down stomach syndrome is a rare type of a large paraoesophageal hiatal hernia, which requires an immediate surgical treatment in case of incarceration. The authors present a case report of a 53-year-old male patient with gastric volvulus related to the upside-down stomach syndrome. Surgical treatment was complicated by an injury to distal oesophagus, which was successfully treated using a self-expandable metallic stent among other methods. Despite the complicated postoperative course with a necessity of reoperation, insertion of an oesophageal stent, thoracotomy for a mediastinal abscess and secondary healing of the laparotomy, the patient was discharged in a good condition with healed oesophageal perforation and laparotomy after 52 days. PMID- 26767906 TI - [Rare situations in treatment of polytraumatised patients - case reports]. AB - Polytrauma is one of the leading causes of mortality in people at productive age. Prompt activation of the rescue system is most important in the treatment. In cases of severe injuries, primary transport to a specialized hospital - trauma center is crucial. Our report is focused on two cases of polytraumatized patients whose treatment was associated with relatively rare situations. One of the patients suffered a pancreatic injury that required pancreaticoduodenectomy. The other patient had a liver injury, which was treated with right lobectomy with a rare complication. The necessity of a multidisciplinary approach to the management of severely injured patients is also emphasized in our report. PMID- 26767907 TI - Reading Test-Sentence Comprehension: An Adapted Version of Lobrot's Lecture 3 Test for Brazilian Portuguese. AB - Our aim was to analyse the linguistic structure of the Lobrot's Lecture 3 (L3) reading test and to describe the procedure for its adaptation to a Brazilian cultural-linguistic context. The resulting adapted version is called the Reading Test-Sentence Comprehension [Teste de Leitura: Compreensao de Sentencas (TELCS)] and was developed using the European Portuguese adaptation of L3 as a reference. The present study was conducted in seven steps: (1) classification of the response alternatives of L3 test; (2) adaptation of the original sentences into Brazilian Portuguese; (3) back-translation; (4) adaptation of the distractors from TELCS; (5) configuration of TELCS; (6) pilot study; and (7) validation and standardization. In comparison with L3, TELCS included new linguistic and structural variables, such as frequency of occurrence of the distractors, gender neutrality and position of the target words. The instrument can be used for a collective screening or individual clinical administration purposes to evaluate the reading ability of second-to-fifth-grade and 7-to-11-year-old students. PMID- 26767909 TI - Editorial: Biotechnology Journal - we are looking forward to a new decade. PMID- 26767911 TI - Sex-specific survival to maturity and the evolution of environmental sex determination. AB - Four decades ago, it was proposed that environmental sex determination (ESD) evolves when individual fitness depends on the environment in a sex-specific fashion--a form of condition-dependent sex allocation. Many biological processes have been hypothesized to drive this sex asymmetry, yet a general explanation for the evolution of sex-determining mechanisms remains elusive. Here, we develop a mathematical model for a novel hypothesis of the evolution of ESD, and provide a first empirical test using data across turtles. ESD is favored when the sex determining environment affects annual survival rates equivalently in males and females, and males and females mature at different ages. We compare this hypothesis to alternative hypotheses, and demonstrate how it captures a crucially different process. This maturation process arises naturally from common life histories and applies more broadly to condition-dependent sex allocation. Therefore, it has widespread implications for animal taxa. Across turtle species, ESD is associated with greater sex differences in the age at maturity compared to species without ESD, as predicted by our hypothesis. However, the effect is not statistically significant and will require expanded empirical investigation. Given variation among taxa in sex-specific age at maturity, our survival-to maturity hypothesis may capture common selective forces on sex-determining mechanisms. PMID- 26767917 TI - Pressure ulcers in trauma patients with suspected spine injury: a prospective cohort study with emphasis on device-related pressure ulcers. AB - Of all patients in a hospital environment, trauma patients may be particularly at risk for developing (device-related) pressure ulcers (PUs), because of their traumatic injuries, immobility, and exposure to immobilizing and medical devices. Studies on device-related PUs are scarce. With this study, the incidence and characteristics of PUs and the proportion of PUs that are related to devices in adult trauma patients with suspected spinal injury were described. From January December 2013, 254 trauma patients were visited every 2 days for skin assessment. The overall incidence of PUs was 28.3% (n = 72/254 patients). The incidence of device-related PUs was 20.1% (n = 51), and 13% (n = 33) developed solely device related PUs. We observed 145 PUs in total of which 60.7% were related to devices (88/145). Device-related PUs were detected 16 different locations on the front and back of the body. These results show that the incidence of PUs and the proportion of device-related PUs is very high in trauma patients. PMID- 26767918 TI - Multiple endocrine neoplasia type 1 (MEN1): An update of 208 new germline variants reported in the last nine years. AB - This review will focus on the germline MEN1 mutations that have been reported in patients with MEN1 and other hereditary endocrine disorders from 2007 to September 2015. A comprehensive review regarding the analysis of 1336 MEN1 mutations reported in the first decade following the gene's identification was performed by Lemos and Thakker in 2008. No other similar papers are available in literature apart from these data. We also checked for the list of Locus-Specific DataBases (LSDBs) and we found five MEN1 free-online mutational databases. 151 articles from the NCBI PubMed literature database were read and evaluated and a total of 75 MEN1 variants were found. On the contrary, 67, 22 and 44 novel MEN1 variants were obtained from ClinVar, MEN1 at Cafe Variome and HGMD (The Human Gene Mutation Database) databases respectively. A final careful analysis of MEN1 mutations affecting the coding region was performed. PMID- 26767920 TI - Universal Adhesives. PMID- 26767919 TI - Digitally guided microdissection aids somatic mutation detection in difficult to dissect tumors. AB - Molecular genetic testing on formalin fixed, paraffin embedded (FFPE) tumors frequently requires dissection of tumor from tissue sections mounted on glass slides. In a process referred to as "manual macrodissection," the pathologist reviews an H&E stained slide at the light microscope and marks areas for dissection, and then the laboratory performs manual dissection from adjacent sections without the aid of a microscope, using the marked reference H&E slide as a guide. Manual macrodissection may be inadequate for tissue sections with low tumor content. We compared manual macrodissection to a new method, digitally guided microdissection, on a series of 32 FFPE pancreatic cancer samples. KRAS hotspot mutation profiling was performed using the Sequenom MassARRAY system (Agena Bioscience). Digitally guided microdissection was performed on multiple smaller areas of high tumor content selected from within the larger areas marked for manual macrodissection. The KRAS mutant allele fraction and estimated neoplastic cellularity were significantly higher in samples obtained by digitally guided microdissection (p < 0.01), and 7 of the 32 samples (22%) showed a detectable mutation only with digitally guided microdissection. DNA quality and yield per cubic millimeter of dissected tissue were similar for both dissection methods. These results indicate a significant improvement in tumor content achievable with digitally guided microdissection. PMID- 26767927 TI - ERRATUM. PMID- 26767921 TI - Baseline predictors of treatment gains in peak propulsive force in individuals poststroke. AB - BACKGROUND: Current rehabilitation for individuals poststroke focuses on increasing walking speed because it is an indicator of community walking ability and quality of life. Propulsive force generated from the paretic limb is critical to walking speed and may reflect actual neural recovery that restores the affected neural systems. A wide variation across individuals in the improvements in paretic propulsive force was observed following an intervention that targeted paretic propulsive force. This study aimed to determine if specific baseline characteristics can be used to predict patients who would respond to the intervention. METHODS: Participants (N = 19) with chronic poststroke hemiparesis walked at their self-selected and maximal walking speeds on a treadmill before and after a 12-week gait training program. Propulsive forces from the paretic limb were analyzed. Pearson correlation coefficient was used to determine the relationships between (1) treatment gains in walking speed and propulsive force following intervention, and (2) treatment gains in propulsive force and baseline propulsive forces. RESULTS: Treatment gains in self-selected walking speed were correlated to treatment gains in paretic propulsive force following intervention. In addition, changes in paretic propulsive force between self-selected and maximal walking speeds at baseline were strongly correlated to treatment gains in paretic propulsive force. CONCLUSIONS: The capacity to modulate paretic propulsive force, rather than the absolute propulsive force during self-selected or maximal walking speed, predicted treatment gains in propulsive force following the intervention. Findings from this research could help to inform clinicians and researchers to target the appropriate patient population for rehabilitation interventions. PMID- 26767924 TI - Light-Mediated Activation of siRNA Release in Diblock Copolymer Assemblies for Controlled Gene Silencing. PMID- 26767929 TI - Beyond the Big Bang: searching for meaning in contemporary physics. PMID- 26767928 TI - Uncertain for a century: quantum mechanics and the dilemma of interpretation. AB - Quantum mechanics, the physical theory describing the microworld, is one of science's greatest triumphs. Remarkably, however, after more than 100 years it is still unclear what quantum mechanics means in terms of basic philosophical questions about the nature of reality. While there are many interpretations of the mathematical machinery of quantum physics, there remain no experimental means to distinguish between most of them. In this contribution, I wish to consider the ways in which the enduring lack of an agreed-upon interpretation of quantum physics influences a number of critical philosophical debates about physics and reality. I briefly review two problems affected by quantum interpretations: the meaning of the term universe and the nature of consciousness. PMID- 26767930 TI - Beyond the Big Bang: searching for meaning in contemporary physics. PMID- 26767931 TI - Periocular Mohs micrographic surgery in Western Australia 2009-2012: A single centre retrospective review and proposal for practice benchmarks. AB - BACKGROUND/OBJECTIVES: Periocular skin tumours pose management challenges with literature supporting a multidisciplinary approach. This retrospective review identifies trends in multidisciplinary management, ascertaining potential benchmarks for practice review. METHODS: A retrospective review of 720 patients with periocular tumours, treated with Mohs micrographic surgery (MMS) at a single free standing Day Surgery Facility between 2009 and 2012. RESULTS: In all, 690 patients were included, with mean age 65 and slight male preponderance. Basal cell carcinoma was the most commonly excised tumour (85.4%) and lower eyelid most common tumour site (58%). Of the cases repaired by Mohs surgeons, 2% involved more than one cosmetic subunit, compared with 23% by oculoplastic surgeons. Of the cases repaired by MMS, 1% had eyelid margin involvement, compared with 64% of the cases by oculoplastic surgeons. Mean preoperative lesion size for cases repaired by Mohs and oculoplastic surgeons was 0.5 cm2 . Mean postoperative defect size was smaller for cases repaired by Mohs surgeons compared with oculoplastic surgeons (1.5 and 1.9 cm2 ). Mean number of stages was less for Mohs surgeon repairs (n = 1.5) compared with oculoplastic surgeon repairs (n = 1.9). Cases repaired by oculoplastic surgeons were more often combination repairs. CONCLUSIONS: This study identifies potential benchmarks for Mohs surgeons when reviewing or establishing a periocular Mohs surgery practice and for doctors referring periocular tumours for surgical removal. These include the proportion of periocular cases managed jointly and the location, size of defect and number of stages involved in tumors repaired by Mohs surgeon alone compared to those repaired by oculoplastic surgeons. PMID- 26767932 TI - Arthroscopic, Computed Tomography, and Radiographic Findings in 25 Dogs With Lameness After Arthroscopic Treatment of Medial Coronoid Disease. AB - OBJECTIVE: To describe the radiographic, computed tomography (CT), and arthroscopic findings in the elbow of dogs admitted for elbow lameness after previous arthroscopic treatment of medial coronoid disease (MCD). STUDY DESIGN: Retrospective case series. ANIMALS: Client-owned dogs (n = 25) admitted for elbow lameness after arthroscopic treatment. METHODS: Clinical records (2005-2009), including radiographs, CT images, and arthroscopic findings, from the first and second presentation of dogs diagnosed with medial coronoid disease were searched and reviewed. RESULTS: Twenty-nine joints were included in this study. The mean age at first treatment was 2.2 years. Second presentation was at a mean of 2.7 years later and progressive osteoarthritis and cartilage damage was noticed in all joints. Arthroscopic findings included a calcified body in 11/29 joints (38%), multiple small calcified bodies in 1/29 joint (3%), loose scar tissue in 12/29 joints (42%), and immobile scar tissue in 2/29 joints (7%). Three of 29 joints (10%) did not have any calcified body or loose scar tissue found but had erosion of the medial compartment as the only pathology diagnosed in the coronoid region. Characteristics of flexor enthesopathy were identified in 9/29 joints (31%). CONCLUSION: Arthroscopic treatment of MCD, even with limited cartilage lesions, may not resolve lameness in some dogs. Calcified bodies or loose scar tissue near the medial coronoid process are a frequent followup finding in these joints. PMID- 26767937 TI - The effects of facial expressions and tears on the speed of sex recognition. AB - The goal of this research was to examine the effects of facial expressions on the speed of sex recognition. Prior research revealed that sex recognition of female angry faces was slower compared with male angry faces and that female happy faces are recognized faster than male happy faces. We aimed to replicate and extend the previous research by using different set of facial stimuli, different methodological approach and also by examining the effects of some other previously unexplored expressions (such as crying) on the speed of sex recognition. In the first experiment, we presented facial stimuli of men and women displaying anger, fear, happiness, sadness, crying and three control conditions expressing no emotion. Results showed that sex recognition of angry females was significantly slower compared with sex recognition in any other condition, while sad, crying, happy, frightened and neutral expressions did not impact the speed of sex recognition. In the second experiment, we presented angry, neutral and crying expressions in blocks and again only sex recognition of female angry expressions was slower compared with all other expressions. The results are discussed in a context of perceptive features of male and female facial configuration, evolutionary theory and social learning context. PMID- 26767938 TI - Coagulopathy of sepsis from nonspecific inhibitors. PMID- 26767933 TI - 2015 Guidance on cancer immunotherapy development in early-phase clinical studies. AB - The development of cancer immunotherapies is progressing rapidly with a variety of technological approaches. They consist of "cancer vaccines", which are based on the idea of vaccination, "effector cell therapy", classified as passive immunotherapy, and "inhibition of immunosuppression", which intends to break immunological tolerance to autoantigens or immunosuppressive environments characterizing antitumor immune responses. Recent reports showing clinical evidence of efficacy of immune checkpoint inhibitors and adoptive immunotherapies with tumor-infiltrating lymphocytes and tumor-specific receptor gene-modified T cells indicate the beginning of a new era for cancer immunotherapy. This guidance summarizes ideas that will be helpful to those who plan to develop cancer immunotherapy. The aims of this guidance are to discuss and offer important points in early phase clinical studies of innovative cancer immunotherapy, with future progress in this field, and to contribute to the effective development of cancer immunotherapy aligned with the scope of regulatory science. This guidance covers cancer vaccines, effector cell therapy, and inhibition of immunosuppression, including immune checkpoint inhibitors. PMID- 26767941 TI - Cost-effectiveness of multisystemic therapy versus usual treatment for young people with antisocial problems. AB - BACKGROUND: Behavioural problems are common among adolescents. The burden on society in social disturbance, health, failures to contribute and costs has triggered innovative community-based interventions such as multisystemic therapy (MST). AIMS: Our aim was to compare the cost-effectiveness of MST and treatment as usual (TAU). METHODS: Cost-effectiveness was assessed alongside a randomised clinical trial. One hundred and sixteen adolescents were allocated to MST or TAU. Follow-up lasted six months. Quality of life (EQ-5D) as perceived by the adolescents was the primary outcome. A societal perspective was used for cost assessment. RESULTS: There was no significant difference between groups in the small improvement experienced in quality of life (EQ-5D average score improvement in both 0.02 points, standard deviation 0.13 MST; 0.23 TAU). Dropout before follow-up was 48% and 69% respectively. Overall costs attributed to these young people were, however, 50% lower in the MST group. The incremental cost effectiveness ratio (ICER) was 384,633? (95% CI: -2,001,433 to 2,024,681?), which indicates dominance of MST over TAU. CONCLUSIONS/IMPLICATIONS FOR PRACTICE: Our study shows that, at worst, MST offers no advantage to young offenders in terms of their experienced quality of life, but 'TAU' included family focused intervention as well as standard supervision. There were some cost advantages for the individual and his/her family in the MST group, but substantial cost benefits for wider society. The case for a large, multi-centre, perhaps international trial is strong as widespread implementation of MST would benefit everyone if these findings are confirmed. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26767942 TI - In vitro metabolism study of a black market product containing SARM LGD-4033. AB - Anabolic agents are often used by athletes to enhance their performance. However, use of steroids leads to considerable side effects. Non-steroidal selective androgen receptor modulators (SARMs) are a novel class of substances that have not been approved so far but seem to have a more favourable anabolic/androgenic ratio than steroids and produce fewer side effects. Therefore the use of SARMs has been prohibited since 2008 by the World Anti-Doping Agency (WADA). Several of these SARMs have been detected on the black market. Metabolism studies are essential to identify the best urinary markers to ensure effective control of emerging substances by doping control laboratories. As black market products often contain non-pharmaceutical-grade substances, alternatives for human excretion studies are needed to elucidate the metabolism. A black market product labelled to contain the SARM LGD-4033 was purchased over the Internet. Purity verification of the black market product led to the detection of LGD-4033, without other contaminants. Human liver microsomes and S9 liver fractions were used to perform phase I and phase II (glucuronidation) metabolism studies. The samples of the in vitro metabolism studies were analyzed by gas chromatography (tandem) mass spectrometry (GC-MS(/MS)), liquid chromatography-high resolution tandem mass spectrometry (LC-(HR)MS/MS). LC-HRMS product ion scans allowed to identify typical fragment ions for the parent compound and to further determine metabolite structures. In total five metabolites were detected, all modified in the pyrrolidine ring of LGD-4033. The metabolic modifications ranged from hydroxylation combined with keto-formation (M1) or cleavage of the pyrrolidine ring (M2), hydroxylation and methylation (M3/M4) and dihydroxylation (M5). The parent compound and M2 were also detected as glucuronide-conjugates. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26767943 TI - Upregulation of cortico-cerebellar functional connectivity after motor learning. AB - Interactions between the cerebellum and primary motor cortex are crucial for the acquisition of new motor skills. Recent neuroimaging studies indicate that learning motor skills is associated with subsequent modulation of resting-state functional connectivity in the cerebellar and cerebral cortices. The neuronal processes underlying the motor-learning-induced plasticity are not well understood. Here, we investigate changes in functional connectivity in source reconstructed electroencephalography (EEG) following the performance of a single session of a dynamic force task in twenty young adults. Source activity was reconstructed in 112 regions of interest (ROIs) and the functional connectivity between all ROIs was estimated using the imaginary part of coherence. Significant changes in resting-state connectivity were assessed using partial least squares (PLS). We found that subjects adapted their motor performance during the training session and showed improved accuracy but with slower movement times. A number of connections were significantly upregulated after motor training, principally involving connections within the cerebellum and between the cerebellum and motor cortex. Increased connectivity was confined to specific frequency ranges in the mu- and beta-bands. Post hoc analysis of the phase spectra of these cerebellar and cortico-cerebellar connections revealed an increased phase lag between motor cortical and cerebellar activity following motor practice. These findings show a reorganization of intrinsic cortico-cerebellar connectivity related to motor adaptation and demonstrate the potential of EEG connectivity analysis in source space to reveal the neuronal processes that underpin neural plasticity. PMID- 26767944 TI - Congenital blindness is associated with large-scale reorganization of anatomical networks. AB - Blindness is a unique model for understanding the role of experience in the development of the brain's functional and anatomical architecture. Documenting changes in the structure of anatomical networks for this population would substantiate the notion that the brain's core network-level organization may undergo neuroplasticity as a result of life-long experience. To examine this issue, we compared whole-brain networks of regional cortical-thickness covariance in early blind and matched sighted individuals. This covariance is thought to reflect signatures of integration between systems involved in similar perceptual/cognitive functions. Using graph-theoretic metrics, we identified a unique mode of anatomical reorganization in the blind that differed from that found for sighted. This was seen in that network partition structures derived from subgroups of blind were more similar to each other than they were to partitions derived from sighted. Notably, after deriving network partitions, we found that language and visual regions tended to reside within separate modules in sighted but showed a pattern of merging into shared modules in the blind. Our study demonstrates that early visual deprivation triggers a systematic large scale reorganization of whole-brain cortical-thickness networks, suggesting changes in how occipital regions interface with other functional networks in the congenitally blind. PMID- 26767945 TI - FTO gene variant modulates the neural correlates of visual food perception. AB - Variations in the fat mass and obesity associated (FTO) gene are currently the strongest known genetic factor predisposing humans to non-monogenic obesity. Recent experiments have linked these variants to a broad spectrum of behavioural alterations, including food choice and substance abuse. Yet, the underlying neurobiological mechanisms by which these genetic variations influence body weight remain elusive. Here, we explore the brain structural substrate of the obesity-predisposing rs9939609 T/A variant of the FTO gene in non-obese subjects by means of multivariate classification and use fMRI to investigate genotype specific differences in neural food-cue reactivity by analysing correlates of a visual food perception task. Our findings demonstrate that MRI-derived measures of morphology along middle and posterior fusiform gyrus (FFG) are highly predictive for FTO at-risk allele carriers, who also show enhanced neural responses elicited by food cues in the same posterior FFG area. In brief, these findings provide first-time evidence for FTO-specific differences in both brain structure and function already in non-obese individuals, thereby contributing to a mechanistic understanding of why FTO is a predisposing factor for obesity. PMID- 26767947 TI - Neuroanatomical assessment of the impact of negative emotion on implicit memory in patients with obsessive compulsive disorder. AB - OBJECTIVE: We performed functional magnetic resonance imaging (fMRI) to discriminate the differential brain activation patterns in patients with obsessive compulsive disorder (OCD) and healthy controls during implicit retrieval tasks with emotionally neutral and unpleasant words. METHODS: Sixteen patients with OCD (mean age: 31.4+/-10.1 years) and 16 healthy controls (mean age: 32.6+/-5.8 years) with no history of neurological or psychiatric illness underwent 3-T fMRI. The stimulation paradigm consisted of the following cycle: rest, encoding of a string of two-syllable words, rest, and retrieval of the previously encoded words with the first consonant omitted. RESULTS: During the implicit retrieval task with emotionally neutral words, no distinct brain activity was observed in either the patients with OCD or healthy controls. On the other hand, during the retrieval task with unpleasant words, the patients with OCD showed predominant activity in the superior/middle temporal pole, medial superior frontal gyrus, and orbitofrontal cortex (uncorrected p<0.001, extent threshold: 30 voxels), whereas the healthy controls did not show any distinct regions of activation. CONCLUSION: This study revealed the differential brain activation patterns between patients with OCD and healthy controls during implicit memory tasks with unpleasant words. Our results suggest that the impact of negative emotion on implicit memory task may be associated with the symptomatology of OCD. This finding may be helpful for understanding the neural mechanisms that underlie implicit memory retrieval, particularly the interaction between emotion and cognition, in patients with OCD. PMID- 26767948 TI - ERbeta up-regulation was involved in silibinin-induced growth inhibition of human breast cancer MCF-7 cells. AB - We previously reported that silibinin induced a loss of cell viability in breast cancer (MCF-7) cells by ERalpha down-regulation. But whether this cytotoxicity depends on another estrogen receptor, ERbeta, has yet to be elucidated. Therefore, we sought to explore the effects of ERbeta modulation on cell viability by using an ERbeta-selective agonist (Diarylprepionitrile, DPN) and an antagonist (PHTPP). Our data demonstrated that ERbeta served as a growth suppressor in MCF-7 cells, and the incubation of silibinin, elevated ERbeta expression, resulting in the tumor growth inhibition. The cytotoxic effect of silibinin was diminished by PHTPP and enhanced by DPN. Silencing of ERbeta by siRNA confirmed these results. Apoptotic cascades, including the sequential activation of caspase-9 and -6, and finally the cleavage of caspase substrates, PARP and ICAD, caused by treatment with silibinin, were all repressed by PHTPP pre-treatment but exacerbated by DPN. Unlike ERalpha, ERbeta did not involve autophagic process in the regulation, since neither autophagic inhibitor (3-MA) nor the inducer (rapamycin) affected the cell survival rates regardless ERbeta activity. Taken together, silibinin induced apoptosis through mitochondrial pathway by up-regulating ERbeta pathways in MCF-7 cells without the involvement of autophagy. PMID- 26767946 TI - Decoding negative affect personality trait from patterns of brain activation to threat stimuli. AB - INTRODUCTION: Pattern recognition analysis (PRA) applied to functional magnetic resonance imaging (fMRI) has been used to decode cognitive processes and identify possible biomarkers for mental illness. In the present study, we investigated whether the positive affect (PA) or negative affect (NA) personality traits could be decoded from patterns of brain activation in response to a human threat using a healthy sample. METHODS: fMRI data from 34 volunteers (15 women) were acquired during a simple motor task while the volunteers viewed a set of threat stimuli that were directed either toward them or away from them and matched neutral pictures. For each participant, contrast images from a General Linear Model (GLM) between the threat versus neutral stimuli defined the spatial patterns used as input to the regression model. We applied a multiple kernel learning (MKL) regression combining information from different brain regions hierarchically in a whole brain model to decode the NA and PA from patterns of brain activation in response to threat stimuli. RESULTS: The MKL model was able to decode NA but not PA from the contrast images between threat stimuli directed away versus neutral with a significance above chance. The correlation and the mean squared error (MSE) between predicted and actual NA were 0.52 (p-value=0.01) and 24.43 (p value=0.01), respectively. The MKL pattern regression model identified a network with 37 regions that contributed to the predictions. Some of the regions were related to perception (e.g., occipital and temporal regions) while others were related to emotional evaluation (e.g., caudate and prefrontal regions). CONCLUSION: These results suggest that there was an interaction between the individuals' NA and the brain response to the threat stimuli directed away, which enabled the MKL model to decode NA from the brain patterns. To our knowledge, this is the first evidence that PRA can be used to decode a personality trait from patterns of brain activation during emotional contexts. PMID- 26767949 TI - PHLPP2 down regulation influences nuclear Nrf2 stability via Akt-1/Gsk3beta/Fyn kinase axis in acetaminophen induced oxidative renal toxicity: Protection accorded by morin. AB - NF-E2 p45-related factor 2 (Nrf2) is a cap 'n' collar (CNC) basic region-leucine zipper (bZIP) transcription factor that imparts cellular defence against xenobiotic and oxidative stress evoked responses by inducing an array of cytoprotective genes. Essential factors that regulate Nrf2 activity and stability during analgesic nephropathy are incompletely understood. In this study, we demonstrate that acetaminophen (a classic analgesic) posit nephrotoxicity both in vitro and in vivo via PHLPP2 activation. Enhanced PHLPP2 levels down regulate p Akt by dephosphorylating it at Ser 473 residue leading to Gsk3beta activation. APAP subsided Nrf2 nuclear accumulation by activating Gsk3beta which phosphorylates Fyn kinase. p-Fyn kinase translocates into the nucleus and phosphorylates Nrf2 (Tyr 568) leading to its nuclear export, ubiquitination and degradation. Therefore, poor prognosis prevails during analgesic nephrotoxicity because of the defects in Akt-1/Gsk3beta/Fyn-Nrf2 signaling pathway. Morin, a bioflavonoid given as co- and pre-treatment with acetaminophen significantly prevented the toxicity induced damage by constitutively stabilizing Nrf2 nuclear retention. Diminished Nrf2 levels by APAP overdose imposed severe proximal tubular damage leading to apoptotic cell death. Morin, as a potent Nrf2 inducer accorded protection against acetaminophen induced renal damages by its molecular intervention with Akt-1/Gsk3beta/Fyn kinase pathway via PHLPP2 de-activation. PMID- 26767951 TI - L-Tryptophan-kynurenine pathway enzymes are therapeutic target for neuropsychiatric diseases: Focus on cell type differences. AB - The kynurenine pathway (KP) is the major route for tryptophan (TRP) metabolism in most mammalian tissues. The KP metabolizes TRP into a number of neuroactive metabolites, such as kynurenine (KYN), kynurenic acid (KYNA), 3-hydroxykynurenine (3-HK), and quinolinic acid (QUIN). Elevated metabolite concentrations in the central nervous system are associated with the pathophysiology of several inflammation-related neuropsychiatric diseases. During an inflammatory response, the initial KP metabolic step is primarily regulated by indoleamine 2,3 dioxygenase 1 (IDO1), which produces KYN from TRP. Following this initial step, the KP has 2 distinct branches; one branch is regulated by kynurenine 3 monooxygenase (KMO) and is primarily responsible for the 3-HK and QUIN production, and the other branch is regulated by kynurenine aminotransferase (KAT), which produces KYNA, an N-methyl-d-aspartate receptor and alpha-7 nicotinic acetylcholine receptor antagonist. Unbalanced KP metabolism has been demonstrated in distinct neuropsychiatric diseases; thus, understanding the mechanisms that regulate KP enzyme expression and activity is important. These enzymes are expressed by specific cell types, and the induction of enzyme expression by inflammatory stimuli also shows cell type specificity. This review provides an overview and discusses the current understanding of the influence of KP enzyme expression and activity in different cell types on the pathophysiological mechanisms of specific neuropsychiatric diseases. Moreover, the potential use of KP enzyme inhibition as a therapeutic strategy for treating neurological diseases is briefly discussed. This article is part of the Special Issue entitled 'The Kynurenine Pathway in Health and Disease'. PMID- 26767950 TI - Broad spectrum immunomodulation using biomimetic blood cell margination for sepsis therapy. AB - Sepsis represents a systemic inflammatory response caused by microbial infection in blood. Herein, we present a novel comprehensive approach to mitigate inflammatory responses through broad spectrum removal of pathogens, leukocytes and cytokines based on biomimetic cell margination. Using a murine model of polymicrobial sepsis induced by cecal ligation and puncture (CLP), we performed extracorporeal blood filtration with the developed microfluidic blood margination (MUBM) device. Circulating bacteremia, leukocytes and cytokines in blood decreased post-filtration and significant attenuation of immune cell and cytokine responses were observed 3-5 days after intervention, indicating successful long term immunomodulation. A dose-dependent effect on long-term immune cell count was also achieved by varying filtration time. As proof of concept for human therapy, the MUBM device was scaled up to achieve ~100-fold higher throughput (~150 mL h( 1)). With further multiplexing, the MUBM technique could be applied in clinical settings as an adjunctive treatment for sepsis and other inflammatory diseases. PMID- 26767952 TI - Increasing brain angiotensin converting enzyme 2 activity decreases anxiety-like behavior in male mice by activating central Mas receptors. AB - Over-activation of the brain renin-angiotensin system (RAS) has been implicated in the etiology of anxiety disorders. Angiotensin converting enzyme 2 (ACE2) inhibits RAS activity by converting angiotensin-II, the effector peptide of RAS, to angiotensin-(1-7), which activates the Mas receptor (MasR). Whether increasing brain ACE2 activity reduces anxiety by stimulating central MasR is unknown. To test the hypothesis that increasing brain ACE2 activity reduces anxiety-like behavior via central MasR stimulation, we generated male mice overexpressing ACE2 (ACE2 KI mice) and wild type littermate controls (WT). ACE2 KI mice explored the open arms of the elevated plus maze (EPM) significantly more than WT, suggesting increasing ACE2 activity is anxiolytic. Central delivery of diminazene aceturate, an ACE2 activator, to C57BL/6 mice also reduced anxiety-like behavior in the EPM, but centrally administering ACE2 KI mice A-779, a MasR antagonist, abolished their anxiolytic phenotype, suggesting that ACE2 reduces anxiety-like behavior by activating central MasR. To identify the brain circuits mediating these effects, we measured Fos, a marker of neuronal activation, subsequent to EPM exposure and found that ACE2 KI mice had decreased Fos in the bed nucleus of stria terminalis but had increased Fos in the basolateral amygdala (BLA). Within the BLA, we determined that ~62% of GABAergic neurons contained MasR mRNA and expression of MasR mRNA was upregulated by ACE2 overexpression, suggesting that ACE2 may influence GABA neurotransmission within the BLA via MasR activation. Indeed, ACE2 overexpression was associated with increased frequency of spontaneous inhibitory postsynaptic currents (indicative of presynaptic release of GABA) onto BLA pyramidal neurons and central infusion of A-779 eliminated this effect. Collectively, these results suggest that ACE2 may reduce anxiety-like behavior by activating central MasR that facilitate GABA release onto pyramidal neurons within the BLA. PMID- 26767954 TI - Functional sites involved in modulation of the GABAA receptor channel by the intravenous anesthetics propofol, etomidate and pentobarbital. AB - GABAA receptors are the major inhibitory neurotransmitter receptors in the brain and are the target for many clinically important drugs. Among the many modulatory compounds are also the intravenous anesthetics propofol and etomidate, and barbiturates. The mechanism of receptor modulation by these compounds is of mayor relevance. The site of action of these compounds has been located to subunit interfaces in the intra-membrane region of the receptor. In alpha1beta2gamma2 GABAA receptors there are five such interfaces, two beta+/alpha- and one each of alpha+/beta-, alpha+/gamma- and gamma+/beta- subunit interfaces. We have used reporter mutations located in the second trans-membrane region in different subunits to probe the effects of changes at these subunit interfaces on modulation by propofol, etomidate and pentobarbital. We provide evidence for the fact that each of these compounds either modulates through a different set of subunit interfaces or through the same set of subunit interfaces to a different degree. As a GABAA receptor pentamer harbors two beta+/alpha- subunit interfaces, we used concatenated receptors to dissect the contribution of individual interfaces and show that only one of these interfaces is important for receptor modulation by etomidate. PMID- 26767953 TI - Differential regulation of synaptic and extrasynaptic alpha4 GABA(A) receptor populations by protein kinase A and protein kinase C in cultured cortical neurons. AB - The GABAA alpha4 subunit exists in two distinct populations of GABAA receptors. Synaptic GABAA alpha4 receptors are localized at the synapse and mediate phasic inhibitory neurotransmission, while extrasynaptic GABAA receptors are located outside of the synapse and mediate tonic inhibitory transmission. These receptors have distinct pharmacological and biophysical properties that contribute to interest in how these different subtypes are regulated under physiological and pathological states. We utilized subcellular fractionation procedures to separate these populations of receptors in order to investigate their regulation by protein kinases in cortical cultured neurons. Protein kinase A (PKA) activation decreases synaptic alpha4 expression while protein kinase C (PKC) activation increases alpha4 subunit expression, and these effects are associated with increased beta3 S408/409 or gamma2 S327 phosphorylation respectively. In contrast, PKA activation increases extrasynaptic alpha4 and delta subunit expression, while PKC activation has no effect. Our findings suggest synaptic and extrasynaptic GABAA alpha4 subunit expression can be modulated by PKA to inform the development of more specific therapeutics for neurological diseases that involve deficits in GABAergic transmission. PMID- 26767955 TI - The bony labyrinth of the middle Pleistocene Sima de los Huesos hominins (Sierra de Atapuerca, Spain). AB - We performed 3D virtual reconstructions based on CT scans to study the bony labyrinth morphology in 14 individuals from the large middle Pleistocene hominin sample from the site of the Sima de los Huesos (SH) in the Sierra de Atapuerca in northern Spain. The Atapuerca (SH) hominins represent early members of the Neandertal clade and provide an opportunity to compare the data with the later in time Neandertals, as well as Pleistocene and recent humans more broadly. The Atapuerca (SH) hominins do not differ from the Neandertals in any of the variables related to the absolute and relative sizes and shape of the semicircular canals. Indeed, the entire Neandertal clade seems to be characterized by a derived pattern of canal proportions, including a relatively small posterior canal and a relatively large lateral canal. In contrast, one of the most distinctive features observed in Neandertals, the low placement of the posterior canal (i.e., high sagittal labyrinthine index), is generally not present in the Atapuerca (SH) hominins. This low placement is considered a derived feature in Neandertals and is correlated with a more vertical orientation of the ampullar line (LSCm < APA), posterior surface of the petrous pyramid (LSCm > PPp), and third part of the facial canal (LSCm < FC3). Some variation is present within the Atapuerca (SH) sample, however, with a few individuals approaching the Neandertal condition more closely. In addition, the cochlear shape index in the Atapuerca (SH) hominins is low, indicating a reduction in the height of the cochlea. Although the phylogenetic polarity of this feature is less clear, the low shape index in the Atapuerca (SH) hominins may be a derived feature. Regardless, cochlear height subsequently increased in Neandertals. In contrast to previous suggestions, the expanded data in the present study indicate no difference across the genus Homo in the angle of inclination of the cochlear basal turn (COs < LSCm). Principal components analysis largely confirms these observations. While not fully resolved, the low placement of the posterior canal in Neandertals may be related to some combination of absolutely large brain size, a wide cranial base, and an archaic pattern of brain allometry. This more general explanation would not necessarily follow taxonomic lines, even though this morphology of the bony labyrinth occurs at high frequencies among Neandertals. While a functional interpretation of the relatively small vertical canals in the Neandertal clade remains elusive, the relative proportions of the semicircular canals is one of several derived Neandertal features in the Atapuerca (SH) crania. Examination of additional European middle Pleistocene specimens suggests that the full suite of Neandertal features in the bony labyrinth did not emerge in Europe until perhaps <200 kya. PMID- 26767957 TI - A new species of Apidium (Anthropoidea, Parapithecidae) from the Sirt Basin, central Libya: First record of Oligocene primates from Libya. AB - A new species of Apidium is the most common primate currently known from a newly discovered site near Zallah Oasis in the Sirt Basin of central Libya. Based on current knowledge of the associated fauna, this new species of Apidium is early Oligocene in age, being roughly contemporaneous with faunas from Quarries G and V in the upper part of the Jebel Qatrani Formation in Egypt that also contain species of Apidium. A phylogenetic analysis based on dental characters indicates that the new species of Apidium from Libya is the sister group of Apidium phiomense. Apidium bowni and Apidium moustafai from the Jebel Qatrani Formation in the Fayum are similar in age to the new species of Apidium from Libya, but both of these Egyptian species are more distantly related to A. phiomense from younger stratigraphic levels in the Fayum. This phylogenetic pattern underscores the benefit of enhanced geographic sampling of the fossil record, even in cases where local records are thought to be reasonably comprehensive and well documented. Oligocene parapithecids can be partitioned into two clades corresponding to the subfamilies Parapithecinae (containing Parapithecus and Simonsius) and Qatraniinae (including Qatrania and Apidium). Climatic deterioration during the early Oligocene may have impacted the macroevolutionary dynamics of early Afro-Arabian anthropoids by fostering the fragmentation of forest habitats, thereby promoting allopatric speciation among widespread populations of Apidium and other arboreal taxa. PMID- 26767956 TI - Reproductive state and rank influence patterns of meat consumption in wild female chimpanzees (Pan troglodytes schweinfurthii). AB - An increase in faunivory is a consistent component of human evolutionary models. Animal matter is energy- and nutrient-dense and can provide macronutrients, minerals, and vitamins that are limited or absent in plant foods. For female humans and other omnivorous primates, faunivory may be of particular importance during the costly periods of pregnancy and early lactation. Yet, because animal prey is often monopolizable, access to fauna among group-living primates may be mediated by social factors such as rank. Wild chimpanzees (Pan troglodytes) across Africa habitually consume insects and/or vertebrates. However, no published studies have examined patterns of female chimpanzee faunivory during pregnancy and early lactation relative to non-reproductive periods, or by females of different rank. In this study, we assessed the influence of reproductive state and dominance rank on the consumption of fauna (meat and insects) by female chimpanzees of Gombe National Park, Tanzania. Using observational data collected over 38 years, we tested (a) whether faunivory varied by reproductive state, and (b) if high-ranking females spent more time consuming fauna than lower-ranking females. In single-factor models, pregnant females consumed more meat than lactating and baseline (meaning not pregnant and not in early lactation) females, and high-ranking females consumed more meat than lower-ranking females. A two factor analysis of a subset of well-sampled females identified an interaction between rank and reproductive state: lower-ranking females consumed more meat during pregnancy than lower-ranking lactating and baseline females did. High ranking females did not significantly differ in meat consumption between reproductive states. We found no relationships between rank or reproductive state with insectivory. We conclude that, unlike insectivory, meat consumption by female chimpanzees is mediated by both reproductive state and social rank. We outline possible mechanisms for these patterns, relate our findings to meat eating patterns in women from well-studied hunter-gatherer societies, and discuss potential avenues for future research. PMID- 26767958 TI - Interpreting locomotor biomechanics from the morphology of human footprints. AB - Fossil hominin footprints offer unique direct windows to the locomotor behaviors of our ancestors. These data could allow a clearer understanding of the evolution of human locomotion by circumventing issues associated with indirect interpretations of habitual locomotor patterns from fossil skeletal material. However, before we can use fossil hominin footprints to understand better the evolution of human locomotion, we must first develop an understanding of how locomotor biomechanics are preserved in, and can be inferred from, footprint morphologies. In this experimental study, 41 habitually barefoot modern humans created footprints under controlled conditions in which variables related to locomotor biomechanics could be quantified. Measurements of regional topography (depth) were taken from 3D models of those footprints, and principal components analysis was used to identify orthogonal axes that described the largest proportions of topographic variance within the human experimental sample. Linear mixed effects models were used to quantify the influences of biomechanical variables on the first five principal axes of footprint topographic variation, thus providing new information on the biomechanical variables most evidently expressed in the morphology of human footprints. The footprint's overall depth was considered as a confounding variable, since biomechanics may be linked to the extent to which a substrate deforms. Three of five axes showed statistically significant relationships with variables related to both locomotor biomechanics and substrate displacement; one axis was influenced only by biomechanics and another only by the overall depth of the footprint. Principal axes of footprint morphological variation were significantly related to gait type (walking or running), kinematics of the hip and ankle joints and the distribution of pressure beneath the foot. These results provide the first quantitative framework for developing hypotheses regarding the biomechanical patterns reflected by fossil hominin footprints by demonstrating the statistically significant effects of specific kinematic variables on patterns of variation in footprint topography. PMID- 26767959 TI - Dental size reduction in Indonesian Homo erectus: Implications for the PU-198 premolar and the appearance of Homo sapiens on Java. AB - The recent recovery of a hominin maxillary third premolar, PU-198, within the faunal collections from Punung Cave (East Java) has led to assertions that Homo sapiens appeared on Java between 143,000 and 115,000 years ago. The taxonomic assignment of PU-198 to H. sapiens was based predominantly on the small size of the specimen, following an analysis which found little to no overlap in premolar size between Homo erectus and terminal Pleistocene/Holocene H. sapiens. Here, we re-evaluate the use of size in the taxonomic assignment of PU-198 in light of 1) new buccolingual and mesiodistal measurements taken on the fossil, 2) comparisons to a larger sample of H. erectus and H. sapiens maxillary third premolars, and 3) evidence of a diachronic trend in post-canine dental size reduction among Javan H. erectus. Our results demonstrate PU-198 to be slightly larger than previously suggested, reveal substantial overlap in premolar size between H. erectus and H. sapiens, and indicate a statistically significant reduction in premolar size between early and late Javan H. erectus. Our findings cast doubt on the assignment of PU-198 to H. sapiens, and accordingly, question the appearance of H. sapiens on Java between 143,000 and 115,000 years ago. PMID- 26767960 TI - Fossil hominin radii from the Sima de los Huesos Middle Pleistocene site (Sierra de Atapuerca, Spain). AB - Complete radii in the fossil record preceding recent humans and Neandertals are very scarce. Here we introduce the radial remains recovered from the Sima de los Huesos (SH) site in the Sierra de Atapuerca between 1976 and 2011 and which have been dated in excess of 430 ky (thousands of years) ago. The sample comprises 89 specimens, 49 of which are attributed to adults representing a minimum of seven individuals. All elements are described anatomically and metrically, and compared with other fossil hominins and recent humans in order to examine the phylogenetic polarity of certain radial features. Radial remains from SH have some traits that differentiate them from those of recent humans and make them more similar to Neandertals, including strongly curved shafts, anteroposterior expanded radial heads and both absolutely and relatively long necks. In contrast, the SH sample differs from Neandertals in showing a high overall gracility as well as a high frequency (80%) of an anteriorly oriented radial tuberosity. Thus, like the cranial and dental remains from the SH site, characteristic Neandertal radial morphology is not present fully in the SH radii. We also analyzed the cross sectional properties of the SH radial sample at two different levels: mid-shaft and at the midpoint of the neck length. When standardized by shaft length, no difference in the mid-shaft cross-sectional properties were found between the SH hominins, Neandertals and recent humans. Nevertheless, due to their long neck length, the SH hominins show a higher lever efficiency than either Neandertals or recent humans. Functionally, the SH radial morphology is consistent with more efficient pronation-supination and flexion-extension movements. The particular trait composition in the SH sample and Neandertals resembles more closely morphology evident in recent human males. PMID- 26767961 TI - In situ ~2.0 Ma trees discovered as fossil rooted stumps, lowermost Bed I, Olduvai Gorge, Tanzania. AB - The discovery of fossil rooted tree stumps in lowermost Lower Bed I from the western Olduvai Basin, Tanzania, age-bracketed by the Naabi Ignimbrite (2.038 +/- 0.005 Ma) and Tuff IA (1.88 +/- 0.05 Ma), provides the first direct, in situ, and to date oldest evidence of living trees at Olduvai Gorge. The tree relicts occur in an interval dominated by low-viscosity mass flow and braided fluvial sediments, deposited at the toe of a largely Ngorongoro Volcano-sourced volcaniclastic fan apron that comprised a widely spaced network of ephemeral braided streams draining northward into the Olduvai Basin. Preservation of the trees occurred through their engulfment by mass flows, post-mortem mold formation resulting from differential decay of woody tissues, and subsequent fluvially related sediment infill, calcite precipitation, and cast formation. Rhizolith preservation was triggered by the interaction of root-induced organic and inorganic processes to form rhizocretionary calcareous root casts. Phytolith analyses were carried out to complete the paleoenvironmental reconstruction. They imply a pronounced seasonality and indicate a wooded landscape with grasses, shrubs, and sedges growing nearby, comparable to the low, open riverine woodland (unit 4c) along the Garusi River and tributaries in the Laetoli area. Among the tree stump cluster were found outsized lithic clasts and those consisting of quartzite were identified as Oldowan stone tool artifacts. In the context of hominin activity, the identification of wooded grassland in association with nearby freshwater drainages and Oldowan artifacts significantly extends our paleoenvironmental purview on the basal parts of Lower Bed I, and highlights the hitherto underrated role of the yet poorly explored western Olduvai Gorge area as a potential ecologically attractive setting and habitat for early hominins. PMID- 26767963 TI - The subtalar joint complex of Australopithecus sediba. AB - The hominin talus has figured prominently in previous studies of the functional morphology of the talocrural joint, but the talocalcaneal and talonavicular joints have received comparatively less attention despite their functional importance as components of the subtalar joint complex. An associated complete talus and calcaneus attributed to the Malapa Hominin 2 (MH2) individual of Australopithecus sediba offers the opportunity to evaluate the subtalar joint complex in an early hominin. Furthermore, detailed morphological comparisons of A. sediba to other fossil hominins such as Australopithecus africanus have not yet been conducted. Here I quantify joint curvatures and angular measurements among extant hominoids and fossil hominins to evaluate the functional morphology of the subtalar joint complex of A. sediba. Australopithecus sediba uniquely combines talocalcaneal joint morphology indicative of mobility with specializations of the talonavicular joint that provide medial midtarsal stabilization. Multivariate analyses of talus and calcaneus variables show that A. sediba is most similar to extant gorillas in the morphology of the subtalar joint complex. In contrast, other hominins, such as OH 8, are more similar to modern humans. The morphological similarity between MH2 (U.W. 88-98/99) and specimens from Sterkfontein, Member 4 (StW 88, StW 102, StW 352) in morphologies of the talonavicular and talocalcaneal joints suggests that A. sediba may have possessed a foot that was functionally similar to that of A. africanus. This combination of morphologies in the A. sediba foot is probably derived among hominins and suggests that arboreality may have been adaptively significant for southern African Australopithecus. PMID- 26767962 TI - Cercopithecoid humeri from Taung support the distinction of major papionin clades in the South African fossil record. AB - Associated cercopithecoid postcrania are rare in the Plio-Pleistocene fossil record, particularly in the case of South African karst cave sites. However, as clear postcranial differences between major papionin clades have been documented, it should be possible to assign isolated papionin postcrania to the Cercocebus/Mandrillus and Papio/Lophocebus/Theropithecus groups wherever sufficient anatomy is preserved. Here, we demonstrate that two partial humeri preserved at Taung, UCMP 56693 and UCMP 125898, are most likely attributable to the Cercocebus/Mandrillus and Papio/Lophocebus/Theropithecus clades, respectively. Univariate analyses (ANOVAs and t-tests) and multivariate analyses (discriminant function analyses) of humeral features, combined with a phylogenetic analysis of 24 humeral characters, all support our assessment. Given that the overwhelming number of craniodental specimens at Taung are attributable to two papionin taxa, Procercocebus antiquus (a member of the Cercocebus/Mandrillus clade) and Papio izodi (a purported fossil species of the modern genus Papio), we assign UCMP 56693 to Pr. antiquus and UCMP 125868 to P. izodi with a high degree of confidence. Implications for cercopithecoid evolution and biogeography are discussed, with a particular emphasis on these two fossil taxa. PMID- 26767964 TI - Cranial vault thickness in primates: Homo erectus does not have uniquely thick vault bones. AB - Extremely thick cranial vaults have been noted as a diagnostic characteristic of Homo erectus since the first fossil of the species was identified, but relatively little work has been done on elucidating its etiology or variation across fossils, living humans, or extant non-human primates. Cranial vault thickness (CVT) is not a monolithic trait, and the responsiveness of its layers to environmental stimuli is unknown. We obtained measurements of cranial vault thickness in fossil hominins from the literature and supplemented those data with additional measurements taken on African fossil specimens. Total CVT and the thickness of the cortical and diploe layers individually were compared to measures of CVT in extant species measured from more than 500 CT scans of human and non-human primates. Frontal and parietal CVT in fossil primates was compared to a regression of CVT on cranial capacity calculated for extant species. Even after controlling for cranial capacity, African and Asian H. erectus do not have uniquely high frontal or parietal thickness residuals, either among hominins or extant primates. Extant primates with residual CVT thickness similar to or exceeding H. erectus (depending on the sex and bone analyzed) include Nycticebus coucang, Perodicticus potto, Alouatta caraya, Lophocebus albigena, Galago alleni, Mandrillus sphinx, and Propithecus diadema. However, the especially thick vaults of extant non-human primates that overlap with H. erectus values are composed primarily of cortical bone, while H. erectus and other hominins have diploe dominated vault bones. Thus, the combination of thick vaults comprised of a thickened diploe layer may be a reliable autapomorphy for members of the genus Homo. PMID- 26767965 TI - Comparative sacral morphology and the reconstructed tail lengths of five extinct primates: Proconsul heseloni, Epipliopithecus vindobonensis, Archaeolemur edwardsi, Megaladapis grandidieri, and Palaeopropithecus kelyus. AB - This study evaluated the relationship between the morphology of the sacrum-the sole bony link between the tail or coccyx and the rest of the body-and tail length (including presence/absence) and function using a comparative sample of extant mammals spanning six orders (Primates, Carnivora, Rodentia, Diprotodontia, Pilosa, Scandentia; N = 472). Phylogenetically-informed regression methods were used to assess how tail length varied with respect to 11 external and internal (i.e., trabecular) bony sacral variables with known or suspected biomechanical significance across all mammals, only primates, and only non-primates. Sacral variables were also evaluated for primates assigned to tail categories ('tailless,' 'nonprehensile short-tailed,' 'nonprehensile long-tailed,' and 'prehensile-tailed'). Compared to primates with reduced tail lengths, primates with longer tails generally exhibited sacra having larger caudal neural openings than cranial neural openings, and last sacral vertebrae with more mediolaterally expanded caudal articular surfaces than cranial articular surfaces, more laterally-expanded transverse processes, more dorsally-projecting spinous processes, and larger caudal articular surface areas. Observations were corroborated by the comparative sample, which showed that shorter-tailed (e.g., Lynx rufus [bobcat]) and longer-tailed (e.g., Acinonyx jubatus [cheetah]) non primate mammals morphologically converge with shorter-tailed (e.g., Macaca nemestrina) and longer-tailed (e.g., Macaca fascicularis) primates, respectively. 'Prehensile-tailed' primates exhibited last sacral vertebrae with more laterally expanded transverse processes and greater caudal articular surface areas than 'nonprehensile long-tailed' primates. Internal sacral variables performed poorly compared to external sacral variables in analyses of extant primates, and were thus deemed less useful for making inferences concerning tail length and function in extinct primates. The tails lengths of five extinct primates were reconstructed from the external sacral variables: Archaeolemur edwardsi had a 'nonprehensile long tail,' Megaladapis grandidieri, Palaeopropithecus kelyus, and Epipliopithecus vindobonensis probably had 'nonprehensile short tails,' and Proconsul heseloni was 'tailless.' PMID- 26767967 TI - Erratum. PMID- 26767968 TI - PBJ is now an open access journal. PMID- 26767966 TI - Persistent C3 vegetation accompanied Plio-Pleistocene hominin evolution in the Malawi Rift (Chiwondo Beds, Malawi). AB - The development of East African savannas is crucial for the origin and evolution of early hominins. These ecosystems, however, vary widely in their fraction of woody cover and today range from closed woodland to open grassland savanna. Here, we present the first Plio-Pleistocene long-term carbon isotope (delta(13)C) record from pedogenic carbonate and Suidae teeth in the southern East African Rift (EAR). These delta(13)C data from the Chiwondo and Chitimwe Beds (Karonga Basin, Northern Malawi) represent a southern hemisphere record in the EAR, a key region for reconstructing vegetation patterns in today's Zambezian Savanna, and permit correlation with data on the evolution and migration of early hominins in today's Somali-Masai Endemic Zone. The sediments along the northwestern shore of Lake Malawi contain fossils attributed to Homo rudolfensis and Paranthropus boisei. The associated hominin localities (Uraha, Malema) are situated between the well-known hominin bearing sites of the Somali-Masai Endemic Zone in the Eastern Rift and the Highveld Grassland in southern Africa, and fill an important geographical gap for hominin research. Persistent delta(13)C values around -90/00 from pedogenic carbonate and suid enamel covering the last ~4.3 Ma indicate a C3 dominated closed environment with regional patches of C4-grasslands in the Karonga Basin. The overall fraction of woody cover of 60-70% reflects significantly higher canopy density in the Malawi Rift than the Eastern Rift through time. The discrepancy between the two savanna types originated in the Late Pliocene, when the Somali-Masai ecosystem started to show increasing evidence for open, C4-dominated landscapes. Based on the Malawi delta(13)C data, the evolution of savanna ecosystems in Eastern Africa followed different patterns along the north-south extent of the EAR. The appearance of C4-grasses is considered a driver of evolutionary faunal shifts, but despite the difference of ecosystem evolution in the north, similar hominins and suids occurred in both landscapes, pointing to distinct habitat flexibility and also nutritional versatility. PMID- 26767969 TI - An open source software for analysis of dynamic contrast enhanced magnetic resonance images: UMMPerfusion revisited. AB - BACKGROUND: Perfusion imaging has become an important image based tool to derive the physiological information in various applications, like tumor diagnostics and therapy, stroke, (cardio-) vascular diseases, or functional assessment of organs. However, even after 20 years of intense research in this field, perfusion imaging still remains a research tool without a broad clinical usage. One problem is the lack of standardization in technical aspects which have to be considered for successful quantitative evaluation; the second problem is a lack of tools that allow a direct integration into the diagnostic workflow in radiology. RESULTS: Five compartment models, namely, a one compartment model (1CP), a two compartment exchange (2CXM), a two compartment uptake model (2CUM), a two compartment filtration model (2FM) and eventually the extended Toft's model (ETM) were implemented as plugin for the DICOM workstation OsiriX. Moreover, the plugin has a clean graphical user interface and provides means for quality management during the perfusion data analysis. Based on reference test data, the implementation was validated against a reference implementation. No differences were found in the calculated parameters. CONCLUSION: We developed open source software to analyse DCE-MRI perfusion data. The software is designed as plugin for the DICOM Workstation OsiriX. It features a clean GUI and provides a simple workflow for data analysis while it could also be seen as a toolbox providing an implementation of several recent compartment models to be applied in research tasks. Integration into the infrastructure of a radiology department is given via OsiriX. Results can be saved automatically and reports generated automatically during data analysis ensure certain quality control. PMID- 26767970 TI - State budget transfers to Health Insurance Funds for universal health coverage: institutional design patterns and challenges of covering those outside the formal sector in Eastern European high-income countries. AB - INTRODUCTION: Many countries from the European region, which moved from a government financed and provided health system to social health insurance, would have had the risk of moving away from universal health coverage if they had followed a "traditional" approach. The Eastern European high-income countries studied in this paper managed to avoid this potential pitfall by using state budget revenues to explicitly pay health insurance contributions on behalf of certain (vulnerable) population groups who have difficulties to pay these contributions themselves. The institutional design aspects of their government revenue transfer arrangements are analysed, as well as their impact on universal health coverage progress. METHODS: This regional study is based on literature review and review of databases for the performance assessment. The analytical framework focuses on the following institutional design features: rules on eligibility for contribution exemption, financing and pooling arrangements, and purchasing arrangements and benefit package design. RESULTS: More commonalities than differences can be identified across countries: a broad range of groups eligible for exemption from payment of health insurance contributions, full state contributions on behalf of the exempted groups, mostly mandatory participation, integrated pools for both the exempted and contributors, and relatively comprehensive benefit packages. In terms of performance, all countries have high total population coverage rates, but there are still challenges regarding financial protection and access to and utilization of health care services, especially for low income people. CONCLUSION: Overall, government revenue transfer arrangements to exempt vulnerable groups from contributions are one option to progress towards universal health coverage. PMID- 26767971 TI - The immediate effect of traditional Malay massage on substance P, inflammatory mediators, pain scale and functional outcome among patients with low back pain: study protocol of a randomised controlled trial. AB - BACKGROUND: The treatment of low back pain is very challenging due to the recurrent nature of the problem. It is believed that traditional Malay massage helps to relieve such back pain but there is a lack of scientific evidence to support both the practice of traditional Malay massage and the mechanism by which it exerts its effect. The aim of this study is to investigate the immediate effect of traditional Malay massage on the pain scale, substance P, inflammatory mediators, and functional outcomes among low back pain patients. METHODS: A non blinded, randomised controlled trial will be conducted. A total of sixty-six patients who fulfil the inclusion criteria will be recruited. The participants will be randomly allocated into intervention (traditional Malay massage) and control (relaxation position) groups. Blood and saliva samples will be collected before and immediately after intervention. All collected samples will be analysed. The primary outcomes are the changes in the level of substance P in both saliva and blood samples between both groups. The secondary outcomes include the levels of inflammatory mediators [i.e. TNF-alpha, IL-1beta, IL-8, monocyte chemotactic protein-1, IL-6 and IL-10, and the soluble form of the intercellular adhesion molecule], the pain intensity as measured by a visual analogous scale and functional outcomes using the Roland-Morris Disability Questionnaire. DISCUSSION: Massage is a type of physical therapy that has been proven to be potentially capable of reducing unpleasant pain sensations by a complex sensory response and chemical mediators such as substance P and various inflammatory mediators. Previous studies conducted using Thai, Swedish, or other forms of massage therapies, have showed inconsistent findings on substance P levels pre and post the interventions. Each massage genre varies in terms of massage and joint mobilization points, as well as the lumbar spinous process. Traditional Malay massage, known locally as "Urut Melayu", involves soft-tissue manipulation of the whole body applied using the hands and fingers. This massage technique combines both deep muscular tissue massage and spiritual rituals. This trial is expected to give rise to new knowledge underlying the mechanisms for pain and inflammation relief that are activated by traditional Malay massage. TRIAL REGISTRATION: Australian New Zealand Clinical Trials ACTRN12615000537550 . PMID- 26767972 TI - Identification of differentially expressed Gnalphas and Gnalpha11 in sheep (Ovis aries) skins associated with white and black coat colors. AB - Guanine nucleotide-binding protein subunit alpha-s (Gnalphas) and guanine nucleotide-binding protein subunit alpha-11 (Gnalpha11) play an important role in coat color formation. To improve our understanding of Gnalphas and Gnalpha11 expression levels and pattern in the skin of black sheep (Ovis aries) compared with white sheep, we analyzed the expression levels through quantitative real time PCR (qPCR) and Western blot, immunohistochemistry and immunofluorescence. qPCR and Western blot results suggested that Gnalphas and Gnalpha11 were significantly expressed at high levels in black sheep skin compared with the white sheep skin. Gnalpha11 expression was higher than Gnalphas expression in both skin colors, transcripts and protein exhibited the same expression pattern in white and black sheep skins. Immunohistochemical results revealed that Gnalphas and Gnalpha11 were localized in the outer root sheath of hair follicle in sheep. Furthermore, the expression of Gnalpha11 in outer root sheath of hair follicle was stronger than that in Gnalphas. Immunofluorescencence further demonstrated that signals of Gnalphas and Gnalpha11 were detected in outer root sheath and hair papilla. These results provide a novel insight into the role of Gnalphas and Gnalpha11 in the regulation of sheep coat color. PMID- 26767973 TI - EndNote as document manager for summative assessment. PMID- 26767974 TI - Possible alendronate-induced polyarticular synovitis. AB - We present a case of polyarticular synovitis following alendronate treatment for osteoporosis. The patient had no evidence of rheumatoid arthritis, pyrophosphate arthropathy, or seronegative/seropositive arthritis. Our main aim in this study is to highlight the potential adverse effects of alendronate and to warn orthopedic surgeons about the possibility of such a side effect that might lead orthopedic surgeons to administer wrong and unnecessary treatments like arthrocentesis. The withdrawal of alendronate is found to be the treatment of choice. Alendronate should be considered as a possible cause of synovitis or polyarthritis in patients treated with this agent in the absence of any other pathology. An association between alendronate and synovitis has rarely been described in the literature. We present a patient who developed polyarticular synovitis after treatment with alendronate and responded to its withdrawal. PMID- 26767975 TI - Thyroid hemiagenesis coexisting with brain cavernoma and pituitary Rathke's cleft cyst. PMID- 26767976 TI - Identification of repressive and active epigenetic marks and nuclear bodies in Entamoeba histolytica. AB - BACKGROUND: In human hosts, Entamoeba histolytica cysts can develop into trophozoites, suggesting that the life cycle of this parasite are regulated by changes in gene expression. To date, some evidence has suggested that epigenetic mechanisms such as DNA methylation and histone modification are involved in the regulation of gene expression in Entamoeba. Some post-translational modifications (PTMs) at the N-terminus of E. histolytica's histones have been reported experimentally, including tri-methylation in the lysine 4 of histone H3 (H3K4me3) and dimethylation in the lysine 27 of histone H3 (H3K27me2), dimethylation of arginine 3 (H4R3me2) and the indirect acetylation of histone H4 in the N-terminal region. However, it is not known which residues of histone H4 are subject to acetylation and/or methylation or where in the nucleus these epigenetic marks are located. METHODS: Histones from trophozoites of E. histolytica were obtained and analyzed by LC-MS/MS. WB assays were performed using antibodies against epigenetic marks (acetylated lysines and methylated arginines). Immunofluorescence assays (IFA) were carried out to determine the distribution of PTMs and the localization of DNA methylation as a heterochromatin marker. Nuclear bodies such as the nucleolus were identified by using antibodies against fibrillarin and nucleolin and speckles by using anti-PRP6 antibody. RESULTS: Some new PTMs in histone H4 of E. histolytica, such as the acetylation of lysines 5, 8, 12 and 16 and the monomethylation of arginine 3, were identified by WB. IFA demonstrated that some marks are associated with transcriptional activity (such as acetylation and/or methylation) and that these marks are distributed throughout the E. histolytica nucleus. Staining with antibodies against anti-pan acetylated lysine H4 histone and 5-methyl cytosine showed that the activation and transcriptional repression marks converge. Additionally, two nuclear bodies, the nucleolus and speckles, were identified in this parasite. CONCLUSIONS: This study provides the first evidence that the nucleus of E. histolytica is not compartmentalized and contains two nuclear bodies, the nucleolus and speckles, the latter of which was not identified previously. The challenge is now to understand how these epigenetic marks and nuclear bodies work together to regulate gene expression in E. histolytica. PMID- 26767978 TI - The effects of centrally injected arachidonic acid on respiratory system: Involvement of cyclooxygenase to thromboxane signaling pathway. AB - Arachidonic acid (AA) is a polyunsaturated fatty acid that is present in the phospholipids of the cell membranes of the body and is abundant in the brain. Exogenously administered AA has been shown to affect brain metabolism and to exhibit cardiovascular and neuroendocrine actions. However, little is known regarding its respiratory actions and/or central mechanism of its respiratory effects. Therefore, the present study was designed to investigate the possible effects of centrally injected AA on respiratory system and the mediation of the central cyclooxygenase (COX) to thromboxane A2 (TXA2) signaling pathway on AA induced respiratory effects in anaesthetized rats. Intracerebroventricular (i.c.v.) administration of AA induced dose- and time-dependent increase in tidal volume, respiratory rates and respiratory minute ventilation and also caused an increase in partial oxygen pressure (pO2) and decrease in partial carbon dioxide pressure (pCO2) in male anaesthetized Spraque Dawley rats. I.c.v. pretreatment with ibuprofen, a non-selective COX inhibitor, completely blocked the hyperventilation and blood gases changes induced by AA. In addition, central pretreatment with different doses of furegrelate, a TXA2 synthesis inhibitor, also partially prevented AA-evoked hyperventilation and blood gases effects. These data explicitly show that centrally administered AA induces hyperventilation with increasing pO2 and decreasing pCO2 levels which are mediated by the activation of central COX to TXA2 signaling pathway. PMID- 26767977 TI - Gray matter volumes in symptomatic and asymptomatic offspring of parents diagnosed with bipolar disorder. AB - Children of parents diagnosed with bipolar disorder (BD), termed high-risk offspring (HRO), are at greater risk of developing psychiatric disorders compared to healthy children of healthy parents (HCO). Gray matter volume (GMV) abnormalities have been observed in HRO, however, these reports are inconsistent. We posit that this variability may be attributed to differences in methodology among offspring studies; in particular, the presence of psychiatric symptoms in HRO. Here, we directly compared GMVs between symptomatic and asymptomatic HRO, and HCO. High-resolution T1-weighted MR images were collected from 31 HRO (18 symptomatic and 13 asymptomatic) and 20 age- and sex-matched HCO. HRO had at least one parent diagnosed with BD. Symptomatic HRO were defined as having a psychiatric diagnosis other than BD, while asymptomatic HRO were required to be free of any psychiatric diagnosis. Scans were processed using voxel-based morphometry methods and between group analyses were performed in SPM. Compared to HCO, the HRO group showed decreased GMV in the right inferior orbitofrontal, right middle frontal, and bilateral superior and middle temporal regions. Both symptomatic and asymptomatic HRO groups showed decreased GMV in these regions separately when compared to HCO. When comparing symptomatic and asymptomatic HRO, GMVs were comparable in all regions except the lateral occipital cortex. Our study compared symptomatic and asymptomatic HRO directly. In doing so, we provided further support for the presence of discrete GMV deficits in HRO, and confirmed that these deficits are present irrespective of the presence of symptoms in HRO. PMID- 26767979 TI - Non-ocular melanomas in cats: a retrospective study of 30 cases. AB - Objectives The aim of the study was to describe the clinical outcome of 30 cats with non-ocular melanomas and to evaluate the association between clinical or pathological parameters and overall survival time. Methods The database of the animal histopathological laboratory of the National Veterinary School of Nantes (Oniris, Nantes, France) was retrospectively searched to identify cases of feline non-ocular melanomas between December 2009 and April 2014. For each case, clinical data, including signalment, location of the primary tumour, staging, treatment and outcome, were collected from the medical records or via interviews with referring veterinarians. Histological and immunohistochemical evaluation included mitotic index, cytonuclear atypias, junctional activity, Melan A and S100 immunostaining, and surgical margins. Univariate analysis to test the prognostic value of the different variables was performed by the Kaplan-Meier product limit method using the log-rank test of significance. Results Thirty cats were included in the study. Eleven had a cutaneous non-auricular melanoma, six had a tumour located on the pinna and 13 had a tumour in the oral cavity. Cats with auricular melanomas were significantly younger than cats with tumours in other locations. Location and presence of clinical signs were not of prognostic significance, but the achromic phenotype was significantly associated with a poorer prognosis. Twenty cats were treated with surgery and survived significantly longer than cats that received only medical treatment or that did not receive any treatment. According to our data, mitotic index, cytonuclear atypias, junctional activity, Melan A or S100 expression, and surgical margins were not associated with survival. Conclusions and relevance We show for the first time, in a large series, that the auricular form of melanoma affected significantly younger cats than other extraocular forms. Most feline non-ocular melanomas are malignant and achromic tumours are associated with a poorer prognosis. According to this study, surgery should be considered as a priority. PMID- 26767980 TI - Biologic variability of N-terminal pro-brain natriuretic peptide in adult healthy cats. AB - Objectives The biologic variability of N-terminal pro-brain natriuretic peptide (NT-proBNP) and its impact on diagnostic utility is unknown in healthy cats and those with cardiac disease. The purpose of this study was to determine the biologic variation of NT-proBNP within-day and week-to-week in healthy adult cats. Methods Adult cats were prospectively evaluated by complete blood count (CBC), biochemistry, total thyroxine, echocardiography, electrocardiography and blood pressure, to exclude underlying systemic or cardiac disease. Adult healthy cats were enrolled and blood samples were obtained at 11 time points over a 6 week period (0, 2 h, 4 h, 6 h, 8 h, 10 h and at weeks 2, 3, 4, 5 and 6). The intra-individual (coefficient of variation [CVI]) biologic variation along with index of individuality and reference change values (RCVs) were calculated. Univariate models were analyzed and included comparison of the six different time points for both daily and weekly samples. This was followed by a Tukey's post-hoc adjustment, with a P value of <0.05 being significant. Results The median daily and weekly CVI for the population were 13.1% (range 0-28.7%) and 21.2% (range 3.9 68.1%), respectively. The index of individuality was 0.99 and 1 for daily and weekly samples, respectively. The median daily and weekly RCVs for the population were 39.8% (range 17.0-80.5%) and 60.5% (range 20.1-187.8%), respectively. Conclusions and relevance This study demonstrates high individual variability for NT-proBNP concentrations in a population of adult healthy cats. Further research is warranted to evaluate NT-proBNP variability, particularly how serial measurements of NT-proBNP may be used in the diagnosis and management of cats with cardiac disease. PMID- 26767981 TI - Population-based comparative analysis of differentially expressed genes between Kashin-Beck disease grades I and II. AB - OBJECTIVES: To identify the differences and similarities of differentially expressed genes in peripheral blood mononuclear cells (PBMCs) between Kashin-Beck disease (KBD) grades I and II. METHOD: In total, 100 patients with KBD and 100 healthy controls were selected from a KBD endemic area and divided into 100 pairs of KBD vs. controls (50 pairs of patients with KBD grade I and healthy controls, 50 pairs of patients with KBD grade II and healthy controls). RNA was isolated from KBD PBMCs and healthy control PBMCs. Microarray analysis was conducted to identify differentially expressed genes in the different stages of KBD. The microarray data obtained were further confirmed using quantitative real-time polymerase chain reaction (qRT-PCR). RESULTS: In total, eight differentially expressed genes in KBD grade I and 69 differentially expressed genes in KBD grade II were identified. Among these genes, six common genes were differentially expressed in both stages of the disease. The expression ratios of four common genes differed significantly between KBD grades I and II. Based on the expression ratios of the four genes, linear discriminant analysis (LDA) correctly classified the KBD grade (I or II) with 81% accuracy. CONCLUSIONS: The similarities and differences of differentially expressed genes in PBMCs of patients with different stages of KBD may play an important role in the pathogenesis of the early phase of KBD. Additionally, six common genes may be considered blood-based genetic biomarkers for the detection and treatment of KBD. PMID- 26767982 TI - Nutritional stress exacerbates hepatic steatosis induced by deletion of the histidine nucleotide-binding (Hint2) mitochondrial protein. AB - The histidine nucleotide-binding protein, Hint2, is a mitochondrial phosphoramidase expressed in liver, brown fat, pancreas, and muscle. The livers of Hint2 knockout (Hint2(-/-)) mice accumulate triglycerides and show a pattern of mitochondrial protein lysine hyperacetylation. The extent and nature of the lysine acetylation changes and the response of Hint2(-/-) mice to nutritional challenges that elicit a modification of protein acetylation have not been investigated. To compare the adaptation of Hint2(-/-) and control (Hint2(+/+)) mice with episodes of fasting and high-fat diet (HFD), we subjected animals to either feeding ad libitum or fasting for 24 h, and to either a HFD or control diet for 8 wk. Triglyceride content was higher in Hint2(-/-) than in Hint2(+/+) livers, whereas plasma triglycerides were fourfold lower. Malonyl-CoA levels were increased twofold in Hint2(-/-) livers. After 24 h fasting, Hint2(-/-) displayed a decrease in body temperature, commensurate with a decrease in mass of brown fat and downregulation of uncoupling protein 1. HFD-treated Hint2(-/-) livers showed more steatosis, and plasma insulin and cholesterol were higher than in Hint(+/+) mice. Several proteins identified as substrates of sirtuin 3 and 5 and active in intermediary and ketone metabolism were hyperacetylated in liver and brown fat mitochondria after both HFD and fasting regimens. Glutamate dehydrogenase activity was downregulated in fed and fasted livers, and this was attributed to an increase in acetylation and ADP-ribosylation. The absence of Hint2 deregulates the posttranslational modification of several mitochondrial proteins, which impedes the adaptation to episodes of nutritional stress. PMID- 26767983 TI - Fluorescence-based gene reporter plasmid to track canonical Wnt signaling in ENS inflammation. AB - In several gut inflammatory or cancer diseases, cell-cell interactions are compromised, and an increased cytoplasmic expression of beta-catenin is observed. Over the last decade, numerous studies provided compelling experimental evidence that the loss of cadherin-mediated cell adhesion can promote beta-catenin release and signaling without any specific activation of the canonical Wnt pathway. In the present work, we took advantage of the ability of lipofectamine-like reagent to cause a synchronous dissociation of adherent junctions in cells isolated from the rat enteric nervous system (ENS) for obtaining an in vitro model of deregulated beta-catenin signaling. Under these experimental conditions, a green fluorescent protein Wnt reporter plasmid called DeltaTop_EGFP3a was successfully tested to screen beta-catenin stabilization at resting and primed conditions with exogenous Wnt3a or lipopolysaccharide (LPS). DeltaTop_EGFP3a provided a reliable and strong fluorescent signal that was easily measurable and at the same time highly sensitive to modulations of Wnt signaling following Wnt3a and LPS stimulation. The reporter gene was useful to demonstrate that Wnt3a exerts a protective activity in the ENS from overstimulated Wnt signaling by promoting a downregulation of the total beta-catenin level. Based on this evidence, the use of DeltaTop_EGFP3a reporter plasmid could represent a more reliable tool for the investigation of Wnt and cross-talking pathways in ENS inflammation. PMID- 26767984 TI - Protective effect of agaro-oligosaccharides on gut dysbiosis and colon tumorigenesis in high-fat diet-fed mice. AB - High-fat diet (HFD)-induced alteration in the gut microbial composition, known as dysbiosis, is increasingly recognized as a major risk factor for various diseases, including colon cancer. This report describes a comprehensive investigation of the effect of agaro-oligosaccharides (AGO) on HFD-induced gut dysbiosis, including alterations in short-chain fatty acid contents and bile acid metabolism in mice. C57BL/6N mice were fed a control diet or HFD, with or without AGO. Terminal restriction fragment-length polymorphism (T-RFLP) analysis produced their fecal microbiota profiles. Profiles of cecal organic acids and serum bile acids were determined, respectively, using HPLC and liquid chromatography-tandem mass spectrometry systems. T-RFLP analyses showed that an HFD changed the gut microbiota significantly. Changes in the microbiota composition induced by an HFD were characterized by a decrease in the order Lactobacillales and by an increase in the Clostridium subcluster XIVa. These changes of the microbiota community generated by HFD treatment were suppressed by AGO supplementation. As supported by the data of the proportion of Lactobacillales order, the concentration of lactic acid increased in the HFD + AGO group. Data from the serum bile acid profile showed that the level of deoxycholic acid, a carcinogenic secondary bile acid produced by gut bacteria, was increased in HFD-receiving mice. The upregulation tended to be suppressed by AGO supplementation. Finally, results show that AGO supplementation suppressed the azoxymethane-induced generation of aberrant crypt foci in the colon derived from HFD-treated mice. Our results suggest that oral intake of AGO prevents HFD-induced gut dysbiosis, thereby inhibiting colon carcinogenesis. PMID- 26767986 TI - Bacteriophage-encoded depolymerases: their diversity and biotechnological applications. AB - Bacteriophages (phages), natural enemies of bacteria, can encode enzymes able to degrade polymeric substances. These substances can be found in the bacterial cell surface, such as polysaccharides, or are produced by bacteria when they are living in biofilm communities, the most common bacterial lifestyle. Consequently, phages with depolymerase activity have a facilitated access to the host receptors, by degrading the capsular polysaccharides, and are believed to have a better performance against bacterial biofilms, since the degradation of extracellular polymeric substances by depolymerases might facilitate the access of phages to the cells within different biofilm layers. Since the diversity of phage depolymerases is not yet fully explored, this is the first review gathering information about all the depolymerases encoded by fully sequenced phages. Overall, in this study, 160 putative depolymerases, including sialidases, levanases, xylosidases, dextranases, hyaluronidases, peptidases as well as pectate/pectin lyases, were found in 143 phages (43 Myoviridae, 47 Siphoviridae, 37 Podoviridae, and 16 unclassified) infecting 24 genera of bacteria. We further provide information about the main applications of phage depolymerases, which can comprise areas as diverse as medical, chemical, or food-processing industry. PMID- 26767985 TI - Predicting the activation states of the muscles governing upper esophageal sphincter relaxation and opening. AB - The swallowing muscles that influence upper esophageal sphincter (UES) opening are centrally controlled and modulated by sensory information. Activation and deactivation of neural inputs to these muscles, including the intrinsic cricopharyngeus (CP) and extrinsic submental (SM) muscles, results in their mechanical activation or deactivation, which changes the diameter of the lumen, alters the intraluminal pressure, and ultimately reduces or promotes flow of content. By measuring the changes in diameter, using intraluminal impedance, and the concurrent changes in intraluminal pressure, it is possible to determine when the muscles are passively or actively relaxing or contracting. From these "mechanical states" of the muscle, the neural inputs driving the specific motor behaviors of the UES can be inferred. In this study we compared predictions of UES mechanical states directly with the activity measured by electromyography (EMG). In eight subjects, pharyngeal pressure and impedance were recorded in parallel with CP- and SM-EMG activity. UES pressure and impedance swallow profiles correlated with the CP-EMG and SM-EMG recordings, respectively. Eight UES muscle states were determined by using the gradient of pressure and impedance with respect to time. Guided by the level and gradient change of EMG activity, mechanical states successfully predicted the activity of the CP muscle and SM muscle independently. Mechanical state predictions revealed patterns consistent with the known neural inputs activating the different muscles during swallowing. Derivation of "activation state" maps may allow better physiological and pathophysiological interpretations of UES function. PMID- 26767987 TI - Construction of an environmental safe Bacillus thuringiensis engineered strain against Coleoptera. AB - Cloning of new toxic genes from Bacillus thuringiensis (Bt) and construction of Bt engineered strains are two key strategies for bio-control of coleopteran pests in agriculture and forestry. In this study, we cloned a new cry3Aa-type gene, cry3Aa8, from wild Bt strain YC-03 against coleopteran, and constructed a Bt engineered strain, ACE-38, containing insecticidal protein-encoding gene cry3Aa8. The engineered strain, with almost four times of Cry3Aa yield compared with strain YC-03, was an antibiotic marker-free strain. Though no selective pressure was presented in the medium, cry3Aa8 in the engineered strain ACE-38 remained stable. The yield of Cry3Aa by strain ACE-38 reached 2.09 mg/ml in the optimized fermentation medium. The activity of strain ACE-38 against Plagiodera versicolora was tested, and the LC50 of ACE-38 cultures in the optimized fermentation medium was 1.13 MUl/ml. Strain ACE-38 is a non-antibiotic Bt engineered strain with high Chrysomelidae toxicity and exhibits good fermentation property. The modified indigenous site-specific recombination system constructed in this study might be useful for the construction of Bt engineered strains containing genes that cannot be expressed in the indigenous site-specific recombination system using plasmid pBMB1205R. PMID- 26767988 TI - Selective oxidation of carotenoid-derived aroma compounds by CYP260B1 and CYP267B1 from Sorangium cellulosum So ce56. AB - Due to their bioactive properties as well as their application as precursors in chemical synthesis, hydroxylated isoprenoids and norisoprenoids are very valuable compounds. The efficient hydroxylation of such compounds remains a challenge in organic chemistry caused by the formation of a variety of side products and lack of overall regio- and stereoselectivity. In contrast, cytochromes P450 are known for their selective oxidation under mild conditions. Here, we demonstrate for the first time the ability of myxobacterial CYP260B1 and CYP267B1 from Sorangium cellulosum So ce56 to oxidize such carotenoid-derived aroma compounds. A focused library of 14 substrates such as ionones, damascones, as well as some of their isomers and derivatives was screened in vitro. Both P450s were capable of an efficient oxidation of all tested compounds. CYP260B1-dependent conversions mainly formed multiple products, whereas conversions by CYP267B1 resulted predominantly in a single product. To identify the main products by NMR spectroscopy, an Escherichia coli-based whole-cell system was used. CYP267B1 showed a hydroxylase activity towards the formation of allylic alcohols. Likewise, CYP260B1 performed the allylic hydroxylation of beta-damascone [(E)-1 (2,6,6-trimethylcyclohex-1-enyl)but-2-en-1-one] and delta-damascone [(E)-1-(2,6,6 trimethylcyclohex-3-enyl)but-2-en-1-one]. Moreover, CYP260B1 showed an epoxidase activity towards beta-ionone [(E)-4-(2,6,6-trimethylcyclohex-1-enyl)but-3-en-2 one] as well as the methyl-substituted alpha-ionone derivatives raldeine [(E)-1 (2,6,6-trimethylcyclohex-2-enyl)pent-1-en-3-one] and isoraldeine [(E)-3-methyl-4 (2,6,6-trimethylcyclohex-2-enyl)but-3-en-2-one]. In addition, to known products, also novel products such as 2-OH-delta-damascone [(E)-1-(5-hydroxy-2,6,6 trimethylcyclohex-3-enyl)but-2-en-1-one], 3-OH-allyl-alpha-ionone [(E)-1-(4 hydroxy-2,6,6-trimethylcyclohex-2-enyl)hepta-1,6-dien-3-one], and 4-OH-allyl-beta ionone [(E)-1-(3-hydroxy-2,6,6-trimethylcyclohex-1-enyl)hepta-1,6-dien-3-one] were identified during our studies. PMID- 26767989 TI - High-efficiency biosynthesis of hypocrellin A in Shiraia sp. using gamma-ray mutagenesis. AB - Hypocrellin A (HA), well known as one of the best natural pigments and bioactive agent to treat skin diseases, is further anticipated to play a vital role in photodynamic therapy (PDT) in anticancer and antiviral treatments. In this study, an HA-producing strain ZZZ816 (Shiraia sp.) was isolated from the moso bamboo (Phyllostachys edulis) seeds, and gamma irradiation was used to mutagenize spores of the original strain. After treatment with cobalt-60 gamma ((60)Cogamma) with different doses (20, 50, 80, 100, 150, 180, 300, and 500 Gy), the 100 Gy was selected as the optimal condition, which led to 77.2 % lethality of spores and 35 % positive mutant frequency. The extracted compound of the most excellent HA producing strain (H-4-2) was precisely analyzed by a combination of seven detection methods, and the maximum HA content was shown to reach 2018.3 mg/L. HA production in H-4-2 increased by 414.9 % compared to that of original strain ZZZ816 (392 mg/L) and was significantly higher than all the other industrial HA producing strains in published reports. PMID- 26767990 TI - L-valine, an antialgal amino acid from Streptomyces jiujiangensis JXJ 0074(T). AB - An antialgal compound was isolated from the cultured broth of Streptomyces jiujiangensis JXJ 0074(T) by using bioassay methods. Based on the data of (1)H NMR, (13)C-NMR, ESI-MS, and thin layer chromatography, the active compound was identified as L-valine, which showed antialgal activity mainly against Microcystis. L-valine exhibited greater antialgal activities than both L-lysine and copper sulfate (CuSO4) did on Microcystis aeruginosa lawn. However, M. aeruginosa recovered growth earlier with higher growth rate in L-valine treatment than in L-lysine treatment. L-valine dissipated completely within 2 days, much quicker than L-lysine (6 days), which resulted in the lysing of more than 80 % M. aeruginosa cells and the release of amount of intracellular microcystin-LR (MC LR) within 2 days. As a resultant, the extracellular MC-LR content was more than twice of the control from day 1 to 5. Exposure to L-valine significantly promoted the synthesis of MC-LR. L-lysine also promoted the release and synthesis of MC-LR with much lesser efficiency than L-valine. L-valine could damage Microcystis severely, causing perforation and collapse of M. aeruginosa cells and decrease of the chlorophyll. The superoxide dismutase (SOD) activity in L-valine-treated cells of M. aeruginosa initially increased with 32.94 +/- 3.37 % higher than the control after 36 h and then decreased quickly. However, the increase rate of superoxide anion radical (O2 (-)) was much higher than that of SOD, which resulted in serious lipid peroxidation and accumulation of malondialdehyde (MDA). To our knowledge, this is the first report showing L-valine active against cyanobacteria. PMID- 26767991 TI - Pancreatic Cystic Mass. PMID- 26767992 TI - Medical use of cannabis products: Lessons to be learned from Israel and Canada. AB - INTRODUCTION: The German government intends to reduce the barriers for the medical use of cannabis products. A discussion on the indications and contraindications of the medical use of cannabis and on the changes of the regulatory framework has already begun in Germany. It is useful to draw from the experiences of other countries with a more liberal medical use of cannabis. METHODS: The Israeli and Canadian experience is outlined by physicians who have been charged with expertise on the medical use of cannabis by their jurisdiction. RESULTS: In Israel, only the plant-based cannabinoid nabiximol (mixture of tetrahydrocannabinol/cannabidiol) can be prescribed for spasticity/chronic pain in multiple sclerosis and for cancer pain. The costs of nabiximole are reimbursed by some, but not by all health maintenance organizations. The medical use of marijuana is permitted; however, it is strictly regulated by the government. Selected companies are allowed to produce marijuana for medical use, and only certain physicians are licensed to prescribe marijuana as a therapeutic drug for specific indications such as chronic neuropathic, and cancer pain, inflammatory bowel diseases, or posttraumatic stress disorder if conventional treatments have failed. The costs of marijuana are not reimbursed by health insurance companies. In Canada, synthetic cannabinoids and the plant-based (nabiximol) are licensed for neuropathic and cancer pain, HIV-related anorexia and chemotherapy-associate nausea. The costs of these synthetic cannabinoids are covered by health insurance companies. The medical use of marijuana as a treatment option is allowed for individual patients suffering from any medical condition when authorized by a medical practitioner or nurse. Licensed producers are the only source for patients to newly access medical cannabis, although those with previous permission to grow may continue cultivation at the present time. The costs of marijuana are not reimbursed by health insurance companies. There are multiple contraindications for the medical use of cannabis products in both countries. CONCLUSIONS: The use of standardized, synthetic, and plant-based cannabis products should be allowed in Germany for defined medical conditions when high level evidence of efficacy and safety exists. The costs should be reimbursed by the health insurance companies. Contraindications for the medical use of cannabis should be defined. Growing marijuana by patients for their medical use should not be allowed. PMID- 26767994 TI - Visualizing the HoxD Gene Cluster at the Nanoscale Level. AB - Transcription of HoxD cluster genes in limbs is coordinated by two topologically associating domains (TADs), neighboring the cluster and containing various enhancers. Here, we use a combination of microscopy approaches and chromosome conformation capture to assess the structural changes occurring in this global architecture in various functional states. We observed that despite their spatial juxtaposition, the TADs are consistently kept as distinct three-dimensional units. Hox genes located at their boundary can show significant spatial segregation over long distances, suggesting that physical elongation of the HoxD cluster occurs. The use of superresolution imaging (STORM [stochastic optical reconstruction microscopy]) revealed that the gene cluster can be in an either compact or elongated shape. The latter configuration is observed in transcriptionally active tissue and in embryonic stem cells, consistent with chromosome conformation capture results. Such morphological changes at HoxD in developing digits seem to be associated with its position at the boundary between two TADs and support the idea that chromatin dynamics is important in the establishment of transcriptional activity. PMID- 26767993 TI - Efficacy, tolerability and safety of cannabinoids in chronic pain associated with rheumatic diseases (fibromyalgia syndrome, back pain, osteoarthritis, rheumatoid arthritis): A systematic review of randomized controlled trials. AB - BACKGROUND: In the absence of an ideal treatment for chronic pain associated with rheumatic diseases, there is interest in the potential effects of cannabinoid molecules, particularly in the context of global interest in the legalization of herbal cannabis for medicinal use. METHODS: A systematic search until April 2015 was conducted in Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, www.cannabis-med.org and clinicaltrials.gov for randomized controlled trials with a study duration of at least 2 weeks and at least ten patients per treatment arm with herbal cannabis or pharmaceutical cannabinoid products in fibromyalgia syndrome (FMS), osteoarthritis (OA), chronic spinal pain, and rheumatoid arthritis (RA) pain. Outcomes were reduction of pain, sleep problems, fatigue and limitations of quality of life for efficacy, dropout rates due to adverse events for tolerability, and serious adverse events for safety. The methodology quality of the randomized controlled trials (RCTs) was evaluated by the Cochrane Risk of Bias Tool. RESULTS: Two RCTs of 2 and 4 weeks duration respectively with nabilone, including 71 FMS patients, one 4-week trial with nabilone, including 30 spinal pain patients, and one 5-week study with tetrahydrocannbinol/cannabidiol, including 58 RA patients were included. One inclusion criterion was pain refractory to conventional treatment in three studies. No RCT with OA patients was found. The risk of bias was high for three studies. The findings of a superiority of cannabinoids over controls (placebo, amitriptyline) were not consistent. Cannabinoids were generally well tolerated despite some troublesome side effects and safe during the study duration. CONCLUSIONS: Currently, there is insufficient evidence for recommendation for any cannabinoid preparations for symptom management in patients with chronic pain associated with rheumatic diseases. PMID- 26767996 TI - Erratum to: Thermodynamic Changes Induced by Intermolecular Interaction Between Ibuprofen and Chitosan: Effect on Crystal Habit, Solubility and In Vitro Release Kinetics of Ibuprofen. PMID- 26767995 TI - Prenucleosomes and Active Chromatin. AB - Chromatin consists of nucleosomes as well as nonnucleosomal histone-containing particles. Here we describe the prenucleosome, which is a stable conformational isomer of the nucleosome that associates with ~80 bp DNA. Prenucleosomes are formed rapidly upon the deposition of histones onto DNA and can be converted into canonical nucleosomes by an ATP-driven chromatin assembly factor such as ACF. Different lines of evidence reveal that there are prenucleosome-sized DNA containing particles with histones in the upstream region of active promoters. Moreover, p300 acetylates histone H3K56 in prenucleosomes but not in nucleosomes, and H3K56 acetylation is found at active promoters and enhancers. These findings therefore suggest that there may be prenucleosomes or prenucleosome-like particles in the upstream region of active promoters. More generally, we postulate that prenucleosomes or prenucleosome-like particles are present at dynamic chromatin, whereas canonical nucleosomes are at static chromatin. PMID- 26767997 TI - A critical Examination of the Phenomenon of Bonding Area - Bonding Strength Interplay in Powder Tableting. AB - PURPOSE: Although the bonding area (BA) and bonding strength (BS) interplay is used to explain complex tableting behaviors, it has never been experimentally proven. The purpose of this study is to unambiguously establish the distinct contributions of each by decoupling the contributions from BA and BS. METHODS: To modulate BA, a Soluplus(r) powder was compressed into tablets at different temperatures and then broken following equilibration at 25 degrees C. To modulate BS, tablets were equilibrated at different temperatures. To simultaneously modulate BA and BS, both powder compression and tablet breaking test were carried out at different temperatures. RESULTS: Lower tablet tensile strength is observed when the powder is compressed at a lower temperature but broken at 25 degrees C. This is consistent with the increased resistance to polymer deformation at lower temperatures. When equilibrated at different temperatures, the tensile strength of tablets prepared under identical conditions increases with decreasing storage temperature, indicating that BS is higher at a lower temperature. When powder compression and tablet breaking are carried out at the same temperature, the profile with a maximum tensile strength at 4 degrees C is observed due to the BA BS interplay. CONCLUSION: By systematically varying temperature during tablet compression and breaking, we have experimentally demonstrated the phenomenon of BA-BS interplay in tableting. PMID- 26767998 TI - Erratum to: Proximal humeral fractures in elderly patients. PMID- 26767999 TI - Rising incidence of fall-induced maxillofacial injuries among older adults. AB - BACKGROUND: Various fall-induced injuries in older adults are a major public health problem. AIM: We aimed to assess the current trends in the fall-induced severe maxillofacial injuries among older adults in Finland, an EU country with a well-defined white population of 5.5 million. METHODS: The injury trends were determined by taking into account all persons 60 years of age or older who were admitted to Finnish hospitals for primary treatment of these injuries between 1999 and 2014. RESULTS: The number of fall-induced maxillofacial injuries among older Finnish adults doubled during the 16-year follow-up, from 434 in 1999 to 981 in 2014. The age-adjusted incidence of injury (per 100 000 persons) also showed a clear increase from 1999 to 2014: from 47.4 to 71.3 in women, and from 39.2 to 59.6 in men. In both sexes, the increase was most prominent in the oldest age group, persons aged 80 years or older. CONCLUSIONS: The number of fall induced severe maxillofacial injuries among older Finns rose considerably between 1999 and 2014-with a rate that could not be explained merely by demographic changes. Further studies are urgently needed to better assess the reasons for the rise and possibilities for injury prevention. PMID- 26768001 TI - Accuracy of circulating adiponectin for predicting gestational diabetes: a systematic review and meta-analysis. AB - AIMS/HYPOTHESIS: Universal screening for gestational diabetes mellitus (GDM) has not been implemented, and this has had substantial clinical implications. Biomarker-directed targeted screening might be feasible. We sought to determine the accuracy of circulating adiponectin for early prediction of GDM. METHODS: A systematic review and meta-analysis of the literature to May 2015 identified studies in which circulating adiponectin was measured prior to a diagnosis of GDM. Data on diagnostic accuracy were synthesised by bivariate mixed effects and hierarchical summary receiver operating characteristic (HSROC) models. RESULTS: Thirteen studies met the eligibility criteria, 11 of which (2,865 women; 794 diagnosed with GDM) had extractable data. Circulating adiponectin had a pooled diagnostic odds ratio (DOR) of 6.4 (95% CI 4.1, 9.9), a summary sensitivity of 64.7% (95% CI 51.0%, 76.4%) and a specificity of 77.8% (95% CI 66.4%, 86.1%) for predicting future GDM. The AUC of the HSROC was 0.78 (95% CI 0.74, 0.81). First trimester adiponectin had a pooled sensitivity of 60.3% (95% CI 46.0%, 73.1%), a specificity of 81.3% (95% CI 71.6%, 88.3%) and a DOR of 6.6 (95% CI 3.6, 12.1). The AUC was 0.79 (95% CI 0.75, 0.82). Pooled estimates were similar after adjustment for age, BMI or specific GDM diagnostic threshold. CONCLUSIONS/INTERPRETATION: Pre-pregnancy and early pregnancy measurement of circulating adiponectin may improve the detection of women at high risk of developing GDM. Prospective evaluation of the combination of adiponectin and maternal characteristics for early identification of those who do and do not require OGTT is warranted. PMID- 26768000 TI - Relationships between adiponectin and matrix metalloproteinase-9 (MMP-9) serum levels and postoperative cognitive dysfunction in elderly patients after general anesthesia. AB - OBJECTIVE: The aim of this study was to evaluate the relationships between the serum levels of adiponectin (ADP) and matrix metalloproteinase-9 (MMP-9) and postoperative cognitive dysfunction (POCD) in elderly patients after general anesthesia. METHODS: The cognitive functions of 98 elderly patients who were scheduled to undergo selective hip replacement surgery under general anesthesia were assessed using the Montreal Cognitive Assessment (MoCA) 3 days before surgery and on postoperative Days 1, 2, 3, and 7. The serum levels of ADP and MMP 9 were determined at the same time points, and the presence of POCD on postoperative Day 3 was recorded. The patients were divided into a POCD group and non-POCD group. RESULTS: Postoperative cognitive dysfunction was observed in 28 patients (28.5 %). Serum MMP-9 levels significantly increased and serum ADP levels significantly decreased in the POCD group at each postoperative time point and in the non-POCD group on postoperative Days 1 and 2 compared to the presurgical levels. Serum MMP-9 levels were significantly higher and serum ADP levels were significantly lower in the POCD group compared with those in the non POCD group at each time point. In the POCD patients, serum MMP-9 levels were significantly and negatively correlated and serum ADP levels were significantly and positively correlated with the MoCA scores. CONCLUSIONS: The increased serum MMP-9 levels and decreased serum ADP levels in elderly patients after general anesthesia might be involved in the POCD pathophysiological process. PMID- 26768002 TI - Simultaneous pancreas-kidney transplantation in patients with type 1 diabetes reverses elevated MBL levels in association with MBL2 genotype and VEGF expression. AB - AIMS/HYPOTHESIS: High levels of circulating mannan-binding lectin (MBL) are associated with the development of diabetic nephropathy and hyperglycaemia induced vasculopathy. Here, we aimed to assess the effect of glycaemic control on circulating levels of MBL and the relationship of these levels with vascular damage. METHODS: We assessed MBL levels and corresponding MBL2 genotype, together with vascular endothelial growth factor (VEGF) levels as a marker of vascular damage, in type 1 diabetes patients with diabetic nephropathy before and after simultaneous pancreas-kidney (SPK) transplantation. We included diabetic nephropathy patients (n = 21), SPK patients (n = 37), healthy controls (n = 19), type 1 diabetes patients (n = 15) and diabetic nephropathy patients receiving only a kidney transplant (n = 15). Fourteen diabetic nephropathy patients were followed up for 12 months after SPK. RESULTS: We found elevated circulating MBL levels in diabetic nephropathy patients, and a trend towards elevated circulating MBL levels in type 1 diabetes patients, compared with healthy control individuals. MBL levels in SPK patients completely normalised and our data indicate that this predominantly occurs in patients with a polymorphism in the MBL2 gene. By contrast, MBL levels in kidney transplant only patients remained elevated, suggesting that glycaemic control but not reversal of renal failure is associated with decreased MBL levels. In line, levels of glucose and HbA1c, but not creatinine levels and estimated GFR, were correlated with MBL levels. VEGF levels were associated with levels of MBL and HbA1c in an MBL-polymorphism dependent manner. CONCLUSIONS/INTERPRETATION: Taken together, circulating MBL levels are associated with diabetic nephropathy and are dependent on glycaemic control, possibly in an MBL2-genotype-dependent manner. PMID- 26768003 TI - Oncology E-Learning for Undergraduate. A Prospective Randomized Controlled Trial. AB - : The e-learning education is a promising method, but there are few prospective randomized publications in oncology. The purpose of this study was to assess the level of retention of information in oncology from undergraduate students of physiotherapy. A prospective, controlled, randomized, crossover study, 72 undergraduate students of physiotherapy, from the second to fourth years, were randomized to perform a course of physiotherapy in oncology (PHO) using traditional classroom or e-learning. Students were offered the same content of the subject. The teacher in the traditional classroom model and the e-learning students used the Articulate(r) software. The course tackled the main issues related to PHO, and it was divided into six modules, 18 lessons, evaluated by 126 questions. A diagnosis evaluation was performed previous to the course and after every module. The sample consisted of 67 students, allocated in groups A (n = 35) and B (n = 32), and the distribution was homogeneous between the groups. Evaluating the correct answers, we observed a limited score in the pre-test (average grade 44.6 %), which has significant (p < 0.001) improvement in post test evaluation (average grade 73.9 %). The correct pre-test (p = 0.556) and post test (p = 0.729) evaluation and the retention of information (p = 0.408) were not different between the two groups. The course in PHO allowed significant acquisition of knowledge to undergraduate students, but the level of information retention was statistically similar between the traditional classroom form and the e-learning, a fact that encourages the use of e-learning in oncology. CLINICAL TRIAL REGISTRATION NUMBER: REBECU1111-1142-1963. PMID- 26768004 TI - Prevalence and recurrence rate of perianal abscess--a population-based study, Sweden 1997-2009. AB - INTRODUCTION: The aim of this study was to assess the impact of diabetes mellitus, Crohn's disease, HIV/aids, and obesity on the prevalence and readmission rate of perianal abscess. METHODS: The study cohort was based on the Swedish National Patient Register and included all patients treated for perianal abscess in Sweden 1997-2009. The prevalence and risk for readmission were assessed in association with four comorbidity diagnoses: diabetes mellitus, Crohn's disease, HIV, and/or AIDS and obesity. RESULTS: A total of 18,877 patients were admitted during the study period including 11,138 men and 4557 women (2.4:1). Crohn's disease, diabetes, and obesity were associated with a significantly higher prevalence of perianal abscess than an age- and gender matched background population (p < 0.05). In univariate analysis, neither age nor gender had any significant impact on the risk for readmission. In a multivariate Cox proportional hazard analysis, Crohns disease was the only significant risk factor for readmission of perianal abscess. CONCLUSION: Crohn's disease, diabetes, and obesity increase the risk for perianal abscess. Of these, Crohn's and HIV has an impact on readmission. The pathogenesis and the influence of diabetes and obesity need further research if we are to understand why these diseases increase the risk for perianal abscess but not its recurrence. PMID- 26768005 TI - Assessing the Costs Associated with Volume-Based Referral for Hepatic Surgery. AB - BACKGROUND: Although proposed as a means for quality improvement, little is known regarding the economic consequences of volume-based referral. The objective of the current study was to investigate the relationship between inpatient costs and hospital volume. METHODS: Patients undergoing elective liver surgery were identified using the Nationwide Inpatient Sample from 2001 to 2012. Multivariable hierarchical regression analyses were performed to calculate and compare risk adjusted costs and postoperative outcomes across hospital volume terciles. RESULTS: A total of 27,813 patients underwent surgery at 2207 hospitals. Although costs were comparable across the three volume groups (all p > 0.05), patients who developed a postoperative complication incurred a higher overall cost (complication vs. no complication; median costs $17,974 [IQR 13,865-25,623] vs. $41,731 [IQR 27,008-64,266], p < 0.001). In contrast, while the incidence of postoperative complications (low vs. intermediate vs. high; 22.0 vs. 19.2 vs. 13.0 %, p < 0.001) and subsequent failure-to-rescue (low vs. intermediate vs. high; 16.6 vs. 24.7 vs. 15.1 %, p < 0.001) was lower at high-volume hospitals, costs associated with "rescue" were substantially higher at high-volume hospitals (low vs. intermediate vs. high; $39,289 vs. $36,157 vs. $48,559, both p < 0.001). CONCLUSIONS: Compared with lower volume hospitals, improved outcomes among patients who developed a complication at high-volume hospitals were associated with an increased cost. PMID- 26768006 TI - Does Conversion in Laparoscopic Colectomy Portend an Inferior Oncologic Outcome? Results from 104,400 Patients. AB - BACKGROUND: Limited data exist regarding the effect of conversion from laparoscopic to open colectomy on perioperative and oncologic outcomes in colon cancer. STUDY DESIGN: The National Cancer Data Base was used to identify patients who underwent colectomy for non-metastatic colon cancer (2010-2012). Patients were stratified into three groups: laparoscopic/robotic-assisted colectomy (MIC), converted colectomy (CC), and open colectomy (OC). Multivariable modeling was applied to compare outcomes from CC and MIC to OC while adjusting for patient, clinical, and tumor characteristics. RESULTS: Of 104,400 patients, 40,328 (38.6 %) underwent MIC, 57,928 (55.5 %) OC, and 6144 (5.9 %) CC. After adjustment, the rate of positive surgical margins was not significantly different between CC and OC (p = 0.44). However, with adjustment, CC versus OC was associated with shorter hospital length of stay (4 % decrease, 95 % CI 2-5 %, p < 0.0001) and lower odds of 30-day mortality (OR 0.77, 95 % CI 0.64-0.94, p = 0.0112). Adjusted overall survival was similar between CC and OC (p = 0.34). CONCLUSIONS: Conversion from laparoscopic to open colectomy was not associated with compromised oncologic outcomes, while maintaining improved short-term outcomes despite being attempted in only 45 % of patients. This data suggests that utilization of laparoscopic colectomy should be attempted for patients with colon cancer. PMID- 26768007 TI - Primary Eosinophilic Gastritis in a Child with Gastric Outlet Obstruction. AB - A 3-year-old girl presented with multiple episodes of vomiting, fever, and hematemesis for the past 2 months. Except for hemoglobin, her rests of the laboratory tests were unremarkable. Her barium X-ray showed absence of the duodenal bulb and the C-loop. Her endoscopy showed deformed stomach with multiple ulcers and diverticuli. The gastric outlet was not visualized. Distal gastrectomy with gastro-duodenal anastomosis was performed. Histopathological findings revealed transmural dense infiltrates of eosinophils, consistent with eosinophilic gastritis. PMID- 26768008 TI - Significance of Portal Vein Invasion and Extent of Invasion in Patients Undergoing Pancreatoduodenectomy for Pancreatic Adenocarcinoma. AB - INTRODUCTION: Several studies have confirmed the safety of pancreatoduodenectomy with portal/mesenteric vein resection and reconstruction in select patients. The effect of vein invasion and extent of invasion on survival is less clear. The purpose of this study was to examine the association between tumor invasion of the portal/mesenteric vein and long-term survival. METHODS: A retrospective review of a prospectively maintained database of patients who underwent pancreatoduodenectomy for pancreatic adenocarcinoma at a single academic medical center (2000-2014) was performed. Survival was compared using the Kaplan-Meier method and log-rank test. P < 0.05 was considered statistically significant. RESULTS: After non-pancreatic periampullary adenocarcinomas and patients with non segmental (lateral wall only) resection of portal/mesenteric vein were excluded, there were 567 eligible patients. Of these, segmental vein resection was performed in 90 (16 %) with end-to-end primary anastomosis (67) or interposition graft reconstruction (23). Patients with vein resection more likely received neoadjuvant systemic therapy (59 vs. 4 %, p < 0.0001). Histopathology of patients undergoing vein resection revealed a distribution of T stage toward larger tumors and higher rates of perineural invasion. Portal/mesenteric vein resection, however, was not associated with differences in hospital stay, postoperative complications, or operative mortality. Patients with or without vein resection had comparable overall survival rates at 1-, 3-, and 5-years. On final surgical histopathology, only 52 of 90 (58 %) vein resections had adenocarcinoma involvement of the venous wall. Of these, depth of invasion was at the level of the adventitia (9), media/intima (34), and full thickness/intraluminal (9). Venous wall invasion (52) did not significantly influence overall survival (14 vs. 21 months, p = 0.08) but was associated with significantly shorter median disease-free survival (11.3 vs. 15.8 months, p = 0.03), predominantly due to local recurrence. The extent of invasion (adventitia, media/intima, full thickness/intraluminal) did not impact overall survival or disease-free survival (14.4 vs. 15.5 vs. 7.4 months, p = 0.08 and 11.2 vs. 12.2 vs. 5 months, 0.59, respectively). Portal/mesenteric vein resection, histopathologic invasion, or the extent of invasion were not independent predictors of overall survival in Cox regression analysis. CONCLUSION: Although Portal/mesenteric vein resection is associated with increased 90-day mortality, venous resection is not prognostic of overall survival. Although a subgroup analysis showed that a direct tumor invasion into the vein wall on final histopathology was associated with a higher rate of local recurrence but with no difference in overall survival (even when stratified according to extent of venous wall invasion), larger studies with an increased power will be needed to confirm these findings. PMID- 26768009 TI - Severe Sepsis in Elderly Patients Undergoing Gastrointestinal Surgery-a Prospective Multicenter Follow-up Study of Finnish Intensive Care Units. AB - BACKGROUND: We aimed to evaluate the outcome of elderly patients with severe sepsis after alimentary tract surgery. METHODS: A prospective study was conducted in 24 intensive care units (ICU) in Finland. Four thousand five hundred consecutive patients were admitted to ICUs and 470 patients fulfilled the criteria for severe sepsis. All patients who had undergone gastrointestinal surgery were included. The outcomes of elderly (>=65 years) and younger patients were compared. The key factor under analysis was death from any cause during the hospitalization or within 1 year after the surgery. RESULTS: A total of 73 elderly patients (and 81 younger patients) were found to have severe alimentary tract surgery-related sepsis. The mean age of the elderly patients was 76.4 years, and 56.2 % were female. The most common indication for surgery was acute cholecystitis (21.9 %), followed by acute diverticulitis (13.7 %), and gastroduodenal ulcer (13.7 %). The anatomic site of the infection was intra abdominal in 86.3 % of cases, the second most common being pulmonary (13.7 %). In hospital mortality was 47.9 % and 1-year mortality 64.4 %. Of the discharged patients, 31.6 % died within 1 year. Patients who died were older and more frequently had concomitant conditions. The ICU scoring systems (APACHE, SAPS, and SOFA) and elevated lactate levels were predictive of increased mortality. CONCLUSION: Severe sepsis among the elderly is a rare but often-fatal infectious event. In addition to high in-hospital mortality, it is also associated with significant 1-year mortality. PMID- 26768010 TI - Body mass index and chronic airflow limitation in a worldwide population-based study. AB - Nutritional status has been associated with clinical outcome in chronic airflow limitation (CAL), but epidemiological studies are scarce. We aimed to assess the relationship between body mass index (BMI) and CAL, taking into account confounding factors. 18,606 participants (49% male, 21% smokers, mean age: 55.8 +/- 11.2 years, mean BMI: 26.7 +/- 5.5 kg/m(2)) of the BOLD initiative from 26 sites in 23 countries were included. CAL was defined as post-bronchodilator forced expiratory volume in the first second/forced vital capacity < lower limit of normal. Low and obese BMI were defined as <21 kg/m(2) and >=30 kg/m(2), respectively. Multivariate logistic regression analysis controlled for confounders age, sex and smoking, and meta-analysis of between-site heterogeneity and clustering. Prevalence of low and obese BMI, smoking history and prevalence of CAL were highly variable between sites. After adjustment for confounders, the meta-analysis of all sites showed that compared to subjects without CAL, low BMI was more frequent, (adjusted odds ratio (OR): 2.23 (95% confidence interval: 1.75, 2.85)) and conversely, obesity was less frequent in subjects with CAL (adjusted OR: 0.78 (0.65, 0.94)). In a worldwide population sample, CAL was associated with lower BMI, even after adjusting for confounding factors age, gender, smoking and between-site heterogeneity. These results indicate a CAL specific association with body composition. PMID- 26768011 TI - Respiratory and lower limb muscle function in interstitial lung disease. AB - Growing evidence suggests that respiratory and limb muscle function may be impaired in patients with interstitial lung disease (ILD). Importantly, muscle dysfunction could promote dyspnoea, fatigue and functional limitation all of which are cardinal features of ILD. This article examines the risk factors for skeletal muscle dysfunction in ILD, reviews the current evidence on overall respiratory and limb muscle function and focuses on the occurrence and implications of skeletal muscle dysfunction in ILD. Research limitations and pathways to address the current knowledge gaps are highlighted. PMID- 26768013 TI - The conserved histone deacetylase Rpd3 and the DNA binding regulator Ume6 repress BOI1's meiotic transcript isoform during vegetative growth in Saccharomyces cerevisiae. PMID- 26768012 TI - Argininosuccinic Aciduria-A Rare Indication for Liver Transplant: Report of Two Cases. AB - Argininosuccinic aciduria is a urea cycle disorder caused by an argininosuccinate lyase enzyme deficiency that ends with nitrogen accumulation as ammonia. Argininosuccinic aciduria patients are at risk for long-term complications including poor neurocognitive outcome, hepatic disease, and systemic hypertension despite strict pharmacologic and dietary therapy. As the liver is the principle site of activity of the urea cycle, it is logical that a liver transplant should be an option, with careful patient selection, even in the absence of cirrhosis. We present 2 pediatric argininosuccinic aciduria patients who underwent a living donor liver transplant from their mothers. After the liver transplant, the general well-being of the patients and their quality of life improved significantly. Liver transplant should be an option for argininosuccinic aciduria patients to prevent further neurologic deterioration and improve the patient's quality of life. PMID- 26768014 TI - Therapeutic concentrations of sulfasalazine interfere with ammonia, but not with alanine-aminotransferase determination in enzymatic tests. PMID- 26768016 TI - Gossypiboma Mimicking a Mesenchymal Tumor: A Report of a Rare Case. AB - BACKGROUND: Gossypiboma is the term for a surgical complication resulting from foreign materials such as a surgical sponge or gauze that was accidentally left inside a patient's body. CASE REPORT: Here, we report the case of a 62-year-old woman with gossypiboma. She underwent surgery due to an abdominal mass that was preoperatively considered a tumor. Intra-postoperatively, it was diagnosed as gossypiboma. CONCLUSIONS: For the prevention of gossypiboma during the pre operative and post-operative periods, counting sponges and surgical equipment must be done very carefully. If there is any doubt postoperatively, direct abdominal imaging may be helpful. PMID- 26768017 TI - Increasing the Availability and Quality of Donor Eyes for Research. PMID- 26768018 TI - Differences in 25-hydroxyvitamin D concentrations and sugar consumption may help explain socioeconomic and racial/ethnic oral health disparities among US older adults. PMID- 26768019 TI - Anatomical and radiological approach to pterygoid implants: a cross-sectional study of 202 cone beam computed tomography examinations. AB - The aim of this study was to define the three-dimensional angulation of the pterygomaxillary corridor in which pterygoid implants should ideally be placed. A secondary objective was to study the bone density in the tuberosity area and pterygoid plate. Two hundred and two cone beam computed tomography files of atrophic posterior maxillae were evaluated. Implant placement was guided by the individual anatomy of each patient. The mean implant angulation was 74.19+/-3.13 degrees in the anteroposterior axis and 81.09+/-2.65 degrees in the buccopalatal axis, relative to the Frankfort plane. Density in the tuberosity area ranged from 285.8 to 329.1DV units and density in the pterygoid plate area from 602.9 to 661.2DV units, with a 95% confidence interval. The density in the pterygoid area was 139.2% greater than in the tuberosity zone. Implant placement should be guided by the individual anatomy of each patient. Statistically significant differences were found between the tuberosity and pterygoid plate in terms of bone density. Based on the results of this study, an implant of at least 15mm long should be used in order to take advantage of the quantity and quality of the bone in this region. PMID- 26768020 TI - Three-Dimensional Flexible Complementary Metal-Oxide-Semiconductor Logic Circuits Based On Two-Layer Stacks of Single-Walled Carbon Nanotube Networks. AB - We have proposed and fabricated stable and repeatable, flexible, single-walled carbon nanotube (SWCNT) thin film transistor (TFT) complementary metal-oxide semiconductor (CMOS) integrated circuits based on a three-dimensional (3D) structure. Two layers of SWCNT-TFT devices were stacked, where one layer served as n-type devices and the other one served as p-type devices. On the basis of this method, it is able to save at least half of the area required to construct an inverter and make large-scale and high-density integrated CMOS circuits easier to design and manufacture. The 3D flexible CMOS inverter gain can be as high as 40, and the total noise margin is more than 95%. Moreover, the input and output voltage of the inverter are exactly matched for cascading. 3D flexible CMOS NOR, NAND logic gates, and 15-stage ring oscillators were fabricated on PI substrates with high performance as well. Stable electrical properties of these circuits can be obtained with bending radii as small as 3.16 mm, which shows that such a 3D structure is a reliable architecture and suitable for carbon nanotube electrical applications in complex flexible and wearable electronic devices. PMID- 26768021 TI - Doctors and patients express concern over prospect of physician assisted death. PMID- 26768025 TI - Annual Review Issue: Breast Pathology. PMID- 26768027 TI - Pathological criteria and practical issues in papillary lesions of the breast - a review. AB - Papillary lesions of the breast include a broad spectrum of lesions, ranging from benign papilloma, papilloma with atypical ductal hyperplasia (ADH) or ductal carcinoma in situ (DCIS) to papillary carcinoma. The accurate diagnosis of mammary papillary lesions is a challenge for pathologists, owing to the overlapping features among these lesions. In this review, some of the diagnostic criteria of papillary lesions are discussed, with special emphasis on some key morphological features, namely fibrovascular cores, epithelial proliferation in a solid pattern, intraductal papilloma complicated by ADH or DCIS, and invasion and its mimics. The roles of immunohistochemistry, and the interpretation of myoepithelial cell markers, hormone receptors, and high molecular weight cytokeratin, are addressed. Finally, novel biomarkers and genetic aberrations in papillary lesions are summarized. PMID- 26768028 TI - An approach to the diagnosis of spindle cell lesions of the breast. AB - Although most breast spindle cell lesions (BSCLs) are rare, they constitute a wide spectrum of diseases, ranging from reactive processes to aggressive malignant tumours. Despite their varied histogenesis and behaviour, some lesions show an overlap of morphological features, making accurate diagnosis a challenging task, particularly in needle core biopsies. Clinical history and immunohistochemistry can help in making a correct diagnosis in morphologically challenging cases. To make an accurate diagnosis, it is important to maintain a wide differential diagnosis and be familiar with the diverse morphological appearances of these different entities. BSCLs can generally be classified into bland-looking and malignant-looking categories. In the former, the commonest diagnosis is scarring. However, it is important to distinguish low-grade spindle cell metaplastic breast carcinoma from other benign entities, as the management is clearly different. In the malignant category, it is important to differentiate metaplastic carcinoma from other malignant primary and metastatic malignant spindle cell tumours of the breast, such as malignant phyllodes tumour, angiosarcoma, and melanoma. This review focuses on the classification and histological and molecular diagnosis of various BSCLs, with an emphasis on the diagnostic approach, including in core biopsies. PMID- 26768029 TI - E-cadherin immunohistochemistry in breast pathology: uses and pitfalls. AB - E-cadherin immunohistochemistry is used commonly in surgical pathology practice to help distinguish lobular carcinoma in situ from ductal carcinoma in situ and invasive lobular carcinoma from invasive ductal carcinoma in histologically problematic or indeterminate cases. However, the interpretation of E-cadherin immunostains is not always straightforward. Failure to recognize the pitfalls and limitations of E-cadherin immunostains can lead to an erroneous diagnosis which may result in inappropriate patient management, particularly for patients with in situ lesions. In this paper we review the uses and, particularly, the pitfalls in the interpretation of E-cadherin immunostains in distinguishing lobular from ductal lesions of the breast. PMID- 26768030 TI - Biomarker assessment and molecular testing for prognostication in breast cancer. AB - Current treatment of breast cancer incorporates clinical, pathological and molecular data. Oestrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) define prognosis and identify tumours for targeted therapy, and remain the sole established single-molecule biomarkers defining the minimum breast cancer pathology data set. Ki67 remains one of the most promising yet controversial biomarkers in breast cancer, implemented routinely in some, but not all, pathology departments. Beyond the single-molecule biomarkers, a host of multigene expression tests have been developed to interrogate the driver pathways and biology of individual breast cancers to predict clinical outcome more accurately. A minority of these assays have entered into clinical practice. This review focuses on the established biomarkers of ER, PR and HER2, the controversial but clinically implemented biomarker Ki67 and the currently marketed gene expression signatures. PMID- 26768026 TI - Phyllodes tumours of the breast: a consensus review. AB - Phyllodes tumours constitute an uncommon but complex group of mammary fibroepithelial lesions. Accurate and reproducible grading of these tumours has long been challenging, owing to the need to assess multiple stratified histological parameters, which may be weighted differently by individual pathologists. Distinction of benign phyllodes tumours from cellular fibroadenomas is fraught with difficulty, due to overlapping microscopic features. Similarly, separation of the malignant phyllodes tumour from spindle cell metaplastic carcinoma and primary breast sarcoma can be problematic. Phyllodes tumours are treated by surgical excision. However, there is no consensus on the definition of an appropriate surgical margin to ensure completeness of excision and reduction of recurrence risk. Interpretive subjectivity, overlapping histological diagnostic criteria, suboptimal correlation between histological classification and clinical behaviour and the lack of robust molecular predictors of outcome make further investigation of the pathogenesis of these fascinating tumours a matter of active research. This review consolidates the current understanding of their pathobiology and clinical behaviour, and includes proposals for a rational approach to the classification and management of phyllodes tumours. PMID- 26768031 TI - Markers of metastatic carcinoma of breast origin. AB - This review summarizes the three major breast-associated markers that can be of assistance in evaluating metastatic carcinomas for which a breast primary diagnosis is entertained. These markers include gross cystic disease fluid protein-15 (GCDFP-15), mammaglobin, and GATA3. The first two are cytoplasmic markers that show comparable sensitivities for breast cancer, although relatively few of the published studies have employed the same antibodies against the target molecule, making direct comparisons challenging. GATA3 is a nuclear transcription factor that shows superior sensitivity to GCDFP-15 and mammaglobin. However, the specificity of GATA3 can pose challenges, inasmuch as carcinomas of the bladder and other sites can show significant levels of positivity. Determination of the optimal panel of antibodies employed in a given clinical setting will thus depend on the non-breast tumours included in the differential diagnosis. PMID- 26768032 TI - Ductal carcinoma in situ - update on risk assessment and management. AB - Ductal carcinoma in situ (DCIS) accounts for ~20-25% of breast cancers. While DCIS is not life-threatening, it may progress to invasive carcinoma over time, and treatment intended to prevent invasive progression may itself cause significant morbidity. Accurate risk assessment is therefore necessary to avoid over- or undertreatment of an individual patient. In this review we will outline the evidence for current management of DCIS, discuss approaches to DCIS risk assessment and challenges facing identification of novel DCIS biomarkers. PMID- 26768033 TI - The cancer genetics and pathology of male breast cancer. AB - Male breast cancer (MBC) is an uncommon and poorly understood disease. Recent molecular studies have shown important differences from female breast cancer which are likely to influence treatment strategies from the current female-based management towards a more tailored approach. Significantly more MBCs than female breast cancers arise with an underlying germline cancer predisposition, and display a vastly different penetrance compared with females. Furthermore, the genophenotypical association of basal-like cancer with BRCA1 present in female breast cancer is not observed in male breast cancer. Differences in somatic changes between male and female breast cancer have also been reported, with particular enrichment of PIK3CA mutations and a paucity of TP53 mutations. In general, chromosomal-based changes, in particular regions of gains, are seen more frequently in male than female breast cancer and methylation is seen less frequently. Clinically, several molecular subtypes with prognostic relevance have been described, including chromosomal complex high and methylation high groups, and subgroups with profiling signatures pertaining to epithelial mesenchymal transition and hormonal therapy insensitivity. As with female breast cancer, attention to male specific multicentre trials based on the individual characteristics are needed, together with establishment of reliable preclinical models to understand more clearly the pathogenesis of male breast cancer and improve the general poor outcome of this disease. PMID- 26768034 TI - Breast cancer stem cells: are we ready to go from bench to bedside? AB - Since the discovery of breast cancer stem cells (BCSCs) more than 10 years ago, a body of exciting research has developed. The intrinsic properties of BCSCs, including self-renewal and the ability to give rise to heterogeneous progeny, make BCSCs a likely source of tumour initiation, heterogeneity, progression and metastasis. BCSCs are also inherently resistant to conventional therapies and are therefore thought to contribute to disease recurrence. In this review, we will focus on both the challenges and recent advances in the characterization of BCSCs with respect to phenotype, molecular signature and their role in the behaviour of the different molecular subtypes of breast cancer. Of most importance is our ability to translate our growing knowledge base into the development of targeted therapies with the goal of reducing adverse outcomes in breast cancer patients. PMID- 26768035 TI - Recommendations for excision following core needle biopsy of the breast: a contemporary evaluation of the literature. AB - Pathologists frequently encounter non-malignant histological findings in percutaneous core needle biopsies (CNBs). Standards for the management of patients with lesions such as atypical ductal hyperplasia, atypical lobular hyperplasia, and lobular carcinoma in situ, as well as other benign lesions, are not well defined, and recommendations for surgical biopsy or continued clinical and radiological follow-up are inconsistent. The frequency with which these lesions are 'upgraded' to carcinoma in excision specimens is widely variable in the literature. Many CNB studies lack careful radiological-pathological correlation, clear criteria for excision, and clinical follow-up for patients on whom excision was not performed. This review of the recent literature emphasizes studies with radiological-pathological correlation, with the goal of developing a contemporary, evidence-based approach to the management of non-malignant lesions of the breast diagnosed on CNB. The data supporting an emerging consensus on which lesions may not require excision are highlighted. The management of non malignant lesions diagnosed on magnetic resonance imaging-guided CNB is also discussed. PMID- 26768038 TI - Hand hygiene: going for gold. PMID- 26768037 TI - Rethinking regulation. PMID- 26768039 TI - Advanced or advancing nursing practice: what is the future direction for nursing? AB - Advanced nursing practice roles have emerged over the last 25 years in response to two major challenges: first, the significant reduction in available doctors; and, second, the rise in numbers of patients with complex health needs. It is suggested that, with a major drive to respond to the first problem, with its emphasis on the development of medical skills, the development of advanced nursing practice (which has the potential to have a significant impact on the second challenge of the rise in long-term conditions) has very much taken second place. Moreover, advanced nursing practice roles have become so medically focused that not only is advanced nursing practice not evident, but neither are the recognised sub-roles that are fundamental to advancing practice. These include innovation, education, research and clinical leadership. This article argues that in the current climate it is essential that advanced nurse practitioners not only demonstrate advanced practice, but also actively embrace the concept of 'advancing' nursing practice as the dominant feature of new roles. PMID- 26768036 TI - Sentinel lymph nodes for breast carcinoma: an update on current practice. AB - Sentinel lymph node (SLN) biopsy has been established as the standard of care for axillary staging in patients with invasive breast carcinoma and clinically negative lymph nodes (cN0). Historically, all patients with a positive SLN underwent axillary lymph node dissection (ALND). The ACOSOG Z0011 trial showed that women with T1-T2 disease and cN0 who undergo breast-conserving surgery and whole-breast radiotherapy can safely avoid ALND. The main goal of SLN examination should be to detect all macrometastases (>2 mm). Gross sectioning of SLNs at 2-mm intervals and microscopic examination of one haematoxylin and eosin-stained section from each SLN block is the preferred method for pathological evaluation of SLNs. The role and timing of SLN biopsy for patients who have received neoadjuvant chemotherapy is controversial, and continues to be explored in clinical trials. SLN biopsies from patients with invasive breast carcinoma who have received neoadjuvant chemotherapy pose particular challenges for pathologists. PMID- 26768040 TI - Recording inpatient weight: implications for medicines administration. AB - AIM: To identify the proportions of hospital inpatients with recorded weights: among all patients, and among those receiving weight-dosed drug therapy. METHOD: Survey of clinical notes of hospital inpatients across a convenience sample of 11 secondary and tertiary referral hospitals in England and Wales in November 2011. RESULTS: 1068 patients were included, and 1061 patient clinical notes were available (99.3%). Nearly all paediatric patients had recorded weights (77/78; 98.7%). Half of adult inpatients had recorded weights (503/983, 51.2%). The proportion of adult inpatients with recorded weights varied by hospital, ranging from 13.5% to 92.5% (p<0.0001). In those receiving gentamicin or therapeutic-dose low molecular weight heparin (t-LMWH), only 64.5% (71/110) had a recorded weight. CONCLUSIONS: Half of adult inpatients, and two-thirds of those receiving gentamicin or t-LMWH, had recorded weights. There was significant variation in rates of weighing adult inpatients across hospitals. This may put patients at increased risk of side effects and problems resulting from malnutrition. PMID- 26768041 TI - Management of the behavioural manifestations of Hunter syndrome. AB - This article reviews the behavioural manifestations of, and the strategies for managing, Hunter syndrome (mucopolysaccharidosis (MPS) type II), a rare X-linked lysosomal storage disorder caused by a deficiency of the enzyme iduronate-2 sulphatase. Hunter syndrome is generally considered to have two manifestations: an attenuated form and a severe form; in the latter, the person has pronounced cognitive decline. Infants with either phenotype usually appear normal at birth, but may show some somatic signs. Children with the severe phenotype show developmental delay and changes in behaviour patterns at about 18 months to 4 years of age. To varying degrees, patients with the severe form manifest behavioural disorders such as hyperactivity, aggression, impulsivity, anxiety and sleep disturbances. Medications, such as antipsychotics, benzodiazepines and anticonvulsants, have been tried with varying degrees of success. Behavioural management strategies may be a worthwhile approach, although published data are lacking. For sleep disturbances, behavioural modification plus melatonin or benzodiazepine may be effective treatments. PMID- 26768042 TI - Shared decision making for patients living with inflammatory arthritis. AB - Providing adequate care for people with inflammatory arthritis is an ongoing challenge. In recent years significant progress has been made in the treatment of inflammatory arthritic conditions. The availability of a wide range of disease modifying anti-rheumatic drugs as well as biologic therapies has not only improved treatment, but also made treatment decisions much more complex. This wider range of improved treatment options happened at the same time as a clear move towards patient-centred care and implementing shared decision making for both medical and surgical conditions. Implementing shared decision making has been reported to be associated with higher satisfaction and better adherence to therapy. Electronic shared decision making has more recently been suggested as a tool for clinical practice. The aim of this article is to look at further integrating shared decision making in standard rheumatology practice in view of the available evidence and the outcomes of a study looking at a recently developed patient shared decision guide. PMID- 26768043 TI - Efficacy of the nurse ethicist in reducing moral distress: what can the NHS learn from the USA? AB - Having first been introduced to nursing 30 years ago, 'moral distress' is not a new concept. Despite this, original research exploring moral distress has been largely absent from nursing literature produced in the UK, yet it has received increasing interest in the USA. Nurse researchers there have sought to explore, measure and understand moral distress. They are now beginning to develop and test ways in which the effects of moral distress can be reduced. The author of this article travelled to various institutions on the east coast of the USA to meet nurses leading the field of research into moral distress. This is the first of two interrelated articles that seek to explore the concept of moral distress. Drawing on both the author's experiences while in the USA and current literature, moral distress will be defined, its known effects described, and ways that nurses can mitigate its effects at a personal level discussed. PMID- 26768044 TI - What do nurses do? Student reflections. AB - The art of caring and the science of curing are accepted elements of a nurse's role, with symbiosis and overlap between them. However, following the publication of the Francis report there is now greater emphasis on developing the caring roles of nurses. The chief nursing officer for England's vision for care staff places care and compassion as central to nurses' roles. Student nurses often enter the profession with idealistic lay beliefs of what a nurse's role exemplifies. These beliefs are then challenged when they are exposed to education and practice. A recent educational evaluative exercise used with adult nursing students highlights their thoughts in response to the simple question: 'What do nurses do?', and how they differ at different stages of their education and training. PMID- 26768045 TI - Pharmacological thromboprophylaxis and total hip or knee replacement. AB - Pharmacological and mechanical thromboprophylaxis reduces the risk of venous thromboembolism (VTE) in patients undergoing total knee/hip replacement (TKR/THR). Nurses play a key role in VTE prevention through clinical care, before and after discharge from hospital, and patient education. Conventional pharmacological agents for VTE prophylaxis include low molecular weight heparins (LMWHs) and fondaparinux. However, parenteral administration, increased bleeding risk, and patient/physician non-adherence to treatment and guidelines, are important limitations. Three non-vitamin K antagonist oral anticoagulants- dabigatran etexilate, rivaroxaban and apixaban--are available in the UK for VTE prevention following THR/TKR. In common with LMWHs and fondaparinux, these offer rapid onset of action and fixed doses without the need for routine coagulation monitoring. An agent for emergency reversal of dabigatran is in development, while there is no antidote for fondaparinux and LMWHs can be partially neutralised by protamine. Oral administration may result in better adherence to treatment and guidelines, reducing the nurse burden after discharge, and enhancing cost-effectiveness. PMID- 26768046 TI - No health without a workforce, no workforce without nurses. AB - Judith Shamian, President of the International Council of Nurses, looks back over 2015 and considers how nurses across the world can address the challenges ahead. PMID- 26768047 TI - Improving care for people nearing end of life. AB - Dion Smyth, Lecturer-Practitioner in Cancer and Palliative Care at Birmingham City University, discusses how important it is for health professionals working across all settings to be aware of the new guidance. PMID- 26768048 TI - Standards for driving and implications for people with diabetes. AB - Richard Griffith, Senior Lecturer in Health Law at Swansea University, discusses the legal standards for driving imposed on individuals with diabetes, and sets out the likely consequences of failing to comply with those standards. PMID- 26768049 TI - Funding nurse education in a climate of austerity. AB - Emeritus Professor Alan Glasper, from the University of Southampton, discusses the Government's plan to increase health professional student numbers, which is also linked to the abolition of student nurse bursaries. PMID- 26768050 TI - From staff nurse to nurse consultant. Writing for publication part 7: structure and presentation. AB - John Fowler, independent education consultant, continues his series for clinical nurses hoping to share their experiences with a wider audience, with advice on developing a potential article for a professional journal. PMID- 26768051 TI - Calling into question the current NHS approach to patient safety: continued. AB - In the second part of a two-part article, John Tingle, Reader in Health Law at Nottingham Trent University, discusses the Health Foundation's recent report into changing the NHS's approach to patient safety. PMID- 26768052 TI - A question of accountability. AB - Sam Foster, Chief Nurse at Heart of England NHS Foundation Trust, considers the pivotal role of the ward leader in the context of staffing challenges. PMID- 26768053 TI - Paediatric and Perinatal Epidemiology: Where we Stand and How's the Future Looking. PMID- 26768054 TI - Implications of Using a Fetuses-at-Risk Approach When Fetuses Are Not at Risk. AB - BACKGROUND: Gestational-age-specific rates of postnatal endpoints are sometimes estimated with denominators based on fetuses-at-risk (FAR), rather than live births. However, as infants can only be included in the numerator after they are born alive, interpretation of such rates is problematic. METHODS: Using simple algebra it can be shown that, at each gestational week, FAR rates of postnatal endpoints are the product of the conventional risk of outcome among live births and the probability of live birth, which increases from near zero early in gestation to close to one in the final weeks. The consequences of such a pattern of live birth on FAR rates are further illustrated in hypothetical scenarios with known conditions. RESULTS: FAR rates of postnatal endpoints will generally increase towards the end of pregnancy due to the rising probability of live birth, regardless of the 'true' effect of immaturity on risk. In the presence of an exposure that increases the probability of early birth, the same mechanism will cause FAR rates to be higher in the exposed group, even if the exposure has no effect. CONCLUSIONS: Gestational-age-specific FAR rates of postnatal outcomes strongly depend on the probability of live birth. Thus, they reflect neither the causal effect of gestational length, nor that of a given exposure. Indeed, if an exposure shortens gestation, FAR rates will be higher in exposed infants even when the exposure has no impact on the outcome under study. These intrinsic limitations should be taken into account when applying FAR analyses to postnatal endpoints. PMID- 26768055 TI - A Consilience of Inductions Supports the Extended Fetuses-at-Risk Model. PMID- 26768056 TI - Quantifying the Risk of Different Types of Perinatal Death in Relation to Gestational Age: Researchers at Risk of Causing Confusion. PMID- 26768057 TI - No Right Answers without Knowing Your Question. PMID- 26768058 TI - Measuring Perinatal Complications: Different Approaches Depending on Who Is at Risk. PMID- 26768059 TI - No Rates Were Harmed in the Making of This Paper: Response to Critiques. PMID- 26768061 TI - Demographic profile and extent of healthcare resource utilisation of patients with severe traumatic brain injury: still a major public health problem. AB - INTRODUCTION: Trauma is the fifth principal cause of death in Singapore, with traumatic brain injury (TBI) being the leading specific subordinate cause. METHODS: This study was an eight-year retrospective review of the demographic profiles of patients with severe TBI who were admitted to the neurointensive care unit (NICU) of the National Neuroscience Institute at Tan Tock Seng Hospital, Singapore, between 2004 and 2011. RESULTS: A total of 780 TBI patients were admitted during the study period; 365 (46.8%) patients sustained severe TBI (i.e. Glasgow Coma Scale score <= 8), with the majority (75.3%) being male. The ages of patients with severe TBI ranged from 14-93 years, with a bimodal preponderance in young adults (i.e. 21-40 years) and elderly persons (i.e. > 60 years). Motor vehicle accidents (48.8%) and falls (42.5%) were the main mechanisms of injury. Invasive line monitoring was frequently employed; invasive arterial blood pressure monitoring and central venous pressure monitoring were used in 81.6% and 60.0% of the patients, respectively, while intracranial pressure (ICP) measurement was required in 47.4% of the patients. The use of tiered therapy to control ICP (e.g. sedation, osmotherapy, cerebrospinal fluid drainage, moderate hyperventilation and barbiturate-induced coma) converged with international practices. CONCLUSION: The high-risk groups for severe TBI were young adults and elderly persons involved in motor vehicle accidents and falls, respectively. In the NICU, the care of patients with severe TBI requires heavy utilisation of resources. The healthcare burden of these patients extends beyond the acute critical care phase. PMID- 26768062 TI - Efficacy of intubation performed by trainees on patients in the lateral position. AB - INTRODUCTION: Anaesthetists may be called upon to emergently secure the airway of a laterally positioned patient. Intubating a patient's trachea in the lateral position may be difficult due to unfamiliarity. This exploratory study aimed to investigate the success rate of lateral intubation performed by novices in a controlled setting. METHODS: In this observational study, all patients who presented for elective surgery requiring the lateral position with planned lateral intubation at Singapore General Hospital were included. The trainee assigned to each patient had no prior indication of the proposed lateral intubation until the start of the case. Verbal instructions were given before the start of and during the procedure. The consultant anaesthetist in attendance could intervene at any point to prevent patient harm or if the trainee requested assistance. Time to intubation, adjuncts used and complications encountered were recorded. RESULTS: A total of 44 consecutive patients were included in this study. The trainees completed 42 of the 44 lateral intubations, with 41 being successfully performed on the first attempt. All patients were intubated successfully in a lateral position within two attempts. The mean duration of intubation was 57.3 +/- 36.4 seconds. There was no difference between left and right lateral intubation. Other than one episode of transient desaturation on pulse oximetry, there were no complications. CONCLUSION: Lateral intubation by trainees had a high success rate when supervised by an experienced operator. Intubation of patients in unconventional positions using routine airway equipment should be included in airway training for trainees. PMID- 26768063 TI - Brucellosis: a retrospective evaluation of 164 cases. AB - INTRODUCTION: Brucellosis is a public health problem that is prevalent in several developing countries. METHODS: The clinical and laboratory characteristics of 164 cases of brucellosis in Bursa, Turkey, were retrospectively evaluated. RESULTS: The ages of the 164 patients ranged from 15-85 years. All of the patients underwent the Rose Bengal test and 163 (99.4%) patients tested positive. 122 (74.4%) patients were diagnosed with acute brucellosis, 31 (18.9%) with subacute brucellosis and 11 (6.7%) with chronic brucellosis. Focal involvement was found in 101 (61.6%) patients. Although patients with focal involvement had a higher white blood cell count (p = 0.002), those without focal involvement had higher aspartate transaminase and alanine transaminase values, and lower platelet values (p = 0.005, 0.007 and 0.039, respectively). Spondylodiscitis was observed on imaging in 58 (66.7%) of the 87 patients who presented with back pain. Among the 118 patients who were examined within the first month of treatment, 79 (66.9%) responded to treatment. The relapse rate was 11.6% among all 164 patients. CONCLUSION: Brucellosis should be considered as a differential diagnosis among patients who present with fever, and joint or back pain. Focal involvement should be investigated in the presence of leucocytosis, and subacute or chronic forms of brucellosis. To identify cases of spondylodiscitis, radiography should be performed in patients who present with back pain. PMID- 26768064 TI - Normative data for hand grip strength and key pinch strength, stratified by age and gender for a multiethnic Asian population. AB - INTRODUCTION: Hand strength is a good indicator of physical fitness and frailty among the elderly. However, there are no published hand strength references for Malaysians aged > 65 years. This study aimed to establish normative data for hand grip strength (HGS) and key pinch strength (KPS) for Malaysians aged >= 60 years, and explore the relationship between hand strength and physical ability. METHODS: Healthy participants aged >= 60 years with no neurological conditions were recruited from rural and urban locations in Malaysia. HGS and KPS were measured using hand grip and key pinch dynamometers. Basic demographic data, anthropometric measures, modified Barthel Index scores and results of the Functional Reach Test (FRT), Timed Up and Go (TUG) test and Jebsen-Taylor Hand Function Test (JTHFT) were recorded. RESULTS: 362 subjects aged 60-93 years were recruited. The men were significantly stronger than the women in both HGS and KPS (p < 0.001). The hand strength of the study cohort was lower than that of elderly Western populations. Significant correlations were observed between hand strength, and residential area (p < 0.001), FRT (r = 0.236, p = 0.028), TUG (r = 0.227, p = 0.009) and JTHFT (r = -0.927, p < 0.001). CONCLUSION: This study established reference ranges for the HGS and KPS of rural and urban elderly Malaysian subpopulations. These will aid the use of hand strength as a screening tool for frailty among elderly persons in Malaysia. Future studies are required to determine the modifiable factors for poor hand strength. PMID- 26768065 TI - Efficacy and safety of topical cyclosporine A 0.05% in vernal keratoconjunctivitis. AB - INTRODUCTION: While corticosteroids are an effective choice of treatment for severe vernal keratoconjunctivitis (VKC), their long-term use is restricted due to side effects. This study was conducted to evaluate the efficacy and safety of topical cyclosporine A (CsA) 0.05% in the treatment of VKC. METHODS: A total of 30 patients with VKC that was resistant to topical corticosteroids, antihistamines and mast cell stabilisers were treated with topical CsA 0.05%. Patients were evaluated at Weeks 4, 8 and 12 after the initiation of therapy. Symptoms and signs observed before and after treatment were recorded and scores were assigned. Scores for symptoms and signs, the need for topical corticosteroids and ocular side effects were evaluated. RESULTS: At baseline, the median values of the symptom and sign scores were 10.0 (range 5.0-18.0) and 6.0 (range 2.0-13.0), respectively. At Week 4 of treatment with topical CsA 0.05%, the median values of the symptom and sign scores were 3.0 (range 0-14.0) and 3.0 (range 0-8.0), respectively. The reductions in the symptom and sign scores were statistically significant. The reduction in the need for corticosteroid was statistically significant by Week 12 of therapy. No significant side effects were reported. CONCLUSION: Topical CsA 0.05%, which can help to reduce corticosteroid usage, is an effective and safe alternative for the treatment of resistant VKC. Further studies are needed to determine the optimal duration of therapy and possibility of recurrence. PMID- 26768067 TI - Incorporating an ontogenetic perspective into evolutionary theory of sexual size dimorphism. AB - Sexual size dimorphism (SSD) describes divergent body sizes of adult males and females. While SSD has traditionally been explained by sexual and fecundity selection, recent advances in physiology and developmental biology emphasize that SSD would occur proximately because of sexual differences in ontogenetic growth trajectories (i.e., growth rate and duration). Notably, these ontogenetic traits are subject to energetic or time constraints and thus traded off with fitness components (e.g., survival and reproduction). To elucidate the importance of such ontogenetic trade-offs in the evolution of SSD, we developed a new theoretical framework by extending quantitative genetic models for the evolution of sexual dimorphism in which we reinterpret the trait as body size and reformulate sex specific fitness in size-dependent manners. More specifically, we assume that higher growth rate or longer growth duration leads to larger body size and higher reproductive success but incurs the cost of lower survivorship or shorter reproduction period. We illustrate how two sexes would optimize ontogenetic growth trajectories in sex-specific ways and exhibit divergent body sizes. The present framework provides new insights into the evolutionary theory of SSD and predictions for empirical testing. PMID- 26768073 TI - Ophthalmologic complications after administration of local anesthesia in dentistry: a systematic review. AB - OBJECTIVE: The aim of this review was to investigate the association between the occurrence of ocular adverse events and dental local anesthesia, the most plausible anatomic mechanisms, and the measures that offer patients a restitutio ad integrum. STUDY DESIGN: This systematic review adopted a structured protocol to access available publications and followed the PRISMA statement. RESULTS: Eighty-nine cases of patients experiencing ocular adverse events after administration of dental local anesthesia have been reported in the literature. Most of the complications manifested as double vision. Only 8% of the complications caused permanent functional damage, either as vision deficit or anisocoria. Complete permanent blindness was not reported. CONCLUSIONS: Ocular complications as a result of dental local anesthesia may be seen as rare occurrences with usually low intensity. However, visual function may become permanently impaired and serious medical conditions may obscure ocular dysfunction. PMID- 26768074 TI - Approaches of robot-assisted neck dissection for head and neck cancer: a review. AB - Robot-assisted surgery is being increasingly used by surgeons because of its enhancement of visualization, precision, and articulation compared with conventional minimally invasive techniques. In recent years, robot-assisted neck dissection (RAND) has begun to be used as an alternative method of neck dissection, one of the classic surgical procedures in the area of head and neck surgery. Currently, there are four kinds of approaches for RAND: (1) modified facelift or retroauricular incision, (2) combined transaxillary and retroauricular incision, (3) transaxillary incision, and (4) transoral incision. RAND may help perform minimally invasive surgery and achieve excellent cosmetic results as well as the desired oncologic outcomes, and this requires selecting an appropriate approach based on the different needs of neck dissections. Although experienced surgeons wishing to avoid large cervical incisions in patients can safely perform RAND, there are still quite a few limitations; in particular, surgical morbidity and oncologic outcomes should be verified by further prospective clinical trials with longer follow-up periods. Also, RAND needs to be standardized and its use disseminated. In this review, we introduce the applications of different approaches for RAND and their indications and determine whether RAND can be more beneficial compared with conventional surgeries. PMID- 26768075 TI - Ameloblastic carcinoma (secondary type) with extensive squamous differentiation areas and dedifferentiated regions. AB - Ameloblastic carcinoma is rare, accounting for 1.5%-2.0% of all odontogenic tumors. Few small series are available, but data on its clinicopathologic characteristics derive mainly from single case reports; therefore, descriptions of new cases may help to better understand the biological characteristics of this rare odontogenic malignancy. In the current report we describe an ameloblastic carcinoma affecting a 27-year-old female patient who had a previous diagnosis of ameloblastoma 7 years before. The carcinoma featured extensive areas of squamous differentiation resembling a primary intraosseous squamous cell carcinoma, as well as areas of dedifferentiation, a poorly documented histologic characteristic of ameloblastic carcinoma. This case provides new insights on the microscopic spectrum of ameloblastic carcinoma, permitting a critical discussion of the current World Health Organization classification of this odontogenic tumor. PMID- 26768077 TI - Maxillary reconstruction assisted by preoperative planning and accurate surgical templates. AB - OBJECTIVE: Surgical reconstruction of maxilla is technically challenging and time consuming. The study reports a new method of maxillary reconstruction assisted by preoperative surgical simulation and accurate transferring templates. STUDY DESIGN: Six patients requiring maxillary reconstruction were enrolled in our study. Templates of maxillary resection, fibula cutting, and positioning were designed based on computed tomography (CT) data and fabricated via rapid prototyping technique. Resection, fibula cutting, and positioning were performed according to the templates. Accuracy was evaluated by measuring deviation, performed by superimposing preoperative planning and postoperative maxilla. RESULTS: The surgery was performed faithfully to the preoperative planning. The facial contour was satisfied. Postoperative CT scans showed high accuracy of the surgical implementation. The average central point deviation, maximum deviation, and rotation were 0.58 mm, 1.53 mm, and 6.0 degrees , respectively. CONCLUSION: With preoperative surgical simulation and templates, maxillary reconstruction can be performed accurately. PMID- 26768078 TI - Re: "Five-year alveolar bone level changes in women of varying skeletal bone mineral density and bone trabeculation--a commentary". PMID- 26768076 TI - Prognostic value of 2-[(18) F]fluoro-2-deoxy-D-glucose positron emission tomography for patients with oral squamous cell carcinoma treated with retrograde superselective intra-arterial chemotherapy and daily concurrent radiotherapy. AB - OBJECTIVE: To investigate whether 2-[(18) F]fluoro-2-deoxy-D-glucose (FDG) uptake of primary tumor in oral squamous cell carcinoma (OSCC) could predict prognosis. STUDY DESIGN: Sixty-nine patients with OSCC who underwent retrograde superselective intra-arterial chemoradiotherapy were recruited and underwent dual time-point FDG positron emission tomography twice, before treatment and 4 weeks after treatment. FDG uptake was defined as the standardized uptake value (SUVmax). The retention index (RI) and the percent change in SUV (% change SUV), derived from the dual-time-point scan, were calculated. RESULTS: On univariate analysis, patients with high pre-SUV, RI, and percent change SUV values had significantly worse overall survival and disease-free survival compared with patients with low values. On multivariate analysis, high pre-RI (>=20.6%) and high percent change SUV (>=60.0%) (delayed-image) were associated with significantly worse overall survival. High pre-SUV (>=9.6) (delayed-image) and high pre-RI (>=20.6%) were associated with significantly shorter disease-free survival. CONCLUSIONS: Dual-time-point FDG positron emission tomography in OSCC provided prognostic information and predicted patient outcome. PMID- 26768079 TI - Hot topics on diabetes in China. AB - China is the country with the largest burden of diabetes worldwide. Action is now taking place at different levels by the Chinese Diabetes Society, which has a major role in coordinating multi-level activities across the country. These include, among others, the implementation of local guidelines for therapy, campaigns for education, trials for type 2 diabetes prevention and the establishment of extensive international collaborations in basic as well as clinical research. In this Special Issue, we briefly report on such initiatives, among which is a scientifically sound approach to exploring Chinese traditional medicine as a therapeutic option for diabetes treatment. PMID- 26768081 TI - Erratum: Guidelines for the cytopathologic diagnosis of epithelioid and mixed type malignant mesothelioma: Complementary Statement from the International Mesothelioma Interest Group, Also Endorsed by the International Academy of Cytology and the Papanicolaou Society of Cytopathology. PMID- 26768084 TI - Dermoscopic features of a case of transient acantholytic dermatosis. PMID- 26768080 TI - Identification of mumps virus protein and lipid composition by mass spectrometry. AB - BACKGROUND: Mumps virus is a negative-sense, single stranded RNA virus consisting of a ribonucleocapsid core enveloped by a lipid membrane derived from host cell, which causes mumps disease preventable by vaccination. Since virus lipid envelope and glycosylation pattern are not encoded by the virus but dependent on the host cell at least to some extent, the aim of this work was to analyse L-Zagreb (L-Zg) mumps virus lipids and proteins derived from two cell types; Vero and chicken embryo fibroblasts (CEF). Jeryl Lynn 5 (JL5) mumps strain lipids were also analysed. METHODS: Virus lipids were isolated by organic phase extraction and subjected to 2D-high performance thin layer chromatography followed by lipid extraction and identification by matrix-assisted laser desorption/ionization mass spectrometry (MALDI MS). Virus samples were also subjected to gel electrophoresis under denaturating conditions and protein bands were excised, in-gel trypsinized and identified by MS as well as tandem MS. RESULTS: Results showed that lipids of both mumps virus strains derived from Vero cells contained complex glycolipids with up to five monosaccharide units whereas the lipid pattern of mumps virus derived from CEF was less complex. Mumps virus was found to contain expected structural proteins with exception of fusion (F) protein which was not detected but on the other hand, V protein was detected. Most interesting finding related to the mumps proteins is the detection of several forms of nucleoprotein (NP), some of which appear to be C-terminally truncated. CONCLUSIONS: Differences found in lipid and protein content of mumps virus demonstrated the importance of detailed biochemical characterization of mumps virus and the methodology described here could provide a means for a more comprehensive quality control in vaccine production. PMID- 26768085 TI - Long Term Functional Outcome of Tibial Tuberosity Advancement vs. Tibial Plateau Leveling Osteotomy and Extracapsular Repair in a Heterogeneous Population of Dogs. AB - OBJECTIVE: To determine a long term function of tibial tuberosity advancement (TTA) for treatment of ruptured cranial cruciate ligament (CCL) in dogs, and to compare this to the long term function of previously reported tibial plateau leveling osteotomy (TPLO), extracapsular reconstruction (ECR), and a population of normal dogs. STUDY DESIGN: Prospective clinical trial. ANIMALS: Dogs with unilateral ruptured CCL treated with TTA (n = 14), TPLO (n = 15), and ECR (n = 23), and normal adult dogs (control, n = 80). MATERIALS AND METHODS: Force plate gait analysis was performed at 1 time point for the normal control group and preoperatively, and at 2 and 8 weeks and 6 and 12 months postoperatively for the treatment groups. Using serial force plates, symmetry indices (SI) were calculated between the operated and unoperated pelvic limbs for peak vertical force (PVF), contact time (CT), and vertical impulse (VI). Ground reaction forces (GRF) of the treatment and control group were compared using a general linear model. RESULTS: Walk SI for dogs with TTA were not significantly different from the control group at 12 months postoperatively. At the trot, neither TTA nor ECR achieved normal GRF. SI of the TPLO group were not different from the normal control group by 6-12 months postoperatively. CONCLUSION: At the walk, TTA achieves normal function by 12 months; however, at the trot TTA is indistinguishable from ECR. TPLO resulted in operated limb function that was similar to the control population by 6-12 months postoperatively at the walk and the trot. PMID- 26768086 TI - CYP2C9 involvement in ACT-453859 metabolism. PMID- 26768088 TI - Form and function in regenerative medicine: introduction. PMID- 26768090 TI - Erratum. PMID- 26768087 TI - Esophagogastric junction contractile integral (EGJ-CI) quantifies changes in EGJ barrier function with surgical intervention. AB - BACKGROUND: Esophagogastric junction contractile integral (EGJ-CI) assesses EGJ barrier function on esophageal high resolution manometry (HRM). We assessed EGJ CI values in achalasia and gastroesophageal reflux disease (GERD) to determine if postoperative EGJ-CI changes reflected surgical intervention. METHODS: Twenty-one achalasia patients (42.8 +/- 3.2 years, 62% F) with HRM before and after Heller myotomy (HM) and 68 GERD patients (53.9 +/- 1.8 years, 66% F) undergoing antireflux surgery (ARS) were compared to 21 healthy controls (27.6 +/- 0.6 years, 52% F). Esophagogastric junction contractile integral (mmHg.cm) was calculated using the distal contractile integral measurement across the EGJ, measured above the gastric baseline and corrected for respiration. Pre and postsurgical EGJ-CI and conventional lower esophageal sphincter pressure (LESP) metrics were compared within and between these groups using non-parametric tests. Correlation between EGJ-CI and conventional LESP metrics was assessed. KEY RESULTS: Baseline EGJ-CI was higher in achalasia compared to GERD (p < 0.001) or controls (p = 0.03). Esophagogastric junction contractile integral declined by 59.2% after HM in achalasia (p = 0.001), and increased by 26.3% after ARS in GERD (p = 0.005). End-expiratory and basal LESP decreased by 74.5% and 64.5% with HM, but increased by only 17.8% and 4.3% with ARS. Differences were noted between Dor vs Toupet fundoplication in achalasia (p = 0.007), and partial vs complete ARS in GERD (p = 0.03). Esophagogastric junction contractile integral correlated modestly with both end-expiratory and basal LESP (Pearson's r of 0.8 for all), but was less robust in GERD (0.7). CONCLUSIONS & INFERENCES: Esophagogastric junction contractile integral has clinical utility in assessing EGJ barrier function at baseline and after surgical intervention to the EGJ, and could complement conventional EGJ metrics. PMID- 26768091 TI - RANZCR Celebrates 80 Years. AB - 2015 marks the 80th anniversary of the formation of the Australian and New Zealand Association of Radiology (ANZAR) in 1935. The association underwent several name changes over the following decades, finally becoming The Royal Australian and New Zealand College of Radiologists (RANZCR) in 1998. The following is the text from the speech given by the President of the College, A/Prof Chris Milross, at the 2015 RANZCR Annual Scientific Meeting to mark the anniversary. PMID- 26768092 TI - The value of follow-up FDG-PET/CT in the management and prognosis of patients with HPV-positive oropharyngeal squamous cell carcinoma. AB - INTRODUCTION: To establish the accuracy of follow-up fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT and the impact of FDG PET/CT result on management decisions and patient outcome prediction (overall and progression free survival) in human papilloma virus (HPV)-positive oropharyngeal squamous cell carcinoma (SCC). PATIENTS AND METHODS: We included 96 HPV-positive oropharyngeal SCC (OPSCC) patients with 254 follow-up PET/CT scans in the study. The PET/CT result accuracy was established with histopathology or 6-month clinical follow-up as reference standard. The impact on change in management was established for each follow-up PET/CT scan. Overall survival was evaluated using Kaplan-Meier plots with a Log-rank test. RESULTS: The sensitivity, specificity, positive predictive value, negative predictive value and accuracy of the follow-up FDG PET/CT were 97.0%, 92.5%, 67.0%, 99.5% and 93.1%, respectively. Follow-up PET/CT results were helpful in excluding tumour in 22% (9/41) of scans performed with prior clinical suspicion of disease and identified potential disease in 9.9% (21/213) scans performed without prior clinical suspicion. There was a change in management after 12.6% (32/254) scans. In 84.3% (214/254) scans, the patients were either observed or the same treatment was continued. The overall survival differed significantly between patients with a negative versus positive follow-up scan (log rank P < 0.001). The median progression free survival was 28 months, if the first follow-up scan performed within 6-12 months post-treatment completion was negative. CONCLUSION: Follow-up FDG PET/CT scans have an impact on the management plan and add value to clinical assessment in patients with HPV positive OPSCC. PMID- 26768096 TI - Ageing gracefully. PMID- 26768093 TI - David Renfrew White (1914-2015). PMID- 26768097 TI - Value of robotic colorectal surgery. PMID- 26768098 TI - When should surgeons retire? (Br J Surg 2016: 103: 35-42). PMID- 26768102 TI - The "Mechanostat Theory" of Frost and the OPG/RANKL/RANK System by Joanna B Tyrovola. PMID- 26768099 TI - Pooled long-term outcomes from two randomized trials of axillary node sampling with axillary radiotherapy versus axillary node clearance in patients with operable node-positive breast cancer. AB - BACKGROUND: The aim was to determine long-term overall, breast cancer-specific and metastasis-free survival as well as axillary relapse rate from a pooled analysis of two randomized trials in women with operable breast cancer. These trials compared axillary node sampling (ANS), combined with axillary radiotherapy (AXRT) if the sampled nodes were involved, with axillary node clearance (ANC). METHODS: Data from two clinical trials at the Edinburgh Breast Unit that randomized patients between 1980 and 1995 were pooled. Long-term survival was analysed using Kaplan-Meier curves and Cox regression, with separate analyses for patients with node-positive (ANS + AXRT versus ANC) and node-negative (ANS versus ANC) disease. RESULTS: Of 855 women randomized, 799 were included in the present analysis after a median follow-up of 19.4 years. Some 301 patients (37.7 per cent) had node-positive disease. There was no evidence of a breast cancer survival advantage for ANS versus ANC in patients with node-negative disease (hazard ratio (HR) 0.88, 95 per cent c.i. 0.58 to 1.34; P = 0.557), or for ANS + AXRT versus ANC in those with node-positive breast cancer (HR 1.07, 0.77 to 1.50; P = 0.688). There was no metastasis-free survival advantage for ANS versus ANC in patients with node-negative tumours (HR 1.03, 0.70 to 1.51; P = 0.877), or ANS + AXRT versus ANC in those with node-positive disease (HR 1.03, 0.75 to 1.43; P = 0.847). Node-negative patients who underwent ANS had a higher risk of axillary recurrence than those who had ANC (HR 3.53, 1.29 to 9.63; P = 0.014). Similarly, among women with node-positive tumours, the risk of axillary recurrence was greater after ANS + AXRT than ANC (HR 2.64, 1.00 to 6.95; P = 0.049). CONCLUSION: Despite a higher rate of axillary recurrence with ANS combined with radiotherapy to the axilla, ANC did not improve overall, breast cancer-specific or metastasis free survival. Axillary recurrence is thus not a satisfactory endpoint when comparing axillary treatments. PMID- 26768103 TI - Ring-reinforced Sano right ventricular to pulmonary artery conduit at Norwood stage I. AB - Reinterventions for proximal conduit obstruction or on the pulmonary arteries are frequent after Sano-modified stage I Norwood palliation of hypoplastic left heart syndrome. We report our experience with a modified Sano stage I, in which the right ventricle-to-pulmonary artery (PA) conduit used is reinforced by external rings to avoid collapse, and the conduit is inserted into the right ventricle through a limited ventriculotomy and 'dunked' into the ventricular cavity. In our experience, this modification was associated with fewer reinterventions or complications with the proximal anastomosis (P = 0.046 and 0.004), improved PA pulse pressure (9.1 +/- 4.1 vs 4.8 +/- 3.8 mmHg in controls, P < 0.001) and Nakata index (213 +/- 76 vs 134 +/- 68 mm(2)/m(2) in controls, P < 0.0001), although overall survival to a median of 20 months was not significantly different from controls. Right ventricular function at stage II-bidirectional Glen was marginally better in patients with the modified Sano conduit, however not to a significant level. Further evaluation of late ventricular function is currently ongoing. PMID- 26768104 TI - Addendum: Highly Efficient Enrichment of Volatile Iodine by Charged Porous Aromatic Frameworks with Three Sorption Sites. PMID- 26768105 TI - Corrigendum: Targeted Fluorination with the Fluoride Ion by Manganese-Catalyzed Decarboxylation. PMID- 26768106 TI - Retracted: Direct Allylation of In Situ Generated Aldehyde Acyl Anions by Synergistic NHC and Palladium Catalysis. PMID- 26768108 TI - Photocatalytically Renewable Micro-electrochemical Sensor for Real-Time Monitoring of Cells. AB - Electrode fouling and passivation is a substantial and inevitable limitation in electrochemical biosensing, and it is a great challenge to efficiently remove the contaminant without changing the surface structure and electrochemical performance. Herein, we propose a versatile and efficient strategy based on photocatalytic cleaning to construct renewable electrochemical sensors for cell analysis. This kind of sensor was fabricated by controllable assembly of reduced graphene oxide (RGO) and TiO2 to form a sandwiching RGO@TiO2 structure, followed by deposition of Au nanoparticles (NPs) onto the RGO shell. The Au NPs-RGO composite shell provides high electrochemical performance. Meanwhile, the encapsulated TiO2 ensures an excellent photocatalytic cleaning property. Application of this renewable microsensor for detection of nitric oxide (NO) release from cells demonstrates the great potential of this strategy in electrode regeneration and biosensing. PMID- 26768109 TI - Theoretical Design and Experimental Realization of Quasi Single Electron Enhancement in Plasmonic Catalysis. AB - By a combination of theoretical and experimental design, we probed the effect of a quasi-single electron on the surface plasmon resonance (SPR)-mediated catalytic activities of Ag nanoparticles. Specifically, we started by theoretically investigating how the E-field distribution around the surface of a Ag nanosphere was influenced by static electric field induced by one, two, or three extra fixed electrons embedded in graphene oxide (GO) next to the Ag nanosphere. We found that the presence of the extra electron(s) changed the E-field distributions and led to higher electric field intensities. Then, we experimentally observed that a quasi-single electron trapped at the interface between GO and Ag NPs in Ag NPs supported on graphene oxide (GO-Ag NPs) led to higher catalytic activities as compared to Ag and GO-Ag NPs without electrons trapped at the interface, representing the first observation of catalytic enhancement promoted by a quasi single electron. PMID- 26768111 TI - Approaches by the US National Institutes of Health to support rigorous scientific research on dietary supplements and natural products. AB - Mechanistic, clinical, and epidemiological research relevant to dietary supplements (DS) is supported by the U.S. National Institutes of Health. The Office of Dietary Supplements and the National Center for Complementary and Integrative Health promote the development and appropriate use of rigorous and comprehensive DS analyses which are critical for research reproducibility, particularly when the investigational DS include chemically complex natural products with unclear mechanisms of action. PMID- 26768112 TI - The effects of subsampling gene trees on coalescent methods applied to ancient divergences. AB - Gene-tree-estimation error is a major concern for coalescent methods of phylogenetic inference. We sampled eight empirical studies of ancient lineages with diverse numbers of taxa and genes for which the original authors applied one or more coalescent methods. We found that the average pairwise congruence among gene trees varied greatly both between studies and also often within a study. We recommend that presenting plots of pairwise congruence among gene trees in a dataset be treated as a standard practice for empirical coalescent studies so that readers can readily assess the extent and distribution of incongruence among gene trees. ASTRAL-based coalescent analyses generally outperformed MP-EST and STAR with respect to both internal consistency (congruence between analyses of subsamples of genes with the complete dataset of all genes) and congruence with the concatenation-based topology. We evaluated the approach of subsampling gene trees that are, on average, more congruent with other gene trees as a method to reduce artifacts caused by gene-tree-estimation errors on coalescent analyses. We suggest that this method is well suited to testing whether gene-tree-estimation error is a primary cause of incongruence between concatenation- and coalescent based results, to reconciling conflicting phylogenetic results based on different coalescent methods, and to identifying genes affected by artifacts that may then be targeted for reciprocal illumination. We provide scripts that automate the process of calculating pairwise gene-tree incongruence and subsampling trees while accounting for differential taxon sampling among genes. Finally, we assert that multiple tree-search replicates should be implemented as a standard practice for empirical coalescent studies that apply MP-EST. PMID- 26768113 TI - Myth or relict: Does ancient DNA detect the enigmatic Upland seal? AB - The biological status of the so-called 'Upland seal' has remained contentious ever since historical records described a distinct seal from the uplands of New Zealand's (NZ) remote sub-Antarctic islands. Subsequent genetic surveys of the NZ fur seal (Arctocephalus forsteri) detected two highly-divergent mtDNA clades, hypothesized to represent a post-sealing hybrid swarm between 'mainland' (Australia-NZ; A. forsteri) and sub-Antarctic (putative 'Upland'; A. snaresensis) lineages. We present ancient-DNA analyses of prehistoric mainland NZ and sub Antarctic fur seals, revealing that both of these genetic lineages were already widely distributed across the region at the time of human arrival. These findings indicate that anthropogenic factors did not contribute to the admixture of these lineages, and cast doubt on the validity of the Upland seal. Human-mediated impacts on Arctocephalus genetic diversity are instead highlighted by a dramatic temporal haplotype frequency-shift due to genetic drift in heavily bottlenecked populations following the cessation of industrial-scale harvesting. These extinction-recolonisation dynamics add to a growing picture of human-mediated change in NZ's coastal and marine ecosystems. PMID- 26768114 TI - Does superior caval vein pressure impact head growth in Fontan circulation? AB - BACKGROUND: Patients with bidirectional cavopulmonary anastomosis have unphysiologically high superior caval vein pressure as it equals pulmonary artery pressure. Elevated superior caval vein pressure may cause communicating hydrocephalus and macrocephaly. This study analysed whether there exists an association between head circumference and superior caval vein pressure in patients with single ventricle physiology. METHODS: We carried out a retrospective analysis of infants undergoing Fontan completion at our institution from 2007 to 2013. Superior caval vein pressures were measured during routine catheterisation before bidirectional cavopulmonary anastomosis and Fontan completion as well as head circumference, adjusted to longitudinal age-dependent percentiles. RESULTS: We included 74 infants in our study. Median ages at bidirectional cavopulmonary anastomosis and Fontan were 4.8 (1.6-12) and 27.9 (7 40.6) months, respectively. Head circumference showed significant growth from bidirectional cavopulmonary anastomosis until Fontan completion (7th (0-100th) versus 20th (0-100th) percentile). There was no correlation between superior caval vein pressure and head circumference before Fontan (R2=0.001). Children with lower differences in superior caval vein pressures between pre-bidirectional cavopulmonary anastomosis and pre-Fontan catheterisations showed increased growth of head circumference (R2=0.19). CONCLUSIONS: Patients with moderately elevated superior caval vein pressure associated with single ventricle physiology did not have a tendency to develop macrocephaly. There is no correlation between superior caval vein pressure before Fontan and head circumference, but between bidirectional cavopulmonary anastomosis and Fontan head circumference increases significantly. This may be explained by catch-up growth of head circumference in patients with more favourable haemodynamics and concomitant venous pressures in the lower range. Further studies with focus on high superior caval vein pressures are needed to exclude or prove a correlation. PMID- 26768115 TI - Reduced cardiolipin content decreases respiratory chain capacities and increases ATP synthesis yield in the human HepaRG cells. AB - Cardiolipin (CL) is a unique mitochondrial phospholipid potentially affecting many aspects of mitochondrial function/processes, i.e. energy production through oxidative phosphorylation. Most data focusing on implication of CL content and mitochondrial bioenergetics were performed in yeast or in cellular models of Barth syndrome. Previous work reported that increase in CL content leads to decrease in liver mitochondrial ATP synthesis yield. Therefore the aim of this study was to determine the effects of moderate decrease in CL content on mitochondrial bioenergetics in human hepatocytes. For this purpose, we generated a cardiolipin synthase knockdown (shCLS) in HepaRG hepatoma cells showing bioenergetics features similar to primary human hepatocytes. shCLS cells exhibited a 55% reduction in CLS gene and a 40% decrease in protein expression resulting in a 45% lower content in CL compared to control (shCTL) cells. Oxygen consumption was significantly reduced in shCLS cells compared to shCTL regardless of substrate used and energy state analyzed. Mitochondrial low molecular weight supercomplex content was higher in shCLS cells (+60%) compared to shCTL. Significant fragmentation of the mitochondrial network was observed in shCLS cells compared to shCTL cells. Surprisingly, mitochondrial ATP synthesis was unchanged in shCLS compared to shCTL cells but exhibited a higher ATP:O ratio (+46%) in shCLS cells. Our results suggest that lowered respiratory chain activity induced by moderate reduction in CL content may be due to both destabilization of supercomplexes and mitochondrial network fragmentation. In addition, CL content may regulate mitochondrial ATP synthesis yield. PMID- 26768116 TI - Electron transfer between the QmoABC membrane complex and adenosine 5' phosphosulfate reductase. AB - The dissimilatory adenosine 5'-phosphosulfate reductase (AprAB) is a key enzyme in the sulfate reduction pathway that catalyzes the reversible two electron reduction of adenosine 5'-phosphosulfate (APS) to sulfite and adenosine monophosphate (AMP). The physiological electron donor for AprAB is proposed to be the QmoABC membrane complex, coupling the quinone-pool to sulfate reduction. However, direct electron transfer between these two proteins has never been observed. In this work we demonstrate for the first time direct electron transfer between the Desulfovibrio desulfuricans ATCC 27774 QmoABC complex and AprAB. Cyclic voltammetry conducted with the modified Qmo electrode and AprAB in the electrolyte solution presented the Qmo electrochemical signature with two additional well-defined one electron redox processes, attributed to the AprAB FAD redox behavior. Moreover, experiments performed under catalytic conditions using the QmoABC modified electrode, with AprAB and APS in solution, show a catalytic current peak develop in the cathodic wave, attributed to substrate reduction, and which is not observed in the absence of QmoABC. Substrate dependence conducted with different electrode preparations (with and without immobilized Qmo) demonstrated that the QmoABC complex is essential for efficient electron delivery to AprAB, in order to sustain catalysis. These results confirm the role of Qmo in electron transfer to AprAB. PMID- 26768117 TI - Targeting the hypoxic response in bone tissue engineering: A balance between supply and consumption to improve bone regeneration. AB - Bone tissue engineering is a promising therapeutic alternative for bone grafting of large skeletal defects. It generally comprises an ex vivo engineered combination of a carrier structure, stem/progenitor cells and growth factors. However, the success of these regenerative implants largely depends on how well implanted cells will adapt to the hostile and hypoxic host environment they encounter after implantation. In this review, we will discuss how hypoxia signalling may be used to improve bone regeneration in a tissue-engineered construct. First, hypoxia signalling induces angiogenesis which increases the survival of the implanted cells as well as stimulates bone formation. Second, hypoxia signalling has also angiogenesis-independent effects on mesenchymal cells in vitro, offering exciting new possibilities to improve tissue-engineered bone regeneration in vivo. In addition, studies in other fields have shown that benefits of modulating hypoxia signalling include enhanced cell survival, proliferation and differentiation, culminating in a more potent regenerative implant. Finally, the stimulation of endochondral bone formation as a physiological pathway to circumvent the harmful effects of hypoxia will be briefly touched upon. Thus, angiogenic dependent and independent processes may counteract the deleterious hypoxic effects and we will discuss several therapeutic strategies that may be combined to withstand the hypoxia upon implantation and improve bone regeneration. PMID- 26768118 TI - TNF alpha signaling is associated with therapeutic responsiveness to vascular disrupting agents in endocrine tumors. AB - ASA404 (Vadimezan) belongs to a class of agents with disrupting properties against tumor vasculature, which is partly mediated by TNFalpha-signaling. Preclinical and early clinical studies have indicated promising results for ASA404, while extended clinical trials performed poorly. Our aim was to investigate the potential therapeutic applicability of ASA404 against endocrine tumors. Moreover, as the reason for the unpredictable clinical anti-tumor activity of ASA 404 remained uncertain in previous studies, we compared two tumor models of endocrine origin with different responses to ASA404 treatment. Specifically, we determined anti-tumoral effects in preclinical models of neuroendocrine tumors of the gastroenteropancreatic system (BON) and adrenocortical cancer (NCI-H295R) in vitro and in xenograft models in vivo. Upon treatment of tumor bearing mice significant anti-tumoral effects, an increase in TNFalpha as well as activation of TNFalpha-specific downstream signaling were evident in the BON tumor model while no comparable effects were detectable for NCI-H295R. We identified TNFAIP3/A20, a key molecule of an inhibitory feedback loop downstream of TNF-receptor 1, CD40, Toll-like receptors, NOD-like receptors and the interleukin-1 receptor signaling cascades, as overexpressed in the adrenocortical carcinoma tumor model. Subsequent analyses of clinical patient samples confirmed a correlation between tumor TNFAIP3 expression levels and overall survival in patients with ACC. Taken together our findings provide evidence that modulation of TNFalpha-signaling could be of relevance both for the clinical course of ACC patients and as a marker of treatment response. PMID- 26768119 TI - Paper-based energy harvesting from salinity gradients. AB - Paper-based microfluidic devices have many advantages such as low cost, flexibility, light weight and easy disposability. Especially, since they can intrinsically generate capillary-driven flow (no pumps are needed), paper-based microfluidic devices are widely used in analytical or diagnostic platforms. Along with advancements in microfluidic paper-based analytical devices (MUPADs), energy generation using paper materials has received significant attention. In this study, environment-friendly and flexible paper-based energy harvesting with a simple configuration is demonstrated by using the principle of reverse electrodialysis (RED). RED is a promising clean energy generation method, which converts Gibbs free energy into electricity by salinity gradients without discharging any pollutants. However, the power efficiency in a conventional RED device is limited by the essential requirement of active pumping for providing high and low concentration electrolytes. Capillary pumping from the proposed paper-based RED can save this waste of energy, and moreover, the flexible device is realized with cost effective materials and a simple fabrication step, and is environmentally friendly. By thoughtful analysis of voltage-current experiments and capillary flow rates in paper channels, the optimized channel width interfacing with a selective membrane is determined as 2 mm and the maximum power and power density are achieved as 55 nW and 275 nW cm(-2), respectively. 25.8% of the generated maximum power is successfully saved by realizing the pumpless RED system. This paper-based RED device can be integrated directly with MUPADs as a practical application. PMID- 26768120 TI - Engineering Herbicide-Resistant Rice Plants through CRISPR/Cas9-Mediated Homologous Recombination of Acetolactate Synthase. PMID- 26768121 TI - PETO Interacts with Other Effectors of Cyclic Electron Flow in Chlamydomonas. AB - While photosynthetic linear electron flow produces both ATP and NADPH, cyclic electron flow (CEF) around photosystem I (PSI) and cytochrome b6f generates only ATP. CEF is thus essential to balance the supply of ATP and NADPH for carbon fixation; however, it remains unclear how the system tunes the relative levels of linear and cyclic flow. Here, we show that PETO, a transmembrane thylakoid phosphoprotein specific of green algae, contributes to the stimulation of CEF when cells are placed in anoxia. In oxic conditions, PETO co-fractionates with other thylakoid proteins involved in CEF (ANR1, PGRL1, FNR). In PETO-knockdown strains, interactions between these CEF proteins are affected. Anoxia triggers a reorganization of the membrane, so that a subpopulation of PSI and cytochrome b6f now co-fractionates with the CEF effectors in sucrose gradients. The absence of PETO impairs this reorganization. Affinity purification identifies ANR1 as a major interactant of PETO. ANR1 contains two ANR domains, which are also found in the N-terminal region of NdhS, the ferredoxin-binding subunit of the plant ferredoxin-plastoquinone oxidoreductase (NDH). We propose that the ANR domain was co-opted by two unrelated CEF systems (PGR and NDH), possibly as a sensor of the redox state of the membrane. PMID- 26768122 TI - Clinicopathological features of five unusual cases of intraosseous myoepithelial carcinomas, mimicking conventional primary bone tumours, including EWSR1 rearrangement in one case. AB - Primary intraosseous myoepithelial tumours, including carcinomas are rare tumours. The concept of histopathological spectrum of these tumours is evolving. We describe clinicopathological and immunohistochemical features of five myoepithelial carcinomas, including molecular cytogenetic results in one case. There were five male patients within age-range of 8-40 years (median = 26). Four tumours occurred in the long bones, including two tumours, each, in the femur and fibula, respectively, while a single tumour occurred in the proximal phalanges. Tumour size (n = 3 cases) varied from 5.6 to 8.6 cm. On radiological imaging, most tumours appeared as expansile, lytic and destructive lesions. Two tumours appeared as sclerotic lesions. Two cases were referred with diagnoses of chondrosarcomas and a single case was referred with two different diagnoses, including an adamantinoma and an osteosarcoma. Histopathological examination in all these cases showed multinodular tumours comprising mostly polygonal cells, exhibiting moderate nuclear atypia and interspersed mitotic figures within a stroma containing variable amount of myxoid, chondroid, hyalinised and osteoid like material. Three tumours revealed prominent squamous differentiation. By immunohistochemistry, tumour cells were positive for EMA (5/5), pan CK (AE1/AE3) (3/3), CK5/6 (4/4), CK MNF116 (1/1), S100 protein (5/5) and GFAP (3/5). The first tumour revealed EWSR1 rearrangement. The first patient, 10 months after tumour resection and a simultaneous lung metastatectomy, is free-of-disease (FOD). The second patient, 11 months after tumour resection is FOD. The third and fourth patients underwent wide resections and are on follow-up. The fifth patient underwent resections, including a lung metastatectomy. Primary intraosseous myoepithelial carcinomas are rare and mimic conventional primary bone tumours. Some primary intraosseous myoepithelial carcinomas display EWSR1 rearrangement. Squamous differentiation may be considered as an addition to their evolving histopathological spectrum. Immunohistochemical stains constitute as a necessary tool for arriving at the correct diagnosis in such cases, which has treatment implications. Surgical resection remains the treatment mainstay. PMID- 26768123 TI - ERP correlates of object recognition memory in Down syndrome: Do active and passive tasks measure the same thing? AB - Event related potentials (ERPs) can help to determine the cognitive and neural processes underlying memory functions and are often used to study populations with severe memory impairment. In healthy adults, memory is typically assessed with active tasks, while in patient studies passive memory paradigms are generally used. In this study we examined whether active and passive continuous object recognition tasks measure the same underlying memory process in typically developing (TD) adults and in individuals with Down syndrome (DS), a population with known hippocampal impairment. We further explored how ERPs in these tasks relate to behavioral measures of memory. Data-driven analysis techniques revealed large differences in old-new effects in the active versus passive task in TD adults, but no difference between these tasks in DS. The group with DS required additional processing in the active task in comparison to the TD group in two ways. First, the old-new effect started 150 ms later. Second, more repetitions were required to show the old-new effect. In the group with DS, performance on a behavioral measure of object-location memory was related to ERP measures across both tasks. In total, our results suggest that active and passive ERP memory measures do not differ in DS and likely reflect the use of implicit memory, but not explicit processing, on both tasks. Our findings highlight the need for a greater understanding of the comparison between active and passive ERP paradigms before they are inferred to measure similar functions across populations (e.g., infants or intellectual disability). PMID- 26768125 TI - Incidence and mortality of postoperative acute kidney injury in non-dialysis patients: comparison between the AKIN and KDIGO criteria. AB - OBJECTIVES: This retrospective study determines whether the kidney disease: improving global outcomes (KDIGO) criteria are superior to acute kidney injury network (AKIN) criteria in detecting non-dialysis AKI events and predicting mortality in chronic kidney disease (CKD) patients after surgery. METHODS: Surgical patients who were admitted to the intensive care unit were enrolled. Non dialysis AKI cases were defined using either KDIGO or AKIN creatinine criteria and stratified by CKD stages. The adjusted hazard ratios (AHRs) for in-hospital mortality are compared to those without AKI. The cumulative survival curves and the predictability for mortality are accessed by Kaplan-Meier method and calculating the area under the curve (AUC) for the receiver operating characteristic (ROC) curve, respectively. RESULTS: From a total of 826 postoperative patients, the overall in-hospital mortality rate was 11.6% (96 cases) and that for AKI according to KDIGO and AKIN criteria was 30.0% (248 cases) and 31.0% (256 cases). The cumulative survival curve stratified by CKD and AKI stages were comparable between KDIGO and AKIN criteria. The discriminative power for mortality stratified by CKD stages for KDIGO and AKIN criteria are as followed: all subjects: 0.678 versus 0.670 (both ps <0.001); non-CKD: 0.800 versus 0.809 (both ps <0.001); early-stage CKD: 0.676 versus 0.676 (both ps <0.001); late-stage CKD: 0.674 versus 0.660 (ps were <0.001 and 0.003). CONCLUSION: The KDIGO criteria are superior to AKIN criteria in predicting mortality after surgery, especially in those with advanced CKD. PMID- 26768124 TI - Relative contributions of visual and auditory spatial representations to tactile localization. AB - Spatial localization of touch is critically dependent upon coordinate transformation between different reference frames, which must ultimately allow for alignment between somatotopic and external representations of space. Although prior work has shown an important role for cues such as body posture in influencing the spatial localization of touch, the relative contributions of the different sensory systems to this process are unknown. In the current study, we had participants perform a tactile temporal order judgment (TOJ) under different body postures and conditions of sensory deprivation. Specifically, participants performed non-speeded judgments about the order of two tactile stimuli presented in rapid succession on their ankles during conditions in which their legs were either uncrossed or crossed (and thus bringing somatotopic and external reference frames into conflict). These judgments were made in the absence of 1) visual, 2) auditory, or 3) combined audio-visual spatial information by blindfolding and/or placing participants in an anechoic chamber. As expected, results revealed that tactile temporal acuity was poorer under crossed than uncrossed leg postures. Intriguingly, results also revealed that auditory and audio-visual deprivation exacerbated the difference in tactile temporal acuity between uncrossed to crossed leg postures, an effect not seen for visual-only deprivation. Furthermore, the effects under combined audio-visual deprivation were greater than those seen for auditory deprivation. Collectively, these results indicate that mechanisms governing the alignment between somatotopic and external reference frames extend beyond those imposed by body posture to include spatial features conveyed by the auditory and visual modalities - with a heavier weighting of auditory than visual spatial information. Thus, sensory modalities conveying exteroceptive spatial information contribute to judgments regarding the localization of touch. PMID- 26768126 TI - Comparable immune responsiveness but increased reactogenicity after subcutaneous versus intramuscular administration of tick borne encephalitis (TBE) vaccine. AB - Evaluation of safety, immunogenicity and efficacy of vaccines during licensing studies is performed in relation to the selected vaccination route. For most adjuvanted vaccines, such as the TBE vaccine FSME-IMMUN, only intramuscular (i.m.) administration is licensed. Yet in certain situations, either because of medical indications, accidental application or due to a lack of sufficient muscular tissue, the vaccine might rather be applied subcutaneously (s.c.). With respect to the TBE vaccine there are currently however no data to support the use of the subcutaneous route of vaccination. In order to compare the reactogenicity and immune responsiveness upon i.m. and s.c. TBE vaccination 116 (58 females and 58 males) participants with a documented primary TBE vaccination course were randomized to receive either an i.m. or s.c. booster. Venous blood was collected before, 7 days, 1 month and 6 months after vaccination to determine antibody titer profiles. PBMC were isolated prior to and 7 days after booster to analyze lymphocyte subpopulations and cytokine production upon antigen restimulation. Subjects were monitored for the occurrence of side effects for 7 days post vaccination. Comparable levels of TBE specific neutralizing antibodies were induced after s.c. and i.m. vaccination. At the cellular level, IL-2, IFN gamma and IL-10 levels did not significantly differ using either route of vaccination and the distribution of T cell subsets was comparable along with a relative decrease of regulatory T-cells after both ways of administration. In contrast to the immunogenicity analyses, the data from safety diaries revealed a significantly higher rate of local, but not of systemic reactions after s.c. administration. In conclusion, this study demonstrates that both routes lead to comparable immune responses to the TBE antigen. The higher rate and intensity of local reactions, particularly among women, after s.c. vaccination however needs to be addressed during counseling. PMID- 26768127 TI - Lipoprotein LpqS deficient M. tuberculosis mutant is attenuated for virulence in vivo and shows protective efficacy better than BCG in guinea pigs. AB - Bacterial lipoproteins are a functionally diverse class of membrane anchored proteins. Lipoproteins constitute nearly 2.5% of the Mycobacterium tuberculosis proteome. Inactivation of genes coding for individual lipoproteins results in attenuated phenotype of the mutants. LpqS is a lipoprotein highly conserved among slow growing pathogenic mycobacteria. Our previous study has shown that the lpqS gene deletion mutant of M. tuberculosis (MtbDeltalpqS) poorly replicates in THP1 (human acute monocytic leukemia cell line) derived macrophagic cell line. In addition, guinea pigs, when infected with the mutant strain exhibited significantly reduced bacterial burden and pathological damage in the infected tissues in comparison with the parental strain infected group. Subsequently, we evaluated the protective efficacy of the mutant by immunization of guinea pigs through aerosol and subcutaneous routes. We observed that immunization of guinea pigs with MtbDeltalpqS offered superior protection in lungs as compared to BCG. In addition, MtbDeltalpqS also prevented the haematogenous spread of the disease which was evident from the significantly reduced splenic bacillary load compared to saline vaccinated animals. The gross pathological observations and the histopathological observations well corroborated the bacterial findings. We also observed that aerogenic route of immunization imparts superior protection compared to subcutaneous route of immunization. These findings well establishes the efficacy of M. tuberculosis mutant in imparting protection against pulmonary TB. PMID- 26768128 TI - Disease burden of enterovirus infection in Taiwan: Implications for vaccination policy. AB - OBJECTIVES: This study aimed to assess the disease burden and economic impacts of human nonpolio enteroviruses (NPEV) and enterovirus A71 (EV-A71) infection in Taiwan. MATERIALS AND METHODS: We included children under five years old (n=983,127-1,118,649) with ICD-9-CM codes 0740 (herpangina) or 0743 (hand-foot and-mouth disease) from the 2006 to 2010 National Health Insurance Database. Severity of enterovirus infection was assessed from outpatient/emergency visits, hospitalization (with/without intensive care unit [ICU] admission), infection with severe complications, and death. We estimated medical costs and indirect costs from the societal perspective. RESULTS: The annual rates of NPEV events for children under five years old ranged from 13.9% to 38.4%, of which 5.1-8.8% were hospitalized. EV-A71 accounted for 7.8% of all NPEV medical costs, but 79.1% of NPEV ICU costs. Travel costs and productivity loss of caregivers were $37.1 (range: $24.5-$64.7) million per year. These costs were not higher in the EV-A71 dominant year ($34.4 million) compared with those in the other years. Productivity losses resulting from premature mortality by NPEV infection were $0.8 (range: $0.0-$2.9) million per year, of which 96.3% were caused by EV-A71. CONCLUSIONS: Diseases associated with NPEV other than EV-A71 were responsible for most of the medical expenses. In addition, caregiver productivity loss by high rates of NPEV infection impacted the society much more than medical costs. A multi-valent vaccine that includes EV-A71 and other serotypes, for example coxsackievirus A16, may be beneficial to the health of children in Taiwan. PMID- 26768129 TI - Intradermal vaccination with un-adjuvanted sub-unit vaccines triggers skin innate immunity and confers protective respiratory immunity in domestic swine. AB - Intradermal (ID) vaccination constitutes a promising approach to induce anti infectious immunity. This route of immunization has mostly been studied with influenza split-virion vaccines. However, the efficacy of ID vaccination for sub unit vaccines in relation to underlying skin innate immunity remains to be explored for wider application in humans. Relevant animal models that more closely mimic human skin immunity than the widely used mouse models are therefore necessary. Here, we show in domestic swine, which shares striking anatomic and functional properties with human skin, that a single ID delivery of pseudorabies virus (PRV) glycoproteins without added adjuvant is sufficient to trigger adaptive cellular and humoral immune responses, and to confer protection from a lethal respiratory infection with PRV. Analysis of early events at the skin injection site revealed up-regulation of pro-inflammatory cytokine and chemokine genes, recruitment of neutrophils and monocytes and accumulation of inflammatory DC. We further show that the sustained induction of pro-inflammatory cytokine genes results from the combined effects of skin puncture, liquid injection in the dermis and viral antigens. These data highlight that immune protection against respiratory infection can be induced by ID vaccination with a subunit vaccine and reveal that adjuvant requirements are circumvented by the mechanical and antigenic stress caused by ID injection, which triggers innate immunity and mobilization of inflammatory DC at the immunization site. ID vaccination with sub unit vaccines may thus represent a safe and efficient solution for protection against respiratory infections in swine and possibly also in humans, given the similarity of skin structure and function in both species. PMID- 26768130 TI - What is the scope of improving immigrant and ethnic minority healthcare using community navigators: A systematic scoping review. AB - INTRODUCTION: Immigrants are among the most vulnerable population groups in North America; they face multidimensional hurdles to obtain proper healthcare. Such barriers result in increased risk of developing acute and chronic conditions. Subsequently a great deal of burden is placed on the healthcare system. Community navigator programs are designed to provide culturally sensitive guidance to vulnerable populations in order to overcome barriers to accessing healthcare. Navigators are healthcare workers who support patients to obtain appropriate healthcare. This scoping review systematically searches and summarizes the literature on community navigators to help immigrant and ethnic minority groups in Canada and the United States overcome barriers to healthcare. METHODS: We systematically searched electronic databases for primary articles and grey literature. Study selection was performed following the preferred reporting items for systematic reviews and meta-analyses (PRISMA) statement. Articles were selected based on four criteria: (1) the study population was comprised of immigrants or ethnic minorities living in Canada or the United States; (2) study outcomes were related to chronic disease management or primary care access; (3) the study reported effects of community navigator intervention; (4) the study was published in English. Relevant information from the articles was extracted and reported in the review. RESULT: Only one study was found in the literature that focused on navigators for immigrants in Canada. In contrast, 29 articles were found that reported navigator intervention programs for immigrant minorities in the United States. In these studies navigators trained and guided members of several ethnic communities for chronic disease prevention and management, to undertake cancer screening as well as accessing primary healthcare. The studies reported substantial improvement in the immigrant and ethnic minority health outcomes in the United States. The single Canadian study also reported positive outcome of navigators among immigrant women. CONCLUSION: Navigator interventions have not been fully explored in Canada, where as, there have been many studies in the United States and these demonstrated significant improvements in immigrant health outcomes. With many immigrants arriving in Canada each year, community navigators may provide a solution to reduce the existing healthcare barriers and support better health outcomes for new comers. PMID- 26768131 TI - Evaluating differently tutored groups in problem-based learning in a German dental curriculum: a mixed methods study. AB - BACKGROUND: It is still unclear to what extent the PBL tutor affects learning in PBL-sessions. This mixed-methods study (Part 1 and 2) evaluated the effects of facilitative (f) versus non-facilitative (nf) tutoring roles on knowledge-gain and group functioning in the field of endodontics. METHODS: Part 1 was a quantitative assessment of tutor effectiveness within a prospective, experimental, single-blind, stratified, randomized, two-group intervention study. Participants attended PBL in the context of a hybrid curriculum. A validated questionnaire was used and knowledge assessments were conducted before and after the intervention. External observers rated tutor performance. Part 2 was a qualitative assessment of tutor effectiveness and consisted of semi-structured expert interviews with tutors and focus group discussions with students. RESULTS: Part 1: f tutors obtained significantly higher scores than nf tutors with respect to learning motivation and tutor effectiveness (p <= 0.05). nf tuition resulted in a slightly larger knowledge gain (p = 0.08). External observers documented a significantly higher activity among facilitative tutors compared to non facilitative tutors. Part 2: Tutors found the f role easier although this led to a less autonomous working climate. The students rated f tutoring as positive in all cases. CONCLUSIONS: With respect to PBL-group performance, students felt that groups guided in a non-facilitative fashion exhibited a higher level of independence and autonomy, especially with increasing PBL experience. In addition, students reported that more preparation was necessary for sessions guided by a non-facilitative tutor. Tutors were able to modify their role and influence group processes in a controlled manner. Results are useful for future "Train-the-Teacher" sessions. PMID- 26768134 TI - Amniotic fluid total antioxidant capacity and nitric oxide in emergency cerclage. AB - OBJECTIVE: Nitric oxide (NO) is one of the reactive oxygen species (ROS) that has been associated with inflammation. Total antioxidant capacity (TAC) neutralizes ROS. We evaluated that amniotic fluid (AF) TAC and NO correlate with the outcome of emergency cerclage. METHODS: Thirty-six women with cervical dilatation (>=2 cm) and bulging membranes between 16 and 24 weeks underwent emergency cerclage. Sixty-seven women between 16 and 24 weeks who had amniocentesis for chromosomal test provided control samples. AF samples were tested for TAC, and NO, and then correlated with pregnancy outcome. RESULTS: AF TAC was significantly lower in cerclage group than control group (cerclage: 92.6 mmol/L versus control: 127.2 mmol/L, p < 0.001). Higher levels of AF TAC were associated with a longer latency from cerclage to delivery (r = 0.62, p < 0.001). NO was similar between two groups (p = 0.35). The mean gestational age at delivery of control group was better than cerclage group (cerclage: 29.5 weeks versus control: 39.4 weeks, p < 0.01). CONCLUSION: Higher levels of AF TAC are correlated with longer prolongation days after cerclage. However, AF NO and iNOS are not different between two groups. PMID- 26768133 TI - Histopathologic findings of spontaneous osteonecrosis of the knee at an early stage: a case report. AB - We histopathologically examined a surgically resected full specimen obtained from an early-stage spontaneous osteonecrosis of the knee (SPONK). On a mid-coronal cut section of the resected medial femoral condyle, a linear fracture line paralleling the subchondral bone endplate was found. Histopathologically, prominent callus formation was seen comprising of reactive woven bone and granulation tissue on both sides of the fracture. Fracture-related bone debris was focally observed at the osteochondral side of the fracture. Definitive features of antecedent bone infarction such as creeping substitution and bone marrow necrosis were not detected. These findings suggested that SPONK was the result of a subchondral fracture rather than primary osteonecrosis. PMID- 26768132 TI - Altered miRNA expression in pulmonary sarcoidosis. AB - BACKGROUND: miRNAs control important cellular functions including angiogenesis/angiostasis or fibrosis and reveal altered expression during pathological processes in the lung. METHODS: The aim of the study was to investigate the expression of selected miRNAs (miR-let7f, miR-15b, miR-16, miR 20a, miR-27b, miR-128a, miR-130a, miR-192 miR-221, miR-222) in patients with pulmonary sarcoidosis (n = 94) and controls (n = 50). The expression was assessed by q-PCR in BALF cells and peripheral blood lymphocytes (PB lymphocytes). For statistical analysis, the Kruskal-Wallis test, Mann-Whitney U- test, Neuman Keuls' multiple comparison test, and Spearman's rank correlation were used. RESULTS: In BALF cells, significantly higher expression of miR-192 and miR-221 and lower expression of miR-15b were found in patients than controls. MiR-27b, miR-192 and miR-221 expression was significantly higher in patients without parenchymal involvement (stages I) than those at stages II-IV. Patients with acute disease demonstrated significantly higher miR-27b, miR-192 and miR-221 expression than those with insidious onset. For PB lymphocytes, patients demonstrated significantly greater miR-15b, miR-27b, miR-192, miR-221 and miR-222 expression, but lower miR-let7f and miR-130a expression, than controls. Stage I patients demonstrated significantly higher miR-16 and miR-15b expression than those in stages II-IV, and patients with the acute form demonstrated higher miR 130a and miR-15b expression. In BALF cells, miR-16 and miR-20a expression was significantly higher in patients with lung volume restriction, and miR-let7f was higher in the PB lymphocytes in patients with obturation. Several correlations were observed between the pattern of miRNA expression, lung function parameters and selected laboratory markers. CONCLUSION: The obtained results suggest that the studied miRNAs play a role in the pathogenesis of sarcoidosis, and that some of them might have negative prognostic value. PMID- 26768135 TI - MicroRNA-25 Negatively Regulates Cerebral Ischemia/Reperfusion Injury-Induced Cell Apoptosis Through Fas/FasL Pathway. AB - MicroRNA-25 (miR-25) has been reported to be a major miRNA marker in neural cells and is strongly expressed in ischemic brain tissues. However, the precise mechanism and effect of miR-25 in cerebral ischemia/reperfusion (I/R) injury needs further investigations. In the present study, the oxygen-glucose deprivation (OGD) model was constructed in human SH-SY5Y and IMR-32 cells to mimic I/R injury and to evaluate the role of miR-25 in regulating OGD/reperfusion (OGDR)-induced cell apoptosis. We found that miR-25 was downregulated in the OGDR model. Overexpression of miR-25 via miRNA-mimics transfection remarkably inhibited OGDR-induced cell apoptosis. Moreover, Fas was predicted as a target gene of miR-25 through bioinformatic analysis. The interaction between miR-25 and 3'-untranslated region (UTR) of Fas mRNA was confirmed by dual-luciferase reporter assay. Fas protein expression was downregulated by miR-25 overexpression in OGDR model. Subsequently, the small interfering RNA (siRNA)-mediated knockdown of Fas expression also inhibited cell apoptosis induced by OGDR model; in contrast, Fas overexpression abrogated the protective effects of miR-25 on OGDR induced cells. Taken together, our results indicate that the upregulation of miR 25 inhibits cerebral I/R injury-induced apoptosis through downregulating Fas/FasL, which will provide a promising therapeutic target. PMID- 26768136 TI - Mitochondrial c-Fos May Increase the Vulnerability of Neuro2a Cells to Cellular Stressors. AB - Although c-Fos expression in mitochondria is known to increase under excitatory injury via kainic acid or N-methyl-D-aspartate injection, the authentic function of c-Fos in mitochondria remains unknown. We found that c-Fos expression in the mitochondria of neuroblastoma Neuro2a cells was augmented by oxygen and glucose deprivation (OGD), which is a common in vitro model for brain ischemia. Then we demonstrated that Neuro2a cells stably expressing c-Fos exclusively in the mitochondria were more vulnerable to stressors such as OGD, rotenone (which is known to induce mitochondrial dysfunction) and hydrogen peroxide (a reactive oxygen species). Since mitochondrial dysfunction and the generation of reactive oxygen species are known to be caused by OGD, our findings indicate that mitochondrial c-Fos increases neuronal vulnerability to brain ischemia. This suggests that mitochondrial c-Fos play a potential role in inducing neuronal death on, and can therefore act as a potential drug target for brain ischemia. PMID- 26768137 TI - A multidimensional antimicrobial stewardship intervention targeting aztreonam use in patients with a reported penicillin allergy. AB - BACKGROUND: Local antimicrobial susceptibility patterns should be considered for antimicrobial therapy decisions. Antibiogram data can guide beta-lactam antibiotic use in the presence of a penicillin allergy, particularly when allergic cross-reactivity among antibiotic agents is unlikely. OBJECTIVE: To evaluate the effect of a multidimensional antimicrobial stewardship intervention to improve antibiogram-driven antibiotic selection for patients with a reported penicillin allergy receiving aztreonam. METHODS: This historically controlled, quasi-experimental study compared historical aztreonam use with prospective antibiotic selection following a pharmacist-led intervention in patients with a penicillin allergy. The impact of this intervention on aztreonam use, antimicrobial selection, patient allergy profile updates, length of stay, in hospital mortality, and antibiotic cost savings was assessed. RESULTS: A significant reduction in median days of aztreonam therapy (4.0 vs. 2.0; p = 0.0001) and median days of therapy per 1000 patient days (14.5 vs. 9.3; p = 0.0001) was found in the intervention group. CONCLUSION: A pharmacist-led antimicrobial stewardship intervention facilitated antibiogram-driven antibiotic therapy while reducing aztreonam use in patients without an anaphylactic penicillin allergy. Further trials are needed to assess the utility of similar antimicrobial stewardship interventions for patients with penicillin allergy. PMID- 26768139 TI - Teaching Medical Students Psychodynamic Psychotherapy: An Interactive Method. PMID- 26768140 TI - Reproductive outcome is optimized by genomic embryo screening, vitrification, and subsequent transfer into a prepared synchronous endometrium. AB - PURPOSE: The aim of this study is to compare implantation and live birth rates (LBR) between fresh euploid embryo transfers versus cryo-all cycles with a subsequent embryo transfer into a prepared endometrium. MATERIAL AND METHODS: This is a retrospective cohort study. Patients who underwent an IVF cycle with PGS with trophectoderm biopsy from January 2011 to July 2015 were included. Patients were divided into three groups: "Fresh Only," "Frozen Embryo Transfer ('FET) Only," and "Fresh ET then FET." For "Fresh Only" group (n = 345), PGS results were received within 24 h. For "FET Only" group (n = 514), results were expected after 24 h, and embryos were cryopreserved after biopsy; only FET was performed in this group (no fresh transfer). For "FET with a previous fresh ET" (n = 139) group, patients underwent a fresh ET with a subsequent FET, in which the same cohort of embryos was utilized. The main outcome measures were pregnancy rate (PR), clinical PR, implantation rate (IR), LBR, and early pregnancy loss rate. RESULTS: IRs were statistically higher in the "FET Only" group when compared to the "Fresh Only" group (59.5 vs. 50.6%, p < 0.01) and the "FET with a previous fresh ET" (59.5 vs. 50.6%, p < 0.05). LBR was statistically significant in the "FET Only" group when compared to the "Fresh Only" group (57.6 vs. 46.5 %, p < 0.005) but not when compared to "FET with a previous fresh ET" group (57.6 vs. 47.7%, p = 0.07). CONCLUSIONS: This analysis suggests euploid embryos to be more likely to implant and achieve a LBR in a synthetic FET cycle than in a fresh cycle. PMID- 26768142 TI - Flowering phenological changes in relation to climate change in Hungary. AB - The importance of long-term plant phenological time series is growing in monitoring of climate change impacts worldwide. To detect trends and assess possible influences of climate in Hungary, we studied flowering phenological records for six species (Convallaria majalis, Taraxacum officinale, Syringa vulgaris, Sambucus nigra, Robinia pseudoacacia, Tilia cordata) based on phenological observations from the Hungarian Meteorological Service recorded between 1952 and 2000. Altogether, four from the six examined plant species showed significant advancement in flowering onset with an average rate of 1.9-4.4 days per decade. We found that it was the mean temperature of the 2-3 months immediately preceding the mean flowering date, which most prominently influenced its timing. In addition, several species were affected by the late winter (January-March) values of the North Atlantic Oscillation (NAO) index. We also detected sporadic long-term effects for all species, where climatic variables from earlier months exerted influence with varying sign and little recognizable pattern: the temperature/NAO of the previous autumn (August-December) seems to influence Convallaria, and the temperature/precipitation of the previous spring (February-April) has some effect on Tilia flowering. PMID- 26768141 TI - The role of fertility preservation in patients with endometriosis. AB - Patients affected with severe endometriosis are at significant risk for ovarian tissue damage, which may lead to infertility, reduced response to ovarian stimulation, and occasionally, premature ovarian failure. The risk for a compromised ovarian reserve in young patients is especially high following repeated surgical intervention and in the presence of bilateral endometriomas. In many cases, enhanced loss of ovarian reserve may also result from the damaging effect of the pathologic process on follicle reservoir even without surgical interventions. Women diagnosed with severe endometriosis and those designated for extensive ovarian surgical intervention are frequently not planning to conceive. In light of recent advances in fertility preservation techniques (FPT), such as oocytes and ovarian tissue freezing, as well as their increasing success rates, we critically evaluate the options for FPT in patients suffering from endometriosis. Personalized counseling should be offered to all patients with endometriosis taking into account age, extent of ovarian involvement, current ovarian reserve, previous and impending surgeries for endometriosis, along with current success rates and possible risks associated with FPT. PMID- 26768143 TI - Spatiotemporal variability and predictability of Normalized Difference Vegetation Index (NDVI) in Alberta, Canada. AB - As one of the most popular vegetation indices to monitor terrestrial vegetation productivity, Normalized Difference Vegetation Index (NDVI) has been widely used to study the plant growth and vegetation productivity around the world, especially the dynamic response of vegetation to climate change in terms of precipitation and temperature. Alberta is the most important agricultural and forestry province and with the best climatic observation systems in Canada. However, few studies pertaining to climate change and vegetation productivity are found. The objectives of this paper therefore were to better understand impacts of climate change on vegetation productivity in Alberta using the NDVI and provide reference for policy makers and stakeholders. We investigated the following: (1) the variations of Alberta's smoothed NDVI (sNDVI, eliminated noise compared to NDVI) and two climatic variables (precipitation and temperature) using non-parametric Mann-Kendall monotonic test and Thiel-Sen's slope; (2) the relationships between sNDVI and climatic variables, and the potential predictability of sNDVI using climatic variables as predictors based on two predicted models; and (3) the use of a linear regression model and an artificial neural network calibrated by the genetic algorithm (ANN-GA) to estimate Alberta's sNDVI using precipitation and temperature as predictors. The results showed that (1) the monthly sNDVI has increased during the past 30 years and a lengthened growing season was detected; (2) vegetation productivity in northern Alberta was mainly temperature driven and the vegetation in southern Alberta was predominantly precipitation driven for the period of 1982-2011; and (3) better performances of the sNDVI-climate relationships were obtained by nonlinear model (ANN-GA) than using linear (regression) model. Similar results detected in both monthly and summer sNDVI prediction using climatic variables as predictors revealed the applicability of two models for different period of year ecologists might focus on. PMID- 26768144 TI - [Irreparable rotator cuff tears. Debridement, partial reconstruction, tendon transfer or reversed shoulder arthroplasty]. AB - Therapeutic options for the treatment of irreparable rotator cuff tears are fluent, are dependent on the patients' claims and demands and on the grade of the ongoing cuff tear arthropathy.A partial rotator cuff reconstruction with sufficient tenolysis combined with interval slide techniques to restore the anterior and posterior force couple may be indicated if there is no fatty degeneration > grade 3 of the rotator cuff muscles in a well-centered joint. The margin convergence technique with side-by-side adaptation of the tendon limbs may reduce the load on the reconstructed tendons.The role of the suprascapular nerve, which can probably be constricted by the retracted rotator cuff, and its therapy has not been completely clarified. When distinct symptoms are present neurolysis may be reasonable.Tendon transfers can be indicated in a cooperative patient < 65 years with a higher grade of muscular atrophy but without degenerative changes > grade II according to Hamada with the loss of active external rotation but performable active flexion. For posterosuperior tears the latissimus dorsi or recently the teres major tendon transfer to the rotator cuff footprint may be appropriate. For nonreconstructable anterosuperior tears a partial transfer of the pectoralis major tendon is possible.Careful subacromial debridement combined with biceps tenotomy and a cautious or reversed decompression may reduce the pain temporarily without having an influence on active motion until with the loss of active elevation the indication for a reversed shoulder arthroplasty is reached.In the mean time, absorbable subacromial spacers may re-center the humeral head, but the effectiveness of this therapy on clinical outcome should be analyzed in further studies. PMID- 26768145 TI - Growing Pains: a Simulation-Based Curriculum for Improving the Transition to Hematology/Oncology Fellowship. AB - Trainee exposure to clinical oncology during residency training is heterogeneous and often modest. The steep learning curve upon entry into fellowship can result in undue stress for fellows and their patients. Simulation-based training has been shown to be superior to classical didactic approaches. We have introduced several innovative simulation-based workshops into the curriculum for the Johns Hopkins Hematology/Oncology Fellowship Training Program in order to address this unmet need. During the first months of training, fellows were engaged in activities emphasizing essential clinical and procedural skills. Specific workshops included the following: (1) chemotherapy writing, (2) cadaveric and simulation-based bone marrow biopsy and intrathecal chemotherapy administration, and (3) simulation-based communication skills training. All first-year fellows in our program participated in these exercises. Pre- and post-workshop surveys were administered to assess knowledge, attitudes, and behaviors; additional distant post-workshop evaluations were disseminated to assess the durability/impact of the curricula and for program evaluation. Overall, participating fellows indicated that the workshops improved patient care and comfort with procedures and patient-centered communication. Continued implementation of these workshops was recommended for program improvement. To the best of our knowledge, ours is amongst the first oncology fellowship training programs to systematically implement simulation-based curricula into our schema for fellowship training. We hypothesize that proactively introducing fellows to these high-yield activities will translate into improved patient care and reduced stress for trainees. Additional investigation into the long-term impact of such curricula remains an area of ongoing need. PMID- 26768147 TI - Electronic Structure of Silicon Nanowires Matrix from Ab Initio Calculations. AB - An investigation of the model of porous silicon in the form of periodic set of silicon nanowires has been carried out. The electronic energy structure was studied using a first-principle band method-the method of pseudopotentials (ultrasoft potentials in the basis of plane waves) and linearized mode of the method of combined pseudopotentials. Due to the use of hybrid exchange correlation potentials (B3LYP), the quantitative agreement of the calculated value of band gap in the bulk material with experimental data is achieved. The obtained results show that passivation of dangling bonds with hydrogen atoms leads to substantial transformation of electronic energy structure. At complete passivation of the dangling silicon bonds by hydrogen atoms, the band gap value takes the magnitude which substantially exceeds that for bulk silicon. The incomplete passivation gives rise to opposite effect when the band gap value decreases down the semimetallic range. PMID- 26768146 TI - Drug eluting balloons as stand alone procedure for coronary bifurcational lesions: results of the randomized multicenter PEPCAD-BIF trial. AB - OBJECTIVES: We set out to investigate the benefit of distal main or side branch treatment with a DCB compared to POBA in coronary bifurcation lesions. BACKGROUND: The standard treatment of bifurcation lesions is application of a DES to the main branch with provisional side branch stenting. While this resulted in considerable improvement in overall MACE rate suboptimal side branch results remained a problem. METHODS: The study was performed from 2011 to 2013 in six German centers. Native bifurcation lesions were included if side branch vessel diameter was >=2 and <=3.5 mm and no proximal main branch lesions was found. After successful predilatation randomization was performed to either DCB application or no further treatment. Follow-up angiograms for QCA analysis were done after 9 months. Primary endpoint was late lumen loss (LLL). RESULTS: 64 patients were successfully randomized. Minimal lumen diameter and grade of stenosis were equal in both groups. Only five stents were used as bail out. Angiographic follow-up was achieved in 75 % of patients. No patient died. There was one NSTEMI in the POBA group. Restenosis rate was 6 % in the DCB group vs 26 % in the POBA group (p = 0.045). TLR was necessary in one patient of the DCB group vs three patients of the POBA. The primary endpoint LLL was 0.13 mm in the DCB vs 0.51 mm in the POBA group (p = 0.013). CONCLUSION: In bifurcation lesions that show only class A or B dissection and recoil not beyond 30 % the use of DCBs is a sound strategy. PMID- 26768148 TI - A Systemic Review on Aloe arborescens Pharmacological Profile: Biological Activities and Pilot Clinical Trials. AB - Since ancient times, plants and herbal preparations have been used as medicine. Research carried out in the last few decades has verified several such claims. Aloe arborescens Miller, belonging to the Aloe genus (Family Asphodelaceae), is one of the main varieties of Aloe used worldwide. The popularity of the plant in traditional medicine for several ailments (antitumor, immunomodulatory, antiinflammatory, antiulcer, antimicrobial and antifungal activity) focused the investigator's interest on this plant. Most importantly, the reported studies have shown the plant effectiveness on various cancer types such as liver, colon, duodenal, skin, pancreatic, intestinal, lung and kidney types. These multiple biological actions make Aloe an important resource for developing new natural therapies. However, the biological activities of isolated compounds such as glycoprotein, polysaccharides, enzyme and phenolics were insufficient. Considering all these, this contribution provides a systematic review outlining the evidence on the biological efficacy of the plant including the pharmacology and the related mechanisms of action, with specific attention to the various safety precautions, and preclinical and clinical studies, indicating the future research prospects of this plant. PMID- 26768149 TI - Effects of a higher dose of alglucosidase alfa on ventilator-free survival and motor outcome in classic infantile Pompe disease: an open-label single-center study. AB - BACKGROUND: Though enzyme-replacement therapy (ERT) with alglucosidase alfa has significantly improved the prospects for patients with classic infantile Pompe disease, some 50 % of treated infants do not survive ventilator-free beyond the age of 3 years. We investigated whether higher and more frequent dosing of alglucosidase alfa improves outcome. METHODS: Eight cross-reactive immunological material (CRIM) positive patients were included in the study. All had fully deleterious mutations in both GAA alleles. Four received a dose of 20 mg/kg every other week (eow) and four received 40 mg/kg/week. Survival, ventilator-free survival, left-ventricular mass index (LVMI), motor outcome, infusion-associated reactions (IARs), and antibody formation were evaluated. RESULTS: All eight patients were alive at study end, seven of them remained ventilator-free. The patient who became ventilator dependent was treated with 20 mg/kg eow. Three of the four patients receiving 20 mg/kg eow learned to walk; two of them maintained this ability at study end. All four patients receiving 40 mg/kg/week acquired and maintained the ability to walk at study end (ages of 3.3-5.6 years), even though their baseline motor functioning was poorer. There were no apparent differences between the two dose groups with respect to the effect of ERT on LVMI, the number of IARs and antibody formation. CONCLUSIONS: Our data may suggest that a dose of 40 mg/kg/week improves outcome of CRIM positive patients over that brought by the currently recommended dose of 20 mg/kg eow. Larger studies are needed to draw definite conclusions. PMID- 26768151 TI - Peptide micelle-mediated curcumin delivery for protection of islet beta-cells under hypoxia. AB - Islet transplantation is one of many therapeutic approaches for the treatment of diabetes. During transplant procedures, the isolated islets are subjected to hypoxic conditions, and undergo the apoptotic process. Curcumin has a cytoprotective effect, and may therefore be useful for the protection of islets under hypoxia. However, curcumin is hydrophobic, and an efficient curcumin carrier is required for effective treatment. In this study, R3V6 peptide micelles, composed of a 3-arginine stretch and 6-valine stretch, were evaluated as a curcumin carrier to INS-1 insulinoma cells. Curcumin was loaded into R3V6 micelles at a weight ratio of 10:3 (R3V6:curcumin). The size and surface charge of the curcumin-loaded R3V6 micelles (R3V6-curcumin) were approximately 250 nm and 17.49 mV, respectively. R3V6-curcumin delivered curcumin to the INS-1 cells more efficiently than either curcumin alone or a simple mixture of R3V6 and curcumin. MTT assay indicated that under hypoxia, R3V6-curcumin protected INS-1 cells more efficiently than curcumin alone. TUNEL and reactive oxygen species (ROS) assays suggested that R3V6-curcumin reduced INS-1 cell apoptosis under hypoxia. These results demonstrate that R3V6 peptide micelles are an effective carrier of curcumin, and that R3V6-curcumin may improve the viability of pancreatic beta-cells in islet transplantation. PMID- 26768152 TI - Analysis of the erythropoietin of a Tibetan Plateau schizothoracine fish (Gymnocypris dobula) reveals enhanced cytoprotection function in hypoxic environments. AB - BACKGROUND: Erythropoietin (EPO) is a glycoprotein hormone that plays a principal regulatory role in erythropoiesis and initiates cell homeostatic responses to environmental challenges. The Qinghai-Tibet Plateau is a natural laboratory for hypoxia adaptation. Gymnocypris dobula is a highly specialized plateau schizothoracine fish that is restricted to > 4500 m high-altitude freshwater rivers and ponds in the Qinghai-Tibet Plateau. The role of EPO in the adaptation of schizothoracine fish to hypoxia is unknown. RESULTS: The EPO and EPO receptor genes from G. dobula and four other schizothoracine fish from various altitudinal habitats were characterized. Schizothoracine EPOs are predicted to possess 2-3 N glycosylation (NGS) sites, 4-5 casein kinase II phosphorylation (CK2) sites, 1-2 protein kinase C (PKC) phosphorylation sites, and four conserved cysteine residues within four helical domains, with variations in the numbers of NGS and CK2 sites in G. dobula. PAML analysis indicated a d N/d S value (omega) = 1.112 in the G. dobula lineage, and a few amino acids potentially under lineage specific positive selection were detected within the G. dobula EPO. Similarly, EPO receptors of the two high-altitude schizothoracines (G. dobula and Ptychobarbus kaznakovi), were found to be statistically on the border of positive selection using the branch-site model (P-value = 0.096), and some amino acids located in the ligand-binding domain and the fibronectin type III domain were identified as potentially positive selection sites. Tissue EPO expression profiling based on transcriptome sequencing of three schizothoracines (G. dobula, Schizothorax nukiangensis Tsao, and Schizothorax prenanti) showed significant upregulation of EPO expression in the brain and less significantly in the gill of G. dobula. The elevated expression together with the rapid evolution of the EPO gene in G. dobula suggested a possible role for EPO in adaptation to hypoxia. To test this hypothesis, Gd-EPO and Sp-EPO were cloned into an expression vector and transfected into the cultured cell line 293 T. Significantly higher cell viability was observed in cells transfected with Gd-EPO than cells harboring Sp EPO when challenged by hypoxia. CONCLUSION: The deduced EPO proteins of the schizothoracine fish contain characteristic structures and important domains similar to EPOs from other taxa. The presence of potentially positive selection sites in both EPO and EPOR in G. dobula suggest possible adaptive evolution in the ligand-receptor binding activity of the EPO signaling cascade in G. dobula. Functional study indicated that the EPO from high-altitude schizothoracine species demonstrated features of hypoxic adaptation by reducing toxic effects or improving cell survival when expressed in cultured cells, providing evidence of molecular adaptation to hypoxic conditions in the Qinghai-Tibet Plateau. PMID- 26768153 TI - On the Values at Equilibrium and Rate Constants in Inter - Conversion Processes. AB - BACKGROUND: Inter - conversion processes of labile molecules obey similar rules to those of reversible chemical reactions. Solving the corresponding linear differential systems is used along this work, as well as in the preceding version. OBJECTIVE: The main purpose of the present mini revue paper is to recall, improve and correct some mathematical methods in determining the optimal values at equilibrium, and remarkable particular rate constants. This part was not proved correctly in my previous work. METHOD: In my previous work, the proof of the equality of the concentrations of the main species at equilibrium was not correct. In the current manuscript, we use increasing velocity in order to obtain this first important result. To this aim, one applies Schwarz inequality and the case when equality occurs. In order to determine significant rate constants, we characterize these special values in terms of the norm of the linear operator defined by the matrix of the differential system. In my previous work, the normal probability density function was used. The latter method was not realistic. RESULTS: Increasing the velocity, one obtains equal optimal values of the concentrations at equilibrium. This method represents a patent in the field. Secondly, characterization of remarkable rate constants (which are also equal) is deduced. The optimal solutions are written explicitly. CONCLUSION: Under suitable conditions, the values at equilibrium and the rate constants are equal. The common value at equilibrium equals the common value of the rate constants. PMID- 26768156 TI - Bacterial dynamin as a membrane puncture repair kit. PMID- 26768157 TI - The Emergency Department Point of Palliative Care Access for Patients With Advanced Cancer. PMID- 26768155 TI - Serum KIBRA mRNA and Protein Expression and Cognitive Functions in Depression. AB - BACKGROUND: Genes participating in synaptic signalling or plasticity in brain regions such as the prefrontal cortex (PFC) and the hippocampus have been implicated in cognition. Recently, a new gene (KIBRA, WWC1) has been added to this group due to its impact on memory performance. Recurrent depressive disorder (rDD) is a multifactorial disease, that one of the typical features is cognitive impairment. The main objective of this study was to perform an analysis of the KIBRA gene on both mRNA and protein levels in patients suffering from rDD and to investigate the relationship between KIBRA expression and cognitive performance. MATERIAL/METHODS: The study comprised 236 subjects: patients with rDD (n=131) and healthy subjects (n=105, HS). Cognitive function assessment was based on: Trail Making Test, The Stroop Test, Verbal Fluency Test and Auditory Verbal Learning Test. RESULTS: Both mRNA and protein expression levels of KIBRA gene were significantly higher in healthy subjects when compared to rDD. The presented relationship is clear even after taking age, education and sex of the examined subjects into consideration. No statistically significant relationship was found in the experiments between any of the conducted tests and KIBRA gene expression on mRNA level for both the rDD and HS groups. The presented study has limitations related to the fact that patients were being treated with antidepressant. This is relevant due to the fact that some antidepressants may affect mRNA expression. Number of patients and healthy subjects may result in the lack of statistical significance in some cases. CONCLUSIONS: 1. The results of our study show decreased expression of the KIBRA gene on both mRNA and protein levels in depression. 2. We did not find any significant relationship between KIBRA gene expression and cognitive functions in case of both the healthy subjects and the patients affected by rDD. PMID- 26768158 TI - Forensic Chemistry and Ambient Mass Spectrometry: A Perfect Couple Destined for a Happy Marriage? AB - Ambient mass spectrometry has been demonstrated, via various proof-of-concept studies, to offer a powerful, rather universal, simple, fast, nondestructive, and robust tool in forensic chemistry, producing reliable evidence at the molecular level. Its nearly nondestructive nature also preserves the sample for further inquiries. This feature article demonstrates the applicability of ambient mass spectrometry in forensic chemistry and explains the challenges that need to be overcome for this technique to make the ultimate step from the academic world into forensic institutes worldwide. We anticipate that the many beneficial and matching figures of merit will bring forensic chemistry and ambient mass spectrometry to a long-term relationship, which is likely to get strongly consolidated over the years. PMID- 26768159 TI - Structural changes of a sodium dodecyl sulfate (SDS) micelle induced by alcohol molecules. AB - Coarse-grained dynamical simulations have been performed to investigate the behavior of a surfactant micelle in the presence of six different alcohols: hexanol, octanol, decanol, dodecanol, tetradecanol, and hexadecanol. The self assembly of sodium dodecyl sulfate (SDS) is modified by the alcohol molecules into cylindrical and bilayer micelles as a function of the alcohol/SDS mass ratio. Therefore, in order to understand, from a molecular point of view, how SDS and alcohol molecules self-organize to form the new micelles, different studies were carried out. Analysis of micelle structures, density profiles, and parameters of order were conducted to characterize the shape and size of those micelles. The density profiles revealed that the alcohol molecules were located at the water-micelle interface next to the SDS molecules at low alcohol/SDS mass ratio. At high alcohol/SDS mass ratios, alcohol molecules moved to the middle of the micelle by increasing their size and by producing a structural change. Moreover, micelle structures and sizes were influenced not only by the alcohol/SDS mass ratio but also by the order of the SDS and alcohol tails. Finally, the size of the micelles and enthalpy calculations were used as order parameters to determine a structural phase diagram of alcohol/SDS mixtures in water. Graphical Abstract Structural transition of SDS/alcohol mixtures. PMID- 26768160 TI - "Make Sure Somebody Will Survive from This": Transformative Practices of Hope among Danish Organ Donor Families. AB - Based on anthropological fieldwork among Danish organ donor families and hospital staff in neurointensive care units, this article explores the transformative practices of hope in Danish organ donation. Focusing on various phases of the organ donation process, I demonstrate how families and professionals practice hope in astounding ways: when hoping for organs, when hoping for the end of patient suffering, when hoping for the usability of the donor body, and when hoping to help future donor families by sharing painful experiences. By focusing on such practices and transformations of hope, this article sheds light on the social negotiations of life and death among families and staffs in medical contexts and describes how the dignity of the deceased donor and the usability of the donor body are closely connected in family attempts to make donation decisions meaningful during and after a tragic death. PMID- 26768162 TI - Eric Harris Davidson: A systems biologist who studied how genomes function. PMID- 26768164 TI - Effects on life satisfaction of older adults after child and spouse bereavement. AB - BACKGROUND: Few studies have compared the impact of different familial losses on life satisfaction (LS). Furthermore, there is a lack of research on the effect of having lost both a child and a spouse among older adults. SAMPLE: A random sample of 1402 individuals, 817 women and 585 men, aged 60-96 years from the Blekinge part of the Swedish National Study of Aging and Care (SNAC-B) participated in this cross-sectional study. AIMS: The first aim was to compare the effects of child or spouse or both child and spouse bereavement on LS and, the second aim, to investigate if there were gender differences within the bereaved groups. RESULTS: The results showed that having lost a child, spouse or both child and spouse had a negative association with LS, although this effect was small. Having experienced multiple losses did not predict more variance than a single child or spouse loss. Gender differences were found within all the bereaved groups with bereaved men having lower LS than bereaved women. Longer time since the loss was associated with higher LS. CONCLUSIONS: Bereaved older adults have somewhat lower LS than non-bereaved and bereaved men seem more affected than bereaved women. Future research needs to address older men's experiences after the loss of a loved one. PMID- 26768166 TI - NHS trust first to face trial for corporate manslaughter after "wholly avoidable" death of patient. PMID- 26768165 TI - Dacomitinib versus erlotinib in patients with EGFR-mutated advanced nonsmall-cell lung cancer (NSCLC): pooled subset analyses from two randomized trials. AB - BACKGROUND: The irreversible epidermal growth factor receptor (EGFR) inhibitors have demonstrated efficacy in NSCLC patients with activating EGFR mutations, but it is unknown if they are superior to the reversible inhibitors. Dacomitinib is an oral, small-molecule irreversible inhibitor of all enzymatically active HER family tyrosine kinases. METHODS: The ARCHER 1009 (NCT01360554) and A7471028 (NCT00769067) studies randomized patients with locally advanced/metastatic NSCLC following progression with one or two prior chemotherapy regimens to dacomitinib or erlotinib. EGFR mutation testing was performed centrally on archived tumor samples. We pooled patients with exon 19 deletion and L858R EGFR mutations from both studies to compare the efficacy of dacomitinib to erlotinib. RESULTS: One hundred twenty-one patients with any EGFR mutation were enrolled; 101 had activating mutations in exon 19 or 21. For patients with exon19/21 mutations, the median progression-free survival was 14.6 months [95% confidence interval (CI) 9.0-18.2] with dacomitinib and 9.6 months (95% CI 7.4-12.7) with erlotinib [unstratified hazard ratio (HR) 0.717 (95% CI 0.458-1.124), two-sided log-rank, P = 0.146]. The median survival was 26.6 months (95% CI 21.6-41.5) with dacomitinib versus 23.2 months (95% CI 16.0-31.8) with erlotinib [unstratified HR 0.737 (95% CI 0.431-1.259), two-sided log-rank, P = 0.265]. Dacomitinib was associated with a higher incidence of diarrhea and mucositis in both studies compared with erlotinib. CONCLUSIONS: Dacomitinib is an active agent with comparable efficacy to erlotinib in the EGFR mutated patients. The subgroup with exon 19 deletion had favorable outcomes with dacomitinib. An ongoing phase III study will compare dacomitinib to gefitinib in first-line therapy of patients with NSCLC harboring common activating EGFR mutations (ARCHER 1050; NCT01774721). CLINICAL TRIALS NUMBER: ARCHER 1009 (NCT01360554) and A7471028 (NCT00769067). PMID- 26768168 TI - Fisher's geometric model predicts the effects of random mutations when tested in the wild. AB - Fisher's geometric model of adaptation (FGM) has been the conceptual foundation for studies investigating the genetic basis of adaptation since the onset of the neo Darwinian synthesis. FGM describes adaptation as the movement of a genotype toward a fitness optimum due to beneficial mutations. To date, one prediction of FGM, the probability of improvement is related to the distance from the optimum, has only been tested in microorganisms under laboratory conditions. There is reason to believe that results might differ under natural conditions where more mutations likely affect fitness, and where environmental variance may obscure the expected pattern. We chemically induced mutations into a set of 19 Arabidopsis thaliana accessions from across the native range of A. thaliana and planted them alongside the premutated founder lines in two habitats in the mid-Atlantic region of the United States under field conditions. We show that FGM is able to predict the outcome of a set of random induced mutations on fitness in a set of A. thaliana accessions grown in the wild: mutations are more likely to be beneficial in relatively less fit genotypes. This finding suggests that FGM is an accurate approximation of the process of adaptation under more realistic ecological conditions. PMID- 26768169 TI - Hospitalised Malaysian children with pandemic (H1N1) 2009 influenza: clinical characteristics, risk factors for severe disease and comparison with the 2002 2007 seasonal influenza. AB - INTRODUCTION: The pandemic caused by the H1N1 influenza virus in 2009 resulted in extensive morbidity and mortality worldwide. As the virus was a novel virus, there was limited data available on the clinical effects of the virus on children in Malaysia. Herein, we describe the clinical characteristics of children hospitalised with H1N1 influenza in a tertiary care centre; we also attempted to identify the risk factors associated with disease severity. METHODS: In this retrospective study, we compared the characteristics of the children who were admitted into the University of Malaya Medical Centre, Malaysia, for H1N1 influenza during the pandemic with those who were admitted for seasonal influenza in 2002-2007. RESULTS: Among the 77 children (aged <= 12 years) admitted to the centre due to H1N1 influenza from 1 July 2009-30 June 2010, nearly 60% were aged < 6 years and 40.3% had an underlying medical condition. The top three underlying medical conditions were bronchial asthma (14.3%), cardiac disease (10.4%) and neurological disorder (11.7%). The risk factors for severe disease were age < 2 years, underlying bronchial asthma and chronic lung disease. The three patients who died had a comorbid medical condition. The underlying cause of the deaths was acute respiratory distress syndrome or shock. CONCLUSION: The clinical presentation of the children infected with the pandemic (H1N1) 2009 influenza virus did not differ significantly from that of children infected with seasonal influenza. However, there were more complaints of fever, cough and vomiting in the former group. PMID- 26768170 TI - A peer victimisation scale based on a behavioural consequences measurement strategy. AB - INTRODUCTION: An accurate assessment of peer victimisation (i.e. bullying) is a necessary precondition for research and intervention. Most assessment instruments use the 'list of acts' measurement strategy, which does not account for the actual physical and psychological damage inflicted by bullying. To resolve this limitation, this study developed a peer victimisation scale (PVS) that includes harmful consequences for judgement and measurement of peer victimisation. METHODS: The PVS is a 40-item self-report questionnaire designed to assess the four aspects of peer victimisation: physical, verbal, relational, and interference and control. A total of 1,469 Grade 3-8 students (49.9% male) were recruited to test the psychometric properties of the PVS. Another 420 Grade 3-8 students were examined by a modified PVS supplemented with a semi-structured interview for scale validation and establishment of the cut-off points for severe bullying. Incidence, age and gender distribution of peer victimisation were also analysed. RESULTS: The PVS demonstrated good internal consistency reliability (Cronbach's alpha 0.73-0.83) and test-retest reliability two weeks later (correlation coefficient [r] = 0.71-0.80). The scores for each dimension were significantly and positively correlated with the scores from the questionnaire interview sample (r = 0.73-0.78), and modestly correlated with the scores for symptoms of anxiety and depression (r = 0.36-0.54). CONCLUSION: The results were consistent with the measurement constructs, demonstrating that the PVS is a reliable and effective instrument for assessing peer victimisation in children. It may enable more reliable longitudinal studies assessing the impact of peer victimisation to be conducted. PMID- 26768171 TI - Acute coronary syndrome in the elderly: the Malaysian National Cardiovascular Disease Database-Acute Coronary Syndrome registry. AB - INTRODUCTION: The elderly are often underrepresented in clinical trials for acute coronary syndrome (ACS), and cardiologists commonly face management dilemmas in the choice of treatment for this group of patients, particularly concerning the use of invasive revascularisation. This study analysed the characteristics of hospitalised elderly patients with ACS, and compared the outcomes of treatments. METHODS: From 29 December 2005 to 26 April 2010, 13,545 patients were admitted for ACS in 16 hospitals across Malaysia. These patients were divided into two groups - elderly (>= 65 years) and non-elderly (< 65 years). The clinical characteristics, treatment received (invasive or non-invasive) and outcomes (in hospital and 30-day all-cause mortality) of the two groups were compared. The elderly patients were then grouped according to the type of treatment received, and the outcomes of the two subgroups were compared. RESULTS: Elderly patients had a higher cardiovascular risk burden and a higher incidence of comorbidities. They were less likely to receive urgent revascularisation for acute ST-segment elevation myocardial infarction (elderly: 73.9% vs. non-elderly: 81.4%) and had longer door-to-needle time (elderly: 60 minutes vs. non-elderly: 50 minutes, p = 0.004). The rate of cardiac catheterisation was significantly lower in the elderly group across all ACS strata. Elderly patients had poorer outcomes than non-elderly patients, but those who received invasive treatment appeared to have better outcomes than those who received non-invasive treatment. CONCLUSION: Elderly patients with ACS tend to be undertreated, both invasively and pharmacologically. Invasive treatment seems to yield better outcomes for this group of patients. PMID- 26768172 TI - Does medical students' clinical performance affect their actual performance during medical internship? AB - INTRODUCTION: This study examines the relationship between the clinical performance of medical students and their performance as doctors during their internships. METHODS: This retrospective study involved 63 applicants to a residency programme conducted at the Chonnam National University Hospital, South Korea, in November 2012. We compared the performance of the applicants during their internship with the clinical performance of the applicants during their fourth year of medical school. The performance of the applicants as interns was periodically evaluated by the faculty of each department, while the clinical performance of the applicants as fourth year medical students was assessed using the Clinical Performance Examination (CPX) and the Objective Structured Clinical Examination (OSCE). RESULTS: The performance of the applicants as interns was positively correlated with their clinical performance as fourth year medical students, as measured by CPX and OSCE. The performance of the applicants as interns was moderately correlated with the patient-physician interactions items addressing communication and interpersonal skills in the CPX. CONCLUSION: The clinical performance of medical students during their fourth year in medical school was related to their performance as medical interns. Medical students should be trained to develop good clinical skills, through actual encounters with patients or simulated encounters using manikins, so that they are able to become competent doctors. PMID- 26768173 TI - Evaluation of validity and reliability of a methodology for measuring human postural attitude and its relation to temporomandibular joint disorders. AB - INTRODUCTION: Temporomandibular joint disorders (TMJDs) are caused by several factors such as anatomical, neuromuscular and psychological alterations. A relationship has been established between TMJDs and postural alterations, a type of anatomical alteration. An anterior position of the head requires hyperactivity of the posterior neck region and shoulder muscles to prevent the head from falling forward. This compensatory muscular function may cause fatigue, discomfort and trigger point activation. To our knowledge, a method for assessing human postural attitude in more than one plane has not been reported. Thus, the aim of this study was to design a methodology to measure the external human postural attitude in frontal and sagittal planes, with proper validity and reliability analyses. METHODS: The variable postures of 78 subjects (36 men, 42 women; age 18-24 years) were evaluated. The postural attitudes of the subjects were measured in the frontal and sagittal planes, using an acromiopelvimeter, grid panel and Fox plane. RESULTS: The method we designed for measuring postural attitudes had adequate reliability and validity, both qualitatively and quantitatively, based on Cohen's Kappa coefficient (> 0.87) and Pearson's correlation coefficient (r = 0.824, > 80%). CONCLUSION: This method exhibits adequate metrical properties and can therefore be used in further research on the association of human body posture with skeletal types and TMJDs. PMID- 26768176 TI - Associations of non-symbolic and symbolic numerical magnitude processing with mathematical competence: a meta-analysis. AB - Many studies have investigated the association between numerical magnitude processing skills, as assessed by the numerical magnitude comparison task, and broader mathematical competence, e.g. counting, arithmetic, or algebra. Most correlations were positive but varied considerably in their strengths. It remains unclear whether and to what extent the strength of these associations differs systematically between non-symbolic and symbolic magnitude comparison tasks and whether age, magnitude comparison measures or mathematical competence measures are additional moderators. We investigated these questions by means of a meta analysis. The literature search yielded 45 articles reporting 284 effect sizes found with 17,201 participants. Effect sizes were combined by means of a two level random-effects regression model. The effect size was significantly higher for the symbolic (r = .302, 95% CI [.243, .361]) than for the non-symbolic (r = .241, 95% CI [.198, .284]) magnitude comparison task and decreased very slightly with age. The correlation was higher for solution rates and Weber fractions than for alternative measures of comparison proficiency. It was higher for mathematical competencies that rely more heavily on the processing of magnitudes (i.e. mental arithmetic and early mathematical abilities) than for others. The results support the view that magnitude processing is reliably associated with mathematical competence over the lifespan in a wide range of tasks, measures and mathematical subdomains. The association is stronger for symbolic than for non symbolic numerical magnitude processing. So symbolic magnitude processing might be a more eligible candidate to be targeted by diagnostic screening instruments and interventions for school-aged children and for adults. PMID- 26768154 TI - Reference tissue normalization in longitudinal (18)F-florbetapir positron emission tomography of late mild cognitive impairment. AB - BACKGROUND: Semiquantitative methods such as the standardized uptake value ratio (SUVR) require normalization of the radiotracer activity to a reference tissue to monitor changes in the accumulation of amyloid-beta (Abeta) plaques measured with positron emission tomography (PET). The objective of this study was to evaluate the effect of reference tissue normalization in a test-retest (18)F-florbetapir SUVR study using cerebellar gray matter, white matter (two different segmentation masks), brainstem, and corpus callosum as reference regions. METHODS: We calculated the correlation between (18)F-florbetapir PET and concurrent cerebrospinal fluid (CSF) Abeta1-42 levels in a late mild cognitive impairment cohort with longitudinal PET and CSF data over the course of 2 years. In addition to conventional SUVR analysis using mean and median values of normalized brain radiotracer activity, we investigated a new image analysis technique-the weighted two-point correlation function (wS2)-to capture potentially more subtle changes in Abeta-PET data. RESULTS: Compared with the SUVRs normalized to cerebellar gray matter, all cerebral-to-white matter normalization schemes resulted in a higher inverse correlation between PET and CSF Abeta1-42, while the brainstem normalization gave the best results (high and most stable correlation). Compared with the SUVR mean and median values, the wS2 values were associated with the lowest coefficient of variation and highest inverse correlation to CSF Abeta1-42 levels across all time points and reference regions, including the cerebellar gray matter. CONCLUSIONS: The selection of reference tissue for normalization and the choice of image analysis method can affect changes in cortical (18)F florbetapir uptake in longitudinal studies. PMID- 26768181 TI - Errata. PMID- 26768180 TI - Primary pulmonary giant cell tumor: (18)F-FDG PET/CT imaging. PMID- 26768183 TI - Deconstructing Chronic Low Back Pain in the Older Adult--Step by Step Evidence and Expert-Based Recommendations for Evaluation and Treatment. Part V: Maladaptive Coping. AB - OBJECTIVE: As part of a series of articles designed to deconstruct chronic low back pain (CLBP) in older adults, this article focuses on maladaptive coping--a significant contributor of psychological distress, increased pain, and heightened disability in older adults with CLBP. METHODS: A modified Delphi technique was used to develop a maladaptive coping algorithm and table providing the rationale for the various components of the algorithm. A seven-member content expert panel and a nine-member primary care panel were involved in the iterative development of the materials. While the algorithm was developed keeping in mind resources available within the Veterans Health Administration (VHA) facilities, panelists were not exclusive to the VHA, and therefore, materials can be applied in both VHA and civilian settings. The illustrative clinical case was taken from one of the contributors' clinical practice. RESULTS: We present a treatment algorithm and supporting table to be used by providers treating older adults who have CLBP and engage in maladaptive coping strategies. A case of an older adult with CLBP and maladaptive coping is provided to illustrate the approach to management. CONCLUSIONS: To promote early engagement in skill-focused treatments, providers can routinely evaluate pain coping strategies in older adults with CLBP using a treatment algorithm. PMID- 26768185 TI - De novo 9q gain in an infant with tetralogy of Fallot with absent pulmonary valve: Patient report and review of congenital heart disease in 9q duplication syndrome. AB - Genomic disruptions, altered epigenetic mechanisms, and environmental factors contribute to the heterogeneity of congenital heart defects (CHD). In recent years, chromosomal microarray analysis (CMA) has led to the identification of numerous copy number variations (CNV) in patients with CHD. Genes disrupted by and within these CNVs thus represent excellent candidate genes for CHD. Microduplications of 9q (9q+) have been described in patients with CHD, however, the critical gene locus remains undetermined. Here we discuss an infant with tetralogy of Fallot with absent pulmonary valve, fetal hydrops, and a 3.76 Mb de novo contiguous gain of 9q34.2-q34.3 detected by CMA, and confirmed by karyotype and FISH studies. This duplicated interval disrupted RXRA (retinoid X receptor alpha; OMIM #180245) at intron 1. We also review CHD findings among previously reported patients with 9q (9q+) duplication syndrome. This is the first report implicating RXRA in CHD with 9q duplication, providing additional data in understanding the genetic etiology of tetralogy of Fallot, CHD, and disorders linked to 9q microduplication syndrome. This report also highlights the significance of CMA in the clinical diagnosis and genetic counseling of patients and families with complex CHD. PMID- 26768186 TI - Phosphoglucomutase-1 deficiency: Intrafamilial clinical variability and common secondary adrenal insufficiency. AB - Phosphoglucomutase 1 (PGM1, EC 5.4.2.2) plays a critical role in glucose homeostasis and is also essential for protein N-glycosylation. The main clinical manifestations of PGM1 deficiency (MIM 614921) reported in 19 patients from different ethnic backgrounds include the following: cleft uvula/palate, Pierre Robin sequence, muscle weakness, dilated cardiomyopathy, growth retardation, elevated serum transaminases, hypoglycemia, and various endocrine abnormalities. We report the variable clinical picture of seven patients with PGM1 deficiency from a consanguineous family. Medical records of the patients were reviewed for clinical details and endocrine evaluation. Whole exome sequencing (WES) was performed. Seven patients aged 2-29 years were included, one patient died at 13 years old when getting off the school bus. All patients have an abnormal palatine structure (cleft palate, bifid uvula) and elevated serum transaminases, 4/7 have short stature (<-2 SDS) and one was diagnosed with growth hormone deficiency. Recurrent episodes of ketotic hypoglycemia were present in 6/7 patients. In two patients, hypoglycemic episodes have spontaneously resolved later on. Four out of seven patients have deteriorating adrenal function with abnormally low cortisol and ACTH levels during hypoglycemia and subnormal response of cortisol to low dose ACTH test . Serum electrolytes were within normal range. Hydrocortisone replacement therapy improved, but not entirely eliminated hypoglycemic episodes. WES revealed a previously described homozygous mutation c.112A>T, p.Asn38Tyr in the PGM1 gene. The clinical picture of PGM1 deficiency is variable among patients with the same mutation and genetic background. ACTH deficiency should be considered in any PGM1 deficient patient with hypoglycemia. PMID- 26768187 TI - Medical foods prescribed to treat methylmalonic acidemia linked with adverse outcomes for some patients: Studies explore impact of unbalanced amino acid formulation on growth, brain development. PMID- 26768188 TI - Sweeping changes proposed for "Common rule": Update would require mandatory informed consent for use of human biospecimens in research. PMID- 26768190 TI - Scalp melanoma: Distinctive high risk clinical and histological features. AB - BACKGROUND/OBJECTIVES: Scalp melanoma has a worse prognosis than melanoma elsewhere, though the reasons for this are poorly understood. Current literature describing the clinicopathological associations of scalp melanoma is sparse. This study aims to compare clinical and histological features of scalp melanoma with other cutaneous head and neck melanomas (CHNM). METHODS: A cross-sectional study was performed of all primary CHNM cases seen by the Victorian Melanoma Service between 1994 and 2014, using prospectively recorded clinical data. Invasive and in situ melanomas were compared separately. RESULTS: Invasive scalp melanoma was associated with male sex (OR, 2.7; 95% CI, 1.9-3.9), increasing age (OR, 1.02 per year increase in age; 95% CI, 1.01-1.03), being first noticed by a person other than self, spouse/relative or doctor (OR, 2.9; 95% CI, 1.5-5.7), amelanosis (OR, 1.6; 95% CI, 1.1-2.3), and increased growth rate (OR, 1.14 per 1 mm/month growth rate increase; 95% CI, 1.04-1.26). Compared with other CHNM, scalp melanoma had greater median Breslow thickness (2.8 vs 1.2 mm) and was independently associated with satellite metastases (OR, 4.7; 95% CI, 1.9-11.5) and nodular subtype (OR, 1.8; 95% CI, 1.1-3.1). In situ scalp melanoma was associated with male sex, increasing age and solar keratoses. CONCLUSION: Scalp melanoma tends to occur in older men, is often rapidly growing and amelanotic, and is associated with high risk histological features. As it is likely to be overlooked, increased recognition of the atypical presentations of scalp melanoma is required. PMID- 26768193 TI - Editorial 2016. PMID- 26768192 TI - Predictors of proton pump inhibitor failure in non-erosive reflux disease: A study with impedance-pH monitoring and high-resolution manometry. AB - BACKGROUND: Approximately one-third of gastroesophageal reflux disease (GERD) patients have symptoms resistant to proton pump inhibitor (PPI). We used the high resolution manometry (HRM) and multichannel intraluminal impedance-pH (MII-pH) monitoring to investigate potential predictors of PPI failure in non-erosive reflux disease (NERD) patients. METHODS: One hundred and seventeen NERD patients were included, within which there were 44 PPI failure patients. The symptomatic questionnaire GerdQ, HRM and 24-hour MII-pH monitoring were performed before PPI therapy. PPI failure was defined as persistent reflux symptoms for more than 1 day during the last week on esomeprazole (20 mg twice daily) for continuous 4 weeks. The predictors for PPI failure were investigated by multivariable logistic regression analysis. KEY RESULTS: Proton pump inhibitor failure patients had lower body mass index (BMI) and more concomitant functional dyspepsia (FD) symptoms. PPI failure patients had a higher percentage of type I esophagogastric junction (EGJ) morphology (p = 0.005), increased EGJ augmentation (p = 0.000), higher prevalence of esophageal motility disorders (p = 0.005) and a higher ratio of negative symptom index (SI, p = 0.000). Multivariable regression analysis showed that concomitance of FD symptoms, EGJ augmentation and negative SI were independent risk factors for PPI failure in NERD. CONCLUSIONS & INFERENCES: Approximately half of PPI failure patients were found to have esophageal motility disorders in HRM. The independent risk factors for PPI failure in NERD were concomitant FD symptoms, increased EGJ augmentation and negative SI. PMID- 26768194 TI - Don't throw the baby out with the bathwater: identifying and mapping paralogs in salmonids. AB - Many eukaryotic genomes contain a large fraction of gene duplicates (or paralogs) as a result of ancient or recent whole-genome duplications (Ohno 1970; Jaillon et al. 2004; Kellis et al. 2004). Identifying paralogs with NGS data is a pervasive problem in both ancient polyploids and neopolyploids. Likewise, paralogs are often treated as a nuisance that has to be detected and removed (Everett et al. 2012). In this issue of Molecular Ecology Resources, Waples et al. (2015) show that exclusion might not be necessary and how we may miss out on important genomic information in doing so. They present a novel statistical approach to detect paralogs based on the segregation of RAD loci in haploid offspring and test their method by constructing linkage maps with and without these duplicated loci in chum salmon, Oncorhynchus keta (Fig.1). Their linkage map including the resolved paralogs shows that these are mostly located in the distal regions of several linkage groups. Particularly intriguing is their finding that these homoeologous regions appear impoverished in transposable elements (TE). Given the role that TE play in genome remodelling, it is noteworthy that these elements are of low abundance in regions showing residual tetrasomic inheritance. This raises the question whether re-diploidization is constrained in these regions and whether they might have a role to play in salmonid speciation. This study provides an original approach to identifying duplicated loci in species with a pedigree, as well as providing a dense linkage map for chum salmon, and interesting insights into the retention of gene duplicates in an ancient polyploid. PMID- 26768195 TI - Making environmental DNA count. AB - The arc of reception for a new technology or method--like the reception of new information itself--can pass through predictable stages, with audiences' responses evolving from 'I don't believe it', through 'well, maybe' to 'yes, everyone knows that' to, finally, 'old news'. The idea that one can sample a volume of water, sequence DNA out of it, and report what species are living nearby has experienced roughly this series of responses among biologists, beginning with the microbial biologists who developed genetic techniques to reveal the unseen microbiome. 'Macrobial' biologists and ecologists--those accustomed to dealing with species they can see and count--have been slower to adopt such molecular survey techniques, in part because of the uncertain relationship between the number of recovered DNA sequences and the abundance of whole organisms in the sampled environment. In this issue of Molecular Ecology Resources, Evans et al. (2015) quantify this relationship for a suite of nine vertebrate species consisting of eight fish and one amphibian. Having detected all of the species present with a molecular toolbox of six primer sets, they consistently find DNA abundances are associated with species' biomasses. The strength and slope of this association vary for each species and each primer set- further evidence that there is no universal parameter linking recovered DNA to species abundance--but Evans and colleagues take a significant step towards being able to answer the next question audiences tend to ask: 'Yes, but how many are there?' PMID- 26768196 TI - Interpreting the flock algorithm: a reply to Anderson & Barry (2015). AB - Anderson & Barry (Molecular Ecology Resources, 2015, 10, 1020-1030) compared a reprogrammed version of flock (Duchesne & Turgeon , Molecular Ecology Resources, 2009, 9, 1333-1344), flockture, to a particular model of structure (Pritchard , Genetics, 2000, 155, 945-959) that they propose is equivalent to flock, a non MCMC, non-Bayesian algorithm. They conclude that structure performs better than flockture at clustering individuals from simulated populations with very low level of differentiation (FST c. 0.008) based on 15 microsatellites or 96 SNPs. We rather consider that both algorithms failed, with proportions of correct allocations lower than 50%. The authors also noted the slightly better performance of flockture with SNPs at intermediate FST values (c. 0.02-0.04) but did not comment. Finally, we disagree with the way the processing time of each program was compared. When compared on the basis of a run leading to a clustering solution, the main output of any clustering algorithm, flock, is, as users can readily experience, much faster. In all, we feel that flock performs at least as well as structure as a clustering algorithm. Moreover, flock has two major assets: high speed and clear, well validated, rules to estimate K, the number of populations. It thus provides a valuable addition to the set of tools at the disposal of the many researchers dealing with real empirical data sets. PMID- 26768198 TI - Erratum. PMID- 26768199 TI - Making Home Birth Safer in the United States Through Strategic Collaboration: The Legacy Health System Experience. PMID- 26768197 TI - Genomic Resources Notes Accepted 1 August 2015 - 31 September 2015. AB - This article documents the public availability of transcriptomic resources for (i) the Hazelnut tree (Corylus avellana L.) and (ii) the oriental rat flea and primary plague vector, Xenopsylla cheopis. PMID- 26768204 TI - Erratum. PMID- 26768200 TI - The Effectiveness of a New Model in Managing Pregnant Women with Iron Deficiency Anemia in Indonesia: A Nonrandomized Controlled Intervention Study. AB - BACKGROUND: Indonesia has a major problem with iron deficiency anemia among pregnant women. A new model named the Four Pillars Approach was designed to improve antenatal care for these women. This study aimed to measure the effectiveness of the model in managing pregnant women with iron deficiency anemia. METHOD: We used a nonrandomized controlled intervention study. The study, with the Four Pillars Approach as intervention versus usual care as its control, was conducted in two provinces in Java (Indonesia) during the period from March 2012 until May 2013. Main outcome measures were a difference of Hb level >= 0.5 g/dL, the number of women who attended five or more antenatal care visits, and birthing with a skilled birth attendant. RESULTS: Three hundred fifty-four participants were enrolled in the study. Participants in the intervention group had an adjusted odds ratio of 25.0 (95% CI 12.03-52.03, p = 0.001) for increased hemoglobin of >= 0.5 g/dL at 35-37 weeks of gestation, compared with the control group. In the intervention group, 95.0 percent of women had five or more antenatal care visits, compared with 57.2 percent (p = 0.001) in the control group. All births in both groups were assisted by skilled birth attendants. CONCLUSION: The Four Pillars Approach is effective in increasing the hemoglobin level and the frequency of antenatal care visits of participants when compared with the usual care for pregnant women with anemia. PMID- 26768205 TI - Clot Length Assessment in Stroke Therapy Decisions. PMID- 26768206 TI - Thrombus Length Estimation on Delayed Gadolinium-Enhanced T1. AB - BACKGROUND AND PURPOSE: Previous studies revealed a close relationship between thrombus length and recanalization rate after intravenous thrombolysis (IVT). As a novel approach, we prospectively adjusted the order of sequence acquisition to obtain delayed gadolinium-enhanced T1 (dGE-T1) and thereby assess thrombus length on dGE-T1 to evaluate its predictive value for recanalization after IVT. METHODS: We reviewed prospectively collected clinical and imaging data from acute ischemic stroke patients with middle cerebral artery occlusion who underwent multimodal magnetic resonance imaging before and 24 hours after IVT. Perfusion-weighted imaging was performed followed by conventional T1. We measured thrombus length on dGE-T1 and examined its association with middle cerebral artery recanalization. RESULTS: Of the included 74 patients, the median age was 66 years and 28 (37.8%) were women. Thrombus length was 8.18+/-4.56 mm on dGE-T1, which was an acceptable predictor for no recanalization (odds ratio, 1.196; 95% confidence interval, 1.015-1.409; P=0.033), with a receiver-operator characteristic of 0.732 (95% confidence interval, 0.619-0.845; P=0.001). The optimal cut-off point was identified at 6.77 mm, which yielded a sensitivity of 77.8%, a specificity of 57.9%, and an odds ratio of 4.81 (95% confidence interval, 1.742-13.292; P=0.002). Moreover, no one achieved recanalization after IVT when length of thrombus exceeded 14 mm on dGE-T1. CONCLUSIONS: The dGE-T1, obtained by simply adjusting scanning order in multimodal magnetic resonance imaging protocol, is a useful tool for thrombus length estimation and middle cerebral artery recanalization prediction after IVT. PMID- 26768207 TI - Sleep Fragmentation, Cerebral Arteriolosclerosis, and Brain Infarct Pathology in Community-Dwelling Older People. AB - BACKGROUND AND PURPOSE: Although several forms of sleep disruption are associated with stroke, few studies have examined the relationship between sleep and histopathologic measures of cerebrovascular disease. We tested the hypothesis that greater sleep fragmentation is associated with a higher burden of cerebral vessel and infarct pathology at autopsy. METHODS: We used ordinal logistic regression models to relate sleep fragmentation measured by actigraphy to the severity of arteriolosclerosis, atherosclerosis, and cerebral amyloid angiopathy, and the number of macroscopic and microscopic infarcts assessed by structured brain autopsy in 315 participants from the Rush Memory and Aging Project. RESULTS: Greater sleep fragmentation was associated with more severe arteriolosclerosis (odds ratio, 1.27; 95% confidence interval, 1.02-1.59; P=0.03 per 1 SD greater sleep fragmentation) and more subcortical macroscopic infarcts (odds ratio, 1.31; 95% confidence interval, 1.01-1.68; P=0.04). These associations were independent of established cardiovascular risk factors and diseases, and several medical comorbidities. CONCLUSIONS: Sleep fragmentation is associated with arteriolosclerosis and subcortical infarcts in older adults. PMID- 26768208 TI - Determinants of Emergency Medical Services Utilization Among Acute Ischemic Stroke Patients in Hubei Province in China. AB - BACKGROUND AND PURPOSE: Emergency medical services (EMS) can effectively shorten the prehospital delay for patients with acute ischemic stroke. This study aimed to investigate EMS utilization and its associated factors in patients with acute ischemic stroke in China. METHODS: A cross-sectional study was conducted from October 1, 2014, to January 31, 2015, which included 2096 patients admitted for acute ischemic stroke from 66 hospitals in Hubei province in China. A multivariable stepwise logistic regression model was undertaken to identify the factors associated with EMS utilization. RESULTS: Of the 2096 participants, only 323 cases (15.4%) used EMS. Those acute ischemic stroke patients who previously used EMS (odds ratio [OR] =9.8), whose National Institutes of Health Stroke Scale score was >=10 (OR=3.7), who lived in urban communities (OR=2.5), who had sudden onset of symptoms (OR=2.4), who experienced their first stroke (OR=1.8), and who recognized initial symptom as stroke (OR=1.4) were more likely to use EMS. Additionally, when acute ischemic stroke patients' stroke symptom were noticed first by others (OR=2.1), rather than by the patients, EMS was more likely to be used. CONCLUSIONS: A very low proportion of patients with acute ischemic stroke used the EMS in Hubei province in China. Considerable education programs are required regarding knowledge of potential symptoms and the importance of EMS for stroke. PMID- 26768209 TI - Heme-Hemopexin Scavenging Is Active in the Brain and Associates With Outcome After Subarachnoid Hemorrhage. AB - BACKGROUND AND PURPOSE: Long-term outcome after subarachnoid hemorrhage (SAH) is potentially linked to cytotoxic heme. Free heme is bound by hemopexin and rapidly scavenged by CD91. We hypothesized that heme scavenging in the brain would be associated with outcome after hemorrhage. METHODS: Using cerebrospinal fluid and tissue from patients with SAH and control individuals, the activity of the intracranial CD91-hemopexin system was examined using ELISA, ultrahigh performance liquid chromatography, and immunohistochemistry. RESULTS: In control individuals, cerebrospinal fluid hemopexin was mainly synthesized intrathecally. After SAH, cerebrospinal fluid hemopexin was high in one third of cases, and these patients had a higher probability of delayed cerebral ischemia and poorer neurological outcome. The intracranial CD91-hemopexin system was active after SAH because CD91 positively correlated with iron deposition in brain tissue. Heme hemopexin uptake saturated rapidly after SAH because bound heme accumulated early in the cerebrospinal fluid. When the blood-brain barrier was compromised after SAH, serum hemopexin level was lower, suggesting heme transfer to the circulation for peripheral CD91 scavenging. CONCLUSIONS: The CD91-heme-hemopexin scavenging system is important after SAH and merits further study as a potential prognostic marker and therapeutic target. PMID- 26768210 TI - The management of acute coronary syndromes: towards optimal treatment of STEMI and non-STEMI. PMID- 26768211 TI - CardioPulse: What's new in the 2015 European Society of Cardiology Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. PMID- 26768212 TI - Multi-vessel revascularization in ST-segment elevation myocardial infarction: where do we stand? AB - In summary, current evidence suggests that it appears to be better to do something rather than nothing. However, the question of single vs. staged complete revascularization, the best timing of the staged PCI (during the index admission or within weeks) and the question of stratification for evidence of ischaemia remain to be answered in upcoming trials. Meanwhile, complete revascularization should not be routinely performed ad-hoc, but based on individual and careful patient and lesion assessments PMID- 26768215 TI - Analysis of tolvaptan and its metabolites in sports drug testing by high performance liquid chromatography coupled to tandem mass spectrometry. AB - Tolvaptan is prohibited by the World Anti-doping Agency (WADA) under class S5 - Diuretics and masking agents. Less than 1% of the administrated dose is excreted by humans in urine. Knowledge concerning the metabolism in humans, and especially the excretion of metabolites in human urine, is limited. An analysis method based on the dilute-and-shoot approach using high-performance liquid chromatography coupled to tandem mass spectrometry (HPLC-MS/MS) for detection was developed and validated. Ion transitions, which are part of this method, can easily be included in already existing screening methods used in routine doping analysis for the detection of diuretics. After administration of a single dose of tolvaptan to one male subject, low concentrations of the drug itself could be detected in urine samples over a time period of 24 h. In addition, hydroxyl metabolites of tolvaptan and one carboxyl metabolite with a cleaved benzazepine ring system were identified. These metabolites showed detection times of up to 150 h. An inclusion of these metabolites in the methods used in doping control analysis seems therefore to be of value. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26768216 TI - Combined two foot flaps with iliac bone graft for reconstruction of the thumb. AB - The purpose of this report was to retrospectively review the results of reconstruction of the thumb by use of combined two foot flaps with an iliac bone graft. From 2009 to 2014, nine patients with traumatic amputation of the thumb had their thumbs reconstructed. The two flaps were based on one pedicle. All flaps survived completely. Patients were followed for a mean of 15.6 months (range, 6-35 months). The appearance of the reconstructed thumb was comparable to a normal one, except for one thumb which required debulking. The appearance of the nail was satisfactory without deformity. The range of joint motion was satisfactory. The two point discrimination of the pulp ranged from 6 mm to >15 mm. The Michigan Hand Questionnaire outcome score was a mean of 76.2 +/- 11.3 points and the Maryland foot rating score a mean of 94.8 +/- 3.4 points. The combined two foot flaps with iliac bone graft might provide an option for the reconstruction of the thumb. LEVEL OF EVIDENCE: III. PMID- 26768217 TI - Congenital absence of the ulnar artery. PMID- 26768218 TI - Wrist arthrodesis in adolescents with cerebral palsy. AB - Twenty adolescents with severe spastic deformities of the wrist (Zancolli type 3) and poor function on the House score were operated on between 2009 and 2014, and included in this retrospective cohort study. All were treated by wrist arthrodesis combining a proximal row carpectomy, curetting of the distal radius in order to imbed the capitate and a dorsal locking plate. The primary endpoint was improvement in the House score. Secondary endpoints included pre- and postoperative wrist flexion deformity, bone union, patient satisfaction regarding appearance and complications. The mean follow-up was 22 months. The mean age at the time of surgery was 16.2 years. Additional soft-tissue release was necessary in eight wrists. The mean House score improved significantly from 0.9 to 2.7. Average flexion deformity improved significantly from 66 degrees to 10 degrees . Bony union was achieved in all patients within 6 months. Four of the 20 patients required hardware removal because of fixed extension of the middle metacarpal. Wrist arthrodesis combining proximal row carpectomy with the use of a dorsal locking plate is a safe and reliable technique to improve function and appearance. LEVEL OF EVIDENCE: IV. PMID- 26768219 TI - The Camitz transfer and its modifications: a review. AB - The Camitz procedure involves transfer of the insertion of the palmaris longus tendon with a strip of the palmar aponeurosis to the insertion of abductor pollicis brevis in order to improve thumb opposition, and is usually done when severe carpal tunnel syndrome results in complete wasting of the thenar muscles. We carried out a systematic review of the published reports of this procedure. Analysis of available outcome data showed improvement in overall hand function in 86-100% of patients undergoing the original Camitz procedure. Several modifications of the original Camitz transfer have been described, with most focusing on the incorporation and placement of pulleys. All studies are limited by their small sample sizes. Overall, there is a lack of studies comparing the Camitz transfer with other opponensplasty techniques and comparing the various modifications of the original procedure. LEVEL OF EVIDENCE: IV. PMID- 26768220 TI - The dorsal distally based flap: a novel approach to the distal interphalangeal joint. PMID- 26768221 TI - Does collagenase injection disrupt or digest the Dupuytren's cord: a magnetic resonance imaging study. AB - Collagenase clostridium histolyticum has been extensively studied as a treatment modality for Dupuytren's contracture. Its mechanism of action has been documented. It is unknown whether injected collagenase weakens the Dupuytren's cord sufficiently to cause failure during manipulation or if there is digestion and reduction in cord volume. We examined five patients with isolated contractures of the ring or middle metacarpalphalangeal (MP) joint using magnetic resonance imaging (MRI) prior to injection with collagenase and again 1 month following injection. All patients had full correction after manipulation which was maintained at follow-up. The Dupuytren's cord was evaluated with respect to volume, signal intensity, inflammatory changes and continuity. Additionally, signal intensity changes of the flexor tendons and neurovascular structures were recorded. MRI demonstrated cord discontinuity, significant reduction of cord volume and a significant increase in cord signal intensity after treatment with collagenase. There was a slight increase in flexor tendon signal intensity that was not significant. These findings suggest that there may be local chemical dissolution of the cord. Future studies may establish whether or not this will have prognostic implications in terms of correction and recurrence following collagenase injection. LEVEL OF EVIDENCE: IV. PMID- 26768222 TI - Lack of Relationship Between Serum Cardiac Troponin I Level and Giant Cell Myocarditis Diagnosis and Outcomes. PMID- 26768223 TI - Learning from the experiences of people with HIV using general practitioner services in London: a qualitative study. AB - Aim To explore the experiences of people with HIV (PWHIV) using general practitioner (GP) services in order to identify barriers to use. BACKGROUND: Traditionally, GPs have little involvement in the care of PWHIV. However, as HIV becomes a chronic condition and the population of PWHIV ages, there is a need to increase this involvement. Despite high levels of GP registration, the majority of PWHIV in London report that their GP is not involved in their HIV care. METHODS: This paper presents qualitative findings from a mixed method study of PWHIV's experiences of clinical services. Survey respondents were purposively sampled to recruit 51 PWHIV who took part in eight focus groups. Participants were asked about their experience of using GP services. Findings Three factors emerged which mediated experiences of GP care. Competence: respondents were concerned about the potential for misdiagnosis of symptoms, lack of awareness of the health needs of PWHIV and experiences of prescribing, which could lead to drug interactions. Continuity: not being able to get appointments quickly enough, not being able to see the same doctor twice and not being able to keep the same GP when one changed address were experienced as impediments to use. Communication: lack of communication between GPs and HIV specialists led to what participants called 'patient ping-pong' where they found themselves acting as a go-between for different clinical specialists trying to make sense of their care. CONCLUSION: Meaningful contact between HIV specialists and GPs is likely to allay concerns about competency as treatment and care decisions can be taken collaboratively between the GP, HIV specialist and patient. A key component of acceptable GP care for PWHIV is likely to be the application of long-term condition management approaches, which includes empowered patient self management. PMID- 26768224 TI - Mechanism of voltage-gated channel formation in lipid membranes. AB - Although several molecular models for voltage-gated ion channels in lipid membranes have been proposed, a detailed mechanism accounting for the salient features of experimental data is lacking. A general treatment accounting for peptide dipole orientation in the electric field and their nucleation and growth kinetics with ion channel formation is provided. This is the first treatment that explains all the main features of the experimental current-voltage curves of peptides forming voltage-gated channels available in the literature. It predicts a regime of weakly voltage-dependent conductance, followed by one of strong voltage-dependent conductance at higher voltages. It also predicts values of the parameters expressing the exponential dependence of conductance upon voltage and peptide bulk concentration for both regimes, in good agreement with those reported in the literature. Most importantly, the only two adjustable parameters involved in the kinetics of nucleation and growth of ion channels can be varied over broad ranges without affecting the above predictions to a significant extent. Thus, the fitting of experimental current-voltage curves stems naturally from the treatment and depends only slightly upon the choice of the kinetic parameters. PMID- 26768225 TI - The roles of apolipoprotein E3 and CYP2D6 (rs1065852) gene polymorphisms in the predictability of responses to individualized therapy with donepezil in Han Chinese patients with Alzheimer's disease. AB - AIM: Polymorphisms in the apolipoprotein E and CYP2D6 genes are widely reported to be related to Alzheimer's disease. However, few studies have focused on the relationship between polymorphisms in apolipoprotein E and CYP2D6 (rs1065852) genes and therapeutic responses to donepezil (DNP). This study explored the influence of apolipoprotein E3 and CYP2D6 (rs1065852) gene polymorphisms on therapeutic responses to donepezil in Han Chinese patients with Alzheimer's disease. MATERIALS AND METHODS: A total of 85 patients with mild to moderate Alzheimer's disease who were treated with 2.5-10mg of DNP per day for at least 3 months were enrolled. Mini-Mental State Examination scores were measured before and after DNP treatment, and the apolipoprotein E3 and CYP2D6 (rs1065852) genotypes of the patients were determined. RESULTS: We found that ApoE E3 non carriers responded better to DNP treatment than E3 carriers (p=0.000) and that CYP2D6*10/*10 patients (MMSE score change: 0.29+/-3.27) exhibited better therapeutic responses to DNP than did CYP2D6*1/*1 and CYP2D6*1/*10 patients (p=0.033). Patients who were ApoE E3 non-carriers and who had the CYP2D6*10/*10 genotype exhibited a trend toward better clinical responses to DNP therapy. CONCLUSIONS: The ApoE E3 allele and the CYP2D6 rs1065852 polymorphism may provide clinically relevant information for predicting therapeutic responses to DNP therapy. PMID- 26768226 TI - Treatment with a muscarinic acetylcholine receptor antagonist impairs the acquisition of conditioned reward learning in rats. AB - The neural mechanisms whereby a reward-associated stimulus gains reinforcing properties and comes to function as a conditioned reward (CR) are not understood. We propose that muscarinic acetylcholine (mACh) receptor stimulation is necessary for this type of learning. Here we tested the hypothesis that mACh receptor antagonism, with scopolamine, would attenuate the acquisition by a food-related stimulus of the capacity to function as a CR. Rats were exposed to 5 pre-exposure sessions during which two levers were present, one producing a light and the other a tone when pressed. This was followed by 3 conditioning sessions in which the levers were absent and the rats were presented with 30 light-food pairings delivered randomly. In the test session, the levers were present and presses on both levers were recorded. Different groups of rats received intraperitoneal injections of scopolamine (0, 0.375, 0.75 and 1mg/kg) either prior to each conditioning session or prior to the test session. All groups showed significantly greater responding on the light lever in the test compared to the pre-exposure sessions, demonstrating the CR effect. In animals treated prior to conditioning the scopolamine groups pressed significantly less on the light lever than the vehicle group. In animals treated prior to the test the increased lever pressing for light was similar for all groups. These data suggest that scopolamine impaired the acquisition of CR but not its expression. The results support the hypothesis that mACh receptor stimulation is important for the acquisition by reward-associated stimuli of the ability to function as CRs. PMID- 26768227 TI - Deformability based sorting of red blood cells improves diagnostic sensitivity for malaria caused by Plasmodium falciparum. AB - The loss of red blood cell (RBC) deformability is part of the pathology of many diseases. In malaria caused by Plasmodium falciparum infection, metabolism of hemoglobin by the parasite results in progressive reduction in RBC deformability that is directly correlated with the growth and development of the parasite. The ability to sort RBCs based on deformability therefore provides a means to isolate pathological cells and to study biochemical events associated with disease progression. Existing methods have not been able to sort RBCs based on deformability or to effectively enrich for P. falciparum infected RBCs at clinically relevant concentrations. Here, we develop a method to sort RBCs based on deformability and demonstrate the ability to enrich the concentration of ring stage P. falciparum infected RBCs (Pf-iRBCs) by >100* from clinically relevant parasitemia (<0.01%). Deformability based sorting of RBCs is accomplished using ratchet transport through asymmetrical constrictions using oscillatory flow. This mechanism provides dramatically improved selectivity over previous biophysical methods by preventing the accumulation of cells in the filter microstructure to ensure that consistent filtration forces are applied to each cell. We show that our approach dramatically improves the sensitivity of malaria diagnosis performed using both microscopy and rapid diagnostic test by converting samples with difficult-to-detect parasitemia (<0.01%) into samples with easily detectable parasitemia (>0.1%). PMID- 26768228 TI - A novel approach to study human posture control: "Principal movements" obtained from a principal component analysis of kinematic marker data. AB - Human upright posture is maintained by postural movements, which can be quantified by "principal movements" (PMs) obtained through a principal component analysis (PCA) of kinematic marker data. The current study expands the concept of "principal movements" in analogy to Newton's mechanics by defining "principal position" (PP), "principal velocity" (PV), and "principal acceleration" (PA) and demonstrates that a linear combination of PPs and PAs determines the center of pressure (COP) variance in upright standing. Twenty-one subjects equipped with 27 markers distributed over all body segments stood on a force plate while their postural movements were recorded using a standard motion tracking system. A PCA calculated on normalized and weighted posture vectors yielded the PPs and their time derivatives, the PVs and PAs. COP variance explained by the PPs and PAs was obtained through a regression analysis. The first 15 PMs quantified 99.3% of the postural variance and explained 99.60% +/- 0.22% (mean +/- SD) of the anterior posterior and 98.82 +/- 0.74% of the lateral COP variance in the 21 subjects. Calculation of the PMs thus provides a data-driven definition of variables that simultaneously quantify the state of the postural system (PPs and PVs) and the activity of the neuro-muscular controller (PAs). Since the definition of PPs and PAs is consistent with Newton's mechanics, these variables facilitate studying how mechanical variables, such as the COP motion, are governed by the postural control system. PMID- 26768229 TI - Gait recording with inertial sensors--How to determine initial and terminal contact. AB - Lightweight inertial sensors are increasingly used for recording of gait in medicine, rehabilitation and sport. Several distinct events during the gait cycle such as heel-strike or toe-off have to be detected in the data obtained from these sensors. We re-investigated the correlation between the data of shank mounted gyroscopes and three reference systems, namely accelerometers, pressure sensitive soles and a motion capture system in a group of 14 young healthy men. We confirmed that the heel strike corresponds to a trough in the gyroscope curve, as several previous reports have stated. However, the toe-off moment clearly did not coincide with another trough of the gyroscope trace, as had been assumed in the past. The heel-off moment was reliably at 51% of the step cycle, irrespective of gait velocity, in our data. These findings are crucial for gait recording systems which aim to assess the temporal as well as spatial descriptors of human gait. PMID- 26768230 TI - Ground reaction forces are more sensitive gait measures than temporal parameters in rodents following rotator cuff injury. AB - Gait analysis is a quantitative, non-invasive technique that can be used to investigate functional changes in animal models of musculoskeletal disease. Changes in ground reaction forces following injury have been observed that coincide with differences in tissue mechanical and histological properties during healing. However, measurement of these kinetic gait parameters can be laborious compared to the simpler and less time-consuming analysis of temporal gait parameters alone. We compared the sensitivity of temporal and kinetic gait parameters in detecting functional changes following rotator cuff injury in rats. Although these parameters were strongly correlated, temporal measures were unable to detect greater than 50% of the functional gait differences between injured and uninjured animals identified simultaneously by ground reaction forces. Regression analysis was used to predict ground reaction forces from temporal parameters. This model improved the ability of temporal parameters to identify known functional changes, but only when these differences were large in magnitude (i.e., between injured vs. uninjured animals, but not between different post operative treatments). The results of this study suggest that ground reaction forces are more sensitive measures of limb/joint function than temporal parameters following rotator cuff injury in rats. Therefore, although gait analysis systems without force plates are typically efficient and easy to use, they may be most appropriate for use when major functional changes are expected. PMID- 26768231 TI - Carbon-based hierarchical scaffolds for myoblast differentiation: Synergy between nano-functionalization and alignment. AB - While several scaffolds have been proposed for skeletal muscle regeneration, multiscale hierarchical scaffolds with the complexity of extracellular matrix (ECM) haven't been engineered successfully. By precise control over nano- and microscale features, comprehensive understanding of the effect of multiple factors on skeletal muscle regeneration can be derived. In this study, we engineered carbon-based scaffolds with hierarchical nano- and microscale architecture with controlled physico-chemical properties. More specifically, we built multiscale hierarchy by growing carbon nanotube (CNT) carpets on two types of scaffolds, namely, interconnected microporous carbon foams and aligned carbon fiber mats. Nanostructured CNT carpets offered fine control over nano-roughness and wettability facilitating myoblast adhesion, growth and differentiation into myocytes. However, microporous foam architecture failed to promote their fusion into multinucleated myotubes. On the other hand, aligned fibrous architecture stimulated formation of multinucleated myotubes. Most importantly, nanostructured CNT carpets interfaced with microscale aligned fibrous architecture significantly enhanced myocyte fusion into multinucleated mature myotubes highlighting synergy between nanoscale surface features and micro-/macroscale aligned fibrous architecture in the process of myogenesis. STATEMENT OF SIGNIFICANCE: Due to limited regenerative potential of skeletal muscle, strategies stimulating regeneration of functional muscles are important. These strategies are aimed at promoting differentiation of progenitor cells (myoblasts) into multinucleated myotubes, a key initial step in functional muscle regeneration. Recent tissue engineering approaches utilize various scaffolds ranging from decellularized matrices to aligned biomaterial scaffolds. Although, majority of them have focused on nano- or microscale organization, a systematic approach to build the multiscale hierarchy into these scaffolds is lacking. Here, we engineered multiscale hierarchy into carbon-based materials and demonstrated that the nanoscale features govern the differentiation of individual myoblasts into myocytes whereas microscale alignment cues orchestrate fusion of multiple myocytes into multinucleated myotubes underlining the importance of multiscale hierarchy in enhancing coordinated tissue regeneration. PMID- 26768232 TI - Examination of failed retrieved temporomandibular joint (TMJ) implants. AB - In the management of end-stage temporomandibular joint disorders (TMD), surgeons must often resort to alloplastic temporomandibular joint (TMJ) total joint replacement (TJR) to increase mandibular function and form, as well as reduce pain. Understanding wear and failure mechanisms of TMJ TJR implants is important to their in vivo longevity. However, compared to orthopedic TJR devices, functional wear of failed TMJ TJR implants has not been examined. Not only do wear and corrosion influence TJR implant in vivo longevity, but so does reactivity of peri-implant tissue to these two events. The aim of this study was to examine and report on the wear of retrieved, failed metal-on-metal (MoM), metal-on-polymer (MoP), and titanium-nitride coated (TiN Coated) TMJ TJR implant components. A total cohort of 31 TMJ TJR devices were studied of which 28 were failed, retrieved TMJ TJRs, 3 were never implanted devices that served as controls. The mean time from implantation to removal was 7.24 years (range 3-15), SD 3.01. Optical microscopy, White Light Interferometry (WLI), Scanning Electron Microscopy (SEM), and Raman spectroscopy were utilized to characterize the surfaces of the devices. Data was acquired and evaluated by analyzing alloy microstructure. Substantial surface damage was observed between the articulating areas of the condylar head and the glenoid fossa components. Damage included pitting corrosion, evidence of deposited corrosion products, specific wear patterns, hard phases, surface depressions, and bi-directional scratches. Electrochemical analysis was performed on the MoM Control, retrieved, failed MoM, and TiN Coated devices. Electrochemical tests consisted of open circuit potential (OCP) and electrochemical impedance spectroscopy (EIS) tests conducted using the condylar head of the retrieved failed devices. EIS confirmed material properties as well as corrosion kinetics in vivo help to mitigate corrosion as reflected by the Raman spectroscopy results. In summary, this study demonstrated the role of wear and corrosion interactions on the early failure of TMJ TJR devices. Since the materials employed in most orthopedic TJR devices are similar to those used in TMJ TJR implants, studies such as this can provide data that will improve future embodiment paradigms for both. Further studies will include in vitro investigation of corrosion kinetics and the underlying tribocorrosion mechanism of TMJ TJR devices. STATEMENT OF SIGNIFICANCE: An attempt is made in this study, to examine the retrieved TMJ implants and conduct surface and electrochemical analysis; further a translation research approach is employed to compare the observations from the total hip replacement (THR) retrievals. A total cohort of 31 TMJ TJR devices were studied of which 28 were failed, retrieved TMJ TJRs, 3 were never implanted devices that served as controls. Data was acquired and evaluated by analyzing alloy microstructure. Substantial surface damage was observed between the articulating areas of the condylar head and the glenoid fossa components. Electrochemical analysis was performed on the MoM Control, retrieved, failed MoM, and TiN Coated devices. This study demonstrated the role of wear and corrosion interactions on the early failure of TMJ TJR devices. Since the materials employed in most orthopedic TJR devices are similar to those used in TMJ TJR implants, a comparison study was conducted. PMID- 26768233 TI - Lifestyle intervention to limit gestational weight gain: the Norwegian Fit for Delivery randomised controlled trial. AB - OBJECTIVE: To examine whether a lifestyle intervention in pregnancy limits gestational weight gain (GWG) and provides measurable health benefits for mother and newborn. DESIGN: Randomised controlled trial. SETTING: Healthcare clinics of southern Norway. POPULATION: Healthy, non-diabetic, nulliparous women, aged >=18 years, with a body mass index of >=19 kg/m2 , and with a singleton pregnancy at <=20 weeks of gestation. METHODS: Women were randomised to an intervention group (with dietary counselling twice by telephone and access to twice-weekly exercise groups) or to a control group (with standard prenatal care). Participants were measured three times during pregnancy and at delivery, and newborns were measured at delivery. Hospital records were reviewed for outcomes of pregnancy and delivery. Assessors were blinded to group allocation. Analysis was performed by intention to treat, assessing GWG using the Student's t-test and linear mixed models, and comparing proportions using the chi-square test. MAIN OUTCOME MEASURES: GWG, rates of pregnancy complications and operative deliveries, and newborn birthweight. RESULTS: A total of 606 women were randomised. Of these, 591 were analysed, with 296 in the intervention group and 295 in the control group. At term, the mean GWG from pre-pregnancy was 14.4 kg for the intervention group and 15.8 kg for the control group (mean difference 1.3 kg; 95% confidence interval, 95% CI 0.3-2.3 kg; P = 0.009). There was no significant difference between groups in the frequency of pregnancy complications or operative deliveries. The intervention demonstrated no effect on the mean birthweight of term infants, or on the proportion of large newborns. CONCLUSIONS: The Norwegian Fit for Delivery lifestyle intervention in pregnancy had no measurable effect on obstetrical or neonatal outcomes, despite a modest but significant decrease in GWG. TWEETABLE ABSTRACT: Norwegian Fit for Delivery RCT: reduced gestational weight gain, unchanged birthweight and obstetric outcomes. PMID- 26768234 TI - A prospective study on vacation weight gain in adults. AB - PURPOSE: To determine if a 1- to 3-week vacation in adults leads to weight gain and whether that gain persists 6weeks later. METHODS: 122 adults going on a 1- to 3-week vacation completed 3 visits. The visits were 1week prior to, 1week post, and 6week post vacation. Height, weight, blood pressure, and waist-to-hip ratio, physical activity (International Physical Activity Questionnaire - IPAQ) and stress (Perceived Stress Scale - PSS) were measured. RESULTS: Body weight increased on vacation (0.32+/-0.08kg, p<0.05) and this increase persisted so that total weight gain was 0.41+/-0.11kg (p<0.05). No difference in weight gain based on BMI was found (0.28+/-0.13kg, 0.39+/-0.14kg, and 0.48+/-0.27kg for normal weight, overweight, and obese, respectively). PSS decreased for the study (17.1+/ 0.5 to 14.9+/-0.6 for pre-vacation to 6-weeks post-vacation, respectively; p<0.001), and total physical activity tended to increase on vacation (3940+/-235 vs. 4313+/-344METs, for pre- vs. post-vacation, respectively; p=0.10) and decreased in the post-vacation period (4313+/-344 vs. 3715+/-306METs, p<0.05). CONCLUSIONS: Vacations resulted in significant weight gain (0.32kg), and this weight gain persisted at the 6-week follow-up period. The weight gain appeared to be driven by increased energy intake above energy requirements. This gain could be a significant contributor to yearly weight gain in adults and therefore affect obesity prevalence. PMID- 26768235 TI - Reducing Trismus After Surgery and Radiotherapy in Oral Cancer Patients: Results of Alternative Operation Versus Traditional Operation. AB - PURPOSE: In patients with oral cancer, trismus (maximum interincisal opening [MIO] <35 mm) can develop as a result of surgery and radiotherapy. The aim of this study was to provide an alternative operation to both eradicate oral cancer and prevent postsurgical trismus. MATERIALS AND METHODS: In our retrospective cohort study of oral cancer patients who underwent operations during 2010 to 2014, the predictor variable was the type of operation (alternative operation or traditional operation) and the outcome variable was MIO. All of the cases were allocated by 2 periods: the traditional operations were performed from 2010 to 2011, and the alternative operations were performed from 2011 to 2014. All patients received marginal mandibulectomy, anterolateral thigh free flap, and adjuvant radiotherapy or concurrent chemoradiotherapy. In addition to traditional marginal mandibulectomy, the alternative operation included ipsilateral coronoidectomy and myotomy of the temporalis muscle insertion, masseter muscle, and medial pterygoid muscle. MIO was measured at 10 time points. The adjusted variables included demographic data, diagnostic parameters, treatment, and response. RESULTS: Of the 36 male patients with oral cancer, 16 were placed in the alternative operation group (AOG; mean age, 53.5 +/- 11.9 years) and 20 were placed in the traditional operation group (TOG; mean age, 50.7 +/- 7.1 years). Regarding the outcome indicator of patient MIO, the preoperative MIO in the AOG was on average 7.5 mm shorter than that in the TOG (P < .01), but it was consistently superior to the MIO in the TOG after the operation. Multivariate analysis of variance showed that patients in the AOG were more likely to have postoperative non-trismus. CONCLUSIONS: The alternative operation exhibited superior postoperative MIO values and similar postoperative complication rates. For the prevention of trismus, it is practical to perform the combined operation simultaneously, cutting all ipsilateral jaw closing muscles and the coronoid process and eradicating the tumor. PMID- 26768238 TI - Advancing Surgical Vision with Fluorescence Imaging. AB - Surgical success depends on the accuracy with which disease and vital tissue can be intraoperatively detected. However, the dominant visualization approach, i.e., human vision, does not see under the tissue surface and operates on low contrast between sites of disease, such as cancer, and the surrounding tissue. Intraoperative fluorescence imaging is emerging as a highly effective method to improve surgical vision and offers the potential to be intergrated seamlessly into the normal workflow of the operating room without causing disruption or undue delay. We review and compare two critical fluorescence imaging directions: one that uses nonspecific fluorescence dyes, addressing tissue perfusion and viability, and one that uses targeted agents, interrogating pathophysiological features of disease. These two approaches present detection sensitivity challenges that may differ by orders of magnitude and require different detection strategies. Nevertheless, fluorescence imaging provides the surgeon with previously unavailable real-time feedback that improves surgical precision and can become essential for interventional decision-making. PMID- 26768236 TI - B-Raf Inhibition in the Clinic: Present and Future. AB - Somatic activating mutations in the B-Raf kinase (BRAF mutations) are present in hairy-cell leukemia, cutaneous melanoma, thyroid carcinomas and, less commonly, in ovarian, colon, lung, and other malignancies. These mutations-in particular the most common substitution, V600E-are oncogenic drivers and important therapeutic targets. The development of small-molecule Raf inhibitors allowed rapid translation of basic advances to the clinic. In BRAF-mutant melanomas, orally bioavailable B-Raf inhibitors, such as vemurafenib, achieve dramatic responses initially, but this is followed by rapid emergence of resistance driven by numerous mechanisms and requiring second-generation treatment approaches. In tumors with wild-type B-Raf, vemurafenib paradoxically activates downstream signaling and cell proliferation and is thus contraindicated, highlighting again the importance of genotype-based clinical decision making. These advances were greatly facilitated by the study of biopsied tumor tissue, especially at the time of drug resistance. Combinatorial approaches targeting the Raf pathway hold promise for even more substantial clinical benefits in the future. PMID- 26768239 TI - Early Combination Antiretroviral Therapy Limits HIV-1 Persistence in Children. AB - Globally, 240,000 infants are newly infected with HIV-1 each year and 3.2 million children are living with the infection. Combination antiretroviral therapy (cART) has reduced HIV-1-related disease and mortality in children but is not curative owing to the early generation of a latent reservoir of long-lived memory CD4(+) T cells bearing replication-competent HIV-1 provirus integrated into cellular DNA. This review focuses on recent advances in our understanding of the establishment of HIV-1 persistence in children and how early initiation of cART in the setting of the developing infant immune system limits the formation of the long-lived latent CD4(+) cell reservoir that remains a barrier to remission or cure. PMID- 26768237 TI - Epigenetic Therapeutics: A New Weapon in the War Against Cancer. AB - The past 15 years have seen an explosion of discoveries related to the cellular regulation of phenotypes through epigenetic mechanisms. This regulation provides a software that packages DNA, without changing the primary base sequence, to establish heritable patterns of gene expression. In cancer, many aspects of the epigenome, controlled by DNA methylation, chromatin, and nucleosome positioning, are altered as one means by which tumor cells maintain abnormal states of self renewal at the expense of normal maturation. Epigenetic and genetic abnormalities thus collaborate in cancer initiation and progression, as exemplified by frequent mutations in genes encoding proteins that control the epigenome. There is growing emphasis on using epigenetic therapies to reprogram neoplastic cells toward a normal state. Many agents targeting epigenetic regulation are under development and entering clinical trials. This review highlights the promise that epigenetic therapy, often in combination with other therapies, will become a potent tool for cancer management over the next decade. PMID- 26768240 TI - Cardiovascular Effects of Incretin-Based Therapies. AB - The incretin-based therapies, dipeptidyl peptidase-4 (DPP4) inhibitors and glucagon-like peptide-1 (GLP-1) analogs, are important new classes of therapy for type 2 diabetes mellitus (T2DM). These agents prolong the action of the incretin hormones, GLP-1 and glucose-dependent insulinotropic polypeptide (GIP), by inhibiting their breakdown. The incretin hormones improve glycemic control in T2DM by increasing insulin secretion and suppressing glucagon levels. The cardiovascular (CV) effects of the incretin-based therapies have been of substantial interest since 2008, when the US Food and Drug Administration began to require that all new therapies for diabetes undergo rigorous assessment of CV safety through large-scale CV outcome trials. This article reviews the most recent CV outcome trials of the DPP-4 inhibitors (SAVOR-TIMI 53, EXAMINE, and TECOS) as evidence that the incretin-based therapies have acceptable CV safety profiles for patients with T2DM. The studies differ with regard to patient population, trial duration, and heart failure outcomes but show similar findings for CV death, nonfatal myocardial infarction, and stroke, as well as hospitalization for unstable angina. PMID- 26768241 TI - Vitamin D and Cardiovascular Disease. AB - Vitamin D is best known for its influence on skeletal health. There is growing recognition, however, that vitamin D has nonskeletal actions, which could have important implications for understanding the consequences of vitamin D deficiency. In epidemiologic studies, vitamin D deficiency has been consistently associated with an increased risk for cardiovascular disease and hypertension. Disruption of vitamin D signaling in animal models promotes hypertension, cardiac hypertrophy, and atherosclerosis. This evidence has led to the initiation of prospective randomized trials of vitamin D supplementation in individuals at risk for cardiovascular disease. The results of these trials should help to guide strategies for screening and management of vitamin D deficiency in the clinic and at the population level. PMID- 26768242 TI - Gadolinium-Induced Fibrosis. AB - Gadolinium-based contrast agents (GBCAs), once believed to be safe for patients with renal disease, have been strongly associated with nephrogenic systemic fibrosis (NSF), a severe systemic fibrosing disorder that predominantly afflicts individuals with advanced renal dysfunction. We provide a historical perspective on the appearance and disappearance of NSF, including its initial recognition as a discrete clinical entity, its association with GBCA exposure, and the data supporting a causative relationship between GBCA exposure and NSF. On the basis of this body of evidence, we propose that the name gadolinium-induced fibrosis (GIF) more accurately reflects the totality of knowledge regarding this disease. Use of high-risk GBCAs, such as formulated gadodiamide, should be avoided in patients with renal disease. Restriction of GBCA use in this population has almost completely eradicated new cases of this debilitating condition. Emerging antifibrotic therapies may be useful for patients who suffer from GIF. PMID- 26768243 TI - Acute Kidney Injury. AB - Acute kidney injury (AKI) is a global public health concern associated with high morbidity, mortality, and healthcare costs. Other than dialysis, no therapeutic interventions reliably improve survival, limit injury, or speed recovery. Despite recognized shortcomings of in vivo animal models, the underlying pathophysiology of AKI and its consequence, chronic kidney disease (CKD), is rich with biological targets. We review recent findings relating to the renal vasculature and cellular stress responses, primarily the intersection of the unfolded protein response, mitochondrial dysfunction, autophagy, and the innate immune response. Maladaptive repair mechanisms that persist following the acute phase promote inflammation and fibrosis in the chronic phase. Here macrophages, growth-arrested tubular epithelial cells, the endothelium, and surrounding pericytes are key players in the progression to chronic disease. Better understanding of these complex interacting pathophysiological mechanisms, their relative importance in humans, and the utility of biomarkers will lead to therapeutic strategies to prevent and treat AKI or impede progression to CKD or end-stage renal disease (ESRD). PMID- 26768244 TI - Rho Kinases in Autoimmune Diseases. AB - The Rho kinases, or ROCKs, are a family of serine-threonine kinases that serve as key downstream effectors for Rho GTPases. The ROCKs are increasingly recognized as critical coordinators of a tissue response to injury due to their ability to modulate a wide range of biological processes. Dysregulated ROCK activity has been implicated in several human pathophysiological conditions ranging from cardiovascular and renal disorders to fibrotic diseases. In recent years, an important role for the ROCKs in the regulation of immune responses is also being uncovered. We provide an overview of the role of the ROCKs in immune cells and discuss studies that highlight the emerging involvement of this family of kinases in the pathogenesis of autoimmune diseases. Given the potential promise of the ROCKs as therapeutic targets, we also outline the approaches that could be employed to inhibit the ROCKs in autoimmune disorders. PMID- 26768245 TI - Critical Illness Brain Injury. AB - A growing body of literature has shown that survivors of critical illness often struggle with cognitive impairment that persists months to years after hospital discharge. We describe the epidemiology of this form of cognitive impairment which we refer to as critical illness brain injury-and review the history and maturation of the investigation of this previously unrecognized, yet common problem. We then review the characteristics of critical illness brain injury, which can vary in severity and typically affects multiple domains of cognition. Finally, we examine known risk factors for critical illness brain injury and, based on these data, suggest approaches to patient management. PMID- 26768246 TI - Risks associated with endotoxins in feed additives produced by fermentation. AB - Increasingly, feed additives for livestock, such as amino acids and vitamins, are being produced by Gram-negative bacteria, particularly Escherichia coli. The potential therefore exists for animals, consumers and workers to be exposed to possibly harmful amounts of endotoxin from these products. The aim of this review was to assess the extent of the risk from endotoxins in feed additives and to calculate how such risk can be assessed from the properties of the additive. Livestock are frequently exposed to a relatively high content of endotoxin in the diet: no additional hazard to livestock would be anticipated if the endotoxin concentration of the feed additive falls in the same range as feedstuffs. Consumer exposure will be unaffected by the consumption of food derived from animals receiving endotoxin-containing feed, because the small concentrations of endotoxin absorbed do not accumulate in edible tissues. In contrast, workers processing a dusty additive may be exposed to hazardous amounts of endotoxin even if the endotoxin concentration of the product is low. A calculation method is proposed to compare the potential risk to the worker, based on the dusting potential, the endotoxin concentration and technical guidance of the European Food Safety Authority, with national exposure limits. PMID- 26768247 TI - A substitution mutation in cardiac ubiquitin ligase, FBXO32, is associated with an autosomal recessive form of dilated cardiomyopathy. AB - BACKGROUND: Familial dilated cardiomyopathy (DCM) is genetically heterogeneous. Mutations in more than 40 genes have been identified in familial cases, mostly inherited in an autosomal dominant pattern. DCM due to recessive mutations is rarely observed. In consanguineous families, homozygosity mapping and whole exome sequencing (WES) can be utilized to identify the genetic defects in recessively inherited DCM. METHODS: In a consanguineous family with four affected siblings with severe DCM, we combined homozygosity mapping, linkage analysis and WES, to uncover the genetic defect. RESULTS: A region of homozygosity (ROH) on chromosome 8q24.13-24.23 was found to be shared by all of the four affected siblings. WES detected ~47,000 variants that were filtered to a homozygous mutation (p.Gly243Arg) in the FBXO32 gene, located within the identified ROH. The mutation segregated with the phenotype, replaced a highly-conserved amino acid, and was not detected in 1986 ethnically-matched chromosomes. FBXO32, which encodes a muscle-specific ubiquitin ligase, has been implicated in the pathogenesis of cardiomyopathy through the ubiquitin proteasome system (UPS). In addition, FBXO32 knockout mice manifest with cardiomyopathy. Screening the index patient for all of the WES variants in 48 genes known to be implicated in hypertrophic and dilated cardiomyopathy was negative. CONCLUSIONS: Our data suggest that FBXO32 is a candidate gene for recessive DCM. Acting as a cardiac ubiquitin ligase, mutated FBXO32 could perturb the degradation of target proteins in the UPS, the impairment of which has been observed in cardiomyopathy. Our work proposes that genes encoding other ubiquitin ligases could also be implicated in familial cardiomyopathy. PMID- 26768248 TI - A Glucuronoxylomannan-Associated Immune Signature, Characterized by Monocyte Deactivation and an Increased Interleukin 10 Level, Is a Predictor of Death in Cryptococcal Meningitis. AB - BACKGROUND: Cryptococcal meningitis remains a significant cause of death among human immunodeficiency virus type 1 (HIV)-infected persons in Africa. We aimed to better understand the pathogenesis and identify immune correlates of mortality, particularly the role of monocyte activation. METHODS: A prospective cohort study was conducted in Cape Town, South Africa. Patients with a first episode of cryptococcal meningitis were enrolled, and their immune responses were assessed in unstimulated and stimulated blood specimens, using flow cytometry and cytokine analysis. RESULTS: Sixty participants were enrolled (median CD4(+) T-cell count, 34 cells/uL). Mortality was 23% (14 of 60 participants) at 14 days and 39% (22 of 57) at 12 weeks. Nonsurvivors were more likely to have an altered consciousness and higher cerebrospinal fluid fungal burden at presentation. Principal component analysis identified an immune signature associated with early mortality, characterized by monocyte deactivation (reduced HLA-DR expression and tumor necrosis factor alpha response to lipopolysaccharide); increased serum interleukin 6, CXCL10, and interleukin 10 levels; increased neutrophil counts; and decreased T-helper cell type 1 responses. This immune signature remained an independent predictor of early mortality after adjustment for consciousness level and fungal burden and was associated with higher serum titers of cryptococcal glucuronoxylomannan. CONCLUSIONS: Cryptococcal-related mortality is associated with monocyte deactivation and an antiinflammatory blood immune signature, possibly due to Cryptococcus modulation of the host immune response. Validation in other cohorts is required. PMID- 26768249 TI - Within-Host Heterogeneity of Mycobacterium tuberculosis Infection Is Associated With Poor Early Treatment Response: A Prospective Cohort Study. AB - The clinical management of tuberculosis is a major challenge in southern Africa. The prevalence of within-host genetically heterogeneous Mycobacterium tuberculosis infection and its effect on treatment response are not well understood. We enrolled 500 patients with tuberculosis in KwaZulu-Natal and followed them through 2 months of treatment. Using mycobacterial interspersed repetitive units-variable number of tandem repeats genotyping to identify mycobacterial heterogeneity, we report the prevalence and evaluate the association of heterogeneity with treatment response. Upon initiation of treatment, 21.1% of participants harbored a heterogeneous M. tuberculosis infection; such heterogeneity was independently associated with a nearly 2-fold higher odds of persistent culture positivity after 2 months of treatment (adjusted odds ratio, 1.90; 95% confidence interval, 1.03-3.50). PMID- 26768250 TI - Use of Hepatitis C Virus (HCV) Immunoglobulin G Antibody Avidity as a Biomarker to Estimate the Population-Level Incidence of HCV Infection. AB - BACKGROUND: Sensitive methods are needed to estimate the population-level incidence of hepatitis C virus (HCV) infection. METHODS: We developed an HCV immunoglobulin G (IgG) antibody avidity assay by modifying the Ortho 3.0 HCV enzyme-linked immunoassay and tested 997 serum or plasma samples from 568 people who inject drugs enrolled in prospective cohort studies. Avidity-based testing algorithms were evaluated by their (1) mean duration of recent infection (MDRI), defined as the average time an individual is identified as having been recently infected, according to a given algorithm; (2) false-recent rate, defined as the proportion of samples collected >2 years after HCV seroconversion that were misclassified as recent; (3) sample sizes needed to estimate incidence; and (4) power to detect a reduction in incidence between serial cross-sectional surveys. RESULTS: A multiassay algorithm (defined as an avidity index of <30%, followed by HCV viremia detection) had an MDRI of 147 days (95% confidence interval [CI], 125 195 days), and the false-recent rates were 0.7% (95% CI, .2%-1.8%) and 7.6% (95% CI, 4.2%-12.3%) among human immunodeficiency virus (HIV)-negative and HIV positive persons, respectively. In various simulated high-risk populations, this algorithm required <1000 individuals to estimate incidence (relative standard error, 30%) and had >80% power to detect a 50% reduction in incidence. CONCLUSIONS: Avidity-based algorithms have the capacity to accurately estimate HCV infection incidence and rapidly assess the impact of public health efforts among high-risk populations. Efforts to optimize this method should be prioritized. PMID- 26768251 TI - Epidemic History and Iatrogenic Transmission of Blood-borne Viruses in Mid-20th Century Kinshasa. AB - BACKGROUND: The human immunodeficiency virus type 1 (HIV-1) pandemic was ignited in Leopoldville (now known as Kinshasa), in the former Belgian Congo. Factors that jump-started its early expansion remain unclear. Nonlethal hepatitis C virus (HCV) and human T-cell lymphotropic virus (HTLV-1) can be used to investigate past iatrogenic transmission. METHODS: We undertook a cross-sectional study of elderly inhabitants of Kinshasa, with serological assays, amplification, and sequencing. Risk factors were assessed through logistic regression. Phylogenetic methods reconstructed the genetic history of HCV. RESULTS: A total of 217 of 839 participants (25.9%) were HCV seropositive; 26 (3.1%) were HTLV-1-seropositive. Amplification products were obtained from 118 HCV-seropositive participants; subtypes 4k (in 47 participants) and 4r (in 38) were most common. Independent risk factors for HCV subtype 4r seropositivity were intramuscular tuberculosis therapy, intravenous injections at hospital A, intravenous injections before 1960, and injections at a colonial-era venereology clinic. Intravenous injections at hospital B and antimalarials were associated with HCV subtype 4k seropositivity. Risk factors for HTLV-1 seropositivity included intravenous injections at hospitals C or D and transfusions. Evolutionary analysis of viral sequences revealed independent exponential amplification of HCV subtypes 4r and 4k from the 1950s onward. CONCLUSIONS: Iatrogenic transmission of HCV and HTLV-1 occurred in mid-20th century Kinshasa, at the same time and place HIV-1 emerged. Iatrogenic routes may have contributed to the early establishment of the pandemic. PMID- 26768252 TI - Phagocytosis and Killing of Carbapenem-Resistant ST258 Klebsiella pneumoniae by Human Neutrophils. AB - Carbapenem-resistant Klebsiella pneumoniae strains classified as multilocus sequence type 258 (ST258) are among the most widespread multidrug-resistant hospital-acquired pathogens. Treatment of infections caused by these organisms is difficult, and mortality is high. The basis for the success of ST258, outside of antibiotic resistance, remains incompletely determined. Here we tested the hypothesis that ST258K. pneumoniae has enhanced capacity to circumvent killing by human neutrophils, the primary cellular defense against bacterial infections. There was limited binding and uptake of ST258 by human neutrophils, and correspondingly, there was limited killing of bacteria. On the other hand, transmission electron microscopy revealed that any ingested organisms were degraded readily within neutrophil phagosomes, thus indicating that survival in the neutrophil assays is due to limited phagocytosis, rather than to microbicide resistance after uptake. Our findings suggest that enhancing neutrophil phagocytosis is a potential therapeutic approach for treatment of infection caused by carbapenem-resistant ST258K. pneumoniae. PMID- 26768253 TI - Target-Agnostic Identification of Functional Monoclonal Antibodies Against Klebsiella pneumoniae Multimeric MrkA Fimbrial Subunit. AB - The increasing incidence of Klebsiella pneumoniae infections refractory to treatment with current broad-spectrum antibiotic classes warrants the exploration of alternative approaches, such as antibody therapy and/or vaccines, for prevention and treatment. However, the lack of validated targets shared by spectrums of clinical strains poses a significant challenge. We adopted a target agnostic approach to identify protective antibodies against K. pneumoniae Several monoclonal antibodies were isolated from phage display and hybridoma platforms by functional screening for opsonophagocytic killing activity. We further identified their common target antigen to be MrkA, a major protein in the type III fimbriae complex, and showed that these serotype-independent anti-MrkA antibodies reduced biofilm formation in vitro and conferred protection in multiple murine pneumonia models. Importantly, mice immunized with purified MrkA proteins also showed reduced bacterial burden following K. pneumoniae challenge. Taken together, these results support MrkA as a promising target for K. pneumoniae antibody therapeutics and vaccines. PMID- 26768254 TI - Determining the Incidence of Hepatitis C Virus Infection in Populations: An Important Tool for Epidemic Control. PMID- 26768255 TI - Surveys, Serologies, and Sequences Reveal History of Iatrogenic Transmission of HIV-1. PMID- 26768256 TI - Vaccination Against Hepatitis B Virus (HBV) in HIV-1-Infected Patients With Isolated Anti-HBV Core Antibody: The ANRS HB EP03 CISOVAC Prospective Study. AB - BACKGROUND: Although an isolated anti-hepatitis B virus (HBV) core antibody (anti HBc) serological profile is frequent in human immunodeficiency virus (HIV) infected patients, data on HBV vaccination in these patients are scarce. METHODS: A prospective multicenter study was conducted to assess the immunogenicity of HBV vaccination in 54 patients with an isolated anti-HBc profile and undetectable HIV load. They were vaccinated with 1 dose (20 ug) of recombinant HBV vaccine. Those with an anti-HBV surface antibody (anti-HBs) level of <10 mIU/mL 4 weeks after vaccination received 3 additional double doses (40 ug) at weeks 5, 9, and 24. RESULTS: At week 4, 25 patients (46%) were responders. Only the ratio of CD4(+) T cells to CD8(+) T cells was associated with this response in multivariate analysis (odds ratio for +0.1, 1.32; 95% confidence interval, 1.07-1.63; P = .008). At week 28 and month 18, 58% of these patients (14 of 24) and 50% (10 of 20), respectively, maintained anti-HBs level of >=10 mIU/mL.Among nonresponding patients at week 4, who received further vaccinations, 89% (24 of 27) and 81% (21 of 26) had an anti-HBs level of >=10 mIU/mL at week 28 and month 18, respectively. The preS2-specific interferon gamma T-cell response increased between week 0 and week 28 in patients who finally responded to reinforced vaccination (P = .03). CONCLUSIONS: All of the patients with an isolated anti-HBc profile who did not have an anti-HBs titer of >100 mIU/mL 4 weeks after a single recall dose of HBV vaccine should be further vaccinated with a reinforced triple double-dose scheme. PMID- 26768258 TI - Development, implementation and evaluation of a clinical research engagement and leadership capacity building program in a large Australian health care service. AB - BACKGROUND: Health professionals need to be integrated more effectively in clinical research to ensure that research addresses clinical needs and provides practical solutions at the coal face of care. In light of limited evidence on how best to achieve this, evaluation of strategies to introduce, adapt and sustain evidence-based practices across different populations and settings is required. This project aims to address this gap through the co-design, development, implementation, evaluation, refinement and ultimately scale-up of a clinical research engagement and leadership capacity building program in a clinical setting with little to no co-ordinated approach to clinical research engagement and education. METHODS/DESIGN: The protocol is based on principles of research capacity building and on a six-step framework, which have previously led to successful implementation and long-term sustainability. A mixed methods study design will be used. Methods will include: (1) a review of the literature about strategies that engage health professionals in research through capacity building and/or education in research methods; (2) a review of existing local research education and support elements; (3) a needs assessment in the local clinical setting, including an online cross-sectional survey and semi-structured interviews; (4) co-design and development of an educational and support program; (5) implementation of the program in the clinical environment; and (6) pre- and post-implementation evaluation and ultimately program scale-up. The evaluation focuses on research activity and knowledge, attitudes and preferences about clinical research, evidence-based practice and leadership and post implementation, about their satisfaction with the program. The investigators will evaluate the feasibility and effect of the program according to capacity building measures and will revise where appropriate prior to scale-up. DISCUSSION: It is anticipated that this clinical research engagement and leadership capacity building program will enable and enhance clinically relevant research to be led and conducted by health professionals in the health setting. This approach will also encourage identification of areas of clinical uncertainty and need that can be addressed through clinical research within the health setting. PMID- 26768257 TI - New Insights Into the Transmissibility of Leishmania infantum From Dogs to Sand Flies: Experimental Vector-Transmission Reveals Persistent Parasite Depots at Bite Sites. AB - Canine leishmaniasis (CanL) is a chronic fatal disease of dogs and a major source of human infection through propagation of parasites in vectors. Here, we infected 8 beagles through multiple experimental vector transmissions with Leishmania infantum-infected Lutzomyia longipalpis. CanL clinical signs varied, although live parasites were recovered from all dog spleens. Splenic parasite burdens correlated positively with Leishmania-specific interleukin 10 levels, negatively with Leishmania-specific interferon gamma and interleukin 2 levels, and negatively with Leishmania skin test reactivity. A key finding was parasite persistence for 6 months in lesions observed at the bite sites in all dogs. These recrudesced following a second transmission performed at a distal site. Notably, sand flies efficiently acquired parasites after feeding on lesions at the primary bite site. In this study, controlled vector transmissions identify a potentially unappreciated role for skin at infectious bite sites in dogs with CanL, providing a new perspective regarding the mechanism of Leishmania transmissibility to vector sand flies. PMID- 26768259 TI - Sarcoidosis: radiographic manifestations in the nails and distal phalanges. AB - Sarcoidosis is a granulomatous disease which can affect multiple organ systems. Clinical and radiologic manifestations depend on the organ system involved and the chronicity of disease. Nail involvement in sarcoidosis is rare, but is clinically relevant as it indicates chronic systemic disease. Nail abnormalities can be identified radiographically, and when seen in patients with known or suspected sarcoidosis, should prompt careful evaluation of the underlying bone for osseous involvement. We describe a case of sarcoidosis with radiographic findings in the nails and distal phalangeal tufts, which were indicative of nail and osseous sarcoid involvement and strongly supported the presence of chronic systemic disease. Although the nail findings resolved clinically and on radiographs after treatment, the osseous findings showed only minimal improvement. To our knowledge, the radiographic findings of nail sarcoidosis have not been previously addressed in the literature. PMID- 26768260 TI - Hip pain. Bisphosphonate-related atypical subtrochanteric femoral fracture in patient with Paget disease. PMID- 26768261 TI - Genetic lineage tracing discloses arteriogenesis as the main mechanism for collateral growth in the mouse heart. AB - AIMS: Capillary and arterial endothelial cells share many common molecular markers in both the neonatal and adult hearts. Herein, we aim to establish a genetic tool that distinguishes these two types of vessels in order to determine the cellular mechanism underlying collateral artery formation. METHODS AND RESULTS: Using Apln-GFP and Apln-LacZ reporter mice, we demonstrate that APLN expression is enriched in coronary vascular endothelial cells. However, APLN expression is reduced in coronary arterial endothelial cells. Genetic lineage tracing, using an Apln-CreER mouse line, robustly labelled capillary endothelial cells, but not arterial endothelial cells. We leveraged this differential activity of Apln-CreER to study collateral artery formation following myocardial infarction (MI). In a neonatal heart MI model, we found that Apln-CreER-labelled capillary endothelial cells do not contribute to the large collateral arteries. Instead, these large collateral arteries mainly arise from pre-existing, infrequently labelled coronary arteries, indicative of arteriogenesis. Furthermore, in an adult heart MI model, Apln-CreER activity also distinguishes large and small diameter arteries from capillaries. Lineage tracing in this setting demonstrated that most large and small coronary arteries in the infarcted myocardium and border region are derived not from capillaries, but from pre existing arteries. CONCLUSION: Apln-CreER-mediated lineage tracing distinguishes capillaries from large arteries, in both the neonatal and adult hearts. Through genetic fate mapping, we demonstrate that pre-existing arteries, but not capillaries, extensively contribute to collateral artery formation following myocardial injury. These results suggest that arteriogenesis is the major mechanism underlying collateral vessel formation. PMID- 26768262 TI - Silencing of Id2 Alleviates Chronic Neuropathic Pain Following Chronic Constriction Injury. AB - Inhibitor of DNA binding/differentiation 2 (Id2) belongs to a helix-loop-helix family of proteins. Recent studies have showed that Id2 plays a pivotal role in neuronal survival and neuroprotection. However, under neuropathic pain conditions, the role of Id2 is still unclear. In this study, we investigated the effect of Id2 on neuropathic pain in a rat chronic constriction injury (CCI) model. Our results demonstrated that Id2 was upregulated in the dorsal root ganglion (DRG) in a CCI rat in a time-dependent manner. Intrathecal short-hairpin RNA (shRNA)-Id2 attenuates mechanical allodynia and thermal hyperalgesia in CCI rats, and inhibits the expression of TNF-alpha and IL-1beta in the DRG in CCI rats. Furthermore, knockdown of Id2 reduces the expression of NF-kappaB p65 in the DRG of CCI rats. Taken together, our findings suggest that knockdown of Id2 may alleviate neuropathic pain by inhibiting the NF-kappaB activation to inhibit the production of pro-inflammatory mediators. Therefore, Id2 may provide an important target of neuropathic pain treatment. PMID- 26768263 TI - Diversity of transcripts and transcript processing forms in plastids of the dinoflagellate alga Karenia mikimotoi. AB - Plastids produce a vast diversity of transcripts. These include mature transcripts containing coding sequences, and their processing precursors, as well as transcripts that lack direct coding functions, such as antisense transcripts. Although plastid transcriptomes have been characterised for many plant species, less is known about the transcripts produced in other plastid lineages. We characterised the transcripts produced in the fucoxanthin-containing plastids of the dinoflagellate alga Karenia mikimotoi. This plastid lineage, acquired through tertiary endosymbiosis, utilises transcript processing pathways that are very different from those found in plants and green algae, including 3' poly(U) tail addition, and extensive substitutional editing of transcript sequences. We have sequenced the plastid transcriptome of K. mikimotoi, and have detected evidence for divergent evolution of fucoxanthin plastid genomes. We have additionally characterised polycistronic and monocistronic transcripts from two plastid loci, psbD-tRNA (Met)-ycf4 and rpl36-rps13-rps11. We find evidence for a range of transcripts produced from each locus that differ in terms of editing state, 5' end cleavage position, and poly(U) tail addition. Finally, we identify antisense transcripts in K. mikimotoi, which appear to undergo different processing events from the corresponding sense transcripts. Overall, our study provides insights into the diversity of transcripts and processing intermediates found in plastid lineages across the eukaryotes. PMID- 26768265 TI - Management approaches for suspected and established Lyme disease used at the Lyme disease diagnostic center. AB - 2015 marks the 27th year that the Lyme Disease Diagnostic Center, located in New York State in the United States, has provided care for patients with suspected or established deer tick-transmitted infections. There are five deer tick transmitted infectious in this geographic area of which Lyme disease is the most common.For patients with erythema migrans, we do not obtain any laboratory testing. However, if the patient is febrile at the time of the visit or reports rigors and high-grade fevers, we consider the possibility of a co-infection and order pertinent laboratory tests.Our preferred management for Lyme disease related facial palsy and/or radiculopathy is a 2-week course of doxycycline. Patients who are hospitalized for Lyme meningitis are usually treated at least initially with ceftriaxone. We have not seen convincing cases of encephalitis or myelitis solely due to Borrelia burgdorferi infection in the absence of laboratory evidence of concomitant deer tick virus infection (Powassan virus). We have also never seen Lyme encephalopathy or a diffuse axonal peripheral neuropathy and suggest that these entities are either very rare or nonexistent.We have found that Lyme disease rarely presents with fever without other objective clinical manifestations. Prior cases attributed to Lyme disease may have overlooked an asymptomatic erythema migrans skin lesion or the diagnosis may have been based on nonspecific IgM seroreactivity. More research is needed on the appropriate management and significance of IgG seropositivity in asymptomatic patients who have no history of Lyme disease. PMID- 26768264 TI - Outcomes of subcutaneous implantable cardioverter-defibrillator implantation in patients on hemodialysis. AB - BACKGROUND: Subcutaneous implantable cardioverter-defibrillator (S-ICD) provides potential benefits in patients on hemodialysis (HD) by reducing the risk of blood stream infection and preserving vascular access sites. We evaluated the safety and efficacy of S-ICD in patients with end-stage renal disease (ESRD) on HD. METHODS: All consecutive patients implanted with S-ICD between October 2012 and April 2015 at our high-volume center were included in this retrospective, single center study. Baseline demographics, procedural details, and short- as well as long-term outcomes were compared between patients on HD and not on HD. RESULTS: A total of 86 S-ICDs were implanted at our institution during the study period. Eighteen (21%) patients were on HD at the time of implant. HD patients were more likely to be implanted for secondary prevention. There was no statistically significant difference in procedural complications between the two groups. HD patients had a longer duration hospital stay after implant (3.6 +/- 5.14 vs. 1.69 +/- 2.29 days, p = 0.021). During a mean follow-up of 205 +/- 208 days in the HD cohort and 242 +/- 238 days in the non-HD cohort (p = 0.268), there was no device or blood stream infection in the HD group, compared with five device infections in the non-HD group. The incidence of inappropriate shocks was similar in both groups. All appropriate shocks were successful in terminating ventricular tachyarrhythmias in both groups. Patients on hemodialysis had worse inpatient as well as long-term mortality after S-ICD implant, compared with non-HD patients. CONCLUSIONS: Our study demonstrates the safety and efficacy of S-ICD in patients on HD. Despite representing a sicker patient population, HD patients implanted with S-ICD had similar procedural outcomes and inappropriate shocks. There was no device or blood stream-related infection in HD patients. All appropriate shocks for ventricular arrhythmias in HD patients were successful. PMID- 26768267 TI - [Not Available]. PMID- 26768268 TI - Circulating ANGPTL8/Betatrophin Concentrations Are Increased After Surgically Induced Weight Loss, but Not After Diet-Induced Weight Loss. AB - BACKGROUND: ANGPTL8/betatrophin is a secreted protein reported to be involved in beta-cell replication that has recently been shown to be more related to lipid metabolism. Weight loss represents a clinical situation of improvement of glucose homeostasis and overall metabolic control. The aim of the present study was to analyze the impact of weight loss induced by either a conventional dietary treatment or bariatric surgery on ANGPTL8/betatrophin concentrations. METHODS: Serum concentrations of ANGPTL8/betatrophin were measured by ELISA in 158 subjects before and 1 year after weight loss induced either by conventional dietary treatment (n = 38) or bariatric surgery (sleeve gastrectomy, n = 20, or Roux-en-Y gastric bypass, n = 100). RESULTS: Massive surgery-induced weight loss after SG or RYGB was accompanied by a statistically significant increase in circulating levels of ANGPTL8/betatrophin (28.1 +/- 13.9 to 40.3 +/- 22.8 ng/mL, P = 0.001 after SG; 24.6 +/- 10.9 to 41.7 +/- 19.4 ng/mL, P < 0.001 after RYGB), while remaining unchanged 25.6 +/- 13.3 to 25.4 +/- 10.7 ng/mL (P = 0.891) after diet-induced weight loss. The change in ANGPTL8/betatrophin levels was positively correlated with the change in HDL-C concentrations. CONCLUSIONS: Our study showed that serum ANGPTL8/betatrophin concentrations were increased in obese subjects after surgically induced weight loss, but not after weight loss achieved by conventional dietary treatment. The change in ANGPTL8/betatrophin concentrations emerged as a significant predictor of the change in HDL-C levels after weight loss. PMID- 26768269 TI - Treatment Discontinuation Following Bariatric Surgery in Obstructive Sleep Apnea: a Controlled Cohort Study. AB - BACKGROUND: Uncontrolled studies looking at the discontinuation of obstructive sleep apnea (OSA) treatment after bariatric surgery (BS) have suggested that surgery improves OSA. However, this discontinuation of OSA treatment by BS patients has never been compared to a matched population without BS. The objectives of this study are to evaluate whether BS increases OSA treatment discontinuation compared to that in matched patients without BS and to identify predictive factors of OSA treatment discontinuation in BS patients. The study took place in an ambulatory, tertiary hospital. METHODS: We included 61 OSA patients who underwent BS in a retrospective controlled cohort study. The computerized matching procedure included age, sex, body mass index, year of starting OSA treatment, treatment type, and duration selected 59 controls matched to 28 patients with BS. The main outcome was OSA treatment discontinuation within 2 years after BS. RESULTS: Patients with BS stopped OSA treatment more often than controls, usually between 6 months and 1 year after BS: hazards ratio (HR (95 %, CI)) 15.93 (3.29, 77.00). Before 6 months or beyond 1 year after BS, treatment discontinuation was not different between BS patients and controls. In univariate analyses, female gender, absence of co-morbidities, greater weight loss, and lower baseline OSA severity were associated with stopping OSA treatment after BS. No factor remained independently associated in multivariate analysis. CONCLUSIONS: Apneic patients having BS stop OSA treatment more than matched controls. Treatment discontinuation may be attributed to recovery or to abandonment. The effect of BS on OSA may have been overestimated in uncontrolled BS studies that ignored basal OSA treatment discontinuation in routine clinical practice. PMID- 26768270 TI - [Medication treatment of rheumatoid arthritis with a history of malignancy. Epidemiological data]. AB - INTRODUCTION: Only insufficient data are available regarding the question whether treatment with immunosuppressants or biologicals is feasible and safe in patients with a history of malignancy. METHOD: Literature search via PubMed, EULAR abstracts and ACR abstracts from 2013 to 2015. RESULTS: The Societe Francaise de Rhumatologie, the Canadian Rheumatology Association and the American College of Rheumatology have tried to make recommendations on this topic. Direct evidence mainly originates from data in three national registries which suggest that treatment with tumor necrosis factor (TNF) inhibitors and rituximab appears to be safe for carefully selected patients, at least if there is a longer interval between treatment with biologicals and oncological treatment. Furthermore, despite partly conflicting data all routine drugs for treating rheumatoid arthritis do not seem to show a consistently increased risk of de novo malignancies. The currently available data are presented for each drug of interest. CONCLUSION: Taking the current literature into account an attempt is made to formulate an algorithm for the medicinal treatment of patients with rheumatoid arthritis and a history of malignancy. PMID- 26768272 TI - [Pigmented villonodular synovitis. A rare differential diagnosis of synovial joint swelling]. AB - BACKGROUND: Pigmented villonodular synovitis (PVNS) describes a rare disease caused by an abnormal proliferation of the synovial membrane in large and small joints. In order to achieve an optimal result of treatment it is necessary to carry out specific diagnostics and a targeted therapy approach. OBJECTIVE: This article gives a review of the epidemiology, etiopathogenesis and diagnostic management of PVNS as well as presenting the current therapy and treatment recommendations. MATERIAL AND METHODS: A systematic search of the literature was performed in the databank of the National Center for Biotechnology Information ( http://www.ncbi.nlm.nih.gov/pubmed ). The search targeted randomized clinical and experimental studies, systematic and non-systematic review articles, expert opinions and case reports related to PVNS, independent of the level of evidence attained by each study. RESULTS: The differential diagnosis of PVNS should be considered in cases of recurrent hemorrhagic joint effusions. The cause of the disease has not yet been exactly clarified. The final diagnosis can ultimately only be confirmed by histological investigations. In order to obtain representative histological tissue samples for the diagnosis, magnetic resonance imaging (MRI) with the appropriate heme sequences should be carried out prior to taking samples. The management of PVNS is often difficult due to the high risk of recurrence depending on the various forms. In view of the high rate of recurrence, therapy should include a complete synovectomy. CONCLUSION: For the surgical approach arthroscopic and open procedures have been described, which are currently controversially discussed with respect to the complication and recurrence rates. Adjuvant interventional therapy forms, such as radiosynoviorthesis are recommended to reduce the recurrence rate. PMID- 26768271 TI - [DGRh recommendations for the implementation of current security aspects in the NSAID treatment of musculoskeletal pain]. AB - NSAIDs exert their anti-inflammatory and analgesic effects by inhibition of COX 2, a key enzyme for proinflammatory prostanoid synthesis. Therapy with NSAIDs is limited by their typical gastrointestinal, cardiovascular and renal side effects, which are caused by inhibition of COX-1 (gastrointestinal toxicity), COX-2 (cardiovascular side effects) or both COX-isoenzymes (renal side effects). Appropriate prevention strategies should be employed in patients at risk. If gastrointestinal risk factors are present, co-administration of a proton pump inhibitor or misoprostol is recommended; in patients with cardiovascular risk, coxibs, diclofenac and high-dose ibuprofen should be avoided. Furthermore, drug interactions and contraindications should be considered. In patients with renal impairment (GFR < 30 ml/min) all NSAIDs must be avoided. Ulcer anamnesis is a contraindication for traditional NSAIDs. Preexisting cardio- or cerebrovascular diseases are contraindications for coxibs. Treatment decisions should be individually based with a continuous monitoring of the risk - benefit ratio and exploitation of non-pharmacological treatment options. PMID- 26768273 TI - Relative efficacy and tolerability of etoricoxib, celecoxib, and naproxen in the treatment of osteoarthritis : A Bayesian network meta-analysis of randomized controlled trials based on patient withdrawal. AB - AIMS: This study aimed to assess the relative efficacy and tolerability of etoricoxib, celecoxib, and naproxen at recommended dosages in patients with osteoarthritis (OA). METHODS: Randomized controlled trials (RCTs) examining the efficacy and tolerability of etoricoxib 30-60 mg, celecoxib 200-400 mg, and naproxen 1000 mg, based on the number of patient withdrawals among those with OA, were included in this network meta-analysis. We performed a Bayesian random effects network meta-analysis to combine direct and indirect evidence from the RCTs. RESULTS: Eight RCTs, including 5,942 patients, met the inclusion criteria. The proportion of patient withdrawals due to lack of efficacy was significantly lower in the etoricoxib 30-60 mg (OR 0.21, 95 % CrI 0.12-0.38), celecoxib 200-400 mg (OR 0.29, 95 % CrI 0.18-0.47), and naproxen 1000 mg (OR 0.31, 95 % CrI 0.18 0.51) groups than in the placebo group. The number of patient withdrawals due to lack of efficacy tended to be lower in the etoricoxib 30-60 mg group than in the naproxen 1000 mg and celecoxib 200-400 mg groups, although they did not reach statistical significance (OR 0.68, 95 % CrI 0.36-1.33 and OR 0.70, 95 % CrI 0.38 1.37, respectively). Ranking probabilities based on the surface under the cumulative ranking curve (SUCRA) indicated that etoricoxib 30-60 mg had the highest probability of being the best treatment based on the number of withdrawals due to lack of efficacy (SUCRA = 0.9168) followed by celecoxib 200 400 mg (SUCRA = 0.5659), naproxen 1000 mg (SUCRA = 0.5171), and placebo (SUCRA = 0.000189). With respect to tolerability, the number of withdrawals due to adverse events was not significantly different among etoricoxib, celecoxib, naproxen, and placebo, although it tended to be lower with etoricoxib and placebo. CONCLUSIONS: Etoricoxib 30-60 mg, celecoxib 200-400 mg, and naproxen 1000 mg were more efficacious than placebo. However, there was no significant difference in efficacy and tolerability between the medications. PMID- 26768274 TI - [Causes and treatment of systemic amyloidosis]. AB - BACKGROUND: Systemic amyloidoses are rare protein deposition disorders, which are often diagnosed in an advanced stage of the disease due to non-specific symptoms. Any chronic inflammatory disease can lead to an AA-type amyloidosis. AIM: This paper summarizes the current state of the art of diagnosis and treatment of AA amyloidosis and presents data from the past 10 years of our amyloidosis center. MATERIAL AND METHODS: Our data represents an analysis of our cohort of patients with amyloidosis and a selective research in the PubMed database for AA amyloidosis. RESULTS: The underlying diseases comprise autoinflammatory syndromes, polyarthritis, and chronic inflammatory bowel and lung diseases. Renal organ involvement is the most prevalent in AA amyloidosis. It can be detected early through the evaluation of proteinuria. The treatment depends on the individual underlying disease. Patients without an associated inflammatory disease are considered to have idiopathic AA amyloidosis and empiric treatment is mandatory. DISCUSSION: Survival of this fatal disease has recently improved due to the new diagnostic tools and treatment options; however, early diagnosis plays a crucial role in the prevention of end-stage renal failure. New therapeutic strategies aim to remove existing amyloid deposits. PMID- 26768275 TI - Global longitudinal strain is an independent predictor of cardiovascular events in patients with maintenance hemodialysis: a prospective study using three dimensional speckle tracking echocardiography. AB - The aim of this study was to investigate subclinical LV changes in patients with maintenance hemodialysis (MHD) using three-dimensional speckle-tracking echocardiography (3DSTE) and to explore its prognostic value. A total of 88 individuals were consecutively enrolled, including 66 subjects with MHD and 22 age- and sex-matched controls. Conventional and Real-time three-dimensional echocardiography was performed and analyzed. Left ventricular volume, strain and time parameters were calculated and compared. The MHD cohort was then followed to record cardiovascular events (CVE). Univariate and multivariate logistic regression analysis was used to identify independent predictors of CVE. Compared with the controls, MHD patients had significantly lower global longitudinal and radial strain (GLS and GRS), and LVEF (GLS: -17.0 +/- 2.3 vs -18.8 +/- 2.3 %; GRS: 37.0 +/- 3.5 vs 39.4 +/- 3.4 %; LVEF: 57.3 +/- 4.2 vs 59.5 +/- 3.5 %, p < 0.05 for all), as well as enlarged LV volume (EDV: 51.3 +/- 14.2 vs 40.4 +/- 7.3 ml/m(2); ESV: 22.0 +/- 6.9 vs 16.3 +/- 3.2 ml/m(2); SV: 29.2 +/- 8.0 vs 24.0 +/- 4.7 ml/m(2), p < 0.01 for all) and LV mass index (LVMi) (107.7 +/- 28.6 vs 83.7 +/- 20.6 g/m(2)). Time to minimum end-systolic volume and to peak longitudinal strain (T-msv and T-ls) were delayed in the MHD group (T-msv: 38.1 +/- 5.2 vs 41.4 +/- 6.4 %; T-ls: 38.1 +/- 4.6 vs 42.1 +/- 6.8 %, p < 0.05). Systolic dyssynchrony index (SDI) of the MHD group was significant larger than that of the controls (6.4 +/- 1.5 vs 4.9 +/- 1.8 %, p < 0.01). CVE occurred in 23 patients within a follow-up of 2 years. GLS and LVMi remained significant predictors of CVE [OR = 3.94, 95 % CI (1.33-11.66) for GLS and OR = 1.04, 95 % CI (1.01-1.07) for LVMi, p = 0.013 and 0.009, respectively]. Subclinical LV deformation and dysfunction exist in MHD patients with preserved LVEF. GLS and LVMi are two important predictors of CVE in MHD patients. Strain assessment in MHD patients may contribute to better vascular risk stratification. PMID- 26768276 TI - Schwannoma of the stomach: a case report. AB - BACKGROUND: Schwannomas, also known as neurilemmomas, are benign slow-growing neoplasms originating from a Schwann cell sheath. These neoplasms are rare among the mesenchymal tumors of the gastrointestinal tract. In the stomach, Schwannomas only represent 0.2 % of all gastric tumors; this makes the presentation of a schwannoma in the stomach of a man in his seventh decade unusual. This case report highlights the rarity of a schwannoma at the greater curvature of the stomach because only a few cases have been reported in the literature. This case describes the importance of including gastric schwannomas in the differential diagnosis when preoperative assessment reveals a submucosal gastric mass with gastrointestinal stromal tumor as a leading differential diagnosis because of its common occurrence at this site. CASE PRESENTATION: A 72-year-old man of Indian origin presented with a painless abdominal mass with nonspecific gastrointestinal upset. An endoscopy showed a submucosal lesion in his stomach measuring 4 * 3 * 2 cm. Histology revealed a benign spindle cell tumor. Immunohistochemistry confirmed the diagnosis of gastric schwannoma. He is on regular follow-up and doing well. CONCLUSIONS: It should be remembered that a schwannoma can present as a mass lesion in the stomach and mimic gastrointestinal stromal tumor. Patients should undergo an endoscopy and a biopsy of the lesion should be done. Many patients do not undergo endoscopy which can delay diagnosis and management. As these tumors have an excellent prognosis, surgical removal is sufficient treatment. Surgeons, radiologists, pathologists and gastroenterologists must be aware of this entity. PMID- 26768278 TI - The expression of beta3-adrenoceptors and their function in the human prostate. AB - BACKGROUND: Little is known about beta3-adrenoceptor (AR) expression and function in human prostate. We examined the expression and distribution of beta-AR subtypes in normal prostate and benign prostatic hyperplasia (BPH) tissues, and investigated which selective beta-AR subtype agonist was most involved in the relaxation of isolated human prostate strips. METHODS: Messenger RNA (mRNA) expression for beta1-, beta2-, and beta3 -ARs was investigated using reverse transcriptase-polymerase chain reactions (RT-PCR). Quantitative analysis of mRNA expression of beta-AR subtypes between normal prostate and BPH tissues was performed using quantitative RT-PCR (qPCR). Distributions were examined by immunohistochemistry (IHC). Strips of human normal prostate or BPH were suspended in organ baths and exposed to isoproterenol, dobutamine, procaterol, and TRK-380 to investigate their relaxant effects on KCl-induced contractions, and their inhibitory effects on electrical field stimulation (EFS)-induced contractions. RESULTS: We confirmed the presence of mRNA for beta1-, beta2-, and beta3-ARs both in normal prostate and in BPH tissues. For beta3-AR, mRNA expression in BPH tissues was significantly higher than in normal prostate tissues, but there was no significant difference in beta1- and beta2-AR expression between normal and BPH tissues. IHC revealed differences in staining intensity between smooth muscle cells and glandular cells, with different proportions for different beta-AR subtypes. Staining of beta3-AR was particularly intense in smooth muscle cells as opposed to glandular cells. Isoproterenol and TRK-380 significantly decreased the tone of KCl-induced contractions of the normal prostate strips. The rank order of relaxant effects was isoproterenol > TRK-380 > procaterol > dobutamine. All selective beta-AR agonists significantly decreased the amplitude of EFS-induced contractions of the normal prostate strips. The rank order of inhibitory effects was isoproterenol > dobutamine >TRK-380 > procaterol. In BPH strips, all selective beta-AR agonists showed no significant relaxant or inhibitory effects on KCl- or EFS-induced contractions. CONCLUSIONS: beta3 -AR is abundant in human prostate smooth muscle, whose relaxation is mediated by beta1- and beta3-AR stimulation. beta3-AR agonists may have clinical use in the treatment of male non BPH patients or neurogenic bladder patients with voiding dysfunction. PMID- 26768277 TI - MicroRNA-mediated susceptible poplar gene expression regulation associated with the infection of virulent Melampsora larici-populina. AB - BACKGROUND: Rust caused by Melampsora larici-populina is one of the most damaging diseases of poplars. Rust is considered to be a model pathogen for genetic studies because both pathogen and host genomes are available. The poplar 'Robusta', whose general rust resistance is defeated by virulent rust E4, provides suitable host material for studies of the gene regulation involved in rust resistance/susceptibility. In this study, we investigated the microRNA mediated susceptible poplar gene expression regulation associated with the infection of virulent rust. We were particularly interested in delineating the host-pathogen interactions with a specific focus on microRNAs (miRNAs). RESULTS: To study the susceptibility of poplar to M. larici-populina, small RNA (sRNA) libraries, a degradome cDNA library and digital gene expression libraries were constructed for rust-inoculated and rust-free susceptible poplar 'Robusta' leaves through high-throughput sequencing. Altogether, 12,722 regulating interactions were identified. The results delineated the framework of post-transcriptional regulation of gene expression in the susceptible poplar, which was infected by the virulent rust. The results indicated that pathogen-associated molecular patterns (PAMPs) and PAMP-triggered immunity were induced by the infection of virulent rust E4 and that miRNAs still functioned at this stage. After this stage, miRNA-regulated R genes, such as TIR-NBS-LRR and CC-NBS-LRR, were not fully functional. Additionally, the rust-responsive miRNAs did not regulate the signaling component genes related to the salicylic acid pathway or the hypersensitive response. CONCLUSIONS: We found that the defense-related post transcriptional regulation of the susceptible poplar 'Robusta' functions normally only at the stage of PAMPs and PAMP-triggered immunity (PTI). More importantly, the miRNA-mediated post-transcriptional regulation of defense signal pathway genes were inactivated by the infection of virulent rust at the stage of effector triggered susceptibility and during the following stages of salicylic acid and hypersensitive responses. This inactivation was the major characteristic of 'Robusta' susceptibility. PMID- 26768280 TI - A novel heat shock protein 27 homozygous mutation: widening of the continuum between MND/dHMN/CMT2. PMID- 26768279 TI - Study of testosterone-guided androgen deprivation therapy in management of prostate cancer. AB - BACKGROUND: Androgen deprivation therapy (ADT) with luteinizing hormone releasing hormone (LHRH) agonists is an effective initial therapy for men with advanced prostate cancer. LHRH agonists are usually administered indefinitely at a fixed interval. METHODS: We recruited men with advanced prostate cancer who had been on fixed-schedule injections of an LHRH agonist for >=1 year and had castrate serum testosterone [<1.75 nmol/l (approx. 50 ng/ml)]. Testosterone levels were measured at 6-week intervals and ADT was withheld until testosterone levels were no longer in the castrate range and then reinstituted. Time to reinstitution of ADT was the primary outcome and was analyzed by the Kaplan-Meier method; Cox regression was used to identify factors predicting delay in reinstitution of treatment. Influence on quality-of-life (QoL) was evaluated by the Expanded Prostate Index Composite (EPIC). RESULTS: Forty-six evaluable men who had received LHRH agonist injections every 12 weeks were recruited. Median time to testosterone recovery (defined as testosterone outside the defined castrate level) after previous injection was >1 year. In univariable analysis, lower baseline testosterone [<=1 vs. >1 nmol/l (approx. 30 ng/dl)] and longer time on ADT (>5 vs. <=5 years) predicted for prolonged time to testosterone recovery, but only lower baseline testosterone remained significant in multivariable analysis (Hazard Ratio = 5.2, P = 0.03). Overall EPIC scores remained stable but improvement from baseline was observed in the hormonal domain (P = 0.002). Median per-patient saving in cost was approximately USD 3,100 (1,050-6,200). CONCLUSIONS: Testosterone-guided ADT reduces exposure to LHRH agonists, with reduction in cost and improvement in some symptoms from ADT. Testosterone-guided ADT should be considered an alternative to fixed schedule treatment by physicians and policy makers. PMID- 26768281 TI - Osteoporotic fractures - the biological perspective. PMID- 26768282 TI - Fracture repair: general aspects and influence of osteoporosis and anti osteoporosis treatment. AB - Bone differs from other tissues in its capacity to self-repair after a fracture. The low bone mass and structural deterioration of bone associated with osteoporosis increases the risk of fragility fracture compared with healthy individuals. The intention of this article is to review the complex process of fracture repair and essential requirements for a successful fracture healing response summarized as the "diamond concept" in terms of aging and osteoporosis. The current preclinical and clinical evidence for a beneficial or harmful influence of anti-osteoporosis medications such as bisphosphonates, parathyroid hormone (PTH), strontium ranelate and antibodies of Wnt-inhibiting signaling proteins on bone healing is presented and discussed. Literature suggests that there are no detrimental consequences of such therapeutics on fracture repair processes. Following a fragility fracture, it seems that early start of preventive anti-osteoporotic treatment right after surgery does not delay the union of the fracture, except perhaps in the case of very rigidly fixed fracture requiring direct bone healing. There is some promising experimental and clinical evidence for possible enhancement of the bone repair process via administration of systemic agents. Further well designed studies in humans are necessary to accumulate more evidence on the positive effects and to translate this knowledge into valid therapeutic applications. PMID- 26768283 TI - Main differences in osteoporotic fracture models: which should I use? AB - Osteoporosis is a global public health problem currently affecting more than 200 million people worldwide. Major research efforts are being made to improve the outcomes for patients with osteoporosis. However, the treatment of fractures associated with osteoporosis remains unsatisfactory. Animal models continue to be an important tool for establishing strategies to treat osteoporotic fractures, and various methods of inducing osteoporosis have been used. Investigators must select a model that best reflects the clinical problem being studied, and the underlying pathophysiology of the osteoporosis in the target patient group. In particular a model for Type I post-menopausal osteoporosis should mimic a fall in oestrogen and rise in osteoclast activity observed with this condition, whereas a model for type II 'senile' osteoporosis should mimic the fall in osteoblast activity. Unfortunately, there is no single all-encompassing model that precisely imitates the underlying osteoporosis or the fracture patterns seen in humans. As such the choice of species and model must be individualised to the scientific question being addressed. This article summarises general considerations when choosing an osteoporotic fracture model and outlines existing models of osteoporosis. The most appropriate model in a range of osteoporotic fracture research scenarios are subsequently considered. PMID- 26768284 TI - Bone mineral density aspects in the femoral neck of hip fracture patients. AB - Elderly people, due to neurological conditions and muscular atrophy, present a greater propensity to falls and thus are very susceptible to hip fractures. Other variables, such as osteoporosis, may also be related to the etiopathogenesis of hip fractures, although osteoporosis is in fact a concurrent disease, and merely a coadjutant cause. Nonetheless, osteoporosis can make fracture patterns more severe and interfere with osteosynthesis. Osteoporosis is the radiological image of osteopenia, a pathological concept meaning a smaller quantity of bone per unit of volume. The radiological expression of osteopenia is therefore that of bone tissue with a lower radiological density than normal. In the context of hip fractures, bone mineral density and bone architecture of the femoral neck together with protein expression profiles and cross-links of this anatomical area are of special interest which is reviewed in the current paper. Spatial variations in bone mineral density in the femoral neck were found in the literature with increased porosity from the periosteal to the endosteal region and also from the distal to the proximal part of the femoral neck. Furthermore, increased crystal size, increased cortical porosity, reduced osteocyte lacunar density and an increased Ca/P ratio associated with higher concentrations of Ca and P were described in hip fracture patients compared to control patients. Osteocalcin/collagen type 1 expression ratio and enzymatic cross-link content in high-density bone was found to be significantly lower in hip fractures compared to controls. In conclusion, further research in bone mineral density and associated parameters are of interest to deepen the understanding of osteoporotic hip fractures. PMID- 26768285 TI - Hip fracture programs: are they effective? AB - This manuscript will evaluate the published evidence on efficacy of organized hip fracture programs to determine if they improve patient outcomes. A detailed literature search was conducted to find manuscripts published in the past 20 years about organized hip fracture care programs. Seventeen programs with published results were identified from this detailed search and these were evaluated and synthesized in the following manuscript. Organized hip fracture programs offer significant benefits to patients, care providers and health systems. The more complex program designs have a more profound effect on improvement in outcomes for hip fracture patients. Most programs have reported reduced length of stay, reduced in-hospital mortality rates, and reduced complications. Some programs have reported reduced costs and reduced readmission rates after implementing an organized hip fracture program. PMID- 26768286 TI - Atypical fractures, a biased perspective. AB - When stress fractures started to show up in the femurs of elderly ladies, it was soon evident that bisphosphonate use lay behind, and the absolute risk increase due to bisphosphonate use was reasonably well estimated already in 2008. Thereafter followed a period of confusion: the term atypical fracture was introduced, with a definition so vague that the true stress fractures tended to disappear in a cloud of ambiguity. This cast doubt on the association with bisphosphonates. The association was then re-established by large epidemiological studies based on radiographic adjudication. Atypical fractures are largely caused by bisphosphonates. With a correct indication, bisphosphonates prevent many more fractures than they cause, at least during the first years of use. With an incorrect indication they are likely to cause more harm than good. PMID- 26768287 TI - Can we induce osteoporosis in animals comparable to the human situation? AB - Osteoporosis is a chronic systemic bone disease of growing relevance due to the on-going demographic change. Since the underlying regulatory mechanisms of this critical illness are still not fully understood and treatment options are not satisfactorily resolved, there is still a great need for osteoporosis research in general and animal models in particular. Ovariectomized rodents are standard animal models for postmenopausal osteoporosis and highly attractive due to the possibility to specifically modify their genetic background. However, some aspects can only be addressed in large animal models; such as metaphyseal fracture healing and advancement of orthopedic implants. Among other large animal models sheep in particular have been proven invaluable for osteoporosis research in this context. In conclusion, today we are able to influence the bone metabolism in animals causing a more or less pronounced systemic bone loss and structural deterioration comparable to the situation found in patients suffering from osteoporosis. However, there is no perfect model for osteoporosis, but a variety of models appropriate for answering specific questions. Though, the appropriateness of an animal model is not only defined in regard to the similarity to human physiology and the disease itself, but also in regard to acquisition, housing requirements, handling, costs, and particularly ethical concerns and animal welfare. PMID- 26768288 TI - Anti-sclerostin - is there an indication? AB - Several decades ago, a clinical condition that included severe bone overgrowth was described in a few patients in South Africa. The autosomal-recessive disease that later was named sclerosteosis was found to be caused by a mutation in the SOTS gene causing a lack of the protein sclerostin. This protein is produced by osteocytes and exerts its effect as an inhibitor of bone formation by blocking the Wnt signaling pathway. By the use of a monoclonal antibody that can block sclerostin a novel therapeutic pathway for rebuilding bone has been described. Preclinical studies have shown increased bone mass following subcutaneously administered anti-sclerostin antibody in animals with induced postmenopausal osteoporosis as well as in intact male rats and non-human primates. In a phase II study the efficacy and safety of an anti-sclerostin antibody, romosozumab, has been evaluated in 419 postmenopausal women for 12 months. 70, 140 or 210 mg was given subcutaneously monthly or every three months and compared to 70 mg of oral alendronate given once a week or 20 MUg of teriparatide subcutaneously once daily. All dose levels of romosozumab were associated with significant increase in BMD with the most pronounced gain in the group receiving 210 mg where lumbar spine BMD increased with 11.3% from baseline. The BMD for the placebo group decreased by 0.1% while the alendronate group increased 4.1% and the teriparatide increased 7.1%. Biochemical markers revealed a transitory increase in the bone formation marker P1NP while no change in the bone resorption marker beta-CTX. In comparison, teriparatide resulted in an increase for both P1NP and beta-CTX for the complete study period. Even though the rapid gain in BMD is promising when considering a treatment option for osteoporosis and other conditions with bone loss, there are so far no published studies on whether anti-sclerostin can reduce the number of fractures. Wnt signaling might also play an important role in fracture healing with substances that causes an upregulation of the Wnt pathway producing enhancement of the fracture healing process. Healing of experimental fractures in various animal models have shown improvement following subcutaneously administered anti-sclerostin antibody. While there are no published reports on the potential effect of systemically administered anti sclerostin antibodies on fracture healing in humans. PMID- 26768289 TI - Use of teriparatide in osteoporotic fracture patients. AB - Teriparatide [PTH (1-34)] is a genetically engineered analog of human parathyroid hormone that acts as an anabolic drug by increasing activity in both osteoblasts and osteoclasts. Intermittent (once-daily) doses of teriparatide seem to stimulate osteoblast activity and therefore result in a net increase of bone formation. It is recommended for use in post-menopausal women (PMW), men with hypogonadal osteoporosis, as well as men and women with glucocorticoid-induced osteoporosis. In vivo studies have generated important findings regarding teriparatide's role in the enhancement of fracture healing. The intention of this article is to review the clinical findings of teriparatide to stimulate fracture healing. The drug was shown in a prospective randomized, double blind study to achieve earlier radiographic cortical bridging of three of four cortices (7.4 weeks) compared to patients who were assigned to the placebo group (9.1 weeks). Another study compared mean time for healing and functional outcome in two groups of elderly women who had suffered osteoporotic pelvic fractures: one group received daily 100 MUg parathyroid hormone (1-84) injections, while the other group received no treatment. Patients who received the PTH (1-84) injections accelerated radiographic and clinical fracture healing (7.8 weeks) when compared to patients who received no treatment (12.6 weeks, p<0.001). Numerous case series state the safety and potential benefits of teriparatide use in patients recovering from fractures. In the following scenarios, teriparatide might be considered in patients with osteoporosis and a fracture: (1) patients with severe osteoporosis with use of bisphosphonates for a number of years with a fracture not expected to predictably unite, e.g. atypical femur fracture or open tibia fracture, (2) in cases where an osteoporotic patient has failed fracture healing and is considering surgical treatment e.g. non-union surgery. It seems prudent to reevaluate these patients frequently and reconsider which drug class of osteoporotic drug is best for the patient. Finally, it must be stressed that we do not recommend teriparatide in osteoporotic patients that may be well treated with bisphosphonates and a fracture is expected to heal uneventfully, nor when patients with metabolically normal bone have a fracture. PMID- 26768290 TI - Ultrasound and fragility fracture: is there a role? AB - Osteoporotic fracture is known to have impaired healing capacity and therefore takes longer time to heal, as compared with younger one. The mechanism of impaired osteoporotic fracture healing is multifactorial, where lower responsiveness to mechanical loading is generally believed to be one factor, yet not absolutely confirmed. In recent years, low intensity pulsed ultrasound (LIPUS) is demonstrated to have good efficacy in treating normal fracture healing, as proven by many randomized controlled trials, as well as in vitro and animal evidences. The effects of LIPUS on osteoporotic fracture healing was also validated in an animal study, which revealed that osteoporotic fractured bone of SD rats showed radiologically and biomechanically comparable responses to LIPUS as age-matched normal fracture healing, in terms of callus width, bridging rate, bone volume fraction, and stiffness etc. Gene expression profiling also confirmed that osteoporotic fractured bone responded to LIPUS very well by upregulating Col1 and BMP2 (osteogenesis) at early phase, VEGF (angiogenesis) at middle phase and RANKL (remodeling) at late phase. These confirm that osteoporotic bones respond well to LIPUS as good as normal bone. These findings may be associated with estrogen receptors (ERs), as estrogen depletion is sensed and relayed by ERs and ERs also function as mechano-sensors. A previous study observed a delayed ERs expression pattern in fracture callus of OVX rats, as compared with SHAM rats, which correlated well with the expression pattern of BMP-2 (callus formation related gene). Hence, the responses of osteoporotic fractured bone to LIPUS may be related to the local ERs expression at fracture callus that needs further experiments to validate. PMID- 26768291 TI - Bone graft substitutes and bone morphogenetic proteins for osteoporotic fractures: what is the evidence? AB - Despite improvements in implants and surgical techniques, osteoporotic fractures remain challenging to treat. Among other major risk factors, decreased expression of morphogenetic proteins has been identified for impaired fracture healing in osteoporosis. Bone grafts or bone graft substitutes are often used for stabilizing the implant and for providing a scaffold for ingrowth of new bone. Both synthetic and naturally occurring biomaterials are available. Products generally contain hydroxyapatite, tricalcium phosphate, dicalcium phosphate, calcium phosphate cement, calcium sulfate (plaster of Paris), or combinations of the above. Products have been used for the treatment of osteoporotic fractures of the proximal humerus, distal radius, vertebra, hip, and tibia plateau. Although there is generally consensus that screw augmentation increased the biomechanical properties and implant stability, the results of using these products for void filling are not unequivocal. In osteoporotic patients, Bone Morphogenetic Proteins (BMPs) have the potential impact to improve fracture healing by augmenting the impaired molecular and cellular mechanisms. However, the clinical evidence on the use of BMPs in patients with osteoporotic fractures is poor as there are no published clinical trials, case series or case studies. Even pre clinical literature on in vitro and in vivo data is weak as most articles focus on the beneficial role for BMPs for restoration of the underlying pathophysiological factors of osteoporosis but do not look at the specific effects on osteoporotic fracture healing. Limited data on animal experiments suggest stimulation of fracture healing in ovariectomized rats by the use of BMPs. In conclusion, there is only limited data on the clinical relevance and optimal indications for the use of bone graft substitute materials and BMPs on the treatment of osteoporotic fractures despite the clinical benefits of these materials in other clinical indications. Given the general compromised outcome in osteoporotic fractures and limited alternatives for enhancement of fracture healing, clinicians and researchers should focus on this important topic and provide more data in this field in order to enable a sound clinical use of these materials in osteoporotic fractures. PMID- 26768292 TI - Stem cell therapy: is there a future for reconstruction of large bone defects? AB - Large bone defects caused by fracture, non-union and bone tumor excision has been a major clinical problem. Autogenous bone grafting and Ilizarov method are commonly performed to treat them. However, bone grafting has limitation in volume of available bone, and Ilizarov method requires long periods of time to treat. Accordingly, there is need for stem cell therapy for bone repair and/or regeneration. Mesenchymal stem cells (MSCs) hold the ability to differentiate into osteoblasts and are available from a wide variety of sources. The route of "intramembranous ossification (direct bone formation)" by transplantation of undifferentiated MSCs has been tested but it did not demonstrate the success initially envisaged. Recently another approach has been examined being the transplantation of "MSCs pre-differentiated in vitro into cartilage-forming chondrocytes" into bone defect, in brief, representing the route of "endochondral ossification (indirect bone formation)". It's a paradigm shift of Stem Cell Therapy for bone regeneration. We have already reported on the healing of large femur defects in rats by transplantation of "MSCs pre-differentiated in vitro into cartilage-forming chondrocytes". We named the cells as Mesenchymal Stem Cell Derived Chondrocytes (MSC-DCs). The success of reconstruction of a massive 15-mm femur defect (approximately 50% of the rat femur shaft length) provides a sound foundation for potential clinical application of this technique. We believe our results may offer a new avenue of reconstruction of large bone defect, especially in view of the their high reproducibility and the excellent biomechanical strength of repaired femora. PMID- 26768293 TI - Effects of macroporous, strontium loaded xerogel-scaffolds on new bone formation in critical-size metaphyseal fracture defects in ovariectomized rats. AB - New bone formation was studied in a metaphyseal fracture-defect in ovariectomized rats stimulated by a plain and a strontium-enriched macroporous silica/collagen scaffold (ScB30 and ScB30Sr20) and a compact silica/collagen xerogel (B30). 45 female Sprague-Dawley rats were randomly assigned to three different treatment groups: (1) ScB30 (n=15), (2) ScB30Sr20 (n=15), and (3) B30 (n=15). 12 weeks after bilateral ovariectomy and multi-deficient diet, a 4 mm wedge-shaped fracture-defect was created at the metaphyseal area of the left femur. A 7-hole T shaped plate at the lateral aspect of the femur stabilized the bone and the defect was filled with ScB30, ScB30Sr20 or B30 subsequently. After six weeks, histomorphometrical analysis revealed a statistically significant higher bone volume/tissue volume ratio in the ScB30Sr20 group compared to ScB30 (p=0.043) and B30 (p=0.0001) indicating an improved formation of new bone by the strontium enriched macroporous silica/collagen scaffold. Furthermore, immunohistochemical results showed increased expression of BMP2 and OPG and a decreased RANKL expression in the ScB30Sr20 group. This was further confirmed with the gene expression analysis where an increase in prominent bone formation markers (ALP, OCN, Runx2, Col1a1 and Col10a1) was seen. No material remnants were found in the scaffold group indicating an almost complete degradation process of the biomaterials. This is confirmed by ToF-SIMS analysis that did not detect any strontium in the ScB30Sr20 group neither in the defect nor in the surrounding tissue. Taken together, this study shows the stimulating effects of strontium through increased bone formation by up regulation of osteoanabolic markers. This work also indicates the importance of material porosity, geometry and biodegradability in bone healing. PMID- 26768294 TI - Medical management of osteoporosis and the surgeons' role. AB - Osteoporosis is a worldwide public health issue and with the aging population the resultant increase in fragility fractures has generated a significant socioeconomic impact. Robust scientific research has increased our knowledge of the endocrine mechanisms and pathophysiology of osteoporosis. This information has led to Level 1 randomized clinical trials which demonstrate the beneficial effects of appropriate regimens in reducing the fracture risk and the coincident mortality. Despite these contributions the public health problem remains and has stubbornly failed many public awareness campaigns by governmental and private professional organizations. Effectiveness in delivering the message is greatly enhanced following the sentinel fragility fracture whether it be distal radius, hip, or spine. The treating orthopedic surgeon has the full attention of the injured patient who can be steered into osteoporosis screening programs and ultimately treatment. Studies in Canada have shown that if the surgeon initiates the process by so much as ordering the bone densitometry exam the patient is more likely to get treatment for their underlying disease than if it is just suggested that the patient see their medical doctor at some future date. The patient takes the cue from the surgeon. Patient compliance goes up and the treatment is instituted. We as surgeons must be part of the solution. This has been emphasized in the worldwide efforts in orthopedic surgery such as the "Bone and Joint Decade" and "Own the Bone" programs. This commitment to bone health and restoration is important. Our patients deserve no less. PMID- 26768296 TI - Determination of urinary coenzyme Q10 by HPLC with electrochemical detection: Reference values for a paediatric population. AB - Kidney dysfunction is being increasingly associated with mitochondrial diseases and coenzyme Q10 (CoQ) deficiency. The assessment of CoQ status requires the biochemical determination of CoQ in biological fluids and different cell types, but no methods have been developed as yet for the analysis of CoQ in excretory systems. The aim of this study was to standardize a new procedure for urinary CoQ determination and to establish reference values for a paediatric population. Urinary CoQ was analyzed by HPLC with electrochemical detection. Reference values (n = 43) were stratified into two age groups (2-10 years: range 24-109 nmol CoQ/gram of pellet protein; 11-17 years: range 43-139 nmol CoQ/gram of pellet protein). In conclusion, urinary CoQ analysis is a noninvasive, reliable, and reproducible method to determine urinary tract CoQ status. PMID- 26768297 TI - Novel challenges associated with novel agents: the evolving scenario in renal cell carcinoma. PMID- 26768295 TI - How do bisphosphonates affect fracture healing? AB - Bisphosphonates (BPs) have been in use for many years for the treatment of osteoporosis, multiple myeloma, Paget's disease, as well as a variety of other diseases in which there is reduced bone mineral density. Given that bisphosphonates inhibit bone resorption, an important stage of fracture healing; this class of compounds has been widely studied in preclinical models regarding their influence on fracture healing. In animal models, bisphosphonate treatment is associated with a larger fracture callus, coincident with a delay in remodeling from primary woven bone to lamellar bone, but there is no delay in formation of the fracture callus. In humans, de novo use of bisphosphonate therapy after fracture does not appear to have a significant effect on fracture healing. Rarely, patients with long term use of Bisphosphonates may develop an atypical fracture and delay in fracture healing has been observed. In summary, bisphosphonates appear safe for use in the setting of acute fracture management in the upper and lower extremity in humans. While much remains unknown about the effects on healing of long-term bisphosphonates, use prior to "typical" fracture, in the special case of atypical fracture, evidence suggests that bisphosphonates negatively influence healing. PMID- 26768301 TI - How to smell really bad, look really good, and last forever!: The season of Ginkgo biloba. PMID- 26768303 TI - Prospective, Interdisciplinary Randomized Clinical Trials for Patients With Cancer in the Emergency Department: A Step Forward for Palliative Oncology Care. PMID- 26768299 TI - Salmonella infection in grey seals (Halichoerus grypus), a marine mammal sentinel species: pathogenicity and molecular typing of Salmonella strains compared with human and livestock isolates. AB - Microbial pollution of the marine environment through land-sea transfer of human and livestock pathogens is of concern. Salmonella was isolated from rectal swabs of free-ranging and stranded grey seal pups (21.1%; 37/175) and compared with strains from the same serovars isolated from human clinical cases, livestock, wild mammals and birds in Scotland, UK to characterize possible transmission routes using pulsed-field gel electrophoresis and multi-locus variable number of tandem repeat analyses. A higher prevalence of Salmonella was found in pups exposed to seawater, suggesting that this may represent a source of this pathogen. Salmonella Bovismorbificans was the most common isolate (18.3% pups; 32/175) and was indistinguishable from isolates found in Scottish cattle. Salmonella Typhimurium was infrequent (2.3% pups; 4/175), mostly similar to isolates found in garden birds and, in one case, identical to a highly multidrug resistant strain isolated from a human child. Salmonella Haifa was rare (1.1% pups; 2/175), but isolates were indistinguishable from that of a human clinical isolate. These results suggest that S. Bovismorbificans may circulate between grey seal and cattle populations and that both S. Typhimurium and S. Haifa isolates are shared with humans, raising concerns of microbial marine pollution. PMID- 26768304 TI - Structure elucidation of uniformly (13)C labeled small molecule natural products. AB - Utilization of (2)H, (13)C, and (15)N isotopically labeled proteins and peptides is now routine in biomolecular NMR investigations. The widespread availability of inexpensive, uniformly (13) C enriched glucose now makes it possible to isolate uniformly (13)C labeled natural products from microbial fermentation. We now wish to describe an approach for the rapid structural characterization of uniformly (13)C labeled natural products that avoids the pitfalls of relying on parameters typically employed in biomolecular NMR studies. PMID- 26768306 TI - Structure elucidation of uniformly 13C labeled small molecule natural products. AB - Utilization of isotopically labeled proteins and peptides is a routinely employed approach in biomolecular NMR investigations. The widespread availability of inexpensive, uniformly (13) C-enriched glucose now makes it possible to produce uniformly (13) C-labeled natural products by microbial fermentation. In this feature article, the authors describe an experimental approach for the rapid structural characterization of uniformly (13) C-labeled natural products based on the Constant-Time HSQC (CT-HSQC) experiment. Rigorous theoretical evaluation of the CT-HSQC experiment allowed the applicability of the experiment to be expanded from the traditional, narrow scope of labeled amino acids to encompass virtually any small molecule or U-(13) C labeled natural product. A suite of experiments including CT-HSQC, (13) C-(13) C COSY, and COSYLR experiments is sufficient for the structure elucidation of uniformly (13) C-labeled small molecules and natural products. Differences in NMR approaches for structure elucidation of natural abundance and uniformly (13) C-labeled molecules are also discussed. The present work provides a researcher working in this area of natural products chemistry with NMR structure elucidation tools for investigating (13) C-labeled small molecules and natural products. PMID- 26768305 TI - Structure elucidation of configurational isomers of nitrile-substituted spirocyclopropyloxindoles by NMR spectroscopy, molecular modeling, and X-ray crystallography. PMID- 26768307 TI - Enhanced delivery of etoposide across the blood-brain barrier to restrain brain tumor growth using melanotransferrin antibody- and tamoxifen-conjugated solid lipid nanoparticles. AB - Melanotransferrin antibody (MA) and tamoxifen (TX) were conjugated on etoposide (ETP)-entrapped solid lipid nanoparticles (ETP-SLNs) to target the blood-brain barrier (BBB) and glioblastom multiforme (GBM). MA- and TX-conjugated ETP-SLNs (MA-TX-ETP-SLNs) were used to infiltrate the BBB comprising a monolayer of human astrocyte-regulated human brain-microvascular endothelial cells (HBMECs) and to restrain the proliferation of malignant U87MG cells. TX-grafted ETP-SLNs (TX-ETP SLNs) significantly enhanced the BBB permeability coefficient for ETP and raised the fluorescent intensity of calcein-AM when compared with ETP-SLNs. In addition, surface MA could increase the BBB permeability coefficient for ETP about twofold. The viability of HBMECs was higher than 86%, suggesting a high biocompatibility of MA-TX-ETP-SLNs. Moreover, the efficiency in antiproliferation against U87MG cells was in the order of MA-TX-ETP-SLNs > TX-ETP-SLNs > ETP-SLNs > SLNs. The capability of MA-TX-ETP-SLNs to target HBMECs and U87MG cells during internalization was verified by immunochemical staining of expressed melanotransferrin. MA-TX-ETP-SLNs can be a potent pharmacotherapy to deliver ETP across the BBB to GBM. PMID- 26768308 TI - Rapid evolutionary loss of metal resistance revealed by hatching decades-old eggs. AB - We investigated the evolutionary response of an ecologically important freshwater crustacean, Daphnia, to a rapidly changing toxin environment. From the 1920s until the 1960s, the use of leaded gasoline caused the aquatic concentration of Pb to increase at least fivefold, presumably exerting rapid selective pressure on organisms for resistance. We predicted that Daphnia from this time of intense pollution would display greater resistance than those hatched from times of lower pollution. This question was addressed directly using the resurrection ecology approach, whereby dormant propagules from focal time periods were hatched and compared. We hatched several Daphnia genotypes from each of two Swiss lakes, during times of higher (1960s /1980s) and lower (2000s) lead stress, and compared their life histories under different laboratory levels of this stressor. Modern Daphnia had significantly reduced fitness, measured as the population growth rate (lambda), when exposed to lead, whereas those genotypes hatched from times of high lead pollution did not display this reduction. These phenotypic differences contrast with only slight differences measured at neutral loci. We infer that Daphnia in these lakes were able to rapidly adapt to increasing lead concentrations, and just as rapidly lost this adaptation when the stressor was removed. PMID- 26768309 TI - Micro Electrochemical pH Sensor Applicable for Real-Time Ratiometric Monitoring of pH Values in Rat Brains. AB - To develop in vivo monitoring meter for pH measurements is still the bottleneck for understanding the role of pH plays in the brain diseases. In this work, a selective and sensitive electrochemical pH meter was developed for real-time ratiometric monitoring of pH in different regions of rat brains upon ischemia. First, 1,2-naphthoquinone (1,2-NQ) was employed and optimized as a selective pH recognition element to establish a 2H(+)/2e(-) approach over a wide range of pH from 5.8 to 8.0. The pH meter demonstrated remarkable selectivity toward pH detection against metal ions, amino acids, reactive oxygen species, and other biological species in the brain. Meanwhile, an inner reference, 6 (ferrocenyl)hexanethiol (FcHT), was selected as a built-in correction to avoid the environmental effect through coimmobilization with 1,2-NQ. In addition, three dimensional gold nanoleaves were electrodeposited onto the electrode surface to amplify the signal by ~4.0-fold and the measurement was achieved down to 0.07 pH. Finally, combined with the microelectrode technique, the microelectrochemical pH meter was directly implanted into brain regions including the striatum, hippocampus, and cortex and successfully applied in real-time monitoring of pH values in these regions of brain followed by global cerebral ischemia. The results demonstrated that pH values were estimated to 7.21 +/- 0.05, 7.13 +/- 0.09, and 7.27 +/- 0.06 in the striatum, hippocampus, and cortex in the rat brains, respectively, in normal conditions. However, pH decreased to 6.75 +/- 0.07 and 6.52 +/- 0.03 in the striatum and hippocampus, upon global cerebral ischemia, while a negligible pH change was obtained in the cortex. PMID- 26768310 TI - Focus on Immunology and Proteomics. PMID- 26768314 TI - Morcellation and myomas: Balancing decisions around minimally invasive treatments for fibroids. AB - Minimally invasive surgery (MIS) is increasingly being used to treat uterine fibroids because of the significant patient and societal benefits of these techniques over traditional laparotomy. Morcellation affords the removal of large fibroids in MIS but carries the risk of disseminating occult malignant tissue. The benefits of MIS for treating fibroids must be carefully weighed against its risks of morcellation. PMID- 26768315 TI - Robotic surgery for early stage cervical cancer: Evolution and current trends. AB - The management of early stage cervical cancer often includes surgery in the form of radical hysterectomy, radical trachelectomy, or radical parametrectomy. Surgical techniques have evolved to include minimal invasive approaches, and more recently, to include robotic assisted techniques. This review highlights the evolution of surgical management of early cervical cancer and specifically explores robotic assisted radical hysterectomy, radical trachelectomy, radical parametrectomy, and the role of neoadjuvant chemotherapy. PMID- 26768316 TI - Pulsatile Supraclavicular Skin Tumor. PMID- 26768317 TI - Dyshydrotic Eczema Secondary to Intravenous Immunoglobulin Infusion: A Report of 2 Cases. PMID- 26768321 TI - Confocal and dermoscopic features of basal cell carcinoma in Gorlin-Goltz syndrome: A case report. AB - Gorlin-Goltz (GS) syndrome is an autosomal dominant disease linked to a mutation in the PTCH gene. Major criteria include the onset of multiple basal cell carcinoma (BCC), keratocystic odontogenic tumours in the jaws and bifid ribs. Dermoscopy and reflectance confocal microscopy represent imaging tools that are able to increase the diagnostic accuracy of skin cancer in a totally noninvasive manner, without performing punch biopsies. Here we present a case of a young woman in whom the combined approach of dermoscopy and RCM led to the identification of multiple small inconspicuous lesions as BCC and thus to the diagnosis of GS syndrome. PMID- 26768311 TI - Viral infection causes a shift in the self peptide repertoire presented by human MHC class I molecules. AB - PURPOSE: MHC class I presentation of peptides allows T cells to survey the cytoplasmic protein milieu of host cells. During infection, presentation of self peptides is, in part, replaced by presentation of microbial peptides. However, little is known about the self peptides presented during infection, despite the fact that microbial infections alter host cell gene expression patterns and protein metabolism. EXPERIMENTAL DESIGN: The self peptide repertoire presented by HLA-A*01;01, HLA-A*02;01, HLA-B*07;02, HLA-B*35;01, and HLA-B*45;01 (where HLA is human leukocyte antigen) was determined by tandem MS before and after vaccinia virus infection. RESULTS: We observed a profound alteration in the self peptide repertoire with hundreds of self peptides uniquely presented after infection for which we have coined the term "self peptidome shift." The fraction of novel self peptides presented following infection varied for different HLA class I molecules. A large part (approximately 40%) of the self peptidome shift arose from peptides derived from type I interferon-inducible genes, consistent with cellular responses to viral infection. Interestingly, approximately 12% of self peptides presented after infection showed allelic variation when searched against approximately 300 human genomes. CONCLUSION AND CLINICAL RELEVANCE: Self peptidome shift in a clinical transplant setting could result in alloreactivity by presenting new self peptides in the context of infection-induced inflammation. PMID- 26768322 TI - Trigger factors in asthma and chronic obstructive pulmonary disease: a single centre cross-sectional survey. AB - INTRODUCTION: The presence of trigger factors may help to distinguish asthma from chronic obstructive pulmonary disease (COPD). Knowing and avoiding trigger factors for both asthma and COPD can facilitate the design of comprehensive management programmes that can aid disease control. This study aimed to describe the relative frequency and range of various trigger factors in asthma and COPD. METHODS: We conducted a telephone-based survey involving asthma and COPD patients on follow-up at a university hospital in Singapore. RESULTS: A total of 779 asthma patients and 129 COPD patients participated in this study. Among these patients, 93.8% of those with asthma and 42.6% of those with COPD had trigger factors (p < 0.001). The median number of trigger factors was greater among asthma patients than among those with COPD (3 vs. 0, p < 0.001). Trigger factors found to be significantly more prevalent among asthma patients compared to those with COPD include tobacco smoke, alcohol, upper respiratory tract infections, incense smoke, perfume, laughter, a dusty environment, air-conditioning, heavy rain, heavy traffic fumes, citrus fruits, gastro-oesophageal reflux, household pets, flowers/pollen, medications and psychological triggers. Trigger factors that were not previously described, such as bathing, fatigue, insufficient sleep, crowded places and overeating, were also reported. CONCLUSION: Trigger factors, although found in both groups of patients, were more common among asthma patients. Knowledge of these trigger factors may be useful in distinguishing between the two diseases and optimising disease management. PMID- 26768323 TI - A fourfold increase of oesophageal variceal bleeding in cirrhotic patients with a history of oesophageal variceal bleeding. AB - INTRODUCTION: Large, recent population-based data for evaluating the predictors of oesophageal variceal bleeding (OVB) among cirrhotic patients is still lacking. This study aimed to determine the cumulative incidence of OVB among cirrhotic patients and identify the predictors of OVB occurrence. METHODS: Patient information on 38,172 cirrhotic patients without a history of OVB, who were discharged between 1 January 2007 and 31 December 2007, was obtained from the Taiwan National Health Insurance Database for this study. All patients were followed up for three years. Death was the competing risk when calculating the cumulative incidences and hazard ratios (HRs) of OVB. RESULTS: OVB was present in 2,609 patients (OVB group) and absent in 35,563 patients (non-OVB group) at hospitalisation. During the three-year follow-up period, the cumulative incidence of OVB was 44.5% and 11.3% in the OVB and non-OVB group, respectively (p < 0.001). Modified Cox regression analysis showed that the HR of OVB history was 4.42 for OVB occurrence (95% confidence interval [CI] 4.13-4.74). Other predictors for OVB occurrence included hepatocellular carcinoma (HR 1.16, 95% CI 1.09-1.24), young age (HR 0.98, 95% CI 0.98-0.98), ascites (HR 1.46, 95% CI 1.37 1.56), alcohol-related disorders (HR 1.20, 95% CI 1.12-1.28), peptic ulcer bleeding (HR 1.26, 95% CI 1.13-1.41) and diabetes mellitus (HR 1.14, 95% CI 1.06 1.23). CONCLUSION: Cirrhotic patients have a fourfold increased risk of future OVB following the first incidence of OVB. PMID- 26768328 TI - Dual testing strategy in autism increases diagnostic yield: Chromosomal microarray and whole-exome sequencing combination may be best for children with multiple physical anomalies, study suggests. PMID- 26768329 TI - Genetic counselor licensure proponents call for more states to adopt licensing laws: Benefits of licensure extend to geneticists, counselors, and patients. PMID- 26768324 TI - Persistent alterations in colonic afferent innervation in a rat model of postinfectious gut dysfunction: Role for changes in peripheral neurotrophic factors. AB - BACKGROUND: Visceral hypersensitivity in the inflamed gut is related partly to the effects of peripheral neurotrophic factors (NTFs) on local afferent neurons. However, alterations in sensory afferents of distant areas remain unexplored. Using the Trichinella spiralis infection model, which causes a jejunitis, we investigated the remodeling of colonic afferents and the potential role of NTFs. METHODS: Rats were infected with T. spiralis. Inflammatory-like changes, mucosal mast cells (MMCs) dynamics, and expression of nerve growth factor and glial cell line-derived NTFs (glial cell-derived neurotrophic factor, artemin, and neurturin) were determined in the colon up to day 30 postinfection. Functional responses of colonic afferents were determined assessing changes in the expression of sensory-related markers in thoracolumbar (TL)/lumbosacral (LS) dorsal root ganglias (DRGs) following intracolonic capsaicin. KEY RESULTS: Trichinella spiralis induced an inflammatory-like response within the colon, partly resolved at day 30 postinfection, except for a persistent MMC infiltrate. While the jejunum of infected animals showed an up-regulation in the expression of NTFs, a transitory down-regulation was observed in the colon. Overall, T. spiralis effects on DRGs gene expression were restricted to a transient down regulation of TPRV1. Stimulation with intracolonic capsaicin induced a down regulation of TRPV1 levels in TL and LS DRGs, an effect enhanced in LS DRGs of infected animals, regardless the postinfection time considered. CONCLUSIONS & INFERENCES: During intestinal inflammation, spread morphological and functional alterations, including remodeling of visceral afferents, are observed outside the primary region affected by the insult. Similar mechanisms might be operating in states of widespread alterations of visceral sensitivity. PMID- 26768332 TI - "Publish or perish" is good for African research. PMID- 26768333 TI - Flying with the winds: differential migration strategies in relation to winds in moth and songbirds. AB - The gamma Y moth selects to migrate in stronger winds compared to songbirds, enabling fast transport to distant breeding sites, but a lower precision in orientation as the moth allows itself to be drifted by the winds. Photo: Ian Woiwod. In Focus: Chapman, J.R., Nilsson, C., Lim, K.S., Backman, J., Reynolds, D.R. & Alerstam, T. (2015) Adaptive strategies in nocturnally migrating insects and songbirds: contrasting responses to winds. Journal of Animal Ecology, In press Insects and songbirds regularly migrate long distances across continents and seas. During these nocturnal migrations, they are exposed to a fluid medium, the air, in which they transport themselves by flight at similar speeds as the winds may carry them. It is crucial for an animal to select the most favourable flight conditions relative to winds to minimize the distance flown on a given amount of fuel and to avoid hazardous situations. Chapman et al. (2015a) showed contrasting strategies in how moths initiate migration predominantly under tailwind conditions, allowing themselves to drift to a larger extent and gain ground speed as compared to nocturnal songbird migrants. The songbirds use more variable flight strategies in relation to winds, where they sometimes allow themselves to drift, and at other occasions compensate for wind drift. This study shows how insects and birds have differentially adapted to migration in relation to winds, which is strongly dependent on their own flight capability, with higher flexibility enabling fine-tuned responses to keep a time programme and reach a goal in songbirds compared to in insects. PMID- 26768331 TI - Screening of CD96 and ASXL1 in 11 patients with Opitz C or Bohring-Opitz syndromes. AB - Opitz C trigonocephaly (or Opitz C syndrome, OTCS) and Bohring-Opitz syndrome (BOS or C-like syndrome) are two rare genetic disorders with phenotypic overlap. The genetic causes of these diseases are not understood. However, two genes have been associated with OTCS or BOS with dominantly inherited de novo mutations. Whereas CD96 has been related to OTCS (one case) and to BOS (one case), ASXL1 has been related to BOS only (several cases). In this study we analyze CD96 and ASXL1 in a group of 11 affected individuals, including 2 sibs, 10 of them were diagnosed with OTCS, and one had a BOS phenotype. Exome sequences were available on six patients with OTCS and three parent pairs. Thus, we could analyze the CD96 and ASXL1 sequences in these patients bioinformatically. Sanger sequencing of all exons of CD96 and ASXL1 was carried out in the remaining patients. Detailed scrutiny of the sequences and assessment of variants allowed us to exclude putative pathogenic and private mutations in all but one of the patients. In this patient (with BOS) we identified a de novo mutation in ASXL1 (c.2100dupT). By nature and location within the gene, this mutation resembles those previously described in other BOS patients and we conclude that it may be responsible for the condition. Our results indicate that in 10 of 11, the disease (OTCS or BOS) cannot be explained by small changes in CD96 or ASXL1. However, the cohort is too small to make generalizations about the genetic etiology of these diseases. PMID- 26768334 TI - EDITORIAL: Stuck in motion? Reconnecting questions and tools in movement ecology. PMID- 26768335 TI - How to capture fish in a school? Effect of successive predator attacks on seabird feeding success. AB - Prey aggregations, such as fish schools, attract numerous predators. This typically leads to the formation of multispecific groups of predators. These aggregations can be seen both as a place of increased competition and as a place of possible facilitation between predators. Consequently, the functional role of such predator-prey aggregation is uncertain, and its effect on individual feeding success is virtually unknown. Using underwater film footage of different predators feeding on fish schools during the sardine run in South Africa, we directly measured the in situ feeding success of individual Cape gannets Morus capensis in different foraging situations. We determined the types of Cape gannet attacks (direct plunge dive or plunge dive followed by underwater pursuit) and we measured the occurrences and timing of attacks from the different species (mostly Cape gannets and long-beaked common dolphins Delphinus capensis). We also estimated the size of the targeted fish schools. These observations were complemented with a simulation model to evaluate the cumulative effect of successive predator attacks on the prey aggregation structure. The probability to capture a fish in one feeding attempt by Cape gannets averaged 0.28. It was lower when gannets engaged in underwater prey pursuit after the plunge compared to direct plunge (0.13 vs. 0.36). We found no effect of the number of prey on gannets' feeding success. However, the timing and frequency of attacks influenced strongly and positively the feeding success of individuals. The probability to capture a fish was the lowest (0.16) when no attack occurred in the few seconds (1-15 s) prior to a dive and the highest (~0.4, i.e. more than twice) when one or two attacks occurred during this time window. The simulation model showed that a prey aggregation disorganized just after an attack and that the maximum of disturbance was obtained a few seconds after the initiation of the successive attacks. Our study suggests that, in multispecies predator assemblages, the cumulative effect (through disorganization of school cohesiveness) of the multiple species attacking a prey aggregation may increase the feeding success of each individual. Therefore, facilitation between predators is likely to overcome competition in these multispecific assemblages. PMID- 26768337 TI - Introduction of subspecialty examinations by the European Board of Ophthalmology (EBO) in close collaboration with European Subspecialty Ophthalmological Societies: FEBO-SA. AB - The European Board of Ophthalmology (EBO) aims to establish common European standards in ophthalmology. The comprehensive EBO Diploma (EBOD) examination has been officially used since 1995 by an increasing number of European countries to assess the level of education in ophthalmology of their residents at the end of their training. The current comprehensive EBOD examination ensures a minimum standard of knowledge. We present an update on the EBO plans to establish a subspecialty advanced EBOD (AdEBOD) examination in order to award ophthalmologists who complete subspecialty training with formal recognition of their expertise. The purpose, structure and process of the AdEBOD examination are presented. PMID- 26768338 TI - Erratum to: Ethnoichthyology of the indigenous Truka people, Northeast Brazil. PMID- 26768339 TI - Structure-Based Virtual Screening for Defeating Drug Resistant Form of EGFR Protein. AB - Epidermal growth factor receptor (EGFR) is a tyrosine kinase with a key role in cell proliferation, death and differentiation. Mutations in EGFR, including substitution of Thr790 by methionine and Leu858 by arginine (T790M/L858R), lead to a lung cancer that is resistant against first generation inhibitors. In fact, second generation inhibitors were developed, but they proved to have had severe side effects because of the significant potency to suppress the wild type protein just as much. To resolve the problem, a step-by-step rational virtual screening was employed over almost sixty million compounds of PubChem Compound Database to filter out selective inhibitor(s) of T790M/L858R subtype. Consequently, the compound CID 133077 was observed, an active metabolite of Axitirome and also a cholesterol lowering prodrug. Selecting this compound can be explained by the oxamic acid part of molecule. Hence, administration of Axitirome or other compounds which contain oxamic acid is suggested in cases with EGFR T790M/L858R drug resistance. PMID- 26768340 TI - International Scientific Collaborations: A Key to Scientific Success. AB - " ...? Cross-cultural collaboration, when it works, is synergistic, and brings understanding between partners that neither is likely to be able to develop alone. There are people in the world that know something, but nobody knows everything. International collaborations in science bring together and capitalize on the dispersal of knowledge and resources across the globe, and the human desire to advance knowledge ...?" Read more in the Editorial by Joseph S. Francisco. PMID- 26768342 TI - Reactivity of Gold Complexes towards Elementary Organometallic Reactions. AB - For a while, the reactivity of gold complexes was largely dominated by their Lewis acid behavior. In contrast to the other transition metals, the elementary steps of organometallic chemistry-oxidative addition, reductive elimination, transmetallation, migratory insertion-have scarcely been studied in the case of gold or even remained unprecedented until recently. However, within the last few years, the ability of gold complexes to undergo these fundamental reactions has been unambiguously demonstrated, and the reactivity of gold complexes was shown to extend well beyond pi-activation. In this Review, the main achievements described in this area are presented in a historical context. Particular emphasis is set on mechanistic studies and structure determination of key intermediates. The electronic and structural parameters delineating the reactivity of gold complexes are discussed, as well as the remaining challenges. PMID- 26768344 TI - Editorial: is it time to share paediatric guideline development? PMID- 26768345 TI - Adverse effects after the use of JWH-210 - a case series from the EU Spice II plus project. AB - Since 2009, more than 140 different synthetic cannabinoids (SC) have been identified in herbal mixtures consumed as recreational drugs. Knowledge of the acute toxicity of each individual compound remains sparse. Here we present a retrospective observational case series of patients presenting to emergency departments with analytically confirmed intake of JWH-210 as the only SC detected in serum samples. Cases were selected from a poison centre database from March 2011 to June 2014. In total, 22 patients were included (aged 12-25 years, median 17.5; 18 males 4 female). JWH-210 was identified in the serum samples in concentrations ranging from 0.18 to 90 ng/mL. Tachycardia, nausea, somnolence, hypokalemia, hypertension, restlessness, and/or agitation were most frequently reported. Diplopia, seizures, syncope, and ECG changes such as T-wave inversion and bradycardia were also noted. Acute adverse effects of JWH-210 typically include central nervous system depression or cerebral seizures, but also signs of sympathomimetic toxicity. Nausea was reported in 80% and typically shows a sudden onset shortly after inhalation, suggesting a central nervous effect possibly mediated by CB1 receptors. Cardiovascular effects are reported in up to 80% of the patients and might not only include alterations in blood pressure and heart rate, but also changes in the electrocardiogram (ECG). JWH-210 as a representative of a strong CB1 receptor agonist confirms previous reports about adverse effects of SC, but shows a distinct quantitative pattern of symptoms, compared to several other SC. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26768346 TI - The Influence of Sugar-Sweetened Beverage Health Warning Labels on Parents' Choices. AB - BACKGROUND AND OBJECTIVES: US states have introduced bills requiring sugar sweetened beverages (SSBs) to display health warning labels. This study examined how such labels may influence parents and which labels are most impactful. METHODS: In this study, 2381 demographically and educationally diverse parents participated in an online survey. Parents were randomly assigned to 1 of 6 conditions: (1) no warning label (control); (2) calorie label; or (3-6) 1 of 4 text versions of a warning label (eg, Safety Warning: Drinking beverages with added sugar[s] contributes to obesity, diabetes, and tooth decay). Parents chose a beverage for their child in a vending machine choice task, rated perceptions of different beverages, and indicated interest in receiving beverage coupons. RESULTS: Regression analyses controlling for frequency of beverage purchases were used to compare the no warning label group, calorie label group, and all warning label groups combined. Significantly fewer parents chose an SSB for their child in the warning label condition (40%) versus the no label (60%) and calorie label conditions (53%). Parents in the warning label condition also chose significantly fewer SSB coupons, believed that SSBs were less healthy for their child, and were less likely to intend to purchase SSBs. All P values <.05 after correcting for multiple comparisons. There were no consistent differences among different versions of the warning labels. CONCLUSIONS: Health warning labels on SSBs improved parents' understanding of health harms associated with overconsumption of such beverages and may reduce parents' purchase of SSBs for their children. PMID- 26768351 TI - Nanofibers: Ratiometric Organic Fibers for Localized and Reversible Ion Sensing with Micrometer-Scale Spatial Resolution (Small 48/2015). AB - On page 6417, L. L. del Mercato, D. Pisignano, and co-workers report a new type of 3D nanostructured pH-sensing organic fiber with embedded ratiometric fluorescent capsules. Upon proton-induced switching, the fibers undergo optical changes that are recorded by fluorescence detectors and correlated to the analyte concentration. The developed electrospinning fabrication approach is facile and versatile and enables the creation of sensitive and highly robust pH-sensing 3D scaffolds for environmental monitoring and biomedical applications, including tissue engineering and wound healing. PMID- 26768347 TI - Adverse Experiences in Early Childhood and Kindergarten Outcomes. AB - OBJECTIVE: To examine associations between adverse childhood experiences (ACEs) in early childhood and teacher-reported academic and behavioral problems in kindergarten. METHODS: We conducted a secondary analysis of data from the Fragile Families and Child Wellbeing Study, a national urban birth cohort. Subjects with primary caregiver-reported information on ACE exposures ascertained at 5 years and teacher-reported outcomes at the end of the child's kindergarten year were included. Outcomes included teacher ratings of academic skills, emergent literacy skills, and behavior. We included 8 ACE exposures on the basis of the original Centers for Disease Control and Prevention Kaiser study and created an ACE score by summing individual adversities. We examined the associations between teacher reported academic and behavioral outcomes and ACE scores by using logistic regression. RESULTS: In the study sample, 1007 children were included. Fifty-five percent had experienced 1 ACE and 12% had experienced >= 3. Adjusting for potential confounders, experiencing >= 3 ACEs was associated with below-average language and literacy skills (adjusted odds ratio [AORs]: 1.8; 95% confidence interval [CI]: 1.1-2.9) and math skills (AOR: 1.8, 95% CI: 1.1-2.9), poor emergent literacy skills, attention problems (AOR: 3.5, 95% CI: 1.8-6.5), social problems (AOR: 2.7, 95% CI: 1.4-5.0), and aggression (AOR: 2.3, 95% CI: 1.2-4.6). CONCLUSIONS: In this study of urban children, experiencing ACEs in early childhood was associated with below-average, teacher-reported academic and literacy skills and behavior problems in kindergarten. These findings underscore the importance of integrated approaches that promote optimal development among vulnerable children. PMID- 26768353 TI - Bioorthogonal Click Chemistry-Based Synthetic Cell Glue. AB - Artificial methods of cell adhesion can be effective in building functional cell complexes in vitro, but methods for in vivo use are currently lacking. Here, a chemical cell glue based on bioorthogonal click chemistry with high stability and robustness is introduced. Tetrazine (Tz) and trans-cyclooctene (TCO) conjugated to the cell surface form covalent bonds between cells within 10 min in aqueous conditions. Glued, homogeneous, or heterogeneous cell pairs remain viable and stably attached in a microfluidic flow channel at a shear stress of 20 dyn cm(-2) . Upon intravenous injection of assembled Jurkat T cells into live mice, fluorescence microscopy shows the trafficking of cell pairs in circulation and their infiltration into lung tissues. These results demonstrate the promising potential of chemically glued cell pairs for various applications ranging from delivering therapeutic cells to studying cell-cell interactions in vivo. PMID- 26768357 TI - Detection and characterization of Pseudomonas syringae pv. actinidifoliorum in kiwifruit in Spain. AB - AIMS: Bacterial canker of kiwifruit caused by Pseudomonas syringae pv. actinidiae (Psa) is currently the major threat to its commercial production worldwide. In 2011, the most virulent type (Psa3) was detected for the first time in Northwest Spain, in the province of Pontevedra. In 2013 surveys, leaves and flower buds with mild symptoms were observed in Actinidia deliciosa 'Hayward' vines in an orchard at the province of A Coruna, suggesting the presence of P. syringae pv. actinidifoliorum (Psaf). METHODS AND RESULTS: Isolates obtained from such orchard were characterized by morphological, biochemical and physiological tests, fatty acids (FA) profile and molecular tests (PCR, BOX-PCR, duplex PCR, multiplex PCR, real-time PCR, PCR-C, phytotoxins, housekeeping and effector genes). Pathogenicity tests were also carried out on plants and fruits of A. deliciosa 'Hayward' and on different cultivated plants and fruits. Results demonstrated the presence of P. syringae pv. actinidifoliorum in Spain. CONCLUSIONS: The work provides new information on the pathovar P. syringae pv. actinidifoliorum, which has only been found previously in New Zealand, Australia and France. SIGNIFICANCE AND IMPACT OF STUDY: The results are relevant for taxonomy of isolates of P. syringae from kiwifruit, especially those of low virulence not belonging to pathovar actinidiae. PMID- 26768356 TI - Region-specific roles of the prelimbic cortex, the dorsal CA1, the ventral DG and ventral CA1 of the hippocampus in the fear return evoked by a sub-conditioning procedure in rats. AB - The return of learned fear is an important issue in anxiety disorder research since an analogous process may contribute to long-term fear maintenance or clinical relapse. A number of studies demonstrate that mPFC and hippocampus are important in the modulation of post-extinction re-expression of fear memory. However, the region-specific role of these structures in the fear return evoked by a sub-threshold conditioning (SC) is not known. In the present experiments, we first examined specific roles of the prelimbic cortex (PL), the dorsal hippocampus (DH, the dorsal CA1 area in particular), the ventral hippocampus (the ventral dentate gyrus (vDG) and the ventral CA1 area in particular) in this fear return process. Then we examined the role of connections between PL and vCA1 with this behavioral approach. Rats were subjected to five tone-shock pairings (1.0-mA shock) to induce conditioned fear (freezing), followed by three fear extinction sessions (25 tone-alone trials each session). After a post-test for extinction memory, some rats were retrained with the SC procedure to reinstate tone-evoked freezing. Rat groups were injected with low doses of the GABAA agonist muscimol to selectively inactivate PL, DH, vDG, or vCA1 120 min before the fear return test. A disconnection paradigm with ipsilateral or contralateral muscimol injection of the PL and the vCA1 was used to examine the role of this pathway in the fear return. We found that transient inactivation of these areas significantly impaired fear return (freezing): inactivation of the prelimbic cortex blocked SC-evoked fear return in particular but did not influence fear expression in general; inactivation of the DH area impaired fear return, but had no effect on the extinction retrieval process; both ventral DG and ventral CA1 are required for the return of extinguished fear whereas only ventral DG is required for the extinction retrieval. These findings suggest that PL, DH, vDG, and vCA1 all contribute to the fear return and connections between PL and vCA1 may be involved in the modulation of this process. PMID- 26768358 TI - Bridging the gap: What have we done and what more can we do to reduce the burden of avoidable death in people with psychotic illness? AB - Despite overwhelming evidence demonstrating a persisting gap in life expectancy between those with psychotic illness and the general population, there has been no widespread implementation of interventions to improve the physical wellbeing of people with psychotic illness. This article explores opportunities to 'Bridge the Gap' in life expectancy. We describe an Australian evidence-based intervention that has substantially improved the physical health of young people recently commenced on antipsychotic medication. Further epidemiological research, accompanied by cultural change within mental health services, is an essential precursor to the implementation of effective and sustainable lifestyle interventions. There are other relatively neglected areas of physical wellbeing for people with psychotic illness, such as screening and diagnosis of malignancies, which need more research and clinical attention. While there has been progress with intervention development and evaluation, translation of evidence-based short-term intervention studies into feasible and sustainable system-wide changes within routine mental health service settings remains a challenge. Developing an implementation framework to support such change is an urgent priority so as to bridge the persisting premature mortality in people living with psychotic illness. PMID- 26768359 TI - Small-molecule inhibitors of USP7 induce apoptosis through oxidative and endoplasmic reticulum stress in cancer cells. AB - USP7 is a deubiquitinating enzyme that involves the ubiquitin proteasome system (UPS) to maintain regulation of protein synthesis and degradation. The well-known substrate of USP7 is the Mdm2-p53 complex. In fact, several studies have reported that functional inhibition of USP7 induces cancer cell apoptosis through activation of p53. However, the contribution of oxidative or endoplasmic reticulum (ER) stress, which is commonly induced by inhibition of the UPS for USP7 inhibitor-mediated apoptosis in cancer cells, has not been investigated. In contrast to previous reports, we show that p53 is not critical during USP7 inhibitor-induced apoptosis in several cancer cells. Inhibition of deubiquitinating enzyme activities by USP7 inhibitors causes ER stress by accumulating polyubiquitinated proteins in cancer cells. Furthermore, we demonstrate that USP7 inhibitors increase intracellular reactive oxygen species and mainly cause cancer cell apoptosis. Taken together, our results reveal that oxidative and ER stress, rather than the Mdm2-p53 axis, mainly contributes to USP7 inhibitor-mediated apoptosis in cancer cells. PMID- 26768360 TI - Identification of genes for sulfolipid synthesis in primitive red alga Cyanidioschyzon merolae. AB - Sulfoquinovosyl diacylglycerol is one of the lipids that construct thylakoid membranes, and is distributed from cyanobacteria to plastids in plants including a red lineage. One of the most primitive red algae, Cyanidioschyzon melorae, similar to cyanobacteria and green plants, possesses homologs of the SQD1 and SQD2 genes that code for UDP-sulfoquinovose and sulfoquinovosyl diacylglycerol synthases, respectively, for the synthesis of sulfoquinovosyl diacylglycerol. We here revealed the structural properties of SQD1 and SQD2 homologs in C. melorae intrinsic to those of the authentic proteins, and verified their enzymatic functions through heterologous expression in cyanobacterial disruptants as to the corresponding genes. The results demonstrated that the system of sulfoquinovosyl diacylglycerol synthesis could have been conserved through evolution of cyanobacteria to plastids in a red lineage, which is compatible with the monophyletic origin of plastids. PMID- 26768361 TI - Crystal structure of YeaZ from Pseudomonas aeruginosa. AB - The Pseudomonas aeruginosa PA3685 locus encodes a conserved protein that shares 49% sequence identity with Escherichia coli YeaZ, which was recently reported as involved in the biosynthesis of threonylcarbamoyl adenosine (t(6)A), a universal modified tRNA nucleoside. Many YeaZ orthologues were reported as "essential for life" among various bacterial species, suggesting a critical role for both these proteins and for the t(6)A biosynthetic pathway. We provide here evidences that PA3685 protein (PaYeaZ) is essential. Additionally, we describe its purification, crystallization, and crystallographic structure. The crystal structure shows that PaYeaZ is composed of two domains one of which is the platform to form protein protein interaction involved either in homodimeric assembly or in the formation of the multiprotein complex required for the synthesis of t(6)A. These features make the PaYeaZ protein a potential target candidate for the design of novel inhibitors able to hinder the complex formation and expected to abolish the crucial activity of t(6)A synthesis. PMID- 26768362 TI - The 340-cavity in neuraminidase provides new opportunities for influenza drug development: A molecular dynamics simulation study. AB - Influenza neuraminidase (NA) is a pivotal target for viral infection control. However, the accumulating of mutations compromise the efficacy of NA inhibitors. Thus, it is critical to design new drugs targeted to different motifs of NA. Recently, a new motif called 340-cavity was discovered in NA subtypes close to the calcium binding site. The presence of calcium is known to influence NA activity and thermostability. Therefore, the 340-cavity is a putative ligand binding site for affecting the normal function of NA. In this study, we performed molecular dynamics simulations of different NA subtypes to explore the mechanism of 340-loop formation. Ligand-binding site prediction and fragment library screening were also carried out to provide evidence for the 340-cavity as a druggable pocket. We found that residues G342 and P/R344 in the 340-loop determine the size of the 340-cavity, and the calcium ion plays an important role in maintaining the conformation of the 340-loop through contacts with G345 and Q347. In addition, the 340-cavity is predicted to be a ligand-binding site by metaPocket, and a sequence analysis method is proposed to predict the existence of the 340-cavity. Our study shows that the 340-cavity is not an occasional or atypical domain in NA subtypes, and it has potential to function as a new hotspot for influenza drug binding. PMID- 26768363 TI - Transcriptional and posttranscriptional regulation of the tomato leaf mould disease resistance gene Cf-9. AB - Plant disease resistance (R) genes confer effector-triggered immunity (ETI) to pathogens carrying complementary effector/avirulence (Avr) genes. They are traditionally recognized to function at translational and/or posttranslational levels. In this study, however, transcriptional and posttranscriptional regulation of Cf-9, a tomato R gene conferring resistance to leaf mould fungal pathogen carrying Avr9, was demonstrated. Expression of the Cf-9 gene was 10.8 54.7 folds higher in the Cf-9/Avr9 tomato lines than in the Cf-9 lines depending on the seedling age, indicating that the Cf-9 gene expression was strongly induced by Avr9. Moreover, expression of the Cf-9 gene in the 5-day-old Cf-9/Avr9 seedlings at 33 degrees C was approximately 80 folds lower than that at 25 degrees C, and was enhanced by 23.4 folds at only 4 h post temperature shift from 33 degrees C to 25 degrees C, demonstrating that the Avr9-mediated induction of the Cf-9 gene expression is reversibly repressed by high temperature. Expression of the Cf-9 gene in the Cf-9 seedlings was similarly affected by temperature as in the Cf-9/Avr9 seedlings, implying that the genetic control of temperature sensitivity of the Cf-9 gene expression is epistasis to its Avr9-mediated induction. Additionally, a miRNA sly-miR6022, TGGAAGGGAGAATATCCAGGA, targeting the leucine-rich repeat (LRR) domain spanning LRR13-LRR14 of the Cf-9 gene transcript was predicted. Over-expression of this miRNA resulted in over 88% reduction of the Cf-9 gene transcripts in both Nicotiana benthamiana and tomato, and thus verifying the function of sly-miR6022 in degrading the Cf-9 gene transcripts. Collectively, our results reveal that the tomato R gene Cf-9 is strongly regulated at transcriptional level by pathogen Avr9 in a temperature sensitive manner and is also regulated at posttranscriptional level by a miRNA sly-miR6022. PMID- 26768364 TI - Core 2 beta-1, 6-N-acetylglucosaminyltransferase-1 expression in prostate biopsy specimen is an indicator of prostate cancer aggressiveness. AB - INTRODUCTION: To avoid over-treatment of early stage prostate cancer (PCa), predictive biomarkers for PCa aggressiveness which can be obtained during pre treatment evaluation are essential. Core 2 beta-1, 6-N-acetylglucosaminyl transferase-1 (GCNT1) is a key enzyme that forms core 2 branched O-glycans, the expression of which is associated with aggressive potential of prostate cancer. We examined whether GCNT1 expression in prostate biopsy specimen can predict cancer recurrence after radical prostatectomy for the patients with with PCa. We then investigated molecular background for aggressive malignant potential mediated by GCNT1 expression. METHODS: Paraffin-embedded PCa biopsy specimens were immunohisto-chemically tested for GCNT1 expression using an anti-GCNT1 monoclonal antibody. We also examined the role of GCNT1 in PCa progression using cell lines which express high or low levels of GCNT1. RESULTS: GCNT1 expression correlated with D' Amico's recurrence risk classification. The GCNT1-positive rate in organ confined PCa was significantly lower than that in PCa with extra prostatic extension. GCNT1-negative tumors were associated with significantly better prostate-specific antigen (PSA)-free survival compared with GCNT1-positive tumors. Multivariate analysis revealed that GCNT1 expression status was an independent risk factor for PSA recurrence after radical prostatectomy. Subsequent basic study revealed that GCNT1-over-expressing cells produced a significantly larger amount of growth factors when co-cultured with prostate stromal cells compared with GCNT1-knocked down cells and formed larger tumors. CONCLUSIONS: GCNT1 expression in prostate biopsy specimen is a significant and independent predictor of recurrence after radical prostatectomy, which can be used in pre-treatment decision making for the patient. Further validation study is necessary to establish clinical implication of GCNT1 in management of PCa. PMID- 26768365 TI - Nur77 inhibits oxLDL induced apoptosis of macrophages via the p38 MAPK signaling pathway. AB - The interaction between macrophages and oxLDL plays a crucial role in the initiation and progression of atherosclerosis. As a key initiator in a number of plaque promoting processes, oxLDL induces variable effects such as cell apoptosis or proliferation. Orphan nuclear receptor Nur77 is potently induced in macrophages by diverse stimuli, suggesting that it is of importance in vascular inflammation resulting in atherosclerosis, but whether Nur77 induction is detrimental or protective is unclear. In our study, we explore the role of Nur77 in the regulation of oxLDL-induced macrophage apoptosis and the signaling pathways that are involved. We found that oxLDL induced Nur77 expression in a dose and time dependent fashion, and cell viability was decreased in parallel. To determine whether Nur77 induction contributes to the loss of cell viability or is a protective mechanism, the effect of Nur77 overexpression was examined. Importantly, Nur77 overexpression inhibited the oxLDL-induced decrease of cell viability, inhibited the production of apoptotic bodies and restored DNA synthesis following oxLDL exposure. Furthermore, we found that Nur77 induction is mediated through the p38 MAPK signaling pathway. After pretreatment with SB203580, cell viability was decreased, the expression of CyclinA2 and PCNA was attenuated and the percentage of cell apoptosis was enhanced. Likewise, Nur77 overexpression increased the expression of the cell cycle genes PCNA and p21, and attenuated the increase in caspase-3. On the other hand, knockdown of Nur77 expression by specific siRNA resulted in the increased expression of caspase 3. The results demonstrate that Nur77 is induced by oxLDL via the p38 MAPK signaling pathway, which is involved in the regulation of cell survival. Nur77 enhanced cell survival via suppressing apoptosis, without affecting cell proliferation of activated macrophages, which may be beneficial in patients with atherosclerosis. PMID- 26768366 TI - Peroxisome proliferator-activated receptor beta/delta (PPARbeta/delta) activates promyogenic signaling pathways, thereby promoting myoblast differentiation. AB - Peroxisome proliferator-activated receptor beta/delta (PPARbeta/delta) regulates postnatal myogenesis by alleviating myostatin activity, but the molecular mechanisms by which it regulates myogenesis are not fully understood. In this study, we investigate molecular mechanisms of PPARbeta/delta in myoblast differentiation. C2C12 myoblasts treated with a PPARbeta/delta agonist, GW0742 exhibit enhanced myotube formation and muscle-specific gene expression. GW0742 treatment dramatically activates promyogenic kinases, p38MAPK and Akt, in a dose dependent manner. GW0742-stimulated myoblast differentiation is mediated by p38MAPK and Akt, since it failed to restore myoblast differentiation repressed by inhibition of p38MAPK and Akt. In addition, GW0742 treatment enhances MyoD reporter activities. Consistently, overexpression of PPARbeta/delta enhances myoblast differentiation accompanied by elevated activation of p38MAPK and Akt. Collectively, these results suggest that PPARbeta/delta enhances myoblast differentiation through activation of promyogenic signaling pathways. PMID- 26768368 TI - Trichostatin A enhances estrogen receptor-alpha repression in MCF-7 breast cancer cells under hypoxia. AB - Estrogen receptor (ER) is a crucial determinant of resistance to endocrine therapy, which may change during the progression of breast cancer. We previously showed that hypoxia induces ESR1 gene repression and ERalpha protein degradation via proteasome-mediated pathway in breast cancer cells. HDAC plays important roles in the regulation of histone and non-histone protein post-translational modification. HDAC inhibitors can induce epigenetic changes and have therapeutic potential for targeting various cancers. Trichostatin A exerts potent antitumor activities against breast cancer cells in vitro and in vivo. In this report, we show that TSA augments ESR1 gene repression at the transcriptional level and downregulates ERalpha protein expression under hypoxic conditions through a proteasome-mediated pathway. TSA-induced estrogen response element-driven reporter activity in the absence of estrogen was synergistically enhanced under hypoxia; however, TSA inhibited cell proliferation under both normoxia and hypoxia. Our data show that the hypoxia-induced repression of ESR1 and degradation of ERalpha are enhanced by concomitant treatment with TSA. These findings expand our understanding of hormone responsiveness in the tumor microenvironment; however, additional in-depth studies are required to elucidate the detailed mechanisms of TSA-induced ERalpha regulation under hypoxia. PMID- 26768367 TI - The epigenetic regulation of HIF-1alpha by SIRT1 in MPP(+) treated SH-SY5Y cells. AB - Both silent information regulator 1 (SIRT1) and hypoxia inducible factor 1 (HIF 1) have been found to play important roles in the pathophysiology of Parkinson's disease (PD). However, their mechanisms and their relationship still require further study. In the present study, we focused on the change and relationship of SIRT1 and HIF-1alpha in PD. PD cell models were established by using methyl-4 phenylpyridinium (MPP(+)), which induced inhibition of cell proliferation, cell cycle arrest and apoptosis. We found that the expression of HIF-1alpha and its target genes VEGFA and LDHA increased and that SIRT1 expression was inhibited in MPP(+) treated cells. With further analysis, we found that the acetylation of H3K14 combined with the HIF-1alpha promoter was dramatically increased in cells treated with MPP(+), which resulted in the transcriptional activation of HIF 1alpha. Moreover, the acetylation of H3K14 and the expression of HIF-1alpha increased when SIRT1 was knocked down, suggesting that SIRT1 was involved in the epigenetic regulation of HIF-1alpha. At last, phenformin, another mitochondrial complex1 inhibitor, was used to testify that the increased HIF-1a was not due to off target effects of MPP(+). Therefore, our results support a link between PD and SIRT1/HIF-1alpha signaling, which may serve as a clue for understanding PD. PMID- 26768369 TI - Comparison between liposomal formulations of amphotericin B. AB - Given the clinical success of commercial amphotericin B lipid products, investigators have begun making generic formulations of liposomal amphotericin B. Generic medicines are an attractive approach to help decrease the cost and accessibility to healthcare, provided that appropriate studies are performed to ensure bioequivalence with the parent product. This is of particular concern for liposomal drugs such as amphotericin B where liposomes are used as a carrier system to reduce the toxicity of the active agent. A favorable therapeutic profile for this form of the drug has to include the proper chemical composition along with strictly controlled manufacturing processes. Studies have shown that a comparison of liposomal amphotericin B products with different or the same chemical compositions, using different methods of production, will vary in size, and have significantly dissimilar in vitro and in vivo toxicities along with reduced efficacy. These results underscore the importance of establishing appropriate bioequivalence testing for liposome products to ensure uniformity of their therapeutic index. PMID- 26768370 TI - cyp51A-based mechanism of azole resistance in Aspergillus fumigatus: Illustration by a new 3D Structural Model of Aspergillus fumigatus CYP51A protein. AB - Mutations of CYP51A protein (Cytochrome P450 14-alpha Sterol demethylase) play a central role in the azole resistance of Aspergillus fumigatus The available structural models of CYP51A protein ofA. fumigatus are built based on that of Homo sapiens and that of Mycobacterium tuberculosis, of which the amino acid homology is only 38% and 29% compared with CYP51A protein ofA. fumigatus, respectively. In the present study, we constructed a new 3D structural model ofA. fumigatus CYP51A protein based on a recently resolved crystal structure of the homologous protein in the fungus S. cerevisiae, which shares 50% amino acid homology with A. fumigatus CYP51A protein. Three azole molecules, itraconazole, voriconazole, and posaconazole, were docked to the wild-type and the mutant A. fumigatus CYP51A protein models, respectively, to illustrate the impact of cyp51A mutations to azole-resistance. We found the mutations that occurred at L98, M220, and Y431 positions would decrease the binding affinity of azoles to the CYP51A protein and therefore would reduce their inhibitory effects. Additionally, the mutations of L98 and G432 would reduce the stability of the protein, which might lead to conformational change of its binding pocket and eventually the resistance to azoles. PMID- 26768371 TI - In vitro activity of Caspofungin combined with Fluconazole on mixed Candida albicans and Candida glabrata biofilm. AB - The objective of this study was to evaluate the antifungal effect of caspofungin (CAS) combined with fluconazole (FLU) on the biofilm biomass and cultivable viability and microstructure of Candida albicans and Candida glabrata mixed biofilm in vitro.Biofilms were formed in a 96-well microtiter plate for crystal violet assay and colony forming unit (CFU) method and grown on plastic coverslip disks for scanning electron microscopy. MIC50 of CAS and FLU against single Candida spp.and mixed Candida spp.biofilms were evaluated using crystal violet assay. Additional,C. albicans and C. glabrata mixed biofilms were incubated with subinhibitory CAS concentration plus FLU and their percentages of Candida biofilm reduction were calculated. We found that percentages of biofilm reduction were significantly decreased when CAS at 0.25MIC and FLU (0.25 or 0.5MIC) were combined (P< .05) but not different when CAS at 0.5 MIC combined with FLU at 0.25 or 0.5MIC, compared to CAS treatment alone. Structural analyses revealed that CAS/FLU combination-treated biofilms showed less hyphae and blastospores with some aberrant cells compared to control group. Although it was evident that a greater CFU of Candida glabrata were demonstrated in every group, the total viable cells derived from CAS/FLU combination-treated biofilms at any ratio were not significantly different from positive control. Overall, CAS/FLU combinations appeared to affect the quantity and cell architecture, but number of viable cell, of Candida albicans and Candida glabrata mixed biofilm. This antifungal effect was CAS concentration dependent. PMID- 26768373 TI - In vitro and ex vivo infection models help assess the molecular aspects of the interaction of Trichophyton rubrum with the host milieu. AB - Dermatophytes are fungal pathogens that cause cutaneous infections such as onychomycosis and athlete's foot in both healthy and immunocompromised patients.Trichophyton rubrum is the most prevalent dermatophyte causing human nail and skin infections worldwide, and because of its anthropophilic nature, animal infection models are limited. The purpose of this work was to compare the expression profile of T. rubrum genes encoding putative virulence factors during growth in ex vivo and in vitro infection models. The efficiency of the ex vivo skin infection model was confirmed by scanning electron microscopy (SEM), which showed that the conidia had produced hyphae that penetrated into the epidermis. Quantitative RT-PCR (qRT-PCR) analysis showed that the expression of some genes is modulated in response to the infection model used, as compared to that observed in cells grown in glucose-containing media. We concluded that ex vivo infection models help assess the molecular aspects of the interaction of T. rubrum with the host milieu, and thus provide insights into the modulation of genes during infection. PMID- 26768372 TI - Reproducibility of CSF quantitative culture methods for estimating rate of clearance in cryptococcal meningitis. AB - Quantitative cerebrospinal fluid (CSF) cultures provide a measure of disease severity in cryptococcal meningitis. The fungal clearance rate by quantitative cultures has become a primary endpoint for phase II clinical trials. This study determined the inter-assay accuracy of three different quantitative culture methodologies. Among 91 participants with meningitis symptoms in Kampala, Uganda, during August-November 2013, 305 CSF samples were prospectively collected from patients at multiple time points during treatment. Samples were simultaneously cultured by three methods: (1) St. George's 100 mcl input volume of CSF with five 1:10 serial dilutions, (2) AIDS Clinical Trials Group (ACTG) method using 1000, 100, 10 mcl input volumes, and two 1:100 dilutions with 100 and 10 mcl input volume per dilution on seven agar plates; and (3) 10 mcl calibrated loop of undiluted and 1:100 diluted CSF (loop). Quantitative culture values did not statistically differ between St. George-ACTG methods (P= .09) but did for St. George-10 mcl loop (P< .001). Repeated measures pairwise correlation between any of the methods was high (r>=0.88). For detecting sterility, the ACTG-method had the highest negative predictive value of 97% (91% St. George, 60% loop), but the ACTG-method had occasional (~10%) difficulties in quantification due to colony clumping. For CSF clearance rate, St. George-ACTG methods did not differ overall (mean -0.05 +/- 0.07 log10CFU/ml/day;P= .14) on a group level; however, individual-level clearance varied. The St. George and ACTG quantitative CSF culture methods produced comparable but not identical results. Quantitative cultures can inform treatment management strategies. PMID- 26768374 TI - Paracoccidioides brasiliensis interacts with dermal dendritic cells and keratinocytes in human skin and oral mucosa lesions. AB - Paracoccidioidomycosis (PCM) is a systemic disease caused by the fungus Paracoccidioides brasiliensis and Paracoccidioides lutzii. In PCM the skin and oral mucosa are often affected. Dendritic cells and keratinocytes of the integument play a role in innate and adaptive immune response against pathogens, due to their function as antigen presenting cells. Aiming to verify the interaction of P. brasiliensis with these cell populations, we studied 52 skin and 47 oral mucosa samples taken from patients with proven diagnosis of PCM. The biopsies were subjected to immunohistochemical and/or immunofluorescence staining with anti-factor XIIIa (marker of dermal dendrocytes), anti-CD207 (marker of mature Langerhans cells), anti-pan cytokeratins (AE1-AE3) and anti-P. brasiliensis antibodies. Analyses with confocal laser microscopy were also performed for better visualization of the interaction between keratinocytes and the fungi. In sum, 42% of oral mucosa samples displayed yeast forms in Factor XIIIa dermal dendrocytes cytoplasm. Langerhans cells in skin and oral mucosa samples did not show yeast cells in their cytoplasm. In sum, 54% of skin and 60% of mucosal samples displayed yeast cells in the cytoplasm of keratinocytes. The parasitism of keratinocytes may represent a possible mechanism of evasion of the fungus to local immune mechanisms. Factor XIIIa dendrocytes and keratinocytes may be acting as antigen-presenting cells to fulfill the probably impaired function of Langerhans cells in skin and oral mucosa of human PCM. PMID- 26768375 TI - Immunomodulatory effect of mesenchymal stem cells on the immune response of macrophages stimulated by Aspergillus fumigatus conidia. AB - Mesenchymal stem cells (MSCs) are known to exert potent immunosuppression and anti-inflammatory effects. There is growing interest in their use for immunotherapy for controlling inflammation as well as acute organ injury. However, there are few reports regarding MSC's immunomodulatory effects in the settings of fungal infection. In this study, we attempted to examine the immunomodulatory effects of MSCs in response to Aspergillus fumigatus We measured the cytokine response of murine MSCs on the immune response of murine macrophages (J774A.1 cells) evoked by A. fumigatus conidia. In addition, we evaluated the effect of granulocyte-macrophage colony-stimulating factor (GM-CSF) on the MSC related cytokine response and fungal growth. As a results, after conidia stimulation, tumor necrosis factor (TNF)-alpha was down-regulated and interleukin (IL)-10 was up-regulated in MSC-treated J774A.1 cells when compared to J774A.1 cells alone. In addition, fungal growth was reduced in MSC-treated J774A.1 cells when compared to J774A.1 cells, which recovered by GM-CSF. However, the effect of MSCs on the cytokine response was not reversed by GM-CSF. NF-kappaB translocation decreased in MSC-treated J774A.1 cells compared to J774A.1 cells alone. In conclusion, MSCs demonstrate immunomodulatory properties in both aspects of cytokines and fungal growth. The anti-inflammatory effect of MSCs with regard to cytokine response might be associated with decreased NF-kappaB translocation, and is not reversed by GM-CSF. PMID- 26768382 TI - Older Women Veterans in the Women's Health Initiative. PMID- 26768383 TI - Improving Our Understanding of Health Issues in Older Women Veterans. PMID- 26768384 TI - Differences in Active and Passive Smoking Exposures and Lung Cancer Incidence Between Veterans and Non-Veterans in the Women's Health Initiative. AB - INTRODUCTION: Women Veterans may have higher rates of both active and passive tobacco exposure than their civilian counterparts, thereby increasing their risk for lung cancer. PURPOSE OF THE STUDY: To compare differences in active and passive smoking exposure and lung cancer incidence among women Veterans and non Veterans using prospective data from the Women's Health Initiative (WHI). DESIGN AND METHODS: We used data from the WHI, which collected longitudinal demographic, clinical, and laboratory data on 161,808 postmenopausal women. We employed linear and multinomial regression and generalized linear models to compare active and passive smoking exposure between Veterans and non-Veterans and Cox proportional hazards models to estimate differences in lung cancer incidence rates. RESULTS: After adjustment, Veterans had 2.54 additional pack years of smoking compared with non-Veterans (95% confidence interval [CI] 1.68, 3.40). Veterans also had a 1% increase in risk of any passive smoking exposure (95% CI 1.00, 1.02) and a 9% increase in risk of any workplace exposure (95% CI 1.07, 1.11) compared with non Veterans. After adjustment for age and smoking exposures, Veterans did not have a higher risk of lung cancer compared with non-Veterans (relative risk = 1.06 95% CI 0.86, 1.30). IMPLICATIONS: Women Veterans had higher rates of tobacco use and exposure to passive smoking, which were associated with a higher risk for lung cancer compared with non-Veterans. Clinicians who care for Veterans need to be aware that older women Veterans have more exposures to risk factors for lung cancer. PMID- 26768385 TI - Association Between Chronic Conditions and Physical Function Among Veteran and Non-Veteran Women With Diabetes. AB - PURPOSE OF THE STUDY: To compare the number of chronic conditions among a list of 12 and their association with physical function among postmenopausal non-Veteran and Veteran women with diabetes. DESIGN AND METHODS: Among women with diabetes from the Women's Health Initiative, we compared the average number of chronic conditions between non-Veterans and Veterans and the association between total number of chronic conditions on subsequent RAND-36 physical function. To examine associations between each condition and subsequent physical function, we compared women with diabetes plus one chronic condition to women with diabetes alone using linear regression in separate models for each condition and for non-Veterans and Veterans. RESULTS: Both non-Veterans (N = 23,542) and Veterans (N = 618) with diabetes had a median of 3 chronic conditions. Decreases in physical function for each additional condition were larger among Veterans than non-Veterans (-6.3 vs. 4.1 points). Decreases in physical function among women with diabetes plus one chronic condition were greater than that reported for diabetes alone for all combinations and were more pronounced among Veterans (non-Veterans: -11.1 to 24.2, Veterans: -16.6 to -40.4 points). Hip fracture, peripheral artery disease, cerebrovascular disease, and coronary disease in combination with diabetes were associated with the greatest decreases in physical function. IMPLICATIONS: Chronic conditions were common among postmenopausal women with diabetes and were associated with large declines in physical function, particularly among Veterans. Interventions to prevent and reduce the impact of these conditions and facilitate coordination of care among women with diabetes may help them maintain physical function. PMID- 26768386 TI - Military Generation and Its Relationship to Mortality in Women Veterans in the Women's Health Initiative. AB - PURPOSE OF THE STUDY: Women's military roles, exposures, and associated health outcomes have changed over time. However, mortality risk-within military generations or compared with non-Veteran women-has not been assessed. Using data from the Women's Health Initiative (WHI), we examined all-cause and cause specific mortality by Veteran status and military generation among older women. DESIGN AND METHODS: WHI participants (3,719 Veterans; 141,802 non-Veterans), followed for a mean of 15.2 years, were categorized into pre-Vietnam or Vietnam/after generations based on their birth cohort. We used cox proportional hazards models to examine the association between Veteran status and mortality by generation. RESULTS: After adjusting for sociodemographic characteristics and WHI study arm, all-cause mortality hazard rate ratios (HRs) for Veterans relative to non-Veterans were 1.16 (95% CI: 1.09-1.23) for pre-Vietnam and 1.16 (95% CI: 0.99 1.36) for Vietnam/after generations. With additional adjustment for health behaviors and risk factors, this excess mortality rate persisted for pre-Vietnam but attenuated for Vietnam/after generations. After further adjustment for medical morbidities, across both generations, Veterans and non-Veterans had similar all-cause mortality rates. Relative to non-Veterans, adjusting for sociodemographics and WHI study arm, pre-Vietnam generation Veterans had higher cancer, cardiovascular, and trauma-related morality rates; Vietnam/after generation Veterans had the highest trauma-related mortality rates (HR = 2.93, 1.64-5.23). IMPLICATIONS: Veterans' higher all-cause mortality rates were limited to the pre-Vietnam generation, consistent with diminution of the healthy soldier effect over the life course. Mechanisms underlying Vietnam/after generation Veteran trauma-related mortality should be elucidated. Efforts to modify salient health risk behaviors specific to each military generation are needed. PMID- 26768387 TI - Alcohol Consumption Levels and All-Cause Mortality Among Women Veterans and Non Veterans Enrolled in the Women's Health Initiative. AB - PURPOSE: To address research gaps regarding women Veterans' alcohol consumption and mortality risk as compared to non-Veterans, the current study evaluated whether alcohol consumption amounts differed between women Veterans and non Veterans, whether Veterans and non-Veterans within alcohol consumption groups differed on all-cause mortality, and whether Veteran status modified the association between alcohol consumption and all-cause mortality. DESIGN AND METHODS: Six alcohol consumption groups were created using baseline data from the Women's Health Initiative Program (N = 145,521): lifelong abstainers, former drinkers, less than 1 drink/week (infrequent drinkers), 1-7 drinks/week (moderate drinkers), 8-14 drinks/week (moderately heavy drinkers), and 15 or more drinks/week (heavy drinkers). The proportions of Veteran and non-Veteran women within each alcohol consumption category were compared. Mortality rates within each alcohol consumption category were compared by Veteran status. Cox proportional hazard models, including a multiplicative interaction term for Veteran status, were fit to estimate adjusted mortality hazard (rate) ratios for each alcohol consumption category relative to a reference group of either lifelong abstainers or moderate drinkers. RESULTS: Women Veterans were less likely to be lifelong abstainers than non-Veterans. Women Veterans who were former or moderate drinkers had higher age-adjusted mortality rates than did non Veterans within these alcohol consumption categories. In the fully adjusted multivariate models, Veteran status did not modify the association between alcohol consumption category and mortality with either lifelong abstainers or moderate drinkers as referents. IMPLICATIONS: The results suggest that healthcare providers may counsel Veteran and non-Veteran women in similar ways regarding safe and less safe levels of alcohol consumption. PMID- 26768388 TI - Aging Well Among Women Veterans Compared With Non-Veterans in the Women's Health Initiative. AB - PURPOSE OF THE STUDY: To examine whether Veteran status influences (a) women's survival to age 80 years without disease and disability and (b) indicators of successful, effective, and optimal aging at ages 80 years and older. DESIGN AND METHODS: The Women's Health Initiative (WHI) enrolled 161,808 postmenopausal women aged 50-79 years from 1993 to 1998. We compared successful aging indicators collected in 2011-2012 via mailed questionnaire among 33,565 women (921 Veterans) who reached the age of 80 years and older, according to Veteran status. A second analysis focused on women with intact mobility at baseline who could have reached age 80 years by December 2013. Multinominal logistic models examined Veteran status in relation to survival to age 80 years without major disease or mobility disability versus having prevalent or incident disease, having mobility disability, or dying prior to age 80 years. RESULTS: Women Veterans aged 80 years and older reported significantly lower perceived health, physical function, life satisfaction, social support, quality of life, and purpose in life scale scores compared with non-Veterans. The largest difference was in physical function scores (53.0 for Veterans vs 59.5 for non-Veterans; p < .001). Women Veterans were significantly more likely to die prior to age 80 years than non-Veteran WHI participants (multivariate adjusted odds ratio = 1.20; 95% confidence interval, 1.04-1.38). In both Veteran and non-Veteran women, healthy survival was associated with not smoking, higher physical activity, healthy body weight, and fewer depressive symptoms. IMPLICATIONS: Intervening upon smoking, low physical activity, obesity, and depressive symptoms has potential to improve chances for healthy survival in older women including Veterans. PMID- 26768389 TI - Mortality in Postmenopausal Women by Sexual Orientation and Veteran Status. AB - PURPOSE OF THE STUDY: To examine differences in all-cause and cause-specific mortality by sexual orientation and Veteran status among older women. DESIGN AND METHODS: Data were from the Women's Health Initiative, with demographic characteristics, psychosocial factors, and health behaviors assessed at baseline (1993-1998) and mortality status from all available data sources through 2014. Women with baseline information on lifetime sexual behavior and Veteran status were included in the analyses (N = 137,639; 1.4% sexual minority, 2.5% Veteran). The four comparison groups included sexual minority Veterans, sexual minority non Veterans, heterosexual Veterans, and heterosexual non-Veterans. Cox proportional hazard models were used to estimate mortality risk adjusted for demographic, psychosocial, and health variables. RESULTS: Sexual minority women had greater all-cause mortality risk than heterosexual women regardless of Veteran status (hazard ratio [HR] = 1.20, 95% confidence interval [CI]: 1.07-1.36) and women Veterans had greater all-cause mortality risk than non-Veterans regardless of sexual orientation (HR = 1.14, 95% CI: 1.06-1.22), but the interaction between sexual orientation and Veteran status was not significant. Sexual minority women were also at greater risk than heterosexual women for cancer-specific mortality, with effects stronger among Veterans compared to non-Veterans (sexual minority * Veteran HR = 1.70, 95% CI: 1.01-2.85). IMPLICATIONS: Postmenopausal sexual minority women in the United States, regardless of Veteran status, may be at higher risk for earlier death compared to heterosexuals. Sexual minority women Veterans may have higher risk of cancer-specific mortality compared to their heterosexual counterparts. Examining social determinants of longevity may be an important step to understanding and reducing these disparities. PMID- 26768390 TI - Trajectories in Physical Activity and Sedentary Time Among Women Veterans in the Women's Health Initiative. AB - PURPOSE OF THE STUDY: Trajectories of physical activity (PA) and sedentary time (ST) after military separation are likely important determinants of women's health outcomes later in life, because low PA and high ST are known contributors to premature mortality risk. Our objective was to compare longitudinal trajectories of recreational PA and ST between Veteran and non-Veteran postmenopausal women from the Women's Health Initiative (WHI). DESIGN AND METHODS: Women Veteran (n = 3,719) and non-Veteran (n = 141,800) WHI participants were included. Self-reported participation in recreational PA, converted to metabolic equivalent (MET)-hours/week, was prospectively assessed over 8 years. Self-reported ST, defined as hours/day sitting or lying down, was collected at baseline and at Years 3 and 6. Generalized estimating equations were used to compare trajectories of PA and ST between Veterans and non-Veterans, adjusted for demographics and lifestyle behaviors. RESULTS: Veterans had higher baseline PA than non-Veterans (13.2 vs 12.5 MET-hours/week, p = .03). PA declined for both groups, with a steeper decline among Veterans (change/visit year -0.19 vs -0.02 MET-hours/week; interaction p < .001). At baseline, Veterans and non-Veterans had similar levels of ST (107.2 vs 105.9 hours/week, p = 0.42). Over time, ST remained stable among Veterans but declined slightly among non-Veterans (change/visit year -0.19 vs -0.49 hours/week; interaction p = .01). IMPLICATIONS: The less favorable longitudinal trajectories of PA and ST we observed for women Veterans may contribute to worse health among these individuals later in life. Understanding barriers to enhancing PA and reducing ST in women Veterans could lead to more effective approaches to intervening on these health behaviors. PMID- 26768392 TI - Who Are the Women Veterans in the Women's Health Initiative? PMID- 26768391 TI - Sleep Disturbance, Diabetes, and Cardiovascular Disease in Postmenopausal Veteran Women. AB - PURPOSE OF THE STUDY: To compare the prevalence and cardiometabolic health impact of sleep disturbance among postmenopausal Veteran and non-Veteran participants in the Women's Health Initiative (WHI). DESIGN AND METHODS: The prevalence of five categories of sleep disturbance--medication/alcohol use for sleep; risk for insomnia; risk for sleep disordered breathing [SDB]; risk for comorbid insomnia and SDB (insomnia + SDB); and aberrant sleep duration [SLD]--was compared in 3,707 Veterans and 141,354 non-Veterans using logistic or multinomial regression. Cox proportional hazards models were used to evaluate the association of sleep disturbance and incident cardiovascular disease (CVD) and Type 2 diabetes in Veterans and non-Veterans. RESULTS: Women Veterans were more likely to have high risk for insomnia + SDB relative to non-Veteran participants. However, prevalence of other forms of sleep disturbance was similar across groups. Baseline sleep disturbance was not differentially associated with cardiometabolic health outcomes in Veteran versus non-Veteran women. Risks for SDB and insomnia + SDB were both linked to heightened risk of CVD and diabetes; SLD was consistently linked with greater risk of CVD and diabetes in non-Veterans but less strongly and consistently in Veterans. IMPLICATIONS: Efforts to identify and treat sleep disturbances in postmenopausal women are needed and may positively contribute to the attenuation of cardiometabolic morbidity risk. Increased awareness of women Veterans' vulnerability to postmenopausal insomnia + SDB may be particularly important for health care providers who treat this population. PMID- 26768393 TI - Hysterectomy and Bilateral Salpingo-Oophorectomy: Variations by History of Military Service and Birth Cohort. AB - INTRODUCTION: Little is known about hysterectomy and bilateral salpingo oophorectomy (BSO), which are associated with both health risks and benefits, among women Veterans. PURPOSE OF THE STUDY: To compare the prevalence of hysterectomy with or without BSO, and early hysterectomy, between postmenopausal Veterans and non-Veterans. DESIGN AND METHODS: We used baseline data from the Women's Health Initiative Clinical Trial and Observational Study. Multinomial logistic regression models examined differences in the prevalence of hysterectomy (neither hysterectomy nor BSO, hysterectomy without BSO, and hysterectomy with BSO) between Veterans and non-Veterans. Generalized linear models were used to determine whether early hysterectomy (before age 40) differed between Veterans and non-Veterans. Analyses were stratified by birth cohort (<65, >=65 years at enrollment). RESULTS: The unadjusted prevalence of hysterectomy without BSO was similar among Veterans and non-Veterans in both birth cohorts (<65: 22% vs 21%; >=65: 22% vs 21%). The unadjusted prevalence of hysterectomy with BSO was equivalent among Veterans and non-Veterans in the >65 cohort (21%), but higher among Veterans in the <65 cohort (22% vs 19%). In adjusted analyses, although no differences were observed in the >65 cohort, Veterans in the <65 cohort had higher odds of hysterectomy without BSO (odds ratio [OR] 1.18, 95% confidence interval [CI] 1.03, 1.36) and with BSO (OR 1.26, 95% CI 1.10, 1.45), as well as elevated risk of early hysterectomy (relative risk 1.32, 95% CI 1.19, 1.47), compared with non-Veterans. IMPLICATIONS: Aging women Veterans may have higher prevalence of hysterectomy and BSO than non-Veterans. This information contributes to understanding the health needs and risks of women Veterans and can inform clinical practice and policy for this population. PMID- 26768396 TI - Air blockage at coronary anastomosis detected by intraoperative epicardial ultrasonography. PMID- 26768394 TI - Fracture Rates and Bone Density Among Postmenopausal Veteran and Non-Veteran Women From the Women's Health Initiative. AB - PURPOSE OF THE STUDY: Postmenopausal osteoporosis can impact quality-of-life even prefracture. To determine whether osteoporosis should be a greater concern in women Veterans versus non-Veterans, we compared fracture rates and bone mineral density (BMD) for Veterans and non-Veterans using Women's Health Initiative data. DESIGN AND METHODS: In this cohort study, participants were women aged 50-79 years. Outcomes were hip, central body, and limb fractures occurring during up to 19 years of follow-up and hip, spine, and whole body BMD collected three times over a 6-year period in a participant subsample. Covariates comprised risk factors for fracture, including fall history and other components of the World Health Organization Fracture Risk Assessment Tool (FRAX). Cox Proportional Hazards models were used to examine fracture rates for Veterans compared with non Veterans. RESULTS: Of 161,808 women, 145,521 self-identified as Veteran (n = 3,719) or non-Veteran (n = 141,802). Baseline FRAX scores showed that Veterans had higher 10-year probabilities for any major fracture (13.3 vs 10.2; p < .01) and hip fracture (4.1 vs 2.2; p < .01) compared with non-Veterans. The age adjusted rate of hip fracture per 1,000 person-years for Veterans was 3.3 versus 2.4 for non-Veterans (p < .01). After adjustment, the hazards ratio for hip fracture was 1.24 (95% confidence interval 1.03-1.49) for Veterans versus non Veterans. Hazards ratios at other anatomic sites did not differ by Veteran status. Mean BMD at baseline and at Years 3 and 6 also did not differ by Veteran status at any site. IMPLICATIONS: Women Veterans had an increased hip fracture rate not explained by differences in well-recognized fracture risk factors. PMID- 26768397 TI - Indications and results of systemic to pulmonary shunts: results from a national database. AB - OBJECTIVES: The systemic-to-pulmonary shunt (SPS) remains an important palliative therapy in many congenital heart defects. Unlike other surgical treatments, the mortality after shunt operations has risen. We used an audit dataset to investigate potential reasons for this change and to report national results. METHODS: A total of 1993 patients classified in 13 diagnoses underwent an SPS procedure between 2000 and 2013. Indication trends by era and also results before repair or next stage are reported. A dynamic hazard model with competing risks and modulated renewal was used to determine predictors of outcomes. RESULTS: The usage of SPS in Tetralogy of Fallot (ToF) has significantly decreased in the last decade, with cases of single ventricle (SV) and pulmonary atresia (PA) with septal communication increasing (P < 0.001 for trends). This is correlated with an increase of early mortality from 5.1% in the first half of the decade to 9.8% in the latter (P = 0.007 for trend). At 1.5 years, 13.9% of patients have died, 17.8% had a shunt reintervention and 68.3% of patients are alive and reintervention-free. Low weight, PA-intact septum, SV and central shunt type are among the factors associated with increased mortality, whereas PA-ventricular septal defect, corrected transposition, isomerism, central shunt and low weight are among those associated with increased reintervention, also having a dynamic effect on the relative risk when compared with ToF patients. Shunt reinterventions are not associated with worse outcomes when adjusted by other covariates, but they do have higher 30-day mortality if occurring earlier than 30 days from the index (P < 0.001). Patients operated in later years were found to have significantly lower survival at a distance from index. CONCLUSIONS: The observed historical rise in mortality for shunt operations relates to complex factors including changing practice for repair of ToF and for univentricular palliation. PA and SV patients are the groups of patients at the highest risk of death. Small size, shunt type and underlying anatomical defect are the main determinants of outcomes. Trends in indication and mortality seem to indicate that more severely ill patients benefit from shunting, but with an increase in mortality. PMID- 26768398 TI - Efficacy of buccal fat pad in the surgical management of oral submucous fibrosis: a prospective study. AB - PURPOSE: Various surgical treatment modalities have been advocated in the surgical management of oral submucous fibrosis with variable results. This prospective study evaluates the efficacy of buccal fat pad in the surgical treatment of oral submucous fibrosis. PATIENTS AND METHOD: In the present study, 20 patients were treated for oral submucous fibrosis with interincisal mouth opening less than 16 mm. Surgical procedure included fibrotomy, all third molar extractions, and coronoidotomy or coronoidectomy followed by reconstruction of fibrotomy defect with buccal pad of fat. Postoperatively, patients were prescribed nutritional and antioxidant supplements along with vigorous mouth opening exercise for 6 months. Regular follow-up was carried out for 2 years. RESULTS: Excellent increase in the interincisal mouth opening was noticed relieving trismus. Patient's ability of masticate and tolerance to regular food was increased significantly. Buccal fat pad underwent rapid epithelization within a period of 5-7 weeks. CONCLUSION: Buccal fat pad can be used effectively in the surgical management of oral submucous fibrosis with good functional and esthetic outcome, with only drawback of supple lobulated fat, which requires delicate handling and its limitation to reach anteriorly beyond the canine region. PMID- 26768395 TI - Association of Pain With Physical Function, Depressive Symptoms, Fatigue, and Sleep Quality Among Veteran and non-Veteran Postmenopausal Women. AB - PURPOSE OF STUDY: To characterize the prevalence and longitudinal effects of pain in older Veteran and non-Veteran women. DESIGN AND METHODS: Data on 144,956 participants in the Women's Health Initiative were analyzed. At baseline, Veteran status, pain severity, and pain interference with activity were assessed. Outcomes of physical function, depressive symptoms, fatigue, and sleep quality were reported at baseline by all study participants and longitudinally on two follow-up occasions (3 years and 13-18 years after baseline) in the observational study participants (n = 87,336). RESULTS: At baseline, a total of 3,687 (2.5%) had a history of military service and 22,813 (15.8%) reported that pain limited their activity level moderately to extremely during the past 4 weeks. Prevalence of pain interference did not differ in Veterans and non-Veterans (16.8% and 15.7%, respectively; p= .09). At baseline, women with moderate-to-extreme pain interference had substantially worse physical function and greater symptoms of depression, fatigue, and insomnia than those with less pain (p < .001 for all comparisons), adjusting for several social, behavioral, and health related factors. There were no significant military service by pain interference interactions for any of the outcomes (p > .2), indicating that the effect of pain interference on outcomes at baseline did not vary between Veterans and non Veterans. Moderate-to-extreme pain interference was associated with a greater rate of decline in physical function over time (p < .001) and higher incidence of limited physical functioning (p < .001), but these effects did not vary by Veteran status. Similar results were observed with pain severity as the exposure variable. IMPLICATIONS: As the Veteran population ages and the number of women exposed to combat operations grows, there will be an increased need for health care services that address not only pain severity and interference but also other disabling comorbid symptoms. PMID- 26768400 TI - Inwardly rectifying potassium channel 4.1 expression in post-traumatic syringomyelia. AB - Post-traumatic syringomyelia (PTS) is a serious neurological disorder characterized by fluid filled cavities that develop in the spinal cord. PTS is thought to be caused by an imbalance between fluid inflow and outflow in the spinal cord, but the underlying mechanisms are unknown. The ion channel Kir4.1 plays an important role in the uptake of K(+) ions from the extracellular space and release of K(+) ions into the microvasculature, generating an osmotic gradient that drives water movement. Changes in Kir4.1 expression may contribute to disturbances in K(+) homeostasis and subsequently fluid imbalance. Here we investigated whether changes in Kir4.1 protein expression occur in PTS. Western blotting and immunohistochemistry were used to evaluate Kir4.1 and glial fibrillary acidic protein (GFAP) expression in a rodent model of PTS at 3 days, 1, 6 or 12 weeks post-surgery. In Western blotting experiments, Kir4.1 expression increased 1 week post-surgery at the level of the cavity. Immunohistochemical analysis examined changes in the spinal parenchyma directly in contact with the syrinx cavity. In these experiments, there was a significant decrease in Kir4.1 expression in PTS animals compared to controls at 3 days and 6 weeks post surgery, while an up-regulation of GFAP in PTS animals was observed at 1 and 12 weeks. This suggests that while overall Kir4.1 expression is unchanged at these time-points, there are many astrocytes surrounding the syrinx cavity that are not expressing Kir4.1. The results demonstrate a disturbance in the removal of K(+) ions in tissue surrounding a post-traumatic syrinx cavity. It is possible this contributes to water accumulation in the injured spinal cord leading to syrinx formation or exacerbation of the underlying pathology. PMID- 26768399 TI - Functional congruity in local auditory cortical microcircuits. AB - Functional columns of primary auditory cortex (AI) are arranged in layers, each composed of highly connected fine-scale networks. The basic response properties and interactions within these local subnetworks have only begun to be assessed. We examined the functional diversity of neurons within the laminar microarchitecture of cat AI to determine the relationship of spectrotemporal processing between neighboring neurons. Neuronal activity was recorded across the cortical layers while presenting a dynamically modulated broadband noise. Spectrotemporal receptive fields (STRFs) and their nonlinear input/output functions (nonlinearities) were constructed for each neuron and compared for pairs of neurons simultaneously recorded at the same contact site. Properties of these local neuron pairs showed greater similarity than non-paired neurons within the same column for all considered parameters including firing rate, envelope phase precision, preferred spectral and temporal modulation frequency, as well as for the threshold and transition of the response nonlinearity. This higher functional similarity of paired versus non-paired neurons was most apparent in infragranular neuron pairs, and less for local supragranular and granular pairs. The functional similarity of local paired neurons for firing rate, best temporal modulation frequency and two nonlinearity aspects was laminar dependent, with infragranular local pair-wise differences larger than for granular or supragranular layers. Synchronous spiking events between pairs of neurons revealed that simultaneous 'Bicellular' spikes, in addition to carrying higher stimulus information than non-synchronized spikes, encoded faster modulation frequencies. Bicellular functional differences to the best matched of the paired neurons could be substantial. Bicellular nonlinearities showed that synchronous spikes act to transmit stimulus information with higher fidelity and precision than non-synchronous spikes of the individual neurons, thus, likely enhancing stimulus feature selectivity in their target neurons. Overall, the well correlated and temporally precise processing within local subnetworks of cat AI showed laminar-dependent functional diversity in spectrotemporal processing, despite high intra-columnar congruity in frequency preference. PMID- 26768402 TI - An integrated hybrid microfluidic device for oviposition-based chemical screening of adult Drosophila melanogaster. AB - Chemical screening using Drosophila melanogaster (the fruit fly) is vital in drug discovery, agricultural, and toxicological applications. Oviposition (egg laying) on chemically-doped agar plates is an important read-out metric used to quantitatively assess the biological fitness and behavioral responses of Drosophila. Current oviposition-based chemical screening studies are inaccurate, labor-intensive, time-consuming, and inflexible due to the manual chemical doping of agar. In this paper, we have developed a novel hybrid agar polydimethylsiloxane (PDMS) microfluidic device for single- and multi concentration chemical dosing and on-chip oviposition screening of free-flying adult stage Drosophila. To achieve this, we have devised a novel technique to integrate agar with PDMS channels using ice as a sacrificial layer. Subsequently, we have conducted single-chemical toxicity and multiple choice chemical preference assays on adult Drosophila melanogaster using zinc and acetic acid at various concentrations. Our device has enabled us to 1) demonstrate that Drosophila is capable of sensing the concentration of different chemicals on a PDMS-agar microfluidic device, which plays significant roles in determining oviposition site selection and 2) investigate whether oviposition preference differs between single- and multi-concentration chemical environments. This device may be used to study fundamental and applied biological questions in Drosophila and other egg laying insects. It can also be extended in design to develop sophisticated and dynamic chemical dosing and high-throughput screening platforms in the future that are not easily achievable with the existing oviposition screening techniques. PMID- 26768404 TI - Charge-based separation of proteins and peptides by electrically induced dynamic pH profiles. AB - A new method for generating complex, dynamic pH profiles in an ampholyte-free separation channel is presented together with the theory behind its operation. The pH is modulated by an array of proton and hydroxide ion injectors placed along the separation channel. The ions generated in-situ by electrically driven water splitting across a bipolar membrane are injected to the channel in the presence of a longitudinal electric field, leading to the formation of a multi step pH profile. Real-time control over the pH profile along the channel facilitates new dynamic separation strategies as well as steering and harvesting of focused molecules, which are both impossible with conventional separation methods. These freedoms are particularly attractive for Lab-on-a-Chip applications. The pH step-like profile alleviates one of the main hurdles of conventional isoelectric separation methods, namely, the slowing down of focused molecules as they approach their focusing spot. As a result, separation is completed within minutes for both peptides and proteins, even with low applied electric fields. We demonstrate protein and peptide separation within minutes, and resolution of DeltapI=0.2. Novel separation strategies based on spatio temporal pH control are demonstrated as well. PMID- 26768401 TI - Utility and validity of DISC1 mouse models in biological psychiatry. AB - We have seen an era of explosive progress in translating neurobiology into etiological understanding of mental disorders for the past 10-15 years. The discovery of Disrupted-in-schizophrenia 1 (DISC1) gene was one of the major driving forces that have contributed to the progress. The finding that DISC1 plays crucial roles in neurodevelopment and synapse regulation clearly underscored the utility and validity of DISC1-related biology in advancing our understanding of pathophysiological processes underlying psychiatric conditions. Despite recent genetic studies that failed to identify DISC1 as a risk gene for sporadic cases of schizophrenia, DISC1 mutant mice, coupled with various environmental stressors, have proven successful in satisfying face validity as models of a wide range of human psychiatric conditions. Investigating mental disorders using these models is expected to further contribute to the circuit level understanding of the pathological mechanisms, as well as to the development of novel therapeutic strategies in the future. PMID- 26768405 TI - From analytical methods to large scale chiral supercritical fluid chromatography using chlorinated chiral stationary phases. AB - While traditional non-chlorinated Cellulose- and Amylose-derivatized phases have been used successfully in supercritical fluid chromatography (SFC) to resolve a broad variety of chiral compounds, some chiral pharmaceutical compounds are not well resolved on these traditional chiral stationary phases (CSP) due to the lack of chiral selectivity. Since there are no universal CSP to resolve all chiral compounds, chlorinated CSP can be complementary to the non-chlorinated CSP. Chlorinated CSP such as 4-Chloro-3-methylphenyl-carbamatecellulose (Lux-Cellulose 4), 3-Chloro-4-methylphenyl-carbamatecellulose (Lux-Cellulose-2), 5-Chloro-2 methylphenyl-carbamateamylose (Lux-Amylose-2) and immobilized 3,5-dichlorophenyl carbamatecellulose (Chiralpak IC) have provided a range of chiral recognition mechanisms which have allowed the authors to successfully achieve chiral SFC resolution on several structurally diverse compounds, which are not well resolved in the non-chlorinated CSP. In addition, chlorinated Lux-Cellulose-4, Chiralpak IC and Lux-Amylose-2 have enabled us to utilize non-alcohol solvents as sample diluents and as co-solvents to significantly improve compound solubility and selectivity. This article will discuss the challenges associated with several SFC applications on both coated and immobilized chlorinated CSP to deliver high quality drug candidates in large quantity. The use of dichloromethane in both sample preparation and as co-solvent in CO2 to increase sample solubility will be presented in preparative example #2 and #3. PMID- 26768406 TI - The term 'non-radiographic axial spondyloarthritis' is much more important to classify than to diagnose patients with axial spondyloarthritis. AB - The term axial spondyloarthritis (axSpA) now is used frequently to describe patients with predominantly axial symptoms who fit into the spectrum of a well recognised rheumatic disease that continues to be known as ankylosing spondylitis (AS). The 2009 Assessment of SpondyloArthritis international Society (ASAS) classification criteria, developed to identify patients with early or atypical disease which could not be classified by the 1984 modified New York (mNY) criteria for AS, have led to a differentiation between non-radiographic axial spondyloarthritis (nr-axSpA) and radiographic axSpA, which is largely synonymous with AS. The main reason to distinguish between these ends of the spectrum of axSpA was that tumor necrosis factor (TNF) inhibitors (TNFi) approved for AS could obtain additional labelling for nr-axSpA and be used to treat all patients manifesting clinical features of axSpA. These two terms are distinguished by the degree of 'radiographic sacroiliitis' assessed by conventional radiography, according to the 1984 mNY criteria for AS. Since this differentiation has been shown to be not very reliable, we argue that the terms nr-axSpA and AS should only be used for classification of patients with axSpA and not as separate diagnoses. Therefore, we propose that only the term axSpA be used to diagnose patients, unless there is a meaningful medical reason to differentiate nr-axSpA from AS. The available data justify performing randomised controlled trials designed to obtain regulatory approval for therapeutic agents in patients across the entire spectrum of axSpA. PMID- 26768407 TI - Bone loss, pain and inflammation: three faces of ACPA in RA pathogenesis. PMID- 26768408 TI - Defining active sacroiliitis on MRI for classification of axial spondyloarthritis: update by the ASAS MRI working group. AB - OBJECTIVES: To review and update the existing definition of a positive MRI for classification of axial spondyloarthritis (SpA). METHODS: The Assessment in SpondyloArthritis International Society (ASAS) MRI working group conducted a consensus exercise to review the definition of a positive MRI for inclusion in the ASAS classification criteria of axial SpA. Existing definitions and new data relevant to the MRI diagnosis and classification of sacroiliitis and spondylitis in axial SpA, published since the ASAS definition first appeared in print in 2009, were reviewed and discussed. The precise wording of the existing definition was examined in detail and the data and a draft proposal were presented to and voted on by the ASAS membership. RESULTS: The clear presence of bone marrow oedema on MRI in subchondral bone is still considered to be the defining observation that determines the presence of active sacroiliitis. Structural damage lesions seen on MRI may contribute to a decision by the observer that inflammatory lesions are genuinely due to SpA but are not required to meet the definition. The existing definition was clarified adding guidelines and images to assist in the application of the definition. CONCLUSION: The definition of a positive MRI for classification of axial SpA should continue to primarily depend on the imaging features of 'active sacroiliitis' until more data are available regarding MRI features of structural damage in the sacroiliac joint and MRI features in the spine and their utility when used for classification purposes. PMID- 26768409 TI - Complications in thyroid surgery. Harmonic Scalpel, Harmonic Focus versus Conventional Hemostasis: A meta-analysis. AB - BACKGROUND: To evaluate the incidence of postoperative complications, hemostatic effects and safety of Total Thyroidectomy (TT) performed using the Harmonic Scalpel (HS), the Harmonic Focus (HF) or Conventional Hemostasis (CH). METHODS: The meta-analysis was performed according to PRISMA guidelines. A literature search was conducted from 2003 to 2014 and stringent criteria were required for inclusion. Thirteen studies concerning an overall population of 1458 compared HS versus CH, whilst 8 studies with 1667 patients compared HF versus CH. RESULTS: There was a significant reduction of operative time (Mean Difference [MD] = 25.49 min.; 95% CI -32.43 to -18.55), intraoperative blood loss (MD = -30.49 mL; 95% CI -53.01 to -7.97), postoperative drainage volume (MD = -12.90 mL; 95% CI 22.83 to -2.98) and postoperative pain (MD = -0.87; 95% CI -1.27 to -0.46) in patients underwent TT with HS. Regarding HF group, a significant reduction of operative time (MD = -25.99 min., 95% CI -34.56 to -17.41), length of hospital stay (MD = -0.57; 95% CI -0.97 to -0.17), transient hypocalcemia (OR = 0.56; 95% CI 0.39 to 0.81) and postoperative pain (MD = -1.33 days; 95% CI -2.49 to -0.17) resulted. CONCLUSIONS: HS TT can be a safe, useful and fast alternative to conventional TT. The newer HF can reduce the rate of hypocalcemia. Future RCTs of larger patient cohorts with more detailed data of postoperative complications, cost-effectiveness and cosmetic results, randomization procedures, intention-to treat analyses and blinding of outcome assessors are needed to draw more meaningful conclusions. PMID- 26768411 TI - Successful second bone marrow transplantation in a Wiskott-Aldrich syndrome patient with systemic vasculitis. PMID- 26768410 TI - Systemic inflammation and higher perception of dyspnea mimicking asthma in obese subjects. AB - BACKGROUND: There are a variable number of obese subjects with self-reported diagnosis of asthma but without current or previous evidence of airflow limitation, bronchial reversibility, or airway hyperresponsiveness (misdiagnosed asthma). However, the mechanisms of asthma-like symptoms in obesity remain unclear. OBJECTIVES: We sought to evaluate the perception of dyspnea during bronchial challenge and exercise testing in obese patients with asthma and misdiagnosed asthma compared with obese control subjects to identify the mechanisms of asthma-like symptoms in obesity. METHODS: In a cross-sectional study we included obese subjects with asthma (n = 25), misdiagnosed asthma (n = 23), and no asthma or respiratory symptoms (n = 27). Spirometry, lung volumes, exhaled nitric oxide levels, and systemic biomarker levels were measured. Dyspnea scores during adenosine bronchial challenge and incremental exercise testing were obtained. RESULTS: During bronchial challenge, patients with asthma or misdiagnosed asthma reached a higher Borg-FEV1 slope than control subjects. Moreover, maximum dyspnea and the Borg-oxygen uptake (V'O2) slope were significantly greater during exercise in subjects with asthma or misdiagnosed asthma than in control subjects. The maximum dyspnea achieved during bronchial challenge correlated with IL-1beta levels, whereas peak respiratory frequency, ventilatory equivalent for CO2, and IL-6 and IL-1beta levels were independent predictors of the Borg-V'O2 slope during exercise (r(2) = 0.853, P < .001). CONCLUSIONS: A false diagnosis of asthma (misdiagnosed asthma) in obese subjects is attributable to an increased perception of dyspnea, which, during exercise, is mainly associated with systemic inflammation and excessive ventilation for metabolic demands. PMID- 26768412 TI - Sensitivity and specificity of Hymenoptera allergen components depend on the diagnostic assay employed. PMID- 26768414 TI - 7alpha-alkylation and 7,7-bis-alkylation of 20-hydroxyecdysone with propargyl bromide in a lithium-ammonia solution and catalytic reductive spirocyclization of 7,7-bis(2-propyn-1-yl)-14-deoxy-Delta(8(14))-20-hydroxyecdysone. AB - 7alpha-Alkylation and 7,7-bis-alkylation of 20-hydroxyecdysone with propargyl bromide in a lithium-ammonia solution resulted in the formation of 7alpha-(2 propyn-1-yl)- and 7,7-bis(2-propyn-1-yl)-14-deoxy-Delta(8(14))-20-hydroxyecdysone in 92% and 75% yield respectively. Upon catalytic hydrogenation (10% Pd-C) of 7,7 bis(2-propyn-1-yl) derivative spirocyclization occurs by geminal 2-propyn-1-yl groups. PMID- 26768415 TI - Novel, major 2alpha- and 2beta-hydroxy bile alcohols and bile acids in the bile of Arapaima gigas, a large South American river fish. AB - Bile alcohols and bile acids from gallbladder bile of the Arapaima gigas, a large South American freshwater fish, were isolated by reversed-phase high-performance liquid chromatography. The structures of the major isolated compounds were determined by electrospray-tandem mass spectrometry and nuclear magnetic resonance using (1)H- and (13)C-NMR spectra. The novel bile salts identified were six variants of 2-hydroxy bile acids and bile alcohols in the 5alpha- and 5beta series, with 29% of all compounds having hydroxylation at C-2. Three C27 bile alcohols were present (as ester sulfates): (24xi,25xi)-5alpha-cholestan 2alpha,3alpha,7alpha,12alpha,24,26-hexol; (25xi)-5beta-cholestan 2beta,3alpha,7alpha,12alpha,26,27-hexol, and (25xi)-5alpha-cholestan 2alpha,3alpha,7alpha,12alpha,26,27-hexol. A single C27 bile acid was identified: (25xi)-2alpha,3alpha,7alpha,12alpha-tetrahydroxy-5alpha-cholestan-26-oic acid, present as its taurine conjugate. Two novel C24 bile acids were identified: the 2alpha-hydroxy derivative of allochenodeoxycholic acid and the 2beta-hydroxy derivative of cholic acid, both occurring as taurine conjugates. These studies extend previous work in establishing the natural occurrence of novel 2alpha- and 2beta-hydroxy-C24 and C27 bile acids as well as C27 bile alcohols in both the normal (5beta) as well as the (5alpha) "allo" A/B-ring juncture. The bile salt profile of A. gigas appears to be unique among vertebrates. PMID- 26768417 TI - Received sensitivity: adapting Ainsworth's scale to capture sensitivity in a multiple-caregiver context. AB - A network of multiple caregivers contributing to the care of an infant is the norm in many non-Western cultural contexts. Current observational measures of caregiver sensitive responsiveness to infant signals focus on single caregivers, failing to capture the total experience of the infant when it comes to the sensitive responsiveness received from multiple sources. The current paper aims to introduce the construct of received sensitivity that captures the sensitivity that an infant experiences from multiple sources in cultural contexts where simultaneous multiple caregiving is common. The paper further presents an adaptation of Ainsworth's Sensitivity versus Insensitivity observation scale to allow for the assessment of sensitivity as received by the infant regardless of who is providing the sensitive responses to its signals. The potential usefulness of the Received Sensitivity scale is illustrated by two case studies of infants from an Agta forager community in the Philippines where infants are routinely taken care of by multiple caregivers. The case studies show that the infants' total experience of being responded to sensitively cannot be simply derived from the sum of individual caregiver sensitivity scores, demonstrating the potential added value of the new Received Sensitivity observation measure. PMID- 26768413 TI - Regulation of gene expression by 17beta-estradiol in the arcuate nucleus of the mouse through ERE-dependent and ERE-independent mechanisms. AB - 17beta-Estradiol (E2) modulates gene expression in the hypothalamic arcuate nucleus (ARC) to control homeostatic functions. In the ARC, estrogen receptor (ER) alpha is highly expressed and is an important contributor to E2's actions, controlling gene expression through estrogen response element (ERE)-dependent and -independent mechanisms. The objective of this study was to determine if known E2 regulated genes are regulated through these mechanisms. The selected genes have been shown to regulate homeostasis and have been separated into three subsections: channels, receptors, and neuropeptides. To determine if ERE dependent or ERE-independent mechanisms regulate gene expression, two transgenic mouse models, an ERalpha knock-out (ERKO) and an ERalpha knock-in/knock-out (KIKO), which lacks a functional ERE binding domain, were used in addition to their wild-type littermates. Females of all genotypes were ovariectomized and injected with oil or estradiol benzoate (E2B). Our results suggest that E2B regulates multiple genes through these mechanisms. Of note, Cacna1g and Kcnmb1 channel expression was increased by E2B in WT females only, suggesting an ERE dependent regulation. Furthermore, the NKB receptor, Tac3r, was suppressed by E2B in WT and KIKO females but not ERKO females, suggesting that ERalpha-dependent, ERE-independent signaling is necessary for Tac3r regulation. The adrenergic receptor Adra1b was suppressed by E2B in all genotypes indicating that ERalpha is not the primary receptor for E2B's actions. The neuropeptide Tac2 was suppressed by E2B through ERE-dependent mechanisms. These results indicate that E2B activates both ERalpha-dependent and independent signaling in the ARC through ERE dependent and ERE-independent mechanisms to control gene expression. PMID- 26768418 TI - The natural history of twin-twin transfusion syndrome stratified by Quintero stage. AB - OBJECTIVE: To describe the natural history of expectantly managed twin-twin transfusion syndrome (TTTS) specific to disease stage. METHODS: This was a retrospective study of monochorionic diamniotic pregnancies diagnosed with TTTS and delivered between 1997 and 2013. Staging was based on Quintero's criteria, with sonogram images reviewed to confirm findings specific to stage. Progression and outcomes were evaluated in pregnancies that did not receive any form of therapy. RESULTS: Thirty-eight pregnancies were diagnosed with TTTS and delivered at our institution, representing 1.6 per 10 000 births. Twenty were expectantly managed, of which 50% were stage I at presentation. Progression occurred in 45% of pregnancies, including 50% initially diagnosed with stage I TTTS. Seventy percent of pregnancies experienced survival of at least one twin, with no stillbirths or neonatal deaths if TTTS resolved. Pregnancies in which TTTS was either stable or improved had higher overall survival, compared with pregnancies that experienced progression, 86% versus 22%, p < 0.001, as well as more frequent survival of one or both twins, 91% versus 44%, p = 0.02. CONCLUSIONS: Among expectantly managed pregnancies with TTTS, most had early disease at diagnosis. Although 45% of cases progressed, which conferred poor prognosis, the majority experienced disease stabilization or improvement. PMID- 26768419 TI - Exposure to airborne particulate matter during pregnancy is associated with preterm birth: a population-based cohort study. AB - BACKGROUND: Test the hypothesis that exposure to fine particulate matter in the air (PM2.5) is associated with increased risk of preterm birth (PTB). METHODS: Geo-spatial population-based cohort study using live birth records from Ohio (2007-2010) linked to average daily measures of PM2.5, recorded by 57 EPA network monitoring stations across the state. Geographic coordinates of the home residence for births were linked to the nearest monitoring station using ArcGIS. Association between PTB and high PM2.5 levels (above the EPA annual standard of 15 MUg/m(3)) was estimated using GEE, with adjustment for age, race, education, parity, insurance, tobacco, birth season and year, and infant gender. An exchangeable correlation matrix for the monitor stations was used in the models. Analyses were limited to non-anomalous singleton births at 20-42weeks with no known chromosome abnormality occurring within 10 km of a monitor station. RESULTS: The frequency of PTB was 8.5 % in the study cohort of 224,921 singleton live births. High PM2.5 exposure (>EPA recommended maximum) occurred frequently during the study period, with 24,662 women (11 %) having high exposure in all three trimesters. Pregnancies with high PM2.5 exposure through pregnancy had increased PTB risk even after adjustment for coexisting risk factors, adjOR 1.19 (95 % CI 1.09-1.30). Assessed per trimester, high 3(rd) trimester PM2.5 exposure resulted in the highest PTB risk, adjOR 1.28 (95 % CI 1.20-1.37). CONCLUSIONS: Exposure to high levels of particulate air pollution, PM2.5, in pregnancy is associated with a 19 % increased risk of PTB; with greatest risk with high 3(rd) trimester exposure. Although the risk increase associated with high PM2.5 levels is modest, the potential impact on overall PTB rates is robust as all pregnant women are potentially at risk. This exposure may in part contribute to the higher preterm birth rates in Ohio compared to other states in the US, especially in urban areas. PMID- 26768420 TI - The lack of clinical value of peritoneal washing cytology in high risk patients undergoing risk-reducing salpingo-oophorectomy: a retrospective study and review. AB - BACKGROUND: To assess the clinical value of peritoneal washing cytology (PWC) in women with BRCA1 or BRCA2 mutations and women from a family with hereditary breast and/or ovarian cancer (HBOC) undergoing risk-reducing salpingo oophorectomy (RRSO) in detecting primary peritoneal cancer (PPC) or occult ovarian/fallopian tube cancer. METHODS: A retrospective study of patients with known BRCA1 or BRCA2 mutation or HBOC who underwent RRSO at the Erasmus Medical Centre, Rotterdam, The Netherlands between January 2000-2014. Patients with an elevated risk of malignancy prior to the procedure were excluded from primary analysis (elevated CA-125, an ovarian mass, abdominal pain or another gynecological malignancy). A review of the literature was conducted. RESULTS: Of the 471 patients who underwent RRSO, a total of 267 cytology samples were available for analysis. Four samples showed malignant cells, all four patients were diagnosed with ovarian and/or fallopian tube cancer at histologic examination. A fifth patient, of whom no cytology sample was obtained during RRSO, developed primary peritoneal cancer 80 months post RRSO. CONCLUSIONS: This study failed to show that cytology is of value during RRSO in detecting primary peritoneal cancer, however 36% of patients with concomitant ovarian or fallopian tube cancer had positive cytology. Therefore, the routine sampling of peritoneal washings during RRSO is not found to be useful to detect subsequent PPC. PMID- 26768421 TI - Simulated consultations: a sociolinguistic perspective. AB - BACKGROUND: Assessment of consulting skills using simulated patients is widespread in medical education. Most research into such assessment is sited in a statistical paradigm that focuses on psychometric properties or replicability of such tests. Equally important, but less researched, is the question of how far consultations with simulated patients reflect real clinical encounters--for which sociolinguistics, defined as the study of language in its socio-cultural context, provides a helpful analytic lens. DISCUSSION: In this debate article, we draw on a detailed empirical study of assessed role-plays, involving sociolinguistic analysis of talk in OSCE interactions. We consider critically the evidence for the simulated consultation (a) as a proxy for the real; (b) as performance; (c) as a context for assessing talk; and (d) as potentially disadvantaging candidates trained overseas. Talk is always a performance in context, especially in professional situations (such as the consultation) and institutional ones (the assessment of professional skills and competence). Candidates who can handle the social and linguistic complexities of the artificial context of assessed role plays score highly--yet what is being assessed is not real professional communication, but the ability to voice a credible appearance of such communication. Fidelity may not be the primary objective of simulation for medical training, where it enables the practising of skills. However the linguistic problems and differences that arise from interacting in artificial settings are of considerable importance in assessment, where we must be sure that the exam construct adequately embodies the skills expected for real-life practice. The reproducibility of assessed simulations should not be confused with their validity. Sociolinguistic analysis of simulations in various professional contexts has identified evidence for the gap between real interactions and assessed role-plays. The contextual conditions of the simulated consultation both expect and reward a particular interactional style. Whilst simulation undoubtedly has a place in formative learning for professional communication, the simulated consultation may distort assessment of professional communication These sociolinguistic findings contribute to the on-going critique of simulations in high-stakes assessments and indicate that further research, which steps outside psychometric approaches, is necessary. PMID- 26768423 TI - Do Serially Recorded Prognostic Scores Predict Outcome Better Than One-Time Recorded Score on Admission? A Prospective Study in Adult Intensive Care Patients. AB - OBJECTIVES: The prognosticating ability of one-time recorded Acute Physiology and Chronic Health Evaluation (APACHE) IV score was compared with serially recorded Mortality Prediction Model (MPM) II scores. DESIGN AND METHODS: A prospective observational study was conducted for a period of 6 months. Acute Physiology and Chronic Health Evaluation IV score was recorded during the first day on intensive care unit (ICU) admission. Mortality Prediction Model II was recorded on admission, 24, 48, and 72 hours. Predicted mortality was compared with observed mortality. The systems were calibrated and tested for discriminant functions. RESULTS: One hundred and fifty patients were studied. The observed mortality was 21.3%. The mean predicted hospital mortality by APACHE IV was 20.6%. The mean predicted hospital mortality rate by serial MPM II measurements was 27.7%, 24.3%, 25.5%, and 25.8%. The area under the receiver-operating characteristic curve was 0.87 for APACHE IV and 0.82, 0.84, 0.85, and 0.89 for MPM II series. Both systems calibrated well with similar degree of goodness of fit. CONCLUSION: Acute Physiology and Chronic Health Evaluation IV on admission predicted hospital mortality better than serially recorded MPM, which overestimated mortality. Also, APACHE IV had a slightly better discrimination compared to MPM II on admission. One-time recording of APACHE IV on admission may be sufficient for prognostication of ICU patients rather than serial MPM scores. PMID- 26768422 TI - Multimodal hybrid imaging agents for sentinel node mapping as a means to (re)connect nuclear medicine to advances made in robot-assisted surgery. AB - PURPOSE: Radical prostatectomy and complementary extended pelvic lymph node dissection (ePLND) of sentinel lymph nodes (SNs) and non-sentinel lymph nodes (LNs) at risk of containing metastases are increasingly being performed using high-tech robot-assisted approaches. Although this technological evolution has clear advantages, the physical nature of robotic systems limits the integrated use of routine radioguided surgery technologies. Hence, engineering effort in robotics are focused on the integration of fluorescence guidance technologies. Using the hybrid SN tracer indocyanine green-(99m)Tc-nanocolloid (radioactive and fluorescent), for the first time in combination with a robot-integrated laparoscope, we investigated whether the robot-assisted approach affects the accuracy of fluorescence detection of SNs identified preoperatively using nuclear medicine. METHODS: The study included 55 patients (Briganti nomogram-based risk >5 % on LN metastases) scheduled for robot-assisted radical prostatectomy, SN biopsy and ePLND. Following indocyanine green-(99m)Tc-nanocolloid injection, preoperative nuclear imaging (lymphoscintigraphy and SPECT/CT) was used to locate the SN(s). The fluorescence laparoscope was used intraoperatively to identify the SN(s) with standard fluorescence settings (in 50 patients) and with customized settings (in 5 patients). The number and location of the SNs, the radioactive, fluorescence (both in vivo and ex vivo) and tumour status of the resected SNs/LNs, and postoperative complications were recorded and analysed. RESULTS: Combined, preoperative lymphoscintigraphy and SPECT/CT imaging identified 212 SNs (median 4 per patient). Intraoperative fluorescence imaging using standard fluorescence settings visualized 80.4 % (148/184 SNs; 50 patients; ex vivo 97.8 %). This increased to 85.7 % (12/14 SNs; 5 patients; ex vivo 100 %) with customized fluorescence settings. SPECT/CT images provided guidance towards the residual SNs. Ex vivo all removed SNs were radioactive. SNs were tumour-positive in 25.4 % of patients (14/55; false-negative rate 7 %, 1/14 patients). In ten patients, the SN was the only tumour-positive LN. Surgical complications were minimal. CONCLUSION: Directly linking 3D preoperative nuclear imaging information on SNs to a robot-integrated fluorescence laparoscope improved the surgeon's use of the technology and did not influence the sensitivity or morbidity of the procedure. To our surprise, however, the detection rates with the current fluorescence camera did not improve. PMID- 26768424 TI - The Cardiovascular Intensive Care Unit-An Evolving Model for Health Care Delivery. AB - Prior to the advent of the coronary care unit (CCU), patients having an acute myocardial infarction (AMI) were managed on the general medicine wards with reported mortality rates of greater than 30%. The first CCUs are believed to be responsible for reducing mortality attributed to AMI by as much as 40%. This drastic improvement can be attributed to both advances in medical technology and in the process of health care delivery. Evolving considerably since the 1960s, the CCU is now more appropriately labeled as a cardiac intensive care unit (CICU) and represents a comprehensive system designed for the care of patients with an array of advanced cardiovascular disease, an entity that reaches far beyond its early association with AMI. Grouping of patients by diagnosis to a common physical space, dedicated teams of health care providers, as well as the development and implementation of evidence-based treatment algorithms have resulted in the delivery of safer, more efficient care, and most importantly better patient outcomes. The CICU serves as a platform for an integrated, team based patient care delivery system that addresses a broad spectrum of patient needs. Lessons learned from this model can be broadly applied to address the urgent need to improve outcomes and efficiency in a variety of health care settings. PMID- 26768425 TI - Hidden Obligatory Fluid Intake in Critical Care Patients. AB - INTRODUCTION: In addition to the fluid intake in the form of intravenous maintenance or boluses in intensive care unit (ICU) patients, there are sources of fluids that may remain unrecognized but contribute significantly to the overall fluid balance. We hypothesized that fluids not ordered as boluses or maintenance infusions-"hidden obligatory fluids"-may contribute more than a liter to the fluid intake of a patient during any random 24 hours of critical care admission. METHODS: Patients admitted to the Harlem Hospital ICU for at least 24 hours were included in this study (N = 98). Medical records and nursing charts were reviewed to determine the sources and volumes of various fluids for the study patients. RESULTS: The mean hidden obligatory volume for an ICU patient was calculated to be 978 mL (standard deviation [SD]: 904, median: 645) and 1571 mL (SD: 1023, median: 1505), with enteral feeds compared to the discretionary volume of 2821 mL (SD: 2367, median: 2595); this obligatory fluid volume was affected by a patient's need for pressor support and renal replacement therapy. CONCLUSION: Hidden obligatory fluids constitute a major source of the fluid intake among patients in a critical care unit. Up to 1.5 L should be taken into account during daily decision making to effectively regulate their volumes. PMID- 26768426 TI - Strain-Specific Altered Regulatory Response of Rab7a and Tau in Creutzfeldt-Jakob Disease and Alzheimer's Disease. AB - There is an increasing demand for the understanding of pathophysiology on neurodegeneration diseases at early stages. Changes in endocytic machinery and the cytoskeleton-associated response are the first alterations observed in Creutzfeldt-Jakob disease (CJD) and Alzheimer's disease AD brain. In this study, we performed a targeted search for endocytic pathway proteins in the different regions of the brain. We found late endosome marker Rab7a which was significantly upregulated in the frontal cortex region in the rapid progressive CJD form (MM1) and rapid progressive AD (rpAD) forms. However, Rab9 expression was significantly downregulated only in CJD-MM1 brain frontal cortex region. In the cerebellum, Rab7a expression showed significant upregulation in both subtype MM1 and VV2 CJD forms, in contrast to Rab9 which showed significant downregulation in both subtype MM1 and VV2 CJD forms at terminal stage of the disease. To check regulatory response at pre-symptomatic stage of the disease, we checked the regulatory interactive response of Rab7a, Rab9, and known biomarkers PrPC and tau forms in frontal cortex at pre-symptomatic stage of the disease in tg340 mice expressing about fourfold of human PrP-M129 with PrP-null background that had been inoculated with human sCJD MM1 brain tissue homogenates (sCJD MM1 mice). In addition, we analyzed 5XFAD mice, exhibiting five mutations in the APP and presenilin genes related to familial Alzheimer's disease (FAD), to validate specific regulatory response of Rab7a, Rab9, tau, and phosphorylated form of tau by immunostaining 5XFAD mice in comparison with the wild-type age-matched mice brain. The cortical region of 5XFAD mice brain showed accumulated form of Rab7a in puncta that co-label for p-Tau, indicating colocalization by using confocal laser-scanning microscopy and was confirmed by using reverse co immunoprecipitation. Furthermore, synthetic RNA (siRNA) against the Rab7a gene decreased expression of Rab7a protein, in cortical primary neuronal cultures of PrPC wild type. This depleted expression of Rab7a led to the increased accumulation of PrPC in Rab9-positive endosomal compartments and consequently an increased co-localization between PrPC/Rab9; however, total tau level decreased. Interestingly, siRNA against tau gene in cortical primary neuronal cultures of PrPC wild-type mice showed enhanced Rab7a and Rab9 expression and increase formation of dendritic spines. The work described highlighted the selective involvement of late endosomal compartment marker Rab7a in CJD, slow and rapid progressive forms of AD pathogenesis. PMID- 26768428 TI - Biomarkers of Delirium in a Low-Risk Community-Acquired Pneumonia-Induced Sepsis. AB - There are different theories about the pathophysiology of sepsis-associated encephalopathy (SAE), and the majority of our knowledge was derived from critically ill patients. 7In less severe sepsis, it is probable that neuroinflammation can be a major aspect of SAE development. We hypothesized that in non-severe septic patients, blood biomarkers of inflammation, endothelial activation, coagulation, and brain function would be different when compared to patients with and without brain dysfunction. A total of 30 patients presenting with community-acquired pneumonia (CAP)-induced sepsis were included of which 10 (33 %) developed SAE. Eight medical patients admitted to the general ward, except due to sepsis or infection, which developed delirium were included as delirium, non-sepsis group. From all measured biomarkers, only brain-derived neurotrophic factor (BDNF), regulated upon activation normal T cell expressed, and presumably secreted (RANTES), and interleukin (IL)-10 where significantly different when compared to SAE and sepsis groups. In addition, SAE patients presented higher levels of BDNF, vascular cellular adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), platelet-derived growth factor (PDGF)-AB/BB and RANTES when compared to delirium patients. In conclusion, the profile of biomarkers differs between SAE, sepsis, and delirium patients, suggesting that pathways related to SAE are different from delirium and from sepsis itself. PMID- 26768427 TI - A Nonrewarding NMDA Receptor Antagonist Impairs the Acquisition, Consolidation, and Expression of Morphine Conditioned Place Preference in Mice. AB - N-methyl-D-aspartate (NMDA) receptor antagonists block morphine-induced conditioned place preference (CPP). Although polyamines are endogenous modulators of the NMDA receptor, it is not known whether polyaminergic agents induce CPP or modulate morphine-induced CPP. Here, we examined whether polyamine ligands modify morphine CPP acquisition, consolidation, and expression. Adult male albino Swiss mice received saline (0.9 % NaCl, intraperitoneally (i.p.)) or morphine (5 mg/kg, i.p.) and were respectively confined to a black or a white compartment for 30 min for four consecutive days for CPP induction. The effect of arcaine (3 mg/kg, i.p.) or spermidine (30 mg/kg, i.p.), respectively, an antagonist and an agonist of the polyamine-binding site at the NMDA receptor, on the acquisition, consolidation, and expression of morphine CPP was studied. In those experiments designed to investigate whether spermidine prevented or reversed the effect of arcaine, spermidine (30 mg/kg, i.p.) was administered 15 min before or 15 min after arcaine, respectively. Arcaine and spermidine did not induce CPP or aversion per se. Arcaine (3 mg/kg, i.p.) impaired the acquisition, consolidation, and expression of morphine CPP. Spermidine prevented the impairing effect of arcaine on the acquisition of morphine CPP but not the impairing effect of arcaine on consolidation or expression of morphine CPP. These results suggest that arcaine may impair morphine CPP acquisition by modulating the polyamine binding site at the NMDA receptor. However, the arcaine-induced impairment of consolidation and expression of morphine CPP seems to involve other mechanisms. PMID- 26768429 TI - Nestin Expression Is Associated with Poor Clinicopathological Features and Prognosis in Glioma Patients: an Association Study and Meta-analysis. AB - Nestin has been identified as a molecular marker of neural progenitor cells and putative glioma stem cells (GSCs). Various studies examining the relationship between nestin expression with the clinical outcome in glioma patients have yielded inconclusive results. Thus, we conducted a systematic review to evaluate the association of nestin with prognosis and clinicopathological features of glioma patients. The electronic searches were performed through the database of PubMed, MEDLINE, Embase, and CNKI. In total, this meta-analysis included 14 studies covering 897 nestin + cases and 704 controls. The correlation between nestin expression and clinicopathological or prognostic parameters was evaluated by Stata 11.0 software. Our results showed that nestin protein abundance was significantly correlated with the histological grade [odds ratio (OR) = 4.36, 95 % confidence interval (CI) = 2.14-8.88, P = 0.003] of glioma. With respect to prognosis, nestin expression was positively correlated with overall survival (OS) [hazard ratio (HR) = 1.98, 95 % CI = 1.30-3.02, P = 0.000] and progression-free survival (PFS) (HR = 1.90, 95 % CI = 1.18-3.07, P = 0.040). The further stratified analysis not only defined the predictive function of nestin in different ages but also revealed that different antibodies did not alter the positive outcomes and higher standard cutoff values were more suitable for the accurate assay of nestin. Taken together, our results indicate that nestin may play an important role in the prediction of the clinicopathology and poor prognosis of glioma patients. This study should be taken into consideration in the development of new diagnostic and therapeutic programs. PMID- 26768430 TI - The Effects of Inhaled Pimpinella peregrina Essential Oil on Scopolamine-Induced Memory Impairment, Anxiety, and Depression in Laboratory Rats. AB - In the present study, we identified the effects of inhaled Pimpinella peregrina essential oil (1 and 3 %, for 21 continuous days) on scopolamine-induced memory impairment, anxiety, and depression in laboratory rats. Y-maze and radial arm maze tests were used for assessing memory processes. Also, the anxiety and depressive responses were studied by means of the elevated plus-maze and forced swimming tests. The scopolamine alone-treated rats exhibited the following: decrease of the spontaneous alternation percentage in Y-maze test, increase of the number of working and reference memory errors in radial arm-maze test, along with decrease of the exploratory activity, the percentage of the time spent and the number of entries in the open arm within elevated plus-maze test and decrease of swimming time and increase of immobility time within forced swimming test. Inhalation of the P. peregrina essential oil significantly improved memory formation and exhibited anxiolytic- and antidepressant-like effects in scopolamine-treated rats. Our results suggest that the P. peregrina essential oil inhalation ameliorates scopolamine-induced memory impairment, anxiety, and depression. Moreover, studies on the P. peregrina essential oil may open a new therapeutic window for the prevention of neurological abnormalities closely related to Alzheimer's disease. PMID- 26768431 TI - Derivation and Evaluation of a Risk-Scoring Tool to Predict Participant Attrition in a Lifestyle Intervention Project. AB - Participant attrition in clinical trials and community-based interventions is a serious, common, and costly problem. In order to develop a simple predictive scoring system that can quantify the risk of participant attrition in a lifestyle intervention project, we analyzed data from the Special Diabetes Program for Indians Diabetes Prevention Program (SDPI-DP), an evidence-based lifestyle intervention to prevent diabetes in 36 American Indian and Alaska Native communities. SDPI-DP participants were randomly divided into a derivation cohort (n = 1600) and a validation cohort (n = 801). Logistic regressions were used to develop a scoring system from the derivation cohort. The discriminatory power and calibration properties of the system were assessed using the validation cohort. Seven independent factors predicted program attrition: gender, age, household income, comorbidity, chronic pain, site's user population size, and average age of site staff. Six factors predicted long-term attrition: gender, age, marital status, chronic pain, site's user population size, and average age of site staff. Each model exhibited moderate to fair discriminatory power (C statistic in the validation set: 0.70 for program attrition, and 0.66 for long-term attrition) and excellent calibration. The resulting scoring system offers a low-technology approach to identify participants at elevated risk for attrition in future similar behavioral modification intervention projects, which may inform appropriate allocation of retention resources. This approach also serves as a model for other efforts to prevent participant attrition. PMID- 26768432 TI - Men's Behavior Predicts Women's Risks for HIV/AIDS: Multilevel Analysis of Alcohol-Serving Venues in South Africa. AB - South Africa has among the highest rates of HIV infection in the world, with women disproportionately affected. Alcohol-serving venues, where alcohol use and sexual risk often intersect, play an important role in HIV risk. Previous studies indicate alcohol use and gender inequity as drivers of this epidemic, yet these factors have largely been examined using person-level predictors. We sought to advance upon this literature by examining venue-level predictors, namely men's gender attitudes, alcohol, and sex behavior, to predict women's risks for HIV. We recruited a cohort of 554 women from 12 alcohol venues (6 primarily Black African, and 6 primarily Coloured [i.e., mixed race] venues) in Cape Town, who were followed for 1 year across four time points. In each of these venues, men's (N = 2216) attitudes, alcohol use, and sexual behaviors were also assessed. Men's attitudes and behaviors at the venue level were modeled using multilevel modeling to predict women's unprotected sex over time. We stratified analyses by venue race. As predicted, venue-level characteristics were significantly associated with women's unprotected sex. Stratified results varied between Black and Coloured venues. Among Black venues where men reported drinking alcohol more frequently, and among Coloured venues where men reported meeting sex partners more frequently, women reported more unprotected sex. This study adds to the growing literature on venues, context, and HIV risk. The results demonstrate that men's behavior at alcohol drinking venues relate to women's risks for HIV. This novel finding suggests a need for social-structural interventions that target both men and women to reduce women's risks. PMID- 26768433 TI - Chronic refractory myofascial pain and denervation supersensitivity as global public health disease. AB - Chronic pain with a 30.3% global prevalence significantly impacts universal health. Low back pain has a 9.4% prevalence worldwide causing the most widespread disability. Neck pain ranks 4th highest regarding years lived with disability with a 4.9% prevalence worldwide. The principal cause of pain in 85% of patients visiting a tertiary pain clinic has a myofascial origin. The root cause is multifocal neuromuscular ischaemia at myofascial trigger points from muscle tightening and shortening following spondylotic radiculopathy induced partial denervation. Chronic refractory myofascial pain (CRMP) is a neuromusculoskeletal disease needing management innovations. Using electrical twitch-obtaining intramuscular stimulation (eToims), we provide objective evidence of denervation supersensitivity in multiple myotomes as cause, aggravation and maintenance of CRMP. This study underscores our previous findings that eToims is safe and efficacious for long-term use in CRMP. eToims aids potential prevention (pre rehabilitation), simultaneous diagnosis, treatment (rehabilitation) and prognosis in real time for acute and CRMP management. PMID- 26768434 TI - Reduction in malignant ventricular arrhythmia and appropriate shocks following surgical correction of bileaflet mitral valve prolapse. AB - BACKGROUND: Bileaflet mitral valve prolapse (MVP) can be associated with malignant ventricular arrhythmias. It is unknown whether surgical correction alone of this mitral valve pathology leads to a reduction in ventricular dysrhythmias. METHODS: We retrospectively analyzed 4477 patients who underwent mitral valve surgery from 1993-2013 at Mayo Clinic in Rochester, MN. Among these, eight patients with bileaflet MVP who had an internal cardioverter defibrillator (ICD) in place both pre- and post-surgery were identified. ICD interrogation records were evaluated for episodes of ventricular tachycardia (VT), ventricular fibrillation (VF), and appropriate ICD shock therapy. RESULTS: Of these eight patients, five had a malignant ventricular arrhythmia prior to surgery. Data was available 4.6 +/- 2.9 years before versus 6.6 +/- 4.2 years following surgical intervention. Among these patients, there was a reduction in VF (0.6 versus 0.14 events per-person-year pre- and post-surgery, respectively), VT (0.4 versus 0.05 events per-person-year pre- and post-surgery, respectively), and ICD shocks (0.95 versus 0.19 events per-person-year pre- and post-surgery) following mitral valve surgery. CONCLUSIONS: We report a series of cases where the surgical correction of bileaflet MVP alone was associated with a reduction in malignant arrhythmia and appropriate shocks. These early observations merit further investigation involving larger cohorts to further evaluate the association between abnormal mechanical forces in degenerative mitral valve disease and ventricular dysrhythmias. PMID- 26768435 TI - Getting to zero: impact of electroanatomical mapping on fluoroscopy use in pediatric catheter ablation. AB - PURPOSE: Over the past several years, alternative imaging techniques including electroanatomic mapping systems such as CARTO(r)3 (C3) have been developed to improve anatomic resolution and potentially limit radiation exposure in electrophysiology (EP) procedures. We retrospectively examined the effect of the introduction of C3 on patient radiation exposure during EP studies and ablation procedures at a children's hospital. METHODS: All patients that underwent EP and ablation procedures between January 2012 and August 2015 were included; demographic information, fluoroscopy time (FT), total radiation dose (RAD), and dose-area product (DAP) were collected. Patients were stratified by time period (before vs. after C3 introduction) in three groups: (1) normal heart, (2) congenital heart disease (CHD), and (3) those requiring trans-septal (TS) access. The normal heart group was further separated by arrhythmia diagnosis (accessory pathway (AP), AV nodal reentry tachycardia (AVNRT), atrial, or ventricular arrhythmia). Mean values were compared using a single sample t test, as well as analysis of covariance to control for age, weight, and arrhythmia diagnosis. RESULTS: Mean FT decreased after introduction of C3 in patients in all three patient groups (p < 0.01). When separated by arrhythmia diagnosis, FT decreased in the AP and AVNRT groups (p < 0.0001). After controlling for age, weight, and arrhythmia diagnosis, there was a statistically significant decrease in FT in all three groups and in both RAD and DAP in the normal heart group. Zero fluoroscopy was achieved in 50/159 (31 %) and <=1 min of FT in 71/159 (45 %) of cases. CONCLUSIONS: We have shown a significant decrease in multiple measures of radiation after introduction of C3. Continued refinements are needed to further decrease radiation utilization and achieve the goal of zero fluoroscopy. PMID- 26768436 TI - Chemotherapy-induced nausea and vomiting: incidence and characteristics of persistent symptoms and future directions NCCTG N08C3 (Alliance). AB - BACKGROUND: Despite newer agents, chemotherapy-induced nausea and vomiting (CINV) continues to remain a distressing side effect to a proportion of patients undergoing systemic anti-cancer therapy. METHODS: We recently performed an unplanned secondary analysis on a previously reported negative phase III trial (N08C3) looking at the efficacy of gabapentin/placebo in combination with dexamethasone and a 5HT3 receptor antagonist in the prevention of CINV for 413 patients undergoing regimens with highly emetogenic chemotherapy (HEC). In the current study, we attempted to better understand the higher than expected rate of overall patient satisfaction, despite a low complete response rate in both arms. Additionally, we looked at patient variables and their relationship to rates of CINV. RESULTS: Approximately one third of patients experienced more than mild nausea and reported scores on the Functional Living Index-Emesis that indicated interference with activities. Thirty-five percent reported nausea greater than 2.5 on a scale of 0 to 10 (0 being none), 19 % reported at least one emetic episode, and 49 % reported taking rescue medication. Nausea and vomiting on day 1, cisplatin therapy, and history of motion sickness significantly predicted delayed CINV. Age, combination chemotherapy (HEC with moderately emetogenic), and getting treatment for breast cancer predicted CINV on day 1. DISCUSSION: These data confirm previous reports that subgroups of patients may be more prone to acute and delayed CINV. Future CINV study design may benefit from a more individualized approach to CINV management, targeting those patients who are truly at risk for CINV despite continued drug development efforts. PMID- 26768438 TI - The impact of the Greek socio-economic crisis on ICU patient recruitment. PMID- 26768437 TI - Efficacy of olanzapine for the prophylaxis and rescue of chemotherapy-induced nausea and vomiting (CINV): a systematic review and meta-analysis. AB - PURPOSE: Olanzapine is a potent antipsychotic medication that inhibits a wide variety of receptors. It has been used in trials for the prophylaxis and rescue of chemotherapy-induced nausea and vomiting (CINV). This study systematically investigates the efficacy of olanzapine in relation to other antiemetics in the prophylaxis and rescue of CINV. METHODS: A literature search of Ovid MEDLINE, EMBASE, and CENTRAL was conducted to identify randomized controlled trials (RCTs) comparing olanzapine to other standard antiemetics for either prevention or rescue. The primary endpoints were the percentage of patients achieving no emesis or no nausea, in the acute, delayed, and overall phases. RESULTS: Ten RCTs in the preventative setting and three RCTs in the breakthrough setting were identified. Subgroup analysis demonstrated a similar degree of benefit from a 5- and 10-mg dose of olanzapine for the no emesis endpoint in the overall phase. In the prophylaxis setting, olanzapine was statistically superior in five of six endpoints and clinically superior in four of six endpoints. In the breakthrough setting, olanzapine was statistically and clinically superior in the only endpoint analyzed: no emesis. CONCLUSION: Olanzapine is more efficacious than other standard antiemetics for the rescue of CINV and its inclusion improves control in the prevention setting. Given the possible reduction in side effects, the use of a 5-mg dose of olanzapine should be considered. Future RCTs should compare the 5-mg versus the 10-mg dosages further and report on the efficacy and percentage of patients developing side effects. Further analyses should be done without the influence of corticosteroids. PMID- 26768439 TI - Prone position acute respiratory distress syndrome patients: less prone to ventilator associated pneumonia? PMID- 26768441 TI - Whistling in the dark. PMID- 26768442 TI - Contracts: No action needed. PMID- 26768443 TI - Oral health guidelines in humanitarian settings. PMID- 26768440 TI - Chronic antiplatelet therapy is not associated with alterations in the presentation, outcome, or host response biomarkers during sepsis: a propensity matched analysis. AB - PURPOSE: Sepsis is a major health burden worldwide. Preclinical investigations in animals and retrospective studies in patients have suggested that inhibition of platelets may improve the outcome of sepsis. In this study we investigated whether chronic antiplatelet therapy impacts on the presentation and outcome of sepsis, and the host response. METHODS: We performed a prospective observational study in 972 patients admitted with sepsis to the mixed intensive care units (ICUs) of two hospitals in the Netherlands between January 2011 and July 2013. Of them, 267 patients (27.5%) were on antiplatelet therapy (95.9% acetylsalicylic acid) before admission. To account for differential likelihoods of receiving antiplatelet therapy, a propensity score was constructed, including variables associated with use of antiplatelet therapy. Cox proportional hazards regression was used to estimate the association of antiplatelet therapy with mortality. RESULTS: Antiplatelet therapy was not associated with sepsis severity at presentation, the primary source of infection, causative pathogens, the development of organ failure or shock during ICU stay, or mortality up to 90 days after admission, in either unmatched or propensity-matched analyses. Antiplatelet therapy did not modify the values of 19 biomarkers providing insight into hallmark host responses to sepsis, including activation of the coagulation system, the vascular endothelium, the cytokine network, and renal function, during the first 4 days after ICU admission. CONCLUSIONS: Pre-existing antiplatelet therapy is not associated with alterations in the presentation or outcome of sepsis, or the host response. PMID- 26768444 TI - Guidelines: Insufficiency concern. PMID- 26768445 TI - Antimicrobial resistance: Antibiotics and consultant oral microbiologist posts. PMID- 26768446 TI - Right of reply: A proud contribution. PMID- 26768447 TI - Social scientists needed to solve the problem of antibiotic overuse. PMID- 26768450 TI - Dentists salute leadership from Welsh Assembly on sugar crisis. PMID- 26768453 TI - New NICE guidelines aim to improve quality of dentistry provision in the UK. PMID- 26768457 TI - Can we improve on situational judgement tests? AB - Situational judgement tests (SJTs) are multiple-choice psychological assessments that claim to measure professional attributes such as empathy, integrity, team involvement and resilience. One of their attractions is the ability to rank large numbers of candidates. Last year SJTs formed a major component (50% of the assessment marks) of the selection process for dental foundation training (DFT). However, it is not clear what SJTs are actually assessing. There is also the concern that applicants who have developed ethical reasoning skills may be disadvantaged by such tests. The DFT selection process needs to explicitly recognise the importance of ethical reasoning. PMID- 26768458 TI - Sectional matrix: Step-by-step directions for their clinical use. AB - The sectional matrix is the best way to achieve a strong contact point in Class II restorations with composite resin in the posterior dental sector. The pre wedging is essential to get a separation between teeth which avoid the matrix deformation during its insertion. This article describes the clinical technique for restoring Class II cavities using a sectional matrix. PMID- 26768463 TI - A survey of oral medicine education, training and practice among dermatologists in the UK and Ireland. AB - BACKGROUND: Oral mucocutaneous diseases are common and patients with these conditions are frequently assessed by dermatologists. An accurate and comprehensive oral examination is important for a complete dermatological assessment. AIM: The aim of this study was to assess education and training, knowledge, and clinical practice of oral medicine among dermatologists in the United Kingdom (UK) and Ireland. METHODS: A cross-sectional survey was conducted by means of an internet-based survey tool. This was available to British Association of Dermatology (BAD) members in UK and Ireland on the association's website. Members were asked to respond to a 10-part questionnaire that enquired about their knowledge of oral diseases, training in oral medicine, performing an oral examination and oral biopsy. RESULTS: Completed responses were received from 95 dermatologists. The majority of respondents were consultant dermatologists (72%) who were university based. While the majority reported that knowledge of oral diseases was important, only 52% were confident in recognising the normal variants of the oral cavity. Just 55% were confident in recognising oral malignancy and even less (42%) the different forms of oral ulceration. Over three quarters had never attended an oral medicine clinic or attended an external oral medicine course as part of their training. Two thirds had not been taught normal oral anatomy or how to perform an oral examination. The majority reported that their training in oral medicine was not adequate to perform their job. CONCLUSIONS: This study shows that in this, albeit small, group of dermatology specialists and trainees most appear ill-equipped to recognise and diagnose diseases of the oral cavity due to a lack of training in oral medicine. PMID- 26768464 TI - A retrospective analysis of episodes of single tooth extraction under general anaesthesia for adults. AB - OBJECTIVES: To investigate the provision of adult dental extraction under general anaesthesia (DGA) at the Royal Cornwall Hospitals NHS Trust (RCHT)-- specifically adult single tooth DGA episodes in regards to numbers, demographics, justifications, and appropriateness regarding the use of resources. METHOD: Data were collected retrospectively from the patient case notes and electronic records for the complete study cohort. This study included all episodes of adult single tooth DGA in all RCHT sites during 2014, except for mandibular third molar and impacted teeth. Each case was tested against the DGA case selection criteria empirically devised for this study. RESULTS: In 2014, 106 episodes of adult single tooth DGA were carried out in RCHT that met the inclusion criteria. Younger females from more socio-economically deprived areas of Cornwall were increasingly likely to have this procedure. Mental disorders were the most prevalent co-morbidity (21.7%) in this cohort. The vast majority of patients (93.4%) had previously tolerated dental treatment without the need for general anaesthesia (GA). Many referrals (46.2%) and listings (30.2%) specifically stated patient demand-driven reasons. None of the cohort had DGA due to failure of sedation. There were potentially 11 episodes that met the DGA case selection criteria. Patients waited for 126 days (median) from the referral date for an operation which took seven minutes (median) to complete. The majority (83%) of the cases were simple exodontia. Twenty patients (18.9%) had previous DGA. CONCLUSION: Potentially a considerable proportion of GA prescription appeared to be driven by patient demand rather than clinical need. This study poses a fundamental question--what drives the demand for DGA? National data collection and specific DGA case selection criteria are recommended. PMID- 26768465 TI - Perceptions of Australian dental practitioners about using telemedicine in dental practice. AB - Objective This study aimed to explore Australian dental practitioners' perceptions of the usefulness of teledentistry in improving dental practice and patient outcomes.Methods A descriptive cross-sectional study involving an anonymous electronic survey of a sample of 169 Australian dental practitioners. We designed a 24-item, 5-point Likert-scale questionnaire assessing perceptions of dentists in four domains: usefulness of teledentistry for patients; usefulness of teledentistry for dental practice; capability of teledentistry to improve practice; and perceived concerns about the use of teledentistry.Results Of the 144 respondents (response rate 85%), 135 completed responses that were suitable for analysis. More than 80% of respondents agreed or strongly agreed that teledentistry would improve dental practice through enhancing communication with peers, guidance and referral of new patients. The majority also felt that teledentistry is quite useful in improving patient management, and increasing patient satisfaction. A substantial proportion of respondents expressed uncertainty with technical reliability, privacy, practice expenses, the cost of setting up teledentistry, surgery time and diagnostic accuracy.Conclusion Dental practitioners generally reported optimism and support to the concept of teledentistry and its integration into current dental practices. Addressing how teledentistry can benefit specific practice issues, would encourage more dentists to use telemedicine in routine practice. PMID- 26768475 TI - Quasi-plane shear wave propagation induced by acoustic radiation force with a focal line region: a simulation study. AB - Shear wave propagation speed has been regarded as an attractive indicator for quantitatively measuring the intrinsic mechanical properties of soft tissues. While most existing techniques use acoustic radiation force (ARF) excitation with focal spot region based on linear array transducers, we try to employ a special ARF with a focal line region and apply it to viscoelastic materials to create shear waves. First, a two-dimensional capacitive micromachined ultrasonic transducer with 64 * 128 fully controllable elements is realised and simulated to generate this special ARF. Then three-dimensional finite element models are developed to simulate the resulting shear wave propagation through tissue phantom materials. Three different phantoms are explored in our simulation study using: (a) an isotropic viscoelastic medium, (b) within a cylindrical inclusion, and (c) a transverse isotropic viscoelastic medium. For each phantom, the ARF creates a quasi-plane shear wave which has a preferential propagation direction perpendicular to the focal line excitation. The propagation of the quasi-plane shear wave is investigated and then used to reconstruct shear moduli sequentially after the estimation of shear wave speed. In the phantom with a transverse isotropic viscoelastic medium, the anisotropy results in maximum speed parallel to the fiber direction and minimum speed perpendicular to the fiber direction. The simulation results show that the line excitation extends the displacement field to obtain a large imaging field in comparison with spot excitation, and demonstrate its potential usage in measuring the mechanical properties of anisotropic tissues. PMID- 26768466 TI - Differentiating success from survival in modern implantology--key considerations for case selection, predicting complications and obtaining consent. AB - The use of dental implants to restore edentulous areas has increased significantly since the 1970s and is now considered, by many, the gold standard restorative treatment. As such it has become increasingly important to understand what constitutes success for these rehabilitations. Increasing focus has been given to acknowledging the difference between success and survival: the two being potentially very different outcomes for such invasive and expensive treatment. This article aims to describe this distinction and ultimately the implications of this for both patient and clinician. PMID- 26768477 TI - The remote ischemic preconditioning algorithm: effect of number of cycles, cycle duration and effector organ mass on efficacy of protection. AB - Remote ischemic preconditioning (rIPC), induced by cycles of transient limb ischemia and reperfusion (IR), is cardioprotective. The optimal rIPC-algorithm is not established. We investigated the effect of cycle numbers and ischemia duration within each rIPC-cycle and the influence of effector organ mass on the efficacy of cardioprotection. Furthermore, the duration of the early phase of protection by rIPC was investigated. Using a tourniquet tightened at the inguinal level, we subjected C57Bl/6NTac mice to intermittent hind-limb ischemia and reperfusion. The rIPC-protocols consisted of (I) two, four, six or eight cycles, (II) 2, 5 or 10 min of ischemia in each cycle, (III) single or two hind-limb occlusions and (IV) 0.5, 1.5, 2.0 or 2.5 h intervals from rIPC to index cardiac ischemia. All rIPC algorithms were followed by 5 min of reperfusion. The hearts were subsequently exposed to 25 min of global ischemia and 60 min of reperfusion in an ex vivo Langendorff model. Cardioprotection was evaluated by infarct size and post-ischemic hemodynamic recovery. Four to six rIPC cycles yielded significant cardioprotection with no further protection by eight cycles. Ischemic cycles lasting 2 min offered the same protection as cycles of 5 min ischemia, whereas prolonged cycles lasting 10 min abrogated protection. One and two hind limb preconditioning were equally protective. In our mouse model, the duration of protection by rIPC was 1.5 h. These findings indicate that the number and duration of cycles rather than the tissue mass exposed to rIPC determines the efficacy of rIPC. PMID- 26768476 TI - Risk stratification of patients with acute symptomatic pulmonary embolism. AB - Patients with acute symptomatic pulmonary embolism (PE) who present with arterial hypotension or shock have a high risk of death (high-risk PE), and treatment guidelines recommend strong consideration of thrombolysis in this setting. For normotensive patients diagnosed with PE, risk stratification should aim to differentiate the group of patients deemed as having a low risk for early complications (all-cause mortality, recurrent venous thromboembolism, and major bleeding) (low-risk PE) from the group of patients at higher risk for PE-related complications (intermediate-high risk PE), so low-risk patients could undergo consideration of early outpatient treatment of PE and intermediate-high risk patients would undergo close observation and consideration of thrombolysis. Clinicians should also use risk stratification and eligibility criteria to identify a third group of patients that should not undergo escalated or home therapy (intermediate-low risk PE). Such patients should initiate standard therapy of PE while in the hospital. Clinical models [e.g., Pulmonary Embolism Severity Index (PESI), simplified PESI (sPESI)] may accurately identify those at low risk of dying shortly after the diagnosis of PE. For identification of intermediate-high risk patients with acute PE, studies have validated predictive models that use a combination of clinical, laboratory and imaging variables. PMID- 26768479 TI - Juvenile osteochondritis dissecans in the lateral femoral condyle requiring osteochondral autograft as a revision procedure: a case report. AB - BACKGROUND: The optimal treatment option for osteochondritis dissecans of the knee is still controversial. We report the case of a boy who developed osteochondritis dissecans in the lateral femoral condyles of his bilateral knees requiring repeat surgical procedures. There has been no literature reporting juvenile osteochondritis dissecans of bilateral knees requiring repeat surgical procedures. CASE PRESENTATION: A 6-year-old Japanese boy presented with pain in his bilateral knees. Although conservative treatment with prohibition of sports activities was continued for 6 months, healing could not be attained. Conservative treatment consisting of prohibition of sports activities that included running and jumping and use of a brace with a locking mechanism at full extension was applied. He was instructed to walk with the brace. Since his lateral femoral osteochondritis dissecans lesion was located at the contact area during flexion, weight bearing with the use of the brace could effectively unload the lesion. Surgery was subsequently conducted on his left knee which had a more advanced stage lesion. Transchondral drilling was performed because the articular surface maintained its smooth continuity. At 9 months after the surgery, no appreciable healing was observed in the follow-up radiographs. Moreover, during the postoperative time course, lesions suggestive of osteochondritis dissecans in his contralateral right knee had become more evident. Based on the diagnosis of delayed union of bilateral osteochondritis dissecans lesions, a second surgery was attempted. The preceding arthroscopic observation of his left knee showed preserved surface continuity with softening and suspected partial detachment. Considering the delayed healing process observed in this patient, autogenous cylindrical osteochondral graft transplantation (8 mm in diameter) was performed as a revision procedure, while transchondral drilling was performed for the stable osteochondritis dissecans lesion in his right knee. Postoperatively, healing was achieved at 6 months. CONCLUSIONS: Following failed conservative treatment, he underwent arthroscopic drilling; however, the osteochondritis dissecans lesion did not heal requiring revision surgery using a cylindrical autogenous osteochondral graft. Finally, clinical and radiological healing was attained 6 months after the second surgery. Initial presentation at a young age with bilateral lesions may be clinical factors related to poor healing response and susceptibility to stress-related subchondral lesions. PMID- 26768478 TI - Pathways of retinoid synthesis in mouse macrophages and bone marrow cells. AB - In vivo pathways of natural retinoid metabolism and elimination have not been well characterized in primary myeloid cells, even though retinoids and retinoid receptors have been strongly implicated in regulating myeloid maturation. With the use of a upstream activation sequence-GFP reporter transgene and retrovirally expressed Gal4-retinoic acid receptor alpha in primary mouse bone marrow cells, we identified 2 distinct enzymatic pathways used by mouse myeloid cells ex vivo to synthesize retinoic acid receptor alpha ligands from free vitamin A metabolites (retinyl acetate, retinol, and retinal). Bulk Kit(+) bone marrow progenitor cells use diethylaminobenzaldehyde-sensitive enzymes, whereas bone marrow-derived macrophages use diethylaminobenzaldehyde-insensitive enzymes to synthesize natural retinoic acid receptor alpha-activating retinoids (all-trans retinoic acid). Bone marrow-derived macrophages do not express the diethylaminobenzaldehyde-sensitive enzymes Aldh1a1, Aldh1a2, or Aldh1a3 but instead, express Aldh3b1, which we found is capable of diethylaminobenzaldehyde insensitive synthesis of all trans-retinoic acid. However, under steady-state and stimulated conditions in vivo, diverse bone marrow cells and peritoneal macrophages showed no evidence of intracellular retinoic acid receptor alpha activating retinoids, despite expression of these enzymes and a vitamin A sufficient diet, suggesting that the enzymatic conversion of retinal is not the rate-limiting step in the synthesis of intracellular retinoic acid receptor alpha activating retinoids in myeloid bone marrow cells and that retinoic acid receptor alpha remains in an unliganded configuration during adult hematopoiesis. PMID- 26768480 TI - Pharmacogenomics to Revive Drug Development in Cardiovascular Disease. AB - Investment in cardiovascular drug development is on the decline as large cardiovascular outcomes trials require considerable investments in time, efforts and financial resources. Pharmacogenomics has the potential to help revive the cardiovascular drug development pipeline by providing new and better drug targets at an earlier stage and by enabling more efficient outcomes trials. This article will review some of the recent developments highlighting the value of pharmacogenomics for drug development. We discuss how genetic biomarkers can enable the conduct of more efficient clinical outcomes trials by enriching patient populations for good responders to the medication. In addition, we assess past drug development programs which support the added value of selecting drug targets that have established genetic evidence supporting the targeted mechanism of disease. Finally, we discuss how pharmacogenomics can provide valuable evidence linking a drug target to clinically relevant outcomes, enabling novel drug discovery and drug repositioning opportunities. PMID- 26768481 TI - Sarcopenia Is a Condition With Increasing Importance in Medical Oncology. PMID- 26768482 TI - Picoliter-Droplet Digital Polymerase Chain Reaction-Based Analysis of Cell-Free Plasma DNA to Assess EGFR Mutations in Lung Adenocarcinoma That Confer Resistance to Tyrosine-Kinase Inhibitors. AB - PURPOSE: The objective of this study was to evaluate the utility of analyzing cell-free plasma DNA (cfDNA) by picoliter-droplet digital polymerase chain reaction (ddPCR) to detect EGFR mutations that confer resistance to tyrosine kinase inhibitors (TKIs) used for treatment of lung adenocarcinoma (LADC). EXPERIMENTAL DESIGN: Thirty-five LADC patients who received epidermal growth factor receptor (EGFR)-TKI therapy, including ten who received tumor rebiopsy after development of resistance, were subjected to picoliter-ddPCR-cfDNA analysis to determine the fraction of cfDNA with TKI-sensitive (L858R and inflame exon 19 deletions) and -resistant (i.e., T790M) mutations, as well as their concordance with mutation status in rebiopsied tumor tissues. RESULTS: cfDNA samples from 15 (94%) of 16 patients who acquired resistance were positive for TKI-sensitive mutations. Also, 7 (44%) were positive for the T790M mutation, with fractions of T790M (+) cfDNA ranging from 7.4% to 97%. T790M positivity in cfDNA was consistent in eight of ten patients for whom rebiopsied tumor tissues were analyzed, whereas the remaining cases were negative in cfDNA and positive in rebiopsied tumors. Prior to EGFR-TKI therapy, cfDNAs from 9 (38%) and 0 of 24 patients were positive for TKI-sensitive and T790M mutations, respectively. Next generation sequencing of cfDNA from one patient who exhibited innate resistance to TKI despite a high fraction of TKI-sensitive mutations and the absence of the T790M mutation in his cfDNA revealed the presence of the L747P mutation, a known driver of TKI resistance. CONCLUSION: Picoliter-ddPCR examination of cfDNA, supported by next-generation sequencing analysis, enables noninvasive assessment of EGFR mutations that confer resistance to TKIs. IMPLICATIONS FOR PRACTICE: Noninvasive monitoring of the predominance of tumors harboring the secondary T790M mutation in the activating mutation in EGFR gene is necessary for precise and effective treatment of lung adenocarcinoma. Because cells harboring the T790M mutation are resistant to epidermal growth factor receptor-tyrosine-kinase inhibitors (TKIs), the predominance of tumor cells harboring the T790M mutations influences the choice of whether to use conventional or next-generation TKIs. Digital polymerase chain reaction-based examination of cfDNA is a promising method; however, its feasibility, including its consistency with examination of rebiopsied tumor tissue, has not been fully proven. Here, picoliter-droplet digital polymerase chain reaction technology is presented as a candidate method for testing cfDNA and assessing the predominance of T790M-mutant tumors. PMID- 26768484 TI - In Reply. PMID- 26768486 TI - Consent Decree: Physician and Institution Ramifications? PMID- 26768487 TI - Are Bolus Dosing Strategies the Intrathecal Version of Novel Waveforms With Spinal Cord Stimulation? PMID- 26768485 TI - Tamoxifen Initiation After Ductal Carcinoma In Situ. AB - BACKGROUND: Endocrine therapy initiation after ductal carcinoma in situ (DCIS) is highly variable and largely unexplained. National guidelines recommend considering tamoxifen for women with estrogen receptor-positive (ER+) DCIS or who undergo excision alone. We evaluated endocrine therapy use after DCIS over a 15 year period in an integrated health care setting to identify factors related to initiation. METHODS: Female Group Health Cooperative enrollees ages 18-89 years with a DCIS diagnosis during 1996-2011 were eligible for inclusion. Endocrine therapy was identified through pharmacy records. Tumor and treatment information were from tumor registry reports; demographics and other risk factors were from questionnaires and electronic medical records. Relative risks (RRs) and 95% confidence intervals (CIs) for endocrine therapy initiation were calculated using multivariable generalized linear models. RESULTS: We identified 727 women with a DCIS diagnosis, including 163 (22%) who initiated endocrine therapy (149 tamoxifen, 14 aromatase inhibitor). Younger women were more likely to initiate endocrine therapy (RR 1.69; 95% CI 1.16-2.46 for ages 45-54 vs. 65-74 years). Compared with breast-conserving surgery (BCS) with radiation, women who had BCS alone (RR 0.46; 95% CI 0.25-0.84) or mastectomy (RR 0.54; 95% CI 0.39-0.75) were less likely to use endocrine therapy. ER testing increased from 4% of DCIS cases in 2001 to 71% in 2011; however, endocrine therapy initiation decreased from 58% of ER+ DCIS in 2001-2005 to 37% in 2009-2011. CONCLUSION: Increasing ER testing since 2001 has not corresponded to parallel increases in endocrine therapy initiation. Age, surgery, and radiation were the primary factors associated with initiation. IMPLICATIONS FOR PRACTICE: National guidelines recommend considering tamoxifen for women with ductal carcinoma in situ (DCIS) who are estrogen receptor-positive (ER+) or who undergo excision alone. In this study, the rapid increase in ER testing caused by tamoxifen's approval in 2000 did not lead to increases in endocrine therapy initiation, despite recognition of an increasing number of DCIS tumors as ER+ each year. Contrary to the suggested guidelines, women who had breast-conserving surgery without radiation were less likely to use tamoxifen than those who had radiation. Future Food and Drug Administration approval of new endocrine agents for DCIS (such as aromatase inhibitors) may provide an opportunity to reemphasize benefits by ER and surgery status. PMID- 26768483 TI - Epidermal Growth Factor Receptor Inhibition in the Management of Squamous Cell Carcinoma of the Lung. AB - Molecular therapies targeting epidermal growth factor receptor (EGFR) have had a profound impact on the management of advanced non-small cell lung cancer (NSCLC). EGFR inhibition with EGFR tyrosine kinase inhibitors (EGFR-TKIs) and anti-EGFR monoclonal antibodies (mAbs) in squamous NSCLC (sqNSCLC) remains controversial in patients whose tumors are not known to harbor EGFR mutations. Recent meta analyses of EGFR-inhibition randomized trials that are adequately powered for histological subgroup analysis and anti-EGFR trials limited to patients with squamous histology afford the opportunity to revisit EGFR treatment in sqNSCLC. In unselected patients with sqNSCLC who are not eligible for chemotherapy, EGFR TKI therapy is a valid treatment option over placebo or best supportive care, with improved progression-free survival noted in randomized controlled trials in both the first- and second-line setting and improved overall survival (OS) in the second-line setting. In patients eligible for chemotherapy, first-line combination regimens with anti-EGFR mAbs have been shown to improve OS over chemotherapy alone in patients with squamous histology in meta-analysis and more recently in the SQUIRE sqNSCLC trial (chemotherapy with and without necitumumab). In sqNSCLC patients who respond to induction chemotherapy, maintenance therapy with erlotinib delays disease progression and may improve the survival of patients with stable disease. In the second-line setting, survival outcomes are comparable between chemotherapy and EGFR-TKIs in meta-analysis, with the latter being more tolerable as a second-line therapy. Newer-generation EGFR-TKI therapies may further benefit patients with sqNSCLC who have failed first-line chemotherapy, given the positive trial results from LUX-Lung 8 (afatinib vs. erlotinib). EGFR is a valid therapeutic target in unselected/EGFR wild-type patients with squamous cell carcinoma of the lung. With the recent approval of immune checkpoint inhibitors in the second-line management of advanced sqNSCLC and their adoption as a new standard of care, there exists an opportunity for novel combination therapies to increase therapeutic efficacy and durable tumor control. As more targeted agents are approved, combination regimens that include an anti-EGFR agent should be evaluated, and the optimal sequencing of targeted therapies should be defined. IMPLICATIONS FOR PRACTICE: Anti-epidermal growth factor receptor (EGFR) therapies remain controversial in unselected/wild-type EGFR squamous non-small cell lung cancer (NSCLC). Recent meta-analyses and squamous-only NSCLC EGFR-inhibition trials have overcome the power limitations of early trials and can now inform the management of squamous NSCLC with anti-EGFR therapies. With the approval of immunotherapeutics in the second-line management of squamous NSCLC, there exists an opportunity for novel combination therapies to improve efficacy and durable tumor control. The optimal timing and sequencing of available second-line targeted therapies, however, have yet to be defined. This review analyzes randomized clinical trials of EGFR inhibition in NSCLC and meta analyses of these trials, with a focus on patients with squamous histology. PMID- 26768488 TI - Complex regulation of ADAR-mediated RNA-editing across tissues. AB - BACKGROUND: RNA-editing is a tightly regulated, and essential cellular process for a properly functioning brain. Dysfunction of A-to-I RNA editing can have catastrophic effects, particularly in the central nervous system. Thus, understanding how the process of RNA-editing is regulated has important implications for human health. However, at present, very little is known about the regulation of editing across tissues, and individuals. RESULTS: Here we present an analysis of RNA-editing patterns from 9 different tissues harvested from a single mouse. For comparison, we also analyzed data for 5 of these tissues harvested from 15 additional animals. We find that tissue specificity of editing largely reflects differential expression of substrate transcripts across tissues. We identified a surprising enrichment of editing in intronic regions of brain transcripts, that could account for previously reported higher levels of editing in brain. There exists a small but remarkable amount of editing which is tissue specific, despite comparable expression levels of the edit site across multiple tissues. Expression levels of editing enzymes and their isoforms can explain some, but not all of this variation. CONCLUSIONS: Together, these data suggest a complex regulation of the RNA-editing process beyond transcript expression levels. PMID- 26768490 TI - Validation of a fast method for quantification of intra-abdominal and subcutaneous adipose tissue for large-scale human studies. AB - Central obesity is the hallmark of a number of non-inheritable disorders. The advent of imaging techniques such as MRI has allowed for a fast and accurate assessment of body fat content and distribution. However, image analysis continues to be one of the major obstacles to the use of MRI in large-scale studies. In this study we assess the validity of the recently proposed fat-muscle quantitation system (AMRA(TM) Profiler) for the quantification of intra-abdominal adipose tissue (IAAT) and abdominal subcutaneous adipose tissue (ASAT) from abdominal MR images. Abdominal MR images were acquired from 23 volunteers with a broad range of BMIs and analysed using sliceOmatic, the current gold-standard, and the AMRA(TM) Profiler based on a non-rigid image registration of a library of segmented atlases. The results show that there was a highly significant correlation between the fat volumes generated by the two analysis methods, (Pearson correlation r = 0.97, p < 0.001), with the AMRA(TM) Profiler analysis being significantly faster (~3 min) than the conventional sliceOmatic approach (~40 min). There was also excellent agreement between the methods for the quantification of IAAT (AMRA 4.73 +/- 1.99 versus sliceOmatic 4.73 +/- 1.75 l, p = 0.97). For the AMRA(TM) Profiler analysis, the intra-observer coefficient of variation was 1.6% for IAAT and 1.1% for ASAT, the inter-observer coefficient of variation was 1.4% for IAAT and 1.2% for ASAT, the intra-observer correlation was 0.998 for IAAT and 0.999 for ASAT, and the inter-observer correlation was 0.999 for both IAAT and ASAT. These results indicate that precise and accurate measures of body fat content and distribution can be obtained in a fast and reliable form by the AMRA(TM) Profiler, opening up the possibility of large-scale human phenotypic studies. PMID- 26768489 TI - Alterations in creatine metabolism observed in experimental autoimmune myocarditis using ex vivo proton magic angle spinning MRS. AB - Experimental autoimmune myocarditis (EAM) in rodents is an accepted model of myocarditis and dilated cardiomyopathy (DCM). Altered metabolism is thought to play an important role in the pathogenesis of DCM and heart failure (HF). Study of the metabolism may provide new diagnostic information and insights into the mechanisms of myocarditis and HF. Proton MRS ((1)H-MRS) has not yet been used to study the changes occurring in myocarditis and subsequent HF. We aimed to explore the changes in creatine metabolism using this model and compare them with the findings in healthy animals. Myocardial function of male young Lewis rats with EAM was quantified by performing left ventricular ejection fraction (LVEF) analysis in short-axis cine images throughout the whole heart. Inflammatory cellular infiltrate was assessed by immunohistochemistry. Myocardial tissue was analyzed using ex vivo proton magic angle spinning MRS ((1)H-MAS-MRS). Myocarditis was confirmed histologically by the presence of an inflammatory cellular infiltrate and CD68 positive staining. A significant increase in the metabolic ratio of Tau/tCr (taurine/total creatine) obtained by (1)H-MAS-MRS was observed in myocarditis compared with healthy controls (21 d acute EAM, 4.38 (+/ 0.23); 21 d control, 2.84 (+/-0.08); 35 d chronic EAM, 4.47 (+/-0.83); 35 d control, 2.59 (+/-0.38); P < 0.001). LVEF was reduced in diseased animals (EAM, 55.2% (+/-11.3%); control, 72.6% (+/-3.8%); P < 0.01) and correlated with Tau/tCr ratio (R = 0.937, P < 0.001). Metabolic alterations occur acutely with the development of myocarditis. Myocardial Tau/tCr ratio as detected by (1)H-MRS correlates with LVEF and is able to differentiate between healthy myocardium and myocardium from rats with EAM. PMID- 26768491 TI - Microvasculature alters the dispersion properties of shear waves--a multi frequency MR elastography study. AB - Magnetic Resonance Elastography (MRE) uses macroscopic shear wave propagation to quantify mechanical properties of soft tissues. Micro-obstacles are capable of affecting the macroscopic dispersion properties of shear waves. Since disease or therapy can change the mechanical integrity and organization of vascular structures, MRE should be able to sense these changes if blood vessels represent a source for wave scattering. To verify this, MRE was performed to quantify alteration of the shear wave speed cs due to the presence of vascular outgrowths using an aortic ring model. Eighteen fragments of rat aorta included in a Matrigel matrix (n=6 without outgrowths, n=6 with a radial outgrowth extent of ~600 um and n=6 with ~850 um) were imaged using a 7 Tesla MR scanner (Bruker, PharmaScan). High resolution anatomical images were acquired in addition to multi frequency MRE (nu = 100, 115, 125, 135 and 150 Hz). Average cs was measured within a ring of ~900 um thickness encompassing the aorta and were normalized to cs0 of the corresponding Matrigel. The frequency dependence was fit to the power law model cs ~nu(y). After scanning, optical microscopy was performed to visualize outgrowths. Results demonstrated that in presence of vascular outgrowths (1) normalized cs significantly increased for the three highest frequencies (Kruskal-Wallis test, P = 0.0002 at 125 Hz and P = 0.002 at 135 Hz and P = 0.003 at 150 Hz) but not for the two lowest (Kruskal-Wallis test, P = 0.63 at 100 Hz and P = 0.87 at 115 Hz), and (2) normalized cs followed a power law behavior not seen in absence of vascular outgrowths (ANOVA test, P < 0.0001). These results showed that vascular outgrowths acted as micro-obstacles altering the dispersion relationships of propagating shear waves and that MRE could provide valuable information about microvascular changes. PMID- 26768492 TI - Classification of brain tumours from MR spectra: the INTERPRET collaboration and its outcomes. AB - The INTERPRET project was a multicentre European collaboration, carried out from 2000 to 2002, which developed a decision-support system (DSS) for helping neuroradiologists with no experience of MRS to utilize spectroscopic data for the diagnosis and grading of human brain tumours. INTERPRET gathered a large collection of MR spectra of brain tumours and pseudo-tumoural lesions from seven centres. Consensus acquisition protocols, a standard processing pipeline and strict methods for quality control of the aquired data were put in place. Particular emphasis was placed on ensuring the diagnostic certainty of each case, for which all cases were evaluated by a clinical data validation committee. One outcome of the project is a database of 304 fully validated spectra from brain tumours, pseudotumoural lesions and normal brains, along with their associated images and clinical data, which remains available to the scientific and medical community. The second is the INTERPRET DSS, which has continued to be developed and clinically evaluated since the project ended. We also review here the results of the post-INTERPRET period. We evaluate the results of the studies with the INTERPRET database by other consortia or research groups. A summary of the clinical evaluations that have been performed on the post-INTERPRET DSS versions is also presented. Several have shown that diagnostic certainty can be improved for certain tumour types when the INTERPRET DSS is used in conjunction with conventional radiological image interpretation. About 30 papers concerned with the INTERPRET single-voxel dataset have so far been published. We discuss stengths and weaknesses of the DSS and the lessons learned. Finally we speculate on how the INTERPRET concept might be carried into the future. PMID- 26768493 TI - Great expectations in acute myeloid leukemia. PMID- 26768494 TI - JAN 40 years on. PMID- 26768496 TI - Differences in soil micro-eukaryotic communities over soil pH gradients are strongly driven by parasites and saprotrophs. AB - A recent large-scale assessment of bacterial communities across a range of UK soil types showed that bacterial community structure was strongly determined by soil pH. We analysed a data set of eukaryotic 454 sequencing 18S rDNA from the surveyed samples and showed significant differences in eukaryotic assemblages according to pH class, mostly between low pH and higher pH soils. Soil eukaryote communities (per sample) differed most at the taxonomic rank approximating to order level. Taxonomies assigned with the Protist Ribosomal Reference and the Silva 119 databases were taxonomically inconsistent, mostly due to differing 18S annotations, although general structure and composition according to pH were coherent. A relatively small number of lineages, mostly putative parasitic protists and fungi, drive most differences between pH classes, with weaker contributions from bacterivores and autotrophs. Overall, soil parasites included a large diversity of alveolates, in particular apicomplexans. Phylogenetic analysis of alveolate lineages demonstrates a large diversity of unknown gregarines, novel perkinsids, coccidians, colpodellids and uncharacterized alveolates. Other novel and/or divergent lineages were revealed across the eukaryote tree of life. Our study provides an in-depth taxonomic evaluation of micro-eukaryotic diversity, and reveals novel lineages and insights into their relationships with environmental variables across soil gradients. PMID- 26768497 TI - Microsatellite Instability and BRAF and KRAS Mutations in Stage III Colon Cancer: Requirements for Accurate Prognosis Assessment. PMID- 26768498 TI - Teaching and technology. PMID- 26768501 TI - Ranking and situational judgement test. PMID- 26768502 TI - Ranking and situational judgement test: response. PMID- 26768503 TI - Value of undergraduate ophthalmology attachment. PMID- 26768504 TI - Value of undergraduate ophthalmology attachment: response. PMID- 26768506 TI - Saving orphan drug legislations: misconceptions and clarifications. AB - Orphan-drug sales are rocketing, with revenue expected to total $176 billion annually by 2020. As a share of the industry, orphan drugs now account for close to 15% of all prescription revenue globally (excluding generics) and the sector is set to grow at more than twice the rate (10.5%) of the overall prescription market (4.3%). But this success also equates to costs--borne by individual patients and cash-strapped health systems. Prices for orphan drugs can be 19 times higher than for other medications, hampering access for patients, many of whom are children. With ever more such expensive drugs reaching the market, the situation is becoming unsustainable and putting the survival of the orphan drug legislation itself at risk. Here the authors consider why there has been an increase in orphan drug designations, how orphan drug prices are set and regulated, before discussing proposals for how changes which could save the legislation. PMID- 26768508 TI - Robust Bayesian Algorithm for Targeted Compound Screening in Forensic Toxicology. AB - As part of forensic toxicological investigation of cases involving unexpected death of an individual, targeted or untargeted xenobiotic screening of post mortem samples is normally conducted. To this end, liquid chromatography (LC) coupled to high-resolution mass spectrometry (MS) is typically employed. For data analysis, almost all commonly applied algorithms are threshold-based (frequentist). These algorithms examine the value of a certain measurement (e.g., peak height) to decide whether a certain xenobiotic of interest (XOI) is present/absent, yielding a binary output. Frequentist methods pose a problem when several sources of information [e.g., shape of the chromatographic peak, isotopic distribution, estimated mass-to-charge ratio (m/z), adduct, etc.] need to be combined, requiring the approach to make arbitrary decisions at substep levels of data analysis. We hereby introduce a novel Bayesian probabilistic algorithm for toxicological screening. The method tackles the problem with a different strategy. It is not aimed at reaching a final conclusion regarding the presence of the XOI, but it estimates its probability. The algorithm effectively and efficiently combines all possible pieces of evidence from the chromatogram and calculates the posterior probability of the presence/absence of XOI features. This way, the model can accommodate more information by updating the probability if extra evidence is acquired. The final probabilistic result assists the end user to make a final decision with respect to the presence/absence of the xenobiotic. The Bayesian method was validated and found to perform better (in terms of false positives and false negatives) than the vendor-supplied software package. PMID- 26768510 TI - International Ranking of Infant Mortality Rates: Taiwan Compared with European Countries. AB - BACKGROUND: Rankings of infant mortality rates are commonly cited international comparisons to assess the health status of individual countries. We compared the infant mortality rate of Taiwan with those of European countries for 2004 according to two definitions. METHODS: First, the countries were ranked on the basis of crude infant, neonatal, and postneonatal mortality rates. The countries were then ranked according to the mortality rates calculated after exclusion of live births with a known birth weight of <1000 g, which is the definition set by the World Health Organization. RESULTS: Taiwan was ranked 11(th), 12(th), and 15(th) among 26 high-income countries for crude infant, neonatal, and postneonatal mortality rates, respectively. The ranks were 12(th), 16(th), and 15(th), respectively, for mortality rates, excluding live births with a birth weight of <1000 g. However, in only seven, four, and 10 countries were the mortality rate ratios statistically significantly lower than Taiwan in infant, neonatal, and postneonatal mortality, respectively, according to the second definition. CONCLUSION: The ranking of Taiwan was similar (11(th) vs. 12(th)) according the two definitions. However, after consideration of the confidence interval, only six countries (Sweden, Finland, Czech Republic, Belgium, Austria, and Germany) had infant mortality rates statistically significantly lower than those of Taiwan in 2004. PMID- 26768511 TI - High-content cell death imaging using quantum dot-based TIRF microscopy for the determination of anticancer activity against breast cancer stem cell. AB - We report a two color monitoring of drug-induced cell deaths using total internal reflection fluorescence (TIRF) as a novel method to determine anticancer activity. Instead of cancer cells, breast cancer stem cells (CSCs) were directly tested in the present assay to determine the effective concentration (EC50 ) values of camptothecin and cisplatin. Phosphatidylserine and HMGB1 protein were concurrently detected to observe apoptotic and necrotic cell death induced by anticancer drugs using quantum dot (Qdot)-antibody conjugates. Only 50-to-100 breast CSCs were consumed at each cell chamber due to the high sensitivity of Qdot-based TIRF. The high sensitivity of Qdot-based TIRF, that enables the consumption of a small number of cells, is advantageous for cost-effective large scale drug screening. In addition, unlike MTT assay, this approach can provide a more uniform range of EC50 values because the average values of single breast CSCs fluorescence intensities are observed to acquire EC50 values as a function of dose. This research successfully demonstrated the possibility that Qdot-based TIRF can be widely used as an improved alternative to MTT assay for the determination of anticancer drug efficacies. PMID- 26768512 TI - Neoadjuvant use of ipilimumab in locally advanced melanoma. AB - Recent advances in immune modulating therapies show great promise for patients with advanced melanoma, however optimal strategies for achieving long-term disease control in locally advanced melanoma are unclear. We present two cases of neoadjuvant ipilimumab, one case in combination with isolated limb infusion (ILI) followed by surgical resection and one followed by surgery alone. Both patients have had durable responses. These cases highlight the ongoing need for prospective trials in the neoadjuvant setting. PMID- 26768513 TI - Comment on: Surgical resection versus transarterial chemoembolization for BCLC stage C hepatocellular carcinoma. PMID- 26768514 TI - Surgery for advanced hepatocellular carcinoma: Time to take action. PMID- 26768515 TI - The impact of sarcopenia on survival and complications in surgical oncology: A review of the current literature--Author response. PMID- 26768516 TI - Dental treatment planning considerations for patients using cannabis: A case report. AB - BACKGROUND AND OVERVIEW: There is a deficit in clinical research on the potential risks involved in treating dental patients who use cannabis for either medicinal or recreational purposes. The aim of this case report is to illustrate the need for additional education for oral health care professionals so they can understand the wide variety of available cannabis options and their potential effects on dental treatment. CASE DESCRIPTION: A 27-year-old man sought care at the dental clinic with a nonrestorable molar requiring extraction. During the review of his medical history, the patient reported taking a "dab" of marijuana approximately 5 hours before his appointment. Because of the admission of recent illicit drug use, no treatment was rendered. The patient was offered an appointment the next day but he refused, citing bias in regard to his cannabis use. CONCLUSIONS AND PRACTICAL IMPLICATIONS: The number of Americans using marijuana is increasing rapidly. Twenty-three states and the District of Columbia have laws legalizing cannabis to some degree, and Alaska, Colorado, Oregon, and Washington have legalized marijuana for recreational use. This drastic upswing in availability and usage will require dentists to address the possible effects of cannabis on dental practices. It is imperative that dental care providers make clinical decisions based on scientific evidence regarding the pharmacologic and psychological effects of marijuana, not on the societal stigma associated with illegal drug use. Dentists should be familiar with popular delivery systems and understand the differences between various marijuana options. Clinical guidelines may need to be developed to help providers assess the patient's degree of cognitive impairment. Dentists should be able to advise patients on the potential consequences of this habit on their oral health. PMID- 26768517 TI - The Genome Editing Revolution in Livestock Marches on. PMID- 26768519 TI - Granulomatous skin involvement in a patient with an unusual NOD2 mutation. AB - Blau syndrome is a rare disorder that is classically characterised by granulomatous arthritis, skin eruptions and uveitis, which occur in the absence of lung involvement. Blau syndrome has been linked to encoding mutations in the NOD-2 gene and is inherited in an autosomal dominant form. The most commonly observed mutations are missense substitutions affecting the arginine residue at position 334. The rare E600A mutation has been described as causing uveitis without skin involvement. Our patient is a 54-year-old man with an unusual heterozygous c.1799A>C(E600A) mutation, who was seen for bilateral lower extremity swelling and pain. On physical examination, he was found to have lower leg oedema with decreased hair growth on the affected area. Biopsy showed non caseating micro-granulomas consistent with a diagnosis of Blau syndrome. The patient had excellent response to colchicine, but this was stopped because he developed elevated transaminases. Thus, we present an unusual genetic form of a rare condition and we demonstrate skin involvement in a subtype where cutaneous involvement has not hitherto been reported. In addition, the type and presentation of the skin involvement is different from that normally found in classic Blau syndrome. Finally, we report his response to colchicine, although it was ultimately not tolerated by this patient. PMID- 26768520 TI - Erratum: Properties of atoms in electronically excited molecules within the formalism of TDDFT [J. Comput Chem. 2014, 35, 820-828]. PMID- 26768522 TI - Genetics of cognitive control: Implications for Nimh's research domain criteria initiative. AB - Cognitive control refers to a set of mental processes that modulate other cognitive and emotional systems in service of goal-directed adaptive behavior. There is growing support for the notion that cognitive control abnormalities are a central component of many of the neuropsychological deficits observed in individuals with mental illnesses, particularly those with psychotic disorders. NIMH's research domain criteria (RDoC) initiative, which is designed to develop biologically informed constructs to better understand psychopathology, designated cognitive control a construct within the cognitive systems domain. Identification of genes that influence cognitive control or its supportive brain systems will improve our understating of the RDoC construct and provide candidate genes for psychotic disorders. We examine evidence for cognitive control deficits in psychosis, determine if these measures could be useful endophenotypes, and explore work linking genetic variation to cognitive control performance. While there is a wealth of evidence to support the notion the cognitive control is a valid endophenotype for psychosis, its genetic underpinning remains ill characterized. However, existing work provides a promising foundation on which future endeavors might build. Confirming existing individual gene associations will go some way to expanding our understanding of the genetics of cognitive control, and by extension, psychotic disorders. Yet, to truly understand the molecular underpinnings of such complex traits, it may be necessary to evaluate genes in tandem, focusing not on single genes but rather on empirically derived gene sets or on functionally defined networks of genes. PMID- 26768523 TI - Editorial: Neuroimaging in clinical psychiatry--when will the pay off begin? AB - For my father's generation, technology and progress are near synonyms. And his face still drops in disappointment when I tell him that we have found no imaging technique to improve the diagnosis, monitoring or treatment of psychiatric illness. His standard comment is: if the neurologists can, why can't you psychiatrists? Why indeed? PMID- 26768524 TI - Commentary: Does helping mothers with ADHD in multiplex families help children? Reflections on Jans et al. (2015). AB - Reflecting on the accompanying article by Jans et al., we draw the following thoughts. Future research on multiplex ADHD families is needed to elucidate mechanisms, timing, and a sequencing of interventions, preferably in treatment naive participants. Furthermore, in addition to symptom measures, it is likely that multi-informant measures of functional impairments such as parenting and parent-child observations may help elucidate the complex mechanisms linking maternal and child ADHD, and eventually lead to more targeted, efficient, and feasible prevention and intervention strategies. PMID- 26768525 TI - The Fragrant Hill Declaration on Cerebral Vascular Disease. PMID- 26768526 TI - Three Italian hospitals where women died in labour are criticised in report. PMID- 26768527 TI - Editorial. PMID- 26768528 TI - Mapping Strategy Associated with QRS Morphology for Catheter Ablation in Patients with Idiopathic Ventricular Outflow Tract Tachyarrhythmia. AB - BACKGROUND: In catheter ablation of idiopathic ventricular arrhythmia (VA), it is still unclear whether pace mapping or activation mapping is more useful for successful catheter ablation. The depth of origin in the ventricular wall especially affects the success rate of endocardial-approached catheter ablation. Thus, we examined the relationship between these tactics and QRS morphology. METHODS: We evaluated the relationship among pace mapping score, activation time, and peak deflection index (PDI) in 28 patients, with a total of 30 origins, who underwent successful catheter ablation of idiopathic VA. RESULTS: All origins were located in the ventricular outflow tract area, including three in the left coronary cusp (LCC). PDI, activation time, and pace mapping score at successful ablation sites were 0.60 +/- 0.08, 26.3 +/- 9.9 ms, and 19.1 +/- 4.6, respectively. The pace mapping score inversely correlated with the PDI (R = 0.540, P = 0.0017), but the activation time did not correlate with the PDI. When excluding the three VAs originating from the LCC, in which perfect pace mapping was obtained from epicardial sites despite high PDI, this correlation coefficient became more intensive (R = -0.734, P < 0.0001). CONCLUSIONS: Our study suggests that pace mapping with an endocardial approach could not reproduce the precise QRS morphology for VA originating from the intramural site of the ventricular wall. With such origins, we should rely on activation mapping to detect the optimal ablation site. PMID- 26768530 TI - Highly Stereoselective Synthesis of Imine-Containing Dibenzo[b,d]azepines by a Palladium(II)-Catalyzed [5+2] Oxidative Annulation of o-Arylanilines with Alkynes. AB - A novel palladium(II)-catalyzed [5+2] oxidative annulation of readily available o arylanilines with alkynes has been developed for building a seven-membered N heterocyclic architecture containing a biaryl linkage. This method is applicable to a wide range of unprotected o-arylanilines and internal alkynes, and results in the chemoselective preparation of imine-containing dibenzo[b,d]azepines in high yields with excellent diastereoselectivity with respect to the two types of stereogenic elements. PMID- 26768533 TI - Redox-Controlled Olefin (Co)Polymerization Catalyzed by Ferrocene-Bridged Phosphine-Sulfonate Palladium Complexes. AB - The facile and reversible interconversion between neutral and oxidized forms of palladium complexes containing ferrocene-bridged phosphine sulfonate ligands was demonstrated. The activity of these palladium complexes could be controlled using redox reagents during ethylene homopolymerization, ethylene/methyl acrylate copolymerization, and norbornene oligomerization. Specifically in norbornene oligomerization, the neutral complexes were not active at all whereas the oxidized counterparts showed appreciable activity. In situ switching between the neutral and oxidized forms resulted in an interesting "off" and "on" behavior in norbornene oligomerization. This work provides a new strategy to control the olefin polymerization process. PMID- 26768532 TI - Structures of Iridoid Synthase from Cantharanthus roseus with Bound NAD(+) , NADPH, or NAD(+) /10-Oxogeranial: Reaction Mechanisms. AB - Structures of the iridoid synthase nepetalactol synthase in the presence of NAD(+) , NADPH or NAD(+) /10-oxogeranial were solved. The 10-oxogeranial substrate binds in a transoid-O1-C3 conformation and can be reduced by hydride addition to form the byproduct S-10-oxo-citronellal. Tyr178 Ozeta is positioned 2.5 A from the substrate O1 and provides the second proton required for reaction. Nepetalactol product formation requires rotation about C1-C2 to form the cisoid isomer, leading to formation of the cis-enolate, together with rotation about C4 C5, which enables cyclization and lactol production. The structure is similar to that of progesterone-5beta-reductase, with almost identical positioning of NADP, Lys146(147), Tyr178(179), and F342(343), but only Tyr178 and Phe342 appear to be essential for activity. The transoid 10-oxogeranial structure also serves as a model for beta-face hydride attack in progesterone 5beta-reductases and is of general interest in the context of asymmetric synthesis. PMID- 26768534 TI - The Molybdenum(V) and Tungsten(VI) Oxoazides [MoO(N3 )3 ], [MoO(N3 )3 ?2 CH3 CN], [(bipy)MoO(N3 )3 ], [MoO(N3 )5 ](2-) , [WO(N3 )4 ], and [WO(N3 )4 ?CH3 CN]. AB - A series of novel molybdenum(V) and tungsten(VI) oxoazides was prepared starting from [MOF4 ] (M=Mo, W) and Me3 SiN3 . While [WO(N3 )4 ] was formed through fluoride-azide exchange in the reaction of Me3 SiN3 with WOF4 in SO2 solution, the reaction with MoOF4 resulted in a reduction of Mo(VI) to Mo(V) and formation of [MoO(N3 )3 ]. Carried out in acetonitrile solution, these reactions resulted in the isolation of the corresponding adducts [MoO(N3 )3 ?2 CH3 CN] and [WO(N3 )4 ?CH3 CN]. Subsequent reactions of [MoO(N3 )3 ] with 2,2'-bipyridine and [PPh4 ][N3 ] resulted in the formation and isolation of [(bipy)MoO(N3 )3 ] and [PPh4 ]2 [MoO(N3 )5 ], respectively. Most molybdenum(V) and tungsten(VI) oxoazides were fully characterized by their vibrational spectra, impact, friction and thermal sensitivity data and, in the case of [WO(N3 )4 ?CH3 CN], [(bipy)MoO(N3 )3 ], and [PPh4 ]2 [MoO(N3 )5 ], by their X-ray crystal structures. PMID- 26768531 TI - Double Strain-Promoted Macrocyclization for the Rapid Selection of Cell-Active Stapled Peptides. AB - Peptide stapling is a method for designing macrocyclic alpha-helical inhibitors of protein-protein interactions. However, obtaining a cell-active inhibitor can require significant optimization. We report a novel stapling technique based on a double strain-promoted azide-alkyne reaction, and exploit its biocompatibility to accelerate the discovery of cell-active stapled peptides. As a proof of concept, MDM2-binding peptides were stapled in parallel, directly in cell culture medium in 96-well plates, and simultaneously evaluated in a p53 reporter assay. This in situ stapling/screening process gave an optimal candidate that showed improved proteolytic stability and nanomolar binding to MDM2 in subsequent biophysical assays. alpha-Helicity was confirmed by a crystal structure of the MDM2-peptide complex. This work introduces in situ stapling as a versatile biocompatible technique with many other potential high-throughput biological applications. PMID- 26768536 TI - Adipose-derived mesenchymal stem cells and platelet-rich plasma synergistically ameliorate the surgical-induced osteoarthritis in Beagle dogs. AB - BACKGROUND: The purpose of this study is to investigate the clinical effects of platelet-rich plasma (PRP) and adipose-derived mesenchymal stem cell (MSC) as the fundamental treatment of osteoarthritis (OA). METHODS: Twenty four Beagle dogs were used as cranial cruciate ligament transection models. The dogs were divided into four groups (n = 6) according to the intra-articular injection materials: the control group with phosphate-buffered saline (PBS), the PRP group with PRP, the MSC group with MSCs emerged in PBS, and the MSC and PRP co-treatment (MP) group with MSCs and PRP. RESULTS: Lameness score, focal compression strength, articular extracellular matrix (ECM) compositions, histopathology, and real-time PCR were used to evaluate the effects of PRP and MSCs on canine OA. In the order of MP, PRP, and MSC group, these all showed positive effects on the evaluated categories. The lameness scores were lower, and the focal compression strengths of the affected femoral articular surface cartilages were higher than those in the OA control group. Also, the inflammatory changes, when evaluated with Mankin scoring and histomorphologic examination, were significantly ameliorated with the treatment of PRP and/or MSCs. The glycosaminoglycan and collagen composition of extracellular matrix was more favorable in the test groups. The ECM-related genes significantly increased through the up-regulation, while the protein expressions of inflammatory cytokines were decreased through the inhibitory effects of PRP and MSCs on chondrocyte apoptosis and inflammatory cytokines. CONCLUSIONS: Taken together, this study suggests that PRP and MSCs treatments have a beneficial effect on OA via the stimulation of ECM synthesis and chondrocyte proliferation and via the inhibition of inflammatory reaction. PMID- 26768537 TI - Forensic analysis of P2P derived amphetamine synthesis impurities: identification and characterization of indene by-products. AB - 1-Phenyl-2-propanone (P2P) is an internationally monitored precursor that has become increasingly difficult for illicit amphetamine producers to source, which means that alternative routes to its preparation have become increasingly important. One such approach includes the hydrolysis of alpha phenylacetoacetonitrile (APAAN) with sulfuric acid. Previously, we reported the identification of 4,6-dimethyl-3,5-diphenylpryid-2-one following implementation of hydrolysis conditions and it was proposed that this compound might serve as one route specific by-product in the APAAN to P2P conversion. This study continued to explore the presence of impurities formed during this conversion and expanded also into a second route of P2P synthesis starting from alpha methylstyrene (AMS). All P2P products underwent the Leuckart procedure to probe the presence of P2P-related impurities that might have carried through to the final product. Two by-products associated with the APAAN hydrolysis route to P2P were identified as 2,3-diacetyl-2,3-diphenylsuccinonitrile (1) and 2-methyl-1 phenyl-1,3-dicarbonitrile-1H-indene (2), respectively. Two by-products associated with the AMS route to P2P and subsequent Leuckart reaction were 1,1,3-trimethyl-3 phenyl-2,3-dihydro-1H-indene (3) and 1-phenyl-N-(phenylethyl)propan-2-amine (4), respectively. The two indenes (2 and 3) identified in synthesized amphetamine originating from P2P suggested that it might be possible to differentiate between the two synthetic routes regarding the use of APAAN and AMS. Furthermore, the association of these compounds with amphetamine production appears to have been reported for the first time. The presence of compounds 1 - 4 in seized amphetamine samples and waste products could facilitate the suggestion whether APAAN or AMS were employed in the synthesis route to the P2P. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26768538 TI - Noninvasive color Doppler sonography of uterine blood flow throughout pregnancy in sheep and goats. AB - In contrast to cattle or horses, uterine blood flow in small ruminants has been investigated predominantly after surgical intervention and chronic instrumentation. The objective of the present study was to investigate the clinical applicability of noninvasive color Doppler sonography to characterize blood flow in the maternal uterine artery of sheep, n = 11 (18 pregnancies) and goats, n = 11 (20 pregnancies). The following parameters were measured transrectally or transabdominally: blood flow volume, time-averaged maximum velocity (TAMV), resistance index (RI), pulsatility index (PI), Time-averaged mean velocity, impedance of blood flow (AB or systolic/diastolic [S/D] velocity ratio), peak velocity of blood flow and blood flow acceleration. Examinations started 2 weeks after breeding and continued at 2-week intervals until parturition. Outcomes for sheep and goats were similar and will be discussed together. Based on noninvasive color Doppler sonography, blood flow volume increased (approximately 60-fold, P < 0.0001) until the end of pregnancy, with a rapid increase early in gestation, and a slow increase after week 18. Time averaged maximum velocity in the uterine artery increased (approximately 4-fold; P < 0.0001) throughout pregnancy in sheep and goats. Furthermore, for uterine artery blood flow, there was an effect of stage of pregnancy on PI and RI (P < 0.001 and P < 0.0001, respectively), both indices decreased until the end of gestation. Time-averaged mean velocity decreased from week 18 to 20 in both species. The blood flow acceleration increased (P < 0.0001) until week 16 and week 14 in sheep and goats, respectively, and then decreased until parturition. Similar to PI and RI, vascular impedance of the uterine decreased (P < 0.0001) throughout pregnancy. This is apparently the first study using noninvasive color Doppler sonography of uterine blood flow throughout physiological pregnancy in small ruminants. Clearly, this technology facilitates repeated, noninvasive assessments, with great potential for future studies. PMID- 26768539 TI - The ubiquitous hyaluronan: Functionally implicated in the oviduct? AB - Hyaluronan (hyaluronic acid) is a simple, nonantigenic, nonsulfated glycosaminoglycan present everywhere in the extracellular compartments of the body. Noteworthy, it is highly conserved phylogenetically, from sauropsida to mammals; and plays a plethora of roles from embryonic/fetal development to adult physiological and pathological events, including tumor development. In reproduction, hyaluronan has proven related to initial events as sperm survival, buildup of the sperm reservoir in the oviduct, regulation of sperm capacitation, and prefertilization to later participate in embryo, fetal, and placental development. Synthesis, binding (via the CD44 membrane receptor), and degradation of hyaluronan occur in male and female genital organs, the oviduct being no exception. This review discusses our current knowledge on roles of this ubiquitous glycosaminoglycan on the survival of immunologically foreign spermatozoa in the pig oviduct, a relevant event for fertility. During preovulatory storage in the functional tubal sperm reservoir, spermatozoa are entrapped in a mucus-like tubal fluid. This fluid contains fluctuating levels of hyaluronan, which is synthesized by the lining epithelium by hyaluronan synthase 3. Both hyaluronan and its CD44 receptor are particularly evident in the deep mucosal furrows of the sperm reservoir, in which most spermatozoa are embedded in; kept alive, uncapacitated but also undetected by the immune system of the female. Hyaluronan is also present in the seminal plasma, and evidence points toward an involvement of hyaluronan and its receptor in the local (tubal and possibly uterine) production of antiinflammatory cytokines, such as interleukin 10, pertaining maternal immune tolerance of these foreign cells. PMID- 26768540 TI - Application of a microfluidic sperm sorter to in vitro production of dairy cattle sex-sorted embryos. AB - Viable sperm from sex-sorted semen without centrifugal treatment was separated by a microfluidic sperm sorter (MFSS) for IVF to improve in vitro embryo production of dairy cattle. The MFSS was originally developed to isolate motile human sperm by two laminar flows in the micro-channel (there are four chambers in an MFSS. Chamber A is the inlet for semen, chamber B is the inlet for the medium, chamber C is the exit chamber for motile sperm, and chamber D is the outlet for nonmotile sperm). Sex-sorted sperm were adjusted to 1 * 10(7) spermatozoa/mL (2 million cells/dose, sperm motility was 30% above after thawing). In a first experiment, diluted sex-sorted semen was mixed with modified Medium199(mM199) containing 5-mM caffeine for 5 minutes, resulting in variations in sperm concentration and quality parameters at chambers A, C, and D. In a second experiment, medium containing sperm from three MFSS chambers was collected and mitochondrial activity of the sperm was determined by flow cytometry, the relative activity of sperm mitochondria in chamber C (1.56 +/- 0.03) was the highest in three observation areas (P < 0.05). Thus, sperm motility and mitochondrial activity of sperm was high in chamber C. In a third experiment, different concentrations of sperm were added to chamber A and dairy cattle IVM oocytes were placed in chamber C, where motile spermatozoa will accumulate, with mM199 containing 5-mM caffeine for 5 minutes, and then cultured in caffeine-free mM199 for 8 hours. The results showed that sperm penetration rate, the monospermic penetration rate, and blastocyst rate of the 10 * 10(6) group (10 * 10(6) sperm/mL) were higher than in the 1 * 10(6) and 5 * 10(6) groups (P < 0.05). In the last experiment, we compared sperm penetration in the MFSS-IVF system with a modified standard IVF method (cocultured in droplets for 8 hours). The normal fertilization index (the ratio of monospermic oocytes to the number of oocytes examined) 8 hours after insemination was higher in the MFSS-IVF system than the modified standard IVF system (P < 0.05). Developmental competence of fertilized oocytes to the blastocyst stage was also higher in the MFSS-IVF system (40.12% +/- 2.61%) than the modified standard IVF technique (24.55% +/- 4.54%). These results demonstrate that a short coculture of dairy cattle oocytes with isolated motile sex-sorted spermatozoa gradually accumulated in the MFSS device improves the efficiencies of normally produced fertilized embryos and blastocyst formation. PMID- 26768541 TI - Cryopreservation of Persian sturgeon (Acipenser persicus) embryos by DMSO-based vitrificant solutions. AB - Vitrification could provide a promising tool for the cryopreservation of fish embryos. To achieve successful cryopreservation, several parameters should be taken into account in the design of a vitrification protocol. In the present study, some relevant factors were investigated (choice of a proper vitrificant solutions and temperature for thawing) using neurulation-stage embryos. Six DMSO based vitrificant solutions (V1-V6) were tested using a 6-step incorporation protocol. DMSO-based vitrificant solutions contained DMSO + permeable cryoprotectants + nonpermeable cryoprotectants. Embryos were immersed in vitrificant solutions for 7 minutes and directly plunged into liquid nitrogen. After vitrification (-196 degrees C for 10 minutes), the thawing was performed in a water bath at 0 or 20 degrees C and then embryos incubated until hatched. Our results demonstrated that some embryos vitrified in 5 of 6 vitrification solutions survived and hatched out, but none survived after vitrification in V2. The highest survival rate (45.45%) was observed in samples frozen with the best vitrificant solution (V6) and thawing combination (20 degrees C). These results establish that cryopreservation of Persian sturgeon (Acipenser persicus) embryos by DMSO-based vitrificant solutions is possible. PMID- 26768542 TI - Potential of Liposomes for Enhancement of Oral Drug Absorption. AB - Oral administration of medication is the first option when patient compliance is considered. However, many barriers face oral absorption of drugs that limit bioavailability in about 90% of therapeutic agents. Utilization of nanoparticulate drug delivery systems is a major strategy for increasing oral absorption. They can improve oral bioavailability through mechanisms such as protection of the drug in the GI tract, increasing cellular contact and residence time of the drug, protection of the drug from presystemic metabolism and efflux and increasing diffusion across the mucosal and epithelial layers. Liposomes are biocompatible carriers employed to improve oral bioavailability of drugs and in addition to the general advantages of nanocarriers for oral delivery, they offer benefits derived from their lipidic bilayer structure. They can better adhere to biomembranes, form mixed-micelle structures with bile salts to increase the solubility of poorly-soluble drugs and are suitable candidates for lymphatic uptake. They have been successful in improving oral bioavailability of a variety of compounds including peptide and proteins, hydrophilic and lipophilic drugs. Stability under GI conditions is the main concern for oral liposomes, however, promising approaches have been suggested to increase the stability of oral liposomes. These include: using appropriate lipid compositions, polymer coating, addition of stabilizing lipids to liposomal structures, preparation of double liposomes and proliposomes and some other innovative methods. The present review focuses on the role of liposomes in improving oral absorption of drugs, the problems encountered, and the types of liposomes designed to overcome these issues. Barriers to oral delivery will be discussed and examples of bioavailability enhancement upon encapsulation in various types of liposomes investigated. PMID- 26768543 TI - The Pitfalls of Rendering an Expert Opinion in Breast Malpractice Cases by Reviewing a CD-ROM. PMID- 26768544 TI - Shorter Perceived Outpatient MRI Wait Times Associated With Higher Patient Satisfaction. AB - PURPOSE: The aim of this study was to assess differences in perceived versus actual wait times among patients undergoing outpatient MRI examinations and to correlate those times with patient satisfaction. METHODS: Over 15 weeks, 190 patients presenting for outpatient MR in a radiology department in which "patient experience" is one of the stated strategic priorities were asked to (1) estimate their wait times for various stages in the imaging process and (2) state their satisfaction with their imaging experience. Perceived times were compared with actual electronic time stamps. Perceived and actual times were compared and correlated with standardized satisfaction scores using Kendall tau correlation. RESULTS: The mean actual wait time between patient arrival and examination start was 53.4 +/- 33.8 min, whereas patients perceived a mean wait time of 27.8 +/- 23.1 min, a statistically significant underestimation of 25.6 min (P < .001). Both shorter actual and perceived wait times at all points during patient encounters were correlated with higher satisfaction scores (P < .001). CONCLUSIONS: Patients undergoing outpatient MR examinations in an environment designed to optimize patient experience underestimated wait times at all points during their encounters. Shorter perceived and actual wait times were both correlated with higher satisfaction scores. As satisfaction surveys play a larger role in an environment of metric transparency and value-based payments, better understanding of such factors will be increasingly important. PMID- 26768545 TI - Know-How on Clinical MRI Research in Iran. PMID- 26768546 TI - Burnout of Radiologists: Frequency, Risk Factors, and Remedies: A Report of the ACR Commission on Human Resources. AB - Burnout is a concern for radiologists. The burnout rate is greater among diagnostic radiologists than the mean for all physicians, while radiation oncologists have a slightly lower burnout rate. Burnout can result in unprofessional behavior, thoughts of suicide, premature retirement, and errors in patient care. Strategies to reduce burnout include addressing the sources of job dissatisfaction, instilling lifestyle balance, finding reasons to work other than money, improving money management, developing a support group, and seeking help when needed. PMID- 26768547 TI - 2015 AMCLC Open-Microphone Session: Improving the IQ (Information Quality) of What We Do. AB - Each year an open-microphone session is hosted by the Council Steering Committee. The committee invited an expert panel to discuss the use of effective communication in appropriate procedure selection and methods and resources to communicate the results of procedures performed in an actionable and clear manner to referring clinicians and patients, as well as downstream data systems. The ACR is actively encouraging radiologists to leverage existing and new technologies to increase their visibility in the health care system. Key features in Imaging 3.0 are results reporting through actionable reports, decision support for results reporting, guidelines for recommendations, tools for actionable reports, and tracking a radiologist's recommendations. The final radiology report is an essential product of our service, but it is increasingly clear that the noninterpretive components of our profession will add the most value to patient care. The radiology report is not the only evidence of our work. Nonetheless, the information quality and content of the radiology report can and must be improved so that it can add value and clinical usefulness toward excellent patient care. We must use appropriate tools and "best knowledge" to deliver actionable and value-added high-quality reports. PMID- 26768549 TI - Isolation and purification of six iridoid glycosides from gardenia jasminoides fruit by medium-pressure liquid chromatography combined with macroporous resin chromatography. AB - Gardeniae fructus is one of the most frequently used herbs in traditional Chinese medicine. In the present study, a process for the enrichment of six iridoid glycosides from Gardeniae fructus was developed using medium-pressure liquid chromatography combined with macroporous resin and reversed-phase chromatography. The purities of different fractions from Gardeniae fructus were assessed using quantitative high-performance liquid chromatography. After fractionation using HPD-100 column chromatography, a 30% ethanol fraction was selected based on high performance liquid chromatography and liquid chromatography with mass spectrometry qualitative analysis to separate and purify. Based on the orientation analysis results, six compounds-deacetyl asperulosidic acid methyl ester, gardenoside, ixoroside, scandoside methyl ester, genipin-1-O-beta-d gentiobioside, and geniposide-were successfully isolated and purified in three to four combined steps from Gardeniae fructus. The purities of these compounds were found by high-performance liquid chromatography analysis to be 97.9, 98.1, 95.5, 96.3, 97.1, and 98.7%, respectively. Moreover, their structures were elucidated by NMR spectroscopy and liquid chromatography with tandem mass spectrometry. The separation process was highly efficient, rapid, and accurate, making it a potential approach for the large-scale production of iridoids in the laboratory and providing several marker compounds for quality control. This procedure may be meaningful for the purification of other natural products used in traditional Chinese medicine. PMID- 26768552 TI - The enhancing effect of genistein on apoptosis induced by trichostatin A in lung cancer cells with wild type p53 genes is associated with upregulation of histone acetyltransferase. AB - Genistein has been shown to enhance the antitumor activity of trichostatin A (TSA) in human lung carcinoma A549 cells. However, whether the combined treatment exerts the same effect in other lung cancer cells is unclear. In the present study we first compared the enhancing effect of genistein on the antitumor effect of TSA in ABC-1, NCI-H460 (H460) and A549 cells. Second, we investigated whether the effects of genistein are associated with increased histone/non-histone protein acetylation. We found that the enhancing effect of genistein on cell growth-arrest in ABC-1 cells (p53 mutant) was less than in A549 and H460 cells. Genistein enhanced TSA induced apoptosis in A549 and H460 cells rather than in ABC-1 cells. After silencing p53 expression in A549 and H460 cells, the enhancing effect of genistein was diminished. In addition, genistein increased TSA-induced histone H3/H4 acetylation in A549 and H460 cells. Genistein also increased p53 acetylation in H460 cells. The inhibitor of acetyltransferase, anacardic acid, diminished the enhancing effect of genistein on all TSA-induced histone/p53 acetylation and apoptosis. Genistein in combination with TSA increased the expression of p300 protein, an acetyltransferase, in A549 and NCI-H460 cells. Furthermore, we demonstrated that genistein also enhanced the antitumor effect of genistein in A549-tumor-bearing mice. Taken together, these results suggest that the enhancing effects of genistein on TSA-induced apoptosis in lung cancer cells were p53-dependent and were associated with histone/non-histone protein acetylation. PMID- 26768555 TI - Remarks on designs enriching for placebo non-responders. AB - BACKGROUND: High response under placebo constitutes a concern in clinical studies, particularly in psychiatry. Discontinuation of placebo responders identified during a placebo run-in is often recommended to avoid failures of clinical trials in the presence of high placebo effects. Evidence for the benefit of this approach is ambiguous. PURPOSE: We investigate under which conditions a placebo lead-in can be beneficial in the context of continuous data, assuming that the data in the placebo run-in and the treatment stage follow a bivariate normal distribution. Placebo responders are defined as patients with an effect during placebo lead-in which is larger than a pre-defined threshold on the absolute value or the absolute or relative change from baseline or a combination thereof. RESULTS: Data are less variable under either placebo or test treatment after placebo responders have been removed. Whether the effect of test over placebo increases or decreases after enrichment for placebo non-responders depends on the parameters of the distribution, in particular the covariance structure, and the threshold in the definition of placebo responders. LIMITATIONS: The results apply in the continuous case, and the binary or ordinary case is not studied. The findings explain to some extent the ambiguity in the assessments of the usefulness of placebo lead-in periods in clinical trials; however, besides the clear statement on variability reduction, it is not straightforward to judge upfront whether placebo lead-in is useful. Concerns relating to the conduct and interpretation of results of such trials are mentioned. PMID- 26768556 TI - Trial design for evaluating novel treatments during an outbreak of an infectious disease. AB - Tragically, the outbreak of Ebola that started in West Africa in 2014 has been far more extensive and damaging than any previous outbreaks. The duration of the outbreak has, for the first time, allowed the clinical evaluation of Ebola treatments. This article discusses the designs used for two such clinical trials which have recruited patients in Liberia and Sierra Leone. General principles are outlined for trial designs intended to be deployed quickly, adapt flexibly and provide results soon enough to influence the course of the current epidemic rather than just providing evidence for use should Ebola break out again. Lessons are drawn for the conduct of clinical research in future outbreaks of infectious diseases, where the sequence of events may or may not be similar to the West African Ebola epidemic. PMID- 26768557 TI - Clinical research during the Ebola virus disease outbreak in Guinea: Lessons learned and ways forward. PMID- 26768558 TI - Randomized controlled trials in the West African Ebola virus outbreak. PMID- 26768548 TI - Fibroblast growth factors, old kids on the new block. AB - The fibroblast growth factors (FGFs) are a family of cell intrinsic regulatory peptides that control a broad spectrum of cellular activities. The family includes canonic FGFs that elicit their activities by activating the FGF receptor (FGFR) tyrosine kinase and non-canonic members that elicit their activities intracellularly and via FGFR-independent mechanisms. The FGF signaling axis is highly complex due to the existence of multiple isoforms of both ligands and receptors, as well as cofactors that include the chemically heterogeneous heparan sulfate (HS) cofactors, and in the case of endocrine FGFs, the Klotho coreceptors. Resident FGF signaling controls embryonic development, maintains tissue homeostasis, promotes wound healing and tissue regeneration, and regulates functions of multiple organs. However, ectopic or aberrant FGF signaling is a culprit for various diseases, including congenital birth defects, metabolic disorder, and cancer. The molecular mechanisms by which the specificity of FGF signaling is achieved remain incompletely understood. Since its application as a druggable target has been gradually recognized by pharmaceutical companies and translational researchers, understanding the determinants of FGF signaling specificity has become even more important in order to get into the position to selectively suppress a particular pathway without affecting others to minimize side effects. PMID- 26768553 TI - Enzymatic oxidative biodegradation of nanoparticles: Mechanisms, significance and applications. AB - Biopersistence of carbon nanotubes, graphene oxide (GO) and several other types of carbonaceous nanomaterials is an essential determinant of their health effects. Successful biodegradation is one of the major factors defining the life span and biological responses to nanoparticles. Here, we review the role and contribution of different oxidative enzymes of inflammatory cells - myeloperoxidase, eosinophil peroxidase, lactoperoxidase, hemoglobin, and xanthine oxidase - to the reactions of nanoparticle biodegradation. We further focus on interactions of nanomaterials with hemoproteins dependent on the specific features of their physico-chemical and structural characteristics. Mechanistically, we highlight the significance of immobilized peroxidase reactive intermediates vs diffusible small molecule oxidants (hypochlorous and hypobromous acids) for the overall oxidative biodegradation process in neutrophils and eosinophils. We also accentuate the importance of peroxynitrite-driven pathways realized in macrophages via the engagement of NADPH oxidase- and NO synthase triggered oxidative mechanisms. We consider possible involvement of oxidative machinery of other professional phagocytes such as microglial cells, myeloid derived suppressor cells, in the context of biodegradation relevant to targeted drug delivery. We evaluate the importance of genetic factors and their manipulations for the enzymatic biodegradation in vivo. Finally, we emphasize a novel type of biodegradation realized via the activation of the "dormant" peroxidase activity of hemoproteins by the nano-surface. This is exemplified by the binding of GO to cyt c causing the unfolding and 'unmasking' of the peroxidase activity of the latter. We conclude with the strategies leading to safe by design carbonaceous nanoparticles with optimized characteristics for mechanism-based targeted delivery and regulatable life-span of drugs in circulation. PMID- 26768559 TI - Ebola clinical trials: Five lessons learned and a way forward. PMID- 26768560 TI - Statistics and logistics: Design of Ebola vaccine trials in West Africa. PMID- 26768561 TI - A viewpoint on European Medicines Agency experience with investigational medicinal products for Ebola. PMID- 26768562 TI - Academics are from Mars, humanitarians are from Venus: Finding common ground to improve research during humanitarian emergencies. PMID- 26768563 TI - Evaluating interventions for Ebola: The need for randomized trials. PMID- 26768564 TI - Conducting clinical trials in outbreak settings: Points to consider. PMID- 26768565 TI - A US Food and Drug Administration perspective on evaluating medical products for Ebola. PMID- 26768566 TI - Clinical validation trial of a diagnostic for Ebola Zaire antigen detection: Design rationale and challenges to implementation. AB - The current Ebola outbreak in West Africa has affected more people than all previous outbreaks combined. The current diagnostic method of choice, quantitative polymerase chain reaction, requires specialized conditions as well as specially trained technicians. Insufficient testing capacity has extended the time from sample collection to results. These delays have led to further delays in the transfer and treatment to Ebola Treatment Units. A sensitive and specific point-of-care device that could be used reliably in low-resource settings by healthcare workers with minimal training would increase the efficiency of triage and appropriate transfer of care. This article describes a study designed to validate the sensitivity and specificity of the ReEBOVTM Rapid Diagnostic Test using venous whole blood and capillary blood obtained via fingerprick. We present the scientific and clinical rationale for the decisions made in the design of a diagnostic validation study to be conducted in an outbreak setting. The multi site strategy greatly complicated implementation. In addition, a decrease in cases in one geographic area along with a concomitant increase in other areas made site selection challenging. Initiation of clinical trials during rapidly evolving outbreaks requires significant cooperation on a national level between research teams implementing studies and clinical care providers. Coordination and streamlining of approval process are essential if trials are to be implemented in a timely fashion. PMID- 26768567 TI - Statistical considerations for a trial of Ebola virus disease therapeutics. AB - The 2014 West African outbreak of Ebola virus ravaged Liberia, Sierra Leone, and Guinea, causing hemorrhagic fever and death. The need to identify effective therapeutics was acute. The usual drug development paradigm of phase I, followed by phase II, and then phase III trials would take too long. These and other factors led to the design of a clinical trial of Ebola virus disease therapeutics that differs from more conventional clinical trial designs. This article describes the Ebola virus disease medical countermeasures trial design and the thinking behind it. PMID- 26768568 TI - Simulation-guided phase 3 trial design to evaluate vaccine effectiveness to prevent Ebola virus disease infection: Statistical considerations, design rationale, and challenges. AB - Starting in December 2013, West Africa was overwhelmed with the deadliest outbreak of Ebola virus known to date, resulting in more than 27,500 cases and 11,000 deaths. In response to the epidemic, development of a heterologous prime boost vaccine regimen was accelerated and involved preparation of a phase 3 effectiveness study. While individually randomized controlled trials are widely acknowledged as the gold standard for demonstrating the efficacy of a candidate vaccine, there was considerable debate on the ethical appropriateness of these designs in the context of an epidemic. A suitable phase 3 trial must convincingly ensure unbiased evaluation with sufficient statistical power. In addition, efficient evaluation of a vaccine candidate is required so that an effective vaccine can be immediately disseminated. This manuscript aims to present the statistical and modeling considerations, design rationale and challenges encountered due to the emergent, epidemic setting that led to the selection of a cluster-randomized phase 3 study design under field conditions. PMID- 26768569 TI - A response adaptive randomization platform trial for efficient evaluation of Ebola virus treatments: A model for pandemic response. AB - The outbreak of Ebola virus disease in West Africa is the largest ever recorded. Numerous treatment alternatives for Ebola have been considered, including widely available repurposed drugs, but initiation of enrollment into clinical trials has been limited. The proposed trial is an adaptive platform design. Multiple agents and combinations will be investigated simultaneously. Additionally, new agents may enter the trial as they become available, and failing agents may be removed. In order to accommodate the many possible agents and combinations, a critical feature of this design is the use of response adaptive randomization to assign treatment regimens. As the trial progresses, the randomization ratio evolves to favor the arms that are performing better, making the design also suitable for all-cause pandemic preparedness planning. The study was approved by US and Sierra Leone ethics committees, and reviewed by the US Food and Drug Administration. Additionally, data management, drug supply lines, and local sites were prepared. However, in response to the declining epidemic seen in February 2015, the trial was not initiated. Sierra Leone remains ready to rapidly activate the protocol as an emergency response trial in the event of a resurgence of Ebola. (ClinicalTrials.gov Identifier: NCT02380625.) In summary, we have designed a single controlled trial capable of efficiently identifying highly effective or failing regimens among a rapidly evolving list of proposed therapeutic alternatives for Ebola virus disease and to treat the patients within the trial effectively based on accruing data. Provision of these regimens, if found safe and effective, would have a major impact on future epidemics by providing effective treatment options. PMID- 26768571 TI - Clinical trials during the Ebola crisis. PMID- 26768570 TI - Design and analysis considerations in the Ebola_Tx trial evaluating convalescent plasma in the treatment of Ebola virus disease in Guinea during the 2014-2015 outbreak. AB - The Ebola virus disease outbreak in 2014-2015 led to a huge caseload with a high case fatality rate. No specific treatments were available beyond supportive care for conditions such as dehydration and shock. Evaluation of treatment with convalescent plasma from Ebola survivors was identified as a priority. We evaluated this intervention in an emergency setting, where randomization was unacceptable. The original trial design was an open-label study comparing patients receiving convalescent plasma and supportive care to patients receiving supportive care alone. The comparison group comprised patients recruited at the start of the trial before convalescent plasma became available, as well as patients presenting during the trial for whom there was insufficient blood group compatible plasma or no staffing capacity to provide additional transfusions. However, during the trial, convalescent plasma was available to treat all new patients. The design was changed to use a comparator group comprising patients previously treated at the same Ebola treatment center prior to the start of the trial. In the analysis, it was planned to adjust for any differences in prognostic variables between intervention and comparison groups, specifically baseline polymerase chain reaction cycle threshold and age. In addition, adjustment was planned for other potential confounders, identified in the analysis, such as patient presenting symptoms and time to treatment seeking. Because plasma treatment started up to 3 days after diagnosis and we could not define a similar time-point for the comparator group, patients who died before the third day after confirmation of diagnosis were excluded from both intervention and comparison groups in a per-protocol analysis. Some patients received additional experimental treatments soon after plasma treatment, and these were excluded. We also analyzed mortality including all patients from the time of confirmed diagnosis, irrespective of whether those in the trial series actually received plasma, as an intention-to-treat analysis. Per-protocol and intention-to-treat approaches gave similar conclusions. An important caveat in the interpretation of the findings is that it is unlikely that all potential sources of confounding, such as any variation in supportive care over time, were eliminated. Protocols and electronic data capture systems have now been extensively field-tested for emergency evaluation of treatment with convalescent plasma. Ongoing studies seek to quantify the level of neutralizing antibodies in different plasma donations to determine whether this influences the response and survival of treated patients. PMID- 26768572 TI - Implementation of an Ebola virus disease vaccine clinical trial during the Ebola epidemic in Liberia: Design, procedures, and challenges. AB - The index case of the Ebola virus disease epidemic in West Africa is believed to have originated in Guinea. By June 2014, Guinea, Liberia, and Sierra Leone were in the midst of a full-blown and complex global health emergency. The devastating effects of this Ebola epidemic in West Africa put the global health response in acute focus for urgent international interventions. Accordingly, in October 2014, a World Health Organization high-level meeting endorsed the concept of a phase 2/3 clinical trial in Liberia to study Ebola vaccines. As a follow-up to the global response, in November 2014, the Government of Liberia and the US Government signed an agreement to form a research partnership to investigate Ebola and to assess intervention strategies for treating, controlling, and preventing the disease in Liberia. This agreement led to the establishment of the Joint Liberia-US Partnership for Research on Ebola Virus in Liberia as the beginning of a long-term collaborative partnership in clinical research between the two countries. In this article, we discuss the methodology and related challenges associated with the implementation of the Ebola vaccines clinical trial, based on a double-blinded randomized controlled trial, in Liberia. PMID- 26768573 TI - Ethical challenges to responding to the Ebola epidemic: the World Health Organization experience. PMID- 26768574 TI - Chronic and remitting trajectories of depressive symptoms in the elderly. Characterisation and risk factors. AB - BACKGROUND: In elderly general population sub-syndromal clinically significant levels of depressive symptoms are highly prevalent and associated with high co morbidity and increased mortality risk. However changes in depressive symptoms over time and etiologic factors have been difficult to characterise notably due to methodological shortcomings. Our objective was to differentiate trajectories of depressive symptoms over 10 years in community-dwelling elderly men and women using statistical modelling methods which take into account intra-subject correlation and individual differences as well as to examine current and life time risk factors associated with different trajectories. METHODS: Participants aged 65 and over were administered standardised questionnaires and underwent clinical examinations at baseline and after 2, 4, 7 and 10 years. Trajectories over time of the Center for Epidemiologic Studies Depression scores were modelled in 517 men and 736 women separately with latent class mixed models which include both a linear mixed model to describe latent classes of trajectories and a multinomial logistic model to characterise the latent trajectories according to baseline covariates (socio-demographic, lifestyle, clinical, genetic characteristics and stressful life events). RESULTS: In both genders two different profiles of symptom changes were observed over the 10-year follow-up. For 9.1% of men and 25% of women a high depressive symptom trajectory was found with a trend toward worsening in men. The majority of the remaining men and women showed decreasing symptomatology over time, falling from clinically significant to very low levels of depressive symptoms. In large multivariate class membership models, mobility limitations [odds ratio (OR) = 4.5, 95% confidence interval (CI) 1.6-12.9 and OR = 4.9, 95% CI 2.3-10.7, in men and women respectively], ischemic pathologies (OR = 2.9, 95% CI 1.0-8.3 and OR = 3.1, 95% CI 1.0-9.9), and recent stressful events (OR = 4.5, 95% CI 1.1-18.5, OR = 3.2, 95% CI 1.6-6.2) were associated with a poor symptom course in both gender as well as diabetes in men (OR = 3.5, 95% CI 1.1-10.9) and childhood traumatic experiences in women (OR = 3.1, 95% CI 1.6-5.8). CONCLUSIONS: This prospective study was able to differentiate patterns of chronic and remitting depressive symptoms in elderly people with distinct symptom courses and risk factors for men and women. These findings may inform prevention programmes designed to reduce the chronic course of depressive symptomatology. PMID- 26768575 TI - Characterization of type I and II procollagen alpha1 chain in Amur sturgeon (Acipenser schrenckii) and comparison of their gene expression. AB - To characterize type I and II collagen in the Amur sturgeon at the molecular level, mRNAs encoding the proalpha chain of both types of collagen were cloned and sequenced. Full sequences of both were obtained, and the molecular phylogeny based on the deduced amino acid sequence indicated that the correct sequences of the target genes were obtained. Analyses of primary structure of the proalpha chains revealed that type I and II collagen share the basic structure of the proalpha chain of fibril collagen, but have different characteristics, especially in residues related to thermal stability. In the triple helical domain, Gly-Pro Pro sequence stabilizing the tripeptide unit was more frequent in type II than in type I, and Gly-Gly, which likely decline in thermal stability, was more frequent in type I than in type II. These results suggested that the denaturation temperature of type II would be remarkably higher than type I. The spatial pattern of gene expression was analyzed by quantitative real-time PCR, which showed that relatively ubiquitous type I gene and strongly skewed distribution of type II gene, which highly expressed only in vertebra, snout cartilage, and notochord. This pattern was similar to the distribution pattern of each collagen protein detected by previous biochemical analyses using Amur and Bester sturgeons. The present study is the first report of the cloning of the full length cDNAs for both of type I and type II collagen in the Amur sturgeon, and is the first comparative analysis of type I and II collagens in a sturgeon species at the molecular level. The results provide basic and general information on collagens in sturgeons. PMID- 26768576 TI - Historical role of alpha-1-antitrypsin deficiency in respiratory and hepatic complications. AB - Alpha-1-antitrypsin (AAT) deficiency is a heritable disease that is commonly associated with complications in the respiratory and hepatic systems. AAT acts as a regulatory enzyme that primarily inhibits neutrophil elastase activity thus protecting tissues from proteolytic damage after inflammation. This paper provides a historical review of the discovery, classification, phenotypic expression, and treatment of AAT deficiency. While its pattern of inheritance has been long understood, the underlying mechanism between AAT deficiency and related diseases remains to be elucidated. Most commonly, AAT deficiency is associated with the development of emphysema in the lungs as well as various liver injuries. Cigarette smoke has been shown to be particularly detrimental in AAT deficient individuals during the development of lung disease. Therefore, understanding familial history may be beneficial when educating patients regarding lifestyle choices. While numerous AAT deficient phenotypes exist in the human populations, only specific variants have been proven to markedly predispose individuals to lung and liver disorders. The exact relationship between AAT levels and the aforementioned diseases is an essential area of further research. It is imperative that clinicians and researchers alike strive to standardize diagnostic criteria and develop safe and effective therapies for this genetic disease. PMID- 26768577 TI - Molecular insight into the activity of LasR protein from Pseudomonas aeruginosa in the regulation of virulence gene expression by this organism. AB - Pseudomonas aeruginosa is an opportunistic human pathogen. This organism attacks human patients suffering from diseases like AIDS, cancer, cystic fibrosis, etc. One of the important virulent factors produced by this organism is Hydrogen Cyanide. This is expressed from the genes encoded by the hcnABC operon. The expressions of the genes encoded by hcnABC operon are mediated mainly by the interactions of LasR protein with the corresponding promoter region of the hcnABC operon. The LasR protein acts as a dimer and binds to the promoter DNA with the help of an autoinducer ligand. However, till date the detailed molecular mechanism of how the LasR protein interacts with the promoter DNA is not clearly known. Therefore, in this work, an attempt has been made to analyze the mode of interactions of the LasR protein with the promoter DNA region of the hcnABC operon. We analyzed the three dimensional structure of the LasR protein from Pseudomonas aeruginosa and docked the protein with the autoinducer ligand. We then docked the ligand-bound-LasR-protein as well the LasR-protein-without-the autoinducer-ligand on to the promoter DNA region of hcnABC operon. We analyzed the details of the interaction profiles of LasR protein with the autoinducer ligand. We also deciphered the details of the LasR promoter-DNA interactions. We compared the modes of DNA bindings by the LasR protein in presence and absence of the autoinducer ligand and tried to analyze the molecular details of the binding of LasR protein with the promoter DNA region of hcnABC operon during hcnABC gene expression. This study may therefore pave the pathway for future experiments to determine the relative effects of the amino acid residues of LasR protein in DNA binding during the transcription of hcnABC operon. PMID- 26768578 TI - Association of thrombogenic genes polymorphisms with hepatocellular carcinoma in HCV Egyptian patients. AB - The rate of development of fibrosis varies among HCV patients and affected by many variables. We aimed to investigate the association between mutations in Factor V, prothrombin gene and thrombospondin 1 polymorphisms with hepatic fibrosis progression rate and development of HCC in patients infected with HCV and if they are potential markers for early prediction of disease progression. A total of 280 HCV-infected patients (70 with mild fibrosis, 70 with advanced fibrosis, 70 cirrhotic patients and 70 HCC patients) and 100 healthy controls were included. Factor V Leiden G1691A, prothrombin G20210A and thrombospondin 1 mutations were analyzed by restriction fragment length polymorphism. We observed that there were no significant differences between Factor V Leiden (G1691A) or TPS-1 (A2210G) polymorphisms in the four patient subgroups and control group. In HCC patients, the frequencies of GA genotype were significantly increased compared with control subject. HCV patients carrying GA genotype were more likely to develop hepatocellular carcinoma (OR=5.4, 95% CI=1.09-27.05; P=0.026).We concluded that the risk of HCC was increased 5-fold in subjects carrying GA genotype of prothrombin G20210A gene. However, there was no evidence for a significant association between thrombogenic genes polymorphisms and progression of fibrosis in HCV Egyptian patients. PMID- 26768579 TI - The early history of Pallister-Hall syndrome-Buried treasure of a sort. AB - Pallister-Hall syndrome was initially recognized under fairly unique circumstances involving exhumation of the very first case. The first two cases had dramatic and unusual features including a hypothalamic hamartoblastoma, imperforate anus, an unusual type of polydactyly with the extra digit being central, hypopituitarism with secondary hypoadrenalism, and lethality after birth (probably due to hypoadrenalism). Within a short time frame, four additional cases were identified. As the full spectrum and variability of anomalies was recognized, it became clear that it was not such a rare disorder. Shortly after familial cases were recognized, the responsible gene was identified at GLI3. However, since other different conditions also involved GLI3, elaborating the domains of the gene and the types of mutations needed to be defined in order to have a clear correlation of the genotype-phenotype relations. PMID- 26768580 TI - siRNA delivery: current trends and future perspectives. PMID- 26768581 TI - Cross-species proteomics in analysis of mammalian sperm proteins. AB - Many proteomics studies are conducted in model organisms for which fully annotated, detailed, high quality proteomes are available. By contrast, many studies in ecology and evolution are conducted in species which lack high quality proteome data, limiting the perceived value of a proteomic approach for protein discovery and quantification. This is particularly true of rapidly evolving proteins in the reproductive system, such as those that have an immune function or are under sexual selection, and can compromise the potential for cross-species proteomics to yield confident identification. In this investigation we analysed the sperm proteome, from a range of ungulates and rodents, and explored the potential of routine proteomic workflows to yield characterisation and quantification in non-model organisms. We report that database searching is robust to cross-species matching for a mammalian core sperm proteome, comprising 623 proteins that were common to most of the 19 species studied here, suggesting that these proteins are likely to be present and identifiable across many mammalian sperm. Further, label-free quantification reveals a consistent pattern of expression level. Functional analysis of this core proteome suggests consistency with previous studies limited to model organisms and has value as a quantitative reference for analysis of species-specific protein characterisation. SIGNIFICANCE: From analysis of the sperm proteome for diverse species (rodents and ungulates) using LC-MS/MS workflows and standard data processing, we show that it is feasible to obtain cross-species matches for a large number of proteins that can be filtered stringently to yield a highly expressed mammalian sperm core proteome, for which label-free quantitative data are also used to inform protein function and abundance. PMID- 26768582 TI - DNA aptamers for the detection of Haemophilus influenzae type b by cell SELEX. AB - Haemophilus influenzae type b (Hib) causes acute bacterial meningitis (ABM) in children, with a mortality rate of about 3-6 % of the affected patients. ABM can lead to death during a period of hours to several days and, hence, rapid and early detection of the infection is crucial. Aptamers, the short single-stranded DNA or RNA with high affinity to target molecules, are selected by a high-flux screening technique known as in vitro screening and systematic evolution of ligands by exponential enrichment technology (SELEX). In this study, whole-cell SELEX was applied for the selection of target-specific aptamers with high affinity to Hib. ssDNA aptamers prepared by lambda exonuclease were incubated with the target cells (Hib). The aptameric binding rate to Hib was characterized for binding affinity after seven SELEX rounds by flow cytometry. The aptamers with higher binding affinity were cloned. Four of 68 aptamer clones were selected for sequencing. The dissociation constant (Kd) of the high-affinity aptamer clones 45 and 63 were 47.10 and 28.46 pM, respectively. These aptamers did not bind to other bacterial species, including the seven meningitis-causing bacteria. They showed distinct affinity to various H. influenzae strains only. These aptamers showed the highest affinity to Hib and the lowest affinity to H. influenzae type c and to other meningitis-causing bacteria. Clone 63 could detect Hib in patients' cerebrospinal fluid (CSF) samples at 60 colony-forming units (CFU)/mL. The results indicate applicability of the aptamers for rapid and early detection of infections brought about by Hib. PMID- 26768583 TI - Should all adjunctive corticosteroid therapy be avoided in the management of hemodynamically stabile Staphylococcus aureus bacteremia? AB - The purpose of this study was to examine the prognostic impact of corticosteroids in hemodynamically stabile Staphylococcus aureus bacteremia (SAB). There were 361 hemodynamically stabile methicillin-sensitive SAB patients with prospective follow-up and grouping according to time-point, dose and indication for corticosteroid therapy. To enable analyses without external interfering corticosteroid therapy all patients with corticosteroid therapy equivalent to prednisone >10 mg/day for >=1 month prior to positive blood culture results were excluded. Twenty-five percent (92) of patients received corticosteroid therapy of which 11 % (40) had therapy initiated within 1 week (early initiation) and 9 % (31) had therapy initiated 2-4 weeks after (delayed initiation) positive blood culture. Twenty-one patients (6 %) had corticosteroid initiated after 4 weeks and were not included in the analyses. A total of 55 % (51/92) received a weekly prednisone dose >100 mg. Patients with early initiated corticosteroid therapy had higher mortality compared to patients treated without corticosteroid therapy at 28 days (20 % vs. 7 %) (OR, 3.11; 95%CI, 1.27-7.65; p < 0.05) and at 90 days (30 % vs. 10 %) (OR, 4.01; 95%CI, 1.82-8.81; p < 0.001). Considering all prognostic markers, early initiated corticosteroid therapy predicted 28-day (HR, 3.75; 95%CI, 1.60-8.79; p = 0.002) and 90-day (HR, 3.10; 95%CI, 1.50-6.39; p = 0.002) mortality in Cox proportional hazards regression analysis. When including only patients receiving early initiated corticosteroid therapy with prednisone >=100 mg/week the negative prognostic impact on 28-day mortality was accentuated (HR 4.8, p = 0.001). Corticosteroid therapy initiation after 1 week of positive blood cultures had no independent prognostic impact. Early initiation of corticosteroid therapy may be associate to increased mortality in hemodynamically stabile SAB. PMID- 26768584 TI - Individualized significance of the -251 A/T single nucleotide polymorphism of interleukin-8 in severe infections. AB - Based on the concept of the individualized nature of sepsis, we investigated the significance of the -251 A/T (rs4073) single nucleotide polymorphism (SNP) of interleukin (IL)-8 in relation to the underlying infection. Genotyping was performed in 479 patients with severe acute pyelonephritis (UTI, n = 146), community-acquired pneumonia (CAP, n = 109), intra-abdominal infections (IAI, n = 119), and primary bacteremia (BSI, n = 105) by restriction fragment length polymorphism of the polymerase chain reaction (PCR) product and compared with 104 healthy volunteers. Circulating IL-8 was measured within the first 24 h of diagnosis by an immunosorbent assay. Carriage of the AA genotype was protective from the development of UTI (odds ratio 0.38, p: 0.007) and CAP (odds ratio 0.30, p: 0.004), but not from IAI and BSI. Protection from the development of severe sepsis/septic shock was provided for carriers of the AA genotype among patients with UTI (odds ratio 0.15, p: 0.015). This was accompanied by greater concentrations of circulating IL-8 among patients with the AA genotype. It is concluded that carriage of rs4073 modifies susceptibility for severe infection in an individualized way. This is associated with a modulation of circulating IL-8. PMID- 26768586 TI - miR214-regulated p53-NOX4/p66shc pathway plays a crucial role in the protective effect of Ginkgolide B against cisplatin-induced cytotoxicity in HEI-OC1 cells. AB - The chemotherapeutic agent, cisplatin, is widely used for the treatment of several neoplastic diseases. The concomitant cytotoxicity in cochlear cells severely limits the maximum dose of cisplatin. Our previous study has shown that Ginkgolide B (GB) could protect against cisplatin-induced ototoxicity. In the present study, we aimed to elucidate the probable mechanism underlying GB mediated protective effects against cisplatin-induced cytotoxicity. The results showed that, in HEI-OC1 auditory cells, both NOX4 and p66(shc) expression was increased by cisplatin. GB significantly reduced NOX4 and p66(shc) expression and superoxide generation. Over-expression of NOX4 or p66(shc) suppressed the inhibitory effects of GB on superoxide generation and the protective effects of GB on loss of cell viability and apoptosis associated with cisplatin. Moreover, p53 expression was increased by cisplatin. GB significantly decreased p53 expression and p53-binding of the promoters of NOX4 and p66(shc). Over-expression of p53 suppressed the inhibitory effects of GB on NOX4 and p66(shc) expression and superoxide generation and the protective effects of GB on loss of cell viability and apoptosis associated with cisplatin. Furthermore, miR214 expression was decreased by cisplatin. GB significantly increased miR214 expression and inhibition of miR214 suppressed the inhibitory effects of GB on p53, NOX4 and p66(shc) expression and superoxide generation and the protective effects of GB against cisplatin-induced cytotoxicity. We demonstrate that GB decreases superoxide generation and the subsequent apoptosis through reduction of p53 mediated NOX4/p66(shc) pathway via up-regulation of miR214, resulting in attenuation of cisplatin-induced cytotoxicity. Our findings have gained an insight into the molecular mechanism of GB-exhibited inhibitory effect on cisplatin-induced cytotoxicity. PMID- 26768585 TI - Piwi-interacting RNAs in cancer: emerging functions and clinical utility. AB - PIWI-interacting RNAs (piRNAs) are emerging players in cancer genomics. Originally described in the germline, there are over 20,000 piRNA genes in the human genome. In contrast to microRNAs, piRNAs interact with PIWI proteins, another member of the Argonaute family, and function primarily in the nucleus. There, they are involved in the epigenetic silencing of transposable elements in addition to the transcriptional regulation of genes. It has recently been demonstrated that piRNAs are also expressed across a variety of human somatic tissue types in a tissue-specific manner. An increasing number of studies have shown that aberrant piRNA expression is a signature feature across multiple tumour types; however, their specific tumorigenic functions remain unclear. In this article, we discuss the emerging functional roles of piRNAs in a variety of cancers, and highlight their potential clinical utilities. PMID- 26768587 TI - Celastrol enhances Nrf2 mediated antioxidant enzymes and exhibits anti-fibrotic effect through regulation of collagen production against bleomycin-induced pulmonary fibrosis. AB - Pulmonary fibrosis (PF) is characterized by excessive accumulation of extracellular matrix components in the alveolar region which distorts the normal lung architecture and impairs the respiratory function. The aim of this study is to evaluate the anti-fibrotic effect of celastrol, a quinine-methide tri terpenoid mainly found in Thunder God Vine root extracts against bleomycin (BLM) induced PF through the enhancement of antioxidant defense system. A single intratracheal instillation of BLM (3 U/kg.bw) was administered in rats to induce PF. Celastrol (5 mg/kg) was given intraperitoneally, twice a week for a period of 28 days. BLM-induced rats exhibits declined activities of enzymatic and non enzymatic antioxidants which were restored upon treatment with celastrol. BLM induced rats show increased total and differential cell counts as compared to control and celastrol treated rats. Histopathological analysis shows increased inflammation and alveolar damage; while assay of hydroxyproline and Masson's trichrome staining shows an increased collagen deposition in BLM-challenged rats that were decreased upon celastrol treatment. Celastrol also reduces inflammation in BLM-induced rats as evidenced by decrease in the expressions of mast cells, Tumor necrosis factor-alpha (TNF- alpha) and matrix metalloproteinases (MMPs) 2 and 9. Further, Western blot analysis shows that celastrol is a potent inducer of NF-E2-related factor 2 (Nrf2) and it restores the activities of Phase II enzymes such as hemoxygenase-1 (HO-1), glutathione-S-transferase (GSTs) and NADP(H): quinine oxidoreductase (NQO1) which were declined upon BLM administration. The results of this study show evidence on the protective effect of celastrol against BLM-induced PF through its antioxidant and anti-fibrotic effects. PMID- 26768588 TI - Prognostic value of protein inhibitor of activated STAT3 in breast cancer patients receiving hormone therapy. AB - BACKGROUND: Deregulated signal transducer and activator of transcription 3 (STAT3) signaling has been well documented in certain cancers. Alterations in specific negative regulators, such as protein inhibitor of activated STAT3 (PIAS3), may contribute to cancer development. METHODS: The expression of total PIAS3 was determined in 100 paired cancerous and non-cancerous breast tissues by immunoblotting and was statistically analyzed along with the clinicopathological characteristics and overall survival of the patients. XTT, immunoblotting, and chromatin immunoprecipitation (Chip) were used to examine the biological effect of PIAS3 in breast cancer cells. RESULTS: Hormone therapy failed to improve the overall survival in patients presenting with increased PIAS3 expression. Ectopic PIAS3 overexpression increased the proliferation and expression of cyclin D1 in estrogen receptor (ER)-positive MCF-7 and T47D cells, but decreased those in ER negative MDA-MB-231 and SKBR3 cells. Furthermore, PIAS3 overexpression attenuated cytotoxicity of tamoxifen and increased proliferation and cyclin D1 expression in MCF-7 cells. PIAS3 also decreased the binding of itself on the cyclin D1 promoter and this decreased binding was not affected by tamoxifen. CONCLUSION: PIAS3 may serve as a biomarker for predicting hormone therapy stratification, although it is limited to those breast cancer patients receiving hormone therapy. PMID- 26768589 TI - The effect of an interactive delirium e-learning tool on healthcare workers' delirium recognition, knowledge and strain in caring for delirious patients: a pilot pre-test/post-test study. AB - BACKGROUND: Studies investigating the effectiveness of delirium e-learning tools in clinical practice are scarce. The aim of this study is to determine the effect of a delirium e-learning tool on healthcare workers' delirium recognition, delirium knowledge and care strain in delirium. METHODS: A pilot pre-posttest study in a convenience sample of 59 healthcare workers recruited from medical, surgical, geronto-psychiatric and rehabilitation units of a university hospital. The intervention consisted of a live information session on how to use the e learning tool and, a 2-month self-active learning program. The tool included 11 e modules integrating knowledge and skill development in prevention, detection and management of delirium. Case vignettes, the Delirium Knowledge Questionnaire, and the Strain of Care for Delirium Index were used to measure delirium recognition, delirium knowledge and experienced care strain in delirium respectively. Subgroup analyses were performed for healthcare workers completing 0 to 6 versus 7 to 11 modules. RESULTS: The delirium recognition score improved significantly (mean 3.1 +/- SD 0.9 versus 2.7 +/- 1.1; P = 0.04), and more healthcare workers identified hypoactive (P = 0.04) and hyperactive (P = 0.007) delirium in the posttest compared to the pretest phase. A significant difference in the change of recognition levels over time between the 0 to 6 and 7 to 11 module groups was demonstrated (P = 0.03), with an improved recognition level in the posttest phase within the 7 to 11 module group (P = 0.007). After adjustment for potential confounders, this difference in the change over time was not significant (P = 0.07) and no change in recognition levels within the 7 to 11 module group was noted (P = 0.19). The knowledge score significantly improved in the posttest compared to the pretest phase (mean 31.7 +/- SD2.6 versus 28.3 +/- 4.5; P < 0.001), with a significant increased level within the 7 to 11 module group (unadjusted P < 0.001/adjusted P = 0.02). Overall, no difference between posttest and pretest phases was documented for care strain (P = 0.46). CONCLUSION: The e learning tool improved healthcare workers' delirium recognition and knowledge. The effect of the tool is related to its level of completion, but was less explicit after controlling for potential confounders and warrants further investigation. The level of strain did not improve. PMID- 26768590 TI - Progressive lengthening of short congenital forearm stump in children for prosthetic fitting. AB - PURPOSE: The sufficient length of congenital forearm stump is essential for prosthetic fitting. In our study we reviewed the results of a series of forearm stump lengthening, observed complications and their outcomes. We evaluated possibilities of combined technique to reduce or avoid problems and complications in forearm stump lengthening. METHODS: We retrospectively reviewed 18 children who have undergone forearm stump lengthening. In all patients the forearm lengthening was performed by means of Ilizarov frame. Additional flexible intramedullary nailing (FIN) was applied in two cases. RESULTS: The mean lengthening gain was 4.6 cm. The planned lengthening gain was obtained in all cases. The mean healing index (HI) was 34.1 days/cm. The most reduced HI was observed in two cases of combined technique (Ilizarov frame with FIN): 25.4 and 27.0 days/cm. Considering complications and outcomes the results were classified according to Lascombes: grade I--5 cases, IIa--10 cases, IIb--2 cases, IIIa--1 case. In the long term follow-up all patients used their prostheses fixed at the forearm stump with natural function of elbow joint. CONCLUSION: Forearm progressive lengthening in children with congenital transverse deficiency of the forearm is justified in order to facilitate prosthetic procedures and to preserve natural function of elbow joint. Sufficient lengthening can be achieved within one operation with a low rate of major complications. In our experience a repeated lengthening of forearm stump is not mandatory. PMID- 26768591 TI - Minimally invasive plate osteosynthesis of acetabular anterior column fractures using the two-incision minimally invasive approach and a preshaped three dimension plate. AB - PURPOSE: To investigate the treatment of acetabular anterior column fractures using a two-incision minimally invasive (TIMI) approach and minimally invasive plate osteosynthesis (MIPO) technique using a preshaped 3D plate. METHODS: A group of 12 consecutive cases of acetabular fractures from March 2013 to July 2014 were treated with the TIMI approach. 3D mirror models of the uninjured side of the hemipelvis were printed preoperatively; the plates used in surgery were preshaped according to these models. MIPO surgical techniques were applied. All patients had a minimum one year radiographic and clinical follow-up. RESULTS: Seven fractures involved the anterior column, four were anterior column with posterior hemitransverse, and one was anterior column with the pubic symphysis. The average surgery time was 200 minutes, and mean blood loss was 1004 ml. The fracture reduction results as assessed by Matta radiographic outcome scores were good in eight, satisfactory in three, and poor in one patient. Functional outcomes according to the Harris hip scores were excellent for seven, good for three, and fair for two. Post-operative complications included incomplete femoral nerve damage and abdominal cavity injury. CONCLUSIONS: The TIMI approach is an alternative to the ilioinguinal approach for anterior column acetabular fracture treatment, especially for fractures involving the dome and quadrilateral plate that are feasible for application of MIPO techniques. The technique of preshaping the 3D plate makes the plate better accommodated to the fracture surface and easier to apply in MIPO procedures. All dissection was between the anatomical interval, which allowed less soft tissue injury and related complications, and caused less bleeding. The fracture types in our case series were relatively simple, and follow-up time was short; more clinical trials are necessary for evaluation of middle- and late-term results. PMID- 26768592 TI - Association Between Interleukin-1A, Interleukin-1B, and Bridging integrator 1 Polymorphisms and Alzheimer's Disease: a standard and Cumulative Meta-analysis. AB - Alzheimer's disease (AD) has been one of the most prevalent health problems among senior population. Interleukin-1A (IL-1A) and IL-1B are two isoforms of IL-1. Recent studies suggested that certain polymorphisms on these two genes are associated with AD. Bridging integrator 1 (BIN1) is considered as common genetic risk factors for AD, whereas different studies have provided various conclusions regarding its role in AD. This study was designed to justify the association between multiple gene polymorphisms and AD through an evidence synthesis approach. We conducted a literature search to identify relevant articles published from 2000 to 2015 from PubMed, Embase, and Cochrane Library, in accordance with inclusion criteria. Pooled odds ratios (ORs) were calculated for the allele model. The effect estimates were summarized by both standard and cumulative meta-analysis. Finally, 54 articles with 88 independent studies were enrolled in this meta-analysis. Mutants in rs1800587 of IL-1A, rs1143634 of IL 1B, rs12989701, and rs744373 of BIN1 were significantly associated with AD onset. The difference effect of same single nucleotide polymorphisms (SNPs) on various ethnicities was also observed in our results. The present meta-analysis suggested that IL-1A, IL-1B, and BIN1 were candidate genes for AD pathogenesis. Polymorphisms of IL-1A, IL-1B, and BIN1 are associated with AD onset. PMID- 26768593 TI - Pramlintide Antagonizes Beta Amyloid (Abeta)- and Human Amylin-Induced Depression of Hippocampal Long-Term Potentiation. AB - Accumulation of amyloid-beta peptide (Abeta) is a pathological hallmark of Alzheimer's disease (AD). We have previously demonstrated that electrophysiological and neurotoxic effects of Abeta and human amylin are expressed via the amylin receptor. Recently, pramlintide, a synthetic analog of amylin, has been reported to improve cognitive function in transgenic AD mouse models. In this study, we examined the effects of pramlintide on Abeta1-42 and human amylin-evoked depression of long-term potentiation (LTP) at Schaeffer collateral-CA1 hippocampal synapses. In mouse hippocampal brain slices, field excitatory postsynaptic potentials (fEPSPs) were recorded from the stratum radiatum layer of the CA1 area in response to electrical stimulation of Schaeffer collateral afferents and LTP induced by 3-theta-burst stimulation (TBS) protocol. Abeta1-42 (50 nM) and human amylin (50 nM), but not Abeta42-1 (50 nM), depressed LTP. Pre-application of pramlintide (250 nM) blocked Abeta- and human amylin induced reduction of LTP without affecting baseline transmission or LTP. We also examined the effects of pramlintide on LTP in transgenic mice (TgCRND8) that over express amyloid precursor protein. In contrast to wild-type controls, where robust LTP was observed, 10- to 12-month-old TgCRND8 mice show blunted LTP. In TgCRND8 mice, basal LTP is enhanced by application of pramlintide. Our data indicate that pramlintide acts as a functional amylin receptor antagonist to reverse the effects of Abeta1-42 and human amylin on LTP and also increases LTP in transgenic mice that demonstrate increased ambient brain amyloid levels. Amylin receptor antagonists may thus serve as potentially useful therapeutic agents in treatment of AD. PMID- 26768594 TI - Inhibition of the Receptor for Advanced Glycation End-Products (RAGE) Attenuates Neuroinflammation While Sensitizing Cortical Neurons Towards Death in Experimental Subarachnoid Hemorrhage. AB - Subarachnoid hemorrhage (SAH) is a threatening and devastating neurological insult with high mortality and morbidity rates. Despite considerable efforts, the underlying pathophysiological mechanisms are still poorly understood. The receptor for advanced glycation end products (RAGE) is a multiligand receptor that has been implicated in various pathological conditions. We previously showed that RAGE was upregulated and may be involved in pathophysiology of SAH. In the current study, we investigated its potential role in SAH. We found that the upregulation of RAGE after SAH was NF-kappaB-dependent positive feedback regulation. Further, pharmacological inhibition of RAGE attenuated neuroinflammation, indicating a possible contributive role of RAGE in inflammation-associated brain injury after SAH. Conversely, however, inhibition of RAGE sensitized neurons, exacerbating cell death, which correlated with augmented apoptosis and diminished autophagy, suggesting that activation of RAGE may protect against SAH-induced neuronal injury. Furthermore, we demonstrate that inhibition of RAGE significantly reduced brain edema and improved neurological function at day 1 but not at day 3 post-SAH. Taken together, these results suggest that RAGE exerts dual role after SAH. Our findings also suggest caution should be exercised in setting RAGE-targeted treatment for SAH. PMID- 26768595 TI - Role of the Endocannabinoid System in the Pathophysiology of Schizophrenia. AB - The endocannabinoid system (ECS) is a group of neuromodulatory lipids, enzymes, and receptors involved in numerous behavioral and physiological processes such as mood, memory, and appetite. Recently, longitudinal and postmortem studies have shown that the ECS might be involved in neuropsychiatric disorders like schizophrenia. However, despite the large amount of research, our knowledge of the ECS and its implication in this debilitating disorder is still largely limited. This review aims at providing a comprehensive overview of the current state of knowledge of the ECS in schizophrenia and presenting some potential antipsychotic compounds that modulate this system. Findings from animal and human studies, and their implications for pharmacotherapy, will be integrated and discussed in this paper. A closer look will be given at the roles of the cannabinoid receptors type 1 (CB1) and type 2 (CB2), as well as the endogenous ligand N-arachidonoylethanolamine (AEA) and 2-arachidonylglycerol (2-AG), in the development of psychotic and schizophrenia-like symptoms. PMID- 26768596 TI - Rapamycin Effectively Impedes Melamine-Induced Impairments of Cognition and Synaptic Plasticity in Wistar Rats. AB - Our previous investigation demonstrated that autophagy significantly reduced melamine-induced cell death in PC12 cells via inhibiting the excessive generation of ROS. In the present study, we further examine if rapamycin, used as an autophagy activator, can play a significant role in protecting neurons and alleviating the impairment of spatial cognition and hippocampal synaptic plasticity in melamine-treated rats. Male Wistar rats were divided into three groups: control, melamine-treated, and melamine-treated + rapamycin. The animal model was established by administering melamine at a dose of 300 mg/kg/day for 4 weeks. Rapamycin was intraperitoneally given at a dose of 1 mg/kg/day for 28 consecutive days. The Morris water maze test showed that spatial learning and reversal learning in melamine-treated rats were considerably damaged, whereas rapamycin significantly impeded the cognitive function impairment. Rapamycin efficiently alleviated the melamine-induced impairments of both long-term potentiation (LTP) and depotentiation, which were damaged in melamine rats. Rapamycin further increased the expression level of autophagy markers, which were significantly enhanced in melamine rats. Moreover, rapamycin noticeably decreased the reactive oxygen species level, while the superoxide dismutase activity was remarkably increased by rapamycin in melamine rats. Malondialdehyde assay exhibited that rapamycin prominently reduced the malondialdehyde (MDA) level of hippocampal neurons in melamine-treated rats. In addition, rapamycin significantly decreased the caspase-3 activity, which was elevated by melamine. Consequently, our results suggest that regulating autophagy may become a new targeted therapy to relieve the damage induced by melamine. PMID- 26768597 TI - Effect of Storage on Acrylamide and 5-hydroxymethylfurfural Contents in Selected Processed Plant Products with Long Shelf-life. AB - This study investigated the effects of storage and temperature duration on the stability of acrylamide (AA) and 5-hydroxymethylfurfural (HMF) in selected foods with long shelf-life. Products were analysed fresh and stored at temperatures of 4 and 25 degrees C after 6 and 12 months (with the exception of soft bread samples, which were analysed after 15 and 30 days). The AA and HMF contents were determined with RP-HPLC coupled to a diode array detector (DAD). AA and HMF were not stable in many processed plant products with a long shelf-life. The highest AA reduction and the largest increase in HMF content were observed in the samples stored at a higher temperature (25 degrees C) for 12 months. It was found that an initial water activity of 0.4 is favourable to HMF formation and that AA reduction may be considerably greater in stored products with a low initial water activity. The kind of product and its composition may also have a significant impact on acrylamide content in stored food. In the final period of storage at 25 degrees C, acrylamide content in 100% cocoa powder, instant baby foods, 20% cocoa powder and instant coffee was 51, 39, 35 and 33% lower than in products before storage, respectively. It was observed that a large quantity of epsilon NH2 and SH groups of amino acids in some products can be assumed as the reason for the significant AA degradation. PMID- 26768598 TI - Telehealth language assessments using consumer grade equipment in rural and urban settings: Feasible, reliable and well tolerated. AB - Introduction Telehealth can be an effective way to provide speech pathology intervention to children with speech and language impairments. However, the provision of reliable and feasible standardised language assessments via telehealth to establish children's needs for intervention and to monitor progress has not yet been well established. Further, there is limited information about children's reactions to telehealth. This study aimed to examine the reliability and feasibility of conducting standardised language assessment with school-aged children with known or suspected language impairment via a telehealth application using consumer grade computer equipment within a public school setting. Method Twenty-three children (aged 8-12 years) participated. Each child was assessed using a standardised language assessment comprising six subtests. Two subtests were administered by a speech pathologist face-to-face (local clinician) and four subtests were administered via telehealth. All subtests were completed within a single visit to the clinic service, with a break between the face to face and telehealth sessions. The face-to-face clinician completed behaviour observation checklists in the telehealth and face to face conditions and provided feedback on the audio and video quality of the application from the child's point of view. Parent feedback about their child's experience was elicited via survey. Results There was strong inter-rater reliability in the telehealth and face-to-face conditions (correlation coefficients ranged from r = 0.96-1.0 across the subtests) and good agreement on all measures. Similar levels of attention, distractibility and anxiety were observed in the two conditions. Clinicians rated only one session of 23 as having poor audio quality and no sessions were rated as having poor visual quality. Parent and child reactions to the use of telehealth were largely positive and supportive of using telehealth to assess rural children. Discussion The findings support the use of telehealth in the language assessment of school-aged children using a web application and commercially available computer equipment. This reliable and innovative service delivery model has the potential to be used by speech pathologists to provide assessments to children in remote communities. PMID- 26768599 TI - Stereoselective synthesis of oxazolidinonyl-fused piperidines of interest as selective muscarinic (M1) receptor agonists: a novel M1 allosteric modulator. AB - Syntheses of (1RS,2SR,6SR)-2-alkoxymethyl-, 2-hetaryl-, and 2-(hetarylmethyl)-7 arylmethyl-4,7-diaza-9-oxabicyclo[4.3.0]nonan-8-ones, of interest as potential muscarinic M1 receptor agonists, are described. A key step in the synthesis of (1RS,2SR,6SR)-7-benzyl-6-cyclobutyl-2-methoxymethyl-4,7-diaza-9 oxabicyclo[4.3.0]nonan-8-one, was the addition of isopropenylmagnesium bromide to 2-benzyloxycarbonylamino-3-tert-butyldimethylsilyloxy-2-cyclobutylpropanal. This gave the 4-tert-butyldimethylsilyloxymethyl-4-cyclobutyl-5 isopropenyloxazolidinone with the 5-isopropenyl and 4-tert butyldimethylsilyloxymethyl groups cis-disposed about the five-membered ring by chelation controlled addition and in situ cyclisation. This reaction was useful for a range of organometallic reagents. The hydroboration-oxidation of (4SR,5RS) 3-benzyl-4-(tert-butyldimethylsilyloxymethyl)-4-cyclobutyl-5-(1-methoxyprop-2-en 2-yl)-1,3-oxazolidin-2-one gave (4SR,5RS)-3-benzyl-4-(tert butyldimethylsilyloxymethyl)-4-cyclobutyl-5-[(SR)-1-hydroxy-3-methoxyprop-2-yl] 1,3-oxazolidin-2-one stereoselectively. 4,7-Diaza-9-oxabicyclo[4.3.0]nonan-8-ones with substituents at C2 that could facilitate C2 deprotonation were unstable with respect to oxazolidinone ring-opening and this restricted both the synthetic approach and choice of 2-heteroaryl substituent. The bicyclic system with a 2 furyl substituent at C2 was therefore identified as an important target. The addition of 1-lithio-1-(2-furyl)ethene to 2-benzyloxycarbonylamino-3-tert butyldimethylsilyloxy-2-cyclobutylpropanal gave (4SR,5RS)-4-tert butyldimethylsilyloxymethyl-4-cyclobutyl-5-[1-(2-furyl)ethenyl]-1,3-oxazolidinone after chelation controlled addition and in situ cyclisation. Following oxazolidinone N-benzylation, hydroboration at 35 degrees C, since hydroboration at 0 degrees C was unexpectedly selective for the undesired isomer, followed by oxidation gave a mixture of side-chain epimeric alcohols that were separated after SEM-protection and selective desilylation. Conversion of the neopentylic alcohols into the corresponding primary amines by reductive amination, was followed by N-nosylation, removal of the SEM-groups and cyclisation using a Mitsunobu reaction. Denosylation then gave the 2-furyloxazolidinonyl-fused piperidines, the (1RS,2SR,6SR)-epimer showing an allosteric agonistic effect on M1 receptors. Further studies resulted in the synthesis of other 2-substituted 4,7-diaza-9-oxabicyclo[4.3.0]nonan-8-ones and an analogous tetrahydropyran. PMID- 26768600 TI - The tae-miR408-Mediated Control of TaTOC1 Genes Transcription Is Required for the Regulation of Heading Time in Wheat. AB - Timing of flowering is not only an interesting topic in developmental biology, but it also plays a significant role in agriculture for its effects on the maturation time of seed. The hexaploid wheat (Triticum aestivum) is one of the most important crop species whose flowering time, i.e. heading time, greatly influences yield. However, it remains unclear whether and how microRNAs regulate heading time in it. In our current study, we identified the tae-miR408 in wheat and its targets in vivo, including Triticum aestivum TIMING OF CAB EXPRESSION-A1 (TaTOC-A1), TaTOC-B1, and TaTOC-D1. The tae-miR408 levels were reciprocal to those of TaTOC1s under long-day and short-day conditions. Wheat plants with a knockdown of TaTOC1s via RNA interference and overexpression of tae-miR408 showed early-heading phenotype. Furthermore, TaTOC1s expression was down-regulated by the tae-miR408 in the hexaploid wheat. In addition, other important agronomic traits in wheat, such as plant height and flag leaf angle, were regulated by both tae-miR408 and TaTOC1s. Thus, our results suggested that the tae-miR408 functions in the wheat heading time by mediating TaTOC1s expression, and the study provides important new information on the mechanism underlying heading time regulation in wheat. PMID- 26768601 TI - Light-Inducible MiR163 Targets PXMT1 Transcripts to Promote Seed Germination and Primary Root Elongation in Arabidopsis. AB - Expression of many plant microRNAs is responsive to hormones and environmental stimuli, but none has yet been associated with light. Arabidopsis (Arabidopsis thaliana) miR163 is 24 nucleotides in length and targets mRNAs encoding several S adenosyl-Met-dependent carboxyl methyltransferase family members. Here, we found that miR163 is highly induced by light during seedling de-etiolation as well as seed germination. Under the same condition, its target PXMT1, encoding a methyltransferase that methylates 1,7-paraxanthine, is down-regulated. Light repression of PXMT1 is abolished in a mir163 null mutant, but the repression can be restored to wild-type levels in complementation lines expressing pri-miR163 gene in the mir163 mutant background. During seed germination, miR163 and its target PXMT1 are predominantly expressed in the radicle, and the expression patterns of the two genes are inversely correlated. Moreover, compared with the wild type, mir163 mutant or PXMT1 overexpression line shows delayed seed germination under continuous light, and seedlings develop shorter primary roots with an increased number of lateral roots under long-day condition. Together, our results indicate that miR163 targets PXMT1 mRNA to promote seed germination and modulate root architecture during early development of Arabidopsis seedlings. PMID- 26768602 TI - High levels of genetic diversity and population structure in an endemic and rare species: implications for conservation. AB - The analysis of genetic structure and variability of isolated species is of critical importance in evaluating whether stochastic or human-caused factors are affecting rare species. Low genetic diversity compromises the ability of populations to evolve and reduces their chances of survival under environmental changes. Petunia secreta, a rare and endemic species, is an annual and heliophilous herb that is bee-pollinated and easily recognizable by its purple and salverform corolla. It was described as a new species of the Petunia genus in 2005. Few individuals of P. secreta have been observed in nature and little is known about this species. All the natural populations of P. secreta that were found were studied using 15 microsatellite loci, two intergenic plastid sequences and morphological traits. Statistical analysis was performed to describe the genetic diversity of this rare species and the results compared with those of more widespread and frequent Petunia species from the same geographic area to understand whether factors associated with population size could affect rare species of this genus. The results showed that despite its rarity, P. secreta presented high genetic diversity that was equivalent to or even higher than that of widespread Petunia species. It was shown that this species is divided into two evolutionary lineages, and the genetic differentiation indices between them and other congeneric species presented different patterns. The major risk to P. secreta maintenance is its rarity, suggesting the necessity of a preservation programme and more biological and evolutionary studies that handle the two evolutionary lineages independently. PMID- 26768603 TI - Phylogeography of a widespread species: pre-glacial vicariance, refugia, occasional blocking straits and long-distance migrations. AB - Phylogeographic studies give us the opportunity to reconstruct the historical migrations of species and link them with climatic and geographic variation. They are, therefore, a key tool to understanding the relationships among biology, geology and history. One of the most interesting biogeographical areas of the world is the Mediterranean region. However, in this area, the description of concordant phylogeographic patterns is quite scarce, which limits the understanding of evolutionary patterns related to climate. Species with one dimensional distribution ranges, such as the strawberry tree (Arbutus unedo), are particularly useful to unravel these patterns. Here, we describe its phylogeographic structure and check for concordance with patterns seen in other Mediterranean plants: longitudinal/latitudinal clines of diversity, evidence for glacial refugia and the role of sea straits in dispersal. We also identify the most likely source for the disjunct Irish population. With this aim, we sequenced four chloroplast non-coding fragments of A. unedo from 23 populations covering its whole distribution. We determined the genetic diversity, population structure, haplotype genealogy and time to the most recent common ancestor. The genealogy revealed two clades that separated during the last 700 ky but before the last glacial maximum. One clade occupies Atlantic Iberia and North Africa, while the other occurs in the Western Mediterranean. The Eastern Mediterranean is inhabited by newer haplotypes derived from both clades, while the Irish population is closely related to Iberian demes. The straits of Sicily and Gibraltar partially restricted the gene flow. We concluded that a vicariance event during the Late Quaternary in the western end of the species' range followed by eastward migration seems a likely explanation for the observed phylogeographic pattern. The role of straits indicates an occasional communication between Europe and North Africa, suggesting that the latter was a novel refugia. The East-West genetic split in Iberia is consistent with the refugia-within-refugia model. Finally, the strawberry tree possibly reached Ireland from Iberia instead of throughout the maritime fringe of France as previously thought. PMID- 26768604 TI - Efficacy and safety of daclatasvir and asunaprevir combination therapy in chronic hemodialysis patients with chronic hepatitis C. AB - BACKGROUND: HCV infection in chronic hemodialysis patients is high, has a poor prognosis and high risk of renal graft failure, and requires nosocomial infection control measures. However, options of anti-HCV therapy in such patients are limited and unsatisfactory. In this study, we report effectiveness and safety of HCV-NS5A-inhibitor daclatasvir (DCV) and protease-inhibitor asunaprevir (ASV) combination therapy for hemodialysis patients with HCV infection. METHODS: This study was registered at the UMIN Clinical Trials Registry as UMIN000016355. Thirty-four dialysis patients were treated with DCV/ASV combination therapy between January 2015 and November 2015. Of those, 21 patients who were followed more than 12 weeks after treatment ended were included. We evaluated the 12-week sustained virologic response (SVR12) and adverse events during treatment. RESULTS: Of the 21 patients, four had compensated liver cirrhosis and three had resistance-associated variant of NS5A (NS5A RAVs)-Y93H at baseline. Overall, total of 95.5 % (20/21) of the patients achieved SVR12. Of note, all patients with cirrhosis or NS5A RAVs achieved SVR12. One relapser patient at 4 weeks post treatment had NS3 D168E RAVs at baseline. A total of 20 patients (95.5 %) completed the 24-week therapy. One patient discontinued treatment at week 12 due to ALT elevations and achieved SVR12. CONCLUSIONS: DAV and ASV combination therapy for chronic hemodialysis patients with HCV infection was highly effective and well tolerated, even in elderly patients and patients with liver cirrhosis and NS5A-RAVs. PMID- 26768606 TI - High-intensity preoperative training improves physical and functional recovery in the early post-operative periods after total knee arthroplasty: a randomized controlled trial. AB - PURPOSE: The benefits of preoperative training programmes compared with alternative treatment are unclear. The purpose of this study was to evaluate the effectiveness of a high-intensity preoperative resistance training programme in patients waiting for total knee arthroplasty (TKA). METHODS: Forty-four subjects (7 men, 37 women) scheduled for unilateral TKA for osteoarthritis (OA) during 2014 participated in this randomized controlled trial. Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), the Physical Functioning Scale of the Short Form-36 questionnaire (SF-36), a 10-cm visual analogue scale (VAS), isometric knee flexion, isometric knee extension, isometric hip abduction, active knee range of motion and functional tasks (Timed Up and Go test and Stair ascent-descent test) were assessed at 8 weeks before surgery (T1), after 8 weeks of training (T2), 1 month after TKA (T3) and finally 3 months after TKA (T4). The intervention group completed an 8-week training programme 3 days per week prior to surgery. RESULTS: Isometric knee flexion, isometric hip abduction, VAS, WOMAC, ROM extension and flexion and all the functional assessments were greater for the intervention group at T2, T3 and T4, whereas isometric knee extension was greater for this group at T2 and T4 compared with control. CONCLUSION: The present study supports the use of preoperative training in end-stage OA patients to improve early postoperative outcomes. High-intensity strength training during the preoperative period reduces pain and improves lower limb muscle strength, ROM and functional task performance before surgery, resulting in a reduced length of stay at the hospital and a faster physical and functional recovery after TKA. The present training programme can be used by specialists to speed up recovery after TKA. LEVEL OF EVIDENCE: I. PMID- 26768605 TI - Diagnostic performance and factors influencing the accuracy of EUS-FNA of pancreatic neuroendocrine neoplasms. AB - BACKGROUND: Multiple studies have investigated sampling adequacy of endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) for pancreatic neuroendocrine neoplasms (pNENs). However, none have described the diagnostic performance of EUS FNA for pNENs, or the influencing factors. The aim of this study was to evaluate the diagnostic accuracy of EUS-FNA, with post-operative pathological diagnosis as the gold standard, and factors predictive of inadequate EUS sampling. METHODS: From 1998 to 2014, a total of 698 patients underwent pancreatic resection and 1455 patients underwent EUS-FNA sampling for pancreatic lesions. A total of 410 cases underwent both surgical resection and preceding EUS-FNA. Of these, 60 cases (49 true pNEN, nine non-diagnostic, two misdiagnoses) were included. We studied diagnostic performance of EUS-FNA and factors that were associated with failed diagnosis. RESULTS: Of the 60 cases, EUS-FNA yield was 49 true-positive cases, two misdiagnoses, and nine non-diagnostic cases (including six suggestive cases). Sensitivity, specificity, and accuracy were 84.5, 99.4, and 97.3 %, respectively; including the six suggestive cases, diagnostic values were 94.8 % sensitivity (55/58), 99.4 % specificity (350/352), and 98.7 % accuracy (405/410). In multivariate analysis, sampling adequacy rates were significantly lower when lesions were located in the pancreatic head [odds ratio (OR) = 10.0] and in tumor rich stromal fibrosis (OR = 10.45). Tumor size, needle type, tumor grading, presence of cystic component, and time period were not significant factors. CONCLUSIONS: EUS-FNA offers high accuracy for pNEN. However, location of the tumor in the pancreatic head and presence of rich stromal fibrosis negatively impacts sampling adequacy. PMID- 26768607 TI - Short-interval two-stage approach to primary total knee arthroplasty for acutely septic osteoarthritic knees. AB - Treatment strategies for advanced knee osteoarthritis with coexistent joint infection are not well established. While in periprosthetic joint infection the two-stage approach has been studied extensively, only few case reports on two stage total knee arthroplasty (TKA) for knee osteoarthritis with coexistent joint infection have been published. The purpose of this paper was to report on our method of implementing a two-stage TKA with intervening antibiotic-loaded articulating cement spacers and a short interval between first- and second-stage procedures to treat two patients with Staphylococcus aureus-infected end-stage knee osteoarthritis. Consistent infection eradication was found at a 1-year follow-up with postoperative range of motion and knee scores comparing favourably with those of other case series. Level of evidence V. PMID- 26768608 TI - One-step surgery with multipotent stem cells and Hyaluronan-based scaffold for the treatment of full-thickness chondral defects of the knee in patients older than 45 years. AB - PURPOSE: The aim of this study is to prospectively evaluate the medium-term effectiveness and regenerative capability of autologous adult mesenchymal stem cells, harvested as bone marrow aspirate concentrate (BMAC), along with a hyaluronan-based scaffold (Hyalofast) in the treatment of ICRS grade 4 chondral lesions of the knee joint, in patients older than 45 years. METHODS: A study group of 20 patients with an age >45 years (mean 50.0 +/- 4.1 years) was compared to a control group of 20 patients with an age <45 years (mean 36.6 +/- 5.0). Patients were prospectively evaluated for 4 years. All patients were evaluated with MRI, KOOS, IKDC, VAS and Tegner scores preoperatively and at two-year and final follow-up. RESULTS: At final follow-up, all scores significantly improved (P < 0.001) as follows: all KOOS score categories; Tegner 2 (range 0-4) to 6 (range 4-8) and 3 (range 0-6) to 6 (range 3-10); IKDC subjective (39.2 +/- 16.5 to 82.2 +/- 8.9) and (40.8 +/- 13.9 to 79.4 +/- 14.6), in the study and control group respectively. In addition, we show that results are affected by lesion size and number but not from concomitant surgical procedures. MRI showed complete filling in 80 % of patients in the study group and 71 % of patients in the control group. Histological analysis conducted in three patients from the study and two patients from the control group revealed good tissue repair with a variable amount of hyaline-like tissue. CONCLUSION: Treatment of cartilage lesions with BMAC and Hyalofast is a viable and effective option that is mainly affected by lesion size and number and not by age. In particular, it allows to address the >45 years population with functional outcomes that are comparable to younger patients at final follow-up. LEVEL OF EVIDENCE: Prospective cohort study, Level II. PMID- 26768609 TI - Evaluation of (188)Re-labeled NGR-VEGI protein for radioimaging and radiotherapy in mice bearing human fibrosarcoma HT-1080 xenografts. AB - Vascular endothelial growth inhibitor (VEGI) is an anti-angiogenic protein, which includes three isoforms: VEGI-174, VEGI-192, and VEGI-251. The NGR (asparagine glycine-arginine)-containing peptides can specifically bind to CD13 (Aminopeptidase N) receptor which is overexpressed in angiogenic blood vessels and tumor cells. In this study, a novel NGR-VEGI fusion protein was prepared and labeled with (188)Re for radioimaging and radiotherapy in mice bearing human fibrosarcoma HT-1080 xenografts. Single photon emission computerized tomography (SPECT) imaging results revealed that (188)Re-NGR-VEGI exhibits good tumor-to background contrast in CD13-positive HT-1080 tumor xenografts. The CD13 specificity of (188)Re-NGR-VEGI was further verified by significant reduction of tumor uptake in HT-1080 tumor xenografts with co-injection of the non radiolabeled NGR-VEGI protein. The biodistribution results demonstrated good tumor-to-muscle ratio (4.98 +/- 0.25) of (188)Re-NGR-VEGI at 24 h, which is consistent with the results from SPECT imaging. For radiotherapy, 18.5 MBq of (188)Re-NGR-VEGI showed excellent tumor inhibition effect in HT-1080 tumor xenografts with no observable toxicity, which was confirmed by the tumor size change and hematoxylin and eosin (H&E) staining of major mouse organs. In conclusion, these data demonstrated that (188)Re-NGR-VEGI has the potential as a theranostic agent for CD13-targeted tumor imaging and therapy. PMID- 26768610 TI - Increased expression of SOX4 is associated with colorectal cancer progression. AB - Sex-determining region Y-related high-mobility group box 4 (SOX4) has been proven to serve as a critical role in cancer progression. However, the pathological role of SOX4 in colorectal cancer (CRC) remains unknown. The aim of this study was to investigate the role of SOX4 in CRC. In this study, we investigated the expression of SOX4 in CRC tissues by immunohistochemistry, quantitative reverse transcription polymerase chain reaction (qRT-PCR), and Western blot. We also evaluated the effect of SOX4 on cell proliferation and invasion by 3-(4,5 dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) and transwell assay. The SOX4 messenger RNA (mRNA) and protein expression were markedly higher in CRC tissues compared with adjacent normal mucosa tissues. Inhibition of SOX4 could suppress CRC cell proliferation, and invasion in vitro. Our findings indicate that targeting SOX4 might provide a new therapeutic modality for the treatment of CRC patients. PMID- 26768612 TI - Expression of Pim-3 in colorectal cancer and its relationship with prognosis. AB - There is increasing evidence suggesting that the establishment of Pim-3 is involved in tumorigenesis. This study aimed to investigate the expression and clinicopathological significance of Pim-3 in colorectal cancer (CRC). Clinical pathology data were collected from 410 CRC patients who received radical resection and were pathologically confirmed at the Sun Yat-Sen University Cancer Center between October 2002 and December 2008. We compared the expression Pim-3 in the primary focus and liver metastasis and investigated the correlations with other clinical-pathological factors. Multivariate analysis showed that perioperative blood transfusion, local invasion, lymph node and liver metastasis, and Pim-3 expression were independent prognostic factors. The expression of Pim-3 in CRC was higher than that in normal tissues. Patients with positive expression had significant decreases in 5-year survival. Pim-3 expression showed a positive correlation with tumor cell differentiation, local infiltration, and lymph node and liver metastasis. In conclusion, Pim-3 might serve as a novel target and prognosis factor for colorectal cancer. PMID- 26768611 TI - Association of DNA repair and xenobiotic pathway gene polymorphisms with genetic susceptibility to gastric cancer patients in West Bengal, India. AB - Gastric cancer is one of the most common malignancies in India. DNA repair gene or xenobiotic pathway gene polymorphisms have recently been shown to affect individual susceptibility to gastric cancer. Here, the possible interaction between common polymorphisms in X-ray repair cross complementing group I (XRCC1) gene and glutathione S-transferase (GST) genes (GSTM1, GSTT1 and GSTP1), smoking and alcohol consumption and overall survival in gastric cancer patients were evaluated. In this population-based case control study, 70 gastric cancer patients and 82 healthy controls were enrolled. The epidemiological data were collected by a standard questionnaire, and blood samples were collected from each individual. XRCC1 Arg194Trp, Arg280His and Arg399Gln polymorphisms were determined by polymerase chain reaction and direct DNA sequencing. GSTM1 and GSTT1 null polymorphisms and GSTP1 Ile105Val polymorphism were identified by multiplex polymerase chain reaction and restriction fragment length polymorphism (RFLP), respectively. The risk of gastric cancer was significantly elevated in individuals with XRCC1 Arg/Gln +Gln/Gln (p = 0.031; odds ratio = 2.32; 95 % confidence interval (CI) 1.07-5.06) and GSTP1 Val/Val genotype (p = 0.009; odds ratio = 8.64; 95 % CI 1.84-40.55). An elevated risk for GC was observed in smokers and alcohol consumers carrying GSTP1 Ile/Val +Val/Val genotype (p = 0.041; odds ratio = 3.71; 95 % CI 0.98-14.12; p = 0.002; odds ratio = 12.31; 95 % CI 1.71-88.59). These findings suggest that XRCC1 rs25487 and GSTP1 rs1695 can be considered as a risk factor associated with gastric cancer and might be used as a molecular marker for evaluating the susceptibility of the disease. PMID- 26768613 TI - MiR-381 inhibits epithelial ovarian cancer malignancy via YY1 suppression. AB - Epithelial ovarian cancer (EOC) is a common type of gynecologic cancer, which accounts for the majority of deaths among all gynecologic malignant tumors in developed countries. A series of recent studies suggested that miR-381 might play important roles in the development of various cancer types. However, the biological function of miR-381 in EOC remains to be investigated. We examined the levels of miR-381 expression in EOC tissues and cell lines. We identified miR-381 target genes by bioinformatic prediction. We also characterized the phenotype regarding cell proliferation, cell migration, and cell invasion in EOC cells lines with altered expression levels of both miR-381 and its target gene, YY1. The expression levels of miR-381 were downregulated in EOC tissues and cell lines. Overexpression of miR-381 significantly inhibited EOC cell proliferation, migration, and invasion. Restoration of YY1 expression partially reversed the phenotype induced by miR-381 overexpression. Knockdown of miR-381 target gene, YY1, mimicked the phenotype induced by miR-381 overexpression. MiR-381 regulated EOC cell through miR-381/YY1/p53 and miR-381/YY1/Wnt signaling axis. We concluded that miR-381 inhibited EOC cell proliferation, migration, and invasion, at least in part, via suppressing YY1 expression. PMID- 26768614 TI - The proliferation impairment induced by AQP3 deficiency is the result of glycerol uptake and metabolism inhibition in gastric cancer cells. AB - Gastric cancer is a big threat to human health. Effective therapeutic cancer target remains to be discovered. Aquaporin 3 (AQP3) belongs to a family of transmembrane channels that are important in transporting water, glycerol, and other small molecules across the cell membrane. Glycerol that is transported by AQP3 is necessary for cell energy generation and lipid synthesis which fulfill the cell biological processes. Previous studies have shown that AQP3 is implicated in disease progression in several cancer types. However, whether AQP3 regulated glycerol uptake and metabolism were involved in cancer progression remains to be further studied. Our study demonstrated that the expression of AQP3 was positively correlated with glycerol level in human gastric cancer tissues. AQP3 inhibition induced proliferation impairment in gastric cancer cells both in vitro and in vivo. AQP3 inhibition that induced glycerol uptake reduction and glycerol administration would rehabilitate the cell proliferation. The energy and lipid production decreased when AQP3 was knocked down since the cellular glycerol level and several lipogenesis enzymes were downregulated. PI3K/Akt signaling pathway, which was involved in the impaired lipid and ATP production, was also inhibited after AQP3 knockdown. Our study indicated that the energy and lipid production inhibition, which were responsible for gastric cancer cell proliferation impairment, were induced by glycerol uptake reduction after AQP3 knockdown. PMID- 26768615 TI - MicroRNA-503 represses epithelial-mesenchymal transition and inhibits metastasis of osteosarcoma by targeting c-myb. AB - Deregulated expression of miRNAs contributes to the development of osteosarcoma. Our previous study has showed that miR-503 was downregulated in osteosarcoma tissues. However, the mechanism of the miR-503 in osteosarcoma development still remains largely undefined. In our study, we found that miR-503 overexpression suppressed cell invasion and migration and inhibited epithelial-to-mesenchymal transition (EMT) of MG-63. Furthermore, we identified that c-myb, an oncogene, was a direct target of miR-503. Moreover, overexpression of c-myb could rescue miR-503-suppressed invasion and EMT. The expression of c-myb was upregulated in osteosarcoma cell lines. Therefore, we conclude that high miR-503 expression suppressed osteosarcoma cell mobility and EMT through targeting c-myb, and this may serve as a therapeutic target. PMID- 26768616 TI - Caveolin-1 affects tumor drug resistance in esophageal squamous cell carcinoma by regulating expressions of P-gp and MRP1. AB - Esophageal squamous cell carcinoma (ESCC) is the most common cancer in China, and multidrug resistance (MDR) remains one of the biggest problems in ESCC chemotherapy. In this study, we aimed to investigate the mechanism of Caveolin-1, an integral membrane protein, on regulating ESCC MDR. First, immunohistochemistry was used to check the protein expression of Caveolin-1, MDR-related protein of P glycoprotein (P-gp), and multidrug resistance protein 1 (MRP1) in 84 pathologically characterized ESCC tissues, matched adjacent tumor, and adjacent normal-looking tissues. The results showed that Caveolin-1 expression level was elevated in ESCC tissues than that of matched adjacent tumor and adjacent normal looking tissues (P < 0.05), and the expression of Caveolin-1 has close correlation with P-gp and MRP1 during tumor genesis of ESCC (P = 0.034, P = 0.009, respectively). Then, Caveolin-1 overexpression and knockdown were used to investigate its effect on expressions of P-gp and MRP1 in ESCC cell line Ec9706. The messenger RNA (mRNA) and protein expression levels of P-gp and MRP1 were checked by real-time quantitative reverse transcription-PCR (qRT-PCR) and Western blot (WB). The results showed that Caveolin-1 overexpression significantly promotes the mRNA and protein expression of MRP1 (P < 0.05), while almost has no effect on the mRNA and protein expression of P-gp (P > 0.05); Cavoelin-1 knockdown inhibits the mRNA and protein expressions of both P-gp and MRP1 (P < 0.05). The similar result was found in another ESCC cell line Eca109. So, it is concluded that Caveolin-1 affects ESCC MDR by regulating the expressions of P-gp and MRP1; therefore, it can be taken as a significant marker and target in tumor therapy. PMID- 26768617 TI - Sprouty4 mediates amphiregulin-induced down-regulation of E-cadherin and cell invasion in human ovarian cancer cells. AB - Sprouty (SPRY) proteins are well-characterized factors that inhibit receptor tyrosine kinase (RTK)-mediated activation of cellular signaling pathways. The down-regulation of SPRY4 expression has been reported in human ovarian cancer. However, the specific roles and mechanisms by which SPRY4 affects ovarian cancer progression are completely unknown. Amphiregulin (AREG) binds exclusively to the epidermal growth factor receptor (EGFR) and has been considered to be a dominant autocrine/paracrine EGFR ligand in ovarian cancer. In the present study, we first examined the effects of AREG on SPRY4 expression and the possible underlying molecular mechanisms involved in this process in two human ovarian cancer cell lines. Our results demonstrated that treatment with AREG up-regulated SPRY4 expression by activating the ERK1/2 signaling pathway. In addition, we showed that small interfering RNA (siRNA)-mediated knockdown of SPRY4 attenuated the AREG-induced down-regulation of E-cadherin by inhibiting the expression of SNAIL but not SLUG. In contrast, overexpression of SPRY4 enhanced AREG-induced down regulation of E-cadherin by increasing the expression of SNAIL. Moreover, SPRY4 knockdown attenuated AREG-induced cell migration and invasion. Overexpression of SPRY4 enhanced AREG-induced cell invasion. This study reveals that SPRY4 is involved in EGFR-mediated human ovarian cancer progression. PMID- 26768618 TI - Pre-treatment VD levels and VDR receptors as potential predictors of occurrence and overall survival in paediatric patients with solid tumours-a single institution pilot study. AB - Recently, vitamin D has been recognized as an important player in the immune system, and multiple studies suggested its involvement in cancer, too. The aims of this study were to investigate selected single nucleotide polymorphisms (SNPs) in the VDR gene, BsmI (rs1544410; A > G), FokI (rs 2228570; C > T), TaqI (rs731236; T > C), ApaI (rs 7975232; C > T) and Cdx-2 (rs11568820; A > G), and to evaluate their possible predictive role for outcomes in patients with paediatric solid tumours. A total of 111 children with paediatric solid tumours were enrolled at the Department of Paediatric Oncology, University Hospital Brno (Brno, Czech Republic) along with a control population of 787 adults; all study subjects were available for genotyping of selected SNPs, and the prediagnostic levels of 25-hydroxycholecalciferol (25(OH)D3) and 1,25-dihydroxycholecalciferol (1,25(OH)2D3) were measured in the cases, too. In FokI, the heterozygote CT genotype was weakly associated with a decreased risk of paediatric solid cancer occurrence 0.82 (0.53-1.28), while the CC genotype was associated with a decreased risk of 0.58 (0.30-1.09), p = 0.09. The 1,25(OH)2D3 prediagnostic levels were indicative of the overall survival in the cases (beta = -0.012, HR 0.988, 95 % CI (0.978-0.998), while higher prediagnostic levels of 1,25(OH)2D3 were associated with a statistically significant increase in overall mortality. We observed multiple effects of the alleles of the investigated polymorphisms and of 1,25(OH)2D3 on overall survival, regardless of the underlying disease. PMID- 26768619 TI - DCT015, a new sorafenib derivate, inhibits tumor growth and angiogenesis in gastric cancer models. AB - The objective of this study is to investigate antiproliferative activities against gastric cancer and anti-angiogenesis of DCT015, a novel sorafenib derivate, and potential mechanisms. The effects of DCT015 on proliferation and apoptosis in gastric cancer cells were evaluated by cytotoxicity assays, apoptosis analysis, flow cytometry analysis, and Western blotting assays. The in vivo antitumor effects were carried out in nude mice bearing gastric cancer. On the other hand, the anti-angiogenesis effects of DCT015 were measured by human umbilical vein endothelial cell (HUVEC) proliferation, migration, tube formation, and Western blotting analysis. The results showed that DCT015 inhibited the proliferation, induced the morphological changes of apoptosis, and increased the apoptosis percentage, as well as increased the "sub-G1" population in gastric cancer cells. DCT015 also significantly decreased the tumor volumes and tumor weights in vivo by oral administration. Immunohistochemistry assay demonstrated that DCT015 inhibited tumor growth and neovascularization. In vitro studies found that DCT015 inhibited both MEK/ERK and PI3K/Akt signaling pathways by Western blotting assays. Moreover, DCT015 significantly inhibited VEGF-induced migration and tube formation in HUVECs. Western blotting analysis showed that DCT015 downregulated VEGF-induced VEGFR2 phosphorylation with the decreased phosphorylation of the downstream key proteins. Taken together, our findings highlight that DCT015 is a promising orally anticancer drug for treating gastric cancer. PMID- 26768620 TI - Macrophages and endothelial cells orchestrate tumor-associated angiogenesis in oral cancer via hedgehog pathway activation. AB - The present study aimed to evaluate the role of Hedgehog (Hh) molecule expression in association with the clinical aspects of oral squamous cell carcinoma (OSCC), as well as angiogenesis and CD163+ macrophages. Twenty-eight cases of OSCC, nine cases of tumor-free resection margins (TM), and four cases of non-neoplastic oral mucosa (NNM) were submitted to immunohistochemistry to detect proteins Sonic Hedgehog (SHH), Indian Hedgehog (IHH), GLI1, CD163, and CD105. Protein colocalization with respect to SHH/CD163, IHH/CD163, GLI1/CD163, and GLI1/CD105 was assessed by immunohistochemical double staining. In tumor parenchyma, SHH and IHH were present in the cytoplasm of neoplastic cells, while GLI1 was observed in cytoplasm and nucleus. Endothelial cells were found to express SHH, IHH, and GLI1 within CD105+ vessels, and a positive correlation between infiltrating macrophage density (IMD) and microvascular density (MVD) was observed in cases of OSCC and TM. When compared to TM and NNM, the OSCC cases demonstrated higher immunoreactivity for SHH (p = 0.01), IHH (p = 0.39), GLI1 (p = 0.03), IMD (p = 0.0002), and MVD (p = 0.0002). Our results suggest the participation of the Hh pathway in OSCC by way of autocrine and paracrine signaling, in addition to the participation of both SHH and IHH ligands. Endothelial cells were also found to exhibit positivity with respect to Hh pathway components and we surmise that these molecules may play a role in tumor angiogenesis. CD163+ macrophages were also observed to express IHH, a ligand of this pathway, in addition to being associated with tumor neovascularization. PMID- 26768624 TI - Recent Developments in the Application of Polymeric Nanoparticles as Drug Carriers. AB - Nanotechnology is an interdisciplinary field of science offering interesting solutions for many branches of human life. Nanomaterials, defined as structures with at least one dimension below 100 nm, are the focus of increasing research attention as versatile tools for nanomedicine. Among the various nanostructures recently described in the literature, polymeric nanoparticles, characterized by satisfying biocompatibility, have aroused great interest as the carriers for various biologically active substances such as drugs, proteins and nucleic acids. These nanoparticles have already been reported as efficient vehicles for therapeutic agents in many disease entities. They can be delivered to the body via different administration routes. This review addresses recent advances in the usage of polymeric nanoparticles as drug carriers described in the years 2013 and 2014. The advantages of polymeric nanocarriers for medical application are highlighted, including their low toxicity, evaluated in vitro and in vivo. Moreover, the classification of polymeric nanoparticles is presented as well as various protocols of their synthesis. PMID- 26768621 TI - Immune-Microbiota Interactions: Dysbiosis as a Global Health Issue. AB - Throughout evolution, microbial genes and metabolites have become integral to virtually all aspects of host physiology, metabolism and even behaviour. New technologies are revealing sophisticated ways in which microbial communities interface with the immune system, and how modern environmental changes may be contributing to the rapid rise of inflammatory noncommunicable diseases (NCDs) through declining biodiversity. The implications of the microbiome extend to virtually every branch of medicine, biopsychosocial and environmental sciences. Similarly, the impact of changes at the immune-microbiota interface are directly relevant to broader discussions concerning rapid urbanization, antibiotics, agricultural practices, environmental pollutants, highly processed foods/beverages and socioeconomic disparities--all implicated in the NCD pandemic. Here, we make the argument that dysbiosis (life in distress) is ongoing at a micro- and macro-scale and that as a central conduit of health and disease, the immune system and its interface with microbiota is a critical target in overcoming the health challenges of the twenty-first century. PMID- 26768626 TI - Effect of Culture in Simulated Microgravity on the Development of Mouse Embryonic Testes. AB - BACKGROUND: All known organisms develop and evolve in the presence of gravitational force, and it is evident that gravity has a significant influence on organism physiology and development. Microgravity is known to affect gene expression, enzyme activity, cytoskeleton organization, mitotic proliferation and intracellular signaling. OBJECTIVES: The aim of the present study was to study some aspects of the development in vitro of mouse embryonic testes in simulated microgravity. MATERIAL AND METHODS: Testes from mouse embryos (12.5-16.5 days post coitum, d.p.c.) were cultured in simulated microgravity and standard static culture conditions. The microgravity condition was provided by a Rotary Cell Culture System (RWV) bioreactor, an apparatus designated for 3D tissue and small organ cultures. After 48 h of the culture in the RWV, testis morphology and size was evaluated. RESULTS: The first observation was that the culture in the RWV bioreactor had a beneficial effect on the testis growth and on the survival of germ cells in comparison to static 2D culture methods. Moreover, we found, that RWV culture caused disorganization the gonadal tissues, namely of the testis cords. CONCLUSIONS: The results suggest that the maintenance of testis cord could be sensitive to microgravity. We hypothesize that while the effect on testis growth is due to a better nutrient and oxygen supply, the testis cord's disorganization might depend on the microgravity conditions simulated by the bioreactor. Considering the complexity of the processes involved in the formation of the testis cords and their dynamic changes during the embryo fetal period, further studies are needed to identify the causes of such effect. PMID- 26768622 TI - T Cell Epitope Peptide Therapy for Allergic Diseases. AB - Careful selection of dominant T cell epitope peptides of major allergens that display degeneracy for binding to a wide array of MHC class II molecules allows induction of clinical and immunological tolerance to allergen in a refined treatment strategy. From the original concept of peptide-induced T cell anergy arising from in vitro studies, proof-of-concept murine models and flourishing human trials followed. Current randomized, double-blind, placebo-controlled clinical trials of mixtures of T cell-reactive short allergen peptides or long contiguous overlapping peptides are encouraging with intradermal administration into non-inflamed skin a preferred delivery. Definitive immunological mechanisms are yet to be resolved but specific anergy, Th2 cell deletion, immune deviation, and Treg induction seem implicated. Significant efficacy, particularly with short treatment courses, in a range of aeroallergen therapies (cat, house dust mite, grass pollen) with inconsequential non-systemic adverse events likely heralds a new class of therapeutic for allergy, Synthetic Peptide Immuno-Regulatory Epitopes (SPIRE). PMID- 26768625 TI - A Furan-Based Lewis-Y-(CD174)-Saccharide Mimetic Inhibits Endothelial Functions and In Vitro Angiogenesis. AB - BACKGROUND: Angiogenesis is a fundamental process underlying cancer progression and autoimmune disease. Lewis Y is known as a regulated glycan-structure supporting human endothelial function and angiogenesis. OBJECTIVES: We hypothesize that Lewis Y based analogues interfere with Lewis Y mediated endothelial functions and angiogenesis. We therefore evaluated the ability of 3, 4-bis [(b-D-galactopyranosyl)osy]-methyl-furan (BGF) a furan-based Lewis-Y saccharide mimetic to inhibit human endothelial adhesion, migration and in vitro angiogenesis. MATERIAL AND METHODS: The ability of BGF and additional furan-based saccharide-mimetics was investigated to inhibit adhesion and migration of human bone marrow endothelial cells (HBMEC). Influence of BGF was tested on a multicelluar in vitro - angiogenesis assay in the presence of VEGF. RESULTS: BGF significantly inhibited HBMEC adhesion and migration stimulated by TNF-alpha by up to 70%. The anti-adhesive effect of BGF was particularly evident when HBMEC adhesion and migration was tested on collagen as extracellular matrix with weaker effect when laminin and fibronectin were used as an extracellular matrix. BGF was ineffective when HBMEC were stimulated with VEGF. The inhibition of endothelial function translated into a significant inhibitory effect of BGF in the multicellular in vitro angiogenesis-assay. BGF reduced the angiogenesis index compared to the positive controls by 32%. CONCLUSIONS: We identified the ability of the furan-based Lewis Y saccharide mimetic BGF as a specific modulator of TNF alpha activated endothelial function and in vitro angiogenesis. BGF and other related glycan analogues should further be explored for their ability to down modulate endothelial activation in TNF-alpha driven pathophysiologic conditions in autoimmune disease and cancer indications. PMID- 26768627 TI - CO2 Flow Dynamics of Bladder Injury During Laparoscopy and the Effect of the Content of the Abdominal Viscera During Injury--Experimental Study. AB - BACKGROUND: Despite the well-known and easily recognizable signs of bladder injury during laparoscopy, some injuries remain unnoticed. Intra-operative diagnosis of a urinary bladder injury provides the opportunity to repair and prevent later complications involving the formation of fistula, infection, ascites and impairment of renal function. Small and unrecognized bladder injuries increase the chance of morbidity and permanent organ dysfunctions. OBJECTIVES: The aim of the study was to evaluate the CO2 flow dynamics of bladder injury occurring during laparoscopy and the effect of the content of the abdominal viscera during injury. MATERIAL AND METHODS: The study involved eight male New Zealand rabbits. Following urinary catheterization of the rabbits with an 8-gauge urinary catheter connected securely to a urinary drainage bag, pneumoperitoneum was created at a pressure level of 12 mm Hg. The experiment consisted of three phases. After the observational phase (Phase 1), the anterior wall of the urinary bladder was perforated with the tip of a 21 G needle (Phase 2) and methylene blue was administrated to evaluate the CO2 flow dynamics (Phase 3). RESULTS: The amount of CO2 consumption and accumulation in the urinary drainage bags differed significantly among the three phases of the experiment (p<0.05). There was no CO2 consumption or accumulation in the urinary drainage bags during Phase 1. The amount of CO2 consumption and accumulation in the urinary drainage bags during Phase 2 was significantly higher than during Phase 3. CONCLUSIONS: Urinary catheterization helps in the diagnosis of small or unnoticed urinary bladder injuries occurring during laparoscopy. CO2 flow and consumption is lower if the viscosity of the content overlying the injury site is higher. PMID- 26768628 TI - Gemcitabine-Based Treatment in Poor-Prognosis Patients with Relapsed and Refractory Hodgkin Lymphoma and Non-Hodgkin Lymphoma--a Multicenter Polish Experience. AB - BACKGROUND: The treatment of patients with relapsed or refractory Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) remains challenging. Gemcitabine is a cytidine analog with a wide spectrum of antitumor activity. Gemcitabine treatment is widely used to treat patients with certain solid tumors and relapsed/refractory hematological malignancies. There are several reports indicating that this compound is active in lymphoid malignancies. In patients with relapsed or refractory HL and NHL, gemcitabine has demonstrated efficacy as a single agent and in combination with other cytostatics. OBJECTIVES: The aim of the study was to analyze the efficacy and toxicity of gemcitabine-based chemotherapy in patients with relapsed or refractory lymphomas. MATERIAL AND METHODS: The study evaluated 68 heavily pretreated patients with relapsed/refractory HL and NHL. The median age of the patients was 36 years. All the patients received gemcitabine-based chemotherapy (gemcitabine monotherapy or gemcitabine in combination with other cytostatics). RESULTS: The overall response rate was 46%. Complete response was achieved by 21% of the patients and partial response by 25%. Out of those who responded to gemcitabine treatment, 26 patients proceeded to autologous stem cell transplant. Toxicities connected with gemcitabine therapy occurred in 44% of the patients and included grade 3/4 neutropenia, thrombocytopenia and anemia. CONCLUSIONS: The results suggest that gemcitabine-based salvage chemotherapy is effective and well tolerated in patients with relapsed/refractory HL and NHL. PMID- 26768629 TI - Determinants of Elevated Levels of Natural Anticoagulants in Healthy Subjects. AB - BACKGROUND: The levels of protein C (PC), free protein S (PS) and antithrombin (AT) are evaluated during thrombophilia screening to exclude their deficiencies. OBJECTIVES: The aim of this study was to investigate factors which determine the elevated levels of natural plasma anticoagulants in healthy individuals. MATERIAL AND METHODS: The PC activity and antigen, free PS antigen and AT activity together with hematological, biochemical, genetic and immunological laboratory tests were assessed in 130 healthy adults (63 males) aged 20-60 (median 41) years. Individuals with personal or family history of cardiovascular diseases and venous thromboembolism were ineligible. RESULTS: The functionally active PC measured by chromogenic assay (values above 140%) was observed in 14 (11%) of subjects, while the PC antigen determined using the enzyme-linked immunosorbent assay (ELISA) was elevated in 5 (4%) of these patients. Free PS measured by immunoturbidimetry and ELISA was increased in 9 (7%) subjects (values above 139% in men and 114% for women) and in 6 (5%) patients (values above 130% in men and 111% for women), respectively. The AT activity above 118% was found in 5 (4%) subjects measured using chromogenic assay. None of the individuals had any deficiency of natural anticoagulants. Increased C-reactive protein (CRP)>3.0 mg/L was associated with elevated PC activity (odd ratio [OR]: 11.14, 95% confidence interval [CI] 1.67-74.23). Increased free PS assessed by immunoturbidimetric assay and PC activity were associated with hypercholesterolemia (OR: 3.57, 95% CI: 1.09-10.06 and OR: 8.61, 95% CI: 1.07-69.04, respectively). Body mass index>=25 kg/m2 was independently associated with elevated PC activity (OR: 3.42, 95% CI: 1.01-11.52). No risk factors for elevated AT activity were identified. CONCLUSIONS: Apart from hypercholesterolemia and overweight, increased serum CRP is associated with elevated PC activity in healthy adults. We confirmed that there are differences in the proportions of subjects with elevated PC and PS depending on the assay used. PMID- 26768630 TI - Assessment of Vitamin D Level in Autoimmune Thyroiditis Patients and a Control Group in the Polish Population. AB - BACKGROUND: Vitamin D, known for its role in calcium-phosphorus homeostasis, is also a significant immunomodulatory factor. Vitamin D deficiency has been reported in some autoimmune disorders. Recently, vitamin D level in autoimmune thyroiditis (HT - Hashimoto's thyroiditis) has become the subject of researchers' interest. OBJECTIVES: This study aims to assess vitamin 25-OH-D3 levels in HT patients in comparison to a control group in the Polish population. This would be the first attempt conducted in this region with such poor sunlight exposure. MATERIAL AND METHODS: The group we studied consisted of 62 subjects diagnosed with HT (mean age 49.15+/-15.51) and 32 healthy controls matched with age and sex (mean age 46.09+/-14.32). All blood samples were collected in the first quarter of the year to minimize the impact of seasonal fluctuations of vitamin D concentrations. RESULTS: In the HT group the mean vitamin D level was 20.09 nmol/L (SD+/-12.66), compared to 30.31 nmol/L (SD+/-19.49) in the controls, p=0.014. None of the patients and the controls was vitamin D sufficient (75-125 nmol/L). The deficiency (<50 nmol/L) was significantly more common among HT patients compared to the controls (61-98.4% vs. 27- 84.4%, p=0.029). CONCLUSIONS: In conclusion, we found that serum vitamin D concentration is significantly lower in HT patients in comparison to the control group. This suggests vitamin D deficit as one of the risk factors for HT development. Observed vitamin D level was also low in the control group, therefore wider supplementation in general population should be recommended. PMID- 26768631 TI - Fibroblast-Like Synovial Cells in Rheumatoid Arthritis--the Impact of Infliximab on Hexosaminidase Activity. AB - BACKGROUND: The effect of multiple infusions of infliximab (INF), a chimeric anti tumor necrosis factor alpha antibody, on the concentration of hexosaminidase (HEX) activity in a synovial cell culture derived from human synovial inflamed fluid obtained from patients suffering from rheumatoid arthritis (RA) has been evaluated. OBJECTIVES: The aim of this study was to prove INF efficacy in RA. MATERIAL AND METHODS: Inflamed synovial fluid was taken from RA patients (a study group) and patients who had undergone knee trauma within 7 days (a control group). The following solutions of infliximab were used: 40, 60 and 140 ug/mL. Determination of the concentration of HEX activity in cell cultures was performed after 24, 48, 72 and 96 h of infliximab administration. To identify synoviocytes in cell culture immunohistochemical staining with vimentin and pancytokeratin was performed. RESULTS: A predominance of fibroblast-like synovial cells has been observed in the study group. In the control group the concentration of HEX activity without adding infliximab to the cell culture was 283.00 nkat/mL. After 96 h of incubation with infliximab, the concentrations of HEX activity in cultured synoviocytes according to infliximab doses of 40, 60 and 140 ug/mL were respectively: 280.00, 271.50 and 293.50 nkat/mL. In the study group, the concentration of HEX activity without adding infliximab to the cell culture was 542.27 nkat/mL. The final concentrations of HEX activity of cultured fibroblast like synovial cells measured after 96 h of incubation with infliximab were: 471.72, 498.27 and 556.72 nkat/mL, according to infliximab doses of 40, 60 and 140 ug/mL. In all groups (besides the infliximab concentration of 140 ug/mL after 96 h of incubation), the level of concentration of HEX activity was significantly higher in the study group compared to the control group, irrespective of infliximab concentration and time of infliximab incubation. CONCLUSIONS: Infliximab changes the concentration of HEX activity depending on the drug dose and time of administration. PMID- 26768632 TI - Fecal Calprotectin as an Activity Marker of Inflammatory Bowel Disease in Children. AB - BACKGROUND: Children constitute 20% of patients with inflammatory bowel diseases (IBD). Still there is a search for a perfect marker for this group of patients which would help in the diagnosis of the disease, in determinating its activity and in monitoring the treatment. OBJECTIVES: Evaluate the usefulness of the application of calprotectin measurement in stool samples from children with IBD, as a marker of the severity of inflammation. MATERIAL AND METHODS: We analysed 156 patients: 58 with ulcerative colitis (UC), 67 with Crohn's disease (CD), and 31 from the control group. In all patients the concentration of calprotectin in the sample of feces, markers of inflammation and hemoglobin were measured. RESULTS: Concentration of calprotectin in feces of patients with IBD was above the normal range in all patients with moderate and severe disease and in the majority with mild disease or in remission, but it was normal in all patients from the control group. CONCLUSIONS: Elevated concentration of fecal calprotectin (FC) was observed in the majority of patients with IBD, but in none from the control group. The number of patients with elevated FC concentration increased together with the disease activity. FC concentration was higher in patients with severe and moderate disease activity. FC concentration in patients with IBD was associated with the increase of inflammatory markers and decreased haemoglobin. Percentage of laboratory abnormalities in children with Crohn's disease and perianal changes was higher. FC concentration can be a noninvasive marker of disease activity in IBD. PMID- 26768633 TI - The Distribution of Liver Steatosis, Fibrosis, Steatohepatitis and Inflammation Activity in Alcoholics According to FibroMax Test. AB - BACKGROUND: The diagnosis of alcoholic liver diseases is based on the history of alcohol abuse, clinical evidence of liver disease and laboratory abnormalities. The new non-invasive biomarkers have higher sensitivity to quantify and predict steatosis and fibrosis than ultrasonography. OBJECTIVES: The aim of this study was to evaluate the prevalence of liver diseases in alcoholics by means of FibroMax. MATERIAL AND METHODS: A total of 142 consecutive alcoholics were enrolled in the study. The prevalence of liver diseases was assayed by means of non-invasive biomarkers: fibrosis by FibroTest, steatosis by SteatoTest, steatohapatitis by AshTest (alcoholic origin) and NashTest (non-alcoholic origin) and necroinflammatory activity by ActiTest. RESULTS: 38.7% of alcoholics do not have fibrosis, 38%--steatosis, 94.1%--alcoholic steatohepatitis, 56.6%--non alcoholic steatohepatitis and 33.6%--necroinflammatory activity. The insignificant fibrosis (F<2) is present in 37.2%, advanced (F>=2)--15.3% and cirrhosis (F4)--in 8.8%. Insignificant steatosis (S<2) is observed in 31.3% and advanced (S>=2) in 30.5%. Minimal alcoholic steatohepatitis (H1) exists in 5.2% patients, moderate (H2) in none of the patient and severe (H3) in only one patient (0.7%). The distribution of NashTest scores is as following: N0--56.6%, N1--38.2% and N2--5.1%. Insignificant inflammatory activity (A<2) is present in 40.8% of alcoholic patients but significant (A>=2) in 25.5%. The frequency of severe steatosis (F3) and necroinflammatory activity (A3) in patients with cirrhosis (F4) is 50% for each of them. CONCLUSIONS: The prevalence of advanced fibrosis and cirrhosis evaluated by means of FibroMax in alcoholics is higher than in alcoholic liver disease (ALD) and lower than in mixed, alcoholic and non alcoholic ones. This may indicate the presence of non-alcoholic liver disease in alcoholics. PMID- 26768634 TI - Viral Hepatitis A in 108 Adult Patients During an Eight-Year Observation at a Single Center in Poland. AB - BACKGROUND: Hepatitis A is related to significant morbidity and occasional mortality. Based on data from the Polish National Institute of Hygiene, from 2000 to 2013 a mean of 213 hepatitis A cases were reported yearly. OBJECTIVES: The aim of the study was to assess selected data in adults hospitalized for symptomatic hepatitis A during an eight-year period in a single center in the Wielkopolska Region of Poland. MATERIAL AND METHODS: All the hepatitis A patients hospitalized in the center from 2005 to 2013 were analyzed retrospectively. Data were extracted from the medical records of these individuals. The disease was confirmed by anti-HAV IgM testing. RESULTS: In total, 108 patients (71 men and 37 women), aged 18-65 years, were identified. All but 1 patient recovered (99.1%) and in 6 cases (5.6%) a relapse occurred. Risk factors for hepatitis A were identified in 56 patients (52%), with travel abroad being the most common one (32 patients); 19 cases were secondary and 5 patients were men who have sex with men. One hepatitis A outbreak was noted in the region during the study period. Acalculous cholecystitis was found in 33.3% of the patients who underwent abdominal ultrasound. This tended to be more common among older individuals (47.8% in patients over 40 vs. 22.6% in patients aged 18-40, p=0.0521). Patients with this finding had significantly higher mean peak ALT in comparison to those with no gallbladder abnormalities. CONCLUSIONS: Although hepatitis A in adults is typically a benign, self-limited disease, it can occasionally have a fatal course. In a significant proportion of patients with an evident risk factor for hepatitis A, the possibility of active prophylaxis was not used. Hepatitis A should be regarded as a sexually transmitted infection. Acalculous cholecystitis is a frequent finding among adults with symptomatic hepatitis A. PMID- 26768635 TI - The Role of Transarterial Embolization in the Treatment of Renal Tumors. AB - BACKGROUND: Renal arterial embolization (RAE) is one of the adjunctive methods in the treatment of renal tumors. Embolization is performed in patients prior to nephrectomy, in patients with inoperable renal tumors as palliative treatment. OBJECTIVES: The purpose of the study was to present and to analyze our own experiences in the embolization of renal tumors. MATERIAL AND METHODS: A retrospective analysis of 33 patients treated using RAE between 2011 and 2013 was carried out. In 30 cases (91%), embolization was performed due to renal carcinoma and in 3 cases (9%) due to angiomyolipoma. In 11 patients intervention was performed as a palliative procedure because of advanced disease. Histoacrylic glue, polyvinyl alcohol, sponge pledgets and embolization coils were used for embolization. RESULTS: In 20 patients (61%), selective RAE was performed, whereas superselective RAE was carried out in 13 patients (39%). The technical success rate of RAE was 100%. In one case the procedure was complicated by reflux of the histoacrylic glue into the common femoral artery with its embolization that required surgical embolectomy. We used histoacrylic glue in 26 embolizations (79%), in 19 procedures (58%) as the only embolization agent. Polyvinyl alcohol was used in 10 procedures (30%), gelatin sponge pledgets and absolute ethanol in 6 patients (18%). In 4 cases (12%), coils were implemented. In 22 patients (67%), one or more components of postembolization syndrome (PES) developed. In all 22 patients with PES (100%), severe lumbar pain was observed and administration of analgesics proved necessary. In 10 patients treated by palliative embolization, both a regression of macrohaematuria and an increase in hemoglobin level were observed. In 10 further patients, the creatinine level decreased following RAE. CONCLUSIONS: RAE is an effective and minimally-invasive intervention burdened with low risk of major complications. PES occurs in about two-third of patients. In the majority of patients after palliative embolization, haematuria decreases and the quality of life improves. PMID- 26768636 TI - Does the Stage of Chronic Kidney Failure Influence the Outcome in Cardiac Surgery? AB - BACKGROUND: The number of patients with chronic kidney failure requiring cardiac surgery is continuously increasing. Additionally, significant worsening in the overall risk profile of this group of patients is noted. OBJECTIVES: To investigate the effect of chronic renal dysfunction both in non-dialysis dependent renal failure and end-stage renal failure patients, on early mortality- morbidity and late survival in a series of cardiac surgery patients at our institution. MATERIAL AND METHODS: 1344 patients who had open heart surgery at our university hospital between 2010 and 2013 were retrospectively reviewed. Chronic renal dysfunction was defined according to preoperative glomerular filtration rate. Patients selection (n=80). Group 1 mild--(GRF 59-30 mL/min), Group 2 moderate--(GFR 29-15 mL/min), Group 3 end stage--(GFR<15 mL/min) renal failure. RESULTS: Chronic renal dysfunction was present in 5.95% of all patients studied. Group 1--55 (68.75%), Group 2--16 (20%), Group 3--9 (11.25%). No difference between the groups in the need for heart inotropic support was noted; however the use of these medications was necessary in 60.6% of all studied patients. Forty nine percent in Group 1, 87.5% in Group 2 and 77% in Group 3, respectively. Renal replacement therapy in the early postoperative period was needed in 12 patients, with significance between the groups (p = 0.001). The overall hospital mortality was 2.5%. Follow-up was completed with a mean of 1.4 years (range 2 months to 4 years). There were 6 (7.5%) late deaths. CONCLUSIONS: Our observations do not exhibit large variations in postoperative complications and deaths in patients with chronic renal failure, depending on the degree of preoperative renal function impairment. It seems that renal failure regardless of the degree of impairment is a factor aggravating the intra and post-operative course in cardiac surgery patients. PMID- 26768637 TI - Comparison of Transobturator Tape and Mini-Sling Tissue Fixation in Female Patients Who Had Stress Urinary Incontinence. AB - BACKGROUND: Urinary incontinence is a significant medico-social problem and its incidence increases up to 70% in the postmenopausal period. OBJECTIVES: We aimed to compare the efficacy and safety of transobturator adjustable tape (TOT) and mini sling in female urinary incontinence. MATERIAL AND METHODS: A total of 69 patients were included in the study. Single surgeon applied TOT (n=56 with ISD) or 13 mini sling (n=13 with ISD). Patients were considered to have ISD identified by a Valsalva leak point pressure (VLPP) measurement<60 cm H2O with a volume of 150 mL in the bladder or by a maximum urethral closure pressure (MUCP) measurement<20 cm H2O with a volume of 200 mL in the bladder. The mean follow-up period was 25 months for TOT group and 24 months for mini sling group (p=0.72). RESULTS: The cough test was negative in 48 of TOT group (86%) and 11 of mini sling group (84.6%). ICIQ-SF scores for the median value decreased from 14 (11 21) preoperatively to 3 (0-9) postoperatively (p<0.05) in the TOT group, and 15 (12-23) preoperatively to 4 (0-10) postoperatively (p<0.05) in the mini sling group. The difference in the decrease of the score between two groups was not statistically significant (p=0.42). There was not any significant complication to note. The mean hospital stay for TOT group was 2.1 days (1-5), and 1.4 days (1-3) for mini sling group (p=0.12). Operation time was was significantly lower in mini sling group than TOT group (11.6 vs. 18.4, p<0.01). CONCLUSION: Both TOT and mini sling procedures are successful and safe procedures in the treatment of female stress urinary incontinence with ISD. PMID- 26768638 TI - Intraocular Pressure Changes After Spinal Anesthesia--Acute and Subacute Effects on Surgery Patients. AB - BACKGROUND: Spinal anesthesia has become appropriate for many surgical procedures. Neuraxial anesthesia can result in acute and late complications like hypotension, bradycardia, local anesthetic toxicity, postdural-puncture headache, backache and spinal nerve damage. Although the body's physiological responses to spinal anesthesia are well understood, its effects on intraocular pressure (IOP) haven't been mentioned before. OBJECTIVES: The aim of this study was to investigate the effects of spinal anesthesia on IOP. MATERIAL AND METHODS: Forty patients receiving spinal anesthesia for subumblical surgery were recruited for the study, after ethics committee approval and patients' written informed consent. IOP was measured by Icare PRO tonometer (Icare, Finland) before spinal anesthesia (BS), immediately after spinal anesthesia (AS) and finally on the first postoperative day (PO1). Both eyes of the patients were included in the study. RESULTS: Thirty-eight patients completed the study. Mean BS, AS and PO1 intraocular pressures were 16.53+/-3.17 (9.40-24.00), 17.08+/-3.16 (10.00-24.00) and 16.76+/-2.80 (10.20-23.00) mm Hg, respectively. Mean IOP measurements were not statistically different among the three groups (p=0.104). CONCLUSIONS: Spinal anesthesia alone has no acute or subacute effects on IOP. Studies can be made to evaluate the chronic effects. Further studies must be focused on the relationship between postdural puncture headache and intraocular pressure changes after spinal anesthesia. PMID- 26768640 TI - Pregnancy and Delivery in Women with Uterine Malformations. AB - BACKGROUND: Uterine defects are the most common malformations of the female reproductive system. They can lead to many obstetric complications, e.g. preterm delivery, intrauterine growth restriction, oligohydramnios and operational delivery. OBJECTIVES: Our aim was to analyze the impact of different types of uterine defects on pregnancy outcomes. MATERIAL AND METHODS: The study involved 94 pregnant women with different types of uterine defects hospitalized at the Department of Fetal--Maternal Medicine and Gynecology, RIPMMH in Lodz, between 1994 and 2012. The patients were divided into 5 groups on the basis of diagnosed defects: arcuate (n=6), bicornuate (n=50), duplex (n=29), septate (n=5) and unicornuate uterus (n=4). In order to avoid correlated data in statistical analysis, our research did not consider the total number of pregnancies and births but the number of patients. The first pregnancy of each patient, if completed after 22-week gestation, was studied and analyzed. RESULTS: Preterm delivery was the most common complication in pregnancy (55 women, 58.5%). The caesarean section was performed in 73 (78%) women. IUGR was diagnosed in 16% of cases. Placental abruption occurred in 13 (14%) and cervical insufficiency in 10 cases (11%), respectively. Prenatal diagnostic showed abnormalities in 12 fetuses (13%). The Apgar score from 0 to 4 points was assigned to 9 newborns (9.6%), 5-7 to 20 children (21.3%) and 8-10 points to 75 cases (69.1%). Normal birth weight (>2500 g) was determined in 51 newborns (54.3%). CONCLUSIONS: Women with uterine defects are subject to an increased risk of complications in pregnancy and delivery, including premature births, low birth weights, births by cesarean section. PMID- 26768639 TI - Prevalence of Lactose Malabsorption and Lactose Intolerance in Pediatric Patients with Selected Gastrointestinal Diseases. AB - BACKGROUND: Lactase is an enzyme involved in the hydrolysis of lactose. Deficiency of the enzyme (hypolactasia) may be determined genetically or arise secondarily to disease of small intestine. Under this condition, lactose enters the colon where it is fermented by intestinal microflora and turns to gases and short-chain fatty acids, causing gastrointestinal symptoms known as lactose intolerance (LI). OBJECTIVES: To investigate the incidence of lactose malabsorption (LM), LI and the coexistence of these two conditions in children with upper gastrointestinal tract diseases (UGTD), malabsorption syndrome, inflammatory bowel disease (IBD) and functional gastrointestinal disorders (FGID). MATERIAL AND METHODS: Hydrogen breath test (HBT) was conducted in 387 pediatric patients in years 2010-2013. Two hundred thirty two children with gastrointestinal tract diseases were selected and assigned to groups - UGTD, malabsorption syndrome, IBD or FGID. For each group the frequency of LM, frequency and severity of LI and the frequency of their co-occurrence were calculated. RESULTS: Lactose malabsorption was observed in 37.08% of patients with gastrointestinal diseases. Positive HBT result was the most common in children with malabsorption syndrome (52.50%) and less common in UGTD (30.85%), especially in ulcer disease (23.53%). Symptoms after lactose ingestion affected 36.64% of the subjects, and were more specific to lactose malabsorbers than to lactose absorbers (72.10% vs. 15.75%). The higher frequency of LI was noted in children with FGID, especially in irritable bowel syndrome (IBS) (65.22%). The lowest incidence of symptoms was obtained in children with UGTD, especially in those with ulcer disease (27.44%). The incidence of LM with LI was noted in 27.16% of all patients and was the highest in IBS (47.83%) and the lowest in ulcer disease (15.78%). CONCLUSIONS: Lactose malabsorption is a common problem in children with gastrointestinal diseases, especially in children with bowel diseases. Lactose intolerance is related to LM, but does not affect all malabsorbers. PMID- 26768641 TI - The Effect of Finishing and Polishing Techniques on the Surface Roughness and the Color of Nanocomposite Resin Restorative Materials. AB - BACKGROUND: Rough, poorly polished surfaces contribute to staining, plaque accumulation, gingival irritation and recurrent caries. Finishing and polishing techniques are critical factors contributing to the longevity of the direct composite resin restorations. OBJECTIVES: The aim of this in vitro study was to evaluate the effects of finishing and polishing systems on surface roughness of six nanocomposite restorative resins. MATERIAL AND METHODS: Thirty specimens of each restorative material (n=180) were placed in a teflon mould (6 mm in diameter and 3 mm in depth) and cured with a LED curing unit. Six specimens from each of restorative material were randomly assigned to four groups for finishing and polishing (carbide burs, diamond burs, aluminium oxide discs, silicon rubber polisher) techniques. Mylar strip formed specimens were served as control group. After finishing and polishing procedures surface roughness was evaluated by a profilometer. The data was analyzed by 2-way analysis of variance and the Tukey HSD test (alpha=0.05). RESULTS: Significant differences were found between the groups in terms roughness (p<0.001). The control group and aluminium oxide discs group had the lowest Ra values and were significantly different from other groups (p<0.001). The roughest surface was obtained with diamond burs followed by silicon rubbers and carbide burs. Overall, the smoothest surfaces were obtained with the use the complete sequence of aluminum oxide discs. CONCLUSIONS: In areas that could not be reached by the aluminum oxide discs, the carbide burs produced satisfactory surface smoothness for the nanocomposite restorative materials. Although mylar matrix strip formed surfaces presents lower surface roughness values, recountouring and polishing of resin restorations are often required in clinical situations. Aluminium oxide discs and carbide finishing burs are suitable for finishing and polishing procedures for nanocomposite restorative resins. PMID- 26768642 TI - Natural and Controlled Demineralization for Study Purposes in Minimally Invasive Dentistry. AB - Artificially induced demineralization of enamel is frequently used during laboratory tests, particularly in minimally invasive dentistry. The aim of this study was to analyze demineralization techniques of hard tooth tissue applicable in the research of materials in minimally invasive dentistry. The most important factor taken into consideration when designing a method is to make a model as closely similar to the natural environment of the human oral cavity as it is possible. In vitro models allow us to maintain stability and control over the environment and guarantee repeatability of the results. There are main models to produce dental caries outside of the body. The first model is chemical and it uses acids. It is simplified and reflects the actual environment of the oral cavity to a lesser degree. The second model is biological and it is more accurate as it uses microorganisms which build the dental plaque. Among in vitro protocols are also used pH-cycling models. Based on the available literature, it was found that bovine teeth and human teeth with demineralization diagnosed while still inside the oral cavity are the most frequently used kind of specimens in research conducted with use of the chemical model. Not a single case of use of the biological and pH-cycling models were found in the available literature related to the research of infiltrants in minimally invasive dentistry. PMID- 26768643 TI - A Comparison of IHC and FISH Cytogenetic Methods in the Evaluation of HER2 Status in Breast Cancer. AB - The HER2 gene is responsible for the formation of the HER2 receptor on the surface of epithelial cells. Increased numbers of this receptor are associated with a worse prognosis in cancer. Increased numbers of copies of the HER2 gene occur in about 20-30% of breast cancer patients, so determining HER2 receptor levels is important in the current diagnosis and treatment of breast cancer. One diagnostic technique is the immunohistochemical (IHC) method, which permits indirect measurement of overexpression of HER2 receptors, based on subjective determination of the intensity of the color reaction. Another technique is the use of fluorescent in situ hybridization (FISH), which permits the exact number of copies of the HER2 gene to be specified. Based on the results of FISH tests, patients can be qualified for treatment with antibodies that partially block HER2 receptors. This treatment causes inhibition of tumor growth signals. Determining the HER2 status in breast cancer with the FISH method allows the further progress of the disease to be predicted, the right treatment to be chosen and the response to the treatment to be foreseen. Because of the widespread use of the FISH and IHC methods, comparing the advantages and disadvantages of these two methods seems to be relevant. PMID- 26768644 TI - Problems and Barriers in Ensuring Effective Acute and Post-Operative Pain Management--an International Perspective. AB - Pain management originated at the turn of the 1960s and 70s in the United States, and spread to Western Europe almost a decade later. It is estimated today that a lack of adequate pain management affects 80% of the global population, and is a serious problem in over 150 countries. At the national level, the greatest burden of inadequate pain management is borne by the elderly, pregnant and breastfeeding women, children, people coping with addictions to harmful substances, and the mentally ill. In spite of enormous progress, there are still significant barriers to comprehensive pain management. Pain management should be considered a priority. It is an interdisciplinary task requiring the cooperation of the whole medical staff. The current review of literature revealed a number of factors limiting the possibility of achieving effective pain management, related to healthcare systems, medical staff and patients. PMID- 26768645 TI - Medical and Ethical Considerations Related to Viable Fetuses with Trisomy 13 in the 36th Week of Pregnancy--a Review of the Literature. AB - Patau syndrome was first described in 1960 as a group of birth defects caused by trisomy of chromosome 13 (T13). Providing accurate information and relevant reproductive genetic counseling that would allow parents to make informed decisions is not easily accomplished because of the limited information available prenatally. Only 1/3 of all cases of T13 are diagnosed prenatally, which means it cannot be expected that most cases will be detected early in pregnancy, that the parents will decide to terminate the pregnancy, and that difficulties will be avoided. There is no good prenatal screening for T13, and there are many kinds and degrees of anomalies. About 60% of cases are first detected in the second trimester, and life expectancy is difficult to predict. When patients choose not to terminate pregnancy, or when the pregnancy has progressed to a viable gestational age, pregnancy termination is no longer an option. Also, nowadays 12% of couples choose to continue pregnancy following chromosomal confirmation of a suspected T13. The aim of this work is to eludicate for health care providers what problems they are likely to face in the care of children with T13 and in contact with their parents. It is crucial for the management of each case to discuss neonatal procedures of resuscitation, alternatives to aggressive resuscitation, the possibilities for correcting some of the defects, and to be prepared to guide the parents through the trauma of having a child with a lethal defect. PMID- 26768646 TI - Protective Effect of Carvacrol on Oxidative Stress and Cellular DNA Damage Induced by UVB Irradiation in Human Peripheral Lymphocytes. AB - Exposure to ultraviolet B (UVB; 280-320 nm) radiation induces the formation of reactive oxygen species (ROS) in the biological system. In this study, we examined the protective effect of carvacrol on UVB-induced lipid peroxidation and oxidative DNA damage with reference to alterations in cellular an-tioxidant status in human lymphocytes. A series of in vitro assays (hydroxyl radical, superoxide, nitric oxide, DPPH (2,2-Diphenyl-1-picryl hydrazyl), and ABTS (2,2 azino-bis-3-ethylbenzothiazoline-6-sulfonic acid) radical scavenging assays) demonstrate antioxidant property of carvacrol in our study. UVB exposure significantly increased thiobarbituric acid reactive substances (TBARS), lipid hydroperoxides (LHPs), % tail DNA and tail moment; decreased % cell viability and antioxidant status in UVB-irradiated lymphocytes. Treatment with carvacrol 30 min prior to UVB-exposure resulted in a significant decline of TBARS, LHP, % tail DNA, and tail moment and increased % cell viability as carvacrol concentration increased. UVB irradiated lymphocytes with carvacrol alone (at 10 MUg/mL) gave no significant change in cell viability, TBARS, LHP, % tail DNA, and tail moment when compared with normal lymphocytes. On the basis of our results, we conclude that carvacrol, a dietary antioxidant, mediates its protective effect through modulation of UVB-induced ROS. PMID- 26768647 TI - Leukocyte Gene Expression and Plasma Concentration in Multiple Sclerosis: Alteration of Transforming Growth Factor-betas, Claudin-11, and Matrix Metalloproteinase-2. AB - Multiple sclerosis is a neurodegenerative disease characterized by the present of leukocytes in the brain tissue and subsequently the formation of sclerotic plaques. Leukocytes penetration into the blood-brain barrier is related to several factors, such as, the conversion of leukocyte gene expression or plasma characteristics. In this frame, we explore alteration of matrix metalloproteinase 2 (MMP-2), transforming growth factor beta (TGF-beta) family, and Claudin-11 (as a main myelin structural protein) in leukocytes and blood plasma of multiple sclerosis patients compared to the normal group. Blood samples were collected from thirteen men affected by MS and fifteen healthy men. Leukocyte gene expression was measured using real-time PCR and plasma parameters were examined by ELISA. The results of this study showed that the gene expression of Claudin-11 was significantly higher in MS group compared with normal. Interestingly, the MMP 2 pattern was similar to Claudin-11 and correlated positively with it. It was observed that, although the expressions of TGF-beta1 and TGF-beta2 are down regulated in the leukocytes of subjects with MS, they showed higher levels of these cytokines in blood plasma. The plasma level of TGF-beta3 in MS patients was higher than normal and correlated with Claudin-11 concentration. In conclusion, the aberrant pattern of Claudin-11, TGF-betas family, and MMP-2 expression in leukocytes of the MS patients was observed in this study. Moreover, the plasma levels of TGF-betas family increased in the MS group. The findings of this study provide clues for further investigations to assay MS pathogenesis. PMID- 26768648 TI - Serial 18F-choline-PET imaging in patients receiving enzalutamide for metastatic castration-resistant prostate cancer: response assessment and imaging biomarkers. AB - AIM: High rate of non-target lesions in metastatic castration-resistant prostate cancer usually limits applicability of Response Evaluation Criteria in Solid Tumors (RECIST) criteria, and this has led to a growing interest in using PET/computed tomography (CT). We prospectively investigated the role of (18)F choline (FCH)-PET/CT in patients receiving enzalutamide after docetaxel. PATIENTS & METHODS: 30 patients were monitored by means of FCH-PET/CT before and during the treatment. A Cox proportional hazards regression model was used to assess the associations between metabolic parameters and clinical outcomes. RESULTS: Univariate analysis showed no significant correlation between biochemical and FCH PET responses. Multivariate analysis showed that only baseline maximum standardized uptake value (SUVmax) significantly correlated with biochemical progression-free survival, radiological progression-free survival and overall survival. CONCLUSION: Our findings suggest that FCH-PET/CT may play a role in defining prognosis of patients receiving enzalutamide because baseline SUVmax proved to be an independent prognostic factor. PMID- 26768649 TI - Accounting for actions and omissions: a discourse analysis of student nurse accounts of responding to instances of poor care. AB - AIMS: To explore how nursing students account for decisions to report or not report poor care witnessed on placement and to examine the implications of findings for educators. BACKGROUND: Concern has been raised about the extent to which cases of poor care go unreported. Failure to report cases may have serious consequences for patient safety. DESIGN: Semistructured interviews were conducted with 13 undergraduate students at a UK university during 2013. They were asked to consider their response to episodes of poor practice witnessed on placement. METHODS: Data were transcribed verbatim and categorized according to whether or not students reported concerns. Cases were analysed in accordance with Potter and Wetherall's version of discourse analysis to identify the discursive strategies used to account for decisions to report or not report poor practice. RESULTS: Participants took care to present themselves in a positive light regardless of whether or not they had reported an episode of concern. Those who had reported tended to attribute their actions to internal factors such as moral strength and a commitment to a professional code. Those who had not or would not report concerns provided accounts which referred to external influences that prevented them from doing so or made reporting pointless. CONCLUSION: This study provides information about how students account for their actions and omissions in relation to the reporting of poor care. Findings suggest ways educators might increase reporting of concerns. PMID- 26768651 TI - Genomic resources for identification of the minimal N2 -fixing symbiotic genome. AB - The lack of an appropriate genomic platform has precluded the use of gain-of function approaches to study the rhizobium-legume symbiosis, preventing the establishment of the genes necessary and sufficient for symbiotic nitrogen fixation (SNF) and potentially hindering synthetic biology approaches aimed at engineering this process. Here, we describe the development of an appropriate system by reverse engineering Sinorhizobium meliloti. Using a novel in vivo cloning procedure, the engA-tRNA-rmlC (ETR) region, essential for cell viability and symbiosis, was transferred from Sinorhizobium fredii to the ancestral location on the S. meliloti chromosome, rendering the ETR region on pSymB redundant. A derivative of this strain lacking both the large symbiotic replicons (pSymA and pSymB) was constructed. Transfer of pSymA and pSymB back into this strain restored symbiotic capabilities with alfalfa. To delineate the location of the single-copy genes essential for SNF on these replicons, we screened a S. meliloti deletion library, representing > 95% of the 2900 genes of the symbiotic replicons, for their phenotypes with alfalfa. Only four loci, accounting for < 12% of pSymA and pSymB, were essential for SNF. These regions will serve as our preliminary target of the minimal set of horizontally acquired genes necessary and sufficient for SNF. PMID- 26768650 TI - Transcriptome profiling in fast versus slow-growing rainbow trout across seasonal gradients. AB - BACKGROUND: Circannual rhythms in vertebrates can influence a wide variety of physiological processes. Some notable examples include annual reproductive cycles and for poikilotherms, seasonal changes modulating growth. Increasing water temperature elevates growth rates in fishes, but increases in photoperiod regime can have similar influences even at constant temperature. Therefore, in order to understand the dynamics of growth in fish it is important to consider the background influence of photoperiod regime on gene expression differences. This study examined the influence of a declining photoperiod regime (winter solstice) compared to an increasing photoperiod regime (spring equinox) on white muscle transcriptome profiles in fast and slow-growing rainbow trout from a commercial aquaculture strain. RESULTS: Slow-growing fish could be characterized as possessing transcriptome profiles that conform in many respects to an endurance training regime in humans. They have elevated mitochondrial and cytosolic creatine kinase expression levels and appear to suppress mTOR-signaling as evidenced by elevated TSC2 expression, and they also have elevated p53 levels. Large fish display a physiological repertoire that may be consistent with strength/resistance physiology having elevated cytoskeletal gene component expression and glycogen metabolism cycling along with higher PI3K levels. In many respects small vs. large fish match eccentric vs. concentric muscle expression patterns, respectively. Lipid metabolic genes are also more elevated in larger fish, the most notable being the G0S2 switch gene. M and Z-line sarcomere remodelling appears to be more prevalent in large fish. Twenty-three out of 26 gene families with previously reported significant SNP-based growth differences were detected as having significant expression differences. CONCLUSIONS: Larger fish display a broader array of genes showing higher expression, and their profiles are more similar to those observed in December lot fish (i.e., an accelerated growth period). Conversely, small fish display gene profiles more similar to seasonal growth decline phases (i.e., September lot fish). Overall, seasonal timing was coupled to greater differences in gene expression compared to differences associated with fish size. PMID- 26768653 TI - Generics, are we there yet? PMID- 26768652 TI - Prognostic Effect of BRAF and KRAS Mutations in Patients With Stage III Colon Cancer Treated With Leucovorin, Fluorouracil, and Oxaliplatin With or Without Cetuximab: A Post Hoc Analysis of the PETACC-8 Trial. AB - Importance: The prognostic value of BRAF and KRAS mutations in patients who have undergone resection for colon cancer and have been treated with combination leucovorin, fluorouracil, and oxaliplatin (FOLFOX)-based adjuvant chemotherapy is controversial, possibly owing to a lack of stratification on mismatch repair status. Objective: To examine the prognostic effect of BRAF and KRAS mutations in patients with stage III colon cancer treated with adjuvant FOLFOX with or without cetuximab. Design, Setting, and Participants: This study included patients with available tumor blocks of resected stage III colon adenocarcinoma who participated between December 2005 and November 2009 in the PETACC-8 phase III randomized trial.Mismatch repair, BRAF V600E, and KRAS exon 2 mutational status were determined on prospectively collected tumor blocks from 2559 patients enrolled in the PETACC-8 trial. The data were analyzed in April 2015. Intervention: Patients were randomly assigned to receive 6 months of FOLFOX4 or FOLFOX4 plus cetuximab after surgical resection for stage III colon cancer. Main Outcomes and Measures: Associations between these biomarkers and disease-free survival (DFS) and overall survival (OS) were analyzed with Cox proportional hazards models. Multivariate models were adjusted for covariates (age, sex, tumor grade, T/N stage, tumor location, Eastern Cooperative Oncology Group performance status). Results: Among the 2559 patients enrolled in the PETACC-8 trial (42.9% female; median [range] age, 60.0 [19.0-75.0] years), microsatellite instability (MSI) phenotype, KRAS, and BRAF V600E mutations were detected in, respectively, 9.9% (177 of 1791), 33.1% (588 of 1776), and 9.0% (148 of 1643) of cases. In multivariate analysis, MSI (hazard ratio [HR] for DFS: 1.10 [95% CI, 0.73-1.64], P = .67; HR for OS: 1.02 [95% CI, 0.61-1.69], P = .94) and BRAF V600E mutation (HR for DFS: 1.22 [95% CI, 0.81-1.85], P = .34; HR for OS: 1.13 [95% CI, 0.64 2.00], P = .66) were not prognostic, whereas KRAS mutation was significantly associated with shorter DFS (HR, 1.55 [95% CI, 1.23-1.95]; P < .001) and OS (HR, 1.56 [95% CI, 1.12-2.15]; P = .008). The subgroup analysis showed in patients with microsatellite-stable tumors that both KRAS (HR for DFS: 1.64 [95% CI, 1.29 2.08], P < .001; HR for OS: 1.71 [95% CI, 1.21-2.41], P = .002) and BRAF V600E mutation (HR for DFS: 1.74 [95% CI, 1.14-2.69], P = .01; HR for OS: 1.84 [95% CI, 1.01-3.36], P = .046) were independently associated with worse clinical outcomes. In patients with MSI tumors, KRAS status was not prognostic, whereas BRAF V600E mutation was associated with significantly longer DFS (HR, 0.23 [95% CI, 0.06 0.92]; P = .04) but not OS (HR, 0.19 [95% CI, 0.03-1.24]; P = .08). Conclusions and Relevance: BRAF V600E and KRAS mutations were significantly associated with shorter DFS and OS in patients with microsatellite-stable tumors but not in patients with MSI tumors. Future trials in the adjuvant setting will have to take into account mismatch repair, BRAF, and KRAS status for stratification. Trial Registration: EudraCT 2005-003463-23. PMID- 26768654 TI - Reimbursement of biosimilars in Poland: is there a link to health technology assessment? AB - INTRODUCTION: Due to their complex structures, biosimilars are not generics. The differences between them are considered during market authorization processes but remain unclear during reimbursement decision-making. METHODS: We analyzed the reimbursement of biopharmaceuticals in Poland with an emphasis on biosimilars and compared the health technology assessment (HTA) process with that defined in other countries. Recommendations provided by the Polish HTA organization and those in other countries were included as source documents. The period of interest covered January 2012 to December 2014. RESULTS: The reimbursement process for biosimilars in Poland is the same as that for generics. In contrast to other countries, a HTA is not involved in decision-making in Poland. DISCUSSION: The short administrative procedure for reimbursement of biosimilars in Poland accelerates the decision-making process; therefore, therapies can be made available to patients more quickly. However, this procedure can potentially lead to underestimation of aspects concerning the effectiveness and safety of biosimilars. PMID- 26768656 TI - Endocannabinoid regulation in white and brown adipose tissue following thermogenic activation. AB - The endocannabinoids and their main receptor, cannabinoid type-1 (CB1), suppress intracellular cyclic AMP levels and have emerged as key players in the control of energy metabolism. CB1 agonists and blockers have been reported to influence the thermogenic function of white and brown adipose tissue (WAT and BAT), affecting body weight through the inhibition and stimulation of energy expenditure, respectively. The purpose of the current study was to investigate the regulation of the endocannabinoid system in WAT and BAT following exposure to either cold or specific agonism of beta3-adrenoceptors using CL316,243 (CL), conditions known to cause BAT activation and WAT browning. To address this question, we performed quantitative PCR-based mRNA profiling of genes important for endocannabinoid synthesis, degradation, and signaling, and determined endocannabinoid levels by LC-MS in WAT and BAT of control, cold-exposed, and CL-treated wild-type mice as well as primary brown adipocytes. Treatment with CL and exposure to cold caused an upregulation of endocannabinoid levels and biosynthetic enzymes in WAT. Acute beta3-adrenoceptor activation increased endocannabinoids and a subset of genes of biosynthesis in BAT and primary brown adipocytes. We suggest that the cold mediated increase in endocannabinoid tone is part of autocrine negative feed-back mechanisms controlling beta3-adrenoceptor-induced BAT activation and WAT browning. PMID- 26768655 TI - A novel diacylglycerol kinase alpha-selective inhibitor, CU-3, induces cancer cell apoptosis and enhances immune response. AB - Diacylglycerol kinase (DGK) consists of 10 isozymes. The alpha-isozyme enhances the proliferation of cancer cells. However, DGKalpha facilitates the nonresponsive state of immunity known as T-cell anergy; therefore, DGKalpha enhances malignant traits and suppresses immune surveillance. The aim of this study was to identify a novel small molecule that selectively and potently inhibits DGKalpha activity. We screened a library containing 9,600 chemical compounds using a newly established high-throughput DGK assay. As a result, we have obtained a promising compound, 5-[(2E)-3-(2-furyl)prop-2-enylidene]-3 [(phenylsulfonyl)amino]2-thioxo-1,3-thiazolidin-4-one) (CU-3), which selectively inhibited DGKalpha with an IC50 value of 0.6 MUM. CU-3 targeted the catalytic region, but not the regulatory region, of DGKalpha. CU-3 competitively reduced the affinity of DGKalpha for ATP, but not diacylglycerol or phosphatidylserine. Moreover, this compound induced apoptosis in HepG2 hepatocellular carcinoma and HeLa cervical cancer cells while simultaneously enhancing the interleukin-2 production of Jurkat T cells. Taken together, these results indicate that CU-3 is a selective and potent inhibitor for DGKalpha and can be an ideal anticancer drug candidate that attenuates cancer cell proliferation and simultaneously enhances immune responses including anticancer immunity. PMID- 26768660 TI - Errata. PMID- 26768659 TI - Errata. PMID- 26768661 TI - Errata. PMID- 26768663 TI - Factor H uptake regulates intracellular C3 activation during apoptosis and decreases the inflammatory potential of nucleosomes. AB - Factor H (FH) binds apoptotic cells to limit the inflammatory potential of complement. Here we report that FH is actively internalized by apoptotic cells to enhance cathepsin L-mediated cleavage of endogenously expressed C3, which results in increased surface opsonization with iC3b. In addition, internalized FH forms complexes with nucleosomes, facilitates their phagocytosis by monocytes and induces an anti-inflammatory biased cytokine profile. A similar cytokine response was noted for apoptotic cells coated with FH, confirming that FH diminishes the immunogenic and inflammatory potential of autoantigens. These findings were supported by in vivo observations from CFH(-/-) MRL-lpr mice, which exhibited higher levels of circulating nucleosomes and necrotic cells than their CFH(+/+) littermates. This unconventional function of FH broadens the established view of apoptotic cell clearance and appears particularly important considering the strong associations with genetic FH alterations and diseases such as systemic lupus erythematosus and age-related macular degeneration. PMID- 26768662 TI - Repression of p53-target gene Bbc3/PUMA by MYSM1 is essential for the survival of hematopoietic multipotent progenitors and contributes to stem cell maintenance. AB - p53 is a central mediator of cellular stress responses, and its precise regulation is essential for the normal progression of hematopoiesis. MYSM1 is an epigenetic regulator essential for the maintenance of hematopoietic stem cell (HSC) function, hematopoietic progenitor survival, and lymphocyte development. We recently demonstrated that all developmental and hematopoietic phenotypes of Mysm1 deficiency are p53-mediated and rescued in the Mysm1(-/-)p53(-/-) mouse model. However, the mechanisms triggering p53 activation in Mysm1(-/-) HSPCs, and the pathways downstream of p53 driving different aspects of the Mysm1(-/-) phenotype remain unknown. Here we show the transcriptional activation of p53 stress responses in Mysm1(-/-) HSPCs. Mechanistically, we find that the MYSM1 protein associates with p53 and colocalizes to promoters of classical p53-target genes Bbc3/PUMA (p53 upregulated modulator of apoptosis) and Cdkn1a/p21. Furthermore, it antagonizes their p53-driven expression by modulating local histone modifications (H3K27ac and H3K4me3) and p53 recruitment. Using double knockout mouse models, we establish that PUMA, but not p21, is an important mediator of p53-driven Mysm1(-/-) hematopoietic dysfunction. Specifically, Mysm1( /-)Puma(-/-) mice show full rescue of multipotent progenitor (MPP) viability, partial rescue of HSC quiescence and function, but persistent lymphopenia. Through transcriptome analysis of Mysm1(-/-)Puma(-/-) MPPs, we demonstrate strong upregulation of other p53-induced mediators of apoptosis and cell-cycle arrest. The full viability of Mysm1(-/-)Puma(-/-) MPPs, despite strong upregulation of many other pro-apoptotic mediators, establishes PUMA as the essential non redundant effector of p53-induced MPP apoptosis. Furthermore, we identify potential mediators of p53-dependent but PUMA-independent Mysm1(-/-)hematopoietic deficiency phenotypes. Overall, our study provides novel insight into the cell type-specific roles of p53 and its downstream effectors in hematopoiesis using unique models of p53 hyperactivity induced by endogenous stress. We conclude that MYSM1 is a critical negative regulator of p53 transcriptional programs in hematopoiesis, and that its repression of Bbc3/PUMA expression is essential for MPP survival, and partly contributes to maintaining HSC function. PMID- 26768666 TI - Comparison of thermoluminescence characteristics in gamma-ray and C(5+) ion beam irradiated LiCaAlF6 :Ce phosphor. AB - We compare the thermoluminescence (TL) behavior of Ce(3+) ion-activated LiCaAlF6 exposed to gamma-rays and a carbon ion beam. The reported phosphor is synthesized using an in-house precipitation method with varying concentrations of activator ion and is characterized by X-ray diffraction (XRD) and TL. Rietveld refinement is performed to study the structural statistics. The TL glow curve consists of a prominent glow peak at 232 degrees C with three shoulders at 115, 159 and 333 degrees C when exposed to gamma-rays from a (60) Co source. When exposed to a C(5+) ion beam, the TL glow curve consists of five peaks with peak temperatures near 156, 221, 250, 287 and 330 degrees C, and is found to vary slightly with changing fluence. Glow curve convolution deconvolution (GCCD) functions are applied to the TL curves for complete analysis of the glow curve structure and TL traps. The order of kinetics (b), activation energy (E) and frequency factor are determined using Chen's peak shape method and theoretical curves are drawn using GCCD functions. A track interaction model (TIM) is used to explain the sublinearity/saturation at higher fluences. Ion beam parameters are analyzed using Monte-Carlo simulation-based SRIM-2013 code. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26768664 TI - Enhanced efferocytosis by dendritic cells underlies memory T-cell expansion and susceptibility to autoimmune disease in CD300f-deficient mice. AB - Homeostasis requires the immunologically silent clearance of apoptotic cells before they become pro-inflammatory necrotic cells. CD300f (CLM-1) is a phosphatidylserine receptor known to positively regulate efferocytosis by macrophages, and CD300f gene-deficient mice are predisposed to develop a lupus like disease. Here we show that, in contrast to CD300f function in macrophages, its expression inhibits efferocytosis by DC, and its deficiency leads to enhanced antigen processing and T-cell priming by these DC. The consequences are the expansion of memory T cells and increased ANA levels in aged CD300f-deficient mice, which predispose CD300f-deficient mice to develop an overt autoimmune disease when exposed to an overload of apoptotic cells, or an exacerbated autoimmunity when combined with FcgammaRIIB deficiency. Thus, our data demonstrates that CD300f helps to maintain immune homeostasis by promoting macrophage clearance of self-antigens, while conversely inhibiting DC uptake and presentation of self-antigens. PMID- 26768667 TI - An unusual complication after interventional cardiology reveals and infrequent condition: Idiopathic CD4 deficiency. AB - Herpes zoster (HZ) is of rare occurrence after interventional procedures with few events reported until now. A 74 year-old man with a past medical history of idiopathic thrombocytopenic purpura, splenectomy, autoimmune hemolytic anemia, and polymyalgia rheumatica developed HZ on the right median nerve 7 days after he underwent a coronariography for managing an acute coronary syndrome. He evolved with cutaneous dissemination and required intravenous acyclovir therapy. Laboratory evaluation disclosed a previously unknown idiophatic CD4 lymphocytopenia. HZ should be added to the list of complications after interventional cardiology and associated immunosuppressive factors ruled out. PMID- 26768665 TI - DeltaNp63 regulates IL-33 and IL-31 signaling in atopic dermatitis. AB - Atopic dermatitis (AD) is the most common inflammatory skin disease with no well delineated cause or effective cure. Here we show that the p53 family member p63, specifically the DeltaNp63, isoform has a key role in driving keratinocyte activation in AD. We find that overexpression of DeltaNp63 in transgenic mouse epidermis results in a severe skin phenotype that shares many of the key clinical, histological and molecular features associated with human AD. This includes pruritus, epidermal hyperplasia, aberrant keratinocyte differentiation, enhanced expression of selected cytokines and chemokines and the infiltration of large numbers of inflammatory cells including type 2 T-helper cells - features that are highly representative of AD dermatopathology. We further demonstrate several of these mediators to be direct transcriptional targets of DeltaNp63 in keratinocytes. Of particular significance are two p63 target genes, IL-31 and IL 33, both of which are key players in the signaling pathways implicated in AD. Importantly, we find these observations to be in good agreement with elevated levels of DeltaNp63 in skin lesions of human patients with AD. Our studies reveal an important role for DeltaNp63 in the pathogenesis of AD and offer new insights into its etiology and possible therapeutic targets. PMID- 26768668 TI - Prevalence of methicillin resistant Staphylococcus aureus [MRSA] colonization or carriage among health-care workers. AB - In Oman, the prevalence of health care associated methicillin resistant Staphylococcus aureus [HA-MRSA] is unknown. Therefore, to estimate the prevalence of HA-MRSA, we collected nasal swabs and swabs from cell phones on sterile polyester swabs and immediately inoculated on the mannitol salt agar containing oxacillin from medical students and hospital health care providers. Antibiotic susceptibility testing of the isolates was then performed using the Kirby Bauer's disc diffusion method. Additionally, a brief survey questionnaire was used to acquire demographic data. Amongst the 311 participants enrolled, nasal colonization with HA-MRSA was found in 47 individuals (15.1%, 95% confidence interval [CI]=11.1%, 19.1%). HA-MRSA was also isolated from the cell phone surfaces in 28 participants (9.0%, 95% CI=8.6%, 9.3%). 5 participants (1.6%) showed positive results both from their nasal swabs and from their cell phones. Antibiotic resistance to erythromycin [48%] and clindamycin [29%] was relatively high. 9.3% HA-MRSA isolates were vancomycin resistant [6.6% nasal carriage]. There was no statistically significant correlation between HA-MRSA isolates and the demographic characteristics or the risk factors namely gender, underlying co morbidities like diabetes, hypertension, skin/soft tissue infections, skin ulcers/wounds, recent exposure to antibiotics, or hospital visits (p>0.05, Chi square test). PMID- 26768670 TI - Re: Hepatocellular nodules resulting from congenital extrahepatic portosystemic shunts can differentiate into potentially malignant hepatocellular adenomas. PMID- 26768669 TI - Nocardia asteroides peritoneal dialysis-related peritonitis: First case in pediatrics, treated with protracted linezolid. AB - Nocardia asteroides is a rare pathogen in peritoneal dialysis-related peritonitis. We report on a 13-year-old female with Nocardia asteroides peritonitis complicated by an intra-abdominal abscess. Linezolid was administered intravenously for 3 months and followed by oral therapy for an additional 5 months with close monitoring for adverse effects. The patient was discharged after 3 months of hospitalization on hemodialysis. The diagnosis and management of such cases can be problematic due to the slow growth and difficulty of identifying Nocardia species. The optimal duration of treatment for Nocardia peritonitis is not known. Linezolid can be used for prolonged periods in cases of trimethoprim/sulfamethoxazole-resistant cases with close monitoring for adverse effects. PMID- 26768672 TI - How to Get Published in JSFA. PMID- 26768671 TI - Response to Re: Hepatocellular nodules resulting from congenital extrahepatic portosystemic shunts can differentiate into potentially malignant hepatocellular adenomas. PMID- 26768673 TI - Utility of Glycated Hemoglobin for Assessment of Glucose Metabolism in Patients With ST-Segment Elevation Myocardial Infarction. AB - Glycated hemoglobin (HbA1c) is an approved and widely used laboratory investigation for diagnosis of diabetes that is not affected by acute changes in blood glucose. Our aim was to analyze the extent to which routine HbA1c measurements diagnose unknown diabetes mellitus (DM) in patients presenting with ST-segment elevation myocardial infarction (STEMI). We also compared outcomes in patients with newly diagnosed DM, previously established DM and those without DM. Consecutive patients undergoing PCI for STEMI from January 2005 to December 2012 were included and routinely performed admission HbA1c was used to identify patients with previously undiagnosed DM (HbA1c >=6.5 and no history of DM or DM therapy) and pre-DM (HbA1c 5.7% to 6.4%). Overall 1,686 consecutive patients underwent primary percutaneous coronary intervention for STEMI during the study period and follow-up data were available for 1,566 patients (90%). A quarter of the patients (24%, n = 405) had history of DM, 7% (n = 118) had previously undiagnosed DM, and 38.7% (n = 652) had pre-DM. Mortality was comparable in patients with known DM and newly diagnosed DM both in-hospital (11.1% vs 11.9%, p = 0.87) and at 3-year follow-up (27.3% and 24%). Patients with DM, including those who were newly diagnosed, had higher mortality at 3 years (26.5%) compared to those with pre-DM (12.1%) or no dysglycemia (11.2%, p <0.01). In conclusion, a substantial number of patients with STEMI have previously undiagnosed DM (7%). These patients have similar in-hospital and long-term mortality as those with known DM, and outcomes are inferior to patients without dysglycemia. PMID- 26768675 TI - Serial Intravascular Ultrasound Findings After Treatment of Chronic Total Occlusions Using Drug-Eluting Stents. AB - Morphologic changes after chronic total occlusion (CTO) treatment with drug eluting stents (DESs) have not been assessed in detail. Our aim was to use both baseline and follow-up intravascular ultrasound studies to evaluate the morphologic changes and, especially, the changes in distal vessel size and the effect of subintimal stenting after treatment of CTOs with DES. We analyzed serial follow-up intravascular ultrasound (baseline and follow-up at 9 +/- 2 months) after DES implantation into 40 CTOs. Overall, 33 CTOs were treated by the anterograde approach; and 7 were treated by the retrograde approach. Minimum lumen cross-sectional area (CSA) trended toward a decrease from baseline to follow-up (4.8 +/- 1.7 vs 4.5 +/- 1.7 mm(2), p = 0.10), although the minimum stent CSA (4.8 +/- 1.7 vs 4.9 +/- 1.7 mm(2), p = 0.26) did not change. The distal reference, but not the proximal reference lumen CSA, increased significantly at follow-up (3.8 +/- 2.0 to 5.1 +/- 2.3 mm(2), p = 0.0004). Late-acquired stent malapposition was seen in 17 patients (42.5%). In 8 CTOs (20%), a part of the stent was implanted into a subintimal space; in these 8 patients, maximum percent neointimal hyperplasia and minimum lumen area was similar in the subintimal segment compared with the adjacent intraplaque segment. The frequency of late acquired stent malapposition was similar. In conclusion, after CTO treatment with DES, distal vessel enlargement was detected. Subintimal stenting after recanalization of CTO was not inferior compared with stenting within the plaque in terms of long-term morphologic impact. PMID- 26768674 TI - Degree and Direction of Change of Body Weight in Cardiac Rehabilitation and Impact on Exercise Capacity and Cardiac Risk Factors. AB - Cardiac rehabilitation (CR) improves functional capacity and reduces mortality in patients with cardiovascular disease. It also improves cardiovascular risk factors and aids in weight reduction. Because of the increase in morbidly obese patients with cardiovascular disease, the prevalence of obesity and patterns of weight change in those undergoing CR merit fresh study. We studied 1,320 participants in a 12-week CR program at our academic medical center. We compared 5 categories: 69 class III obese (body mass index [BMI] >=40) patients, 128 class II obese patients (BMI 35.0 to 39.9), 318 class I obese patients (BMI 30.0 to 34.9), 487 overweight patients (BMI 25.0 to 29.9), and 318 normal weight patients (BMI 18.5 to 24.9). Exercise capacity in METs, weight, blood pressure, and fasting lipid profile were measured before and after CR. Overall, 131 patients gained weight, 827 had no significant weight change, and 363 lost weight (176 lost 3% to 5% of their baseline weight, 161 lost 5% to 10%, and 26 lost >10%). Exercise capacity, blood pressure, and low-density lipoprotein cholesterol improved in all patients. Class III obese patients had the smallest improvement in peak METs (p <0.001), but the greatest weight loss. Patients who lost >10% of their baseline weight had the greatest improvements in exercise capacity, low density lipoprotein, and triglycerides. In conclusion, after CR, a minority of patients lost weight. Most patients had no significant weight change and some even gained weight. The greatest loss was seen in class III obese patients. All patient groups showed improvements in exercise capacity and risk factors, regardless of the direction or degree of weight change. PMID- 26768676 TI - The role of STK 11 gene testing in individuals with oral pigmentation. AB - Peutz-Jeghers syndrome (PJS) is a rare, autosomal dominant condition characterised by mucocutaneous pigmented lesions, gastrointestinal polyposis and a significant risk of cancer. Laugier-Hunziker syndrome (LHS) is a benign condition with similar dermatological features, but with no systemic complications. STK 11 gene testing allows clinicians to differentiate between these two disorders. This case report compares the dermatological similarities in four individuals with PJS or LHS and illustrates the potential benefit of genetic testing. There is > 90% likelihood of identifying a mutation in STK 11 if a patient fulfils the diagnostic criteria for PJS. Lifelong risk management is advised for these individuals with confirmed PJS. Diagnostic confirmation is important to provide rational management, in particular, endoscopic cancer surveillance, and psychological support. STK 11 testing can confirm those at risk of PJS, who require lifelong surveillance, and possibly release those with a simple dermatosis, such as LHS, from invasive and thus potentially harmful surveillance. PMID- 26768679 TI - Electroclinical features of a patient with GLUT1 deficiency syndrome and adult onset periodic weakness. PMID- 26768678 TI - 'PrP systemic deposition disease': clinical and pathological characteristics of novel familial prion disease with 2-bp deletion in codon 178. AB - BACKGROUND AND PURPOSE: A novel TYPE of prion disease associated mainly with autonomic-sensory polyneuropathy was reported by us previously. METHODS: Here the autopsy pathology for patient 1 (the sister) and the clinical characteristics of her younger brother (patient 2) are newly reported. Polymerase chain reaction based restriction fragment length polymorphism analysis of the prion protein gene (PRNP) was performed on both patients and their father (normal control). RESULTS: Polymerase chain reaction based restriction fragment length polymorphism analysis revealed a 2-bp deletion (CT) in codon 178 that causes an additional variable 25 amino acids at the C terminal, from the mutation site to the premature stop codon at codon 203, in both patients 1 and 2 but not in their father. The autopsy of patient 1 showed remarkable prion protein (PrP) deposits in the sympathetic ganglion and peripheral nerves, correlated to her severe autonomic sensory failure. PrP deposits were also found in the central nervous system and peripheral organs such as the heart, lung, stomach, jejunum, ileum, colon, urinary bladder and adrenal gland. The symptoms and biopsy findings of patient 2 were nearly the same as those reported previously for patient 1. His cognitive function was well preserved, but autonomic functions were severely impaired. His biopsied samples showed PrP deposits in the sural nerve and nerve plexuses of the stomach and colon. CONCLUSION: The present unique 2-bp deletion (CT) in codon 178 induced a 'PrP systemic deposition disease' such as pan-autonomic failure, sensory neuropathy and mild cognitive impairment with a specific pathology. PMID- 26768680 TI - Deep brain bilateral pallidal stimulation in chorea-acanthocytosis caused by a homozygous VPS13A mutation. PMID- 26768682 TI - Pessimism and Homework in CBT for Depression. AB - OBJECTIVE: To investigate the moderating effects of attributional style on the relationship between client-rated benefits of homework completion and depression throughout a course of cognitive behavior therapy (CBT). METHOD: A total of 28 clients, aged 20 to 65 years, experiencing their first major depressive episode completed up to 20 sessions of CBT plus a follow-up session at 2 months. Clients, therapists, and independent observers completed the measures. Multilevel modeling was used for a within-person longitudinal analysis of data. RESULTS: Pessimism slightly moderated the relationship between quantity-quality of homework completion and depression severity over time. Decreases in depression severity were largely independent of level of homework completion. CONCLUSION: While CBT is effective in reducing depression, pessimistic attributional style can affect the perception that clients bring to the quantity and quality of homework completion. Clinicians could thus focus on dealing with pessimistic style for treatment and homework to moderate the severity of depression. PMID- 26768684 TI - Treatment for Ischemic Stroke: A New Approach from the Ancient Art of War. PMID- 26768685 TI - Pharmacotherapy for Alcohol Dependence: The 2015 Recommendations of the French Alcohol Society, Issued in Partnership with the European Federation of Addiction Societies. AB - BACKGROUND: The latest French good practice recommendations (GPRs) for the screening, prevention, and treatment of alcohol misuse were recently published in partnership with the European Federation of Addiction Societies (EUFAS). This article aims to synthesize the GPRs focused on the pharmacotherapy of alcohol dependence. METHODS: A four-member European steering committee defined the questions that were addressed to an 18-member multiprofessional working group (WG). The WG developed the GPRs based on a systematic, hierarchical, and structured literature search and submitted the document to two review processes involving 37 French members from multiple disciplines and 5 non-French EUFAS members. The final GPRs were graded A, B, or C, or expert consensus (EC) using a reference recommendation grading system. RESULTS: The treatment of alcohol dependence consists of either alcohol detoxification or abstinence maintenance programs or drinking reduction programs. The therapeutic objective is the result of a decision made jointly by the physician and the patient. For alcohol detoxification, benzodiazepines (BZDs) are recommended in first-line (grade A). BZD dosing should be guided by regular clinical monitoring (grade B). Residential detoxification is more appropriate for patients with a history of seizures, delirium tremens, unstable psychiatric comorbidity, or another associated substance use disorder (grade B). BZDs are only justified beyond a 1-week period in the case of persistent withdrawal symptoms, withdrawal events or associated BZD dependence (grade B). BZDs should not be continued for more than 4 weeks (grade C). The dosing and duration of thiamine (vitamin B1) during detoxification should be adapted to nutritional status (EC). For relapse prevention, acamprosate and naltrexone are recommended as first-line medications (grade A). Disulfiram can be proposed as second-line option in patients with sufficient information and supervision (EC). For reducing alcohol consumption, nalmefene is indicated in first line (grade A). The second-line prescription of baclofen, up to 300 mg/day, to prevent relapse or reduce drinking should be carried out according to the "temporary recommendation for use" measure issued by the French Health Agency (EC). During pregnancy, abstinence is recommended (EC). If alcohol detoxification is conducted during pregnancy, BZD use is recommended (grade B). No medication other than those for alcohol detoxification should be initiated in pregnant or breastfeeding women (EC). In a stabilized pregnant patient taking medication to support abstinence, the continuation of the drug should be considered on a case by-case basis, weighing the benefit/risk ratio. Only disulfiram should be always stopped, given the unknown risks of the antabuse effect on the fetus (EC). First line treatments to help maintain abstinence or reduce drinking are off-label for people under 18 years of age and should thus be considered on a case-by-case basis after the repeated failure of psychosocial measures alone (EC). Short half life BZDs should be preferred for the detoxification of elderly patients (grade B). The initial doses of BZDs should be reduced by 30 to 50% in elderly patients (EC). In patients with chronic alcohol-related physical disorders, abstinence is recommended (EC). Any antidepressant or anxiolytic medication should be introduced after a psychiatric reassessment after 2-4 weeks of alcohol abstinence or low-risk use (grade B). A smoking cessation program should be offered to any smokers involved in an alcohol treatment program (grade B). PMID- 26768686 TI - Infused total nucleated cell dose is a better predictor of transplant outcomes than CD34+ cell number in reduced-intensity mobilized peripheral blood allogeneic hematopoietic cell transplantation. AB - Mobilized peripheral blood is the most common graft source for allogeneic hematopoietic stem cell transplantation following reduced-intensity conditioning. In assessing the effect of donor cell dose and graft composition on major transplant outcomes in the reduced-intensity setting, prior studies focused primarily on CD34(+)cell dose and reported conflicting results, especially in relation to survival end-points. While the impact of total nucleated cell dose has been less frequently evaluated, available studies suggest higher total nucleated cell dose is associated with improved survival outcomes in the reduced intensity setting. In order to further explore the relationship between CD34(+)cell dose and total nucleated cell dose on reduced-intensity transplant outcomes, we analyzed the effect of donor graft dose and composition on outcomes of 705 patients with hematologic malignancies who underwent reduced-intensity peripheral blood stem cell transplantation at the Dana Farber Cancer Institute from 2000 to 2010. By multivariable analysis we found that higher total nucleated cell dose (top quartile; >=10.8 * 10(10)cells) was associated with improved overall survival [HR 0.69 (0.54-0.88),P=0.0028] and progression-free survival [HR 0.68 (0.54-0.85),P=0.0006]. Higher total nucleated cell dose was independently associated with decreased relapse [HR 0.66 (0.51-0.85),P=0.0012] and increased incidence of chronic graft-versus-host disease [HR 1.4 (1.12-1.77),P=0.0032]. In contrast, higher doses of CD34(+)cells (top quartile; >=10.9 * 10(6)/kg) had no significant effect on graft-versus-host disease or survival outcomes. These data suggest total nucleated cell dose is a more relevant prognostic variable for reduced-intensity transplant outcomes than the more commonly studied CD34(+)cell dose. PMID- 26768687 TI - Impact of post-brentuximab vedotin consolidation on relapsed/refractory CD30+ Hodgkin lymphomas: a large retrospective study on 240 patients enrolled in the French Named-Patient Program. AB - Brentuximab vedotin was reported to be effective and safe against refractory/relapsed Hodgkin lymphoma in cohorts of between 12 to 102 patients. Herein we report our retrospective analysis of the French experience with brentuximab vedotin used alone to treat 240 refractory/relapsed Hodgkin lymphoma patients enrolled in a named patient program between 2011 and 2013. All patients had histologically documented CD30+ Hodgkin lymphoma; 74% had refractory disease or early relapses. After a median of 3 lines of chemotherapy, brentuximab vedotin was infused intravenously (1.8 mg/kg every 3 weeks). The primary endpoint was best response. Response at the end of treatment, its duration, survival data and toxicity profile were secondary endpoints. Patients received a median of 6 cycles; 68 underwent a consolidation thereafter. The best response was observed after a median of 4 cycles in 145 (60.4%) patients: 33.8% complete response/unconfirmed complete response, 26.7% partial response. Objective responses were observed as decreased (39.3%) in the 28 patients >60 years. The median response duration was 8.4 months. With median follow-up at 16.1 months, median progression-free survival was 6.8 months and this was significantly longer for patients transplanted after brentuximab vedotin (a median of 18,8 months); median overall survival was not reached. No death has been linked to brentuximab vedotin toxicity. The most common adverse events were peripheral sensory neuropathy (29.3%) and hematological toxicity. The results of this analysis support the previously reported brentuximab vedotin efficacy with manageable toxicity. Because of the short-term responses in most patients, a high-dose therapy with stem cell transplantation for responders should be considered as quickly as possible. PMID- 26768688 TI - Interleukin-15-activated cytokine-induced killer cells may sustain remission in leukemia patients after allogeneic stem cell transplantation: feasibility, safety and first insights on efficacy. PMID- 26768689 TI - Mutation status of essential thrombocythemia and primary myelofibrosis defines clinical outcome. PMID- 26768691 TI - Creation and validation of a novel body condition scoring method for the magellanic penguin (Spheniscus magellanicus) in the zoo setting. AB - This research aims to validate a novel, visual body scoring system created for the Magellanic penguin (Spheniscus magellanicus) suitable for the zoo practitioner. Magellanics go through marked seasonal fluctuations in body mass gains and losses. A standardized multi-variable visual body condition guide may provide a more sensitive and objective assessment tool compared to the previously used single variable method. Accurate body condition scores paired with seasonal weight variation measurements give veterinary and keeper staff a clearer understanding of an individual's nutritional status. San Francisco Zoo staff previously used a nine-point body condition scale based on the classic bird standard of a single point of keel palpation with the bird restrained in hand, with no standard measure of reference assigned to each scoring category. We created a novel, visual body condition scoring system that does not require restraint to assesses subcutaneous fat and muscle at seven body landmarks using illustrations and descriptive terms. The scores range from one, the least robust or under-conditioned, to five, the most robust, or over-conditioned. The ratio of body weight to wing length was used as a "gold standard" index of body condition and compared to both the novel multi-variable and previously used single-variable body condition scores. The novel multi-variable scale showed improved agreement with weight:wing ratio compared to the single-variable scale, demonstrating greater accuracy, and reliability when a trained assessor uses the multi-variable body condition scoring system. Zoo staff may use this tool to manage both the colony and the individual to assist in seasonally appropriate Magellanic penguin nutrition assessment. PMID- 26768690 TI - High-risk HLA alleles for severe acute graft-versus-host disease and mortality in unrelated donor bone marrow transplantation. AB - HLA molecules play an important role for immunoreactivity in allogeneic hematopoietic stem cell transplantation. To elucidate the effect of specific HLA alleles on acute graft-versus-host disease, we conducted a retrospective analysis using 6967 Japanese patients transplanted with T-cell-replete marrow from an unrelated donor. Using unbiased searches of patient and donor HLA alleles, patient and/or donor HLA-B*51:01 (patient: HR, 1.37,P<0.001; donor: HR, 1.35,P<0.001) and patient HLA-C*14:02 (HR, 1.35,P<0.001) were significantly associated with an increased risk of severe acute graft-versus-host disease. The finding that donor HLA-C*14:02 was not associated with severe acute graft-versus host disease prompted us to elucidate the relation of these high-risk HLA alleles with patient and donor HLA-C allele mismatches. In comparison to HLA-C allele match, patient mismatched HLA-C*14:02 showed the highest risk of severe acute graft-versus-host disease (HR, 3.61,P<0.001) and transplant-related mortality (HR, 2.53,P<0.001) among all patient mismatched HLA-C alleles. Although patient HLA-C*14:02 and donor HLA-C*15:02 mismatch was usually KIR2DL-ligand mismatch in the graft-versus-host direction, the risk of patient mismatched HLA-C*14:02 for severe acute graft-versus-host disease was obvious regardless of KIR2DL-ligand matching. The effect of patient and/or donor HLA-B*51:01 on acute graft-versus host disease was attributed not only to strong linkage disequilibrium of HLA C*14:02 and -B*51:01, but also to the effect of HLA-B*51:01 itself. With regard to clinical implications, patient mismatched HLA-C*14:02 proved to be a potent risk factor for severe acute graft-versus-host disease and mortality, and should be considered a non-permissive HLA-C mismatch in donor selection for unrelated donor hematopoietic stem cell transplantation. PMID- 26768692 TI - Impact of Contact Force Monitoring in Acute Pulmonary Vein Isolation Using an Anatomic Approach. A Randomized Study. AB - BACKGROUND: The impact of contact force (CF) monitoring in pulmonary vein (PV) isolation after a circumferential anatomic ablation (CAA) is unknown. We analyze the usefulness of CF monitoring in acute PV isolation and procedure parameters using a CAA. METHODS: Fifty patients with paroxysmal atrial fibrillation were randomized into CF-on (CF >10 grams; n = 25) or CF-off (CF blinded; n = 25) groups. We performed a first round of CAA with a ThermoCool((r)) SmartTouch((r)) catheter blinded to the LASSO((r)) catheter (Biosense Webster, Diamond Bar, CA, USA), with radiofrequency (RF) lesions tagged with the VisiTag(TM) Module. After the CAA, each PV was reviewed with the LASSO((r)) catheter recording the segments with gaps. RESULTS: All the PVs were isolated with a CAA in 20 patients of the CF on versus eight of the CF-off (P = 0.001). Of the 45 segments with gaps in the left PVs, 38 were from the CF-off (P = 0.0001). Of the eight segments with gaps in the right PVs, seven were from the CF-off (P = 0.06). The CF in the left PVs was higher in the CF-on (16.3 +/- 3.2 grams vs 10.5 +/- 4.3 grams; P = 0.0001) and similar in the right PVs (17.6 +/- 3.6 grams vs 15.2 +/- 5.3 grams; P = 0.08). All of the gaps were closed with additional RF LASSO((r)) -guided touch up. Procedure and fluoroscopy times were shorter in the CF-on (139 +/- 24 minutes vs 157 +/- 32 minutes and 20 +/- 6 minutes vs 24 +/- 7 minutes; both P = 0.039). At 12 months the patients free of AF recurrence was 84% CF-on versus 75% CF-off (log-rank P = 0.4) [corrected]. CONCLUSIONS: In paroxysmal atrial fibrillation, a CAA guided by CF reduces PV gaps and shortens the procedure parameters at the expense of the left PVs. PMID- 26768696 TI - Stabilizing Pentacene By Cyclopentannulation. AB - A new class of stabilized pentacene derivatives with externally fused five membered rings are prepared by means of a key palladium-catalyzed cyclopentannulation step. The target compounds are synthesized by chemical manipulation of a partially saturated 6,13-dibromopentacene precursor that can be fully aromatized in a final step through a DDQ-mediated dehydrogenation reaction (DDQ=2,3-dichloro-5,6-dicyano-1,4-benzoquinone). The new 1,2,8,9 tetraaryldicyclopenta[fg,qr]pentacene derivatives have narrow energy gaps of circa 1.2 eV and behave as strong electron acceptors with lowest unoccupied molecular orbital energies between -3.81 and -3.90 eV. Photodegradation studies reveal the new compounds are more photostable than 6,13 bis(triisopropylsilylethynyl)pentacene (TIPS-pentacene). PMID- 26768697 TI - The Synthesis of Structurally Diverse Macrocycles By Successive Ring Expansion. AB - Structurally diverse macrocycles and medium-sized rings (9-24 membered scaffolds, 22 examples) can be generated through a telescoped acylation/ring-expansion sequence, leading to the insertion of linear fragments into cyclic beta ketoesters without performing a discrete macrocyclization step. The key beta ketoester motif is regenerated in the ring-expanded product, meaning that the same sequence of steps can then be repeated (in theory indefinitely) with other linear fragments, allowing macrocycles with precise substitution patterns to be "grown" from smaller rings using the successive ring-expansion (SuRE) method. PMID- 26768698 TI - Synthesis of Carbazole Alkaloids by Ring-Closing Metathesis and Ring Rearrangement-Aromatization. AB - Aprocess for the assembly of carbazole alkaloids has been developed on the basis of ring-closing metathesis (RCM) and ringrearrangement-aromatization (RRA) as the key steps. This method is based on allyl Grignard addition to isatin derivatives to provide smooth access to 2,2-diallyl 3-oxindole derivatives through a 1,2 allyl shift. The diallyl derivatives were used as RCM precursors to afford a novel class of spirocyclopentene-3-oxindole derivatives, which underwent a novel RRA reaction to afford carbazole derivatives. The synthetic sequence to carbazoles was shortened by combining the RCM and RRA steps in an orthogonal tandem catalytic process. The utility of this methodology was further demonstrated by the straightforward synthesis of carbazole alkaloids, including amukonal derivative, girinimbilol, heptaphylline, and bis(2-hydroxy-3 methylcarbazole). PMID- 26768700 TI - Screening, resilience, patient navigation and information needs--key areas in cancer control. PMID- 26768701 TI - Ebola outbreak in west Africa is officially over. PMID- 26768703 TI - Giant serpentine aneurysm. PMID- 26768702 TI - A retrospective analysis of the InterTan nail and proximal femoral nail anti rotation-Asia in the treatment of unstable intertrochanteric femur fractures in the elderly. AB - BACKGROUND: The purpose of this study was to compare the clinical outcomes of elderly patients undergoing surgery for treatment of unstable trochanteric fractures receiving either proximal femoral nails anti-rotation-Asia (PFNA-IIs) or InterTan nails (ITs). METHODS: Between January 1, 2012, and June 31, 2015, 168 elderly patients with unstable intertrochanteric femur fractures enrolled in this study. The only intervention was ITs or PFNA-IIs of the unstable trochanteric femur fractures. Follow-up was at 1, 3, 6, and 12 months postoperatively and yearly thereafter. Intraoperative variables and postoperative complications were compared between the two groups. RESULTS: Eight patients died, six were too infirmed for follow-up, and seven were lost during follow-up, leaving 147 patients meeting the criteria were evaluated at a mean follow-up of 20 months (range 16-26 months). Significant differences were observed between the two groups regarding local complications (IT, n = 10 vs. PFNA-II, n = 20), varus collapse of the head/neck or femoral shaft fractures at the tip of the nail (IT, n = 1 vs. PFNA-II, n = 8), femoral neck shortening (IT, 4.4 +/- 1.1 mm vs. PFNA II, 7.4 +/- 2.4 mm), fracture healing time (IT, 14.7 +/- 2.1 weeks vs. PFNA-II, 15.7 +/- 2.4 weeks), femoral shaft fractures (IT, n = 0 vs. PFNA-II, n = 4), rotational loss of reduction (IT, n = 0 vs. PFNA-II, n = 9), lateral cortex fractures of the proximal femur or lateral greater trochanter fractures (IT, n = 8 vs. PFNA-II, n = 1), operative time (IT, 71.9 +/- 6.8 min vs. PFNA-II, 52.3 +/- 4.0 min), intraoperative blood loss (IT, 190.6 +/- 6.0 mL vs. PFNA-II, 180.9 +/- 10.8 mL), fluoroscopy time (IT, 5.0 +/- 0.48 min vs. PFNA-II, 2.8 +/- 0.33 min), hospital stay (IT, 9.65 +/- 0.95 days vs. PFNA-II, 8.58 +/- 0.93 days), cut-out (IT, n = 0 vs. PFNA-II, n = 6), and tip-apex distance (IT, 26.7 +/- 0.91 mm vs. PFNA-II, 23.2 +/- 1.22 mm). No significant differences existed for the other observation indexes (p > 0.05). CONCLUSIONS: The IT nail may have more advantage for patients with unstable intertrochanteric fractures of the femur. However, for those complicated with lateral greater trochanter fractures, lateral cortex fractures of the proximal femurs, or unfit for surgery, the PFNA-II nail could be a good option. In addition, a large-sample, multicenter observational study is required for evaluation of its long-term efficacy, and optimal management strategies for specific unstable fracture patterns, different sorts of bone quality, and different levels of patient demand. PMID- 26768704 TI - Pericatheter encrustations: an unusual cause of a retained Foley catheter. AB - Urethral catheterisation is a common bedside procedure in hospitals. After they have served their purpose, indwelling Foley catheters can be removed by deflating their balloon. The incidence of a retained Foley catheter, however, is not uncommon, failure to deflate the intravesicular balloon being the most common reason. Causes of retained Foley catheters are many and the method to deal with each varies with the inciting cause. Pericatheter concretion or encrustation, an unusual cause of difficulty in removal of the catheter, is often difficult to recognise and hence is prone to faulty management. We report a case of a patient with a retained Foley catheter due to pericatheter encrustations; multiple attempts to remove it were made before the patient presented to our hospital. The case is being reported for the unusual location of retention, and the associated diagnostic and therapeutic dilemma. PMID- 26768693 TI - Taking a bite out of spinal cord injury: do dental stem cells have the teeth for it? AB - Dental stem cells are an emerging star on a stage that is already quite populated. Recently, there has been a lot of hype concerning these cells in dental therapies, especially in regenerative endodontics. It is fitting that most research is concentrated on dental regeneration, although other uses for these cells need to be explored in more detail. Being a true mesenchymal stem cell, their capacities could also prove beneficial in areas outside their natural environment. One such field is the central nervous system, and in particular, repairing the injured spinal cord. One of the most formidable challenges in regenerative medicine is to restore function to the injured spinal cord, and as yet, a cure for paralysis remains to be discovered. A variety of approaches have already been tested, with graft-based strategies utilising cells harbouring appropriate properties for neural regeneration showing encouraging results. Here we present a review focusing on properties of dental stem cells that endorse their use in regenerative medicine, with particular emphasis on repairing the damaged spinal cord. PMID- 26768705 TI - HaNDL syndrome in a 14-year-old girl. AB - Transient headache and neurological deficits with cerebrospinal fluid lymphocytosis (HaNDL syndrome) consists of recurrent headaches with focal neurological signs, which can include motor, sensory and aphasic symptoms. Although considered rare, it is becoming increasingly recognised in clinical practice due to the accumulation of case reports. The pathophysiology remains unclear although changes in the neurovascular resemble those found in migraine, which are thought to be triggered by an infectious process. HaNDL can mimic various serious, including life-threatening, diseases, such as stroke and meningoencephalitis, which is why vigorous tests should be sought before this diagnosis of exclusion can be reached. Treatment is symptomatic and the prognosis is excellent. A literature review of the topic is discussed. We report an adolescent girl who presented with recurrent expressive dysphasia and right-sided hypoaesthesia and moderate occipital headaches who was diagnosed with HaNDL syndrome. PMID- 26768706 TI - Tubercular osteomyelitis of the lateral-third of the clavicle. AB - An elderly women with a chronic history of pain and swelling of the right clavicle was investigated. She also had constitutional symptoms. Clinical examination showed mild inflammatory signs over the lateral one-third of the clavicle and the swelling was hard. Clavicle X-ray showed a lytic lesion in the lateral-third of the clavicle and MRI revealed a focal hyperintense area with cortical breach involving the superior cortex of the clavicle. The diagnosis was confirmed as tubercular osteomyelitis after the biopsy, which showed chronic granulomatous inflammation, and the culture was positive for Mycobacterium tuberculosis. Pain resolved by 6 weeks, swelling by 4 months and complete radiological resolution was seen at 15 months after the initiation of antitubercular therapy. No deficit in function was seen. No relapse was noted at 1-year follow-up. PMID- 26768707 TI - Congenital isolated transverse colon dilatation. PMID- 26768708 TI - Endoscopic resection of a giant fibrovascular polyp of the oesophagus with the assistance of ultrasonic shears. AB - Giant fibrovascular polyps of the oesophagus are rare benign tumours originating from the upper oesophagus. A 58-year-old woman presented with a 6-week history of a sore throat, odynophagia and progressive dysphagia, managing only a soft diet. CT of the neck and thorax, and barium swallow, both demonstrated a giant fibrovascular polyp measuring approximately 7 cm in length arising from the proximal oesophagus. The patient underwent endoscopic resection of the polyp with the assistance of ultrasonic shears. We present the case of a giant fibrovascular polyp and describe our novel technique for successful endoscopic resection using ultrasonic shears. PMID- 26768709 TI - Multilocus sequence typing analysis reveals that Cryptococcus neoformans var. neoformans is a recombinant population. AB - Cryptococcus neoformans var. neoformans (serotype D) represents about 30% of the clinical isolates in Europe and is present less frequently in the other continents. It is the prevalent etiological agent in primary cutaneous cryptococcosis as well as in cryptococcal skin lesions of disseminated cryptococcosis. Very little is known about the genotypic diversity of this Cryptococcus subtype. The aim of this study was to investigate the genotypic diversity among a set of clinical and environmental C. neoformans var. neoformans isolates and to evaluate the relationship between genotypes, geographical origin and clinical manifestations. A total of 83 globally collected C. neoformans var. neoformans isolates from Italy, Germany, France, Belgium, Denmark, Greece, Turkey, Thailand, Japan, Colombia, and the USA, recovered from different sources (primary and secondary cutaneous cryptococcosis, disseminated cryptococcosis, the environment, and animals), were included in the study. All isolates were confirmed to belong to genotype VNIV by molecular typing and they were further investigated by MLST analysis. Maximum likelihood phylogenetic as well as network analysis strongly suggested the existence of a recombinant rather than a clonal population structure. Geographical origin and source of isolation were not correlated with a specific MLST genotype. The comparison with a set of outgroup C. neoformans var. grubii isolates provided clear evidence that the two varieties have different population structures. PMID- 26768710 TI - Gnomoniopsis smithogilvyi causes chestnut canker symptoms in Castanea sativa shoots in Switzerland. AB - A screening of Castanea sativa scions for grafting for the presence of endophytes showed that the opportunistic fungal pathogen Gnomoniopsis smithogilvyi was the most abundant member of the endophytic flora. This fungus is known as a pathogen affecting chestnut fruits in Italy and Australia. Here, we present evidence that it causes cankers very similar to the ones due to Cryphonectria parasitica infection on twigs and scions of chestnut trees. We found natural infections of G. smithogilvyi in healthy grafted plants as well as in scions from chestnut trees. The identity of the fungus isolated from asymptomatic tissues was verified by applying Koch's postulates and corroborated by DNA sequencing of four different gene regions. In contrast to C. parasitica that appears on the bark as yellow to orange pycnidia, stromata and slimy twisted tendrils, G. smithogilvyi forms orange to red and black pycnidia, gray stromata and cream-colored to beige slimy twisted tendrils on the bark. These Swiss strains are closely related to G. smithogilvyi strains from Australia and from New Zealand, Gnomoniopsis sp. and Gnomoniopsis castanea from New Zealand, Italy, France and Switzerland. While the strains from Ticino are genetically very close to G. smithogilvyi and G. castanea from Italy, the differences between the strains from Ticino and Geneva suggest two different origins. The present study supports the hypothesis that a single species named G. smithogilvyi, which is known to be the agent of chestnut rot, also causes wood cankers on chestnut. PMID- 26768712 TI - Associate Editor for Oncology: Surena F. Matin. PMID- 26768711 TI - Inflammation and Symptom Change in Interstitial Cystitis or Bladder Pain Syndrome: A Multidisciplinary Approach to the Study of Chronic Pelvic Pain Research Network Study. AB - OBJECTIVE: To explore inflammatory factors that influence symptom changes in interstitial cystitis or bladder pain syndrome (IC or BPS). This longitudinal, prospective study examined the association of inflammation elicited by Toll-like receptor (TLR) stimulation in peripheral blood mononuclear cells (PBMCs) and diurnal cortisol rhythms with changes in painful and urinary symptoms of IC or BPS and symptom flares over a 48-week period. MATERIALS AND METHODS: Participants were 24 women meeting criteria for IC or BPS who supplied blood for isolation of PBMCs and 3 days of salivary cortisol samples prior to a baseline visit. Participants completed the Genitourinary Pain Index (pain and urinary subscales) and reported symptom flares every 2 weeks for 48 weeks. Mixed effects longitudinal and regression models were used to determine if inflammatory variables were associated with the changes in IC or BPS symptoms (time * variable interactions), and the probability of a symptom flare. RESULTS: Elevated TLR-4 inflammation (P = .031) and elevated TLR-2 inflammation (P = .045) from PBMCs, and flattened diurnal cortisol slope (P = .012) were each associated with less improvement in genitourinary pain over time. Additionally, elevated TLR-4 inflammation was associated with less improvement in urinary symptoms (P = .018), whereas TLR-2 inflammation and cortisol slopes were not (both P > .16). In contrast, no inflammatory measure was associated with an increased likelihood of reporting a symptom flare (all P > .25). CONCLUSION: TLR-mediated inflammation and diurnal cortisol slope may be useful as markers of symptom changes in IC or BPS. PMID- 26768714 TI - Biology of Bone Metastases in Prostate Cancer. AB - Advanced-stage prostate cancer (PCa) patients are often diagnosed with bone metastases. Bone metastases remain incurable and therapies are palliative. PCa cells prevalently cause osteoblastic lesions, characterized by an excess of bone formation. The prevailing concept indicates that PCa cancer cell secrete an excess of paracrine factors stimulating osteoblasts directly or indirectly, thereby leading to an excess of bone formation. The exact mechanisms by which bone formation stimulates PCa cell growth are mostly elusive. In this review, the mechanisms of PCa cancer cell osteotropism, the cancer cell-induced response within the bone marrow/bone stroma, and therapeutic stromal targets will be summarized. PMID- 26768713 TI - The Variable Flow Characteristics for Different Brands of 3-Way Urinary Catheters: Proposing an Alternate and Accurate Standardised Labelling System. AB - OBJECTIVE: To evaluate an alternative catheter labelling approach for 3-way catheters based on the drainage channel and irrigation channel cross-sectional area (CSA), which impacts catheter flow rate characteristics. MATERIALS AND METHODS: Three-way 22Fr catheters from Bard (Bard Limited), Rusch Simplastic (Teleflex Medical), Dover (COVIDIEN), and Rusch Golden were included in the study. Irrigation channel, drainage channel, and overall CSAs were digitally measured with an image-processing program. Irrigation channel and drainage channel flow rates were measured and correlated with their corresponding catheter CSA values. RESULTS: Catheter CSA and French value did not predict flow-rate characteristics, but irrigation channel CSA and drainage channel CSA were predictive. The 22Fr Rusch Simplastic catheter had the largest irrigation channel CSA (2.87 mm(2)) and drainage channel CSA (12.6 mm(2)), and had the greatest irrigation (5.27 +/- 0.02 ml/s) and drainage flow rates (14.42 +/- 0.22 ml/s). Twenty-two French gauge Rusch Golden catheters had the smallest irrigation channel CSA (1.34 mm(2)) and drainage channel CSA (7.82 mm(2)) and the lowest irrigation (1.83 +/- 0.03 ml/s) and drainage flow rates (1.83 +/- 0.03 ml/s). CONCLUSION: An alternative catheter labelling system to include overall CSA, irrigation channel CSA, and drainage channel CSA values would provide more accurate and transparent data relevant to anticipated drainage and irrigation flow rates. The proposed labelling method will assist urologists in selecting 3 way catheters for bladder irrigation. PMID- 26768715 TI - Alternative Viewpoint Against Breast Cancer Based on Selective Serotonin Receptors 5HTR3A and 5HTR2A Antagonists that can Mediate Apoptosis in MCF-7 Cell Line. AB - BACKGROUND: Neurotransmitters had progressive effects on various cancers via their different type of receptors. OBJECTIVE: This study was conducted to determine the pattern of serotonin receptors, respectively, 5HTR2A and 5HTR3A gene expression in MCF-7 cells and evaluate their selective antagonist effects on them. METHOD: RT-PCR was performed to determine the pattern of serotonin receptor gene expression in human breast cancer cell line (MCF-7). MCF-7 cells were cultured and treated via different doses of tropisetron (5HTR3A antagonist) and ketanserin (5HTR2A antagonist) for 48 hours. Oxidative and reductive enzyme activity was carried out by MTT assay. Subsequently, nuclear morphology of cells was observed by mixed dye florescent staining. To validate cell proliferation inhibition, Real time PCR was carried out for determining the descending rate of proliferating cell nuclear antigen (PCNA) gene expression in treating MCF-7 cells. Assessment of quantification of apoptosis and its discrimination with necrosis at single cell level using Flowcytometry technique was performed. RESULTS: Results showed that 5HTR2A and 5HTR3A have expression in MCF-7 cells. Based on our finding, tropisetron and ketanserin had suppression effects on MCF-7 cells proliferation. (93.35% in tropisetron 50 umoll(-1) and 72.36% in Ketanserin 25umoll(-1) concentration). CONCLUSION: Therefore, the use of tropisetron and ketanserin as an antagonist of serotonin receptor may be as new approaches are recommended for the treatment of breast cancer cells. PMID- 26768717 TI - In Memoriam: Dr. Yoshio Kato. PMID- 26768720 TI - Rare case of temporary intestinal obstruction induced by novel tag-less Agile patency capsule in a patient with Crohn's disease. PMID- 26768722 TI - A novel hot-melt extrusion formulation of albendazole for increasing dissolution properties. AB - The main aim of the research focused on the production of hot-melt extrusion (HME) formulations with increased dissolution properties of albendazole (ABZ). Therefore, HME was applied as a continuous manufacturing technique to produce amorphous solid dispersions of the poorly water soluble drug ABZ combined with the polymer matrix polyvinylpyrrolidone PVP K12. HME formulations of ABZ-PVP K12 comprised a drug content of 1%, 5% and 10% w/w. The main analytical characterisation techniques used were scanning electron microscopy (SEM), micro computed tomography (MU-CT), X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC) and dissolution profile studies. The application of SEM, XRPD and DSC evidenced drug physical transformation from crystalline to amorphous state and therefore, the achievement of an amorphous solid dispersion. The introduction of a novel technique, MU-CT, to characterise the internal structure of these materials revealed key information regarding materials distribution and void content. Dissolution profile studies evidenced a high increase in drug release profile compared to pure ABZ. These promising results can lead to a great enhancement of the oral bioavailability of ABZ dosage forms. Therefore, HME is a potential continuous manufacturing technique to overcome ABZ poor solubility properties and lead to a significant increase in the therapeutic effect. PMID- 26768716 TI - Enzyme Activity Assays for Protein Kinases: Strategies to Identify Active Substrates. AB - Protein kinases are an important class of enzymes and drug targets. New opportunities to discover medicines for neglected diseases can be leveraged by the extensive kinase tools and knowledge created in targeting human kinases. A valuable tool for kinase drug discovery is an enzyme assay that measures catalytic function. The functional assay can be used to identify inhibitors, estimate affinity, characterize molecular mechanisms of action (MMOAs) and evaluate selectivity. However, establishing an enzyme assay for a new kinases requires identification of a suitable substrate. Identification of a new kinase's endogenous physiologic substrate and function can be extremely costly and time consuming. Fortunately, most kinases are promiscuous and will catalyze the phosphotransfer from ATP to alternative substrates with differing degrees of catalytic efficiency. In this manuscript we review strategies and successes in the identification of alternative substrates for kinases from organisms responsible for many of the neglected tropical diseases (NTDs) towards the goal of informing strategies to identify substrates for new kinases. Approaches for establishing a functional kinase assay include measuring auto-activation and use of generic substrates and peptides. The most commonly used generic substrates are casein, myelin basic protein, and histone. Sequence homology modeling can provide insights into the potential substrates and the requirement for activation. Empirical approaches that can identify substrates include screening of lysates (which may also help identify native substrates) and use of peptide arrays. All of these approaches have been used with a varying degree of success to identify alternative substrates. PMID- 26768724 TI - Incorporation of acetaminophen as an active pharmaceutical ingredient into porous lactose. AB - A new formulation method for solid dosage forms with drug loadings from 0.65 +/- 0.03% to 39 +/- 1% (w/w) of acetaminophen (APAP) as a model drug has been presented. The proposed method involves the production of highly-porous lactose with a BET surface area of 20 +/- 1 m(2)/g as an excipient using a templating method and the incorporation of drug into the porous structure by adsorption from a solution of the drug in ethanol. Drug deposition inside the carrier particles, rather than being physically distributed between them, eliminated the potential drug/carrier segregation, which resulted in excellent blend uniformities with relative standard deviations of less than 3.5% for all drug formulations. The results of DSC and XRD tests have shown deposition of nanocrystals of APAP inside the nanopores of lactose due the nanoconfinement phenomenon. FTIR spectroscopy has revealed no interaction between the adsorbed drug and the surface of lactose. The final loaded lactose particles had large BET surface areas and high porosities, which significantly increased the crushing strengths of the produced tablets. In vitro release studies in phosphate buffer (pH 5.8) have shown an acceptable delivery performance of 85% APAP release within 7 minutes for loaded powders filled in gelatin capsules. PMID- 26768726 TI - Self-assembled dipeptide-based nanostructures: tiny tots with great applications. PMID- 26768725 TI - Nanostructured lipid carrier mediates effective delivery of methotrexate to induce apoptosis of rheumatoid arthritis via NF-kappaB and FOXO1. AB - Present study was designed to develop novel nano-structured lipid carriers (NLCs) formulated by lipid mixture and chemical permeation enhancer-based hydrogel for an effective transdermal delivery of methotrexate (MTX). The prepared NLCs were optimized with different preparative variables such as particle size <200 nm, poly-dispersity index (PDI) <0.2, and entrapment efficiency ~85%. The drug incorporated into NLCs-gel base showed excellent spread ability without any grittiness during rheological behavior and texture profile analysis. The in vitro release showed biphasic release pattern with initial fast release of drug (>50%) in 8h followed by sustained release (up to 85%) by the end of 48thh. NLCs showed greater uptake in human hyper-proliferative keratinocyte cell line (HaCaT). NLCs showed increased expression of inflammatory mediators as well asapoptosis in U937 monocytic cells. The greater expression of pro-apoptotic gene Bim regulated by NF kappaB-IkB and FOXO1 is supported by fold regulations calculated for various apoptotic and pro-inflammatory biomarkers carried out by RT-PCR. The immunocytochemistry to detect IL-6 expression and immunofluorescence assay suggested that induced apoptosis occurs in experimentally induced in vitro arthritis model treated with NLCs-MTX. We saw reduced inflammation and triggered apoptosis through NF-kappaB & FOXO1 pathways induced by MTX loaded NLCs in rheumatoid arthritic cells. In addition, formulated NLCs exhibit better skin permeation with higher permeation flux & enhancement ratio as shown by confocal laser scanning microscopy (CLSM). Moreover, histopathological examinations of skin are suggestive of safety potential of NLCs. PMID- 26768723 TI - Host-mediated Leishmania donovani treatment using AR-12 encapsulated in acetalated dextran microparticles. AB - Leishmaniasis is a disease caused by parasites of Leishmania sp., which effects nearly 12 million people worldwide and is associated with treatment complications due to widespread parasite resistance toward pathogen-directed therapeutics. The current treatments for visceral leishmaniasis (VL), the systemic form of the disease, involve pathogen-mediated drugs and have long treatment regimens, increasing the risk of forming resistant strains. One way to limit emergence of resistant pathogens is through the use of host-mediated therapeutics. The host mediated therapeutic AR-12, which is FDA IND-approved for cancer treatment, has shown activity against a broad spectrum of intracellular pathogens; however, due to hydrophobicity and toxicity, it is difficult to reach therapeutic doses. We have formulated AR-12 into microparticles (AR-12/MPs) using the novel biodegradable polymer acetalated dextran (Ace-DEX) and used this formulation for the systemic treatment of VL. Treatment with AR-12/MPs significantly reduced liver, spleen, and bone marrow parasite loads in infected mice, while combinatorial therapies with amphotericin B had an even more significant effect. Overall, AR-12/MPs offer a unique, host-mediated therapy that could significantly reduce the emergence of drug resistance in the treatment of VL. PMID- 26768728 TI - Non-pharmacological interventions for managing dementia-related sleep problems within community dwelling pairs: A mixed-method approach. AB - Dementia-related sleep problems can be complex and challenging. Environmental interventions which resynchronise the sleep/wake cycle have been trialled with promising results for people with dementia in institutionalised settings. However, there is less research concerning community-dwelling people with dementia and their family carers. This study involved a five-week feasibility study including timed light therapy, exercise and sleep education. Sleep and physical and mental functioning were measured at the beginning and end of the trial using objective measures, standardised questionnaires and structured participant feedback. Of 15 community-dwelling pairs who participated, nine completed the trial. The case studies presented here reveal that it is feasible for this population to use non-pharmacological interventions, with positive outcomes. However, there are also issues that can mask benefits or prevent compliance. The options for treating dementia are limited. Environmental interventions may help manage dementia-related sleep problems and further trials would be worthwhile to improve compliance and evaluate effectiveness. PMID- 26768727 TI - Disparities in Mortality and Morbidity in Pediatric Asthma Hospitalizations, 2007 to 2011. AB - OBJECTIVE: Asthma is a leading cause of pediatric admissions. Although several factors including race have been linked to increased overall asthma morbidity and mortality, few studies have explored factors associated with inpatient asthma outcomes. We examined factors associated with mortality and morbidity in children admitted for asthma. METHODS: Data were obtained from the US Nationwide Inpatient Sample for 2007 to 2011. Patients 2 to 18 years old with a primary diagnosis of asthma were included. Predictor variables were sociodemographic and hospital factors and acute/chronic secondary diagnoses. Outcomes were mortality, intubation, length of stay (LOS), and costs. Weighted national estimates were calculated. Multivariable analyses were performed. RESULTS: There were 97,379 (478,546 weighted) asthma admissions. Most patients were male (60.6%); 30% were white, 28% black, and 18% Hispanic. Mortality rate was 0.03%, and 0.3% were intubated. Median LOS was 2 (interquartile range, 1-3) days. Median costs were $2,950 (interquartile range, $1990-$4610). Native American race, older age (13-18 years), and West region were significant independent predictors of mortality. Intubation rate was lower in Hispanic compared with white children (P = .028). LOS was shorter in Asian compared with white children (P = .022) but longer in children with public insurance and from low income areas (P < .001). Average costs were higher in black, Hispanic, and Asian compared with white children (P < .05). CONCLUSIONS: With the exception of Native Americans, race/ethnicity is not associated with inpatient asthma mortality and has varied effects on morbidity. Recognition of factors associated with increased asthma mortality and morbidity might allow for earlier, more effective treatment and avoidance of complications. PMID- 26768729 TI - Relationship between high sensitivity troponins and estimated glomerular filtration rate. AB - BACKGROUND: Diagnosis of acute coronary syndrome may be challenging because of high troponin concentrations in patients with chronic kidney disease. OBJECTIVE: the aim of this study is to investigate the difference between high sensitivity troponin T and troponin I in four groups of patients separated according to eGFR values and the effect of renal function both on troponin T and troponin I. METHODS: 119 outpatients were divided into 4 groups according to their eGFR values as Group 1: eGFR<30, Group 2: eGFR between 30 and 60, Group 3: eGFR between 60 and 90 and Group 4: eGFR >90mL/min/1.73m(2). The cardiac troponin T and I concentrations were measured concurrently. RESULTS: Troponin T values of all patients who have eGFR values lower than 30mL/min/1.73m(2) were above the decision point, but cTnI values of only 2 patients were above the decision limit (40ng/L) in this group. There was a strong and significant negative relationship between eGFR and hs-cTnT [log(y)=2.3-0.72log(x); R(2)=0.625] whereas there was no significant relationship between eGFR and hs-cTnI [log(y)=1.28-0.08log(x); R(2)=0.013] when eGFR was taken into consideration as a continuous variable. CONCLUSION: In this study, we found that cTnT increases with decreasing eGFR values, but cTnI is not affected by the change in eGFR values. PMID- 26768730 TI - Percutaneous posterior tibial nerve stimulation in the treatment of refractory anal fissure. PMID- 26768732 TI - Cetuximab plus platinum-based chemotherapy in head and neck squamous cell carcinoma: a randomized, double-blind safety study comparing cetuximab produced from two manufacturing processes using the EXTREME study regimen. AB - BACKGROUND: Cetuximab, in combination with platinum chemotherapy plus 5 fluoruracil (5-FU), is approved for the first-line treatment of recurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN). Cetuximab manufactured by ImClone (US commercial cetuximab) potentially results in higher systemic exposures than cetuximab manufactured by Boehringer Ingelheim (BI-manufactured cetuximab). This prospective, randomized, double-blind study compared the safety profiles of the two cetuximab formulations. METHODS: Patients with previously untreated locoregionally recurrent and/or metastatic SCCHN were randomly assigned to receive the same dose of US commercial cetuximab (Arm A) or BI-manufactured cetuximab (Arm B), each in combination with cisplatin or carboplatin plus 5-FU. The primary outcome was all-grade, all-cause treatment emergent adverse events (TEAEs). RESULTS: The majority of patients experienced >= 1 TEAE, regardless of causality (Arm A: 75/77 patients, 97.4%; Arm B: 68/71 patients, 95.8%). TEAEs with the highest incidence included nausea, fatigue, and hypomagnesemia in both arms. The absolute risk difference between the two arms for patients experiencing at least one adverse event (AE) was 0.029 (p = 0.281, 95% confidence interval [CI]: -0.024, 0.082) for AEs regardless of causality and 0.005 (p = 0.915, 95% CI: -0.092, 0.103) for AEs possibly related to study drug. There were no significant differences between the two arms in the incidence of acneiform rash, cardiac events, infusion reactions, or hypomagnesemia. Overall survival, progression-free survival, and overall response rates were similar in the two arms. CONCLUSIONS: There were no clinically meaningful differences in safety between US commercial cetuximab and BI-manufactured cetuximab in combination with platinum-based therapy with 5-FU in patients with locoregionally recurrent and/or metastatic SCCHN. The use of US commercial cetuximab in this combination chemotherapy regimen did not result in any unexpected safety signals. The efficacy results of this study are consistent with the efficacy results of the cetuximab arm of the EXTREME study. TRIAL REGISTRATION: ClinicalTrials.gov NCT01081041 ; date of registration: March 3, 2010). PMID- 26768731 TI - Deregulated expression of cryptochrome genes in human colorectal cancer. AB - BACKGROUND: Circadian disruption and deranged molecular clockworks are involved in carcinogenesis. The cryptochrome genes (CRY1 and CRY2) encode circadian proteins important for the functioning of biological oscillators. Their expression in human colorectal cancer (CRC) and in colon cancer cell lines has not been evaluated so far. METHODS: We investigated CRY1 and CRY2 expression in fifty CRCs and in the CaCo2, HCT116, HT29, SW480 cell lines. RESULTS: CRY1 (p = 0.01) and CRY2 (p < 0.0001) expression was significantly changed in tumour tissue, as confirmed in a large independent CRC dataset. In addition, lower CRY1 mRNA levels were observed in patients in the age range of 62-74 years (p = 0.018), in female patients (p = 0.003) and in cancers located at the transverse colon (p = 0.008). Lower CRY2 levels were also associated with cancer location at the transverse colon (p = 0.007). CRC patients displaying CRY1 (p = 0.042) and CRY2 (p = 0.043) expression levels over the median were hallmarked by a poorer survival rate. Survey of selected colon cancer cell lines evidenced variable levels of cryptochrome genes expression and time-dependent changes in their mRNA levels. Moreover, they showed reduced apoptosis, increased proliferation and different response to 5-fluorouracil and oxaliplatin upon CRY1 and CRY2 ectopic expression. The relationship with p53 status came out as an additional layer of regulation: higher CRY1 and CRY2 protein levels coincided with a wild type p53 as in HCT116 cells and this condition only marginally affected the apoptotic and cell proliferation characteristics of the cells upon CRY ectopic expression. Conversely, lower CRY and CRY2 levels as in HT29 and SW480 cells coincided with a mutated p53 and a more robust apoptosis and proliferation upon CRY transfection. Besides, an heterogeneous pattern of ARNTL, WEE and c-MYC expression hallmarked the chosen colon cancer cell lines and likely influenced their phenotypic changes. CONCLUSION: Cryptochrome gene expression is altered in CRC, particularly in elderly subjects, female patients and cancers located at the transverse colon, affecting overall survival. Altered CRY1 and CRY2 expression patterns and the interplay with the genetic landscape in colon cancer cells may underlie phenotypic divergence that could influence disease behavior as well as CRC patients survival and response to chemotherapy. PMID- 26768733 TI - Building Common Ground for Environmental Flows using Traditional Techniques and Novel Engagement Approaches. AB - Despite increased understanding of the science of environmental flows, identification and implementation of effective environmental flow policies remains elusive. Perhaps the greatest barrier to implementing flow policies is the framework for water management. An alternative management approach is needed when legal rights for environmental flows do not exist, or are ineffective at protecting ecosystems. The research presented here, conducted in the U.S. state of Arizona, provides an empirical example of engagement to promote social learning as an approach to finding ways to provide water for the environment where legal rights for environmental flows are inadequate. Based on our engagement process we propose that identifying and then building common ground require attention to the process of analyzing qualitative data and the methods for displaying complex information, two aspects not frequently discussed in the social learning or stakeholder engagement literature. The results and methods from this study can help communities develop an engagement process that will find and build common ground, increase stakeholder involvement, and identify innovative solutions to provide water for the environment that reflect the concerns of current water users. PMID- 26768735 TI - Why Go There? Evolution of Mobility and Spatial Cognition in Women and Men : An Introduction to the Special Issue. AB - Males in many non-monogamous species have larger ranges than females do, a sex difference that has been well documented for decades and seems to be an aspect of male mating competition. Until recently, parallel data for humans have been mostly anecdotal and qualitative, but this is now changing as human behavioral ecologists turn their attention to matters of individual mobility. Sex differences in spatial cognition were among the first accepted psychological sex differences and, like differences in ranging behavior, are documented for a growing set of species. This special issue is dedicated to exploring the possible adaptive links between these cognitive and ranging traits. Multiple hypotheses, at various levels of analysis, are considered. At the functional (ultimate) level, a mating-competition hypothesis suggests that range expansion may augment mating opportunities, and a fertility-and-parental-care hypothesis suggests that range contraction may facilitate offspring provisioning. At a more mechanistic (proximate) level, differences in cue availability may support or inhibit particular sex-specific navigation strategies, and spatial anxiety may usefully inhibit travel that would not justify its costs. Studies in four different cultures-Twe, Tsimane, Yucatec Maya, and Faroese-as well as an experimental study using virtual reality tools are the venue for testing these hypotheses. Our hope is to stimulate more research on the evolutionary and developmental processes responsible for this suite of linked behavioral and cognitive traits. PMID- 26768734 TI - A systematic review and meta-analysis of selected motor learning principles in physiotherapy and medical education. AB - BACKGROUND: Learning of procedural skills is an essential component in the education of future health professionals. There is little evidence on how procedural skills are best learnt and practiced in education. There is a need for educators to know what specific interventions could be used to increase learning of these skills. However, there is growing evidence from rehabilitation science, sport science and psychology that learning can be promoted with the application of motor learning principles. The aim of this review was to systematically evaluate the evidence for selected motor learning principles in physiotherapy and medical education. The selected principles were: whole or part practice, random or blocked practice, mental or no additional mental practice and terminal or concurrent feedback. METHODS: CINAHL, Cochrane Central, Embase, Eric and Medline were systematically searched for eligible studies using pre-defined keywords. Included studies were evaluated on their risk of bias with the Cochrane Collaboration's risk of bias tool. RESULTS: The search resulted in 740 records, following screening for relevance 15 randomised controlled trials including 695 participants were included in this systematic review. Most procedural skills in this review related to surgical procedures. Mental practice significantly improved performance on a post-acquisition test (SMD: 0.43, 95% CI 0.01 to 0.85). Terminal feedback significantly improved learning on a transfer test (SMD: 0.94, 95% CI 0.18 to 1.70). There were indications that whole practice had some advantages over part practice and random practice was superior to blocked practice on post-acquisition tests. All studies were evaluated as having a high risk of bias. Next to a possible performance bias in all included studies the method of sequence generation was often poorly reported. CONCLUSIONS: There is some evidence to recommend the use of mental practice for procedural learning in medical education. There is limited evidence to conclude that terminal feedback is more effective than concurrent feedback on a transfer test. For the remaining parameters that were reviewed there was insufficient evidence to make definitive recommendations. PMID- 26768736 TI - Over-the-Counter Codeine-from Therapeutic Use to Dependence, and the Grey Areas in Between. AB - Codeine is a widely used analgesic, that is available for sale in pharmacies over the counter (OTC) in a number of countries including the UK, South Africa, Ireland, France and Australia. In these countries with OTC codeine sales there has been emerging concerns about misuse of and dependence on codeine containing combination analgesics, with increasing numbers of people presenting for help with codeine dependence at primary care and addiction treatment services. This has led to many countries reviewing availability of codeine in OTC available preparations, and considering possible measures to reduce harms from misuse of OTC codeine containing combination analgesics. PMID- 26768737 TI - Advanced hemodynamic monitoring in the critically ill patient: Nice to have or need to treat? PMID- 26768739 TI - Current Role of Ivabradine in Stable Coronary Artery Disease Without Heart Failure. AB - Increase in heart rate represents a significant contribution in the pathophysiology of coronary artery disease and heart failure, by promoting atherosclerotic process and endothelial dysfunction. Thus, it negatively influences cardiovascular risk in the general population. The aim of this review is to analyze the current, controversial, and future role of ivabradine as an anti-anginal agent in the setting of coronary artery disease without heart failure. Ivabradine represents a selective heart rate-lowering agent that increased diastolic perfusion time and improving energetics in the ischemic myocardium. PMID- 26768738 TI - Interventional Options for Coronary Artery Calcification. AB - Coronary artery calcification is an integral process in atherogenesis. When it is moderate or severe, coronary artery calcification presents several challenges to percutaneous coronary intervention. Historically, these difficulties have caused percutaneous coronary intervention of calcified lesions to be associated with lower rates of procedural success, higher rates of angiographic complications, and higher rates of subsequent adverse cardiovascular events. With growth of technologies and maturation of technique for atheroablation, in particular rotational atherectomy and orbital atherectomy, percutaneous coronary intervention of calcified coronary lesions has become possible with an extremely high success rate and a favorable safety profile. In this focused review, we present an updated overview of the pathobiology of coronary artery calcification and discuss the current slate of options for interventional management of calcified coronary lesions. PMID- 26768741 TI - Angina Pectoris and Myocardial Ischemia in the Absence of Obstructive Coronary Artery Disease: Role of Diagnostic Tests. AB - Patients with chest pain and nonobstructive coronary artery disease (NO-CAD) at angiography constitute a heterogeneous population. In most patients with stable exercise-induced chest pain, microvascular angina (MVA) is the likely diagnosis. Some clinical findings and results of diagnostic tests suggest that angina is caused by coronary microvascular (CMV) dysfunction rather than obstructive CAD, but a definitive diagnosis requires demonstration of impaired CMV dilation and/or increased constriction. About 10 % of patients presenting with an acute coronary syndrome also shows NO-CAD at angiography, and CMV constriction can be responsible for the syndrome in a number of cases. Diagnostic tests are not expected to have a prognostic role in patients with stable MVA with normal coronary arteries, due to the excellent prognosis of these patients, whereas their prognostic role in the more general population of NO-CAD patients with chest pain (either stable or acute) needs to be established in adequate studies. PMID- 26768742 TI - Protection from Cerebral Embolic Events During Transcatheter Aortic Valve Replacement. AB - Transcatheter aortic valve replacement (TAVR) has been a major advancement in the treatment of high-risk patients with severe aortic stenosis. One of the primary concerns in applying this procedure to a broader patient population is the risk of embolic stroke. Cerebral emboli have been shown to originate from atheromatous plaques within the aorta and from the degenerate stenotic aortic valve itself. Thus, there has been significant interest in embolic protection devices designed to either filter or deflect potential cerebral emboli during TAVR. Here, we review the rationale and current data for embolic protection devices used during TAVR. PMID- 26768740 TI - Vascular Imaging Before Transcatheter Aortic Valve Replacement (TAVR): Why and How? AB - Transcatheter aortic valve replacement (TAVR) has become an alternative to surgical intervention for symptomatic or severe aortic valve stenosis in patients with high surgical risk. Successful TAVR requires a multimodality imaging approach for appropriate patient selection and prosthesis sizing. Here, we describe individual imaging modalities and report their respective roles in this emerging field. To date, echocardiography remains the traditional test for determining patient candidacy and prosthesis selection, but computed tomography (CT) has been taking on an increasingly important role in the evaluation of both the aortic root anatomy and aortoiliofemoral vessels as a single examination. Cardiac magnetic resonance (CMR) is useful in grading the severity of aortic stenosis and should be considered a reasonable alternative to CT for the evaluation of the aortic annulus, e.g., when the administration of contrast media is contraindicated. PMID- 26768744 TI - Can graft choice affect return to sport following revision anterior cruciate ligament reconstruction surgery? AB - INTRODUCTION: With the increasing number of primary anterior cruciate ligament (ACL) reconstructions, revision surgery has become more frequent. The purpose of the present study is to retrospectively compare the clinical outcome of contralateral hamstring tendon autografts vs. allografts for ACL revision surgery, specifically with regard to patient satisfaction, return to preinjury activity level, and postoperative functional outcomes. MATERIALS AND METHODS: Between 2004 and 2011, 59 patients underwent ACL revision surgery. 44 were successfully recontacted and retrospectively reviewed at an average follow-up of 5.2 years. 23 subjects underwent revision ACL reconstruction with contralateral autogenous hamstring tendon grafts; 21 underwent allograft revision ACL surgery. Clinical, arthrometric, and functional evaluations were performed. The Tegner, Knee Injury and Osteoarthritis Outcome Score (KOOS), International Knee Documentation Committee (IKDC) Subjective Knee Form were used. Objective evaluation included range of motion, Lachman test, pivot-shift test and KT-1000 instrumented laxity testing. RESULTS: No major complications were reported. Follow-up examination showed that there were no significant differences IKDC and KOOS scores between the groups. The percentage of patients returning to pre injury level was high in both groups. Anterior tibial translation according to manual laxity testing and as measured with KT-1000 arthrometer was not statistically different in the two groups. With regard to return to sports, patients undergoing revision surgery with autografts experienced a quicker return to sports compared to patients who underwent allograft revision surgery. CONCLUSIONS: The use of contralateral hamstring tendon autografts for ACL revision surgery produced similar subjective and objective outcomes at 5.2 years follow-up compared to revision with allograft patellar or Achilles tendon. Patients undergoing revision surgery with autografts experienced a quicker return to sports compared to patients who underwent allograft revision surgery. PMID- 26768743 TI - Current State of Stem Cell Therapy for Ischemic Heart Disease. AB - Improvements in the care of patients with ischemic cardiovascular disease have led to improved survival but also a burgeoning population of patients with advanced ischemic heart disease. Cell therapies offer a novel approach toward cardiac "rejuvenation" via stimulation of new blood vessel growth, enhancing tissue perfusion, and via preservation or even regeneration of myocardial tissue, leading to improvements in cardiac performance after myocardial infarction and in patients with advanced heart failure. Here, we summarize and offer some thoughts on the state of the field of cell therapy for ischemic heart disease, targeting three separate conditions that have been the subject of significant clinical research: enhancing left ventricular recovery after MI, improving outcomes and symptoms in patients with congestive heart failure (CHF), and treatment of patients with refractory angina, despite maximal medical therapy. PMID- 26768746 TI - Inhibition of proliferation and induction of apoptosis in RB116 retinoblastoma cells by afatinib treatment. AB - The present study investigates the effect of afatinib on the growth, induction of apoptosis in RB116 cells, and reduction of carcinoma growth in the mice transplanted with RB116 cells. The results from MTT assay revealed that afatinib inhibited the growth of RB116 cells in a dose-dependent manner. Proliferation of RB116 cells was reduced to 64 % on treatment with 200 MUM concentration of afatinib after 48 h. Afatinib treatment of RB116 cells at 200 MUM concentration induced apoptosis and necrosis in 49.7 and 9.4 %, respectively, after 48 h. In the RB116-transplanted mice, treatment with afatinib at 10-mg/kg doses for 45 days caused a significant (p < 0.005) reduction in the tumor volume compared to the control group. The tissue lysates of the mice containing RB116 transplant showed a significant decrease in the expressions of Ki67 and p53 in the afatinib treatment group after 45 days. However, the expression of caspase-3 was increased and of Bcl-2 remained unaltered on treatment with afatinib. Measurement of the body weight of afatinib-treated animals showed no reduction during the study. Thus, afatinib can be of therapeutic value for the treatment of retinoblastoma. PMID- 26768745 TI - Alpinetin targets glioma stem cells by suppressing Notch pathway. AB - Glioma is among the most common human malignancies with poor prognosis. Glioma stem cells (GSCs) are the culprit of glioma, suggesting that GSCs are potential therapeutic targets. Notch signaling pathway plays a pivotal role for the function of GSCs, implying that suppression of Notch pathway may be an effective strategy for GSC-targeting therapy. In this study, we found that alpinetin, a natural compound, can suppress the proliferation and invasiveness of GSCs and induce apoptosis in GSCs. Immunoblot analysis and luciferase assay revealed that Notch signaling was suppressed by alpinetin. Furthermore, restoration of Notch signaling activity rescued the effect of alpinetin on GSC's function. The anti tumor activity of alpinetin was further confirmed in an animal model. Collectively, targeting of GSC by alpinetin is an effective strategy for glioma therapy. PMID- 26768747 TI - Involvement of CASP3 promoter polymorphism (-1337 C > G) in the development and progression of non-small cell lung cancer. AB - Downregulation of CASP3 gene expression has been observed to be associated with various malignancies, and promoter polymorphisms in the CASP3 gene may have a great impact on the CASP3 transcriptional activity. The present study aimed to analyze the possible impact of the CASP3 (-1337 C > G, rs1405937) polymorphism on the expression profile of CASP3 gene and ultimately its association in the development of non-small cell lung cancer. A case-control study of 100 non-small cell lung cancer patients and 100 cancer free healthy controls was conducted, wherein genotype and expression profile of CASP3 gene were evaluated using serum DNA and serum RNA, respectively, by primer-introduced restriction fragment analysis and real-time PCR techniques. Compared to the CASP3 CC genotype, odds ratio of 11.1 was found to be associated to the homozygous GG genotype with more than sixfold decrease of CASP3 gene expression in non-small cell lung cancer patients. Significant trend of decrease in caspase 3 expression was observed with the increase in severity of the disease. Patients with CASP3 (-1337GG) genotype had significantly shorter overall survival compared to CASP3 (-1337CC) genotype carriers. In addition, significantly poor overall survival was also reflected by patients with higher fold decrease in CASP3 gene expression. CASP3 (-1337 GG) genotype was found to be associated with significantly lower CASP3 gene expression especially among patients with advanced status of the disease, suggesting that CASP3 (-1337C > G) polymorphism may be involved in the development and progression of non-small cell lung cancer. PMID- 26768748 TI - Effects of a one-year physical activity programme for women with systemic lupus erythematosus - a randomized controlled study. AB - OBJECTIVES: To study the effects of a one-year physical activity programme on aerobic capacity, physical activity and health-related quality of life (HRQL) in patients with systemic lupus erythematosus (SLE) by a randomized control design. METHODS: Thirty-five women with low or moderate disease activity and organ damage were randomized to intervention (I) or control (C) group. The intervention during months 0-3 consisted of education, supervised aerobic exercise at high intensity and individual coaching, as well as self-managed physical activity at low-to moderate intensity. During months 4-12, the physical activity was self-managed and the coaching was successively reduced over time. Outcome measures included: maximal oxygen uptake (VO2 max) from a bicycle ergometer test, self-reported physical activity and HRQL (SF-36). RESULTS: VO2 at sub-max. and max. increased, independent of group, during the one-year study period (main effect of time p < 0.0001). VO2 max. increased between baseline and month 3 (p < 0.0001), between months 3 and 6 (p = 0.01) and the increase was sustained at month 12 (ns). Frequency of physical activity at high intensity also increased, independent of group, during the study period. It was increased at months 3, 6 and 12 compared to baseline (p = 0.02, p < 0.001, p = 0.03). Improvement in mental health between baseline and month 6 (p = 0.002) was seen for the I-group, not the C-group (p = 0.03). Disease activity and organ damage did not change. CONCLUSIONS: Physical activity and aerobic capacity increased after supervised exercise and coaching, and the improvement was sustained during the one-year programme. However, no interactions between the group differences were seen, which suggests that repeated measurements could motivate to increased physical activity and thereby to increased aerobic capacity. As sub-max. VO2 increased over time, training induced changes in VO2 on-kinetics could be another explanation. Little influence on HRQL was seen after the programme. The study indicates that physical activity at high intensity over one year is tolerated by patients with mild to moderate SLE. PMID- 26768749 TI - Subclinical arteriosclerosis and osteoprotegerin levels in a population with systemic lupus erythematous in the south of Europe. PMID- 26768751 TI - Dependence of norfloxacin diffusion across bilayers on lipid composition. AB - Antibiotic resistance is a growing concern in medicine and raises the need to develop and design new drug molecules that can efficiently inhibit bacterial replication. Spurring the passive uptake of the drug molecules is an obvious solution. However our limited understanding of drug-membrane interactions due to the presence of an overwhelming variety of lipids constituting cellular membranes and the lack of facile tools to probe the bio-physical interactions between drugs and lipids imposes a major challenge towards developing new drug molecules that can enter the cell via passive diffusion. Here, we used a label-free micro fluidic platform combined with giant unilamellar lipid vesicles to investigate the permeability of membranes containing mixtures of DOPE and DOPG in DOPC, leading to a label-free measurement of passive membrane-permeability of autofluorescent antibiotics. A fluoroquinolone drug, norfloxacin was used as a case study. Our results indicate that the diffusion of norfloxacin is strongly dependent on the lipid composition which is not expected from the traditional octanol-lipid partition co-efficient assay. The anionic lipid, DOPG, slows the diffusion process whereas the diffusion across liposomes containing DOPE increases with higher DOPE concentration. Our findings emphasise the need to investigate drug-membrane interactions with focus on the specificity of drugs to lipids for efficient drug delivery, drug encapsulation and targeted drug delivery. PMID- 26768750 TI - Identification of genomic aberrations in hemangioblastoma by droplet digital PCR and SNP microarray highlights novel candidate genes and pathways for pathogenesis. AB - BACKGROUND: The genetic mechanisms underlying hemangioblastoma development are still largely unknown. We used high-resolution single nucleotide polymorphism microarrays and droplet digital PCR analysis to detect copy number variations (CNVs) in total of 45 hemangioblastoma tumors. RESULTS: We identified 94 CNVs with a median of 18 CNVs per sample. The most frequently gained regions were on chromosomes 1 (p36.32) and 7 (p11.2). These regions contain the EGFR and PRDM16 genes. Recurrent losses were located at chromosome 12 (q24.13), which includes the gene PTPN11. CONCLUSIONS: Our findings provide the first high-resolution genome-wide view of chromosomal changes in hemangioblastoma and identify 23 candidate genes: EGFR, PRDM16, PTPN11, HOXD11, HOXD13, FLT3, PTCH, FGFR1, FOXP1, GPC3, HOXC13, HOXC11, MKL1, CHEK2, IRF4, GPHN, IKZF1, RB1, HOXA9, and micro RNA, such as hsa-mir-196a-2 for hemangioblastoma pathogenesis. Furthermore, our data implicate that cell proliferation and angiogenesis promoting pathways may be involved in the molecular pathogenesis of hemangioblastoma. PMID- 26768753 TI - A randomized controlled pilot study feasibility of a tablet-based guided audio visual relaxation intervention for reducing stress and pain in adults with sickle cell disease. AB - AIM: To test feasibility of a guided audio-visual relaxation intervention protocol for reducing stress and pain in adults with sickle cell disease. BACKGROUND: Sickle cell pain is inadequately controlled using opioids, necessitating further intervention such as guided relaxation to reduce stress and pain. DESIGN: Attention-control, randomized clinical feasibility pilot study with repeated measures. METHODS: Randomized to guided relaxation or control groups, all patients recruited between 2013-2014 during clinical visits, completed stress and pain measures via a Galaxy Internet-enabled Android tablet at the Baseline visit (pre/post intervention), 2-week posttest visit and also daily at home between the two visits. Experimental group patients were asked to use a guided relaxation intervention at the Baseline visit and at least once daily for 2 weeks. Control group patients engaged in a recorded sickle cell discussion at the Baseline visit. Data were analysed using linear regression with bootstrapping. RESULTS: At baseline, 27/28 of consented patients completed the study protocol. Group comparison showed that guided relaxation significantly reduced current stress and pain. At the 2-week posttest, 24/27 of patients completed the study, all of whom reported liking the study. Patients completed tablet-based measures on 71% of study days (69% in control group, 72% in experiment group). At the 2 week posttest, the experimental group had significantly lower composite pain index scores, but the two groups did not differ significantly on stress intensity. CONCLUSION: This study protocol appears feasible. The tablet-based guided relaxation intervention shows promise for reducing sickle cell pain and warrants a larger efficacy trial. TRIAL REGISTRATION: The ClinicalTrials.gov Identifier is: NCT02501447. PMID- 26768752 TI - Does Family Structure Play a Role in Depression in Adolescents Admitted to Psychiatric Inpatient Care? AB - We examined whether adolescents' family structure associate with depression in a clinical sample of 508 adolescents (age 13-17 years) treated in psychiatric hospital between April 2001 and March 2006. Psychiatric disorders of adolescents were based on the K-SADS-PL-interview. Adolescents with depression were characterized by a single parent family background (58 %), but less commonly by a child welfare placement (37 %). Depression in adolescents was significantly related to female gender and a single parent family background, but less significantly related to comorbid psychotic or conducts disorders. The association between family structure and depression presents a challenge to mental health services. Early screening for depression in adolescents admitted for psychiatric treatment from "at risk" family types is important to enhance their future wellbeing and coping strategies. PMID- 26768755 TI - Expression profile of FGF receptors in preimplantation ovine embryos and the effect of FGF2 and PD173074. AB - Fibroblast growth factors (FGFs) and their receptors (FGFRs) are increasingly recognized as important regulators of embryo development in mammals. This study investigated the importance of FGF signaling during in vitro development of ovine embryo. The mRNAs of four FGFR subtypes were detected throughout preimplantation development of in vitro fertilized (IVF) embryos, peaked in abundance at the morula stage, and decreased significantly at the blastocyst stage. To gain insight into the role of these mRNAs in embryo development, IVF embryos were cultured in the presence of FGF2 (100 or 500 ng/ml: beginning from days 1 or 4 to 7) or PD173074 (1 uM: beginning from days 1 to 7) as usual treatments for activation or inhibition of FGFRs, respectively. FGF2-supplementation did not affect the percentage of embryos that developed to the blastocyst, blastocyst cell count and the proportion of cells allocated in inner cell mass (ICM) and trophectoderm (TE) compared to control (p > 0.05). Also, increasing the dosage or duration of FGF2 treatment did not significantly alter blastocyst yield or differential cell count (p > 0.05). PD173074-mediated inhibition of FGFRs did not significantly affect blastocyst yield (p > 0.05). Assessment of expression profiles of lineage-associated markers revealed that FGF2 (500 ng/ml) supplementation: (i) significantly increased expression of putative hypoblast marker (GATA4), (ii) significantly decreased expression of putative epiblast (EPI) marker (NANOG) and (iii) did not change TE markers (CDX2 and IFNT) and pluripotency makers (OCT4, SOX2 and REX1). In summary, FGF2-mediated activation of FGFRs may promote a switch in transcriptional profile of ovine ICM from EPI- to hypoblast-associated gene expression. PMID- 26768756 TI - Work organization, exposure to workplace hazards and sickness presenteeism in the European employed population. AB - BACKGROUND: Aim of the study was to identify work organization features and workplace hazards associated with sickness presenteeism (SP) among European workers. METHODS: The study was conducted on data from the European Working Conditions Survey 2010 and included a study population of 30,279 employees. The relationship between work-related factors and SP was assessed through Poisson multivariate robust regression models, adjusting for significant (P < 0.05) individual and work-related characteristics. RESULTS: SP for at least 2 days in the previous year was reported by 35% of the workers. In fully adjusted model, several psychosocial (decision authority, skill discretion, reward, abuse; psychological, cognitive, and emotional demand), and organizational factors (shift work, working with clients, long work hours) were positively associated with SP, whereas job insecurity and exposure to physical factors (lifting or moving people, vibration) decreased SP risk. CONCLUSIONS: Our results support the importance of work-related factors, especially psychosocial exposures and organizational features, in determining workers' SP. PMID- 26768757 TI - Eula Bingham, PhD: Former Assistant Secretary for Occupational Safety and Health, US Department of Labor. PMID- 26768758 TI - The crossroads of autoimmunity and immunodeficiency: Lessons from polygenic traits and monogenic defects. AB - Autoimmune and immunodeficiency diseases are outcomes of a dysfunctional immune system and represent 2 sides of the same coin. Multiple single-gene defects have been identified, resulting in rare diseases with features of both autoimmunity and immunodeficiency. On the other hand, more common autoimmune diseases, such as rheumatoid arthritis and systemic lupus erythematosus, show a polygenic inheritance pattern. Not surprisingly, the genes implicated in single-gene disorders have also been shown to be linked to polygenic disorders. In this review article, we discuss the contribution of various immune system genes to common polygenic autoimmune disorders, as well as the pathophysiologic pathways and clinical features of monogenic defects that result in autoimmune disease. We also explore the hypotheses underlying the development of autoimmune disease and the overlap between immunodeficiency and autoimmunity. PMID- 26768759 TI - Alterations in immune function with biologic therapies for autoimmune disease. AB - Autoimmune disorders, including rheumatoid arthritis, inflammatory bowel disease, psoriasis, and others, are characterized by dysregulation of various aspects of normal immunity and inflammation. Biologic agents targeting key components of the dysregulated immune response have dramatically improved patient outcomes and transformed treatment paradigms for a number of systemic inflammatory autoimmune diseases. Despite their excellent efficacy, because they do affect normal immune responsiveness, biologic agents can potentially be associated with a variety of adverse effects. Important potential adverse effects related to the use of biologic agents include immunosuppression, which might result in outcomes such as infection, and autoimmunity, that could result in paradoxical inflammation or even autoimmune disease. In this article the current clinical evidence and immunologic mechanisms of the adverse effects related to biologic agents are discussed. PMID- 26768760 TI - Autoimmunity of the lung and oral mucosa in a multisystem inflammatory disease: The spark that lights the fire in rheumatoid arthritis? AB - There is a growing body of evidence to suggest that autoimmunity in patients with rheumatoid arthritis (RA) is initiated outside the joint. This is supported by the observation that circulating autoantibodies, including both rheumatoid factor and anti-citrullinated protein antibody, can be detected in many subjects years before the development of initial joint symptoms leading to an RA diagnosis. Of the potential extra-articular sites implicated in disease initiation, mucosal tissues have garnered increasing attention. Several lines of investigation have separately implicated mucosal tissues from varying anatomic locations as possible initiating sites for RA, including those from the lung and oral cavity. In this review we summarize recent reports incriminating these mucosal tissues as the initial site of autoantibody generation and inflammation in patients with RA. PMID- 26768764 TI - Historical classics: Editorial. PMID- 26768765 TI - Cysts of the larynx--Classification. PMID- 26768763 TI - The extended phenotype of LPS-responsive beige-like anchor protein (LRBA) deficiency. AB - BACKGROUND: LPS-responsive beige-like anchor protein (LRBA) deficiency is a primary immunodeficiency caused by biallelic mutations in LRBA that abolish LRBA protein expression. OBJECTIVE: We sought to report the extended phenotype of LRBA deficiency in a cohort of 22 LRBA-deficient patients. METHODS: Clinical criteria, protein detection, and genetic sequencing were applied to diagnose LRBA deficiency. RESULTS: Ninety-three patients met the inclusion criteria and were considered to have possible LRBA deficiency. Twenty-four patients did not express LRBA protein and were labeled as having probable LRBA deficiency, whereas 22 were genetically confirmed as having definitive LRBA deficiency, with biallelic mutations in LRBA. Seventeen of these were novel and included homozygous or compound heterozygous mutations. Immune dysregulation (95%), organomegaly (86%), recurrent infections (71%), and hypogammaglobulinemia (57%) were the main clinical complications observed in LRBA-deficient patients. Although 81% of LRBA deficient patients had normal T-cell counts, 73% had reduced regulatory T (Treg) cell numbers. Most LRBA-deficient patients had low B-cell subset counts, mainly in switched memory B cells (80%) and plasmablasts (92%), with a defective specific antibody response in 67%. Of the 22 patients, 3 are deceased, 2 were treated successfully with hematopoietic stem cell transplantation, 7 are receiving immunoglobulin replacement, and 15 are receiving immunosuppressive treatment with systemic corticosteroids alone or in combination with steroid sparing agents. CONCLUSION: This report describes the largest cohort of patients with LRBA deficiency and offers guidelines for physicians to identify LRBA deficiency, supporting appropriate clinical management. PMID- 26768766 TI - Advances in office-based diagnosis and treatment in laryngology. PMID- 26768767 TI - Improved survival of porcine acute liver failure by a bioartificial liver device implanted with induced human functional hepatocytes. AB - Acute liver failure (ALF) is a life-threatening illness. The extracorporeal cell based bioartificial liver (BAL) system could bridge liver transplantation and facilitate liver regeneration for ALF patients by providing metabolic detoxification and synthetic functions. Previous BAL systems, based on hepatoma cells and non-human hepatocytes, achieved limited clinical advances, largely due to poor hepatic functions, cumbersome preparation or safety concerns of these cells. We previously generated human functional hepatocytes by lineage conversion (hiHeps). Here, by improving functional maturity of hiHeps and producing hiHeps at clinical scales (3 billion cells), we developed a hiHep-based BAL system (hiHep-BAL). In a porcine ALF model, hiHep-BAL treatment restored liver functions, corrected blood levels of ammonia and bilirubin, and prolonged survival. Importantly, human albumin and alpha-1-antitrypsin were detectable in hiHep-BAL-treated ALF pigs. Moreover, hiHep-BAL treatment led to attenuated liver damage, resolved inflammation and enhanced liver regeneration. Our findings indicate a promising clinical application of the hiHep-BAL system. PMID- 26768769 TI - Anti-cancer effects of vitamin C revisited. AB - Vitamin C was first suggested to have cancer-fighting properties in the 1930s and has been the subject of controversy ever since. Despite repeated reports of selective cancer cell toxicity induced by high-dose vitamin C treatment in vitro and in mouse models, the mechanism of action has remained elusive. PMID- 26768770 TI - Master and commander: epigenetic regulation of macrophages. AB - Macrophages are important innate immune cells with functions in tissue repair and remodeling, induction and resolution of inflammation, as well as elimination of invading pathogens. In a recent study, Schmidt and colleagues describe the open epigenetic landscape of the human inflammatory macrophages, and the transcriptional regulators responsible for their rapid response to environmental signals. PMID- 26768768 TI - SIRT6 safeguards human mesenchymal stem cells from oxidative stress by coactivating NRF2. AB - SIRT6 belongs to the mammalian homologs of Sir2 histone NAD(+)-dependent deacylase family. In rodents, SIRT6 deficiency leads to aging-associated degeneration of mesodermal tissues. It remains unknown whether human SIRT6 has a direct role in maintaining the homeostasis of mesodermal tissues. To this end, we generated SIRT6 knockout human mesenchymal stem cells (hMSCs) by targeted gene editing. SIRT6-deficient hMSCs exhibited accelerated functional decay, a feature distinct from typical premature cellular senescence. Rather than compromised chromosomal stability, SIRT6-null hMSCs were predominately characterized by dysregulated redox metabolism and increased sensitivity to the oxidative stress. In addition, we found SIRT6 in a protein complex with both nuclear factor erythroid 2-related factor 2 (NRF2) and RNA polymerase II, which was required for the transactivation of NRF2-regulated antioxidant genes, including heme oxygenase 1 (HO-1). Overexpression of HO-1 in SIRT6-null hMSCs rescued premature cellular attrition. Our study uncovers a novel function of SIRT6 in maintaining hMSC homeostasis by serving as a NRF2 coactivator, which represents a new layer of regulation of oxidative stress-associated stem cell decay. PMID- 26768772 TI - Emergency Department-Initiated Palliative Care in Advanced Cancer: A Randomized Clinical Trial. AB - Importance: The delivery of palliative care is not standard of care within most emergency departments (EDs). Objective: To compare quality of life, depression, health care utilization, and survival in ED patients with advanced cancer randomized to ED-initiated palliative care consultation vs care as usual. Design, Setting, and Participants: A single-blind, randomized clinical trial of ED initiated palliative care consultation for patients with advanced cancer vs usual care took place from June 2011 to April 2014 at an urban, academic ED at a quaternary care referral center. Adult patients with advanced cancer who were able to pass a cognitive screen, had never been seen by palliative care, spoke English or Spanish, and presented to the ED met eligibility criteria; 136 of 298 eligible patients were approached and enrolled in the ED and randomized via balanced block randomization. Interventions: Intervention participants received a comprehensive palliative care consultation by the inpatient team, including an assessment of symptoms, spiritual and/or social needs, and goals of care. Main Outcomes and Measures: The primary outcome was quality of life as measured by the change in Functional Assessment of Cancer Therapy-General Measure (FACT-G) score at 12 weeks. Secondary outcomes included major depressive disorder as measured by the Patient Health Questionnaire-9, health care utilization at 180 days, and survival at 1 year. Results: A total of 136 participants were enrolled, and 69 allocated to palliative care (mean [SD], 55.1 [13.1] years) and 67 were randomized to usual care (mean [SD], 57.8 [14.7] years). Quality of life, as measured by a change in FACT-G score from enrollment to 12 weeks, was significantly higher in patients randomized to the intervention group, who demonstrated a mean (SD) increase of 5.91 (16.65) points compared with 1.08 (16.00) in controls (P = .03 using the nonparametric Wilcoxon test). Median estimates of survival were longer in the intervention group than the control group: 289 (95% CI, 128-453) days vs 132 (95% CI, 80-302) days, although this did not reach statistical significance (P = .20). There were no statistically significant differences in depression, admission to the intensive care unit, and discharge to hospice. Conclusions and Relevance: Emergency department-initiated palliative care consultation in advanced cancer improves quality of life in patients with advanced cancer and does not seem to shorten survival; the impact on health care utilization and depression is less clear and warrants further study. Trial Registration: clinicaltrials.gov Identifier: NCT01358110. PMID- 26768771 TI - Casilio: a versatile CRISPR-Cas9-Pumilio hybrid for gene regulation and genomic labeling. PMID- 26768776 TI - Numbering the uncounted, focusing the unseen. PMID- 26768774 TI - Reconstruction plates for midshaft clavicular fractures: A retrospective cohort study. AB - BACKGROUND: For the fixation of displaced midshaft clavicular fractures different plates are available, each with its specific pros and cons. The ideal plating choice for this lesion remains subject to ongoing discussion. Reconstruction plates are cheap and easily bendable, but their strength and stability have been questioned. The aim of this study was to evaluate the failure rate of reconstruction plates in the fixation of clavicular fractures. MATERIALS AND METHODS: A multicenter, retrospective cohort study of all consecutive patients with a displaced, midshaft clavicular fracture (Robinson type 2a/2b) treated with a 3.5-mm reconstruction plate between 2006 and 2013 were evaluated. The primary outcome measure was reoperation rate due to implant failure. Secondary outcome measures were nonunion, symptomatic malunion and elective plate removal. RESULTS: One hundred and eleven patients were analyzed. During a median follow-up of 8 months, 14 patients (12.6%) had implant failure, of which 7 (6.3%) required a reoperation. Three nonunions (2.7%) and no symptomatic malunions occurred. Plate removal was indicated in 37.8% of patients because of implant irritation. DISCUSSION: The incidence of reoperation due to implant failure following clavicular plate fixation with a reconstruction plate is 6.3%. Although comparison with other plate types is difficult since rates in literature vary greatly, reoperation rates in other plates are reported around 2-3%, suggesting that reconstruction plates have a higher incidence of implant failure warranting reoperation. Therefore, especially in patients with known risk factors for complications (e.g. smoking, osteoporosis, comminuted fractures), a stronger plate than a reconstruction plate should be considered. LEVEL OF EVIDENCE: Level IV. Retrospective study. PMID- 26768777 TI - Kangaroo Mother Care in African countries. PMID- 26768778 TI - Measuring tumor metabolic heterogeneity on positron emission tomography: utility in cervical cancer. PMID- 26768779 TI - Combined modality therapy in the adjuvant treatment of uterine serous carcinoma. PMID- 26768780 TI - DNA methylation in human papillomavirus-infected cervical cells is elevated in high-grade squamous intraepithelial lesions and cancer. AB - OBJECTIVE: DNA methylation has been shown to be a potential biomarker for early cancer detection. The aim of this study was to evaluate DNA methylation profiles according to liquid-based Pap (LBP) test results and to assess their diagnostic value in a Korean population. METHODS: A total of 205 patients with various Papanicolaou test results were enrolled to this study (negative, 26; atypical squamous cells of undetermined significance, 39; low grade squamous intraepithelial lesion, 44; high grade squamous intraepithelial lesion (HSIL), 48; and cancer, 48). DNA methylation analysis of four genes, ADCYAP1, PAX1, MAL, and CADM1, was performed on residual cervical cells from LBP samples using a quantitative bisulfite pyrosequencing method. To evaluate the diagnostic performance of the four methylated genes for cancer detection, receiver operating characteristic (ROC) curves were drawn. Sensitivities and specificities were also tested at cutoffs determined from the ROC curves. RESULTS: Cervical cancer cells showed dramatically increased methylation levels for the four genes analyzed. ADCYAP1 and PAX1 also trended toward elevated methylation levels in HSIL samples, although the levels were much lower than those in cancer cells. The sensitivities of methylated ADCYAP1, PAX1, MAL, and CADM1 for the detection of cancer were 79.2%, 75.0%, 70.8%, and 52.1%, and the specificities were 92.0%, 94.0%, 94.7%, and 94.0%, respectively. Methylated ADCYAP1 and PAX1 demonstrated relatively better discriminatory ability than did methylated MAL and CADM1 (area under the curves 0.911 and 0.916 vs. 0.854 and 0.756, respectively). CONCLUSION: DNA methylation status, especially in the ADCYAP1 and PAX1 genes, showed relatively good specificity, ranging from 90% to 94%. The possible additive and complementary roles of DNA methylation testing with respect to conventional cervical cancer screening programs will need to be validated in prospective population-based studies. PMID- 26768781 TI - Prognostic value of preoperative intratumoral FDG uptake heterogeneity in early stage uterine cervical cancer. AB - OBJECTIVE: We investigated the prognostic value of intratumoral [18F]fluorodeoxyglucose (FDG) uptake heterogeneity (IFH) derived from positron emission tomography/computed tomography (PET/CT) in patients with cervical cancer. METHODS: Patients with uterine cervical cancer of the International Federation of Obstetrics and Gynecology (FIGO) stage IB to IIA were imaged with [18F]FDG PET/CT before radical surgery. PET/CT parameters such as maximum and average standardized uptake values (SUV(max) and SUV(avg)), metabolic tumor volume (MTV), total lesion glycolysis (TLG), and IFH were assessed. Regression analyses were used to identify clinicopathological and imaging variables associated with progression-free survival (PFS). RESULTS: We retrospectively reviewed clinical data of 85 eligible patients. Median PFS was 32 months (range, 6 to 83 months), with recurrence observed in 14 patients (16.5%). IFH at an SUV of 2.0 was correlated with primary tumor size (p<0.001), SUV(tumor) (p<0.001), MTV(tumor) (p<0.001), TLG(tumor) (p<0.001), depth of cervical invasion (p<0.001), and negatively correlated with age (p=0.036). Tumor recurrence was significantly associated with TLG(tumor) (p<0.001), MTV(tumor) (p=0.001), SUV(LN) (p=0.004), IFH (p=0.005), SUV(tumor) (p=0.015), and FIGO stage (p=0.015). Multivariate analysis identified that IFH (p=0.028; hazard ratio, 756.997; 95% CI, 2.047 to 279,923.191) was the only independent risk factor for recurrence. The Kaplan Meier survival graphs showed that PFS significantly differed in groups categorized based on IFH (p=0.013, log-rank test). CONCLUSION: Preoperative IFH was significantly associated with cervical cancer recurrence. [18F]FDG based heterogeneity may be a useful and potential predicator of patient recurrence before treatment. PMID- 26768782 TI - Definitive treatment of primary vaginal cancer with radiotherapy: multi institutional retrospective study of the Korean Radiation Oncology Group (KROG 12 09). AB - OBJECTIVE: To assess the outcome of the treatment of primary vaginal cancer using definitive radiotherapy (RT) and to evaluate the prognostic factors of survival. METHODS: The medical records of nine institutions were retrospectively reviewed to find the patients with vaginal cancer treated with definitive RT with or without chemotherapy. A total of 138 patients met the inclusion criteria. None had undergone curative excision. RESULTS: The median follow-up time of the survivors was 77.6 months and the median survival time was 46.9 months. The 5 year overall survival, cancer-specific survival (CSS), and progression-free survival (PFS) rates were 68%, 80%, and 68.7%, respectively. In the survival analysis, the multivariate analysis showed that a lower the International Federation of Gynecology and Obstetrics (FIGO) stage and prior hysterectomy were favorable prognostic factors of CSS, and a lower FIGO stage and diagnosed prior to year 2000 were favorable prognostic factors of PFS. In the subgroup analysis of the patients with available human papillomavirus (HPV) results (n=27), no statistically significant relationship between the HPV status and recurrence or survival was found. Grade 3 or 4 acute and late toxicity were present in 16 and 9 patients, respectively. The FIGO stage and the tumor size were predictors of severe late toxicity. CONCLUSION: The data clearly showed that a higher FIGO stage was correlated with a worse survival outcome and higher severe late toxicity. Therefore, precise RT and careful observation are crucial in advanced vaginal cancer. In this study, the HPV status was not related to the survival outcome, but its further investigation is needed. PMID- 26768783 TI - Outcomes of laparoscopic fertility-sparing surgery in clinically early-stage epithelial ovarian cancer. AB - OBJECTIVE: Fertility-sparing surgery (FSS) is becoming an important technique in the surgical management of young women with early-stage epithelial ovarian cancer (EOC). We retrospectively evaluated the outcome of laparoscopic FSS in presumed clinically early-stage EOC. METHODS: We retrospectively searched databases of patients who received laparoscopic FSS for EOC between January 1999 and December 2012 at Samsung Medical Center. Women aged <=40 years were included. The perioperative, oncological, and obstetric outcomes of these patients were evaluated. RESULTS: A total of 18 patients was evaluated. The median age of the patients was 33.5 years (range, 14 to 40 years). The number of patients with clinically stage IA and IC was 6 (33.3%) and 12 (66.7%), respectively. There were 7 (38.9%), 5 (27.8%), 3 (16.7%), and 3 patients (16.7%) with mucinous, endometrioid, clear cell, and serous tumor types, respectively. Complete surgical staging to preserve the uterus and one ovary with adnexa was performed in 4 patients (22.2%). Two out of them were upstaged to The International Federation of Gynecology and Obstetrics stage IIIA1. During the median follow-up of 47.3 months (range, 11.5 to 195.3 months), there were no perioperative or long term surgical complications. Four women (22.2%) conceived after their respective ovarian cancer treatments. Three (16.7%) of them completed full-term delivery and one is expecting a baby. One patient had disease recurrence. No patient died of the disease. CONCLUSION: FSS in young patients with presumed clinically early stage EOC is a challenging and cautious procedure. Further studies are urgent to determine the safety and feasibility of laparoscopic FSS in young patients with presumed clinically early-stage EOC. PMID- 26768784 TI - Clinical significance of human papillomavirus genotyping. AB - Cervical cancer is the fourth most common cancer in women worldwide, and the human papillomavirus (HPV) is the main causative agent for its development. HPV is a heterogeneous virus, and a persistent infection with a high-risk HPV contributes to the development of cancer. In recent decades, great advances have been made in understanding the molecular biology of HPV, and HPV's significance in cervical cancer prevention and management has received increased attention. In this review, we discuss the role of HPV genotyping in cervical cancer by addressing: clinically important issues in HPV virology; the current application of HPV genotyping in clinical medicine; and potential future uses for HPV genotyping. PMID- 26768786 TI - Sentinel lymph node detection in endometrial cancer: does injection site make a difference? PMID- 26768788 TI - Fine structure of tooth enamel in the yellowing human teeth: SEM and HRTEM studies. AB - OBJECTIVE: The aim of this study was to clarify an influence of the fine structure of human tooth enamel to the yellowing teeth. MATERIALS AND METHODS: Sound maxillary first premolars of 15-50-year-old females that were extracted for the orthodontic treatment were used as the test samples. The tooth enamel sections of these teeth that prepared by ion polishing were observed by scanning electron microscopy (SEM). Furthermore, the fine structure of substance filling the inter-rod spaces was analyzed by high resolution transmission electron microscopy (HRTEM). RESULTS: In white tooth, the inter-rod spaces were observed at the width of about 0.1 MUm, while in yellow tooth, the inter-rod spaces were not clearly observed by SEM. HRTEM observations revealed for the first time that the inter-rod spaces were filled with fine particles of poorly crystallized hydroxyapatite in the yellow tooth. In yellow tooth, it was considered that the color of the inner dentin was recognized due to the decrease of light scattering by filling the tooth enamel inter-rod spaces. The generation of particles in the tooth enamel inter-rod spaces was considered to be caused by the long-time progression of calcification. CONCLUSIONS: These results suggested that the change in fine structure, filling in inter-rod spaces of tooth enamel, was related to progression of calcification in the inter-rod spaces with advancing age and one of the factors of yellowness of human tooth. PMID- 26768789 TI - Fluorescent imaging of endothelial glycocalyx layer with wheat germ agglutinin using intravital microscopy. AB - Endothelial glycocalyx (GCX) is located on the apical surface of vascular endothelial cells and is composed of a negatively-charged network of proteoglycans and glycoproteins. The GCX plays an important role in maintaining the integrity of vascular walls and preventing leakage of plasma. Therefore, degradation of the GCX is believed to lead to pathological leakage of plasma. Because the GCX is a very thin layer, its ultrastructural image has been demonstrated on electron microscope. To explore the function of the GCX, it should be visualized by a microscope in vivo. Thus, we developed in vivo visualization technique of the GCX under fluorescence microscopy using a mouse dorsal skinfold chamber (DSC) model. To label and visualize the GCX, we used fluorescein isothiocyanate (FITC)-labeled lectin, which has a high specificity for sugar moieties. We examined the affinity of the different lectins to epivascular regions under an intravital fluorescent microscope. Among seven different lectins we examined, FITC labeled Triticum vulgaris (wheat germ) agglutinin (WGA) delineated the GCX most clearly. Binding of WGA to the GCX was inhibited by chitin hydrolysate, which contained WGA-binding polysaccharide chains. Furthermore, the septic condition attenuated this structure, suggesting structural degradation of endothelial GCX layer. In conclusion, FITC-labeled WGA lectin enabled visualization of endothelial GCX under in vivo fluorescence microscopy. PMID- 26768790 TI - Erratum: Anchorage of annulus fibrosus within the vertebral endplate with reference to disc herniation. PMID- 26768785 TI - Toward precision medicine for preserving fertility in cancer patients: existing and emerging fertility preservation options for women. AB - As the number of young cancer survivors increases, quality of life after cancer treatment is becoming an ever more important consideration. According to a report from the American Cancer Society, approximately 810,170 women were diagnosed with cancer in 2015 in the United States. Among female cancer survivors, 1 in 250 are of reproductive age. Anticancer therapies can result in infertility or sterility and can have long-term negative effects on bone health, cardiovascular health as a result of reproductive endocrine function. Fertility preservation has been identified by many young patients diagnosed with cancer as second only to survival in terms of importance. The development of fertility preservation technologies aims to help patients diagnosed with cancer to preserve or protect their fertility prior to exposure to chemo- or radiation therapy, thus improving their chances of having a family and enhancing their quality of life as a cancer survivor. Currently, sperm, egg, and embryo banking are standard of care for preserving fertility for reproductive-age cancer patients; ovarian tissue cryopreservation is still considered experimental. Adoption and surrogate may also need to be considered. All patients should receive information about the fertility risks associated with their cancer treatment and the fertility preservation options available in a timely manner, whether or not they decide to ultimately pursue fertility preservation. Because of the ever expanding number of options for treating cancer and preserving fertility, there is now an opportunity to take a precision medicine approach to informing patients about the fertility risks associated with their cancer treatment and the fertility preservation options that are available to them. PMID- 26768792 TI - Reply. PMID- 26768793 TI - Reply. PMID- 26768791 TI - Biomarkers in localized prostate cancer. AB - Biomarkers can improve prostate cancer diagnosis and treatment. Accuracy of prostate-specific antigen (PSA) for early diagnosis of prostate cancer is not satisfactory, as it is an organ- but not cancer-specific biomarker, and it can be improved by using models that incorporate PSA along with other test results, such as prostate cancer antigen 3, the molecular forms of PSA (proPSA, benign PSA and intact PSA), as well as kallikreins. Recent reports suggest that new tools may be provided by metabolomic studies as shown by preliminary data on sarcosine. Additional molecular biomarkers have been identified by the use of genomics, proteomics and metabolomics. We review the most relevant biomarkers for early diagnosis and management of localized prostate cancer. PMID- 26768794 TI - Reply. PMID- 26768795 TI - Eosinophilic annular erythema: A late but complete response to hydroxychloroquine. AB - A 69-year-old woman with a 12-month history of asymptomatic erythematous, non scaly, annular and arciform plaques on her face, trunk and extremities is presented. The skin lesions had been unresponsive to treatment with systemic corticosteroids and antihistamines. Skin biopsy demonstrated superficial and deep dermal inflammatory infiltration consisting mainly of eosinophils and a few neutrophils. Dermal interstitial mucin deposition was also detected in the absence of vasculitis, flame figures or granulomatous reaction. The patient was diagnosed as having eosinophilic annular erythema and treated with hydroxychloroquine (2 * 200 mg/day, p.o.). Response to treatment was observed after 7 weeks and full recovery was achieved after 10 weeks. Eosinophilic annular erythema is rarely reported in the literature. Although hydroxychloroquine is a good choice for treatment, response time can vary between patients. PMID- 26768796 TI - Use of ZnO:Tb down-conversion phosphor for Ag nanoparticle plasmon absorption using a He-Cd ultraviolet laser. AB - Although noble metal nanoparticles (NPs) have attracted some attention for potentially enhancing the luminescence of rare earth ions for phosphor lighting applications, the absorption of energy by NPs can also be beneficial in biological and polymer applications where local heating is desired, e.g. photothermal applications. Strong interaction between incident laser light and NPs occurs only when the laser wavelength matches the NP plasmon resonance. Although lasers with different wavelengths are available and the NP plasmon resonance can be tuned by changing its size and shape or the dielectric medium (host material), in this work, we consider exciting the plasmon resonance of Ag NPs indirectly with a He-Cd UV laser using the down-conversion properties of Tb(3+) ions in ZnO. The formation of Ag NPs was confirmed by X-ray diffraction, transmission electron microscopy and UV-vis diffuse reflectance measurements. Radiative energy transfer from the Tb(3+) ions to the Ag NPs resulted in quenching of the green luminescence of ZnO:Tb and was studied by means of spectral overlap and lifetime measurements. The use of a down-converting phosphor, possibly with other rare earth ions, to indirectly couple a laser to the plasmon resonance wavelength of metal NPs is therefore successfully demonstrated and adds to the flexibility of such systems. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26768797 TI - STANDARDISED OUTCOMES IN NEPHROLOGY-HAEMODIALYSIS (SONG-HD): USING THE DELPHI METHOD TO GAIN CONSENSUS ON CORE OUTCOMES FOR HAEMODIALYSIS TRIALS. PMID- 26768798 TI - SELF-REPORTED MEDICATION ADHERENCE IN PATIENTS WITH END-STAGE KIDNEY DISEASE UNDERGOING ONLINE-HAEMODIAFILTRATION. AB - INTRODUCTION: Non-adherence to therapeutic regimens is a recognised problem in the dialysis population that compromises the opportunity to achieve maximum treatment effect and, therefore, might lead to increased morbidity and mortality. In this study, we aimed to evaluate the prevalence of self-reported medication non-adherence in patients with end-stage kidney disease (ESKD) undergoing online haemodiafiltration (OL-HDF), as well as to evaluate the factors that could affect medication adherence. PATIENTS AND METHODS: We evaluated 122 patients with ESKD undergoing OL-HDF. Patients' reported medication adherence was measured by the Measure Treatment Adherence (MTS) scale. Social support was evaluated by the abbreviated Lubben Social Network Scale (LSNS); depression status by the Geriatric Depression Scale (GDS). Socio-demographic, co-morbidity and clinical data were also evaluated. RESULTS: Our results showed that 10.7% of patients with ESKD perceived themselves as non-adherent to medication. When two groups of patients (adherent and non-adherents) were compared, significantly higher levels of triglycerides, and higher diastolic and systolic blood pressure were found in the non-adherent group. Significant correlations were found between the MTS score, and diastolic blood pressure, age and GDS score. Multiple regression analysis identified age and the GDS score as independent variables significantly associated with the MTS score. CONCLUSIONS: Non-adherence to therapeutic regimens in patients with ESKD is associated with higher levels of triglycerides and higher blood pressure and are, therefore, at a higher cardiovascular risk. Moreover, we found that age and depression status are important variables in non adherence to therapeutic regimens. PMID- 26768800 TI - A Preliminary Test of the Interpersonal Psychological Theory of Suicidal Behavior in Young People With a First Episode of Psychosis. AB - OBJECTIVES: The interpersonal-psychological theory (IPT) of suicidal behavior suggests that an individual who does not feel they belong and believes they are a burden combined with the capability to attempt suicide is more likely to attempt suicide. The study aimed to investigate this hypothesis in the context of psychosis. METHOD: Young people with a first episode of psychosis (N = 45) who considered suicide, attempted suicide, and had no history of suicide or attempt were compared on self-report measures of suicidal desire, capability for suicide, and substance use. RESULTS: No significant differences were found between groups in terms of suicidal desire or capability. All participants perceived they were a burden, did not feel they belonged, and had the capability for suicide. Poisoning (n = 22) was the most frequently reported method of a suicide attempt. Of those who had attempted suicide, 50% (n = 7) reported that it had been related to a psychotic episode. Of the participants, 30 reported previous suicidal ideation mainly to completely end or stop the distress they were experiencing. Levels of depression were significantly different between groups; moderate levels of depression were reported in the suicidal ideation and attempt groups. CONCLUSION: The concepts of IPT appear to resonate with the experience of psychosis, regardless of suicidality. Specific features of psychosis and their influence on suicidality are worth further exploration. PMID- 26768801 TI - End of year note, again (Redux ad Infinitum?). PMID- 26768806 TI - How Helicobacter pylori senses, targets and interacts with the gastric epithelium. AB - Helicobacter pylori is a human-specific pathogen that chronically infects about 50% of the world's population. After travelling through the harsh environment of the stomach lumen, H. pylori colonizes the mucosal surface and within the glands of the human stomach. During colonization, H. pylori uses motility and its chemotaxis signalling system to sense the environment to reach the gastric epithelium for colonization, where it is able to attach to the epithelial surface. The H. pylori population inside the stomach contains a subgroup of bacteria that are attached to the gastric epithelium and a larger subgroup of non attached bacteria that are freely swimming. To establish a tight interaction between H. pylori and epithelial cells, the bacterium produces a variety of adhesins and delivers virulence factors. These lead to alterations in the host signalling pathways, inducing pro-inflammatory responses, apoptosis, uncontrolled cell proliferation, and eventually peptic ulcers and gastric cancer. To prevent disease and find a vaccine or better treatments, it is crucial to understand how H. pylori is able to sense its niche for chronic infection inside the stomach and how its virulence factors interact with the epithelial target cells. PMID- 26768808 TI - Clinical Genetics in the age of Genomics and Genome editing. PMID- 26768807 TI - Long-Term Outcomes Following Transvenous Lead Extraction. AB - BACKGROUND: Complications related to a cardiac implantable electronic device sometimes require transvenous lead extraction (TLE). We report long-term follow up of patients undergoing TLE, particularly mortality, recurrent device infection, and need for repeat procedures. METHODS AND RESULTS: Consecutive patients undergoing TLE at a high-volume center were assessed for characteristics, indications, and outcomes. One thousand and six leads were extracted from 510 patients. Clinical success rate was 98.2% and complete procedural success was 92.2%, with one intraprocedural death. The mean follow-up was 5.5 +/- 4.9 years (range 0.2-18 years). Cumulative mortality was 3.3% at 30 days, 7.7% at 6 months, 10.0% at 1 year, and 33.0% at 10 years. Factors associated with increased long-term mortality included cardiac device infection (CDI; 33% vs 17% for non-CDI; chi2 13.8, P = 0.0003), procedural complications (43% vs 27% for no complications; chi2 4.2, P = 0.04), age (75.0 +/- 10.9 years in patients who died vs 62.7 +/- 17.2 years; P < 0.0001), and impaired renal function (creatinine 142.5 +/- 106.4 MUmol/L in patients who died vs 106.3 +/- 90.7 MUmol/L; P = 0.001). The rate of CDI after TLE was 3.9% (mean 11.6 months post extraction, range 0.3-84 months) and is higher in patients with retained lead fragments (13.5% vs 3.0% with complete removal; chi2 10.7, P = 0.001). CONCLUSION: Long-term mortality following TLE is high, particularly in those with systemic infection, procedural complications, advanced age, and renal impairment. Retained fragments are a risk factor for CDI post extraction. PMID- 26768809 TI - Peritoneal Dialysis Registry With 2012 Survey Report. AB - Since 2009, the peritoneal dialysis (PD) registry survey has been carried out as part of the annual nationwide survey conducted by the Statistical Survey Committee of the Japanese Society for Dialysis Therapy with the cooperation of the Japanese Society for Peritoneal Dialysis. In this report, the current status of PD patients is presented on the basis of the results of the survey conducted at the end of 2012. The subjects were PD patients who lived in Japan and participated in the 2012 survey. Descriptive analysis of various items was performed, which included the current status of the combined use of PD and another dialysis method such as hemodialysis (HD) or hemodiafiltration (HDF), the method of exchanging dialysate, the use of an automated peritoneal dialysis (APD) machine, and the rates of peritonitis and catheter exit-site infection. From the results of the facility survey in 2012, the number of PD patients was 9514, a decrease of 128 from 2011. Among the entire dialysis patient population, 3.1% were PD patients, a decrease of 0.1%. Among the studied patients, 347 had a peritoneal catheter and underwent peritoneal lavage, 175 were started on PD in 2012 but introduced to other blood purification methods in the same year, and 1932 underwent both PD and another dialysis method such as HD or HDF. The percentage of patients who underwent PD and another dialysis method increased with PD vintage: <1 year, 4.8%; 1 to <2 years, 9.2%; 2 to <4 years, 16.3%; 4 to <8 years, 32.0%; and >=8 years, 47.5%. The percentage of PD patients who completely manually exchanged the dialysate was 29.8%. The percentages of PD patients who used a double-bag exchange system with ultraviolet-light irradiation and those who used the same system but with a sterile connecting device were 54.7 and 13.9%, respectively. The percentage of patients on PD for <1 year using an APD machine was 43.4%, and it decreased with a PD vintage of >=2 years. The mean rate of peritonitis was 0.22 per patient per year. The mean rate of catheter exit site infections was 0.36 per patient per year. PMID- 26768811 TI - 10th Congress of the International Society for Apheresis 13-16 May 2015 Cancun, Mexico. PMID- 26768814 TI - The ISFA wishes to acknowledge the following 2015 Corporate Sponsors. PMID- 26768810 TI - An Overview of Regular Dialysis Treatment in Japan (As of 31 December 2013). AB - A nationwide survey of 4325 dialysis facilities was conducted at the end of 2013, among which 4268 (98.7%) responded. The number of new dialysis patients was 38,095 in 2013. Since 2008, the number of new dialysis patients has remained almost the same without any marked increase or decrease. The number of dialysis patients who died in 2013 was 30,751. The dialysis patient population has been growing every year in Japan; it was 314,438 at the end of 2013. The number of dialysis patients per million at the end of 2013 was 2470. The crude death rate of dialysis patients in 2013 was 9.8%. The mean age of new dialysis patients was 68.7 years and the mean age of the entire dialysis patient population was 67.2 years. The most common primary cause of renal failure among new dialysis patients was diabetic nephropathy (43.8%). The actual number of new dialysis patients with diabetic nephropathy has almost been unchanged for the last few years. Diabetic nephropathy was also the most common primary disease among the entire dialysis patient population (37.6%), followed by chronic glomerulonephritis (32.4%). The percentage of dialysis patients with diabetic nephropathy has been increasing continuously, whereas the percentage of dialysis patients with chronic glomerulonephritis has been decreasing. The number of patients who underwent hemodiafiltration (HDF) at the end of 2013 was 31,371, a marked increase from that in 2012. This number is more than twice that at the end of 2011 and approximately 1.5 times the number at the end of 2012. In particular, the number of patients who underwent online HDF increased approximately fivefold over the last 2 years. Among 151,426 dialysis patients with primary causes of renal failure other than diabetic nephropathy, 10.8% had a history of diabetes. Among those with a history of diabetes, 26.8% used glycoalbumin as an indicator of blood glucose level; and 33.0 and 27.6% were administered insulin and dipeptidyl peptidase (DPP)-4 inhibitor, respectively, as a medication of diabetes. The facility survey showed that 9392 patients underwent peritoneal dialysis (PD). The patient survey revealed that 1920 of these PD patients also underwent another dialysis method using extracorporeal circulation, such as hemodialysis (HD) or HDF. The number of patients who underwent HD at home at the end of 2013 was 461, a marked increase from that at the end of 2012 (393). PMID- 26768815 TI - Pyoderma gangrenosum-like oral ulcerations in an elderly patient. AB - OBJECTIVE: To present a case of pyoderma gangrenosum (PG)-like oral ulcerations in an elderly patient. BACKGROUND: PG is an uncommon idiopathic, ulcerative, chronic inflammatory cutaneous disorder of unknown etiology, which is associated with systemic diseases found in more than 50% of patients. Oral lesions of PG are extremely rare and have not been previously reported on chronic leukemia patient. CLINICAL REPORT: This report presents the first case of a 73 year-old man who had PG-like oral ulcerations which offered the possibility of an initial finding of chronic myeloid leukemia. CONCLUSION: Clinicians should always take into consideration that PG in the oral mucosa is a recalcitrant ulcer and can precede the development of underlying clonal malignancy. PMID- 26768820 TI - A Rotational BODIPY Nucleotide: An Environment-Sensitive Fluorescence-Lifetime Probe for DNA Interactions and Applications in Live-Cell Microscopy. AB - Fluorescent probes for detecting the physical properties of cellular structures have become valuable tools in life sciences. The fluorescence lifetime of molecular rotors can be used to report on variations in local molecular packing or viscosity. We used a nucleoside linked to a meso-substituted BODIPY fluorescent molecular rotor (dC(bdp)) to sense changes in DNA microenvironment both in vitro and in living cells. DNA incorporating dC(bdp) can respond to interactions with DNA-binding proteins and lipids by changes in the fluorescence lifetimes in the range 0.5-2.2 ns. We can directly visualize changes in the local environment of exogenous DNA during transfection of living cells. Relatively long fluorescence lifetimes and extensive contrast for detecting changes in the microenvironment together with good photostability and versatility for DNA synthesis make this probe suitable for analysis of DNA-associated processes, cellular structures, and also DNA-based nanomaterials. PMID- 26768821 TI - Stabilization of a Silaaldehyde by its eta(2) Coordination to Tungsten. AB - Treatment of pyridine-stabilized silylene complexes [(eta(5)-C5 Me4R)(CO)2(H)W=SiH(py)(Tsi)] (R = Me, Et; py = pyridine; Tsi = C(SiMe3)3) with an N-heterocyclic carbene (Me)I(i)Pr (1,3-diisopropyl-4,5-dimethylimidazol-2 ylidene) caused deprotonation to afford anionic silylene complexes [(eta(5)-C5Me4 R)(CO)2W=SiH(Tsi)][H(Me)I(i)Pr] (R = Me (1-Me); R = Et (1-Et)). Subsequent oxidation of 1-Me and 1-Et with pyridine-N-oxide (1 equiv) gave anionic eta(2) silaaldehydetungsten complexes [(eta(5)-C5Me4R)(CO)2W{eta(2) O=SiH(Tsi)}][H(Me)I(i)Pr] (R = Me (2-Me); R = Et (2-Et)). The formation of an unprecedented W-Si-O three-membered ring was confirmed by X-ray crystal structure analysis. PMID- 26768819 TI - A High-Throughput Platform for Formulating and Screening Multifunctional Nanoparticles Capable of Simultaneous Delivery of Genes and Transcription Factors. AB - Simultaneous delivery of multiple genes and proteins (e.g., transcription factors; TFs) is an emerging issue surrounding therapeutic research due to their ability to regulate cellular circuitry. Current gene and protein delivery strategies, however, are based on slow batch synthesis, which is ineffective, poorly controlled, and incapable of simultaneous delivery of both genes and proteins with synergistic functions. Consequently, advances in this field have been limited to in vitro studies. Here, by integrating microfluidic technologies with a supramolecular synthetic strategy, we present a high-throughput approach for formulating and screening multifunctional supramolecular nanoparticles (MFSNPs) self-assembled from a collection of functional modules to achieve simultaneous delivery of one gene and TF with unprecedented efficiency both in vitro and in vivo. We envision that this new approach could open a new avenue for immunotherapy, stem cell reprogramming, and other therapeutic applications. PMID- 26768822 TI - Synthesis of a Two-Dimensional Covalent Organic Monolayer through Dynamic Imine Chemistry at the Air/Water Interface. AB - A two-dimensional covalent organic monolayer was synthesized from simple aromatic triamine and dialdehyde building blocks by dynamic imine chemistry at the air/water interface (Langmuir-Blodgett method). The obtained monolayer was characterized by optical microscopy, scanning electron microscopy, and atomic force microscopy, which unambiguously confirmed the formation of a large (millimeter range), unimolecularly thin aromatic polyimine sheet. The imine linked chemical structure of the obtained monolayer was characterized by tip enhanced Raman spectroscopy, and the peak assignment was supported by spectra simulated by density functional theory. Given the modular nature and broad substrate scope of imine formation, the work reported herein opens up many new possibilities for the synthesis of customizable 2D polymers and systematic studies of their structure-property relationships. PMID- 26768823 TI - Reaction of Diazo Compounds with Difluorocarbene: An Efficient Approach towards 1,1-Difluoroolefins. AB - A transition-metal-free difluoromethylenation of diazo compounds that proceeds under mild conditions has been developed and is based on the use of TMSCF2 Br as the difluoromethylene source and tetrabutylammonium bromide (TBAB) as the promoter. The chemoselective formal carbene dimerization reaction is achieved owing to the electronic properties and the relative stability of the difluorocarbene intermediate. PMID- 26768824 TI - Dative Bonding between Group 13 Elements Using a Boron-Centered Lewis Base. AB - An electron-rich monovalent boron compound is used as a Lewis base to prepare adducts with Group 13 Lewis acids using both its boron and nitrogen sites. The hard Lewis acid AlCl3 binds through a nitrogen atom of the Lewis base, while softer Lewis acids GaX3 (Cl, Br, I) bind at the boron atom. The latter are the first noncluster Lewis adducts between a boron-centered Lewis base and a main group Lewis acid. PMID- 26768826 TI - New pharmacist roles and the physician shortage. PMID- 26768827 TI - Feasibility and acceptability of delivering adolescent health interventions alongside HPV vaccination in Tanzania. AB - BACKGROUND: Human papillomavirus (HPV) vaccination offers an opportunity to strengthen provision of adolescent health interventions (AHI). We explored the feasibility of integrating other AHI with HPV vaccination in Tanzania. METHODS: A desk review of 39 policy documents was preceded by a stakeholder meeting with 38 policy makers and partners. Eighteen key informant interviews (KIIs) with health and education policy makers and district officials were conducted to further explore perceptions of current programs, priorities and AHI that might be suitable for integration with HPV vaccination. RESULTS: Fourteen school health interventions (SHI) or AHI are currently being implemented by the Government of Tanzania. Most are delivered as vertical programmes. Coverage of current programs is not universal, and is limited by financial, human resource and logistic constraints. Limited community engagement, rumours, and lack of strategic advocacy has affected uptake of some interventions, e.g. tetanus toxoid (TT) immunization. Stakeholder and KI perceptions and opinions were limited by a lack of experience with integrated delivery and AHI that were outside an individual's area of expertise and experience. Deworming and educational sessions including reproductive health education were the most frequently mentioned interventions that respondents considered suitable for integrated delivery with HPV vaccine. CONCLUSIONS: Given programme constraints, limited experience with integrated delivery and concern about real or perceived side-effects being attributed to the vaccine, it will be very important to pilot-test integration of AHI/SHI with HPV vaccination. Selected interventions will need to be simple and quick to deliver since health workers are likely to face significant logistic and time constraints during vaccination visits. PMID- 26768828 TI - QUESTION 1: Should we be using bisphosphonates for osteonecrosis complicating childhood acute lymphoblastic leukaemia? PMID- 26768829 TI - Female genital mutilation: making the case for good practice. PMID- 26768830 TI - Systematic review of the toxicity of short-course oral corticosteroids in children. AB - BACKGROUND: Short-course oral corticosteroids are commonly used in children but are known to be associated with adverse drug reactions (ADRs). This review aimed to identify the most common and serious ADRs and to determine their relative risk levels. METHODS: A literature search of EMBASE, MEDLINE, International Pharmaceutical Abstracts, CINAHL, Cochrane Library and PubMed was performed with no language restrictions to identify studies in which oral corticosteroids were administered to patients aged 28 days to 18 years of age for up to and including 14 days of treatment. Each database was searched from their earliest dates to December 2013. All studies providing clear information on ADRs were included. RESULTS: Thirty-eight studies including 22 randomised controlled trials (RCTs) met the inclusion criteria. The studies involved a total of 3200 children in whom 850 ADRs were reported. The three most frequent ADRs were vomiting, behavioural changes and sleep disturbance, with respective incidence rates of 5.4%, 4.7% and 4.3% of patients assessed for these ADRs. Infection was one of the most serious ADRs; one child died after contracting varicella zoster. When measured, 144 of 369 patients showed increased blood pressure; 21 of 75 patients showed weight gain; and biochemical hypothalamic-pituitary-adrenal axis suppression was detected in 43 of 53 patients. CONCLUSIONS: Vomiting, behavioural changes and sleep disturbance were the most frequent ADRs seen when short-course oral corticosteroids were given to children. Increased susceptibility to infection was the most serious ADR. TRIAL REGISTRATION NUMBER: CRD42014008774. By PROSPERO International prospective register of systematic reviews. PMID- 26768831 TI - Respiratory complications of the rheumatological diseases in childhood. AB - Pleuropulmonary manifestations of rheumatological diseases are rare in children but pose a significant risk to overall morbidity and mortality. We have reviewed the literature to provide an overview of the respiratory complications of the commonest rheumatological diseases to occur in children (juvenile systemic lupus erythematosus, scleroderma, juvenile dermatomyositis, mixed connective tissue disease, granulomatosis with polyangitis and juvenile idiopathic arthritis). Pulmonary function testing in these patients can be used to refine the differential diagnosis and establish disease severity, but also has a role in ongoing monitoring for respiratory complications. Early detection of pulmonary involvement allows for prompt and targeted therapies to achieve the best outcome for the child. This is best achieved with joint specialist paediatric rheumatology and respiratory reviews in a multidisciplinary setting. PMID- 26768832 TI - Thymic Epithelial Tumor-Associated Cytopenia: A 10-Year Observational Study in France. AB - INTRODUCTION: Thymic epithelial tumor (TET)-associated cytopenia is rare but difficult to treat. METHODS: We performed a multicenter, retrospective study of TET and associated forms of cytopenia in France. Cases were collected by the French National Reference Center for Autoimmune Cytopenia and the French National Thymic Malignancy Interest Group (Reseau Tumeurs Thymiques et Cancer) and through a call for cases by the French Society of Internal Medicine. RESULTS: Thirty-six cases were recorded between 2002 and 2014 and followed up for a median of 38 months (interquartile range, 23-106 months). Thirty-two patients underwent surgery for TET, and 14 of the latter were in complete remission at last follow up. Cytopenia can occur before, simultaneously, or after diagnosis of TET. The most common types of cytopenia were pure red cell aplasia (in 30% of cases) and Good syndrome (GS) (also in 30% of cases). Eleven patients displayed two or more episodes of cytopenia. Eighteen patients received steroids as their first-line treatment, leading to a complete response in nine. Other first-line treatments (cyclosporine and rituximab) were less effective but should be considered as treatment options. Infections developed in 84% of the patients with GS; this did not appear to be related to the presence or absence of immunosuppressive treatment or chemotherapy. Eight patients died during the follow-up period (two died of cytopenia and five of infections). CONCLUSIONS: The optimal treatment for TET-associated cytopenia has not been clearly defined and the outcome does not appear to be correlated with TET progression. For GS, prophylactic immunoglobulin replacement therapy and prophylactic antibiotic therapy can be recommended. PMID- 26768833 TI - Endothelium dependent hyperpolarization-type relaxation compensates for attenuated nitric oxide-mediated responses in subcutaneous arteries of diabetic patients. AB - Diabetes impairs endothelium-dependent relaxations. The present study evaluated the contribution of different endothelium-dependent relaxing mechanisms to the regulation of vascular tone in subcutaneous blood vessels of humans with Type 2 diabetes mellitus. Subcutaneous arteries were isolated from tissues of healthy controls and diabetics. Vascular function was determined using wire myography. Expressions of proteins were measured by Western blotting and immunostaining. Endothelium-dependent relaxations to acetylcholine were impaired in arteries from diabetics compared to controls (P = 0.009). Acetylcholine-induced nitric oxide (NO)-mediated relaxations [in the presence of an inhibitor of cyclooxygenases (COX; indomethacin) and small and intermediate conductance calcium-activated potassium channel blockers (UCL1684 and TRAM 34, respectively)] were attenuated in arteries from diabetics compared to controls (P < 0.001). However, endothelium dependent hyperpolarization (EDH)-type relaxations [in the presence of indomethacin and the NO synthase blocker, l-NAME] were augmented in arteries from diabetics compared to controls (P = 0.003). Endothelium-independent relaxations to sodium nitroprusside (NO donor) and salbutamol (beta-adrenoceptor agonist) were preserved, but those to prostacyclin were attenuated in diabetics compared to controls (P = 0.017). In arteries of diabetics, protein expressions of endothelial NO synthase, prostacyclin synthase and prostacyclin receptors were decreased, but those of COX-2 were increased. These findings suggest that in human diabetes, the impairment of endothelium-dependent relaxations is caused by a diminished NO bioavailability; however, EDH appears to compensate, at least in part, for this dysfunction. PMID- 26768834 TI - Uterine leiomyosarcoma and endometrial stromal sarcoma have unique miRNA signatures. AB - OBJECTIVE: To compare the microRNA (miRNA) profiles of uterine endometrial stromal sarcoma (ESS) and leiomyosarcoma (LMS), and to compare the miRNA signatures of primary and metastatic uterine LMS. METHODS: Eight primary LMS, 9 primary ESS and 8 metastatic LMS were analyzed for miRNA profiles using TaqMan Human miRNA Array Cards. Findings for 20 differentially expressed miRNAs were validated in a series of 44 uterine sarcomas (9 primary uterine ESS, 17 primary uterine LMS, 18 metastatic LMS) using qPCR. Frizzled-6 protein expression was analyzed in 30 LMS (15 primary, 15 metastases). Frizzled-6 was silenced in SK-LMS 1 uterine LMS cells using siRNA and the effect on invasion, wound healing and matrix metalloproteinase-2 (MMP2) activity was assessed. RESULTS: Ninety-four miRNAs were significantly differentially expressed in ESS and LMS, of which 76 were overexpressed in ESS and 18 overexpressed in LMS. Forty-nine miRNAs were differentially expressed in primary and metastatic LMS, of which 45 were overexpressed in primary LMS and 4 in metastases. Differential expression was confirmed for 10/20 miRNA analyzed using qPCR. Frizzled-6 silencing in SK-LMS-1 cells significantly inhibited cellular invasion, wound healing and MMP-2 activity. CONCLUSIONS: Differential miRNA signatures of ESS and LMS provide novel data regarding transcriptional regulation in these cancers, based on which new potential diagnostic markers, prognostic biomarkers and therapeutic targets may be explored. Differences in miRNA profiles of primary and metastatic LMS may improve our understanding of disease progression in this aggressive malignancy. PMID- 26768835 TI - Magnitude of risk for nodal metastasis associated with lymphvascular space invasion for endometrial cancer. AB - OBJECTIVES: While lymphvascular space invasion (LVSI) is a risk factor for nodal metastasis in endometrial cancer, the magnitude of risk is poorly described. We examined the risk of nodal metastasis associated with LVSI for various combinations of tumor grade and depth of invasion and examined the effect of LVSI on survival. METHODS: We identified patients with T1A (<50% myoinvasion) and T1B (>50% myoinvasion) endometrioid adenocarcinomas of the endometrium diagnosed between 2010 and 2012 and recorded in the National Cancer Database. The risk of nodal metastasis associated with LVSI stratified by grade and stage is reported. The association of LVSI and survival was examined using Kaplan-Meier analyses and Cox proportional hazards models. RESULTS: We identified 25,907 patients, including 3928 (15.2%) with LVSI. Among patients with LVSI, 21.0% had positive lymph nodes, compared to 2.1% in patients without LVSI (P<0.0001). In analyses stratified by stage and grade, LVSI was associated with increased risks of LN metastasis by a magnitude of 3 to over 10-fold. In a multivariable model controlling for clinical and demographic characteristics, the risk ratio of nodal disease with LVSI was 9.29 (95% CI, 7.29-11.84) for T1A tumors and 4.64 (95% CI 3.99-5.39) for T1B tumors. LVSI was associated with decreased survival even after adjustment for the presence of lymph node metastases (HR=1.92, 95% CI 1.56-2.36). CONCLUSIONS: LVSI is independently associated with lymph node metastases in women with apparent early-stage endometrial cancer and an independent predictor of survival even after adjustment for the presence of lymph node metastases. PMID- 26768836 TI - Cardiovascular outcomes associated with use of clarithromycin: population based study. AB - STUDY QUESTION: What is the association between clarithromycin use and cardiovascular outcomes? METHODS: In this population based study the authors compared cardiovascular outcomes in adults aged 18 or more receiving oral clarithromycin or amoxicillin during 2005-09 in Hong Kong. Based on age within five years, sex, and calendar year at use, each clarithromycin user was matched to one or two amoxicillin users. The cohort analysis included patients who received clarithromycin (n=108,988) or amoxicillin (n=217,793). The self controlled case series and case crossover analysis included those who received Helicobacter pylori eradication treatment containing clarithromycin. The primary outcome was myocardial infarction. Secondary outcomes were all cause, cardiac, or non-cardiac mortality, arrhythmia, and stroke. STUDY ANSWER AND LIMITATIONS: The propensity score adjusted rate ratio of myocardial infarction 14 days after the start of antibiotic treatment was 3.66 (95% confidence interval 2.82 to 4.76) comparing clarithromycin use (132 events, rate 44.4 per 1000 person years) with amoxicillin use (149 events, 19.2 per 1000 person years), but no long term increased risk was observed. Similarly, rate ratios of secondary outcomes increased significantly only with current use of clarithromycin versus amoxicillin, except for stroke. In the self controlled case analysis, there was an association between current use of H pylori eradication treatment containing clarithromycin and cardiovascular events. The risk returned to baseline after treatment had ended. The case crossover analysis also showed an increased risk of cardiovascular events during current use of H pylori eradication treatment containing clarithromycin. The adjusted absolute risk difference for current use of clarithromycin versus amoxicillin was 1.90 excess myocardial infarction events (95% confidence interval 1.30 to 2.68) per 1000 patients. WHAT THIS STUDY ADDS: Current use of clarithromycin was associated with an increased risk of myocardial infarction, arrhythmia, and cardiac mortality short term but no association with long term cardiovascular risks among the Hong Kong population. FUNDING, COMPETING INTERESTS, DATA SHARING: ID was funded by grants from the Medical Research Council for this project. LS was funded by a grant from the Wellcome Trust. The authors have no competing interests. No additional data are available. PMID- 26768837 TI - Repeat transcatheter aortic valve implantation using a latest generation balloon expandable device for treatment of failing transcatheter heart valves. AB - BACKGROUND: Paravalvular leakage (PVL) is a known complication of transcatheter aortic valve implantation (TAVI) and is associated with poor outcome. Besides balloon-post-dilatation, valve-in-valve (ViV) procedures can be taken into consideration to control this complication. Herein we present initial experience with use of the latest generation balloon-expandable Edwards Sapien 3(r) (S3) transcatheter heart valve (THV) for treatment of failing THVs. METHODS: Between 01/2014 and 12/2014 three patients (two male, age: 71-80 y, log EUROScore I: 11.89 - 32.63) with failing THVs were refered to our institution for further treatment. THV approach with secondary implantation of an S3 was chosen after mutual agreement of the local interdisciplinary heart team at an interval of 533 1119 days from the index procedure. The performed procedures consisted of: S3 in Sapien XT, JenaValve and CoreValve. RESULTS: Successful transfemoral implantation with significant reduction of PVL was achieved in all cases. No intraprocedural complications occurred regarding placement of the S3 with a postprocedural effective orifice area (EOA) of 1.5-2.5 cm(2) and pressure gradients of max/mean 14/6-36/16 mmHg. 30-day mortality was 0%. At the latest follow-up of 90-530 days, all patients are alive and well with satisfactory THV function. Regarding VARC-2 criteria one major bleeding and one TIA was reported. CONCLUSIONS: In the instance of moderate or severe aortic regurgitation after TAVI, S3 ViV deployment is an excellent option to reduce residual regurgitation to none or mild. For further assertions concerning functional outcomes long-term results have to be awaited. PMID- 26768838 TI - Impact of Renal Replacement Therapy in Childhood on Long-Term Socioprofessional Outcomes: A 30-year Follow-Up Study. AB - OBJECTIVE: To evaluate socioprofessional outcomes after 30 years of renal replacement therapy (RRT) and explore predictors of these outcomes. STUDY DESIGN: The cohort comprised all Dutch patients, born before 1979, who started RRT at age <15 years in 1972-1992. Outcomes including family life, educational attainment, and professional life were obtained in 2000 and 2010 in 80 out of 152 survivors. Participants also completed the Course of Life Questionnaire in 2000, which retrospectively assessed the achievement of developmental milestones while growing up. Socioprofessional outcomes in 2010 were compared with the age-matched general population and with outcomes obtained in 2000. Logistic regression analysis was performed to identify determinants of socioprofessional outcomes. RESULTS: Mean age and time on RRT in 2010 were 40.6 years (range 32.1-52.4) and 28.9 years (range 18.1-39.7), respectively. Patients were less likely to be employed (62.5% vs 81.0%) and have children (28.8% vs 64.8%) compared with the age-matched general population. Comorbidities, dialysis, short stature, and fewer milestones on autonomy were associated with adverse outcomes. Compared with 2000, in 2010 more patients lived with a partner (68.8% vs 43.0%), and more patients had completed a high level educational degree (22.5% vs 13.9%). However, more patients were unable to work on medical grounds in 2010 (36.3% vs 16.3%). CONCLUSIONS: Survivors of pediatric end-stage renal disease may gain social autonomy and optimal educational attainment at an older age compared with their general population counterparts. Awareness among health care professionals of the potential of these children and tailored psychosocial interventions might improve socioprofessional development. PMID- 26768839 TI - Adding insult to injury: autoimmune haemolytic anaemia complicated by pulmonary embolism. AB - Autoimmune haemolytic anaemia (AIHA) is a disease characterised by the production of pathological antibodies that attach to the surface of a patient's own red blood cells, resulting in haemolysis. It can present in either an acute or a chronic manner. In addition to the obvious consequence of anaemia, there are other potentially deadly complications that can arise from AIHA, such as venous thromboembolism (VTE) and pulmonary hypertension. We report a case of a 52-year old woman who developed a pulmonary embolism (PE) soon after being diagnosed with AIHA. Despite having a very small pulmonary venous clot burden, she developed profound haemodynamic compromise with severe right ventricular dysfunction, which quickly reversed with inhaled nitric oxide treatment. This case makes an interesting observation of cell-free haemoglobin-associated nitric oxide scavenging as a mechanism of pulmonary hypertension and highlights the possible benefit of nitric oxide in treatment. PMID- 26768840 TI - Simultaneous preconcentration of polar and non-polar organophosphorus pesticides from water samples by using a new sorbent based on mesoporous silica. AB - A new mesoporous silica based on the sol-gel material cyanopropyltriethoxysilane (CNPrTEOS) was successfully synthesized by the hydrolysis and condensation of CNPrTEOS in the presence of ammonium solution as catalyst and methanol as solvent. It was used as a solid-phase extraction sorbent for the simultaneous extraction of three organophosphorus pesticides, namely, polar dicrotophos and non-polar diazinon and chlorpyrifos. Analysis was performed using high performance liquid chromatography with UV detection. CNPrTEOS was characterized by FTIR spectroscopy, field-emission scanning electron microscopy and nitrogen gas adsorption. The surface area and average pore diameter of the optimum sol-gel CNPrTEOS are 379 m(2) /g and 4.7 nm (mesoporous), respectively. The proposed solid-phase extraction based on CNPrTEOS exhibited good linearity in the range of 0.8-100 MUg/L, satisfactory precision (1.15-3.82%), high enrichment factor (800) and low limit of detection (0.072-0.091 MUg/L). The limits of detection obtained using the proposed solid-phase extraction method are well below the maximum residue limit set by European Union and are also lower (13.6-48.5*) than that obtained by using a commercial CN-SPE cartridge (0.98-4.41 MUg/L). The new mesoporous sol-gel CNPrTEOS showed promising alternative as SPE sorbent material for the simultaneous extraction of polar and non-polar organophosphorus pesticides. PMID- 26768841 TI - Editorial: Cells and Gene Therapy - "Do You Like Green Eggs and Ham?". PMID- 26768843 TI - Editorial Comment to Failure of botulinum toxin injection for neurogenic detrusor overactivity: Switch of toxin versus second injection of the same toxin. PMID- 26768844 TI - Sensing surface morphology of biofibers by decorating spider silk and cellulosic filaments with nematic microdroplets. AB - Probing the surface morphology of microthin fibers such as naturally occurring biofibers is essential for understanding their structural properties, biological function, and mechanical performance. The state-of-the-art methods for studying the surfaces of biofibers are atomic force microscopy imaging and scanning electron microscopy, which well characterize surface geometry of the fibers but provide little information on the local interaction potential of the fibers with the surrounding material. In contrast, complex nematic fluids respond very well to external fields and change their optical properties upon such stimuli. Here we demonstrate that liquid crystal droplets deposited on microthin biofibers- including spider silk and cellulosic fibers--reveal characteristics of the fibers' surface, performing as simple but sensitive surface sensors. By combining experiments and numerical modeling, different types of fibers are identified through the fiber-to-nematic droplet interactions, including perpendicular and axial or helicoidal planar molecular alignment. Spider silks align nematic molecules parallel to fibers or perpendicular to them, whereas cellulose aligns the molecules unidirectionally or helicoidally along the fibers, indicating notably different surface interactions. The nematic droplets as sensors thus directly reveal chirality of cellulosic fibers. Different fiber entanglements can be identified by depositing droplets exactly at the fiber crossings. More generally, the presented method can be used as a simple but powerful approach for probing the surface properties of small-size bioobjects, opening a route to their precise characterization. PMID- 26768845 TI - Long noncoding RNA UPAT promotes colon tumorigenesis by inhibiting degradation of UHRF1. AB - Many long noncoding RNAs (lncRNAs) are reported to be dysregulated in human cancers and play critical roles in tumor development and progression. Furthermore, it has been reported that many lncRNAs regulate gene expression by recruiting chromatin remodeling complexes to specific genomic loci or by controlling transcriptional or posttranscriptional processes. Here we show that an lncRNA termed UPAT [ubiquitin-like plant homeodomain (PHD) and really interesting new gene (RING) finger domain-containing protein 1 (UHRF1) Protein Associated Transcript] is required for the survival and tumorigenicity of colorectal cancer cells. UPAT interacts with and stabilizes the epigenetic factor UHRF1 by interfering with its beta-transducin repeat-containing protein (TrCP) mediated ubiquitination. Furthermore, we demonstrate that UHRF1 up-regulates Stearoyl-CoA desaturase 1 and Sprouty 4, which are required for the survival of colon tumor cells. Our study provides evidence for an lncRNA that regulates protein ubiquitination and degradation and thereby plays a critical role in the survival and tumorigenicity of tumor cells. Our results suggest that UPAT and UHRF1 may be promising molecular targets for the therapy of colon cancer. PMID- 26768846 TI - Unstable FoxP3+ T regulatory cells in NZW mice. AB - Regulatory T (Treg) cells that express the transcription factor FoxP3 play a key role in self-tolerance and the control of inflammation. In mice and humans, there is a wide interindividual range in Treg frequency, but little is known about the underlying genetic or epigenetic mechanisms. We explored this issue in inbred strains of mice, with a special focus on the low proportion of Treg cells found in NZW mice. Mixed bone marrow chimera experiments showed this paucity to be intrinsic to NZW Treg cells, a dearth that could be tied to poor stability of the Treg pool and of FoxP3 expression. This instability was not a consequence of differential epigenetic marks, because Treg-specific CpG hypomethylation profiles at the Foxp3 locus were similar in all strains tested. It was also unrelated to the high expression of IFN signature genes in NZW, as shown by intercross to mice with an Ifnar1 knockout. NZW Tregs were less sensitive to limiting doses of trophic cytokines, IL-2 and -33, for population homeostasis and for maintenance of FoxP3 expression. Gene-expression profiles highlighted specific differences in the transcriptome of NZW Tregs compared with those of other strains, but no single defect could obviously account for the instability. Rather, NZW Tregs showed a general up-regulation of transcripts normally repressed in Treg cells, and we speculate that this network-level bias may account for NZW Treg instability. PMID- 26768849 TI - Short-term safety evaluation of the offspring conceived by 7272 artificial insemination cycles with donor spermatozoon. AB - This case-control study was designed to investigate the safety of the AID technology. The health status of the offspring conceived by 1620 couples who underwent 7272 AID cycles in our Center for Reproductive Medicine between June 2006 and December 2012 was retrospectively analysed. The control group included 1018 women who naturally conceived and delivered in the same period. Twin birth rate was significantly higher in the AID group (no triplet birth) than in the control group (2.01% versus 0.39%, P < 0.01). In the AID group, Caesarean delivery was used in 1299 cases (81.65%), spontaneous vaginal delivery (18.04%) and forceps-assisted vaginal delivery (0.31%).There was no significant difference in male/female ratio of the offspring between AID and control groups (113.55 : 100 versus 113.36 : 100, P > 0.05). Compared to natural pregnancy, a pregnancy through AID resulted in higher multiple birth rate, premature delivery rate and neonatal congenital malformation rate. Increased multiple birth rate was attributable to ovulation induction, and increased rate of low-birthweight infants was related to multiplets and premature delivery. Caesarean delivery was preferred in couples who received AID treatment. The male/female ratio of the AID offspring was similar between natural pregnancy and AID pregnancy. PMID- 26768847 TI - Genomic incompatibilities in the diploid and tetraploid offspring of the goldfish * common carp cross. AB - Polyploidy is much rarer in animals than in plants but it is not known why. The outcome of combining two genomes in vertebrates remains unpredictable, especially because polyploidization seldom shows positive effects and more often results in lethal consequences because viable gametes fail to form during meiosis. Fortunately, the goldfish (maternal) * common carp (paternal) hybrids have reproduced successfully up to generation 22, and this hybrid lineage permits an investigation into the genomics of hybridization and tetraploidization. The first two generations of these hybrids are diploids, and subsequent generations are tetraploids. Liver transcriptomes from four generations and their progenitors reveal chimeric genes (>9%) and mutations of orthologous genes. Characterizations of 18 randomly chosen genes from genomic DNA and cDNA confirm the chimera. Some of the chimeric and differentially expressed genes relate to mutagenesis, repair, and cancer-related pathways in 2nF1. Erroneous DNA excision between homologous parental genes may drive the high percentage of chimeric genes, or even more potential mechanisms may result in this phenomenon. Meanwhile, diploid offspring show paternal-biased expression, yet tetraploids show maternal-biased expression. These discoveries reveal that fast and unstable changes are mainly deleterious at the level of transcriptomes although some offspring still survive their genomic abnormalities. In addition, the synthetic effect of genome shock might have resulted in greatly reduced viability of 2nF2 hybrid offspring. The goldfish * common carp hybrids constitute an ideal system for unveiling the consequences of intergenomic interactions in hybrid vertebrate genomes and their fertility. PMID- 26768852 TI - Changes and Challenges. PMID- 26768850 TI - Effects of low-carbohydrate diets v. low-fat diets on body weight and cardiovascular risk factors: a meta-analysis of randomised controlled trials. AB - The effects of low-carbohydrate (LC) diets on body weight and cardiovascular risk are unclear, and previous studies have found varying results. Our aim was to conduct a meta-analysis of randomised controlled trials (RCT), assessing the effects of LC diets v. low-fat (LF) diets on weight loss and risk factors of CVD. Studies were identified by searching MEDLINE, Embase and Cochrane Trials. Studies had to fulfil the following criteria: a RCT; the LC diet was defined in accordance with the Atkins diet, or carbohydrate intake of <20% of total energy intake; twenty subjects or more per group; the subjects were previously healthy; and the dietary intervention had a duration of 6 months or longer. Results from individual studies were pooled as weighted mean difference (WMD) using a random effect model. In all, eleven RCT with 1369 participants met all the set eligibility criteria. Compared with participants on LF diets, participants on LC diets experienced a greater reduction in body weight (WMD -2.17 kg; 95% CI -3.36, -0.99) and TAG (WMD -0.26 mmol/l; 95% CI -0.37, -0.15), but a greater increase in HDL-cholesterol (WMD 0.14 mmol/l; 95% CI 0.09, 0.19) and LDL-cholesterol (WMD 0.16 mmol/l; 95% CI 0.003, 0.33). This meta-analysis demonstrates opposite change in two important cardiovascular risk factors on LC diets--greater weight loss and increased LDL-cholesterol. Our findings suggest that the beneficial changes of LC diets must be weighed against the possible detrimental effects of increased LDL cholesterol. PMID- 26768848 TI - Sensing of latent EBV infection through exosomal transfer of 5'pppRNA. AB - Complex interactions between DNA herpesviruses and host factors determine the establishment of a life-long asymptomatic latent infection. The lymphotropic Epstein-Barr virus (EBV) seems to avoid recognition by innate sensors despite massive transcription of immunostimulatory small RNAs (EBV-EBERs). Here we demonstrate that in latently infected B cells, EBER1 transcripts interact with the lupus antigen (La) ribonucleoprotein, avoiding cytoplasmic RNA sensors. However, in coculture experiments we observed that latent-infected cells trigger antiviral immunity in dendritic cells (DCs) through selective release and transfer of RNA via exosomes. In ex vivo tonsillar cultures, we observed that EBER1-loaded exosomes are preferentially captured and internalized by human plasmacytoid DCs (pDCs) that express the TIM1 phosphatidylserine receptor, a known viral- and exosomal target. Using an EBER-deficient EBV strain, enzymatic removal of 5'ppp, in vitro transcripts, and coculture experiments, we established that 5'pppEBER1 transfer via exosomes drives antiviral immunity in nonpermissive DCs. Lupus erythematosus patients suffer from elevated EBV load and activated antiviral immunity, in particular in skin lesions that are infiltrated with pDCs. We detected high levels of EBER1 RNA in such skin lesions, as well as EBV microRNAs, but no intact EBV-DNA, linking non-cell-autonomous EBER1 presence with skin inflammation in predisposed individuals. Collectively, our studies indicate that virus-modified exosomes have a physiological role in the host-pathogen stand off and may promote inflammatory disease. PMID- 26768853 TI - English vowel identification and vowel formant discrimination by native Mandarin Chinese- and native English-speaking listeners: The effect of vowel duration dependence. AB - The purpose of this study was to examine the relationship between English vowel identification and English vowel formant discrimination for native Mandarin Chinese- and native English-speaking listeners. The identification of 12 English vowels was measured with the duration cue preserved or removed. The thresholds of vowel formant discrimination on the F2 of two English vowels,/Lambda/and/i/, were also estimated using an adaptive-tracking procedure. Native Mandarin Chinese speaking listeners showed significantly higher thresholds of vowel formant discrimination and lower identification scores than native English-speaking listeners. The duration effect on English vowel identification was similar between native Mandarin Chinese- and native English-speaking listeners. Moreover, regardless of listeners' language background, vowel identification was significantly correlated with vowel formant discrimination for the listeners who were less dependent on duration cues, whereas the correlation between vowel identification and vowel formant discrimination was not significant for the listeners who were highly dependent on duration cues. This study revealed individual variability in using multiple acoustic cues to identify English vowels for both native and non-native listeners. PMID- 26768854 TI - Carbon nanotubes in drug delivery: just a carrier? PMID- 26768855 TI - Is There an Influence of Routine Daily Transcranial Doppler Examination on Clinical Outcome in Patients After Aneurysmal Subarachnoid Hemorrhage? AB - BACKGROUND: Transcranial Doppler (TCD) is widely used as a daily routine method to detect vasospasm in patients after aneurysmal subarachnoid hemorrhage (aSAH); however, there are only limited data about the real benefit of this examination. Therefore, the clinical outcome of 2 cohorts with and without daily TCD after aSAH was assessed. METHODS: All patients included in this study received a standardized diagnostic and treatment protocol. Fifty patients admitted with aSAH from January 2013 to December 2013 received daily TCD measurements; 39 patients admitted from January 2014 to September 2014 received no TCD measurements. Data on clinical grade (Hunt and Hess grade), severity of bleeding (Barrow Neurological Institute grade), localization of aneurysm, and angiographic or clinically relevant vasospasm were collected prospectively. The Glasgow Outcome Scale, modified Rankin Scale, and the National Institute of Health Stroke Scale were used as clinical outcome parameters. RESULTS: Patient baseline characteristics and clinical data were comparable; treatment modality of the aneurysm was not different between the groups (P = 0.7756). No significant difference between the Hunt and Hess grade (P = 0.818) and the Barrow Neurological Institute grade (P = 0.1551) was observed. There was also no significance concerning the incidence of angiographic or clinically relevant vasospasm between both groups (P = 0.5842 and P = 0.7933). Glasgow Outcome Scale, mRS, and National Institute of Health Stroke Scale as the primary outcome parameters showed no significant difference in morbidity and mortality between both groups (mortality P = 0.8544). CONCLUSIONS: With the limitation of an explorative cohort study, the results indicate that routine TCD studies do not improve the overall outcome of patients after aSAH. PMID- 26768856 TI - Family planning knowledge, attitudes and practices among bariatric healthcare providers. AB - OBJECTIVE: This survey aimed to identify the family planning knowledge, attitudes and practices of bariatric providers in the perioperative period. STUDY DESIGN: We developed a quantitative survey based on semistructured interviews with six bariatric providers. We mailed the survey to the American Society of Metabolic and Bariatric Surgery members with plans to use data from the first 275 responders to assess knowledge, attitudes and practices regarding family planning. RESULTS: Over 70% of 272 respondents recommended that women avoid pregnancy for 12-24months after bariatric procedures. Most (73.0%) considered female reproductive health discussions very important, and most feel comfortable (70.4%) with these discussions. The majority considered the most effective contraceptive methods to be safe for women after gastric bypass; only a minority (35.3%) provided contraceptive services or referrals, and few (4.9%) have accurate knowledge of contraceptive effectiveness. Respondents most frequently preferred the patient's own gynecologist (80.9%) or bariatric surgeon (71.0%) discuss contraception. Discussing contraception was associated with provider age 40-49years, training region in southeast or midwest and degrees of physician assistant or nurse practitioner with adjusted odds ratios exceeding 2.0. CONCLUSION: Bariatric providers consider reproductive health very important, and while most are comfortable having these conversations, few have accurate knowledge of contraceptive safety and effectiveness. Most would prefer patients see their gynecologists to discuss contraception. These findings suggest an opportunity for gynecologists to educate themselves and bariatric colleagues about contraception recommendations after bariatric surgery and collaborate with bariatric centers in their area to meet the needs of these patients. IMPLICATIONS: Gynecologists must become educated and involved in the care of female bariatric patients to discuss reproductive health concerns and to counsel effectively regarding contraception after bariatric surgery. PMID- 26768857 TI - Core competencies in sexual and reproductive health for the interprofessional primary care team. AB - OBJECTIVE: A primary care workforce that is well prepared to provide high-quality sexual and reproductive health (SRH) care has the potential to enhance access to care and reduce health disparities. This project aimed to identify core competencies to guide SRH training across the primary care professions. STUDY DESIGN: A six-member interprofessional expert working group drafted SRH competencies for primary care team members. Primary care providers including family physicians, nurses, nurse practitioners and certified nurse midwives, physician assistants and pharmacists were invited to participate in a three-round electronic Delphi survey. In each round, participants voted by email to retain, eliminate or revise each competency, with their suggested edits to the competencies incorporated by the researchers after each round. RESULTS: Fifty providers from six professions participated. In Round 1, 17 of 33 draft competencies reached the 75% predetermined agreement level to be accepted as written. Five were combined, reducing the total number to 28. Based on Round 2 feedback, 21 competencies were reworded, and 2 were combined. In Round 3, all 26 competencies reached at least 83.7% agreement, with 9 achieving 100% agreement. CONCLUSION: The 33 core competencies encompass professional ethics and reproductive justice, collaboration, SRH services and conditions affecting SRH. These core competencies will be disseminated and adapted to each profession's scope of practice to inform required curricula. IMPLICATIONS: SRH competencies for primary care can inform the required curricula across professions, filling the gap between an established standard of care necessary to meet patient needs and the outcomes of that care. PMID- 26768859 TI - A quick guide to light microscopy in cell biology. AB - Light microscopy is a key tool in modern cell biology. Light microscopy has several features that make it ideally suited for imaging biology in living cells: the resolution is well-matched to the sizes of subcellular structures, a diverse range of available fluorescent probes makes it possible to mark proteins, organelles, and other structures for imaging, and the relatively nonperturbing nature of light means that living cells can be imaged for long periods of time to follow their dynamics. Here I provide a brief introduction to using light microscopy in cell biology, with particular emphasis on factors to be considered when starting microscopy experiments. PMID- 26768858 TI - Women's experiences seeking abortion care shortly after the closure of clinics due to a restrictive law in Texas. AB - OBJECTIVE: In 2013, Texas passed legislation restricting abortion services. Almost half of the state's clinics had closed by April 2014, and there was a 13% decline in abortions in the 6 months after the first portions of the law went into effect, compared to the same period 1 year prior. We aimed to describe women's experiences seeking abortion care shortly after clinics closed and document pregnancy outcomes of women affected by these closures. STUDY DESIGN: Between November 2013 and November 2014, we recruited women who sought abortion care at Texas clinics that were no longer providing services. Some participants had appointments scheduled at clinics that stopped offering care when the law went into effect; others called seeking care at clinics that had closed. Texas resident women seeking abortion in Albuquerque, New Mexico, were also recruited. RESULTS: We conducted 23 in-depth interviews and performed a thematic analysis. As a result of clinic closures, women experienced confusion about where to go for abortion services, and most reported increased cost and travel time to obtain care. Having to travel farther for care also compromised their privacy. Eight women were delayed more than 1 week, two did not receive care until they were more than 12 weeks pregnant and two did not obtain their desired abortion at all. Five women considered self-inducing the abortion, but none attempted this. CONCLUSIONS: The clinic closures resulted in multiple barriers to care, leading to delayed abortion care for some and preventing others from having the abortion they wanted. IMPLICATIONS: The restrictions on abortion facilities that resulted in the closure of clinics in Texas created significant burdens on women that prevented them from having desired abortions. These laws may also adversely affect public health by moving women who would have had abortions in the first trimester to having second-trimester procedures. PMID- 26768860 TI - Second Metatarsal Transfer Lesions Due to First Metatarsal Shortening After Distal Chevron Metatarsal Osteotomy for Hallux Valgus. AB - BACKGROUND: The first metatarsal bone can shorten after a distal chevron metatarsal osteotomy (DCMO). This shortening can result in a postoperative second metatarsal transfer lesion. The aim of the present study was to investigate the occurrence of second metatarsal transfer lesions after DCMO. METHODS: This study involved 185 feet (138 patients), with hallux valgus (HV) deformity, treated with DCMO with Akin osteotomy. The mean patient age was 51.7 years (range, 21 to 74). Patients were followed for an average of 28 months, between June 2004 and June 2010. We measured the length of first metatarsal relative to second metatarsal preoperatively and postoperatively, using Morton's and Hardy-Clapham's methods. A second metatarsal transfer lesion was defined as a newly developed lesion, including metatarsalgia, a painful callosity, or a painless callosity, which was not present prior to the DCMO. The relation of the shortened first metatarsal after DCMO with the occurrence of second metatarsal transfer lesion was evaluated. RESULTS: Second metatarsal transfer lesions (painless callosity) developed in 5 feet (2.7%) of 185 feet. Twenty-four preoperative second metatarsal lesions were improved postoperatively. The median shortening of the first metatarsal bone after DCMO was 0.6 mm according to Morton's method (range, 6.4 to 6.4), and 1.9 according to Hardy-Clapham's method (range, -5.8 to 5.8). According to the extent of first metatarsal shortening after DCMO by Hardy Clapham's method and Morton's method, there was no significant difference of the occurrence of second transfer metatarsal lesions (P = .259 and P = .176, respectively). CONCLUSIONS: In our study, second metatarsal transfer lesions developed in 2.7% of feet after DCMO. The occurrence of second metatarsal transfer lesions did not appear to be correlated with the degree of first metatarsal shortening in cases with less than 5.8 mm shortening. LEVEL OF EVIDENCE: Level IV, retrospective case series. PMID- 26768861 TI - High-sensitivity C-reactive protein, apolipoproteins, and residual diuresis in chronic kidney disease patients undergoing hemodialysis. AB - BACKGROUND: Residual diuresis (RD) is the simplest method for measuring renal residual function in patients with chronic kidney disease (CKD). A reduction in RD is associated with intensification of the inflammatory process caused by uremia. However, little is known regarding the relation between RD and inflammatory markers in these patients. We verify possible associations among the hs-CRP, atherogenic factors, and RD, in patients with CKD undergoing hemodialysis. METHODS: This study enrolled 80 patients with CKD undergoing hemodialysis. Patients were stratified according to RD in anuric (RD-) group (n = 47) and non-anuric (RD+) group (n = 33). Urine volumes were collected in a 24 h period during the interdialytic period. Serum high-sensitivity C-reactive protein (hs-CRP), and apolipoprotein (Apo) A1 and B levels were measured after fasting for 12 h. RESULTS: Serum hs-CRP levels were higher in the RD- group than in the RD+ group (P = 0.015). In the total group, hs-CRP was significantly correlated with RD (r = - 0.25, P = 0.025) and Apo AI (r = - 0.25, P = 0.024). A greater proportion of patients had reduced plasma concentrations of Apo AI in the RD- group (31.9 %) compared with the RD+ group (9.1 %) (P = 0.014). CONCLUSION: This study shows a relationship between RD and the hs-CRP in patients undergoing hemodialysis. Although the inflammatory state was verified in a large part of the CKD population, patients without RD had more elevated hs-CRP serum levels than those with RD. PMID- 26768862 TI - Effect of Pre/Postconditioning at Temporary Clipping. AB - Intracranial aneurysms and their treatment is one of the leading problems of neurosurgery that create high mortality and morbidity. The technique of safe clipping is as generally used depends on the temporary occlusion of the cerebral vasculature during surgery. However, there is no exact data about temporary clipping or timing of this procedure. Preconditioning by exposure to sublethal hypoxic stress, hours or days before severe hypoxia, decreases cell death, and this resistance of the brain to injury is known as ischemic tolerance. Brief alternating periods of reperfusion-reocclusion at the beginning of reperfusion is defined as postconditioning. Cerebral ischemic pre/postconditioning protects against stroke, but is clinically feasible only when the occurrence of stroke is predictable. Brief, repetitive occlusion and release of the main trunk of a vessel during early aneurysm surgery or before long-lasting temporary artery occlusion may protect the brain against later possible vasospasm/ischemia. PMID- 26768863 TI - Protective Effect of Ad-VEGF-Bone Mesenchymal Stem Cells on Cerebral Infarction. AB - AIM: To understand the mechanism of intracerebroventricular transplantation of vascular endothelial growth factor (VEGF) genemodified bone mesenchymal stem cells (BMSCs) in rats after cerebral infarction. MATERIAL AND METHODS: The middle cerebral artery occlusion ischemia/reperfusion (MCAO I/R) model was established in rats using the Zea-Longa suture method. A recombinant adenovirus (Ad-VEGF) was engineered to express VEGF. The rats were divided into 3 groups. Control BMSC infected with control adenovirus (BMSC-Ad), BMSC infected by Ad-VEGF (BMSC-Ad VEGF), and phosphate buffered saline (PBS) suspension were injected into the intracerebroventricular system of the rats in groups 1, 2 and 3 respectively, 24 hours after middle cerebral artery occlusion (MCAO). The neurological function of rats was evaluated with the modified Neurological Severity Scores (mNSS). The infarct volume of brain in rats was determined using 2,3,5-triphenyltetrazolium chloride (TTC) stain at 14 days. GFAP and pGSK3beta expression of ischemic penumbra was determined using immunohistochemical method. GFAP, pAKT, AKT, and pGSK3beta expressions were determined with Western blot. RESULTS: Functional improvement was accelerated in animals receiving BMSC-Ad, while improvement at all times between 7 days and 28 days post MCAO was significantly greater in animals transplanted with BMSC-Ad-VEGF than for other treated animals. The number of GFAP-labeled cells was prevented by post-ischemic BMSC-Ad-VEGF treatment; pMCAO activate the PI3K/AKT/GSK3beta pathway to reduce reactive gliosis. CONCLUSION: Our findings demonstrate that PI3K/AKT/GSK3beta pathway could reduce reactive gliosis, ameliorate neurological deficit, diminish the percentage of cerebral infarction volume in rats, and facilitate angiogenesis. PMID- 26768864 TI - Three Dimensional Microanatomy of the Ophthalmic Artery: Spontaneous Intracranial Extracranial Anastomosis Site within the Orbital Cavity. AB - AIM: The aim was to evaluate three-dimensional structure of the ophthalmic artery (OphA). MATERIAL AND METHODS: The raw data of the Three-dimensional Computerized Tomography Angiography (3D-CTA) were transferred to computer and recorded in a software program. RESULTS: The study group consisted of 45 (24 female and 21 male) patients. The mean age of the patients was 56 +/- 9.5 years. It was found that the entry point of the OphA to the orbital cavity was inferior to the optic foramen in 29 (64.44%) of the cases. The length of the postcanalicular prelacrimal was 0.54 +/- 0.13 centimeters at the right side and 0.51 +/- 0.13 centimeters at the left side. The distance of the postlacrimal-presupraorbital segment was 0.43 +/- 0.11 centimeters at the right and left sides. The location of the anastomosing site was 0.97 +/- 0.42 centimeters from the supraorbital notch. CONCLUSION: The results of this study showed us that this technique could be used in the evaluation of the three-dimensional microsurgical anatomy of the OphA and its critical extracranial-intracranial anastomosing site. PMID- 26768865 TI - Operative Management of Intraventricular Central Neurocytomas: An Analysis of a Surgical Experience with 32 Cases. AB - AIM: To better understand the clinical characteristics of central neurocytoma (CN), as well as to assess the optimum therapeutic schedule. MATERIAL AND METHODS: This was a retrospective study of 32 patients with CN who visited our department between January 2008 and January 2013. We analyzed the clinical and radiological presentations, tumor characteristics, surgical strategies, and the prognosis. RESULTS: We performed operation guided by combined intraoperative magnetic resonance imaging (iMRI) and neuronavigation in 25 patients. The iMRI detected residual tumor in 9 cases, and further resection was performed in 5 cases. Total and nearly total tumor resection was achieved in 29 cases (91%). There was no significant difference between transcortical and transcallosal approaches in complications. Two cases (6%) with recurrence received respectively repeat salvage surgery and radiosurgery at 46 and 50 months after surgery. Thirty patients (94%) had excellent functional outcome (Karnofsky Performance Score >=80) and 28 patients (88%) resumed their occupations. CONCLUSION: Our study demonstrates radical surgery with excellent neurological outcomes is the primary treatment of CN. The techniques of resection guided by combined iMRI and neuronavigation seems to enable a higher complete resection rate and reduce the morbidity rate during surgery. We suggest careful clinical observation after initial surgery, and repeat salvage surgery or radiosurgery for recurrent CN. PMID- 26768866 TI - Microsurgical Outcomes of Secondary Epilepsy from Hippocampal Lesions: A Report of 56 Cases and Literature Review. AB - AIM: To explore the treatment efficacy of microsurgery for secondary epilepsy from hippocampal lesions. MATERIAL AND METHODS: The clinical data, pathological findings, surgical methods and surgical outcomes of 56 patients with secondary epilepsy from hippocampal lesions were retrospectively analyzed. RESULTS: Postoperative pathological examinations confirmed that 27 patients had gliomas, 17 patients had vascular malformations and 12 patients had hippocampal sclerosis. Twenty-nine patients underwent selective resection of the lesioned tissue and the surrounding infiltrated tissue, and 26 patients underwent a more generous removal of the anterior temporal lobe, lesioned tissue, infiltrated tissue and medial structures of the temporal lobe. Fifty patients were followed up with an average follow-up duration of 25.5 months. At postoperative one year, the remission rate of epilepsy that achieved Engel grade I was 80.8% (21/26) and 83.3% (20/24) for the selective resection and more generous resection, respectively, indicating that the difference between the two methods was insignificant. CONCLUSION: Microsurgery is the first choice for the treatment of secondary epilepsy from hippocampal lesions. Various operative routes and methods can be selected based on the lesion natures. Long-term favorable outcome of seizure control following microsurgery can be achieved in most of the patients. PMID- 26768867 TI - Surgery for Pyogenic Brain Abscess over 30 Years: Evaluation of the Roles of Aspiration and Craniotomy. AB - AIM: To evaluate the roles of craniotomy and aspiration in the treatment of pyogenic brain abscess throughout 30 years of computerized tomography. MATERIAL AND METHODS: A retrospective study of 224 patients who were surgically treated at Istanbul Medical Faculty, Department of Neurosurgery between 1982 and 2012 was undertaken. The records were analyzed for demographic, clinical and radiological findings, surgical interventions (resection, free-hand aspiration and image guided aspiration), data regarding abscesses (etiological factors, site, size, number, localization and identified microorganism), corticosteroid and antibiotic usage and complications, and the outcomes were reviewed. RESULTS: The male-to female ratio was 2.2, and the mean age was 26.2+/-1.25 years. The most common presenting symptom was headache (56.7%), followed by nausea and vomiting (28.5%). Otitis media and mastoiditis were the most common causes of abscess (41.9%), and 44 patients had multiple abscesses. Aerobic gram-positive microorganisms were the most frequently isolated pathogens in culture (51.5%). Primary surgical interventions were as follows: craniotomy and resection (38.8%), free-hand aspiration (49.1%) and image-guided aspiration (12.1%). The aspiration-to resection ratio was 1.36 (64/47) in the first decade, 2.94 (50/17) in the second decade and 1 (23/23) in the last decade. Age, level of consciousness at the time of admission and potent corticosteroid usage were found to be significantly associated with mortality (p=0.001, p<=0.001 and p=0,038, respectively). The total morbidity and mortality ratios were 4.9% and 9.8%, respectively. Seizures were more common in patients of craniotomy group (p=0.023). CONCLUSION: Treatment of pyogenic brain abscess remains challenging, despite advances in surgical and imaging technology, and craniotomy retains a significant role in surgical treatment. PMID- 26768868 TI - Microsurgical Treatment of Tuberculum Sellae Meningiomas with Visual Impairments: A Chinese Experience of 56 Cases. AB - AIM: Tuberculum sellae meningiomas (TSMs) are suprasellar lesions that commonly extend to the medial side of the optic nerve, resulting in visual impairments in the affected eye as the initial and most common symptoms. The primary goal of surgical treatment for TSM is the preservation or improvement of visual function. The aim of the present study was to assess the clinical outcomes of TSMs treated with microsurgery at our center. MATERIAL AND METHODS: A retrospective analysis was performed on 56 patients with TSMs associated with visual impairments who visited our neurosurgery center between January 2008 and January 2012. These patients underwent microsurgery using the unilateral subfrontal approach (n=22), the lateral frontal base approach (n=28), or the frontotemporal approach (n=6). Outcomes were complete tumor removal, improvements of visual impairments and survival to the surgery. After surgery, patients were classified according to Simpson classification: Grade I in 22 cases, grade II in 28 cases, and grade IV in 6 cases. RESULTS: Postoperatively, visual impairments were improved in 47 cases, unchanged in 7 cases, and worsened in 2 cases. There was no patient's death. CONCLUSION: TSMs are operated in China with favorable outcomes. PMID- 26768869 TI - The Anatomy of Circulus Arteriosus Cerebri (Circle of Willis): A Study in Turkish Population. AB - AIM: The function of the circle of Willis, an arterial polygon, is to protect the brain from ischemia. The aim of this study is to define the structural characteristics of the circle of Willis within the Turkish adult population, along with variations and arteries involved in the measurement of diameters and lengths on cadavers. MATERIAL AND METHODS: The circle of Willis was evaluated in 100 fresh adult cadavers. Structures of the circle of Willis were evaluated as being typical or atypical images and according to the diameter of AComP. All arteries forming the circle's length and diameters were measured. RESULTS: All arteries forming the circle of Willis as 91% were anatomically observed. The typical structure in which hypoplasia arteries is not involved was obtained as 8%. The atypical circle of Willis with aplasia was seen as 9%. 87% of adult, 9% fetal, and 4% transitional configuration in the samples were detected. The variations of the circle of Willis were more common in the posterior portion. Hypoplasia was found to be the most common variation and noted as a maximum in AComP (85%). Aplasia was noted as the second most common variation after hypoplasia and again the most common in AComP (5%). CONCLUSION: Advances in radiological methods which provide images of cerebral vessels and the development of cerebrovascular surgery have increased the importance of the circle of Willis in neurosurgery and neurology. The structure of the circle of Willis is of great importance in occlusive cerebrovascular diseases and cerebrovascular surgery. PMID- 26768870 TI - Single Operation with Simplified Incisions to Build an Experimental Cerebral Aneurysm Model by Induced Hemodynamic Stress and Estrogen Deficiency in Rats. AB - AIM: To implement a surgical technique consisting of simplified incisions that allows all required procedures to be performed in one single operation for the purpose of reducing surgical stress in experimental animals. MATERIAL AND METHODS: Experimental animals (rats) were assigned to one of four groups: Group 0 was the (normal) control group, Group 1 consisted of rats that had an operation using multiple incisions, Group 2 consisted of rats who received a midline incision and were raised for 3 months, and Group 3 consisted of rats who also received a midline incision, but had been raised for 6 months. Rat blood pressure was measured by tail cuff method. The surgical characteristics and outcomes of the rats in Groups 1 and 2 were compared. Aneurysmal lesions of both branching and non-branching sites were compared amongst the 4 groups by observation of the cerebral vascular corrosion casts through a scanning electron microscope. Histological analyses of the induced aneurysms were performed. RESULTS: The simplified incision technique significantly reduced the length of surgery and need for anesthesia redose during the operation. No aneurysms formed in the normal control rats. The incidence of saccular aneurysm formation significantly increased in Group 3. Histological analyses confirmed the aneurysms induced in the rats shared the same characteristics as human aneurysms. CONCLUSION: Our modified surgical method reduced the surgical stress in rats. It also successfully induced both saccular and fusiform cerebral aneurysms. While longer incubation duration for aneurysm formation could be applied in future researches. PMID- 26768871 TI - Application of the Enterprise Stent in Atherosclerotic Intracranial Arterial Stenosis: A Series of 60 Cases. AB - AIM: We assessed the safety and effectiveness of the Enterprise stent in treating atherosclerotic intracranial arterial stenosis (AIAS). MATERIAL AND METHODS: This was a retrospective study conducted with 60 consecutive patients with 62 AIAS lesions who received the Enterprise stent at the Department of Neurosurgery, Second Hospital of Shandong University between June 2012 and January 2014. All patients were assessed using the modified Rankin scoring system at discharge. Clinical follow-ups and digital subtraction angiography (DSA) were performed at 1, 3, 6 and 12 months postoperatively. RESULTS: There were 42 men and 18 women with a mean age of 56.8 +/- 8.0 years. Fourteen lesions (22.6%) were at the anterior and 48 (77.4 %) were at the posterior circulation. The mean stenosis rate was 76.3 +/- 12.7%. The mean stenotic vessel length was 7.7 +/- 2.0 mm. The technical success rate was 100%. The mean post-stent residual stenosis rate was 22.8 +/- 4.8%. Five patients (8.3%) had perioperative complications, but no disability or mortality occurred within 30 days. The mean follow-up duration was 6.2 months. DSA was used to evaluate 45 lesions (72.6%) six months postoperatively: 6 (13.3%) had postoperative restenoses, 2 at the anterior circulation, and 4 at the posterior circulation. Of these 6, 4 (66.7%) were immediate residual stenoses after stenting. The residual stenosis rate was identified as a risk factor for restenosis. Five (8.3%) ischemic events, consistent with the vascular lesions, occurred. CONCLUSION: Application of the Enterprise stent was safe and efficacious. The technical success rate was high while the perioperative complication rate was low. PMID- 26768872 TI - Predictors of Surgical Results in Patients with Primary Pontine Hemorrhage. AB - AIM: Prediction of outcome for surgical patients with primary pontine hemorrhage (PPH) is seldom reported although many predictors from clinical and radiological features have been identified in conservative patients. The purpose of this study was to assess the prognostic factors affecting the 30-day mortality and 3-month functional outcome in surgical patients after PPH. MATERIAL AND METHODS: Forty five patients with large PPH ( > 5 ml) and Glasgow Coma Scale (GCS) score < 8 were treated surgically at West China Hospital. The demographic, clinical, imaging and follow-up data were collected retrospectively. Factors affecting the mortality and functional outcome were statistically analyzed. RESULTS: Fourteen patients (31.1%) died within 30 days and 7 patients (15.6%) gained a favorable functional recovery within 3 months. A multivariate analysis showed that the hematoma volume, GCS score on admission, age, and type of hemorrhage were all significantly related to the 30-day mortality, while the hematoma volume, GCS score on admission, rostrocaudal extension were associated with the 3-month functional outcome. The presence of hydrocephalus was not found responsible for the surgical outcomes. CONCLUSION: The identification of these prognostic factors is helpful for selecting the candidates for surgical treatment. Those with younger age, smaller hematoma without rostrocaudal extension, unilateral hemorrhage, and higher GCS score may benefit from surgery. PMID- 26768873 TI - Endoscope-Assisted Keyhole Technique for Hypertensive Cerebral Hemorrhage in Elderly Patients: A Randomized Controlled Study in 184 Patients. AB - AIM: Hypertensive cerebral hemorrhage (HCH) is a potentially life-threatening cerebrovascular disease with high mortality. In case of a massive hematoma, surgical drainage is a crucial treatment. The aim of the present study was to assess the efficacy of the endoscope-assisted keyhole technique in elderly patients with intracerebral hematoma who needed a flap craniotomy as traditional treatment. MATERIAL AND METHODS: One hundred-eighty-four elderly patients with HCH, who had craniotomy indications after conservative treatment for 6-24 hours after onset, were randomly divided into two groups. In the craniotomy group, traditional hematoma drainage was performed. In the keyhole group, an endoscope assisted keyhole technique was used. Anesthesia time, blood loss, hematoma drainage rate, and complications were compared. The clinical primary outcome was the six-month efficacy rate (defined by the activities of daily living (ADL) score). RESULTS: Anesthesia time was longer in the craniotomy group (3.43 +/- 0.65 vs. 1.53 +/- 0.52 h, P < 0.01), and blood losses were more important (256 +/ 129 vs. 96 +/- 39 ml P < 0.01). There was no difference in hematoma drainage rate between the two groups (77.25 +/- 13.44 vs. 83.52 +/- 27.51% P > 0.05). Complications, including tracheotomy (P < 0.01), pulmonary infection (P < 0.01) and hypoproteinemia (P < 0.05) were more frequent in the craniotomy group. There was no difference in the occurrence of other complications, including revision surgery digestive tract ulcer and epilepsy. Proportion of patients with good prognosis (ADL I-III) was larger in the keyhole group (P < 0.05). CONCLUSION: In elderly HCH patients with an indication for hematoma drainage, better outcomes were achieved using an endoscope-assisted keyhole technique. PMID- 26768874 TI - Clinical Results of Median Corpectomy in Cervical Spondylotic Patients with Myelopathy. AB - AIM: To determine the factors in choosing the right surgical technique for patients with cervical spondylotic myelopathy. MATERIAL AND METHODS: 60 patients were operated with anterior median corpectomy and anterior fusion for cervical myelopathy in Ankara Ataturk Education and Research Hospital between the years 2006-2011. All data were obtained from patient files retrospectively. Patients were evaluated in the preoperative and early postoperative stages and 45 days after discharge by referring to their neurological examinations, Japanese Orthopaedic Association (JOA) and Nurick scores and radiological findings. RESULTS: The average age of the patients was 53.8 +/- 9.9 years (38-78) and 45 were male (75%) and 15 were female (25%). Diabetics made up 16.7% (n=10) of the group and nondiabetics 83.3% (n=50). Of the nondiabetic patients, the Nurick score on the first month after surgery was statistically lower than the preoperative and after 24 hours Nurick score (p < 0.001). In the patients in the group that had 1 or 2 myelopathic findings, the Nurick score on the first month after surgery was statistically lower than the preoperative and after 24 hours Nurick score (p < 0.001). The JOA score one month after surgery was statistically lower in patients with myelomalacia than in patients without myelomalacia (p=0.002). CONCLUSION: Median corpectomy and anterior fusion technique had better scores in patients that had few and early myelopathic symptoms, no myelomalacia on MRI, and no systemic disease. PMID- 26768875 TI - Effect of Using High-Speed Drill in Anterior Cervical Discectomy and Fusion. AB - AIM: The objective of this study was to investigate the effect of using 2 different surgical techniques (curette or high-speed drill) in anterior cervical discectomy surgery on the healing of cases. MATERIAL AND METHODS: Fifty-four operated cervical disc hernia cases were retrospectively examined in 2 groups. Discectomy and osteophytectomy were carried out in Group A by using a high-speed drill, while a curette was used for group B. Preoperative and postoperative computerized tomography and direct radiography were performed. Cervical disc height, cervical and segmental lordotic angles were calculated. The visual analogue scale and Odom's criteria were used in the assessment of pain and clinical healing. The fusion ratio of both groups was compared. The Mann-Whitney U test was used to compare data from the groups. RESULTS: Satisfactory results were obtained in the groups where high-speed drill and curette were used. Independently from the surgical technique, pain scores were significantly reduced in both groups after surgery. No radiologically significant differences were identified between the two groups within the postoperative period. CONCLUSION: Either high-speed drill or curette can be chosen for the osteophytectomy and discectomy stages of anterior cervical discectomy operations. PMID- 26768877 TI - Demographical Aspects of Central Large Lumbar Disc Herniation. AB - AIM: The purpose of this study was to investigate the risk factors for the development of the central large disc herniations and to compare the demographic data between central mass prolapse and broad-based central disc herniation. MATERIAL AND METHODS: Between 2002 and 2007, 1630 patients underwent surgery and a large disc herniation was the main problem in 59 patients (3.6%). We performed a retrospective analysis of the demographic data of these patients. Magnetic resonance (MR) images were evaluated according to the disc type and level. Variables were evaluated both at baseline and follow-up, with special emphasis on physical job characteristics, sports activities, and MR - based morphologic findings. RESULTS: Central large disc herniation was diagnosed in 59 patients consisting of 41 males and 18 females. The average age was 34.7 years. 36 patients had a central mass prolapse that occupied more than 50% of the spinal canal. Intraoperative observations confirmed that 29 out of 36 central disc prolapse patients (80.5%) had intact posterior longitudinal ligaments. Interestingly, the condition in these 29 patients was found to have a direct relation with age and occupation or other body training sports activities. CONCLUSION: The size of the large central disc herniation, physical activity, age and gender are major factors in the development of disc herniation. PMID- 26768876 TI - Empty Bladed PEEK Cage for Interbody Fusion after Anterior Cervical Discectomy. AB - AIM: Cervical disc herniation (CDH) can be treated using different anterior and posterior methods. Anterior cervical discectomy and fusion (ACDF) is currently gold standard and provides bony fusion and good clinical outcome. Recently many studies reported good clinical and radiological outcomes in cases who underwent anterior cervical discectomy (ACD) and reconstruction with empty cage. This study aimed to review our results after cervical microdiscectomy reconstructed with empty polyether ether ketone (PEEK) cage. MATERIAL AND METHODS: Twenty-five cases with single level CDH who underwent microdiscectomy were included to this study. Reconstruction was performed using empty bladed cervical PEEK cages. Clinical (Visual analogue scale (VAS) and Odom scores) and radiological results (intervertebral disc and foraminal heights, mean cervical spine lordosis angle, and fusion rate) were reviewed one day and one year after surgery. RESULTS: There were 18 males and 7 females, aged between 25 and 54 years (mean: 40.8). Mean neck and arm VAS scores reduced from 2.9 to 1.4, and from 7.2 to 1.8, respectively. Odom scores were found to be 1.6 and 1.4 at 1st day and one year postoperatively, respectively. Subsidence was seen in three cases (12%). There was no significant change in heights of neural foramina and intervertebral discs, and no change in cervical spine lordosis, when compared postoperative 1st day and one year radiographs. Fusion was detected in 92% of cases in one year. CONCLUSION: Bladed cervical cages are safe with almost no risk of dislocation. Empty cages provide acceptable rates of fusion and subsidence. PMID- 26768878 TI - Comparative Biochemical and Motor Function Analysis of Alpha Lipoic Acid and N Acetyl Cysteine Treatment on Rats with Experimental Spinal Cord Injury. AB - AIM: Spinal Cord Injury (SCI) is a devastating health problem both for the patient and the clinician. Numerous treatment modalities have been studied to reverse the effects of spinal cord injury. Herein is reported the effects and the comparison of Alpha Lipoic Acid and N-Acetyl Cysteine on rats with SCI. MATERIAL AND METHODS: 38 adult male Sprague-Dawley rats were randomly divided into 5 groups: only laminectomy, laminectomy and trauma, laminectomy trauma and Alpha Lipoic Acid 100 mg/kg IP administration, laminectomy trauma and N-Acetyl Cysteine 300 mg/kg IP administration, and vehicle group (PEG). The trauma model was the Modified Allen Weight drop method. After the procedure, the rats' motor function was evaluated using the modified Tarlov Scale and consequently they were sacrificed and the spinal cord tissue was analyzed biochemically for inflammation markers. RESULTS: Both Alpha Lipoic Acid and N-Acetyl Cysteine administration after the injury significantly improved the results. There was no statistically significant difference in between the agents. CONCLUSION: Although these agents both proven to be effective in ameliorating the effects of SCI, there was not enough evidence in this research to conclude the benefit of one agent over the other. PMID- 26768879 TI - The Effects of Adipose Tissue-Derived Mesenchymal Stem Cell Transplantation During the Acute and Subacute Phases Following Spinal Cord Injury. AB - AIM: To investigate the effectiveness of rat adipose tissue-derived (rAT) mesenchymal stem cell (MSC) transplantation on the functional restoration and regeneration of spinal cord injury (SCI). MATERIAL AND METHODS: Six of 48 Wistar albino rats were sacrificed to obtain MSCs, and the remaining rats were divided randomly into six groups. SCI was performed using the clip compression method. The control and transplantation groups were injected with physiological saline and a rAT-MSC suspension at the injury sites, respectively. Each animal was evaluated using the Basso, Beattie and Bresnahan (BBB) rating system and sacrificed at 28 days post-injury period (p.i.). The regeneration process was evaluated based on immunostaining against beta3-tubulin, BDNF, CNTF, and CNPase. RESULTS: rAT-MSC transplantation into the SCI site substantially improved the tissue regeneration and functional recovery (p < 0.05). However, the rAT-MSC transplantation at 9 days p.i. was not more efficient on functional recovery than the transplantation immediately after injury. The expression of beta3-tubulin, BDNF and CNTF at the injury site indicated the potential for functional regeneration. CONCLUSION: The adaptive nature of rat-MSCs enabled the remodulation and regeneration of the lesion site, decreasing the importance of transplantation time in the treatment of SCI. PMID- 26768880 TI - The Human Tail: A Simple Skin Appendage or Cutaneous Stigma of an Anomaly? AB - AIM: The human tail is a term to describe skin-covered protrusions in the lumbosacral and coccygeal region, ascribing to the resemblance to the tails in the animals. The first reports dates back to second half of the 19th century, the etiological bases could not been ascertained yet. They are mainly classified as true or pseudo-tails. MATERIAL AND METHODS: Five cases with human tails were diagnosed and managed in our hospital between 2010 and 2014. Their demographic and lesion characteristics are presented. RESULTS: Three of the 5 cases were male patients. The ages ranged between 1 day and 50 years at the time of diagnosis. The patients were diagnosed basically by the external appearance of the lesions without neurological deficits. Detailed examination revealed several associated lesions: two dermal sinus tracts, one tethered spinal cord and one club-foot in one-day preemie. Two patients had true and 3 had pseudo-tails. Four of them underwent surgery but the last one did not accept surgery. Surgery consisted of simple excision of the lesion in 2 patients with true tails and excision and removal of dermal sinus tract and untethering when necessary in the other 2 pseudo-tails. CONCLUSION: The presented study indicated that true human tails are simple skin appendages without any associated spinal anomalies. However, pseudo tails are potentially complex lesions with a high risk of spinal dysraphisms; warranting further diagnostic work-up and more extensive surgical technique if necessary. The key to managing human tails is making a clear distinction between true tails and pseudo-tails. PMID- 26768881 TI - The Outcomes of Late Term Surgical Treatment of Penetrating Peripheral Nerve Injuries. AB - AIM: The aim of this retrospective study was to evaluate the follow-up results of patients who received late-term surgical treatment for peripheral nerve lesions caused by penetrating injuries. MATERIAL AND METHODS: The study included 25 patients who underwent surgery for peripheral nerve injuries in our clinic between 2007 and 2013. The patients were evaluated with respect to age, gender, etiology of the trauma, the affected nerve, clinical examinations, electrophysiological findings, surgical techniques and functional outcomes. RESULTS: The study included 30 nerves of 25 patients (19 male, 6 female; mean age 30.1 years). The mean time between the initial injury and admission to our clinic was 11.5 months (range, 3 to 30 months). Cuts caused by glass were the most common cause of injury (68.5%). The most commonly injured nerves in our patients were the median nerve (43.4%) and ulnar nerve (26.6%). External neurolysis and decompression were performed in eleven patients, epineurotomy and internal neurolysis were performed in eight patients, epineural repair was performed in fourteen patients, fascicular repair was performed in three patients, and interfascicular anastomosis using sural nerve grafting was performed in five patients. Postoperative motor strength and electrophysiological analyses showed significant improvements. Better outcomes were obtained in cases with median nerve injuries rather than other nerve injuries. Additionally, patients undergoing external neurolysis and decompression exhibited better outcomes than those undergoing other surgical approaches. CONCLUSION: Although surgical treatment is recommended as early as possible for peripheral nerve injuries, late term surgical treatments may provide positive outcomes. PMID- 26768883 TI - Gynecomastia and Hyperprolactinemia Secondary to Advanced Allergic Fungal Rhinosinusitis in a Pediatric Patient. AB - Hyperprolactinemia is a rare entity in the pediatric population. The most common causes of hyperprolactinemia include drug use, hypothyroidism and renal insufficiency, though rarely a pituitary or sellar mass is discovered. We present an immunocompetent pediatric patient who presented with gynecomastia and was found to have hyperprolactinemia. Imaging showed a sphenoid mass and referral was made for a pituitary tumor. The mass was not a pituitary tumor and he was formally diagnosed with allergic fungal sinusitis and treated surgically. There are no previous reports of allergic fungal rhinosinusitis causing pituitary dysfunction in a pediatric patient. We also present a brief review and discussion of the treatment of allergic fungal sinusitis. PMID- 26768882 TI - Association of Craniovertebral Junction Anomalies, Klippel-Feil Syndrome, Ruptured Dermoid Cyst and Mirror Movement in One Patient: A Unique Case and Literature Review. AB - The Klippel-Feil syndrome (KFS) has been reported to be associated with intracranial neoplasms, most frequently epidermoid or dermoid cysts. To our knowledge, however, patients who present with a posterior fossa dermoid cyst (DC) and KFS are extremely rare with only 24 previously reported cases in the English literature worldwide. Therefore, we present the first report of a patient with a craniocervical ruptured DC accompanied by craniovertebral junction (CVJ) anomalies, KFS and mirror movement. Meanwhile, a literature review of KFS accompanying with posterior fossa DC discusses these conditions from the embryological, anatomical, clinical and therapeutic perspectives. Additionally, the combination of CVJ anomalies, KFS and DC may represent a new syndrome that has previously gone unnoticed. PMID- 26768884 TI - Biphasic Pulmonary Blastoma Associated with Cerebral Metastasis. AB - Pulmonary blastoma is a very rare malignant tumor of the lungs. A biphasic pulmonary blastoma was histologically diagnosed by a characteristic finding as it was mainly constituted of immature tumor tissue that had both epithelial and mesenchymal components. We present a case of a 68-year-old man with biphasic pulmonary blastoma. The patient underwent cranial metastatectomy and left lung upper lobectomy. Although the tumor was resected, there was rapid metastasis to the cranial, liver, kidney and multiple bones. Although radiotherapy and chemotherapy were administrated, the patient died about 6 months postoperatively. Close follow-up and aggressive chemotherapy should be considered for such tumours. In the light of this case, the authors review the pathologic, clinical, radiological and therapeutic features of this very rare malignant lung tumor. PMID- 26768885 TI - Intracranial Hemangiopericytoma in a Child: A Case Report with Magnetic Resonance Spectroscopy Findings. AB - Hemangiopericytoma is a hypervascular soft tissue sarcoma with a predilection for the extremities. It has two clinical types according to the age of presentation: Infantile hemangiopericytoma ( < 1 years) and adult type hemangiopericytoma ( > 1 years). The intracranial location is very rare and accounts for only 0.4-1% of all primary brain tumors, with only 10% detected in the pediatric age group. The differential diagnosis of this rare tumor from other extra-axial masses plays an important role in proper treatment planning. There are few case reports in adult patients indicating that magnetic resonance spectroscopy (MRS) can play a role in the differential diagnosis. Here, we present imaging findings of this rare tumor, including MRS at 3.0T of an intracranial hemangiopericytoma in a 4.5 year old boy. PMID- 26768886 TI - Temporal Dermoid Cyst with Unusual Imaging Appearance: Case Report. AB - Intracranial dermoid cysts are benign, slow growing tumors derived from ectopic inclusions of epithelial cells during closure of neural tube. These lesions, accounting for less than 1% of intracranial tumors, have characteristic computed tomography (CT) and magnetic resonance imaging (MRI) appearances that generally permits preoperative diagnosis. However, the radiologic features are uncommon and the cyst can be easily misdiagnosed with other tumors in rare cases. Herein, we report a case of a left temporoparietal dermoid cyst in a 48-year-old woman that was peroperatively and histopathologically proven but not advocated on CT and MRI. Clinical, radiological and histopathological features of a dermoid cyst are reviewed. PMID- 26768887 TI - Trigeminal Neuralgia as an Unusual Isolated Symptom of Pituitary Adenoma: Case Report and Review of the Literature. AB - Pituitary adenomas account for approximately 10% of intracranial tumors and 5% are locally invasive. Cavernous sinus invasion by pituitary tumors presents mostly with cranial nerve palsies, especially involving the third, fourth and sixth cranial nerves, which is well documented in the literature. However, an isolated complaint of trigeminal neuralgia due to pituitary adenoma is an extremely rare entity with a limited number of reported cases. A 51-year-old female patient presented to our clinic with complaints of pain and numbness on the left side of face for six months, with each event lasting 5-10 seconds. No improvement was obtained with administration of carbamazepine therapy. Magnetic resonance imaging of the sellar region revealed a mass with the left cavernous sinus invasion. The patient underwent surgery via endoscopic transsphenoidal approach and after than radiosurgery with gamma-knife. The patient's complaints resolved totally after gamma-knife radiosurgery. We report herein a case of pituitary adenoma with an isolated complaint of trigeminal neuralgia. Pituitary adenomas may be presented with cavernous sinus invasion and multiple cranial nerve palsies but isolated trigeminal neuralgia due to pituitary adenoma is an extremely rare entity. PMID- 26768888 TI - Semi-automated quantification of living cells with internalized nanostructures. AB - BACKGROUND: Nanostructures fabricated by different methods have become increasingly important for various applications in biology and medicine, such as agents for medical imaging or cancer therapy. In order to understand their interaction with living cells and their internalization kinetics, several attempts have been made in tagging them. Although methods have been developed to measure the number of nanostructures internalized by the cells, there are only few approaches aimed to measure the number of cells that internalize the nanostructures, and they are usually limited to fixed-cell studies. Flow cytometry can be used for live-cell assays on large populations of cells, however it is a single time point measurement, and does not include any information about cell morphology. To date many of the observations made on internalization events are limited to few time points and cells. RESULTS: In this study, we present a method for quantifying cells with internalized magnetic nanowires (NWs). A machine learning-based computational framework, CellCognition, is adapted and used to classify cells with internalized and no internalized NWs, labeled with the fluorogenic pH-dependent dye pHrodoTM Red, and subsequently to determine the percentage of cells with internalized NWs at different time points. In a "proof of-concept", we performed a study on human colon carcinoma HCT 116 cells and human epithelial cervical cancer HeLa cells interacting with iron (Fe) and nickel (Ni) NWs. CONCLUSIONS: This study reports a novel method for the quantification of cells that internalize a specific type of nanostructures. This approach is suitable for high-throughput and real-time data analysis and has the potential to be used to study the interaction of different types of nanostructures in live cell assays. PMID- 26768889 TI - Advantages and Disadvantages of Prophylactic Abdominal Drainage in Distal Pancreatectomy. AB - BACKGROUND: A method to completely prevent postoperative pancreatic fistula (PF) in distal pancreatectomy (DP) is lacking. Hence, prophylactic abdominal drains could be used to prevent PF from developing into life-threatening complications. METHODS: In 152 consecutive patients undergoing DP, three drains were placed routinely toward the pancreatic stump, supra-pancreatic space, and left subphrenic space. Abdominal drains were removed after surgery gradually based on amylase levels and positivity for bacterial infection in abdominal fluids. RESULTS: Postoperative symptomatic PF occurred in 57 of 152 patients (37.5 %). Prevalence of severe postoperative complications (Clavien-Dindo grade >= IIIa) was 16 %, with surgery-associated mortality observed in one patient (0.7 %). Prevalence of infection in drained abdominal fluids increased gradually and was >10 % on postoperative day (POD)-7. Severe postoperative complications led to longer postoperative hospital stays and higher treatment costs. Multivariate analyses revealed that a body mass index >= 25 kg/m(2), serum albumin level <= 3.8 g/dL, and white blood cell count at POD-3 >= 15,000/MUL were independent predictors for development of severe postoperative complications. CONCLUSION: Use of prophylactic abdominal drains in DP seems to be effective for preventing PF from developing into fatal complications. However, definitive criteria should be established for enhancing safety and cost efficiency of DP through selective use and early removal of prophylactic drains. PMID- 26768890 TI - Patient preference in psychological treatment and associations with self-reported outcome: national cross-sectional survey in England and Wales. AB - BACKGROUND: Providers of psychological therapies are encouraged to offer patients choice about their treatment, but there is very little information about what preferences people have or the impact that meeting these has on treatment outcomes. METHOD: Cross-sectional survey of people receiving psychological treatment from 184 NHS services in England and Wales. 14,587 respondents were asked about treatment preferences and the extent to which these were met by their service. They were also asked to rate the extent to which therapy helped them cope with their difficulties. RESULTS: Most patients (12,549-86.0 %, 95 % CI: 85.5-86.6) expressed a preference for at least one aspect of their treatment. Of these, 4,600 (36.7 %, 95 % CI: 35.8-37.5) had at least one preference that was not met. While most patients reported that their preference for appointment times, venue and type of treatment were met, only 1,769 (40.5 %) of the 4,253 that had a preference for gender had it met. People who expressed a preference that was not met reported poorer outcomes than those with a preference that was met (Odds Ratios: appointment times = 0.29, venue = 0.32, treatment type = 0.16, therapist gender = 0.32, language in which treatment was delivered = 0.40). CONCLUSIONS: Most patients who took part in this survey had preferences about their treatment. People who reported preferences that were not met were less likely to state that treatment had helped them with their problems. Routinely assessing and meeting patient preferences may improve the outcomes of psychological treatment. PMID- 26768891 TI - Heterogeneity of intrahepatic fat distribution determined by (18)F-FDG PET and CT. AB - OBJECTIVES: Hepatic steatosis is common but less is known of the heterogeneity of hepatic fat distribution and its clinical significance. Our objective was to measure the regional variabilities within the liver of standardised uptake values (SUV) as potential markers of hepatic fat distribution heterogeneity. METHODS: Twenty-four patients having routine, clinically indicated PET/CT with (18)F-FDG and a wide range of fatty liver severity were selected. Maximum SUV (SUVmax), average SUV (SUVave), both calculated using lean body mass, and CT density were measured in 12 * 2-cm diameter ROIs in each patient. SUVave was also measured over the left ventricular cavity (SUVLV). Mean values of SUV indices, their ratios with SUVLV, and CT density in the 12 ROIs were calculated. Regional variabilities of SUV indices were expressed as coefficients of variation (CV; standard deviation/mean). Body mass index (BMI) was estimated from height and body weight, and %body fat and lean body mass from height, weight and gender. RESULTS: Mean SUVmax/SUVave correlated significantly with mean CT density (r = 0.51; p < 0.02). In contrast, mean SUVmax, mean SUVave and their ratios with SUVLV showed no correlation with CT density. Mean CT density correlated with weight (r = -0.59; p < 0.005), BMI (r = -0.57; p < 0.01) and %body fat (r = 0.49; p < 0.02). Corresponding correlation coefficients for mean SUVmax/SUVave were 0.74 (p < 0.001), 0.65 (p < 0.001) and 0.46 (p < 0.03). In contrast, mean SUVmax, mean SUVave and their ratios with SUVLV showed no correlation with BMI, weight and %body fat. The CV of SUVmax/SUVave (r = -0.67; p < 0.001), but not the CVs of SUVmax or SUVave, correlated with mean CT density. CONCLUSIONS: SUVmax/SUVave and CT density are markers of hepatic steatosis. The regional variability of SUVmax/SUVave may be a marker of hepatic fat distribution heterogeneity. The novel concept is introduced that hepatic fat distribution heterogeneity may be a marker of hepatic pathology and of clinical value, and deserves further exploration with texture analysis. PMID- 26768892 TI - Is off-label repeat prescription of ketamine as a rapid antidepressant safe? Controversies, ethical concerns, and legal implications. AB - BACKGROUND: Depressive disorders are a common form of psychiatric illness and cause significant disability. Regulation authorities, the medical profession and the public require high safety standards for antidepressants to protect vulnerable psychiatric patients. Ketamine is a dissociative anaesthetic and a derivative of a hallucinogen (phencyclidine). Its abuse is a major worldwide public health problem. Ketamine is a scheduled drug and its usage is restricted due to its abuse liability. Recent clinical trials have reported that ketamine use led to rapid antidepressant effects in patients suffering from treatment resistant depression. However, various flaws in study designs, and possible biased reporting of results, may have influenced those findings. Further analyses of ketamine use are needed to ensure patient safety. DISCUSSION: The use of ketamine in research and treatment of depressive disorders is controversial. Recently, mental health professionals raised ethical concerns about an ongoing ketamine trial in the UK. Also, a Canadian agency reviewed the existing evidence and did not recommend prescribing ketamine to treat depressive disorders. Findings obtained from tightly controlled research settings cannot be easily translated to clinical practice as substance abuse is commonly comorbid with depressive disorders. An effective antidepressant should reduce severity of depressive symptoms without liability problems. Although the US FDA has not approved the use of ketamine to treat depressive disorders, some psychiatrists offer off-label repeat prescription of ketamine. Prescribing ketamine for treating depressive disorders requires substantial empirical evidence. Clinicians should also consider research findings on ketamine abuse. Depressive disorders can be chronic conditions and the current evidence does not rule out the risk of substance abuse after repeat prescription of ketamine. Off-label ketamine use in treating depressive disorders may breach ethical and moral standards, especially in countries seriously affected by ketamine abuse. This article presents two real world clinical vignettes which highlight ethical principles and theories, including autonomy, nonmaleficience, fidelity and consequentialism, as related to off-label ketamine use. CONCLUSION: We urge clinicians to minimise the risk of harming patients by considering the empirical evidence on ketamine properties and attempting all standard antidepressant therapies before considering the off-label use of ketamine. PMID- 26768893 TI - Epidemiological characteristics and clinicopathological features of bluetongue in sheep and cattle, during the 2014 BTV serotype 4 incursion in Greece. AB - During 2014, an outbreak of Bluetongue virus (BTV) infections attributed to serotype 4 occurred in Greece and spread to south-eastern Europe. In the present article, the clinical and epidemiological data of 15 sheep flocks and 5 dairy cattle herds affected in Greece are described. In sheep, the most frequent clinical signs observed were fever, hyporexia, and edema of the face. A number of clinically affected sheep had chronic laminitis resulting in chronic lameness. Confirmation of suspect clinical cases was performed using BTV-specific real-time RT-PCR, and serotype 4-specific RT-PCR. The average morbidity of bluetongue in the sheep flocks was estimated to be 15.3 % (95 % C.I. 6.8-23.8 %) and the average mortality and case fatality were 4.5 % (95 % C.I. 1.5-7.6 %) and 32.0 % (95 % C.I. 18.1-42.9 %), respectively. The BTV seroprevalence and the ratio of clinical manifestations-to-infections determined in seven of these flocks, were on average 36.5 % (95 % C.I. 15.7-57.3 %) and 24.6 % (95 % C.I. 12.8-36.3 %). BTV ratio of clinical manifestations-to-infections was higher in the imported western European sheep breeds examined compared to the local ones. In dairy cattle, the average herd prevalence of viremia was 48.8 % (95 % C.I. 15.3-82.4 %) and none had signs associated with bluetongue. The results of this study indicate that the 2014 Greek BTV-4 has significant impact on the health status and the viability of sheep in affected flocks but does not cause clinical signs in cattle, despite the high prevalence of viremia. PMID- 26768894 TI - Performance, nitrogen balance and microbial efficiency of beef cattle under concentrate supplementation strategies in intensive management of a tropical pasture. AB - The objective of this study was to evaluate the effect of concentrate supplementation strategies on the nutritional characteristics of beef cattle in intensive management of tropical pasture. Twenty-four Nellore steer at 250 kg body weight (BW) were used, divided into two plots, with 12 animals in each plot. The experimental area consisted of 32 paddocks with 0.25 ha of Panicum maximum cv. Mombaca. The experiment consisted of 96-day experimental periods, with three periods of 32 days. The strategies studied were P = exclusively on pasture and without concentrate supplementation (control), ES = pasture and supplemented with a concentrate low in protein, PS = pasture and supplemented with high protein content, and PES = pasture and supplementation with balanced protein-energy. There was reduced intake of DM in animals of the treatment P in relation to supplemented pasture, regardless of supplementation. Animals fed on ES showed an intake of more nutrients than the animals on PS. The CP and TDN were also lower in P than in pastures where animals received the additional types of concentrate, and the PS animals showed greater digestibility of CP and TDN than the ES animals. However, the animals exhibited similar weight gains. Animals on P ingested smaller amounts of N and had lower fecal excretion compared to the supplemented animals, but there was no difference between treatments in nitrogen balance. Urea nitrogen and urea from the blood were higher in the supplemented animals than in animals fed on pasture; these levels were also higher in PS animals compared to animals receiving ES. Both the purines absorbed and microbial protein production were similar between treatments. However, the animals fed with concentrate supplementation, independent of the strategy involved, showed higher microbial efficiency compared to animals fed exclusively on pasture. PMID- 26768895 TI - Spiritual Exploration in the Prenatal Genetic Counseling Session. AB - Religion and spirituality (R/S) are important components of many individuals' lives, and spirituality is often employed by women coping with pregnancy complications. To characterize how prenatal genetic counselors might address spiritual issues with patients, 283 English and Spanish speaking women receiving prenatal genetic counseling in Houston, Texas were surveyed post-counseling using both the Brief RCope and questions regarding interest in spiritual exploration. Genetic counselors were concurrently surveyed to identify religious/spiritual language used within sessions and perceived importance of R/S. Genetic counselors were significantly more likely to identify R/S as important to a patient when patients used religious/spiritual language (p < 0.001). Conversely, when no religious/spiritual terms were present, the counselor felt uncertain about the importance of R/S 63 % of the time. However, 67 % of patients reported that they felt comfortable sharing their faith as it relates to their pregnancy, and 93 % reported using positive religious coping. Less than 25 % reported a desire for overt religious actions such as prayer or scripture exploration. Therefore, most patients' desires for spiritual exploration center in the decision making and coping processes that are in line with the genetic counseling scope of practice. Thus, counselors should feel empowered to incorporate spiritual exploration into their patient conversations. PMID- 26768896 TI - Ravages of Diabetes on Gastrointestinal Sensory-Motor Function: Implications for Pathophysiology and Treatment. AB - Symptoms related to functional and sensory abnormalities are frequently encountered in patients with diabetes mellitus. Most symptoms are associated with impaired gastric and intestinal function. In this review, we discuss basic concepts of sensory-motor dysfunction and how they relate to clinical findings and gastrointestinal abnormalities that are commonly seen in diabetes. In addition, we review techniques that are available for investigating the autonomic nervous system, neuroimaging and neurophysiology of sensory-motor function. Such technological advances, while not readily available in the clinical setting, may facilitate stratification and individualization of therapy in diabetic patients in the future. Unraveling the structural, mechanical, and sensory remodeling in diabetes disease is based on a multidisciplinary approach that can bridge the knowledge from a variety of scientific disciplines. The final goal is to increase the understanding of the damage to GI structures and to sensory processing of symptoms, in order to assist clinicians with developing an optimal mechanics based treatment. PMID- 26768897 TI - Assessing Upper Esophageal Sphincter Function in Clinical Practice: a Primer. AB - The upper esophageal sphincter constitutes an important anatomic and functional landmark in the physiology of pharyngeal swallowing. A variety of clinical circumstances may call for a dedicated evaluation of this mechanism, from the etiologic evaluation of indeterminate symptoms to the generation of complex locoregional therapeutic strategies. Multiple diagnostic tools exist for the assessment of pharyngeal swallowing generally and of upper esophageal sphincter function specifically, some well established and others not yet settled into routine practice. This report reviews five specific modalities for use in making this assessment, outlining the strengths, weaknesses, and logistical considerations of each with respect to its potential use in clinical settings. In many cases, these studies will provide complementary information regarding pharyngeal function, suggesting the relative advantage of a multimodal evaluation. PMID- 26768898 TI - Blood transfusion, colloid therapy and the possible saving of albumin volumes during surgery: data analysis of the survey for certified hospitals of the Japanese Society of Anesthesiologists. AB - PURPOSE: Third-generation hydroxyethyl starch (HES) 130/0.4 has a larger dose limitation (up to 50 mL/kg/day) than HES 70/0.5 (up to 1000 mL/day) which has been used in Japan for 40 years. The aim of this study was to survey the current intraoperative blood transfusion and volume therapy and to predict the possible reduction of intraoperative albumin consumption assuming further replacement by HES 130/0.4 using data obtained from a survey by the Japanese Society of Anesthesiologists (JSA), although HES130/0.4 was not launched in Japan during this survey period. METHODS: In a JSA survey conducted at JSA-certified hospitals, 12,856 patients with a certain amount of blood loss were analyzed for 1 month (April, 2012). The patients were divided into two groups-group A included patients aged >=11 years and group B included patients aged <10 years. The possible lower volume of intraoperative albumin was calculated assuming that HES 130/0.4 was used up to a dose of 50 mL/kg. RESULTS: Blood loss (total 15,111 L; 15,057 L in group A and 54 L in group B) was treated with allogeneic transfusion (total 7970 L; 7893 L in group A and 77 L in group B) and auto-transfusion (total 1777 L; 1771 L in group A and 6 L in group B) in both groups (n = 11,670 and 119). Albumin (total 1391 L; 1376 L in group A and 15 L in group B), and HES 70/0.5 (total 7645 L; 7638 L in group A and 7 L in group B) were used in both groups (n = 10,850 and 116). Five percent and 4.4 % albumin (total 1189 L; 1180 L in group A and 9 L in group B) could be replaced by HES 130/0.4 if HES 130/0.4 had been used up to a dose of 50 mL/kg. CONCLUSION: Blood loss (15,111 L) was replaced with allogeneic transfusion (53 %), auto-transfusion (12 %), albumin (9 %) and HES 70/0.5 (51 %) during surgery in April 2012. The predicted volume of 5 and 4.4 % albumin saved during this 1-month period if HES 130/0.4 had been used up to a dose of 50 mL/kg was 1189 L (86 % of actual amount used). PMID- 26768899 TI - Urbanisation and greening of Indian cities: Problems, practices, and policies. AB - Progress of the Indian economy is threatened by the impact of climate change. Generation of urban heat islands (UHIs), waning of urban green cover, increase in carbon emissions and air pollution deteriorate the living environment. Rise in urban temperatures and heat stress induced mortality remain major concerns. Although the National Action Plan on Climate Change emphasises the national missions of 'enhanced energy efficiency', and 'green India', little research has been devoted to explore the passive cooling potential of urban greenery in India, thus lending uniqueness to this study. The manifestations of unplanned urban development (UHIs, escalated carbon emissions, air pollution) are discussed and corroborated with identification of contributory factors. Contemporary greening practices and bye-laws in four major Indian cities (New Delhi, Pune, Chennai, and Visakhapatnam) are analysed and compared with global best practices. The findings are used to propose planning guidelines which are expected to assist in consolidating natural sustainability of emerging economies. PMID- 26768900 TI - Management of pyometra after LeFort colpocleisis resistant to drainage. PMID- 26768902 TI - Sudden death of a child due to respiratory diphtheria. AB - A four-year-old girl presented to the emergency department with respiratory distress. Death occurred despite attempted resuscitation. The illness was not clinically diagnosed. Her father revealed that she had a fever and sore throat for the last four days and was not immunised for diphtheria. Characteristic gross and microscopic pathology of respiratory diphtheria and microbiological findings were observed. The cause of death was acute respiratory failure consequent upon upper airway obstruction from diphtheria. Forensic pathologists should remember that the diphtheria cases can cause sudden death especially in developing countries. PMID- 26768903 TI - Self-assembly of three-dimensional ensembles of magnetic particles with laterally shifted dipoles. AB - We consider a model of colloidal spherical particles carrying a permanent dipole moment which is laterally shifted out of the particles' geometrical centres, i.e. the dipole vector is oriented perpendicular to the radius of the particles. Varying the shift delta from the centre, we analyse ground state structures for two, three and four hard spheres, using a simulated annealing procedure. We also compare earlier ground state results. We then consider a bulk system at finite temperatures and different densities. Using molecular dynamics simulations, we examine the equilibrium self-assembly properties for several shifts. Our results show that the shift of the dipole moment has a crucial impact on both the ground state configurations as well as the self-assembled structures at finite temperatures. PMID- 26768901 TI - Type VI secretion systems of human gut Bacteroidales segregate into three genetic architectures, two of which are contained on mobile genetic elements. AB - BACKGROUND: Type VI secretion systems (T6SSs) are contact-dependent antagonistic systems employed by Gram negative bacteria to intoxicate other bacteria or eukaryotic cells. T6SSs were recently discovered in a few Bacteroidetes strains, thereby extending the presence of these systems beyond Proteobacteria. The present study was designed to analyze in a global nature the diversity, abundance, and properties of T6SSs in the Bacteroidales, the most predominant Gram negative bacterial order of the human gut. RESULTS: By performing extensive bioinformatics analyses and creating hidden Markov models for Bacteroidales Tss proteins, we identified 130 T6SS loci in 205 human gut Bacteroidales genomes. Of the 13 core T6SS proteins of Proteobacteria, human gut Bacteroidales T6SS loci encode orthologs of nine, and an additional five other core proteins not present in Proteobacterial T6SSs. The Bacteroidales T6SS loci segregate into three distinct genetic architectures with extensive DNA identity between loci of a given genetic architecture. We found that divergent DNA regions of a genetic architecture encode numerous types of effector and immunity proteins and likely include new classes of these proteins. TheT6SS loci of genetic architecture 1 are contained on highly similar integrative conjugative elements (ICEs), as are the T6SS loci of genetic architecture 2, whereas the T6SS loci of genetic architecture 3 are not and are confined to Bacteroides fragilis. Using collections of co-resident Bacteroidales strains from human subjects, we provide evidence for the transfer of genetic architecture 1 T6SS loci among co-resident Bacteroidales species in the human gut. However, we also found that established ecosystems can harbor strains with distinct T6SS of all genetic architectures. CONCLUSIONS: This is the first study to comprehensively analyze of the presence and diversity of T6SS loci within an order of bacteria and to analyze T6SSs of bacteria from a natural community. These studies demonstrate that more than half of our gut Bacteroidales, equivalent to about 1/4 of the bacteria of this ecosystem, encode T6SSs. The data reveal several novel properties of these systems and suggest that antagonism between or distributed defense among these abundant intestinal bacteria may be common in established human gut communities. PMID- 26768905 TI - Writing within an international context. AB - For Health Information and Libraries Journal, 2015 has had a distinctly international feel to it, something we have consciously been fostering for the past eight years. This issue is no exception in mirroring the journal's Regular Feature International Perspectives and Initiatives, edited by Jeannette Murphy, in shining a light on the best international practice the health information and libraries sector has to offer. PMID- 26768904 TI - Temporal patterns of change in vital signs and Cardiac Arrest Risk Triage scores over the 48 hours preceding fatal in-hospital cardiac arrest. AB - AIM: To determine temporal patterns of vital sign and Cardiac Arrest Risk Triage score changes over the 48-hour period preceding cardiac arrest in an ICU setting. BACKGROUND: Vital sign instability usually occurs prior to cardiac arrest. However, few studies have been conducted on the temporal patterns of individual vital signs preceding cardiac arrest. DESIGN: A retrospective case-control study. METHODS: The study subjects were 140 ICU patients (1 June 2011-31 December 2012): 46 died of cardiac arrest (case group), 45 died of other illnesses (control I group) and 49 were discharged after recovering (control II group). RESULTS: Initial detectable changes in blood pressure appeared 18-20 hours and became dramatic at 5-10 hours before cardiac arrest. Noticeable changes in heart rates began at 4 hours and became more prominent at 2 hours pre-arrest. No apparent patterns in respiratory rate changes were observed. Body temperatures usually indicated a hypothermic state pre-arrest. Cardiac Arrest Risk Triage scores were 16-18 at 48 hours pre-arrest and then continuously increased to 20. Only mean values of systolic blood pressures were significantly different between the three study groups. Mean diastolic blood pressures, heart rates, respiratory rates and Cardiac Arrest Risk Triage scores differed between the case and control II groups and between the control I and II groups. CONCLUSION: The study demonstrates vital sign instability preceded cardiac arrest and that the temporal patterns of changes in individual vital signs and Cardiac Arrest Risk Triage scores differed between groups. The findings of this study may aid the development of management strategies for cardiac arrest. PMID- 26768906 TI - Addressing Library Anxiety (LA) in student nurses: a study in an NHS Foundation Trust Hospital library and information service. AB - Library anxiety is a concept which has been recognised in academic library circles since the early 1990s. It can result in students actively avoiding the library for the duration of their studies. Madeleine Still is Trust Librarian at North Tees & Hartlepool NHS Foundation Trust and while studying for an MSc, recognised that some student nurses were exhibiting signs of library anxiety. She decided to make it the focus of her MSc dissertation, and this article discusses her research project as well as highlighting the measures she has taken to address the issues she uncovered. Madeleine graduated in July 2013 with an MSc in Information & Library Studies from Robert Gordon University. PMID- 26768907 TI - International trends in health science librarianship part 17: a comparison of health science libraries with academic and research libraries. AB - Over the last 4 years this Regular Feature has looked at trends in health science librarianship in the 21st century. Although there are still a few more regions to be covered in this series, this issue explores general trends in academic and research libraries with a view to discovering whether the trends identified for health science libraries are similar. Are health science libraries unique? Or do their experiences mirror those found in the wider world of academic and research libraries? PMID- 26768908 TI - Preparing students for research: faculty/librarian collaboration in a pre doctoral physical therapy research course. AB - In this article, guest writers Susan Bigelow and Dr Salome Brooks from Springfield College, Massachusetts, present an overview of their evaluative research study in which a faculty professor and the liaison librarian collaborated to develop an information literacy course entitled Physical Therapy (PT) and Health care Research Skills, in order to teach necessary information literacy skills to upper-level undergraduate PT students. Triangulation of the Physical Therapy and Information Literacy standards in alignment with the course objectives strengthened the collaboration, course development and expectations of student performance. Student performance was assessed through formal and expected evaluative means, and the preliminary evidence suggests some key successes in the course outcomes. PMID- 26768909 TI - David Lawrence Sackett (born 17 November 1934; died 13 May 2015). PMID- 26768912 TI - From the Editors. PMID- 26768911 TI - Daily music exposure dose and hearing problems using personal listening devices in adolescents and young adults: A systematic review. AB - OBJECTIVE: This systematic review aimed to explore the evidence on whether the preferred listening levels (PLLs) and durations of music listening through personal listening devices (PLDs) in adolescents and young adults exceed the current recommended 100% daily noise dose; together with the impact on hearing and possible influential factors of such listening behaviours. DESIGN: A systematic search was conducted using multiple online bibliographic databases. STUDY SAMPLE: The 26 studies were included on the basis of the inclusion and exclusion criteria. RESULTS: The results showed that up to 58.2% of participants exceeded the 100% daily noise dose, particularly in the presence of background noise. Significantly positive correlations were found among background noise levels and mean PLLs, as well as the proportion of participants exceeding the 100% daily noise dose. Moreover, significantly worse hearing thresholds were found in PLD users using audiometry, and significantly poor results in otoacoustic emission (OAE), even in the participants with self-reported 'normal hearing'. CONCLUSION: It is crucial to develop appropriate standards and safe recommendations for daily music exposure dose in future studies. Providing an essential guide and effective education to adolescents and young adults will help raise awareness, increase knowledge, and consequently change attitudes and listening habits. PMID- 26768914 TI - Secretion of wound healing mediators by single and bi-layer skin substitutes. AB - Limitations of current treatments for skin loss caused by major injuries leads to the use of skin substitutes. It is assumed that secretion of wound healing mediators by these skin substitutes plays a role in treating skin loss. In our previous study, single layer keratinocytes (SK), single layer fibroblast (SF) and bilayer (BL; containing keratinocytes and fibroblasts layers) skin substitutes were fabricated using fibrin that had shown potential to heal wounds in preclinical studies. This study aimed to quantify the secretion of wound healing mediators, and compare between single and bi-layer skin substitutes. Skin samples were digested to harvest fibroblasts and keratinocytes, and expanded to obtain sufficient cells for the construction of skin substitutes. Acellular fibrin (AF) construct was used as control. Substitutes i.e. AF, SK, SF and BL were cultured for 2 days, and culture supernatant was collected to analyze secretion of wound healing mediators via multiplex ELISA. Among 19 wound healing mediators tested, BL substitute secreted significantly higher amounts of CXCL1 and GCSF compared to SF and AF substitute but this was not significant with respect to SK substitute. The BL substitute also secreted significantly higher amounts of CXCL5 and IL-6 compared to other substitutes. In contrast, the SK substitute secreted significantly higher amounts of VCAM-1 compared to other substitutes. However, all three skin substitutes also secreted CCL2, CCL5, CCL11, GM-CSF, IL8, IL 1alpha, TNF-alpha, ICAM-1, FGF-beta, TGF-beta, HGF, VEGF-alpha and PDGF-BB factors, but no significant difference was seen. Secretion of these mediators after transplantation may play a significant role in promoting wound healing process for the treatment of skin loss. PMID- 26768915 TI - Does infrared or ultraviolet light damage the lens? AB - In daylight, the human eye is exposed to long wavelength ultraviolet radiation (UVR), visible radiation and short wavelength infrared radiation (IRR). Almost all the UVR and a fraction of the IRR waveband, respectively, left over after attenuation in the cornea, is absorbed in the lens. The time delay between exposure and onset of biological response in the lens varies from immediate-to short-to-late. After exposure to sunlight or artificial sources, generating irradiances of the same order of magnitude or slightly higher, biological damage may occur photochemically or thermally. Epidemiological studies suggest a dose dependent association between short wavelength UVR and cortical cataract. Experimental data infer that repeated daily in vivo exposures to short wavelength UVR generate photochemically induced damage in the lens, and that short delay onset cataract after UVR exposure is photochemically induced. Epidemiology suggests that daily high-intensity short wavelength IRR exposure of workers, is associated with a higher prevalence of age-related cataract. It cannot be excluded that this effect is owing to a thermally induced higher denaturation rate. Recent experimental data rule out a photochemical effect of 1090 nm in the lens but other wavelengths in the near IRR should be investigated. PMID- 26768916 TI - The role of light in measuring ocular biomechanics. AB - The cornea is a highly specialised tissue with a unique set of biomechanical properties determined by its complex structure. The maintenance of these mechanical properties is fundamental to maintain clear vision as the cornea provides the majority of the focussing power of the eye. Changes to the biomechanics of the cornea can occur during ageing, disease, and trauma, or as a result of surgery. Recently there has been increased interest in the mechanical properties of the cornea as knowledge of these properties has significant implications for the improvement of current ocular treatments including PRK and LASIK, and for the diagnosis and tracking of corneal diseases and therapy such as keratoconus and crosslinking. Biomechanics are also important for the development of artificial corneal replacements. This paper describes the use of a novel, non destructive lateral electronic speckle pattern shearing interferometer (ESPSI). The data generated via this technique give a full-field view of the mechanical response of the cornea under simulated physiological loading conditions, and enables strain and displacement to be determined in three planes. The technique allows corneal stiffness to be quantified and enables changes and non homogeneities that occur due to surgery or disease to be detected. PMID- 26768917 TI - What is light? The visible spectrum and beyond. AB - In this International Year of Light, it is particularly appropriate to review the historical concept of what is light and the controversies surrounding the extent of the visible spectrum. Today we recognize that light possesses both a wave and particle nature. It is also clear that the limits of visibility really extend from about 310 nm in the ultraviolet (in youth) to about 1100 nm in the near infrared, but depend very much on the radiance, that is, 'brightness' of the light source. The spectral content of artificial lighting are undergoing very significant changes in our lifetime, and the full biological implications of the spectral content of newer lighting technologies remain to be fully explored. PMID- 26768918 TI - Is optical coherence tomography an effective device for evaluation of tear film meniscus in patients with acne rosacea? AB - PURPOSE: To investigate the tear meniscus using Fourier-domain optical coherence tomography (FD-OCT) in patients with acne rosacea and to determine the relationship between tear film break-up tests (TBUT), Schirmer test and FD-OCT values and to compare them with that of healthy controls. METHODS: One hundred and four patients with acne rosacea and 104 body mass index age-sex-matched healthy subjects were enrolled in this prospective case-control study. Tear meniscus height (TMH), tear meniscus depth (TMD), and tear meniscus cross sectional area (TMA) were measured using FD-OCT (RTVue-100); TBUT, Schirmer test and dry eye questionnaire (OSDI) were evaluated. Correlation was assessed using Spearman's correlation coefficient. RESULTS: Mean TMH, TMD, TMA, TBUT, and Schirmer test values of acne rosacea patients were significantly lower than and OSDI score significantly higher than those of controls. Tear mensicus values were significantly correlated with OSDI scores, TBUT, and Schirmer test results. The intraobserver intraclass correlation coefficient (ICC) for tear parameters ranged from 0.90 to 0.96 and interobserver ICC ranged from 0.92 to 0.94, which revealed high reproducibility for all measurements parameters both acne rosacea and control subjects. Accuracy of dry eye diagnosis by FD-OCT was 60.4% for TMH, 58.7% for TMD, and 64.8% for TMA. CONCLUSION: Tear meniscus measurement with FD OCT could provide acceptable specificity and sensitivity in diagnosis of dry eye in acne rosacea patients. PMID- 26768920 TI - Low-energy light bulbs, computers, tablets and the blue light hazard. AB - The introduction of low energy lighting and the widespread use of computer and mobile technologies have changed the exposure of human eyes to light. Occasional claims that the light sources with emissions containing blue light may cause eye damage raise concerns in the media. The aim of the study was to determine if it was appropriate to issue advice on the public health concerns. A number of sources were assessed and the exposure conditions were compared with international exposure limits, and the exposure likely to be received from staring at a blue sky. None of the sources assessed approached the exposure limits, even for extended viewing times. PMID- 26768919 TI - Signalling by melanopsin (OPN4) expressing photosensitive retinal ganglion cells. AB - Over the past two decades there have been significant advances in our understanding of both the anatomy and function of the melanopsin system. It has become clear that rather than acting as a simple irradiance detector the melanopsin system is in fact far more complicated. The range of behavioural systems known to be influenced by melanopsin activity is increasing with time, and it is now clear that melanopsin contributes not only to multiple non-image forming systems but also has a role in visual pathways. How melanopsin is capable of driving so many different behaviours is unclear, but recent evidence suggests that the answer may lie in the diversity of melanopsin light responses and the functional specialisation of photosensitive retinal ganglion cell (pRGC) subtypes. In this review, we shall overview the current understanding of the melanopsin system, and evaluate the evidence for the hypothesis that individual pRGC subtypes not only perform specific roles, but are functionally specialised to do so. We conclude that while, currently, the available data somewhat support this hypothesis, we currently lack the necessary detail to fully understand how the functional diversity of pRGC subtypes correlates with different behavioural responses, and ultimately why such complexity is required within the melanopsin system. What we are lacking is a cohesive understanding of how light responses differ between the pRGC subtypes (based not only on anatomical classification but also based on their site of innervation); how these diverse light responses are generated, and most importantly how these responses relate to the physiological functions they underpin. PMID- 26768921 TI - The design and validation of an optical coherence tomography-based classification system for focal vitreomacular traction. AB - PURPOSE: To develop and validate a classification system for focal vitreomacular traction (VMT) with and without macular hole based on spectral domain optical coherence tomography (SD-OCT), intended to aid in decision-making and prognostication. METHODS: A panel of retinal specialists convened to develop this system. A literature review followed by discussion on a wide range of cases formed the basis for the proposed classification. Key features on OCT were identified and analysed for their utility in clinical practice. A final classification was devised based on two sequential, independent validation exercises to improve interobserver variability. RESULTS: This classification tool pertains to idiopathic focal VMT assessed by a horizontal line scan using SD-OCT. The system uses width (W), interface features (I), foveal shape (S), retinal pigment epithelial changes (P), elevation of vitreous attachment (E), and inner and outer retinal changes (R) to give the acronym WISPERR. Each category is scored hierarchically. Results from the second independent validation exercise indicated a high level of agreement between graders: intraclass correlation ranged from 0.84 to 0.99 for continuous variables and Fleiss' kappa values ranged from 0.76 to 0.95 for categorical variables. CONCLUSIONS: We present an OCT-based classification system for focal VMT that allows anatomical detail to be scrutinised and scored qualitatively and quantitatively using a simple, pragmatic algorithm, which may be of value in clinical practice as well as in future research studies. PMID- 26768922 TI - Teaching practices of thoracic epidural catheterizations in different grade of anesthesia residents. AB - BACKGROUND AND OBJECTIVES: In this study, we aimed to clarify the importance of residency grade and other factors which influence the success of thoracic epidural catheterization in thoracotomy patients. METHODS: After the ethical committee approval, data were recorded retrospectively from the charts of 415 patients. All patients had given written informed consent. The thoracic epidural catheterization attempts were divided into two groups as second-third year (Group I) and fourth year (Group II) according to residency grade. We retrospectively collected demographic data, characteristics of thoracic epidural catheterization attempts, and all difficulties and complications during thoracic epidural catheterization. RESULTS: Overall success rate of thoracic epidural catheterization was similar between the groups. Levels of catheter placement, number and duration of thoracic epidural catheterization attempts were not different between the groups (p>0.05). Change of needle insertion level was statistically higher in Group II (p=0.008), whereas paresthesia was significantly higher in Group I (p=0.007). Dural puncture and postdural puncture headache rates were higher in Group I. Higher body mass index and level of the insertion site were significant factors for thoracic epidural catheterization failure and postoperative complication rate and those were independence from residents' experience (p<0.001, 0.005). CONCLUSION: Body mass index and level of insertion site were significant on thoracic epidural catheterization failure and postoperative complication rate. We think that residents' grade is not a significant factor in terms overall success rate of thoracic epidural catheterization, but it is important for outcome of these procedures. PMID- 26768923 TI - Effect of nitrous oxide on fentanyl consumption in burned patients undergoing dressing change. AB - BACKGROUND AND OBJECTIVES: Thermal injuries and injured areas management are important causes of pain in burned patients, requiring that these patients are constantly undergoing general anesthesia for dressing change. Nitrous oxide (N2O) has analgesic and sedative properties; it is easy to use and widely available. Thus, the aim of this study was to evaluate the analgesic effect of N2O combined with fentanyl in burned patients during dressing change. METHOD: After approval by the institutional Ethics Committee, 15 adult burned patients requiring daily dressing change were evaluated. Patient analgesia was controlled with fentanyl 0.0005% administered by intravenous pump infusion on-demand. Randomly, in one of the days a mixture of 65% N2O in oxygen (O2) was associated via mask, with a flow of 10 L/min (N2O group) and on the other day only O2 under the same flow (control group). RESULTS: No significant pain reduction was seen in N2O group compared to control group. VAS score before dressing change was 4.07 and 3.4, respectively, in N2O and control groups. Regarding pain at the end of the dressing, patients in N2O group reported pain severity of 2.8; while the control group reported 2.87. There was no significant difference in fentanyl consumption in both groups. CONCLUSIONS: The association of N2O was not effective in reducing opioid consumption during dressing changes. PMID- 26768924 TI - Effects of a novel method of anesthesia combining propofol and volatile anesthesia on the incidence of postoperative nausea and vomiting in patients undergoing laparoscopic gynecological surgery. AB - BACKGROUND: We investigated the effects of a novel method of anesthesia combining propofol and volatile anesthesia on the incidence of postoperative nausea and vomiting in patients undergoing laparoscopic gynecological surgery. METHODS: Patients were randomly divided into three groups: those maintained with sevoflurane (Group S, n=42), propofol (Group P, n=42), or combined propofol and sevoflurane (Group PS, n=42). We assessed complete response (no postoperative nausea and vomiting and no rescue antiemetic use), incidence of nausea and vomiting, nausea severity score, vomiting frequency, rescue antiemetic use, and postoperative pain at 2 and 24h after surgery. RESULTS: The number of patients who exhibited a complete response was greater in Groups P and PS than in Group S at 0-2h (74%, 76% and 43%, respectively, p=0.001) and 0-24h (71%, 76% and 38%, respectively, p<0.0005). The incidence of nausea at 0-2h (Group S=57%, Group P=26% and Group PS=21%, p=0.001) and 0-24h (Group S=62%, Group P=29% and Group PS=21%, p<0.0005) was also significantly different among groups. However, there were no significant differences among groups in the incidence or frequency of vomiting or rescue antiemetic use at 0-24h. CONCLUSION: Combined propofol and volatile anesthesia during laparoscopic gynecological surgery effectively decreases the incidence of postoperative nausea. We term this novel method of anesthesia "combined intravenous-volatile anesthesia (CIVA)". PMID- 26768925 TI - A randomised comparative study of the effect of Airtraq optical laryngoscope vs. Macintosh laryngoscope on intraocular pressure in non-ophthalmic surgery. AB - BACKGROUND: We compared intraocular pressure changes following laryngoscopy and intubation with conventional Macintosh blade and Airtraq optical laryngoscope. METHODS: Ninety adult patients were randomly assigned to study group or control group. Study group (n=45) - Airtraq laryngoscope was used for laryngoscopy. Control group (n=45) - conventional Macintosh laryngoscope was used for laryngoscopy. Preoperative baseline intraocular pressure was measured with Schiotz tonometer. Laryngoscopy was done as per group protocol. Intraocular pressure and haemodynamic parameters were recorded just before insertion of the device and subsequently three times at an interval of one minute after insertion of the device. RESULTS: Patient characteristics, baseline haemodynamic parameters and baseline intraocular pressure were comparable in the two groups. Following insertion of the endotracheal tube with Macintosh laryngoscope, there was statistically significant rise in heart rate and intraocular pressure compared to Airtraq group. There was no significant change in MAP. Eight patients in Macintosh group had tongue-lip-dental trauma during intubation, while only 2 patients received upper airway trauma in Airtraq group. CONCLUSION: We conclude that Airtraq laryngoscope in comparison to Macintosh laryngoscope results in significantly fewer rises in intraocular pressure and clinically less marked increase in haemodynamic response to laryngoscopy and intubation. PMID- 26768926 TI - Comparison of sevoflurane concentration for insertion of proseal laryngeal mask airway and tracheal intubation in children (correlation with BIS). AB - BACKGROUND: Sevoflurane is an inhalational agent of choice in paediatric anaesthesia. For management of airways in children a suitable alternative to ETT is a paediatric proseal laryngeal mask airway (benchmark second generation SAD). Various studies have shown that less sevoflurane concentration is required for LMA insertion in comparison to TI. BIS is a useful monitor of depth of anaesthesia. AIMS: To compare concentration of sevoflurane (end tidal and MAC value) required for proseal laryngeal mask airway insertion and tracheal intubation in correlation with BIS index. METHOD: The prospective randomised single blind study was done in children between 2 and 9 years of ASA I and II and they were randomly allocated to Group P (proseal laryngeal mask airway insertion) and Group TI (tracheal intubation). No sedative premedication was given. Induction was done with 8% sevoflurane and then predetermined concentration was maintained for 10 min. Airway was secured either by proseal laryngeal mask airway or endotracheal tube without using muscle relaxant. End tidal sevoflurane concentration, MAC, BIS, and other vital parameters were monitored every minute till insertion of an airway device. Insertion conditions were observed. Statistical analysis was done by ANOVA and Students t test. RESULTS: Difference between ETLMI (2.49 +/- 0.44) and ETTI (2.81 +/- 0.65) as well as MACLMI (1.67 +/ 0.13) and MACTI (1.77 +/- 0.43) was statistically very significant, while BISLMI (49.05 +/- 10.76) and BISTI (41.25 +/- 3.25) was significant. Insertion conditions were comparable in both the groups. CONCLUSION: We can conclude that in children airway can be secured safely with proseal laryngeal mask airway using less sevoflurane concentration in comparison to tracheal intubation and this was supported by BIS index. PMID- 26768927 TI - Comparative effects of vitamin C on the effects of local anesthetics ropivacaine, bupivacaine, and lidocaine on human chondrocytes. AB - BACKGROUND: Intra-articular injections of local anesthetics are commonly used to enhance post-operative analgesia following orthopedic surgery as arthroscopic surgeries. Nevertheless, recent reports of severe complications due to the use of intra-articular local anesthetic have raised concerns. OBJECTIVES: The study aims to assess use of vitamin C in reducing adverse effects of the most commonly employed anesthetics - ropivacaine, bupivacaine and lidocaine - on human chondrocytes. METHODS: The chondrocyte viability following exposure to 0.5% bupivacaine or 0.75% ropivacaine or 1.0% lidocaine and/or vitamin C at doses 125, 250 and 500 MUM was determined by LIVE/DEAD assay and annexin V staining. Expression levels of caspases 3 and 9 were assessed using antibodies by Western blotting. Flow cytometry was performed to analyze the generation of reactive oxygen species. RESULTS: On exposure to the local anesthetics, chondrotoxicity was found in the order ropivacaine 20 breaths/min, accessory muscle usage, difficulty with swallowing or speaking, and requiring reintubation. The clinical approach of our anesthesiologists toward reversal agents was examined using an 8 question mini-survey shortly after the study. RESULTS: The incidence of PORC was 43% (n = 179) for TOFR < 0.9, and 15% (n = 61) for TOFR < 0.7. The incidence of TOFR < 0.9 was significantly higher in women, in those with ASA physical status 3, and with anesthesia of short duration (p < 0.05). In addition, 66% (n = 272) of the 415 patients arriving at the recovery room had received neostigmine. A TOFR < 0.9 was found in 46% (n = 126) of the patients receiving neostigmine. CONCLUSIONS: When routine objective neuromuscular monitoring is not available, PORC remains a clinical problem despite the use of NMBDs. The timing and optimal antagonism of the neuromuscular blockade, and routine objective neuromuscular monitoring is recommended to enhance patient safety. PMID- 26768932 TI - Digital block with or without the addition of epinephrine in the anesthetic solution. AB - BACKGROUND AND OBJECTIVES: Review of various techniques for digital blocks with local anesthetic, with or without epinephrine. CONTENTS: Description of various procedures and comparison of results reported in the literature, mainly on latency and quality of anesthesia, details on vasoconstrictor effect of epinephrine, intraoperative bleeding, necessity of tourniquet use, duration of anesthesia and postoperative analgesia, blood flow and digital SpO2 behavior, local and systemic complications, and also approaches and drugs to be used in certain situations of ischemia. CONCLUSIONS: The advantages of adding epinephrine to the anesthetic solution are minor when compared to the risks of the procedure, and it seems dangerous to use a vasoconstrictor in the fingers, unless the safety of the technique and the possibility of discarding the tourniquet are definitely proven. PMID- 26768933 TI - Role of noninvasive ventilation in perioperative patients with neuromuscular disease: a clinical case. AB - The inclusion body myositis is an inflammatory myopathy that leads to chronic muscle inflammation associated with muscle weakness. It is characterized by a restrictive ventilatory syndrome requiring ventilatory support under non-invasive ventilation. The authors describe a clinical case and the anaesthetic management of a patient with inclusion body myopathy candidate for vertebroplasty, which highlights the importance of locoregional anaesthesia and of noninvasive ventilation and includes assisted cough techniques, maintained throughout the perioperative period. PMID- 26768934 TI - Treatment of patients with painful blind eye using stellate ganglion block. AB - BACKGROUND AND OBJECTIVES: management of pain in painful blind eyes is still a challenge. Corticosteroids and hypotensive agents, as well as evisceration and enucleation, are some of the strategies employed so far that are not always effective and, depending on the strategy, cause a deep emotional shock to the patient. Given these issues, the aim of this case report is to demonstrate a new and viable option for the management of such pain by treating the painful blind eye with the stellate ganglion block technique, a procedure that has never been described in the literature for this purpose. CASE REPORT: six patients with painful blind eye, all caused by glaucoma, were treated; in these patients, VAS (visual analogue scale for pain assessment, in which 0 is the absence of pain and 10 is the worst pain ever experienced) ranged from 7 to 10. We opted for weekly sessions of stellate ganglion block with 4 mL of bupivacaine (0.5%) without vasoconstrictor and clonidine 1 mcg/kg. Four patients had excellent results at VAS, ranging between 0 and 3, and two remained asymptomatic (VAS=0), without the need for additional medication. The other two used gabapentin 300 mg every 12h. CONCLUSION: currently, there are several therapeutic options for the treatment of painful blind eye, among which stand out the retrobulbar blocks with chlorpromazine, alcohol and phenol. However, an effective strategy with low rate of serious complications, which is non-mutilating and improves the quality of life of the patient, is essential. Then, stellate ganglion block arises as a demonstrably viable and promising option to meet this demand. PMID- 26768935 TI - When one port does not return blood: two case reports of rare causes for misplaced central venous catheters. AB - We present two cases of misplaced central venous catheters having in common the absence of free blood return from one lumen immediately after placement. The former is a case of right hydrothorax associated with central venous catheterization with the catheter tip in intra-pleural location. In this case the distal port was never patent. In the latter case there was an increased aspiration pressure through the middle port due to a catheter looping. The absence of free flow on aspiration from one lumen of a central catheter should not be undervalued. In these circumstances the catheter should not be used and needs to be removed. PMID- 26768936 TI - Continuous spinal anaesthesia with minimally invasive haemodynamic monitoring for surgical hip repair in two patients with severe aortic stenosis. AB - BACKGROUND AND OBJECTIVES: Aortic stenosis increases perioperative morbidity and mortality, perioperative invasive monitoring is advised for patients with an aortic valve area <1.0 cm(2) or a mean aortic valve gradient >30 mmHg and it is important to avoid hypotension and arrhythmias. We report the anaesthetic management with continuous spinal anaesthesia and minimally invasive haemodynamic monitoring of two patients with severe aortic stenosis undergoing surgical hip repair. CASE REPORT: Two women with severe aortic stenosis were scheduled for hip fracture repair. Continuous spinal anaesthesia with minimally invasive haemodynamic monitoring was used for anaesthetic management of both. Surgery was performed successfully after two consecutive doses of 2mg of isobaric bupivacaine 0.5% in one of them and four consecutive doses in the other. Haemodynamic conditions remained stable throughout the intervention. Vital signs and haemodynamic parameters remained stable throughout the two interventions. CONCLUSION: Our report illustrates the use of continuous spinal anaesthesia with minimally invasive haemodynamic monitoring as a valid alternative to general or epidural anaesthesia in two patients with severe aortic stenosis who are undergoing lower limb surgery. However, controlled clinical trials would be required to establish that this technique is safe and effective in these type or patients. PMID- 26768937 TI - Lumbar spinal anesthesia with cervical nociceptive blockade. Critical review of a series of 1,330 procedures. AB - BACKGROUND AND OBJECTIVES: The manufacture of minimally traumatic needles and synthesis of pharmacological adjuncts with safe and effective action on inhibitory and neuromodulatory synapses distributed along the nociceptive pathways were crucial for a new expansion phase of spinal anesthesia. The objectives of this paper are present our clinical experience with 1330 lumbar spinal anesthesia performed with purposeful nociceptive blockade of the thoracic and cervical spinal nerves corresponding to dermatomes C4 or C3; warn about the method pathophysiological risks, and emphasize preventive standards for the safe application of the technique. CONTENT: Review of the historical background and anatomical spinal anesthesia with cervical levels of analgesia. Description of the technique used in our institution; population anesthetized; and surgery performed with the described method. Critical exposition of the physiological, pathophysiological, and clinical effects occurred and registered during anesthesia-surgery and postoperative period. CONCLUSION: Spinal anesthesia with nociceptive blockade to dermatome C4, or C3, is an effective option for surgery on somatic structures distal to the metamer of the third cervical spinal nerve, lasting no more than four or five hours. The method safety depends on the unrestricted respect for the essential rules of proper anesthesia. PMID- 26768938 TI - Translation and transcultural adaptation of Pain Quality Assessment Scale (PQAS) to Brazilian version. AB - INTRODUCTION: Most cancer patients are treated with chemotherapy, and peripheral neuropathy is a serious and common clinical problem affecting patients undergoing cancer treatment. However, the symptoms are subjective and underdiagnosed by health professionals. Thus, it becomes necessary to develop self-report instruments to overcome this limitation and improve the patient's perception about his medical condition or treatment. OBJECTIVE: Translate and culturally adapt the Brazilian version of the Pain Quality Assessment Scale, constituting a useful tool for assessing the quality of neuropathic pain in cancer patients. METHOD: The procedure followed the steps of translation, back translation, analysis of Portuguese and English versions by a committee of judges, and pretest. Pretest was conducted with 30 cancer patients undergoing chemotherapy following internationally recommended standards, and the final versions were compared and evaluated by a committee of researchers from Brazil and MAPI Research Trust, the scale's creators. RESULTS: Versions one and two showed 100% semantic equivalence with the original version. Back-translation showed difference between the linguistic translation and the original version. After evaluation by the committee of judges, a flaw was found in the empirical equivalence and idiomatic equivalence. In pretest, two people did not understand the item 12 of the scale, without interfering in the final elaboration. CONCLUSION: The translated and culturally adapted instrument is now presented in this publication, and currently it is in the process of clinical validation in Brazil. PMID- 26768940 TI - Update on Journal Policy of Aedine Mosquito Genera and Subgenera. PMID- 26768939 TI - Profile of drug administration errors in anesthesia among anesthesiologists from Santa Catarina. AB - INTRODUCTION: Anesthesiology is the only medical specialty that prescribes, dilutes, and administers drugs without conferral by another professional. Adding to the high frequency of drug administration, a propitious scenario to errors is created. OBJECTIVE: Access the prevalence of drug administration errors during anesthesia among anesthesiologists from Santa Catarina, the circumstances in which they occurred, and possible associated factors. MATERIALS AND METHODS: An electronic questionnaire was sent to all anesthesiologists from Sociedade de Anestesiologia do Estado de Santa Catarina, with direct or multiple choice questions on responder demographics and anesthesia practice profile; prevalence of errors, type and consequence of error; and factors that may have contributed to the errors. RESULTS: Of the respondents, 91.8% reported they had committed administration errors, adding the total error of 274 and mean of 4.7 (6.9) errors per respondent. The most common error was replacement (68.4%), followed by dose error (49.1%), and omission (35%). Only 7% of respondents reported neuraxial administration error. Regarding circumstances of errors, they mainly occurred in the morning (32.7%), in anesthesia maintenance (49%), with 47.8% without harm to the patient and 1.75% with the highest morbidity and irreversible damage, and 87.3% of cases with immediate identification. As for possible contributing factors, the most frequent were distraction and fatigue (64.9%) and misreading of labels, ampoules, or syringes (54.4%). CONCLUSION: Most respondents committed more than one error in anesthesia administration, mainly justified as a distraction or fatigue, and of low gravity. PMID- 26768941 TI - A Note on Variations in Morphological Features of the Phlebotomine Sand Fly Sergentomyia bailyi (Diptera: Psychodidae) in a Population From Pondicherry UT, India. AB - Morphological variations were observed in specimens of the sand fly species Sergentomyia bailyi Sinton 1931 collected from Pondicherry Union Territory, India. Examination of morphological characteristics showed differences in the length of sensilla chaeticum on antennal flagellomere 3 (A3) in males and females, in the size and shape of the spermathecae in females, and in the position of accessory spines on the gonostyle of males. In our previous study, DNA barcoding characterization of this sand fly species collected from Pondicherry UT revealed molecular variations within the S. bailyi population. This study confirms the existence of a species complex within S. bailyi population at Pondicherry UT. PMID- 26768942 TI - A Birthday. PMID- 26768943 TI - Preoperative biliary drainage does not increase major complications in pancreaticoduodenectomy: a large single center experience from the Massachusetts General Hospital. AB - BACKGROUND: The impact of preoperative biliary drainage (PBD) on perioperative morbidity and mortality in pancreatic surgery is still under debate. The aim of this study was to investigate outcomes of stented vs. non-stented patients undergoing pancreatoduodenectomy (PD). METHODS: We retrospectively compared 500 consecutive patients who underwent PBD prior to PD with 500 patients who did not. Ninety-day mortality and morbidity were assessed. RESULTS: The overall postoperative morbidity and mortality was 37% and 1.4%, respectively. Major complications (Clavien >= III) occurred in 16% of patients. The overall morbidity and mortality was not significantly higher in patients who underwent PBD. However, the rate of wound infection was significantly higher in patients who underwent PBD (19% vs. 9%, P = 0.001). When comparing intraoperative bile cultures of stented patients with and without wound infection, the presence of Enterobacter species (OR 2.4, 95% CI 1.5-4.1, P = 0.001) and Citrobacter species (OR 2.3, 95% CI 1.1-5.2, P = 0.037) in the bile significantly increased the likelihood of wound infection. CONCLUSION: Preoperative biliary drainage is associated with bactobilia and wound infection, but does not affect the overall morbidity and mortality of patients undergoing PD. PMID- 26768944 TI - What are the disruptive symptoms of behavioral disorders after traumatic brain injury? A systematic review leading to recommendations for good practices. AB - Behavioral disorders are major sequelae of severe traumatic brain injury. Before considering care management of these disorders, and in the absence of a precise definition for TBI-related behavioral disorder, it is essential to refine, according to the data from the literature, incidence, prevalence, predictive factors of commonly admitted disruptive symptoms. METHODS: Systematic review of the literature targeting epidemiological data related to behavioral disorders after traumatic brain injury in order to elaborate good practice recommendations according to the methodology established by the French High Authority for Health. RESULTS: Two hundred and ninety-nine articles were identified. The responsibility of traumatic brain injury (TBI) in the onset of behavioral disorders is unequivocal. Globally, behavioral disorders are twice more frequent after TBI than orthopedic trauma without TBI (Masson et al., 1996). These disorders are classified into disruptive primary behaviors by excess (agitation 11-70%, aggression 25-39%, irritability 29-71%, alcohol abuse 7-26% drug abuse 2-20%), disruptive primary behaviors by default (apathy 20-71%), affective disorders - anxiety - psychosis (depression 12-76%, anxiety 0.8-24,5%, posttraumatic stress 11-18%, obsessive-compulsive disorders 1.2-30%, psychosis 0.7%), suicide attempts and suicide 1%. DISCUSSION: The improvement of care management for behavioral disorders goes through a first step of defining a common terminology. Four categories of posttraumatic behavioral clinical symptoms are defined: disruptive primary behaviors by excess, by default, affective disorders-psychosis-anxiety, suicide attempts and suicide. All these symptoms yield a higher prevalence than in the general population. They impact all of life's domains and are sustainable over time. PMID- 26768945 TI - Education and Imaging. Hepatobiliary and Pancreatic: Gall bladder duplication presenting with gall-stone pancreatitis: Use of hepatobiliary specific MRCP in preoperative evaluation of ductal anatomy. PMID- 26768946 TI - Education and Imaging. Hepatobiliary and Pancreatic: Replaced common hepatic artery on left gastric artery: a rare anomaly and implication for pancreaticoduodenectomy. PMID- 26768952 TI - Fertility-sparing surgery in epithelial ovarian cancer. AB - Since the last two decades, the feasibility of fertility-sparing surgery in early stage epithelial ovarian cancer has been explored by several teams. Despite the impossibility of conducting a randomized trial to validate this management, evidence-based data suggest that in selected cases, the preservation of the uterus and at least one part of the ovary does not lead to a high risk of relapse. Conservative surgery maintains organ function, enables patients of childbearing age to preserve their fertility and improves their quality of life. In this review, we analyze the main series in the literature on this topic in order to highlight the selected criteria for conservative management and to summarize oncological and fertility outcomes. PMID- 26768953 TI - New lymphatic structures in colon cancer. PMID- 26768955 TI - Cerebral microglia activation in hepatitis C virus infection correlates to cognitive dysfunction. AB - Hepatitis C virus (HCV) infection may induce chronic fatigue and cognitive dysfunction. Virus replication was proven within the brain and HCV-positive cells were identified as microglia and astrocytes. We hypothesized that cerebral dysfunction in HCV-afflicted patients is associated with microglia activation. Microglia activation was assessed in vivo in 22 patients with chronic HCV infection compared to six healthy controls using [(11) C]-PK11195 Positron Emission Tomography (PET) combined with magnetic resonance tomography for anatomical localization. Patients were subdivided with regard to their PCR status, Fatigue Impact Scale score (FIS) and attention test sum score (ATS). A total of 12 patients (54.5%) were HCV PCR positive [of which 7 (58.3%) had an abnormal FIS and 7 (58.3%) an abnormal ATS], 10 patients (45.5%) were HCV PCR negative (5 (50%) each with an abnormal FIS or ATS). Patients without attention deficits showed a significantly higher accumulation of [(11) C]-PK11195 in the putamen (P = 0.05), caudate nucleus (P = 0.03) and thalamus (P = 0.04) compared to controls. Patients with and without fatigue did not differ significantly with regard to their specific tracer binding in positron emission tomography. Preserved cognitive function was associated with significantly increased microglia activation with predominance in the basal ganglia. This indicates a probably neuroprotective effect of microglia activation in HCV-infected patients. PMID- 26768954 TI - Surgery and hormone therapy trends in octogenarians with invasive breast cancer. AB - BACKGROUND: There has been a trend toward minimizing surgery in elderly women with estrogen receptor-positive (ER+) breast cancer. METHODS: Using the National Cancer Data Base, we selected 95,357 women >=80 years with invasive, ER+ breast cancer. Chi-square test and logistic regression were used to analyze trends in surgery and hormone therapy. RESULTS: From 2004 to 2012, 90% of women were treated with surgery first and 10% were treated with primary nonoperative management. Of those undergoing nonoperative management, 72% received endocrine therapy and 27% had no treatment. The rate of primary nonoperative treatment doubled from 7% in 2004 to 14% in 2012. Multivariate logistic regression adjusted for patient, facility, and tumor factors identified more advanced clinical stage, older age, African-American race, and treatment at Academic facilities as independent predictors of receiving primary nonsurgical management. CONCLUSIONS: There has been an increase over time in primary nonoperative management of ER+ breast cancer in octogenarians. PMID- 26768956 TI - Best of the 2015 AcademyHealth Annual Research Meeting. PMID- 26768957 TI - What Influences Patients' Decisions When Choosing a Health Care Provider? Measuring Preferences of Patients with Knee Arthrosis, Chronic Depression, or Alzheimer's Disease, Using Discrete Choice Experiments. AB - OBJECTIVE: To investigate what influences patients' health care decisions and what the implications are for the provision of information on the quality of health care providers to patients. DATA SOURCES/STUDY SETTING: Dutch patient samples between November 2006 and February 2007. STUDY DESIGN: Discrete choice experiments were conducted in three patient groups to explore what influences choice for health care providers. DATA COLLECTION: Data were obtained from 616 patients with knee arthrosis, 368 patients with chronic depression, and 421 representatives of patients with Alzheimer's disease. PRINCIPAL FINDINGS: The three patients groups chose health care providers on a different basis. The most valued attributes were effectiveness and safety (knee arthrosis); continuity of care and relationship with the therapist (chronic depression); and expertise (Alzheimer's disease). Preferences differed between subgroups, mainly in relation to patients' choice profiles, severity of disease, and some background characteristics. CONCLUSIONS: This study showed that there is substantial room for (quality) information about health care providers in patients' decision processes. This information should be tailor-made, targeting specific patient segments, because different actors and factors play a part in their search and selection process. PMID- 26768958 TI - Opportunistic bilateral salpingectomy during gynaecological surgery for benign disease: A survey of current Australian practice. AB - BACKGROUND: Recent evidence supports the fallopian tube as the site of origin for many pelvic serous cancers (PSC) including epithelial ovarian cancers (EOC). As a result, a change in practice with opportunistic bilateral salpingectomy (OBS) at the time of hysterectomy has been advocated as a preventative strategy for PSC in a low-risk population. AIMS: The aim of this study was to assess current clinical practice in Australia with respect to OBS during gynaecological surgery for benign indications. MATERIALS AND METHODS: An anonymous online survey was sent to all active Royal Australian and New Zealand College of Obstetrics and Gynaecology (RANZCOG) Fellows in Australia. Data regarding clinician demographics and the proportion of clinicians offering OBS were collected. Reasons for and against offering or discussing OBS were sought. A descriptive analysis was performed. RESULTS: The response rate was 26% (280/1490) with 70% of respondents offering or discussing OBS to women undergoing gynaecological surgery for benign indications, usually at the time of abdominal (96%) or laparoscopic (76%) hysterectomy. The main reason for offering or discussing OBS was current evidence to suggest the fallopian tubes as the site of origin for most EOC. Main reasons for not offering OBS were insufficient evidence to benefit the woman (36%) or being unaware of recent evidence (33%). CONCLUSIONS: The survey responses indicate that OBS is frequently discussed or offered in Australia, usually at the time of hysterectomy. Given the lack of robust evidence to suggest a benefit at a population-based level, a national registry is recommended to monitor outcomes. PMID- 26768959 TI - Re: Surgical simulation stimulation. PMID- 26768960 TI - Re: Women's belief about the duration of pregnancy and the earliest gestational age to safely give birth. PMID- 26768962 TI - Editorial (Thematic Issue: New Insights into a Classical Pathway: Key Roles of the Mevalonate Cascade in Different Diseases (Part I)). PMID- 26768963 TI - The role of HIF in immunity and inflammation. AB - Uncontrolled or non-resolving inflammation underpins a range of disease states including rheumatoid arthritis, inflammatory bowel disease and atherosclerosis. Hypoxia is a prominent feature of chronically inflamed tissues. This is due to elevated oxygen consumption by highly metabolically active inflamed resident cells and activated infiltrating immunocytes, as well as diminished oxygen supply due to vascular dysfunction. Tissue hypoxia can have a significant impact upon inflammatory signaling pathways in immune and non-immune cells and this can impact upon disease progression. In this review, we will discuss the relationship between tissue hypoxia and inflammation and identify how hypoxia-sensitive signaling pathways are potential therapeutic targets in chronic inflammatory disease. PMID- 26768964 TI - Compound Heterozygous Triadin Mutation Causing Cardiac Arrest in Two Siblings. AB - We present the case of two siblings who both presented with an out-of-hospital cardiac arrest at 2 years of age. Both siblings underwent internal cardiac defibrillator implantation and both had recurrent episodes of ventricular fibrillation (VF). A compound heterozygous mutation in the triadin gene was discovered; one of these mutations has been described previously in the homozygous state, and the other one is unreported. The combination of these mutations has resulted in a particularly arrhythmogenic phenotype, with cardiac arrest occurring at a very young age and recurrent episodes of VF despite beta blockade. Flecainide seems to have been very effective in preventing clinical arrhythmias for this particular mutation. PMID- 26768965 TI - Radiotherapy Boost for the Dominant Intraprostatic Cancer Lesion-A Systematic Review and Meta-Analysis. AB - External beam radiotherapy (EBRT) for prostate cancer can be performed with a high dose of 86 Gy; however, one-tenth or more of the patients will develop recurrence. Prostate cancer is mainly multifocal, but a dominant intraprostatic lesion (DIL) is often the site of local recurrence after EBRT. We undertook a systematic review and meta-analysis to clarify whether functional imaging might identify the DIL and whether a RT boost to the DIL might be increased to an ultrahigh dose level of >= 90 Gy without increased toxicity. Of 62 selected studies, 13 reported the size of the DIL. The mean of the median DIL volumes was 2.4 cm(3) (95% confidence interval, 0.9-4.4 cm(3)). Eighteen diagnostic studies with 1205 patients evaluated the diagnostic accuracy using multiparametric magnetic resonance imaging for intraprostatic cancer lesions. Evaluating 14,654 prostate segments, the diagnostic accuracy was 77%. Eleven therapeutic studies with 988 patients reported a RT boost for the DIL. The summary boost dose for the DIL was a mean of 89 Gy in 5 studies using intensity modulated RT (calculated as the equivalent dose in 2-Gy fractions) and a mean of 141 Gy in 4 studies using a combination of EBRT and brachytherapy (P = .018, t test). In 1 therapeutic study, 239 patients had a 98% 10-year disease-free survival rate. Many of our therapeutic studies used a boost dose to the DIL of > 90 Gy. The reported boost for DIL is effective and safe. PMID- 26768966 TI - Combined Chemohormonal Strategy in Hormone-Sensitive Prostate Cancer: A Pooled Analysis of Randomized Studies. AB - BACKGROUND: A meta-analysis of the efficacy of chemohormonal regimens versus standard therapy in the management of advanced hormone-sensitive prostate cancer was conducted. MATERIALS AND METHODS: The eligible studies included randomized studies evaluating chemohormonal regimens in the setting of high-risk localized or metastatic hormone-sensitive prostate cancer. RESULTS: The search strategy yielded 900 potentially relevant citations from the searched databases. After exclusion of the ineligible studies, 10 studies were included in the qualitative analysis, among which 5 studies that had evaluated a docetaxel-hormonal therapy combination were included in the final quantitative analysis. For metastatic hormone-sensitive disease, the pooled hazard ratio (HR) for progression-free survival (PFS) was 0.63 (95% confidence interval [CI], 0.57-0.70; P < .00001), and the pooled HR for overall survival (OS) was 0.75 (95% CI, 0.65-0.86; P = .0001). For high-risk localized disease, the pooled HR for PFS was 0.68 (95% CI, 0.58-0.80; P < .00001), and the pooled HR for OS was 0.83 (95% CI, 0.61-1.13; P = .23). CONCLUSION: The results of the present meta-analysis have demonstrated that docetaxel-hormonal regimens are associated with superior OS and PFS in patients with metastatic disease and superior PFS but not OS in patients with high-risk localized disease. This option should be considered strongly in fit patients with adequate performance status. PMID- 26768967 TI - Therapeutic advantage of inhaled tacrolimus-bound albumin nanoparticles in a bleomycin-induced pulmonary fibrosis mouse model. AB - Tacrolimus (Tac) is an immunosuppressant that inhibits translocation of nuclear factor of activated T cells and has therapeutic potential for pulmonary fibrosis. Here, we investigated the therapeutic efficacy of a sustained-release type inhaled Tac formulation for treating bleomycin-induced pulmonary fibrosis. Inhalation has many meaningful advantages over injections, such as improved patient compliance, safety, and therapeutic effect. To this end, we fabricated inhalable albumin nanoparticles with bound Tac (Tac Alb-NPs) at a daily therapeutic dose (60 MUg/mouse) using a high-pressure homogenizer via nanoparticle albumin-bound technology. The Tac Alb-NPs were spherical, ~ 182.1 +/ 28.5 nm in size, with a zeta potential of -34.5 +/- 0.3 mV, and the Tac incorporation efficiency was as high as ~ 85.3%. The bound tacrolimus was released gradually from Tac Alb-NPs for ~ 24 h, which was sufficient time for pulmonary delivery. Most of all, the inhaled Tac Alb-NPs displayed remarkable anti-fibrotic efficacy in mice with bleomycin-induced pulmonary fibrosis, which was much better than the efficacy resulting from intraperitoneal administration of Tac (60 MUg/mouse) based on histopathological results (hematoxylin and eosin and Masson's trichrome staining). Furthermore, the inhaled Cy5.5-labelled Tac Alb NPs were visualized throughout the lungs of mice for ~ 48 h, indicating direct exposure to fibrotic tissues in lung lesions. In conclusion, Tac Alb-NPs offer great potential as an inhalation delivery formulation for treating pulmonary fibrosis. Additionally, these NPs would be particularly useful as an effective and safe prototype for delivering practically insoluble therapeutic agents into the lungs. PMID- 26768969 TI - Metabolic rate in fishes: definitions, methods and significance for conservation physiology. PMID- 26768968 TI - Birth defects data from surveillance hospitals in Dalian city, China, 2006-2010. AB - OBJECTIVE: The objective of this study is to disclose characteristics of birth defects in perinatal infants in Dalian and provide an epidemiological basis for controlling birth defects. METHODS: Data used in this study were collected from surveillance hospitals in Dalian during 2006-2010. Comparison analysis and trend analysis were conducted by performing Chi-square tests. RESULTS: The perinatal prevalence of birth defects from 2006 to 2010 was 101.14 per 10 000 live births and was decreased by about 29% from 115.49 per 10 000 live births in 2006 to 81.16 per 10 000 live births in 2010. The prevalence in urban was higher than that in rural areas significantly. The three leading birth defects were congenital heart disease, cleft lip and/or palate, and polydactyly or syndactyly. About 572 cases identified by antenatal diagnosis were terminated pregnancy before 28 weeks of gestation, so the prevalence of birth defects would decrease from 126.29/10 000 to 101.14/10 000. CONCLUSIONS: Dalian has experienced a decreasing temporal trend of birth defects' prevalence; however, it is still confronted with the challenge to reduce the prevalence of birth defects. Congenital heart diseases are the focus to prevent birth defects. It is necessary to keep the surveillance system function properly, provide preconception health care service extensively, and improve the ability of prenatal diagnosis. PMID- 26768970 TI - Oxygen consumption rate v. rate of energy utilization of fishes: a comparison and brief history of the two measurements. AB - Accounting for energy use by fishes has been taking place for over 200 years. The original, and continuing gold standard for measuring energy use in terrestrial animals, is to account for the waste heat produced by all reactions of metabolism, a process referred to as direct calorimetry. Direct calorimetry is not easy or convenient in terrestrial animals and is extremely difficult in aquatic animals. Thus, the original and most subsequent measurements of metabolic activity in fishes have been measured via indirect calorimetry. Indirect calorimetry takes advantage of the fact that oxygen is consumed and carbon dioxide is produced during the catabolic conversion of foodstuffs or energy reserves to useful ATP energy. As measuring [CO2 ] in water is more challenging than measuring [O2 ], most indirect calorimetric studies on fishes have used the rate of O2 consumption. To relate measurements of O2 consumption back to actual energy usage requires knowledge of the substrate being oxidized. Many contemporary studies of O2 consumption by fishes do not attempt to relate this measurement back to actual energy usage. Thus, the rate of oxygen consumption (MO2 ) has become a measurement in its own right that is not necessarily synonymous with metabolic rate. Because all extant fishes are obligate aerobes (many fishes engage in substantial net anaerobiosis, but all require oxygen to complete their life cycle), this discrepancy does not appear to be of great concern to the fish biology community, and reports of fish oxygen consumption, without being related to energy, have proliferated. Unfortunately, under some circumstances, these measures can be quite different from one another. A review of the methodological history of the two measurements and a look towards the future are included. PMID- 26768971 TI - Sources of variation in oxygen consumption of aquatic animals demonstrated by simulated constant oxygen consumption and respirometers of different sizes. AB - As intermittent-flow respirometry has become a common method for the determination of resting metabolism or standard metabolic rate (SMR), this study investigated how much of the variability seen in the experiments was due to measurement error. Experiments simulated different constant oxygen consumption rates (MO2 ) of a fish, by continuously injecting anoxic water into a respirometer, altering the injection rate to correct for the washout error. The effect of respirometer-to-fish volume ratio (RFR) on SMR measurement and variability was also investigated, using the simulated constant MO2 and the MO2 of seven roach Rutilus rutilus in respirometers of two different sizes. The results show that higher RFR increases measurement variability but does not change the mean SMR established using a double Gaussian fit. Further, the study demonstrates that the variation observed when determining oxygen consumption rates of fishes in systems with reasonable RFRs mainly comes from the animal, not from the measuring equipment. PMID- 26768972 TI - Experimental methods in aquatic respirometry: the importance of mixing devices and accounting for background respiration. AB - In light of an increasing trend in fish biology towards using static respirometry techniques without the inclusion of a mixing mechanism and without accurately accounting for the influence of microbial (background) respiration, this paper quantifies the effect of these approaches on the oxygen consumption rates (MO2 ) measured from juvenile barramundi Lates calcarifer (mean +/- s.e. mass = 20.31 +/ 0.81 g) and adult spiny chromis damselfish Acanthochromis polyacanthus (22.03 +/ 2.53 g). Background respiration changed consistently and in a sigmoidal manner over time in the treatment with a mixing device (inline recirculation pump), whereas attempts to measure background respiration in the non-mixed treatment yielded highly variable estimates of MO2 that were probably artefacts due to the lack of water movement over the oxygen sensor during measurement periods. This had clear consequences when accounting for background respiration in the calculations of fish MO2 . Exclusion of a mixing device caused a significantly lower estimate of MO2 in both species and reduced the capacity to detect differences between individuals as well as differences within an individual over time. There was evidence to suggest that the magnitude of these effects was dependent on the spontaneous activity levels of the fish, as the difference between mixed and non-mixed treatments was more pronounced for L. calcarifer (sedentary) than for A. polyacanthus (more spontaneously active). It is clear that respirometry set-ups for sedentary species must contain a mixing device to prevent oxygen stratification inside the respirometer. While more active species may provide a higher level of water mixing during respirometry measurements and theoretically reduce the need for a mixing device, the level of mixing cannot be quantified and may change with diurnal cycles in activity. To ensure consistency across studies without relying on fish activity levels, and to enable accurate assessments of background respiration, it is recommended that all respirometry systems should include an appropriate mixing device. PMID- 26768973 TI - The determination of standard metabolic rate in fishes. AB - This review and data analysis outline how fish biologists should most reliably estimate the minimal amount of oxygen needed by a fish to support its aerobic metabolic rate (termed standard metabolic rate; SMR). By reviewing key literature, it explains the theory, terminology and challenges underlying SMR measurements in fishes, which are almost always made using respirometry (which measures oxygen uptake, MO2 ). Then, the practical difficulties of measuring SMR when activity of the fish is not quantitatively evaluated are comprehensively explored using 85 examples of MO2 data from different fishes and one crustacean, an analysis that goes well beyond any previous attempt. The main objective was to compare eight methods to estimate SMR. The methods were: average of the lowest 10 values (low10) and average of the 10% lowest MO2 values, after removing the five lowest ones as outliers (low10%), mean of the lowest normal distribution (MLND) and quantiles that assign from 10 to 30% of the data below SMR (q0.1 , q0.15 , q0.2 , q0.25 and q0.3 ). The eight methods yielded significantly different SMR estimates, as expected. While the differences were small when the variability was low amongst the MO2 values, they were important (>20%) for several cases. The degree of agreement between the methods was related to the c.v. of the observations that were classified into the lowest normal distribution, the c.v. MLND (C.V.MLND ). When this indicator was low (<=5.4), it was advantageous to use the MLND, otherwise, one of the q0.2 or q0.25 should be used. The second objective was to assess if the data recorded during the initial recovery period in the respirometer should be included or excluded, and the recommendation is to exclude them. The final objective was to determine the minimal duration of experiments aiming to estimate SMR. The results show that 12 h is insufficient but 24 h is adequate. A list of basic recommendations for practitioners who use respirometry to measure SMR in fishes is provided. PMID- 26768974 TI - The measurement of specific dynamic action in fishes. AB - Specific dynamic action (SDA) is the postprandial increase in oxygen uptake. Whereas it is easy to measure in fishes that remain calm and motionless during the entire digestion period, spontaneous locomotor activity is a frequent problem that leads to overestimation of SDA amplitude and magnitude (area under the curve, bound by the standard metabolic rate, SMR). Few studies have attempted to remove the effect of fish activity on SDA. A new method, non-parametric quantile regression, is described to estimate SDA even when pronounced circadian activity cycles are present. Data from juvenile Atlantic cod Gadus morhua are used to demonstrate its use and advantages compared with traditional techniques. Software (scripts in the R language) is provided to facilitate its use. PMID- 26768975 TI - Measuring respiration rates in marine fish larvae: challenges and advances. AB - Metabolic costs can be extremely high in marine fish larvae and gaining reliable estimates of the effects of intrinsic and extrinsic factors on those costs is important to understand environmental constraints on early growth and survival. This review provides an historical perspective of measurements of larval marine fish respiration (O2 consumption) including the methods (Winkler, manometric, polarographic, paramagnetic and optodes) and systems (closed system to intermittent-flow) used. This study compares and systematically reviews the results (metabolic rates, ontogenetic changes and taxonomic differences) obtained from 59 studies examining 53 species from 30 families. Standard (anaesthetized or darkness), routine and active respiration rates were reported in 14, 94 and 8% of the studies and much more work has been performed on larvae of temperate (88%) compared with tropical (9%) and polar (3%) species. More than 35% of the studies have been published since 2000 owing to both advances in oxygen sensors and the growing emphasis on understanding physiological effects of environmental change. Common protocols are needed to facilitate cross-taxa comparisons such as the effect of temperature (Q10 : 1.47-3.47), body mass (slope of allometric changes in O2 consumption rate from 0.5 to 1.3) and activity level on metabolic costs as measured via respiration rate. A set of recommendations is provided that will make it easier for researchers to design measurement systems, to judge the reliability of measurements and to make inter-comparisons among studies and species. PMID- 26768976 TI - Responses by fishes to environmental hypoxia: integration through Fry's concept of aerobic metabolic scope. AB - The problem of understanding the effect of the environment on fish activities and performance, in any generalized way, remains intractable. Solving this issue is, however, a key to addressing contemporary environmental concerns. As suggested 20 years ago by W. H. Neill, the authors returned to the drawing board, using as a background the conceptual scheme initially proposed by F. E. J. Fry. They revisited the effect of ambient oxygen availability upon fish metabolism and clarified the definitions of limiting, critical and incipient lethal oxygen (ILO) levels. The concepts of oxy-conformer and oxy-regulator are revisited, and P. W. Hochachka's idea of scope for survival is explored. Finally, how the cardiovascular system contributes to the capacity of fishes to respond to the reduced oxygen availability is considered. Various hands-on recommendations and software (R scripts) are provided for researchers interested in investigating these concepts. PMID- 26768977 TI - Effect of closed v. intermittent-flow respirometry on hypoxia tolerance in the shiner perch Cymatogaster aggregata. AB - This study compares the critical oxygen saturation (O2 crit ) levels of the shiner perch Cymatogaster aggregata obtained using two different methods wherein hypoxia is induced either by the fish's respiration (closed respirometry) or by degassing oxygen with nitrogen (intermittent-flow respirometry). Fish exhibited loss of equilibrium at a higher O2 saturation in the closed respirometry method when compared with the intermittent-flow method. Utilization of closed respirometry yielded O2 crit measurements that were almost twice as high as those obtained with intermittent-flow respirometry. The lower hypoxia tolerance in closed respirometry is consistent with additional stress, caused by a build-up of ammonia and carbon dioxide and a faster rate in dissolved oxygen decline. The results indicate that these two methods of determining hypoxia tolerance in aquatic organisms are not comparable, and that much care should be given to method choice. PMID- 26768978 TI - Measuring maximum and standard metabolic rates using intermittent-flow respirometry: a student laboratory investigation of aerobic metabolic scope and environmental hypoxia in aquatic breathers. AB - Metabolic rate is one of the most widely measured physiological traits in animals and may be influenced by both endogenous (e.g. body mass) and exogenous factors (e.g. oxygen availability and temperature). Standard metabolic rate (SMR) and maximum metabolic rate (MMR) are two fundamental physiological variables providing the floor and ceiling in aerobic energy metabolism. The total amount of energy available between these two variables constitutes the aerobic metabolic scope (AMS). A laboratory exercise aimed at an undergraduate level physiology class, which details the appropriate data acquisition methods and calculations to measure oxygen consumption rates in rainbow trout Oncorhynchus mykiss, is presented here. Specifically, the teaching exercise employs intermittent flow respirometry to measure SMR and MMR, derives AMS from the measurements and demonstrates how AMS is affected by environmental oxygen. Students' results typically reveal a decline in AMS in response to environmental hypoxia. The same techniques can be applied to investigate the influence of other key factors on metabolic rate (e.g. temperature and body mass). Discussion of the results develops students' understanding of the mechanisms underlying these fundamental physiological traits and the influence of exogenous factors. More generally, the teaching exercise outlines essential laboratory concepts in addition to metabolic rate calculations, data acquisition and unit conversions that enhance competency in quantitative analysis and reasoning. Finally, the described procedures are generally applicable to other fish species or aquatic breathers such as crustaceans (e.g. crayfish) and provide an alternative to using higher (or more derived) animals to investigate questions related to metabolic physiology. PMID- 26768981 TI - Central composite design with the help of multivariate curve resolution in loadability optimization of RP-HPLC to scale-up a binary mixture. AB - Chromatographic method development for preparative targets is a time-consuming and subjective process. This can be particularly problematic because of the use of valuable samples for isolation and the large consumption of solvents in preparative scale. These processes could be improved by using statistical computations to save time, solvent and experimental efforts. Thus, contributed by ESI-MS, after applying DryLab software to gain an overview of the most effective parameters in separation of synthesized celecoxib and its co-eluted compounds, design of experiment software that relies on multivariate modeling as a chemometric approach was used to predict the optimized touching-band overloading conditions by objective functions according to the relationship between selectivity and stationary phase properties. The loadability of the method was investigated on the analytical and semi-preparative scales, and the performance of this chemometric approach was approved by peak shapes beside recovery and purity of products. PMID- 26768980 TI - Trophic contamination by pyrolytic polycyclic aromatic hydrocarbons does not affect aerobic metabolic scope in zebrafish Danio rerio. AB - The effect of trophic exposure to pyrolitic polycyclic aromatic hydrocarbons (PAH) on aerobic metabolism of zebrafish Danio rerio was investigated. There were no significant differences in standard metabolic rate (SMR), active metabolic rate (AMR) or aerobic metabolic scope (AS) at any sublethal concentration of PAH in the diet of adult or juvenile fish. This suggests that under these experimental conditions, exposure to PAH in food did not influence aerobic metabolism of this species. PMID- 26768979 TI - Modelling and interpreting fish bioenergetics: a role for behaviour, life-history traits and survival trade-offs. AB - Bioenergetics is used as the mechanistic foundation of many models of fishes. As the context of a model gradually extends beyond pure bioenergetics to include behaviour, life-history traits and function and performance of the entire organism, so does the need for complementing bioenergetic measurements with trade offs, particularly those dealing with survival. Such a broadening of focus revitalized and expanded the domain of behavioural ecology in the 1980s. This review makes the case that a similar change of perspective is required for physiology to contribute to the types of predictions society currently demands, e.g. regarding climate change and other anthropogenic stressors. PMID- 26768983 TI - Movember Is Mustache Month. PMID- 26768987 TI - Novel treatment of severe combined immunodeficiency utilizing ex-vivo T-cell depleted haploidentical hematopoietic stem cell transplantation and CD45RA+ depleted donor lymphocyte infusions. AB - BACKGROUND: Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative treatment available for severe combined immunodeficiency (SCID); although, there is a high incidence of severe infections and an increased risk of graft-versus host-disease (GvHD) with HSCT. Early intervention is a crucial prognostic factor and a HLA-haploidentical parental donor is often available. Haploidentical HSCT protocols utilizing extensively ex vivo T-cell depleted grafts (CliniMACs system) have proven efficient in preventing GvHD, but cause a delay in early T-cell recovery that increases the risk of viral infections. Here, we present a novel approach for treating SCID that combines selective depletion of GvHD-inducing alpha/beta (alpha/beta) T-cells from the haploidentical HSCT graft with a subsequent donor lymphocyte infusion (DLI) enriched for CD45RO+ memory T-cells. RESULTS: Our patient was diagnosed with SCID (T-B + NK+ phenotype). At 9 months of age, he received a T cell receptor(TCR)alpha/beta-cell depleted graft from his haploidentical mother, following a reduced intensity conditioning regimen with no additional GvHD prophylaxis. Engraftment was rapid with complete donor chimerism and no signs of GvHD. However, at 12 weeks post HSCT, the patient was still T-cell lymphopenic with clinical symptoms of multiple severe viral infections. Consequently, therapeutic DLIs were initiated for enhanced anti-viral immunity. The patient was treated with CD45RA+ depleted haploidentical maternal donor lymphocytes enriched from unmobilized whole blood, and a total T-cell dose of no more than 25 x10(3) CD3+ cells/kg with >99.9% purity of CD3 + CD45RO+ memory T-cells was transferred. Following the DLI, a prompt increase in CD3 + CD4+ and CD3 + CD8+ counts was observed with a subsequent clearance of viral infections. No acute or chronic GvHD was observed. CONCLUSIONS: Automated depletion of CD45RA+ naive T-cells from unmobilized whole blood is a simple and rapid strategy to provide unmanipulated DLIs, with a potentially broad repertoire of pathogen specific memory T-cells. In the haploidentical setting, CD45RA+ depleted DLIs can be safely administered at low T cell doses for efficient enhancement of viral immunity and limited risk of GvHD. We demonstrate the successful use of this approach following TCR-alpha/beta-cell depleted HSCT for the treatment of SCID. PMID- 26768988 TI - Pay in the NHS: did the consultants' salaries include waiting list initiatives? PMID- 26768991 TI - Microbial stress priming: a meta-analysis. AB - Microbes have to cope with complex and dynamic environments, making it likely that anticipatory responses provide fitness benefits. Mild, previous stressors can prepare microbes (stress priming) to further and potentially damaging stressors (triggering). We here quantitatively summarize the findings from over 250 trials of 34 studies including bacteria and fungi, demonstrating that priming to stress has a beneficial impact on microbial survival. In fact, survival of primed microbes was about 10-fold higher compared with that in non-primed microbes. Categorical moderators related to microbial taxonomy and the kind of stress applied as priming or as triggering revealed significant differences of priming effect size among 14 different microbial species, 6 stress categories and stressor combination. We found that priming by osmotic, physiological and temperature stress had the highest positive effect sizes on microbial response. Cross-protection was evident for physiological, temperature and pH stresses. Microbes are better prepared against triggering by oxidative, temperature and osmotic stress. Our finding of an overall positive mean effect of priming regardless of the microbial system and particular stressor provides unprecedentedly strong evidence of the broad ecological significance of microbial stress priming. These results further suggest that stress priming may be an important factor in shaping microbial communities. PMID- 26768989 TI - Geographic Factors and Human Papillomavirus (HPV) Vaccination Initiation among Adolescent Girls in the United States. AB - BACKGROUND: This study is among the first to explore geographic factors that may be associated with human papillomavirus (HPV) vaccine uptake in the United States. METHODS: Data from the 2011 and 2012 National Immunization Survey-Teen for 20,565 female adolescents aged 13 to 17 years were analyzed to examine associations of HPV vaccine initiation (receipt of at least one dose) with ZIP code-level geographic factors. Logistic regression including individual and geographic factors was used to estimate the odds of HPV vaccine initiation. RESULTS: Approximately 53% of girls initiated the HPV vaccine in both years. Girls in high poverty communities had higher HPV vaccine initiation compared with those in low poverty communities [61.1% vs. 52.4%; adjusted OR (AOR), 1.18; 95% confidence intervals (CI), 1.04-1.33]. Initiation was higher among girls in communities where the majority of the population was Hispanic (69.0% vs. 49.9%; AOR, 1.64; 95% CI, 1.43-1.87) or non-Hispanic mixed race (60.4% vs. 49.9%; AOR, 1.30; 95% CI, 1.17-1.44) compared with majority non-Hispanic white communities. Interactions between individual-level race/ethnicity and community racial-ethnic composition indicated significantly higher odds of initiation among Hispanic girls living in Hispanic communities compared with Hispanic girls living in predominantly non-Hispanic White (NHW) (AOR, 2.23; 95% CI, 1.87-2.65) or non Hispanic Black (NHB) (AOR, 1.90; 95% CI, 1.20-3.04) communities, respectively. CONCLUSION: Initiation rates of HPV vaccination among teen girls were highest in the poorest communities and among Hispanics living in communities where the racial-ethnic composition was predominantly Hispanic or mixed race. IMPACT: Given low HPV vaccination rates in the United States, these results provide important evidence to inform public health interventions to increase HPV vaccination. PMID- 26768992 TI - Careful Conversations and Careful Sex: HIV Posttesting Experiences Among African American Men in Rural Florida. AB - PURPOSE: In the United States, black/African American (black) men bear the greatest burden of human immunodeficiency virus (HIV), accounting for 42% of new HIV infections in 2012 despite being 6% of the population. In Florida, heterosexual HIV transmission has increased among black men. Few studies have examined HIV testing experiences for black heterosexual men (BHM) in the rural South. This study describes the post-HIV-testing trial experiences of BHM in rural Florida. METHODS: We conducted 12 focus groups (4-7 participants per group) in 3 rural Florida counties with BHM who participated in a larger randomized HIV testing trial. Interviews were professionally transcribed and data were analyzed using NVivo 10. The qualitative analysis was informed by the strengths perspective (ie, emphasis on abilities rather than risks) and used a thematic analytical approach. RESULTS: Sixty-seven men participated (median age 41.5 years); 39 (58%) earned a monthly income of less than $500, 38 (57%) attained education through high school or higher, 37 (55%) were unmarried, and 40 (60%) reported practicing monogamy; all who tested for HIV were negative for HIV. We identified 3 main themes based on self-reported actions: (1) risk reduction (eg, more consistent condom use, fewer sex partners), (2) sexual health communications with sex partners (eg, negotiating HIV testing with sex partners, getting to know partners better), and (3) health communications with peers and family (eg, disclosing test results, encouraging others to get tested). CONCLUSIONS: Among BHM, being in this HIV testing study facilitated increased protective behaviors and communications for HIV prevention. Interventions for BHM in rural areas warrant incorporating these strategies to encourage routine HIV testing. PMID- 26768994 TI - Characterization and Transcriptional Profile of Genes Involved in Glycoalkaloid Biosynthesis in New Varieties of Solanum tuberosum L. AB - Before commercial release, new potato (Solanum tuberosum) varieties must be evaluated for content of toxic compounds such as glycoalkaloids (GAs), which are potent poisons. GA biosynthesis proceeds via the cholesterol pathway to alpha chaconine and alpha-solanine. The goal of this study was to evaluate the relationship between total glycoalkaloid (TGA) content and the expression of GAME, SGT1, and SGT3 genes in potato tubers. TGA content was measured by HPLC-MS, and reverse transcription quantitative polymerase chain reactions were performed to determine the relative expression of GAME, SGT1, and SGT3 genes. We searched for cis-elements of the transcription start site using the PlantPAN database. There was a relationship between TGA content and the relative expression of GAME, SGT1, and SGT3 genes in potato tubers. Putative promoter regions showed the presence of several cis-elements related to biotic and abiotic stresses and light. These findings provide an important step toward understanding TGA regulation and variation in potato tubers. PMID- 26768995 TI - Time to say 'goodbye'. PMID- 26768993 TI - Replication characteristics of equine herpesvirus 1 and equine herpesvirus 3: comparative analysis using ex vivo tissue cultures. AB - Replication kinetics and invasion characteristics of equine herpesvirus-1 and -3 (EHV-1/-3) in nasal and vaginal mucosae were compared using explants. The explants were cultured during 96 h with little change in viability. The tissues were inoculated with EHV-1 03P37 (neuropathogenic), 97P70 (abortigenic) and EHV-3 04P57, collected at 0, 24, 48 and 72 h post inoculation (pi) and stained for viral antigens. Both EHV-1 and EHV-3 replicated in a plaquewise manner. The plaques were already observed at 24 h pi, their size increased over time and did not directly cross the basement membrane (BM). However, EHV-1 infected the monocytic cells (MC) and hijacked these cells to invade the lamina propria. In contrast, EHV-3 replication was fully restricted to epithelial cells; the virus did not breach the BM via a direct cell-to-cell spread nor used infected MC. EHV 1-induced plaques were larger in nasal mucosa compared to vaginal mucosa. The opposite was found for EHV-3-induced plaques. Both EHV-1 strains replicated with comparable kinetics in nasal mucosa. However, the extent of replication of the abortigenic strain in vaginal mucosa was significantly higher than that of the neuropathogenic strain. Two-to-five-fold lower numbers of EHV-1-infected MC underneath the BM were found in vaginal mucosa than in nasal mucosa. Our study has shown that (i) EHV-1 has developed in evolution a predisposition for respiratory mucosa and EHV-3 for vaginal mucosa, (ii) abortigenic EHV-1 replicates better in vaginal mucosa than neuropathogenic EHV-1 and (iii) EHV-3 demonstrated a strict epithelial tropism whereas EHV-1 in addition hijacked MC to invade the lamina propria. PMID- 26768996 TI - Allergic contact dermatitis caused by methylisothiazolinone in hair gel. PMID- 26768997 TI - Allergic contact dermatitis caused by Mirvaso(r), brimonidine tartrate gel 0.33%, a new topical treatment for rosaceal erythema. PMID- 26768999 TI - Pollination biology from micro-morphological adaptations to community ecology of plant-pollinator interactions. PMID- 26768998 TI - Compensatory renal hypertrophy and the handling of an acute nephrotoxicant in a model of aging. AB - Aging often results in progressive losses of functioning nephrons, which can lead to a significant reduction in overall renal function. Because of age-related pathological changes, the remaining functional nephrons within aged kidneys may be unable to fully counteract physiological and/or toxicological challenges. We hypothesized that when the total functional renal mass of aged rats is reduced by 50%, the nephrons within the remnant kidney do not fully undergo the functional and physiological changes that are necessary to maintain normal fluid and solute homeostasis. We also tested the hypothesis that the disposition and handling of a nephrotoxicant are altered significantly in aged kidneys following an acute, 50% reduction in functional renal mass. To test these hypotheses, we examined molecular indices of renal cellular hypertrophy and the disposition of inorganic mercury (Hg(2+)), a model nephrotoxicant, in young control, young uninephrectomized (NPX), aged control and aged NPX Wistar rats. We found that the process of aging reduces the ability of the remnant kidney to undergo compensatory renal growth. In addition, we found that an additional reduction in renal mass in aged animals alters the disposition of Hg(2+) and potentially alters the risk of renal intoxication by this nephrotoxicant. To our knowledge, this study represents the first report of the handling of a nephrotoxicant in an aged animal following a 50% reduction in functional renal mass. PMID- 26769000 TI - Multigene characterization of a new 'Candidatus Phytoplasma rubi'-related strain associated with blackberry witches' broom. AB - A new phytoplasma was identified in naturally infected blackberry plants exhibiting witches' broom symptoms in Portugal. The 16S rRNA gene sequence revealed that it is related to 'Candidatus Phytoplasma rubi' (16SrV-E ribosomal subgroup) and RFLP analysis revealed a unique profile following MseI endonuclease digestion of R16F2n/R2 amplicons that distinguished it from the strains belonging to previously established 16SrV phytoplasma subgroups. The in silico restriction analyses confirmed that the phytoplasma strain from blackberry is different from all the other strains reported in group 16SrV. Phylogeny of the 16S rRNA gene sequences, sequence analyses of 16S-23S, tuf, rplV-rpsC, rplF-rplR, rplO-SecY-map and uvrB-degV genetic loci, as well as the variability of unique oligonucleotide sequences defined for 'Candidatus Phytoplasma rubi' confirmed the uniqueness of this phytoplasma strain from Portugal for which a novel ribosomal subgroup, 16SrV I, is proposed. The representative of this new subgroup was named blackPort phytoplasma (Portuguese blackberry phytoplasma). PMID- 26769002 TI - Structural modifications in polymeric micelles to impart multifunctionality for improved drug delivery. AB - Polymeric micelles are macromolecular nanoconstructs which are formed by self assembly of synthetic amphiphilic block copolymers. These copolymers could be chemically modified to expand their functionality and hence obtain a multifunctional micelle which could serve several functions simultaneously, for example, long circulation time along with active targeting, smart polymeric micelles providing on-demand drug release for example, pH responsive micelles, redox- and light-sensitive micelles, charge-conversion micelles and core/shell cross-linked micelles. Additionally, micelles could be tailored to carry a contrast agent or siRNA/miRNA along with the drug for greater clinical benefit. The focus of the current commentary would be to highlight such chemical modifications which impart multifunctionality to a single carrier and discuss challenges involved in clinical translation of these multifunctional micelles. PMID- 26769003 TI - Lamin A is involved in the development of vascular calcification induced by chronic kidney failure and phosphorus load. AB - Vascular calcification remains one of the main factors associated to morbidity and mortality in both ageing and chronic kidney disease. Both hyperphosphataemia, a well-known promoter of vascular calcification, and abnormal processing defects of lamin A/C have been associated to ageing. The main aim of this study was to analyse the effect of phosphorus load in the differential expression pattern of genes and proteins, particularly of lamin A/C, which are involved in phenotypic change of the vascular smooth muscle cells to osteoblast-like cells. The in vivo study of the calcified abdominal aortas from nephrectomized rats receiving a high phosphorus diet showed among others, a repression of muscle related proteins and overexpression of lamin A/C. Similar results were observed in vitro, where primary vascular smooth muscle cells cultured in calcifying medium showed increased expression of prelamin A and lamin A and abnormalities in the nuclear morphology. Co-immunoprecipitation assays showed novel and important physical interactions between lamin A and RUNX2 during the process of calcification. In fact, the knockdown of prelamin A and lamin A inhibited the increase of Runx2, osteocalcin and osteopontin gene expression, calcium deposition, nuclear abnormalities and the RUNX2 protein translocation into the nucleus of the cell. These in vivo and in vitro results highlight the important role played by lamin A in the process of vascular calcification. PMID- 26769004 TI - Inhibition of TGFbeta signaling decreases osteogenic differentiation of fibrodysplasia ossificans progressiva fibroblasts in a novel in vitro model of the disease. AB - Fibrodysplasia ossificans progressiva is a rare genetic disorder characterized by progressive heterotopic ossification. FOP patients develop soft tissue lumps as a result of inflammation-induced flare-ups which leads to the irreversible replacement of skeletal muscle tissue with bone tissue. Classical FOP patients possess a mutation (c.617G>A; R206H) in the ACVR1-encoding gene which leads to dysregulated BMP signaling. Nonetheless, not all FOP patients with this mutation exhibit equal severity in symptom presentation or disease progression which indicates a strong contribution by environmental factors. Given the pro inflammatory role of TGFbeta, we studied the role of TGFbeta in the progression of osteogenic differentiation in primary dermal fibroblasts from five classical FOP patients based on a novel method of platelet lysate-based osteogenic transdifferentiation. During the course of transdifferentiation the osteogenic properties of the cells were evaluated by the mRNA expression of Sp7/Osterix, Runx2, Alp, OC and the presence of mineralization. During transdifferentiation the expression of osteoblast markers Runx2 (p<0.05) and Alp were higher in patient cells compared to healthy controls. All cell lines exhibited increase in mineralisation. FOP fibroblasts also expressed higher baseline Sp7/Osterix levels (p<0.05) confirming their higher osteogenic potential. The pharmacological inhibition of TGFbeta signaling during osteogenic transdifferentiation resulted in the attenuation of osteogenic transdifferentiation in all cell lines as shown by the decrease in the expression of Runx2 (p<0.05), Alp and mineralization. We suggest that blocking of TGFbeta signaling can decrease the osteogenic transdifferentiation of FOP fibroblasts. PMID- 26769005 TI - Association between allopurinol use and hip fracture in older patients. AB - BACKGROUND: Allopurinol reduces oxidative stress and interacts with purinergic signalling systems important in bone metabolism and muscle function. We assessed whether allopurinol use was associated with a reduced incidence of hip fracture in older people. METHODS: Analysis of prospective, routinely-collected health and social care data on patients undergoing health and social work assessment in a single geographical area over a 12year period. Exposure to allopurinol was derived from linked community prescribing data, and hospitalisation for hip fracture and comorbid disease was derived from linked hospitalisation data. Fine and Gray modelling was used to model time to hip fracture accounting for the competing risk of death, incorporating previous use of allopurinol, cumulative exposure to allopurinol as a time dependent variable, and covariate adjustments. RESULTS: 17,308 patients were alive at the time of first social work assessment without previous hip fracture; the mean age was 73years. 10,171 (59%) were female, and 1155 (8%) had at least one exposure to allopurinol. 618 (3.6%) sustained a hip fracture, and 4226 (24%) died during a mean follow-up of 7.2years. In fully-adjusted analyses, each year of allopurinol exposure conferred a hazard ratio of 1.01 (95% CI 0.99, 1.02; p=0.37) for hip fracture and 1.00 (0.99, 1.01; p=0.47) for death. Previous use of allopurinol conferred a hazard ratio of 0.76 (0.45, 1.26; p=0.28) for hip fracture and 1.13 (0.99, 1.29; p=0.07) for death. CONCLUSION: Greater cumulative use of allopurinol was not associated with a reduced risk of hip fracture or death in this cohort. PMID- 26769006 TI - Effect of anti-sclerostin therapy and osteogenesis imperfecta on tissue-level properties in growing and adult mice while controlling for tissue age. AB - Bone composition and biomechanics at the tissue-level are important contributors to whole bone strength. Sclerostin antibody (Scl-Ab) is a candidate anabolic therapy for the treatment of osteoporosis that increases bone formation, bone mass, and bone strength in animal studies, but its effect on bone quality at the tissue-level has received little attention. Pre-clinical studies of Scl-Ab have recently expanded to include diseases with altered collagen and material properties such as osteogenesis imperfecta (OI). The purpose of this study was to investigate the role of Scl-Ab on bone quality by determining bone material composition and tissue-level mechanical properties in normal wild type (WT) tissue, as well as mice with a typical OI Gly?Cys mutation (Brtl/+) in type I collagen. Rapidly growing (3-week-old) and adult (6-month-old) WT and Brtl/+ mice were treated for 5weeks with Scl-Ab. Fluorescent guided tissue-level bone composition analysis (Raman spectroscopy) and biomechanical testing (nanoindentation) were performed at multiple tissue ages. Scl-Ab increased mineral to matrix in adult WT and Brtl/+ at tissue ages of 2-4wks. However, no treatment related changes were observed in mineral to matrix levels at mid cortex, and elastic modulus was not altered by Scl-Ab at any tissue age. Increased mineral-to-matrix was phenotypically observed in adult Brtl/+ OI mice (at tissue ages>3wks) and rapidly growing Brtl/+ (at tissue ages>4wks) mice compared to WT. At identical tissue ages defined by fluorescent labels, adult mice had generally lower mineral to matrix ratios and a greater elastic modulus than rapidly growing mice, demonstrating that bone matrix quality can be influenced by animal age and tissue age alike. In summary, these data suggest that Scl-Ab alters the matrix chemistry of newly formed bone while not affecting the elastic modulus, induces similar changes between Brtl/+ and WT mice, and provides new insight into the interaction between tissue age and animal age on bone quality. PMID- 26769007 TI - The association of race/ethnicity and risk of atypical femur fracture among older women receiving oral bisphosphonate therapy. AB - PURPOSE: Several epidemiologic studies suggest that compared to white women, Asians have a greater propensity to suffer an atypical femur fracture (AFF) while taking bisphosphonate therapy. This study examines the relative risk of AFF following bisphosphonate initiation for Asian compared to white women. METHODS: Using data from a large integrated northern California healthcare delivery system, we examined diaphyseal femur fracture outcomes among women age>=50years old who initiated oral bisphosphonate therapy during 2002-2007. An AFF was defined by the 2013 American Society of Bone and Mineral Research Task Force criteria. The risk of radiographically-confirmed AFF was examined for Asian compared to white women, adjusting for differences in bisphosphonate exposure and other potential risk factors. RESULTS: Among 48,390 women (65.3% white, 17.1% Asian) who newly initiated bisphosphonate therapy and were followed for a median of 7.7years, 68 women experienced an AFF. The rate of AFF was 18.7 per 100,000 person-years overall and eight-fold higher among Asian compared to white women (64.2 versus 7.6 per 100,000 person-years). Asians were also more likely to have longer bisphosphonate treatment duration compared to whites (median 3.8 versus 2.7years). The age-adjusted relative hazard for AFF was 8.5 (95% confidence interval 4.9-14.9) comparing Asian to white women, and was only modestly reduced to 6.6 (3.7-11.5) after adjusting for bisphosphonate duration and current use. CONCLUSIONS: Our study confirms marked racial disparity in AFF risk that should be further investigated, particularly the mechanisms accounting for this difference. These findings also underscore the need to further examine the association of bisphosphonate duration and AFF in women of Asian race, as well as differential risk across Asian subgroups. In the interim, counseling of Asian women about osteoporosis drug continuation should include consideration of their potentially higher AFF risk. PMID- 26769008 TI - [Surgical treatment of ulnar collateral ligament injuries of the thumb metacarpophalangeal joint]. AB - OBJECTIVE: Reconstruction of the ruptured ulnar collateral ligament of the metacarpophalangeal (MP) joint of the thumb. INDICATIONS: Ruptured ulnar collateral ligament of the thumb MP joint with instability: joint opening of more than 30 degrees in flexion and more than 20 degrees in extension, Stener lesion, displaced avulsion fractures. CONTRAINDICATIONS: Abrasions, wound-healing disturbance, skin disease, osteoarthritis. SURGICAL TECHNIQUE: Curved skin incision dorsoulnar above the thumb MP joint. Protection of the branches of the superficial radial nerve. Incision of the adductor aponeurosis. Exposing the ulnar collateral ligament; opening and examination of the joint. Depending on the injury, primary suture repair, transosseous suture, repair with a bone anchor, osteosynthesis with K-wires or small screws in avulsion fracture, ligament reconstruction in chronic instability or older injury. POSTOPERATIVE TREATMENT: Cast splint of the MP joint until swelling subsides; cast immobilization for 6 weeks; range-of-motion exercises, avoiding forced radial deviation of the MP joint for 3 months. RESULTS: Complete joint stability 3 months postoperatively in all 34 patients with rupture of the ulnar collateral ligament. PMID- 26769009 TI - Effect of time-dependent cryotherapy on redox balance of quadriceps injuries. AB - Muscle trauma represents a high number of injuries in professional sport and recreation and may occur through several mechanisms. This study aims at analyzing time-dependent effects of cryotherapy on the redox balance in lesioned quadriceps muscles in F1 mice. Twenty male F1 mice were divided into five groups: (a) animals were not subjected to muscle lesioning or treatment (CTR); (b) quadriceps muscle was lesioned without treatment (L); (c) quadriceps muscle was lesioned and treated with cryotherapy for 5 min (LC5); (d) quadriceps muscle was lesioned and treated with cryotherapy for 20 min (LC20); and quadriceps muscle was lesioned and treated with cryotherapy for 40 min (LC40). The mice were euthanized; the quadriceps muscles were collected and subjected to analyses for levels of protein, hydroperoxides, nitrite, catalase (CAT) activity, oxidized glutathione (GSSG) and reduced glutathione (GSH). Protein levels were reduced in L (-39%; p < 0.05), LC5 (-54%; p < 0.05), LC20 (-40%; p < 0.05) and LC40 (-50%; p < 0.05) compared to CTR. There was an increase in lipid peroxidation in L (158%; p < 0.05), LC5 (300%; p < 0.01), LC20 (292%; p < 0.01) and LC40 (362%; p < 0.01) compared to CTR. We observed a significant increase in CAT activity in L (164%; p < 0.05) and LC5 (193%; p < 0.01) compared to CTR; a significant reduction in GSH in L (-60%; p < 0.05) and LC20 (-61%; p < 0.05) compared to CTR; and a significant increase in GSSG in LC5 (171%; p < 0.05) compared to CTR. In addition, GSH/GSSG was reduced in L (-89%; p < 0.01), LC5 (-95%; p < 0.01), LC20 (-59%; p < 0.05), and LC40 (-82%; p < 0.01) compared to CTR. This study showed that the cryotherapy does not improve the oxidative stress in lesioned muscles. PMID- 26769010 TI - Anti-vascular endothelial growth factor for control of wound healing in glaucoma surgery. AB - BACKGROUND: Trabeculectomy is performed as a treatment for glaucoma to lower intraocular pressure (IOP). The surgical procedure involves creating a channel through the wall of the eye. However scarring during wound healing can block this channel which will lead to the operation failing. Anti-vascular endothelial growth factor (VEGF) agents have been proposed to slow down healing response and scar formation. OBJECTIVES: To assess the effectiveness of anti-VEGF therapies administered by subconjunctival injection for the outcome of trabeculectomy at 12 months follow-up and to examine the balance of benefit and harms when compared to any other anti-scarring agents or no additional anti-scarring agents. SEARCH METHODS: We searched CENTRAL (which contains the Cochrane Eyes and Vision Trials Register) (2015, Issue 10), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to November 2015), EMBASE (January 1980 to November 2015), the ISRCTN registry (www.isrctn.com/editAdvancedSearch), ClinicalTrials.gov (www.clinicaltrials.gov) and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 12 November 2015. SELECTION CRITERIA: We included randomised controlled trials (RCTs) of anti-VEGF therapies administered by subconjunctival injection compared to any other anti-scarring agents or no additional anti-scarring agents (no treatment or placebo) in trabeculectomy surgery. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. Our primary outcome was successful trabeculectomy at 12 months after surgery which was defined as achieving a target IOP (usually no more than 21 mm Hg) without any additional intervention. Other outcomes included: qualified success (achieving target IOP with or without additional intervention), mean IOP and adverse events. MAIN RESULTS: We included five RCTs (175 participants, 177 eyes) that met the inclusion criteria in this review.One trial conducted in Iran (37 participants, 37 eyes) compared anti-VEGF (bevacizumab 0.2 mg) versus control (sham injection) in people with refractory glaucoma. We judged this study to be at low risk of bias.The primary outcome of this review was not reported; mean IOP at three months was 15.1 mm Hg (standard deviation 1.0) in both anti-VEGF and control groups.Four trials compared anti-VEGF to mitomycin C (MMC) (138 particpants, 140 eyes). These studies were conducted in India, Iran, Turkey and the USA. The anti-VEGF agent used in these four trials was bevacizumab 2.5 mg (two trials), bevacizumab 1.25 mg three times and ranibizumab 0.5 mg. Two trials were at high risk of bias in two domains and one trial was at high risk of bias in four domains.Only one of these trials reported the primary outcome of this review (42 participants, 42 eyes). Low quality evidence from this trial showed that people receiving bevacizumab 2.5 mg during primary trabeculectomy were less likely to achieve complete success at 12 months compared to people receiving MMC but the confidence interval (CI) was wide and compatible with increased chance of complete success for anti-VEGF (risk ratio (RR) 0.71, 95% CI 0.46 to 1.08), Assuming that approximately 81% of people receiving MMC achieve complete success, the anticipated success using anti-VEGF agents would be between 37.2% and 87.4%. The same trial suggested no evidence for any difference in qualified success between bevacizumab and MMC (RR 1.00, 95% CI 0.87 to 1.14, moderate quality evidence). Two trials of primary trabeculectomy provided data on mean IOP at 12 months; one trial of bevacizumab 2.5 mg and one trial of ranibizumab 0.5 mg. Mean IOP was 1.86 mm Hg higher (95% CI 0.15 to 3.57) in the anti-VEGF groups compared to the MMC groups (66 people, low quality evidence). Data were reported on wound leak, hypotony, shallow anterior chamber and endophthalmitis, but these events occurred rarely and currently there are not enough data available to detect any differences, if any, between the two treatments. AUTHORS' CONCLUSIONS: The evidence is currently of low quality which is insufficient to refute or support anti-VEGF subconjunctival injection for control of wound healing in glaucoma surgery. The effect on IOP control of anti VEGF agents in glaucoma patients undergoing trabeculectomy is still uncertain, compared to MMC.Further RCTs of anti-VEGF subconjunctival injection in glaucoma surgery are required, particularly compared to sham treatment with at least 12 months follow-up. PMID- 26769011 TI - Spontaneous flow in polar active fluids: the effect of a phenomenological self propulsion-like term. AB - We present hybrid lattice Boltzmann simulations of extensile and contractile active fluids where we incorporate phenomenologically the tendency of active particles such as cell and bacteria, to move, or swim, along the local orientation. Quite surprisingly, we show that the interplay between alignment and activity can lead to completely different results, according to geometry (periodic boundary conditions or confinement between flat walls) and nature of the activity (extensile or contractile). An interesting generic outcome is that the alignment interaction can transform stationary active patterns into continuously moving ones: the dynamics of these evolving patterns can be oscillatory or chaotic according to the strength of the alignment term. Our results suggest that flow-polarisation alignment can have important consequences on the collective dynamics of active fluids and active gel. PMID- 26769012 TI - Optimising treatment of CF pulmonary exacerbation: a tough nut to crack. PMID- 26769013 TI - Lung cancer screening: what we can learn from UKLS? PMID- 26769014 TI - Untangling the protease web in COPD: metalloproteinases in the silent zone. PMID- 26769015 TI - Validation of the DECAF score to predict hospital mortality in acute exacerbations of COPD. AB - BACKGROUND: Hospitalisation due to acute exacerbations of COPD (AECOPD) is common, and subsequent mortality high. The DECAF score was derived for accurate prediction of mortality and risk stratification to inform patient care. We aimed to validate the DECAF score, internally and externally, and to compare its performance to other predictive tools. METHODS: The study took place in the two hospitals within the derivation study (internal validation) and in four additional hospitals (external validation) between January 2012 and May 2014. Consecutive admissions were identified by screening admissions and searching coding records. Admission clinical data, including DECAF indices, and mortality were recorded. The prognostic value of DECAF and other scores were assessed by the area under the receiver operator characteristic (AUROC) curve. RESULTS: In the internal and external validation cohorts, 880 and 845 patients were recruited. Mean age was 73.1 (SD 10.3) years, 54.3% were female, and mean (SD) FEV1 45.5 (18.3) per cent predicted. Overall mortality was 7.7%. The DECAF AUROC curve for inhospital mortality was 0.83 (95% CI 0.78 to 0.87) in the internal cohort and 0.82 (95% CI 0.77 to 0.87) in the external cohort, and was superior to other prognostic scores for inhospital or 30-day mortality. CONCLUSIONS: DECAF is a robust predictor of mortality, using indices routinely available on admission. Its generalisability is supported by consistent strong performance; it can identify low-risk patients (DECAF 0-1) potentially suitable for Hospital at Home or early supported discharge services, and high-risk patients (DECAF 3-6) for escalation planning or appropriate early palliation. TRIAL REGISTRATION NUMBER: UKCRN ID 14214. PMID- 26769016 TI - A randomised trial of hypertonic saline during hospitalisation for exacerbation of cystic fibrosis. AB - BACKGROUND: The mucoactive effects of hypertonic saline should promote exacerbation resolution in people with cystic fibrosis (CF). OBJECTIVES: To determine the effects of hypertonic saline inhalation during hospitalisation for exacerbation of CF on length of stay, lung function, symptoms, oxygenation, exercise tolerance, quality of life, bacterial load and time to next hospitalisation. METHODS: 132 adults with an exacerbation of CF were randomised to inhale three nebulised doses a day of either 4 mL 7% saline or a taste-masked control of 0.12% saline, throughout the hospital admission. The primary outcome measure was length of hospital stay. RESULTS: All participants tolerated their allocated saline solution. There was no significant difference in length of stay, which was 12 days in the hypertonic saline group and 13 days in controls, with a mean between-group difference (MD) of 1 day (95% CI 0 to 2). The likelihood of regaining pre-exacerbation FEV1 by discharge was significantly higher in the hypertonic saline group (75% vs 57%), and the number needed to treat was 6 (95% CI 3 to 65). On a 0-100 scale, the hypertonic saline group had significantly greater reduction in symptom severity than the control group at discharge in sleep (MD=13, 95% CI 4 to 23), congestion (MD=10, 95% CI 3 to 18) and dyspnoea (MD=8, 95% CI 1 to 16). No significant difference in time to next hospitalisation for a pulmonary exacerbation was detected between groups (HR=0.86 (CI 0.57 to 1.30), p=0.13). Other outcomes did not significantly differ. CONCLUSIONS: Addition of hypertonic saline to the management of a CF exacerbation did not reduce the length of hospital stay. Hypertonic saline speeds the resolution of exacerbation symptoms and allows patients to leave hospital with greater symptom resolution. TRIAL REGISTRATION NUMBER: ACTRN12605000780651. PMID- 26769017 TI - Long-term impact of developing a postoperative pulmonary complication after lung surgery. AB - INTRODUCTION: Postoperative pulmonary complications (PPC) such as atelectasis and pneumonia are common following lung resection. PPCs have a significant clinical impact on postoperative morbidity and mortality. We studied the long-term effects of PPCs and sought to identify independent risk factors. METHODS: A prospective observational study involved all patients following lung resection in a regional thoracic centre over 4 years. PPCs were assessed daily in hospital using the Melbourne group scale based on chest X-ray, white cell count, fever, purulent sputum, microbiology, oxygen saturations, physician diagnosis and intensive therapy unit (ITU)/high-dependency unit readmission. Follow-up included hospital length of stay (LOS), 30-day readmissions, and mortality. RESULTS: 86 of 670 patients (13%) who had undergone a lung resection developed a PPC. Those patients had a significantly longer hospital LOS in days (13, 95% CI 10.5-14.9 vs 6.3, 95% CI 5.9 to 6.7; p<0.001) and higher rates of ITU admissions (28% vs 1.9%; p<0.001) and 30-day hospital readmissions (20.7% vs 11.9%; p<0.05). Significant independent risk factors for development of PPCs were COPD and smoking (p<0.05), not age. Excluding early postoperative deaths, developing a PPC resulted in a significantly reduced overall survival in months (40, 95% CI 34 to 44 vs 46, 95% CI 44 to 47; p=0.006). Those who developed a PPC had a higher rate of non-cancer related deaths (11% vs 5%; p=0.020). PPC is a significant independent risk factor for late deaths in non-small cell lung cancer patients (HR 2.0, 95% CI 1.9 to 3.2; p=0.006). CONCLUSIONS: Developing a PPC after thoracic surgery is common and is associated with a poorer long-term outcome. PMID- 26769019 TI - Life satisfaction after traumatic brain injury: comparison of ratings with the Life Satisfaction Questionnaire (LiSat-11) and the Satisfaction With Life Scale (SWLS). AB - BACKGROUND: An optimal life satisfaction (LS) is considered an important long term outcome after a traumatic brain injury (TBI). It is, however, not clear to what extent a single instrument captures all aspects of LS, and different instruments may be needed to comprehensively describe LS. The aim of this study was to compare self-ratings of life satisfaction after a TBI with two commonly used instruments. METHODS: Life Satisfaction Questionnaire (LiSat-11), comprising eleven items and Satisfaction With Life Scale (SWLS), comprising five items, were administered to 67 individuals (51 men and 16 women). Secondary analysis of data collected as part of a survey of individuals with TBI 6 to 15 years post TBI. RESULTS: Item 1 in LiSat-11 ('Life as a whole') and the total SWLS score was strongly correlated (Spearman's rho = 0.66; p < 0.001). The total score in SWLS had the strongest correlation with items in LiSat-11. All items in LiSat-11, except 'Family life' and 'Partner relationship', were moderately to strongly correlated with items in SWLS. The item 'Partner relationship' in LiSat-11 did not correlate with any of the items in SWLS or the total score. The item 'If I could live my life over, I would change nothing' in SWLS had the weakest correlations with items in LiSat-11. Items 'Vocation' and 'Leisure' in LISat-11 were most strongly correlated with items in SWLS, whereas the item 'ADL' in LiSat 11 was more weakly correlated with items in SWLS. CONCLUSIONS: The strength of the relationships implies that the two instruments assess similar but not identical aspects of LS and therefore complement each other when it is rated. PMID- 26769020 TI - Right hepatic artery from splenic artery: the four-leaf clover of hepatic surgery. AB - The anatomy of hepatic arteries is one of the most variable. Accurate awareness of all the possible anatomic variations is crucial in the upper GI surgery and especially in liver and pancreas transplantation. The most frequent anatomical variants are: a replaced or accessory right hepatic artery (RHA) from the superior mesenteric artery (6.3-21 %), a replaced or accessory left hepatic artery (LHA) from the left gastric artery (LGA) (3-18 %) or a combination of these two variants (up to 7.4 %). Herein, we describe the case of a 67-year-old cadaveric organ donor who presented a RHA originating from the splenic artery (SA) associated with both a CHA originating from the celiac trunk (CT) and a LHA originating from the LGA. PMID- 26769021 TI - Internet-based treatment for Romanian adults with panic disorder: protocol of a randomized controlled trial comparing a Skype-guided with an unguided self-help intervention (the PAXPD study). AB - BACKGROUND: Efficacy of self-help internet-based cognitive behavior therapy (ICBT) for anxiety disorders has been confirmed in several randomized controlled trials. However, the amount and type of therapist guidance needed in ICBT are still under debate. Previous studies have shown divergent results regarding the role of therapist guidance and its impact on treatment outcome. This issue is central to the development of ICBT programs and needs to be addressed directly. The present study aims to compare the benefits of regular therapist guidance via online real-time audio-video communication (i.e. Skype) to no therapist guidance during a 12-week Romanian self-help ICBT program for Panic Disorder. Both treatments are compared to a waiting-list control group. METHODS/DESIGN: A parallel group randomized controlled trial is proposed. The participants, 192 Romanian adults fulfilling diagnostic criteria for panic disorder according to a diagnostic interview, conducted via secured Skype or telephone, are randomly assigned to one of the three conditions: independent use of the internet-based self-help program PAXonline, the same self-help treatment with regular therapist support via secured Skype, and waiting-list control group. The primary outcomes are severity of self-report panic symptoms (PDSS-SR) and diagnostic status (assessors are blind to group assignment), at the end of the intervention (12 weeks) and at follow-up (months 3 and 6). The secondary measures address symptoms of comorbid anxiety disorders, depression, quality of life, adherence and satisfaction with ICBT. Additional measures of socio-demographic characteristics, personality traits, treatment expectancies, catastrophic cognitions, body vigilance and working alliance are considered as potential moderators and/ or mediators of treatment outcome. DISCUSSION: To the best of our knowledge, the present study is the first effort to investigate the efficacy of a self-help internet-based intervention with therapist guidance via real-time video communication. A direct comparison between therapist guided versus unguided self directed intervention for panic disorder will also be addressed for the first time. Findings from this study will inform researchers and practitioners about the added value of online video-therapy guidance sessions and the type of patients who may benefit the most from guided and unguided ICBT for Panic disorder. TRIAL REGISTRATION: ACTRN12614000547640 (Australian New Zealand Clinical Trials Registry). Registered 22/05/2014. PMID- 26769022 TI - Wellbeing and Arthritis Incidence: the Survey of Health, Ageing and Retirement in Europe. AB - BACKGROUND: A number of studies provide evidence for an association between psychosocial factors and risk of incident arthritis. Current evidence is largely limited to the examination of negative factors such as perceived stress, but positive factors such as subjective wellbeing may also play a role. PURPOSE: The purpose of the current study was to investigate whether people with higher subjective wellbeing have a lower risk of developing arthritis. METHODS: We used Cox proportional hazards regression to examine the prospective relationship between wellbeing (measured using the CASP-12) and incidence of arthritis over a 9-year period. The sample consisted of 13,594 participants aged >=50 years from the Survey of Health, Ageing and Retirement in Europe. RESULTS: There was a significant association between greater wellbeing and reduced incident arthritis that was stronger at younger ages. In sex-adjusted analyses, for a standard deviation increase in CASP-12 score, the hazard ratios (95 % confidence intervals) for incident arthritis in people aged <65 and >=65 years were 0.73 (0.69-0.77) and 0.80 (0.77-0.85), respectively. After further adjustment for other established risk factors, these associations were attenuated but remained significant in both age groups: the fully adjusted hazard ratios were 0.82 (0.77 0.87) and 0.88 (0.82-0.95), respectively. CONCLUSIONS: These results provide evidence for an association between greater wellbeing and reduced risk of incident arthritis and, more generally, support the theory that psychosocial factors are implicated in the aetiology of this disease. Future research needs to delineate the mechanisms underlying the association between wellbeing and arthritis risk. PMID- 26769023 TI - Dispositional and Situational Avoidance and Approach as Predictors of Physical Symptom Bother Following Breast Cancer Diagnosis. AB - BACKGROUND: Few studies examine whether dispositional approach and avoidance coping and stressor-specific coping strategies differentially predict physical adjustment to cancer-related stress. PURPOSE: This study examines dispositional and situational avoidance and approach coping as unique predictors of the bother women experience from physical symptoms after breast cancer treatment, as well as whether situational coping mediates the prediction of bother from physical symptoms by dispositional coping. METHOD: Breast cancer patients (N = 460) diagnosed within the past 3 months completed self-report measures of dispositional coping at study entry and of situational coping and bother from physical symptoms every 6 weeks through 6 months. RESULTS: In multilevel structural equation modeling analyses, both dispositional and situational avoidance predict greater symptom bother. Dispositional, but not situational, approach predicts less symptom bother. Supporting mediation models, dispositional avoidance predicts more symptom bother indirectly through greater situational avoidance. Dispositional approach predicts less symptom bother through less situational avoidance. CONCLUSION: Psychosocial interventions to reduce cancer related avoidance coping are warranted for cancer survivors who are high in dispositional avoidance and/or low in dispositional approach. PMID- 26769024 TI - How do nursing home doctors involve patients and next of kin in end-of-life decisions? A qualitative study from Norway. AB - BACKGROUND: Ethically challenging critical events and decisions are common in nursing homes. This paper presents nursing home doctors' descriptions of how they include the patient and next of kin in end-of-life decisions. METHODS: We performed ten focus groups with 30 nursing home doctors. Advance care planning; aspects of decisions on life-prolonging treatment, and conflict with next of kin were subject to in-depth analysis and condensation. RESULTS: The doctors described large variations in attitudes and practices in all aspects of end-of life decisions. In conflict situations, many doctors were more concerned about the opinion of next of kin than ensuring the patient's best interest. CONCLUSIONS: Many end-of-life decisions appear arbitrary or influenced by factors independent of the individual patient's values and interests and are not based on systematic ethical reflections. To protect patient autonomy in nursing homes, stronger emphasis on legal and ethical knowledge among nursing home doctors is needed. PMID- 26769025 TI - Hemodialysis patients with intradialytic rise in blood pressure display higher baseline aortic stiffness and negligible drop in augmentation index with dialysis. AB - BACKGROUND: In hemodialysis patients, the intradialytic rise in blood pressure (BP) is associated with increased mortality risk. However, the mechanisms of this adverse effect are not yet elucidated. This study examined whether intradialytic rise in BP is associated with increased arterial stiffness and wave reflections, which are powerful cardiovascular risk predictors in hemodialysis. METHODS: The pattern of intradialytic hemodynamic response was evaluated in 70 prevalent hemodialysis patients, by measuring seated brachial BP before and after the mid week dialysis session. All patients had pre- and post-dialysis determination of aortic pulse wave velocity (PWV) and heart rate-adjusted augmentation index [AIx(75)], as measures of arterial stiffness and wave reflections, with the Sphygmocor device. RESULTS: Intradialytic rise in brachial systolic BP (SBP) was evident in 17 patients, whereas intradialytic change in SBP (DeltaSBP) of -10 to 0 mmHg was observed in 23 and DeltaSBP greater than -10 mmHg in 30 patients. Participants with intradialytic SBP rise had significantly higher pre-dialysis aortic PWV (10.4 +/- 1.6 vs 8.3 +/- 1.9 vs 9.4 +/- 2.4 m/s, P < 0.01) and AIx(75) (28.1 +/- 7.3 vs 21.7 +/- 8.6 vs 25.8 +/- 8.2%, P < 0.05) than those experiencing intradialytic DeltaSBP of -10 to 0 and greater than -10 mmHg, respectively. Patients with rise in SBP during dialysis exhibited also lower intradialytic reduction in AIx(75) (-1.5 +/- 4.9 vs -5.4 +/- 5.9 vs -6.7 +/- 5.3%, P < 0.001). CONCLUSIONS: This study shows that aortic stiffness and wave reflections are higher and not affected by dialysis procedure in patients with intradialytic SBP rise, suggesting that accelerated arteriosclerosis may be one possible explanation for the heightened cardiovascular risk associated with intradialytic hypertension. PMID- 26769026 TI - Final Results of a 3-Year Literacy-Informed Intervention to Promote Annual Fecal Occult Blood Test Screening. AB - This three arm study was designed to make CRC screening with FOBTs more accessible, understandable and actionable for patients cared for in predominantly rural Federally Qualified Health Centers. Patients in an enhanced version of usual care received an annual CRC recommendation and FOBT kit; those in the education arm additionally received brief literacy and culturally appropriate education and those in the nurse arm received the education by a nurse manager who followed up by telephone. Baseline FOBT rates in this population were 3 %. We evaluated if FOBT rates could be sustained over 3 years. A three-arm, quasi experimental evaluation was conducted among eight clinics in Louisiana. Screening efforts included: (1) enhanced usual care, (2) literacy-informed education of patients, and (3) education plus nurse support. Overall, 961 average-risk patients, ages 50-85, eligible for routine CRC screenings were recruited. The primary outcome was completing three annual FOBT tests. Of 961 patients enrolled, 381 (39.6 %) participants did not complete a single FOBT, 60.4 % completed at least one FOBT of which 318 (33.1 %) completed only one, 162 (16.9 %) completed two and 100 (10.4 %) completed three FOBTs over the 3-year period (the primary study outcome). The primary outcome, return of three FOBT kits over the 3-year period, was achieved by 4.7 % in enhanced care, 11.4 % in education and 13.6 % in the nurse arm (p = 0.005). Overall 3-year FOBT screening rates were not sustained with any of the three interventions, despite reports of promising interim results at years 1 and 2. New strategies for sustaining FOBT screening over several years must be developed. PMID- 26769027 TI - Toll-like Receptor Expression Profile of Human Dental Pulp Stem/Progenitor Cells. AB - INTRODUCTION: Human dental pulp stem/progenitor cells (DPSCs) show remarkable regenerative potential in vivo. During regeneration, DPSCs may interact with their inflammatory environment via toll-like receptors (TLRs). The present study aimed to depict for the first time the TLR expression profile of DPSCs. METHODS: Cells were isolated from human dental pulp, STRO-1-immunomagnetically sorted, and seeded out to obtain single colony-forming units. DPSCs were characterized for CD14, CD34, CD45, CD73, CD90, CD105, and CD146 expression and for their multilineage differentiation potential. After incubation of DPSCs in basic or inflammatory medium (interleukin-1beta, interferon-gamma, interferon-alpha, tumor necrosis factor-alpha), TLR expression profiles were generated (DPSCs and DPSCs i). RESULTS: DPSCs showed all characteristics of stem/progenitor cells. In basic medium DPSCs expressed TLRs 1-10 in different quantities. The inflammatory medium upregulated the expression of TLRs 2, 3, 4, 5, and 8, downregulated TLRs 1, 7, 9, and 10, and abolished TLR6. CONCLUSIONS: The current study describes for the first time the distinctive TLR expression profile of DPSCs in uninflamed and inflamed conditions. PMID- 26769028 TI - Final Irrigation Regimens Affect Fracture Resistance Values of Root-filled Teeth. AB - INTRODUCTION: The purpose of this study was to compare the effect of different final irrigation solutions on fracture resistance values (FRVs) of endodontically treated teeth. METHODS: Eighty extracted decoronated human incisors were used. Ten randomly selected roots were used as the negative control group. The remaining roots were prepared by the ProTaper system (Dentsply Maillefer, Ballaigues, Switzerland) up to F2. Ten prepared roots were selected as the positive control. The other prepared roots were divided into 6 (n = 10) groups according to the final irrigation solution used: 5 mL saline, 17% EDTA, EDTA with a surfactant (REDTA), chlorhexidine, QMix (Dentsply Tulsa Dental Specialties, Tulsa, OK), and BioPure MTAD (Dentsply Tulsa Dental Specialties). In all groups, the final irrigation was performed for 1 minute except for the BioPure MTAD group; in this group, it was applied for 5 minutes according to the manufacturer's instructions. The specimens were filled with a single gutta-percha cone and AH 26 sealer (Dentsply, De Trey, Konstanz, Germany). After being stored under 37 degrees C and 100% humidity for a week, the specimens were loaded in a vertical direction at 1 mm/min speed until they were vertically fractured. The results were analyzed by the Kruskal-Wallis and Siegel Castellan tests. RESULTS: The negative control group showed the highest FRV. There were statistically significant differences between the negative and positive control groups (P < .05). Specimens irrigated with REDTA and QMix showed a higher FRV compared with the positive control group (P < .05). Specimens exposed to chlorhexidine and BioPure MTAD showed a lower FRV compared with the negative control group (P < .05). CONCLUSIONS: Root canal preparation weakens the tooth. The final irrigation regimen has an impact on the FRV. A short time exposure to irrigation solutions (REDTA and QMix) that include surfactants probably contributed to the higher FRV, instead of a long time exposure as done with BioPure MTAD. PMID- 26769031 TI - Proteins with Highly Evolvable Domain Architectures Are Nonessential but Highly Retained. AB - The functions of proteins are usually determined by domains, and the sequential order in which domains are connected to make up a protein chain is known as the domain architecture. Here, we constructed evolutionary networks of protein domain architectures in species from three major life lineages (bacteria, fungi, and metazoans) by connecting any two architectures between which an evolutionary event could be inferred by a model that assumes maximum parsimony. We found that proteins with domain architectures with a higher level of evolvability, indicated by a greater number of connections in the evolutionary network, are present in a wider range of species. However, these proteins tend to be less essential to the organism, are duplicated more often during evolution, have more isoforms, and, intriguingly, tend to be associated with functional categories important for organismal adaptation. These results reveal the presence, in many genomes, of genes coding for a core set of nonessential proteins that have a highly evolvable domain architecture and thus a repertoire of genetic materials accessible for organismal adaptation. PMID- 26769030 TI - Indispensability of Horizontally Transferred Genes and Its Impact on Bacterial Genome Streamlining. AB - Why are certain bacterial genomes so small and compact? The adaptive genome streamlining hypothesis posits that selection acts to reduce genome size because of the metabolic burden of replicating DNA. To reveal the impact of genome streamlining on cellular traits, we reduced the Escherichia coli genome by up to 20% by deleting regions which have been repeatedly subjects of horizontal transfer in nature. Unexpectedly, horizontally transferred genes not only confer utilization of specific nutrients and elevate tolerance to stresses, but also allow efficient usage of resources to build new cells, and hence influence fitness in routine and stressful environments alike. Genome reduction affected fitness not only by gene loss, but also by induction of a general stress response. Finally, we failed to find evidence that the advantage of smaller genomes would be due to a reduced metabolic burden of replicating DNA or a link with smaller cell size. We conclude that as the potential energetic benefit gained by deletion of short genomic segments is vanishingly small compared with the deleterious side effects of these deletions, selection for reduced DNA synthesis costs is unlikely to shape the evolution of small genomes. PMID- 26769032 TI - Different potential risk of injury from thoracic pedicle screw insertion between left and right main-stem bronchus in Lenke 1 type adolescent idiopathic scoliosis. AB - PURPOSE: The changed relative anatomic position of trachea with increased potential risk of injury from thoracic pedicle screw (TPS) has been reported in Lenke 1 type adolescent idiopathic scoliosis (AIS) patients. However, such change of main-stem bronchus has not been investigated. The purposes of this study were to evaluate the altered positions of both left and right main-stem bronchus in Lenke 1 type patients and to assess the potential risks of main-stem bronchus injuries from TPS screw insertion in these patients. METHODS: A total of 19 Lenke 1 type AIS patients and 15 normal teenagers were included. Axial computed tomography (CT) images at T5 level were obtained in all these subjects to evaluate the main-stem bronchus-vertebral distance (MVD, the closet distance between the main-stem bronchus and vertebral body) and main-stem bronchus vertebral angle (MVA, defined as 0 degrees when the main-stem bronchus was located directly lateral to the left and 180 degrees when directly lateral to the right) on both left and right sides. The percentage of main-stem bronchus located adjacent to vertebrae and in the direction of screw passage was calculated to analyze potential risks of injuries from pedicle screw placement. RESULTS: Both the average left and right MVD were significantly smaller in AIS patients when compared with normal teenagers at T5 level (P < 0.05). Both the mean left and right MVA were lower in AIS patients than those in normal teenagers at T5 level (P < 0.05). All the AIS patients (100 %) had the right main-stem bronchus with high risk of injury from right TPS placement and only five AIS patients (26.3 %) had left main-stem bronchus with high risk of injury from left TPS placement at T5 level. No main-stem bronchus was found to be at risk of injury from TPS placement on both two sides in normal teenagers at this level. CONCLUSIONS: Both the right and left main-stem bronchus were located much closer to the vertebrae in Lenke 1 type AIS patients when compared with normal teenagers. However, the potential risk of injury of main-stem bronchus from TPS placement was higher on the right side than that on the left side. PMID- 26769033 TI - Psychometric properties including reliability, validity and responsiveness of the Majeed pelvic score in patients with chronic sacroiliac joint pain. AB - PURPOSE: The Majeed scoring system is a disease-specific outcome measure that was originally designed to assess pelvic injuries. The aim of this study was to determine the psychometric properties of the Majeed scoring system for chronic sacroiliac joint pain. METHODS: Internal consistency, content validity, criterion validity, construct validity and responsiveness to change was assessed prospectively for the Majeed scoring system in a cohort of 60 patients diagnosed with sacroiliac joint pain. This diagnosis was confirmed with CT-guided sacroiliac joint anaesthetic block. RESULTS: The overall Majeed score showed acceptable internal consistency (Cronbach alpha = 0.63). Similarly, it showed acceptable floor (0 %) and ceiling (0 %) effects. On the other hand, the domains of pain, work, sitting and sexual intercourse had high (>30 %) floor effects. Significant correlation with the physical component of the Short Form-36 (p = 0.005) and Oswestry disability index (p <= 0.001) was found indicating acceptable criterion validity. The overall Majeed score showed acceptable construct validity with all five developed hypotheses showing significance (p <= 0.05). The overall Majeed score showed acceptable responsiveness to change with a large (>=0.80) effect size and standardized response mean. CONCLUSION: Overall the Majeed scoring system demonstrated acceptable psychometric properties for outcome assessment in chronic sacroiliac joint pain. Thus, its use in this condition is adequate. However, some domains demonstrated suboptimal performance indicating that improvement might be achieved with the development of an outcome measure specific for sacroiliac joint dysfunction and degeneration. PMID- 26769034 TI - Does usage of a parachute in contrast to free fall prevent major trauma?: a prospective randomised-controlled trial in rag dolls. AB - PURPOSE: It is undisputed for more than 200 years that the use of a parachute prevents major trauma when falling from a great height. Nevertheless up to date no prospective randomised controlled trial has proven the superiority in preventing trauma when falling from a great height instead of a free fall. The aim of this prospective randomised controlled trial was to prove the effectiveness of a parachute when falling from great height. METHODS: In this prospective randomised-controlled trial a commercially acquirable rag doll was prepared for the purposes of the study design as in accordance to the Declaration of Helsinki, the participation of human beings in this trial was impossible. Twenty-five falls were performed with a parachute compatible to the height and weight of the doll. In the control group, another 25 falls were realised without a parachute. The main outcome measures were the rate of head injury; cervical, thoracic, lumbar, and pelvic fractures; and pneumothoraxes, hepatic, spleen, and bladder injuries in the control and parachute groups. An interdisciplinary team consisting of a specialised trauma surgeon, two neurosurgeons, and a coroner examined the rag doll for injuries. Additionally, whole-body computed tomography scans were performed to identify the injuries. RESULTS: All 50 falls-25 with the use of a parachute, 25 without a parachute-were successfully performed. Head injuries (right hemisphere p = 0.008, left hemisphere p = 0.004), cervical trauma (p < 0.001), thoracic trauma (p < 0.001), lumbar trauma (p < 0.001), pelvic trauma (p < 0.001), and hepatic, spleen, and bladder injures (p < 0.001) occurred more often in the control group. Only the pneumothoraxes showed no statistically significant difference between the control and parachute groups. CONCLUSIONS: A parachute is an effective tool to prevent major trauma when falling from a great height. PMID- 26769029 TI - Neurogenesis in the Hippocampus of Patients with Temporal Lobe Epilepsy. AB - The mobilization of endogenous neural stem cells in order to substitute lost neurons in the adult brain may reduce the negative effects of patients with chronic neurodegenerative diseases. However, abnormal neurogenesis may be harmful and could lead to the worsening of patients' symptoms. In the brains of patients and animal models with temporal lobe epilepsy (TLE), increased newly generated neurons in the subgranular zone (SGZ) at early stages after brain insults have been speculated to be involved in epileptogenesis. However, this argument is unsupported by evidence showing that (1) hippocampal neurogenesis is reduced at chronic stages of intractable TLE, (2) decreased neurogenesis is involved in epileptogenesis, and (3) spontaneous recurrent seizures occur before newly generated neurons are integrated into hippocampal neural pathways. Therefore, the hypothesis of increased neurogenesis in epileptogenesis may need to be re evaluated. In this paper, we systemically reviewed brain neurogenesis and relevant molecules in the regulation of neurogenesis in SGZ. We aimed to update researchers and epileptologists on current progresses on pathophysiological changes of neurogenesis at different stages of TLE in patients and animal models of TLE. The interactions among neurogenesis, epileptogenesis and cognitive impairment, and molecules' mechanism involved in neurogenesis would also be discussed. Future research directions are proposed at the end of this paper. PMID- 26769036 TI - Analysis of the reliability of surgeons' ability to differentiate between idiopathic and degenerative spinal deformity in adults radiologically. What descriptive parameters help them decide? AB - PURPOSE: Adult spinal deformity (ASD) may be classified as idiopathic (ID) or degenerative (DD) (or other) based on classifier's perception, the reliability of and factors inherent to which remain unknown. The aim of this study is to evaluate the inter- and intra-observer reliability of surgeons' perception in differentiating ID from DD and to identify the determinants of this differentiation. METHODS: From a multicentric prospective database of ASD, 179 patients were identified with the diagnosis of ID (n = 103) or DD (n = 76); without previous surgery; and a lumbar coronal curve larger than 20 degrees . Standing antero-posterior and lateral X-rays of these patients were sent to five experienced spine surgeons to be identified as DD or ID (or other); followed by a second round after reshuffling. Weighted kappa statistics were used, the strength of agreement for the kappa coefficient was considered as; 0.81-1 = almost perfect, 0.61-0.8 = substantial, 0.41-0.60 = moderate, 0.21-0.40 = fair, 0.01 0.20 = slight, and <=0 = poor. Patients were then stratified based on the number of agreements on a total of 10 rounds as excellent (10 out of 10), good (more than 7 out of 10) and fair/poor (7 and less). These excellent and good agreements were further compared for additional radiological parameters. RESULTS: Agreement levels were moderate to substantial for intra but mostly fair for inter-observer comparisons. For ID patients, there were 42 cases with excellent and 38 with very good agreement whereas for DD, there were no excellent and only 17 cases with very good agreement. Upon comparison of these (ID vs DD for at least very good cases), it was seen that they were different for some coronal parameters such as lumbar Cobb angle (larger in ID, p < 0.001), central sacral vertical line (CSVL) modifier (C more common in ID, p = 0.007) and presence of rotatory subluxation (less common in DD, p = 0.017), but very different for sagittal parameters (lumbar lordosis, sagittal vertical axis, T2 sagittal tilt, pelvic tilt, sacral slope, and global tilt; increased sagittal imbalance in DD, all p <= 0.001). CONCLUSION: Surgeons in this study demonstrated reasonable (moderate to substantial) intra-observer agreement, but only fair agreement amongst them. Alarming as it may appear, we should be cautious in interpreting these results based on only radiology and no clinical information. In patients with good agreement, the most consistent radiologic determinant of degenerative ASD appeared to be the presence of sagittal imbalance. PMID- 26769035 TI - A proposed classification system for guiding surgical strategy in cases of severe spinal deformity based on spinal cord function. AB - PURPOSE: Spinal cord function classification systems are not useful for guiding surgery in patients with severe spinal deformities. The aim of this study is to propose a classification system for determining a surgical strategy that minimizes the risk of neurological dysfunction in patients with severe spinal deformities. METHODS: The records of 89 patients with severe spinal deformities treated with vertebral column reconstruction from 2008 to 2013 were retrospectively analyzed. Based on neurophysiological monitoring, magnetic resonance imaging, and neurological symptoms patients were categorized into three groups: group A, normal spinal cord, normal evoked potentials and no neurological symptoms; group B, spinal cord abnormalities and/or abnormal evoked potentials but no neurological symptoms; group C, neurological symptoms with or without spinal cord abnormalities/abnormal evoked potentials. Outcomes and complications were compared between the groups. RESULTS: A total of 89 patients (51 male, 38 female) were included with 47 (52.8 %), 16 (18.0 %), and 26 (29.2 %) patients in groups A, B and C, respectively, and a mean follow-up 34.5 months. There were no differences in age, gender, average preoperative scoliosis, and kyphosis among three groups, but there were differences with respect to the causes of severe spinal deformity and the corrective rate of scoliosis and kyphosis. Changes in intraoperative evoked potentials were different in these three types according to this new classification, and the recovery rates of changes in the three groups were 71.1, 50.0, and 14.1 %, respectively. Postoperative spinal cord injury was positively related to intraoperative changes of evoked potentials. CONCLUSION: The classification system may be useful for guiding surgical decisions in patients with severe spinal deformities to minimize the risk of neurological complications. PMID- 26769037 TI - Are lumbar multifidus fatigue and transversus abdominis activation similar in patients with lumbar disc herniation and healthy controls? A case control study. AB - PURPOSE: The aims of this study were to assess lumbar multifidus fatigue (LM) and transversus abdominis activation (TrA) in individuals with lumbar disc herniation associated with low back pain. METHODS: Sixty individuals were divided into the lumbar herniation (LHG, n = 30) and control groups (CG, n = 30). Fatigue of the LM was assessed using surface electromyography during the Sorensen effort test, and activation of the TrA with a pressure biofeedback unit. Pain intensity was determined using a visual analog scale and the McGill pain questionnaire. The Oswestry disability questionnaire and the Borg scale for self-evaluating exertion were used to assess functional disability. RESULTS: Fatigue was significantly more intense and the TrA activation was insufficient (p < 0.01) in individuals with disc herniation relative to the control group. The LHG had mild functional disability and moderate pain. There were differences in the initial exertion self evaluation between groups, which were not observed in the final exertion evaluation. CONCLUSION: Individuals with lumbar disc herniation associated with low back pain have increased fatigue of the LM and decreased activation of the TrA, when compared to the control group. PMID- 26769038 TI - Pretreatment screening for distant metastases in the Dutch head and neck centers: 10 years later. AB - To evaluate the current practice and change in practice concerning screening for distant metastases in head and neck squamous cell carcinoma patients, we performed a survey with the same questionnaire as 10 years ago among the eight centers of the Dutch Head and Neck Society treating head and neck cancer in The Netherlands. Factors related to extensive lymph node metastases are the most frequent indication for screening for distant metastases. The combinations of whole body PET-CT and contrast-enhanced chest CT are nowadays the diagnostic techniques for routinely screening for distant metastases. Screening for distant metastases is performed more frequently than 10 years ago. Although the sensitivity of the diagnostic pathway needs to be improved, most centers are satisfied with the current diagnostic pathway. A reduction of variation in indications and diagnostic techniques used for screening for distant metastases is observed during the last 10 years. In future guidelines patients' selection and diagnostic tests need to be specified in more detail. PMID- 26769039 TI - Differences in Body Build in Children of Different Ethnic Groups and their Impact on the Prevalence of Stunting, Thinness, Overweight, and Obesity. AB - BACKGROUND: The prevalence of stunting, thinness, overweight, and obesity among children differs by ethnicity. It is not known whether differences in body build across the ethnic groups influence the interpretation of nutritional parameters. OBJECTIVE: To explore the differences in body build across the 5 main ethnic groups in Malaysia and to determine whether differences in body build have an impact on the interpretation of nutrition indicators. METHODS: A total of 3227 children aged 2.0 to 12.9 years who participated in the South East Asian Nutrition Surveys (SEANUTS) in Malaysia were included in this analysis. Body weight, height, sitting height, wrist and knee breadths, and biceps and subscapular skinfolds were measured, and relative leg length, slenderness index, and sum of skinfolds were calculated. Z scores for height-for-age (HAZ) and body mass index-for-age (BAZ) were calculated using the World Health Organization (WHO) 2007 growth standards. RESULTS: Differences in relative leg length and slenderness across the ethnic groups were correlated with HAZ and BAZ. Correction for differences in body build did, in some ethnic groups, have significant impact on the prevalence of stunting, thinness, overweight, and obesity, and the pattern of prevalence across ethnic groups changed. CONCLUSION: At the population level, corrections for body build had only minor and mostly nonsignificant effects on prevalence, but at an individual level, corrections for body build placed a substantial number of children in different height or weight categories. Whether these misclassifications warrant additional assessment of body build in clinical practice will need further investigation. PMID- 26769040 TI - The SDGs Will Require Integrated Agriculture, Nutrition, and Health at the Community Level. AB - Child malnutrition is an urgent and complex issue and requires integrated approaches across agriculture, nutrition, and health. This issue has gained prominence at the global level. While national-level efforts are underway in many countries, there is little information on how to integrate at the community level. Here, we offer a community-based approach using cadres of agricultural and community health workers, drawing on qualitative work we have conducted in Tanzania. Agriculture is an important driver of nutritional and health outcomes, and improving child health will require practical solutions for integration that can add to the evidence base. PMID- 26769041 TI - Central nervous system infections caused by varicella-zoster virus. AB - We carried out a clinical and epidemiological study of adult patients with varicella-zoster virus central nervous system infection diagnosed by PCR in cerebrospinal fluid. Twenty-six patients were included. Twelve (46.2 %) patients were diagnosed with meningitis and fourteen (53.8 %) with meningoencephalitis. Twelve (46.2 %) had cranial nerves involvement (mainly the facial (VII) and vestibulocochlear (VIII) nerves), six (23.1 %) had cerebellar involvement, fourteen (53.8 %) had rash, and four (15.4 %) developed Ramsay Hunt syndrome. Three (11.5 %) patients had sequelae. Length of stay was significantly lower in patients diagnosed with meningitis and treatment with acyclovir was more frequent in patients diagnosed with meningoencephalitis. We believe routine detection of varicella-zoster virus, regardless of the presence of rash, is important because the patient may benefit from a different clinical management. PMID- 26769044 TI - Phosphorus chemistry: discoveries and advances. PMID- 26769042 TI - Antidepressant, anxiolytic and procognitive effects of rivastigmine and donepezil in the chronic mild stress model in rats. AB - BACKGROUND: The treatment of depression in old age is complicated by frequent co morbidity with cognitive impairment. Anti-dementia drugs have some efficacy to improve cognitive performance and there is an inconsistent literature regarding the effect of such drugs on depressive symptoms. Here, we have investigated whether anti-dementia drugs would have antidepressant-like and pro-cognitive effects in a well-validated animal model of depression and cognitive impairment, chronic mild stress (CMS). METHODS: Rats were subjected to CMS for a total of 8 weeks. After 2 weeks, subgroups of stressed and non-stressed animals were treated daily, for 5 weeks followed by 1 week of drug withdrawal, with vehicle, imipramine (10 mg/kg), rivastigmine (2 mg/kg), donepezil (0.3 mg/kg) or memantine (5 mg/kg). Sucrose intake was tested weekly, and animals were also tested in the elevated plus maze (at week 7) and in an object recognition task (at weeks 7 and 8). RESULTS: CMS decreased sucrose intake, had an anxiogenic effect in the elevated plus maze, and impaired performance in the object recognition test. Imipramine, rivastigmine and donepezil normalized performance in all three tests. Memantine had anxiolytic and pro-cognitive effects, but did not reverse CMS induced anhedonia. DISCUSSION: The fact that all three anti-dementia drugs reversed CMS-induced cognitive impairment and that cholinesterase inhibitors, but not memantine, have antidepressant-like effects in this model suggest that different mechanisms may underlie CMS-induced anhedonia and cognitive impairment. We discuss the clinical implications of these findings. PMID- 26769043 TI - Genome-wide transcriptome analysis of soybean primary root under varying water deficit conditions. AB - BACKGROUND: Soybean is a major crop that provides an important source of protein and oil to humans and animals, but its production can be dramatically decreased by the occurrence of drought stress. Soybeans can survive drought stress if there is a robust and deep root system at the early vegetative growth stage. However, little is known about the genome-wide molecular mechanisms contributing to soybean root system architecture. This study was performed to gain knowledge on transcriptome changes and related molecular mechanisms contributing to soybean root development under water limited conditions. RESULTS: The soybean Williams 82 genotype was subjected to very mild stress (VMS), mild stress (MS) and severe stress (SS) conditions, as well as recovery from the severe stress after re watering (SR). In total, 6,609 genes in the roots showed differential expression patterns in response to different water-deficit stress levels. Genes involved in hormone (Auxin/Ethylene), carbohydrate, and cell wall-related metabolism (XTH/lipid/flavonoids/lignin) pathways were differentially regulated in the soybean root system. Several transcription factors (TFs) regulating root growth and responses under varying water-deficit conditions were identified and the expression patterns of six TFs were found to be common across the stress levels. Further analysis on the whole plant level led to the finding of tissue-specific or water-deficit levels specific regulation of transcription factors. Analysis of the over-represented motif of different gene groups revealed several new cis elements associated with different levels of water deficit. The expression patterns of 18 genes were confirmed byquantitative reverse transcription polymerase chain reaction method and demonstrated the accuracy and effectiveness of RNA-Seq. CONCLUSIONS: The primary root specific transcriptome in soybean can enable a better understanding of the root response to water deficit conditions. The genes detected in root tissues that were associated with key hormones, carbohydrates, and cell wall-related metabolism could play a vital role in achieving drought tolerance and could be promising candidates for future functional characterization. TFs involved in the soybean root and at the whole plant level could be used for future network analysis between TFs and cis elements. All of these findings will be helpful in elucidating the molecular mechanisms associated with water stress responses in soybean roots. PMID- 26769045 TI - Induction of Angiogenesis by a Type III Phosphodiesterase Inhibitor, Cilostazol, Through Activation of Peroxisome Proliferator-Activated Receptor-gamma and cAMP Pathways in Vascular Cells. AB - OBJECTIVE: Peripheral arterial disease is highly prevalent in the elderly and in the subjects with cardiovascular risk factors such as diabetes. Approximately 2% to 4% of those affected with peripheral arterial disease commonly complain of intermittent claudication. Cilostazol, a type III phosphodiesterase inhibitor, is the only Food and Drug Administration-approved drug for the treatment of intermittent claudication. Cilostazol has been shown to be beneficial for the improvement of pain-free walking distance in patients with intermittent claudication in a series of randomized clinical trials. However, the underlying mechanism how cilostazol improved intermittent claudication symptoms is still unclear. APPROACH AND RESULTS: In this study, the effect of cilostazol on ischemic leg was investigated in mouse ischemic hindlimb model. Administration of cilostazol significantly increased the expression of hepatocyte growth factor (HGF), vascular endothelial growth factor, angiopoietin-1, and peroxisome proliferator-activated receptor-gamma in vasculature. The capillary density in ischemic leg was also significantly increased in cilostazol treatment group when compared with control and aspirin treatment group. However, an increase in capillary density and the expression of growth factors was almost completely abolished by coadministration of HGF-neutralizing antibody, suggesting that cilostazol enhanced angiogenesis mainly through HGF. In vitro experiment revealed that cilostazol treatment increased HGF production in vascular smooth muscle cells via 2 major pathways: peroxisome proliferator-activated receptor-gamma and cAMP pathways. CONCLUSIONS: Our data suggest that the favorable effects of cilostazol on ischemic leg might be through the angiogenesis through the induction of HGF via peroxisome proliferator-activated receptor-gamma and cAMP pathways. PMID- 26769046 TI - Bone Morphogenic Protein 4-Smad-Induced Upregulation of Platelet-Derived Growth Factor AA Impairs Endothelial Function. AB - OBJECTIVE: Bone morphogenic protein 4 (BMP4) is an important mediator of endothelial dysfunction in cardio-metabolic diseases, whereas platelet-derived growth factors (PDGFs) are major angiogenic and proinflammatory mediator, although the functional link between these 2 factors is unknown. The present study investigated whether PDGF mediates BMP4-induced endothelial dysfunction in diabetes mellitus. APPROACH AND RESULTS: We generated Ad-Bmp4 to overexpress Bmp4 and Ad-Pdgfa-shRNA to knockdown Pdgfa in mice through tail intravenous injection. SMAD4-shRNA lentivirus, SMAD1-shRNA, and SMAD5 shRNA adenovirus were used for knockdown in human and mouse endothelial cells. We found that PDGF-AA impaired endothelium-dependent vasodilation in aortas and mesenteric resistance arteries. BMP4 upregulated PDGF-AA in human and mouse endothelial cells, which was abolished by BMP4 antagonist noggin or knockdown of SMAD1/5 or SMAD4. BMP4 impared relaxation in mouse aorta was also ameliorated by PDGF-AA neutralizing antibody. Tail injection of Ad-Pdgfa-shRNA ameliorates endothelial dysfunction induced by Bmp4 overexpression (Ad-Bmp4) in vivo. Serum PDGF-AA was elevated in both diabetic patients and diabetic db/db mice compared with nondiabetic controls. Pdgfa-shRNA or Bmp4-shRNA adenovirus reduced serum PDGF-AA concentration in db/db mice. PDGF-AA neutralizing antibody or tail injection with Pdgfa-shRNA adenovirus improved endothelial function in aortas and mesenteric resistance arteries from db/db mice. The effect of PDGF-AA on endothelial function in mouse aorta was also inhibited by Ad-Pdgfra-shRNA to inhibit PDGFRalpha. CONCLUSIONS: The present study provides novel evidences to show that PDGF-AA impairs endothelium-dependent vasodilation and PDGF-AA mediates BMP4 induced adverse effect on endothelial cell function through SMAD1/5- and SMAD4 dependent mechanisms. Inhibition of PGDF-AA ameliorates vascular dysfunction in diabetic mice. PMID- 26769047 TI - Inhibition of Thrombin With PPACK-Nanoparticles Restores Disrupted Endothelial Barriers and Attenuates Thrombotic Risk in Experimental Atherosclerosis. AB - OBJECTIVE: A role for thrombin in the pathogenesis of atherosclerosis has been suggested through clinical and experimental studies revealing a critical link between the coagulation system and inflammation. Although approved drugs for inhibition of thrombin and thrombin-related signaling have demonstrated efficacy, their clinical application to this end may be limited because of significant potential for bleeding side effects. Thus, we sought to implement a plaque localizing nanoparticle-based approach to interdict thrombin-induced inflammation and hypercoagulability in atherosclerosis. APPROACH AND RESULTS: We deployed a novel magnetic resonance spectroscopic method to quantify the severity of endothelial damage for correlation with traditional metrics of vessel procoagulant activity after dye-laser injury in fat-fed apolipoprotein E-null mice. We demonstrate that a 1-month course of treatment with antithrombin nanoparticles carrying the potent thrombin inhibitor PPACK (d-phenylalanyl-l prolyl-l-arginyl chloromethylketone) nanoparticle (1) reduces the expression and secretion of proinflammatory and procoagulant molecules, (2) diminishes plaque procoagulant activity without the need for systemic anticoagulation, (3) rapidly restores disrupted vascular endothelial barriers, and (4) retards plaque progression in lesion-prone areas. CONCLUSIONS: These observations illustrate the role of thrombin as a pleiotropic atherogenic molecule under conditions of hypercholesterolemia and suggest the utility of its inhibition with locally acting antithrombin nanoparticle therapeutics as a rapid-acting anti-inflammatory strategy in atherosclerosis to reduce thrombotic risk. PMID- 26769050 TI - Obituary: T. Joseph Scanlon, 1933-2015: (Editorial Board member, Disasters, 2013 15). PMID- 26769048 TI - Coagulation Factor XI Promotes Distal Platelet Activation and Single Platelet Consumption in the Bloodstream Under Shear Flow. AB - OBJECTIVE: Coagulation factor XI (FXI) has been shown to contribute to thrombus formation on collagen or tissue factor-coated surfaces in vitro and in vivo by enhancing thrombin generation. Whether the role of the intrinsic pathway of coagulation is restricted to the local site of thrombus formation is unknown. This study was aimed to determine whether FXI could promote both proximal and distal platelet activation and aggregate formation in the bloodstream. APPROACH AND RESULTS: Pharmacological blockade of FXI activation or thrombin activity in blood did not affect local platelet adhesion, yet reduced local platelet aggregation, thrombin localization, and fibrin formation on immobilized collagen and tissue factor under shear flow, ex vivo. Downstream of the thrombus formed on immobilized collagen or collagen and 10 pmol/L tissue factor, platelet CD62P expression, microaggregate formation, and progressive platelet consumption were significantly reduced in the presence of FXI function-blocking antibodies or a thrombin inhibitor in a shear rate- and time-dependent manner. In a non-human primate model of thrombus formation, we found that inhibition of FXI reduced single platelet consumption in the bloodstream distal to a site of thrombus formation. CONCLUSIONS: This study demonstrates that the FXI-thrombin axis contributes to distal platelet activation and procoagulant microaggregate formation in the blood flow downstream of the site of thrombus formation. Our data highlight FXI as a novel therapeutic target for inhibiting distal platelet consumption without affecting proximal platelet adhesion. PMID- 26769052 TI - From the Editors. PMID- 26769053 TI - Joanna Burger: Respect for All Living Things. PMID- 26769049 TI - Fibrotic Aortic Valve Stenosis in Hypercholesterolemic/Hypertensive Mice. AB - OBJECTIVE: Hypercholesterolemia and hypertension are associated with aortic valve stenosis (AVS) in humans. We have examined aortic valve function, structure, and gene expression in hypercholesterolemic/hypertensive mice. APPROACH AND RESULTS: Control, hypertensive, hypercholesterolemic (Apoe(-/-)), and hypercholesterolemic/hypertensive mice were studied. Severe aortic stenosis (echocardiography) occurred only in hypercholesterolemic/hypertensive mice. There was minimal calcification of the aortic valve. Several structural changes were identified at the base of the valve. The intercusp raphe (or seam between leaflets) was longer in hypercholesterolemic/hypertensive mice than in other mice, and collagen fibers at the base of the leaflets were reoriented to form a mesh. In hypercholesterolemic/hypertensive mice, the cusps were asymmetrical, which may contribute to changes that produce AVS. RNA sequencing was used to identify molecular targets during the developmental phase of stenosis. Genes related to the structure of the valve were identified, which differentially expressed before fibrotic AVS developed. Both RNA and protein of a profibrotic molecule, plasminogen activator inhibitor 1, were increased greatly in hypercholesterolemic/hypertensive mice. CONCLUSIONS: Hypercholesterolemic/hypertensive mice are the first model of fibrotic AVS. Hypercholesterolemic/hypertensive mice develop severe AVS in the absence of significant calcification, a feature that resembles AVS in children and some adults. Structural changes at the base of the valve leaflets include lengthening of the raphe, remodeling of collagen, and asymmetry of the leaflets. Genes were identified that may contribute to the development of fibrotic AVS. PMID- 26769054 TI - A metabonomic analysis reveals novel regulatory mechanism of Huangqi injection on leucopenia mice. AB - CONTEXT: Huangqi injection (HQI), extracted from Astragali Radix, which has capability on treating the leucopenia. However, the potential metabolic mechanism is poorly understood. OBJECTIVE: To investigate the effect of HQI on cyclophosphamide (Cy)-induced leucopenia in mice, the nuclear magnetic resonance (NMR)-based metabolomic profiling technique coupled with multivariate statistical analysis was applied. MATERIALS AND METHODS: NMR analysis was used to identify the various compounds of HQI, and high-performance liquid chromatography was applied to determine the contents of major compounds. A experimental mice model of leucopenia induced by Cy and NMR-based metabolomic approach was used to evaluate the pharmacological effect of HQI and to investigate its probable acting mechanism on leucopenia. RESULTS: HQI increased body weight and elevated the white blood cell (WBC), monocytes (MO), neutrophils (NE), and lymphocyte (LY) levels of Cy-treated mice. In addition, the levels of most perturbed endogenous metabolites could be reversed after HQI treatment. Correlations between WBC, MO, NE, LY, and altered metabolite profiles in spleen were greater than that in serum, and the correlation in MO was more evident than those for WBC, NE, and LY. DISCUSSION AND CONCLUSION: HQI showed obvious efficacy on the mice model of leucopenia. And the drug action of HQI on leucopenia was probably related with regulating metabolic pathways of energy metabolism, amino acids metabolism, oxidative stress, and choline metabolism. However, various compounds were present in the HQI, and the bioactive compounds responsible for the drug actions should be further investigated. PMID- 26769055 TI - Prof. Theodor M. Fliedner (1 October 1929-9 November 2015): haematopoietic stem cell and radiation biology and pioneer. PMID- 26769056 TI - CD8alphaalpha TCRalphabeta Intraepithelial Lymphocytes in the Mouse Gut. AB - The epithelium of the mouse small intestine harbors an abundant CD8alphaalpha(+)TCRalphabeta(+) intraepithelial lymphocyte (IEL) population. This unique IEL subset is a self-reactive population that requires exposure to self agonists for selection in the thymus, similarly to other regulatory T cell populations. After leaving the thymus, these cells directly seed the intestinal epithelium, which provides a unique combination of cellular interactions together with cytokines, nutrients, and antigens that guide the lineage-specific differentiation and function of these IELs. For instance, epithelial cells and nearby immune cells secrete a number of cytokines, including interleukin-15 (IL 15), IL-7, and transforming growth factor-beta, resulting in an assortment of cellular responses, including activation of master transcription factors, cell proliferation, and cytokine secretion. Recent advances have also highlighted the importance of diet-derived substances and commensal metabolites, such as the aryl hydrocarbon receptor ligands and vitamin D, in controlling the survival and gene expression of CD8alphaalpha(+)TCRalphabeta(+) IELs. Furthermore, these cells function in the epithelium and require constant communication between cells in the form of cell-to-cell contacts. These interactions tune the antigen sensitivity of the TCR and maintain the quiescence of the CD8alphaalpha(+)TCRalphabeta(+) IELs. Finally, we discuss how these cells might contribute to tolerance and immunopathological responses in the gut. Therefore, an increased understanding of CD8alphaalpha(+)TCRalphabeta(+) IELs in the gut will help us understand how these cells participate in immune regulation and protection. PMID- 26769058 TI - A single adenovirus-mediated relaxin delivery attenuates established liver fibrosis in rats. AB - BACKGROUND: Liver fibrosis is characterized by an excess accumulation and repressed degradation of extracellular matrix. Although methods of alleviating already established liver fibrosis have scarcely been reported, continuous relaxin (RLX) infusion has demonstrated some promising results. In the present study, we investigated whether a single adenoviral delivery of RLX would attenuate established liver fibrosis in rats. METHODS: Rats were given thioacetamide (TAA) for 8 weeks and infected once with either RLX-expressing adenovirus (TAA + RLX) or control virus (TAA + Vector) via the tail vein. They were sacrificed either 3 days or 3 weeks after adenovirus infection. RESULTS: Morphometric analysis of picrosirius red stained area demonstrated that the TAA + RLX group had significantly decreased fibrosis at week 3 when liver fibrosis of the TAA + Vector group remained unchanged. Although the liver and serum RLX levels were elevated on day 3 and reversed by week 3, expression of RLX receptor (Rxfp1; relaxin-like family peptide receptor-1) in TAA + RLX rats was sustained and elevated. The production of tissue cyclic adenosine monophosphate, which is a second messenger of activated Rxfp1, was still enhanced in the TAA + RLX group by week 3. Expression of lysyl oxidase homolog 2, which contributes to collagen cross-linking and is up-regulated by TAA treatment, was significantly decreased by week 3 in the TAA + RLX group. Expression of tissue inhibitor of metalloprotiase-2 was alleviated in the TAA + RLX group at week 3, whereas that of TAA + Vector rats was still elevated. CONCLUSIONS: A single adenoviral delivery of RLX in the liver attenuated established hepatic fibrosis by suppressing collagen cross-linking and enhancing collagen degradation. PMID- 26769059 TI - Introduction. Apple Pickers or Federal Judges: Strong versus Weak Incentives in Physician Payment. PMID- 26769060 TI - Driven to Care: Aligning External Motivators with Intrinsic Motivation. PMID- 26769057 TI - Role of MicroRNAs in NAFLD/NASH. AB - MicroRNAs (miRNAs) are highly conserved, small, 18-25 nucleotide, non-coding RNAs that regulate gene expression at the post-transcriptional level. Each miRNA can regulate hundreds of target genes, and vice versa each target gene can be regulated by numerous miRNAs, suggesting a very complex network and explaining how miRNAs play pivotal roles in fine-tuning essentially all biological processes in all cell types in the liver. Here, we summarize the current knowledge on the role of miRNAs in the pathogenesis and diagnosis of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) with an outlook to the broader aspects of metabolic syndrome. Furthermore, we discuss the role of miRNAs as potential biomarkers and therapeutic targets in NAFLD/NASH. PMID- 26769061 TI - Strong versus Weak Incentives: The Role of Policy, Management, and Theory in a New Research Agenda. PMID- 26769063 TI - Intraoperative Endoscopic Suction-Assisted Evaluation of the Nasal Valve. AB - IMPORTANCE: The study sought to identify a new method for measuring internal nasal valve patency. OBJECTIVE: To determine whether intraoperative endoscopic suction-assisted evaluation of the internal nasal valve is a useful technique to assess internal nasal valve area and function. DESIGN, SETTING, AND PARTICIPANTS: A study of 20 patients undergoing cosmetic and functional septorhinoplasty from May 1 through October 31, 2012, at a private surgical practice was performed. A follow-up study was performed 3 years postoperatively on 7 patients. A photograph of the internal nasal valve was taken endoscopically with and without suction preoperatively, postoperatively, and at 3-year follow-up. Measurement of the internal nasal valve surface areas was then performed by an evaluator masked to patient groupings. MAIN OUTCOMES AND MEASURES: Outcome measures were surface area of the internal nasal valve as measured by standardized, endoscopic photography preoperatively, postoperatively, and at 3 years with and without suction and Nasal Obstruction Symptom Evaluation (NOSE) scale scores at 3 years comparing preoperative and postoperative symptoms. RESULTS: Among the 20 patients studied, 13 were female and the mean age was 26 years. No difference was found in the observed static surface area of the internal nasal valve comparing preoperative and postoperative values (72 418 vs 76 973 square pixels, P = .58). No difference was found in the observed static surface area of the internal nasal valve comparing preoperative (56 426 square pixels) and postoperative (60 011 square pixels) values (P = .58). No difference was found in the observed surface area of the internal nasal valve under negative pressure comparing preoperative (54 194 square pixels) and immediate postoperative (58 325 square pixels) values (P = .97). At 3 years, the resting surface area of the internal nasal valve was not increased with an internal nasal valve surface area mean of 56 426 square pixels preoperatively and 84 352 postoperatively (P = .09). The surface area of the internal nasal valve was increased when exposed to negative sniff pressures in the 3-year follow-up by 45% (P = .03). The surface area measured a mean of 47 683 square pixels preoperatively and 85 612 square pixels at the 3-year mark under negative pressure. CONCLUSIONS AND RELEVANCE: The study outlines a novel technique for measuring internal nasal valve surface area and compliance preoperatively and postoperatively. Surgery on the internal nasal valve has a greater effect on the dynamic function of the internal nasal valve (ie, stiffness that can be accounted for by a mere increase in nasal valve size when measured endoscopically). The study lays the groundwork for future studies using this technique. LEVEL OF EVIDENCE: 4. PMID- 26769062 TI - A specific mutation in TBL1XR1 causes Pierpont syndrome. AB - BACKGROUND: The combination of developmental delay, facial characteristics, hearing loss and abnormal fat distribution in the distal limbs is known as Pierpont syndrome. The aim of the present study was to detect and study the cause of Pierpont syndrome. METHODS: We used whole-exome sequencing to analyse four unrelated individuals with Pierpont syndrome, and Sanger sequencing in two other unrelated affected individuals. Expression of mRNA of the wild-type candidate gene was analysed in human postmortem brain specimens, adipose tissue, muscle and liver. Expression of RNA in lymphocytes in patients and controls was additionally analysed. The variant protein was expressed in, and purified from, HEK293 cells to assess its effect on protein folding and function. RESULTS: We identified a single heterozygous missense variant, c.1337A>G (p.Tyr446Cys), in transducin beta like 1 X-linked receptor 1 (TBL1XR1) as disease-causing in all patients. TBL1XR1 mRNA expression was demonstrated in pituitary, hypothalamus, white and brown adipose tissue, muscle and liver. mRNA expression is lower in lymphocytes of two patients compared with the four controls. The mutant TBL1XR1 protein assembled correctly into the nuclear receptor corepressor (NCoR)/ silencing mediator for retinoid and thyroid receptors (SMRT) complex, suggesting a dominant-negative mechanism. This contrasts with loss-of-function germline TBL1XR1 deletions and other TBL1XR1 mutations that have been implicated in autism. However, autism is not present in individuals with Pierpont syndrome. CONCLUSIONS: This study identifies a specific TBL1XR1 mutation as the cause of Pierpont syndrome. Deletions and other mutations in TBL1XR1 can cause autism. The marked differences between Pierpont patients with the p.Tyr446Cys mutation and individuals with other mutations and whole gene deletions indicate a specific, but as yet unknown, disease mechanism of the TBL1XR1 p.Tyr446Cys mutation. PMID- 26769064 TI - Comparative effects of nodularin and microcystin-LR in zebrafish: 1. Uptake by organic anion transporting polypeptide Oatp1d1 (Slco1d1). AB - Microcystin-LR (MC-LR) and nodularin are hepatotoxins produced by several cyanobacterial species. Their toxicity is based on active cellular uptake and subsequent inhibition of protein phosphatases PP1/2A, leading to hyperphosphorylation and cell death. To date, uptake of MC-LR and nodularin in fish is poorly understood. Here, we investigated the role of the organic anion transporting polypeptide Oatp1d1 in zebrafish (drOatp1d1, Slco1d1) in cellular uptake in zebrafish. We stably transfected CHO and HEK293 cell lines expressing drOatp1d1. In both transfectants, uptake of MC-LR and nodularin was demonstrated by competitive inhibition of uptake with fluorescent substrate lucifer yellow. Direct uptake of MC-LR was demonstrated by immunostaining, and indirectly by the high cytotoxicity in stable transfectants. By means of a synthesized fluorescent labeled MC-LR derivative, direct uptake was further confirmed in HEK293 cells expressing drOatp1d1. Additionally, uptake and toxicity was investigated in the permanent zebrafish liver cell line ZFL. These cells had only a low relative abundance of drOatp1d1, drOatp2b1 and drOatp1f transcripts, which correlated with the lack of MC-LR induced cytotoxicity and transcriptional changes of genes indicative of endoplasmic reticulum stress, a known effect of this toxin. Our study demonstrates that drOatp1d1 functions as an uptake transporter for both MC LR and nodularin in zebrafish. PMID- 26769065 TI - Clinical 3-tesla FLAIR* MRI improves diagnostic accuracy in multiple sclerosis. AB - OBJECTIVE: To evaluate clinical fluid-attenuated inversion recovery (FLAIR)* 3T magnetic resonance imaging (MRI), which is sensitive to perivenular inflammatory demyelinating lesions, in diagnosing multiple sclerosis (MS). BACKGROUND: Central veins may be a distinguishing feature of MS lesions. FLAIR*, a combined contrast derived from clinical MRI scans, has not been studied as a clinical tool for diagnosing MS. METHODS: Two experienced MS neurologists evaluated 87 scan pairs (T2-FLAIR/FLAIR*), separately and side-by-side, from 68 MS cases, 8 healthy volunteers, and 11 individuals with other neurological diseases. Raters judged cases based on experience, published criteria, and a visual assessment of the "40% rule," whereby MS is favored if >40% of lesions demonstrate a central vein. Diagnostic accuracy was determined with area under the receiver operating characteristic curve (AUC), and inter-rater reliability was assessed with Cohen's kappa (kappa). RESULTS: Diagnostic accuracy was high: rater 1, AUC 0.94 (95% confidence interval: 0.89, 0.97) for T2-FLAIR, 0.95 (0.92, 0.98) for FLAIR*; rater 2, 0.94 (0.90, 0.98) and 0.90 (0.85, 0.95). AUC improved when images were considered together: rater 1, 0.99 (0.98, 1.00); rater 2, 0.98 (0.96, 0.99). Inter-rater agreement was substantial for T2-FLAIR (kappa = 0.68) and FLAIR* (kappa = 0.74), despite low agreement on the 40% rule (kappa = 0.47) ([Formula: see text] in all cases). CONCLUSIONS: Joint clinical evaluation of T2-FLAIR and FLAIR* images modestly improves diagnostic accuracy for MS and does not require counting lesions with central veins. PMID- 26769066 TI - Genetic predictors of relapse rate in pediatric MS. AB - BACKGROUND: Genetic ancestry, sex, and individual alleles have been associated with multiple sclerosis (MS) susceptibility. OBJECTIVE: To determine whether established risk factors for disease onset are associated with relapse rate in pediatric MS. METHODS: Whole-genome genotyping was performed for 181 MS or high risk clinically isolated syndrome patients from two pediatric MS centers. Relapses and disease-modifying therapies were recorded as part of continued follow-up. Participants were characterized for 25-hydroxyvitamin D serum status. Ancestral estimates (STRUCTURE v2.3.1), human leukocyte antigen (HLA)-DRB1*15 carrier status (direct sequencing), sex, and a genetic risk score (GRS) of 110 non-HLA susceptibility single-nucleotide polymorphisms (SNPs) were evaluated for association with relapse rate with Cox and negative binomial regression models. RESULTS: Over 622 patient-years, 408 relapses were captured. Girls had greater relapse rate than boys (incident rate ratio (IRR) = 1.40, 95% confidence interval (CI) = 1.04-1.87, p = 0.026). Participants were genetically diverse; ~40% (N = 75) had <50% European ancestry. HLA-DRB1*15 status modified the association of vitamin D status (pixn = 0.022) with relapse rate (per 10 ng/mL, in DRB1*15+ hazard ratio (HR) = 0.72, 95% CI = 0.58-0.88, p = 0.002; in DRB1*15- HR = 0.96, 95% CI = 0.83-1.12, p = 0.64). Neither European ancestry nor GRS was associated with relapse rate. CONCLUSION: We demonstrate that HLA-DRB1*15 modifies the association of vitamin D status with relapse rate. Our findings emphasize the need to pursue disease-modifying effects of MS genes in the context of environmental factors. PMID- 26769068 TI - Demographics of Australian horse owners: results from an internet-based survey. AB - OBJECTIVES: To obtain information on the demographics of Australian horse owners. METHODS: An invitation to participate in an opt-in, internet-based survey was sent to 7000 persons who had registered an email address to receive information from the Australian Horse Industry Council Inc. These horse owners represented approximately 1.75% of the total horse owners in Australia. The survey was available for completion between 1 and 31 July 2009. RESULTS: There were 3377 (48%) useable responses. The respondents were a self-selected group of approximately 0.85% of the estimated total horse owners in Australia. The overall geographic distribution of respondents was the same as the general population at a state and territory level. In general, respondents were female and aged between 31 and 60 years; most lived in rural areas of Queensland, New South Wales or Victoria; had at least a secondary education, but no formal horse industry qualification; had a higher weekly income if based in a capital city; earned less than 10% of weekly income from horse-related activities; were a member of more than one horse industry organisation; reported an affiliation with one of more than 300 different horse industry organisations; spent 10-30% of their daily time with horses; and preferred to receive information by email. CONCLUSIONS: The responses from this survey of horse owners provided demographic information that was previously unavailable. Horse owners tended to be older than the general population, had a higher level of education attainment, were in higher weekly income brackets and lived mostly in non-metropolitan areas of Australia. Because of the self-selection and small sample size, the results need to be interpreted with caution. Nevertheless, the present results are compatible with other smaller random and non-random surveys of horse owners internationally. PMID- 26769069 TI - Client knowledge, attitudes and practices regarding zoonoses: a metropolitan experience. AB - OBJECTIVE: To assess knowledge, attitudes and practices in relation to zoonoses among pet owners. METHODS: Questionnaire completed by 81 clients attending a small animal practice in Sydney, Australia. RESULTS: Most (64.5%) clients reported that they were not concerned about contracting a disease from their pet, but 7.9% and 3.9% of clients were a little or very concerned, respectively; 23.7% of clients stated that they had not considered the possibility. Although respondents indicated that they had heard of a number of zoonoses, knowledge of animal sources and exposure pathways was generally low, particularly for the more important zoonoses in Australia such as toxoplasmosis, psittacosis and Q fever. Only 37.0%, 12.3% and 11.1%, respectively, of clients had heard of these diseases. Most respondents (84.1%) indicated that they viewed veterinarians as having the primary responsibility for providing information about zoonoses, yet less than half (48.1%) recalled ever getting information from their veterinarian. Likewise, many respondents (48.1%) indicated that medical professionals played a role in providing information about zoonoses, yet less than one-quarter (23.5%) recalled ever getting information from their doctor. CONCLUSION: The low level of knowledge among pet owners about sources and exposure pathways indicates a need to strengthen communication between veterinarians, doctors and their clients around the possible risks of zoonoses and appropriate prevention strategies. PMID- 26769070 TI - Clinical effects of the use of a bipolar vessel sealing device for soft palate resection and tonsillectomy in dogs, with histological assessment of resected tonsillar tissue. AB - OBJECTIVE: To investigate whether soft palate resection and tonsillectomy with a bipolar vessel sealing device (BVSD) improves clinical respiratory score. To document histopathological changes to tonsillar tissue following removal with a BVSD. METHODS & RESULTS: Case series of 22 dogs with clinical signs of upper respiratory obstruction related to brachycephalic airway syndrome. Soft palate and tonsils were removed using a BVSD. Alarplasty and saccullectomy were also performed if indicated. A clinical respiratory score was assigned preoperatively, 24-h postoperatively and 5 weeks postoperatively. Excised tonsillar samples were measured and then assessed histologically for depth of tissue damage deemed to be caused by the device. Depth of tissue damage was compared between two power settings of the device. Soft palate resection and tonsillectomy with a BVSD lead to a significant improvement in respiratory scores following surgery. Depth of tissue damage was significantly less for power setting 1 compared with power setting 2. Using power setting 1, median calculated depth of tonsillar tissue damage was 3.4 mm (range 1.2-8.0). One dog experienced major complications. CONCLUSION: Soft palate resection and tonsillectomy with a BVSD led to significant improvement in clinical respiratory score. PMID- 26769071 TI - Balloon occlusion of the caudal vena cava for vascular contrast studies as an aid to intravascular coil embolisation for the treatment of intrahepatic portosystemic shunts in three dogs. AB - CASE REPORT: Three dogs were treated with fluoroscopically guided coil embolisation of intrahepatic portosystemic shunts. A large-diameter vascular occlusion balloon was used to improve the vascular contrast studies required to perform this procedure. This technique improved identification of vascular structures and allowed completion of the procedures without the need for digital subtraction angiography. CLINICAL SIGNIFICANCE: Interventional radiological procedures are an emerging area of veterinary medicine and procedural modifications may help expand their use in clinical practice. PMID- 26769072 TI - Review of psittacine beak and feather disease and its effect on Australian endangered species. AB - BACKGROUND: Since it was first described in the early 1980s, psittacine beak and feather disease (PBFD) has become recognised as the dominant viral pathogen of psittacine birds in Australia. Our aim was to evaluate and review the effect of PBFD and its position as a key threatening process to Australian psittacine bird species. We review the origin/evolutionary pathways and potential threat of PBFD to endangered psittacine bird populations and captive-breeding flocks. CONCLUSIONS: The most recent beak and feather disease virus (BFDV) phylogenetic analyses indicate that all endangered Australian psittacine bird species are susceptible to, and equally likely to be infected by, BFDV genotypes from a range of host psittacine species. Management of the disease in captive-breeding programs has relied on testing and culling, which has proven costly. The risk of PBFD should be considered very carefully by management teams contemplating the establishment of captive-breeding flocks for endangered species. Alternative disease prevention tools, including vaccination, which are increasingly being used in wildlife health, should be considered more seriously for managing and preventing PBFD in captive flocks of critically endangered species. PMID- 26769073 TI - Beak and feather disease virus genotypes in Australian parrots reveal flexible host-switching. AB - OBJECTIVE: To discover beak and feather disease virus (BFDV) genotypes in Australian parrots that might threaten vulnerable and endangered psittacine bird species. METHODS: Phylogenetic analyses of new DNA sequence data from Australian birds including the Rep gene (n = 55) and nine whole genomes, were compared with all available published BFDV genomes to assess host- and geographically-based divergence as well as probable host-switch events. RESULTS: Strong support for flexible host-switching and recombination was detected, indicating active cross species transmission in various subpopulations. CONCLUSION: The data suggested that all endangered Australian psittacine bird species are equally likely to be infected by BFDV genotypes from any other close or distantly related host reservoir species. PMID- 26769074 TI - Can we help people too? PMID- 26769075 TI - Axitinib for the treatment of metastatic renal cell carcinoma. AB - Renal cell carcinoma is a cancer that results from a genetic inactivation of the VHL tumor suppressor gene leading to an upregulation of VEGF. Targeted therapies against VEGF receptors have piqued substantial interest among clinicians and researchers, and these drugs are now the standard of care in the treatment of advanced renal cell carcinoma. One of these VEGF receptor inhibitors, axitinib, has been shown to be a superior second-line therapy when compared with sorafenib. Although axitinib has clinical activity and a manageable safety profile in patients with treatment-naive metastatic renal cell carcinoma, utility in the front-line setting is area of ongoing investigation. Another area of ongoing research is dose titration of axitinib to achieve the maximum clinical benefit. Interestingly, the axitinib-related side effect of hypertension has shown to be associated with more favorable clinical outcomes. This article describes the development of axitinib and discusses the current indications for clinical use in the management of metastatic renal cell carcinoma. PMID- 26769076 TI - Upregulation of Bpifb1 expression in the parotid glands of non-obese diabetic mice. AB - OBJECTIVE: To define the increased mRNA expression of Bpifb1, a member of the bactericidal/permeability-increasing protein family, in parotid acinar cells from non-obese diabetic (NOD) mice, an animal model for Sjogren's syndrome. MATERIALS AND METHODS: Parotid acinar cells were prepared from female NOD (NOD/ShiJcl) mice with or without diabetes, as well as from control (C57BL/6JJcl) mice. Total RNA and homogenate were prepared from the parotid acinar cells. Embryonic cDNA from a Mouse MTC(TM) Panel I kit was used. The expression of Bpifb1 was determined by cDNA microarray analysis, RT-PCR, real-time PCR, northern blotting and in situ hybridization. RESULTS: The expression of Bpifb1 mRNA was high in parotid acinar cells from diabetic and non-diabetic NOD mice at 5-50 weeks of age. Acinar cells in the C57BL/6 mice had a low expression of Bpifb1 mRNA at an age >8 weeks, but had a relatively high expression in the foetus and infantile stages. CONCLUSIONS: Bpifb1 mRNA is upregulated in parotid acinar cells in NOD mice, but its expression is not related to the onset of diabetes. These findings suggest that high expression levels of Bpifb1 might predict disease traits before the onset of autoimmunity. PMID- 26769077 TI - Our Journal JEADV--the business card of our Academy. PMID- 26769078 TI - Corrigendum. PMID- 26769079 TI - Environmental drivers of microbial community shifts in the giant barrel sponge, Xestospongia muta, over a shallow to mesophotic depth gradient. AB - The giant barrel sponge, Xestospongia muta, is a high microbial abundance sponge found on Caribbean coral reefs along shallow to mesophotic depth gradients where multiple abiotic factors change with depth. Sponges were collected along a depth gradient at Little Cayman (LC) and Lee Stocking Island (LSI), and the microbiome of these samples was analysed using 16S rRNA amplicon sequencing. Statistically significant shifts in community structure and dissimilarity (~ 40%) were detected from 10 to 90 m in LC sponges, but a similar shift was not identified in sponges from 10 to 60 m at LSI (only 17% dissimilar). Additionally, inorganic nutrient levels steadily increased with depth at LSI but not at LC. Based on bulk stable isotopic variability, sponges collected from LC were generally more enriched in (15) N and less enriched in (13) C as depth increased, suggesting a transition from dependency on photoautotrophy to heterotrophy as depth increased. Patterns of stable isotopic enrichment were largely invariant at LSI, which is also reflected in the more stable microbial community along the depth gradient. It appears that environmental factors that change with depth may contribute to differences in X. muta microbial assemblages, demonstrating the importance of contemporaneous environmental sampling in studies of the microbiome of sponges. PMID- 26769080 TI - Differences in Women's Use of Medical Help for Becoming Pregnant by the Level of Urbanization of County of Residence in Georgia. AB - PURPOSE: Our goal was to determine if there are differences by place of residence in visiting a doctor for help getting pregnant in a population-based study. METHODS: Using data from the Furthering Understanding of Cancer, Health, and Survivorship in Adult (FUCHSIA) Women's Study, a cohort study of fertility outcomes in reproductive-aged women in Georgia, we fit models to estimate the association between geographic type of residence and seeking help for becoming pregnant. FINDINGS: The prevalence of visiting a doctor for help getting pregnant ranged from 13% to 17% across geographic groups. Women living in suburban counties were most likely to seek medical care for help getting pregnant compared with women living in urbanized counties (adjusted prevalence ratio (aPR) = 1.14, 95% CI: 0.74-1.75); among women who reported infertility this difference was more pronounced (aPR = 1.59, 95% CI: 1.00-2.53). Women living in rural counties were equally likely to seek fertility care compared with women in urbanized counties in the full sample and among women who experienced infertility. CONCLUSIONS: Women living in urban and rural counties were least likely to seek infertility care, suggesting that factors including but not limited to physical proximity to providers are influencing utilization of this type of care. Increased communication about reproductive goals and infertility care available to meet these goals by providers who women see for regular care may help address these barriers. PMID- 26769081 TI - Creatine kinase-myocardial band for chest pain and suspected acute coronary syndrome. PMID- 26769082 TI - Purification and Characterization of Anacardium occidentale (Cashew) Allergens Ana o 1, Ana o 2, and Ana o 3. AB - In this study a fast and simple purification procedure for the three known allergens from cashew (7S globulin Ana o 1, 11S globulin Ana o 2, and 2S albumin Ana o 3) is described. The purified allergens are characterized by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), Western blot, glycoprotein stain, and protein identification. The purified proteins still bind IgE, and this IgE binding varied between different pools of patient serum. Ana o 1 was found to be a glycoprotein. Ana o 3 has been studied more in detail to identify both the small and large subunits, both displaying microheterogeneity, and epitope mapping of Ana o 3 has been performed. PMID- 26769083 TI - Silver nanoparticles and electroporation: Their combinational effect on Leishmania major. AB - Leishmaniasis is an emerging and uncontrolled disease. The use of routine drugs has been limited due to proven side effects and drug resistance. Interestingly, novel approaches such as nanotechnology have been applied as a therapeutic modality. Silver nanoparticles have shown antileishmanial effects but because of their nonspecific and toxic effects on normal cells, their use has been limited. On the other hand, it has been demonstrated that electric pulses induce electropores on cell membranes resulting in higher entrance of certain molecules into cells. There is a hypothesis proposing that use of electroporation and silver nanoparticles simultaneously can induce greater accumulation of particles in infected cells, besides higher toxicity. In this study, after applying electric pulses with different concentrations of silver nanoparticles (SNPs), cell survival rate was determined by standard viability assays. On the basis of these data, 2 MUg/ml of SNPs and 700 V/cm with 100 MUs duration of electroporation were selected as the non-lethal condition. Promastigotes and infected macrophage cells received both treatments and the survival percentage and Infection Index were calculated. In parasites and cells receiving both treatments, higher toxicity was observed in comparison to each treatment given individually, showing a synergic effect on promastigotes. Therefore, application of electric pulses could overcome limitations in using the antileishmanial properties of silver nanoparticles. PMID- 26769086 TI - Non-IgE mediated cow's milk allergy in EuroPrevall. PMID- 26769084 TI - Tumor-associated macrophages correlate with the clinicopathological features and poor outcomes via inducing epithelial to mesenchymal transition in oral squamous cell carcinoma. AB - BACKGROUND: Both tumor-associated macrophages (TAMs) and the epithelial to mesenchymal transition (EMT) of cancer cells play key roles in promoting tumor progression. However, whether TAMs could induce EMT in the progression of oral squamous cell carcinoma (OSCC) remains undefined. RESULTS: Here we detected the expression of macrophages markers CD68 and CD163, epithelial marker E-cadherin and mesenchymal marker vimentin in 127 OSCC patients by using semi-quantitative immunohistochemistry. CD68 and CD163 expression was not confined to the infiltrating TAMs, but also detected in cancer cells. The high number of CD68 positive macrophages was correlated with poor overall survival. Meanwhile, the expression of CD163 both in macrophages and in cancer cells was associated with poor overall survival and had a significant prognostic impact in OSCC. Importantly, the expression of CD163 in cancer cells had a significant relationship with E-cadherin and vimentin. Furthermore, the incubation of TAMs conditioned medium resulted in a fibroblast-like appearance of cancer cells (HN4, HN6 and SCC9) together with the decreased/increased expression of E-cadherin/ vimentin, which were correlated with the enhanced ability of migration and invasion. CONCLUSIONS: Our results indicate that TAMs could promote the EMT of cancer cells, thereby leading to the progression of oral cancer. PMID- 26769087 TI - Protective effect of R. glutinosa oligosaccharides against high L-carnitine diet induced endothelial dysfunction and hepatic injury in mice. AB - Current research for the first time demonstrated that endothelial dysfunction and hepatic injury in mice were induced by ingestion of 3% l-carnitine water for consecutive 10 weeks. Interestingly, oral administration of dietary raffinose family oligosaccharides (RFOs) at 400 and 800 mg/kg bw significantly reduced the impact of l-carnitine on the serum total cholesterol, triglycerides, high- and low-density lipoproteins, alanine aminotransferase, aspartate amino-transferase, NO, endothelin-1 and C-reactive protein. Furthermore, l-carnitine-induced elevation of hepatic lipid contents and malonaldehyde formation, and the inhibition of SOD and GSH-Px activities in mice were markedly ameliorated by oral administration of RFOs. Moreover, histopathology of H&E and Oil Red O staining of the liver also confirmed the protective effect of RFOs against hepatic steatosis and oxidative injury induced by high l-carnitine diet in mice. These findings for the first time suggest that RFOs may alleviate endothelial dysfunction and liver injury from ingestion of high l-carnitine diet. PMID- 26769088 TI - Phosphorylation of psyllium seed polysaccharide and its characterization. AB - Psyllium is widely used as a medicinally active natural polysaccharide for treating conditions like constipation, diarrhea, and irritable bowel syndrome, inflammatory bowel disease, ulcerative colitis and colon cancer. Studies have been performed to characterize and modify the polysaccharide obtained from psyllium seed husk and to evaluate its use as a pharmaceutical excipient, but no studies have been performed to evaluate the properties of the polysaccharide present in psyllium seeds. The present study focuses on phosphorylation of psyllium seed polysaccharide (PPS) using sodium tri-meta phosphate as the cross linking agent. The modified phosphorylated psyllium seed polysaccharide was then evaluated for physicochemical properties, rheological properties, spectral analysis, thermal analysis, crosslinking density and acute oral toxicity studies. The modified polysaccharide (PhPPS) has a high swelling index due to which it can be categorized as a hydrogel. The percent increase in swelling of PhPPS as compared to PPS was found to be 90.26%. The PPS & PhPPS mucilages of all strengths were found to have shear thinning properties. These findings are suggestive of the potential use of PhPPS as gelling & suspending agent. PhPPS was found to have a mucoadhesive property which was comparable with carbopol. PMID- 26769089 TI - White kidney bean lectin exerts anti-proliferative and apoptotic effects on cancer cells. AB - A 60-kDa glucosamine binding lectin, white kidney bean lectin (WKBL), was purified from Phaseolus vulgaris cv. white kidney beans, by application of anion exchange chromatography on Q-Sepharose, affinity chromatography on Affi-gel blue gel, and FPLC-size exclusion on Superdex 75. The anti-proliferative activity of WKBL on HONE1 cells and HepG2 cells was stronger than the activity on MCF7 cells and WRL68 cells (IC50 values for a 48-h treatment with WKBL on HONE1 cells: 18.8 MUM; HepG2 cells: 19.7 MUM; MCF7 cells: 26.9 MUM; and WRL68 cells: >80 MUM). The activity could be reduced by addition of glucosamine, which occupies the binding sites of WKBL, indicating that carbohydrate binding is crucial for the activity. Annexin V-FITC and PI staining, JC-1 staining and Hoechst 33342 staining revealed that apoptosis was induced on WKBL-treated HONE1 cells and HepG2 cells, but not as obviously on MCF7 cells. Cell cycle analysis also showed a slight cell cycle arrest on HONE1 cells after WKBL treatment. Western blotting suggested that WKBL induced apoptosis of HONE1 cells occurred through the extrinsic apoptosis pathway, with detection of increased level of active caspase 3, 8 and 9. PMID- 26769090 TI - Expression and biochemical characterization of recombinant alpha-l-rhamnosidase r Rha1 from Aspergillus niger JMU-TS528. AB - A putative cDNA of alpha-l-rhamnosidase was PCR-cloned from Aspergillus niger JMU TS528 and further extracellular over-expressed in Pichia pastoris GS115. The activity of the recombinant alpha-l-rhamnosidase r-Rha1 was 711.9U/mL, eightfold higher than the native alpha-l-rhamnosidase from A. niger JMU-TS528. r-Rha1 is a N-glycosylated protein of 90kDa and possesses broad substrate specificities by hydrolyzing alpha-1,2, alpha-1,3 alpha-1,4, and alpha-1,6 linkages to beta-d glucosides. This is the first report presenting that alpha-l-rhamnosidase showed activity on four kinds of glucosidic linkages. Compared with other previously characterized alpha-l-rhamnosidases, r-Rha1 showed a good thermostability and wide range of pH-stability with the optimum pH of 5.0 and temperature of 60 degrees C. r-Rha1 activity was not greatly affected by representative metal ions and other detected effectors and showed excellent tolerance abilities against glucose and ethanol. These beneficial characteristics of r-Rha1 suggest that r Rha1 should be considered a potential new biocatalyst for food and drug industrial applications. PMID- 26769091 TI - Editorial. PMID- 26769092 TI - Charts on NHS pay did not provide a fair comparison. PMID- 26769093 TI - Association between circulating CD34-positive cells and serum alkaline phosphatase in relation to body mass index for elderly Japanese men. AB - BACKGROUND: Recent studies have confirmed an association between bone metabolism and vascular homeostasis. However, no study has examined the relationship between serum alkaline phosphatase (ALP) (a marker of bone metabolism) and circulating immature cell such as CD34-positive cells (a marker of vascular homeostasis). METHODS: We conducted a cross-sectional study of this association in 272 elderly Japanese men (60-79 years). Because low body mass index (BMI) status is a known characteristic of Japanese with a high incidence rate of stroke, we used a stratified analysis based on BMI. RESULTS: Multivariable linear regression analysis adjusted for confounding factors showed a significant correlation between serum ALP and the number of circulating CD34-positive cells, especially for participants with low BMI (<23 kg/m(2)). The parameter estimates (beta) and 95% confidence intervals (CI) for one standard deviation increments in serum ALP levels (62 IU/L) for the circulating CD34-positive cell count were beta = 0.25 (0.04, 0.45) for total subjects, beta = 0.45 (0.16, 0.75) for participants with low BMI (<23 kg/m(2)), and beta = 0.04 (-0.25, 0.34) for participants with high BMI (>=23 kg/m(2)). CONCLUSION: Serum ALP correlates positively with circulating CD34-positive cells among a general population of elderly Japanese men, especially those with low BMI (<23 kg/m(2)). These findings suggest that serum ALP levels may constitute an efficient tool for estimating the risk of insufficient vascular homeostasis, especially for participants with relatively few classical cardiovascular risk factors. PMID- 26769094 TI - The Relationship between the Profiles of SVC and Sustainability of SVC Fibrillation Induced by Provocative Electrical Stimulation. AB - BACKGROUND: Superior vena cava (SVC) can be a focus of atrial fibrillation (AF). However, distinctive features that identify SVC arrhythmogenicity remain unclear. Sustainability of fibrillation within the SVC might help with identifying SVC arrhythmogenicity. The purpose of this study was to investigate the relationship between the anatomical and electrical profiles of SVC and sustainability of SVC fibrillation induced by proactive electrical stimulation. METHODS: Consecutive 36 patients with paroxysmal or persistent AF who underwent repetitive pulmonary vein isolation (PVI) session were included in the study. After successful PVI, periodic rapid electrical stimuli were delivered to the SVC to induce SVC fibrillation. SVC fibrillation was defined as follows: (1) the local fibrillatory electrical activity persisted longer than 3 seconds, (2) the local fibrillatory activity penetrated through the atrium and maintained AF, and (3) the frequency of local activity was higher than that of any other atrial components such as coronary sinus and right atrial appendage. RESULTS: SVC fibrillation was induced in seven patients. The group with SVC fibrillation had significantly longer SVC sleeve and longer left atrial diameter compared with the group without SVC fibrillation. All patients with SVC fibrillation were free from AF recurrence after SVC isolation. CONCLUSIONS: The SVC sleeve longer than 30 mm had sustainability of SVC fibrillation induced by electrical stimulation. This finding advocates that arrhythmogenic substrate may exist in the SVC with long myocardial sleeve. PMID- 26769095 TI - Biochemical Markers of Renal Function. AB - Kidney damage can be induced by ischemia, autoimmune diseases, hypertension, allograft rejection, metabolic or genetic disorders, infections or toxins. The influence of these factors could result in acute kidney injury (AKI) defined as an unexpected decrease in urine output or renal function, or encourage the development of chronic kidney disease (CKD). Biomarkers of renal function, measured in urine and serum, are in increasing use in order to estimate the severity and nature of kidney injury, and consequently apply appropriate therapy and improve patient management. The determined values of biomarkers can suggest the potential risk of kidney disease and the type of renal injury, predict the disease progression, as well as be helpful for assessing the response to an applied therapy. Although novel biomarkers are in practical use, serum creatinine, the indicator of glomerular filtration rate is still the most frequently used biomarker of renal function despite its known limitations. In recent decades, numerous studies resulted in discovering urinary and serum proteins that can serve as biomarkers for early and accurate detection of AKI and its development, as well as the identification of CKD. This review gives an overview of the most important renal biomarkers investigated in kidney diseases, classified in following types: functional biomarkers, up-regulated proteins, enzymes, and cycle arrest biomarkers. It describes their properties, physiological roles, and discusses the utility of these molecules in different clinical settings. PMID- 26769096 TI - Plants and the changing environment. PMID- 26769097 TI - Cyanobacterial production of 1,3-propanediol directly from carbon dioxide using a synthetic metabolic pathway. AB - Production of chemicals directly from carbon dioxide using light energy is an attractive option for a sustainable future. The 1,3-propanediol (1,3-PDO) production directly from carbon dioxide was achieved by engineered Synechococcus elongatus PCC 7942 with a synthetic metabolic pathway. Glycerol dehydratase catalyzing the conversion of glycerol to 3-hydroxypropionaldehyde in a coenzyme B12-dependent manner worked in S. elongatus PCC 7942 without addition of vitamin B12, suggesting that the intrinsic pseudovitamin B12 served as a substitute of coenzyme B12. The highest titers of 1,3-PDO (3.79+/-0.23 mM; 288+/-17.7 mg/L) and glycerol (12.62+/-1.55 mM; 1.16+/-0.14 g/L), precursor of 1,3-PDO, were reached after 14 days of culture under optimized conditions in this study. PMID- 26769100 TI - Functional genomics identifies regulators of the phototransduction machinery in the Drosophila larval eye and adult ocelli. AB - Sensory perception of light is mediated by specialized Photoreceptor neurons (PRs) in the eye. During development all PRs are genetically determined to express a specific Rhodopsin (Rh) gene and genes mediating a functional phototransduction pathway. While the genetic and molecular mechanisms of PR development is well described in the adult compound eye, it remains unclear how the expression of Rhodopsins and the phototransduction cascade is regulated in other visual organs in Drosophila, such as the larval eye and adult ocelli. Using transcriptome analysis of larval PR-subtypes and ocellar PRs we identify and study new regulators required during PR differentiation or necessary for the expression of specific signaling molecules of the functional phototransduction pathway. We found that the transcription factor Kruppel (Kr) is enriched in the larval eye and controls PR differentiation by promoting Rh5 and Rh6 expression. We also identified Camta, Lola, Dve and Hazy as key genes acting during ocellar PR differentiation. Further we show that these transcriptional regulators control gene expression of the phototransduction cascade in both larval eye and adult ocelli. Our results show that PR cell type-specific transcriptome profiling is a powerful tool to identify key transcriptional regulators involved during several aspects of PR development and differentiation. Our findings greatly contribute to the understanding of how combinatorial action of key transcriptional regulators control PR development and the regulation of a functional phototransduction pathway in both larval eye and adult ocelli. PMID- 26769101 TI - Vegfa signaling promotes zebrafish intestinal vasculature development through endothelial cell migration from the posterior cardinal vein. AB - The mechanisms underlying organ vascularization are not well understood. The zebrafish intestinal vasculature forms early, is easily imaged using transgenic lines and in-situ hybridization, and develops in a stereotypical pattern thus making it an excellent model for investigating mechanisms of organ specific vascularization. Here, we demonstrate that the sub-intestinal vein (SIV) and supra-intestinal artery (SIA) form by a novel mechanism from angioblasts that migrate out of the posterior cardinal vein and coalesce to form the intestinal vasculature in an anterior to posterior wave with the SIA forming after the SIV. We show that vascular endothelial growth factor aa (vegfaa) is expressed in the endoderm at the site where intestinal vessels form and therefore likely provides a guidance signal. Vegfa/Vegfr2 signaling is required for early intestinal vasculature development with mutation in vegfaa or loss of Vegfr2 homologs causing nearly complete inhibition of the formation of the intestinal vasculature. Vegfc and Vegfr3 function, however, are dispensable for intestinal vascularization. Interestingly, ubiquitous overexpression of Vegfc resulted in an overgrowth of the SIV, suggesting that Vegfc is sufficient to induce SIV development. These results argue that Vegfa signaling directs endothelial cells to migrate out of existing vasculature and coalesce to form the intestinal vessels. It is likely that a similar mechanism is utilized during vascularization of other organs. PMID- 26769104 TI - Building on the First 75 Years of Food Science. PMID- 26769102 TI - Thiol/disulfide homeostasis in predicting adverse perinatal outcomes at 24-28 weeks of pregnancy in gestational diabetes. AB - OBJECTIVE: The main aim of this study was to investigate thiol/disulfide homeostasis at 24-28 weeks of pregnancy and to evaluate whether it is predictive for adverse perinatal outcomes or not in gestational diabetes mellitus (GDM). METHODS: A total of 110 pregnant women at 24-28 weeks of pregnancy (74 GDM patients and 36 age- and BMI-matched healthy pregnant women) were enrolled in this prospective case-control study. Thiol/disulfide homeostasis was evaluated with a novel spectrophotometric method to determine if there is an association with adverse perinatal outcomes in GDM, by using logistic regression analysis. RESULTS: GDM patients, with decreased native thiol levels at 24-28 weeks (OR: 4.890, 95% CI: 1.355-5.764, p = 0.015) and with higher pre-pregnancy BMI (OR: 1.280, 95% CI: 1.072-1.528, p = 0.006), were found to be at increased risk of adverse perinatal outcomes in GDM. There were no statistically significant differences in thiol/disulfide homeostasis between diet- and insulin-treated GDM subgroups. Additionally, 1-h and 2-h glucose levels on 100 g OGTT were found to be predictive for the insulin need in achieving good glycemic control in GDM (OR: 1.022, 95% CI: 1.005-1.038, p = 0.010 and OR: 1.019, 95% CI: 1.004-1.035, p = 0.015). CONCLUSIONS: GDM patients, with decreased native thiol levels at 24-28 weeks of pregnancy and with higher pre-pregnancy BMI, have an increased risk of possible adverse perinatal outcomes. Also, increased 1-h and 2-h glucose levels on 100 g OGTT can predict the need for insulin treatment for GDM. PMID- 26769107 TI - Heavy metal accumulation in tissues of two sea cucumbers, Holothuria leucospilota and Holothuria scabra in the northern part of Qeshm Island, Persian Gulf. AB - The concentrations of some heavy metals (Cd, Cu, Zn andPb) were investigated in the sediments and the two species of sea cucumber (Holothuria leucospilota and Holothuria scabra) from northern part of Qeshm Island, Persian Gulf. The levels of Cu, Zn and Pb in sediment varied significantly among sampling sites (p<0.05). The highest levels of Zn and Pb in H. leucospilota were recorded in body wall whereas the highest contents of Zn and Pb in H. scabra were measured in respiratory tree organ, respectively. Cu and Cd were the most abundant elements in gonads of H. leucospilota while highest levels of Cd and Cu in H. scabra were measured in the gonad and derm, respectively. Cu and Zn concentrations were below permissible limits for human consumption while Cd and Pb were above permissible limits for human consumption. PMID- 26769108 TI - Identifying nitrogen sources to thermal tide pools in Kapoho, Hawai'i, U.S.A, using a multi-stable isotope approach. AB - Nitrogen (N) enrichment often results in coastal eutrophication, even in remote areas like Hawai'i. Therefore, determining N sources to coastal waters is important for their management. This study identified N sources to tide pools in Kapoho, Hawai'i, and determined their relative importance using three stable isotopes (delta(15)N, delta(18)O, delta(11)B). Surface waters and macroalgal tissues were collected along 100-m onshore-offshore transects in areas of high groundwater input for three months at low tide. Water samples from possible N sources were also collected. Mixing model output, along with macroalgal delta(15)N values, indicated that agriculture soil (34%) was the largest anthropogenic N source followed by sewage (27%). These findings suggest that more effective fertilizer application techniques and upgrading sewage treatment systems can minimize N leaching into groundwater. Overall, our multi-stable isotope approach for identifying N sources was successful and may be useful in other coastal waters. PMID- 26769109 TI - Development of mucoadhesive thio-carboxymethyl cellulose for application in buccal delivery of drugs. AB - AIM: L-cysteine (CYS) was covalently attached to carboxymethyl cellulose (CMC) to obtain the thiolated conjugate CMCCYS. Methodology & results: CMCCYS and controls were investigated in terms of safety, disintegration, erosion and mucoadhesiveness. Furthermore, mechanical, physicochemical properties, mucoadhesive strength, swelling behavior and residence time were evaluated. Exhibiting 99.61 +/- 2.51% cell viability, CMCCYS was considered as non toxic at all. Furthermore, CMCCYS displayed 2.8-fold higher polymer stability as well as 5.8-fold less erosion than unmodified CMC. Mucoadhesive strength assay displayed 1.6-fold improved adhesion on buccal mucosa as well as 2.7-fold improved mucoadhesiveness on the rotating cylinder. CONCLUSION: Chemical modification of well-known CMC encourage further evaluation and application of the mucoadhesive potential for the buccal delivery. PMID- 26769110 TI - Pancreaticoduodenectomy for locally advanced colon cancer in hereditary nonpolyposis colorectal cancer. AB - BACKGROUND: Hereditary nonpolyposis colorectal cancer (HNPCC), or Lynch syndrome, accounts for 3% of newly diagnosed cases of colorectal cancer. While a partial or subtotal colectomy is indicated for early stage disease, there is a paucity of data addressing locally advanced disease involving the foregut. CASE PRESENTATION: We report two patients with hereditary nonpolyposis colorectal cancer presenting with locally advanced colon cancer surgically managed by pancreaticoduodenectomy with en bloc partial colectomy and a review of the literature. CONCLUSIONS: Locally advanced colorectal cancer in HNPCC is a rare clinical entity that requires special surgical consideration. Multidisciplinary treatment, including multi-visceral resection, offers the best long-term outcome. PMID- 26769111 TI - Antimicrobial Activity of ILTI, a Kunitz-Type Trypsin Inhibitor from Inga laurina (SW.) Willd. AB - Over the last few years, a growing number of proteinase inhibitors have been isolated from plants and particularly from seeds and have shown antimicrobial activity. A 20,000 Da serine peptidase inhibitor, named ILTI, was isolated from Inga laurina seeds and showed potent inhibitory enzymatic activity against trypsin. The aim of this study was to determine the effects of ILTI on the growth of pathogenic and non-pathogenic microorganisms. We observed that ILTI strongly inhibited in particular the growth of Candida tropicalis and Candida buinensis, inducing cellular agglomeration. However, it was ineffective against human pathogenic bacteria. We also investigated the potential of ILTI to permeabilize the plasma membrane of yeast cells. C. tropicalis and C. buinensis were incubated for 24 h with the ILTI at different concentrations, which showed that this inhibitor induced changes in the membranes of yeast cells, leading to their permeabilization. Interestingly, ILTI induced the production of reactive oxygen species (ROS) in C. tropicalis and C. buinensis cells. Finally, ILTI was coupled with fluorescein isothiocyanate, and subsequent treatment of C. tropicalis and C. buinensis with DAPI revealed the presence of the labeled protein in the intracellular spaces. In conclusion, our results indicated the ability of peptidase inhibitors to induce microbial inhibition; therefore, they might offer templates for the design of new antifungal agents. PMID- 26769112 TI - [Securing the sustainability of biobanks]. AB - Active research sites in biomedicine need professionally structured, sustainable biobanks that represent established resources and technology platforms across different locations and disciplines. Currently, the funding of research biobanks is not uniformly regulated, mainly because of the different focuses, services and concepts. On the other hand, the samples and associated data of biobanks gain significant value over time, and therefore their long-term storage should be envisaged right from the start.The sustainability of biobank structures can be viewed from various perspectives, but financial sustainability certainly represents the most demanding challenge. The financing of biobanks can be achieved by a well-balanced model consisting of institutional resources and other funding sources such as infrastructure and research projects, complemented by reimbursement. Structural measures such as the creation of centralized biobank structures and involvement in consortia and networks contribute to the long-term use and exchange of samples across biobanks. In turn, a quality-controlled and transparent documentation of all processes and structures is required, which guarantees the utilization of the sparse financial resources for the most efficient use of the precious resource of human biomaterial. The long-term goal is the sustainable financing of an infrastructure that is essential for any modern biomedical research and provides benefit for the society. PMID- 26769113 TI - Impact of Body Weight and Body Composition on Ovarian Cancer Prognosis. AB - Measures of body weight and anthropometrics such as body mass index (BMI) are commonly used to assess nutritional status in clinical conditions including cancer. Extensive research has evaluated associations between body weight and prognosis in ovarian cancer patients, yet little is known about the potential impact of body composition (fat mass (FM) and fat-free mass (FFM)) in these patients. Thus, the purpose of this publication was to review the literature (using PubMed and EMBASE) evaluating the impact of body weight and particularly body composition on surgical complications, morbidity, chemotherapy dosing and toxicity (as predictors of prognosis), and survival in ovarian cancer patients. Body weight is rarely associated with intra-operative complications, but obesity predicts higher rates of venous thromboembolism and wound complications post operatively in ovarian cancer patients. Low levels of FM and FFM are superior predictors of length of hospital stay compared to measures of body weight alone, but the role of body composition on other surgical morbidities is unknown. Obesity complicates chemotherapy dosing due to altered pharmacokinetics, imprecise dosing strategies, and wide variability in FM and FFM. Measurement of body composition has the potential to reduce toxicity if the results are incorporated into chemotherapy dosing calculations. Some findings suggest that excess body weight adversely affects survival, while others find no such association. Limited studies indicate that FM is a better predictor of survival than body weight in ovarian cancer patients, but the direction of this relationship has not been determined. In conclusion, body composition as an indicator of nutritional status is a better prognostic tool than body weight or BMI alone in ovarian cancer patients. PMID- 26769115 TI - The Role of Narrow Band Imaging in Head and Neck Cancers. AB - Early diagnosis of malignant tumors in the head and neck region is very difficult. Therefore, endoscopic systems with narrow band imaging (NBI), which enhances image contrast, have an important clinical value in detecting superficial mucosal lesions. In particular, highlighting of the intraepithelial microvasculature helps determine the nature of the lesion. This new image enhanced technology already has proven effective in the early diagnosis of head and neck squamous cell carcinoma, including laryngeal, hypopharyngeal, oropharyngeal, nasopharyngeal, and oral cancers, as well as of unknown primary cervical lymph node metastasis. NBI laryngoscopy can be applied easily in clinical practice and has become a valuable tool in diagnosing head and neck cancers early, providing the option of minimally invasive treatment such as endoscopic or partial surgical resection. PMID- 26769114 TI - Advances in Local and Systemic Therapies for Hepatocellular Cancer. AB - Global incidence and mortality of hepatocellular carcinoma (HCC) has increased over the past two decades. Although transplantation and surgical resection offer a chance for cure and long-term survival, most patients present with more advanced tumor stage when these therapies are not possible. Although rarely curative, locoregional therapy with transarterial chemoembolization or radioembolization offers a survival benefit for those with liver-isolated HCC who are not amenable to curative therapies. Patients with metastatic disease or macrovascular invasion are treated with systemic therapy; however, median survival remains below 1 year. Patients with severe liver dysfunction or poor performance status should be treated with best supportive care given poor prognosis and no survival benefit for treatment. Lack of predictive and prognostic biomarkers in intermediate and advanced HCC tumors has hampered integration of clinical and molecular data to aid tailoring treatment decisions. However, with increasingly complex treatment decisions, optimal outcomes are achieved through multidisciplinary care. PMID- 26769116 TI - Communication About Sexuality in Advanced Illness Aligns With a Palliative Care Approach to Patient-Centered Care. AB - Treatment-related sexual complications are common in cancer patients although rarely discussed in the palliative care setting. Sexuality is an important survivorship issue and remains relevant even in the terminal setting. There are multiple barriers in dialoguing about intimacy and sexual functioning from the patient and provider perspectives. Palliative care providers, while not expected to be sexual health experts, can provide comprehensive patient-centered care by including sexual health as part of their evaluation. They can explore how sexual dysfunction can impair functioning and utilize an interdisciplinary approach to manage symptoms. Palliative care providers can help patients identify their goals of care and explore what anticipated sexual changes and treat-related side effects are tolerable and intolerable to the patient's quality of life. Principles on addressing sexuality in the palliative setting and practical ways of incorporating sexual history into the palliative care assessment are provided. PMID- 26769119 TI - A mechanical model for morphological response of endothelial cells under combined wall shear stress and cyclic stretch loadings. AB - The shape and morphology of endothelial cells (ECs) lining the blood vessels are a good indicator for atheroprone and atheroprotected sites. ECs of blood vessels experience both wall shear stress (WSS) and cyclic stretch (CS). These mechanical stimuli influence the shape and morphology of ECs. A few models have been proposed for predicting the morphology of ECs under WSS or CS. In the present study, a mathematical cell population model is developed to simulate the morphology of ECs under combined WSS and CS conditions. The model considers the cytoskeletal filaments, cell-cell interactions, and cell-extracellular matrix interactions. In addition, the reorientation and polymerization of microfilaments are implemented in the model. The simulations are performed for different conditions: without mechanical stimuli, under pure WSS, under pure CS, and under combined WSS and CS. The results are represented as shape and morphology of ECs, shape index, and angle of orientation. The model is validated qualitatively and quantitatively with several experimental studies, and good agreement with experimental studies is achieved. To the best of our knowledge, it is the first model for predicting the morphology of ECs under combined WSS and CS condition. The model can be used to indicate the atheroprone regions of a patient's artery. PMID- 26769118 TI - Advances in the Management of Gastric and Gastroesophageal Cancers. AB - Management of gastric and gastroesophageal cancers is a complex, evolving paradigm. Involvement of multimodality specialties is the key. In gastric cancer, data are conflicting with regard to the specific roles of surgery, chemotherapy, and radiation, particularly between Asian and Western studies. However, current ongoing phase III trials will further elucidate the optimal treatment for this heterogeneous disease. For resectable gastroesophageal junction (GEJ) tumors, the publication of a landmark study in 2012 out of the Netherlands revealed a clear benefit in the utilization of trimodality therapy. This changed practice almost immediately around the world. In unresectable gastroesophageal disease, chemoradiation has been firmly established as a paradigm for treatment. The optimal chemotherapy regimen is still in flux. However, for both gastric and GEJ tumors, technological breakthroughs in genomics and pharmacologic targeting will soon provide physicians more options in the armamentarium to fight these diseases and, one day, individually personalize treatment. PMID- 26769117 TI - Clinically Relevant Physical Benefits of Exercise Interventions in Breast Cancer Survivors. AB - Evidence is currently limited for the effect of exercise on breast cancer clinical outcomes. However, several of the reported physical benefits of exercise, including peak oxygen consumption, functional capacity, muscle strength and lean mass, cardiovascular risk factors, and bone health, have established associations with disability, cardiovascular disease risk, morbidity, and mortality. This review will summarize the clinically relevant physical benefits of exercise interventions in breast cancer survivors and discuss recommendations for achieving these benefits. It will also describe potential differences in intervention delivery that may impact outcomes and, lastly, describe current physical activity guidelines for cancer survivors. PMID- 26769120 TI - Electronic self-monitoring of mood using IT platforms in adult patients with bipolar disorder: A systematic review of the validity and evidence. AB - BACKGROUND: Various paper-based mood charting instruments are used in the monitoring of symptoms in bipolar disorder. During recent years an increasing number of electronic self-monitoring tools have been developed. The objectives of this systematic review were 1) to evaluate the validity of electronic self monitoring tools as a method of evaluating mood compared to clinical rating scales for depression and mania and 2) to investigate the effect of electronic self-monitoring tools on clinically relevant outcomes in bipolar disorder. METHODS: A systematic review of the scientific literature, reported according to the Preferred Reporting items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines was conducted. MEDLINE, Embase, PsycINFO and The Cochrane Library were searched and supplemented by hand search of reference lists. Databases were searched for 1) studies on electronic self-monitoring tools in patients with bipolar disorder reporting on validity of electronically self-reported mood ratings compared to clinical rating scales for depression and mania and 2) randomized controlled trials (RCT) evaluating electronic mood self-monitoring tools in patients with bipolar disorder. RESULTS: A total of 13 published articles were included. Seven articles were RCTs and six were longitudinal studies. Electronic self-monitoring of mood was considered valid compared to clinical rating scales for depression in six out of six studies, and in two out of seven studies compared to clinical rating scales for mania. The included RCTs primarily investigated the effect of heterogeneous electronically delivered interventions; none of the RCTs investigated the sole effect of electronic mood self-monitoring tools. Methodological issues with risk of bias at different levels limited the evidence in the majority of studies. CONCLUSIONS: Electronic self-monitoring of mood in depression appears to be a valid measure of mood in contrast to self-monitoring of mood in mania. There are yet few studies on the effect of electronic self-monitoring of mood in bipolar disorder. The evidence of electronic self-monitoring is limited by methodological issues and by a lack of RCTs. Although the idea of electronic self-monitoring of mood seems appealing, studies using rigorous methodology investigating the beneficial as well as possible harmful effects of electronic self-monitoring are needed. PMID- 26769122 TI - Smoke-free legislation reduces hospital admissions for childhood lower respiratory tract infection. AB - BACKGROUND: Previous studies showed reduction of hospital admissions for asthma after implementation of comprehensive smoke-free legislation. We aimed to evaluate the impact of comprehensive smoke-free legislation implemented in Hong Kong in 2007 on hospital admissions for childhood lower respiratory tract infection (LRTI). METHODS: We obtained data on 75 870 hospital admissions for LRTI among children <=18 years of age between January 2004 and December 2012 from all Hospital Authority hospitals. Using a negative binomial regression model, we assessed the impact of smoke-free legislation on admission counts. RESULTS: After legislation implementation, there was an immediate effect with a change in the admission count of -33.5% (95% CI -36.4% to -30.5%), and a change in time trend to -13.9% per year (95% CI -16.0% to -11.7%). Overall, the legislation was associated with a net 47.4% reduction in admission counts in the first year. We estimated that the legislation was associated with a reduction of 13 635 admissions in the first 6 years after implementation. The immediate reduction and change in time trend was more apparent among school-age than preschool children. CONCLUSIONS: Implementation of comprehensive smoke-free legislation was associated with a significant reduction in hospital admissions for childhood LRTI. PMID- 26769121 TI - Diagnosis and neurocognitive profiles in first-episode non-affective psychosis patients. AB - This study explored whether there are distinguishable neurocognitive profiles in diagnostic subgroups of first-episode non-affective psychosis (FEP) patients. Four hundred and eighty-seven individuals with diagnoses of non-affective psychosis disorders were evaluated 6 months after first contact with psychiatric services. Individuals with schizophrenia (n = 257), schizophreniform (n = 141), brief psychotic disorder (n = 54), and psychosis not otherwise specified (n = 35) were compared on baseline neuropsychological variables using analyses of variance and covariance with potential clinical, premorbid, and sociodemographic confounders. The brief psychotic disorder subgroup was the least impaired on global cognitive function, in particular when compared to the schizophrenia subgroup, and specifically on executive function, processing speed, and motor dexterity domains. However, with the exception of the processing speed domain, profile differences could be explained by sex, age, psychotic and negative symptoms, years of education, and premorbid IQ. These results suggest processing speed as a diagnostic marker for brief psychotic disorder in FEP patients. Further, there are quantitative and qualitative differences across the schizophrenia spectrum disorders subgroups, indicating different profiles with varying degrees of deficit. PMID- 26769124 TI - SPIRIT: Systematic Planning of Intelligent Reuse of Integrated Clinical Routine Data. A Conceptual Best-practice Framework and Procedure Model. AB - BACKGROUND: Secondary use of clinical routine data is receiving an increasing amount of attention in biomedicine and healthcare. However, building and analysing integrated clinical routine data repositories are nontrivial, challenging tasks. As in most evolving fields, recognized standards, well-proven methodological frameworks, or accurately described best-practice approaches for the systematic planning of solutions for secondary use of routine medical record data are missing. OBJECTIVE: We propose a conceptual best-practice framework and procedure model for the systematic planning of intelligent reuse of integrated clinical routine data (SPIRIT). METHODS: SPIRIT was developed based on a broad literature overview and further refined in two case studies with different kinds of clinical routine data, including process-oriented nursing data from a large hospital group and high-volume multimodal clinical data from a neurologic intensive care unit. RESULTS: SPIRIT aims at tailoring secondary use solutions to specific needs of single departments without losing sight of the institution as a whole. It provides a general conceptual best-practice framework consisting of three parts: First, a secondary use strategy for the whole organization is determined. Second, comprehensive analyses are conducted from two different viewpoints to define the requirements regarding a clinical routine data reuse solution at the system level from the data perspective (BOTTOM UP) and at the strategic level from the future users perspective (TOP DOWN). An obligatory clinical context analysis (IN BETWEEN) facilitates refinement, combination, and integration of the different requirements. The third part of SPIRIT is dedicated to implementation, which comprises design and realization of clinical data integration and management as well as data analysis solutions. CONCLUSIONS: The SPIRIT framework is intended to be used to systematically plan the intelligent reuse of clinical routine data for multiple purposes, which often was not intended when the primary clinical documentation systems were implemented. SPIRIT helps to overcome this gap. It can be applied in healthcare institutions of any size or specialization and allows a stepwise setup and evolution of holistic clinical routine data reuse solutions. PMID- 26769123 TI - Choline Kinase Alpha (CHKalpha) as a Therapeutic Target in Pancreatic Ductal Adenocarcinoma: Expression, Predictive Value, and Sensitivity to Inhibitors. AB - Choline kinase alpha (CHKalpha) plays a crucial role in the regulation of membrane phospholipid synthesis and has oncogenic properties in vitro. We have analyzed the expression of CHKalpha in cell lines derived from pancreatic ductal adenocarcinoma (PDAC) and have found increased CHKalpha expression, associated with differentiation. CHKalpha protein expression was directly correlated with sensitivity to MN58b, a CHKalpha inhibitor that reduced cell growth through the induction of apoptosis. Accordingly, CHKalpha knockdown led to reduced drug sensitivity. In addition, we found that gemcitabine-resistant PDAC cells displayed enhanced sensitivity to CHKalpha inhibition and, in vitro, MN58b had additive or synergistic effects with gemcitabine, 5-fluorouracil, and oxaliplatin, three active drugs in the treatment of PDAC. Using tissue microarrays, CHKalpha was found to be overexpressed in 90% of pancreatic tumors. While cytoplasmic CHKalpha did not relate to survival, nuclear CHKalpha distribution was observed in 43% of samples and was associated with longer survival, especially among patients with well/moderately differentiated tumors. To identify the mechanisms involved in resistance to CHKalpha inhibitors, we cultured IMIM-PC-2 cells with increasingly higher concentrations of MN58b and isolated a subline with a 30-fold higher IC50. RNA-Seq analysis identified upregulation of ABCB1 and ABCB4 multidrug resistance transporters, and functional studies confirmed that their upregulation is the main mechanism involved in resistance. Overall, our findings support the notion that CHKalpha inhibition merits further attention as a therapeutic option in patients with PDAC and that expression levels may predict response. PMID- 26769125 TI - Follicular lymphoma: 2015 update on diagnosis and management. AB - DISEASE OVERVIEW: Follicular lymphoma is generally an indolent B cell lymphoproliferative disorder of transformed follicular center B cells. Follicular lymphoma (FL) is characterized by diffuse lymphoadenopathy, bone marrow involvement, splenomegaly, and less commonly other extranodal sites of involvement. In general, cytopenias can occur but constitutional symptoms of fever, night sweats, and weight loss are uncommon. DIAGNOSIS: Diagnosis is based on histology of preferably a biopsy of a lymph node. Immunohistochemical staining is positive in virtually all cases for cell surface CD19, CD20, CD10, and monoclonal immunoglobulin, as well as cytoplasmic expression of bcl-2 protein. The overwhelming majority of cases have the characteristic t(14;18) translocation involving the IgH/bcl-2 genes. RISK STRATIFICATION: The Follicular Lymphoma International Prognostic Index prognostic model for FL uses five independent predictors of inferior survival: age >60 years, hemoglobin <12 g/dL, serum LDH > normal, Ann Arbor stage III/IV, number of involved nodal areas > 4. The presence of 0, 1, 2, and >= 3 adverse factors defines low, intermediate, and high-risk disease. With the use of more modern therapies, outcomes have improved. RISK ADAPTED THERAPY: Observation continues to be adequate for asymptomatic patients with low bulk disease and no cytopenias, with no survival advantage for early treatment with either chemotherapy or rituximab alone. For patients needing therapy, most patients are treated with chemotherapy plus rituximab, which has improved response rates, duration of response and overall survival. Randomized studies have shown additional benefit for maintenance rituximab both following chemotherapy-rituximab and single agent rituximab. Experimental therapies as well as stem cell transplantation (SCT) are considered for recurrent disease. PMID- 26769126 TI - Simultaneous detection of circulating immunological parameters and tumor biomarkers in early stage breast cancer patients during adjuvant chemotherapy. AB - BACKGROUND: Chemotherapy-induced immune suppression has mainly been studied in patients with advanced cancer, but the influence of chemotherapy on the immune system in early stage cancer patients has so far not been studied systematically. The aim of the present study was to monitor the immune system during anthracycline- and taxane-based adjuvant chemotherapy in early stage breast cancer patients, to assess the impact of circulating tumor cells on selected immune parameters and to reveal putative angiogenic effects of circulating endothelial cells. METHODS: Peripheral blood samples from 20 early stage breast cancer patients were analyzed using a flow cytometric multi-color of antibodies to enumerate lymphocyte and dendritic cell subsets, as well as endothelial and tumor cells. An enzyme-linked immunosorbent assay (ELISA) was used to measure the levels of various serological factors. RESULTS: During chemotherapy, all immunological parameters and angiogenesis surrogate biomarkers showed significant decreases. The numbers of circulating tumor cells showed significant inverse correlations with the numbers of T helper cells, a lymphocyte subset directly related to effective anti-tumor responses. Reduced T helper cell numbers may contribute to systemic immunosuppression and, as such, the activation of dormant tumor cells. CONCLUSIONS: From our results we conclude that adjuvant chemotherapy suppresses immune function in early stage breast cancer patients. In addition, we conclude that the presence of circulating tumor cells, defined as pan cytokeratin(+), CD326(+), CD45(-) cells, may serve as an important indicator of a patient's immune status. Further investigations are needed to firmly define circulating tumor cells as a predictor for the success of breast cancer adjuvant chemotherapy. PMID- 26769128 TI - Antiarthritis Effect of Morin is Associated with Inhibition of Synovial Angiogensis. AB - Morin, a flavonoid isolated from Morus alba L. (Moraceae), possesses anti inflammatory, antiangiogenic among other biological activities. This study investigated its effect on type II collagen-induced arthritis (CIA) in rats and explored the underlying mechanisms in view of synovial angiogenesis. Morin administered po attenuated arthritic progression as indicated by reduction of arthritis scores and paw swelling. It also markedly reduced serum levels of the proinflammatory cytokines, tumor necrosis factor alpha (TNF-alpha) and interleukin-6 (IL-6), but increased the level of anti-inflammatory cytokine interleukin-10, and ameliorated histopathological changes of joints. Morin markedly inhibited expression of CD31, vascular endothelial growth factor (VEGF), and basic fibroblast growth factor in synovial membrane tissues, and decreased serum levels of VEGF in CIA rats. In vitro, morin markedly inhibited VEGF-induced migration and tube formation in human umbilical vein endothelial cells. These results indicate that morin had antirheumatoid potential, and its mechanism might be associated with inhibition of synovial angiogenesis. PMID- 26769129 TI - Extending metabolome coverage for untargeted metabolite profiling of adherent cultured hepatic cells. AB - MS-based metabolite profiling of adherent mammalian cells comprises several challenging steps such as metabolism quenching, cell detachment, cell disruption, metabolome extraction, and metabolite measurement. In LC-MS, the final metabolome coverage is strongly determined by the separation technique and the MS conditions used. Human liver-derived cell line HepG2 was chosen as adherent mammalian cell model to evaluate the performance of several commonly used procedures in both sample processing and LC-MS analysis. In a first phase, metabolite extraction and sample analysis were optimized in a combined manner. To this end, the extraction abilities of five different solvents (or combinations) were assessed by comparing the number and the levels of the metabolites comprised in each extract. Three different chromatographic methods were selected for metabolites separation. A HILIC-based method which was set to specifically separate polar metabolites and two RP-based methods focused on lipidome and wide-ranging metabolite detection, respectively. With regard to metabolite measurement, a Q-ToF instrument operating in both ESI (+) and ESI (-) was used for unbiased extract analysis. Once metabolite extraction and analysis conditions were set up, the influence of cell harvesting on metabolome coverage was also evaluated. Therefore, different protocols for cell detachment (trypsinization or scraping) and metabolism quenching were compared. This study confirmed the inconvenience of trypsinization as a harvesting technique, and the importance of using complementary extraction solvents to extend metabolome coverage, minimizing interferences and maximizing detection, thanks to the use of dedicated analytical conditions through the combination of HILIC and RP separations. The proposed workflow allowed the detection of over 300 identified metabolites from highly polar compounds to a wide range of lipids. PMID- 26769127 TI - Dissection of transcriptional and cis-regulatory control of differentiation in human pancreatic cancer. AB - The histological grade of carcinomas describes the ability of tumor cells to organize in differentiated epithelial structures and has prognostic and therapeutic impact. Here, we show that differential usage of the genomic repertoire of transcriptional enhancers leads to grade-specific gene expression programs in human pancreatic ductal adenocarcinoma (PDAC). By integrating gene expression profiling, epigenomic footprinting, and loss-of-function experiments in PDAC cell lines of different grade, we identified the repertoires of enhancers specific to high- and low-grade PDACs and the cognate set of transcription factors acting to maintain their activity. Among the candidate regulators of PDAC differentiation, KLF5 was selectively expressed in pre-neoplastic lesions and low grade primary PDACs and cell lines, where it maintained the acetylation of grade specific enhancers, the expression of epithelial genes such as keratins and mucins, and the ability to organize glandular epithelia in xenografts. The identification of the transcription factors controlling differentiation in PDACs will help clarify the molecular bases of its heterogeneity and progression. PMID- 26769130 TI - Evidence for ferritin as dominant iron-bearing species in the rhizobacterium Azospirillum brasilense Sp7 provided by low-temperature/in-field Mossbauer spectroscopy. AB - For the ubiquitous diazotrophic rhizobacterium Azospirillum brasilense, which has been attracting the attention of researchers worldwide for the last 35 years owing to its significant agrobiotechnological and phytostimulating potential, the data on iron acquisition and its chemical speciation in cells are scarce. In this work, for the first time for azospirilla, low-temperature (at 80 K, 5 K, as well as at 2 K without and with an external magnetic field of 5 T) transmission Mossbauer spectroscopic studies were performed for lyophilised biomass of A. brasilense (wild-type strain Sp7 grown with (57)Fe(III) nitrilotriacetate complex as the sole source of iron) to enable quantitative chemical speciation analysis of the intracellular iron. In the Mossbauer spectrum at 80 K, a broadened quadrupole doublet of high-spin iron(III) was observed with a few percent of a high-spin iron(II) contribution. In the spectrum measured at 5 K, a dominant magnetically split component appeared with the parameters typical of ferritin species from other bacteria, together with a quadrupole doublet of a superparamagnetic iron(III) component and a similarly small contribution from the high-spin iron(II) component. The Mossbauer spectra recorded at 2 K (with or without a 5 T external field) confirmed the assignment of ferritin species. About 20% of total Fe in the dry cells of A. brasilense strain Sp7 were present in iron(III) forms superparamagnetic at both 5 and 2 K, i.e. either different from ferritin cores or as ferritin components with very small particle sizes. PMID- 26769131 TI - Direct detection of endogenous MicroRNAs and their post-transcriptional modifications in cancer serum by capillary electrophoresis-mass spectrometry. AB - MicroRNA molecules (miRNAs) are a class of small, single-stranded, non-coding RNA molecules that regulate cellular messenger RNA and their corresponding proteins. Extracellular miRNAs circulate in the bloodstream inside exosomes or in complexes with proteins and lipoproteins. The miRNA sequences and their quantitative levels are used as unique signatures associated with cancer diagnosis and prognosis after anticancer treatment. MicroRNAs are modified through a series of processing events after transcription like 5'-end phosphorylation, 3'- end adenylation or uridylation, terminal nucleotide deletion. The problem is that existing bioanalytical methods such as microarrays and a quantitative polymerase chain reaction are sensitive, but not capable of identifying the post-transcriptional modifications of miRNA. Here we report a capillary electrophoresis-mass spectrometry (CE-MS) method, which performs a multiplex, direct analysis of miRNAs from biological samples. Using the CE-MS method, we detected two endogenous human circulating miRNAs, a 23-nucleotide long 5'-phosporylated miRNA with 3'-uridylation (iso-miR-16-5p), and a 22-nucleotide long 5'-phosporylated miRNA (miR-21-5p) isolated from B-cell chronic lymphocytic leukemia serum. The CE separation and following MS analysis provides label-free quantitation and reveals modifications of miRNAs. MicroRNA profiling of serum samples with CE-MS has the potential to be a versatile and minimally invasive bioassay that could lead to better clinical diagnostics and disease treatment. PMID- 26769132 TI - Optimization of strawberry disinfection by fogging of a mixture of peracetic acid and hydrogen peroxide based on microbial reduction, color and phytochemicals retention. AB - The fogging of strawberries using a environmentally friendly sanitizer mixture of peracetic acid (5%) and hydrogen peroxide (20%) was performed in a model chamber and modeled as a function of the concentration (3.4, 20.0, 60.0, 100.0 and 116.6 uL sanitizer L(-) (1) air chamber) and the treatment time (5.7, 15.0, 37.5, 60.0 and 69.3 min). The sanitizer fogging was adequate for reducing total mesophilic microbial and yeasts and moulds counts of fruits until seven days of storage at 2C. However, sanitizer oxidant properties adversely affected the content of total anthocyanins, total phenolics, vitamin C, and antioxidant capacity to various degrees, with some deleterious changes in the fruits color, depending on the fogging conditions. A multiple numeric response optimization was developed based on 2.0 log microbiological reduction, maximum phytochemicals and antioxidant capacity retentions, with no changes in the fruits color, being the optimal fogging conditions achieved: 10.1 uL sanitizer L(-1) air chamber and 29.6 min. The fogging of strawberries at these conditions may represent a promising postharvest treatment option for extending their shelf-life without affecting their sensory quality and bioactive properties. PMID- 26769133 TI - Assessment of cardiac autonomic tone in conscious rats. AB - Cardiac autonomic tone can be assessed either by estimating separately vagal and sympathetic tones or by evaluating the net effect of their interaction, the so called sympathovagal balance (SVB). To compare the most commonly used methods in rats, telemetric recordings of the electrocardiogram were performed in normotensive WKY rats, and in groups of spontaneously hypertensive (SHR) rats that were either untreated or chronically treated with the cholinesterase inhibitor, pyridostigmine, to enhance vagal tone. Cardiac autonomic blockers were administered alone and in combination, so that heart rate (HR) could be measured (1) under resting conditions, (2) with either autonomic branch blocked, and (3) with both branches blocked (which provided intrinsic HR, iHR). SVB was assessed as the ratio of resting HR to iHR. This calculation pointed to a sympathetic predominance in untreated SHRs and even more so in WKY rats, and to a marked vagal predominance in pyridostigmine-treated SHRs. By contrast, the ratio between low and high frequency components (LF/HF) of RR interval spectra did not significantly differ between the groups. Each autonomic tone was quantified as the HR change induced by its selective blocker or as the difference between iHR and HR after blockade of its counterpart. Both pharmacological methods indicated vagal enhancement in treated SHRs, but provided opposite results in terms of vagal vs. sympathetic predominance. These data seriously question the use of the LF/HF ratio as an index of SVB, and the possibility to reliably estimate vagal and sympathetic tones separately through current pharmacological approaches in conscious rats. PMID- 26769135 TI - Cosmetic Drugs of Antiquity. PMID- 26769136 TI - Old and new therapeutics for Rheumatoid Arthritis: in vivo models and drug development. AB - Development of novel drugs for treatment of chronic inflammatory diseases is to a large extent dependent on the availability of good experimental in vivo models in order to perform preclinical tests of new drugs and for the identification of novel drug targets. Here, we review a number of existing rodent models for Rheumatoid Arthritis in the context of how these models have been utilized for developing established therapy in Rheumatoid Arthritis and, furthermore, the present use of animal models for studies of novel drug candidates. We have studied the literature in the field for the use of in vivo models during development of anti-rheumatic drugs; from Methotrexate to various antibody treatments, to novel drugs that are, or have recently been, in clinical trials. For novel drugs, we have explored websites for clinical trials. Although a single Rheumatoid Arthritis in vivo model cannot mirror the complexity of disease development, there exist a number of good animal models for Rheumatoid Arthritis, each defining some parts in disease development, which are useful for studies of drug response. We find that many of the established drugs were not tested in in vivo models before being used in the clinic, but rather animal models have been subsequently used to find mechanisms for efficacy. Finally, we report a number of novel drugs, tested in preclinical in vivo models, presently in clinical trials. PMID- 26769134 TI - Caenorhabditis elegans susceptibility to gut Enterococcus faecalis infection is associated with fat metabolism and epithelial junction integrity. AB - BACKGROUND: Gut bacteria-host interactions have been implicated in the pathogenesis of numerous human diseases, but few mechanisms have been described. The genetically tractable nematode worm Caenorhabditis elegans can be infected with pathogenic bacteria, such as the human gut commensal Enterococcus faecalis, via feeding, making it a good model for studying these interactions. RESULTS: An RNAi screen of 17 worm candidate genes revealed that knockdown of the transcription factor nhr-49, a master regulator of fat metabolism, shortens worm lifespan upon infection with E. faecalis (and other potentially pathogenic bacteria) compared to Escherichia coli. The functional similarity of nhr-49 to the mammalian peroxisome proliferator-activated receptors (PPARs) suggests that this is mediated through a link between fatty acid metabolism and innate immunity. In addition, knockdown of either dlg-1 or ajm-1, which encode physically interacting proteins in the C. elegans epithelial junction, also reduces worm lifespan upon E. faecalis challenge, demonstrating the importance of the intestinal epithelium as an immune barrier. CONCLUSIONS: The protective roles identified for nhr-49, dlg-1, and ajm-1 suggest mechanistic interactions between the gut microbiota, host fatty acid metabolism, innate immunity, and epithelial junction integrity that are remarkably similar to those implicated in human metabolic and inflammatory diseases. PMID- 26769138 TI - Combined use of heat-shock protein 70 and glutamine synthetase is useful in the distinction of typical hepatocellular adenoma from atypical hepatocellular neoplasms and well-differentiated hepatocellular carcinoma. AB - Well-differentiated hepatocellular carcinoma can mimic high-grade dysplastic nodule in cirrhotic liver and hepatocellular adenoma in non-cirrhotic liver. This study evaluates the efficacy of combined use of heat-shock protein 70 (HSP70), glutamine synthetase (GS) and glypican-3 in this setting. Immunohistochemistry for these three markers was done in 17 typical hepatocellular adenoma, 15 high grade dysplastic nodules, 20 atypical hepatocellular neoplasms (14 clinically atypical and 6 pathologically atypical), 14 very well-differentiated hepatocellular carcinoma, and 43 well-differentiated hepatocellular carcinoma. All three markers were negative in typical adenomas. HSP70 was positive in 10, 71, and 67% of atypical neoplasms, very well-differentiated and well differentiated HCC, respectively, while GS was positive in 60, 50, and 60% of atypical neoplasms, very well-differentiated and well-differentiated hepatocellular carcinoma, respectively. Glypican-3 was negative in all atypical neoplasms and very well-differentiated hepatocellular carcinoma, and was positive in 27% of well-differentiated hepatocellular carcinoma. Positive staining with at least one marker (HSP70 and/or GS) was seen in 85% of very well-differentiated hepatocellular carcinoma, which was similar to well-differentiated hepatocellular carcinoma (78%, P=0.4), and pathologically atypical cases (100%, P=0.5), but significantly higher compared with clinically atypical cases (43%. P=0.03) and none of typical adenomas (P<0.001). Positive staining with both GS and HSP70 was seen significantly more often in hepatocellular carcinoma compared with atypical neoplasms (45 vs 10%, P=0.004). Both these markers were also more often expressed in very well-differentiated hepatocellular carcinoma compared with atypical cases (38 vs 10%, P=0.06). In conclusion, the combined use of GS and HSP70 can be useful in the diagnosis of very well-differentiated hepatocellular carcinoma. These stains can also help in the distinction of typical adenoma from atypical hepatocellular neoplasms. Glypican-3 has low sensitivity and is not useful in this setting. PMID- 26769137 TI - Cholangiocarcinoma with intraductal tubular growth pattern versus intraductal papillary growth pattern. AB - Intraductal neoplasms of the bile duct are macroscopically characterized by exophytic or polypoid growth patterns and have a favorable prognosis. Although some tumors with a predominantly tubular microscopic pattern have been reported, they have not been well characterized clinicopathologically. The purpose of the present study was to compare the newly recognized cholangiocarcinoma with an intraductal tubular growth pattern and cholangiocarcinoma with an intraductal papillary growth pattern and to investigate the pathological and prognostic significance of the former. This study analyzed 161 patients with tumors with exophytic or polypoid growth patterns from a large series of 733 cholangiocarcinoma cases surgically resected from January 1998 to May 2013. The study patients were divided into two groups: those whose tumors showed a predominantly tubular growth pattern (n=52) and those whose tumors exhibited a predominantly papillary growth pattern (n=109). Tubular growth pattern was associated with combined vascular resection and the absence of macroscopic mucin. Several histological indexes were significantly higher for the tubular growth pattern than the papillary one, including tubular adenocarcinoma, depth of invasion, microscopic lymphatic invasion, venous invasion, perineural invasion, and necrosis. Although the survival curves overlapped (P=0.693), the rate of liver metastasis was significantly higher for the tubular growth pattern than for the papillary one (P=0.012). Genomic DNA analysis focusing on somatic mutations in codons 12 and 13 of KRAS and codon 600 of BRAF revealed only one (4%) KRAS and no BRAF mutation among the 25 tubular cases examined. In conclusion, the tubular growth pattern exhibited differences in some histologic indexes, in addition to a higher hepatic metastasis rate and a lower KRAS mutation frequency, compared with the papillary growth pattern, but no difference in prognosis was observed. The distinctiveness of this tubular neoplasm should be further examined in the future. PMID- 26769139 TI - The immune microenvironment of breast ductal carcinoma in situ. AB - The host immune response has a key role in breast cancer progression and response to therapy. However, relative to primary invasive breast cancers, the immune milieu of breast ductal carcinoma in situ (DCIS) is less understood. Here, we profile tumor infiltrating lymphocytes and expression of the immune checkpoint ligand programmed death ligand 1 (PD-L1) in 27 cases of DCIS with known estrogen receptor (ER), progesterone receptor, and human epidermal growth factor 2 (HER-2) expression using tissue microarrays. Twenty-four cases were pure DCIS and three had associated invasive ductal carcinoma. Tumors were stained by immunohistochemistry for PD-L1, as well as the lymphocyte markers CD3, CD4, CD8, FoxP3, and CD20. The expression of PD-L1 by DCIS carcinoma cells and tumor infiltrating lymphocytes was determined, and the average tumor infiltrating lymphocytes per high power field were manually scored. None of the DCIS cells expressed PD-L1, but 81% of DCIS lesions contained PD-L1+ tumor infiltrating lymphocytes. DCIS with moderate-diffuse tumor infiltrating lymphocytes was more likely to have PD-L1+ tumor infiltrating lymphocytes (P=0.004). Tumor infiltrating lymphocytes with high levels of PD-L1 expression (>50% cells) were seen only in triple-negative DCIS (P=0.0008), and PD-L1-tumor infiltrating lymphocytes were seen only in ER+/HER-2-DCIS (P=0.12). The presence of PD-L1+ tumor infiltrating lymphocytes was associated with a younger mean patient age (P=0.01). Further characterization of the DCIS immune microenvironment may identify useful targets for immune-based therapy and breast cancer prevention. PMID- 26769140 TI - Mismatch repair deficiency as a prognostic factor in mucinous colorectal cancer. AB - There is some uncertainty about pathological grading of mucinous colorectal adenocarcinoma, defined as colorectal cancer demonstrating at least 50% mucinous differentiation. Under the WHO 2000 classification mucinous colorectal cancer was considered high grade. However under the current WHO 2010 classification microsatellite unstable/mismatch repair-deficient (MSI/MMRd) mucinous colorectal cancer is considered low grade, whereas microsatellite stable/mismatch repair proficient (MSS/MMRp) tumours are high grade. However there is little empirical evidence for this approach. We therefore compared the long term survival of patients with MSI/MMRd vs MSS/MMRp mucinous colorectal cancer in a large unselected cohort of patients undergoing surgery at our institution from 1998 to 2011. There were 2608 patients in the cohort, of which 264 (10.1%) were mucinous. 95 (36%) of the mucinous tumours were microsatellite unstable. The all-cause 5 year survival of mucinous MSI/MMRd colorectal cancer was similar to that of non mucinous low-grade colorectal cancer (73 vs 67%, P=0.368), and significantly better than that of both non-mucinous high-grade (73 vs 53%, P<0.001) and mucinous MSS/MMRp colorectal cancer (73 vs 57%, P=0.023). The 5-year survival of mucinous MSS/MMRp colorectal cancer was slightly better than that of non-mucinous high-grade patients (57 vs 53%, P=0.027), but significantly worse than that of non-mucinous low-grade colorectal cancer (57 vs 67%, P=0.018). In multivariate Cox regression analysis, conventional histological grade based on glandular differentiation maintained prognostic significance (P=0.003) whereas MSI/MMRd status just failed to be statistically significant (P=0.062). Our findings support the WHO 2010 approach that as a group mucinous MSS/MMRp colorectal cancers are biologically aggressive. However, grading based exclusively on MSI/MMR status may be overly simplistic as conventional grading based on the degree of glandular differentiation still holds greater prognostic significance in multivariate analysis. PMID- 26769141 TI - High-definition CpG methylation of novel genes in gastric carcinogenesis identified by next-generation sequencing. AB - Gastric cancers are the most frequent gastric malignancy and usually arise in the sequence of Helicobacter pylori-associated chronic gastritis. CpG methylation is a central mechanism of epigenetic gene regulation affecting cancer-related genes, and occurs early in gastric carcinogenesis. DNA samples from non-metaplastic gastric mucosa with variable levels of gastritis (non-metaplastic mucosa), intestinal metaplasia, or gastric cancer were screened with methylation arrays for CpG methylation of cancer-related genes and 30 gene targets were further characterized by high-definition bisulfite next-generation sequencing. In addition, data from The Cancer Genome Atlas were analyzed for correlation of methylation with gene expression. Overall, 13 genes had significantly increased CpG methylation in gastric cancer vs non-metaplastic mucosa (BRINP1, CDH11, CHFR, EPHA5, EPHA7, FGF2, FLI1, GALR1, HS3ST2, PDGFRA, SEZ6L, SGCE, and SNRPN). Further, most of these genes had corresponding reduced expression levels in gastric cancer compared with intestinal metaplasia, including novel hypermethylated genes in gastric cancer (FLI1, GALR1, SGCE, and SNRPN), suggesting that they may regulate neoplastic transformation from non-malignant intestinal metaplasia to cancer. Our data suggest a tumor-suppressor role for FLI1 in gastric cancer, consistent with recently reported data in breast cancer. For the genes with strongest methylation/expression correlation, namely FLI1, the expression was lowest in microsatellite-unstable tumors compared with other gastric cancer molecular subtypes. Importantly, reduced expression of hypermethylated BRINP1 and SGCE was significantly associated with favorable survival in gastric cancer. In summary, we report novel methylation gene targets that may have functional roles in discrete stages of gastric carcinogenesis and may serve as biomarkers for diagnosis and prognosis of gastric cancer. PMID- 26769143 TI - The effects of fundus photography on the multifocal electroretinogram. AB - PURPOSE: To determine the effect of flash fundus photography (FFP) on the multifocal electroretinogram (mfERG). METHODS: Ten subjects underwent mfERG testing on three separate dates. Subjects received either mfERG without FFP, mfERG at 5 and 15 min after FFP, or mfERG at 30 and 45 min after FFP on each date. The FFP groups received 10 fundus photographs followed by mfERG testing, first of the right eye then of the left eye 10 min later. Data were averaged and analyzed in six concentric rings at each time point. Average amplitude and implicit times of the N1, P1, and N2 peaks for each concentric ring at each time point after FFP were compared to baseline. RESULTS: Flash fundus photography did not lead to a significant change of amplitude or implicit times of N1, P1, or N2 at 5 min after light exposure. CONCLUSIONS: These findings suggest that it is acceptable to perform mfERG testing without delay after performance of FFP. PMID- 26769142 TI - Telomere profiles and tumor-associated macrophages with different immune signatures affect prognosis in glioblastoma. AB - Telomere maintenance is a hallmark of cancer and likely to be targeted in future treatments. In glioblastoma established methods of identifying telomerase and alternative lengthening of telomeres leave a significant proportion of tumors with no defined telomere maintenance mechanism. This study investigated the composition of these tumors using RNA-Seq. Glioblastomas with an indeterminate telomere maintenance mechanism had an increased immune signature compared with alternative lengthening of telomeres and telomerase-positive tumors. Immunohistochemistry for CD163 confirmed that the majority (80%) of tumors with an indeterminate telomere maintenance mechanism had a high presence of tumor associated macrophages. The RNA-Seq and immunostaining data separated tumors with no defined telomere maintenance mechanism into three subgroups: alternative lengthening of telomeres like tumors with a high presence of tumor-associated macrophages and telomerase like tumors with a high presence of tumor-associated macrophages. The third subgroup had no increase in tumor-associated macrophages and may represent a distinct category. The presence of tumor-associated macrophages conferred a worse prognosis with reduced patient survival times (alternative lengthening of telomeres with and without macrophages P=0.0004, and telomerase with and without macrophages P=0.013). The immune signatures obtained from RNA-Seq were significantly different between telomere maintenance mechanisms. Alternative lengthening of telomeres like tumors with macrophages had increased expression of interferon-induced proteins with tetratricopeptide repeats (IFIT1-3). Telomerase-positive tumors with macrophages had increased expression of macrophage receptor with collagenous structure (MARCO), CXCL12 and sushi-repeat containing protein x-linked 2 (SRPX2). Telomerase-positive tumors with macrophages were also associated with a reduced frequency of total/near total resections (44% vs >76% for all other subtypes, P=0.014). In summary, different immune signatures are found among telomere maintenance mechanism-based subgroups in glioblastoma. The reduced extent of surgical resection of telomerase positive tumors with macrophages suggests that some tumor-associated macrophages are more unfavorable. PMID- 26769144 TI - Barriers to Repair in Maxillofacial Trauma. AB - IMPORTANCE: Multiple factors can be associated with the delayed repair of maxillofacial injuries that may be associated with increased morbidity. OBJECTIVE: To assess factors affecting timing of repair and barriers which may exist in the management of maxillofacial trauma. DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study at a tertiary care facility used the Current Procedural Terminology coding to identify adult patients undergoing operative repair of maxillofacial injuries between January 2010 and December 2013. Demographic information, presence and severity of concomitant injuries, as well as fracture-specific data including fracture type(s), mechanism of injury, and documented complications were recorded. Identifiable delays for medical, logistical, or other reasons were also documented. Multivariate regression modeling was used to determine factors associated with increased time to repair. A comparative analysis was used to identify association between complications and time to operative repair. MAIN OUTCOMES AND MEASURES: Time to operative repair from date of presentation; association of known operative delay and perioperative complications. RESULTS: Overall, 780 patients were included in the study. Of patients meeting inclusion criteria, mean (SD) age was 36.7 (14.2) years (range, 18-88 years), and 616 patients (79%) were male. Average time to repair was 6.5 days (range, 0-43 days), and 138 patients (17.7%) were observed to have a documented reason for delay for medical reasons (n = 62 [44.9%]), operating room logistical factors (n = 17 [12.3%]), or other reasons (n = 59 patients [42.8%]) either as a function of delayed patient presentation or failure of patients to make scheduled appointments or operations. Injury severity score (rho = 0.45; P < .001), concurrent injuries (P < .001), decreased Glasgow Coma Scale (P < .001) and inpatient status at time of surgery (P < .001), were associated with increased time to repair. The observed complication rate was 13.6%. There was no statistically significant association between known operative delay and development of complications (chi21 = 2.92; P = .08). CONCLUSIONS AND RELEVANCE: Management of maxillofacial trauma appears to occur in a timely manner. Patient injury severity appears to have the greatest effect on timing of repair. While delays in operative repair may be unavoidable in certain circumstances, streamlining and managing causes of known delay may help improve and expedite patient care. LEVEL OF EVIDENCE: 3. PMID- 26769145 TI - Factors associated with postoperative complications in elderly patients with skin cancer: A retrospective study of 241 patients. AB - OBJECTIVES: The increasing frequency of skin tumors and longer life expectancy of the general population are likely to increase the frequency of dermatological surgery among elderly patients. The purpose of this study is to assess the rate of postoperative complications related to dermatological surgery in elderly patients and highlight the factors associated with these complications. METHODS: We conducted a retrospective monocentric study of patients aged >75 years who presented at our multidisciplinary consultation specialized for skin tumors from January 2008 to December 2010. The clinical characteristics, demographic information, and cancer history of these patients were analyzed. Postoperative complications (dehiscence, infection, hematomas, and other sequelae) were identified to establish the postoperative complication rate and determine risk factors. RESULTS: We included 241 patients. Basal cell carcinoma, squamous cell carcinoma, and melanoma accounted for 46%, 25%, and 28% of tumors, respectively. Skin carcinomas were mainly located on the face (93% of basal cell carcinomas and 72% of squamous cell carcinomas), and melanomas were mainly located on the limbs (50%). The average number of comorbidities was 3.0+/-1.5. The average postoperative complication rate was 20%. Multivariate analysis identified three independent risk factors: male gender (p<0.033), histological type (squamous cell carcinoma and melanoma) (p<0.008), and insufficient surgical resection (p<0.004). CONCLUSION: This study highlighted a high rate of postoperative complications in this elderly population. Three significant postoperative risk factors were identified. They may be used to assess a patient's operational risk as well as geriatric assessment tools. PMID- 26769146 TI - Utilization of palliative care and acute care services in older adults with advanced cancer. AB - OBJECTIVES: There is a gap in knowledge regarding the rates of utilization of palliative care services (PCS) and acute care services (ACS) among older patients with advanced cancer close to end of life. We analyzed the utilization of these services among older adults (65 years and older) and compared them to those in younger adults (40-64 years) with advanced cancer. MATERIALS AND METHODS: A retrospective chart review of 567 veterans who died with advanced cancer between 2002 and 2009 and utilized PCS and ACS prior to death was conducted after IRB approval. To assess PCS utilization, we studied the mean duration between day of hospice referral and time of death (DOR) and the mean length of stay with hospice (LoS). The frequency of emergency room visits (ERVLM), hospital admissions (HALM), and ICU admissions (ICULM) in the last month of life was used as a measure for ACS. The differences among older and younger patients were compared using two sample t-tests. RESULTS: Older adults had earlier referral to PCS [mean DOR: 47.3 versus 34.5 days, p=0.015], longer stay with hospice [mean LoS: 32.5 versus 20.2 days, p=0.007], fewer hospital [HALM: 0.7 versus 0.9, p=0.043], and ICU admissions [ICULM: 0.1 versus 0.2, p=0.030] per patient. The proportion of patients utilizing ER visits [53.5 % versus 59.5%, p=0.173] and hospital admissions [58.6% versus 65.1%, p=0.13] in the last month of life was similar in both age groups with fewer older adults utilizing ICU care [13.2% versus 19.5%, p=0.047]. CONCLUSION: Older patients with cancer are likely to be referred to PCS earlier than younger patients and spend a longer duration with PCS prior to death. However, there continues to be significant utilization of ACS in all patients with advanced cancer. Better understanding of the goals of care in older adults with cancer and education of oncology providers regarding the need to utilize and integrate palliative care services earlier in the course of disease is imperative. PMID- 26769147 TI - Exploring the mechanisms of genome-wide long-range interactions: interpreting chromosome organization. AB - Developments in chromosome conformation capture (3C) technologies have revealed that the three-dimensional organization of a genome leads widely separated functional elements to reside in close proximity. However, the mechanisms responsible for mediating long-range interactions are still not completely known. In this review, we firstly evaluate and compare the current seven 3C-based methods, summarize their advantages and discuss their limitations to our current understanding of genome structure. Then, software packages available to perform the analysis of 3C-based data are described. Moreover, we review the insights into the two main mechanisms of long-range interactions, which regulate gene expression by bringing together promoters and distal regulatory elements and by creating structural domains that contain functionally related genes with similar expression landscape. At last, we summarize what is known about the mediating factors involved in stimulation/repression of long-range interactions, such as transcription factors and noncoding RNAs. PMID- 26769148 TI - Effects of surface-active block copolymers with oxyethylene and fluoroalkyl side chains on the antifouling performance of silicone-based films. AB - Block copolymers made from a poly(dimethyl siloxane) (Si) and a poly(meth)acrylate carrying oxyethylene (EG) or fluoroalkyl (AF) side chains were synthesized and incorporated as surface-active components into a silicone matrix to produce cross-linked films with different surface hydrophilicity/phobicity. Near-edge X-ray absorption fine structure (NEXAFS) studies showed that film surfaces containing Si-EG were largely populated by the siloxane, with the oxyethylene chains present only to a minor extent. In contrast, the fluorinated block was selectively segregated to the polymer-air interface in films containing Si-AF as probed by NEXAFS and X-ray photoelectron spectroscopy (XPS) analyses. Such differences in surface composition were reflected in the biological performance of the coatings. While the films with Si-EG showed a higher removal of both Ulva linza sporelings and Balanus amphitrite juveniles than the silicone control, those with Si-AF exhibited excellent antifouling properties, preventing the settlement of cyprids of B. amphitrite. PMID- 26769149 TI - Accuracy, Validity, and Reliability of an Electronic Visual Analog Scale for Pain on a Touch Screen Tablet in Healthy Older Adults: A Clinical Trial. AB - BACKGROUND: New technology for clinical data collection is rapidly evolving and may be useful for both researchers and clinicians; however, this new technology has not been tested for accuracy, reliability, or validity. OBJECTIVE: This study aims to test the accuracy of visual analog scale (VAS) for pain on a newly designed application on the iPad (iPadVAS) and measure the reliability and validity of iPadVAS compared to a paper copy (paperVAS). METHODS: Accuracy was determined by physically measuring an iPad scale on screen and comparing it to the results from the program, with a researcher collecting 101 data points. A total of 22 healthy community dwelling older adults were then recruited to test reliability and validity. Each participant completed 8 VAS (4 using each tool) in a randomized order. Reliability was measured using interclass correlation coefficient (ICC) and validity measured using Bland-Altman graphs and correlations. RESULTS: Of the measurements for accuracy, 64 results were identical, 2 results were manually measured as being 1 mm higher than the program, and 35 as 1 mm lower. Reliability for the iPadVAS was excellent with individual ICC 0.90 (95% CI 0.82-0.95) and averaged ICC 0.97 (95% CI 0.95-1.0) observed. Linear regression demonstrated a strong relationship with a small negative bias towards the iPad (-2.6, SD 5.0) with limits of agreement from -12.4 to 7.1. CONCLUSIONS: The iPadVAS provides a convenient, user-friendly, and efficient way of collecting data from participants in measuring their current pain levels. It has potential use in documentation management and may encourage participatory healthcare. TRIAL REGISTRATION: Australia New Zealand Clinical Trials Registry (ANZCTR): 367297; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=367297&isReview= rue (Archived by Webcite at http://www.webcitation.org/6d9xYoUbD). PMID- 26769150 TI - Rejoinder to "On the Misuse of Taylor Expansion". PMID- 26769151 TI - On the Misuse of Taylor Expansion. PMID- 26769152 TI - Detection of Borrelia burgdorferi sensu stricto and Borrelia garinii DNAs in patient with Hyperkeratosis lenticularis perstans (Flegel disease). AB - Determination of the causative agent of erythema-like skin lesions in case of nonspecific superficial perivascular dermatitis was supported by histological examination and led to the latter diagnosis of Hyperkeratosis lenticularis perstans (Flegel disease) in patient. The presence of antibodies against Borrelia burgdorferi in patient serum was confirmed by a routine ELISA method and verified by Western blot technique. Skin biopsy and blood specimens were analyzed by PCR and multilocus sequence analysis (MLSA). Western blot method revealed IgG antibody response against two specific antigens, 17 and 83 kDa proteins. The recombinant test detected IgG antibody response against p100 and p41 antigens. The sequence analysis of amplicons from the selected genomic loci obtained from skin biopsy and serum samples revealed the presence of two species from B. burgdorferi sensu lato complex as a co-infection in this patient-B. burgdorferi sensu stricto (s.s.) and Borrelia garinii. PMID- 26769153 TI - Prevalence, predictors and economic consequences of no-shows. AB - BACKGROUND: Patients not attending to clinic appointments (no-show) significantly affects delivery, cost of care and resource planning. We aimed to evaluate the prevalence, predictors and economic consequences of patient no-shows. METHOD: This is a retrospective cohort study using administrative databases for fiscal years 1997-2008. We searched administrative databases for no-show frequency and cost at a large medical center. In addition, we estimated no-show rates and costs in another 10 regional hospitals. We studied no-show rates in primary care and various subspecialty settings over a 12-year period, the monthly and seasonal trends of no-shows, the effects of implementing a reminder system and the economic effects of missed appointments. RESULTS: The mean no-show rate was 18.8% (2.4%) in 10 main clinics with highest occurring in subspecialist clinics. No show rate in the women clinic was higher and the no-show rate in geriatric clinic was lower compared to general primary care clinic (PCP). The no-show rate remained at a high level despite its reduction by a centralized phone reminder (from 16.3% down to 15.8%). The average cost of no-show per patient was $196 in 2008. CONCLUSIONS: Our data indicates that no-show imposed a major burden on this health care system. Further, implementation of a reminder system only modestly reduced the no-show rate. PMID- 26769154 TI - Multiple cutaneous collagenomas in the setting of multiple endocrine neoplasia type 1. PMID- 26769158 TI - Corrigendum. PMID- 26769159 TI - Corrigendum. PMID- 26769161 TI - Prenatal nicotine exposure induces poor articular cartilage quality in female adult offspring fed a high-fat diet and the intrauterine programming mechanisms. AB - Prenatal nicotine exposure (PNE) induces skeletal growth retardation and dyslipidemia in offspring displaying intrauterine growth retardation (IUGR). Cholesterol accumulation resulting from cholesterol efflux dysfunction may reduce the quality of articular cartilage through fetal programming. This study evaluated the quality of articular cartilage of female adult offspring fed a high fat diet and explored the mechanisms using a rat IUGR model established by the administration of 2.0mg/kg/d of subcutaneous nicotine from gestational days 11 20. The results demonstrated an increased OARSI (Osteoarthritis Research Society International) score and total cholesterol content, decreased serum corticosterone, and increased IGF1 and dyslipidemia with catch-up growth in PNE adult offspring. Cartilage matrix, IGF1 and cholesterol efflux pathway expression were reduced in PNE fetuses and adult offspring. Therefore, PNE induced poor articular cartilage quality in female adult offspring fed a high-fat diet via a dual programming mechanism. PMID- 26769162 TI - Arsenite response in Coccomyxa sp. Carn explored by transcriptomic and non targeted metabolomic approaches. AB - Arsenic is a toxic metalloid known to generate an important oxidative stress in cells. In the present study, we focused our attention on an alga related to the genus Coccomyxa, exhibiting an extraordinary capacity to resist high concentrations of arsenite and arsenate. The integrated analysis of high throughput transcriptomic data and non-targeted metabolomic approaches highlighted multiple levels of protection against arsenite. Indeed, Coccomyxa sp. Carn induced a set of transporters potentially preventing the accumulation of this metalloid in the cells and presented a distinct arsenic metabolism in comparison to another species more sensitive to that compound, i.e. Euglena gracilis, especially in regard to arsenic methylation. Interestingly, Coccomyxa sp. Carn was characterized by a remarkable accumulation of the strong antioxidant glutathione (GSH). Such observation could explain the apparent low oxidative stress in the intracellular compartment, as suggested by the transcriptomic analysis. In particular, the high amount of GSH in the cell could play an important role for the tolerance to arsenate, as suggested by its partial oxidation into oxidized glutathione in presence of this metalloid. Our results therefore reveal that this alga has acquired multiple and original defence mechanisms allowing the colonization of extreme ecosystems such as acid mine drainages. PMID- 26769163 TI - Presence of Undeclared Food Allergens in Cumin: The Need for Multiplex Methods. AB - Beginning in the autumn of 2014, millions of dollars of food and over 675 products were recalled in the United States due to the presence of undeclared peanut, attributed to cumin used in the manufacture of the products. Initial analyses also indicated the presence of almond. Subsequent research showed that the presence of peanut and almond did not fully explain the analytical results for the cumin samples. Using a combination of mass spectrometry, DNA-based methods (i.e., PCR and Sanger DNA Sequencing), microscopy, and antibody-based technologies (i.e., ELISA, Western blot analysis, and a novel xMAP multiplex assay) the presence of peanut was confirmed. Screening for secondary sources of adulteration (e.g., tree nuts, mahleb, peach, and cherry) supported the assessment that the cumin contained multiple contaminants. These results demonstrate the limitations of single analyte-specific assays and the need for orthogonal multiplex methods to detect food allergens irrespective of varietal or other differences. PMID- 26769164 TI - Flavobacterium lutivivi sp. nov., isolated from activated sludge. AB - A Gram-stain-negative, strictly aerobic, yellow, rod-shaped bacterium, designated strain HQQT, was isolated from a municipal wastewater treatment plant in Hebei Province, PR China. Comparative 16S rRNA gene sequence analyses showed that strain HQQT is a member of the genus Flavobacterium and is closely related to 'Flavobacterium shanxiense' CCTCC AB 2014079T (94.8 %) and Flavobacterium macrobrachii DSM 22219T (94.7 %). Phylogenetic analysis showed that strain HQQT clustered with Flavobacterium fontis JCM 18212T and Flavobacterium squillarum KCTC 23915T. The polar lipid profile of strain HQQT revealed the presence of phosphatidylethanolamine, six unknown aminolipids, one unknown glycolipid and one unknown lipid and the only isoprenoid quinone was MK-6. The dominant fatty acids of strain HQQT were iso-C15 : 0, C15 : 0 and C16 : 1omega7c. The DNA G+C content of strain HQQT is 32 mol%. On the basis of the phylogenetic and phenotypic data, strain HQQT represents a novel species of the genus Flavobacterium, for which the name Flavobacterium lutivivi sp. nov. is proposed. The type strain is HQQT ( = CGMCC 1.15347T = KCTC 42935T). PMID- 26769165 TI - Updates of pathologic myopia. AB - Complications from pathologic myopia are a major cause of visual impairment and blindness, especially in east Asia. The eyes with pathologic myopia may develop loss of the best-corrected vision due to various pathologies in the macula, peripheral retina and the optic nerve. Despite its importance, the definition of pathologic myopia has been inconsistent. The refractive error or axial length alone often does not adequately reflect the 'pathologic myopia'. Posterior staphyloma, which is a hallmark lesion of pathologic myopia, can occur also in non-highly myopic eyes. Recently a revised classification system for myopic maculopathy has been proposed to standardize the definition among epidemiological studies. In this META-PM (meta analyses of pathologic myopia) study classification, pathologic myopia was defined as the eyes having chorioretinal atrophy equal to or more severe than diffuse atrophy. In addition, the advent of new imaging technologies such as optical coherence tomography (OCT) and three dimensional magnetic resonance imaging (3D MRI) has enabled the detailed observation of various pathologies specific to pathologic myopia. New therapeutic approaches including intravitreal injections of anti-vascular endothelial growth factor agents and the advance of vitreoretinal surgeries have greatly improved the prognosis of patients with pathologic myopia. The purpose of this review article is to provide an update on topics related to the field of pathologic myopia, and to outline the remaining issues which need to be solved in the future. PMID- 26769167 TI - Why magnetic and electromagnetic effects in biology are irreproducible and contradictory? AB - The main source of magnetic and electromagnetic effects in biological systems is now generally accepted and demonstrated in this paper to be radical pair mechanism which implies pairwise generation of radicals in biochemical reactions. This mechanism was convincingly established for enzymatic adenosine triphosphate (ATP) and desoxynucleic acid (DNA) synthesis by using catalyzing metal ions with magnetic nuclei ((25)Mg, (43)Ca, (67)Zn) and supported by magnetic field effects on these reactions. The mechanism, is shown to function in medicine as a medical remedy or technology (trans-cranial magnetic stimulation, nuclear magnetic control of the ATP synthesis in heart muscle, the killing of cancer cells by suppression of DNA synthesis). However, the majority of magnetic effects in biology remain to be irreproducible, contradictory, and enigmatic. Three sources of such a state are shown in this paper to be: the presence of paramagnetic metal ions as a component of enzymatic site or as an impurity in an uncontrollable amount; the property of the radical pair mechanism to function at a rather high concentration of catalyzing metal ions, when at least two ions enter into the catalytic site; and the kinetic restrictions, which imply compatibility of chemical and spin dynamics in radical pair. It is important to keep in mind these factors to properly understand and predict magnetic effects in magneto-biology and biology itself and deliberately use them in medicine. PMID- 26769168 TI - Does exposure to environmental radiofrequency electromagnetic fields cause cognitive and behavioral effects in 10-year-old boys? AB - The relationship between exposure to electromagnetic fields from non-ionizing radiation and adverse human health effects remains controversial. We aimed to explore the association of environmental radiofrequency-electromagnetic fields (RF-EMFs) exposure with neurobehavioral function of children. A subsample of 123 boys belonging to the Environment and Childhood cohort from Granada (Spain), recruited at birth from 2000 through 2002, were evaluated at the age of 9-11 years. Spot electric field measurements within the 100 kHz to 6 GHz frequency range, expressed as both root mean-square (S(RMS) and maximum power density (S(MAX)) magnitudes, were performed in the immediate surrounds of childrens dwellings. Neurocognitive and behavioral functions were assessed with a comprehensive battery of tests. Multivariate linear and logistic regression models were used, adjusting for potential confounders. All measurements were lower than reference guideline limits, with median S(RMS) and S(MAX) values of 285.94 and 2759.68 MUW/m(2), respectively. Most of the cognitive and behavioral parameters did not show any effect, but children living in higher RF exposure areas (above median S(RMS) levels) had lower scores for verbal expression/comprehension and higher scores for internalizing and total problems, and obsessive-compulsive and post-traumatic stress disorders, in comparison to those living in areas with lower exposure. These associations were stronger when S(MAX) values were considered. Although some of our results may suggest that low level environmental RF-EMF exposure has a negative impact on cognitive and/or behavior development in children; given limitations in the study design and that the majority of neurobehavioral functioning tasks were not affected, definitive conclusions cannot be drawn. PMID- 26769169 TI - Desktop exposure system and dosimetry for small scale in vivo radiofrequency exposure experiments. AB - This paper describes a new approach to the risk assessment of exposure from wireless network devices, including an exposure setup and dosimetric assessment for in vivo studies. A novel desktop reverberation chamber has been developed for well-controlled exposure of mice for up to 24 h per day to address the biological impact of human exposure scenarios by wireless networks. The carrier frequency of 2.45 GHz corresponds to one of the major bands used in data communication networks and is modulated by various modulation schemes, including Global System for Mobile Communications (GSM), Universal Mobile Telecommunications System (UMTS), Radio Frequency Identification (RFID), and wireless local area network, etc. The system has been designed to enable exposures of whole-body averaged specific absorption rate (SAR) of up to 15 W/kg for six mice of an average weight of 25 g or of up to 320 V/m incident time-averaged fields under loaded conditions without distortion of the signal. The dosimetry for whole-body SAR and organ averaged SAR of the exposed mice, with analysis of uncertainty and variation analysis, is assessed. The experimental dosimetry based on temperature measurement agrees well with the numerical dosimetry, with a very good SAR uniformity of 0.4 dB in the chamber. Furthermore, a thermal analysis and measurements were performed to provide better understanding of the temperature load and distribution in the mice during exposure. PMID- 26769170 TI - Ever-growing data sets pose (new) challenges to genomic prediction models. PMID- 26769172 TI - Left Ventricular Pacing through Coronary Sinus Is Feasible and Safe for Patients with Prior Tricuspid Valve Intervention. AB - BACKGROUND: In the presence of tricuspid valve intervention, right ventricular lead implantation is associated with the potential risk of tricuspid valve malfunction leading to a tricuspid regurgitation. Few cases have been reported with successful left ventricular pacing via the coronary sinus (CS) after tricuspid valve replacement or repair. In this retrospective study, we present the long-term clinical outcomes of 17 patients who underwent CS lead implantation and left ventricular pacing. METHODS: Seventeen consecutive patients referred to our institution with an indication of postprocedural pacemaker (PM) implantation after tricuspid valve intervention were retrospectively included in the study. The indication for device implantation in all patients was atrial fibrillation with a symptomatic pause >= 3.0 seconds. Thus, all devices implanted were ventricular rate responsive (VVIR). RESULTS: All device implantations were successful and uncomplicated. Mean operation time was 60 +/- 8 minutes. Mean fluoroscopy time was 8.3 +/- 2.1 minutes. Mean R-wave sensing was 7.5 +/- 2.0 mV with a mean slew rate of 2.2 V/s. A mean pacing threshold of 1.9 +/- 0.3 V/0.4 ms was accepted as patients were not PM-dependent. The pacing impedance was 743.5 +/ 109.71 Ohm. At 2-year follow-up, pacing sensing, threshold, and impedance values were unchanged and no lead dislodgement has been noted. CONCLUSIONS: In patients with tricuspid valve intervention, left ventricular pacing might be the treatment of choice for permanent ventricular pacing, with all the advantages of the endovenous route as a minimally invasive approach. PMID- 26769173 TI - Factors affecting the severity of central centrifugal cicatricial alopecia. AB - BACKGROUND: Central centrifugal cicatricial alopecia (CCCA) is a type of scarring hair loss primarily seen in African-American women. The risk factors that affect the severity of disease remain unclear. OBJECTIVES: This study was designed to elucidate risk factors that may be associated with severity of CCCA. METHODS: A cross-sectional survey study was conducted. Women with biopsy-confirmed CCCA responded to a questionnaire and were grouped according to a photographic scale of central scalp alopecia. The severity of disease was considered: grade 1 and 2 disease was interpreted as early-stage CCCA, and grade 3-5 disease was interpreted as advanced-stage CCCA. Data from the questionnaire were compared with levels of severity to determine the strength of associations with severity of disease. RESULTS: A total of 38 women with biopsy-confirmed CCCA were recruited to participate in this study. Early-stage CCCA was seen in 22 subjects (57.9%), and advanced-stage CCCA was noted in 16 subjects (42.1%). The average duration of hair loss was 5.7 years in early-stage disease and 10.1 years in advanced-stage disease. There was a positive correlation between duration of hair loss and degree of hair loss (Spearman's correlation 0.471, P = 0.003). CONCLUSIONS: This study reports on data sourced from patients with biopsy confirmed CCCA and examines the relationships between various factors and severity of CCCA. The findings demonstrate that duration of hair loss is positively associated with severity of disease and that androgen-related conditions are prevalent in those affected with CCCA. PMID- 26769174 TI - The last but not the end. PMID- 26769175 TI - Nearly 1 billion myopes at risk of myopia-related sight-threatening conditions by 2050 - time to act now. PMID- 26769176 TI - A less myopic future: what are the prospects? PMID- 26769177 TI - Animal models in myopia research. AB - Our current understanding of the development of refractive errors, in particular myopia, would be substantially limited had Wiesel and Raviola not discovered by accident that monkeys develop axial myopia as a result of deprivation of form vision. Similarly, if Josh Wallman and colleagues had not found that simple plastic goggles attached to the chicken eye generate large amounts of myopia, the chicken model would perhaps not have become such an important animal model. Contrary to previous assumptions about the mechanisms of myopia, these animal models suggested that eye growth is visually controlled locally by the retina, that an afferent connection to the brain is not essential and that emmetropisation uses more sophisticated cues than just the magnitude of retinal blur. While animal models have shown that the retina can determine the sign of defocus, the underlying mechanism is still not entirely clear. Animal models have also provided knowledge about the biochemical nature of the signal cascade converting the output of retinal image processing to changes in choroidal thickness and scleral growth; however, a critical question was, and still is, can the results from animal models be applied to myopia in children? While the basic findings from chickens appear applicable to monkeys, some fundamental questions remain. If eye growth is guided by visual feedback, why is myopic development not self-limiting? Why does undercorrection not arrest myopic progression even though positive lenses induce myopic defocus, which leads to the development of hyperopia in emmetropic animals? Why do some spectacle or contact lens designs reduce myopic progression and others not? It appears that some major differences exist between animals reared with imposed defocus and children treated with various optical corrections, although without the basic knowledge obtained from animal models, we would be lost in an abundance of untestable hypotheses concerning human myopia. PMID- 26769178 TI - Analysis of physical activity in emmetropic and myopic university students during semester and holiday periods: a pilot study. AB - BACKGROUND: Previous studies (mostly questionnaire-based in children) suggest that outdoor activity is protective against myopia. There are few studies on young adults investigating both the impact of simply being outdoors versus performing physical activity. The aim was to study the relationship between the refractive error of young adults and their physical activity patterns. METHODS: Twenty-seven university students, aged 18 to 25 years, wore a pedometer (Omron HJ720ITE) for seven days both during the semester and holiday periods. They simultaneously recorded the type of activity performed, its duration, the number of steps taken (from the pedometer) and their location (indoors/outdoors) in a logbook. Mean spherical refractive error was used to divide participants into three groups (emmetropes: +1.00 to -0.50 D, low myopes: -0.62 to -3.00 D, higher myopes: -3.12 D or greater myopia). RESULTS: There were no significant differences between the refractive groups during the semester or holiday periods; the average daily times spent outdoors, the duration of physical activity, the ratio of physical activity performed outdoors to indoors and amount of near work performed were similar. The peak exercise intensity was similar across all groups: approximately 100 steps per minute, a brisk walk. Up to one-third of all physical activity was performed outdoors. There were some significant differences in activities performed during semester and holiday times. For example, low myopes spent significantly less time outside (49 +/- 47 versus 74 +/- 41 minutes, p = 0.005) and performed less physical activity (6,388 +/- 1,747 versus 6,779 +/- 2,746 steps per day; p = 0.03) during the holidays compared to during semester. CONCLUSIONS: The fact that all groups had similar low exercise intensity but many were not myopic suggests that physical activity levels are not critical. There were differences in the activity patterns of low myopes during semester and holiday periods. This study highlights the need for a larger longitudinal-based study with particular emphasis on how discretionary time is spent. PMID- 26769179 TI - The relationship between image degradation and myopia in the mammalian eye. AB - BACKGROUND: In all species studied, myopia develops if the eye is deprived of detailed vision during development (form deprivation myopia). However, different degrees of spatial image deprivation produce different effects and have not been described in the mammalian eye. Therefore, the effect of image degradation on guinea pig emmetropisation was investigated. METHODS: Eighty-one guinea pigs wore a treatment on one eye from 6 to 13 days of age. There were four treatments: a translucent diffuser (no lines or edges were visible through the diffuser); one of five Bangerter foils (BF: 0.8, 0.6, 0.4, 0.2, light perception only), which differed in their cut-off spatial frequencies; a 'ring mount' control with no filter; or one of two neutral density filters that reduced luminance only (ND, optical density grades 0.1 and 0.6). Refractive error and ocular elongation were measured after seven days of treatment. RESULTS: The extent of induced myopia and ocular growth were related to the amount of image degradation (mean difference between the treated and untreated eyes changed in a graded manner -7.0 D to -0.2 D and from 85 um to seven um respectively, for spatial frequency cut-offs between zero and 24 cycles per degree). Corresponding reductions in luminance from ND filters did not increase eye growth and caused significantly less myopia than the BFs that caused a similar luminance decrement. The greatest myopia occurred when no or limited spatial information was available to the eye, but moderate myopia still occurred with spatial frequency cut-offs of six and 12 cycles per degree, well beyond the visual acuity range of guinea pigs. CONCLUSION: Excessive ocular growth and myopia are most robust when induced by spatial frequency reductions within the visual acuity range but can also be induced beyond this. Either the mechanism of ocular growth can detect supra-threshold spatial frequencies, possibly due to aliasing, or it is sensitive to small amounts of contrast degradation. PMID- 26769180 TI - Choroidal thickness predicts ocular growth in normal chicks but not in eyes with experimentally altered growth. AB - BACKGROUND: In hatchling chicks, the thickness of the choroid is quite variable. It has been postulated that thickness per se or the changes occurring during early life might play a causal role in the regulation of ocular growth. We tested this notion by measuring ocular dimensions in several experimental conditions that alter ocular growth and in the fellow eyes. METHODS: Chicks aged 12 to 14 days wore monocular lenses or diffusers (+10 D, n = 23; -10 D, n = 16; diffusers, n = 16) for four to five days. Fellow untreated eyes served as controls. A separate group of completely untreated birds aged eight days were also tested (n = 12). We tested two drugs known to alter ocular growth. The dopaminergic agonist quinpirole was injected daily for five days into eyes wearing negative lenses (n = 47). The muscarinic agonist oxotremorine was injected one time into normal eyes (n = 27). All eyes were measured using high-frequency A-scan ultrasonography at the start and end of the experiment. Spearman's correlation coefficient was used in all analyses. RESULTS: Choroidal thickness predicted ocular growth rates in normal eyes: eyes with thinner choroids grew faster than those with thicker choroids (p = 0.0001). Furthermore, there was a negative correlation between initial thickness and the change in thickness (p = 0.0353). By contrast, eyes wearing lenses or diffusers did not show a correlation between initial thickness and growth rate. For lens-wearing eyes injected with quinpirole, which slowed growth, initial choroidal thickness predicted subsequent growth rate (p = 0.0126), similar to normal eyes. This was not so for oxotremorine, which stimulated growth. CONCLUSIONS: The loss of the association between choroidal thickness and subsequent growth rate in eyes with experimentally altered growth implies an uncoupling of the choroidal response from the visual regulation of ocular growth. The negative correlation between initial thickness and ocular growth in eyes injected with quinpirole suggests potential therapeutic benefits to thicker choroids. PMID- 26769181 TI - MicroRNA-106b is involved in transforming growth factor beta1-induced cell migration by targeting disabled homolog 2 in cervical carcinoma. AB - BACKGROUND: MicroRNA-106b (miR-106b) was recently identified as an oncogene participating in cancer progression. Transforming growth factor beta1(TGF-beta1) is an indispensable cytokine regulating the local microenvironment, thereby promoting cervical cancer progression. However, the roles of miR-106b in cervical carcinoma progression and TGF-beta1-involvement in the tumorigenesis of cervical cancer remain unknown. METHODS: The expression of miR-106b in human cervical specimens was detected by real-time PCR analysis and in situ hybridization assay. The effect of miR-106b on cell migration was analyzed by scratch and transwell assays. TGF-beta1 was used to induce cell migration. The expression of the miR 106b target gene DAB2 in human cervical tissues and cell lines were measured by qRT-PCR, western blot and immunohistochemistry. Dual-luciferase reporter assay was used to identify DAB2 as a miR-106b-directed target gene. RESULTS: miR-106b was frequently up-regulated in human cervical carcinoma specimens and cervical cancer cell lines. Over-expression of miR-106b significantly promoted HeLa and SiHa cells migration. Likewise, inhibition of miR-106b decreased HeLa and SiHa cells migration. The multifunctional cytokine TGF-beta facilitates metastasis in cervical carcinoma. miR-106b inhibitor treatment decreased the TGF-beta1 stimulated migration of HeLa and SiHa cells. DAB2, a predicted target gene of miR 106b, was inhibited by TGF-beta1 partly through miR-106b and was involved in TGF beta1-induced cervical cancer cell migration. The expression of DAB2 was low in cervical cancer tissues, and negatively correlated with miR-106b expression. Finally, DAB2 was identified as a miR-106b-directed target gene by dual luciferase reporter assay. CONCLUSION: Our data suggest that the TGF-beta1/miR 106b/DAB2 axis may be involved in the pathogenesis of cervical carcinoma. PMID- 26769182 TI - 61-Year-Old Man With Chronic Diarrhea. PMID- 26769183 TI - Impaired Heart Rate Response to Exercise in Diabetes and Its Long-term Significance. AB - OBJECTIVE: To investigate the effect of diabetes mellitus on exercise heart rate and the role of impaired heart rate in excess mortality in diabetes. PATIENTS AND METHODS: Patients without cardiovascular disease who underwent exercise testing from September 1, 1993, through December 31, 2010, were included. Mortality was determined from Mayo Clinic records and the Minnesota Death Index. Multivariate linear regression was used to compare heart rate responses in patients with vs without diabetes. Cox regression was used to determine the effect of abnormal heart rate recovery and abnormal chronotropic index on survival. RESULTS: A total of 21,396 patients (65.4% men) with a mean +/- SD age of 51+/-11 years, including 1200 patients with diabetes (5.4%), were included. Patients with diabetes had a higher resting heart rate (81+/-14 vs 77+/-13 beats/min), lower peak heart rate (154+/-20 vs 165+/-19 beats/min), heart rate reserve (73+/-19 vs 88+/-19 beats/min), chronotropic index (0.86+/-0.22 vs 0.99+/-0.20), and heart rate recovery (15+/-8 vs 19+/-9 beats/min) vs patients without diabetes. There were 1362 deaths (6.4%) during a mean +/- SD follow-up of 11.9+/-4.9 years. Adjusting for age, sex, and heart rate-lowering drug use, a chronotropic index less than 0.8 contributed significantly to risk in patients with diabetes (hazard ratio [HR], 2.21; 95% CI, 1.62-3.00; P<.001) and patients without diabetes (HR, 1.94; 95% CI, 1.71-2.20; P<.001), as did abnormal heart rate recovery (patients with diabetes: HR, 2.21; 95% CI, 1.60-5.05; P<.001; patients without diabetes: HR, 1.75; 95% CI, 1.55-1.97). CONCLUSIONS: Patients with diabetes exhibit abnormal heart rate responses to exercise, which are independently predictive of reduced long-term survival in patients with diabetes as in patients without diabetes. PMID- 26769184 TI - Heavy Testosterone Use Among Bodybuilders: An Uncommon Cohort of Illicit Substance Users. AB - OBJECTIVE: To identify and characterize patterns of use among a contemporary cohort of current anabolic-androgenic steroid (AAS) users. PATIENTS AND METHODS: An anonymous, self-administered, 49-item questionnaire was posted on message boards of Internet websites popular among AAS users and administered via SurveyMonkey from February 1, 2015, to June 1, 2015. Thirty-seven questions were analyzed for this study. RESULTS: A total of 231 male respondents met the inclusion criteria. Most were white, were older than 25 years, were employed with above average income, and had received a formal education beyond high school. Ninety-three percent began using AAS after the age of 18 years, and 81% reported using 400 mg or more of testosterone per week. Factors associated with longer duration of use (>5 years) included higher incomes (>=$75,000, P=.003), increased testosterone dosages (>600 mg per week, P=.007), older age (>=35 years, P<.001), being married (P<.001), and being self-employed (P<.001). The Internet was the most common source of testosterone (53%). Ninety-three percent used at least one additional performance-enhancing drug. Seventy-seven percent had routine laboratory tests performed, and 38% reported laboratory abnormalities at some point. Nearly all experienced subjective adverse effects while using and not using testosterone. Fifty-three percent reported use of other illegal substances, most commonly (90%) beginning before AAS initiation. Ten percent had a criminal conviction, 91% of which preceded AAS use. Fifty percent were felonies. CONCLUSION: The population of AAS users is disparate from that of other drugs of abuse. Laboratory test abnormalities and adverse effects are common and should be taken into account when counseling patients who may be using AASs. PMID- 26769186 TI - Proteomics in Marine Organisms. PMID- 26769185 TI - 47-Year-Old Man With Pruritus. PMID- 26769189 TI - EDITORIAL. PMID- 26769191 TI - Safety of vaginal delivery in very low birthweight vertex singletons: a meta analysis. AB - OBJECTIVE: The objective of this study is to assess the safety of vaginal delivery in VLBW singletons in the vertex presentation. METHODS: MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and Web of Science databases were searched for studies on mode of delivery and neonatal outcome in VLBW singletons in the vertex presentation. A total of 28 studies met our inclusion criteria. RESULTS: Vaginal delivery was not associated with an increase in overall neonatal mortality compared with cesarean delivery (OR 0.87, 95% CI 0.72-1.04). Vaginal delivery was associated with a significant decrease in mortality for the 1250 1500 g birthweight category (OR 0.57, 95% CI 0.36-0.92), while an increase in mortality in the 500-750 g category was not significant (OR 1.5, 95% CI 0.86 2.61). Severe intraventricular hemorrhage (IVH) was not associated with mode of delivery (OR 1.05, 95% CI 0.85-1.29), but the only two high quality study that assessed IVH of all grades found an increase in risk for IVH in vaginal delivery (OR 1.33, 95% CI 1.16-1.51). CONCLUSIONS: Vaginal delivery does not appear to increase the risk for neonatal mortality. However, current available data on neonatal morbidity are limited. More high-quality studies are needed to assess the association between mode of delivery and neonatal morbidity. PMID- 26769192 TI - Placentophagy in wild chimpanzees (Pan troglodytes verus) at Bossou, Guinea. AB - Despite intensive observation of nonhuman great apes during long-term field studies, observations of great ape births in the wild are rare. Research on wild chimpanzees (Pan troglodytes verus) at Bossou in the Republic of Guinea has been ongoing for 35 years, yet chimpanzee parturitions have been observed on only two occasions. Here we provide information regarding both chimpanzee births, with detailed information from the close observation of one. During this birth, the mother built a day nest in a tree before parturition. After giving birth, the mother consumed the placenta, and the other chimpanzees in her party gathered near her and her neonate. However, she did not share the placenta, and consumed it all herself. In the second observation, the mother also built a nest in a tree and subsequently gave birth. Thereafter, she shared the placenta with some individuals and consumed part of the placenta herself. Although maternal placentophagy is a ubiquitous behavior among the majority of non-human primates, observations of placenta sharing by wild primates are infrequent, and the proximate and ultimate explanations for the behavior remain unclear. PMID- 26769194 TI - Kiyoteru Tokuyasu: a pioneer of cryo-ultramicrotomy. AB - In July 2015 Professor K.T. Tokuyasu passed away in San Diego giving us the opportunity to reflect on the contribution this electron microscopist made to the field of immunocytochemistry. His work provided a sensitive, minimally invasive approach to producing thin sections of biological material for labeling with antibodies. His approach has been applied to a wide range of biological applications and provided important information on cellular processes. PMID- 26769195 TI - New pathways for improved quantification of energy-dispersive X-ray spectra of semiconductors with multiple X-ray lines from thin foils investigated in transmission electron microscopy. AB - Theoretical approaches to quantify the chemical composition of bulk and thin layer specimens using energy-dispersive X-ray spectroscopy in a transmission electron microscope are compared to experiments investigating (In)GaAs and Si(Ge) semiconductors. Absorption correctors can be improved by varying the take-off angle to determine the depth of features within the foil or the samples thickness, or by definition of effective k-factors that can be obtained from plots of k-factors versus foil thickness or, preferably, versus the K/L intensity ratio for a suitable element. The latter procedure yields plots of self consistent absorption corrections that can be used to determine the chemical composition, iteratively for SiGe using a set of calibration curves or directly from a single calibration curve for InGaAs, for single X-ray spectra without knowledge of sample thickness, density or mass absorption coefficients. PMID- 26769193 TI - SF3B1 and EIF1AX mutations occur in primary leptomeningeal melanocytic neoplasms; yet another similarity to uveal melanomas. AB - INTRODUCTION: Like uveal melanomas, primary leptomeningeal melanocytic neoplasms (LMNs) frequently carry GNAQ and GNA11 mutations. However, it is currently unknown whether these LMNs harbor mutations in BAP1, SF3B1 and/or EIF1AX like uveal melanomas as well. In this study, we used Sanger sequencing for the detection of mutations in SF3B1 (hotspots in exon 14 and 15) and EIF1AX (exon 1 and 2 and flanking intronic regions) in a series of 24 primary LMNs. Additionally, BAP1 immunohistochemistry was used as a surrogate marker for the detection of inactivating mutations in the BAP1 gene. RESULTS: Mutations in either SF3B1 or EIF1AX were identified in 8 out of 24 primary LMNs (33 %). The presence of these mutations was mutually exclusive and occurred in primary LMNs of different malignancy grades (melanocytomas, intermediate-grade melanocytic tumors, melanomas). Complete absence of nuclear BAP1 staining as is typically seen in BAP1-mutated tumors was not observed. CONCLUSIONS: Our finding that an SF3B1 or EIF1AX mutation is present in a substantial subset of primary LMNs underscores that these tumors genetically resemble uveal melanoma and are different from cutaneous melanoma at the genetic level. This information may not only aid in the differential diagnosis of primary versus metastatic melanocytic tumor in/around the central nervous system, but also in the identification of more promising therapeutic approaches targeting the molecular pathways involved in the oncogenesis of LMNs. As none of the primary LMNs in our series showed complete loss of nuclear BAP1 protein, it is unlikely that BAP1 mutations are frequent in these tumors but the role of this gene warrants further investigation. PMID- 26769196 TI - 1,3-Dinitrobenzene neurotoxicity - Passage effect in immortalized astrocytes. AB - Age-related disturbances in astrocytic mitochondrial function are linked to loss of neuroprotection and decrements in neurological function. The immortalized rat neocortical astrocyte-derived cell line, DI-TNC1, provides a convenient model for the examination of cellular aging processes that are difficult to study in primary cell isolates from aged brain. Successive passages in culture may serve as a surrogate of aging in which time-dependent adaptation to culture conditions may result in altered responses to xenobiotic challenge. To investigate the hypothesis that astrocytic mitochondrial homeostatic function is decreased with time in culture, low passage DI-TNC1 astrocytes (LP; #2-8) and high passage DI TNC1 astrocytes (HP; #17-28) were exposed to the mitochondrial neurotoxicant 1,3 dinitrobenzene (DNB). Cells were exposed in either monoculture or in co-culture with primary cortical neurons. Astrocyte mitochondrial membrane potential, morphology, ATP production and proliferation were monitored in monoculture, and the ability of DI-TNC1 cells to buffer K(+)-induced neuronal depolarization was examined in co-cultures. In HP DI-TNC1 cells, DNB exposure decreased proliferation, reduced mitochondrial membrane potential and significantly decreased mitochondrial form factor. Low passage DI-TNC1 cells effectively attenuated K(+)-induced neuronal depolarization in the presence of DNB whereas HP counterparts were unable to buffer K(+) in DNB challenge. Following DNB challenge, LP DI-TNC1 cells exhibited greater viability in co-culture than HP. The data provide compelling evidence that there is an abrupt phenotypic change in DI-TNC1 cells between passage #9-16 that significantly diminishes the ability of DI-TNC1 cells to compensate for neurotoxic challenge and provide neuroprotective spatial buffering. Whether or not these functional changes have an in vivo analog in aging brain remains to be determined. PMID- 26769197 TI - Surgery for retrohepatic caval thrombus in patients with advanced renal cell carcinoma: a case series. AB - BACKGROUND: Thrombotic involvement of the inferior vena cava (IVC) occurs in about 10% of all patients with renal cell carcinoma (RCC). It is treated with radical resection of tumor and thrombus. We present the results of a recent case series of 20 patients with retrohepatic IVC thrombus. METHODS: Our cohort of 20 patients included 16 primary resections (radical nephrectomy and thrombectomy with and without vascular graft), three recurrences primarily operated on elsewhere (thrombectomy and vascular graft), and one recurrence due to a new liver metastasis. RESULTS: All surviving patients were discharged with a patent IVC. The overall mortality rate was 10%, and the overall complication rate was 35%. Both are in keeping with results presented worldwide. CONCLUSIONS: Our series provides a corroborating extension to the existing dataset on RCC-related IVC thrombus removal. It confirms that the radical surgical approach can be performed safely and successfully with respect to venous patency. PMID- 26769199 TI - The Disjointed Historical Trajectory of Anorexia Nervosa Before 1970. AB - Responses in pre-modern eras to anorexia nervosa (as now understood) varied widely, from religious piety and sanctity through fear and superstition. While noting briefly the limited conceptualizations from pre-modern history this article is primarily focused from the late 19th century, commencing with helpful but tentative formulations of anorexia nervosa for early-modern medicine that were laid out, consistently between themselves, by Lesegue, Gull and Osler. Yet that promising biomedical advent was superseded for more than a half-century by deep, internal divisions and bitter rifts that festered between three medical disciplines: neurology; Freudian psychotherapy; and Kraepelinian biological psychiatry. Mid-20th century developments preceded the 1960-1980s' improved understanding of suffering and movement toward effective remediation introduced by Dr. Hilde Bruch. PMID- 26769198 TI - Interventions for Children Affected by Armed Conflict: a Systematic Review of Mental Health and Psychosocial Support in Low- and Middle-Income Countries. AB - Over one billion children under the age of 18 live in countries affected by armed conflict. This systematic review replicates an earlier study, aiming to provide a comprehensive update of the most current developments in interventions for children affected by armed conflict. For the period 2009-2015, a total of 1538 records were collected from PubMed, PsycINFO, and PILOTS. Twenty-four studies met the inclusion criteria, and the included interventions involve data from 4858 children. Although the number of publications and level of evidence has improved since the previous review, there is still a general lack of rigor and clarity in study design and reported results. Overall, interventions appeared to show promising results demonstrating mostly moderate effect sizes on mental health and psychosocial well-being. However, these positive intervention benefits are often limited to specific subgroups. There is a need for increased diversification in research focus, with more attention to interventions that focus at strengthening community and family support, and to young children, and improvements in targeting and conceptualizing of interventions. PMID- 26769200 TI - Recent advances in peptides for enhancing transdermal macromolecular drug delivery. AB - Transdermal delivery of drugs, a compelling route of systemic drug delivery, provides painless, reliable, targeted, efficient and cost effective therapeutic regimen for patients. However, its use is limited by skin barrier especially the stratum corneum barrier. Moreover, transdermal delivery of macromolecules remains a challenge. Naturally, varieties of physical methods, chemical enhancers and drug carriers have been used to counteract this limitation. Recently, transdermal peptides discovered as safer, more efficient and more specific enhancers could promote the delivery of macromolecules across the skin. Herein, the underlying transdermal peptides are included. Subsequently, we have discussed typical applications and the possible mechanism of two groups of biologically inspired transdermal peptide enhancers, namely cell penetration peptides and transdermal enhanced peptides. PMID- 26769201 TI - Editorial: Intentional rounding: unpacking the ritual, routine and evidence impasse. PMID- 26769202 TI - Carers' views on patient self-care in chronic heart failure. AB - AIMS AND OBJECTIVES: To examine carers' views on patient self-care in chronic heart failure (CHF). BACKGROUND: Self-care, a key strategy in the long-term management of CHF, can be complex and difficult to master. Carers play a key role in supporting patients in self-care, yet their views on it are rarely sought. DESIGN: A qualitative approach was adopted with a purposeful sample of carers of patients with CHF residing in Australia. METHODS: Carers who identified themselves as providing informal care to a person diagnosed with chronic heart failure were interviewed about their views on patient self-care. Data were collected by face-to-face interviews with a semi-structured interview guide. Qualitative content analysis of the interviews was undertaken by two nurses and one psychologist. RESULTS: Four key themes were identified pertaining to CHF patient self-care: hindrance to engagement; roles and relationships; social support and community engagement and competency. Most carers viewed patients' fatigue and inactivity, mood and coping, and memory loss as major challenges to engagement in self-care. They viewed emotional support and encouragement, independence and organised routines as important aspects of their relationship with the patient and as facilitators of self-care, but also required for themselves support from their families, communities and healthcare professionals. They also viewed patient and carer experience and knowledge as being essential to successful self-care. CONCLUSION: Carers viewed self-care as an important issue for patients with CHF and indicated that they could play an enhanced role with the provision of better support and knowledge from their families, communities and health care professionals. RELEVANCE TO CLINICAL PRACTICE: Carers are closely involved in supporting patients in CHF self-care, even though their views are rarely considered in the organisation and delivery of heart failure management programmes. Therefore, their important contribution should be acknowledged and supported in contemporary heart failure health services. PMID- 26769203 TI - Regulated and unregulated nurses in the acute hospital setting: Tasks performed, delayed or not completed. AB - AIMS: Investigate the number and type of tasks performed, delayed or not completed by regulated and unregulated (assistant) nurses. BACKGROUND: Assistants in Nursing change the work environment of the nurses with whom they work. As the number of Assistants in Nursing working on acute units grows, it is important to understand how their presence influences nursing care. DESIGN: Descriptive analysis of survey data from 62 acute nursing units across three Australian states between 2008-2010. METHODS: All staff providing nursing care to patients were asked to complete a survey that included demographics, the number of tasks delayed/incomplete and the completion of six specific tasks. Nonparametric tests compared Assistants in Nursing (n = 25) to regulated nurses (n = 1630), and regulated nurses on units with no Assistants in Nursing (n = 1356) to those on units with up to 5% assistants (n = 76) and over 5% assistants (n = 198). RESULTS: More regulated nurses on units with zero, or up to 5% Assistants in Nursing, completed tasks usually associated with assistants' scope of practice, relative to those on units with over 5% Assistants in Nursing. Statistically significant differences were found between the units in delays responding to the patient bell and in the planning of nursing care. CONCLUSION: This study suggests that Assistants in Nursing have an impact on the nature and timeliness of care provided in acute hospital units, that is relative to the proportion of staffing they comprise, to the effectiveness of integration and to the clarity of their scope of practice and associated delegation. RELEVANCE TO CLINICAL PRACTICE: With increasing employment of Assistants in Nursing in acute hospital settings comes the requirement to optimise their use. This needs to include a well-articulated scope of practice, clear delegation of tasks and effective integration with the rest of the care team. PMID- 26769204 TI - Scholarly work products of the doctor of nursing practice: one approach to evaluating scholarship, rigour, impact and quality. AB - AIMS AND OBJECTIVES: The aim of this investigation was to evaluate, monitor and manage the quality of projects conducted and work produced as evidence of scholarship upon completion of Doctor of Nursing Practice education. BACKGROUND: The Doctor of Nursing Practice is a relatively new degree which prepares nurses for high impact careers in diverse practice settings around the globe. Considerable variation characterises curricula across schools preparing Doctors of Nursing Practice. Accreditation assures curricula are focused on attainment of the Doctor of Nursing Practice essentials, yet outcomes have not been reported to help educators engage in programme improvement. This work has implications for nursing globally because translating strong evidence into practice is key to improving outcomes in direct care, leadership, management and education. The Doctor of Nursing Practice student learns to accomplish translation through the conduct of projects. Evaluating the rigour and results of these projects is essential to improving the quality, safety and efficacy of translation, improvements in care and overall system performance. DESIGN: A descriptive study was conducted to evaluate the scholarly products of Doctor of Nursing Practice education in one programme across four graduating classes. METHODS: A total of 80 projects, conducted across the USA and around the globe, are described using a modification of the Uncertainty, Pace, Complexity Model. RESULTS: The per cent of students considered to have produced high quality work in relation to target expectations as well as the per cent that conducted means testing increased over the four study years. CONCLUSIONS: Evaluation of scope, complexity and rigour of scholarly work products has driven improvements in the curriculum and informed the work of faculty and advisors. RELEVANCE TO CLINICAL PRACTICE: Methods, evaluation and outcomes conformed around a set of expectations for scholarship and rigour have resulted in measurable outcomes, and quality publications have increased over time. PMID- 26769205 TI - Use of a single parameter track and trigger chart and the perceived barriers and facilitators to escalation of a deteriorating ward patient: a mixed methods study. AB - AIMS AND OBJECTIVES: To investigate nurses' use of a single parameter track and trigger chart to inform implementation of the National Early Warning Scoring tool. To report the characteristics of patients with triggers, the frequency of different triggers, and the time taken to repeat observations. To explore the barriers and facilitators perceived by nursing staff relating to patient monitoring. BACKGROUND: Sub-optimal care of the deteriorating patient has been described for almost two decades. Organisations have responded by implementing strategies that improve monitoring and facilitate a timely response to patient deterioration. While these systems have been widely adopted the evidence-base to support their use is inconsistent. DESIGN: A mixed method service evaluation was carried out in an acute University hospital. METHODS: Physiological triggers (n = 263) and characteristics of triggering patients (n = 74) were recorded from surgical and medical wards. Descriptive statistics were displayed. Questionnaires were distributed (n = 105) to student nurses, health care assistants and registered nurses. Themes and sub-themes were identified from content analysis. RESULTS: Hypotension was the most frequent abnormality. There was variability in the time to repeat observations following a trigger. A high proportion of triggers were identified in older patients, as was a trend of longer time intervals between trigger and repeat observations. Nurses reported a number of barriers and facilitators to monitoring patients including: 'workload', 'equipment', 'interactions between staff' and 'interactions with patients'. CONCLUSIONS: This study identified a number of barriers and facilitators to monitoring and escalation of abnormal vital signs, highlighting the complexity of the process and the need for a system-wide approach to a deteriorating patient. RELEVANCE TO CLINICAL PRACTICE: The trend of longer delays following a trigger in older patients has not been identified previously and could reflect a knowledge gap of the physiological changes and response to acute illness in older people. PMID- 26769206 TI - Assimilation into daily practice: implementing and sustaining a randomised controlled trial in a children's clinical service. AB - AIMS AND OBJECTIVES: To explore nurses' experiences of being involved in a clinically based randomised-controlled trial in a children's hospital. BACKGROUND: Numerous studies have explored the barriers to research utilisation by nurses. However, there is little information available on the methodological challenges and practical implementation of a study in a busy clinical setting. DESIGN: A qualitative exploratory descriptive design using semi-structured interviews was adopted. METHODS: A purposeful sample of eight nurses responsible for implementing the research protocols, the consent process and data collection for the randomised-controlled trial were interviewed between March-June 2013. Data were analysed using a thematic network analysis framework. RESULTS: The analysis of the data yielded the global theme of 'Expectations vs. Reality' as participants discussed their experience of being part of a nurse-led randomised controlled trial in a busy children's burns service. This global theme arose from three organising themes: developing nursing practice; enhanced research knowledge and time to engage. CONCLUSIONS: The findings from this study suggest that nurses in a busy tertiary children's hospital were generally very positive about being part of a nurse-led randomised-controlled trial. Although the benefits outweighed the challenges of engaging in research for the nurses in this study, this level of commitment and motivation can be difficult to maintain. Collaboration with nurses in clinical practice and the development of support structures can help to promote sustainable engagement in research. RELEVANCE TO CLINICAL PRACTICE: The findings highlight the importance of developing robust structures which support nurses at clinical level to engage in research without feeling they must choose between competing priorities of patient care and research activity. PMID- 26769207 TI - The impact of research education on student nurse attitude, skill and uptake of evidence-based practice: a descriptive longitudinal survey. AB - AIMS AND OBJECTIVES: To measure the impact of an undergraduate research education program on the attitude, skill and uptake of evidence-based practice among undergraduate student nurses. BACKGROUND: The contribution of evidence-based practice to clinical decision-making, quality of care and patient outcomes is well-documented. One approach to improving evidence-based practice uptake in clinical practice is through the provision of undergraduate research education; notwithstanding, the impact of research training on nursing practice is poorly established. DESIGN: Descriptive longitudinal survey. METHODS: Three hundred and fifty four third-year nursing students enrolled in a Bachelor of Nursing program of a large Australian University were invited. Pre- (Phase 1) and post-completion (Phase 2) of a 16-week research education program, participants were asked to complete the Evidence-Based Practice Attitude and Utilization Survey; an 82-item online questionnaire measuring attitudes, skills and use of evidence-based practice, and barriers and facilitators of evidence-based practice uptake. RESULTS: The survey was completed by 84 (24%) participants in Phase 1 and 33 (39% of Phase 1) participants in Phase 2. Program exposure resulted in a significant improvement in median skill and use subscores, but not median attitude subscore. Participants perceived inadequate skills in the interpretation, appraisal and application of research findings to clinical practice as being less of a barrier to evidence-based practice uptake posteducation, and access to online critical appraisal tools as being significantly more useful in facilitating evidence-based practice uptake posteducation. CONCLUSIONS: The findings suggest that undergraduate research education may have a significant effect on nursing students' research skills and use of evidence-based practice, and minimise barriers to evidence-based practice uptake posteducation. RELEVANCE TO CLINICAL PRACTICE: Undergraduate research education may play an important role in improving student nurse uptake of evidence-based practice; whether these changes can be sustained when transitioning from student nurse to registered nurse is a question for further research. PMID- 26769208 TI - Factors associated with medication adherence in patients living with cirrhosis. AB - AIMS AND OBJECTIVES: Medication adherence in people with cirrhosis is largely unknown. This study aims to determine adherence patterns and factors associated with adherence in patients with cirrhosis. BACKGROUND: Prescribed medications are a pivotal component in the clinical management of cirrhosis with potential to retard disease progression and reduce complication risks. Medication adherence is necessary to optimise health outcomes. Understanding why medications are missed may help to develop strategies and inform nursing practice. DESIGN: Prospective cohort study. METHODS: Participants (n = 29) diagnosed with cirrhosis attending a tertiary hospital consented to complete a self-reported survey. Demographic information, adherence to medications, patient knowledge and quality of life data were collected, collated, checked and analysed using SPSS version 21. RESULTS: Less than half of the 28 patients who completed the adherence questionnaire (n = 13, 46%) reported that they had never missed medication. Being forgetful, being away from home and falling asleep contributed to nonadherence. Having less abdominal symptoms, less fatigue and increased emotional well-being were significantly associated with patients never missing medications. CONCLUSIONS: To our knowledge this is the first published study to describe adherent behaviour and the reasons medications are missed in this population. The percentage of nonadherent participants is of concern considering the potential morbidity risk that is associated with missed medications and rebound symptoms of cirrhosis. Strategies to improve and sustain adherence levels are required including enhanced adherence counselling offered to patients who are deteriorating or experience periodic exacerbation of symptoms. RELEVANCE TO CLINICAL PRACTICE: Study findings have the potential to change clinical practice especially the way nurses target motivational adherence counselling, key treatment messages, education and adherence monitoring. The results presented here provide a basis for developing adherence strategies and nursing management plans to improve adherence and health outcomes in people with cirrhosis. PMID- 26769209 TI - Sleep quality and adverse outcomes for patients with acute myocardial infarction. AB - AIMS AND OBJECTIVES: This study aimed to analyse the relationship between the worsening of clinical outcomes (cardiovascular death, recurrent cardiovascular ischaemic events and stroke) and sleep quality, daytime sleepiness and risk for obstructive sleep apnoea syndrome in patients admitted to cardiac care units due to an acute myocardial infarction. BACKGROUND: There is evidence that sleep disorders can contribute to the worsening of cardiovascular diseases. DESIGN: This is a descriptive study with follow-up. METHODS: Data collection was conducted in a large university hospital in Brazil from October 2013 to March 2014. Patients admitted with acute myocardial infarction provided data about sleep quality, daytime sleepiness and risk factors for obstructive sleep apnoea syndrome by answering specific questionnaires. Clinical data were obtained from medical charts. Data were analysed with descriptive statistics and multiple logistic regression models. RESULTS: The worsening of clinical outcome occurred in 12.4% of patients and was independently associated to poor sleep quality. CONCLUSION: Poor sleep quality, excessive daytime sleepiness and high risk for obstructive sleep apnoea syndrome were frequent in hospitalised patients with acute myocardial infarction and affect negatively the process of recovery. RELEVANCE TO CLINICAL PRACTICE: It is important to evaluate sleep quality and sleep disorders, aiming at preventing and reducing unfavourable outcomes of cardiovascular disease, particularly for acute myocardial infarction patients. PMID- 26769210 TI - Cultural adaptation and analysis of the psychometric properties of the Brazilian version of the Spiritual Distress Scale. AB - AIMS AND OBJECTIVES: To culturally adapt and test the psychometric properties of the Brazilian version of the Spiritual Distress Scale. BACKGROUND: In Brazil, there is currently a lack of validated instruments that assess the spiritual dimension, which includes the spiritual distress phenomenon that can be experienced at different moments in a person's life. This can include times when a person is affected by a disease such as cancer, which occurs suddenly and causes significant life changes. DESIGN: Methodological and cross-sectional study. METHODS: Cultural adaptation of the Spiritual Distress Scale was performed using translation and back-translation stages, evaluation of cultural equivalence, committee review and pretesting. An interview using the Brazilian version of the scale was conducted with 170 patients in a cancer treatment unit of a charitable general hospital (not state funded). The following psychometric properties were evaluated: construct validity (divergence and factor analysis) and internal consistency/reliability (Cronbach's alpha and Kappa). RESULTS: Reliability analysis in the intra- and inter-rater phase showed that more than half of the items had Kappa values > 0.75. A correlation between the Spiritual Well-Being Scale and the Spiritual Distress Scale was found. Overall, the Spiritual Distress Scale showed a Cronbach's alpha of 0.87, with three of its four domains showing significant parameters. CONCLUSION: The Brazilian version of the Spiritual Distress Scale proved to be a reliable, valid and efficient instrument that is capable of assessing spiritual distress. The Brazilian Spiritual Distress Scale presented reliability and validity parameters that correspond to the original English version of the scale. RELEVANCE TO CLINICAL PRACTICE: The existence of an internationally validated instrument that assesses spiritual distress will assist healthcare professionals and researchers in recognising this phenomenon in clinical practice. PMID- 26769211 TI - Nurses perspectives on long-term condition self-management: a qualitative study. AB - AIMS AND OBJECTIVES: This study explored nurses' attitudes, views and beliefs about their role in long-term condition self-management. BACKGROUND: Nurses are well-placed to assist individuals in long-term condition self-management. Yet, there is limited research exploring underlying beliefs of nurses regarding their role in long-term condition self-management and how those beliefs may impact on the practice of self-management. DESIGN: A descriptive, cross-sectional qualitative design. PARTICIPANTS: A purposive sample of nurses (n = 14) working in primary care and secondary care settings in New Zealand. METHODS: One focus group and two interviews were conducted. Data were analysed through thematic analysis by the three authors. RESULTS: All nurses interviewed described promoting patient self-management of long-term conditions and the approaches they took to do so in practice. The nurses described a strong sense of accountability in relation to their practice. They worked to ensure patient follow-up and referrals as necessary and described themselves as lynch pins in the management of long-term conditions. Nurses also recognised that patients would engage at different levels in the self-management process. However, the sense of accountability did raise a question around the balance between professional accountability and responsibility for the management of the condition and the reality of nurses' ability to work with patients as partners in the self management of long-term conditions. CONCLUSIONS: Nurses described both understanding of the importance of promoting patient self-management but also a strong sense of professional accountability to provide quality care. Nurses recognised that they needed to work to find a balance between these two positions. RELEVANCE TO CLINICAL PRACTICE: In order for nurses to work as an advocate to support optimal care it is vital that nurses recognise where patient's boundaries and capabilities lie. Nurses are at risk of blurring the boundaries and may not always support people to make choices that promote and/or maintain "self" control (or autonomy) in long-term condition management. PMID- 26769212 TI - Survivors speak: a qualitative analysis of motivational factors influencing breast cancer survivors' participation in a sprint distance triathlon. AB - AIMS AND OBJECTIVES: To examine motivational factors influencing breast cancer survivors to participate in triathlon training, complete a triathlon and maintain an exercise thereafter. BACKGROUND: Routine exercise has been shown to improve quality of life and reduce recurrence for breast cancer survivors. Yet physical and psychological factors present barriers for initiating and maintaining an exercise routine. Research is limited in exploring factors of exercise motivation from the survivor's perspective. DESIGN: Qualitative design using focus groups and individual follow-up phone interviews to explore motivation for exercise initiation and maintenance. METHODS: One to two weeks after completing a triathlon, 11 breast cancer survivors who trained together participated in one of three focus groups to discuss their experience. Five months post triathlon 6 of the 11 participants were successfully contacted and phone interviews were conducted to explore exercise maintenance. Focus groups and interviews were analysed using content and thematic analysis. RESULTS: Five themes emerged (1) Champion for Exercise, (2) Part of a Team, (3) Everyone Had a Story, (4) Not Really Exercise and (5) What Do We Do Now? Overall, survivors recognised their need for lifestyle change (e.g. moving from a sedentary lifestyle to a more active one). More importantly, they identified the team approach to exercise initiation was crucial in their success in sustaining a behavioural change. CONCLUSIONS: Emphasis needed on developing team exercise training programmes for survivors. Nurses can play a critical role in discussing with survivors, the benefits of exercise initiation and maintenance. RELEVANCE TO CLINICAL PRACTICE: Breast cancer survivors are hesitant to initiate routine exercise. Training with women who share a common lived experience increases the likelihood of success. Nurses are in a position to encourage breast cancer survivors to participate in group exercise programmes as a way to improve quality of life. PMID- 26769213 TI - The impact of an integrated nursing handover system on nurses' satisfaction and work practices. AB - AIMS AND OBJECTIVES: This study examined the impact of an Integrated Nursing Handover System--structured content, a minimum data set and an electronic module within the patient clinical information system--on nurses' satisfaction with handover and changes to practice. BACKGROUND: Poor transfer of patient information between clinicians at handover has been associated with adverse patient outcomes. DESIGN: A mixed methods pre-post evaluative approach was used. METHODS: The Integrated Nursing Handover System was introduced and evaluated within an Australian hospital. Changes to nurses' satisfaction were measured using the modified Bradley Clinical Handover Survey (n = 40 pre, n = 80 post). Three focus groups with clinicians (2) and mangers and educators (1) examined changes to clinical practice. The location of handover was observed. RESULTS: Nurses' satisfaction with handover was improved. A two stage approach to handover emerged: nurses received handover of all patients within meeting rooms followed by handover delivered at the bedside. Major categories identified through content analysis included: implementation and the transition, work practice changes and bedside handover, accessible and standardised patient information, accountability for information transfer and a central repository of patient information. CONCLUSION: An integrated system has been implemented with positive outcomes of: improved nurse satisfaction with handover, nurses being informed about all patients, enhanced patient transfers and improved patient information for all health professionals. Further research into the potential use of stored patient handover data for research is recommended. RELEVANCE TO CLINICAL PRACTICE: This comprehensive system of nursing handover represents the first integrated system of this nature ever reported in the nursing and health literature. This integrated nursing handover system has been successfully implemented resulting in delivery of more comprehensive, logical and standardised patient information at handover. PMID- 26769214 TI - Rethinking the intensive care environment: considering nature in nursing practice. AB - AIMS AND OBJECTIVES: With consideration of an environmental concept, this paper explores evidence related to the negative impacts of the intensive care unit environment on patient outcomes and explores the potential counteracting benefits of 'nature-based' nursing interventions as a way to improve care outcomes. BACKGROUND: The impact of the environment in which a patient is nursed has long been recognised as one determinant in patient outcomes. Whilst the contemporary intensive care unit environment contains many features that support the provision of the intensive therapies the patient requires, it can also be detrimental, especially for long-stay patients. DESIGN: This narrative review considers theoretical and evidence-based literature that supports the adoption of nature based nursing interventions in intensive care units. METHODS: Research and theoretical literature from a diverse range of disciplines including nursing, medicine, psychology, architecture and environmental science were considered in relation to patient outcomes and intensive care nursing practice. CONCLUSION: There are many nature-based interventions that intensive care unit nurses can implement into their nursing practice to counteract environmental stressors. These interventions can also improve the environment for patients' families and nurses. RELEVANCE TO CLINICAL PRACTICE: Intensive care unit nurses must actively consider and manage the environment in which nursing occurs to facilitate the best patient outcomes. PMID- 26769215 TI - [In Process Citation]. PMID- 26769218 TI - Publication footprints and pitfalls of bibliometry. PMID- 26769217 TI - [Cutaneous sarcoidosis after treatment with interferon for hepatitis C: A not entirely rare but often overlooked reaction]. AB - Sarcoidosis (aka Boeck's sarcoid) is a granulomatous autoimmune disease of unknown etiology, which may affect the lungs and many other organs. A case of multifocal cutaneous sarcoidosis after treatment with pegylated interferon-alpha and ribavirin for chronic hepatitis C is demonstrated. Several related cases of this not entirely rare complication of immunotherapy have been reported in the literature. PMID- 26769219 TI - Proteomics of vitreous in neovascular age-related macular degeneration. AB - Neovascular age-related macular degeneration (nAMD) has been described as a predominantly inflammatory and proangiogenic retino-choroidal disease. Vitreous humor (VH) is the adjacent and accessible compartment which, due to the vicinity to the retina, might best represent changes of protein-based mediators of nAMD. The aim of this clinical-experimental study was to analyze the nAMD associated VH proteome of previously untreated patients whilst taking different groups of nAMD into account, based on their clinical presentation (clinical diagnosis groups). Electrophoresis coupled online to mass spectrometry (CE-MS) as well as liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) were used to analyze VH of 108 nAMD patients and 24 controls with idiopathic floaters. A total of 101 different proteins with at least two unique peptides could be identified. Using a stringent statistical analysis with implementation of the closed test principle, we were able to identify four proteins that may be involved in the pathophysiology of nAMD: Clusterin, opticin, pigment epithelium-derived factor and prostaglandin-H2 d-isomerase. Using independent samples, ROC-Area under the curve was determined proving the validity of the results: Clusterin 0.747, opticin 0.656, pigment epithelium-derived factor 0.514, prostaglandin-H2 d isomerase 0.712. In addition, validation through ELISA measurements was performed. The identified proteins may serve as potential biomarkers or even targets of therapy for nAMD. PMID- 26769221 TI - Author's reply to St Leger and Kay. PMID- 26769220 TI - Macromolecular markers in normal human retina and applications to human retinal disease. AB - Macromolecular cell markers are essential for the classification and characterization of the highly complex and cellularly diverse vertebrate retina. Although a plethora of markers are described in the current literature, the immunoreactivity of these markers in normal human tissue has not been fully determined. This is problematic as they are quintessential to the characterization of morphological changes associated with human retinal disease. This review provides an overview of the macromolecular markers currently available to assess human retinal cell types. We draw on immunohistochemical studies conducted in our laboratories to describe marker immunoreactivity in human retina alongside comparative descriptions in non-human tissues. Considering the growing number of eye banks services offering healthy and diseased human retinal tissue, this review provides a point of reference for future human retina studies and highlights key species specific disease applications of some macromolecular markers. PMID- 26769216 TI - A Molecular View of Pathological Microcalcification in Breast Cancer. AB - Breast microcalcification is a potential diagnostic indicator for non-palpable breast cancers. Microcalcification type I (calcium oxalate) is restricted to benign tissue, whereas type II (calcium hydroxyapatite) occurs both in benign as well as in malignant lesions. Microcalcification is a pathological complication of the mammary gland. Over the past few decades, much attention has been paid to exploit this property, which forms the basis for advances in diagnostic procedures and imaging techniques. The mechanism of its formation is still poorly understood. Hence, in this paper, we have attempted to address the molecular mechanism of microcalcification in breast cancer. The central theme of this communication is "how a subpopulation of heterogeneous breast tumor cells attains an osteoblast-like phenotype, and what activities drive the process of pathophysiological microcalcification, especially at the invasive or infiltrating front of breast tumors". The role of bone morphogenetic proteins (BMPs) and tumor associated macrophages (TAMs) along with epithelial to mesenchymal transition (EMT) in manipulating this pathological process has been highlighted. Therefore, this review offers a novel insight into the mechanism underlying the development of microcalcification in breast carcinomas. PMID- 26769222 TI - Proteins dominate in the surface layers formed on materials exposed to extracellular polymeric substances from bacterial cultures. AB - The chemical compositions of the surface conditioning layers formed by different types of solutions (from isolated EPS to whole culture media), involving different bacterial strains relevant for biocorrosion were compared, as they may influence the initial step in biofilm formation. Different substrata (polystyrene, glass, steel) were conditioned and analyzed by X-ray photoelectron spectroscopy. Peak decomposition and assignment were validated by correlations between independent spectral data and the ubiquitous presence of organic contaminants on inorganic substrata was taken into account. Proteins or peptides were found to be a major constituent of all conditioning layers and polysaccharides were not present in appreciable concentrations; the proportion of nitrogen which may be due to DNA was lower than 15%. There was no significant difference between the compositions of the adlayers formed from different conditioning solutions, except for the adlayers produced with tightly bound EPS extracted from D. alaskensis. PMID- 26769223 TI - SLFN14-related thrombocytopenia: identification within a large series of patients with inherited thrombocytopenia. PMID- 26769224 TI - Involvement of GABAB Receptor Signaling in Antipsychotic-like Action of the Novel Orthosteric Agonist of the mGlu4 Receptor, LSP4-2022. AB - Considering that ligands of metabotropic glutamate and GABA receptors may exert beneficial effects on schizophrenia, we assessed the actions of the first mGlu>4 selective orthosteric agonist, LSP4-2022, in several tests reflecting positive, negative, and cognitive symptoms of schizophrenia. Moreover, we investigated the possible involvement of GABAB receptors in LSP4-2022-induced actions. Hyperactivity induced by MK-801 or amphetamine and DOI-induced head twitches in mice were used as the models of positive symptoms. The social interaction test, modified forced swim test (FST), and novel object recognition (NOR) test were used as the models of negative and cognitive symptoms of schizophrenia. LSP4-2022 inhibited hyperactivity (in a dose-dependent manner, 0.5-2 mg/kg) induced by MK 801 or amphetamine and DOI-induced head twitches. In mGlu4 receptor knockout mice, LSP4-2022 was not effective. However, it reversed MK-801-induced impairment in the social interaction test and the MK-801-induced increase of immobility in the modified FST. In the NOR test, LSP4-2022 was active at a dose of 2 mg/kg. GABAB receptor antagonist, CGP55845 (10 mg/kg), reversed LSP4-2022-induced effects in hyperactivity and head twitch tests. At the same time, the simultaneous administration of subeffective doses of LSP4-2022 (0.1 mg/kg) and a positive allosteric modulator of GABAB receptor PAM, GS39783 (0.1 mg/kg), induced clear antipsychotic-like effects in those two tests. Such an interaction between mGlu4 and GABAB receptors was not observed in the social interaction and NOR tests. Therefore, we suggest that the activation of the mGlu4 receptor is a promising approach facilitating the discovery of novel antipsychotic drugs, and that the interplay between mGlu4 and GABAB receptors may become the basis for a novel therapy for schizophrenic patients with predomination of positive symptoms. PMID- 26769226 TI - C-reactive protein point-of-care testing and antibiotic prescribing for acute respiratory tract infections in rural primary health centres of North Ethiopia: a cross-sectional study. AB - Unjustified antibiotic prescribing for acute upper respiratory infections (URTIs) is probably more common in poor-resource settings where physicians are scarce. Introducing C-reactive protein (CRP) point-of-care testing in such settings could reduce the misuse of antibiotics, which could avert antibiotic resistance. However, information useful for the applicability of CRP test in resource-limited settings is lacking. This study aimed to elicit the frequency of antibiotic prescribing and distribution of CRP levels in remote, rural settings in Ethiopia. We included 414 patients with acute URTIs from four health centres. Health professionals recorded the clinical features of the patients, but the laboratory professionals measured the CRP levels of all patients at the point of care. The most prominent respiratory causes for consultation were acute URTIs combined (44.4%), and lower respiratory tract infections-pneumonia (29.71%) and acute bronchitis (25.84%). The CRP distribution was <20 mg/l, 20-99 mg/l and 100 mg/l or more in 66.6%, 27.9% and 5.5% of the patients, respectively. The CRP levels were significantly different among these clinical diagnoses (X(2)=114.3, P<0.001, d.f.=4). A wide range of antibiotics was administered for 87.8% of the patients, regardless of the diagnostic or prognostic nature of their diseases. Antibiotic prescribing for acute URTIs in the rural areas of Ethiopia is unduly high, with high proportions of mild, self-limiting illness, mostly URTIs. Implementation of CRP point-of-care testing in such resource-constrained settings, with low- or middle-grade healthcare professionals, could help reconcile the inappropriate use of antibiotics by withholding from patients who do not benefit from antibiotic treatment. PMID- 26769227 TI - Chronic myeloid leukemia: First-line drug of choice. AB - The advent of tyrosine kinase inhibitors (TKIs) has drastically changed the treatment outcome of chronic myeloid leukemia (CML). Imatinib was the first TKI approved, and has been considered the standard of care for more than a decade. Second generation compounds, namely dasatinib and nilotinib, are highly effective in newly diagnosed patients as well as those who fail imatinib. Second generation TKIs have been demonstrated to induce deeper and faster responses compared to imatinib, however no survival advantage has been observed so far. Today, the expected survival of CML patients, if properly managed, is likely to be similar to the general population. Clinicians are faced the challenge of making decision for which TKI to choose upfront. Comorbidities of the patient, the side effect profile, and the cost of the TKI of interest should be an important consideration in decision making. Whatever TKI is chosen as frontline, noncompliance or treatment failure should be recognized early as a prompt intervention increases the chance of achieving best possible response. Herein, we review the frontline options for the management of patients with CML and how to best choose these agents. PMID- 26769225 TI - Inflammation and Immune Regulation as Potential Drug Targets in Antidepressant Treatment. AB - Growing evidence supports a mutual relationship between inflammation and major depression. A variety of mechanisms are outlined, indicating how inflammation may be involved in the pathogenesis, course and treatment of major depression. In particular, this review addresses 1) inflammatory cytokines as markers of depression and potential predictors of treatment response, 2) findings that cytokines interact with antidepressants and non-pharmacological antidepressive therapies, such as electroconvulsive therapy, deep brain stimulation and physical activity, 3) the influence of cytokines on the cytochrome (CYP) p450-system and drug efflux transporters, and 4) how cascades of inflammation might serve as antidepressant drug targets. A number of clinical trials have focused on agents with immunmodulatory properties in the treatment of depression, of which this review covers nonsteroidal anti-inflammatory drugs (NSAIDs), cytokine inhibitors, ketamine, polyunsaturated fatty acids, statins and curcumin. A perspective is also provided on possible future immune targets for antidepressant therapy, such as toll-like receptor-inhibitors, glycogen synthase kinase-3 inhibitors, oleanolic acid analogs and minocycline. Concluding from the available data, markers of inflammation may become relevant factors for more personalised planning and prediction of response of antidepressant treatment strategies. Agents with anti-inflammatory properties have the potential to serve as clinically relevant antidepressants. Further studies are required to better define and identify subgroups of patients responsive to inflammatory agents as well as to define optimal time points for treatment onset and duration. PMID- 26769228 TI - Myelodysplastic syndromes: Contemporary review and how we treat. AB - Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal stem cell disorders with an inherent tendency for leukemic transformation. Diagnosis is currently based on the presence of peripheral blood cytopenias, peripheral blood and bone marrow dysplasia/blasts, and clonal cytogenetic abnormalities. With the advent of next generation sequencing, recurrent somatic mutations in genes involved in epigenetic regulation (TET2, ASXL1, EZH2, DNMT3A, IDH1/2), RNA splicing (SF3B1, SRSF2, U2AF1, ZRSR2), DNA damage response (TP53), transcriptional regulation (RUNX1, BCOR, ETV6) and signal transduction (CBL, NRAS, JAK2) have been identified in MDS. Conventional prognostication is by the revised International prognostic scoring system (IPSS-R) with additional adverse prognosis conferred by presence of ASXL1, EZH2, or TP53 mutations. Currently Food and Drug administration (FDA)-approved drugs for the treatment of MDS are not curative and their effect on survival is limited; they include the hypomethylating agents (HMA) azacitidine and decitabine and lenalidomide for MDS with isolated del(5q). To date, allogeneic stem cell transplant (ASCT) remains the only treatment option for possible cure. Given the current lack of drugs with convincing evidence of favorable effect on survival, we consider ASCT as the treatment of choice for most patients with symptomatic disease, and especially for those with high-risk disease. For nontransplant candidates, participation in clinical trials is preferred over conventional therapy. There is not one right way of treatment for patients who are not candidates for either ASCT or clinical trials and palliative drugs of choice depend on the clinical problem, such as symptomatic anemia (ESAs, danazol, HMA), thrombocytopenia (HMA), or neutropenia (myeloid growth factors). Conversely, there is no controlled evidence to support the use of iron chelating agents in MDS. Going forward, we believe it is time to incorporate mutation information in clinically derived prognostic models in MDS and encourage development of novel drugs with disease-modifying activity. PMID- 26769229 TI - In Memoriam: Charles H. Southwick (August 8, 1928 -July 12, 2015). PMID- 26769230 TI - Evaluation of the Escherichia coli HK82 and BS87 strains as tools for AlkB studies. AB - Within a decade the family of AlkB dioxygenases has been extensively studied as a one-protein DNA/RNA repair system in Escherichia coli but also as a group of proteins of much wider functions in eukaryotes. Two strains, HK82 and BS87, are the most commonly used E. coli strains for the alkB gene mutations. The aim of this study was to assess the usefulness of these alkB mutants in different aspects of research on AlkB dioxygenases that function not only in alkylated DNA repair but also in other metabolic processes in cells. Using of HK82 and BS87 strains, we found the following differences among these alkB(-) derivatives: (i) HK82 has shown more than 10-fold higher MMS-induced mutagenesis in comparison to BS87; (ii) different specificity of Arg(+) revertants; (iii) increased induction of SOS and Ada responses in HK82; (iv) the genome of HK82, in comparison to AB1157 and BS87, contains additional mutations: nalA, sbcC, and nuoC. We hypothesize that in HK82 these mutations, together with the non-functional AlkB protein, may result in much higher contents of ssDNA, thus higher in comparison to BS87 MMS-induced mutagenesis. In the light of our findings, we strongly recommend using BS87 strain in AlkB research as HK82, bearing several additional mutations in its genome, is not an exact derivative of the AB1157 strain, and shows additional features that may disturb proper interpretation of obtained results. PMID- 26769231 TI - Association between plasma phosphorus and renal outcome: A prospective cohort of patients majorly with glomerulonephritis. AB - AIM: Studies investigating the association between blood phosphorus and renal outcomes yielded inconsistent results, and studies from Asian population are extremely limited. We initiated the present cohort study, aiming to prospectively examine the association between blood phosphorus and adverse renal outcomes in a prospective chronic kidney disease (CKD) cohort of Chinese patients majorly with glomerulonephritis. METHODS: A total of 1430 patients were involved in the study. Linear regression analyses were used to assess the relationship between phosphorus and the slope of estimated glomerular filtration rate (eGFR). Cox regression analyses were used to assess the association between phosphorus and composite outcomes, which were defined as the presence of at least one of: eGFR halving, end stage renal disease, or death. RESULTS: During follow-up for an average of 41.4 months, 196 patients developed composite outcomes. The time average plasma phosphorus was independently associated with the slope of eGFR (beta = -0.18, 95% CI: -4.42 to -2.19, P < 0.001). Each 1 mg/dL increases of baseline and time-average phosphorus were respectively associated with a 1.33 (95% confidence interval (CI): 1.09-1.63; P = 0.005) and 2.79 (95%CI: 2.21-3.52; P < 0.001) fold higher risk of composite outcomes. Compared with participants in the bottom quartile of time-average phosphorus, those in the top quartile were at increased risk of composite outcomes, with a hazard ratio of 6.52 (95% CI: 3.05 13.90; P < 0.001). CONCLUSION: Plasma phosphorus level is an independent risk factor of adverse renal outcomes in Chinese CKD patients majorly with glomerulonephritis. Compared with baseline value, time-average phosphorus has a stronger relationship with renal prognosis. PMID- 26769232 TI - Gender Dysphoria and Gender Incongruence: An evolving inter-disciplinary field. PMID- 26769233 TI - Ushering Hypertension Into a New Era of Precision Medicine. PMID- 26769234 TI - Frontostriatal circuits, resting state functional connectivity and cognitive control in internet gaming disorder. AB - Converging evidence has identified cognitive control deficits in internet gaming disorder (IGD). Recently, mounting evidence had revealed that resting state functional connectivity (RSFC) and structural connectivity of frontostriatal circuits could modulate cognitive control in healthy individuals. Unfortunately, relatively little is known about the thoroughly circuit-level characterization of the frontostriatal pathways (both the dorsal and ventral striatum) during resting state and their association with cognitive control in IGD. In the current study, the differences of striatum volume and RSFC networks were investigated between 43 young IGD individuals and 44 healthy controls. Meanwhile, cognitive control deficits were assessed by Stroop task performances. The neuroimaging findings were then correlated with the Stroop task behaviors. In IGD subjects, we demonstrated an increased volume of right caudate and nucleus accumbens (NAc) as well as reduced RSFC strength of dorsal prefrontal cortex (DLPFC)-caudate and orbitofrontal cortex (OFC)-NAc. NAc volumes were positively correlated with internet addiction test scores in IGD. The caudate volume and DLPFC-caudate RSFC was correlated with the impaired cognitive control (more incongruent errors in Stroop task) in IGD. Consistent with substance use disorder (SUD) findings, we detected striatum volume and frontostriatal circuits RSFC differences between IGD and healthy controls, which provided evidence of some degree of the similarity between IGD and SUD. More importantly, the cognitive control deficits in IGD were correlated with the reduced frontostrital RSFC strength. It is hoped that our results could shed insight on the neurobiological mechanisms of IGD and suggest potential novel therapeutic targets for treatment. PMID- 26769236 TI - Crowdsourcing Diagnosis for Patients With Undiagnosed Illnesses: An Evaluation of CrowdMed. AB - BACKGROUND: Despite visits to multiple physicians, many patients remain undiagnosed. A new online program, CrowdMed, aims to leverage the "wisdom of the crowd" by giving patients an opportunity to submit their cases and interact with case solvers to obtain diagnostic possibilities. OBJECTIVE: To describe CrowdMed and provide an independent assessment of its impact. METHODS: Patients submit their cases online to CrowdMed and case solvers sign up to help diagnose patients. Case solvers attempt to solve patients' diagnostic dilemmas and often have an interactive online discussion with patients, including an exchange of additional diagnostic details. At the end, patients receive detailed reports containing diagnostic suggestions to discuss with their physicians and fill out surveys about their outcomes. We independently analyzed data collected from cases between May 2013 and April 2015 to determine patient and case solver characteristics and case outcomes. RESULTS: During the study period, 397 cases were completed. These patients previously visited a median of 5 physicians, incurred a median of US $10,000 in medical expenses, spent a median of 50 hours researching their illnesses online, and had symptoms for a median of 2.6 years. During this period, 357 active case solvers participated, of which 37.9% (132/348) were male and 58.3% (208/357) worked or studied in the medical industry. About half (50.9%, 202/397) of patients were likely to recommend CrowdMed to a friend, 59.6% (233/391) reported that the process gave insights that led them closer to the correct diagnoses, 57% (52/92) reported estimated decreases in medical expenses, and 38% (29/77) reported estimated improvement in school or work productivity. CONCLUSIONS: Some patients with undiagnosed illnesses reported receiving helpful guidance from crowdsourcing their diagnoses during their difficult diagnostic journeys. However, further development and use of crowdsourcing methods to facilitate diagnosis requires long-term evaluation as well as validation to account for patients' ultimate correct diagnoses. PMID- 26769239 TI - Telocytes: novel interstitial cells present in the testis parenchyma of the Chinese soft-shelled turtle Pelodiscus sinensis. AB - Telocytes (TCs) are novel interstitial cells that have been found in various organs, but the existence of TCs in the testes has not yet been reported. The present ultrastructural and immunohistochemical study revealed the existence of TCs and differentiate these cells from the peritubular cells (Pc) in contact with the surrounding structures in the testes. Firstly, our results confirmed the existence of two cell types surrounding seminiferous tubules; these were Pc (smooth muscle like characteristics) and TCs (as an outer layer around Pc). Telocytes and their long thin prolongations called telopodes (Tps) were detected as alternations of thin segments (podomers) and thick bead-like portions (podoms), the latter of which accommodate the mitochondria and vesicles. The spindle and irregularly shaped cell bodies were observed with small amounts of cytoplasm around them. In contrast, the processes of Pc contained abundant actin filaments with focal densities, irregular spine-like outgrowths and nuclei that exhibited irregularities similar to those of smooth muscle cells. The TCs connected with each other via homocellular and heterocellular junctions with Pc, Leydig cells and blood vessels. The Tps of the vascular TCs had bands and shed more vesicles than the other TCs. Immunohistochemistry (CD34) revealed strong positive expression within the TC cell bodies and Tps. Our data confirmed the existence and the contact of TCs with their surroundings in the testes of the Chinese soft-shelled turtle Pelodiscus sinensis, which may offer new insights for understanding the function of the testes and preventing and treating testicular disorders. PMID- 26769240 TI - One size does not fit all-qualitative process evaluation of the Healthy School Start parental support programme to prevent overweight and obesity among children in disadvantaged areas in Sweden. AB - BACKGROUND: Parental support interventions have shown some effectiveness in improving children's dietary and physical activity habits and preventing overweight and obesity. To date, there is limited research on barriers and facilitators of school-based parental support interventions targeting overweight and obesity. This study aimed to describe barriers and facilitators influencing implementation of the Healthy School Start (HSS) intervention in disadvantaged areas in Stockholm, Sweden, from the perspective of parents and teachers. METHODS: Focus groups and individual interviews with teachers (n = 10) and focus groups with parents (n = 14) in the intervention group of the HSS were undertaken, guided by the Consolidated Framework for Implementation Research (CFIR). Transcriptions were analysed using qualitative content analysis in two steps: deductive sorting in two domains of the CFIR (intervention characteristics and process), and subsequent inductive analysis. RESULTS: The overarching theme "tailoring the intervention to increase participant engagement" was found. Among teachers, barriers and facilitators were related to how the intervention was introduced, perceptions of the usefulness of the classroom material, preparation ahead of the start of the intervention, cooperation between home and school and children's and parents' active engagement in the intervention activities. For parents, barriers and facilitators were related to the perceived relevance of the intervention, usefulness of the material, experiences of the Motivational Interviewing (MI) sessions, the family member targeted by the intervention, cooperation between home and school and parents' ability to act as good role models. CONCLUSION: It seems important to tailor the intervention to the abilities of the target group in order to increase participant engagement. Including activities that focus on parents as role models and cooperation between parents seems important to bring about changes in the home environment. It also appears important to include activities that target cooperation between home and school. PMID- 26769241 TI - Prognostic significance of a preoperative magnetic resonance imaging assessment of the distance of mesorectal extension in clinical T3 lower rectal cancer. AB - PURPOSES: The aim of this study was to evaluate the association between the mesorectal extensions on high-resolution magnetic resonance imaging (MRI) and the prognosis of patients with clinical T3 lower rectal cancer. METHODS: Fifty-eight patients with clinical T3 lower rectal cancer were investigated using high resolution MRI. One radiologist who was blinded to the clinicopathological findings retrospectively examined the MRI-predicted circumferential resection margin (mrCRM) and the distance of mesorectal extension (mrDME) on the scans. If the imaging showed a tumor <=1 mm from the mesorectal fascia, then the mrCRM involvement was defined as potentially present. The tumors were divided into two groups: mrDME <=4 mm and mrDME >4 mm. RESULTS: A survival analysis showed that mrCRM-positive patients had a significantly poorer prognosis in the RFS (p < 0.01) and LRFS (p < 0.01). Patients with mrDME >4 mm revealed a significantly poorer prognosis than those with mrDME <=4 mm in the OS (p = 0.04), RFS (p < 0.01), and LRFS (p = 0.04). A multivariate analysis revealed that both mrCRM and mrDME on MRI had a significant impact on the RFS (p = 0.01 and 0.03, respectively). CONCLUSION: The mrDME, as well as the mrCRM, may be an important preoperative prognostic factor for patients with clinical T3 lower rectal cancer. PMID- 26769242 TI - Gap-junctional channel and hemichannel activity of two recently identified connexin 26 mutants associated with deafness. AB - Gap-junction channels (GJCs) are formed by head-to-head association of two hemichannels (HCs, connexin hexamers). HCs and GJCs are permeable to ions and hydrophilic molecules of up to Mr ~1 kDa. Hearing impairment of genetic origin is common, and mutations of connexin 26 (Cx26) are its major cause. We recently identified two novel Cx26 mutations in hearing-impaired subjects, L10P and G109V. L10P forms functional GJCs with slightly altered voltage dependence and HCs with decrease ATP/cationic dye selectivity. G109V does not form functional GJCs, but forms functional HCs with enhanced extracellular Ca(2+) sensitivity and subtle alterations in voltage dependence and ATP/cationic dye selectivity. Deafness associated with G109V could result from decreased GJCs activity, whereas deafness associated to L10P may have a more complex mechanism that involves changes in HC permeability. PMID- 26769243 TI - Cardiovascular risk associated with the use of glitazones, metformin and sufonylureas: meta-analysis of published observational studies. AB - BACKGROUND: The results of observational studies evaluating and comparing the cardiovascular safety of glitazones, metformin and sufonylureas are inconsistent.To conduct and evaluate heterogeneity in a meta-analysis of observational studies on the risk of acute myocardial infarction (AMI) or stroke in patients with type 2 diabetes using non-insulin blood glucose-lowering drugs (NIBGLD). METHODS: We systematically identified and reviewed studies evaluating NIBGLD in patients with type 2 diabetes indexed in Medline, Embase, or the Cochrane Library that met prespecified criteria. The quality of included studies was assessed with the RTI item bank. Results were combined using fixed- and random-effects models, and the Higgins I(2) statistic was used to evaluate heterogeneity. Sensitivity analyses by study quality were conducted. RESULTS: The summary relative risk (sRR) (95% CI) of AMI for rosiglitazone versus pioglitazone was 1.13 (1.04-1.24) [I(2) = 55%]. In the sensitivity analysis, heterogeneity was reduced [I(2) = 16%]. The sRR (95% CI) of stroke for rosiglitazone versus pioglitazone was 1.18 (1.02-1.36) [I(2) = 42%]. There was strong evidence of heterogeneity related to study quality in the comparisons of rosiglitazone versus metformin and rosiglitazone versus sulfonylureas (I (2) >= 70%). The sRR (95% CI) of AMI for sulfonylurea versus metformin was 1.24 (1.14-1.34) [I(2) = 41%] and for pioglitazone versus metformin was 1.02 (0.75-1.38) [I(2) = 17%]. Sensitivity analyses decreased heterogeneity in most comparisons. CONCLUSION/INTERPRETATION: Sulfonylureas increased the risk of AMI by 24% compared with metformin; an imprecise point estimate indicated no difference in risk of AMI when comparing pioglitazone with metformin. The presence of heterogeneity precluded any conclusions on the other comparisons. The quality assessment was valuable in identifying methodological problems in the individual studies and for analysing potential sources of heterogeneity. PMID- 26769244 TI - Pharmacokinetics, metabolism, and excretion of (14)C-labeled belinostat in patients with recurrent or progressive malignancies. AB - BACKGROUND: Belinostat, a potent pan-inhibitor of histone deacetylase (HDAC) enzymes, is approved in the United States (US) for relapsed/refractory peripheral T-cell lymphoma. In nonclinical studies, bile and feces were identified as the predominant elimination routes (50-70%), with renal excretion accounting for ~30 50%. A Phase 1 human mass balance study was conducted to identify species dependent variations in belinostat metabolism and elimination. METHODS: Patients received a single 30-min intravenous (i.v.) infusion of (14)C-labeled belinostat (1500 mg). Venous blood samples and pooled urine and fecal samples were evaluated using liquid chromatography-tandem mass spectroscopy for belinostat and metabolite concentrations pre-infusion through 7 days post-infusion. Total radioactivity was determined using liquid scintillation counting. Continued treatment with nonradiolabled belinostat (1000 mg/m(2) on Days 1-5 every 21 days) was permitted. RESULTS: Belinostat was extensively metabolized and mostly cleared from plasma within 8 h (N = 6), indicating that metabolism is the primary route of elimination. Systemic exposure for the 5 major metabolites was >20% of parent, with belinostat glucuronide the predominant metabolite. Mean recovery of radioactive belinostat was 94.5% +/- 4.0%, with the majority excreted within 48 and 96 h in urine and feces, respectively. Renal elimination was the principal excretion route (mean 84.8% +/- 9.8% of total dose); fecal excretion accounted for 9.7% +/- 6.5%. Belinostat was well tolerated, with mostly mild to moderate adverse events and no treatment-related severe/serious events. CONCLUSION: Mass balance was achieved (~95% mean recovery), with metabolism identified as the primary route of elimination. Radioactivity was predominantly excreted renally as belinostat metabolites. PMID- 26769245 TI - Post-progression survival in patients with advanced hepatocellular carcinoma resistant to sorafenib. AB - BACKGROUND: Since the approval of sorafenib, no other agent has been proven to show survival benefits in clinical trials involving patients with advanced hepatocellular carcinoma (HCC) resistant to sorafenib. Prognostic factors for survival after tumor progression in sorafenib-treated patients are critical for designing second-line trials. METHODS: To determine the factors affecting the post-progression survival (PPS) after sorafenib treatment, additional analyses were conducted using fixed data obtained from our previous prospective study. Data on patients with advanced HCC treated with sorafenib were analyzed in view of patient characteristics at the time of tumor progression and the progression pattern (intra-/extrahepatic growth or emergence of new intra-/extrahepatic lesions). RESULTS: Of the 89 enrolled patients, 70 were diagnosed with disease progression according to the Response Evaluation Criteria in Solid Tumors version 1.1. Multivariate Cox's regression analysis revealed that Child-Pugh scores of >=7, macrovascular invasion (MVI), and alpha-fetoprotein of >400 ng/mL were independent predictors of poor PPS. Although both extrahepatic metastasis (EHM) and MVI were characteristics of advanced HCC, EHM was not determined as a prognostic factor. Additionally, the emergence of new extrahepatic lesions also served as an independent indicator of a poor prognosis. The PPS of the patients was well stratified according to the index based on the sum of these prognostic factors, ranging from 0 to 4. CONCLUSIONS: Child-Pugh score of >=7, AFP of >400 ng/mL, MVI, and new extrahepatic lesions at the time of progression may be utilized to assess the prognosis and taken into consideration when designing second-line trials. PMID- 26769246 TI - Two stages of parafoveal processing during reading: Evidence from a display change detection task. AB - We used a display change detection paradigm (Slattery, Angele, & Rayner Human Perception and Performance, 37, 1924-1938 2011) to investigate whether display change detection uses orthographic regularity and whether detection is affected by the processing difficulty of the word preceding the boundary that triggers the display change. Subjects were significantly more sensitive to display changes when the change was from a nonwordlike preview than when the change was from a wordlike preview, but the preview benefit effect on the target word was not affected by whether the preview was wordlike or nonwordlike. Additionally, we did not find any influence of preboundary word frequency on display change detection performance. Our results suggest that display change detection and lexical processing do not use the same cognitive mechanisms. We propose that parafoveal processing takes place in two stages: an early, orthography-based, preattentional stage, and a late, attention-dependent lexical access stage. PMID- 26769247 TI - Hyperglycemia alters E-NTPDases, ecto-5'-nucleotidase, and ectosolic and cytosolic adenosine deaminase activities and expression from encephala of adult zebrafish (Danio rerio). AB - Hyperglycemia is the main feature for the diagnosis of diabetes mellitus (DM). Some studies have demonstrated the relationship between DM and dysfunction on neurotransmission systems, such as the purinergic system. In this study, we evaluated the extracellular nucleotide hydrolysis and adenosine deamination activities from encephalic membranes of hyperglycemic zebrafish. A significant decrease in ATP, ADP, and AMP hydrolyses was observed at 111-mM glucose-treated group, which returned to normal levels after 7 days of glucose withdrawal. A significant increase in ecto-adenosine deaminase activity was observed in 111-mM glucose group, which remain elevated after 7 days of glucose withdrawal. The soluble-adenosine deaminase activity was significantly increased just after 7 days of glucose withdrawal. We also evaluated the gene expressions of ecto nucleoside triphosphate diphosphohydrolases (E-NTPDases), ecto-5'-nucleotidase, ADA, and adenosine receptors from encephala of adult zebrafish. The entpd 2a.1, entpd 2a.2, entpd 3, and entpd 8 mRNA levels from encephala of adult zebrafish were decreased in 111-mM glucose-treated and glucose withdrawal groups. The gene expressions of adenosine receptors (adora 1 , adora 2aa , adora 2ab , and adora 2b ) were decreased in 111-mM glucose-treated and glucose withdrawal groups. The gene expression of ADA (ada 2a.1) was decreased in glucose withdrawal group. Maltodextrin, used as a control, did not affect the expression of adenosine receptors, ADA and E-NTPDases 2, 3, and 8, while the expression of ecto-5' nucleotidase was slightly increased and the E-NTPDases 1 decreased. These findings demonstrated that hyperglycemia might affect the ecto-nucleotidase and adenosine deaminase activities and gene expression in zebrafish, probably through a mechanism involving the osmotic effect, suggesting that the modifications caused on purinergic system may also contribute to the diabetes-induced progressive cognitive impairment. PMID- 26769248 TI - The work of local healthcare innovation: a qualitative study of GP-led integrated diabetes care in primary health care. AB - BACKGROUND: Service delivery innovation is at the heart of efforts to combat the growing burden of chronic disease and escalating healthcare expenditure. Small scale, locally-led service delivery innovation is a valuable source of learning about the complexities of change and the actions of local change agents. This exploratory qualitative study captures the perspectives of clinicians and managers involved in a general practitioner-led integrated diabetes care innovation. METHODS: Data on these change agents' perspectives on the local innovation and how it works in the local context were collected through focus groups and semi-structured interviews at two primary health care sites. Transcribed data were analysed thematically. Normalization Process Theory provided a framework to explore perspectives on the individual and collective work involved in putting the innovation into practice in local service delivery contexts. RESULTS: Twelve primary health care clinicians, hospital-based medical specialists and practice managers participated in the study, which represented the majority involved in the innovation at the two sites. The thematic analysis highlighted three main themes of local innovation work: 1) trusting and embedding new professional relationships; 2) synchronizing services and resources; and 3) reconciling realities of innovation work. As a whole, the findings show that while locally-led service delivery innovation is designed to respond to local problems, convincing others to trust change and managing the boundary tensions is core to local work, particularly when it challenges taken-for-granted practices and relationships. Despite this, the findings also show that local innovators can and do act in both discretionary and creative ways to progress the innovation. CONCLUSIONS: The use of Normalization Process Theory uncovered some critical professional, organizational and structural factors early in the progression of the innovation. The key to local service delivery innovation lies in building coalitions of trust at the point of service delivery and persuading organizational and institutional mindsets to consider the opportunities of locally-led innovation. PMID- 26769249 TI - Influence of Drug Properties and Formulation on In Vitro Drug Release and Biowaiver Regulation of Oral Extended Release Dosage Forms. AB - Bioequivalence (BE) studies are often required to ensure therapeutic equivalence for major product and manufacturing changes. Waiver of a BE study (biowaiver) is highly desired for such changes. Current regulatory guidelines allow for biowaiver of proportionally similar lower strengths of an extended release (ER) product provided it exhibits similar dissolution to the higher strength in multimedia. The objective of this study is to demonstrate that (1) proportionally similar strengths of ER tablets exhibiting similar in vitro dissolution profiles do not always assure BE and (2) different strengths that do not meet the criteria for dissolution profile similarity may still be bioequivalent. Four marketed ER tablets were used as model drug products. Higher and lower (half) strength tablets were prepared or obtained from commercial source. In vitro drug release was compared using multi-pH media (pH 1.2, 4.5, 6.8) per regulatory guidance. In vivo performance was assessed based on the available in vivo BE data or established in vitro-in vivo relationships. This study demonstrated that the relationship between in vitro dissolution and in vivo performance is complex and dependent on the characteristics of specific drug molecules, product design, and in vitro test conditions. As a result, proportionally similar strengths of ER dosage forms that meet biowaiver requirements per current regulatory guidelines cannot ensure bioequivalence in all cases. Thus, without an established relationship between in vitro and in vivo performance, granting biowaiver based on passing in vitro tests may result in the approval of certain bioinequivalent products, presenting risks to patients. To justify any biowaiver using in vitro test, it is essential to understand the effects of drug properties, formulation design, product characteristics, test method, and its in vivo relevance. Therefore, biowaiver requirements of different strengths of ER dosage forms specified in the current regulatory guidance should be reevaluated to assure consistent safety and efficacy among different strengths. PMID- 26769250 TI - Influence of Copolymer Composition on In Vitro and In Vivo Performance of Celecoxib-PVP/VA Amorphous Solid Dispersions. AB - Previous studies suggested that an amorphous solid dispersion with a copolymer consisting of both hydrophobic and hydrophilic monomers could improve the dissolution profile of a poorly water-soluble drug compared to the crystalline form. Therefore, this study investigated the influence of the copolymer composition of polyvinylpyrrolidone/vinyl acetate (PVP/VA) on the non-sink in vitro dissolution behavior and in vivo performance of celecoxib (CCX) amorphous solid dispersions. The study showed that the hydrophilic monomer vinylpyrrolidone (VP) was responsible for the generation of CCX supersaturation whereas the hydrophobic monomer vinyl acetate (VA) was responsible for the stabilization of the supersaturated solution. For CCX, there was an optimal copolymer composition around 50-60% VP content where further replacement of VP monomers with VA monomers did not have any biopharmaceutical advantages. A linear relationship was found between the in vitro AUC(0-4h) and in vivo AUC(0-24h) for the CCX:PVP/VA systems, indicating that the non-sink in vitro dissolution method applied in this study was useful in predicting the in vivo performance. These results indicated that when formulating a poorly water-soluble drug as an amorphous solid dispersion using a copolymer, the copolymer composition has a significant influence on the dissolution profile and in vivo performance. Thus, the dissolution profile of a drug can theoretically be tailored by changing the monomer ratio of a copolymer with respect to the required in vivo plasma concentration profile. As this ratio is likely to be drug dependent, determining the optimal ratio between the hydrophilic (dissolution enhancing) and hydrophobic (crystallization inhibiting) monomers for a given drug is imperative. PMID- 26769251 TI - The Effects of Spatial Enclosure on Social Interaction Between Older Adults With Dementia and Young Children. AB - OBJECTIVE: To examine the impact of spatial enclosures on social interaction between older adults with early stage dementia and young children. BACKGROUND: Intergenerational interaction through meaningful activities can promote positive affects and behaviors of children and older adults. The development of social interaction is closely related to the physical environment in association with personal competence of older adults with dementia and young children. However, minimal attention has been given to the role of physical environment in influencing intergenerational interaction. METHODS: A quasi-experiment examined the functional relationship between the amount of spatial enclosure and the types of social behaviors of older adults with dementia and young children. Semi structured interviews, aided by a photographic simulation, were developed to explore the participants' perceptions of and experiences with the different degrees of spatial enclosure. RESULTS: Findings showed that the semienclosed spatial plan impacted both prosocial and antisocial behaviors of older adults with dementia in their interactions with young children. This apparent discrepancy was associated with two conflicting perceptions: a sense of openness and the lack of control due to distraction created by the loose visual boundary. There was no correlation between the elder-child neutral behaviors and the degrees of spatial enclosure. CONCLUSION: This study suggests that spaces with moderate openness without visual and acoustic distraction are the most desirable to promote prosocial behaviors of older adults with dementia and young children. Additionally, elder-child prosocial behaviors were likely facilitated by specific design features such as adequate personal space, the perception of openness, and possible spaces that provide both prospect and refuge in relation to spatial enclosure. PMID- 26769252 TI - Atypical Teratoid/Rhabdoid Tumor (AT/RT) Arising From Ependymoma: A Type of AT/RT Secondarily Developing From Other Primary Central Nervous System Tumors. AB - Atypical teratoid/rhabdoid tumors (AT/RT) are rare, aggressive, embryonal brain tumors that occur most frequently in very young children; they are characterized by rhabdoid cells and loss of INI1 protein nuclear expression. Here, we report the case of a 24-year-old man with a left frontal lobe tumor that was composed mainly of rhabdoid cells showing loss of INI1 nuclear reactivity and polyphenotypic immunohistochemical expression, with a small INI1-positive component of ependymoma. Array comparative genomic hybridization separately conducted for each histologically distinct component revealed 22 shared identical copy number alterations, including loss of heterozygosity of chromosome 22q containing the INI1 locus. Furthermore, we found the C11orf95-RELA fusion gene, the genetic hallmark of supratentorial ependymomas, not only in the ependymoma component but also in the AT/RT component by fluorescence in situ hybridization analysis, suggesting that the AT/RT cells secondarily progressed from the preexisting ependymoma cells. A second genetic inactivating event in the INI1 gene was not detected in the AT/RT component. There are several reported cases of AT/RT (or INI1-negative rhabdoid tumors) arising in the setting of other primary brain tumors (gangliogliomas, pleomorphic xanthoastrocytomas, and high-grade gliomas), but the present case PMID- 26769253 TI - Altered Levels of Visinin-Like Protein 1 Correspond to Regional Neuronal Loss in Alzheimer Disease and Frontotemporal Lobar Degeneration. AB - Recent studies have implicated the neuronal calcium-sensing protein visinin-like 1 protein (Vilip-1) as a peripheral biomarker in Alzheimer disease (AD), but little is known about expression of Vilip-1 in the brains of patients with AD. We used targeted and quantitative mass spectrometry to measure Vilip-1 peptide levels in the entorhinal cortex (ERC) and the superior frontal gyrus (SF) from cases with early to moderate stage AD, frontotemporal lobar degeneration (FTLD), and cognitively and neuropathologically normal elderly controls. We found that Vilip-1 levels were significantly lower in the ERC, but not in SF, of AD subjects compared to normal controls. In FTLD cases, Vilip-1 levels in the SF were significantly lower than in normal controls. These findings suggest a unique role for cerebrospinal fluid Vilip-1 as a biomarker of ERC neuron loss in AD. PMID- 26769254 TI - Subjectivity is a strength: a comment on "an algorithm was developed to assign GRADE levels of evidence to comparisons within systematic reviews". PMID- 26769255 TI - The purpose of rating quality of evidence differs in an overview, as compared to guidelines or recommendations. PMID- 26769256 TI - A Rasch analysis of the Brief Pain Inventory Interference subscale reveals three dimensions and an age bias. AB - OBJECTIVES: The Brief Pain Inventory is composed of two quantifiable scales: pain severity and pain interference. The reported factor structure of the interference subscale is not consistent in the extant literature, with no clear choice between a single- or two-factor structure. Here, we report on the results of Rasch-based analysis of the interference subscale using a large population-based ambulatory patient database (the Quebec Pain Registry). STUDY DESIGN: Observational cohort. RESULTS: A total of 1,000 responses were randomly drawn from a total database of 5,654 for this analysis. Both the original 7-item and an expanded 10-item version (Tyler 2002) of the interference subscale were evaluated. Rasch analysis revealed significant misfit of both versions of the scale, with the original 7-item version outperforming the expanded 10-item version. Analysis of dimensionality revealed that both versions showed improved model fit when considered two subscales (affective and physical interference) with the item on sleep interference removed or considered separately. Additionally, significant uniform differential item functioning was identified for 6 of the 7 original items when the sample was stratified by age above or below 55 years. The interference subscale achieved adequate model fit when considered as two separate subscales with age as a mediator of response, while interpreting the sleep interference item separately. A transformation matrix revealed that in all cases, ordinal level change at the extreme ends of the scale appears to be more meaningful than does a similar change at the midpoints. CONCLUSIONS: The Interference subscale of the BPI should be interpreted as two separate subscales (Affective Interference, Physical Interference) with the sleep item removed or interpreted separately for optimal fit to the Rasch model. Implications for research and clinical use are discussed. PMID- 26769257 TI - Reporting quality of N-of-1 trials published between 1985 and 2013: a systematic review. AB - OBJECTIVES: To evaluate the quality of reporting of single-patient (N-of-1) trials published in the medical literature based on the CONSORT Extension for N of-1 Trials (CENT) statement and to examine factors that influence reporting quality in these trials. STUDY DESIGN AND SETTING: Through a search of 10 electronic databases, we identified N-of-1 trials in clinical medicine published between January 1, 1985, and December 31, 2013. Two reviewers screened articles for eligibility and independently extracted data. Quality assessment was performed using the CENT statement. Discrepancies were resolved by consensus. RESULTS: We identified 112 eligible N-of-1 trials published in 87 journals and involving a total of 2,278 patients. Overall, kappa agreement between the two evaluators for compliance with CENT criteria was 0.80 (95% confidence interval: 0.79, 0.82). Trials assessed pharmacology and therapeutics (87%), behavior (11%), or diagnosis (2%). Although 87% of articles described the trial design (including the planned number of subjects and length of treatment period), the median percentage of specific CENT elements reported in the Methods was 41% (range, 16 87%), and the median percentage in the Results was 38% (range, 32-93%). First authors were predominantly from North America (46%), Europe (29%), and Australia (17%). Quality of reporting was higher in articles published in journals with relatively high-impact factors (P = 0.004). CONCLUSION: The quality of reporting of published N-of-1 trials is variable and in need of improvement. Because the CENT guidelines were not published until near the end of the period of this review, these results represent a baseline from which improvement may be expected in the future. PMID- 26769258 TI - Collecting and validating experiential expertise is doable but poses methodological challenges. AB - OBJECTIVES: To give an overview of important methodological challenges in collecting, validating, and further processing experiential expertise and how to address these challenges. STUDY DESIGN AND SETTING: Based on our own experiences in studying the concept, operationalization, and contents of experiential expertise, we have formulated methodological issues regarding the inventory and application of experiential expertise. RESULTS: The methodological challenges can be categorized in six developmental research stages, comprising the conceptualization of experiential expertise, methods to harvest experiential expertise, the validation of experiential expertise, evaluation of the effectiveness, how to translate experiential expertise into acceptable guidelines, and how to implement these. The description of methodological challenges and ways to handle those are illustrated using diabetes mellitus as an example. CONCLUSION: Experiential expertise can be defined and operationalized in terms of successful illness-related behaviors and translated into recommendations regarding life domains. Pathways have been identified to bridge the gaps between the world of patients' daily lives and the medical world. PMID- 26769259 TI - Cell fate in animal and human blastocysts and the determination of viability. AB - Understanding the mechanisms underlying the first cell differentiation events in human preimplantation development is fundamental for defining the optimal conditions for IVF techniques and selecting the most viable embryos for further development. However, our comprehension of the very early events in development is still very limited. Moreover, our knowledge on early lineage specification comes primarily from studying the mouse model. It is important to recognize that although mammalian embryos share similar morphological landmarks, the timing and molecular control of developmental events may vary substantially between species. Mammalian blastocysts comprise three cell types that arise through two sequential rounds of binary cell fate decisions. During the first decision, cells located on the outside of the developing embryo form a precursor lineage for the embryonic part of the placenta: the trophectoderm and cells positioned inside the embryo become the inner cell mass (ICM). Subsequently, ICM cells differentiate into embryonic lineages that give rise to a variety of tissues in the developing foetus: either the epiblast or extraembryonic primitive endoderm. Successful formation of all three lineages is a prerequisite for implantation and development to term. A comprehensive understanding of the lineage specification processes in mammals is therefore necessary to shed light on the causes of early miscarriages and early pregnancy pathologies in humans. PMID- 26769261 TI - Post-traumatic Pott's puffy tumour: A case report. AB - INTRODUCTION: Osteomyelitis of the frontal sinus is a rare clinical entity and generally occurs as a complication of trauma to the forehead or frontal sinusitis. It can be responsible for life-threatening complications, as the first symptoms may appear to be minor. Early diagnosis and appropriate management to prevent central nervous system complications significantly reduce the morbidity and mortality. CASE REPORT: The authors report the case of a 34-year-old man with Pott's puffy tumour following trauma to the frontal sinus. DISCUSSION: The diagnosis was suggested clinically and confirmed radiologically. Treatment was surgical with craniotomy and external drainage. PMID- 26769260 TI - Decrease in expression of maternal effect gene Mater is associated with maternal ageing in mice. AB - STUDY HYPOTHESIS: What factors in mouse oocytes are involved in the ageing related decline in oocyte quality? STUDY FINDING: The maternal effect gene Mater is involved in ageing-related oocyte quality decline in mice. WHAT IS KNOWN ALREADY: Premature loss of centromere cohesion is a hallmark of ageing-related oocyte quality decline; the maternal effect gene Mater (maternal antigen that embryos require, also known as Nlrp5) is required for preimplantation embryo development beyond the 2-cell stage, and mRNA expression of Mater decreases with maternal ageing. STUDY DESIGN, SAMPLES/MATERIALS, METHODS: Mater protein expression level in mature oocytes from 7 young (5-8 weeks old) to 7 old mice (41 68 weeks old) was compared by immunoblotting analysis. Wild-type and Mater-null mice were used to examine whether Mater is necessary for maintaining normal centromere cohesion by means of cytogenetic karyotyping, time-lapse confocal microscopy and immunofluorescence staining. MAIN RESULTS AND THE ROLE OF CHANCE: Mater protein is decreased in mature oocytes from old versus young mice (P = 0.0022). Depletion of Mater from oocytes leads to a reduction in centromere cohesion, manifested by precocious sister chromatid separation, enlargement of sister centromere distance and misalignment of chromosomes in the metaphase plate during meiosis I and II. LIMITATIONS, REASONS FOR CAUTION: This study was conducted in mice. Whether or not the results are applicable to human remains further elucidation. In addition, we were unable to confirm if the strain of mice (C57BL/6XSv129) at the age of 41-68 weeks old has the 'cohesin-loss' phenotype. WIDER IMPLICATIONS OF THE FINDINGS: Investigating Mater's functional mechanisms could provide fresh insights into understanding how the ageing-related oocyte quality decline occurs. LARGE SCALE DATA: N/A. STUDY FUNDING AND COMPETING INTERESTS: This work was supported by the research grant from Chinese NSFC to P.Z. (31071274). We have no conflict of interests to declare. PMID- 26769262 TI - Tracheal rhinoscleroma. AB - INTRODUCTION: Tracheal rhinoscleroma is an infectious granulomatosis of the tracheobronchial tract caused by a Gram-negative bacillus. Exclusively tracheal involvement has been rarely reported in the literature. The purpose of this study was to report a case of subglottic stenosis secondary to rhinoscleroma. SUMMARY: A 46-year-old North African woman with no medical or surgical history presented with inspiratory dyspnoea that had been present for several years. Endoscopic examination under general anaesthesia revealed tracheal stenosis. Histological examination of mucosal biopsies demonstrated Mikulicz cells and culture of bacteriological samples taken during a second biopsy confirmed the diagnosis of rhinoscleroma. CO2 laser subglottic obstruction relief was performed and treatment with ofloxacin was initiated. No recurrence of tracheal stenosis was observed with a follow-up of 6 months. DISCUSSION: The diagnosis of rhinoscleroma is based on histological and bacteriological examination. Cultures are positive in 60% of cases, but negative cultures do not exclude the diagnosis of rhinoscleroma. Specific treatment consists of long-term antibiotic therapy, while surgery may be indicated for symptomatic treatment. PMID- 26769263 TI - Bacteroides caecicola sp. nov. and Bacteroides gallinaceum sp. nov., isolated from the caecum of an Indonesian chicken. AB - Six strains of anaerobic bacteria, C13EG70T, C13EG118, C13EG186T, C13GAMG5, C13GAMG28 and C13GAMG40, were isolated from the caecum of a healthy chicken bred in Bogor, Indonesia. Phylogenetic analysis showed the isolates were separated into two groups. Group I (C13EG70T and C13EG118) showed nearly identical 16S rRNA gene sequences (99.9 % sequence similarity). Group II (C13EG186T, C13GAMG5, C13GAMG28 and C13GAMG40) showed nearly identical 16S rRNA gene sequences (>99.4 % sequence similarity). The isolates showed low 16S rRNA gene sequence similarities to recognized species of the genus Bacteroides. High gene sequence similarities were found between type strains (C13EG70T and C13EG186T) and Bacteroides salanitronis JCM 13657T (87.9, 91.5 %, respectively). Physiological, biochemical and genotypic characteristics demonstrated that these strains could be separated from the type strain of B. salanitronis. It is concluded that Group I and Group II represent novel species. Two novel species of the genus Bacteroides are proposed as Bacteroides caecicola sp. nov. (type strain C13EG70T = LIPI12-4 Ck732T = JSAT12-4-Ck732T = InaCC B449T = NBRC 110958T) and Bacteroides gallinaceum sp. nov. (type strain C13EG186T = LIPI12-4-Ck844T = JSAT12-4-Ck884T = InaCC B451T = NBRC 110963T). PMID- 26769265 TI - Genetic evaluation of early egg production and maturation traits using two different approaches in Japanese quail. AB - The objective of the current study was to evaluate a multi-trait selection program based on aggregated breeding values using an animal model Best Linear Unbiased Prediction (BLUP) in Japanese quail. The estimated genetic gain was compared by both mixed model and least squares methods. Data of 1,682 female Japanese quails were collected through four consecutive generations to estimate genetic gain, depending on aggregated breeding values, for age at first egg (AFE), body weight at sexual maturity (BWSM), and days needed to produce the first ten eggs (DN10). Estimates of cumulative selection response were favorable for all the studied traits and significant for AFE (-3.03) and BWSM(10.38), but not significant for DN10(-0.15). Estimates of direct heritability were moderate for AFE (0.21) and BWSM(0.25) but low for DN10(0.08), while estimates of maternal heritability were moderate for AFE (0.19) but low for BWSM(0.04) and DN10(0.01). High (0.45 to 0.56) genetic and low (-0.01 to -0.18) phenotypic correlations were observed among the studied traits. Negative (-0.23 to -0.95) correlations between additive genetic and maternal genetic effects were observed for all traits. Genetic trends were -0.76 (P=0.031), 2.54 (P=0.037), and -0.06 (P=0.052) with calculated product-moment correlations between breeding values, estimated by BLUP and phenotypic selection methods, of 0.78 (P=0.002), 0.77 (P=0.004), and 0.61 (P=0.007) for AFE, BWSM, and DN10, respectively. Aggregated breeding value estimation based on animal model BLUP could be an effective method of constructing a selection program to achieve a favorable selection response in egg production traits in Japanese quail. PMID- 26769266 TI - Development of a highly immunogenic Newcastle disease virus chicken vaccine strain of duck origin. AB - Newcastle disease virus (NDV) strain NDRL0901 was developed as a live vaccine candidate for control of Newcastle disease. NDV isolate KR/duck/13/07 (DK1307) of duck origin was used as the selected vaccine strain. DK1307 was passaged 6 times in chickens. Then a single clone from the chicken-adapted virus (DK1307C) was finally selected, and the vaccine strain was named NDRL0901. DK1307C and the clone NDRL0901 viruses showed enhanced immunogenicity compared to the DK1307 virus. Principal component analysis based on fusion and hemagglutinin neuraminidase genes revealed the codon usage pattern in the dataset is distinct separating duck viral sequences and avian sequences, and passage of the duck origin virus into the chicken host causes deviation in the codon usage pattern. The NDRL0901 virus was avirulent and did not acquire viral virulence even after 7 back passages in chickens. When day-old chicks were vaccinated with the NDRL0901 virus via spray, eye drops, and drinking water, the vaccinated birds showed no clinical signs and had significant protection efficacy (>80%) against very virulent NDV (Kr005 strain) infection regardless of the administration route employed. The results indicate that the NDRL0901 strain is safe in chickens and can offer protective immunity. PMID- 26769267 TI - Effects of different limestone particle sizes in the diet of broiler breeders post molting on their performance, egg quality, incubation results, and pre starter performance of their progeny. AB - An experiment was conducted to test the hypothesis that a coarse limestone diet improves productivity, reproductive performance and the calcium utilization of molted broiler breeders. In total, 640 broiler breeder females, 73-week-old and sixty-four 27-week-old cockerels, Cobb 500, were evaluated during 10 weeks, according to a randomized block design composed of 4 treatments with 8 replicates each. Treatments consisted of diets with the inclusion of 100% fine limestone fine PS (0.2 mm GMD-geometric mean diameter); PS1: 30% fine limestone+70% limestone with 1.0 mm GMD; PS2: 30% fine limestone+70% limestone with 2.0 mm GMD; and PS3: 30% fine limestone+70% limestone with 3.0 mm GMD. Calcium retention in the gizzard of the breeders, bone characteristics, and breeder performance, egg characteristics, eggshell quality, incubation performance, chick quality and yield, chick pre-starter live performance, and chick bone characteristics were determined. There was no significant difference (P>0.05) in the rate of lay, percentage of non-settable eggs, egg weight, egg shape index, egg specific gravity, eggshell weight, thickness, and percentage hatchability and egg weight loss of broiler breeders fed with diets with different limestone particle sizes. The chick quality and yield, chick pre-starter live performance, and chick bone characteristics were not affected (P>0.05) by any of the limestone particle sizes. It was concluded that live and reproductive performance parameters of broiler breeders post molting is not affected by limestone particle size in the feed. PMID- 26769268 TI - The use of FTA cards for transport and detection of gyrA mutation of Campylobacter jejuni from poultry. AB - The purpose of the present study was to evaluate a technique involving the use of commercially available FTA classic card (Whatman) for transporting and detection of DNA to use in PCR analysis and genetic sequencing of Campylobacter jejuni of poultry origin. Fifty isolates of Campylobacter jejuni were obtained from broiler carcasses in Rio Grande do Sul, Brazil. Antimicrobial susceptibility testing to ciprofloxacin revealed that all 50 isolates were resistant to ciprofloxacin. Each isolate was transferred to Brucella broth tubes and incubated overnight at 41.5 degrees C. Cell cultures were diluted to match a McFarland Turbidity Standard 0.5, and 110 MUL of the cell suspension were applied to one circle on Whatman FTA classic cards. The samples were then covered and allowed to dry at room temperature. Cards were identified and stored at room temperature until further use (3 mo after collection). FTA cards were shipped for analysis to the Department of Poultry Science, University of Arkansas. Amplification of the Campylobacter gyrA gene was successful and demonstrated strong bands for a large amplicon for all 50 samples preserved on FTA cards. Mutations present in each gene were confirmed by DNA sequencing. Then, 7 samples were chosen for the sequencing. The detection of a mutation regarding ciprofloxacin-resistant isolates revealed that 7 samples had a mutation in the gyrA gene. In conclusion, the characteristics of the profiles suggest that the DNA has maintained its integrity after 3 mo of storage at room temperature and is a suitable template for PCR and sequencing from Campylobacter samples. The application of this technology has potential in numerous methodologies, especially when working in remote areas and in developing countries where access to laboratory facilities and equipment is limited. PMID- 26769269 TI - Lectin staining of the uterovaginal junction and sperm-storage tubule epithelia in broiler hens. AB - Mammalian sperm bind to terminal carbohydrates associated with glycoconjugates on the apical surface of oviduct epithelial cells in the caudal region of the oviduct and undergo cellular and molecular modifications associated with capacitation prior to ovulation. In contrast, chicken sperm are stored for up to 23 d in sperm-storage tubules (SST) localized in the uterovaginal junction (UVJ). Little is known of the cellular and molecular mechanisms that regulate sperm storage in and release from the SST. The purpose of this study was to identify glycoconjugates associated with the SST epithelial cell surface using lectins. Virgin hens and hens of higher and lower fertility in egg production for 6 to 16 wk were used in this study. Sections of UVJ mucosa containing SST were stained with fluorescent conjugated lectins and examined by confocal microscopy. Carbohydrate moieties associated with the UVJ and SST epithelia differed in their lectin binding patterns. No differences in the lectin binding patterns within the 2 epithelia were discernible between the virgin and younger and older hens. Minor differences were observed between the higher and lower fertility hens. Only lectins specific for galactose and N-acetylgalactosamine moieties were localized to the luminal surface of the SST. While resident sperm may be closely apposed to the SST epithelial cell apical microvilli, it is unlikely that sperm binding to the microvilli via terminal carbohydrates associated with glycoconjugates is a requisite for prolonged storage. However, the possibility of SST epithelial cell communication with resident sperm via shedding microvillous vesicles characterized by surface glycoconjugates with terminal galactose and N acetylgalactosamine moieties is currently being investigated. PMID- 26769270 TI - Temperature effect on proliferation and differentiation of satellite cells from turkeys with different growth rates. AB - Poultry selected for growth have an inefficient thermoregulatory system and are more sensitive to temperature extremes. Satellite cells are precursors to skeletal muscle and mediate all posthatch muscle growth. Their physiological functions are affected by temperature. The objective of the current study was to determine how temperature affects satellite cells isolated from the pectoralis major (p. major) muscle (breast muscle) of turkeys selected for increased 16 wk body weight (F line) in comparison to a randombred control line (RBC2) from which the F line originated. Pectoralis major muscle satellite cells were thermally challenged by culturing between 33 degrees C and 43 degrees C to analyze the effects of cold and heat on proliferation and differentiation as compared to control temperature of 38 degrees C. Expression levels of myogenic regulatory factors: myogenic differentiation factor 1 (MYOD1) and myogenin (MYOG) were quantified by quantitative polymerase chain reaction (qPCR). At all sampling times, proliferation increased at a linear rate across temperature in both the RBC2 and F lines. Differentiation also increased at a linear rate across temperature from 33 to 41 degrees C at all sampling times in both the F and RBC2 lines. Satellite cells isolated from F line turkeys were more sensitive to both hot and cold temperatures as proliferation and differentiation increased to a greater extent across temperature (33 to 43 degrees C) when compared with the RBC2 line. Expression of MYOD1 and MYOG increased as temperatures increased from 33 to 41 degrees C at all sampling times in both the F and RBC2 lines. These results demonstrate that satellite cell function is sensitive to both cold and hot temperatures and p. major muscle satellite cells from F line turkeys are more sensitive to temperature extremes than RBC2 satellite cells. PMID- 26769271 TI - Assessing Salmonella typhimurium persistence in poultry carcasses under multiple thermal conditions consistent with composting and wet rendering. AB - Mitigation of Salmonella associated with poultry carcasses is primarily accomplished by rendering or carcass composting. While rendering temperatures and pressures are well established for pathogen inactivation in poultry carcasses, parameters controlling composting processes are less defined in part because multiple conditions and procedures are utilized. Consequently, limited knowledge exists describing the impacts of composting with varying temperature and mixing protocols with respect to the inactivation of Salmonella in poultry carcasses. To improve the existing knowledge of Salmonella survival in poultry carcasses, inactivation of Salmonella enterica serovar Typhimurium (ST) LT2 was investigated. The impacts of various composting temperatures (55, 62.5 degrees C) and low-rendering (i.e., pasteurization) temperatures (70, 78 degrees C) on Salmonella inactivation were tested in a bench-top setting using a ground carcass slurry and whole birds under mixed and non-mixed conditions. Results showed that the ground carcass slurry and the whole carcass exposed to temperatures consistent with composting had no detectable Salmonella after 110 h with a level of detection of one CFU/mL of ground carcass slurry and one CFU/g of whole carcasses, respectively. In addition, grinding of carcasses as opposed to whole carcasses was more predictable with respect to Salmonella heat inactivation. Furthermore, results showed that constant mixing decreased the overall time required to eliminate Salmonella under composting and low-rendering temperatures. PMID- 26769272 TI - Increased water contamination and grow-out Pekin duck mortality when raised with water troughs compared to pin-metered water lines using a United States management system. AB - Controversy has developed as to whether or not pin-metered water lines or water troughs are more appropriate for Pekin ducks. We hypothesized that water troughs would show improved duck body conditions and environmental quality compared to pin-metered water lines. To test this hypothesis, we housed ducks in 2 barns, one with water lines and one with water troughs. Water troughs were constructed to meet RSPCA guidelines for number and density of ducks and with recently described verandas. Ducks were divided into 4 pens per barn (n=1,000 ducks/pen). The study was then repeated (n=8 pens per water source) in a cross-over design so the barns each contained the opposite water source to the first experiment. We scored the ducks' body condition using an established scoring rubric and analyzed using SAS Proc GLM-Mix as binomial data. Ducks housed with water troughs showed higher (thus worse condition; P<0.001) scores for eyes, nostrils, feather quality, feather cleanliness, and foot pads. We also compared water condition, water quality, and duck mortality using a Student t test for both water sources each week. We found that the water troughs showed higher iron (P<0.001), nitrites (P<0.001), pH (P<0.01), and bacterial growth (P<0.001). The bacterial growth was shown to have higher (P<0.001)E. coli, coliforms, and Staphylococcusin the water troughs. Water lines typically showed no bacterial growth in culture-based assays. Ducks housed with water troughs used greater (P=0.001) volumes of water compared to ducks housed with water lines. Ducks with water troughs also showed a greater percent (P=0.008) mortality at all ages compared to ducks with water lines. These data suggest that water troughs may not be beneficial for duck welfare and could adversely impact both environment and duck or human health. PMID- 26769273 TI - Maintenance valine, isoleucine, and tryptophan requirements for poultry. AB - Poultry maintenance requirements for valine, isoleucine, and tryptophan were measured by nitrogen balance using different unit systems. The nitrogen balance trial lasted 5 d with 48 h of fasting (with roosters receiving only water+sucrose) and the last 72 h for feeding and excreta collection. Forty grams of each diet first-limiting in valine, isoleucine, or tryptophan was fed by tube each day (3 d) to give a range of intakes from 0 to 101, 0 to 119, and 0 to 34 mg/kg BW d of valine, isoleucine, and tryptophan, respectively. A nitrogen-free diet containing energy, vitamins, and minerals, meeting the rooster requirements, was offered ad libitum during these three d. To confirm that the amino acids studied were limiting, a treatment was added with a control diet formulated by adding 0.24 g/kg of L-valine, 0.21 g/kg of L-isoleucine, and 0.10 g/kg of L tryptophan to the diets with lower amino acid level. Excreta were collected during the last 3 d of the balance period and the nitrogen content of the excreta was analyzed. For each amino acid, a linear regression between nitrogen retention (NR) and amino acid intake was performed. The equations from linear regression were: NR=-98.6 (+/-10.1)+2.4 (+/-0.2)*Val, NR=-46.9 (+/-7.1)+2.3 (+/-0.1)*Ile, NR=-39.5 (+/-7.7)+7.3 (+/-0.4)*Trp; where Val, Ile, and Trp are the intakes of valine, isoleucine, and tryptophan in mg/kg body weight per d, respectively. The valine, isoleucine, and tryptophan required to maintain the body at zero NR were calculated to be 41, 20, and 5 mg/kg body weight per d, respectively. For the system unit mg per kg of metabolic weight, the intake of valine, isoleucine, and tryptophan was 59, 32, and 9, respectively. Considering the degree of maturity of the animal and body protein content (BPm (0.73)*u), the amounts of valine, isoleucine, and tryptophan required for maintenance were calculated to be 247, 134, and 37 mg per unit of maintenance protein (BPm (0.73)*u) per d. Maintenance requirement is more adequately expressed as body protein content. PMID- 26769274 TI - Transfer of bioactive compounds from pasture to meat in organic free-range chickens. AB - The aim of this study was to analyze the transfer of bioactive compounds from the pasture to the body and meat of organic free-range chickens and to verify the effect of these compounds on the oxidative processes of the meat. Starting at 21 d of age, 100 male naked-neck birds were divided into two homogeneous groups: an indoor group (0.12 m(2)/bird) and an outdoor group (0.12 m(2)/bird indoor and 10 m(2)/bird of forage paddock). At slaughter (81 d of age), blood samples were collected, and the carcasses were stored for 24 h at 4 degrees C (20 birds/group). The grass samples had higher values of carotenoids, tocopherols, and flavonoids respect to standard feed (based on dry matter comparison). The polyunsaturated fatty acid ( PUFA: ) content was also greater in grass, especially the n-3 series (so named because its first double bond occurs after the third carbon atom counting from the methyl at the end of the molecule). The antioxidant profile of the grass improved the antioxidant status of the crop and gizzard contents in the outdoor chickens. The higher antioxidant intake resulted in a higher plasma concentration of antioxidants in outdoor birds; thiobarbituric acid reactive substances ( TBARS: ) and the antioxidant capacity of the plasma were also better in the outdoor than the indoor group. The meat of the outdoor birds had higher levels of antioxidants, mainly due to the higher amount of tocopherols and tocotrienols. Despite the higher antioxidant protection in the drumstick of the outdoor group, the TBARs value was greater, probably due to the kinetic activity of birds, the higher percentage of PUFAs, and the peroxidability index. In conclusion, grazing improved the nutritional value of the meat (PUFA n 3 and the ratio between n-6 and n-3 PUFA) with a minor negative effect on the oxidative stability. Suitable strategies to reduce such negative effects (e.g., reduction of kinetic activity in the last days of rearing) should be studied. PMID- 26769275 TI - Single TRAM domain RNA-binding proteins in Archaea: functional insight from Ctr3 from the Antarctic methanogen Methanococcoides burtonii. AB - TRAM domain proteins present in Archaea and Bacteria have a beta-barrel shape with anti-parallel beta-sheets that form a nucleic acid binding surface; a structure also present in cold shock proteins (Csps). Aside from protein structures, experimental data defining the function of TRAM domains is lacking. Here, we explore the possible functional properties of a single TRAM domain protein, Ctr3 (cold-responsive TRAM domain protein 3) from the Antarctic archaeon Methanococcoides burtonii that has increased abundance during low temperature growth. Ribonucleic acid (RNA) bound by Ctr3 in vitro was determined using RNA seq. Ctr3-bound M. burtonii RNA with a preference for transfer (t)RNA and 5S ribosomal RNA, and a potential binding motif was identified. In tRNA, the motif represented the C loop; a region that is conserved in tRNA from all domains of life and appears to be solvent exposed, potentially providing access for Ctr3 to bind. Ctr3 and Csps are structurally similar and are both inferred to function in low temperature translation. The broad representation of single TRAM domain proteins within Archaea compared with their apparent absence in Bacteria, and scarcity of Csps in Archaea but prevalence in Bacteria, suggests they represent distinct evolutionary lineages of functionally equivalent RNA-binding proteins. PMID- 26769277 TI - Deep intronic mis-splicing mutation in JAK3 gene underlies T-B+NK- severe combined immunodeficiency phenotype. AB - Severe combined immune deficiency (SCID) is a group of genetically heterogeneous diseases caused by an early block in T cell differentiation and present with life threatening infections, often within the first year of life. Janus kinase (JAK)3 gene mutations have been found to cause autosomal recessive T-B+ SCID phenotype. In this study we describe three patients with a novel deep intronic mis-splicing mutation in JAK3 as a cause of T-B+NK- SCID highlighting the need for careful evaluation of intronic regulatory elements of known genes associated with clearly defined clinical phenotypes. We present the cases and discuss the current literature. PMID- 26769276 TI - Uncoupling complement C1s activation from C1q binding in apoptotic cell phagocytosis and immunosuppressive capacity. AB - Complement activation contributes to inflammation in many diseases, yet it also supports physiologic apoptotic cells (AC) clearance and its downstream immunosuppressive effects. The roles of individual complement components in AC phagocytosis have been difficult to dissect with artificially depleted sera. Using human in vitro systems and the novel antibody complement C1s inhibitor TNT003, we uncoupled the role of the enzymatic activation of the classical pathway from the opsonizing role of C1q in mediating a) the phagocytosis of early and late AC, and b) the immunosuppressive capacity of early AC. We found that C1s inhibition had a small impact on the physiologic clearance of early AC, leaving their immunosuppressive properties entirely unaffected, while mainly inhibiting the phagocytosis of late apoptotic/secondary necrotic cells. Our data suggest that C1s inhibition may represent a valuable therapeutic strategy to control classical pathway activation without causing significant AC accumulation in diseases without defects in AC phagocytosis. PMID- 26769278 TI - The Importance of Being Me: Magic Methyls, Methyltransferase Inhibitors, and the Discovery of Tazemetostat. AB - Posttranslational methylation of histones plays a critical role in gene regulation. Misregulation of histone methylation can lead to oncogenic transformation. Enhancer of Zeste homologue 2 (EZH2) methylates histone 3 at lysine 27 (H3K27) and abnormal methylation of this site is found in many cancers. Tazemetostat, an EHZ2 inhibitor in clinical development, has shown activity in both preclinical models of cancer as well as in patients with lymphoma or INI1 deficient solid tumors. Herein we report the structure-activity relationships from identification of an initial hit in a high-throughput screen through selection of tazemetostat for clinical development. The importance of several methyl groups to the potency of the inhibitors is highlighted as well as the importance of balancing pharmacokinetic properties with potency. PMID- 26769279 TI - APIC survey finds U.S. healthcare facilities are more prepared to confront Ebola compared to last year: Staffing and infection control resources remain issues. PMID- 26769280 TI - Factors influencing nurse compliance with Standard Precautions. AB - BACKGROUND: Exposure to blood and bodily fluids represents a significant occupational risk for nurses. The most effective means of preventing bloodborne pathogen transmission is through adherence to Standard Precautions (SP). Despite published guidelines on infection control and negative health consequences of noncompliance, significant issues remain around compliance with SP to protect nurses from bloodborne infectious diseases, including hepatitis B virus, hepatitis C virus (HCV), and HIV. METHODS: A descriptive correlational study was conducted that measured self-reported compliance with SP, knowledge of HCV, and perceived susceptibility and severity of HCV plus perceived benefits and barriers to SP use. Relationships between the variables were examined. Registered nurses (N = 231) working in ambulatory settings were surveyed. RESULTS: Fewer than one fifth (17.4%) of respondents reported compliance with all 9 SP items. Mean score for correct responses to the HCV knowledge test was 81%. There was a significant relationship between susceptibility of HCV and compliance and between barriers to SP use and compliance. CONCLUSIONS: This study explored reasons why nurses fail to adopt behaviors that protect them and used the Health Belief Model for the theoretical framework. It concentrated on SP and HCV because more than 5 million people in the United States and 200 million worldwide are infected with HCV, making it 1 of the greatest public health threats faced in this century. Understanding reasons for noncompliance will help determine a strategy for improving behavior and programs that target the aspects that were less than satisfactory to improve overall compliance. It is critical to examine factors that influence compliance to encourage those that will lead to total compliance and eliminate those that prevent it. PMID- 26769281 TI - Preventing and controlling human noroviruses in South Carolina long-term care facilities: An analysis of institutional policies and procedures. AB - BACKGROUND: Long-term care (LTC) facilities are the number one setting for human norovirus (HuNoV) outbreaks in the United States (60%). METHODS: We aimed to determine alignment of policies and procedures in LTC facilities in South Carolina with Centers for Disease Control and Prevention (CDC) recommendations and to determine readability based on Federal Plain Language Guidelines and Microsoft Word readability statistics. RESULTS: Most facilities (n = 21) had procedures for hand hygiene, but recommendations for handwashing events and duration varied greatly. Less than half (n = 11) had separate procedures devoted to HuNoV outbreak control. Fifteen required disinfection of bodily fluids. Seven had procedures for exclusion of sick staff during an outbreak. Both hand hygiene and bodily fluid cleanup procedures had low mean scores for readability. Mean Flesch Reading Ease and Flesch-Kincaid Grade Level for both procedures were in the range of difficult to understand. CONCLUSION: Most LTC policies and procedures were not consistent with CDC recommendations for HuNoV. Moreover, readability of all procedures is needed so LTC workers can easily understand and implement prevention and control procedures. PMID- 26769282 TI - Adding innovative practices and technology to central line bundle reduces bloodstream infection rate in challenging pediatric population. AB - A specialized pediatric hospital serves many patients with short bowel syndrome. The patients' fecal residue plus frequent access of intravenous lines increases bloodstream infection (BSI) risk. To reduce BSIs, the hospital first implemented an alcohol-dispensing disinfection cap and then added 3 more interventions, with both the cap-only phase and the multipronged phase successfully lowering the hospital's BSI rate. PMID- 26769283 TI - Increasing the efficiency of a targeted methicillin-resistant Staphylococcus aureus screening program. AB - An interdisciplinary team implemented a screening program targeting patients with a history of methicillin-resistant Staphylococcus aureus (MRSA), to reduce unnecessary contact isolation. After converting from a 2-step culture-based protocol to single polymerase chain reaction (PCR) testing, we increased the efficiency of the screening program from 77% to 100%. Despite the higher cost of PCR-based testing, this program remained cost-saving. PMID- 26769284 TI - Pilot testing and validation of an atopic dermatitis screening and evaluation questionnaire. AB - BACKGROUND: Atopic dermatitis (AD) is a major public health concern worldwide. Given its rising prevalence, there is a pressing need to study its epidemiology. To date, no validated, cost-effective, and patient self-administered screening instrument exists that can reliably distinguish AD from other skin conditions. Our aim is to develop an instrument that can validate a self-reported AD diagnosis quickly and with reasonable accuracy in a population at a distance. METHODS: A one-page, 13-question atopic dermatitis screening and evaluation questionnaire (ADSEQ) was generated after literature review and consultation with dermatologists. The questionnaire was administered to 121 patients with and without AD in a dermatology clinic. Sensitivity, specificity, positive predictive value, and negative predictive value were calculated for all questions. The questions with the highest sensitivities were selected for logistic regression analysis, and a receiver operating characteristics curve was plotted. RESULTS: Four scoring algorithms using different combinations of responses were then developed. A combination of Q7 (itching) and Qpic (the image questions combined) had the highest sensitivity (96.3%) and specificity (84%) for a diagnosis of AD. Cronbach's alpha coefficient was 0.71, indicating acceptable internal consistency. Other algorithms combining Qpic and questions about past diagnosis (Q1) or family history of atopy (Q5) also had sensitivities and specificities in the 80s or 90s. CONCLUSIONS: In this pilot study, we found that our questionnaire was a valid and reliable self-administered tool for distinguishing individuals with AD from individuals without AD. PMID- 26769292 TI - Summing up 2015. PMID- 26769291 TI - The effect of two different GH dosages on final height and bone geometry. AB - BACKGROUND: Growth hormone (GH) has a strong positive influence on bone, stimulating both bone elongation and increase in size. The aim of the study was to compare the effect of two different GH dosages on final height and bone geometry in two groups of GH-deficient children. METHODS: We evaluated 121 children (86 m, 35f). Group 1 (77 patients) treated with GH at a mean dose of 0.16 mg/kg/week and group 2 (44 patients) at 0.3 mg/kg/week. Bone geometry was evaluated at final height from a digitalized X-ray of the left hand considering the following parameters: metacarpal index (MI), cross-sectional area (CSA), cortical area (CA) and medullary area (MA). RESULTS: At baseline, group 2 was shorter than group 1 (-1.54 vs -1.01 SDS; p < 0.005), while at final height there was no difference. Height gain was significantly greater in group 2 than in group 1 (1.62 vs 1.13 SDS; p < 0.001). Bone geometry: MI was significantly greater in group 2 (0.62 vs 0.55; p < 0.001) as well as CA (46.87 vs 42.69 cm(2); p < 0.005), while MA was significantly lower in group 2 (8.48 vs 11.65 cm(2); p < 0.002). CONCLUSION: Higher GH doses elicit a significantly greater statural gain and a greater bone cortical area. PMID- 26769296 TI - On-resin macrocycles with the help from a Friend--Histidine. PMID- 26769293 TI - Imaging and Right Ventricular Pacing Lead Position: A Comparison of CT, MRI, and Echocardiography. AB - BACKGROUND: Right ventricular nonapical (RVNA) pacing may reduce the risk of heart failure. Fluoroscopy is the standard approach to determine lead tip position, but is inaccurate. We compared cardiac computed tomography (CT), magnetic resonance imaging (MRI), two-dimensional and three-dimensional transthoracic echocardiography (TTE), and chest x-ray (CXR) to assess which provides the optimal assessment of right ventricular (RV) lead tip position. METHODS: Eighteen patients with MRI-conditional pacemakers (10 RVNA and eight apical [RVA] leads) underwent contrast CT, MRI, TTE, and a standard postimplant posteroanterior and lateral CXR. To compare images, the RV was arbitrarily partitioned into three long-axis segments (right ventricular outflow tract, middle, and apex), and two short-axis segments (septal and nonseptal). Agreement between modalities was assessed. RESULTS: RV lead tip position was identified in all patients on CT, TTE, and CXR, but was not identified in seven (39%) patients on MRI due to device-related artifact. Of 10 leads deemed to be nonapical/septal during implant, 70% were identified as nonapical on CXR, 60% on CT, 60% on MRI, and 80% on TTE. On CT imaging only 10% were truly septal, 20% on MRI, 30% on CXR, and 80% on TTE. Agreement was better between modalities when assessing position of the designated RVA leads. CONCLUSION: During implant leads intended for the septum are not confirmed as such on subsequent imaging, and marked heterogeneity is apparent between modalities. MRI is limited by artifact, and discrepancy exists between TTE and CT in identifying septal lead position. CT gave the clearest definition of lead tip position. PMID- 26769297 TI - Comparison of graft-versus-host disease-free, relapse-free survival of transplantation using matched sibling donor, matched unrelated donor or unrelated cord blood after myeloablative conditioning for adult patients with hematological malignancies. AB - The novel composite endpoint of graft-versus-host disease/relapse-free survival (GRFS) was proposed to evaluate ideal healthy recovery without ongoing morbidity in patients undergoing allogeneic hematopoietic cell transplantation (HCT). We herein analyzed long-term GRFS based on the data of 256 patients with hematological malignancies who underwent allogeneic HCT after myeloablative conditioning. The probabilities of GRFS in the entire cohort were 60.1% at 1 year, and 48.6% at 5 years. Compared with unrelated cord blood, the probability of treatment failure as defined by GRFS at 5 years was similar with matched sibling donor (hazard ratio [HR]: 1.33; p = 0.28), but was significantly higher with matched unrelated donor (HR: 1.96; p = 0.01) in multivariate analysis. Unrelated cord blood achieved the highest proportion of patients who had not experienced any GRFS events at 5 years. These data suggest that long-term GRFS after HCT was similar in matched sibling donor recipients to unrelated cord blood recipients. PMID- 26769298 TI - Prevention and rehabilitation of osteoporosis. AB - Osteoporosis is a frequent disease in postmenopausal women. Despite the fact that fragility fractures cause many problems, osteoporosis is still underdiagnosed and undertreated. This manuscript outlines the topics diagnosis of osteoporosis, fracture risk prevention, and therapy after fracture. Regular physical activities, a sufficient intake of calcium, and a normal vitamin D level are important for bone health. Depending on the personal fracture risk, the patient may also be prescribed bone-specific medication to prevent fragility fractures. In case of a prevalent osteoporotic fracture, the initiation or adaptation of bone-specific therapy is indispensable. Since most osteoporotic fractures occur during a fall, fall risk reduction is an important measure to inhibit a new fracture. Rehabilitation of patients with fragility fractures varies with different localizations of the fracture and should be performed by a multidisciplinary team. PMID- 26769299 TI - Expert consensus on maintenance treatment for metastatic colorectal cancer in China. AB - The impact of maintenance therapy on progression-free survival and overall survival as well as quality of life of Chinese patients with metastatic colorectal cancer has long been under discussion. Recently, some phase III clinical trials have revealed that maintenance therapy can significantly prolong the progression-free survival while maintain an acceptable safety profile. Based on this evidence and common treatment practice in China, we now generated one Expert Consensus on Maintenance Treatment for Metastatic Colorectal Cancer in China to further specify the necessity of maintenance therapy, suitable candidates for such treatment, and appropriate regimens. PMID- 26769301 TI - Expression of GRIM-19 in adenomyosis and its possible role in pathogenesis. AB - OBJECTIVE: To study the expression of the gene associated with retinoid interferon (IFN)-induced mortality 19 (GRIM-19) in the endometrial tissue of patients with adenomyosis and to describe the possible pathogenic mechanisms of this phenomenon. DESIGN: Experimental study using human samples and cell lines. SETTING: University-affiliated hospital. PATIENT(S): Ectopic and eutopic endometrial tissues were obtained from 30 patients with adenomyosis, whereas normal endometrial specimens were obtained from 10 control patients without adenomyosis. INTERVENTION(S): Patients with rapid pathology report-confirmed adenomyosis were recruited, and eutopic and ectopic endometrial tissue samples were collected from patients who had undergone hysterectomies by either the transabdominal or laparoscopic method at Qilu Hospital. Normal endometrial tissue was collected from a group of control patients without adenomyosis. MAIN OUTCOME MEASURE(S): Immunohistochemistry (IHC) was performed to evaluate the expression of GRIM-19, phospho-signal transducer and activator of transcription 3 (Y705) (Y705) (pSTAT3(Y705)), and vascular endothelial growth factor (VEGF) in endometrial tissue samples. The protein levels of GRIM-19, pSTAT3(Y705), STAT3, and VEGF were detected by Western blot. Apoptosis in endometrial specimens was assayed by TUNEL. Immunohistochemistry with an antibody directed against CD34 was performed to detect new blood vessels in the endometrial tissue. GRIM-19 small interfering RNA and a recombinant plasmid carrying GRIM-19 were constructed to evaluate the effects of GRIM-19 on the downstream factors pSTAT3(Y705), STAT3, and VEGF in Ishikawa cells. RESULT(S): The expression of GRIM-19 was down regulated in the eutopic endometria of patients with adenomyosis compared with the endometria of patients in the control group, and it was further reduced in the endometrial glandular epithelial cells of adenomyotic lesions. Apoptosis was reduced in the eutopic endometrium compared with the control group, and it was significantly reduced in ectopic endometrial tissues. In addition, the ectopic and eutopic endometria of patients with adenomyosis displayed a much higher microvessel density. In the eutopic and ectopic endometria of patients with adenomyosis, the expression levels of pSTAT3(Y705) and VEGF were significantly higher than in the controls. Furthermore, down-regulation of GRIM-19 in Ishikawa cells significantly promoted the activation of both pSTAT3(Y705) and its dependent gene VEGF. CONCLUSION(S): Aberrant expression of GRIM-19 may be associated with adenomyosis through the regulation of apoptosis and angiogenesis. PMID- 26769300 TI - Factors affecting pregnancy outcomes in young women treated with fertility preserving therapy for well-differentiated endometrial cancer or atypical endometrial hyperplasia. AB - BACKGROUND: Patients hoping to preserve their fertility receive conservative treatment with high-dose medroxyprogesterone acetate (MPA) for well differentiated endometrioid adenocarcinoma (EC) or atypical endometrial hyperplasia (AEH) . Such treatment generally involves frequent intrauterine operations, including dilation and curettage (D&C) and endometrial biopsy (EMB), which could result in endometritis, endometrial thinning, or intrauterine adhesion. In turn, any of these outcomes could adversely affect implantation and pregnancy development. The current study thus aimed to identify factors that might affect pregnancy following conservative treatment by MPA. METHODS: We compared a pregnancy group (45 patients) with a non-pregnancy group (53 patients) of MPA-treated patients to evaluate the factors affecting clinical pregnancy establishment. We undertook a multivariate logistic regression analysis based on factors shown by univariate analysis to be significantly different between the groups. Univariate analysis identified number of D&C, endometrial thickness, duration of MPA administration, age of pregnancy permission (the age at which a patient was first allowed to attempt pregnancy after disappearance of the lesion), period of disappearance of lesions, and recurrence as independent variables. RESULTS: The odds ratios (95 % confidence interval) of multivariate analysis for disease recurrence, endometrial thickness during ovulation, and age of pregnancy permission were 0.283 (0.102-0.785), 1.677 (1.251-2.248), and 0.889 (0.792-0.998), respectively. There was no significant difference in the other independent variables between groups. CONCLUSIONS: We identified three factors considered to affect pregnancy establishment following conservative treatment with MPA: recurrence, endometrial thickness during ovulation, and the age of the pregnancy permission. Introduction of infertility treatment including assisted reproductive technology (ART) soon after achieving tumor disappearance by MPA would therefore be beneficial for patients with disease recurrence, thin endometrium, or a higher age of pregnancy permission. PMID- 26769302 TI - Comparative assessment of five serum antimullerian hormone assays for the diagnosis of polycystic ovary syndrome. AB - OBJECTIVE: To determine whether the different antimullerian hormone (AMH) immunoassays on the market offer the same performance for the diagnosis of polycystic ovary syndrome (PCOS). DESIGN: A total of 95 serum AMH samples were retrospectively evaluated for a period of 3 months in the same laboratory. SETTING: Academic center laboratory. PATIENT(S): Forty-eight control women with regular menses and no hyperandrogenism and 47 patients with classic PCOS (i.e., hyperandrogenism plus oligoanovulation) attending our department for infertility. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): AMH measurement using five commercial assays. Method comparison and evaluation of the diagnostic performance by receiver operating characteristic analysis. RESULT(S): Values obtained with Gen II and AL-105i ELISAs were similar to those provided by EAI AMH/MIS, whereas automatic assays generated lower values. A significant mean difference was observed between Access Dxi (1.35 ng/mL) or Cobas (1.73 ng/mL) and EIA AMH/MIS ELISA. By ROC analysis each assay displayed similar efficiency for PCOS diagnosis. Sensitivities varied from 49% to 74% when setting the specificity at 92%. Cluster analysis run in the control group identified a subgroup of asymptomatic women with polycystic ovary morphology (PCOM). After exclusion of PCOM, the 95th percentile of controls was 4.2 ng/mL (30 pmol/L) with the automatic assays and 5.6 ng/mL (40 pmol/L) with the manual assays. CONCLUSION(S): Performance of the different AMH assays for PCOS diagnosis is comparable, providing that different threshold values are used for manual and automatic assays. Measurement of serum AMH level appears as a robust tool for the definition of PCOM. PMID- 26769303 TI - Oral follicle-stimulating hormone agonist tested in healthy young women of reproductive age failed to demonstrate effect on follicular development but affected thyroid function. AB - OBJECTIVE: To assess the safety, pharmacokinetics, and pharmacodynamics of MK 8389. DESIGN: Double-blind, placebo-controlled, parallel-group, ascending dose study. SETTING: Two clinical research organizations. PATIENT(S): Healthy young women. INTERVENTION(S): Once-daily oral doses of MK-8389 or placebo for 14 days. MAIN OUTCOME MEASURE(S): Safety, including thyroid function tests (TFTs), pharmacokinetics, and follicular development (follicle size and number and serum E2 and inhibin B levels). RESULT(S): Treatment with MK-8389 was generally safe and well tolerated. An effect on TFTs was observed, which was transient and did not lead to clinical signs or symptoms but prevented dose escalation above 40 mg. MK-8389 was rapidly absorbed, slowly eliminated, and showed a large peak-to trough ratio. No clinically meaningful effect was seen on follicle size and numbers, which was consistent with the low E2 levels. At doses >20 mg, inhibin B levels were increased, suggesting early follicular development at higher doses. CONCLUSION(S): Oral administration of MK-8389 demonstrated acceptable systemic exposure and was generally well tolerated. This study failed to demonstrate a clinically meaningful effect of MK-8389 on follicular development, whereas MK 8389 unexpectedly affected thyroid function. This study did not explore doses above 40 mg given the changes observed in TFTs, which may relate to high MK-8389 peak concentrations. CLINICAL TRIAL REGISTRATION NUMBER: EudraCT Number 2010 022396-57. PMID- 26769304 TI - Long-chain polyunsaturated fatty acid biosynthesis in chordates: Insights into the evolution of Fads and Elovl gene repertoire. AB - Long-chain polyunsaturated fatty acids (LC-PUFA) are major components of complex lipid molecules and are also involved in numerous critical biological processes. Studies conducted mainly in vertebrates have demonstrated that LC-PUFA can be biosynthesized through the concerted action of two sets of enzymes, namely fatty acyl desaturases (Fads) and elongation of very long-chain fatty acid (Elovl) proteins. While LC-PUFA research is a thriving field, mainly focused on human health, an integrated view regarding the evolution of LC-PUFA biosynthetic genetic machinery in chordates is yet to be produced. Particularly important is to understand whether lineage specific life history trajectories, as well as major biological transitions, or particular genomic processes such as genome duplications have impacted the evolution of LC-PUFA biosynthetic pathways. Here we review the gene repertoire of Fads and Elovl in chordate genomes and the diversity of substrate specificities acquired during evolution. We take advantage of the magnitude of genomic and functional data to show that combination duplication processes and functional plasticity have generated a wide diversity of physiological capacities in extant lineages. A clear evolutionary framework is provided, which will be instrumental for the full clarification of functional capacities between the various vertebrate groups. PMID- 26769306 TI - Organ Damage and Quality of Life in Antiphospholipid Syndrome. AB - Antiphospholipid syndrome (APS) affects young patients in the most productive years of their life, and the consequences of organic or tissue damage involve a decrease in health-related quality of life (HRQoL). While acute disease manifestations of APS are well known, information on the long-term prognosis and damage in affected patients is still very limited. Systemic lupus erythematosus (SLE) patients would be expected to experience long-term complications and even die as a consequence of APS. Organ damage in APS has been evaluated using different methods and definitions, including the SLICC/ACR Damage Index (SDI), which tend to underestimate aPL-related damage. A new damage index in APS has been proposed (DIAPS), and it seems to be more accurate than SDI. Given the implications for morbidity and mortality, it is imperative to assess accurately aPL-related damage and HRQoL in patients with APS. PMID- 26769305 TI - Graphene-based platforms for cancer therapeutics. AB - Graphene is a multifunctional carbon nanomaterial and could be utilized to develop platform technologies for cancer therapies. Its surface can be covalently and noncovalently functionalized with anticancer drugs and functional groups that target cancer cells and tissue to improve treatment efficacies. Furthermore, its physicochemical properties can be harnessed to facilitate stimulus responsive therapeutics and drug delivery. This review article summarizes the recent literature specifically focused on development of graphene technologies to treat cancer. We will focus on advances at the interface of graphene based drug/gene delivery, photothermal/photodynamic therapy and combinations of these techniques. We also discuss the current understanding in cytocompatibility and biocompatibility issues related to graphene formulations and their implications pertinent to clinical cancer management. PMID- 26769307 TI - Current Research in Outcome Measures for Pediatric Rheumatic and Autoinflammatory Diseases. AB - A rational management of children and adolescents with rheumatic and autoinflammatory diseases requires the regular assessment of the level of disease activity and of child health and well-being through the use of well-validated outcome measures. Ideally, such instruments should be simple and feasible and easily applicable in standard clinical practice. In recent years, a number of novel outcome measures have been developed and validated for use in pediatric patients with rheumatic and autoinflammatory illnesses. Furthermore, there has been an increased focus on the appraisal of child and parent perception of the disease impact. The new tools have markedly enlarged the spectrum of disorders and health domains that can be assessed in a standardized way. This progress will help to enhance the reliability of research studies and clinical trials. The aim of the present review is to provide an update of the recent advances in this field of research. PMID- 26769309 TI - Will reduced host connectivity curb the spread of a devastating epidemic? AB - The white-nose syndrome (WNS), caused by the fungal pathogen Pseudogymnoascus destructans, is threatening the cave-dwelling bat fauna of North America by killing individuals by the thousands in hibernacula each winter since its appearance in New York State less than ten years ago. Epidemiological models predict that WNS will reach the western coast of the USA by 2035, potentially eliminating most populations of susceptible bat species in its path (Frick et al. 2015; O'Regan et al. 2015). These models were built and validated using distributional data from the early years of the epidemic, which spread throughout eastern North America following a route driven by cave density and winter severity (Maher et al. 2012). In this issue of Molecular Ecology, Wilder et al. (2015) refine these findings by showing that connectivity among host populations, as assessed by population genetic markers, is crucial in determining the spread of the pathogen. Because host connectivity is much reduced in the hitherto disease free western half of North America, Wilder et al. make the reassuring prediction that the disease will spread more slowly west of the Great Plains. PMID- 26769308 TI - Causality of Chlamydiae in Arthritis and Spondyloarthritis: a Plea for Increased Translational Research. AB - Current molecular genetic understanding of the metabolically active persistent infection state of Chlamydia trachomatis and Chlamydia pneumoniae in the synovium in patients with arthritis and spondyloarthritis favors a causal relationship. Here, we examine how adequately the accepted criteria for that etiologic relationship are fulfilled, emphasizing the situation in which these microorganisms cannot be cultivated by standard or other means. We suggest that this unusual situation of causality by chlamydiae in rheumatic disease requires establishment of a consensus regarding microorganism-specific terminology as well as the development of new diagnostic and classification criteria. Recent studies demonstrate the value of molecular testing for diagnosis of reactive arthritis, undifferentiated spondyloarthritis, and undifferentiated arthritis caused by C. trachomatis and C. pneumoniae in clinical practice. Data regarding combination antibiotic therapy is consistent with the causative role of chlamydiae for these diseases. Observations of multiple intra-articular coinfections require more research to understand the implications and to respond to them. PMID- 26769312 TI - [Skin and aging]. PMID- 26769311 TI - [Environmentally induced (extrinsic) skin aging]. AB - Chronic exposure to ultraviolet light, particularly as a component of natural sunlight, is a major cause of environmentally induced aging of the skin. In addition, other environmental factors for premature skin aging include longer wavelength radiation in the visible light region and in particular in the shortwave infrared radiation region. Furthermore, particulate and gaseous components of air pollution significantly contribute to the aging process. PMID- 26769313 TI - [Definitions for wound treatment]. PMID- 26769315 TI - The Theater of War: What Ancient Greek Tragedies Can Teach Us Today by Bryan Doerries, Alfred A. Knopf, 2015. PMID- 26769314 TI - The two pore channel TPC2 is dispensable in pancreatic beta-cells for normal Ca2+ dynamics and insulin secretion. AB - Ca(2+) signals are central to the stimulation of insulin secretion from pancreatic beta-cells by glucose and other agents, including glucagon-like peptide-1 (GLP-1). Whilst Ca(2+) influx through voltage-gated Ca(2+) channels on the plasma membrane is a key trigger for glucose-stimulated secretion, mobilisation of Ca(2+) from acidic stores has been implicated in the control of more localised Ca(2+) changes and membrane potential. Nicotinic acid adenine dinucleotide phosphate (NAADP), generated in beta-cells in response to high glucose, is a potent mobiliser of these stores, and has been proposed to act through two pore channels (TPC1 and TPC2, murine gene names Tpcn1 and Tpcn2). Whilst the role of TPC1 in the control of Ca(2+) mobilisation and insulin secretion was recently confirmed, conflicting data exist for TPC2. Here, we used the selective and efficient deleter strain, Ins1Cre to achieve beta-cell selective deletion of the Tpcn2 gene in mice. betaTpcn2 KO mice displayed normal intraperitoneal and oral glucose tolerance, and glucose-stimulated Ca(2+) dynamics and insulin secretion from islets were similarly normal. GLP-1-induced Ca(2+) increases involved an increase in oscillation frequency from 4.35 to 4.84 per minute (p=0.04) at 8mM glucose, and this increase was unaffected by the absence of Tpcn2. The current data thus indicate that TPC2 is not absolutely required for normal glucose- or incretin-stimulated insulin secretion from the beta-cell. Our findings suggest that TPC1, whose expression tended to increase in Tpcn2 null islets, might be sufficient to support normal Ca(2+) dynamics in response to stimulation by nutrients or incretins. PMID- 26769317 TI - Realizing privacy preserving genome-wide association studies. AB - MOTIVATION: As genomics moves into the clinic, there has been much interest in using this medical data for research. At the same time the use of such data raises many privacy concerns. These circumstances have led to the development of various methods to perform genome-wide association studies (GWAS) on patient records while ensuring privacy. In particular, there has been growing interest in applying differentially private techniques to this challenge. Unfortunately, up until now all methods for finding high scoring SNPs in a differentially private manner have had major drawbacks in terms of either accuracy or computational efficiency. RESULTS: Here we overcome these limitations with a substantially modified version of the neighbor distance method for performing differentially private GWAS, and thus are able to produce a more viable mechanism. Specifically, we use input perturbation and an adaptive boundary method to overcome accuracy issues. We also design and implement a convex analysis based algorithm to calculate the neighbor distance for each SNP in constant time, overcoming the major computational bottleneck in the neighbor distance method. It is our hope that methods such as ours will pave the way for more widespread use of patient data in biomedical research. AVAILABILITY AND IMPLEMENTATION: A python implementation is available at http://groups.csail.mit.edu/cb/DiffPriv/ CONTACT: bab@csail.mit.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26769318 TI - Reducing health inequalities among girls and adolescent women living in poverty: the success of Bangladesh. AB - BACKGROUND: Bangladesh has made dramatic improvements in the health of girls and women in the last 20 years. This paper examines whether gender inequalities in health are evident among older children and adolescents among extremely poor households and identifies future health challenges for improving the health of girls and women. SUBJECTS AND METHODS: Gender inequalities in health were examined using data from a school health survey of school children and adolescents (n = 900, 6.5-13.5 years). Anthropometric status, household possessions and number of siblings were measured. Under-nutrition was assessed as stunting (height-for-age z-score) and thinness (BMI-for-age z-score). RESULTS: The prevalence of under-nutrition was high (35.3% stunting; 42.4% thinness), but there were no significant differences according to gender or socio-economic indicators (via possession score). Girls had more younger siblings (p < 0.05), while boys had more older siblings (p < 0.05). CONCLUSIONS: These findings accord with the national picture of successful reductions in gender inequalities in health through low cost, community-based health programmes and education policies targeting the poorest sectors. The prevalence of under-nutrition, however, remains high. Reproductive behaviours may still be influenced by poverty and the gender of existing offspring. Future challenges lie in reducing the adverse health consequences to women and their infants associated with early age at marriage and childbirth. PMID- 26769319 TI - Problems with treating snake bite in India. PMID- 26769320 TI - Facial Swelling in an Infant. PMID- 26769322 TI - The spiral ganglion and Rosenthal's canal in beluga whales. AB - With the increase of human activity and corresponding increase in anthropogenic sounds in marine waters of the Arctic, it is necessary to understand its effect on the hearing of marine wildlife. We have conducted a baseline study on the spiral ganglion and Rosenthal's canal of the cochlea in beluga whales (Delphinapterus leucas) as an initial assessment of auditory anatomy and health. We present morphometric data on the length of the cochlea, number of whorls, neuron densities along its length, Rosenthal's canal length, and cross-sectional area, and show some histological results. In belugas, Rosenthal's canal is not a cylinder of equal cross-sectional area, but its cross-section is greatest near the apex of the basal whorl. We found systematic variation in the numbers of neurons along the length of the spiral ganglion, indicating that neurons are not dispersed evenly in Rosenthal's canal. These results provide data on functionally important structural parameters of the beluga ear. We observed no signs of acoustic trauma in our sample of beluga whales. PMID- 26769321 TI - Serum retinol and pulmonary function in young people with cystic fibrosis. PMID- 26769324 TI - Does nursing represent a unique angle of vision? If so, what is it? PMID- 26769323 TI - Performance of pairwise shape dissimilarity morphometrics on nonmammalian taxa (Insecta: Neuroptera: Mantispidae). AB - Morphometric dissimilarity metrics aim to quantify the variation between compared specimens such that inferences about their relatedness and alpha taxonomy can be made. Recently, the technique has developed metrics that purport to quantify shape dissimilarity between specimens-employing the use of least squares regression analysis. These metrics have been well applied by studies in the hominin fossil record with an arguably unsubstantiated backing for the technique. Originally postulated was the log10 sem metric which subsequently led to the standard error test of the null hypothesis metric. Following this, the standard deviation of logged ratios (SLR ) metric arose as a pairwise dissimilarity metric that constrains the regression to a zero-intercept, that is, a significant development in the robustness of the technique. This metric was tested on extant primates in order to evaluate its effectiveness alongside the two other metrics. It was shown to be the most reliable for comparisons between specimens of primates, but was unable to discriminate between heterospecific and conspecific comparisons. Arguably, an alternative model organism with which to compare the technique is lacking. This study considers shape dissimilarity metrics with respect to a group of nonmammalian organisms (mantidflies) and tests the metrics against three lines of evidence (morphology, CO1-DNA, and geographic distribution) that can delimit the species-level taxonomy for the group. It is shown that the metrics are unable to discriminate between pairwise comparisons of closely related species, resulting in biologically erroneous groupings, and contradicting the groupings derived from morphological, CO1-DNA, and distributional comparisons. It is thus asserted that the technique is unsuitable for use in alpha taxonomy as an additional line of evidence in mantidflies. It is further supposed that morphometrics in general should be employed with caution in studies of evolutionary history as phylogeny is not the only information contained within morphometric data. PMID- 26769325 TI - Presbyopia: physiology, prevention and pathways to correction. PMID- 26769327 TI - Do small-aperture presbyopic corrections influence the visual field? AB - PURPOSE: To explore the effect of small-aperture optics, designed to aid presbyopes by increasing ocular depth-of-focus, on measurements of the visual field. METHODS: Simple theoretical and ray-tracing models were used to predict the impact of different designs of small-aperture contact lenses or corneal inlays on the proportion of light passing through natural pupils of various diameters as a function of the direction in the visual field. The left eyes of five healthy volunteers were tested using three afocal, hand-painted opaque soft contact lenses (www.davidthomas.com). Two were opaque over a 10 mm diameter but had central clear circular apertures of 1.5 and 3.0 mm in diameter. The third had an annular opaque zone with inner and outer diameters of 1.5 and 4.0 mm, approximately simulating the geometry of the KAMRA inlay (www.acufocus.com). A fourth, clear lens was used for comparison purposes. Visual fields along the horizontal meridian were evaluated up to 50 degrees eccentricity with static automated perimetry (Medmont M700, stimulus Goldmann-size III; www.medmont.com). RESULTS: According to ray-tracing, the two lenses with the circular apertures were expected to reduce the relative transmittance of the pupil to zero at specific field angles (around 60 degrees for the conditions of the experimental measurements). In contrast, the annular stop had no effect on the absolute field but relative transmittance was reduced over the central area of the field, the exact effects depending upon the natural pupil diameter. Experimental results broadly agreed with these theoretical expectations. With the 1.5 and 3.0 mm pupils, only minor losses in sensitivity (around 2 dB) in comparison with the clear-lens case occurred across the central 10 degrees radius of field. Beyond this angle, sensitivity losses increased, to reach about 7 dB at the edge of the measured field (50 degrees ). The field results with the annular stop showed at most only a slight loss in sensitivity (<=3 dB) across the measured field. CONCLUSION: The present theoretical and experimental results support earlier clinical findings that KAMRA-type annular stops, unlike circular artificial pupils, have only minor effects on measurements of the visual field. PMID- 26769328 TI - Winners in the 2014 Naylor Prize competition. PMID- 26769326 TI - Accommodative movements of the lens/capsule and the strand that extends between the posterior vitreous zonule insertion zone & the lens equator, in relation to the vitreous face and aging. AB - PURPOSE: To elucidate the dynamic accommodative movements of the lens capsule, posterior lens and the strand that attaches to the posterior vitreous zonule insertion zone and posterior lens equator (PVZ INS-LE), and their age-related changes. METHODS: Twelve human subjects (ages 19-65 years) and 12 rhesus monkeys (ages 6-27 years) were studied. Accommodation was induced pharmacologically (humans) or by central electrical stimulation (monkeys). Ultrasound biomicroscopy was used to image intraocular structures in both species. Surgical procedures and contrast agents were utilized in the monkey eyes to elucidate function and allow visualization of the intraocular accommodative structures. RESULTS: Human: The posterior pole of the lens moves posteriorly during accommodation in proportion to accommodative amplitude and ciliary muscle movement. Monkey: Similar accommodative movements of the posterior lens pole were seen in the monkey eyes. Following extracapsular lens extraction (ECLE), the central capsule bows backward during accommodation in proportion to accommodative amplitude and ciliary muscle movement, while the peripheral capsule moves forward. During accommodation the ciliary muscle moved forward by ~1.0 mm, pulling forward the vitreous zonule and the PVZ INS-LE structure. During the accommodative response the PVZ INS-LE structure moved forward when the lens was intact and when the lens substance and capsule were removed. In both the monkey and the human eyes these movements declined with age. CONCLUSIONS: The accommodative shape change of the central capsule may be due to the elastic properties of the capsule itself. For these capsule/lens accommodative posterior movements to occur, the vitreous face must either allow for it or facilitate it. The PVZ INS-LE structure may act as a 'strut' to the posterior lens equator (pushing the lens equator forward) and thereby facilitate accommodative forward lens equator movement and lens thickening. The age-related posterior restriction of the ciliary muscle, vitreous zonule and the PVZ-INS LE structure dampens the accommodative lens shape change. Future descriptions of the accommodative mechanism, and approaches to presbyopia therapy, may need to incorporate these findings. PMID- 26769329 TI - British Congress of Optometry and Visual Science, 7-8th September 2015, City University. PMID- 26769330 TI - Biomechanics of Step Initiation After Balance Recovery With Implications for Humanoid Robot Locomotion. AB - Balance-recovery stepping is often necessary for both a human and humanoid robot to avoid a fall by taking a single step or multiple steps after an external perturbation. The determination of where to step to come to a complete stop has been studied, but little is known about the strategy for initiation of forward motion from the static position following such a step. The goal of this study was to examine the human strategy for stepping by moving the back foot forward from a static, double-support position, comparing parameters from normal step length (SL) to those from increasing SLs to the point of step failure, to provide inspiration for a humanoid control strategy. Healthy young adults instrumented with joint reflective markers executed a prescribed-length step from rest while marker positions and ground reaction forces (GRFs) were measured. The participants were scaled to the Gait2354 model in opensim software to calculate body kinematic and joint kinetic parameters, with further post-processing in matlab. With increasing SL, participants reduced both static and push-off back foot GRF. Body center of mass (CoM) lowered and moved forward, with additional lowering at the longer steps, and followed a path centered within the initial base of support (BoS). Step execution was successful if participants gained enough forward momentum at toe-off to move the instantaneous capture point (ICP) to within the BoS defined by the final position of both feet on the front force plate. All lower extremity joint torques increased with SL except ankle joint. Front knee work increased dramatically with SL, accompanied by decrease in back ankle work. As SL increased, the human strategy changed, with participants shifting their CoM forward and downward before toe-off, thus gaining forward momentum, while using less propulsive work from the back ankle and engaging the front knee to straighten the body. The results have significance for human motion, suggesting the upper limit of the SL that can be completed with back ankle push-off before additional knee flexion and torque is needed. For biped control, the results support stability based on capture-point dynamics and suggest strategy for center-of-mass trajectory and distribution of ground force reactions that can be compared with robot controllers for initiation of gait after recovery steps. PMID- 26769331 TI - Natural Product-Based Antibiotics: Synthesis and SAR-Studies. AB - Efficient control of the infectious diseases in the era of the emerging bacterial resistance demands consistent development of new antibiotic agents with novel modes of action. With some notable exceptions, the majority of the currently used antibiotics are natural product-derived compounds which were elaborated upon lead structures discovered by screening of various isolates. In this review, we summarized some selected examples of recent advances in the area of natural product based antibiotic development with particular emphasis on the synthetic and SAR-elucidation aspects. PMID- 26769332 TI - A randomized, double-blind, placebo-controlled, dose-escalation study of the safety and efficacy of INCB039110, an oral janus kinase 1 inhibitor, in patients with stable, chronic plaque psoriasis. AB - BACKGROUND: Chronic plaque psoriasis is partially mediated by elevation of proinflammatory cytokines, including several within the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway. OBJECTIVE: To evaluate the safety and efficacy of the oral selective JAK1 inhibitor INCB039110 in stable, chronic plaque psoriasis. METHODS: This was a phase 2, randomized, double-blind, placebo-controlled, dose-escalation study of INCB039110 (100 mg once daily, 200 mg once daily, 200 mg twice daily and 600 mg once daily) for 28 days. The primary endpoint was mean percent change from baseline in the static Physician Global Assessment (sPGA) at day 28. The protocol was institutional review board approved. RESULTS: Of 50 patients, 48 completed the study. At day 28, mean percent reduction from baseline in sPGA was 22.2% for INCB039110 100 mg once daily (p = 0.270 vs. placebo), 29.4% for 200 mg once daily (p = 0.118), 35.2% for 200 mg twice daily (p = 0.053), 42.4% for 600 mg once daily (p = 0.003) and 12.5% for placebo. Across groups, 11.1% to 45.5% achieved an sPGA score of 1 versus 0% for placebo. INCB039110 was generally well tolerated; the most common treatment-emergent adverse event was nasopharyngitis (18.4%). CONCLUSION: INCB039110 produced significant improvements in sPGA, demonstrating proof of concept in chronic plaque psoriasis. PMID- 26769333 TI - Brain reactivity to alcohol and cannabis marketing during sobriety and intoxication. AB - Drugs of abuse stimulate striatal dopamine release and activate reward pathways. This study examined the impact of alcohol and cannabis marketing on the reward circuit in alcohol and cannabis users while sober and intoxicated. It was predicted that alcohol and cannabis marketing would increase striatal activation when sober and that reward sensitivity would be less during alcohol and cannabis intoxication. Heavy alcohol (n = 20) and regular cannabis users (n = 21) participated in a mixed factorial study involving administration of alcohol and placebo in the alcohol group and cannabis and placebo in the cannabis group. Non drug users (n = 20) served as between group reference. Brain activation after exposure to alcohol and cannabis marketing movies was measured using functional magnetic resonance imaging and compared between groups while sober and compared with placebo while intoxicated. Implicit alcohol and cannabis cognitions were assessed by means of a single-category implicit association test. Alcohol and cannabis marketing significantly increased striatal BOLD activation across all groups while sober. Striatal activation however decreased during intoxication with alcohol and cannabis. Implicit associations with cannabis marketing cues were significantly more positive in alcohol and cannabis users as compared with non-drug using controls. Public advertising of alcohol or cannabis use elicits striatal activation in the brain's reward circuit. Reduction of marketing would reduce brain exposure to reward cues that motivate substance use. Conversely, elevated dopamine levels protect against the reinforcing potential of marketing. PMID- 26769334 TI - Natural Language Search Interfaces: Health Data Needs Single-Field Variable Search. AB - BACKGROUND: Data discovery, particularly the discovery of key variables and their inter-relationships, is key to secondary data analysis, and in-turn, the evolving field of data science. Interface designers have presumed that their users are domain experts, and so they have provided complex interfaces to support these "experts." Such interfaces hark back to a time when searches needed to be accurate first time as there was a high computational cost associated with each search. Our work is part of a governmental research initiative between the medical and social research funding bodies to improve the use of social data in medical research. OBJECTIVE: The cross-disciplinary nature of data science can make no assumptions regarding the domain expertise of a particular scientist, whose interests may intersect multiple domains. Here we consider the common requirement for scientists to seek archived data for secondary analysis. This has more in common with search needs of the "Google generation" than with their single-domain, single-tool forebears. Our study compares a Google-like interface with traditional ways of searching for noncomplex health data in a data archive. METHODS: Two user interfaces are evaluated for the same set of tasks in extracting data from surveys stored in the UK Data Archive (UKDA). One interface, Web search, is "Google-like," enabling users to browse, search for, and view metadata about study variables, whereas the other, traditional search, has standard multioption user interface. RESULTS: Using a comprehensive set of tasks with 20 volunteers, we found that the Web search interface met data discovery needs and expectations better than the traditional search. A task * interface repeated measures analysis showed a main effect indicating that answers found through the Web search interface were more likely to be correct (F1,19=37.3, P<.001), with a main effect of task (F3,57=6.3, P<.001). Further, participants completed the task significantly faster using the Web search interface (F1,19=18.0, P<.001). There was also a main effect of task (F2,38=4.1, P=.025, Greenhouse-Geisser correction applied). Overall, participants were asked to rate learnability, ease of use, and satisfaction. Paired mean comparisons showed that the Web search interface received significantly higher ratings than the traditional search interface for learnability (P=.002, 95% CI [0.6-2.4]), ease of use (P<.001, 95% CI [1.2-3.2]), and satisfaction (P<.001, 95% CI [1.8-3.5]). The results show superior cross-domain usability of Web search, which is consistent with its general familiarity and with enabling queries to be refined as the search proceeds, which treats serendipity as part of the refinement. CONCLUSIONS: The results provide clear evidence that data science should adopt single-field natural language search interfaces for variable search supporting in particular: query reformulation; data browsing; faceted search; surrogates; relevance feedback; summarization, analytics, and visual presentation. PMID- 26769335 TI - Increased R2* in the Caudate Nucleus of Asymptomatic Welders. AB - Welding has been associated with neurobehavioral disorders. Welding fumes contain several metals including copper (Cu), manganese (Mn), and iron (Fe) that may interact to influence welding-related neurotoxicity. Although welding-related airborne Fe levels are about 10-fold higher than Mn, previous studies have focused on Mn and its accumulation in the basal ganglia. This study examined differences in the apparent transverse relaxation rates [R2* (1/T2*), estimate of Fe accumulation] in the basal ganglia (caudate nucleus, putamen, and globus pallidus) between welders and controls, and the dose-response relationship between estimated Fe exposure and R2* values. Occupational questionnaires estimated recent and lifetime Fe exposure, and blood Fe levels and brain magnetic resonance imaging (MRI) were obtained. Complete exposure and MRI R2* and R1 (1/T1: measure to estimate Mn accumulation) data from 42 subjects with welding exposure and 29 controls were analyzed. Welders had significantly greater exposure metrics and higher whole-blood Fe levels compared with controls. R2* in the caudate nucleus was significantly higher in welders after controlling for age, body mass index, respirator use, caudate R1, and blood metals of Cu and Mn, whereas there was no difference in R1 values in the basal ganglia between groups. The R2* in the caudate nucleus was positively correlated with whole-blood Fe concentration. This study provides the first evidence of higher R2* in the caudate nucleus of welders, which is suggestive of increased Fe accumulation in this area. Further studies are needed to replicate the findings and determine the neurobehavioral relevance. PMID- 26769337 TI - Molecular physiology of anion channels: dual function proteins and new structural motifs--a special issue. PMID- 26769338 TI - Erratum to: Plasma pharmacokinetics and synovial concentrations of S-flurbiprofen plaster in humans. PMID- 26769336 TI - Toxicological Assessment of CoO and La2O3 Metal Oxide Nanoparticles in Human Small Airway Epithelial Cells. AB - Cobalt monoxide (CoO) and lanthanum oxide (La2O3) nanoparticles are 2 metal oxide nanoparticles with different redox potentials according to their semiconductor properties. By utilizing these two nanoparticles, this study sought to determine how metal oxide nanoparticle's mode of toxicological action is related to their physio-chemical properties in human small airway epithelial cells (SAEC). We investigated cellular toxicity, production of superoxide radicals and alterations in gene expression related to oxidative stress, and cellular death at 6 and 24 h following exposure to CoO and La2O3(administered doses: 0, 5, 25, and 50 ug/ml) nanoparticles. CoO nanoparticles induced gene expression related to oxidative stress at 6 h. After characterizing the nanoparticles, transmission electron microscope analysis showed SAEC engulfed CoO and La2O3nanoparticles. CoO nanoparticles were toxic after 6 and 24 h of exposure to 25.0 and 50.0 ug/ml administered doses, whereas, La2O3nanoparticles were toxic only after 24 h using the same administered doses. Based upon the Volumetric Centrifugation Methodin vivoSedimentation, Diffusion, and Dosimetry, the dose of CoO and La2O3nanoparticles delivered at 6 and 24 h were determined to be: CoO: 1.25, 6.25, and 12.5 ug/ml; La2O3: 5, 25, and 50 ug/ml and CoO: 4, 20, and 40 ug/ml; and La2O3: 5, 25, 50 ug/ml, respectively. CoO nanoparticles produced more superoxide radicals and caused greater stimulation of total tyrosine and threonine phosphorylation at both 6 and 24 h when compared with La2O3nanoparticles. Taken together, these data provide evidence that different toxicological modes of action were involved in CoO and La2O3metal oxide nanoparticle-induced cellular toxicity. PMID- 26769339 TI - Erratum to: The Normal-Theory and Asymptotic Distribution-Free (ADF) Covariance Matrix of Standardized Regression Coefficients: Theoretical Extensions and Finite Sample Behavior. PMID- 26769340 TI - Generalized Fiducial Inference for Binary Logistic Item Response Models. AB - Generalized fiducial inference (GFI) has been proposed as an alternative to likelihood-based and Bayesian inference in mainstream statistics. Confidence intervals (CIs) can be constructed from a fiducial distribution on the parameter space in a fashion similar to those used with a Bayesian posterior distribution. However, no prior distribution needs to be specified, which renders GFI more suitable when no a priori information about model parameters is available. In the current paper, we apply GFI to a family of binary logistic item response theory models, which includes the two-parameter logistic (2PL), bifactor and exploratory item factor models as special cases. Asymptotic properties of the resulting fiducial distribution are discussed. Random draws from the fiducial distribution can be obtained by the proposed Markov chain Monte Carlo sampling algorithm. We investigate the finite-sample performance of our fiducial percentile CI and two commonly used Wald-type CIs associated with maximum likelihood (ML) estimation via Monte Carlo simulation. The use of GFI in high-dimensional exploratory item factor analysis was illustrated by the analysis of a set of the Eysenck Personality Questionnaire data. PMID- 26769341 TI - Prevalence of coronary artery disease and its risk factors in Kerala, South India: a community-based cross-sectional study. AB - BACKGROUND: There are no recent data on prevalence of coronary artery disease (CAD) in Indians. The last community based study from Kerala, the most advanced Indian state in epidemiological transition, was in 1993 that reported 1.4% definite CAD prevalence. We studied the prevalence of CAD and its risk factors among adults in Kerala. METHODS: In a community-based cross sectional study, we selected 5167 adults (mean age 51 years, men 40.1%) using a multistage cluster sampling method. Information on socio-demographics, smoking, alcohol use, physical activity, dietary habits and personal history of hypertension, diabetes, and CAD was collected using a structured interview schedule. Anthropometry, blood pressure, electrocardiogram, and biochemical investigations were done using standard protocols. CAD and its risk factors were defined using standard criteria. Comparisons of age adjusted prevalence were done using two tailed proportion tests. RESULTS: The overall age-adjusted prevalence of definite CAD was 3.5%: men 4.8%, women 2.6% (p < 0.001). Prevalence of any CAD was 12.5%: men 9.8%, women 14.3% (p < 0.001). There was no difference in definite CAD between urban and rural population. Physical inactivity was reported by 17.5 and 18% reported family history of CAD. Other CAD risk factors detected in the study were: overweight or obese 59%, abdominal obesity 57%, hypertension 28%, diabetes 15%, high total cholesterol 52% and low level of high density lipoprotein cholesterol 39%. Current smoking was reported only be men (28%). CONCLUSION: The prevalence of definite CAD in Kerala increased nearly three times since 1993 without any difference in urban and rural areas. Most risk factors of CAD were highly prevalent in the state. Both population and individual level approaches are warranted to address the high level of CAD risk factors to reduce the increasing prevalence of CAD in this population. PMID- 26769342 TI - Comparing the quality of pro- and anti-vaccination online information: a content analysis of vaccination-related webpages. AB - BACKGROUND: The exponential increase in health-related online platforms has made the Internet one of the main sources of health information globally. The quality of health contents disseminated on the Internet has been a central focus for many researchers. To date, however, few comparative content analyses of pro- and anti vaccination websites have been conducted, and none of them compared the quality of information. The main objective of this study was therefore to bring new evidence on this aspect by comparing the quality of pro- and anti-vaccination online sources. METHODS: Based on past literature and health information quality evaluation initiatives, a 40-categories assessment tool (Online Vaccination Information Quality Codebook) was developed and used to code a sample of 1093 webpages retrieved via Google and two filtered versions of the same search engine. The categories investigated were grouped into four main quality dimensions: web-related design quality criteria (10 categories), health-specific design quality criteria (3 categories), health related content attributes (12 categories) and vaccination-specific content attributes (15 categories). Data analysis comprised frequency counts, cross tabulations, Pearson's chi-square, and other inferential indicators. RESULTS: The final sample included 514 webpages in favor of vaccination, 471 against, and 108 neutral. Generally, webpages holding a favorable view toward vaccination presented more quality indicators compared to both neutral and anti-vaccination pages. However, some notable exceptions to this rule were observed. In particular, no differences were found between pro- and anti-vaccination webpages as regards vaccination-specific content attributes. CONCLUSIONS: Our analyses showed that the overall quality of pro-vaccination webpages is superior to anti-vaccination online sources. The developed coding scheme was proven to be a helpful and reliable tool to judge the quality of vaccination-related webpages. Based on the results, we advance recommendations for online health information providers as well as directions for future research in this field. PMID- 26769344 TI - Factors influencing the work efficiency of district health managers in low resource settings: a qualitative study in Ghana. AB - BACKGROUND: There is increasing evidence that good district management practices can improve health system performance and conversely, that poor and inefficient management practices have detrimental effects. The aim of the present study was to identify factors contributing to inefficient management practices of district health managers and ways to improve their overall efficiency. METHODS: Nineteen semi-structured interviews were conducted with district health managers in three districts of the Eastern Region in Ghana. The 19 interviews conducted comprised 90% of the managerial workforce in these districts in 2013. A thematic analysis was carried out using the WHO's leadership and management strengthening framework to structure the results. RESULTS: Key factors for inefficient district health management practices were identified to be: human resource shortages, inadequate planning and communication skills, financial constraints, and a narrow decision space that constrains the authority of district health managers and their ability to influence decision-making. Strategies that may improve managerial efficiency at both an individual and organizational level included improvements to planning, communication, and time management skills, and ensuring the timely release of district funds. CONCLUSIONS: Filling District Health Management Team vacancies, developing leadership and management skills of district health managers, ensuring a better flow of district funds, and delegating more authority to the districts seems to be a promising intervention package, which may result in better and more efficient management practices and stronger health system performance. PMID- 26769343 TI - Epidermal growth factor attenuates blood-spinal cord barrier disruption via PI3K/Akt/Rac1 pathway after acute spinal cord injury. AB - After spinal cord injury (SCI), disruption of blood-spinal cord barrier (BSCB) elicits blood cell infiltration such as neutrophils and macrophages, contributing to permanent neurological disability. Previous studies show that epidermal growth factor (EGF) produces potent neuroprotective effects in SCI models. However, little is known that whether EGF contributes to the integrity of BSCB. The present study is performed to explore the mechanism of BSCB permeability changes which are induced by EGF treatment after SCI in rats. In this study, we demonstrate that EGF administration inhibits the disruption of BSCB permeability and improves the locomotor activity in SCI model rats. Inhibition of the PI3K/Akt pathways by a specific inhibitor, LY294002, suppresses EGF-induced Rac1 activation as well as tight junction (TJ) and adherens junction (AJ) expression. Furthermore, the protective effect of EGF on BSCB is related to the activation of Rac1 both in vivo and in vitro. Blockade of Rac1 activation with Rac1 siRNA downregulates EGF-induced TJ and AJ proteins expression in endothelial cells. Taken together, our results indicate that EGF treatment preserves BSCB integrity and improves functional recovery after SCI via PI3K-Akt-Rac1 signalling pathway. PMID- 26769345 TI - Imaging heterogeneity of peptide delivery and binding in solid tumors using SPECT imaging and MRI. AB - BACKGROUND: As model system, a solid-tumor patient-derived xenograft (PDX) model characterized by high peptide receptor expression and histological tissue homogeneity was used to study radiopeptide targeting. In this solid-tumor model, high tumor uptake of targeting peptides was expected. However, in vivo SPECT images showed substantial heterogeneous radioactivity accumulation despite homogenous receptor distribution in the tumor xenografts as assessed by in vitro autoradiography. We hypothesized that delivery of peptide to the tumor cells is dictated by adequate local tumor perfusion. To study this relationship, sequential SPECT/CT and MRI were performed to assess the role of vascular functionality in radiopeptide accumulation. METHODS: High-resolution SPECT and dynamic contrast-enhanced (DCE)-MRI were acquired in six mice bearing PC295 PDX tumors expressing the gastrin-releasing peptide (GRP) receptor. Two hours prior to SPECT imaging, animals received 25 MBq (111)In(DOTA-(betaAla)2-JMV594) (25 pmol). Images were acquired using multipinhole SPECT/CT. Directly after SPECT imaging, MR images were acquired on a 7.0-T dedicated animal scanner. DCE-MR images were quantified using semi-quantitative and quantitative models. The DCE MR and SPECT images were spatially aligned to compute the correlations between radioactivity and DCE-MRI-derived parameters over the tumor. RESULTS: Whereas histology, in vitro autoradiography, and multiple-weighted MRI scans all showed homogenous tissue characteristics, both SPECT and DCE-MRI showed heterogeneous distribution patterns throughout the tumor. The average Spearman's correlation coefficient between SPECT and DCE-MRI ranged from 0.57 to 0.63 for the "exchange related" DCE-MRI perfusion parameters. CONCLUSIONS: A positive correlation was shown between exchange-related DCE-MRI perfusion parameters and the amount of radioactivity accumulated as measured by SPECT, demonstrating that vascular function was an important aspect of radiopeptide distribution in solid tumors. The combined use of SPECT and MRI added crucial information on the perfusion efficiency versus radiopeptide uptake in solid tumors and showed that functional tumor characteristics varied locally even when the tissue appeared homogenous on current standard assessment techniques. PMID- 26769346 TI - Preparation of Controlled-Release Fine Particles Using a Dry Coating Method. AB - Wet coating methods use organic solvents to prepare layered particles that provide controlled-release medications. However, this approach has disadvantages in that it can cause particle agglomeration, reduce pharmaceutical stability, and leave residual organic solvents. We used a dry coating method to overcome these issues. Fine particles (less than 50 MUm in diameter) of controlled-release theophylline were created using theophylline (TP; model drug), polyethylene glycol 20,000 (PEG; drug fixative), hydrogenated castor oil (HCO; controlled release material), hydrogenated rapeseed oil (HRSO; controlled-release material), and cornstarch (CS; core particle). An ultrahigh-speed mixer was employed to mix TP and CS for 5 min at 28,000 rpm. Subsequent addition of PEG produced single core particles with a drug reservoir coating. Addition of HCO and HRSO to these particles produced a controlled-release layer on their surface, resulting in less than 10% TP dissolution after 8 h. We successfully demonstrated that this dry coating method could be used to coat 16-MUm CS particles with a drug reservoir layer and a controlled-release layer, producing multi-layer coated single-core particles that were less than 50 MUm in diameter. These can be used to prepare controlled-release tablets, capsules, and orally disintegrating tablets. PMID- 26769347 TI - Effects of ivermectin on Danio rerio: a multiple endpoint approach: behaviour, weight and subcellular markers. AB - Ivermectin (IVM) is a broad acting antihelmintic used in various veterinary pharmaceuticals. It has been shown that IVM enters the aquatic compartment and adversely affects organisms including fish. This study is based on the hypothesis that long term exposure to IVM affects fish and thus, the main objective was to assess the chronic effects of 0.25 and 25 ug IVM/L to zebrafish using multiple endpoints representative of several levels of biological organization: weight, behaviour (swimming and feeding) and subcellular markers including biomarkers for oestrogenicity (vitellogenin-VTG), oxidative stress (catalase-CAT and glutathione S-transferase-GST) and neurotransmission (cholinesterase-ChE). Concentrations as low as 0.25 ug IVM/L disrupted the swimming behaviour, causing fish to spend more time at the bottom of aquaria. Such reduction of the swimming performance affected the feeding ability which is likely responsible for the weight loss. The effects on weight were gender differentiated, being more pronounced in males (0.25 ug IVM/L) than in females (25 ug IVM/L). Fish exposed to 25 ug/L exhibited darker coloration and mild curvature of the spine. No effects on VTG and AChE were observed, but a reduction on CAT and GST levels was observed in fish exposed to 25 ug IVM/L, although these alterations probably only reflect the general condition of the fish which was significantly compromised at this concentration. Despite that predicted environmental concentrations of IVM are below 0.25 ug/L, the behavioural effects may be translated into important ecological impacts, e.g. at predator-prey interactions where fish competitive advantage can be decreased. Future work should address the link between behaviour disruption and population fitness. The current study was based on a one experiment and multiple endpoint (anchored) approach, allowing the results to be integrated and linked towards a mechanistic understanding. PMID- 26769349 TI - Hybrid bone HDP SPECT/CT in evaluation of painful degenerative scoliosis. PMID- 26769350 TI - Septic arthritis and empyema of the sacroiliac joint after lumbar discectomy and instrumentation. PMID- 26769348 TI - IFNalpha gene/cell therapy curbs colorectal cancer colonization of the liver by acting on the hepatic microenvironment. AB - Colorectal cancer (CRC) metastatic dissemination to the liver is one of the most life-threatening malignancies in humans and represents the leading cause of CRC related mortality. Herein, we adopted a gene transfer strategy into mouse hematopoietic stem/progenitor cells to generate immune-competent mice in which TEMs-a subset of Tie2(+) monocytes/macrophages found at peritumoral sites-express interferon-alpha (IFNalpha), a pleiotropic cytokine with anti-tumor effects. Utilizing this strategy in mouse models of CRC liver metastasis, we show that TEMs accumulate in the proximity of hepatic metastatic areas and that TEM mediated delivery of IFNalpha inhibits tumor growth when administered prior to metastasis challenge as well as on established hepatic lesions, improving overall survival. Further analyses unveiled that local delivery of IFNalpha does not inhibit homing but limits the early phases of hepatic CRC cell expansion by acting on the radio-resistant hepatic microenvironment. TEM-mediated IFNalpha expression was not associated with systemic side effects, hematopoietic toxicity, or inability to respond to a virus challenge. Along with the notion that TEMs were detected in the proximity of CRC metastases in human livers, these results raise the possibility to employ similar gene/cell therapies as tumor site specific drug-delivery strategies in patients with CRC. PMID- 26769351 TI - Visual loss after corrective surgery for pediatric scoliosis: incidence and risk factors from a nationwide database. AB - BACKGROUND CONTEXT: Perioperative visual loss (POVL) after spinal deformity surgery is an uncommon but severe complication. Data on the incidence and risk factors of this complication after corrective surgery in the pediatric population are limited. PURPOSE: The present study aimed to investigate nationwide estimates of POVL after corrective surgery for pediatric scoliosis. STUDY DESIGN: This is a retrospective study that uses a nationwide database. PATIENT SAMPLE: The sample includes 42,339 patients under the age of 18 who underwent surgery for idiopathic scoliosis. OUTCOME MEASURES: The outcome measures were incidence of POVL and risk factors. METHODS: Patients under the age of 18 who underwent elective surgery for idiopathic scoliosis between 2002 and 2011 were identified using the Nationwide Inpatient Sample database. The incidence of POVL (ischemic optic neuropathy, central retinal artery occlusion, or cortical blindness) was estimated after application of discharge weights. Demographics, comorbidities, and operative parameters were compared between patients with and without visual loss. A multivariate logistic regression was performed to identify significant risk factors for POVL development. No funds were received in support of this work. RESULTS: The incidence of POVL was 1.6 per 1,000 procedures (0.16%). Patients with visual loss were significantly more likely to be younger and male, have Medicaid as insurance, and undergo fusion of eight or more spinal levels compared with patients without visual loss. Following multivariate analysis, older patients (odds ratio [OR]: 0.84; 95% confidence interval [CI]: 0.77-0.91) and female patients (OR: 0.08; 95% CI: 0.04-0.14) were significantly less likely to develop POVL compared with younger and male patients. On the other hand, having Medicaid as insurance (OR: 2.13;95% CI: 1.32-3.45), history of deficiency anemia (OR: 8.64; 95% CI: 5.46-14.31), and fusion of eight or more spinal levels (OR: 2.40; 95% CI: 1.34-4.30) were all independently associated with POVL. CONCLUSIONS: In this nationwide study, the incidence of POVL after scoliosis surgery in patients under the age of 18 was estimated at 0.16%, similar to the rate reported in adult patients. Cortical blindness accounted for all cases of POVL in the present study. Younger patients, patients with history of deficiency anemia, and patients undergoing long-segment fusions may be at increased risk of POVL after corrective surgery for pediatric scoliosis. PMID- 26769352 TI - Assessment of clasp design and flexural properties of acrylic denture base materials for use in non-metal clasp dentures. AB - PURPOSE: The purpose of this study was to investigate the possibilities of utilizing new acrylic denture base materials in resin clasps using three-point flexural tests and cantilever beam tests. METHODS: Seven non-metal clasp denture (NMCD) materials and four acrylic denture base materials were used for three point flexural tests and six NMCD materials and three acrylic denture base materials were used for cantilever beam tests. The flexural strength, elastic modulus, and 0.05% proof stress were measured by three-point flexural tests according to International Organization for Standardization (ISO) 20795-1. And load at 0.5mm deformation, elastic modulus were measured by Cantilever beam tests. RESULTS: For the three-point flexural tests, only materials that met the conditions for both flexural strength and elastic modulus were the polycarbonate Reigning N (REN) and the acrylics Acron (AC), Pro Impact (PI), Procast DSP (PC) and IvoBase High Impact (HI) which are required in ISO 20795-1, Type 3 denture base materials. And for cantilever beam tests there was no significant difference between PI and either EstheShot (ES), EstheShot Bright (ESB), REN or Acry Tone (ACT) in load at 0.5mm deformation, and no significant difference between PI and either Lucitone FRS (LTF), ES, ESB, REN or ACT in elastic modulus. CONCLUSIONS: The results thus suggested that some of the acrylic materials used as denture base materials may also be usable for NMCDs, and that the flexural properties of the acrylic material PI resemble those of ES, ESB and ACT, meaning that similar clasp designs may also be feasible. PMID- 26769355 TI - Recent Advances in C-H Functionalization. PMID- 26769358 TI - Differential interaction between iron and mutant alpha-synuclein causes distinctive Parkinsonian phenotypes in Drosophila. AB - Alpha-synuclein aggregation is the central hallmark of both sporadic and familial Parkinson's disease (PD). Patients with different PD-causing genetic defects of alpha-synuclein usually show distinctive clinical features that are atypical to sporadic PD. Iron accumulation is invariably found in PD. Recent studies showed that mutant and wild-type alpha-synuclein may have differential interaction with iron and mutant alpha-synuclein toxicity could be preferentially exacerbated by iron. We hence hypothesized that iron overload could selectively influence mutant alpha-synuclein toxicity and disease phenotypes. To test the hypothesis, we investigated if Drosophila melanogaster over-expressing A53T, A30P, and wild-type (WT) alpha-synuclein have different responses to iron treatment. We showed that iron treatment induced similar reduction of survival rate in all flies but induced a more severe motor decline in A53T and A30P mutant alpha-synuclein expressing flies, suggesting interaction between mutant alpha-synuclein and iron. Although no significant difference in total head iron content was found among these flies, we demonstrated that iron treatment induced selective DA neuron loss in motor-related PPM3 cluster only in the flies that express A53T and A30P mutant alpha-synuclein. We provided the first in vivo evidence that iron overload could induce distinctive neuropathology and disease phenotypes in mutant but not WT alpha-synuclein expressing flies, providing insights to the cause of clinical features selectively exhibited by mutant alpha-synuclein carriers. PMID- 26769359 TI - High glucose and hyperglycemic sera from type 2 diabetic patients impair DC differentiation by inducing ROS and activating Wnt/beta-catenin and p38 MAPK. AB - Type 2 is the type of diabetes with higher prevalence in contemporary time, representing about 90% of the global cases of diabetes. In the course of diabetes, several complications can occur, mostly due to hyperglycemia and increased reactive oxygen species (ROS) production. One of them is represented by an increased susceptibility to microbial infections and by a reduced capacity to clear them. Therefore, knowing the impact of hyperglycemia on immune system functionality is of utmost importance for the management of the disease. In this study, we show that medium containing high glucose reduced the in-vitro differentiation of monocytes into functional DCs and their activation mediated by PAMPs or DAMPs. Most importantly, the same effects were mediated by the hyperglycemic sera derived by type 2 diabetic patients, mimicking a more physiologic condition. DC dysfunction caused by hyperglycemia may be involved in the inefficient control of infections observed in diabetic patients, given the pivotal role of these cells in both the innate and adaptive immune response. Searching for the molecular mechanisms underlying DC dysfunction, we found that canonical Wnt/beta-catenin and p38 MAPK pathways were activated in the DCs differentiated either in the presence of high glucose or of hyper-glycemic sera. Interestingly, the activation of these pathways and the DC immune dysfunction were partially counteracted by the anti-oxidant quercetin, a flavonoid already known to exert several beneficial effects in diabetes. PMID- 26769360 TI - Lipoic acid improves neuronal insulin signalling and rescues cognitive function regulating VGlut1 expression in high-fat-fed rats: Implications for Alzheimer's disease. AB - The concept of central insulin resistance and dysfunctional insulin signalling in sporadic Alzheimer's disease (AD) is now widely accepted and diabetes is recognized as one of the main risk factors for developing AD. Moreover, some lines of evidence indicated that VGlut1 is impaired in frontal regions of AD patients and this impairment is correlated with the progression of cognitive decline in AD. The present work hypothesizes that ketosis associated to insulin resistance could interfere with the normal activity of VGlut1 and its role in the release of glutamate in the hippocampus, which might ultimately lead to cognitive deficits. High fat diet (HFD) rats showed memory impairments and both peripheral (as shown by increased fasting plasma insulin levels and HOMA index) and hippocampal (as shown by decreased activation of insulin receptor, IRS-1 and pAkt) insulin pathway alterations, accompanied by increased ketone bodies production. All these effects were counteracted by alpha-lipoic acid (LA) administration. VGlut1 levels were significantly decreased in the hippocampus of HFD rats, and this decrease was reversed by LA. Altogether, the present results suggest that HFD induced alterations in central insulin signalling could switch metabolism to produce ketone bodies, which in turn, in the hippocampus, might lead to a decreased expression of VGlut1, and therefore to a decreased release of glutamate and hence, to the glutamatergic deficit described in AD. The ability of LA treatment to prevent the alterations in insulin signalling in this model of HFD might represent a possible new therapeutic target for the treatment of AD. PMID- 26769361 TI - ROS/oxidative stress signaling in osteoarthritis. AB - Osteoarthritis is the most common joint disorder with increasing prevalence due to aging of the population. Its multi-factorial etiology includes oxidative stress and the overproduction of reactive oxygen species, which regulate intracellular signaling processes, chondrocyte senescence and apoptosis, extracellular matrix synthesis and degradation along with synovial inflammation and dysfunction of the subchondral bone. As disease-modifying drugs for osteoarthritis are rare, targeting the complex oxidative stress signaling pathways would offer a valuable perspective for exploration of potential therapeutic strategies in the treatment of this devastating disease. PMID- 26769357 TI - The Phormidolide Biosynthetic Gene Cluster: A trans-AT PKS Pathway Encoding a Toxic Macrocyclic Polyketide. AB - Phormidolide is a polyketide produced by a cultured filamentous marine cyanobacterium and incorporates a 16-membered macrolactone. Its complex structure is recognizably derived from a polyketide synthase pathway, but possesses unique and intriguing structural features that prompted interest in investigating its biosynthetic origin. Stable isotope incorporation experiments confirmed the polyketide nature of this compound. We further characterized the phormidolide gene cluster (phm) through genome sequencing followed by bioinformatic analysis. Two discrete trans-type acyltransferase (trans-AT) ORFs along with KS-AT adaptor regions (ATd) within the polyketide synthase (PKS) megasynthases, suggest that the phormidolide gene cluster is a trans-AT PKS. Insights gained from analysis of the mode of acetate incorporation and ensuing keto reduction prompted our reevaluation of the stereochemistry of phormidolide hydroxy groups located along the linear polyketide chain. PMID- 26769362 TI - Effect of the pituitary adenylate cyclase-activating polypeptide on the autophagic activation observed in in vitro and in vivo models of Parkinson's disease. AB - Parkinson's disease (PD) is a neurodegenerative disorder that leads to destruction of the midbrain dopaminergic (DA) neurons. This phenomenon is related to apoptosis and its activation can be blocked by the pituitary adenylate cyclase activating polypeptide (PACAP). Growing evidence indicates that autophagy, a self degradation activity that cleans up the cell, is induced during the course of neurodegenerative diseases. However, the role of autophagy in the pathogenesis of neuronal disorders is yet poorly understood and the potential ability of PACAP to modulate the related autophagic activation has never been significantly investigated. Hence, we explored the putative autophagy-modulating properties of PACAP in in vitro and in vivo models of PD, using the neurotoxic agents 1-methyl 4-phenylpyridinium (MPP(+)) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), respectively, to trigger alterations of DA neurons. In both models, following the toxin exposure, PACAP reduced the autophagic activity as evaluated by the production of LC3 II, the modulation of the p62 protein levels, and the formation of autophagic vacuoles. The ability of PACAP to inhibit autophagy was also observed in an in vitro cell assay by the blocking of the p62-sequestration activity produced with the autophagy inducer rapamycin. Thus, the results demonstrated that autophagy is induced in PD experimental models and that PACAP exhibits not only anti-apoptotic but also anti-autophagic properties. PMID- 26769363 TI - Vascular contributions to cognitive impairment, clinical Alzheimer's disease, and dementia in older persons. AB - There is growing evidence suggesting that vascular pathologies and dysfunction play a critical role in cognitive impairment, clinical Alzheimer's disease, and dementia. Vascular pathologies such as macroinfarcts, microinfarcts, microbleeds, small and large vessel cerebrovascular disease, and white matter disease are common especially in the brains of older persons where they contribute to cognitive impairment and lower the dementia threshold. Vascular dysfunction resulting in decreased cerebral blood flow, and abnormalities in the blood brain barrier may also contribute to the Alzheimer's disease (AD) pathophysiologic process and AD dementia. This review provides a clinical-pathological perspective on the role of vessel disease, vascular brain injury, alterations of the neurovascular unit, and mixed pathologies in the Alzheimer's disease pathophysiologic process and Alzheimer's dementia. This article is part of a Special Issue entitled: Vascular Contributions to Cognitive Impairment and Dementia edited by M. Paul Murphy, Roderick A. Corriveau and Donna M. Wilcock. PMID- 26769364 TI - Site-Specific Cryo-focused Ion Beam Sample Preparation Guided by 3D Correlative Microscopy. AB - The development of cryo-focused ion beam (cryo-FIB) for the thinning of frozen hydrated biological specimens enabled cryo-electron tomography (cryo-ET) analysis in unperturbed cells and tissues. However, the volume represented within a typical FIB lamella constitutes a small fraction of the biological specimen. Retaining low-abundance and dynamic subcellular structures or macromolecular assemblies within such limited volumes requires precise targeting of the FIB milling process. In this study, we present the development of a cryo-stage allowing for spinning-disk confocal light microscopy at cryogenic temperatures and describe the incorporation of the new hardware into existing workflows for cellular sample preparation by cryo-FIB. Introduction of fiducial markers and subsequent computation of three-dimensional coordinate transformations provide correlation between light microscopy and scanning electron microscopy/FIB. The correlative approach is employed to guide the FIB milling process of vitrified cellular samples and to capture specific structures, namely fluorescently labeled lipid droplets, in lamellas that are 300 nm thick. The correlation procedure is then applied to localize the fluorescently labeled structures in the transmission electron microscopy image of the lamella. This approach can be employed to navigate the acquisition of cryo-ET data within FIB-lamellas at specific locations, unambiguously identified by fluorescence microscopy. PMID- 26769365 TI - Mushroom Clouds for Vitamin D? PMID- 26769366 TI - Paenibacillus bovis sp. nov., isolated from raw yak (Bos grunniens) milk. AB - Strain BD3526T, isolated from raw yak milk collected in Tibet, China, was studied to determine its taxonomic status. The strain was Gram-reaction positive, motile, catalase-positive, aerobic or facultatively anaerobic. The DNA G+C content of the strain was 47.5 mol% and its peptidoglycan contained meso-diaminopimelic acid. The predominant menaquinone was MK-7. The major cellular fatty acids were anteiso C15 : 0, anteiso-C17 : 0 and C16 : 0. Based on 16S rRNA gene sequence analysis, similarities among strain BD3526T and its most closely related species, Paenibacillus shenyangensis A9T, 'Paenibacillus dauci' H9, 'Paenibacillus wulumuqiensis' Y24 and Paenibacillus hunanensis DSM 22170T were 99.0, 98.5, 97.3 and 96.7 %, respectively. Levels of DNA-DNA relatedness among strain BD3526T and P. hunanensis DSM 22170T and Paenibacillus polymyxa ATCC 842T ( = DSM 36T), the type species of the genus, were 41.2 and 45.6 %, respectively. In silico genome to-genome comparison showed that the DNA-DNA hybridization values among strain BD3526T and P. shenyangensis A9T, 'P. dauci' H9 and 'P. wulumuqiensis' Y24 were lower than 70 %. Based on its molecular and physiological properties, strain BD3526T ( = DSM 28815T = CGMCC 8333T) is identified as the type strain of a novel species within the genus Paenibacillus, for which the name Paenibacillus bovis is proposed. PMID- 26769367 TI - Serum osteopontin level and common carotid artery intima-media wall thickness in psoriasis. AB - BACKGROUND: The association between psoriasis and cardiovascular disease is well documented, but the underlying mechanisms remain unknown. The relationship between osteopontin and psoriasis has been studied. High serum levels of osteopontin are reported in psoriasis, with increased cardiovascular risk factors in these patients. OBJECTIVES: We evaluate the extent of subclinical atherosclerosis by measuring the mean intima-media wall thickness (MIMT) of the common carotid artery (CCA) in patients with psoriasis and assessing its correlation with osteopontin to identify vascular risk factors associated with psoriasis. METHODS: Intima-media wall thickness of the CCA and plasma osteopontin were determined in 40 patients and 40 age- and sex-matched healthy control subjects. RESULTS: Median serum osteopontin was significantly higher in patients with psoriasis than in healthy control subjects. Mean intima-media wall thickness of the CCA was positively associated with plasma osteopontin level (r = 0.47, P < 0.0001), body mass index (r = 0.62, P < 0.0001), age (r = 0.54, P < 0.0001), total cholesterol (r = 0.54, P < 0.0001), and triglycerides (r = 0.65, P < 0.0001). CONCLUSIONS: This study shows higher levels of plasma osteopontin and MIMT-CCA in psoriasis patients than in healthy controls. This is the first study to show a positive correlation between plasma osteopontin and MIMT-CCA. PMID- 26769375 TI - Heartbeat: Beta-blockers for aortic regurgitation. PMID- 26769376 TI - Niacin: old habits die hard. PMID- 26769377 TI - Long-term survival with an unrepaired single ventricle: what is your dangerous idea? PMID- 26769378 TI - Activity of the kynurenine pathway and its interplay with immunity in patients with pulmonary arterial hypertension. AB - OBJECTIVE: We evaluated blood concentrations of kynurenine pathway metabolites, natural and induced regulatory T cells (nTreg, iTreg), and Th17 cells in order to examine the activity of the kynurenine pathway and its relation to immune status in patients with pulmonary arterial hypertension (PAH). METHODS: Plasma concentrations of tryptophan, kynurenine, kynurenic acid, anthranilic acid, and 3 hydroxykynurenine were quantified in 26 patients with PAH (vs 30 healthy controls) at baseline and after 6 months, and assessed them in relation to clinical parameters, frequencies of lymphocyte subsets, and outcome. RESULTS: The PAH group presented higher concentrations of tryptophan (52.9 (IQR 46.3-57.5) vs 40.3 (35.2-46.3) umol/L, p=0.00003), kynurenine 2.8 (2.4-3.4) vs 1.9 (1.5-2.3) umol/L, p=0.000007), kynurenine/tryptophan ratio (0.051 (0.044-0.064) vs 0.043 (0.039-0.055), p=0.03), iTreg frequencies (10.5 (8.8-13.9)% vs 6.8 (5.2-9.5)%, p=0.002) and iTreg/Th17 (1.73 (1.2-2.8) vs 0.93 (0.61-1.27), p=0.003) together with lower ratios of kynurenic acid/kynurenine, 3-hydroxykynurenine/kynurenine, and anthranilic acid/kynurenine. Kynurenine concentrations and kynurenine/tryptophan ratio correlated positively with iTreg/Th17, and inversely with Th17 subsets, whereas kynurenic acid/kynurenine and anthranilic acid/kynurenine ratios correlated positively with Th17. Adverse outcomes occurred in 9 of 26 patients and they showed higher baseline concentrations of kynurenine (3.6 (2.8-4.3) vs 2.7 (2.1-3.2) umol/L, p=0.033). Median kynurenine values >=3.4 umol/L (67% sensitivity, 94% specificity) identified patients with a worse clinical course. CONCLUSIONS: PAH is characterised by upregulated tryptophan metabolism and enhanced biosynthesis of kynurenine. Elevated kynurenine concentration is associated with an adverse clinical course. Dysregulated immunity, delineated by Treg-Th17 imbalance, is directly related to diverse activation of the kynurenine pathway, indicating the potential interplay between kynurenines and the immune system in PAH. PMID- 26769379 TI - Correction. AB - Tietjens J, Teerlink JR. Serelaxin and acute heart failure. Heart 2016;102:95-9. In this review the latest set of competing interests were not included in the published version. They are as follows; JT has no competing interests. JRT has received research grants and consulting fees from Amgen, Bayer, Cytokinetics, Novartis, and Trevena. PMID- 26769380 TI - Total and high-molecular-weight adiponectin are associated with incident atrial fibrillation. PMID- 26769381 TI - Adiponectin and atrial fibrillation in older adults. PMID- 26769383 TI - Improving Access to Maternity Care for Women with Opioid Use Disorders: Colocation of Midwifery Services at an Addiction Treatment Program. AB - Perinatal drug and alcohol use is associated with serious medical and psychiatric morbidity for pregnant and postpartum women and their newborns. Participation in prenatal care has been shown to improve outcomes, even in the absence of treatment for substance use disorders. Unfortunately, women with substance use disorders often do not receive adequate prenatal care. Barriers to accessing care for pregnant women with substance use disorders include medical and psychiatric comorbidities, transportation, caring for existing children, housing and food insecurity, and overall lack of resources. In a health care system where care is delivered by each discipline separately, lack of communication between providers causes poorly coordinated services and missed opportunities. The integration of mental health and substance use treatment services in medical settings is a goal of health care reform. However, this approach has not been widely promoted in the context of maternity care. The Dartmouth-Hitchcock Medical Center Perinatal Addiction Treatment Program provides an integrated model of care for pregnant and postpartum women with substance use disorders, including the colocation of midwifery services in the context of a dedicated addiction treatment program. A structured approach to screening and intervention for drug and alcohol use in the outpatient prenatal clinic facilitates referral to treatment at the appropriate level. Providing midwifery care within the context of a substance use treatment program improves access to prenatal care, continuity of care throughout pregnancy and the postpartum, and availability of family planning services. The evolution of this innovative approach is described. This article is part of a special series of articles that address midwifery innovations in clinical practice, education, interprofessional collaboration, health policy, and global health. PMID- 26769382 TI - Lactate induces FGF21 expression in adipocytes through a p38-MAPK pathway. AB - FGF21 (fibroblast growth factor 21), first described as a main fasting-responsive molecule in the liver, has been shown to act as a true metabolic regulator in additional tissues, including muscle and adipose tissues. In the present study, we found that the expression and secretion of FGF21 was very rapidly increased following lactate exposure in adipocytes. Using different pharmacological and knockout mice models, we demonstrated that lactate regulates Fgf21 expression through a NADH/NAD-independent pathway, but requires active p38-MAPK (mitogen activated protein kinase) signalling. We also demonstrated that this effect is not restricted to lactate as additional metabolites including pyruvate and ketone bodies also activated the FGF21 stress response. FGF21 release by adipose cells in response to an excess of intermediate metabolites may represent a physiological mechanism by which the sensing of environmental metabolic conditions results in the release of FGF21 to improve metabolic adaptations. PMID- 26769384 TI - Interprofessional Obstetric Ultrasound Education: Successful Development of Online Learning Modules; Case-Based Seminars; and Skills Labs for Registered and Advanced Practice Nurses, Midwives, Physicians, and Trainees. AB - Ultrasound is an important aid in the clinical diagnosis and management of normal and complicated pregnancy and childbirth. The technology is widely applied to maternity care in the United States, where comprehensive standard ultrasound examinations are routine. Targeted scans are common and used for an increasing number of clinical indications due to emerging research and a greater availability of equipment with better image resolution at lower cost. These factors contribute to an increased demand for obstetric ultrasound education among students and providers of maternity care, despite a paucity of data to inform education program design and evaluation. To meet this demand, from 2012 to 2015 the University of California, San Francisco nurse-midwifery education program developed and implemented an interprofessional obstetric ultrasound course focused on clinical applications commonly managed by maternity care providers from different professions and disciplines. The course included matriculating students in nursing and medicine, as well as licensed practitioners such as registered and advanced practice nurses, midwives, and physicians and residents in obstetrics and gynecology and family medicine. After completing 10 online modules with a pre- and posttest of knowledge and interprofessional competencies related to teamwork and communication, trainees attended a case based seminar and hands-on skills practicum with pregnant volunteers. The course aimed to establish a foundation for further supervised clinical training prior to independent practice of obstetric ultrasound. Course development was informed by professional guidelines and clinical and education research literature. This article describes the foundations, with a review of the challenges and solutions encountered in obstetric ultrasound education development and implementation. Our experience will inform educators who wish to facilitate obstetric ultrasound competency development among new and experienced maternity care providers in academic and clinical settings. This article is part of a special series of articles that address midwifery innovations in clinical practice, education, interprofessional collaboration, health policy, and global health. PMID- 26769385 TI - The Midwifery Workforce: ACNM 2012 and AMCB 2013 Core Data. AB - INTRODUCTION: Core data are crucial for detailing an accurate profile of the midwifery workforce in the United States. The American College of Nurse-Midwives (ACNM) and the American Midwifery Certification Board, Inc. (AMCB), at the request and with support from the US Health Resources and Services Administration (HRSA), are engaged in a collaborative effort to develop a data collection strategy (the Midwifery MasterFile) that will reflect demographic and practice characteristics of certified nurse-midwives (CNMs) and certified midwives (CMs) in the United States. METHODS: Two independent datasets, one collected by ACNM in 2012 and one by AMCB in 2013, were examined to determine key workforce information. ACNM data were collected from the online Core Data Survey sent to ACNM members. AMCB data were extracted from information submitted online by applicants seeking initial certification in 2013 and applicants seeking to recertify following 5 years of initial certification. RESULTS: The ACNM 2012 survey was partially or fully completed by 36% (n = 2185) of ACNM members (N = 6072). AMCB respondents included 100% of new certificants (N = 539) and those applying for recertification in 2013 (n = 1323) of the total 11,682 certificants in the AMCB database. These two datasets demonstrate that midwives remain largely white, female, and older in age, with most engaged in clinical midwifery while employed primarily by hospitals and medical centers. Differences were reported between the ACNM membership and AMCB certification datasets in the numbers of midwives holding other certifications, working full-time, attending births, and providing newborn care. DISCUSSION: The new collaboration among HRSA, ACNM, and AMCB, represented as the Midwifery MasterFile, provides the opportunity to clearly profile CNMs/CMs, distinct from advanced practice registered nurses, in government reports about the health care workforce. This information is central to identifying and marketing the role and contribution of CNMs/CMs in the provision of primary and reproductive health care services. PMID- 26769386 TI - Current Resources for Evidence-Based Practice, November/December 2015. PMID- 26769387 TI - National Partnership for Maternal Safety Consensus Bundle on Obstetric Hemorrhage. AB - In the article, "National Partnership for Maternal Safety Consensus Bundle on Obstetric Hemorrhage," published in the July/August 2015 issue of the Journal of Midwifery & Women's Health (60[4]:458-464), reference 39 contains an error in the first author's name. The correct citation is: 39. Evensen A, Anderson J. Postpartum hemorrhage: third stage pregnancy. In: Leeman L, editor. Advanced life support in obstetrics provider syllabus. Leawood (KS): American Academy of Family Physicians; 2014. PMID- 26769388 TI - A Mixed-Methods Study of Immigrant Somali Women's Health Literacy and Perinatal Experiences in Maine. AB - A Mixed-Methods Study of Immigrant Somali Women's Health Literacy and Perinatal Experiences in Maine Volume 60, Issue 6, 790, Article first published online: 8 December 2015 In the article, "A Mixed-Methods Study of Immigrant Somali Women's Health Literacy and Perinatal Experiences in Maine," published in the September/October 2015 issue of the Journal of Midwifery & Women's Health (60[5]:593-603), there are errors in the fifth author's credentials and biography. The correct credentials and biography are: Vince Salyers, EdD, RN, is the Associate Dean of the Faculty of Health and Community Studies at Mount Royal University in Calgary, Canada. PMID- 26769390 TI - Share With Women. Birth Control: What Method is Right for Me? PMID- 26769391 TI - Pavel Ivanovich Karpov (1873-1932?)--the Russian Prinzhorn: art of the insane in Russia. AB - The complicated relationship between the discipline of mental health and the arts has barely been studied systematically. Mental hospitals, shelters and prisons- institutions that accommodate the mentally ill--sometimes promote but often discourage and disrupt the patients' artistic creativity and the images created. In psychiatric circles, the recognition of patient art was a long, slow and frustrating process. Among the Western psychiatrists who studied the creative activity of the mentally ill, researchers usually mention such names as C. Lombroso, M. Shearing, V. Morgentaller, H. Prinzhorn and others, but rarely refer to their Russian colleagues and contemporaries. Pavel Ivanovich Karpov (1873 1932?), a Russian psychiatrist, was one of the most extensive researchers in the field of the art of the insane, but unfortunately his name is little known among modern psychiatrists. For his clinical and scientific contributions, he deserves to be remembered in the history of psychiatry. PMID- 26769392 TI - Bipolar disorder and its outcomes: two cohorts, 1875-1924 and 1994-2007, compared. AB - We compared admission rates and outcomes for bipolar disorder patients using the medical records of patients with a first hospital admission in 1875-1924 retrospectively diagnosed based on International Classification of Diseases (ICD) 10 criteria, and patients with a first admission in 1994-2007. The incidences of first admissions in the historical and contemporary periods are comparable: 1.2 and 1.3 per hundred thousand per year, respectively. Manic episodes constituted a greater proportion of admissions historically, while depressive episodes made up more in the contemporary sample. There is no evidence for a reduction in the mean inter-admission intervals with duration of illness. This study suggests that modern treatments may have decreased lengths of stay in hospital, but at a cost of contributing to more admissions. It also points to a shift in the threshold for admissions. PMID- 26769396 TI - Cassane diterpenes from the seed kernels of Caesalpinia sappan. AB - Eight structurally diverse cassane diterpenes named tomocins A-H were isolated from the seed kernels of Vietnamese Caesalpinia sappan Linn. Their structures were determined by extensive NMR and CD spectroscopic analysis. Among the isolated compounds, tomocin A, phanginin A, F, and H exhibited mild preferential cytotoxicity against PANC-1 human pancreatic cancer cells under nutrition deprived condition without causing toxicity in normal nutrient-rich conditions. PMID- 26769397 TI - Nanobubbles: a promising efficient tool for therapeutic delivery. AB - In recent decades ultrasound-guided delivery of drugs loaded on nanocarriers has been the focus of increasing attention to improve therapeutic treatments. Ultrasound has often been used in combination with microbubbles, micron-sized spherical gas-filled structures stabilized by a shell, to amplify the biophysical effects of the ultrasonic field. Nanometer size bubbles are defined nanobubbles. They were designed to obtain more efficient drug delivery systems. Indeed, their small sizes allow extravasation from blood vessels into surrounding tissues and ultrasound-targeted site-specific release with minimal invasiveness. Additionally, nanobubbles might be endowed with improved stability and longer residence time in systemic circulation. This review will describe the physico chemical properties of nanobubbles, the formulation parameters and the drug loading approaches, besides potential applications as a therapeutic tool. PMID- 26769398 TI - Cerium dioxide nanoparticles increase immunogenicity of the influenza vaccine. AB - We have demonstrated the influence of cerium dioxide nanoparticles on the immunogenicity of the influenza vaccine on an example of liquid split inactivated Vaxigrip vaccine. Antibody titers were analyzed using the hemagglutination inhibition (HI) assay. Seroprotection, seroconversion, the geometric mean titers (GMTs) and the factor increase (FI) in the GMTs were calculated. The effect of nano-ceria surface stabilizer on the enhancement of immunogenicity was shown. The vaccine modified by citrate-stabilized nano-ceria, in contrast to a non-modified Vaxigrip vaccine, did not provide an adequate level of seroprotection, and seroconversion after vaccination was 66.7% on days 49-63 for virus strain A(H1N1) and 100% on day 49 for virus strain B/Yamagata. For the low immunogenic influenza B virus, the rise in antibody titers (GMT/IF) was 24.38/3.28 after the first injection and 50.40/6.79 on day 49. For the vaccine modified by non-stabilized nano-ceria, for all virus strains under study, on day 63, upon immunization notable levels of seroprotection, seroconversion and GMT/IF were registered (higher than for the non-modified Vaxigrip vaccine). The successful attempt to modify the influenza vaccine demonstrates the possible ways of increasing the specific activity of vaccines using nano-ceria. PMID- 26769399 TI - The KSHV RNA regulator ORF57: target specificity and its role in the viral life cycle. AB - Kaposi's sarcoma-associated herpesvirus (KSHV) encodes ORF57, which enhances the expression of intron-less KSHV genes on multiple post-transcriptional levels mainly affecting RNA stability and export to the cytoplasm. Yet, it remains elusive how ORF57 recognizes viral RNAs and discriminates them from cellular messenger RNAs (mRNAs). Although one common binding motif on three separate KSHV RNAs has been described, most other lytic genes lack this sequence element. In this article we will review the sequence requirements for ORF57 to enhance RNA expression and discuss a model how ORF57 achieves specificity for viral RNAs. Finally, the role of ORF57 is integrated into the viral life cycle as a complex interplay with other viral and host factors and with implications for cellular gene expression. PMID- 26769400 TI - What do we publish and promote in AOGS? PMID- 26769401 TI - Editorial Comment. PMID- 26769402 TI - Time-dependent estimates of molecular evolutionary rates: evidence and causes. AB - We are writing in response to a recent critique by Emerson & Hickerson (2015), who challenge the evidence of a time-dependent bias in molecular rate estimates. This bias takes the form of a negative relationship between inferred evolutionary rates and the ages of the calibrations on which these estimates are based. Here, we present a summary of the evidence obtained from a broad range of taxa that supports a time-dependent bias in rate estimates, with a consideration of the potential causes of these observed trends. We also describe recent progress in improving the reliability of evolutionary rate estimation and respond to the concerns raised by Emerson & Hickerson (2015) about the validity of rates estimated from time-structured sequence data. In doing so, we hope to dispel some misconceptions and to highlight several research directions that will improve our understanding of time-dependent biases in rate estimates. PMID- 26769403 TI - Model misspecification confounds the estimation of rates and exaggerates their time dependency. AB - While welcoming the comment of Ho et al. (2015), we find little that undermines the strength of our criticism, and it would appear they have misunderstood our central argument. Here we respond with the purpose of reiterating that we are (i) generally critical of much of the evidence presented in support of the time dependent molecular rate (TDMR) hypothesis and (ii) specifically critical of estimates of MU derived from tip-dated sequences that exaggerate the importance of purifying selection as an explanation for TDMR over extended timescales. In response to assertions put forward by Ho et al. (2015), we use panmictic coalescent simulations of temporal data to explore a fundamental assumption for tip-dated tree shape and associated mutation rate estimates, and the appropriateness and utility of the date randomization test. The results reveal problems for the joint estimation of tree topology, effective population size and MU with tip-dated sequences using BEAST. Given the simulations, BEAST consistently obtains incorrect topological tree structures that are consistent with the substantial overestimation of MU and underestimation of effective population size. Data generated from lower effective population sizes were less likely to fail the date randomization test yet still resulted in substantially upwardly biased estimates of rates, bringing previous estimates of MU from temporally sampled DNA sequences into question. We find that our general criticisms of both the hypothesis of time-dependent molecular evolution and Bayesian methods to estimate MU from temporally sampled DNA sequences are further reinforced. PMID- 26769406 TI - Colorectal cancer mortality reduction is associated with having at least 1 colonoscopy within the previous 10 years among a population-wide cohort of screening age. AB - BACKGROUND AND AIMS: Colonoscopy has been demonstrated to be effective in colorectal cancer (CRC) mortality reduction, although current screening guidelines have yet to be evaluated. We assessed the protective benefit of colonoscopy within the previous 10 years and whether this effect is maintained with age. METHODS: We used administrative data to compare risk of CRC death (CCD) across colonoscopy utilization among a population-wide cohort comprising individuals aged 60 to 80 years (N = 1,509,423). Baseline and time-dependent colonoscopy exposure models were assessed in the context of competing "other causes of death" (OCDs). Cumulative incidence of CCD and OCD across colonoscopy exposure, over follow-up, was estimated. Relative hazards were computed by age strata (60-69 years, 70-74 years, 75+ years) and proximal and distal cancer subsites. RESULTS: At least 1 colonoscopy during 10 years before baseline was estimated to provide a 51% reduced hazard of CCD (hazard ratio [HR] 0.49; 95% confidence interval [CI], 0.45-0.54) over the following 8 years. When colonoscopy was modeled as a time-dependent covariate, the risk of CCD was further diminished (multivariable-adjusted HR 0.36; 95% CI, 0.33-0.38). Stratified analyses suggested moderately attenuated CCD risk reduction among the oldest age group; however, consideration of OCDs suggest that this is related to competing risks. CCD risk reduction related to colonoscopy was lower for proximal cancers. CONCLUSIONS: Colonoscopy within the previous 10 years provides substantial protective benefit for average-risk individuals over 60 years. CCD risk reduction may be maintained well beyond 74 years, a common upper age limit recommended by screening guidelines. PMID- 26769404 TI - Y chromosome haplotype distribution of brown bears (Ursus arctos) in Northern Europe provides insight into population history and recovery. AB - High-resolution, male-inherited Y-chromosomal markers are a useful tool for population genetic analyses of wildlife species, but to date have only been applied in this context to relatively few species besides humans. Using nine Y chromosomal STRs and three Y-chromosomal single nucleotide polymorphism markers (Y-SNPs), we studied whether male gene flow was important for the recent recovery of the brown bear (Ursus arctos) in Northern Europe, where the species declined dramatically in numbers and geographical distribution during the last centuries but is expanding now. We found 36 haplotypes in 443 male extant brown bears from Sweden, Norway, Finland and northwestern Russia. In 14 individuals from southern Norway from 1780 to 1920, we found two Y chromosome haplotypes present in the extant population as well as four Y chromosome haplotypes not present among the modern samples. Our results suggested major differences in genetic connectivity, diversity and structure between the eastern and the western populations in Northern Europe. In the west, our results indicated that the recovered population originated from only four male lineages, displaying pronounced spatial structuring suggestive of large-scale population size increase under limited male gene flow within the western subpopulation. In the east, we found a contrasting pattern, with high haplotype diversity and admixture. This first population genetic analysis of male brown bears shows conclusively that male gene flow was not the main force of population recovery. PMID- 26769405 TI - The aggregate site frequency spectrum for comparative population genomic inference. AB - Understanding how assemblages of species responded to past climate change is a central goal of comparative phylogeography and comparative population genomics, an endeavour that has increasing potential to integrate with community ecology. New sequencing technology now provides the potential to perform complex demographic inference at unprecedented resolution across assemblages of nonmodel species. To this end, we introduce the aggregate site frequency spectrum (aSFS), an expansion of the site frequency spectrum to use single nucleotide polymorphism (SNP) data sets collected from multiple, co-distributed species for assemblage level demographic inference. We describe how the aSFS is constructed over an arbitrary number of independent population samples and then demonstrate how the aSFS can differentiate various multispecies demographic histories under a wide range of sampling configurations while allowing effective population sizes and expansion magnitudes to vary independently. We subsequently couple the aSFS with a hierarchical approximate Bayesian computation (hABC) framework to estimate degree of temporal synchronicity in expansion times across taxa, including an empirical demonstration with a data set consisting of five populations of the threespine stickleback (Gasterosteus aculeatus). Corroborating what is generally understood about the recent postglacial origins of these populations, the joint aSFS/hABC analysis strongly suggests that the stickleback data are most consistent with synchronous expansion after the Last Glacial Maximum (posterior probability = 0.99). The aSFS will have general application for multilevel statistical frameworks to test models involving assemblages and/or communities, and as large-scale SNP data from nonmodel species become routine, the aSFS expands the potential for powerful next-generation comparative population genomic inference. PMID- 26769407 TI - A proposed staging system and stage-specific interventions for familial adenomatous polyposis. AB - BACKGROUND AND AIMS: It is not possible to accurately count adenomas in many patients with familial adenomatous polyposis (FAP). Nevertheless, polyp counts are critical in evaluating each patient's response to interventions. However, the U.S. Food and Drug Administration no longer recognizes the decrease in polyp burden as a sufficient chemoprevention trial treatment endpoint requiring a measure of "clinical benefit." To develop endpoints for future industry-sponsored chemopreventive trials, the International Society for Gastrointestinal Hereditary Tumors (InSIGHT) developed an FAP staging and intervention classification scheme for lower-GI tract polyposis. METHODS: Twenty-four colonoscopy or sigmoidoscopy videos were reviewed by 26 clinicians familiar with diagnosis and treatment of FAP. The reviewers independently assigned a stage to a case by using the proposed system and chose a stage-specific intervention for each case. Our endpoint was the degree of concordance among reviewers staging and intervention assessments. RESULTS: The staging and intervention ratings of the 26 reviewers were highly concordant (rho = 0.710; 95% credible interval, 0.651-0.759). Sixty-two percent of reviewers agreed on the FAP stage, and 90% of scores were within +/-1 stage of the mode. Sixty percent of reviewers agreed on the intervention, and 86% chose an intervention within +/-1 level of the mode. CONCLUSIONS: The proposed FAP colon polyposis staging system and stage-specific intervention are based on a high degree of agreement on the part of experts in the review of individual cases of polyposis. Therefore, reliable and clinically relevant means for measuring trial outcomes can be developed. Outlier cases showing wide scatter in stage assignment call for individualized attention and may be inappropriate for enrollment in clinical trials for this reason. PMID- 26769408 TI - Yield of repeat forward-view examination of the right side of the colon in screening and surveillance colonoscopy. AB - BACKGROUND AND AIMS: Colonoscopy is less protective for cancers of the right side of the colon than for distal colon cancers. Repeat examination of the right side of the colon has been suggested to increase adenoma detection and potentially provide greater protection against the development of cancers of the right side of the colon. Our prospective study assessed the yield of a second forward-view examination of the right side of the colon done immediately after the initial examination. METHODS: All men 50 to 75 years of age undergoing screening or surveillance colonoscopy at the West Haven Veterans Affairs Medical Center were invited to participate. A second forward-view examination was performed if the Boston Bowel Preparation Scale score was 8 to 9 (scale = 0-9) with right a side of the colon segment score of 2 to 3 (scale = 0-3). The primary outcome was the per-patient adenoma detection rate (including sessile serrated polyps) on a repeated examination of the right side of the colon, defined as the number of patients with >=1 adenoma on the second examination of the right side of the colon divided by total number of patients. An increase in the adenoma detection rate (ADR) was a secondary outcome. RESULTS: Repeated examination of the right side of the colon, performed in 280 patients, revealed additional adenomas in 43 patients (15.4%; 95% confidence interval [CI] of difference, 11.3%-21.0%). The overall ADR increased by 3.2% (95% CI, 1.1%-5.3%) after the second examination of the right side of the colon; the ADR for the right side of the colon increased by 6.7% (95% CI, 3.8%-9.7%). Ten patients (3.6%) had a change in their screening/surveillance interval with the addition of findings on the second examination of the right side of the colon. CONCLUSION: A substantial 15.4% of patients had additional adenomas detected on a second forward-view examination of the right side of the colon, whereas the overall ADR increased significantly by 3.2%. Given the lack of additional training or equipment required, repeated forward-view examination of the right side of the colon is a simple, readily available method to achieve a modest improvement in the ADR. PMID- 26769409 TI - Multimodal endoscopic management of iatrogenic transverse colon injuries from a percutaneous endoscopic gastrostomy tube. PMID- 26769410 TI - Single-session endoscopic resection and focal radiofrequency ablation for short segment Barrett's esophagus with early neoplasia. AB - BACKGROUND AND AIMS: The management of early neoplasia in Barrett's esophagus (BE) requires endoscopic resection of visible lesions, followed by radiofrequency ablation (RFA) of the remaining BE. We evaluated the safety and efficacy of combining endoscopic resection and focal RFA in a single endoscopic session in patients with early BE neoplasia. METHODS: This was a retrospective analysis of patients with early BE neoplasia and a visible lesion undergoing combined endoscopic resection and focal RFA in a single session. Consecutive ablation procedures were performed every 8 to 12 weeks until complete endoscopic and histologic eradication of dysplasia and intestinal metaplasia were reached. RESULTS: Forty patients were enrolled, with a median C1M2 BE segment, a visible lesion with a median diameter of 15 mm, and invasive carcinoma in 68% of cases. Endoscopic resection was performed by using the multiband mucosectomy technique in 80% of cases, and the Barrx(90) catheter (Barrx Medical, Sunnyvale, Calif) was used for focal ablation. When an intention-to-treat analysis was used, both complete remission of all neoplasia and intestinal metaplasia were 95% after a median follow-up of 19 months. Stenoses occurred in 33% of cases and were successfully managed with a median number of 2 dilations. In 43% of patients, 1 single-session treatment resulted in complete histologic remission of intestinal metaplasia. CONCLUSIONS: Combining endoscopic resection and focal RFA in a single session appears to be effective. Less-aggressive RFA regimens could limit the adverse event rates. PMID- 26769413 TI - Binding to and Inhibition of Insulin-Regulated Aminopeptidase by Macrocyclic Disulfides Enhances Spine Density. AB - Angiotensin IV (Ang IV) and related peptide analogs, as well as nonpeptide inhibitors of insulin-regulated aminopeptidase (IRAP), have previously been shown to enhance memory and cognition in animal models. Furthermore, the endogenous IRAP substrates oxytocin and vasopressin are known to facilitate learning and memory. In this study, the two recently synthesized 13-membered macrocyclic competitive IRAP inhibitors HA08 and HA09, which were designed to mimic the N terminus of oxytocin and vasopressin, were assessed and compared based on their ability to bind to the IRAP active site, and alter dendritic spine density in rat hippocampal primary cultures. The binding modes of the IRAP inhibitors HA08, HA09, and of Ang IV in either the extended or gamma-turn conformation at the C terminus to human IRAP were predicted by docking and molecular dynamics simulations. The binding free energies calculated with the linear interaction energy method, which are in excellent agreement with experimental data and simulations, have been used to explain the differences in activities of the IRAP inhibitors, both of which are structurally very similar, but differ only with regard to one stereogenic center. In addition, we show that HA08, which is 100 fold more potent than the epimer HA09, can enhance dendritic spine number and alter morphology, a process associated with memory facilitation. Therefore, HA08, one of the most potent IRAP inhibitors known today, may serve as a suitable starting point for medicinal chemistry programs aided by MD simulations aimed at discovering more drug-like cognitive enhancers acting via augmenting synaptic plasticity. PMID- 26769415 TI - Publication of Professional Association Position Papers. PMID- 26769414 TI - Comparison of Steroid Modulation of Spontaneous Inhibitory Postsynaptic Currents in Cultured Hippocampal Neurons and Steady-State Single-Channel Currents from Heterologously Expressed alpha1beta2gamma2L GABA(A) Receptors. AB - Neuroactive steroids are efficacious modulators of gamma-aminobutyric acid type A receptor (GABA(A)) receptor function. The effects of steroids on the GABA(A) receptor are typically determined by comparing steady-state single-channel open probability or macroscopic peak responses elicited by GABA in the absence and presence of a steroid. Due to differences in activation conditions (exposure duration, concentration of agonist), it is not obvious whether modulation measured using typical experimental protocols can be used to accurately predict the effect of a modulator on native receptors under physiologic conditions. In the present study, we examined the effects of 14 neuroactive steroids and analogs on the properties of spontaneous inhibitory postsynaptic currents (sIPSCs) in cultured rat hippocampal neurons. The goal was to determine whether the magnitude of modulation of the decay time course of sIPSCs correlates with the extent of modulation and kinetic properties of potentiation as determined in previous single-channel studies. The steroids were selected to cover a wide range of efficacy on heterologously expressed rat alpha1beta2gamma2L GABA(A) receptors, ranging from essentially inert to highly efficacious (strong potentiators of single-channel and macroscopic peak responses). The data indicate a strong correlation between prolongation of the decay time course of sIPSCs and potentiation of single-channel open probability. Furthermore, changes in intracluster closed time distributions were the single best predictor of prolongation of sIPSCs. We infer that the information obtained in steady-state single-channel recordings can be used to forecast modulation of synaptic currents. PMID- 26769416 TI - We need to address more than the crisis in student clinical education, what about jobs? Response to August 2015 Viewpoint. PMID- 26769417 TI - Modified activities acted as a mediator to facilitate engagement and address the needs and personal preferences of people with dementia. PMID- 26769418 TI - People with dementia report that relationships, purposefulness, wellness and an attachment to their living environment are the most important factors associated with quality of life. PMID- 26769419 TI - Vale, Janet Barbara Bell Editor Australian Occupational Therapy Journal 1987 to 1991: 1936-2015. PMID- 26769420 TI - Position Statement: Occupational therapy in palliative care. PMID- 26769421 TI - Position Statement: Occupational therapy in oncology. PMID- 26769422 TI - Position Statement: Provision of bed sticks and poles. PMID- 26769424 TI - Corrigendum. PMID- 26769426 TI - Effects of Lead Exposure, Flock Behavior, and Management Actions on the Survival of California Condors (Gymnogyps californianus). AB - Translocation is an increasingly important tool for managing endangered species, but factors influencing the survival of translocated individuals are not well understood. Here we examine intrinsic and extrinsic drivers of survival for critically endangered California condors (Gymnogyps californianus) whose wild population recovery is reliant upon releases of captively bred stock. We used known fate models and information-theoretic methods to compare the ability of hypothesized covariates, most of which serve as proxies for lead exposure risk, to predict survival rates of condors in California. Our best supported model included the following predictors of survival: age of the recovery program, precipitation, proportion of days observed feeding on proffered carcasses, maximum blood lead concentration over the preceding 18 months, and time since release. We found that as flocks have increased in size and age, condors are increasingly likely to range more widely and less likely to be observed feeding on proffered food, and these "wilder" behaviors were associated with lower survival. After accounting for these behaviors, we found a positive survival trend, which we attribute to ongoing improvements in management. Our findings illustrate that the survival of translocated animals, such as highly social California condors, is influenced by behaviors that change through time. PMID- 26769427 TI - The Role of Animal Translocations in Conserving British Wildlife: An Overview of Recent Work and Prospects for the Future. AB - We provide an overview of terrestrial animal translocations carried out for conservation purposes in Britain, summarising what has been achieved in recent decades and discussing the issues raised by this approach to conservation. In the last 40 years, at least nine species have been reintroduced following extinction in Britain (or at least one country within Britain), including five birds, one mammal, one amphibian and two invertebrates. Many more species have been translocated within Britain to establish additional populations in order to improve conservation status. We discuss the guidelines and protocols used to assess translocation projects in Britain, notably the IUCN guidelines, most recently revised in 2013. We also discuss the likely use of species translocations in future and suggest that, in our increasingly fragmented landscapes, they will have an important role to play in conservation restoration, especially for animals with limited mobility. Moving species around is a complex undertaking and our understanding of the inherent risks involved, including the risks from disease, has improved significantly in recent years. Conservation translocations should be considered in the context of species recovery targets and high standards should be maintained so that disease risks and other potentially negative impacts are minimised. PMID- 26769428 TI - Monitoring for the Management of Disease Risk in Animal Translocation Programmes. AB - Monitoring is best viewed as a component of some larger programme focused on science or conservation. The value of monitoring is determined by the extent to which it informs the parent process. Animal translocation programmes are typically designed to augment or establish viable animal populations without changing the local community in any detrimental way. Such programmes seek to minimize disease risk to local wild animals, to translocated animals, and in some cases to humans. Disease monitoring can inform translocation decisions by (1) providing information for state-dependent decisions, (2) assessing progress towards programme objectives, and (3) permitting learning in order to make better decisions in the future. Here we discuss specific decisions that can be informed by both pre-release and post-release disease monitoring programmes. We specify state variables and vital rates needed to inform these decisions. We then discuss monitoring data and analytic methods that can be used to estimate these state variables and vital rates. Our discussion is necessarily general, but hopefully provides a basis for tailoring disease monitoring approaches to specific translocation programmes. PMID- 26769429 TI - Effect of bone morphogenetic protein-4 on in vitro growth, steroidogenesis and subsequent developmental competence of the oocyte-granulosa cell complex derived from bovine early antral follicles. AB - BACKGROUND: Bone morphogenetic proteins (BMPs) play important regulatory roles during folliculogenesis. Theca-derived BMP-4 may be beneficial to in vitro growth culture of early antral follicle-derived oocyte-granulosa cell complexes (OGCs), which is lacking in theca-derived products. METHODS: BMP-4 (0 [control], 10 and 50 ng/mL) was added to growth culture medium. Growth, steroidogenesis and the subsequent developmental competence of OGCs derived from bovine early antral follicles (0.5-1 mm) were examined. RESULTS: At 4, 8 and 12 days of growth culture, progesterone production by granulosa cells was suppressed by the addition of BMP-4 compared to the control (P < 0.05). At 12 days, both the OGC survivability and granulosa cell number in the 50 ng/mL BMP-4 treated group were lower than those of control (48.2 % vs. 67.8 %; 4.96 * 10(4) vs. 8.5 * 10(4) cells; P < 0.05, respectively), while no difference was found between 10 ng/mL and the control. The mean diameters of granulosa cell in the BMP-4 treated groups were smaller than that of the control (P < 0.05). However, the granulosa cell viability, oocyte diameter, oocyte nuclear maturation rate and normal fertilization rate were similar in all of the experimental groups, regardless of the amount of BMP-4 addition (P ? 0.05). BMP-4 treated in vitro-grown oocytes showed lower blastocyst rates than untreated ones (P < 0.05). CONCLUSIONS: BMP-4 addition during in vitro growth culture suppressed progesterone production and decreased the diameter of granulosa cells, suggesting its effect on steroidogenesis; importantly, it did not affect oocyte growth, nuclear maturation and fertilization. However, BMP-4 impaired subsequent embryonic development, and in higher concentration (50 ng/mL) even compromised OGC viability by suppressing proliferation of granulosa cells. PMID- 26769430 TI - Predictors of leptin concentration and association with cardiovascular risk in patients with coronary artery disease: results from the AtheroGene study. AB - CONTEXT: Leptin is produced in white adipose tissue, but also in human coronary atherosclerotic lesions. OBJECTIVE: The aim of this study is to assess the prognostic value of leptin in patients with proven coronary artery disease (CAD) (N = 1907). METHODS: AtheroGene is a contemporary CAD cohort study (N = 3229). Median follow-up time was 3.8 (Quartile 1/3 with 2.8/4.9) years. RESULTS: Leptin concentration was associated with a hazard ratio (HR) for the fully adjusted model of HR = 1.32 in women but was not significant in men. The endpoint cardiovascular death and non-fatal myocardial infarction was observed in 167 patients. CONCLUSION: In women with known CAD, increased leptin concentration is useful for predicting cardiovascular death and non-fatal myocardial infarction. PMID- 26769432 TI - Chemical Pathology in the Movies: Extraordinary Measures, directed by Tom Vaughan, 2010. PMID- 26769431 TI - Fluorescence Visualization-Guided Surgery for Early-Stage Oral Cancer. AB - IMPORTANCE: The prevalence of genetically altered cells in oral cancers has a negative influence on the locoregional recurrence rate and lowers survival. Fluorescence visualization (FV) can identify clinically occult, high-risk oral lesions by allowing health care professionals and surgeons to visualize and map occult disease. This process may improve overall survival by decreasing rates of locoregional recurrence. OBJECTIVE: To assess the efficacy of FV-guided surgery in reducing locoregional recurrence and improving overall survival. DESIGN, SETTING, AND PARTICIPANTS: A retrospective, case-control observational study was conducted on patients registered at a single oral oncology clinic from September 1, 2004, to August 31, 2009. The study included 246 patients 18 years or older with a diagnosis of a high-grade lesion (severe dysplasia or carcinoma in situ) or squamous cell carcinoma of less than 4 cm who underwent curative surgical treatment with at least 1 follow-up visit. Among these patients, 154 underwent surgery with FV guidance (FV group) and the other 92 underwent conventional surgery (control group). Demographic and lesional characteristics and outcomes were collected, and the key factors for the efficacy of FV-guided surgery were examined. Follow-up was completed on December 31, 2011, and data were analyzed from May 1 to November 30, 2013. MAIN OUTCOMES AND MEASURES: Local recurrence of oral lesions with a histologic grade of severe dysplasia or higher, the presence of regional failure (ie, a metastatic lesion in the cervical lymph nodes), or disease-free survival after surgery. RESULTS: Among the 246 patients included in the study (mean [SD] age, 60 [12] years; 108 women and 138 men), 156 had squamous cell carcinoma and 90 had high-grade lesions. There were no significant differences between the FV (n = 154) and control (n = 92) groups in age, smoking history, anatomical site of the lesion, tumor size, and previous oral cancer. Among the 156 patients with squamous cell carcinoma, the 92 patients in the FV group showed significant reduction in the 3-year local recurrence rate, from 40.6% (26 of 64 patients) to 6.5% (6 of 92 patients) (P < .001). Among the 90 patients with high-grade lesions, the 62 patients in the FV group showed a reduction in local recurrence rate from 11 of 28 patients (39.3%) to 5 of 62 patients (8.1%) (P < .001). The data also indicated that, compared with conventional surgery, the FV-guided approach for squamous cell carcinoma was associated with less regional failure (14 of 92 patients [15.2%] vs 16 of 64 [25.0%]; P = .08) and death (12 of 92 patients [13.0%] vs 13 of 64 [20.3%]; P = .22), although these differences were not statistically significant. CONCLUSIONS AND RELEVANCE: In this study, the use of FV as part of the surgical margin decision process significantly reduced the rate of local recurrence in preinvasive high-grade and early-stage oral cancers. An ongoing multicenter, phase 3, randomized surgical trial has completed accrual, and the data will be used to validate the results of this study. PMID- 26769436 TI - How far have we come? PMID- 26769435 TI - Factors underlying elevated troponin I levels following pacemaker primo implantation. AB - BACKGROUND: Cardiac troponins are routinely used as markers of myocardial damage. Originally, they were only intended for use in diagnosing acute coronary syndromes; however, we now know that raised serum troponin levels are not always caused by ischemia. There are many other clinical conditions that cause damage to cardiomyocytes, leading to raised levels of troponin. However, the specificity of cardiac troponins towards the myocardium is absolute. Our work focuses on mechanical damage to the myocardium and on monitoring the factors that raise the levels of cardiospecific markers after primo-implantation of a pacemaker with an actively fixed electrode. AIMS: (i) To determine whether the use of a primo implanted pacemaker with an electrode system with active fixation will raise troponin levels over baseline. (ii) To assess whether troponin I elevation is dependent on procedure complexity. METHODS: We enrolled 219 consecutive patients indicated for pacemaker primo-implantation; cardiospecific marker values (troponin I, CKMB, myoglobin) were determined before the implantation procedure and again at 6- and 18-h intervals after the procedure. We monitored duration of cardiac skiascopy, number of attempts to place the electrode (active penetration into the tissue) and intervention range (single-chamber versus dual-chamber pacing), and we assessed the clinical data. RESULTS: The average age of the enrolled patients was 78.2 +/- 8.0 years (median age, 80 years); women constituted 45% of the group. We implanted 128 dual-chamber and 91 single-chamber devices with an average skiascopic time of 38.6 +/- 22.0 s (median, 33.5 s). Troponin I serum levels increased from an initial 0.03 +/- 0.07 MUg/L (median, 0.01) to 0.18 +/- 0.17 MUg/L (median, 0.13) and 0.09 +/- 0.18 MUg/L (median, 0.04) at 6 and 18 h, respectively. The differences were statistically significant (P < 0.001 or P < 0.001). We confirmed a correlation between troponin increase and duration of skiascopy (P < 0.001). We also demonstrated a correlation between increased troponin I and number of attempts to place a pacemaker electrode (penetration into the tissue) at 6 h (P < 0.001) post-implantation. CONCLUSION: We detected slightly elevated troponin I levels in patients with primo-implanted pacemakers using electrodes with active fixation. We demonstrated a direct correlation between myocardial damage (number of electrode penetrations into the myocardium) and troponin I elevation, as well as between complexity (severity) of the implantation procedure (indicated by prolonged skiascopy) and raised troponin I. The described phenomenon demonstrates the loss of the diagnostic role of troponin I early after pacemaker primo-implantation in patients with concomitant chest pain. PMID- 26769433 TI - Patient-reported outcomes in trials of patients with polymyalgia rheumatica: a systematic literature review. AB - Patient-reported outcomes (PROs) are being increasingly recognized as important measures by rheumatologists. The objective of this review was to evaluate the frequency of use of PROs in studies of patients with polymyalgia rheumatica (PMR). A systematic literature search was performed in PubMed (up to April 2015) to identify any type of clinical studies reporting any type of PROs in patients with PMR. Articles were excluded if they did not include adults with PMR or did not report any PROs. Characteristics of each study such as study design, follow up, treatment assessed if any, number of patients, mean age, gender, and a description of PROs used were collected to perform a descriptive analysis. From 118 initial studies captured, 28 articles met the predefined criteria, and 20 were finally included in this review. Ten studies (50 %) were randomized clinical trials (RCTs), and 8 (40 %) were cohorts. The most frequently reported domains were: pain (90 %), being the most frequent tool using a visual analogue scale; morning stiffness in minutes (85 %); and function (25 %), evaluated through the Health Assessment Questionnaire. Other domains such as patient global assessment, fatigue, quality of life, and anxiety and depression were infrequently reported. A larger proportion of PROs were included in cohorts in comparison with RCT. Pain and morning stiffness are the most frequently reported PROs. Other domains that may appear relevant for patients are infrequently reported, especially function. PMID- 26769434 TI - The association of interleukin-31 polymorphisms with interleukin-31 serum levels and risk of systemic lupus erythematosus. AB - Interleukin-31 (IL-31) is the most recently discovered member of the gp130/IL-6 cytokine family which is produced mainly by activated Th2 cells. IL-31 was proved to play a crucial role in autoimmune and inflammatory diseases such as atopic dermatitis, asthma, cutaneous T cell lymphomas, Kawasaki disease and allergic rhinitis. Previous studies have identified that IL-31 could significantly induce the release of proinflammatory cytokines IL-6. Moreover, a large number of studies have shown that IL-6 plays an important role in the pathogenesis of systemic lupus erythematosus (SLE). However, up to date, no study to data was reported on the relationship between IL-31 and SLE. Therefore, in the present study, we investigated the association between IL-31 polymorphisms and its serum levels with the risk of SLE in a Chinese population. We analyzed two single nucleotide polymorphisms of IL-31 gene rs7977932 C/G and rs4758680 G/T in 190 patients with SLE and 250 age- and sex-matched controls, using polymerase chain reaction-single base extension and DNA sequencing methods. Soluble IL-31 (sIL-31) levels were measured by ELISA. From this study, we found that there were significant differences in the genotype and allele frequencies of IL-31 gene rs7977932 C/G polymorphism between the group of patients with SLE and the control group (P < 0.05). sIL-31 levels were increased in patients with SLE compared with controls (P < 0.01). Moreover, genotypes carrying the IL-31 rs7977932 G variant allele were associated with increased IL-31 levels compared to the homozygous wild-type genotype in patients with SLE. The rs7977932 C/G polymorphism of IL-31 gene and its sIL-31 levels were associated with SLE in the Chinese population. Our data suggest that IL-31 gene may play a role in the development of SLE. PMID- 26769444 TI - Sex- and age-specific incidence of healthcare-register-recorded eating disorders in the complete swedish 1979-2001 birth cohort. AB - OBJECTIVE: To investigate the sex- and age-specific incidence of healthcare register-recorded anorexia nervosa (AN) and other eating disorders (OED) in a complete birth cohort, and assess whether incidence varies by diagnostic period and (sub-) birth cohort. METHOD: We used the actuarial method and Poisson models to examine the incidence of AN and OED from 1987 to 2009 (when individuals were 8 30 years old) for a cohort of 2.3 million individuals (48.7% female) born from 1979 to 2001 in Sweden, identified using Swedish registers. RESULTS: For both sexes, incidences of AN and OED increased considerably for diagnostic periods after 2000, but differed little by birth cohort. In 2009, AN incidence in the peak age category was 205.9 cases/100,000 persons (95% CI: 178.2, 233.5) for females (14-15 years), versus 12.8 cases/100,000 (95% CI: 5.6, 20.1) for males (12-13 years). OED incidence in the peak age category was 372.1 cases/100,000 (95% CI: 336.4, 407.9) for females (16-17 years), versus 22.2 cases/100,000 (95% CI: 13.3, 31.1) for males (14-15 years). DISCUSSION: Our finding of an increase in healthcare-register-recorded eating disorders for diagnostic periods after 2000 likely reflects improved detection and expanded register coverage in Sweden. The peak of eating disorder incidence in adolescence, which began unexpectedly early for AN in males, suggests the importance of vigilance for signs of AN in young boys and early primary prevention efforts. Waiting until later could miss critical windows for intervention that could prevent disorders from taking root. PMID- 26769445 TI - Therapist adherence in the strong without anorexia nervosa (SWAN) study: A randomized controlled trial of three treatments for adults with anorexia nervosa. AB - OBJECTIVE: To develop a psychotherapy rating scale to measure therapist adherence in the Strong Without Anorexia Nervosa (SWAN) study, a multi-center randomized controlled trial comparing three different psychological treatments for adults with anorexia nervosa. The three treatments under investigation were Enhanced Cognitive Behavioural Therapy (CBT-E), the Maudsley Anorexia Nervosa Treatment for Adults (MANTRA), and Specialist Supportive Clinical Management (SSCM). METHOD: The SWAN Psychotherapy Rating Scale (SWAN-PRS) was developed, after consultation with the developers of the treatments, and refined. Using the SWAN PRS, two independent raters initially rated 48 audiotapes of treatment sessions to yield inter-rater reliability data. One rater proceeded to rate a total of 98 audiotapes from 64 trial participants. RESULTS: The SWAN-PRS demonstrated sound psychometric properties, and was considered a reliable measure of therapist adherence. The three treatments were highly distinguishable by independent raters, with therapists demonstrating significantly more behaviors consistent with the actual allocated treatment compared to the other two treatment modalities. There were no significant site differences in therapist adherence observed. DISCUSSION: The findings provide support for the internal validity of the SWAN study. The SWAN-PRS was deemed suitable for use in other trials involving CBT-E, MANTRA, or SSCM. PMID- 26769447 TI - Seven days in medicine: 9-15 January. PMID- 26769446 TI - The Influence of Component Alignment and Ligament Properties on Tibiofemoral Contact Forces in Total Knee Replacement. AB - The study objective was to investigate the influence of coronal plane alignment and ligament properties on total knee replacement (TKR) contact loads during walking. We created a subject-specific knee model of an 83-year-old male who had an instrumented TKR. The knee model was incorporated into a lower extremity musculoskeletal model and included deformable contact, ligamentous structures, and six degrees-of-freedom (DOF) tibiofemoral and patellofemoral joints. A novel numerical optimization technique was used to simultaneously predict muscle forces, secondary knee kinematics, ligament forces, and joint contact pressures from standard gait analysis data collected on the subject. The nominal knee model predictions of medial, lateral, and total contact forces during gait agreed well with TKR measures, with root-mean-square (rms) errors of 0.23, 0.22, and 0.33 body weight (BW), respectively. Coronal plane component alignment did not affect total knee contact loads, but did alter the medial-lateral load distribution, with 4 deg varus and 4 deg valgus rotations in component alignment inducing +17% and -23% changes in the first peak medial tibiofemoral contact forces, respectively. A Monte Carlo analysis showed that uncertainties in ligament stiffness and reference strains induce +/-0.2 BW uncertainty in tibiofemoral force estimates over the gait cycle. Ligament properties had substantial influence on the TKR load distributions, with the medial collateral ligament and iliotibial band (ITB) properties having the largest effects on medial and lateral compartment loading, respectively. The computational framework provides a viable approach for virtually designing TKR components, considering parametric uncertainty and predicting the effects of joint alignment and soft tissue balancing procedures on TKR function during movement. PMID- 26769448 TI - Adaptive responses of Bacillus cereus ATCC14579 cells upon exposure to acid conditions involve ATPase activity to maintain their internal pH. PMID- 26769455 TI - A comparison of two methods of heart rate variability assessment at high altitude. AB - Heart rate variability (HRV) is a useful index of autonomic function and has been linked to the development of high altitude (HA) related illness. However, its assessment at HA has been undermined by the relative expense and limited portability of traditional HRV devices which have mandated at least a minute heart rate recording. In this study, the portable ithleteTM HRV system, which uses a 55 s recording, was compared with a reference method of HRV which utilizes a 5 min electrocardiograph recording (CheckMyHeartTM ). The root mean squares of successive R-R intervals (RMSSD) for each device was converted to a validated HRV score (lnRMSSD * 20) for comparison. Twelve healthy volunteers were assessed for HRV using the two devices across seven time points at HA over 10 days. There was no significant change in the HRV values with either the ithlete (P = 0.3) or the CheckMyHeartTM (P = 0.19) device over the seven altitudes. There was also a strong overall correlation between the ithleteTM and CheckMyHeartTM device (r = 0.86; 95% confidence interval: 0.79-0.91). The HRV was consistently, though non significantly higher with ithleteTM than with the CheckMyHeartTM device [mean difference (bias) 1.8 l; 95% CI -12.3 to 8.5]. In summary, the ithleteTM and CheckMyHeartTM system provide relatively similar results with good overall agreement at HA. PMID- 26769456 TI - Recent Advances in Management of Myocarditis. PMID- 26769453 TI - Cocaine craving during protracted withdrawal requires PKCepsilon priming within vmPFC. AB - In individuals with a history of drug taking, the capacity of drug-associated cues to elicit indices of drug craving intensifies or incubates with the passage of time during drug abstinence. This incubation of cocaine craving, as well as difficulties with learning to suppress drug-seeking behavior during protracted withdrawal, are associated with a time-dependent deregulation of ventromedial prefrontal cortex (vmPFC) function. As the molecular bases for cocaine-related vmPFC deregulation remain elusive, the present study assayed the consequences of extended access to intravenous cocaine (6 hours/day; 0.25 mg/infusion for 10 day) on the activational state of protein kinase C epsilon (PKCepsilon), an enzyme highly implicated in drug-induced neuroplasticity. The opportunity to engage in cocaine seeking during cocaine abstinence time-dependently altered PKCepsilon phosphorylation within vmPFC, with reduced and increased p-PKCepsilon expression observed in early (3 days) and protracted (30 days) withdrawal, respectively. This effect was more robust within the ventromedial versus dorsomedial PFC, was not observed in comparable cocaine-experienced rats not tested for drug-seeking behavior and was distinct from the rise in phosphorylated extracellular signal regulated kinase observed in cocaine-seeking rats. Further, the impact of inhibiting PKCepsilon translocation within the vmPFC using TAT infusion proteins upon cue-elicited responding was determined and inhibition coinciding with the period of testing attenuated cocaine-seeking behavior, with an effect also apparent the next day. In contrast, inhibitor pretreatment prior to testing during early withdrawal was without effect. Thus, a history of excessive cocaine taking influences the cue reactivity of important intracellular signaling molecules within the vmPFC, with PKCepsilon playing a critical role in the manifestation of cue-elicited cocaine seeking during protracted drug withdrawal. PMID- 26769457 TI - Trophic factors for Parkinson's disease: To live or let die. AB - Trophic factors show great promise in laboratory studies as potential therapies for PD. However, multiple double-blind, clinical trials have failed to show benefits in comparison to a placebo control. This article will review the scientific rationale for testing trophic factors in PD, the results of the different clinical trials that have been performed to date, and the possible explanations for these failed outcomes. We will also consider future directions and the likelihood that trophic factors will become a viable therapy for patients with PD. PMID- 26769458 TI - Parkinson's disease and prion disease: Straining the comparison. PMID- 26769459 TI - Rasagiline for the symptomatic treatment of fatigue in Parkinson's disease. AB - BACKGROUND: Fatigue affects 40% to 50% of all PD patients and is a leading cause of disability, with no clearly established or efficacious established treatments. METHODS: In this double-blinded, placebo-controlled, pilot trial, we investigated whether rasagiline improved fatigue among PD patients. Subjects were randomized to 1 mg daily of rasagiline or placebo for 12 weeks. The primary endpoint was a change in the Modified Fatigue Impact Scale from baseline to week 12. RESULTS: Thirty PD subjects (16 men), with Modified Fatigue Impact Scale baseline score of 67 +/- 15, were randomized (16 to rasagiline vs. 14 to placebo). Significant improvement was noted in the mean Modified Fatigue Impact Scale score of the rasagiline group (12 points) as compared to placebo (8.5 points) from baseline to week 12 (P = 0.003). CONCLUSION: In this pilot study, rasagiline at a dose of 1 mg per day improved fatigue. Larger randomized studies are needed to confirm this finding. PMID- 26769460 TI - Lysosomal alterations in peripheral blood mononuclear cells of Parkinson's disease patients. AB - BACKGROUND: Reduced expression of lysosomal-associated membrane protein 2a and heatshock-cognate 70 proteins, involved in chaperone-mediated autophagy and of glucocerebrosidase, is reported in PD brains. The aim of this study was to identify systemic alterations in lysosomal-associated membrane protein 2a, heatshock cognate-70, and glucocerebrosidase levels/activity in peripheral blood mononuclear cells from PD patients. METHODS: Protein/mRNA levels were assessed in PD patients from genetically undetermined background, alpha-synuclein (G209A/A53T), or glucocerebrosidase mutation carriers and age-/sex-matched controls. RESULTS: Heatshock cognate 70 protein levels were reduced in all PD groups, whereas its mRNA levels were decreased only in the genetically undetermined group. Glucocerebrosidase protein levels were decreased only in the genetic PD groups, whereas increased mRNA levels and decreased activity were detected only in the glucocerebrosidase mutation group. CONCLUSIONS: Reduced heatshock cognate-70 levels are suggestive of an apparent systemic chaperone mediated autophagy dysfunction irrespective of genetic background. Glucocerebrosidase activity may serve as a screening tool to identify glucocerebrosidase mutation carriers with PD. PMID- 26769461 TI - Coffee consumption and risk of levodopa-induced dyskinesia in Parkinson's disease: The FRAGAMP study. PMID- 26769462 TI - Very late-onset Sandhoff disease presenting as Kennedy disease. PMID- 26769468 TI - Irreversible Electroporation (IRE) in Renal Tumors. AB - Small renal masses (SRMs) have been traditionally managed with surgical resection. Minimally invasive nephron-sparing treatment methods are preferred to avoid harmful consequences of renal insufficiency, with partial nephrectomy (PN) considered the gold standard. With increase in the incidence of the SRMs and evolution of ablative technologies, percutaneous ablation is now considered a viable treatment alternative to surgical resection with comparable oncologic outcomes and better nephron-sparing property. Traditional thermal ablative techniques suffer from unique set of challenges in treating tumors near vessels or critical structures. Irreversible electroporation (IRE), with its non-thermal nature and connective tissue-sparing properties, has shown utility where traditional ablative techniques face challenges. This review presents the role of IRE in renal tumors based on the most relevant published literature on the IRE technology, animal studies, and human experience. PMID- 26769469 TI - The increase in healthcare costs associated with frailty in older people discharged to a post-acute transition care program. AB - BACKGROUND: older people are high users of healthcare resources. The frailty index can predict negative health outcomes; however, the amount of extra resources required has not been quantified. OBJECTIVE: to quantify the impact of frailty on healthcare expenditure and resource utilisation in a patient cohort who entered a community-based post-acute program and compare this to a cohort entering residential care. METHODS: the interRAI home care assessment was used to construct a frailty index in three frailty levels. Costs and resource use were collected alongside a prospective observational cohort study of patients. A generalized linear model was constructed to estimate the additional cost of frailty and the cost of alternative residential care for those with high frailty. RESULTS: participants (n = 272) had an average age of 79, frailty levels were low in 20%, intermediate in 50% and high in 30% of the cohort. Having an intermediate or high level of frailty increased the likelihood of re-hospitalisation and was associated with 22 and 43% higher healthcare costs over 6 months compared with low frailty. It was less costly to remain living at home than enter residential care unless >62% of subsequent hospitalisations in 6 months could be prevented. CONCLUSIONS: the frailty index can potentially be used as a tool to estimate the increase in healthcare resources required for different levels of frailty. This information may be useful for quantifying the amount to invest in programs to reduce frailty in the community. PMID- 26769470 TI - Effect of soil temperature on root resistance: implications for different trees under Mediterranean conditions. AB - The effect of temperature on radial root hydraulic specific resistance (Rp) is a known phenomenon; however, the impact ofRpvariations expected from soil temperature changes over the tree root system is unknown. The present article analyses the relations hip ofRpwith temperature in olive 'Picual' and a hybrid rootstock, GF677, at five different temperatures, showing that a variation of 3- and 4.5-folds exists for olive 'Picual' and GF677 in the range from 10 to 20 degrees C. The functions obtained were scaled up to show the theoretical changes of total radial root system resistance in a common tree orchard in a Mediterranean climate at a daily and seasonal scale, using recorded soil temperature values: a difference between summer and winter of 3.5-fold for olive 'Picual' and 9-fold for GF677 was observed. Nevertheless,Rpchanges are not only related to temperature, as cavitation or circadian rhythms in aquaporin expression may also play a role. The results obtained from an experiment with the two cultivars submitted to constant pressure and temperature during several hours exhibited a variation inRp, but this was of lower magnitude than that observed due to temperature changes. Finally, a comparison ofRpat 25 degrees C between GF677 and GN15 (another rootstock obtained from the same parental as GF677) showed significant differences. According to our results, diurnal and seasonal changes inRpdue to temperature variations are of significant importance, and it would therefore be advisable to assess them explicitly into soil-plant-atmosphere continuum models. PMID- 26769472 TI - After nine years as Editor-in-Chief. PMID- 26769471 TI - Biomechanical evaluation of fixation strength among different sizes of pedicle screws using the cortical bone trajectory: what is the ideal screw size for optimal fixation? AB - BACKGROUND: The cortical bone trajectory (CBT) has attracted attention as a new minimally invasive technique for lumbar instrumentation by minimizing soft-tissue dissection. Biomechanical studies have demonstrated the superior fixation capacity of CBT; however, there is little consensus on the selection of screw size, and no biomechanical study has elucidated the most suitable screw size for CBT. The purpose of the present study was to evaluate the effect of screw size on fixation strength and to clarify the ideal size for optimal fixation using CBT. METHOD: A total of 720 analyses on CBT screws with various diameters (4.5-6.5 mm) and lengths (25-40 mm) in simulations of 20 different lumbar vertebrae (mean age: 62.1 +/- 20.0 years, 8 males and 12 females) were performed using a finite element method. First, the fixation strength of a single screw was evaluated by measuring the axial pullout strength. Next, the vertebral fixation strength of a paired-screw construct was examined by applying forces simulating flexion, extension, lateral bending, and axial rotation to the vertebra. Lastly, the equivalent stress value of the bone-screw interface was calculated. RESULTS: Larger-diameter screws increased the pullout strength and vertebral fixation strength and decreased the equivalent stress around the screws; however, there were no statistically significant differences between 5.5-mm and 6.5-mm screws. The screw diameter was a factor more strongly affecting the fixation strength of CBT than the screw fit within the pedicle (%fill). Longer screws significantly increased the pullout strength and vertebral fixation strength in axial rotation. The amount of screw length within the vertebral body (%length) was more important than the actual screw length, contributing to the vertebral fixation strength and distribution of stress loaded to the vertebra. CONCLUSIONS: The fixation strength of CBT screws varied depending on screw size. The ideal screw size for CBT is a diameter larger than 5.5 mm and length longer than 35 mm, and the screw should be placed sufficiently deep into the vertebral body. PMID- 26769473 TI - Clinical and economic burden associated with cardiovascular events among patients with hyperlipidemia: a retrospective cohort study. AB - BACKGROUND: Annual direct costs for cardiovascular (CV) diseases in the United States are approximately $195.6 billion, with many high-risk patients remaining at risk for major cardiovascular events (CVE). This study evaluated the direct clinical and economic burden associated with new CVE up to 3 years post-event among patients with hyperlipidemia. METHODS: Hyperlipidemic patients with a primary inpatient claim for new CVE (myocardial infarction, unstable angina, ischemic stroke, transient ischemic attack, coronary artery bypass graft, percutaneous coronary intervention and heart failure) were identified using IMS LifeLink PharMetrics Plus data from January 1, 2006 through June 30, 2012. Patients were stratified by CV risk into history of CVE, modified coronary heart disease risk equivalent, moderate- and low-risk cohorts. Of the eligible patients, propensity score matched 243,640 patients with or without new CVE were included to compare healthcare resource utilization and direct costs ranging from the acute (1-month) phase through 3 years post-CVE date (follow-up period). RESULTS: Myocardial infarction was the most common CVE in all the risk cohorts. During the acute phase, among patients with new CVE, the average incremental inpatient length of stay and incremental costs ranged from 4.4-6.2 days and $25,666-$30,321, respectively. Acute-phase incremental costs accounted for 61-75% of first-year costs, but incremental costs also remained high during years 2 and 3 post-CVE. CONCLUSIONS: Among hyperlipidemic patients with new CVE, healthcare utilization and costs incurred were significantly higher than for those without CVE during the acute phase, and remained higher up to 3 years post-event, across all risk cohorts. PMID- 26769474 TI - A bioluminescent arsenite biosensor designed for inline water analyzer. AB - Whole-cell biosensors based on the reporter gene system can offer rapid detection of trace levels of organic or metallic compounds in water. They are well characterized in laboratory conditions, but their transfer into technological devices for the surveillance of water networks remains at a conceptual level. The development of a semi-autonomous inline water analyzer stumbles across the conservation of the bacterial biosensors over a period of time compatible with the autonomy requested by the end-user while maintaining a satisfactory sensitivity, specificity, and time response. We focused here on assessing the effect of lyophilization on two biosensors based on the reporter gene system and hosted in Escherichia coli. The reporter gene used here is the entire bacterial luciferase lux operon (luxCDABE) for an autonomous bioluminescence emission without the need to add any substrate. In the cell-survival biosensor that is used to determine the overall fitness of the bacteria when mixed with the water sample, lux expression is driven by a constitutive E. coli promoter PrpoD. In the arsenite biosensor, the arsenite-inducible promoter P ars involved in arsenite resistance in E. coli controls lux expression. Evaluation of the shelf life of these lyophilized biosensors kept at 4 degrees C over a year evidenced that about 40 % of the lyophilized cells can be revived in such storage conditions. The performances of the lyophilized biosensor after 7 months in storage are maintained, with a detection limit of 0.2 MUM arsenite for a response in about an hour with good reproducibility. These results pave the way to the use in tandem of both biosensors (one for general toxicity and one for arsenite contamination) as consumables of an autonomous analyzer in the field. PMID- 26769475 TI - The removal of illicit drugs and morphine in two waste water treatment plants (WWTPs) under tropical conditions. AB - The consumption of drugs of abuse has been recently investigated in Martinique using the back-calculation approach, also called the "sewage epidemiology" method. Results demonstrated a very high consumption considering the international data. Wastewater treatment plants (WWTPs) are located just behind the Martinique island shoreline, and effluents could impact the vulnerable corals and marine seagrass ecosystem. The present article aims to determine a WWTP's efficiency by comparing the influent and effluent of two WWTPs, with different residence times and biological treatments, located either outdoors or indoors. In parallel, a degradation study is conducted using spiked wastewater exposed to tropical and ambient temperatures. Results demonstrate the consistent efficiency of the two processes, especially for the outdoor WWTP which uses the activated sludge process. The positive effect of the tropical temperature is showed by the increase of cocaine degradation at 31 degrees C. Thus, low illicit drug residue concentrations in effluent would indicate that wastewater treatment is efficient and even enhanced under tropical context. This fact should be confirmed with others molecules. Furthermore, our results highlight the need for subsequent studies of sludge contamination because of their local recycling as compost. PMID- 26769476 TI - Polycyclic aromatic hydrocarbon-contaminated soils: bioaugmentation of autochthonous bacteria and toxicological assessment of the bioremediation process by means of Vicia faba L. AB - Two bacterial strains, Achromobacter sp. (ACH01) and Sphingomonas sp. (SPH01), were isolated from a heavily polycyclic aromatic hydrocarbon (PAH)-contaminated soil (5431.3 +/- 102.3 ppm) for their capacity to use a mixture of anthracene, pyrene, phenanthrene and fluorene as sole carbon sources for growth and for the capacity to produce biosurfactants. The two strains were exploited for bioaugmentation in a biopile pilot plant to increase the bioavailability and the degradation of the residual PAH contamination (99.5 +/- 7.1 ppm) reached after 9 months of treatment. The denaturing gel gradient electrophoresis (DGGE) profile of the microbial ecology of the soil during the experimentation showed that the bioaugmentation approach was successful in terms of permanence of the two strains in the soil in treatment. The bioaugmentation of the two bacterial isolates positively correlated with the PAH depletion that reached 7.9 +/- 2 ppm value in 2 months of treatment. The PAH depletion was assessed by the loss of the phyto genotoxicity of soil elutriates on the model plant Vicia faba L., toxicological assessment adopted also to determine the minimum length of the decontamination process for obtaining both the depletion of the PAH contamination and the detoxification of the soil at the end of the process. The intermediate phases of the bioremediation process were the most significant in terms of toxicity, inducing genotoxic effects and selective DNA fragmentation in the stem cell niche of the root tip. The selective DNA fragmentation can be related to the selective induction of cell death of mutant stem cells that can compromise offsprings. PMID- 26769477 TI - An ecological risk assessment of heavy metal contamination in the surface sediments of Bosten Lake, northwest China. AB - Bosten Lake, a typical rump lake in an oasis in northwest China, was chosen to evaluate the distribution, sources, pollution status, and potential ecological risk of heavy metals. Sediment samples were collected from the lake, and results showed that the values of the eight heavy metals all fell within the Second Soil National Standard, while the average and maximum values of the metals were higher than the background values of the study. Multivariate statistical analysis showed that sediment concentrations of Cd, Pb, Hg, and Zn were mainly influenced by man sources. In comparison, Cu, Ni, Cr, and As were primarily natural in origin. Enrichment factor analysis (EF) and the geo-accumulation index evaluation method (I geo) showed that Cd, Hg, and Pb fell under low and partial serious pollution levels, while Zn, As, Cr, Ni, and Cu mainly were characterized under no pollution and low pollution levels. The potential ecological hazards index (RI) showed that among the eight heavy metals, Pb, Hg, and Cd posed the highest potential ecological risk, with potential ecological hazards indices (RI) of 29.06, 27.71, and 21.54 %, respectively. These findings demonstrated that recent economic development in the area of the basin has led to heavy metal accumulation in the surface sediments of the lake. PMID- 26769478 TI - Inhibition effects of high calcium concentration on anaerobic biological treatment of MSW leachate. AB - With the increasing use of municipal solid waste incineration (MSWI) and more stringent limits on landfilling of organic waste, more MSWI bottom ash is being landfilled, and the proportion of inorganic wastes in landfills is increasing, causing the increased Ca concentrations in landfill leachate. In this research, the inhibition effect of Ca concentration on the anaerobic treatment of landfill leachate was studied using a biochemical methane potential experiment. Slight inhibition of methane production occurred when the addition of Ca concentration was less than 2000 mg/L. When the addition of Ca concentration was between 6000 and 8000 mg/L, methane production was significantly reduced (to 29.4-34.8 % of that produced by the BLK reactor), and the lag phase was increased from 8.55 to 16.32 d. Moreover, when the dosage of Ca concentration increased from zero to 8000 mg/L, reductions in solution Ca concentration increased from 929 to 2611 mg/L, and the proportion of Ca in the residual sludge increased from 22.58 to 46.87 %. Based on the results, when the dosage of Ca concentration was less than 4000 mg/L, the formation of Ca precipitates on the surface of sludge appeared to prevent mass transfer and was the dominant reason for the reduction in methane production and sludge biomass. At higher Ca concentrations (6000-8000 mg/L), the severe inhibition of methane production appeared to be caused by the toxic effect of highly concentrated Ca on sludge as well as mass transfer blockage. PMID- 26769479 TI - A new approach for the modelling of chestnut wood photo-degradation monitored by different spectroscopic techniques. AB - The aim of this work is to study the colour and chemical modifications of the surfaces in chestnut wood samples as a consequence of irradiating in a controlled environment. The changes were investigated by a new analytical approach by combining traditional techniques such as reflectance spectrophotometry in the visible range and Fourier transform infrared spectroscopy with new hyperspectral imaging, in order to obtain forecast models to describe the phenomenon. The statistical elaboration of the experimental data allowed to validate the measurements and to obtain models enabling to relate the investigated parameters; the elaboration of the hyperspectral images by chemometric methods allowed for studying the changes in the reflectance spectra. A result of great importance is the possibility to correlate the oxidation of wood chemical components with the colour change in a totally non-invasive modality. This result is particularly relevant in the field of cultural heritage and in general in the control processes of wooden materials. PMID- 26769480 TI - Soil concentration profiles and diffusion and emission of nitrous oxide influenced by the application of biochar in a rice-wheat annual rotation system. AB - Field experiments were carried out to determine biochar effects on nitrous oxide (N2O) concentration profiles, diffusion, and emissions in paddy soil under rice wheat annual rotation in southeastern China. An in situ soil gas device was adapted to measure N2O concentrations at depths of 7, 15, 30, and 50 cm. Five treatments were installed as N0B0, N0B1, N1B0, N1B1, and N1B2 (B0, B1, and B2 designated as biochar at 0, 20, and 40 t ha(-1), respectively, while N0 and N1 as nitrogen at 0 and 250 kg N ha(-1) crop(-1), respectively). The results showed that N2O concentrations were higher in the 15 and 30 cm depths than other depths. With positive diffusive fluxes, the 7 cm in the rice season and 15 cm in the wheat season were main production sites. The surface N2O emissions and topsoil diffusive fluxes showed good agreement. N application strongly increased soil N2O profiles and surface emissions. Relative to N1B0, N1B1 decreased N2O concentration, surface emissions, and diffusive fluxes by 25.2, 31.8, and 26.5 %, respectively, while N1B2 decreased them averagely by 40.7, 43.2, and 44.2 %, correspondingly. Therefore, the gas gradient method is effective for estimating N2O emissions, and biochar can decrease N2O production when N was applied. PMID- 26769481 TI - Degradation of benzophenone-3 by the ozonation in aqueous solution: kinetics, intermediates and toxicity. AB - Benzophenone-3 (BP-3) is a popular ultraviolet absorbing chemical and has an adverse impact on aquatic ecosystems and human health. We determined the reaction kinetic constants of BP-3 and its de-proton pattern reacting with the molecular ozone or hydroxyl radical (.OH) for the first time. The obtained constant of the molecular ozone reacting with BP-3 or BP-3(-) was 1.03(+/-0.21) * 10(2) or 1.85(+/-0.098) * 10(5) M(-1) s(-1), respectively. And, the constant for BP-3 reacting with .OH was 9.74(+/-0.21) * 10(9) or 10.13(+/-0.25) * 10(9) M(-1) s(-1) as using 4-chlorobenzoic acid and benzotriazole as reference compounds, respectively. The intermediates generated in the molecular ozone (12 kinds) or .OH oxidation (18 kinds) were identified by LC-MS/MS. The removal efficiency of BP-3 in ozonation was dependent on the initial concentration of ozone, BP-3, and matrix water quality. The detoxification of BP-3 ozonation was depended on initial ozone dose using Chlorella vulgaris as the probe. Higher ozone dose increased the toxicity of the solution for more BP-3 being degraded and more intermediates formed, suggesting that the sole ozonation is not an effect approach for the degradation of BP-3 and some other energy should be combined. PMID- 26769482 TI - Comparison of serious inhaler technique errors made by device-naive patients using three different dry powder inhalers: a randomised, crossover, open-label study. AB - BACKGROUND: Serious inhaler technique errors can impair drug delivery to the lungs. This randomised, crossover, open-label study evaluated the proportion of patients making predefined serious errors with Pulmojet compared with Diskus and Turbohaler dry powder inhalers. METHODS: Patients >=18 years old with asthma and/or COPD who were current users of an inhaler but naive to the study devices were assigned to inhaler technique assessment on Pulmojet and either Diskus or Turbohaler in a randomised order. Patients inhaled through empty devices after reading the patient information leaflet. If serious errors potentially affecting dose delivery were recorded, they repeated the inhalations after watching a training video. Inhaler technique was assessed by a trained nurse observer and an electronic inhalation profile recorder. RESULTS: Baseline patient characteristics were similar between randomisation arms for the Pulmojet-Diskus (n = 277) and Pulmojet-Turbohaler (n = 144) comparisons. Non-inferiority in the proportions of patients recording no nurse-observed serious errors was demonstrated for both Pulmojet versus Diskus, and Pulmojet versus Turbohaler; therefore, superiority was tested. Patients were significantly less likely to make >=1 nurse-observed serious errors using Pulmojet compared with Diskus (odds ratio, 0.31; 95 % CI, 0.19-0.51) or Pulmojet compared with Turbohaler (0.23; 0.12-0.44) after reading the patient information leaflet with additional video instruction, if required. CONCLUSIONS: These results suggest Pulmojet is easier to learn to use correctly than the Turbohaler or Diskus for current inhaler users switching to a new dry powder inhaler. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01794390 (February 14, 2013). PMID- 26769485 TI - [Medical professional responsibility and clinical safety in the the practice of Orthopaedic Surgery and Traumatology]. PMID- 26769484 TI - Access to health services by lesbian, gay, bisexual, and transgender persons: systematic literature review. AB - BACKGROUND: The relationship between users and health services is considered essential to strengthen the quality of care. However, the Lesbian, Gay, Bisexual, and Transgender population suffer from prejudice and discrimination in access and use of these services. This study aimed to identify the difficulties associated with homosexuality in access and utilization of health services. METHOD: A systematic review conducted using PubMed, Cochrane, SciELO, and LILACS, considering the period from 2004 to 2014. The studies were evaluated according to predefined inclusion and exclusion criterias. Were included manuscripts written in English or Portuguese, articles examining the Lesbian, Gay, Bisexual, and Transgender population's access to health services and original articles with full text available online. RESULTS: The electronic databases search resulted in 667 studies, of which 14 met all inclusion criteria. Quantitative articles were predominant, showing the country of United States of America to be the largest producer of research on the topic. The studies reveal that the homosexual population have difficulties of access to health services as a result of heteronormative attitudes imposed by health professionals. The discriminatory attendance implies in human rights violations in access to health services. CONCLUSIONS: The non-heterosexual orientation was a determinant factor in the difficulties of accessing health care. A lot must still be achieved to ensure access to health services for sexual minorities, through the adoption of holistic and welcoming attitudes. The results of this study highlight the need for larger discussions about the theme, through new research and debates, with the aim of enhancing professionals and services for the health care of Lesbian, Gay, Bisexual, and Transgender Persons. PMID- 26769486 TI - [Clinical safety and professional liability claims in Orthopaedic Surgery and Traumatology]. AB - The specialist in orthopaedic and traumatological surgery, like any other doctor, is subject to the current legal provisions while exercising their profession. Mandatory training in the medical-legal aspects of health care is essential. Claims against doctors are a reality, and orthopaedic and traumatological surgery holds first place in terms of frequency of claims according to the data from the General Council of Official Colleges of Doctors of Catalonia. Professionals must be aware of the fundamental aspects of medical professional liability, as well as specific aspects, such as defensive medicine and clinical safety. The understanding of these medical-legal aspects in the routine clinical practice can help to pave the way towards a satisfactory and safe professional career. The aim of this review is to contribute to this training, for the benefit of professionals and patients. PMID- 26769483 TI - Niche Regulation of Limbal Epithelial Stem Cells: Relationship between Inflammation and Regeneration. AB - Human limbal palisades of Vogt are the ideal site for studying and practicing regenerative medicine due to their accessibility. Nonresolving inflammation in limbal stroma is common manifestation of limbal stem cell (SC) deficiency and presents as a threat to the success of transplanted limbal epithelial SCs. This pathologic process can be overcome by transplantation of cryopreserved human amniotic membrane (AM), which exerts anti-inflammatory, antiscarring and anti angiogenic action to promote wound healing. To determine how AM might exert anti inflammation and promote regeneration, we have purified a novel matrix, HC HA/PTX3, responsible for the efficacy of AM efficacy. HC-HA complex is covalently formed by hyaluronan (HA) and heavy chain 1 (HC1) of inter-alpha-trypsin inhibitor by the catalytic action of tumor necrosis factor-stimulated gene-6 (TSG 6) and are tightly associated with pentraxin 3 (PTX3) to form HC-HA/PTX3. In vitro reconstitution of the limbal niche can be established by reunion between limbal epithelial progenitors and limbal niche cells on different substrates. In 3-dimensional Matrigel, clonal expansion indicative of SC renewal is correlated with activation of canonical Wnt signaling and suppression of canonical bone morphogenetic protein (BMP) signaling. In contrast, SC quiescence can be achieved in HC-HA/PTX3 by activation of canonical BMP signaling and non-canonical planar cell polarity (PCP) Wnt signaling, but suppression of canonical Wnt signaling. HC HA/PTX3 is a novel matrix mitigating nonresolving inflammation and restoring SC quiescence in the niche for various applications in regenerative medicine. PMID- 26769487 TI - Programmed Death Ligand-1 on Microglia Regulates Th1 Differentiation via Nitric Oxide in Experimental Autoimmune Encephalomyelitis. AB - Microglia are considered to be potential antigen-presenting cells and have the ability to present antigen under pathological conditions. Nevertheless, whether and how microglia are involved in immune regulation are largely unknown. Here, we investigated the suppressive activity of microglia during experimental autoimmune encephalomyelitis (EAE) induced by myelin oligodendrocyte glycoprotein, with the goal of understanding their role in regulating the T cell reaction. Using flow cytometric analysis, we found that microglia were characterized by increased cell number and up-regulated programmed death ligand-1 (PD-L1) at the peak phase of EAE. Meanwhile, both the CD4(+) T cells and microglia that infiltrated the central nervous system expressed higher levels of PD1, the receptor for PD-L1, accompanied by a decline of Th1 cells. In an ex vivo co-culture system, microglia from EAE mice inhibited the proliferation of antigen-specific CD4(+) T cells and the differentiation of Th1 cells, and this was significantly inhibited by PD-L1 blockade. Further, microglia suppressed Th1 cells via nitric oxide (NO), the production of which was dependent on PD-L1. Thus, these data suggest a scenario in which microglia are involved in the regulation of EAE by suppressing Th1-cell differentiation via the PD-L1-NO pathway. PMID- 26769488 TI - Association of Optic Radiation Integrity with Cortical Thickness in Children with Anisometropic Amblyopia. AB - Previous studies have indicated regional abnormalities of both gray and white matter in amblyopia. However, alterations of cortical thickness associated with changes in white matter integrity have rarely been reported. In this study, structural magnetic resonance imaging and diffusion tensor imaging (DTI) data were obtained from 15 children with anisometropic amblyopia and 15 age- and gender-matched children with normal sight. Combining DTI and surface-based morphometry, we examined a potential linkage between disrupted white matter integrity and altered cortical thickness. The fractional anisotropy (FA) values in the optic radiations (ORs) of children with anisometropic amblyopia were lower than in controls (P < 0.05). The cortical thickness in amblyopic children was lower than controls in the following subregions: lingual cortex, lateral occipitotemporal gyrus, cuneus, occipital lobe, inferior parietal lobe, and temporal lobe (P < 0.05, corrected), but was higher in the calcarine gyrus (P < 0.05, corrected). Node-by-node correlation analysis of changes in cortical thickness revealed a significant association between a lower FA value in the OR and diminished cortical thickness in the following subregions: medial lingual cortex, lateral occipitotemporal gyrus, lateral, superior, and medial occipital cortex, and lunate cortex. We also found a relationship between changes of cortical thickness and white matter OR integrity in amblyopia. These findings indicate that developmental changes occur simultaneously in the OR and visual cortex in amblyopia, and provide key information on complex damage of brain networks in anisometropic amblyopia. Our results also support the hypothesis that the pathogenesis of anisometropic amblyopia is neurodevelopmental. PMID- 26769489 TI - TNP-ATP is Beneficial for Treatment of Neonatal Hypoxia-Induced Hypomyelination and Cognitive Decline. AB - Our previous study together with other investigations have reported that neonatal hypoxia or ischemia induces long-term cognitive impairment, at least in part through brain inflammation and hypomyelination. However, the detailed mechanisms are not fully understood. Here, we used a rodent model of neonatal hypoxia by subjecting postnatal day 0 (P0) rat pups to systemic hypoxia (3.5 h). We found that neonatal hypoxia increased the glutamate content and initiated inflammatory responses at 4 h and 1 day after hypoxia, caused hypomyelination in the corpus callosum, and impaired hippocampus-dependent learning and memory when assessed 30 60 days after hypoxia. Interestingly, much of the hypoxia-induced brain damage was ameliorated by treatment with the ATP analogue 2',3'-0-(2,4,6-trinitrophenyl) adenosine 5'-triphosphate (TNP-ATP; blocks all ionotropic P2X1-7 receptors), whereas treatment with pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid (PPADS; inhibits P2X1-3 and P2X5-7 receptors) was less neuroprotective. Our data indicated that activation of ionotropic ATP receptors might be partially, if not fully, involved in glutamate deregulation, neuroinflammation, hypomyelination, and cognitive dysfunction after neonatal hypoxia. PMID- 26769491 TI - Disruption of PHO13 improves ethanol production via the xylose isomerase pathway. AB - Xylose is the second most abundant sugar in lignocellulosic materials and can be converted to ethanol by recombinant Saccharomyces cerevisiae yeast strains expressing heterologous genes involved in xylose assimilation pathways. Recent research demonstrated that disruption of the alkaline phosphatase gene, PHO13, enhances ethanol production from xylose by a strain expressing the xylose reductase (XR) and xylitol dehydrogenase (XDH) genes; however, the yield of ethanol is poor. In this study, PHO13 was disrupted in a recombinant strain harboring multiple copies of the xylose isomerase (XI) gene derived from Orpinomyces sp., coupled with overexpression of the endogenous xylulokinase (XK) gene and disruption of GRE3, which encodes aldose reductase. The resulting YDeltaGP/XK/XI strain consumed 2.08 g/L/h of xylose and produced 0.88 g/L/h of volumetric ethanol, for an 86.8 % theoretical ethanol yield, and only YDeltaGP/XK/XI demonstrated increase in cell concentration. Transcriptome analysis indicated that expression of genes involved in the pentose phosphate pathway (GND1, SOL3, TAL1, RKI1, and TKL1) and TCA cycle and respiratory chain (NDE1, ACO1, ACO2, SDH2, IDH1, IDH2, ATP7, ATP19, SDH4, SDH3, CMC2, and ATP15) was upregulated in the YDeltaGP/XK/XI strain. And the expression levels of 125 cell cycle genes were changed by deletion of PHO13. PMID- 26769492 TI - Effect of biogeochemical interactions on bioaccessibility of arsenic in soils of a former smelter site in Republic of Korea. AB - The total concentration-based regulations for soil remediation do not consider the possible changes in bioaccessibility of remaining arsenic (As) in soils due to biogeochemical interactions after remediation. This study used As-contaminated soil and pore water samples that were collected from the rice paddy and forest/farmland located in the vicinity of a former smelter site in Republic of Korea to elucidate the changes in As bioaccessibility due to biogeochemical interactions. Bioaccessibility and chemical forms of As in soils were determined by using an in vitro method and sequential extraction, respectively, and soil microbial community was evaluated. Bioaccessibility of As in the rice paddy soil samples was higher than that in the forest/farmland soil samples. This could be attributed to relatively higher dependence of bioaccessible As in the rice paddy soils on the soil concentration of iron (Fe), aluminum, or manganese, which could lead to greater changes in bioaccessible As via reductive dissolution. The strong linear relationship (R 2 = 0.90, p value <=0.001) between the pore water As and Fe concentrations, and the greater portion of bacterial species related to reductive dissolution of Fe oxides in the rice paddies can support the higher As bioaccessibility promoted by reductive dissolution. Therefore, it is necessary to consider the potential changes in the bioaccessible As due to biogeochemical interactions in remediation of As-contaminated soils, particularly when soils are likely to be reused under reductive dissolution-promoting conditions (e.g., flooded conditions). PMID- 26769494 TI - Using Kinetic Network Models To Probe Non-Native Salt-Bridge Effects on alpha Helix Folding. AB - Salt-bridge interactions play an important role in stabilizing many protein structures, and have been shown to be designable features for protein design. In this work, we study the effects of non-native salt bridges on the folding of a soluble alanine-based peptide (Fs peptide) using extensive all-atom molecular dynamics simulations performed on the Folding@home distributed computing platform. Using Markov State Models, we show how non-native salt-bridges affect the folding kinetics of Fs peptide by perturbing specific conformational states. Furthermore, we present methods for the automatic detection and analysis of such states. These results provide insight into helix folding mechanisms and useful information to guide simulation-based computational protein design. PMID- 26769490 TI - The Orphan Nuclear Receptor TLX/NR2E1 in Neural Stem Cells and Diseases. AB - The human TLX gene encodes an orphan nuclear receptor predominantly expressed in the central nervous system. Tailess and Tlx, the TLX homologues in Drosophila and mouse, play essential roles in body-pattern formation and neurogenesis during early embryogenesis and perform crucial functions in maintaining stemness and controlling the differentiation of adult neural stem cells in the central nervous system, especially the visual system. Multiple target genes and signaling pathways are regulated by TLX and its homologues in specific tissues during various developmental stages. This review aims to summarize previous studies including many recent updates from different aspects concerning TLX and its homologues in Drosophila and mouse. PMID- 26769497 TI - Editorial. PMID- 26769495 TI - Hyaluronate nanoparticles included in polymer films for the prolonged release of vitamin E for the management of skin wounds. AB - Lecithin and hyaluronic acid were used for the preparation of polysaccharide decorated nanoparticles loaded with vitamin E using the cationic lipid dioctadecyldimethylammonium bromide (DODMA). Nanoparticles showed mean particle size in the range 130-350 nm and narrow size distribution. Vitamin E encapsulation efficiency was higher than 99%. These nanoparticles were incorporated in polymeric films containing Aloe vera extract, hyaluronic acid, sodium alginate, polyethyleneoxide (PEO) and polyvinylalcohol (PVA) as an innovative treatment in skin wounds. Films were thin, flexible, resistant and suitable for application on burn wounds. Additionally, in vitro occlusion study highlighted the dependence of the occlusive effect on the presence of nanoparticles. The results obtained show that the bioadhesive films containing vitamin E acetate and Aloe vera could be an innovative therapeutic system for the treatment of skin wounds, such as burns. The controlled release of the vitamin along with a reduction in water loss through damaged skin provided by the nanoparticle-loaded polymer film are considered important features for an improvement in wound healing and skin regeneration. PMID- 26769498 TI - Technologies for the utilisation of biogenic waste in the bioeconomy. AB - A brief review has been done of technologies involved in the exploitation of biogenic wastes, in order to provide an introduction to the subject from the technological perspective. Biogenic waste materials and biomass have historically been utilised for thousands of years, but a new conversation is emerging on the role of these materials in modern bioeconomies. Due to the nature of the products and commodities now required, a modern bioeconomy is not simply a rerun of former ones. This new dialogue needs to help us understand how technologies for managing and processing biogenic wastes--both established and novel--should be deployed and integrated (or not) to meet the requirements of the sustainability, closed loop and resource-security agendas that evidently sit behind the bioeconomy aspirations now being voiced in many countries and regions of the world. PMID- 26769499 TI - Extractability and characteristics of proteins deriving from wheat DDGS. AB - Wheat Distillers' Dried Grains with Solubles (DDGS) and in-process samples were used for protein extraction. Prolamins were the predominant protein components in the samples. The absence of extractable alpha- and gamma-gliadins in DDGS indicated protein aggregation during the drum drying processing stage. Prolamin extraction was performed using 70% (v/v) ethanol or alkaline-ethanol solution in the presence of reducing agent. DDGS extracts had relatively low protein contents (14-44.9%, w/w), regardless of the condition applied. The wet solids were the most suitable raw material for protein extraction, with recovery yields of ~ 55% (w/w) and protein content of ~ 58% (w/w) in 70% (v/v) ethanol. Protein extracts from wet solids were significantly rich in glutamic acid and proline. Mass balance calculations demonstrated the high carbohydrate content (~ 50%, w/w) of solid residues. Overall, the feasibility of utilising in-process samples of DDGS for protein extraction with commercial potential was demonstrated. PMID- 26769500 TI - Coupling of ultrafiltration and enzymatic hydrolysis aiming at valorizing shrimp wastewater. AB - The objective of this work was to obtain a protein hydrolysate from the wastewater generated during shrimp cooking, by coupling ultrafiltration and enzymatic hydrolysis processes. Initially, the effluent was concentrated by ultrafiltration, reaching a protein concentration factor of 3.2. The concentrated effluent was then enzymatically hydrolyzed, aiming at obtaining peptides with antioxidant capacity. The effects of some process variables--temperature (55-75 degrees C), pH (7-9) and enzyme/substrate (E/S) ratio (0.1-2.5%)--on the degree of hydrolysis and the antioxidant capacity were evaluated. The increase in temperature and pH resulted in lower degree of hydrolysis and higher antioxidant capacity. The conditions selected as the most suitable were: temperature of 75 degrees C, pH of 9.0 and E/S ratio of 0.1%. The hydrolysates produced at these conditions were also evaluated for total amino acid content and electrophoretic profile, showing a suitable amount of essential amino acids that covers the recommended daily needs. PMID- 26769501 TI - Optimisation of the extraction and purification of chondroitin sulphate from head by-products of Prionace glauca by environmental friendly processes. AB - The goal of the present work was to optimise the different environmental friendly processes involved in the extraction and purification of chondroitin sulphate (CS) from Prionace glauca head wastes. The experimental development was based on second order rotatable designs and evaluated by response surface methodology combined with a previous kinetic approach. The sequential stages optimised were: (1) the enzymatic hydrolysis of head cartilage catalysed by alcalase (55.7 degrees C/pH 8.2); (2) the chemical treatment of enzyme hydrolysates by means of alkaline-hydroalcoholic saline solutions (NaOH: 0.54 M, EtOH: 1.17 v, NaCl: 2.5%) to end the protein hydrolysis and to precipitate and selectively redissolve CS versus the peptidic material and (3) the selective purification and concentration of CS and the concomitant protein permeation of extracts which were obtained from previous treatment using ultrafiltration and diafiltration (UF-DF) technologies at two different cut-offs. PMID- 26769502 TI - Bioactive properties of peptides obtained from Argentinian defatted soy flour protein by Corolase PP hydrolysis. AB - Enzymatic hydrolysis of soybean meal protein isolate (SPI) obtained under two temperature conditions with Corolase PP was studied, assessing the impact of hydrolysis on potential antioxidant and antihypertensive activities. The protein was isolated from soybean meal under controlled conditions of time and temperature (70 degrees C, 1h; 90 degrees C, 30 min). Degree of hydrolysis assessed the progress of hydrolysis at different sampling times. For hydrolysates the antioxidant and angiotensin-converting-enzyme (ACE) inhibitory activities were measured. As observed, the DH was increasing until reaching 20% at 10h with disappearance of globular proteins and generation of low molecular weight peptides (less than 3kDa). A significant increase in antioxidant and ACE inhibitory capacities was observed. Five main peptides were identified, which may explain through their sequences the bioactive properties analyzed. Through this study was possible to obtain for the first time with Corolase PP soy hydrolysates with potential antioxidant and ACE inhibitory activities, which can be used to obtain new added value functional ingredients from soy meal. PMID- 26769503 TI - Structural and thermo-rheological analysis of solutions and gels of a beta lactoglobulin fraction isolated from bovine whey. AB - A beta-Lactoglobulin fraction (r-betaLg) was isolated from milk whey hydrolysates produced with cardosins from Cynara cardunculus. The impact of the technological process on the r-betaLg structure and how in turn this determined its heat induced gelation was investigated. Results were analysed taking pure beta-Lg (p betaLg) as control sample. The process induced changes in the r-betaLg native conformation causing exposure of hydrophobic groups, lower thermal stability and also, shorter thermal treatments needed to give rise to non-native and aggregated species. At pH 3.2, r-betaLg and p-betaLg solutions exhibited two gelation steps, with the advantage that r-betaLg protein may form stable gels at lower temperature than p-betaLg. At pH 7.2, a specific thermo-viscoelastic stability to 73 degrees C was found, which corresponded to the gel point in both protein solutions. The difference was that while for p-betaLg solution in sol state delta<45 degrees (solid-like), however for r-betaLg solution delta>45 degrees (fluid-like). PMID- 26769504 TI - Cheese whey: A cost-effective alternative for hyaluronic acid production by Streptococcus zooepidemicus. AB - This study focuses on the optimisation of cheese whey formulated media for the production of hyaluronic acid (HA) by Streptococcus zooepidemicus. Culture media containing whey (W; 2.1g/L) or whey hydrolysate (WH; 2.4 g/L) gave the highest HA productions. Both W and WH produced high yields on protein consumed, suggesting cheese whey is a good nitrogen source for S. zooepidemicus production of HA. Polysaccharide concentrations of 4.0 g/L and 3.2g/L were produced in W and WH in a further scale-up to 5L bioreactors, confirming the suitability of the low-cost nitrogen source. Cheese whey culture media provided high molecular weight (>3000 kDa) HA products. This study revealed replacing the commercial peptone by the low cost alternative could reduce HA production costs by up to a 70% compared to synthetic media. PMID- 26769505 TI - Experimental protocol for the recovery and evaluation of bioactive compounds of tarbush against postharvest fruit fungi. AB - The aim of this study was to recover and evaluate in vitro the antifungal activity of bioactive compounds of tarbush Flourensia cernua against fruit postharvest fungi and their antioxidant capacity. A yield of 15% of bioactive compounds of tarbush was obtained by infusion method and heating using water as solvent. A concentration of 4000 mg/L showed a higher antioxidant activity against the ABTS radical (3.21 MUMol/g) in comparison with the DPPH radical (7.62 MUMol/g); however the DPPH radical showed a better correlation with the content of tannins. The BCT showed values of IC50 between 1519 and 3310 mg/L against Rhizopus stolonifer, Botrytis cinerea, Fusarium oxysporum and Colletotrichum gloeosporioides. Antifungal activity is attributable mainly to gallic acid and flavonoids identified by infrared and HPLC analysis. In this study, the BCT have shown to be a possible natural alternative of antioxidant and antifungal compounds for use against postharvest fruit fungi. PMID- 26769506 TI - Valorisation of food waste to produce new raw materials for animal feed. AB - This study assesses the suitability of vegetable waste produced by food industry for use as a raw material for animal feed. It includes safety and nutritional viability, technical feasibility and environmental evaluation. Vegetable by products were found to be nutritionally and sanitarily appropriate for use in animal feed. The drying technologies tested for making vegetable waste suitable for use in the animal feed market were pulse combustion drying, oven and microwave. The different meal prototypes obtained were found to comply with all the requirements of the animal feed market. An action plan that takes into account all the stages of the valorisation process was subsequently defined in agreement with local stakeholders. This plan was validated in a pilot-scale demonstration trial. Finally, the technical feasibility was studied and environmental improvement was performed. This project was funded by the European LIFE+ program (LIFE09 ENV/ES/000473). PMID- 26769507 TI - Consumer acceptance and sensory profiling of reengineered kitoza products. AB - Kitoza refers to a traditional way of preparing beef and pork in Madagascar. However, in order to improve some drawbacks previous identified, the product was submitted to a reengineering process. The acceptance and sensory profiling of improved Kitoza products among Portuguese consumers was investigated. A local smoked loin sausage was selected as basis for comparison. Firstly, a Focus Group study was performed to identify sensory descriptors for Kitoza products and explore product perception. Subsequently, a Flash Profile and a consumer sensory acceptance study were conducted. Flash Profile's results showed that beef- and pork-based Kitoza products investigated differed considerably in all sensory dimensions. The Portuguese sausage was characterized as having a more intense and lasting after taste, as well as displaying a higher degree of (meat) doneness. The acceptance study yielded higher overall liking ratings for pork- than for beef-based Kitoza, although the Portuguese sausage remained the most appreciated product. PMID- 26769508 TI - Valorisation of side streams from wheat milling and confectionery industries for consolidated production and extraction of microbial lipids. AB - Crude enzymes produced via solid state fermentation (SSF) using wheat milling by products have been employed for both fermentation media production using flour rich waste (FRW) streams and lysis of Rhodosporidium toruloides yeast cells. Filter sterilization of crude hydrolysates was more beneficial than heat sterilization regarding yeast growth and microbial oil production. The initial carbon to free amino nitrogen ratio of crude hydrolysates was optimised (80.2g/g) in fed-batch cultures of R. toruloides leading to a total dry weight of 61.2g/L with microbial oil content of 61.8% (w/w). Employing a feeding strategy where the glucose concentration was maintained in the range of 12.2-17.6g/L led to the highest productivity (0.32 g/L.h). The crude enzymes produced by SSF were utilised for yeast cell treatment leading to simultaneous release of around 80% of total lipids in the broth and production of a hydrolysate suitable as yeast extract replacement. PMID- 26769509 TI - Ultrasound assisted extraction and characterization of pectin from tomato waste. AB - Pectin was extracted from tomato waste using two different extraction methods to assess its potential utilization as an alternative source of commercial pectin production. Tomato waste was treated with ammonium oxalate/oxalic acid by conventional extraction (CE), under reflux and ultrasound assisted extraction (UAE) at 37 kHz and temperatures of 60 degrees C and 80 degrees C. The pectin obtained from these methods was analysed and compared in terms of yield, chemical properties and structure. Among examined methods, CE at 60 degrees C resulted with the highest yield, but UAE during 15 min of sonication produced the pectin of better quality (anhydrouronic acid, methoxy and calcium pectate contents and degree of esterification). NMR and FTIR spectroscopy of isolated pectins revealed predominantly esterified structure, irrespective of extraction conditions. The comparison of the pectin yields obtained after extraction at 80 degrees C, indicate that similar values were found at times of 24h and 15 min for CE and UAE, respectively. According to obtained results it can be concluded that main advantage of UAE is considerable shortening of extraction procedure with strong emphasis on environmental friendly processing approach. Therefore, these results suggested that UAE could be used as an efficient technique for the extraction of pectin from tomato waste and by-products. PMID- 26769510 TI - Development of pectin films with pomegranate juice and citric acid. AB - The influence of pomegranate juice (PJ, replacing water as solvent) and citric acid (CA) on properties of pectin films was studied. PJ provided the films with a bright red color, and acted as a plasticizer. Increasing PJ/water ratio from 0/100 to 100/0 resulted in enhanced elongation (from 2% to 20%), decreased strength (from 10 to <2 MPa) and modulus (from 93 to <10 MPa), increased water vapor permeability (WVP, from 3 to 9 g.mm.kPa(-1).h(-1).m(-2)), and decreased insoluble matter (IM, from 35% to 24%). Although a crosslinking effect by CA was not confirmed, it has been suggested to occur from its effects on films. CA noticeably increased IM (from <10% to almost 40%); moreover, when measured on a dry film basis, the CA effects presented a noticeable tendency to increases strength and modulus, and to decrease WVP. The red color density was decreased by CA, suggesting a destabilization of anthocyanins. PMID- 26769511 TI - Pomegranate peel pectin films as affected by montmorillonite. AB - The industrial production of pomegranate juice has been favored by its alleged health benefits derived from its antioxidant properties. The processing of pomegranate juice involves squeezing juice from the fruit with the seeds and the peels together, leaving a pomace consisting of approximately 73 wt% peels. In this study, pectin was extracted from pomegranate peels, and used to produce films with different contents of montmorillonite (MMT) as a nanoreinforcement material. The nanoreinforcement improved the tensile strength and modulus of films when added at up to 6 wt%, while the further addition of MMT (to 8 wt%) reduced the reinforcement effect, probably because of dispersion problems. The elongation was decreased with increasing MMT concentrations. The water vapor permeability decreased with increasing MMT contents up to 8 wt% MMT, indicating that the increased tortuosity of the permeant path was effective on barrier properties of the film. PMID- 26769512 TI - Optimization of pectin extraction from banana peels with citric acid by using response surface methodology. AB - A central composite design was used to determine effects of pH (2.0-4.5), extraction temperature (70-90 degrees C) and time (120-240 min) on the yield, degree of methoxylation (DM) and galacturonic acid content (GA) of pectins extracted from banana peels with citric acid. Changes in composition during the main steps of pectin extraction were followed by Fourier transform infrared (FTIR) spectroscopy. FTIR was also used to determine DM and GA of pectins. Harsh temperature and pH conditions enhanced the extraction yield, but decreased DM. GA presented a maximum value at 83 degrees C, 190 min, and pH 2.7. The yield of galacturonic acid (YGA), which took into account both the extraction yield and the pectin purity, was improved by higher temperature and lower pH values. The optimum extraction conditions, defined as those resulting in a maximum YGA while keeping DM at a minimum of 51%, were: 87 degrees C, 160 min, pH 2.0. PMID- 26769513 TI - Novel inexpensive fungi proteases: Production by solid state fermentation and characterization. AB - A comparative study was carried out for proteases production using agroindustrial residues as substrate for solid state fermentation (SSF) of several fungal strains. High protease production was observed for most of the microorganisms studied, as well as very different biochemical characteristics, including activities at specific temperatures and a wide range of pH values. The enzymes produced were very different regarding optimum pH and they showed stability at 50 degrees C. Aspergillus oryzae showed stability at all pH values studied. Penicillium roquefortii and Aspergillus flavipes presented optimum activity at temperatures of 50 degrees C and 90 degrees C, respectively. Lyophilized protease from A. oryzae reached 1251.60 U/g and yield of 155010.66 U/kg of substrate. Therefore, the substrate as well as the microorganism strain can modify the biochemical character of the enzyme produced. The high protease activity and stability established plus the low cost of substrates, make these fungal proteases potential alternatives for the biotechnological industry. PMID- 26769514 TI - Ethanol from a biorefinery waste stream: Saccharification of amylase, protease and xylanase treated wheat bran. AB - Biorefining aims to exploit the full value of plant material by sequentially extracting and valorising its components. Many studies focus on the saccharification of virgin biomass sources, but it may be more efficient to pre extract high-value components before hydrolysis to fermentable sugars. In the current study, a bran residue from de-starched, protein depleted and xylanase treated wheat bran has been subjected to hydrothermal pretreatment, saccharification and fermentation procedures to convert the residue to ethanol. The most effective pretreatment conditions (>190 degrees C, 10 min) and saccharification conditions were identified following bench-scale liquid hot water pretreatment. Pre-extraction of enzymatically-hydrolysable starch and xylan reduced the release of furfural production, particularly when lower pretreatment severities were used. Pilot-scale steam explosion of the lignocellulosic residue followed by cellulase treatment and conversion to ethanol at a high substrate concentration (19%) gave an ethanol titre of ~ 25 g/L or a yield of 93% of the theoretical maximum. PMID- 26769515 TI - Chemical characterization of hydrothermally pretreated and enzyme-digested wheat straw: An evaluation of recalcitrance. AB - There is great interest in understanding changes that occur to cell wall constituents during saccharification of pretreated lignocellulose, particularly in relation to recalcitrance of the residues. This paper reports the effects of hydrothermal pretreatment followed by enzyme hydrolysis on the extractability and properties of recalcitrant wheat straw polymers. The results show that the undigested residue had lost much of its archestructure. Compositional analysis portrayed a considerable loss of cross-linking di-ferulic acid phenolics, hemicellulosic and cellulosic sugars. The remaining cellulosic and non-cellulosic polysaccharides were much more readily extractable in alkali and molecular profiling revealed the presence of low Mw oligomers in the fractions suggesting the partial enzyme hydrolysis of hemicelluloses and cellulose. Simultaneous saccharification and fermentation of the pretreated and enzyme-digested residues surprisingly resulted in ethanol yields of up to 99% of the theoretical. This is discussed in relation to the "recalcitrant" nature of the original pretreated and enzyme digested biomass. PMID- 26769516 TI - [Expected effect of retinal thickness after focal photocoagulation in diabetic macular oedema]. AB - BACKGROUND: Macular oedema is a form of diabetic retinopathy that can be treated with photocoagulation. The expected effect of treatment varies, and may depend on the previous characteristics of retinal thickening. OBJECTIVE: To determine whether the change in retinal thickness after focal photocoagulation for diabetic macular oedema varies due to the presence of anatomical features that may justify a separate assessment. MATERIAL AND METHODS: Non-experimental, comparative, retrospective, longitudinal study. The mean percentage change in macular volume was compared in eyes with diabetic macular oedema, 3 weeks after focal photocoagulation. The analysis was stratified according to the presence of central and perifoveal temporal thickening (Mann-Whitney U). A regression analysis was performed to identify the contribution of the anatomical variables before photocoagulation to the change in macular volume. RESULTS: A total of 72 eyes were evaluated. The mean change of macular volume in the sample was -0.68+/ 3.84%. In the multiple regression analysis, the changes of perifoveal temporal (beta 0.54, p<0.001) and central field thickness (beta 0.3, p =0.01) contributed to the change of macular volume (R=0.64). Macular volume decreased by a mean of 2.1+/-4.3% in eyes with temporal perifoveal thickening, and increased by 0.5+/ 2.8% (p =0.007) in eyes with no thickening. CONCLUSION: Perifoveal temporal thickening before photocoagulation changes the expected effect of this therapy on macular volume in eyes with focal diabetic macular oedema. It is recommended to evaluate the effect separately, and according to the perifoveal temporal thickness. PMID- 26769517 TI - [Blunt chest trauma with pneumomediastinum and pneumoperitoneum secondary to Macklin effect. Case report]. AB - BACKGROUND: Pneumomediastinum is the presence of free air around mediastinal structures, which may be spontaneous or secondary, and can occur in 10% of patients with blunt chest trauma, with the Macklin effect being its main pathophysiology. CLINICAL CASE: A 21 year old male, hit by motor vehicle, with alveolopalatal fracture and blunt chest trauma, who, 72 hrs after admission, shows subcutaneous emphysema in the anterior chest. A simple tomography of the chest and abdomen was performed, finding a pneumomediastinum, bilateral pulmonary contusions and pneumoperitoneum. Oesophageal, tracheobronchial or intra-abdominal viscera injuries were ruled out, establishing the cause of pneumomediastinum and pneumoperitoneum due to the Macklin effect. This required conservative management in intensive care unit, with a favourable clinical course and discharged after a 10 day hospital stay. DISCUSSION: Macklin effect is caused by dissection of air medially along the bronchoalveolar sheath (interstitial emphysema), secondary to alveolar breakdown and extending into mediastinal and other anatomical structures (pneumoperitoneum). It has been documented in blunt trauma, as well as in acute asthma, positive pressure ventilation, or after Valsalva manoeuvres. The imaging method of choice is computed tomography, and its characteristic findings, interstitial emphysema adhering to a bronchus and pulmonary blood vessel. CONCLUSIONS: In the presence of pneumomediastinum and pneumoperitoneum is necessary to rule out oesophageal and tracheobronchial injury before establishing the Macklin effect as its cause. The diagnosis is made with computed tomography and managed conservatively. PMID- 26769518 TI - [Thymoma in childhood. A case report and review of literature]. AB - BACKGROUND: Mediastinal tumours in children are rare. Around 25% of them can be malignant. The thymoma is an uncommon neoplasm, and during adulthood it corresponds to 30% of anterior mediastinum tumours. The peak incidence is between 55-65 years. CLINICAL CASE: A case of lymphocytic thymoma case is reported in a 4 year old patient with no previous or associated symptomatology. There was only a volume increase on the anterior neck region. The neck radiography and neck and chest tomography confirmed an anterior mediastinal mass surrounding the aorta and vena cava, as well as multiple mediastinal lymph nodes CONCLUSIONS: Early diagnosis and complete resection are the basis for management and prognosis. PMID- 26769519 TI - [Outcomes, controversies and gastric volume after laparoscopic sleeve gastrectomy in the treatment of obesity]. AB - BACKGROUND: Laparoscopic sleeve gastrectomy is a surgical procedure for the treatment of morbid obesity. However, there are still controversies regarding its efficiency in terms of weight reduction and incidence of complications. In this prospective study, the experience is presented of a referral centre for the treatment of morbid obesity with laparoscopic sleeve gastrectomy. MATERIAL AND METHODS: A prospective study on 73 patients subjected to laparoscopic sleeve gastrectomy from February 2009 to September 2013. Patients were followed-up for a period of 12 months, evaluating the development of complications, reduction of gastric volume, and the weight loss associated with the surgery, as well as their impact on the improvement of comorbidities present at beginning of the study. RESULTS: There was a statistically a significantly reduction between the preoperative body mass index (BMI) and the BMI at 12 months after laparoscopic sleeve gastrectomy (p < 0.001), despite there being an increase in the gastric volume during follow-up, measured at one month and 12 months after surgery (p < 0.001). Five patients (6.85%) had complications, with none of them serious and with no deaths in the whole series. CONCLUSIONS: Laparoscopic sleeve gastrectomy is a safe and effective technique for the treatment of morbid obesity. Its use is associated with a significant reduction in the presence of comorbidities associated with obesity. Multicentre studies with a longer period of monitoring are required to confirm the efficacy and safety of this surgical technique. PMID- 26769520 TI - [Unnecessary routine laboratory tests in patients referred for surgical services]. AB - BACKGROUND: To question the usefulness of the lab analysis considered routine testing for the identification of abnormalities in the surgical care. OBJECTIVE: To determine the percentage of unnecessary laboratory tests in the preoperative assessment as well as to estimate the unnecessary expenses. MATERIALS AND METHODS: A descriptive, cross-sectional study of patients referred for surgical evaluation between January 1st and March 31st 2013. The database of laboratory testing and electronic files were reviewed. Reference criteria from surgical services were compared with the tests requested by the family doctor. RESULTS: In 65% of the patients (n=175) unnecessary examinations were requested, 25% (n=68) were not requested the tests that they required, and only 10% of the patients were requested laboratory tests in accordance with the reference criteria (n=27). The estimated cost in unnecessary examinations was $1,129,552 in a year. DISCUSSION: The results were similar to others related to this theme, however, they had not been revised from the perspective of the first level of attention regarding the importance of adherence to the reference criteria which could prevent major expenditures. CONCLUSION: It is a priority for leaders and operational consultants in medical units to establish strategies and lines of action that ensure compliance with institutional policies so as to contain spending on comprehensive services, and which in turn can improve the medical care. PMID- 26769521 TI - [Turnbull-cutait technique in low rectal cancer: Case report]. AB - BACKGROUND: The surgical treatment for low rectal cancer involves an ultra-low anterior resection with complete mesorectal resection and coloanal anastomosis. Two-stage coloanal anastomosis such as the Turnbull-Cutait technique represents an option for patients with low rectal cancer. CLINICAL CASE: A 69 year-old female patient with a diagnosis of adenocarcinoma (T2N1), located 4 cm from the anal margin. She received neoadjuvant radiotherapy. An ultra-low anterior resection and total resection of the mesorectum were performed. The intestinal transit was reconstructed by coloanal anastomosis using the Turnbull-Cutait technique. CONCLUSION: Coloanal anastomosis with the Turnbull-Cutait technique represents a primary option for patients with low rectal cancer, avoiding a loop ileostomy, its economic impact and on their quality of life. PMID- 26769522 TI - [Retropneumoperitoneum due to endoscopic dilation. Is conservative management possible?]. AB - BACKGROUND: The incidence of anastomotic stricture varies due to the different definitions given to the condition. In most cases they are asymptomatic, and if there are symptoms, they are usually those of a partial intestinal obstruction. CASE REPORT: The case is presented of an 80 year old patient who underwent a lower anterior resection for rectal neoplasm. After ileostomy closure, he presented with subocclusive symptoms caused by stenosis of colorectal anastomosis. This stenosis was managed with endoscopic dilations, and one of these dilations produced an anastomotic perforation with pneumoperitoneum, retropneumoperitoneum, and pneumothorax. Once the patient was clinically and haemodynamically stable, the perforation was treated with conservative measures, resolving the complication satisfactorily. CONCLUSIONS: The literature describes several management options for colorectal anastomoses strictures, such as surgical resection, rubber dilators, endoscopic dilation, all of which might produce colonic perforation. Its management ranges from conservative measures to surgical intervention. PMID- 26769523 TI - [Portal perfusion with right gastroepiploic vein flow in liver transplant]. AB - BACKGROUND: Liver transplantation in patients with liver cirrhosis, portal vein thrombosis, and cavernous transformation of the portal vein, is a complex procedure with high possibility of liver graft dysfunction. It is performed in 2 19% of all liver transplants, and has a significantly high mortality rate in the post-operative period. Other procedures to maintain portal perfusion have been described, however there are no reports of liver graft perfusion using right gastroepiploic vein. CLINICAL CASE: A 20 year-old female diagnosed with cryptogenic cirrhosis, with a Child-Pugh score of 7 points (class "B"), and MELD score of 14 points, with thrombosis and cavernous transformation of the portal vein, severe portal hypertension, splenomegaly, a history of upper gastrointestinal bleeding due to oesophageal varices, and left renal agenesis. The preoperative evaluation for liver transplantation was completed, and the right gastroepiploic vein of 1-cm diameter was observed draining to the infrahepatic inferior vena cava and right suprarenal vein. An orthotopic liver transplantation was performed from a non-living donor (deceased on January 30, 2005) using the Piggy-Back technique. Portal vein perfusion was maintained using the right gastroepiploic vein, and the outcome was satisfactory. The patient was discharged 13 days after surgery. CONCLUSIONS: Liver transplantation was performed satisfactorily, obtaining an acceptable outcome. In this case, the portal perfusion had adequate blood flow through the right gastroepiploic vein. PMID- 26769524 TI - [Omental torsion. Case Report]. AB - BACKGROUND: Omental torsion is an infrequent cause of acute abdomen and its symptoms are non-specific, often presenting with pain at the right iliac fossa as the only symptom. Its aetiology remains unknown, but different risk factors have been associated with the disease, including obesity, congenital malformations, and tumours. These risk factors have been classified as predisposing or triggering, primary or secondary, and external or internal. CLINICAL CASE: The is a case of a 24-year-old male who complained about pain in the right iliac fossa without any other symptoms. The diagnosis was acute appendicitis, but during the laparoscopic approach, omental torsion was found. CONCLUSION: The diagnosis of omental torsion is is complex. However, computed tomography and ultrasound have been used successfully. The treatment for omental torsion is the resection of necrotised tissue by a laparoscopic approach. PMID- 26769525 TI - [Wilkie Syndrome. A case report]. AB - BACKGROUND: Wilkie syndrome, also referred as superior mesenteric artery syndrome, is an unusual cause of a proximal small bowel obstruction. It is characterised by the compression of the duodenum in its third portion due to a narrowing of the space between the superior mesenteric artery and the aorta. Its presentation symptoms are consistent and include the obstruction of the proximal small bowel. However, the physical and laboratory findings are non-specific. Nevertheless, many imaging methods are useful for its diagnosis. The management of this condition varies between observation and surgery, depending on each particular case. CLINICAL CASE: The case is presented of a 19 year-old male who began with acute, intense abdominal pain, nausea, vomiting, and diarrhoea. On examination, he had abdominal wall rigidity and hyperesthesia. Imaging studies were requested, revealing a decreased superior mesenteric artery angle, a shortening of the aortic mesenteric distance, and a decrease in the calibre of the third duodenal portion, all findings concomitant with Wilkie syndrome. Conservative treatment was applied and the patient was discharged without complications. CONCLUSIONS: Wilkie syndrome continues to be an unknown condition to the general practitioner, and the underdiagnosis of this condition may put a patient at risk of serious complications. A high index of suspicion is required to reach a diagnosis. Early treatment should give a good outcome most of the time. PMID- 26769526 TI - [Dysmorphic neonatal syndrome and Ogilvie syndrome]. AB - BACKGROUND: Acute colonic pseudo-obstruction, or Ogilvie syndrome, is a motility abnormality characterised by rapid and progressive dilation of the large intestine. To achieve a diagnosis it is fundamental to exclude mechanical obstruction with imaging studies such as computer axial tomography. The combined incidence of Ogilvie and dysmorphic syndrome has not been described. CLINICAL CASE: Female patient of 28 years old with a history of infant cerebral palsy came to emergency room with 4 days of intestinal obstruction. She had hypokalaemia that was reverted, but persisted with obstruction. Later after 72h with recovery of fluids and electrolytes and administration of prokinetics, the obstruction reversed. She was discharged with no complications. CONCLUSIONS: Non-invasive medical treatment solves most cases. Promising results have been achieved with neostigmine. In the event of no response to drug therapy, the next step is endoscopic treatment. Even with high recurrence this is preferred due to its lower level of complications in contrast to surgical decompression. Neonatal dysmorphic syndrome is often associated with disorders of the central nervous system. So far, there have been no reports on the incidence of this disease with Ogilvie syndrome, although 9% of cases have been described as associated with neurological events. Conservative management in this disease is the initial approach. Interventions should be reserved for when conservative treatment fails. PMID- 26769528 TI - [Primary non-Hodgkin's lymphoma of the breast. A case report]. AB - BACKGROUND: Primary breast lymphomas, a rare subtype of non-Hodgkin's lymphoma, represent 0.04 to 0.5% of all breast cancers, 0.38 to 0.7% of all lymphomas, and 1.7 to 2.2% of extranodal lymphomas. The treatment choice is based on chemotherapy containing anthracycline and rituximab. Surgery is limited to being less invasive and only for diagnostic purposes. Radiotherapy has an important role as consolidation therapy, particularly in patients with negative nodes. CLINICAL CASE: A 70 year old woman with a breast nodule in the left upper outer quadrant, with slow growth, expansive, painless, and accompanied by skin changes, malaise, weight loss, fatigue, chill, and sweating. There was tissue replacement by the mammary gland tumour, skin changes due to invasion, and a 5cm axillary lymphadenopathy. The mammography showed skin thickening and a dense pattern of 80% of breast tissue replacement, and the lymphadenopathy with loss of radiolucent centre and soft tissue invasion. The biopsy confirmed a diffuse high grade large cell lymphoma. She received an Rituximab (R-CHOP) chemotherapy scheme and radiotherapy with tangential and supraclavicular and axillary fields. After completing the chemotherapy, the patient is on follow-up, and at 15 months she is alive without disease activity. CONCLUSIONS: Primary lymphoma of the breast is a rare entity. Multimodal treatment with combined chemo-radiotherapy is the cornerstone. Surgery is reserved only for diagnostic purposes. PMID- 26769527 TI - [Applicability of 3/4D transperineal ultrasound for the diagnosis of anal sphincter injury during the immediate pospartum]. AB - BACKGROUND: The most common cause of anal sphincter injuries in women is vaginal birth. Endo-anal ultrasound is currently used for the diagnosis of anal sphincter defect. However, due to the inconvenience caused, it is not an applicable technique during the immediate post-partum. The aim of this study was to determine whether transperineal ultrasound in 3/4D is a useful diagnostic method for the assessment of anal sphincter during the immediate post-partum. MATERIAL AND METHODS: A prospective study was conducted on the vaginal deliveries performed between September 2012 and June 2013 in the Valme University Hospital (Seville). Obstetric and foetal parameters that could influence the onset of perineal tears were studied. The patients underwent a transperineal 3/4D ultrasound and a multislice study (48hours after birth). RESULTS: The study included 146 puerperal women. The sphincter complex was assessed in all of them during the immediate post-partum. External anal injuries were observed in 10.3% of the cases. In 8.2% of cases, the primary suture of the external anal sphincter was detected during ultrasound examination, and 2.1% of asymptomatic lesions were diagnosed only with post-partum ultrasound. None of the patients reported discomfort or pain. CONCLUSIONS: The 3-dimensional transperineal ultrasound is helpful in determining the primary repair of the anal sphincter during the immediate post-partum, with no discomfort for patients, as well as for establishing those early sphincter injuries that go unnoticed during vaginal delivery. PMID- 26769529 TI - [The importance of master's degree and doctorate degree in general surgery]. AB - BACKGROUND: The Doctor of Philosophy is the highest academic degree that can be obtained in universities. Graduate Education Program in Medicine in Mexico is divided into 2 major categories: Medical Specialty and Master studies/Doctor of Philosophy. The objective of this study was to demonstrate the importance of master's degrees and Doctor of Philosophy in general surgery. MATERIAL AND METHODS: A literature search in PubMed and Medline among others, from 1970 to 2015 with subsequent analysis of the literature reviews found. DISCUSSION: The physicians who conducted doctoral studies stand out as leaders in research, teaching and academic activities. Dual training with a doctorate medical specialty is a significant predictor for active participation in research projects within the best educational institutions. RESULTS: It is important to study a PhD in the education of doctors specialising in surgery, who show more training in teaching, research and development of academic activities. Currently, although there is a little proportion of students who do not finish the doctoral program, the ones who do are expected to play an important role in the future of medical scientific staff. It has been shown that most doctors with Doctor of Philosophy have wide range of career options. CONCLUSION: The importance of doctoral studies in the formation of general surgery is due to various reasons; the main one being comprehensively training physician scientists who can develop in clinical, teaching and research. PMID- 26769530 TI - [Adherence to a stability exercise program in patients with chronic low back pain]. AB - BACKGROUND: Chronic low back pain is a major cause of disability. The most effective intervention is exercise, with higher benefits in terms of pain and function. OBJECTIVE: Knowing the level of adherence to therapeutic exercise is essential to assess the effectiveness of health services, for planning strategies, optimising resources, and promoting the full recovery of patients in less time. MATERIAL AND METHODS: A prospective, observational study with 6 months follow-up was performed on 31 patients with chronic low back pain who underwent a lumbar stability program. Rating scales for pain, function, anxiety, depression and fear of avoidance were applied. Adherence was recorded using daily therapy diary. Parametric tests were performed to determine correlations of interest, and to evaluate the changes presented over time. RESULTS: The percentage of adherence was 82-84% during the 3 trimesters. There were no correlations between adherence and socio-demographic variables, depression, anxiety, or fear of avoidance. Patients categorised as adherent showed faster and more significant improvements in pain and function (p > 0.05). CONCLUSIONS: At the end of the study all patients had a significant improvement in pain and function. Depressed patients showed higher scores on scales of pain and disability at the beginning and end of the study. However, neither depression, anxiety, nor fear of running activity were predictors of non-adherence to the therapy. PMID- 26769531 TI - [Experience in training in emergencies, Division of Special Projects in Health, Instituto Mexicano del Seguro Social]. AB - BACKGROUND: There has been interest in the Division of Special Projects in Health to offer the Instituto Mexicano del Seguro Social personnel resources for training and quality thereby respond to potential contingencies. Presented here is their experience in this field. OBJECTIVE: To describe and analyse the productivity in different training programs in emergencies and disasters developed by the Division of Special Projects in Health, Mexican Social Security Institute (IMSS). MATERIAL AND METHODS: Observational study in which different training activities conducted by the Division of Special Projects in Health between 1989 and 2014 are described. Descriptive statistics were used. RESULTS: In these 25 years have trained 20,674 participants; 19.451 IMSS and 1,223 other health institutions. The most productive courses were life support (BLS/ACLS) (47.17%), distance courses "Hospital medical evacuation plans and units" (14.17%), the workshop-run "Evacuation of hospital units with an emphasis on critical areas" (5.93%) and course "Programme Evaluators of Hospital Insurance" (8.43%). CONCLUSIONS: Although the Special Projects Division Health has primarily operational functions, it nevertheless has neglected its responsibility to maintain constantly trained and updated institute staff that every day is in a position to face any type of emergency and disaster. This increases the chance that the answer to any contingency is more organised and of higher quality, always to the benefit of the population. PMID- 26769532 TI - [Congenital anomaly band, a rare cause of intestinal obstruction in children. Case report]. AB - BACKGROUND: Intestinal obstruction in children may be congenital, acquired, intrinsic or extrinsic. Most intestinal obstructions in children are the result of postoperative adhesions. Those caused by anomalous congenital band are extremely rare. CLINICAL CASE: Patient of a 1-year-old male, with no previous history of abdominal surgery or trauma. He suffered with vomiting of bile content and loss of appetite at home three days before admission. On physical examination, he was irritable, with abdominal distention, absence of peristalsis and abdominal tenderness, with no signs of peritoneal irritation being found. The blood count reported leucocytosis and the x-rays show dilated small bowel loops, fluid levels and absence of air in rectal ampulla. An open laparotomy was subsequently performed, and the intraoperative findings were consistent with a congenital band extending from the anti-mesenteric wall of the jejunum to the root of mesentery, compressing the ileum at 50cm from the ileocecal valve, causing ischaemia. The band was ligated and divided, with an uneventful postoperative course. He was discharged 4 days later without complications. CONCLUSIONS: The anomalous congenital band is not associated with abdominal problems, such as remnants of previous laparotomies or embryological structures, such as vitelline vessels or omphalomesenteric yolk duct. These bands seem to have a congenital origin and cause bowel obstruction by trapping between the band and the mesentery. The diagnosis of anomalous congenital band is extremely difficult and no imaging study is useful for the diagnosis, and only exploratory laparotomy or laparoscopy is useful for diagnosis and treatment of this problem. PMID- 26769534 TI - [Recurrent benign multicystic peritoneal mesothelioma: Approach to this rare condition]. AB - BACKGROUND: Benign multicystic mesothelioma is a rare benign tumour derived from the peritoneal mesothelium. The aim of this paper is to present a case of this rare tumour and review the clinical features, diagnosis and treatment of this disease. CLINICAL CASE: The case is presented of a 22-year-old female diagnosed with multicystic mesothelioma after an urgent resection of intra-abdominal tumour in the context of acute abdominal pain. In the subsequent follow-up, the patient had a recurrence of the lesion, and at 2 years was treated by further resection. CONCLUSIONS: Benign multicystic mesothelioma is a benign tumour of unknown origin, and with a non-specific clinical manifestation. The most effective treatment is surgical, although there is a high tendency to local recurrence. PMID- 26769533 TI - [Moderately differentiated adenocarcinoma of the third duodenal portion]. AB - BACKGROUND: Duodenal carcinoma is very rare. It represents 33-45% of the all tumours of the small bowel. The symptoms are non-specific, and the diagnosis is often accidental. CLINICAL CASE: A 35-year old man was admitted to our hospital with post-prandial abdominal pain. Upper gastrointestinal examination revealed a tumour of the third duodenal portion, which was diagnosed, using endoscopic biopsy, as a tubular adenoma with high grade dysplasia. The computed axial tomography scan, the magnetic resonance imaging, and the endoscopic ultrasound showed the neoplasia of the third duodenal portion with no lymph node or peritoneal metastases. Partial resection of the duodenum was performed. The definitive histopathological diagnosis was primary adenocarcinoma of the third duodenal portion. pT2 N0M0, originated in a tubular adenoma. CONCLUSIONS: Primitive neoplasia of the duodenum is very rare. Duodeno-cephalo-pancreatectomy is recommended in proximally located tumours, while segmental resection of the duodenum is appropriate for distal locations, with the same survival. PMID- 26769535 TI - [Gallstone ileus after endoscopic retrograde cholangiopancreatography]. AB - BACKGROUND: Gallstone ileus is caused by the exit of a gallstone from the gallbladder or bile duct into the small intestine, resulting in bowel obstruction if this stone becomes lodged in a small bowel loop. CLINICAL CASE: The case is presented of a 78 year-old woman with an episode of intestinal obstruction. After studying the main cause of the obstruction, it was decided to perform a laparotomy where a gallstone located in the terminal ileum was causing the obstruction. No fistula was observed between the gallbladder and the bile duct and the intestinal tract. It is important to note the history of an endoscopic retrograde cholangiopancreatography performed a few months earlier, as it would probably be the cause of the passage of the gallstone to the small bowel. CONCLUSION: Few reports of gallstone ileus have been described in the literature after performing an endoscopic retrograde cholangiopancreatography. In these cases, the intestinal obstruction usually occurs several months after the endoscopic retrograde cholangiopancreatography, so the diagnosis is often delayed. Surgery is usually the definitive treatment and it consists of the removal the stone by enterotomy and performing a cholecystectomy. Biliary enteric fistula repair is not necessary since this does not form. PMID- 26769536 TI - Historical Perspectives of The American Association for Thoracic Surgery: Fredrick G. Kergin, MD (1907-1974). PMID- 26769538 TI - Mitral valve-in-valve hemodynamic performance: An in vitro study. AB - OBJECTIVES: The valve-in-valve (VinV) procedure may be used in high-risk patients with failed mitral surgical bioprostheses. The objective of this in vitro study was to assess the hemodynamic function of different VinV configurations. METHODS: A double activation duplicator was used to test 11 valve configurations (surgical bioprostheses alone) and 15 VinV configurations (Sapien [Edwards Lifesciences, Irvine, Calif] implanted within the surgical bioprosthesis) under 8 different hemodynamic conditions. The internal orifice diameter (IOD) of the surgical bioprosthesis was measured with a Smartscope (OGP Multi Sensor Measuring Instruments, Singapore). RESULTS: The VinV procedure was associated with significant deterioration in antegrade hemodynamic parameters compared with valve configuration (effective orifice area, 1.51 +/- 0.21 cm(2) vs 1.65 +/- 0.37 cm(2); P < .001 and regurgitant fraction, 11.5% +/- 7.2% vs 4.8% +/- 3.8%; P < .001). Among the 120 tested experimental VinV situations, moderate or greater mitral stenosis occurred in 52 situations and mild or greater regurgitation occurred in 28 situations. The IOD of the surgical bioprosthesis was the main independent determinant of effective orifice area and regurgitant fraction. An IOD < 22 mm was associated with higher risk of significant mitral stenosis, particularly when the oversizing was >20%, and IOD > 23 mm was associated with higher risk of paravalvular regurgitation when oversizing was <8%. CONCLUSIONS: This in vitro study shows that VinV within mitral surgical bioprostheses provides satisfactory hemodynamic results in the majority of patients. However, significant mitral stenosis is more likely to occur when the IOD of the surgical bioprosthesis is <22 mm, and particularly when the percentage of oversizing is >20%. Significant paravalvular regurgitation is rare and occurs with larger IODs and lower percentage of oversizing (8%). PMID- 26769539 TI - Association of class I and II HLA alleles and haplotypes with susceptibility to vitiligo: a study of patients with vitiligo from southeast Brazil. AB - BACKGROUND: The association of vitiligo with the HLA complex has been previously described in various populations worldwide. However, until now, no similar study has been conducted in Brazil. The aim of this study was to determine the association of HLA alleles with vitiligo in the population of southeast Brazil. METHODS: DNA samples from 116 patients with vitiligo and 243 healthy controls were obtained using the salting-out technique. HLA class I (A*, B*, C*) and class II (DRB1* and DQB1*) alleles were amplified by polymerase chain reaction with specific oligonucleotide sequences. RESULTS: The case-control study identified susceptibility associations with alleles HLA-A*02 (P = 0.0001, Pc = 0.0020, odds ratio [OR] = 2.68, 95% confidence interval [CI] = 1.69-4.26) and HLA-DRB1*07 (P = 0.0001, Pc = 0.0013, OR = 2.69, 95% CI = 1.66-4.34). The alleles HLA-A*32 (P = 0.0156, Pc = 0.3120, OR = 22.43, 95% CI = 1.12-449.46) and HLA-DQB1*06 (P = 0.0207, Pc = 0.1035, OR = 0.28, 95% CI = 0.10-0.81) were associated with both localized and generalized vitiligo. The haplotype analysis revealed that A*02 B*51-C*15-DRB1*07-DQB1*02 (P = 0.0113), A*02-B*15-C*07-DRB1*13-DQB1*06 (P = 0.0340), and A*29-B*44-C*16-DRB1*07-DQB1*02 (P = 0.0340) were associated with a predisposition to the disease. CONCLUSIONS: Our results show that HLA alleles and haplotypes may contribute to the pathogenesis of vitiligo in the Brazilian population. PMID- 26769537 TI - Mitigation of myocardial fibrosis by molecular cardiac surgery-mediated gene overexpression. AB - OBJECTIVE: Heart failure is accompanied by up-regulation of transforming growth factor beta signaling, accumulation of collagen and dysregulation of sarcoplasmic reticulum calcium adenosine triphosphatase cardiac isoform 2a (SERCA2a). We examined the fibrotic response in small and large myocardial infarct, and the effect of overexpression of the SERCA2a gene. METHODS: Ischemic cardiomyopathy was induced via creation of large or small infarct in 26 sheep. Animals were divided into 4 groups: small infarct; large infarct with heart failure; gene treated (large infarct with heart failure followed by adeno-associated viral vector, serotype 1.SERCA2a gene construct transfer by molecular cardiac surgery with recirculating delivery); and control. RESULTS: Heart failure was significantly less pronounced in the gene-treated and small-infarct groups than in the large-infarct group. Expression of transforming growth factor beta signaling components was significantly higher in the large-infarct group, compared with the small-infarct and gene-treated groups. Both the angiotensin II type 1 receptor and angiotensin II were significantly elevated in the small- and large-infarct groups, whereas gene treatment diminished this effect. Active fibrosis with de novo collagen synthesis was evident in the large-infarct group; the small-infarct and gene-treated groups showed less fibrosis, with a lower ratio of de novo to mature collagen. CONCLUSIONS: The data presented provide evidence that progression of fibrosis is mediated through increased transforming growth factor beta and angiotensin II signaling, which is mitigated by increased SERCA2a gene expression. PMID- 26769540 TI - The New World arenavirus Tacaribe virus induces caspase-dependent apoptosis in infected cells. AB - The Arenaviridae is a diverse and growing family of viruses that already includes more than 25 distinct species. While some of these viruses have a significant impact on public health, others appear to be non-pathogenic. At present little is known about the host cell responses to infection with different arenaviruses, particularly those found in the New World; however, apoptosis is known to play an important role in controlling infection of many viruses. Here we show that infection with Tacaribe virus (TCRV), which is widely considered the prototype for non-pathogenic arenaviruses, leads to stronger induction of apoptosis than does infection with its human-pathogenic relative Junin virus. TCRV-induced apoptosis occurred in several cell types during late stages of infection and was shown to be caspase-dependent, involving the activation of caspases 3, 7, 8 and 9. Further, UV-inactivated TCRV did not induce apoptosis, indicating that the activation of this process is dependent on active viral replication/transcription. Interestingly, when apoptosis was inhibited, growth of TCRV was not enhanced, indicating that apoptosis does not have a direct negative effect on TCRV infection in vitro. Taken together, our data identify and characterize an important virus-host cell interaction of the prototypic, non pathogenic arenavirus TCRV, which provides important insight into the growing field of arenavirus research aimed at better understanding the diversity in responses to different arenavirus infections and their functional consequences. PMID- 26769550 TI - A network of amygdala connections predict individual differences in trait anxiety. AB - In this study we demonstrate that the pattern of an amygdala-centric network contributes to individual differences in trait anxiety. Individual differences in trait anxiety were predicted using maximum likelihood estimates of amygdala structural connectivity to multiple brain targets derived from diffusion-tensor imaging (DTI) and probabilistic tractography on 72 participants. The prediction was performed using a stratified sixfold cross validation procedure using a regularized least square regression model. The analysis revealed a reliable network of regions predicting individual differences in trait anxiety. Higher trait anxiety was associated with stronger connections between the amygdala and dorsal anterior cingulate cortex, an area implicated in the generation of emotional reactions, and inferior temporal gyrus and paracentral lobule, areas associated with perceptual and sensory processing. In contrast, higher trait anxiety was associated with weaker connections between amygdala and regions implicated in extinction learning such as medial orbitofrontal cortex, and memory encoding and environmental context recognition, including posterior cingulate cortex and parahippocampal gyrus. Thus, trait anxiety is not only associated with reduced amygdala connectivity with prefrontal areas associated with emotion modulation, but also enhanced connectivity with sensory areas. This work provides novel anatomical insight into potential mechanisms behind information processing biases observed in disorders of emotion. PMID- 26769553 TI - Professor Kenneth Sunderland Holt (May 1, 1925-June 25, 2015): a personal tribute. PMID- 26769552 TI - The cost-effectiveness of cardiac computed tomography for patients with stable chest pain. AB - OBJECTIVE: To assess the cost-effectiveness of cardiac CT compared with exercise stress testing (EST) in improving the health-related quality of life of patients with stable chest pain. METHODS: A cost-utility analysis alongside a single centre randomised controlled trial carried out in Northern Ireland. Patients with stable chest pain were randomised to undergo either cardiac CT assessment or EST (standard care). The main outcome measure was cost per quality adjusted life year (QALY) gained at 1 year. RESULTS: Of the 500 patients recruited, 250 were randomised to cardiac CT and 250 were randomised to EST. Cardiac CT was the dominant strategy as it was both less costly (incremental total costs -L50.45; 95% CI -L672.26 to L571.36) and more effective (incremental QALYs 0.02; 95% CI 0.02 to 0.05) than EST. At a willingness-to-pay threshold of L20 000 per QALY the probability of cardiac CT being cost-effective was 83%. Subgroup analyses indicated that cardiac CT appears to be most cost-effective in patients with a likelihood of coronary artery disease (CAD) of <30%, followed by 30%-60% and then >60%. CONCLUSIONS: Cardiac CT is cost-effective compared with EST and cost effectiveness was observed to vary with likelihood of CAD. This finding could have major implications for how patients with chest pain in the UK are assessed, however it would need to be validated in other healthcare systems. TRIAL REGISTRATION NUMBER: (ISRCTN52480460); results. PMID- 26769554 TI - Commentary on the palliative care for children: education, collaboration and compassion. PMID- 26769556 TI - Corrigendum. PMID- 26769551 TI - Brain volumetric changes and cognitive ageing during the eighth decade of life. AB - Later-life changes in brain tissue volumes--decreases in the volume of healthy grey and white matter and increases in the volume of white matter hyperintensities (WMH)--are strong candidates to explain some of the variation in ageing-related cognitive decline. We assessed fluid intelligence, memory, processing speed, and brain volumes (from structural MRI) at mean age 73 years, and at mean age 76 in a narrow-age sample of older individuals (n = 657 with brain volumetric data at the initial wave, n = 465 at follow-up). We used latent variable modeling to extract error-free cognitive levels and slopes. Initial levels of cognitive ability were predictive of subsequent brain tissue volume changes. Initial brain volumes were not predictive of subsequent cognitive changes. Brain volume changes, especially increases in WMH, were associated with declines in each of the cognitive abilities. All statistically significant results were modest in size (absolute r-values ranged from 0.114 to 0.334). These results build a comprehensive picture of macrostructural brain volume changes and declines in important cognitive faculties during the eighth decade of life. PMID- 26769557 TI - Accurate and semi-automated analysis of bacterial association with mammalian cells. AB - To efficiently and accurately quantify the interactions of bacteria with mammalian cells, a reliable fluorescence microscopy assay was developed. Bacteria were engineered to become rapidly and stably fluorescent using Green Fluorescent Protein (GFP) expressed from an inducible Tet promoter. Upon application of the fluorescent bacteria onto a monolayer, extracellular bacteria could be discriminated from intracellular bacteria by antibody staining and microscopy. All bacteria could be detected by GFP expression. External bacteria stained orange, whereas internalised bacteria did not. Internalised bacteria could thus be discriminated from external bacteria by virtue of being green but not orange fluorescent. Image acquisition and counting of various fluorophore-stained entities were accomplished with a high-content screening platform. This allowed for semi-automated and accurate counting of intracellular and extracellular bacteria. PMID- 26769558 TI - Development and evaluation of multiplex PCR assays for rapid detection of virulence-associated genes in Arcobacter species. AB - As the pathogenicity of Arcobacter species might be associated with various virulence factors, this study was aimed to develop and optimize three single-tube multiplex PCR (mPCR) assays that can efficiently detect multiple virulence associated genes (VAGs) in Arcobacter spp. including the Arcobacter butzleri, Arcobacter cryaerophilus and Arcobacter skirrowii, respectively. The recognized target virulence factors used in the study were fibronectin binding protein (cj1349), filamentous hemagglutinin (hecA), hemolysin activation protein (hecB), hemolysin (tlyA), integral membrane protein virulence factor (mviN), invasin (ciaB), outer membrane protein (irgA) and phospholipase (pldA). Identical results were obtained between singleplex PCR and mPCR assays and no cross- and/or non specific amplification products were obtained when tested against other closely related bacterial species. The sensitivities of these three mPCR assays were ranging from 1ngMUL(-1) to 100ngMUL(-1) DNA. The developed assays with combinations of duplex or triplex PCR primer pairs of VAGs were further evaluated and validated by applying them to isolates of the A. butzleri, A. cryaerophilus and A. skirrowii recovered from fecal samples of human and animal origins. The findings revealed that the distribution of the ciaB (90%), mviN (70%), tlyA (50%) and pldA (45%) genes among these target species was significantly higher than the hecA (16%), hecB (10%) and each of irgA and cj1349 (6%) genes, respectively. The newly developed mPCR assays can be used as rapid technique and useful markers for the detection, prevalence and profiling of VAGs in the Arcobacter spp. Moreover, these assays can easily be performed with a high throughput to give a presumptive identification of the causal pathogen in epidemiological investigation of human infections. PMID- 26769559 TI - Trends in lung cancer in elderly in Denmark, 1980-2012. AB - BACKGROUND: Lung cancer is an increasing problem in the older patient population due to the improvement in life expectation of the Western population. In this study we examine trends in lung cancer incidence and mortality in Denmark from 1980 to 2012 with special focus on the elderly. MATERIAL AND METHODS: Lung cancer was defined as ICD-10 codes C33-34. Data derived from the NORDCAN database with comparable data on cancer incidence, mortality, prevalence, and relative survival in the Nordic countries, where the Danish data were delivered from the Danish Cancer Registry and the Danish Cause of Death Registry with follow-up for death or emigration until the end of 2013. RESULTS: In 2012, about 50% of lung cancers were diagnosed among persons aged 70 years or more. For men and women older than 75 years the incidence rates have been increasing and for those aged 80-84 years, the rates have doubled since 1980. Due to the poor survival, similar trends were seen in mortality rates. Over the period, the one-year relative survival rates almost doubled in patients aged 70 years or more, but still only 25% of the patients aged 80-89 years survived their lung cancer for one year. CONCLUSION: The incidence of lung cancer is closely linked to the pattern of tobacco smoking with the differences between gender and age groups reflecting smoking behavior in birth cohorts. Elderly patients with lung cancer are a heterogeneous group in whom treatment should be offered according to comorbidity and a geriatric assessment. PMID- 26769561 TI - Lifting strength in two-person teamwork. AB - This study examined the effects of lifting range, hand-to-toe distance, and lifting direction on single-person lifting strengths and two-person teamwork lifting strengths. Six healthy males and seven healthy females participated in this study. Two-person teamwork lifting strengths were examined in both strength matched and strength-unmatched groups. Our results showed that lifting strength significantly decreased with increasing lifting range or hand-to-toe distance. However, lifting strengths were not affected by lifting direction. Teamwork lifting strength did not conform to the law of additivity for both strength matched and strength-unmatched groups. In general, teamwork lifting strength was dictated by the weaker of the two members, implying that weaker members might be exposed to a higher potential danger in teamwork exertions. To avoid such overexertion in teamwork, members with significantly different strength ability should not be assigned to the same team. PMID- 26769562 TI - Lactobacillus acidophilus modulates inflammatory activity by regulating the TLR4 and NF-kappaB expression in porcine peripheral blood mononuclear cells after lipopolysaccharide challenge. AB - A total of forty weaned pigs ((Landrace * Yorkshire) * Duroc) were used to evaluate the effects of Lactobacillus acidophilus on inflammatory activity after lipopolysaccharide (LPS) challenge. Experimental treatments were as follows: (T1) control diet+saline challenge; (T2) control diet with 0.1% L. acidophilus+saline challenge; (T3) control diet+LPS challenge; and (T4) control diet with 0.1% L. acidophilus+LPS challenge. On d-14, piglets were challenged with saline (T1 and T2) or LPS (T3 and T4). Blood samples were obtained at 0, 2, 4, 6 and 12 h after being challenged and analysed for immune cell cytokine production and gene expression pattern. The L. acidophilus treatment increased the average daily weight gain (ADWG) and average daily feed intake (ADFI) compared with the control diet. With the control diet, the LPS challenge (T3) increased the number of immune cells and expression of TNF-alpha and IL-6 compared with the saline challenge (T1). Whereas with the saline challenge L. acidophilus treatment (T2) increased the number of leucocytes and CD4 compared with the control diet (T1), with the LPS challenge L. acidophilus treatment (T4) decreased the number of leucocytes, lymphocytes, CD4+ and CD8+ and expression of TNF-alpha and IL-6 compared with the control diet (T3). L. acidophilus treatment decreased the expression of TRL4 and NF-kappaB in peripheral blood mononuclear cells (PBMC) after LPS challenge, which leads to inhibition of TNF-alpha, IFN-gamma, IL-6, IL 8 and IL1B1 and to induction of IL-4 and IL-10. We suggested that L. acidophilus improved ADWG and ADFI and protected against LPS-induced inflammatory responses by regulating TLR4 and NF-kappaB expression in porcine PBMC. PMID- 26769564 TI - Endothelial cilia protect against atherosclerosis. PMID- 26769563 TI - Attenuation of pattern recognition receptor signaling is mediated by a MAP kinase kinase kinase. AB - Pattern recognition receptors (PRRs) play a key role in plant and animal innate immunity. PRR binding of their cognate ligand triggers a signaling network and activates an immune response. Activation of PRR signaling must be controlled prior to ligand binding to prevent spurious signaling and immune activation. Flagellin perception in Arabidopsis through FLAGELLIN-SENSITIVE 2 (FLS2) induces the activation of mitogen-activated protein kinases (MAPKs) and immunity. However, the precise molecular mechanism that connects activated FLS2 to downstream MAPK cascades remains unknown. Here, we report the identification of a differentially phosphorylated MAP kinase kinase kinase that also interacts with FLS2. Using targeted proteomics and functional analysis, we show that MKKK7 negatively regulates flagellin-triggered signaling and basal immunity and this requires phosphorylation of MKKK7 on specific serine residues. MKKK7 attenuates MPK6 activity and defense gene expression. Moreover, MKKK7 suppresses the reactive oxygen species burst downstream of FLS2, suggesting that MKKK7-mediated attenuation of FLS2 signaling occurs through direct modulation of the FLS2 complex. PMID- 26769565 TI - Endothelial primary cilia inhibit atherosclerosis. AB - Primary cilia are microtubule-based structures present on most mammalian cells that are important for intercellular signaling. Cilia are present on a subset of endothelial cells where they project into the vessel lumen and are implicated as mechanical sensors of blood flow. To test the in vivo role of endothelial cilia, we conditionally deleted Ift88, a gene required for ciliogenesis, in endothelial cells of mice. We found that endothelial primary cilia were dispensable for mammalian vascular development. Cilia were not uniformly distributed in the mouse aorta, but were enriched at vascular branch points and sites of high curvature. These same sites are predisposed to the development of atherosclerotic plaques, prompting us to investigate whether cilia participate in atherosclerosis. Removing endothelial cilia increased atherosclerosis in Apoe(-/-) mice fed a high fat, high-cholesterol diet, indicating that cilia protect against atherosclerosis. Removing endothelial cilia increased inflammatory gene expression and decreased eNOS activity, indicating that endothelial cilia inhibit pro-atherosclerotic signaling in the aorta. PMID- 26769566 TI - Factors Associated With Mortality in Pediatric vs Adult Nasopharyngeal Carcinoma. AB - IMPORTANCE: Nasopharyngeal carcinoma (NPC) is endemic in some Asian regions but is uncommon in the United States. Little is known about the racial, demographic, and biological characteristics of the disease in pediatric patients. OBJECTIVES: To improve understanding of the differences between pediatric and adult NPC and to determine whether race conferred a survival difference among pediatric patients with NPC. DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study included all 17 317 patients with a primary diagnosis of NCP in the National Cancer Data Base from January 1, 1998, to December 31, 2011. Of these, 699 patients were 21 years or younger (pediatric); 16 618 patients, older than 21 years (adult). Data were analyzed after data collection. EXPOSURE: Pediatric age at diagnosis of NPC. MAIN OUTCOMES AND MEASURES: Demographic, tumor, and treatment characteristics of pediatric patients with NPC were compared with those of adults using the chi2 test for categorical variables. An adjusted Cox proportional hazards regression model was used to examine survival differences in pediatric patients relative to adult patients. In addition, the risk for pediatric mortality by race was estimated. RESULTS: Of the 17 317 patients, a total of 699 pediatric and 16 618 adult patients were identified with a primary diagnosis of NPC (female, 239 pediatric patients [34.2%] and 5153 adult patients [32.4%]). Pediatric patients were most commonly black (299 of 686 [43.6%]), whereas adults were most likely to be non-Hispanic white (9839 of 16 504 [60.0%]; P < .001). Pediatric patients were less likely to be Asian (39 of 686 [5.7%]) than were adults (3226 of 16 405 [19.7%]; P < .001). Pediatric patients were more likely to have regional nodal evaluation and to present with stage IV disease (227 of 643 [35.3%] and 330 of 565 [58.4%], respectively) than were adult patients (3748 of 15 631 [24.0%] and 6553 of 13 721 [47.8%], respectively; P < .001 for both comparisons). Pediatric patients had a lower risk for mortality relative to adults (hazard ratio, 0.37; 95% CI, 0.25-0.56). No difference in mortality by racial group was found among pediatric patients (hazard ratio, 1.10; 95% CI, 0.82-1.40). CONCLUSIONS AND RELEVANCE: Pediatric patients with NPC were more commonly black and presented more frequently with stage IV disease. Pediatric patients had a decreased mortality risk relative to adults, even after adjusting for covariables. Asian race was not associated with increased mortality in pediatric patients with NPC. Racial differences are not associated with an increased risk for mortality among pediatric patients. PMID- 26769568 TI - Cholangiocarcinoma: Current opinion on clinical practice diagnostic and therapeutic algorithms: A review of the literature and a long-standing experience of a referral center. AB - In the oncology landscape, cholangiocarcinoma is a challenging disease in terms of both diagnosis and treatment. Besides anamnesis and clinical examination, a definitive diagnosis of cholangiocarcinoma should be supported by imaging techniques (US, CT, MRI) and invasive investigations (ERC or EUS with brushing and FNA or US or CT-guided biopsy) followed by pathological confirmation. Surgery is the main curative option, so resectability of the tumour should be promptly assessed. Moreover, jaundice must be evaluated at the outset because biliary tract decompression with drainage and stent placement may be required. If the patient is resectable, pre-operative assessment of postoperative liver function is mandatory. After a curative resection, an adjuvant therapy may be administered. Otherwise, in cases with macroscopic residual disease after surgery or locally recurrent or unresectable cholangiocarcinoma at the diagnosis, first line chemotherapy is the preferred strategy, possibly associated with radiotherapy and/or locoregional treatments. As the diagnostic and therapeutic pathway for cholangiocarcinoma can be declined in different modalities, patients should be promptly referred to a multidisciplinary team in a tertiary centre, familiar with this rare but lethal disease. Hence, the aim of the present paper is to focus on diagnostic and therapeutic algorithms based on the common guidelines and also on the clinical practice of multispecialist expert groups. PMID- 26769567 TI - Antisense transcription as a tool to tune gene expression. AB - A surprise that has emerged from transcriptomics is the prevalence of genomic antisense transcription, which occurs counter to gene orientation. While frequent, the roles of antisense transcription in regulation are poorly understood. We built a synthetic system in Escherichia coli to study how antisense transcription can change the expression of a gene and tune the response characteristics of a regulatory circuit. We developed a new genetic part that consists of a unidirectional terminator followed by a constitutive antisense promoter and demonstrate that this part represses gene expression proportionally to the antisense promoter strength. Chip-based oligo synthesis was applied to build a large library of 5,668 terminator-promoter combinations that was used to control the expression of three repressors (PhlF, SrpR, and TarA) in a simple genetic circuit (NOT gate). Using the library, we demonstrate that antisense promoters can be used to tune the threshold of a regulatory circuit without impacting other properties of its response function. Finally, we determined the relative contributions of antisense RNA and transcriptional interference to repressing gene expression and introduce a biophysical model to capture the impact of RNA polymerase collisions on gene repression. This work quantifies the role of antisense transcription in regulatory networks and introduces a new mode to control gene expression that has been previously overlooked in genetic engineering. PMID- 26769569 TI - Prognostic and predictive markers in pancreatic adenocarcinoma. AB - Pancreatic ductal adenocarcinoma is characterized by a poor prognosis and a low median survival, despite improvements observed for many other solid tumours. Intensive research efforts have been undertaken during the last decades to discover new prognostic and treatment predictive biomarkers for pancreatic ductal adenocarcinoma. The mainstay of medical treatment for the disease has been the well-tolerated nucleoside analogue, gemcitabine. The only targeted agent currently used in pancreatic ductal adenocarcinoma patients is the epithelial growth factor receptor inhibitor erlotinib in combination with gemcitabine. Recently, treatment regimens such as a combination of fluorouracil-leucovorin irinotecan-oxaliplatin (FOLFIRINOX) and the combination of nab-paclitaxel with gemcitabine have been introduced for metastatic pancreatic ductal adenocarcinoma. Although these treatment regimens significantly improve survival of patients, there are no good predictive biomarkers available that can be used to identify who would benefit most from them. Therefore, the search for predictive biomarkers that would facilitate personalization of chemotherapy is highly relevant. PMID- 26769570 TI - The development of ORACLe: a measure of an organisation's capacity to engage in evidence-informed health policy. AB - BACKGROUND: Evidence-informed policymaking is more likely if organisations have cultures that promote research use and invest in resources that facilitate staff engagement with research. Measures of organisations' research use culture and capacity are needed to assess current capacity, identify opportunities for improvement, and examine the impact of capacity-building interventions. The aim of the current study was to develop a comprehensive system to measure and score organisations' capacity to engage with and use research in policymaking, which we entitled ORACLe (Organisational Research Access, Culture, and Leadership). METHOD: We used a multifaceted approach to develop ORACLe. Firstly, we reviewed the available literature to identify key domains of organisational tools and systems that may facilitate research use by staff. We interviewed senior health policymakers to verify the relevance and applicability of these domains. This information was used to generate an interview schedule that focused on seven key domains of organisational capacity. The interview was pilot-tested within four Australian policy agencies. A discrete choice experiment (DCE) was then undertaken using an expert sample to establish the relative importance of these domains. This data was used to produce a scoring system for ORACLe. RESULTS: The ORACLe interview was developed, comprised of 23 questions addressing seven domains of organisational capacity and tools that support research use, including (1) documented processes for policymaking; (2) leadership training; (3) staff training; (4) research resources (e.g. database access); and systems to (5) generate new research, (6) undertake evaluations, and (7) strengthen relationships with researchers. From the DCE data, a conditional logit model was estimated to calculate total scores that took into account the relative importance of the seven domains. The model indicated that our expert sample placed the greatest importance on domains (2), (3) and (4). CONCLUSION: We utilised qualitative and quantitative methods to develop a system to assess and score organisations' capacity to engage with and apply research to policy. Our measure assesses a broad range of capacity domains and identifies the relative importance of these capacities. ORACLe data can be used by organisations keen to increase their use of evidence to identify areas for further development. PMID- 26769572 TI - Prenatal vitamin A supplementation associated with adverse child behavior at 3 years in a prospective birth cohort in Japan. AB - BACKGROUND: Many pregnant women take vitamin supplements during pregnancy. The aim of this paper was to clarify the effects of dietary supplementation prior to and/or during pregnancy on child behavior. METHODS: A prospective birth cohort study from pregnancy to 3 years of age involving 1271 pairs of Japanese pregnant women and their newborns, was carried out. The women completed a self administered questionnaire during the third trimester of pregnancy. To evaluate deviations in child behavior as an endpoint, each mother completed the Japanese Child Behavior Checklist for ages 2-3 years after 3 years of birth. Participant characteristics were compared between supplement takers and non-takers. RESULTS: Among many kinds of supplements, intake of supplemental vitamin A/beta-carotene prior to and/or during pregnancy was associated with hazardous effects on child behavior at 3 years of age (total t-score, P = 0.003; internal t-score, P = 0.027; external t-score, P = 0.013). This association held true even after adjusting for age, number of deliveries, infertility treatment, consumption of fast food, smoking status, maternal and paternal education, maternal and paternal income, gestational age at birth, anthropometry at birth (weight, height, head circumference and body circumference), and the State-Trait Anxiety Inventory at 3 years of age by means of multiple imputation. CONCLUSIONS: Intake of supplemental vitamin A prior to and/or during pregnancy may worsen child behavior at 3 years of age. PMID- 26769573 TI - Hospital steam sterilizer usage: could we switch off to save electricity and water? AB - OBJECTIVES: Steam sterilization in hospitals is an energy and water intensive process. Our aim was to identify opportunities to improve electricity and water use. The objectives were to find: the time sterilizers spent active, idle and off; the variability in sterilizer use with the time of day and day of the week; and opportunities to switch off sterilizers instead of idling when no loads were waiting, and the resultant electricity and water savings. METHODS: Analyses of routine data for one year of the activity of the four steam sterilizers in one hospital in Melbourne, Australia. We examined active sterilizer cycles, routine sterilizer switch-offs, and when sterilizers were active, idle and off. Several switch-off strategies were examined to identify electricity and water savings: switch off idle sterilizers when no loads are waiting and switch off one sterilizer after 10:00 h and a second sterilizer after midnight on all days. RESULTS: Sterilizers were active for 13,430 (38%) sterilizer-hours, off for 4822 (14%) sterilizer-hours, and idle for 16,788 (48%) sterilizer-hours. All four sterilizers were simultaneously active 9% of the time, and two or more sterilizers were idle for 69% of the time. A sterilizer was idle for two hours or less 13% of the time and idle for more than 2 h 87% of the time. A strategy to switch off idle sterilizers would reduce electricity use by 66 MWh and water use by 1004 kl per year, saving 26% electricity use and 13% of water use, resulting in financial savings of AUD$13,867 (UKL6,517) and a reduction in 79 tonnes of CO2 emissions per year. An alternative switch-off strategy of one sterilizer from 10:00 h onwards and a second from midnight would have saved 30 MWh and 456 kl of water. CONCLUSIONS: The methodology used of how hospital sterilizer use could be improved could be applied to all hospitals and more broadly to other equipment used in hospitals. PMID- 26769571 TI - Surgical Modification of the Murine Calvaria Osteolysis Model. AB - The murine calvaria model has been adopted for evaluation of osteolysis and inflammation induced by polyethylene (PE) or metal wear debris. However, this model suffers from several complications. The purpose of our study is to introduce a surgical modification with lower complication rates, thus providing more accurate results. Forty C57/BL6 mice were divided into two groups, both receiving polyethylene particles. Surgical modifications were performed in group 1, and group 2 underwent traditional surgeries. The incidence of fluid leakage was recorded on the operative day. Curst formation, wound dehiscence, and bone exposure were recorded on day 7. Histological osteolysis was demonstrated by HE staining of tissue slices. Micro-CT was used for quantifying evaluation of osteolysis in two groups. Intraoperative fluid leakage was significantly reduced in group 1. Postoperative crust formation, wound dehiscence, and bone exposure were also significantly decreased in group 1. HE staining results revealed obvious osteolysis in group 1 and more obvious osteolysis in group 2. Bone volume fraction (BVF) was (0.32 +/- 0.03) in group 1 compared to group 2 (0.24 +/- 0.05). Bone mineral density (BMD) was (1.11 +/- 0.03) in group 1 compared to group 2 (1.01 +/- 0.02). Surgical modifications provide a reliable way for establishment of the murine calvaria osteolysis model. PMID- 26769574 TI - Research participation registers can increase opportunities for patients and the public to participate in health services research. AB - Members of the public and patients repeatedly indicate their willingness to take part in research, but current United Kingdom research governance involves complex rules about gaining consent. Research participation registers that seek consent from participants to be approached about future studies have several potential benefits, including: increased research participation across clinical and healthy populations; simplified recruitment to health care research; support for people's autonomy in decision making; and improved efficiency and generalizability of research. These potential benefits have to be balanced against ethical and governance considerations. With appropriate processes in place, seeking prospective consent from patients and members of the public to be approached about future studies could potentially increase public participation in health research without compromising informed consent and other ethical principles. PMID- 26769575 TI - Race, Ethnicity, and Adolescent Violent Victimization. AB - The risk of adolescent violent victimization in the United States varies considerably across racial and ethnic populations; it is unknown whether the sources of risk also vary by race and ethnicity. This study examined the correlates of violent victimization for White, Black, and Hispanic youth. Data collected from 11,070 adolescents (51 % female, mean age = 15.04 years) during the first two waves of the National Longitudinal Study of Adolescent to Adult Health were used to estimate group-specific multilevel logistic regression models. The results indicate that male, violent offending, peer deviance, gang membership, and low self-control were significantly associated with increased odds of violent victimization for all groups. Some activities-including getting drunk, sneaking out, and unstructured socializing with peers-were risk factors for Black adolescents only; skipping school was a risk factor only for Hispanic adolescents. Although there are many similarities across groups, the findings suggest that minority adolescents are particularly vulnerable to violent victimization when they engage in some activities and minor forms of delinquency. PMID- 26769576 TI - Peer and Individual Risk Factors in Adolescence Explaining the Relationship Between Girls' Pubertal Timing and Teenage Childbearing. AB - Girls with early pubertal timing are at elevated risk for teenage childbearing; however, the modifiable mechanisms driving this relationship are not well understood. The objective of the current study was to determine whether substance use, perceived peer substance use, and older first sexual partners mediate the relationships among girls' pubertal timing, sexual debut, and teenage childbearing. Data are from Waves 1-15 of the female cohort of the National Longitudinal Surveys of Youth 1997 (NLSY97), a nationwide, ongoing cohort study of U.S. men and women born between 1980 and 1984. The analytic sample (n = 2066) was 12-14 years old in 1997 and ethnically diverse (51 % white, 27 % black, 22 % Latina). Using structural equation modeling, we found substance use in early adolescence and perceived peer substance use each partially mediated the relationships among girls' pubertal timing, sexual debut, and teenage childbearing. Our findings suggest early substance use behavior as one modifiable mechanism to be targeted by interventions aimed at preventing teenage childbearing among early developing girls. PMID- 26769578 TI - Editorial Comment. PMID- 26769577 TI - Functional characterization of duplicated B-class MADS-box genes in Japanese gentian. AB - KEY MESSAGE: The heterodimer formation between B-class MADS-box proteins of GsAP3a and GsPI2 proteins plays a core role for petal formation in Japanese gentian plants. We previously isolated six B-class MADS-box genes (GsAP3a, GsAP3b, GsTM6, GsPI1, GsPI2, and GsPI3) from Japanese gentian (Gentiana scabra). To study the roles of these MADS-box genes in determining floral organ identities, we investigated protein-protein interactions among them and produced transgenic Arabidopsis and gentian plants overexpressing GsPI2 alone or in combination with GsAP3a or GsTM6. Yeast two-hybrid and bimolecular fluorescence complementation analyses revealed that among the GsPI proteins, GsPI2 interacted with both GsAP3a and GsTM6, and that these heterodimers were localized to the nuclei. The heterologous expression of GsPI2 partially converted sepals into petaloid organs in transgenic Arabidopsis, and this petaloid conversion phenomenon was accelerated by combined expression with GsAP3a but not with GsTM6. In contrast, there were no differences in morphology between vector-control plants and transgenic Arabidopsis plants expressing GsAP3a or GsTM6 alone. Transgenic gentian ectopically expressing GsPI2 produced an elongated tubular structure that consisted of an elongated petaloid organ in the first whorl and stunted inner floral organs. These results imply that the heterodimer formation between GsPI2 and GsAP3a plays a core role in determining petal and stamen identities in Japanese gentian, but other B-function genes might be important for the complete development of petal organs. PMID- 26769579 TI - Editorial Comment. PMID- 26769581 TI - Comparison of standardized versus individualized caloric prescriptions in the nutritional rehabilitation of inpatients with anorexia nervosa. AB - OBJECTIVE: Sparse research informs how caloric prescriptions should be advanced during nutritional rehabilitation of inpatients with anorexia nervosa (AN). This study compared the impact of a standardized caloric increase approach, in which increases occurred on a predetermined schedule, to an individualized approach, in which increases occurred only following insufficient weight gain, on rate, pattern, and cumulative amount of weight gain and other weight restoration outcomes. METHOD: This study followed a natural experiment design comparing AN inpatients consecutively admitted before (n = 35) and after (n = 35) an institutional change from individualized to standardized caloric prescriptions. Authors examined the impact of prescription plan on weekly weight gain in the first treatment month using multilevel modeling. Within a subsample remaining inpatient through weight restoration (n = 40), multiple regressions examined the impact of caloric prescription plan on time to weight restoration, length of hospitalization, maximum caloric prescription, discharge BMI, and incidence of activity restriction and edema. RESULTS: There were significant interactions between prescription plan and quadratic time on average weekly weight gain (p = .03) and linear time on cumulative weekly weight gain (p < .001). Under the standardized plan, patients gained in an accelerated curvilinear pattern (p = .04) and, therefore, gained cumulatively greater amounts of weight over time (p < .001). Additionally, 30% fewer patients required activity restriction under the standardized plan. DISCUSSION: Standardized caloric prescriptions may confer advantage by facilitating accelerated early weight gain and lower incidence of bedrest without increasing the incidence of refeeding syndrome. PMID- 26769583 TI - Erratum to: comparison of the three-dimensional organization of sperm and fibroblast genomes using the Hi-C approach. PMID- 26769584 TI - Transparent motives: Advocates expand their efforts to improve access to health care quality data. PMID- 26769582 TI - Comparative genome-wide analysis reveals that Burkholderia contaminans MS14 possesses multiple antimicrobial biosynthesis genes but not major genetic loci required for pathogenesis. AB - Burkholderia contaminans MS14 shows significant antimicrobial activities against plant and animal pathogenic fungi and bacteria. The antifungal agent occidiofungin produced by MS14 has great potential for development of biopesticides and pharmaceutical drugs. However, the use of Burkholderia species as biocontrol agent in agriculture is restricted due to the difficulties in distinguishing between plant growth-promoting bacteria and the pathogenic bacteria. The complete MS14 genome was sequenced and analyzed to find what beneficial and virulence-related genes it harbors. The phylogenetic relatedness of B. contaminans MS14 and other 17 Burkholderia species was also analyzed. To research MS14's potential virulence, the gene regions related to the antibiotic production, antibiotic resistance, and virulence were compared between MS14 and other Burkholderia genomes. The genome of B. contaminans MS14 was sequenced and annotated. The genomic analyses reveal the presence of multiple gene sets for antimicrobial biosynthesis, which contribute to its antimicrobial activities. BLAST results indicate that the MS14 genome harbors a large number of unique regions. MS14 is closely related to another plant growth-promoting Burkholderia strain B. lata 383 according to the average nucleotide identity data. Moreover, according to the phylogenetic analysis, plant growth-promoting species isolated from soils and mammalian pathogenic species are clustered together, respectively. MS14 has multiple antimicrobial activity-related genes identified from the genome, but it lacks key virulence-related gene loci found in the pathogenic strains. Additionally, plant growth-promoting Burkholderia species have one or more antimicrobial biosynthesis genes in their genomes as compared with nonplant growth-promoting soil-isolated Burkholderia species. On the other hand, pathogenic species harbor multiple virulence-associated gene loci that are not present in nonpathogenic Burkholderia species. The MS14 genome as well as Burkholderia species genome show considerable diversity. Multiple antimicrobial agent biosynthesis genes were identified in the genome of plant growth-promoting species of Burkholderia. In addition, by comparing to nonpathogenic Burkholderia species, pathogenic Burkholderia species have more characterized homologs of the gene loci known to contribute to pathogenicity and virulence to plant and animals. PMID- 26769585 TI - Young investigator challenge: Cytomorphologic analysis of cerebrospinal fluid in 70 pediatric patients with medulloblastoma and review of the literature focusing on novel diagnostic and prognostic tests. AB - BACKGROUND: Medulloblastoma (MB) is the most common malignant pediatric brain tumor and is currently treated with combined therapies. Recent advances in genetics and protein expression in this entity have led to the elaboration of a new molecular classification, and novel targeted therapies are currently under trial. This objective of this study was to describe the cytomorphologic features of MB in cerebrospinal fluid (CSF). METHODS: The authors conducted a retrospective study of 194 CSF samples from 70 pediatric patients who had a history of primary MB. The samples consisted of CSF cytospins that were stained according to the May-Grunwald Giemsa and/or Papanicolaou methods. RESULTS: In 32 patients, it was possible to establish a confident diagnosis of metastatic MB. Common morphologic features included cell clustering, nuclear irregularity, molding and enlargement, and prominent nucleoli. Multinucleation as well as mitotic and apoptotic figures were less frequently observed. Fifteen samples that presented neither cell clustering nor nuclear molding were classified as suspicious. CONCLUSIONS: Cell clustering with nuclear molding is a key feature for the diagnosis of leptomeningeal metastasis of MB. PMID- 26769586 TI - Young investigator challenge: Comparison of 2 different methods of manual slide screening in semiautomated gynecologic cytology. AB - BACKGROUND: Negative gynecologic cytology cases (ie, those diagnosed as negative for intraepithelial lesion or malignancy) are manually reviewed by 2 methods using semiautomated screening: 1) immediate full slide review (FSR) after fields of-view analysis (FOV) (FOV + FSR), and 2) quality-assurance/high-risk, quintile directed full manual review (FMR). Data supporting current guidelines were limited. The authors investigated FMR, FOV + FSR, and the review process in general. METHODS: Gynecologic cytology cases from 2009 to 2014 at Massachusetts General Hospital were analyzed. The data comprised 93,169 patients, 194,656 specimens, and 49,979 human papillomavirus (HPV) tests. RESULTS: In patients who underwent FMR, the epithelial cell abnormality (ECA) rate was correlated with the HPV-positive rate (correlation coefficient [r(2) ] = 0.82; Y = 0.19X + 0.02), and both rates decreased with age. For patients who underwent FOV + FSR, the ECA rate was also related to the HPV-positive rate (r(2) = 0.86; Y = 0.39X + 0.11), and both rates decreased with age. The FMR group had similar HPV-positive rates compared to the FOV + FSR group (2%-52% vs 9%-68%, respectively). HPV-positive patients had a higher risk of ECA than HPV-negative patients (40% vs 8%; P < .0001). Currently, manual review allocates resources inefficiently, to older, HPV negative patients as compared to younger, HPV-positive patients. Additionally, too many patients who have HPV-positive specimens with ECA proceed from primary screening to FMR. This imbalance can be observed in the slope of the line comparing the FMR ECA rate with the HPV-positive rate (which might serve as a surrogate marker for adequacy of FOV + FSR screening). Therefore, laboratories should try to reduce the number of HPV-positive cases that reach FMR. CONCLUSIONS: Current review procedures devote too few resources to younger patients. FMR should be assigned according to HPV status and age. The slope of the line comparing the FMR ECA rate with the FMR HPV-positive rate might be a useful surrogate marker of screening accuracy. PMID- 26769587 TI - From the picket line: junior doctors speak out. PMID- 26769588 TI - Dysregulation of sirtuins and key metabolic genes in skeletal muscle of pigs with spontaneous intrauterine growth restriction is associated with alterations of circulating IGF-1. AB - Prenatal and early postnatal life determines future health, and intrauterine growth restriction (IUGR) - associated low birth weight predisposes to metabolic syndrome in adulthood. We hypothesize here that IUGR might induce hormonal and gene expression alterations predisposing to metabolic disease. Using a porcine model of spontaneous IUGR, we determined in utero (71, 112days post-conception) and early-postnatal (2days post-birth) IGF-1, insulin and leptin levels, and in parallel we investigated, in skeletal muscle, the developmental expression patterns of sirtuins and metabolic and signaling genes IRS1, GLUT4, HK2 and GAPDH. IUGR was associated with impaired IGF-1 plasmatic levels. Gene expression of sirtuin 1, 5, 6, 7, GLUT4 and HK2 exhibited significant correlations with gestational age or body weight. SIRT1 and HK2 expression displayed an age- and weight-dependent downregulation in controls, which was lost in IUGR pigs. Conversely, SIRT2 and GLUT4 were upregulated in IUGR pigs. Within the set of genes studied, we found a significant correlation between IGF-1 levels and gene expression in control, but not IUGR samples, indicating that lower IGF-1 may be a limiting factor in IUGR. IUGR-dependent gene alterations were partly linked to epigenetic changes on histone H3 acetylation and methylation. Overall, our data indicate that several sirtuins and metabolic genes display specific gene expression trajectories during fetal and early postnatal life. Gene expression alterations observed in IUGR are correlated to IGF-1 dysregulation. Given the importance of the genes studied in metabolic control, their perinatal alterations might contribute to the predisposition to metabolic disease of adulthood. PMID- 26769589 TI - Disruption of steroidogenesis after dimethoate exposure and efficacy of N acetylcysteine in rats: an old drug with new approaches. AB - Organophosphates (OPs) like dimethoate (DMT), are pesticides used worldwide, which can affect both animals and human. Whereas their toxicity is due to acetylcholinesterase inhibition, their secondary toxic effects have been related to free oxygen radical biosynthesis. The present study was designed to investigate the reprotoxic effects of DMT and the protective role of N acetylcysteine (NAC) in male rat. DMT (20 mg/ kg/body weight) was administered daily to rats via gavage in corn oil and NAC (2 g/l) was added to drinking water for 30 days. Rats were sacrificed on the 30th day, 2 h after the last administration. Markers of testis injury (steroidogenesis impairment) and oxidative stress (lipid peroxidation, reduced glutathione, and antioxidant status) were assessed. In DMT-exposed rats, the serum level of testosterone was decreased. Further, a significant increase in lipid peroxidation level and a significant decrease in the activities of antioxidant enzymes were observed in the testis of rats during DMT intoxication. Real-time PCR (RT-PCR) analysis demonstrated a decrease in messenger RNA (mRNA) levels for testicular steroidogenic acute regulatory StAR protein, cytochrome P450scc, 3beta hydroxysteroid dehydrogenase (3beta-HSD), and 17beta hydroxysteroid dehydrogenase (17beta-HSD) in the testis after DMT exposure. No significant changes in the oxidative stress status and selected reproductive variables were observed on CTN group, whereas NAC restored the oxidative stress and the steroidogenesis on NAC group. Dimethoate induces reprotoxicity and oxidative stress. N-acetylcysteine showed therapeutic recovery effects against dimethoate toxicity. PMID- 26769591 TI - Experimental study on treatment of acetabular anterior column fractures: applyment of a minimally invasive percutaneous lag screw guide apparatus. AB - BACKGROUND: The aim of this study was to design a new minimally invasive percutaneous lag screw guide apparatus and to verify its adjuvant treatment of acetabular anterior column fracture on pelvis specimens. METHODS: This guide apparatus was self-developed based on the principles of "two points form a line" and "Rectangle". Using C-arm fluoroscopy, this guide apparatus was used to conduct minimally invasive percutaneous lag screw internal fixation of acetabular anterior column fractures. Ten hollow lag screws were placed into 5 pelvis specimens. RESULT: Result showed no sign of any screws puncturing the cortex or entering into the hip joint on radiological assessment. The cross-section reconstructed vertical distance to the screw, on the cross-section acetabular notch and the cross-section of the screw where the distance of between the screw and the iliopectineal line's arc roof was at its shortest, indicate that at all points (T, R-r) under the line with an inclination of 1 (namely T = R-r) the screw is within the cortex and does not puncture the acetabula anterior column or enter into the hip joint. CONCLUSIONS: We may conclude that this self-developed guide apparatus solves the screw precision problem during the treatment of acetabular anterior column fractures through a minimally invasive percutaneous lag screw. PMID- 26769590 TI - Widespread occurrence and seasonal variation of pharmaceuticals in surface waters and municipal wastewater treatment plants in central Finland. AB - The presence of five selected pharmaceuticals, consisting of four anti inflammatory drugs, diclofenac, ibuprofen, ketoprofen, naproxen, and an antiepileptic drug carbamazepine, was determined at four municipal wastewater treatment plants (WWTPs) and in the receiving waterway in central Finland. The samples were taken from influents and effluents of the WWTPs and from surface water of six locations along the water way, including northern Lake Paijanne. In addition, seasonal variation in the area was determined by comparing the concentrations in the winter and summer. The samples were analyzed by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) in the multiple reaction monitoring mode. The concentrations in the influents and effluents ranged from hundreds of nanogram per liter to microgram per liter while ranged from tens of nanogram per liter in northern parts of the waterway to hundreds of nanogram per liter in northern Lake Paijanne near the city area. In addition, the concentrations were higher in the winter compared to summer time in surface water due to decreased temperature and solar irradiation. On the other hand, higher concentrations of ibuprofen, ketoprofen, and naproxen were found in summer at the WWTPs, possibly due to seasonal variations in consumption. In conclusion, there are considerable amounts of pharmaceuticals not only in influents and effluents of the WWTPs but also in lake water along the waterway and in northern Lake Paijanne. PMID- 26769592 TI - Identification of N-octylnortadalafil and its Stereoisomers in Dietary Supplements with Chiral Liquid Chromatography-Circular Dichroism. AB - A direct chiral liquid chromatography-circular dichroism (LC-CD) method was developed for the simple and rapid identification of N-octylnortadalafil [(6R, 12aR)-6-(1,3-benzodioxol-5-yl)-2-octyl-2,3,6,7,12,12a hexahydropyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione; RR-OTDF] and its stereoisomers in dietary supplements. Samples were extracted with methanol. Compounds were then separated by chiral LC-CD using Chiralcel OD-RH (4.6 * 150 mm, 5 um) with 5 mM ammonium formate (pH 3)/0.1% formic acid in acetonitrile (95:5, v/v) mixture solution (mobile phase A) and 0.1% formic acid in acetonitrile (mobile phase B). The isocratic elution used was mobile phase A / mobile phase B (3:7, v/v) at a flow rate of 1 ml/min. The column temperature was held at 30 degrees C. RR-OTDF and its stereoisomers were separated within 20 min with the resolution factors being over 2.0. Using this method, RR-OTDF and (6R, 12aS)-6-(1,3-benzodioxol-5-yl)-2-octyl-2,3,6,7,12,12a hexahydropyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione were detected in a dietary supplement. PMID- 26769595 TI - Editor's Note. PMID- 26769597 TI - Thallium Transfer from Hydrochloric Acid Media into Pure Ionic Liquids. AB - Pure hydrophobic ionic liquids are known to extract metallic species from aqueous solutions. In this work we have systematically investigated thallium (Tl) extraction from aqueous hydrochloric acid (HCl) solutions into six pure fluorinated ionic liquids, namely imidazolium- and pyrrolidinium-based ionic liquids with bis(trifluoromethanesulfonyl)imide and bis(fluorosulfonyl)-imide anions. The dependence of the Tl extraction efficiency on the structure and composition of the ionic liquid ions, metal oxidation state, and initial metal and aqueous acid concentrations have been studied. Tl concentrations were on the order of picomolar (analyzed using radioactive tracers) and millimolar (analyzed using inductively coupled plasma mass spectrometry). The extraction of the cationic thallium species Tl(+) is higher for ionic liquids with more hydrophilic cations, while for the TlX(z)(3-z) anionic species (where X = Cl(-) and/or Br( )), the extraction efficiency is greater for ionic liquids with more hydrophobic cations. The highest distribution value of Tl(III) was approximately 2000. An improved mathematical model based on ion exchange and ion pair formation mechanisms has been developed to describe the coextraction of two different anionic species, and the relative contributions of each mechanism have been determined. PMID- 26769593 TI - Gamma-variate plasma clearance versus urinary plasma clearance of 51 Cr-EDTA in patients with cirrhosis with and without fluid retention. AB - In patients with fluid retention, the plasma clearance of 51 Cr-EDTA (Clexp obtained by multiexponential fit) may overestimate the glomerular filtration rate (GFR). The present study was undertaken to compare a gamma-variate plasma clearance (Clgv) with the urinary plasma clearance of 51 Cr-EDTA (Clu ) in patients with cirrhosis with and without fluid retention. A total of 81 patients with cirrhosis (22 without fluid retention, 59 with ascites) received a quantitative intravenous injection of 51 Cr-EDTA followed by plasma and quantitative urinary samples for 5 h. Clgv was determined from the injected dose relative to the plasma concentration-time area, obtained by a gamma-variate iterative fit. Clexp and Clu were determined by standard technique. In patients without fluid retention, Clgv , Clexp and Clu were closely similar. The difference between Clgv and Clu (Clgv - Clu = DeltaCl) was mean -0.6 ml min-1 1.73 m-2 . In patients with ascites, DeltaCl was significantly higher (11.8 ml min-1 1.73 m-2 , P<0.0001), but this value was lower than Clexp - Clu (17.5 mL min-1 1.73 m-2 , P<0.01). DeltaCl increased with lower values of GFR (P<0.001). In conclusion, in patients with fluid retention and ascites Clgv and Clexp overestimates GFR substantially, but the overestimation is smaller with Clgv . Although Clu may underestimate GFR slightly, patients with ascites should collect urine quantitatively to obtain a reliable measurement of GFR. PMID- 26769598 TI - Determining the Minimal Required Radioactivity of 18F-FDG for Reliable Semiquantification in PET/CT Imaging: A Phantom Study. AB - In pursuit of as-low-as-reasonably-achievable (ALARA) doses, this study investigated the minimal required radioactivity and corresponding imaging time for reliable semiquantification in PET/CT imaging. METHODS: Using a phantom containing spheres of various diameters (3.4, 2.1, 1.5, 1.2, and 1.0 cm) filled with a fixed (18)F-FDG concentration of 165 kBq/mL and a background concentration of 23.3 kBq/mL, we performed PET/CT at multiple time points over 20 h of radioactive decay. The images were acquired for 10 min at a single bed position for each of 10 half-lives of decay using 3-dimensional list mode and were reconstructed into 1-, 2-, 3-, 4-, 5-, and 10-min acquisitions per bed position using an ordered-subsets expectation maximum algorithm with 24 subsets and 2 iterations and a gaussian 2-mm filter. SUVmax and SUVavg were measured for each sphere. RESULTS: The minimal required activity (+/-10%) for precise SUVmax semiquantification in the spheres was 1.8 kBq/mL for an acquisition of 10 min, 3.7 kBq/mL for 3-5 min, 7.9 kBq/mL for 2 min, and 17.4 kBq/mL for 1 min. The minimal required activity concentration-acquisition time product per bed position was 10-15 kBq/mL?min for reproducible SUV measurements within the spheres without overestimation. Using the total radioactivity and counting rate from the entire phantom, we found that the minimal required total activity-time product was 17 MBq?min and the minimal required counting rate-time product was 100 kcps?min. CONCLUSION: Our phantom study determined a threshold for minimal radioactivity and acquisition time for precise semiquantification in (18)F-FDG PET imaging that can serve as a guide in pursuit of achieving ALARA doses. PMID- 26769594 TI - Is statin-modified reduction in lipids the most important preventive therapy for cardiovascular disease? A pro/con debate. AB - The most prescribed medications in the world are statins, lipid modifiers that have been available for over 25 years and amongst the most investigated of all drug classes. With over a million patient years of trial data and publications in the most prestigious medical journals, it is remarkable that quite so much debate remains as to their place in healthcare. They have had a bittersweet passage, with vocal concerns over their possible risks, from suicide to cancer, and allegations that they do not work in women or the elderly, to statements that the whole published dataset, on over 200,000 patients consenting to enter trials, was fatally compromised by being industry-funded by and large. On the other side, there have been billions of dollars spent on generating their evidence base followed by promotion which has returned that investment many times over in profits, and a powerful scientific lobby that argue they are wonder drugs and that continued nihilism on their value risks patient lives. So who is right? PMID- 26769599 TI - The Evaluation of Lupus Myocarditis with 13N-Ammonia and 18F-FDG PET. AB - Although the use of (13)N-ammonia and (18)F-FDG PET shows great promise as a tool for diagnosing heart involvement in inflammatory diseases, it can be equally powerful for following disease progression and treatment outcome. We describe a case in which (18)F-FDG PET was effective in following up the treatment outcome of lupus myocarditis. PMID- 26769600 TI - Assessment of Whether Patients' Knowledge, Satisfaction, and Experience Regarding Their 18F-Fluoride PET/CT Examination Affects Image Quality. AB - The aim of this study was to investigate patients' previous knowledge, satisfaction, and experience regarding an (18)F-fluoride PET/CT examination and to explore whether any discomfort or pain during the examination was associated with reduced image quality. A further aim was to explore whether patients' health related quality of life (HRQoL) was associated with their satisfaction and experience regarding the examination. METHODS: Between November 2011 and April 2013, 50 consecutive patients with a histopathologic diagnosis of prostate cancer who were scheduled for (18)F-fluoride PET/CT were asked to participate in the study. A questionnaire was used to collect information on the patients' previous knowledge and experience regarding the examination. Image quality was assessed according to an arbitrary scale. The European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30) and the prostate cancer-specific module (QLQ-PR25) were used to assess HRQoL. RESULTS: Forty-six patients (96%) completed the questionnaire. Twenty-six percent did not at all know what a (18)F-fluoride PET/CT examination was. Most (52%-70%) were satisfied to a very high degree with the care provided by the nursing staff but were less satisfied with the information given before the examination. Image quality was similar between patients who were exhausted or claustrophobic during the examination and those who were not. No correlations between HRQoL and the patients' experience regarding (18)F-fluoride PET/CT were found. CONCLUSION: Most patients were satisfied with the care provided by the nursing staff, but there is still room for improvement, especially regarding the information provided before the examination. A long examination time may be strenuous for the patient, but there was no difference in image quality between patients who felt discomfort or pain during the examination and those who did not. PMID- 26769601 TI - Development of a 2-Layer Double-Pump Dynamic Cardiac Phantom. AB - The conventional dynamic cardiac phantom used in the field of nuclear medicine has a structure for which the size of the external side of the heart (the outer membrane substituting the myocardial layer) is fixed and only the inner side (the inner membrane substituting the ventricle part) moves anteroposteriorly. Therefore, its usefulness in technical evaluation is limited. Hence, we developed a new dynamic cardiac phantom in which the outer and inner membranes freely move. METHODS: Using a SPECT/CT system, we performed validation by filling the myocardial layer of the dynamic cardiac phantom with solution and the ventricle part with contrast medium. We evaluated myocardial wall motions of 3 segments (basal, mid, and apical) by setting the stroke ratios at 20:20 and 10:10 (ventricle-to-myocardial layer ratio). RESULTS: The myocardial wall motions (mean +/- SD) at the stroke ratio of 20:20 were 7.50 +/- 0.44, 11.15 +/- 0.56, and 9.90 +/- 0.24 mm in the basal, mid, and apical segments, respectively. The wall motions (mean +/- SD) at the stroke ratio of 10:10 were 3.82 +/- 0.43, 5.63 +/- 0.39, and 4.53 +/- 0.10 mm, respectively. CONCLUSION: In our dynamic cardiac phantom, different movements could be induced in the myocardial wall by freely changing the stroke ratio. These results suggest that the use of this phantom can realize technical evaluation that presumes various clinical conditions. PMID- 26769602 TI - Don't Be So Quick to Raise the White Flag on the Nuclear Medicine Advanced Associate as a Career Path. PMID- 26769603 TI - Editorial: Gerontological nursing in a time of change. PMID- 26769605 TI - Treatment intensity, age and outcome in medical ICU patients: results of a French administrative database. AB - BACKGROUND: Intensive care unit (ICU) patients are aging, and older age has been associated with higher mortality in ICU. As previous studies have reported that older age was also associated with less intensive treatment, we investigated the relationship between age, treatment intensity and mortality in medical ICU patients. METHODS: Data were extracted from the administrative database of 18 medical ICUs. Patients with a unique medical ICU stay and a Simplified Acute Physiology Score II (without age-related points) >15 were included. Treatment intensity was described with a novel indicator, which is a four-group classification based upon the most frequent ICU procedures. The relationship between age, treatment intensity and hospital mortality was analyzed with the estimation of standardized mortality ratio in the four groups of treatment intensity. RESULTS: A total of 23,578 patients, including 3203 patients aged >=80 years, were analyzed. Hospital mortality increased from 13 % for the younger patients (age < 40 years) to 38 % for the older patients (age >= 80 years), while Simplified Acute Physiology Score II (without age-related points) increased only from 36 (age < 40 years) to 43 (age >= 80). Hospital mortality increased with age in the four groups of treatment intensity. Standardized mortality ratio increased with age among the patients with less intensive treatment but was not associated with age among the patients with the highest treatment intensity. CONCLUSION: Our results support the fact that the increase in mortality with age among ICU patients is not related to an increase in severity. Using a new tool to estimate ICU treatment intensity, our study suggests that mortality of ICU patients increases with age whatever the treatment intensity is. Further investigations are required to determinate whether this increase in mortality among older ICU patients is related to undertreatment or to a lower efficiency of organ support treatment. PMID- 26769606 TI - Functional assessment and quality of life in essential tremor with bilateral or unilateral DBS and focused ultrasound thalamotomy. AB - BACKGROUND: Thalamic deep brain stimulation (DBS) has largely replaced radiofrequency thalamotomy as the treatment of choice for disabling, medication refractory essential tremor. Recently, the development of transcranial, high intensity focused ultrasound has renewed interest in thalamic lesioning. The purpose of this study is to compare functional outcomes and quality of life in essential tremor patients treated with either bilateral Vim DBS or unilateral procedures (focused ultrasound or DBS). We hypothesized that all three would effectively treat the dominant hand and positively impact functional outcomes and quality of life as measured with the Clinical Rating Scale for Tremor and the Quality of Life in Essential Tremor Questionnaire. METHODS: This is a retrospective study of medication-refractory essential tremor patients treated at the University of Virginia with bilateral Vim DBS (n = 57), unilateral Vim DBS (n = 13), or unilateral focused ultrasound Vim thalamotomy (n = 15). Tremor was rated for all patients before and after treatment, using the Clinical Rating Scale for Tremor and Quality of Life in Essential Tremor Questionnaire. RESULTS: Patients undergoing bilateral DBS treatment had more baseline tremor and worse quality of life scores. Patients had significant improvements in tremor symptoms and quality of life with all three treatments. Both DBS procedures improved axial tremor. No difference was seen in the degree of improvement in upper extremity tremor score, disability, or overall quality of life between bilateral and either unilateral procedure. CONCLUSIONS: Bilateral thalamic DBS improves overall tremor more than unilateral DBS or focused ultrasound treatment; however, unilateral treatments are equally effective in treating contralateral hand tremor. Despite the greater overall tremor reduction with bilateral DBS, there is no difference in disability or quality of life comparing bilateral versus unilateral treatments. PMID- 26769607 TI - A novel mutation of PDE8B Gene in a Japanese family with autosomal-dominant striatal degeneration. AB - BACKGROUND: Autosomal-dominant striatal degeneration is a rare autosomal-dominant neurodegenerative movement disorder characterized by slowly progressive parkinsonism. Recently, a mutation of the cyclic nucleotide phosphodiesterase 8B gene was reported to be a causal gene mutation of this disease. METHODS: We report on the clinical characteristics of 2 patients of a Japanese family with autosomal-dominant striatal degeneration and the result of gene mutation analysis of this family. RESULTS: Clinical features of the patients are slowly progressive parkinsonism and brain MRI showing high signal intensity in T2-weighted images in the striatum. We found a heterozygous nonsense mutation in the first exon of cyclic nucleotide phosphodiesterase 8B gene, which is predicted to disrupt all important functional domains of the cyclic nucleotide phosphodiesterase 8B protein. CONCLUSIONS: This family is the second family with autosomal-dominant striatal degeneration after the first German family, confirming that cyclic nucleotide phosphodiesterase 8B gene is the causative gene for this disease. PMID- 26769608 TI - Corrigendum. PMID- 26769612 TI - Editorial: Adolescent Idiopathic Scoliosis - What Pediatricians Should Know About. PMID- 26769609 TI - Registers of the Swedish total population and their use in medical research. AB - The primary aim of the Swedish national population registration system is to obtain data that (1) reflect the composition, relationship and identities of the Swedish population and (2) can be used as the basis for correct decisions and measures by government and other regulatory authorities. For this purpose, Sweden has established two population registers: (1) The Population Register, maintained by the Swedish National Tax Agency ("Folkbokforingsregistret"); and (2) The Total Population Register (TPR) maintained by the government agency Statistics Sweden ("Registret over totalbefolkningen"). The registers contain data on life events including birth, death, name change, marital status, family relationships and migration within Sweden as well as to and from other countries. Updates are transmitted daily from the Tax Agency to the TPR. In this paper we describe the two population registers and analyse their strengths and weaknesses. Virtually 100 % of births and deaths, 95 % of immigrations and 91 % of emigrations are reported to the Population Registers within 30 days and with a higher proportion over time. The over-coverage of the TPR, which is primarily due to underreported emigration data, has been estimated at up to 0.5 % of the Swedish population. Through the personal identity number, assigned to all residents staying at least 1 year in Sweden, data from the TPR can be used for medical research purposes, including family design studies since each individual can be linked to his or her parents, siblings and offspring. The TPR also allows for identification of general population controls, participants in cohort studies, as well as calculation of follow-up time. PMID- 26769613 TI - Bracing Scoliosis - State of the Art (Mini-Review). AB - Spinal bracing is indicated in moderate to severe curves during growth. Brace effectiveness in halting progression of adolescent idiopathic scolisosis has been shown in a Cochrane review and in a randomized controlled trial (RCT). The outcome of brace treatment is dependent on the extent of in-brace correction and compliance. We have reviewed the literature on bracing to determine the types of brace that offer the best in-brace correction. MATERIALS AND METHODS: The literature has been searched for papers on bracing with documented in-brace corrections and long-term results. RESULTS: The in-brace percentage of correction of asymmetric braces is generally higher than that of the symmetric braces. According to the literature found in our search, long-term corrections are possible when starting treatment early, at an immature stage and with asymmetric braces of recent standards. CONCLUSIONS: Bracing today is supported by high quality evidence (Level I). Asymmetric braces have led to better corrections than that described for symmetric braces. An improvement of the average corrective effect has been described due to the latest CAD / CAM development. Long-term corrections are possible when starting brace treatment early, at an immature stage and with asymmetric braces of recent standards. PMID- 26769614 TI - Congenital Scoliosis (Mini-review). AB - Congenital scoliosis is a lateral deformity of the spine with a disturbance of the sagittal profile caused by malformations of vertebra and ribs. Typically, early surgical intervention is the suggested treatment (before three-years-old) for young patients with congenital scoliosis. While a previous study was conducted in 2011 to investigate long-term studies supporting the necessity for this recommendation and no evidence was found, this current review, is an updated search for evidence published from 2011 through March 2015. This also failed to find any prospective or randomized controlled studies to support the hypothesis that spinal fusion surgery in patients with congenital scoliosis should be considered as evidence-based treatment. Contradictory results exist on the safety of hemivertebra resection and segmental fusion using pedicle screw fixation. When using the VEPTR (vertical expandable prosthetic titanium rib) device, studies show a high rate of complications exist. It is difficult to predict the final outcome for patients with congenital scoliosis. However, it is possible that many patients with congenital scoliosis may be able to avoid spinal surgery with the application of advanced bracing technology. Therefore, it is only prudent to advocate for conservative management first before spinal surgery is considered. PMID- 26769615 TI - Vitiligo in Children: A Birds Eye View. AB - Vitiligo in children is a distinct subset of vitiligo and differs from adult vitiligo. Characteristic features include family history of autoimmune or endocrine disease, higher incidence of segmental vitiligo, development of early or premature graying, increased incidence of autoantibodies and poor response to topical PUVA. The exact prevalence of vitiligo in children varies between 0.1-4% of the world population and seems to be higher in India than in other countries and it occurs more frequently in females. Around 12% to 35% of pediatric vitiligo patients have family members with the disease. The most common type of vitiligo in pediatric patients is vitiligo vulgaris, representing 78% of cases. The most commonly associated autoimmune disease is thyroiditis. Phototherapy and topical corticosteroids are the most commonly used treatments for adult vitiligo but are less useful in the pediatric population. PMID- 26769616 TI - Extracorporeal membrane oxygenation: a breakthrough for respiratory failure. AB - Extracorporeal membrane oxygenation (ECMO) is a method for providing long-term treatment of a patient in a modified heart-lung machine. Desaturated blood is drained from the patient, oxygenated and pumped back to a major vein or artery. ECMO supports heart and lung function and may be used in severe heart and/or lung failure when conventional intensive care fails. The Stockholm programme started in 1987 with treatment of neonates. In 1995, the first adult patient was accepted onto the programme. Interhospital transportation during ECMO was started in 1996, which enabled retrieval of extremely unstable patients during ECMO. Today, the programme has an annual volume of about 80 patients. It has been characterized by, amongst other things, minimal patient sedation. By 31 December 2014, over 900 patients had been treated, the vast majority for respiratory failure, and over 650 patients had been transported during ECMO. The median ECMO duration was 5.3, 5.7 and 7.1 days for neonatal, paediatric and adult patients, respectively. The survival to hospital discharge rate for respiratory ECMO was 81%, 70% and 63% in the different age groups, respectively, which is significantly higher than the overall international experience as reported to the Extracorporeal Life Support Organization (ELSO) Registry (74%, 57% and 57%, respectively). The survival rate was significantly higher in the Stockholm programme compared to ELSO for meconium aspiration syndrome, congenital diaphragmatic hernia in neonates and pneumocystis pneumonia in paediatric patients. PMID- 26769617 TI - Editorial: Do-Not-Resuscitate Orders and Advance Directives--Existential Issues for Orthopaedic Patients with Life-threatening Conditions. PMID- 26769618 TI - CORR Insights((r)): Are Frozen Sections and MSIS Criteria Reliable at the Time of Reimplantation of Two-stage Revision Arthroplasty? PMID- 26769619 TI - Cochrane in CORR ((r)): Double-bundle Versus Single-bundle Reconstruction for Anterior Cruciate Ligament Rupture in Adults (Review). PMID- 26769620 TI - CORR Insights(r): Smoking is Associated with Increased Blood Loss and Transfusion Use After Lumbar Spinal Surgery. PMID- 26769621 TI - CORR Insights(r): How Do Orthopaedic Devices Change After Their Initial FDA Premarket Approval? PMID- 26769623 TI - A unique approach to demonstrating that apical bud temperature specifically determines leaf initiation rate in the dicot Cucumis sativus. AB - MAIN CONCLUSION: Leaf initiation rate is largely determined by the apical bud temperature even when apical bud temperature largely deviates from the temperature of other plant organs. We have long known that the rate of leaf initiation (LIR) is highly sensitive to temperature, but previous studies in dicots have not rigorously demonstrated that apical bud temperature controls LIR independent of other plant organs temperature. Many models assume that apical bud and leaf temperature are the same. In some environments, the temperature of the apical bud, where leaf initiation occurs, may differ by several degrees Celsius from the temperature of other plant organs. In a 28-days study, we maintained temperature differences between the apical bud and the rest of the individual Cucumis sativus plants from -7 to +8 degrees C by enclosing the apical buds in transparent, temperature-controlled, flow-through, spheres. Our results demonstrate that LIR was completely determined by apical bud temperature independent of other plant organs temperature. These results emphasize the need to measure or model apical bud temperatures in dicots to improve the prediction of crop development rates in simulation models. PMID- 26769624 TI - Prevalence and Determinants of Child Maltreatment among School-Going Adolescent Girls in a Semi-Urban Area of Delhi, India. AB - The study examines family characteristics that put adolescent girls at increased risk of abuse, mainly physical, sexual and emotional abuse and neglect. Stratified random sampling was done among classes 7th to 12th of government girls' schools of a semi-urban area of Delhi, and a total of 1060 adolescent girls participated. Majority were in mid-adolescence. Approximately 70% study subjects faced at least one form of maltreatment. Physical abuse was faced by 42.6%, sexual abuse by 26.6%, emotional abuse by 37.9% and neglect by 40.1% of study subjects. The most frequent perpetrator of physical and emotional abuse was mother, and of sexual abuse were friends, relatives or neighbours. No or low education of father increased odds of physical and emotional abuse, while odds of physical abuse and neglect were lower if mothers were housewives. Excessive arguments between parents and history of maltreatment in parents increased odds of child maltreatment in study subjects. PMID- 26769627 TI - Delineation of G-Quadruplex Alkylation Sites Mediated by 3,6-Bis(1-methyl-4 vinylpyridinium iodide)carbazole-Aniline Mustard Conjugates. AB - A new G-quadruplex (G-4)-directing alkylating agent BMVC-C3M was designed and synthesized to integrate 3,6-bis(1-methyl-4-vinylpyridinium iodide)carbazole (BMVC) with aniline mustard. Various telomeric G-4 structures (hybrid-2 type and antiparallel) and an oncogene promoter, c-MYC (parallel), were constructed to react with BMVC-C3M, yielding 35 % alkylation yield toward G-4 DNA over other DNA categories (<6 %) and high specificity under competition conditions. Analysis of the intact alkylation adducts by electrospray ionization mass spectroscopy (ESI MS) revealed the stepwise DNA alkylation mechanism of aniline mustard for the first time. Furthermore, the monoalkylation sites and intrastrand cross-linking sites were determined and found to be dependent on G-4 topology based on the results of footprinting analysis in combination with mass spectroscopic techniques and in silico modeling. The results indicated that BMVC-C3M preferentially alkylated at A15 (H26), G12 (H24), and G2 (c-MYC), respectively, as monoalkylated adducts and formed A15-C3M-A21 (H26), G12-C3M-G4 (H24), and G2 C3M-G4/G17 (c-MYC), respectively, as cross-linked dialkylated adducts. Collectively, the stability and site-selective cross-linking capacity of BMVC-C3M provides a credible tool for the structural and functional characterization of G 4 DNAs in biological systems. PMID- 26769628 TI - Palladium-Catalyzed Arylation of Unactivated gamma-Methylene C(sp(3) )-H and delta-C-H Bonds with an Oxazoline-Carboxylate Auxiliary. AB - A palladium-catalyzed arylation of unactivated gamma-methylene C(sp(3) )?H and remote delta-C?H bonds by using an oxazoline-carboxylate directing group has been developed. Arylation occurs with a broad substrate scope and high tolerance of functional groups (i.e., halogen, nitro, cyano, ether, trifluoromethyl, amine, and ester). The oxazoline-type auxiliary can be removed under acidic conditions. PMID- 26769625 TI - Full Expression of Cardiomyopathy Is Partly Dependent on B-Cells: A Pathway That Involves Cytokine Activation, Immunoglobulin Deposition, and Activation of Apoptosis. AB - BACKGROUND: Limited information exists on the role of B-cell-dependent mechanisms in the progression of heart failure (HF). However, in failing human myocardium, there is evidence of deposition of activated complement components as well as anticardiac antibodies. We aimed to determine the contribution of B-cells in HF progression using a nonsurgical mouse model of nonischemic cardiomyopathy (CMP). METHODS AND RESULTS: CMP protocol involved the use of l-NAME and NaCl in the drinking water and angiotensin-II infusion for 35 days. At day 35, mice were analyzed by cardiac magnetic resonance imaging, gene expression, and histology. Mice (12 weeks old) were divided into 4 groups, all in C57BL/6 background: wild type (WT) CMP; severe combined immunodeficiency (SCID) CMP (T- and B-cell deficient); CD22(-) CMP (B-cell depleted); and Nude CMP (T-cell deficient), with their respective controls. We performed B-cell depletion and reconstitution protocols. The protective effect of B-cell depletion was demonstrated by a significant reduction of cell hypertrophy and collagen deposition and a preserved ejection fraction in the CD22(-) CMP group compared to WT CMP. Once SCID mice underwent B-cell reconstitution with isolated CMP B-cells, the CMP phenotype was restored. Furthermore, deposition of IgG3 and apoptosis in the myocardium follows the development of CMP; in addition, in vitro studies demonstrated that activated B-cells stimulate collagen production by cardiac fibroblasts. CONCLUSIONS: The absence of B-cells in this model of HF resulted in less hypertrophy and collagen deposition, preservation of left ventricular function, and, in association with these changes, a reduction in expression of proinflammatory cytokines, immunoglobulin G deposition, and apoptosis in the myocardium. Taken together, these data suggest that B-cells play a contributory role in an angiotensin-II induced HF model. PMID- 26769632 TI - Academic mentorship in dermatology. PMID- 26769631 TI - Mutational and functional analysis of N-linked glycosylation of envelope fusion protein F of Helicoverpa armigera nucleopolyhedrovirus. AB - The envelope fusion (F) protein of baculoviruses is a heavily N-glycosylated protein that plays a significant role in the virus infection cycle. N-Linked glycosylation of virus envelope glycoprotein is important for virus envelope glycoprotein folding and its function in general. There are six predicted N glycosylation sites in the F (HaF) protein of Helicoverpa armigera nucleopolyhedrovirus (HearNPV). The N-glycosylation site located in the F(2) subunit (N104) of HaF has been identified and functionally characterized previously (Long et al., 2007). In this study, the other five potential N glycosylation sites located in the HaF1 subunit, namely, N293, N361, N526, N571 and N595, were analysed extensively to examine their N-glycosylation and relative importance to the function of HaF. The results showed that four of these five potential glycosylation sites in the F(1) subunit, N293, N361, N526 and N571, were N-glycosylated in F proteins of mature HearNPV budded viruses (BVs) but that N595 was not. In general, the conserved site N526 was critical to the functioning of HaF, as absence of N-glycosylation of N526 reduced the efficiency of HaF folding and trafficking, consequently decreased fusogenicity and modified the subcellular localization of HaF proteins, and thus impaired virus production and infectivity. The absence of N-glycosylation at other individual sites was found to have different effects on the fusogenicity and subcelluar distribution of HaF proteins in HzAM1 cells. In summary, N-glycosylation plays comprehensive roles in HaF function and virus infectivity, which is further discussed. PMID- 26769633 TI - (c)Copyright: why it matters. PMID- 26769634 TI - What is the risk of inadvertent exposure to topical retinoids during first trimester pregnancy? PMID- 26769635 TI - Cardiovascular disease risk factors in patients with hidradenitis suppurativa. PMID- 26769636 TI - Vulvovaginal photodynamic therapy for genital erosive lichen planus. PMID- 26769637 TI - A booster for the varicella vaccine. PMID- 26769638 TI - Onset and severity of atopic dermatitis, atopy and hand eczema in adolescents. PMID- 26769639 TI - The future of U.K. dermatology translational research through the Oracle of Delphi. PMID- 26769640 TI - Connexins help fill the Gap: markers and therapeutic targets for chronic nonhealing wounds. PMID- 26769641 TI - Towards a targeted therapy for pyoderma gangrenosum. PMID- 26769642 TI - Assessing the efficacy of oral immunotherapy for the desensitisation of peanut allergy in children (STOP II): a phase 2 randomised controlled trial: a critical appraisal. AB - AIM: Anagnostou et al. investigated the efficacy of oral immunotherapy (OIT) in treating peanut allergy. SETTING AND DESIGN: An unmasked randomized controlled crossover trial of 7-16 year olds with double-blind placebo-controlled food challenge (DBPCFC)-proven peanut allergy. The first phase compared an active group undergoing 26 weeks of OIT with daily ingestion of peanut protein vs. a control group avoiding peanuts. Both groups underwent DBPCFC to peanut at 26 weeks. In the second phase the control group was then offered OIT for 26 weeks. STUDY EXPOSURE: Participants undergoing OIT attended hospital every 2 weeks to initiate and increase their daily peanut protein dose through nine stages (2, 5, 12.5, 25, 50, 100, 200, 400 and 800 mg - about five peanuts), subsequently maintaining consumption at the highest tolerated dose. Primary outcome The primary outcome compared the proportions of active- and control-group participants able to ingest a cumulative dose of 1400 mg of peanut protein (about 10 peanuts) during their DBPCFC at the end of the first phase without reacting. Secondary outcomes Further outcomes included the proportion of participants who tolerated the top maintenance dosage of 800 mg protein up to 26 weeks; the proportion of the control group who were desensitized or tolerated daily ingestion of 800 mg protein in the second phase; threshold changes in no observed adverse effect level after OIT (NOAEL: defined as the highest dose of peanut protein tolerated in milligrams of protein during challenge or immunotherapy); change in quality of life; number and type of adverse events; and immunological parameters (basophil reactivity, peanut-specific IgE, total IgE and skin-prick test). RESULTS: Primary outcome Twenty-four of 39 (62%) of the active group were able to tolerate the 1400 mg of peanut protein during their DBPCFC after 26 weeks of OIT, compared with none of the 46 control participants (P < 0.001). Secondary outcomes Twenty-five of 46 (54%) of the control group had a negative 1400-mg peanut protein challenge at the end of phase 2. Combining the two groups, 49 of 85 children (58%) were desensitized. Thirty-three of 39 (85%) active participants in phase one and 42 of 46 (91%) control participants in phase two tolerated 800 mg of OIT daily - a combined result of 75 of 85 (88%) trial participants. The median absolute change in NOAEL between baseline and 26 weeks was 1345 mg (P = 0.002), or a 25.5-fold increase (P < 0.001) for the active group. Both the active and control groups demonstrated a significant improvement (decrease) in Food Allergy Quality of Life scores after OIT in the under-13-year-old participants: 1.61 and -1.41, respectively (both P < 0.001). Mild side-effects predominated, with 54 (57%) reporting abdominal pain and 31 (33%) reporting vomiting. However, 21 (22%) also reported wheezing and one (1%) laryngeal oedema. One participant received adrenaline by self-administration on two occasions for wheezing. CONCLUSIONS: Anagnostou et al. concluded that OIT successfully induced desensitization in challenge-proven peanut-allergic children and resulted in a clinically and socially meaningful increase in tolerated peanut protein. Quality of life improved after intervention and there was a good safety profile. PMID- 26769643 TI - Author response to Marrs et al., Assessing the efficacy of oral immunotherapy for the desensitisation of peanut allergy in children (STOP II): a phase 2 randomised controlled trial: a critical appraisal. PMID- 26769644 TI - More work needed to crack the nut. AB - The STOP II study provides high-quality evidence on the efficacy, safety and impact on quality of life of oral immunotherapy (OIT) in peanut-allergic children. Although the results are promising, significant concerns and knowledge gaps remain regarding the safety of OIT, its ability to induce long-term tolerance once regular peanut intake is stopped and, accordingly, long-term adherence. Peanut OIT therefore needs to be restricted to research studies aiming to complete the current evidence gaps. PMID- 26769645 TI - Epidermal necrolysis: 60 years of errors and advances. AB - Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare conditions characterized by extensive epidermal detachment and mucositis. Both are associated with a high mortality rate and significant long-term morbidity. Since the initial report introducing the term TEN in 1956, diagnosis of the condition has been fraught with difficulties that continue to exist today. The terms 'erythema multiforme major' (EMM) and SJS, and their relationship to TEN have also been confusing to clinicians. It is now recognized that EMM is a different entity from SJS and TEN in terms of demographics, causality and severity. SJS and TEN represent a continuum of disease, and differ only by the extent of epidermal detachment and therefore severity. The term 'epidermal necrolysis' (EN) is used in this article to describe the spectrum of disease that includes SJS and TEN. Important advances in understanding the pathomechanism and treatment of EN have been made over the years. These include the recognition of human leucocyte antigen (HLA) associations (e.g. HLA-B*1502 with carbamazepine induced TEN) and understanding of the pathogenic roles of drug-specific cytotoxic T cells and granulysin. It was previously believed that widespread keratinocyte death in EN is predominantly mediated by soluble Fas-ligand and that intravenous immunoglobulin therapy is useful in blocking this mechanism with resultant survival benefits. Further studies have since proven these theories to be incorrect. This short review describes the key advances in the terminology, classification, causality and treatment of EN, and identifies future priorities and challenges in the understanding and management of this condition. PMID- 26769647 TI - Corrigendum. PMID- 26769646 TI - Conflicts of interest in medical publishing: it's all about trustworthiness. AB - Openness and transparency are vital for the trustworthiness of scientific journals and researchers. The term 'conflict of interest' should be defined broadly. Both financial and nonfinancial conflicts of interest may influence the reporting and evaluation of medical research. This should not hinder scientific cooperation between academic and industry-affiliated researchers. In the name of transparency, scientific journals should disclose the identity of a paper's peer reviewers and publish more information on the authors. PMID- 26769652 TI - Erratum. PMID- 26769651 TI - General practice based psychosocial interventions for supporting carers of people with dementia or stroke: a systematic review. AB - BACKGROUND: Particularly with ageing populations, dementia and stroke and their resultant disability are worldwide concerns. Much of the support for people with these conditions comes from unpaid carers or caregivers. The carers' role is often challenging and carers themselves may need support. General practice is often the first point of contact for people with these conditions and their carers, making it potentially an important source of support. This systematic review therefore synthesised the available evidence for the impact of supportive interventions for carers provided in general practice. METHODS: PRISMA guidelines were adopted and the following databases were searched: MEDLINE; EMBASE; the Cochrane Library; PsycINFO; CINAHL Plus; Applied Social Sciences Index and Abstracts and Healthcare Management Information Consortium. RESULTS: Two thousand four hundred eighty nine results were identified. Four studies, involving 447 carers, fitted the inclusion criteria. Three of these came from the United States of America. None investigated supportive interventions for carers of people with stroke. Primarily by the provision of information and educational materials, the interventions focussed on improving carer mental health, dementia knowledge, caregiving competence and reducing burden, difficulties and frustrations. Overall the evidence suggests that these interventions may improve carer well-being and emotional health but the impact on physical health and social variables was less clear. However, the diversity of the carer outcomes and the measures used means that the findings must be viewed with caution. CONCLUSIONS: Unpaid carers pay an essential role in caring for people with stroke and dementia and the dearth of literature investigating the impact of supportive interventions for these carers of is surprising. The available evidence suggests that it may be possible to offer support for these carers in general practice but future research should consider focussing on the same outcome measures in order to allow comparisons across interventions. PMID- 26769653 TI - Central administration of the anorexigenic peptide neuromedin U decreases alcohol intake and attenuates alcohol-induced reward in rodents. AB - By investigating the neurochemical mechanisms through which alcohol activates the brain reward systems, novel treatment strategies for alcohol use disorder (AUD), a chronic relapsing disease, can be developed. In contrast to the common view of the function of gut-brain peptides, such as neuromedin U (NMU), to regulate food intake and appetite, a novel role in reinforcement mediation has been implied. The anorexigenic effects of NMU are mediated via NMU2 receptors, preferably in the arcuate nucleus and paraventricular nucleus. The expression of NMU2 receptors is also expressed in several reward-related areas in the brain, suggesting a role in reward regulation. The present experiments were therefore set up to investigate the effect of intracerebroventricular administration of NMU on alcohol-mediated behaviors in rodents. We found that central administration of NMU attenuated alcohol-induced locomotor stimulation, accumbal dopamine release and the expression of conditioned place preference in mice. In addition, NMU dose dependently decreased alcohol intake in high, but not in low, alcohol-consuming rats. Central NMU administration did not alter the blood alcohol concentrations nor change the corticosterone levels in rodents. Given that AUD is a major health care challenge causing an enormous cost to society and novel treatment strategies are warranted, our data suggest that NMU analogues deserve to be evaluated as novel treatment of AUD in humans. PMID- 26769655 TI - New Editor-in-chief. PMID- 26769657 TI - Annexin A1 localization and its relevance to cancer. AB - Annexin A1 (ANXA1) is a Ca(2+)-regulated phospholipid-binding protein involved in various cell processes. ANXA1 was initially widely studied in inflammation resolution, but its overexpression was later reported in a large number of cancers. Further in-depth investigations have revealed that this protein could have many roles in cancer progression and act at different levels (from cancer initiation to metastasis). This is partly due to the location of ANXA1 in different cell compartments. ANXA1 can be nuclear, cytoplasmic and/or membrane associated. This last location allows ANXA1 to be proteolytically cleaved and/or to become accessible to its cognate partners, the formyl-peptide receptors. Indeed, in some cancers, ANXA1 is found at the cell surface, where it stimulates formyl-peptide receptors to trigger oncogenic pathways. In the present review, we look at the different locations of ANXA1 and their association with the deregulated pathways often observed in cancers. We have specifically detailed the non-classic pathways of ANXA1 externalization, the significance of its cleavage and the role of the ANXA1-formyl-peptide receptor complex in cancer progression. PMID- 26769658 TI - Renin-angiotensin system as a potential therapeutic target in stroke and retinopathy: experimental and clinical evidence. AB - As our knowledge expands, it is now clear that the renin-angiotensin (Ang) system (RAS) mediates functions other than regulating blood pressure (BP). The RAS plays a central role in the pathophysiology of different neurovascular unit disorders including stroke and retinopathy. Moreover, the beneficial actions of RAS modulation in brain and retina have been documented in experimental research, but not yet exploited clinically. The RAS is a complex system with distinct yet interconnected components. Understanding the different RAS components and their functions under brain and retinal pathological conditions is crucial to reap their benefits. The aim of the present review is to provide an experimental and clinical update on the role of RAS in the pathophysiology and treatment of stroke and retinopathy. Combining the evidence from both these disorders allows a unique opportunity to move both fields forward. PMID- 26769659 TI - Long-term renal and cardiovascular risk after preeclampsia: towards screening and prevention. AB - Preeclampsia (PE) is a hypertensive pregnancy disorder complicating up to 1-5% of pregnancies, and a major cause of maternal and fetal morbidity and mortality. In recent years, observational studies have consistently shown that PE carries an increased risk for the mother to develop cardiovascular and renal disease later in life. Women with a history of PE experience a 2-fold increased risk of long term cardiovascular disease (CVD) and an approximate 5-12-fold increased risk of end-stage renal disease (ESRD). Recognition of PE as a risk factor for renal disease and CVD allows identification of a young population of women at high risk of developing of cardiovascular and renal disease. For this reason, current guidelines recommend cardiovascular screening and treatment for formerly preeclamptic women. However, these recommendations are based on low levels of evidence due to a lack of studies on screening and prevention in formerly preeclamptic women. This review lists the incidence of premature CVD and ESRD observed after PE and outlines observed abnormalities that might contribute to the increased CVD risk with a focus on kidney-related disturbances. We discuss gaps in current knowledge to guide optimal screening and prevention strategies. We emphasize the need for research on mechanisms of late disease manifestations, and on effective screening and therapeutic strategies aimed at reducing the late disease burden in formerly preeclamptic women. PMID- 26769660 TI - Association between alcohol consumption and serum paraoxonase and arylesterase activities: a cross-sectional study within the Bavarian population. AB - High alcohol consumption is an important risk factor for chronic disease and liver degeneration. Paraoxonase (PON1) and arylesterase (AE) are functions of the enzyme paraoxonase, which is synthesised by the liver. Paraoxonase circulates in plasma bound to HDL and hydrolyses lipid peroxides, protecting lipoproteins against oxidative modification. It has been shown that excessive alcohol consumption leads to a reduction of serum PON1 and AE activities; however, studies investigating the association with low and moderate alcohol consumption are scarce. We investigated the cross-sectional association between alcohol consumption and serum activities of PON1 and AE using data from the population based Bavarian Food Consumption Survey II survey. PON1 and AE activities were quantified in serum samples of 566 male and female study participants (aged 18-80 years), and dietary intake including alcohol consumption was estimated from three 24-h dietary recalls. The association between alcohol consumption and PON1 and AE activities was analysed using linear regression, adjusted for age, sex and socio economic status. There was no strong association between alcohol consumption and enzymatic activities of PON1 and AE in the Bavarian population. PON1 activity was seen to be lowest in non-drinkers (0 g/d) and highest in people who consumed 15.1 30 g of alcohol/d. AE activity increased across alcohol consumption categories, with a mean maximum difference of 14 U/ml (P for linear trend 0.04). These associations were attenuated after adjustment for blood concentrations of HDL. The results of this study do not support the hypothesis that alcohol consumption is related to important alterations in PON1 and AE activities. PMID- 26769662 TI - Occupational therapists in Emergency Departments. PMID- 26769661 TI - Changes in Unknown Primary Squamous Cell Carcinoma of the Head and Neck at Initial Presentation in the Era of Human Papillomavirus. AB - IMPORTANCE: The presence of human papillomavirus (HPV) in unknown primary squamous cell carcinoma (UPSCC) of the head and neck at initial presentation focuses the investigation for the primary tumor on the oropharynx. The trends, frequency, and detection rate of UPSCCs have not been evaluated in the context of HPV tumor status. OBJECTIVES: To determine the frequency of UPSCC over time and to evaluate the proportion of HPV-positive UPSCCs. DESIGN, SETTING, AND PARTICIPANTS: Retrospective, single-institutional case series of patients diagnosed with UPSCC and evaluated at the Johns Hopkins Hospital from January 1, 2005, to June 1, 2014. Human papillomavirus tumor status was determined by p16 immunohistochemical analysis and/or high-risk HPV DNA by in situ hybridization as clinically available. MAIN OUTCOMES AND MEASURES: Number and clinical characteristics of UPSCC cases over time. RESULTS: Eighty-four UPSCC cases were eligible for analysis. The mean age of the patients was 57.3 years (range 29-80 years), and 88.1% (n = 74) were male. The frequency of UPSCC increased significantly over time (P for trend = .01) and was significantly higher during later calendar periods (14 cases during 2005-2008 vs 39 cases during 2012-2014, P = .03). A total of 69 cases (90.7%) with available HPV tumor status were HPV positive. The patients with HPV-positive UPSCC were significantly more likely to be male (91% vs 42.9%, P = .005) and younger (56.1 vs 67.7 years, P = .002) than the HPV-negative patients with UPSCC. The overall primary tumor site detection rate was 59.3% (n = 48). There was a nonsignificant increase in the detection rate from calendar periods 2005-2008 to 2012-2014 (50.0% vs 64.9%, P = .38). Since transoral robotic surgery was adopted in the diagnostic evaluation of UPSCC in 2011, a nonsignificant increase in the detection of primary tumors was observed (53.8% vs 64.3%, P = .34). CONCLUSIONS AND RELEVANCE: The frequency of UPSCC has increased significantly in recent calendar periods, and most cases are HPV-positive. As expected, patients with HPV-positive UPSCC tend to be male and younger. PMID- 26769663 TI - [Not Available]. PMID- 26769664 TI - [Geriatric traumatology]. PMID- 26769667 TI - Lessons learned in Andrology: Yves Clermont, an interview by Lonnie D. Russell. PMID- 26769665 TI - Vascular endothelial growth factor-C protects heart from ischemia/reperfusion injury by inhibiting cardiomyocyte apoptosis. AB - VEGF-C is a newly identified proangiogenic protein playing an important role in vascular disease and angiogenesis. However, its role in myocardial ischemia/reperfusion (I/R) injury remains unknown. The objective of this study was to determine the role and mechanism of VEGF-C in myocardial ischemia reperfusion injury. Rat left ventricle myocardium was injected with recombinant human VEGF-C protein (0.1 or 1.0 ug/kg b.w.) 1 h prior to myocardial ischemia reperfusion (I/R) injury. 24 h later, the myocardial infarction size, the number of TUNEL-positive cardiomyocytes, the levels of creatine kinase (CK), CK-MB, cardiac troponin, malondialdehyde (MDA) content, and apoptosis protein Bax expression were decreased, while Bcl2 and pAkt expression were increased in VEGF C-treated myocardium as compared to the saline-treated I/R hearts. VEGF-C also improved the function of I/R-injured hearts. In the H2O2-induced H9c2 cardiomyocytes, which mimicked the I/R injury in vivo, VEGF-C pre-treatment decreased the LDH release and MDA content, blocked H2O2-induced apoptosis by inhibiting the pro-apoptotic protein Bax expression and its translocation to the mitochondrial membrane, and consequently attenuated H2O2-induced decrease of mitochondrial membrane potential and increase of cytochrome c release from mitochondria. Mechanistically, VEGF-C activated Akt signaling pathway via VEGF receptor 2, leading to a blockade of Bax expression and mitochondrial membrane translocation and thus protected cardiomyocyte from H2O2-induced activation of intrinsic apoptotic pathway. VEGF-C exerts its cardiac protection following I/R injury via its anti-apoptotic effect. PMID- 26769666 TI - Parametric response mapping of contrast-enhanced biphasic CT for evaluating tumour viability of hepatocellular carcinoma after TACE. AB - OBJECTIVES: To determine the feasibility and role of parametric response mapping (PRM) for quantitative assessment of regional contrast-enhancement patterns in hepatocellular carcinoma (HCC). METHODS: Biphasic CT of 19 patients receiving repetitive conventional transarterial chemoembolisation (cTACE) for intermediate stage HCC were retrospectively analysed at baseline and follow-up at 3, 6, and 9 months. Voxel-based registration of arterial and porto-venous phases, with segmentation of the largest target lesion was performed. Frequency distribution plots of density-pairs of segmented voxels were generated. To differentiate necrotic, hypervascular and non-hypervascular tumour, and lipiodol/calcification, thresholds of 30, 100, and 300 HU were applied. Changes in density frequency plots over time were analysed and compared to response and assessment criteria (WHO, RECIST, EASL, mRECIST) and survival. RESULTS: PRM was feasible in all cases. Tumour volumes and hypervascular/non-hypervascular volume ratio showed significant longitudinal decrease (p < 0.05). Hypervascular volume at baseline was inversely correlated to survival (R = -0.57, p = 0.005). The only predictive parameter following cTACE to show significant survival difference was the change of the viable/non-viable ratio (p = 0.044), whereas common response assessment criteria showed no significant difference in survival. CONCLUSIONS: PRM allows a quantitative and more precise assessment of regional tumour vascularisation patterns and may be helpful for TACE treatment planning and response assessment. KEY POINTS: * PRM allows more precise assessment of tumour vascularisation compared to conventional evaluation * PRM is beneficial for cTACE treatment planning and response assessment * PRM allows a quantitative assessment of regional contrast enhancement patterns. PMID- 26769668 TI - The prevalence of and risk factors for prostatitis-like symptoms and its relation to erectile dysfunction in Chinese men. AB - The aim of this study was to describe the prevalence of and risk factors for prostatitis-like symptoms and its relation to erectile dysfunction (ED) among southern Chinese men. Data were collected from 2790 men attending the Fangchenggang Area Male Healthy and Examination Survey from September 2009 to December 2009. The prostatitis-like symptoms were assessed by the NIH Chronic Prostatitis Symptom Index and ED was assessed using the 5-item International Index of Erectile Function. Lifestyle and demographic characteristics were obtained through a questionnaire. Prevalence of prostatitis-like symptoms was 12.4% among 2790 Chinese men aged 20-84 years. In smokers who smoked >=20 cigarettes per day (age-adjusted OR = 1.29; 95% CI = 1.00-1.66; p = 0.04), physical inactivity (age-adjusted OR = 1.31; 95% CI = 1.03-1.66; p = 0.02) was a significant risk factor for prostatitis-like symptoms. Alcohol consumption (daily drinking) also was a risk factor for prostatitis-like symptoms, although the differences were not statistically significant (age-adjusted OR = 1.36; 95% CI = 0.96-1.92; p = 0.07). Those with diabetes may also be at higher risk for prostatitis-like symptoms (age-adjusted OR = 1.37; 95% CI = 0.85-2.21; p = 0.19). In addition, men with ED were more likely to have had prostatitis-like symptoms (age-adjusted OR = 1.86; 95% CI = 0.47-2.36; p < 0.0001), and the ORs increased with increasing severity of ED status (mild ED, mild to moderate ED, and moderate to severe ED were 1.57, 2.62, and 3.24, respectively. Test for trend, p = 0.0001). Our results show that prostatitis-like symptoms are prevalent in Southern China affecting men of all ages. Smoking, drinking, lack of physical activity, and elevated plasma glucose level were associated with an increased risk of prostatitis-like symptoms. In addition, our results reveal that ED accounted for a large proportion (61.5%) among men with prostatitis-like symptoms; we also confirm the magnitude of ED associated with prostatitis-like symptoms. Thus, interventions to evaluate and improve ED might help ameliorate prostatitis-like symptoms and vice versa. PMID- 26769670 TI - Choroidal thickness maps from spectral domain and swept source optical coherence tomography: algorithmic versus ground truth annotation. AB - BACKGROUND/AIMS: The purpose of the study was to create a standardised protocol for choroidal thickness measurements and to determine whether choroidal thickness measurements made on images obtained by spectral domain optical coherence tomography (SD-OCT) and swept source (SS-) OCT from patients with healthy retina are interchangeable when performed manually or with an automatic algorithm. METHODS: 36 grid cell measurements for choroidal thickness for each volumetric scan were obtained, which were measured for SD-OCT and SS-OCT with two methods on 18 eyes of healthy volunteers. Manual segmentation by experienced retinal graders from the Vienna Reading Center and automated segmentation on >6300 images of the choroid from both devices were statistically compared. RESULTS: Model-based comparison between SD-OCT/SS-OCT showed a systematic difference in choroidal thickness of 16.26+/-0.725 MUm (p<0.001) for manual segmentation and 21.55+/ 0.725 MUm (p<0.001) for automated segmentation. Comparison of automated with manual segmentations revealed small differences in thickness of -0.68+/-0.513 MUm (p=0.1833). The correlation coefficients for SD-OCT and SS-OCT measures within eyes were 0.975 for manual segmentation and 0.955 for automatic segmentation. CONCLUSION: Choroidal thickness measurements of SD-OCT and SS-OCT indicate that these two devices are interchangeable with a trend of choroidal thickness measurements being slightly thicker on SD-OCT with limited clinical relevance. Use of an automated algorithm to segment choroidal thickness was validated in healthy volunteers. PMID- 26769671 TI - Long-term surgical outcomes and factors for recurrence after unilateral lateral rectus muscle recession. AB - AIM: To evaluate long-term surgical outcomes and risk factors for recurrence after unilateral lateral rectus muscle recession (ULR) in children with small to moderate angle intermittent exotropia (IXT). METHODS: 214 patients with basic type IXT of 15-24 prism dioptres (PD) who underwent ULR were included. The main outcome measure was success rate at 2 years after surgery and at final follow-up. The risk factors related to recurrence were evaluated using univariable and multivariable logistic regression analyses. RESULTS: Success rate at postoperative 2 years was 92.5% and at final examination after a mean follow-up of 3.9 years was 83.2%. No overcorrection was observed. Preoperative exodeviation of 20-24 PD was the significant risk factor for recurrence according to both univariable (OR=3.577, p=0.022) and multivariable analysis (OR=3.265, p=0.034). CONCLUSIONS: The overall long-term successful alignment rate of ULR for 15-24 PD of IXT was good. However, patients with 20-24 PD of IXT showed worse prognosis compared with 15-19 PD of IXT. PMID- 26769672 TI - Changes observed in diabetic retinopathy: eight-year follow-up of a Spanish population. AB - BACKGROUND/AIMS: To determine the changes in the incidence of diabetic retinopathy (DR), diabetic macular oedema (DMO) and their risk factors in a population-based study of patients with diabetes mellitus (DM) referred to our 16 Primary Health Care Areas (HCAs). METHODS: Prospective population-based study of a total of 15 396 Caucasian patients with DM, who represent 86.53% of the total patients with DM in our HCAs, were studied over an 8-year follow-up period. All patients were screened with a mean follow-up of 3.18+/-1.11 times for each patient over the 8 years. RESULTS: The yearly mean value of any DR was 8.37+/ 2.19% (8.09%-8.99%); of advanced DR yearly mean value of 0.46+/-0.22% (0.03 0.78); and of DMO a yearly mean value of 2.19+/-0.18% (2%-2.49%). A clear increase was observed in the last 3 years, any DR increased from 8.09% in 2007 to 8.99% in 2014, and DMO from 2% in 2007 to 2.49% in 2014. These increases were more evident in some age groups. For patients with any DR aged 41-50 and 51-60 and for patients with advanced DR aged 41-50, 51-60 and 61-70, the increase was more marked, related to an increase in HbA1c values or to patients treated with insulin. CONCLUSIONS: An increase in the incidence of DR and DMO was observed, especially in the younger patients aged between 31 and 70 years. This is linked to bad metabolic control of DM. Our results suggest a greater number of ocular complications in the near future, such as neovascular glaucoma, if these current findings are not addressed. PMID- 26769673 TI - Combined positron emission tomography/computed tomography (PET/CT) for imaging of orbital tumours and tumours extending into the orbit. AB - OBJECTIVE: To assess clinical and radiological performance of combined positron emission tomography/computed tomography (PET/CT) in patients with secondary and primary intraorbital tumours. METHODS: 14 adults with secondary and 1 child with primary orbital masses underwent combined whole-body PET/CT. Radiopharmaceutical tracers applied were (18F)-fluorodeoxyglucose, (18F)-fluoroethylcholine (FEC) and (68Ga)-DOTATATE. Histopathology and/or all conventional radiographic work-up and clinical course served as standard of reference. Descriptive statistics and Fisher's exact test were used for analysis. RESULTS: PET/CT detected all orbital masses. All 15 patients had malignant disease. Local osseous infiltration was correctly identified in 11 patients. Lymph node metastases were present in two of eight patients (25%) with haematogenous orbital metastases and in five of six patients (83%) with infiltrative carcinoma (p=0.05). Further distant metastases were present in all eight patients suffering from orbital metastases, but only one patient with infiltrative carcinoma (17%) presented with disseminated disease (p=0.003). In one metastasis, PET/CT excluded vital orbital tumour tissue after radiation therapy. Local recurrence was detected in another patient suffering from prostate cancer. CONCLUSION: PET/CT is a sensitive tool for the detection and localisation of orbital masses, enabling assessment of both morphology and cell metabolism. Detailed imaging of the head and neck region with a small field of-view should be performed when suspecting lymphatic metastases. As metastatic disease to the orbit is associated with advanced disease, focus should be laid on whole-body imaging for staging of these patients. Different radiopharmaceutical tracers can be applied to distinguish the origin of orbital metastases. PMID- 26769674 TI - Genetic deletion of keratin 8 corrects the altered bone formation and osteopenia in a mouse model of cystic fibrosis. AB - Patients with cystic fibrosis (CF) display low bone mass and alterations in bone formation. Mice carrying the F508del genetic mutation in the cystic fibrosis conductance regulator (Cftr) gene display reduced bone formation and decreased bone mass. However, the underlying molecular mechanisms leading to these skeletal defects are unknown, which precludes the development of an efficient anti osteoporotic therapeutic strategy. Here we report a key role for the intermediate filament protein keratin 8 (Krt8), in the osteoblast dysfunctions in F508del-Cftr mice. We found that murine and human osteoblasts express Cftr and Krt8 at low levels. Genetic studies showed that Krt8 deletion (Krt8(-/-)) in F508del-Cftr mice increased the levels of circulating markers of bone formation, corrected the expression of osteoblast phenotypic genes, promoted trabecular bone formation and improved bone mass and microarchitecture. Mechanistically, Krt8 deletion in F508del-Cftr mice corrected overactive NF-kappaB signaling and decreased Wnt-beta catenin signaling induced by the F508del-Cftr mutation in osteoblasts. In vitro, treatment with compound 407, which specifically disrupts the Krt8-F508del-Cftr interaction in epithelial cells, corrected the abnormal NF-kappaB and Wnt-beta catenin signaling and the altered phenotypic gene expression in F508del-Cftr osteoblasts. In vivo, short-term treatment with 407 corrected the altered Wnt beta-catenin signaling and bone formation in F508del-Cftr mice. Collectively, the results show that genetic or pharmacologic targeting of Krt8 leads to correction of osteoblast dysfunctions, altered bone formation and osteopenia in F508del-Cftr mice, providing a therapeutic strategy targeting the Krt8-F508del-CFTR interaction to correct the abnormal bone formation and bone loss in cystic fibrosis. PMID- 26769675 TI - Phosphatidylserine enhances IKBKAP transcription by activating the MAPK/ERK signaling pathway. AB - Familial dysautonomia (FD) is a genetic disorder manifested due to abnormal development and progressive degeneration of the sensory and autonomic nervous system. FD is caused by a point mutation in the IKBKAP gene encoding the IKAP protein, resulting in decreased protein levels. A promising potential treatment for FD is phosphatidylserine (PS); however, the manner by which PS elevates IKAP levels has yet to be identified. Analysis of ChIP-seq results of the IKBKAP promoter region revealed binding of the transcription factors CREB and ELK1, which are regulated by the mitogen-activated protein kinase (MAPK)/extracellular regulated kinase (ERK) signaling pathway. We show that PS treatment enhanced ERK phosphorylation in cells derived from FD patients. ERK activation resulted in elevated IKBKAP transcription and IKAP protein levels, whereas pretreatment with the MAPK inhibitor U0126 blocked elevation of the IKAP protein level. Overexpression of either ELK1 or CREB activated the IKBKAP promoter, whereas downregulation of these transcription factors resulted in a decrease of the IKAP protein. Additionally, we show that PS improves cell migration, known to be enhanced by MAPK/ERK activation and abrogated in FD cells. In conclusion, our results demonstrate that PS activates the MAPK/ERK signaling pathway, resulting in activation of transcription factors that bind the promoter region of IKBKAP and thus enhancing its transcription. Therefore, compounds that activate the MAPK/ERK signaling pathway could constitute potential treatments for FD. PMID- 26769676 TI - Fine mapping the MHC region identified four independent variants modifying susceptibility to chronic hepatitis B in Han Chinese. AB - Several genome-wide association studies (GWAS) have demonstrated the association between genetic variants in the major histocompatibility complex (MHC) region and chronic hepatitis B (CHB) virus infection, but it is still unknown about the disease-causing loci and potential mechanisms owing to the complicated linkage disequilibrium for this region. To systematically characterize the MHC variations in relation to the CHB infection, we fine mapped the MHC region on our existing GWAS data with SNP2HLA taken the Pan-Asian panel as reference and finally identified four independent associations. The HLA-DPbeta1 amino acid positions 84 87, which drove the effect of reported single nucleotide polymorphisms rs9277535 and rs3077, showed the most significant association (OR = 0.65, P = 2.03 * 10( 8)). The Leu-15 of HLA-C, conferring the effect of rs3130542, increased the risk of CHB infection independently (OR = 1.61, P = 3.42 * 10(-7)). The HLA DRbeta1*13, in perfect LD with glutamic at site 71, and rs400488, an expression quantitative trait locus for HLA-J, were newly identified to be associated with CHB infection independently (OR = 1.84, P = 3.84 * 10(-9); OR = 0.28, P = 6.27 * 10(-7), respectively). HLA-DPbeta1 positions 84-87 and HLA-DRbeta1 position 71 implicated the P1 and P4 in the antigen-binding groove, whereas HLA-C position 15 affected the signal peptide. These four independent loci together can explain ~ 6% of the phenotypic variance for CHB infection, accounting for 72.94% of that explained by known genetic variations. We fine mapped the MHC region and identified four loci that independently drove the chronic HBV infection. The results provided a deeper understanding of the GWAS signals and identified additional susceptibility loci which were missed in previous association studies. PMID- 26769678 TI - Residence-Based Fear of Crime: A Routine Activities Approach. AB - Most fear-of-crime research uses resident's neighborhood as a key reference location to measure fear, yet the location effects of one's own dwelling unit on crime-specific fear has not been explicitly studied theoretically in the literature. Drawing upon routine activities theory, this study undertakes an investigation into the levels and determinants of residence-based fear of crime across three racial/ethnic groups-Whites, African Americans, and non-White Hispanics. Data used in the analyses were collected from a random-sample telephone survey of 1,239 respondents in Houston, Texas. The results derived from factor analyses revealed that residents do distinguish between fear in the neighborhood and fear at home. Proximity to motivated offenders measured by perception of crime was found to be the most salient predictor of fear, followed by the measures of target vulnerability and capable guardianship. In addition, residence-based fear varies significantly across racial/ethnic groups. The significance of these findings and the policy implications are highlighted. PMID- 26769679 TI - The Development of a Program Engagement Theory for Group Offending Behavior Programs. AB - Offender engagement in group offending behavior programs is poorly understood and under-theorized. In addition, there is no research on facilitators' engagement. This article presents the first ever theory to address this gap. A Program Engagement Theory (PET) was derived from a constructivist grounded theory analysis that accounts for both facilitators' and offenders' engagement in group offending behavior programs (GOBPs). Interviews and session observations were used to collect data from 23 program facilitators and 28 offenders (group members). The analysis revealed that group members' engagement involved shared identities and moving on as a group. In turn, this was dependent on facilitators personalising treatment frameworks and establishing a hook to help group members move on. The PET emphasizes the importance of considering change during treatment as a process rather than simply a program outcome. Solution-focused (SF) programs were more conducive to engagement and the change process than offence-focused programs. PMID- 26769677 TI - Sensory and autonomic deficits in a new humanized mouse model of familial dysautonomia. AB - Familial dysautonomia (FD) is an autosomal recessive neurodegenerative disease that affects the development and survival of sensory and autonomic neurons. FD is caused by an mRNA splicing mutation in intron 20 of the IKBKAP gene that results in a tissue-specific skipping of exon 20 and a corresponding reduction of the inhibitor of kappaB kinase complex-associated protein (IKAP), also known as Elongator complex protein 1. To date, several promising therapeutic candidates for FD have been identified that target the underlying mRNA splicing defect, and increase functional IKAP protein. Despite these remarkable advances in drug discovery for FD, we lacked a phenotypic mouse model in which we could manipulate IKBKAP mRNA splicing to evaluate potential efficacy. We have, therefore, engineered a new mouse model that, for the first time, will permit to evaluate the phenotypic effects of splicing modulators and provide a crucial platform for preclinical testing of new therapies. This new mouse model, TgFD9; Ikbkap(Delta20/flox) was created by introducing the complete human IKBKAP transgene with the major FD splice mutation (TgFD9) into a mouse that expresses extremely low levels of endogenous Ikbkap (Ikbkap(Delta20/flox)). The TgFD9; Ikbkap(Delta20/flox) mouse recapitulates many phenotypic features of the human disease, including reduced growth rate, reduced number of fungiform papillae, spinal abnormalities, and sensory and sympathetic impairments, and recreates the same tissue-specific mis-splicing defect seen in FD patients. This is the first mouse model that can be used to evaluate in vivo the therapeutic effect of increasing IKAP levels by correcting the underlying FD splicing defect. PMID- 26769681 TI - Acute kidney injury: highlights from the ERA-EDTA Congress in London. AB - The ERA-EDTA 52nd Congress was held in London, 28-31 May 2015. In the scientific programme, overall, during the symposium, there were 18 lectures, 3 minilectures, 15 free communications and 135 poster presentations on acute kidney injury (AKI). Among many excellent reports and presentations, I selected three hot topics on AKI for the readership of Nephrology Dialysis Transplantation. PMID- 26769680 TI - A single 60-min bout of peristaltic pulse external pneumatic compression transiently upregulates phosphorylated ribosomal protein s6. AB - We investigated whether a single 60-min bout of whole leg, peristaltic pulse external pneumatic compression (EPC) altered select growth factor-related mRNAs and/or various phospho(p)-proteins related to cell growth, proliferation, inflammation and apoptosis signalling (e.g. Akt-mTOR, Jak-Stat). Ten participants (8 males, 2 females; aged 22.2 +/- 0.4 years) reported to the laboratory 4 h post prandial, and vastus lateralis muscle biopsies were obtained prior to (PRE), 1 h and 4 h post-EPC treatment. mRNA expression was analysed using real-time RT-PCR and phosphophorylated and cleaved proteins were analysed using an antibody array. No changes in selected growth factor-related mRNAs were observed following EPC. All p-proteins significantly altered by EPC decreased, except for p-rps6 (Ser235/236) which increased 31% 1 h post-EPC compared to PRE levels (P = 0.016). Notable decreases also included p-BAD (Ser112; -28%, P = 0.004) at 4 h post-EPC compared to PRE levels. In summary, an acute bout of EPC transiently upregulates p-rps6 as well as affecting other markers in the Akt-mTOR signalling cascade. Future research should characterize whether chronic EPC application promotes alterations in lower-limb musculature and/or enhances exercise-induced training adaptations. PMID- 26769682 TI - Long-term outcomes of persistent disease and relapse in primary membranous nephropathy. AB - BACKGROUND: Primary membranous nephropathy is associated with variable clinical course ranging from spontaneous remission to slow progression to end stage renal failure. Achieving remission confers better renal survival in primary membranous nephropathy (PMN). Longer term outcomes such as patient survival and relapse of active disease remain poorly understood. METHODS: We performed a retrospective study of 128 consecutive adult patients diagnosed with biopsy proven PMN at a single UK centre between 1980 and 2010. These patients were followed prospectively over a median of 128 months. We assessed impact of persistent disease and relapse on Stage 5 chronic kidney disease (CKD-5) and patient survival and present longer term cumulative incidences of different end points. RESULTS: One hundred patients achieved partial remission (PartRem) and 28 patients did not achieve remission (NoRem). Nine per cent of patients achieving first remission developed CKD-5 and 75% of those with NoRem developed CKD-5 [hazard ratio (HR) 0.07, 95% confidence interval 0.03-0.19). Relapse following PartRem occurred in 31 patients (31%) during follow-up and was significantly associated with progression to CKD-5. Progression to CKD-5 was strongly associated with death (47 versus 6%, HR 23.4; P < 0.01). Cumulative incidence at 15 years following first presentation included: death, 14%; CKD-5, 28%; and relapse 40% (in patients who achieved first remission). CONCLUSIONS: Our data strongly suggest that mortality in PMN is seen in patients with disease progression to CKD-5. Achieving remission is strongly associated with improved renal survival after first presentation and following relapse. We suggest that patients who achieve remission should be followed up in longer term, and better strategies to help improve outcomes are needed in clinical practice. PMID- 26769685 TI - The Auditory Rehabilitation Outcomes Network: an international initiative to develop core sets of patient-centred outcome measures to assess interventions for hearing loss. PMID- 26769683 TI - Zoster vaccination is associated with a reduction of zoster in elderly patients with chronic kidney disease. AB - BACKGROUND: Growing epidemiological evidence demonstrates increased zoster risks in people with chronic kidney disease (CKD). Study objectives were to determine zoster vaccine effectiveness in individuals with CKD in pragmatic use. METHODS: A population-based cohort study was undertaken in a 5% random sample of US Medicare from 2007 to 2009 involving 766 330 eligible individuals aged >=65 years who were (29 785) and were not (736 545) exposed to the zoster vaccine. Incidence rates for zoster in vaccinated and unvaccinated individuals and hazard ratios for zoster comparing vaccinated with unvaccinated were determined for individuals with CKD. Time-updated Cox proportional hazards models were used, adjusting for relevant confounders. RESULTS: CKD was present in 183 762 (24%) of individuals (15% of vaccinees). Adjusted vaccine effectiveness [95% confidence intervals (CIs)] in individuals with CKD was 0.49 (0.36-0.65). The adjusted vaccine effectiveness in participants with both CKD and diabetes mellitus was 0.46 (95% CI 0.09-0.68). Vaccine effectiveness estimates were similar to those previously reported for the general population [vaccine effectiveness 0.48 (95% CI 0.39 0.56)]. CONCLUSIONS: Zoster vaccine is effective against incident zoster in older individuals with CKD. Extra efforts are warranted to increase vaccine uptake in individuals with CKD given the known low uptake in these higher risk individuals. PMID- 26769686 TI - Management of paediatric otogenic cerebral venous sinus thrombosis: a systematic review. AB - BACKGROUND: Otogenic paediatric cerebral venous sinus thrombosis (CVST) is rare but has potential clinical sequelae. Its management has long been debated mainly concerning the role of surgery and the use of anticoagulant therapy. OBJECTIVE OF REVIEW: To review the current literature and examine the medical and surgical management of paediatric otogenic CVST and its clinical and radiological outcome. TYPE OF REVIEW: Systematic review. SEARCH STRATEGY: The electronic databases (MEDLINE, EMBASE, Cochrane) were searched from inception to November 2014 using text words 'cerebral venous sinus thrombosis OR cerebral venous thrombosis OR lateral sinus thrombosis OR sigmoid sinus thrombosis' AND 'otogenic OR mastoiditis OR otitis media' AND 'children OR paediatric OR pediatric'. EVALUATION METHOD: Inclusion criteria were applied by two reviewers and data extraction was carried out. The type of otological surgery (conservative versus extensive) and the use of anticoagulants with their clinical and radiological outcomes were tabulated. RESULTS: Thirty-six studies (15 case reports and 21 case series) were included with a total of 190 patients. A total of 92.1% of patients underwent otological surgery, and 69.5% had conservative surgery and 30.5% extensive otological surgery. Anticoagulants were used in 59%. A total of 79.2% of patients were reported to have had a good clinical outcome. Within this group, 56% had conservative surgery and anticoagulants. Follow-up scans were documented in 61.6% of patients and complete recanalisation was observed in 51%. Complete recanalisation was observed in 47% of those who had been anticoagulated and 55% of those who received no anticoagulation. CONCLUSIONS: Conservative otological surgery with the combination of anticoagulation was the most common treatment modality found in the group of patients with good clinical outcome. However, given the current low level of evidence, a multicentre collaborative study is needed to help establish the optimum surgical approach and the role of anticoagulation in managing paediatric otogenic CVST. PMID- 26769687 TI - A simple technique for the single-handed management of anterior epistaxis. PMID- 26769688 TI - Response: opportunities for certificate of completion of training. PMID- 26769689 TI - Re: Application of phenol as topical anaesthesia using the Derlacki elevator for myringotomy. PMID- 26769690 TI - Utilisation and expenditure of radiotherapy among nasopharyngeal cancer patients in Taiwan. PMID- 26769691 TI - Sialography--more than an image. PMID- 26769692 TI - Re: A validation study on the use of intra-operative video recording as an objective assessment tool for core ENT surgery. PMID- 26769693 TI - Letter to the editor. PMID- 26769694 TI - Response to COA-2015-0283 'Letter to the editor'. PMID- 26769695 TI - A sutured cartilage-perichondrium island cap for titanium ossiculoplasty. PMID- 26769696 TI - Oncoplastic surgery combining abdominal advancement flaps with volume displacement techniques to breast-conserving surgery for small- to medium-sized breasts. AB - BACKGROUND: An abdominal advancement flap (AAF) is a flap that pulls the elevated abdominal skin up, creating the shape of the inferior portion of the breast by making a neo-inframammary fold. We used an AAF combined with volume displacement techniques to fill the defect left after breast-conserving surgery (BCS). METHODS: Forty-one small- to medium-sized breast patients whose resection area included the lower portion of the breast underwent this procedure from October 2010 to December 2014. We evaluated efficacy of this procedure. RESULTS: The excision volume ranged from 10 to 35 %. Complications after surgery were observed in two patients (partial necrosis of the nipple-areola complex and partial necrosis of the breast skin in one patient each). There was no fat necrosis of the flap in any of the patients. The cosmetic results were found to be excellent in 7 cases, good in 23, fair in 9 and poor in 2. In 11 cases with an unacceptable outcome, 9 cases were in the inner portion. In patients with the tumor in the inner portion, the proportion of unacceptable cases was 50 %. In the cases other than the inner portion, the proportion of unacceptable cases was 8.7 % (p < 0.01). In the cases with larger breasts, unacceptable cases were more frequently observed (p < 0.05). CONCLUSIONS: We believe that an AAF combined with volume displacement techniques may be useful following BCS in the lower portion of a small- to medium-sized breast, except in cases where the tumors is located in the inner potion. PMID- 26769697 TI - Comparative effectiveness of granulocyte colony-stimulating factors to prevent febrile neutropenia and related complications in cancer patients in clinical practice: A systematic review. AB - INTRODUCTION: Febrile neutropenia (FN) is a serious side-effect of myelosuppressive chemotherapy. Several clinical trials and observational studies have evaluated the effects of prophylactic granulocyte colony-stimulating factors (G-CSFs) on risk of FN and related complications; however, no systematic reviews have focused on effectiveness in routine clinical practice. Here, we perform a systematic review assessing the comparative effectiveness of prophylaxis with a long-acting G-CSF (pegfilgrastim) versus short-acting G-CSFs (filgrastim, lenograstim, and filgrastim biosimilars) in cancer patients in real-world clinical settings. METHODS: A systematic review was performed based on a pre specified protocol and was consistent with the Cochrane Collaboration Handbook (2009) and the Centre for Reviews and Dissemination's Guidance for Undertaking Reviews in Health Care (2011). MEDLINE, Embase, BIOSIS, Cumulative Index to Nursing and Allied Health Literature, and Cochrane Library databases were searched for articles published from January 2002 to June 2014. Congress databases (MASCC/ASCO/ESMO) and Google Scholar were searched for abstracts published from January 2012 to August 2014. Filgrastim (NEUPOGEN(r)), lenograstim and nivestim (a filgrastim biosimilar) were the only short-acting G-CSFs and pegfilgrastim (Neulasta(r)) was the only long-acting G-CSF described in eligible studies. Outcomes of interest were FN, FN-related hospitalisation and other FN related complications (death, chemotherapy dose delays and reductions, antimicrobial treatment, severe neutropenia and costs and resource use). RESULTS: Of 1259 unique records identified, 18 real-world observational studies met predefined inclusion criteria; 15 were retrospective studies, and 3 were prospective studies. Multiple tumour types, chemotherapy regimens and geographical regions were included. Seven studies provided statistical comparisons of the risk of FN; risk of FN among patients receiving prophylaxis with pegfilgrastim versus short-acting G-CSF was significantly lower in three studies, numerically lower in three studies, and numerically higher in one study. Six studies provided statistical comparisons of the risk of FN-related hospitalisation; risk of FN-related hospitalisation among patients receiving prophylaxis with pegfilgrastim versus short-acting G-CSF was significantly lower in all six studies, though some variation was seen in subanalyses. Data for other outcomes were sparse with available results being generally consistent with the results seen for risk of FN and FN-related hospitalisation. CONCLUSIONS: Based on the findings from this review of real-world comparative effectiveness studies, risks of FN and FN-related complications were generally lower for prophylaxis with pegfilgrastim versus prophylaxis with short-acting G-CSFs. PMID- 26769698 TI - Exercise and Physical Activity for the Post-Aortic Dissection Patient: The Clinician's Conundrum. AB - Despite the paucity of evidence, it is often presumed, and is physiologically plausible, that sudden, acute elevations in blood pressure may transiently increase the risk of recurrent aortic dissection (AD) or rupture in patients with a prior AD, because a post-dissection aorta is almost invariably dilated and may thus experience greater associated wall stress as compared with a nondilated aorta. Few data are available regarding the specific types and intensities of exercise that may be both safe and beneficial for this escalating patient population. The purpose of this editorial/commentary is to further explore this conundrum for clinicians caring for and counseling AD survivors. Moderate intensity cardiovascular activity may be cardioprotective in this patient cohort. It is likely that severe physical activity restrictions may reduce functional capacity and quality of life in post-AD patients and thus be harmful, underscoring the importance of further exploring the role of physical activity and/or structured exercise in this at-risk patient population. PMID- 26769699 TI - Survivors of Aortic Dissection: Activity, Mental Health, and Sexual Function. AB - BACKGROUND: Currently no research exists assessing lifestyle modifications and emotional state of acute aortic dissection (AAD) survivors. We sought to assess activity, mental health, and sexual function in AAD survivors. HYPOTHESIS: Physical and sexual activity will decrease in AAD survivors compared to pre dissection. Incidence of anxiety and depression will be significant after AAD. METHODS: A cross sectional survey was mailed to 197 subjects from a single academic medical center (part of larger IRAD database). Subjects were >=18 years of age surviving a type A or B AAD between 1996 and 2011. 82 surveys were returned (overall response rate 42%). RESULTS: Mean age +/- SD was 59.5 +/- 13.7 years, with 54.9% type A and 43.9% type B patients. Walking remained the most prevalent form of physical activity (49 (60%) pre-dissection and 47 (57%) post dissection). Physical inactivity increased from 14 (17%) before AAD to 20 (24%) after AAD; sexual activity decreased from 31 (38%) to 9 (11%) mostly due to fear. Most patients (66.7%) were not exerting themselves physically or emotionally at AAD onset. Systolic blood pressure (SBP) at 36 months post-discharge for patients engaging in >=2 sessions of aerobic activity/week was 126.67 +/- 10.30 vs. 141.10 +/- 11.87 (p-value 0.012) in those who did not. Self-reported new-onset depression after AAD was 32% and also 32% for new-onset anxiety. CONCLUSIONS: Alterations in lifestyle and emotional state are frequent in AAD survivors. Clinicians should screen for unfounded fears or beliefs after dissection that may reduce function and/or quality of life for AAD survivors. PMID- 26769700 TI - Clinical characteristics of 15 cases of chronic subdural hematomas due to spontaneous intracranial hypotension with spinal cerebrospinal fluid leak. AB - The etiology of chronic subdural hematoma (CSDH) in patients is diverse. The primary objective of this article was to discuss one of the causes, spontaneous intracranial hypotension with spinal cerebrospinal fluid (CSF) leak, which is usually neglected by the neurosurgeon. All the consecutive 15 patients who underwent operation for CSDHs between June 2012 and June 2014 at Sir Run Run Shaw Hospital of Zhejiang University were included in this retrospective cohort study. The clinical and imaging data of these patients with CSDHs due to spinal CSF leak were retrospectively studied. Fifteen patients, with a mean age of 53.8 +/- 8.3 years, underwent operations for CSDH. Hematomas were unilateral in 4 patients and bilateral in 11 patients. Among these patients, eight patients had recurrence of hematomas after operation due to neglect of spinal CSF leak. All patients had fully recovery. Spinal CSF leak is a cause of cSDH, which is overlooked by the doctor. PMID- 26769701 TI - Dynamics of soil available phosphorus and its impact factors under simulated climate change in typical farmland of Taihu Lake region, China. AB - Global climate change affects the availability of soil nutrients, thereby influencing crop productivity. This research was conducted to investigate the effects of elevated CO2, elevated temperature, and the interaction of the elevated CO2 and temperature on the soil available phosphorus (P) of a paddy wheat rotation in the Taihu Lake region, China. Winter wheat (Triticum aestivum L.) was cultivated during the study period from 2011 to 2014 at two CO2 levels (350 MUL*L(-1) ambient and 500 MUL*L(-1) elevated by 150 MUL*L(-1)) and two temperatures (ambient and 2 degrees C above the ambient). Soil available P content increased at the first season and decreased at the last season during the three wheat growing seasons. Soil available P content showed seasonal variation, whereas dynamic changes were not significant within each growing season. Soil available P content had no obvious trends under different treatments. But for the elevated temperature, CO2, and their combination treatments, soil available P content decreased in a long time period. During the period of wheat ripening stage, significant positive correlations were found between soil available P content and saturated hydraulic conductivity (Ks) and organic matter, but significant negative correlations with soil clay content and pH value; the correlation coefficients were 0.9400 (p < 0.01), 0.9942 (p < 0.01), -0.9383 (p < 0.01), and -0.6403 (p < 0.05), respectively. Therefore, Ks, organic matter, soil clay, and pH were the major impact factors on soil available P content. These results can provide a basis for predicting the trend of soil available P variation, as well as guidance for managing the soil nutrients and best fertilization practices in the future climate change scenario. PMID- 26769702 TI - Multiple modes of water quality impairment by fecal contamination in a rapidly developing coastal area: southwest Brunswick County, North Carolina. AB - Fecal contamination of surface waters is a significant problem, particularly in rapidly developing coastal watersheds. Data from a water quality monitoring program in southwest Brunswick County, North Carolina, gathered in support of a regional wastewater and stormwater management program were used to examine likely modes and sources of fecal contamination. Sampling was conducted at 42 locations at 3-4-week intervals between 1996 and 2003, including streams, ponds, and estuarine waters in a variety of land use settings. Expected fecal sources included human wastewater systems (on-site and central), stormwater runoff, and direct deposition by animals. Fecal coliform levels were positively associated with rainfall measures, but frequent high fecal coliform concentrations at times of no rain indicated other modes of contamination as well. Fecal coliform levels were also positively associated with silicate levels, a groundwater source signal, indicating that flux of fecal-contaminated groundwater was a mode of contamination, potentially elevating FC levels in impacted waters independent of stormwater runoff. Fecal contamination by failing septic or sewer systems at many locations was significant and in addition to effects of stormwater runoff. Rainfall was also linked to fecal contamination by central sewage treatment system failures. These results highlight the importance of considering multiple modes of water pollution and different ways in which human activities cause water quality degradation. Management of water quality in coastal regions must therefore recognize diverse drivers of fecal contamination to surface waters. PMID- 26769703 TI - The Problem of Atrial Fibrillation in Patients with Chronic Kidney Disease. AB - Chronic kidney disease (CKD) is associated with the risk of multiple life threatening complications such as: progression to chronic renal failure and cardiovascular disease including coronary heart disease, heart failure and peripheral arterial disease. Also, atrial fibrillation (AF) is common in this group of patients. Factors contributing to the occurrence of AF in patients undergoing dialysis include: age, presence of coronary heart disease, echocardiographic abnormalities (low ejection fraction, atrial enlargement, valvular calcification, left ventricular hypertrophy), heart failure, chronic obstructive pulmonary disease, hypertension, stroke, malnutrition (low levels of albumin, total cholesterol and high-density lipoprotein (HDL), secondary hyperparathyroidism, low predialysis systolic blood pressure, duration of renal replacement therapy as well as the method of renal replacement therapy (more frequent in haemodialysis patients). The optimal management of thromboprophylaxis in patients with CKD and AF is complex due to the fact that in patients with CKD many physiologic mechanisms are altered which lead to substantial changes in haemostasis and thus this group of patients is characterized by an increased risk of thrombotic and haemorrhagic complications. Recommendations concerning the treatment of patients with AF do not include guidelines on how to manage patients with advanced CKD, due to the lack of large randomized trials assessing the efficacy and benefits of drugs in these patients. Patients with CKD and permanent, persistent, and paroxysmal AF ought to be treated as a group with high risk of bleeding and ischaemic stroke. In case of patients with no or only one moderate risk factors, it seems that anticoagulation with antiplatelet drugs can be considered as efficient therapy, while in patients with >=2 risk factors an oral anticoagulation therapy may be used. During long-term treatment, the international normalized ratio (INR) must be controlled at least every 14 days and adjusted within a target range of 2.0-2.5. Moreover, renal function should be evaluated before initiation of direct thrombin or factor Xa inhibitors and re evaluated when clinically indicated and at least annually. PMID- 26769704 TI - Fermented Brown Rice Extract Causes Apoptotic Death of Human Acute Lymphoblastic Leukemia Cells via Death Receptor Pathway. AB - Mixture of brown rice and rice bran fermented with Aspergillus oryzae, designated as FBRA, has been reported to reveal anti-carcinogenic and anti-inflammatory effects in rodents. Then, to test its potential anti-cancer activity, the aqueous extract was prepared from FBRA powder, and the effect of this extract on human acute lymphoblastic leukemia Jurkat cells was directly examined. The exposure to FBRA extract reduced the cell viability in a concentration- and time-dependent manner. The reduction of the cell viability was accompanied by the DNA fragmentation, and partially restored by treatment with pan-caspase inhibitor. Further studies showed that FBRA extract induced the cleavage of caspase-8, -9, and -3, and decreased Bcl-2 protein expression. Moreover, the expression of tBid, DR5, and Fas proteins was enhanced by FBRA extract, and the pretreatment with caspase-8 inhibitor, but not caspase-9 inhibitor, restored the reduction of the cell viability induced by FBRA extract. These findings suggested that FBRA extract could induce the apoptotic death of human acute lymphoblastic leukemia cells probably through mainly the death receptor-mediated pathway and supplementarily through the tBid-mediated mitochondrial pathway, proposing the possibility that FBRA was a potential functional food beneficial to patients with hematological cancer. PMID- 26769705 TI - Aspergillus fumigatus Produces Two Arabinofuranosidases From Glycosyl Hydrolase Family 62: Comparative Properties of the Recombinant Enzymes. AB - The genes of two alpha-L-arabinofuranosidases (AbfI and II) from family GH 62 have been identified in the genome of Aspergillus fumigatus wmo. Both genes have been expressed in Pichia pastoris and the enzymes have been purified and characterized. AbfI is composed of 999 bp, does not contain introns and codes for a protein (ABFI) of 332 amino acid residues. abfII has 1246 bp, including an intron of 51 bp; the protein ABFII has 396 amino acid residues; it includes a family 1 carbohydrate-binding module (CBM) in the N-terminal region, followed by a catalytic module. The sequence of ABFI and the catalytic module of ABFII show a 79 % identity. Both enzymes are active on p-nitrophenyl alpha-L-arabinofuranoside (pNPAra) with KM of 94.2 and 3.9 mM for ABFI and II, respectively. Optimal temperature for ABFI is 37 degrees C and for ABFII 42 degrees C, while the pH optimum is about 4.5 to 5 for both enzymes. ABFII shows a higher thermostability. When assayed using natural substrates, both show higher activity over rye arabinoxylan as compared to wheat arabinoxylan. ABFII only is active on sugar beet pulp arabinan and both are inactive towards debranched arabinan. The higher thermostability, higher affinity for pNPAra and wider activity over natural substrates shown by ABFII may be related to the presence of a CBM. The availability of the recombinant enzymes may be useful in biotechnological applications for the production of arabinose. PMID- 26769706 TI - Pretreatment of Corn Stover by Low Moisture Anhydrous Ammonia (LMAA) in a Pilot Scale Reactor and Bioconversion to Fuel Ethanol and Industrial Chemicals. AB - Corn stover (CS) adjusted to 50, 66, and 70 % moisture was pretreated by the low moisture anhydrous ammonia (LMAA) process in a pilot-scale ammoniation reactor. After ammoniation, the 70 % moisture CS was treated at 90 and 100 degrees C whereas the others were treated at 90 degrees C only. The 70 % moisture pretreated CS then was subjected to a storage study under non-sterile conditions for 3 months. It was found that storage time did not have significant effects on the compositions of the pretreated materials and their hydrolysis by commercial enzymes. The 70 % moisture CS treated at 90 degrees C was used for preparation of a mix sugar hydrolysate (MSH) using combination of cellulase and xylanase. The MSH was used to prepare a corn mash at 9.5 wt% solid then subjected to ethanol fermentation by Escherichia coli KO11. The 66 % moisture CS treated at 90 degrees C was hydrolyzed with xylanase to make a xylose-rich hydrolysate (XRH), which was subsequently used for butyric acid fermentation by Clostridium tyrobutyricum. The resultant cellulose-enriched residue was hydrolyzed with cellulase to make a glucose-rich hydrolysate (GRH), which was subsequently used for succinic acid fermentation by E. coli AFP184. PMID- 26769707 TI - Jasmonates are induced by the PAMP flg22 but not the cell death-inducing elicitor Harpin in Vitis rupestris. AB - Plants employ two layers of defence that differ with respect to cell death: pathogen-associated molecular pattern (PAMP)-triggered immunity (PTI) and effector-triggered immunity (ETI). In our previous work, we have comparatively mapped the molecular events in a cell system derived from the wild American grape Vitis rupestris, where cell death-independent defence can be triggered by PAMP flg22, whereas the elicitor Harpin activates a cell death-related ETI-like response. Both defence responses overlapped with respect to early events, such as calcium influx, apoplastic alkalinisation, oxidative burst, mitogen-activated protein kinase (MAPK) signalling, activation of defence-related genes and accumulation of phytoalexins. However, timing and amplitude of early signals differed. In the current study, we address the role of jasmonates (JAs) as key signalling compounds in hypersensitive cell death. We find, in V. rupestris, that jasmonic acid and its bioactive conjugate jasmonoyl-isoleucine (JA-Ile) rapidly accumulate in response to flg22 but not in response to Harpin. However, Harpin can induce programmed cell death, whereas exogenous methyl jasmonate (MeJA) fails to do so, although both signals induce a similar response of defence genes. Also in a second cell line from V. vinifera cv. 'Pinot Noir', where Harpin cannot activate cell death and where flg22 fails to induce JA and JA-Ile, defence genes are activated in a similar manner. These findings indicate that the signal pathway culminating in cell death must act independently from the events culminating in the accumulation of toxic stilbenes. PMID- 26769708 TI - Aluminium-induced excessive ROS causes cellular damage and metabolic shifts in black gram Vigna mungo (L.) Hepper. AB - Aluminium-induced oxidative damage caused by excessive ROS production was evaluated in black gram pulse crop. Black gram plants were treated with different aluminium (Al3+) concentrations (10, 50 and 100 MUM with pH 4.7) and further the effects of Al3+ were characterised by means of root growth inhibition, histochemical assay, ROS content analysis, protein carbonylation quantification and 1H-NMR analysis. The results showed that aluminium induces excessive ROS production which leads to cellular damage, root injury, stunt root growth and other metabolic shifts. In black gram, Al3+ induces cellular damage at the earliest stage of stress which was characterised from histochemical analysis. From this study, it was observed that prolonged stress can activate certain aluminium detoxification defence mechanism. Probably excessive ROS triggers such defence mechanism in black gram. Al3+ can induce excessive ROS initially in the root region then transported to other parts of the plant. As much as the Al3+ concentration increases, the rate of cellular injury and ROS production also increases. But after 72 h of stress, plants showed a lowered ROS level and cellular damage which indicates the upregulation of defensive mechanisms. Metabolic shift analysis also showed that the black gram plant under stress has less metabolic content after 24 h of treatment, but gradually, it was increased after 72 h of treatment. It was assumed that ROS played the most important role as a signalling molecule for aluminium stress in black gram. PMID- 26769709 TI - Arabidopsis response regulator 22 inhibits cytokinin-regulated gene transcription in vivo. AB - Cytokinin signaling in Arabidopsis is carried out by a two-component system (TCS) multi-step phosphorelay mechanism that involves three different protein families: histidine kinases (AHKs), phosphotransfer proteins (AHPs), and response regulators (ARRs) that are in turn, subdivided into A-, B- and C-type ARRs depending on their function and structure. Upon cytokinin perception, AHK proteins autophosphorylate; this phosphate is then transferred from the AHKs to the AHPs to finally reach the ARRs. When B-type ARRs are activated by phosphorylation, they function as transcription factors that regulate the expression of cytokinin-dependent genes such as the A-type ARRs, among many others. In cytokinin signaling, while A- and B-type ARR function is well understood, it is still unclear if C-type ARRs (ARR22 and ARR24) play a role in this mechanism. Here, we describe a novel method suitable to study TCS activity natively as an in vivo system. We also show that ARR22 inhibits gene transcription of an A-type ARR upon cytokinin treatment in vivo. Consequently, we propose that ARR22, by acting as a phosphatase on specific AHPs, disrupts the TCS phosphorelay and prevents B-type ARR phosphorylation, and thus their activation as transcription factors, explaining the observed deactivation of cytokinin responsive genes. PMID- 26769710 TI - Distinct chromatin environment associated with phosphorylated H3S10 histone during pollen mitosis I in orchids. AB - Pollen developmental pathway in plants involving synchronized transferal of cellular divisions from meiosis (microsporogenesis) to mitosis (pollen mitosis I/II) eventually offers a unique "meiosis-mitosis shift" at pollen mitosis I. Since the cell type (haploid microspore) and fate of pollen mitosis I differ from typical mitosis (in meristem cells), it is immensely important to analyze the chromosomal distribution of phosphorylated H3S10 histone during atypical pollen mitosis I to comprehend the role of histone phosphorylation in pollen development. We investigated the chromosomal phosphorylation of H3S10 histone during pollen mitosis I in orchids using immunostaining technique. The chromosomal distribution of H3S10ph during pollen mitosis I revealed differential pattern than that of typical mitosis in plants, however, eventually following the similar trends of mitosis in animals where H3S10 phosphorylation begins in the pericentromeric regions first, later extending to the whole chromosomes, and finally declining at anaphase/early cytokinesis (differentiation of vegetative and generative cells). The study suggests that the chromosomal distribution of H3S10ph during cell division is not universal and can be altered between different cell types encoded for diverse cellular processes. During pollen development, phosphorylation of histone might play a critical role in chromosome condensation events throughout pollen mitosis I in plants. PMID- 26769711 TI - Antibodies against Clonorchis sinensis LDH could cross-react with LDHB localizing on the plasma membrane of human hepatocarcinoma cell SMMC-7721 and induce apoptosis. AB - Lactate dehydrogenase (LDH) is a terminal enzyme in anaerobic glycolytic pathway. It widely exists in various organisms and is in charge of converting the glycolysis product pyruvic acid to lactic acid. Most parasites, including Clonorchis sinensis, predominantly depend on glycolysis to provide energy. Bioinformatic analysis predicts that the LDHs from many species have more than one transmembrane region, suggesting that it may be a membrane protein. C. sinensis LDH (CsLDH) has been confirmed as a transmembrane protein mainly located in the tegument. The antibodies against CsLDH can inhibit the worm's energy metabolism, kill the worm, and may have the same effects on human cancer cells. In this study, we cloned and characterized human LDHA (HsLDHA), HsLDHB, and CsLDH. Semi-quantitative real-time RCP showed that HsLDHB only existed in hepatocarcinoma cell SMMC-7721. Confocal microscopy and Western blot experiments revealed that HsLDHB was localized in the plasma membrane of SMMC-7721 cells, and the antibodies against CsLDH could cross-react with it. This cross-reaction could inhibit the enzymatic activity of HsLDHB. The cancer cells co-cultured with anti CsLDH sera showed a significant decrease in cell proliferation rate and increases in caspase 9 and reactive oxygen species (ROS) levels. Therefore, anti-CsLDH antibodies can induce the apoptosis of cancer cells SMMC-7721 and may serve as a new tool to inhibit tumor. PMID- 26769712 TI - Down-Regulation of ClC-3 Expression Reduces Epidermal Stem Cell Migration by Inhibiting Volume-Activated Chloride Currents. AB - ClC-3, a member of the ClC chloride (Cl(-)) channel family, has recently been proposed as the primary Cl(-) channel involved in cell volume regulation. Changes in cell volume influence excitability, contraction, migration, pathogen-host interactions, cell proliferation, and cell death processes. In this study, expression and function of ClC-3 channels were investigated during epidermal stem cell (ESC) migration. We observed differential expression of CLC-3 regulates migration of ESCs. Further, whole-cell patch-clamp recordings and image analysis demonstrated ClC-3 expression affected volume-activated Cl(-) current (I Cl,Vol) within ESCs. Live cell imaging systems, designed to observe cellular responses to overexpression and suppression of ClC-3 in real time, indicated ClC-3 may regulate ESC migratory dynamics. We employed IMARIS software to analyze the velocity and distance of ESC migration in vitro to demonstrate the function of ClC-3 channel in ESCs. As our data suggest volume-activated Cl(-) channels play a vital role in migration of ESCs, which contribute to skin repair by migrating from neighboring unwounded epidermis infundibulum, hair follicle or sebaceous glands, ClC-3 may represent a new and valuable target for stem cell therapies. PMID- 26769714 TI - Complications of Deep Sedation for Individual Procedures (Lumbar Puncture Alone) Versus Combined Procedures (Lumbar Puncture and Bone Marrow Aspirate) in Pediatric Oncology Patients. AB - BACKGROUND AND OBJECTIVES: Pediatric oncology patients frequently undergo procedural sedation. The goal of this study was to determine the safety of combining procedures into a single sedation encounter and to assess if the magnitude of any complication is significant enough to justify separate sedation encounters for multiple procedures. METHODS: This retrospective review included pediatric oncology patients sedated for lumbar puncture alone or combined procedures (lumbar puncture and bone marrow aspirate) from January 2012 to January 2014. Demographic characteristics, medication dosing, procedural success, sedation duration, and adverse events (AEs) with associated required interventions were recorded. Sedation-related complications were separated into serious adverse events (SAEs) and AEs. Data were analyzed by using multivariable modeling. RESULTS: Data from 972 sedation encounters involving 96 patients, each having 1 to 28 encounters (mean+/-SD, 10+/-5), were reviewed. Ninety percent were individual procedures and 10% were combined procedures. Overall, there were few SAEs, and airway obstruction was the most common SAE. Combined procedures required 0.31 mg/kg more propofol (P<.001) and took 1.4 times longer (P<.001) than individual procedures. In addition, when adjusting for possible confounding factors, the odds of having an SAE were 4.8 (95% confidence interval, 1.37 16.65); P=.014) times higher for combined procedures. All SAEs and AEs were manageable by the sedation team. CONCLUSIONS: Combining procedures was associated with higher propofol doses, prolonged duration, and a small increase in likelihood of SAEs compared with individual procedures. All AEs fell within the scope of management by the sedation team. Balancing the increased, but manageable, risks versus the advantages of family/patient convenience, enhanced resource utilization, and minimization of potential neurotoxicity from anesthetics supports combining procedures when possible. PMID- 26769713 TI - Genetic polymorphisms associated with heart failure: A literature review. AB - OBJECTIVE: To review possible associations reported between genetic variants and the risk, therapeutic response and prognosis of heart failure. METHODS: Electronic databases (PubMed, Web of Science and CNKI) were systematically searched for relevant papers, published between January 1995 and February 2015. RESULTS: Eighty-two articles covering 29 genes and 39 polymorphisms were identified. CONCLUSION: Genetic association studies of heart failure have been highly controversial. There may be interaction or synergism of several genetic variants that together result in the ultimate pathological phenotype for heart failure. PMID- 26769715 TI - Concurrent whole brain radiotherapy and RRx-001 for melanoma brain metastases. PMID- 26769716 TI - Exercise and pregnancy: focus on advice for the competitive and elite athlete. PMID- 26769717 TI - Quantitative In Silico Analysis of Retention of Phenylthiohydantoin-Amino Acids in Reversed-Phase Ion-Pair Liquid Chromatography. AB - The retention mechanisms of phenylthiohydantoin (PTH)-amino acids in reversed phase ion-pair liquid chromatography were quantitatively analyzed in silico. The most significant interaction for the retention was the Lewis acid-base interaction between an aromatic ring of a PTH-amino acid and a hydroxyl-group hydrogen of tetra-alkyl ammonium hydroxide. Solvent effects, addition of molecular interaction (MI) energy values between an analyte and solvent molecules, significantly improved the relationship between the MI energy values, calculated using a molecular mechanics program, and logk values, measured via chromatography. The correlation coefficient between the calculated MI energy values and the logk values was 0.98 (n = 19). PMID- 26769718 TI - Novel Conductive Carbon Black and Polydimethlysiloxane ECG Electrode: A Comparison with Commercial Electrodes in Fresh, Chlorinated, and Salt Water. AB - In this study, we evaluated the performance of two novel conductive carbon black (CB) and polydimethlysiloxane (PDMS) bio-potential electrodes, with and without an integrated flexible copper mesh, against commercially available electrodes (Polar((r)) textile, Silver-coated textile, and carbon rubber). The electrodes were tested in three types of water (fresh/unfiltered, chlorinated, and salt water). Our testing revealed that our CB/PDMS electrode with integrated copper mesh provided a high-fidelity ECG signal morphologies without any amplitude degradation in all of the types of water tested (N = 10). The non-meshed CB/PDMS electrodes were also subjected to a long-term durability test by the US Navy SCUBA divers during which the electrodes maintained ECG signal quality for a 6 h period of continuous use. The results of a material degradation analysis revealed the CB/PDMS composite material does not exhibit significant changes in physical integrity after prolonged exposure to the test conditions. The newly developed meshed CB/PDMS electrodes have the potential to be used in a wide variety of both dry and wet environments including the challenge of obtaining ECG signals in salt water environments. PMID- 26769719 TI - Combined assessment of polymorphisms in the LHCGR and FSHR genes predict chance of pregnancy after in vitro fertilization. AB - STUDY QUESTION: Can gonadotrophin receptor variants separately or in combination, be used for the prediction of pregnancy chances in in vitro fertilization (IVF) trials? SUMMARY ANSWER: The luteinizing hormone/human chorionic gonadotrophin receptor (LHCGR) variant N312S and the follicle-stimulating hormone receptor (FSHR) variant N680S can be utilized for the prediction of pregnancy chances in women undergoing IVF. WHAT IS KNOWN ALREADY: The FSHR N680S polymorphism has been shown to affect the ovarian response in response to gonadotrophin treatment, while no information is currently available regarding variants of the LHCGR in this context. STUDY DESIGN, SIZE, DURATION: Cross-sectional study, duration from September 2010 to February 2015. Women undergoing IVF were consecutively enrolled and genetic variants compared between those who became pregnant and those who did not. The study was subsequently replicated in an independent sample. Granulosa cells from a subset of women were investigated regarding functionality of the genetic variants. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women undergoing IVF (n = 384) were enrolled in the study and genotyped. Clinical variables were retrieved from medical records. For replication, an additional group of n = 233 women was utilized. Granulosa cells from n = 135 women were isolated by flow cytometry, stimulated with Follitropin alpha or Menotropin, and the downstream targets 3',5'-cyclic adenosine monophosphate (cAMP) and inositol 1,4,5 trisphosphate (IP3) measured with enzyme-linked immunosorbent assay. MAIN RESULTS AND THE ROLE OF CHANCE: Women homozygous for serine (S) in both polymorphisms displayed higher pregnancy rates than women homozygous asparagine (N) (OR = 14.4, 95% CI: [1.65, 126], P = 0.016). Higher pregnancy rates were also evident for women carrying LHCGR S312, regardless of FSHR variant (OR = 1.61, 95% CI: [1.13, 2.29], P = 0.008). These women required higher doses of FSH for follicle recruitment than women homozygous N (161 versus 148 IU, P = 0.030). When combining the study cohort with the replication cohort (n = 606), even stronger associations with pregnancy rates were noted for the combined genotypes (OR = 11.5, 95% CI: [1.86, 71.0], P = 0.009) and for women carrying LHCGR S312 (OR = 1.49, 95% CI: [1.14, 1.96], P = 0.004). A linear significant trend with pregnancy rate and increasing number of G alleles was also evident in the merged study population (OR = 1.34, 95% CI: [1.10, 1.64], P = 0.004). A lower cAMP response in granulosa cells was noted following Follitropin alpha stimulation for women homozygous N in both polymorphisms, compared with women with other genotypes (0.901 pmol cAMP/mg total protein versus 2.19 pmol cAMP/mg total protein, P = 0.035). LIMITATIONS, REASONS FOR CAUTION: Due to racial differences in LHCGR genotype distribution, these results may not be applicable for all populations. WIDER IMPLICATIONS OF THE FINDINGS: Despite that >250 000 cycles of gonadotrophin stimulations are performed annually worldwide prior to IVF, it has not been possible to predict neither the pregnancy outcome, nor the response to the hormone with accuracy. If LHCGR and FSHR variants are recognized as biomarkers for chance of pregnancy, more individualized and thereby more efficient treatment modalities can be developed. STUDY FUNDING, COMPETING INTERESTS: This work was supported by Interreg IV A, EU (grant 167158) and ALF governments grant (F2014/354). Merck-Serono (Darmstadt, Germany) supported the enrollment of the subjects. The authors declare no conflict of interest. PMID- 26769720 TI - Practice patterns of adjunctive therapy for venous leg ulcers. AB - Objectives Venous leg ulcers (VLU) are the most severe clinical sequelae of venous reflux and post thrombotic syndrome. There is a consensus that ablation of refluxing vein segments and treatment of significant venous obstruction can heal VLUs. However, there is wide disparity in the use and choice of adjunctive therapies for VLUs. The purpose of this study was to assess these practice patterns among members of the American Venous Forum. Methods The AVF Research Committee conducted an online survey of its own members, which consisted of 16 questions designed to determine the specialty of physicians, location of treatment, treatment practices and reimbursement for treatment of VLUs Results The survey was distributed to 667 practitioners and a response rate of 18.6% was achieved. A majority of respondents (49.5%) were vascular specialists and the remaining were podiatrists, dermatologists, primary care doctors and others. It was found that 85.5% were from within the USA, while physicians from 14 other countries also responded. Most of the physicians (45%) provided adjunctive therapy at a private office setting and 58% treated less than 5 VLU patients per week. All respondents used some form of compression therapy as the primary mode of treatment for VLU. Multilayer compression therapy was the most common form of adjunctive therapy used (58.8%) and over 90% of physicians started additional modalities (biologics, negative pressure, hyperbaric oxygen and others) when VLUs failed compression therapy, with a majority (65%) waiting less than three months to start them. Medicare was the most common source of reimbursement (52.4%). Conclusions Physicians from multiple specialties treat VLU. While most physicians use compression therapy, there is wide variation in the selection and point of initiation for additional therapies once compression fails. There is a need for high-quality data to help establish guidelines for adjunctive treatment of VLUs and to disseminate them to physicians across multiple specialties to ensure standardized high-quality treatment of patients with VLUs. PMID- 26769721 TI - The effect of a subsequent pregnancy after transjugular coil embolisation for pelvic vein reflux. AB - Background Pelvic venous reflux has been proven to contribute to the development of primary and recurrent varicose veins, vulval/labial varicose veins and pelvic congestion syndrome. It is associated with lower limb varicose veins in 20% of patients who have a history of at least one prior vaginal delivery. Pelvic vein embolisation is known to be a safe and effective treatment for the abolition of pelvic venous reflux. However, the effect of a subsequent pregnancy on a previously embolised patient remains largely unknown. This study aims to report the effect of pregnancy on patients that have undergone pelvic vein embolisation. Methods Patients that had previously undergone pelvic vein embolisation for pelvic venous reflux at our unit were sent a questionnaire asking if they had had a pregnancy and subsequently delivered post-embolisation. Patients responding positively were invited to attend our unit for transvaginal duplex ultrasonography of their pelvic veins. Post-pregnancy transvaginal duplex ultrasonography results were compared to pre-embolisation and 6-week post embolisation scans. Results Eight women, aged 32-48 years (mean 38.8), were retrospectively analysed. Parity prior to embolisation ranged from 1 to 5 (mean 2.8). Initial outcomes at 6 weeks Pelvic venous reflux was completely eliminated in five patients, two patients achieved complete elimination of truncal reflux with very minor vulval reflux and one patient had persistent, mild reflux in the right internal iliac vein. Post-pregnancy outcomes Pelvic venous reflux was completely eliminated in three patients and five patients displayed pelvic venous reflux in at least one truncal vein, with or without concurrent vulval reflux. No patient showed any coil displacement or embolisation as a result of the pregnancy. Conclusions Pregnancy is associated with recurrent reflux in the pelvic veins in women who had previously been treated with coil embolisation. Following recovery from pregnancy, repeat embolisation can eliminate recurrent reflux. Pregnancy appears to be safe following coil embolisation of pelvic veins. PMID- 26769723 TI - Are We Missing Something Pertinent? A Bias Analysis of Unmeasured Confounding in the Firearm-Suicide Literature. AB - Despite the magnitude and consistency of risk estimates in the peer-reviewed literature linking firearm availability and suicide, inferring causality has been questioned on the theoretical basis that existing studies may have failed to account for the possibility that members of households with firearms differ from members of households without firearms in important ways related to suicide risk. The current bias analysis directly addresses this concern by describing the salient characteristics that such an unmeasured confounder would need to possess in order to yield the associations between firearm availability and suicide observed in the literature when, in fact, the causal effect is null. Four US studies, published between 1992 and 2003, met our eligibility criteria. We find that any such unmeasured confounder would need to possess an untenable combination of characteristics, such as being not only 1) as potent a suicide risk factor as the psychiatric disorders most tightly linked to suicide (e.g., major depressive and substance use disorders) but also 2) an order of magnitude more imbalanced across households with versus without firearms than is any known risk factor. No such confounder has been found or even suggested. The current study strongly suggests that unmeasured confounding alone is unlikely to explain the association between firearms and suicide. PMID- 26769722 TI - Association Between Substance Use and Gun-Related Behaviors. AB - Gun-related violence is a public health concern. This study synthesizes findings on associations between substance use and gun-related behaviors. Searches through PubMed, Embase, and PsycINFO located 66 studies published in English between 1992 and 2014. Most studies found a significant bivariate association between substance use and increased odds of gun-related behaviors. However, their association after adjustment was mixed, which could be attributed to a number of factors such as variations in definitions of substance use and gun activity, study design, sample demographics, and the specific covariates considered. Fewer studies identified a significant association between substance use and gun access/possession than other gun activities. The significant association between nonsubstance covariates (e.g., demographic covariates and other behavioral risk factors) and gun-related behaviors might have moderated the association between substance use and gun activities. Particularly, the strength of association between substance use and gun activities tended to reduce appreciably or to become nonsignificant after adjustment for mental disorders. Some studies indicated a positive association between the frequency of substance use and the odds of engaging in gun-related behaviors. Overall, the results suggest a need to consider substance use in research and prevention programs for gun-related violence. PMID- 26769724 TI - Effectiveness of Interventions to Promote Safe Firearm Storage. AB - Despite supportive evidence for an association between safe firearm storage and lower risk of firearm injury, the effectiveness of interventions that promote such practices remains unclear. Guided by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist, we conducted a systematic review of randomized and quasi-experimental controlled studies of safe firearm storage interventions using a prespecified search of 9 electronic databases with no restrictions on language, year, or location from inception through May 27, 2015. Study selection and data extraction were independently performed by 2 investigators. The Cochrane Collaboration's domain-specific tool for assessing risk of bias was used to evaluate the quality of included studies. Seven clinic- and community-based studies published in 2000-2012 using counseling with or without safety device provision met the inclusion criteria. All 3 studies that provided a safety device significantly improved firearm storage practices, while 3 of 4 studies that provided no safety device failed to show an effect. Heterogeneity of studies precluded conducting a meta-analysis. We discuss methodological considerations, gaps in the literature, and recommendations for conducting future studies. Although additional studies are needed, the totality of evidence suggests that counseling augmented by device provision can effectively encourage individuals to store their firearms safely. PMID- 26769725 TI - Low Incidence of Adverse Effects Using a Progressive Regimen of Benznidazole in Chagas Disease. PMID- 26769726 TI - Sexual and reproductive healthcare provided onsite in an inner-city community drug and alcohol service. PMID- 26769727 TI - Revisiting the NIH Stroke Scale as a screening tool for proximal vessel occlusion: can advanced imaging be targeted in acute stroke? AB - BACKGROUND AND PURPOSE: Most patients with stroke-like symptoms screened by advanced imaging for proximal occlusion will not have a thrombus accessible by neurointerventional techniques. Development of a sensitive clinical scoring system for rapidly identifying patients with an emergent large vessel occlusion could help target limited resources and reduce exposure to unnecessary imaging. METHODS: This historical cohort study included patients who underwent non contrast CT and CT angiography in the emergency department for stroke-like symptoms. NIH Stroke Scale (NIHSS) criteria were extended to include resolved symptoms and dichotomized as present or absent. Combinations of NIHSS criteria were considered as tests for proximal occlusion. RESULTS: Proximal cerebral vascular occlusion was present in 19.2% (100/522) of the population and, of these, 13% (13/100) had an NIHSS score of 0. The presence on examination or history of diminished consciousness with inability to answer questions, leg weakness, dysarthria, or gaze deviation had 96% sensitivity and 39% specificity for proximal occlusion. If implemented in this population, the use of CT angiography would have been decreased by 32.4% (169/522 patients) while missing 0.76% with proximal occlusions (4/522). Half of those missed (2/4) would have been identified as large vessel infarcts on non-contrast CT, while the remainder (2/4) were transient ischemic attacks associated with carotid stenosis. CONCLUSIONS: In this cohort, specific NIHSS criteria were highly sensitive for emergent large vessel occlusion and, if validated, may allow for clinical screening prior to advanced imaging with CT angiography. PMID- 26769728 TI - Combined use of Onyx and coils for transarterial balloon-assisted embolization of traumatic carotid-cavernous fistulas: a report of 16 cases with 17 fistulas. AB - OBJECTIVE: The combination of coils and Onyx for the treatment of carotid cavernous fistulas (CCFs) is an interesting new development. The purpose of the current study is to evaluate our preliminary experience with the combined use of coils and Onyx for the treatment of traumatic CCFs. METHODS: Between April 2009 and July 2014, 16 patients with 17 traumatic CCFs were embolized with the so called 'armored concrete' treatment modality using coils, Onyx-18, and a non detachable balloon via the transarterial approach. The outcomes were assessed both clinically and radiologically. Digital subtraction angiography (DSA) follow up was performed 3 or 6 months after endovascular treatment while clinical follow up was continued until December 2014. RESULTS: Obliteration of the CCFs was obtained with patency of the parent artery in all 16 cases. Follow-up DSA demonstrated stable occlusion of all the fistulas. Symptoms related to the CCFs were either resolved immediately or gradually over 2 months. No worsening of the cranial neuropathies was observed during the follow-up period which averaged 32.6 months. CONCLUSIONS: The 'armored concrete' treatment modality using coils, Onyx, and a non-detachable balloon promises to be a safe, economical, and effective alternative in the management of traumatic CCFs. PMID- 26769729 TI - Vessel wall imaging for intracranial vascular disease evaluation. AB - Accurate and timely diagnosis of intracranial vasculopathies is important owing to the significant risk of morbidity with delayed and/or incorrect diagnosis both from the disease process and inappropriate therapies. Conventional luminal imaging techniques for analysis of intracranial vasculopathies are limited to evaluation of changes in the vessel lumen. Vessel wall MRI techniques can allow direct characterization of pathologic changes of the vessel wall. These techniques may improve diagnostic accuracy and improve patient outcomes. Extracranial carotid vessel wall imaging has been extensively investigated in patients with atherosclerotic disease and has been shown to accurately assess plaque composition and identify vulnerable plaque characteristics that may predict stroke risk beyond luminal stenosis alone. This review provides a brief history of vessel wall MRI, an overview of the intracranial vessel wall MRI techniques, its applications, and imaging findings of various intracranial vasculopathies pertinent to the neurointerventionalist, neurologist, and neuroradiologist. We searched MEDLINE, PubMed, and Google for English publications containing any of the following terms: 'intracranial vessel wall imaging', 'intracranial vessel wall', and 'intracranial vessel wall MRI'. PMID- 26769730 TI - Extracorporeal membrane oxygenation as a bridge to lung transplantation: what lessons might we learn from volume and expertise? AB - OBJECTIVES: We sought to evaluate the effect of centre volume on survival when extracorporeal membrane oxygenation (ECMO) is used as a bridge to lung transplantation (LTx). METHODS: We performed a retrospective analysis of the United Network for Organ Sharing data on adult lung transplantations performed between 2000 and 2014. Centres were categorized based on volume of transplants into low-, medium- and high-volume centres (1-5, 6-15 and >15, respectively). Baseline characteristics were assessed and a Kaplan-Meier analysis was used to estimate survival with log-rank test. We used multivariate Cox regression analysis to estimate the risk of post-transplant 1-year mortality between centres. RESULTS: A total of 342 adult recipients were bridged on ECMO. Of these recipients, 88 (25.7%) were bridged in low, 89 (26%) in medium and 165 (48.2%) in high-volume centres. Patients in medium-volume centres were more likely to be older compared with those in low-volume and high-volume centres with a median age of 56, 46 and 49 years, respectively. High-volume centres reported the highest proportion (94.6%) of bilateral lung recipients, followed by low-volume (86.4%) and medium-volume centres (77.5%). The 30-day survival for the three groups was similar but 1-year survival was higher in high-volume centres (80.8) compared with medium-volume centres (70.0%) and low-volume centres (61.9%). The risk of 1 year mortality in low-volume centres was higher compared with high-volume centres in adjusted analysis (hazard ratio 2.74, 95% confidence interval 1.61-4.68, P = 0.01). CONCLUSIONS: Lowest volume centres have lowest survival and there exists a volume threshold at which better outcomes are achieved. PMID- 26769731 TI - Matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 in diagnosis of pleural effusion of malignant origin. AB - OBJECTIVES: The aim of the present study was to evaluate the diagnostic accuracy of matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 in differentiating benign from malignant exudative pleural effusions. METHODS: This is a unicentre observational study including 97 consecutive patients with exudative pleural effusions. Metalloproteinase-9, tissue inhibitor of metalloproteinase-1, lactate dehydrogenase, ferritin, carcinoembryonic antigen and carbohydrate antigen 15-3 were measured in pleural effusion and serum by enzyme-linked immunosorbent assay. The activity of metalloproteinase-9 was also evaluated by substrate zymography. The data were correlated with final diagnosis of pleural effusions to evaluate the diagnostic accuracy. RESULTS: Of the 97 eligible patients, 6 were excluded. Of the 91 patients included in the study, 70 had malignant pleural effusions and 21 had benign pleural effusions. Both in sera and pleural effusions, matrix metalloproteinase-9 (P < 0.0001), tissue inhibitor of metalloproteinase-1 (P < 0.0001) and carcinoembryonic antigen (P < 0.0001) levels were higher in neoplastic patients than in benign group. Zymography analysis showed a most prominent band at a molecular weight of 92 kDa (metalloproteinase-9) whereas a less intense band was observed at 72 kDa (metalloproteinase-2). A significant correlation was found between metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 levels in pleural effusion (P < 0.0001; r = 0.8) and serum (P < 0.03; r = 0.2). Pleural effusion metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 levels showed higher value of sensitivity (97 and 91%, respectively) and specificity (90 and 95%, respectively) compared with other standard markers. Serum metalloproteinase 9 and tissue inhibitor of metalloproteinase-1 levels showed similar results. Among 70 neoplastic patients, 29 had negative pleural cytology. Of these, 25 presented elevated levels of metalloproteinase-9 and tissue inhibitor of metalloproteinase-1, whereas 4 patients had elevated levels of one of the two markers. CONCLUSIONS: Our results showed that metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 might be valuable markers in differentiating benign from malignant pleural effusions. Their levels are neither influenced by the histology and tumour origin nor by the presence of tumour cells in pleural effusions. Thus, their use in clinical practice could help in the selection of patients needing more invasive procedures, such as thoracoscopic biopsy. PMID- 26769732 TI - Accuracy of physician prognosis in heart failure and lung cancer: Comparison between physician estimates and model predicted survival. AB - BACKGROUND: Anticipating adverse outcomes guides decisions but can be particularly challenging in heart failure. AIM: We sought to assess the accuracy and comfort of physicians in predicting prognosis in heart failure. DESIGN: Cross sectional survey PARTICIPANTS/SETTING: Faculty and trainees in internal medicine, cardiology, and oncology estimated survival for three standardized patients: (1) 59-year-old patient with stage IV lung cancer; (2) 79-year-old woman with New York Heart Association class 4 heart failure symptoms and preserved ejection fraction; and (3) 40-year-old man with New York Heart Association class 3 heart failure symptoms and reduced ejection fraction of 20%. Survival predictions were derived from surveillance, epidemiology, and end results-Medicare database and the Seattle Heart Failure Model. Accuracy was defined as <2-fold difference between the clinician and model estimate. RESULTS: Totally, 79% (338/427) of participants responded. Physicians were more accurate in survival estimates for lung cancer than heart failure (74% vs 48%, respectively; p < 0.001). Cardiologists were more accurate in predicting survival in heart failure symptoms and reduced ejection fraction compared to generalists (67% vs 45%; p = 0.005) and oncologists (39%; p = 0.041) but no different at predicting heart failure symptoms and preserved ejection fraction. Cardiologists predicted longer survival in heart failure compared to others (p < 0.05). Physicians felt more uncomfortable discussing palliative care with heart failure patients compared to lung cancer. CONCLUSIONS: Less than half of physicians accurately estimate survival in heart failure. Cardiologists were more accurate than other specialties for heart failure symptoms and reduced ejection fraction but no different for heart failure symptoms and preserved ejection fraction. PMID- 26769733 TI - Preferences regarding disclosure of prognosis and end-of-life care: A survey of cancer patients with advanced disease in a lower-middle-income country. AB - BACKGROUND: Cancer patients' preferences regarding disclosure of prognosis and end-of-life care remain under-reported from low- and middle-income countries where cancer poses an increasing demand on scarce healthcare resources. A better knowledge of these preferences can help in achievement of shared treatment goals. AIM: To survey preferences of adult cancer patients regarding disclosure of prognosis and end-of-life care DESIGN: A multidimensional questionnaire was developed to survey consecutively sampled patients. A fifth of the participants completed a repeat survey 3 months later. SETTING/PARTICIPANTS: Adult patients at a specialist cancer center in Pakistan. RESULTS: In total, 520 patients were surveyed initially (participation rate 98.6%) and 100 completed the repeat survey. Three in five respondents wanted a healthcare provider to give them detailed information about their prognosis and life expectancy. Those who wanted information withheld were significantly more likely to be female, to have a lower socioeconomic status, or to have lung cancer. Only two in five patients agreed that they wanted to die at home and more than 90% wanted all possible care till end-of-life. Yet, a little over half also agreed that they did not wish to be placed on a ventilator. In rank ordering preferences about end-of-life, respondents ranked "religious wellbeing" as the highest and "avoiding inappropriate prolongation of dying" as the lowest of six options. CONCLUSION: A majority of adult cancer patients surveyed in this study wanted a truthful disclosure about their disease prognosis and expressed a preference for hospital based care at end-of-life. Healthcare providers should find ways to tailor prognostic information to patients' expressed information needs. PMID- 26769734 TI - Double microcatheter technique for coil embolization of small aneurysms with unfavorable configurations: A comparative study of the aneurysms that are <=3 mm or >3 mm. AB - INTRODUCTION: The endovascular coiling of small ruptured aneurysms with difficult geometries presents a significant treatment challenge. We report our initial experience and the technical details of dual microcatheter coil embolizations that were applied in these difficult lesions. METHOD AND RESULTS: Eighty-five small aneurysms (<7 mm) that exhibited difficult configurations, such as a wide neck or an important branch vessel arising from the fundus, were successfully treated using a dual microcatheter technique. The packing attenuation, adverse events during the procedures, and angiographic occlusions from 21 very small aneurysm (<=3 mm) were recorded and compared with our coiling results of 64 small aneurysms (>3 mm, <7 mm). There were no significant differences in intraprocedural ruptures or procedure-related thromboembolisms between the two groups. At the last post-procedure clinical follow-up, a good clinical outcome (an modified Rankin Scale (mRS) of 0-2) was observed in 18 of the patients (85.7%). The recanalization rates at follow-up were significantly lower in the very small aneurysm group compared to the small aneurysm group (p < 0.05) and the mean packing density in the very small aneurysm group was significantly higher compared to the small aneurysm group (35.2% vs 24.8%, p < 0.05). CONCLUSION: The dual technique was feasible, safe, and effective for coil embolization of aneurysms with difficult configurations and, in particular, it provided an alternative option for treating very small aneurysms. PMID- 26769735 TI - Pipeline embolization device deployment via an envoy distal access XB guiding catheter-biaxial platform: A technical note. AB - With the increased reliance on the Pipeline embolization device (PED) for the treatment of complex intracranial aneurysms, our experience in managing intraoperative complications and challenges continues to accumulate amid a scarcity of reports on rescue strategies and innovative techniques. We describe the case of a 50-year-old woman who presented for elective repeat embolization of a right posterior communicating artery aneurysm with some residual aneurysmal filling. During the procedure the patient developed severe vasospasm due to vessel irritation and this led us to proceed to deploy the PED through a biaxial construct composed of the 6 French Envoy MPD DA XB, and the Marksman catheters. The biaxial construct in select patients may provide the required stability while eliminating the need for an intermediate catheter, minimizing embolic risk, and allowing for less irritation to the vessel. Larger studies are required for further validation. PMID- 26769736 TI - Time density curve analysis for C-arm FDCT PBV imaging. AB - INTRODUCTION: Parenchymal blood volume (PBV) estimation using C-arm flat detector computed tomography (FDCT) assumes a steady-state contrast concentration in cerebral vasculature for the scan duration. Using time density curve (TDC) analysis, we explored if the steady-state assumption is met for C-arm CT PBV scans, and how consistent the contrast-material dynamics in cerebral vasculature are across patients. METHODS: Thirty C-arm FDCT datasets of 26 patients with aneurysmal-SAH, acquired as part of a prospective study comparing C-arm CT PBV with MR-PWI, were analysed. TDCs were extracted from the 2D rotational projections. Goodness-of-fit of TDCs to a steady-state horizontal-line-model and the statistical similarity among the individual TDCs were tested. Influence of the differences in TDC characteristics on the agreement of resulting PBV measurements with MR-CBV was calculated. RESULTS: Despite identical scan parameters and contrast-injection-protocol, the individual TDCs were statistically non-identical (p < 0.01). Using Dunn's multiple comparisons test, of the total 435 individual comparisons among the 30 TDCs, 330 comparisons (62%) reached statistical significance for difference. All TDCs deviated significantly (p < 0.01) from the steady-state horizontal-line-model. PBV values of those datasets for which the TDCs showed largest deviations from the steady-state model demonstrated poor agreement and correlation with MR-CBV, compared with the PBV values of those datasets for which the TDCs were closer to steady-state. CONCLUSION: For clinical C-arm CT PBV examinations, the administered contrast material does not reach the assumed 'ideal steady-state' for the duration of scan. Using a prolonged injection protocol, the degree to which the TDCs approximate the ideal steady-state influences the agreement of resulting PBV measurements with MR-CBV. PMID- 26769737 TI - Whole brain C-arm computed tomography parenchymal blood volume measurements. AB - INTRODUCTION: C-arm flat detector computed tomography (FDCT) parenchymal blood volume (PBV) imaging in the neuro-interventional suite is a new technique for which detailed whole brain measurements have not been previously reported. This study aims to create a catalogue of PBV measurements for various anatomical regions encompassing the whole brain, using a three-dimensional volume-of interest (3D-VOI) analysis. METHODS: We acquired and analysed 30 C-arm FDCT datasets from 26 patients with aneurysmal subarachnoid haemorrhage (SAH), as part of a prospective study comparing C-arm computed tomography (CT) PBV with magnetic resonance perfusion-weighted imaging (MR-PWI). We calculated the PBV values for various brain regions with an automated analysis, using 58 pre-defined atlas based 3D-VOIs encompassing the whole brain. VOIs partially or completely overlapping regions of magnetic resonance diffusion weighted imaging (MR-DWI) abnormality or magnetic resonance cerebral blood flow (MR-CBF) asymmetry were excluded from the analysis. RESULTS: Of the 30 C-arm CT PBV datasets, 14 (54%; 12 patients) had areas of restricted diffusion, the majority of which were focal. The PBV values for the cerebral cortex and cerebral white matter were 4.01 +/- 0.47 (mean +/- SD) and 3.01 +/- 0.39 ml per 100 ml. Lobar PBV values were: frontal lobe 4.2 +/- 0.8, temporal lobe 4.2 +/- 0.9, parietal lobe 3.9 +/- 0.7 and occipital lobe 4.3 +/- 0.8 ml/100 ml. The basal ganglia and brainstem PBV values were 3.4 +/- 0.7 and 4.6 +/- 0.6 ml/100 ml, respectively. CONCLUSIONS: Compared with the typical reference cerebral blood volume (CBV) values reported in the literature for Positron Emission Tomography (PET), the PBV values were relatively high for the white matter and relatively low for the cortical grey matter. The reported catalogue of PBV values for various brain regions would be useful to inform future studies and could be used in clinical practice, when interpreting PBV maps. PMID- 26769738 TI - Focal stenosis of the sigmoid sinus causing intracranial venous hypertension: Case report, endovascular management, and review of the literature. AB - Regardless of the underlying pathology, elevated intracranial pressure is the endpoint of any impairment in either cerebrospinal fluid (CSF) absorption (including arachnoid villi) or intracranial venous drainage. In all age groups, the predominant final common pathway for CSF drainage is the dural venous sinus system. Intracranial venous hypertension (ICVH) is an important vascular cause of intracranial hypertension (and its subsequent sequelae), which has often been ignored due to excessive attention to the arterial system and, specifically, arteriovenous shunts. Various anatomical and pathological entities have been described to cause ICVH. For the second time, we present a unique case of severe focal stenosis in the distal sigmoid sinus associated with concurrent hypoplasia of the contralateral transverse sinus causing a significant pressure gradient and intracranial hypertension, which was treated with endovascular stent placement and angioplasty. PMID- 26769739 TI - Degenerative lumbar spinal stenosis treatment with AperiusTM PerCLIDTM system and Falena(r) interspinous spacers: 1-year follow-up of clinical outcome and quality of life. AB - PURPOSE: Evaluation of the efficacy of the Falena((r)) and AperiusTM PerCLIDTM interspinous devices in the treatment of degenerative lumbar spinal stenosis with neurogenic intermittent claudication refractory to conservative treatment. MATERIALS AND METHODS: We retrospectively analyzed data from 24 patients (20 male and 4 female patients; 61 +/- 7 years old), treated with an implantation of the AperiusTM PerCLIDTM system, and from 35 patients (29 male and 6 female patients; 65 +/- 9 years old) treated with the Falena((r)) interspinous device.Patient pain intensity was evaluated by a 10-point visual analog scale (VAS), with a score (ranging from 0 = no pain to 10 = unbearable pain) that was collected before the procedure, at baseline; and at months 1, 6 and 12 after the interventional procedure. The assessment of quality of life (QOL) impairment was evaluated by the Oswestry Disability Index (ODI) questionnaire, which was administered beforehand at baseline; and at months 1, 6 and 12 after the interventional procedure. The vertebral canal area was measured by magnetic resonance imaging (MRI) scans before the treatment and at the one-year follow-up. RESULTS: All patients completed the study with no complications. Both the Falena group and Aperius group of surgery patients showed a statistically significant reduction of their VAS and ODI scores at the 6- and 12-month follow-up (p < 0.0001). A statistically significant increase in the vertebral canal area was observed both in the group that received Falena (p < 0.0001) and in the group that received Aperius (p = 0.0003). At the 1-year follow-up, we observed that there was a higher increase of vertebral canal area in those patients whom were treated with the Falena device (p < 0.001). CONCLUSIONS: The implantation of Falena((r)) and AperiusTM PerCLIDTM interspinous devices is an effective and safe procedure, in the medium term. PMID- 26769740 TI - Characterization of Myocardial Repolarization Reserve in Adolescent Females With Anorexia Nervosa. AB - BACKGROUND: Patients with anorexia nervosa exhibit abnormal myocardial repolarization and are susceptible to sudden cardiac death. Exercise testing is useful in unmasking QT prolongation in disorders associated with abnormal repolarization. We characterized QT adaptation during exercise in anorexia. METHODS AND RESULTS: Sixty-one adolescent female patients with anorexia nervosa and 45 age- and sex-matched healthy volunteers performed symptom-limited cycle ergometry during 12-lead ECG monitoring. Changes in the QT interval during exercise were measured, and QT/RR-interval slopes were determined by using mixed effects regression modeling. Patients had significantly lower body mass index than controls; however, resting heart rates and QT/QTc intervals were similar at baseline. Patients had shorter exercise times (13.7+/-4.5 versus 20.6+/-4.5 minutes; P<0.001) and lower peak heart rates (159+/-20 versus 184+/-9 beats/min; P<0.001). The mean QTc intervals were longer at peak exercise in patients (442+/ 29 versus 422+/-19 ms; P<0.001). During submaximal exertion at comparable heart rates (114+/-6 versus 115+/-11 beats/min; P=0.54), the QTc interval had prolonged significantly more in patients than controls (37+/-28 versus 24+/-25 ms; P<0.016). The RR/QT slope, best described by a curvilinear relationship, was more gradual in patients than in controls (13.4; 95% confidence interval, 12.8-13.9 versus 15.8; 95% confidence interval, 15.3-16.4 ms QT change per 10% change in RR interval; P<0.001) and steepest in patients within the highest body mass index tertile versus the lowest (13.9; 95% confidence interval, 12.9-14.9 versus 12.3; 95% confidence interval, 11.3-13.3; P=0.026). CONCLUSIONS: Despite the absence of manifest QT prolongation, adolescent anorexic females have impaired repolarization reserve in comparison with healthy controls. Further study may identify impaired QT dynamics as a risk factor for arrhythmias in anorexia nervosa. PMID- 26769741 TI - Text Messaging and Patient Engagement in an Increasingly Mobile World. PMID- 26769742 TI - Mobile Phone Text Messages to Support Treatment Adherence in Adults With High Blood Pressure (SMS-Text Adherence Support [StAR]): A Single-Blind, Randomized Trial. AB - BACKGROUND: We assessed the effect of automated treatment adherence support delivered via mobile phone short message system (SMS) text messages on blood pressure. METHODS AND RESULTS: In this pragmatic, single-blind, 3-arm, randomized trial (SMS-Text Adherence Support [StAR]) undertaken in South Africa, patients treated for high blood pressure were randomly allocated in a 1:1:1 ratio to information only, interactive SMS text messaging, or usual care. The primary outcome was change in systolic blood pressure at 12 months from baseline measured with a validated oscillometric device. All trial staff were masked to treatment allocation. Analyses were intention to treat. Between June 26, 2012, and November 23, 2012, 1372 participants were randomized to receive information-only SMS text messages (n=457), interactive SMS text messages (n=458), or usual care (n=457). Primary outcome data were available for 1256 participants (92%). At 12 months, the mean adjusted change in systolic blood pressure compared with usual care was 2.2 mm Hg (95% confidence interval, -4.4 to -0.04) with information-only SMS and 1.6 mm Hg (95% confidence interval, -3.7 to 0.6) with interactive SMS. Odds ratios for the proportion of participants with a blood pressure <140/90 mm Hg were 1.42 (95% confidence interval, 1.03-1.95) for information-only messaging and 1.41 (95% confidence interval, 1.02-1.95) for interactive messaging compared with usual care. CONCLUSIONS: In this randomized trial of an automated adherence support program delivered by SMS text message in a general outpatient population of adults with high blood pressure, we found a small reduction in systolic blood pressure control compared with usual care at 12 months. There was no evidence that an interactive intervention increased this effect. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02019823. South African National Clinical Trials Register, number SANCTR DOH-27-1212-386; Pan Africa Trial Register, number PACTR201411000724141. PMID- 26769743 TI - Congenital Heart Defects and Indices of Fetal Cerebral Growth in a Nationwide Cohort of 924 422 Liveborn Infants. AB - BACKGROUND: Neurodevelopmental disorders are the most common and distressful comorbidities associated with congenital heart defects (CHD). Head circumference at birth (HC), a proxy for prenatal cerebral growth, is an established risk factor for neurodevelopmental disorders. METHODS AND RESULTS: In a nationwide cohort, we included all 924 422 liveborn Danish singletons, 1997 to 2011. CHD was present in 5519. The association between CHD and growth indices was analyzed by multivariable linear regression, adjusted for potential confounders. We report mean differences in gestational age-specific z scores in comparison with the general population. CHD was associated with lower HC z scores, -0.10 (95% confidence interval [CI], -0.13 to -0.08). Several CHD subtypes were associated with smaller HC, eg, hypoplastic left heart syndrome, -0.39 (95% CI, -0.58 to 0.21); common arterial trunk, -0.41 (95% CI, -0.74 to -0.09); and major ventricular septal defects, -0.25 (95% CI, -0.35 to -0.15). Other single ventricle defects, transposition of the great arteries, tetralogy of Fallot, and anomalous pulmonary venous return, were also associated with smaller HC. Transposition of the great arteries was associated with smaller HC relative to birth weight, -0.26 (95% CI, -0.39 to -0.13). Major ventricular septal defects were associated with larger HC relative to birth weight. The results were consistent under various conditions, eg, when siblings of infants with CHD (n=5311) or infants with other major malformations (n=24 974) were used as the reference. CONCLUSIONS: Several subtypes of CHD were associated with smaller HC. The associations with major ventricular septal defects, common arterial trunk, and anomalous pulmonary venous return have not previously been described. Only infants with transposition of the great arteries had smaller HC relative to birth weight. PMID- 26769744 TI - Speed Reading: You Can't Always Get What You Want, but Can You Sometimes Get What You Need? PMID- 26769745 TI - So Much to Read, So Little Time: How Do We Read, and Can Speed Reading Help? AB - The prospect of speed reading--reading at an increased speed without any loss of comprehension--has undeniable appeal. Speed reading has been an intriguing concept for decades, at least since Evelyn Wood introduced her Reading Dynamics training program in 1959. It has recently increased in popularity, with speed reading apps and technologies being introduced for smartphones and digital devices. The current article reviews what the scientific community knows about the reading process--a great deal--and discusses the implications of the research findings for potential students of speed-reading training programs or purchasers of speed-reading apps. The research shows that there is a trade-off between speed and accuracy. It is unlikely that readers will be able to double or triple their reading speeds (e.g., from around 250 to 500-750 words per minute) while still being able to understand the text as well as if they read at normal speed. If a thorough understanding of the text is not the reader's goal, then speed reading or skimming the text will allow the reader to get through it faster with moderate comprehension. The way to maintain high comprehension and get through text faster is to practice reading and to become a more skilled language user (e.g., through increased vocabulary). This is because language skill is at the heart of reading speed. PMID- 26769747 TI - Neuropsychological Deficits in Adult ADHD: Evidence for Differential Attentional Impairments, Deficient Executive Functions, and High Self-Reported Functional Impairments. AB - OBJECTIVE: This study is aimed to investigate neuropsychological deficits in adult ADHD. METHOD: Neuropsychological deficits in terms of executive functions, divided, selective, and sustained attention, were investigated in a group of adults with ADHD using a series of neuropsychological tests as well as electroencephalography (EEG). Subjective ratings of everyday life attention and memory problems were also collected. RESULTS: Adults with ADHD showed impairments in executive functions, divided attention and sustained attention, compared with adult controls. Performance on selective attention tasks in adults with ADHD was instead no different from control participants' performance. EEG results confirmed neuropsychological findings by showing a selective impairment on P3 event-related potential (ERP) amplitude indicative of sustained attention deficits. Higher subjective ratings of everyday attentional and memory problems were also found in the ADHD group compared with the control group. CONCLUSION: This pattern of results suggests differential impairments of attentional skills. Impaired executive functions and higher subjective functional impairments were also found. PMID- 26769748 TI - Identifying public expectations of genetic biobanks. AB - Understanding public priorities for biobanks is vital for maximising utility and efficiency of genetic research and maintaining respect for donors. This research directly assessed the relative importance the public place on different expectations of biobanks. Quantitative and qualitative results from a national sample of 800 Australians revealed that the majority attributed more importance to protecting privacy and ethical conduct than maximising new healthcare benefits, which was in turn viewed as more important than obtaining specific consent, benefit sharing, collaborating and sharing data. A latent class analysis identified two distinct classes displaying different patterns of expectations. One placed higher priority on behaviours that respect the donor ( n = 623), the other on accelerating science ( n = 278). Additional expectations derived from qualitative data included the need for biobanks to be transparent and to prioritise their research focus, educate the public and address commercialisation. PMID- 26769749 TI - Experiments in engagement: Designing public engagement with science and technology for capacity building. AB - Public engagement with science and technology is now widely used in science policy and communication. Touted as a means of enhancing democratic discussion of science and technology, analysis of public engagement with science and technology has shown that it is often weakly tied to scientific governance. In this article, we suggest that the notion of capacity building might be a way of reframing the democratic potential of public engagement with science and technology activities. Drawing on literatures from public policy and administration, we outline how public engagement with science and technology might build citizen capacity, before using the notion of capacity building to develop five principles for the design of public engagement with science and technology. We demonstrate the use of these principles through a discussion of the development and realization of the pilot for a large-scale public engagement with science and technology activity, the Futurescape City Tours, which was carried out in Arizona in 2012. PMID- 26769750 TI - Not all NOTCH Is Created Equal: The Oncogenic Role of NOTCH2 in Bladder Cancer and Its Implications for Targeted Therapy. AB - PURPOSE: Recent molecular analyses of bladder cancer open the door to significant advances in targeted therapies. NOTCH has been identified as a tumor suppressor in bladder cancer, but prior reports have focused on NOTCH1 Here we hypothesized that NOTCH2 is an oncogene suitable for therapeutic targeting in bladder cancer. EXPERIMENTAL DESIGN: We studied genomic aberrations of NOTCH, compared survival and tumor progression according to NOTCH2 expression levels, and studied NOTCH2 function in vitro and vivo RESULTS: We report a high rate of NOTCH2 copy number gain in bladder cancer. High NOTCH2 expression was identified especially in the basal subtype and in mesenchymal tumors. NOTCH2 activation correlated with adverse disease parameters and worse prognosis by immunohistochemistry. Forced overexpression of the intracellular domain of NOTCH2 (N2ICD) induced cell growth and invasion by cell-cycle progression, maintenance of stemness and epithelial-to mesenchymal transition (EMT). These effects were abrogated by silencing of CSL, indicating that the effects were mediated through the canonical NOTCH signaling pathway. In an orthotopic xenograft model, forced overexpression of N2ICD increased growth, invasion, and metastasis. To explore the potential for therapeutic targeting of NOTCH2, we first silenced the receptor with shRNA and subsequently treated with a specific inhibitory antibody. Both interventions decreased cell growth, invasion, and metastasis in vitro and in the orthotopic xenograft model. CONCLUSIONS: We have demonstrated that NOTCH2 acts as an oncogene that promotes bladder cancer growth and metastasis through EMT, cell cycle progression, and maintenance of stemness. Inhibition of NOTCH2 is a rational novel treatment strategy for invasive bladder cancer. Clin Cancer Res; 22(12); 2981-92. (c)2016 AACR. PMID- 26769751 TI - An Endothelial Gene Signature Score Predicts Poor Outcome in Patients with Endocrine-Treated, Low Genomic Grade Breast Tumors. AB - PURPOSE: The ability of vascular genes to provide treatment predictive information in breast cancer patients remains unclear. As such, we assessed the expression of genes representative of normal endothelial microvasculature (MV) in relation to treatment-specific patient subgroups. EXPERIMENTAL DESIGN: We used expression data from 993 breast tumors to assess 57 MV genes (summarized to yield an MV score) as well as the genomic grade index (GGI) and PAM50 signatures. MV score was compared with CD31 staining by correlation and gene ontology (GO) analysis, along with clinicopathologic characteristics and PAM50 subtypes. Uni-, multivariate, and/or t-test analyses were performed in all and treatment-specific subgroups, along with a clinical trial cohort of patients with metastatic breast cancer, seven of whom received antiangiogenic therapy. RESULTS: MV score did not correlate with microvessel density (correlation = 0.096), but displayed enrichment for angiogenic GO terms, and was lower in Luminal B tumors. In endocrine-treated patients, a high MV score was associated with decreased risk of metastasis [HR 0.58; 95% confidence interval (CI), 0.38-0.89], even after adjusting for histologic grade, but not GGI or PAM50. Subgroup analysis showed the prognostic strength of the MV score resided in low genomic grade tumors and MV score was significantly increased in metastatic breast tumors after treatment with sunitinib + docetaxel (P = 0.031). CONCLUSIONS: MV score identifies two groups of better and worse survival in low-risk endocrine-treated breast cancer patients. We also show normalization of tumor vasculature on a transcriptional level in response to an angiogenic inhibitor in human breast cancer samples. Clin Cancer Res; 22(10); 2417-26. (c)2016 AACR. PMID- 26769752 TI - Evaluation of Temporal Changes in Cardiovascular Biomarker Concentrations Improves Risk Prediction in an Elderly Population from the Community. AB - BACKGROUND: There is increasing interest in measurements of cardiovascular (CV) biomarker concentrations for risk prediction in the general population. We investigated the prognostic utility of a panel of novel CV biomarkers including biomarker changes over time. METHODS: We measured concentrations of N-terminal pro-B-type natriuretic peptide (NT-proBNP), midregional proadrenomedullin, high sensitivity cardiac troponin I, growth-differentiation factor-15 (GDF-15), soluble ST2 (sST2), and galectin-3 at baseline and 5 years later in 1016 elderly individuals participating in the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study. Assessed outcomes included all-cause mortality and fatal and nonfatal CV events (in participants without CV disease at baseline) during 10 years of follow-up. RESULTS: GDF-15 exhibited the strongest association with all-cause mortality (n = 158) with a hazard ratio (HR) per 1-SD increase in standardized ln GDF-15 of 1.68 (95% CI, 1.44-1.96). NT-proBNP was the only biomarker to predict CV events (n = 163; HR 1.54 [95% CI, 1.30-1.84]). GDF-15 and NT-proBNP also improved metrics of discrimination and reclassification of the respective outcomes. Changes in GDF-15 concentrations between 70 and 75 years predicted all-cause mortality whereas changes in NT-proBNP predicted both outcomes. The other biomarkers and their temporal changes provided only moderate prognostic value apart from sST2 which had a neutral relationship with adverse events. CONCLUSIONS: Evaluation of temporal changes in GDF-15 and NT-proBNP concentrations improves risk prediction in an elderly population. These findings are of considerable interest given the emphasis on biomarkers as tools to identify and monitor at-risk individuals with preclinical and potentially modifiable stages of CV disease. PMID- 26769753 TI - Your Viral Past: A Comprehensive Method for Serological Profiling to Explore the Human Virome. PMID- 26769754 TI - Steroid-exacerbated HIV-associated cutaneous Kaposi's sarcoma immune reconstitution inflammatory syndrome: 'Where a good intention turns bad'. AB - A 51-year-old man with head and neck skin lesions was diagnosed with Kaposi's sarcoma (KS) as his initial presentation of acquired immunodeficiency syndrome. Following initiation of antiretroviral therapy and subsequent full virologic suppression, his facial lesions worsened, consistent with immune reconstitution inflammatory syndrome (IRIS). He was started on glucocorticoids in an attempt to ameliorate the KS-IRIS but experienced paradoxical worsening of the KS lesions. Steroids were subsequently discontinued and he required chemotherapy for severe and cosmetically disfiguring skin lesions. This article describes the potential for worsening of KS lesions in individuals started on glucocorticoids for KS-IRIS as this has been reported rarely in published literature. The mechanisms underlying this phenomenon remain poorly understood but potential explanations are offered in the case discussion. This article aims to raise clinician awareness on the harms of steroid use in patients with KS-IRIS. PMID- 26769755 TI - Infectious syphilis in women: what's old is new again? AB - The aim of this study was to examine trends in infectious syphilis epidemiology among women in Winnipeg, Canada. A descriptive study of syphilis among Winnipeg residents between 2003 and 30 June 2015 was undertaken. Adjusted rate ratios (ARR) and 95% confidence intervals (95%CI) from Poisson regression analyses are reported. Characteristics of men and women were compared using logistic regression, with adjusted odds ratios (AOR) reported. Between 2014 and 2015, the rate of syphilis was 1.7/100,000, representing a five-fold increase since 2006 2013. All cases have been heterosexual, 90% 20-39 years of age, and 59% living in Winnipeg's inner core. Approximately 24% were pregnant at diagnosis; no cases of congenital syphilis have been reported. Compared to men, women were more likely to report alcohol use (AOR: 3.8, 95% CI: 1.2-11.9) and co-infection with chlamydia (AOR: 5.0, 95% CI: 1.1-22.9). In conclusion, the rates of infectious syphilis are increasing among women. Prenatal screening and education for inner core women and the health care providers serving them should be prioritized. PMID- 26769756 TI - Hepatitis B immune reconstitution syndrome in a patient with HIV infection. AB - South Africa has a high rate of HIV and hepatitis B co-infection. The national HIV treatment guidelines include anti-retrovirals that treat both viruses. We describe a HIV-positive patient who presented with liver histology-confirmed hepatitis B immune reconstitution inflammatory syndrome whilst on a regimen containing lamivudine and tenofovir. PMID- 26769757 TI - Validation of the Revised Brief Diabetes Knowledge Test (DKT2). AB - PURPOSE: The purpose of this study is to examine the reliability and validity of the revised Diabetes Knowledge Test (DKT2). The original test was updated to reflect current diabetes care and education guidelines. The test has 2 components: a 14-item general test and a 9-item insulin use subscale. METHODS: Two samples were used to evaluate the DKT2. The first came from an online survey company (Qualtrics, LCC) (n = 101) and the second from University of Michigan's (UofM) Diabetes Registry (n = 89). Cronbach's coefficient alpha was used to calculate reliability. To examine validity, comparisons by type of diabetes, insulin use and oral medication use, and educational level were completed. Correlations between diabetes duration and both the general test and insulin subscale were calculated for the UofM sample. RESULTS: The two samples differed demographically. While the reliabilities between the samples were disparate, when combined, the coefficient alphas demonstrated reliability for both the general test (.77) and the insulin use subscale (.84). The validation comparisons proved to be similar; different results occurred between samples but when combined demonstrated validity. CONCLUSIONS: The reliability and validity tests were inconsistent by sample. The different results can, in part, be attributed to the demographic differences between the 2 samples. With the exception of age, the samples differed in every other measured variable. However, when the samples were combined, the analyses supported the reliability and validity of the Diabetes Knowledge Test 2. The DKT2 is a quick and low-cost method of assessing general knowledge of diabetes and diabetes self-care. PMID- 26769758 TI - Work of breathing during CPAP and heated humidified high-flow nasal cannula. AB - OBJECTIVE: To determine whether continuous positive airway pressure (CPAP) compared with heated humidified, high-flow nasal cannula (HHFNC) in infants with evolving or established bronchopulmonary dysplasia (BPD) reduced the work of breathing (WOB) and thoracoabdominal asynchrony (TAA) and improved oxygen saturation (SaO2). DESIGN: Randomised crossover study. SETTING: Tertiary neonatal unit. PATIENTS: 20 infants (median gestational age of 27.6 weeks (range 24.6-31.9 weeks)) were studied at a median postnatal age of 30.9 weeks (range 28.1-39.1 weeks). INTERVENTIONS: Infants were studied on 2 consecutive days. On the first study day, they were randomised to either CPAP or HHFNC each for 2 h, the order being reversed on the second day. MAIN OUTCOME MEASURES: The WOB was assessed by measuring the pressure time product of the diaphragm (PTPdi). PTPdi, TAA and SaO2 were assessed during the final 5 min of each 2 h period and the results on the two study days were meaned. RESULTS: There were no significant differences in the results on CPAP versus HHFNC: mean PTPdi 226 (range 126-294) versus 224 cm H2O/s/min (95% CI for difference: -27 to 22; p=0.85) (range 170-318) (p=0.82), mean TAA 13.4 degrees (range 4.51 degrees -23.32 degrees ) versus 14.01 degrees (range 4.25 degrees -23.86 degrees ) (95% CI for difference: -3.9 to 2.8: p=0.73) (p=0.63) and mean SaO2 95% (range 93%-100%) versus 95% (94%-99%), (95% CI for difference -1.8 to 0.5; p=0.25) (p=0.45). CONCLUSION: In infants with evolving or established BPD, CPAP compared with HHFNC offered no significant advantage with regard to the WOB, degree of asynchrony or oxygen saturation. PMID- 26769760 TI - Functional neurological symptoms: welcome to the new normal. PMID- 26769761 TI - Explaining functional disorders in the neurology clinic: a photo story. PMID- 26769765 TI - Annual Incidence of Nephrolithiasis among Children and Adults in South Carolina from 1997 to 2012. AB - BACKGROUND AND OBJECTIVES: The prevalence of nephrolithiasis in the United States has increased substantially, but recent changes in incidence with respect to age, sex, and race are not well characterized. This study examined temporal trends in the annual incidence and cumulative risk of nephrolithiasis among children and adults living in South Carolina over a 16-year period. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We performed a population-based, repeated cross sectional study using the US Census and South Carolina Medical Encounter data, which capture all emergency department visits, surgeries, and admissions in the state. The annual incidence of nephrolithiasis in South Carolina from 1997 to 2012 was estimated, and linear mixed models were used to estimate incidence rate ratios for age, sex, and racial groups. The cumulative risk of nephrolithiasis during childhood and over the lifetime was estimated for males and females in 1997 and 2012. RESULTS: Among an at-risk population of 4,625,364 people, 152,925 unique patients received emergency, inpatient, or surgical care for nephrolithiasis. Between 1997 and 2012, the mean annual incidence of nephrolithiasis increased 1% annually from 206 to 239 per 100,000 persons. Among age groups, the greatest increase was observed among 15-19 year olds, in whom incidence increased 26% per 5 years (incidence rate ratio, 1.26; 95% confidence interval, 1.22 to 1.29). Adjusting for age and race, incidence increased 15% per 5 years among females (incidence rate ratio, 1.15; 95% confidence interval, 1.14 to 1.16) but remained stable for males. The incidence among blacks increased 15% more per 5 years compared with whites (incidence rate ratio, 1.15; 95% confidence interval, 1.14 to 1.17). These changes in incidence resulted in doubling of the risk of nephrolithiasis during childhood and a 45% increase in the lifetime risk of nephrolithiasis for women over the study period. CONCLUSIONS: The incidence of kidney stones has increased among young patients, particularly women, and blacks. PMID- 26769767 TI - Singer K, Bornstein FP, Wile SA. Thrombotic thrombocytopenic purpura. Blood. 1947;2(6):542-554. PMID- 26769764 TI - eGFR and Outcomes in Patients with Acute Decompensated Heart Failure with or without Elevated BUN. AB - BACKGROUND AND OBJECTIVES: In patients with heart failure, the association of renal dysfunction and BUN levels with outcomes is unclear. The aim of our study was to investigate the association between the eGFR at discharge and outcomes in patients with heart failure with or without an elevated BUN level at discharge. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Of 4842 patients enrolled in the Acute Decompensated Heart Failure Syndromes Registry, 4449 patients discharged alive after hospitalization for acute decompensated heart failure were investigated to assess the association of eGFR in the context of serum BUN level at discharge with all-cause mortality. The enrolled patients were divided into four groups on the basis of the discharge levels of eGFR (<45 or >=45 ml/min per 1.73 m(2)) and BUN (>=25 or <25 mg/dl). The median follow-up period after discharge was 517 (381-776) days. RESULTS: The all-cause mortality rate after discharge was 19.1%. After adjustment for multiple comorbidities, an eGFR<45 ml/min per 1.73 m(2) was associated with a significantly higher risk of all-cause mortality in patients with a BUN>=25 mg/dl (hazard ratio, 1.58; 95% confidence interval, 1.33 to 1.88; P<0.001) but not in patients with a BUN<25 mg/dl (hazard ratio, 0.97; 95% confidence interval, 0.76 to 1.26; P=0.84) relative to those with an eGFR>=45 ml/min per 1.73 m(2) and a BUN<25 mg/dl. Among patients with an eGFR>=45 ml/min per 1.73 m(2), a BUN>=25 mg/dl was associated with a significantly higher risk of all-cause mortality than a BUN<25 mg/dl (hazard ratio, 1.34; 95% confidence interval, 1.04 to 1.73; P=0.02). CONCLUSIONS: We showed that elevation of BUN at discharge significantly modified the relation between eGFR at discharge and the risk of all-cause mortality after discharge, suggesting that the association between eGFR and outcomes may be largely dependent on concomitant elevation of BUN. PMID- 26769766 TI - Bicarbonate Concentration, Acid-Base Status, and Mortality in the Health, Aging, and Body Composition Study. AB - BACKGROUND AND OBJECTIVES: Low serum bicarbonate associates with mortality in CKD. This study investigated the associations of bicarbonate and acid-base status with mortality in healthy older individuals. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We analyzed data from the Health, Aging, and Body Composition Study, a prospective study of well functioning black and white adults ages 70-79 years old from 1997. Participants with arterialized venous blood gas measurements (n=2287) were grouped into <23.0 mEq/L (low), 23.0-27.9 mEq/L (reference group), and >=28.0 mEq/L (high) bicarbonate categories and according to acid-base status. Survival data were collected through February of 2014. Mortality hazard ratios (HRs; 95% confidence intervals [95% CIs]) in the low and high bicarbonate groups compared with the reference group were determined using Cox models adjusted for demographics, eGFR, albuminuria, chronic obstructive pulmonary disease, smoking, and systemic pH. Similarly adjusted Cox models were performed according to acid base status. RESULTS: The mean age was 76 years, 51% were women, and 38% were black. Mean pH was 7.41, mean bicarbonate was 25.1 mEq/L, 11% had low bicarbonate, and 10% had high bicarbonate. Mean eGFR was 82.1 ml/min per 1.73 m(2), and 12% had CKD. Over a mean follow-up of 10.3 years, 1326 (58%) participants died. Compared with the reference group, the mortality HRs were 1.24 (95% CI, 1.02 to 1.49) in the low bicarbonate and 1.03 (95% CI, 0.84 to 1.26) in the high bicarbonate categories. Compared with the normal acid-base group, the mortality HRs were 1.17 (95% CI, 0.94 to 1.47) for metabolic acidosis, 1.21 (95% CI, 1.01 to 1.46) for respiratory alkalosis, and 1.35 (95% CI, 1.08 to 1.69) for metabolic alkalosis categories. Respiratory acidosis did not associate with mortality. CONCLUSIONS: In generally healthy older individuals, low serum bicarbonate associated with higher mortality independent of systemic pH and potential confounders. This association seemed to be present regardless of whether the cause of low bicarbonate was metabolic acidosis or respiratory alkalosis. Metabolic alkalosis also associated with higher mortality. PMID- 26769768 TI - Big data, thromboembolism, and immunoglobulin. PMID- 26769769 TI - FCR holds up to the test of time: CLL8 follow-up. PMID- 26769770 TI - The sting of WASP deficiency: autoimmunity exposed. PMID- 26769771 TI - ALK-negative anaplastic large-cell lymphoma. PMID- 26769772 TI - DNA binding modes of leukemia oncoproteins. PMID- 26769773 TI - Genetic and nongenetic determinants of mean platelet volume. PMID- 26769774 TI - Long term opioid analgesic use is linked to increased risk of depression, study shows. PMID- 26769775 TI - Staff perceptions on patient motives for attending GP-led urgent care centres in London: a qualitative study. AB - OBJECTIVES: General practitioner (GP)-led urgent care centres were established to meet the growing demand for urgent care. Staff members working in such centres are central in influencing patients' choices about which services they use, but little is known about staff perceptions of patients' motives for attending urgent care. We hence aimed to explore their perceptions of patients' motives for attending such centres. DESIGN: A phenomenological, qualitative study, including semistructured interviews. The interviews were analysed using thematic content analysis. SETTING: 2 GP-led urgent care centres in 2 academic hospitals in London. PARTICIPANTS: 15 staff members working at the centres including 8 GPs, 5 emergency nurse practitioners and 2 receptionists. RESULTS: We identified 4 main themes: 'Confusion about choices', 'As if increase of appetite had grown; By what it fed on', 'Overt reasons, covert motives' and 'A question of legitimacy'. The participants thought that the centres introduce convenient and fast access for patients. So convenient, that an increasing number of patients use them as a regular alternative to their community GP. The participants perceived that patients attend the centres because they are anxious about their symptoms and view them as serious, cannot get an appointment with their GP quickly and conveniently, are dissatisfied with the GP, or lack self-care skills. Staff members perceived some motives as legitimate (an acute health need and difficulties in getting an appointment), and others as less legitimate (convenience, minor illness, and seeking quicker access to hospital facilities). CONCLUSIONS: The participants perceived that patients attend urgent care centres because of the convenience of access relative to primary care, as well as sense of acuity and anxiety, lack self-care skills and other reasons. They perceived some motives as more legitimate than others. Attention to unmet needs in primary care can help in promoting balanced access to urgent care. PMID- 26769776 TI - Is preoperative physical activity related to post-surgery recovery? A cohort study of patients with breast cancer. AB - OBJECTIVE: The aim of our study is to assess the association between preoperative level of activity and recovery after breast cancer surgery measured as hospital stay, length of sick leave and self-assessed physical and mental recovery. DESIGN: A prospective cohort study. SETTING: Patients included were those scheduled to undergo breast cancer surgery, between February and November 2013, at two participating hospitals in the Western Region of Sweden. PARTICIPANTS: Patients planned for breast cancer surgery filled out a questionnaire before, as well as at 3 and 6 weeks after the operation. The preoperative level of activity was self-assessed and categorised into four categories by the participants using the 4-level Saltin-Grimby Physical Activity Level Scale (SGPALS). MAIN OUTCOME MEASURE: Our main outcome was postoperative recovery measured as length of sick leave, in-hospital stay and self-assessed physical and mental recovery. RESULTS: 220 patients were included. Preoperatively, 14% (31/220) of participants assessed themselves to be physically inactive, 61% (135/220) to exert some light physical activity (PA) and 20% (43/220) to be more active (level 3+4). Patients operated with mastectomy versus partial mastectomy and axillary lymph node dissection versus sentinel node biopsy were less likely to have a short hospital stay, relative risk (RR) 0.88 (0.78 to 1.00) and 0.82 (0.70 to 0.96). More active participants (level 3 or 4) had an 85% increased chance of feeling physically recovered at 3 weeks after the operation, RR 1.85 (1.20 to 2.85). No difference was seen after 6 weeks. CONCLUSIONS: The above study shows that a higher preoperative level of PA is associated with a faster physical recovery as reported by the patients 3 weeks post breast cancer surgery. After 6 weeks, most patients felt physically recovered, diminishing the association above. No difference was seen in length of sick leave or self-assessed mental recovery between inactive or more active patients. PMID- 26769777 TI - Proliferation of gynaecological scientific societies and their financial transparency: an Italian survey. AB - OBJECTIVES: To determine the number of Italian obstetrical and gynaecological societies, and to ascertain their financial transparency. DESIGN: Internet-based national survey and website content analysis. PARTICIPANTS: Currently active, not privately owned, non-religious, apolitical, obstetrical and gynaecological associations. METHODS: From October 2014 to June 2015, scientific societies were identified using combinations of search terms, and examining the website of the two main Italian obstetrical and gynaecological organisations. Individual societies' websites were scrutinised by two independent investigators. PRIMARY AND SECONDARY OUTCOME MEASURES: Number of Italian obstetrical and gynaecological associations and its variation over time; 12 information categories defining the general characteristics of the societies and their websites, and the financial transparency of the associations. RESULTS: The initial web search yielded 56 professional obstetrical and gynaecological associations but nine were excluded for various reasons. Of the remaining 47 professional associations, 17 covered both obstetrics and gynaecology, four were specialised in obstetrics, 26 in gynaecology and 46 provided continuing medical education (CME) activities. The number of societies has quadrupled in the last 35 years, increasing at a mean rate of one additional society per year. The headquarters of the associations were located in the offices of a professional congress organiser in 15 instances, and advertisements or links to industry products were present in 12 societies' websites. Bylaws were accessible in 32 websites. No information was publicly available regarding competing interests, financial statements and quantitative external funding. CONCLUSIONS: The number of obstetrical and gynaecological societies is remarkably high in Italy, particularly in the gynaecological area. Despite CME activity provision, transparency of societies regarding financial issues and competing interests was almost non-existent. Policies addressing the interactions between medical associations and industry are available and should be implemented. PMID- 26769778 TI - Effects of obstructive sleep apnoea risk on postoperative respiratory complications: protocol for a hospital-based registry study. AB - INTRODUCTION: Obstructive sleep apnoea (OSA), the most common type of sleep disordered breathing, is associated with significant immediate and long-term morbidity, including fragmented sleep and impaired daytime functioning, as well as more severe consequences, such as hypertension, impaired cognitive function and reduced quality of life. Perioperatively, OSA occurs frequently as a consequence of pre-existing vulnerability, surgery and drug effects. The impact of OSA on postoperative respiratory complications (PRCs) needs to be better characterised. As OSA is associated with significant comorbidities, such as obesity, pulmonary hypertension, myocardial infarction and stroke, it is unclear whether OSA or its comorbidities are the mechanism of PRCs. This project aims to (1) develop a novel prediction score identifying surgical patients at high risk of OSA, (2) evaluate the association of OSA risk on PRCs and (3) evaluate if pharmacological agents used during surgery modify this association. METHODS: Retrospective cohort study using hospital-based electronic patient data and perioperative data on medications administered and vital signs. We will use data from Partners Healthcare clinical databases, Boston, Massachusetts. First, a prediction model for OSA will be developed using OSA diagnostic codes and polysomnography procedural codes as the reference standard, and will be validated by medical record review. Results of the prediction model will be used to classify patients in the database as high, medium or low risk of OSA, and we will investigate the effect of OSA on risk of PRCs. Finally, we will test whether the effect of OSA on PRCs is modified by the use of intraoperative pharmacological agents known to increase upper airway instability, including neuromuscular blockade, neostigmine, opioids, anaesthetics and sedatives. ETHICS AND DISSEMINATION: The Partners Human Research Committee approved this study (protocol number: 2014P000218). Study results will be made available in the form of manuscripts for publication and presentations at national and international meetings. PMID- 26769779 TI - Cross-sectional associations between high-deprivation home and neighbourhood environments, and health-related variables among Liverpool children. AB - OBJECTIVES: (1) To investigate differences in health-related, home and neighbourhood environmental variables between Liverpool children living in areas of high deprivation (HD) and medium-to-high deprivation (MD) and (2) to assess associations between these perceived home and neighbourhood environments and health-related variables stratified by deprivation group. DESIGN: Cross-sectional study. SETTING: 10 Liverpool primary schools in 2014. PARTICIPANTS: 194 children aged 9-10 years. MAIN OUTCOME MEASURES: Health-related variables (self-reported physical activity (PA) (Physical Activity Questionnaire for Older Children, PAQ C), cardiorespiratory fitness, body mass index (BMI) z-scores, waist circumference), home environment variables: (garden/backyard access, independent mobility, screen-based media restrictions, bedroom media) and neighbourhood walkability (Neighbourhood Environment Walkability Scale for Youth, NEWS-Y). EXPLANATORY MEASURES: Area deprivation. RESULTS: There were significant differences between HD and MD children's BMI z-scores (p<0.01), waist circumference (p<0.001) and cardiorespiratory fitness (p<0.01). HD children had significantly higher bedroom media availability (p<0.05) and independent mobility scores than MD children (p<0.05). MD children had significantly higher residential density and neighbourhood aesthetics scores, and lower crime safety, pedestrian and road traffic safety scores than HD children, all of which indicated higher walkability (p<0.01). HD children's BMI z-scores (beta=-0.29, p<0.01) and waist circumferences (beta=-0.27, p<0.01) were inversely associated with neighbourhood aesthetics. HD children's PA was negatively associated with bedroom media (beta=-0.24, p<0.01), and MD children's PA was positively associated with independent mobility (beta=0.25, p<0.01). MD children's independent mobility was inversely associated with crime safety (beta=-0.28, p<0.01) and neighbourhood aesthetics (beta=-0.24, p<0.05). CONCLUSIONS: Children living in HD areas had the least favourable health-related variables and were exposed to home and neighbourhood environments that are unconducive to health promoting behaviours. Less access to bedroom media equipment and greater independent mobility were strongly associated with higher PA in HD and MD children, respectively. Facilitating independent mobility and encouraging outdoor play may act as effective strategies to enhance PA levels and reduce sedentary time in primary school-aged children. PMID- 26769780 TI - Newspaper coverage of maternal health in Bangladesh, Rwanda and South Africa: a quantitative and qualitative content analysis. AB - OBJECTIVE: To examine newspaper coverage of maternal health in three countries that have made varying progress towards Millennium Development Goal 5 (MDG 5): Bangladesh (on track), Rwanda (making progress, but not on track) and South Africa (no progress). DESIGN: We analysed each country's leading national English language newspaper: Bangladesh's The Daily Star, Rwanda's The New Times/The Sunday Times, and South Africa's Sunday Times/The Times. We quantified the number of maternal health articles published from 1 January 2008 to 31 March 2013. We conducted a content analysis of subset of 190 articles published from 1 October 2010 to 31 March 2013. RESULTS: Bangladesh's The Daily Star published 579 articles related to maternal health from 1 January 2008 to 31 March 2013, compared to 342 in Rwanda's The New Times/The Sunday Times and 253 in South Africa's Sunday Times/The Times over the same time period. The Daily Star had the highest proportion of stories advocating for or raising awareness of maternal health. Most maternal health articles in The Daily Star (83%) and The New Times/The Sunday Times (69%) used a 'human-rights' or 'policy-based' frame compared to 41% of articles from Sunday Times/The Times. CONCLUSIONS: In the three countries included in this study, which are on different trajectories towards MDG 5, there were differences in the frequency, tone and content of their newspaper coverage of maternal health. However, no causal conclusions can be drawn about this association between progress on MDG 5 and the amount and type of media coverage of maternal health. PMID- 26769781 TI - Role of parenting styles in adolescent substance use: results from a Swedish longitudinal cohort study. AB - OBJECTIVE: Adolescent substance use is an area of concern because early substance use is associated with a higher risk of adverse outcomes. Parenting style, defined as the general style of parenting, as well as substance-specific parenting practices may influence children's substance use behaviour. The present study aims to probe the impact of parenting style on adolescent substance use. METHOD: A cohort of 1268 adolescents (48% girls), aged 12-13 years at baseline, from 21 junior high schools was assessed in the first semester of junior high school, and then again in the last semester of the 9th grade, 32 months later. Parenting style, operationalised as a fourfold classification of parenting styles, including established risk factors for adolescent substance use, were measured at baseline. RESULTS: Neglectful parenting style was associated with worse substance use outcomes across all substances. After adjusting for other proximal risk factors in multivariate analyses, parenting style was found to be unrelated to substance use outcomes with one exception: authoritative parenting style was associated with less frequent drinking. Association with deviant peers, delinquent behaviour, provision of alcohol by parents, and previous use of other substances were associated with substance use outcomes at follow-up. CONCLUSIONS: The results of the present study indicate that parenting style may be less important for adolescent substance use outcomes than what has previously been assumed, and that association with deviant peers and delinquent behaviour may be more important for adolescent substance use outcomes than general parenting style. PMID- 26769782 TI - Non-psychotropic medication and risk of suicide or attempted suicide: a systematic review. AB - OBJECTIVES: To establish which non-psychotropic medications have been assessed in relation to risk of suicide or attempted suicide in observational studies, document reported associations and consider study strengths and limitations. DESIGN: Systematic review. METHODS: Four databases (Embase, Medline, PsycINFO and International Pharmaceutical Abstracts) were searched from 1990 to June 2014, and reference lists of included articles were hand-searched. Case-control, cohort and case only studies which reported suicide or attempted suicide in association with any non-psychotropic medication were included. OUTCOME MEASURES: The outcomes eligible for inclusion were suicide and attempted suicide, as defined by the authors of the included study. RESULTS: Of 11,792 retrieved articles, 19 were eligible for inclusion. Five studies considered cardiovascular medication and antiepileptics; two considered leukotriene receptor antagonists, isotretinoin and corticosteroids; one assessed antibiotics and another assessed varenicline. An additional study compared multiple medications prescribed to suicide cases versus controls. There was marked heterogeneity in study design, outcome and exposure classification, and control for confounding factors; particularly comorbid mental and physical illness. No increased risk was associated with cardiovascular medications, but associations with other medications remained inconclusive and meta-analysis was inappropriate due to study heterogeneity. CONCLUSIONS: Whether non-psychotropic medications are associated with increased risk of suicide or attempted suicide remains largely unknown. Robust identification of suicide outcomes and control of comorbidities could improve quantification of risk associated with non-psychotropic medication, beyond that conferred by underlying physical and mental illnesses. PMID- 26769783 TI - Gaps in understanding health and engagement with healthcare providers across common long-term conditions: a population survey of health literacy in 29,473 Danish citizens. AB - OBJECTIVES: To (1) quantify levels of subjective health literacy in people with long-term health conditions (diabetes, cardiovascular disease, chronic obstructive pulmonary disease, musculoskeletal disorders, cancer and mental disorders) and compare these to levels in the general population and (2) examine the association between health literacy, socioeconomic characteristics and comorbidity in each long-term condition group. DESIGN: Population-based survey in the Central Denmark Region (n=29,473). MAIN OUTCOME MEASURES: Health literacy was measured using two scales from the Health Literacy Questionnaire (HLQ): (1) Ability to understand health information and (2) Ability to actively engage with healthcare providers. RESULTS: People with long-term conditions reported more difficulties than the general population in understanding health information and actively engaging with healthcare providers. Wide variation was found between disease groups, with people with cancer having fewer difficulties and people with mental health disorders having more difficulties in actively engaging with healthcare providers than other long-term condition groups. Having more than one long-term condition was associated with more difficulty in engaging with healthcare providers and understanding health information. People with low levels of education had lower health literacy than people with high levels of education. CONCLUSIONS: Compared with the general population, people with long-term conditions report more difficulties in understanding health information and engaging with healthcare providers. These two dimensions are critical to the provision of patient-centred healthcare and for optimising health outcomes. More effort should be made to respond to the health literacy needs among individuals with long-term conditions, multiple comorbidities and low education levels, to improve health outcomes and to reduce social inequality in health. PMID- 26769784 TI - Prevalence of dry eye disease in visual display terminal workers: a systematic review and meta-analysis. AB - OBJECTIVE: To evaluate the prevalence and risk factors of dry eye disease (DED) in workers using visual display terminals (VDT). DESIGN: Systematic review and meta-analysis. DATA SOURCES: We searched PubMed, Cochrane Library, Embase and Science Direct databases for studies reporting DED prevalence in VDT workers. RESULTS: 16 of the 9049 identified studies were included, with a total of 11,365 VDT workers. Despite a global DED prevalence of 49.5% (95% CI 47.5 to 50.6), ranging from 9.5% to 87.5%, important heterogeneity (I(2)=98.8%, p<0.0001) was observed. Variable diagnosis criteria used within studies were: questionnaires on symptoms, tear film anomalies and corneoconjunctival epithelial damage. Some studies combined criteria to define DED. Heterogeneous prevalence was associated with stratifications on symptoms (I(2)=98.7%, p<0.0001), tears (I(2)=98.5%, p<0.0001) and epithelial damage (I(2)=96.0%, p<0.0001). Stratification of studies with two criteria adjusted the prevalence to 54.0% (95% CI 52.1 to 55.9), whereas studies using three criteria resulted in a prevalence of 11.6% (95% CI 10.5 to 12.9). According to the literature, prevalence of DED was more frequent in females than in males and increased with age. CONCLUSIONS: Owing to the disparity of the diagnosis criteria studied to define DED, the global prevalence of 49.5% lacked reliability because of the important heterogeneity. We highlight the necessity of implementing common DED diagnostic criteria to allow a more reliable estimation in order to develop the appropriate preventive occupational actions. PMID- 26769785 TI - Association between shelter crowding and incidence of sleep disturbance among disaster evacuees: a retrospective medical chart review study. AB - OBJECTIVES: We determined whether crowding at emergency shelters is associated with a higher incidence of sleep disturbance among disaster evacuees and identified the minimum required personal space at shelters. DESIGN: Retrospective review of medical charts. SETTING: 30 shelter-based medical clinics in Ishinomaki, Japan, during the 46 days following the Great Eastern Japan Earthquake and Tsunami in 2011. PARTICIPANTS: Shelter residents who visited eligible clinics. OUTCOME MEASURES: Based on the result of a locally weighted scatter-plot smoothing technique assessing the relationship between the mean space per evacuee and cumulative incidence of sleep disturbance at the shelter, eligible shelters were classified into crowded and non-crowded shelters. The cumulative incidence per 1000 evacuees was compared between groups, using a Mann Whitney U test. To assess the association between shelter crowding and the daily incidence of sleep disturbance per 1000 evacuees, quasi-least squares method adjusting for potential confounders was used. RESULTS: The 30 shelters were categorised as crowded (mean space per evacuee <5.0 m(2), 9 shelters) or non crowded (>= 5.0 m(2), 21 shelters). The study included 9031 patients. Among the eligible patients, 1079 patients (11.9%) were diagnosed with sleep disturbance. Mean space per evacuee during the study period was 3.3 m(2) (SD, 0.8 m(2)) at crowded shelters and 8.6 m(2) (SD, 4.3 m(2)) at non-crowded shelters. The median cumulative incidence of sleep disturbance did not differ between the crowded shelters (2.3/1000 person-days (IQR, 1.6-5.4)) and non-crowded shelters (1.9/1000 person-days (IQR, 1.0-2.8); p=0.20). In contrast, after adjusting for potential confounders, crowded shelters had an increased daily incidence of sleep disturbance (2.6 per 1000 person-days; 95% CI 0.2 to 5.0/1000 person-days, p=0.03) compared to that at non-crowded shelters. CONCLUSIONS: Crowding at shelters may exacerbate sleep disruptions in disaster evacuees; therefore, appropriate evacuation space requirements should be considered. PMID- 26769787 TI - Association between toothbrushing and risk factors for cardiovascular disease: a large-scale, cross-sectional Japanese study. AB - OBJECTIVES: To clarify the association between toothbrushing and risk factors for cardiovascular disease--namely, hypertension (HT), diabetes mellitus (DM), dyslipidaemia (DL), hyperuricaemia (HUA) and chronic kidney disease (CKD). DESIGN: A large-scale, single-centre, cross-sectional study. SETTING: St Luke's International Hospital, Center for Preventive Medicine, Tokyo, Japan, between January 2004 and June 2010. PARTICIPANTS: This study examined the toothbrushing practices of 85,866 individuals according to the 3-category frequency criterion: 'after every meal', 'at least once a day' and 'less than once a day'. The ORs by frequency were calculated for the prevalences of HT, DM, DL, HUA and CKD according to binominal logistic regression analyses adjusted for age, gender, body mass index and lifestyle habits--smoking, drinking, walk time and sleep time. RESULTS: The prevalences of the risk factors were as follows: HT ('after every meal': 13.3%, 'at least once a day': 17.9% and 'less than once a day': 31.0%), DM (3.1%, 5.3% and 17.4%, respectively), DL (29.0%, 42.1% and 60.3%, respectively), HUA (8.6%, 17.5% and 27.2%, respectively) and CKD (3.8%, 3.1% and 8.3%, respectively). The prevalences were significantly higher in the 'less than once a day' group than in the 'after every meal' group for DM (OR=2.03; 95% CI 1.29 to 3.21) and DL (OR=1.50; 95% CI 1.06 to 2.14), but not for HT, HUA and CKD. CONCLUSIONS: Even taking into account lifestyle habits, a lower frequency of toothbrushing was associated with high prevalences of DM and DL. Toothbrushing practices may be beneficial for oral health improvement and also for prevention of certain systemic diseases. PMID- 26769786 TI - Outcomes After Kidney injury in Surgery (OAKS): protocol for a multicentre, observational cohort study of acute kidney injury following major gastrointestinal and liver surgery. AB - INTRODUCTION: Acute kidney injury (AKI) is associated with increased morbidity and mortality following cardiac surgery. Data focusing on the patterns of AKI following major gastrointestinal surgery could inform quality improvement projects and clinical trials, but there is a lack of reliable evidence. This multicentre study aims to determine the incidence and impact of AKI following major gastrointestinal and liver surgery. METHODS AND ANALYSIS: This prospective, collaborative, multicentre cohort study will include consecutive adults undergoing gastrointestinal resection, liver resection or reversal of ileostomy or colostomy. Open and laparoscopic procedures in elective and emergency patients will be included in the study. The primary end point will be the incidence of AKI within 7 days of surgery, identified using an adaptation of the National Algorithm for Detecting Acute Kidney Injury, which is based on the Kidney Disease Improving Global Outcomes (KDIGO) AKI guidelines. Secondary outcomes will include persistent renal dysfunction at discharge and 1 year postoperatively. The 30-day adverse event rate will be measured using the Clavien-Dindo scale. Data on factors that may predispose to the development of AKI will be collected to identify variables associated with AKI. Based on our previous collaborative studies, a minimum of 114 centres are expected to be recruited, contributing over 6500 patients in total. ETHICS AND DISSEMINATION: This study will be registered as clinical audit at each participating hospital. The protocol will be disseminated through local and national medical student networks in the UK and Ireland. PMID- 26769788 TI - RAPP, a systematic e-assessment of postoperative recovery in patients undergoing day surgery: study protocol for a mixed-methods study design including a multicentre, two-group, parallel, single-blind randomised controlled trial and qualitative interview studies. AB - INTRODUCTION: Day surgery is a well-established practice in many European countries, but only limited information is available regarding postoperative recovery at home though there is a current lack of a standard procedure regarding postoperative follow-up. Furthermore, there is also a need for improvement of modern technology in assessing patient-related outcomes such as mobile applications. This article describes the Recovery Assessment by Phone Points (RAPP) study protocol, a mixed-methods study to evaluate if a systematic e assessment follow-up in patients undergoing day surgery is cost-effective and improves postoperative recovery, health and quality of life. METHODS AND ANALYSIS: This study has a mixed-methods study design that includes a multicentre, two-group, parallel, single-blind randomised controlled trial and qualitative interview studies. 1000 patients >17 years of age who are undergoing day surgery will be randomly assigned to either e-assessed postoperative recovery follow-up daily in 14 days measured via smartphone app including the Swedish web version of Quality of Recovery (SwQoR) or to standard care (ie, no follow-up). The primary aim is cost-effectiveness. Secondary aims are (A) to explore whether a systematic e-assessment follow-up after day surgery has a positive effect on postoperative recovery, health-related quality of life (QoL) and overall health; (B) to determine whether differences in postoperative recovery have an association with patient characteristic, type of surgery and anaesthesia; (C) to determine whether differences in health literacy have a substantial and distinct effect on postoperative recovery, health and QoL; and (D) to describe day surgery patient and staff experiences with a systematic e-assessment follow-up after day surgery.The primary aim will be measured at 2 weeks postoperatively and secondary outcomes (A-C) at 1 and 2 weeks and (D) at 1 and 4 months. TRIAL REGISTRATION NUMBER: NCT02492191; Pre-results. PMID- 26769789 TI - High-heeled shoes and musculoskeletal injuries: a narrative systematic review. AB - OBJECTIVES: To conduct the first systematic review from an epidemiological perspective regarding the association between high-heeled shoe wear and hallux valgus, musculoskeletal pain, osteoarthritis (OA) and both first-party and second party injury in human participants without prior musculoskeletal conditions. SETTING: A systematic review of international peer-reviewed scientific literature across seven major languages. DATA SOURCES: Searches were conducted on seven major bibliographic databases in July 2015 to initially identify all scholarly articles on high-heeled shoes. Supplementary manual searches were conducted. Titles, abstracts and full-text articles were sequentially screened to identify all articles assessing epidemiological evidence regarding the association between high-heeled shoe wear and hallux valgus, musculoskeletal pain, OA and both first party and second-party injury in human participants without prior musculoskeletal conditions. Standardised data extraction and quality assessment (Threats to Validity tool) were conducted. PRIMARY AND SECONDARY OUTCOME MEASURES: Musculoskeletal pain or OA as assessed by clinical diagnosis or clinical assessment tool. First-party or second-party injury. RESULTS: 644 unique records were identified, 56 full-text articles were screened and 18 studies included in the review. Four studies assessed the relationship with hallux valgus and three found a significant association. Two studies assessed the association with OA and neither found a significant association. Five studies assessed the association with musculoskeletal pain and three found a significant association. Eight studies assessed first-party injury and seven found evidence of a significant injury toll associated with high-heeled shoes. One study provided data on second party injury and the injury toll was low. CONCLUSIONS: High-heeled shoes were shown to be associated with hallux valgus, musculoskeletal pain and first-party injury. No conclusive evidence regarding OA and second-party injury was found. Societal and clinical relevance of these findings is discussed. Concern is expressed about the expectation to wear high-heeled shoes in some work and social situations and access by children. PMID- 26769790 TI - Using a Delphi process to define priorities for prison health research in Canada. AB - OBJECTIVES: A large number of Canadians spend time in correctional facilities each year, and they are likely to have poor health compared to the general population. Relatively little health research has been conducted in Canada with a focus on people who experience detention or incarceration. We aimed to conduct a Delphi process with key stakeholders to define priorities for research in prison health in Canada for the next 10 years. SETTING: We conducted a Delphi process using an online survey with two rounds in 2014 and 2015. PARTICIPANTS: We invited key stakeholders in prison health research in Canada to participate, which we defined as persons who had published research on prison health in Canada since 1994 and persons in the investigators' professional networks. We invited 143 persons to participate in the first round and 59 participated. We invited 137 persons to participate in the second round and 67 participated. PRIMARY AND SECONDARY OUTCOME MEASURES: Participants suggested topics in the first round, and these topics were collated by investigators. We measured the level of agreement among participants that each collated topic was a priority for prison health research in Canada for the next 10 years, and defined priorities based on the level of agreement. RESULTS: In the first round, participants suggested 71 topics. In the second round, consensus was achieved that a large number of suggested topics were research priorities. Top priorities were diversion and alternatives to incarceration, social and community re-integration, creating healthy environments in prisons, healthcare in custody, continuity of healthcare, substance use disorders and the health of Aboriginal persons in custody. CONCLUSIONS: Generated in an inclusive and systematic process, these findings should inform future research efforts to improve the health and healthcare of people who experience detention and incarceration in Canada. PMID- 26769791 TI - Trends in incidence, prevalence and prescribing in type 2 diabetes mellitus between 2000 and 2013 in primary care: a retrospective cohort study. AB - OBJECTIVE: To investigate trends in incident and prevalent diagnoses of type 2 diabetes mellitus (T2DM) and its pharmacological treatment between 2000 and 2013. DESIGN: Analysis of longitudinal electronic health records in The Health Improvement Network (THIN) primary care database. SETTING: UK primary care. PARTICIPANTS: In total, we examined 8,838,031 individuals aged 0-99 years. OUTCOME MEASURES: The incidence and prevalence of T2DM between 2000 and 2013, and the effect of age, sex and social deprivation on these measures were examined. Changes in prescribing patterns of antidiabetic therapy between 2000 and 2013 were also investigated. RESULTS: Overall, 406,344 individuals had a diagnosis of T2DM, of which 203,639 were newly diagnosed between 2000 and 2013. The incidence of T2DM rose from 3.69 per 1000 person-years at risk (PYAR) (95% CI 3.58 to 3.81) in 2000 to 3.99 per 1000 PYAR (95% CI 3.90 to 4.08) in 2013 among men; and from 3.06 per 1000 PYAR (95% CI 2.95 to 3.17) to 3.73 per 1000 PYAR (95% CI 3.65 to 3.82) among women. Prevalence of T2DM more than doubled from 2.39% (95% CI 2.37 to 2.41) in 2000 to 5.32% (95% CI 5.30 to 5.34) in 2013. Being male, older, and from a more socially deprived area was strongly associated with having T2DM, (p<0.001). Prescribing changes over time reflected emerging clinical guidance and novel treatments. In 2013, metformin prescribing peaked at 83.6% (95% CI 83.4% to 83.8%), while sulfonylureas prescribing reached a low of 41.4% (95% CI 41.1% to 41.7%). Both remained, however, the most commonly used pharmacological treatments as first-line agents and add-on therapy. Thiazolidinediones and incretin based therapies (gliptins and GLP-1 analogues) were also prescribed as alternate add-on therapy options, however were rarely used for first-line treatment in T2DM. CONCLUSIONS: Prevalent cases of T2DM more than doubled between 2000 and 2013, while the number of incident cases increased more steadily. Changes in prescribing patterns observed may reflect the impact of national policies and prescribing guidelines on UK primary care. PMID- 26769793 TI - Prevalence and associated factors of smoking in middle and high school students: a school-based cross-sectional study in Zhejiang Province, China. AB - OBJECTIVES: To determine the prevalence and associated factors of smoking in a Chinese adolescent population. SETTING: A multistage, stratified cluster sampling technique was used in the present cross-sectional study conducted in Zhejiang Province of China. Based on socioeconomic status, school levels and geographical positions, 253 middle school classes, 122 academic school classes and 115 vocational high school classes located in 12 urban areas and 18 rural areas were chosen. PARTICIPANTS: A total of 9617 middle school students, 5495 academic high school students and 4430 vocational high school students were recruited in this survey. PRIMARY AND SECONDARY OUTCOME MEASURES: Ever, current smoking status and associated factors were collected via a self-administered questionnaire. Logistic regression models were used to examine the associations between current smoking and the associated factors. ORs with their 95% CIs were reported. RESULTS: Overall, the prevalence of ever-smokers and current smokers was 33.83% and 7.93%, respectively. Focused on current smokers, significantly higher risks of adolescent smoking were observed in an older age group, boys, rural areas and vocational high school. Other significant factors were parents smoking, secondhand smoke exposure, parental divorce or separation, living with family, school performance and belief that smoking is harmful. CONCLUSIONS: The prevalence of smoking was relatively high among Chinese adolescents in Zhejiang Province. Factors related to personal characteristics, family and school were associated with adolescent smoking. PMID- 26769792 TI - Comparative safety and effectiveness of cognitive enhancers for Alzheimer's dementia: protocol for a systematic review and individual patient data network meta-analysis. AB - INTRODUCTION: Alzheimer's dementia (AD) is the most common cause of dementia, and several organisations, such as the National Institute for Health and Care Excellence, suggest that management of patients with AD should be tailored to their needs. To date, little research has been conducted on the treatment effect in different subgroups of patients with AD. The aim of this study is to examine the comparative effectiveness and safety of cognitive enhancers for different patient characteristics. METHODS AND ANALYSIS: We will update our previous literature search from January 2015 forward, using the same terms and electronic databases (eg, MEDLINE) from our previous review. We will additionally search grey literature and scan the reference lists of the included studies. Randomised clinical trials of any duration conducted at any time comparing cognitive enhancers alone or in any combination against other cognitive enhancers, or placebo in adults with AD will be eligible. The outcomes of interest are cognition according to the Mini-Mental State Examination, and overall serious adverse events. For each outcome and treatment comparison, we will perform a Bayesian hierarchical random-effects meta-analysis combining the individual patient data (IPD) from each eligible study. If the identified treatment comparisons form a connected network diagram, we will perform an IPD network meta analysis (NMA) to estimate subgroup effects for patients with different characteristics, such as AD severity and sex. We will combine aggregated data from studies that we will not be able to obtain IPD, with the IPD provided by the original authors, in a single model. We will use the PRISMA-IPD and PRISMA-NMA statements to report our findings. ETHICS AND DISSEMINATION: The findings of this study will be of interest to stakeholders, including decision makers, guideline developers, clinicians, methodologists and patients, and they will help to improve guidelines for the management of patients with AD. TRIAL REGISTRATION NUMBER: CRD42015023507. PMID- 26769794 TI - Low cost mesh for hernia repair is as good as commercial mesh, trial finds. PMID- 26769795 TI - Should we cluster patients or symptoms? The myth of symptom clusters based on 'depression, insomnia, pain' and 'depression, fatigue, pain'. AB - CONTEXT: 'Depression, fatigue, pain' (DFP) and 'depression, insomnia, pain' (DIP) symptom clusters (SCs) have been proposed in cancer. These symptoms are common and co-occur, that is, they constitute clusters of patients rather than symptoms. OBJECTIVES: The following research questions were addressed: (1) What is the frequency of co-occurrence of two symptom groups (DFP and DIP) in advanced cancer? (2) What is the degree of symptom item association within each symptom group? (3) Were either of these symptom trios associated with prognosis? METHODS: We reanalysed a symptom data set of 1000 patients with advanced cancer. We identified the frequency of co-occurrence of two symptom groups: DFP and DIP, using both prevalence and severity data. The symptom associations were tested by chi(2) and Spearman correlations. We also determined whether either of these symptom trios were associated with a major biological outcome, that is, survival by time-to-event analyses. RESULTS: (1) Although DFP and DIP co-occured in about a quarter of the population, they were not SCs, but rather patient clusters. (2) Many persons had only one symptom from any symptom pair, and correlation coefficients were low for all symptom pairs. (3) Neither DFP nor DIP were associated with survival. CONCLUSIONS: Neither DFP nor DIP symptom item combinations constituted a specific cancer SC contrary to prior reports. DFP co occurred in 27% and DIP in only 20%. Additionally, these symptom combinations were not associated with a biological outcome, that is, poor prognosis. Patient subgroups identified by shared symptom experiences alone do not identify SCs. PMID- 26769796 TI - Cardiovascular risks associated with clarithromycin. PMID- 26769800 TI - Defra dismisses call for legal protection of VN title. PMID- 26769797 TI - Decreased N-TAF1 expression in X-linked dystonia-parkinsonism patient-specific neural stem cells. AB - X-linked dystonia-parkinsonism (XDP) is a hereditary neurodegenerative disorder involving a progressive loss of striatal medium spiny neurons. The mechanisms underlying neurodegeneration are not known, in part because there have been few cellular models available for studying the disease. The XDP haplotype consists of multiple sequence variations in a region of the X chromosome containingTAF1, a large gene with at least 38 exons, and a multiple transcript system (MTS) composed of five unconventional exons. A previous study identified an XDP specific insertion of a SINE-VNTR-Alu (SVA)-type retrotransposon in intron 32 ofTAF1, as well as a neural-specific TAF1 isoform, N-TAF1, which showed decreased expression in post-mortem XDP brain compared with control tissue. Here, we generated XDP patient and control fibroblasts and induced pluripotent stem cells (iPSCs) in order to further probe cellular defects associated with this disease. As initial validation of the model, we compared expression ofTAF1and MTS transcripts in XDP versus control fibroblasts and iPSC-derived neural stem cells (NSCs). Compared with control cells, XDP fibroblasts exhibited decreased expression ofTAF1transcript fragments derived from exons 32-36, a region spanning the SVA insertion site. N-TAF1, which incorporates an alternative exon (exon 34'), was not expressed in fibroblasts, but was detectable in iPSC-differentiated NSCs at levels that were ~threefold lower in XDP cells than in controls. These results support the previous findings that N-TAF1 expression is impaired in XDP, but additionally indicate that this aberrant transcription might occur in neural cells at relatively early stages of development that precede neurodegeneration. PMID- 26769801 TI - Low pathogenic avian influenza confirmed in Fife. PMID- 26769802 TI - Defra plans L65 million investment to improve resilience to animal disease. PMID- 26769799 TI - New Wistar Kyoto and spontaneously hypertensive rat transgenic models with ubiquitous expression of green fluorescent protein. AB - The Wistar Kyoto (WKY) rat and the spontaneously hypertensive (SHR) rat inbred strains are well-established models for human crescentic glomerulonephritis (CRGN) and metabolic syndrome, respectively. Novel transgenic (Tg) strains add research opportunities and increase scientific value to well-established rat models. We have created two novel Tg strains using Sleeping Beauty transposon germline transgenesis, ubiquitously expressing green fluorescent protein (GFP) under the rat elongation factor 1 alpha (EF1a) promoter on the WKY and SHR genetic backgrounds. The Sleeping Beauty system functioned with high transgenesis efficiency; 75% of new rats born after embryo microinjections were transgene positive. By ligation-mediated PCR, we located the genome integration sites, confirming no exonic disruption and defining a single or low copy number of the transgenes in the new WKY-GFP and SHR-GFP Tg lines. We report GFP-bright expression in embryos, tissues and organs in both lines and show preliminaryin vitroandin vivoimaging data that demonstrate the utility of the new GFP expressing lines for adoptive transfer, transplantation and fate mapping studies of CRGN, metabolic syndrome and other traits for which these strains have been extensively studied over the past four decades. PMID- 26769798 TI - 5-HT2A and 5-HT2C receptors as hypothalamic targets of developmental programming in male rats. AB - Although obesity is a global epidemic, the physiological mechanisms involved are not well understood. Recent advances reveal that susceptibility to obesity can be programmed by maternal and neonatal nutrition. Specifically, a maternal low protein diet during pregnancy causes decreased intrauterine growth, rapid postnatal catch-up growth and an increased risk for diet-induced obesity. Given that the synthesis of the neurotransmitter 5-hydroxytryptamine (5-HT) is nutritionally regulated and 5-HT is a trophic factor, we hypothesised that maternal diet influences fetal 5-HT exposure, which then influences development of the central appetite network and the subsequent efficacy of 5-HT to control energy balance in later life. Consistent with our hypothesis, pregnant rats fed a low-protein diet exhibited elevated serum levels of 5-HT, which was also evident in the placenta and fetal brains at embryonic day 16.5. This increase was associated with reduced levels of 5-HT2CR, the primary 5-HT receptor influencing appetite, in the fetal, neonatal and adult hypothalamus. As expected, a reduction of 5-HT2CR was associated with impaired sensitivity to 5-HT-mediated appetite suppression in adulthood. 5-HT primarily achieves effects on appetite by 5-HT2CR stimulation of pro-opiomelanocortin (POMC) peptides within the arcuate nucleus of the hypothalamus (ARC). We show that 5-HT2ARs are also anatomically positioned to influence the activity of ARC POMC neurons and that mRNA encoding 5-HT2AR is increased in the hypothalamus ofin uterogrowth-restricted offspring that underwent rapid postnatal catch-up growth. Furthermore, these animals at 3 months of age are more sensitive to appetite suppression induced by 5-HT2AR agonists. These findings not only reveal a 5-HT-mediated mechanism underlying the programming of susceptibility to obesity, but also provide a promising means to correct it, by treatment with a 5-HT2AR agonist. PMID- 26769803 TI - European Medicines Agency to review guidance on colistin use in animals. PMID- 26769804 TI - Vet chosen as 'life coach of the year'. PMID- 26769805 TI - WSAVA publishes updated guidance on vaccination of dogs and cats. PMID- 26769806 TI - Genetic index to help breed dairy cows with greater resistance to bovine TB. PMID- 26769807 TI - Context is key in veterinary education. AB - Debate about whether a veterinary education adequately prepares new graduates for a career in practice is not new, and the way students are taught, and what they are taught, is constantly evolving. A session at the BVA Congress explored how veterinary education might need to change to produce the vets of the future. Georgina Mills reports. PMID- 26769808 TI - Equine welfare: challenging the status quo. PMID- 26769809 TI - Veterinary involvement in poultry production. AB - The worldwide poultry sector is expected to grow substantially over the next few decades, as the world looks to feed a rapidly expanding population. In a further article in Veterinary Record's series looking at the state of different sectors of the veterinary profession, Daniel Parker looks at veterinary involvement in the poultry sector. PMID- 26769810 TI - Clostridium chauvoei-associated meningoencephalitis in a calf. AB - .Meningoencephalitis in a calf associated with Clostridium chauvoei infection. .Bovine papular stomatitis in calves. .Otitis media due to Mycoplasma bovis in calves. .Sporadic porcine abortion due to Nocardia species. .Spotty liver disease in hens. These are among matters discussed in the disease surveillance report for September 2015 from SAC Consulting: Veterinary Services (SAC C VS). PMID- 26769811 TI - How common is equine herpesvirus type 1 infection? PMID- 26769812 TI - Diagnosing CRGV in dogs with skin lesions. PMID- 26769820 TI - Attracting and retaining farm vets. AB - James Allcock, of Lambert, Leonard & May, a farm-only vet practice in Shropshire, describes the steps the practice has taken to help with recruitment and retention of farm vets. PMID- 26769821 TI - Vandals force volunteer doctors to close clinic in Calais's refugee camp. PMID- 26769822 TI - Patterns of Shelter Use Among Men New to Homelessness in Later Life: Duration of Stay and Psychosocial Factors Related to Departure. AB - People who become homeless for the first time in late life are a growing but understudied population. This study draws on administrative data from one shelter (N = 1,214 first-time homeless) to assess the extent to which age is related to shelter stay and, to examine psychosocial factors that may be associated with shelter departure. Our bivariate and survival analysis results suggest that older homeless men stay in the shelter 2 weeks longer than younger clients. Older men with pending legal issues and mobility concerns were more likely to leave the shelter than those without such concerns. Findings highlight the impact of age and other psychosocial variables on shelter stay, and provide direction from which to address homelessness among men who are new to homelessness in later life. PMID- 26769823 TI - Workability and Requests for Flexible Work Arrangements Among Older Adults: The Role of a Time and Place Management Intervention. AB - This article investigates the effect of an intervention on the workability of older adults (i.e., the competence, health, and other mental and physical characteristics that workers need to meet the demands of their jobs). We used data from health care workers ( N = 437) who participated in a "time and place management" (TPM) intervention. Although related to flexible work options that aim to give workers more choice and control over the time and place of their work, TPM is conceptually distinct in that it focuses on the processes and guidelines necessary to the successful management of choice and control rather than the options alone. We focused on how the TPM intervention moderated the relationship between age and workability over time, with a particular focus on variation by baseline workability. Our results indicated that the intervention can benefit older workers with low workability. PMID- 26769824 TI - Older Adults' Opinions on Fall Prevention in Relation to Physical Activity Level. AB - The purpose of this study was to explore and describe older adults' opinions regarding actions to prevent falls and to analyze differences in the opinions of highly versus less physically active older adults. An open-ended question was answered by 262 individuals aged 75 to 98 years living in the community. The answers were analyzed using qualitative content analysis, and differences in the categories were compared between highly and less physically active persons. Physical activity was measured according to a five-level scale. The content analysis resulted in eight categories: assistive devices, avoiding hazards, behavioral adaptive strategies, being physically active, healthy lifestyle, indoor modifications, outdoor modifications, and seeking assistance. Behavioral adaptive strategies were mentioned to a greater extent by highly active people, and indoor modifications were more often mentioned by less active older adults. Support for active self-directed behavioral strategies might be important for fall prevention among less physically active older adults. PMID- 26769825 TI - Acute carbon monoxide poisoning in a regional hospital in Hong Kong: historical cohort study. AB - OBJECTIVES: This study aimed to describe the clinical profiles of all patients with carbon monoxide poisoning admitted to a regional hospital in order to enhance the vigilance of health care professionals for delayed neurological sequelae associated with carbon monoxide poisoning and to identify the prognostic factors associated with their development. This study also aimed to assess the impact of hyperbaric oxygen therapy on the development of delayed neurological sequelae in these patients. METHODS: This was a historical cohort study in which all patients with a diagnosis of carbon monoxide poisoning managed in a regional hospital in Hong Kong from 12 February 2003 to 8 November 2013 were recruited. Main outcome measures included delayed neurological sequelae. RESULTS: Of the clinical profiles of 93 patients analysed, 24 patients received hyperbaric oxygen therapy and did not develop delayed neurological sequelae. Seven patients who did not receive hyperbaric oxygen therapy developed delayed neurological sequelae. Comparison of groups with and without delayed neurological sequelae (excluding hyperbaric oxygen therapy-treated patients) revealed that loss of consciousness (P=0.038), Glasgow Coma Scale score of 3 (P=0.012), elevated troponin level (P<0.001), higher creatine kinase level (P=0.008), and intubation requirement (P=0.007) were possible prognostic factors for the development of delayed neurological sequelae. CONCLUSION: Although not statistically significant, this study showed a 100% protective effect of hyperbaric oxygen therapy against development of severe delayed neurological sequelae in patients with severe carbon monoxide poisoning. Further study with better study design is warranted. Loss of consciousness, low Glasgow Coma Scale score, intubation requirement, elevated troponin and higher creatine kinase levels were possible prognostic factors for development of delayed neurological sequelae in patients with severe carbon monoxide poisoning. A well-defined treatment protocol, appropriate follow up duration and neuropsychiatric tests together with a hospital-based hyperbaric chamber are recommended for management of patients with severe carbon monoxide poisoning. PMID- 26769826 TI - The non-neuronal heart's acetylcholine in health and disease. AB - In this review we describe the history of almost one century lasting investigations which eventually provided evidence convincing that cardiac myocytes possess all elements of the system of synthesis, intracellular transport and release of acetylcholine (ACh) independent of parasympathetic cholinergic innervation. The myocytes synthesis and release of ACh is tightly connected with their contractile activity. Moreover, it is necessary for maintaining the balance of autonomic control of the heart, particularly important in the heart failure. It has an antyhypertrophic activity and protects myocardium against ischemic/reperfusion injury which shows that it is involved in the regulation of the important cellular signaling pathways. These properties of the non-neuronal ACh system of the heart also rise the hope that it might be used for the therapeutic measures. PMID- 26769827 TI - New insights into tryptophan and its metabolites in the regulation of bone metabolism. AB - Osteoporosis, a debilitating disease caused by an imbalance between the action of osteoblasts and osteoclasts, is becoming an increasing problem in today's aging population. Although many advances in this field have addressed certain aspects of disease progression and pain management, new approaches to treatment are required. This review focuses on the influence of tryptophan, its metabolites and their influence on bone remodeling. Tryptophan is a precursor to serotonin, melatonin, kynurenines and niacin. Changes of tryptophan levels were noticed in bone metabolic diseases. Moreover, some works indicate that tryptophan plays a role in osteoblastic differentiation. Serotonin can exert different effects on bones, which depend on site of serotonin synthesis. Gut-derived serotonin inhibits bone formation, whereas brain-derived serotonin enhances bone formation and decreases bone resorption. Melatonin, increased differentiation of human mesenchymal stem cells into the osteoblastic cell lineage. Results of melatonin action on bone are anabolic and antiresorptive. Activation of the second tryptophan metabolic pathway, the kynurenine pathway, is associated with osteoblastogenesis and can be implicated in the occurrence of bone diseases. Oxidation products like kynurenine stopped proliferation of bone marrow mesenchymal stem cells. This may result in inhibition of osteoblastic proliferation and differentiation. Kynurenic acid acts as an antagonist at glutamate receptors, which are expressed on osteoclasts. Quinolinic acid activates N-methyl-D-aspartate receptors. 3-hydroxyanthranilic acid exhibits pro oxidant and antioxidant activity. Decreased concentration of 3-hydroxyanthranilic acid can be one of the causes of osteoporosis. 3-hydroxykynurenine reduced the viability of osteoblast-like cells. Picolinic acid exerted osteogenic effect in vitro. Kynurenine derivatives exert various effects on bones. Discovery of the exact mechanism of action of tryptophan metabolites on bones may take us a step closer to understanding the complicated mechanism of bone metabolism, which in turn may result in finding a new, effective therapy for treating bone diseases. PMID- 26769828 TI - Immunomodulatory effect of riboflavin deficiency and enrichment - reversible pathological response versus silencing of inflammatory activation. AB - Ariboflavinosis, that is, vitamin B2 deficiency, is a common problem affecting the populations of both developing and affluent countries. Teenagers, elderly people, pregnant women, and alcohol abusers represent groups that are particularly susceptible to this condition. This study was aimed to determine the effect of different riboflavin concentrations (deficiency and supplementation) on macrophages response induced by bacteria or yeast-derived factors i.e. lipopolysaccharide (LPS) and zymosan, respectively. Mouse macrophage RAW 264.7 cells were cultured for 5 days in a medium with a riboflavin concentration corresponding to moderate riboflavin deficiency (3.1 nM), physiological state (10.4 nM), or vitamin pill supplementation (300 nM). On the third or fourth day of deprivation, the medium in some groups was supplemented with riboflavin (300 nM). Macrophages activation were assessed after LPS or zymosan stimulation. Short term (5 days) riboflavin deprivation resulted in the pathological macrophages activation, manifested especially in a reduction of cell viability and excess release of tumor necrosis factor-alpha (TNF-alpha) and high-mobility group box 1 (HMGB1) protein. Moreover, the levels of inducible nitric oxide synthase (iNOS), nitric oxide (NO), heat shock protein (Hsp72), interleukin 1beta (IL-1beta), monocyte chemoattractant protein-1 (MCP-1), and interleukin 10 (IL-10) decreased after riboflavin deprivation, but medium enrichment with riboflavin (300 nM) on the third or fourth day reversed this effect. In the riboflavin-supplemented group, LPS-stimulated macrophages showed lower mortality accompanied by higher Hsp72 expression, reduction of Toll-like receptor 4 (TLR4) and TNF-alpha, and elevation of NO, IL-6, and IL-10. Moreover, the TLR6, NO, iNOS, IL-1beta, MCP-1, and the keratinocyte chemoattractant (KC) levels significantly decreased in the zymosan-stimulated groups maintained in riboflavin-enriched medium. We conclude that short-term riboflavin deficiency significantly impairs the ability of macrophages to induce proper immune response, while riboflavin enrichment decreases the proinflammatory activation of macrophages. PMID- 26769829 TI - Analysis of the correlations between oxidative stress, gelatinases and their tissue inhibitors in the human subjects with obstructive sleep apnea syndrome. AB - Obstructive sleep apnea syndrome (OSAS) is commonly associated with endothelial dysfunction, atherosclerosis and cardiovascular disorders. On the basis of this observation, our aim was to examine the oxidative status and the matrix metalloproteases (MMP) profile in a group of subjects with OSAS. We enrolled 48 subjects with OSAS defined after a 1-night cardiorespiratory sleep study, who were subsequently subdivided in two subgroups according to the severity of OSAS (low grade = L-OSAS; high grade= H-OSAS). We measured the parameters of oxidative stress, such as lipid peroxidation, protein oxidation, total antioxidant status (TAS), nitric oxide metabolites (NOx), and the plasma concentrations of the gelatinases (MMP-2 and MMP-9) and their tissue inhibitors (TIMP-1 and TIMP-2). We found a significant impairment of oxidative status in H-OSAS compared to L-OSAS and higher plasma levels of MMP-9 and TIMP-1 in H-OSAS compared to L-OSAS. In this study we observed a positive correlation between TBARS and MMP-9, a positive correlation between PC and MMP-9, and a negative correlation between NOx and MMP 9, especially in the whole group of OSAS subjects. These data underline how strong interrelationships among some parameters of the oxidative stress, in particular those reflecting lipid peroxidation, protein oxidation and NOx, and MMP-9 are evident in OSAS subjects. All these information may be useful in the clinical practice keeping in mind the cardiovascular complications generally accompanying the obstructive sleep apnea syndrome. PMID- 26769830 TI - Crossfit training changes brain-derived neurotrophic factor and irisin levels at rest, after wingate and progressive tests, and improves aerobic capacity and body composition of young physically active men and women. AB - Brain-derived neurotrophic factor (BDNF) is a protein that stimulates processes of neurogenesis, the survival of neurons and microglia, stimulates neuroplasticity, and takes part in the differentiation of cells developed in the hippocampus. BDNF is also released from skeletal muscles during exercise and can facilitate cross-talk between the nervous and muscular system. Irisin, the exercise hormone, is also released from skeletal muscles and is involved in oxidation processes in the organism. It is a vital issue from the point of view of prophylaxis and treatment through exercise of age-related diseases (e.g. senile dementia), obesity, type-2 diabetes. The aim of the study was to assess the changes in BDNF and irisin levels in young people after a 3-month CrossFit training program. At baseline and after the training, levels of BDNF and irisin were assayed before and after Wingate and progressive tests. Physical performance, body mass and composition, and muscle circumferences were also measured. There were noted: an improvement in aerobic capacity, an increase in VO2max, a reduction in adipose tissue percentage in women and an increase in LBM in all subjects. After CrossFit training the resting BDNF level increased significantly in all subjects while the resting level of irisin decreased in women, without changes in men. The resting level of BDNF at baseline was higher in men than in women. At baseline we observed an increased level of BDNF in women after Wingate and progressive tests, but in men only after the progressive test. After 3 months of CrossFit training the level of BDNF increased in all subjects, and also was higher in men than in women. In women we did not observe significant differences after both tests in comparison to rest. After the training BDNF was lower in men after Wingate and progressive tests than at rest. At baseline irisin level decreased in women after the Wingate and progressive tests. Changes in men were not observed after both tests. There were no differences in irisin levels between the baseline and 3 months after the training after Wingate and progressive tests. A beneficial influence of CrossFit training on the subjects' body composition, anaerobic capacity and cardiovascular fitness as well as an increase in BDNF makes it possible to assume that this type of training could have a very high application value, especially in a therapeutic process leading to improving a patient's wellbeing. PMID- 26769831 TI - The effect of pregnane X receptor agonists on postprandial incretin hormone secretion in rats and humans. AB - We recently showed that pregnane X receptor (PXR) agonists cause hyperglycaemia during oral glucose tolerance test (OGTT) in rats and healthy volunteers (Rifa-1 study). We now aimed to determine if the secretion of incretin hormones, especially glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP), are affected by PXR agonists since these gut-secreted hormones are major regulators of postprandial glucose metabolism. The Rifa-2 study had a one-phase, open-label design. Twelve subjects were given 600 mg of rifampicin a day for a week. OGTT with glucose, insulin, and incretin hormone measurements was performed before and after the rifampicin dosing. Incretins and insulin were analysed in previously collected rat OGTT samples after pregnenolone 16alpha-carbonitrile (PCN) or control treatment for 4 days. Rifampicin treatment did not affect glucose, insulin, GLP-1, GIP, glucagon, and peptide YY levels statistically significantly. Incremental AUCs (AUCincr) of glucose and insulin tended to increase (41% increase in glucose AUCincr, P = 0.21, 95% confidence interval (CI) of the difference -47, 187; 24% increase in insulin AUCincr, P = 0.084, CI of the difference -110, 1493). Glucagon AUC was increased in women (53% increase, P = 0.028) and decreased in men (19% decrease, P < 0.001) after rifampicin dosing. In combined analysis of human Rifa-1 and Rifa-2 studies, glucose AUCincr was elevated by 63% (P = 0.010) and insulin AUCincr by 37% (P = 0.011). PCN increased rat insulin level at 60 min time point but did not affect incretin and insulin AUCs statistically significantly. In conclusion, PXR agonists do not affect the secretion of incretin hormones. The regulation of glucagon secretion by PXR may be sexually dimorphic in humans. The mechanism of disrupted glucose metabolism induced by PXR activation requires further study. PMID- 26769832 TI - Hemoglobin - a novel ligand of hepatocyte ectopic F1-ATPase. AB - The liver is largely responsible for free hemoglobin uptake, but the molecular mechanism of this phenomenon has never been revealed. This paper presents the results of the study on hemoglobin binding components of the hepatocyte membrane that were purified using affinity chromatography on a hemoglobin matrix and identified by peptide mass fingerprinting. Both F1-ATPase alpha and beta subunits were retrieved. The binding was confirmed via an intrinsic fluorescence quenching study using a purified recombinant F1-ATPase beta subunit, and the dissociation constant for the complex was estimated from the saturation binding curve (Kd = 7.5 x 10(-7) M). The results indicate that haemoglobin binds to hepatocyte ectopic F1-ATPase. We suggested the plausible role of the receptor in endocytosis of haemoglobin by the hepatocyte. PMID- 26769833 TI - Perivascular tissue mediated relaxation - a novel player in human vascular tone regulation. AB - Perivascular tissue (PVT) modulates vascular tone, releasing adventitia/adipocyte derived relaxing factor (ADRF). Its physiological role remains unclear. We studied isolated internal thoracic artery (ITA) segments obtained from 132 patients subjected to coronary artery bypass grafting. The vessels were skeletonized in vitro and the ITA rings and PVT were incubated in separate isolated organ baths. Skeletonized ITA segments were first precontracted with 10( 5.5)mol/L 5-hydroxytryptamine hydrochloride. The PVT was next transferred to the ITA tissue bath. This resulted in relaxation of ITA, presumably related to ADRF release from PVT which was floating freely in the tissue bath. The in-vitro relaxation responses were then correlated to patients' characteristics - including demographics, clinical and laboratory data, as well as therapy. Perivascular tissue transfer resulted in 49.7 +/- 26.2% relaxation of precontracted ITA segments. In multiple linear regression modelling, the relaxation of ITAto PVT was negatively related to patient age (beta = -0.67; 95% CI -1.17 - -0.17; P = 0.009), symptoms of CCS class 4 angina (beta = -20.11; 95%CI -32.25 - -7.97; P = 0.001), and positively to body mass (beta = 0.37; 95%CI 0.08 - 0.67; P = 0.01) and lack of heart failure symptoms (NYHA class 1) (beta = 9.06; 95%CI 0.33 - 17.79; P = 0.04). The relaxation response to PVT was not related to patients' sex, diabetes, hypertension, lipid profile or therapy in both univariate and multivariate analysis. PVT might play an important role in regulating vascular tone in humans as exemplified by its changing physiological function with age and in atherosclerosis. PMID- 26769834 TI - Ultrastructural evidence of a secretory role for melatonin in the human parotid gland. AB - In vivo animal studies show that pentagastrin, cholecystokinin and melatonin cause the secretion and synthesis of salivary proteins. Melatonin occurs in large amounts in the gut and is released into the blood on food intake. In vitro experiments suggest that pentagastrin exerts secretory activity in human salivary glands, as judged by ultrastructural changes, reflecting secretion, and an actual protein output. Currently, it is hypothesised that melatonin induces secretory exocytotic events in the human parotid gland. Human parotid tissues were exposed to a high single concentration of melatonin in vitro, processed for high resolution scanning electron microscopy and then assessed morphometrically with the emphasis on the membrane of the intercellular canaliculi, a site of protein secretion. Compared with controls and in terms of density, the melatonin-exposed parotid tissues displayed increases in protrusions (signalling anchored granules) and microbuds (signalling membrane recycling and/or vesicle secretion) and decreases in microvilli (signalling cytoskeletal re-arrangement related to exocytosis), phenomena abolished or very largely reduced by the melatonin receptor blocker, luzindole. In conclusion, acinar serous cells of parotid tissue displayed in vitro exocytotic activity to melatonin, signalling protein secretion. Whether, under physiological conditions, melatonin influences the secretion of human parotid glands remains to be explored, however. PMID- 26769835 TI - Influence of an upright body position on the size of intrapulmonary blood shunts in patients with advanced liver cirrhosis. AB - Hepatopulmonary syndrome (HPS) is a complication of liver cirrhosis and is responsible for chronic hypoxemia and its negative health consequences. The most relevant diagnostic criterion of HPS is evidence of pathological intrapulmonary blood shunting (IPBS). There is still insufficient knowledge about the subclinical forms of HPS. The aim of this study was to determine whether an erect posture in patients with liver cirrhosis had a significant effect on IPBS, the diagnosis of HPS and oxygen saturation. Thirty cirrhotic patients considered for liver transplantation were enrolled in this study. Pulse oximetry and lung perfusion scintigraphy were conducted in patients while they were in supine and upright body positions. Pathological IPBS was observed in 16% and 20% of patients examined in the supine and upright body positions, respectively (mean difference 0.59%; P = 0.046). Postural-related IPBS changes were markedly greater in patients with HPS (1.76%; P = 0.011). Oxygen saturation was significantly lower in the erect posture compared to the supine posture (mean difference 1.2%; P = 0.02); however, there was no relationship between oxygen saturation and IPBS. In conclusion, an erect posture in patients with advanced liver cirrhosis leads to a subtle increase in IPBS, which is more pronounced in patients with HPS, and oxygen saturation measurements are not sensitive enough to detect these changes. PMID- 26769836 TI - Comparison of acetaminophen toxicity in primary hepatocytes isolated from transgenic mice with different appolipoprotein E alleles. AB - The nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor, important for combating electrophilic and oxidative stress in the liver and other organs. This encompasses detoxification of hepatotoxic drugs, including acetaminophen (APAP). Recently, an association between apolipoprotein E (ApoE) genotype and Nrf2 expression was described. We compared the toxicity of APAP on primary culture hepatocytes isolated from transgenic mice carrying two different human ApoE alleles and wild-type controls. The cells were exposed to APAP in concentrations from 0.5 to 4 mM for up to 24 hours. APAP led to a dose-dependent hepatotoxicity from 1 mM after 16 h exposure in all mice tested. The toxicity was higher in hepatocytes isolated from both transgenic strains than in wild-type controls and most pronounced in ApoE3 mice. Concurrently, there was a decline in mitochondrial membrane potential, especially in ApoE3 hepatocytes. The formation of reactive oxygen species was increased after 24 hours with 2.5 mM APAP in hepatocytes of all strains tested, with the highest increase being in the ApoE3 genotype. The activity of caspases 3 and 7 did not differ among groups and was minimal after 24 hour incubation with 4 mM APAP. We observed higher lipid accumulation in hepatocytes isolated from both transgenic strains than in wild type controls. The expression of Nrf2-dependent genes was higher in ApoE3 than in ApoE4 hepatocytes and some of these genes were induced by APAP treatment. In conclusion, transgenic mice with ApoE4 and ApoE3 alleles displayed higher susceptibility to acute APAP toxicity in vitro than wild-type mice. Of the two transgenic genotypes tested, ApoE3 allele carriers were more prone to injury. PMID- 26769837 TI - The influence of pretreatment with ghrelin on the development of acetic-acid induced colitis in rats. AB - Ghrelin has been primarily shown to exhibit protective and therapeutic effect in the gut. Pretreatment with ghrelin inhibits the development of acute pancreatitis and accelerates pancreatic recovery in the course of this disease. In the stomach, ghrelin reduces gastric mucosal damage induced by ethanol, stress or alendronate, as well as accelerates the healing of acetic acid-induced gastric and duodenal ulcer. The aim of present studies was to investigate the effect of pretreatment with ghrelin on the development of acetic acid-induced colitis. Studies have been performed on male Wistar rats. Animals were treated intraperitoneally with saline (control) or ghrelin (4, 8 or 16 nmol/kg/dose). Saline or ghrelin was given twice: 8 and 1 h before induction of colitis. Colitis was induced by a rectal enema with 1 ml of 4% solution of acetic acid and the severity of colitis was assessed 1 or 24 hours after induction of inflammation. Rectal administration of acetic acid induced colitis in all animals. Damage of colonic wall was seen at the macroscopic and microscopic level. This effect was accompanied by a reduction in colonic blood flow and mucosal DNA synthesis. Moreover, induction of colitis significantly increased mucosal concentration of pro-inflammatory interleukin-1beta (IL-1beta), activity of myeloperoxidase and concentration of malondialdehyde (MDA). Mucosal activity of superoxide dismutase (SOD) was reduced. Pretreatment with ghrelin reduced the area and grade of mucosal damage. This effect was accompanied by an improvement of blood flow, DNA synthesis and SOD activity in colonic mucosa. Moreover, ghrelin administration reduced mucosal concentration of IL-1beta and MDA, as well as decreased mucosal activity of myeloperoxidase. Administration of ghrelin protects the large bowel against the development of the acetic acid-induced colitis and this effect seems to be related to the ghrelin-evoked anti-inflammatory and anti-oxidative effects. PMID- 26769838 TI - Combination of hyperhomocysteinemia and ischemic tolerance in experimental model of global ischemia in rats. AB - Epidemiological studies show positive relationship between mild-to-moderate hyperhomocysteinemia (hHcy) and the risk of cerebrovascular diseases. The study determines whether hyperhomocysteinemia (risk factor of brain ischemia) alone or in combination with the ischemic preconditioning (IPC) affects the ischemia induced neurodegenerative changes and imbalance in MAPK/p-ERK1/2 and MAPK/p-p38 expression in the rat brains. hHcy was induced by subcutaneous administration of homocysteine (0.45 MUmol/g body weight) twice a day at 8 h intervals for 14 days. Rats were preconditioned by 5 min ischemia and 2 days later, 15 min of global forebrain ischemia was induced by four vessel occlusion. We observed that hHcy alone significantly increased neurodegeneration by Fluoro-Jade C and TUNEL possitive cells in hippocampus as well as in cortex. We found elevated level of MAPK/p-ERK and decreased level of MAPK/p-p38 after pre-ischemic challenge by Western blot and fluorescent immunohistochemistry. In conclusion, preconditioning even if combined with hHcy could preserve the neuronal tissue from lethal ischemic effect. This study provides evidence for the interplay and tight integration between ERK and p38 MAPKs signalling mechanisms in response to the hHcy and also if in association with brain ischemia/IPC challenge in the rat brain. PMID- 26769839 TI - Exposure to sixty minutes of hyperoxia upregulates myocardial humanins in patients with coronary artery disease - a pilot study. AB - In experimental setting the concept of myocardial preconditioning by hyperoxia has been introduced and different intracellular protective mechanisms and their effects have been described. To study whether similar protective phenotype can be induced by hyperoxia also in humans, gene expression profile after hyperoxic exposure was analyzed. Adult patients were randomized to be ventilated with either FiO2 0.4 (n = 14) or 1.0 (n = 10) for 60 minutes before coronary artery bypass grafting. A tissue sample from the right atrial appendage was taken for gene analysis and expression profile analysis on genome wide level by RNA-seq analysis was applied. Exposure to > 96% oxygen for 60 minutes significantly changed the expression of 20 different genes, including upregulation of two different humanins - MTRNR2L2 and MTRNR2L8, and activated a "cell survival" network as detected by Ingenuity Pathway Analyses. We concluded that administration of > 96% oxygen for 1 hour changes gene expression in the myocardium of the patients with coronary artery disease and may enhance cell survival capability. PMID- 26769840 TI - Rumex acetosa L. induces vasorelaxation in rat aorta via activation of PI3 kinase/Akt- AND Ca(2+)-eNOS-NO signaling in endothelial cells. AB - Rumex acetosa L. (RA) (Polygonaceae) is an important traditional Chinese medicine (TCM) commonly used in clinic for a long history in China and the aerial parts of RA has a wide variety of pharmacological actions such as diuretic, anti hypertensive, anti-oxidative, and anti-cancer effects. However, the mechanisms involved are to be defined. The purpose of the present study was to evaluate the vasorelaxant effect and define the mechanism of action of the ethanol extract of Rumex acetosa L. (ERA) in rat aorta. ERA was examined for its vascular relaxant effect in isolated phenylephrine-precontracted rat thoracic aorta and its acute effects on arterial blood pressure. In addition, the roles of the nitric oxide synthase (NOS)-nitric oxide (NO) signaling in the ERA-induced effects were tested in human umbilical vein endothelial cells (HUVECs). The phosphorylation levels of Akt and eNOS were assessed by Western blot analysis in the cultured HUVECs. ERA induced endothelium-dependent vasorelaxation. The ERA-induced vasorelaxation was abolished by L-NAME (an NOS inhibitor) or ODQ (a sGC inhibitor), but not by indomethacin. Inhibition of PI3-kinase/Akt signaling pathway markedly reduced the ERA-induced vasorelaxation. In HUVECs, ERA increased NO formation in a dose dependent manner, which was inhibited by L-NAME and by removing extracellular Ca(2+). In addition, ERA promoted phosphorylation of Akt and eNOS, which was prevented by wortmannin and LY294002, indicating that ERA induces eNOS phosphorylation through the PI3-kinase/Akt pathway. Further, in anesthetized rats, intravenously administered ERA decreased arterial blood pressure in a dose dependent manner through an activation of the NOS-NO system. In summary, the ERA- induced vasorelaxation was dependent on endothelial integrity and NO production, and was mediated by activation of both the endothelial PI3-kinase/Akt- and Ca(2+) eNOS-NO signaling and muscular NO-sGC-cGMP signaling. PMID- 26769841 TI - Understanding patient-centred readmission factors: a multi-site, mixed-methods study. AB - IMPORTANCE: Patient concerns at or before discharge inform many transitional care interventions; few studies examine patients' perceptions of self-care and other factors related to readmission. OBJECTIVES: To characterise patient-reported or caregiver-reported factors contributing to readmission. DESIGN, SETTING AND PARTICIPANTS: Cross-sectional, national study of general medicine patients readmitted within 30 days at 12 US hospitals. Interviews included multiple-choice survey and open-ended survey questions of patients or their caregivers. MEASUREMENTS: Multiple-choice survey quantified post-discharge difficulty in seven domains of self-care: medication use, contacting providers, transportation, basic needs (eg, food and shelter), diet, social support and substance abuse. Open-ended responses were coded into themes that added depth to the domains above or captured additional patient-centred concerns. RESULTS: We interviewed 1066 readmitted patients. 91% reported understanding their discharge plan; however, only 37% reported that providers asked about barriers to carrying out the plan. 52% reported experiencing difficulty in >=1 self-care domains ranging in frequency from 22% (diet) to 7% (substance use); 26% experienced difficulty in two or more domains. Among 508 patients (48% overall) who reported no difficulties in these domains, two-thirds either could not attribute their readmission to any specific difficulty (34%) or attributed their readmission to progression or persistence of their disease despite following their discharge plan (31%). Only 20% attributed their readmission to early discharge (8%), poor quality hospital care (6%) or issues such as inadequate discharge instructions or follow-up care (6%). LIMITATIONS: The study population included only patients readmitted at academic medical centres and may not be representative of community based care. CONCLUSION: Patients readmitted within 30 days reported understanding their discharge plans, but frequent difficulties in self-care and low anticipatory guidance for resolving these issues after discharge. PMID- 26769842 TI - An Age Old Problem? Estimating the Impact of Dementia on Past Human Populations. AB - OBJECTIVE: To model the impact of dementia on past societies. METHOD: We consider multiple lines of evidence indicating elderly individuals to have been more common throughout the past than is frequently accepted. We then apply known dementia incidence/prevalence rates to plausible assumptions of past population structures to suggest prevalence in the past. RESULTS: Dementia prevalence in premodern societies is likely to have been around 5% of the rate seen in modern, developed countries but with a total past incidence running into billions. DISCUSSION: Dementia is often seen as a "modern" challenge that humans have not had to contend with before. We argue that this condition has had considerably greater effects than previously envisaged and is a challenge that humans have already withstood successfully, on one hand at a lower incidence but on the other without the considerable clinical, technological, and social advances that have been made in recent times. PMID- 26769844 TI - Metabonomic analysis of ovarian tumour cyst fluid by proton nuclear magnetic resonance spectroscopy. AB - The majority of ovarian tumours are of the epithelial type, which can be sub classified as benign, borderline or malignant. Epithelial tumours usually have cystic spaces filled with cyst fluid, the metabolic profile of which reflects the metabolic activity of the tumour cells, due to their close proximity. The approach of metabonomics using 1H-NMR spectroscopy was employed to characterize the metabolic profiles of ovarian cyst fluid samples (n = 23) from benign, borderline and malignant ovarian tumours in order to shed more light into ovarian tumour and cancer development. The analysis revealed that citrate was elevated in benign versus malignant tumours, while the amino acid lysine was elevated in malignant versus non-malignant tumours, both at a 5% significance level. Choline and lactate also had progressively increasing levels from benign to borderline to malignant samples. Finally, hypoxanthine was detected exclusively in a sub-cohort of the malignant tumours. This metabonomic study demonstrates that ovarian cyst fluid samples have potential to be used to distinguish between the different types of ovarian epithelial tumours. Furthermore, the respective metabolic profiles contain mechanistic information which could help identify biomarkers and therapeutic targets for ovarian tumours. PMID- 26769843 TI - Identification of stem-like cells and clinical significance of candidate stem cell markers in gastric cancer. AB - The existence of gastric cancer stem cells (CSCs) has not been definitively proven and specific cell surface markers for identifying gastric CSCs have largely not been identified. Our research aimed to isolate potential gastric CSCs and clarify their clinical significance, while defining markers for GCSC identification and verification. Here, we report that spheroid cells possess stem cell-like properties, and overexpress certain stem cell markers. CD133 or CD44 positive cells also exhibit properties of CSCs. The expression of Oct4, Sox2, Gli1, CD44, CD133, p-AKT, and p-ERK was significantly higher in metastatic lesions compared to that in primary lesions. Elevated expression of some of these proteins was correlated with a more aggressive phenotype and poorer prognosis, including Oct4, Sox2, Gli1, CD44, and p-ERK. Multivariate Cox proportional hazards model analysis showed that only CD44 is an independent factor. Knockdown of CD44 down-regulated the stem cell-like properties, which was accompanied by the down-regulation of p-ERK and Oct4. Oct4 overexpression could reverse the decreased CSCs properties induced by CD44 knockdown. Taken together, our research revealed that spheroid cell culture, and CD133 or CD44-labeled FACS methods can be used to isolate gastric CSCs. Some CSC markers have clinical significance in predicting the prognosis. CD44 is an independent prognostic factor and maintains the properties of CSCs in CD44-p-ERK-Oct4 positive feedback loop. PMID- 26769845 TI - Tumor vascularity and lipiodol deposition as early radiological markers for predicting risk of disease progression in patients with unresectable hepatocellular carcinoma after transarterial chemoembolization. AB - This study evaluated the factors impacting overall survival (OS) and time to progression (TTP) in patients with unresectable hepatocellular carcinoma (HCC) who received transarterial chemoembolization (TACE). HCC patients were grouped based on tumor vascularity and lipidiol deposition after TACE. Tumor vascularity was classified based on contrast enhancement on arterial phase baseline CT scans. Lipiodol deposition was evaluated using CT scans. The progression-free rate was significantly higher in patients with good blood supply + good lipiodol deposition compared to those with good blood supply + poor lipiodol deposition. In patients with poor lipidiol deposition, risk of death was significantly positively correlated with stage, and negatively correlated with number of TACE procedures and degree of lipidiol deposition after the first TACE. Risk of disease progression in these patients was positively correlated with tumor size, and negatively correlated with number of TACE procedures and degree of lipidiol deposition after the first TACE. Our data showed that tumor vascularity and lipiodol deposition can be used as early radiological markers to identify patients who do not respond to TACE, and who can be considered earlier for alternative combination treatment strategies. Our data also indicated that poor lipiodol retention may predict a poor TTP and OS despite the blood supply status. PMID- 26769846 TI - Increased hepatic receptor interacting protein kinase 3 expression due to impaired proteasomal functions contributes to alcohol-induced steatosis and liver injury. AB - Chronic alcohol exposure increased hepatic receptor-interacting protein kinase (RIP) 3 expression and necroptosis in the liver but its mechanisms are unclear. In the present study, we demonstrated that chronic alcohol feeding plus binge (Gao-binge) increased RIP3 but not RIP1 protein levels in mouse livers. RIP3 knockout mice had decreased serum alanine amino transferase activity and hepatic steatosis but had no effect on hepatic neutrophil infiltration compared with wild type mice after Gao-binge alcohol treatment. The hepatic mRNA levels of RIP3 did not change between Gao-binge and control mice, suggesting that alcohol-induced hepatic RIP3 proteins are regulated at the posttranslational level. We found that Gao-binge treatment decreased the levels of proteasome subunit alpha type-2 (PSMA2) and proteasome 26S subunit, ATPase 1 (PSMC1) and impaired hepatic proteasome function. Pharmacological or genetic inhibition of proteasome resulted in the accumulation of RIP3 in mouse livers. More importantly, human alcoholics had decreased expression of PSMA2 and PSMC1 but increased protein levels of RIP3 compared with healthy human livers. Moreover, pharmacological inhibition of RIP1 decreased Gao-binge-induced hepatic inflammation, neutrophil infiltration and NF kappaB subunit (p65) nuclear translocation but failed to protect against steatosis and liver injury induced by Gao-binge alcohol. In conclusion, results from this study suggest that impaired hepatic proteasome function by alcohol exposure may contribute to hepatic accumulation of RIP3 resulting in necroptosis and steatosis while RIP1 kinase activity is important for alcohol-induced inflammation. PMID- 26769847 TI - Mcl-1 dynamics influence mitotic slippage and death in mitosis. AB - Microtubule-binding drugs such as taxol are frontline treatments for a variety of cancers but exactly how they yield patient benefit is unclear. In cell culture, inhibiting microtubule dynamics prevents spindle assembly, leading to mitotic arrest followed by either apoptosis in mitosis or slippage, whereby a cell returns to interphase without dividing. Myeloid cell leukaemia-1 (Mcl-1), a pro survival member of the Bcl-2 family central to the intrinsic apoptosis pathway, is degraded during a prolonged mitotic arrest and may therefore act as a mitotic death timer. Consistently, we show that blocking proteasome-mediated degradation inhibits taxol-induced mitotic apoptosis in a Mcl-1-dependent manner. However, this degradation does not require the activity of either APC/C-Cdc20, FBW7 or MULE, three separate E3 ubiquitin ligases implicated in targeting Mcl-1 for degradation. This therefore challenges the notion that Mcl-1 undergoes regulated degradation during mitosis. We also show that Mcl-1 is continuously synthesized during mitosis and that blocking protein synthesis accelerates taxol induced death-in-mitosis. Modulating Mcl-1 levels also influences slippage; overexpressing Mcl-1 extends the time from mitotic entry to mitotic exit in the presence of taxol, while inhibiting Mcl-1 accelerates it. We suggest that Mcl-1 competes with Cyclin B1 for binding to components of the proteolysis machinery, thereby slowing down the slow degradation of Cyclin B1 responsible for slippage. Thus, modulating Mcl-1 dynamics influences both death-in-mitosis and slippage. However, because mitotic degradation of Mcl-1 appears not to be under the control of an E3 ligase, we suggest that the notion of network crosstalk is used with caution. PMID- 26769848 TI - Targeted near infrared hyperthermia combined with immune stimulation for optimized therapeutic efficacy in thyroid cancer treatment. AB - Treatment of thyroid cancer has incurred much focus because of its high prevalency. As a new strategy treating thyroid cancer, hyperthermia takes several advantages compared with surgery or chemotherapy, including minimal invasion, low systematic toxicity and the ability to enhance the immunogenicity of cancer cells with the expression Hsp70 which serves as Toll-like receptors-4 (TLR-4 agonist). However, Hsp70 as a molecular chaperone can protect cells from heat induced apoptosis and therefore compromise the tumor killing effect of hyperthermia. In this study, to solve this problem, a combined hyperthermia therapy was employed to treat thyroid cancer. We prepared a probe with the tumor targeting agent AG to monitor thyroid tumor issue and generate heat to kill tumor cells in vivo. At the same time Quercetin (inhibitor of HSP70) and lipopolysaccharide (LPS) (agonist of TLR-4) were used for the combined hyperthermia therapy. The results showed that compared with free IR820, AG modification facilitated much enhanced cellular uptake and greatly pronounced tumor targeting ability. The combined therapy exhibited the most remarkable tumor inhibition compared with the single treatments both in vitro and in vivo. These findings verified that the new therapeutic combination could significantly improve the effect of hyperthermia and shed light on a novel clinical strategy in thyroid cancer treatment. PMID- 26769849 TI - TRAF6 regulates melanoma invasion and metastasis through ubiquitination of Basigin. AB - TRAF6 plays a crucial role in the regulation of the innate and adaptive immune responses. Although studies have shown that TRAF6 has oncogenic activity, the role of TRAF6 in melanoma is unclear. Here, we report that TRAF6 is overexpressed in primary as well as metastatic melanoma tumors and melanoma cell lines. Knockdown of TRAF6 with shRNA significantly suppressed malignant phenotypes including cell proliferation, anchorage-independent cell growth and metastasis in vitro and in vivo. Notably, we demonstrated that Basigin (BSG)/CD147, a critical molecule for cancer cell invasion and metastasis, is a novel interacting partner of TRAF6. Furthermore, depletion of TRAF6 by shRNA reduced the recruitment of BSG to the plasma membrane and K63-linked ubiquitination, in turn, which impaired BSG dependent MMP9 induction. Taken together, our findings indicate that TRAF6 is involved in regulating melanoma invasion and metastasis, suggesting that TRAF6 may be a potential target for therapy or chemo-prevention in melanoma. PMID- 26769850 TI - DANGER is involved in high glucose-induced radioresistance through inhibiting DAPK-mediated anoikis in non-small cell lung cancer. AB - 18F-labeled fluorodeoxyglucose (FDG) uptake during FDG positron emission tomography seems to reflect increased radioresistance. However, the exact molecular mechanism underlying high glucose (HG)-induced radioresistance is unclear. In the current study, we showed that ionizing radiation-induced activation of the MEK-ERK-DAPK-p53 signaling axis is required for anoikis (anchorage-dependent apoptosis) of non-small cell lung cancer (NSCLC) cells in normal glucose media. Phosphorylation of DAPK at Ser734 by ERK was essential for p53 transcriptional activity and radiosensitization. In HG media, overexpressed DANGER directly bound to the death domain of DAPK, thus inhibiting the catalytic activity of DAPK. In addition, inhibition of the DAPK-p53 signaling axis by DANGER promoted anoikis-resistance and epithelial-mesenchymal transition (EMT), resulting in radioresistance of HG-treated NSCLC cells. Notably, knockdown of DANGER enhanced anoikis, EMT inhibition, and radiosensitization in a mouse xenograft model of lung cancer. Taken together, our findings offered evidence that overexpression of DANGER and the subsequent inhibitory effect on DAPK kinase activity are critical responses that account for HG-induced radioresistance of NSCLC. PMID- 26769851 TI - Inhibition of breast cancer cell motility with a non-cyclooxygenase inhibitory derivative of sulindac by suppressing TGFbeta/miR-21 signaling. AB - Compelling efficacy on intervention of tumorigenesis by nonsteroidal anti inflammatory drugs (NSAIDs) has been documented intensively. However, the toxicities related to cyclooxygenase (COX) inhibition resulting in suppression of physiologically important prostaglandins limit their clinical use for human cancer chemoprevention. A novel derivative of the NSAID sulindac sulfide (SS), referred as sulindac sulfide amide (SSA), was recently developed, which lacks COX inhibitory activity, yet shows greater suppressive effect than SS on growth of various cancer cells. In this study, we focus on the inhibitory activity of SSA on breast tumor cell motility, which has not been studied previously. Our results show that SSA treatment at non-cytotoxic concentrations can specifically reduce breast tumor cell motility without influencing tumor cell growth, and the mechanism of action involves the suppression of TGFbeta signaling by directly blocking Smad2/3 phosphorylation. Moreover, miR-21, a well-documented oncogenic miRNA for promoting tumor cell metastasis, was also found to be involved in inhibitory activity of SSA in breast tumor cell motility through the modulation of TGFbeta pathway. In conclusion, we demonstrate that a non-COX inhibitory derivative of sulindac can inhibit breast tumor metastasis by a mechanism involving the TGFbeta/miR-21 signaling axis. PMID- 26769852 TI - MRP3 as a novel resistance factor for sorafenib in hepatocellular carcinoma. AB - The mechanism of resistance of hepatocellular carcinoma (HCC) to sorafenib is unknown and no useful predictive biomarker for sorafenib treatment has been reported. Accordingly, we established sorafenib-resistant HCC cells and investigated the underlying mechanism of resistance to sorafenib. Sorafenib resistant cell lines were established from the HCC cell line PLC/PRF5 by cultivation under continuous exposure to increasing concentration of sorafenib. The IC50 values of the 2 resistant clones PLC/PRF5-R1 and PLC-PRF5-R2 were 9.2+/ 0.47 MUM (1.8-fold) and 25+/-5.1 MUM (4.6-fold) respectively, which were significantly higher than that of parental PLC/PRF5 cells (5.4+/-0.17 MUM) (p < 0.01 respectively), as determined by MTT assay. Western blot analysis of signal transduction-related proteins showed no significant differences in expression of AKT/pAKT, mTOR/pmTOR, or ERK/pERK between the 2 resistant clones versus parent cells, suggesting no activation of an alternative signal transduction pathway. Likewise, when expression of membrane transporter proteins was determined, there were no significant differences in expression levels of BSEP, MDR1, MRP2, BCRP, MRP4 and OCT1 between resistant clones and parent cells. However, the expression levels of MRP3 in the 2 resistant clones were significantly higher than that of parent cells. When MRP3 gene was knocked down by siRNA in PLC-PRF5-R2 cells, the sensitivity of the cells to sorafenib was restored. In the analysis of gene mutation, there was no mutation in the activation segment of Raf1 kinase in the resistant clones. Our data clearly demonstrate that the efflux transporter MRP3 plays an important role in resistance to sorafenib in HCC cells. PMID- 26769853 TI - Gene copy number variations in the leukocyte genome of hepatocellular carcinoma patients with integrated hepatitis B virus DNA. AB - Integration of hepatitis B virus (HBV) DNA into the human liver cell genome is believed to promote HBV-related carcinogenesis. This study aimed to quantify the integration of HBV DNA into the leukocyte genome in hepatocellular carcinoma (HCC) patients in order to identify potential biomarkers for HBV-related diseases. Whole-genome comparative genomic hybridization (CGH) chip array analyses were performed to screen gene copy number variations (CNV) in the leukocyte genome, and the results were confirmed by quantitative polymerase chain reaction (qPCR). The commonly detected regions included chromosome arms 19p, 5q, 1q and 15p, where 200 copy number gain events and 270 copy number loss events were noted. In particular, gains were observed in 5q35.3 (OR4F3) and 19p13.3 (OR4F17) in 90% of the samples. Successful homologous recombination of OR4F3 and the HBV P gene was demonstrated, and the amplification at 5q35.3 is potentially associated with the integration of HBV P gene into natural killer cells isolated from peripheral blood mononuclear cells (PBMCs). Receiver operating characteristic (ROC) curve analysis indicated that the combination of OR4F3 and OR4F17 a novel potential biomarker of HBV-related diseases. PMID- 26769854 TI - Allele-specific recognition by LILRB3 and LILRA6 of a cytokeratin 8-associated ligand on necrotic glandular epithelial cells. AB - The LILRs are a family of receptors that regulate the activities of myelomonocytic cells. We found that specific allelic variants of two related members of the LILR family, LILRB3 and LILRA6, interact with a ligand exposed on necrotic glandular epithelial cells. The extracellular domains of LILRB3 and LILRA6 are very similar and their genes are highly polymorphic. A commonly occurring allele, LILRB3*12, displayed particularly strong binding of these necrotic cells and further screening of the products of LILRB3 alleles identified motifs that correlated with binding. Immunoprecipitation of the ligand from epithelial cell lysates using recombinant LILRB3*12, identified cytokeratins 8, 18 and 19. Purified proteins obtained from epithelial cell lysates, using anti cytokeratin 8 antibodies, were able to activate LILRB3*12 reporter cells. Knock down of cytokeratin 8 in epithelial cells abrogated expression of the LILRB3 ligand, while staining with recombinant LILRB3*12 showed co-localisation with cytokeratin 8 and 18 in permeabilised breast cancer cells. Necrosis is a common feature of tumours. The finding of a necrosis-associated ligand for these two receptors raises the possibility of a novel interaction that alters immune responses within the tumour microenvironment. Since LILRB3 and LILRA6 genes are highly polymorphic the interaction may influence an individual's immune response to tumours. PMID- 26769855 TI - Activating the branch-forming splicing pathway by reengineering the ribozyme component of a natural group II intron. AB - When assayed in vitro, group IIC self-splicing introns, which target bacterial Rho-independent transcription terminators, generally fail to yield branched products during splicing despite their possessing a seemingly normal branchpoint. Starting with intron O.i.I1 from Oceanobacillus iheyensis, whose crystallographically determined structure lacks branchpoint-containing domain VI, we attempted to determine what makes this intron unfit for in vitro branch formation. A major factor was found to be the length of the helix at the base of domain VI: 4 base pairs (bp) are required for efficient branching, even though a majority of group IIC introns have a 3-bp helix. Equally important for lariat formation is the removal of interactions between ribozyme domains II and VI, which are specific to the second step of splicing. Conversely, mismatching of domain VI and its proposed first-step receptor in subdomain IC1 was found to be detrimental; these data suggest that the intron-encoded protein may promote branch formation partly by modulating the equilibrium between conformations specific to the first and second steps of splicing. As a practical application, we show that by making just two changes to the O.i.I1 ribozyme, it is possible to generate sufficient amounts of lariat intron for the latter to be purified and used in kinetic assays in which folding and reaction are uncoupled. PMID- 26769857 TI - Radiation dose to the global flying population. AB - Civil airliner passengers and crew are exposed to elevated levels of radiation relative to being at sea level. Previous studies have assessed the radiation dose received in particular cases or for cohort studies. Here we present the first estimate of the total radiation dose received by the worldwide civilian flying population. We simulated flights globally from 2000 to 2013 using schedule data, applying a radiation propagation code to estimate the dose associated with each flight. Passengers flying in Europe and North America exceed the International Commission on Radiological Protection annual dose limits at an annual average of 510 or 420 flight hours per year, respectively. However, this falls to 160 or 120 h on specific routes under maximum exposure conditions. PMID- 26769856 TI - Structural and functional insights into the fly microRNA biogenesis factor Loquacious. AB - In the microRNA (miRNA) pathway, Dicer processes precursors to mature miRNAs. For efficient processing, double-stranded RNA-binding proteins support Dicer proteins. In flies, Loquacious (Loqs) interacts with Dicer1 (dmDcr1) to facilitate miRNA processing. Here, we have solved the structure of the third double-stranded RNA-binding domain (dsRBD) of Loqs and define specific structural elements that interact with dmDcr1. In addition, we show that the linker preceding dsRBD3 contributes significantly to dmDcr1 binding. Furthermore, our structural work demonstrates that the third dsRBD of Loqs forms homodimers. Mutations in the dimerization interface abrogate dmDcr1 interaction. Loqs, however, binds to dmDcr1 as a monomer using the identified dimerization surface, which suggests that Loqs might form dimers under conditions where dmDcr1 is absent or not accessible. Since critical sequence elements are conserved, we suggest that dimerization might be a general feature of dsRBD proteins in gene silencing. PMID- 26769859 TI - A PET Tracer for Renal Organic Cation Transporters, 11C-Metformin: Radiosynthesis and Preclinical Proof-of-Concept Studies. AB - Organic cation transporters (OCTs) in the kidney proximal tubule (PT) participate in renal excretion of drugs and endogenous compounds. PT function is commonly impaired in kidney diseases, and consequently quantitative measurement of OCT function may provide an important estimate of kidney function. Metformin is a widely used drug and targets OCT type 2 located in the PT. Thus, we hypothesized that (11)C-labeled metformin would be a suitable PET tracer for quantification of renal function. METHODS: (11)C-metformin was prepared by (11)C-methylation of 1 methylbiguanide. In vitro cell uptake of (11)C-metformin was studied in LLC-PK1 cells in the presence of increasing doses of unlabeled metformin. In vivo small animal PET studies in Sprague-Dawley rats were performed at baseline and after treatment with OCT inhibitors to evaluate renal uptake of (11)C-metformin. Kidney and liver pharmacokinetics of (11)C-metformin was investigated in vivo by dynamic (11)C-metformin PET/CT in 6 anesthetized pigs, and renal clearance of (11)C metformin was compared with renal clearance of (51)Cr-ethylenediaminetetraacetic acid (EDTA). Formation of (11)C metabolites was investigated by analysis of blood and urine samples. RESULTS: The radiochemical yield of (11)C-metformin was 15% +/ 3% (n= 40, decay-corrected), and up to 1.5 GBq of tracer were produced with a radiochemical purity greater than 95% in less than 30 min. Dose-dependent uptake of (11)C-metformin in LLC-PK1 cells was rapid. Rat small-animal PET images showed (11)C-metformin uptake in the kidney and liver, the kinetics of which were changed after challenging animals with OCT inhibitors. In pigs, 80% of the injected metformin dose was rapidly present in the kidney, and a high dose of metformin caused a delayed renal uptake and clearance compared with baseline consistent with transporter-mediated competition. Renal clearance of (11)C metformin was approximately 3 times the renal clearance of (51)Cr-EDTA. CONCLUSION: We successfully synthesized an (11)C-metformin tracer, and PET studies in rats and pigs showed a rapid kidney uptake from the blood and excretion into the bladder similar to other radiopharmaceuticals developed for gamma-camera renography. PMID- 26769858 TI - Correlation of Intraprostatic Tumor Extent with 68Ga-PSMA Distribution in Patients with Prostate Cancer. AB - We evaluated the diagnostic value and accuracy of prostate-specific membrane antigen (PSMA) PET for the intraprostatic delineation of prostate cancer before prostatectomy. METHODS: We identified 6 patients with biopsy-proven high-risk prostate cancer who were referred for (68)Ga-PSMA PET/CT before radical prostatectomy to rule out metastasis. After prostatectomy, a histologic map of the prostate was reconstructed. The histologic extent and Gleason score of each segment of the prostate were compared with (68)Ga-PSMA PET images resliced to the histologic axis. Sensitivity, specificity, positive and negative predictive value, and positive and negative likelihood ratios were calculated. The SUV of each segment was measured, and median values were compared. RESULTS: Of the 132 segments, 112 were eligible for analysis. The correlation of histologic results with (68)Ga-PSMA PET images showed a specificity and sensitivity of 92%. The positive and negative likelihood ratio and the positive and negative predictive value for detection of prostate cancer on (68)Ga-PSMA PET were 11.5, 0.09, 96%, and 85%, respectively. The median SUVmax of true-positive prostate segments was significantly higher than that of true-negative segments (11.0 +/- 7.8 vs. 2.7 +/ 0.9, P< 0.001), and a cutoff of 4 revealed a sensitivity and specificity of 86.5% and an accuracy of 87.5%. CONCLUSION: These preliminary results show that the intraprostatic localization and extent of prostate cancer may be estimated by (68)Ga-PSMA PET. This imaging method may be helpful for identifying target lesions before prostate biopsy and may support decision making before focal or radical therapy. PMID- 26769860 TI - Biokinetic Modeling and Dosimetry for Optimizing Intraperitoneal Radioimmunotherapy of Ovarian Cancer Microtumors. AB - A biokinetic model was constructed to evaluate and optimize various intraperitoneal radioimmunotherapies for micrometastatic tumors. The model was used to calculate the absorbed dose to both anticipated microtumors and critical healthy organs and demonstrated how intraperitoneal targeted radiotherapy can be optimized to maximize the ratio between them. METHODS: The various transport mechanisms responsible for the biokinetics of intraperitoneally infused radiolabeled monoclonal antibodies (mAbs) were modeled using a software package. Data from the literature were complemented by pharmacokinetic data derived from our clinical phase I study to set parameter values. Results using the beta emitters (188)Re, (177)Lu, and (90)Y and the alpha-emitters (211)At, (213)Bi, and (212)Pb were compared. The effects of improving the specific activity, prolonging residence time by introducing an osmotic agent, and varying the activity concentration of the infused agent were investigated. RESULTS: According to the model, a 1.7-L infused saline volume will decrease by 0.3 mL/min because of lymphatic drainage and by 0.7 mL/min because of the transcapillary convective component. The addition of an osmotic agent serves to lower the radiation dose to the bone marrow. Clinically relevant radioactivity concentrations of alpha- and beta-emitters bound to mAbs were compared. For alpha-emitters, microtumors receive high doses (>20 Gy or 100 Sv [relative biological effect = 5]). Since most of the tumor dose originates from cell-bound radionuclides, an increase in the specific activity would further increase the tumor dose without affecting the dose to peritoneal fluid or bone marrow. For beta-emitters, tumors will receive almost entirely nonspecific irradiation. The dose from cell-bound radiolabeled mAbs will be negligible by comparison. For the long-lived (90)Y, tumor doses are expected to be low at the maximum activity concentration delivered in clinical studies. CONCLUSION: According to the presented model, alpha-emitters are needed to achieve radiation doses high enough to eradicate microscopic tumors. PMID- 26769861 TI - 68Ga-NOTA-UBI-29-41 as a PET Tracer for Detection of Bacterial Infection. AB - The cationic peptide (68)Ga-NOTA-UBI-29-41 was synthesized and characterized. Biodistribution and PET/CT examinations were performed for evaluation of its biologic behavior. Differentiation of infection from sterile inflammation was investigated using microbiology methods at the sites of bacterial infections. METHODS: Labeling of UBI-29-41 conjugated with NOTA with (68)Ga was optimized at 20 degrees C-100 degrees C and pH 3.5-5.5. Radiochemical purity, stability up to 260 min, and binding to serum proteins were determined. In vitro binding to Staphylococcus aureus was evaluated from 9.14 * 10(7) to 1.17 * 10(10) cfu/mL. Of 3 groups of Mus musculus Swiss male mice, the first was inoculated intramuscularly with 1.2 * 10(8) cfu of S. aureus to provoke infection, and the second, with 1.2 * 10(8) cfu of heat shock-treated S. aureus to generate sterile inflammation. The third mouse was not treated and served as a control. After 24 h, (68)Ga-NOTA-UBI-29-41 was administrated intravenously, and biodistribution was performed at 30, 60, and 120 min. PET/CT dynamic studies (120 min) were acquired. Sinograms were reconstructed using 3D maximum-likelihood expectation maximization and analyzed with software. Infected or inflamed muscles were dissected, homogenized, and cultured in tryptic soy agar medium. Recovered S. aureus was calculated as cfu/g. RESULTS: (68)Ga-NOTA-UBI-29-41 showed high renal excretion (83.2% +/- 7.3%) of injected dose and rapid blood clearance. More than 95% was bound in vitro to 5 * 10(9) cfu/mL. A significantly higher (P< 0.05) accumulation of (68)Ga-NOTA-UBI-29-41 was observed at sites of S. aureus inoculation in infected mice (ratio of target to nontarget, 5.0 at 60 min and 4.1 at 120 min) compared with animals with inflammation (ratio of target to nontarget, 1.6 at 60 min and 1.2 at 120 min). CONCLUSION: The difference in uptake of (68)Ga-NOTA-UBI 29-41 in the infected muscles compared with the inflamed muscles was clearly observed in the PET/CT images and positively correlated with the degree of infection. PMID- 26769862 TI - Microfluidic Preparation of a 89Zr-Labeled Trastuzumab Single-Patient Dose. AB - (89)Zr-labeled antibodies are being investigated in several clinical trials; however, the time requirement for synthesis of clinical doses can hinder patient throughput because of scheduling difficulties. Additionally, low specific activity due to poor labeling efficiency can require larger amounts of the radiopharmaceutical to be administered, possibly leading to adverse side effects. Here, we describe the design and evaluation of a microfluidic reactor capable of synthesizing a single clinical dose of (89)Zr-labeled antibody. (89)Zr-labeled trastuzumab was chosen for this validation because it is currently being evaluated in clinical trials for imaging human epidermal growth factor receptor 2 positive cancer patients. METHODS: A microreactor fabricated from polydimethylsiloxane/glass was silanated with trimethoxy(octadecyl) silane to reduce antibody adsorption. Desferrioxamine-p-benzyl-isothiocyanate (DFO-Bz-NCS) was conjugated to trastuzumab in an 8:1 molar ratio following the literature procedures using aseptic techniques. Radiolabeling was performed by pumping (89)Zr-oxalate and DFO-Bz-trastuzumab into the microfluidic reactor at a total rate of 20 MUL/min in ratios varying from 1:37 to 1:592 mg:MBq at 37 degrees C to achieve optimal labeling. RESULTS: Silanated reactors showed low antibody adsorption in comparison to unmodified reactors (95% monoclonal antibody recovered vs. 0% recovered). Labeling of the modified trastuzumab was shown to be achievable at a specific activity above the reported literature value of 220 MBq/mg. A high radiochemical purity was achieved without an incubation period at specific activities of less than 148 MBq/mg; however, specific activities up to 592 MBq/mg could be achieved with an incubation period. Clinical doses were able to be prepared and passed all quality control guidelines set by the Food and Drug Administration. Samples were sterile, colorless, and radiochemically pure (100%); maintained the ability to bind to the intended receptor; formed a minimal amount of aggregates (1%-4%); and were completed within 45-60 min. CONCLUSION: (89)Zr labeled trastuzumab for use in a clinical setting was synthesized in a microfluidic reactor in under an hour while reducing the amount of handling required by a technician. Use of this compact platform not only could enable the use of radiolabeled antibodies to become a common practice, but also could spread the use of radiolabeled antibodies beyond locations with cyclotron facilities. PMID- 26769863 TI - Measurement of Tumor Hypoxia in Patients with Advanced Pancreatic Cancer Based on 18F-Fluoroazomyin Arabinoside Uptake. AB - Pancreatic cancers are thought to be unusually hypoxic, which might sensitize them to drugs that are activated under hypoxic conditions. In order to develop this idea in the clinic, a minimally invasive technique for measuring the oxygenation status of pancreatic cancers is needed. METHODS: We tested the potential for minimally invasive imaging of hypoxia in pancreatic cancer patients, using the 2-nitroimidazole PET tracer (18)F-fluoroazomycin arabinoside (or (18)F-1-alpha-D-[5-fluoro-5-deoxyarabinofuranosyl]-2-nitroimidazole [(18)F FAZA]). Dynamic and static scans were obtained in 21 patients with either locally advanced or metastatic disease. The hypoxic fraction was determined in the 2-h static scans as the percentage of voxels with SUVs more than 3 SDs from the mean values obtained for skeletal muscle. RESULTS: Hypoxia was detected in 15 of 20 evaluable patients, with the hypoxic fraction ranging from less than 5% to greater than 50%. Compartmental analysis of the dynamic scans allowed us to approximate the tumor perfusion as mL/min/g of tissue, a value that is independent of the extent of hypoxia derived from tracer uptake in the 2-h static scan. There was no significant correlation between tumor perfusion and hypoxia; nor did we see an association between tumor volume and hypoxia. CONCLUSION: Although pancreatic cancers can be highly hypoxic, a substantial proportion appears to be well oxygenated. Therefore, we suggest that a minimally invasive technique such as the one described in this study be used for patient stratification in future clinical trials of hypoxia-targeting agents. PMID- 26769864 TI - 68Ga-DOTATATE Compared with 111In-DTPA-Octreotide and Conventional Imaging for Pulmonary and Gastroenteropancreatic Neuroendocrine Tumors: A Systematic Review and Meta-Analysis. AB - Neuroendocrine tumors (NETs) are uncommon tumors with increasing incidence and prevalence. Current reports suggest that (68)Ga-DOTATATE PET/CT imaging improves diagnosis and staging of NETs compared with (111)In-DTPA-octreotide and conventional imaging. We performed a systematic review of (68)Ga-DOTATATE for safety and efficacy compared with octreotide and conventional imaging to determine whether available evidence supports U.S. Food and Drug Administration approval. METHODS: Medline, EMBASE, Web of Science, and Cochrane Reviews electronic databases were searched from January 1999 to September 2015. Results were restricted to human studies comparing diagnostic accuracy of (68)Ga-DOTATATE with octreotide or conventional imaging for pulmonary or gastroenteropancreatic NET and for human studies reporting safety/toxicity for (68)Ga-DOTATATE with 10 subjects or more thought to have NETs. Direct communication with corresponding authors was attempted to obtain missing information. Abstracts meeting eligibility criteria were collected by a research librarian and assembled for reviewers; 2 reviewers independently determined whether or not to include each abstract. If either reviewer chose inclusion, the abstract was accepted for review. RESULTS: Database and bibliography searches yielded 2,479 articles, of which 42 were eligible. Three studies compared the 2 radiopharmaceuticals in the same patient, finding (68)Ga-DOTATATE to be more sensitive than octreotide. Nine studies compared (68)Ga-DOTATATE with conventional imaging. (68)Ga-DOTATATE estimated sensitivity, 90.9% (95% confidence interval, 81.4%-96.4%), and specificity, 90.6% (95% confidence interval, 77.8%-96.1%), were high. Five studies were retained for safety reporting only. Report of harm possibly related to (68)Ga-DOTATATE was rare (6 of 974), and no study reported major toxicity or safety issues. CONCLUSION: No direct comparison of octreotide and (68)Ga-DOTATATE imaging for diagnosis and staging in an unbiased population of NETs has been published. Available information in the peer-reviewed literature regarding diagnostic efficacy and safety supports the use of (68)Ga-DOTATATE for imaging of NETs where it is available. PMID- 26769866 TI - First Experience with Chemokine Receptor CXCR4-Targeted PET Imaging of Patients with Solid Cancers. AB - CXCR4 is a chemokine receptor that is overexpressed in various human cancers and is involved in tumor metastasis. The aim of this proof-of-concept study was to evaluate a novel CXCR4-targeted PET probe in patients with solid cancers with reported in vitro evidence of CXCR4 overexpression and to estimate its potential diagnostic value. METHODS: Twenty-one patients with histologically proven pancreatic cancer, laryngeal cancer, non-small cell lung cancer, prostate cancer, melanoma, breast cancer, hepatocellular carcinoma, glioblastoma, sarcoma, or cancer of unknown primary underwent PET imaging using the novel CXCR4 nuclear probe (68)Ga-pentixafor. The SUVmax of the liver, spleen, and bone marrow was measured to determine physiologic tracer distribution. For evaluation of tracer accumulation in solid cancers, SUVmax and tumor-to-background (T/B) ratios were determined in a total of 43 malignant lesions, including 8 primary tumors, 3 locally recurrent tumors, and 32 metastases. When available, the SUVmax of malignant lesions was compared with the corresponding SUVmax measured in routine (18)F-FDG PET. RESULTS: Moderate tracer accumulation was detectable in the liver, bone marrow, and spleen, with a mean SUVmax of 3.1, 3.7, and 5.6, respectively. By visual interpretation criteria, 9 of 11 primary and locally recurrent tumors were detectable, exhibiting a mean SUVmax of 4.7 (range, 2.1-10.9) and a mean T/B ratio of 2.9. Twenty of 32 evaluated metastases were visually detectable (mean SUVmax, 4.5 [range, 3.2-13.8]; mean T/B ratio, 2.8). The highest signal was detected in a patient with non-small cell lung cancer (SUVmax, 10.9; T/B ratio, 8.4) and a patient with cancer of unknown primary (SUVmax, 13.8; T/B ratio, 8.1). Compared with (18)F-FDG PET, which was additionally performed in 10 patients, (68)Ga-pentixafor PET had a lower SUVmax in all measured malignant lesions. CONCLUSION: On the basis of these first observations in a small and heterogeneous patient cohort, the in vitro CXCR4 expression profile of solid cancers and metastases described in the previous literature does not seem to sufficiently depict the in vivo distribution revealed by CXCR4-targeted PET. Moreover, the detectability of solid cancers seems to be generally lower for (68)Ga-pentixafor than for (18)F-FDG PET. PMID- 26769865 TI - Safety and Efficacy of 68Ga-DOTATATE PET/CT for Diagnosis, Staging, and Treatment Management of Neuroendocrine Tumors. AB - Our purpose was to evaluate the safety and efficacy of (68)Ga-DOTATATE PET/CT compared with (111)In-pentetreotide imaging for diagnosis, staging, and restaging of pulmonary and gastroenteropancreatic neuroendocrine tumors. METHODS: (68)Ga DOTATATE PET/CT and (111)In-pentetreotide scans were obtained for 78 of 97 consecutively enrolled patients with known or suspected pulmonary or gastroenteropancreatic neuroendocrine tumors. Safety and toxicity were measured by comparing vital signs, serum chemistry values, or acquisition-related medical complications before and after (68)Ga-DOTATATE injection. Added value was determined by changes in treatment plan when (68)Ga-DOTATATE PET/CT results were added to all prior imaging, including (111)In-pentetreotide. Interobserver reproducibility of (68)Ga-DOTATATE PET/CT scan interpretation was measured between blinded and nonblinded interpreters. RESULTS: (68)Ga-DOTATATE PET/CT and (111)In-pentetreotide scans were significantly different in impact on treatment (P < 0.001). (68)Ga-DOTATATE PET/CT combined with CT or liver MRI changed care in 28 of 78 (36%) patients. Interobserver agreement between blinded and nonblinded interpreters was high. No participant had a trial-related event requiring treatment. Mild, transient events were tachycardia in 1, alanine transaminase elevation in 1, and hyperglycemia in 2 participants. No clinically significant arrhythmias occurred. (68)Ga-DOTATATE PET/CT correctly identified 3 patients for peptide-receptor radiotherapy incorrectly classified by (111)In-pentetreotide. CONCLUSION: (68)Ga-DOTATATE PET/CT was equivalent or superior to (111)In pentetreotide imaging in all 78 patients. No adverse events requiring treatment were observed. (68)Ga-DOTATATE PET/CT changed treatment in 36% of participants. Given the lack of significant toxicity, lower radiation exposure, and improved accuracy compared with (111)In-pentetreotide, (68)Ga-DOTATATE imaging should be used instead of (111)In-pentetreotide imaging where available. PMID- 26769868 TI - You can't always get what you want. PMID- 26769867 TI - Evaluation of the Efficacy of Targeted Imaging Agents. AB - This paper presents our adaptation of Fryback and Thornbury's hierarchical scheme for modeling the efficacy of diagnostic imaging systems. The original scheme was designed to evaluate new medical imaging systems but is less successful when applied to evaluate new radiopharmaceuticals. The proposed adaptation, which is specifically directed toward evaluating targeted imaging agents, has 6 levels: in vitro characterization, in vivo animal studies, initial human studies, impact on clinical care (change in management), impact on patient outcome, and societal efficacy. These levels, particularly the first four, implicitly define the sequence of studies needed to move an agent from the radiochemistry synthesis laboratory to the clinic. Completion of level 4 (impact on clinical care) should be sufficient for initial approval and reimbursement. We hope that the adapted scheme will help streamline the process and assist in bringing new targeted radiopharmaceuticals to approval over the next few years. PMID- 26769869 TI - Family Medicine Research That Provides Compelling, Urgent Data to Improve Patient Care. AB - Herein is positive, mixed, and negative news-albeit all useful-on family medicine topics. The time to depression remission can be dramatically reduced. There is compelling evidence on how to improve medication reconciliation. There is a major underestimated determinant of the length of intrauterine device use. Data on the convoluted nature of the International Classification of Diseases, 10th Revision, transition could cause heart sink for doctors. Another article notes how family physicians can improve the usability of electronic health records by working with vendors. Targeting abstinence for patients with alcohol dependency and daily use may help. Charlson comorbidity scores plus a polypharmacy measure are useful to estimate readmission risk. This issue also includes excellent reviews on pre exposure prophylaxis for HIV prevention and breast milk oversupply. The Robert Graham Center provides data on the types of medical professionals working with family physicians in their offices. See the related commentary on page 4 by Rosenthal for a discussion on the patient-centered medical home articles also published in this issue. PMID- 26769870 TI - Are We Learning More about Patient-centered Medical Homes (PCMHs), or Learning More about Primary Care? PMID- 26769871 TI - The Diversity of Providers on the Family Medicine Team. AB - Family physicians are increasingly incorporating other health care providers into their practice teams to better meet the needs of increasingly complex and comorbid patients. While a majority of family physicians report working with a nurse practitioner, only 21% work with a behavioral health specialist. A better understanding of optimal team composition and function in primary care is essential to realizing the promise of a patient-centered medical home and achieving the triple aim. PMID- 26769872 TI - Time to Remission for Depression with Collaborative Care Management (CCM) in Primary Care. AB - BACKGROUND: Collaborative care management (CCM) has been shown to have superior outcomes to usual care (UC) for depressed patients with a fixed end point. This study was a survival analysis over time comparing CCM with UC using remission (9 item Patient Health Questionnaire [PHQ-9] score <5) and persistent depressive symptoms (PDSs; PHQ-9 score >=10) as end points. METHODS: A retrospective cohort study of 7340 patients with depression cared for at 4 outpatient primary care clinics was conducted from March 2008 through June 2013. All adult patients diagnosed with depression (International Classification of Diseases, 9th Revision [ICD-9], codes 296.2-3) or dysthymia (ICD-9 code 300.4) with an initial PHQ-9 score >=10 were included. CCM was implemented at all clinics between 2008 and 2010. Kaplan-Meyer survival curves for time to remission and PDSs were plotted. A Cox proportional hazards model was used to adjust for expected differences between patients choosing CCM versus UC. RESULTS: Median time to remission was 86 days (95% confidence interval [CI], 81-91 days) for the CCM group versus 614 days (95% CI, 565-692 days) for the UC group. Likewise, median duration of PDSs was 31 days (95% CI, 30-33 days) for the CCM group versus 154 days (95% CI, 138-182 days) for the UC group. In the Cox proportional hazards model, which controlled for covariates such as age, sex, race, diagnosis, and initial PHQ-9 score, CCM was associated with faster remission (hazard ratio of the CCM group [HRCCM], 2.48; 95% CI, 2.31-2.65). CONCLUSIONS: This study demonstrated that patients enrolled in CCM have a faster rate of remission and a shorter duration of PDSs than patients choosing UC. PMID- 26769874 TI - Patient or Clinician: Duration of Use of Intrauterine Devices Based on Who Initiated Discussion of Placement. AB - BACKGROUND: Although safe and effective, intrauterine devices (IUDs) are underutilized in the United States. The objective of this study was to determine whether patient- and clinician-initiated discussions were associated with the duration of Mirena (52 mg levonorgestrel-releasing) IUD use. METHODS: Retrospective chart review identified Mirena IUDs that were placed and removed for reasons other than the desire for pregnancy from January 1, 2005, to January 1, 2012, at 1 academic center (n = 148). Multivariable linear regression examined the independent association between duration of use and source of discussion initiation. RESULTS: IUDs placed after patient-initiated discussions were used for 473 days longer than those placed after clinician-initiated discussions (P < .001). CONCLUSION: Patient-initiated discussions of Mirena IUDs are associated with a significantly longer duration of use. Patient influences outside the clinical encounter may be important in optimizing use. PMID- 26769873 TI - Improving the Effectiveness of Medication Review: Guidance from the Health Literacy Universal Precautions Toolkit. AB - BACKGROUND: Although routine medication reviews in primary care practice are recommended to identify drug therapy problems, it is often difficult to get patients to bring all their medications to office visits. The objective of this study was to determine whether the medication review tool in the Agency for Healthcare Research and Quality Health Literacy Universal Precautions Toolkit can help to improve medication reviews in primary care practices. METHODS: The toolkit's "Brown Bag Medication Review" was implemented in a rural private practice in Missouri and an urban teaching practice in California. Practices recorded outcomes of medication reviews with 45 patients before toolkit implementation and then changed their medication review processes based on guidance in the toolkit. Six months later we conducted interviews with practice staff to identify changes made as a result of implementing the tool, and practices recorded outcomes of medication reviews with 41 additional patients. Data analyses compared differences in whether all medications were brought to visits, the number of medications reviewed, drug therapy problems identified, and changes in medication regimens before and after implementation. RESULTS: Interviews revealed that practices made the changes recommended in the toolkit to encourage patients to bring medications to office visits. Evaluation before and after implementation revealed a 3-fold increase in the percentage of patients who brought all their prescription medications and a 6-fold increase in the number of prescription medications brought to office visits. The percentage of reviews in which drug therapy problems were identified doubled, as did the percentage of medication regimens revised. CONCLUSIONS: Use of the Health Literacy Universal Precautions Toolkit can help to identify drug therapy problems. PMID- 26769875 TI - Simulation of ICD-9 to ICD-10-CM Transition for Family Medicine: Simple or Convoluted? AB - OBJECTIVE: The objective of this study was to examine the impact of the transition from International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM), to Interactional Classification of Diseases, 10th Revision, Clinical Modification (ICD-10-CM), on family medicine and to identify areas where additional training might be required. METHODS: Family medicine ICD-9 CM codes were obtained from an Illinois Medicaid data set (113,000 patient visits and $5.5 million in claims). Using the science of networks, we evaluated each ICD 9-CM code used by family medicine physicians to determine whether the transition was simple or convoluted. A simple transition is defined as 1 ICD-9-CM code mapping to 1 ICD-10-CM code, or 1 ICD-9-CM code mapping to multiple ICD-10-CM codes. A convoluted transition is where the transitions between coding systems is nonreciprocal and complex, with multiple codes for which definitions become intertwined. Three family medicine physicians evaluated the most frequently encountered complex mappings for clinical accuracy. RESULTS: Of the 1635 diagnosis codes used by family medicine physicians, 70% of the codes were categorized as simple, 27% of codes were convoluted, and 3% had no mapping. For the visits, 75%, 24%, and 1% corresponded with simple, convoluted, and no mapping, respectively. Payment for submitted claims was similarly aligned. Of the frequently encountered convoluted codes, 3 diagnosis codes were clinically incorrect, but they represent only <0.1% of the overall diagnosis codes. CONCLUSIONS: The transition to ICD-10-CM is simple for 70% or more of diagnosis codes, visits, and reimbursement for a family medicine physician. However, some frequently used codes for disease management are convoluted and incorrect, and for which additional resources need to be invested to ensure a successful transition to ICD-10-CM. PMID- 26769876 TI - Alcohol Use Disorder Treatment: The Association of Pretreatment Use and the Role of Drinking Goal. AB - BACKGROUND: In a recent study conducted in a family medicine setting, the medication acamprosate was found not to be efficacious in the treatment of alcohol dependence, but a drinking goal of abstinence was found to have positive effects on alcohol use outcomes. The purpose of this secondary analysis was to further understand which patients with an alcohol use disorder may be most successfully treated in a primary care setting. METHODS: The study was exploratory and used a trajectory-based approach based on data from the acamprosate treatment trial of 100 participants (recruited mostly by advertisement) who were randomly assigned to receive either acamprosate or a matching placebo. Post hoc trajectories of alcohol use before treatment were identified to examine whether trajectory classes and their interactions with treatment arm (acamprosate or placebo), pretreatment drinking goal (abstinence or a reduction), and time predicted alcohol use outcomes. RESULTS: Three distinct trajectory classes were identified: frequent drinkers, nearly daily drinkers, and consistent daily drinkers. Consistent daily drinkers with a goal of abstinence significantly improved over time on the primary outcome measure of percent days abstinent when compared with frequent and nearly daily drinkers. In addition, all participants with a goal of abstinence, regardless of trajectory class, significantly reduced their percentage of heavy drinking days over time. CONCLUSIONS: Patients with an alcohol use disorder who have a drinking goal of abstinence, in particular consistent daily drinkers, may maximally benefit from alcohol use disorder treatment, including the use of medication, in a primary care setting. PMID- 26769877 TI - Admission Data Predict High Hospital Readmission Risk. AB - PURPOSE: The purpose of this study was to identify data available at the time of hospital admission that predict readmission risk. METHODS: We performed a retrospective multiple regression analysis of 958 adult, nonpregnant patients admitted to the Family Medicine Service between June 2012 and October 2013. Data were abstracted from hospital administrative sources and electronic medical records. The outcome was 30-day hospital readmission. Candidate readmission predictors included polypharmacy (>=6 medicines), Charlson comorbidity index, age, sex, insurance status, emergency department use, smoking, nursing report of cognitive issues, patient report of social support or financial issues, and a history of heart failure, pneumonia, or chronic obstructive pulmonary disease. RESULTS: Patients at the Family Medicine Service had a 14% readmission risk. Bivariate analysis showed that high Charlson scores (>=5), polypharmacy, heart failure, pneumonia, or chronic obstructive pulmonary disease each increased readmission risk (P < .05). A logistic model showed an estimated odds ratio for readmission for high Charlson scores of 1.7 (95% confidence interval, 1.1-2.6) and of 2.1 for polypharmacy (95% confidence interval, 1.3-3.7). The model yielded a readmission risk estimate of 6% if neither a high Charlson score nor polypharmacy was present, 9% if only the Charlson score was high, 12% if only polypharmacy was present, and 19% if both were present. The receiver operating characteristics curve for the 2-factor model yielded an estimated area under the curve of 85%. Cross-validation supported this result. CONCLUSIONS: Polypharmacy and higher Charlson score at admission predict readmission risk as well as or better than published risk prediction models. The model could help to conserve limited resources and to target interventions for reducing readmission among the highest-risk patients. PMID- 26769878 TI - Effects of Patient-centered Medical Home Transformation on Child Patient Experience. AB - INTRODUCTION: Patient experience, 1 of 3 aims for improving health care, is rarely included in studies of patient-centered medical home (PCMH) transformation. This study examines the association between patient experience and National Committee on Quality Assurance (NCQA) PCMH transformation. METHODS: This was a cross-sectional study of parent-reported child patient experience from PCMH and non-PCMH practices. It used randomly sampled experience surveys completed by 2599 patients at 29 pediatric and family medicine PCMH (n = 21) and non-PCMH (n = 8) practices in Vermont from 2011 to 2013. Patient experiences related to child development and prevention were assessed using the Consumer Assessment of Health care Providers and Systems (CAHPS). RESULTS: A 10-point increase in NCQA score at PCMH practices is associated with a 3.1% higher CAHPS child prevention score (P = .004). Among pediatric practices, PCMH recognition is associated with 7.7% (P < .0005) and 7.2% (P < .0005) higher CAHPS child development and prevention composite scores, respectively. Among family medicine practices, PCMH recognition is associated with 7.4% (P = .001) and 11.0% (P < .0005) lower CAHPS child development and prevention composite scores, respectively. CONCLUSIONS: Our results suggest that PCMH recognition may improve child patient experience at pediatric practices and worsen experience at family medicine practices. These findings warrant further investigation into the differential influence of NCQA PCMH transformation on family medicine and pediatric practices. PMID- 26769879 TI - The Cost to Successfully Apply for Level 3 Medical Home Recognition. AB - BACKGROUND: The National Committee for Quality Assurance patient-centered medical home recognition program provides practices an opportunity to implement medical home activities. Understanding the costs to apply for recognition may enable practices to plan their work. METHODS: Practice coaches identified 5 exemplar practices (3 pediatric and 2 family medicine practices) that received level 3 recognition. This analysis focuses on 4 that received recognition in 2011. Clinical, informatics, and administrative staff participated in 2- to 3-hour interviews. We determined the time required to develop, implement, and maintain required activities. We categorized costs as (1) nonpersonnel, (2) developmental, (3) those used to implement activities, (4) those used to maintain activities, (5) those to document the work, and (6) consultant costs. Only incremental costs were included and are presented as costs per full-time equivalent (pFTE) provider. RESULTS: Practice size ranged from 2.5 to 10.5 pFTE providers, and payer mixes ranged from 7% to 43% Medicaid. There was variation in the distribution of costs by activity by practice, but the costs to apply were remarkably similar ($11,453-15,977 pFTE provider). CONCLUSION: The costs to apply for 2011 recognition were noteworthy. Work to enhance care coordination and close loops were highly valued. Financial incentives were key motivators. Future efforts to minimize the burden of low-value activities could benefit practices. PMID- 26769880 TI - Patient Navigators Connecting Patients to Community Resources to Improve Diabetes Outcomes. AB - BACKGROUND: Despite the recognized importance of lifestyle modification in reducing risk of developing type 2 diabetes and in diabetes management, the use of available community resources by both patients and their primary care providers (PCPs) remains low. The patient navigator model, widely used in cancer care, may have the potential to link PCPs and community resources for reduction of risk and control of type 2 diabetes. In this study we tested the feasibility and acceptability of telephone-based nonprofessional patient navigation to promote linkages between the PCP office and community programs for patients with or at risk for diabetes. METHODS: This was a mixed-methods interventional prospective cohort study conducted between November 2012 and August 2013. We included adult patients with and at risk for type 2 diabetes from six primary care practices. Patient-level measures of glycemic control, diabetes care, and self-efficacy from medical records, and qualitative interview data on acceptability and feasibility, were used. RESULTS: A total of 179 patients participated in the study. Two patient navigators provided services over the phone, using motivational interviewing techniques. Patient navigators provided regular feedback to PCPs and followed up with the patients through phone calls. The patient navigators made 1028 calls, with an average of 6 calls per patient. At follow-up, reduction in HbA1c (7.8 +/- 1.9% vs 7.2 +/- 1.3%; P = .001) and improvement in patient self-efficacy (3.1 +/- 0.8 vs 3.6 +/- 0.7; P < .001) were observed. Qualitative analysis revealed uniformly positive feedback from providers and patients. CONCLUSIONS: The patient navigator model is a promising and acceptable strategy to link patient, PCP, and community resources for promoting lifestyle modification in people living with or at risk for type 2 diabetes. PMID- 26769881 TI - Facilitators and Barriers to Care Coordination in Patient-centered Medical Homes (PCMHs) from Coordinators' Perspectives. AB - BACKGROUND: Care coordinators are increasingly featured in patient-centered medical home (PCMH) projects, yet little research examines how coordinators themselves define and experience their role. This is the first study describing experiences of care coordinators across the US from their own perspectives. METHODS: This qualitative study used a 5-month private, online discussion forum to gather data from 25 care coordinators from PCMH practices representing diversity in practice size, setting, and type. Participants answered questions and interacted with one another, creating an online social learning collaborative while allowing for data collection for research. RESULTS: Coordinators identified barriers and facilitators in their work at the organization/system level, the interpersonal level, and the individual level. Some factors emerged as both barriers and facilitators, including the functionality of clinical information technology; the availability of community resources; interactions with clinicians and other health care facilities; interactions with patients; and self-care practices for mental health and wellness. Colocation and full integration into practices were other key facilitators, whereas excessive case loads and data management responsibilities were felt to be important barriers. CONCLUSIONS: While all the barriers and facilitators were important to performing coordinators' roles, relationship building materialized as key to effective care coordination, whether with clinicians, patients, or outside organizations. We discuss implications for practice and provide suggestions for further research. PMID- 26769882 TI - Stakeholder Engagement in a Patient-Reported Outcomes (PRO) Measure Implementation: A Report from the SAFTINet Practice-based Research Network (PBRN). AB - PURPOSE: Patient-reported outcome (PRO) measures offer value for clinicians and researchers, although priorities and value propositions can conflict. PRO implementation in clinical practice may benefit from stakeholder engagement methods to align research and clinical practice stakeholder perspectives. The objective is to demonstrate the use of stakeholder engagement in PRO implementation. METHOD: Engaged stakeholders represented researchers and clinical practice representatives from the SAFTINet practice-based research network (PBRN). A stakeholder engagement process involving iterative analysis, deliberation, and decision making guided implementation of a medication adherence PRO measure (the Medication Adherence Survey [MAS]) for patients with hypertension and/or hyperlipidemia. RESULTS: Over 9 months, 40 of 45 practices (89%) implemented the MAS, collecting 3,247 surveys (mean = 72, median = 30, range: 0 - 416). Facilitators included: an electronic health record (EHR) with readily modifiable templates; existing staff, tools and workflows in which the MAS could be integrated (e.g., health risk appraisals, hypertension-specific visits, care coordinators); and engaged leadership and quality improvement teams. CONCLUSION: Stakeholder engagement appeared useful for promoting PRO measure implementation in clinical practice, in a way that met the needs of both researchers and clinical practice stakeholders. Limitations of this approach and opportunities for improving the PRO data collection infrastructure in PBRNs are discussed. PMID- 26769883 TI - Impact of Case Mix Severity on Quality Improvement in a Patient-centered Medical Home (PCMH) in the Maryland Multi-Payor Program. AB - BACKGROUND: We present data on quality of care (QC) improvement in 35 of 45 National Quality Forum metrics reported annually by 52 primary care practices recognized as patient-centered medical homes (PCMHs) that participated in the Maryland Multi-Payor Program from 2011 to 2013. METHODS: We assigned QC metrics to (1) chronic, (2) preventive, and (3) mental health care domains. The study used a panel data design with no control group. Using longitudinal fixed-effects regressions, we modeled QC and case mix severity in a PCMH. RESULTS: Overall, 35 of 45 quality metrics reported by 52 PCMHs demonstrated improvement over 3 years, and case mix severity did not affect the achievement of quality improvement. From 2011 to 2012, QC increased by 0.14 (P < .01) for chronic, 0.15 (P < .01) for preventive, and 0.34 (P < .01) for mental health care domains; from 2012 to 2013 these domains increased by 0.03 (P = .06), 0.04 (P = .05), and 0.07 (P = .12), respectively. In univariate analyses, lower National Commission on Quality Assurance PCMH level was associated with higher QC for the mental health care domain, whereas case mix severity did not correlate with QC. In multivariate analyses, higher QC correlated with larger practices, greater proportion of older patients, and readmission visits. Rural practices had higher proportions of Medicaid patients, lower QC, and higher QC improvement in interaction analyses with time. CONCLUSIONS: The gains in QC in the chronic disease domain, the preventive care domain, and, most significantly, the mental health care domain were observed over time regardless of patient case mix severity. QC improvement was generally not modified by practice characteristics, except for rurality. PMID- 26769884 TI - Strategies for Primary Care Stakeholders to Improve Electronic Health Records (EHRs). AB - The use of electronic health records (EHRs) and the vendors that develop them have increased exponentially in recent years. While there continues to emerge literature on the challenges EHRs have created related to primary care provider satisfaction and workflow, there is sparse literature on the perspective of the EHR vendors themselves. We examined the role of EHR vendors in optimizing primary care practice through a qualitative study of vendor leadership and developers representing 8 companies. We found that EHR vendors apply a range of strategies to elicit feedback from their clinical users and to engage selected users in their development and design process, but priorities are heavily influenced by the macroenvironment and government regulations. To improve the "marriage" between primary care and the EHR vendor community, we propose 6 strategies that may be most impactful for primary care stakeholders seeking to influence EHR development processes. PMID- 26769885 TI - Teamlets in Primary Care: Enhancing the Patient and Clinician Experience. AB - Many primary care practices have created a team structure in which a clinician and medical assistant "teamlet" form the core of a larger team. The larger team comprises a few teamlets supported by other clinical personnel. Patients are empaneled to a particular teamlet. The teamlet structure, which turns large practices into small units, is attractive to patients, most of whom prefer small rather than large practices. Clinicians working in stable teamlets, with the same medical assistant every day, have less burnout than clinicians working with different medical assistants on different days. The teamlet model can thus create positive experiences for clinicians and patients alike. PMID- 26769886 TI - Diagnosis and Management of Breast Milk Oversupply. AB - Managing breastfeeding problems is an essential part of newborn care. While much is written on breast milk undersupply, little is written on oversupply, sometimes known as hyperlactation or hypergalactia. Infants of mothers with oversupply may have increased or decreased weight gain. Some may have large, frothy stools. They may develop a disordered latch. Mothers may report overly full, leaking breasts. Thyroid function should be assessed. Treatment is mostly anecdotal and includes methods to maintain breast fullness, such as block feedings. Pseudoephedrine and oral contraceptive pills may decrease the supply. Dopamine agonists such as carbergoline can be used as a last resort. PMID- 26769887 TI - Preexposure Prophylaxis (PrEP) for HIV Prevention: The Primary Care Perspective. AB - Until recently there have been few primary care office-based strategies to reduce the transmission of HIV. In May 2014 the Centers for Disease Control and Prevention published updated practice guidelines recommending the use of preexposure prophylaxis (PrEP) with daily oral dosing of tenofovir/emtricitabine to help prevent HIV infection in high-risk individuals (strength of recommendation, A). Knowledge of PrEP among primary care providers is low, however, and this intervention is likely reaching only a small fraction of eligible patients. PrEP is recommended for certain injection drug users, nonmonogamous men who have sex with men, heterosexual women who have sex with men who have sex with men or injection drug users, and those in HIV serodiscordant relationships. Providers should obtain baseline laboratory values and provide initial counseling before prescribing PrEP. Regular office visits are necessary to ensure adherence, provide ongoing counseling, and monitor for side effects, including nausea, abdominal pain, headache, and, less commonly, increased creatinine. Guidelines and toolkits have been developed to assist in incorporating PrEP into primary care practice. PrEP is gaining widespread acceptance and has become a crucial tool in the fight to stop the spread of HIV. PMID- 26769888 TI - Translating New Lung Cancer Screening Guidelines into Practice: The Experience of One Community Hospital. AB - INTRODUCTION: In December 2013 the US Preventive Services Task Force issued a recommendation for lung cancer screening with annual low-dose computed tomography (LDCT). As screening guidelines emerge and change, this creates an environment for studying the translation of these guidelines into practice. This study assessed how these guidelines were implemented in a community hospital setting and the resulting radiologic findings. METHODS: This observational study examined the radiologic outcomes of LDCT lung cancer screening guidelines and the resulting notification. RESULTS: During the first year after publication of the guidelines, 94 screening LDCT scans were ordered. Of these, 21 (22.3%) did not meet the criteria outlined by the US Preventive Services Task Force. Among the 72 cases that did met published criteria, 65.3% of scans detected nodules, and among the remaining 35.6%, half had another clinically significant finding. DISCUSSION: This study shows that new lung cancer screening guidelines, as implemented at a community hospital, resulted in radiologic findings that required follow-up in more than half of patients. Clinicians must be aware of these potential incidental findings when talking to patients about the decision to order screenings. PMID- 26769889 TI - Stakeholders' Recommendations to Improve Patient-centered "LGBTQ" Primary Care in Rural and Multicultural Practices. AB - PURPOSE: Individuals among gender/sexual minorities share experiences of stigma and discrimination, yet have distinctive health care needs influenced by ethnic/racial minority and rural realities. METHODS: We collected qualitative data from lesbian/gay/bisexual/transgender (LGBT) and queer persons across the largely rural, multicultural state of New Mexico, particularly those from understudied ethnic groups, regarding factors facilitating or impeding patient centered primary care. The themes identified formed the basis for a statewide summit on LGBT health care guidelines and strategies for decreasing treatment gaps. RESULTS: Three to 15 individuals, ages 18 to 75 years, volunteered for 1 of 4 town hall dialogues (n = 32), and 175 people took part in the summit. Participants acknowledged health care gaps pertinent to LGBT youth, elders, American Indians, and Latinos/Latinas, expressing specific concern for rural residents. CONCLUSIONS: This preliminary research emphasizes the need to improve primary care practices that treat rural and ethnic-minority LGBT people and offers patient-driven recommendations to enhance care delivery while clinic-level transformations are implemented. PMID- 26769890 TI - Family Medicine: Bridge to Life. AB - Reflecting on the suicide of a close friend, this essay explores what comprises, and inspires a will to live, and how those in Family Medicine can address suicide risk even in the face of debilitating or terminal illness. Research indicates that the will to live is a measurable indicator of general well-being, distinct from depression, and an important predictor of a person's motivation to "hold on to life". As such, understanding what is at the heart of a desire to live should alter clinical practice. This essay offers ideas for ways in which to create bridges for patients that could help sustain life. PMID- 26769892 TI - Re: Clinical Decisions Made in Primary Care Clinics Before and After Choosing WiselyTM. PMID- 26769891 TI - Re: Reporting and Using Near-Miss Events to Improve Patient Safety in Diverse Primary Care Practices: A Collaborative Approach to Learning from Our Mistakes. PMID- 26769893 TI - Correction to "Novel Anticoagulants in Atrial Fibrillation: A Primer for the Primary Physician". PMID- 26769894 TI - Do active design buildings change health behaviour and workplace perceptions? AB - BACKGROUND: Occupying new, active design office buildings designed for health promotion and connectivity provides an opportunity to evaluate indoor environment effects on healthy behaviour, sedentariness and workplace perceptions. AIMS: To determine if moving to a health-promoting building changed workplace physical activity, sedentary behaviour, workplace perceptions and productivity. METHODS: Participants from four locations at the University of Sydney, Australia, relocated into a new active design building. After consent, participants completed an online questionnaire 2 months before moving and 2 months after. Questions related to health behaviours (physical activity and sitting time), musculoskeletal issues, perceptions of the office environment, productivity and engagement. RESULTS: There were 34 participants (60% aged 25-45, 78% female, 84% employed full-time); 21 participants provided complete data. Results showed that after the move participants spent less work time sitting (83-70%; P < 0.01) and more time standing (9-21%; P < 0.01), while walking time remained unchanged. Participants reported less low back pain (P < 0.01). Sixty per cent of participants in the new workplace were in an open-plan office, compared to 16% before moving. Participants perceived the new work environment as more stimulating, better lit and ventilated, but noisier and providing less storage. No difference was reported in daily physical activity, number of stairs climbed or productivity. CONCLUSIONS: Moving to an active design building appeared to have physical health-promoting effects on workers, but workers' perceptions about the new work environment varied. These results will inform future studies in other new buildings. PMID- 26769895 TI - A two-centre evaluation of RAPIDEC(r) CARBA NP for carbapenemase detection in Enterobacteriaceae, Pseudomonas aeruginosa and Acinetobacter spp. AB - OBJECTIVES: We evaluated the RAPIDEC((r)) CARBA NP assay (bioMerieux SA, Marcy l'Etoile, France), a colorimetric test for rapid detection of carbapenemases, at two sites: Karolinska University Laboratory and PHE's national reference laboratory. METHODS: A total of 138 bacterial isolates previously characterized as positive for class A, B and/or D carbapenemase genes and 138 supposed non carbapenemase producers were tested with RAPIDEC((r)) CARBA NP according to the manufacturer's protocol. Two carbapenemase-producing isolates carried both NDM and OXA-48-like genes. Molecular detection of the expected carbapenemase gene(s) was used as the gold standard, and was performed by conventional and real-time PCR in-house assays. RESULTS: The RAPIDEC((r)) CARBA NP assay detected 135 of 138 carbapenemase producers; one OXA-48-producing Klebsiella pneumoniae and two Acinetobacter baumannii producing OXA-23 or OXA-24 were not detected. Among 'negative' controls, 135 of 138 isolates were negative by RAPIDEC((r)) CARBA NP. The exceptions were one Klebsiella oxytoca, which was later found to produce GES 5 carbapenemase, one Pseudomonas aeruginosa with OprD loss and increased efflux, and one Enterobacter cloacae with impermeability. When numbers were adjusted for the GES-5 producer, the overall sensitivity of the RAPIDEC((r)) CARBA NP test was 97.8% and its specificity was 98.5%. CONCLUSIONS: The assay took less than 2.5 h to carry out, was user-friendly and had a high overall performance, making it an attractive option for clinical laboratories. PMID- 26769897 TI - Does cadmium exposure contribute to depressive symptoms in the elderly population? AB - BACKGROUND: To date, the association of the neurotoxic agent cadmium (Cd) with depression in elderly people has been poorly evaluated. By investigating the relationship between blood cadmium levels and scores on a depression screening test, we aimed to investigate the impact of cadmium exposure on elderly depression. METHODS: From 2008 to 2010, a total of 395 elderly participants residing in Seoul, Korea, were evaluated 3 times. Demographic data and lifestyle information were obtained via a systemised questionnaire, and blood samples were collected for analysis. Participants underwent the Korean Version of the Short Form Generic Depression Scale test (SGDS-K) for screening depression and associations were estimated using logistic regression models adjusted for potential confounders. RESULTS: Blood cadmium levels were associated with depressive symptoms in the first visit data analysis. By analysing the first visit data, the highest quartile blood cadmium group (Q4) showed increased risk for depressive symptoms compared to the lowest quartile group (Q1) (OR 3.50, 95% CI 1.22 to 10.00). However, the data of the second and third visits suggested that blood cadmium may be protective against depressive symptoms (second visit data, Q4 vs Q1, OR 0.78, 95% CI 0.19 to 3.14; third visit data, Q4 vs Q1, OR 0.58, 95% CI 0.04 to 8.77). CONCLUSIONS: Owing to inconsistent results in analyses between blood cadmium levels and depressive symptoms, we cannot conclude any solid association between blood cadmium levels and depressive symptoms in the elderly population. To clarify the relationship, other prospective studies are needed in the future. PMID- 26769896 TI - Phylogeny, resistome and mobile genetic elements of emergent OXA-48 and OXA-245 Klebsiella pneumoniae clones circulating in Spain. AB - OBJECTIVES: The global emergence of OXA-48-producing Klebsiella pneumoniae clones is a significant threat to public health. We used WGS and phylogenetic analysis of Spanish isolates to investigate the population structure of blaOXA-48-like expressing K. pneumoniae ST11 and ST405 and to determine the distribution of resistance genes and plasmids encoding blaOXA-48-like carbapenemases. METHODS: SNPs identified in whole-genome sequences were used to reconstruct phylogenetic trees, identify resistance determinants and de novo assemble the genomes of 105 blaOXA-48-like-expressing K. pneumoniae isolates. RESULTS: Genome variation was generally lower in outbreak-associated isolates compared with those associated with sporadic infections. The relatively limited variation observed within the outbreak-associated isolates was on average 7-10 SNPs per outbreak. Of 24 isolates from suspected sporadic infections, 7 were very closely related to isolates causing hospital outbreaks and 17 were more diverse and therefore probably true sporadic cases. On average, 14 resistance genes were identified per isolate. The 17 ST405 isolates from sporadic cases of infection had four distinct resistance gene profiles, while the resistance gene profile differed in all ST11 isolates from sporadic cases. Sequence analysis of 94 IncL/M plasmids carrying blaOXA-48-like genes revealed an average of two SNP differences, indicating a conserved plasmid clade. CONCLUSIONS: Whole-genome sequence analysis enabled the discrimination of outbreak and sporadic isolates. Significant inter-regional spread within Spain of highly related isolates was evident for both ST11 and ST405 K. pneumoniae. IncL/M plasmids carrying blaOXA-48-like carbapenemase genes were highly conserved geographically and across the outbreaks, sporadic cases and clones. PMID- 26769898 TI - Structural and functional dissection of Toxoplasma gondii armadillo repeats only protein. AB - Rhoptries are club-shaped, regulated secretory organelles that cluster at the apical pole of apicomplexan parasites. Their discharge is essential for invasion and the establishment of an intracellular lifestyle. Little is known about rhoptry biogenesis and recycling during parasite division. In Toxoplasma gondii, positioning of rhoptries involves the armadillo repeats only protein (ARO) and myosin F (MyoF). Here, we show that two ARO partners, ARO-interacting protein (AIP) and adenylate cyclase beta (ACbeta) localize to a rhoptry subcompartment. In absence of AIP, ACbeta disappears from the rhoptries. By assessing the contribution of each ARO armadillo (ARM) repeat, we provide evidence that ARO is multifunctional, participating not only in positioning but also in clustering of rhoptries. Structural analyses show that ARO resembles the myosin-binding domain of the Caenorhabditis elegans myosin chaperone UNC-45. A conserved patch of aromatic and acidic residues denotes the putative MyoF-binding site, and the overall arrangement of the ARM repeats explains the dramatic consequences of deleting each of them. Finally, Plasmodium falciparum ARO functionally complements ARO depletion and interacts with the same partners, highlighting the conservation of rhoptry biogenesis in Apicomplexa. PMID- 26769899 TI - Alpha-Dystrobrevin-1 recruits Grb2 and alpha-catulin to organize neurotransmitter receptors at the neuromuscular junction. AB - Neuromuscular junctions (NMJs), the synapses made by motor neurons on muscle fibers, form during embryonic development but undergo substantial remodeling postnatally. Several lines of evidence suggest that alpha-dystrobrevin, a component of the dystrophin-associated glycoprotein complex (DGC), is a crucial regulator of the remodeling process and that tyrosine phosphorylation of one isoform, alpha-dystrobrevin-1, is required for its function at synapses. We identified a functionally important phosphorylation site on alpha-dystrobrevin-1, generated phosphorylation-specific antibodies to it and used them to demonstrate dramatic increases in phosphorylation during the remodeling period, as well as in nerve-dependent regulation in adults. We then identified proteins that bind to this site in a phosphorylation-dependent manner and others that bind to alpha dystrobrevin-1 in a phosphorylation-independent manner. They include multiple members of the DGC, as well as alpha-catulin, liprin-alpha1, Usp9x, PI3K, Arhgef5 and Grb2. Finally, we show that two interactors, alpha-catulin (phosphorylation independent) and Grb2 (phosphorylation dependent) are localized to NMJs in vivo, and that they are required for proper organization of neurotransmitter receptors on myotubes. PMID- 26769901 TI - MBD3L2 promotes Tet2 enzymatic activity for mediating 5-methylcytosine oxidation. AB - Ten-eleven translocation (Tet) proteins are key players involved in the dynamic regulation of cytosine methylation and demethylation. Inactivating mutations of Tet2 are frequently found in human malignancies, highlighting the essential role of Tet2 in cellular transformation. However, the factors that control Tet enzymatic activity remain largely unknown. Here, we found that methyl-CpG-binding domain protein 3 (MBD3) and its homolog MBD3-like 2 (MBD3L2) can specifically modulate the enzymatic activity of Tet2 protein, but not Tet1 and Tet3 proteins, in converting 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC). Moreover, MBD3L2 is more effective than MBD3 in promoting Tet2 enzymatic activity through strengthening the binding affinity between Tet2 and the methylated DNA target. Further analysis revealed pronounced decreases in 5mC levels at MBD3L2 and Tet2 co-occupied genomic regions, most of which are promoter elements associated with either cancer-related genes or genes involved in the regulation of cellular metabolic processes. Our data add new insights into the regulation of Tet2 activity by MBD3 and MBD3L2, and into how that affects Tet2-mediated modulation of its target genes in cancer development. Thus, they have important applications in understanding how dysregulation of Tet2 might contribute to human malignancy. PMID- 26769902 TI - Dynamic distributions of long double-stranded RNA in Tetrahymena during nuclear development and genome rearrangements. AB - Bi-directional non-coding transcripts and their ~29-nt small RNA products are known to guide DNA deletion in Tetrahymena, leading to the removal of one-third of the genome from developing somatic nuclei. Using an antibody specific for long double-stranded RNAs (dsRNAs), we determined the dynamic subcellular distributions of these RNAs. Conjugation-specific dsRNAs were found and show sequential appearances in parental germline, parental somatic nuclei and finally in new somatic nuclei of progeny. The dsRNAs in germline nuclei and new somatic nuclei are likely transcribed from the sequences destined for deletion; however, the dsRNAs in parental somatic nuclei are unexpected, and PCR analyses suggested that they were transcribed in this nucleus. Deficiency in the RNA interference (RNAi) pathway led to abnormal aggregations of dsRNA in both the parental and new somatic nuclei, whereas accumulation of dsRNAs in the germline nuclei was only seen in the Dicer-like gene mutant. In addition, RNAi mutants displayed an early loss of dsRNAs from developing somatic nuclei. Thus, long dsRNAs are made in multiple nuclear compartments and some are linked to small RNA production whereas others might participate in their regulations. PMID- 26769900 TI - Hic-5 mediates the initiation of endothelial sprouting by regulating a key surface metalloproteinase. AB - During angiogenesis, endothelial cells must coordinate matrix proteolysis with migration. Here, we tested whether the focal adhesion scaffold protein Hic-5 (also known as TGFB1I1) regulated endothelial sprouting in three dimensions. Hic 5 silencing reduced endothelial sprouting and lumen formation, and sprouting defects were rescued by the return of Hic-5 expression. Pro-angiogenic factors enhanced colocalization and complex formation between membrane type-1 matrix metalloproteinase (MT1-MMP, also known as MMP14) and Hic-5, but not between paxillin and MT1-MMP. The LIM2 and LIM3 domains of Hic-5 were necessary and sufficient for Hic-5 to form a complex with MT1-MMP. The degree of interaction between MT1-MMP and Hic-5 and the localization of the complex within detergent resistant membrane fractions were enhanced during endothelial sprouting, and Hic 5 depletion lowered the surface levels of MT1-MMP. In addition, we observed that loss of Hic-5 partially reduced complex formation between MT1-MMP and focal adhesion kinase (FAK, also known as PTK2), suggesting that Hic-5 bridges MT1-MMP and FAK. Finally, Hic-5 LIM2-LIM3 deletion mutants reduced sprout initiation. Hic 5, MT1-MMP and FAK colocalized in angiogenic vessels during porcine pregnancy, supporting that this complex assembles during angiogenesis in vivo. Collectively, Hic-5 appears to enhance complex formation between MT1-MMP and FAK in activated endothelial cells, which likely coordinates matrix proteolysis and cell motility. PMID- 26769903 TI - A PHANTOM FOR DETERMINATION OF CALIBRATION COEFFICIENTS AND MINIMUM DETECTABLE ACTIVITIES USING A DUAL-HEAD GAMMA CAMERA FOR INTERNAL CONTAMINATION MONITORING FOLLOWING RADIATION EMERGENCY SITUATIONS. AB - The purpose of this study was to derive calibration coefficients (in terms of cps kBq(-1)) and minimum detectable activities, MDA, (in terms of kBq and corresponding dose rate) for the dual head gamma camera part of an SPECT/CT instrument when used for in vivo internal contamination measurements in radiation emergency situations. A cylindrical-conical PMMA phantom with diameters in the range of 7-30 cm was developed in order to simulate different body parts and individuals of different sizes. A series of planar gamma camera investigations were conducted using an SPECT/CT modality with the collimators removed for (131)I and (137)Cs, radionuclides potentially associated with radiation emergencies. Energy windows of 337-391 and 490-690 keV were selected for (131)I and (137)Cs, respectively. The measurements show that the calibration coefficients for (137)Cs range from 10 to 19 cps kBq(-1) with MDA values in the range of 0.29-0.55 kBq for phantom diameters of 10-30 cm. The corresponding values for (131)I are 12-37 cps kBq(-1) with MDA values of 0.08-0.26 kBq. An internal dosimetry computer program was used for the estimation of minimum detectable dose rates. A thyroid uptake of 0.1 kBq (131)I (representing MDA) corresponds to an effective dose rate of 0.6 uSv d(-1) A (137)Cs source position representing the colon with an MDA of 0.55 kBq corresponds to an effective dose rate was 1 uSv y(-1) This method using a simple phantom for the determination of calibration coefficients, and MDA levels can be implemented within the emergency preparedness plans in hospitals with nuclear medicine departments. The derived data will help to quickly estimate the internal contamination of humans following radiation emergencies. PMID- 26769904 TI - INFLUENCE OF THE IN-PLANE ARTEFACT IN CHEST TOMOSYNTHESIS ON PULMONARY NODULE SIZE MEASUREMENTS. AB - The aim of the present study was to investigate how the in-plane artefact present in the scan direction around structures in tomosynthesis images should be managed when measuring the size of nodules in chest tomosynthesis images in order to achieve acceptable measurement accuracy. Data from measurements, performed by radiologists, of the longest diameter of artificial nodules inserted in chest tomosynthesis images were used. The association between the measurement error and the direction of the longest nodule diameter, relative to the scan direction, was evaluated using the Kendall rank correlation coefficient. All of the radiologists had chosen to not include the artefact in the measurements. Significant association between measurement error and the direction of the longest diameter was found for nodules larger than 12 mm, which indicates that, for these nodules, there is a risk of underestimating the nodule size if the in-plane artefact is omitted from manual diameter measurements. PMID- 26769905 TI - ELECTRIC AND MAGNETIC FIELDS <100 KHZ IN ELECTRIC AND GASOLINE-POWERED VEHICLES. AB - Measurements were conducted to investigate electric and magnetic fields (EMFs) from 120 Hz to 10 kHz and 1.2 to 100 kHz in 9 electric or hybrid vehicles and 4 gasoline vehicles, all while being driven. The range of fields in the electric vehicles enclosed the range observed in the gasoline vehicles. Mean magnetic fields ranged from nominally 0.6 to 3.5 uT for electric/hybrids depending on the measurement band compared with nominally 0.4 to 0.6 uT for gasoline vehicles. Mean values of electric fields ranged from nominally 2 to 3 V m-1 for electric/hybrid vehicles depending on the band, compared with 0.9 to 3 V m-1 for gasoline vehicles. In all cases, the fields were well within published exposure limits for the general population. The measurements were performed with Narda model EHP-50C/EHP-50D EMF analysers that revealed the presence of spurious signals in the EHP-50C unit, which were resolved with the EHP-50D model. PMID- 26769906 TI - MANAGEMENT OF PATIENT DOSES FROM DIGITAL X-RAY CHEST SCREENING EXAMINATIONS. AB - An anthropomorphic phantom study was carried out in 2013-14 in two hospitals, one located in Russia (Mariinsky Hospital, Saint Petersburg) and the other in Sweden (Skane University Hospital, Malmo). The aim of the study was to investigate the possibilities to reduce the patient dose from digital X-ray chest screening examinations. The existing chest imaging protocols were adjusted by changing the tube voltage, total filtration and grid in order to determine the most dose effective combination of the examination parameters. It was possible to achieve up to 50 % dose-area product (DAP) and 30 % effective dose reduction by raising the tube voltage from 100 to 125 or 150 kV, and simultaneously decrease the total filtration to the minimum allowed by the X-ray unit (3 mm Al). The absence of a grid allowed to further reduce the DAP and effective dose by up to 80 %. Comparison between Russian and Swedish X-ray units showed the same trend in DAP and effective dose reduction, but the absolute dose values were lower by almost a factor of 10 for the Swedish units due to different image receptors and automatic exposure control settings. PMID- 26769907 TI - AN ASSESSMENT OF THE DOSE REDUCTION OF COMMERCIALLY AVAILABLE LEAD PROTECTIVE GLASSES FOR INTERVENTIONAL RADIOLOGY STAFF. AB - In light of the proposal from the International Commission on Radiological Protection for a lowered eye dose limit, now adopted by a European Union Council Directive, lead glasses may be required for some staff in interventional radiology to ensure that occupational exposure is as low as reasonably practicable. To investigate the lens protection offered from various models of lead glasses exposed to X-rays coming from a source to the left and below, calibrated radiochromic film was positioned in the lens area of a head phantom. When the source-to-eye angles were large, the dose reduction factors (the ratio of eye dose without protection to dose with protection) to the right lens area were much lower than to the left lens area, particularly with smaller-lensed glasses, due to gaps in protection between the face and the glasses. The results of this study reiterate the importance of employers providing eyewear based on the morphology of, and fit to, individual workers' faces. PMID- 26769908 TI - VGC ANALYZER: A SOFTWARE FOR STATISTICAL ANALYSIS OF FULLY CROSSED MULTIPLE READER MULTIPLE-CASE VISUAL GRADING CHARACTERISTICS STUDIES. AB - Visual grading characteristics (VGC) analysis is a non-parametric rank-invariant method for analysis of visual grading data. In VGC analysis, image quality ratings for two different conditions are compared by producing a VGC curve, similar to how the ratings for normal and abnormal cases in receiver operating characteristic (ROC) analysis are used to create an ROC curve. The use of established ROC software for the analysis of VGC data has therefore previously been proposed. However, the ROC analysis is based on the assumption of independence between normal and abnormal cases. In VGC analysis, this independence cannot always be assumed, e.g. if the ratings are based on the same patients imaged under both conditions. A dedicated software intended for analysis of VGC studies, which takes possible dependencies between ratings into account in the statistical analysis of a VGC study, has therefore been developed. The software-VGC Analyzer-determines the area under the VGC curve and its uncertainty using non-parametric resampling techniques. This article gives an introduction to VGC Analyzer, describes the types of analyses that can be performed and instructs the user about the input and output data. PMID- 26769909 TI - ASSESSMENT OF EFFECTIVE DOSE FROM CONE BEAM CT IMAGING IN SPECT/CT EXAMINATION IN COMPARISON WITH OTHER MODALITIES. AB - The aim of this study was to assess radiation dose from the cone beam computed tomography (CBCT) component of single photon emission tomography/computed tomography (SPECT/CT) examinations and to compare it with the radiopharmaceutical related dose as well as dose from multidetector computed tomography (MDCT). Effective dose (ED) from computed tomography (CT) was estimated using dose-length product values and anatomy-specific conversion factors. The contribution from the SPECT component was evaluated using ED per unit administered activity for the radiopharmaceuticals listed in the International Commission on Radiological Protection Publications 80 and 106. With the exception of cardiac studies (0.11 mSv), the CBCT dose (3.96-6.04 mSv) was similar to that from the radiopharmaceutical accounting for 29-56 % of the total ED from the examination. In comparison with MDCT examinations, the CBCT dose was 48 and 42 % lower for abdomen/pelvis and chest/abdomen/pelvis scans, respectively, while in the chest the CBCT scan resulted in higher dose (23 %). Radiation dose from the CT component should be taken into consideration when evaluating total SPECT/CT patient dose. PMID- 26769911 TI - Computers in the clinical encounter: a scoping review and thematic analysis. AB - OBJECTIVE: Patient-clinician communication has been associated with increased patient satisfaction, trust in the clinician, adherence to prescribed therapy, and various health outcomes. The impact of health information technology (HIT) on the clinical encounter in general and patient-clinician communication in particular is a growing concern. The purpose of this study was to review the current literature on HIT use during the clinical encounter to update best practices and inform the continuous development of HIT policies and educational interventions. METHODS: We conducted a literature search of four databases. After removing duplicates, reviewing titles and abstracts, performing a full-text review, and snowballing from references and citations, 51 articles were included in the analysis. We employed a qualitative thematic analysis to compare and contrast the findings across studies. RESULTS: Our analysis revealed that the use of HIT affects consultations in complex ways, impacting eye contact and gaze, information sharing, building relationships, and pauses in the conversation. Whether these impacts are positive or negative largely depends on the combination of consultation room layout, patient and clinician styles of interaction with HIT as well as each other, and the strategies and techniques employed by clinicians to integrate HIT into consultations. DISCUSSION: The in-depth insights into the impact of HIT on the clinical encounter, especially the strategies and techniques employed by clinicians to adapt to using HIT in consultations, can inform policies, educational interventions, and research. CONCLUSION: In contrast to the common negative views of HIT, it affects the clinical encounter in multiple ways. By applying identified strategies and best practices, HIT can support patient clinician interactions rather than interfering with them. PMID- 26769910 TI - Structured scaffolding for reflection and problem solving in diabetes self management: qualitative study of mobile diabetes detective. AB - OBJECTIVE: To investigate subjective experiences and patterns of engagement with a novel electronic tool for facilitating reflection and problem solving for individuals with type 2 diabetes, Mobile Diabetes Detective (MoDD). METHODS: In this qualitative study, researchers conducted semi-structured interviews with individuals from economically disadvantaged communities and ethnic minorities who are participating in a randomized controlled trial of MoDD. The transcripts of the interviews were analyzed using inductive thematic analysis; usage logs were analyzed to determine how actively the study participants used MoDD. RESULTS: Fifteen participants in the MoDD randomized controlled trial were recruited for the qualitative interviews. Usage log analysis showed that, on average, during the 4 weeks of the study, the study participants logged into MoDD twice per week, reported 120 blood glucose readings, and set two behavioral goals. The qualitative interviews suggested that individuals used MoDD to follow the steps of the problem-solving process, from identifying problematic blood glucose patterns, to exploring behavioral triggers contributing to these patterns, to selecting alternative behaviors, to implementing these behaviors while monitoring for improvements in glycemic control. DISCUSSION: This qualitative study suggested that informatics interventions for reflection and problem solving can provide structured scaffolding for facilitating these processes by guiding users through the different steps of the problem-solving process and by providing them with context-sensitive evidence and practice-based knowledge related to diabetes self-management on each of those steps. CONCLUSION: This qualitative study suggested that MoDD was perceived as a useful tool in engaging individuals in self-monitoring, reflection, and problem solving. PMID- 26769912 TI - Endogenous GLP1 and GLP1 analogue alter CNS responses to palatable food consumption. AB - Glucagon-like peptide-1 (GLP1) affects appetite, supposedly mediated via the central nervous system (CNS). In this study, we investigate whether modulation of CNS responses to palatable food consumption may be a mechanism by which GLP1 contributes to the central regulation of feeding. Using functional MRI, we determined the effects of endogenous GLP1 and treatment with the GLP1 analogue liraglutide on CNS activation to chocolate milk receipt. Study 1 included 20 healthy lean individuals and 20 obese patients with type 2 diabetes (T2DM). Scans were performed on two occasions: during infusion of the GLP1 receptor antagonist exendin 9-39 (blocking actions of endogenous GLP1) and during placebo infusion. Study 2 was a randomised, cross-over intervention study carried out in 20 T2DM patients, comparing treatment with liraglutide to insulin, after 10 days and 12 weeks. Compared with lean individuals, T2DM patients showed reduced activation to chocolate milk in right insula (P = 0.04). In lean individuals, blockade of endogenous GLP1 effects inhibited activation in bilateral insula (P <= 0.03). Treatment in T2DM with liraglutide, vs insulin, increased activation to chocolate milk in right insula and caudate nucleus after 10 days (P <= 0.03); however, these effects ceased to be significant after 12 weeks. Our findings in healthy lean individuals indicate that endogenous GLP1 is involved in the central regulation of feeding by affecting central responsiveness to palatable food consumption. In obese T2DM, treatment with liraglutide may improve the observed deficit in responsiveness to palatable food, which may contribute to the induction of weight loss observed during treatment. However, no long-term effects of liraglutide were observed. PMID- 26769914 TI - New Beginnings. PMID- 26769915 TI - Social Structural Influences on Healthy Aging: Community-Level Socioeconomic Conditions and Survival Probability of Becoming a Centenarian for Those Aged 65 to 69 in South Korea. AB - This study estimated the associations between community-level socioeconomic conditions and survival probability of becoming a centenarian (SPBC) for those aged 65 to 69 in South Korea to determine the social structural influences on healthy aging. The indicators of socioeconomic and data of centenarians were obtained from Statistics Korea database 2014: population census and social survey. Significant positive correlations were found between SPBC and community level socioeconomic conditions (minimum cost of living and economically active population, water supply and sewerage, pave a road with asphalt, and urbanization). SPBC male and female predictors had higher economic level and base facilities (R2)=0.578, p<.001). The study provides evidence that community-level socioeconomic conditions are important correlates of SPBC for those aged 65 to 69 in South Korea. These strategies should include social structural influences on successful aging in the overall socioeconomic conditions. PMID- 26769916 TI - Involvement of Extracellular Signal-Regulated Kinase 5 in Kinin B1 Receptor Upregulation in Isolated Human Umbilical Veins. AB - The upregulated kinin B1 receptors exert a pivotal role in modulating inflammatory processes. In isolated human umbilical veins (HUVs), kinin B1 receptor is upregulated as a function of in vitro incubation time and proinflammatory stimuli. The aim of this study was to evaluate, using functional and biochemical methods, the involvement of extracellular signal-regulated kinase 5 (ERK5), p38 mitogen-activated protein kinase (MAPK), c-Jun N-terminal kinase (JNK), and extracellular signal-regulated kinase 1/2 (ERK1/2) on the kinin B1 receptor upregulation process in HUV. Real-time polymerase chain reaction analysis revealed for the first time that kinin B1 receptor mRNA expression closely parallels the functional sensitization to kinin B1 receptor selective agonist des-Arg(10)-kallidin (DAKD) in HUV. Moreover, the selective inhibition of ERK5, p38 MAPK, and JNK, but not ERK1/2, produced a dose-dependent rightward shift of the concentration-response curves to DAKD after 5-hour incubation and a reduction in kinin B1 receptor mRNA expression. Biochemical analyses showed that ERK5, p38 MAPK, and JNK phosphorylation is maximal during the first 2 hours postisolation, followed by a significant reduction in the last 3 hours. None of the treatments modified the responses to serotonin, an unrelated agonist, suggesting a specific effect on kinin B1 receptor upregulation. The present work provides for the first time pharmacologic evidence indicating that ERK5 plays a significant role on kinin B1 receptor upregulation. Furthermore, we confirm the relevance of p38 MAPK and JNK as well as the lack of effect of ERK1/2 in this process. This study may contribute to a better understanding of MAPK involvement in inflammatory and immunologic diseases. PMID- 26769913 TI - Androgen receptor (AR) in cardiovascular diseases. AB - Cardiovascular diseases (CVDs) are still the highest leading cause of death worldwide. Several risk factors have been linked to CVDs, including smoking, diabetes, hyperlipidemia, and gender among others. Sex hormones, especially the androgen and its receptor, androgen receptor (AR), have been linked to many diseases with a clear gender difference. Here, we summarize the effects of androgen/AR on CVDs, including hypertension, stroke, atherosclerosis, abdominal aortic aneurysm (AAA), myocardial hypertrophy, and heart failure, as well as the metabolic syndrome/diabetes and their impacts on CVDs. Androgen/AR signaling exacerbates hypertension, and anti-androgens may suppress hypertension. Androgen/AR signaling plays dual roles in strokes, depending on different kinds of factors; however, generally males have a higher incidence of strokes than females. Androgen and AR differentially modulate atherosclerosis. Androgen deficiency causes elevated lipid accumulation to enhance atherosclerosis; however, targeting AR in selective cells without altering serum androgen levels would suppress atherosclerosis progression. Androgen/AR signaling is crucial in AAA development and progression, and targeting androgen/AR profoundly restricts AAA progression. Men have increased cardiac hypertrophy compared with age-matched women that may be due to androgens. Finally, androgen/AR plays important roles in contributing to obesity and insulin/leptin resistance to increase the metabolic syndrome. PMID- 26769917 TI - Stereoselective Effects of Abused "Bath Salt" Constituent 3,4 Methylenedioxypyrovalerone in Mice: Drug Discrimination, Locomotor Activity, and Thermoregulation. AB - 3,4-Methylenedioxypyrovalerone (MDPV) is a common constituent of illicit "bath salts" products. MDPV is a chiral molecule, but the contribution of each enantiomer to in vivo effects in mice has not been determined. To address this, mice were trained to discriminate 10 mg/kg cocaine from saline, and substitutions with racemic MDPV, S(+)-MDPV, and R(-)-MDPV were performed. Other mice were implanted with telemetry probes to monitor core temperature and locomotor responses elicited by racemic MDPV, S(+)-MDPV, and R(-)-MDPV under a warm (28 degrees C) or cool (20 degrees C) ambient temperature. Mice reliably discriminated the cocaine training dose from saline, and each form of MDPV fully substituted for cocaine, although marked potency differences were observed such that S(+)-MDPV was most potent, racemic MDPV was less potent than the S(+) enantiomer, and R(-)-MDPV was least potent. At both ambient temperatures, locomotor stimulant effects were observed after doses of S(+)-MDPV and racemic MDPV, but R(-)-MDPV did not elicit locomotor stimulant effects at any tested dose. Interestingly, significant increases in maximum core body temperature were only observed after administration of racemic MDPV in the warm ambient environment; neither MDPV enantiomer altered core temperature at any dose tested, at either ambient temperature. These studies suggest that all three forms of MDPV induce biologic effects, but R(-)-MDPV is less potent than S(+)-MDPV and racemic MDPV. Taken together, these data suggest that the S(+)-MDPV enantiomer is likely responsible for the majority of the biologic effects of the racemate and should be targeted in therapeutic efforts against MDPV overdose and abuse. PMID- 26769918 TI - An Important Role for N-Acylethanolamine Acid Amidase in the Complete Freund's Adjuvant Rat Model of Arthritis. AB - The endogenous lipid amides, palmitoylethanolamide (PEA) and oleoylethanolamide (OEA), exert marked antinociceptive and anti-inflammatory effects in animal models by engaging nuclear peroxisome proliferator-activated receptor-alpha. PEA and OEA are produced by macrophages and other host-defense cells and are deactivated by the cysteine amidase, N-acylethanolamine acid amidase (NAAA), which is highly expressed in macrophages and B-lymphocytes. In the present study, we examined whether a) NAAA might be involved in the inflammatory reaction triggered by injection of complete Freund's adjuvant (CFA) into the rat paw and b) administration of 4-cyclohexylbutyl-N-[(S)-2-oxoazetidin-3-yl]-carbamate (ARN726), a novel systemically active NAAA inhibitor, attenuates such reaction. Injection of CFA into the paw produced local edema and heat hyperalgesia, which were accompanied by decreased PEA and OEA content (assessed by liquid chromatography/mass spectrometry) and increased NAAA levels (assessed by Western blot and ex vivo enzyme activity measurements) in paw tissue. Administration of undec-10-ynyl-N-[(3S)-2-oxoazetidin-3-yl] carbamate (ARN14686), a NAAA-preferring activity-based probe, revealed that NAAA was catalytically active in CFA-treated paws. Administration of ARN726 reduced NAAA activity and restored PEA and OEA levels in inflamed tissues, and significantly decreased CFA-induced inflammatory symptoms, including pus production and myeloperoxidase activity. The results confirm the usefulness of ARN726 as a probe to investigate the functions of NAAA in health and disease and suggest that this enzyme may provide a new molecular target for the treatment of arthritis. PMID- 26769920 TI - Toxicological Differences Between NMDA Receptor Antagonists and Cholinesterase Inhibitors. AB - Cholinesterase inhibitors (ChEIs), represented by donepezil, rivastigmine, and galantamine, used to be the only approved class of drugs for the treatment of Alzheimer's disease. After the approval of memantine by the Food and Drug Administration (FDA), N-methyl-d-aspartic acid (NMDA) receptor antagonists have been recognized by authorities and broadly used in the treatment of Alzheimer's disease. Along with complementary mechanisms of action, NMDA antagonists and ChEIs differ not only in therapeutic effects but also in adverse reactions, which is an important consideration in clinical drug use. And the number of patients using NMDA antagonists and ChEIs concomitantly has increased, making the matter more complicated. Here we used the FDA Adverse Event Reporting System for statistical analysis , in order to compare the adverse events of memantine and ChEIs. In general, the clinical evidence confirmed the safety advantages of memantine over ChEIs, reiterating the precautions of clinical drug use and the future direction of antidementia drug development. PMID- 26769921 TI - Draft Genome Sequence of an Enterobacter Species Associated with Illnesses and Powdered Infant Formula. AB - This is the first report of the draft genome sequence of an Enterobacter species that may have been transmitted from powdered infant formula (PIF) to infants, resulting in illness. Enterobacter spp. are currently permitted in PIF, but the transmission of this strain indicates that the microbiological criteria for PIF may need revision. PMID- 26769919 TI - 2-Substituted 3beta-Aryltropane Cocaine Analogs Produce Atypical Effects without Inducing Inward-Facing Dopamine Transporter Conformations. AB - Previous structure-activity relationship studies indicate that a series of cocaine analogs, 3beta-aryltropanes with 2beta-diarylmethoxy substituents, selectively bind to the dopamine transporter (DAT) with nanomolar affinities that are 10-fold greater than the affinities of their corresponding 2alpha enantiomers. The present study compared these compounds to cocaine with respect to locomotor effects in mice, and assessed their ability to substitute for cocaine (10 mg/kg, i.p.) in rats trained to discriminate cocaine from saline. Despite nanomolar DAT affinity, only the 2beta-Ph2COCH2-3beta-4-Cl-Ph analog fully substituted for cocaine-like discriminative effects. Whereas all of the 2beta compounds increased locomotion, only the 2beta-(4-ClPh)PhCOCH2-3beta-4-Cl Ph analog had cocaine-like efficacy. None of the 2alpha-substituted compounds produced either of these cocaine-like effects. To explore the molecular mechanisms of these drugs, their effects on DAT conformation were probed using a cysteine-accessibility assay. Previous reports indicate that cocaine binds with substantially higher affinity to the DAT in its outward (extracellular)- compared with inward-facing conformation, whereas atypical DAT inhibitors, such as benztropine, have greater similarity in affinity to these conformations, and this is postulated to explain their divergent behavioral effects. All of the 2beta- and 2alpha-substituted compounds tested altered cysteine accessibility of DAT in a manner similar to cocaine. Furthermore, molecular dynamics of in silico inhibitor-DAT complexes suggested that the 2-substituted compounds reach equilibrium in the binding pocket in a cocaine-like fashion. These behavioral, biochemical, and computational results show that aryltropane analogs can bind to the DAT and stabilize outward-facing DAT conformations like cocaine, yet produce effects that differ from those of cocaine. PMID- 26769922 TI - Genome Sequence of Listeria monocytogenes Strain F6540 (Sequence Type 360) Collected from Food Samples in Ontario, Canada. AB - Comparative genomic analysis between pathogenic and nonpathogenic Listeria monocytogenes strains provides a good model for studying the virulence of this organism. Here, we report the genome sequence of the nonpathogenic L. monocytogenes strain F6540 (sequence type 360) identified specifically in food samples in Ontario, Canada, in 2010. PMID- 26769923 TI - Genome Sequence of a Typical Ultramicrobacterium, Curvibacter sp. Strain PAE-UM, Capable of Phthalate Ester Degradation. AB - Curvibacter sp. strain PAE-UM, isolated from river sediment, is a typical ultramicrobacterium capable of phthalate ester degradation. The genome of Curvibacter sp. PAE-UM consists of 3,284,473 bp, and its information will provide insights into the molecular mechanisms underlying its degradation ability. PMID- 26769925 TI - Draft Genome Sequence of Lactobacillus farciminis NBRC 111452, Isolated from Koso, a Japanese Sugar-Vegetable Fermented Beverage. AB - Here, we report the draft genome sequence of the Lactobacillus farciminis strain NBRC 111452, isolated from koso, a Japanese sugar-vegetable fermented beverage. This genome information is of potential use in studies of Lactobacillus farciminis as a probiotic. PMID- 26769924 TI - Complete Genome Sequence of Helicobacter pylori Strain 29CaP Isolated from a Mexican Patient with Gastric Cancer. AB - Helicobacter pylori infection is a risk factor for the development of gastric cancer and other gastroduodenal diseases. We report here the complete genome sequence of H. pylori strain 29CaP, isolated from a Mexican patient with gastric cancer. The genomic data analysis revealed a cag-negative H. pylori strain that contains a prophage sequence. PMID- 26769926 TI - Complete Genome and Plasmid Sequences of Three Canadian Isolates of Salmonella enterica subsp. enterica Serovar Heidelberg from Human and Food Sources. AB - Isolates of Salmonella enterica subsp. enterica serovar Heidelberg are often associated with poultry products and may cause severe human illness. Here, we report the fully assembled genome and plasmid sequences of three S. Heidelberg strains with phage types 9, 29, and 41. PMID- 26769927 TI - Draft Genome Sequences of Achromobacter piechaudii GCS2, Agrobacterium sp. Strain SUL3, Microbacterium sp. Strain GCS4, Shinella sp. Strain GWS1, and Shinella sp. Strain SUS2 Isolated from Consortium with the Hydrocarbon-Producing Alga Botryococcus braunii. AB - A variety of bacteria associate with the hydrocarbon-producing microalga Botryococcus braunii, some of which may influence its growth. We report here the genome sequences for Achromobacter piechaudii GCS2, Agrobacterium sp. strain SUL3, Microbacterium sp. strain GCS4, and Shinella sp. strains GWS1 and SUS2, isolated from a laboratory culture of B. braunii, race B, strain Guadeloupe. PMID- 26769928 TI - Complete Genome Sequence of Enterococcus faecalis Strain P8-1 Isolated from Wild Magellanic Penguin (Spheniscus magellanicus) Feces on the South Coast of Brazil. AB - Enterococcus faecalis strains have a ubiquitous nature that allows them to survive in different niches. Studies involving enterococci isolated from marine animals are scarce. Therefore, in this study, we report the complete genome sequence of E. faecalis strain P8-1 isolated from feces of a Magellanic penguin on the south coast of Brazil. PMID- 26769929 TI - Complete Genome Sequence of the Hyperthermophilic and Piezophilic Archaeon Thermococcus barophilus Ch5, Capable of Growth at the Expense of Hydrogenogenesis from Carbon Monoxide and Formate. AB - We report here the complete sequence and fully manually curated annotation of the genome of strain Ch5, a new member of the piezophilic hyperthermophilic species Thermococcus barophilus. PMID- 26769930 TI - Draft Genome Sequence of Actinobaculum massiliense Strain FC3. AB - Actinobaculum massiliense strain FC3 was isolated from the urine of a patient with acute cystitis. The 2.06-Mb genome of strain FC3 contains 17 toxin/antitoxin modules and 9 bacteriocin-encoding genes that may play a role in virulence. The genome also exhibits 693 genes acquired by lateral gene transfer. PMID- 26769931 TI - Draft Genome Sequence of a Novel Desulfobacteraceae Member from a Sulfate Reducing Bioreactor Metagenome. AB - Sulfate-reducing bacteria are important players in the global sulfur cycle and of considerable commercial interest. The draft genome sequence of a sulfate-reducing bacterium of the family Desulfobacteraceae, assembled from a sulfate-reducing bioreactor metagenome, indicates that heavy-metal- and acid-resistance traits of this organism may be of importance for its application in acid mine drainage mitigation. PMID- 26769932 TI - Genome Sequence of Nitrosomonas communis Strain Nm2, a Mesophilic Ammonia Oxidizing Bacterium Isolated from Mediterranean Soil. AB - The complete genome sequence of Nitrosomonas communis strain Nm2, a mesophilic betaproteobacterial ammonia oxidizer isolated from Mediterranean soils in Corfu, Greece, is reported here. This is the first genome to describe a cluster 8 Nitrosomonas species and represents an ammonia-oxidizing bacterium commonly found in terrestrial ecosystems. PMID- 26769933 TI - Complete Genome Sequence of Human Respiratory Syncytial Virus Isolated in Mexico. AB - Human respiratory syncytial virus (HRSV) is a member of the Paramyxoviridae family, which causes lower respiratory tract infections in neonates and children younger than 5 years. Here, we report the complete genome sequence of HRSV, isolated from a nasopharyngeal swab of a pregnant woman with cardiac complications. PMID- 26769934 TI - Draft Genome Sequence of the Oral Commensal Streptococcus oralis 89a with Interference Activity against Respiratory Pathogens. AB - We report the draft genome sequence of the oral commensal Streptococcus oralis 89a isolated from the throat of a healthy child during a streptococcal tonsillitis outbreak in Umea, Sweden. S. oralis 89a was known to have interference activity against respiratory pathogens in which the colicin V was the potential bacteriocin-encoding gene. PMID- 26769935 TI - Whole-Genome Sequence of a Beijing Extensively Drug-Resistant Mycobacterium tuberculosis Clinical Isolate from Buenaventura, Colombia. AB - Extensively drug-resistant Mycobacterium tuberculosis (XDR-TB) has been reported to the WHO by 100 countries, including Colombia. An estimated 9.0% of people with multidrug-resistant TB have XDR-TB. We report the genome sequence of a Beijing XDR-TB clinical isolate from Buenaventura, Colombia. The genome sequence is composed of 4,298,162 bp with 4,359 genes. PMID- 26769936 TI - Complete Genome Sequence of Klebsiella pneumoniae subsp. pneumoniae KP617, Coproducing OXA-232 and NDM-1 Carbapenemases, Isolated in South Korea. AB - The prevalence of Klebsiella pneumoniae coproducing carbapenemase metallo-beta lactamase 1 (NDM-1) and OXA-48 has been increasing globally since 2013. The complete genome of KP617 was sequenced and assembled into a circular chromosome and two plasmids. This sequence provides the genetic background for understanding the evolution of carbapenemase genes in K. pneumoniae KP617. PMID- 26769937 TI - De Novo Assembly of Candida sojae and Candida boidinii Genomes, Unexplored Xylose Consuming Yeasts with Potential for Renewable Biochemical Production. AB - Candida boidinii and Candida sojae yeasts were isolated from energy cane bagasse and plague-insects. Both have fast xylose uptake rate and produce great amounts of xylitol, which are interesting features for food and 2G ethanol industries. Because they lack published genomes, we have sequenced and assembled them, offering new possibilities for gene prospection. PMID- 26769938 TI - Draft Genome Sequence of a Selenite- and Tellurite-Reducing Marine Bacterium, Lysinibacillus sp. Strain ZYM-1. AB - Lysinibacillus sp. ZYM-1, a Gram-positive strain isolated from marine sediments, reduces selenite and tellurite efficiently. Meanwhile, it also exhibits high resistance to Zn2+ and Mn2+. Here, we report the draft genome sequence of strain ZYM-1, which contains genes related to selenite and tellurite reduction and also metal resistance. PMID- 26769939 TI - Draft Genome Sequence of Alternaria alternata ATCC 34957. AB - We report the draft genome sequence of Alternaria alternata ATCC 34957. This strain was previously reported to produce alternariol and alternariol monomethyl ether on weathered grain sorghum. The genome was sequenced with PacBio technology and assembled into 27 scaffolds with a total genome size of 33.5 Mb. PMID- 26769940 TI - Draft Genome Sequence of Algoriphagus sp. Strain NH1, a Multidrug-Resistant Bacterium Isolated from Coastal Sediments of the Northern Yellow Sea in China. AB - Algoriphagus sp. NH1 is a multidrug-resistant bacterium isolated from coastal sediments of the northern Yellow Sea in China. Here, we report the draft genome sequence of NH1, with a size of 6,131,579 bp, average G+C content of 42.68%, and 5,746 predicted protein-coding sequences. PMID- 26769941 TI - Draft Genome Sequence of Altererythrobacter troitsensis JCM 17037, Isolated from the Sea Urchin Strongylocentrotus intermedius. AB - The habitats of the genus Altererythrobacter are various, including marine sediment, seawater, rhizosphere of wild rice, desert sand, etc. The genome of the type strain of Altererythrobacter troitsensis JCM 17037, isolated from sea urchin, was sequenced. This study would not only facilitate the understanding of the physiology, adaptation, and evolution of the Altererythrobacter species, but also provide a good resource for the study of synthesis of astaxanthin, since several enzymes involved in the production of astaxanthin were predicted. PMID- 26769942 TI - Draft Genome Sequences of Two Novel Acidimicrobiaceae Members from an Acid Mine Drainage Biofilm Metagenome. AB - Bacteria belonging to the family Acidimicrobiaceae are frequently encountered in heavy metal-contaminated acidic environments. However, their phylogenetic and metabolic diversity is poorly resolved. We present draft genome sequences of two novel and phylogenetically distinct Acidimicrobiaceae members assembled from an acid mine drainage biofilm metagenome. PMID- 26769943 TI - Genome Sequences of Rotavirus A Strains Ty-1 and Ty-3, Isolated from Turkeys in Ireland in 1979. AB - To obtain complete genome sequences of turkey rotavirus A strains Ty-1 and Ty-3, we sequenced the gene segments that had not been decoded previously. The genotype constellations of the respective strains were determined to be G17-P[38]-I4-R4-C4 M4-A16-N4-T4-E4-H4 and G7-P[35]-I4-R4-C4-M4-A16-N4-T4-E11-H14. Notably, their VP4 and NSP5 genes were classified into novel genotypes. PMID- 26769944 TI - Draft Genome Sequence of Streptococcus orisasini SH06, Isolated from a Healthy Thoroughbred Gastrointestinal Tract. AB - Streptococcus orisasini SH06 was isolated from a healthy thoroughbred gastrointestinal tract. Here, we report the draft genome sequence of this organism. This paper is the first published report of the genomic sequence of S. orisasini. PMID- 26769945 TI - Draft Genome Sequence of the Pathogenic Filamentous Fungus Aspergillus lentulus IFM 54703T. AB - Aspergillus lentulus, a sibling species of Aspergillus fumigatus, has been reported as a causative agent of aspergillosis, and exhibited low susceptibility to azole. Here, we present the draft genome sequence of A. lentulus strain IFM 54703(T) for the first time. PMID- 26769946 TI - Complete Genome Sequence of Arthrobacter sp. Strain LS16, Isolated from Agricultural Soils with Potential for Applications in Bioremediation and Bioproducts. AB - Here we report the complete genomic sequence of the bacterium Arthrobacter sp. strain LS16, consisting of a single circular chromosome of 3.85 Mb with no identified plasmid. Data contained within will facilitate future genetic modification and engineering of the Arthrobacter sp. LS16 metabolic network to enhance traits relevant to bioremediation and bioproducts. PMID- 26769947 TI - Draft Genome Sequence of "Cohnella kolymensis" B-2846. AB - A draft genome sequence of "Cohnella kolymensis" strain B-2846 was derived using IonTorrent sequencing technology. The size of the assembly and G+C content were in agreement with those of other species of this genus. Characterization of the genome of a novel species of Cohnella will assist in bacterial systematics. PMID- 26769948 TI - Permanent Draft Genome Sequences for Two Variants of Frankia sp. Strain CpI1, the First Frankia Strain Isolated from Root Nodules of Comptonia peregrina. AB - Frankia stains CpI1-S and CpI1-P are members of Frankia lineage Ia that are able to reinfect plants of the Betulaceae and Myricaceae families. Here, we report two 7.6-Mbp draft genome sequences with 6,396 and 6,373 candidate protein-coding genes for CpI1-S and CpI1-P, respectively. PMID- 26769949 TI - Correction for Weigand et al., Complete Genome Sequences of Two Bordetella hinzii Strains Isolated from Humans. PMID- 26769950 TI - Influence of decompression sickness on vasocontraction of isolated rat vessels. AB - Studies conducted in divers indicate that endothelium function is impaired following a dive even without decompression sickness (DCS). Our previous experiment conducted on rat isolated vessels showed no differences in endothelium dependent vasodilation after a simulated dive even in the presence of DCS, while contractile response to phenylephrine was progressively impaired with increased decompression stress. This study aimed to further investigate the effect of DCS on vascular smooth muscle. Thirty-two male Sprague-Dawley rats were submitted to the same hyperbaric protocol and classified according to the severity of DCS: no DCS (without clinical symptoms), mild-DCS, or severe-DCS (dead within 1 h). A control group remained at atmospheric pressure. Isometric tension was measured in rings of abdominal aorta and mesenteric arteries. Single dose contraction was assessed with KCl solution. Dose-response curves were obtained with phenylephrine and endothelin-1. Phenylephrine-induced contraction was observed in the presence of antioxidant tempol. Additionally, plasma concentrations of angiotensin II, angiotensin-converting enzyme, and thiobarbituric acid reactive substances (TBARS) were assessed. Response to phenylephrine was impaired only among mild-DCS in both vessels. Dose-response curves to endothelin-1 were impaired after mild DCS in mesenteric and severe-DCS in aorta. KCl-induced contraction was affected after hyperbaric exposure regardless of DCS status in aorta only. These results confirm postdive vascular dysfunction is dependent on the type of vessel. It further evidenced that vascular dysfunction is triggered by DCS rather than by diving itself and suggest the influence of circulating factor/s. Diving-induced impairment of the L-type voltage-dependent Ca(2+) channels and/or influence of renin-angiotensin system is proposed. PMID- 26769952 TI - Development and validation of a computational finite element model of the rabbit upper airway: simulations of mandibular advancement and tracheal displacement. AB - The mechanisms leading to upper airway (UA) collapse during sleep are complex and poorly understood. We previously developed an anesthetized rabbit model for studying UA physiology. On the basis of this body of physiological data, we aimed to develop and validate a two-dimensional (2D) computational finite element model (FEM) of the passive rabbit UA and peripharyngeal tissues. Model geometry was reconstructed from a midsagittal computed tomographic image of a representative New Zealand White rabbit, which included major soft (tongue, soft palate, constrictor muscles), cartilaginous (epiglottis, thyroid cartilage), and bony pharyngeal tissues (mandible, hard palate, hyoid bone). Other UA muscles were modeled as linear elastic connections. Initial boundary and contact definitions were defined from anatomy and material properties derived from the literature. Model parameters were optimized to physiological data sets associated with mandibular advancement (MA) and caudal tracheal displacement (TD), including hyoid displacement, which featured with both applied loads. The model was then validated against independent data sets involving combined MA and TD. Model outputs included UA lumen geometry, peripharyngeal tissue displacement, and stress and strain distributions. Simulated MA and TD resulted in UA enlargement and nonuniform increases in tissue displacement, and stress and strain. Model predictions closely agreed with experimental data for individually applied MA, TD, and their combination. We have developed and validated an FEM of the rabbit UA that predicts UA geometry and peripharyngeal tissue mechanical changes associated with interventions known to improve UA patency. The model has the potential to advance our understanding of UA physiology and peripharyngeal tissue mechanics. PMID- 26769951 TI - Role of CO2 in the cerebral hyperemic response to incremental normoxic and hyperoxic exercise. AB - Cerebral blood flow (CBF) is temporally related to exercise-induced changes in partial pressure of end-tidal carbon dioxide (PetCO2 ); hyperoxia is known to enhance this relationship. We examined the hypothesis that preventing PetCO2 from rising (isocapnia) during submaximal exercise with and without hyperoxia [end tidal Po2(PetO2 ) = 300 mmHg] would attenuate the increases in CBF. Additionally, we aimed to identify the magnitude that breathing, per se, influences the CBF response to normoxic and hyperoxic exercise. In 14 participants, CBF (intra- and extracranial) measurements were measured during exercise [20, 40, 60, and 80% of maximum workload (Wmax)] and during rest while ventilation (Ve) was volitionally increased to mimic volumes achieved during exercise (isocapnic hyperpnea). While Vewas uncontrolled during poikilocapnic exercise, during isocapnic exercise and isocapnic hyperpnea, Vewas increased to prevent PetCO2 from rising above resting values (~40 mmHg). Although PetCO2 differed by 2 +/- 3 mmHg during normoxic poikilocapnic and isocapnic exercise, except for a greater poikilocapnic compared with isocapnic increase in blood velocity in the posterior cerebral artery at 60% Wmax, the between condition increases in intracranial (~12-15%) and extracranial (15-20%) blood flow were similar at each workload. The poikilocapnic hyperoxic increases in both intra- and extracranial blood-flow (~17-29%) were greater compared with poikilocapnic normoxia (~8-20%) at intensities >40% Wmax(P< 0.01). During both normoxic and hyperoxic conditions, isocapnia normalized both the intracranial and extracranial blood-flow differences. Isocapnic hyperpnea did not alter CBF. Our findings demonstrate a differential effect of PetCO2 on CBF during exercise influenced by the prevailing PetO2. PMID- 26769953 TI - Local trauma in human patellar tendon leads to widespread changes in the tendon gene expression. AB - Low cellular activity and slow tissue turnover in human tendon may prolong resolution of tendinopathy. This may be stimulated by moderate localized traumas such as needle penetrations, but whether this results in a widespread cellular response in tendons is unknown. In an initial hypothesis-generating study, a trauma-induced tendon cell activity (increased total RNA and collagen I mRNA) was observed after repeated patellar tendon biopsies in young men. In a subsequent controlled study, 25 young men were treated with two 0.8-mm-diameter needle penetrations [n = 13, needle-group (NG)] or one 2.1-mm-diameter needle biopsy [n = 12, biopsy-group (BG)] in one patellar tendon. Four weeks later biopsies were taken from treated (5 mm lateral from trauma site) and contralateral tendons for analyses of RNA content (ribogreen assay), DNA content (PCR based), and gene expression for relevant target genes (Real-time RT-PCR) (NG, n = 11 and BG, n = 8). Intervention increased RNA content, and mRNA expression of collagen I and III and TGF-beta1 (P < 0.05), with biopsy treatment having greatest effect (tendency for RNA and collagen I). Results for DNA content were inconclusive, and no changes were detected in expression of insulin-like growth factor-I, connective tissue growth factor, scleraxis, decorin, fibromodulin, tenascin-C, tenomodulin, VEGFa, CD68, IL-6, MMP12, and MMP13. In conclusion, a moderate trauma to a healthy human tendon (e.g., biopsy sampling) results in a widespread upregulation of tendon cell activity and their matrix protein expression. The findings have implications for design of studies on human tendon and may provide perspectives in future treatment strategies in tendinopathy. PMID- 26769954 TI - Paracrine and endocrine modes of myostatin action. AB - Myostatin (MSTN) is a secreted signaling molecule that normally acts to limit muscle mass. In adult animals, MSTN is made almost exclusively by skeletal muscle and circulates in the blood. A critical question is whether this circulating MSTN protein can enter the active pool to regulate muscle growth or whether all of the activity of MSTN results from locally produced protein. Here, we addressed this question in mice by using a Cdx2-Cre transgene in conjunction with a conditional Mstn-flox allele to generate mice in which Mstn was targeted in a regionally restricted manner. Specifically, we generated mosaic mice in which MSTN production was eliminated in posteriorly located muscles but not in anteriorly located muscles, resulting in mice in which circulating levels of MSTN were reduced roughly by half. Analysis of posteriorly located vs. anteriorly located muscles of these mice revealed clear differential effects indicative of an important paracrine role for MSTN in regulating muscle mass. Significant, albeit more subtle, effects consistent with an endocrine mode of MSTN action were also seen in these mice. These findings have important implications not only for the understanding of the physiological control of muscle mass but also for therapeutic strategies to target MSTN to treat patients with muscle loss. PMID- 26769955 TI - Interaction between environmental temperature and hypoxia on central and peripheral fatigue during high-intensity dynamic knee extension. AB - This study investigated causative factors behind the expression of different interaction types during exposure to multistressor environments. Neuromuscular fatigue rates and time to exhaustion (TTE) were investigated in active men (n = 9) exposed to three climates [5 degrees C, 50% relative humidity (rh); 23 degrees C, 50% rh; and 42 degrees C, 70% rh] at two inspired oxygen fractions (0.209 and 0.125 FiO2; equivalent attitude = 4,100 m). After a 40-min rest in the three climatic conditions, participants performed constant-workload (high intensity) knee extension exercise until exhaustion, with brief assessments of neuromuscular function every 110 s. Independent exposure to cold, heat, and hypoxia significantly (P < 0.01) reduced TTE from thermoneutral normoxia (reductions of 190, 405, and 505 s from 915 s, respectively). The TTE decrease was consistent with a faster rate of peripheral fatigue development (P < 0.01) compared with thermoneutral normoxia (increase of 1.6, 3.1, and 4.9%/min from 4.1%/min, respectively). Combined exposure to hypoxic-cold resulted in an even greater TTE reduction (-589 s), likely due to an increase in the rate of peripheral fatigue development (increased by 7.6%/min), but this was without significant interaction between stressors (P > 0.198). In contrast, combined exposure to hypoxic heat reduced TTE by 609 s, showing a significant antagonistic interaction (P = 0.003) similarly supported by an increased rate of peripheral fatigue development (which increased by 8.3%/min). A small decline (<0.4%/min) in voluntary muscle activation was observed only in thermoneutral normoxia. In conclusion, interaction type is influenced by the impact magnitude of the effect of the individual stressors' effect on exercise capacity, whereby the greater the effect of stressors, the greater the probability that one stressor will be abolished by the other. This indicates that humans respond to severe and simultaneous physiological strains on the basis of a worst-strain-takes precedence principle. PMID- 26769956 TI - PlanHab: the combined and separate effects of 16 days of bed rest and normobaric hypoxic confinement on circulating lipids and indices of insulin sensitivity in healthy men. AB - PlanHab is a planetary habitat simulation study. The atmosphere within future space habitats is anticipated to have reduced Po2, but information is scarce as to how physiological systems may respond to combined exposure to moderate hypoxia and reduced gravity. This study investigated, using a randomized-crossover design, how insulin sensitivity, glucose tolerance, and circulating lipids were affected by 16 days of horizontal bed rest in normobaric normoxia [NBR: FiO2 = 0.209; PiO2 = 133.1 (0.3) mmHg], horizontal bed rest in normobaric hypoxia [HBR: FiO2 = 0.141 (0.004); PiO2 = 90.0 (0.4) mmHg], and confinement in normobaric hypoxia combined with daily moderate intensity exercise (HAMB). A mixed-meal tolerance test, with arterialized-venous blood sampling, was performed in 11 healthy, nonobese men (25-45 yr) before (V1) and on the morning ofday 17of each intervention (V2). Postprandial glucose and c-peptide response were increased at V2 of both bed rest interventions (P< 0.05 in each case), with c-peptide:insulin ratio higher at V2 in HAMB and HBR, both in the fed and fasted state (P< 0.005 in each case). Fasting total cholesterol was reduced at V2 in HAMB [-0.47 (0.36) mmol/l;P< 0.005] and HBR [-0.55 (0.41) mmol/l;P< 0.005]. Fasting HDL was lower at V2 in all interventions, with the reduction observed in HBR [-0.30 (0.21) mmol/l] greater than that measured in HAMB [-0.13 (0.14) mmol/l;P< 0.005] and NBR [-0.17 (0.15) mmol/l;P< 0.05]. Hypoxia did not alter the adverse effects of bed rest on insulin sensitivity and glucose tolerance but appeared to increase insulin clearance. The negative effect of bed rest on HDL was compounded in hypoxia, which may have implications for long-term health of those living in future space habitats. PMID- 26769958 TI - Effect of superoxide anion scavenger on rat hearts with chronic intermittent hypoxia. AB - Only very limited information regarding the protective effects of the superoxide anion scavenger on chronic intermittent hypoxia-induced cardiac apoptosis is available. The purpose of this study is to evaluate the effects of the superoxide anion scavenger on cardiac apoptotic and prosurvival pathways in rats with sleep apnea. Forty-two Sprague-Dawley rats were divided into three groups, rats with normoxic exposure (Control, 21% O2, 1 mo), rats with chronic intermittent hypoxia exposure (Hypoxia, 3-7% O2vs. 21% O2per 40 s cycle, 8 h per day, 1 mo), and rats with pretreatment of the superoxide anion scavenger and chronic intermittent hypoxia exposure (Hypoxia-O2 (-)-Scavenger, MnTMPyP pentachloride, 1 mg/kg ip per day; 3-7% O2vs. 21% O2per 40 s cycle, 8 h per day, 1 mo) at 5-6 mo of age. After 1 mo, the protein levels and apoptotic cells of excised hearts from three groups were measured by Western blotting and terminal deoxynucleotide transferase mediated dUTP nick end labeling (TUNEL) assay. The superoxide anion scavenger decreased hypoxia-induced myocardial architecture abnormalities, left ventricular hypertrophy, and TUNEL-positive apoptosis. The superoxide anion scavenger decreased hypoxia-induced Fas ligand, Fas death receptors, Fas-associated death domain (FADD), activated caspase-8, and activated caspase-3 (Fas-dependent apoptotic pathway) as well as Bad, activated caspase-9 and activated caspase-3 (mitochondria-dependent apoptotic pathway), endonuclease G (EndoG), apoptosis inducing factor (AIF), and TUNEL-positive apoptosis. The superoxide anion scavenger increased IGF-1, IGF-1R, p-PI3k, p-Akt, p-Bad, Bcl-2, and Bcl-xL (survival pathway). Our findings imply that the superoxide anion scavenger might prevent cardiac Fas-mediated and mitochondrial-mediated apoptosis and enhance the IGF-1-related survival pathway in chronic intermittent hypoxia. The superoxide anion scavenger may prevent chronic sleep apnea-enhanced cardiac apoptotic pathways and enhances cardiac survival pathways. PMID- 26769957 TI - Regional heterogeneity in the reactivity of equine small pulmonary blood vessels. AB - Regional differences in large equine pulmonary artery reactivity exist. It is not known if this heterogeneity extends into small vessels. The hypothesis that there is regional heterogeneity in small pulmonary artery and vein reactivity to sympathomimetics (phenylephrine and isoproterenol) and a parasympathomimetic (methacholine) was tested using wire myography on small vessels from caudodorsal (CD) and cranioventral (CV) lung of 12 horses [9 mares, 3 geldings, 8.67 +/- 0.81 (age +/- SE) yr, of various breeds that had never raced]. To study relaxation, vessels were precontracted with U46619 (10(-6) M). Methacholine mechanism of action was investigated using L-nitroarginine methylester (L-NAME, 100 MUM) and indomethacin (10 MUM). Phenylephrine did not contract any vessels. Isoproterenol relaxed CD arteries more than CV arteries (maximum relaxation 28.18% and 48.67%; Log IC50 +/- SE -7.975 +/- 0.1327 and -8.033 +/- 0.1635 for CD and CV, respectively, P < 0.0001), but not veins. Methacholine caused contraction of CD arteries (maximum contraction 245.4%, Log EC50 +/- SE -6.475 +/- 0.3341), and relaxation of CV arteries (maximum relaxation 40.14%, Log IC50 +/- SE -6.791 +/- 0.1954) and all veins (maximum relaxation 50.62%, Log IC50 +/- SE -6.932 +/- 0.1986) in a nonregion-dependent manner. L-NAME (n = 8, P < 0.0001) and indomethacin (n = 7, P < 0.0001) inhibited methacholine-induced relaxation of CV arteries, whereas indomethacin augmented CD artery contraction (n = 8, P < 0.0001). Our data demonstrate significant regional heterogeneity in small blood vessel reactivity when comparing the CD to the CV region of the equine lung. PMID- 26769959 TI - Comparative Genomics between Two Xenorhabdus bovienii Strains Highlights Differential Evolutionary Scenarios within an Entomopathogenic Bacterial Species. AB - Bacteria of the genus Xenorhabdus are symbionts of soil entomopathogenic nematodes of the genus Steinernema. This symbiotic association constitutes an insecticidal complex active against a wide range of insect pests. Within Xenorhabdus bovienii species, the X. bovienii CS03 strain (Xb CS03) is nonvirulent when directly injected into lepidopteran insects, and displays a low virulence when associated with its Steinernema symbiont. The genome of Xb CS03 was sequenced and compared with the genome of a virulent strain, X. bovienii SS 2004 (Xb SS-2004). The genome size and content widely differed between the two strains. Indeed, Xb CS03 had a large genome containing several specific loci involved in the inhibition of competitors, including a few NRPS-PKS loci (nonribosomal peptide synthetases and polyketide synthases) producing antimicrobial molecules. Consistently, Xb CS03 had a greater antimicrobial activity than Xb SS-2004. The Xb CS03 strain contained more pseudogenes than Xb SS-2004. Decay of genes involved in the host invasion and exploitation (toxins, invasins, or extracellular enzymes) was particularly important in Xb CS03. This may provide an explanation for the nonvirulence of the strain when injected into an insect host. We suggest that Xb CS03 and Xb SS-2004 followed divergent evolutionary scenarios to cope with their peculiar life cycle. The fitness strategy of Xb CS03 would involve competitor inhibition, whereas Xb SS-2004 would quickly and efficiently kill the insect host. Hence, Xenorhabdus strains would have widely divergent host exploitation strategies, which impact their genome structure. PMID- 26769960 TI - Pervasive polymorphic imprinted methylation in the human placenta. AB - The maternal and paternal copies of the genome are both required for mammalian development, and this is primarily due to imprinted genes, those that are monoallelically expressed based on parent-of-origin. Typically, this pattern of expression is regulated by differentially methylated regions (DMRs) that are established in the germline and maintained after fertilization. There are a large number of germline DMRs that have not yet been associated with imprinting, and their function in development is unknown. In this study, we developed a genome wide approach to identify novel imprinted DMRs in the human placenta and investigated the dynamics of these imprinted DMRs during development in somatic and extraembryonic tissues. DNA methylation was evaluated using the Illumina HumanMethylation450 array in 134 human tissue samples, publicly available reduced representation bisulfite sequencing in the human embryo and germ cells, and targeted bisulfite sequencing in term placentas. Forty-three known and 101 novel imprinted DMRs were identified in the human placenta by comparing methylation between diandric and digynic triploid conceptions in addition to female and male gametes. Seventy-two novel DMRs showed a pattern consistent with placental specific imprinting, and this monoallelic methylation was entirely maternal in origin. Strikingly, these DMRs exhibited polymorphic imprinted methylation between placental samples. These data suggest that imprinting in human development is far more extensive and dynamic than previously reported and that the placenta preferentially maintains maternal germline-derived DNA methylation. PMID- 26769961 TI - Glioma-associated Oncogene 2 Is Essential for Trophoblastic Fusion by Forming a Transcriptional Complex with Glial Cell Missing-a. AB - Cell-cell fusion of human villous trophoblasts, referred to as a process of syncytialization, acts as a prerequisite for the proper development and functional maintenance of the human placenta. Given the fact that the main components of the Hedgehog signaling pathway are expressed predominantly in the syncytial layer of human placental villi, in this study, we investigated the potential roles and underlying mechanisms of Hedgehog signaling in trophoblastic fusion. Activation of Hedgehog signaling by a variety of approaches robustly induced cell fusion and the expression of syncytial markers, whereas suppression of Hedgehog signaling significantly attenuated cell fusion and the expression of syncytial markers in both human primary cytotrophoblasts and trophoblast-like BeWo cells. Moreover, among glioma-associated oncogene (GLI) family transcriptional factors in Hedgehog signaling, knockdown of GLI2 but not GLI1 and GLI3 significantly attenuated Hedgehog-induced cell fusion, whereas overexpression of the GLI2 activator alone was sufficient to induce cell fusion. Finally, GLI2 not only stabilized glial cell missing-a, a pivotal transcriptional factor for trophoblastic syncytialization, but also formed a transcriptional heterodimer with glial cell missing-a to transactivate syncytin-1, a trophoblastic fusogen, and promote trophoblastic syncytialization. Taken together, this study uncovered a so far uncharacterized role of Hedgehog/GLI2 signaling in trophoblastic fusion, implicating that Hedgehog signaling, through GLI2, could be required for human placental development and pregnancy maintenance. PMID- 26769963 TI - The Glycine-Alanine Dipeptide Repeat from C9orf72 Hexanucleotide Expansions Forms Toxic Amyloids Possessing Cell-to-Cell Transmission Properties. AB - Hexanucleotide expansions, GGGGCC, in the non-coding regions of the C9orf72 gene were found in major frontotemporal lobar dementia and amyotrophic lateral sclerosis patients (C9FTD/ALS). In addition to possible RNA toxicity, several dipeptide repeats (DPRs) are translated through repeat-associated non-ATG initiated translation. The DPRs, including poly(GA), poly(GR), poly(GP), poly(PR), and poly(PA), were found in the brains and spinal cords of C9FTD/ALS patients. Among the DPRs, poly(GA) is highly susceptible to form cytoplasmic inclusions, which is a characteristic of C9FTD/ALS. To elucidate DPR aggregation, we used synthetic (GA)15 DPR as a model system to examine the aggregation and structural properties in vitro. We found that (GA)15 with 15 repeats fibrillates rapidly and ultimately forms flat, ribbon-type fibrils evidenced by transmission electron microscopy and atomic force microscopy. The fibrils are capable of amyloid dye binding and contain a characteristic cross-beta sheet structure, as revealed by x-ray scattering. Furthermore, using neuroblastoma cells, we demonstrated the neurotoxicity and cell-to-cell transmission property of (GA)15 DPR. Overall, our results show the structural and toxicity properties of GA DPR to facilitate future DPR-related therapeutic development. PMID- 26769962 TI - REH2C Helicase and GRBC Subcomplexes May Base Pair through mRNA and Small Guide RNA in Kinetoplastid Editosomes. AB - Mitochondrial mRNAs in Trypanosoma brucei undergo extensive insertion and deletion of uridylates that are catalyzed by the RNA editing core complex (RECC) and directed by hundreds of small guide RNAs (gRNAs) that base pair with mRNA. RECC is largely RNA-free, and accessory mitochondrial RNA-binding complex 1 (MRB1) variants serve as scaffolds for the assembly of mRNA-gRNA hybrids and RECC. However, the molecular steps that create higher-order holoenzymes ("editosomes") are unknown. Previously, we identified an RNA editing helicase 2 associated subcomplex (REH2C) and showed that REH2 binds RNA. Here we showed that REH2C is an mRNA-associated ribonucleoprotein (mRNP) subcomplex with editing substrates, intermediates, and products. We isolated this mRNP from mitochondria lacking gRNA-bound RNP (gRNP) subcomplexes and identified REH2-associated cofactors 1 and 2 ((H2)F1 and (H2)F2). (H2)F1 is an octa-zinc finger protein required for mRNP-gRNP docking, pre-mRNA and RECC loading, and RNP formation with a short synthetic RNA duplex. REH2 and other eukaryotic DEAH/RHA-type helicases share a conserved regulatory C-terminal domain cluster that includes an oligonucleotide-binding fold. Recombinant REH2 and (H2)F1 constructs associate in a purified complex in vitro. We propose a model of stepwise editosome assembly that entails controlled docking of mRNP and gRNP modules via specific base pairing between their respective mRNA and gRNA cargo and regulatory REH2 and (H2)F1 subunits of the novel mRNP that may control specificity checkpoints in the editing pathway. PMID- 26769964 TI - Structural Basis of Cyclic Nucleotide Selectivity in cGMP-dependent Protein Kinase II. AB - Membrane-bound cGMP-dependent protein kinase (PKG) II is a key regulator of bone growth, renin secretion, and memory formation. Despite its crucial physiological roles, little is known about its cyclic nucleotide selectivity mechanism due to a lack of structural information. Here, we find that the C-terminal cyclic nucleotide binding (CNB-B) domain of PKG II binds cGMP with higher affinity and selectivity when compared with its N-terminal CNB (CNB-A) domain. To understand the structural basis of cGMP selectivity, we solved co-crystal structures of the CNB domains with cyclic nucleotides. Our structures combined with mutagenesis demonstrate that the guanine-specific contacts at Asp-412 and Arg-415 of the alphaC-helix of CNB-B are crucial for cGMP selectivity and activation of PKG II. Structural comparison with the cGMP selective CNB domains of human PKG I and Plasmodium falciparum PKG (PfPKG) shows different contacts with the guanine moiety, revealing a unique cGMP selectivity mechanism for PKG II. PMID- 26769965 TI - Heparin Decreases in Tumor Necrosis Factor alpha (TNFalpha)-induced Endothelial Stress Responses Require Transmembrane Protein 184A and Induction of Dual Specificity Phosphatase 1. AB - Despite the large number of heparin and heparan sulfate binding proteins, the molecular mechanism(s) by which heparin alters vascular cell physiology is not well understood. Studies with vascular smooth muscle cells (VSMCs) indicate a role for induction of dual specificity phosphatase 1 (DUSP1) that decreases ERK activity and results in decreased cell proliferation, which depends on specific heparin binding. The hypothesis that unfractionated heparin functions to decrease inflammatory signal transduction in endothelial cells (ECs) through heparin induced expression of DUSP1 was tested. In addition, the expectation that the heparin response includes a decrease in cytokine-induced cytoskeletal changes was examined. Heparin pretreatment of ECs resulted in decreased TNFalpha-induced JNK and p38 activity and downstream target phosphorylation, as identified through Western blotting and immunofluorescence microscopy. Through knockdown strategies, the importance of heparin-induced DUSP1 expression in these effects was confirmed. Quantitative fluorescence microscopy indicated that heparin treatment of ECs reduced TNFalpha-induced increases in stress fibers. Monoclonal antibodies that mimic heparin-induced changes in VSMCs were employed to support the hypothesis that heparin was functioning through interactions with a receptor. Knockdown of transmembrane protein 184A (TMEM184A) confirmed its involvement in heparin-induced signaling as seen in VSMCs. Therefore, TMEM184A functions as a heparin receptor and mediates anti-inflammatory responses of ECs involving decreased JNK and p38 activity. PMID- 26769966 TI - Transmembrane Protein 184A Is a Receptor Required for Vascular Smooth Muscle Cell Responses to Heparin. AB - Vascular cell responses to exogenous heparin have been documented to include decreased vascular smooth muscle cell proliferation following decreased ERK pathway signaling. However, the molecular mechanism(s) by which heparin interacts with cells to induce those responses has remained unclear. Previously characterized monoclonal antibodies that block heparin binding to vascular cells have been found to mimic heparin effects. In this study, those antibodies were employed to isolate a heparin binding protein. MALDI mass spectrometry data provide evidence that the protein isolated is transmembrane protein 184A (TMEM184A). Commercial antibodies against three separate regions of the TMEM184A human protein were used to identify the TMEM184A protein in vascular smooth muscle cells and endothelial cells. A GFP-TMEM184A construct was employed to determine colocalization with heparin after endocytosis. Knockdown of TMEM184A eliminated the physiological responses to heparin, including effects on ERK pathway activity and BrdU incorporation. Isolated GFP-TMEM184A binds heparin, and overexpression results in additional heparin uptake. Together, these data support the identification of TMEM184A as a heparin receptor in vascular cells. PMID- 26769968 TI - Stimulating the Release of Exosomes Increases the Intercellular Transfer of Prions. AB - Exosomes are small extracellular vesicles released by cells and play important roles in intercellular communication and pathogen transfer. Exosomes have been implicated in several neurodegenerative diseases, including prion disease and Alzheimer disease. Prion disease arises upon misfolding of the normal cellular prion protein, PrP(C), into the disease-associated isoform, PrP(Sc). The disease has a unique transmissible etiology, and exosomes represent a novel and efficient method for prion transmission. The precise mechanism by which prions are transmitted from cell to cell remains to be fully elucidated, although three hypotheses have been proposed: direct cell-cell contact, tunneling nanotubes, and exosomes. Given the reported presence of exosomes in biological fluids and in the lipid and nucleic acid contents of exosomes, these vesicles represent an ideal mechanism for encapsulating prions and potential cofactors to facilitate prion transmission. This study investigates the relationship between exosome release and intercellular prion dissemination. Stimulation of exosome release through treatment with an ionophore, monensin, revealed a corresponding increase in intercellular transfer of prion infectivity. Conversely, inhibition of exosome release using GW4869 to target the neutral sphingomyelinase pathway induced a decrease in intercellular prion transmission. Further examination of the effect of monensin on PrP conversion revealed that monensin also alters the conformational stability of PrP(C), leading to increased generation of proteinase K-resistant prion protein. The findings presented here provide support for a positive relationship between exosome release and intercellular transfer of prion infectivity, highlighting an integral role for exosomes in facilitating the unique transmissible nature of prions. PMID- 26769967 TI - Protein Kinase Calpha (PKCalpha) Is Resistant to Long Term Desensitization/Down regulation by Prolonged Diacylglycerol Stimulation. AB - Sustained activation of PKCalpha is required for long term physiological responses, such as growth arrest and differentiation. However, studies with pharmacological agonists (e.g. phorbol 12-myristate 13-acetate (PMA)) indicate that prolonged stimulation leads to PKCalpha desensitization via dephosphorylation and/or degradation. The current study analyzed effects of chronic stimulation with the physiological agonist diacylglycerol. Repeated addition of 1,2-dioctanoyl-sn-glycerol (DiC8) resulted in sustained plasma membrane association of PKCalpha in a pattern comparable with that induced by PMA. However, although PMA potently down-regulated PKCalpha, prolonged activation by DiC8 failed to engage known desensitization mechanisms, with the enzyme remaining membrane-associated and able to support sustained downstream signaling. DiC8-activated PKCalpha did not undergo dephosphorylation, ubiquitination, or internalization, early events in PKCalpha desensitization. Although DiC8 efficiently down-regulated novel PKCs PKCdelta and PKCepsilon, differences in Ca(2+) sensitivity and diacylglycerol affinity were excluded as mediators of the selective resistance of PKCalpha. Roles for Hsp/Hsc70 and Hsp90 were also excluded. PMA, but not DiC8, targeted PKCalpha to detergent-resistant membranes, and disruption of these domains with cholesterol-binding agents demonstrated a role for differential membrane compartmentalization in selective agonist-induced degradation. Chronic DiC8 treatment failed to desensitize PKCalpha in several cell types and did not affect PKCbetaI; thus, conventional PKCs appear generally insensitive to desensitization by sustained diacylglycerol stimulation. Consistent with this conclusion, prolonged (several-day) membrane association/activation of PKCalpha is seen in self-renewing epithelium of the intestine, cervix, and skin. PKCalpha deficiency affects gene expression, differentiation, and tumorigenesis in these tissues, highlighting the importance of mechanisms that protect PKCalpha from desensitization in vivo. PMID- 26769969 TI - Phosphorylation of TAR DNA-binding Protein of 43 kDa (TDP-43) by Truncated Casein Kinase 1delta Triggers Mislocalization and Accumulation of TDP-43. AB - Intracellular aggregates of phosphorylated TDP-43 are a major component of ubiquitin-positive inclusions in the brains of patients with frontotemporal lobar degeneration and ALS and are considered a pathological hallmark. Here, to gain insight into the mechanism of intracellular TDP-43 accumulation, we examined the relationship between phosphorylation and aggregation of TDP-43. We found that expression of a hyperactive form of casein kinase 1 delta (CK1delta1-317, a C terminally truncated form) promotes mislocalization and cytoplasmic accumulation of phosphorylated TDP-43 (ubiquitin- and p62-positive) in cultured neuroblastoma SH-SY5Y cells. Insoluble phosphorylated TDP-43 prepared from cells co-expressing TDP-43 and CK1delta1-317 functioned as seeds for TDP-43 aggregation in cultured cells, indicating that CK1delta1-317-induced aggregated TDP-43 has prion-like properties. A striking toxicity and alterations of TDP-43 were also observed in yeast expressing TDP-43 and CK1delta1-317. Therefore, abnormal activation of CK1delta causes phosphorylation of TDP-43, leading to the formation of cytoplasmic TDP-43 aggregates, which, in turn, may trigger neurodegeneration. PMID- 26769970 TI - Germ Cell Nuclear Factor (GCNF) Represses Oct4 Expression and Globally Modulates Gene Expression in Human Embryonic Stem (hES) Cells. AB - Oct4 is considered a key transcription factor for pluripotent stem cell self renewal. It binds to specific regions within target genes to regulate their expression and is downregulated upon induction of differentiation of pluripotent stem cells; however, the mechanisms that regulate the levels of human Oct4 expression remain poorly understood. Here we show that expression of human Oct4 is directly repressed by germ cell nuclear factor (GCNF), an orphan nuclear receptor, in hES cells. Knockdown of GCNF by siRNA resulted in maintenance of Oct4 expression during RA-induced hES cell differentiation. While overexpression of GCNF promoted repression of Oct4 expression in both undifferentiated and differentiated hES cells. The level of Oct4 repression was dependent on the level of GCNF expression in a dose-dependent manner. mRNA microarray analysis demonstrated that overexpression of GCNF globally regulates gene expression in undifferentiated and differentiated hES cells. Within the group of altered genes, GCNF down-regulated 36% of the genes, and up-regulated 64% in undifferentiated hES cells. In addition, GCNF also showed a regulatory gene pattern that is different from RA treatment during hES cell differentiation. These findings increase our understanding of the mechanisms that maintain hES cell pluripotency and regulate gene expression during the differentiation process. PMID- 26769973 TI - The Ankle-Brachial Index Is Associated With Cardiovascular Complications After Noncardiac Surgery. PMID- 26769974 TI - Building on the strengths of Pacific mental health: Experience from Samoa. PMID- 26769975 TI - Severe alcohol use disorder after bariatric surgery. PMID- 26769971 TI - Pyruvate Dehydrogenase Kinase-mediated Glycolytic Metabolic Shift in the Dorsal Root Ganglion Drives Painful Diabetic Neuropathy. AB - The dorsal root ganglion (DRG) is a highly vulnerable site in diabetic neuropathy. Under diabetic conditions, the DRG is subjected to tissue ischemia or lower ambient oxygen tension that leads to aberrant metabolic functions. Metabolic dysfunctions have been documented to play a crucial role in the pathogenesis of diverse pain hypersensitivities. However, the contribution of diabetes-induced metabolic dysfunctions in the DRG to the pathogenesis of painful diabetic neuropathy remains ill-explored. In this study, we report that pyruvate dehydrogenase kinases (PDK2 and PDK4), key regulatory enzymes in glucose metabolism, mediate glycolytic metabolic shift in the DRG leading to painful diabetic neuropathy. Streptozotocin-induced diabetes substantially enhanced the expression and activity of the PDKs in the DRG, and the genetic ablation of Pdk2 and Pdk4 attenuated the hyperglycemia-induced pain hypersensitivity. Mechanistically, Pdk2/4 deficiency inhibited the diabetes-induced lactate surge, expression of pain-related ion channels, activation of satellite glial cells, and infiltration of macrophages in the DRG, in addition to reducing central sensitization and neuroinflammation hallmarks in the spinal cord, which probably accounts for the attenuated pain hypersensitivity. Pdk2/4-deficient mice were partly resistant to the diabetes-induced loss of peripheral nerve structure and function. Furthermore, in the experiments using DRG neuron cultures, lactic acid treatment enhanced the expression of the ion channels and compromised cell viability. Finally, the pharmacological inhibition of DRG PDKs or lactic acid production substantially attenuated diabetes-induced pain hypersensitivity. Taken together, PDK2/4 induction and the subsequent lactate surge induce the metabolic shift in the diabetic DRG, thereby contributing to the pathogenesis of painful diabetic neuropathy. PMID- 26769972 TI - Redox-coupled structural changes in nitrite reductase revealed by serial femtosecond and microfocus crystallography. AB - Serial femtosecond crystallography (SFX) has enabled the damage-free structural determination of metalloenzymes and filled the gaps of our knowledge between crystallographic and spectroscopic data. Crystallographers, however, scarcely know whether the rising technique provides truly new structural insights into mechanisms of metalloenzymes partly because of limited resolutions. Copper nitrite reductase (CuNiR), which converts nitrite to nitric oxide in denitrification, has been extensively studied by synchrotron radiation crystallography (SRX). Although catalytic Cu (Type 2 copper (T2Cu)) of CuNiR had been suspected to tolerate X-ray photoreduction, we here showed that T2Cu in the form free of nitrite is reduced and changes its coordination structure in SRX. Moreover, we determined the completely oxidized CuNiR structure at 1.43 A resolution with SFX. Comparison between the high-resolution SFX and SRX data revealed the subtle structural change of a catalytic His residue by X-ray photoreduction. This finding, which SRX has failed to uncover, provides new insight into the reaction mechanism of CuNiR. PMID- 26769976 TI - DSM-5 and the RANZCP training requirements. PMID- 26769977 TI - Cogan's syndrome and treatment-resistant psychosis. PMID- 26769978 TI - Substance use outcomes following treatment: Findings from the Australian Patient Pathways Study. AB - BACKGROUND AND AIMS: Our understanding of patient pathways through specialist Alcohol and Other Drug treatment and broader health/welfare systems in Australia remains limited. This study examines how treatment outcomes are influenced by continuity in specialist Alcohol and Other Drug treatment, engagement with community services and mutual aid, and explores differences between clients who present with a primary alcohol problem relative to those presenting with a primary drug issue. METHOD: In a prospective, multi-site treatment outcome study, 796 clients from 21 Alcohol and Other Drug services in Victoria and Western Australia completed a baseline interview between January 2012 and January 2013. A total of 555 (70%) completed a follow-up assessment of subsequent service use and Alcohol and Other Drug use outcomes 12-months later. RESULTS: Just over half of the participants (52.0%) showed reliable reductions in use of, or abstinence from, their primary drug of concern. This was highest among clients with meth/amphetamine (66%) as their primary drug of concern and lowest among clients with alcohol as their primary drug of concern (47%), with 31% achieving abstinence from all drugs of concern. Continuity of specialist Alcohol and Other Drug care was associated with higher rates of abstinence than fragmented Alcohol and Other Drug care. Different predictors of treatment success emerged for clients with a primary drug problem as compared to those with a primary alcohol problem; mutual aid attendance (odds ratio = 2.5) and community service engagement (odds ratio = 2.0) for clients with alcohol as the primary drug of concern, and completion of the index treatment (odds ratio = 2.8) and continuity in Alcohol and Other Drug care (odds ratio = 1.8) when drugs were the primary drugs of concern. CONCLUSION: This is the first multi-site Australian study to include treatment outcomes for alcohol and cannabis users, who represent 70% of treatment seekers in Alcohol and Other Drug services. Results suggest a substantial proportion of clients respond positively to treatment, but that clients with alcohol as their primary drug problem may require different treatment pathways, compared to those with illicit drug issues, to maximise outcomes. PMID- 26769979 TI - Service use by Australian children for emotional and behavioural problems: Findings from the second Australian Child and Adolescent Survey of Mental Health and Wellbeing. AB - OBJECTIVE: To identify the proportion of children and adolescents in Australia and the proportion of those with mental disorders who used services for emotional and behavioural problems, the type of services used and what characteristics were associated with service use. METHOD: During 2013-2014, a national face-to-face household survey of mental health and wellbeing (Young Minds Matter) was conducted, involving 6310 parents and carers of 4- to 17-year-olds (55% of eligible households) and self-report surveys from 2967 11- to 17-year-olds in these households (89% of eligible youth). The survey identified 12-month mental disorders based on the Diagnostic Interview Schedule for Children-Version IV and asked about service use for emotional or behavioural problems in the previous 12 months. RESULTS: Overall, 17.0% of all 4- to 17-year-olds used services for emotional or behavioural problems in the previous 12 months. Of those with mental disorders, 56.0% used services (48.9% of 4- to 11-year-olds; 65.1% of 12- to 17 year-olds). Service use was highest among 4- to 17-year-olds with major depressive disorder (79.6%) and lowest for those with attention deficit/hyperactivity disorder (52.7%). Two-fifths (41.2%), 72.5% and 87.6% of those with mild, moderate and severe disorders used services. General practitioners, psychologists, paediatricians and counsellors/family therapists were the most commonly accessed health service providers. Two-fifths with mental disorders had attended school services. About 5% of adolescents reported use of online personal support or counselling for help with their problems. From multivariate models, service use was higher in sole carer families, but also among those living in the least socially and economically disadvantaged compared to the most disadvantaged areas. CONCLUSION: Rates of service use for mental disorders in Australia's children and adolescents appear to have increased substantially. Health services and schools are the major providers of services for emotional and behavioural problems, but telephone counselling and online services have become well-established parts of the service environment. PMID- 26769980 TI - Brain gray matter alterations and associated demographic profiles in adults with autism spectrum disorder: A meta-analysis of voxel-based morphometry studies. AB - BACKGROUND: There is increasing evidence that children with autism spectrum disorder are accompanied by specific anatomical alterations. However, the anatomical abnormalities in adults with autism spectrum disorder are poorly understood. This study was aimed to identify the neuroanatomical substrates underlying the pathophysiology of adults with autism spectrum disorder. We also investigated the relationship between neuroanatomical alterations and clinical and demographic characteristics. METHODS: A total of 13 datasets were enrolled, of which 12 studies compared whole-brain differences of 382 adult patients with autism and 393 healthy control subjects. We conducted a meta-analysis to quantitatively estimate regional gray matter volume abnormalities in individuals with autism using the effect-size signed differential mapping. RESULTS: The voxel wise meta-analysis revealed that relative to controls, adults with autism spectrum disorder had significantly increased gray matter volume in the middle temporal gyrus, superior temporal gyrus, postcentral gyrus and parahippocampal gyrus, and reduced gray matter volume in the anterior cingulate cortex and cerebellum. Variations in gray matter volume were significantly associated with the mean age and mean total IQ score of the patients, as well as with the percentage of male patients with autism. CONCLUSION: These findings confirmed that the neuroanatomical alterations in the fronto-temporal cortices, limbic system and cerebellum in adult individuals with autism were different from the children and young adolescent's autism. The effects of demographic characteristics on the brain morphological changes allow us to further clarify the neurobiological mechanisms and developmental trajectory in adult population with autism spectrum disorder. PMID- 26769981 TI - Changes in metabolic parameters in patients with severe mental illness over a 10 year period: A retrospective cohort study. AB - BACKGROUND: Diabetes, obesity and metabolic syndrome are highly prevalent in patients with severe mental illness and can impose a major physical health burden. OBJECTIVE: To determine how anthropometric and metabolic features changed over time in a retrospective cohort of people with Severe Mental Illness living in Cheshire, UK. METHODS: In all, 1307 individuals on the severe mental illness Register were followed up between 2002 and 2012 in UK general practice. Subjects were identified through a pseudanonymised search of general practice registers. RESULTS: Baseline body mass index was 28.6 kg/m2 increasing to 31.0 at 10-year follow-up ( r2 = 0.84; p = 0.0002). There was a significant increase in fasting blood glucose from 5.72 to 6.79 mmol/L ( r2 = 0.48; p = 0.026). Correspondingly, there was a strong positive univariate relation between increase in body mass index and fasting blood glucose ( r2 = 0.54; p < 0.0001) taking into account all measurements. Fasting blood glucose also increased slightly with age ( p = 0.028). With increasing use of statins, total cholesterol fell from 4.5 to 3.9 mmol/L ( r2 = 0.88; p = 0.0001), as did low-density lipoprotein cholesterol from 3.43 to 2.35 mmol/L ( r2 = 0.94; p = 0.0001). In multivariate models, adjusting for age, gender, smoking and blood pressure, each unit increase in body mass index (odds ratio = 1.07 [1.01, 1.13]; p = 0.031) and triglycerides (odds ratio = 1.28 (1.06, 1.55); p = 0.009) was independently associated with an increased risk of having type 2 diabetes. CONCLUSION: Increasing body mass index relates to increasing rates of dysglycaemia over time. Measures to encourage weight reduction should be key strategies to reduce dysglycaemia rates in severe mental illness. Prescribing statins may have been effective in improving the lipid profile in this group. PMID- 26769982 TI - Korean Immigrant Women's Health Care Utilization in the United States: A Systematic Review of Literature. AB - A systematic literature review was performed to review empirical evidence, published between 1946 and 2015, regarding Korean immigrant women's health care utilization and factors affecting their health care utilization in the United States. Andersen's behavioral model of health services utilization was used as a framework and was expanded to analyze the pattern of health services utilization and to identify characteristics of access to health care. A total of 32 reports were included. Variables were categorized into 1 of 5 individual determinants: cultural, enabling, predisposing, need, and reinforcing factor. A total of 423 relationships were found between individual determinants and health care utilization. All reinforcing variables were effective in increasing Korean immigrant women's health care utilization in a positive way. Interventions targeting multiple factors were strongly effective in encouraging Korean immigrant women to utilize health services for cancer screening. However, these studies yielded inconsistent findings related to outcome measures due to the variability of measurement criteria. PMID- 26769984 TI - THE RESPONSE OF DRUG EXPENDITURE TO NON-LINEAR CONTRACT DESIGN: EVIDENCE FROM MEDICARE PART D. AB - We study the demand response to non-linear price schedules using data on insurance contracts and prescription drug purchases in Medicare Part D. We exploit the kink in individuals' budget set created by the famous "donut hole," where insurance becomes discontinuously much less generous on the margin, to provide descriptive evidence of the drug purchase response to a price increase. We then specify and estimate a simple dynamic model of drug use that allows us to quantify the spending response along the entire non-linear budget set. We use the model for counterfactual analysis of the increase in spending from "filling" the donut hole, as will be required by 2020 under the Affordable Care Act. In our baseline model, which considers spending decisions within a single year, we estimate that "filling" the donut hole will increase annual drug spending by about $150, or about 8 percent. About one-quarter of this spending increase reflects "anticipatory" behavior, coming from beneficiaries whose spending prior to the policy change would leave them short of reaching the donut hole. We also present descriptive evidence of cross-year substitution of spending by individuals who reach the kink, which motivates a simple extension to our baseline model that allows - in a highly stylized way - for individuals to engage in such cross year substitution. Our estimates from this extension suggest that a large share of the $150 drug spending increase could be attributed to cross-year substitution, and the net increase could be as little as $45 per year. PMID- 26769983 TI - Social status drives social relationships in groups of unrelated female rhesus macaques. AB - Strong social relationships confer health and fitness benefits in a number of species, motivating the need to understand the processes through which they arise. In female cercopithecine primates, both kinship and dominance rank are thought to influence rates of affiliative behaviour and social partner preference. Teasing apart the relative importance of these factors has been challenging, however, as female kin often occupy similar positions in the dominance hierarchy. Here, we isolated the specific effects of rank on social relationships in female rhesus macaques by analysing grooming patterns in 18 social groups that did not contain close relatives, and in which dominance ranks were experimentally randomized. We found that grooming was asymmetrically directed towards higher-ranking females and that grooming bouts temporarily decreased the likelihood of aggression between grooming partners, supporting the idea that grooming is associated with social tolerance. Even in the absence of kin, females formed the strongest grooming relationships with females adjacent to them in rank, a pattern that was strongest for the highest-ranking females. Using simulations, we show that three rules for allocating grooming based on dominance rank recapitulated most of the relationships we observed. Finally, we evaluated whether a female's tendency to engage in grooming behaviour was stable across time and social setting. We found that one measure, the rate of grooming females provided to others (but not the rate of grooming females received), exhibited modest stability after accounting for the primary effect of dominance rank. Together, our findings indicate that dominance rank has strong effects on social relationships in the absence of kin, suggesting the importance of considering social status and social connectedness jointly when investigating their health and fitness consequences. PMID- 26769985 TI - MORAL HAZARD IN HEALTH INSURANCE: DO DYNAMIC INCENTIVES MATTER? AB - Using data from employer-provided health insurance and Medicare Part D, we investigate whether healthcare utilization responds to the dynamic incentives created by the nonlinear nature of health insurance contracts. We exploit the fact that, because annual coverage usually resets every January, individuals who join a plan later in the year face the same initial ("spot") price of healthcare but a higher expected end-of-year ("future") price. We find a statistically significant response of initial utilization to the future price, rejecting the null that individuals respond only to the spot price. We discuss implications for analysis of moral hazard in health insurance. PMID- 26769987 TI - Health systems strengthening, universal health coverage, health security and resilience. PMID- 26769988 TI - A shortage of oral morphine in Egypt. PMID- 26769990 TI - Healing invisible wounds of the Syrian conflict. AB - Mental health services are becoming more widely available than ever before to the Syrian population in spite of the crisis. Dale Gavlak reports. PMID- 26769991 TI - Research partnerships to solve health problems. AB - The research landscape in sub-Saharan Africa has transformed over the last two decades. Charles Mgone talks to Fiona Fleck about building partnerships. PMID- 26769992 TI - Estimating mortality using data from civil registration: a cross-sectional study in India. AB - OBJECTIVE: To analyse the design and operational status of India's civil registration and vital statistics system and facilitate the system's development into an accurate and reliable source of mortality data. METHODS: We assessed the national civil registration and vital statistics system's legal framework, administrative structure and design through document review. We did a cross sectional study for the year 2013 at national level and in Punjab state to assess the quality of the system's mortality data through analyses of life tables and investigation of the completeness of death registration and the proportion of deaths assigned ill-defined causes. We interviewed registrars, medical officers and coders in Punjab state to assess their knowledge and practice. FINDINGS: Although we found the legal framework and system design to be appropriate, data collection was based on complex intersectoral collaborations at state and local level and the collected data were found to be of poor quality. The registration data were inadequate for a robust estimate of mortality at national level. A medically certified cause of death was only recorded for 965,992 (16.8%) of the 5,735,082 deaths registered. CONCLUSION: The data recorded by India's civil registration and vital statistics system in 2011 were incomplete. If improved, the system could be used to reliably estimate mortality. We recommend improving political support and intersectoral coordination, capacity building, computerization and state-level initiatives to ensure that every death is registered and that reliable causes of death are recorded - at least within an adequate sample of registration units within each state. PMID- 26769993 TI - Prevention of neural tube defects by the fortification of flour with folic acid: a population-based retrospective study in Brazil. AB - OBJECTIVE: To determine if the fortification of wheat and maize flours with iron and folic acid - which became mandatory in Brazil from June 2004 - is effective in the prevention of neural tube defects. METHODS: Using data from national information systems on births in central, south-eastern and southern Brazil, we determined the prevalence of neural tube defects among live births and stillbirths in a pre-fortification period - i.e. 2001-2004 - and in a post fortification period - i.e. 2005-2014. We distinguished between anencephaly, encephalocele, meningocele, myelomeningocele and other forms of spina bifida. FINDINGS: There were 8554 neural tube defects for 17,925,729 live births notified between 2001 and 2014. For the same period, 2673 neural tube defects were reported for 194,858 stillbirths. The overall prevalence of neural tube defects fell from 0.79 per 1000 pre-fortification to 0.55 per 1000 post-fortification (prevalence ratio, PR: 1.43; 95% confidence interval, CI: 1.38-1.50). For stillbirths, prevalence fell from 17.74 per 1000 stillbirths pre-fortification to 11.70 per 1000 stillbirths post-fortification. The corresponding values among live births were 0.57 and 0.44, respectively. CONCLUSION: The introduction of the mandatory fortification of flour with iron and folic acid in Brazil was followed by a significant reduction in the prevalence of neural tube defects in our study area. PMID- 26769994 TI - Medical tourism in Thailand: a cross-sectional study. AB - OBJECTIVE: To investigate the magnitude and characteristics of medical tourism in Thailand and the impact of such tourism on the Thai health system and economy. METHODS: In 2010, we checked the records of all visits to five private hospitals that are estimated to cover 63% of all foreign patients. We reviewed hospital records of foreign patients and obtained data on their countries of origin, diagnoses and interventions. We surveyed 293 medical tourists to collect demographic characteristics and information on their expenditure and travelling companions. To help understand the impact of medical tourism on the Thai health system, we also interviewed 15 hospital executives and 28 service providers from the private hospitals. FINDINGS: We obtained 911,913 records of hospital visits, of which 324,906 came from 104,830 medical tourists. We estimated that there were 167,000 medical tourists in Thailand in 2010. Of the medical tourists who attended our study hospitals, 67,987 (64.8%) came from the eastern Mediterranean region or Asia and 109,509 (34%) of them were treated for simple and uncomplicated conditions - i.e. general check-ups and medical consultations. The mean self-reported non-medical expenditure was 2750 United States dollars. According to the hospital staff interviewed, medical tourism in 2010 brought benefits to - and apparently had no negative impacts on - the Thai health system and economy. CONCLUSION: We estimate that the total number of medical tourists visiting Thailand is about 10% of previous national government estimates of 1.2 million. Such tourists appear to bring economic benefits to Thailand and to have negligible effects on the health system. PMID- 26769995 TI - Schistosomiasis in school-age children in Burkina Faso after a decade of preventive chemotherapy. AB - OBJECTIVE: To assess the impact of a decade of biennial mass administration of praziquantel on schistosomiasis in school-age children in Burkina Faso. METHODS: In 2013, in a national assessment based on 22 sentinel sites, 3514 school children aged 7-11 years were checked for Schistosoma haematobium and Schistosoma mansoni infection by the examination of urine and stool samples, respectively. We analysed the observed prevalence and intensity of infections and compared these with the relevant results of earlier surveys in Burkina Faso. FINDINGS: S. haematobium was detected in 287/3514 school children (adjusted prevalence: 8.76%, range across sentinel sites: 0.0-56.3%; median: 2.5%). The prevalence of S. haematobium infection was higher in the children from the Centre-Est, Est and Sahel regions than in those from Burkina Faso's other eight regions with sentinel sites (P < 0.001). The adjusted arithmetic mean intensity of S. haematobium infection, among all children, was 6.0 eggs per 10 ml urine. Less than 1% of the children in six regions had heavy S. haematobium infections - i.e. at least 50 eggs per 10 ml urine - but such infections were detected in 8.75% (28/320) and 11.56% (37/320) of the children from the Centre-Est and Sahel regions, respectively. Schistosoma mansoni was only detected in two regions and 43 children - i.e. 1 (0.31%) of the 320 from Centre-Sud and 42 (8.75%) of the 480 from Hauts Bassins. CONCLUSION: By mass use of preventive chemotherapy, Burkina Faso may have eliminated schistosomiasis as a public health problem in eight regions and controlled schistosome-related morbidity in another three regions. PMID- 26769996 TI - An integrated national mortality surveillance system for death registration and mortality surveillance, China. AB - In China, sample-based mortality surveillance systems, such as the Chinese Center for Disease Control and Prevention's disease surveillance points system and the Ministry of Health's vital registration system, have been used for decades to provide nationally representative data on health status for health-care decision making and performance evaluation. However, neither system provided representative mortality and cause-of-death data at the provincial level to inform regional health service needs and policy priorities. Moreover, the systems overlapped to a considerable extent, thereby entailing a duplication of effort. In 2013, the Chinese Government combined these two systems into an integrated national mortality surveillance system to provide a provincially representative picture of total and cause-specific mortality and to accelerate the development of a comprehensive vital registration and mortality surveillance system for the whole country. This new system increased the surveillance population from 6 to 24% of the Chinese population. The number of surveillance points, each of which covered a district or county, increased from 161 to 605. To ensure representativeness at the provincial level, the 605 surveillance points were selected to cover China's 31 provinces using an iterative method involving multistage stratification that took into account the sociodemographic characteristics of the population. This paper describes the development and operation of the new national mortality surveillance system, which is expected to yield representative provincial estimates of mortality in China for the first time. PMID- 26769997 TI - Reporting guidelines for implementation and operational research. AB - In public health, implementation research is done to improve access to interventions that have been shown to work but have not reached many of the people who could benefit from them. Researchers identify practical problems facing public health programmes and aim to find solutions that improve health outcomes. In operational research, routinely-collected programme data are used to uncover ways of delivering more effective, efficient and equitable health care. As implementation research can address many types of questions, many research designs may be appropriate. Existing reporting guidelines partially cover the methods used in implementation and operational research, so we ran a consultation through the World Health Organization (WHO), the Alliance for Health Policy & Systems Research (AHPSR) and the Special Programme for Research and Training in Tropical Diseases (TDR) and developed guidelines to facilitate the funding, conduct, review and publishing of such studies. Our intention is to provide a practical reference for funders, researchers, policymakers, implementers, reviewers and editors working with implementation and operational research. This is an evolving field, so we plan to monitor the use of these guidelines and develop future versions as required. PMID- 26769999 TI - Supporting the production of pharmaceuticals in Africa. PMID- 26769998 TI - A staff support programme for rural hospitals in Nepal. AB - PROBLEM: District hospitals in Nepal struggle to provide essential services such as caesarean sections. APPROACH: Retention of health workers is critical to the delivery of long-term, quality health-care services. To promote retention and enhance performance in rural public hospitals, the Government of Nepal and the Nick Simons Institute progressively implemented a rural staff support programme in remote hospitals. After competitive selection for a compulsory-service scholarship and training, family practice doctors who could do basic surgery, orthopaedics and obstetrics were hired under a binding three-year contract in each participating hospital. Comfortable living quarters and an Internet connection were provided for the resident doctors; in-service training for all staff and capacity development for each hospital's management committee were provided. LOCAL SETTING: Nepal's mountainous landscape, poverty and inequitable rural/urban distribution of health workers pose barriers to adequate health care. RELEVANT CHANGES: Between 2011 and 2015 family practice doctors were maintained in all seven programme hospitals. All hospitals became providers of comprehensive emergency obstetric care and served more patients. Compared with hospitals not within the programme, deliveries increased significantly (203% versus 71% increase, respectively; P = 0.002). The programme recently expanded to 14 hospitals. LESSONS LEARNT: A package of human resource supports can improve the retention of doctors and the use of remote hospitals. Factors contributing to the success of this programme were compulsory-service scholarship, central personnel management, performance-based incentives and the provision of comfortable living quarters. PMID- 26770000 TI - Providing health care in rural and remote areas: lessons from the international space station. PMID- 26770002 TI - Semiparametric Theory for Causal Mediation Analysis: efficiency bounds, multiple robustness, and sensitivity analysis. AB - Whilst estimation of the marginal (total) causal effect of a point exposure on an outcome is arguably the most common objective of experimental and observational studies in the health and social sciences, in recent years, investigators have also become increasingly interested in mediation analysis. Specifically, upon evaluating the total effect of the exposure, investigators routinely wish to make inferences about the direct or indirect pathways of the effect of the exposure not through or through a mediator variable that occurs subsequently to the exposure and prior to the outcome. Although powerful semiparametric methodologies have been developed to analyze observational studies, that produce double robust and highly efficient estimates of the marginal total causal effect, similar methods for mediation analysis are currently lacking. Thus, this paper develops a general semiparametric framework for obtaining inferences about so-called marginal natural direct and indirect causal effects, while appropriately accounting for a large number of pre-exposure confounding factors for the exposure and the mediator variables. Our analytic framework is particularly appealing, because it gives new insights on issues of efficiency and robustness in the context of mediation analysis. In particular, we propose new multiply robust locally efficient estimators of the marginal natural indirect and direct causal effects, and develop a novel double robust sensitivity analysis framework for the assumption of ignorability of the mediator variable. PMID- 26770003 TI - How has Radical Right Support Transformed Established Political Conflicts? The Case of Austria. PMID- 26770005 TI - Almost an Earthquake: The Austrian Parliamentary Election of 2013. PMID- 26770004 TI - Coalition Policy-Making under Constraints: Examining the Role of Preferences and Institutions. PMID- 26770006 TI - Risky decision making in a laboratory driving task is associated with health risk behaviors during late adolescence but not adulthood. AB - Adolescence is characterized by increasing incidence of health risk behaviors, including experimentation with drugs and alcohol. To fill the gap in our understanding of the associations between risky decision-making and health risk behaviors, we investigated associations between laboratory-based risky decision making using the Stoplight task and self-reported health risk behaviors. Given that there has been no examination of potential age differences in the associations between risky decision-making and health risk behaviors, we also examined whether the association of risky decision-making with health risk behaviors is consistent across adolescence and adulthood using two-group structural equation modeling (SEM). The results indicated significant differences across the two age groups: adolescents (17-20 year olds) who took more risks on the Stoplight task reported greater frequency and earlier onset of substance use, whereas stoplight performance was not associated with substance use frequency or onset among adults (31-61 year olds). Our findings suggest that a laboratory based measure of risky decision-making is significantly related to health risk behaviors among adolescents but not among adults. PMID- 26770007 TI - Developing policy analytics for public health strategy and decisions-the Sheffield alcohol policy model framework. AB - This paper sets out the development of a methodological framework for detailed evaluation of public health strategies for alcohol harm reduction to meet UK policy-makers needs. Alcohol is known to cause substantial harms, and controlling its affordability and availability are effective policy options. Analysis and synthesis of a variety of public and commercial data sources is needed to evaluate impact on consumers, health services, crime, employers and industry, so a sound evaluation of impact is important. We discuss the iterative process to engage with stakeholders, identify evidence/data and develop analytic approaches and produce a final model structure. We set out a series of steps in modelling impact including: classification and definition of population subgroups of interest, identification and definition of harms and outcomes for inclusion, classification of modifiable components of risk and their baseline values, specification of the baseline position on policy variables especially prices, estimating effects of changing policy variables on risk factors including price elasticities, quantifying risk functions relating risk factors to harms including 47 health conditions, crimes, absenteeism and unemployment, and monetary valuation. The most difficult model structuring decisions are described, as well as the final results framework used to provide decision support to national level policymakers in the UK. In the discussion we explore issues around the relationship between modelling and policy debates, valuation and scope, limitations of evidence/data, how the framework can be adapted to other countries and decisions. We reflect on the approach taken and outline ongoing plans for further development. PMID- 26770008 TI - Evaluation of the In Vivo and In Vitro Effects of Fructose on Respiratory Chain Complexes in Tissues of Young Rats. AB - Hereditary fructose intolerance (HFI) is an autosomal-recessive disorder characterized by fructose and fructose-1-phosphate accumulation in tissues and biological fluids of patients. This disease results from a deficiency of aldolase B, which metabolizes fructose in the liver, kidney, and small intestine. We here investigated the effect of acute fructose administration on the activities of mitochondrial respiratory chain complexes, succinate dehydrogenase (SDH), and malate dehydrogenase (MDH) in cerebral cortex, liver, kidney, and skeletal muscle of male 30-day-old Wistar rats. The rats received subcutaneous injection of sodium chloride (0.9%; control group) or fructose solution (5 MUmol/g; treated group). One hour later, the animals were euthanized and the cerebral cortex, liver, kidney, and skeletal muscle were isolated and homogenized for the investigations. Acute fructose administration increased complex I-III activity in liver. On the other hand, decreased complexes II and II-III activities in skeletal muscle and MDH in kidney were found. Interestingly, none of these parameters were affected in vitro. Our present data indicate that fructose administration elicits impairment of mitochondrial energy metabolism, which may contribute to the pathogenesis of the HFI patients. PMID- 26770010 TI - Spatial Variation in EU Poverty with Respect to Health, Education and Living Standards. AB - We examine the European Union (EU) countries and within-country areas (i.e., large urban areas, small urban areas, and rural areas) that are the most disadvantageous with respect to multidimensional poverty and in each of the investigated dimensions, i.e., health, education, and living standards. To this end, we construct the Multidimensional Poverty Index and its sub-indices: the Poverty in Health Index, Poverty in Education Index, and Poverty in Standard of Living Index. All of these indices provide information regarding the fraction of people who live in poverty, as well as information on the poverty intensity experienced by the poor. Our results indicate that the scale of poverty in the EU countries is diversified, with Denmark and Sweden being the most affluent countries, and Latvia, Bulgaria, and Romania being the most disadvantageous. We demonstrate that there are countries with no differences in the levels of poverty within a country, such as Denmark, Sweden, Spain, Finland, and the Czech Republic, and countries, usually less affluent ones such as Romania, Bulgaria and Lithuania, where considerable geographical inequality is present. In general, in countries with a high and moderately high number of poor, the worst situation with respect to the scale of poverty is observed in rural areas, and the best situation is observed in large urban areas, with the exception of Greece, Italy, and Portugal, where in large urban areas, the situation is the worst. In countries with a low number of poor, in general, the poverty is relatively higher in large urban areas. PMID- 26770011 TI - For Whom Money Matters Less: Social Connectedness as a Resilience Resource in the UK. AB - The current literature shows that both absolute and relative income are important for happiness, but there is little work emphasising how the strength of the relationship is dependent on personal and social factors. I hypothesise that social connectedness influences the money-happiness relationship because the effect of money is in part felt through the acquisition of social status, whereas status (and associated psychological benefits such as self-worth) can alternatively be gained through social connectedness. In particular, it is theorised that 'weak ties' when co-existing with good quality informal ties have a separable and additional benefit to subjective well-being, and that it is the socially isolated who have the most to gain from doing well financially. Social connectedness is conceptualised as a 'resilience resource' which has a buffering effect on subjective well-being. Data from the British Household Panel Survey are used, first to establish a measurement schema of connectedness using latent class analysis, and secondly in a multilevel model of life satisfaction with observations from seven consecutive years nested within individuals. The results show that connectedness makes a larger difference to satisfaction in times of financial stress, and that the satisfaction of the socially isolated can 'catch up' to some degree with those with larger networks when things are going well financially. The findings also confirm that those for whom money makes the smallest contribution to happiness are those with both strong and weak ties. Weak ties have an additional benefit compared to having strong ties alone. In summary, connectedness has the power to narrow the well-being gap that exists between times of financial struggle and times of relative comfort. It suggests that the psychological benefits of social integration have the capacity to displace money as a source of status and self-worth, and similarly that the importance of money may be exaggerated where these psychological gains are not available through other domains of life. PMID- 26770009 TI - Steroid Hormone Receptor Signals as Prognosticators for Urothelial Tumor. AB - There is a substantial amount of preclinical or clinical evidence suggesting that steroid hormone receptor-mediated signals play a critical role in urothelial tumorigenesis and tumor progression. These receptors include androgen receptor, estrogen receptors, glucocorticoid receptor, progesterone receptor, vitamin D receptor, retinoid receptors, peroxisome proliferator-activated receptors, and others including orphan receptors. In particular, studies using urothelial cancer tissue specimens have demonstrated that elevated or reduced expression of these receptors as well as alterations of their upstream or downstream pathways correlates with patient outcomes. This review summarizes and discusses available data suggesting that steroid hormone receptors and related signals serve as biomarkers for urothelial carcinoma and are able to predict tumor recurrence or progression. PMID- 26770012 TI - Alizarin Dye based ultrasensitive plasmonic SERS probe for trace level Cadmium detection in drinking water. AB - Alizarin functionalized on plasmonic gold nanoparticle displays strong surface enhanced Raman scattering from the various Raman modes of Alizarin, which can be exploited in multiple ways for heavy metal sensing purposes. The present article reports a surface enhanced Raman spectroscopy (SERS) probe for trace level Cadmium in water samples. Alizarin, a highly Raman active dye was functionalized on plasmonic gold surface as a Raman reporter, and then 3-mercaptopropionic acid, 2,6-Pyridinedicarboxylic acid at pH 8.5 was immobilized on the surface of the nanoparticle for the selective coordination of the Cd (II). Upon addition of Cadmium, gold nanoparticle provide an excellent hotspot for Alizarin dye and Raman signal enhancement. This plasmonic SERS assay provided an excellent sensitivity for Cadmium detection from the drinking water samples. We achieved as low as 10 ppt sensitivity from various drinking water sources against other Alkali and heavy metal ions. The developed SERS probe is quite simple and rapid with excellent repeatability and has great potential for prototype scale up for field application. PMID- 26770014 TI - Combining functional weed ecology and crop stable isotope ratios to identify cultivation intensity: a comparison of cereal production regimes in Haute Provence, France and Asturias, Spain. AB - This investigation combines two independent methods of identifying crop growing conditions and husbandry practices-functional weed ecology and crop stable carbon and nitrogen isotope analysis-in order to assess their potential for inferring the intensity of past cereal production systems using archaeobotanical assemblages. Present-day organic cereal farming in Haute Provence, France features crop varieties adapted to low-nutrient soils managed through crop rotation, with little to no manuring. Weed quadrat survey of 60 crop field transects in this region revealed that floristic variation primarily reflects geographical differences. Functional ecological weed data clearly distinguish the Provence fields from those surveyed in a previous study of intensively managed spelt wheat in Asturias, north-western Spain: as expected, weed ecological data reflect higher soil fertility and disturbance in Asturias. Similarly, crop stable nitrogen isotope values distinguish between intensive manuring in Asturias and long-term cultivation with minimal manuring in Haute Provence. The new model of cereal cultivation intensity based on weed ecology and crop isotope values in Haute Provence and Asturias was tested through application to two other present day regimes, successfully identifying a high-intensity regime in the Sighisoara region, Romania, and low-intensity production in Kastamonu, Turkey. Application of this new model to Neolithic archaeobotanical assemblages in central Europe suggests that early farming tended to be intensive, and likely incorporated manuring, but also exhibited considerable variation, providing a finer grained understanding of cultivation intensity than previously available. PMID- 26770015 TI - The Relationship between Training and Mental Health among Caregivers of Individuals with Polytrauma. AB - This was a hypothesis-generating exploration of relationships between caregiver training during TBI/polytrauma rehabilitation and caregiver mental health. In this cross-sectional study, 507 informal caregivers to US service members with TBI who received inpatient rehabilitation care in a Veterans Affairs' Polytrauma Rehabilitation Center from 2001 to 2009 completed a retrospective, self-report survey. Embedded in the survey were measures of caregiver mental health, including the National Institutes of Health's Patient Reported Outcome Measurement Information System (PROMIS) Anxiety and Depression Short Forms, the Rosenberg Self-Esteem scale, and the Zarit Burden Short Form. Though no groups endorsed clinical levels, mental health symptoms varied by caregiver training category (Trained, Not Trained, and Did Not Need Training). Caregivers who did not receive training on how to navigate healthcare systems endorsed higher depression and burden and lower self-esteem than those who did. Caregivers who did not receive training in supporting their care recipients' emotions endorsed higher anxiety, depression, and burden and lower self-esteem than those who did. Analyses also suggested a different association between training and mental health based on caregivers' relationship to the care recipient and the intensity of care recipient needs. Potential hypotheses for testing in future studies raised by these findings are discussed. PMID- 26770016 TI - Tumor-Induced Local and Systemic Impact on Blood Vessel Function. AB - Endothelial dysfunction plays a role in several processes that contribute to cancer-associated mortality. The vessel wall serves as a barrier for metastatic tumor cells, and the integrity and activation status of the endothelium serves as an important defense mechanism against metastasis. In addition, leukocytes, such as cytotoxic T-cells, have to travel across the vessel wall to enter the tumor tissue where they contribute to killing of cancer cells. Tumor cells can alter the characteristics of the endothelium by recruitment of leukocytes such as neutrophils and macrophages, which further stimulate inflammation and promote tumorigenesis. Recent findings also suggest that leukocyte-mediated effects on vascular function are not limited to the primary tumor or tissues that represent metastatic sites. Peripheral organs, such as kidney and heart, also display impaired vascular function in tumor-bearing individuals, potentially contributing to organ failure. Here, we discuss how vascular function is altered in malignant tissue and distant organs in individuals with cancer and how leukocytes function as potent mediators of these tumor-induced effects. PMID- 26770017 TI - Advances in T Helper 17 Cell Biology: Pathogenic Role and Potential Therapy in Multiple Sclerosis. AB - The discovery of the T helper (Th) 17 lineage, involved in the protection against fungal and extracellular bacterial infections, has profoundly revolutionized our current understanding of T cell-mediated responses in autoimmune diseases, including multiple sclerosis (MS). Indeed, recent data demonstrate the pathogenic role of Th17 cells in autoimmune disorders. In particular, studies in MS and in its animal model (EAE, experimental autoimmune encephalomyelitis) have revealed a crucial role of Th17 cells in the pathogenesis of autoimmune demyelinating diseases in both mice and humans. Over the past years, several important aspects concerning Th17 cells have been elucidated, such as the factors which promote or inhibit their differentiation and the effector cytokines which mediate their responses. The identification of the features endowing Th17 cells with high pathogenicity in MS is of particular interest, and discoveries in Th17 cell biology and function could lead to the design of new strategies aimed at modulating the immune response in MS. Here, we will discuss recent advances in this field, with particular focus on the mechanisms conferring pathogenicity in MS and their potential modulation. PMID- 26770019 TI - Metalloproteinases and Their Tissue Inhibitors in Comparison between Different Chronic Pneumopathies in the Horse. AB - In chronic respiratory disease, matrix metalloproteinases (MMPs) contribute to pathological tissue destruction when expressed in excess, while tissue inhibitors of metalloproteinases (TIMPs) counteract MMPs with overexpression leading to fibrosis formation. They may be out of balance in equine pneumopathies and serve as biomarkers of pulmonary inflammation. We hypothesized that MMPs and TIMPs correlate to clinical findings and bronchoalveolar lavage fluid cytology in different equine chronic pneumopathies. Using a scoring system, 61 horses were classified controls as free of respiratory disease (n = 15), recurrent airway obstruction (RAO, n = 17), inflammatory airway disease (IAD, n = 18), or chronic interstitial pneumopathy (CIP, n = 11). Zymography and equine MMP and TIMP assays were used to detect MMP-2, MMP-8, MMP-9 as well as TIMP-1, and TIMP-2 in BALF supernatant. MMP-2, TIMP-1, and TIMP-2 concentrations were significantly increased in RAO and IAD compared to controls. MMP-9 concentration and MMP-8 activity evaluated by fluorimetry were significantly increased in RAO, IAD, and CIP. These results were confirmed by zymography for MMP-2 and MMP-9 activity in 52 horses. In conclusion, MMPs and TIMPs correlate well with clinical and cytologic findings. These findings support the usefulness of MMPs, TIMPs, and their ratios to evaluate the severity of respiratory disease and may help to identify subclinical cases. PMID- 26770020 TI - Differential Expression of MUC12, MUC16, and MUC20 in Patients with Active and Remission Ulcerative Colitis. AB - Background. Patients with UC have shown an important defect in the secretion and maintenance of the mucosal barrier as part of inadequate expression of mucin genes. The aim of the present study was to determine the expression of MUC12, MUC16, and MUC20 in colonic tissue from patients with UC in regard to their clinical outcomes. Methods. We included a total of 40 patients with UC and 30 normal controls. Mucin gene expression was performed by RT-PCR and protein expression was detected by immunohistochemistry. Results. Patients with active UC showed no significant expression of MUC12 gene in mucosa compared to the group of patients with UC in remission and the normal control group. MUC16 gene expression was significantly increased in the UC active and remission groups compared to the normal control group (P = 0.03). MUC20 gene expression was found significantly decreased in patients with active UC compared to both remission group (P = 0.001) and normal controls (P = 0.001). Furthermore, an association was found between MUC20 gene expression and the presence of histological remission in patients with UC (P = 0.003, OR = 0.37). Conclusions. An increased gene expression of MUC16 and MUC20 was found in patients with remission UC. PMID- 26770018 TI - Role of Sphingolipids in the Pathobiology of Lung Inflammation. AB - Sphingolipid bioactivities in the respiratory airways and the roles of the proteins that handle them have been extensively investigated. Gas or inhaled particles or microorganisms come into contact with mucus components, epithelial cells, blood barrier, and immune surveillance within the airways. Lung structure and functionality rely on a complex interplay of polar and hydrophobic structures forming the surfactant layer and governing external-internal exchanges, such as glycerol-phospholipids sphingolipids and proteins. Sphingolipids act as important signaling mediators involved in the control of cell survival and stress response, as well as secreted molecules endowed with inflammation-regulatory activities. Most successful respiratory infection and injuries evolve in the alveolar compartment, the critical lung functional unit involved in gas exchange. Sphingolipid altered metabolism in this compartment is closely related to inflammatory reaction and ceramide increase, in particular, favors the switch to pathological hyperinflammation. This short review explores a few mechanisms underlying sphingolipid involvement in the healthy lung (surfactant production and endothelial barrier maintenance) and in a selection of lung pathologies in which the impact of sphingolipid synthesis and metabolism is most apparent, such as acute lung injury, or chronic pathologies such as cystic fibrosis and chronic obstructive pulmonary disease. PMID- 26770021 TI - Peripheral NMDA Receptors Mediate Antidromic Nerve Stimulation-Induced Tactile Hypersensitivity in the Rat. AB - We investigated the role of peripheral NMDA receptors (NMDARs) in antidromic nerve stimulation-induced tactile hypersensitivity outside the skin area innervated by stimulated nerve. Tetanic electrical stimulation (ES) of the decentralized L5 spinal nerve, which induced enlargement of plasma extravasation, resulted in tactile hypersensitivity in the L4 plantar dermatome of the hind-paw. When intraplantar (i.pl.) injection was administered into the L4 dermatome before ES, NMDAR and group-I metabotropic Glu receptor (mGluR) antagonists and group-II mGluR agonist but not AMPA/kainate receptor antagonist prevented ES-induced hypersensitivity. I.pl. injection of PKA or PKC inhibitors also prevented ES induced hypersensitivity. When the same injections were administered after establishment of ES-induced hypersensitivity, hypersensitivity was partially reduced by NMDAR antagonist only. In naive animals, i.pl. Glu injection into the L4 dermatome induced tactile hypersensitivity, which was blocked by NMDAR antagonist and PKA and PKC inhibitors. These results suggest that the peripheral release of Glu, induced by antidromic nerve stimulation, leads to the expansion of tactile hypersensitive skin probably via nociceptor sensitization spread due to the diffusion of Glu into the skin near the release site. In addition, intracellular PKA- and PKC-dependent mechanisms mediated mainly by NMDAR activation are involved in Glu-induced nociceptor sensitization and subsequent hypersensitivity. PMID- 26770023 TI - Synergistic Stimulation with Different TLR7 Ligands Modulates Gene Expression Patterns in the Human Plasmacytoid Dendritic Cell Line CAL-1. AB - OBJECTIVE: TLR7 ligation in plasmacytoid dendritic cells is promising for the treatment of cancer, allergy, and infectious diseases; however, high doses of ligands are required. We hypothesized that the combination of structurally different TLR7 ligands exponentiates the resulting immune response. METHODS: CAL 1 (human pDC line) cells were incubated with the TLR7-specific adenine analog CL264 and single-stranded 9.2s RNA. Protein secretion was measured by ELISA. Microarray technique was used to detect modified gene expression patterns upon synergistic stimulation, revealing underlying functional groups and networks. Cell surface binding properties were studied using FACS analysis. RESULTS: CL264 in combination with 9.2s RNA significantly enhanced cytokine and interferon secretion to supra-additive levels. This effect was due to a stronger stimulation of already regulated genes (by monostimulation) as well as to recruitment of thus far unregulated genes. Top scoring canonical pathways referred to immune-related processes. Network analysis revealed IL-1beta, IL-6, TNF, and IFN-beta as major regulatory nodes, while several minor regulatory nodes were also identified. Binding of CL264 to the cell surface was enhanced by 9.2s RNA. CONCLUSION: Structurally different TLR7 ligands act synergistically on gene expression patterns and on the resulting inflammatory response. These data could impact future strategies optimizing TLR7-targeted drug design. PMID- 26770024 TI - Insights from the predicted epitope similarity between Mycobacterium tuberculosis virulent factors and its human homologs. AB - Mycobacterium tuberculosis is known to be associated with several autoimmune diseases such as systemic lupus erythematous, rheumatoid arthritis and multiple sclerosis. This is attributed to sequence similarity between virulent factors and human proteins. Therefore, it is of interest to identify such regions in the virulent factors to assess potential autoimmune related information. M. tb specific virulent factors were downloaded from the VFDB database and its human homologs were identified using the sequence comparison search tool BLASTP. Both virulent proteins and their corresponding human homologs were further scanned for epitopes (B cell and HLA class I and II allele specific) using prediction programs (BCPRED and NETMHC). Data shows the presence of matching 22 B-cell, 79 HLA class II and 16 HLA class I specific predicted epitopes in these virulent factors having human homologs. A known peptide (HAFYLQYKNVKVDFA) associated with autoimmune atopic dermatitis is shown in the superoxide dismutase homolog structures of the bacterium (PDB ID: 1IDS) and human (PDB ID: 2QKC). This data provides insight into the understanding of infection-associated auto-immunity. PMID- 26770025 TI - Molecular docking based screening of G6PS with 1, 5 Benzothiazepine derivates for a potential inhibitor. AB - Glucosamine-6-phosphate synthase (G6PS) (EC 2.6.1.16) is a known target for anti bacterial and anti-fungal infections. Therefore, it is of interest to design potential inhibitors using 1, 5 benzo-thiazepine skeleton with appropriate modifications. We report the binding data for 20 derivatives of the skeleton molecule to G6PS having binding energy from -7.35 to -9.99 Kcal/mol with predicted IC50 value range of 4.11 to 47.68 nano-molar. It should be noted that this data should be further evaluated using in vitro and in vivo studies for safety, activity, efficacy and toxicity. PMID- 26770027 TI - Shape based virtual screening and molecular docking towards designing novel pancreatic lipase inhibitors. AB - Increase in obesity rates and obesity associated health issues became one of the greatest health concerns in the present world population. With alarming increase in obese percentage there is a need to design new drugs related to the obesity targets. Among the various targets linked to obesity, pancreatic lipase was one of the promising targets for obesity treatment. Using the in silico methods like structure based virtual screening, QikProp, docking studies and binding energy calculations three molecules namely zinc85531017, zinc95919096 and zinc33963788 from the natural database were reported as the potential inhibitors for the pancreatic lipase. Among them zinc95919096 presented all the interactions matching to both standard and crystal ligand and hence it can be further proceeded to drug discovery process. PMID- 26770026 TI - Primary ovarian cancer cell inhibition by human Wharton's Jelly stem cells (hWJSCs): Mapping probable mechanisms and targets using systems oncology. AB - Ovarian cancer is one of the most lethal gynaecological cancers. Its subtle onset and absence of symptoms in early stages are associated with poor prognosis and high mortality. Identification of early biomarkers would aid in ovarian cancer control. Mesenchmal stem cells (MSCs) and/or their secretory products are identified to have cancer inhibitory properties. Therefore, it is of interest to study the anticancer properties of human Wharton's jelly stem cells conditioned medium (hWJSCs-CM) on primary ovarian carcinoma cells in vitro. Primary cultures of epithelial ovarian carcinoma cells (EOCs) and hWJSCs were used in this study. EOCs were exposed to hWJSC-CM (100%) for 24h-72h and changes in mophology and cell proliferation were monitored. Treatment with hWJSC-CM showed altered morphological changes that resulted in death of EOCs. Colorimetric assay [MTT, (3 (4, 5-dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide)] showed mean decreases in EOC proliferation by 16.21%, 23.89% and 40.08% at 24h, 48h and 72h respectively compared to control. Ingenuity Pathway Analysis (IPA, Igenuity Systems, USA) deduced important molecular pathways and signaling networks associated with cancer cell death and these correlated with significant expression of tumour suppresors and apoptotic genes in hWJSCs. Secretory products of hWJSC-CM induced cell death of EOCs via apoptosis. IPA identification of canonical genes/pathways involved in EOCs that overlap with hWJSCs tumour suppressors and apoptosis genes further support this hypotheis. Additional in vitro and in vivo studies are necessary to validate EOCs inhibition with hWJSC extracts towards their mechanism of action. PMID- 26770022 TI - Phosphodiesterase-5 Inhibitors: Action on the Signaling Pathways of Neuroinflammation, Neurodegeneration, and Cognition. AB - Phosphodiesterase type 5 inhibitors (PDE5-Is) have recently emerged as a potential therapeutic strategy for neuroinflammatory, neurodegenerative, and memory loss diseases. Mechanistically, PDE5-Is produce an anti-inflammatory and neuroprotection effect by increasing expression of nitric oxide synthases and accumulation of cGMP and activating protein kinase G (PKG), the signaling pathway of which is thought to play an important role in the development of several neurodiseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS). The aim of this paper was to review present knowledge of the signaling pathways that underlie the use of PDE5-Is in neuroinflammation, neurogenesis, learning, and memory. PMID- 26770029 TI - Computational identification of putative miRNAs and their target genes in pathogenic amoeba Naegleria fowleri. AB - Naegleria fowleri is a parasitic unicellular free living eukaryotic amoeba. The parasite spreads through contaminated water and causes primary amoebic meningoencephalitis (PAM). Therefore, it is of interest to understand its molecular pathogenesis. Hence, we analyzed the parasite genome for miRNAs (microRNAs) that are non-coding, single stranded RNA molecules. We identified 245 miRNAs using computational methods in N. fowleri, of which five miRNAs are conserved. The predicted miRNA targets were analyzed by using miRanda (software) and further studied the functions by subsequently annotating using AmiGo (a gene ontology web tool). PMID- 26770028 TI - Molecular docking analysis of known flavonoids as duel COX-2 inhibitors in the context of cancer. AB - Cyclooxygenase-2 (COX-2) catalyzed synthesis of prostaglandin E2 and it associates with tumor growth, infiltration, and metastasis in preclinical experiments. Known inhibitors against COX-2 exhibit toxicity. Therefore, it is of interest to screen natural compounds like flavanoids against COX-2. Molecular docking using 12 known flavanoids against COX-2 by FlexX and of ArgusLab were performed. All compounds showed a favourable binding energy of >-10 KJ/mol in FlexX and > -8 kcal/mol in ArgusLab. However, this data requires in vitro and in vivo verification for further consideration. PMID- 26770030 TI - Review of the Registration in the Clinical Research Information Service. AB - Clinical research registration is required in many countries to improve transparency of clinical research and to ensure subject safety. Developed in February 2010, the Clinical Research Information Service (CRIS) is an online registration system for clinical studies in Korea and one of the primary registries of the World Health Organization (WHO) International Clinical Trials Registry Platform. The present analysis investigated the characteristics of studies registered in the CRIS between February 2010 and December 2014. Data for the analysis were extracted from the CRIS database. As of December 31, 2014, 1,323 clinical studies were registered. Of these, 938 (70.9%) were interventional studies and 385 (29.1%) were observational studies. A total of 248 (18.7%) studies were funded by government sources, 1,051 (79.4%) by non-government sources, and 24 (1.8%) by both. The most frequently studied disease category based on the ICD-10 classification was the digestive system (13.1%), followed by the nervous system (9.4%) and musculoskeletal system (9.1%). Only 17.8% of the studies were registered prior to enrollment of the first subject. Comparing the number of registered or approved clinical studies between the CRIS, the Ministry of Food and Drug Safety, and ClinicalTrials.gov suggests that a considerable number of clinical studies are not registered with the CRIS; therefore, we would suggest that such registration should be the mandatory legal requirement. PMID- 26770031 TI - Estimates of Radiation Doses and Cancer Risk from Food Intake in Korea. AB - The aim of this study was to estimate internal radiation doses and lifetime cancer risk from food ingestion. Radiation doses from food intake were calculated using the Korea National Health and Nutrition Examination Survey and the measured radioactivity of (134)Cs, (137)Cs, and (131)I from the Ministry of Food and Drug Safety in Korea. Total number of measured data was 8,496 (3,643 for agricultural products, 644 for livestock products, 43 for milk products, 3,193 for marine products, and 973 for processed food). Cancer risk was calculated by multiplying the estimated committed effective dose and the detriment adjusted nominal risk coefficients recommended by the International Commission on Radiation Protection. The lifetime committed effective doses from the daily diet are ranged 2.957-3.710 mSv. Excess lifetime cancer risks are 14.4-18.1, 0.4-0.5, and 1.8-2.3 per 100,000 for all solid cancers combined, thyroid cancer, and leukemia, respectively. PMID- 26770032 TI - Immunogenicity and Safety of a Live Attenuated Zoster Vaccine (ZOSTAVAXTM) in Korean Adults. AB - A live attenuated zoster vaccine (ZOSTAVAXTM, Merck & Co., Inc.) was approved by the Korea Ministry of Food and Drug Safety in 2009. However, the immunogenicity and safety of the vaccine has not been assessed in Korean population. This is multi-center, open-label, single-arm study performed with 180 healthy Korean adults >= 50 yr of age. The geometric mean titer (GMT) and geometric mean fold rise (GMFR) of varicella zoster virus (VZV) antibodies were measured by glycoprotein enzyme-linked immunosorbent assay (gpELISA) at 4 weeks post vaccination. Subjects were followed for exposure to varicella or herpes zoster (HZ), the development of any varicella/varicella-like or HZ/HZ-like rashes, and any other clinical adverse experiences (AEs) for 42 days post-vaccination. For the 166 subjects included in the per-protocol population, the GMT at Day 1 was 66.9. At 4 weeks post-vaccination, the GMT for this population was 185.4, with a GMFR of 2.8 (95% CI, 2.5-3.1). Of the 180 subjects vaccinated, 62.8% experienced >= 1 AE, with 53.3% of subjects reporting injection-site AEs. The most frequently reported injection-site AEs were erythema (45.0%) with the majority being mild in intensity. Overall, 44 (24.4%) subjects experienced >= 1 systemic AE, 10 (5.5%) subjects experienced a systemic vaccine-related AE, and 3 (1.7%) subjects experienced >= 1 serious AE not related to vaccine. No subjects reported a VZV like rash. There was no subject of death and no subject discontinued due to an adverse event. A single dose of zoster vaccine induced VZV-specific gpELISA antibody response and was generally well-tolerated in healthy Korean adults >=50 yr of age (registry at www.clinicaltrial.gov No. NCT01556451). PMID- 26770033 TI - Allergenic Characterization of 27-kDa Glycoprotein, a Novel Heat Stable Allergen, from the Pupa of Silkworm, Bombyx mori. AB - Boiled silkworm pupa is a traditional food in Asia, and patients with silkworm pupa food allergy are common in these regions. Still now only one allergen from silkworm, arginine kinase, has been identified. The purpose of this study was to identify novel food allergens in silkworm pupa by analyzing a protein extract after heat treatment. Heat treated extracts were examined by proteomic analysis. A 27-kDa glycoprotein was identified, expressed in Escherichia coli, and purified. IgE reactivity of the recombinant protein was investigated by ELISA. High molecular weight proteins (above 100 kDa) elicited increased IgE binding after heat treatment compared to that before heat treatment. The molecular identities of these proteins, however, could not be determined. IgE reactivity toward a 27-kDa glycoprotein was also increased after heating the protein extract. The recombinant protein was recognized by IgE antibodies from allergic subjects (33.3%). Glycation or aggregation of protein by heating may create new IgE binding epitopes. Heat stable allergens are shown to be important in silkworm allergy. Sensitization to the 27-kDa glycoprotein from silkworm may contribute to elevation of IgE to silkworm. PMID- 26770034 TI - Prevalence and Relationships of Iron Deficiency Anemia with Blood Cadmium and Vitamin D Levels in Korean Women. AB - Anemia, iron deficiency (ID), and iron deficiency anemia (IDA) are common disorders. This study was undertaken to determine the prevalence of anemia, ID, and IDA in Korean females. We examined the associations between IDA, heavy metals in blood, vitamin D level and nutritional intakes. The study was performed using on data collected from 10,169 women (aged >= 10 yr), including 1,232 with anemia, 2,030 with ID, and 690 with IDA during the fifth Korea National Health and Nutrition Examination Survey (KNHANES V; 2010-2012). Prevalence and 95% confidence intervals were calculated, and path analysis was performed to identify a multivariate regression model incorporating IDA, heavy metals in blood, vitamin D level, and nutritional intakes. The overall prevalence of anemia, ID and IDA was 12.4%, 23.11%, and 7.7%, respectively. ID and IDA were more prevalent among adolescents (aged 15-18 yr; 36.5% for ID; 10.7% for IDA) and women aged 19-49 yr (32.7% for ID; 11.3% for IDA). The proposed path model showed that IDA was associated with an elevated cadmium level after adjusting for age and body mass index (beta=0.46, P<0.001). Vitamin D levels were found to affect IDA negatively (beta=-0.002, P<0.001). This study shows that the prevalence of anemia, ID, and IDA are relatively high in late adolescents and women of reproductive age. Path analysis showed that depressed vitamin D levels increase the risk of IDA, and that IDA increases cadmium concentrations in blood. Our findings indicate that systematic health surveillance systems including educational campaigns and well balanced nutrition are needed to control anemia, ID, and IDA. PMID- 26770035 TI - Utilization Patterns of Coagulation Factor Consumption for Patients with Hemophilia. AB - Hemophilia is a serious rare disease that requires continuous management and treatment for which the medicine is costly at the annual average of 100 million KRW for an individual. The aim of this study was to investigate trends in the utilization of coagulation factor (CF) used for hemophilia treatment using the National Health Insurance database from 2010 to 2013 in Korea and compare the utilization of CF with other countries. The consumption of CF per capita (IU) in Korea was not more than other countries with similar income to Korea. However, CF usage per patient IU was higher because the prevalence rate of hemophilia in Korea was lower than in other countries while the number of serious patients was much more. Therefore, it is difficult to say that the consumption of hemophilia medicine in Korea is higher than that in other countries. The consumption and cost of hemophilia medicine in Korea is likely to increase due to the increased utilization of expensive bypassing agents and the widespread use of prophylaxis for severe hemophilia. Even during the research period, it increased slightly and other countries show a similar trend. Thus, hemophilia patient management should accompany active monitoring on the health and cost outcomes of pharmaceutical treatment in the future. This study is expected to contribute to further insight into drug policies for other countries that face similar challenges with high price pharmaceuticals. PMID- 26770036 TI - Total Lesion Glycolysis Using 18F-FDG PET/CT as a Prognostic Factor for Locally Advanced Esophageal Cancer. AB - Standardized uptake value (SUV), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) have been considered prognostic factors for survival in many cancers. However, their prognostic value for radiotherapy-treated squamous esophageal cancer has not been evaluated. In this study, SUV, MTV, and TLG were measured to predict their prognostic role in overall survival (OS) in 38 esophageal cancer patients who had undergone (18)F-FDG PET/CT before radiotherapy. TLG demonstrated higher sensitivity and specificity for predicting OS than MTV and SUV; and a better OS was observed in patients with low TLG compared to those with high TLG in locally advanced disease (OS, 46.9 months; 95% confidence interval [CI], 33.50-60.26 vs. 25.3 months; 95% CI, 8.37-42.28; P=0.003). Multivariate analyses in these patients determined that TLG and the use of combination chemotherapy were the independent prognostic factors for OS (hazard ratio [HR], 7.12; 95% CI, 2.038-24.857; P=0.002 and HR, 6.76; 95% CI, 2.149-21.248; P=0.001, respectively). These results suggest that TLG is an independent prognostic factor for OS and a better predictor of survival than MTV and SUV in patients with locally advanced esophageal cancer treated with radiotherapy. PMID- 26770037 TI - Mutations in SLC12A3 and CLCNKB and Their Correlation with Clinical Phenotype in Patients with Gitelman and Gitelman-like Syndrome. AB - Gitelman's syndrome (GS) is caused by loss-of-function mutations in SLC12A3 and characterized by hypokalemic metabolic alkalosis, hypocalciuria, and hypomagnesemia. Long-term prognosis and the role of gene diagnosis in GS are still unclear. To investigate genotype-phenotype correlation in GS and Gitelman like syndrome, we enrolled 34 patients who showed hypokalemic metabolic alkalosis without secondary causes. Mutation analysis of SLC12A3 and CLCNKB was performed. Thirty-one patients had mutations in SLC12A3, 5 patients in CLCNKB, and 2 patients in both genes. There was no significant difference between male and female in clinical manifestations at the time of presentation, except for early onset of symptoms in males and more profound hypokalemia in females. We identified 10 novel mutations in SLC12A3 and 4 in CLCNKB. Compared with those with CLCNKB mutations, patients with SLC12A3 mutations were characterized by more consistent hypocalciuria and hypomagnesemia. Patients with 2 mutant SLC12A3 alleles, compared with those with 1 mutant allele, did not have more severe clinical and laboratory findings except for lower plasma magnesium concentrations. Male and female patients did not differ in their requirement for electrolyte replacements. Two patients with concomitant SLC12A3 and CLCNKB mutations had early-onset severe symptoms and showed different response to treatment. Hypocalciuria and hypomagnesemia are useful markers in differentiation of GS and classical Bartter's syndrome. Gender, genotypes or the number of SLC12A3 mutant alleles cannot predict the severity of disease or response to treatment. PMID- 26770038 TI - Erythropoiesis-stimulating Agents and Anemia in Patients with Non-dialytic Chronic Kidney Disease. AB - Anemia is common in patients with advanced chronic kidney disease (CKD). Though erythropoiesis-stimulating agents (ESAs) have been strongly endorsed in guidelines, it is of particular financial interest. Recently, the reimbursement of ESAs in non-dialytic patients was started by the Korean National Health Insurance System. Thus, we investigated the impact of the reimbursement of ESAs on the anemia care in non-dialytic CKD patients. Medical records of patients with advanced CKD (estimated GFR <30 mL/min/1.73 m(2)) were reviewed. Use of ESAs, blood transfusion, and hemoglobin concentrations were analyzed from one year prior to reimbursement to three years following. We used multivariable modified Poisson regression to estimate the utilization prevalence ratio (PRs). A total of 1,791 medical records were analyzed. The proportion of patients receiving ESAs increased from 14.8% before reimbursement to a peak 33.6% in 1 yr after reimbursement; thereafter, ESA use decreased to 22.4% in 3 yr after reimbursement (compared with baseline; PR, 2.19 [95% CI, 1.40-3.42]). In patients with Hb <10 g/dL, the proportion of receiving ESAs increased from 32.1% before reimbursement to 66.7% in 3 yr after reimbursement (compared with baseline; PR, 2.04 [95% CI, 1.25-3.32]). Mean hemoglobin concentrations were 10.06+/-1.54 g/dL before reimbursement and increased to 10.78+/-1.51 g/dL in 3 yr after the reimbursement change (P=0.001). However, the requirement of blood transfusion was not changed over time. With the reimbursement of ESAs, the advanced CKD patients were more likely to be treated with ESAs, and the hemoglobin concentrations increased. PMID- 26770039 TI - Optimal Cutoff Points of Anthropometric Parameters to Identify High Coronary Heart Disease Risk in Korean Adults. AB - Several published studies have reported the need to change the cutoff points of anthropometric indices for obesity. We therefore conducted a cross-sectional study to estimate anthropometric cutoff points predicting high coronary heart disease (CHD) risk in Korean adults. We analyzed the Korean National Health and Nutrition Examination Survey data from 2007 to 2010. A total of 21,399 subjects aged 20 to 79 yr were included in this study (9,204 men and 12,195 women). We calculated the 10-yr Framingham coronary heart disease risk score for all individuals. We then estimated receiver-operating characteristic (ROC) curves for body mass index (BMI), waist circumference, and waist-to-height ratio to predict a 10-yr CHD risk of 20% or more. For sensitivity analysis, we conducted the same analysis for a 10-yr CHD risk of 10% or more. For a CHD risk of 20% or more, the area under the curve of waist-to-height ratio was the highest, followed by waist circumference and BMI. The optimal cutoff points in men and women were 22.7 kg/m(2) and 23.3 kg/m(2) for BMI, 83.2 cm and 79.7 cm for waist circumference, and 0.50 and 0.52 for waist-to-height ratio, respectively. In sensitivity analysis, the results were the same as those reported above except for BMI in women. Our results support the re-classification of anthropometric indices and suggest the clinical use of waist-to-height ratio as a marker for obesity in Korean adults. PMID- 26770040 TI - Hepatitis A in Korea from 2011 to 2013: Current Epidemiologic Status and Regional Distribution. AB - The hepatitis A virus (HAV) has been the leading cause of viral hepatitis in Korea since the 2000s. We aimed to describe the current status and regional differences in hepatitis A incidence. We studied the total number of hepatitis A cases reported to the Korea Centers for Disease Control and Prevention through the National Infectious Diseases Surveillance System between 2011 and 2013. Additionally, National Health Insurance Review and Assessment Service data and national population data from Statistics Korea were used. In total, 7,585 hepatitis A cases were reported; 5,521 (10.9 cases per 100,000 populations), 1,197 (2.3 cases per 100,000 populations), and 867 (1.7 cases per 100,000 populations) in 2011, 2012, and 2013, respectively. Fifty-eight patients were infected outside of the country and 7,527 patients represented autochthonous HAV infection cases. Autochthonous HAV infection occurred more frequently among men than women (4,619 cases, 6.1 cases per 100,000 population vs. 2,908 cases, 3.9 cases per 100,000 population). The incidence rate was higher in the 20-29 yr-old group (2,309 cases, 11.6 cases per 100,000 populations) and 30-39 yr-old group (3,306 cases, 13.6 cases per 100,000 populations). The majority of cases were reported from March to June (53.6%, 4,038/7,527). Geographic analyses revealed a consistently high relative risk (RR) of HAV infection in mid-western regions (2011, RR, 1.25, P=0.019; 2012, RR, 2.53, P<0.001; 2013, RR, 1.86, P<0.001). In summary, we report that hepatitis A incidence has been decreasing gradually from 2011 to 2013 and that some regions show the highest prevalence rates of HAV infection in Korea. PMID- 26770041 TI - Reappraisal of the Immunogenicity and Safety of Three Hepatitis A Vaccines in Adolescents. AB - Although the overall incidence of hepatitis A in Korea has been decreasing, adolescents remain highly vulnerable to its outbreaks. This study was conducted to compare the immunogenicity and safety of three hepatitis A vaccines in Korean adolescents. Healthy anti-hepatitis A virus seronegative subjects aged 13 to 19 yr were randomized in three equal groups to receive two doses of AvaximTM, Epaxal(r), or Havrix(r), 6 to 12 months apart. Seroconversion rates one month after the first dose were 98%, 95%, and 93% for AvaximTM, Epaxal(r), and Havrix(r), respectively. Seroconversion rates reached 100% for all vaccine groups one month after the second dose. Anti-HAV geometric mean concentrations (GMCs) were 7,207.7 mIU/mL (95% CI, 6023.1-8684.7), 1,750.5 mIU/mL (95% CI, 1362.9 2248.3), and 1,953.5 mIU/mL (95% CI, 1459.4-2614.7) after two doses of AvaximTM, Epaxal(r), and Havrix(r) respectively. AvaximTM was significantly more immunogenic than Epaxal(r) and Havrix(r), whereas there were no significant differences in antibody responses between Epaxal(r) and Havrix(r). Local and systemic solicited adverse events (AEs) were mostly of mild-to-moderate intensity and resolved within 5 days. No serious AEs were reported. In conclusion, all three vaccines are highly immunogenic and well-tolerated in Korean adolescents. (Clinical Trial Registry NCT00483470). PMID- 26770042 TI - Venous Thromboembolism Following Hip and Knee Replacement Arthroplasty in Korea: A Nationwide Study Based on Claims Registry. AB - The aim of this study was to examine the incidence and trends of clinically relevant venous thromboembolism (VTE) including deep vein thrombosis (DVT) and pulmonary embolism (PE) after hip and knee replacement arthroplasty (HKRA) in Korea. Between January 1 and December 31, 2010, 22,127 hip replacement arthroplasty (HRA) patients and 52,882 knee replacement arthroplasty (KRA) patients were enrolled in the analysis using the administrative claims database of the Health Insurance Review and Assessment Service (HIRA). All available parameters including procedure history and clinically relevant VTE during the 90 days after HKRA were identified based on diagnostic and electronic data interchange (EDI) codes. The overall incidence of VTE, DVT, and PE during the 90 days was 3.9% (n=853), 2.7% (n=597), and 1.5% (n=327) after HRA, while the incidence was 3.8% (n=1,990), 3.2% (n=1,699), and 0.7% (n=355) after KRA. The incidence of VTE after HKRA was significantly higher in patients who had previous VTE history (odds ratio [OR], 10.8 after HRA, OR, 8.5 after KRA), chronic heart failure (2.1, 1.3), arrhythmia (1.8, 1.7), and atrial fibrillation (3.4, 2.1) than in patients who did not. The VTE incidence in patients with chemoprophylaxis was higher than that in patients without chemoprophylaxis. The incidence of VTEs revealed in this retrospective review was not low compared with the results of the studies targeting other Asian or Caucasian populations. It may warrant routine prevention including employment of chemoprophylaxis. However, the limitation of the reviewed data mandates large scale prospective investigation to affirm this observation. PMID- 26770043 TI - Survival and Functional Outcomes after Hip Fracture among Nursing Home Residents. AB - Following the implementation of a long-term care insurance system for the elderly in Korea, many nursing homes have been established and many more patients than ever before have been living at nursing homes. Despite the fact that this is a high-risk group vulnerable to hip fractures, no study has yet been conducted in Korea on hip fracture incidence rates and prognoses among patients residing at nursing homes. We recently studied 46 cases of hip fracture in nursing homes; more specifically, we investigated the most common conditions under which fractures occur, and examined the degree of recovery of ambulatory ability and the mortality within 1 yr. Among those who had survived after 1 yr, the number of non-functional ambulators increased from 8 hips before hip fracture to 19 hips at final post-fracture follow-up. These individuals showed poor recovery of ambulatory ability, and the number who died within one year was 11 (23.9%), a rate not significantly different from that among community-dwelling individuals. It was evident that hip-joint-fracture nursing home residents survived for similar periods of time as did those dwelling in the community, though under much more uncomfortable conditions. The main highlight of this report is that it is the first from Korea on nursing home residents' ambulatory recovery and one-year mortality after hip fracture. The authors believe that, beginning with the present study, the government should collect and evaluate the number of hips fractured at nursing facilities in order to formulate criteria that will help to enable all patients to select safer and better-quality nursing facilities for themselves or their family members. PMID- 26770044 TI - Biochemical Markers of Oxidative Stress in Saudi Women with Recurrent Miscarriage. AB - This study was undertaken to investigate the antioxidant/oxidant status in recurrent miscarriage patients. Antioxidants including glutathione peroxidase (GPx), catalase (CAT), glutathione reductase (GR), reduced glutathione (GSH) and selenium (Se), as well as the oxidants hydrogen peroxide (H2O2), oxidised glutathione (GSSG) and lipid peroxidation were assayed in plasma, whole blood and placental tissue of non-pregnant women (NP), healthy pregnant women (HP), and recurrent miscarriage (RM) patients. Results indicated that all antioxidant activities and levels in plasma and whole blood of HP women were consistently moderately lower, and much more significantly lower in RM patients when both were compared to those seen in NP women (P<0.05 and P<0.001, respectively). Furthermore, whereas plasma antioxidant activities and levels were significantly lower in RM patients, those of whole blood and placental tissue were much more significantly lower when compared with HP women (P<0.001). Concurrent with these findings there were consistent increases of equal statistical significance and magnitude in the levels of all investigated oxidants assayed in all samples when compared in between subjects of the study as indicated above. Data thus illustrated a distinct shift in favor of oxidative reactions and reactive oxygen species (ROS) generation, and very significant decreases in the GSH/GSSG ratios in whole blood and placental tissue of RM patients when compared to HP and NP women (P<0.001). The above noted oxidative stress could have been a major causative factor of recurrent miscarriage. PMID- 26770045 TI - Comprehensive Application of the International Classification of Headache Disorders Third Edition, Beta Version. AB - The purpose of this study was to test the feasibility and usefulness of the International Classification of Headache Disorders, third edition, beta version (ICHD-3beta), and compare the differences with the International Classification of Headache Disorders, second edition (ICHD-2). Consecutive first-visit patients were recruited from 11 headache clinics in Korea. Headache classification was performed in accordance with ICHD-3beta. The characteristics of headaches were analyzed and the feasibility and usefulness of this version was assessed by the proportion of unclassified headache disorders compared with ICHD-2. A total of 1,627 patients were enrolled (mean age, 47.4+/-14.7 yr; 62.8% female). Classification by ICHD-3beta was achieved in 97.8% of headache patients, whereas 90.0% could be classified by ICHD-2. Primary headaches (n=1,429, 87.8%) were classified as follows: 697 migraines, 445 tension-type headaches, 22 cluster headaches, and 265 other primary headache disorders. Secondary headache or painful cranial neuropathies/other facial pains were diagnosed in 163 patients (10.0%). Only 2.2% were not classified by ICHD-3beta. The main reasons for missing classifications were insufficient information (1.6%) or absence of suitable classification (0.6%). The diagnoses differed from those using ICHD-2 in 243 patients (14.9%). Among them, 165 patients were newly classified from unclassified with ICHD-2 because of the relaxation of the previous strict criteria or the introduction of a new diagnostic category. ICHD-3beta would yield a higher classification rate than its previous version, ICHD-2. ICHD-3beta is applicable in clinical practice for first-visit headache patients of a referral hospital. PMID- 26770046 TI - Korean Version of Inventory of Complicated Grief Scale: Psychometric Properties in Korean Adolescents. AB - We aimed to validate the Inventory of Complicated Grief (ICG)-Korean version among 1,138 Korean adolescents, representing a response rate of 57% of 1,997 students. Participants completed a set of questionnaires including demographic variables (age, sex, years of education, experience of grief), the ICG, the Children's Depression Inventory (CDI) and the Lifetime Incidence of Traumatic Events-Child (LITE-C). Exploratory factor analysis was performed to determine whether the ICG items indicated complicated grief in Korean adolescents. The internal consistency of the ICG-Korean version was Cronbach's alpha=0.87. The test-retest reliability for a randomly selected sample of 314 participants in 2 weeks was r=0.75 (P<0.001). Concurrent validity was assessed using a correlation between the ICG total scores and the CDI total scores (r=0.75, P<0.001). The criterion-related validity based on the comparison of ICG total scores between adolescents without complicated grief (1.2 +/- 3.7) and adolescent with complicated grief (3.2 +/- 6.6) groups was relatively high (t=5.71, P<0.001). The data acquired from the 1,138 students was acceptable for a factor analysis (Kaiser-Meyer-Olkin Measure of Sampling Adequacy=0.911; Bartlett's Test of Sphericity, chi(2)=13,144.7, P<0.001). After omission of 3 items, the value of Cronbach's alpha increased from 0.87 for the 19-item ICG-Korean version to 0.93 for the 16-item ICG-Korean version. These results suggest that the ICG is a useful tool in assessing for complicated grief in Korean adolescents. However, the 16-item version of the ICG appeared to be more valid compared to the 19-item version of the ICG. We suggest that the 16-item version of the ICG be used to screen for complicated grief in Korean adolescents. PMID- 26770047 TI - Factors Affecting Length of Hospital Stay and Mortality in Infected Diabetic Foot Ulcers Undergoing Surgical Drainage without Major Amputation. AB - This study aimed to investigate factors affecting length of hospital stay and mortality of a specific group of patients with infected diabetic foot ulcer who underwent surgical drainage without major amputation, which is frequently encountered by orthopedic surgeons. Data on length of hospital stay, mortality, demographics, and other medical information were collected for 79 consecutive patients (60 men, 19 women; mean age, 66.1 [SD, 12.3] yr) with infected diabetic foot ulcer who underwent surgical drainage while retaining the heel between October 2003 and May 2013. Multiple linear regression analysis was performed to determine factors affecting length of hospital stay, while multiple Cox regression analysis was conducted to assess factors contributing to mortality. Erythrocyte sedimentation rate (ESR, P=0.034), glycated hemoglobin (HbA1c) level (P=0.021), body mass index (BMI, P=0.001), and major vascular disease (cerebrovascular accident or coronary artery disease, P=0.004) were significant factors affecting length of hospital stay, whereas age (P=0.005) and serum blood urea nitrogen (BUN) level (P=0.024) were significant factors contributing to mortality. In conclusion, as prognostic factors, the length of hospital stay was affected by the severity of inflammation, the recent control of blood glucose level, BMI, and major vascular disease, whereas patient mortality was affected by age and renal function in patients with infected diabetic foot ulcer undergoing surgical drainage and antibiotic treatment. PMID- 26770048 TI - Effects of Dexmedetomidine Infusion on the Recovery Profiles of Patients Undergoing Transurethral Resection. AB - Transurethral resection has been the gold standard in the operative management of benign prostatic hyperplasia and bladder tumor; however, it is associated with several complications that may cause patient discomfort. We evaluated the usefulness of continuous infusion of dexmedetomidine on emergence agitation, hemodynamic status, and recovery profiles in patients undergoing elective surgery by a randomized clinical trial. Sixty patients aged 30 to 80 yr who were scheduled for elective transurethral resection under general anesthesia were included in this study. Participants were randomly assigned to two groups (control group, group C; dexmedetomidine group, group D). A total of 60 male patients were enrolled in this study and randomly assigned to group C (n=30) or group D (n=30). The quality of emergence in group D was marked by a significantly lower incidence of emergence agitation than in group C (P=0.015). Patients in group D therefore felt less discomfort induced by the indwelling Foley catheter than those in group C (P=0.022). No statistically significant differences were found between the two groups with respect to side effects including bradycardia (P=0.085), hypotension (P=0.640), and postoperative nausea and vomiting (P=0.389). Our study showed that intraoperative dexmedetomidine infusion effectively reduced the incidence and intensity of emergence agitation and catheter-induced bladder discomfort without delaying recovery time and discharge time, thus providing smooth emergence during the recovery period in patients undergoing transurethral resection (Clinical Trial Registry No. KT0001683). PMID- 26770049 TI - The State of Anesthetic Services in Korea: A National Survey of the Status of Anesthesia Provider in the 2011-2013 Period. AB - Active involvement of anesthesiologists in perioperative management is important to ensure the patients' safety. This study aimed to investigate the state of anesthetic services in Korea by identifying anesthetic service providers. From the insurance claims data of National Health Insurance for 3 yr, the Korean state of anesthetic services was analyzed. The claims for anesthesia from the medical institutions which hire their own anesthesiologist or with an anesthesiologist invitation fee are assumed to be the anesthesia performed by anesthesiologists. The annual anesthetic data were similar during the study period. In 2013, total counts of 2,129,871 were composed with general anesthesia (55%), regional anesthesia (36%) and procedural sedation with intravenous anesthetics (9%). About 80% of total cases of general anesthesia were performed in general hospitals, while more than 60% of the regional anesthesia and sedation were performed in the clinics and hospitals under 100 beds. Non-anesthesiologists performed 273,006 cases of anesthesia (13% of total) including 36,008 of general anesthesia, 143,134 of regional anesthesia, and 93,864 of sedation, mainly in the clinics and hospitals under 100 beds. All procedural sedations in the institutions without direct employed anesthesiologist were performed by non-anesthesiologists. Significant numbers of anesthesia are performed by non-anesthesiologist in Korea. To promote anesthetic services that prioritize the safety of patients, the standard to qualify anesthetic service is required. Surgeons and patients need to enhance their perception of anesthesia, and the payment system should be revised in a way that advocates anesthesiologist-performed anesthetic services. PMID- 26770050 TI - The Effect of Emergency Medical Service Use and Inter-hospital Transfer on Prehospital Delay among Ischemic Stroke Patients: A Multicenter Observational Study. AB - The time between symptom onset and arrival at an emergency department (ED) (S2D) is a crucial time for optimal intravenous reperfusion care for ischemic stroke. We aimed to analyze the effect of emergency medical services (EMS) utilization and inter-hospital transfer on S2D in Korea. Ischemic stroke patients were prospectively enrolled from November 2007 to December 2012 in 23 tertiary and teaching hospital EDs in Korea. Of 31,443 adult ischemic stroke patients, 20,780 were categorized into 4 groups based on modes of EMS utilization and inter hospital transfer: direct transport to destination ED by EMS (EMS direct; n=6,257, 30.1%), transfer after transport to another ED by EMS (EMS indirect; n=754, 3.6%), direct transport to the ED without using EMS (non-EMS direct; n=8,928, 43.0%), and transfer after visiting another hospital without using EMS (non-EMS indirect; n=4,841, 23.3%). Our primary outcome variable was of S2D within 2 hr (S2D <= 2 hr) and found that 30.8% of all patients and 52.3%, 16.4%, 25.9%, and 13.9% of EMS direct, EMS indirect, non-EMS direct, and non-EMS indirect, respectively, achieved S2D <= 2 hr. Adjusted odds ratio for S2D <= 2 hr were 6.56 (95% confidence interval [CI], 5.94-7.24), 2.27 (95% CI, 2.06-2.50), and 1.07 (95% CI, 0.87-1.33) for EMS direct, non-EMS direct, and EMS indirect, respectively. Patients directly transported to destination hospitals by the EMS show the highest proportion of therapeutic time window for optimal care in ischemic stroke. PMID- 26770051 TI - Calcified Pulmonary Nodules Identified in a 350-Year-Old-Joseon Mummy: the First Report on Ancient Pulmonary Tuberculosis from Archaeologically Obtained Pre modern Korean Samples. AB - We found calcified pulmonary nodules in a middle-aged female mummy discovered from 350-yr-old Joseon tomb of Korea. In the CT scan, we found six radiopaque nodules in right lung, through the levels of thoracic vertebrae 1 to 6. We also found presumptive pleural adhesions in right thoracic cavity of CT images. We re confirmed radiological findings by our post-factum dissection on the same mummy. By the differential diagnosis, we speculate that the radiopaque calcification nodules and associated pleural adhesion could have been caused by tuberculosis. This is the first-ever report on the pulmonary tuberculosis identified in archaeologically obtained, pre-modern Korean samples. PMID- 26770052 TI - Examining the genetic and environmental associations among spelling, reading fluency, reading comprehension and a high stakes reading test in a combined sample of third and fourth grade students. AB - The present study is an examination of the genetic and environmental effects on the associations among reading fluency, spelling and earlier reading comprehension on a later reading comprehension outcome (FCAT) in a combined sample of 3rd and 4th grade students using data from the 2011-2012 school year of the Florida Twin project on Reading (Taylor et al., 2013). A genetically sensitive model was applied to the data with results indicating a common genetic component among all four measures, along with shared and non-shared environmental influences common between reading fluency, spelling and FCAT. PMID- 26770053 TI - Simultaneous Development of a Multidimensional Fatalism Measure in English and Spanish. AB - Fatalism has been shown to predict several health behaviors, but researchers often find inconsistent results for the same behaviors across studies. This may be partially attributable to the diversity of fatalism measures that have been used in previous studies. A review of the literature revealed 51 different scales, all purported to measure fatalism, but often with heterogeneous content (Esparza 2005). A study done by Esparza (2005) retrieved 29 scales, including the most frequently used scales, and performed an exploratory factor analysis, obtaining as a result five factors: fatalism, helplessness, internality, luck, and divine control. The purpose of this study was to develop a multidimensional fatalism scale based on the previous findings by Esparza (2005). This scale was developed simultaneously in English and Spanish in order to linguistically "decenter" item content. The factor structure was cross-validated and measurement invariance was assessed across language versions. According to the measurement invariance analysis, this test is invariant across English and Spanish in its factor structure, loadings, variances, and covariances. This study results suggest that this scale may be used interchangeably in both English and Spanish. PMID- 26770055 TI - Turning Numbers into Knowledge: Sensors for Safety, Health, Well-being, and Productivity. AB - The industrial hygiene community has witnessed exponential growth in the use of sensors, especially by individuals. Remote wireless sensors are now monitoring worker health, the environment, agriculture, work sites, disaster relief, and "smart" buildings and facilities. PMID- 26770054 TI - Self-Complexity and Self-Concept Differentiation - What Have We Been Measuring for the Past 30 Years? AB - Research on the relation between the structure of the self-concept and psychological well-being has yielded seemingly inconsistent and even conflicting results. This article presents studies that examined the validity of often-used measures of self-complexity and self-concept differentiation and tested their ability to predict personal identity and active cognitive processing. The findings revealed several conceptual and methodological problems that continue to plague self-structure research, including the conflating of self-concept content and self-concept structure. In short, our data indicated that the commonly used indices of self-complexity and self-concept differentiation cannot be considered pure measures of the underlying dimensions of self-structure. In addition, only weak correlations of the self-structure variables with measures of personal identity and thinking dispositions have been found. Moreover, once the theoretically irrelevant sources of variance were controlled, the effects of the included structural features of the self-concept on the outcomes of interest either did not occur or were less pronounced. Given the above, it seems reasonable to suggest that at least some of the conclusions regarding the adaptive value of self-structural variables drawn from previous research in this field need revision. PMID- 26770056 TI - The Random Forests statistical technique: An examination of its value for the study of reading. AB - Studies investigating individual differences in reading ability often involve data sets containing a large number of collinear predictors and a small number of observations. In this paper, we discuss the method of Random Forests and demonstrate its suitability for addressing the statistical concerns raised by such datasets. The method is contrasted with other methods of estimating relative variable importance, especially Dominance Analysis and Multimodel Inference. All methods were applied to a dataset that gauged eye-movements during reading and offline comprehension in the context of multiple ability measures with high collinearity due to their shared verbal core. We demonstrate that the Random Forests method surpasses other methods in its ability to handle model overfitting, and accounts for a comparable or larger amount of variance in reading measures relative to other methods. PMID- 26770057 TI - Evaluation and validity of the Danish version of the Adult Strabismus Questionnaire AS-20. AB - PURPOSE: Assessing health-related quality of life in patients with strabismus is important in evaluating the clinical benefits of strabismus treatment. The purpose of this study was to translate the Adult Strabismus Quality of Life Questionnaire (AS-20) into Danish and evaluate its reliability and validity in adult patients with strabismus in Denmark. METHODS: The AS-20 was translated into Danish in accordance with standard international adopted methods. We presented the questionnaire to 64 adults with strabismus and to 13 non-strabismic adult controls. We tested the reliability of the Danish version by reassuring test retest reliability, estimated the internal consistency, and analyzed the validity (discriminatory power) of the questionnaire by comparing patient scores with scores from control individuals. RESULTS: The Danish AS-20 produced high level of internal consistency (Cronbach's alpha values) for both subscales (psychosocial: 0.95 and functional: 0.85). We found good discriminatory power of the AS-20. The patients scored significantly lower not only on AS-20 composite score (median =63, interquartile range [IQR] =44-79) compared to healthy individuals (median =98, IQR =93-100) (P<0.0001) but also on all individual questions in both subscales (psychosocial: 1-10 and functional: 11-20). CONCLUSION: The Danish version of AS-20 shows high reliability and validity, and in our opinion, AS-20 is therefore a suitable instrument for evaluating self-perceived psychosocial and functional influence of strabismus. PMID- 26770058 TI - Efficacy and safety of topical herbal medicine treatment on recurrent aphthous stomatitis: a systemic review. AB - This study aimed to evaluate the efficacy and safety of topical treatment with natural herbal medicines on recurrent aphthous stomatitis (RAS). Nine electronic databases were searched to identify the randomized controlled trials and clinical controlled trials that reported the potential effect of natural herbal medicines on RAS published in Chinese or English. Ulcer size and duration, and remission of pain were assessed as main outcome measures. The methodological quality of the studies was evaluated using the Cochrane Handbook for Systemic Review of Interventions and Rev Man software. Thirteen trials with a total of 1,515 patients were included in the present analysis, which showed that topical treatment with natural herbal medicines seemed to benefit RAS patients by reducing ulcer size, shortening ulcer duration, and relieving pain without severe side effects. In conclusion, there is some evidence of the efficacy of topically applied natural herbal medicines with regards to improved RAS outcome measures and fewer side effects. However, given the limitations of this study, the evidence remains insufficient. Well-designed and high-quality randomized controlled trials are required for further exploration. PMID- 26770059 TI - Affective network and default mode network in depressive adolescents with disruptive behaviors. AB - AIM: Disruptive behaviors are thought to affect the progress of major depressive disorder (MDD) in adolescents. In resting-state functional connectivity (RSFC) studies of MDD, the affective network (limbic network) and the default mode network (DMN) have garnered a great deal of interest. We aimed to investigate RSFC in a sample of treatment-naive adolescents with MDD and disruptive behaviors. METHODS: Twenty-two adolescents with MDD and disruptive behaviors (disrup-MDD) and 20 age- and sex-matched healthy control (HC) participants underwent resting-state functional magnetic resonance imaging (fMRI). We used a seed-based correlation approach concerning two brain circuits including the affective network and the DMN, with two seed regions including the bilateral amygdala for the limbic network and the bilateral posterior cingulate cortex (PCC) for the DMN. We also observed a correlation between RSFC and severity of depressive symptoms and disruptive behaviors. RESULTS: The disrup-MDD participants showed lower RSFC from the amygdala to the orbitofrontal cortex and parahippocampal gyrus compared to HC participants. Depression scores in disrup MDD participants were negatively correlated with RSFC from the amygdala to the right orbitofrontal cortex. The disrup-MDD participants had higher PCC RSFC compared to HC participants in a cluster that included the left precentral gyrus, left insula, and left parietal lobe. Disruptive behavior scores in disrup-MDD patients were positively correlated with RSFC from the PCC to the left insular cortex. CONCLUSION: Depressive mood might be correlated with the affective network, and disruptive behavior might be correlated with the DMN in adolescent depression. PMID- 26770061 TI - Alpha-fetoprotein-L3 and Golgi protein 73 may serve as candidate biomarkers for diagnosing alpha-fetoprotein-negative hepatocellular carcinoma. AB - Currently, there is no reliable biomarker for use in diagnosing alpha-fetoprotein (AFP)-negative hepatocellular carcinoma (HCC). Such a biomarker would aid in making an early diagnosis of AFP-negative HCC, ensuring the timely initiation of treatment. This study examined AFP-L3 and Golgi protein 73 (GP73) as candidate biomarkers for AFP-negative HCC. The affinity adsorption method and enzyme-linked immunoassays were separately used to determine serum levels of AFP-L3 and GP73 in 50 patients with AFP-negative HCC, 30 non-HCC patients, and 50 healthy subjects. Fifty percent of patients with AFP-negative HCC tested positive for AFP-L3, while 3.33% of non-HCC patients and 2.00% of healthy subjects were AFP-L3 positive. Patients with AFP-negative HCC had significantly higher serum levels of AFP-L3 compared to non-HCC patients and healthy individuals; however, there was no significant difference in the AFP-L3 levels of non-HCC patients and healthy subjects. Sixty-six percent of patients with AFP-negative HCC tested positive for GP73, while 10% of non-HCC patients and 0% of healthy subjects were GP73 positive. Patients with AFP-negative HCC had significantly higher serum levels of GP73 compared to non-HCC patients and healthy subjects, but there was no significant difference between the GP73 levels of non-HCC patients and healthy individuals. Moreover, 20 patients with AFP-negative HCC were both AFP-L3- and GP73-positive, while no non-HCC patients or healthy subjects tested positive for both markers. Either AFP-L3 or GP73 may be used as a biomarker for diagnosing AFP negative HCC, while their combined use provides improved diagnostic accuracy and greater sensitivity. PMID- 26770060 TI - Profile of panitumumab as first-line treatment in patients with wild-type KRAS metastatic colorectal cancer. AB - Targeted therapies against EGFR, vascular endothelial growth factor, and vascular endothelial growth factor receptor have expanded treatment options for patients with metastatic colorectal cancer (mCRC). Unfortunately, biomarkers to identify patients that are most likely to derive benefit from targeted therapies in this disease are still needed. Indeed, only RAS mutations have been identified as predictive of lack of benefit from monoclonal antibodies against EGFR in patients with mCRC. Panitumumab is a fully humanized monoclonal antibody against EGFR. In this study, we review data to support the use of panitumumab in combination with a chemotherapy backbone, in the first line setting in patients with RAS wild-type mCRC. Ongoing efforts are aimed at identifying smaller subsets of patients within the RAS wild-type group that will derive the largest benefit from anti-EGFR therapy. In the meantime, treatment with anti-EGFR therapy should be reserved for patients with RAS wild-type mCRC. PMID- 26770062 TI - Detection of lung adenocarcinoma with ROS1 rearrangement by IHC, FISH, and RT-PCR and analysis of its clinicopathologic features. AB - OBJECTIVE: To detect ROS1 rearrangement using three different assays, including immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), and reverse transcription polymerase chain reaction (RT-PCR), and to analyze the clinicopathologic features of ROS1 rearrangement in patients with lung adenocarcinoma. METHODS: One hundred eighty-three consecutive patients with lung adenocarcinoma with operation and follow-up data were analyzed for ROS1 rearrangement by IHC, FISH, and RT-PCR. PCR products of the RT-PCR-positive samples were sequenced for confirmation of the specific fusion partners. RESULTS: Three of the 183 (1.64%) cases were identified to be positive for ROS1 rearrangement through all three methods. The fusion patterns were CD74 e6-ROS1 e32, CD74 e6-ROS1 e34, and TPM3 e8-ROS1 e35, respectively. FISH-positive cases showed two types of signals, single 3' signals (green) and split red and green signals. Using FISH as a standard method, the sensitivity and specificity of ROS1 IHC with 1+ staining or more were 100% and 96.67%, respectively. The sensitivity and specificity of RT-PCR were both 100%. Univariate analysis identified female sex (P=0.044), Stage I disease (P<0.001), and ROS1-negative status (P=0.022) to be significantly associated with longer overall survival. CONCLUSION: IHC, FISH, and RT-PCR are all effective methods for the detection of ROS1 rearrangement. IHC would be a useful screening method in routine pathologic laboratories. RT-PCR can detect exact fusion patterns. ROS1 rearrangement may be a worse prognostic factor. The exact correlation of ROS1 rearrangement with prognosis and whether different fusion types are correlated with different responses to targeted therapy need to be further investigated. PMID- 26770063 TI - Exosomal microRNA-141 is upregulated in the serum of prostate cancer patients. AB - PURPOSE: Novel biomarkers for the diagnosis of prostate cancer (PCa) are urgently required. Increasing evidence suggests that exosomal microRNAs (miRNAs or miRs) in serum may be potential noninvasive biomarkers for certain diseases. The objective of the present study was to investigate and assess whether exosomal miR 141 is an effective biomarker for human PCa. METHODS: In the present study, exosomes were isolated from the serum of patients with PCa, patients with benign prostate hyperplasia (BPH), and healthy volunteers. The total RNA was extracted from the exosomes and the level of miR-141 was analyzed by quantitative reverse transcription-polymerase chain reaction. The expression levels of miR-141 were compared between the whole serum and the serum exosomes of the three groups. Subsequently, the relevance of the exosomal expression of miR-141 to the clinicopathological factors in PCa was investigated. RESULTS: The expression of miR-141 was higher in exosomes compared with whole serum (control group, P=0.0003; BPH group, P=0.0016; PCa group, P<0.0001). The level of serum exosomal miR-141 was significantly higher in the patients with PCa compared with the patients with BPH and the healthy controls (3.85-fold, P=0.0007 and 4.06-fold, P=0.0005, respectively). In addition, the expression levels were significantly higher in metastatic PCa compared with localized PCa (P<0.0001). Receiver operating characteristic curve revealed that the serum exosomal miR-141 yielded an area under the curve of 0.8694, with 80% sensitivity and 87.1% specificity in discriminating patients with metastatic PCa from the patients with localized PCa. CONCLUSION: Serum exosomes may serve as a more suitable material compared with the whole serum for measuring circulating miR-141 levels in patients with PCa. Exosomal miR-141 is upregulated in the serum from patients with PCa compared with patients with BPH or the healthy volunteers, and it may be a useful potential biomarker for the diagnosis of metastatic PCa. PMID- 26770064 TI - Clinical impacts of a micropapillary pattern in lung adenocarcinoma: a review. AB - Lung adenocarcinoma with a micropapillary pattern (MPPAC) has recently drawn increased attention among researchers. Micropapillary-predominant adenocarcinoma (MPA), which is defined by micropapillary pattern (MPP), is the primary histological pattern observed semiquantitatively in 5% increments on resection specimens, and MPA was formally determined to be a new histological subtype according to the new multidisciplinary classification in 2011. According to published studies, MPPAC is most common in males and nonsmokers and is associated with lymphatic invasion, pleural invasion, and lymph node metastases. MPPAC often presents as part-solid and lobulated nodules in computed tomography scans. MPP tends to have a higher maximum standardized uptake value as determined by fluorodeoxyglucose positron emission tomography combined with computed tomography, indicating a high risk of recurrence. Molecular markers, including vimentin, napsin A, phosphorylated c-Met, cytoplasmic maspin, Notch-1, MUC1, and tumoral CD10, may have higher expression in MPPAC than other subtypes; conversely, markers such as MUC4 and surfactant apoprotein A have lower expression in MPPAC. MPPAC with EGFR mutations can benefit from treatment with EGFR tyrosine kinase inhibitors. Furthermore, a complete lobectomy may be more suitable than limited resection for MPPAC because of the low sensitivity of intraoperative frozen sections and the high risk of lymph node metastasis. MPA benefits more from adjuvant chemotherapy than do other histological subtypes, whereas MPA does not benefit from adjuvant radiotherapy. Of note, MPP is associated with poor prognosis in early-stage lung adenocarcinoma, but the prognostic value of MPP is controversial in advanced-stage lung adenocarcinoma. PMID- 26770065 TI - Budget impact analysis of sofosbuvir-based regimens for the treatment of HIV/HCV coinfected patients in northern Italy: a multicenter regional simulation. AB - OBJECTIVES: Chronic hepatitis C virus (HCV) is a leading cause of hospitalization and death in populations coinfected with human immunodeficiency virus (HIV). Sofosbuvir (SOF) is a pan-genotypic drug that should be combined with other agents as an oral treatment for HCV. We performed a 5-year horizon budget impact analysis of SOF-based regimens for the management of HIV/HCV-coinfected patients. METHODS: A multicenter, prospective evaluation was conducted, involving four Italian Infectious Diseases Departments (Galliera, San Martino, Sanremo, and La Spezia). All 1,005 genotype-coinfected patients (30% cirrhotics) under observation were considered (patients in all disease-stages were considered: chronic hepatitis C, cirrhosis, transplant, hepatocellular carcinoma). Disease stage costs per patient were collected; the expected disease progression in the absence of treatment and sustained virological response (SVR) success rate for SOF-based regimens were calculated based on the literature and expert opinion. Drug prices were based on what the National Health Service paid for them. The comparison of "no treatment" disease progression costs versus the economic impact of SOF-based regimens was investigated. RESULTS: Over the following 5 years, the disease progression scenario resulted in direct costs of approximately ?54 million. Assuming an SVR success rate of 90%, average SOF-based regimens cost up to ?50,000 per person, resulting in a final cost of more than ?56 million, so this option is not economically viable. At the average price of ?12,000, SOF based regimens, expense was ?17 million, saving 68%. At this price level, the economic resources invested in treating mild to moderate fibrosis stage patients would be equal to the amount of direct costs of disease management in this stage, resulting in a valid return of investment in the short-term. CONCLUSION: Given the high rates of SVR, in the Italian Healthcare System, SOF-based regimens, price is a determinant and a predictor of the overall cost for the Hepatitis C patient's management. At the average price per therapy of ?12,000 over the next 5 years, SOF-based regimens are becoming highly sustainable. PMID- 26770071 TI - Nurses' perceptions of and satisfaction with the use of automated dispensing cabinets at the Heart and Cancer Centers in Qatar: a cross-sectional study. AB - BACKGROUND: Automated dispensing cabinets (ADCs) were introduced in 2010 and 2012 at the Heart Hospital (HH) and National Center for Cancer Care and Research (NCCCR), both run by Hamad Medical Corporation in Qatar. These medication distribution systems provide computer-controlled storage, dispensing, and tracking of drugs at the point of care in patient care units. The purpose of this study was to assess nurses' perceptions of and satisfaction with the use of ADCs at HH and NCCCR. METHODS: A cross-sectional study was conducted in the two institutions in May and November 2012 using a piloted, validated, online, and anonymous questionnaire. The questionnaire consisted of four parts: nurses' sociodemographic and practice characteristics, 21 questions about their perceptions, one question about their overall satisfaction, and one about the system's ease of use. The self-administered survey was distributed to 503 nurses working at HH and NCCCR over three weeks using Survey Monkey(r). RESULTS: The survey response rate was 80 % (n = 403). No significant difference was found in perception scores between the two institutions (p = 0.06). Ninety-four percent (n = 378) of nurses agreed that the medication delivery system allowed them to do their job more safely, and 90 % (n = 363) nurses agreed that they now spent less time waiting for medication from the pharmacy than they did before the ADC system was introduced. Eighty seven percent (n = 349) nurses agreed that they were able to administer medication more efficiently with the ADC system. The overall satisfaction rate (either "very satisfied" or "satisfied") for the two hospitals was 91 %. CONCLUSIONS: The nurses' perceptions of and levels of satisfaction with the ADC system were very good over the 6 months after complete implementation and integration at HH and NCCCR. ADCs appear to increase efficiency in the medication process and should therefore improve the quality of care. PMID- 26770072 TI - Isolation and characterization of Bradykinin potentiating peptides from Agkistrodon bilineatus venom. AB - BACKGROUND: Snake venom is a source of many pharmacologically important molecules. Agkistrodon bilineatus commonly known as Cantil, is spread over Central America particularly in Mexico and Costa Rica. From the venom of Agkistrodon bilineatus we have isolated and characterised six hypotensive peptides, and two bradykinin inhibitor peptides. The IC-50 value of four synthesized peptides was studied, towards angiotensin converting enzyme, in order to study the structure-function relationship of these peptides. RESULTS: The purification of the peptides was carried out by size exclusion chromatography, followed by reverse phase chromatography. Sequences of all peptides were determined applying MALDI-TOF/TOF mass spectrometry. These hypotensive peptides bear homology to bradykinin potentiating peptides and venom vasodilator peptide. The peptide with m/z 1355.53 (M + H)(+1), and the corresponding sequence ZQWAQGRAPHPP, we identified for the first time. A precursor protein containing a fragment of this peptide was reported at genome level, (Uniprot ID P68515), in Bothrops insularis venom gland. These proline rich hypotensive peptides or bradykinin potentiating peptides are usually present in the venom of Crotalinae, and exhibit specificity in binding to the C domain of somatic angiotensin converting enzyme. Four of these hypotensive peptides, were selected and synthesized to obtain the required quantity to study their IC50 values in complex with the angiotensin converting enzyme. The peptide with the sequence ZLWPRPQIPP displayed the lowest IC50 value of 0.64 MUM. The IC50 value of the peptide ZQWAQGRAPHPP was 3.63 MUM. CONCLUSION: The canonical snake venom BPPs classically display the IPP motif at the C-terminus. Our data suggest that the replacement of the highly conserved hydrophobic isoleucine by histidine does not affect the inhibitory activity, indicating that isoleucine is not mandatory to inhibit the angiotensin converting enzyme. The evaluation of IC 50 values show that the peptide with basic pI value exhibits a lower IC 50 value. PMID- 26770070 TI - Person-centred information to parents in paediatric oncology (the PIFBO study): A study protocol of an ongoing RCT. AB - BACKGROUND: Parents of children with cancer experience a demanding situation and often suffer from psychological problems such as stress. Trying to coping with the complex body of information about their child's disease is one factor that contributes to this stress. The aim of this study is to evaluate an intervention for person-centred information to parents of children with cancer that consists of four sessions with children's nurses trained in the intervention method. METHODS/DESIGN: This is a multi-centre RCT with two parallel arms and a 1:1 allocation ratio. The primary outcome is illness-related parental stress. Secondary outcomes are post-traumatic stress symptoms, anxiety, depression, satisfaction with information, expected and received knowledge, and experiences with health care providers. A process evaluation is performed to describe experiences and contextual factors. Data are collected using web questionnaires or paper forms according to the parents' preference, audio recording of the intervention sessions, and qualitative interviews with parents and the intervention nurses. DISCUSSION: Few studies have evaluated information interventions for parents of children with cancer using large multi-centre RCTs. This intervention is designed to be performed by regular staff children's nurses, which will facilitate implementation if the intervention proves to be effective. TRIAL REGISTRATION: Clinical trials NCT02332226 (December 11, 2014). PMID- 26770074 TI - Assessing a Science Graduate School Recruitment Symposium. AB - Ciencia Puerto Rico, a non-profit organization dedicated to promoting science, research and scientific education among Latinos, organized an educational symposium to provide college science majors the tools, opportunities and advice to pursue graduate degrees and succeed in the STEM disciplines. In this article we share our experiences and lessons learned, for others interested in developing large-scale events to recruit underrepresented minorities to STEM and in evaluating the effectiveness of these efforts. PMID- 26770073 TI - Validation of a modified thromboelastometry approach to detect changes in fibrinolytic activity. AB - BACKGROUND: Thus far, validated whole blood assays used in in vitro fibrinolysis experiments using thromboelastometry (ROTEM) are lacking or have yet to be tested in humans. The objective was first, to establish a standardized modified ROTEM approach to detect both hypo- and hyperfibrinolysis. And second, to perform a technical and clinical validation of the assay. METHODS: Blood was used of healthy volunteers, patients with sepsis, patients after cardiothoracic surgery, pregnant women, and cirrhotic liver disease patients. A whole blood tissue factor (TF) activated ROTEM assay with and without the addition of recombinant tissue plasminogen activator (rTPA) was developed. Plasma fibrinolysis determinants were measured in all volunteers and patients. RESULTS: Thirty five pM TF and additions of 125 and 175 ng/ml rTPA resulted in full lysis within 60 min in healthy volunteers. Coefficients of variation were below 10 % without and below 20 % with rTPA addition. In sepsis the hypofibrinolytic ROTEM profiles with 175 ng/ml rTPA were in line with the plasma determinants (high PAI-1, high fibrinogen, low tPA activity, and high d-dimers). After cardiothoracic surgery, reduced fibrinogen and platelet levels accounted for the reduced maximum clot firmness. The hypofibrinolytic profile is attributed to tranexamic acid use and elevated PAI-1 levels. The lowest rTPA concentration in cirrhosis resulted in hyperfibrinolysis in only few of the patients. In pregnancy normal profiles were found. DISCUSSION: Our high rTPA concentration demonstrates hypofibrinolytic profiles adequately in sepsis and after cardiothoracic surgery. Our low rTPA concentration of 125 ng/ml seems too high for demonstrating hyperfibrinolysis in cirrhotic liver disease. CONCLUSIONS: We were able to present a validated whole blood ROTEM approach to fibrinolysis testing using added rTPA, which can be of added value next to classical plasma based fibrinolysis assays. PMID- 26770076 TI - (Integrative) "Whole Health" Tops Interests for VA in the President's Planning Budget ... plus more. PMID- 26770075 TI - Glutathione! PMID- 26770077 TI - The Case is Closed: Editorial Bias Prevents Reasonable Evaluation of Dietary Supplements. PMID- 26770078 TI - Patrick Hanaway, md: Transforming Scientific Understanding of Nutrition to Clinical Understanding and Practice. PMID- 26770079 TI - Pranayam for Treatment of Chronic Obstructive Pulmonary Disease: Results From a Randomized, Controlled Trial. AB - CONTEXT: Existing medications for chronic obstructive pulmonary disease (COPD) do not modify the long-term decline in lung functions. The increasing prevalence of COPD requires the development of interventions beyond the usual medical treatment, with a specific focus on rehabilitation. Controlled breathing (pranayam) is a specific set of respiratory exercises within yoga that has been shown to improve the resting respiratory rate, vital capacity, maximum voluntary ventilation, breath-holding time, and maximal inspiratory and expiratory pressures. OBJECTIVE: In this study, pranayam was analyzed as an adjunct treatment for medically stable individuals with moderate to severe COPD. DESIGN: The research team carried out a case control study. SETTING: This study took place at a tertiary care institution, with the participation of the departments of Physiology, Yoga and Naturopathy, and Pulmonary Medicine at Pandit Bhagwat Dayal Sharma Postgraduate Institute of Medical Sciences in Rohtak, Haryana, India. PARTICIPANTS: Participants were 50 medically stable individuals with moderate to severe COPD. INTERVENTION: Twenty-five participants in the intervention arm (IA) were trained to practice pranayam for 30 min 2 */d and also received the usual medical treatment. The control group also included 25 participants, and they received the usual medical treatment only, without pranayam. OUTCOME MEASURES: The COPD assessment test (CAT) score and the body mass index, obstruction, dyspnea, exercise (BODE) capacity index were assessed at baseline and at 3 mo. The results were expressed using standard statistical methods. RESULTS: For the IA, a significant improvement occurred in the CAT score (21.2 +/- 2.6-17.4 +/- 2.5, P < .001) and in the impact level, which moved from high (>20) to medium (10-20) after 3 mo of practicing pranayam. The control arm (CA) showed no significant improvement in the CAT score (21.6 +/- 2.7-21.4 +/- 2.7). Although the IA showed a significant improvement in a 6-min walk test (6MWT) when compared to the CA, (1) the IA's forced expiratory volume in 1 sec (FEV1), which is a measure of airflow that is commonly impaired in COPD patients and which is associated with poor functional status, showed no significant improvements, and (2) the IA's BODE capacity index showed no significant improvements. CONCLUSION: The current study shows that pranayam has been demonstrated as useful for individuals with moderate to severe COPD. Significant improvements in the IA's CAT scores after 3 mo of practice suggests that pranayam can improve the subjective experience of health, disease severity, and functional status for COPD patients, without much improvement in FEV1 actually occurring and with airflow limitation not fully reversible but usually progressive. The research team concluded that pranayam is a useful adjunct treatment and can be an effective rehabilitation program for individuals with COPD. PMID- 26770080 TI - Immune Modulation From Five Major Mushrooms: Application to Integrative Oncology. AB - This review discusses the immunological roles of 5 major mushrooms in oncology: Agaricus blazei, Cordyceps sinensis, Grifola frondosa, Ganoderma lucidum, and Trametes versicolor. These mushrooms were selected based on the body of research performed on mushroom immunology in an oncology model. First, this article focuses on how mushrooms modify cytokines within specific cancer models and on how those cytokines affect the disease process. Second, this article examines the direct effect of mushrooms on cancer. Finally, this article presents an analysis of how mushrooms interact with chemotherapeutic agents, including their effects on its efficacy and on the myelosuppression that results from it. For these 5 mushrooms, an abundance of in vitro evidence exists that elucidates the anticancer immunological mechanisms. Preliminary research in humans is also available and is promising for treatment. PMID- 26770081 TI - Medicinal Mushrooms: Ancient Remedies Meet Modern Science. PMID- 26770082 TI - Joan Grinzi, rn, and David Getoff, ccn: Preserving and Advancing the Nutrition Research of Weston A. Prince, dds, and Francis M. Pottenger, Jr, md. PMID- 26770083 TI - Fire and Rain. PMID- 26770084 TI - Mitochondria-Fundamental to Life and Health. PMID- 26770085 TI - Letter to the Editor. PMID- 26770086 TI - Letter to the Editor. PMID- 26770087 TI - Institute for Integrative Health in $1-Million Grant to Explore Nature's Effect on Wounded Warriors ... plus more. PMID- 26770088 TI - Michael Greger, md: Reversing Chronic Disease Through Diet; Addressing the 2015 USDA Dietary Guidelines Committee. PMID- 26770089 TI - A Randomized, Controlled Pilot Study of the Effects of Acupuncture on Circulating Endothelial Progenitor Cells in Coronary Heart Disease. AB - CONTEXT: Coronary heart disease (CHD) remains the number one killer of men and women in the United States, and despite traditional secondary prevention, individuals with the disease remain at risk. Endothelial progenitor cells (EPCs) may have beneficial effects on atherosclerosis, angiogenesis, and vascular repair and may contribute systemically to ongoing endogenous repair processes. Traditional acupuncture (TA), a modality used in the practice of Chinese medicine, appears to have beneficial effects in many areas associated with CHD. OBJECTIVE: The study examined the effects of TA on circulating EPCs in individuals with CHD. DESIGN: The research team performed a randomized, controlled pilot study. SETTING: All interventions were performed at the Cedars Sinai Medical Center in Los Angeles, CA. PARTICIPANTS: The study included 13 participants in 3 groups: (1) TA (n = 5), (2) sham acupuncture (SA, n = 5), or (3) waiting control (WC, n = 3). INTERVENTION: The TA group received acupuncture treatments for 12 wk at CHD-specific sites, while the SA group received no-needle pressure at nonacupuncture sites for the same period, and the WC group received no intervention. OUTCOME MEASURES: The study measured the number of EPCs circulating in peripheral blood to determine cell surface markers for expressions of cluster of differentiation 34, 133 (CD34+/CD133+) and vascular endothelial growth factor receptor 2 (VEGF-R2+). RESULTS: Eight men and 5 women with a mean age of 59 +/- 10.9 y were included. Compared with their measurements at baseline, members of the TA group had a significantly greater change in the level of EPCs expressing CD34+/VEGF-R2+ compared with the SA group (P = .04). No group differences were evident in immature EPCs expressing CD34+/CD133+. CONCLUSION: The study's results suggest that TA can alter the number of EPCs circulating in peripheral blood by increasing the mobilization of the VEGF-R2+ EPC subpopulations. Further studies are warranted to evaluate whether TA can beneficially affect CHD via augmentation of EPC regenerative pathways. PMID- 26770092 TI - Sara Speck, md, and Daniel Tripps, phd: A New Integrative Cardiology Model. PMID- 26770090 TI - Conventional Practitioners' Communication of Integrative Alternatives for Chronic Back Pain: An Evidence-based, Patient-centered Model. AB - Chronic back pain is one of the most common conditions treated in the United States. Informed consent is the communication of treatment alternatives, benefits, and risks and must be provided to patients in most instances. The alternatives provided during this discussion should include all options supported by research evidence and the patient's preferences. This article proposes a model for chronic back pain that includes the communication of complementary therapies as part of a patient-centered, integrative approach to informed consent. The content of informed consent is determined by common law (court cases), legislation, regulations, and evidence-based research. The practitioner's and patient's knowledge and the patient's values should be used to filter this information. Finally, shared decision making should be used to arrive at the patient's final decision regarding informed consent for treatment. PMID- 26770091 TI - Escharotic Treatment for ECC-positive CIN3 in Childbearing Years: A Case Report. AB - A persistent human papillomavirus (HPV) infection of a high-risk type is necessary for cervical cancer to develop. The severity of the diagnosis, together with colposcopy findings, determines the standard for treatment, and ablative or excisional options may be recommended. Escharotic treatment, together with an oral, anticarcinogenic HPV protocol and a vaginal-suppository protocol, is an alternative treatment, especially for those women of childbearing age who are concerned about the possibility of obstetrical complications associated with the use of loop electrosurgical excision (LEEP). The aim of the current case study was to observe the effect of an ablative escharotic treatment for a woman with severe dysplasia, cervical intraepithelial neoplasia grade 3 (CIN3). A 28-y-old female visited the National College of Natural Medicine clinic to obtain suggestions for alternative treatments following a satisfactory colposcopy and a biopsy revealing a high-risk HPV effect, severe dysplasia CIN3, and a positive endocervical curettage (ECC). She refused the recommended standard of care, a LEEP, because of concerns about the potential for future obstetrical complications. As an alternative, she elected to receive an escharotic treatment at a frequency of 2 treatments/wk for 5 wk. In addition to the escharotic treatment, she followed an oral protocol consisting of vitamins and botanical medicine for 1 y and she completed a 12-wk regime of vaginal suppositories following the escharotic. The authors followed her for 2 y. The woman's Papanicolaou (Pap) test at the 6-mo follow-up revealed negative cervical cytology for intraepithelial lesion or malignancy, and her follow-up ECC was negative. Liquid-based Pap results were normal, and HPV testing was negative at her 1-y follow-up. Her Pap continued to remain normal at her 2-y follow-up. For women with high-grade cervical neoplasias and positive ECCs, with satisfactory colposcopies, escharotic treatment, accompanied by oral supplementation, holds promise as an effective alternative to LEEP and other excisional procedures. PMID- 26770093 TI - American Idolatry. PMID- 26770094 TI - The Vilification of Cholesterol (for Profit?). PMID- 26770095 TI - The US Medical Industry Turns Toward "Health Creation" ... plus more. PMID- 26770096 TI - Antonio C. Bianco, md, phd: Is T4 Enough for Patients With Hypothyroid Dysfunction? PMID- 26770097 TI - Bioavailability of a Sustained Release Formulation of Curcumin. AB - CONTEXT: Curcumin has a number of beneficial effects, such as functioning as a potent antioxidant,1 anti-inflammatory, 2 and anticancer agent. Because of its poor oral bioavailability, very high oral doses and repeated dosing have been used to obtain effective plasma levels, with mixed results. High doses of curcumin may cause gastric disturbance, often resulting in poor patient compliance. OBJECTIVE: The objective of this study was to compare the relative bioavailability of MicroActive Curcumin-an advanced, micronized formulation of curcumin that is 25% curcuminoids in a sustained release matrix-with that of an unformulated, 95% pure curcumin powder. DESIGN: A dissolution study compared the solubility of the formulated and the unformulated curcumin. The research team also performed a single-dose, 12-h, crossover uptake study with 10 participants and a high-dose tolerability and accumulation study with 3 participants, comparing the 2 forms of curcumin. SETTING: The study was done in MAZE Laboratories (Purchase, NY, USA). PARTICIPANTS: Ten healthy male and female volunteers, aged 21-66 y, took part in the single-dose study. Three participants, 2 female and 1 male aged 40-55 y, took part in the tolerability and accumulation study. The participants were people from the community. INTERVENTION: For the dissolution study, the research team filled hard gelatin capsules with unformulated 95% curcumin powder and the MicroActive Curcumin powder to the equivalent of 25 mg curcuminoids. For the single-dose study, participants received 500 mg of curcumin in 2 forms. MicroActive Curcumin capsules were administered after breakfast, and blood samples were drawn at 1, 2, 4, 8, and 12 h postdose. After a 7-d washout period, the protocol was repeated for unformulated, 95% curcumin powder capsules. For the tolerability study, the unformulated, 95% curcumin powder was given at a dose that provided 2 g of curcumin for 7 d followed by 5 g of curcumin for an additional 7 d. After a washout period of 14 d, the protocol was repeated with MicroActive Curcumin. Participants then continued to take the MicroActive Curcumin for >3 mo. OUTCOME MEASURES: For the dissolution study, the curcumin was quantified at room temperature using reverse-phase, high-performance liquid chromatography (HPLC) with a Phenomenex Luna column (150 * 4.6 mm, 5 MUm) (Phenomenex Inc, Torrance, CA, USA). For the single-dose and the tolerability studies, hydrolysis of conjugates and extraction of curcuminoids from the plasma were performed. The curcuminoids were quantified using reverse-phase HPLC with an ultraviolet-visible detector as described above. RESULTS: The dissolution study indicated that the sustained-release curcumin had greater dissolution for 12 h at all points tested, compared with the unformulated curcumin. Very little of the unformulated curcumin powder had been released at the end of the 12 h. The results of the single-dose uptake study indicated that the sustained-release formula was 9.7 * more bioavailable than the unformulated powder (P < .001, paired t test). Additionally, all participants showed uptake from the sustained-release formulation. That formulation also resulted in significant increases in the plasma demethoxylated curcuminoids, but the research team did not observe the same increases for the unformulated curcumin powder. The sustained-release formulation was well tolerated, without adverse effects in the high-dose tolerability study. CONCLUSIONS: Formulation of micronized curcumin in a combination of surfactants, oils, and polymers improves the absorption of curcumin. In addition, the unique plasma demethylated curcuminoid profile may enhance the therapeutic effects of MicroActive Curcumin not observed with unformulated curcumin at moderate and well-tolerated doses. MicroActive Curcumin was well tolerated, without any adverse effects in a high-dose tolerability study. These properties have the potential to make high-dose curcumin supplementation more accessible through simplified incorporation into food and beverage preparations. PMID- 26770098 TI - Yoga as Therapy for Neurodegenerative Disorders: A Case Report of Therapeutic Yoga for Adrenomyeloneuropathy. AB - Yoga is a promising therapeutic modality for neurodegenerative diseases. This case study presents a therapeutic yoga protocol for adrenomyeloneuropathy (AMN) and its effect on a patient's quality of life (QOL), agility, balance, and peripheral dexterity. A 61-y-old man diagnosed with AMN who was experiencing (1) peripheral neuropathy in his legs and feet, (2) lower-back pain (LBP), and (3) osteoarthritis received 60-min weekly therapeutic yoga sessions for a 10-mo period. Yoga therapy included hatha yoga asanas (poses) and pranayama (breathing exercises). Hatha yoga asanas were aligned with 7 Berg Balance Scale (BBS) indicators to measure improvement in balance and range of motion. The 10-mo course of therapeutic yoga resulted in improved LBP; improved flexion of the patient's hips, knees, and ankles; improved propulsion phase of walking; and improvement in the patient's ability to stand and balance without an assistive device. The effect of yoga therapy on the patient in this case study aligns with current QOL improvements noted in current research on yoga therapy for neurological disorders. The described concepts and methods of employing therapeutic yoga provide insights for clinicians into a modality that is low risk and low cost and that can support individuals with other neurological disorders, such as multiple sclerosis (MS), fibromyalgia (FM), and diseases of the peripheral nervous system. Further study is warranted to help determine the safety and efficacy of yoga therapy for these conditions. PMID- 26770099 TI - Adrenal and Thyroid Supplementation Outperforms Nutritional Supplementation and Medications for Autoimmune Thyroiditis. AB - One of the many challenges for any physician is determining the correct course of treatment for patients with more than 1 area of complaint. Should the physician treat the symptoms or the underlying cause of a condition? If treating the cause, what and who determines the cause? Further complicating the issue, doctors must succeed in getting patients to follow the prescribed treatment, which has always been and will continue to be an issue in reaching therapeutic goals. In late 2009, a 49-year-old Caucasian woman visited the Natural Health Center of Medical Lake (NHCML) in Medical Lake, WA, complaining of multiple symptoms. One symptom was a goiter that had not been relieved with a prescription for 0.375 mg of Synthroid daily. Her comorbidities included mixed hyperlipidemia; multiple joint pains; alopecia; fatigue; bilateral, lower-extremity edema; and severe gastric disruption with bloating and acid reflux. After initial success from treatment, with a complete reduction of her presenting goiter and most of her other symptoms, the patient withdrew herself from her prescription medication and her nutritional supplementation. After 4 wk, the patient visited NHCML with indications of severe hypothyroidism, including a severely enlarged goiter of the right wing. After 6 wk of treatment with iodine and a glandular nutritional supplement (GTA Forte), her symptoms of severe hypothyroidism abated. Subsequent treatment for adrenal insufficiency, which was diagnosed at NHCML using salivary adrenal stress-index testing for cortisol rhythm and load, allowed complete resolution of her presenting complaints. This result persisted even at the 3-y follow-up to a greater degree than did the results from the use of thyroid nutritional supplementation and Synthroid, both alone and combined. The hypothalamus-pituitary-adrenal (HPA) axis may contribute to the existence of thyroid-type symptoms, particularly for those individuals with subclinical thyroid conditions. The treatment of the feedback mechanisms for the HPA axis may provide a valuable framework for treatment of mixed hyperlipidemia because normalizing or improving thyroid stimulating hormone (TSH) levels can reduce serum cholesterol levels. PMID- 26770100 TI - Alan Goldhamer, dc: Water Fasting-The Clinical Effectiveness of Rebooting Your Body. PMID- 26770101 TI - When Words Collide. PMID- 26770102 TI - Homocysteine: Friend or Foe? PMID- 26770104 TI - Mimi Guarneri, md, facc, abihm: Healing Through Science and Compassion. PMID- 26770103 TI - Muddled Recommendations From Agencies on Integrated Pain Care ... plus more. PMID- 26770105 TI - Transformative Learning: The Role of Research in Traditional Clinical Disciplines. AB - One of an educator's main tasks is to develop the intellectual openness of students that is necessary for transformative learning to take place. An initial step in removing the constraint of assumption is to employ the process of unlearning in the classroom. Unlearning in its simplest form can be described as the process through which the student learns to ask questions about a subject on which they are passionate, and through critical reflection, to construct and validate a new understanding based on observations and information generated by the original questions. Developing the ability to improvise and innovate are clear and positive indications that unlearning has occurred, and the Maryland University of Integrative Health's (MUIH's) educators have found that integrating research methods into class and group projects can accelerate the unlearning process. MUIH promotes students' effort to solve interesting problems using the community found within the classroom. The natural state of relativism found in group processes lends itself to making explicit the assumptions each individual brings to the process. MUIH's methods include engaging students in visual deconstruction of research data found in graphs, tables, and images; having students identify the end point of a line of inquiry; and evaluating a previously accumulated body of evidence to determine if it supports a product's claims (eg, claims about general health, structure-function, or therapeutic value). The ultimate aim in asking students to take part in research embedded in coursework is to provide an assessment of their abilities that is more closely linked to discipline-specific experience. MUIH's method of ingraining a culture of inquiry into both classroom and independent research serves to enhance students' self awareness about the constraints of their own a priori thinking and to nurture a deeper trust in their own informed intuition. PMID- 26770106 TI - Glucevia Fraxinus excelsior Extract Effectively Controls Blood Glucose Levels in Randomized, Controlled Trial. PMID- 26770108 TI - Mitochondrial Medicine Arrives to Prime Time in Clinical Care: Nutritional Biochemistry and Mitochondrial Hyperpermeability ("Leaky Mitochondria") Meet Disease Pathogenesis and Clinical Interventions. PMID- 26770109 TI - Rick Smith, Environmentalist: Understanding the Personal Impact of Toxins and Our Various Roles in Making a Difference. PMID- 26770107 TI - Mitochondrial Dysfunction and Chronic Disease: Treatment With Natural Supplements. AB - Loss of function in mitochondria, the key organelle responsible for cellular energy production, can result in the excess fatigue and other symptoms that are common complaints in almost every chronic disease. At the molecular level, a reduction in mitochondrial function occurs as a result of the following changes: (1) a loss of maintenance of the electrical and chemical transmembrane potential of the inner mitochondrial membrane, (2) alterations in the function of the electron transport chain, or (3) a reduction in the transport of critical metabolites into mitochondria. In turn, these changes result in a reduced efficiency of oxidative phosphorylation and a reduction in production of adenosine-5'-triphosphate (ATP). Several components of this system require routine replacement, and this need can be facilitated with natural supplements. Clinical trials have shown the utility of using oral replacement supplements, such as l-carnitine, alpha-lipoic acid (alpha-lipoic acid [1,2-dithiolane-3 pentanoic acid]), coenzyme Q10 (CoQ10 [ubiquinone]), reduced nicotinamide adenine dinucleotide (NADH), membrane phospholipids, and other supplements. Combinations of these supplements can reduce significantly the fatigue and other symptoms associated with chronic disease and can naturally restore mitochondrial function, even in long-term patients with intractable fatigue. PMID- 26770110 TI - Help Me, Rwanda. PMID- 26770111 TI - "Niacin Doesn't Work and Is Harmful!" Proclaim the Headlines. Yet Another Highly Publicized Questionable Study to Discredit Integrative Medicine. PMID- 26770112 TI - David Jones, md: Shaping the Practice of Medicine. PMID- 26770114 TI - Howard Hindin, dds: Becoming Physicians of the Mouth. PMID- 26770113 TI - Regarding Ignorance and Shamelessness in the US Medical Industry ... plus more. PMID- 26770115 TI - The Sodium Debate: More or Less About More or Less. PMID- 26770116 TI - Deep Friction Massage in Treatment of Radiation-induced Fibrosis: Rehabilitative Care for Breast Cancer Survivors. AB - Treatment for invasive breast cancer usually involves some combination of surgery, radiation therapy, chemotherapy, hormone therapy, and/or targeted therapy. For approximately 50% of patients, radiation therapy is a component of the therapies used. As a result, radiation-induced fibrosis is becoming a common and crippling side effect, leading to muscle imbalance with a lessened range of motion as well as pain and dysfunction of the vascular and lymphatic systems. No good estimates are available for how many patients experience complications from radiation. Radiation-induced fibrosis can affect the underlying fascia, muscles, organs, and bones within the primary target field and the larger secondary field that is caused by the scatter effect of radioactive elements. For breast cancer patients, the total radiation field may include the neck, shoulder, axillary, and thoracic muscles and the ribs for both the ipsilateral (cancer-affected) and contralateral sides. This case study indicates that therapy using deep friction massage can affect radiation-induced fibrosis beneficially, particularly in the thoracic muscles and the intercostals (ie, the muscles between the ribs). When delivered in intensive sessions using deep friction techniques, massage has the potential to break down fibrotic tissues, releasing the inflammation and free radicals that are caused by radiation therapy. In the course of the massage, painful and debilitating spasms resulting from fibrosis can be relieved and the progressive nature of the radiation-induced fibrosis interrupted. PMID- 26770118 TI - Remembering Mrs Castellanos. PMID- 26770117 TI - Highlights From the Institute for Functional Medicine's 2014 Annual Conference: Functional Perspectives on Food and Nutrition: The Ultimate Upstream Medicine. PMID- 26770120 TI - Tipping Point? Cleveland Clinic Announces Partnership With Hyman/Hanaway and the Institute for Functional Medicine ... plus more. PMID- 26770119 TI - Toxins From the Gut. PMID- 26770122 TI - Canaries in the Phosphate-Toxicity Coal Mines. AB - Phosphorus is an essential mineral for cell structure and function but, when consumed in excess of the body's requirements, has many adverse effects on metabolism and health. Recently published research has revealed that the average American consumes far more phosphorus than the recommended dietary allowance (RDA) (700 mg/d for adults). Some individuals' daily phosphorus intake exceeds even an adult's tolerable upper limit (4000 mg/d). Until now, understanding of the adverse effects caused by high phosphorus intake has come from patients with chronic kidney disease (CKD), in whom high levels of serum phosphates are strongly associated with increased cardiovascular and all-cause mortality. Due to their impaired renal function, CKD patients cannot clear excess phosphorus, for which reason they must avoid processed foods, virtually all of which are laden with phosphate-containing food additives. Recently, it has become apparent that CKD patients are our canaries in the phosphate-toxicity coal mines. Excessive phosphorus consumption has now been shown to be clearly associated with cardiovascular disease, osteoporosis, and all-cause mortality in the general, healthy population. PMID- 26770121 TI - Part 1: The Human Gut Microbiome in Health and Disease. AB - The bacterial cells harbored within the human gastrointestinal tract (GIT) outnumber the host's cells by a factor of 10 and the genes encoded by the bacteria resident within the GIT outnumber their host's genes by more than 100 times. These human digestive-tract associated microbes are referred to as the gut microbiome. The human gut microbiome and its role in both health and disease has been the subject of extensive research, establishing its involvement in human metabolism, nutrition, physiology, and immune function. Imbalance of the normal gut microbiota have been linked with gastrointestinal conditions such as inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS), and wider systemic manifestations of disease such as obesity, type 2 diabetes, and atopy. In the first part of this review, we evaluate our evolving knowledge of the development, complexity, and functionality of the healthy gut microbiota, and the ways in which the microbial community is perturbed in dysbiotic disease states; the second part of this review covers the role of interventions that have been shown to modulate and stabilize the gut microbiota and also to restore it to its healthy composition from the dysbiotic states seen in IBS, IBD, obesity, type 2 diabetes, and atopy. PMID- 26770123 TI - Bruce Ames, phd, and Rhonda Patrick, phd: Discussing the Triage Concept and the Vitamin D-Serotonin Connection. PMID- 26770124 TI - Leader of the Pack. PMID- 26770125 TI - Acidosis: An Old Idea Validated by New Research. PMID- 26770127 TI - Jeffrey Bland, phd, and Patrick Hanaway, md: Taking the Omics Revolution to the Street. PMID- 26770126 TI - End of a (Lucky) Era for Integrative Health Policy: Republican Wins Sweep Key Integrative Leaders From Powerful Committee Chairs ... plus more. PMID- 26770128 TI - Part 2: Treatments for Chronic Gastrointestinal Disease and Gut Dysbiosis. AB - Part 1 of this review discussed the connection between the human gut microbiota and health. Manipulation of the intestinal microbiota holds promise as a prospective therapy for gut dysbiosis, ameliorating symptoms of gastrointestinal and systemic diseases and restoring health. The concept of probiotics has existed for more than 100 y, and modern research methods have established sound scientific support for the perceived benefits of probiotic bacteria, which mainly include Lactobacillus and Bifidobacterium genera. On the basis of these evidence based functional approaches, dietary interventions that supplement the normal diet with probiotics or prebiotics are now considered as potentially viable alternatives or adjuncts to the use of steroids, immunosuppressants, and/or surgical interventions. Studies investigating the impact on gastrointestinal disorders, such as diarrhea, inflammatory bowel disease (IBD), irritable bowel syndrome (IBS); and systemic metabolic diseases, such as type 2 diabetes and obesity, in response to the use of probiotics and prebiotics are reviewed. Further, fecal microbial transplantation (FMT) is discussed as an exciting development in the treatment of gut dysbiosis using microbes. PMID- 26770129 TI - Proper Calcium Use: Vitamin K2 as a Promoter of Bone and Cardiovascular Health. AB - Inadequate calcium intake can lead to decreased bone mineral density, which can increase the risk of bone fractures. Supplemental calcium promotes bone mineral density and strength and can prevent osteoporosis. Recent scientific evidence, however, suggests that elevated consumption of calcium supplements may raise the risk for heart disease and can be connected with accelerated deposit of calcium in blood-vessel walls and soft tissues. In contrast, vitamin K2 is associated with the inhibition of arterial calcification and arterial stiffening. An adequate intake of vitamin K2 has been shown to lower the risk of vascular damage because it activates matrix GLA protein (MGP), which inhibits the deposits of calcium on the walls. Vitamin K, particularly as vitamin K2, is nearly nonexistent in junk food, with little being consumed even in a healthy Western diet. Vitamin K deficiency results in inadequate activation of MGP, which greatly impairs the process of calcium removal and increases the risk of calcification of the blood vessels. An increased intake of vitamin K2 could be a means of lowering calcium-associated health risks. PMID- 26770131 TI - Gerald Krystal, phd: The Effects of Protein and Carbohydrates on Cancer. PMID- 26770132 TI - Fear of Flying. PMID- 26770133 TI - Issue 75! PMID- 26770130 TI - Integrative Treatment of Pediatric Obesity: Psychological and Spiritual Considerations. AB - This article presents an integrative approach to the problem of pediatric obesity, which is a multifaceted medical condition that is epidemic in the United States and elsewhere in the world. In this article, definitions of pediatric obesity are provided, and its prevalence, etiological factors, medical complications, and comorbidities are reviewed. Psychological and spiritual factors associated with pediatric obesity are discussed, together with their importance to integrative treatment. This review suggests that the use of psychological interventions, such as cognitive behavioral therapy (CBT) and animal-assisted therapy (AAT), can be considered in conjunction with medical and educational interventions to treat pediatric obesity successfully. PMID- 26770135 TI - Stuart Tomc, Cannabinoid Educator: Staying in Step With the State of Research. PMID- 26770134 TI - The Joint Commission Moves Integrative Approach Ahead of Pharmaceuticals for Pain Management ... plus more. PMID- 26770136 TI - Clinical Assessment of Low-dose Osteoinductive Protein as a Stand-alone Regimen in Self-reported Osteoarthritis. AB - CONTEXT: Osteoarthritis, sometimes called degenerative joint disease, is the most common form of arthritis. It affects more than 20 million people in the United States, who mostly are older than age 45 y. No specific treatment exists to halt the progressive cartilage degeneration of osteoarthritis or to repair the damaged cartilage. Alternatives to pharmaceuticals include natural therapies and nutritional supplements. OBJECTIVE: The present study examined the clinical response to daily supplementation with bioactive protein complex containing a collagen type 2 network, with associated growth factors, and osteoinductive proteins, known as bone morphogenetic proteins (BMPs). DESIGN: The research team designed an open-label preliminary study. SETTING: Joint evaluations were self administered by participants at their residences. PARTICIPANTS: Participants were 44 individuals with self-reported osteoarthritis in the hip, knee, or ankle (ie, in weight-bearing joints). INTERVENTION: Participants self-administered orally a low-dose form of the ingredient (ie, 150 mg of Cyplexinol((r)) Standard, once daily for 4 wk). OUTCOME MEASURES: Four parameters-pain intensity, frequency of pain, activity level, and strength-were evaluated using a visual analog scale (VAS), both at baseline and at the end of the 4-wk period. RESULTS: Pain intensity decreased 45% on a 10-cm VAS from 2.85 cm (P = .0001; 95% CI, 2.54, 3.16) at baseline to 1.41 cm (P = .0001; 95% CI, 1.18, 1.64) at wk 4. Pain frequency decreased 55% from 3.16 cm (P = .0001; 95% CI, 2.88, 3.44) at baseline to 1.22 cm (P = .0001; 95% CI, 0.85, 1.59) at wk 4. Activity level increased from 1.58 cm (P = .0001; 95% CI, 1.34, 1.82) at baseline to 2.91 cm (P = .0001; 95% CI, 2.71, 3.11) at wk 4. Strength increased 80% from 1.24 cm (P = .0001; 95% CI, 0.91, 1.57) at baseline to 2.10 cm (P = .0001; 95% CI, 1.73, 2.47) at wk 4. CONCLUSIONS: The 44 participants reported subjective improvements in pain frequency and intensity as well as in activity level following administration of Cyplexinol((r)). The results from this study identify the possible pathways associated with cartilage degradation, pain, and inflammation, which should be the focus of future research, and they suggest that the ingredient can be effective in helping to maintain joint homeostasis. PMID- 26770137 TI - A Taste-intensity Visual Analog Scale: An Improved Zinc Taste-test Protocol. AB - CONTEXT: Studies employing methods for measurement of zinc sulfate taste acuity have had diverse results, and although the studies have had limitations in design and implementation, they have suggested salient findings beyond the assessment of taste acuity. These findings have included, but were not limited to, relationships between zinc sulfate taste acuity and weight, levels of serum zinc, diastolic hypertension, levels of salivary carbonic anhydrase 6, and frequency of illness. However, current protocols for zinc sulfate taste assessment are problematic and warrant improvement. OBJECTIVE: The current study intended to compare the ranking scale for the original Bryce-Smith and Simpson zinc taste test (BS-ZTT) with a novel, taste-intensity visual analog scale (TI-VAS) to explore the potential for improved zinc sulfate taste-acuity measurement. DESIGN: Participants were administered a 0.1% solution of zinc sulfate and assessed using the 2 scales. SETTING: The study took place at West Liberty University, in West Liberty, WV, USA. PARTICIPANTS: Participants were 500 West Liberty University students who volunteered to participate in the study. RESULTS: A strong, statistically significant, positive correlation existed between the BS-ZTT and the TI-VAS scores (r s = 0.79; P < .0001; n = 491). CONCLUSIONS: The study found that the BS-ZTT offered a limited number of ordinal variable ranks and depended on an examiner's evaluation. Conversely, the TI-VAS had an expanded range of variables and was independent of the examiner. The TI-VAS can be used as a taste acuity test for zinc sulfate and as a benchmark for future analyses of zinc sulfate taste acuity and zinc taste tests. PMID- 26770139 TI - Nancy Sudak, md: On Unifying the Voices of Integrative Practice. PMID- 26770140 TI - Ginseng and Jet Engines. PMID- 26770141 TI - Hard to be Healthy in North America. PMID- 26770138 TI - Nutritional and Metabolic Biomarkers in Autism Spectrum Disorders: An Exploratory Study. AB - CONTEXT: Autism spectrum disorder (ASD) is currently on the rise, now affecting approximately 1 in 68 children in the United States according to a 2010 surveillance summary from the Centers for Disease Control and Prevention (CDC). This figure is an estimated increase of 78% from the figure in 2002. The CDC suggests that more investigation is needed to understand this astounding increase in autism in such a short period. OBJECTIVE: The aim of this pilot study was to determine whether a group of children with ASD exhibited similar variations in a broad array of potential correlates, including medical histories, symptoms, genetics, and multiple nutritional and metabolic biomarkers. DESIGN: This study was a retrospective, descriptive chart review. SETTING: The study took place at the University of Kansas Medical Center (KUMC). PARTICIPANTS: Participants were 7 children with ASD who had sought treatment at the Integrative Medicine Clinic at the medical center. RESULTS: A majority of the children exhibited an elevated copper:zinc ratio and abnormal vitamin D levels. Children also demonstrated abnormal levels of the essential fatty acids: (1) alpha-linolenic acid (ALA)- C13:3W3, and (2) linoleic acid (LA)-C18:2W6; high levels of docosahexaenoic acid (DHA); and an elevated omega-6:omega-3 ratio. Three of 7 children demonstrated abnormal manganese levels. Children did not demonstrate elevated urine pyruvate or lactate but did have abnormal detoxification markers. Three of 7 patients demonstrated abnormalities in citric acid metabolites, bacterial metabolism, and fatty acid oxidation markers. A majority demonstrated elevated serum immunoglobulin G (IgG) antibodies to casein, egg whites, egg yolks, and peanuts. A majority had absent glutathione S-transferase (GSTM) at the 1p13.3 location, and 3 of 7 children were heterozygous for the glutathione S-transferase I105V (GSTP1). A majority also exhibited genetic polymorphism of the mitochondrial gene superoxide dismutase A16V (SOD2). CONCLUSIONS: The findings from this small group of children with ASD points to the existence of nutritional, metabolic, and genetic correlates of ASD. These factors appear to be important potential abnormalities that warrant a case control study to evaluate their reliability and validity as markers of ASD. PMID- 26770142 TI - Going, Going, Nearly Gone: Licensed "CAM" Practitioners Disappearing From the National Institutes of Health NCCIH Advisory Council ... plus more. PMID- 26770143 TI - Kevin Spelman, phd-Keeping It Together: The Other Compounds in Cannabis and the Benefits of Whole-herb Use. PMID- 26770144 TI - Denis Wilson, md: Low Body Temperature as an Indicator for Poor Expression of Thyroid Hormone. PMID- 26770145 TI - Evaluation of the Effects of BioCell Collagen, a Novel Cartilage Extract, on Connective Tissue Support and Functional Recovery From Exercise. AB - CONTEXT: Little is known about the effect of nutritional supplementation on metabolic optimization for enhancing adaptation and recovery of the connective tissue elements that support musculoskeletal function. OBJECTIVE: The study aimed to determine the potential effect of supplementation with a novel, hydrolyzed chicken sternal cartilage extract-called BioCell Collagen-on biomarkers and functional indices of recovery from intense exercise. DESIGN: The research team designed a randomized, double-blind, placebo-controlled pilot study. SETTING: The study was conducted at the Center for Applied Health Sciences in Stow, OH, USA. PARTICIPANTS: Participants were 8 healthy, recreationally active individuals, with a mean age of 29.3 y. INTERVENTION: Participants ingested either 3 g of a novel, hydrolyzed chicken sternal cartilage extract called BioCell Collagen ("supplement") or 3 g of a placebo daily for 6 wk prior to challenge with an upper-body, muscle-damaging resistance exercise (UBC) on day 43 and a rechallenge on day 46 to assess functional recovery. OUTCOME MEASURES: Primary endpoints were levels of 3 blood biomarkers-creatine kinase (CK), lactate dehydrogenase (LDH), and C-reactive protein (CRP)- and scores on a clinical pain scale and a perceived recovery scale (PRS). RESULTS: The extract attenuated the post-UBC increase in serum markers for muscle tissue damage: CK, LDH, and CRP. For the intervention group vs the placebo group, the mean changes were as follows: (1) an increase in CK of 20 U/L vs 4726 U/L, respectively; (2) a decrease in LDH of 3.5 U/L vs an increase of 82.9 U/L, respectively; and (3) an increase in CRP of 0.07 mg/L vs an increase of 0.7 mg/L, respectively. The performance decrement in bench press repetitions to failure was 57.9% on day 43 and 57.8% on day 46 for the intervention group vs 72.2% on day 43 and 65% on day 46 for the placebo group. The overall trend for the performance decrement, together with the results for the PRS, suggested that a more robust muscular recovery and adaptive response occurred with use of the extract. The supplement was well tolerated. CONCLUSIONS: The study's preliminary data are promising with regard to the beneficial effects of the extract on connective tissue protection and recovery in those engaged in routine resistance training and cardiovascular exercise. A larger study is warranted to confirm and refine these findings. PMID- 26770146 TI - Rauwolfia in the Treatment of Hypertension. AB - Rauwolfia serpentina is a safe and effective treatment for hypertension. The plant was used by many physicians throughout India in the 1940s and then was used throughout the world in the 1950s, including in the United States and Canada. It fell out of popularity when adverse side effects, including depression and cancer, became associated with it. This author reviews the scientific literature with regard to the use of Rauwolfia and the treatment of hypertension. The author reviews the plant's botany, chemistry, and pharmacology and provides a researched and documented method of action for the active ingredients. With special emphasis on the plant's role in treating high blood pressure, the author looks at medical uses of the plant, critically examining its adverse side effects, toxicology, and carcinogenicity. The author refutes the association between the plant and carcinogenicity and discusses the importance of correct dosing and of screening patients to minimize the occurrence of depression. He concludes with the recommendation of use of low dose Rauwolfia (LDR) for suitable patients with hypertension. The plant provides clinicians with a safe and effective adjunct to pharmaceuticals in the treatment of high blood pressure. PMID- 26770147 TI - The Continuum of Health Professions. AB - The large number of health care professions with overlapping scopes of practice is intimidating to students, confusing to patients, and frustrating to policymakers. As abundant and diverse as the hundreds of health care professions are, they possess sufficient numbers of common characteristics to warrant their placement on a common continuum of health professions that permits methodical comparisons. From 2009-2012, the author developed and delivered experimental courses at 2 community colleges for the purposes of creating and validating a novel method for comparing health care professions. This paper describes the bidirectional health professions continuum that emerged from these courses and its potential value in helping students select a health care career, motivating health care providers to seek interprofessional collaboration, assisting patients with the selection of health care providers, and helping policymakers to better understand the health care professions they regulate. PMID- 26770149 TI - Michael Smith, md: Treat the Underlying Causes of Weight Gain to Facilitate Successful Weight Loss. PMID- 26770148 TI - The Effect of Dietary Change in a Patient With Ichthyosis Vulgaris: A Case Report. AB - Ichthyosis vulgaris (IV) is a genetic skin condition of autosomal dominant inheritance. The main symptom associated with IV is scaling of the skin. Traditional treatment involves the application of various topical creams or ointments. The current case study documents significant improvement in the symptoms of a 20-y-old female patient with IV through use of dietary change based on food-sensitivity testing and supplement use- fish oil, vitamin D, and probiotics. She had previously used traditional topical therapies with less than optimal results. More research is required to substantiate the changes documented in this report. PMID- 26770150 TI - A Pirate Looks at 60. PMID- 26770151 TI - Is Challenge Testing Valid for Assessing Body Metal Burden? PMID- 26770152 TI - Casey Health Institute: Integrative Center Marches Into PCMH and ACO Worlds ... plus more. PMID- 26770153 TI - Andrew Campbell, md: Mechanisms of the Gut-Brain Axis. PMID- 26770154 TI - Integrative Therapies and Cardiovascular Disease in the Breast Cancer Population: A Review, Part 1. AB - The cardiovascular toxicities of breast cancer treatment are important health problems, with potential public health consequences. Integrative therapies may represent important tools for prevention in this population. This article reviews the cardiotoxicity of conventional breast cancer therapy, including chemotherapy, radiation, and hormonal therapy. Data are presented on the benefits of substances such as curcumin, melatonin, Ginkgo biloba, resveratrol, coenzyme Q10, and l carnitine. Although clinical studies on many of these substances are limited both in size and number, preclinical studies are available for several, and this article summarizes the potential mechanisms of action. Areas for future research are also identified. PMID- 26770155 TI - The Health Professions' Continuum Cleft. AB - The continuum of health professions is interrupted by a natural and unavoidable gap that separates conventional from complementary and alternative health care and that may aptly be called the continuum cleft. The cleft occurs as a consequence of the development of professional silos during the professionalization process and of the emergence of professional cysts related to the efforts of some professions to insulate their patients from the perceived risks imposed by other professions. The continuum cleft can cause costly and potentially hazardous compromises to the continuity of care for >73 million Americans annually. Interprofessional educational experiences derived from collaboration in the health sciences among Oregon's uniquely diverse educational institutions may provide some guidelines for mending the continuum cleft. PMID- 26770157 TI - Michael Smith, md: Treat the Underlying Causes of Weight Gain to Facilitate Successful Weight Loss. PMID- 26770158 TI - Mark Blumenthal: Quality and Efficacy of Herbal Medicines. PMID- 26770159 TI - No Satisfaction. PMID- 26770156 TI - Nothing Boring About Boron. AB - The trace mineral boron is a micronutrient with diverse and vitally important roles in metabolism that render it necessary for plant, animal, and human health, and as recent research suggests, possibly for the evolution of life on Earth. As the current article shows, boron has been proven to be an important trace mineral because it (1) is essential for the growth and maintenance of bone; (2) greatly improves wound healing; (3) beneficially impacts the body's use of estrogen, testosterone, and vitamin D; (4) boosts magnesium absorption; (5) reduces levels of inflammatory biomarkers, such as high-sensitivity C-reactive protein (hs-CRP) and tumor necrosis factor alpha (TNF-alpha); (6) raises levels of antioxidant enzymes, such as superoxide dismutase (SOD), catalase, and glutathione peroxidase; (7) protects against pesticide-induced oxidative stress and heavy metal toxicity; (8) improves the brains electrical activity, cognitive performance, and short-term memory for elders; (9) influences the formation and activity of key biomolecules, such as S-adenosyl methionine (SAM-e) and nicotinamide adenine dinucleotide (NAD(+)); (10) has demonstrated preventive and therapeutic effects in a number of cancers, such as prostate, cervical, and lung cancers, and multiple and non-Hodgkin's lymphoma; and (11) may help ameliorate the adverse effects of traditional chemotherapeutic agents. In none of the numerous studies conducted to date, however, do boron's beneficial effects appear at intakes > 3 mg/d. No estimated average requirements (EARs) or dietary reference intakes (DRIs) have been set for boron-only an upper intake level (UL) of 20 mg/d for individuals aged >= 18 y. The absence of studies showing harm in conjunction with the substantial number of articles showing benefits support the consideration of boron supplementation of 3 mg/d for any individual who is consuming a diet lacking in fruits and vegetables or who is at risk for or has osteopenia; osteoporosis; osteoarthritis (OA); or breast, prostate, or lung cancer. PMID- 26770160 TI - Conventional Laboratory Tests to Assess Toxin Burden. PMID- 26770161 TI - Functional Medicine: An Operating System for Integrative Medicine. PMID- 26770162 TI - The Blue Zone Intersection: What Role for Integrative Health in Community Health? ... plus more. PMID- 26770163 TI - Dale E. Bredesen, md: Reversing Cognitive Decline. PMID- 26770164 TI - Research Battles: Survival Tips From a Veteran. AB - Studies of nonorthodox medical treatments may go awry because of inherent flaws in designs that are better suited for trials of pharmaceutical products. Unintended consequences may follow from efforts at randomization, the lack of lead-in periods, required visits for medical assessment, inadequate screening, and a lack of trial publicity. A veteran of a mismanaged trial shares her experiences. PMID- 26770165 TI - Integrative Therapies and Cardiovascular Disease in the Breast Cancer Population: A Review, Part 2. AB - In Part 1 of the current review, the cardiotoxicity of standard breast cancer treatment was reviewed. Part 2 presents a comprehensive review of the current evidence for lifestyle factors, including nutrition and exercise. Part 2 describes the results of several dietary interventions in breast cancer survivors. Specific dietary factors that may promote cardiovascular health in this population, including essential fatty acids and plant phytosterols, are also reviewed. In addition, the mechanisms by which exercise may provide a benefit are discussed, and evidence for the important role of attainment and maintenance of a healthy weight is outlined. Finally, recommendations for lifestyle changes in the survivor population are discussed, and opportunities for future research in this population are identified. PMID- 26770166 TI - Whole-person Integrative Eating: A Program for Treating Overeating, Overweight, and Obesity. AB - The whole-person integrative eating (WPIE) model and program provides insights into the underlying causes of overeating as well as a comprehensive program for treating overeating, overweight, and obesity. A wide range of guidelines on food and eating from ancient food wisdom from Eastern healing systems, world religions, and cultural traditions, as well as Western nutritional science, were distilled into 6 principles: (1) eat fresh, whole foods; (2) eat with positive feelings; (3) eat with mindfulness; (4) eat with gratitude; (5) eat with loving regard; and (6) eat while dining with others. To assess how well individuals follow these guidelines, an 80-item questionnaire was developed and administered to a large sample of 5256 Americans who participated in a 6-wk, 18-lesson online e-course on integrative eating. Based on a factor analysis of the items, 7 distinct overeating styles emerged that are opposite of the perennial principles: (1) emotional eating, (2) fast foodism, (3) food fretting, (4) task snacking, (5) sensory disregard, (6) unappetizing atmosphere, and (7) solo dining. All were significantly and independently related to overeating frequency, and 5 of the 7 were significantly related to being overweight or obese. The case study presented here demonstrates how a 64-y-old woman who struggled with obesity throughout adolescence and adulthood was able to replace her 7 overeating styles with the 6 perennial integrative-eating guidelines for optimal eating. At the beginning of the year's coaching intervention, Barbara weighed 107 kg and wore a size 3*; 1 y later, she weighed approximately 75 kg and wears a medium, size 12. She has attributed her weight loss to the wholeness of the integrative-eating program she practices. PMID- 26770167 TI - Nutritional Approach for Relief of Joint Discomfort: A 12-week, Open-case Series and Illustrative Case Report. AB - CONTEXT: Tetrahydro iso-alpha acids (THIAAs), derived from Humulus lupulus (hops), have demonstrated anti-inflammatory effects in vitro and in an animal model of rheumatoid arthritis (RA). Undenatured type 2 collagen has been found to be effective in clinical studies in RA and osteoarthritis (OA). OBJECTIVE: The study intended to evaluate the efficacy and safety of a proprietary tablet containing 150 mg of n-enriched THIAA (nTHIAA) and 10 mg of undenatured type 2 collagen (UC-II) (containing 25% UC-II) in patients with arthritis. DESIGN: The study was an open-label case series. This article also includes a case history for 1 participant. SETTING: The study was conducted at the Functional Medicine Research Center (FMRC) in Gig Harbor, WA, USA, from February 2013-June 2013. PARTICIPANTS: Participants were 17 adults, 12 women, and 5 men aged 39-69 y, who had chronic joint pain involving various joints, 13 with probable OA and 4 with possible RA. INTERVENTION: Participants took 2 tablets of nTHIAA + UC-II 2 */d with meals for 12 wk. OUTCOME MEASURES: Participants completed arthritis-related and quality-of-life questionnaires, at weeks 2, 4, 8, and 12: (1) the visual analog scale for pain (VAS-P); (2) the medical symptoms questionnaire (MSQ), with the analysis particularly focusing on the joint/muscle subscale and total scores; (3) the health and wellness outcome questionnaire (MOS-SF36), with the analysis particularly focusing on the physical and mental subscales; (4) the arthritis impact questionnaire (AIQ), with the analysis particularly focusing on the arthritis symptoms and daily living subscales; (5) the health assessment questionnaire (HAQ-DI) with the analysis particularly focusing on question 26 (Q26), which indicates overall pain during the week prior to the survey; and (6) the arthritis impact measurement scales 2 (AIMS2). At 12 wk, participants also completed the visual analog scale for efficacy (VAS-E). RESULTS: All participants completed the 12-wk evaluation, and all reported improvements in pain. Significant improvements in scores on the questionnaires were observed as early as 2 wk. For example, the total score on the MSQ was significantly decreased from a mean of 20.76 +/- 2.90 (SE) at baseline to 12.24 +/- 2.81 after 2 wk (P < .001). At 12 wk, the participants rated the supplement's efficacy at 7.6 +/- 0.6 of 10. At baseline, 13 of the 17 participants were using analgesics for joint pain, compared with only 4 participants at 12 wk. Two of those 4 had reduced their analgesic dosages. The studied supplement was well tolerated, and no serious side effects occurred. CONCLUSIONS: The supplement containing nTHIAA and UC-II is safe and efficacious in participants with chronic joint pain. PMID- 26770168 TI - Personalized Lifestyle Medicine Institute, October 2014: A Seminal Moment in the 21st Century's Transformation of Health Care. PMID- 26770169 TI - Barbara Dossey, phd, rn: Developing a Healing Approach in Nursing. PMID- 26770170 TI - Case Reports, Clinical Practice Guidelines, and Evidence. PMID- 26770171 TI - Quit Your Bellyaching. PMID- 26770066 TI - Study of the [Formula: see text] and [Formula: see text] decays with the ATLAS detector. AB - The decays [Formula: see text] and [Formula: see text] are studied with the ATLAS detector at the LHC using a dataset corresponding to integrated luminosities of 4.9 and 20.6 fb[Formula: see text] of pp collisions collected at centre-of-mass energies [Formula: see text] TeV and 8 TeV, respectively. Signal candidates are identified through [Formula: see text] and [Formula: see text] decays. With a two dimensional likelihood fit involving the [Formula: see text] reconstructed invariant mass and an angle between the [Formula: see text] and [Formula: see text] candidate momenta in the muon pair rest frame, the yields of [Formula: see text] and [Formula: see text], and the transverse polarisation fraction in [Formula: see text] decay are measured. The transverse polarisation fraction is determined to be [Formula: see text], and the derived ratio of the branching fractions of the two modes is [Formula: see text], where the first error is statistical and the second is systematic. Finally, a sample of [Formula: see text] decays is used to derive the ratios of branching fractions [Formula: see text] and [Formula: see text], where the third error corresponds to the uncertainty of the branching fraction of [Formula: see text] decay. The available theoretical predictions are generally consistent with the measurement. PMID- 26770172 TI - Radiology Undergraduate and Resident Curricula: A Narrative Review of the Literature. AB - OBJECTIVE: The purpose of this study was to examine the literature regarding radiology curricula for both undergraduates and residents. METHODS: A review of the literature was performed using relevant key words. Articles were retrieved through December 2012 using PubMed, ScienceDirect, ERIC, Proquest, and ICL databases along with a manual review of references. RESULTS: Of the 4716 unique abstracts reviewed by the author, 142 were found to be relevant to the purpose of this study. Undergraduate radiology education, radiology curriculum, and radiology pedagogy vary widely between disciplines and between colleges within disciplines. Formal radiology education is not taught at all medical programs and little radiology training is incorporated into non-radiology residencies. This results in some medical graduates not being taught how to interpret basic radiology images and not learning contraindications and indications for ordering diagnostic imaging tests. There are no definitive studies examining how to incorporate radiology into the curriculum, how to teach radiology to either undergraduates or residents, or how to assess this clinical competency. CONCLUSIONS: This review shows that radiology education is perceived to be important in undergraduate and residency programs. However, some programs do not include radiology training, thus graduates from those programs do not learn radiology essentials. PMID- 26770176 TI - The McAndrews Leadership Lecture: Origins. AB - OBJECTIVE: This article describes the origins and rationale for the McAndrews Leadership Lecture and explains why the American Chiropractic Association honors George and Jerome McAndrews. DISCUSSION: George and Jerome McAndrews' backgrounds demonstrate their leadership contributions to the chiropractic profession. Jerome McAndrews, a chiropractor, held substantial leadership roles in the chiropractic profession. George McAndrews, a lawyer, administered a permanent injunction forbidding the American Medical Association's restraint of trade toward the chiropractic profession. CONCLUSION: The American Chiropractic Association has established the McAndrews Leadership Lecture to honor their contributions to the chiropractic profession. PMID- 26770178 TI - The John A. Sweaney Lecture: Athens, Greece, May 2015, Given by Dr Vivian H.E. Kil. To Inspire the Chiropractic Profession to Dream More, Learn More, Do More, and Become More. AB - The following is The John A. Sweaney Lecture delivered by Dr Vivian H.E. Kil at the Biannual Meeting of the World Federation of Chiropractic in Athens, Greece, on May 12, 2015. PMID- 26770175 TI - Radiologists as Educators: A Narrative Review of the Literature. AB - OBJECTIVE: The purpose of this study was to examine literature on how radiologists are trained to be effective educators for both residents and undergraduates in the health professions. METHODS: A review of the literature was performed using relevant key words. Articles were retrieved through from 1990 through December 2012 using PubMed, ScienceDirect, ERIC, Proquest, and ICL databases along with a manual review of references. RESULTS: Of the 4716 unique abstracts reviewed by the author, 51 were found to be relevant to the purpose of this study. Faculty teaching skills seem to be solidified during residency. This may be due to a failure to include scholarship of teaching and learning in education and faculty development. Preliminary research shows that creating opportunity for faculty development is beneficial with much of this literature focused on explaining educational concepts to radiologists. CONCLUSION: The literature examining faculty training in the area of radiology education is sparse. Several articles address the need for more academic radiologists and the need for better training of academic radiologists. The few articles aimed at providing insight to radiologists in this area introduce basic educational concepts such as lecture creation, examination writing, and learning styles or simply delineating what makes an effective educator. PMID- 26770177 TI - The McAndrews Leadership Lecture: February 2015, by Dr Scott Haldeman. Challenges of the Past, Challenges of the Present. AB - The McAndrews Leadership Lecture was developed by the American Chiropractic Association to honor the legacy of Jerome F. McAndrews, DC, and George P. McAndrews, JD, and their contributions to the chiropractic profession. This article is a transcription of the presentation made by Dr Scott Haldeman on February 28, 2015, in Washington, DC, at the National Chiropractic Leadership Conference. PMID- 26770174 TI - Student Evaluations, Outcomes, and National Licensure Examinations in Radiology Education: A Narrative Review of the Literature. AB - OBJECTIVE: The purpose of this study was to examine literature on radiological student evaluation and outcome assessments including national board examinations. METHODS: A review of the literature was performed using relevant key words. Articles were retrieved through December 2012 using PubMed, ScienceDirect, ERIC, Proquest, and ICL databases along with a manual review of references. RESULTS: Of the 4716 unique abstracts reviewed by the author, 54 were found to be relevant to the purpose of this study. Student grade point average correlates with board scores in the nursing, chiropractic, and medical professions. Scores on the chiropractic college admission test and undergraduate grade point average correlate with success in professional college. There is a correlation between board scores and college attended. Board preparation programs do not appear to affect board examination scores. CONCLUSION: Although evaluations can be effective teaching tools, they are not used by many radiology programs. Some programs have inadequate evaluations and do not allow students to review their evaluations. There are no definitive links between mastery of radiology and specific evaluations, outcomes, or pre-professional/clinical grades. Studies suggest that board examination scores reflect long-term mastery of knowledge rather than short-term memorization of facts. PMID- 26770179 TI - Identification of teratogenic polymethoxy-1-alkenes from Cylindrospermopsis raciborskii, and taxonomically diverse freshwater cyanobacteria and green algae. AB - Cylindrospermopsis raciborskii is among the most commonly recognized toxigenic cyanobacteria associated with harmful algal blooms (HAB) in freshwater systems, and specifically associated with multiple water-soluble toxins. Lipophilic metabolites from C. raciborskii, however, were previously shown to exert teratogenicity (i.e. inhibition of vertebrate development) in the zebrafish (Danio rerio) embryo model, specifically suggesting the presence of additional bioactive compounds unrelated to the currently known toxins. In the present study, a series of known teratogenic polymethoxy-1-alkenes (PMA) were identified, purified and chemically characterized from an otherwise well-characterized strain of toxigenic C. raciborskii. Although PMA have been previously identified in other cyanobacteria, this is the first time they have been identified from this recognized HAB species. Following their identification from C. raciborskii, the taxonomic distribution of the PMA was additionally investigated by chemical screening of a freshwater algal (i.e. cyanobacteria, green algal) culture collection. Screening suggests that these compounds are distributed among phylogenetically diverse taxa. Furthermore, parallel screening of the algal culture collection, using the zebrafish embryo model of teratogenicity, the presence of PMA was found to closely correlate with developmental toxicity of these diverse algal isolates. Taken together, the data suggest PMA contribute to the toxicity of C. raciborskii, as well as apparently several other taxonomically disparate cyanobacterial and green algal genera, and may, accordingly, contribute to the toxicity of diverse freshwater HAB. PMID- 26770173 TI - Pedagogical Approaches to Diagnostic Imaging Education: A Narrative Review of the Literature. AB - OBJECTIVE: The purpose of this study was to examine literature on how radiology is taught and learned by both radiology residents and undergraduates in the health professions. METHODS: A review of the literature was performed using relevant key words. Articles were retrieved through December 2012 using PubMed, ScienceDirect, ERIC, Proquest, and ICL databases along with a manual review of references. RESULTS: Of the 4716 unique abstracts reviewed by the author, 91 were found to be relevant to the purpose of this study. The literature retrieved reported pedagogical approaches to teaching radiology including the following: problem solving, technology as teacher, independent learning tools, visiting lectureships, case based teaching, and conferences. There was some exploration of the relative effectiveness of educational formats. Suggestions for future research identify 7 areas of relative consistency. CONCLUSION: Radiology is a clinical skill that requires integration science, clinical information, clinical experiences, and information recorded on diagnostic imaging studies. The research in this area focuses on problem solving, the use of algorithm/scripts, introducing uncertainty in clinical scenarios, incorporating technology in learning environments, active learning techniques, and methods of independent learning. Although the literature in this area is still in its infancy, the research examining the relative effectiveness of these various educational formats is often contradictory, suggesting that this is a complex area of study with numerous factors influencing student learning. PMID- 26770180 TI - Metabolomic biomarkers for personalised glucose lowering drugs treatment in type 2 diabetes. AB - We aimed to identify metabolites to predict patients' response to glucose lowering treatment during the first 5 years after detection of type 2 diabetes. Metabolites were measured by GC-MS in baseline samples from 346 screen-detected type 2 diabetes patients in the ADDITION-NL study. The response to treatment with metformin and/or sulphonylurea (SU) was analysed to identify metabolites predictive of 5 year HbA1c change by multiple regression analysis. Baseline glucose and 1,5 anhydro-glucitol were associated with HbA1c decrease in all medication groups. In patients on SU no other metabolite was associated with HbA1c decrease. A larger set of metabolites was associated with HbA1c change in the metformin and the combination therapy (metformin + SU) groups. These metabolites included metabolites related to liver metabolism, such as 2 hydroxybutanoic acid, 3-hydroxybutanoic acid, 2-hydroxypiperidine and 4 oxoproline). Metabolites involved in oxidative stress and insulin resistance were higher when the HbA1c decrease was larger in the metformin/sulphonylurea group. The associations between baseline metabolites and responsiveness to medication are in line with its mode of action. If these results could be replicated in other populations, the most promising predictive candidates might be tested to assess whether they could enhance personalised treatment. PMID- 26770181 TI - Withaferin A Inhibits Helicobacter pylori-induced Production of IL-1beta in Dendritic Cells by Regulating NF-kappaB and NLRP3 Inflammasome Activation. AB - Helicobacter pylori infection is associated with chronic gastritis, peptic ulcer, and gastric cancer. There is evidence that IL-1beta is associated with the development of gastric cancer. Therefore, downregulation of H. pylori-mediated IL 1beta production may be a way to prevent gastric cancer. Withaferin A (WA), a withanolide purified from Withania somnifera, is known to exert anti-inflammatory and anti-tumor effects. In the present study, we explored the inhibitory activity of WA on H. pylori-induced production of IL-1beta in murine bone marrow-derived dendritic cells (BMDCs) and the underlying cellular mechanism. Co-treatment with WA decreased IL-1beta production by H. pylori in BMDCs in a dose-dependent manner. H. pylori-induced gene expression of IL-1beta and NLRP3 (NOD-like receptor family, pyrin domain containing 3) were also suppressed by WA treatment. Moreover, IkappaB-alpha phosphorylation by H. pylori infection was suppressed by WA in BMDCs. Western blot analysis revealed that H. pylori induced cleavage of caspase-1 and IL-1beta, as well as increased procaspase-1 and pro IL-1beta protein levels, and that both were suppressed by co-treatment with WA. Finally, we determined whether WA can directly inhibit ac tivation of the NLRP3 inflammasome. NLRP3 activators induced IL-1beta secretion in LPS-primed macrophages, which was inhibited by WA in a dose-dependent manner, whereas IL-6 production was not affected by WA. Moreover, cleavage of IL-1beta and caspase-1 by NLRP3 activators was also dose-dependently inhibited by WA. These findings suggest that WA can inhibit IL-1beta production by H. pylori in dendritic cells and can be used as a new preventive and therapeutic agent for gastric cancer. PMID- 26770182 TI - 3,3'-Diindolylmethane Inhibits Flt3L/GM-CSF-induced-bone Marrow-derived CD103(+) Dendritic Cell Differentiation Regulating Phosphorylation of STAT3 and STAT5. AB - The intestinal immune system maintains oral tolerance to harmless antigens or nutrients. One mechanism of oral tolerance is mediated by regulatory T cell (Treg)s, of which differentiation is regulated by a subset of dendritic cell (DC)s, primarily CD103(+) DCs. The aryl hydrocarbon receptor (AhR), a ligand activated transcription factor, plays an important role in regulating immunity. The intestines are exposed to various AhR ligands, including endogenous metabolites and phytochemicals. It was previously reported that AhR activation induced tolerogenic DCs in mice or in cultures of bone marrow-derived DCs. However, given the variety of tolerogenic DCs, which type of tolerogenic DCs is regulated by AhR remains unknown. In this study, we found that AhR ligand 3,3' diindolylmethane (DIM) inhibited the development of CD103(+) DCs from mouse bone marrow cells stimulated with Flt3L and GM-CSF. DIM interfered with phosphorylation of STAT3 and STAT5 inhibiting the expression of genes, including Id2, E2-2, IDO-1, and Aldh1a2, which are associated with DC differentiation and functions. Finally, DIM suppressed the ability of CD103(+) DCs to induce Foxp3(+) Tregs. PMID- 26770183 TI - The Anti-inflammatory Effect of GV1001 Mediated by the Downregulation of ENO1 induced Pro-inflammatory Cytokine Production. AB - GV1001 is a peptide derived from the human telomerase reverse transcriptase (hTERT) sequence that is reported to have anti-cancer and anti-inflammatory effects. Enolase1 (ENO1) is a glycolytic enzyme, and stimulation of this enzyme induces high levels of pro-inflammatory cytokines from concanavalin A (Con A) activated peripheral blood mononuclear cells (PBMCs) and ENO1-expressing monocytes in healthy subjects, as well as from macrophages in rheumatoid arthritis (RA) patients. Therefore, this study investigated whether GV1001 downregulates ENO1-induced pro-inflammatory cytokines as an anti-inflammatory peptide. The results showed that GV1001 does not affect the expression of ENO1 in either Con A-activated PBMCs or RA PBMCs. However, ENO1 stimulation increased the production of pro-inflammatory cytokines such as tumor necrosis factor (TNF) alpha, interleukin (IL)-1beta, and IL-6, and these cytokines were downregulated by pretreatment with GV1001. Moreover, p38 mitogen-activated protein kinase (MAPK) and nuclear factor (NF)-kappaB were activated when ENO1, on the surface of Con A-activated PBMCs and RA PBMCs, was stimulated, and they were successfully suppressed by pre-treatment with GV1001. These results suggest that GV1001 may be an effective anti-inflammatory peptide that downregulates the production of pro inflammatory cytokines through the suppression of p38 MAPK and NF-kappaB activation following ENO1 stimulation. PMID- 26770184 TI - Anti-inflammatory Effect of Alloferon on Ovalbumin-induced Asthma. AB - Asthma is a well-known inflammatory lung disease; however, the specific underlying mechanism is largely unknown. We previously demonstrated that alloferon effectively downregulates pulmonary inflammation. In this study, we examined whether alloferon has a therapeutic effect on asthma. Alloferon remarkably decreased the number of eosinophils, macrophages, and neutrophils in the bronchoalveolar lavage fluid (BALF) from ovalbumin (OVA)-induced asthma mice. It was synergistically decreased with 2.5 mg/kg prednisolone (PDA). Inflammatory cell infiltration around the bronchioles and in the alveolus of OVA-induced asthma mice was effectively prevented by alloferon alone and combined treatment with alloferon and PDS. The production of IL-5 and IL-17 was decreased by alloferon alone and combined treatment with alloferon and PDS. There was no change the level of total immunoglobulin (Ig) following alloferon administration; however, total Ig was decreased by PDS. IgG2a levels were not changed by either alloferon alone or alloferon in combination with PDS. However, the levels of OVA specific IgG1 and IgE were decreased by alloferon and PDS. In conclusion, our results suggest that a combination of alloferon and prednisolone is effective for the treatment of asthma, as it prevents inflammatory cell infiltration via the downregulation of IL-5 and IL-17 production and decreases IgG1 and IgE production via the suppression of T helper type 2 immune response. PMID- 26770185 TI - Comparative Analysis of Dibutyric cAMP and Butyric Acid on the Differentiation of Human Eosinophilic Leukemia EoL-1 Cells. AB - Purification of enough numbers of circulating eosinophils is difficult because eosinophils account for less than 5% peripheral blood leukocytes. Human eosinophilic leukemia EoL-1 cells have been considered an in vitro source of eosinophils as they can differentiate into mature eosinophil-like cells when incubated with dibutyryl cAMP (dbcAMP) or butyric acid. In this study, the viability and phenotypic maturation of EoL-1 cells stimulated by either dbcAMP or butyric acid were comparatively analyzed. After treatment with 100 uM dbcAMP or 0.5 uM butyric acid, EoL-1 cells showed morphological signs of differentiation, although the number of nonviable EoL-1 cells was significantly increased following butyric acid treatment. Stimulation of EoL-1 cells with 0.5 uM butyric acid more effectively induced the expression of mature eosinophil markers than stimulation with dbcAMP. These results suggest that treatment of EoL-1 cells with 0.5 uM butyric acid for limited duration could be an effective strategy for inducing their differentiation. Considering that expression of CCR3 was not sufficient in EoL-1 cells stimulated with 0.5 uM butyric acid, treatment of the chemically stimulated EoL-1 cells with cytokines, which primarily support eosinophil maturation, would help to obtain differentiated EoL-1 cells with greater functional maturity. PMID- 26770186 TI - Expression of Nucleotide-oligomerization Domain (NOD) and Related Genes in Mouse Tissues Infected with Mycobacterium leprae. AB - The nucleotide-oligomerization domain (NOD) is an important molecule involved in host defense against bacterial infection. To study the role of NODs in the host response to Mycobacterium leprae, we measured the mRNA levels of NODs and related genes in infected mouse tissues. The mRNA expression of NOD1, NOD2, caspase-1 and ASC was increased in mouse footpads. Whereas NOD2 expression in macrophages was increased at 2 and 24 h post-infection with M. leprae, there was no expression of NOD1 at these time points. An increase in caspase-1 expression was observed at 2 h and continued at 24 h. However, the expression of ASC was increased only at the early time point. The expression of caspase-1 is regulated by NOD2-dependent pathway in established HEK 293. Our results suggest NOD2, rather than NOD1, may be associated with the host response to M. leprae and that caspase-1 activation is essential for the host response. PMID- 26770187 TI - Effect of Ixeris dentata Nakai Extract on Nitric Oxide Production and Prostaglandin E2 Generation in LPS-stimulated RAW264.7 Cells. AB - Inflammation is the basis of severe acute and chronic diseases. This study investigated the anti-inflammatory property of a crude methanol extract (MeOH-ex) and the solvent fractions of Ixeris dentata Nakai (IDN) in LPS-stimulated murine macrophage-like cell line RAW264.7. Here, we showed that the ethyl acetate fraction (EtOAc-fr) had the most potent inhibitory activity on LPS-induced nitric oxide (NO) production among the tested samples, i.e., IDN MeOH-ex and the three different solvent fractions (chloroform, n-hexane, and EtOAc). We further found that the EtOAc-fr significantly inhibited LPS-induced prostaglandin PGE2 (PGE2) generation in RAW264.7 cells. Furthermore, the treatment with EtOAc-fr effectively suppressed the expression of inducible NO synthase (iNOS) and cyclooxygenase 2 (COX-2). These results suggest that the EtOAc-fr of IDN MeOH-ex exhibits an anti-inflammatory activity in vitro by inhibiting LPS-induced NO production and PGE2 generation via suppression of iNOS and COX-2 expression. PMID- 26770188 TI - Ginsenoside Rg1 and 20(S)-Rg3 Induce IgA Production by Mouse B Cells. AB - Ginsenosides are the major components of ginseng, which is known to modulate blood pressure, metabolism, and immune function, and has been used to treat various diseases. It has been reported that ginseng and several ginsenosides have immunoregulatory effects on the innate and T cell-mediated immune response. However, their effects on the humoral immune response have not been fully explored. The present study examined the direct effects of red ginseng extract (RGE) and ginsenosides on mouse B cell proliferation and on antibody production and the expression of germline transcripts (GLT) by mouse B cells in vitro. RGE slightly reduced B cell proliferation, but increased IgA production by LPS stimulated B cells. Furthermore, ginsenoside Rg1 and 20(S)-Rg3 selectively induced IgA production and expression of GLTalpha transcripts by LPS-stimulated B cells. Collectively, these results suggest that ginsenoside Rg1 and 20(S)-Rg3 can drive the differentiation of B cells into IgA-producing cells through the selective induction of GLTalpha expression. PMID- 26770189 TI - Relevance Feedback Based Query Expansion Model Using Borda Count and Semantic Similarity Approach. AB - Pseudo-Relevance Feedback (PRF) is a well-known method of query expansion for improving the performance of information retrieval systems. All the terms of PRF documents are not important for expanding the user query. Therefore selection of proper expansion term is very important for improving system performance. Individual query expansion terms selection methods have been widely investigated for improving its performance. Every individual expansion term selection method has its own weaknesses and strengths. To overcome the weaknesses and to utilize the strengths of the individual method, we used multiple terms selection methods together. In this paper, first the possibility of improving the overall performance using individual query expansion terms selection methods has been explored. Second, Borda count rank aggregation approach is used for combining multiple query expansion terms selection methods. Third, the semantic similarity approach is used to select semantically similar terms with the query after applying Borda count ranks combining approach. Our experimental results demonstrated that our proposed approaches achieved a significant improvement over individual terms selection method and related state-of-the-art methods. PMID- 26770190 TI - Serum Liver Fibrosis Markers for Predicting the Presence of Gastroesophageal Varices in Liver Cirrhosis: A Retrospective Cross-Sectional Study. AB - Background and Aims. A retrospective cross-sectional study was conducted to evaluate the role of hyaluronic acid (HA), laminin (LN), amino-terminal propeptide of type III procollagen (PIIINP), and collagen IV (CIV) in predicting the presence of gastroesophageal varices (GEVs) in patients with liver cirrhosis. Methods. We enrolled 118 patients with liver cirrhosis who underwent the tests for the four serum liver fibrosis markers and upper gastrointestinal endoscopy at the same admissions. The predictive values of the four serum liver fibrosis markers were evaluated by the areas under the receiving operator characteristics curves (AUROCs) with 95% confidence intervals (CIs). Results. The prevalence of GEVs was 88% (104/118). The AUROCs for HA, LN, PIIINP, and CIV levels in predicting the presence of GEVs were 0.553 (95% CI: 0.458 to 0.644, P = 0.5668), 0.490 (95% CI: 0.397 to 0.584, P = 0.9065), 0.622 (95% CI: 0.528 to 0.710, P = 0.1099), and 0.560 (95% CI: 0.466 to 0.652, P = 0.4909). The PIIINP level at a cut-off value of 31.25 had a sensitivity of 73.1% and a specificity of 57.1%. Conclusions. The present study did not recommend HA, LN, PIIINP, and CIV levels to evaluate the presence of GEVs in liver cirrhosis. PMID- 26770191 TI - Bufalin Inhibits HCT116 Colon Cancer Cells and Its Orthotopic Xenograft Tumor in Mice Model through Genes Related to Apoptotic and PTEN/AKT Pathways. AB - Aims. To investigate the anticolorectal cancer (CRC) effects of Bufalin, a bioactive polyhydroxysteroid from Venenum Bufonis, using HCT116 human CRC cell and an established orthotopic xenograft model in mice, and to explore the mechanisms of action. Material and Methods. Cultured HCT116 cells or BALB/c mice with orthotopic tumor were treated by Bufalin (positive control: 5-FU). Cell proliferation, apoptosis, and cycling were determined by MTT, Annexin V/PI staining, and flow cytometry, respectively. In mice, tumor inhibition rate and animal survival were calculated. The expressions of PTEN/phosphate-PTEN, AKT/phosphate-AKT, Bad, Bcl-xl, Bax, or Caspase-3 in cells and/or tumors were determined by Western blot or immunohistochemical staining. Results. Bufalin significantly inhibited cell proliferation and induced cell apoptosis and cycle arrest in a dose/time-dependent manner. In the animal model, Bufalin treatment resulted in significant inhibition of tumor growth and prolonged survival. In the Bufalin-treated cultured cells and/or xenograft tumors, the expressions of PTEN, Bad, Bax, and Caspase-3 were significantly increased, while p-AKT and Bcl-xL significantly decreased. Conclusions. Our results indicate that Bufalin inhibit cell proliferation and orthotopic tumor growth by inducing cell apoptosis through the intrinsic apoptotic pathway, which is of pivotal significance in the identification of an anticancer drug that may synergize with Bufalin. PMID- 26770193 TI - Application of Fractional Wave Packet Transform for Robust Watermarking of Mammograms. AB - Exchanging of medical data requires efficient authentication and protection of medical data that can be illegally modified. Watermarking plays an important role in protecting, sharing, and securing medical data. In this work, a robust nonblind medical image watermarking scheme is proposed. The process involves two steps: the embedding and the extraction phase. During the embedding phase, l level FRWPT is performed on the host image and the watermark is embedded into the modified reference image. In the second phase, inverse FRWPT is performed on the watermarked image to extract the watermark from the watermarked image. The proposed scheme is tested on mammograms images and is subjected to common attacks like Gaussian filtering, median filtering, compression, sharpening, and contrast adjustments. Experimental results show that the proposed scheme is robust. PMID- 26770192 TI - A Prospective Study of Bipolar Transurethral Resection of Prostate Comparing the Efficiency and Safety of the Method in Large and Small Adenomas. AB - Bipolar technology offers a new perspective in the treatment of BPH. Purpose. To present our experience with the TURis system (Olympus, Tokyo, Japan). Materials and Methods. From February 2011 till December 2013 in a prospective study, 93 patients were treated for BPH. They were evaluated with IPSS, QoL, uroflow (Q max), and residual urine (RU), preoperatively as well as 6 and 9 months postoperatively. Based on the prostate volume, the patients were divided into two groups: group A (n = 48) with prostates >= 75 cc and group B (n = 45) with smaller prostate glands. All patients underwent bipolar TURP or/and plasma vaporization. Results. The postoperative improvement for IPSS, QoL, Q max, and RU was statistically significant. The operation time was longer in group A in comparison with group B (P < 0.001). The former group also had higher infection and stricture formation rates; however, there was no statistical difference between the two groups. Conclusions. Treatment with the TURis constitutes an effective technique and can be offered to large prostates with results equivalent to those in small ones. Regarding safety, large adenomas treated with TURis are not at a higher risk for urethral stricture but their odds to develop urogenital infections are relatively higher compared to the smaller adenomas. PMID- 26770194 TI - Flexural Stiffness of Myosin Va Subdomains as Measured from Tethered Particle Motion. AB - Myosin Va (MyoVa) is a processive molecular motor involved in intracellular cargo transport on the actin cytoskeleton. The motor's processivity and ability to navigate actin intersections are believed to be governed by the stiffness of various parts of the motor's structure. Specifically, changes in calcium may regulate motor processivity by altering the motor's lever arm stiffness and thus its interhead communication. In order to measure the flexural stiffness of MyoVa subdomains, we use tethered particle microscopy, which relates the Brownian motion of fluorescent quantum dots, which are attached to various single- and double-headed MyoVa constructs bound to actin in rigor, to the motor's flexural stiffness. Based on these measurements, the MyoVa lever arm and coiled-coil rod domain have comparable flexural stiffness (0.034 pN/nm). Upon addition of calcium, the lever arm stiffness is reduced 40% as a result of calmodulins potentially dissociating from the lever arm. In addition, the flexural stiffness of the full-length MyoVa construct is an order of magnitude less stiff than both a single lever arm and the coiled-coil rod. This suggests that the MyoVa lever arm-rod junction provides a flexible hinge that would allow the motor to maneuver cargo through the complex intracellular actin network. PMID- 26770067 TI - Searches for scalar leptoquarks in pp collisions at [Formula: see text] = 8 TeV with the ATLAS detector. AB - Searches for pair-produced scalar leptoquarks are performed using 20 fb[Formula: see text] of proton-proton collision data provided by the LHC and recorded by the ATLAS detector at [Formula: see text] TeV. Events with two electrons (muons) and two or more jets in the final state are used to search for first (second) generation leptoquarks. The results from two previously published ATLAS analyses are interpreted in terms of third-generation leptoquarks decaying to [Formula: see text] and [Formula: see text] final states. No statistically significant excess above the Standard Model expectation is observed in any channel and scalar leptoquarks are excluded at 95 % CL with masses up to [Formula: see text] 1050 GeV for first-generation leptoquarks, [Formula: see text] 1000 GeV for second generation leptoquarks, [Formula: see text] 625 GeV for third-generation leptoquarks in the [Formula: see text] channel, and 200 [Formula: see text] 640 GeV in the [Formula: see text] channel. PMID- 26770195 TI - Developing of the Computer Method for Annotation of Bacterial Genes. AB - Over the last years a great number of bacterial genomes were sequenced. Now one of the most important challenges of computational genomics is the functional annotation of nucleic acid sequences. In this study we presented the computational method and the annotation system for predicting biological functions using phylogenetic profiles. The phylogenetic profile of a gene was created by way of searching for similarities between the nucleotide sequence of the gene and 1204 reference genomes, with further estimation of the statistical significance of found similarities. The profiles of the genes with known functions were used for prediction of possible functions and functional groups for the new genes. We conducted the functional annotation for genes from 104 bacterial genomes and compared the functions predicted by our system with the already known functions. For the genes that have already been annotated, the known function matched the function we predicted in 63% of the time, and in 86% of the time the known function was found within the top five predicted functions. Besides, our system increased the share of annotated genes by 19%. The developed system may be used as an alternative or complementary system to the current annotation systems. PMID- 26770196 TI - Thyroid Function, Prevalent Coronary Heart Disease, and Severity of Coronary Atherosclerosis in Patients Undergoing Coronary Angiography. AB - This study investigated if free T4 and TSH concentrations or thyroid function categories were associated with prevalent CHD and the severity of coronary atherosclerosis in a population undergoing coronary angiography. This was a cross sectional study including 1799 patients who were consecutively admitted and underwent coronary angiography. We evaluated the severity of coronary atherosclerosis using Gensini score. In the entire study population, free T4 level was inversely associated with prevalent CHD (OR = 0.95, 95% CI 0.91-0.99, P = 0.01) and the natural log-transformed Gensini score (ln(Gensini score)) (beta = -0.03, 95% CI -0.05--0.01, P = 0.005). The odds of CHD increased gradually across hyperthyroidism, subclinical hypothyroidism, and overt hypothyroidism groups using the euthyroid group as the reference, and the trend is borderline significant (P for trend = 0.051). When comparing to the euthyroid group, ln(Gensini score) of the overt hypothyroidism group was significantly higher (P = 0.009), but the trend was not significant (P for trend = 0.08). A significant association of thyroid function with CHD or ln(Gensini score) in euthyroid patients was not observed. The present study demonstrated an association of thyroid function with prevalent CHD and the severity of coronary atherosclerosis in a population undergoing coronary angiography. However, this association was not observed in euthyroid individuals. PMID- 26770197 TI - The Prevalence of HIV in Cancer Patients at the Surgical Oncology Unit of Donka University Hospital of Conakry (Guinea). AB - Aim. To determine the prevalence of HIV infection among patients seen at the surgical oncology unit of Donka (Conakry, Guinea). Method. We conducted a retrospective and descriptive study of HIV infection in cancer patients from May 2007 to December 2012. Social characteristics (age, gender, marital status, and education) and immune status (HIV type, CD4 count) were reviewed. Results. Out of 2598 cancer patients, 54 (2.1%) tested positive for HIV. There were 11 (20.4%) defining AIDS and 43 (79.6%) nondefining AIDS cancers. The most frequent cancers were breast (14) (26.0%), non-Hodgkin lymphoma (6) (11.1%), liver (6) (11.1%), eye and annexes (6) (11.1%), and cervical cancer (5) (9.3%). These patients were female in 34 (63.0%) and had a median age of 39 years and body mass index was 20,3 Kg/m(2). They were unschooled in 40 (74.1%) and married in 35 (64.8%). CD4 count showed a median of 317 cells/mL. Antiretroviral treatment was performed in 40 (74.1%). Conclusion. HIV prevalence is higher in patients in our unit of surgical oncology. Breast cancer was the most common in this association. A national survey of a large sample is needed to determine the true prevalence and impact of HIV on cancer prognosis. PMID- 26770198 TI - Simultaneous Detection and Estimation of Catechol, Hydroquinone, and Resorcinol in Binary and Ternary Mixtures Using Electrochemical Techniques. AB - Cyclic voltammetry (CV) and differential pulse voltammetry (DPV) were performed with a glassy carbon electrode (GCE) modified with polyglutamic acid (PGA) on the three dihydroxybenzene isomers, catechol (CT), hydroquinone (HQ), and resorcinol (RS). At bare GCE, these isomers exhibited voltammograms with highly overlapped redox peaks that impeded their simultaneous detection in binary and ternary mixtures. On the contrary, at PGA modified GCE binary and ternary mixtures of the dihydroxybenzene isomers showed well-resolved redox peaks in both CV and DPV experiments. This resolving ability of PGA modified GCE proves its potential to be exploited as an electrochemical sensor for the simultaneous detection of these isomers. PMID- 26770203 TI - Modeling Neurological Disease by Rapid Conversion of Human Urine Cells into Functional Neurons. AB - Somatic cells can be directly converted into functional neurons by ectopic expression of defined factors and/or microRNAs. Since the first report of conversion mouse embryonic fibroblasts into functional neurons, the postnatal mouse, and human fibroblasts, astroglia, hepatocytes, and pericyte-derived cells have been converted into functional dopaminergic and motor neurons both in vitro and in vivo. However, it is invasive to get all these materials. In the current study, we provide a noninvasive approach to obtain directly reprogrammed functional neurons by overexpression of the transcription factors Ascl1, Brn2, NeuroD, c-Myc, and Myt1l in human urine cells. These induced neuronal (iN) cells could express multiple neuron-specific proteins and generate action potentials. Moreover, urine cells from Wilson's disease (WD) patient could also be directly converted into neurons. In conclusion, generation of iN cells from nonneural lineages is a feasible and befitting approach for neurological disease modeling. PMID- 26770204 TI - Effect of Periodic Granulocyte Colony-Stimulating Factor Administration on Endothelial Progenitor Cells and Different Monocyte Subsets in Pediatric Patients with Muscular Dystrophies. AB - Muscular dystrophies (MD) are heterogeneous group of diseases characterized by progressive muscle dysfunction. There is a large body of evidence indicating that angiogenesis is impaired in muscles of MD patients. Therefore, induction of dystrophic muscle revascularization should become a novel approach aimed at diminishing the extent of myocyte damage. Recently, we and others demonstrated that administration of granulocyte colony-stimulating factor (G-CSF) resulted in clinical improvement of patients with neuromuscular disorders. To date, however, the exact mechanisms underlying these beneficial effects of G-CSF have not been fully understood. Here we used flow cytometry to quantitate numbers of CD34+ cells, endothelial progenitor cells, and different monocyte subsets in peripheral blood of pediatric MD patients treated with repetitive courses of G-CSF administration. We showed that repetitive cycles of G-CSF administration induced efficient mobilization of above-mentioned cells including cells with proangiogenic potential. These findings contribute to better understanding the beneficial clinical effects of G-CSF in pediatric MD patients. PMID- 26770201 TI - Comparison of the Effects of Different Cryoprotectants on Stem Cells from Umbilical Cord Blood. AB - Purpose. Cryoprotectants (CPA) for stem cells from umbilical cord blood (UCB) have been widely developed based on empirical evidence, but there is no consensus on a standard protocol of preservation of the UCB cells. Methods. In this study, UCB from 115 donors was collected. Each unit of UCB was divided into four equal parts and frozen in different kinds of cryoprotectant as follows: group A, 10% ethylene glycol and 2.0% dimethyl sulfoxide (DMSO) (v/v); group B, 10% DMSO and 2.0% dextran-40; group C, 2.5% DMSO (v/v) + 30 mmol/L trehalose; and group D, without CPA. Results. CD34(+), cell viability, colony forming units (CFUs), and cell apoptosis of pre- and postcryopreservation using three cryoprotectants were analyzed. After thawing, significant differences in CD34(+) count, CFUs, cell apoptosis, and cell viability were observed among the four groups (P < 0.05). Conclusion. The low concentration of DMSO with the addition of trehalose might improve the cryopreservation outcome. PMID- 26770206 TI - Mesenchymal Stem/Stromal Cells from Discarded Neonatal Sternal Tissue: In Vitro Characterization and Angiogenic Properties. AB - Autologous and nonautologous bone marrow mesenchymal stem/stromal cells (MSCs) are being evaluated as proangiogenic agents for ischemic and vascular disease in adults but not in children. A significant number of newborns and infants with critical congenital heart disease who undergo cardiac surgery already have or are at risk of developing conditions related to inadequate tissue perfusion. During neonatal cardiac surgery, a small amount of sternal tissue is usually discarded. Here we demonstrate that MSCs can be isolated from human neonatal sternal tissue using a nonenzymatic explant culture method. Neonatal sternal bone MSCs (sbMSCs) were clonogenic, had a surface marker expression profile that was characteristic of bone marrow MSCs, were multipotent, and expressed pluripotency-related genes at low levels. Neonatal sbMSCs also demonstrated in vitro proangiogenic properties. Sternal bone MSCs cooperated with human umbilical vein endothelial cells (HUVECs) to form 3D networks and tubes in vitro. Conditioned media from sbMSCs cultured in hypoxia also promoted HUVEC survival and migration. Given the neonatal source, ease of isolation, and proangiogenic properties, sbMSCs may have relevance to therapeutic applications. PMID- 26770205 TI - The Comparison of the Immunologic Properties of Stem Cells Isolated from Human Exfoliated Deciduous Teeth, Dental Pulp, and Dental Follicles. AB - Aim. To compare the effects of various mesenchymal stem cells, those isolated from human exfoliated deciduous teeth (SHEDs), dental pulp stem cells (DPSCs), and dental follicle stem cells (DFSCs), on human peripheral blood mononuclear cells (PBMCs). Method. Mesenchymal stem cells were isolated from three sources in the orofacial region. Characterization and PCR analyses were performed. Lymphocytes were isolated from healthy peripheral venous blood. Lymphocytes were cocultured with stem cells in the presence and absence of IFN-gamma and stimulated with anti-CD2, anti-CD3, and anti-CD28 for 3 days. Then, lymphocyte proliferation, the number of CD4(+)FoxP3(+) T regulatory cells, and the levels of Fas/Fas ligand, IL-4, IL-10, and IFN-gamma in the culture supernatant were measured. Results. The DFSCs exhibited an enhanced differentiation capacity and an increased number of CD4(+)FoxP3(+) T lymphocytes and suppressed the proliferation and apoptosis of PBMCs compared with SHEDs and DPSCs. The addition of IFN-gamma augmented the proliferation of DFSCs. Furthermore, the DFSCs suppressed IL-4 and IFN-gamma cytokine levels and enhanced IL-10 levels compared with the other cell sources. Conclusion. These results suggest that IFN-gamma stimulates DFSCs by inducing an immunomodulatory effect on the PBMCs of healthy donors while suppressing apoptosis and proliferation and increasing the number of CD4(+)FoxP3(+) cells. PMID- 26770207 TI - Potential Role of Activating Transcription Factor 5 during Osteogenesis. AB - Human adipose-derived stem cells are an abundant population of stem cells readily isolated from human adipose tissue that can differentiate into connective tissue lineages including bone, cartilage, fat, and muscle. Activating transcription factor 5 is a transcription factor of the ATF/cAMP response element-binding protein (CREB) family. It is transcribed in two types of mRNAs (activating transcription factor 5 isoform 1 and activating transcription factor 5 isoform 2), encoding the same single 30-kDa protein. Although it is well demonstrated that it regulates the proliferation, differentiation, and apoptosis, little is known about its potential role in osteogenic differentiation. The aim of this study was to evaluate the expression levels of the two isoforms and protein during osteogenic differentiation of human adipose-derived stem cells. Our data indicate that activating transcription factor 5 is differentially expressed reaching a peak of expression at the stage of bone mineralization. These findings suggest that activating transcription factor 5 could play an interesting regulatory role during osteogenesis, which would provide a powerful tool to study bone physiology. PMID- 26770199 TI - Amnion and Chorion Membranes: Potential Stem Cell Reservoir with Wide Applications in Periodontics. AB - The periodontal therapy usually aims at elimination of disease causing bacteria and resolution of inflammation. It involves either resective or regenerative surgery to resolve the inflammation associated defects. Over the years, several methods have been used for achievement of periodontal regeneration. One of the oldest biomaterials used for scaffolds is the fetal membrane. The amniotic membranes of developing embryo, that is, amnion (innermost lining) and chorion (a layer next to it), have the properties with significant potential uses in dentistry. This paper reviews the properties, mechanism of action, and various applications of these placental membranes in general and specifically in Periodontics. PMID- 26770202 TI - Maintenance of Self-Renewal and Pluripotency in J1 Mouse Embryonic Stem Cells through Regulating Transcription Factor and MicroRNA Expression Induced by PD0325901. AB - Embryonic stem cells (ESCs) have the ability to grow indefinitely and retain their pluripotency in culture, and this self-renewal capacity is governed by several crucial molecular pathways controlled by specific regulatory genes and epigenetic modifications. It is reported that multiple epigenetic regulators, such as miRNA and pluripotency factors, can be tightly integrated into molecular pathways and cooperate to maintain self-renewal of ESCs. However, mouse ESCs in serum-containing medium seem to be heterogeneous due to the self-activating differentiation signal of MEK/ERK. Thus, to seek for the crucial miRNA and key regulatory genes that establish ESC properties in MEK/ERK pathway, we performed microarray analysis and small RNA deep-sequencing of J1 mESCs treated with or without PD0325901 (PD), a well-known inhibitor of MEK/ERK signal pathway, followed by verification of western blot analysis and quantitative real-time PCR verification; we found that PD regulated the transcript expressions related to self-renewal and differentiation and antagonized the action of retinoic acid- (RA ) induced differentiation. Moreover, PD can significantly modulate the expressions of multiple miRNAs that have crucial functions in ESC development. Overall, our results demonstrate that PD could enhance ESC self-renewal capacity both by key regulatory genes and ES cell-specific miRNA, which in turn influences ESC self-renewal and cellular differentiation. PMID- 26770200 TI - Maternal and Pediatric Health Outcomes in relation to Gestational Vitamin D Sufficiency. AB - Juxtaposed with monumental improvement in maternal-fetal outcomes over the last century, there has been the recent emergence of rising rates of gestational complications including preterm birth, operative delivery, and gestational diabetes. At the same time, there has been a burgeoning problem with widespread vitamin D deficiency among populations of many developed nations. This paper provides a brief review of potential health outcomes recently linked to gestational vitamin D deficiency, including preterm birth, cesarean delivery, and gestational diabetes. Although immediate costs for obstetric complications related to gestational vitamin D insufficiency may be modest, the short- and long term costs for pediatric healthcare resulting from such gestational complications may be enormous and present an enduring burden on healthcare systems. With increasing evidence pointing to fetal origins of some later life disease, securing vitamin D sufficiency in pregnancy appears to be a simple, safe, and cost-effective measure that can be incorporated into routine preconception and prenatal care in the offices of primary care clinicians. Education on gestational nutritional requirements should be a fundamental part of medical education and residency training, instruction that has been sorely lacking to date. PMID- 26770208 TI - Human Mesenchymal Stromal Cells from Different Sources Diverge in Their Expression of Cell Surface Proteins and Display Distinct Differentiation Patterns. AB - When germ-free cell cultures became a laboratory routine, hopes were high for using this novel technology for treatment of diseases or replacement of cells in patients suffering from injury, inflammation, or cancer or even refreshing cells in the elderly. Today, more than 50 years after the first successful bone marrow transplantation, clinical application of hematopoietic stem cells is a routine procedure, saving the lives of many every day. However, transplanting other than hematopoietic stem and progenitor cells is still limited to a few applications, and it mainly applies to mesenchymal stromal cells (MSCs) isolated from bone marrow. But research progressed and different trials explore the clinical potential of human MSCs isolated from bone marrow but also from other tissues including adipose tissue. Recently, MSCs isolated from bone marrow (bmMSCs) were shown to be a blend of distinct cells and MSCs isolated from different tissues show besides some common features also some significant differences. This includes the expression of distinct antigens on subsets of MSCs, which was utilized recently to define and separate functionally different subsets from bulk MSCs. We therefore briefly discuss differences found in subsets of human bmMSCs and in MSCs isolated from some other sources and touch upon how this could be utilized for cell-based therapies. PMID- 26770209 TI - Insight into Reepithelialization: How Do Mesenchymal Stem Cells Perform? AB - Wound reepithelialization is a cooperative multifactorial process dominated by keratinocyte migration, proliferation, and differentiation that restores the intact epidermal barrier to prevent infection and excessive moisture loss. However, in wounds that exhibit impaired wound healing, such as chronic nonhealing wounds or hypertrophic scars, the reepithelialization process has failed. Thus, it is necessary to explore a suitable way to mitigate these abnormalities to promote reepithelialization and achieve wound healing. Mesenchymal stem cells (MSCs) have the capacity for self-renewal as well as potential multipotency. These cells play important roles in many biological processes, including anti-inflammation, cell migration, proliferation, and differentiation, and signal pathway activation or inhibition. The mechanism of the involvement of MSCs in reepithelialization is still not fully understood. An abundance of evidence has shown that MSCs participate in reepithelialization by inhibiting excessive inflammatory responses, secreting important factors, differentiating into multiple skin cell types, and recruiting other host cells. This review describes the evidence for the roles that MSCs appear to play in the reepithelialization process. PMID- 26770210 TI - Decellularized Extracellular Matrix as an In Vitro Model to Study the Comprehensive Roles of the ECM in Stem Cell Differentiation. AB - Stem cells are a promising cell source for regenerative medicine. Stem cell differentiation must be regulated for applications in regenerative medicine. Stem cells are surrounded by extracellular matrix (ECM) in vivo. The ECM is composed of many types of proteins and glycosaminoglycans that assemble into a complex structure. The assembly of ECM molecules influences stem cell differentiation through orchestrated intracellular signaling activated by many ECM molecules. Therefore, it is important to understand the comprehensive role of the ECM in stem cell differentiation as well as the functions of the individual ECM molecules. Decellularized ECM is a useful in vitro model for studying the comprehensive roles of ECM because it retains a native-like structure and composition. Decellularized ECM can be obtained from in vivo tissue ECM or ECM fabricated by cells cultured in vitro. It is important to select the correct decellularized ECM because each type has different properties. In this review, tissue-derived and cell-derived decellularized ECMs are compared as in vitro ECM models to examine the comprehensive roles of the ECM in stem cell differentiation. We also summarize recent studies using decellularized ECM to determine the comprehensive roles of the ECM in stem cell differentiation. PMID- 26770211 TI - BMP6-Engineered MSCs Induce Vertebral Bone Repair in a Pig Model: A Pilot Study. AB - Osteoporotic patients, incapacitated due to vertebral compression fractures (VCF), suffer grave financial and clinical burden. Current clinical treatments focus on symptoms' management but do not combat the issue at the source. In this pilot study, allogeneic, porcine mesenchymal stem cells, overexpressing the BMP6 gene (MSC-BMP6), were suspended in fibrin gel and implanted into a vertebral defect to investigate their effect on bone regeneration in a clinically relevant, large animal pig model. To check the effect of the BMP6-modified cells on bone regeneration, a fibrin gel only construct was used for comparison. Bone healing was evaluated in vivo at 6 and 12 weeks and ex vivo at 6 months. In vivo CT showed bone regeneration within 6 weeks of implantation in the MSC-BMP6 group while only minor bone formation was seen in the defect site of the control group. After 6 months, ex vivo analysis demonstrated enhanced bone regeneration in the BMP6-MSC group, as compared to control. This preclinical study presents an innovative, potentially minimally invasive, technique that can be used to induce bone regeneration using allogeneic gene modified MSCs and therefore revolutionize current treatment of challenging conditions, such as osteoporosis-related VCFs. PMID- 26770214 TI - Clinical Observation of Employment of Umbilical Cord Derived Mesenchymal Stem Cell for Juvenile Idiopathic Arthritis Therapy. AB - Juvenile idiopathic arthritis (JIA), known as Juvenile rheumatoid arthritis, is the most common type of arthritis in children aged under 17. It may cause sequelae due to lack of effective treatment. The goal of this study is to explore the therapeutic effect of umbilical cord mesenchymal stem cells (UC-MSCs) for JIA. Ten JIA patients were treated with UC-MSCs and received second infusion three months later. Some key values such as 28-joint disease activity score (DAS28), TNF-alpha, IL-6, and regulatory T cells (Tregs) were evaluated. Data were collected at 3 months and 6 months after first treatment. DAS28 score of 10 patients was between 2.6 and 3.2 at three months after infusion. WBC, ESR, and CRP were significantly decreased while Tregs were remarkably increased and IL-6 and TNF-alpha were declined. Similar changes of above values were found after 6 months. At the same time, the amount of NSAIDS and steroid usage in patients was reduced. However, no significant changes were found comparing the data from 3 and 6 months. These results suggest that UC-MSCs can reduce inflammatory cytokines, improve immune network effects, adjust immune tolerance, and effectively alleviate the symptoms and they might provide a safe and novel approach for JIA treatment. PMID- 26770212 TI - Pluripotency Factors on Their Lineage Move. AB - Pluripotent stem cells are characterised by continuous self-renewal while maintaining the potential to differentiate into cells of all three germ layers. Regulatory networks of maintaining pluripotency have been described in great detail and, similarly, there is great knowledge on key players that regulate their differentiation. Interestingly, pluripotency has various shades with distinct developmental potential, an observation that coined the term of a ground state of pluripotency. A precise interplay of signalling axes regulates ground state conditions and acts in concert with a combination of key transcription factors. The balance between these transcription factors greatly influences the integrity of the pluripotency network and latest research suggests that minute changes in their expression can strengthen but also collapse the network. Moreover, recent studies reveal different facets of these core factors in balancing a controlled and directed exit from pluripotency. Thereby, subsets of pluripotency-maintaining factors have been shown to adopt new roles during lineage specification and have been globally defined towards neuroectodermal and mesendodermal sets of embryonic stem cell genes. However, detailed underlying insights into how these transcription factors orchestrate cell fate decisions remain largely elusive. Our group and others unravelled complex interactions in the regulation of this controlled exit. Herein, we summarise recent findings and discuss the potential mechanisms involved. PMID- 26770215 TI - BMI1, ALDH1A1, and CD133 Transcripts Connect Epithelial-Mesenchymal Transition to Cancer Stem Cells in Lung Carcinoma. AB - Epithelial-mesenchymal transition (EMT) is the underlying mechanism of tumor invasion and metastasis. Evidences from lung cancer cellular models show EMT can trigger conversion to a cancer stem cell (CSC) phenotype. In this study, we assessed mRNA expression levels of EMT-inducing transcription factors (BMI1, TWIST1), CSC (CD133, ALDH1A1), and epithelial (EpCAM) markers in primary tumor and whole blood samples obtained from 57 patients with operable non-small-cell lung cancer (NSCLC) as well as in circulating tumor cells (CTCs) of 13 patients with metastatic disease; then possible associations between marker expressions were evaluated. In primary tumors as well as in whole blood, correlations between BMI1 and ALDH1A1 and between BMI1 and CD133 mRNA expressions were identified. No correlations between TWIST1 and CSC markers were observed. BMI1 mRNA expression in tumors positively correlated with BMI1 mRNA expression in blood. The immunohistochemical analysis confirmed coexpression of BMI1 and CSC markers in tumors. Gene expression profiling in CTCs revealed upregulated expression of EMT/CSC markers in CTCs. Our results suggest CSCs are present in both, tumor tissue and blood of NSCLC patients, whereas Bmi1 may play an important role in initiation and maintenance of CSCs and might be involved in the blood-borne dissemination of NSCLC. PMID- 26770213 TI - Exosomes and Their Therapeutic Potentials of Stem Cells. AB - Exosomes, a group of vesicles originating from the multivesicular bodies (MVBs), are released into the extracellular space when MVBs fuse with the plasma membrane. Numerous studies indicate that exosomes play important roles in cell-to cell communication, and exosomes from specific cell types and conditions display multiple functions such as exerting positive effects on regeneration in many tissues. It is widely accepted that the therapeutic potential of stem cells may be mediated largely by the paracrine factors, so harnessing the paracrine effects of stem and progenitor cells without affecting these living, replicating, and potentially pluripotent cell populations is an advantage in terms of safety and complexity. Ascending evidence indicated that exosomes might be the main components of paracrine factors; thus, understanding the role of exosomes in each subtype of stem cells is far-reaching. In this review, we discuss the functions of exosomes from different types of stem cells and emphasize the therapeutic potentials of exosomes, providing an alternative way of developing strategies to cure diseases. PMID- 26770216 TI - Parasitic Zoonoses in Humans and Their Dogs from a Rural Community of Tropical Mexico. AB - A cross-sectional study was made on 89 inhabitants and their dogs from a rural community of Yucatan, Mexico, to determine the serological prevalence of some zoonotic parasitic agents. Samples were taken to monitor the presence and intensity of infection with gastrointestinal parasites in dogs. In humans, the serological prevalence of T. canis, T. gondii, and T. spiralis was 29.2%, 91.0%, and 6.7%, respectively. No associations were found between positive cases and studied variables. From the total of blood samples taken from dogs, 87 (97.6%) were seropositive to T. gondii; only 52 viable fecal samples were collected from dogs of which 46.2% had the presence of gastrointestinal parasites with low to moderate intensity; from those, 12% had the presence of T. canis. This study demonstrates the presence of the studied zoonotic agents in the area particularly T. gondii which suggest a common source of infection in dogs and humans and a high number of oocyts present in the environment. Preventive measures must be designed towards good prophylactic practices in domestic and backyard animals (T. canis and T. spiralis). Contaminated sources with T. gondii (food and water) should be further investigated in order to design effective control measures. PMID- 26770217 TI - Adipokines and Cysteinyl Leukotrienes in the Pathogenesis of Asthma. AB - Background. The prevalence of obesity has increased dramatically over the last decades, and its association with asthma is being increasingly recognized. Aims. Our hypothesis is that increased leptin and decreased adiponectin levels in obese subjects play a direct role in regulating inflammation in asthmatics. We wanted to examine the hypothesis that cysteinyl leukotrienes (cys-LT), inflammatory mediators that are regulated by adipokines, are involved in the pathogenesis of asthma. Methods. We studied a population of asthmatics and nonasthmatics, who in turn were divided into obese and nonobese categories. We examined leptin and its ratio to adiponectin, in asthmatics and nonasthmatics, with and without obesity. In addition, we measured cys-LT levels in exhaled breath condensate (EBC) and in peripheral blood monocytes (PBM) in these groups. Results. Leptin levels were increased in obese asthmatics compared to obese nonasthmatics. The leptin/adiponectin (L/A) ratio was higher in obese asthmatics compared to obese nonasthmatics. EBC cys-LT levels were elevated in asthmatics compared to nonasthmatics. Discussion. Proinflammatory adipokines, released from adipose tissue, may promote an asthma phenotype through enhanced cys-LT production that may result in more prevalent and difficult to control airway disease. PMID- 26770218 TI - Assessing factors related to waist circumference and obesity: application of a latent variable model. AB - BACKGROUND: Because the use of BMI (Body Mass Index) alone as a measure of adiposity has been criticized, in the present study our aim was to fit a latent variable model to simultaneously examine the factors that affect waist circumference (continuous outcome) and obesity (binary outcome) among Iranian adults. METHODS: Data included 18,990 Iranian individuals aged 20-65 years that are derived from the third National Survey of Noncommunicable Diseases Risk Factors in Iran. Using latent variable model, we estimated the relation of two correlated responses (waist circumference and obesity) with independent variables including age, gender, PR (Place of Residence), PA (physical activity), smoking status, SBP (Systolic Blood Pressure), DBP (Diastolic Blood Pressure), CHOL (cholesterol), FBG (Fasting Blood Glucose), diabetes, and FHD (family history of diabetes). RESULTS: All variables were related to both obesity and waist circumference (WC). Older age, female sex, being an urban resident, physical inactivity, nonsmoking, hypertension, hypercholesterolemia, hyperglycemia, diabetes, and having family history of diabetes were significant risk factors that increased WC and obesity. CONCLUSIONS: Findings from this study of Iranian adult settings offer more insights into factors associated with high WC and high prevalence of obesity in this population. PMID- 26770219 TI - Pediatric thyroid surgery and management of thyroid nodules - an institutional experience over a 10-year period. AB - BACKGROUND: We reviewed our institutional experience in the diagnosis and management of pediatric thyroid nodules and well-differentiated thyroid carcinoma (WDTC), highlighting the unique challenges in this population. METHODS: IRB approved retrospective chart review was conducted on patients who underwent fine needle aspiration (FNA) or thyroid surgery from 1/1/2001 to 12/31/2010 at Rady Children's Hospital San Diego, a tertiary referral center in Southern California. Patients thus identified who completed their initial treatment at our institution were included. RESULTS: Total of 79 subjects qualified; 20 had FNA only, and 59 underwent thyroid surgery. Of the latter, 29 had benign histology and 30 had WDTC. Average age was 14.5 years with a female: male ratio of 4:1 for WDTC versus 1.6:1 for benign nodules. When compared to final pathology, malignancy rate was high in indeterminate FNA cytology at 60 %. Neck metastasis was noted in 40 % and pulmonary spread in 10 % of patients. There was a 2.75 fold increase in malignant cases (n = 22) treated during 2006-2010 compared to 2001-2005 (n = 8) with more advanced disease at initial presentation. Ninety percent of WDTC patients received adjuvant I-131 treatment with an initial average dose of 132.4 mCi. Despite aggressive initial presentation, 26/30 patients had no evidence of disease at last follow-up, with an average length of 40.3 months. CONCLUSIONS: In recent years, we are managing significantly more WDTC cases at our institution with advanced disease at the onset. Malignancy rate on indeterminate cytology is higher than reported in adults with an overall high rate of malignancy in thyroid nodules removed in this cohort. Disease control and short-term outcome is still excellent. The recently published pediatric guidelines for WDTC will further standardize management. PMID- 26770068 TI - Measurements of the Higgs boson production and decay rates and coupling strengths using pp collision data at [Formula: see text] and 8 TeV in the ATLAS experiment. AB - Combined analyses of the Higgs boson production and decay rates as well as its coupling strengths to vector bosons and fermions are presented. The combinations include the results of the analyses of the [Formula: see text] and [Formula: see text] decay modes, and the constraints on the associated production with a pair of top quarks and on the off-shell coupling strengths of the Higgs boson. The results are based on the LHC proton-proton collision datasets, with integrated luminosities of up to 4.7 [Formula: see text] at [Formula: see text] TeV and 20.3 [Formula: see text] at [Formula: see text] TeV, recorded by the ATLAS detector in 2011 and 2012. Combining all production modes and decay channels, the measured signal yield, normalised to the Standard Model expectation, is [Formula: see text]. The observed Higgs boson production and decay rates are interpreted in a leading-order coupling framework, exploring a wide range of benchmark coupling models both with and without assumptions on the Higgs boson width and on the Standard Model particle content in loop processes. The data are found to be compatible with the Standard Model expectations for a Higgs boson at a mass of 125.36 GeV for all models considered. PMID- 26770220 TI - Postinfectious bronchiolitis obliterans in children: lessons from bronchiolitis obliterans after lung transplantation and hematopoietic stem cell transplantation. AB - Postinfectious bronchiolitis obliterans (PIBO) is an irreversible obstructive lung disease characterized by subepithelial inflammation and fibrotic narrowing of the bronchioles after lower respiratory tract infection during childhood, especially early childhood. Although diagnosis of PIBO should be confirmed by histopathology, it is generally based on history and clinical findings. Irreversible airway obstruction is demonstrated by decreased forced expiratory volume in 1 second with an absent bronchodilator response, and by mosaic perfusion, air trapping, and/or bronchiectasis on computed tomography images. However, lung function tests using spirometry are not feasible in young children, and most cases of PIBO develop during early childhood. Further studies focused on obtaining serial measurements of lung function in infants and toddlers with a risk of bronchiolitis obliterans (BO) after lower respiratory tract infection are therefore needed. Although an optimal treatment for PIBO has not been established, corticosteroids have been used to target the inflammatory component. Other treatment modalities for BO after lung transplantation or hematopoietic stem cell transplantation have been studied in clinical trials, and the results can be extrapolated for the treatment of PIBO. Lung transplantation remains the final option for children with PIBO who have progressed to end-stage lung disease. PMID- 26770221 TI - Parental satisfaction with pediatric emergency care: a nationwide, cross sectional survey in Korea. AB - PURPOSE: This study attempted to examine parental satisfaction with pediatric emergency care (PEC) in Korea and investigate the features influencing overall satisfaction. METHODS: A nationwide, cross-sectional survey was conducted among parents who had taken their children to an Emergency Department (ED) in the three years prior to the study. A 21-item, structured questionnaire was administered to the parents through a web-based system. Participants' satisfaction levels and the strength of the association between PEC components and overall satisfaction were rated using a 7-point Likert scale. RESULTS: In total, 1,000 parents participated in the survey, of which 402 (40.2%) stated that they were generally satisfied with the delivered PEC. Female participants, mothers, and parents with low-acuity patients were more likely to be dissatisfied with the delivered PEC. Although the ED environment was the lowest level of satisfaction, it did not significantly influence the respondents' overall levels of satisfaction. The most influential factors in terms of overall satisfaction were "nurses' professionalism" and "doctors' attitude and proper explanation". CONCLUSION: Parents' overall level of satisfaction with PEC is relatively low and is closely related to factors associated with ED personnel. PMID- 26770222 TI - High degree of supervision improves adherence to inhaled corticosteroids in children with asthma. AB - PURPOSE: Adherence to treatment with inhaled corticosteroids (ICS) is a critical determinant of asthma control. The objective of this study was to assess factors that determine adherence to ICS therapy in children with asthma. METHODS: Fifty eight children with asthma, aged 5 to 16 years, used ICS with or without a spacer for 3 months. Adherence rates as measured from questionnaires and canisters, asthma symptom scores, and inhalation technique scores were assessed every 30 days. The degree of supervision by caregivers was assessed at day 30. RESULTS: Adherence rates measured using canisters were lower at day 60 than at day 30 (P=0.044) and did not change thereafter (74.4%+/-17.4% at day 30, 66.5%+/-18.4% at day 60, and 67.4%+/-22.2% at day 90). Adherence rates at days 60 and 90 and during the total study period were significantly different when measured by using questionnaires versus canisters (P<0.001, P=0.022, and P=0.001, respectively). In the comparison of adherence rates repeatedly measured at days 30, 60, and 90 and adherence rates during the total study period among the 3 groups, adherence rates in the high-degree supervision group were significantly higher than those in the low-degree supervision group (82.0+/-16.0 vs. 66.1+/-14.5, 75.4+/-14.4 vs. 56.2+/ 18.4, 75.0+/-18.3 vs. 55.0+/-19.7 [P=0.027]; 77.9+/-12.2 vs. 59.1+/-11.4 [P=0.021]) after adjustment for sex and age. CONCLUSION: The level of caregiver supervision is an important factor affecting adherence to ICS therapy in children with asthma. Therefore, a high degree of supervision may be required to increase adherence to ICS therapy in children with asthma. PMID- 26770069 TI - Measurements of fiducial cross-sections for [Formula: see text] production with one or two additional b-jets in pp collisions at [Formula: see text]=8 TeV using the ATLAS detector. AB - Fiducial cross-sections for [Formula: see text] production with one or two additional b-jets are reported, using an integrated luminosity of 20.3 fb[Formula: see text] of proton-proton collisions at a centre-of-mass energy of 8 TeV at the Large Hadron Collider, collected with the ATLAS detector. The cross section times branching ratio for [Formula: see text] events with at least one additional b-jet is measured to be 950 [Formula: see text] 70 (stat.) [Formula: see text] (syst.) fb in the lepton-plus-jets channel and 50 [Formula: see text] 10 (stat.) [Formula: see text] (syst.) fb in the [Formula: see text] channel. The cross-section times branching ratio for events with at least two additional b jets is measured to be 19.3 [Formula: see text] 3.5 (stat.) [Formula: see text] 5.7 (syst.) fb in the dilepton channel ([Formula: see text], [Formula: see text], and ee) using a method based on tight selection criteria, and 13.5 [Formula: see text] 3.3 (stat.) [Formula: see text] 3.6 (syst.) fb using a looser selection that allows the background normalisation to be extracted from data. The latter method also measures a value of 1.30 [Formula: see text] 0.33 (stat.) [Formula: see text] 0.28 (syst.)% for the ratio of [Formula: see text] production with two additional b-jets to [Formula: see text] production with any two additional jets. All measurements are in good agreement with recent theory predictions. PMID- 26770223 TI - Clinical characteristics of lung abscess in children: 15-year experience at two university hospitals. AB - PURPOSE: Information on the clinical features of lung abscess, which is uncommon in children, at hospitalizationis helpful to anticipate the disease course and management. There is no report concerning lung abscess in Korean children. We aimed to identify the clinical characteristics of pediatric lung abscess and compare the difference between primary and secondary abscess groups. METHODS: The medical records of 11 lung abscess patients (7 males and 4 females) from March 1998 to August 2011 at two university hospitals were retrospectively reviewed. The clinical characteristics, symptoms, underlying disease, laboratory and radiologic findings, microbiological results, and treatments were examined. RESULTS: Six patients had underlying structural-related problems (e.g., skeletal anomalies). No immunologic or hematologic problem was recorded. The mean ages of the primary and secondary groups were 2.4 and 5.3 years, respectively, but the difference was not statistically significant. The mean length of hospital stay was similar in both groups (22.8 days vs. 21.4 days). Immunologic studies were performed in 3 patients; the results were within the normal range. Most patients had prominent leukocytosis. Seven and 4 patients had right and left lung abscess, respectively. Staphylococcus aureus, Streptococcus pneumoniae, and antimycoplasma antibodies were detected in both groups. Two patients with primary lung abscess were administered antibiotics in the absence of other procedures, while 8 underwent interventional procedures, including 5 with secondary abscess. CONCLUSION: The most common symptoms were fever and cough. All patients in the primary group were younger than 3 years. Structural problems were dominant. Most patients required interventional procedures and antibiotics. PMID- 26770224 TI - A prospective study to assess the efficacy and safety of oral propranolol as first-line treatment for infantile superficial hemangioma. AB - PURPOSE: To determine the efficacy and safety of oral propranolol as a first-line treatment for superficially located infantile hemangioma (IH) and propose an assessment tool to measure treatment response. METHODS: Patients with superficial IH under 1 year of age were prospectively recruited between May 2012 and December 2013 at the Department of Pediatrics of Chungbuk National University Hospital. Propranolol was administered to 12 infants (median age, 3.8 months) while monitoring cardiovascular and adverse metabolic effects. If a patient showed no adverse events, the dosage was gradually increased up to 3 mg/kg/day and maintained for 1 year. We used our own scoring system to assess treatment response using parameters like change in color, and longest diameter, and thickness of the IH. RESULTS: Eleven out of 12 patients completed the protocol with consistent improvement of hemangiomas during therapy. Patients on propranolol showed a more than 50% involution in the first 3 months, with additional steady involution until 1 year. Patients with the highest scores at 1 month maintained their score and showed better responses until treatment termination. The patient with the lowest score at 1 month did not show any further regression and stopped propranolol treatment 4 months after initiation. In two children with recurrences after successful therapeutic regression, propranolol was effective after being reintroduced. Propranolol treatment was not interrupted in any patient due to adverse events. CONCLUSION: Oral propranolol at 3 mg/kg/day showed a consistent, rapid, and therapeutic effect on superficial IHs without significant adverse events. PMID- 26770225 TI - Intercontinental comparison of caustic ingestion in children. AB - PURPOSE: To investigate the caustic ingestion in children among different continents according to demographic characteristics (core purpose), main symptoms, common caustic agents, signs and symptoms, management, treatment and complications. METHODS: This systematic review was performed by searching the databases Science Direct, ProQuest, Google Scholar, and PubMed, electronically and manually. We included studies that were published from 1980 to 2013, at University of Medical Sciences of Tabriz, Iran. A strategic search was performed with keywords including caustic, corrosive, ingestion and children, and was limited to articles in English and Persian. Statistical analysis was performed by SPSS ver. 18. RESULTS: Of 63 selected articles of caustic ingestion with 9,888 samples, the proportion of Africa was 3 articles (4.8%) and 95 samples (1%), America 9 articles (14.3%) and 305 sample (3%), Asia 29 articles (46%) and 2,780 samples (28.1%), Europe 17 articles (27%) and 3,002 samples (30.4%), and Oceania 5 articles (7.9%) and 3,706 samples (37.5%). The average age was in the Africa 3.07+/-2.02 years, America 3.17+/-1.83 years, Asia 3.34+/-1.58 years, Europe 3.58+/-2.09 years and Oceania 3.52+/-2.02 years. Sex distribution was in Africa 76 males (0.91%) and 19 females (0.23%), America 49 males (0.58%) and 41 females (0.49%), Asia 1,575 males (18.76%) and 1,087 females (12.95%), Europe 1,018 males (12.13%) and 823 females (9.8%), and Oceania 1,918 males (22.85%) and 1,788 females (21.3%). Statistical analysis of the data indicated higher consumption in Europe and Oceania in the boys with higher average age of years. CONCLUSION: The comparison of caustic ingestion indicated that the cause substances of caustic ingestion in children are different among continents, therefore prevention strategy and different treatment guidelines among continents will be needed. PMID- 26770227 TI - Alveolar rhabdomyosarcoma with massive disseminated intravascular coagulopathy treated with systemic chemotherapy. AB - It is uncommon for pediatric patients with rhabdomyosarcoma to present with clinical and/or laboratory features of disseminated intravascular coagulation (DIC). We report a case of metastatic alveolar rhabdomyosarcoma with severe bleeding because of DIC in a 13-year-old boy. He experienced persistent oozing at the site of a previous operation, gross hematuria, and massive epistaxis. Two weeks after initiating combination chemotherapy consisting of vincristine, doxorubicin, and cyclophosphamide, the patients' laboratory indications of DIC began to resolve. During this period, the patient received massive blood transfusion of a total of 311 units (26 units of red blood cells, 26 units of fresh frozen plasma, 74 units of platelet concentrates, 17 units of single donor platelets, and 168 units of cryoprecipitate), antithrombin-III and a synthetic protease inhibitor. Despite chemotherapy and radiation therapy, he died 1 year later because of disease progression. In children with metastatic rhabdomyosarcoma and massive DIC, prompt chemotherapy and aggressive supportive care is important to decrease malignancy-triggered procoagulant activities. PMID- 26770226 TI - Giant coronary aneurysm caused by Kawasaki disease: consistency between catheter angiography and electrocardiogram gated dual-source computed tomography angiography. AB - We present the case of a 5-year-old child with coronary complications due to Kawasaki disease; this patient unintentionally underwent both dual-source computed tomography (DSCT) coronary angiography and invasive coronary angiographic examination in 2 months. This case highlights the strong consistency of the results between DSCT coronary angiography and invasive coronary angiography. Compared to conventional invasive coronary angiography, DSCT coronary angiography offered additional advantages such as minimal invasiveness and less radiation exposure. PMID- 26770228 TI - Issues Related to the Updated 2014 Korean Guidelines for Tuberculosis. AB - Tuberculosis (TB) remains a major public health problem in South Korea. The Joint Committee for the Development of Korean Guidelines for Tuberculosis published the Korean Guidelines for Tuberculosis in 2011 to provide evidence-based practical recommendations to health care workers caring for patients with TB in South Korea. After reviewing recent national and international scientific data on TB, the committee updated the Korean guidelines for TB in 2014. This article presents some practical issues related to the 2014 updated guidelines: namely use of the Mycobacterium tuberculosis - polymerase chain reaction assay and the Xpert MTB/RIF assay in the diagnosis of TB, as well as medical treatment for patients with multidrug-resistant TB. PMID- 26770232 TI - Risk Factors for Mechanical Ventilation in Patients with Scrub Typhus Admitted to Intensive Care Unit at a University Hospital. AB - BACKGROUND: The purpose of this study was to evaluate the risk factors for mechanical ventilation in the patients with scrub typhus admitted to intensive care unit (ICU) at a university hospital. METHODS: We retrospectively selected and analyzed clinical data from the medical records of 70 patients (32 men, 38 women) admitted to the ICU with scrub typhus between 2004 and 2014. The patients had a mean+/-standard deviation age of 71.2+/-11.1 years and were evaluated in two groups: those who had been treated with mechanical ventilation (the MV group, n=19) and those who had not (the non-MV group, n=51). Mean ages of the MV group and the non-MV group were 71.2+/-8.3 years and 71.2+/-11.1 years, respectively. RESULTS: Significant differences between the two groups were observed with respect to acute respiratory failure (p=0.008), Acute Physiology and Chronic Health Evaluation (APACHE) II score (p=0.015), Sequential Organ Failure Assessment (SOFA) score (p=0.013), death (p=0.014), and ICU duration (p<0.01). Multivariate analysis indicated that the following factors were significantly associated with mechanical ventilation: acute respiratory failure (p=0.011), SOFA score (p=0.005), APACHE II score (p=0.011), platelet count (p=0.009), and lactate dehydrogenase (LDH) (p=0.011). CONCLUSION: Thus, five factors-acute respiratory failure, SOFA score, APACHE II score, platelet count, and LDH-can be the meaningful indicators for mechanical ventilation for the patients with scrub typhus admitted to ICU. PMID- 26770234 TI - A Case of Pneumonia Caused by Raoultella planticola. AB - Raoultella species are gram-negative, non-motile, aerobic bacilli that are primarily considered as environmental bacteria. Raoultella planticola is reportedly a rare cause of human infections. Also, the definite pathological mechanism of Raoultella planticola is currently unknown. We report a case of pneumonia caused by Raoultella planticola. PMID- 26770231 TI - Outcome of Inhaler Withdrawal in Patients Receiving Triple Therapy for COPD. AB - BACKGROUND: The purpose of this study was to document outcomes following withdrawal of a single inhaler (step-down) in chronic obstructive pulmonary disease (COPD) patients on triple therapy (long-acting muscarinic antagonist and a combination of long-acting beta2-agonists and inhaled corticosteroid), which a common treatment strategy in clinical practice. METHODS: Through a retrospective observational study, COPD patients receiving triple therapy over 2 years (triple group; n=109) were compared with those who had undergone triple therapy for at least 1 year and subsequently, over 9 months, initiated inhaler withdrawal (step down group, n=39). The index time was defined as the time of withdrawal in the stepdown group and as 1 year after the start of triple therapy in the triple group. RESULTS: Lung function at the index time was superior and the previous exacerbation frequency was lower in the stepdown group than in the triple group. Step-down resulted in aggravating disease symptoms, a reduced overall quality of life, decreasing exercise performance, and accelerated forced expiratory volume in 1 second (FEV1) decline (54.7+/-15.7 mL/yr vs. 10.7+/-7.1 mL/yr, p=0.007), but there was no observed increase in the frequency of exacerbations. CONCLUSION: Withdrawal of a single inhaler during triple therapy in COPD patients should be conducted with caution as it may impair the exercise capacity and quality of life while accelerating FEV1 decline. PMID- 26770230 TI - The Korean Cough Guideline: Recommendation and Summary Statement. AB - Cough is one of the most common symptom of many respiratory diseases. The Korean Academy of Tuberculosis and Respiratory Diseases organized cough guideline committee and cough guideline was developed by this committee. The purpose of this guideline is to help clinicians to diagnose correctly and treat efficiently patients with cough. In this article, we have stated recommendation and summary of Korean cough guideline. We also provided algorithm for acute, subacute, and chronic cough. For chronic cough, upper airway cough syndrome (UACS), cough variant asthma (CVA), and gastroesophageal reflux disease (GERD) should be considered. If UACS is suspicious, first generation anti-histamine and nasal decongestant can be used empirically. In CVA, inhaled corticosteroid is recommended in order to improve cough. In GERD, proton pump inhibitor is recommended in order to improve cough. Chronic bronchitis, bronchiectasis, bronchiolitis, lung cancer, aspiration, angiotensin converting enzyme inhibitor, habit, psychogenic cough, interstitial lung disease, environmental and occupational factor, tuberculosis, obstructive sleep apnea, peritoneal dialysis, and idiopathic cough can be also considered as cause of chronic cough. Level of evidence for treatment is mostly low. Thus, in this guideline, many recommendations are based on expert opinion. Further study regarding treatment for cough is mandatory. PMID- 26770233 TI - Severe Endobronchial Inflammation Induced by Aspiration of a Ferrous Sulfate Tablet. AB - Iron supplements such as ferrous sulfate tablets are usually used to treat iron deficiency anemia in some elderly patients with primary neurologic disorders or decreased gag reflexes due to stroke, senile dementia, or parkinsonism. While the aspiration of ferrous sulfate is rarely reported, it is a potentially life threatening condition that can lead to airway necrosis and bronchial stenosis. A detailed history and high suspicion of aspiration are required to avoid delays in diagnosis and treatment. The diagnosis can be confirmed by bronchoscopic examination and a tissue biopsy. Early removal of the aspirated tablet prevents acute complications, such as bronchial necrosis, hemoptysis, and lobar consolidation. Tablet removal is also necessary to prevent late bronchial stenosis. We presented the first case in Korea of a ferrous sulfate tablet aspiration that induced severe endobronchial inflammation. PMID- 26770235 TI - Real-Time Polymerase Chain Reaction Assay: A Response to Recent Letter to the Editor. PMID- 26770229 TI - The Role of Innate and Adaptive Immune Cells in the Immunopathogenesis of Chronic Obstructive Pulmonary Disease. AB - Chronic obstructive pulmonary disease (COPD) is a chronic and progressive inflammatory disease of the airways and lungs that results in limitations of continuous airflow and is caused by exposure to noxious gasses and particles. A major cause of morbidity and mortality in adults, COPD is a complex disease pathologically mediated by many inflammatory pathways. Macrophages, neutrophils, dendritic cells, and CD8+ T-lymphocytes are the key inflammatory cells involved in COPD. Recently, the non-coding small RNA, micro-RNA, have also been intensively investigated and evidence suggest that it plays a role in the pathogenesis of COPD. Here, we discuss the accumulated evidence that has since revealed the role of each inflammatory cell and their involvement in the immunopathogenesis of COPD. Mechanisms of steroid resistance in COPD will also be briefly discussed. PMID- 26770237 TI - The Association between Dairy Intake and Breast Cancer in Western and Asian Populations: A Systematic Review and Meta-Analysis. AB - PURPOSE: To date, studies investigating the association between dairy consumption and breast cancer in women have produced conflicting results. As diet is an important, modifiable factor affecting cancer development, the aim of this study was to examine the association between dairy consumption and breast cancer risk. METHODS: PubMed, Embase, and Cochrane Library databases were searched with a priority for prospective cohort studies. Case-control studies were also considered in case of the absence of a cohort study. RESULTS: We analyzed 22 prospective cohort studies (1,566,940 participants) and five case-control studies (33,372 participants). High and modest dairy consumption (>600 and 400-600 g/day, respectively) significantly reduced the risk of breast cancer compared with low dairy consumption (<400 g/day; risk ratio [RR], 0.90, 95% confidence interval [CI], 0.83-0.98, and RR, 0.94, 95% CI, 0.91-0.98, respectively). A significant linear relationship between dairy consumption and breast cancer risk was found on dose-response analysis. Subgroup analysis found that yogurt (RR, 0.91; 95% CI, 0.83-0.99) and low-fat dairy (RR, 0.85; 95% CI, 0.75-0.96) reduced the risk of breast cancer, while other dairy product types did not. A reduced risk was observed for people in the United States (RR, 0.91; 95% CI, 0.83-0.99) and in those followed for >=10 years (RR, 0.90; 95% CI, 0.81-0.99). Additionally, the highest level of dairy consumption among Asians was associated with a reduced risk of breast cancer (odds ratio, 0.74; 95% CI, 0.62-0.88). CONCLUSION: Dairy consumption was inversely associated with the risk of developing breast cancer and this effect was dependent on the dose, dairy-type, and time. PMID- 26770238 TI - High MicroRNA-370 Expression Correlates with Tumor Progression and Poor Prognosis in Breast Cancer. AB - PURPOSE: Deregulation of microRNA-370 (miR-370) has been reported in various cancers, in which it can act as either an oncogene or a tumor suppressor gene. However, the clinicopathologic significance of miR-370 expression in breast cancer has not been studied. METHODS: The expression of miR-370 was determined with quantitative real-time polymerase chain reaction in 60 formalin-fixed, paraffin-embedded primary breast cancer tissues. Additionally, the protein expression levels of previously known targets of miR-370, such as FOXM1, FOXO1, and FOXO3a, were detected using immunohistochemistry. Finally, we analyzed its correlation with target protein expression, clinicopathologic features, and clinical outcome. RESULTS: High levels of miR-370 expression correlated with lymph node metastasis (p=0.009), advanced stage (p=0.002), and frequent perineural invasion (p=0.042). Moreover, patients with high miR-370 expression had poor disease-free survival compared with the low-expression group. However, no correlation was observed between miR-370 and its target protein expression. CONCLUSION: Our results indicate that upregulation of miR-370 in breast cancer is correlated with breast cancer progression and that it might be a potential biomarker for predicting clinical outcomes. PMID- 26770239 TI - Synergistic Effect of Trabectedin and Olaparib Combination Regimen in Breast Cancer Cell Lines. AB - PURPOSE: Trabectedin induces synthetic lethality in tumor cells carrying defects in homologous recombinant DNA repair. We evaluated the effect of concomitant inhibition of nucleotide-excision repair and poly (ADP-ribose) polymerase (PARP) activity with trabectedin and PARP inhibitors, respectively, and whether the synthetic lethality effect had the potential for a synergistic effect in breast cancer cell lines. Additionally, we investigated if this approach remained effective in BRCA1-positive breast tumor cells. METHODS: We have evaluated the in vitro synergistic effect of combinations of trabectedin and three different PARP inhibitors (veliparib, olaparib, and iniparib) in four breast cancer cell lines, each presenting a different BRCA1 genetic background. Antiproliferative activity, DNA damage, cell cycle perturbations and poly(ADP-ribosyl)ation were assessed by MTT assay, comet assay, flow cytometry and western blot, respectively. RESULTS: The combination of trabectedin and olaparib was synergistic in all the breast cancer cell lines tested. Our data indicated that the synergy persisted regardless of the BRCA1 status of the tumor cells. Combination treatment was associated with a strong accumulation of double-stranded DNA breaks, G2/M arrest, and apoptotic cell death. Synergistic effects were not observed when trabectedin was combined with veliparib or iniparib. CONCLUSION: Collectively, our results indicate that the combination of trabectedin and olaparib induces an artificial synthetic lethality effect that can be used to kill breast cancer cells, independent of BRCA1 status. PMID- 26770236 TI - New Findings on Breast Cancer Stem Cells: A Review. AB - Since the introduction of the "cancer stem cell" theory, significant developments have been made in the understanding of cancer and the heterogenic structure of tumors. In 2003, with the isolation of cancer stem cells from the first solid tumor, breast cancer, and recognition of the tumorigenicity of these cells, this theory suggested that the main reason for therapy failure might be the presence of cancer stem cells. This review article describes breast cancer stem cell origin, the related cellular and molecular characteristics, signaling pathways, and therapy resistance mechanisms. The databases PubMed, SCOPUS, and Embase were explored, and articles published on these topics between 1992 and 2015 were investigated. It appears that this small subpopulation of cells, with the capacity for self-renewal and a high proliferation rate, originate from normal stem cells, are identified by specific markers such as CD44(+)/CD24(-/low), and enhance a tumor's capacity for metastasis, invasion, and therapy resistance. Cancer stem cell characteristics depend on their interactions with their microenvironment as well as on the inducing factors and elements. Although uncertainties about breast cancer stem cells exist, many of researchers believe that cancer stem cells should be considered as possible therapeutic targets. PMID- 26770240 TI - Loss of Tumor Suppressor ARID1A Protein Expression Correlates with Poor Prognosis in Patients with Primary Breast Cancer. AB - PURPOSE: Somatic mutations of the chromatin remodeling AT-rich interactive domain 1A (SWI-like) gene (ARID1A) have been identified in many human cancers, including breast cancer. The purpose of this study was to evaluate the nuclear expression of ARID1A in breast cancers by immunohistochemistry (IHC) and to correlate the findings to clinicopathologic variables including prognostic significance. METHODS: IHC was performed on tissue microarrays of 476 cases of breast cancer. Associations between ARID1A expression and clinicopathologic characteristics and molecular subtype were retrospectively analyzed. RESULTS: Low expression of ARID1A was found in 339 of 476 (71.2%) cases. Low expression of ARID1A significantly correlated with positive lymph node metastasis (p=0.027), advanced pathologic stage (p=0.001), low Ki-67 labeling index (p=0.003), and negative p53 expression (p=0.017). The ARID1A low expression group had significantly shorter disease-free and overall survival than the ARID1A high expression group (p<0.001 and p<0.001, respectively). Multivariate analysis demonstrated that low expression of ARID1A was a significant independent predictive factor for poor disease-free and overall survival in patients with breast cancer (disease-free survival: hazard ratio, 0.38, 95% confidence interval [CI], 0.20-0.73, p=0.004; overall survival: hazard ratio, 0.11, 95% CI, 0.03-0.46, p=0.003). In patients with luminal A type disease, patients with low ARID1A expression had significantly shorter disease-free and overall survival rates than patients with high ARID1A expression (p=0.022 and p=0.018, respectively). CONCLUSION: Low expression of ARID1A is an independent prognostic factor for disease-free and overall survival in breast cancer patients and may be associated with luminal A type disease. Although the biologic function of ARID1A in breast cancer remains unknown, low expression of ARID1A can provide valuable prognostic information. PMID- 26770241 TI - Prognostic Impact and Clinicopathological Correlation of CD133 and ALDH1 Expression in Invasive Breast Cancer. AB - PURPOSE: CD133 and aldehyde dehydrogenase 1 (ALDH1) expression are reliable poor prognosis markers associated with the presence of adverse biomarkers and subtypes of breast cancer. The aim of our study was to investigate and compare the clinical impact of CD133 and ALDH1 expression in invasive breast cancer. METHODS: A total of 291 consecutive patients with invasive breast cancer who underwent breast cancer operations from 2005 to 2010 at a single institution were included in this retrospective review. CD133 and ALDH1 expression were determined by immunohistochemistry. RESULTS: CD133 and ALDH1 expression were positive in 24.7% and 22.0% of the patients, respectively, and were associated with tumor size, cancer stage, estrogen receptor negativity, nonluminal subtype, triple-negative breast cancer, and recurrence. CD133 expression was significantly associated with lymph node metastasis, progesterone receptor negativity, human epidermal growth factor receptor 2 positivity, chemotherapy, and poor disease-free (p=0.002) and overall survival (p=0.014), but ALDH1 expression was not. Cancer stage (p<0.001) was an independent prognostic factor for disease-free survival in multivariate analysis. Cancer stage (p<0.001) and receipt of radiotherapy (p=0.045) were independent prognostic factors for overall survival in multivariate analysis. CONCLUSION: CD133 or the combination of CD133 and ALDH1 expression were more widely associated with the presence of adverse biomarkers and subtypes of breast cancer, compared to ALDH1 expression alone, and these markers may have a potential predictive role and be a helpful tool in the management for patients with invasive breast cancer. PMID- 26770242 TI - Safety Results of Docetaxel-(Taxotere(r))-Based Chemotherapy in Early Breast Cancer Patients of Asia-Pacific Region: Asia-Pacific Breast Initiative II. AB - PURPOSE: The goal of this registry was to collect patient characteristics and safety data from patients from the Asia-Pacific region with early breast cancer receiving adjuvant chemotherapy containing docetaxel (Taxotere(r)). METHODS: This registry was open-label, international, longitudinal, multicenter, and observational in design and included a prospective group of consecutive early breast cancer patients with an intermediate-to-high risk of recurrence being treated with various docetaxel-based (anthracycline and non-anthracycline) adjuvant chemotherapy regimens during 2009-2013 in real-world clinical settings. RESULTS: The analysis included 1,712 patients, 79% of whom received docetaxel based, anthracycline-containing regimens, while 21% received non-anthracycline containing regimens. Patients receiving adjuvant docetaxel-based chemotherapy were followed for 1.5 years. Chemotherapy-related adverse events (AEs) were reported by 76.2% of patients (anthracycline-containing vs. non-anthracycline containing regimens: 76.8% vs. 74.1%). Serious AEs were reported in 12% of patients (12.3% vs. 10%). National Cancer Institute Common Terminology Criteria for Adverse Events grade 3 or higher neutropenia was reported in 20% of patients (21.6% vs. 13.9%), leukopenia in 7.4% of patients (5.4% vs. 14.8%), and vomiting in 1.6% of patients (1.8% vs. 0.6%). Treatment-related death was reported in 27 patients (1.6%), while only 3% of patients had a relapse. Low-density lipoprotein cholesterol/high-density lipoprotein cholesterol (HDL-C) and total cholesterol/HDL-C ratios increased after chemotherapy. A clinically insignificant reduction of 1.9% in left ventricular ejection fraction, from 66.43 to 64.53, was observed 1.5 years after therapy was completed. CONCLUSION: The Asia-Pacific Breast initiative II registry identified a variety of important facts regarding patient population characteristics, disease epidemiology and treatment response for early breast cancer patients of the Asia-Pacific region receiving docetaxel based chemotherapy. Docetaxel-based chemotherapy did not show any significant safety concerns for early breast cancer patients of the Asia-Pacific region, and thus may represent a safe adjuvant chemotherapy regimen for these patients. PMID- 26770243 TI - Concurrent Gonadotropin-Releasing Hormone Agonist Administration with Chemotherapy Improves Neoadjuvant Chemotherapy Responses in Young Premenopausal Breast Cancer Patients. AB - PURPOSE: This study aimed to determine the oncologic efficacy of gonadotropin releasing hormone (GnRH) agonist treatment concurrent with chemotherapy in a neoadjuvant setting. METHODS: A retrospective analysis was performed on 332 cases of invasive breast cancer in patients who were <40 years old at diagnosis and received GnRH agonists concurrent with neoadjuvant chemotherapy (GnRH agonist group) or neoadjuvant chemotherapy alone (neochemotherapy-alone group) from December 2010 to September 2014. Pathologic complete response rates (pCR) and Ki 67 changes were evaluated between the two groups. RESULTS: Median age was 32+/ 3.9 and 36+/-3.0 years in the GnRH agonist group and neochemotherapy-alone group, respectively (p<0.001). After adjustment for tumor size, grade, lymph node metastasis, hormone receptor (HR) status, and chemotherapy regimen, the GnRH agonist group exhibited a higher pCR rate with an odds ratio (OR) of 2.98 (95% confidence interval [CI], 1.37-6.34) and a greater decrease in Ki-67 expression after treatment (p=0.05) than the neochemotherapy-alone group. For HR-negative tumors, the GnRH agonist group showed a higher pCR rate (multivariate OR, 3.50; 95% CI, 1.37-8.95) and a greater decrease in Ki-67 expression (p=0.047). For HR positive breast cancer, the pCR rate, change in Ki-67 index, and clinical response were higher, and preoperative endocrine prognostic index scores were lower, in the GnRH agonist group, but these did not reach statistical significance. CONCLUSION: Concurrent administration of GnRH agonists during neoadjuvant chemotherapy improved pCR rates and suppressed Ki-67 expression, especially in HR-negative tumors. PMID- 26770244 TI - Metastasis-Free Interval Is Closely Related to Tumor Characteristics and Has Prognostic Value in Breast Cancer Patients with Distant Relapse. AB - PURPOSE: We investigated the relationships between metastasis-free interval (MFI) and tumor characteristics, and assessed the prognostic value of MFI for survival after metastasis in patients with metastatic breast cancer. Furthermore, we compared MFI among the subtypes. METHODS: We identified 335 patients with postoperative tumor recurrence at distant site(s). All patients underwent curative resection and had a MFI of at least 6 months. MFI was categorized as short (<2 years), intermediate (>=2 years and <5 years), or long (>=5 years). Overall survival after metastasis (OSM) was estimated. RESULTS: Patients with a shorter MFI were younger, more likely to have initial metastasis to visceral organs, and had a larger tumor with a higher stage and grade as well as a higher rate of nodal involvement at initial diagnosis. Among 136 patients with known disease subtypes, shorter MFI was associated with the triple-negative subtype while longer MFI was associated with the hormone receptor-positive/human epidermal growth factor receptor 2 negative subtype. Mortality after metastasis declined sharply with increasing MFI up to approximately 2 years, and continued gradually declining between 2 and 5 years. An MFI longer than 5 years did not add any survival benefit. MFI was a significant prognostic factor for OSM independent of nodal status, stage, metastatic site, and hormone receptor status of the metastasized cancer. CONCLUSION: MFI is closely related to biological characteristics of both primary tumors and their metastases, and has a prognostic value for survival after metastasis. We therefore suggest investigation into treatments targeting improvement of MFI as a potential novel strategy. PMID- 26770245 TI - Risk of Second Primary Malignancy in Breast Cancer Survivors: A Nested Population Based Case-Control Study. AB - PURPOSE: Evolving therapies have improved the prognoses of patients with breast cancer; and currently, the number of long-term survivors is continuously increasing. However, these patients are at increased risk of developing a second cancer. Thus, late side effects are becoming an important issue. In this study, we aimed to investigate whether patient and tumor characteristics, and treatment type correlate with secondary tumor risk. METHODS: This case-control study included 305 patients with a diagnosed second malignancy after almost 6 months after the diagnosis of primary breast cancer and 1,525 controls (ratio 1:5 of cases to controls) from a population-based cohort of 6,325 women. The control patients were randomly selected from the cohort and matched to the cases according to age at diagnosis, calendar period of diagnosis, disease stage, and time of follow-up. RESULTS: BRCA1 or BRCA2 mutation, human epidermal growth factor receptor 2 (HER2)+ status, chemotherapy, and radiotherapy were related to increased risk of developing a second cancer, whereas hormonotherapy showed a protective effect. Chemotherapy, radiotherapy, and estrogenic receptor level <10% increased the risk of controlateral breast cancer. HER2+ status increased the risk of digestive system and thyroid tumors, while BRCA1 or BRCA2 mutation increased the risk of cancer in the genital system. CONCLUSION: Breast cancer survivors are exposed to an excess of risk of developing a second primary cancer. The development of excess of malignancies may be related either to patient and tumor characteristics, such as BRCA1 or BRCA2 mutation and HER2+ status, or to treatments factors. PMID- 26770246 TI - Independent Prognostic Factors for Overall Survival after Salvage Operation for Ipsilateral Breast Tumor Recurrence Following Breast-Conserving Surgery. AB - PURPOSE: Few studies address independent prognostic factors after ipsilateral breast tumor recurrence (IBTR) following breast-conserving surgery (BCS). Locoregional recurrence is associated with distant metastases and increased mortality rates. Therefore anticipating prognoses after IBTR and evaluating risk factors for overall survival following a second salvage operation are important. We evaluated independent prognostic factors affecting overall survival after a second operation for IBTR. METHODS: We retrospectively identified 11,073 patients who underwent breast cancer surgery between November 1995 and December 2011. Locoregional recurrence occurred in 787 patients. Among them, IBTR developed in 165 patients selected for analysis. Excluding eight patients who refused further treatment, we analyzed 157 patients who underwent a second operation (partial mastectomy, 28 [17.8%]; total mastectomy, 129 [82.2%]) for IBTR. Excluding 26 patients with incomplete data, we evaluated the clinicopathol-ogical features influencing overall survival at the first and the second operation in the 131 patients who underwent a second operation. RESULTS: The median age of patients at the first operation was 43.6 years (range, 27-69 years). The median duration from the first to the second operation was 45.0 months (range, 2.5-164.6 months). The 5-year overall survival rate after IBTR was 87.1%. In the multivariable analyses, duration from the first to the second operation, histopathology, lymph node status, and adjuvant chemotherapy, radiotherapy, and endocrine therapy at the first operation were independent prognostic factors for overall survival. Positive estrogen receptor status and endocrine therapy at the second operation were also associated with increased overall survival following salvage operations for IBTR. CONCLUSION: The time interval to IBTR following BCS is related to overall survival after salvage operation for IBTR and it is important to undergo optimal adjuvant treatments according to risk factors after the first operation because those risk factors affect overall survival for IBTR following BCS. PMID- 26770247 TI - Histologic Grade and Decrease in Tumor Dimensions Affect Axillary Lymph Node Status after Neoadjuvant Chemotherapy in Breast Cancer Patients. AB - PURPOSE: The purposes our study was to find out any histologic factors associated with negative conversion of axillary lymph node (ALN) after neoadjuvant chemotherapy (NAC). We also evaluated the association between the decrease in size of primary breast tumor and negative conversion of ALN. METHODS: From January 2012 to November 2014, we included 133 breast cancer patients who underwent NAC and who had ALN metastases which were confirmed on fine-needle aspiration or core needle biopsy at initial diagnosis. All 133 patients underwent initial magnetic resonance imaging (MRI) at the time of diagnosis and preoperative MRI after completion of NAC. We measured the longest dimension of primary breast cancer on MRI. RESULTS: Of 133 patients, 39 patients (29%) showed negative conversion of ALN and of these 39 patients, 25 patients (64%) showed pathologic complete remission of primary breast. On univariate analysis, mean percent decrease in longest dimension, estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2 status and histologic grade were significantly associated with the ALN status after NAC (p<0.001, p=0.001, p< 0.001, p=0.001, p=0.002, respectively). On multivariate logistic regression analysis, percent decrease in longest dimension (odds ratio, 1.026; 95% confidence interval [CI], 1.009-1.044) and histologic grade (odds ratio, 3.964; 95% CI, 1.151-13.657) were identified as being independently associated with the ALN status after NAC. The area under the receiver operating characteristic curve was 0.835 with the best cutoff value of 80% decrease in longest dimension. Combination of high histologic grade and more than 80% decrease in longest dimension showed 64% sensitivity and 92% specificity. CONCLUSION: High histologic grade and more than 80% decrease in primary tumor dimension were associated with negative conversion of ALN after NAC. PMID- 26770248 TI - Malignant Adenomyoepithelioma of the Breast and Responsiveness to Eribulin. AB - Adenomyoepithelioma (AME) of the breast is an uncommon tumor characterized by its dual differentiation into luminal cells and myoepithelial cells. In most cases these tumors have a benign clinical course, but distant metastases have been reported. We present the case of a 51-year-old woman diagnosed with malignant AME. The patient underwent a right modified radical mastectomy, and pathological examination confirmed the diagnosis of malignant AME. Ten months after the operation, multiple hepatic, pleural, and abdominal wall metastases were detected. A number of palliative chemotherapeutic agents were tried, including anthracycline and taxanes. However, the disease continued to progress, and superior vena cava syndrome developed as a result of direct tumor invasion. The patient received salvage eribulin monotherapy. After two cycles of this treatment, her clinical symptoms were ameliorated, and a computed tomography scan showed a partial response. Eribulin chemotherapy was thus effective in treating malignant AME in this case. PMID- 26770249 TI - Primary Neuroendocrine Carcinoma of the Breast with Clinical Features of Inflammatory Breast Carcinoma: A Case Report and Literature Review. AB - Primary neuroendocrine carcinoma of the breast (NECB) is a very rare type of invasive breast carcinoma. Most NECBs appear on breast imaging as solid masses of varied shapes and margins, and have worse clinical outcomes than does invasive ductal carcinoma, not otherwise specified. However, there have been no reports to date regarding NECB with features of inflammatory breast carcinoma. Here, we describe the clinical, radiol-ogic, and pathologic findings of the first reported case of primary NECB presenting as inflammatory breast carcinoma. The patient complained of diffuse right breast enlargement and erythema. Mammography identified severe breast edema and axillary lymphadenopathy. Ultrasound detected an irregular, angular, hypoechoic mass with dermal lymphatic dilatation. On magnetic resonance imaging, the mass had rim enhancement and the entire right breast showed heterogeneous enhancement with malignant kinetic features. Pathology identified the mass as a primary NECB with positive for synaptophysin, CD56, estrogen and progesterone receptors. PMID- 26770250 TI - Comment to "Vitamin D Receptor Poly(A) Microsatellite Polymorphism and 25 Hydroxyvitamin D Serum Levels: Association with Susceptibility to Breast Cancer". PMID- 26770251 TI - The Use of Complementary and Alternative Medicine by Korean Breast Cancer Women: Is It Associated with Severity of Symptoms? AB - Background. Use of complementary and alternative medicine (CAM) among patients with breast cancer could be associated with severity of the cancer symptoms experienced, but there is little evidence to prove this. This study tried to investigate any difference in the severity of breast cancer symptoms between CAM users and nonusers. Methods. The study followed cross-sectional design using structured survey questionnaire. Survey participants were recruited from four different healthcare settings in Seoul, South Korea. The survey instrument comprised 39 items including questions on demographics, use of CAM, and six main symptoms associated with breast cancer and cancer treatment. Results. Out of 288 participants, 67% stated using one or more modalities of CAM. Age, education, and time duration since diagnosis of cancer were significantly associated with use of CAM. About 90% of the CAM users experienced side effects of cancer treatment. CAM users reported more severe anxiety and skin/hair changes than nonusers. Conclusions. CAM was used by those breast cancer patients who experience more severe symptoms to alleviate the conditions associated with breast cancer and cancer treatment. Our findings revealed motivation behind the CAM use, which has profound implications for clinicians to recognize patient-perceived needs. PMID- 26770252 TI - Strong Manual Acupuncture Stimulation of "Huantiao" (GB 30) Reduces Pain-Induced Anxiety and p-ERK in the Anterior Cingulate Cortex in a Rat Model of Neuropathic Pain. AB - Persistent neuropathic pain is associated with anxiety. The phosphorylation of extracellular signal-regulated kinase (p-ERK) in the anterior cingulate cortex (ACC) plays an important role in pain-induced anxiety. Acupuncture is widely used for pain and anxiety. However, little is known about which acupuncture technique is optimal on pain-induced anxiety and the relationship between acupuncture effect and p-ERK. The rat model was induced by L5 spinal nerve ligation (SNL). Male adult SD rats were randomly divided into control, SNL, strong manual acupuncture (sMA), mild manual acupuncture (mMA), and electroacupuncture (EA) group. Bilateral "Huantiao" (GB 30) were stimulated by sMA, mMA, and EA, respectively. The pain withdrawal thresholds (PWTs) and anxiety behavior were measured, and p-ERK protein expression and immunoreactivity cells in ACC were detected. PWTs increased significantly in both sMA and EA groups. Meanwhile, anxiety-like behavior was improved significantly in the sMA and mMA groups. Furthermore, the overexpression of p-ERK induced by SNL was downregulated by strong and mild manual acupuncture. Therefore, strong manual acupuncture on bilateral "Huantiao" (GB 30) could be a proper therapy relieving both pain and pain-induced anxiety. The effect of different acupuncture techniques on pain induced anxiety may arise from the regulation of p-ERK in ACC. PMID- 26770253 TI - Identification of Proteins Implicated in the Increased Heart Rate in ShenSongYangXin-Treated Bradycardia Rabbits by iTRAQ-Based Quantitative Proteomics. AB - The present study tries to identify proteins implicated in bradycardia rabbits in hearts after ShenSongYangXin (SSYX, a traditional Chinese medicine) treatment. Eighteen adult rabbits were randomly assigned to three groups: sham, model, and SSYX treatment groups. Heart rate was recorded in rabbits and proteins were isolated from ventricular muscle. We used isobaric tags for elative and absolute quantitation (iTRAQ) coupled with two-dimensional liquid chromatography-tandem mass spectrometry to identify altered proteins after SSYX treatment. The heart rate decreased after six weeks due to the injury of the sinoatrial node in the model group. This effect was partially reversed by 4-week SSYX treatment. A total of a2988 proteins were quantified by performing the iTRAQ-based experiments. Of these, 86 proteins were differentially expressed according to our criteria (42 upregulated and 44 downregulated). The identification of key proteins implicated in the treatment of bradycardia could serve as a foundation to better understand and further explore the molecular mechanism of SSYX treatment. PMID- 26770254 TI - Fuyuan Decoction Enhances SOX9 and COL2A1 Expression and Smad2/3 Phosphorylation in IL-1beta-Activated Chondrocytes. AB - Fuyuan Decoction (FYD), a herbal formula in China, has been widely used for osteoarthritis (OA) treatment. Herein, we determined the effects of FYD on the expression of transcription factor SOX9 and its target gene collagen type II, alpha 1 (COL2A1) as well as the activation of Smad2/3 in interleukin- (IL-) 1beta stimulated SW1353 chondrosarcoma cells. Serum-derived FYD (FYD-CS) was prepared to treat SW1353 cells with or without SB431542, a TGF-beta1 receptor inhibitor. Cell cycle progression was tested by flow cytometry. The expression of SOX9 and COL2A1 and the activation of Smad2/3 (p-Smad2/3) were analyzed by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and/or western blot. The results showed that, after treatment, FYD-CS, while inducing S-phase cell cycle arrest, enhanced cell proliferation and protected the cells against IL 1beta- and/or SB431542-induced cell growth inhibition. Furthermore, FYD-CS reversed the decreased expression of COL2A1 and SOX9 induced by IL-1beta and SB431542 and blocked the decreased phosphorylation of Smad2/3 induced by IL-1beta alone or in combination with SB431542. Our results suggest that FYD promotes COL2A1 and SOX9 expression as well as Smad2/3 activation in IL-1beta-induced chondrocytes, thus benefiting cell survival. PMID- 26770255 TI - In Vitro Antimicrobial Activity and Effect on Biofilm Production of a White Grape Juice (Vitis vinifera) Extract. AB - Background. The aim of the present study was to evaluate the antimicrobial effect of a white grape juice extract (WGJe) against a range of Gram-positive and Gram negative bacteria, yeasts, and the fungus Aspergillus niger. WGJe was also tested on the production of bacterial biofilms in vitro. Results. WGJe inhibited in vitro most Gram-positive bacteria tested, Staphylococcus aureus ATCC 6538P being the most sensitive strain (MIC values of 3.9 MUg/mL). The effect was bactericidal at the concentration of 500 MUg/mL. Amongst the Gram-negative bacteria, Escherichia coli was the only susceptible strain (MIC and MBC of 2000 MUg/mL). No effect on the growth of Candida sp. and the fungus Aspergillus niger was detected (MIC values > 2000 MUg/mL). WGJe inhibited the biofilms formation of E. coli and Pseudomonas aeruginosa with a dose-dependent effect. Conclusions. WGJe exerted both bacteriostatic and bactericidal activity in vitro. The presented results could be used to develop novel strategies for the treatment of skin infections and against potential respiratory pathogens. PMID- 26770256 TI - Identification of a Potential Target of Capsaicin by Computational Target Fishing. AB - Capsaicin, the component responsible for the pungency of chili peppers, shows beneficial effects in many diseases, although the underlying mechanisms remain unclear. In the present study, the potential targets of capsaicin were predicted using PharmMapper and confirmed via chemical-protein interactome (CPI) and molecular docking. Carbonic anhydrase 2 was identified as the main disease related target, with the pharmacophore model matching well with the molecular features of capsaicin. The relation was confirmed by CPI and molecular docking and supported by previous research showing that capsaicin is a potent inhibitor of carbonic anhydrase isoenzymes. The present study provides a basis for understanding the mechanisms of action of capsaicin or those of other natural compounds. PMID- 26770257 TI - Feeding cessation alters host morphology and bacterial communities in the ascidian Pseudodistoma crucigaster. AB - BACKGROUND: Ascidians can associate with abundant and diverse consortia of microbial symbionts, yet these communities remain unexamined for the majority of host ascidians and little is known about host-symbiont interactions. METHODS: We coupled electron microscopy and 16S rRNA gene tag pyrosequencing to investigate the bacterial communities associated with the colonial ascidian Pseudodistoma crucigaster, a species endemic to the Mediterranean Sea that has a life cycle with two phases: actively-filtering (active) and non-filtering (resting) forms. RESULTS: Resting colonies exhibited a reduced branchial sac (feeding apparatus) and a thickened cuticle. Electron microscope images also suggested higher abundance of colonizing microorganisms on surfaces of resting colonies. Accordingly, bacterial sequences associated with environmental sources (sediment and biofilms, >99 % similarity) were detected exclusively in resting colonies. Bacterial communities of P. crucigaster colonies (active and resting) were dominated by 3 core taxa affiliated (>94 % similarity) with previously described symbiotic Alphaproteobacteria in marine invertebrates. Shifts in rare bacteria were detected when ascidians entered the resting phase, including the appearance of strictly anaerobic lineages and nitrifying bacterial guilds. CONCLUSIONS: These findings suggest that physical (thickened cuticle) and metabolic (feeding cessation) changes in host ascidians have cascading effects on associated bacteria, where modified oxygen concentrations and chemical substrates for microbial metabolism may create anaerobic microhabitats and promote colonization by environmental microorganisms. PMID- 26770258 TI - Serum levels of brain-derived neurotrophic factor (BDNF), proBDNF and plasma 3 methoxy-4-hydroxyphenylglycol levels in chronic schizophrenia. AB - BACKGROUND: We investigated the serum levels of brain-derived neurotrophic factor (BDNF), proBDNF and plasma 3-methoxy-4-hydroxyphenylglycol (MHPG) levels in patients with chronic schizophrenia. METHODS: Sixty-eight patients who met the DSM-IV-TR criteria and had a chronic schizophrenia (CS) duration of >= 5 years were enrolled. Their serum brain-derived BDNF and proBDNF levels were measured by enzyme-linked immunosorbent assays, and their plasma MHPG levels were analyzed by high-performance liquid chromatography with electrochemical detection. RESULTS: The plasma MHPG levels were significantly lower in the CS group (3.9 +/- 1.8 ng/ml) compared to those in the group of 32 age- and sex-matched healthy controls (5.1 +/- 2.4 ng/ml). The serum BDNF levels were significantly lower in the CS group (8.9 +/- 4.8 ng/ml) compared to the control group (12.2.1 +/- 6.8 ng/ml). No correlation was observed between plasma MHPG and BDNF in the CS group. CONCLUSION: These results suggest that hypo-activity of noradrenergic neurons and decreased BDNF secretion exist in chronic schizophrenic patients. PMID- 26770260 TI - Peptide-mediated microalgae harvesting method for efficient biofuel production. AB - BACKGROUND: Production of biofuels from microalgae has been recognized to be a promising route for a sustainable energy supply. However, the microalgae harvesting process is a bottleneck for industrialization because it is energy intensive. Thus, by displaying interactive protein factors on the cell wall, oleaginous microalgae can acquire the auto- and controllable-flocculation function, yielding smarter and energy-efficient harvesting. RESULTS: Towards this goal, we established a cell-surface display system using the oleaginous diatom Fistulifera solaris JPCC DA0580. Putative cell wall proteins, termed frustulins, were identified from the genome information using a homology search. A selected frustulin was subsequently fused with green fluorescent protein (GFP) and a diatom cell-surface display was successfully demonstrated. The antibody-binding assay further confirmed that the displayed GFP could interact with the antibody at the outermost surface of the cells. Moreover, a cell harvesting experiment was carried out using silica-affinity peptide-displaying diatom cells and silica particles where engineered cells attached to the silica particles resulting in immediate sedimentation. CONCLUSION: This is the first report to demonstrate the engineered peptide-mediated harvesting of oleaginous microalgae using a cell surface display system. Flocculation efficiency based on the silica-affinity peptide-mediated cell harvesting method demonstrated a comparable performance to other flocculation strategies which use either harsh pH conditions or expensive chemical/biological flocculation agents. We propose that our peptide-mediated cell harvest method will be useful for the efficient biofuel production in the future. PMID- 26770261 TI - Iteratively refining breast cancer intrinsic subtypes in the METABRIC dataset. AB - BACKGROUND: Multi-gene lists and single sample predictor models have been currently used to reduce the multidimensional complexity of breast cancers, and to identify intrinsic subtypes. The perceived inability of some models to deal with the challenges of processing high-dimensional data, however, limits the accurate characterisation of these subtypes. Towards the development of robust strategies, we designed an iterative approach to consistently discriminate intrinsic subtypes and improve class prediction in the METABRIC dataset. FINDINGS: In this study, we employed the CM1 score to identify the most discriminative probes for each group, and an ensemble learning technique to assess the ability of these probes on assigning subtype labels using 24 different classifiers. Our analysis is comprised of an iterative computation of these methods and statistical measures performed on a set of over 2000 samples. The refined labels assigned using this iterative approach revealed to be more consistent and in better agreement with clinicopathological markers and patients' overall survival than those originally provided by the PAM50 method. CONCLUSIONS: The assignment of intrinsic subtypes has a significant impact in translational research for both understanding and managing breast cancer. The refined labelling, therefore, provides more accurate and reliable information by improving the source of fundamental science prior to clinical applications in medicine. PMID- 26770262 TI - Practice patterns in NAFLD and NASH: real life differs from published guidelines. AB - BACKGROUND: Management guidelines from the American Association for the Study of Liver Diseases/American College of Gastroenterology/American Gastroenterology Association published in 2012 for nonalcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) recommend weight loss, vitamin E and pioglitazone as effective therapies for the treatment of biopsy-confirmed NASH. However, little is known about how physicians in the US diagnose NASH or whether published guidelines are being followed. METHODS: We assessed current diagnostic and treatment patterns of the management of NAFLD and NASH among academic gastroenterologists and hepatologists in the US using a standardized survey developed to collect information regarding respondents' practice environments, diagnostic techniques, and medication usage in patients with NAFLD/NASH. RESULTS: We invited 482 gastroenterologists and hepatologists, predominantly from academic centers, of whom 163 completed the survey. Only 24% of providers routinely perform liver biopsy, predominantly among patients with elevated serum aminotransferases. Vitamin E is prescribed regularly by 70% while only 14% routinely prescribe pioglitazone. Despite recommendations to the contrary, ~25% prescribe pioglitazone or vitamin E without biopsy confirmation of NASH. Metformin is used as frequently as pioglitazone despite its proven lack of efficacy in NASH. Overall, 40-73% adhere to published guidelines, depending on the specific question. There was no significant difference seen in adherence to guidelines between gastroenterologists and hepatologists. CONCLUSION: This survey suggests that clinical practice patterns among gastroenterologists and hepatologists for the management of NASH frequently diverge from published practice guidelines. Although liver biopsy remains the gold standard to diagnose NASH, less than 25% of respondents routinely require it to make the diagnosis of NASH. We conclude that NASH is underdiagnosed in gastroenterology and hepatology practices, highlighting the need to refine noninvasive diagnostic tools. PMID- 26770263 TI - Degree of concordance between single balloon enteroscopy and capsule endoscopy for obscure gastrointestinal bleeding after an initial positive capsule endoscopy finding. AB - INTRODUCTION: In patients with obscure gastrointestinal bleeding (OBGIB) capsule endoscopy (CE) is the initial diagnostic procedure of choice. Often patients undergo single balloon enteroscopy (SBE) with both diagnostic and therapeutic intention after CE. Although SBE offers a therapeutic benefit, long procedure times, complexity, and invasiveness are drawbacks. We aimed to evaluate the diagnostic correlation between these two modalities after an initial positive CE finding. METHODS: We performed a retrospective review of 418 patients who underwent CE at our institution from January 2010 to May 2014. A total of 95 patients were analyzed after selecting patients that underwent SBE originally after a positive CE result for the evaluation for OGIB. Agreement beyond chance was evaluated using the kappa coefficient. A p value less than 5% was considered statistically significant. RESULTS: The mean age of our population was 65.8 +/- 12.2 and it was female predominant: 57/95 (60%). The most frequent positive findings were vascular lesions found on SBE in 31.6% and on CE in 41.1%. There was a strong agreement when identifying active bleeding and clots [kappa=0.97; 95% confidence interval (CI) 0.92-1.03; p ? 0.0001], and a moderate agreement when diagnosing vascular lesions (0.41; 95% CI 0.21-0.61; p ? 0.0001). There was fair agreement for ulcers (0.26; 95% CI 0.07-0.59; p = 0.005). There was a low correlation between masses, polyps, and others. CONCLUSION: CE still remains the initial test of choice in evaluating stable patients with OBGIB since it has strong-to-fair concordance for the major small bowel findings. However, in cases of severe overt small bowel bleeding, balloon-assisted enteroscopy can be considered the initial procedure of choice since it is therapeutic as well as diagnostic and this approach avoids delays in treatment. Further research should focus on methods to improve interpretation of CE and enhance the ability to evaluate the entire small bowel with SBE. PMID- 26770259 TI - RNA as a stable polymer to build controllable and defined nanostructures for material and biomedical applications. AB - The value of polymers is manifested in their vital use as building blocks in material and life sciences. Ribonucleic acid (RNA) is a polynucleic acid, but its polymeric nature in materials and technological applications is often overlooked due to an impression that RNA is seemingly unstable. Recent findings that certain modifications can make RNA resistant to RNase degradation while retaining its authentic folding property and biological function, and the discovery of ultra thermostable RNA motifs have adequately addressed the concerns of RNA unstability. RNA can serve as a unique polymeric material to build varieties of nanostructures including nanoparticles, polygons, arrays, bundles, membrane, and microsponges that have potential applications in biomedical and material sciences. Since 2005, more than a thousand publications on RNA nanostructures have been published in diverse fields, indicating a remarkable increase of interest in the emerging field of RNA nanotechnology. In this review, we aim to: delineate the physical and chemical properties of polymers that can be applied to RNA; introduce the unique properties of RNA as a polymer; review the current methods for the construction of RNA nanostructures; describe its applications in material, biomedical and computer sciences; and, discuss the challenges and future prospects in this field. PMID- 26770264 TI - EUS-guided cholecystoduodenostomy for acute cholecystitis with an anti-stent migration and anti-food impaction system; a pilot study. AB - BACKGROUND: Recently, endoscopic ultrasound-guided gall bladder drainage (EUS GBD) has been reported using a self-expandable metallic stent. To prevent stent migration and food flowing into the common bile duct through the cystic duct, we perform a novel EUS-guided cholecystoduodenostomy. The aim of our study was to evaluate the safety and feasibility of EUS-guided cholecystoduodenostomy with an anti-stent migration and anti-food impaction system. METHODS: A total of 16 consecutive patients who underwent EUS-guided cholecystoduodenostomy for acute cholecystitis were included in this study. RESULTS: Technical and clinical success was obtained in all patients. The median procedure time was 26.9 min (range 19-42 min). Median follow-up time was 181.5 days (range 18-604 days), and in this time, recurrence of acute cholecystitis was not seen in all patients. Adverse events such as stent migration and cholangitis were not seen in any patients, although pneumoperitoneum was seen in one patient. CONCLUSION: Our technique may be favorable and effective for the prevention of adverse events on EUS-GBD. PMID- 26770265 TI - Ustekinumab for the treatment of Crohn's disease: can it find its niche? AB - Crohn's disease is an immune-mediated disease that results in panenteric chronic inflammation in genetically predisposed individuals exposed to an appropriate environment. The past two decades have witnessed the emergence of an important class of drugs known as anti-tumour necrosis factor (TNF) agents in the treatment of Crohn's disease. Unfortunately, the utility of these agents have been hampered by primary and secondary nonresponse in a significant proportion of patients. Ustekinumab, a monoclonal antibody to the p40 subunit of interleukin (IL) 12 and 23, is a novel pharmacotherapy for this patient cohort that offers an out-of class option. It is approved for use in psoriasis and psoriatic arthritis, and has now been evaluated in phase II trials for moderate-to-severe Crohn's disease. We here review the published literature and describe a potential clinical role for its use in this disease cohort. PMID- 26770266 TI - The potential utility of tight junction regulation in celiac disease: focus on larazotide acetate. AB - Celiac disease (CD) is a common chronic immune disease triggered by gluten. Gliadin peptides pass through the epithelial layers, either paracellularly or transcellularly, to launch a potent adaptive immune response in the lamina propria. This aberrant immune response leads to diverse gastrointestinal and extra-gastrointestinal symptoms. Currently, the only treatment for CD is a strict lifelong adherence to a gluten-free diet (GFD), which can be challenging. An early effect of gluten in CD is an increase in gut permeability. Larazotide acetate, also known as AT-1001, is a synthetic peptide developed as a permeability regulator primarily targeting CD. In vitro studies indicate that larazotide acetate is capable of inhibiting the actin rearrangement caused by gliadin and clinical studies have been conducted using this peptide as a therapy for CD. PMID- 26770267 TI - Blue laser imaging endoscopy system for the early detection and characterization of colorectal lesions: a guide for the endoscopist. AB - Blue laser imaging is a new system for image-enhanced endoscopy using laser light. Blue laser imaging utilizes two monochromatic lasers (410 and 450 nm) instead of xenon light. A 410 nm laser visualizes vascular microarchitecture, similar to narrow band imaging, and a 450 nm laser provides white light by excitation. According to three recently published reports, the diagnostic ability of polyp characterization using blue laser imaging compares favorably with narrow band imaging. No published data are available to date regarding polyp detection with blue laser imaging. However, blue laser imaging has the possibility to increase the detection of colorectal polyps by depicting brighter and clearer endoscopic images, even at a distant view, compared with first-generation image enhanced endoscopy. A clinical trial to compare the detection between blue laser imaging and xenon light is warranted. PMID- 26770268 TI - A gastrointestinal anti-infectious biotherapeutic agent: the heat-treated Lactobacillus LB. AB - Experimental in vitro and in vivo studies support the hypothesis that heat treated, lyophilized Lactobacillus acidophilus LB cells and concentrated, neutralized spent culture medium conserve the variety of pharmacological, antimicrobial activities of the live probiotic strain against several infectious agents involved in well-established acute and persistent watery diarrhoea and gastritis. Heat-treated cells and heat-stable secreted molecules trigger multiple strain-specific activities explaining the therapeutic efficacy of L. acidophilus LB. This review discusses the current body of knowledge on the antimicrobial mechanisms of action exerted by L. acidophilus LB demonstrated in in vitro and in vivo experimental studies, and the evidence for the therapeutic efficacy of this anti-infectious biotherapeutic agent proved in randomized clinical trials for the treatment of acute and persistent watery diarrhoea associated with several intestinal infectious diseases in humans. PMID- 26770269 TI - The role of ferric carboxymaltose in the treatment of iron deficiency anemia in patients with gastrointestinal disease. AB - Iron deficiency anemia (IDA) is the most common form of nutritional anemia worldwide. Iron plays a pivotal role in vital functioning of almost every organ system. IDA affects both physical and psychological functioning of humans. Oral iron is considered as first-line therapy for the treatment of IDA due to low cost, good safety profile and ease of administration. However, the absorption of oral iron is affected by several factors and incidence of gastrointestinal side effects can lead to lack of adherence to therapy as well as poor efficacy. This has led to the emergence of intravenous iron therapy which is clearly superior to oral iron with higher increment of hemoglobin levels and rapid replenishment of iron stores. Ferric carboxymaltose (FCM) is a novel non-dextran intravenous iron form which has been approved for use in patients with iron deficiency who have had inadequate response to oral iron therapy, intolerance to oral iron, or nondialysis-dependent chronic kidney disease. The safety and efficacy of using FCM for the treatment of IDA has been demonstrated in several clinical trials. One dose can provide a large amount of iron and has a very short infusion time. It should be considered as first-line therapy in patients with active inflammation like inflammatory bowel disease when gastrointestinal absorption of oral iron may be compromised. It should also be given to patients who have inadequate response to oral iron therapy. It has been shown to be noninferior to other intravenous iron formulations with a good safety profile and produced fewer anaphylactic reactions. PMID- 26770270 TI - Management of patients with faecal incontinence. AB - Faecal incontinence, defined as the involuntary loss of solid or liquid stool, is a common problem affecting 0.8-8.3% of the adult population. Individuals suffering from faecal incontinence often live a restricted life with reduced quality of life. The present paper is a clinically oriented review of the pathophysiology, evaluation and treatment of faecal incontinence. First-line therapy should be conservative and usually include dietary adjustments, fibre supplement, constipating agents or mini enemas. Biofeedback therapy to improve external anal sphincter function can be offered but the evidence for long-term effect is poor. There is good evidence that colonic irrigation can reduce symptoms and improve quality of life, especially in patients with neurogenic faecal incontinence. Surgical interventions should only be considered if conservative measures fail. Sacral nerve stimulation is a minimally invasive procedure with high rate of success. Advanced surgical procedures should be restricted to highly selected patients and only performed at specialist centres. A stoma should be considered if other treatment modalities fail. PMID- 26770272 TI - Association between caffeine consumption and nonalcoholic fatty liver disease: a systemic review and meta-analysis. AB - OBJECTIVES: Caffeine consumption is reported to be associated with reduced hepatic fibrosis in patients with chronic liver diseases. We performed a systematic review and meta-analysis to assess the association between caffeine consumption and prevalence or hepatic fibrosis of nonalcoholic fatty liver disease (NAFLD) in observational studies. METHODS: We searched the literature of all languages from PubMed, EMBASE, and the Cochrane library from 1 January 1980 through 10 January 2015. Total caffeine consumption was defined as the daily intake of caffeine (mg/day) from all caffeine-containing products. Combined and subgroup analyses stratified by study designs, study locations, and type of caffeine intake were performed. RESULTS: Four cross-sectional and two case control studies with a total of 20,064 subjects were included in the meta analysis. Among these, three studies with 18,990 subjects were included in the analysis for prevalence of NAFLD while the other three studies with 1074 subjects were for hepatic fibrosis. Total caffeine consumption (mg/day) was not significantly associated with either the prevalence [pooled mean difference (MD) 2.36; 95% confidence interval (CI) -35.92 to 40.64] or hepatic fibrosis (higher versus lower stages; pooled MD -39.95; 95% CI -132.72 to 52.82) of NAFLD. Subgroup analyses stratified by study designs and locations were also not significant. However, after stratifying by type of caffeine intake, regular coffee caffeine intake (mg/day) was significantly associated with reduced hepatic fibrosis of NAFLD (pooled MD -91.35; 95% CI -139.42 to -43.27; n = 2 studies). CONCLUSION: Although total caffeine intake is not associated with the prevalence or hepatic fibrosis of NAFLD, regular coffee caffeine consumption may significantly reduce hepatic fibrosis in patients with NAFLD. PMID- 26770273 TI - Acquired factor VII deficiency following FOLFOX in a patient with colorectal cancer who was also DPD deficient. PMID- 26770271 TI - Nausea: a review of pathophysiology and therapeutics. AB - The sensation of nausea is a common occurrence with diverse causes and a significant disease burden. Nausea is considered to function as a protective mechanism, warning the organism to avoid potential toxic ingestion. Less adaptive circumstances are also associated with nausea, including post-operative nausea, chemotherapy-induced nausea, and motion sickness. A common definition of nausea identifies the symptom as a precursor to the act of vomiting. The interaction, though present, does not appear to be a simple relationship. Nausea is unfortunately the 'neglected symptom', with current accepted therapy generally directed at improving gastrointestinal motility or acting to relieve emesis. Improved understanding of the pathophysiological basis of nausea has important implications for exploiting novel mechanisms or developing novel therapies for nausea relief. PMID- 26770274 TI - Successful use of volumetric laser endomicroscopy in imaging a rectal polyp. PMID- 26770275 TI - Anti-inflammatory effects of 4'-demethylnobiletin, a major metabolite of nobiletin. AB - Nobiletin, a citrus flavonoid has been associated with various beneficial biological activities. 4'-Demethylnobiletin (4DN) is a major metabolite of nobiletin and its tissue level was found to be much higher than that of nobiletin after oral administration of nobiletin in mice. Anti-inflammatory effects of 4DN were studied in lipopolysaccharide (LPS)-treated RAW 264.7 macrophages. The results showed 4DN not only dose-dependently inhibited LPS-induced nitric oxide production, but also significantly reduced expression of pro-inflammatory mediators, namely PGE2, IL-1beta and IL-6. 4DN potently suppressed the expression of iNOS and COX-2 at both protein and mRNA levels. 4DN also inhibited nuclear translocation of NF-kappaB and AP-1. Furthermore, we demonstrated that 4DN activated transcription factor Nrf2 and its dependent genes including HO-1 and NQO1 whose expression may contribute to anti-inflammatory effects. The results demonstrated anti-inflammatory effects of 4DN and provided a scientific basis for using nobiletin as a nutraceutical to inhibit inflammation-driven diseases. PMID- 26770277 TI - Position paper of the German Society of Oto-Rhino-Laryngology, Head and Neck Surgery and the German Society of Phoniatrics and Pediatric Audiology - Current state of clinical and endoscopic diagnostics, evaluation, and therapy of swallowing disorders in children. AB - Swallowing disorders are frequent. The main concern is mortality due to aspiration-induced pneumonia and malnutrition. In addition, quality of life is severely affected. The demographic trend indicates an increase of dysphagia in the future. Neurodegenerative diseases, tumors of the digestive tract, and sequelae of tumor treatment in the head and neck region are the main pathologic entities. Predominantly ENT physicians and phoniatricians are asked for diagnostics and therapy, and will coordinate the interdisciplinary treatment according to the endoscopic findings. A differentiated approach in history, diagnostics, and symptom-oriented treatment is necessary for these mostly complex disorders. Integration of non-medical staff such as speech therapists, physiotherapists, and occupational therapists in planning and executing an effective therapy expands and completes the patient-oriented care. Conservative treatment by these therapists is an important pillar in the treatment. Parts of the specific diagnostics can be taken over in close cooperation. In particular, an interdisciplinary cooperation with the staff of intensive care medicine is essential. The diagnostic procedures of specific endoscopy as described in this position paper are part of the primary and fundamental tasks of ENT specialists and phoniatrists. Endoscopy is a medical service that is basically not delegable. Consequently, substitution of the physician is excluded. PMID- 26770278 TI - Orphan diseases of the nose and paranasal sinuses: Pathogenesis - clinic - therapy. AB - Rare rhinological diseases are a diagnostic challenge. Sometimes it takes months or even years from the primary manifestation of the disease until the definitive diagnosis is establibshed. During these times the disease proceeds in an uncontrolled or insufficiently treated way. (Irreversible) damage results and sometimes life-threatening situations occur. The unexpected course of a (misdiagnosed) disease should lead to further diagnostic reflections and steps in order to detect also rare diseases as early as possible. The present paper discusses granulomatous diseases of the nose and paranasal sinuses caused by mycobacteria, treponema, Klebsiella, fungi, and protozoa as well as vasculitis, sarcoidosis, rosacea, cocaine-induced midline destruction, nasal extranodal NK/T cell lymphoma, and cholesterol granuloma. Furthermore, diseases with disorders of the mucociliary clearance such as primary ciliary dyskinesia and cystic fibrosis are presented, taking into consideration the current literature. PMID- 26770279 TI - Optimized imaging of the midface and orbits. AB - A variety of imaging techniques are available for imaging the midface and orbits. This review article describes the different imaging techniques based on the recent literature and discusses their impact on clinical routine imaging. Imaging protocols are presented for different diseases and the different imaging modalities. PMID- 26770280 TI - Trauma of the midface. AB - Fractures of the midface pose a serious medical problem as for their complexity, frequency and their socio-economic impact. Interdisciplinary approaches and up-to date diagnostic and surgical techniques provide favorable results in the majority of cases though. Traffic accidents are the leading cause and male adults in their thirties are affected most often. Treatment algorithms for nasal bone fractures, maxillary and zygomatic fractures are widely agreed upon whereas trauma to the frontal sinus and the orbital apex are matter of current debate. Advances in endoscopic surgery and limitations of evidence based gain of knowledge are matters that are focused on in the corresponding chapter. As for the fractures of the frontal sinus a strong tendency towards minimized approaches can be seen. Obliteration and cranialization seem to decrease in numbers. Some critical remarks in terms of high dose methylprednisolone therapy for traumatic optic nerve injury seem to be appropriate. Intraoperative cone beam radiographs and preshaped titanium mesh implants for orbital reconstruction are new techniques and essential aspects in midface traumatology. Fractures of the anterior skull base with cerebrospinal fluid leaks show very promising results in endonasal endoscopic repair. PMID- 26770281 TI - Hemostatic management of patients undergoing ear-nose-throat surgery. AB - Perioperative hemostatic management is increasingly important in the field of otolaryngology. This review summarizes the key elements of perioperative risk stratification, thromboprophylaxis and therapies for bridging of antithrombotic treatment. It gives practical advice based on the current literature with focus on patients undergoing ENT surgery. PMID- 26770276 TI - Comprehensive review on rhino-neurosurgery. AB - In the past 2 decades, an innovative and active field of surgical collaboration has been evolved and established combining the expertise of neurosurgery and rhinosurgery in the endonasal treatment of different lesions affecting the anterior skull base together with the adjacent intranasal and intradural areas. Important prerequisites for this development were improvements of technical devices, definitions of transnasal surgical corridors, and approvements in endonasal reconstructions, e.g. by use of pedicled nasal mucosal flaps. Due to these improvements, the rate of perioperative infectious complications remained acceptable. Interdisciplinary surgical teams (4-hands-2-minds) have been established constituting specialized centers of "rhino-neurosurgery". With growing expertise of these groups, it could be shown that oncological results and perioperative complications were comparable to traditional surgery while at the same time the patients' morbidity could be reduced. The present review encompasses the recent literature focusing on the development, technical details, results, and complications of "rhino-neurosurgery". PMID- 26770284 TI - Principles of infection prevention and reprocessing in ENT endoscopy. AB - This article gives an overview on the principles of reprocessing of rigid and flexible endoscopes used in ENT units including structural and spatial requirements based on general and ENT-specific risks of infection associated with diagnostic and therapeutic endoscopy. The underlying legal principles as well as recommendations from scientific societies will be exemplified in order to give a practical guidance to the otorhinolaryngologist. Preliminary results of a small nation-wide survey on infection control standards based on data of 29 ENT practices in Germany reveal current deficits of varying degree concerning infection control management including reprocessing of endoscopes. The presented review aims to give support to the establishment of a structured infection control management program including the evaluation of results by means of a prospective surveillance. PMID- 26770283 TI - Pathophysiology of chronic rhinosinusitis, pharmaceutical therapy options. AB - Research in immunology has brought great progress in knowledge of inflammatory processes in the last 2 decades, which also has an impact on the upper airways. Our understanding of the pathophysiology of chronic rhinosinusitis developed from a rather mechanistic point of view with a focus on narrow clefts and mucociliary clearance to the appreciation of a complex network of immunological pathways forming the basis of disease. We today differentiate various forms of inflammation, we start to understand complex immune-regulatory networks and the reasons for their failure, and have already developed innovative approaches for therapy for the most severely ill subjects. Due to this new knowledge in inflammation and remodeling processes within mucosal tissue, specifically on the key driving factors, new diagnostic tools and therapeutic approaches for chronic rhinosinusitis have developed; the differentiation of endotypes based on pathophysiological principles will be crucial for the use of innovative therapies, mostly humanized monoclonal antibodies. Several hundred of those antibodies are currently developed for various indications and will impact our specialty as well as pneumology to a great extent. PMID- 26770286 TI - Handwriting or Typewriting? The Influence of Pen- or Keyboard-Based Writing Training on Reading and Writing Performance in Preschool Children. AB - Digital writing devices associated with the use of computers, tablet PCs, or mobile phones are increasingly replacing writing by hand. It is, however, controversially discussed how writing modes influence reading and writing performance in children at the start of literacy. On the one hand, the easiness of typing on digital devices may accelerate reading and writing in young children, who have less developed sensory-motor skills. On the other hand, the meaningful coupling between action and perception during handwriting, which establishes sensory-motor memory traces, could facilitate written language acquisition. In order to decide between these theoretical alternatives, for the present study, we developed an intense training program for preschool children attending the German kindergarten with 16 training sessions. Using closely matched letter learning games, eight letters of the German alphabet were trained either by handwriting with a pen on a sheet of paper or by typing on a computer keyboard. Letter recognition, naming, and writing performance as well as word reading and writing performance were assessed. Results did not indicate a superiority of typing training over handwriting training in any of these tasks. In contrast, handwriting training was superior to typing training in word writing, and, as a tendency, in word reading. The results of our study, therefore, support theories of action-perception coupling assuming a facilitatory influence of sensory-motor representations established during handwriting on reading and writing. PMID- 26770287 TI - Writing, Reading, and Listening Differentially Overload Working Memory Performance Across the Serial Position Curve. AB - Previous research has assumed that writing is a cognitively complex task, but has not determined if writing overloads Working Memory more than reading and listening. To investigate this, participants completed three recall tasks. These were reading lists of words before recalling them, hearing lists of words before recalling them, and hearing lists of words and writing them as they heard them, then recalling them. The experiment involved serial recall of lists of 6 words. The hypothesis that fewer words would be recalled overall when writing was supported. Post-hoc analysis revealed the same pattern of results at individual serial positions (1 to 3). However, there was no difference between the three conditions at serial position 4, or between listening and writing at positions 5 and 6 which were both greater than recall in the reading condition. This suggests writing overloads working memory more than reading and listening, particularly in the early serial positions. The results show that writing interferes with working memory processes and so is not recommended when the goal is to immediately recall information. PMID- 26770288 TI - How the Learning Path and the Very Structure of a Multifloored Environment Influence Human Spatial Memory. AB - Few studies have explored how humans memorize landmarks in complex multifloored buildings. They have observed that participants memorize an environment either by floors or by vertical columns, influenced by the learning path. However, the influence of the building's actual structure is not yet known. In order to investigate this influence, we conducted an experiment using an object-in-place protocol in a cylindrical building to contrast with previous experiments which used rectilinear environments. Two groups of 15 participants were taken on a tour with a first person perspective through a virtual cylindrical three-floored building. They followed either a route discovering floors one at a time, or a route discovering columns (by simulated lifts across floors). They then underwent a series of trials, in which they viewed a camera movement reproducing either a segment of the learning path (familiar trials), or performing a shortcut relative to the learning trajectory (novel trials). We observed that regardless of the learning path, participants better memorized the building by floors, and only participants who had discovered the building by columns also memorized it by columns. This expands on previous results obtained in a rectilinear building, where the learning path favoured the memory of its horizontal and vertical layout. Taken together, these results suggest that both learning mode and an environment's structure influence the spatial memory of complex multifloored buildings. PMID- 26770289 TI - Association of polymorphisms with a family history of cancer and the presence of germline mutations in the BRCA1/BRCA2 genes. AB - INTRODUCTION: Breast cancer (BC) is an important public health problem worldwide. In Brazil, breast cancer is the most frequently diagnosed tumor and the leading cause of cancer death in women. Hereditary cancer represents approximately 5 to 10 % of BC cases. Even outside the hereditary cancer context, the presence of polymorphisms acting as genetic modifiers may contribute to a better or worse prognosis. Not much is known about the hereditary BC epidemiology in Brazil or about the influence of polymorphisms on hereditary predisposition. OBJECTIVE: This study examined the role of five different polymorphisms in four groups of women with BC: Group 1: women with a germline mutation in the BRCA1/2 genes; Group 2: women with variants of uncertain significance in BRCA1/2 and Group 3: women with no mutations in BRCA1/2. PATIENTS AND METHODS: The women included in groups 1, 2 and 3 were patients from the Department of Oncogenetics of the Barretos Cancer Hospital who had undergone genetic testing because of a clinical suspicion of hereditary predisposition syndrome. The constitutive DNA was analyzed for the presence of polymorphisms at rs2981582 (FGFR2 gene); rs3803662 (TNRC9); rs889312 (MAP3K1); rs3817198 (LSP1 gene); and rs13281615 (8q24). The analyses were performed using PCR amplification and bi-directional sequencing. RESULTS: No differences were identified in the frequency of the polymorphisms that were analyzed among the three groups. However, some associations were identified, such as the occurrence of bilateral breast cancer and homozygosity for the G allele in rs13281615 as well as the correlation between the SNPs rs2981582 and rs13281615 and the number of cancer cases in the family. Regarding the G allele of rs13281615, we observed that the proportion of individuals who were homozygous for this allele increased with the number of generations affected by cancer, regardless of the group where the patients were included. Concerning the rs2981582 we could observe that individuals from group 1 and homozygous CC had fewer cancer (and also fewer breast cancer) cases. Regarding the hormone receptors, we observed an increased frequency in C homozygotes (rs3803662) among estrogen receptor-negative individuals from groups 1 and 3. For rs2981582 (FGFR2), we observed an increased frequency of the T allele in women who were positive for the estrogen and progesterone receptors regardless of the BRCA1/2 mutational status (p = 0.020 and p = 0.014, respectively). CONCLUSION: The results presented here provide interesting data on the modifying effect of polymorphisms on a family history of cancer; this may be a variable to consider in the analysis of tumor diversity, and of the family history observed in families with hereditary breast cancer (even in those harboring the same type of genetic alteration). PMID- 26770285 TI - Epidemiology of chronic rhinosinusitis, selected risk factors, comorbidities, and economic burden. AB - Chronic rhinosinusitis (CRS) is a relevant and prevalent medical condition in Germany, Europe and the world. If analysed in detail, the prevalence of CRS shows regional and temporary variety. In this review, currently available data regarding the prevalence of CRS is therefore sorted by country and/or region, time point of data collection and the CRS-definition employed. Risk factors like smoking and gastroesophageal reflux are discussed regarding their influence on CRS prevalence. Moreover, comorbidities of CRS, like asthma, conditions of the cardiovascular system and depression are listed and their influence on CRS is discussed. Furthermore, data on CRS prevalence in special cohorts, like immunocompromised patients, are presented. To estimate the economic burden of CRS, current data e.g. from Germany and the USA are included in this review. PMID- 26770290 TI - A hospital-based study of initial observation for low-risk prostate cancer and its predictors in the United States. AB - INTRODUCTION: Initial observation (IO) is a strategy to minimize prostate cancer overtreatment. We sought to evaluate contemporary trends in IO utilization for low-risk prostate cancer in the United States and to identify factors associated with its uptake. METHODS: Using the National Cancer Database, we identified men with low-risk prostate cancer diagnosed between 2004 and 2011. IO utilization was plotted over time. Multivariate logistic regression was performed to determine the influence of diagnosis year and other factors on IO selection. RESULTS: Of the 219 971 men with low-risk prostate cancer, 21 231 (9.7%) underwent IO. Beginning in 2008, IO use increased significantly with time (range: 7.5%-14.3%). Compared to 2004, patients diagnosed in 2011 had 2.5 times the odds of choosing IO (odds ratio [OR] 2.5, confidence interval [CI] 2.3-2.6, p < 0.01). Aside from diagnosis year, age, race, Charlson score, clinical T stage, and PSA level predicted IO use (p < 0.01). Other predictors of IO included hospital type, insurance provider, and household income. Specifically, comprehensive cancer centres, private insurance, and higher income predicted decreased IO usage (OR 0.5, CI 0.5-0.5, p < 0.01; OR 0.4, CI 0.4-0.4, p < 0.01; and OR 0.8, CI 0.8-0.9, p < 0.01, respectively). Less educated men were also less likely to undergo observation (OR 0.8, CI 0.8-0.9, p < 0.01). Treatment within the western United States was significantly, but weakly, associated with increased use of IO (p < 0.01). CONCLUSIONS: In recent years, low-risk prostate cancer has been increasingly managed with IO, appropriately driven by patient and disease factors. Unexpectedly, observation usage also varies by race, hospital, insurance, income, and geography, suggesting that non-clinical factors may affect treatment selection. PMID- 26770291 TI - The Worldwide Economic Impact of Neurogenic Bladder. AB - Costs of neurogenic bladder vary widely and depend on a number of factors including severity of disease, symptomatology, patient insurance, and devices required. Recognition of how each treatment strategy will impact the patient financially could help guide selection of treatment as well as improve compliance with the chosen regimen. We have attempted to provide an overview of long term cost considerations for the neurogenic bladder patient. Armed with this information, the practitioner can better help the patient select a bladder care regimen that balances the desire to both minimize symptoms now and preserve urinary tract integrity for the future, yet still remain cost effective. PMID- 26770292 TI - A modified classification tree method for personalized medicine decisions. AB - The tree-based methodology has been widely applied to identify predictors of health outcomes in medical studies. However, the classical tree-based approaches do not pay particular attention to treatment assignment and thus do not consider prediction in the context of treatment received. In recent years, attention has been shifting from average treatment effects to identifying moderators of treatment response, and tree-based approaches to identify subgroups of subjects with enhanced treatment responses are emerging. In this study, we extend and present modifications to one of these approaches (Zhang et al., 2010 [29]) to efficiently identify subgroups of subjects who respond more favorably to one treatment than another based on their baseline characteristics. We extend the algorithm by incorporating an automatic pruning step and propose a measure for assessment of the predictive performance of the constructed tree. We evaluate the proposed method through a simulation study and illustrate the approach using a data set from a clinical trial of treatments for alcohol dependence. This simple and efficient statistical tool can be used for developing algorithms for clinical decision making and personalized treatment for patients based on their characteristics. PMID- 26770293 TI - Comparison of conservative and operative treatment for distal radius fracture: a meta-analysis of randomized controlled trials. AB - BACKGROUND: The authors conducted a meta-analysis to compare the effectiveness and safety of conservative and operative treatment for distal radius fracture. METHODS: PubMed, EMBASE, and the Cochrane Library were searched to identify the relevant studies published up to February of 2015. All randomized controlled trials published to compare the conservative and operative treatment were included in the study. Results were pooled using meta-analysis to compare the efficacy and safety of conservative and operative treatment for distal radius fracture. RESULTS: The databases were derived from seven qualified studies that included a total of 523 patients in which 269 cases adopted conservative treatment while 253 cases adopted operative treatment. Overall, compared with the conservative treatment- treated the distal radius fracture, operative therapies resulted in significantly better radiographic (P<0.05), however, no significant differences of the functional outcomes and complication rate were observed between the two methods (P>0.05). CONCLUSION: Surgical treatment seems to be more effective distal radius fracture compared with conservative treatment when the radiographic outcomes were analyzed, and no significant differences were deteched in the functional outcomes and complication rate. PMID- 26770294 TI - The association between three IL-6 polymorphisms and HBV-related liver diseases: a meta-analysis. AB - BACKGROUND: A quantity of case-control studies have been performed to address the association between the three interleukin-6 (IL-6) polymorphisms (-572G/C, 597G/A and -174G/C) and the risk of HBV related liver diseases. However, previous research results are inconsistent. We conducted this meta-analysis to clarify the correlation between these IL-6 polymorphisms and HBV related liver diseases. METHODS: We searched in PubMed, EMBASE, Cochrane Library as well as Chinese databases including China National Knowledge Infrastructure (CNKI) and WanFang database for all the relevant studies up to April 15, 2015. The data were extracted by two independent authors. Odds ratios (ORs) and 95% confidence intervals (95% CI) were calculated. RESULTS: A total of 10 studies consisting of 3879 cases and 2812 controls were included in this metaanalysis. For IL-6 polymorphism -572G/C, an association with increased chronic hepatitis B (CHB) risk was observed under in allelic, homozygous, heterozygous, dominant and recessive model. However, IL-6 polymorphisms (-572G/C) were not related to Inactive Carrier (IC), Liver Cirrhosis (LC) and Hepatocellular Carcinoma (HCC) risk in this study. We also found that IL-6 polymorphisms (-597G/A) were related to CHB in allelic, heterozygous, recessive model. For IL-6 polymorphism -174G/C, we did not find any association with CHB risk. CONCLUSION: The present meta analysis indicated that IL-6 polymorphisms -572G/C and -597G/A significantly associate with CHB risk, but might not be significantly related to the progressive HBV such as LC and HCC. IL-6 polymorphisms -174G/C might not significantly associate with HBV related liver diseases. PMID- 26770295 TI - Meta-analysis of survival with the molecular adsorbent recirculating system for liver failure. AB - This study aims to assess the treatment effects of the molecular adsorbent recirculating system (MARS) in patients with acute and acute-on-chronic liver failure. We searched MEDLINE, EMBASE, and the Cochrane Controlled Trials Registry database between January 1966 and January 2014. We included randomized controlled trials, which compared the treatment effects of MARS with standard medical treatment. Study quality assessed according to Consolidated Standards of Reporting Trials (CONSORT) criteria. The risk ratio was used as the effect-size measure according to a fixed-effects model. The search strategy revealed 72 clinical studies, 10 of which were randomized controlled trials that met the criteria and were included. Four addressed ALF (93 patients) and six addressed AOCLF (453 patients). The mean CONSORT score was 15 (range 10-20). By meta analysis, MARS significantly improved survival in ALF (risk ratio 0.61; 95% CI 0.38, 0.97; P = 0.04). There was no significant survival benefit in AOCLF (risk ratio 0.88; 95% CI 0.74, 1.06; P = 0.16). MARS significantly improved survival in patients with acute liver failure, however, there is no evidence that it improved survival in patients with acute-on-chronic liver failure. In conclusion, the present meta-analysis indicates that MARS therapy can improve survival in patients with ALF. It is necessary to develop MARS treatment because of the increasing demand for liver transplantation and the risk of liver failure. PMID- 26770296 TI - Clinical outcome of direct pulp capping with MTA or calcium hydroxide: a systematic review and meta-analysis. AB - Direct pulp capping is one of the most common dental practices in endodontic therapy. This systematic review and meta-analysis aim to determine whether the effect of mineral trioxide aggregate (MTA) and calcium hydroxide for direct pulp capping is different, as measured by the clinical and radiographic analysis. The study list was obtained by searching PubMed, Springer Link, Scopus and Cochrane Database. Only those papers that met the inclusion criteria were analyzed. The results indicated that four studies met the inclusion criteria. Statistically significant difference was found between the success rates of MTA and calcium hydroxide treated teeth that needed direct pulp capping (P=0.002). Clinical assessments of the MTA versus calcium hydroxide for direct pulp capping suggested that MTA was superior to calcium hydroxide in direct pulp capping resulting in a lower failure rate (risk difference 0.1 [95% CI 0.04 to 0.16]). In conclusion, MTA has a higher clinical success rate for direct pulp capping comparing to calcium hydroxide, and might be a suitable replacement for calcium hydroxide. PMID- 26770297 TI - Kikuchi-Fujimoto disease associated with Sjogren's syndrome: a case report and review of the literature. AB - Kikuchi-Fujimoto disease (KFD), known as subacute necrotizing histiocytic lymphadenitis, is an extremely rare, benign and self-limited disease, and has been infrequently reported with autoimmune diseases. Here we report a 17-year-old girl pathologically diagnosed as KFD who suffered recurrence of KFD and developed into Sjogren's syndrome (SS) after four years and then performed a systematic literature search about KFD associated with SS in which seven patients was reviewed in detail. The results show that SS may be prior to, simultaneous with or following KFD and it developed mainly in young (average age: 25 years), female patients (4/5) after KFD with an average latency of 43 months. Therefore, long follow-up and appropriate clinical and laboratory workup are highly encouraged to exclude underlying SS conditions in young women with KFD. PMID- 26770298 TI - A simple and rapid method for detection of paraquat in human plasma by high performance liquid chromatography. AB - We have developed an effective analytical method to determine the concentration of paraquat in human plasma by high-performance liquid chromatography (HPLC), which can provide methodological support for diagnosis, therapy, and prognostic evaluation of acute poisoning related to paraquat. The plasma samples were deproteinized with 35% perchloric acid. Then the paraquat was extracted from the samples and separated on Ultimate XB-C18 column with a mobile phase consisting of 0.1 M phosphate buffer (containing 75 mM sodium heptane sulfonate) and methyl cyanides (PH 3.0), flow rate of 1 mL/min, column temperature of 28 degrees C and a detection wave length on 258 nm. A good linearity was obtained within the range of 0.2 to 500 g/ml in human plasma. The average rate of absolute and relative recovery were about 100.6% and 101.31%, accompanied by the variations less than 3% and 6% respectively. The within- and between-day relative standard deviations were all less than 6%. After repeated freeze and thaw of plasma samples, no significant difference was observed for the concentration of paraquat (P>0.05). The method was validated by successfully applying in one patient with acute paraquat poisoning. Due to the celerity, accuracy and no-interference by other components of blood sample, this method was suitable for determination the concentration of paraquat in human plasma. PMID- 26770299 TI - The structure and function of NKAIN2-a candidate tumor suppressor. AB - The deletion of chromosomal region 6q was commonly found in several types of human cancers, although the tumor suppressor genes (TSGs) located within this genomic region are not well established. Our recent work detected recurrent chromosomal truncation at the Na(+)/K(+) transporting ATPase interacting 2 (NKAIN2) gene in prostate cancer, which was also found to be truncated in leukemia and lymphoma, suggesting that NKAIN2 is potentially one of the TSGs located in the 6q commonly deleted region in human cancers. NKAIN2 gene consists of eight coding exons that span approximately 1 Mb of genomic DNA on chromosome 6q and there are four main splice variants. The function of this gene is not well investigated and the limited knowledge of this gene pointed to nervous system development. The chromosomal translocations in nervous development disorders usually lead to inactivation of this gene. In human tumors, both chromosomal deletion and translocation may also inactivate this gene and consequently contribute to tumorigenesis. Further genetic and cellular functional studies are required to establish its tumor suppressor role. PMID- 26770300 TI - Progress in treating ruptured infundibular dilatation at the origin of the intracranial posterior communicating artery. AB - Infundibular dilatation (ID) can occur at the origin of the intracranial posterior communicating artery. When this type of widening is less than 3 mm in diameter and the ID reaches the posterior communicating artery, it can be called posterior communicating artery infundibular dilatation (Pcom-ID). Currently, Pcom ID is considered a normal anatomic variation, and the majority of Pcom-IDs are stable. However, in some cases, rupture occurs in a Pcom-ID; furthermore, Pcom IDs can evolve into aneurysms. There are not many studies on Pcom-ID rupture hemorrhage; therefore, we performed a retrospective evaluation of published studies on Pcom-ID rupture hemorrhage and conducted a classification analysis for this condition. It is reasonable to classify Pcom-ID into three types: Type 1, direct rupture of the Pcom-ID; Type 2, bleb rupture of Pcom-ID; and Type 3, Pcom ID rupture caused by an aneurysm. This type of classification can provide meaningful guidance for treating ruptured Pcom-ID. In addition, the present study also included a systematic review and summarization of the literature on each type. This investigation was aimed to improve the understanding of Pcom-ID rupture hemorrhage. PMID- 26770301 TI - Exosomes as potent regulators of HCC malignancy and potential bio-tools in clinical application. AB - Exosomes are small membranous vesicles about 30~100 nm in diameter and formed from inward budding of the limiting membrane of multi-vesicular bodies (MVB). Exosomes are secreted by most cell types (including hepatocellular carcinoma cells) into the extracellular environment and can be isolated from various body fluids. Exosomes have broad biological function through delivering contained molecules to the target cells. Although limited studies on hepatocellular carcinoma (HCC) exosomes, increasing observations suggest that exosomes are important in HCC metastatic and prognosis, and exosomes are potential new molecular biomarkers for diagnosis and prognosis of HCC. In this review, we briefly summarize the latest findings on HCC exosomes, and their potential functions for novel diagnostic and therapeutic approaches of HCC. PMID- 26770302 TI - Meta-analysis of association of the matrix metalloproteinase 2 (-735 C/T) polymorphism with cancer risk. AB - The association between matrix metalloproteinase 2 (MMP2) gene polymorphisms and cancer risk has been investigated in many published studies; however, the currently available results are inconclusive. Therefore, we performed a meta analysis to provide conclusive evidence for an association between the MMP2 polymorphism (-735 C/T) and cancer risk. Sixteen case-control studies with 11792 individuals were included in this meta-analysis. The odds ratio (OR) and 95% confidence interval (95% CI) were used to investigate the strength of the association. Overall, the MMP2 polymorphism (-735 C/T) was not associated with cancer risk in any of the models. However, the subgroup analysis revealed that dominant model (C/T+T/T vs. C/C: OR=1.24, 95% CI=1.01-1.53) and codominant 1 model (C/T vs. C/C: OR=1.30, 95% CI=1.05-1.62) were significantly associated with cancer risk in the Caucasian population. In conclusion, our meta-analysis indicated that the MMP2 polymorphism (-735 C/T) might be genetic risk factor for the carcinogenesis in Caucasians. However, more studies with a larger sample size are needed to provide more precise evidence. PMID- 26770303 TI - Stem cells as cellular vehicles for gene therapy against glioblastoma. AB - Glioblastoma (GBM) is the most common and deadliest primary tumor in adults, with current treatments having limited specific and efficient delivery of therapeutic drugs to tumor sites or cells. Therefore, the development of alternative treatment options is urgently needed. Stem cells are considered as ideal cellular vehicles for gene therapy against glioblastoma. In this paper, we reviewed the recent studies investigating the use of different types of stem cells as cellular vehicles and the gene of interests against the glioblastoma, as well as the future directions of the application of cellular vehicles mediated therapy for glioblastoma. PMID- 26770304 TI - Competing endogenous RNA in cancer: a new pattern of gene expression regulation. AB - The competing endogenous RNA (ceRNA) hypothesis was introduced. There is a new hypothesis about mRNA, pseudogene transcripts and long noncoding RNAs (lncRNAs) regulate each other's expression by using microRNA response elements (MREs) to compete for the binding of microMRA (miRNA). To date, numbers lines of evidence in bioinformatics, cell biology and animal models from several famous laboratories have supported the ceRNA hypothesis. We also trace the history of the concept of ceRNA and discuss the molecular mechanisms of ceRNAs in cancers and their possible applications. In this review, we try to give readers a concise and reliable illustration on the mechanism, research approaches, and perspective of ceRNA in cancer. PMID- 26770306 TI - Analysis on value of CT and MRI clinical application in diagnosis of middle-aged patients with multiple cerebral infarction. AB - OBJECTIVE: To compare the application of MRI and CT imageological examination in diagnosis of middle-aged patients with multiple cerebral infarction. METHODS: 218 cases of patients with multiple cerebral infarction were selected for CT and MRI examinations, and the clinical value of CT and MRI examinations in diagnosis and imaging of middle-aged patients with multiple cerebral infarction was compared and analyzed. RESULTS: For the 218 cases of patients, the total detection rate of CT examination was 56.88% and that of MRI examination was 95.87%, indicating a statistically significant difference (x (2)=6.795, P=0.008). For the 85 patients in the group of less than 24 h, the detection rate of CT examination was 37.65% and that of MRI examination was 94.12%, and the comparative analysis between two groups suggested a statistically significant difference (x (2)=6.357, P=0.006); for the 70 cases in the group of 24~72 h, the detection rate of CT examination was 48.57%, and that of MRI examination was 97.14%, suggesting a statistically significant difference (x (2)=5.315, P=0.026); for the 63 cases in the group of greater than 72 h, the detection rate of CT and MRI examinations showed no statistically significant difference (P>0.05). This showed that the cerebral infarction detection rate of MRI examination was significantly higher than that of CT examination in the group of less than 24 h and the group of 24~72 h, while the difference in the cerebral infarction detection rate was not significant in the group of greater than 72 h. The number of lesions detected by MRI examination was significantly higher than that by CT examination (P<0.01); the capability of MRI examination to detect small lesions of cerebral infarction was significantly stronger than that of CT examination (P<0.05). CONCLUSION: MRI has significant advantages in diagnosis of middle-aged patients with multiple cerebral infarction when compared to CT. PMID- 26770305 TI - Autotaxin-LPA receptor axis in the pathogenesis of lung diseases. AB - Lysophosphatidic acid (LPA) is a small lipid which mediates a variety of cellular functions via the activation of LPA receptors. LPA is generated from lysophosphatidylcholine by the extracellular enzyme, autotaxin (ATX). Elevated ATX expression, LPA production and their signaling pathways have been reported in multiple pathological conditions of lung tissue, including inflammation, fibrosis and cancer. Emerging evidence has highlighted the importance of ATX and LPA receptors in the pathogenesis of lung diseases. Here, we briefly review the current knowledge of different roles of the ATX-LPA receptor axis in lung diseases focusing on inflammation, fibrosis and cancer. PMID- 26770307 TI - The efficacy of spleen-preserving distal pancreatectomy with or without splenic vessel preservation: a meta-analysis. AB - BACKGROUND: Spleen-preserving distal pancreatectomy can be performed with splenic vessel preservation (SPDP-SVP) or splenic vessel resection (SPDP-SVR). This meta analysis aimed to evaluate the clinical outcomes of patients undergoing SPDP-SVP or SPDP-SVR. METHOD: A systematic literature search of PubMed, Embase, and the Cochrane Library was performed. The operative time, estimated blood loss, postoperative complications, pancreatic fistula (Grade B+C) rates, splenic infarction rates, gastric/perigastric varices rates and postoperative hospital stay were evaluated. RevMan 5.3 software was used to evaluate the differences between groups. RESULTS: Nine studies involving 639 patients were included in this meta-analysis, of whom 402 underwent SPDP-SVP and 237 underwent SPDP-SVR. Patients who underwent SPDP-SVP had lower splenic infarction and gastric/perigastric varices rates. The operative time, estimated blood loss, postoperative complications, pancreatic fistula (Grade B+C) rates and postoperative hospital stays were comparable between these two groups. CONCLUSIONS: SPDP-SVP and SPDP-SVR are both safe, feasible procedures for the management of benign or low-grade malignant pancreatic body or tail tumors. However, SPDP-SVR is related to higher incidence rates of early splenic ischemia and gastric/perigastric varices. PMID- 26770309 TI - Radial versus femoral artery access for percutaneous coronary angiography and intervention: a systematic review and meta-analysis of randomized controlled trials in Chinese population. AB - To compare the feasibility, efficiency and safety of coronary angiography (CAG) and interventional procedures between the radial and femoral catheterization approaches in Chinese population using systematic review and meta-analysis, we conducted a search of the studies comparing radial and femoral catheterization approaches in patients underwent either CAG or percutaneous coronary intervention (PCI) in Chinese population. Fixed-effect relative risk (RR) for the primary end points and the second end points were compared between the two approaches. A total of 27 studies (n=8,749 patients) were finally included in the analysis. The success rate of radial approach was slightly lower than that of femoral approach in patients receiving CAG (P=0.004), but similar in patients receiving a further PCI treatment (P=0.11). The risk of major adverse cardiovascular events (MACEs) was similar between two approaches (P=0.27). Radial catheterization had a significantly lower rate of puncture site complications (P<0.00001), but a lower rate of puncture success rate (P=0.02). In patients with acute myocardial infarction (AMI), there was no difference in neither the risk of MACEs nor PCI success rate between two approaches (P=0.23 and 0.45, respectively), but a board line decrease of puncture success rate was observed in radial catheterization group (P=0.04). There were no significant differences in the volumes of contrast media, X-ray exposure time and operation time between the two approaches (all P>0.05). Thus, we concluded that radial approach is a safe method for CAG or PCI compared to traditional femoral approach in Chinese population due to their similar success rate of the procedure and risk of MACEs, and a decreased risk of puncture site complications. PMID- 26770308 TI - ISG15 as a novel prognostic biomarker for hepatitis B virus-related hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide. Interferon-alpha (IFN-alpha) has recently been recognized to harbor therapeutic potential in prevention and treatment of HCC. IFN-stimulated gene 15 (ISG15) is an ubiquitin-like molecule that is strongly upregulated by type I interferons as a primary response to diverse microbial and cellular stress stimuli. Several studies have shown that the overexpression of ISG15 is correlated with multiply tumor types. However, the role of ISG15 in hepatitis B virus (HBV)-related HCC remains undetermined. ISG15 expression was found to be obviously higher in HBV-related HCC tissues than that in non-tumor tissues. ISG15 is a novel prognostic marker for predicting 5-year overall survival of HBV related HCC patients. Overexpression of ISG15 was associated with clinicopathological characteristics and poor patient outcomes. ISG15 may serve as a novel prognostic marker for HBV-related HCC. Therefore, ISG15 may represent a novel HCC marker with prognostic significance and may be helpful in selecting patients for and predicting response to the treatment of HBV-related HCC. PMID- 26770310 TI - Transthoracic versus abdominal-transhiatal resection for treating Siewert type II/III adenocarcinoma of the esophagogastric junction: a meta-analysis. AB - Our study aimed to explore the differences in short and long-term outcomes about the transthoracic (TH) and abdominal-transhiatal (TH) approaches for treating esophagogastric junction (AEG). A systematic review of PubMed, EMbase, Cochrane Library, China National Knowledge Infrastructure and CBMdisc was performed. All original articles comparing TH with TA were included in the study. Meta-analysis was conducted using odd ratios (OR) and weighted mean differences (WMDs).Thirteen studies including 2489 patients with adenocarcinoma of the esophagogastric junction, with 1050 patients underwent TA and 1437 patients underwent TH were pooled for this study. There were no significant difference between two approaches concerning duration of operation, blood loss, anastomotic leakage and positive of proximal incisal margin. Lymph node excised also showed no significant differences between two procedures in RCTs while in TA group of Non RCTs, the number of lymph node dissection is higher. TH approach was associated with a longer length of hospital stay and had higher incidence of respiratory and cardiovascular complications and early postoperative mortality. Overall analysis of 1, 3, 5-year survival showed no significant difference between two approaches. Based on the study, TA approach had a positive impact than TH for AEG with respect to respiratory and cardiovascular complications, hospital stay and early mortality rates. There were no significant differences between the two approaches for long-term survival. Therefore, two surgical approaches are acceptable, and the elders with poor cardiopulmonary function, we recommended TA approach for treating it. PMID- 26770311 TI - Morphometric and ultrastructural analysis of the effect of bromocriptine and cyclosporine on the vasospastic femoral artery of rats. AB - Vasospasm is the main causes of mortality and morbidity in patiens with subarachnoid hemorrhage (SAH). The arterial narrowing mechanism that develops after SAH is not yet fully understood but many studies showed that hypotension, neurogenic reflexes, clots in the subarachnoidal space, spasmogenic agents, humoral and celluler immunity play a role in the etiology. In this study we investigate the effects of Bromocriptine and Cyclosporine A in vasospasm secondary to SAH on rat femoral artery from ultrastructural and morphometric perspectives. 120 male Sprague-Dawley rats divided into 12 groups: Vasospasm (V), control (K), surgical control (CK) groups, vasospasm+Bromocriptine and/or Cyclosporine-A groups (VCyA, VBr, VBr+CyA), Bromocriptine and/or Cyclosporine-A control groups (CK, BK, Br+CyAK), Bromocriptine and/or Cyclosporine-A surgical control groups (BCK, CyCK, Br+CyACK). In order to create SAH model, 0, 1 cm(3) blood injected into silastic sheath wrapped rat femoral artery. Bromocriptine (2 mg/kg/d) and Cyclosporine A (10 mg/kg/d) combinations applied to control, surgical control and vasospastic models. Light microscopy, transmission electron microscopy and scanning electron microscopy used during this study. Statistical evaluation of the morphometric measurement data concerning vascular wall thickness and luminal cross-sectional areas of all groups were performed using Mann-Whitney U, Wilcoxon-signed rank, and Student-t tests. Cyclosporine A, whose effects in the prevention of vasospasm have been demonstrated in previous studies. In this study we discovered that Bromocriptine demonstrated strong effects similar to Cyclosporine-A. Bromocriptine and Cyclosporine A markedly prevent the development of chronic morphologic vasospasm following SAH. The combined use of both drugs does not change this preventive effect. PMID- 26770312 TI - Clinical characteristics and prognosis of childhood rhabdomyosarcoma: a ten-year retrospective multicenter study. AB - PURPOSE: Rhabdomyosarcoma (RMS) is the most frequent soft tissue sarcoma in children. We have retrospectively explored the treatment results of childhood RMS and identified prognostic factors in multicenter in China, in order to lay the foundation for further multicenter study. METHODS: This retrospective study was carried out analyzing the medical records of 161 patients with the pathological diagnosis of RMS from January, 2001 to February, 2014 at 5 large cancer centers in China. The data was reviewed clinico-epidemiological factors. Age, gender, histology type, primary site, tumor size, intergroup rhabdomyosarcoma study (IRS) group and results of treatments were evaluated. Patients were followed up to Dec 31, 2014. RESULTS: The median age of our patients was 51 months. 10.5% of our patients were infants. The genitourinary system was the most common primary site of tumor (43.5%). The proportion of primary site of head and neck except parameningeal, at 28.2% (42 cases), while the proportion of parameningeal region was 4.6% (7 cases). The histological findings were as follows: 130 cases (80.7%) with embryonal, 19 cases (11.9%) with alveolar and 5 cases (3.1%) with botryoid type. According to the classification system of the IRS group, 1 case (0.6%) was group I, 54 cases (33.5%) were group II, 46 cases (28.6%) were group III and 60 cases (37.3 %) were group IV. 149 patients were treated and followed-up regularly, Patients in Beijing children's hospital (n=95) were enrolled in IRS II/COG-D9803, D9802 protocols. while the other patients (n=54) started on treatment according to Chinese Anti-cancer Association protocol. There were median time of 51 months for following up, 60 occurred event. The ten-year event free survival rate was 53.4+/-5.1%, overall survival was 65.3+/-6.3%. The relations between outcome and age (0.046), primary site (0.022), pathologic subtype (0.013), tumor size (0.008) and IRS group (P=0.000) were associated significantly with event free survival. Among the variables, age (P=0.028) and IRS group (P=0.000) were associated significantly with overall survival. Multivariate analysis showed that overall survival for RMS was dependent on IRS group (P=0.026). CONCLUSIONS: The epidemiological characteristics of our patients are quite similarly to the worldwide data. Except for the higher prevalence of group IV in our patients and the higher percentage of patients with primary tumor site in the genitourinary system, this study showed that overall survival for RMS is depended on disease group. PMID- 26770282 TI - Comprehensive review on endonasal endoscopic sinus surgery. AB - Endonasal endoscopic sinus surgery is the standard procedure for surgery of most paranasal sinus diseases. Appropriate frame conditions provided, the respective procedures are safe and successful. These prerequisites encompass appropriate technical equipment, anatomical oriented surgical technique, proper patient selection, and individually adapted extent of surgery. The range of endonasal sinus operations has dramatically increased during the last 20 years and reaches from partial uncinectomy to pansinus surgery with extended surgery of the frontal (Draf type III), maxillary (grade 3-4, medial maxillectomy, prelacrimal approach) and sphenoid sinus. In addition there are operations outside and beyond the paranasal sinuses. The development of surgical technique is still constantly evolving. This article gives a comprehensive review on the most recent state of the art in endoscopic sinus surgery according to the literature with the following aspects: principles and fundamentals, surgical techniques, indications, outcome, postoperative care, nasal packing and stents, technical equipment. PMID- 26770313 TI - Voice outcomes after laser surgery vs. radiotherapy of early glottic carcinoma: a meta-analysis. AB - BACKGROUND: Radiotherapy and laser resection are established treatment modalities for early glottic carcinoma. To date, there is no confirmed conclusion which treatment is better for early glottic cancer. The objective of this study was to conduct a meta-analysis to compare the voice outcomes after laser resection (LS) and radiotherapy (RT) of Tis-T1N0M0 glottic carcinoma. METHODS: we searched the relevant electronic studies and performed a meta-analysis based on 13 published studies. The Chi-square based I(2)-statistic test was performed to evaluate possible heterogeneity across the studies. Additionally, random-effects models were used to calculate mean differences with 95% confidence intervals (CIs). RESULTS: Overall, a total of 13 published studies were included in our study, with 368 patients in the RT group and 440 patients in the LS group, respectively. No significant differences in Voice Handicap Index (VHI), jitter and shimmer were found between RT and endoscopic LS among patients with Tis-T1N0M0 glottic carcinoma and T1aN0M0 laryngeal cancer. However, the acoustic voice analysis parameters of Fo values were significantly lower in RT group than that in LS group. CONCLUSION: The results from this meta-analysis support that the LS has more advantages than RT in terms of voice quality. However, more studies on voice outcome need to validate our findings. PMID- 26770314 TI - Diagnosis and comprehensive treatment of esophageal leiomyoma: clinical analysis of 77 patients. AB - To investigate the diagnosis and comprehensive treatment of esophageal leiomyoma. The clinical data of 77 cases of esophageal leiomyoma patients were analyzed between 2005 and 2013. Its diagnosis, treatment and prognosis were analyzed. 39 cases of patients were with eating choking feeling, 18 cases presented with chest pain and weight loss and 20 cases without any symptoms. Preoperative endoscopic ultrasonography of each patient was diagnosed as possibility of esophageal submucosal tumor. 3 All patients underwent tumor enucleation, in which tumor electrotomy under gastroscope were done for 2 cases, complete video-assisted thoracoscopic (CVATS) resection of tumor for 24 cases, thoracoscope assisted small incision tumor resection for 29 cases, conventional thoracic tumor resection for 22 cases. The comparison and the difference of complete video assisted thoracoscopic surgery group and the thoracoscope assisted small incision group for the operation time, bleeding volume, drainage volume, extubation time, hospitalization time and fasting time were not statistically significant (P < 0.05). All the patients recovered well and postoperative pathology of each patient was esophageal leiomyoma. They were followed up for 6 months to 8 years, average for 4 years, not recurrence of esophageal leiomyoma. Endoscopic ultrasonography is the most accurate method in diagnosis of esophageal leiomyoma. Esophageal leiomyoma which less than 1.0 cm in diameter, regular shape, originated in the muscularis mucosa, endoscopic electrotomy can be used as the preferred; Surgical operation is the main treatment of esophageal leiomyoma, three kinds of operation way has its own corresponding clinical indications, according to the clinical characteristics of patients and operator' habits to choose the corresponding operation way, all can achieve good treatment effect. PMID- 26770315 TI - Association between vitamin D and non-alcoholic fatty liver disease/non-alcoholic steatohepatitis: results from a meta-analysis. AB - The prevalence and impact of non-alcoholic fatty liver disease (NAFLD) and non alcoholic steatohepatitis (NASH) have continued to increase in recent years. Previous reports have shown that hypovitaminosis D is associated with the prevalence and severity of non-alcoholic fatty liver disease (NAFLD). The aim of this study was to systematically evaluate the association of vitamin D levels, as measured by serum 25-hydroxy vitamin D [25(OH)D], with NAFLD and NASH. We searched all of the publications that assessed the association between vitamin D and NAFLD/NASH in the PubMed and EMBASE databases up to November 2014. In total, twenty-nine articles met the eligibility criteria, including twenty-seven studies about NAFLD and four studies about NASH, which were identified and included in the meta-analysis. Twenty-nine cross-sectional and case-control studies evaluated the association between vitamin D and NAFLD/NASH. Twenty-three studies provided data for a quantitative meta-analysis. Compared with the controls, the NAFLD patients had significantly lower levels of 25(OH)D (SMD-0.76; 95% CI-0.97 to 0.54) and were 1.26 times more likely to be vitamin D deficient (OR 1.26, 95% CI: 1.15 to 1.38). Compared with the controls, the NASH patients had significantly lower levels of 25(OH)D (SMD-1.30; 95% CI-2.37 to -0.23). Although the cross sectional studies did not allow us to determine a causal nexus, our meta-analysis found lower serum 25(OH)D levels in NAFLD/NASH patients than in subjects without NAFLD/NASH, which suggests that hypovitaminosis D could play a role in the pathogenesis of NAFLD/NASH. Further studies are required to establish the causality between vitamin D status and NAFLD. PMID- 26770316 TI - Gingko biloba extract (Ginaton) ameliorates dextran sulfate sodium (DSS)-induced acute experimental colitis in mice via reducing IL-6/STAT3 and IL-23/IL-17. AB - This study explored the underlying mechanism of Gingko biloba extract (Ginaton) on dextran sulfate sodium (DSS)-induced acute experimental colitis in mice. 40 male C57BL/6 mice were randomly divided into four groups: normal control group, Ginaton group, Ginaton treatment group, and DSS group. After 7 days administration, mice were sacrificed and colons were collected for H-E staining, immunohistochemistry, real-time PCR and Western blot. By observing clinical disease activity and histological damage, we assessed the effect of Ginaton on DSS-induced acute experimental colitis in mice and observed the effect of Ginaton on normal mice. We also explored the specific mechanism of Ginaton on DSS-induced acute experimental colitis in mice through examining the expression of inflammatory related mediators (gp130, STAT3, p-STAT3, ROR-gammat) and cytokines (IL-6, IL-17, IL-23). Ginaton-treated DSS mice showed significant improvement over untreated DSS mice. Specifically, Ginaton improved clinical disease activity (DAI score, weight closs, colon shortening, and bloody stool) and histological damage, and reduced the expression of inflammatory-related mediators (p-STAT3, gp130, ROR-gammat) and cytokines (IL-6, IL-17, IL-23). In addition, clinical disease activity, histological damage, the expression of inflammatory related mediators (STAT3, p-STAT3, gp130, ROR-t) and cytokines (IL-6, IL-17, IL-23) in mice of Ginaton group were similar to normal control group. In conclusion, Ginaton ameliorates DSS-induced acute experimental colitis in mice by reducing IL 17 production, which is at least partly involved in inhibiting IL-6/STAT3 signaling pathway and IL-23/IL-17 axis. Moreover, Ginaton itself does not cause inflammatory change in normal mice. These results support that Ginaton can be as a potential clinical treatment for ulcerative colitis (UC). PMID- 26770317 TI - Role of human cytomegalovirus in the proliferation and invasion of extravillous cytotrophoblasts isolated from early placentae. AB - AIM: We investigated the role of human cytomegalovirus (HCMV) and its mechanism in extravillous cytotrophoblast (EVT) proliferation and invasion in vitro. METHODS: Differential enzymatic digestion combined with gradient centrifugation, was used to isolate primary EVT from human chorionic villi collected from early placentae of healthy pregnant women. HCMV infection was determined by immunofluorescence staining of HCMVpp65 antigen expression. An MTT assay was used to examine the role of HCMV in the proliferation of EVT. Quantitative real-time polymerase chain reaction (qRT-PCR), immunocytochemical staining and Western blots were carried out in a control group (EVT) and a virus group (EVT+HCMV) to examine the expression of major genes and protein in TGF-beta/Smad signaling pathways in EVT 48 h after inoculation with HCMV. An in vitro cell invasion assay was performed to analyze the influence of HCMV on EVT invasion. RESULTS: HCMV significantly inhibited the proliferation of EVT 48 h after viral infection (P < 0.05). The expression of TGF-beta1, Smad1, Smad2, Smad3, Smad4, and Smad5 genes was significantly increased (P < 0.05), but that of TGF-beta2, TGF-beta3, TGFbetaRI, TGFbetaRII, Smad7, MMP2, and MMP9 was significantly decreased in the virus group 48 h after HCMV infection (P < 0.05). Smad7, MMP-2 and MMP-9 protein levels were significantly decreased and the TGF-beta1 protein level was significantly increased in infected EVT (all P < 0.05). CONCLUSIONS: HCMV may act on multiple steps of the TGF-beta/Smad signaling pathway to impede EVT proliferation and invasion. PMID- 26770318 TI - A six-microRNA set as prognostic indicators for bile duct cancer. AB - MicroRNAs (miRNAs) play important roles in cancer progression by altering transcriptional control. The purpose of this study is to identify and explore specific miRNAs as prognostic and predictive biomarkers for bile duct cancer (BDC) by analyzing Next-generation data. miRNA expression profiles and corresponding clinical information of BDC samples were extracted from The Cancer Genome Atlas (TCGA). The differentially expressed miRNAs were determined by SAMR package in R software. Target genes of those miRNAs were predicted by Targetscan. Functional enrichment analysis and hypergeometric test analysis of target genes were performed. Then, diagnosis accuracy of miRNAs was judged by ROC Curves analysis. Total 120 differentially expressed miRNAs were obtained, of which six important miRNAs were selected and predicted as prognosis and predicting biomarkers in BDC. Besides, functional analysis showed that both enriched pathways were significantly related with ion binding, which might involve in the carcinogenesis of BDC. Moreover, top 3 important pathways sharing the most influence were noted. Our results demonstrated that hsa-miR-483-5p, hsa-miR-675, hsa-miR-139-3p, hsa-miR-598, hsa-miR-625 and hsa-miR-187 could serve as prognostic and predictive markers for survival of BDC patients and could potentially be provided as targets for future therapy. PMID- 26770319 TI - Diagnostic value of bone-specific alkaline phosphatase in lung carcinoma patients with bone metastases: a meta-analysis. AB - Aim and Backgrounds: The accurate diagnosis of lung carcinoma patients with bone metastases is crucial for therapy and the prevention of complications. We performed a systematic review and meta-analysis to evaluate the diagnostic value of serum bone-specific alkaline phosphatase (BALP) in lung carcinoma patients with bone metastases. METHODS: Such databases as PubMed, Embase, Cochrane Library, Web of Science, Ovid, BioMed Central, Biosis previews and four Chinese databases (Chinese Biomedical Literature Database-disc (CBM), Chinese National Knowledge Infrastructure (CNKI), Technology of Chongqing (VIP) and Wan Fang DATA) were retrieved on computer, and the relevant journals were also manually searched to collect the trials on BALP in diagnosis of lung carcinoma patients with bone metastases. The meta-analysis was conducted by using Meta-Disc 1.4 software. RESULTS: A total of 8 studies were included, and there were 848 lung carcinoma patients diagnosed by gold standard, patients were divided into two groups: 419 cases with bone metastases and 429 cases without bone metastases. The meta analysis showed that, the pooled sensitivity (SEN), specificity (SPE), positive likelihood ratio (PLR), negative likelihood ratio (NLR) and diagnostic odds ratio (DOR) was 0.48 [95% CI (0.43 to 0.53)], 0.86 [95% CI (0.82 to 0.89)], 3.14 [95% CI (2.47 to 3.99)], 0.62 [95% CI (0.56 to 0.68)], 6.66 [95% CI (4.62 to 9.60)] respectively. And the AUC of SROC was 0.78, (Q*=0.72). CONCLUSION: BALP has greater diagnostic value in detecting lung carcinoma patients with bone metastases. However, further large scale studies are required to confirm the predictive value. PMID- 26770320 TI - Dexmedetomidine attenuates isoflurane-induced cognitive impairment through antioxidant, anti-inflammatory and anti-apoptosis in aging rat. AB - As a kind of alpha2 adrenergic receptor agonists, dexmedetomidine generates sedation, anti-anxiety and anesthesia effects by hyperpolarizing noradrenergic nerve cells in locus coeruleus. This study was designed to investigate the neuroprotective of dexmedetomidine attenuates isoflurane-induced cognitive impairment, and the possible underlying mechanism in aging rat. Firstly, we used isoflurane-induced aging rat model to analyze the therapeutical effect of dexmedetomidine on cognitive impairment. Next, commercial ELISA kits were used to analyze tumor necrosis factor alpha (TNF-alpha), interleukin-1beta (IL-1beta), methane dicarboxylic aldehyde (MDA) and superoxide dismutase (SOD) and caspase-3 levels. In addition, Western blotting was used to detect the protein expression of P38 MAPK, PTEN and phosphorylation-Akt (p-Akt) expression. Our results showed that the neuroprotective of dexmedetomidine significantly attenuates isoflurane induced cognitive impairment in aging rat. Moreover, dexmedetomidine significantly inhibited these TNF-alpha, IL-1beta, MDA, SOD and caspase-3 activities in isoflurane-induced aging rat. Meanwhile, the neuroprotective effects of dexmedetomidine on isoflurane-induced cognitive impairment significantly suppressed Bcl-xL/Bad rate, P38 MAPK and PTEN protein expression and activated p-Akt protein expression in aging rat. Collectively, neuroprotective effect of dexmedetomidine attenuates isoflurane-induced cognitive impairment through antioxidant, anti-inflammatory and anti-apoptosis in aging rat. PMID- 26770321 TI - Coexistence of multiple rare spinal abnormalities in type 1 neurofibromatosis: a case report and literature review. AB - Orthopaedic involvement is the most common clinical presentation of Neurofibromatosis type 1 (NF-1) patients with the spinal abnormalities more frequently affected. In the spinal deformities of NF-1 patients, despite the scoliosis is the most frequent finding, several distinctive radiographic features, such as dural ectasia, defective pedicles, and spondylolisthesis, are relatively less common. Here, we reported a 16-year-old boy diagnosed with NF-1 who presented with dural ectasia, defective pedicles, and spondylolisthesis concomitantly, described the surgical treatment and provided a literature review. The boy complained of low back and leg pain for two months. On clinical examination, the patient showed multiple cafe au lait spots on his back and no neurological deficit. He had a family history of neurofibromatosis as his father suffering from NF-1. Imaging results demonstrated mild scoliosis, posterior scalloping of the lumber spine, L5 spondylolisthesis on plain radiographs, and marked dural ectasia of L3-L5 on MRI. Furthermore, the CT scan showed presence of thin pedicles at L3, bilateral symmetrical pedicle clefts at L4, and pars interarticularis fractures at L5. The patient received a long level posterior fusion from L1 to S1 with pedicle screws. Iliac crest autogenous graft mixed with artificial bone were used to achieve solid arthrodesis. At nine-month follow-up, the patient was asymptomatic and able to live a normal life. Our observation demonstrated that familiarity with those distinctive features in NF-1 patients could be contributed to making an early diagnosis and optimizing treatment. PMID- 26770322 TI - Hawthorn leaf flavonoids alleviate nonalcoholic fatty liver disease by enhancing the adiponectin/AMPK pathway. AB - Hawthorn (Crataeguspinnatifida) belongs to the genus Rosaceae family of plants. The hawthorn leaf, Crataeguspinnatifida Bunge, is used for both condiment and medicinal purposes to prevent and treat metabolic dysfunctions, such as hyperlipidemia, hypertension, and cardiovascular disease in traditional Chinese medicine. However, its effects on nonalcoholic fatty liver disease (NAFLD) remain obscure. The purpose of the present study was to investigate the protective effect of hawthorn leaf flavonoids (HLF), the dominant bioactive extracts of hawthorn leaves, on high fat diet (HFD)-induced hepatic steatosis and to elucidate its underlying mechanisms. HLF supplementation significantly lowered body weight, liver weight, liver/body weight ratio, improved serum parameters and liver dysfunction and markedly decreased hepatic lipid accumulation in HFD-fed rats. In addition, HLF intervention dramatically increased circulating adiponectin levels and up-regulated the expression of adiponectin receptors, particularly adiponectin receptor 2 (AdipoR2) in the liver. Moreover, adenosine monophosphate (AMP)-activated protein kinase (AMPK) was also activated, as well as AMPK-mediated alteration of sterol regulatory element binding protein-1c (SREBP-1c), peroxisome proliferator-activated receptor alpha (PPARalpha) and their downstream targets. Taken together, our data suggest that HLF ameliorates hepatic steatosis by enhancing the adiponectin/AMPK pathway in the liver of HFD induced NAFLD rats. PMID- 26770323 TI - Expression of KAP1 in epithelial ovarian cancer and its correlation with drug resistance. AB - KAP1 is a universal corepressor for Kruppel-associated box zinc finger proteins. In this study, expression level of KAP1 and its association with drug resistance and expression of P-gp and BCRP in epithelial ovarian cancer were investigated. Immunohistological staining of KAP1 in cancer and matched paraneoplastic tissues was evaluated in 242 patients with epithelial ovarian cancer. Immunohistological staining of P-gp and BCRP were also evaluated, and the associations with the expression of KAP1 in epithelial ovarian cancer were investigated. MTT assay for cell proliferation and clonogenic survival assay were applied to determine the effect of KAP1 on the sensitivity of DDP, through up-regulating the level of KAP1 expression of SKOV3 using KAP1 plasmid and down-regulating the level of KAP1 expression of SKOV3/DDP using siRNA. The results demonstrated that the expression levels of KAP1 in cancer tissues were higher than matched paraneoplastic tissues (t = 21.39, P<0.001). The patients with higher KAP1 expression often had drug resistance, and the level of KAP1 expression was positively correlated with the expression of P-gp and BCRP (P = 0.07 and P<0.001 respectively). Up-regulated the expression of KAP1 in SKOV3 cell line induced the up-regulated expression of BCRP and P-gp, increasing the resistance of chemotherapeutic drug, and down-regulated the expression of KAP1 got opposite effects. KAP1 expression correlated with aggressive clinical features in ovarian cancer, maybe through regulating the expression of P-gp and BCRP. PMID- 26770324 TI - Analysis of differentially expressed genes based on microarray data of glioma. AB - Glioma represents one of the main causes of cancer-related death worldwide. Unfortunately, its exact molecular mechanisms remain poorly understood, which limits the prognosis and therapy. This study aimed to identify the critical genes, transcription factors and the possible biochemical pathways that may affect glioma progression at transcription level. After downloading micro-array data from Gene Expression Omnibus (GEO), the differentially expressed genes (DEGs) between glioma and normal samples were screened. We predicted novel glioma related genes and carried on online software DAVID to conduct GO enrichment and transcription factor analysis of these selected genes. String software was applied to construct a PPI protein interaction network, as well as to find the key genes and transcription factors in the regulation of glioma. A total of 97 DEGs were identified associated with cancer, the GO enrichment analysis indicated these DEGs were mainly relevant to immune responses as well as regulation of cell growth. In addition, the transcription factor analysis showed these DEGs were regulated by the binding sites of transcription factors GLI2, SP1, SMAD7, SMAD3, RELA, STAT5B, CTNNB1, STAT5A, TFAP2A and SP3. PPI protein interaction network analysis demonstrated the hub nodes in the interaction network were EGFR, TGFB1, FN1 and MYC. The hub DEGs may be the most critical in glioma and could be considered as drug targets for glioma therapy after further exploration. Besides, with the identification of regulating transcription factors, the pathogenesis of glioma at transcription level might be brought to light. PMID- 26770325 TI - Meta-analysis of diffusion-weighted magnetic resonance imaging in identification of colorectal cancer. AB - PURPOSE: This meta-analysis aimed to evaluate the performance of diffusion weighted magnetic resonance imaging (DWI) in identification of colorectal cancer. METHODS: A systematic literature search was performed for studies that evaluated the diagnostic accuracy of DWI in identification of colorectal cancer. Methodological quality was assessed by Quality Assessment for Studies of Diagnostic Accuracy 2 (QUADAS 2) tool. After extracting data, we estimated the pooled sensitivity, specificity, likelihood ratios, and constructed summary receiver operating characteristics (SROC) curve. RESULTS: Ten studies involving 367 malignant lesions and 178 benign lesions were considered eligible after full text review. The pooled sensitivity and specificity were 0.95 (95% CI: 0.90-0.97) and 0.93 (95% CI: 0.85-0.97), respectively. Positive likelihood ratio and negative likelihood ratio were 12.8 (95% CI: 5.99-27.4) and 0.06 (95% CI: 0.03 0.11), respectively. The area under SROC curve was 0.98. CONCLUSIONS: Our meta analysis indicates that DWI is a highly accurate diagnostic method in identification of colorectal cancer. PMID- 26770326 TI - Transversus abdominis plane block versus local anaesthetic wound infiltration for postoperative analgesia: A systematic review and meta-analysis. AB - BACKGROUND: Transversus abdominis plane (TAP) block and local anaesthetic wound infiltration can provide effective pain relief at the wound site after surgery. However, the relative efficacy of two techniques for postoperative analgesia remains controversial. METHODS: We searched PUBMED, EMBASE and CENTRAL databases for randomized controlled trials (RCTs) comparing TAP block with wound infiltration for pain relief after surgery. The primary outcomes were pain scores at rest and on movement at 1, 8 and 24 hours postoperatively and cumulative morphine consumption over 24 hours. The secondary outcomes were time to first rescue analgesic, number of rescue analgesic use and opioids-related side effects. RESULTS: Nine RCTs with a total of 500 participants were included. TAP block was associated with significant lower rest and dynamic pain scores at 8 hour [MD = -1.08, 95% CI (-1.89-0.26), P = 0.009] and 24 hour [MD = -0.83, 95% CI (-1.60, -0.06), P = 0.03] postoperatively than wound infiltration, but no significant difference was found at 1 hour [MD = -0.94, 95% CI (-1.97, 0.09), P = 0.08] postoperatively. In adults, TAP block significantly reduced 24-hour overall morphine consumption by 3.85 mg [MD = -3.85, 95% CI (-7.47, -0.22), P = 0.04] compared with wound infiltration. Subgroup analysis showed that adults received TAP block appeared to have lower rest pain scores at 24 hour than children (P = 0.008). CONCLUSION: TAP block provides superior analgesia compared with wound infiltration in the setting of a multimodal analgesic regimen. Subgroup analysis indicated that adults may have benefits additional to the analgesic effect than children. PMID- 26770327 TI - Association between the CD28 IVS3 +17T>C (rs3116496) polymorphism and cancer susceptibility: a meta-analysis involving 8,843 subjects. AB - The possible association between CD28 IVS3 +17T>C (rs3116496) polymorphism and cancer susceptibility has been widely investigated. However, the results are conflicting. To verify the association more precisely, we performed a meta analysis of 11 publications involving a total of 8,843 subjects. In this meta analysis, 11 publications were included by searching PubMed and EMBASE databases up to May 23, 2014. The cancer susceptibility associated with the CD28 IVS3 +17T>C polymorphism was evaluated by odds ratios (ORs) with 95% confidence intervals (95% CIs). Heterogeneity, sensitivity and publication bias analyses were also assessed. The result suggested that the CD28 IVS3 +17T>C polymorphism is not associated with cancer susceptibility in overall cancer. In a stratified analysis by ethnicity, the association of CD28 IVS3 +17T>C polymorphism with cancer susceptibility was significant in Asians. In a stratified analysis by the origin of cancer cells and system of cancer, CD28 IVS3 +17T>C polymorphism was not associated with cancer susceptibility. In summary, this meta-analysis demonstrated that the CD28 IVS3 +17T>C polymorphism may be a cancer susceptibility factor in Asians. PMID- 26770328 TI - Elevated serum levels of IL-6 and IL-17 may associate with the development of ankylosing spondylitis. AB - PURPOSE: A meta-analysis was undertaken to examine the correlation between ankylosing spondylitis (AS) progression and serum levels of pro-inflammatory cytokines, Interleukin-6 (IL-6) and Interleukin-17 (IL-17) in AS patients. METHODS: PubMed, EBSCO, Cochrane Library database, Ovid, Springer link, WANFANG, China national knowledge infrastructure (CNKI) and VIP databases(last updated search in October, 2014) were exhaustively searched for published case-control studies using keywords related to IL-6, IL-17 and AS. The search results were screened using stringent inclusion and exclusion criteria, and the data from selected high-quality studies was analyzed with Comprehensive Meta-analysis 2.0 software. RESULTS: Thirteen case-control studies were selected for this meta analysis and contained a pooled total of 514 AS patients and 358 healthy controls. Our main result revealed strikingly higher serum levels of IL-6 and IL 17 in AS patients, compared to healthy controls (IL-6: SMD = 2.51, 95% CI = 1.33~3.70, P = 0.01; IL-17: SMD = 3.05, 95% CI = 2.09~4.02, P < 0.001). Ethnicity based subgroup analysis showed a statistically correlation of high IL-6 and IL-17 serum levels with AS both in Asian (IL-6: SMD = 3.15, 95% CI = 0.75~5.55, P < 0.001; IL-17: SMD = 3.30, 95% CI = 1.93~4.66, P < 0.001) and Caucasian populations (IL-6: SMD = 1.34, 95% CI = 0.33~2.35, P = 0.009; IL-17: SMD = 2.52, 95% CI = 1.06~3.98, P = 0.001). CONCLUSION: Meta-analysis of pooled data from thirteen high-quality studies revealed a strong correlation between elevated IL-6 and IL-17 serum levels and the development of AS. Therefore, IL-6 and IL-17 could be used as markers for diagnosis and assessment of treatment outcomes in AS patients. PMID- 26770329 TI - Prognostic significance of MiR-34a in solid tumors: a systemic review and meta analysis with 4030 patients. AB - PURPOSE: The aim of the present meta-analysis and systematic review was to explore the association between the expression of miR-34a and prognosis in solid tumor. METHODS: PubMed, Google Scholar, Web of Science and NCBI databases were used to search studies to evaluate the effect of miR-34a expression on clinical outcomes, including overall survival (OS), recurrence-free survival (RFS), disease-free survival (DFS), progression-free survival (PFS) and event-free survival (EFS) in solid tumor. The pooled random effect models were performed to calculate pooled hazard ratio (HR), 95% confidence interval (CI) to assess the association. RESULTS: Twenty-three eligible studies with 4030 patients were included in this meta-analysis. It was confirmed that increased expression of miR 34a was in relevant with better DFS/RFS/PFS/EFS, which was identified with both univariate and multivariate models (univariate model: HR = 0.62, 95% CI: 0.42 0.92, P = 0.019; multivariate model: HR = 0.55, 95% CI: 0.34-0.88, P = 0.013). Furthermore, in the analysis of relationship between miR-34a and DFS/RFS/PFS/EFS, the results remained similar when excluding the studies contributed to the heterogeneity (univariate analysis: HR = 0.57, 95% CI: 0.46-0.70, P < 0.001; multivariate analysis: HR = 0.57, 95% CI: 0.43-0.75, P < 0.001). With univariate analysis, it was also demonstrated that miR-34a overexpression might be positively associated with a favorable OS in solid tumor (HR = 0.73, 95% CI: 0.54 1.00, P = 0.005) with considering an obvious heterogeneity. CONCLUSION: Our current study supports the notion that miR-34a may be a potential biomarker to predict OS and RFS/PFS/DFS/EFS in solid tumor. PMID- 26770330 TI - Association of rs7754840 G/C polymorphisms in CDKAL1 with type 2 diabetes: a meta analysis of 70141 subjects. AB - The reported association of the CDKAL1 rs7754840 G/C gene polymorphism with T2DM susceptibility remains controversial. In this study, this association was further investigated using a meta-analysis of 33,149 patients and 36,992 controls from 32 independent studies. The random-effect models were used in order to evaluate the pooled odds ratios (ORs) and their 95% confidence intervals (CIs). A significant relationship between the CDKAL1 rs7754840 G/C gene polymorphism and T2DM was observed under allelic (OR: 1.37, 95% CI: 1.22, 1.55, P < 0.001), recessive (OR: 1.58, 95% CI: 1.20-2.08, P < 0.001), dominant (OR: 1.13, 95% CI: 1.21-1.33, P = 0.01), and homozygous (OR: 1.27, 95% CI: 1.21-1.33, P < 0.001), and heterozygous (OR: 0.83, 95% CI: 0.75-0.93, P < 0.001). Overall, the CDKAL1 rs7754840 G/C gene polymorphism was found to be significantly associated with an increased T2DM risk; the C allele of the CDKAL1 rs7754840 G/C gene polymorphism may confer susceptibility to T2DM. PMID- 26770331 TI - Pharmacokinetics of silybin nanoparticles in mice bearing SKOV-3 human ovarian carcinoma xenocraft. AB - The particle fabrication technique was used to fabricate monodisperse size and shape specific poly (lactide-co-glycolide) particles loaded with the silybin. Response surface methodology (RSM) using the central composite rotatable design (CCRD) model was used to optimize formulations of silybin nanoparticles. Further the optimized nanoparticles are characterized for particle size, zeta potential, surface morphology, entrapment efficiency, in-vitro drug release, silybin availability for tumor, plasma, lung, spleen, liver were determined. The significant findings were the optimal formulation of PLGA concentration 10 mg, PVA concentration 2000 and PET width of 6 gave rise to the EE of 88%, mean diameter of 223 nm and zeta potential of 25-mV. Release studies were investigated at pH 1.2 and pH 6.8. It was studied that lower the pH, faster the release of sylibin. The nanoparticles had~15-fold higher plasma exposure as measured by AUC contrasted to pure silybin. The nanoparticles had a 60% increase altogether tumor silybin presentation contrasted with pure silybin. Nanoparticles had higher silybin presentation in the spleen and liver contrasted with pure silybin suspension as expected for a nanoparticle formulation. The lung silybin presentation for the nanoparticle was additionally 2-fold higher than that of the pure silybin suspension. The results of pharmacokinetic parameters and oral bioavailability data exhibited that drug-nanoparticle complex could enhance the oral absorption of silybin and as well as the use of particles with smaller feature size may be preferred to decrease clearance by organs of the mononuclear phagocyte system. PMID- 26770333 TI - A20 overexpression alleviates pristine-induced lupus nephritis by inhibiting the NF-kappaB and NLRP3 inflammasome activation in macrophages of mice. AB - BACKGROUND: Lupus nephritis is an autoimmune inflammatory disease and urgently needs effective anti-inflammation therapies. A20, tumor necrosis factor alpha induced protein 3 (TNFAIP3), is a key negative regulator of inflammation, however whether A20 can regulate lupus nephritis has not been clarified. This study aimed at investigating the potential therapeutic effect of A20 on renal inflammation in mouse pristine model oflupus. METHODOLOGY/PRINCIPAL FINDINGS: Female BALB/c mice were intraperitoneally injected with pristine to establish lupus renal injury. The levels of serum IL-1beta, IL-6 and autoantibodies and the degrees of renal injury and CCL2 and F4/80 levels were measured. The levels of the NF-kappaB and NLRP3 inflammasome activation in peritoneal macrophages were determined. We found that injection with pristine increased the levels of serum IL-1beta, IL-6, autoantibodies and CCL20 and F4/80 expression in the kidney and induced renal injury, accompanied by enhancing the NF-kappaB and NLRP3 inflammasome activation in macrophages of mice. In contrast, treatment with Ad-A20, but not with Ad control, significantly mitigated pristine-induced inflammatory responses and renal injury,and reduced the NF-kappaB and NLRP3 inflammasome activation in macrophages in mice. CONCLUSION/SIGNIFICANCE: Our data indicated that induction of A20 overexpression inhibited pristane induced lupus inflammation and renal injury in mice and may be a new therapeutic strategy for treatment of lupus nephritis. PMID- 26770332 TI - Peroxisome proliferator-activated receptor gamma rs1801282 C>G polymorphism is associated with polycystic ovary syndrome susceptibility: a meta-analysis involving 7,069 subjects. AB - In the peroxisome proliferator-activated receptor gamma (PPARG) gene, a polymorphism (rs1801282 C>G), has been shown to change an amino acid residue and then results in alternation of PPARG function. A number of studies have explored the relationship between PPARG rs1801282 C>G variants and polycystic ovary syndrome (PCOS) risk, but yielding inconsistent findings, especially in Asian population. This study aimed to assess the role of PPARG rs1801282 C>G polymorphism in susceptibility to PCOS. Databases of Pubmed, Embase and China National Knowledge Internet (CNKI) were searched until August 2, 2015. The association of PPARG 1801282 C>G polymorphism with PCOS risk was evaluated by crude odds ratios (ORs) with their 95% confidence intervals (CIs). Finally, there were twenty-three studies involving 3,458 PCOS cases and 3,611 controls included in our pooled analysis. Significant associations were identified between PPARG rs1801282 C>G variants and decreased PCOS risk in three genetic comparison models (OR, 0.78; 95% CI, 0.69-0.89; P < 0.001 for G vs. C; OR, 0.77; 95% CI, 0.68-0.89; P < 0.001 for GG+CG vs. CC and OR, 0.79; 95% CI, 0.68-0.91; P = 0.001 for CG vs. CC). In a subgroup analysis by race, significant correlation was also observed between PPARG rs1801282 C>G variants and decreased PCOS risk in three genetic models: G vs. C (OR, 0.83; 95% CI, 0.71-0.97; P = 0.019) and GG+CG vs. CC (OR, 0.83; 95% CI, 0.70-0.99; P = 0.033) among Caucasians and in one genetic models: G vs. C (OR, 0.72; 95% CI, 0.59-0.88; P = 0.001) among Asians. In summary, our results demonstrate that PPARG rs1801282 C>G polymorphism may be a protective factor for PCOS. PMID- 26770335 TI - Insulin receptor substrate-1 (IRS-1) rs1801278G>A polymorphism is associated with polycystic ovary syndrome susceptibility: a meta-analysis. AB - The correlation between insulin receptor substrate-1 (IRS-1) rs1801278G>A polymorphism and polycystic ovary syndrome (PCOS) has been widely studied. However, the results of these studies are conflicting. The current study provides an assessment of the association between the genetic susceptibilities of IRS-1 rs1801278G>A polymorphism and PCOS. A comprehensive meta-analysis was carried out in over 4,555 subjects included in twenty publications which were published up to June 26, 2015. Our findings suggested that the IRS-1 rs1801278G>A genotype was correlated with the susceptibility of PCOS in the allele comparison, heterozygote comparison and the dominant genetic model. In the dominant genetic model, variant A allele carriers (AA+GA) of IRS-1 rs1801278G>A polymorphism increased the susceptibility of PCOS comparing to the homozygote GG [odds ratio (OR)=1.82, 95% confidence interval (CI) 1.30-2.53 for AA+GA vs. GG]. The analysis by different ethnicity groups highlighted that Caucasian population (OR=1.96, 95% CI 1.26-3.04 for AA+GA vs. GG) had significant increased PCOS susceptibility. Bias diagnosis indicated there are slight publication biases in some genetic models, suggesting that these findings should be interpreted with very caution. In summary, our findings suggested that IRS-1 rs1801278G>A polymorphism may be a risk factor for PCOS. PMID- 26770334 TI - A new rodent model of cerebral hyperperfusion. AB - BACKGROUND: Most studies of hyperperfusion and hyperperfusion syndrome after carotid endarterectomy or carotid stenting are based on clinical observation or meta-analyses in patients, whereas there is little corresponding fundamental research since proper animal model that can reproduce phenotype stably is not available. Therefore, we developed a rat model in which the pathophysiologic process of hyperperfusion can be mimicked. METHODS: Global ischemia was induced by occluding bilateral common carotid arteries (BCAO) for 2 weeks. After that, the ligature was loosened to allow reperfusion. Phenylephrine was administered at concentrations of 10, 20, 30, 40, 50, 80, and 120 MUg/mL for rapidly elevating blood pressure. Relative cerebral blood flow in relation to mean arterial pressure (MAP) was measured with Laser Doppler techniques. Sham animals underwent the same surgical operation but without artery-occlusion and received the same concentrations of phenylephrine. RESULTS: Mild hypertension rapidly increased cerebral blood flow. Phenylephrine at different concentrations produced different effects on blood pressure. Hyperperfusion can be induced by phenylephrine at around 30 MUg/mL, whereas phenylephrine at 80 MUg/ml or higher induced arrhythmia and further cardiac dysfunction thus failed to induce hyperperfusion. CONCLUSIONS: Our data suggest that 30-50 MUg/mL phenylephrine mildly elevated MAP and cerebral blood flow to the level exceeding 100% of baseline. This hyperperfusion model possesses several advantages including high phenotype reproducibility, low experimental failure rate and low animal mortality rate. It can be applied to study carotid stenosis or ischemia/reperfusion injury in rats. PMID- 26770336 TI - Rs5498 polymorphism may be a risk factor for coronary heart disease in Chinese population: evidence from a meta-analysis involving 5537 subjects. AB - Despite large numbers of studies from Chinese population related to the association between rs5498 polymorphism and coronary heart disease (CHD) risk, the results are inconsistent probably due to the difference in the nationalities. To further evaluate the impact of the rs5498 polymorphism on CHD risk of different nationalities population, we performed this meta-analysis. We comprehensively searched the eligible studies for the present meta-analysis through China National Knowledge Infrastructure (CNKI), PubMed, EMBASE databases. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were obtained to evaluate the strength of the association between rs5498 polymorphism and CHD risk. Finally, a total of 18 studies including 5537 subjects met the inclusion criteria. The pooled result showed that the rs5498 polymorphism was significantly associated with an increased risk of CHD in allele comparison model (OR=1.43, 95% CI=1.17-1.73, P=0.000), homozygote model (OR=1.23, 95% CI=1.03-1.46, P=0.000), heterozygote model (OR=1.23, 95% CI=1.03-1.46, P=0.018), dominant model (OR=1.45, 95% CI=1.21-1.74, P=0.001) and recessive model (OR=2.17, 95% CI=1.70-2.77, P=0.002). But subgroup analysis only supported the results from data of Han and Zhuang population in South China and North China. We did not find any evidences revealing some relationship between them in the Uygur population of Northwest China. Totally, the results of our meta-analysis indicate that the rs5498 polymorphism may be associated with coronary heart disease in Han and Zhuang population but not in Uyghur population. A large number of well-designed and multiracial studies should be conducted to re-evaluate the relationship. PMID- 26770337 TI - Influence of cell printing on biological characters of chondrocytes. AB - OBJECTIVE: To establish a two-dimensional biological printing technique of chondrocytes and compare the difference of related biological characters between printed chondrocytes and unprinted cells so as to control the cell transfer process and keep cell viability after printing. METHODS: Primary chondrocytes were obtained from human mature and fetal cartilage tissues and then were regularly sub-cultured to harvest cells at passage 2 (P2), which were adjusted to the single cell suspension at a density of 1*10(6)/mL. The experiment was divided into 2 groups: experimental group P2 chondrocytes were transferred by rapid prototype biological printer (driving voltage value 50 V, interval in x-axis 300 MUm, interval in y-axis 1500 MUm). Afterwards Live/Dead viability Kit and flow cytometry were respectively adopted to detect cell viability; CCK-8 Kit was adopted to detect cell proliferation viability; immunocytochemistry, immunofluorescence and RT-PCR was employed to identify related markers of chondrocytes; control group steps were the same as the printing group except that cell suspension received no printing. RESULTS: Fluorescence microscopy and flow cytometry analyses showed that there was no significant difference between experimental group and control group in terms of cell viability. After 7-day in vitro culture, control group exhibited higher O.D values than experimental group from 2nd day to 7th day but there was no distinct difference between these two groups (P>0.05). Inverted microscope observation demonstrated that the morphology of these two groups had no significant difference either. Similarly, Immunocytochemistry, immunofluorescence and RT-PCR assays also showed that there was no significant difference in the protein and gene expression of type II collagen and aggrecan between these two groups (P>0.05). Conclusion Cell printing has no distinctly negative effect on cell vitality, proliferation and phenotype of chondrocytes. Biological printing technique may provide a novel approach for realizing the oriented, quantificational and regular distribution of chondrocytes in a two-dimensional plane and lay the foundation for the construction of three dimensional cell printing or even organ printing system. PMID- 26770338 TI - The CDKN2A-CDKN2B rs4977756 polymorphism and glioma risk: a meta-analysis. AB - The association between the rs4977756 single nucleotide polymorphism (SNP) and glioma risk has been studied, but these studies have yielded conflicting results. In order to explore this association, we performed a meta-analysis. A comprehensive literature search was performed using PubMed and EMBASE database. Six articles including 12 case-control studies in English with 12022 controls and 6871 cases were eligible for the meta-analysis. Subgroup analyses were conducted by ethnicity and source of controls. Our meta-analysis found that rs4977756 polymorphism was associated with glioma risks in homozygote, heterozygote, dominant, recessive and additive genetic models (GG versus AA: OR=1.55, 95% CI=1.42-1.69, Ph=0.996, I(2)=0.0%; AG versus AA: OR=1.20, 95% CI=1.12-1.28, Ph=0.934, I(2)=0.0%; recessive model: OR=1.39, 95% CI=1.28-1.50, Ph=0.995, I(2)=0.0%; dominant model: OR=1.29, 95% CI=1.21-1.37, Ph=0.923, I(2)=0.0%; additive model: OR=1.24, 95% CI=1.19-1.30, Ph=0.966, I(2)=0.0%). Moreover, our results suggested that CDKN2A-CDKN2B rs4977756 polymorphism was associated with a notable increased risk of glioma in Europeans. However, in Asians, we could not come to a conclusion because of lack of studies. Sensitivity analysis showed the omission of any study made no significant difference. No evidence of publication bias was produced. Our meta-analysis suggested that rs4977756 polymorphism was associated with increased risk of glioma. Moreover, additional studies should be further investigated to draw a more accurate conclusion. PMID- 26770339 TI - Up-regulation of Dectin-1 in airway epithelial cells promotes mice defense against invasive pulmonary aspergillosis. AB - INTRODUCTION: With the growing number of immunocompromised patients, the incidence of invasive pulmonary aspergillosis increases. Innate immunity plays a significant role in defensing against fungal infection. Airway epithelial cells induce immune responses like the production of cytokine and chemokine via Dectin 1 signaling pathway in response to Aspergillus fumigatus. Thus, we hypothesized that up-regulation of Dectin-1 on airway epithelium cells would promote the defense against A. fumigatus. METHODS: We designed an adenoviral vector encoding full-length Dectin-1, and then transfected it into mice airway epithelial cells via intratracheal injection before the invasion of A. fumigatus. Transfect mice model was verified by using real-time PCR and immunohistochemistry. And also, we studied the effects of up-regulation of Dectin-1 on the production of proinflammatory cytokines, histological changes, fungal burden and survival rate during A. fumigatus infection. RESULTS: The expression level of Dectin-1 in lungs of mice with Dectin-1 recombinant adenoviral vector significantly increased. And also, the mice had higher production of TNF-alpha, GM-CSF and IL-1beta, lower fungal burden, more recruitment of neutrophils into lungs and higher survival rate in response to A. fumigatus infection. CONCLUSIONS: The administration of Dectin-1 recombinant adenoviral vector through trachea can elevate the expression of Dectin-1 on airway epithelium, and also, its function during the course of A. fumigatus infection was demonstrated. PMID- 26770340 TI - What were the advantages of microendoscopic discectomy for lumbar disc herniation comparing with open discectomy: a meta-analysis? AB - The purpose of this study was to compare the safety and efficacy of micro endoscopic discectomy (MED) and open discectomy (OD) for lubmar disc herniation (LDH). Randomised controlled trials (RCTs) comparing MED with OD for LDH were searched comprehensively in PubMed, EMBASE, the Cochrane Library. Relevant studies retrieved, data extracted and the quality of included studies were independently performed by two authors. RevMan software (Version 5.2.0) was used to analyse and synthesis relevant data of the included studies. Nine RCTs involving 774 patients were obtained and reported the relevant outcome measures. Compared with OD group, there were significant difference in the general operation indicators including operation time, blood loss, site of incision, hospital stay and time of return to work, biochemical indexes including C reactive protein (CRP) and interleukin-6 (IL-6) in MED group. Meanwhile, there were no difference in effective rate, complication including total complications, dural leaks occurred and recurrence of the disc herniation, compared MED group with OD group. MED had slighter trauma, milder blood loss and shorter healing time than OD. The results demonstrated MED has great efficacy and safety comparable to OD. So we think that MED can be used routinely for LDH patients, especially the patients of old and intolerable major surgery. Meanwhile, it is necessary for surgeon to master indication and contraindication of MED and improve the operative technique. PMID- 26770341 TI - Quantitative analysis of tightness of nuchal cord and its relationship with fetal intrauterine distress. AB - The perinatal outcomes of pregnancies with nuchal cord (NC) are uncertain and reports disagree about the incidence of cesarean section due to NC. Variable tightness of the NC may be a contributor to this controversy. The study was to examine whether the tightness of NC affect fetal intrauterine distress by determining valuable ultrasonic indicators. Total 149 singleton pregnancies between 36 and 41 weeks without pregnancy complications were recruited. The pregnant women, whose fetuses have NC, formed the study group and the others made up the control group. The ratio of peak systolic velocity and end diastolic velocity (S/D), pulsatility index (PI) of fetal umbilical artery (UA), middle cerebral artery (MCA) and renal artery (RA) were examed by ultrasound. We found that mean levels of S/D and PI of RA and the incidence of fetal distress and intervention rate during delivery were higher in the study group than those in control group (p<0.05). In contrast, the levels of RI of RA and flow spectrum parameters of UA and MCA showed no difference between the two groups (p>0.05). In addition, as compared with the control group, the mean levels of S/D and PI of RA, S/D of UA were higher in the tight subgroup (p<0.05). The S/D of UA and S/D, PI of RA were increased with D and A1/A, but there were no significant correlations between D or A1/A and fetal distress in study group. In summary, NC affects the level of flow spectrum parameters of RA and UA, especially in tight NC cases, which increases the rate of fetal intrauterine distress. A1/A% and D are valuable ultrasonographic indicator to describe the tightness of NC and predict the fetal hemodynamics, but they could not predict the fetal distress in our study. PMID- 26770342 TI - Efficacy and safety of rituximab combined with chemotherapy in the treatment of diffuse large B-cell lymphoma: a meta-analysis. AB - The aim of this study is to systematically evaluate the safety and efficacy of rituximab plus CHOP (R-CHOP combined regimen) in patients with previously untreated diffuse large B cell lymphoma (DLBCL). Electronic database were searched for randomized-controlled studies only comparing R-CHOP to CHOP standard alone in patients with untreated DLBCL were included. The risk ratios (RRs) with their 95% corresponding intervals (95% CI) were employed to estimate the efficacy of overall response (OR), complete response (CR), risk of dying and relapse rate in followed-up period. Total ten case-control studies containing 2941 patients met the inclusion criteria. The addition of R to standard CHOP were showed to increase the proportion of CR (RR=1.23, 95% CI=1.13-1.35, P<0.00001) and OR (RR=1.39, 95% CI=1.24-1.55, P<0.00001) in a fixed-effect model, indicating that rituximab combined with CHOP regimen is efficacy than CHOP alone. It did not increase the overall risk of dying as a consequence of infection (RR=0.79, 95% CI=0.55-1.13, P=0.20). Furthermore, the relapse rates is significantly lower in R CHOP (RR=0.52, 95% CI=0.38-0.71, P<0.0001). The adverse effects were also not significant (P>0.05). In summary, R-CHOP regimen is superior to standard CHOP in terms of overall response and complete response. It does not increase the incidence of adverse effects. However, more studies concerning different age groups and special patients are needed to discuss the potential role of R in DLBCL. PMID- 26770343 TI - Classification of non-allergic rhinitis based on inflammatory characteristics. AB - The study aims to investigate nasal and lower airway inflammation in patients with non-allergic rhinitis (NAR), and to discuss a method of NAR classification based on inflammatory characteristics and its clinical significance. A total of 117 NAR patients admitted to our hospital from June 2010 to June 2011 were enrolled in this study, 162 healthy participants were employed as healthy controls. Nasal and lower airway inflammation were evaluated using the skin prick test, nasal and pulmonary visual analogue scale scoring, cell blood count, nasal douche, induced sputum assay, nasal provocation test, and bronchial provocation test. Compared to the healthy controls, NAR patients have significant higher levels of nasal douche eosinophils, more induced sputum eosinophils as well as blood eosinophils, and higher rates of nasal and bronchial provocation. Patient with high level of eosinophil in nasal douch tended to be with higher concentrations of eosinophils in induced sputum. Scores on the nasal and bronchial provocation tests are also correlated to each other. Among all NAR patients, 28 cases (23.9%) were with no abnormality detectable by eosinophil measurement or a provocation test, 39 cases (33.3%) were with elevated levels of eosinophils, and 50 cases (42.7%) exhibited a nasal provocation response. Based on this, all studied NAR cases were classified into 3 groups: non-specific type (group A, 28/117), increased eosinophil type (group B, 39/117), and hyper reactive type (group C, 50/117). Some NAR cases may be considered as systemic inflammatory disease characterized by increased nasal eosinophil and nasal hyperreactivity. PMID- 26770344 TI - Brucella outer membrane protein Omp25 induces microglial cells in vitro to secrete inflammatory cytokines and inhibit apoptosis. AB - Omp25 protein, an outer membrane protein of Brucella, can cause damage to the central nervous system. As one type of macrophage, microglial cells play a role in immune surveillance and immune protection in the central nervous system; therefore, they are major targets of bacterial attack. The present study examined BV2 mouse microglial cells that were stimulated with different concentrations of Omp25 recombinant protein, and the secretion of inflammatory cytokines by the BV2 cells as well as their level of apoptosis were observed. The objective of the study was to preliminarily illustrate the possible mechanism that Omp25 uses to damage the central nervous system. Mouse BV2 microglial cells were incubated with different concentrations of Omp25 for 24 h, and an enzyme-linked immunosorbent assay (ELISA) was used to detect the secretion of the inflammatory cytokines interleukin (IL)-6, tumour necrosis factor (TNF)-alpha and HMGB1 (high mobility group box-1 protein); reverse transcription polymerase chain reaction (RT-PCR) was used to detect the expression of TLR4 (Toll-like receptor 4) mRNA; Annexin V fluorescein isothiocyanate (FITC) double staining was used to detect apoptosis in the BV2 cells. After the BV2 cells were stimulated with different concentrations of Omp25, the levels of IL-6, TNF-alpha and HMGB1 was increased, and the difference was statistically significant compared with the control group (P<0.05). The secretion of TNF-alpha and HMGB1 showed a trend toward an initial increase followed by a decrease. The expression level of TLR4 mRNA was increased. Omp25 protein can inhibit apoptosis in BV2 cells. The outer membrane protein Omp25 of Brucella promotes microglial cells to secrete inflammatory cytokines and inhibit apoptosis. TLR4 may be involved in the immune response of the central nervous system to Brucella infection. PMID- 26770345 TI - Efficiency of muscle strength training on motor function in patients with coronary artery disease: a meta-analysis. AB - BACKGROUND: Existing literature has shown that patients with coronary artery disease (CAD) can benefit greatly from the strength training; therefore, the strength training should play a more important role in cardiac rehabilitation. However, the medical community may still have conservation to apply the strength training owing to no comprehensive study so far to compare the effectiveness of the strength training to the other trainings, such as aerobic training. OBJECTIVE: To evaluate the effect of strength training on motor function in patients with CAD. METHODS: Published articles from the earliest date available to July 2015 were identified using electronic searches. Two reviewers selected independently relevant randomized controlled trials (RCTs) investigating exercise program with strength training versus control interventions (exercise without strength training, including aerobic training and no exercise group) for the treatment of CAD patients. We examined effects of exercise with strength training versus control interventions on peak oxygen uptake (VO2peak), duration of exercise test and muscle strength. Two reviewers extracted data independently. RESULTS: Twenty seven trials that represented 1151 participants passed the selection criteria and were evaluated for the effects of strength training in CAD patients. For improving VO2peak [SMD (95%CI) = 0.58 (0.11, 1.06)] and muscle strength [upper limb, SMD (95% CI) =0.44 (0.34, 0.55); lower limb, SMD (95% CI) =0.33 (0.16, 0.50)], exercise program with strength training were significantly more effective than one without it. But there is no significantly difference on duration of exercise test [SMD (95%CI) = 0.17 (-0.04, 0.39)] in strength training group than in control group. CONCLUSIONS: We conclude strength training is effective in improving muscle strength and VO2peak, in CAD patients, when compared to patients with control group. Furthermore, our evaluations suggest that strength training does not compromise clinical trial completion or safety. PMID- 26770347 TI - DC targeting DNA vaccines induce protective and therapeutic antitumor immunity in mice. AB - BACKGROUND: Anti-CD11c antibodies target to the CD11c receptor that mediates antigen presentation to T cells by dendritic cells (DCs). To exploit these properties for immunization purposes, we obtained DC-targeting DNA vaccines by fusing tumor-associated antigen HER2/neu ectodomain to single chain antibody fragment (scFv) from N418 (scFv(N418)), a monoclonal antibody binding the mouse DC-restricted surface molecule CD11c, and explored its antitumoral efficacy and underlying mechanisms in mouse breast cancer models. METHODS: Induction of humoral and cellular immune responses and antitumoral activity of the DNA vaccines were tested in transplantable HER2/neu-expressing murine tumor models and in transgenic BALB-neuT mice developing spontaneous Neu-driven mammary carcinomas. RESULTS: Upon injection of the breast tumor cell line D2F2/E2 (stably expressing human wild-type HER2), scFv(N418)-HER2 immunized mice were protected against tumor growth. Even more important for clinical applications, we were able to substantially slow the growth of implanted D2F2/E2 cells by injection of scFv(N418)-HER2 conjugates into tumor bearing hosts. The existing tumors were eradicated by treatment with scFv(N418)-HER2 combined with low-dose cyclophosphamide (CTX), which can make a temporary regulatory T cells (Treg) depletion. What's more, in combination with the low-dose CTX, vaccination with scFv(N418)-neu significantly retarded the development of spontaneous mammary carcinomas in transgenic BALB-neuT mice. CONCLUSION: Our results show that DNA vaccine which targeting of dendritic cells in situ by the means of antibody antigen conjugates may be a novel way to induce long-lasting antitumor immunity. PMID- 26770346 TI - Effects of diclofenac sodium and octreotide on treatment of caerulein-induced acute pancreatitis in mice. AB - BACKGROUND: Research continues to develop novel therapeutic modalities that particularly focus on the pathogenesis of acute pancreatitis. This study aimed to assess the effects of diclofenac sodium and octreotide, alone or in combination, on pancreatic enzymes, pancreatic myeloperoxidase activity, histopathology and apoptosis of pancreas cells, using a model of experimentally induced acute pancreatitis. OBJECTIVES: We aimed to demonstrate effects of diclofenac sodium, octreotide and their combined use on pancreatic enzymes, activity of pancreatic myeloperoxidase (MPO) activity, histopathology and apoptosis of pancreas on treatment of caerulin-induced experimental acute pancreatitis. MATERIALS AND METHODS: Caerulin-induced acute pancreatitis model was created using a total of 58 male BALB-C mice of 25 gr in seven groups. Serum amylase, lipase levels and pancreatic myeloperoxidase activity were examined as well as apoptotic values in pancreatic acinar cells through TUNNEL method. Histopathology of pancreas was evaluated for presence of edema, hemorrhage, parenchymal necrosis, fat necrosis, leukocyte infiltration, and fibrosis. RESULTS: In the diclofenac sodium group, apoptotic values in the pancreatic acinar cells were found to be statistically lower than in the acute pancreatitis group in terms of parenchymal necrosis and hemorrhage scores (P = 0.007, P = 0.002, and P = 0.052, respectively). No statistically significant differences were found in serum level of amylase, lipase, pancreatic myeloperoxidase activity and the other histopathological scores (P > 0.05). CONCLUSION: Diclofenac sodium, a cost-effective agent with a favorable side-effect profile, may represent a novel therapeutic agent for the treatment of acute pancreatitis. Findings of this study suggest a better efficacy for diclofenac sodium monotherapy as compared to octreotide alone or octreotide/diclofenac combination. PMID- 26770348 TI - Differential diagnosis between Crohn's disease and intestinal tuberculosis using integrated parameters including clinical manifestations, T-SPOT, endoscopy and CT enterography. AB - BACKGROUND: The aim of the study was to evaluate clinical manifestations, T-SPOT, endoscopy and CT enterography to differentiate Crohn's disease (CD) from intestinal tuberculosis (ITB). METHODS: 128 in patients with suspected CD and ITB were prospectively enrolled in the study. Demographic, clinical, laboratory, endoscopic and CT enterographic data were collected. After treatment for 6 months, when a definite diagnosis was reached, the differential diagnostic value of each parameter was analyzed. Multivariable logistic regression was used to analyze further, parameters of statistical significance to establish a mathematical regression equation. Receiver operating characteristic curves were plotted. RESULTS: Clinical parameters helpful in differentiating CD from ITB included diarrhea, night sweat and perianal disease. Endoscopic parameters were useful in differentiating CD from ITB including transverse ulcers, longitudinal ulcers, rodent-like ulcers and patulous ileocecal valve. CT enterographic parameters aided the identification of the two conditions. The sensitivity, specificity, accuracy, positive predictive value and negative predictive value of a mathematical regression model established for 6 parameters of clinical endoscopy and CT enterography were 97.8%, 96.8%, 97.6%, 98.9% and 93.7% respectively, whereas those for T-SPOT were 96.8%, 91.3%, 92.7%, 78.9% and 98.8% respectively. CONCLUSIONS: T-SPOT is useful to exclude a diagnosis of ITB. Differentiating CD from ITB is a difficult clinical problem that requires a consideration of clinical, T-SPOT, endoscopic and CT enterographic parameters for accurate diagnosis. PMID- 26770349 TI - Preparation and brain delivery of nasal solid lipid nanoparticles of quetiapine fumarate in situ gel in rat model of schizophrenia. AB - To investigate the brain delivery in rat by nasal Quetiapine fumarate (QF) loaded with solid lipid nanoparticles in situ gel (QF-SLN-gel). QF-SLN-gel was prepared through micro-emulsion technique. The rat model of schizophrenia was established by intraperitoneal injection of (+)-MK-801, evaluated by stereotypic behavior, Mori's Water Maze (MWM) test and hematoxylin and eosin (HE) staining of hippocampus. The animals were administrated with QF via oral, nasal or tail vein approach and the concentration of QF in blood and brain was determined using high performance liquid chromatography (HPLC). The QF-SLN-gel was even and transparent, having size of 117.8+/-2.67 d.nm, potential of 57.2+/-0.24 mV and EF of 97.6+/-0.58%. After administration of QF-SLN-gel, the concentration of QF in blood and brain of rats in nasal QF-SLN-gel group was similar with that of rats in tail vein QF group, but significantly higher than that of rats in oral QF group. The hippocampal morphology changes induced by (+)-MK-801 were ameliorated by QF, with advantage of nasal QF-SLN-gel over tail vein QF. The nasal QF-SLN-gel had stable and good brain delivery and could ameliorate the damages in rat model of schizophrenia induced by (+)-MK-801. PMID- 26770350 TI - Benzyl isothiocyanate inhibits breast cancer cell tumorigenesis via repression of the FoxH1-Mediated Wnt/beta-catenin pathway. AB - The mechanisms underlying the growth inhibitory effect of Benzyl isothiocyanate (BITC) against breast cancer are still not fully understood. Therefore, we further investigated the mechanism in BITC triggering breast cancer. In the present study, we found that the overexpression of FOXH1 in breast cancers tissues and cells, and FOXH1 significantly promoted cell proliferation, invasion and tumorigenesis in vitro. FOXH1 significantly increased the expression levels of beta-catenin, cyclinD1, and c-myc proteins in breast cancer cells. Furthermore, sibeta-catenin reduced FOXH1 promotion of cell proliferation and invasion in breast cancer cells. Taken together, these results suggest that FOXH1 promoted breast cancer cell growth and invasion by potentiating the Wnt/beta catenin pathway, suggesting that FOXH1 may be a potential molecular target for breast cancer prevention and therapy. Furthermore, BITC treatment has remarkable effect on the expression level of FOXH1 and beta-catenin mRNA and protein in MCF 7 cells, MDA-MB-231 cells and SUM 159 cells. BITC treatment has an obvious significance on transcriptional activity of FOXH1. Cell growth and invasion inhibition resulting from BITC exposure were significantly augmented by FoxH1 knockdown. In conclusion, the present study provides novel insights into the molecular circuitry of BITC-induced cell death involving FoxH1-mediated tumorigenesis. Thus, the present study provides a novel insight into the underlying mechanism of tumorigenesis in BITC triggering breast cancer, indicating the therapeutic potential of FOXH1 in the treatment of breast cancer. PMID- 26770351 TI - Tissue distribution model and pharmacokinetics of nuciferine based on UPLC-MS/MS and BP-ANN. AB - Nuciferine has shown remarkable biological activities and been considered as a promising drug. In this study, a sensitive and selective ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed and validated for determination of nuciferine in tissue and plasma. An electrospray ionization source was applied and operated in positive ion mode; multiple reactions monitoring (MRM) mode was used for quantification using target fragment ions m/z 296.0->265.1 for nuciferine, and m/z 322.0->307.0 for berberrubine internal standard (IS). Based on the UPLC-MS/MS method, the tissue distribution profile of nuciferine in mice and plasma pharmacokinetics in rat were studied. The results showed nuciferine was absorbed through intestinal tract and distributed into tissues rapidly. The bioavailability of nuciferine was identified at 17.9%. It can across through blood brain barrier, the concentrations in liver and kidney are highest, then followed by spleen, lung heart and brain. Nuciferine is eliminated quickly in the tissues and plasma, the t1/2 within 5 hour. The concentrations in these tissues are correlated to each other, and can be predicted by a back-propagation artificial neural network model. PMID- 26770352 TI - Association of interleukin-17 gene polymorphisms and Helicobacter pylori infection with gastric cancer susceptibility: a cumulative and comprehensive meta analysis. AB - BACKGROUND: The association between Interleukin-17(IL-17) gene polymorphisms and Helicobacter pylori (H. pylori) infection and gastric cancer susceptibility were inconsistent. We therefore performed a comprehensive meta-analysis about all three genetic polymorphisms of IL-17 to derive a more precise estimation. METHODS: PubMed, Embase, CNKI and Wanfang databases were researched on the associations between IL-17A rs2275913G>A, rs3748067C>T and IL-17F rs763780 T>C and gastric cancer risk. Odds ratio (OR) with a 95% confidence interval (CI) was applied to assess the relationships. Publication bias, sensitivity and cumulative analysis was conducted to guarantee the strength of meta-analysis. RESULTS: Overall, eleven related studies involving 4,478 cases and 5,612 controls were collected. Significantly increased risk between IL-17A rs2275913G>A polymorphism and gastric cancer were observed (A vs. G: OR = 1.22, 95% CI = 1.08-1.37, P<0.01, I(2) = 72.3%; AA vs. GG: OR = 1.55, 95% CI = 1.21-1.99, P<0.01, I(2) = 74.3%; GA + AA vs. GG: OR = 1.19, 95% CI = 1.05-1.39, P<0.01, I(2) = 48.2%; AA vs. GG + GA: OR = 1.50, 95% CI = 1.16-1.95, P<0.01, I(2) = 81.2%). For IL-17F rs3748067C>T and rs763780 T>C polymorphisms, only few significantly increased risk could be found in genetic models. Moreover, H. pylori infection also be proved to increase the risk of gastric cancer combined with rs3748067C>T mutation. CONCLUSIONS: Our meta analysis suggests that the three IL-17 polymorphisms were associated with a significantly increased risk of gastric cancer, especially in Chinese. PMID- 26770353 TI - Nucleostemin regulates proliferation and migration of gastric cancer and correlates with its malignancy. AB - OBJECTIVE: The aim of this study was to investigate the effects of nucleostemin (NS) knocking down in SGC- 7901 gastric cancer cell line and investigates its correlation with the metastasis and TNM stage ingastric cancer (GC) patients. METHODS: NS expression was assessed using immunohistochemistry in 421 patients with GC. The correlation between NS expression, clinicopathological features and prognosis was analyzed. NS gene silencing was performed using a specific small interfering RNA (NS-siRNA). The gene expression level of NS was evaluated by PCR. The viability and growth rate of SGC-7901 cells were determined by trypan blue exclusion test. Cell cycle distribution of the cells was analyzed by flow cytometry. RESULTS: High NS expression was correlated with node metastasis, distant metastasis and TNM stage. Kaplan-Meier survival analysis revealed that patients with low NS expression had significantly longer survival than those with high NS expression. Moreover, our results showed that NS knocking down inhibited proliferation and viability of SGC-7901 cells in a time-dependent manner. Cell cycle studies revealed that NS depletion resulted in G1 cell cycle arrest at short times of transfection (24 h) followed with apoptosis at longer times (48 and 72 h), suggest that post-G1 arrest apoptosis is occurred in SGC-7901 cells. CONCLUSION: Overall, these results point to essential role of NS in SGC-7901 cells, thus, this gene might be considered as a promising target for treatment of GC. PMID- 26770354 TI - Application of intelligent optimal kV scanning technology (CARE kV) in dual source computed tomography (DSCT) coronary angiography. AB - This study aims to evaluate the applications and values of dual-source computed tomography (DSCT) intelligent optimal kV scanning technology (CARE kV) in coronary CT angiography (CCTA). 150 patients with normal body mass index were performed DSCT coronary angiography, then randomly divided into the "Semi", 120,100 and 80 kV Group, and the 2 "on" groups, with 30 patients in each group. The first 5 groups used the reference voltage as 120 kV, and the reference current as 400 mAs, while the other group used the reference voltage as 100 kV, and the reference current as 400 mAs. The image quality, average CT value, image noise, signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR) and radiation dose were comparatively analyzed among the 5 groups. The image quality scores of the five groups showed no significant difference (P > 0.05); the average CT values and image noises had significance (P < 0.05), while SNR and CNR showed no significant difference (P > 0.05). The 80 kV group showed the biggest noise, with the CT value as 700 HU, while the radiation dose was the lowest, followed by the on group. As for the patients with normal body mass index (BMI), CARE kV-"on" could obtain high-quality images and lower radiation dose for CCTA, while the operation was simple and convenient. PMID- 26770355 TI - Controlled attenuation parameter for assessment of hepatic steatosis grades: a diagnostic meta-analysis. AB - AIM: to evaluate the performance and accuracy of Controlled attenuation parameter CAP for hepatic steatosis detection. METHODS: PubMed, EBSCO, Elsevier Science, Ovid, and Wiley were selected to search studies until August 31, 2014. Quality Assessment of Diagnostic Accuracy Studies checklist was used to assess the quality of included studies. Heterogeneity was evaluated using Q test. Sensitivity, specificity, diagnostic odds ratio (DOR), and the area under curve (AUC) with its 95% confidence intervals (CIs) were calculated to evaluate the accuracy of CAP for assessment of hepatic steatosis stage (>= S1, >= S2 and >= S3). RESULTS: Totally 11 studies (13 cohorts) with high methodological qualities were identified. The summary point estimations with 95% CIs of sensitivity, specificity, AUC and DORs were 0.78 (0.71, 0.84), 0.79 (0.70, 0.86), 0.86 (0.82, 0.88), and 14 (7, 27) for >= S1; 0.82 (0.74, 0.88), 0.79 (0.73, 0.85), 0.88 (0.85, 0.90) and 18 (10, 30) for >= S2; 0.86 (0.82, 0.89), 0.89 (0.86, 0.92), 0.94 (0.91, 0.96) and 51 (35, 76) for >= S3. Significant heterogeneity was found among the studies in >= S1 and >= S3. Threshold effect was existed in >= S3, but not in >= S1 and >= S2. Publication bias was not existed in >= S1 and >= S2 except >= S3. CONCLUSION: CAP provides good sensitivity and specificity for detection of >= S1, >= S2, and >= S3 steatosis. However, future studies with large samples are still necessary to confirm the clinical application. PMID- 26770356 TI - Association between Cytotoxic T-lymphocyte antigen 4 (CTLA-4) +49 G>A (rs231775) polymorphism and esophageal cancer: from a case-control study to a meta-analysis. AB - The aim of this study was to evaluate the association between CTLA-4 +49 G>A polymorphism and esophageal cancer (EC) susceptibility in a hospital based case control study and a subsequent meta-analysis. We implemented genotyping analyses for CTLA-4 +49 G>A polymorphism with 629 esophageal squamous cell carcinoma cases and 686 controls in a Chinese Han population. Polymerase chain reaction ligase detection reaction (PCR-LDR) method was used to identify genotypes of CTLA-4 +49 G>A polymorphism. We first assessed the association between CTLA-4 +49 G>A polymorphism and EC risk in a hospital based case-control study, and then performed a comprehensive meta-analysis to derive a more precise estimation. Our results demonstrated that CTLA-4 +49 G>A polymorphism was not associated with EC risk. This case-control study and further meta-analysis, failed to identify the association between CTLA-4 +49 G>A polymorphism and EC risk. And additional, further well designed studies with large sample sizes and detailed gene environment data are required. PMID- 26770357 TI - Association between injury to the retinacula of Weitbrecht and femoral neck fractures: anatomical and clinical observations. AB - Currently, there is no objective indicator for surgical procedures in elderly patients with femoral neck fractures. The purpose of this study was to determine the severity of damage to the retinacula of Weitbrecht based on the type of femoral neck fracture, anatomical and clinical observations. Data from 44 patients treated with artificial femoral head replacement were analyzed for the association between Garden type fracture and severity of injury to Weitbrecht's retinacula. Additionally, 18 cases (Pauwels type III fracture) after Watson-Jones surgical approach and internal fixations were used to investigate the bone healing and femoral head necrosis. Among 44 patients (Garden type was III-IV, 79.6%), significant associations were found between Garden type fracture and lateral (P < 0.001), anterior (P = 0.045), and medial (P = 0.004) retinacular injury. Significant positive Spearman correlation coefficients between Garden type and the severity of injury to Weitbrecht's retinacula were Rho = 0.561 with P < 0.001 for lateral, Rho = 0.338 with P = 0.025 for anterior, and Rho = 0.469 with P = 0.001 for medial retinacula. Additionally, 4 out of 18 Pauwels type III fracture cases were observed severe damages on Weitbrecht's retinacula and resulting bone necrosis. In conclusion, this study provided the anatomical and histological correlations between fracture displacement and degree of retinacula injury. PMID- 26770358 TI - Fentanyl inhibits cell viability in human pancreatic cancer cell line and tumor growth in pancreatic cancer cell-transplanted mice. AB - Pancreatic cancer is a kind of devastating disease with a high mortality rate. Fentanyl has been widely applied to anesthesia and analgesia in pancreatic cancer therapy, and is also demonstrated to inhibit the growth of some kinds of cancer cells in existed studies. To investigate the functions of fentanyl in pancreatic cancer, we conducted a series of in vivo and in vitro experiments using human pancreatic cancer cells SW1990 and fentanyl treatment. The cells were transplanted to BALB/c nude mice to generate pancreatic tumor for monitoring tumor growth. Viability, apoptosis, migration and invasion, and cell cycle of SW1990 cells were also analyzed. To reveal the functional mechanisms of fentanyl, the expression changes of factors in these cellular activities were detected. Results showed a significant inhibition of pancreatic tumor growth in the fentanyl-treated group. Fentanyl also inhibited viability of SW1990 cells in vitro. Detailed results showed fentanyl led to promoted cell apoptosis via arresting cells in G0/G1 phase. It also suppressed cell migration and invasion. Further proofs indicated that the factors related to cell apoptosis (Bcl-2, p53 and Caspase-3), cell cycle (p21, Cyclin D1 and CDK4) and epithelial-mesenchymal transition (E-cadherin, Vimentin and alpha-SMA) showed the corresponding expression changes. Fentanyl might execute its functions via the suppressed MAPK pathways, since the key factors, p38, ERK1/2 and JNK were all down-regulated by fentanyl. This study indicated fentanyl could inhibit viability and growth of pancreatic cancer cells, providing a possible strategy for pancreatic cancer treatment. PMID- 26770359 TI - Manifestation of the Se, Cd and Mo levels in different components of the peripheral blood of Sprague-Dawley rats poisoned via the respiratory tract. AB - This study aimed to explore the effects of exogenous element exposure via the respiratory tract on the Se, Cd and Mo concentrations in different components of the peripheral blood in rats as well as to determine the correlations of the three trace elements concentrations among the components. The Sprague-Dawley rats were randomly divided into a control group and several experimental groups treated with different doses. The rats were exposed to a mixed trace element solution through 10 days of intratracheal instillation. The whole blood of all rats was collected and separated into three parts with Percoll density gradient centrifugation. The Se, Cd and Mo levels in whole blood, plasma, red blood cells (RBCs) and peripheral blood mononuclear cells (PBMCs) were determined by inductively coupled plasma mass spectrometry. The concentrations of the three trace elements increased together with the increase of the given doses (P<0.05), except Cd and Mo in the PBMCs. The three trace elements lacked linearity with the exposure doses in the PBMCs (r, 0.249-0.508), while the opposite was the case for the other components of the peripheral blood (r, 0.806-0.934). The correlation coefficients were higher (0.842-0.962) among the whole blood, plasma and RBCs than between PBMCs and other components, such as Se (0.376-0.529), Cd (0.495 0.604) and, especially, Mo (0.160-0.257). In conclusion, PBMCs might provide information about endogenous factors, and whole blood could more accurately reflect the effects of exogenous factors compared to other blood components. PMID- 26770360 TI - Association of MTHFR genetic polymorphisms with venous thromboembolism in Uyghur population in Xinjiang, China. AB - BACKGROUND: The aim of this study was to reveal the association between Methylene tetrahydrofolate reductase (MTHFR) gene mutations (C677T, A1298C and C1317T) and risk of venous thromboembolism (VTE) in Han and Uyghur population in Xinjiang. MATERIAL AND METHOD: We conducted a case control study composed of 246 cases, including 86 Uyghur and 160 Han ethnic diagnosed VTE were admitted in the First Affiliated Hospital of Xinjiang Medical University between January 2008 to December 2012, and 292 population including 122 Uyghur ethnic and 170 Han ethnic were studied as controls. To detect the polymorphism of MTHFR gene C677T, A1298T, and C1317T, Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was applied. Fluorescence polarization immunoassay was adopted to determine the plasma levels Homocysteine (Hcy), folic acid and vitaminB12 (VitB12). The association of the polymorphism of MTHFR and levels Hcy, folic acid and VitB12 with VTE was analyzed. RESULTS: The MTHFR gene C677T genotypes distribution in Uyghur VTE patients and control groups were: TT (27.91% vs. 12.29%), CT (41.86% vs. 52.46%) and CC (30.23% vs. 35.25%), respectively; and in Han VTE patients and control groups were: TT (27.49% vs. 14.71%), CT (44.38% vs. 53.53%) and CC (28.13% vs. 31.76%), respectively, and there were significant differences in TT genotype of MTHFRC677T between VTE patients and controls in both Uyghur and Han ethnic (Uyghur: x(2)=8.070, P=0.005; Han: x(2)=8.159, P=0.004). However, there were no significant differences in the MTHFR gene A1298T and C1317T genotyping distribution frequency in Uygur and Han ethnic between VTE patients and controls (P>0.05). Plasma levels of Hcy in MTHFR gene TT genotype were statistically higher than CT and CC genotype (P<0.05). After adjusting for age, gender, smoking, hypertension, hyperlipidemia, diabetes and MTHFR genotype for plasma Hcy levels, multifactor logistic regression analysis showed (OR=1.025, 95% CI 1.003-1.046, P=0.024) and obesity (OR=4.660, 95% CI 1.417-15.324, P=0.011) were independent risk factors for Uygur ethnic with VTE while plasma Hcy levels (OR=1.020, 95% CI 1.006-1.034, P=0.004) and smoking (OR=2.867, 95% CI 1.062 6.586, P=0.024) were independent risk factors for Han ethnic with VTE. CONCLUSIONS: Our finding supports significant role of MTHFR gene in VTE and evidence of genetically determined HHcy contribute a risk for VTE, and a smoker with tHcy has positive association with a risk of VTE. PMID- 26770361 TI - Heart calcium sensitizer on morbidity and mortality of high-risk surgical patients with MODS: systematic review and meta-analysis. AB - A total of 440 patients from 10 studies were included in a systematic review to evaluate the association between improved survivals from multiple organ dysfunction syndromes in patients undergoing surgical operation. Health Inter Network Initiatives (HINARI), MEDLINE and EMBASE were searched. Exclusion criteria were duplicate publications, non-human experimental studies, and no mortality data. The primary endpoint was postoperative mortality. Levosimendan was found to be associated with a reduction in postoperative mortality (11/235 [4.7%] in the levosimendan group v 26/205 [12.7%] in the control, odds ratio of 0.35 [0.18-0.71], P for effect as 0.003, P for heterogeneity 0.22, and I(2) as 27.4% (440 patients included), cardiac troponin release, and atrial fibrillation. No difference was found in terms of myocardial infarction, acute renal failure, time on mechanical ventilation, intensive care unit, and hospital stay. Calcium sensitizer for congestive heart failure; Levosimendan has cardioprotective effects that could result in a reduced operative mortality. PMID- 26770362 TI - A novel treatment strategy in hepatocellular carcinoma by down-regulation of histone deacetylase 1 expression using a shRNA lentiviral system. AB - Up to now, effective treatment methods for hepatocellular carcinoma (HCC), the fifth most prevalent cancer worldwide, have remained very limited. Previous studies have shown that histone deacetylase 1 (HDAC1) is highly expressed in HCC. The adoption of HDAC inhibitors in HCC treatment has also been studied, however, only moderate efficacy was observed. In the current study, using a clinically approved shRNA lentiviral system, we investigated whether the down-regulation of HDAC1 on mRNA level could suppress HCC progression. Our results showed that HDAC1 shRNA lentivirus infection could significantly reduce HCC Hep3B cell viability but have little impact on normal liver cell THLE-3. Cell cycle analysis revealed that HDAC1 shRNA lentivirus treatment could arrest HCC cells at G1 phase, which was probably achieved by modulating expression of cell cycle-related proteins including Cyclin D1, p21 and p27. Invasion assay showed that HDAC1 knock-down could dramatically reduce the invasiveness of HCC cells, which was correlated to the altered expression of some epithelial-mesenchymal transition related proteins including ZO-1, E-cadherin and Vimentin. Taken together, our findings have shown that down-regulation of HDAC1 on mRNA level using shRNA lentiviral system might be a novel alternative treatment strategy for HCC. PMID- 26770363 TI - Isoflurane attenuates murine lupus nephritis by inhibiting NLRP3 inflammasome activation. AB - The NOD-like receptor family-pyrin domain containing 3 (NLRP3) inflammasome is an essential factor in enhancing inflammation and autoimmunity. Anesthetic isoflurane (ISO) exerts a novel pharmacological action in anti-inflammation. However, whether ISO hinders the pathogenesis of lupus nephritis (LN) by inhibiting NLRP3 inflammasome activation remains unclear. In this study, 12-week old MRL/lpr and C57BL/6 mice were treated with and without 1.4% ISO for eight weeks. ISO administration significantly reduced mortality, serum anti-dsDNA level, renal immune complex deposition, and the ratio of Th17 to Treg cells in MRL/lpr mice. ISO treatment remarkably reduced the levels of blood urea nitrogen, proteinuria, interleukin (IL)-17, IL-1beta, and tumor necrosis factor-alpha, as well as the infiltration of macrophages. ISO also abrogated renal NLRP3 inflammasome formation and activation. These results suggest that ISO may be a promising therapeutic agent for LN partly because it restricts NLRP3 inflammasome activation. PMID- 26770364 TI - Association between the COMT 158 G/A polymorphism and lung cancer risk: a meta analysis. AB - Catechol-O-methyltransferase (COMT) 158 G/A gene polymorphism seem to associate with lung cancer, but the results are inconclusive. This meta-analysis aims to investigate the association between COMT 158 G/A gene polymorphism and lung cancer susceptibility. We searched PubMed, Embase, China National Knowledge Infrastructure (CNKI), VIP Chinese science and technology periodical database (VIP) and Wanfang databases up to March 25, 2015 for articles on the connection between the COMT 158 G/A polymorphism and the risk of lung cancer. Pooled odds ratio (OR) and corresponding 95% confidence interval (CI) were used to estimate the connection. STATA (Version 12.0) was adopted for data analysis. Overall, 6 articles of 7 studies including 2,293 cases and 2,768 controls were included in our meta-analysis. In general analysis, no significant association was found between COMT 158 G/A polymorphism and the risk of lung cancer (AA + AG vs. GG: OR 1.14, 95% CI 0.90-1.44, P=0.28). However, in subgroup analysis of different method of genotyping, we found significant increase of lung cancer risk (OR 1.30, 95% CI 1.04-1.62, I(2)=61.5%, P=0.02), also there was significant association between COMT 158 G/A polymorphism and the risk of lung cancer in Chinese non smoker women of unsorted cancer type (OR 1.48, 95% CI 1.24-1.77, I(2)=0%, P=0.00). The study indicates that COMT 158 G/A G->A gene transition might contribute to lung cancer, especially in Chinese non-smoker women. PMID- 26770365 TI - MicroRNA-9 is a ponderable index for the prognosis of human hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is one of the most common primary malignant tumors of the liver worldwide; however, despite its significance, there is a lack of treatment methods and clear prognoses. MicroRNA-9 (miR-9) is known to play an important role in tumor tumorigenesis and progression. Talin-1, which plays a significant role in regulating the transmutation of carcinoma, has been demonstrated to be downregulated by miR-9 in epithelial ovarian cancer. In the present study, we researched the potential role of miR-9 in the prognosis of HCC. The expression levels of miR-9 and Talin-1 mRNA in HCC tissues (n = 60), adjacent non-cancerous tissues (n = 60), and normal liver tissues (n = 20) were detected using a real-time quantitative assay; protein expression levels of Talin-1 were detected using western blot. The expression levels of miR-9 were significantly higher in HCC tissues (P < 0.001) than in normal liver and adjacent non-cancerous tissues. These levels were significantly associated with tumor grade, tumor size, portal vein tumor thrombus, integral capsule, and 2.0-year disease-free survival rate (P < 0.05). High levels of miR-9 were strongly associated with the malignant progression of HCC, and overexpression of miR-9 is a risk factor that has a statistically significant effect on survival rate. miR-9 could play a role as an HCC tumor activator by regulating the expression of Talin-1; therefore, miR-9 might be a potentially valuable biomarker for the prognosis in HCC patients. PMID- 26770366 TI - MiR-202 promotes endometriosis by regulating SOX6 expression. AB - OBJECTIVES: This study is to investigate the role and mechanism of microRNA-202 (miR-202) in endometriosis. METHODS: Forty-five cases of ectopic endometrial tissues, 25 cases of eutopic endometrial tissues and 26 cases of normal endometrial tissues were collected. MiR-202 expression was detected by quantitative RT-PCR. The protein expressions of SOX6 (sex determining region Y box 6) and its downstream proteins (p21, cyclin D1 and pRb (retinoblastoma protein)) were detected by immunochemistry and western blot. MTT and transwell assays were used to examine cell proliferation and cell migration. The dual luciferase assay was applied to validate whether miR-202 can directly target SOX6 gene. RESULTS: MiR-202 was highly expressed in eutopic and ectopic endometrial tissues than normal endometrial tissues (P < 0.05), and the expression was higher in tissues with III/IV stages than I/II stages (P < 0.05). The expression of SOX6 protein was lower in ectopic endometrial tissues than in normal endometrial tissues. In ectopic endometrial tissues, the expression of p21 was decreased while cyclin D1 and pRb was up-regulated than in normal endometrial tissues (P < 0.05). In cultured endometrial cells, miR-202 down-regulation induced up regulation of SOX6 and p21 whereas down-regulation of cyclin D1 and pRb. MiR-202 promoted the proliferation and metastasis of endometrial cells. And, miR-202 could complementary bind to SOX6 3'UTR to regulate the expression of SOX6. CONCLUSION: MiR-202 was up-regulated in the endometriosis. Through targeting SOX6 and its downstream proteins (p21, cyclin D1 and pRb), miR-202 can promote the progression of endometriosis. PMID- 26770367 TI - Role of ultrasonography in the evaluation of correlation between strain and elasticity of common carotid artery in patients with diabetic nephropathy. AB - OBJECTIVE: This study aimed to investigate the correlation between strain and elasticity of the common carotid artery (CCA) by ultrasonography and evaluate its clinical significance in patients with diabetic nephropathy (DN). METHODS: A total of 68 DN patients and 54 healthy subjects were randomly recruited from the Ultrasound Department from April 2014 to March 2015. The maximum of circumferential strain (CSmax), maximum of circumferential strain rate (CSRmax), compliance coefficient (CC) and stiffness index (beta) of the CCA were determined by ultrasonography in all the patients, and correlation analysis was performed. RESULTS: The CC, CSmax and CSRmax in DN group were significantly lower than in healthy controls (P<0.05), but beta was markedly higher than in control group (P<0.05). There was a significantly positive correlation of CSmax and CSRmax with CC and a negative correlation with beta in both control group and DN group. CONCLUSION: There is significant correlation between strain and elastic of the CCA. CSmax and CSRmax may be used to reflect the mechanical characteristics of CCA. PMID- 26770368 TI - The protective effects of Masson pine pollen aqueous extract on CCl4-induced oxidative damage of human hepatic cells. AB - OBJECTIVE: We observed the effects of Masson pine pollen aqueous extracts (MPPAE) on CCl4-induced oxidative damage of the human hepatic cell line L-02. METHODS: We created an in vitro model of oxidative liver damage by treating L-02 human hepatic cells with 40 mmol/L CCl4. Effects of different concentrations of MPPAE on cell proliferation, morphology, and change of functional indexes were observed after addition of CCl4. RESULTS: CCl4 was toxic to proliferation, cell morphology, and functionality of hepatic cells. It decreased proliferation by 29.3-38.4% and increased AST and ALT activities by 22.3% and 99.2%, respectively. The oxidative stress also disrupted hepatic cell growth and induced pyknosis. Although MPPAE did not prevent decreased proliferation of L-02 cells, the treatment alleviated some CCl4-induced cell morphology changes and inhibited the abnormal rise of ALT (39.8%-70.1%) and AST (14.75-27.25%) activities in a dose dependent manner. A high dose of MPPAE (400 mg/L) ameliorated nucleus deformation to an almost normal appearance. CONCLUSIONS: According to our in vitro model, MPPAE specifically prevented the changes in cell morphology and functional injury caused by CCL4 treatment; however, it offered limited protection against damage induced reduction of proliferation. PMID- 26770370 TI - Correlation of lymphovascular invasion with clinicopathological factors in invasive breast cancer: a meta-analysis. AB - OBJECTIVES: Lymphovascular invasion (LVI) has been associated with a poor outcome in patients with breast cancer, but it is not included in international TNM staging system and molecular subtype criterion. The current studies have reported the relation between LVI and the tumor size (T), the status of axillary lymph node (ALN), age, histological grade in invasive breast cancer, but the results were debatable. So the meta-analysis was conducted to confirm the relation between LVI and the four clinicopathological factors. METHODS: Literature was searched by entering the terms: breast AND (neoplasm OR cancer OR carcinoma) AND (lymphovascular OR "lymphatic vessel" OR "vascular vessel" OR "blood vessel" OR "lymph vessel") AND (invasion OR "carcinoma embolus") AND (lymph node OR grade OR size OR clinicopathological) in PubMed, The merged odds ratio (OR) and 95% confidence interval (CI) were estimated using fixed-effect or random-effect model, RevMan 5.3 was used to analyze the relation between LVI and tumor size, status of ALN, age, histological grade in invasive breast cancer respectively. The fail-safe number was used to estimate publication bias. RESULTS: The analysis included 6 studies, LVI positive rate was significant lower in T<=2 cm, ALN negative, age >50 y and histological grade 1 groups statistically. The OR and 95% CI were 0.53 [0.46, 0.61], 0.23 [0.15, 0.35], 1.62 [1.42, 1.85], 0.36 [0.17, 0.77] respectively. CONCLUSIONS: LVI was significantly correlated with the expression status of the tumor size, status of ALN, age, histological grade in invasive breast cancer, and was consistent with adverse features of the four factors. PMID- 26770369 TI - Pachymic acid inhibits tumorigenesis in gallbladder carcinoma cells. AB - BACKGROUND: Gallbladder cancer, with high aggressivity and extremely poor prognosis, is the most common malignancy of the bile duct. Thus, seeking targets gallbladder tumor cells is an attractive goal towards improving clinical treatment. MATERIAL AND METHODS: In this study, we investigated the effects of pachymic acid (PA) on the tumorigenesis of human gallbladder cancer cells. RESULTS: We found that PA significantly reduced cell growth in a dose- and time dependent fashion. Meanwhile, cell cycle arrest at G0 phase was induced by PA. PA also significantly inhibited cancer cell migration, invasion in a dose-dependent manner. Interestingly, we demonstrated that cancer cell adhesion ability was suppressed dose-dependently, which may contribute to the inhibition of cell invasion. Finally, we showed that PA inhibited AKT and ERK signaling pathways. And oncoproteins, such as PCNA, ICAM-1 and RhoA which are involved intumorigenesis, were also downregulated by PA. CONCLUSION: Our study reveals that PA is able to inhibit gallbladder cancer tumorigenesis involving affection of AKT and ERK signaling pathways. Together, these results encourage further studies of PA as a promising candidate for gallbladder cancer therapy. PMID- 26770371 TI - Effect of high mobility group box 1 on the human retinal pigment epithelial cell in high-glucose condition. AB - Diabetic retinopathy (DR) remains a prevalent complication of diabetes and one of the leading causes of blindness among working-age adults. However, the detailed molecular mechanism of the development of DR was still unclear by now. HMGB1 is a non-histone DNA-binding protein and serves as a structural component to facilitate the assembly of nucleoprotein complexes in the nucleus. In the present study, we examined the serum level of HMGB1 and VEGFA in the DR patients. Besides, we also detect the association between HMGB1 and VEGFA level. In the advanced in-vitro study, we detect the protective effect of HMGB1 on the RPE cells in high glucose condition. In this study, we demonstrated that HMGB1 and VEGFA expressions were upregulated in serum samples of DR patients. Advanced analysis showed that HMGB1 and VEGFA level was positively associated. In the in vitro study, it was found that up-regulation of HMGB1 inhibited the RPE cell viability and induce the apoptosis. Besides, HMGB1 treatment would up-regulate the expression of VEGFA in the RPE cells in high glucose condition. In conclusion, we have demonstrated that HMGB1 and VEGFA are key players in the ability to suppress cell viability and induce apoptosis. The result of this current experiments shed light into the mechanism by which HMGB1 works. Besides, we also present the data of case control study data, our results showed that HMGB1 might be used as biomarkers of DR. PMID- 26770372 TI - Robot-assisted thoracic surgery versus open thoracic surgery for lung cancer: a system review and meta-analysis. AB - The aim of this meta-analysis is to compare the perioperative morbidity and mortality outcomes of robotic-assisted thoracic surgery (RATS) with open thoracic surgery (OTS) for patients with lung cancer. We searched articles indexed in the Pubmed and Sciencedirect published as of July 2015 that met our predefined criteria. A meta-analysis was performed by combining the results of reported incidences of perioperative morbidity and mortality. The relative risk (RR) was used as a summary statistic. Five eligible articles with 2433 subjects were considered in the analysis (5 articles for morbidity, while 3 articles for mortality). Overall, pooled analysis indicated that perioperative morbidity and mortality rate was significantly lower among patients who underwent RATS than patients who underwent OTS (for morbidity: RR, 0.83; 95% CI, 0.75 to 0.92; P<0.01; for mortality: RR, 0.14; 95% CI, 0.03 to 0.59; P=0.007). No evidence of publication bias was observed. In conclusion, this meta-analysis showed that RATS resulted in significantly lower perioperative morbidity and mortality rate compared with OTS cases. Thus, we suggest RATS be an appropriate alternative to OTS for lung cancer resection. RATS should be studied further in selected centers and compared with OTS in a randomized fashion to better define its potential advantages and disadvantages. PMID- 26770373 TI - Sulforaphane exerts neuroprotective effects via suppression of the inflammatory response in a rat model of focal cerebral ischemia. AB - Inflammatory damage plays an important role in cerebral ischemic pathogenesis and may represent a promising target for treatment. Sulforaphane exerts protective effects in a rat model of focal cerebral ischemia/reperfusion injury by alleviating brain edema. However, the possible mechanisms of sulforaphane after cerebral ischemia/reperfusion injury have not been fully elucidated. Therefore, in the present study, we investigated the effect of sulforaphane on inflammatory reaction and the potential molecular mechanisms in cerebral ischemia rats. We found that sulforaphane significantly attenuated the blood-brain barrier (BBB) disruption; decreased the levels of pro-inflammatory cytokines tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta; reduced the nitric oxide (NO) levels and inducible nitric oxide synthase (iNOS) activity; inhibited the expression of iNOS and cyclooxygenase-2 (COX-2). In addition, sulforaphane inhibits the expression of p-NF-kappaB p65 after focal cerebral ischemia reperfusion injury. Taken together, our results suggest that sulforaphane suppresses the inflammatory response via inhibiting the NF-kappaB signaling pathway in a rat model of focal cerebral ischemia, and sulforaphane may be a potential therapeutic agent for the treatment of cerebral ischemia injury. PMID- 26770374 TI - Application of three dimensional reconstruction technique in selection of incision of thoracic surgical operation with robot. AB - OBJECTIVE: To evaluate a new method to plan the incisions of thoracic surgical operation with robot using three-dimensional (3D) reconstruction techniques. METHODS: Three-dimensional reconstruction techniques were used to reconstruct the chest CT of patients with the software OSIRIX (APPLE(r)). Tumor location, size and relationship with the vein and artery were unambiguously obtained. The location of the incision was predetermined prior to the surgery. The operation time, set up time and work time were evaluated to assess the efficacy of this preplanning methodology. RESULTS: A total of 4 cases are reported here. Tumors of different homogeneities were assessed, located in a 3D mode, and preplanned incisions successfully made to perform the procedure. This resulted in overall reduction of operation time and also provided effective visualization of the tumor during surgery. CONCLUSION: Our results suggest that this method can show the location of tumor, help in planning of appropriate incisions and define 3D anatomical relationships. PMID- 26770375 TI - Wnt5a/FZD5/CaMKII signaling pathway mediates the effect of BML-111 on inflammatory reactions in sepsis. AB - AIMS: This study aims to investigate the effect of 5(S), 6(R)-7-trihydroxymethyl heptanoate (BML-111) on the Wnt5a/frizzled-5 (FZD5)/calcium/calmodulin-dependent protein kinase II (CaMKII) signaling pathway in septic mice, and to explore whether this pathway mediates the effect of BML-111 on inflammatory response in lipopolysaccharide (LPS)-induced RAW 264.7 cells. METHODS: The cecal ligation and puncture-induced mouse model of sepsis was constructed, and the mice were pretreated with BML-111. In vitro, LPS-induced RAW 264.7 cells were incubated with various concentrations of BML-111. Activation of Wnt5a/FZD5/CaMKII signaling pathway was achieved by transfection of the Wnt5a overexpression plasmid. The levels of interleukin-1 beta (IL-1beta), IL-6 and IL-8 in the mouse serum and cell supernatant were determined by ELISA assay. The expression of Wnt5a, FZD5 and CaMKIIdelta was examined by western blot analysis. RESULTS: The results from the in vivo studies revealed that BML-111 shows inhibitory effect on IL-1beta, IL 6 and IL-8 expression in the serum of septic mice, and suppresses the expression of Wnt5a, FZD5 and CaMKIIdelta protein. The in vitro studies demonstrated that BML-111 inhibits Wnt5a, FZD5 and CaMKIIdelta proteins in a dose-dependent manner. BML-111 suppressed the levels of IL-1beta, IL-6 and IL-8 in LPS-induced RAW 264.7 cells; however, this effect could be attenuated by transfection of the Wnt5a overexpression plasmid. CONCLUSION: This study firstly demonstrated that BML-111 suppresses Wnt5a/FZD5/CaMKII signaling pathway in sepsis, and Wnt5a/FZD5/CaMKII signaling pathway mediates the effect of BML-111 on inflammatory reactions. These findings provided a novel molecular basis for the potential effect of BML-111 in sepsis. PMID- 26770376 TI - ProTaper and WaveOne systems three-dimensional comparison of device parameters after the shaping technique. A micro-CT study on simulated root canals. AB - AIM: The aim of this study is to highlights possible differences in the volume of shaping and canal surface area after the using of common endodontic devices ProTaper Universal and WaveOne systems. METHODS: Forty ISO 15, 0.02 taper, S shaped endo-training Blocks (Dentsply, Maillefer) were assigned in two groups (n = 20 for each group). For each block the initial working length (WL) was evaluated with a 10 K-files (Dentsply Maillefer), so the glide path was created with PathFile 1, 2 and 3 (Dentsply Maillefer) at the WL. After that, simulated canals in the group 1 were shaped with S1, S2, F1 and F2 at WL; while in group 2 it was used single-file WaveOne primary in reciprocating motion. After shaping, the resin blocks were analysed with Skyscan 1172 scanner (Skyscan, Kontich, Belgium) and then volumetrically at a source voltage of 65 kV and a source current of 153 uA. RESULTS: No statistically differences (P > 0.05) have been found in terms of volume and surface area after the use of ProTaper Universal and WaveOne systems. CONCLUSIONS: Although, results from micro-CT analysis revealed that Wave One result in a decrease of volume and surface area of shaping than ProTaper Universal, differences are not statistically significant. PMID- 26770377 TI - Ulnius formation for forearm fracture with segmental radial defect. AB - One-bone forearm functions best when the proximal ulna and distal radius are present and joined (the ulnius). Six open forearm fractures accompanied by segmental radial defect were treated by the ulnius formation in a one-stage procedure. All patients had a stable and pain-free forearm, and were satisfied with the function and cosmetic appearance of the forearm. PMID- 26770378 TI - Synchronous bilateral primary breast malignant phyllodes tumor and carcinoma of the breast with Paget's disease: a case report and review of the literature. AB - Synchronous bilateral primary breast malignant phyllodes tumor or/and carcinoma of the breast with Paget's disease is rare. In the article, we present a case of bilateral carcinoma of the breast with Paget's disease of the right breast and malignant phyllodes tumor of the left breast. A 44-years-old Chinese woman presented with a 1 month history of the right breast nipple with eczema and fester and growing and palpable mass of left breast. Molybdenum target X-ray revealed microcalcification in the right breast, which was highly suspected of malignant tumor, and round-like mass with smooth surface and homogeneous density in the left breast. Color ultrasound showed a lobulated lump which circumferential blood flows around in the left breast, and which did not show any mass in the right breast. The patient was undertaken the bilateral modified radical mastectomy. The histological diagnosis was Paget's disease associated with infiltrating ductal carcinoma in the right breast and malignant phyllodes tumor the left breast. The patient also received 6 cycles of the postoperative adjuvant chemotherapy by using T.T. regimen comprised docetaxel (100 mg) and pirarubicin (60 mg). PMID- 26770379 TI - Association between three interleukin-10 gene polymorphisms and coronary artery disease risk: a meta-analysis. AB - BACKGROUND: Previous studies have investigated the associations between interleukin-10 (IL-10) gene polymorphisms (-592C/A, -819C/T and -1082G/A) and risk of coronary artery disease (CAD). However, the results were inconsistent. The aim of this study was to clarify the relationship between IL-10 polymorphisms and CAD risk by a meta-analysis approach. METHODS: The PubMed, Embase, Web of Science, China National Knowledge Infrastructure (CNKI) and Wanfang databases were searched according to predefined criteria for all relevant studies published before June 1, 2015. Pooled odds ratios (ORs) and 95% confidence intervals (95% CIs) were computed to assess the association. RESULTS: 24 eligible studies were enrolled including 9736 CAD patients and 8606 controls. We observed a significant decreased risk of CAD for IL-10 -819C/T polymorphism (T allele vs. C allele:OR = 0.91, 95% CI = 0.84-0.99; TT vs. CT + CC:OR = 0.82, 95% CI = 0.69-0.98), especially in Asians (T allele vs. C allele:OR = 0.76, 95% CI = 0.60-0.96; TT vs. CC:OR = 0.51, 95% CI = 0.27-0.96; TT vs. CT + CC:OR = 0.62, 95% CI = 0.44-0.88). Moreover, we found IL-10 -1082G/A polymorphism might contribute to an increased CAD risk in Asians (AA vs. GG:OR = 1.89, 95% CI = 1.36-2.64; AA vs. AG + GG:OR = 1.39, 95% CI = 1.14-1.68) but not in other ethnic groups. However, no significant association between the IL-10 -592C/A polymorphism and CAD risk was observed. CONCLUSIONS: Our results indicated that IL-10 -819C/T and IL-10 -1082G/A polymorphisms significantly and race-specifically correlate with CAD risk. PMID- 26770380 TI - Prophylactic use of gentamicin/flucloxacillin versus cefuroxime in surgery: a meta analysis of clinical studies. AB - PURPOSE: To conduct meta-analyses of all available studies comparing efficacies of prophylactic cefuroxime and prophylactic gentamicin/flucloxacillin (Gen/Flu) in preventing post-operative wound infections and their association with risks of Clostridium difficile infections and post-operative renal impairment. METHODS: Published studies including both prophylactic cefuroxime and prophylactic Gen/Flu used in surgery were included for meta analysis. Outcomes were analyzed using a random-effect model or a fixed-effect model depending on the heterogeneity across the included studies. RESULTS: Gen/Flu prophylaxis showed similar efficacy as cefuroxime prophylaxis in preventing post-operative wound infections and was associated with a significantly lower risk of Clostridium difficile infection, but it was associated with a higher risk of post-operative renal impairment, especially in orthopedic surgery. CONCLUSIONS: Our findings that Gen/Flu prophylaxis was associated with significantly higher risk of post-operative renal impairment dictate that benefits and risks of Gen/Flu prophylaxis should be carefully assessed and balanced, and each patient should be evaluated individually so that a proper antibiotic prophylaxis regimen could be chosen. PMID- 26770381 TI - Optimal sample volumes of human trabecular bone in MUCT analysis within vertebral body and femoral head. AB - Trabecular bones of different skeletal sites have different bone morphologies. How to select an appropriate volume of region of interest (ROI) to reflect the microarchitecture of trabecular bone in different skeletal sites was an interesting problem. Therefore, in this study, the optimal volumes of ROI within vertebral body and femoral head, and if the relationships between volumes of ROI and microarchitectural parameters were affected by trabecular bone morphology were studied. Within vertebral body and femoral head, different cubic volumes of ROI (from (1 mm)(3) to (20 mm)(3)) were set to compare with control groups(whole volume of trabecular bone). Five microarchitectural parameters (BV/TV, Tb.N, Tb.Th, Tb.Sp, and BS/BV) were obtained. Nonlinear curve fitting functions were used to explore the relationships between the microarchitectural parameters and the volumes of ROI. The volumes of ROI could affect the microarchitectural parameters when the volume was smaller than (8 mm)(3) within the vertebral body and smaller than (13 mm)(3) within the femoral head. As the volume increased, the variable tendencies of BV/TV, Tb.N, and Tb.Sp were different between these two skeletal sites. The curve fitting functions between these two sites were also different. The relationships between volumes of ROI and microarchitectural parameters were affected by the different trabecular bone morphologies within lumbar vertebral body and femoral head. When depicting the microarchitecture of human trabecular bone within lumbar vertebral body and femoral head, the volume of ROI would be larger than (8 mm)(3) and (13 mm)(3). PMID- 26770382 TI - Expressions of lysophosphatidic acid receptors in the development of human ovarian carcinoma. AB - AIM: To investigate the associations between the expressions of three lysophosphatidic acid (LPA) receptors (LPA1-3) and the development of ovarian carcinoma (OC). METHOD: Ovarian tissue specimens, including normal ovarian epithelium tissues, benign ovarian tumor tissues and OC tissues were collected from patients who underwent surgical resections between March 2012 and December 2014. Immunohistochemical staining was used to detect LPA receptor expressions in ovarian tissues. Reverse transcription-polymerase chain reaction and Western blotting were used to detect mRNA and protein expression of LPA receptors, respectively. Association analysis between LPA receptors protein expression and clinical pathological characteristics was conducted. The value of LPA2 and LPA3 in discriminating OC was confirmed by receiver-operator characteristic (ROC) curves analysis. RESULTS: The positive expression rates of LPA2 and LPA3 in OC group was obviously higher than normal control and benign groups. The LPA2 and LPA3 mRNA and protein levels in OC group were higher than in normal control and benign groups. LPA2 and LPA3 mRNA expression levels were positively correlated with LPA2 and LPA3 protein expression in OC group. ROC curve analysis revealed that LPA2 yield a specificity of 96.3% and a sensitivity of 97.9%, and LPA3 yield a specificity of 98.5% and a sensitivity of 97.9% for the detection of OC. CONCLUSION: LPA2 and LPA3 were highly expressed in OC tissues, which may be involved in the development of OC. Further, LPA2 and LPA3 had higher sensitivity and specificity in distinguishing the OC from benign ovarian tumors, which could be potential diagnostic indictors in OC. PMID- 26770383 TI - Protective effects of the antihistamine promethazine aginst acute paraxon-methyl and dicrotophos toxicity in adult rats. AB - Organophosphorus compound poisoning (OPC) is a global issue. The problem is aggravated with the threats of terrorist use, unintentional use and irresponsible practice as happened recently in turmoil countries. The purpose of the current study was to investigate the old-generation antihistamine promethazine (PROM), a drug with multi pharmacological actions, as an antidote to extremely and highly toxic (WHO's class IA and IB) OPC poisoning in experimental animal models conducted on adult male wistar rats. Experimental groups were treated intraperitoneal (i.p.) with LD70 of methyl paraoxon (MPOX), class IA and dicrotophos (DCP), class IB alone and a combination of simultaneously i.p. injection of PROM. Mortality was recorded at 30 minutes, 1, 2, 3, 4, 24, 48 hours post injections. RBC-AChE was measured in survivals. MPOX was chosen for further studies with atropine (ATR) and pralidoxime (PAM). In addition to Kaplan-Meir survival analysis, serum lactate dehydrogenase (LDH) and creatinine kinase (CK) from serum were measured in all experimental groups with MPOX. The results revealed significant protection by PROM in both MPOX and DCP intoxicated rats, though the inhibition of RBC-AChE was high. The observed results show that groups treated with a combination of MPOX and PROM or MPOX, PROM, and PAM were protected higher than those treated with MPOX and ATR or MPOX, ATR, and PAM though statistically not significantly different (P <= 0.05). No effect was observed on the activity of LDH and CK. The study concludes that PROM may be effectively used in OPC poisoning. However, risk/benefits trials and further studies with different doses and other OPC groups are warranted. PMID- 26770384 TI - Sitagliptin downregulates retinol-binding protein 4 and upregulates glucose transporter type 4 expression in a type 2 diabetes mellitus rat model. AB - The present study was designed to investigate the effects of sitagliptin on metabolic parameters as well as the expression levels of retinol-binding protein 4 (RBP4) and glucose transporter type 4 (GLUT4) in a rat model of type 2 diabetes mellitus. A rat model of type 2 diabetes mellitus was established by a combination of a high-fat diet and intraperitoneal injection of low-dose streptozotocin. Rats were divided into three groups: normal control group, diabetes group, and diabetes + sitagliptin group. Body weight, glycemic parameters, lipid profiles, fasting insulin (FINS) and serum RBP4 levels were assessed at baseline and after 6 weeks of therapy. Western blotting was used to detect the tissue RBP4 and GLUT4 expression levels. After treatment for 6 weeks, the diabetes + sitagliptin group displayed significantly improve levels of blood sugar, blood grease, and insulin sensitizing functions (P < 0.05) than the diabetes group. Sitagliptin markedly down regulated RBP4 expression levels and up regulated GLUT4 expression levels in adipose tissue and skeletal muscle. The results indicate that sitagliptin can modulate the RBP4-GLUT4 system in adipose tissue and skeletal muscle. Modulation of the RBP4-GLUT4 system may be one of the mechanisms by which sitagliptin ameliorates the symptoms of type 2 diabetes mellitus. PMID- 26770385 TI - In vitro, ex vivo and in vivo anti-hypertensive activity of Chrysophyllum cainito L. extract. AB - Chrysophyllum cainito L., a traditional herbal medicine, could have the potential for management of hypertension due to presence of polyphenolic compounds. The extracts and fractions of the pulp of plant were evaluated for in vitro (inhibition of angiotensin I converting enzyme/ACE assay), ex vivo (isolated aorta relaxation assay) and in vivo (salt induced hypertensive rat assay). The alcoholic and aqueous extract (ALE and AQE respectively) of fruit of plant C. cainito was having 14.8 and 9.2% yield respectively. The fractionation with ethyl alcohol (EAF) and butanol (BTF) yielded 2.52 & 2.17% respectively from ALE and 0.46 & 0.31% respectively from AQE with respect to fruit pulp dry weight. More phenolic content was found in ALE (3.75+/-0.15 mg gallic acid equivalent or GAE g(-1) of dry power of fruit pulp) compared to AQE and maximum in ethyl acetate fraction of ALE (ALE-EAF) (2.32+/-0.21 mg GAE g(-1) of dry power of fruit pulp) among all fractions. ACE inhibition activity was found to be maximum in ALE-EAF 62.5+/-7.34%. While ex vivo study using isolated tissue of aorta showed again showed maximum activity (62.82+/-6.19 and 46.47+/-8.32% relaxation with 50 ug mL( 1) and 10 ug mL(-1) GAE concentration respectively). ALE-EAF reduced the elevated arterial pressure of salt induced hypertensive rat significantly to the level of normotensive animal group. Results of ALE-EAF have shown its potential as a source for novel constituent for the treatment hypertension and should further be studied for isolation of specific constituent for more effectiveness. PMID- 26770386 TI - Impacts of thyroxine combined with donepezil on hippocampal ultrastructures and expressions of synaptotagmin-1 and SNAP-25 in adult rats with hypothyroidism. AB - The study aims to observe the impacts of thyroxine (T4) combined with donepezil (DON) on hippocampal ultrastructures and expressions of synaptotagmin-1 and SNAP 25 in adult rats with hypothyroidism. All rats were randomly divided into five groups: the normal control group (CON), the hypothyroidism group (Hypo), the T4 treatment group (T4), the DON treatment group (DON) and the T4+DON combined treatment group (T4+DON). Technique of Electron Microscope (TEM) was used to observe the hippocampal ultrastructures of each group, Western blot and real-time RT-PCR were performed to analyze the protein and mRNA expressions of syt-1 and SNAP-25 in the hippocampus of each group. TEM revealed that the Hypo group exhibited the significant vacuolar degeneration of mitochondria in the hippocampal neurons, the free ribosomes were sparse, the synaptic structures were damaged, and the number of synaptic vesicles was reduced, the above injuries in the T4 or DON group were improved, and the performance of the T4+DON group was the most close to the CON group. From the protein and mRNA levels, the dorsal hippocampal syt-1 expression of the Hypo group was significantly reduced, while SNAP-25 was significantly increased, the expressions were partially recovered after the T4 treatment, and the T4+DON combined treatment made the expression return to normal. The adult hypothyroid rats exhibited pathological damages in the hippocampal ultrastructures, the expression of syt-1 was downregulated, while that of SNAP-25 was upregulated, the T4+DON combined therapy could repair the above injuries, and the roles were better than the single drug treatment. PMID- 26770387 TI - TGF-beta1 C-509T and T869C polymorphisms and cancer risk: a meta analysis. AB - Objective The association between polymorphism of TGF-beta1 and cancer risk has been discussed. Method A comprehensive electronic search was performed to identify articles published up until 12 December 2014 in Medline and Embase databases. The statistical analysis was performed by STATA 11.0 software and Review Manager 5.1 software. RESULTS: In the present meta analysis, for C-509T (31 studies, 12944 cases and 15530 controls), no significant cancer risk was found in the overall analysis. In subgroup analysis, C-509T polymorphism was associated with decreased cancer risk in Asian population (OR=0.73 and 95% CI=0.59-0.90 for CT vs. CC), and there were no significant risks in gastric cancer, breast cancer, and other cancers. For T869C (11 studies, 2730 cases and 2973 controls), significantly increased risks of cancer were observed, and the ORs (95% CI) were 1.81 (1.18-2.78) for CC vs. TT, 1.50 (1.07-2.09) for TC vs. TT, 1.61 (1.13-2.30) for TC+CC vs. TT and 1.38 (1.11-1.73) for C-allele vs. T-allele, respectively. Subgroup analyses stratified by ethnicity and types of cancer were also performed, and the results indicated that T869C polymorphism was associated with cancer risk in Caucasion [1.93 (1.52-2.46) for TC vs. TT], but not in Asian [1.23 (0.80-1.90) for TC vs. TT]. We also observed that the T869C was associated with increased risk of squamous cell cancer of head and neck (SCCHN) [1.34 (1.07 1.67) for TC vs. TT]. Conclusion Decreased cancer risk association was observed in Asian for C-509T and significantly increased risk of cancer was observed for T869C. PMID- 26770388 TI - Association between EPHX1 rs1051740 and lung cancer susceptibility: a meta analysis. AB - BACKGROUND: Microsomal epoxide hydrolase 1 (EPHX1) may play an important role in epigenetic change and DNA repair concerned with lung cancer. Several studies have investigated the association between EPHX1 rs1051740 and lung cancer risk, but there is no consensus. Therefore, we performed a meta-analysis to further identify the relationship. METHODS: The Pubmed and Embase databases were searched for eligible studies. An odds ratio (OR) with 95% confidence intervals (CIs) was used to assess the correlation between EPHX1 rs1051740 polymorphism and lung cancer risk through a meta-analysis. RESULTS: Overall, no significant relationship was found between EPHX1 rs1051740 and lung cancer risk (CC vs. TT: OR=1.10, 95% CI=0.88-1.36; CC+CT vs. TT: OR=1.02, 95% CI=0.88-1.18; CC vs. TT+CT: OR=1.08, 95% CI=0.91-1.27; C vs. T: OR=1.04, 95% CI=0.93-1.17; CT vs. TT: OR=0.98, 95% CI=0.85-1.13). Nevertheless, further subgroup analysis by ethnicity demonstrated that EPHX1 rs1051740 with CC genotype or C allele was an increased risk for lung cancer in Asians (CC vs. TT: OR=1.54, 95% CI=1.23-1.94; CC vs. TT+CT: OR=1.43, 95% CI=1.20-1.71; C vs. T: OR=1.26, 95% CI=1.08-1.47). CONCLUSIONS: This meta-analysis indicates that EPHX1 rs1051740 with CC genotype or C allele may be a risk factor in Asians. PMID- 26770389 TI - Morphological changes and expression of MMPs and TIMPs in rabbit degenerated lateral meniscus after PCL-transection. AB - INTRODUCTION: Whether the expression level of MMP-1, MMP-13 and TIMP-1 has association with the degeneration of lateral meniscus after posterior cruciate ligament (PCL) fracture is poorly understood. The aim of this study was to investigate the influence of PCL fracture on lateral meniscus, including morphological changes, histological changes and roles of matrix metalloproteinase 1 (MMP-1), matrix metalloproteinase-13 (MMP-13) and tissue inhibitor of metalloproteinase-1 (TIMP-1) expression level in the secondary injury. MATERIALS AND METHODS: Sixty male rabbits were used as PCL transection models and randomized into the PCL-transection side, which underwent PCL transection surgery, and the control side, which underwent PCL exposure without transection. On 4, 8, 12, 16 and 24 weeks after PCL-transection, 12 rabbits were randomly killed for H&E staining to determine the histological changes of lateral meniscus. Immunohistochemical staining was undertaken to evaluate the expression level of MMP-1, MMP-13 and TIMP-1 in lateral meniscus. The results were statistically analyzed using SPSS 15.0. RESULTS: The lateral meniscus of PCL transection side presented abnormal morphology. Histological evaluation score of meniscal degeneration in PCL-transection group was higher than that in the control group with statistical difference (P < 0.05). The expression levels of MMP-1, MMP-13 and TIMP-1 were significantly elevated in meniscus of the PCL transection group with statistical difference (P < 0.05). MMP-1 expression displayed an increasing trend firstly then kept stable after PCL transection; MMP 13 and TIMP-1 expression displayed high level firstly then decreased in advanced stage after PCL transection. CONCLUSIONS: PCL transaction may induce a coordinated response of degeneration of lateral meniscus in a time-dependent manner. The high expression level of MMP-1, MMP-13 and TIMP-1 would contribute to the degeneration of lateral meniscus after PCL transection. PMID- 26770390 TI - Lack of association between XPC Lys939Gln polymorphism and prostate cancer risk: an updated meta-analysis based on 3039 cases and 3253 controls. AB - Several studies have evaluated the relationship between xeroderma pigmentosum complementation group C (XPC) variants and prostate cancer (PCa) risk. However, the results remain inconclusive. The objective of this study was to identify the role of XPC Lys939Gln variant on PCa occurrence. Relevant case-control studies published between 2000 and 2014 were retrieved in electronic databases. The pooled odds ratio (ORs) and 95% confidence interval (CI) were employed to calculate the strength of association. Finally, a total of eight articles including 3039 PCa patients and 3203 healthy controls were screened out. Our results found that the frequency of C allele was a little higher in PCa cases than that in control, but it was not associated with the increased risk of PCa (C vs. A: OR=1.05, 95% CI=0.98-1.13, P=0.19). This insignificant association was also observed in other genetic models (P>0.05). In subgroup analysis by ethnicity, no significant relationship was found in any study-population (Asian, Caucasian and African) as well. In conclusions, our results indicated that XPC Lys939Gln polymorphism was not associated with PCa susceptibility. Further large well-designed epidemiologic studies with gene-gene and gene-environment interaction should be included and considered. PMID- 26770391 TI - Pharmacokinetic and bioavailability study of angeloylgomisin H in rat plasma by UPLC-MS/MS. AB - Angeloylgomisin H, as a major lignin in the fruits, was reported to have the potential to improve insulin-stimulated glucose uptake by activating PPAR-gamma. In this work, a sensitive and selective UPLC-MS/MS method for determination of angeloylgomisin H in rat plasma is developed. After addition of rutin as an internal standard (IS), protein precipitation by acetonitrile was used to prepare samples. Chromatographic separation was achieved on a UPLC BEH C18 column (2.1 mm * 100 mm, 1.7 MUm) with 0.1% formic acid and acetonitrile as the mobile phase with gradient elution. An electrospray ionization source was applied and operated in positive ion mode; multiple reactions monitoring (MRM) mode was used for quantification using target fragment ions m/z 523.2-315.1 for angeloylgomisin H, and m/z 611.1-303.1 for IS. Calibration plots were linear throughout the range 5 2000 ng/mL for angeloylgomisin H in rat plasma. Mean recoveries of angeloylgomisin H in rat plasma ranged from 86.2% to 92.5%. RSD of intra-day and inter-day precision were both < 11%. The accuracy of the method was between 93.0% and 104.1%. The method was successfully applied to pharmacokinetic study of angeloylgomisin H after either oral or intravenous administration. The absolute bioavailability of angeloylgomisin H was reported as high as 4.9%. PMID- 26770392 TI - Vasectomy and the risk of prostate cancer: a meta-analysis of cohort studies. AB - BACKGROUND: The relationship of vasectomy to prostate cancer has great public health significance. However, the results of observational studies were conflicting. To determine whether vasectomy is associated with the risk of prostate cancer, we performed a meta-analysis of cohort studies. METHODS: A literature search was carried out using Pubmed, Embase, Cochrane Libraryl, and China National Knowledge Infrastructure (CNKI) between January 1966 and July 2013. Before meta-analysis, between-study heterogeneity and publication bias were assessed using adequate statistical tests. Fixed-effect and random-effect models were used to estimate summary relative risks (RR) and the corresponding 95% confidence intervals (CIs). Potential sources of heterogeneity were detected by meta-regression. Subgroup analyses and sensitivity analysis were also performed. RESULTS: A total of nine cohort studies contributed to the analysis. There was heterogeneity among the studies but no publication bias. Pooled results indicated that vasectomy was not associated with a significant increase of total prostate cancer risk (RR = 1.07, 95% CI [0.79, 1.46]). When stratified the various studies by geographic location, we found a significant association between vasectomy and increased PCa risk among studies conducted in the USA (RR = 1.54, 95% CI [1.23, 1.93]), however, there was no significant association between vasectomy and PCa risk among studies conducted in non-USA countries (RR = 0.74, 95% CI [0.50, 1.09]). Furthermore, sensitivity analysis confirmed the stability of the results. CONCLUSIONS: In conclusion, the present meta-analysis of cohort studies suggested that vasectomy was not associated with increased risk of prostate cancer. More in depth studies are warranted to report more detailed results, including stratified results by age at vasectomy, tumor grade, and tumor stage. PMID- 26770393 TI - Association between sodium iodide symporter and differentiated Thyroid cancer: a meta-analysis of 9 studies. AB - CONTEXT: As many studies proved that sodium iodide symporter (NIS) plays a key role in radioactive iodide (RAI) therapy of thyroid cancer, however, a growing number of studies suggests that part of differentiated thyroid carcinomas (DTC) with overexpression of NIS are insensitive to RAI well. OBJECTIVE: The aim of this meta-analysis is to assess the expression of NIS in differentiated thyroid cancer, compared with normal thyroid tissue. DATA SOURCES: PUBMED, Sinomed, CNKI, Wanfang and VIP were searched for relevant case-control studies up to now. STUDY SELECTION: Studies that concerning the qualitative expression NIS in DTC were included. DATA EXTRACTION: Working independently, authors used a standard form to extract data. For quality assessment, Newcastle-Ottawa Scale (NOS) were applied. DATA SYNTHESIS: Totally nine eligible studies included, involving 765 cases and 473 controls. The results revealed that the expression of NIS had a statistically increased in DTC, compared with controls (OddsRadio OR: 1.47, 95% CI: 1.12 to 1.94, Z=2.78, P=0.005). Since the existence of the significant heterogeneity, subgroup analysis and sensitivity analysis were performed and found that the heterogeneity came from the different criteria evaluate positive NIS expression (Liu 2008, Mu 2010) and the small simple size of the control group (Lin. J D2001). The heterogeneity disappeared or dropped to below 50% after remove these studies. CONCLUSION: Our study shows that the expression of NIS is significantly increased in DTC, which could help explain the reason for individual with a poor response to RAI therapy. In other word, the reduced iodide uptake in thyroid cancer may not caused by the decreased expression of NIS, function of NIS protein or its post-transcriptional translocation might be the point. PMID- 26770394 TI - Expression profile and kinetics of cytokines and chemokines in patients with chronic hepatitis C. AB - Cytokines and chemokines play an important role in defense against viral infection and modulating immune response. However, expression prolife of serum cytokines and chemokines, which were associated with the outcome of patients in response to anti-HCV treatment have not been fully elucidated. The current study aimed to determine the expression pattern of cytokines and chemokines in chronic HCV infection and their association with outcome in response to therapy. Seventy two patients with HCV infection were enrolled, and fifty-one received peg interferon alpha-2a and ribavirin therapy for 48 weeks. Thirty-nine cytokines and chemokines were analyzed by Luminex 200 and ELISA. In comparison to healthy individuals, production of IL-8 and IL-10 were increased in chronic hepatitis C patients. In contrast, IFN-gamma, IL-7, and IL-15 were remarkably decreased, especially in HCV genotype 1b infection. HCV RNA load is closely associated with IL-10 and IL-15 expressions, and inhibition of HCV replication was accompanied by reduction in IL-10 and elevation in IL-7 and IL-15. Skewed cytokines and chemokines expression existed in chronic HCV infection, and might play an important role in persistent HCV infection. Exploiting the expression pattern of cytokines and chemokines may help to develop a better understanding of the pathogenesis of chronic HCV infection. PMID- 26770395 TI - Screening feature genes of astrocytoma using a combined method of microarray gene expression profiling and bioinformatics analysis. AB - The aim of our study was to find feature genes associated with astrocytoma and correlative gene functions which can distinguish cancer tissue from adjacent non tumor astrocyte tissues. Gene expression profile GSE15824 was downloaded from Gene Expression Omnibus database which included 8 astrocytoma tissues and 3 adjacent non-tumor astrocyte samples. The raw data were first transformed into probe-level data and the differentially expressed genes (DEGs) between tissues of patients with astrocytoma and normal specimen were identified using T-test in samr package of R. The Database for Annotation, Visualization and Integrated Discovery (DAVID) was applied to analyze the gene ontology (GO) enrichment on gene functions and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Finally, corresponding protein-protein interaction (PPI) networks of DEGs was constructed using the Cytoscape based on the data collected from STRING online datasets. A total of 3072 genes, including 1799 up-regulated genes and 1273 down regulated genes, were filtered as DEGs, and we learnt that the DEGs including AQP4, PMP2, SRARCL1 and SLC1A2CAMs etc and that AQP4 was most significantly related to cell osmotic pressure. Three feature genes in KEGG pathway are highly enriched in cancer specimen while two genes are in the normal tissues. The discovery of featured genes significantly related to the regulation of cell osmotic pressure, has the potential to use in clinic for diagnosis of astrocytoma in future. In addition, it has a great significance on studying mechanism, distinguishing normal and cancer tissues, and exploring new treatments for astrocytoma. However, further experiments were needed to confirm our result. PMID- 26770396 TI - Analysis on the metabolite composition of serum samples from patients with papillary thyroid carcinoma using nuclear magnetic resonance. AB - OBJECTIVE: Analysis of the metabolic differences among the papillary thyroid carcinoma (group T) patients, benign thyroid tumor patients (group B) and healthy controls (group H) by nuclear magnetic resonance hydrogen spectrum. METHODS: collect twenty serum specimens each from group T, group B and group H. Collect image archive. Use Topspin software, AMIX software and SIMCA-P+ software to calibrate, integrate with PCA and PLS-DA, research the three groups' serum for endogenous metabolic differences. RESULTS: The data of group T and group H established a discrimination model, and the model is correct (P<0.05). The content of metabolites in the serum of team T increased including valine, leucine, isoleucine, lactic acid, alanine, glutamic acid, lysine, glycine, while the lipids, choline, tyrosine decreased. The data of group B and group H established a discrimination model and the model is correct (P<0.05). The content of metabolites in the serum of team B increased including Trimethyl glycine, tyrosine, phenylalanine, valine, leucine, isoleucine, lactic acid, alanine, glutamic acid, while the Lipids and lysine reduced. CONCLUSION: Compared with team H, there is an obvious metabolic difference in team T and team B. It not only involves glucose metabolism but also the metabolism of lipids, amino acids and nucleic acid. PMID- 26770397 TI - Comparison of a reverse-transverse cross pin technique with a same side cross pin type II external skeletal fixator in 89 dogs. AB - The objective of this study was to determine whether a novel reverse-transverse cross pin insertion technique could increase the stability of type II external skeletal fixators (ESF) in dogs compared with an alternate, same side cross pin ESF. Reverse-transverse cross pin technique and type II ESFs same side cross pin technique were applied and compared among subjects. Two of 42 ESFs (4.8%) applied with the reverse-transverse cross pin technique and 39 of 47 ESFs (83%) applied with the same side cross pin technique were subjectively unstable at the time of fixator removal (P < 0.001). The same side cross pin ESFs had significantly more pin tract new bone formation than the reverse-transverse ESFs (P = 0.038). In summary, this approach may provide a method of treating a variety of musculoskeletal conditions and soft tissue cases, which reverse-transverse cross pin ESFs are tolerated in dogs for a variety of conditions. PMID- 26770398 TI - The survivin suppressant YM155 reverses doxorubicin resistance in osteosarcoma. AB - Doxorubicin (DOX) is one of the widely used chemotherapeutic drugs for the treatment of human osteosarcoma (OS). However, acquisition of DOX resistance is common in patients with OS, leading to local and distant failure. In this study, we demonstrate that survivin expression is significantly upregulated in OS primary tumors compared to paired normal tissue. In addition, survivin expression was further increased in DOX resistant cells (MG63/DOX) as compared to its parent cells (MG63). Thus, we hypothesize that targeting of survivin in OS could reverse the DOX resistant phenotype in tumor cells thereby enhancing the therapeutic efficacy of DOX. We test the efficacy of YM155, a small molecule survivin inhibitor, either as a single agent or in combination with DOX in vitro and in vivo. We found that combination treatment of YM155 and DOX in DOX resistant cells (MG63/DOX) could significantly inhibited cell proliferation and colony formation, induce cell apoptosis and promoted caspase-3, -8, and -9 activity in vitro, and promoted tumor regression in established OS xenograft models. Taken together, the evidence presented here supports the favorable preclinical evaluation that YM155 could overcome DOX the resistance in tumor cells thereby enhancing the effectiveness of DOX in OS, suggesting that YM155 in combination with DOX has potential in the treatment of osteosarcoma. PMID- 26770399 TI - Vitamin D3 alters Toll-like receptor 4 signaling in monocytes of pregnant women at risk for preeclampsia. AB - Vitamin D deficiency during pregnancy is thought to play a role in the development of preeclampsia; however, the underlying mechanism is not fully understood. In this study, a randomized double-blind placebo-controlled clinical trial was performed among 60 pregnant women at risk for pre-eclampsia according to abnormal uterine artery Doppler waveform. Subjects were randomly divided into 2 groups to receive a daily dose of 2000 IU vitamin D3 supplements (n=30) or receive placebo (n=30) between gestational weeks 20-32 for a total of 12 consecutive weeks. Because vitamin D3 supplementation can induce anti inflammatory cytokine signaling, peripheral blood monocytes were investigated by flow cytometry for expression of toll-like receptor 4 (TLR4), an important mediator of innate immune response. The pro-inflammatory cytokines secretion of tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, and IL-1 from monocytes, which are typically upregulated in preeclampsia, was also assessed. The incidence of preeclampsia was significantly lower in patients treated with vitamin D3 compared to the placebo group. Both the mean fluorescence intensity and the positive percentage of monocytes TLR4 in the vitamin D group were significantly lower compared to the placebo group, as well as the concentrations of secreted TNF-alpha, IL-6, and IL-1, while the concentration of IL-10 was higher. In the placebo group, the positive frequency of monocytes TLR4 was negatively correlated with the concentration of serum 25-hydroxyvitamin D in preeclampsia patients. Based on these results, we conclude that vitamin D3 supplementation for patients at risk of preeclampsia leads to a decrease in the expression of peripheral blood monocytes TLR4 and a subsequent decrease in pro-inflammatory cytokine secretion. Therefore, inhibiting the expression of monocytes TLR4 through vitamin D3 supplement may be a new approach to preeclampsia prevention. PMID- 26770400 TI - Anemia management trends in patients on peritoneal dialysis in the past 10 years. AB - OBJECTIVE: This study is to investigate anemia management trends in patients on peritoneal dialysis in Huashan Hospital in the past 10 years. METHODS: A total of 463 cases of patients receiving peritoneal dialysis from July 2004 to March 2014 were analyzed retrospectively. The patients enrolled in this study all were elder than 18 years old, those who had been followed up for at least 1 quarter. Clinical data of anemia including hemoglobin, serum iron, iron saturation, dosage of erythropoietin (EPO) and iron supplements were collected quarterly and then analyzed those data. RESULTS: In the first period of 25 quarters, in a certain range, increased dose of erythropoietin and iron content, can make the patient's hemoglobin gradually increased to the ideal level, which helps to treat the symptoms of anemia patients. Results of comparation before and after the education program showed that with the enhance the EPO injection compliance and treat anemia with the proper dose of EPO, the PD patients have stable level of Hemoglobin, accompanying with the decreased dose of oral Iron and intravenous iron. CONCLUSION: It was shown that hemoglobin value was constantly stable. Treat anemia with proper dose of EPO individually could cure anemia effectively with the reducing of iron supplement improvement peritoneal dialysis patients' anemia related knowledge, and the good compliance of injection of EPO, serum iron and iron saturation could still keep stable, although declined intake of iron supplements. Therefore, optimizing anemia management in peritoneal dialysis patients is helpful to improve their quality of life. PMID- 26770401 TI - Clinical experience of multiple flaps for the reconstruction of dorsal digital defects. AB - OBJECTIVE: In this report, we present our experience with reconstruction of the skin defects on the dorsum of the digits using multiple flaps. METHODS: Between November 2010 and March 2013, 45 patients with dorsal digital defects underwent reconstruction using homodigital dorsal digital fasciocutaneous flap (n = 17), heterodigital dorsal digital fasciocutaneous flap (n = 14), dorsal metacarpal artery fasciocutaneous flap (n = 8) and free venous flaps (n = 6). The average flap size was 1.5 * 1.5 cm to 2.0 * 2.5 cm. Donor sites were covered with full thickness skin graft. RESULTS: All flaps survived completely and the donor sites healed without complications. The mean follow-up period was 18 weeks. During the follow up period, 7 patients treated with reverse homodigital fasciocutaneous flaps developed swelling in the distal portion of flaps, 3 patients treated with reverse dorsal metacarpal artery fasciocutaneous flaps developed mild swelling in the distal portion of flaps but survive well, and 4 patients treated with free venous flaps experienced venous congestion. Of the 14 patients treated with heterodigital fasciocutaneous flaps, there were 11 cases with a retrograde pedicle and 3 cases with a direct pedicle. No full-thickness graft necrosis was noted. CONCLUSION: Multiple options are available for the repair of skin defects on the dorsum of the digits. Besides, the use of a heterodigital fasciocutaneous flap was a simple, safe, and less invasive regimen for repairing dorsal digital skin defects. PMID- 26770403 TI - Ferric nitrilotriacetate (Fe-NTA)-induced reactive oxidative species protects human hepatic stellate cells from apoptosis by regulating Bcl-2 family proteins and mitochondrial membrane potential. AB - Reactive oxidative species (ROS)-induced apoptosis of human hepatic stellate (HSC) is one of the treatments for liver fibrosis. However, how ROS (reactive oxygen species) affect HSC apoptosis and liver fibrosis is still unknown. In our study, ROS in human HSC cell line LX-2 was induced by ferric nitrilotriacetate (Fe-NTA) and assessed by superoxide dismutase (SOD) activity and methane dicarboxylic aldehyde (MDA) level. We found that in LX2 cells Fe-NTA induced notable ROS, which played a protective role in HSCs cells apoptosis by inhibiting Caspase-3 activation. Fe-NTA-induced ROS increased mRNA and protein level of anti apoptosis Bcl-2 and decreased mRNA protein level of pro-apoptosis gene Bax, As a result, maintaining mitochondrial membrane potential of HSCs. Fe-NTA-induced ROS play a protective role in human HSCs by regulating Bcl-2 family proteins and mitochondrial membrane potential. PMID- 26770402 TI - Changes in platelet function following cold storage of RBC suspensions. AB - OBJECTIVE: To provide a basis for the cold-storage of human platelets as a way to assess changes in platelet function. METHODS: Red blood cell suspensions (11 U and 50 U) were randomly selected at different storage times (3-28 days) and evidence of platelet activation (CD62P) and thromboelastography (TEG) reaction times were investigated. RESULTS: After 21 days of storage at 4 degrees C, a large number of activated platelets (PAC1+62P+, PAC1-62P+) within the red blood cell suspension (RBCs) retained their function and had TEG-maximum amplitude (TEG MA) indices in the normal range. CONCLUSION: We report that platelets in RBC suspensions retain high activity when stored at 4 degrees C for 21 days. The results provide important information for studies that involve storing platelets under cold conditions. PMID- 26770404 TI - Comparison of cytokine expressions in acute myocardial infarction and stable angina stages of coronary artery disease. AB - OBJECTIVE: To investigate the differential gene expression of cytokines and compare their impacts on the immune functions among the acute myocardial infarction patients (AMI), the stable angina patients (SA) and the controls. METHODS: 20 patients with AMI, 20 patients with SA and 20 healthy volunteers were recruited into the study. Whole human genome microarray analysis was used to detect the gene expression differences in interferons, interleukins, chemokines, tumor necrosis factors and associated receptors in peripheral blood mononuclear cells (PBMCs) among three groups. RESULTS: Compared with SA patients and the controls respectively, in AMI patients, IFNalpha2, IFNalphaR1, IFNalphaR2, IFNgammaR1, IFNgammaR2, L1beta, IL16, IL18, Cxcl1, Cxcl2, Cxcl6, CxcR2, CxcR4, LIGHT, TNFR1, LT-betaR, CD137, TRAILR, and TWEAKR mRNA expressions were significantly up-regulated (P<0.05), while Ccl5, Ccl24, Ccl28, CcR5, TWEAK, CD40, CD27, and BAFFR mRNA expressions were significantly down-regulated (P<0.05). But, there was no significant difference in cytokine expression between the SA patients and the controls. CONCLUSION: In AMI patients, mRNA expression levels of cytokines were imbalanced, indicating the dysfunction of the immune system. Together with no significant change of cytokines was observed between the SA and controls, showing the different cytokine related immune activity in the AMI and SA patients. PMID- 26770405 TI - Identifying the genes regulated by IDH1 via gene-chip in glioma cell U87. AB - Glioma is the most common form of primary brain tumor. Increasing evidence show that IDH1 gene mutation is implicated in glioma. However, the mechanism involved in the progression of glioma remains unclear until now. In the study reported here, we used gene chip to identifying the genes regulated with IDH mutanted at R132. The results showed that IDH1-mutant leads to 1255 up-regulated genes and 1862 down-regulated genes in U87 cell lines. Meanwhile, GO and gene-network was performed and shown IDH1-mutant mainly affect small molecule metabolic process, mitotic cell cycle and apoptosis. This result will lay a foundation for further study of IDH1 gene function in the future. PMID- 26770406 TI - Prognostic value of long noncoding RNA MALAT1 in digestive system malignancies. AB - BACKGROUND: MALAT1, a newly discovered long noncoding RNA (lncRNA), has been reported to be highly expressed in many types of cancers. This meta-analysis summarizes its potential prognostic value in digestive system malignancies. METHODS: A quantitative meta-analysis was performed through a systematic search in PubMed, Cochrane Library, Web of Science and Chinese National Knowledge Infrastructure (CNKI) for eligible papers on the prognostic impact of MALAT1 in digestive system malignancies from inception to Apr. 25, 2015. Pooled hazard ratios (HRs) with 95% confidence interval (95% CI) were calculated to summarize the effect. RESULTS: Five studies were included in the study, with a total of 527 patients. A significant association was observed between MALAT1 abundance and poor overall survival (OS) of patients with digestive system malignancies, with pooled hazard ratio (HR) of 7.68 (95% confidence interval [CI]: 4.32-13.66, P<0.001). Meta sensitivity analysis suggested the reliability of our findings. No publication bias was observed. CONCLUSIONS: MALAT1 abundance may serve as a novel predictive factor for poor prognosis in patients with digestive system malignancies. PMID- 26770407 TI - Overexpression of heparanase is associated with preeclampsia by inhibiting invasion of trophocytes. AB - BACKGROUND: Preeclampsia is associated with inadequate invasion of trophocytes and spiral artery remodeling. As a beta-D-glucuronidase enzyme, Heparanase is related to tumor angiogenesis, development and invasion. Trophocytes have similar characteristics to tumor cells, and heparanase could therefore play an important role in the pathogenesis of preeclampsia. METHODS: The expression of heparanase in severe preeclampsia and normal placentas was detected via real-time PCR, immunohistochemistry and western blotting. The effects of heparanase on trophocytes migration and invasion were investigated by culturing the HTR-8/Svneo cell line with recombinant human heparanase protein in vitro. RESULTS: The levels of inactive 65-kDa heterologous heparanase dimers were obviously increased, and the content of the 50-kDa active polypeptide was decreased in severe preeclampsia. Furthermore, exogenous heparanase protein could reduce the migration and invasion of HTR-8/Svneo cells. CONCLUSION: Our results suggested that heparanase might be an important factor in the pathogenesis of severe preeclampsia. PMID- 26770408 TI - miR-525-5p inhibits ADAMTS13 and is correlated with Ischemia/reperfusion injury induced neuronal cell death. AB - The understanding of molecular mechanism underlying ischemia/reperfusion-induced neuronal death and neurological dysfunction may provide therapeutic targets for ischemic stroke. In this study, miR-525-5p is clearly reduced in the ischemic brain after oxygen-glucose deprivation (OGD). Using TargetScan, MicroCosm Targets version 5, and microRNA.org databases, we identified miR-525-5p as a possible regulator of the ADAMTS13. We validated that ADAMTS13 is a target for miR-525-5p with a luciferase reporter activity assay. Moreover, adult rats subjected to focal cerebral ischemia exhibited a substantial reduction of miR-525-5p expression, which was inversely upregulated by ADAMTS13 expression. In vivo treatment with miR-525-5p agomir effectively decreased ADAMTS13 mRNA and protein levels in the ischemic region. Furthermore, knockdown of cerebral miR-525-5p reduced cell death and infarct size. In addition, the knockdown of ADAMTS13 by ADAMTS13 siRNA apparently abrogated the protective effect of miR-525-5p antagomir on OGD-induced cell death. Our data demonstrate that miR-525-5p is an endogenous regulator of ADAMTS13 that improves ischemia/reperfusion (I/R)-induced brain injury and dysfunction. PMID- 26770409 TI - Up-regulation of microRNA-664 inhibits cell growth and increases cisplatin sensitivity in cervical cancer. AB - BACKGROUND: Cervical cancer is one of the leading causes of cancer-related death in woman worldwide. In the present study, we investigated the role of microRNA 664 (miR-664) in regulating cancer migration and chemotherapy sensitivity in cervical cancer. METHODS: Quantitative real-time PCR (qPCR) was used to assess the mRNA levels of miR-664 in both cervical cancer cell lines and cancer tissues from human patients. Lentiviral vector containing miR-664 mimics (lv-miR-664) was used to upregulate endogenous miR-664 in cervical cancer HeLa cells. The effects of miR-664 up-regulation on cervical cancer cell migration and cisplatin sensitivity were assessed by MTT and Cisplatin assays. Furthermore, the effect of miR-664 up-regulation on E-Cadherin expression was examined by western blot. E Cadherin was then silenced by siRNA to examine its effect on miR-664 regulation on cervical cancer cell. RESULTS: MiR-664 was downregulated in both cervical cancer cell lines and cancer tissues in patients. In HeLa cells, lentivirus mediated miR-664 up-regulation reduced cancer cell migration and increased chemosensitivity to cisplatin. Western blot showed E-Cadherin was upregulated upon miR-664 overexpression in HeLa cells. Genetic silencing of E-Cadherin by siRNA reversed the inhibitory effect of miR-664 up-regulation on cervical cancer cell migration. CONCLUSION: Our study demonstrated that miR-664 played an important role in regulating cervical cancer, possibly modulated by E-Cadherin. PMID- 26770410 TI - Massive cryptogenic hemoptysis undergoing pulmonary resection: clinical and pathological characteristics and management. AB - Massive cryptogenic hemoptysis is a common presenting symptom and cause of hospitalization for respiratory diseases, and represents a challenging condition in the clinical. This study aimed to analyze the clinical and pathologic data and management of patients with massive cryptogenic hemoptysis. We retrospectively reviewed 12 patients with massive cryptogenic hemotysis in our hospital between January 2003 and December 2012. Bronchoscopy showed submucosal vascular abnormalities in 4 patients. Of 6 patients managed with conservative measures, bleeding was completely controlled in 2 patients. Of 10 hemoptysis patients, three were controlled by bronchial arterial embolization, and seven by surgery. Pathological examination showed a superficial dysplastic, tortuous and dilated bronchial artery under the bronchial epithelium in 4 patients, and bronchiole dilation in 2 patients, indicating Dieulafoy's disease of the bronchus and bronchiectasis. No malignance developed within the follow-up. In conclusion, Dieulafoy's disease of the bronchus and bronchiectasis should be suspected in patients with massive cryptogenic hemoptysis. BAE and surgical treatment should be considered in case that massive hemoptysis could not be controlled by conservative management. PMID- 26770411 TI - Radiofrequency ablation of advanced lung tumors: imaging features, local control, and follow-up protocol. AB - To prospectively observe imaging features and local control of advanced lung tumors after radiofrequency ablation (RFA), and to propose a follow-up protocol post-ablation. 58 stage IV malignant lung tumor patients were enrolled in our study. One hundred of lung lesions were performed 77 sessions of RFA. Enhanced computed tomographic (CT) images of pre-ablation, 1-month, and 3-month post ablation and thereafter every 3 months were obtained. Positron emission tomographic/CT (PET/CT) was performed pre-ablation, 3-month post-ablation and thereafter every 6 months. The CT size, shape, enhancement, and PET/CT metabolic activity of the ablated zone were analyzed to assess local lesion control. There was significant difference in lesion size between pre-ablation and 1-month post ablation (P=0.000), 1 and 3-month post-ablation (P=0.000), 3 and 6-month post ablation (P=0.006). Metabolic activity of the ablated zone after 3 months decreased markedly as compared with pre-ablation (p=0.001). Local control rate was 88%, and forms of definite recurrence or residual included increased size, nodular enhancement, and central enhancement. Time to local progression (TTLP), progression-free survival (PFS), and overall survival (OS) were 15.4+/-7.5, 9.6+/ 5.8 and 18.0+/-7.0 months respectively. No death related to operation occurred, and the main complication rate was 29%, of which 9% needed clinical management. RFA is a safe and effective approach for local control of lung tumors even if in advanced patients. To obtain definite CT evaluation, lesion size at 1-month post ablation as the baseline is appropriate, with efficacy assessment 6-month post ablation. PET/CT is a useful tool to predict recurrence or residual at least 3 months post-ablation. PMID- 26770412 TI - Equilibrium radionuclide angiocardiography for the evaluation of right ventricular ejection fraction in patients with cardiac disorders. AB - OBJECTIVE: To compare correlation between right ventricular ejection fraction (RVEF) derived from MRI and equilibrium radionuclide angiocardiography (ERNA) depicted from the left anterior oblique (LAO) view and anterior (ANT) view [designated as ERNA (LAO) and ERNA (ANT), respectively]. METHODS: Twenty-one patients with cardiac disorders received ERNA and cardiac MRI examination within 2 weeks were enrolled in this study. The region of interest (ROI) in right ventricle was depicted from the LAO and anterior (ANT) views to calculate the ERNA (LAO) and ERNA (ANT). Cardiac MRI was performed as served as reference standard to compare correlation between RVEF derived from MRI and ERNA (LAO)/ERNA (ANT), respectively. The repeatability was evaluated according to the intraclass correlation coefficient (ICC). RESULTS: RVEF obtained through MRI was closely correlated with that obtained through ERNA (LAO) view (r=0.883) and ERNA (ANT) view (r=0.891), respectively. Bland-Altam analysis indicated the RVEF derived from the ERNA (LAO) view was obviously underestimated in patients with right ventricular enlargement. Meanwhile, the RVEF derived from the anterior view was much closer to the RVEF derived from MRI compared with that obtained from the LAO view. CONCLUSIONS: ERNA is effective for the determination of RVEF. LAO is still preferred for the determination of RVEF, but the RVEF may be underestimated in the patients with right ventricular enlargement. Determination of RVEF based on ANT is solely recommended in the determination of RVEF in patients with right ventricular enlargement and serves as a control. PMID- 26770413 TI - Identification of a novel molecular probe for recognition of human osteosarcoma cell using the cell-SELEX method. AB - Osteosarcoma is the most common primary malignant bone tumor in adolescents and young adults. The lack of specific probes for human osteosarcoma hinders the early diagnosis and treatment of metastatic disease. In the present study, we have designed a novel aptamer using the cell-based Systematic Evolution of Ligands Exponential Enrichment (cell-SELEX) technique that specifically recognizes the U-2 OS human osteosarcoma cell line. Candidate aptamer families were identified through nine rounds of selection followed by sequence analysis and fluorescent labeling in addition to specific binding to U-2 OS cells. We identified one aptamer that showed high affinity and specificity to target cells, but did not recognize non-osteosarcoma negative control tumor cell lines. Moreover, we show that the selected aptamer can effectively be used as a molecular probe for specific recognition of clinical osteosarcoma samples. The generation of aptamer libraries can be used not only for the specific diagnosis of osteosarcoma, but also to build a platform for developing probe-carrier antitumor drugs complexes and targeted therapies for osteosarcoma. PMID- 26770414 TI - Involvement of Bcl-2-associated athanogene (BAG)-family proteins in the neuroprotection by rasagiline. AB - Rasagiline, a novel monoamine oxidase (MAO)-B inhibitor, has a mild to moderate effect in relieving Parkinson's disease (PD) symptoms as well as unique neuroprotective effects. Previous studies demonstrated rasagiline protect neurons by regulating Bcl-2 family proteins. Our study aimed to study whether Bcl-2 associated athanogene (BAG)-family proteins, which were reported closely associated with neurodegenerative disease, were involved in the neuroprotective effect of rasagiline. We found that after the administration of 1-methy1-4-phenvl 1,2,3,6-tetrahvdropvridine (MPTP), BAG2 and BAG5 proteins were up-regulated in the substantia nigra dopaminergic neurons of PD mouse model. A further increase of BAG2 and BAG5 was detected after intragastric administration of rasagiline to post-MPTP lesioned mice. Thus, the current study proved the association of BAG family proteins with PD, and suggested the involvement and a positive role of BAG2, BAG5 in the neuroprotection of rasagiline. These preliminary results implicate a novel pathway for further study on neuroprotection of rasagiline. PMID- 26770415 TI - Correlation analysis of urine metabolites and clinical staging in patients with ovarian cancer. AB - This study is to investigate the correlation between urine metabolites and clinical staging in patients with ovarian cancer. The urina sanguinis from 56 cases of primary epithelial ovarian cancer patients and 15 healthy volunteers was collected and the urine metabolites were extracted. Ultra high performance liquid chromatography/time-of-flight mass spectrometry (UPLC-Q-TOF-MS) analysis was performed. Principal component analysis (PCA) and partial least squares discriminant analysis (PLS-DA) were used to analyze the mass spectrometry data. Database retrieval and comparison of the screened metabolites were performed and one-way ANOVA and least significant difference (LSD) t test were carried out. PCA analysis of UPLC-Q-TOF-MS results showed that the score plots of samples from healthy people and patients with ovarian cancer at different clinical stages were separated. Further PLS-DA analysis significantly improved the classification results. The R(2)X was 0.757, the R(2)Y was 0.977 and the Q(2)Y was 0.87, indicating that the model stability and predictability were good. Eight metabolites, including N-acetylneuraminic acid-9-phosphate, 5'-methioadenosine, uric acid-3-nucleoside, pseudouridine, L-valine, succinic acid, L-proline and beta-nicotinamide mononucleotide were identified. The contents of these metabolites increased with the development of the disease. There was correlation between urine metabolites and clinical staging in patients with ovarian cancer. PMID- 26770416 TI - Correlation of human papilloma virus with oral squamous cell carcinoma in Chinese population. AB - Previous studies indicated that oral squamous cell carcinomas (OSCC) might be related to human papilloma virus (HPV) infection. However, the relationship between OSCC in a Chinese population and oral HPV infection is still unclear. In this study, we evaluate the relationship of OSCC with HPV infection in a Chinese population via a meta-analysis. The reports on HPV and OSCC in a Chinese population published between January, 1994, and October, 2015 were retrieved via CNKI/WANFANG/pubmed databases. According to the inclusion criteria, we selected 26 eligible case-control studies. After testing the heterogeneity of the studies by the Cochran Q test, the meta-analyses for HPV and HPV16 were performed using the random effects model. Quantitative meta-analyses showed that, compared with normal oral mucosa the combined odds ratio of OSCC with HPV infection were 1.98 (95% CI: 1.34-2.92). The test for overall effect showed that the P value was less than 0.05 (Z = 3.46). Forest plot analyses were seen in Figures 2 and 3. Publication bias and bias risk analysis using RevMan 5.3 software were measured indicators of the graphics of the basic symmetry. High incidences of HPV infection were found in the samples of Chinese OSCC. For the Chinese population, HPV infection elevates the risk of OSCC tumorigenesis. PMID- 26770417 TI - Comparison the effects of pressurized salt ice packs with water ice packs on patients following total knee arthroplasty. AB - The aim of this study was to estimate the effects of pressurized salt ice packs (PIP) with water ice packs (WIP) which are used to relieve pain and decrease swelling on patients following total knee arthroplasty (TKA). Sixty-nine patients undergoing primary unilateral TKA were randomly divided into two groups (PIP group and WIP group). We used a visual analog scale (VAS) to score knee pain and the score was recorded. The knee bilateral girth, the slipping times of the ice pack, and the times of wound dressing or bed moist were recorded during cryotherapy. The scores of pain between the two groups were significant difference in 12 h, 24 h, 48 h and 72 h after TKA (P < 0.05). No significant difference was found for the girth measurements of the operative knee on the two levels in 12 h, 24 h and 72 h, respectively. However, there was statistically difference for girth measurements between the two groups in 48 h after TKA (P < 0.05). PIP is a cheap, safe and simple method, which is more effective than WIP on reducing pain and swelling degree of patients. Thus, PIP is recommended in clinical nursing work. PMID- 26770418 TI - The neuroprotective effects of aspirin following crush injury to rat sciatic nerve. AB - Aspirin has been reported to be neuroprotective and produce some benefits for central nervous system diseases. However, the possibility of using aspirin as a neuroprotective agent for peripheral nerve injuries has rarely been reported thus far. The aim of the present study was to investigate the possibly beneficial effects of aspirin on sciatic nerve crush injury therapy in rats. Crush injury animal model was prepared with Sprague-Dawley rats. The animals were evenly divided into high-dose aspirin group, low-dose aspirin group, and vehicle group. Aspirin solution or normal saline were intraperitoneally injected once a day for 28 days after sciatic nerve crush injury. A sham-operative group was also added as normal control. The results from walking track analysis and electrophysiological assessment indicated that motor functional recovery in the aspirin groups were better than that in the vehicle group. Morphometric analysis of regenerated nerves and Fluoro-Gold retrograde tracing demonstrated that axonal regeneration in the aspirin groups was superior to that in the vehicle group. Our findings suggest that aspirin might be used as a neuroprotective agent for treating peripheral nerve injuries. PMID- 26770419 TI - Tissue engineered skin for diabetic foot ulcers: a meta-analysis. AB - To evaluate the effectiveness of tissue engineered skin in the management of diabetic foot ulcer. We searched PubMed, EMBASE and ISI Web of Science database in order to obtain the randomized controlled trial with interventions of tissue engineered skin. A meta-analysis was used to compare the effectiveness between tissue engineered skin and conventional treatment in the patients with diabetic foot ulcer. This meta-analysis was performed by STATA 11 software. The risk factor was analyzed by random effect model pooled odds ratio (OR) and 95% confidence interval (CI). Moreover, the funnel plot was used to assess the published bias of articles. Eight studies were included, and a total of 1060 cases were involved for this meta-analysis. The OR of tissue engineered skin for diabetic foot ulcers was 1.76 (95% CI: 1.35-2.30). A subgroup analysis was conducted for different types of tissue engineering skin, combined OR was 1.91 (95% CI: 1.12-3.27) for Derma graft, 2.05 (95% CI: 1.20-3.50) for Graft skin and 1.57 (95% CI: 0.91-2.70) for Hyalo graft 3D. Applying tissue engineered skin is more effective in the improvement of wound closure in patients with diabetic foot ulcers, compared with conventional treatment. PMID- 26770420 TI - Modified technique for correction of isolated radial head dislocation without apparent ulnar bowing: a retrospective case study. AB - OBJECTIVE: There is currently no general consensus on the optimal treatment of chronic radial head dislocation. MATERIAL AND METHODS: Considering that the annular ligament is important in maintaining elbow stability, we developed a modified method for annular ligament reconstruction in pediatric cases of radial head dislocation without ulnar bowing. We retrospectively investigated the therapeutic outcomes of this technique in a series of cases. We used our modified technique for the treatment of five patients between January 2006 and January 2012. The average age of the patients at the time of injury was 9 years (range, 6 14 years), and the patients were followed up for 1 to 3 years. RESULTS: The perioperative and follow-up data of the patients were examined. All five surgical procedures were completed uneventfully and had been tolerated well by the patients, with minimal complications. Remarkable improvement was noted in all the cases at the end of the follow-up period. CONCLUSIONS: Our modified technique for annular ligament reconstruction was effective in achieving good reduction of the radial head dislocation with minimal complications in pediatric cases of isolated radial head dislocation without apparent ulnar bowing. PMID- 26770421 TI - Long-term follow-up of successful treatment for dandy-walker syndrome (DWS). AB - BACKGROUND: Various managements of Dandy-Walker syndrome (DWS) from open excision of the cysts to CSF diversion have been reported. However, optimal treatment for DWS remains elusive. METHODS: Cyst fenestration was employed firstly, but failed 15 days after the surgery. Then a ventriculoperitoneal (VP) shunt was inserted and the patient discharged from hospital 13 days after the second surgery. During the 12-year follow-up, CT scanning, MRI, and X-radiation were performed. RESULTS: CT scanning showed that the size of ventricular system gradually returned to normal. MRI revealed similar changes of the ventricular system, and further revealed the development of supratentorial brain. The results of X-radiation during the follow-up years showed that the peritoneal end of the shunt might be already out of the abdominal cavity. Slow refilling of the shunt valve may suggest that the shunt could be probably not functional. CONCLUSION: The treatment of the patient was successfully, and the abnormal cerebral ventricle system gradually recovered during the 12-year follow-up. Because the patient might be probably independent on the shunt, further choice of the shunt removal should be thinking thoroughly, considering both safety and quality of life for the patient. PMID- 26770422 TI - Expression of MICA in oral squamous carcinoma cells and its effect on NK cells. AB - OBJECTIVE: This study aims to observe the expression of MHC-class I chain related protein A (MICA) in oral squamous carcinoma cell and explore its effects on NK cells. METHODS: Normal oral mucosa epithelial cell line NOK and oral squamous carcinoma cell lines OEC-M1, SAS and SCC-25 were used in this study. MICA expression in the cells was detected by western blotting and RT-PCR methods, sMICA was detected by ELISA method. The cells were transfected by pEGFP-MICA and pEGFP-NC respectively using Lipofectamine 2000 kit. The transfected cells were co cultured with NK92 cells. Killing activity of NK92 cells was detected by LDH release method and NKG2D was detected by Flow cytometry. ADAM10 and ADAM17 were detected by ELISA method. RESULTS: MICA expression in OEC-M1, SAS and SCC-25 cells were lower than that of NOK cells (P<0.01), sMICA levels in OEC-M1, SAS and SCC-25 cells were higher than that of NOK cells (P<0.01). Over-expression of MICA in SCC-25 cells could significantly increase the killing activity of NK92 cells (P<0.01), up-regulate NKG2D (P<0.01) and decrease ADAM10 and ADAM17 contents (P<0.01). CONCLUSIONS: MICA expressed lowly in oral squamous cell carcinoma cells, over-expression of MICA could significantly increase the killing activity of NK92 cells, which could be related with the regulation of ADAM. PMID- 26770423 TI - Pre-operative lymph node status of gastric cancer evaluated by multidetector computed tomography. AB - The purpose of the present study was to perform a meta-analysis to evaluate the diagnostic value of Multidetector computed tomography (MDCT) in the pre-operative lymph node (N) staging in gastric cancer (GC) patients. The Medline, Embase and Web of Knowledge were searched for studies assessing the diagnostic value of MDCT in the pre-operative evaluation of TNM staging in GC patients. We pooled the sensitivity, specificity, positive and negative Likelihood ratio (LR+ and LR-), Diagnostic Odds Ratio (DOR) and constructed summary receiver operating characteristic curves (ROC). A total of 30 studies including 6637 GC patients were analyzed. The pooled estimates of sensitivity, specificity, LR+, LR- and DOR of MDCT in the detection of pre-operative N staging in GC patients were 0.67 (95% CI: 0.66-0.69 ), 0.84 (95% CI: 0.83-0.85), 3.25 (95% CI: 2.69-3.93), 0.36 (95% CI: 0.28-0.46) and 10.31 (95% CI: 7.66-13.88), respectively. The results of a summary ROC showed that the AUC and Q* were 0.8338 and 0.7661, respectively. As a control, the AUC and Q* of endoscopic ultrasonography were 0.8063 and 0.7414, respectively. Currently, it is necessary to recommend the routine clinical application of MDCT in the preoperative evaluation of lymph node status in GC patients. PMID- 26770424 TI - Effect of simvastatin on the expression of nephrin, podocin, and vascular endothelial growth factor (VEGF) in podocytes of diabetic rat. AB - This study aims to investigate the effects and mechanisms of simvastatin on podocyte injuries in diabetic rats. Streptozotocin was used to induce diabetes in a rat model. Three groups were tested: normal control (NC) group, diabetes mellitus control (DM) group, and simvastatin (SVT) group. The serum creatinine, cholesterol, and urinary albumin excretion rate (UAER) were measured 4 to 8 weeks after administering either saline or the drug. Renal pathological changes were observed, and immunohistochemistry was performed to determine the expression of nephrin, podocin, and vascular endothelial growth factor (VEGF). Real-time PCR was performed to detect the mRNA expression levels of nephrin, podocin, and VEGF. Serum creatinine levels and the UAER were higher in the DM group than in the NC group (P < 0.01). The protein and mRNA expression levels of nephrin and podocin were lower in the DM group than in the NC group (P < 0.01); whereas, the expression of VEGF protein and mRNA was higher in the DM group than in the NC group (P < 0.01). Simvastatin (SVT) could reduce serum creatinine levels and the UAER, maintain the expression of nephrin and podocin, reduce the expression of VEGF, and improve the pathological changes of podocytes, which were much more pronounced at 8 weeks (P < 0.01). Simvastatin could maintain the distribution of nephrin and podocin in podocytes, inhibit VEGF expression, and thus improve podocyte injuries and protect kidney functions in diabetic rats. PMID- 26770425 TI - Meta-analysis of association between the genetic polymorphisms on chromosome 11q and Alzheimer's disease susceptibility. AB - Alzheimer's disease (AD) is a neurodegenerative disease mostly occurred in the elderly. Genetic mutation is one of well-established risk factors for AD. Several polymorphisms on chromosome 11q were reported to be associated with AD susceptibility. Hence we performed a meta-analysis to systematically assess the association between the most-reported polymorphisms on chromosome 11q (rs10793294, rs7115850, rs7101429, rs4945261, rs2373115, rs670142, rs610932, rs541458 and rs3851179) and AD risk. A comprehensive literature search in the electronic databases was performed to identify all eligible studies. The pooled odds ratios (OR) and 95% confidence intervals (95% CI) were calculated to evaluate the association between 11q variants and AD risk by using the allelic model. Sensitivity analysis was carried out to analyze the influence of single study on the overall results. Begg's funnel plots and Egger's test were used to assess the publication biases among studies. All the statistical analyses were conducted by using STATA 12.0 Software (Stata Corp, College Station, TX, USA). A total of 35 eligible articles were included in our meta-analysis. Our data showed that the polymorphism of rs610932 were significantly associated with lower AD risk with a pooled OR of 0.88 (95% CI: 0.84-0.92, P=0.005). The other SNPs of rs494526 (OR=0.83, 95% CI: 0.65-1.00, P<0.001), rs2373115 (OR=0.85, 95% CI: 0.75 0.95, P<0.001) and rs670139 (OR=1.09, 95% CI: 1.05-1.12, P=0.554) were shown to be correlated with lower AD risk. Subgroup analysis revealed a similar result in Caucasians. But only the rs610932 polymorphism was found to be associated with lower AD risk in Asians. The polymorphism of rs610932 was shown to be a risk factor for AD while the other three genetic variants (rs494526, rs2373115 and rs610932) may act as protective factors against AD. PMID- 26770426 TI - Sarcopenia as a prognostic factor in hepatolithiasis-associated intrahepatic cholangiocarcinoma patients following hepatectomy: a retrospective study. AB - BACKGROUND: Sarcopenia is closely associated with poor performance status and high mortality in cancer patients. The present study is to determine the correlation between sarcopenia and prognosis of hepatectomy for hepatolithiasis associated intrahepatic cholangiocarcinoma (IHHCC). METHODS: Sixty-seven eligible IHHCC patients who underwent hepatectomy, between January 2000 and August 2014 were retrospectively evaluated. Sarcopenia was determined from skeletal muscle index (SMI), assessed by skeletal muscle mass on axial computed tomography images. Factors contributing to overall survival (OS) and recurrence-free survival (RFS) were analyzed by univariate and multivariate analyses. RESULTS: Sarcopenia occurred in 33 (49.3%) out of 67 patients. Median OS of the enrolled patients was 12 months. Sarcopenic patients had a shorter OS compared with non sarcopenic patients (P < 0.001). On univariate analyses, sarcopenia was significantly associated with overall survival (OS) and recurrence-free survival (RFS; both P < 0.05). On multivariate analysis, sarcopenic patients suffered poor overall survival (P < 0.001) and recurrence-free survival (P = 0.011) compared with non-sarcopenic patients. CONCLUSIONS: Preoperative sarcopenia is an independent biomarker of poor prognosis in IHHCC patients following hepatectomy. The identification of sarcopenia may enhance a clinical consideration on decision making for IHHCC patients before surgery. PMID- 26770427 TI - The utility of biomarker risk prediction score in patients with chronic heart failure. AB - Chronic heart failure (CHF) remains a leading cause of cardiovascular death worldwide. Current risk models allow better prognosis, however further tools for assessing risk are needed. Thus, this study was aimed to evaluate whether biomarker risk prediction score is powerful tool for risk assessment of three year fatal and non-fatal cardiovascular events in CHF patients. METHODS: A prospective study on the incidence of fatal and non-fatal cardiovascular events, as well as the frequency of occurrence of death from any cause in a cohort of 388 patients with CHF during 3 years of observation was performed. Circulating levels of NT-pro brain natriuretic peptide (NT-pro-BNP), galectin-3, high-sensitivity C reactive protein (hs-CRP), osteoprotegerin and its soluble receptor sRANKL, osteopontin, osteonectin, adiponectin, endothelial apoptotic microparticles (EMPs) and mononuclear progenitor cells (MPCs) were measured at baseline. RESULTS: Median follow-up of patients included in the study was 2.76 years. There were 285 cardiovascular events determined, including 43 deaths and 242 readmissions. Independent predictors of clinical outcomes in patients with CHF were NT-pro-BNP, galectin-3, hs-CRP, osteoprotegerin, CD31(+)/annexin V(+) EMPs and EMPs/CD14(+)CD309(+) MPCs ratio. Index of cardiovascular risk was calculated by mathematical summation of all ranks of independent predictors, which occurred in the patients included in the study. The findings showed that the average value of the index of cardiovascular risk in patients with CHF was 3.17 points (95% CI = 1.65-5.10 points). Kaplan-Meier analysis showed that patients with CHF and the magnitude of the risk of less than 4 units have an advantage in survival when compared with patients for whom obtained higher values of ranks cardiovascular risk score. CONCLUSION: Biomarker risk score for cumulative cardiovascular events, constructed by measurement of circulating NT-pro-BNP, galectin-3, hs-CRP, osteoprotegerin, CD31(+)/annexin V(+) EMPs and EMPs/CD14(+)CD309(+) MPCs ratio, reliably predicts the probability survival of patients with CHF, regardless of age, gender, state of the contractile function of the left ventricle and the number of comorbidities. PMID- 26770428 TI - Comparison of CO2 laser and conventional laryngomicrosurgery treatments of polyp and leukoplakia of the vocal fold. AB - The efficacies of CO2 laser and conventional laryngeal microsurgery for vocal cord benign (vocal cord polyp) and precancerous (vocal cord leukoplakia) lesions were compared. Patients with bilateral vocal cord polyps (n = 60) and leukoplakia (n = 30) were divided randomly into two groups. One group was treated with throat microsurgical instruments and underwent routine lesion resection (conventional group) and the other with CO2 laser (laser group). For the subjective assessment, the tools GRABS and VHI were used. The objective assessment, A multi-dimensional voice program module for voice spectrum analysis was used. The laser group was slightly worse than the conventional group 1 week post-surgery by stroboscopic findings. The subjective and objective data of the two groups pre-and post surgery showed that the voice recovery of the laser group was significantly better than that of the conventional group (P < 0.05). CO2 laser laryngeal microsurgery for vocal cord polyp and leukoplakia can improve significantly the vocal cord morphology and pronunciation quality. The procedure is especially more effective than conventional surgery in patients with vocal cord leukoplakia. PMID- 26770429 TI - Functional magnetic resonance and diffusion tensor imaging analysis of verbal working memory in patients with temporal lobe epilepsy. AB - OBJECTIVE: This study aimed to investigate the relationships between brain functions and verbal working memory (VWM) impairments in patients with temporal lobe epilepsy (TLE). METHODS: Functional magnetic resonance imaging was performed on 15 healthy controls and 15 patients with TLE while they performed the N-back task in order to compare the brain areas that were activated during VWM. Diffusion tensor imaging was then performed to examine the integrity of the VWM related fiber bundles. RESULTS: The patient group exhibited a significant reduction in the activation of the brain areas that were negatively activated in the VWM task in the control group (P < 0.05), and no activation was observed in the patient group in the brain areas that were positively activated in the VWM task in the control group. The fractional anisotropy values of both cingulate bundles were significantly reduced in the patient group compared with those in the control group (P < 0.05), and these values were positively correlated with the number of activated pixels in the ipsilateral prefrontal areas (left: r = 0.790, P < 0.05; right: r = 0.852, P < 0.05). CONCLUSIONS: Patients with TLE exhibited impaired VWM functions that were related to subtle alterations in the cingulate bundles. PMID- 26770430 TI - Control and prevention of myocardial fibrosis using Pyk2-related non-kinase. AB - OBJECTIVE: To investigate the antifibrotic effect of Pyk2-related non-kinase (PRNK) and explore the possibility of using adenovirus carrying PRNK gene for targeted inhibition of Pyk2 to treat myocardial fibrosis. METHOD: Adenovirus carrying PRNK gene was constructed and the angiotention II (Ang II)-induced rat cardiac fibroblasts (CFs) were transfected with the adenovirus. The expressions of PRNK and phosphorylated Pyk2 proteins in CFs were detected. After the preparation of rat model of abdominal aortic stenosis, the rats were infected by the adenovirus expressing PRNK gene. Four groups were set up: sham operation group, PRNK group, drug intervention group and operation group. Myocardial collagen volume fraction (CVF) and perivascular collagen area (PVCA) were measured through Van Gieson (VG) staining, and the content of blue-stained collagen was analyzed by Masson's trichrome staining. TUNEL method was used to detect myocardial cell apoptosis, and secretions of type I and IV collagen in myocardial tissues were detected by ELISA; expressions of PRNK and phosphorylated Pyk2 proteins were detected by Western Blot. RESULTS: Adenoviral vector carrying PRNK gene was successfully constructed; rat CFs were effectively transfected by the adenovirus that expressed PRNK gene stably. The adenoviruses were injected into rats with myocardial interstitial fibrosis via the tail vein. CVF, PVCA and grayscale of blue-stained collagen in the treatment groups were significantly lower than those in the control group, while the apoptosis rate of CFs in the former was significantly higher than that in the latter. In the transfection group, PRNK protein was upregulated in CFs, and the phosphorylated Pyk2 protein was downregulated. PPARgamma agonist rosiglitazone (RSG) was injected as a comparison. The secretions of type I and IV collagen in myocardial tissues and serum did not show significant differences, and they were all much lower than those of the control. CONCLUSION: Adenoviral vector provides an effective means for the transfer of genes in researches on the mechanism and prevention and control of myocardial fibrosis. Targeted inhibition of Pyk2 using PRNK is a new pathway to achieve an antifibrotic action. Highly expressed in CFs, PRNK inhibits myocardial fibrosis by inhibiting the phosphorylation of Pyk2 through competitive binding. We preliminarily demonstrate the feasibility of using adenoviral vector carrying PRNK gene for targeted inhibition of Pyk2 to treat myocardial fibrosis. PMID- 26770431 TI - AS-IV protects against kidney IRI through inhibition of NF-kappaB activity and PUMA upregulation. AB - OBJECTIVE: To determine and explore the effect of Astragalus saponin IV (AS-IV) on ischemia/reperfusion (IR)-induced renal injury and its mechanisms. METHODS: Experimental model of renal I/R was induced in rats by bilateral renal artery clamp for 45 min followed by reperfusion of 6 h. Rats were divided into three groups: 1 sham 2 IRI 3 IRI/AS-IV. In IRI/AS-IV groups, AS-IV was orally administered once a day to rats at 2 mg.kg(-1).d(-1) for 7 days prior to ischemia. At 6 h after reperfusion, the inflammatory cytokines and renal function was assessed and NF-kappaB activity and PUMA expression was detected. Apoptotic cells was detected by TUNEL assay. RESULTS: AS-IV significantly decreased serum and tissue levels of IL-6 and TNF-alpha, and reduced apoptotic cell counts and histological damage. AS-IV down-regulated the phosphorylation of p65 subunit of NF-kappaB (NF-kappaB p65) and PUMA expression, and the NF-kappaB activity compared to the I/R groups. CONCLUSIONS: AS-IV provided protection against IRI induced renal injury by reducing apoptosis and inflammation through inhibition of NF-kappaB activity and PUMA expression. AS-IV pre-treatment ameliorated tubular damage and suppressed the NF-kappaB p65 expression. PMID- 26770432 TI - The effect of inflammatory cytokines and the level of vitamin D on prognosis in Crimean-Congo hemorrhagic fever. AB - Crimean-Congo haemorrhagic fever (CCHF) is a tick-borne viral disease. Its pathogenesis basically involves endothelial damage. The aim of this study was to determine serum IL2, IL6, IL 10 and 25 OH Vitamin D levels in patients with CCHF and also to reveal their role in the clinical course and prognosis of the disease. Diagnosis of CCHF was confirmed using the positive polymerase chain reaction (PCR) test and/or positive IgM antibody by enzyme-linked immunosorbent assay (ELISA). Serum IL-2, IL-6, IL-10 and total 25 OH Vitamin D levels were also measured using ELISA. Eighty CCHF patients and 110 healthy controls were enrolled. IL2, IL6 and IL10 levels were significantly higher in the patient group. IL 6 and IL 10 levels were significantly higher in the fatal group. There was a positive correlation between Vitamin D and AST (r=0.402; P<0.001), and another positive correlation between IL-6 and CK (r=0.714; P<0.001). High IL6 and L10 levels are a significant indicator of fatality. Cytokines are only one of the factors responsible for mortality. We conclude that the pathogenesis of the disease can be better understood by elucidating the complicated cytokine network. PMID- 26770433 TI - Danshen improves damaged cardiac angiogenesis and cardiac function induced by myocardial infarction by modulating HIF1alpha/VEGFA signaling pathway. AB - OBJECTIVE: The traditional Chinese medicinal Danshen (Salvia miltiorrhiza), has long been used to treat cardiovascular diseases, however, the mechanism underlying its effects remain unclear. Here, this study would to investigate the effects of Danshen injection on myocardial infarction-induced cardiac damage. METHODS: Danshen was injected into mice models at low dose (3 g/kg per day) or at high dose (6 g/kg per day) after left anterior descending coronary artery (LAD) ligation. After 4 weeks, cardiac function was evaluated by echocardiography. Paraffin sections of the hearts were used for isolectin GS-IB4 staining. Protein and mRNA expression levels of HIF1alpha and VEGFA were evaluated by western blotting and real-time polymerase chain reaction (RT-PCR). RESULTS: The hearts showed significantly impaired angiogenesis and slightly increase of HIF1alpha and VEGFA expression after LAD ligation. The angiogenesis defect and heart failure were partially rescued in Danshen treatment mice with great increase of HIF1alpha and VEGFA mRNA levels and protein expression. CONCLUSION: These results illustrated that the protective effects of Danshen injection in responsive cardiac angiogenesis were at least in part due to increased HIF1alpha and VEGFA expression. PMID- 26770434 TI - Comparison of transcranial ultrasound and cranial MRI in evaluations of brain injuries from neonatal asphyxia. AB - Full-term infants with early-stage brain injuries from asphyxia were examined with two-dimensional ultrasound and color Doppler to assess the use of ultrasound in evaluating early brain injuries after neonatal asphyxia. The sonographic features of ultrasound and color Doppler were compared to those of magnetic resonance imaging (MRI). Ultrasound was used to monitor the brain parenchyma, lateral ventricles, and cerebral hemodynamics in the asphyxia group and full-term control group 24, 48, and 72 h after birth. MRI and diffusion-weight imaging (DWI) were performed within 72 h. Cerebral edema changes were most obvious with ultrasound within 48 h of asphyxia, while the cerebral hemodynamic changes were most obvious within 24 h. These results suggested that ultrasound detected early cerebral edema better than MRI did. PMID- 26770435 TI - Gingipains from Porphyromonas gingivalis promote the transformation and proliferation of vascular smooth muscle cell phenotypes. AB - The aim of the present study was to ascertain the effect of Porphyromonas gingivalis cysteine protease gingipain on the proliferation of rat aortic smooth muscle cells (RASMCs). Gingipains were isolated and purified from the supernatant of P. gingivalis W83, which was cultured under standard anaerobic conditions; primary RASMCs were also cultured. RASMCs were exposed to 200, 100, 50, 25, 12, 6, 3, 1, and 0 MUg/mL activated gingipains and the proliferation was evaluated using a cell counting kit-8 (CCK-8) assay after 48 h. alpha-Smooth muscle actin (alpha-SMA) and osteopontin (OPN) expression were measured by immunohistochemical staining. In addition, RASMCs were stimulated with 5, 10, 20, and 40 MUM KYT-1 (arg-gingipain inhibitor) and KYT-36 (lys-gingipain inhibitor) in combination with the gingipain extracts. Different concentrations of gingipains significantly promoted the proliferation of RASMCs, except those treated with 1 MUg/mL, compared to the untreated controls. The proliferation was sustained at a concentration above 12 MUg/mL. Immunohistochemical staining showed OPN expression after gingipain stimulation. The proliferative effects of gingipains on RASMCs were blocked after treatment with 10 MUM KYT-1 or 10 MUM KYT-36 (P < 0.0001); however, the difference between KYT-1 and KYT-36 groups was not statistically significant. These results demonstrated that gingipains can promote phenotypic transformation and proliferation of RASMCs and their effects were blocked by KYT 1 and KYT-36, which help us to ascertain whether Rgp or Kgp contributes to the development of atherosclerosis. PMID- 26770436 TI - Long term prognosis of acute coronary syndrome with chronic renal dysfunction treated in different therapy units at department of cardiology: a retrospective cohort study. AB - Coronary care unit is common in hospitals and clinical centers which offer intensive care and therapy for severe coronary artery disease patients. However, if coronary care unit could improve the long term prognosis of acute coronary syndrome patients with renal dysfunction remain unknown. Accordingly, we designed this study to evaluate the differences of incidence of major adverse cardiovascular events for acute coronary syndromes patients with renal dysfunction who treated in coronary care unit or normal unit. The primary end point was all cause mortality. A total of 414 acute coronary syndromes patients with renal dysfunction involved in the study. The results showed that during 12 48 months follow-up, death of any cause occurred in 1.8% patients (4 of 247) in coronary care unit group, as compared with 1.8% in the normal group (3 of 167) (hazard ratio, 1.098; 95% confidence interval, 0.246 to 4.904; P=0.903). Kaplan Meier survival analysis showed that there were no significant differences between the two groups with respect to the risk of death (P=0.903), revascularization (P=0.948), stroke (P=0.542), heart failure (P=0.198). This trial firstly revealed that acute coronary syndromes patients with renal dysfunction treated in coronary care unit and normal units. Our study showed that acute coronary syndromes patients with renal dysfunction treated in coronary care unit obtained no significant benefits compared with patients in normal units, although there was a declining tendency of the risk of major adverse cardiovascular effectswith patients in coronary care unit. PMID- 26770437 TI - Analysis on clinical characteristics of intracranial Arachnoid Cysts in 488 pediatric cases. AB - To summarize the clinical characteristics of intracranial arachnoid cysts (IACs) in pediatric cases. A retrospective analysis was carried out on clinical characteristics of IACs in 488 pediatric cases who were treated at our hospital from January 2003 to September 2013. There were 342 males and 146 females (male to-female ratio, 2.34:1), aged 5.61+/-3.25 years on average. 221 cases (45.29%) were diagnosed accidentally, 267 cases had clinical complaints (54.71%), among which relationships between clinical complaints and IACs were identified in 123 (46.07%). Simple IACs occurred in 364 cases (4.59%), and concurrent congenital abnormalities occurred in 124 cases (4.59%). In terms of location, 355 had IACs in middle cranial fossa (72.75%), 82 cases in posterior cranial fossa (16.80%), 20 cases in anterior cranial fossa (4.10%), 12 cases in dorsolateral surface (2.46%), 7 cases in suprasellar cistern (1.43%), 5 cases in cerebral ventricle (1.02%), 5 cases in quadrigeminal cistern (1.02%), and 2 cases in interhemispheric region (0.41%). There were 449 cases with single IAC (92.01%) and 39 cases with multiple IACs (7.99%). On MRI, the cysts produced tension in 127 cases (26.02%), but not in the remaining 361 cases (73.98%). Surgery was performed on 76 of 488 cases (15.57%), while conservative observation was accepted in 412 cases (84.43%). For the former, the symptoms and the cyst volume were improved to varying extent; for the latter, the follow-up lasting for 3-72 months (average 32.43+/-8.92 months) showed that the cyst volume remained stable in 407 cases (98.78%), enlarged with aggravated symptoms in 3 cases (0.73%), and shrank in 2 cases (0.49%). Clinical complaints of IACs varied in pediatric cases, and the relationships between clinical complaints and IACs were established only partially. Some pediatric cases were combined with other congenital abnormalities. The cyst volume largely remained stable during the disease course, and surgery was required for only a few IACs. PMID- 26770438 TI - Expression and significance of TWIST, a zinc finger transcription factor, in laryngeal carcinoma among Chinese population: a meta-analysis. AB - TWIST, an epithelial-mesenchymal transition inducer, has been implicated in the progression of a variety of cancers. Published evidence concerning the association of TWIST expression with laryngeal carcinoma risk has generated inconclusive results. Thus, we aimed to conduct a meta-analysis to address this controversy. A meta-analysis assessing the expression of TWIST in laryngeal cancer was conducted. Eligible studies for the period up to Jun 2015 were identified. After rigorous screening, a total of four studies met the inclusion criteria and they happened to be conducted on Chinese population. The results showed that TWIST positive expression rate in laryngeal cancer tissues was higher than that in normal tissues (OR=8.91, 95% CI=4.55-17.46). TWIST expression might have a correlation with low differentiation (OR=5.40, 95% CI=2.02-14.44), advanced clinical stage (OR=6.52, 95% CI=3.61-11.78), presence of lymph node metastasis (OR=9.10, 95% CI=4.26-19.41) and distant metastasis (OR=8.12, 95% CI=2.10-31.42), but not age and gender. The data suggested that TWIST might play critical roles in the development of laryngeal carcinoma. Further well-designed studies are warranted to get a more conclusive result. PMID- 26770439 TI - Lack of associations between rs2910164 and rs11614913 polymorphisms and the risk of ischemic stroke. AB - Emerging evidence suggests that single nucleotide polymorphisms (SNPs) in microRNA genes may play a role in the development of cerebrovascular diseases including ischemic stroke through functionally modulating the expression of microRNA target genes. However, the current studies regarding the associations of the common microRNA polymorphisms with susceptibility to ischemic stroke have obtained discrepant results, which prompted us to perform a meta-analysis for a more precise estimation of the concerned associations. Relevant studies evaluating the associations between two common polymorphisms (miR-146a rs2910164 and miR-196a2 rs11614913) and the risk of ischemic stroke were retrieved from the PubMed, Embase, Cochrane Library, Google Scholar, Chinese Wanfang, Chinese Biomedical Database, and Chinese National Knowledge Infrastructure databases. The odds ratio (OR) with its 95% confidence interval (95% CI) were pooled to assess the strength of the associations using RevMan 5.2 and Stata 12.0 software. A total of 5 case-control studies with 2069 cases and 2061 controls on rs2910164, 4 case-control studies with 1873 cases and 1856 controls on rs11614913 polymorphisms were enrolled in the meta-analysis. Overall, neither allele frequency nor genotype distribution of the two common polymorphisms was found to be associated with risk for ischemic stroke in all genetic models. The subgroup analysis revealed a significant association between miR-146a rs2910164 polymorphism and increased risk of ischemic stroke in large sample size group and in Koreans under homozygous, allele, dominant and recessive models. The present meta-analysis suggests that the two common polymorphisms (rs2910164, rs11614913) may not contribute to the susceptibility to ischemic stroke. However, more well designed studies with large sample size are warranted to further validate the results in different ethnicities. PMID- 26770440 TI - Massive localized malignant pleural mesothelioma (LMPM): manifestations on computed tomography in 6 cases. AB - OBJECTIVE: Our study analyzed the clinical symptoms and computed tomography (CT) manifestations of massive localized malignant pleural mesothelioma (LMPM) patients to improve the knowledge and diagnosis of this disease. METHODS: Our study collected 6 massive LMPM patients pathologically confirmed by CT in the department of Radiology of the People's Hospital of Yuyao, Zhejiang Province, from January, 2007 to June, 2013; data of patients were also collected. The clinical symptoms, clinicopathological characteristics, CT manifestations, treatments and prognosis of enrolled patients were analyzed. RESULTS: Our study enrolled 6 LMPM patients (2 males; 4 females) classified to epitheliated type (n = 4) and sarcomatous type (n = 2) with mean age of 62.7 +/- 7.4, and 5 of them had a history of asbestos exposure. CT manifestations revealed that large soft tissue mass close to pleura, which was smooth and lobulated, was discovered in all patients with maximum diameter of 10~15 cm and mean diameter of 13.67 +/- 1.15 cm; The mean value of CT was 36.29 +/- 2.62 HU; after enhancement, the mean value was increased to 76.36 +/- 7.73 HU; patients showed zones of small patchy necrosis and large patchy necrosis. The following presentations were founded: enlargement of tumor vessel which showed arborization (2 patients), mass wrap around the descending aorta in left lower chest (1 patient), strips of fat density in mediastinum superior (1 patient), pleural tail sign (3 patients). Among 6 patients, pleural effusion (n = 4), mediastinal lymph node enlargement (n = 3), invasion and destruction of local ribs (n = 2). Median survival time of patients were 20 months (2 cases conducted operation), 24 (2 cases chose combined radiotherapy and chemotherapy) and less than 6 months (2 cases underwent chemotherapy). CONCLUSION: To sum up, CT showed important diagnostic values on massive LMPM patients; patients with a history of asbestos exposure, large soft tissue mass of pleura with an abundant blood supply and wrap around large vessels might increase the risk of massive LMPM. PMID- 26770441 TI - Polymorphisms of ERCC1 and XRCC1 predict the overall survival of advanced gastric cancer patients receiving oxaliplatin-based chemotherapy. AB - The aim of the present study was to evaluate the clinical outcome of excision repair cross-complementing protein 1 (ERCC1) and X-ray repair cross-complementing protein 1 (XRCC1) gene polymorphisms in 89 patients receiving oxaliplatin/5 fluorouracil-based chemotherapy as a first-line treatment regimen for advanced gastric cancer. ERCC1 codon 118C/T and XRCC1 codon 399A/G polymorphisms were identified using quantitative polymerase chain reactions, and the associations between disease control rate (DCR), median overall survival (mOS) and gene polymorphisms were analyzed. Following two cycles of chemotherapy, a complete response was observed in two patients, a partial response in 18 patients, stable disease in 38 patients and progressive disease in 31 patients. It was determined that ERCC1 and XRCC1 polymorphisms are not associated with DCR (P=0.662 and P=0.631, respectively). The mOS of patients exhibiting ERCC1 and XRCC1 polymorphisms was eight months, and although no significant association was identified between ERCC1 codon 118 genotypes and mOS (P>0.05), the combination of ERCC1 and XRCC1 polymorphisms, as well as the specific presence of the XRCC1 codon 399A/G polymorphism, was associated with mOS (P<0.05). Thus, the present study indicated that the XRCC1 polymorphism and the combination of XRCC1 and ERCC1 polymorphisms were independent predictors for mOS; however, the XRCC1 and ERCC1 genes were not able to predict the DCR. PMID- 26770442 TI - Staged treatment of thoracic and lumbar spinal tuberculosis with flow injection abscess. AB - The study was to investigate the feasibility and effectiveness of posterior-only approach combining with puncture drainage under CT-guide in staged treatment of thoracic and lumbar spinal tuberculosis with flow injection abscess. We retrospectively analyzed 15 patients (came from 72 cases with thoracic and lumbar spinal tuberculosis) with flow injection abscesses underwent surgery from January 2007 to February 2009, and evaluated the American Spinal Injury Association (ASIA) scoring system of nerve function, erythrocyte sedimentation rate (ESR), C reactive protein (CRP), abscess absorption time and the Oswestry Disability Index (ODI), preoperatively and postoperatively. 15 patients were followed up for 13-37 months, no recurrence of tuberculosis, no fixation loosening and neurologic symptoms aggravated. The flow injection abscesses are absorbed within 3-6 months postoperative operation. In final follow-up, ESR went down to 5.2+/-2.1 mm/h from preoperative 79.6+/-14.8 mm/h, CRP decreased from preoperative 49.3+/-7.5 mg/L to 1.8+/-0.7 mg/L, ODI changed from 75.13+/-20.15 to 16.72+/-8.62, all of them changed significantly (P<0.05). In conclusions, one-stage posterior debridement, interbody fusion, pedicle screw fixation and two-stage CT-guided interventional therapy were safe and effective in treatment of the thoracic and lumbar spinal tuberculosis with flow injection abscess. PMID- 26770443 TI - Efficacy of video-assisted thoracoscopic surgery for 29 patients with tuberculosis-destroyed lung. AB - BACKGROUND: Incompleteness of interlobar fissures and pleural adhesions, common in tuberculous destroyed lung (TDL), are among "technical contraindications" for video-assisted thoracoscopic surgery (VATS). The efficacy and safety of VATS in the treatment of TDL, has not yet been detailed in. OBJECTIVE: The objective of the present study is to observe the efficacy and safety of VATS in the management of TDL. METHODS: A retrospective review of anatomic lobectomy by VATS on 29 cases of TDL was performed in the Department of Thoracic Surgery of Wuhan Medical Treatment Center between October 2010 and October 2013. RESULTS: All the 29 surgeries by VATS were successfully completed. No death case was reported. Operative duration of VATS was 75~400 min, with an average of 185.4 min; intraoperative amount of bleeding ranged 50 to 2300 ml, with an average of 575.6 ml; the incidence of postoperative complication was 21.4% (6/28). Postoperative complications occurred in 6 cases, among which there were 2 cases of persistent postoperative pulmonary air leak, 2 cases of pleural effusion, one case of thoracic hemorrhage and one case of arrhythmia complicated with left heart failure. There was one patient who was converted from VATS to open thoracic surgery half-way. CONCLUSION: Our results have shown the efficacy, safety and a breakthrough in the "technical contraindications" of VATS in the management of TDL. PMID- 26770444 TI - Assessment of postoperative perfusion with contrast-enhanced ultrasonography in kidney transplantation. AB - The aim of this study was to use contrast-enhanced ultrasound (CEUS) to evaluate renal perfusion after kidney transplantation and investigate the clinical significance of CEUS in monitoring postoperative renal perfusion. Thirty-five patients who underwent kidney transplantations were included in this study and divided into two groups-normal and abnormal-based on their serum creatinine (SCr) levels. Conventional ultrasound and CEUS were used to monitor renal perfusion after kidney transplantation. The differences in the results between the two groups were then compared. Color doppler ultrasonography showed that there were significant differences in the resistance index (RI) and the pulsatility index (PI) of the interlobar artery between the groups. Furthermore, CEUS indicated a significant difference between the two groups regarding the slope rate of the cortical ascending curve (A1), the medullary ascending curve (A2), and the derived peak intensity (DPI1). CEUS precisely showed the characteristics of microcirculation in renal parenchyma after kidney transplantation. It also detected changes in the microcirculation, which was a new method of evaluating tissue perfusion in transplanted kidneys. PMID- 26770445 TI - Application value of computer assisted surgery system in precision surgeries for pediatric complex liver tumors. AB - We discussed the diagnostic and treatment value and clinical significance of computer assisted surgery system (Higemi) in precision surgeries for pediatric complex liver tumors. A total of 21 pediatric cases receiving hepatectomy for tumors in the portal vein and giant liver tumors from June 2012 to January 2015 were analyzed. Higemi was used for 3-dimensional (3D) reconstruction of thin slice CT images and surgical planning. Tumors were precisely located and blood vessel neighborhood was determined so as to evaluate surgical feasibility. In addition, pathological classification, surgical time, intraoperative blood loss, transfusion rate and complications were predicted. After 3D reconstruction using Higemi, the neighboring relationship of tumors with blood vessels and the running direction of the blood vessels were clearly visualized. Of 21 cases, 10 cases had tumors located in the left lobe, 5 cases in the right lobe, 3 cases showing involvement of right trilobes, and 3 cases in the middle lobe. Lobes exceeding one third of the total liver volume were resected in 18 cases. Postoperative pathological examination indicated 10 cases of hepatoblastoma, 3 cases of hepatocellular carcinoma, 3 cases of hamartoma, 3 cases of infantile hemangioendothelioma, 1 case of teratoma and 1 case of undifferentiated malignant mesenchymoma. The surgical time was 90-240 min with an average of 130 min; the medium intraoperative blood loss was 60 ml and the minimum blood loss was 3 ml; the transfusion rate was 42.9% (9/21). Surgeries were successful in 20 cases, who were discharged after recovery. However, one case had giant liver tumor combined with severe obstructive jaundice and hepatic insufficiency and died of postoperative liver failure and DIC. 3D reconstruction of CT data using Higemi can clearly visualize the running direction of blood vessels and the neighboring relationship with tumors. Higemi can improve the precision and safety of complex hepatectomy. PMID- 26770446 TI - Consumptive hypothyroidism due to a gastrointestinal stromal tumor expressing type 3 iodothyronine deiodinase. AB - CONTEXT: Gastrointestinal stromal tumors (GISTs) are responsive to sunitinib (the tyrosine kinase inhibitor), this agent is widely used in prevention relapse of GISTs and neo-adjuvant chemotherapy in GIST patients without operation opportunity. The use of these agents has both advantages and disadvantages. On the one hand, it can improve the outcome for patient. On the other hand, it may lead to consumptive hypothyroidism, a rare syndrome caused by increased catabolism of T4 and T3 by increased type 3 iodothyronine deiodinase (D3) activity. D3 is the major physiologic inactivator of thyroid hormone, this selenoenzyme catalyzes the inner-ring deiodination of T(4) to reverse T(3) and T(3) to 3, 3;-diiodothyronine, both of which are biologically inactive [1]. Increased monitoring and supernormal thyroid hormone supplementation are required for affected patient. OBJECTIVE: The aim of the study was to report the first case of consumptive hypothyroidism in an athyreotic patient after surgical resection of gastrointestinal stromal tumor. DESIGN, SETTING, AND PATIENT: A 60 year-old athyreotic male was presented and he was euthyroid when receiving a stable therapeutic dose of thyroid hormone which was used to treat consumptive hypothyroidism resulting from the side effects of sunitinib, which is used for treatment of neo-adjuvant chemotherapy in gastrointestinal stromal tumor. With a discovery of large D3-expressing gastrointestinal stromal tumor, this patient suffered from marked Hyperthyrotropinemia, which instantly worsened after surgical resection of the gastrointestinal stromal tumor and then continued for 12 weeks after the surgical resection, in spite of further increases in levothyroxine therapy. The patient also had low serum T3 and elevated serum reverse T3 (rT3). INTERVENTION: The patient's consumptive hypothyroidism caused by marked overexpression of the thyroid hormone-inactivating D3 within the gastrointestinal stromal tumor and adjacent normal gastrointestinal tissue. MAIN OUTCOME MEASURES AND RESULTS: D3 immunostaining of the patient's gastrointestinal stromal tumor was positive, with no significant immunoreactivity in adjacent normal gastrointestinal tissue. The expression levels of CD34, CD117, and DOG1 in peri-tumor tissue samples was lower than that in tumor tissue. The mRNA expression level of KIT exon17 in peri-tumor tissue was higher than that in tumor tissue. CONCLUSIONS: This is the first case report of consumptive hypothyroidism in an adult after surgical partial resection of the gastrointestinal stromal tumor. This case demonstrates that hyperthyrotropinemia may worsen after surgical resection of the gastrointestinal stromal tumor. PMID- 26770447 TI - Pharmacokinetic study of ACT-132577 in rat plasma by ultra performance liquid chromatography-tandem mass spectrometry. AB - It was reported that macitentan was metabolized predominantly by cytochrome P450 3A4, and ACT-132577, its pharmacologically active metabolite, is fivefold less potent at blocking ET receptors than macitentan. In this work, a sensitive and selective ultra performance liquid chromatography-tandem mass spectrometry (UPLC MS/MS) method for determination of ACT-132577 in rat plasma was developed and validated. After addition of diazepam as an internal standard (IS), protein precipitation by acetonitrile was used to prepare samples. Chromatographic separation was achieved on a UPLC BEH C18 column (2.1 mm * 100 mm, 1.7 MUm) with 0.2% formic acid and methanol as the mobile phase with gradient elution. An electrospray ionization source was applied and operated in positive ion mode; multiple reactions monitoring (MRM) mode was used for quantification using target fragment ions m/z 546.9->200.6 for ACT-132577, and m/z 285.1->193.1 for IS. Calibration plots were linear throughout the range 10-4000 ng/mL for ACT-132577 in rat plasma. Mean recovery of ACT-132577 in rat plasma ranged from 82.6% to 90.6%, matrix effect of ACT-132577 in rat plasma ranged from 101.4% to 115.2%. RSD of intra-day and inter-day precision were both less than 11%. The accuracy of the method ranged from 96.1% to 103.5%. The method was successfully applied to pharmacokinetic study of ACT-132577 after oral and intravenous administration of macitentan. PMID- 26770448 TI - Application of MSI in MRI-negative focal cortical dysplasia patients with epilepsy. AB - BACKGROUND: Focal cortical dysplasia (FCD) is the most common cause of intractable epilepsy in children and adolescent. PURPOSE: To evaluate the application value of magnetic source imaging (MSI) in treatment of magnetic resonance imaging (MRI)-negative FCD patients with epilepsy. METHODS: MSI characteristics of 17 cases of MRI-negative focal cortical dysplasia patients with epilepsy were retrospectively analyzed. All patients were treated by surgery. RESULTS: In 17 patients, there were 3 cases of FCD Ia, 7 cases of FCDIb, 3 cases of FCDIIa and 4 cases of FCDIIb. FCD was located at temporal lobe in 8 cases, occipital lobe in 3 cases, frontal lobe in 2 cases and two lobes in 4 cases. In follow-up, 14 patients obtained satisfied curative effect. 1 patient was improved significantly and 2 patients were fine. The concordance between MSI and electrocorticogram in localizing epileptogenic foci was 65%. CONCLUSION: MSI is a new prospective noninvasive functional neuroimaging technique for identifying and delineating epileptogenic foci in MRI-negative FCD patients. PMID- 26770449 TI - Combined treatment of fasudil and glutamate decreased the viability of human glioblastoma cells by excitotoxicity through NMDAR in vitro. AB - Glioblastoma (GBM) is the most common brain tumor with high abilities of proliferation, migration and invasion. As is well-known, the peritumoral excitotoxic neuronal cell loss caused by glutamate, secreted by GBM cells, through activated N-methyl-D aspartate receptor (NMDAR) of neuronal cell. What's more, glutamate benefits the migration of GBM cells. However, the glutamate will not kill the GBM cells itself, which may be due to the deficiency of NMDAR. Fasudil, a ROCK inhibitor, was applied for subarachnoid hemorrhage (SAH) in clinic for many years. And it was found to be of potential to inhibit the proliferation, migration and invasion of GBM cells. In present study, we applied fasudil on the primary human GBM cells to further investigate the reduction of cell viability combined with glutamate. Combination treatment of glutamate and fasudil could significantly decrease the cell viability and elevate the level of LDH compared with fasudil treatment alone. What's more, MK-801, a NMDAR antagonist, could partially abolish this death caused by combination treatment. Further study found that the expression level of NMDAR-2B was elevated after treatment with fasudil in GBM cells. These results demonstrated fasudil could increase the expression level of NMDAR, which is necessary for glutamate to work. In a word, our research has provided a new sight of medicine combination in the treatment of GBM. PMID- 26770450 TI - miR-503 inhibits cell proliferation and invasion in glioma by targeting L1CAM. AB - Deregulated microRNAs and their roles in tumorigenesis have attracted much attention in recent years. Although miR-503 has been reported to be aberrant expression in several cancers, its role in glioma remains unknown. In this study, we focused on the expression and mechanisms of miR-503 in glioma development. We found that miR-503 was downregulated in glioma cell lines and tumor tissues, and the restoration of miR-503 reduced cell proliferation invasion. Furthermore, bioinformatics analysis indicated that L1CAM was a putative target of miR-503. In a Luciferase reporter system, we confirmed that L1CAM was a direct target gene of miR-503. These findings indicate that miR-503 suppresses glioma cell growth by negatively regulating the expression of L1CAM. Collectively, our data identify the important roles of miR-503 in glioma pathogenesis, indicating its potential application in cancer therapy. PMID- 26770451 TI - Buyanghuanwu Tang therapy for neonatal rats with hypoxic ischemic encephalopathy. AB - BACKGROUND: Neonatal hypoxic-ischemic encephalopathy (HIE) is a clinical syndrome manifested by neurological symptoms in the first days of life in term infants. PURPOSE: To investigate the therapy effect of Buyanghuanwu Tang (BYHWT), a decoction with 7 herbal ingredients, on neonatal rats with hypoxic ischemic encephalopathy (HIE) and its mechanism. METHODS: 50 3-week male Sprague-Dawley rats were divided into normal control group, model group, BYHWT 1d group, BYHWT 3d group and BYHWT 7d group, 10 rats in each group. The HIE model of was established in later 4 groups. The later 3 groups were treated with BYHWT for 1, 3 and 7 days, respectively, and the normal control group and model group were treated with PBS. The Morris water maze test and dynamic (18)F-FDG-PET/CT imaging were performed. The changes of hippocampal tissue observed by histopathologic examination, and the expressions of JNK1/JNK2 and TNF-alpha protein were observed western blotting. RESULTS: Compared with model group, the impaired performance on distance and latency parameters was mitigated in BYHWT 1d group, BYHWT 3d group and BYHWT 7d group (P < 0.01), the FDG uptake was decreased in BYHWT 3d group and BYHWT 7d group, the apoptotic cells and inflammatory cells were significantly decreased in BYHWT 3d group and BYHWT 7d group, and the expressions of JNK1/JNK2 and TNF-alpha protein were significantly decreased in BYHWT 7d group (P < 0.05). CONCLUSION: BYHWT can delay the HIE onset and preserve the motor function, primarily by regulating inflammation, apoptosis and inhibition by mediating JNK signaling. PMID- 26770452 TI - Association between vegetables consumption and the risk of age-related cataract: a meta-analysis. AB - BACKGROUND: Quantification of the association between the consumption of vegetables and risk of age-related cataract is still conflicting. We therefore conducted a meta-analysis to summarize the evidence from epidemiological studies of vegetables consumption with the risk of age-related cataract. METHODS: Pertinent studies were identified by searching of PubMed and Web of Science. The random effect model was used to combine the results. Meta-regression and subgroups analyses were used to explore potential sources of between-study heterogeneity. Publication bias was estimated using Egger's regression asymmetry test. RESULTS: Finally, 9 articles involving 6,464 cataract cases and 112,447 participants were included in this meta-analysis. Pooled results suggested that highest vegetables consumption level compared with lowest level was inverse with the risk of age-related cataract [summary relative risk (RR) = 0.723, 95% CI = 0.594-0.879, I(2) = 72.8%]. The associations were also significant in America [summary RR = 0.872, 95% CI = 0.791-0.960] and Europe [summary RR = 0.507, 95% CI = 0.416-0.619], but not in the other population. No publication bias was found. CONCLUSIONS: Higher vegetables consumption might be inversely associated with risk of cataract. PMID- 26770453 TI - Serum miR-96 is a promising biomarker for hepatocellular carcinoma in patients with chronic hepatitis B virus infection. AB - MicroRNAs (miRNAs) are involved in cancer biology, and some distinctive serum miRNAs could be useful for cancer diagnosis and prognosis. However, little is known about whether serum miR-96 is a satisfactory biomarker for hepatocellular carcinoma (HCC). Four hundreds and fourteen participants were enrolled in this study, and they were divided into four age- and gender-matched groups, including the HCC group (n = 104), liver cirrhosis (LC) group (n = 90), chronic hepatitis B (CHB) group (n = 100) and healthy control group (n = 120). Serum miR-96 was measured by real-time PCR, the levels of which were calculated by the 2(-DeltaCt) method. Serum miR-96 levels in the HCC patients were remarkably higher than in the other groups (P < 0.01), and the serum miR-96 levels discriminated HCC patients from CHB patients with an area under the ROC curve (AUC) of 0.803 (77.9% sensitivity and 75.3% specificity). Furthermore, the AUC for combined miR-96 and alpha-fetoprotein (AFP) was 0.889 (83.6% sensitivity and 82.4% specificity). High serum miR-96 levels in HCC patients were associated with larger tumor size, higher prevalence of lymph node metastasis, higher TNM stage and worse overall survival (OS) (P < 0.05). Our findings suggest that serum miR-96 is a promising biomarker for HCC patients with chronic HBV infection. PMID- 26770454 TI - miR-125b suppresses the proliferation of hepatocellular carcinoma cells by targeting Sirtuin7. AB - Previous studies have shown that microRNAs are involved in many human cancers. However, the role of miR-125b in hepatocellular carcinoma (HCC) has not been fully understood. In our study, we detected the expression of miR-125b using Real time quantitative-polymerase chain reaction (RT-PCR) and found that the expressions of miR-125b were significantly inhibited in HCC tissues and cell lines. The levels of miR-125b were associated with the degree of HCC malignancy. Otherwise, MTT assay showed that the proliferation was significantly decreased after transfection of miR-125b mimics into HepG2 cells; while the proliferation was significantly increased in HepG2 cells transfected with miR-125b inhibitors. Furthermore, TargetScan was conducted to predict the target gene of miR-125b and Sirtuin7 (SIRT7) was chosen to a potential target gene. And then we used luciferase reporter assay and western blot to confirm that SIRT7 is a direct target gene. Western blot indicated that transfection of miR-125b mimics could significantly inhibit the expression of SIRT7 in HepG2 cells, whereas, transfection of miR-125b inhibitor could significantly increase the expression of SIRT7 in HepG2 cells. These results suggest that miR-125b can inhibit the proliferation of HCC by adjusting the expression of SIRT7 and may be a key element of HCC progression. PMID- 26770455 TI - Downregulation of cell cycle-related proteins in ovarian cancer line and cell cycle arrest induced by microRNA. AB - OBJECTIVE: The effect of miR-449 and miR-34 on the growth, cell cycle and target gene expressions of ovarian cancer cell line SKOV3 and SKOV3-ipl was discussed. METHOD: Real-time quantitative reverse transcription PCR was employed to detect the expressions of miR-449a/b and miR-34b, c in SKOV3 and SKOV3-ipl cells. The two miRNAs were successfully expressed in SKOV3-ipl cells by transfection. The variations in cell growth rate and cell cycle were determined by MTS assay and flow cytometry, respectively. The expressions of cell cycle-related proteins were detected by Western Blot. RESULTS: miR-449b and miR-34c induced the decline of the adhesiveness of SKOV3-ipl cells by 20%-30%. The number of cells arrested in G1-phase increased and the number of cells arrested in S-phase decreased significantly. The cell cycle-related proteins CDK6 and CDC254 were downregulated. miR-449b caused the expression of CDK6 and CDC25A to decrease. After the co-transfection with miR-449b and miR-34c, the relevant proteins were downregulated more significantly. The expressions of CDK6, CDC25A and cyclin A were decreased significantly. CONCLUSION: miR-449b and miR-34c can induce cell cycle arrest in SKOV3-ipl cells and the downregulation of CDK6, CDC25A and cyclin A. PMID- 26770456 TI - Long non-coding RNA PCAT-1 over-expression promotes proliferation and metastasis in non-small cell lung cancer cells. AB - Long non-coding RNAs (lncRNAs) have emerged as major players in governing fundamental biological processes, and play a functional role in tumorigenesis. Prostate cancer-associated transcript1 (PCAT-1) is a novel lncRNA that promotes cell proliferation in prostate cancer. However, the role of PCAT-1 on non-small cell lung cancer (NSCLC) remains unclear. In the present study, we firstly investigated PCAT-1 expression in NSCLC tissues and cell lines by using quantitative real-time PCR (QRT-PCR). Our results indicated that PCAT-1 was increased in NSCLC tissues and cell lines. PCAT-1 suppression using PCAT-1 small hairpin RNA (shRNA) with A549 cells inhibited cell proliferation, migration and invasion, while over-expression of PCAT-1 by synthetic plasmid vectors was shown to promote cell proliferation, migration and invasion. Our data suggested that PCAT-1 could play an oncogenic role in NSCLC progression. Silencing PCAT-1 is a potential novel therapeutic approach for lung cancer. PMID- 26770457 TI - Lack of association between GSTP1 Ile105Val polymorphism and coronary heart disease risk: a meta-analysis. AB - Many epidemiological studies have evaluated the association between GSTP1 Ile105Val polymorphism and coronary heart disease risk, but the results were inconsistent. This study aims re-evaluate the association between GSTP1 Ile105Val Polymorphism and coronary heart disease risk with a meta-analysis. We performed a search in the PubMed, Springer and Elsevier and ran a meta-analysis based on 8 case-control studies that included 3,888 cases and 3,476 controls. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of the association. The results showed that there was no significant association between GSTP1 Ile105Val Polymorphism and coronary heart disease risk susceptibility in the overall population (GG vs. AA: OR = 0.98, 95% CI = 0.84 1.15; GA vs. AA: OR = 1.04, 95% CI = 0.84-1.29; GA/GG vs. AA: OR = 1.02, 95% CI = 0.84-1.25; GG vs. AA/GA: OR = 0.94, 95% CI = 0.81-1.09). Subgroup analysis stratified by ethnicity and source of control showed no significant association with any genetic model. Our meta-analysis showed that GSTP1 Ile105Val polymorphisms might not be significantly associated with coronary heart disease risk. PMID- 26770458 TI - Diagnostic accuracy of ascitic cholesterol concentration for malignant ascites: a meta-analysis. AB - Many studies have investigated whether ascitic cholesterol can aid in diagnosis of malignant related ascites (MRA), and the results have varied considerably. To gain a more reliable answer to this question, we meta-analyzed the literature on using ascitic cholesterol as diagnostic tests to help identify MRA. Literature databases were systematically searched for studies examining accuracy of ascitic cholesterol for diagnosing MRA. Data on sensitivity, specificity, positive/negative likelihood ratio (PLR/NLR), and diagnostic odds ratio (DOR) were pooled using random effects models. Summary receiver operating characteristic (SROC) curves and area under the curve (AUC) were used to summarize overall test performance. At last, our meta-analysis included 8 studies involving 743 subjects. Summary estimates for ascitic cholesterol in the diagnosis of MRA were as follows: sensitivity, 0.82 (95% CI 0.78 to 0.86); specificity, 0.90 (95% CI 0.87 to 0.93); PLR, 9.24 (95% CI 4.58 to 18.66); NLR, 0.16 (95% CI 0.08 to 0.32); and DOR, 66.96 (95% CI 18.83 to 238.11). The AUC was 0.96. The ascitic cholesterol level is helpful for the diagnosis of MRA. Nevertheless, the results of ascitic cholesterol assays should be interpreted in parallel with the results of traditional tests and clinical information. PMID- 26770459 TI - Postmortem redistribution of lidocaine after epidural injection in beagle dogs. AB - OBJECTIVES: An animal model using beagle dog has been established to investigate the postmortem redistribution of lidocaine. MATERIALS AND METHODS: 18 dogs were euthanized and injected lidocaine (13 mg/kg) via epidural immediately. An autopsy was performed at 0, 12, 24, 48, 72, 96 hours after drug administration. All animals were stored in supine position at room temperature. For the other groups, lidocaine was given via epidural 6, 12, 24 hours after dogs were euthanized. Followed treatments were as above described. All samples were treated for detection of the concentration of lidocaine. RESULTS: It was found that lidocaine could diffuse via blood vessel rapidly post administration. And the concentration of lidocaine in the blood from ventriculus sinister increased obviously in a time dependent manner. Meanwhile, the postmortem tissue distribution of lidocaine was significantly different. However, the process of postmortem redistribution of lidocaine was obviously delayed in dogs which were given drugs after death. CONCLUSIONS: Together results revealed the process of postmortem redistribution of lidocaine via epidural injection, and provided the method to distinguish the lidocaine-induced death and drug administration after death. PMID- 26770460 TI - Effect of Smac in combination with cisplatin on esophageal cancer cell line ECA109. AB - OBJECTIVE: This study was to investigate inhibiting effect of structurally unique Second mitochondria-derived activator of caspase (Smac) in combination with cisplatin on esophageal cancer cell line ECA109. METHODS: PcDNA3.1-Smac (ECA109/Smac group), pcDNA3.1 (ECA109/neo group) and PBS (ECA109 or control group) were transfected into ECA109 cells respectively, and transfected cells which expressed Smac stably were got. Smac protein expression was analyzed by Western blot. The invasive ability of cells was examined. Flow cytometry was used to analyze apoptosis induced by cisplatin with Annexin V/PI double staining technique. RESULTS: Smac gene was successfully transfected into ECA109 cell, over expression of Smac could decrease cell invasive ability obviously compared to control group (P<0.05). Apoptosis rate of cells induced by cisplatin in ECA109/Smac group was significant higher than that in ECA109/neo and ECA109 group (P<0.05). CONCLUSION: It indicated that over-expression of Smac increases the sensitivity of esophageal cancer ECA109 cells to cisplatin treatment, combination of conventional anticancer drug with Smac may be beneficial for the treatment of esophageal cancer. PMID- 26770461 TI - gammadelta T cells and Foxp3(+) Treg cells infiltration in children with biliary atresia and its significance. AB - To investigate the changes in the proportion of gammadelta T cells and Foxp3(+) Treg cells in children with BA (biliary atresia). The distribution of gammadelta T cells in the liver tissues and the proportion of gammadelta T cells and Foxp3(+) Treg cells were observed and detected in BA Group (32 cases) and control group (CG) (12 cases) by using immunohistochemical methods and flow cytometry. The periportal bile duct of liver in BA Group was surrounded by a large number of gammadelta T cells and a certain degree of Foxp3(+) Treg cells infiltration. Additionally, the proportion of gammadelta T cells and Foxp3(+) Treg cells was significantly higher than that in CG (P<0.05). And significantly negative correlation was revealed in the proportion of gammadelta T cells and Foxp3(+) Treg cells (P<0.05). The increase of gammadelta T cells or inhibition of Foxp3(+) Treg cell proliferation in liver tissues of patients with biliary atresia exacerbated the progressive inflammatory injury of bile ducts. PMID- 26770462 TI - Paranasal sinus mucoceles: our clinical experiments. AB - OBJECTIVES: We present the clinical and radiological features, treatment protocols, and medium-long-term results of our patients following surgery for paranasal sinus mucocele, along with a review of the relevant literature. MATERIALS AND METHODS: A total of 18 patients (11 women and 7 men) who underwent surgery for paranasal sinus mucocele at Kocaeli University Faculty of Medicine, Department of Otolaryngology, between 2006 and 2013 were examined retrospectively. The mean patient age was 41 (range 4-73). Demographic and radiological features, symptoms, treatment protocols, and postoperative outcomes were recorded. RESULTS: The most frequently affected sinus was the maxillary sinus (n=9, 50%) followed by the frontal sinus (n=6, 33%) and sphenoidal sinus (n=3, 16%). The main symptom was headache. Endoscopic marsupialization of the mucocele was applied in all 18 patients, while frontal sinus exploration with the osteoplastic flap procedure was performed in one patient and the Caldwell-Luc operation was performed in another patient. The Caldwell-Luc procedure was subsequently required in one patient (6%) and endoscopic revision surgery was required in another patient (6%). CONCLUSION: Sinus mucocele that enlarges, eroding the surrounding bone tissue, and induces various clinical symptoms due to the impression of the expansile mass, is treated surgically, and must be planned carefully to prevent serious complications. PMID- 26770463 TI - Prospective evaluation of preoperative concerns for Chinese patients with spinal degenerative disease. AB - Objective of this study is to analyze preoperative concerns of patients suffering from spinal degenerative disease in a Chinese population. A total of 94 patients with spinal degenerative disease were included, and they were divided into four groups: male and female group, older (>=60 year-old) and younger group (<60 year old). Questionnaire was designed through patients counseling, preliminary formulation, pilot test and final revision. Each patient was required to select three items of greatest concern. "Attention rate" (AR) was defined as ratio of selected times of one item upon case number within the group. AR of three most concerned items between male and female group, as well as older and younger group were compared and analyzed. All participants selected "recurrence of symptoms following operation" (41/94), "clinical outcome" (35/94) and "postoperative rehabilitation and daily activity" (30/94) as their three top items of concern. Both male and female groups selected "recurrence of symptoms following operation" (22/47, 19/47), "clinical outcome" (21/47, 14/47), "postoperative rehabilitation and daily activity" (15/47, 15/47) and "limb paralysis" (13/47, 14/47) as their most concerned items, revealing no statistical difference (P>0.05). Older group chose "clinical outcome" (17/46) as their most concerned item, followed by "limb paralysis" (14/46), "postoperative rehabilitation and daily activity" (14/46) and "recurrence of symptoms following operation" (12/46). Younger group chose "recurrence of symptoms following operation" (29/48), "clinical outcome" (18/48) and "postoperative rehabilitation and daily activity" (16/48) as their three top concerned items. AR of "recurrence of symptoms following operation" between older and younger group demonstrated statistical difference (P<0.001), while AR of remaining items of greatest concern between both groups were not statistically different (P>0.05). For Chinese patients, high level concerns are associated with surgical outcome and most of them reveal no gender-associated or age-associated difference. Assessing preoperative concerns empowers better preoperative counseling between surgeons and patients and more informed decision for patients. PMID- 26770464 TI - Tumor abnormal protein (TAP) examination contributes to primary diagnosis of bladder cancer. AB - OBJECTIVE: This study aims to investigate the application value of tumor abnormal protein (TAP) examination in the diagnosis of urothelial carcinoma of the bladder. METHOD: Abnormal sugar chain glycoproteins in the peripheral blood of 87 patients with urothelial carcinoma of the bladder were detected, and compared with non-tumor patients accompanied by hematuria. RESULT: TAP examination showed that the positive rate of the abnormal sugar chain glycoprotein in the peripheral blood of the 87 patients with urothelial carcinoma of the bladder was 78.16%, whereas that of the non-tumor patients was 10.81%. The former is significantly higher than the latter (P<0.01). CONCLUSION: TAP examination can be used to detect urothelial carcinoma of the bladder, and would be helpful in the diagnosis of urothelial carcinoma of the bladder by combining the clinical signs and symptoms. PMID- 26770465 TI - Yiqi Huayu recipe relieves nerve root constriction induced radicular neuralgia by down-regulating TRPV4 expression in dorsal root ganglion. AB - The aim of this study was to observe the effects of Yiqi Huayu recipe on TRPV4 expression in radicular neuralgia model induced by chronic constriction to the rat lumber nerve root. Healthy male SD rats were divided into 3 groups for radicular neuralgia (RN) model construction: the sham operation group, model groups (day 3, 7, 14 and 28), and medication groups (day 3, 7, 14 and 28). Von Frey hairs test was performed to detect the 50% with drawal threshold (50% TPW) for rats of each group. The expression of TRPV4 in dorsal root ganglion was detected at both mRNA and protein level. Rats from all model groups displayed hyperalgesia with significantly reduced 50% TPW values compared with sham operation group (P<0.01); Yiqi Huayu recipe medication groups showed higher 50% TPW than model group since 7 days post medication (P<0.01); the medication groups showed decreased TRPV4 expression than that of model groups (P<0.01). In conclusion, Yiqi Huayu recipe alleviates nerve root constriction induced radicular neuralgia by repressing TRPV4 expression in dorsal root ganglion. PMID- 26770466 TI - Relation between qualitative and quantitative 3-dimensional ultrasound and ki-67 expression in breast cancer. AB - To investigate the relation between quantitative blood flow parameters on 3 dimensional (3D) color histogram, 3D ultrasound characteristics and Ki-67 expression in breast cancer. Three-dimensional ultrasound characteristics and histological classifications of 76 breast tumors in 75 confirmed cases were analyzed. Relations of tumor volume (V), vascularization index (VI), flow index (FI) and vascularization-flow index (VFI) on 3D color histogram to Ki-67 expression were studied by statistical methods. VI and VFI measurements of tumors in positive Ki-67 expression group were obviously increased compared with the negative expression group (P<0.05). V and FI measurements of positive expression group were higher than those of the negative expression group, but the difference was not significant (P>0.05). Cases showing positive expression of Ki-67 were more likely to have lymph node metastases (P<0.05), and Ki-67 expression positively correlated with histological classification (P<0.05). However, the two groups did not show significant differences in the findings of "sun-like symptom" (P>0.05). Qualitative and quantitative 3D ultrasound characteristics correlated with positive expression of Ki-67 in breast cancer. Quantitative analysis with 3D color histogram more accurately evaluates blood supply of breast tumors, providing references for predicting biological behaviors and prognosis of breast cancer. PMID- 26770467 TI - Rare malposition following left jugular vein catheterization: Case reports and a literature review. AB - The number of patients requiring chronic hemodialysis via a tunneled cuffed catheter is increasing. The right internal jugular vein (IJV) is generally the preferred site of percutaneous insertion. In certain situations, for example, in patients with a history of multiple access failures, catheterization of the left IJV is an important option. In this report, we present two rare cases of catheter malposition after left IJV catheterization; catheter adjustments, with the help of chest radiographs, resulted in a positive outcome in both cases. These cases exemplify the difficulties associated with left IJV catheterization, of which there are few reports in the published literature. PMID- 26770468 TI - Development of a self-assessment tool for measuring competences of obstetric nurses in rooming-in wards in China. AB - INTRODUCTION: To provide high-quality nursing care, a reliable and feasible competency assessment tool is critical. Although several questionnaire-based competency assessment tools have been reported, a tool specific for obstetric nurses in rooming-in wards is lacking. Therefore, the purpose of this research is to develop a competency assessment tool for obstetric rooming-in ward nurses. METHODS: A literature review was conducted to create an individual intensive interview with 14 nurse managers, educators, and primary nurses in rooming-in wards. Expert reviews (n = 15) were conducted to identify emergent themes in a Delphi fashion. A competency assessment questionnaire was then developed and tested with 246 rooming-in ward nurses in local hospitals. RESULTS: We constructed a three-factor linear model for obstetric rooming-in nurse competency assessment. Further refinement resulted in a self-assessment questionnaire containing three first-tier, 12 second-tier, and 43 third-tier items for easy implementation. The questionnaire was reliable, contained satisfactory content, and had construct validity. DISCUSSION: Our competency assessment tool provides a systematic, easy, and operational subjective evaluation model for nursing managers and administrators to evaluate obstetric rooming-in ward primary nurses. The application of this tool will facilitate various human resources functions, such as nurse training/education effect evaluation, and will eventually promote high-quality nursing care delivery. PMID- 26770469 TI - 16S rRNA gene sequencing is a non-culture method of defining the specific bacterial etiology of ventilator-associated pneumonia. AB - Ventilator-associated pneumonia (VAP) is an acquired respiratory tract infection following tracheal intubation. The most common hospital-acquired infection among patients with acute respiratory failure, VAP is associated with a mortality rate of 20-30%. The standard bacterial culture method for identifying the etiology of VAP is not specific, timely, or accurate in identifying the bacterial pathogens. This study used 16S rRNA gene metagenomic sequencing to identify and quantify the pathogenic bacteria in lower respiratory tract and oropharyngeal samples of 55 VAP patients. Sequencing of the 16S rRNA gene has served as a valuable tool in bacterial identification, particularly when other biochemical, molecular, or phenotypic identification techniques fail. In this study, 16S rRNA gene sequencing was performed in parallel with the standard bacterial culture method to identify and quantify bacteria present in the collected patient samples. Sequence analysis showed the colonization of multidrug-resistant strains in VAP secretions. Further, this method identified Prevotella, Proteus, Aquabacter, and Sphingomonas bacterial genera that were not detected by the standard bacterial culture method. Seven categories of bacteria, Streptococcus, Neisseria, Corynebacterium, Acinetobacter, Staphylococcus, Pseudomonas and Klebsiella, were detectable by both 16S rRNA gene sequencing and standard bacterial culture methods. Further, 16S rRNA gene sequencing had a significantly higher sensitivity in detecting Streptococcus and Pseudomonas when compared to standard bacterial culture. Together, these data present 16S rRNA gene sequencing as a novel VAP diagnosis tool that will further enable pathogen-specific treatment of VAP. PMID- 26770470 TI - A study on change of macular retinal thickness and its relationship with vision before and after operation to idiopathic macular epiretinal membranes. AB - OBJECTIVE: To evaluate the change of macular retinal thickness and vision before and after 23G minimally invasive vitrectomy to idiopathic macular epiretinal membranes. METHODS: Clinical data of 40 patients who were confirmed as idiopathic epiretinal membrane and accept vitrectomy combined with internal limiting membrane peeling was retrospectively analyzed. In regular follow-up before and after operation, OCT (optical coherence tomography) inspection was conducted for the best corrected visual acuity, intraocular pressure, eye-ground photography, and fundus oculi. In addition, the follow eye which has no relevant ophthalmological disease was treated as the control group. RESULTS: The vision greatly improves after operation, and the thickness in central fovea of macula significantly decreases. Postoperative vision shows obvious linear correlation with postoperative thickness in central fovea of macula. The thickness in division 9 of macula sharply decreases after operation, while the retina in central macula and nasal sides significantly thickens compared with normal group. CONCLUSION: Internal limiting membrane peeling can enhance the vision of patients and improve macula morphology, while the status in central macula and nasal side has not completely recovered. PMID- 26770471 TI - Investigation of PI3K/PKB/mTOR/S6K1 signaling pathway in relationship of type 2 diabetes and Alzheimer's disease. AB - The aim of this study was to investigate the roles of PI3K/PKB/mTOR/S6K1 signaling pathway in the risk-increasing mechanisms of type 2 diabetes mellitus (T2DM) towards the Alzheimer's disease (AD). Based on the high-sugar high-fat diet, the single intraperitoneal injection of streptozotocin was performed to induce the T2DM rat model; the immunohistochemistry and RT-PCR technique were then performed to detect the expression levels of mTOR, PI3K, PKB, S6K1 and phosphorylated Tau protein in the hippocampal tissues of each group. The related metabolic indicators of the T2DM group and the T2DM + AD group were significantly higher than the normal control group and the AD group (P<0.01); the Morris water maze test of the AD group and the learning and memory of the T2DM + AD group were than significantly decreased than the T2DM group (P<0.01); the T2DM + AD group exhibited significantly increased expression levels of mTOR, S6K1 and Tau protein in the hippocampal tissues than the AD group and the T2DM group (P<0.05), and while the expression levels of PI3K and PKB were decreased (P<0.05). Among the possible mechanisms through which T2DM increased the risk of AD, the dystransduction of insulin signaling pathway (PI3K/PKB/mTOR/S6K1) was the important cause of hyperphosphorylation of Tau protein, thus it prompted the AD occurrence. PMID- 26770472 TI - Carotid artery evaluation and coronary calcium score: which is better for the diagnosis and prevention of atherosclerotic cardiovascular disease? AB - In recent clinical practice guidelines for risk assessment for a first atherosclerotic cardiovascular disease (ASCVD) event, it is not routinely recommended to measure carotid intima-media thickness (CIMT) or the coronary calcium score (CACS). The aim of this study was to elucidate the effect of combining carotid artery evaluation and CACS as surrogate markers or predictive values. A total of 938 patients (562 male (59.9%), mean age 61.5+/-11.6 years) with ASCVD (n=690) or without (n=248) were enrolled in this study. The diagnosis of ASCVD was established with CT angiography. These patients had undergone carotid scanning (HP Sonos-5500; Philips, Bothell, WA, USA) at St. Mary's Hospital between September 2003 and March 2009. ASCVD outcomes were evaluated with a median follow-up of 1451 days. Thirty participants experienced initial ASCVD events during this study. Another 118 patients suffered secondary ASCVD events. After propensity score matching, multivariate analysis revealed that CACS was associated with ASCVD [Odds ratio 1.002, 95% confidence interval (CI) 1.002 1.003, P<0.001]. For primary prevention in patients without ASCVD, we found that carotid plaques [Hazard ratio (HR) 2.409, 95% CI 1.093-5.309, P=0.029] are also associated with ASCVD events. Carotid plaques are also associated with ASCVD events with regard to secondary prevention [HR 1.723, 95% CI 1.188-2.499, P=0.004] in patients with ASCVD. We propose that CACS assessment is useful in the diagnosis of, and as a surrogate marker of ASCVD in patients with risk factors. Our results also suggest that carotid artery evaluation may have a valuable predictive method in primary and secondary ASCVD prevention and risk assessment. Therefore, although there are no synergic effects of combining carotid artery evaluation and CACS, carotid ultrasound seems to be a better predictive method for assessing ASCVD events than CACS. PMID- 26770473 TI - Absence of non-alcoholic fatty liver disease in the presence of insulin resistance is a strong predictor for colorectal carcinoma. AB - BACKGROUND: Colorectal carcinoma (CRC) and non-alcoholic fatty liver disease (NAFLD) share common risk factors. Insulin resistance (IR) has an important role in both diseases. It has been speculated that the prevalence of colorectal neoplasms might be increased in patients with NAFLD. However, It is unclear whether NAFLD is an actual risk factor or any association is incidental coexistance due to the role of IR in both disease. We aimed to assess the risk for CRC in patients with NAFLD in relation to IR. METHOD: This study was designed prospectively and cross-sectionally. We determined NAFLD by ultrasonography and measured IR by the homeostatic model of assessment-insulin resistance model. RESULTS: The prevalences of CRC and adenoma were shown to be significantly higher in patients with IR (respectively; P: 0.005, P: 0.008). But prevalence of CRC was found to be significantly lower in subjects with NAFLD (P: 0.001). On multivariate logistic regression analysis, the risks of colorectal adenoma and carcinoma were significantly associated with the presence of IR (respectively; OR: 2.338, 95% CI: 1.080-4.993, P: 0.003 and : 5.023, 95% CI: 1.789-9.789, P: 0.001). The risk for CRC was significantly associated with the absence of NAFLD (OR: 7.380, 95% CI: 3.069-7.961, P: 0.010). The absence of NAFLD in the presence of IR was associated with significantly high risk for CRC (OR: 5.218, 95% CI: 1.538-7.448, P: 0.017). CONCLUSION: The risk of CRC can increased in subjects with IR but without NAFLD. The absence of NAFLD in the presence of IR may predict the CRC. PMID- 26770474 TI - Surgical treatment of selected patients with multilevel contiguous thoracolumbar spinal tuberculosis by only posterior instrumentation without any bone fusion. AB - The retrospective clinical study is to determine the feasibility and efficacy of surgical management of multilevel contiguous thoracolumbar spinal tuberculosis (MCTLST) by only posterior instrumentation without posterior or anterior bone fusion and without anterior fixation in the study of eleven selected cases. Eleven selected cases with MCTLST were treated with combined posterior instrumentation and debridement and/or decompression without any bone fusion. The mean follow-up was 33.1 months (range 20-48 months). The kyphosis angle ranged from 9.2 to 40.4 degrees before operation, 27.8 degrees in average. The American Spinal Injury Association (ASIA) score system was used to evaluate the neurological deficits and erythrocytesedimentationrate (ESR) used to judge the activity of tuberculosis, which were collected at certain time. Spinal tuberculosis (STB) was completely cured in all eleven patients. There was no recurrent tuberculosis infection. The postoperative kyphosis angle was 7.1 degrees to 12.5 degrees , 9.6 degrees in average and there was no significant loss of the correction at the final follow-up. Solid fusion was achieved in all cases. Neurological condition in all patients was improved after surgery. In conclusions, combined posterior instrumentation and debridement and/or decompression without any bone fusion can be a feasible and effective method in treatment of patients with MCTLST. However, the strict selection of patients was the critical of the surgery success. PMID- 26770475 TI - Efficacy of paclitaxel-based doublet regimens combining with intraperitoneal chemotherapy for advanced gastric cancer with peritoneal metastasis. AB - We aim to evaluate the efficacy and safety of paclitaxel-based doublet intravenous chemotherapy (IVC) with and without intraperitoneal chemotherapy (IPC) as the first-line treatment in advanced gastric cancer (AGC) with peritoneal metastasis (PM). 173 AGC patients with peritoneal metastasis were enrolled. All patients received paclitaxel-based doublet systemic chemotherapy Among them, 117 patients received IVC+IPC and 56 patients received IVC alone. The median OS of patients in the IP+ group was longer than the IP- group, however, there was no statistical difference between the two groups (11.1 months vs. 10.1 months, P = 0.072). In the multivariate analysis, the ECOG PS and IVC+/-IPC were independent prognostic factors for PFS and OS. There were no significant differences in the incidence of grade 3 and 4 toxicity between the IP+(DDP), IP+(FUDR) and IP- groups. Paclitaxel-based doublet regimens combining with IPC is effective, feasible and tolerated in AGC patients with PM. PMID- 26770476 TI - Relationship between hOGG1 Ser326Cys gene polymorphism and coronary artery lesions in patients with diabetes mellitus. AB - To study the relationship between human 8-oxoguanine glycosylase (hOGG1) Ser326Cys gene polymorphism and coronary artery lesions in patients with diabetes mellitus, we analyzed 323 patients with diabetic mellitus, who underwent coronary angiography. Using PCR-RFLP, these patients were grouped into three genotypes: Cys/Cys (n=85), Ser/Ser (n=121), and Ser/Cys (n=117). Several clinical data, including history of diseases and biochemical indices were recorded. hOGG1 mRNA expression and 8-hydroxy deoxyguanosine (8-OHdG) were measured by RT-PCR and ELISA, respectively. The quantities and severity of coronary artery with lesions were analyzed from coronary angiography. The Gensini and SYNTAX scores were detected by the unitary criteria. The 8-OHdG levels showed statistical difference among the three genotypes (F=21.56, P<0.05). Also, 8-OHdG in Cys/Cys genotype was higher than Ser/Ser and Ser/Cys genotype (q=2.32, q=3.12, P<0.05). In terms of the expression of hOGGl mRNA, the measure of hOGGl/beta-actin showed significant difference among the three groups (F=12.56, P<0.05). On comparing two groups, hOGGl/beta-actin in Cys/Cys genotype was higher thanSer/Ser and Ser/Cys genotypes (q=2.32, q=3.12, P<0.05). Percentage of 3-vessel lesions was high in Cys/Cys genotype and percentage of 1-vessel lesions was low in Ser/Cys genotype. Gensini and SYNTAX scores and ratio of complex lesions were significantly higher in the Cys/Cys genotype than the other two genotypes (FGensini=47.16, FSYNTAX=55.12; P<0.05). hOGG1 Ser326Cys polymorphism showed correlation with coronary artery lesions in patients with diabetes mellitus, and Cys/Cys genotype may have more impact on the severity of lesions. PMID- 26770477 TI - Improved donor liver position selection and revascularization for heterotopic auxiliary liver transplantation with portal vein arterialization. AB - PURPOSE: To establish an animal model of improved donor liver position selection and revascularization for heterotopic auxiliary liver transplantation with portal vein arterialization (HALT-PVA). METHODS: Sprague-Dawley rats were utilized to establish models. Improved HALT-PVA was conducted for the experimental rat: hepatic common artery of donor liver was end-to-side anastomosed to portal vein which was end-to-side anastomosed to the left common iliac artery of host rat, while the segments of inferior vena cava superior and inferior to the donor liver were end-to-side anastomosed to the inferior vena cava of host rat, respectively. For the control rats, liver transplantations were conducted through end-to-end anastomosis between portal vein of donor liver and stand tube placed in right renal artery of host rat, and end-to-side anastomosis between the inferior vena cava inferior to the donor liver with the inferior vena cava of host rat, while the inferior vena cava superior to the donor liver was stitched up. Besides, hepaticoenterostomy were performed to all rats and survival status were monitored. ALT, AST, TBil and CHE were tested continuously after operation, and pathological examination of liver tissues were performed. RESULTS: The survival rate was 93.3% (14/15). ALT, AST, TBil and CHE for experimental group showed a rapider recovery of liver functions than controls. Pathological examinations of liver tissues from the experimental-group rats showed better presentation than the control-group rats. CONCLUSIONS: The improved HALT-PVA better accords with the normal anatomy, with little detriment to implanted liver, and therefore is a good model for HALT-PVA related research. PMID- 26770479 TI - Positive expression of cyclin D1 is an indicator for the evaluation of the prognosis of breast cancer. AB - AIMS: The present study is to detect the expression of cyclin D1 in different clinical molecular subtypes in breast cancer, and to analyze its relationship to the expression of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor-2 (Her-2), tumor size, clinical stages, histological grades, age of menarche, and prognosis. METHODS: In the present study, we retrospectively reviewed the clinical information of 226 patients with breast cancer who were hospitalized at The First Affiliated Hospital of Xinjiang Medical University between January 2000 and December 2012. Immunohistochemical method was used to detect the expression of cyclin D1 in breast cancer tissues. Pearson's Chi-square test was performed to compare the expression of cyclin D1 under different clinical indicators, and under different immune indexes and subtypes. Spearman rank correlation method was used to analyze the correlation between cyclin D1 expression and ER, PR, Her-2, tumor size, clinical stages, histological grades and age of menarche. Kaplan-Meier was employed to calculate the survival time of tumor-free survival time. Log-rank method was used to analyze the survival curves. RESULTS: The expression of cyclin D1 was not significantly correlated to tumor size, clinical stages, histological grades, age of menarche, or PR, but was correlated to ER. Higher cyclin D1 positive rate corresponded to higher ER positive rate. The expression of cyclin D1 was negatively correlated to Her-2 expression (P < 0.05). Higher cyclin D1 positive rate corresponded to lower Her-2 positive rate. In cyclin D1 positive group, the percentage of Luminal A type was the highest. In cyclin D1 negative group, the percentage of Luminal B type was the highest. Higher cyclin D1 positive rate led to longer tumor-free survival time. CONCLUSIONS: The expression of cyclinD1 is significantly correlated to ER and Her-2. Positive expression of cyclin D1 suggests good prognosis, and can be used as an indicator for the evaluation of the prognosis of breast cancer. PMID- 26770478 TI - Propofol sedation versus no sedation in detection of pharyngeal and upper gastrointestinal superficial squamous cell carcinoma using endoscopic narrow band imaging: a multicenter prospective trial. AB - Intravenous propofol can provide a superior quality of sedation compared to standard sedation for upper gastrointestinal endoscopy. However, the utility of propofol sedation for the endoscopic early detection of superficial pharyngeal and esophageal squamous cell carcinoma has not been investigated. In a multicenter, prospective trial, 255 patients with esophageal squamous cell carcinomas (ESCCs) were assigned to receive propofol sedation or no sedation according to their own willingness. The primary aim was to compare the detection rates of superficial cancer in the pharyngeal region and the esophagus between two groups. The secondary aim was to evaluate factors associated with technical adequacy. The detection rate was higher in the propofol sedation vs. no sedation group for H&N region (6.06% vs. 2.40%), but not significantly (P=0.22). However, the small lesion (less than 10 mm in diameter) detection rate was higher in sedation vs. no sedation group for H&N region (88.89% vs. 33.33%; P=0.048). The median time for pharyngeal observation in the sedation group was faster than in the no sedation group (20.6 s vs. 44.3 s; P<0.001). Ninety-five percent of H&N region evaluations were totally complete in sedation compared with sixty percent in the no sedation group (P<0.001). The overall p value indicated that only smoking habit was associated with incomplete pharyngeal observation (P<0.05), and it was more difficult to accomplish a complete pharyngeal observation in patients who smoked more than 10 packs per day. Intravenous propofol sedation compared to no intravenous sedation during conventional upper gastrointestinal endoscopy can facilitate a more complete pharyngeal examination and increase the detection rate of superficial H&N squamous cell carcinoma in high risk patients. PMID- 26770480 TI - Operative strategy and clinical outcomes of ROI-C(TM) fusion device in the treatment of Hangman's fracture. AB - OBJECTIVE: to compare the clinical outcomes of anterior fusion with ROI-C(TM) and titanium plate in the treatment of Hangman's fractures. METHODS: From Dec 2005 to Jan 2015, a total of 21 patients with Hangman's fracture, who underwent anterior internal fixation with titanium plate or ROI-C(TM), were retrospectively reviewed. All patients underwent anteroposterior, lateral, and flexion-extension radiography and computed tomography of cervical spine preoperatively and postoperatively at 3 days and 3 months. Cervical visual analog scale (VAS) score, Bazaz dysphagia score, angular displacement (AD), horizontal displacement (HD), fusion rate, and blood loss were measured. RESULTS: The VAS and Bazaz dysphagia score at postoperative 3 days were significantly lower in ROI-C(TM) group, as compared to titanium plate group (P<0.05). AD and HD were significantly decreased in both groups after operation (P<0.05). The postoperative rate of complete reduction of spondylolisthesis was significantly higher in ROI-C(TM) group than that in titanium plate group (P<0.05). The operative time and blood loss was significantly decreased in ROI-C(TM) group, as compared to titanium plate group (P<0.05). CONCLUSION: ROI-C(TM) device showed superiority to titanium plate in the treatment of Hangman's fractures, suggesting that anterior operation with ROI C(TM) device may be a better choice for treating Hangman's fractures. PMID- 26770481 TI - Association between left ventricular end-diastolic pressure and coronary artery disease as well as its extent and severity. AB - Patients with myocardial ischemia exhibit increased left ventricular end diastolic pressure (LVEDP). The study was to evaluate the relationship between LVEDP measured by left cardiac catheterization and coronary artery disease (CAD) as well as its extent and severity evaluated by coronary angiography (CAG). 912 patients who underwent CAG and left cardiac catheterization were enrolled. There were 313 patients without CAD and 599 with CAD according to CAG. The extent and severity of coronary artery was evaluated by number of vessels and Gensini score. Analyze the correlation of LVEDP and CAD as well as its extent and severity. LVEDP was significantly higher in CAD patients than non-CAD (9.58+/-5.78 mmHg vs 10.9+/-5.46 mmHg, P<0.001), and was correlated independently with the presence of CAD (OR = 0.11, per 5 mmHg increase, 95% CI 1.02-1.29, P = 0.02). LVEDP was increased with an increase of number of vessels. By linear regression analysis, LVEDP was significantly associated with Gensini score (standardized beta = 0.034, P = 0.001). In non-CAD group, LVEDP was only correlated with age (r = 0.123, P = 0.030). In conclusion, our findings suggest that elevated LVEDP was significantly associated with CAD as well as its extent and severity. LVEDP was only correlated with age in non-CAD patients. LVEDP measurement provides incremental clinical value for CAD and non-CAD patients. PMID- 26770482 TI - A new characterization for nonarteritic anterior ischemic optic neuropathy. AB - This study is to investigate the clinical characteristics of patients with nonarteritic anterior ischemic optic neuropathy (NAION). Totally 133 patients (156 eyes) were included in this study. At the first visit and follow-up visits, the patients were subjected to the ophthalmic evaluations, including the fundus photography, visual field (VF) test, fluorescein fundus angiography, and optical coherence tomography (OCT). The visual acuity (VA) of 156 eyes and the VF of 148 eyes were evaluated. For the VA assessment, 59 (38%), 67 (43%), and 30 (19%) cases presented with an initial VA >= 20/40, between 20/40 and 20/400, and <= 20/400, respectively. VA was improved in 44% and deteriorated in 8% of the patients with VA < 20/20 after NAION onset. Inferior or superior altitudinal defects, constricted fields, and nasal steps were the most common VF defects. In the eyes with VF defects, 32 cases (22%) were improved, and 25 cases (17%) were worsened. In the 61 cases (39%) with VA <= 20/200 at NAION onset, neuroepithelial detachment in the fovea was found in 37 eyes (61%). For the optic disc assessment, retinal nerve fiber layer (RNFL) thickening was the most common symptom of NAION. Out of the 36 eyes with ONA or DR, 72% showed VA improvement after the NAION occurrence in the contralateral eye. Poor microcirculation perfusion in the bilateral optic nerve hypoplasia (ONH) might be the underlying mechanism for NAION, which could be relieved by compromising the blood supply to the one side. PMID- 26770483 TI - Prognostic significance of reduced immunohistochemical expression of E-cadherin in endometrial cancer-results of a meta-analysis. AB - OBJECTIVE: Previous studies which investigated the relationship between reduced E cadherin and prognosis of endometrial cancer were ambiguous and conflicting. Therefore, the aim of the present study was to evaluate the relationship between reduced expression of E-cadherin and endometrial cancer by meta-analysis approach. METHOD: AfterPubmed and Embasewere deliberately searched via the internet, 8 pieces of literaturewere totally included in final meta-analysis. After the data had been abstracted, the pulled odds ratio (OR) and hazard ratio (HR) were calculated by STATA with random or fixed effect model depending on their heterogeneity. The publication bias of included literature were tested by Begg's funnel plot and Egger's test. RESULTS: The pulled data showed that the reduced expression of E-cadherin was significantly associated with overall survival (OS), HR=2.42, 95% CI: 1.50-3.89. The clinical parameters such as lymph node metastasis (LNM), myometrial invasion (MI), International Federation of Gynecology and Obstetrics (FIGO) stage, histological type and pathological type were also significantly associated with reduced expression of E-cadherin. The results of publication biasshowed there were no significant publication bias. CONCLUSION: Endometrial cancer patients with reduced expression of E-cadherin may have a poorer prognosis than those with normal or higher expression of E cadherin. PMID- 26770484 TI - The clinical characteristics of 80 cases of acquired immunodeficiency syndrome associated Kaposi's sarcoma in Xinjiang Autonomous Region and the effect of different treatments on the prognosis. AB - To analyze the clinical features of AIDS-related Kaposi's sarcoma (AIDS-KS) patients in Xinjiang Autonomous Region and the impact of CD4 (+)T lymphocyte count, highly active antiretroviral therapy (HAART) and systemic chemotherapy on the prognosis. The clinical information of 80 AIDS-KS patients admitted in Sixth People's Hospital of Xinjiang Autonomous Region from January 2008 to August 2014 was retrospectively reviewed. Population characteristics, extent of lesions, KS progress, CD4 (+)T lymphocyte count, combined opportunistic infections, treatment and prognosis of these patients were analyzed. The 80 patients were divided into five groups according to treatment methods, including HAART, HAART + chemotherapy, chemotherapy + HAART, chemotherapy, and untreated groups. The efficacy and prognosis of the five groups were compared. Among the 80 patients, 74 (92.50%) patients were Uygur. The average age was 39.5+/-9.9 years and male-to female ratio was 3:1. The median of baseline CD4 (+)T lymphocyte count was 152.5 cells/MUL and the interquartile was 233.25 cells/MUL. CD4 (+)T lymphocyte counts were significantly increased after treatment in HAART, HAART + chemotherapy, and chemotherapy + HAART groups (P < 0.05). CD4 (+)T lymphocyte count in chemotherapy groups was significantly reduced after treatment (P < 0.05). The untreated group had the highest mortality rate (33.3%). In HAART group, KS-associated immune reconstitution inflammatory response syndrome (KS-IRIS) appeared in 45.5% cases and 2 death cases were caused by KS-IRIS. In Xinjiang Autonomous Region, the incidence of AIDS-KS is high in young Uygur male people. HAART followed by chemotherapy has ideal efficacy, reduces the incidence of KS-IRIS and improves the prognosis. PMID- 26770485 TI - Tree-in-bud pattern of chest CT images for diagnosis of Mycobacterium abscesses. AB - OBJECTIVES: Changes of chest CT images in Mycobacterium and non-Mycobacterium abscesses in patients with lung disease were with a view to making an early diagnosis. METHODS: 124 primary patients diagnosed with non-tuberculosis Mycobacterium infections with a positive sputum acid-fast smear were enrolled in this retrospective study. CT images and clinical data of these patients were analyzed. RESULTS: The 52 Mycobacterium abscess lung disease cases included bronchiectasis 82.7% (43/52), which was more easily detected bilaterally than unilaterally (29/52 vs. 14/52), lung consolidation 44.2% (23/52), nodules 44.2% (22/52), cavities 32.7% (17/52), tree-in-bud pattern 42.3% (22/52) and patchy shadow 63.5% (33/52) in CT images. Tree-in-bud pattern was more common in Mycobacterium abscess compared with non-Mycobacterium abscess lung disease (42.3% vs. 18.1%, P = 0.004). A significant difference of the lung area involved by tree in-bud in CT was found between non-Mycobacteria abscess and Mycobacterium abscess lung disease (17.0% vs. 7.2%, P < 0.001), and tree-in-bud occurred more readily unilaterally (21.2% vs. 6.9%, P = 0.029), and in the inferior lobe of the right lung (3.2% vs. 0.2%, P = 0.029) in Mycobacterium abscess lung disease. Patchy shadow was more common in non-Mycobacterium abscess lung disease (63.5% vs. 80.1%, P = 0.041). Further multi-factor analysis confirmed that tree-in-bud was an independent predictor of Mycobacterium abscess lung disease. CONCLUSIONS: Different CT results existed between non-Mycobacterium abscess and Mycobacterium abscess lung diseases. The tree-in-bud pattern might be helpful to choose a suitable therapy in patients, with an acid-fast bacilli smear-positive diagnosis of lung disease. PMID- 26770486 TI - Efficacy of FOLFOXIRI versus XELOXIRI plus bevacizumab in the treatment of metastatic colorectal cancer. AB - BACKGROUND: Chemotherapy with capecitabine combined with leucovorin, oxaliplatin, and irinotecan plus bevacizumab (XELOXIRI-Bev) or fluorouracil, leucovorin, oxaliplatin, and irinotecan plus bevacizumab (FOLFOXIRI-Bev), is recently introduced as first-line treatment for metastatic colorectal cancer (mCRC). The comparison between the two strategies above in clinical efficacy has not been assessed. METHODS: We retrospectively reviewed 138 patients with untreated metastatic colorectal cancer to receive either FOLFOXIR-Bev (group 1) or XELOXIRI Bev (group 2). Up to 12 cycles of treatment were administered, followed by fluorouracil plus bevacizumab until disease progression. The primary end point was progression-free survival. RESULTS: The mean progression-free survival was 13.5 months in the group 1, as compared with 10.4 months in the group 2 (hazard ratio for progression, 0.3; 95% confidence interval [CI], 0.12 to 0.83; P = 0.032). The objective response rate was 71% in the group 1 and 52.2% in the group 2 (P = 0.006). Overall survival was not found significant difference between the two groups (group 1 vs. 2; 31.3 vs. 24.6 months; hazard ratio for death, 0.6; 95% CI, 0.29 to 1.15; P = 0.115). The incidences of grade 3 or 4 neurotoxicity, stomatitis, diarrhea, and neutropenia were significantly higher in the group 1. CONCLUSION: FOLFOXIR-Bev, as compared with XELOXIRI-Bev, improved the outcomes in patients with mCRC, but increased the incidence of some adverse events. PMID- 26770487 TI - Characteristics of non-valvular atrial fibrillation patients who benefit most from anticoagulation treatment. AB - OBJECTIVES: The objective was to determine who will benefit most from oral anticoagulation (OAC) for non-valvular atrial fibrillation (NVAF) patients aged >= 75 years. BACKGROUND: It was unclear whether all of NVAF aged >= 75 should receive OAC. METHODS: We recruited NVAF >= 75 years without QAC who were divided into three groups according to CHA2DS-VASc scores. The clinical endpoints were ischemic stroke (IS), thromboembolism (TE), or death. RESULTS: The patients with CHA2DS2-VASc score of 6-9 were not appropriate for anticoagulation with the highest HAS-BLED scores. CHA2DS2-VASc of 2 had little risk for IS/TE. We further divided CHA2DS2-VASc of 3-5 into three subgroups with estimated glomerular filtration rate (eGFR; ml/min/1.73 m(2)): < 30, 30-60, and > 60. The patients with eGFR < 30 had the highest bleeding risk with a comparable IS/TE. CONCLUSIONS: NVAF with CHA2DS2-VASc of 3-5 and eGFR > 30 ml/min/1.73 m(2) represent the most appropriate population for anticoagulation. PMID- 26770488 TI - Clinical analysis of tumor and non-tumor patients complicated with pulmonary embolism. AB - OBJECTIVE: To analyze the differences of the clinical characteristics and risk factors between tumor and non-tumor patients complicated with pulmonary embolism. METHODS: A retrospective analysis was conducted on 96 hospitalized patients complicated with pulmonary embolism admitted into 307 Hospital of PLA from January 2009 to December 2014. 96 cases were divided into tumor group (n=52) and non-tumor group (n=44) according to whether they were accompanied with malignant tumors. The relevant characteristics of tumor group, comparison of the risk factors and laboratory results between two groups were assessed. RESULTS: Lung cancer was prone to pulmonary embolism in malignant tumors and adenocarcinoma was the commonest pathological type. 31 (59.6%) cases developed pulmonary embolism within 3 months after tumor was diagnosed. The level of serum D-dimer and leukemia in tumor group were higher than that in non-tumor group (3241.06+/ 4514.16 MUg/L vs 1238.49+/-1236.69 MUg/L and 9.68+/-5.53*10(9)/L vs 7.90+/ 3.84*10(9)/L), with a significant statistical difference (P=0.004 and 0.015). The level of serum platlet in tumor group were lower than that in non-tumor group (204.63+/-132.58*10(9)/L vs 222.26+/-76.92*10(9)/L), with a significant statistical difference (P=0.023). Coronary heart disease, chronic lung disease, diabetes, hyperlipemia and cerebral infarction were significantly different between two groups (P<0.01). Unexplained dyspnea (51/96, 53.1%) was the main symptom of pulmonary embolism, yet no significant difference was found between the two groups. 33 cases (34.4%) combined with deep venous thrombosis of lower limb, right lower limb more than the left. Right main pulmonary artery and its branches embolism were seen in 46 cases (47.9%) according to imaging examination, and no significant difference between two groups. After thrombolytic and anticoagulant therapy, only 9 cases died of Pulmonary embolism. CONCLUSION: There is no obvious and significant difference in clinical symptoms between tumor and non-tumor patients complicated with pulmonary embolism. Using of anticoagulant and thrombolytic therapy can obtain good curative effect upon diagnosis. PMID- 26770489 TI - A retrospective study of primary breast augmentation: recovery period, complications and patient satisfaction. AB - BACKGROUND: The most critical thing in breast augmentation surgery is to determine the location for implant placement. However, few researches on this were carried out in China. We therefore conducted this retrospective study to compare the recovery period, complications and patient satisfaction at two different implant placement locations-the subglandular plane and the subpectoral plane. METHODS: A total of 144 patients were included. All of them have undergone primary aesthetic breast augmentation with cohesive silicone gel implant. Then they were divided into two groups according to the implant location: group A (in the subglandular plane) and group B (in the subpectoral plane). Data collected were patient data, surgery-related indicators, recovery, complications and patient satisfaction. RESULTS: Thirty-nine patients were assigned to group A, and 105 patients to group B. In terms of patient data, no significant difference was found in age, follow-up time and the size of prosthesis between the two groups, but there existed statistically significant difference in body mass index (BMI) and the preoperative mammary tissue thickness (P < 0.05). For surgery-related indicators and recovery, group A was better than group B in surgical blood loss, duration of pain and indwelling drainage tube, with statistical significance (P < 0.05). But regarding the complications, significant difference was found only in the nipple-areola numbness (P < 0.05). Overall, 76% of the patients reported they were "satisfied" with the outcome or the outcome was "perfect". CONCLUSION: Implant placement in the subglandular plane has a shorter recovery period than that in the subpectoral plane. The occurrence of complications and degree of patient satisfaction are similar in the two groups. PMID- 26770490 TI - Pharmacokinetics of ambroxol and clenbuterol tablets in healthy Chinese volunteers. AB - OBJECTIVE: To investigate the pharmacokinetics of Ambroxol and Clenbuterol Tablets in Chinese healthy volunteers after a single or multiple dosages oral administration. METHODS: A total of 9 healthy adult subjects were given Ambroxol and Clenbuterol Tablets in a single dosage or multiple dosages respectively. LC/MS/MS were used for the determination of Ambroxol and Clenbuterol of in plasma. The important pharmacokinetic parameters were calculated by DAS 2.0 software (compartment model). RESULTS: Single and multiple dosage groups of Ambroxol and Clenbuterol were all fitted two-compartment model. The pharmacokinetics fitted first order kinetics process. No difference in pharmacokinetics of Ambroxol in single and multiple dosage groups volunteers was observed, Which showed no marked changes, suggesting that multiple dosing did not influence the velocity of drug metabolism. Moreover, parameters of Clenbuterol had significant difference between the single and multiple dosage groups (P<0.05), showing there was accumulation in the body. 9 subjects had completed single or multiple dosages oral administration test, with no adverse drug reactions appeared during the test. CONCLUSION: There was no obvious accumulation of Ambroxol after repeated dosing. But obvious accumulation of Clenbuterol was noted in multiple-dose administration. The established method is sensitive, accurate, reliable and specific, and it can meet the requirement of clinical pharmacokinetic trial. PMID- 26770491 TI - Effect of dexmedetomidine on rats with renal ischemia-reperfusion injury and the expression of tight junction protein in kidney. AB - To explore the protective effect of dexmedetomidine (Dex) on rats with renal ischemia-reperfusion injury and the influence of Dex on the expression of tight junction protein in kidney. Grouped 40 SPF male rats into 4 groups, sham operation group (group S), ischemia-reperfusion group (group I/R), pretreatment with Dex group (group Pre/Dex), post-treatment with Dex group (group Post/Dex), randomly, 10 rats each group. Rats in group S were anaesthetized and set up with removal of right kidney; rats in group I/R were set up with removal of right kidney and left renal artery clamping for 45 min followed by 60 min reperfusion; rats in group Pre/Dex were intravenous injected with Dex (1 MUg/kg) for 30 min after indwelling catheter via femoral vein puncture; rats in group Post/Dex were intravenous injected with Dex (1 MUg/kg) for 30 min after left renal reperfusion. The kidneys in each group were made out pathologic slices after 6 h I/R, stained with HE; blood samples were taken with separation plasma, creatinine (Scr) and urea nitrogen (BUN) were detected by automatic biochemical analyzer; IL-1beta and TNF-alpha were detected by Enzyme-linked Immunosorbent Assay (ELISA); the expression level of tight junction protein ZO-1 and protein occludin in kidney were detected by Western-blot. The results of HE staining showed that, comparing to group S, the tissue of kidney in group I/R were damaged heavily with tubules dilatation and inflammation obviously, while lightened in group Pre/Dex and group Post/Dex. The results of detection of renal function and inflammatory factors showed that, comparing to group S, Scr, BUN, IL-1beta and TNF-alpha were all enhanced in group I/R, group Pre/Dex and group Post/Dex, significantly (P < 0.05), while the inflammatory factors in group Pre/Dex and group Post/Dex were lower than in group I/R, significantly (P < 0.05). The results of Western-blot showed that the expression of protein ZO-1 and occludin in group Pre/Dex and group Post/Dex were higher than in group I/R, significantly (P < 0.05). Dex could reduce renal dysfunction induced by I/R, inhibit inflammatory response, up regulate the expression of protein ZO-1 and occludin and protect renal. PMID- 26770492 TI - Development and evaluation of the quantitative real-time PCR assay in detection and typing of herpes simplex virus in swab specimens from patients with genital herpes. AB - Genital herpes (GH), which is caused mainly by herpes simplex virus (HSV)-2 and HSV-1, remains a worldwide problem. Laboratory confirmation of GH is important, particularly as there are other conditions which present similarly to GH, while atypical presentations of GH also occur. Currently, virus culture is the classical method for diagnosis of GH, but it is time consuming and with low sensitivity. A major advance for diagnosis of GH is to use Real-time polymerase chain reaction (PCR). In this study, to evaluate the significance of the real time PCR method in diagnosis and typing of genital HSV, the primers and probes targeted at HSV-1 DNA polymerase gene and HSV-2 glycoprotein D gene fraction were designed and applied to amplify DNA from HSV-1 or HSV-2 by employing the real time PCR technique. Then the PCR reaction system was optimized and evaluated. HSV in swab specimens from patients with genital herpes was detected by real-time PCR. The real-time PCR assay showed good specificity for detection and typing of HSV, with good linear range (5*10(2)~5*10(8) copies/ml, r=0.997), a sensitivity of 5*10(2) copies/ml, and good reproducibility (intra-assay coefficients of variation 2.29% and inter-assay coefficients of variation 4.76%). 186 swab specimens were tested for HSV by real-time PCR, and the positive rate was 23.7% (44/186). Among the 44 positive specimens, 8 (18.2%) were positive for HSV-1 with a viral load of 8.5546*10(6) copies/ml and 36 (81.2%) were positive for HSV-2 with a viral load of 1.9861*10(6) copies/ml. It is concluded that the real-time PCR is a specific, sensitive and rapid method for the detection and typing of HSV, which can be widely used in clinical diagnosis of GH. PMID- 26770493 TI - RASAL2 inhibited the proliferation and metastasis capability of nasopharyngeal carcinoma. AB - Recently, RASAL2 has been found to function as a tumor and metastasis suppressor. RASAL2 inhibited tumor growth, progression, and metastasis in several cancers. However, the regulatory effect of RASAL2 in NPC still remains unclear. The purpose of this paper was to identify the role of RASAL2 in the metastasis of NPC. The expression of RASAL2 in human NPC was obviously down-regulated by real time PCR analysis. Furthermore, knock-down of RASAL2 with siRNA treatment resulted in a promotion of cell proliferation and migration in vitro. Additionally, transwell analysis results revealed that the number of invasion cells was increased of cells treated with RASAL2 siRNA. We further explored the mechanism and demonstrated that the down-regulated RASAL2 promoted migration and invasion via EMT induction with E-cadherin decreased expression and vimentin, N cadherin, and Snail increased expression in NPC cells.In conclusion, RASAL2 inhibited the proliferation and metastasis capability of NPC cells. PMID- 26770494 TI - Laparoscopic versus open hepatectomy for hepatocellular carcinoma: short- and long-term outcomes comparison. AB - Despite the theoretical advantages of laparoscopic hepatectomy, it is still not considered the standard treatment for hepatocellular carcinoma patients because of criticism concerning oncologic stability. This study aimed at examining the short- and long-term follow-up results of laparoscopic hepatectomy versus open hepatectomy for hepatocellular carcinoma and at investigating clinical outcomes, oncologic safety, and any potential advantages of laparoscopic hepatectomy for hepatocellular carcinoma. A series of 53 patients who underwent laparoscopic hepatectomy (Lap group) for hepatocellular carcinoma were matched with 53 patients who underwent open hepatectomy during the same time period (Open group). The short- and long-term outcomes were compared between the two groups of patients. The patients who underwent the laparoscopic procedure showed a significantly faster recovery and less blood loss compared with patients who underwent open surgery. No differences were found in 5-year overall and disease free survival rates. Our results suggested that the laparoscopic approach was as safe as the open alternative. Laparoscopic hepatectomy has been shown to be a favorable surgical option with better short-term outcomes and similar long-term oncological control compared with open hepatectomy. PMID- 26770495 TI - Association of acylation-stimulating protein and receptor gene polymorphisms with coronary heart disease in Han and Hui populations. AB - OBJECTIVE: This study was to analyze the acylation-stimulating protein (ASP) (301T>C) and C5a-like receptor 2 (C5L2) (698C>T) gene polymorphisms in Han and Hui populations, and investigate their association with coronary heart disease (CHD). METHODS: 245 Han CHD patients and 110 Hui CHD patients from Shandong, Jinan, China were included in this study. Biochemical analysis was performed to assess the blood sugar and lipid levels in these patients, and the TaqMan genotyping assay was used to determine the genotype distribution. RESULTS: Our results showed that the C allele frequency in the ASP (301T>C) polymorphism in the Hui population was significantly higher than normal controls, while no significant differences were observed in the Han population, which might contribute to the genetic susceptibility of CHD in the Hui population. Moreover, for C5L2 (698C>T) gene polymorphism in both Han and Hui populations, the frequencies of the C/T genotype and T allele were significantly higher in the CHD patients compared with normal controls. Moreover, there were slight differences in the association of ASP and C5L2 gene polymorphisms with blood sugar and lipid levels between Han and Hui populations. CONCLUSIONS: Our results suggest differential ASP and C5L2 genotype distributions between Han and Hui patients, which might be associated with the different CHD-related genetic susceptibilities in these populations. These findings might contribute to a better understanding of the etiology and pathogenesis of CHD in different regions and populations. PMID- 26770496 TI - Two novel mutations of FBN1 in Jordanian patients with Marfan syndrome. AB - Marfan syndrome is an autosomal dominant inheritance disorder with a 1/5000-live birth prevalence. More than 3000 mutations have been characterized thus far in the FBN1 gene. The goal of this study is to facilitate Marfan syndrome diagnosis in Jordanian patients using a molecular genetic testing. All of the 65 coding exons and flanking intronic sequences of the FBN1 gene were amplified using polymerase chain reaction and were subjected to sequencing in five unrelated Jordanian patients suspected of having Marfan syndrome. Four different mutations were identified, including two novel mutations: the c.1553dupG frame-shift (p.Tyr519Ilefs*14) and the c.6650G>A (p.Cys2217Tyr) missense mutations. Two other missense mutations, c.2243G>A (p.Cys748Tyr) and c.2432G>A (p.Cys811Tyr), have been previously detected. Patient number five was heterozygous for the synonymous substitution variant c.1875T>C (p.Asn625Asn; rs#25458). Additionally, eight variants in the intronic sequence of the FBN1 gene were identified, of which the c.2168-46A>G mutation was a new variant. The data provide molecular-based evidence linking Marfan syndrome to pathogenic mutations in the FBN1 gene among Jordanians for the first time. Thus, our results will contribute to the better management of the disease using molecular tools and will help in genetic counseling of the patients' families. PMID- 26770498 TI - Effect of diphenoxylate on CYP450 isoforms activity in rats. AB - In order to investigate the effects of diphenoxylate on the metabolic capacity of cytochrome P450 (CYP) enzymes, a cocktail method was employed to evaluate the activities of CYP2B6, CYP2D6, CYP2C19, CYP1A2, CYP3A4, CYP2C9. The rats were randomly divided into diphenoxylate group (Low, Medium, High) and control group. The diphenoxylate group rats were given 12, 24, 48 mg/kg (Low, Medium, High) diphenoxylate by continuous intragastric administration for 7 days. Six probe drugs bupropion, metroprolol omeprazole, phenacetin, testosterone and tolbutamide were given to rats through intragastric administration, and the plasma concentrations were determined by UPLC-MS/MS. Statistical pharmacokinetics difference for omeprazole, phenacetin and tolbutamide in rats were observed by comparing diphenoxylate group with control group. Continuous 7 days-intragastric administration of diphenoxylate induces the activities of CYP2C19, CYP1A2 and CYP2C9 of rats. Induction of drug metabolizing enzyme by diphenoxylate would reduce the efficacy of other drug. Additionally, high dosage diphenoxylate may cause hepatotoxicity. PMID- 26770497 TI - APJ receptor A445C gene polymorphism in Turkish patients with coronary artery disease. AB - Coronary artery disease (CAD) is a disease in which a waxy substance called plaque builds up inside the coronary arteries. Apelin is a novel endogenous peptide with inotropic and vasodilatory properties and is the ligand for the angiotensin receptor-like 1 (APJ) receptor. We aimed to determine genotype and allele frequencies of APJ receptor A445C gene polymorphism in Turkish patients with CAD and healthy controls by RFLP-PCR. This study was performed on 159 unrelated CAD patients and 62 healthy controls. We obtained AA, AC and CC genotype frequencies in CAD patients as 41.5%, 49.1% and 9.4%, respectively. In the control group, frequencies of genotypes were found as 35.5% for AA, 48.4% for AC and 16.1% for CC. We did not observe difference in APJ receptor A445C polymorphism between CAD patients and healthy controls (chi(2) = 2.178; df = 2; P = 0.336). The A allele was encountered in 66% (210) of the CAD and 59.7% (74) of the controls. The C allele was seen in 34% (108) of the CAD and 40.3% (50) of the controls. Allele frequencies of interested genes were not significantly different between groups (chi(2) = 1.57; df = 1; p = 0.225). The frequencies of APJ receptor A445C genotype were not significantly different between control and patients. None of the three APJ receptor A445C genotypes, AA, AC and CC displayed significant difference in CAD patients. We did not find any difference in the clinical parameters except for weight and diastolic blood pressure levels in the AA, AC and CC genotypes of patients. Individuals with CC genotypes had significantly higher weight, systolic and diastolic blood pressure levels and systolic blood pressure than other genotypes, P <= 0.05. In addition, HDL-C level was found decreased, but this reduction was not statistically significant. Contrarily, the low levels of weight, SBP, DBP and TC were statistically significant in the subjects with AA genotype in CAD. In conclusion, CC genotype carriers may have more risk than other genotypes in the development of hypertension in CAD, but not AAgenotype carriers. We suggest that this polymorphism may not be a marker of CAD, but it may cause useful in function of the apelin/APJ system and may be a genetic predisposing factor for diagnostic processes and can be helpfull in finding new treatment strategies. We think that it is required to further comprehensive studies in order to make clear this situation in CAD. PMID- 26770499 TI - Short term results comparison of intraarticular platelet-rich plasma (prp) and hyaluronic acid (ha) applications in early stage of knee osteoarthritis. AB - OBJECTIVE: The aim of this study is to compare the short-term results of intra articular platelet-rich plasma (PRP) and hyaluronic acid (HA) administrations in early knee osteoarthritis. MATERIALS AND METHODS: One hundred and eighteen patients (mean age: 59.3+/-8.55) who were clinically and radiologically documented with a knee osteoarthritis diagnosis between May and December 2013 were evaluated. For the radiological evaluation, the Kellgren-Lawrence radiological classification scale was employed. The data of stage 1 and 2 patients with osteoarthritis were gathered retrospectively according to the Kellgren-Lawrence classification. The patients were given intra-articular PRP or HA treatments a total of three times, one week apart. 61 patients (102 knees) were involved in the PRP group, and 57 patients (97 knees) were involved in the HA group. The patients were evaluated using the Knee Society's Knee Scoring System (KSS) and the Visual Analog Scale (VAS) scoring system before the treatment and at three and six months after the treatment. RESULTS: In the PRP and HA groups, when pre-treatment KSS and VAS scores were compared with post treatment three and six-month scores, a statistically significant difference was seen. When the groups were compared with each other, there was no significant difference between pre-treatment KSS and VAS pain scores; however, a significant difference was found between post-treatment three and six-month scores. CONCLUSION: In this study, the intra-articular PRP administration was more efficient than the HA administration in early knee osteoarthritis. PMID- 26770500 TI - Intact parathormone measurement 1 hour after total thyroidectomy as a predictor of symptomatic hypocalcemia. AB - OBJECTIVE: Postoperative iPTH assay may predict significant hypocalcemia after thyroid surgery. The present study aimed to evaluate the ability of iPTH assay to monitor parathyroid function and to identify the risk of postoperative hypocalcemia in patients underwent thyroid surgery. MATERIALS AND METHODS: One hundred patients participated in the study (7 male and 93 female). Hypocalcemia was defined as a serum calcium concentration less than 8.0 mg/dL and symptoms of hypocalcemia. Concomitant serum calcium and iPTH levels were measured before operation and at 1(st) h for iPTH, 24(th) h for calcium after thyroidectomy. RESULTS: Postoperative hypocalcemia was observed in 31 patients. The mean postoperative serum calcium concentration in normocalcemic patients was 8.8 +/- 0.5 mg/dL, whereas it was 7.6 +/- 0.3 mg/dL in hypocalcemic patients. The mean postoperative 1(st) hour iPTH of patients in the hypocalcemia group was 9.1 +/- 4.9 pg/mL, whereas patients of the normocalcemia group had a mean postoperative iPTH of 35.8 +/- 20.2 pg/mL. CONCLUSION: Postoperative 1(st) hour iPTH < 8 pg/mL with drop in iPTH level >= 81.5% together showed the highest diagnostic accuracy in predicting postoperative hypocalcemia. PMID- 26770501 TI - Urinary BLCA1 is specific for urothelial cancer detection in Chinese ethnicity. AB - AIM: To study the potential of BLCA1 for detection of urothelial cancer including urinary bladder cancer (UBC) and upper tract urothelial cancer (UTUC). METHOD: An antibody for BLCA1 was generated and indirect ELISA was used to detect urinary BLCA1 level. Clinicopathological parameters were studied for the association with BLCA1 level. Urine samples from UBC and UTUC patients, together with cases with other urological disorders were collected and tested. RESULTS: Urinary BLCA1 level in UBC and UTUC patients were significantly higher than that in normal controls. This was also proven when urothelial cancers were grouped as a whole, where as the level did not differ between UBC and UTUC samples. BLCA1 was also significantly higher in urothelial cancer samples compared to other urological disorders such as patients with long-dwelling catheter, glandular cystitis, BPH and other benign conditions. Cut-off value at 0.0009 OD/MUg yielded a sensitivity of 92.7% and a specificity of 92.9% for UBC. CONCLUSION: Urinary BLCA1 is a promising marker for urothelial cancers including UBC and UTUC with high sensitivity and specificity. PMID- 26770502 TI - Evaluation of carotid artery elasticity changes in patients with cerebral small vessel disease. AB - BACKGROUND: The purpose of this study is to evaluate the intima-media thickness (IMT) and arterial elasticity of the common carotid artery (CCA) in patients with cerebral small vessel disease (SVD) by applying radiofrequency (RF) ultrasound technology. METHODS: Fifty SVD subjects (SVD group) and fifty-three matched controls (Control group) were enrolled in the study. Structural and functional changes in the common carotid arterial wall were investigated by quality intima media thickness (QIMT) and quanlity arterial stiffness (QAS) with a Mylab Twice ultrasound instrument. The vessel related variables between these two groups were analyzed. RESULTS: There was a significant higher value of CCA-IMT in SVD group than that in control group (P<0.01). Pulse wave velocity (PWV), stiffness coefficient (alpha) and stiffness index (beta) were remarkably greater (P<0.01) while compliance coefficient (CC) decreased significantly (P<0.01) in the SVD group than control group. Furthermore, significant difference was found on IMT between left and right CCA in SVD (P<0.01) and control group (P<0.01) while no significant difference was found on CC, alpha, beta and PWV between left and right CCA in SVD (P>0.05) and control group (P>0.05). CONCLUSIONS: Decreased arterial elasticity of the CCA in patients with SVD compared with normal subjects. Ultrasound RF technology can be used to non-invasively and quantitatively detect the change in the structure and function of the CCA in SVD subjects for evaluating preclinical atherosclerosis. PMID- 26770503 TI - Effect of progesterone intervention on the dynamic changes of AQP-4 in hypoxic ischaemic brain damage. AB - To observe the effect of progesterone (PROG) on blood-brain barrier (BBB) permeability, brain tissue water content and dynamic changes of aquaporin-4 (AQP 4) in neonatal rats with hypoxic-ischaemic brain damage (HIBD). 72 neonatal Wistar rats, aged 7 days old, were randomly divided into control, hypoxic ischaemic (6, 24 and 72 h, and 7 d subgroups) and drug groups (6, 24 and 72 h, and 7 d subgroups). The HIBD animal model was established. BBB was detected via an Evans blue tracer. Brain water content was determined by the dry/wet method. The AQP-4 expression in the cerebral cortex was observed through immunohistochemistry and Western blot. BBB permeability in the cerebral cortex of the neonatal rats, brain water content and AQP-4 expression in the hypoxia ischaemia group were significantly higher than those of the control group after hypoxia for 6 h (P < 0.05), continued to rise within 24 h and then reached the peak at 72 h. BBB permeability in the cerebral cortex of the neonatal rats, brain water content and AQP-4 expression in the drug group were significantly lower than those of the hypoxia-ischaemia group after hypoxia for 6, 24 and 72 h (P < 0.05). Moreover, BBB permeability and BBB expression were positively correlated with the AQP-4 expression. In conclusion, PROG protects the brain of HIBD neonatal rats by alleviating the damage of BBB and cerebral oedema. The protective effect of PROG may be related to the down-regulation of AQP-4 expression in the cerebral cortex of neonatal rats. PMID- 26770504 TI - Association between polymorphism of the norepinephrine transporter gene rs2242446 and rs5669 loci and depression disorders. AB - OBJECTIVE: To explore the association between polymorphism of the norepinephrine transporter (NET) gene rs2242446 and rs5669 loci and depression in Chinese Han population. METHODS: A case-control study was carried out, the gene types and allele distributions of NFT gene rs2242446 and rs5569 loci in 302 depression patients and 302 healthy controls were detected by Taqman SNP genotyping technology. RESULTS: The gene types and allele frequency distributions of NFT gene rs2242446 and rs5569 loci had significant differences between case group and control group (rs2242446, x(2)=26.045, P<0.05, x(2)=8.827, P<0.05, rs5569, x(2)=42.47, P<0.05, x(2)=20.9, P<0.05). The CC genotype of NET gene rs2242446 locus and rs5569 loci was a protective factor of depression compared with the CT and TT genotypes. CONCLUSION: The NET genepoly morphism of rs2242446 and rs5569 loci was a ssociated with depression in Chinese Han population, in which the CC genotype of rs2242446 and rs5569 loci was a protective factor of depression. PMID- 26770505 TI - Expression of DKK1 and beta-catenin in epidermal neoplasms and their correlation. AB - OBJECTIVE: To investigate the expression of Dickkopf-1 (DKK1) and beta-catenin and their correlation in epidermal neoplasms. METHODS: Immunohistochemical staining was applied to detect the expression of DKK1 and beta-catenin in tissue samples of 19 cases of seborrheic keratosis (SK), 16 cases of actinic keratosis (AK), 24 cases of Bowen's disease (BD), 25 cases of cutaneous squamous cell carcinoma (SCC), and 22 cases of normal epidermal tissue (NET). RESULTS: DKK1 was expressed in cytoplasm in normal epidermis. The positive expression rates of DKK1 in SK, AK, BD and SCC were 63.16%, 50.00%, 12.50% and 8.00%, respectively. beta catenin was expressed in cell membrane in normal epidermis. The abnormal expression rates of beta-catenin in SK, AK, BD and SCC were 15.79%, 56.25%, 91.67% and 96.00%, respectively. Additionally, significant negative correlation was observable between the expression of beta-catenin and DKK1 (r=-0.692, P=0.000). CONCLUSION: The Wnt signaling pathway may play an important role in the process of epidermal neoplasms formation. The loss of DKK1 promotes the abnormal expression of beta-catenin through Wnt signaling pathway. PMID- 26770506 TI - Correlation between polymorphism of endothelial nitric oxide synthase and avascular necrosis of femoral head. AB - OBJECTIVE: We analyzed the correlation between mutation in intron 4 and exon 7 of endothelial nitric oxide synthase (eNOS) and avascular necrosis of femoral head (ANFH). METHOD: A total of 260 ANFH cases without history of hip joint injuries were diagnosed and subject to staging according to Ficat standard, with 262 health subjects as control. Venous blood was collected to extract genome DNA, which was then amplified by PCR. The polymorphism of 27 bp repeat sequence in intron 4 and G894T polymorphism in exon 7 of eNOS gene was detected. RESULTS: The b/b, b/a and a/a genotype frequency of intron 4 was 77.7%, 19.2% and 3.1% in ANFH group, respectively, and that in the control group was 58.0%, 32.8% and 9.2%, respectively. The b allele frequency in ANFH group was obviously higher than that in the control (P<0.0001). The frequency of 894 G/G wild type, G/T heterozygote and T/T homozygote in eNOS exon 7 was analyzed by PCR-RLFP: 65.4%, 26.5% and 8.1% in ANFH group, and 46.2%, 37.8% and 16% in normal control, respectively. The frequency of TT genotype in ANFH was obviously higher than that in the control group (P<0.001). CONCLUSION: Polymorphism of eNOS was correlated with ANFH. PMID- 26770507 TI - The clinical comparative study on high and low viscosity bone cement application in vertebroplasty. AB - OBJECTIVE: To investigate the clinical effect of high and low viscosity bone cement in vertebroplasty for treatment of osteoporotic vertebral compression fractures. METHODS: 40 cases of patients with osteoporotic thoracolumbar compression fractures admitted into department of orthopeadics in our hospital were reviewed. All patients were divided into high viscosity bone cement group (20 cases) and low viscosity bone cement group (20 cases). Visual Analog Score (VAS), Oswestry Dability Index (ODI), injured vertebral height restoration (Cobb Angle) and bone cement leakage rate, subsequent fracture rate of vertebrae body with or without surgical treatment were measured. RESULTS: Compared with the low viscosity bone cement group, the VAS score, ODI score and Cobb angle of high viscosity bone cement group had a statistical difference (P<0.05). The postoperative complications in high viscosity bone cement group were lower than those in low viscosity bone cement group (P<0.05). CONCLUSION: Compared with low viscosity bone cement, bone cement leakage rate reduced obviously in high viscosity bone cement with good clinical effect and prognosis in vertebroplasty for treatment of osteoporotic thoracolumbar compression fractures. PMID- 26770508 TI - Elevated serum interleukin-35 levels correlate with poor prognosis in patients with clear cell renal cell carcinoma. AB - Increasing evidences have demonstrated that serum interleukin-35 (IL-35) levels are closely associated with the development, progression, and poor prognosis of a variety of cancers. However, the relationship between IL-35 and the progression of human clear cell renal cell carcinoma (ccRCC) are poorly understood. The aim of present study was to assess the expression of IL-35 and determine its clinical significance in human ccRCCs. Enzyme-linked immunosorbent assay (ELISA) was performed to examine the serum IL-35 levels in 132 patients with ccRCC and 100 healthy controls. The association of IL-35 levels with clinicopathological parameters and prognosis of ccRCC patients was statistically analyzed. Serum IL 35 levels in patients with ccRCC (25.86+/-11.78 pg/ml) were significantly higher than those in healthy controls (10.05+/-9.47 pg/ml, P<0.001). High serum IL-35 levels were significantly correlated with pathologic stage (P<0.001), fuhrman grade (P<0.001), tumor size (P=0.012), T stage (P=0.007), N classification (P=0.002), metastasis (P<0.001) and recurrence (P=0.001). The Kaplan-Meier survival analysis demonstrated that high serum IL-35 levels were significantly associated with poor overall survival (log-rank, P<0.001). Multivariate analysis demonstrated that serum IL-35 levels (HR=2.919, 95% CI =1.871-4.830, P=0.001) and pathologic stage (HR=2.541, 95% CI =1.227-3.987, P=0.002) were an independent prognostic factor for the overall survival of ccRCC patients. In conclusion, high serum IL-35 levels are associated with poor prognosis in patients with ccRCC. IL 35 may represent a promising and useful prognostic biomarker for ccRCC. PMID- 26770509 TI - Prognostic influence of smoking on esophageal squamous cell carcinoma. AB - BACKGROUND: Smoking is well-known as a risk factor for esophageal squamous cell carcinoma. However, little is known about the effect of this factor on survival. METHODS: Esophageal cancer patients who underwent esophagectomy without any preoperative therapy were retrospectively reviewed. Patients' postoperative overall and disease-free survivals were compared between 2 groups (non-heavy smokers and heavy smokers). RESULTS: A total of 109 cases were evaluated in this study. The 5-year OS rate of the non-heavy smokers was 53.2% and 32.3% for the heavy group. The 5-year DFS rate of the non-heavy smokers was 51.1% and 27.4% for the heavy group. Kaplan-Meier survival analysis revealed that heavy smokers had significantly poorer OS (P=0.018) and DFS (P=0.009) than non-heavy smokers. In multivariate analysis, smoking was found to be an independent prognostic factor for OS (P=0.003; HR: 2.186; 95% CI: 1.309-3.650) and DFS (P=0.001; HR: 2.471; 95% CI: 1.467-4.163). CONCLUSION: Smoking was associated with survival among patients with ESCC, and it was recognized as an independent factor in both OS and DFS. PMID- 26770510 TI - Application of liver three-dimensional printing in hepatectomy for complex massive hepatocarcinoma with rare variations of portal vein: preliminary experience. AB - BACKGROUND: To discuss the role of Liver 3D printing in the treatment of complex massive hepatocarcinoma with rare variations of portal vein. METHODS: Data of enhanced computed tomography (CT) were imported into the medical image three dimensional visualization system (MI-3DVS) to create Standard Template Library (STL) files, which were read by 3D printer to construct life-size 3D physical liver model. The preoperative surgical planning was performed on the 3D model according to individualized segmentation, volume calculation, and virtual operation. RESULTS: The 3D printing liver model was consistent with the model in MI-3DVS. The segment 4 portal vein (S4PV) was absent and variant S4PV originated from right anterior portal vein (RAPV). The preoperative surgical planning was designed according to the relationship between tumor and portal vein variation. Theoretically, the residual liver volume was 40.76%, if the right hemihepatctomy was carried out after the trunk of right portal vein (RPV) ligated. However, the actual residual volume was only 21.37% due to the variant S4PV originates from RAPV, thus, right trisegmentectomy would have to be performed. Interestingly, after optimization, the residual liver volume increased to 57.25% as narrow margin right hemihepatectomy with the variant S4PV reserved were performed. The final resection was determined to be narrow-margin right hemihepatectomy. The actual surgical procedure was consistent with the preoperative surgical planning. CONCLUSION: Liver 3D printing may be a safe and effective technique to improve the success rate of surgery and reduce the operation risk for patients with complex massive hepatocarcinoma with variations of portal vein. PMID- 26770511 TI - Megaloblastic anemia with hypotension and transient delirium as the primary symptoms: report of a case. AB - The present study describes a case of an elderly patient that was hospitalized secondary to hypotension and delirium. Physical examination at admission revealed bilateral positive Babinski's sign. Laboratory examination revealed severe anemia. Bone marrow examination showed megaloblastic changes of the granulocyte and erythroid series, as well as other dyshaematopoiesis. The conditions of the patient rapidly improved after vitamin B12 treatments. Because the clinical manifestations of megaloblastic anemia are complex, this disease is often misdiagnosed in the geriatric population. Bone marrow examinations can aid in the diagnosis of anemia, but the results from these tests cannot always differentiate the type of anemia. Clinical management of the disorder is reliant upon proper classification of the type of anemia. The prognosis of megaloblastic anemia is typically good and a simple regimen of folic acid and/or vitamin B12 is effective. PMID- 26770512 TI - Association of follistatin-like 3 concentrations in serum and synovial fluid with the radiographic severity of knee osteoarthritis. AB - OBJECTIVE: Follistatin-like 3 (FSTL3), a circulating glycoprotein, is correlated with obesity and inflammation, which are potential mechanisms of osteoarthritis (OA). This study aims to determine the correlation of FSTL3 concentrations in serum and synovial fluid (SF) with the radiographic severity of OA. METHODS: This study consisted of 200 patients with knee OA and 148 healthy controls. The radiological grading of OA in the knee was performed in accordance with Kellgren Lawrence (KL) grading system. RESULTS: Knee OA patients had higher serum FSTL3 concentrations compared with healthy controls. Knee OA patients with KL grade 4 showed significantly elevated FSTL3 concentrations in serum and SF compared with those with KL grades 2 and 3. Moreover, knee OA patients with KL grade 3 had significantly higher FSTL3 concentrations in serum and SF compared with those with KL grade 2. FSTL3 concentrations in serum and SF of knee OA patients were significantly correlated with KL grading criteria. CONCLUSIONS: FSTL3 concentrations in serum and SF are correlated with the radiographic severity of OA. PMID- 26770513 TI - Transpedicular wedge osteotomy for treatment of kyphosis after L1 fracture using intraoperative, full rotation, three-dimensional image (O-arm)-based navigation: a case report. AB - There has been a large series in the literature reporting on results of osteotomy for the correction of kyphotic deformity secondary to post-traumatic thoracolumbar fracture. However, there are few reports on using intraoperative, full rotation, three dimensional image (O-arm)-based navigation, transpedicular wedge osteotomy for the correction of kyphotic deformity in old thoracolumbar fracture. A 45-year-old woman with L1 old fracture, presented to us with a Cobb angle of 45 degrees. The preoperative standard anteroposterior, lateral views and computed tomography (CT) reconstructions revealed kyphotic deformity. After attaching the reference arc of the 3D-imaging system, the thoracolumbar spine was screened using an O-arm without anatomical registration. The location, angle and depth of osteotomy, as well as screw fixation were performed using a guide tube while referring to the reconstructed 3D-anatomical views. The surgery was successful without nervous and vascular injuries. Using intraoperative, full rotation, three dimensional image (O-arm)-based navigation, the transpedicular wedge osteotomy is a safe and effective treatment for kyphosis after the thoracolumbar fracture, which can insert the pedicular screw accurately, trace the real-time wedge osteotomy and reduce the loss of correction of kyphotic deformity. PMID- 26770514 TI - Age plays an important role in the relationship between smoking status and obesity risk: a large scale cross-sectional study of Chinese adults. AB - OBJECTIVE: To study the role of age plays in the relationship between smoking status and obesity in both Chinese men and women. METHODS: From Chinese Physical and Psychological Database, participants were divided into non-smokers, current smokers, and former smokers. Body mass index (BMI), waist circumference (WC), fat percentage, fat mass, and fat free mass were measured. The mean, standard deviation and frequency of these indicators were calculated for each age bracket. One-way ANOVA and post-hoc test analyses were used to detect the difference among these three groups. RESULTS: In men, from 19 to 24 years old, BMI, WC and fat free mass of current smokers were higher than that of non-smokers (P<0.01). However, fat mass and fat percentage of current smokers were lower than that of non-smokers but higher than that of former smokers (P<0.01). From 25 to 34 years old, BMI and fat mass of former smokers were higher than non-smokers and current smokers (P<0.01). In addition, WC and fat free mass of non-smokers were lower than that of current smokers and former smokers (P<0.01). From 45 to older, BMI, WC, fat mass, fat free mass and fat percentage of former smokers were higher than that of current smokers (P<0.01). From 55 to older, BMI, WC, fat mass, fat free mass and fat percentage of current smokers were lower than that of non-smokers (P<0.01). In women, smoking status might not be significantly related to obesity (P>0.05). CONCLUSION: For young men, smoking might have an effect on increasing fat free mass, BMI and WC, and decreasing fat mass and fat percentage. For middle and older men, smoking might have an effect on decreasing fat free mass, fat mass, BMI, WC, and fat percentage. Obesity risk should be paid more attention in smoking cessation programs for those former smokers. PMID- 26770515 TI - Extravascular lung water monitoring of renal replacement therapy in lung water scavenging for septic acute kidney injury. AB - This study aims to investigate the extravascular lung water index (EVLWI) in lung water scavenging of sepsis patients with acute kidney injury (AKI) by renal replacement therapy (RRT). 57 septic acute kidney injury patients with EVLWI > 7 ml/kg were selected and randomly divided into two groups: the treatment group with continued RRT for 24 h per day, the control group with RRT for <=8 h per day. Fluid resuscitation and RRT were performed simultaneously. After fluid resuscitation, EVLWI, hemodynamics, oxygenation index, blood lactate, and intensive care unit (ICU) stay were determined. The values of EVLWI, pulmonary vascular permeability index (PVPI), and blood lactate decreased and the intrathoracic blood volume index (ITBVI) increased significantly at 24 h, 48 h and 72 h, after RRT, compared with those before RRT in the two groups (P < 0.05). The values of EVLWI at 48 h and 72 h after RRT in the treatment group were significantly lower than that in the control group (P < 0.05). The cardiac index (CI) at 48 h and 72 h after RRT in the treatment group was significantly higher than that before RRT (P < 0.05). The values of PVPI, ITBVI, CI, blood lactate, transcutaneous oxygen saturation pulse (SPO2), oxygenation index (PO2/FiO2) and arterial oxygen (PO2) before and 24 h, 48 h, and 72 h after RRT. The 28d mortality had no significant difference in the two groups (P > 0.05). The average ICU stay for the treatment group was significantly shorter than that of the control group (P < 0.05). EVLWI monitoring of septic patients with AKI in RRT time had clinical reference value. PMID- 26770516 TI - Analysis of genetic variations in CYP2C9, CYP2C19, CYP2D6 and CYP3A5 genes using oligonucleotide microarray. AB - The cytochrome P450 enzymes play a critical role in the metabolism of many commonly prescribed drugs. Among them, the most important enzymes are highly polymorphic CYP2C9, CYP2C19, CYP2D6 and CYP3A5, which are responsible for about 40% of the metabolism of clinical used drugs. Here we developed a novel CYP450 oligonucleotide microarray that allow for detection of 32 known variations of CYP genes from a single multiplex reaction, including 19 polymorphisms of CYP2D6 gene, 8 polymorphisms of CYP2C9 gene, 4 polymorphisms of CYP2C19 gene and 1 polymorphism of CYP3A5 gene. 229 genomic DNA samples from unrelated Han subjects were analyzed. The microarray results showed to have high call rate and accuracy according to concordance with genotypes identified by independent bidirectional sequencing. Furthermore, we found that the major CYP2C9, CYP2C19, CYP2D6 and CYP3A5 alleles in Chinese Han population were CYP2C9*3 (allelic frequency of 10.7%), CYP2C9*2 (20.31%), CYP2C19*2 (5.68%), CYP2D6*10 (58.52%), CYP2D6*2 (13.76) and CYP3A5*3 (70.69%). With flexible DNA preparation, the microarray can significantly facilitates the process of detecting genetics variations in CYP2C9, CYP2C19, CYP2D6 and CYP3A5 gene and provide safe and effective therapy for individual patients. PMID- 26770517 TI - Clinical analysis on anti-N-methyl-D-aspartate receptor encephalitis cases: Chinese experience. AB - As a kind of autoimmune encephalitis which was just identified, the clinical manifestations of the anti-N methyl-D aspartate (anti-NMDA) receptor encephalitis are complex, diverse and in severe condition. The immunotherapy has shown good effect on the treatment but in generally, the diagnosis and treatment are still in the experience accumulation stage. More clinical research in different population is necessary, for example, in the Chinese population. This study was completed in anti-NMDA receptor encephalitis patients who were diagnosed in Beijing Xuan Wu Hospital (China) during the time from 2011 to 2013. Total 33 patients were involved with the average age of 29.7 years old when the diseases were onset. With diverse clinical manifestations, most patients displayed positively by NMDAR antibody test and 63.6% of them were associated with elevated CSF-lgA. Patients also showed abnormal MRI and EEG. Only three patients had teratomas. With hormone therapy, gamma globulin treatment or plasma exchange, more than three quarters of patients fully recovered and the others had moderate symptoms. Based on our results, we suggest that NMDAR antibody test would be helpful to make a timely diagnosis and to administer immunotherapy. PMID- 26770518 TI - Genetic variations in MTHFR and gastric cardia adenocarcinoma susceptibility in the Chinese Han population. AB - Methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms are associated with many types of cancers. The purpose of our study was to evaluate the effect of MTHFR single nucleotide polymorphisms (SNPs) on gastric cardia adenocarcinoma (GCA). We conducted a hospital-based case-control study. Three hundred and thirty cases with GCA and 608 controls were recruited. The ligation detection reaction (LDR) method was used to determine genotypes. The genotype MTHFR rs1801133 TT was significantly more frequent in cases than in controls (adjusted odds ratio (OR) = 1.46, 95% confidence interval (CI) = 1.04-2.05, P = 0.029) in a recessive model, after adjusting for age, sex and smoking and alcohol use. The haplotype MTHFR Grs4845882Ars4846048Trs1801133Crs9651118Ars3753584 was more frequent in cases than in controls (crude OR = 5.32, 95% CI = 2.34-12.10, P < 0.001). No association between other genotypes and haplotypes was observed. Our results suggest that the genotype MTHFR rs1801133 TT and the MTHFR Grs4845882Ars4846048Trs1801133Crs9651118Ars3753584 haplotype may be associated with susceptibility to GCA. Further studies are needed to confirm these findings. PMID- 26770519 TI - Efficacy of medical thoracoscopic talc pleurodesis in malignant pleural effusion caused by different types of tumors and different pathological classifications of lung cancer. AB - The aim of this study was to assess the efficacy and complications and compare the efficacy of medical thoracoscopic talc pleurodesis among patients with different types of tumors and different pathological classifications of lung cancer as well as to evaluate the role of postoperative negative pressure chest tube drainage. A total of 1061 patients with malignant pleural effusion who underwent thoracoscopic pleurodesis were analyzed retrospectively. The complications, postoperative drainage time, and efficacy of pleurodesis among patients with different types of tumors and different pathological classifications of lung cancer were assessed. The overall response rate (ORR) was 88.03%. Major complications included chest pain (68%) and fever (47%). The postoperative drainage time was 4.74 +/- 1.56 days. Postoperative negative pressure chest tube drainage significantly shortened the drainage time (negative vs. non-negative: 4.56 +/- 1.49 days vs. 4.81 +/- 1.59 days, P = 0.037). Pleurodesis was less effective in treating effusion caused by lung cancer (72.3%) and mesothelioma (68.2%) than that caused by breast cancer (84.4%) and other tumors (87.8%) (P = 0.009). The efficacy in the treatment of effusion caused by adenocarcinoma (66.7%) was slightly less than that caused by other types of lung cancer (P = 0.311). In conclusion, medical thoracoscopic talc pleurodesis is a palliative and effective treatment for malignant pleural effusion. In addition, postoperative simple negative pressure chest tube drainage significantly shortens the drainage time. However, thoracoscopic pleurodesis is less effective for the treatment of effusion caused by lung cancer and pleural mesothelioma compared with that caused by other types of cancers. PMID- 26770520 TI - Therapeutic efficacy of brucea javanica oil emulsion (BJOE) combined with transcatheter hepatic arterial chemoembolization (TACE) in patients with primary liver cancer. AB - This study is to investigate the effects of brucea javanica oil emulsion (BJOE) combined with transcatheter hepatic arterial chemoembolization (TACE) on primary liver cancer (PLC) and the related mechanisms. Totally 64 PLC patients were divided into the TACE monotherapy and BJOE/TACE combination therapy groups. The short- and long-term efficacies, and the toxicity and tolerability profiles, of these treatments were evaluated. The serum levels of soluble Fas (sFas) and soluble Fas ligand (sFasL) were detected with ELISA. For the short-term efficacy, the response rate (RR) in the TACE monotherapy and BJOE/TACE combination therapy groups were 50% (16/32) and 78.12% (25/32), respectively. Survival analysis showed that, the combination therapy significantly elevated the 1-, 2-, and 3 year survival rates of PLC patients, compared with the monotherapy. No significant differences were observed in the toxicity and tolerability profiles between these therapies. ELISA showed that, the serum sFas/sFasL levels were significantly increased in PLC patients. At 1 m after the combination therapy, the serum sFas/sFasL levels were significantly higher than before treatment. At 3 m and 6 m after treatment, the serum sFas/sFasL levels were gradually declined. The short- and long-term efficacies of the BJOE/TACE combination therapy for PLC are superior to the TACE monotherapy. The combination therapy could promote liver cancer cell apoptosis by regulating the expression of sFas/sFasL. Serum sFas/sFasL levels might be used as the predictive marker for the disease pathogenesis and prognosis, and the treatment efficacy. PMID- 26770521 TI - Polyphylla saponin I has antiviral activity against influenza A virus. AB - OBJECTIVE: In the present study, the antiviral effects of polyphylla saponin I isolated from Parispolyphylla on influenza A virus are investigated both in vitro and in vivo. METHODS: Column chromatography and reversed phase liquid chromatography separation technology were used to extract and purify polyphylla saponin I. The purity of polyphylla saponin I was assayed by high performance liquid chromatography. Methyl thiazolyl tetrazolium assay and analyses of cytopathic effects were performed to examine the antiviral activity of polyphylla saponin I upon MDCK cells infected with influenza A virus. Model mice were made by intranasal inoculation of influenza a virus. Mice infected with influenza A virus were orally administered polyphylla saponin I and oseltamivir twice a day for 5 days to study their antiviral efficacy in vivo. RESULTS: Polyphylla saponin I had no cytotoxicity on MDCK cells at the concentration of 50 MUg/mL. Polyphylla saponin I (6.25, 12.5, 25 and 50 MUg/mL) and oseltamivir (40 MUg/mL) had remarkable inactivation effects on influenza A virus, prevention effects on influenza A virus adsorption on MDCK cells, and inhibitory effects on the reproduction of influenza A virus in MDCK cells. In addition, polyphylla saponin I (5 and 10 mg/kg), and oseltamivir (3 mg/kg) significantly reduced viral hemagglutination titer, improved the pathologic histology of lung tissues, and decreased the mortality of mice infected with influenza A virus. Polyphylla saponin I (5 and 10 mg/kg) prolonged the survival time of mice from 8.5+/-0.3 days to 13.2+/-0.5 days, with the prolonged life rates being 49.4% and 55.3%, respectively. CONCLUSION: Polyphylla saponin I has antiviral activity on influenza A virus both in vitro and in vivo. PMID- 26770522 TI - Conservative management of cesarean scar pregnancies: a prospective randomized controlled trial at a single center. AB - PURPOSE: To assess clinical outcomes related to conservative management of women with cesarean scar pregnancies (CSPs), specifically through uterine artery embolization (UAE) with local and systemic methotrexate (MTX) treatment (UAE MTX), or ultrasound-guided local and systemic MTX treatment (USG-MTX). METHODS: Forty-five patients with CSP were randomly allocated to receive UAE-MTX (n = 24) or USG-MTX (n = 21). Participants' clinical outcomes were compared, and clinical characteristics of failed cases were evaluated relative to successful cases. RESULTS: The 2 groups were similar in clinical characteristics, success rate (83.3% cf. 80.9%), time to normalization of serum beta (beta) human chorionic gonadotropin (beta-hCG), and percentage of patients receiving multiple doses of systemic MTX. However, within the failed cases, the percentages of patients with gestational sac > 5 cm (87.5%), or type II CSP (75.0%) was significantly higher than in the successful cases (13.5% and 18.9%, respectively; P < 0.001, both), without regard to treatment group. According to the logistic regression model, a gestational sac diameter > 5 cm or type II CSP were independent risk factors for failed CSP management (gestational sac > 5 cm: OR 51.87, 95% CI 3.48-775.91, P < 0.01; type II CSP: OR 15.54, 95% CI 1.25-193.36, P < 0.05). CONCLUSION: The conservative treatments UAE-MTX and USG-MTX were similarly effective in treating CSP patients. Either treatment was likely to fail for CSP patients with gestational sac > 5 cm or type II CSP. PMID- 26770523 TI - Electroacupuncture with different current intensities to treat knee osteoarthritis: a single-blinded controlled study. AB - BACKGROUND: To assess the efficacy of Electroacupuncture (EA) stimulation with high-intensity compared with low-intensity on knee osteoarthritis (KOA). METHODS: Participants with KOA were randomized to either high-intensity EA group or low intensity EA group. EA was applied unilaterally on the affected leg with the local points GB34, ST34, EX-LE4, EX-LE5, ST36, and SP9. The visual analogue scale (VAS) and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) were measured before and after participation. Plasma TNFalpha, IL-1beta, IL-6, and apelin levels were also assessed by enzyme immunoassay (ELA) before and after treatment. RESULTS: Of 80 participants who consented to study participation, 77 completed the program. The patients showed a significant improvement in their pain, stiffness, and physical function on the VAS and WOMAC, accompanying with a significantly reduction in plasma levels of apelin and TNFalpha. Furthermore, high-intensity group exhibited statistically significant improvements in stiffness and physical function symptoms compared with low intensity group. Plasma level of IL-6 was significantly decreased only after high intensity EA treatment. Furthermore, apelin level was significantly inhibited in high-intensity EA group than in low-intensity EA group. CONCLUSIONS: Both high- and low-intensity EA treatments alleviate the clinical symptoms of KOA patients. High-intensity EA is more effective than low-intensity EA. Changes in plasma levels of TNFalpha, apelin and IL-6 may be involved in the therapeutic effect of EA on KOA. PMID- 26770524 TI - The prevalence of hyperprolactinemia in non-functioning pituitary macroadenomas. AB - OBJECTIVE: The prevalence of hyperprolactinemia in non-functioning pituitary macroadenomas (NFPMAs) is not well known, and hyperprolactinemia caused by a NFPMA is currently associated with diagnostic uncertainty. Thus, the aim of this study was to evaluate the prevalence of hyperprolactinemia in NFPMAs. METHODS: A meta-analysis of all existing articles in PubMed was conducted. The search string was designed as "(non-functioning pituitary tumor OR non-functioning pituitary tumor OR non-functioning pituitary macroadenomas OR non-functioning pituitary macroadenomas OR non-functioning pituitary adenomas OR non-functioning pituitary adenomas) and hyperprolactinemia". References of the articles found were also reviewed. Study selection and data extraction were performed independently by two reviewers. Data were analyzed with STATA 11.0 software (StataCorp LP, USA). The fixed effects model was used to evaluate these studies. RESULTS: The search identified 57 published studies, seven of which were accepted for the final meta analysis. The authors found an overall estimated 40.2% prevalence of (95% CI, 36.6%-43.7%) hyperprolactinemia in NFPMAs. CONCLUSIONS: Given the high frequency of hyperprolactinemia in NFPMAs, a diagnosis of NFPMA or prolactinoma should be made more carefully. PMID- 26770525 TI - Roles of PD-1, Tim-3 and CTLA-4 in immunoregulation in regulatory T cells among patients with sepsis. AB - OBJECTIVE: This study aims to elucidate the roles of PD-1, Tim-3 and CTLA-4 in sepsis. METHODS: Sepsis patients (n = 182) were selected as sepsis group and divided into three subgroups: mild sepsis group, severe sepsis group and septic shock group; 185 healthy volunteers were enrolled as control group. Flow cytometry and blood routine examination were performed for T lymphocytes and surface co-stimulatory molecules expressions. Pearson correlation test was applied for the correlation of co-stimulatory molecules expressions on T lymphocytes with critical illness in sepsis. Logistic regression analysis was conducted for risk factors in sepsis. RESULTS: Heart rate and WBC in subgroups were higher than control group (P < 0.05). The differences in APACHE II, SAP II and SOFA score among subgroups were statistically significant (P < 0.05). Compared with control group, lymphocyte ratio and percentage of CD4(+) T cells reduced in subgroups (P < 0.05). The differences in expression levels of CD4(+)PD 1(+), CD8(+)PD-1(+), and CD8(+)CTLA-4(+) showed statistical significances (P < 0.05). Apparently, expression levels of CD4(+)TIM-3(+), CD8(+)TIM-3(+), CD4(+)PD 1(+), CD8(+)PD-1(+), and CD4(+)CTLA-4(+) were positively correlated with APACHE II score (all P < 0.05). Logistic regression analysis showed that heart rate and expression level of CD4(+)PD-1(+) might be risk factors while the percentage of CD4(+) T cells might be a protective factor for sepsis (P < 0.05). CONCLUSION: PD 1 aggravates immune responses consistent with promotion of T cell exhaustion in sepsis. Expression level of CD4(+)PD-1(+) and heart rate are potential risk factors while percentage of CD4(+) T cells is a possible protective factor for sepsis. PMID- 26770526 TI - Relationships of related genetic polymorphisms and individualized medication of tacrolimus in patients with renal transplantation. AB - The aim of this study was to establish clinical and genetic factors-based individual administration model of tacrolimus for Chinese Han patients after renal transplantation (RT). The genetic polymorphisms of CYP3A4, CYP3A5 and MDR1 in 216 RT patients were detected by PCR-RFLP, the genetic and clinical factors and blood concentration/dose * body weight (C/D) values of tacrolimus were performed the single factor correlation analysis, and established the dose prediction algorithm of tacrolimus by stepwise multiple regression analysis. CYP3A5*3, hematocrit and albumin were correlated with the C/D values of tacrolimus, the best regression model could explain 28.3% reason of individual dose differences of tacrolimus, among which CYP3A5*3 polymorphism could explain 23.5%. The genetic factors played an important role in the dose differences of tacrolimus, the patients should be checked CYP3A5*3 genotype before administration of tacrolimus to predict the tacrolimus doses, thus helping to improve the safety and effectiveness of tacrolimus application. PMID- 26770527 TI - Value of serum marker HE4 in pulmonary carcinoma diagnosis. AB - An effective blood test is valuable to aid clinicians in making case management decisions. The present study was to analyze the value of four serum tumor markers for the diagnosis of pulmonary carcinoma. The case group consisted of 80 pulmonary carcinoma patients, which were compared to a control group of 30 patients with benign pulmonary disease and a control group of 30 healthy individuals. Serum levels of carcinoma embryonic antigen (CEA), cytokeratin protein fragment 21-1 (CYFRA21-1), neuron-specific enolase (NSE), and human epididymis protein 4 (HE4) were detected using electrochemiluminescence. Serum CEA, NSE, CYFRA21-1, and HE4 levels were significantly higher in pulmonary carcinoma patients than those in both control groups (P < 0.05). Serum CEA and HE4 levels were significantly higher in adenocarcinoma patients, while serum CYFRA21-1 levels were significantly higher in squamous cell carcinoma patients and serum NSE levels were significantly higher in small cell lung cancer (SCLC) patients (P < 0.05). Analysis of area-under-the-receiver operating characteristic (ROC) curves (AUC) revealed that serum CYFRA21-1, CEA, and HE4 levels were valuable for squamous cell carcinoma, serum CEA and HE4 levels were valuable for adenocarcinoma, and serum NSE level was valuable for SCLC (P < 0.05). Serum CEA and HE4 levels of pulmonary carcinoma patients with metastasis were higher than those with TNM stage I-II or III-IV disease without metastasis. In brief, detection of serum HE4 levels may be useful in auxiliary diagnosis and evaluation of the progression of pulmonary carcinoma. PMID- 26770528 TI - Effects of acupuncturing Pishu combined with Ginsenoside Rg3 on the immune function of rats with chronic fatigue. AB - OBJECTIVE: This study was designed to investigate the effects of acupuncturing Pishu combined with Ginsenoside Rg3 on the immune function of rats with chronic fatigue. METHODS: Forty male SD rats were equally randomized into control group, chronic fatigue system group (CFS), Ginsenoside Rg3 (Rg3) group, acupuncture group and acupuncture combined with Ginsenoside Rg3 (A+Rg3) group. Rats with chronic fatigue were established by bounding and forced swimming in cold water once daily for 21 days except control group, then the rats in the acupuncture and A+Rg3 group were treated by manual acupuncture stimulation of bilateral "Pishu" once daily for 7 days. Ginsenoside Rg3 was administered by intravenous to the rats of the A+Rg3 and Rg3 group for 7 days in dosages of 2 mg/kg body weight, and two markers of physical fatigue were evaluated: body weight and blood lactic acid (LA). The percentages of CD3(+) lymphocytes, CD4(+) lymphocytes, and CD8(+) lymphocytes in the spleens of the rats were evaluated using flow cytometric analysis. Serum IFN-gamma (IFN-gamma) and IL-4 contents were detected by ELISA. RESULTS: Increased body weight and reduced blood LA concentrations were found in the rat of Rg3 group and A+Rg3 group than that in CFS group. The rat of Rg3 group and A+Rg3 group also showed a significant increase in the percentage of CD4(+) lymphocytes and a significant decrease in the percentage of CD8(+) lymphocytes and correct CD4(+)/CD8(+) ratio. Compared with the CFS group, the level of IFN gamma in the Rg3, acupuncture and A+Rg3 groups was reduced and IL-4 was increased. CONCLUSIONS: Acupuncture and Rg3 can improve the immune system activity of CFS rats and acupuncturing Pishu combined with Rg3 was significantly superior compared with Rg3 and acupuncture, respectively. PMID- 26770529 TI - A clinical exploration of neoadjuvant chemotherapy with tegafur, gimeracil, and oteracil potassium capsules combined with oxaliplatin for advanced gastric cancer. AB - BACKGROUND: Advanced gastric cancer refers to tumor invasion into the gastric muscularis propria or even the layer beyond, and has low early gastric cancer diagnosis rate. PURPOSE: To determine the clinical efficacy and side effects of neoadjuvant chemotherapy with tegafur, gimeracil, and oteracil potassium capsules (TGOP) combined with oxaliplatin (SOX regimen) in patients with advanced gastric cancer. METHODS: We evaluated 25 patients with advanced gastric cancer who were admitted and treated with neoadjuvant chemotherapy with the SOX regimen (intravenous injection of 130 mg/m(2) oxaliplatin on day 1 followed by oral administration of 60 mg TGOP twice daily on days 1-14), every 3 weeks. The clinical efficacy and side effects of the SOX regimen were evaluated after two courses of treatment, before surgery. RESULTS: Of the 25 patients enrolled in this study, 23 completed two courses of neoadjuvant chemotherapy, and of these, 12 achieved downstaging as determined by the clinical TNM stage, resulting in a total response rate of 52.2%. The 23 patients underwent surgery, with 22 receiving radical resection (95.7%). Among these 23 patients, R0 resection was achieved in 16 (69.6%) and pathological complete remission was observed in one. CONCLUSION: Neoadjuvant chemotherapy with TGOP combined with oxaliplatin was effective for advanced gastric cancer and had tolerable side effects. PMID- 26770531 TI - Effects of combined traditional Chinese medicine with immunosuppressive agents for patients with myasthenia gravis. AB - Myasthenia gravis (MG) is a kind of autoimmune disease induced by transferring dysfunction of neuromuscular junction. In the present study, we developed an integrated therapy combined with traditional Chinese medicine and immuno suppressive agents to seek for an effective treatment of MG. 220 MG patients were randomly divided into two groups with different therapies. Plasma levels of acetylcholine receptors antibodies (AchRAb) and CD4(+)CD25(+) regulatory T cells (CD4(+)CD25(+)Treg) were conducted through ELISA and flow cytometry. The amount of AchRAb (8.52+/-0.96 vs. 5.22+/-0.46) and CD4(+)CD25(+)Treg (1.94+/-1.21 vs. 3.21+/-0.96) in Group A receiving integrated therapy were significantly improved compared with Group B; the clinical performance of group treated with the integrated therapy was also much better. The integrated therapy in the present study could significantly improve the condition of MG with high recovery rate and low recurrence rate, which can be employed in future clinical treatment of MG. PMID- 26770530 TI - Comparison of the effect of the Trendelenburg and passive leg raising positions on internal jugular vein size in critically ill patients. AB - Central vein catheterization is a common procedure performed on patients under intensive care. The safe and successful placement of the central venous catheter depends on vein size. Although used for this purpose, the Trendelenburg position can be hazardous in some patients. The aim of this study was to compare the effects of the Trendelenburg and passive leg raising (PLR) positions on the size of the right internal jugular vein (IJV) in mechanically ventilated patients under intensive care. Seventy-eight mechanically ventilated patients under intensive care were included into the study. Sonographic images of the right IJV were recorded in supine (control), 10 degrees Trendelenburg and 40 degrees PLR positions. Anterior-posterior and transverse diameter, cross-sectional area (CSA), and depth were calculated from the recorded images. The size of the right IJV (CSA, transverse and vertical diameters) was significantly larger in the Trendelenburg and PLR positions than in supine position. An increase of 26% in the IJV CSA was obtained in the Trendelenburg position and 23% in the PLR position, compared to the supine position. There was no significant difference between the measurements obtained from the Trendelenburg and PLR positions. The study shows that the Trendelenburg and PLR positions increase the size of the IJV to a similar extent in mechanically ventilated patients under intensive care. PMID- 26770532 TI - Clinical data analysis of 19 cases of community-acquired adenovirus pneumonia in immunocompetent adults. AB - The aim of this study was to investigate the characteristics of clinical manifestations, laboratory tests and imaging changes of community-acquired adenovirus pneumonia in immunocompetent adults. A retrospective study was performed on 19 adult community-acquired adenovirus pneumonia cases in Yantai, whereby the clinical data were collected and analyzed. Of 19 cases, 14 (73.68%) had fever and 17 (89.47%) had cough symptoms. Moreover, 14 cases (73.68%) had normal white blood cell counts, while 11 cases (57.89%) exhibited a reduction in lymphocyte proportion. Among the 19 cases, 17 cases exhibited lesions in a single lung, while 2 cases involved bilateral lungs. The lesions predominantly exhibited ground glass-like changes. The clinical manifestations of adult community acquired adenovirus pneumonia patients with normal immune functions were mild, with such presenting symptoms as fever, cough, and sputum; most patients did not exhibit high levels of white blood cells or low lymphocyte counts, and the imaging features (ground glass-like effusion) were indicative of single-lung involvement. PMID- 26770533 TI - Changes of ribbon synapses number of cochlear hair cells in C57BL/6J mice with age(Delta). AB - To investigate the changes of ribbon synapses (RS) number in cochlear hair cells in C57BL/6J mice with age. Basilar membranes within the cochlea of C57BL/6J mice aged 2, 6, 10 and 12 months were harvested (5 mice in each age group). The presynaptic and postsynaptic membranes were subject to double immunohistochemical staining and observed with a laser confocal microscope. The number of RS in each segment of basilar membrane was counted by using 3D reconstruction technique. Compared with 2-month-old mice, reduction of RS number in basilar membrane inside cochlea mainly occurred to the basal turn among C57BL/6J mice aged 6 months. The number of RS in each turn among 10-month-old mice decreased considerably, and such decrease continued in the top turn and middle turn in mice aged 12 months. In contrast, the number of RS in the basal turn increased slightly. Reduction of RS probably takes place in the early stage of C57BL/6J mice presbycusis. Early prevention of presbycusis can be achieved through measures to mitigate the reduction of RS. PMID- 26770534 TI - Cross-sectional comparison of ultrasonography scoring systems for primary Sjogren's syndrome. AB - To choose the best ultrasound scoring system for clinic practice, ultrasound was performed for 94 cases with suspected primary Sjogren's syndrome (pSS) and 3 US scoring systems created by Hocevar, Salaffi, Millic were employd to assess for bilateral parotid glands and submandibular glands. The US evaluation was blinded to the final diagnosis of pSS according to 2002 classification criteria. 44 cases were finally diagnosed with pSS, 14 were diagnosed with secondary Sjogren's syndrome, and 36 were diagnosed with Sicca syndromes. Hocevar's method had the best likelihood ratio and accuracy, but Milic's scoring system was recommended for its excellent balance between the diagnostic value and inter/intra observation agreement value. PMID- 26770535 TI - Gonadotropin-releasing hormone agonist for oocyte triggering in endometrial preparation of letrozole stimulation protocols does not affect clinical outcome of frozen-thawed embryo transfer. AB - OBJECTIVE: This study aims to evaluate the effectiveness of GnRH agonist in comparison with hCG for triggering final oocyte maturation in endometrial preparation of letrozole stimulation protocols for frozen-thawed embryo transfer. METHODS: The frozen-thawed embryo transfer cycles (FET) that use the letrozole stimulation protocols for endometrial preparation were divided into two groups according the different method of triggering final oocyte maturation. The serum LH and E2 levels, and the endometrial thickness on the day of triggering, the clinical pregnancy rates, the miscarriage rates and live birth rates were compared. RESULTS: There were no significant differences in the age, the endometrial thickness, the number of embryos transferred between the two groups. The clinical pregnancy rate, abortion rate and live birth rates of the group A were similar compared with the group B, P<0.05. CONCLUSION: Using GnRH agonist for oocyte triggering in endometrial preparation of letrozole stimulation protocols for frozen-thawed embryo transfer does not affect the clinical outcome compared with hCG under the same luteal phase support. PMID- 26770536 TI - Effects of basic drugs on prognosis of acute lung injury in mice. AB - The aim of this study was to investigate the effects of basic drugs that alkalizes blood, on prognosis of acute lung injury in mice. Mice were randomized into three groups: Group normal saline, Group THAM, injected with 3.64% tri (hydroxymethyl) methylamine (THAM), and Group NaHCO3, injected with 5% NaHCO3 (n=26, each group). The acute lung injury model was established by intraperitoneal injection of lipopolysaccharide (LPS; 50 mg/kg), followed by infusion of varying concentrations of the above solution into tail vein at the rate of 0.5 ml/h (controlled by micro pump) for over 2 h. Thirty minutes later, 6 mice from each group were randomly selected for blood gas analysis; then, the mice were killed and their lung tissues were sampled for detection of relative indicators, and the remaining mice were observed for signs of mortality for 72 h. Arterial pH, bicarbonate (HCO3 (-)), and BE and mortality of group THAM and NaHCO3 increased significantly compared to the corresponding parameters of the group normal saline (P<0.05); compared to the group normal saline, group NaHCO3 had increased blood [Na(+)] and decreased [K(+)] and [Ca(2+)] (P<0.05). Blood [Na(+)] of group THAM decreased while the lactic acid concentration increased (P<0.05) compared to the corresponding values of the group normal saline. Malondialdehyde (MDA) and myeloperoxidase (MPO) activity and wet-to-dry lung weight ratio (W/D) of group THAM and NaHCO3 increased significantly relative to group normal saline (P<0.05). Compared with the biopsy results of (A), pathological biopsy of (B) and (C) clearly revealed alveolar wall thickening, edema of alveolar epithelial cells, and infiltration of large neutrophils. Alkalizing blood could neither inhibit inflammatory reactions in LPS mouse model nor reduce the mortality rate of mice with acute lung injury, while excessive alkalization of blood could increase mice mortality. PMID- 26770537 TI - Efficacy of silodosin in the treatment of distal ureteral stones 4 to 10 mm in diameter. AB - PURPOSE: Few studies have investigated the efficacy of silodosin, a recently introduced selective alpha 1-A adrenoceptor antagonist, in medical expulsive therapy (MET) for ureteral calculi. The results of these studies, which all evaluated the efficacy of 8 mg/day, indicate that silodosin is a potential treatment for ureteral calculi. This study investigated the efficacy of 4 mg/day of silodosin for MET of distal ureteral stones 4 to 10 mm in diameter. MATERIAL AND METHOD: After 70 patients had been randomized into 2 groups of 35 patients each, both the control and experimental groups (groups 1 and 2, respectively) were advised to take 75 mg/day of diclofenacsodiumas needed for pain relief but only the experimental group to take 4 mg/day of silodosin. After 21 days, the groups were compared regarding the stone expulsion rate and duration, number of renalcolicepisodes, and analgesicdosage. RESULTS: The median expulsion rates were 71.4% and 91.4% in groups 1 and 2, respectively, and the difference between them was significant (P=0.031). The median expulsion durations were 12.91+/-6.14 and 8.03+/-4.99 days, respectively, and the difference between them was significant (P<0.001). No significant differences were found regarding the median number of renal colic episodes or median analgesic dosage. While no patients in group 1 experienced side effects, 5 patients (14%) in group 2 experienced retrograde ejaculation. CONCLUSION: These results indicate that 4 mg/day of silodos in facilitates the expulsion of distal ureteral stones 4 to 10 mm in diameter but does not significantly reduce the number of renal colic episodes or analgesic dosage. PMID- 26770538 TI - Perioperative and long-term outcomes of laparoscopy and laparotomy for endometrial carcinoma. AB - OBJECTIVE: To compare the efficacy and the clinical value of laparoscopic surgery and traditional abdominal surgery for the treatment of endometrial carcinoma. Meanwhile, assessing the value of preoperative MRI in the depth of myometrial invasion of endometrial carcinoma. METHODS: we retrospectively analyzed 32 patients with endometrial carcinoma who underwent laparoscopic surgery in Department of Obstetrics and Gynecology in the Subei People's Hospital from September 2008 to March 2015, comparing data using the same surgeons' traditional laparotomy cases during the same period. Data collected includes patient demography, intraoperative and postoperative clinical parameters and follow-up data. RESULT: All laparoscopic and laparotomy surgery were successful. laparoscopic surgery was better than traditional surgery with less blood loss, more early postoperative anal exhaust time, less postoperative hospital stay, and no seriously complications, there were significant differences (all P<0.05). The average operative time, in the laparoscopy group, was a little longer than the laparotomy group with no statistical significance (P>0.05). There were no differences in the two groups in terms of the number of excised lymph nodes and the recurrence and mortality rate (P>0.05). The sensitivity and specificity of the MRI imaging in assessment of deep myometrial invasion of endometrial carcinoma were 89.3% and 96.2%, respectively. CONCLUSION: Compared to conventional approaches, laparoscopic surgery showed favorable short-term outcomes with comparable survival. People with endometrial cancer can, therefore, be as safely managed using laparoscopy as laparotomy. MRI is of high value in assessing deep myometrial invasion in patients with endometrial carcinoma. PMID- 26770539 TI - Effect of acute paraquat poisoning on CYP450 isoforms activity in rats by cocktail method. AB - Paraquat is a highly effective contact herbicide that is marketed worldwide as a fantastical, non-selective compound for broadleaf weed control. As compared to most pesticides, paraquat is extremely toxic to humans and the lack of strategies to manage paraquat poisoning has resulted in high fatality rates. The rats were randomly divided into acute paraquat poisoning group and control group. The paraquat group rats were given 36 mg/kg paraquat by intragastric administration. The influence of acute paraquat poisoning on the activities of CYP450 isoforms CYP2B6, CYP1A2, CYP2C9, CYP2D6, CYP3A4 and CYP2C19 were evaluated by cocktail method, they were responded by the changes of pharmacokinetic parameters of bupropion, phenacetin, tolbutamide, metoprolol, midazolam and omeprazole. The six probe drugs were given to rats through intragastric administration, and the plasma concentrations were determined by UPLC-MS/MS. In the results of paraquat group compared to control group, there was statistical pharmacokinetic difference for bupropion, tolbutamide, metoprolol, midazolam and omeprazole. Acute paraquat poisoning may induce the activities of CYP2C19, and inhibit of CYP2B6, CYP2C9, CYP2D6 and CYP3A4 in rats. This may give advising for reasonable drug use after acute paraquat poisoning. PMID- 26770540 TI - Evaluation of neck circumference as a predictor of central obesity and insulin resistance in Chinese adults. AB - OBJECTIVES: To evaluate whether neck circumference (NC) could be used as a valid and effective method for identifying obesity and insulin resistance (IR) in Chinese adults. METHODS: A total of 3307 adults aged 20-65 years were randomly recruited from two communities of Tongzhou, Beijing. Height, weight, waist circumference (WC), hip circumference (HC), neck circumference (NC), blood pressure, fasting plasma glucose (FPG), fasting serum insulin (FINS), total cholesterol (TC), serum triglyceride (TG), High-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and Urinary albumin (UAlb) were measured. Pearson correlation coefficient was used to explore the relationship between NC and other measurements. Furthermore, the best cutoff values of NC for central obesity identification were determined by applying the receiver operating characteristic (ROC) curve analysis. RESULTS: NC correlated positively with BMI, SBP and WC In both sexes. Both WC and NC correlated significantly positively with IR. A positive correlation between NC and FPG as well as a negative correlation between NC and HDL were found in obese men. NC>=38.5 cm for men and >=34.5 cm for women were determined to be the best cutoff levels for identifying subjects with central obesity, with 82.9% accuracy for men and 79.9% accuracy for women. CONCLUSIONS: NC correlated positively with BMI and WC in both genders, indicating that NC could be used as a valid marker for both overall obesity and central obesity. In addition, measuring NC was shown to be a useful test for IR identification. Large number of NC is suggested to be associated with high risk of developing metabolic disorders, such as diabetes and dyslipidemia. PMID- 26770541 TI - The application of a trauma index to assess injury severity and prognosis in hospitalized patients with acute trauma. AB - OBJECTIVE: The aim of this study was to determine the application value of a trauma index (TI) to assess condition and likelihood of death in hospitalized patients with acute trauma (AT). METHODS: Trauma index scores and injury severity scores (ISS) were assessed in 1,802 randomly selected cases of AT-hospitalized patients. The receiver operating characteristic (ROC) curve was used to compare the clinical values of TI and ISS values to predict outcomes in AT-hospitalized patients. RESULTS: The area under the ROC curve for TI scores was 0.896 (95% CI [0.881, 0.909]), while for ISS, it was 0.792 (95% CI [0.773, 0.811]). This difference was not statistically significant (z = 3.236, P = 0.001). Potentially critical disease conditions in AT-hospitalized patients were best identified when TI scores were >= 16 points and ISS values were >= 22 points. CONCLUSIONS: Trauma Index scores exhibited a higher resolution for outcome prediction in AT hospitalized patients compared to ISS values. The implementation of this scale was simple, reliable, easy to learn, and could quickly identify disease, which is vital for early detection and treatment of critical trauma patients. PMID- 26770542 TI - Influences of continuous femoral nerve block on knee function and quality of life in patients following total knee arthroplasty. AB - OBJECTIVE: Continuous femoral nerve block (CFNB), guided by ultrasound combined nerve stimulations, offers advantages for both sides and provides effective postoperative analgesia after total knee arthroplasty (TKA). The objective of this study was to evaluate the medium-term impact of continuous femoral nerve block on knee function and quality of life in patients following TKA. METHODS: This was a follow-up study. Total 168 adult patients scheduled for elective TKA were randomly allocated to receive postoperative continuous femoral nerve block guided by ultrasound combined nerve stimulator (group CFNB, n = 82) or patient controlled epidural analgesia (group PCEA, n = 86). Quality of life, knee function, patient satisfaction, pain medication and associated adverse effects were compared at 1, 3, 6, and 12 months postoperatively. Quality of life was assessed using the Medical Outcomes Study Short Form-36 Health Survey (MOS SF 36), and clinical results were assessed using the Hospital for Special Surgery (HSS) Knee Scoring System. Patient satisfaction scores were divided into four categories. RESULTS: A total of 162 patients completed the 12-month follow-up. The CFNB group patients had significantly improved SF-36 scores and physical function at 1 month postoperatively (P < 0.05); the remaining seven dimensions were similar between the two groups. No differences were observed at 3, 6 or 12 months. HSS scores for the four observational time points were comparable. The CFNB group patients reported less pain; improved knee function, maximum flexion and strength; less celecoxib consumption and fewer side effects at 1 month than the PCEA group patients. The satisfaction score at 12 months decreased significantly, compared with that at 1 month in both groups (3.6 to 2.95 and 3.4 to 2.45, respectively). No difference in satisfaction score was observed between the two groups. CONCLUSIONS: Continuous femoral nerve block not only could provide effective postoperative analgesia but also could improve joint function and quality of life in patients at one month postoperatively. Continuous femoral nerve block is a good choice for postoperative analgesia after TKA. PMID- 26770543 TI - Expression and significance of CD4(+)CD25(+)CD127(-) regulatory T cells in peripheral blood of patients with different phenotypes of Guillain-Barre syndrome. AB - OBJECTIVE: This study aims to investigate the changes of immune status and significance in patients with Guillain-Barre syndrome (GBS). METHODS: The proportion of CD4(+)CD25(+)CD127(-) regulatory T cells in peripheral blood before immunotherapy for 41 patients with GBS (including 29 classic type and 12 variant type) and 42 normal control patients (healthy volunteers) were evaluated by flow cytometry. And molybdenum three phenol red method was used to detect cerebrospinal fluid protein content of 28 patients with GBS (including 19 with classic type and 9 with variant type). RESULTS: Compared with healthy control group, the CD4(+)CD25(+)CD127(-) of GBS group had obvious difference (P<0.05). Of which, the CD4(+)CD25(+)CD127(-) regulatory T cells of the classic GBS group had no significant changes compared with the variant group (P>0.05), as well as the cerebrospinal fluid protein content between classic and variant GBS groups. The decrease of the proportion of CD4(+)CD25(+)CD127(-) regulatory T cells suggested abnormal expression of immune function in GBS patients. CONCLUSION: The decrease of GBS regulatory T cell number or function indicated that the immune regulatory T cells mediated imbalance of immune regulation involved in the pathogenesis of GBS. PMID- 26770544 TI - Clinical characteristics and mutation analysis of two Chinese children with 17a hydroxylase/17,20-lyase deficiency. AB - Combined with the literature, recognize the clinical features and molecular genetic mechanism of the disease. 17a-hydroxylase/17,20-lyase deficiency, a rare form of congenital adrenal hyperplasia, is caused by mutations in the cytochrome P450c17 gene (CYP17A1), and characterized by hypertension, hypokalemia, female sexual infantilism or male pseudohermaphroditism. We presented the clinical and biochemical characterization in two patients (a 13 year-old girl (46, XX) with hypokalemia and lack of pubertal development, a 11 year-old girl (46, XY) with female external genitalia and severe hypertension). CYP17A1 mutations were detected by PCR and direct DNA sequencing in patients and their parents. A homozygous mutation c.985_987delTACinsAA (p.Y329KfsX418) in Exon 6 was found in patient 1, and a homozygous deletion mutation c.1459_1467delGACTCTTTC (p.Asp487_Phe489del) in exon 8 in patient 2. The patients manifested with hypertension, hypokalemia, sexual infantilism should be suspected of having 17a hydroxylase/17,20-lyase deficiency. Definite diagnosis is depended on mutation analysis. Hydrocortisone treatment in time is crucial to prevent severe hypertension and hypokalemia. PMID- 26770545 TI - Prognostic significance of Glasgow prognostic score in patients with stage II colorectal cancer. AB - Glasgow prognostic score (GPS), one information based prognostic score, has been previously shown to be a prognostic factor in varieties cancers mostly in advanced tumors. This study aimed to explore its value in patients with relatively early stage colorectal cancer (CRC). A total of 99 CRC patients with stage II from 2005 to 2010 operated in our hospital were enrolled in this study. C-reactive protein (CRP), albumin (ALB), Karnofsky Performance Status (KPS) score as well as a variety of biochemical variables before the operation was acquired from the database retrospectively. The value of GPS was calculated and its association with the clinical factors was further investigated. The prognostic significance was analyzed by univariate and multivariate analyses. Increased preoperative GPS was found associated with elevated carcinoembryonic antigen (CEA) and decreasing of KPS. Kaplan-Meier analysis and log-rank test revealed that a higher GPS predicted a higher risk of postoperative mortality in stage II CRC (P < 0.001). Furthermore, multivariate analysis demonstrated the GPS to be a risk factor for postoperative mortality (HR 3.215; P=0.025). The preoperative GPS might be a potential useful indicator for postoperative survival in patients with stage II CRC. PMID- 26770546 TI - Correlation of burnout with social support in hospital nurses. AB - Burnout is common in industrial countries. In this study, our aim is to investigate the relationship between burnout and social support (SS) among hospital nurses. A cross-sectional survey was conducted in 7 hospitals from three provinces of China. A total of 1212 registered hospital nurses were included, the respond rate is 94.4% (1144/1212). A self-administered questionnaire consisting of socio-demographic characteristics, burnout and SS was used in this study. A revised version of Maslach Burnout Inventory (MBI) was applied to evaluate the burnout and SS was measured by nine questions. Logistic regression analysis was used to explore the association between burnout and SS after controlling for age, gender, marital status, working years, income, educational level, and profession. According to the results obtained from the study, 66% of the staff suffered from emotional exhaustion (EE) in moderate or severe degree, 65% of them suffered from depersonalization (DP) and 63% feel lower personal achievements (PAs). It means that higher level of EE, DP and lower PAs were considered care providers in the hospital nurse. Further correlation analysis indicated that the score of EE, DP and PAs were negative associated with the score of SS (P<0.05). The univariate analysis and multivariate analysis results also revealed that the SS score negative associated with DP score and positively associated with PAs score after controlling for age, gender, marital status, working years, income, educational level and job title. SS have a significantly influences on depersonalization in hospitals nurse. This study also suggests that we should pay more attention to the relationship between burnout and reduced personal accomplishment in future studies. PMID- 26770547 TI - Effect of both preoperative andpostoperative cryoceutical treatment on hemostasis and postoperative pain following total knee arthroplasty. AB - AIM: We aimed to evaluate the hemostatic effects and the clinical outcomes of preoperative and postoperative cryoceutical treatment (C-tx) following total knee arthroplasty. PATIENTS AND METHOD: 42 patients received C-tx both preoperatively, and postoperatively. In the control group, 45 patients did not receive any C-tx. Amount of bloody drainage and verbal rating pain scores were noted. RESULTS: We found significant difference in both the preoperative and postoperative hemoglobin levels and blood drainage (P<0.001). However, there was no significant difference in the average verbally rated pain scores (P>0.05). CONCLUSION: C-tx performed preoperatively and postoperatively for total knee arthroplasty is effective in decreasing perioperative and postoperative hemorrhage. However, it had no superior effect on the control of postoperative pain. PMID- 26770548 TI - Administration time-dependent effects of combination therapy on ambulatory blood pressure in hypertensive subjects. AB - The aim of this study was to explore the influence of combination therapy in different administration time on antihypertensive efficacy and blood pressure variability in patients with essential hypertension. A total of 86 patients with stage II to III essential hypertension were randomly divided into 4 groups: taking indapamide and losartan potassium together in the morning or in the evening 2 to 4 hours before sleep, indapamide in the morning and losartan potassium in the evening, losartan potassium in the morning and indapamide in the evening. Ambulatory blood pressure monitoring was performed before and 12 weeks after the medication. The result showed that statistically significant reductions from baseline of systolic blood pressure/diastolic blood pressure occurred in all treatment groups. There was no significant difference of the reductions or SI among the four groups, neither the rate of decline of BP in the night or the circadian rhythm. In group B, the numbers of rapid rise in BP in the morning hours were significantly less after the medication, while not in the other groups. It is concluded that independent of the administration time, both once daily treatment and component-based dual therapy had significant antihypertensive effect, but the night taken-together combination resulted in reductions of BP, SI and morning blood pressure peak that may have advantages over the other combinations, without the increased incidence of hypotension at night. Medicines should be taken 2 to 4 hours before sleep. PMID- 26770549 TI - Correlation between rs198388 and rs198389 polymorphismsin brainnatriuretic peptide (NPPB) gene and susceptibility to congenital heart diseases in a Chinese population. AB - OBJECTIVE: We discussed the correlation between SNP loci (rs198389 and rs198388) in brain natriuretic peptide gene (NPPB) and susceptibility to congenital heart diseases (CHD). METHOD: Multiplex SNaPshot technique was adopted for profiling of SNP genotypes at loci rs198389 and rs198388 in NPPB gene among 150 cases of CHDand 150 normal controls. RESULTS: The distribution frequency of 3 genotypes (AA, AG and GG) at locus rs198389 was 40.7%, 36.0% and 23.3% in CHD group, respectively, showing significant differences compared with the normal controls (P<0.001). Gallele was associated with higher risk of CHD (OR=2.48, 95% CI=1.77 3.48). The distribution frequency of CC, CTand TT genotypes at locus rs198388 was 60.7%, 17.3% and 22.0% in CHD group, respectively, also showing significant differences compared with the normal controls (P<0.001). C allele could increase the risk of CHD (OR=1.92, 95% CI=1.48-2.48). CONCLUSION: SNP loci rs198389 and rs198388 in NPPB gene were correlated with genetic susceptibility to CHD. PMID- 26770550 TI - Observations on the curative effect of lactulose for postpartum constipation based on a large sample study. AB - To evaluate the efficacy and safety of lactulose in the intervention treatment of postpartum women with constipation. METHODS: The study adopted the multicenter clinical survey with a big sample which enrolled 4781 valid questionnaires from postpartum women in 18 different districts. All of them were treated with lactulose oral solution. Their constipation-related symptoms and routine examination on blood, urine and stool were monitored before and after lactulose intervention. The treatment duration lasted 2 weeks and all the patients were followed for 4 weeks. RESULT: Their stool consistency, daily defecation frequencies, defecating time and dyschezia were improved significantly after lactulose intervention, and the good therapeutic effect was remained at the off medication session. Furthermore, abnormal rate of each index in blood, urine and stool examination showed a decreased trend. CONCLUSION: Lactulose offered good therapeutic benefit and could be developed as an effective intervention to postpartum women with constipation. PMID- 26770551 TI - Red blood cell distribution width as a prognostic biomarker for mortality in traumatic brain injury. AB - OBJECTIVE: Traumatic brain injury (TBI) often cause morbidity and mortality, but it is hard to obtained predictive biomarkers. Red blood cell distribution width (RDW) has been reported as a mortalmarker in cardiovascular disease. But it is unknown whethr RDW is associated with the mortality of TBI patients. The aim of this study is to identify whether RDW is a prognostic biomarker for TBI mortality. METHODS: A total of 122 patients with TBI were included retrospectively. Patients were divided into Survival Group and Non-survival Group, RDW was compared between 2 groups. Receiver Operating Curve (ROC) was used to evaluate the mortality predictive performances. RESULTS: 122 patients were included, the male-female ratio was 2.59 (88/34) with their median age of 49.5 (17-89) years. 13 (11.93%) of them were divided into Non-survival Group. We observed significant difference in RDW between two groups (P < 0.05). The cut-off level for RDW in TBI was >= 12.85, with the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) were 65.4%, 95.7%, 69.7%, 82.6%, respectively; and area under the curve was 0.805 (95% confidence interval [CI]: 0.703-0.906). CONCLUSIONS: Red cell distribution width is a predictor of mortality in patients with TBI. PMID- 26770552 TI - Needle infusion avoids using sutures and prevents hypotony in the 23 gauge sutureless vitrectomy. AB - OBJECTIVE: To investigate the effects of needle infusion on preventing wound leakage and hypotony in sutureless vitrectomy. METHODS: We retrospectively reviewed 230 consecutive eyes of 23-gauge pars plana vitrectomy with or without needle infusion, and further measured the wound leakage and intraocular pressure (IOP) without using a suture. RESULTS: In the eyes with primary needle infusion inserted before infusion cannula removal, IOP was stable during and after infusion cannula removal. No suture was needed in the procedure. Postoperative hypotony did not occurred in all eyes with needle infusion either. CONCLUSION: Needle infusion inserted before infusion cannula removal can avoid using sutures and prevent hypotony intraoperatively and postoperatively. PMID- 26770553 TI - Relationship between vitamin D and glycemic control in patients with type 2 diabetes mellitus. AB - Herein I investigated the impact of vitamin D on glycemic control in patients with type 2 diabetes mellitus. 128 patients with type 2 diabetes mellitus were enrolled in this study (mean (S.D) age: 57.7+/-10 years, 26.6% were female). It was collected clinical and laboratory characteristics of patients from hospital records retrospectively. Patients were divided into two groups according to the HBA1c values: good glycemic control (HbA1c<=7%) and poor glycemic control (HbA1c>7%). It was compared 25 hydroxyvitamin (OH) D and other collected laboratory parameters between the two groups. The vitamin D deficiency rate was 98.3%. In the result with ROC curve analyzes and Mann Whitney U test vitamin D was'nt significantly associated with glycemic control (P value >0.05). Among other parameters result with ROC curve analyzes and student t test RDW-CV was found to be significantly associated with glycemic control (P value <0.05). Although high level of vitamin D deficiency, present study indicated that vitamin D was'nt significantly related to glycemic control in type 2 diyabetes mellitus. Even so RDW-CV was significantly related to glycemic control. PMID- 26770554 TI - Pyoderma gangrenosum of articulations carpi associated with ulcerative colitis: one case report. AB - Pyoderma gangrenosum (PG), an extra-intestinal manifestation of ulcerative colitis (UC), is extremely rare. Up to now, there is no any data reported the occurrence of PG in joints, especially in China. The management of PG associated with UC is a therapeutic challenge. Our report here showed that a female patient diagnosed as UC complained a pustule in the dorsal side of left wrist, primarily was diagnosed as bone tuberculosis. The pustule progressed rapidly into a severe painful necrolytic cutaneous ulcer with a pale purple irregular destructive ulcer edge, this patient was diagnosed by UC complicated with PG, and skin lesions were cured by UC treatment. Here, we for the first time present a case acquired correct diagnosis and successful treatment of UC associated with PG of articulations carpi. We report this case here in order to provide more information about this disease to more doctors, furthermore, to decrease the rates of misdiagnosis and missed diagnosis. PMID- 26770555 TI - Pathogen distribution and drug resistance in a burn ward: a three-year retrospective analysis of a single center in China. AB - To investigate the spread of multiple-resistant strain in a burn ward to inform clinical administration of antibiotic drugs, burn wound treatment and decision making for infection control. A 3-year retrospective analysis was conducted. Specimens from wounds, blood, catheter, sputum, urine and stool collected from inpatients of the Second Affiliated Hospital of Zhejiang University of Medicine between January 1, 2011 and December 31, 2013 were cultured and strains were identified by automatic bacteria analysis. Sensitivity to 30 commonly used antibiotics was assessed by K-B disk diffusion. A total of 2212 strains of pathogenic bacteria or fungi were isolated (33.9% Gram-positive and 52.7% Gram negative bacteria and 13.4% fungi), including 1466 from wound extracts, 128 from blood culture, 335 from urine culture, 5 from stool culture, 153 from sputum culture and 125 from catheters. The most frequently detected pathogens in wound secretions were Staphylococcus aureus, Pseudomonas aeruginosa and Acinetobacter baumannii. The Gram-positive bacteria Staphylococcus epidermidis, Enterococcus faecalis and Enterococcus faecium, and the Gram-negative bacteria Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Stenotrophomonas maltophilia, Proteus mirabilis were also frequently detected. The most frequently detected strains of fungi were Candida albicans; tropicalis, glabrata and parapsilosis, and all were highly sensitive to itraconazole, fluconazole and voriconazole but resistant to ketoconazole. Attention should be paid to MRSA, multi-resistant A. baumanni, ESBL-producing enterobacteriaceae and Carbapenem-resistant P. aeruginosa. Understanding the distribution of bacterial infections in Chinese hospitals will be crucial to reduce hospital-acquired infection and drug resistance. PMID- 26770556 TI - Serum lipid profiles, the prevalence of dyslipidemia and the risk factors in two isolated Chinese minorities. AB - Both Jing and Mulao nationalities are the isolated minorities in China. Little is known about the prevalence of dyslipidemia between the two ethnic groups. Therefore, the aim of this study was to compare the differences in serum lipid profiles, the prevalence of dyslipidemia and their risk factors between the Jing and Mulao populations. A cross-sectional study of dyslipidemia was conducted in Dongxing city, Guangxi, China, during Dec 2011 and Jan 2012. A total of 1254 subjects of Jing and 1251 participants of Mulao were surveyed by a stratified randomized sampling. Information on demography, diet and lifestyle was collected with standardized questionnaire. Serum lipid levels were detected using the commercially available kits. The levels of low-density lipoprotein cholesterol (LDL-C), apolipoprotein (Apo) A1, and the ratio of ApoA1 to ApoB were lower but the levels of ApoB were higher in Jing than in Mulao (P < 0.001 for all). The prevalence of hypertriglyceridemia (32.38% vs. 24.38%), high ApoB (35.25% vs. 15.35%) and low ApoA1/ApoB ratio (22.65% vs. 16.87%) was higher and low high density lipoprotein cholesterol (0.48% vs. 2.16%), high LDL-C (17.54% vs. 40.53%) and low ApoA1 (5.98% vs. 11.43%) was lower in Jing than in Mulao (P < 0.001 for all). The risk factors for serum lipid parameters and hyperlipidemia were different between the two ethnic groups. Serum lipid profiles, the prevalence of dyslipidemia and their risk factors are different between the Jing and Mulao populations. These differences may result from the combined effects of different diet, lifestyle, and genetic factors. PMID- 26770557 TI - Higher serum total bilirubin concentration is associated with lower risk of renal insufficiency in an adult population. AB - BACKGROUND: Chronic inflammation is proposed to play a central role in the pathogenesis of chronic kidney disease (CKD), and serum bilirubin has antioxidant and anti-inflammatory effects. We investigated the association between serum total bilirubin (Tb) concentration and renal function in an adult population. METHODS: We conducted a cross-sectional study and collected anthropometric measurements, fasting blood tests, lifestyle habits and medical history of 3876 subjects attending a health examination. Renal insufficiency was defined as estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m(2) calculated by using the CKD-EPI equation. RESULTS: Serum Tb concentrations were higher in subjects without renal insufficiency than in those with renal insufficiency. Multivariable linear regression analysis showed that Tb concentration was positively associated with eGFR after adjusting for important CKD risk factors (P=0.04). Multivariable logistic regression analysis also revealed that higher Tb concentration (each increment of 1.71 MUmol/L) (0.1 mg/dL) was associated with a reduced risk of renal insufficiency: odds ratios were 0.94 (P=0.005) for men and 0.90 (P=0.015) for women, respectively. When subjects were divided into quartiles of serum Tb, multivariable-adjusted odds ratios for renal insufficiency comparing the fourth to the first Tb quartile were 0.49 (P=0.001) for men and 0.35 (P=0.003) for women. A stepwise exclusion of subjects, first those with possible liver disease and second, those with CKD stage 4 and 5, showed consistent results. CONCLUSION: Higher serum Tb concentration was associated with lower risk of renal insufficiency, regardless of other conventional CKD risk factors. PMID- 26770558 TI - Role of abnormal anterior pituitary hormones-growth hormone and prolactin in active systemic lupus erythematosus. AB - BACKGROUND: The role of anterior pituitary hormones in systemic lupus erythematosus (SLE) remains controversial. AIMS AND OBJECTIVES: We determined the expression levels of human growth hormone (GH), prolactin (PRL), and their receptors in subjects presenting with SLE, and modulation of disease severity. MATERIALS AND METHODS: Forty-seven subjects and ten healthy controls were assessed for possible association between SLE disease activity and levels of serum PRL, GH and thyrotropin-releasing hormone (TRH). In peripheral blood mononuclear cells (PBMC), specific binding and mRNA expression of receptors for GH (GHR), and PRL (PRLR) were determined by receptor-ligand binding assay (RLBA) and RT-PCR. PBMC of recruited subjects were treated with hPRL and rhGH to assess IgG production and antibodies against dsDNA. RESULTS: In active SLE subjects we found elevated PRL and GH levels. Study subject PBMCs displayed augmented GHR and PRLR protein and mRNA expression. Study subjects also showed a positive correlation in serum PRL levels and specific antibodies against dsDNA, SLE disease activity index (SLEDAI), and proteinuria. However, a negative correlation was found between serum PRL levels and complement component C3. We found a positive correlation between specific binding rates of PRLR and GHR and both SLE activity and dsDNA antibody titers. Enhanced IgG and anti-dsDNA secretion was observed in cultured PBMC stimulated by PRL or GH with/without PHA, PWM, IL-2 or IL-10. In active SLE, a close association was found between augmented PRL and GH levels, expression and specific binding activities of PRLR and GHR, and changes in the specific titer of anti-dsDNA. CONCLUSION: Anterior pituitary hormones play an important role in the pathogenesis of SLE. High levels of growth hormone (GH) and prolactin (PRL) play a role in pathogenesis of SLE, which is correlated with SLE disease activity and antibodies against dsDNA. The mechanism of GH and PRL in SLE was complicated and should be studied further. PMID- 26770559 TI - Genetic polymorphisms in the androgen metabolism pathway and risk of prostate cancer in low incidence Malaysian ethnic groups. AB - Androgens are involved in prostate cancer (PCa) cell growth. Genes involved in androgen metabolism mediate key steps in sex steroid metabolism. This study attempted to investigate whether single nucleotide polymorphisms (SNPs) in the androgen metabolism pathway are associated with PCa risk in low incidence Asian ethnic groups. We genotyped 172 Malaysian subjects for cytochrome P450 family 17 (CYP17A1), steroid-5-alpha-reductase, polypeptide 1 and 2 (SRD5A1 and SRD5A2), and insulin-like growth factor 1 (IGF-1) genes of the androgen metabolism pathway and assessed the testosterone, dihydrotestosterone and IGF-1 levels. SNPs in the CYP17A1, SRD5A1, SRD5A2, and IGF-1 genes were genotyped using real-time polymerase chain reaction. Although we did not find significant association between SNPs analysed in this study with PCa risk, we observed however, significant association between androgen levels and the IGF-1 and several SNPs. Men carrying the GG genotype for SNP rs1004467 (CYP17A1) had significantly elevated testosterone (P = 0.012) and dihydrotestosterone (DHT) levels (P = 0.024) as compared to carriers of the A allele. The rs518673 of the SRD5A1 was associated with prostate specific antigen (PSA) levels. Our findings suggest CYP17A1 rs1004467 SNP is associated with testosterone and DHT levels indicating the importance of this gene in influencing androgen levels in the circulatory system of PCa patients, hence could be used as a potential marker in PCa assessment. PMID- 26770560 TI - Whole-exome sequencing and whole genome re-sequencing for prenatal diagnosis of achondroplasia. AB - OBJECTIVE: To investigate the feasibility of whole exome sequencing (WES) and whole genome re-sequencing (WGS) in the prenatal diagnosis of achondroplasia (ACH). METHODS: Eleven highly suspected with ACH or hypochondroplasia (HCH) fetuses and their parents were enrolled in this study. Routine prenatal examinations were carried out in all pregnant women. WGS was performed for the detection of copy number variation (CNV). WES was conducted to determine the mutation of fibroblast growth factor receptor 3 (FGFR3) gene in one special family with rickets and dwarfism. Moreover, all subjects were performed Sanger sequencing for the screening of high frequent mutation sites in FGFR3 gene. RESULTS: For ultrasound (US) examination, short femur was noted in all fetuses with FL less than 4SD and 2SD in 8 cases and one case compared with those of normal gestational weeks, respectively. CNV abnormality was identified in 5 cases, including heterozygous deletion in 4 cases and heterozygous duplication in one case. Among these variation, one case was acknowledged to be pathogenic, one case was identified as genomic polymorphism, while the pathogenicity remained unknown in other 3 cases. For the exome and Sanger sequencing, heterozygous mutation p.Tyr278Cys (833A>G) was noted in the fetus and husband of the special family, while homozygous c.1959+19G>A mutation was identified in another case. CONCLUSION: Multiple sequencing technologies may provide an additional diagnostic tool and facilitates genetic counseling in the patients with ACH. Further improvement of gene sequencing should be done in the prenatal diagnosis for the mutant screening in other genes. PMID- 26770561 TI - Correlation between bone mineral density and serum trace element contents of elderly males in Beijing urban area. AB - Trace element levels are associated with the incidence of osteoporotic fractures, but related mechanisms remain unknown. Trace elements may interfere with growth, development and maintenance of bones. Therefore, we investigated whether plasma trace element levels are associated with bone mineral density in elderly males in Beijing. After epidemiologically investigating 91 elderly males with age ranging from 50 years to 80 years, we obtained a total of 30 healthy (group 1), 31 osteopoenic (group 2) and 30 osteoporotic (group 3) subjects. Blood was collected, and serum concentrations of trace elements were detected. Elderly males in the three groups were carefully matched in terms of body mass index. Iron, manganese, zinc, copper, selenium, cadmium and lead were analysed by inductively coupled plasma-mass spectrometry. Bone mineral density (BMD) was measured by QDR-2000 dual-energy X-ray absorptiometry. Correlation between BMD and serum element contents was analysed using SPSS16.0. The plasma levels of manganese, zinc, copper, selenium and lead were similar in all of the groups (P>0.05). Cadmium was significantly and negatively correlated with BMD of the lumbar vertebrae (P<0.05). Moreover, cadmium and iron contents significantly differed in osteoporotic and healthy groups. These elements may directly and correlatively affect BMD in elderly males. Many trace elements may directly and correlatively influence BMD. Future studies should be conducted to evaluate serum and bone levels of these trace elements to determine the relationship of these trace elements with osteoporosis. PMID- 26770562 TI - Baseline prognostic factors and statistic model to predict early virological response in lamivudine-treated patients with chronic hepatitis B. AB - Lamivudine is a potent nucleoside analogue used in treating chronic hepatitis B (CHB). However, resistance to the drug remains a problem. We analyzed all lamivudine recipients in this trial to determine the baseline characteristics and a model to predict early virological response reflecting the long-term effect of lamivudine. In this prospective trial, 230 patients who had not treated with nucleotide analogue with chronic HBV infection were assigned to receive 100 mg of lamivudine once daily for 24 weeks at least. All patients were followed up every 2 week. Cox proportional hazard regression model analyses were employed to evaluate baseline variables and to develop a statistical model. Female (P = 0.042), baseline higher serum aspartate aminotransferase (AST) (P = 0.002), and lower level of HBV-DNA (P = 0.016) were identified to be associated with higher possibility of early virological response. A model was established based on these variables to calculate the risk scores (R) for CHB patients. R > -0.45 suggested early virological response to lamivudine. The model was validated among an independent set of 40 patients. The gender as well as baseline AST and HBV-DNA levels can predict early virological response. The model provides a better tool for response prediction based on the three prognostic factors. PMID- 26770563 TI - The comparison of the harmonic focus shears device with conventional clamp binding in total thyroidectomy. AB - AIM: Harmonic Focus (HF) is an ultrasonic device developed most recently for thyroid surgery. The aim of this study was to compare the surgical completeness and outcome of total thyroidectomy in two patient groups. One group was treated by HF and one by Conventional Dissection (CD). METHODS: Total thyroidectomy was performed in 38 patients with CD, and in 38 patients with HF. RESULTS: When compared to conventional haemostasis, a reduction was observed in the duration of surgery in the HF group, and the amount of blood loss was reduced by 29%, and 46%, respectively. The number of intraoperative device changes was decreased by 70%. The utilisation of special materials to obtain haemostasis was also significantly decreased. HF was found to be as safe as the conventional haemostasis technique. CONCLUSIONS: Our study has demonstrated the beneficial effects and relative safety of HF in thyroid surgery. Further studies are needed about the financial benefits provided by reductions in human resources, and in materials employed for haemostasis. PMID- 26770564 TI - Quantification of anti-sperm antibody and soluble MICA/MICB levels in the serum of infertile people of the Li ethnic group in China. AB - OBJECTIVE: To investigate the presence of anti-sperm antibodies (AsAb) and the correlation between AsAb positivity and the expression of soluble major histocompatibility complex class I chain-related A and B (sMICA or sMICB) in the sera of infertile people of the Li nationality from Hainan, China. METHOD: A total of 136 people (68 couples) from five villages in the Wuzhishan region, Hainan province participated in this study. Among them, 31 couples were included in the fertile group and 37 couples in the infertile group. AsAb and sMICA/sMICB levels in serum were detected by ELISA. The median sMICA/sMICB levels between and among groups were compared by Mann-Whitney rank U testing and Kruskal-Wallis H testing, and the AsAb positivity rate was compared by Pearson Chi-Square testing. Correlation analysis was performed by calculating the Spearman's rho coefficient for nonparametric data. RESULTS: The serum levels for the fertile group (AsAb: 15.5 [4.0~127.0] U/ml, sMICA: 18.33 [13.30~52.40] pg/ml, sMICB: 27.72 [18.63~47.43] pg/ml) were not statistically different from those for the infertile group (AsAb: 18.0 [9.8~95.0] U/ml, sMICA: 20.95 [15.78~23.81] pg/ml, sMICB: 26.26 [18.06~61.38] pg/ml). However, grouping based on AsAb positivity revealed a statistically significant difference for the sMICA/sMICB levels (AsAb positive group: sMICA: 5.56 [4.30~17.23] pg/ml, sMICB: 16.13 [7.54~25.43] pg/ml; AsAb negative group: sMICA: 22.00 [18.05~66.13] pg/ml, sMICB: 36.51 [20.53~67.22] pg/ml; P < 0.01). These results suggest that AsAb is negatively associated with both sMICA (Spearman's coefficient, -0.475, P < 0.01) and sMICB (Spearman's coefficient, -0.381; P < 0.01). The analysis also shows that sMICA levels are positively associated with sMICB levels (Spearman's coefficient, 0.635; P < 0.01). CONCLUSION: AsAb can be detected in the serum of fertile and infertile Li people. However, there appears to be limited clinical value in the conventional detection of AsAb, sMICA and sMICB in serum for diagnosing infertility. People with positive AsAb expression have lower levels of sMICA/sMICB expression in serum, which may be one mechanism by which people produce AsAb. PMID- 26770565 TI - 8-10 year follow-up survival of dental implants in maxillae with or without autogenous bone graft reconstruction. AB - The aim of this research was to ascertain the survival of implants installed in the atrophic maxillae of patients treated with or without autogenous bone graft at 8 to 10 years of follow-up. A retrospective study was conducted using clinical and imaging analysis. 42 adult patients were selected, treated with osseointegrated implants in a fixed maxillary prosthesis model with suprastructure using 6 to 8 implants; of these, 22 underwent reconstruction with a bone graft taken from the anterior iliac crest and 20 were treated without any type of bone graft. The sequence of removal, installation and management of the grafts followed routine patterns, and the implant installation and prosthesis preparation also followed parameters established in previous publications. Variables of implant survival, stage of loss and bone stability of the implants were analyzed with the Wilcoxon signed-rank test, considering a value of P<0.05 to obtain statistical significance. After 8 to 10 years of follow-up the 306 implants installed in the 42 patients were evaluated. 162 implants were in the bone graft group, where 8.0% of implants were lost in the pre-loading stage, 3.7% in the post-loading stage and 88.7% had complete survival. In the group without bone graft, 6.17% were lost in the pre-loading stage, 1.85% in the post-loading stage and 90.97% had complete survival. There was no significant difference in the survival of the implants between the two groups (P=0.082). Cervical bone loss between the groups showed no significant differences either (P=0.241). The implants in grafted maxillae with cases of severe maxillary atrophy are just as efficient as implants installed in maxillae without bone graft. PMID- 26770566 TI - Association of serum SPARC level with severity of coronary artery lesion in type 2 diabetic patients with coronary heart disease. AB - OBJECTIVE: To investigate the association of serum SPARC level with the severity of coronary artery lesion in type 2 diabetic patients with coronary heart disease. METHODS: 120 patients with type 2 diabetic patients were the subjects. Enzyme-linked immunosorbent assay (ELISA) was used to detect levels of serum SPARC and Gensini score was used to assess extent of coronary artery lesions. The patients were divided into 4 groups: A group was the healthy control group with 40 patients. According to angiography and the World Health Organization (WHO) diagnostic criteria for diabetes the rest were divided into B, C, D group: there were 40 cases in group B (simple type 2 diabetes mellitus group), 40 cases were in group C (simple CHD group), and 40 cases were in D group (type 2 diabetes combined with coronary heart disease group). RESULTS: Compared with that in group A, the serum SPARC level in group B, C and D increased significantly (4.22+/ 1.19) MUg/L, (3.71+/-1.05) MUg/L and (5.96+/-1.40) MUg/L vs (3.60+/-0.40) MUg/L (P<0.05 ). Moreover, the serum SPARC level in group D was the highest (P<0.05). Serum SPARC level, insulin resistance (IR), and glycosylated hemoglobin (HbA1c) were the vital factors contributing to coronary heart disease. Serum SPARC level was positively correlated with the Gensini scores in group D (r=0.770, P<0.05), whereas it was not related to the Gensini scores in group C (r=0.520, P>0.05). Pearson correlation analysis showed that serum SPARC level was positively correlated with triglyceride, fasting insulin, Homeostasis Model Assessment for Insulin Resistance Index (r=0.780, 0.762 and 0.891, respectively; P<0.05). CONCLUSION: Serum SPARC level elevated in T2DM patients with coronary heart disease, which was correlated with the severity of coronary artery disease significantly. PMID- 26770567 TI - Experiences of patients with abnormal extubation of PICC tubes: a qualitative study. AB - OBJECTIVE: To explore the experiences of patients with abnormal extubation of PICC tubes. METHODS: Using phenomenological research methods, 15 cases of patients with abnormal extubation of PICC tubes were enrolled in semi-structured interviews. Data were analyzed by Nancy's phenomenological procedure. RESULTS: After abnormal extubation, patients exhibited conflicting complicated mood which combined negative experience and positive experience. Negative experience was mainly for complaint, helpless, worry and fear. Positive experience was mainly for relief and peace of mind. CONCLUSIONS: Patients with abnormal extubation often possessed negative experience. So nursing staff should be suggested to communicate with patients before extubation in order to reduce the dispute between nurses and patients. At the same time, we should summarize and analyze the reasons and factors for abnormal extubation, and take targeted intervention measures in clinical to ensure the safety and effectiveness of PICC extubation. PMID- 26770568 TI - Leukoaraiosis rather than lacunes predict poor outcome and chest infection in acute ischemic stroke patients. AB - In this study, we determine the effects of leukoaraiosis and lacunes on the clinical outcome and relative complications of acute ischemic stroke patients. From January 2007 to June 2008, 323 consecutive patients with acute brain infarction were prospectively studied. Leukoaraiosis was defined as moderate or severe white matter hyperintensities, and lacunes were counted as follows: none (0 lacune), few (1-2 lacunes), and many (>=3 lacunes). During a three-month period after the onset of stroke, patient outcomes and the incidence of complications were assessed. Backward stepwise logistic regression was used to identify the independent predictors of adverse outcome and complications after stroke. During the follow-up, 128 patients (39.63%) experienced adverse outcomes (i.e., death or disability), and 69 patients (21.36%) developed chest infections. Leukoaraiosis was an independent predictor of adverse outcome and chest infection (adverse outcome: odds ratio, 3.971, 95% confidence interval, 1.954-8.073; chest infection: odds ratio, 1.809, 95% confidence interval, 1.220-2.681), whereas no associations were observed between lacunes and adverse outcomes or complications after stroke. In conclusion, Leukoaraiosis but not lacunes was an independent predictor of adverse outcomes and chest infection in acute ischemic stroke patients. The difference between the effects of lacunes and leukoaraiosis may reflect the heterogeneity of these two primary features of small vessel diseases. PMID- 26770569 TI - Classification and surgical treatment for 180 cases of adrenocortical hyperplastic disease. AB - OBJECTIVE: To review and discuss the diagnostic and surgical therapeutic methods of adrenocortical hyperplastic disease. METHODS: A retrospective analysis was done to 180 adrenocortical hyperplasia patients (74 males, 109 females, aged 6~76 (average 40.1). Studies were done to the relationship between patients' clinical characteristics, biochemical, endocrinological and imaging examination results, the therapeutic effects. RESULTS: Among all 180 cases, there are 107 Cushing disease (CD), 19 ectopic adrenocorticotropin adrenal hyperplasia (EAAH), 28 adrenocorticotropin independent macronodular adrenal hyperplasia (AIMAH), 4 primary pigmented nodular adrenocortical hyperplasia (PPNAH), and 28 Idiopathic Hyperaldosteronism (IHA). Twenty-four-hour urinary free cortisol (24 h UFC) excretion of CD, EAAH, AIMAH and PPNAH patients were 95.2~535.7 ug (average 287.6 ug), 24.8~808.2 ug (average 307.9 ug), 102.5~3127.0 ug (average 852.5 ug), and 243.8~1124.6 ug (average 564.3 ug). Both low and high-dose dexamethasone suppression tests (DDST) were not suppressed in AIMAH, PPNAH and EAAH groups, but HDDST was suppressed in CD group. CT thin scanning results of 180 patients all showed enlargements in the affected side adrenal gland. Unilateral adrenalectomies were performed in 102 hypercortisolism cases. Local lesion excisions were done to 21 IHA patients. 57 patients had surgeries in both sides of the adrenal glands (39 bilateral total adrenalectomies, 16 total adrenalectomy in one side andsubtotal adrenalectomy in the other, 2 bilateral subtotal adrenalectomies). 106 (59%) patients were followed up for 4~158 (average 32) months. CONCLUSION: Unilateral adrenalectomy was the first choice for operable adrenocortical hyperplasia patients. The operation mode for the other adrenal gland should be based on the type of hyperplasia and clinical observation. PMID- 26770570 TI - Correlation analysis between serum lipoprotein (a) and the incidence of aortic valve sclerosis. AB - This clinical trial explores the correlation between serum lipoprotein and the severity of aortic valve sclerosis in patients diagnosed with aortic valve sclerosis (AVS). A total of 1260 subjects diagnosed with AVS were enrolled in this study between May 2005 and June 2013 and divided into the young-aged (30-59 years, n=217), middle-aged (60-74 years, n=561) and elderly groups (75-93 years, n=482). In each group, patients were sub-grouped into AVS and healthy controls according to angiography findings. Parameters including triglyceride (TG), serum total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), free fatty acid (FFA), lipoprotein (a) [Lp(a)], apolipoprotein A1 (ApoAl) and apolipoprotein B (ApoB) were accurately measured. Correlation between these parameters and the severity of AVS was statistically evaluated. In the middle-aged and elderly groups, serum Lp(a), TC and LDL-C were significantly higher in patients with AVS compared with healthy counterparts (both P<0.05). In the elderly group, serum HDL-C in AVS patients was significantly lower than healthy subjects (P<0.05). In the young-aged group, serum Lp(a) and ApoB were significantly increased compared with healthy counterparts (both P<0.05). Gemini score in the elderly group was significantly higher than the other groups (both P<0.01). No statistical significance was observed in Lp(a) levels among groups I, II and III. The number of coronary stenosis in group III was significantly increased than those in groups I and II (P<0.01). Lp(a), LDL-C and aging act as independent risk factors of AVS and promote the incidence and progress of AVS. PMID- 26770571 TI - Does aggressive and expectant management of severe preeclampsia affect the neurologic development of the infant? AB - OBJECTIVE: To compare and evaluate the influences of expectant and aggressive management of severe preeclampsia on the first year neurologic development of the infants in pregnancies between 27 and 34 weeks of pregnancy. METHODS: Seventy women with severe preeclampsia between 27 and 34 weeks of gestation were included in the study. 37 patients were managed aggressively (Group 1) and 33 patients were managed expectantly (Group 2). Glucocorticoids, magnesium sulfate infusion and antihypertensive drugs were administered to each group. After glucocorticoid administration was completed Group 1 was delivered either by cesarean section or vaginal delivery. In Group 2 magnesium sulfate infusion was stopped after glucocorticoid administration was completed. Antihypertensive drugs were given, bed rest and intensive fetal monitorization were continued in this group. RESULTS: The average weeks of gestation, one minute and five minute apgar scores and hospitalization time in intensive care unit were similar in both groups (P > 0.05). Three neonatal complications in Group 2 and five in Group 1 were detected according to the Denver Developmental Screening Test-II and one pathologic case was detected in both groups following neurologic examination. Neonatal mortality was seen in seven patients in Group 1 and one in Group 2. There were no significant differences between groups in terms of neonatal mortality and morbidity and maternal morbidity (P > 0.05). The average latency period was 3.45 +/- 5.48 days in Group 2 and none in Group 1. CONCLUSION: There was no significant difference in the first year neurological development of infants whose mothers underwent either expectant and aggressive management for severe preeclampsia. PMID- 26770572 TI - Observations on factors that influence thyroid nodules in diabetic and non diabetic patients in the Zhejiang province of China. AB - BACKGROUND: To determine the incidence of diabetes and thyroid nodules and factors influencing them. METHODS: A questionnaire was used for the epidemiological investigation of metabolic disorders, especially diabetes. Thyroid hormones and other indicator levels as well as ultrasound examinations were performed. RESULTS: Of 842 cases, 43 had diabetes, with an incidence rate of 5.1%, while 799 cases were non-diabetic, accounting for 94.9%. The incidence rate of thyroid nodules was 81.4% (35/43) in diabetic patients and 70.7% (565/799) in non-diabetic patients. Statistical analysis showed that the pathogenesis of thyroid was not obviously associated with diabetes. A further analysis of clinical features and thyroid nodules in diabetic patients revealed that the morbidity of thyroid nodules was correlated with age but had no relation to gender. The incidence of thyroid nodules was 92.9% in patients > 60 years. The morbidity of thyroid nodules was not only associated with age but also gender in non-diabetic patients, with a relatively high probability in female patients > 60 years. Logistic regression analysis revealed that follicle stimulating hormone (FSH), thyroid stimulating hormone (TSH), and glutamate pyruvate transaminase (GPT) were risk factors for developing thyroid nodules in all subjects; for males aged > 60 years, TSH and thyroxine were risk factors; for female subjects, FSH, TSH and GPT were the main factors. CONCLUSIONS: Diabetes is not a risk factor for thyroid nodules but an age > 60 years is an important factor for high morbidity of thyroid nodules. PMID- 26770573 TI - XRCC1 Arg194Trp and Arg399Gln polymorphisms and risk of extrahepatic cholangiocarcinoma: a hospital-based case-control study in China. AB - BACKGROUND: Extrahepatic cholangiocarcinoma (ECCA) is a rare but devastating malignancy. Up to 90% of patients presenting with ECCA have no identifiable risk factors. The base excision repair (BER) pathway has a principal role in the repair of mutations caused by oxidized or reduced bases. The XRCC1 is one of the key proteins in the BER pathway. In this study, we investigated the influence of XRCC1 Arg194Trp and Arg399Gln polymorphisms on ECCA incidence. METHODS: The study included 189 ECCA patients and 216 controls. Genotypes were detected by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) method. RESULTS: For codon 194, the genotype frequencies of C/C, T/C and T/T were 51.3, 43.4 and 5.3%, respectively, in the ECCA cases compared with 54.2, 38.9 and 6.9%, respectively, in the controls. No statistically significant differences were observed in the genotype frequencies of codon 194 between the two groups compared to the control (TC, OR: 0.85, 95% CI: 0.57-1.28, TT, OR: 1.24, 95% CI: 0.54-2.89, TC+TT, OR: 0.89, 95% CI: 0.60-1.32). For codon 399, the genotype frequencies of G/G, G/A and A/A were 54.0, 37.0 and 9.0%, respectively, in the ECCA cases compared with 56.1, 39.8 and 4.1%, respectively, in the controls. No statistically significant differences were observed in the genotype frequencies codon 399 between the two groups compared to the control (GA, OR: 1.04, 95% CI: 0.69-1.56, AA, OR: 0.45, 95% CI: 0.19-1.04, GA+AA, OR: 0.92, 95% CI: 0.62-1.36). Meanwhile, no statistically significant differences were found in the haplotype and risk of developing ECCA compared to the control (CA, OR: 0.83, 95% CI: 0.49 1.39, TG, OR: 0.96, 95% CI: 0.58-1.60, TA, OR: 0.83, 95% CI: 0.38-1.82). CONCLUSION: The present study suggested that Arg194Trp and Arg399Gln polymorphism in the DNA repair gene XRCC1 was not statistically associated with risk of ECCA. It would be necessary to confirm these findings in a large sample size and multiethnic population study in future. PMID- 26770574 TI - Association of peroxisome proliferator-activated receptor-gamma gene polymorphisms and gene-gene interaction with asthma risk in a Chinese adults population. AB - AIMS: To investigate the association between single nucleotide polymorphism (SNP) of peroxisome proliferator-activated receptors gamma (PPAR gamma) and additional gene-gene interactions on asthma risk. METHODS: A total of 882 subjects (602 males, 280 females), with a mean age of 61.3+/-14.8 years old, including 430 asthma patients and 452 normal subjects were selected in this study, including the genotyping of polymorphisms. Logistic regression was performed to investigate association between SNP and asthma. Generalized MDR (GMDR) was used to analysis the interaction among four SNP. RESULTS: Asthma risk was significantly lower in carriers of Ala allele of the rs1805192 polymorphism than those with Pro/Pro (Pro/Ala+ Ala/Ala versus Pro/Pro, adjusted OR (95% CI)=0.70 (0.51-0.94). In addition, we also found a significant association between rs10865710 and asthma, asthma risk was significantly lower in carriers of G allele of the rs10865710 polymorphism than those with CC (CG+ GG versus CC, adjusted OR (95% CI)=0.68 (0.55-0.95). There was a significant three-locus model (P=0.0107) involving rs1805192, rs10865710 and rs709158, indicating a potential gene-gene interaction among rs1805192, rs10865710 and rs709158. Overall, the three-locus models had a cross-validation consistency of 10 of 10, and had the testing accuracy of 60.72% after covariates adjustment. CONCLUSIONS: Our results support an important association of rs1805192 and rs10865710 with asthma, and additional interaction among rs1805192, rs10865710 and rs709158. PMID- 26770575 TI - Comparison between nitroglycerin and remifentanil in acute hypervolemic hemodilution combined with controlled hypotension during intracranial aneurysm surgery. AB - Allogenetic transfusion has long been considered to be a relatively safe and extremely effective blood transfusion treatment. However, acute hypervolemic hemodilution (AHH) combined with the remifentanil-induced controlled hypotension (CH) have rarely been examined. Herein, 40 intracranial aneurysm surgery patients were randomly divided into nitroglycerin group (A group, n=20) and remifentanil group (B group, n=20). During intracranial aneurysm surgery, MAP, HR, Hb, and Hct were recorded. SjvO2, PjvO2, SaO2, PaO2 were measured, and CaO2, Da-jvO2, CjvO2, CERO2, VADL were calculated. In addition, The venous blood samples were collected for determining PT, TT, APTT, FBG, VIII, VWF and electrolytes. The results show that HR in nitroglycerin group dramatically accelerated and HR in remifentanil group slowed at 30 minutes after hypotension and 5 minutes after aneurysm occlusion (P<0.01) after hypotension. Compared with A group, the SjvO2 and CjvO2 of B group increased significantly and the Da-jvO2 and CERO2 decreased significantly at T3, T4. In addition, There were no significant differences between after AHH and before AHH in two groups (P>0.05) on TT, PT, APTT, FIB, VIII, VWF, Na(+), Cl(-), K(+), Ca(2+). These results suggest that AHH combined with remifentanil-based CH significantly lowered cerebral metabolic rate of oxygen and had effects on blood coagulation without clinical hemorrhagic signs increased and had important clinical significance for blood conservation. PMID- 26770576 TI - The association between phospholipase C epsilon gene (PLCE1) polymorphisms and colorectal cancer risk in a Chinese Han population: a case-control study. AB - BACKGROUND: Heritable factors contribute to the development of colorectal cancer (CRC). We investigated the association between single nucleotide polymorphisms in phospholipase C epsilon 1 (PLCE1) and CRC susceptibility. METHODS: We selected eight tag single nucleotide polymorphisms (tSNPs) and investigated whether they were associated with CRC in Chinese Han population. In this study, we used Sequenom MassARRAY technology and genotyped 276 CRC cases and 385 controls. The effects of the polymorphisms on the risk of CRC were expressed as odds ratios (ORs) with 95% confidence intervals (95% CIs), evaluated by different genetic models using unconditional logistic regression analysis adjusted for age and gender. We also analyzed the risk of the eight PLCE1 tSNPs in different histology of CRC. RESULTS: Based on x(2) tests, rs753724 (OR = 1.49, 95% CI: 1.10-2.03, P = 0.010) and rs10882424 (OR = 1.32, 95% CI: 1.02-1.70, P = 0.037) in PLCE1 were associated with CRC. In genetic model analyses, we found that rs753724 in PLCE1 may increase CRC risk (OR = 1.48, 95% CI: 1.09-2.03, P = 0.013) in the log additive model, and rs11187842 in PLCE1 may increase CRC risk (OR = 3.09, 95% CI: 1.17-8.14, P = 0.018) in the recessive model. Rs753724 TT (OR = 4.31, P = 0.010), rs11187842 TT (OR = 5.78, P = 0.003), and rs10882424 GG (OR = 2.64, P = 0.022) in PLCE1 may increase rectal cancer in a recessive model. CONCLUSIONS: Our results suggest that PLCE1 may be associated with CRC in Han Chinese population. PMID- 26770577 TI - Clinical and endoscopic-pathological characteristics of colorectal polyps: an analysis of 1,234 cases. AB - PURPOSE: To analyze the correlation of clinical symptom and endoscopic pathological characteristics of colorectal polyps. METHODS: A retrospective study was performed on 1,234 continuous colorectal polyp patients. Their clinical, colonoscopic and pathological data were collected and analyzed. RESULTS: In 1,234 patients, 46.0% cases were asymptomatic, and 54.0% cases were symptomatic, and the female to male ratio was 2.23:1 and 1.74:1, respectively (P = 0.048). The mean polyp size in symptomatic group was significantly larger than asymptomatic group [7.6+/-5.1 mm (95% CI: 7.2, 8.0) vs. 6.3+/-3.7 mm (95% CI: 6.0, 6.6), P < 0.001]. Tubu-villous polyp and villous polyp occurred more frequently in symptomatic group, compared with asymptomatic group (P = 0.002). In symptomatic group, 37.4% cases complained of abdominal pain and 62.6% cases complained of bowel habit alteration. The polyp number in abdominal pain group was larger than bowel habit alteration group (P = 0.036). Three major symptoms of bowel habit alteration were diarrhea, constipation and hematochezia, with proportion of 54.2% (278/513), 27.7% (142/513) and 18.1% (93/513), respectively. The hematochezia group had larger polyp size than diarrhea group (P = 0.001) and consisted of more villous component than the constipation patients (P = 0.005). CONCLUSION: Almost half of colorectal polyp patients do not complain of bowel symptoms, especially the male. Colorectal polyp patients have bowel habit alteration more commonly than abdominal pain. Half of patients with bowel habit alteration demonstrate diarrhea. The hematochezia patients are more susceptible to advanced adenomas than the diarrhea and constipation ones. PMID- 26770578 TI - Intensified glucose self-monitoring with education in Saudi DM patients. AB - The purpose of this study is to assess the impact of intensified SMBG with patient education on DM patients at the Eastern province of Saudi Arabia. 60 poorly controlled adult type 1 and 2 DM patients (30 intervention; 30 control) were included in this 4-month case-control study. All patients were subjected to the same educational program at baseline. Controls were followed up after 3 months. The intervention group was followed monthly. Fasting blood glucose, HbA1c and lipid profile levels were the main outcome measures. The intervention arm showed significant reduction in the post-fasting glucose (P<0.001) and HbA1c (P<0.001) levels as well as a significant increase in glucose testing (P<0.001) than pre-levels. Both post-fasting glucose and HbA1c levels were significantly lower in the intervention arm than the control arm (P<0.001 and P=0.001, respectively). The intervention group also showed higher improvement in knowledge, attitude and behavior than the controls (P<0.001). Short duration of structured periodic SMBG with patient education significantly improved glycemic control in all DM patients, regardless of the type or mode of treatment. It facilitated timely and aggressive treatment modification and encouraged patient self-care behavior. PMID- 26770579 TI - Genetic variants at 6p21, 10q23, 16q21 and 22q12 are associated with esophageal cancer risk in a Chinese Han population. AB - OBJECTIVE: A number of recently published genome-wide association studies (GWAS) identified several genetic loci at 6p21, 10q23, 16q12 and 22q12 that were associated with digestive tract tumors, including esophageal cancer (EC). We conducted a case-control study in a Chinese Han population including 360 EC cases and 310 controls to evaluate whether these variants are related to EC susceptibility. METHODS: All these SNPs were genotyped using Sequenom Mass-ARRAY technology. For each SNP, genotypic frequencies in controls were tested for departure from Hardy-Weinberg Equilibrium (HWE) using an exact test. A P-value of 0.05 was considered the threshold for statistical significance. We compared the allele frequencies of cases and controls using the chi-squared (chi(2)) test. Associations between the gene and the risk of esophagus cancer were tested using various genetic models (co-dominant, dominant, recessive, and log-additive) and analysis by SNP stats. Odds ratios and 95% confidence intervals (CIs) were calculated by unconditional logistic regression with adjustments for age and gender. RESULTS: We found significant association with risk of EC for five reported SNPs, including rs2274223 in PLCE1 at 10q23 [odds ratio (OR) = 1.390; 95% confidence interval (CI) = 1.075-1.798], rs10484761 near UNC5CL at 6p21 (OR = 1.422, 95% CI = 1.014-1.994), rs4785204 in HEATR3 at 16q12 (OR = 1.427; 95% CI = 1.116-1.824), rs4822983 in CHEK2 at 22q12 (OR = 1.361, 95% CI = 1.052-1.762), and rs738722 in CHEK2 at 22q12 (OR = 1.343, 95% CI = 1.053-1.713). CONCLUSION: Our findings, combined with previous studies, indicated that rs10484761 at 6p21, rs2274223 at 10q23, rs4785204 at 16q12, rs4822983 and rs738722 at 22q12 may be used as genetic biomarkers for EC susceptibility in Chinese Han population. PMID- 26770580 TI - A comparison of ankle block and spinal anesthesia for foot surgery. AB - Regional anesthesia methods in the lower extremity include central blocks where spinal and epidural anesthesia are performed as well as peripheral nerve blocks, which are performed by injecting anesthetics locally to nerves. The study aimed to provide a retrospective comparison of unilateral spinal block and ankle block methods in foot operations. Some 60 ASA I-III patients who underwent operation under regional anesthesia were retrospectively examined. Two groups, known as the Unilateral Spinal Block Group (Group S) (n=30) and the Ankle Block Group (Group A) (n=30), were designed. Average blood pressure (ABP), heart rate (HR), block formation time (BFT), time for being ready for operation (TBRFO), total operation duration (TOD), visual analogue scale (VAS), first analgesic need time (FANT) and any complications were all recorded. The BFTs were longer in Group A than Group S, while the FANTs were longer in Group A postoperatively. When these decreases in Group A and Group S were compared with the basal values before the block, all decreases in Group S following the block were considered statistically significant (P<0.05), while the decreases in Group A in the 5(th) and 15(th) minutes were not considered statistically significant. The VASs measured postoperatively at the 6(th), 12(th) and 24(th) hours of Group A were lower than those of Group S (P<=0.05). Despite the longer block formation, the ankle block is safer when compared to the spinal anesthesia, which involves risky hemodynamic changes in patients with associated diseases. PMID- 26770581 TI - Seroprevalence of hepatitis a and associated factors among 1-15 year old children in Eastern Turkey. AB - BACKGROUND: Hepatitis A is a common infectious disease during childhood worldwide. Recently, great deal of changes in the epidemiology has been reported. The seroepidemiologic studies of this infection are not sufficient in Eastern region of Turkey. OBJECTIVE: To investigate the seroprevalence and association with socio-demographic variables of hepatitis A in 1-15 year old children in Van. PATIENTS AND METHODS: This study was performed on 510 one to fifteen year old children from outpatient pediatric clinics in Yuzuncu Yil University, Faculty of Medicine during last three months of 2009. Anti-HAV IgG was measured in sera by enzyme-linked immunosorbent assay. The information about subjects was recorded on standardized forms and a chart review survey was performed. RESULTS: The overall ratio for seropositivity was 54.9%. Statistical significance was found between hepatitis A seroprevalence and age, collective use of domestic items, fresh water resources, localization and type of toilet and the number of households. CONCLUSION: This study provided the most recent data of seropositivity and revealed the preliminary indication of epidemiological shift in seroprevalence of Hepatitis A virus in a region with high endemicity. PMID- 26770582 TI - Prevalence of ESBLs-producing Pseudomonas aeruginosa isolates from different wards in a Chinese teaching hospital. AB - This study was to explore the molecular dissemination of P. aeruginosa producing extended spectrum beta-lactamase (ESBLs) recovered from the different wards in a teaching hospital, Jilin. Among 240 isolates, 91 strains were isolated from burn wards and 149 strains from surgical wards. A total of 210 strains (87.5%) produced ESBLs, 30 strains (12.5%) didn't produce ESBLs. All ESBLs isolates showed identical antimicrobial susceptibility profiles. The genotypic prevalence of ESBLs for bla SHV-12, bla TEM-24, bla CTX-M-1, bla CTX-M-2, bla CTX-M-3, bla PER and bla VEB genes was 17.6%, 20.5%, 14.3%, 9.6%, 12.9%, 13.8% and 11.4% respectively. All P. aeruginosa strains producing ESBLs had three to six plasmids and contained class 1 integrons, which transferred resistance to E. coli C 600 by conjuation. The data indicated a high prevalence of ESBL among P. aeruginosa isolates in this region and their enzyme types were diverse. PMID- 26770583 TI - Survey and coping strategies for job stress of new nurses in pharmacy intravenous admixture service: a pilot study. AB - To survey the nurse stress and analyze stressors in new nurses from pharmacy intravenous admixture service (PIAS). A questionnaire survey referring to the revised stressor scale was carried out on 52 new nurses of PIAS in four hospitals in Harbin. The average stress score for all participants was 2.43+/-0.63, as medium level of stress. The stressors were classified into 6 categories: ensuring up-to-date knowledge of professional nursing skills, increased workload and work time, interpersonal relationship, ensuring knowledge of equipments, attending educational programs, and decreased occupational demand. The most important stressors included fear of medical accident occurrence, fear of failure in performance assessment, fear of occupational injuries, feeling fatigue and lack of sleep. Considering the various kinds of stressors in the working places, it was necessary for managers' to use appropriate strategies to cope with the job stress in new nurses of PIAS. PMID- 26770584 TI - Awakening from anesthesia using propofol or sevoflurane with epidural block in radical surgery for senile gastric cancer. AB - OBJECTIVE: To study the awakening of the elderly patients from propofol intravenous general anesthesia or sevoflurane inhalation general anesthesia combined with epidural block after radical gastric cancer surgery. METHOD: Eighty cases receiving selective radical surgery for gastric cancer were included. They were aged 65-78 years and classified as ASA grade I-II. Using a random number table, the cases were divided into 4 groups (n = 20): propofol intravenous general anesthesia (P group), sevoflurane inhalation general anesthesia (S group), propofol intravenous general anesthesia combined with epidural block (PE group), and sevoflurane inhalation general anesthesia combined with epidural block (SE group). For P and PE group, target controlled infusion of propofol was performed; for S and SE group, sevoflurane was inhaled to induce and maintain general anesthesia; for PE and SE group, before general anesthesia induction, epidural puncture and catheterization at T7-8 was performed. After surgery, perform patient controlled intravenous analgesia (PCIA) or patient controlled epidural analgesia (PCEA), and maintain VAS <= 3. The recorded indicators were as follows: time to recovery of spontaneous respiration, time to awakening, time of endotracheal tube removal, time to orientation, time to achieve modified Aldrete scores >= 9, modified OAA/S and Aldrete scores upon endotracheal tube removal (T1), 5 min after removal (T2), 15 min after removal (T3) and 30 min after removal (T4), dose of intraoperative remifentanil, intraoperative hypotension, and emergence agitation. RESULTS: Time to awakening, time of endotracheal tube removal, time to orientation, and time to achieve modified Aldrete scores >= 9 in PE and SE group were obviously shortened compared with P and S group (P < 0.05); modified OAA/S and Aldrete scores at T1 and T2 in PE and SE group were significantly higher than those in P and S group (P < 0.05), and the scores of SE group at T1 were much higher compared to PE group (P < 0.05). Dose of intraoperative remifentanil in PE and SE group was significantly lower than that in P and S group. CONCLUSION: Compared to propofol intravenous general anesthesia or sevoflurane inhalation general anesthesia, propofol or sevoflurane general anesthesia combined with epidural block was more conducive to increasing the awakening quality of the senile patients from anesthesia after radical gastric cancer surgery. Moreover, sevofluorane inhalation general anesthesia combined with epidural block achieved a more stable hemodynamics and a shortened time to awakening. PMID- 26770585 TI - Application of two micron laser vaporesection combined with transurethral resection of the prostate in treatment of benign prostatic hyperplasia: analysis of 340 cases. AB - PURPOSE: To evaluate clinical efficacy and safety of two micron laser vaporesection combined with transurethral resection of the prostate (TURP) in treating benign prostatic hyperplasia (BPH). METHODS: In total, 340 BPH patients aged 62-86 years, were treated with two micron laser vaporesection plus TURP. Mean prostatic volume was measured as 38-182 ml. Operative time, intraoperative hemorrhage volume, time of postoperative bladder irrigation, time of indwelling urinary catheter and surgical complications were examined. International Prostate Symptom Score (IPSS), quality of life score (QOL), maximal urinary flow rate (Qmax) and post void residual urine volume (PVR) were analyzed. RESULTS: All cases underwent the surgery successfully. No transurethral resection syndrome was noted. Mean operative time was (72+/-15) min. Mean intra operative hemorrhage volume was (48.4+/-13.0) ml. Four patients were transfused with 2 U of suspended red blood cells. Time of postoperative bladder irrigation ranged from 0.5-2.5 d. Time of indwelling urinary catheter was 3-6 d. After removing urinary catheter, mild urinary irritation symptoms were noted in 19 cases. Ten patients developing urinary infection were recovered following anti-infection therapy. One with secondary urethral stenosis was healed after urethral dilatation for three times. Postoperative IPSS, QOL, Qmax and PVR were (6.0+/-2.0), (2.0+/-0.2), (18.5+/-1.6) ml/s and (11.0+/-4.0) ml, significantly improved compared with preoperative levels (all P<0.05). Fifty eight cases with normal sexual function retained sexual function postoperatively and had no retrograde ejaculation. CONCLUSIONS: Two micron laser vaporesection plus TURP is efficacious and safe in treating BPH with mild lower urinary tract symptoms and perioperative complications. PMID- 26770586 TI - Determination of the normative values of the masseter muscle by single-fiber electromyography in myasthenia gravis patients. AB - The purpose of this study is to obtain normative values of the masseter muscle of myasthenia gravis (MG) patients and healthy volunteers by single-fiber electromyography (SFEMG). Stimulation of SFEMG in the masseter muscle was studied in 15 healthy volunteers (men 8, women 7; mean age 40.2, range 21-77) and 30 patients affected by MG (men 16, women 14; mean age 42.8, range 12-75). The mean consecutive difference (MCD) of the individual fiber and the mean MCD per study were determined in the normal group. We recommend the upper normal limit for the individual fibers of jitter and the mean MCD per study in the healthy Chinese adults of 33 us and 22 us respectively. Furthermore, in the MG group, the percentage of jitter > upper normal limit jitter and the impulse blocking percentage were detected, which were all significantly different compared to the normal control group (P < 0.01). The overall sensitivity was 90%, with the abnormality in 6 of the 9 ocular MG patients and 100% abnormality in the generalized MG patients. The masseter muscle SFEMG has a high degree of sensitivity. The masseter should be considered for SFEMG in the diagnosis of MG, and added routinely to the tested muscles. PMID- 26770587 TI - Study on the efficacies of splenic pedicle transection by using manual manipulation and Endo-GIA procedure for laparoscopic splenectomy. AB - Laparoscopy splenectomy (LS) was adopted in surgery from 1980s, it has become the main way of exploring for treating spleen diseases. Compared with conventional open surgery, LS has been gradually accepted by physicians and patients due to its advantages, including minimal surgical injury, less intraoperative blood loss, quick postoperative recovery, shorter hospital period, better cosmetic result, less risk of postoperative infections and improved postoperative quality of life Here, we try to investigate the splenic pedicle transection by using Endo GIA (a linear stapling device) procedure and manual manipulation of secondary splenic pedicle for LS. A retrospective study was conducted on 60 patients who underwent LS. And patients were divided into two groups. 30 patients (group A) received splenic pedicle transection with Endo-GIA procedure and in the other 30 patients (group B) underwent secondary splenic pedicle transection for LS. Perioperative outcome measures of each group were recorded, including operation duration, intraoperative blood loss, postoperative flatus pass time, postoperative complications, drainage duration, hospital cost and length of hospital stay. Surgeries were successfully achieved in 60 patients. The operative duration of group A was significantly shorter than that of group B. However, group B was significantly superior over Endo-GIA group in terms of the intraoperative blood loss, postoperative flatus pass time, drainage duration, length of hospital stay and total cost of hospital stays. No significant differences were observed in postoperative fever, ascites and hyperamylasemia between two groups. Both of these two approaches for LS are safe and feasible. However, compared with Endo-GIA procedure, manual manipulation of secondary splenic pedicle for LS may leading to less intraoperative blood loss, results in less hospital expense, and hence can be widely adopted in clinical practice. PMID- 26770588 TI - The use of vancomycin in the treatment of adult patients with methicillin resistant Staphylococcus aureus (MRSA) infection: a survey in a tertiary hospital in China. AB - BACKGROUND: Vancomycin is frequently used in the treatment of methicillin resistant Staphylococcus aureus (MRSA). OBJECTIVES: To determine MRSA infection status and the use of vancomycin in its treatment at a teaching hospital in China. METHODS: We retrospectively reviewed 140 cases of MRSA infection that were treated from January 2013 to October 2014. We analyzed the etiology of MRSA infection and the use of vancomycin in these cases. RESULTS: MRSA infection mainly occurred in elderly patients concomitant with a variety of diseases, which incidence was more in men than women. More cases of MRSA infection were encountered in the ICU than in other departments. The positive culture results for MRSA were obtained in the sputum (38.57%), pharyngeal swab (19.29%), blood (5.71%), and wound secretion (11.43%) samples. The MRSA patients were sensitive to vancomycin, with the minimum inhibitory concentration (MIC) being 1 MUg/mL in 53.80% of the cases and 2 MUg/mL in 44.10% of the cases, respectively. Among the 35 (25%) cases treated with vancomycin, 23 were cured, while 3 died and 7 (20%) were considered as an unreasonable application. CONCLUSIONS: MRSA infection mainly appeared in patients admitted to the ICU. The MIC of vancomycin had a tendency to increase gradually. PMID- 26770589 TI - Risk factors of fatigue status among Chinese adolescents. AB - In recent years, fatigue is common among adolescents. The aim of this study is to evaluate fatigue status and find related factors of fatigue among students ranged from 13-26 years from Wuhu, China. This is a case-control, cross-sectional observational study. The students from six middle schools (high school? 26 years old?) in Wuhu city were recruited, Self-Rating Fatigue Scale (SFS) was used to measure the fatigue status among students ranged from 13-26 years, and some demographic characteristics of students also was determined. A total of 726 students are included in our study. A significant difference was observed between fatigue status and grade, a balanced diet, the partial eclipse, picky for food, lack of sleep, excessive fatigue, drinking (P < 0.05). The risk factors of fatigue status include myopia, partial eclipse, picky for food, lacking of sleep, drinking; grade while a balanced diet is the protective factor of fatigue. Therefore, the school should pay more attention to the fatigue among students in middle school in China, and take some properly measures to reduce the fatigue. PMID- 26770590 TI - The effect of GSTT1, GSTM1 and GSTP1 gene polymorphisms on the susceptibility of age-related cataract in Chinese Han population. AB - OBJECTIVE: Age-related cataract (ARC) is one of the most common eye diseases in the elderly worldwide, especially in China. The genetic polymorphisms of many glutathione S-transferases coding genes are likely to be closely related to the development of ARC, especially the GSTT1, the GSTM1 and the GSTP1. This investigation is aimed to determine the possible associations of GSTT1, GSTM1 and GSTP1 polymorphisms with the susceptibility of ARC in Chinese Han Population. METHODS: A case-control study including ARC cases (n = 312) and controls (n = 256) in Chinese Han Population was performed. GSTT1 and GSTM1 polymorphisms were detected by duplex polymerase chain reaction (PCR), and two SNPs (rs1695, A/G and rs1138272, C/T) in GSTP1 gene were genotyped by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) method, all the results were verified by sequencing method. RESULTS: The GSTT1 null genotype carriers had a much higher risk of ARC compared with non-null genotype (chi(2) = 14.091, P<0.001), and the allele G carriers also had a increased risk over the allele A carriers in the SNP (rs1695, A/G) in GSTP1 gene (chi(2) = 7.696, P = 0.006), while the GSTM1 polymorphism and the SNP (rs1138272, C/T) in GSTP1 gene seem had no association with the susceptibility of ARC in Chinese Han Population. CONCLUSIONS: These preliminary results indicated carriage of null GSTT1 and GSTP1 Val/Val genotypes may contribute to genetic susceptibility to ARC in Chinese Han Population, and these genetic polymorphisms might be used as molecular markers for detecting ARC susceptibility. PMID- 26770591 TI - Comparison of the effects of formaldehyde and gaseous ozone on HBV-contaminated hospital quilts. AB - BACKGROUND: Besides being highly infectious, Hepatitis B virus (HBV) is a major cause of liver disease worldwide. In hospital settings, it is easy for the environment and quilts to be contaminated by HBV patient blood and body fluids. Therefore, HBV can be transmitted to other patients via contaminated environmental surfaces or quilts, resulting in an HBV nosocomial infection. Formaldehyde and ozone are commonly used disinfectants that may influence this infectious situation. OBJECTIVE: To investigate the clinical effectiveness of formaldehyde and gaseous ozone for the terminal cleaning of hospital quilts contaminated by HBV. METHODS: Thin cloth and thick cotton soaked with the serum from high HBV copy number patients were prepared and disinfected using formaldehyde fumigation and gaseous ozone at different times. The copy numbers of HBV DNA in the HBV-contaminated cloth and cotton samples were measured quantitatively with fluorescent quantitative polymerase chain reaction (PCR). RESULTS: When gaseous ozone was used to disinfect HBV-contaminated quilts for 23 minutes (min), 36 min, 49 min, and 90 min, the HBV DNA copy number displayed no significant decrease compared with the copy number before disinfection (P > 0.05). In comparison, the copy number of the HBV DNA in the cloth group decreased significantly (P < 0.05) after formaldehyde fumigation disinfection for 1 hour (h), and there was no difference when longer times and increased concentrations were used. In the thick cotton group, there was also a significant decrease (P < 0.05) of the HBV DNA copy numbers, but the decrease was not as dramatic. In addition, in this group, the disinfection effect observed at 4 h was the strongest. CONCLUSIONS: The application of ozone to disinfect HBV-contaminated hospital quilts possibly has no effect, whereas, formaldehyde oxide fumigation effectively reduced HBV copy numbers. PMID- 26770592 TI - IL-21 polymorphisms rs907715 and rs2221903 are associated with decreased non small cell lung cancer susceptibility. AB - The etiology of lung cancer is still incompletely understood. Previous studies have suggested the association between IL-21 polymorphisms and autoimmune diseases, however, little is known about its role in lung cancer susceptibility. Here, we investigated the role of two SNPs of IL-21 gene in a cohort of non-small cell lung cancer (NSCLC) patients. A total of 128 NSCLC patients and 156 healthy controls were genotyped. Multivariate logistic regression was used to analyze the association between IL-21 polymorphisms and NSCLC risk. Our data showed that both rs907715 and rs2221903 were significantly associated with lung cancer susceptibility, and patients carrying rs907715A (P = 0.007, adjusted OR = 0.60, 95% CI = 0.42-0.87) or rs2221903G (P = 0.020, adjusted OR = 0.52, 95% CI = 0.30 0.90) allele had a decreased risk of NSCLC. Further study identified that the association between IL-21 polymorphisms and NSCLC risk was limited to lung adenocarcinoma. Haplotype analysis revealed that the AG (P = 0.006, OR = 0.072 95% CI = 0.011-0.451) and AA (P = 0.022, OR = 0.657, 95% CI = 0.458-0.941) haplotypes of rs907715/rs2221903 were associated with a decreased risk of NSCLC, whereas the GA (P = 0.0001, OR = 1.932, 95% CI = 1.378-2.710) haplotype was associated with an increased risk. In conclusion, our study demonstrates the association between IL-21 polymorphisms (rs907715 and rs2221903) and NSCLC risk in a Chinese Han population, indicating their potential role in lung cancer detection and treatment. PMID- 26770593 TI - Identification of plasma vascular endothelia-cadherin as a biomarker for coronary artery disease in Type 2 diabetes mellitus patients. AB - OBJECTS: To examine how vascular endothelia (VE)-cadherin plasma levels are correlated with parameters associated with endothelial function such as endothelin-1, nitric oxide, nitric oxide synthase and HbA1c in type 2 diabetic patients with coronary artery disease. METHODS: VE-cadherin levels were analyzed by enzyme-linked immunosorbent assays. Spearman's correlation and multiple stepwise regression analyses were used to examine the relationship between plasma VE-cadherin and other factors. RESULTS: By univariate correlation analysis, plasma VE-cadherin levels were significantly associated with age, total cholesterol, triglyceride, hemoglobin A1c, and endothelin-1. Multiple regression analysis (adjusted for age, total cholesterol, and triglyceride) showed that plasma VE-cadherin levels were independently and significantly associated with HbA1c and ET-1. Plasma VE-cadherin levels were significantly highest in patients with diabetes mellitus and coronary artery disease. While patients with diabetes mellitus had higher levels of VE-cadherin compared with healthy subjects. CONCLUSIONS: This study found that VE-cadherin levels might be a biomarker for some endothelial dysfunction associated with coronary artery disease in type 2 diabetes mellitus. PMID- 26770594 TI - Serum somatostatin and neuron-specific enolase might be biochemical markers of vascular dementia in the early stage. AB - OBJECTIVES: To estimate whether serum somatostatin (SS) and neuron-specific enolase (NSE), the representative neuropeptide relative to learning and memory, to be biochemical markers of the vascular dementia (VaD) in the early stage. METHODS: 42 patients with VaD were randomized in the VaD group and 38 stroke patients without dementia was in the control group. Radioimmunoassay was used to detect SS in the serum and CSF, and Enzyme linked immunosorbent assay to detect NSE in the serum and CSF. SS and NSE in CSF were compared 3 days after stroke. SS and NSE contends in serum were compared 3 days, 3 months and 6 months poststroke. RESULTS: CSF and serum SS contents in VaD group were lower than that in the control group (P<0.05). SS in the frontal cortex, hippocampus and the temporal lobe, thalamus were lower than that in the occipital lobe (P<0.05); Serum NSE contents in VaD group were significantly higher than that of control group 3 days after stroke, 3 months and 6 months (P<0.01, respectively), and has a tendency to increase (P<0.05); SS contents significantly lower than that in the control group with the trend to decrease (P<0.05). CONCLUSIONS: NSE increased and SS decreased with the lower content in the frontal cortex, hippocampus and the temporal lobe which has close relationship with learning and memory, thus Serum NSE and SS might be the biochemical markers of VaD in the early stage. PMID- 26770595 TI - Assessment of second-line treatments for patients with uncontrolled moderate asthma. AB - AIM: To evaluate the best second-line treatments for patients with uncontrolled moderate asthma. METHODS: A single-center, random study was conducted in adult patients with uncontrolled moderate asthma to evaluate the effects of add-on treatments. After add-on treatments for 4 and 12 weeks, the concentration of exhaled nitric oxide (FeNO), average daily durnal peak expiratory flow (PEF) variability and asthma control test (ACT) score were measured. RESULTS: 94 patients have been divided into three groups to take different add-on treatments, in tiotropium bromide group, montelukast sodium group and double-dose inhaled corticosteroid (ICS) group. After four weeks, most patients improved their symptoms and ACT scores, with lower concentration of FeNO and small PEF variability. In double-dose ICS group, almost all patients took the complete controls of asthma, compared to those in other two groups. After additional 12 weeks' therapy, patients in all three groups nearly achieved complete controls of asthma. There were two patients with pneumonia in double-dose ICS group. Patients in double-dose ICS group had higher ACT scores, lower concentrations of FeNO and smaller PEF variabilities, but a higher risk of pneumonia, compared to those in other two groups. The differences of PEF variabilities and ACT scores between tiotropium group and double-dose ICS group were not significant. CONCLUSION: Tiotropium in combination with ICS plus LABA showed the similar effects with double-dose ICS plus LABA, without adverse effects, which might be the best option for optimal control of asthma. PMID- 26770596 TI - The change in cerebral glucose metabolism after electroacupuncture: a possible marker to predict the therapeutic effect of deep brain stimulation for refractory anorexia nervosa. AB - Some reports have demonstrated that deep brain stimulation (DBS) is a promising treatment for patients who suffer from intractable anorexia nervosa. However, the nature of DBS may not be viewed as a standard clinical treatment option for anorexia nervosa because of the unpredictable outcome before DBS. Just like DBS in the brain, electroacupuncture at acupoints is also efficient in treating refractory anorexia nervosa. Some neuroimaging studies using functional magnetic resonance imaging, single-photon emission computed tomography (SPECT), and positron emission tomography (PET) had revealed that both DBS and electroacupuncture at acupoints with electrical stimulation are related to the changes in cerebral glucose metabolism. Therefore, we hypothesize that the changes in cerebral glucose metabolism after electroacupuncture might be useful to predict the therapeutic effect of deep brain stimulation for refractory anorexia nervosa. PMID- 26770597 TI - Status of trace elements and antioxidants in premenopausal and postmenopausal phase of life: a comparative study. AB - The aim of the study was to determine the extent of free radical damage in the form of oxidative stress, the antioxidant status and correlate with trace element levels in postmenopausal females as compared to premenopausal females. Participants between the ages of 30-60 years were recruited for the study and status of antioxidant enzymes and trace metals level was determined. The serum Calcium (Ca) levels after menopause was higher than that of the premenopausal group (P<0.001). The changes in copper (Cu) and Zinc (Zn) between the groups were not significant (p>0.05). In postmenopausal women, antioxidant enzymes like superoxide dismutase (SOD) and glutathione peroxidase (GPX), catalase (CAT) significantly decreased (P<0.001) in postmenopausal women showing oxidative stress in the cells. Concentrations of vitamin-C pointed out a significant decrease (P<0.05) in postmenopausal women when compared with premenopausal women. PMID- 26770598 TI - Expression of eosinophils be beneficial to early clinical diagnosis of brucellosis. AB - OBJECTIVE: Investigate the expression and significance of eosinophils in brucellosis. METHODS: Retrospective analysis of clinical data for 151 brucellosis patients (BR group), complete blood count and blood bacterial culture etc.; in addition, 150 general bacterial infection patients (BI group) and 135 persons in healthy physical condition upon testing (NC group) are selected respectively as the control groups to comparatively study expression of white blood cells and eosinophils for brucellosis patients. Adopt t test to compare measurement data. RESULTS: In comparison with BI group, WBC, NE, EO, MO, NE% and EO% in BR group are reduced but LY, LY% and MO% are increased and such difference shows statistical significance (P<0.01). In comparison with NC group, difference of WBC and NE in BR group shows no statistical significance (P>0.05). NE%, EO and EO% are reduced but MO, LY% and MO% are increased and such difference shows statistical significance (P<0.01). LY is increased and the difference shows statistical significance (P<0.05). White blood cell count is normal or is reduced among most of Brucellosis patients, accounting for 90.73% (137/151); the patients whose eosinophils are reduced account for 75.50% (114/151) and those whose eosinophils disappear are about 18.54% (28/151). CONCLUSION: There is an incidence rate of eosinophils decrease or disappearance in Brucellosis and it shows the indication significance in the diagnosis of early disease. PMID- 26770599 TI - A survey and analysis of using traditional Chinese medicine during pregnancy. AB - BACKGROUND: The usage of Traditional Chinese Medicine (TCM) during pregnancy is very common for Chinese people. However, there are only a few studies relevant to the usage of TCM during pregnancy-providing very little knowledge on the benefits or harmful effects of these medicines to pregnant women or the fetus. OBJECTIVES: The purpose of this study is to survey the current situation of TCM usage during pregnancy, and to explore the factors that affect the use of TCM. METHODS: Data was collected from pregnant patients who delivered in our hospital, from March 2012 to August 2012. All patients who agreed to join this study were asked to fill-up a questionnaire. RESULTS: 1,010 patients were willing to participate in this study. 11.2% (113, 1,010) of patients used at least one kind of TCM during pregnancy. The average TCM usage is 2.1 species. The most commonly used drugs are Antai pill (39 cases, 34.5%), Xiaochaihu granules (31 cases, 27.4%), and Shengxuening tablets (23 cases, 20.4%). Patients who smoke during pregnancy (OR=1.8, 95% CI: 0.7~5.1), drink during pregnancy (OR=1.6, 95% CI: 0.4~6.1), have been hospitalized during pregnancy (OR=4.8, 95% CI: 2.9~7.9), have pregnancy complications (OR=2.7, 95% CI: 1.5~4.9) and those who are infertile (OR=2.6, 95% CI: 1.4~4.8) have higher chances of using TCM during pregnancy. CONCLUSIONS: Pregnant women commonly use TCM during pregnancy. Pregnant women who smoke, drink, hospitalized during pregnancy, experience pregnancy complications and infertility are more likely to use TCM. PMID- 26770600 TI - Magnetic resonance imaging for detection of depth of myometrial invasion and cervical invasion in patients with endometrial carcinoma. AB - AIMS: The aim of this study was to evaluate clinical significance of depth of myometrial invasion and cervical invasion by magnetic resonance imaging (MRI) in patients with endometrial carcinoma. METHODS: Between September 2011 and October 2014 on 98 patients who were diagnosed with and treated for endometrial carcinoma at Subei People's Hospital in China included in this study. Main outcome measure was the correlation between the depth of myometrial invasion and cervical invasion by preoperative MRI, transvaginal sonography, hysteroscopy with directed biopsy study and the subsequent histopathological findings following examination of the hysterectomy specimen. RESULTS: The mean age was 54.6 years old and the most common histological subtype was the endometrioid type of endometrial adenocarcinoma (87.8%). In the evaluation of deep myometrial invasion (>50%), sensitivity, specificity, positive and negative predictive value and positive and negative likelihood ratios of MRI were 70.00%, 94.87%, 77.78%, 92.50%, 13.65, 0.316, respectively. For cervical invasion, these values were 72.73%, 98.85%, 88.89%, 96.63%, 63.27, 0.30, respectively. CONCLUSION: MRI is the superior diagnostic method to detect the myometrial invasion and cervical invasion. PMID- 26770601 TI - Twin pregnancy after intracytoplasmic sperm injection in woman aged 49 using autologous oocytes by mild ovarian stimulation: a case report. AB - There were few reports about infertile women aged 45 and above undergoing IVF/ICSI. We are reporting the case of an aged 49 woman who delivered the twins after ICSI using autologous oocytes by mild ovarian stimulation. The patient presented with 26-year primary infertility caused by double fallopian tubes obstruction and man oligoasthenozoospermia. We gave her the treatment with mild ovarian stimulation cycle of clomiphene citrate (CC) and follicle stimulating hormone (FSH) undergoing ICSI, and transferred two fertilization-blastocysts. The outcome measured was the live birth. The twins were delivered by cesarean section operation at 37 pregnancy weeks for the moderate pregnancy-induced hypertension. In summary, we found it is feasible for women with advanced age to undergo ART while the accompanied risk of pregnancy complications and other issues need to be further evaluated. PMID- 26770602 TI - Pediatric anaplastic large cell lymphoma misdiagnosed as multiple organ abscesses: a case report and literature review. AB - We report the case of a 6-year-old male with fever, left maxillofacial swelling, cervical and mediastinal masses, and lymphadenopathy who developed respiratory failure and shock caused by tracheal compression and superior vena cava reflux disorder. The initial diagnosis was maxillary sinus, cervical, and mediastinal abscesses. Initial treatments included maxillary sinus abscess resection, neck abscess incision drainage, and antibiotics. Anaplastic large cell lymphoma (ALCL) was diagnosed ultimately according to pathological and immunohistochemical examination of cervical lesion biopsy tissue. We analyze the reasons for misdiagnosis by comparing clinical and pathological features of ALCL to other systemic illnesses that cause lymphadenopathy. PMID- 26770603 TI - A rare thymoma case with seven paraneoplastic syndromes. AB - Thymoma is a kind of epithelial tumor of the thymus which about 30-50% patients accompanied by paraneoplastic disorders. However, the coexistence of seven symptoms in an individual is rare. This report represented a patient, diagnosed of thymoma, with myasthenia gravis, erythema multiforme, plasma cell cheilitis, recurrent oral ulcer, vitiligo, Raynaud's phenomenon and fissured tongue. Detailed clinical manifestations, serum immune biomarkers, imaging study, electrophysiology examination and pathology results are described in this case. PMID- 26770604 TI - Value of (18)F-FDG-PET/CT in ocular sebaceous adenocarcinoma: a case report and literature review. AB - Ocular sebaceous adenocarcinoma is a rare malignant tumor. We report an unusual case of orbital sebaceous adenocarcinoma in a 48-year-old woman. The patient underwent F-18 2-fluoro-2-deoxy-glucose positron emission tomography/computed tomography ((18)F-FDG-PET/CT) to determine the initial clinical stage. (18)F-FDG PET/CT showed strong uptake in the orbital lesion, but neither regional lymphatic nor distant metastases were seen. (18)F-FDG-PET/CT plays a role in the diagnosis, staging, restaging, and follow-up of ocular sebaceous carcinoma, although its application has some limitations in other primary and ocular malignancies due to the rarity of ocular sebaceous carcinoma. PMID- 26770605 TI - Anesthetic management of a patient with giant retroperitoneal liposarcoma: case report with literature review. AB - Patients with giant retroperitoneal liposarcomas are considered at great risks of perioperative complications and require meticulous anaesthetic management. There have been few reports about anaesthetic management of giant retroperitoneal liposarcoma. We present the case of a 66-year-old patient who suffered from a giant retroperitoneal liposarcoma (diameter 45 cm and weigh 4.5 kg), needing a resection surgery under general anesthesia. We successfully managed anesthesia procedures in this patient using FloTrac/Vigileo(TM) monitoring system without major perioperative complications. The surgery was completed uneventfully and the patient recovered smoothly. After reviewing the literature, we summarize FloTrac/Vigileo(TM) monitoring system is useful to help anaesthesiologists adjust infusion rate to maintain the stability of circulatory state. Anesthetic monitoring, fluid management and temperature control need to be focused in the anesthetic management. PMID- 26770606 TI - Decompression of the inferior alveolar nerve to treat the pain of the mandible caused by fibrous dysplasia-case report. AB - Fibrous dysplasia is a kind of benign bone lesion characterized by the manifestation of the replacement of the normal substance of bone by fibro-osseous connective tissue. A patient diagnosed fibrous dysplasia had unbearable pain in the left mandibular region only. To treat the patient, an navigation template was designed to guide the decompression of inferior alveolar nerve, and piezosurgery was performed to do the osteotomy. After the surgery, the pain disappeared. The sensation of the lower lip recovered. PMID- 26770607 TI - Challenge in preoperative diagnosis of retroperitoneal mucinous cyst in a pediatric patient. AB - Mucinous cystic lesions of the retroperitoneum can be either neoplastic or non neoplastic. It is very important to make a correct diagnosis, or at least, an accurate classification, to proceed with an optimal treatment strategy. In spite of advantage of ultrasound and X-ray image examinations, it is still a challenge to make differential diagnosis of retroperitoneal mucinous cyst from gangliocytoma because both tumors have similar density under the image assessment. In this article, we reported an asymptomatic 8-year-old boy with multiple bronchogenic cysts in both lung and adrenal area on the left side, the latter was considered to be a gangliocytoma preoperatively by ultrasound and computed tomography, but confirmed as bronchogenic cyst by histopathology post laparoscopic resection. The differential diagnosis, imaging features and treatment of bronchogenic cyst are discussed and the relative literatures are reviewed. PMID- 26770608 TI - IgG4-related tubulointerstitial nephritis associated with only lymphadenopathy and without elevated serum IgG4 or renal imaging abnormalities: a case report and literature review. AB - IgG4-related tubulointerstitial nephritis (IgG4-TIN) is the most common renal manifestation of IgG4-related kidney disease (IgG4-RKD) and may cause acute or chronic renal dysfunction. Imaging often shows heterogeneous densities in the kidneys, such as a mass or multiple nodules. Serology usually demonstrates high levels of serum IgG4 and total IgG. Most patients have other organs involvement by IgG4 related disease. Although lymphadenopathy is frequently observed in patients with IgG4-TIN, it is rarely presented as the only extrarenal lesion. Herein, we present a rare case of IgG4-TIN associated with only lymphadenopathy and without elevated serum IgG4 or renal imaging abnormalities. A 61-year-old Chinese man was admitted to our hospital with seven months history of generalized lymphadenopathy and five months history of renal dysfunction. His renal imaging was normal. He had no current or previous clinical, radiographic, and/or histologic evidence of other organ involvement except for the lymphadenopathy. Renal biopsy indicated plasma cell-rich TIN with an increased number of IgG4 positive plasma cells and storiform fibrosis. Repeated lymph nodes biopsy revealed IgG4-related lymphadenopathy. However, he did not have elevated serum IgG4 or total IgG levels. Oral prednisone therapy improved his renal function and lymphadenopathy. These findings supported our final diagnosis of IgG4-TIN. Clinicians should be aware of this condition and steroid therapy should be considered for such patients. An early diagnosis and appropriate therapy can induce remission and preserve renal function. PMID- 26770609 TI - Alveolar proteinosis in extremis: a critical case treated with whole lung lavage without extracorporeal membrane oxygenation. AB - Pulmonary alveolar proteinosis is a rare idiopathic lung disease characterized by the accumulation of lipoproteinaceous material within the alveoli, which impairs gas transfer and decreases the ventilation/perfusion ratio, and can lead to respiratory failure. Whole lung lavage is the most effective therapy for pulmonary alveolar proteinosis, but may not be tolerated by patients with severe respiratory failure. Extracorporeal membrane oxygenation support is advocated for such patients to ensure appropriate oxygenation during lung lavage. We report a case of a 39-year-old patient with pulmonary alveolar proteinosis and severe life threatening respiratory failure, with an oxygen index of 51 when under mechanical ventilation. The patient was successfully treated with bilateral whole lung lavage without extracorporeal oxygenation. The results suggest that there is improved ventilation and perfusion matching when one lung is ventilated while the other is lavaged, may be the mechanism of which severe respiratory failure patient due to pulmonary alveolar proteinosis can complete whole lung lavage under one lung ventilation. PMID- 26770610 TI - Small magnet aspiration as a pediatric emergency: a case report. AB - Tracheobronchial airway foreign body aspiration (FBA) in children is a common and serious pediatric medical emergency. With the increasing use of small magnets in home offices, in toys and the kitchen, inhalation of small magnets has become an increasing risk to children. We present a case of a 9-year-old boy who presented with cough and dyspnea three days following inhalation of an 3 cm-sized oval magnet. The history and the chest radiograph were important in planning for the removal of the aspirated foreign body. In this case, we removed the inhaled magnet using rigid bronchoscopy under general anesthetic. We herein reviewed the recent reports on the incidence and management of small foreign body aspiration as a pediatric emergency. PMID- 26770611 TI - A case of mediastinum undifferentiated high grade pleomorphic sarcoma. AB - Primary anterior mediastinum undifferentiated high grade pleomorphic sarcoma is rare that most physician including thoracic surgeon would not experience this disease. Huge anterior mediastinum tumor pressed the heart and it invaded into the left pulmonary arterial trunk. We did the mediastinum tumor resection, left pneumonectomy and left phrenic, sympathetic and vagus nerve merger excision. But the recurrence lesions were detected in the right lung, the left thoracic cavity and thoracic vertebrae within one month after operation. We reported a case of aggressively progressed undifferentiated high grade pleomorphic sarcoma originated from the anterior mediastinum. PMID- 26770612 TI - Application of lariat lock catch knot suture in the achilles tendon rupture. AB - The aim of this study was to summarize the clinical experience of repairing the Achilles tendon rupture by lariat lock catch knot suture. Between January 2011 and February, 2014, 32 cases of the Achilles tendon rupture were treated by lariat lock catch knot suture. There were 26 males and 6 females, with the average age of 39 years (range 17-53 years), including 13 left knees and 19 right knees. 29 wounds healed by first intention, and 3 cases who were performed local flap transfer due to necrosis of skin were healed by second intention. Thirty-two cases were followed up 10-25 months (13 months on average). No re-rupture of Achilles tendon or deep infection occurred during follow-up period. According to Arner-Lindholm assessment standard, the results were excellent in 19 cases and good in 13 cases, the excellent and good rate was 100%. Lariat lock catch knot suture is a safe and effective method for repairing Achilles tendon. PMID- 26770613 TI - Catheter ablation of ventricular tachycardia related to a septo-apical left ventricular aneurysm. AB - A 60-year-old male patient with previous myocardial infarction (30 years ago) presented to our cardiology department for sustained monomorphic ventricular tachycardia. The patient presented multiple episodes of tachycardia treated by his internal cardiac defibrillator. Radiofrequency ablation was proposed as curative treatment. The mechanism of the ventricular tachycardia was demonstrated by electrophysiological study using three-dimensional mapping system: Carto 3 (Biosense Webster). Ventricular tachycardia was induced either mechanically or by programmed ventricular stimulation. The tachycardia cycle length was 380 msec. The voltage map confirmed the presence of the septo-apical aneurysm with a local voltage < 0.5 mV. Activation mapping revealed a figure-in-8 circuit of VT with the entrance point inside the dense scar and the exit point at the border zone (between the aneurysm and the healthy tissue of the left ventricular septo-apical region). Radiofrequency energy was delivered at the isthmus of the tachycardia rendering it uniducible by programmed ventricular stimulation. PMID- 26770614 TI - Piriform sinus carcinoma with a paraneoplastic syndrome misdiagnosed as adult onset Still's disease: a case report. AB - Paraneoplastic syndromes (PS) occur less commonly in association with otolaryngologic neoplasms than other carcinomas such as those of lung or breast. Piriform sinus carcinoma with PS is extremely rare. We here report a case of piriform sinus carcinoma accompanied by PS that was initially misdiagnosed as adult onset Still's disease and describe our diagnosis and treatment. One lesson we have drawn from the experience of this misdiagnosis is that PS symptoms may manifest before the primary tumor is evident and complicate the diagnostic process. PMID- 26770615 TI - Intracranial granulocytic sarcoma: two cases and literature review. AB - Intracranial granulocytic sarcoma was a relatively rare tumor composed of myeloid blasts and/or immature myeloid cells in an extramedullary site which is associated with acute/chronic myeloid leukemia. In this paper, two cases of intracranial granulocytic sarcoma, one male aged 36 and one 28-year-old female, were reported to improve the diagnosis and treatment of such diseases. Diagnostic and treatment procedures for them were retrospectively summarized and relevant literature reviews were combined. Pathological biopsy was conducted to validate the diagnosis. Surgical resections in combination with chemotherapy were performed. The differential diagnosis of intracranial granulocytic sarcoma from malignant lymphomas and alternative small round cell malignancy was confirmed by biopsy and immunohistochemistry. PMID- 26770616 TI - Intraoral management of iatrogenically displaced lower third molar roots in the sublingual space: a report of 2 cases. AB - Surgical removal of the mandibular third molars is one of the most common procedures performed by dentists, as well as by oral and maxillofacial surgeons. Accidental displacement of teeth or roots into the fascial spaces, during surgical removal of the mandibular third molars, is a rare, but serious complication. Herein, we present 2 cases of iatrogenically displaced mandibular third molar roots into the sublingual space, which were successfully removed under local anesthesia intraorally. In addition to methods to minimize the risk of accidental tooth or root displacement, the importance of recognizing this complication and the methods of retrieval are also discussed. PMID- 26770617 TI - Favorable outcome of extended treatment with adding pegylated Interferonalpha-2a to entecavir for HBeAg-positive chronic hepatitis B: a case report. AB - Hepatitis B virus (HBV) surface antigen (HBsAg) to anti-HBsAg (anti-HBs) seroconversion is the best and final objective of all available chronic hepatitis B (CHB) therapies. Unfortunately, this goal is not commonly obtained with current therapeutic approaches. Here, we reported a case that a Chinese CHB patient successfully achieved HBsAg seroconversion under extended individualized therapeutic schedule. At 48 weeks after entecavir (ETV) monotherapy, pegylated interferon alpha-2a (PEG-IFN-alpha-2a) was added, and the titers of HBsAg decreased and HBsAg loss was achieved. After 96 weeks of combination therapy, PEG IFN-alpha-2a was stopped and ETV monotherapy was continued for additional 24 weeks. HBsAg seroconversion was sustained, 48 weeks after the end of all treatment. PMID- 26770618 TI - Idiopathic tension mediastinal emphysema cured by video-assisted thoracic surgery: a case report. AB - Mediastinal emphysema is a status of gas retention in mediastinum, usually caused by airway system injury or esophagus rupture. Healthy people without trauma and basic disease emerging unexplained mediastinal emphysema are called idiopathic mediastinal emphysema. While tension pneumomediastinum is an exceptional and potentially lethal condition, the increased intramediastinal pressure with a severe oppression of heart, vena cava and pulmonary vein leads to impaired central venous return through the cavae system, restricted right heart diastolic filling, and collapse of the cardiac chambers, resulting in reduced stroke volume, cardiac output and dysaemia. This young people-prone disease was initially reported by Hamman in 1939 and usually has a good prognosis so that no special treatments were needed. In this study, however, we presented a young boy with idiopathic tension mediastinal emphysema combined with dysaemia and respiratory failure. Fortunately, he was finally successful treated by VATS after heteropathy and incision on suprasternal fossae. PMID- 26770619 TI - Giant bullous emphysema in the right middle lobe. AB - Giant bullous emphysema, or vanishing lung syndrome, typically occurs in young, thin male smokers with large bullae in one or more upper lobes occupying at least one-third of the hemithorax. We present here a rare case of giant bullous emphysema in a mid-age nonsmoking female who was seen for progressive shortness of breath and cough. Chest computed tomography found a giant bulla in the middle lobe of right lung. The patient underwent successful thoracoscopic bullectomy and is currently without residual symptoms. PMID- 26770620 TI - Treatment of the coronoid process fractures with anteromedial approach: a case report. AB - This study aimed to explore the clinical effect of the coronoid process fractures with anteromedial approach. 18 cases of coronoid process fractures treated with the anteromedial approach were enrolled. Causes of injury included traffic injuries in 3 cases and fall on the ground in 15 cases. There were 6 cases of type I, 10 cases of type II, and 2 cases of type III according to the O'Driscoll classification. The time from injury to operation was 2-10 days (mean, 3.9 days). Fractures were fixed by using mini-plate or screws. All cases were followed-up for 12-24 months (average 14.9 months). The bony union time was 8-14 weeks with an average of 10.6 weeks. The mean flexion at last follow-up was 122 degrees (range, 90 degrees -140 degrees ), the mean extension loss was 20 degrees (range, 0 degrees -50 degrees ), and the mean pronation was 67 degrees (range, 22 degrees -90 degrees ), while the mean supination was 61 degrees (range, 30 degrees -88 degrees ). Elbows were stable in the flexion-extension and varus valgus in all cases. According to the MEPS elbow performance score, results were excellent in 14 cases, good in 3 cases and fair in 1 case. According to the Broberg and Morrey elbow performance score, results were excellent in 9 cases, good in 4 cases, and fair in 1 case. In conclusion, the anteromedial approach facilitates the reduction and fixation of the coronoid process fractures and has advantages of clear exposure, convenient placement of internal fixation, small invasion and good clinical results. PMID- 26770621 TI - Ovarian torsion caused by hyperreactio luteinalis in the third trimester of pregnancy: a case report. AB - In this case report, a rare case of an adnexal torsion caused by hyperreactio luteinalis (HL) in the third trimester is described, since adnexal torsions are mainly restricted to the first trimester of pregnancy. In an emergency Cesarean section, the patient gave birth to a healthy female baby weighing 3,300 g and we found an enlarged benign multiple luteinized follicular cyst mass in the right adnexum, which led to an adnexal torsion. After detorsion, both ovaries recovered to their normal sizes two months after the intervention. PMID- 26770622 TI - Diagnosis and treatment of Paget's disease of the breast: an analysis of 72 cases. AB - OBJECTIVE: Clinical features, prognostic factors and principle of surgical treatment for Paget's disease of the breast were analyzed, so as to optimize the treatment of Pagent's disease of the breast. METHOD: Seventy-two cases of Paget's disease of the breast treated at Affiliated Union Hospital and Hospital of Integrated Traditional Chinese and Western Medicine, Huazhong University of Science and Technology, from January 1991 to January 2010 were recruited. Their clinical data were analyzed retrospectively. RESULTS: Among 72 cases, 52 cases had nipple-areolar complex lesions, 43 had palpable masses and 18 had palpable, enlarged axillary lymph nodes; 45 cases received radical mastectomy or modified radical mastectomy. Intraoperative pathological examination was performed for 9 cases who were not discovered to have breast lumps or enlarged axillary lymph nodes preoperatively; and 4 of them were diagnosed as lower axillary lymph node metastasis or invasive ductal carcinoma, and modified radical mastectomy was adopted for these cases. Fifty-two cases received postoperative pathological examination to reveal that the average number of metastatic lymph nodes was 3.1. Among the cases presenting with lymph node metastases, those negative for ER/PR accounted for 78%; Her-2-positive cases accounted for 56%. Thirty-seven cases were followed up for an average of 29 months postoperatively, and 5 of them were found with local recurrence and 7 with distant metastases. CONCLUSION: Most cases of Paget's disease of the breast were associated with invasive ductal carcinoma and lymph node metastases. These cases had low ER/PR positive rate, high Her-2 positive rate and poor prognosis. PMID- 26770623 TI - Seven patients diagnosed as intracranial hemorrhage combined with intracranial tumor: case description and literature review. AB - In the present study, 7 patients with brain hemorrhage combined with intracranial tumor were investigated for about 3 years. Furthermore, the previous reports related with such cases were also reviewed. In all of these patients, hemorrhage was a main characteristic of the diagnosed neoplasm. The clinical data were identified by computed tomography (CT) scanning in the present study. CT scanning results demonstrated that there was a neoplastic core with high or low density and multifocal clots generally at the borders of the tumors. Increase of tumor tissues with intravenous injection of approximate 70% hypaque was analyzed in all the 7 patients with brain hemorrhage. The parts that were increased showed peripheral distributions corresponding to the hemorrhage sites. In conclusion, the intracranial brain hemorrhage related with the several types of tumors, including hemangiopericytoma, metastatic carcinomas, oligodendroglioma, and glioblastoma multiforme, which may be helpful to these patients. PMID- 26770624 TI - Improved vacuum sealing drainage in the treatment of gas gangrene: a case report. AB - In this case, improved vacuum sealing drainage was used for gas gangrene treatment, which is different from traditional therapies of gas gangrene and this is the first report of using improved vacuum sealing drainage to treat gas gangrene. The patient was a 12-year-old Asian Male who was presented to the Emergency Department with a one-day history of left femoral progressing swelling, paining and fevering. Four days ago, rusty iron bars were plugged into the muscle of the left femoral when he played. Then he was taken to the local clinic and injected with tetanus antitoxin. A diagnosis of gas gangrene was made and modified vacuum sealing drainage device was used after thorough debridement. After two weeks' treatment, left femoral was kept and gas gangrene was cured successfully. PMID- 26770625 TI - Long-term disease control in a refractory multiple myeloma patient treated with bortezomib mono-therapy: a case report and review of literature. AB - Multiple myeloma (MM) accounts for 1.5% of all cancers and approximately 13% of all hematologic malignancies. Therapy for MM has substantially improved after the application of immunomodulatory drugs and proteasome inhibitors. The first proteasome inhibitor, bortezomib, can be considered a major milestone in treatment of MM, greatly improving the response rates and overall survival in front-line and relapsed/refractory settings. However, the prognosis of patients with progressive disease remains poor. In this article, we report a case of refractory MM patient who gained a long time disease control by bortezomib mono therapy and do a critical review of the literature. We aim to share our experience of efficiency and safety of the long term mono-therapy of bortezomib in a refractory MM. PMID- 26770626 TI - A hypothesis-effect of T cell epitope fusion peptide specific immunotherapy on signal transduction. AB - Asthma is a chronic nonspecific inflammatory disease of the airway primarily mediated by different inflammatory cells, including mast cells, eosinophils and T cells. We hereby specially focused on a signal pathway for Janus kinase-signal transducer and activators of transduction (JAK-STATs), which has been the interest of study in asthma since it more likely regulates cellular proliferation and differentiation, and consequently modulates immune system. In our consideration, knowledge on this signal pathway may provide an avenue for rational options in treatment of asthma on control of immune response basis. PMID- 26770627 TI - Effects of exogenous neurotrophin-3 on myocyte apoptosis and Ca(2+)-ATP enzyme levels following nerve injury in rats. AB - This study aims to determine the influence of neurotrophin-3 (NT-3) plasmids on neuronal apoptosis and Ca(2+)-ATP enzyme levels in injured muscles. We also investigated the mechanism underlying the role of NT-3 in delaying muscle atrophy following a peripheral nerve injury. Sixty adult Wistar rats were used to generate the peripheral nerve injury models. The rats were randomly assigned to the saline and NT-3 groups. Related indicators, such as caspase-3 protein expression, skeletal muscle cell apoptosis, and Ca(2+)-ATP enzyme expression were quantified. The expression levels of caspase-3 and the histone-muscle cell apoptosis rate in the NT-3 group decreased at different post-operative times following peripheral nerve injury, whereas NT-3 expression and the sarcoplasmic reticulum Ca(2+)-ATP enzyme levels increased. Statistically significant differences were observed in the NT-3 group as compared to the saline group (P < 0.05). NT-3 mitigated muscle atrophy following peripheral nerve damage by inhibiting caspase-3 gene expression and increasing Ca(2+)-ATP enzymatic activity, ultimately reducing muscle apoptosis. PMID- 26770628 TI - Percutaneous transhepatic embolization of gastroesophageal varices combined with partial splenic embolization for the treatment of variceal bleeding and hypersplenism. AB - This study aims to evaluate the therapeutic results of percutaneous transhepatic embolization of gastroesophageal varices combined with partial splenic embolization in patients with liver cirrhosis, and to explore the role of this minimally invasive treatment as an alternative to surgery. 25 patients with liver cirrhosis were received percutaneous transhepatic embolization of gastroesophageal varices combined with partial splenic embolization. Another 25 patients with liver cirrhosis underwent Hassab's operation. They were followed up, and received endoscopy, B ultrasound, liver function and hematologic examination at 24 months after the therapy. In minimal invasive group, before treatment and after 24 month following up after treatment, improved varices, improved portal hypertension and improved hypersplenism were showed comparing with the surgery group, and that they were measured by endoscopic visualization, ultrasound and blood counts. the white blood cell and platelet count were 2.33+/ 0.65 (10(9)/L) and 3.63+/-1.05 (10(10)/L), 7.98+/-3.0 (10(9)/L) and 16.3+/-9.10 (10(10)/L) (P<0.05); the diameter of the portal vein were 1.47+/-0.25 cm, 1.31+/ 0.23 cm (P<0.05). Esophageal varices passed from grade III to lower grade II in 11 patients, and from grade II to lower grade I in 6 patients at 24 month following up. In surgical group, the white blood cell and platelet count were 2.2+/-0.60 (10(9)/L), 4.1+/-1.25 (10(10)/L) before treatment; 9.3+/-2.56 (10(9)/L), 32.1+/-12.47 (10(10)/L) after the treatment at 24 month following up (P<0.05). The diameter of the portal vein were 1.43+/-0.22 cm before the treatment and 1.28+/-0.18 cm after the treatment (P<0.05). Esophageal varices passed from grade III to lower grade II in 13 patients, and from grade II to lower grade I in 7 patients. The combination of PGEV and PSE can be considered as an option for the treatment of variceal bleeding with hypersplenism. PMID- 26770629 TI - Human mutL homolog 1 expression characteristic and prognostic effect on patients with sporadic colorectal cancer. AB - The aim of the present study was to analyze the relationship between aberrant human mutL homolog 1 (hMLH1) expression and clinicopathological parameters of patients with sporadic colorectal cancer, and to explore the prognostic effect of aberrant hMLH1 expression in these patients. The relationship was measured by chi square test and Fisher's exact test. Survival analysis was performed with Kaplan Meier analysis and Cox regression model to measure 5-year disease-free survival (DFS) and 5-year overall survival (OS) rates. Totally 17.13% of the patients with sporadic colorectal cancer showed aberrant nuclear staining for hMLH1 expression. Aberrant hMLH1 expression was related with tumor pathologic types, tumor location and TNM staging (P<0.05) in the patients with sporadic colorectal cancer. Cox regression analysis indicated important prognostic factors were age (RR: 1.021, 95% CI: 1.003-1.039, P=0.023), mucinous adenocarcinoma (RR: 2.603, 95% CI: 1.705 3.974, P<0.0001), TNM staging (RR: 2.071, 95% CI: 1.170-3.666, P=0.012), lymphangion invasion (RR: 2.013, 95% CI: 1.227-3.303, P=0.006) and aberrant hMLH1 expression (RR: 0.414, 95% CI: 0.216-0.791, P=0.008). Consequently, hMLH1 expression level is related with some clinicopathologic features. Aberrant hMLH1 expression plays a significant part in prognosis for patients with sporadic colorectal cancer and it will promisingly become an independent prognostic factor. PMID- 26770630 TI - Halichondrin B amide acts as tubulin binding agent to exhibit anti-tumor efficacy in hematologic cancers. AB - Since microtubule dynamics play an indispensable role in cell division, cell motility, cellular transport, cell polarity and cell signalling, the microtubule appears as a highly attractive target for anticancer drug design. The present study demonstrates the role of halichondrin B amide (HCBA), an analog of halichondrin Bas an antitumor agent, its mechanism of action and pharmacokinetics. The results revealed that HCBA effectively inhibitscell growth in a variety of tumor types in vitro. The HCT116 DPC4 (-/-) colon cancer cell line was the most sensitive with an IC50 of 2.02 MUM, compared to 3.78 MUM in the parental HCT116. It also effectively reduced tumor growth in SCID mice human tumor xenografts of MV-4-11 acute myeloid leukemia, MM.1S multiple myeloma and DU 145 prostate cancer. HCBA caused accumulation of H69S, MM.1S, U266 and 8226/S cells in G2/M-phase after 24 h. There was a significant increase in the positive histone H3 cells from a baseline value of 4.38 to 53.45% in 8226/S cells and from 4.32 to 43.83% in MM.1S cells on treatment with HCBA. The results from pharmacokinetic studies demonstrated relatively high oral bioavailability of 83% with distribution in both plasma and bone marrow. In non-tumor bearing SCID mice injected with a single acute lethal dose of HCBA no myelosuppression was observed. Flow cytometry analysis showed cell cycle arrest in metaphase. It also caused inhibition of tubulin polymerization. Thus, HCBA appears to be a potent agent to arrest cell cyclin the metaphase and inhibit tubulin polymerization. Compared to other existing microtubule destabilizing agents HCBA has good oral bioavailability and lacks MDR cross-resistance acute myelosuppression. PMID- 26770631 TI - Formulation and evaluation of PLGA nanoparticles loaded capecitabine for prostate cancer. AB - The objective of this work is to prepare and evaluate Poly (D, L-Lactide-co glycolide) (PLGA) Nanoparticles (NPs) of Capecitabine, an anticancer agent loaded by solvent displacement method using stabilizer (poly vinyl alcohol). The prepared NPs were characterized by FT-IR, DSC, drug loading, entrapment efficiency, particle size, surface morphology by Atomic force microscopy (AFM), X ray diffraction and in-vitro studies. FT-IR and DSC studies indicated that there was no interaction between the drug and polymer. The morphological studies performed by AFM showed uniform and spherical shaped discrete particles without aggregation and smooth in surface morphology with a nano size range of 144 nm. X ray diffraction was performed to reveal the crystalline nature of the drug after encapsulation. The NPs formed were spherical in shape with zeta potentials (-14.8 mV). In vitro release studies were carried and showed drug release up to 5 days. The drug release followed zero order kinetics and a Fickian transport mechanism. Nanoparticles obtained a high encapsulation efficiency of 88.4% and drug loading of 16.98%. Drug released from Capecitabine loaded PLGA NPs (84.1%) was for 5 days. It is concluded from the present investigation that PLGA NPs of Capecitabine may effectively deliver the drug to the prostate for the treatment of prostate cancer. PMID- 26770632 TI - Expression of Tau protein in rats with cognitive dysfunction induced by cerebral hypoperfusion. AB - The aim of this study was to investigate the relationship between chronic cerebral hypoperfusion and the occurrence and development of Alzheimer's disease (AD). A cerebral hypoperfusion rat model was established by two vessels occlusion (2VO). The cognitive function of the rats with chronic cerebral hypoperfusion and the expression of p-Tau protein in the hippocampus were observed dynamically. Before the operation, no differences were observed in the cognitive functions of the control and 2VO group (P > 0.05). However, a significant difference was found at 2, 4, 8, and 12 weeks after the operation. The shock number required to reach the "learned" standard in the 2VO group increased remarkably compared with that of the control group (P < 0.01). With the passage of time, the shock number in the model group increased gradually. The p-Tau-positive cells in the CA1 region of the hippocampus also increased markedly in the model group in a time-dependent manner as compared with that in the control group (P < 0.01). Cerebral hypoperfusion can cause and aggravate the phosphorylation of Tau protein in the brain, leading to cognitive dysfunction. Therefore, this protein is an important initiating and promoting factor involved in the development of AD. PMID- 26770633 TI - Efficacy of different monotherapies in second-line treatment for small cell lung cancer: a meta-analysis of randomized controlled trials. AB - Second-line chemotherapy has been proved to be effective on patients with relapsed or refractory small cell lung cancer (SCLC). Although topotecan has been approved by many countries for the monotherapy with an acknowledged efficacy, its efficacy of low response rate and short median survival time is disappointing. Considering the optimal regimen of second-line therapy is yet uncertain, we conducted this meta-analysis to provide theoretical basis for making clinical decisions. A comprehensive electronic search was performed to identify eligible studies. The ending points included response, overall survival (OS), and adverse events. Odds ratios and 95% confidence interval were calculated to compare the effects. Six trials with 1369 patients were included. With regard to response rate, only amrubicin showed a significant improvement compared with topotecan. Irinotecan and etoposide did not show any advantages. When targeted on OS, neither of these monotherapy regimens exhibited any advantage when compared to topotecan. When aimed at toxicity, amrubicin showed a better effect on reducing hematologic toxicity, but a worse outcome on increasing the nonhematologic toxicity, whereas others showed equal efficacy. There is no strong evidence that any advantage for second-line treatment of SCLC when compared with topotecan, except amrubicin. And amrubicin seems to be superior to topotecan in terms of response rates, with a lower toxicity than topotecan, which is of high value in clinical application, and may be the direction of second-line monotherapy in the future. PMID- 26770634 TI - A correlation study on the effects of DNMT1 on methylation levels in CD4(+) T cells of SLE patients. AB - OBJECTIVE: To study the effect of DNMT1 on CD4(+) T cells in the peripheral blood of systemic lupus erythematosus (SLE) patients. METHODS: To investigate the differential expression of DNMT1 in CD4(+) T cells of SLE patients and healthy individuals, a DNMT1 lentiviral plasmid (pLenti6.3/V5-DNMT1) and a control plasmid (pLenti6.3/V5-GW/LacZ) were constructed and transfected into CD4(+) T cells from the peripheral blood of SLE patients. The transcriptional and translational expression of DNMT1, global genomic DNA methylation, and the production of IgG antibody in the CD4(+) T cells in the peripheral blood of SLE patients were assessed using qPCR analysis, western blotting, flow cytometry, and ELISA, respectively. RESULTS: The expression level of DNMT1 in SLE patients was significantly lower than that in normal humans. The expression of DNMT1 was found to be positively correlated with the methylation level of genomic DNA and negatively correlated with the IgG titration level. DNA sequencing results confirmed that the DNMT1 lentiviral plasmid was successfully constructed. After the CD4(+) T cells from the peripheral blood of SLE patients were transfected with the pLenti6.3/V5-DNMT1 plasmid, the transcription level of the DNMT1 gene was upregulated and abundance of DNMT1 protein significantly increased. Global genomic DNA methylation was enhanced, while the production of IgG antibody was reduced. CONCLUSION: DNMT1 can inhibit the autoimmune response in SLE patients by reversing the abnormally low DNA methylation level in the CD4(+) T cells. PMID- 26770635 TI - Hepatic venous pressure gradient is a useful predictor in guiding treatment on prevention of variceal rebleeding in cirrhosis. AB - BACKGROUND: The best therapy to prevent esophageal variceal (EV) rebleeding in cirrhotic patients who are non-responsive to pharmacological therapy have not been determined. AIMS: To evaluate efficacy of a strategy to assign different treatments according to hepatic vein pressure gradient (HVPG) values to prevent EV rebleeding in non-responders. METHODS: This study is a non-randomized controlled prospective study. 109 cirrhotic patients with EV bleeding who were non-responders based on two HVPG measurements were enrolled and divided two groups: 55 patients (EVL+beta-blocker group) were treated with endoscopic variceal ligation (EVL) and nonselective beta-blocker; 54 patients (HVPG-guided group) were treated with EVL and nonselective beta-blocker if HVPG <= 16 mmHg (low-HVPG), with percutaneous transhepatic variceal embolization (PTVE) if HVPG > 16 mmHg and <= 20 mmHg (medium-HVPG), or with transjugular intrahepatic portosystemic shunt (TIPS) if HVPG > 20 mmHg (high-HVPG). Patients were followed up for rebleeding and mortality. RESULTS: The mean follow-up period was 17.0 months; rebleeding was higher in the EVL+beta-blocker group than HVPG-guided group (25.5%, 9.3%, P = 0.026); 3-year probability of rebleeding in the EVL+Beta blocker group increased with elevated levels of HVPG (12.5% vs 46.4% vs 64.9%, chi(2) = 11.551, P = 0.003), and 3-year probability of survival was no difference (96.6% vs 85.7% vs 90.9%, chi(2) = 2.638, P = 0.267). Rebleeding rate in PTVE group (7.7%) was lower than that in EVL+beta-blockergroup with medium-HVPG (35.7%), but there was no difference. Rebleeding rate in TIPS group (7.7%) was lower than that in EVL+beta-blockergroup with high-HVPG (45.5%), but there was no difference. CONCLUSIONS: HVPG measurement was useful for making decisions to select EVL and Beta-blocker, PTVE or TIPS in secondary prophylaxis. HVPG-guided treatment is feasible and effective in preventing esophageal varices rebleeding. PMID- 26770636 TI - Study on like-stem characteristics of tumor sphere cells in human gastric cancer line HGC-27. AB - Stem-like cancer cells are called cancer stem cells (CSCs) or tumor stem cells (TSCs). Methods for sorting CSCs are mainly based on the marker (CD133+/CD44+) or side population cells. However, CD133+/CD44+ cells or side population cells are very rare or even undetectable. In the present study, the tumor sphere of human gastric cancer (HGC) cell line HGC-27 was used for CSCs enrichment, and stem-like characteristics were verified by Hoechst 33342 staining technology, cell growth rate assays, sphere differentiation assay, clone formation, chemotherapy resistance study and tumor formation in an animal model. Our results demonstrated that the tumor sphere cells of HGC-27 cell line could be used to enrich CSCs, which may contribute to human gastric cancer stem cell biology research. PMID- 26770637 TI - Bioactivity of umbilical cord blood dendritic cells and anti-leukemia effect. AB - OBJECTIVE: We investigated the effect of umbilical cord blood dendritic cells (DCs) on in vitro proliferation, immunophenotypes and levels of homologous cytokine-induced killer cells (CIK) and the toxicity on leukemia cells. METHOD: Mononuclear cell-induced DC-CIK cells derived from umbilical cord blood were collected and co-cultured in the proportion of 1:5. Cord blood CIK cells or peripheral blood DC-CIK cells were used as control. Phenotypes were analyzed by flow cytometry; vial cell counting was performed using trypan blue, and the killing activity of effector cells against leukemia cells was measured by MTT assay. The levels of interferon-r (IFN-r), tumor necrosis factor-a (TNF-alpha) and interleukin-12 (IL-12) were determined by ELISA. RESULTS: The proliferative capacity of DC-CIK cells was obviously improved compared with cord blood CIK cells and peripheral blood DC-CIK cells (P<0.05, P<0.05). During the co-culture of cord blood DC-CIK cells, the ratios of CD 3 (+) CD 8 (+) and CD 3 (+) CD 56 (+) cells were obviously higher than that of CIK cells under the same conditions (P<0.05). On day 3 of co-culture, the levels of IL-12, IFN-r and TNF-a in cultured supernatant of cord blood DC-CIK cells were all higher than those secreted by CIK cells cultured alone (P<0.01, P<0.05, P<0.05). When the effector to target ratio was 2.5-20:1, the killing effect of cord blood DC-CIK cells against each subtype of acute leukemia cells was obviously higher than that of CIK cells (P<0.05). No significant differences in killing effect were observed for different subtypes. This finding was consistent with the killing effect of peripheral blood DC-CIK cells against leukemia cells. CONCLUSION: Cord blood DCs can enhance the proliferative capacity of homologous CIK cells and its anti leukemia effect. Though cord blood DC-CIK cells showed a higher proliferative capacity than peripheral blood DC-CIK cells, the two types of DC-CIK cells did not differ significantly in terms of cytoxicity. With a high availability and the low probability of graft rejection reaction, cord blood DC-CIK cells have a brighter prospect for application in immunotherapy. PMID- 26770638 TI - Development, reliability and validity of the psychosocial adaptation scale for Parkinson's disease in Chinese population. AB - OBJECTIVE: To develop psychosocial adaptation scale for Parkinson's disease (PD) in Chinese population and evaluate its reliability and validity. METHODS: The items were designed by literature review, expert consultation and semi-structured interview. The methods of corrected item-total correlation, discrimination analysis and exploratory factor analysis were used for items selection. 427 valid scales from PD patients were collected in the study to test the reliability and validity. RESULTS: The scale incorporated six dimensions: anxiety, self-esteem, attitude, self-acceptance, self-efficacy and social support, a total of 32 items. The scale possessed good internal consistency. The test-retest correlation coefficient was 0.99 and average content validation rate was 0.97. The Hoehn and Yahr stage were correlated with total score of the scale. CONCLUSIONS: The psychosocial adaptation scale in this study showed good reliability and validity, it can be used as a reliable and valid instrument to evaluate the psychosocial adaptation of PD objectively and effectively. PMID- 26770639 TI - Alteration of apoptotic protease activating factor 1 expression and possible role in ONOO(-)-induced apoptosis in human cerebral vascular smooth muscle cells. AB - The study was to investigate the change of apoptotic protease activating factor 1 (Apaf1) expression in the human cerebral vascular smooth muscle cells (HCVSMCs) in response to peroxynitrite (ONOO(-)). HCVSMCs were cultured in vitro and ONOO( ) of different concentrations was directly added to the culture medium. The total proteins were extracted and the alteration of Apaf1 expression was examined by the means of Western-blot. Apaf-1 siRNA (h) was put into another plate of HCVSMCs for transfection. The transfected cells were also incubated in different concentrations of ONOO(-). The change of Apaf1 protein expression after siRNA transfection was examined by the means of Western-blot. The morphological changes were observed by acridine orange staining to determine whether cells experienced apoptosis in response to ONOO(-) before and after siRNA. The Flow cytometry analysis was used to examine the change of cells apoptotic rates in response to ONOO(-) before and after siRNA. Obviously, there was up-regulated Apaf1 expression at protein level in the course of HCVSMCs apoptosis induced by ONOO( ). When Apaf1 expression was suppressed, the apoptotic sum of HCVSMCs didn't change. This study demonstrates that Apaf1 gene is involved in ONOO(-)-induced apoptosis in HCVSMCs. Whether HCVSMCs treated by ONOO(-) undergo apoptosis depends on Apaf1 level. PMID- 26770640 TI - Impact of over distraction on occurrence of axial symptom after anterior cervical discectomy and fusion. AB - OBJECTIVE: A retrospective review was undertaken to evaluate the impact of over distraction on cervical axial symptoms (AS) after anterior cervical discectomy and fusion (ACDF). METHODS: The retrospective review included 421 patients who underwent ACDF for one or two segments. Of these, 78 patients for whom complete follow-up data were available were selected for inclusion in the analysis. X-rays of the cervical vertebra were performed immediately after the surgery, 3 months postsurgery, and at a final follow up (6-24 months). According to the presence/absence of AS, the patients were divided into a symptom group (Group S) and a nonsymptom group (Group N). The ratio of intervertebral height change, change in the overall cervical curvature, change in the local curvature of the surgical segment, cervical total range of motion (ROM), and Japanese Orthopaedic Association (JOA) recovery rate were compared and analyzed. A linear regression analysis of the ratio of intervertebral height change and the symptom and severity of the AS according to the Visual Analogue Scale (VAS) was carried out. RESULTS: The total incidence of AS was 33.97%. C5 nerve root palsy occurred in one case in Group S after the surgery. The neurologic symptoms of both groups were significantly alleviated after the surgery. The ratio of intervertebral height change in Group S was significantly higher than that in Group N at the last follow-up (P < 0.05). However, the changes in the overall cervical curvature, local curvature of the surgical segment, cervical ROM, and JOA recovery rates were not statistically significant (P > 0.05). In Group S, 37% of the patients had symptoms that occurred in the chest area, and the ratio of intervertebral height change was significantly positively correlated with the VAS score of the AS (r = 0.893). CONCLUSIONS: The occurrence of postoperative AS will significantly increase if the ratio of intervertebral height change of the surgical segment after ACDF is over 10%. PMID- 26770641 TI - Effects of electroacupuncture combined with clean intermittent catheterization on urinary retention after spinal cord injury: a single blind randomized controlled clinical trial. AB - PURPOSE: This study aimed to evaluate the therapeutic effects of electroacupuncture (EA) combined with clean intermittent catheterization (CIC) on spinal cord injury (SCI) induced urinary retention. METHODS: A total of 107 patients with SCI induced urinary retention were randomly divided into 3 groups, including group 1 (CIC treatment), group 2 (EA combined with CIC treatment), and group 3 (sham acupuncture combined with CIC treatment). After different treatments, the residual urine volume, voided volume (each time), number of bladder balance patients, and frequency of CIC were recorded and compared. RESULTS: There were no significant differences between group 1 and 3 in number of bladder balance patients and voided volume (ml) at the 1(st) month. The rate of patients reaching bladder balance was significantly higher in group 2 than group 1 and 3 (P<0.05). The frequency of CIC was significantly less in group 2 than the other groups (P<0.001). The voided volume at the 1(st) and the 3(rd) month after surgery was significantly higher in group 2 than that in group 1 and 3 (P<0.001). Meanwhile, after 1 month and 3 months of treatment, residual urine volume was significantly reduced in group 2 compared with that in group 1 and 3 (P<0.001). CONCLUSION: The therapeutic effects of EA were effective for SCI induced urinary retention by reducing residual urine volume and the frequency of CIC, increasing voided volume, and promoting the balance of vesical function. PMID- 26770642 TI - Combination of CO2 laser-assisted uvulopalatopharyngoplasty and nasal cavity expansion enhances treatment of obstructive sleep apnea-hypopnea syndrome. AB - This study aimed to investigate the methods, effects, and application value of a combination of CO2 laser-assisted uvulopalatopharyngoplasty (UPPP) and selective nasal cavity expansion for the treatment of multiplanar narrowing-induced obstructive sleep apnea hypopnea syndrome (OSAHS). Ninety-three patients with OSAHS and multiplanar stenosis were treated with CO2 laser-assisted modified UPPP and selective surgical expansion of the nasal cavity, with 12 completing the operation in stages. Six months after the operation, 23 patients (24.7%) were effectively cured, 52 (55.9%) had excellent efficacy, and 18 (19.4%) were cured, and the total efficacy was 100%. One year after the surgery, the surgical outcomes of 65 patients were reviewed, and the surgeries were ineffective in four (6.2%), effective in 14 (21.5%), very effective in 36 (55.4%), and curative in 11 (16.9%), and the total efficacy was 93.8%. Another 93 cases were treated with the traditional UPPP method only. At the six-month postoperative review, 18 (19.4%) were effectively cured, 30 (32.3%) had excellent efficacy, and 10 (10.8%) were cured, while the surgery was ineffective in 35 (37.6%). The total efficacy was 62.4%. One year after the surgery, the surgical outcomes of 75 patients were reviewed, and the surgeries were ineffective in 29 (38.7%), effective in 14 (18.7%), very effective in 24 (32.0%), and curative in eight (10.7%), and the total efficacy was 61.3%. Compared to the traditional operative methods, the treatment with one operation involving CO2-laser-assisted UPPP and selective nasal cavity expansion was thoroughly effective on multiple stenosis sites, including nasal, nasopharyngeal, and oropharyngeal airways. However, potential complications must be carefully avoided. PMID- 26770643 TI - Prevention options for ventriculoperitoneal shunt infections: a retrospective analysis during a five-year period. AB - Shunt infection is the most common and dreaded complication in patients with hydrocephalus. For the purpose of reducing the high morbidity and mortality, how to prevent is a vital step. A retrospective analysis of 384 CSF cerebrospinal fluid (CSF) shunt procedures was undertaken from 2006 to 2010 in our neurosurgery department. Infection diagnosis was established by subjecting the CSF to biochemical and microbiological parameters. The patients' demographic and clinical characteristics, various treatment procedures and outcome were evaluated. The infection rate of ventriculoperitoneal (VP) shunt was 12.5% in 2006, which dropped to 2% and stabilized at lower level from 2008. The most common causes of hydrocephalus were traumatic injury and brain tumor. Fever and consciousness disturbance were the major clinical symptoms. Gram-negative rods episodes was the most frequently isolated microorganisms accounting for 58%, followed by S. aureus , S. epidermidis and Staphylococcus haemolyticus. With the removal of shunt and intravenous antibiotics therapy, 82% of the patients survived. Majority of the isolates were sensitive to the carbopenem antibiotics and vancomycin. The mean length of hospital stay was 47 days. Prompt shunt removal and perioperative antibiotic prophylaxis seems to be essential for the survival of patients with VP shunt infection. PMID- 26770644 TI - Mycophenolate mofetil inhibits hypertrophy and apoptosis of podocyte in vivo and in vitro. AB - OBJECTIVE: The present study aimed to examine the effect of mycophenolate mofetil (MMF), a new immunosuppressive agent, on hypertrophy and apoptosis of podocyte, and investigate the underlying mechanisms. METHODS: Cultured rat podocyte were exposed to 5.6 mmol/L normal glucose or 25 mmol/L high glucose with mycophenolic acid (MPA) or Valsartan for 72 h. For animal studies, streptozotocin-induced diabetic rats were untreated or treated with MMF or Valsartan for 16 weeks. After 16 weeks of treatment, the weight of kidney and body, 24 hours urinary protein excretion and serum glucose was detected. Histomorphology of renal tissue was observed by optical microscope and electron microscope. Apoptosis of podocytes were determined by transferase-mediated dUTP nick-end labeling (TUNEL) test. The protein expressions of p21(cip1), p27(kip1), bax and bcl-2 were examined by Western blot. RESULTS: p27(kip1), p21(cip1) protein expression in podocytes exposed to high glucose for 72 h and in 16 weeks diabetic glomeruli significantly increased (P<0.01). The expressions of bax, cleaved caspase-3 increased while the expression of bcl-2 decreased in diabetic glomeruli as well as in high glucose. But they were all ameliorated in the groups treated with either MMF or Valsartan. CONCLUSION: MMF can inhibit abnormal hypertrophy and apoptosis of podocytes in the early stage of diabetes, partly by regulating the expression of cell cycle related protein p27(kip1), p21(cip1) and apoptosis related genes, such as bax, bcl-2 and cleaved caspase-3. These suggest that the protective effects of MMF on renal function maybe partly through inhibiting abnormal renal cell growth by regulating cell cycle or apoptosis related genes. PMID- 26770646 TI - Reduced beta 2 glycoprotein I improve diabetic nephropathy via inhibiting TGF beta1-p38 MAPK pathway [Retraction]. AB - [This retracts the article on p. 6852 in vol. 8, PMID: 26221223.]. PMID- 26770645 TI - Erratum: Mannose-capped lipoarabinomannan from Mycobacterium tuberculosis induces IL-37 production via upregulating ERK1/2 and p38 in human type II alveolar epithelial cells. AB - The major surface lipoglycan of Mycobacterium tuberculosis (M. tb), mannose capped lipoarabinomannan (ManLAM), is an immunosuppressive epitope of M. tb. Interleukin (IL)-37, is a newly identified anti-inflammatory cytokine, which reduces systemic and local inflammation. However, the correlation between ManLAM and IL-37 remains unknown. Therefore, in this study, we investigate the possible role and relative molecular mechanism of ManLAM in IL-37 production of human type II alveolar epithelial cells by using A549 cell line. Here, we report that M. tb induced IL-37 mRNA and protein expression in a time-dependent manner. We next fractionated components of M. tb using chloroform: methanol (C:M) and water. In sharp contrast to the C:M phase, water phase was mainly responsible for the production of IL-37. Since ManLAM is the major component of water phase, we found that ManLAM induced IL-37 mRNA and protein expression in a time and dose dependent manner, while this activity was almost totally abolished by the ERK1/2 (U0126) and p38 (SB203580) inhibitor. ManLAM stimulation significantly induced ERK1/2 and p38 phosphorylation in A549 cells, as well as cell surface TLR2 expression. After interfering TLR2 expression, ERK1/2 and p38 phosphorylation levels were markedly decreased, and also IL-37 production. Though ManLAM also promoted TLR4 expression on A549 cells, TLR4 interference showed no influence on ManLAM-induced IL-37 production. Our results indicate that ManLAM induces IL-37 production in human type II alveolar epithelial cells via up-regulating TLR2/p38 or ERK1/2 pathway, and this provide an important evidence to explain the pathological role of ManLAM that contribute to the persistence of M. tb.[This corrects the article on p. 7279 in vol. 8, PMID: 26221267.]. PMID- 26770647 TI - Acute Exercise-Induced Mitochondrial Stress Triggers an Inflammatory Response in the Myocardium via NLRP3 Inflammasome Activation with Mitophagy. AB - Increasing evidence has indicated that acute strenuous exercise can induce a range of adverse reactions including oxidative stress and tissue inflammation. However, little is currently known regarding the mechanisms that underlie the regulation of the inflammatory response in the myocardium during acute heavy exercise. This study evaluated the mitochondrial function, NLRP3 inflammasome activation, and mitochondrial autophagy-related proteins to investigate the regulation and mechanism of mitochondrial stress regarding the inflammatory response of the rat myocardium during acute heavy exercise. The results indicated that the mitochondrial function of the myocardium was adaptively regulated to meet the challenge of stress during acute exercise. The exercise-induced mitochondrial stress also enhanced ROS generation and triggered an inflammatory reaction via the NLRP3 inflammasome activation. Moreover, the mitochondrial autophagy-related proteins including Beclin1, LC3, and Bnip3 were all significantly upregulated during acute exercise, which suggests that mitophagy was stimulated in response to the oxidative stress and inflammatory response in the myocardium. Taken together, our data suggest that, during acute exercise, mitochondrial stress triggers the rat myocardial inflammatory response via NLRP3 inflammasome activation and activates mitophagy to minimize myocardial injury. PMID- 26770648 TI - Protective Effect of Peroxisome Proliferator-Activated Receptor alpha Activation against Cardiac Ischemia-Reperfusion Injury Is Related to Upregulation of Uncoupling Protein-3. AB - Activation of peroxisome proliferator-activated receptor alpha (PPARalpha) confers cardioprotection, while its mechanism remains elusive. We investigated the protective effect of PPARalpha activation against cardiac ischemia reperfusion injury in terms of the expression of uncoupling protein (UCP). Myocardial infarct size and UCP expression were measured in rats treated with WY 14643 20 mg/kg, a PPARalpha ligand, or vehicle. WY-14643 increased UCP3 expression in vivo. Myocardial infarct size was decreased in the WY-14643 group (76 +/- 8% versus 42 +/- 12%, P<0.05). During reperfusion, the incidence of arrhythmia was higher in the control group compared with the WY-14643 group (9/10 versus 3/10, P<0.05). H9c2 cells were incubated for 24 h with WY-14643 or vehicle. WY-14643 increased UCP3 expression in H9c2 cells. WY-14643 decreased hypoxia-stimulated ROS production. Cells treated with WY-14643 were more resistant to hypoxia-reoxygenation than the untreated cells. Knocking-down UCP3 by siRNA prevented WY-14643 from attenuating the production of ROS. UCP3 siRNA abolished the effect of WY-14643 on cell viability against hypoxia-reoxygenation. In summary, administration of PPARalpha agonist WY-14643 mitigated the extent of myocardial infarction and incidence of reperfusion-induced arrhythmia. PPARalpha activation conferred cytoprotective effect against hypoxia-reoxygenation. Associated mechanisms involved increased UCP3 expression and resultant attenuation of ROS production. PMID- 26770649 TI - Antioxidant, Anti-inflammatory, and Antiulcer Potential of Manuka Honey against Gastric Ulcer in Rats. AB - Gastric ulcers are among the most common diseases affecting humans. This study aimed at investigating the gastroprotective effects of manuka honey against ethanol-induced gastric ulcers in rats. The mechanism by which honey exerts its antiulcer potential was elucidated. Four groups of rats were used: control, ethanol (ulcer), omeprazole, and manuka honey. Stomachs were examined macroscopically for hemorrhagic lesions in the glandular mucosa, histopathological changes, and glycoprotein detection. The effects of oxidative stress were investigated using the following indicators: gastric mucosal nitric oxide (NO), reduced glutathione (GSH), lipid peroxide (MDA, measured as malondialdehyde) glutathione peroxidase (GPx), superoxide dismutase (SOD), and catalase. Plasma tumour necrosis factor-alpha, interleukin-1beta, and IL-6 were also measured. Manuka honey significantly decreased the ulcer index, completely protected the mucosa from lesions, and preserved gastric mucosal glycoprotein. It significantly increased gastric mucosal levels of NO, GSH, GPx, and SOD. Manuka honey also decreased gastric mucosal MDA and plasma TNF-alpha, IL-1beta, and IL-6 concentrations. In conclusion, manuka honey likely exerted its antiulcer, effect by keeping enzymatic (GPx and SOD) and nonenzymatic (GSH and NO) antioxidants as well as inflammatory cytokines (TNF-alpha, IL-1beta, and IL-6) in a reduced form, inhibited lipid peroxidation (MDA), and preserved mucous glycoproteins levels. PMID- 26770650 TI - Tempol, a Membrane-Permeable Radical Scavenger, Exhibits Anti-Inflammatory and Cardioprotective Effects in the Cerulein-Induced Pancreatitis Rat Model. AB - To date, it remains unclear whether mild form of acute pancreatitis (AP) may cause myocardial damage which may be asymptomatic for a long time. Pathogenesis of AP-related cardiac injury may be attributed in part to ROS/RNS overproduction. The aim of the present study was to evaluate the oxidative stress changes in both the pancreas and the heart and to estimate the protective effects of 1-oxyl 2,2,6,6-tetramethyl-4-hydroxypiperidine (tempol) at the early phase of AP. Cerulein-induced AP led to the development of acute edematous pancreatitis with a significant decrease in the level of sulfhydryl (-SH) groups (oxidation marker) both in heart and in pancreatic tissues as well as a substantial increase in plasma creatine kinase isoenzyme (CK-MB) activity (marker of the heart muscle lesion) which confirmed the role of oxidative stress in the pathogenesis of cardiac damage. The tempol treatment significantly reduced the intensity of inflammation and oxidative damage and decreased the morphological evidence of pancreas injury at early AP stages. Moreover, it markedly attenuated AP-induced cardiac damage revealed by normalization of the -SH group levels and CK-MB activity. On the basis of these studies, it is possible to conclude that tempol has a profound protective effect against cardiac and pancreatic damage induced by AP. PMID- 26770651 TI - NRF2 Regulates HER2 and HER3 Signaling Pathway to Modulate Sensitivity to Targeted Immunotherapies. AB - NF-E2 related factor-2 (NRF2) is an essential transcription factor for multiple genes encoding antioxidants and detoxification enzymes. NRF2 is implicated in promoting cancer therapeutic resistance by its detoxification function and crosstalk with proproliferative pathways. However, the exact mechanism of this intricate connectivity between NRF2 and growth factor induced proliferative pathway remains elusive. Here, we have demonstrated that pharmacological activation of NRF2 by tert-butylhydroquinone (tBHQ) upregulates the HER family receptors, HER2 and HER3 expression, elevates pAKT levels, and enhances the proliferation of ovarian cancer cells. Preactivation of NRF2 also attenuates the combined growth inhibitory effects of HER2 targeting monoclonal antibodies, Pertuzumab and Trastuzumab. Further, tBHQ caused transcriptional induction of HER2 and HER3, while SiRNA-mediated knockdown of NRF2 prevented this and further caused transcriptional repression and enhanced cytotoxicity of the HER2 inhibitors. Hence, NRF2 regulates both HER2 and HER3 receptors to influence cellular responses to HER2 targeting monoclonal antibodies. This deciphered crosstalk mechanism reinforces the role of NRF2 in drug resistance and as a relevant anticancer target. PMID- 26770652 TI - SOD2 Mediates Amifostine-Induced Protection against Glutamate in PC12 Cells. AB - BACKGROUND: Cytoprotectant amifostine attenuates radiation-induced oxidative injury by increasing intracellular manganese superoxide dismutase (SOD2) in peripheral tissue. However, whether amifostine could protect neuronal cells against oxidative injury has not been reported. The purpose of this study is to explore the protection of amifostine in PC12 cells. METHODS: PC12 cells exposed to glutamate were used to mimic neuronal oxidative injury. SOD assay kit was taken to evaluate intracellular Cu/Zn SOD (SOD1) and SOD2 activities; western blot analysis and immunofluorescence staining were performed to investigate SOD2 protein expression; MTT, lactate dehydrogenase (LDH), release and cell morphology were used to evaluate cell injury degree, and apoptotic rate and cleaved caspase 3 expression were taken to assess apoptosis; mitochondrial superoxide production, intracellular reactive oxygen species (ROS), and glutathione (GSH) and catalase (CAT) levels were evaluated by reagent kits. RESULTS: Amifostine increased SOD2 activity and expression, decreased cell injury and apoptosis, reduced mitochondrial superoxide production and intracellular ROS generation, and restored intracellular GSH and CAT levels in PC12 cells exposed to glutamate. SOD2-siRNA, however, significantly reversed the amifostine-induced cytoprotective and antioxidative actions. CONCLUSION: SOD2 mediates amifostine-induced protection in PC12 cells exposed to glutamate. PMID- 26770653 TI - Elevated Levels of Urinary Markers of Oxidative DNA and RNA Damage in Type 2 Diabetes with Complications. AB - The mechanisms underlying progression of type 2 diabetes are complex and varied. Recent studies indicated that oxidative stress provided a new sight. To further assess the relationship between nucleic acid oxidation and complications in patients with type 2 diabetes and explore its possible molecular mechanisms, we studied 1316 subjects, including 633 type 2 diabetes patients and 683 age- and sex-matched healthy controls. Urinary levels of DNA oxidation marker 8-oxo-7,8 dihydro-2'-deoxyguanosine (8-oxodGuo) and RNA oxidation marker 8-oxo-7,8 dihydroguanosine (8-oxoGuo) were measured by ultraperformance liquid chromatography and mass spectrometry (UPLC-MS/MS). Serum glucose, HbA1c, total cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides (TG) were also determined. The results showed significantly elevated levels of both the urinary 8-oxodGuo and 8-oxoGuo in diabetes patients with/without complications compared with age-matched healthy control subjects (p = 0.02 and p < 0.001, resp.). Patients with complications, especially macrovascular complications, exhibited higher levels of 8-oxoGuo than those without complications, while there was no difference in the concentrations of serum glucose and lipids. The finding indicates the role for oxidative damage to DNA and RNA, as a molecular mechanism contributing to the progression of type 2 diabetes. Elevated levels of 8-oxoGuo may be a risk factor for type 2 diabetes complications, especially in diabetic macrovascular complications. PMID- 26770654 TI - Nitroxyl (HNO): A Reduced Form of Nitric Oxide with Distinct Chemical, Pharmacological, and Therapeutic Properties. AB - Nitroxyl (HNO), the one-electron reduced form of nitric oxide (NO), shows a distinct chemical and biological profile from that of NO. HNO is currently being viewed as a vasodilator and positive inotropic agent that can be used as a potential treatment for heart failure. The ability of HNO to react with thiols and thiol containing proteins is largely used to explain the possible biological actions of HNO. Herein, we summarize different aspects related to HNO including HNO donors, chemistry, biology, and methods used for its detection. PMID- 26770655 TI - Low-Dose Aronia melanocarpa Concentrate Attenuates Paraquat-Induced Neurotoxicity. AB - Herbicides containing paraquat may contribute to the pathogenesis of neurodegenerative disorders such as Parkinson's disease. Paraquat induces reactive oxygen species-mediated apoptosis in neurons, which is a primary mechanism behind its toxicity. We sought to test the effectiveness of a commercially available polyphenol-rich Aronia melanocarpa (aronia berry) concentrate in the amelioration of paraquat-induced neurotoxicity. Considering the abundance of antioxidants in aronia berries, we hypothesized that aronia berry concentrate attenuates the paraquat-induced increase in reactive oxygen species and protects against paraquat-mediated neuronal cell death. Using a neuronal cell culture model, we observed that low doses of aronia berry concentrate protected against paraquat-mediated neurotoxicity. Additionally, low doses of the concentrate attenuated the paraquat-induced increase in superoxide, hydrogen peroxide, and oxidized glutathione levels. Interestingly, high doses of aronia berry concentrate increased neuronal superoxide levels independent of paraquat, while at the same time decreasing hydrogen peroxide. Moreover, high dose aronia berry concentrate potentiated paraquat-induced superoxide production and neuronal cell death. In summary, aronia berry concentrate at low doses restores the homeostatic redox environment of neurons treated with paraquat, while high doses exacerbate the imbalance leading to further cell death. Our findings support that moderate levels of aronia berry concentrate may prevent reactive oxygen species-mediated neurotoxicity. PMID- 26770656 TI - Resveratrol Regulates Mitochondrial Biogenesis and Fission/Fusion to Attenuate Rotenone-Induced Neurotoxicity. AB - It has been confirmed that mitochondrial impairment may underlie both sporadic and familial Parkinson's disease (PD). Mitochondrial fission/fusion and biogenesis are key processes in regulating mitochondrial homeostasis. Therefore, we explored whether the protective effect of resveratrol in rotenone-induced neurotoxicity was associated with mitochondrial fission/fusion and biogenesis. The results showed that resveratrol could not only promote mitochondrial mass and DNA copy number but also improve mitochondrial homeostasis and neuron function in rats and PC12 cells damaged by rotenone. We also observed effects with alterations in proteins known to regulate mitochondrial fission/fusion and biogenesis in rotenone-induced neurotoxicity. Therefore, our findings suggest that resveratrol may prevent rotenone-induced neurotoxicity through regulating mitochondrial fission/fusion and biogenesis. PMID- 26770657 TI - The Responses of Tissues from the Brain, Heart, Kidney, and Liver to Resuscitation following Prolonged Cardiac Arrest by Examining Mitochondrial Respiration in Rats. AB - Cardiac arrest induces whole-body ischemia, which causes damage to multiple organs. Understanding how each organ responds to ischemia/reperfusion is important to develop better resuscitation strategies. Because direct measurement of organ function is not practicable in most animal models, we attempt to use mitochondrial respiration to test efficacy of resuscitation on the brain, heart, kidney, and liver following prolonged cardiac arrest. Male Sprague-Dawley rats are subjected to asphyxia-induced cardiac arrest for 30 min or 45 min, or 30 min cardiac arrest followed by 60 min cardiopulmonary bypass resuscitation. Mitochondria are isolated from brain, heart, kidney, and liver tissues and examined for respiration activity. Following cardiac arrest, a time-dependent decrease in state-3 respiration is observed in mitochondria from all four tissues. Following 60 min resuscitation, the respiration activity of brain mitochondria varies greatly in different animals. The activity after resuscitation remains the same in heart mitochondria and significantly increases in kidney and liver mitochondria. The result shows that inhibition of state-3 respiration is a good marker to evaluate the efficacy of resuscitation for each organ. The resulting state-3 respiration of brain and heart mitochondria following resuscitation reenforces the need for developing better strategies to resuscitate these critical organs following prolonged cardiac arrest. PMID- 26770658 TI - Sperm Oxidative Stress Is Detrimental to Embryo Development: A Dose-Dependent Study Model and a New and More Sensitive Oxidative Status Evaluation. AB - Our study aimed to assess the impact of sperm oxidative stress on embryo development by means of a dose-dependent model. In experiment 1, straws from five bulls were subjected to incubation with increasing H2O2 doses (0, 12.5, 25, and 50 MUM). Motility parameters were evaluated by Computed Assisted System Analysis (CASA). Experiment 2 was designed to study a high (50 MUM) and low dose (12.5 MUM) of H2O2 compared to a control (0 MUM). Samples were incubated and further used for in vitro fertilization. Analyses of motility (CASA), oxidative status (CellROX green and 2'-7' dichlorofluorescein diacetate), mitochondrial potential (JC-1), chromatin integrity (AO), and sperm capacitation status (chlortetracycline) were performed. Embryos were evaluated based on fast cleavage (30 h.p.i.), cleavage (D = 3), development (D = 5), and blastocyst rates (D = 8). We observed a dose-dependent deleterious effect of H2O2 on motility and increase on the percentages of positive cells for CellROX green, capacitated sperm, and AO. A decrease on cleavage and blastocyst rates was observed as H2O2 increased. Also, we detected a blockage on embryo development. We concluded that sperm when exposed to oxidative environment presents impaired motility traits, prooxidative status, and premature capacitation; such alterations resulting in embryo development fail. PMID- 26770660 TI - Role of Galectin-3 in Obesity and Impaired Glucose Homeostasis. AB - Galectin-3 is an important modulator of several biological functions. It has been implicated in numerous disease conditions, particularly in the long-term complications of diabetes because of its ability to bind the advanced glycation/lipoxidation end products that accumulate in target organs and exert their toxic effects by triggering proinflammatory and prooxidant pathways. Recent evidence suggests that galectin-3 may also participate in the development of obesity and type 2 diabetes. It has been shown that galectin-3 levels are higher in obese and diabetic individuals and parallel deterioration of glucose homeostasis. Two studies in galectin-3 knockout mice fed a high-fat diet (HFD) have shown increased adiposity and adipose tissue and systemic inflammation associated with altered glucose homeostasis, suggesting that galectin-3 negatively modulates the responsiveness of innate and adaptive immunity to overnutrition. However, these studies have also shown that impaired glucose homeostasis occurs in galectin-3 knockout animals independently of obesity. Moreover, another study reported decreased weight and fat mass in HFD-fed galectin-3 knockout mice. In vitro, galectin-3 was found to stimulate differentiation of preadipocytes into mature adipocytes. Altogether, these data indicate that galectin-3 deserves further attention in order to clarify its role as a potential player and therapeutic target in obesity and type 2 diabetes. PMID- 26770662 TI - GEODESIC CURVATURE FLOW ON SURFACES FOR AUTOMATIC SULCAL DELINEATION. AB - Sulcal folds (sulci) on the cortical surface are important landmarks of interest for investigating brain development and disease. Accurate and automatic delineation of the sulci is a challenging problem due to substantial variability in their shapes across populations. We present a geodesic curvature flow method for an automatic and accurate delineation of sulcal curves. We assume as input an atlas brain surface mesh on which a set of sulcal curves have been delineated. The sulcal curves are transferred to approximate corresponding locations on the subject brain using a transformation defined by an automatic surface based registration method. The locations of these curves are then refined to follow the true sulcal fundi more closely using geodesic curvature flow on the cortical surface. We present a level set based formulation of this flow on non-flat surfaces which represents the sulcal curves as zero level sets. We also incorporate a curvature based weighting that drives the sulcal curves to the bottoms of the sulcal valleys in the cortical folds. The resulting PDE is discretized on a triangulated mesh using finite elements. Finally, we present a validation by comparing sets of automatically delineated sulcal curves with sets of manually delineated sulcal curves and show that the proposed method is able to find them accurately. PMID- 26770661 TI - The Role of Dopamine and Its Dysfunction as a Consequence of Oxidative Stress. AB - Dopamine is a neurotransmitter that is produced in the substantia nigra, ventral tegmental area, and hypothalamus of the brain. Dysfunction of the dopamine system has been implicated in different nervous system diseases. The level of dopamine transmission increases in response to any type of reward and by a large number of strongly additive drugs. The role of dopamine dysfunction as a consequence of oxidative stress is involved in health and disease. Introduce new potential targets for the development of therapeutic interventions based on antioxidant compounds. The present review focuses on the therapeutic potential of antioxidant compounds as a coadjuvant treatment to conventional neurological disorders is discussed. PMID- 26770659 TI - Roles of Oxidative Stress in Polycystic Ovary Syndrome and Cancers. AB - Oxidative stress (OS) has received extensive attention in the last two decades, because of the discovery that abnormal oxidation status was related to patients with chronic diseases, such as diabetes, cardiovascular, polycystic ovary syndrome (PCOS), cancer, and neurological diseases. OS is considered as a potential inducing factor in the pathogenesis of PCOS, which is one of the most common complex endocrine disorders and a leading cause of female infertility, affecting 4%-12% of women in the world, as OS has close interactions with PCOS characteristics, just as insulin resistance (IR), hyperandrogenemia, and chronic inflammation. It has also been shown that DNA mutations and alterations induced by OS are involved in cancer pathogenesis, tumor cell survival, proliferation, invasion, angiogenesis, and so on. Furthermore, recent studies show that the females with PCOS are reported to have an increasing risk of cancers. As a result, the more serious OS in PCOS is regarded as an important potential incentive for the increasing risk of cancers, and this study aims to analyze the possibility and potential pathogenic mechanism of the above process, providing insightful thoughts and evidences for preventing cancer potentially caused by PCOS in clinic. PMID- 26770663 TI - MODELING CHRONIC DISEASE PATIENT FLOWS DIVERTED FROM EMERGENCY DEPARTMENTS TO PATIENT-CENTERED MEDICAL HOMES. AB - Chronic Disease is defined as a long lasting health condition, which can develop and/or worsen over an extended time, but which can also be controlled. The monetary and budgetary toll due to its persistent nature has become unsustainable and requires pressing actions to limit their incidence and burden. This paper demonstrates the utility of the System Dynamics approach to simulate the behavior of key factors involved in the implementation of chronic disease management. We model the patient flow diversion from emergency departments (ED) to patient centered medical homes (PCMH), with emphasis on the visit rates, as well as the effect of insurance coverage, in an effort to assure continuity of quality care for Asthma patients at lower costs. The model is used as an evaluative method to identify conditions of a maintained health status through adequate policy planning, in terms of resources and capacity. This approach gives decision makers the ability to track the level of implementation of the intervention and generate knowledge about dynamics between population demands and the intervention effectiveness. The functionality of the model is demonstrated through the consideration of hypothetical scenarios executed using sensitivity analysis. PMID- 26770664 TI - A randomized, placebo-controlled trial of D-cycloserine for the enhancement of social skills training in autism spectrum disorders. AB - BACKGROUND: Researchers have demonstrated that d-cycloserine (DCS) can enhance the effects of behavioral interventions in adults with anxiety and enhances prosocial behavior in animal models of autism spectrum disorders (ASD). This study extended upon this background by combining DCS with behavioral social skills therapy in youth with ASD to assess its impact on the core social deficits of ASD. We hypothesized that DCS used in combination with social skills training would enhance the acquisition of social skills in children with ASD. METHODS: A 10-week, double-blind, placebo-controlled trial of DCS (50 mg) given 30 min prior to weekly group social skills training was conducted at two sites. Children with ASD were randomized to receive 10 weeks (10 doses) of DCS or placebo in a 1:1 ratio. RESULTS: No statistically significant difference attributable to drug treatment was observed in the change scores for the primary outcome measure, the Social Responsiveness Scale (SRS), total score (p = 0.45), or on secondary outcome measures. CONCLUSIONS: The results of this trial demonstrated no drug related short-term improvement on the primary outcome measure, or any of the secondary outcome measures. However, an overall significant improvement in SRS total raw score was observed from baseline to end of treatment for the entire group of children with ASD. This suggests a need to further study the efficacy of the social skills training protocol. Limitations to the current study and areas for future research are discussed. TRIAL REGISTRATION: ClinicalTrials.govNCT01086475. PMID- 26770666 TI - Lixisenatide in type 2 diabetes: latest evidence and clinical usefulness. AB - Type 2 diabetes (T2D) is a highly prevalent disorder that affects millions of people worldwide. The hallmark of T2D is hyperglycemia and, while many treatment modalities exist, achieving and maintaining glycemic control can be challenging. Glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) are an appealing treatment option as they improve glycemic control, reduce weight, and limit the risk of hypoglycemia. Lixisenatide is a once-daily GLP-1 RA that has been evaluated in the GetGoal clinical trial program and has demonstrated efficacy and tolerability across a spectrum of patients. The feature that most distinguishes lixisenatide from other GLP-1 RAs is its ability to substantially reduce postprandial glucose (PPG) for the meal immediately following injection. Because of its positive effects on PPG, lixisenatide is being considered as a replacement for prandial insulin, and a fixed dose combination product containing lixisenatide and basal insulin is in development. Lixisenatide is a promising new addition to the antidiabetic armamentarium, but due to the lack of real-world experience with the drug, its exact place in therapy is unknown. PMID- 26770665 TI - Increased expression of the PI3K catalytic subunit p110delta underlies elevated S6 phosphorylation and protein synthesis in an individual with autism from a multiplex family. AB - BACKGROUND: Dysfunctions in the PI3K/mTOR pathway have gained a lot of attention in autism research. This was initially based on the discovery of several monogenic autism spectrum disorders with mutations or defects in PI3K/mTOR signaling components. Recent genetic studies corroborate that defective PI3K/mTOR signaling might be a shared pathomechanism in autism disorders of so far unknown etiology, but functional molecular analyses in human cells are rare. The goals of this study were to perform a functional screen of cell lines from patients with idiopathic autism for defects in PI3K/mTOR signaling, to test if further functional analyses are suitable to detect underlying molecular mechanisms, and to evaluate this approach as a biomarker tool to identify therapeutic targets. METHODS: We performed phospho-S6- and S6-specific ELISA experiments on 21 lymphoblastoid cell lines from the AGRE collection and on 37 lymphoblastoid cell lines from the Simons Simplex Collection and their healthy siblings. Cell lines from one individual with increased S6 phosphorylation and his multiplex family were analyzed in further detail to identify upstream defects in PI3K signaling associated with autism diagnosis. RESULTS: We detected significantly increased S6 phosphorylation in 3 of the 21 lymphoblastoid cell lines from AGRE compared to a healthy control and in 1 of the 37 lymphoblastoid cell lines from the Simons Simplex Collection compared to the healthy sibling. Further analysis of cells from one individual with elevated S6 phosphorylation showed increased expression of the PI3K catalytic subunit p110delta, which was also observed in lymphoblastoid cells from other autistic siblings but not unaffected members in his multiplex family. The p110delta-selective inhibitor IC87114 reduced elevated S6 phosphorylation and protein synthesis in this cell line. CONCLUSIONS: Our results suggest that functional analysis of PI3K/mTOR signaling is a biomarker tool to identify disease-associated molecular defects that could serve as therapeutic targets in autism. Using this approach, we discovered impaired signaling and protein synthesis through the PI3K catalytic subunit p110delta as an underlying molecular defect and potential treatment target in select autism spectrum disorders. Increased p110delta activity was recently associated with schizophrenia, and our results suggest that p110delta may also be implicated in autism. PMID- 26770667 TI - Ponesimod, a selective S1P1 receptor modulator: a potential treatment for multiple sclerosis and other immune-mediated diseases. AB - The first oral treatment for relapsing multiple sclerosis, the nonselective sphingosine-1-phosphate receptor (S1PR) modulator fingolimod, led to identification of a pivotal role of sphingosine-1-phosphate and one of its five known receptors, S1P1R, in regulation of lymphocyte trafficking in multiple sclerosis. Modulation of S1P3R, initially thought to cause some of fingolimod's side effects, prompted the search for novel compounds with high selectivity for S1P1R. Ponesimod is an orally active, selective S1P1R modulator that causes dose dependent sequestration of lymphocytes in lymphoid organs. In contrast to the long half-life/slow elimination of fingolimod, ponesimod is eliminated within 1 week of discontinuation and its pharmacological effects are rapidly reversible. Clinical data in multiple sclerosis have shown a dose-dependent therapeutic effect of ponesimod and defined 20 mg as a daily dose with desired efficacy, and acceptable safety and tolerability. Phase II clinical data have also shown therapeutic efficacy of ponesimod in psoriasis. These findings have increased our understanding of psoriasis pathogenesis and suggest clinical utility of S1P1R modulation for treatment of various immune-mediated disorders. A gradual dose titration regimen was found to minimize the cardiac effects associated with initiation of ponesimod treatment. Selectivity for S1P1R, rapid onset and reversibility of pharmacological effects, and an optimized titration regimen differentiate ponesimod from fingolimod, and may lead to better safety and tolerability. Ponesimod is currently in phase III clinical development to assess efficacy and safety in relapsing multiple sclerosis. A phase II study is also ongoing to investigate the potential utility of ponesimod in chronic graft versus host disease. PMID- 26770668 TI - Eosinophilic airway inflammation: role in asthma and chronic obstructive pulmonary disease. AB - The chronic lung diseases, asthma and chronic obstructive pulmonary disease (COPD), are common affecting over 500 million people worldwide and causing substantial morbidity and mortality. Asthma is typically associated with Th2 mediated eosinophilic airway inflammation, in contrast to neutrophilic inflammation observed commonly in COPD. However, there is increasing evidence that the eosinophil might play an important role in 10-40% of patients with COPD. Consistently in both asthma and COPD a sputum eosinophilia is associated with a good response to corticosteroid therapy and tailored strategies aimed to normalize sputum eosinophils reduce exacerbation frequency and severity. Advances in our understanding of the multistep paradigm of eosinophil recruitment to the airway, and the consequence of eosinophilic inflammation, has led to the development of new therapies to target these molecular pathways. In this article we discuss the mechanisms of eosinophilic trafficking, the tools to assess eosinophilic airway inflammation in asthma and COPD during stable disease and exacerbations and review current and novel anti-eosinophilic treatments. PMID- 26770669 TI - Ocular itch associated with allergic conjunctivitis: latest evidence and clinical management. AB - Allergic conjunctivitis is one of the most common allergic conditions worldwide. Its incidence is increasing due to changing climate, pollution, increased pollen loads, and the subject's heightened immunological sensitivity in response to these environmental changes. The pathophysiology predominantly involves immunoglobulin E-related mast-cell activation, with release of histamine and other mediators contributing to the propagation of the response by calling in other immune cells and further inflammation. This article presents the evolution of ocular allergy treatments, from vasoconstrictors, to antihistamines and mast cell stabilizers, to the dual-acting agents, as well as corticosteroid and immunomodulatory options. Future targets for allergy treatment are also discussed. PMID- 26770670 TI - A review of the medical treatment of primary sclerosing cholangitis in the 21st century. AB - Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease that progresses to end-stage liver disease and cirrhosis. Recurrent biliary inflammation is thought to lead to dysplasia, and as such PSC confers a high risk of cholangiocarcinoma. PSC accounts for 10% of all UK liver transplants, although transplantation does not guarantee a cure with 20% recurrence in the graft. At present there are no effective medical treatment options for PSC, and trials of novel therapeutic agents are limited by the time taken to reach clinically significant endpoints with no well defined early surrogate markers for disease outcome. Moreover, PSC appears to be a heterogeneous disease with regards to disease distribution, associated inflammatory bowel disease and subsequent disease outcome, further compounding the issue. Thus existing trials have taken place in heterogeneous groups, are likely to be underpowered to detect any individual subgroups effect. The current mainstay of medical treatment is still with ursodeoxycholic acid, although there is no evidence that it alters long-term outcome. Small pilot studies of immunosuppressive agents have taken place, but despite evidence that may support studies in larger groups, these have not been conducted. Recent advances in our understanding of the disease pathogenesis may therefore pave the way for trials of novel therapeutic agents in PSC, even given the limitations described. This review explores the controversial evidence underlying current treatment strategies and discounted treatments, and explores prospective agents that may bring new hope to the treatment of PSC in the 21st century. PMID- 26770671 TI - High-intensity interval training (HIT) for effective and time-efficient pre surgical exercise interventions. AB - The advancement of perioperative medicine is leading to greater diversity in development of pre-surgical interventions, implemented to reduce patient surgical risk and enhance post-surgical recovery. Of these interventions, the prescription of pre-operative exercise training is gathering momentum as a realistic means for enhancing patient surgical outcome. Indeed, the general benefits of exercise training have the potential to pre-operatively optimise several pre-surgical risks factors, including cardiorespiratory function, frailty and cognitive function. Any exercise programme incorporated into the pre-operative pathway of care needs to be effective and time efficient in that any fitness gains are achievable in the limited period between the decision for surgery and operation (e.g. 4 weeks). Fortunately, there is a large volume of research describing effective and time-efficient exercise training programmes within the discipline of sports science. Accordingly, the objective of our commentary is to synthesise contemporary exercise training research, both from non-clinical and clinical populations, with the overarching aim of informing the development of effective and time-efficient pre-surgical exercise training programmes. The development of such exercise training programmes requires the careful consideration of several key principles, namely frequency, intensity, time, type and progression of exercise. Therefore, in light of more recent evidence demonstrating the effectiveness and time efficiency of high-intensity interval training-which involves brief bouts of intense exercise interspersed with longer recovery periods-the principles of exercise training programme design will be discussed mainly in the context of such high-intensity interval training programmes. Other issues pertinent to the development, implementation and evaluation of pre operative exercise training programmes, such as individual exercise prescription, training session monitoring and potential barriers and risks to high-intensity exercise are also discussed. The evidence presented suggests that individually prescribed and supervised high-intensity interval training programmes, encompassing a variety of exercise modes represent an effective and safe means of exercise therapy prior to surgery. PMID- 26770672 TI - Mechanisms involved in curcumin-induced human neutrophil apoptosis: Evidence that curcumin activates the endoplasmic reticulum stress-induced cell apoptosis pathway. AB - Curcumin was previously reported to accelerate neutrophil apoptosis, but the mechanism is unclear. Herein, we confirmed that curcumin induces human neutrophil apoptosis as assessed by cytology and by increase in the cell surface expression of annexin-V and CD16 shedding. Curcumin activated caspase-3 and the cleavage of the two cytoskeletal proteins lamin B1 and vimentin. In addition, curcumin activated protein kinase RNA-like endoplasmic reticulum kinase and eukaryotic initiation factor 2 alpha and reduced de novo protein synthesis and the protein expression of the two chaperone proteins, HSP70 and HSP90. We conclude that curcumin acts as an endoplasmic reticulum stressor in human neutrophils. The ability of curcumin to activate the endoplasmic reticulum stress-induced cell apoptotic pathway is part of its mode of action in primary cells like mature neutrophils. PMID- 26770673 TI - A randomized, controlled study of an educational intervention to improve recall of auxiliary medication labeling and adherence to antibiotics. AB - PURPOSE: To evaluate whether medication counseling with emphasis on auxiliary labels improves recall of auxiliary label information and adherence to medication schedules. METHODS: A prospective, randomized study of an educational intervention in community pharmacies near Baltimore, Maryland. Fifty literate, English-speaking adults receiving one of the 18 commonly dispensed antibiotics were randomized to receive a counseling session or no counseling. Five to seven days after medication pickup, a structured phone interview was conducted to capture data on recall of auxiliary labels and adherence. RESULTS: A total of 39 subjects completed the phone interview (78%). The rate of correct recall was high: 77% correct recall for all three labels. Among those with incorrect recall, 7 out of 9 subjects received no counseling (p = 0.11). The auxiliary labels incorrectly recalled were all related to dietary restrictions. CONCLUSION: The findings from this study suggest that medication counseling emphasizing auxiliary label information may lead to improved recall and adherence to antibiotics. Additional studies are required to confirm the preliminary findings and determine whether they correspond to improved adherence. Information most commonly misunderstood were related to dietary restrictions. Additional research focusing on counseling related to dietary restrictions is recommended. PMID- 26770674 TI - Should we think about wrist extensor after flexor tendon repair? AB - OBJECTIVE: To evaluate the activity of wrist extensor muscle, correlating with wrist motion during gripping after flexor tendon repair. DESIGN: Cross-sectional clinical measurement study. SETTING: Laboratory for biomechanics and rehabilitation. SUBJECTS: A total of 11 patients submitted to rehabilitation by early passive motion of the fingers with wrist flexion position were evaluated after 8 weeks of fingers flexor tendon repair and 11 healthy volunteers, all ranging from 20 to 37 years of age. INTERVENTION: Volunteers performed an isometric standardized gripping task. MAIN MEASURES: We used electrogoniometry to analyze wrist range of motion and surface electromyography, considering 100% maximum voluntary contraction to represent the amplitude of electromyographic activity of the extensor carpi radialis and flexor digitorum superficialis. RESULTS: Patients with flexor tendon repair showed co-activation deficit between wrist extensor (extensor carpi radialis) and flexor finger muscles (flexor digitorum superficialis) during gripping in the intermediate phase of rehabilitation, despite some recovering mobility for wrist extension (p <= 0.05). A moderate correlation between range of motion and extensor carpi radialis was present only for injured group (r = 0.32). Total active motion score, which represents finger active excursion, was regular or poor in 65% of cases, all with nerve repair associated. CONCLUSION: Wrist extensors have an important synergist role at handgrip, although some imbalance can be present after flexor tendon repair. These preliminary findings suggest that emphasis could be directed to add synergistic wrist motion in rehabilitation protocols after flexor tendon repair. Future studies with early active rehabilitation are necessary. PMID- 26770675 TI - Sildenafil dilates ophthalmic artery in type 2 diabetic patients. AB - BACKGROUND: Conflicting reports exist on the effect of sildenafil on ophthalmic artery blood flow; many visual disturbances due to vascular insult were reported with the use of sildenafil in diabetic patients like nonarteritic ischemic optic neuropathy. OBJECTIVES: The present work aimed to investigate whether sildenafil modulates ophthalmic artery vasoreactivity in patients with type 2 diabetes mellitus. Literature reports on this aspect are lacking. METHODS: A total of 35 male subjects were enrolled in this study, 18 with type 2 diabetes mellitus matched with 17 normal individuals. Ophthalmic artery was insonated through a transorbital window using colored Doppler equipment with transcranial Doppler facility. Ophthalmic artery reactivity was assessed using breath holding/hyperventilation test, before and after giving 50 mg oral sildenafil. RESULTS: It was found that in both normal subjects and diabetic patients, sildenafil increased baseline control of mean flow velocity of ophthalmic artery significantly (p < 0.05), breath holding caused a decrease of MFVopa (p < 0.05), and subsequent hyperventilation caused increase of MFVopa (p < 0.05). There was no statistically significant change in breath holding index and full range of vasodilatation of ophthalmic artery (p > 0.05) after sildenafil, in normal and diabetic groups. There was a significant increase of resistive index of ophthalmic artery flow in diabetic patients compared with that of normal subject (p < 0.05). Sildenafil decreased resistive index of ophthalmic artery flow significantly only in diabetic patients (p < 0.05). CONCLUSION: Sildenafil increased MFVopa, but had no significant effect on vasoreactivity of ophthalmic artery; sildenafil decreased resistive index only in type 2 diabetic patients. PMID- 26770676 TI - Feasibility of the Nintendo WiiFitTM for improving walking in individuals with a lower limb amputation. AB - OBJECTIVES: To evaluate the feasibility of the Nintendo WiiFitTM as an adjunct to usual therapy in individuals with a lower limb amputation. METHODS: The study was a Multiple Baseline (AB) Single Subject Research Design. Subjects were >=19 years old, had their first unilateral transtibial or transfemoral amputation <=12 months ago, and were participating in prosthetic training. WiiFit training was provided for 30 min, 5 times a week, for a minimum of 2 and a maximum of 6 weeks in addition to usual therapy. Feasibility indicators were safety, post intervention fatigue and pain levels, adherence, and subject's acceptability of the program as measured by the Short Feedback Questionnaire-modified (SFQ-M). The primary clinical outcome was walking capacity assessed by the 2 Minute Walk Test (2MWT). The secondary clinical outcomes were the Short Physical Performance Battery, L-test, and Activities-Specific Balance Confidence. RESULTS: Subjects (4 transtibial; 2 transfemoral) had a median age of 48.5 years (range = 45-59 years). No adverse events associated with the intervention occurred. Median pain and fatigue levels were 1.3 (range = 0.5-3.5) and 3.1 (range = 1.4-4.1), respectively. Median adherence was 80%. Subjects found the WiiFit enjoyable and acceptable (median SFQ-M = 35). Five subjects showed statistical improvement on the 2MWT and four on the secondary outcomes (p < 0.05). CONCLUSION: The WiiFit intervention was found to be feasible in individuals with unilateral lower limb amputation. This research provides the foundation for future clinical research investigating the use of the WiiFit as a viable adjunctive therapy to improve outcomes in individuals with unilateral lower limb amputation who are participating in prosthetic training. PMID- 26770677 TI - Sitagliptin ameliorates the progression of atherosclerosis via down regulation of the inflammatory and oxidative pathways. AB - BACK GROUND: Atherosclerosis is the major cause of death. The most common risk factors are hyperlipidemia, diabetes, and other factors like chronic infection and inflammation. OBJECTIVE: This study was undertaken to assess the effect of sitagliptin on atherosclerosis via interfering with inflammatory and oxidative pathways. MATERIALS AND METHODS: A total of 18 local domestic male rabbits were included in this study. The animals were randomly divided into three groups (6 rabbits in each group): Group I normal were fed with chow (oxiod) diet for 12 weeks. Group II were fed with 1% cholesterol enriched diet for 12 weeks. Group III rabbits fed with cholesterol enriched diet for 6 weeks, and then continued on cholesterol enriched diet and treated with sitagliptin 125 mg/kg/day orally for the next 6 weeks. Blood samples were collected at the start of the study, at 6 weeks of the study and then at the end of treatment to measure serum lipids profile, hsCRP and TNFalpha. At end of the study, the aorta was removed for measurement of MDA, glutathione and, aortic intima-media thickness. RESULTS: Sitagliptin results in a significant reduction (p < 0.05) in serum level of total cholesterol (TC), triglycerides (TG), high sensitive C-reactive protein (hsCRP) and TNFalpha with a significant increase (p < 0.05) in serum HDL level. There was a significant reduction (p < 0.05) in aortic MDA, in comparison to the untreated control group. Furthermore, sitagliptin causes significant increment (p < 0.05) in aortic GSH in comparison to induced untreated group. Regarding histopathological results, sitagliptin results in a significant reduction (p < 0.05) in atherosclerotic lesions in comparison to the induced untreated group and significant reduction in aortic intima-media thickness (p < 0.05). CONCLUSION: Sitagliptin reduced atherosclerosis progression in hyperlipidemic rabbit via its effect on lipid parameters and interfering with inflammatory and oxidative stress. PMID- 26770678 TI - Pharmacists' journey to clinical pharmacy practice in Ethiopia: Key informants' perspective. AB - OBJECTIVE: Clinical pharmacy practice has developed internationally to expand the role of a pharmacist well beyond the traditional roles of compounding and supplying drugs to roles more directly in caring for patients and providing medication consultation to staff. This area of practice is at the infant stage in Ethiopia. The aim of this study was to explore key informants' perspective in the implementation of clinical pharmacy practice in Jimma University Specialized Hospital, Ethiopia. METHOD: A qualitative study was conducted through in-depth interviews with the heads of departments (internal medicine, paediatrics, surgery, nurse, pharmacy, medical director, administration) and pharmacy student representatives. Qualitative data analysis was done after audiotapes were transcribed verbatim and notes were compiled. RESULTS: All of the respondents interviewed express diverse and conflicting perspectives on pharmacists' role, varying from a health-care professional to a business man. Despite this, the current pace of change worldwide takes the professions' mission to that of a provider of clinical pharmacy services. The data ascertained the change in pharmacy practice, and integrating clinical pharmacy services within the health care system should be seen as a must. Pharmacists should delineate from a business perspective and focus on widening the scope of the profession of pharmacy and should come close to the patient to serve directly. CONCLUSIONS: Although the perception of people on traditional roles of pharmacists was weak, there were promising steps in developing clinical pharmacy practice within the health-care system. Moreover, the results of this study revealed a high demand for this service among health-care providers. PMID- 26770679 TI - Placental blood transfusion in newborn babies reaches a plateau after 140 s: Further analysis of longitudinal survey of weight change. AB - OBJECTIVE: With the introduction of active management of the third stage of labour in the 1960s, it became usual practice to clamp and cut the umbilical cord immediately following birth. The timing of this cord clamping is controversial, as blood may beneficially be transferred to the baby if clamping of the cord is delayed slightly. There is no agreement, however, on how long the delay should be before clamping the cord. This study aimed to establish when blood ceased to flow in the umbilical cord to determine how long to delay clamping of the umbilical cord following delivery of the term newborn to maximise placental transfusion. METHODS: This observational study collected longitudinal weight measurements set in a hospital labour ward. A total of 26 mothers at term and their singleton babies participated in the study. In this reanalysis, the velocity of weight change over the first minutes of life determined by functional data analysis was estimated. RESULTS: We found that the flow velocity in the umbilical cord was on average 0 at 125 s after placing the baby on the scales, which was typically 140 s after birth. CONCLUSIONS: To maximise placental transfusion, cord clamping should be delayed for at least 140 s following birth of the baby. PMID- 26770680 TI - Exploring patient priorities among long-term conditions in multimorbidity: A qualitative secondary analysis. AB - OBJECTIVE: A lack of agreement between health-care providers and patient priorities can impact the health-care provider-patient relationship, treatment concordance and potentially health outcomes. Evidence suggests that people living with multiple morbidities do prioritise among their long-term conditions. However, the evidence revealing the underlying reasons behind this prioritisation remains limited. Given the potential implications for day-to-day self-management activity and ultimately patient outcomes, this study aims to explore how and why people with multimorbidity prioritise some long-term conditions over others and what the potential implications may be for self-management activity, and in turn, suggest how such information may help clinicians negotiate the management of multimorbidity patients. METHODS: A secondary analysis of qualitative data was conducted utilising four existing data sets collated from the three research centres involved. Purposive sampling provided a sample of 41 participants who had multimorbidity. The research team collectively coded and analysed the data thematically. RESULTS: All participants, except two, identified one 'main' priority long-term condition. Current priorities were arrived at by participants making comparisons between their long-term conditions, specifically by trading off the various attributes, impacts and perceived consequences of their individual long-term conditions. Two main themes emerged as to why participants identified a particular main long-term condition: (a) proximate issues surrounding barriers to functional health and (b) prioritisation of long-term conditions perceived to have a particular future risk. CONCLUSIONS: The recent focus on multimorbidity within the medical literature reflects its prevalence. It is therefore important to understand the complexities of the multimorbidity illness experience. We have added to the limited literature on condition prioritisation by revealing some novel understandings of the process of condition prioritisation which can feed into patient-provider consultations in order to allow better communication and treatment planning as well as, ultimately, optimise patient outcomes. PMID- 26770681 TI - Patients' attitudes and perceptions of two health-related quality-of-life questionnaires used to collect patient-reported outcome measures in the English National Health Service: A qualitative study of patients undergoing cardiac interventions. AB - OBJECTIVES: To explore patients' views on the EuroQol-5D and Coronary Revascularisation Outcome Questionnaire, tools currently used for collecting patient-reported outcome measures in the English National Health Service. The key questions were as follows: (1) whether patients consider them sensitive enough to detect change in their health after cardiovascular disease interventions and (2) whether they consider the health-related quality-of-life questions as meaningful. METHODS: Data were collected on patients' views using focus groups. We held four focus groups selecting participants on the basis of their baseline and follow-up EuroQol-5D scores. Data were analysed using framework analysis and grounded theory. RESULTS: Focus group participants confirmed that they had derived substantial health benefits from their cardiac interventions despite the lack of measurable effects on the EuroQol-5D scores. Participants felt that the EuroQol 5D questionnaire was limited because of the following reasons: Their health fluctuates from day to day.They had difficulty assessing their general health status on the visual analogue scale.They felt that the Coronary Revascularisation Outcome Questionnaire was limited because of the following reasons: They did not understand the clinical terms used.The impact of tiredness on their quality of life was not captured.They were unable to distinguish between the effects of their heart condition and other health issues.Additionally, neither questionnaire considers the adjustments people have made to their domestic arrangements to improve their health-related quality of life. CONCLUSION: This study provides evidence that the two questionnaires do not capture some aspects of health that patients consider important. Furthermore, the presence of co-morbidities masks the symptoms relating to the heart disease and the effect of their cardiac interventions. Future work on patient-reported outcome measures should consider developing new questionnaires that address these major concerns. PMID- 26770682 TI - A prospective observational study on different poisoning cases and their outcomes in a tertiary care hospital. AB - OBJECTIVES: Poisonings and snake bites constitute major health-care problems worldwide. This observational study was conducted to identify factors associated with outcomes in such cases and to suggest strategies to improve them. METHODS: This is a prospective study conducted in the emergency medicine department of a tertiary care hospital. The study included 102 poisoning and 64 snake bite cases. Data regarding demographics, mode of poisoning, lag time in treatment, first aid, outside and indoor treatment, co-morbid illness, duration of hospitalisation and final outcome were collected in a prestructured proforma. RESULTS: The age of the patients ranged from 11 to 68 years and incidence was more common among males (69.9%) compared to females (30.1%). The major types of poisonings included organophosphorus compounds (16.3%), aluminium phosphide (12%), drug overdose (10.8%) and corrosives (6%). There were 18 (18.6%) and 1 (1.6%) deaths in poisoning and snake bite cases, respectively. In poisoning cases, the duration of hospitalisation was significantly decreased if patient received outside treatment (p = 0.02) and if he or she had lesser lag time in reaching the hospital (p = 0.009). CONCLUSIONS: Measures to reduce lag time and provide immediate treatment at initial encounter may be effective in reducing duration of hospitalisation and possibly mortality in poisoning and snake bite cases. PMID- 26770683 TI - A walking intervention to reduce inflammation in patients with diabetes and peripheral arterial/artery disease: A pilot study. AB - OBJECTIVES: In this pilot study, we sought to determine whether walking reduces inflammation in patients with diabetes mellitus and peripheral arterial/artery disease. METHODS: We obtained blood samples from patients with diabetes mellitus and peripheral arterial/artery disease. Intervention participants were advised to walk for 50 min 3 days per week for 6 months. Participants completed assessments of comorbidities and walking ability. Difference-in-difference analyses were used to assess the relationship between group assignment and each biomarker over time. RESULTS: We randomized 55 participants (control = 25 and intervention = 30). At 6 months and based on p values of <0.20, vascular cellular adhesion molecule, beta 2 microglobulin, total cholesterol, and triglycerides demonstrated a greater decrease among participants randomized to the intervention compared to the control. CONCLUSIONS: Walking may reduce inflammation in persons with diabetes mellitus and peripheral arterial/artery disease. Further research is needed to determine the impact of walking on inflammation in persons with vascular disease. PMID- 26770684 TI - Trouble with ataxia: A longitudinal qualitative study of the diagnosis and medical management of a group of rare, progressive neurological conditions. AB - OBJECTIVES: An exploratory investigation of diagnosis and management in progressive ataxias: rare neurological conditions usually affecting balance, mobility and speech. METHODS: A longitudinal qualitative study into the experiences of people with ataxia and neurologists. Thematic analysis and follow up interviews were used to determine diagnosis and management issues over time. RESULTS: People with ataxia recruited via two hospital departments and Ataxia UK were interviewed at baseline (n = 38) and 12-month follow-up (n = 31). Eight consultant neurologists were interviewed once. Patient accounts were diverse, but many expressed frustration at having an incurable condition and dissatisfaction with service outcomes. At follow-up, there was variation in their contact and satisfaction with helping agencies. Service issues regarding continuity of care and the primary/secondary care interface were evident. Neurologists' accounts also varied. One-half reported that there is nothing that can be done, and one half favoured specialist referral to increase the likelihood of finding an underlying aetiology within budget constraints. CONCLUSIONS: Diagnostic uncertainties existing at baseline remained for patients at follow-up interviews, although some had learned to deal with the uncertainties brought by the diagnosis of a largely untreatable condition. Care pathways only seemed to operate in the case of defined conditions, such as Friedreich's Ataxia, the most commonly inherited cause. The findings point to a need to develop the evidence base to inform the relative utility of diagnostic procedures in the context of finite resources for patient care and support. PMID- 26770685 TI - Comparison of sequentially measured Aloka echo-tracking one-point pulse wave velocity with SphygmoCor carotid-femoral pulse wave velocity. AB - OBJECTIVES: Recently, echo-tracking-derived measures of arterial stiffness have been introduced in clinical practice for the assessment of one-point pulse wave velocity. The purpose of this study was to find a relation between carotid femoral pulse wave velocity and one-point carotid pulse wave velocity, and to find a value of one-point carotid pulse wave velocity that predicts carotid femoral pulse wave velocity higher than 12 m/s. METHODS: A total of 160 consecutive subjects (112 male/48 female, mean age = 51.5 +/- 14.1 years; 96 healthy, 44 hypertensives, 13 with aortic valve disease, and 7 with left ventricular dysfunction) were studied. Carotid-femoral pulse wave velocity was measured with the SphygmoCor system and one-point carotid pulse wave velocity with high-definition echo-tracking system (ProSound Alpha10; Aloka, Tokyo, Japan). RESULTS: Both carotid-femoral pulse wave velocity and one-point carotid pulse wave velocity correlated significantly with each other (r = 0.539, p < 0.001) and with age (one-point carotid pulse wave velocity r = 0.618, carotid femoral pulse wave velocity r = 0.617, p < 0.0001 for both). Median value of carotid-femoral pulse wave velocity (7.2 m/s, 95% confidence interval = 6.2-8.9) was systematically higher than that of one-point carotid pulse wave velocity (5.8 m/s, 95% confidence interval = 5-6.6). The area under the receiver operating characteristic curve was 0.85, identifying the cutoff for one-point pulse wave velocity of 6.65 m/s as the best predictor of carotid-femoral pulse wave velocity more than 12 m/s (sensitivity = 0.818, specificity = 0.819). CONCLUSIONS: One point carotid pulse wave velocity correlates with carotid-femoral pulse wave velocity, and the cutoff of 6.65 m/s was the best predictor of carotid-femoral pulse wave velocity over 12 m/s. PMID- 26770686 TI - A specially tailored vancomycin continuous infusion regimen for renally impaired critically ill patients. AB - BACKGROUND: Vancomycin remains the gold standard for treatment of methicillin resistant Staphylococcus aureus. Specially designed continuous infusion of vancomycin leads to better therapy. METHODOLOGY: A total of 40 critically ill patients who suffered from pneumonia susceptible to vancomycin, had serum creatinine >1.4 mg%, and oliguria <0.5 mL/kg/h for 6 h were included in the study with respiratory culture sensitivity to vancomycin <=2 mg/L. Patients' clinical, microbiological, and biological data were obtained by retrospective analysis of the corresponding medical files before and after vancomycin treatment. Patients with serum creatinine level >=4 mg% and patients who received renal replacement therapy during the treatment period were excluded. The patients were divided into two groups-group 1 (intermittent dosing) and group 2 (continuous infusion) based on the following formula: rate of vancomycin continuous infusion (g/day) = [0.0205 creatinine clearance (mL/min) + 3.47] * [target vancomycin concentration at steady state (ug/mL)] * (24/1000). Trough vancomycin serum levels were also assessed using high-performance liquid chromatographic technique. Patients' outcomes such as clinical improvement, adverse events, and 15-day mortality were reported. RESULTS: Group 2 showed significant reduction in blood urea nitrogen, creatinine serum levels, white blood cells, partial carbon dioxide pressure, body temperature, and Sequential Organ Failure Assessment score, while significant increase in partial oxygen pressure and saturated oxygen was also observed. A significantly shorter duration of treatment with a comparable vancomycin serum levels was also reported with group 2. CONCLUSION: After treatment, comparison in patients' criteria supports the superiority of using continuous infusion of vancomycin according to this equation in renally impaired patients. PMID- 26770687 TI - Intimate partner violence influence on deliveries assisted by skilled health personnel. AB - OBJECTIVE: Millennium Development Goal 5 calls for increasing proportions of deliveries assisted by skilled health personnel to reduce maternal mortality. This study aims to identifying the implication of exposure to intimate partner violence on these proportions. METHODOLOGY: This study used domestic violence modules data of Demographic and Health Surveys of six countries from 2005 to 2007. Proportions of assisted deliveries were examined by sociodemographic characteristics and exposure to intimate partner violence in the studied countries. Influence on the proportion was examined against exposure to intimate partner violence through odds ratio and 95% of logistic regression analysis after controlling for women age, residence (urban/rural), household wealth level, economic level of country, educational level and working status of women and their husbands/partners. RESULTS: Data sets of 18,507 participants over 20 years of age showed that almost three-quarters (73%) of women had deliveries assisted by skilled health personnel. One-third of the women were ever exposed to intimate partner violence (37%) and 9% of them to the severe level. Exposure to intimate partner violence statistically significantly lowered this proportion to 69% (odds ratio: 0.73; 95% confidence interval: 0.67-0.78) meanwhile severe violence lowered it to 65% (odds ratio 0.64; 95% confidence interval: 0.58-0.72). When running multiple regression analysis, exposure to intimate partner violence retained its statistically significant decreasing influence on proportions and was not biased by the other stronger socioeconomic characteristics. CONCLUSION AND RECOMMENDATIONS: Intimate partner violence has an independent influence on reducing assisted deliveries by skilled health personnel. Programs working for increasing proportions of assisted deliveries by skilled health personnel are recommended to integrate protection women from violence. PMID- 26770688 TI - Ayahuasca and cancer treatment. AB - OBJECTIVES: Comprehensively review the evidence regarding the use of ayahuasca, an Amerindian medicine traditionally used to treat many different illnesses and diseases, to treat some types of cancer. METHODS: An in-depth review of the literature was conducted using PubMed, books, institutional magazines, conferences and online texts in nonprofessional sources regarding the biomedical knowledge about ayahuasca in general with a specific focus in its possible relations to the treatment of cancer. RESULTS: At least nine case reports regarding the use of ayahuasca in the treatment of prostate, brain, ovarian, uterine, stomach, breast, and colon cancers were found. Several of these were considered improvements, one case was considered worse, and one case was rated as difficult to evaluate. A theoretical model is presented which explains these effects at the cellular, molecular, and psychosocial levels. Particular attention is given to ayahuasca's pharmacological effects through the activity of N,N dimethyltryptamine at intracellular sigma-1 receptors. The effects of other components of ayahuasca, such as harmine, tetrahydroharmine, and harmaline, are also considered. CONCLUSION: The proposed model, based on the molecular and cellular biology of ayahuasca's known active components and the available clinical reports, suggests that these accounts may have consistent biological underpinnings. Further study of ayahuasca's possible antitumor effects is important because cancer patients continue to seek out this traditional medicine. Consequently, based on the social and anthropological observations of the use of this brew, suggestions are provided for further research into the safety and efficacy of ayahuasca as a possible medicinal aid in the treatment of cancer. PMID- 26770689 TI - Risk-assessment score for screening diabetes mellitus among Omani adults. AB - PURPOSE: The purpose of this study was to evaluate a self-administered risk assessment scoring system for identifying Omani adults with type 2 diabetes mellitus (T2DM). METHODS: An exploratory cross-sectional design was used. Simple random sampling was used to select 93 adults in Muscat. Ethical approval was obtained from the College of Nursing Research and Ethics Committee. The Finnish Diabetes Risk Score (FINDRISC) was used to collect the data in 2009. Informed consent was obtained from the participants. Data were analysed with the Pearson chi-square test. RESULTS: A total of 9.7% of the adults had very high FINDRISC and 17.2% had slightly elevated risk of developing T2DM within 10 years. The risk assessment (family history, waist circumference, body mass index, physical activity, dietary intake, hypertension and high blood glucose) of T2DM was significant and positively related to the prediction of T2DM among Omani adults. PMID- 26770690 TI - Primary care practitioner and patient understanding of the concepts of multimorbidity and self-management: A qualitative study. AB - OBJECTIVES: The aim of this article is to offer insight into how professionals and patients understand and experience multimorbidity and how these accounts differ, and how they affect attitudes and engagement with self-management. METHODS: Semi-structured interviews with 20 primary healthcare practitioners and 20 patients with at least 2 long-term conditions (including coronary heart disease, diabetes, osteoarthritis, chronic obstructive pulmonary disease and depression). Thematic analysis was used, and themes were identified using an open coding method. RESULTS: Practitioners associated multimorbidity with complexity and uncertainty in the clinic, leading to emotional strain and 'heart sink'. Patient accounts differed. Some described multimorbidity as problematic when it exacerbated their symptoms and caused emotional and psychological strain. Others did not perceive multimorbidity as problematic. Self-management was seen by practitioners and patients to be a key element of managing multiple conditions, but drivers for prompting and engaging in self-management differed between patients and practitioners. CONCLUSION: This study suggests that recommendations for clinical practice for multimorbid patients should take into account the gap in perceptions between practitioner and patients about experiences of multimorbidity. Not least, practice would need to reflect the tension between practitioners' and patients' accounts about the role and benefits of self management in the presence of multimorbidity. PMID- 26770691 TI - Science and technology of the emerging nanomedicines in cancer therapy: A primer for physicians and pharmacists. AB - Nanomedicine, the medical applications of devices based on nanotechnology, promises an endless range of applications from biomedical imaging to drug and gene delivery. The size range of the nanomaterials is strictly defined as 1-100 nm, although many marketed nanomedicines are in the submicron range of 100-1000 nm. The major advantages of using nanomaterials as a carrier for anticancer agents are the possibility of targeted delivery to the tumor; their physical properties such as optical and magnetic properties, which can be exploited for developing contrast agents for tumor imaging; their ability to hold thousands of molecules of a drug and deliver at the required site and also the ability to overcome solubility and stability issues. Currently, there are several nanotechnology-enabled diagnostic and therapeutic agents undergoing clinical trials and a few already approved by Food and Drug Administration. Targeted delivery of anticancer agents is achieved by exploiting a unique characteristic of the rapidly dividing tumor cells called "the enhanced permeability and retention effect." Nanoparticles with mean diameter between 100 and 200 nm or even above 200 nm have also been reported to be taken up by tumor cells via the enhanced permeability and retention effect. In addition to this passive targeting based on size, the nanoparticle surface may be modified with a variety of carefully chosen ligands that would interact with specific receptors on the surface of the tumor cells, thus imparting additional specificity for active targeting. Regional release of a drug contained in a nanoparticulate system by the application of external stimuli such as hyperthermia to a thermosensitive device is another innovative strategy for targeted delivery. Nanoparticles protect the enclosed drug from rapid elimination from the body, keep them in circulation for prolonged periods and often evade expulsion by the efflux pump mechanisms, which also leads to avoidance of development of resistance. This review focuses on the science and technology of Food and Drug Administration approved cancer nanomedicines such as Abraxane, Doxil, DaunoXome and those drug delivery systems that have reached an advanced stage of clinical development utilizing liposomes, albumin nanospheres, thermosensitive devices and gold nanoshells. PMID- 26770692 TI - Increased expression of ADAMTS13 mRNA correlates with ischemic cerebrovascular disease in systemic lupus erythematosus patients. AB - OBJECTIVE: We investigated ADAMTS13 (a disintegrin-like and metalloprotease with thrombospondin type 1 motif, member 13) messenger RNA levels as a biomarker of disease features in systemic lupus erythematosus. METHODS: We measured and compared messenger RNA (mRNA) levels of ADAMTS13 in peripheral blood cells in patients with systemic lupus erythematosus and healthy control subjects by whole genome microarray. We retrospectively analyzed the correlations of ADAMTS13 mRNA expression with clinical features, laboratory parameters, therapeutic features, and disease activity (according to the Systemic Lupus Erythematosus Disease Activity Index). We also examined the association of three single nucleotide polymorphisms (rs4962145, rs2285467, and rs685523) of the ADAMTS13 gene with patient characteristics. RESULTS: In 309 patients, the median ADAMTS13 mRNA expression levels were significantly higher in blood cells of systemic lupus erythematosus patients than in 23 healthy controls (p = .03). Notably, ADAMTS13 mRNA expression levels were significantly higher in systemic lupus erythematosus patients with a history of stroke (p = .02) or transient ischemic attack (p = .02). Among the three single nucleotide polymorphisms analyzed, rs2285467 was significantly associated with stroke (p = .03) and anticardiolipin antibodies (p = .04). CONCLUSIONS: Increased expression of ADAMTS13 mRNA in blood cells is associated with the presence of ischemic cerebrovascular disease in systemic lupus erythematosus patients and suggests a potential role for ADAMTS13 in the pathogenesis of ischemic cerebrovascular disease in these patients. PMID- 26770693 TI - Performance of the 10-item Center for Epidemiologic Studies Depression scale for caregiving research. AB - OBJECTIVES: The Center for Epidemiologic Studies Depression (CESD) scale has been useful in a broad spectrum of health research on patient and population outcomes. A brief version is used when depressive symptoms are not the primary focus. Rasch (item response) analysis previously demonstrated potential problems with positively worded items. We tested the 10-item CESD (CESD-10) scale and considered an 8-item version with both psychometric and Rasch analyses. METHODS: This was a special sample of 2067 caregivers from three existing US databases. We describe item response patterns and internal constancy in addition to Rasch scale results. RESULTS: There were few problems with missing data, and internal consistency was high (alpha = 0.86-0.88) for both CESD versions. Rasch analysis indicated that one of the positive items ("hopeful about future") could be dropped. CONCLUSIONS: We partly confirmed prior work that suggested dropping positive items for the CESD-10. Among caregivers, item-level problems and scaling problems seem minimal. At present, there is not a strong rationale for dropping the CESD-10 positive items: the one poorly performing positive item might be explained by the special caregiver sample. PMID- 26770695 TI - Evaluation of pharmacist counseling in improving knowledge, attitude, and practice in chronic kidney disease patients. AB - BACKGROUND: Chronic kidney disease is a public health problem with an increasing incidence and prevalence, poor outcomes, and high cost. Patient involvement forms the keystone in the management of chronic kidney disease. This study evaluated effects of pharmacist-provided counseling in dialysis patients in terms of their knowledge, attitude, and practice outcomes. METHODS: A total of 64 patients with chronic kidney disease were enrolled into the prospective, pre-post study based on the inclusion and exclusion criteria. The knowledge, attitude, and practice of patients regarding chronic kidney disease were assessed and recorded via baseline questionnaire. Case group patients were counseled regarding chronic kidney disease, their medication, diet, and lifestyle, and they were also provided with informative leaflet, whereas in the control group patients, the pharmacist did not intervene. After 1-month intervention, knowledge, attitude, and practice scores of patients of both groups were measured using the same knowledge, attitude, and practice questionnaire. Effectiveness of counseling on case group patients was evaluated by comparing the mean knowledge, attitude, and practice scores before and after counseling by paired t-test. RESULTS: Mean knowledge, attitude, and practice scores before intervention were 8.16 +/- 4.378, 38.19 +/- 3.217, and 6.69 +/- 0.896, respectively, and these scores were changed to 13.75 +/- 3.510, 38.78 +/- 3.035, and 6.91 +/- 0.777, respectively, after the intervention (p < 0.05). CONCLUSIONS: The pharmacist-provided counseling is effective in improving knowledge, attitude, and practice of patients toward the disease management. PMID- 26770694 TI - One of the most urgent vascular circumstances: Acute limb ischemia. AB - Acute limb ischemia is a sudden decrease in limb perfusion that threatens limb viability and requires urgent evaluation and management. Most of the causes of acute limb ischemia are thrombosis of a limb artery or bypass graft, embolism from the heart or a disease artery, dissection, and trauma. Assessment determines whether the limb is viable or irreversibly damaged. Prompt diagnosis and revascularization by means of catheter-based thrombolysis or thrombectomy and by surgery reduce the risk of limb loss and mortality. Amputation is performed in patients with irreversible damage. Despite urgent revascularization, amputation rate is 10%-15% in patients during hospitalization, mostly above the knee, and mortality within 1 year is 10%-15% due to the coexisting conditions. PMID- 26770696 TI - Characteristics, risk factors and case fatality rate of stroke in hospitalized patients in semi-urban South-South Nigeria. AB - BACKGROUND: Stroke causes death and disability worldwide. Hypertension is the most prevalent risk factor. In Nigeria, studies on outcome and risk factors of stroke are from urban-based hospitals. This study aims to look at stroke outcome and the major modifiable risk factors of hospitalized stroke patients in semi urban Nigeria. METHODS: The medical records of stroke patients admitted between March 2008 and February 2010 were reviewed retrospectively. The relevant demographic, clinical and laboratory data of each patient were retrieved. RESULTS: A total of 99 cases of stroke made up of 51 males and 48 females were reviewed. Mean age of the subjects was 66.22 +/- 12.67 years. Mean systolic blood pressure and diastolic blood pressure at presentation were 171.41 +/- 39.10 mmHg and 100.44 +/- 21 mmHg, respectively. About 61.6% were known hypertensives, while 31.3%, not previously known to be hypertensive, had SBP >= 140 mmHg and/or diastolic blood pressure >= 90 mmHg. Overall, 85.9% of the subjects had SBP >= 140 mmHg and/or DBP >= 90 mmHg. In all, 46.5% had SBP >= 180 mmHg, and 63% of this number had SBP >= 200 mmHg; 42.4% had DBP >= 110 mmHg. Other major risk factors were hypercholesterolaemia (34.4%), diabetes mellitus (16.6%), previous cerebrovascular accident (15.2%) and smoking (9.4%). In all, 31.3% had two or more modifiable stroke risk factors. 36.4% of the subjects were comatose. Overall case fatality rate was 45.8%, 75% of the subjects with coma died, compared to 27.6% without coma (p < 0.01). CONCLUSION: Mortality in our stroke patients is high. Hypertension is the commonest modifiable risk factor, and the presence of coma at presentation is associated with poor prognosis. PMID- 26770697 TI - Early feeding and neonatal hypoglycemia in infants of diabetic mothers. AB - OBJECTIVES: To examine the effects of early formula feeding or breast-feeding on hypoglycemia in infants born to 303 A1-A2 and 88 Class B-RF diabetics. METHODS: Infants with hypoglycemia (blood glucose < 40 mg/dL) were breast-fed or formula fed, and those with recurrences were given intravenous dextrose. RESULTS: Of 293 infants admitted to the well-baby nursery, 87 (30%) had hypoglycemia, corrected by early feeding in 75 (86%), while 12 (14%) required intravenous dextrose. In all, 98 infants were admitted to the newborn intensive care unit for respiratory distress (40%), prematurity (33%) or prevention of hypoglycemia (27%). Although all newborn intensive care unit patients received intravenous dextrose, 22 (22%) had hypoglycemia. Of 109 hypoglycemia episodes, 89 (82%) were single low occurrences. At discharge, 56% of well-baby nursery and 43% of newborn intensive care unit infants initiated breast-feeding. CONCLUSIONS: Hypoglycemia among infants of diabetic mothers can be corrected by early breast-feeding or formula feeding. PMID- 26770698 TI - Antioxidant effect of garlic (Allium sativum) and black seeds (Nigella sativa) in healthy postmenopausal women. AB - OBJECTIVES: The objective of this study is to investigate the antioxidant effects of garlic extract and crude black seeds' consumption on blood oxidant/antioxidant levels in healthy postmenopausal women. METHODS: In total, 30 healthy postmenopausal women (mean age = 50.31 +/- 4.23 years) participated. They ingested two garlic soft gels per day (each is equivalent to 1000 mg of fresh garlic bulb) and crude black seed grounded to powder in a dose of 3 g/day for 8 weeks. Oxidant (malondialdehyde) activity in plasma and antioxidants superoxide dismutase and glutathione peroxidase activities in erythrocytes were studied. RESULTS: Significant low levels of plasma malondialdehyde with increased erythrocyte glutathione peroxidase and superoxide dismutase activities. DISCUSSION: Menopause is associated with an increase in oxidative stress and a decrease in some antioxidant parameters. Consumption of garlic extracts and crude black seeds may have a beneficial effect on improved balance between blood oxidants and antioxidants in healthy postmenopausal women. PMID- 26770699 TI - Clinical assessment of the warming sensation accompanying flavor 316282 in a cold and cough syrup containing paracetamol, phenylephrine hydrochloride, and guaifenesin. AB - OBJECTIVE: The primary objective was to assess the warming sensation caused by flavor 316282 in a cold and cough product in the target population. METHODS: A single-cohort, single-treatment arm, open-label study. Subjects received one 30 mL dose of syrup containing flavor 316282, paracetamol, phenylephrine hydrochloride, and guaifenesin and recorded onset and disappearance of any warming sensation in the mouth/throat. Subjects' assessment of strength and appeal of the sensation, taste, texture, and acceptability of the product as a cold and cough remedy was investigated using questionnaires. RESULTS: A total of 51 subjects were included; 47 (92.1%) experienced a warming sensation. The median duration of the warming sensation was 100 s (95% confidence interval = 82 s, 112 s). The majority of subjects rated the syrup as excellent, good, or fair for treatment of cough and cold symptoms (96.1%), taste (80.4%), and texture (98.0%). There were no safety concerns, and the syrup was well tolerated. Most subjects liked the warming sensation. CONCLUSIONS: Flavor 316282 in a cold and cough syrup is associated with a warming sensation. The syrup is well tolerated, safe, and palatable. PMID- 26770700 TI - Comparable mid-term survival in patients undergoing elective fenestrated endovascular aneurysm repair and endovascular aneurysm repair for abdominal aortic aneurysm. AB - OBJECTIVE: To evaluate mid-term survival in patients undergoing elective fenestrated endovascular aneurysm repair and standard endovascular aneurysm repair for abdominal aortic aneurysm. METHODS: Consecutive patients treated from 2007 to 2011 with elective fenestrated endovascular aneurysm repair (n = 81) and endovascular aneurysm repair (n = 201) were evaluated concerning age, cardiovascular medication, comorbidities, and mid-term mortality. RESULTS: Patients in the elective fenestrated endovascular aneurysm repair group were younger than the endovascular aneurysm repair group (p = 0.006). In comparison with the endovascular aneurysm repair group, a lower proportion of patients in the elective fenestrated endovascular aneurysm repair group had diabetes (p = 0.013) and anemia (p = 0.003), and a higher proportion had arterial hypertension (p = 0.009). When entering age, endovascular aneurysm repair or fenestrated endovascular aneurysm repair operation, diabetes, anemia, and hypertension in a Cox regression model, only age (hazard ratio: 1.07; 95% confidence interval: 1.03 1.11; p < 0.001) was a risk factor for mid-term mortality. CONCLUSION: Careful patient selection and medical optimization resulted in comparable mid-term survival in patients undergoing elective fenestrated endovascular aneurysm repair and endovascular aneurysm repair. PMID- 26770701 TI - Medical errors in hospitalized pediatric trauma patients with chronic health conditions. AB - OBJECTIVE: This study compares medical errors in pediatric trauma patients with and without chronic conditions. METHODS: The 2009 Kids' Inpatient Database, which included 123,303 trauma discharges, was analyzed. Medical errors were identified by International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis codes. The medical error rates per 100 discharges and per 1000 hospital days were calculated and compared between inpatients with and without chronic conditions. RESULTS: Pediatric trauma patients with chronic conditions experienced a higher medical error rate compared with patients without chronic conditions: 4.04 (95% confidence interval: 3.75-4.33) versus 1.07 (95% confidence interval: 0.98-1.16) per 100 discharges. The rate of medical error differed by type of chronic condition. After controlling for confounding factors, the presence of a chronic condition increased the adjusted odds ratio of medical error by 37% if one chronic condition existed (adjusted odds ratio: 1.37, 95% confidence interval: 1.21-1.5), and 69% if more than one chronic condition existed (adjusted odds ratio: 1.69, 95% confidence interval: 1.48-1.53). In the adjusted model, length of stay had the strongest association with medical error, but the adjusted odds ratio for chronic conditions and medical error remained significantly elevated even when accounting for the length of stay, suggesting that medical complexity has a role in medical error. Higher adjusted odds ratios were seen in other subgroups. CONCLUSION: Chronic conditions are associated with significantly higher rate of medical errors in pediatric trauma patients. Future research should evaluate interventions or guidelines for reducing the risk of medical errors in pediatric trauma patients with chronic conditions. PMID- 26770702 TI - A randomised controlled feasibility study investigating the use of eccentric and concentric strengthening exercises in the treatment of rotator cuff tendinopathy. AB - OBJECTIVES: To conduct a feasibility study to compare concentric and eccentric rotator cuff strengthening exercises for rotator cuff tendinopathy. METHODS: A total of 11 patients with rotator cuff tendinopathy who were on the waiting list for arthroscopic subacromial decompression surgery were randomised to perform eccentric rotator cuff strengthening exercises, concentric strengthening exercises or no exercises. Patients were evaluated in terms of levels of pain and function using the Oxford Shoulder Score and a Visual Analogue Scale initially, at 4 weeks and at 8 weeks. RESULTS: The study design was found to be acceptable to patients and achieved a high level of 86% compliance. The drop-out rate was 0%. Two patients performing eccentric strengthening exercises improved sufficiently to cancel their planned surgery. CONCLUSION: Further research in this area is recommended. The study design was feasible and power calculations have been conducted to aid future research planning. PMID- 26770703 TI - Pancreatitis Quality of Life Instrument: Development of a new instrument. AB - OBJECTIVES: The goal of this project was to develop the first disease-specific instrument for the evaluation of quality of life in chronic pancreatitis. METHODS: Focus groups and interview sessions were conducted, with chronic pancreatitis patients, to identify items felt to impact quality of life which were subsequently formatted into a paper-and-pencil instrument. This instrument was used to conduct an online survey by an expert panel of pancreatologists to evaluate its content validity. Finally, the modified instrument was presented to patients during precognitive testing interviews to evaluate its clarity and appropriateness. RESULTS: In total, 10 patients were enrolled in the focus groups and interview sessions where they identified 50 items. Once redundant items were removed, the 40 remaining items were made into a paper-and-pencil instrument referred to as the Pancreatitis Quality of Life Instrument. Through the processes of content validation and precognitive testing, the number of items in the instrument was reduced to 24. CONCLUSIONS: This marks the development of the first disease-specific instrument to evaluate quality of life in chronic pancreatitis. It includes unique features not found in generic instruments (economic factors, stigma, and spiritual factors). Although this marks a giant step forward, psychometric evaluation is still needed prior to its clinical use. PMID- 26770704 TI - The population health approach: A qualitative study of conceptual and operational definitions for leaders in Canadian healthcare. AB - OBJECTIVES: The population health approach is increasingly recognized for its role in health system reform; however, its broad scope and definition have been criticized for being a barrier to clear communication. This qualitative study examined the way senior healthcare leaders in Canada conceptualize and operationalize the population health approach in planning and decision-making. FINDINGS: Core elements of the population health approach included focusing on health and wellness rather than illness, taking a population rather than individual orientation, understanding needs and solutions through community outreach, addressing health disparities/health in vulnerable groups, addressing the social determinants of health and inter-sectoral action and partnerships. CONCLUSION: The population health approach is increasingly recognized for its role in reducing healthcare demand and contributing to health system sustainability. This study demonstrated the growing need to clarify terminology among multiform partners to establish a foundation for future healthcare integration and inter-sectoral action. PMID- 26770705 TI - Development of an interprofessional program for cardiovascular prevention in primary care: A participatory research approach. AB - BACKGROUND: The chronic care model provides a framework for improving the management of chronic diseases. Participatory research could be useful in developing a chronic care model-based program of interventions, but no one has as yet offered a description of precisely how to apply the approach. OBJECTIVES: An innovative, structured, multi-step participatory process was applied to select and develop (1) chronic care model-based interventions program to improve cardiovascular disease prevention that can be adapted to a particular regional context and (2) a set of indicators to monitor its implementation. METHODS: Primary care clinicians (n = 16), administrative staff (n = 2), patients and family members (n = 4), decision makers (n = 5), researchers, and a research coordinator (n = 7) took part in the process. Additional primary care actors (n = 26) validated the program. RESULTS: The program targets multimorbid patients at high or moderate risk of cardiovascular disease with uncontrolled hypertension, dyslipidemia or diabetes. It comprises interprofessional follow-up coordinated by case-management nurses, in which motivated patients are referred in a timely fashion to appropriate clinical and community resources. The program is supported by clinical tools and includes training in motivational interviewing. A set of 89 process and clinical indicators were defined. CONCLUSION: Through a participatory process, a contextualized interventions program to optimize cardiovascular disease prevention and a set of quality indicators to monitor its implementation were developed. Similar approach might be used to develop other health programs in primary care if program developers are open to building on community strengths and priorities. PMID- 26770706 TI - Chamber dimensions and functional assessment with coronary computed tomographic angiography as compared to echocardiography using American Society of Echocardiography guidelines. AB - BACKGROUND: The correlation between normal cardiac chamber linear dimensions measured during retrospective coronary computed tomographic angiography as compared to transthoracic echocardiography using the American Society of Echocardiography guidelines is not well established. METHODS: We performed a review from January 2005 to July 2011 to identify subjects with retrospective electrocardiogram-gated coronary computed tomographic angiography scans for chest pain and transthoracic echocardiography with normal cardiac structures performed within 90 days. Dimensions were manually calculated in both imaging modalities in accordance with the American Society of Echocardiography published guidelines. Left ventricular ejection fraction was calculated on echocardiography manually using the Simpson's formula and by coronary computed tomographic angiography using the end-systolic and end-diastolic volumes. RESULTS: We reviewed 532 studies, rejected 412 and had 120 cases for review with a median time between studies of 7 days (interquartile range (IQR25,75) = 0-22 days) with no correlation between the measurements made by coronary computed tomographic angiography and transthoracic echocardiography using Bland-Altman analysis. We generated coronary computed tomographic angiography cardiac dimension reference ranges for both genders for our population. CONCLUSION: Our findings represent a step towards generating cardiac chamber dimensions' reference ranges for coronary computed tomographic angiography as compared to transthoracic echocardiography in patients with normal cardiac morphology and function using the American Society of Echocardiography guideline measurements that are commonly used by cardiologists. PMID- 26770707 TI - Efficacy of a nonsurgical treatment regimen in patients with bisphosphonate related osteonecrosis of the jaws in Saudi Arabia. AB - OBJECTIVES: The objective of this study was to evaluate the effectiveness of a nonsurgical treatment regimen in the long-term control of necrotic areas of the jaws and pain in such patients. METHODS: A total of 96 patients suffering from the disease were included in this study. All patients received nonsurgical treatment regimen for 10 days, and repeated every 3 months for 2 years. The size of the osteonecrotic lesions was measured and the pain level was self-assessed with a visual analog scale. RESULTS: The patients showed a statistically significant (F = 16.1; p < .01; r(2) = .95) gradual decrease in the size of exposed bone areas during the nonsurgical therapy (from 12.5 to 8.8 mm). Pain scores ranged from 0 to 3 score scale. Complete resolution of the disease was observed in some patients. CONCLUSIONS: This conservative nonsurgical treatment regimen seems to provide successful treatment in reduction of the sizes of exposed bone areas in the majority of patients. PMID- 26770708 TI - A pilot study on the application of a symptom-based score for the diagnosis of cow's milk protein allergy. AB - OBJECTIVE: A challenge is the recommended test to diagnose cow's milk protein allergy. However, many parents and physicians prefer to not challenge because the procedure may cause (severe) symptoms. In clinical routine, diagnostic testing is only available for IgE-mediated allergy. The aim of this study was to test the diagnostic accuracy of a symptom-based score to select infants at risk of having cow's milk protein allergy. METHODS: A symptom-based score was developed and consensus was reached that a score of >=12 would select infants at risk of cow's milk protein allergy. Diagnosis of cow's milk protein allergy was demonstrated with a positive challenge after 1-month elimination diet. RESULTS: An open challenge was performed in 85/116 (73%) infants suspected of cow's milk protein allergy based on a symptom-based score >= 12 and was positive in 59/85 (69%). Although "a challenge test" was planned in the protocol, 27% of the parents refused the challenge. The mean decrease after 1 month of elimination diet with an extensive hydrolysate was -8.07 (95% confidence interval = -8.74, -7.40). If the symptom-based score during the elimination diet decreased to 6 or lower, 80% of the infants had a positive challenge test. If the symptom-based score remained >7, the challenge test was positive in only 48% (p < 0.001). CONCLUSION: In daily practice, a symptom-based score of >=12 is a useful tool to select infants at risk of cow's milk protein allergy. If an elimination diet reduces the symptom based score to <=6, the challenge test is positive in 80%. PMID- 26770709 TI - Assessing the scientific research productivity of a leading toxicology journal: A case study of Human & Experimental Toxicology from 2003 to 2012. AB - BACKGROUND: Bibliometric studies are increasingly being used for research assessments. Bibliometric indicators involve the application of statistical methods to scientific publications to obtain the bibliographics for each journal. The main objective of this study was to conduct a bibliometric evaluation of Human & Experimental Toxicology retrieved from the Scopus database. METHODS: This study obtained data from Scopus published from 1 January 2003 till 31 December 2012. The keywords entered in Scopus to accomplish the objective of this study were 'Human', 'Experimental' and 'Toxicology' as 'Source Title'. Research productivity was evaluated based on a methodology developed and used in other bibliometric studies by analysing (a) total and trends in Human & Experimental Toxicology contributions in research between 2003 and 2012; (b) Human & Experimental Toxicology authorship patterns and productivity; (c) collaboration patterns; and (d) the citations received by the publications. RESULTS: There were 1229 research articles published in Human & Experimental Toxicology. Of the articles included, 947 (77.1%) were original articles and 104 (8.5%) were review articles. The Hirsch-index of the retrieved documents was 35. The largest number of publications in Human & Experimental Toxicology was from the United States (19.6%), followed by India (12.8%) and Turkey (10.9%). The total number of citations was 9119, with a median (interquartile range) of 3 (1-9) in 6797 documents. The highest median (interquartile range) number of citations was 8 (2.7-12.7) for France, followed by 7.5 (2-22.5) for Iran and 6 (3-13.5) for the United Kingdom. The country most often citing articles that were published in Human & Experimental Toxicology was the United States, which made citations in 1508 documents, followed by India with citations in 792 documents. CONCLUSION: The documents in Human & Experimental Toxicology focus principally on original data, with very few review articles. Review articles tend to have higher citation rates than original articles, and hence, the editors and authors of Human & Experimental Toxicology might usefully promote the submission of reviews in the future to improve the impact of the journal. PMID- 26770710 TI - Who is watching the watchmen: Is quality reporting ever harmful? AB - BACKGROUND: Quality reporting is increasingly used as a tool to encourage health systems, hospitals, and their practitioners to deliver the greatest health benefit. However, quality reporting systems may have unintended negative consequences, such as inadvertently encouraging "cherry-picking" by inadequately adjusting for patients who are challenging to take care of, or underpowering to reliably detect meaningful differences in care. There have been no reports seeking to identify a minimum level of accuracy that ought to be viewed as a prerequisite for quality reporting. METHOD: Using a decision analytic model, we seek to delineate minimal standards for quality measures to meet, using the simplest assumptions to illustrate what those standards may be. RESULTS: We find that even under assumptions regarding optimal performance of the quality reporting system (sensitivity and specificity of 1), we can identify a minimal level of accuracy required for the quality reporting system to "do no harm": the increase in health-related quality of life from a higher rather than lower quality practitioner must be greater than the number of practitioners per patient divided by the proportion of patients willing to switch from a lower to a higher quality provider. CONCLUSION: Quality measurement systems that have not been demonstrated to improve health outcomes should be held to a specific standard of measurement accuracy. PMID- 26770711 TI - Single incision thoracoscopic sympathectomy for palmar and axillary hyperhidrosis. AB - BACKGROUND: Primary hyperhidrosis is characterized by excessive sweating beyond physiological needs. It is a common disease (incidence 2.8%) that causes intense discomfort for patients. In the last decade, advantages of Single-Incision Thoracoscopic Sympathectomy have become clear, particularly in decreasing morbidity of sympathectomy. PATIENTS AND METHODS: From January 2010 to December 2012, 39 patients (29 females and 10 males) with primary palmar or axillary hyperhidrosis were treated by thoracoscopic sympathectomy. The age ranged from 18 to 40 years with a mean of 26.28 years. We used single incision thoracoscopic electrocoagulation through 10 mm incision for thoracic sympathetic chain (T2-T4). RESULTS: The mean follow-up was 23.6 +/- 14.2 months (range = 4-24 months). A total of 97.42% of patients were satisfied with the results. A total of 72.5% of patients had cure, one patient (2.5%) and another patient (2.5%) presented with recurrent axillary hyperhidrosis. The morbidity was 10.2% with no mortality. Percentage of compensatory sweating and gustatory sweating were 5.1% (p = .353) and 2.5% (p = .552), respectively. The result of sympathectomy in patients with both palmar and axillary hyperhidrosis was significantly better (17, 43.58%) compared to palmar type (14, 35.89%) or axillary type (7, 17.94%). CONCLUSION: Thoracoscopic sympathectomy is a simple, safe, and cost-effective therapy with good results and low complications. PMID- 26770712 TI - Single-incision versus conventional laparoscopic appendectomy: A case-match study. AB - BACKGROUND: Three-port laparoscopic appendectomy is considered standard in many countries for the surgical treatment of acute appendicitis. Single-incision laparoscopic technique has been recently introduced and is supposed to minimize the aggression induced by surgery. Regarding appendectomy, comparison with standard laparoscopy, benefits and drawbacks of this novel technique remain to be evaluated. The goal of this study was to assess single-incision laparoscopic appendectomy compared to conventional laparoscopic appendectomy in terms of operation time, length of hospital stay, complication rate, and postoperative antibiotherapy rate. METHODS: From February 2011 to December 2011, single incision laparoscopic appendectomy was proposed to patients admitted to the emergency room of the University Hospital of Lausanne (CHUV, Lausanne, Switzerland), diagnosed with uncomplicated acute appendicitis. Preoperative patients' information, technical difficulties during the operation, and postoperative follow-ups were recorded. Every patient who underwent single incision laparoscopic appendectomy (n = 20) was matched 1:3 conventional laparoscopic appendectomy (n = 60), controlling for age, gender, body mass index, American Society of Anesthesiologists score, and histopathological findings. RESULTS: No statistically significant differences for median operation time, length of hospital stay, complication rate, and need for postoperative antibiotherapy were found. In 5 out of 20 single-incision laparoscopic appendectomy patients the Endoloop((r)) Ligature was judged difficult to put in place. CONCLUSION: This study suggests that single-incision laparoscopic appendectomy is a feasible and effective operative technique for uncomplicated acute appendicitis. PMID- 26770713 TI - The difficult intraoperative nasogastric tube intubation: A review of the literature and a novel approach. AB - Nasogastric tube intubation of a patient under general anesthesia with an endotracheal tube in place can pose a challenge to the most experienced anesthesiologist. Physiologic and pathologic variations in a patient's functional anatomy can present further difficulty. While numerous techniques to the difficult nasogastric tube intubation have been described, there is no consensus for a standard approach. Therefore, selecting the most appropriate approach requires a working knowledge of the techniques available, mindful consideration of individual patient and clinical factors, and the operator's experience and preference. This article reviews the relevant literature regarding various approaches to the difficult nasogastric tube intubation with descriptions of techniques and results from comparative studies if available. Additionally, we present a novel approach using a retrograde technique for the difficult intraoperative nasogastric tube intubation. PMID- 26770715 TI - Risk adjustment of health-care performance measures in a multinational register based study: A pragmatic approach to a complicated topic. AB - OBJECTIVES: Health-care performance comparisons across countries are gaining popularity. In such comparisons, the risk adjustment methodology plays a key role for meaningful comparisons. However, comparisons may be complicated by the fact that not all participating countries are allowed to share their data across borders, meaning that only simple methods are easily used for the risk adjustment. In this study, we develop a pragmatic approach using patient-level register data from Finland, Hungary, Italy, Norway, and Sweden. METHODS: Data on acute myocardial infarction patients were gathered from health-care registers in several countries. In addition to unadjusted estimates, we studied the effects of adjusting for age, gender, and a number of comorbidities. The stability of estimates for 90-day mortality and length of stay of the first hospital episode following diagnosis of acute myocardial infarction is studied graphically, using different choices of reference data. Logistic regression models are used for mortality, and negative binomial models are used for length of stay. RESULTS: Results from the sensitivity analysis show that the various models of risk adjustment give similar results for the countries, with some exceptions for Hungary and Italy. Based on the results, in Finland and Hungary, the 90-day mortality after acute myocardial infarction is higher than in Italy, Norway, and Sweden. CONCLUSION: Health-care registers give encouraging possibilities to performance measurement and enable the comparison of entire patient populations between countries. Risk adjustment methodology is affected by the availability of data, and thus, the building of risk adjustment methodology must be transparent, especially when doing multinational comparative research. In that case, even basic methods of risk adjustment may still be valuable. PMID- 26770714 TI - MicroRNAs and cardiovascular medicine. AB - MicroRNAs are non-coding RNA sequences that act as regulators of gene expression. They are aberrantly expressed in many pathological conditions. Cardiovascular diseases are among the leading causes of morbidity and mortality in the general population. Various knock-in and knockdown approaches have shown abnormal signature patterns of microRNAs in cardiovascular conditions like cardiac hypertrophy, myocardial infarction, heart failure, arrhythmias and vascular proliferative diseases. Since a single microRNA targets many genes, modulating a single microRNA involved in a disease carries a possible risk of undesirable side effects. The review focuses on current understanding of microRNAs in cardiovascular conditions, the possible underlying mechanisms and various approaches of modulating microRNAs. PMID- 26770716 TI - Delivery room triage of large for gestational age infants of diabetic mothers. AB - OBJECTIVE: To review our 4-year experience (2008-2011) with delivery room triage of large for gestational age infants of diabetic mothers. DESIGN/METHODS: Retrospective cohort investigation of 311 large for gestational age infants of diabetic mothers (White's Class A1 (77), A2 (87), B (77), and C-R (70)). RESULTS: Of 311 women, 31% delivered at 34-36 weeks gestational age and 69% at term. While 70% were delivered by cesarean, 30% were vaginal deliveries. A total of 160 asymptomatic infants were triaged from the delivery room to the well baby nursery. Of these, 55 (34%) developed hypoglycemia. In 43 cases, the hypoglycemia was corrected by early feedings; in the remaining 12, intravenous dextrose treatment was required. A total of 151 infants were triaged from the delivery room to the neonatal intensive care unit. Admission diagnoses included respiratory distress (51%), prevention of hypoglycemia (27%), prematurity (21%), and asphyxia (1%). Hypoglycemia affected 66 (44%) of all neonatal intensive care unit infants. CONCLUSION: Safe triage of asymptomatic large for gestational age infants of diabetic mothers from the delivery room to well baby nursery can be accomplished in the majority of cases. Those infants in need of specialized care can be accurately identified and effectively treated in the neonatal intensive care unit setting. PMID- 26770717 TI - Cognitive, behavioural and psychological barriers to the prevention of severe hypoglycaemia: A qualitative study of adults with type 1 diabetes. AB - OBJECTIVES: Severe hypoglycaemia affects approximately one in three people with type 1 diabetes and is the most serious side effect of insulin therapy. Our aim was to explore individualistic drivers of severe hypoglycaemia events. METHODS: In-depth semi-structured interviews were conducted with a purposive sample of 17 adults with type 1 diabetes and a history of recurrent severe hypoglycaemia, to elicit experiences of hypoglycaemia (symptoms/awareness, progression from mild to severe and strategies for prevention/treatment). Interviews were analysed using an adapted grounded theory approach. RESULTS: Three main themes emerged: hypoglycaemia-induced cognitive impairment, behavioural factors and psychological factors. Despite experiencing early hypoglycaemic symptoms, individuals often delayed intervention due to impaired/distracted attention, inaccurate risk assessment, embarrassment, worry about rebound hyperglycaemia or unavailability of preferred glucose source. Delay coupled with use of a slow-acting glucose source compromised prevention of severe hypoglycaemia. CONCLUSION: Our qualitative data highlight the multifaceted, idiosyncratic nature of severe hypoglycaemia and confirm that individuals with a history of recurrent severe hypoglycaemia may have specific thought and behaviour risk profiles. Individualised prevention plans are required, emphasising both the need to attend actively to mild hypoglycaemic symptoms and to intervene promptly with an appropriate, patient-preferred glucose source to prevent progression to severe hypoglycaemia. PMID- 26770718 TI - Opportunistic hearing screening in elderly inpatients. AB - OBJECTIVE: To determine the prevalence of occult hearing loss in elderly inpatients, to evaluate feasibility of opportunistic hearing screening and to determine subsequent provision of hearing aids. MATERIALS AND METHODS: Subjects (>65 years) were recruited from five elderly care wards. Hearing loss was detected by a ward-based hearing screen comprising patient-reported assessment of hearing disability and a whisper test. Subjects failing the whisper test or reporting hearing difficulties were offered formal audiological assessment. RESULTS: Screening was performed on 51 patients aged between 70 and 95 years. Of the patients, 21 (41%) reported hearing loss and 16 (31%) failed the whisper test. A total of 37 patients (73%) were referred for audiological assessment with 17 (33%) found to have aidable hearing loss and 11 were fitted with hearing aids (22%). DISCUSSION: This study highlights the high prevalence of occult hearing loss in elderly inpatients. Easy two-step screening can accurately identify patients with undiagnosed deafness resulting in significant proportions receiving hearing aids. KEY SENTENCES: Approximately 14% of the elderly population use hearing aids despite a reported prevalence of deafness in up to 55%.The use of hearing aids is associated with an improvement in physical, emotional, mental and social well-being.An easy screening test for hearing loss consists of patient reported hearing loss and a whisper test.Opportunistic screening of elderly inpatients resulted in referral of 73% of screened patients for formal audiology.Of the screened patients, 22% were provided with hearing aids. PMID- 26770719 TI - Past and present in abdominal surgery management for Cushing's syndrome. AB - INTRODUCTION: Data on specific abdominal surgery and Cushing's syndrome are infrequent and are usually included in the adrenalectomy reports. Current literature suggests the feasibility and reproducibility of the surgical adrenalectomies for patients diagnosed with non-functioning tumours and functioning adrenal tumours including pheochromocytoma, Conn's syndrome and Cushing's syndrome. DISCUSSION: Medical treatment for Cushing's syndrome is feasible but follow-up or clinical situations force the patient to undergo a surgical procedure. Laparoscopic surgery has become a gold standard nowadays in a broad spectrum of pathologies. Laparoscopic adrenalectomies are also standard procedures nowadays. However, despite the different characteristics and clinical disorders related to the laparoscopically removed adrenal tumours, the intraoperative and postoperative outcomes do not significantly differ in most cases between the different groups of patients, techniques and types of tumours. Tumour size, hormonal type and surgeon's experience could be different factors that predict intraoperative and postoperative complications. Transabdominal and retroperitoneal approaches can be considered. Outcomes for Cushing's syndrome do not differ depending on the surgical approach. Novel technologies and approaches such as single-port surgery or robotic surgery have proven to be safe and feasible. CONCLUSION: Laparoscopic adrenalectomy is a safe and feasible approach to adrenal pathology, providing the patients with all the benefits of minimally invasive surgery. Single-port access and robotic surgery can be performed but more data are required to identify their correct role between the different surgical approaches. Factors such as surgeon's experience, tumour size and optimal technique can affect the outcomes of this surgery. PMID- 26770720 TI - Does classroom-based Crew Resource Management training improve patient safety culture? A systematic review. AB - AIM: To evaluate the evidence of the effectiveness of classroom-based Crew Resource Management training on safety culture by a systematic review of literature. METHODS: Studies were identified in PubMed, Cochrane Library, PsycINFO, and Educational Resources Information Center up to 19 December 2012. The Methods Guide for Comparative Effectiveness Reviews was used to assess the risk of bias in the individual studies. RESULTS: In total, 22 manuscripts were included for review. Training settings, study designs, and evaluation methods varied widely. Most studies reporting only a selection of culture dimensions found mainly positive results, whereas studies reporting all safety culture dimensions of the particular survey found mixed results. On average, studies were at moderate risk of bias. CONCLUSION: Evidence of the effectiveness of Crew Resource Management training in health care on safety culture is scarce and the validity of most studies is limited. The results underline the necessity of more valid study designs, preferably using triangulation methods. PMID- 26770721 TI - Neonatal outcomes following in utero exposure to buprenorphine/naloxone or methadone. AB - OBJECTIVES: To study neonatal outcomes following buprenorphine/naloxone and methadone exposure during pregnancy. METHODS: This study is a retrospective review of clinical and demographic information of 58 infants whose mothers were treated with buprenorphine/naloxone and 92 infants whose mothers were treated with methadone for opioid dependence during pregnancy. RESULTS: Gestational age, birth weight, prematurity, admission to neonatal intensive care unit, and length of stay were similar between both groups of infants. Neonatal abstinence syndrome occurred less frequently among infants of mothers treated with buprenorphine/naloxone than those treated with methadone (64% and 80%, respectively, p = 0.03). All infants with neonatal abstinence syndrome were treated postnatally with methadone. There was a trend toward shorter duration of treatment and lower cumulative dosages of methadone among the buprenorphine/naloxone-exposed infants. CONCLUSIONS: No apparent significant adverse neonatal outcomes were detected following treatment with either maintenance medication; however, further prospective research is necessary to examine the safety and efficacy of buprenorphine/naloxone in pregnancy and its effects on the neonate. PMID- 26770722 TI - Older adults fighting obesity with bariatric surgery: Benefits, side effects, and outcomes. AB - The aging population is growing exponentially worldwide. Associated with this greater life expectancy is the increased burden of chronic health conditions, many of which are exacerbated by the continued rise in obesity. In the US, the prevalence of obesity in adults aged 60 years and older increased from 23.6% to 37% in 2010. OBJECTIVES: This review examines bariatric surgery as a treatment option for obese adults > 60 years old. The most common types of weight-loss surgery are laparoscopic adjustable gastric banding, vertical sleeve gastrectomy, Roux-en-Y gastric bypass, and the duodenal switch. METHODS: A comprehensive literature search found 349 articles that referred to bariatric surgery in older adults. Of these, 70 relevant articles on bariatric surgery for older adults were utilized for this article. RESULTS: Weight-loss surgery procedures were found to be equally safe for both older adults and their younger counterparts. Pre surgical psychological assessment is critical for positive outcomes for older adults. Benefits of bariatric surgery include a decrease in comorbidities, chronic disease risk, and medication use coupled with improved mobility and quality of life outcomes. Side effects include surgical failure, changes in psychological status, and increased physical and mental stress. CONCLUSIONS: Bariatric surgery can offer patients an effective and long-lasting treatment for obesity and related diseases. There does not appear to be any one bariatric procedure that is recommended for older adults, so individual needs should be taken into consideration when exploring options. Costs range from US$17,000 for laparoscopic procedures to US$26,000 for open gastric surgeries. Estimated savings start accruing within 3 months of surgery making bariatric surgery a serious cost saving consideration. PMID- 26770723 TI - Evaluation of the impact of a flowchart-type leaflet for cancer inpatients. AB - OBJECTIVES: This study aimed to evaluate the benefits of an interactive and visual flowchart-type leaflet for head and neck cancer inpatients who received induction chemotherapy, docetaxel, cisplatin, and 5-fluorourasil (DCF), or docetaxel, cisplatin, and S-1 (DCS) from September 2009 to April 2012. The flowchart-type leaflet group used a flowchart-type leaflet during chemotherapy, while the non-flowchart-type leaflet group did not. METHODS: A retrospective cohort study was performed using patient records. The endpoints of this study were to determine the following: the number of emergency hospital admissions/visits, incidence of Grade 2 or higher non-haematological adverse drug reactions, nonadherence to treatment, and the number of telephone calls from subjects. RESULTS: A total of 109 subjects were identified as follows: 49 in the flowchart-type leaflet group (139 chemotherapy sessions) and 60 in the non flowchart-type leaflet group (163 chemotherapy sessions). No significant differences were observed in age, performance status, or chemotherapy regimen. The incidence of emergency hospital admissions was significantly lower in the flowchart-type leaflet than in the non-flowchart-type leaflet group (1% vs 10%, p < 0.01). No difference was seen between groups (12% vs 19%, p = 0.1) in the nonadherence rate of supportive medication for adverse drug reactions. Telephone call rates were significantly higher in the flowchart-type leaflet (16%, 30 calls) than in the non-flowchart-type leaflet group (7%, 11 calls) in each chemotherapy regimen. Of the 30 calls from patients in the FCL group, 24 (80%) were made to the hospital, compared with only 5 (45%) of the 11 calls from patients in the non-flowchart-type leaflet group. CONCLUSIONS: Our results suggest that the flowchart-type leaflet can reduce nonadherence and improve patient judgment during chemotherapy, leading to a decrease in emergency hospital admissions. PMID- 26770724 TI - Gene promoter polymorphism of RUNX2 and risk of osteoporosis in postmenopausal Indonesian women. AB - OBJECTIVES: Osteoporosis is a metabolic bone disease of reduced bone mass density (BMD) and elevated risk of fracture due to an imbalance in bone formation and resorption. The risk and incidence of osteoporosis increase towards advanced age, particularly in postmenopausal women, and the risk is known to be affected by the variation in the expression of the associated regulatory genes. This work aimed to clarify the impact of variation in RUNX2 (runt domain transcription factor 2), which is an osteoblast-specific transcription factor that normally stimulates bone formation and osteoblast differentiation, regarding single-nucleotide polymorphism within RUNX2 promoter (P1) and risk of osteoporosis in postmenopausal Indonesian women. METHODS: Using DNA sampling from blood, the variation at the single-nucleotide polymorphism (-330, G->T, rs59983488) at the RUNX2 P1 promoter was investigated using polymerase chain reaction-restriction fragment length polymorphism for 180 consenting postmenopausal Indonesian women. The subjects were examined for bone mass density and classification to normal and those with osteopenia or osteoporosis by T-scoring with dual-energy X-ray absorptiometry. Chi-square testing and logistic regression were mainly used for statistical assessment. RESULTS: The results showed a general trend with increased risk of osteoporosis associated with the genotype TT (mutant type) and the corresponding T allele of the tested polymorphism of RUNX2 promoter P1. The trend was, however, not significant in multivariate testing adjusted for age and time after menopause. CONCLUSION: To confirm the potential risk with TT genotype would require testing of a much larger sample of subjects. As the tested single nucleotide polymorphism only represents one of the relevant candidate locations of RUNX2, the results are taken nevertheless to suggest an impact by overall RUNX2 variation in the risk of osteoporosis in Indonesian postmenopausal women. PMID- 26770725 TI - Neutrophil-lymphocyte ratio is associated with low high-density lipoprotein cholesterol in healthy young men. AB - OBJECTIVE: It has been reported that the neutrophil-lymphocyte ratio is significantly elevated in patients with low high-density lipoprotein cholesterol (<35 mg/dL). But in this study, some patients had hypertension that may have affected the neutrophil-lymphocyte ratio. This study consisted of 1274 asymptomatic healthy young men. In contrast with the previous study, we investigated the neutrophil-lymphocyte ratio in healthy young men with low high density lipoprotein cholesterol compared with controls. METHODS: We studied 1274 asymptomatic young males (military personnel screening) who underwent routine health check-up. Of them, 102 subjects had low high-density lipoprotein cholesterol. RESULTS: The neutrophil-lymphocyte ratio was significantly higher among the men with low high-density lipoprotein cholesterol than that of the control group (P < 0.001). CONCLUSION: We conclude that the neutrophil-lymphocyte ratio is significantly elevated in asymptomatic healthy young men with low high density lipoprotein cholesterol compared with control participants. PMID- 26770726 TI - Challenging conversations with terminally ill patients and their loved ones: Strategies to improve giving information in palliative care. AB - OBJECTIVE: The aim of the study was to explore the skills and strategies employed by professionals when having difficult conversations to provide information to loved ones as part of palliative care. METHOD: A qualitative design was chosen with in-depth interviews with nurses, assistant nurses and doctors a Hospital in Sweden and were analysed using content analysis. RESULTS: The interviews produced examples of strategies used by professionals when imparting difficult information to patient and loved ones. The results fell into three areas: 'Who is giving information', 'Structuring the conversation' and 'Different ways to convey a difficult message'. CONCLUSION: Using conversational skills and strategies in combination with a carefully planned structure appeared to facilitate difficult conversations with patients and loved ones. Further research is required, related to the specific circumstances in which the conversation takes place. PMID- 26770727 TI - Looking after yourself: Clinical understandings of chronic-care self-management strategies in rural and urban contexts of the United Kingdom and Australia. AB - OBJECTIVES: This article reports on the outcomes of two similar projects undertaken during 2011-2012 in Australia (Rural Northern New South Wales) and the United Kingdom (Urban Northern United Kingdom) that sought to identify the strategies that health professionals employ to actively involve patients with chronic conditions in the planning and delivery of their care. In particular, this study explored understandings and contexts of care that impacted on the participants' practices. This study was informed by the global shift to partnership approaches in health policy and the growing imperative to deliver patient or client-centred care. METHODS: An ethnomethodological design was used, as ethnomethodology does not dictate a set of research methods or procedures, but rather is congruent with any method that seeks to explore what people do in their routine everyday lives. Focus groups and interviews were employed to explore the strategies used by a range of primary health-care providers, such as general practitioners, nurses, social workers, diabetes educators, dieticians and occupational therapists, to support clients to effectively manage their own chronic conditions. RESULTS: Data from both studies were synthesised and analysed thematically, with the themes reflecting the context, similarities and differences of the two studies that the participants felt had either facilitated or blocked their efforts to support their clients to adopt self-care strategies. CONCLUSION: Supporting patients/clients to engage in actively self-managing their health-care needs requires changes to clients' and clinicians' traditional perspectives on their roles. The barriers and enablers to supporting clients to manage their own health needs were similar across both locations and included tensions in role identity and functions, the discourse of health-care professionals as 'experts' who deliver care and their level of confidence in being facilitators who 'educate' clients to effectively manage their health-care needs, rather than only the 'providers' of care. PMID- 26770728 TI - Assessment of major adverse cardiovascular events and ischemic stroke with coronary computed tomography angiography based upon angiographic diagnosis in a high-volume single center. AB - BACKGROUND: Patient prognosis has been shown to directly correlate with the severity of coronary artery disease diagnosed by coronary computed tomography angiography (CCTA). Although the presence of coronary artery calcium has been associated with increased incidence of ischemic stroke, there are no data on the incidence of ischemic stroke based upon the severity of coronary artery disease by CCTA. Therefore, we sought to investigate the rate of major adverse cardiovascular events, including ischemic stroke, based upon the severity of coronary artery disease by CCTA over a 6-year period in a high-volume single military center. METHODS: We performed a retrospective chart review of all CCTA studies to evaluate the incidence of all-cause mortality, non-fatal myocardial infarction, ischemic stroke, and late revascularization (>90 days following CCTA) from January 2005 until July 2012. We reviewed 1518 CCTA reports, dividing patients into groups with obstructive (>=50% stenosis), non-obstructive (<50% stenosis), and no coronary artery disease (no angiographic disease). Subsequent major adverse cardiovascular events data (incidence of all-cause mortality, ischemic stroke, non-fatal myocardial infarction, and late revascularization) were obtained. RESULTS: Over a review period of 6 years with a resultant median follow-up period of 22 months (interquartile range = 13-34 months), the major adverse cardiovascular events rate was significantly higher with obstructive coronary artery disease compared to both non-obstructive coronary artery disease and no coronary artery disease (8.9% vs 0.7%, p < 0.001; 8.9% vs 1.6%, p < 0.001). The incidence of ischemic stroke alone was also significantly higher in those with obstructive coronary artery disease compared to those with no coronary artery disease (3.8% vs 0.4%, p < 0.001). CONCLUSION: Being free of disease on CCTA was associated with excellent cardiovascular prognosis. Obstructive coronary artery disease was associated with a significantly increased incidence of ischemic stroke. There was also a direct correlation between the severity of coronary artery disease on CCTA and cardiovascular prognosis over the follow-up period of 24 months. PMID- 26770729 TI - Long-term post-marketing surveillance of mizoribine for the treatment of lupus nephritis: Safety and efficacy during a 3-year follow-up. AB - OBJECTIVE: To determine the safety and efficacy of long-term use of mizoribine by undertaking a 3-year post-marketing surveillance study. METHODS: Subjects were all lupus nephritis patients newly treated with mizoribine between 1 October 2003 and 30 September 2005 at contracted study sites. RESULTS: Mizoribine was administered to 881 lupus nephritis patients in the safety analysis set consisting of 946 patients recruited from 281 contracted study sites after satisfying the eligibility criteria. There were 301 events of adverse drug reactions that were observed in 196 (20.7%) of the 946 subjects. There were 34 events of serious adverse drug reactions in 31 patients (3.2%). No deterioration in hematological and biochemical test values was observed, but immunological testing showed significant improvements in C3, CH50, and anti-DNA antibody titers. The negative rate of proteinuria also increased over time. The median steroid dosage was 15 mg/day at the commencement of treatment, but was reduced to 10 mg/day at 12 months and 8 mg/day at 36 months. CONCLUSION: The findings of the 3-year long-term drug use surveillance study indicated that mizoribine can be used over the long term with relatively few adverse drug reactions, suggesting its suitability for use in maintenance drug therapy. PMID- 26770730 TI - A systematic review investigating the relationship between efficacy and stimulation parameters when using transcutaneous electrical nerve stimulation after knee arthroplasty. AB - OBJECTIVE: To evaluate the clinical efficacy of transcutaneous electric nerve stimulation in the treatment of postoperative knee arthroplasty pain and to relate these results to the stimulation parameters used. DATA SOURCES: PubMed, Pedro and Web of Knowledge were systematically screened for studies investigating effects of transcutaneous electric nerve stimulation on postoperative knee arthroplasty pain. REVIEW METHODS: Studies were screened for their methodological and therapeutical quality. We appraised the influence of the stimulation settings used and indicated whether or not a neurophysiological and/or mechanistic rationale was given for these stimulation settings. RESULTS: A total of 5 articles met the inclusion criteria. In total, 347 patients were investigated. The number of patients who received some form of transcutaneous electric nerve stimulation was 117, and 54 patients received sham transcutaneous electric nerve stimulation. Pain was the primary outcome in all studies. The stimulation settings used in the studies (n = 2) that reported significant effects differed from the others as they implemented a submaximal stimulation intensity. Stimulation parameters were heterogeneous, and only one study provided a rationale for them. CONCLUSION: This review reveals that an effect of transcutaneous electric nerve stimulation might have been missed due to low methodological and therapeutical quality. Justifying the choice of transcutaneous electric nerve stimulation parameters may improve therapeutical quality. PMID- 26770731 TI - Family history of Alzheimer's disease limits improvement in cognitive function after bariatric surgery. AB - BACKGROUND/OBJECTIVE: Bariatric surgery can reverse cognitive impairments associated with obesity. However, such benefits may be attenuated in individuals with a predisposing risk for cognitive impairment such as family history of Alzheimer's disease. METHODS: In all, 94 bariatric surgery participants completed a computerized cognitive test battery before and 12 weeks after surgery. Family history of Alzheimer's disease was obtained through self-report. RESULTS: In the overall sample, cognitive function improved in memory and attention/executive function 12 weeks post-surgery. Repeated measures showed similar rates of improvements in attention/executive function between patients with and without a family history of Alzheimer's disease. In contrast, only individuals without a family history of Alzheimer's disease exhibited post-operative improvements in memory. A family history of Alzheimer's disease was associated with greater post surgery rates of cognitive impairment. CONCLUSIONS: Family history of Alzheimer's disease may limit post-surgery cognitive benefits. Future studies should examine whether weight loss can modify the course of cognitive decline in patients at risk for Alzheimer's disease. PMID- 26770732 TI - Characterization of the sleep-wake cycle of the Neotropical rodent Proechimys guyannensis. AB - OBJECTIVES: To better understand the sleep-wake cycle characteristics in the female Neotropical rodent Proechimys guyannensis related to comparative neurobiology. METHODS: Surface neocortical and hippocampal electrodes were chronically implanted in the brains of female Wistar and Proechimys animals. In addition, electrodes for the study of muscle activity were implanted into the neck muscle of both species. After surgical recovery and a period of adaptation, animals were continuously registered for periods as long as 48 h. RESULTS: In both the light and dark phases of the cycle, significant differences in some electrographic patterns were observed between the Proechimys and Wistar animals. Although Proechimys has nocturnal activities and a pattern of polyphasic sleep similar to Wistar rats, the analysis of its sleep-wakefulness cycle indicates that the Neotropical rodent sleeps less with consequent longer periods of wakefulness when compared to Wistar rats. CONCLUSIONS: Together with previous findings of different neuroanatomical, neurophysiologic and behavioral characteristics, this study allow us to better understand adaptive differences of the Neotropical rodent Proechimys. PMID- 26770733 TI - Lay and health care professional understandings of self-management: A systematic review and narrative synthesis. AB - OBJECTIVES: Self-management is widely promoted but evidence of effectiveness is limited. Policy encourages health care professionals to support people with long term conditions to learn self-management skills, yet little is known about the extent to which both parties share a common understanding of self-management. Thus, we compared health care professional and lay understandings of self management of long-term conditions. METHODS: Systematic review and narrative synthesis of qualitative studies identified from relevant electronic databases, hand-searching of references lists, citation tracking and recommendations by experts. RESULTS: In total, 55 studies were included and quality was assessed using a brief quality assessment tool. Three conceptual themes, each with two subthemes were generated: traditional and shifting models of the professional patient relationship (self-management as a tool to promote compliance; different expectations of responsibility); quality of relationship between health care professional and lay person (self-management as a collaborative partnership; self management as tailored support) and putting self-management into everyday practice (the lived experience of self-management; self-management as a social practice). CONCLUSION: Self-management was conceptualised by health care professionals as incorporating both a biomedical model of compliance and individual responsibility. Lay people understood self-management in wider terms, reflecting biomedical, psychological and social domains and different expectations of responsibility. In different ways, both deviated from the dominant model of self-management underpinned by the concept of self-efficacy. Different understandings help to explain how self-management is practised and may help to account for limited evidence of effectiveness of self-management interventions. PMID- 26770734 TI - Detection of asymptomatic renal Leptospira infection in abattoir slaughtered cattle in southeastern Georgia, United States. AB - OBJECTIVES: Leptospirosis is one of the most widespread zoonotic infectious diseases affecting humans and animals. Several animal species, including cattle, can act as potential asymptomatic carriers facilitating zoonotic transmission of Leptospira. This study was conducted to assess the occurrence of asymptomatic renal Leptospira carriers among cattle slaughtered in southeastern Georgia, United States. METHODS: A battery of diagnostic tests, including dark field microscopy, direct fluorescent antibody staining, polymerase chain reaction, and culture, were performed on a set of bovine kidneys (n = 37) collected from an abattoir in southeastern Georgia, United States. Virulence of a field isolate obtained from this study was tested in a hamster experimental model. RESULTS: Motile spirochete-like structures were observed by dark field microscopy in 23 (59%) out of 37 kidney samples tested. In all, 29 samples (78%) were positive by direct fluorescent antibody staining. Only 11 (29.7%) samples by polymerase chain reaction and 3 (8.1%) by culture were positive for Leptospira sp. The isolates obtained by culture were confirmed as Leptospira borgpetersenii. Hamsters experimentally infected with one of the Leptospira field isolates obtained from this study did not show clinical signs but developed renal infection with interstitial nephritis and tubular necrosis. CONCLUSIONS: This study confirms that asymptomatic Leptospira renal infection is present among cattle in the region. Our findings underscore the need for future studies to assess the potential environmental contamination and transmission to humans in contact with infected cattle. PMID- 26770735 TI - Depression and heart rate variability in firefighters. AB - INTRODUCTION: Depression has been found to increase the risk of mortality in patients with coronary artery disease through a mechanism of changing cardiac autonomic tone which is reflected by alteration of heart rate variability indices. This study investigated whether such mechanism existed in firefighters who were at high risk of depression and sudden cardiac death. METHODS AND RESULTS: In total, 107 firefighters were recruited. All completed Beck Depression Inventory and underwent 24-h ambulatory electrocardiographic monitoring. The root mean-square of successive differences, standard deviation of all normal-to-normal intervals index, and the percentage of differences between adjacent normal-to normal intervals >50 ms were significantly lower in depressed than in non depressed firefighters after controlling for hypertension, age, and body mass index (40.1 +/- 18.8 vs 62.5 +/- 77.4, p < 0.01; 63.0 +/- 19.2 vs 72.1 +/- 34.8, p < 0.01; 8.4 +/- 7.2 vs 12.7 +/- 10.9, p < 0.01, respectively). CONCLUSION: Decreased vagal tone is a possible mechanism linking depression and sudden cardiac death in firefighters. PMID- 26770736 TI - Health-related quality of life and sense of coherence among people with obesity: Important factors for health management. AB - OBJECTIVES: The purpose of this study was to evaluate whether health-related quality of life and levels of sense of coherence among people with obesity are correlated with body mass index, age, and gender. METHODS: A cross-sectional, descriptive research design was used. Subjects (n = 157) were selected from a sample of participants in an ongoing survey and had a body mass index >30 kg/m(2). Data were collected using the Short Form-36 Health Survey and the Sense of Coherence Scale. RESULTS: The mean body mass index of women was higher than that of men. Compared to men, a greater proportion of women had a low sense of coherence. There was a significant relationship between low physical health and high body mass index. Female gender and older age correlated with a low sense of coherence and showed a significant association with high body mass index. CONCLUSION: To increase the health-related quality of life, people with obesity need support to help manage their life situation based on their individual needs and personal resources. PMID- 26770738 TI - Hereditary spherocytosis: Consequences of delayed diagnosis. AB - OBJECTIVE: To determine whether patients with undiagnosed hereditary spherocytosis hospitalized for transfusions might have avoided hospitalization via earlier diagnosis. STUDY DESIGN: Charts of all (N = 30) patients with hereditary spherocytosis seen in pediatric hematology at West Virginia University Charleston were reviewed. Family and transfusion history and presence of neonatal jaundice were recorded. Complete blood count and reticulocyte values during infancy were available for 20 of 30 patients, while baseline steady-state values were available for all 30. RESULTS: Transfusions were given to 22 patients; 12 of 14 with an aplastic crisis were undiagnosed. In 10 of 12, the severity of anemia led to hospitalization (3 to intensive care). All 10 had prior mean corpuscular hemoglobin concentration and/or red cell distribution width elevations and a history of neonatal jaundice; 7 of 10 had a positive family history. CONCLUSIONS: Undiagnosed hereditary spherocytosis may lead to inpatient transfusions for severe anemia. Earlier detection of hereditary spherocytosis is easily achievable and may reduce hospitalizations via closer monitoring. PMID- 26770737 TI - Natural products as potential cancer therapy enhancers: A preclinical update. AB - Cancer is a multifactorial disease that arises as a consequence of alterations in many physiological processes. Recently, hallmarks of cancer were suggested that include sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis, along with two emerging hallmarks including reprogramming energy metabolism and escaping immune destruction. Treating multifactorial diseases, such as cancer with agents targeting a single target, might provide partial treatment and, in many cases, disappointing cure rates. Epidemiological studies have consistently shown that the regular consumption of fruits and vegetables is strongly associated with a reduced risk of developing chronic diseases, such as cardiovascular diseases and cancer. Since ancient times, plants, herbs, and other natural products have been used as healing agents. Moreover, the majority of the medicinal substances available today have their origin in natural compounds. Traditionally, pharmaceuticals are used to cure diseases, and nutrition and herbs are used to prevent disease and to provide an optimal balance of macro- and micro-nutrients needed for good health. We explored the combination of natural products, dietary nutrition, and cancer chemotherapeutics for improving the efficacy of cancer chemotherapeutics and negating side effects. PMID- 26770739 TI - Impact of a pilot pharmacy health-care professional out-of-school time physical activity and nutrition education program with exercise on fourth and fifth graders in a rural Texas community. AB - OBJECTIVES: Childhood obesity continues to be a problem. Children in rural populations are more likely to be overweight or obese and a lack of resources in those areas may contribute to this problem. We aimed to assess the impact of a pilot pharmacy health-care professional out-of-school time vigorous physical activity and nutrition education program on fourth and fifth graders in a rural Texas community. METHODS: We conducted a prospective 12-week cohort study from August to November 2012. Thirty-three children, aged 8-11 years, in Bailey County, Texas, were enrolled in the study. Body mass index, body mass index percentile, blood pressure, waist circumference, and a diet preferences and activities knowledge survey were obtained at 0, 4, 8, and 12 weeks. Study participants completed a twice weekly physical activity and nutrition education program with exercise over weeks 1-4 with no intervention during weeks 5-12. RESULTS: Thirty-one (94%) of the 33 children, predominately Hispanic girls, completed the program. Body mass index (-0.30 (95% confidence interval, -0.44 to 0.17); P = <0.0001), body mass index percentile (-2.75 (95% confidence interval, 4.89 to -0.62); P = 0.0026), systolic blood pressure (-1.9 (95% confidence interval, -2.9 to -0.9); P = <0.0001), and waist circumference (-0.47 (95% confidence interval, -0.85 to -0.10); P = <0.0001) mean change decreased between baseline and week 12 with no intervention for 8 weeks. Positive survey results at 3 months indicated a decrease in fried/sweet foods; increase in exercise; decreases in video games and computer use; and a change in knowledge regarding the selection of the most healthy food group servings per day. CONCLUSION: In this pharmacy health-care directed pilot study, participants had a reduction of body mass index, body mass index percentile, systolic blood pressure, waist circumference, and improvement in certain survey results at the end of 12 weeks despite no further intervention after 4 weeks. PMID- 26770740 TI - A highly efficient method for generation of therapeutic quality human pluripotent stem cells by using naive induced pluripotent stem cells nucleus for nuclear transfer. AB - Even after several years since the discovery of human embryonic stem cells and induced pluripotent stem cells (iPSC), we are still unable to make any significant therapeutic benefits out of them such as cell therapy or generation of organs for transplantation. Recent success in somatic cell nuclear transfer (SCNT) made it possible to generate diploid embryonic stem cells, which opens up the way to make high-quality pluripotent stem cells. However, the process is highly inefficient and hence expensive compared to the generation of iPSC. Even with the latest SCNT technology, we are not sure whether one can make therapeutic quality pluripotent stem cell from any patient's somatic cells or by using oocytes from any donor. Combining iPSC technology with SCNT, that is, by using the nucleus of the candidate somatic cell which got reprogrammed to pluripotent state instead that of the unmodified nucleus of the candidate somatic cell, would boost the efficiency of the technique, and we would be able to generate therapeutic quality pluripotent stem cells. Induced pluripotent stem cell nuclear transfer (iPSCNT) combines the efficiency of iPSC generation with the speed and natural reprogramming environment of SCNT. The new technique may be called iPSCNT. This technique could prove to have very revolutionary benefits for humankind. This could be useful in generating organs for transplantation for patients and for reproductive cloning, especially for childless men and women who cannot have children by any other techniques. When combined with advanced gene editing techniques (such as CRISPR-Cas system) this technique might also prove useful to those who want to have healthy children but suffer from inherited diseases. The current code of ethics may be against reproductive cloning. However, this will change with time as it happened with most of the revolutionary scientific breakthroughs. After all, it is the right of every human to have healthy offspring and it is the question of reproductive freedom and existence. PMID- 26770741 TI - Evaluation of a free amino acid-based formula in infants with presumptive food protein-induced proctocolitis. AB - OBJECTIVE: Food protein-induced proctocolitis usually occurs early in life and is characterized by blood-streaked stools and pain during defecation in an otherwise healthy infant. While many infants with food protein-induced proctocolitis respond well to a casein hydrolysate formula, some require an amino acid-based formula. The objective of the study was to measure the change in physician-rated symptom score from enrollment to study completion in infants with presumptive food protein-induced proctocolitis fed with a specific amino acid-based formula. METHODS: In this study, infants <=6 months of age diagnosed with presumptive food protein-induced proctocolitis received an amino acid-based formula for 42 days. Intake, stool patterns, weight, stool occult blood, and questionnaires assessing infant feeding and stool patterns and parental formula satisfaction were collected. RESULTS: The full analysis set included 43 infants. The mean age at enrollment was 59 +/- 5 days. A significant improvement was observed from enrollment to exit in physician-rated symptom score (9.1 +/- 0.5 to 4.8 +/- 0.5, p < 0.0001), the number of infants with occult blood in stool, and weight-for-age Z-scores during the study. Parental satisfaction with the formula was high. CONCLUSION: The results confirm that the amino acid-based formula studied is efficacious for managing symptoms of presumptive food protein-induced proctocolitis. PMID- 26770742 TI - The efficacy of betulinic acid in triple-negative breast cancer. AB - PURPOSE: The treatment of triple-negative breast cancer remains a daunting challenge with the standard-of-care treatments eventually failing due to acquired drug resistance, toxic side effects and the presence of a deregulated immune response. New treatments for overcoming these drawbacks include the use of plant extracts. STUDY DESIGN: In this study, the efficacy of betulinic acid, a naturally abundant phytochemical exhibiting anti-inflammatory and anti proliferative activity, has been evaluated for the treatment of triple-negative breast cancer MDA-MB-231 and MDA-MB-468 cell lines. Furthermore, the ability of betulinic acid to inhibit angiogenesis was also determined. RESULTS: Here, we report that betulinic acid was able to inhibit the inflammatory response, inhibit angiogenesis and cause cell cycle arrest ultimately causing apoptosis in triple negative breast cancer cells. Our findings support that the identification of naturally occurring anti-tumour compounds may provide a chemotherapeutic approach for the treatment of triple-negative breast cancer. CONCLUSION: Overall, our results provide a molecular basis for the ability of betulinic acid to mediate apoptosis, suppress inflammation and inhibit angiogenesis in triple-negative breast cancer cell lines. PMID- 26770743 TI - Development of a measure of knowledge use by stakeholders in rehabilitation technology. AB - OBJECTIVES: Uptake of new knowledge by diverse and diffuse stakeholders of health care technology innovations has been a persistent challenge, as has been measurement of this uptake. This article describes the development of the Level of Knowledge Use Survey instrument, a web-based measure of self-reported knowledge use. METHODS: The Level of Knowledge Use Survey instrument was developed in the context of assessing effectiveness of knowledge communication strategies in rehabilitation technology. It was validated on samples representing five stakeholder types: researchers, manufacturers, clinician-practitioners, knowledge brokers, and consumers. Its structure is broadly based on Rogers' stages of innovation adoption. Its item generation was initially guided by Hall et al's Levels of Use framework. Item selection was based on content validity indices computed from expert ratings (n 1 = 4; n 2 = 3). Five representative stakeholders established usability of the web version. The version included 47 items (content validity index for individual items >0.78; content validity index for a scale or set of items >0.90) in self-reporting format. Psychometrics were then established for the version. RESULTS: Analyses of data from small (n = 69) and large (n = 215) samples using the Level of Knowledge Use Survey instrument suggested a conceptual model of four levels of knowledge use-Non-awareness, Awareness, Interest, and Use. The levels covered eight dimensions and six user action categories. The sequential nature of levels was inconclusive due to low cell frequencies. The Level of Knowledge Use Survey instrument showed adequate content validity (~ 0.88; n = 3) and excellent test-retest reliability (1.0; n = 69). It also demonstrated good construct validity (n = 215) for differentiating among new knowledge outputs (p < 0.001) and among stakeholder types (0.001 < p <= 0.013). It showed strong responsiveness to change between baseline and follow-up testing (0.001 < p <= 0.002; n = 215). CONCLUSION: The Level of Knowledge Use Survey instrument is valid and reliable for measuring uptake of innovations across diffuse stakeholders of rehabilitation technologies and therefore also for tracking changes in knowledge use. PMID- 26770744 TI - Legionella pneumophila cases in a community hospital: A 12-month retrospective review. AB - BACKGROUND: Legionella pneumonia has long been recognized as an important cause of community-acquired pneumonia associated with significant morbidity and mortality; however, the description of the incidence of this disease is restricted to sporadic cases in the literature. With the advent of an inexpensive and rapid urine antigen test, routine testing has become more common. We report findings of a retrospective review of 266 patients who were admitted with a clinical diagnosis of community-acquired pneumonia over a 12-month period and were tested for Legionella pneumophila serogroup 1, reporting the prevalence and determinants of Legionella infection. METHODS: Chart reviews of 266 patients admitted for community-acquired pneumonia and who underwent urine antigen testing for Legionella pneumophila during a 1-year time period were conducted, looking at demographic information as well as clinical and laboratory presentation, reporting on the prevalence and determinants of urine antigen positivity using multivariate logistic regression analysis. RESULTS: Legionella pneumophila serogroup 1 was found in 2.3% of cases of community-acquired pneumonia. We also found that altered mental status, diarrhea, history of lung disease, and alcohol intake were significantly associated with pneumonia associated with Legionella. The presence of these four factors had a low sensitivity in predicting Legionella infection (33%); however, they had a positive predictive value of 98%, with a specificity of 100. All the Legionella-infected patients in our study required admission to the intensive care unit, and one of them developed Guillain-Barre syndrome, which to our knowledge represents the only reported case of this syndrome related to Legionella infection in an adult in the English scientific literature. CONCLUSION: Legionella pneumophila serogroup 1 is a common cause of sporadic cases of community-acquired pneumonia associated with a high morbidity and protean manifestations. Clinical features have a poor sensitivity in identifying cases, and routine urine antigen testing in patients with suggestive clinical symptoms appears to be a rational approach in the evaluation of community-acquired pneumonia. PMID- 26770745 TI - Screening for elevated risk of liver disease in preschool children (aged 2-5 years) being seen for obesity management. AB - OBJECTIVES: Elevated alanine aminotransferase can heighten concern for the presence of nonalcoholic fatty liver disease in obese children. Guidelines recommend alanine aminotransferase screening of obese children start at the age of 10 years. We examined alanine aminotransferase values routinely obtained for tertiary obesity care among preschool (2-5 years) and school-age children. METHODS: Medical records of children attending a tertiary obesity clinic and with alanine aminotransferase measured within 6 months of the initial visit were reviewed. Children with known genetic abnormalities were excluded. Children were grouped by age to focus attention on groups not covered by screening guidelines. Associations with elevated alanine aminotransferase (>30 IU/L) were examined. RESULTS: A total of 284 records were analyzed (73 preschool, 143 young school-age (6-9 years), 68 older school-age (10-11 years)). Children were primarily Hispanic and had body mass index >= 99th percentile (preschool children 92%, young school age 73%, older school-age 59%). In all, 26% of preschool children had elevated alanine aminotransferase (young school-age 30%, older school-age 44%). Preschool children with elevated alanine aminotransferase had higher body mass index compared to preschool children with alanine aminotransferase <= 30 IU/L (median body mass index 27.8 kg/m(2) vs 24.0 kg/m(2); Mann-Whitney U test, p = 0.003), but there was no disparity for elevated alanine aminotransferase related to Hispanic ethnicity. For older children, Hispanic ethnicity, not body mass index, predicted elevated alanine aminotransferase. CONCLUSION: Alanine aminotransferase elevation was common in these preschool children. Screening severely obese children for elevated alanine aminotransferase should begin at the age of 2 years. PMID- 26770746 TI - Pilot validation of objective malnutrition-inflammation scores in pediatric and adolescent cohort on chronic maintenance dialysis. AB - BACKGROUND: In recognition of the challenges inherent with the use of single-item indices for the diagnosis of malnutrition-inflammation morbidity in pediatric dialysis patients, to enhance accuracy, we validated a composite scoring system in a pilot study. The objective malnutrition-inflammation score seeks to validate the use of a composite scoring system as a tool for assessing malnutrition inflammation burden in a pediatric dialysis population. METHODS: We enrolled 20 patients on hemodialysis (n = 14) and peritoneal dialysis (n = 6) over a period of 12 months. We derived composite scores from selected indices of renal pathology, nutrition, dialysis adequacy, protein catabolism, and dialysis modality. We assessed reliability by a test-retest method and measured validity by defining the relationship of the indices with serum C-reactive protein in a multiple regression analysis. We calculated sensitivity, specificity, accuracy, and precision for the malnutrition-inflammation score. RESULTS: The mean age was 12.8 years (standard deviation = 6.1), and male-female ratio was 12:8. Patients (n = 8) with elevated serum C-reactive protein (>0.3 mg/dL) had higher composite score for malnutrition-inflammation morbidity. Similarly, the pediatric cohort on hemodialysis had higher score than those on peritoneal dialysis. Upon reliability testing, a low value of typical error (0.07) and high correlation coefficient (r = 0.95) supported validity of the instrument. Moreover, multiple regression analysis showed a strong predictive relationship (R(2) = 0.9, p = 0.03) between the indices and serum C-reactive protein. Sensitivity of malnutrition inflammation score was 62.5%, specificity was 83%, accuracy was 75%, and precision was 71%. CONCLUSION: Using criterion-validation method, we established the potential use of multi-diagnostic approach to quantify malnutrition inflammation morbidity in a pediatric dialysis cohort. Given the small sample size, large-scale population-specific studies are needed to ratify these findings and to demonstrate its clinical effectiveness. PMID- 26770747 TI - Does educational intervention improve doctors' knowledge and perceptions of generic medicines and their generic prescribing rate? A study from Malaysia. AB - OBJECTIVES: To investigate the impact of an educational intervention on doctors' knowledge and perceptions towards generic medicines and their generic (international non-proprietary name) prescribing practice. METHODS: This is a single-cohort pre-/post-intervention pilot study. The study was conducted in a tertiary care hospital in Perak, Malaysia. All doctors from the internal medicine department were invited to participate in the educational intervention. The intervention consisted of an interactive lecture, an educational booklet and a drug list. Doctors' knowledge and perceptions were assessed by using a validated questionnaire, while the international non-proprietary name prescribing practice was assessed by screening the prescription before and after the intervention. RESULTS: The intervention was effective in improving doctors' knowledge towards bioequivalence, similarity of generic medicines and safety standards required for generic medicine registration (p = 0.034, p = 0.034 and p = 0.022, respectively). In terms of perceptions towards generic medicines, no significant changes were noted (p > 0.05). Similarly, no impact on international non-proprietary name prescribing practice was observed after the intervention (p > 0.05). CONCLUSION: Doctors had inadequate knowledge and misconceptions about generic medicines before the intervention. Moreover, international non-proprietary name prescribing was not a common practice. However, the educational intervention was only effective in improving doctors' knowledge of generic medicines. PMID- 26770748 TI - Heart rate variability evaluation in the assessment and management of in-utero drug-exposed infants. AB - AIM: To determine whether heart rate variability parameters vary between in-utero drug-exposed infants and controls. To determine correlations between Finnegan score and heart rate variability parameters. To differentiate those drug-exposed infants who require treatment from those infants who do not. METHODS: A total of 24 jaundiced control subjects and 25 in-utero drug-exposed infants were enrolled. The Finnegan score and an electrocardiographic rhythm strip were obtained at 4-h intervals. RR intervals (time between consecutive R waves) were manually tabulated from the rhythm strip and analyzed. Time-domain heart rate variability parameters were calculated and analyzed for both groups. RESULTS: Heart rate variability parameters were cumulatively lower over 3 days in in-utero drug exposed infants compared with controls (p < 0.05). Root mean square of differences of standard deviation of RR intervals on first day of life, and standard deviation of RR intervals, percentage of consecutive RR intervals greater than 50 ms, and root mean square of differences of standard deviation of RR intervals on the second day of life were significantly lower between in-utero drug-exposed infants and control infants. Three out of five parameters were significantly lower in in-utero drug-exposed infants pre-treatment versus post treatment (p = 0.001, p = 0.0001, and p = 0.021, respectively). Root mean square of differences of standard deviation of RR intervals was able to differentiate in utero drug-exposed infants requiring opiate therapy and in-utero drug-exposed infants that did not (p = 0.02). CONCLUSION: Heart rate variability analysis can contribute to the management of in-utero drug-exposed infants. Heart rate variability could be used in dose titration. PMID- 26770749 TI - Efficacy of chemotherapy after hormone therapy for hormone receptor-positive metastatic breast cancer. AB - OBJECTIVE: According to the guidelines for metastatic breast cancer, hormone therapy for hormone receptor-positive metastatic breast cancer without life threatening metastasis should be received prior to chemotherapy. Previous trials have investigated the sensitivity of chemotherapy for preoperative breast cancer based on the efficacy of neoadjuvant hormone therapy. In this retrospective study, we investigated the efficacy of chemotherapy for metastatic breast cancer in hormone therapy-effective and hormone therapy-ineffective cases. METHODS: Patients who received chemotherapy after hormone therapy for metastatic breast cancer between 2006 and 2013 at our institution were investigated. RESULTS: A total of 32 patients received chemotherapy after hormone therapy for metastatic breast cancer. The median patient age was 59 years, and most of the primary tumors exhibited a T2 status. A total of 26 patients had an N(+) status, while 7 patients had human epidermal growth factor receptor 2-positive tumors. A total of 13 patients received clinical benefits from hormone therapy, with a rate of clinical benefit of subsequent chemotherapy of 30.8%, which was not significantly different from that observed in the hormone therapy-ineffective patients (52.6%). A total of 13 patients were able to continue the hormone therapy for more than 1 year, with a rate of clinical benefit of chemotherapy of 38.5%, which was not significantly different from that observed in the short-term hormone therapy patients (47.4%). The luminal A patients were able to continue hormone therapy for a significantly longer period than the non-luminal A patients (median survival time: 17.8 months vs 6.35 months, p = 0.0085). However, there were no significant differences in the response to or duration of chemotherapy. CONCLUSION: The efficacy of chemotherapy for metastatic breast cancer cannot be predicted based on the efficacy of prior hormone therapy or tumor subtype, and clinicians should administer chemotherapy in all cases of hormone receptor positive metastatic breast cancer, if needed. PMID- 26770750 TI - Continuity of medication management and continuity of care: Conceptual and operational considerations. AB - OBJECTIVE: Continuity of care is considered foundational to high-quality care. Traditional continuity of care constructs may adequately characterize care quality in general populations, but may merit reconceptualization for patients with multiple chronic conditions. Specifically, interactions between multiple chronic condition patients and providers involve complex medication management; therefore care continuity measurement may be more relevant if focused on the provider subset who prescribes essential medications for chronic conditions-a construct we call continuity of medication management. Our objective was to explore conceptual distinctions between continuity of medication management and continuity of care, survey existing evidence in this area, and discuss implications of our findings for future research and intervention development. METHODS: In this topical review, we discuss conceptual distinctions between continuity of medication management and continuity of care, review the limited continuity of medication management-related empirical evidence, and discuss implications for future research and interventions. RESULTS: Continuity of medication management represents a potential conceptual and measurement advance by reflecting interpersonal continuity and management continuity, and may provide a means of identifying patients at high-risk of adverse events. Empirical evidence also establishes support for continuity of medication management as a meaningful measure of care continuity. Finally, continuity of medication management may also be a potential target for future intervention to improve care delivery among multiple chronic condition patients. CONCLUSION: If continuity of medication management is validated in diverse populations, correlated with patient outcomes, and responsive to change, then it may be an important target for improving the health and health care of multiple chronic condition patients. PMID- 26770751 TI - Development of practice principles for the management of ongoing suicidal ideation in young people diagnosed with major depressive disorder. AB - OBJECTIVES: There is a lack of clear guidance regarding the management of ongoing suicidality in young people experiencing major depressive disorder. This study utilised an expert consensus approach in identifying practice principles to complement relevant clinical guidelines for the treatment of major depressive disorder in young people. The study also sought to outline a broad treatment framework for clinical intervention with young people experiencing ongoing suicidal ideation. METHODS: In-depth focus groups were undertaken with a specialist multidisciplinary clinical team (the Youth Mood Clinic at Orygen Youth Health Clinical Program, Melbourne) working with young people aged 15-25 years experiencing ongoing suicidal ideation. Each focus group was audio recorded and transcribed verbatim using orthographic conventions. Principles of grounded theory and thematic analysis were used to analyse and code the resultant data. RESULTS: The identified codes were subsequently synthesised into eight practice principles reflecting engagement and consistency of care, ongoing risk assessment and documentation, individualised crisis planning, engaging systems of support, engendering hopefulness, development of adaptive coping, management of acute risk, and consultation and supervision. CONCLUSIONS: The identified practice principles provide a broad management framework, and may assist to improve treatment consistency and clinical management of young people experiencing ongoing suicidal ideation. The practice principles may be of use to health professionals working within a team-based setting involved in the provision of care, even if peripherally, to young people with ongoing suicidal ideation. Findings address the lack of treatment consistency and shared terminology and may provide containment and guidance to multidisciplinary clinicians working with this at-risk group. PMID- 26770752 TI - Tumor microvessel density-associated mast cells in canine nodal lymphoma. AB - OBJECTIVE: Mast cells are associated in angiogenesis in various human and animal neoplasms. However, association of mast cells with tumor microvessel density in canine lymphoma was not previously documented. The objective of the study is to determine if mast cells are increased in canine nodal lymphomas and to evaluate their correlation with tumor microvessel density and grading of lymphomas. METHODS: Nodal lymphomas from 33 dogs were studied and compared with nonneoplastic lymph nodes from 6 dogs as control. Mast cell count was made on Toluidine blue stained sections. Immunohistochemistry using antibody against Factor VIII was employed to visualize and determine microvessel density. RESULTS: The mast cell count in lymphoma (2.95 +/- 2.4) was significantly higher (p < 0.05) than that in the control (0.83 +/- 0.3) and was positively correlated with tumor microvessel density (r = 0.44, p = 0.009). Significant difference was not observed in mast cell count and tumor microvessel density among different gradings of lymphomas. CONCLUSIONS: Mast cells are associated with tumor microvessel density in canine nodal lymphoma with no significant difference among gradings of lymphomas. Mast cells may play an important role in development of canine nodal lymphomas. Further detailed investigation on the role of mast cells as important part of tumor microenvironment in canine nodal lymphomas is recommended. PMID- 26770753 TI - Efficacy of 13.3 mg/24 h versus 4.6 mg/24 h rivastigmine patch on activities of daily living in severe Alzheimer's disease. AB - OBJECTIVE: Investigate efficacy of 13.3 mg/24 h rivastigmine patch in patients with severe Alzheimer's disease on Alzheimer's Disease Cooperative Study Activities of Daily Living Scale-Severe Impairment Version items and domains. METHODS: Retrospective analysis of the 24-week, randomized, double-blind ACTivities of daily living and cognitION (ACTION) study, using factor analysis to establish "best fit" for Alzheimer's Disease Cooperative Study-Activities of Daily Living Scale-Severe Impairment Version items into domains. Treatment differences (13.3 vs 4.6 mg/24 h patch) on items and domains were assessed. RESULTS: Overall, 632 patients provided Alzheimer's Disease Cooperative Study Activities of Daily Living Scale-Severe Impairment Version data. Factor analysis yielded four domains. The 13.3 versus 4.6 mg/24 h patch demonstrated significantly greater efficacy on "Daily function" (p = 0.038), supported by greatest effect sizes on items within this domain, and trend toward greater efficacy on "Communication" (p = 0.052). No significant between-group differences were observed on "Independence" (p = 0.600) or "Environment" (p = 0.261). CONCLUSION: The 13.3 mg/24 h patch was superior to 4.6 mg/24 h patch on "Daily function" in severe Alzheimer's disease. PMID- 26770754 TI - The stenting strategy of drug-eluting stents for coronary artery disease in patients on dialysis. AB - BACKGROUND: Reports regarding the relationship between the length and diameter of implanted drug-eluting stents and clinical and angiographic outcomes in dialysis patients are limited. AIM: We investigated the efficiency of drug-eluting stents for coronary artery disease in patients on dialysis from the viewpoint of stent sizing. METHODS: Sirolimus-eluting stents were implanted in 88 lesions and bare metal stents were implanted in 43 lesions. We compared stenting strategy, major adverse cardiac events, and angiographic results between sirolimus-eluting stent and bare metal stent groups. RESULTS: Stent diameter was smaller and stent length was longer in the sirolimus-eluting stent group than in the bare metal stent group in our routine practices. There was no significant between-group difference in late diameter loss. Rates of angiographic restenosis and target lesion revascularization were significantly higher in the sirolimus-eluting stent group than in the bare metal stent group. Although stent length was significantly longer and stent diameter was smaller in the sirolimus-eluting stent group, sirolimus-eluting stents did not improve the subsequent clinical and angiographic results compared with bare metal stents in dialysis patients. CONCLUSION: In dialysis patients, a longer length and/or smaller diameter sirolimus-eluting stent implantation was associated with high rates of restenosis and target lesion revascularization compared with bare metal stents. PMID- 26770755 TI - Evaluating developmental screening in clinical practice. AB - OBJECTIVE: To demonstrate a method of evaluating accuracy of developmental screening modeled on the evidence-based medical literature. METHOD: A retrospective review was performed on 418 children screened with the Denver II by a trained technician. Two models for analyzing screening data were examined, using predictive values and likelihood ratios (LR+ and LR-). RESULTS: The technician, working at 20% time, screened 44% of eligible children. There were 129/418 (31%) children with Suspect Denver II results, 115/418 who were referred, 81/115 (70%) who were evaluated by Early Intervention, and 64/81 (79%) who qualified for services. The uncorrected positive predictive value for the Denver II alone (44%) was insufficient to meet the preset standard of 60%, but the LR+ of 4.16 indicated a significant contribution of test information to improving predictive value. Combining test results with information from the parent technician conference to achieve a referral decision resulted in an uncorrected predictive value of 56%, which rose with correction for children referred but not evaluated to 72% (LR+ 10.33). Negative predictive values and likelihood ratios of a negative test and a non-referral decision achieved recommended levels. Parents who expressed concern were significantly more likely to complete recommended evaluation than those who did not (82% vs 58%, p < .01). Results were in the same range as in published studies with other screening tests but showed three areas for improvement: screening more children, more carefully supervising some referral decisions, and getting more children to evaluation. CONCLUSION: Levels of predictive accuracy above 60% can be obtained by combining different types of information about development to make decisions about referral for more complete evaluation. Systematic study of such combinations could lead to improved predictive accuracy of screening programs and support attempts to close the gap between referral and evaluation. PMID- 26770756 TI - A succinct rating scale for radiology report quality. AB - CONTEXT: Poorly written radiology reports are common among residents and are a significant challenge for radiology education. While training may improve report quality, a professionally developed reliable and valid scale to measure report quality does not exist. OBJECTIVES: To develop a measurement tool for report quality, the quality of report scale, with rigorous validation through empirical data. METHODS: A research team of an experienced psychometrician and six senior radiologists conducted qualitative and quantitative studies. Five items were identified for the quality of report scale, each measuring a distinct aspect of report quality. Two dedicated training sessions were designed and implemented to help residents generate high-quality reports. In a blinded fashion, the quality of report scale was applied to 804 randomly selected reports issued before (n = 403) and after (n = 401) training. Full-scale psychometrical assessments were implemented onto the quality of report scale's item- and scale-scores from the reports. The quality of report scale scores were correlated with report professionalism and attendings' preference and were compared pre-/post-training. RESULTS: The quality of report scale showed sound psychometrical properties, with high validity and reliability. Reports with higher quality of report scale score were more professional and preferable by attendings. Training improved the quality of report scale score, empirically validating the quality of report scale further. CONCLUSION: While succinct and practitioner friendly, the quality of report scale is a reliable and valid measure of radiology report quality and has the potential to be easily adapted to other fields such as pathology, where similar training would be beneficial. PMID- 26770757 TI - Influence of angiotensin II receptor blocker combination tablet prescription on drug number and cost. AB - OBJECTIVES: Combination therapy using an angiotensin II receptor blocker is expected to promote medication adherence and alleviate economic burden among patients by reducing the number of drugs taken, and thereby to lower associated medical costs. In the present retrospective study, we conducted a survey on the use of angiotensin II receptor blocker-containing combination tablets as anti hypertensive drugs, in particular angiotensin II receptor blocker/diuretic and angiotensin II receptor blocker/calcium channel blocker combinations, in order to investigate the number of prescribed drugs and drug cost. METHODS: We performed a retrospective study of patients who visited the outpatient clinic of GifuMunicipalHospital and received anti-hypertensive agents between June 2006 and December 2011. RESULTS: No reductions in the number of prescribed drugs or drug cost were seen following a change in prescription to an angiotensin II receptor blocker/diuretic. Patients receiving an angiotensin II receptor blocker/calcium channel blocker had a significant reduction in the number of prescribed drugs and a slight decrease in drug cost. CONCLUSION: In this study, a reduction in the number of prescribed drugs and a decrease in economic burden were not observed after prescription of angiotensin II receptor blocker-containing combination tablets. In order to assess the usefulness of angiotensin II receptor blocker combination tablets, further studies are necessary to investigate their hypotensive effects, safety profile, and other factors. PMID- 26770758 TI - Evaluation of the response to vaccination with hepatitis B vaccine in pediatric patients diagnosed with celiac disease. AB - BACKGROUND: A gap exists in the literature on celiac disease populations and the response to hepatitis B vaccination. OBJECTIVE: To identify pediatric patients with celiac disease who received the primary hepatitis B vaccination and investigate their response to vaccine. DESIGN/METHODS: Patients underwent blood draw for hepatitis B surface antibody titers. Patients with undetectable or non protective HBsAb titers were contacted. Study outcome measures and patient characteristics variables were summarized by means, standard deviations, medians, and ranges. A two-sample t-test was used to compare normally distributed continuous variables between responders and non-responders. RESULTS: In all, 58% of patients did not meet the threshold for "protective" antibody titers. The mean time between completion of hepatitis B vaccination and diagnosis of celiac disease was 8.1 years for responders versus 10.5 years for non-responders. In a multivariate analysis, time between completion of vaccine and diagnosis of celiac disease was statistically significant predictor of response with an adjusted odds ratio of 0.69 (95% confidence interval: 0.50-0.95; p = 0.021). CONCLUSION: Our celiac disease population shows a high hepatitis B vaccine failure. The time between completion of vaccine series and diagnosis of celiac disease is an independent predictor for response. PMID- 26770759 TI - Assessing usability, label comprehension, pen robustness and pharmacokinetics of a self-administered prefilled autoinjector pen of methotrexate in patients with rheumatoid arthritis. AB - OBJECTIVE: To assess usability, bioavailability, and safety of subcutaneous self administration of 0.3 mL of methotrexate 50 mg/mL solution via a prefilled autoinjector pen (methotrexate pen) in patients with rheumatoid arthritis. METHODS: The study enrolled methotrexate-naive and methotrexate-experienced patients aged >=16 years. Visit 1 (Day 1) included methotrexate pen usage training with documentation, patient self-injection, and a patient-training questionnaire completed by the healthcare professional. Visit 2 (Days 8-10) included evaluation of patient self-injection through four scenarios: holding needle in place for 5 s, confirming methotrexate delivery, skin pinch, and pen disposal. At Visit 2, patient opinion and training retention (since Visit 1) were also assessed. Pharmacokinetic parameters were assessed in 25 patients, who were stratified by body weight and randomized to receive injections in the abdomen or the upper thigh. RESULTS: At Visit 1, 12 of 106 patients had questions about the pen, and 4 required self-injection assistance. At Visit 2, the mean performance rating for all scenarios was >=9.8 (scale: 1 (very difficult)-10 (very easy)). Successful completion rates were 96.2%-100%; 91.3%-100% of patients required no assistance. Impressions of the pen were favorable; 98.1% of patients passed the written examination. All methotrexate pens effectively delivered 0.3 mL methotrexate and were intact after use. Body weight >100 kg significantly decreased total and peak methotrexate exposure when administered abdominally. No adverse effects resulted in drug discontinuation. CONCLUSION: The methotrexate pen was used with a high degree of effectiveness, satisfaction, and safety, indicating that this delivery system may be a viable option for patients requiring subcutaneous methotrexate. PMID- 26770760 TI - Is objective and accurate cognitive assessment across the menstrual cycle possible? A feasibility study. AB - OBJECTIVES: Variation in plasma hormone levels influences the neurobiology of brain regions involved in cognition and emotion processing. Fluctuations in hormone levels across the menstrual cycle could therefore alter cognitive performance and wellbeing; reports have provided conflicting results, however. The aim of this study was to assess whether objective assessment of cognitive performance and self-reported wellbeing during the follicular and luteal phases of the menstrual cycle is feasible and investigate the possible reasons for variation in effects previously reported. METHODS: The Cambridge Neuropsychological Test Automated Battery and Edinburgh Postnatal Depression Scale were used to assess the cognitive performance and wellbeing of 12 women. Data were analysed by self-reported and hormone-estimated phases of the menstrual cycle. RESULTS: Recruitment to the study and assessment of cognition and wellbeing was without issue. Plasma hormone and peptide estimation showed substantial individual variation and suggests inaccuracy in self-reported menstrual phase estimation. CONCLUSION: Objective assessment of cognitive performance and self-assessed wellbeing across the menstrual cycle is feasible. Grouping data by hormonal profile rather by self-reported phase estimation may influence phase-mediated results. Future studies should use plasma hormone and peptide profiles to estimate cycle phase and group data for analyses. PMID- 26770761 TI - Mental health utilization among older Veterans with coexisting depression and dementia. AB - OBJECTIVE: We compared mental health service utilization among older, depressed Veterans (60 years or older) with and without coexisting dementia. METHODS: This retrospective study examined data from the 2010 Veterans Health Administration National Patient Care Database outpatient treatment files of Veterans with a newly recognized diagnosis of depression (N = 177,710). RESULTS: Approximately 48.84% with coexisting depression and dementia and 32.00% with depression only received mental health services within 12 months of diagnosis (p < .0001). Veterans with coexisting depression and dementia were more likely to receive medication-management appointments (33.40% vs 20.62%), individual therapy (13.39% vs 10.91%), and family therapy (3.77% vs 1.19%) than depressed Veterans without dementia. CONCLUSION: In general, Veterans with recently diagnosed depression are significantly underusing Veterans Affairs mental health treatment services. Those Veterans who have comorbid dementia are more likely than those with just depression to be enrolled in mental health treatments. Systemic improvements are needed to increase use of mental health services for older, depressed Veterans. PMID- 26770762 TI - Variability of cutaneous and nasal population levels between patients colonized and infected by multidrug-resistant bacteria in two Brazilian intensive care units. AB - OBJECTIVE: To compare cutaneous and nasal population levels between patients colonized and infected by multidrug-resistant organisms in two intensive care units. METHODS: A prospective cohort study was performed in adult intensive care units of two hospitals in Belo Horizonte, Brazil (April 2012 to February 2013). Clinical and demographic data were first collected by reviewing patients' charts. Then, samples collected with nasal, groin, and perineum swabs were cultivated in selective media for 48 h at 37 degrees C. After isolation, determination of antimicrobial susceptibility and biochemical identification were performed. RESULTS: A total of 53 cases of colonization were observed by the following bacteria in decreasing frequencies: imipenem-resistant Acinetobacter baumannii (50.9%), vancomycin-resistant Enterococcus faecalis (43.4%), extended-spectrum beta-lactamase-producing Klebsiella pneumoniae (37.7%), imipenem-resistant Pseudomonas aeruginosa (32.1%), oxacillin-resistant Staphylococcus aureus (7.5%), and imipenem-resistant Klebsiella pneumoniae (5.7%). Among these colonization cases, 26 (49.0%) were followed by infection with bacteria phenotypically similar to those of the colonization. A relation between high population levels of colonization by most of the multidrug-resistant organisms at anatomical sites and a subsequent infection was observed. After colonization/infection, bacterial population levels decreased progressively and spontaneously until disappearance by day 45 in all the anatomical sites and for all the multidrug-resistant organisms. CONCLUSION: There was a correlation between high population levels of colonization by multidrug-resistant organisms at anatomical sites and a subsequent infection. Reduction in multidrug-resistant organism populations after colonization at anatomical sites could be a preventive measure to reduce evolution to infection as well as transmission of these bacteria between patients in intensive care unit. PMID- 26770763 TI - Autonomic dysfunction independently predicts poor cardiovascular outcomes in asymptomatic individuals with type 2 diabetes in the DIAD study. AB - OBJECTIVE: The primary aim of this secondary analysis was to determine whether cardiac autonomic neuropathy independently predicted adverse cardiac outcomes in asymptomatic individuals with type 2 diabetes. Additional aims include the determination of the correlation of standard autonomic testing measures and power spectral analysis of heart rate variability, and the association of diabetes related and cardiac risk factors with cardiac autonomic neuropathy measures. METHODS: Cardiac autonomic neuropathy was assessed at the study entry into the Detection of Ischemia in Asymptomatic Diabetics study, using autonomic heart rate and blood pressure testing, and power spectral analysis of heart rate variability. All participants were prospectively followed for the composite clinical outcome of cardiac death, acute coronary syndromes, heart failure, or coronary revascularization. RESULTS: Over 5 years of follow-up, 94 of 1119 (8.4%) subjects developed symptomatic cardiac disease. In unadjusted bivariate analyses, abnormalities in several cardiac autonomic neuropathy tests, including lower Valsalva and Standing Heart Rate Ratios, higher resting Heart Rate, greater systolic blood pressure decrease on standing, and lower low-frequency power, were predictive of symptomatic disease. Independent predictors of poor cardiac outcome were a lower Valsalva Heart Rate Ratio, non-Black ethnicity, longer diabetes duration, higher glycated hemoglobin (HbA1c), insulin use, reported numbness in the extremities, higher pulse pressure, family history of coronary artery disease, and higher waist-to-hip ratio. Clinical factors independently associated with a lower Valsalva Heart Rate Ratio were insulin use, clinical proteinuria, higher pulse pressure, use of angiotensin-converting enzyme inhibitor and non Black ethnicity. CONCLUSION: Cardiac autonomic neuropathy predicted adverse cardiac outcomes in asymptomatic type 2 diabetes without known cardiac disease. Clinical variables may help to identify patients who might have cardiac autonomic neuropathy and warrant consideration for autonomic testing. PMID- 26770764 TI - Diagnosis of Helicobacter pylori by carbon-13 urea breath test using a portable mass spectrometer. AB - CONTEXT: In the non-invasive detection of markers of disease, mass spectrometry is able to detect small quantities of volatile markers in exhaled air. However, the problem of size, expense and immobility of conventional mass spectrometry equipment has restricted its use. Now, a smaller, less expensive, portable quadrupole mass spectrometer system has been developed. Helicobacter pylori has been implicated in the development of chronic gastritis, gastric and duodenal ulcers and gastric cancer. OBJECTIVES: To compare the results obtained from the presence of H. pylori by a carbon-13 urea test using a portable quadrupole mass spectrometer system with those from a fixed mass spectrometer in a hospital-based clinical trial. METHODS: Following ethical approval, 45 patients attending a gastroenterology clinic at the Royal Liverpool University Hospital exhaled a breath sample into a Tedlar gas sampling bag. They then drank an orange juice containing urea radiolabelled with carbon and 30 min later gave a second breath sample. The carbon-13 content of both samples was measured using both quadrupole mass spectrometer systems. If the post-drink level exceeded the pre-drink level by 3% or more, a positive diagnosis for the presence of H. pylori was made. RESULTS: The findings were compared to the results using conventional isotope ratio mass spectrometry using a laboratory-based magnetic sector instrument off site. The results showed agreement in 39 of the 45 patients. CONCLUSIONS: This study suggests that a portable quadrupole mass spectrometer is a potential alternative to the conventional centralised testing equipment. Future development of the portable quadrupole mass spectrometer to reduce further its size and cost is indicated, together with further work to validate this new equipment and to enhance its use in mass spectrometry diagnosis of other medical conditions. PMID- 26770765 TI - Effectiveness of balance exercises in the acute post-operative phase following total hip and knee arthroplasty: A randomized clinical trial. AB - OBJECTIVES: To determine the effectiveness of balance exercises in the acute post operative phase following total hip arthroplasty or total knee arthroplasty. METHODS: Patients who had total hip arthroplasty (n = 30) or total knee arthroplasty (n = 33) were seen in their residence 1-2 times per week for 5 weeks. At the first post-operative home visit, patients were randomly assigned to either typical (TE, n = 33) or typical plus balance (TE + B, n = 30) exercise groups. The TE group completed seven typical surgery-specific joint range-of motion and muscle strengthening exercises, while the TE + B group completed the typical exercises plus three balance exercises. Patients were assessed before and 5 weeks after administering the rehabilitation program using four outcome measures: (1) the Berg Balance Scale, (2) the Timed Up and Go test, (3) the Western Ontario McMaster Universities Osteoarthritis Index, and (4) the Activities-specific Balance Confidence Scale. RESULTS: Post-intervention scores for all four outcome measures were significantly improved (p < 0.01) over baseline scores. Patients who participated in the TE + B group demonstrated significantly greater improvement on the Berg Balance Scale and the Timed Up and Go tests (p < 0.01). CONCLUSION: Balance exercises added to a typical rehabilitation program resulted in significantly greater improvements in balance and functional mobility compared to typical exercises alone. PMID- 26770766 TI - Obesity indices as predictors of pattern of self-reported arthritis among elderly women in Southwestern Nigeria. AB - OBJECTIVES: This study assessed obesity indices and pattern of arthritis among elderly women in Osun State, Southwestern Nigeria. METHODS: The cross-sectional descriptive study was carried out among 350 elderly women selected by multistage sampling technique. Research instruments used in data collection were semi structured, interviewer-administered pre-tested questionnaires that were analyzed using the Statistical Package for Social Sciences software version 17.0. RESULTS: The mean age of the participants was 69.1 (+/-1.4) years. A total of 232 (66.3%) of them had complaints of joint pains (Awoka as expressed in the local language). Pattern of arthritis showed that 172 (74.0%) had recurrent joint pains, while 35 (15.1%) had joint swelling; the knee joint was mostly affected. A total of 97 (28.0%) were overweight while 84 (24.0%) were obese. Obese women were twice more likely to have arthritis when compared to the nonobese (odds ratio: 2.4, 95% confidence interval: 1.8-9.4, p = 0.001). CONCLUSION: There is a need to give high priority to weight reduction strategies targeted at the elderly and the entire population. PMID- 26770767 TI - Population health in New Zealand 2000-2013: From determinants of health to targets. AB - OBJECTIVE: To determine how 'population health' has been understood in practice and policy and has influenced health system restructuring in New Zealand since 2000. METHODS: Interviews in 2007-2008 with managers, clinicians, government policy advisors and academics were undertaken to explore the relationships between population health, determinants of health, and health system restructuring. This was augmented by a review of major government health policies from 2009 to 2013 to establish which notions of population health were reflected. RESULTS: Population health shifted from a broad notion of health determinants to focus on a small number of quantifiable health targets driven by financial incentives. Meantime, an emphasis on 'quality and safety' impeded population health activities. District Health Board programmes to identify high risk individuals, by disease or hospital service utilisation, diverted attention from broader population health outcomes. District Health Boards were not held accountable for integrating a population health approach in service planning and did not initiate or lead intersectoral work. Community consultation was limited. Primary Health Organisations, although mandated to address population health, typically aligned with the small-business model of general practice making service integration difficult to achieve. In policy, 'population health' dropped from favour in the mid-2000s, although many documents, outside the health sector, carried forward these values. CONCLUSION: A progressively narrower focus on a small number of health targets and on organisational processes undermined earlier policy intentions and health system restructuring that sought to improve broader population health outcomes. PMID- 26770768 TI - Nonconvulsive seizures and status epilepticus in pediatric head trauma: A national survey. AB - OBJECTIVES: It remains uncertain whether nonconvulsive seizures and nonconvulsive status epilepticus in pediatric traumatic brain injury are deleterious to the brain and/or impact the recovery from injury. Consequently, optimal electroencephalographic surveillance and management is unknown. We aimed to determine specialists' opinion regarding the detection and treatment of nonconvulsive seizures or nonconvulsive status epilepticus in pediatric traumatic brain injury, regardless of their practice. METHODS: In 2012, 183 surveys were sent to all 93 neurologists, 27 neurosurgeons, and 63 intensivists in the14 tertiary pediatric hospitals across Canada. The survey included an initial scenario of pediatric TBI that evolved into three further scenarios. Each scenario had required responses and an embedded branching logic algorithm ascertaining clinical management. The survey instrument assimilated data about the importance of nonconvulsive status epilepticus and nonconvulsive seizures detection and treatment, and whether they are a cause of brain injury that adversely affects neurologic outcomes. RESULTS: Of the 79 specialists who replied (43% response rate), 68%-78% elected to order an electroencephalographic across all four scenarios, and one-third (31%-36%; scenario dependent) would request an urgent electroencephalographic (within the hour) in the comatose pediatric traumatic brain injury patient. In the absence of pharmacologic paralysis or intracranial pressure spikes, half-hour electroencephalographic (41%-55%) was preferred over ?24-h continuous electroencephalographic monitoring (29%-40%). Finally, nonconvulsive status epilepticus (81%-87%) and nonconvulsive seizures (61%-73%) were considered to be a cause of poor neurologic outcomes warranting aggressive pharmacologic management. CONCLUSION: The Canadian specialists' opinion is that nonconvulsive seizures and nonconvulsive status epilepticus are biomarkers of brain injury and contribute to worsened outcomes. This suggests the urgency of future outcome-oriented research in the identification and management of nonconvulsive seizures or nonconvulsive status epilepticus. PMID- 26770769 TI - 'Croque&bouge': A feasible and acceptable programme for obesity prevention in preschoolers at risk and their parents. AB - OBJECTIVES: To conceptualize and pilot test a programme of three workshops aiming to prevent the development of overweight in susceptible preschool children. METHODS: Three workshops were conducted, targeting both parents and children. The curriculum for parents included discussions on feeding responsibilities, healthy eating, taste development, neophobia and physical activity recommendations. Children participated in various play activities with fruits and vegetables and read stories about hunger and satiety feelings. Recruitment was organized through paediatricians and child-care centres. Evaluation of the programme focused on feasibility, adequacy for children's age, parents' perception of impact and, for children, change of the ability to recognize and willingness to taste fruits and vegetables. RESULTS: A total of 21 children and one of their parents participated in the programme. The programme was found to be feasible and adequate for the targeted community. Parents reported perceiving a positive impact of the intervention; however, this finding was not statistically significant. The major difficulty was identifying and recruiting families and engaging the parents in a discussion about weight. CONCLUSIONS: This short programme aiming to improve parents' ability to offer healthy environment and promote healthy eating behaviour was feasible and acceptable for families with young children. When developing and implementing such programmes, close collaboration with paediatricians and other health providers should be sought in order to identify and reach children at risk of obesity and their family. PMID- 26770770 TI - Cerium oxide nanoparticle aggregates affect stress response and function in Caenorhabditis elegans. AB - OBJECTIVE: The continual increase in production and disposal of nanomaterials raises concerns regarding the safety of nanoparticles on the environmental and human health. Recent studies suggest that cerium oxide (CeO2) nanoparticles may possess both harmful and beneficial effects on biological processes. The primary objective of this study is to evaluate how exposure to different concentrations (0.17-17.21 ug/mL) of aggregated CeO2 nanoparticles affects indices of whole animal stress and survivability in Caenorhabditis elegans. METHODS: Caenorhabditis elegans were exposed to different concentrations of CeO2 nanoparticles and evaluated. RESULTS: Our findings demonstrate that chronic exposure of CeO2 nanoparticle aggregates is associated with increased levels of reactive oxygen species and heat shock stress response (HSP-4) in Caenorhabditis elegans, but not mortality. Conversely, CeO2 aggregates promoted strain-dependent decreases in animal fertility, a decline in stress resistance as measured by thermotolerance, and shortened worm length. CONCLUSION: The data obtained from this study reveal the sublethal toxic effects of CeO2 nanoparticle aggregates in Caenorhabditis elegans and contribute to our understanding of how exposure to CeO2 may affect the environment. PMID- 26770771 TI - An open-label, in-use study assessing the warming sensation accompanying IFF Flavour 316282 and the acceptability and local tolerability of a syrup containing paracetamol and pseudoephedrine for the short-term treatment of symptoms of an upper respiratory tract infection. AB - OBJECTIVE: The primary objective was to assess the warming sensation caused by IFF Flavour 316282 in a syrup used for short-term treatment by patients suffering from nasal congestion and mild to moderate body pain, headache, fever or sore throat associated with an upper respiratory tract infection. METHODS: A single cohort, single treatment arm, open-label study. Subjects received one 30 mL dose of syrup containing IFF Flavour 316282, paracetamol and pseudoephedrine and recorded onset and disappearance of any warming sensation in the mouth/throat. Subjects' assessments of strength and appeal of the sensation, taste, texture and acceptability of the product was investigated using questionnaires. RESULTS: A total of 56 subjects were included; 53 (94.6%) experienced a warming sensation. The median duration of the warming sensation was 114 s (95% confidence interval: 87-120 s). All subjects rated the syrup as excellent, good or fair for treating their symptoms; 100% and 94.6% of subjects respectively described texture and taste as excellent, good or fair. There were no safety concerns, and the syrup was well tolerated. Most subjects liked the warming sensation. CONCLUSIONS: IFF Flavour 316282 in a syrup for treatment of upper respiratory tract infection symptoms is associated with a warming sensation. The syrup is well tolerated, safe and palatable. PMID- 26770772 TI - Effect of exercise training on clot strength in patients with peripheral artery disease and intermittent claudication: An ancillary study. AB - OBJECTIVES: Patients with peripheral artery disease have walking impairment, greater thrombotic risk, and are often treated with exercise training. We sought to determine the effect of a 3-month-long exercise program on clot strength among patients with peripheral artery disease and intermittent claudication. METHODS: Twenty-three symptomatic peripheral artery disease patients were randomly assigned to a walking exercise program or to an attention control group who performed light resistance exercise. We investigated the effect of exercise training on clot strength and time to clot formation was assessed by thromboelastography. RESULTS: After 3 months of exercise, clot strength (maximal amplitude) and time to clot formation (R) did not change significantly from baseline, even after improvements in claudication onset time (p < 0.01) and peak walking time (p < 0.05). Furthermore, changes in clot formation parameters were not significantly different between groups. Among the 10 individuals demonstrating a reduction in clot strength (reduced maximal amplitude), one was a smoker (10%) compared to 9 of 13 non-responders (69%) whose maximal amplitude was unchanged or increased (p = 0.0097). CONCLUSION: In this ancillary study, a 12 week walking program improved ambulatory function in peripheral artery disease patients with claudication, but does not modify clot strength or time to clot formation. Larger studies are needed to confirm these hypothesis generating findings and to determine whether a different amount or type of exercise may induce a change in clotting in this patient population. PMID- 26770773 TI - Chromogranin A and cortisol at intraoperative repeated noxious stimuli: Surgical stress in a dog model. AB - OBJECTIVES: Biomarkers representing sympathetic tone and the surgical stress response are measured to objectively evaluate surgical techniques and anaesthetic protocols. If a part of the intraoperative procedure is repeated on the contralateral organ, one animal may potentially serve as its own control and, if so, may minimize the problem of individual differences of the stress response to anaesthesia and surgery. This study aimed to investigate the use of chromogranin A for measurement of the intraoperative sympathetic tone. Additional aims were to investigate chromogranin A and cortisol as indicators of the intraoperative surgical stress response caused by repeated noxious stimuli in dogs subjected to ovariohysterectomy and thereby to investigate the possibility of one dog serving as its own control. METHODS: Experiments were carried out on 10 dogs subjected to ovariohysterectomy. Perioperative blood samples (0-6) were collected after premedication, immediately before induction of anaesthesia (0), after induction of anaesthesia and before incision (1), before (2) and after (3) removal of the first ovary, after a 15-min pause before removal of the second ovary (4), after removal of the second ovary (5) and after closing the abdomen (6). Plasma chromogranin A and cortisol were analysed. RESULTS: Plasma chromogranin A did not change. Plasma cortisol concentration did not change between before anaesthesia and opening of the abdomen. Plasma cortisol increased at removal of the first ovary. Cortisol did not change at removal of the second ovary but remained increased compared to initial sample. CONCLUSION: The results suggest chromogranin A is a poor indicator of intraoperative sympathetic tone during elective surgery in dogs. Cortisol measurement was useful for assessment of intraoperative noxious stimuli. However, at these test conditions, neither plasma chromogranin A nor plasma cortisol was useful for assessment of repeated intraoperative noxious stimuli where one dog served as its own control. PMID- 26770774 TI - Chest pain and high-sensitivity troponin: What is the evidence? AB - The number of attendances and admissions of patients with chest pain to hospitals in England and Wales is increasing. Initial assessment may be unrewarding. Consequently, cardiac troponin has become the mainstay of investigation for non ST-segment-elevation myocardial infarction and unstable angina, although only a small proportion of patients are eventually diagnosed as such. Current National Institute for Healthcare and Clinical Excellence guidance recommends measuring cardiac troponin levels on presentation and 10-12 h after onset of symptoms. A more effective diagnostic tool is needed. The aims are twofold: to increase accuracy of acute coronary syndrome diagnosis thus implementing the most appropriate management at an earlier stage while reducing costs and to provide a more rapid diagnosis to ease the anxieties of patients. Three key issues have been highlighted. The first is that many current studies do not have a 'normal/reference' population, making comparison between two studies difficult to interpret. Second, whether newer 'high-sensitivity' cardiac troponin tests can be used to rule out a myocardial infarction in a patient with chest pain is discussed. Third, whether a 'high-sensitivity' cardiac troponin has great enough specificity to differentiate between the number of other causes of raised troponin in a single test or whether serial testing is needed is assessed. A strategy for such serial testing is discussed. Finally, use of 'high-sensitivity' cardiac troponin in risk stratification of other disease processes is highlighted, which is likely to become common practice, changing the way we manage patients with, and without, chest pain. PMID- 26770775 TI - The impact of a Continuum of Care Resident Pharmacist on heart failure readmissions and discharge instructions at a community hospital. AB - PURPOSE: To examine the impact of a Continuum of Care Resident Pharmacist on (1) heart failure 30-day hospital readmissions and (2) compliance with Joint Commission Heart Failure core measure 1 at a community hospital. METHODS: The Continuum of Care Network led by a Continuum of Care Resident Pharmacist was established in August 2011. The Continuum of Care Resident Pharmacist followed Continuum of Care Network patients and retrospectively collected data from August 2011 to December 2012. Thirty-day readmission rates for Continuum of Care Network heart failure patients versus non-Continuum of Care Network heart failure patients were compared and analyzed. Joint Commission Heart Failure core measure 1 compliance rates were retrospectively collected from January 2011 and compared to data after establishment of the Continuum of Care Network. RESULTS: In all, 162 Continuum of Care Network patients and 470 non-Continuum of Care Network patients were discharged with a diagnosis of heart failure from August 2011 to December 2012. Continuum of Care Network heart failure patients had a lower 30 day all-cause readmission rate compared to non-Continuum of Care Network heart failure patients (12% versus 24%, respectively; p = 0.005). In addition, Heart Failure core measure 1 compliance rates improved from the 80th percentile to the 90th percentile after implementation of the Continuum of Care Network (p = 0.004). The top three interventions performed by the Continuum of Care Resident Pharmacist were discharge counseling (74.1%), providing a MedActionPlan(TM) (68.5%), and resolving medication reconciliation discrepancies (64.8%). CONCLUSION: The study findings suggest that a Continuum of Care Resident Pharmacist contributed to lowered heart failure readmission rates and improved Heart Failure core measure 1 compliance rates. Future randomized, controlled trials are needed to confirm these findings. PMID- 26770776 TI - Cigarette smoke condensate and individual constituents modulate DNA methyltransferase expression in human liver cells. AB - OBJECTIVES: Previous studies found higher expression levels of DNA methyltransferase 1 in liver samples from smokers compared to those from non smokers. In contrast, expression levels of DNA methyltransferase 3a and DNA methyltransferase 3b were similar in smokers and non-smokers. This study extends these studies to establish a causal linkage to cigarette smoke exposure by examining whether DNA methyltransferase expression is modulated by cigarette smoke condensate. METHODS: These experiments were conducted in an in vitro system using HepG2 human liver cells. The dose range of cigarette smoke condensate was 0.1-120 ug/mL. The duration of exposure was up to 72 h. RESULTS: In a 24-h exposure, DNA methyltransferase 1 expression was found to increase significantly in a dose-dependent manner (greater than threefold at 100 ug/mL cigarette smoke condensate). Expression levels of DNA methyltransferase 3a and DNA methyltransferase 3b were, however, not affected under these conditions. The effect of two cigarette constituents, nicotine and cotinine, on DNA methyltransferase 1 expression was also examined. Nicotine exposure significantly increased DNA methyltransferase 1 expression in a dose-dependent manner (greater than twofold at 50 uM). However, under these conditions, cotinine did not increase DNA methyltransferase 1 expression. CONCLUSION: These results clearly provide additional support of the modulating effect of cigarette smoke on DNA methyltransferase 1 expression. Given the potential of alterations in DNA methyltransferase expression to affect cellular function, this pathway may play a critical role in cigarette smoke-induced toxicity. PMID- 26770777 TI - Advantage of impulse oscillometry over spirometry to diagnose chronic obstructive pulmonary disease and monitor pulmonary responses to bronchodilators: An observational study. AB - OBJECTIVES: This retrospective study was a comparative analysis of sensitivity of impulse oscillometry and spirometry techniques for use in a mixed chronic obstructive pulmonary disease group for assessing disease severity and inhalation therapy. METHODS: A total of 30 patients with mild-to-moderate chronic obstructive pulmonary disease were monitored by impulse oscillometry, followed by spirometry. Lung function was measured at baseline after bronchodilation and at follow-up (3-18 months). The impulse oscillometry parameters were resistance in the small and large airways at 5 Hz (R5), resistance in the large airways at 15 Hz (R15), and lung reactance (area under the curve X; AX). RESULTS: After the bronchodilator therapy, forced expiratory volume in 1 second (FEV1) readings evaluated by spirometry were unaffected at baseline and at follow-up, while impulse oscillometry detected an immediate improvement in lung function, in terms of AX (p = 0.043). All impulse oscillometry parameters significantly improved at follow-up, with a decrease in AX by 37% (p = 0.0008), R5 by 20% (p = 0.0011), and R15 by 12% (p = 0.0097). DISCUSSION: Impulse oscillometry parameters demonstrated greater sensitivity compared with spirometry for monitoring reversibility of airway obstruction and the effect of maintenance therapy. Impulse oscillometry may facilitate early treatment dose optimization and personalized medicine for chronic obstructive pulmonary disease patients. PMID- 26770779 TI - Unrestricted access to medical research articles. PMID- 26770778 TI - Direct effects of Facio-Oral Tract Therapy((r)) on swallowing frequency of non tracheotomised patients with acute neurogenic dysphagia. AB - OBJECTIVES: The aim of this study was to investigate the direct effect of Facio Oral Tract Therapy((r)) on swallowing frequency of non-tracheotomised patients with acute neurogenic dysphagia. METHODS: Within a pre-, post-/during and follow up study design, 19 non-tracheotomised dysphagic patients were included consecutively and treated according to three specific preselected Facio-Oral Tract Therapy stimulation techniques. RESULTS: The primary outcome was the direct effect of the three different Facio-Oral Tract Therapy stimulation techniques on the number of swallows. We found a significant effect of Facio-Oral Tract Therapy on swallowing frequency as compared to baseline with an increase by 65.63% and medium effect size of D = 0.62. No significant difference could be demonstrated when comparing baseline to follow-up. CONCLUSION: For the first time, this positive therapy effect could be demonstrated on a population of non tracheotomised patients. Facio-Oral Tract Therapy seems to be an appropriate means for improving effectiveness and safety of swallowing. Since improvement was not long lasting, it appears to be reasonable to apply therapy frequently during the day with the plausible result of minimising the amount of aspirated saliva and thereby reducing the risk of aspiration pneumonia. Further studies may consider choosing a randomised controlled trial design to demonstrate that change in swallow frequency is related to the target intervention only. PMID- 26770780 TI - Types of vicarious learning experienced by pre-dialysis patients. AB - OBJECTIVE: Haemodialysis and peritoneal dialysis renal replacement treatment options are in clinical equipoise, although the cost of haemodialysis to the National Health Service is L16,411/patient/year greater than peritoneal dialysis. Treatment decision-making takes place during the pre-dialysis year when estimated glomerular filtration rate drops to between 15 and 30 mL/min/1.73 m(2). Renal disease can be familial, and the majority of patients have considerable health service experience when they approach these treatment decisions. Factors affecting patient treatment decisions are currently unknown. The objective of this article is to explore data from a wider study in specific relation to the types of vicarious learning experiences reported by pre-dialysis patients. METHODS: A qualitative study utilised unstructured interviews and grounded theory analysis during the participant's pre-dialysis year. The interview cohort comprised 20 pre-dialysis participants between 24 and 80 years of age. Grounded theory design entailed thematic sampling and analysis, scrutinised by secondary coding and checked with participants. Participants were recruited from routine renal clinics at two local hospitals when their estimated glomerular filtration rate was between 15 and 30 mL/min/1.73 m(2). RESULTS: Vicarious learning that contributed to treatment decision-making fell into three main categories: planned vicarious leaning, unplanned vicarious learning and historical vicarious experiences. CONCLUSION: Exploration and acknowledgement of service users' prior vicarious learning, by healthcare professionals, is important in understanding its potential influences on individuals' treatment decision-making. This will enable healthcare professionals to challenge heuristic decisions based on limited information and to encourage analytic thought processes. PMID- 26770781 TI - Physical therapy intervention in patients with non-cardiac chest pain following a recent cardiac event: A randomized controlled trial. AB - OBJECTIVES: To assess the effect of two different physical therapy interventions in patients with stable coronary heart disease and non-cardiac chest pain. METHODS: A randomized controlled trial was carried out at a university hospital in Norway. A total of 30 patients with known and stable coronary heart disease and self-reported persistent chest pain reproduced by palpation of intercostal trigger points were participating in the study. The intervention was deep friction massage and heat pack versus heat pack only. The primary outcome was pain intensity after the intervention period and 3 months after the last treatment session, measured by Visual Analogue Scale, 0 to 100. Secondary outcome was health-related quality of life. RESULTS: Treatment with deep friction massage and heat pack gave significant pain reduction compared to heat pack only (-17.6, 95% confidence interval: -30.5, -4.7; p < 0.01), and the reduction was persistent at 3 months' follow-up (-15.2, 95% confidence interval: -28.5, -1.8; p = 0.03). Health-related quality of life improved in all three domains in patients with no significant difference between groups. CONCLUSION: Deep friction massage combined with heat pack is an efficient treatment of musculoskeletal chest pain in patients with stable coronary heart disease. PMID- 26770782 TI - The Hispanic pharmacist: Value beyond a common language. AB - OBJECTIVE: To highlight the added value of bilingual Hispanic pharmacists in the care of Hispanic patients by sharing their patients' language and culture. SUMMARY: Inability to speak and/or write in the patients' native language severely impairs our best efforts to deliver good health care. This is a widely recognized cause of non-compliance or less than favorable possible health outcomes in Hispanic patients. What has received less attention, however, is that the ability to speak Spanish alone may not remove completely the barrier for non compliance among Hispanics. Bilingual Spanish-English pharmacists do not have the language barrier, but if they do not recognize and accept cultural differences, their impact in their patients' response may still be limited. CONCLUSION: It is time to recognize the added value of Hispanic pharmacists to Hispanic patients' health outcomes. Understanding and sharing a culture allows the pharmacist to make medication education and interventions relevant to the patient and spark interest in their own health care. Thus, in caring for the health of our patients, cultural barriers may be more challenging to conquer than language barriers; deep appreciation and acceptance of our patients' belief system cannot be acquired by just reading about it, having a computerized program, or hiring an interpreter. PMID- 26770783 TI - Credentials for a PharmD graduate: The voyage never ends. AB - Doctor of Pharmacy (PharmD) is a professional pharmacy degree qualification offered by universities world-wide. While the graduates from the West are familiar with scope and job opportunities that present on completion of a PharmD degree, graduates from Asia and the Middle-East are coming to grips with the future of PharmD program and the role that it could play in career advancement. Through this review, we would like to highlight that numerous credential programs are available which can be added to the armory of PharmD graduates for advancement of their professional careers. The credentials detailed in this review are designed for PharmD graduates to optimize pharmaceutical care in specialized clinical settings such as geriatrics and ambulatory medicine. We have assembled an extensive list of post-PharmD educational opportunities to enhance professional practice for pharmacy graduates. PMID- 26770784 TI - Pharmacy students screening for pre-diabetes/diabetes with a validated questionnaire in community pharmacies during their experiential rotation in Alberta, Canada. AB - PURPOSE: Type 2 diabetes is a major condition impacting morbidity, mortality, and health care costs in Canada. Pharmacists are very accessible and are in an ideal position to promote public health education. The primary goal of this study was to incorporate public health promotion and education into a community pharmacy experiential education rotation for fourth year pharmacy students to screen for the risk of pre-diabetes/diabetes in adults. A secondary goal was to determine the frequency of common risk factors for pre-diabetes/diabetes in adults in the community setting. METHOD: Fourth year pharmacy students were invited to recruit all adults 25 years or older attending community pharmacies to complete a pre diabetes/diabetes risk assessment questionnaire. If the participants were at risk, the participants were provided education about risk reduction for developing pre-diabetes/diabetes. RESULTS: A total of 340 participants completed a risk assessment questionnaire. Over 90% of people approached agreed to complete a risk assessment questionnaire. The common risk factors were overweight (154/45%), hypertension (102/30%), taking medications for hypertension (102/30%), and having symptoms of diabetes (111/33%). The ethnic minorities have 2.56 (confidence interval = 1.48-44.1) times greater odds of having a family history of diabetes compared to non-minority subjects. CONCLUSION: Pharmacy students are able to screen community-based patients for pre-diabetes/diabetes risks. The most common risk factors presented were overweight, hypertension, and taking medications for hypertension. PMID- 26770785 TI - Factor structure and measurement invariance of the Health Education Impact Questionnaire: Does the subjectivity of the response perspective threaten the contextual validity of inferences? AB - OBJECTIVE: On-going evidence is required to support the validity of inferences about change and group differences in the evaluation of health programs, particularly when self-report scales requiring substantial subjectivity in response generation are used as outcome measures. Following this reasoning, the aim of this study was to replicate the factor structure and investigate the measurement invariance of the latest version of the Health Education Impact Questionnaire, a widely used health program evaluation measure. METHODS: An archived dataset of responses to the most recent version of the English-language Health Education Impact Questionnaire that uses four rather than six response options (N = 3221) was analysed using exploratory structural equation modelling and confirmatory factor analysis appropriate for ordered categorical data. Metric and scalar invariance were studied following recent recommendations in the literature to apply fully invariant unconditional models with minimum constraints necessary for model identification. RESULTS: The original eight-factor structure was replicated and all but one of the scales (Self Monitoring and Insight) was found to consist of unifactorial items with reliability of ?0.8 and satisfactory discriminant validity. Configural, metric and scalar invariance were established across pre-test to post-test and population sub-groups (sex, age, education, ethnic background). CONCLUSION: The results support the high level of interest in the Health Education Impact Questionnaire, particularly for use as a pre test/post-test measure in experimental studies, other pre-post evaluation designs and system-level monitoring and evaluation. PMID- 26770786 TI - Self-reported osteoporosis prevention in inhaled corticosteroid users in community pharmacy setting. AB - OBJECTIVES: The use of inhaled corticosteroids is the standard maintenance therapy in asthma therapy and as adjunct therapy in moderate to severe chronic obstructive pulmonary disease. A dose-related increase in fracture risk is associated with inhaled corticosteroid use; there is an inverse relationship between bone mineral density and duration and cumulative dose of inhaled corticosteroid. Adequate intake of calcium and vitamin D are cornerstones of osteoporosis prevention. The objectives are to assess whether the proportion of patients receiving inhaled corticosteroids are taking calcium and vitamin D; the association between long-term inhaled corticosteroid use and abnormal bone mineral density or fractures; and how many qualified patients received bone mineral density scans. METHODS: Patients who filled a prescription for inhaled corticosteroids at selected community pharmacies across Alberta were recruited for a survey of their osteoporosis prevention activities. RESULTS: A total of 256 patients from 12 community pharmacies were included. The average age was 60 +/- 17.4 years with 65% female. There were 21%, 51%, and 28% of patients on high, medium, and low dose inhaled corticosteroids, respectively. Only 17% of patients >50 years old received recommended calcium and vitamin D supplementation and 87 (73%) of the qualified patients received bone mineral density scan. CONCLUSION: Osteoporosis prevention in inhaled corticosteroid users is currently poorly addressed. More promotion is needed to raise pharmacist awareness of the risks of inhaled corticosteroids. PMID- 26770787 TI - A prospective non-interventional study for evaluation of quality of life in patients with Alzheimer's disease treated with rivastigmine transdermal patch. AB - OBJECTIVES: The primary objective of this multicentre, prospective, observational study was to assess whether there is improvement in the patients' quality of life under treatment with rivastigmine transdermal patch, as it is evaluated both by patients and their caregivers. Compliance to treatment and safety were secondary endpoints. METHODS: In total, 1509 patients with mild to moderate Alzheimer's disease, already treated with rivastigmine transdermal patch 4.6 or 9.5 mg/24 h, were enrolled within a 2.4-month period and prospectively followed up for 2 months on an outpatient basis. The 'Quality of Life in Alzheimer's disease (QOL AD): Patient and Caregiver Report' questionnaire was used to evaluate quality of life as an effectiveness measure. RESULTS AND CONCLUSION: A significant improvement in quality of life, as indicated by a change of 2.7 and 2.5 points in the mean patients' and caregiver's QOL-AD: Patient and Caregiver Report score respectively (both p < 0.001) from baseline to end of study was recorded. No serious adverse events were reported. Compliance was high, with 100% compliance reported for almost 9 out of 10 patients at study end. PMID- 26770788 TI - The validity and reliability of attending evaluations of medicine residents. AB - OBJECTIVES: To assess the reliability and validity of faculty evaluations of medicine residents. METHODS: We conducted a retrospective study (2004-2012) involving 228 internal medicine residency graduates at the Medical College of Wisconsin who were evaluated by 334 attendings. Measures included evaluations of residents by attendings, based on six competencies and interns and residents' performance on the American Board of Internal Medicine certification exam and annual in-service training examination. All residents had at least one in-service training examination result and 80% allowed the American Board of Internal Medicine to release their scores. RESULTS: Attending evaluations had good consistency (Cronbach's alpha = 0.96). There was poor construct validity with modest inter-rater reliability and evidence that attendings were rating residents on a single factor rather than the six competencies intended to be measured. There was poor predictive validity as attending ratings correlated weakly with performance on the in-service training examination or American Board of Internal Medicine certification exam. CONCLUSION: We conclude that attending evaluations are poor measures for assessing progress toward competency. It may be time to move beyond evaluations that rely on global, end-of-rotation appraisals. PMID- 26770789 TI - Relationship between care dependency and behavioral symptoms among elderly in patients with Alzheimer's disease in Japan and the Netherlands. AB - OBJECTIVE: This study investigates the influence of personal characteristics and health-related variables on the care dependency status among elderly in-patients with clinically diagnosed Alzheimer's disease in two countries. METHODS: A descriptive cross-cultural survey was administered to a convenience sample of 137 elderly in-patients. Patients were recruited from a hospital in Japan (N = 77) and from a nursing home in the Netherlands (N = 60). RESULTS: In both countries, almost all participants are assessed on the severity level of care dependency in the range of "completely care dependent" (Japan: 35.1%; the Netherlands: 20.0%), or "to a great extent care dependent" (Japan: 24.7%; the Netherlands: 45.0%), to "partially care dependent" (Japan: 22.1%; the Netherlands: 21.7%). CONCLUSION: This study demonstrates that there is no interdependence between the severity level of care dependency and personal characteristics of patients with Alzheimer's disease in both countries. Regarding the interplay of health-related variables on the severity level of care dependency, a difference was found between countries. PMID- 26770790 TI - Questions people ask about stroke: What's changed in 20 years? AB - OBJECTIVES: Care for patients after stroke has been transformed over the last two decades. We explored one patient-centred outcome: the type and range of questions asked after stroke through a publically available helpline. We compared data from 1990 to 2013 to see whether the positive changes in stroke care are reflected in the types and quantity of inquiries from patients and their families. METHODS: All of the inquiries received by the UK Stroke Association helpline between 1 April 2013 and 31 March 2014 were collated and compared to the data collected and previously reported by Hanger and Mulley between May and September 1990. RESULTS: In 1990, the most common inquiry was for more information about stroke (22.5% (429/1908)). In 2013, the most common question remained the same, with 25.4% (2601/10,233) of all callers asking what is a stroke. Specific medical questions increased from 4.2% (80/1908) in 1990 to 10.5% (1074/10,233) in 2013. Queries about support with home care reduced from 9.4% (180/1908) in 1990 to 2.6% (257/10,233) in 2013. Questions about recovery and rehabilitation were frequent in both 1990 (11.1% (212/1908)) and 2013 (13.2% (1353/10,233)). CONCLUSION: The transformation in stroke services has not been reflected in this patient-level outcome in the United Kingdom. Many stroke survivors and their families still struggle with understanding their condition and treatment options. PMID- 26770791 TI - Data reporting constraints for the lymphatic filariasis mass drug administration activities in two districts in Ghana: A qualitative study. AB - OBJECTIVES: Timely and accurate health data are important for objective decision making and policy formulation. However, little evidence exists to explain why poor quality routine health data persist. This study examined the constraints to data reporting for the lymphatic filariasis mass drug administration programme in two districts in Ghana. This qualitative study focused on timeliness and accuracy of mass drug administration reports submitted by community health volunteers. METHODS: The study is nested within a larger study focusing on the feasibility of mobile phone technology for the lymphatic filariasis programme. Using an exploratory study design, data were obtained through in-depth interviews (n = 7) with programme supervisors and focus group discussions (n = 4) with community health volunteers. Results were analysed using thematic content analysis. RESULTS: Reasons for delays in reporting were attributed to poor numeracy skills among community health volunteers, difficult physical access to communities, high supervisor workload, poor adherence reporting deadlines, difficulty in reaching communities within allocated time and untimely release of programme funds. Poor accuracy of data was mainly attributed to inadequate motivation for community health volunteers and difficulty calculating summaries. CONCLUSION: This study has shown that there are relevant issues that need to be addressed in order to improve the quality of lymphatic filariasis treatment coverage reports. Some of the factors identified are problems within the health system; others are specific to the community health volunteers and the lymphatic filariasis programme. Steps such as training on data reporting should be intensified for community health volunteers, allowances for community health volunteers should be re-evaluated and other non-monetary incentives should be provided for community health volunteers. PMID- 26770792 TI - Strategic initiatives to maintain pharmaceutical care and clinical pharmacists sufficiency in Saudi Arabia. AB - OBJECTIVES: The shortage of clinical pharmacists in Saudi Arabia has limited the full implementation of pharmaceutical care in most of its hospitals. The National Guard Health Affairs hospitals. This work discussed the Department of Pharmaceutical Care, and the King Saud Bin Abdulaziz University for Health Sciences College of Pharmacy four initiatives that were planned in 2009-2010 to develop and recruit clinical pharmacists, practitioners, or faculty. METHODS: The combined initiatives were aimed at (1) instituting a 4-year clinical skills development career ladder, (2) expanding the National Guard Health Affairs postgraduate residency program, (3) offering scholarships to qualified pharmacy graduates to pursue the PharmD degree and a PGY-1 residency training in the United States, and (4) recruiting non-Saudi clinical pharmacists educated and trained in the United States to ameliorate the current shortage of practitioner. RESULTS: The current number of clinical pharmacists practicing at the National Guard Health Affairs at central region is 24, most of whom are Board Certified by the American Pharmacists Association Board of Pharmacy Specialties. CONCLUSIONS: The four initiatives, based on current trends, suggest that 60-65 positions will be added by 2017-2018, barring attrition. Saudi Arabia and many developing countries will continue to experience a shortage in clinical pharmacists due to the high demand for clinical pharmacy services. A multifaceted approach is recommended to address the problem. PMID- 26770793 TI - Understanding the role of the healthcare professional in patient self-management of allergic rhinitis. AB - OBJECTIVE: Allergic rhinitis is a common, usually long-standing, condition that may be self-diagnosed or have a formal diagnosis. Our aim was to identify how allergic rhinitis sufferers self-manage their condition. METHODS: A sample of 276 self-identified adult allergy sufferers pooled from social media completed an online survey comprising 13 questions. The survey was fielded by a professional research organization (Lab42). The main outcome measures included the use of prescription and/or non-prescription allergy medication, and interactions with physician and/or pharmacist with respect to medication use. RESULTS: Of the respondents, 53% (146/276) indicated that they used both prescription and over the-counter medication to manage their allergy symptoms. Of those who used prescription medication, 53% reported that they discussed their prescription medication in great detail with their physician when it was prescribed, while 42% spoke about it briefly. Following the initial prescription, few discussions about the prescription occur with the physician (45% indicate several discussions, 40% indicate one or two discussions, and 10% indicate no discussions). In most cases (~75% of the time), allergy prescription refills did not require a doctor visit with patients obtaining refills through phone calls to the doctor's office or through the pharmacy. Two-thirds of patients (69%) report that they have discussed their prescription allergy medication with a pharmacist, with greater than half of respondents having discussed the use of the non-prescription medication with their doctor. CONCLUSION: Patients with diagnosed allergic rhinitis appear to be self-managing their condition with few interactions with their doctor about their allergy prescription. Interactions with a pharmacist about allergy medication (prescription and non-prescription) appear to be more common than interactions with a physician. PMID- 26770794 TI - A qualitative study of recruiting for investigations in primary care: Plan, pay, minimise intermediaries and keep it simple. AB - OBJECTIVES: We sought successful strategies to recruit patient and practitioner participants for studies from primary care. METHODS: We interviewed people who had participated and who had not participated in a randomised controlled trial that did not reach recruitment target and successful primary care researchers. The participants and non-participants were mostly Pacific peoples. Interviews were recorded, transcribed, and analysed and reported using qualitative description. The study took place in New Zealand in 2013-2014. RESULTS: A total of 31 people were interviewed. Researchers agreed that recruitment was usually the single most important phase of research but was usually under-planned and under-funded. All researchers recommended a pilot study that addressed recruitment. Successful researchers actively monitored recruitment and adapted the process as needed. Most projects were undertaken by our researchers recruited via an intermediary such as a general practice nurse. Strategies were adapted to the target population, such as specific acute or chronic conditions, age, ethnicity and gender. Intermediaries were actively recruited and retained in a manner that was often more intense than actual participant recruitment and retention. 'Layers' of intermediaries were kept to a minimum as each layer needed to be actively recruited and retained and each layer reduced participant recruitment rates. The task of intermediaries was kept simple and minimal and they were paid in some manner. Similarly, participant workload was kept to a minimum and they were paid in some manner that was intended to cover their participation costs and perhaps a little more. Even the most experienced researchers did not always achieve recruitment targets. Our interviews focused on patient participants but included recruiting general practitioners, nurses and others as research subjects. CONCLUSION: Strategy details varied with the target population but had in common the need to intensively recruit and retain intermediaries, minimise layers of intermediaries, and the need to pay and minimise workload for both intermediaries and participants. PMID- 26770795 TI - Quality use of medicine in a developing economy: Measures to overcome challenges in the Malaysian healthcare system. AB - Malaysia inherits a highly subsidized tax-based public healthcare system complemented by a fee-for-service private sector. Population health in Malaysia has considerably improved since independence using a relatively small amount of gross domestic product (~4%). Brain drain of highly specialized personnel, growth in healthcare spending, demographic and disease pattern changes and increase in patients' demands and expectations towards better medical care are exerting pressure on the sustainability of the system to continuously provide efficient and effective services at relatively low cost. Malaysia has adopted and implemented some of the quality use of medicine concepts such as National Essential Medicine List, health technology assessment and promotion of generic medicines in their health policy, but so far the results may not be optimal. Activities to further promote these strategies are needed for successful implementation to achieve more positive and sustained beneficial outcomes. Better strategic planning, management and collaboration between various stakeholders, considering the needs and barriers of the strategies, are important to ensure effective implementation of the strategies. More emphasis should be placed upon more equitable and rational distribution of healthcare resources to cater for rapid urbanization. Additionally, a sustainable health financing structure that is more progressive and does not encourage moral hazard should be established. In conclusion, Malaysia has achieved good outcomes in population health with relatively low financial inputs since independence. However, changes in the overall environment have created issues which would threaten the long-term viability of the healthcare system if not tackled properly. The numbers of internationally trialled strategies could be used to deal with these challenges. In addition, coordinated implementation of these strategies and effective engagement and communication between various stakeholders are necessary to further strengthen the Malaysian healthcare system effectively. PMID- 26770796 TI - Clinical characteristics of patients with Rutherford category IV, compared with V and VI. AB - OBJECTIVE: Patients categorized Rutherford category IV might have different characteristics compared with Rutherford category V and VI. Our study aims were to estimate the clinical differences between Rutherford category IV and Rutherford category V and VI, for those underwent endovascular therapy for isolated infrapopliteal disease, and also to find risk factors for endovascular therapy in Rutherford category IV. METHODS: Based on the Japanese multi-center registry data, 1091 patients with 1332 limbs (Rutherford category IV: 226 patients with 315 limbs, Rutherford category V and VI: 865 patients with 1017 limbs) were analyzed retrospectively. RESULTS: Patients' backgrounds and lesions' characteristics had significant differences. Both freedom rate from major adverse limb event with perioperative death and amputation-free survival rate at 1 year were better in Rutherford category IV than Rutherford category V and VI (93.6% vs 78.3%, 87.7% vs 66.7%) and those maintained to 3 years (p < 0.0001). Significant predictors for major adverse limb event/perioperative death were small body mass index (<18.5 kg/m(3)) and initial endovascular therapy success, and those for amputation-free survival were small body mass index (<18.5 kg/m(3)), non ambulatory status, high systematic inflammatory reaction (C-reactive protein > 3.0 mg/dL), chronic obstructive pulmonary disease, and coronary artery disease in Rutherford category IV. CONCLUSION: From the present results, Rutherford category IV should be recognized to have quite different backgrounds and better outcome from Rutherford category V and VI. PMID- 26770797 TI - A systematic review and meta-analysis of plasma amyloid 1-42 and tau as biomarkers for Alzheimer's disease. AB - OBJECTIVE: Amyloid 1-42 (Abeta42) and tau in cerebrospinal fluid are currently used as markers for diagnosis of Alzheimer's disease. Conflicting reports exist regarding their plasma levels in Alzheimer's disease patients. A meta-analysis was performed to statistically validate the use of plasma Abeta42 and tau as biomarkers for Alzheimer's disease. METHODS: Different databases were searched using the search key: (amyloid OR amyloid1-42 OR Abeta42) AND (tau OR total tau) AND plasma AND (alzheimer's OR alzheimer's disease), and for databases not accepting boolean search, records were retrieved using the search key: plasma + amyloid + tau + alzheimer's. A total of 1880 articles for Abeta42 and 1508 articles for tau were shortlisted. The abstracts were screened, and 69 articles reporting plasma Abeta42 levels and 6 articles reporting plasma tau were identified. After exclusion, 25 studies reporting plasma Abeta42 and 6 studies reporting total tau were analysed in Review Manager version 5.2 using weighted mean difference method, and the bias between studies was assessed using the funnel plot. RESULTS: Plasma Abeta42 and tau did not vary significantly between Alzheimer's disease patients and controls. The funnel plot showed that there was no bias between studies for Abeta42, while possible bias existed for tau due to availability of limited studies. CONCLUSION: This analysis pinpoints that plasma Abeta42 and tau could not serve as reliable markers independently for diagnosis of Alzheimer's disease and a cohort study with age, sex and apolipoprotein E correction is warranted for their possible use as Alzheimer's disease markers. PMID- 26770798 TI - Pharmacy collected medication histories in an observation unit. AB - BACKGROUND: Clear processes to facilitate medication reconciliation in a hospital setting are still undefined. The observation unit allows for a high patient turnover rate, where obtaining accurate medication histories is critical. OBJECTIVES: The objective of this study was to assess the ability of pharmacists and student pharmacists to identify discrepancies in medication histories obtained at triage in observation patients. METHODS: Pharmacists and student pharmacists obtained a medication history for each patient placed in observation status. Patients were excluded if they were unable to provide a medication history and family, caregiver, or community pharmacy was also unable to provide the history. A comparison was made between triage and pharmacy collected medication histories to identify discrepancies. RESULTS: A total of 501 medications histories were collected, accounting for 3213 medication records. There were 1176 (37%) matched medication records and 1467 discrepancies identified, including 808 (55%) omissions, 296 (20.2%) wrong frequency, 278 (19%) wrong dose, 51 (3.5%) discontinued, and 34 (2.3%) wrong medication. There was an average of 2.9 discrepancies per patient profile. In all, 76 (15%) of the profiles were matched. The median time to obtain a medication history was 4 min (range: 1-48 min). CONCLUSION: Pharmacy collected medication histories in an observation unit identify discrepancies that can be reconciled by the interdisciplinary team. PMID- 26770799 TI - Periodontal disease and liver cirrhosis: A systematic review. AB - OBJECTIVES: Studies suggest that periodontal disease, a source of subclinical and persistent infection, may be associated with various systemic conditions, including liver cirrhosis. The aim of this study was to examine the literature and determine the relationship between periodontal disease and liver cirrhosis and to identify opportunities and directions for future research in this area. METHODS: A systematic review of English articles in the PubMed, EMBASE, and Scopus databases was conducted using search terms including 'liver cirrhosis', 'end-stage liver disease', 'liver diseases', 'oral health', 'periodontal disease', 'mouth disease', 'gingivitis', and 'periodontitis'. RESULTS: Thirteen studies published between 1981 and 2014 were found to include data on oral health and periodontal disease in cirrhotic patients. Studies indicated an increased incidence of periodontal disease in patients with liver cirrhosis, measured with several different periodontal indices. The reported prevalence of periodontal disease in cirrhosis patients ranged from 25.0% to 68.75% in four studies and apical periodontitis was found in 49%-79% of the patients. One study found that mortality was lower among patients who underwent dental treatment versus non treated patients. Another study suggested an association between periodontal disease and the progression of liver cirrhosis, but data are sparse and conflicting as to whether periodontal disease is correlated to cirrhosis aetiology and severity. CONCLUSION: Despite the clinical reality of periodontal disease in liver cirrhosis patients, there are few published studies. Before clinical implications can be addressed, more data on the prevalence of and correlation between periodontal disease and liver cirrhosis aetiology, duration, and progression are needed. PMID- 26770800 TI - Benchmarking facilities providing care: An international overview of initiatives. AB - We performed a literature review of existing benchmarking projects of health facilities to explore (1) the rationales for those projects, (2) the motivation for health facilities to participate, (3) the indicators used and (4) the success and threat factors linked to those projects. We studied both peer-reviewed and grey literature. We examined 23 benchmarking projects of different medical specialities. The majority of projects used a mix of structure, process and outcome indicators. For some projects, participants had a direct or indirect financial incentive to participate (such as reimbursement by Medicaid/Medicare or litigation costs related to quality of care). A positive impact was reported for most projects, mainly in terms of improvement of practice and adoption of guidelines and, to a lesser extent, improvement in communication. Only 1 project reported positive impact in terms of clinical outcomes. Success factors and threats are linked to both the benchmarking process (such as organisation of meetings, link with existing projects) and indicators used (such as adjustment for diagnostic-related groups). The results of this review will help coordinators of a benchmarking project to set it up successfully. PMID- 26770801 TI - Effects of viewing a preferred nature image and hearing preferred music on engagement, agitation, and mental status in persons with dementia. AB - BACKGROUND: The purpose of the described exploratory study was to test proactive strategies for enhancing engagement and cognitive ability while diminishing dementia-related disordered behaviors of those diagnosed with Alzheimer's disease and other dementias. Study participants resided in an Memory Care unit of an assisted living community. METHOD: The researchers measured the effects of exposure to music and nature images on engagement using the Individualized Dementia Engagement and Activities Scale tool, on cognitive ability using the Montreal Cognitive Assessment, and on agitation using the Cohen-Mansfield Agitation Inventory. RESULT: The within-subject study design revealed that use of both music and nature images hold promise for reducing undesirable behaviors and improving engagement of residents. CONCLUSION: The authors suggest caregivers for those with Alzheimer's disease and other dementias can effectively use nature images and music to improve engagement and reduce disordered behaviors, thus potentially enhancing quality of life for the care recipient as well as the caregiver while possibly reducing the costs of medications used to control dementia-related undesirable behaviors. PMID- 26770802 TI - Mapping the terrain: A conceptual schema for a mental health medication support service in community pharmacy. AB - OBJECTIVE: Mental health-related problems pose a serious issue for primary care, and community pharmacy could make a significant contribution, but there is a dearth of information. METHODS: This article reports synthesis of the literature on mental health interventions across a range of pharmacy models, and pharmacy services in contexts beyond mental health. To best inform the design of a community pharmacy medication support intervention for mental health consumers, the literature was reported as a conceptual schema and subsequent recommendations for development, implementation and evaluation of the service. A broad conceptualisation was taken in this review. In addition to mental health and community pharmacy literature, policy/initiatives, organisational culture and change management principles, and evaluative processes were reviewed. Key words were selected and literature reviews undertaken using EMBASE, PubMed, CINAHL and Web of Science. RESULTS: Recommendations were made around: medication support intervention design, consumer recruitment, implementation in community pharmacy and evaluation. Surprisingly, there is a scarce literature relating to mental health interventions in community pharmacy. Even so, findings from other pharmacy models and broader medicines management for chronic illness can inform development of a medication support service for mental health consumers. Key learnings include the need to expand medicines management beyond adherence with respect to both intervention design and evaluation. CONCLUSION: The conceptual framework is grounded in the need for programmes to be embedded within pharmacies that are part of the health system as a whole. PMID- 26770803 TI - Risk of new-onset diabetes associated with statin use. AB - OBJECTIVE: To identify and assess studies investigating the association between statins and new-onset diabetes and determine the clinical significance of this risk. DATA SOURCES: A MEDLINE (1977-April 2015), Google Scholar (1997-April 2015), and International Pharmaceutical Abstracts (1977-April 2015) search was performed using the search terms hydroxymethylglutaryl-CoA reductase inhibitors, hydroxymethylglutaryl-CoA reductase inhibitors/adverse effects, statins, adverse effects, diabetes mellitus, diabetes mellitus/etiology, and drug-induced. Citations of identified articles and clinical practice guidelines were also reviewed. STUDY SELECTION AND DATA EXTRACTION: Articles describing results from original investigations or meta-analyses specifically designed to assess the association between statins and new-onset diabetes and published in English were included. DATA SYNTHESIS: A total of 13 cohort studies and seven meta-analyses were included. In all, 11 were retrospective cohort studies and reported some degree of increased risk of new-onset diabetes associated with statins. The two prospective cohort studies differed. One identified increased risk of new-onset diabetes, but the other did not. Increased risk was not identified when any statin was compared to placebo alone, individual statins were compared, or in the single meta-analysis that included observational studies. Overall, the meta analyses suggest that statin therapy is associated with an increased risk of new onset diabetes when compared to placebo or active control, and when intensive therapy is compared to moderate therapy. CONCLUSION: Statins have been associated with a small, but statistically significant risk of new-onset diabetes. Patients with risk factors for developing diabetes mellitus may be at higher risk. This risk is likely outweighed by the benefits of reducing cardiovascular risk. PMID- 26770804 TI - Patient complaints in healthcare services in Vietnam's health system. AB - BACKGROUND: There is growing recognition of patient rights in health sectors around the world. Patients' right to complain in hospitals, often visible in legislative and regulatory protocols, can be an important information source for service quality improvement and achievement of better health outcomes. However, empirical evidence on complaint processes is scarce, particularly in the developing countries. To contribute in addressing this gap, we investigated patients' complaint handling processes and the main influences on their implementation in public hospitals in Vietnam. METHODS: The study was conducted in two provinces of Vietnam. We focused specifically on the implementation of the Law on Complaints and Denunciations and the Ministry of Health regulation on resolving complaints in the health sector. The data were collected using document review and in-depth interviews with key respondents. Framework approach was used for data analysis, guided by a conceptual framework and aided by qualitative data analysis software. RESULTS: Five steps of complaint handling were implemented, which varied in practice between the provinces. Four groups of factors influenced the procedures: (1) insufficient investment in complaint handling procedures; (2) limited monitoring of complaint processes; (3) patients' low awareness of, and perceived lack of power to change, complaint procedures and (4) autonomization pressures on local health facilities. While the existence of complaint handling processes is evident in the health system in Vietnam, their utilization was often limited. Different factors which constrained the implementation and use of complaint regulations included health system-related issues as well as social and cultural influences. CONCLUSION: The study aimed to contribute to improved understanding of complaint handling processes and the key factors influencing these processes in public hospitals in Vietnam. Specific policy implications for improving these processes were proposed, which include improving accountability of service providers and better utilization of information on complaints. PMID- 26770805 TI - Endobronchial ultrasound-guided transbronchial needle aspiration in the staging of lung cancer patients. AB - OBJECTIVE: Mediastinoscopy as diagnostic procedure for evaluation of mediastinum in patients with non-small-cell lung cancer has long been considered the reference standard. However, less invasive method has occurred. Endobronchial ultrasound-guided transbronchial needle aspiration came into widespread use and has resulted in controversy as to whether it is a good replacement for mediastinoscopy. We chose to demonstrate the usefulness of endobronchial ultrasound-guided transbronchial needle aspiration in evaluating the mediastinum in patients with non-small-cell lung cancer. MATERIAL AND METHODS: Over a 48 month period, 1841 patients underwent endobronchial ultrasound-guided transbronchial needle aspiration at our healthcare centre. In all patients, 2964 biopsies from the lymph node group N2 and 783 from group N1 were taken. The mean short axis of the lymph nodes biopsied was 2.0 (range: 0.6-2.6). The mean number of lymph node stations biopsied per patient was 2.6. Patients with a negative result of endobronchial ultrasound-guided transbronchial needle aspiration underwent mediastinoscopy. All patients with a negative result in endobronchial ultrasound-guided transbronchial needle aspiration and mediastinoscopy underwent surgical resection with lymph node sampling. RESULTS: The metastases to lymph nodes N2/N3 and N1 were found in 1111 (60.3%) and 199 (9.3%), respectively. Mediastinoscopy was performed in 730 patients with a positive result in 83 (11.4%) patients. In the group of operated patients, metastatic N1 disease was found in 264 (14.1%). In the group of the operated patients, mediastinal involvement of disease (N2) was found in 30 patients (4.5%). The sensitivity, negative predictive value and diagnostic accuracy for hilar lymph node staging for endobronchial ultrasound-guided transbronchial needle aspiration were 57%, 96% and 96%, respectively. The sensitivity, negative predictive value and diagnostic accuracy per patient for mediastinal lymph node staging for endobronchial ultrasound-guided transbronchial needle aspiration and mediastinoscopy were 91%, 85%, 93% and 73%, 95.5%, 97%, respectively. The specificity and positive predictive value of both tests were 100%. CONCLUSION: The clinical usefulness of endobronchial ultrasound-guided transbronchial needle aspiration is undeniable according to diagnostic performance data. Endobronchial ultrasound-guided transbronchial needle aspiration should be considered complementary to mediastinoscopy in the evaluation of patients with radiographically abnormal mediastinum. PMID- 26770806 TI - A cross-sectional assessment of health-related quality of life among type 2 diabetes patients in Riyadh, Saudi Arabia. AB - OBJECTIVE: This study aimed to describe the health-related quality of life profile among type 2 diabetes patients in Riyadh, Saudi Arabia. METHOD: A cross sectional study was undertaken using a cohort of 75 patients attending the University Diabetic Centre at King Abdulaziz University Hospital, Riyadh, Saudi Arabia. EuroQoL-5 dimension (EQ-5D) scale was used for the assessment of health related quality of life. EQ-5D was scored using values derived from the UK general population survey. Inferential statistics were applied to evaluate associations between study variables. The Statistical Package for Social Sciences version 20.0 was used for data analysis; p <0.05 was set as the level of statistical significance. RESULTS: Fifty-eight (77.35%) respondents were male with a mean 12.6 +/- 8.4 years of history of diabetes. Thirty-four (45.3%) were categorised into the age group of 45-55 years with a mean age of 54 +/- 9.2 years. Forty-four (58.7%) were using oral hypoglycaemic agents and 40 (53.3%) had a university level of education. A moderate level of health-related quality of life (0.70 +/- 0.22) was measured in the study cohort. Gender was significantly associated with health-related quality of life scores (p = 0.001). The mean EQ-5D score was lower in females compared to male patients (0.58 +/- 0.23 vs 0.74 +/- 0.20). There were no statistically significant associations between health related quality of life scores and age groups, duration of diabetes, marital status, educational level and type of treatment. CONCLUSION: This study has highlighted that Saudi diabetes patients have low levels of health-related quality of life. Healthcare professionals need to consider this when planning holistic patient treatment approaches. PMID- 26770807 TI - Oral sucrose for heel lance enhances adenosine triphosphate use in preterm neonates with respiratory distress. AB - OBJECTIVE: To examine the effects of oral sucrose on procedural pain, and on biochemical markers of adenosine triphosphate utilization and oxidative stress in preterm neonates with mild to moderate respiratory distress. STUDY DESIGN: Preterm neonates with a clinically required heel lance that met study criteria (n = 49) were randomized into three groups: (1) control (n = 24), (2) heel lance treated with placebo and non-nutritive sucking (n = 15) and (3) heel lance treated with sucrose and non-nutritive sucking (n = 10). Plasma markers of adenosine triphosphate degradation (hypoxanthine, xanthine and uric acid) and oxidative stress (allantoin) were measured before and after the heel lance. Pain was measured using the Premature Infant Pain Profile. Data were analyzed using repeated measures analysis of variance, chi-square and one-way analysis of variance. RESULTS: We found that in preterm neonates who were intubated and/or were receiving ?30% FiO2, a single dose of oral sucrose given before a heel lance significantly increased markers of adenosine triphosphate use. CONCLUSION: We found that oral sucrose enhanced adenosine triphosphate use in neonates who were intubated and/or were receiving ?30% FiO2. Although oral sucrose decreased pain scores, our data suggest that it also increased energy use as evidenced by increased plasma markers of adenosine triphosphate utilization. These effects of sucrose, specifically the fructose component, on adenosine triphosphate metabolism warrant further investigation. PMID- 26770808 TI - Single high dose gentamicin for perioperative prophylaxis in orthopedic surgery: Evaluation of nephrotoxicity. AB - BACKGROUND: Recent studies described an increase in acute kidney injury when high dose gentamicin was included in perioperative prophylaxis for orthopedic surgeries. To this effect, we compared the rate of nephrotoxicity for selected orthopedic surgeries where gentamicin was included (Gentamicin Group) to those where it was not included (Control Group) for perioperative prophylaxis and evaluated risk factors for nephrotoxicity. METHODS: Spine, hip and knee surgeries performed between April 2011 and December 2013 were reviewed retrospectively. Gentamicin was given to eligible patients based on age, weight and Creatinine Clearance. Nephrotoxicity was assessed using Risk, Injury, Failure, Loss, End stage kidney disease (RIFLE) criteria. RESULTS: Among selected surgeries (N = 1590 in Gentamicin Group: hip = 926, spine = 600, knee = 64; N = 2587 in CONTROL GROUP: hip = 980, spine = 902, knee = 705), patients' body weight, serum creatinine, comorbidities and surgery duration were similar in Gentamicin Group and CONTROL GROUP. Gentamicin median dose was 4.5 mg/kg of dosing weight. Nephrotoxicity rate was 2.5% in Gentamicin Group and 1.8% in CONTROL GROUP, p = 0.17. Most cases of nephrotoxicity were Risk category by RIFLE criteria (67% in Gentamicin Group and 72% in CONTROL GROUP, p = 0.49). In logistic regression, risk factors for nephrotoxicity were hospital stay >1 day prior to surgery (odds ratio = 8.1; 95% confidence interval = 2.25-28.97, p = 0.001), knee or hip surgery (odds ratio = 4.7; 95% confidence interval = 2.9-9.48, p = 0.0005) and diabetes (odds ratio = 1.95; 95% confidence interval = 1.13-3.35, p = 0.016). Receipt of gentamicin was not an independent predictor of nephrotoxicity (odds ratio = 1.5; 95% confidence interval = 0.97-2.35, p = 0.07). CONCLUSION: In this cohort, rate of nephrotoxicity was similar between Gentamicin Group and Control Group. Single high dose gentamicin is a safe and acceptable option for perioperative prophylaxis in eligible patients undergoing orthopedic surgeries. PMID- 26770809 TI - Treating hepatitis C in American Indians/Alaskan Natives: A survey of Project ECHO((r)) (Extension for Community Healthcare Outcomes) utilization by Indian Health Service providers. AB - BACKGROUND: American Indians/Alaskan Natives have a high mortality associated with hepatitis C virus, yet treatment rates are low. The ECHO (Extension for Community Healthcare Outcomes) model(TM), a videoconferencing technology for primary care providers, is underutilized at Indian Health Service facilities. PURPOSE: To ascertain Indian Health Service providers' benefit of and barriers to utilizing hepatitis C virus TeleECHO clinics. METHODS: We electronically sent an Active Participant Survey to Indian Health Service providers utilizing hepatitis C virus TeleECHO clinic and a Non-Participant Survey to other Indian Health Service providers interested in this clinic. RESULTS: In total, 100% of Active Participant Survey respondents perceive moderate to major benefit of hepatitis C virus TeleECHO clinic in managing hepatitis C virus, and 67% of Non-Participant Survey respondents reported lack of administrative time as the major barrier to utilizing this resource. CONCLUSION: Indian Health Service providers participating in hepatitis C virus TeleECHO clinic perceive this resource as highly beneficial, but widespread utilization may be impractical without allocating time for participation. PMID- 26770810 TI - Genome mapping of postzygotic hybrid necrosis in an interspecific pear population. AB - Deleterious epistatic interactions in plant inter- and intraspecific hybrids can cause a phenomenon known as hybrid necrosis, characterized by a typical seedling phenotype whose main distinguishing features are dwarfism, tissue necrosis and in some cases lethality. Identification of the chromosome regions associated with this type of incompatibility is important not only to increase our understanding of the evolutionary diversification that led to speciation but also for breeding purposes. Development of molecular markers linked to the lethal genes will allow breeders to avoid incompatible inbred combinations that could affect the expression of important agronomic tratis co-segregating with these genes. Although hybrid necrosis has been reported in several plant taxa, including Rosaceae species, this phenomenon has not been described previously in pear. In the interspecific pear population resulting from a cross between PEAR3 (Pyrus bretschneideri * Pyrus communis) and 'Moonglow' (P. communis), we observed two types of hybrid necrosis, expressed at different stages of plant development. Using a combination of previously mapped and newly developed genetic markers, we identified three chromosome regions associated with these two types of lethality, which were genetically independent. One type resulted from a negative epistatic interaction between a locus on linkage group 5 (LG5) of PEAR3 and a locus on LG1 of 'Moonglow', while the second type was due to a gene that maps to LG2 of PEAR3 and which either acts alone or more probably interacts with another gene of unknown location inherited from 'Moonglow'. PMID- 26770811 TI - Insidious manifestation of pyogenic liver abscess caused by Streptococcus intermedius and Micrococcus luteus: a case report. AB - Pyogenic liver abscesses are caused by various microorganisms and usually present with fever, abdominal pain, leukocytosis and liver enzyme abnormalities. This case presents the insidious manifestation of a pyogenic liver abscess in a 34 year-old immunocompetent male, where classical manifestations of a liver abscess were absent. The microorganisms cultured from the abscess belonged to oral cavity's and gastrointestinal tract's normal flora. PMID- 26770812 TI - FUS-ERG gene fusion in isolated myeloid sarcoma showing uncommon clinical features. AB - FUS-ERG gene fusion has not been reported in cases of myeloid sarcoma (MS), a subtype of acute myeloid leukemia involving extramedullary anatomic sites. Here, we report a case of a 48-year-old man with primary isolated MS of the anterior mediastinum, who later developed multiple extramedullary recurrences without bone marrow infiltration throughout the course. G-banding analysis of the cells in pericardial effusion at recurrence showed complex karyotypic abnormalities including t(16;21)(p11.2;q22). FUS break-apart fluorescent in situ hybridization analysis showed split signals in biopsy sections at initial diagnosis and recurrence. Reverse transcriptase polymerase chain reaction and direct sequencing demonstrated the presence of the FUS-ERG chimeric gene transcript. The patient underwent cord blood transplantation, but died of pneumonia on day 64. To our knowledge, this is the first report of isolated MS carrying FUS-ERG gene fusion. In future study, relationship between the fusion gene and uncommon clinical features should be investigated in isolated MS. PMID- 26770813 TI - Clinical and neuroimaging features as diagnostic guides in neonatal neurology diseases with cerebellar involvement. AB - Cerebellar abnormalities are encountered in a high number of neurological diseases that present in the neonatal period. These disorders can be categorized broadly as inherited (e.g. malformations, inborn errors of metabolism) or acquired (e.g. hemorrhages, infections, stroke). In some disorders such as Dandy Walker malformation or Joubert syndrome, the main abnormalities are located within the cerebellum and brainstem. In other disorders such as Krabbe disease or sulfite oxidase deficiency, the main abnormalities are found within the supratentorial brain, but the cerebellar involvement may be helpful for diagnostic purposes. In In this article, we review neurological disorders with onset in the neonatal period and cerebellar involvement with a focus on how characterization of cerebellar involvement can facilitate accurate diagnosis and improved accuracy of neuro-functional prognosis. PMID- 26770814 TI - ITPR1 gene p.Val1553Met mutation in Russian family with mild Spinocerebellar ataxia. AB - BACKGROUND: Spinocerebellar ataxias (SSAs) are a highly heterogeneous group of inherited neurological disorders. The symptoms of ataxia vary in individual patients and even within the same SCA subtype. A study of a four-generation family with autosomal dominant (AD) non-progressive SCA with mild symptoms was conducted. The genotyping of this family revealed no frequent pathogenic mutations. So the objective of this study was to identify the genetic causes of the disease in this family with the technology of whole-exome sequencing (WES). METHODS AND RESULTS: WES, candidate variant analysis with further Sanger sequencing, mRNA secondary structure prediction, and RSCU analysis were performed; a heterozygous missense mutation in ITPR1 was identified. CONCLUSION: Our study confirms the fact that ITPR1 gene plays a certain role in the pathogenesis of SCAs, and, therefore, we suggest that c.4657G>A p.Val1553Met) is a disease-causing mutation in the family studied. PMID- 26770815 TI - Energy drinks in the Gulf Cooperation Council states: A review. AB - Energy drinks have become a popular beverage worldwide. This review was carried out to have an overview among adolescents and emerging adults in the Gulf Co operation Council states about energy drinks consumption rates and other related issues such as starting age and patterns of energy drink consumption. The Medline and Embase databases were searched separately using different terms such as energy drinks, energy beverages, and caffeinated drinks. Data related to the rates of energy drinks use were entered in STATA for statistical analysis. Then, these data were used to conduct meta-analysis to estimate the rate of energy drink consumption. Overall, meta-analysis results showed that the estimated rates of energy drinks consumption is 46.9% (95% CIs, 33.2 -66.1; nine studies) with I square 3.7%. Findings indicated that individuals start to consume energy drinks at approximately 16 years old, and males were found to consume energy drinks more frequently than females. Results from this review carry several recommendations for policy and enforcement, public education and research that can help policy and decision makers to achieve the goal of safer use of energy drinks. PMID- 26770816 TI - Low yield of unselected testing in patients with acutely abnormal liver function tests. AB - OBJECTIVES: To audit the diagnostic yield and cost implications of the use of a 'liver screen' for inpatients with abnormal liver function tests. DESIGN: We performed a retrospective audit of inpatients with abnormal liver function tests. We analysed all investigations ordered including biochemistry, immunology, virology and radiology. The final diagnosis was ascertained in each case, and the diagnostic yield and cost per positive diagnosis for each investigation were calculated. SETTING: St Thomas' NHS Trust. PARTICIPANTS: All inpatients investigated for abnormal liver function tests over a 12-month period. MAIN OUTCOME MEASURES: We calculated the percentage of courses due to each diagnosis, the yield of each investigation and the cost per positive diagnosis for each investigation. RESULTS: A total of 308 patients were included, and a final diagnosis was made in 224 patients (73%) on the basis of both clinical data and investigations. There was considerable heterogeneity in the tests included in an acute liver screen. History and ultrasound yielded the most diagnoses (40% and 30%, respectively). The yield of autoimmune and metabolic screens was minimal. CONCLUSIONS: Our results demonstrate the low yield of unselected testing in patients with abnormal liver function tests. A thorough history, ultrasound and testing for blood-borne viruses are the cornerstones of diagnosis. Specialist input should be sought before further testing. Prospective studies to evaluate the yield and cost-effectiveness of different testing strategies are needed. PMID- 26770817 TI - Aviation and healthcare: a comparative review with implications for patient safety. AB - Safety in aviation has often been compared with safety in healthcare. Following a recent article in this journal, the UK government set up an Independent Patient Safety Investigation Service, to emulate a similar well-established body in aviation. On the basis of a detailed review of relevant publications that examine patient safety in the context of aviation practice, we have drawn up a table of comparative features and a conceptual framework for patient safety. Convergence and divergence of safety-related behaviours across aviation and healthcare were derived and documented. Key safety-related domains that emerged included Checklists, Training, Crew Resource Management, Sterile Cockpit, Investigation and Reporting of Incidents and Organisational Culture. We conclude that whilst healthcare has much to learn from aviation in certain key domains, the transfer of lessons from aviation to healthcare needs to be nuanced, with the specific characteristics and needs of healthcare borne in mind. On the basis of this review, it is recommended that healthcare should emulate aviation in its resourcing of staff who specialise in human factors and related psychological aspects of patient safety and staff wellbeing. Professional and post qualification staff training could specifically include Cognitive Bias Avoidance Training, as this appears to play a key part in many errors relating to patient safety and staff wellbeing. PMID- 26770818 TI - Evolution of invasiveness through increased resource use in a vacant niche. AB - Non-native plants are now a pervasive feature of ecosystems across the globe1. One hypothesis for this pattern is that introduced species occupy open niches in recipient communities2,3. If true, then non-native plants should often benefit from low competition for limiting resources that define niches. Many plants have evolved larger size after introduction, consistent with increased access to limiting resources4-9. It has been difficult to test whether larger size reflects adaptation to exploit open resources, however, because vacant niches are generally challenging to identify in plants. Here we take advantage of a situation in which a highly invasive non-native plant, Centaurea solstitialis L. (yellow starthistle, hereafter 'YST'), occupies a well-described environmental niche, wherein water is a known limiting resource10,11. We use a glasshouse common environment and climatic niche modeling to reveal that invading YST has evolved a higher-fitness life history at the expense of increased dependence on water. Critically, historical declines in resident competitors have made water more available for introduced plants11,12, demonstrating how native biodiversity declines can open niches and create opportunities for introduced species to evolve increased resource use, a potentially widespread basis for introduction success and the evolution of invasive life histories. PMID- 26770819 TI - Time dependence of evolutionary metrics during the 2009 pandemic influenza virus outbreak. AB - With the expansion of DNA sequencing technology, quantifying evolution in emerging viral outbreaks has become an important tool for scientists and public health officials. Although it is known that the degree of sequence divergence significantly affects the calculation of evolutionary metrics in viral outbreaks, the extent and duration of this effect during an actual outbreak remains unclear. We have analyzed how limited divergence time during an early viral outbreak affects the accuracy of molecular evolutionary metrics. Using sequence data from the first 25 months of the 2009 pandemic H1N1 (pH1N1) outbreak, we calculated each of three different standard evolutionary metrics-molecular clock rate (i.e., evolutionary rate), whole gene dN/dS, and site-wise dN/dS-for hemagglutinin and neuraminidase, using increasingly longer time windows, from 1 month to 25 months. For the molecular clock rate, we found that at least three to four months of temporal divergence from the start of sampling was required to make precise estimates that also agreed with long-term values. For whole gene dN/dS, we found that at least two months of data were required to generate precise estimates, but six to nine months were required for estimates to approach their long term values. For site-wise dN/dS estimates, we found that at least six months of sampling divergence was required before the majority of sites had at least one mutation and were thus evolutionarily informative. Furthermore, eight months of sampling divergence was required before the site-wise estimates appropriately reflected the distribution of values expected from known protein-structure-based evolutionary pressure in influenza. In summary, we found that evolutionary metrics calculated from gene sequence data in early outbreaks should be expected to deviate from their long-term estimates for at least several months after the initial emergence and sequencing of the virus. PMID- 26770820 TI - Trigeminal Neuralgia and Radiofrequency Lesioning. AB - Trigeminal Neuralgia is a disorder that is characterized with electrical-type shocking pain in the face and jaw. This pain may either present as sharp unbearable pain unilateral or bilaterally. There is no definite etiology for this condition. There are various treatment methods that are currently being used to relieve the pain. One of the pharmacological treatments is Carbamazepine and the most prevalent surgical treatments include Gamma Knife Surgery (GKS), Microvascular Decompression (MVD) and Radiofrequency Lesioning (RFL). Although, MVD is the most used surgical method it is not an option for all the patients due to the intensity of the procedure. RFL is used when MVD is not suitable. In this paper we present the various treatments and Monte-Carlo based pharmacokinetic simulations of Carbamazepine in treatment of Trigeminal Neuralgia. PMID- 26770821 TI - Plasmodium falciparum msp2 Genotypes and Multiplicity of Infections among Children under Five Years with Uncomplicated Malaria in Kibaha, Tanzania. AB - Genetic diversity of Plasmodium falciparum may pose challenges in malaria treatment and prevention through chemotherapy and vaccination. We assessed Plasmodium falciparum genetic diversity and multiplicity of infection (MOI) of P. falciparum infections and sort relationship of parasitaemia with P. falciparum msp2 genotypes as well as with the number of infecting clones. The study was carried out in Kibaha, Tanzania. Ninety-nine children under five years with uncomplicated malaria were recruited. Genetic diversity was analyzed by genotyping the msp2 gene using PCR-Restriction Fragment Length Polymorphism. Thirty-two different msp2 alleles were obtained. The msp2 3D7 allelic frequency was higher (48.1%) and more prevalent than FC27 (27.3%) (p < 0.05). Twenty-four percent of the infections were mixed alleles. The individuals with FC27 had high parasitemia compared to those with 3D7 alleles (p = 0.038). The mean MOI was low (1.4 clones, 95% CI 1.2-1.5). The P. falciparum population among children at Kibaha is composed of distinct P. falciparum clones, and parasites having 3D7 are more frequent than those with FC27 alleles. Individuals with parasite having FC27 alleles have high parasite densities suggesting that parasites with FC27 alleles may associate with severity of disease in Kibaha. Low MOI at Kibaha suggests low malaria transmission rate. PMID- 26770823 TI - The Significance of Asthma Follow-Up Consultations for Adherence to Asthma Medication, Asthma Medication Beliefs, and Asthma Control. AB - Objective. The aim was to investigate adherence to asthma medication treatment, medication beliefs, and asthma control in relation to asthma follow-up consultations in asthmatics in the general population. A further aim was to describe associations between adherence, medication beliefs, and asthma control. Method. In the population-based West Sweden Asthma Study, data allowing calculation of adherence for 4.5 years based on pharmacy records were obtained from 165 adult asthmatics. Additional data were collected through questionnaires and structured interviews. Results. The mean adherence value for filled prescriptions for regular asthma medication was 68% (median 55.3%) but varied over the year under study. Adherence to combination inhalers with corticosteroids and long-acting beta(2) agonists was higher than adherence to single inhalers with corticosteroids only. More than one-third of participants reported not having seen an asthma nurse or physician for several years. Regular asthma follow up consultations were associated with both higher adherence and the belief that asthma medication was necessary but were not associated with asthma control. Conclusions. Adherence to asthma medication treatment was low and varied over the year under study. The current study suggests that quality improvements in asthma care are needed if adherence to asthma medication is to be improved. PMID- 26770822 TI - Bridging the Gap between Evidence and Practice for Adults with Medically Refractory Temporal Lobe Epilepsy: Is a Change in Funding Policy Needed to Stimulate a Shift in Practice? AB - Objective. Surgery for medically refractory epilepsy (MRE) in adults has been shown to be effective but underutilized. Comprehensive health economic evaluations of surgery compared with continued medical management are limited. Policy changes may be necessary to influence practice shift. Methods. A critical review of the literature on health economic analyses for adults with MRE was conducted. The MEDLINE, EMBASE, CENTRAL, CRD, and EconLit databases were searched using relevant subject headings and keywords pertaining to adults, epilepsy, and health economic evaluations. The screening was conducted independently and in duplicate. Results. Four studies were identified (1 Canadian, 2 American, and 1 French). Two were cost-utility analyses and 2 were cost-effectiveness evaluations. Only one was conducted after the effectiveness of surgery was established through a randomized trial. All suggested surgery to be favorable in the medium to long term (7-8 years and beyond). The reduction of medication use was the major cost-saving parameter in favor of surgery. Conclusions. Although updated evaluations that are more generalizable across settings are necessary, surgery appears to be a favorable option from a health economic perspective. Given the limited success of knowledge translation endeavours, funder-level policy changes such as quality-based purchasing may be necessary to induce a shift in practice. PMID- 26770825 TI - Aorto-Uni-Iliac Stent Grafts with and without Crossover Femorofemoral Bypass for Treatment of Abdominal Aortic Aneurysms: A Parallel Observational Comparative Study. AB - We investigated the safety and efficacy of primary aorto-uni-iliac (AUI) endovascular aortic repair (EVAR) without fem-fem crossover in patients with abdominal aortic aneurysm (AAA) and concomitant aortoiliac occlusive disease. 537 EVARs were implemented between 2002 and 2015 in University Hospital Galway, a tertiary referral center for aortic surgery and EVAR. We executed a parallel observational comparative study between 34 patients with AUI with femorofemoral crossover (group A) and six patients treated with AUI but without the crossover (group B). Group B patients presented with infrarenal AAAs with associated total occlusion of one iliac axis and high comorbidities. Technical success was 97% (n = 33) in group A and 85% (n = 5) in group B (P = 0.31). Primary and assisted clinical success at 24 months were 88% (n = 30) and 12% (n = 4), respectively, in group A, and 85% (n = 5) and 15% (n = 1), respectively, in group B (P = 0.125). Reintervention rate was 10% (n = 3) in group A and 0% in group B (P = 0.084). No incidence of postoperative critical lower limb ischemia or amputations occurred in the follow-up period. AUI without crossover bypass is a viable option in selected cases. PMID- 26770824 TI - The Role of the Craniocervical Junction in Craniospinal Hydrodynamics and Neurodegenerative Conditions. AB - The craniocervical junction (CCJ) is a potential choke point for craniospinal hydrodynamics and may play a causative or contributory role in the pathogenesis and progression of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, MS, and ALS, as well as many other neurological conditions including hydrocephalus, idiopathic intracranial hypertension, migraines, seizures, silent-strokes, affective disorders, schizophrenia, and psychosis. The purpose of this paper is to provide an overview of the critical role of the CCJ in craniospinal hydrodynamics and to stimulate further research that may lead to new approaches for the prevention and treatment of the above neurodegenerative and neurological conditions. PMID- 26770826 TI - Spatiotemporal Changes Posttreatment in Peripheral Arterial Disease. AB - Accumulating evidence suggests revascularization of peripheral arterial disease (PAD) limbs results in limited improvement in functional gait parameters, suggesting underlying locomotor system pathology. Spatial and temporal (ST) gait parameters are well studied in patients with PAD at baseline and are abnormal when compared to controls. The purpose of this study was to systematically review and critically analyze the available data on ST gait parameters before and after interventions. A full review of literature was conducted and articles were included which examined ST gait parameters before and after intervention (revascularization and exercise). Thirty-three intervention articles were identified based on 154 articles that evaluated ST gait parameters in PAD. Four articles fully assessed ST gait parameters before and after intervention and were included in our analysis. The systematic review of the literature revealed a limited number of studies assessing ST gait parameters. Of those found, results demonstrated the absence of improvement in gait parameters due to either exercise or surgical intervention. Our study demonstrates significant lack of research examining the effectiveness of treatments on ST gait parameters in patients with PAD. Based on the four published articles, ST gait parameters failed to significantly improve in patients with PAD following intervention. PMID- 26770827 TI - Training a Spinal Cord Injury Rehabilitation Team in Motivational Interviewing. AB - Background. An acute spinal cord injury (ASCI) is a severe condition that requires extensive and very specialized management of both physical and psychological dimensions of injured patients. Objective. The aim of the part of the study reported here was twofold: (1) to describe burnout, empathy, and satisfaction at work of these professionals and (2) to explore whether a tailored program based on motivational interviewing (MI) techniques modifies and improves such features. Methods. This paper presents findings from an intervention study into a tailored training for professionals (N = 45) working in a spinal cord injury (SCI) unit from a general hospital. Rehabilitation professionals' empathy skills were measured with the Jefferson Scale of Physician Empathy (JSPE), burnout was measured with the Maslach Burnout Inventory (MBI), and additional numeric scales were used to assess the perceived job-related stress and perceived satisfaction with job. Results. Findings suggest that professionals are performing quite well and they refer to satisfactory empathy, satisfaction at work, and no signs of burnout or significant stress both before and after the training. Conclusions. No training effect was observed in the variables considered in the study. Some possible explanations for these results and future research directions are discussed in depth in this paper. The full protocol of this study is registered in ClinicalTrials.gov (identifier: NCT01889940). PMID- 26770828 TI - Clinical Presentation and Antibiotic Susceptibility of Contact Lens Associated Microbial Keratitis. AB - Introduction. In recent years, the number of contact lens wearers has dramatically increased in Iran, particularly in youngsters. The purpose of current study was to assess the clinical presentation and antibiotic susceptibility of contact lens related microbial keratitis in Ahvaz, southwest of Iran. Methodology. A cross-sectional investigation of 26 patients (33 eyes) with contact lens induced corneal ulcers who were admitted to Imam Khomeini Hospital, Ahwaz City, from June 2012 to June 2013 was done. In order to study microbial culture and susceptibility of corneal ulcers, all of them were scraped. Results. Eight samples were reported as sterile. Pseudomonas aeruginosa (80%) in positive cultures was the most widely recognized causative organism isolated. This is followed by Staphylococcus aureus 12% and Enterobacter 8%. The results showed that 84% of the microorganism cases were sensitive to ciprofloxacin, while imipenem, meropenem, and ceftazidime were the second most effective antibiotics (76%). Conclusion. Results of current study show the importance of referring all contact lens wearers with suspected corneal infection to ophthalmologists for more cure. The corneal scraping culture and contact lens solution should be performed to guide antibiotic therapy. PMID- 26770829 TI - Evaluation of In Vivo Acaricidal Effect of Soap Containing Essential Oil of Chenopodium ambrosioides Leaves on Rhipicephalus lunulatus in the Western Highland of Cameroon. AB - A study on the acaricidal properties of foam soap containing the essential oil of Chenopodium ambrosioides leaves was carried out on Rhipicephalus lunulatus. Four doses (0.03, 0.06, 0.09, and 0.12 uL of essential oil per gram of soap) and a control (soap without essential oil) with four replications for each treatment were used for in vitro trial. Each replication consisted of 10 ticks in a Petri dish with filter paper impregnated with the foam soap on the bottom. Following in vitro trials, three doses (0.06, 0.09, and 0.12 uL/g) and the control in two replications were selected for in vivo test based on mortality rate recorded from the in vitro trial. Each replication was made up of 10 goats naturally infested with ticks. Results show that soap containing essential oil is toxic to R. lunulatus. The in vivo mortality rate in the control on day 8 was 22.69% whereas the highest dose (0.12 uL/g) killed 96.29% of the ticks on day 8. The LD50 of the foam soap containing essential oil was 0.037 and 0.059 uL/g on day 2 in the laboratory and on the farm, respectively. This indicates the potentially high efficiency of this medicated soap on this parasite. PMID- 26770830 TI - Enhanced Bioremediation of Soil Artificially Contaminated with Petroleum Hydrocarbons after Amendment with Capra aegagrus hircus (Goat) Manure. AB - This study was carried out to evaluate the biostimulant potentials of Capra aegagrus hircus manure for bioremediation of crude oil contaminated soil (COCS) under tropical conditions. 1 kg of COCS sample was amended with 0.02 kg of C. a. hircus manure and monitored at 14-day intervals for total petroleum hydrocarbon (TPH), nutrient content, and changes in microbial counts. At the end of the study period, there was 62.08% decrease in the concentration of TPH in the amended sample compared to 8.15% decrease in the unamended sample, with significant differences (P < 0.05) in TPH concentrations for both samples at different time intervals. Similarly, there was a gradual decrease in the concentrations of total organic carbon, nitrogen, phosphorus, and potassium in both samples. The culturable hydrocarbon-utilizing bacteria (CHUB) increased steadily from 8.5 * 10(5) cfu/g to 2.70 * 10(6) cfu/g and from 8.0 * 10(5) cfu/g to 1.78 * 10(6) cfu/g for both samples. Acinetobacter, Achromobacter, Bacillus, Flavobacterium, Klebsiella, Micrococcus, Pseudomonas, and Staphylococcus were isolated from amended sample with Pseudomonas being the predominant isolated bacterial genus. This study demonstrated that C. a. hircus manure is a good biostimulant, which enhanced the activities of indigenous hydrocarbonoclastic bacteria resulting in significant decrease in TPH concentration of COCS. PMID- 26770831 TI - Usefulness of Ki-67, Mitoses, and Tumor Size for Predicting Metastasis in Carcinoid Tumors of the Lung: A Study of 48 Cases at a Tertiary Care Centre in Canada. AB - Background. Evaluation of Ki-67 index in lung carcinoid tumors (LCTs) has been of interest in order to identify high risk subsets. Our objectives are (1) to evaluate the usefulness of Ki-67 index, mitoses, and tumor size in predicting metastasis and (2) to compare the Manual Conventional Method (MCM) and the Computer Assisted Image Analysis Method (CIAM) for Ki-67 calculation. Methods. We studied 48 patients with LCTs from two academic centres in Canada. For Ki-67 calculation, digital images of 5000 cells were counted using an image processing software and 2000 cells by MCM. Mitoses/10 HPF was counted. Results. We had 37 typical carcinoids (TCs) and 11 atypical carcinoids (ACs). 7/48 patients developed metastasis. There was a positive relationship between metastasis and carcinoid type (P = 0.039) and metastasis and mitoses (>=2) (P = 0.017). Although not statistically significant, the mean Ki-67 index for ACs was higher than for TCs (0.95% versus 0.72%, CIAM, P = 0.299). Similarly, although not statistically significant, the mean Ki-67 index for metastatic group (MG) was higher than for nonmetastatic group (NMG) (1.01% versus 0.71% by CIAM, P = 0.281). However when Ki-67 index data was categorized at various levels, there is suggestion of a useful cutoff (>=0.50%) to predict metastasis (P = 0.106, CIAM). A significantly higher proportion of patients with mitosis >=2 and Ki-67 index >=0.50% had metastasis (P = 0.033) compared to other patients. Similarly patients with tumor size >=3 cm and Ki-67 >=0.50% had a greater percentage of metastases than others (P = 0.039). Although there was a strong correlation between two (MCM versus CIAM) counting methods (r = 0.929, P = 0.001), overall the calculated Ki-67 index was slightly higher by MCM (range 0 to 6.4, mean 1.5) compared to CIAM (range 0 to 2.9, mean 0.75). Conclusion. This study confirms that mitoses >=2 is a powerful predictor of metastasis in LCTs. Although this is a small sample size, there is suggestion that analysis of Ki-67 index along with mitoses and tumor size may be a useful adjunct for predicting metastasis in LCTs. PMID- 26770832 TI - Hsp90 Inhibitors for the Treatment of Chronic Myeloid Leukemia. AB - Chronic myeloid leukemia (CML) is a hematological malignancy that arises due to reciprocal translocation of 3' sequences from c-Abelson (ABL) protooncogene of chromosome 9 with 5' sequence of truncated break point cluster region (BCR) on chromosome 22. BCR-ABL is a functional oncoprotein p210 that exhibits constitutively activated tyrosine kinase causing genomic alteration of hematopoietic stem cells. BCR-ABL specific tyrosine kinase inhibitors (TKIs) successfully block CML progression. However, drug resistance owing to BCR-ABL mutations and overexpression is still an issue. Heat-shock proteins (Hsps) function as molecular chaperones facilitating proper folding of nascent polypeptides. Their increased expression under stressful conditions protects cells by stabilizing unfolded or misfolded peptides. Hsp90 is the major mammalian protein and is required by BCR-ABL for stabilization and maturation. Hsp90 inhibitors destabilize the binding of BCR-ABL protein thus leading to the formation of heteroprotein complex that is eventually degraded by the ubiquitin proteasome pathway. Results of many novel Hsp90 inhibitors that have entered into various clinical trials are encouraging. The present review targets the current development in the CML treatment by availing Hsp90 specific inhibitors. PMID- 26770833 TI - Factors That Could Impact on Liver Fibrosis Staging by Transient Elastography. AB - Transient elastography (TE) based on liver stiffness measurement (LSM) is one of the most validated noninvasive methods for liver fibrosis staging in patients with chronic liver diseases. This method is painless, has no potential complications, is rapid (<10 min), and can be performed at the patient's bedside. However, several points should be considered when interpreting TE results. This review aims to discuss the critical points that might influence liver stiffness and TE results. Spectrum bias and the impact of the prevalence of fibrosis stages should be taken into account when interpreting the studies that validated this method using liver biopsy as a gold-standard. LSM might be influenced by nonfasting status, flare of transaminases, heart failure, extrahepatic cholestasis, presence of steatosis, aetiology of liver disease, type and position of probe, and operator's experience. In addition, interobserver variability can impact on the management of patients with chronic liver diseases. TE should be performed by an experienced operator (>100 exams), in a 3-hour fasting status, and its results should be handled by specialist clinicians that are aware of the limitations of this method. PMID- 26770834 TI - EEG Derived Neuronal Dynamics during Meditation: Progress and Challenges. AB - Meditation advances positivity but how these behavioral and psychological changes are brought can be explained by understanding neurophysiological effects of meditation. In this paper, a broad spectrum of neural mechanics under a variety of meditation styles has been reviewed. The overall aim of this study is to review existing scientific studies and future challenges on meditation effects based on changing EEG brainwave patterns. Albeit the existing researches evidenced the hold for efficacy of meditation in relieving anxiety and depression and producing psychological well-being, more rigorous studies are required with better design, considering client variables like personality characteristics to avoid negative effects, randomized controlled trials, and large sample sizes. A bigger number of clinical trials that concentrate on the use of meditation are required. Also, the controversial subject of epileptiform EEG changes and other adverse effects during meditation has been raised. PMID- 26770835 TI - Sleep Habits of Elementary and Middle School Children in South Texas. AB - Background. Sleep difficulties, including insufficient sleep and inadequate sleep hygiene, have been prevalent among children. Sleep deprivation can lead to poor grades, sleepiness, and moodiness. We undertook this study to assess the prevalence of sleep abnormalities among elementary and middle school students in South Texas and how the groups compare with one another. Method. After approval from the appropriate school district for a sleep education program, a baseline survey was taken of elementary and middle school students, using the Children's Sleep Habit Questionnaire-Sleep Self-Report Form, which assessed the domains of bedtime resistance, sleep onset delay, sleep anxiety, sleep duration, night awakening, and daytime sleepiness. Results. The survey was completed by 499 elementary and 1008 middle school children. Trouble sleeping was reported by 43% in elementary school, compared with 29% of middle school children. Fifty percent of middle school children did not like sleeping, compared with 26% in elementary school. Bedtime resistance, sleep onset delay, and nighttime awakening were more common among elementary school students. Daytime sleepiness was more common among the middle school children when compared to elementary school children. Conclusions. Sleep abnormalities are present in elementary school children with changes in sleep habits into middle school. PMID- 26770836 TI - Reorganization of Anatomical Connectome following Electroconvulsive Therapy in Major Depressive Disorder. AB - Objective. Electroconvulsive therapy (ECT) is considered one of the most effective and fast-acting treatment options for depressive episodes. Little is known, however, about ECT's enabling brain (neuro)plasticity effects, particular for plasticity of white matter pathway. Materials and Methods. We collected longitudinal diffusion tensor imaging in the first-episode, drug-naive major depressive disorder (MDD) patients (n = 24) before and after a predefined time window ECT treatment. We constructed large-scale anatomical networks derived from white matter fiber tractography and evaluated the topological reorganization using graph theoretical analysis. We also assessed the relationship between topological reorganization with improvements in depressive symptoms. Results. Our investigation revealed three main findings: (1) the small-worldness was persistent after ECT series; (2) anatomical connections changes were found in limbic structure, temporal and frontal lobes, in which the connection changes between amygdala and parahippocampus correlate with depressive symptom reduction; (3) significant nodal strength changes were found in right paralimbic network. Conclusions. ECT elicits neuroplastic processes associated with improvements in depressive symptoms that act to specific local ventral frontolimbic circuits, but not small-world property. Overall, ECT induced topological reorganization in large-scale brain structural network, opening up new avenues to better understand the mode of ECT action in MDD. PMID- 26770837 TI - Activation of the Mammalian Target of Rapamycin in the Rostral Ventromedial Medulla Contributes to the Maintenance of Nerve Injury-Induced Neuropathic Pain in Rat. AB - The mammalian target of rapamycin (mTOR), a serine-threonine protein kinase, integrates extracellular signals, thereby modulating several physiological and pathological processes, including pain. Previous studies have suggested that rapamycin (an mTOR inhibitor) can attenuate nociceptive behaviors in many pain models, most likely at the spinal cord level. However, the mechanisms of mTOR at the supraspinal level, particularly at the level of the rostral ventromedial medulla (RVM), remain unclear. Thus, the aim of this study was to elucidate the role of mTOR in the RVM, a key relay region for the descending pain control pathway, under neuropathic pain conditions. Phosphorylated mTOR was mainly expressed in serotonergic spinally projecting neurons and was significantly increased in the RVM after spared nerve injury- (SNI-) induced neuropathic pain. Moreover, in SNI rat brain slices, rapamycin infusion both decreased the amplitude instead of the frequency of spontaneous excitatory postsynaptic currents and reduced the numbers of action potentials in serotonergic neurons. Finally, intra-RVM microinjection of rapamycin effectively alleviated established mechanical allodynia but failed to affect the development of neuropathic pain. In conclusion, our data provide strong evidence for the role of mTOR in the RVM in nerve injury-induced neuropathic pain, indicating a novel mechanism of mTOR inhibitor-induced analgesia. PMID- 26770838 TI - Acute Myocarditis in a Patient with Newly Diagnosed Granulomatosis with Polyangiitis. AB - A 22-year-old woman recently diagnosed with granulomatosis with polyangiitis (GPA) was admitted to the department of cardiology due to chest pain and shortness of breath. The ECG showed widespread mild PR-segment depression, upwardly convex ST-segment elevation, and T-wave inversion. The troponin T level was elevated at 550 ng/L. Transthoracic echocardiography showed basal inferoseptal thinning and hypokinesis, mild pericardial effusion, and an overall preserved left ventricular ejection fraction of 55%. Global longitudinal strain, however, was clearly reduced. Cardiac magnetic resonance imaging (MRI) showed findings consistent with myocarditis but the etiology of the apical hypokinesis could not be determined with certainty and may well have been due to a myocardial infarction, a notion supported by a coronary angiogram displaying slow flow in the territory of the left anterior descending artery. Finally, an endomyocardial biopsy confirmed the diagnosis of myocarditis. The cardiac symptoms subsided upon treatment with high-dose prednisolone and rituximab. PMID- 26770839 TI - Aneurysm of the Left Coronary Artery in Postoperative Bland-White-Garland Syndrome. AB - We report a case of anomalous left coronary artery from the pulmonary artery (ALCAPA) or Bland-White-Garland syndrome, present the challenges of performing a differential diagnosis, and discuss the treatment of the syndrome. Although ALCAPA is a rare congenital heart disease, it is one of the most common causes of myocardial ischemia in childhood and presents a diagnostic challenge. A four-year old girl was referred to a pediatric cardiologist for evaluation of mitral valve regurgitation murmur and heart failure. The transthoracic echocardiogram demonstrated the left coronary artery (LCA) not arising from the aorta, presence of coronary collateral circulation, and moderate mitral valve regurgitation. ALCAPA was confirmed using angiotomography. The LCA was surgically reimplanted into the aorta. After 3 years of postoperative follow-up, the patient developed an LCA aneurysm. Diagnosis of cardiac ischemia in childhood remains a challenge, and careful evaluation of coronary arteries on the echocardiogram is an important tool. In this report, we present a case of ALCAPA with an uncommon postoperative outcome. PMID- 26770840 TI - Ventricular Tachycardia from a Central Line Fracture Fragment Embolus: A Rare Complication of a Commonly Used Procedure-A Case Report and Review of the Relevant Literature. AB - A 22-year-old male admitted with multiple gunshot wounds (GSW) had central line placed initially for hemodynamic monitoring and later for long term antibiotics and total parenteral nutrition (TPN). On postoperative day 4 he presented with bouts of nonsustained ventricular tachycardia; the cause was unknown initially and later attributed to a catheter fragment accidentally severed and lodged in the right heart. Percutaneous retrieval technique was used to successfully extract the catheter fragment and complete recovery was achieved. PMID- 26770841 TI - Split-Framework in Mandibular Implant-Supported Prosthesis. AB - During oral rehabilitation of an edentulous patient with an implant-supported prosthesis, mandibular flexure must be considered an important biomechanical factor when planning the metal framework design, especially if implants are installed posterior to the interforaminal region. When an edentulous mandible is restored with a fixed implant-supported prosthesis connected by a fixed full-arch framework, mandibular flexure may cause needless stress in the overall restorative system and lead to screw loosening, poor fit of prosthesis, loss of the posterior implant, and patient's discomfort due to deformation properties of the mandible during functional movements. The use of a split-framework could decrease the stress with a precise and passive fit on the implants and restore a more natural functional condition of the mandible, helping in the longevity of the prosthesis. Therefore, the present clinical report describes the oral rehabilitation of an edentulous patient by a mandibular fixed implant-supported prosthesis with a split-framework to compensate for mandibular flexure. Clinical Significance. The present clinical report shows that the use of a split-framework reduced the risk of loss of the posterior implants or screws loosening with acceptable patient comfort over the period of a year. The split-framework might have compensated for the mandibular flexure during functional activities. PMID- 26770842 TI - The Solitary Variant of Mandibular Intraosseous Neurofibroma: Report of a Rare Entity. AB - Neurofibroma (NF) is a benign neoplasm derived from peripheral nerve cells. NF may extend either as a solitary lesion or as part of a generalized syndrome of neurofibromatosis. Intraorally, the intraosseous variant of neurofibroma is a very rare tumor. The literature provides only few cases of solitary intraosseous neurofibroma of the mandible. We report a case of 28-year-old female who was diagnosed with a solitary intraosseous neurofibroma involving the lower left quadrant of the mandible. The present case is rare in regard to its dimensions and its location. PMID- 26770843 TI - Megace Mystery: A Case of Central Adrenal Insufficiency. AB - Megestrol acetate (MA) is a synthetic progestin with both antineoplastic and orexigenic properties. In addition to its effects on the progesterone receptor, MA also binds the glucocorticoid receptor. Some patients receiving MA therapy have been reported to develop clinical features of glucocorticoid excess, while others have experienced the clinical syndrome of cortisol deficiency-either following withdrawal of MA therapy or during active treatment. We describe a patient who presented with clinical and biochemical features of central adrenal insufficiency. Pituitary function was otherwise essentially normal, and the etiology of the isolated ACTH suppression was initially unclear. The use of an exogenous glucocorticoid was suspected but was initially denied by the patient; ultimately, the culprit medication was uncovered when a synthetic steroid screen revealed the presence of MA. The patient's symptoms improved after she was switched to hydrocortisone. Clinicians should be aware of the potential effects of MA on the hypothalamic-pituitary-adrenal (HPA) axis. PMID- 26770844 TI - Lanreotide Autogel in the Treatment of Persistent Diarrhea following a Total Colectomy. AB - Diarrhea is one of the most common complications following colectomy in patients with slow transit constipation (STC). Early postoperative diarrhea is usually treated with opioid agonists; however, to date, published data on the management of persistent diarrhea after colectomy for STC are scarce. Here, we report a case of severe diarrhea after a total colectomy with ileorectal anastomosis. One year after the surgery, the patient presented with persistent diarrhea. Treatment with a long-acting somatostatin analogue, lanreotide Autogel, was initiated. One month after the first injection of lanreotide Autogel the diarrhea was resolved. The patient's stool transit was markedly improved (type 4 or type 5 according to the Bristol Stool Chart compared to type 7 before the treatment), positively affecting the patient's quality of life (mean score of 2.1 on the Irritable Bowel Syndrome Quality of Life questionnaire compared to 3.9 before the treatment). This case report describes a successful use of lanreotide Autogel in a patient with persistent diarrhea after a total colectomy. PMID- 26770845 TI - Mitchell-Riley Syndrome: A Novel Mutation in RFX6 Gene. AB - A novel RFX6 homozygous missense mutation was identified in an infant with Mitchell-Riley syndrome. The most common features of Mitchell-Riley syndrome were present, including severe neonatal diabetes associated with annular pancreas, intestinal malrotation, gallbladder agenesis, cholestatic disease, chronic diarrhea, and severe intrauterine growth restriction. Perijejunal tissue similar to pancreatic tissue was found in the submucosa, a finding that has not been previously reported in this syndrome. This case associating RFX6 mutation with structural and functional pancreatic abnormalities reinforces the RFX6 gene role in pancreas development and beta-cell function, adding information to the existent mutation databases. PMID- 26770846 TI - Aberrant "Barbed-Wire" Nuclear Projections of Neutrophils in Trisomy 18 (Edwards Syndrome). AB - We discuss the significance of neutrophils with increased, aberrant nuclear projections mimicking "barbed-wire" in a newborn child with trisomy 18 (T18). Increased, aberrant nuclear projections have been previously reported in trisomy of the D group of chromosomes (chromosomes 13, 14, and 15), and we report similar findings in a patient with T18. The peripheral blood smear showed relative neutrophilia with the majority (37%) of neutrophils showing two or more thin, rod shaped or spike-shaped, and often pedunculated aberrant nuclear projections. The number of projections ranged from 2 to 6 per cell, averaged 2 per affected neutrophil, and ranged in length from 0.22 MUm to 0.83 MUm. This case confirms that the morphologic finding described is not restricted to trisomy of one of the chromosomes in group D, as implied in the literature. PMID- 26770847 TI - Paraspinal and Extensive Epidural Abscess: The Great Masqueraders of Abdominal Pain. AB - Paraspinal and epidural abscesses are rare conditions often diagnosed later in the disease process that can have significant morbidity and mortality. Predisposing risk factors include diabetes, human immunodeficiency virus, intravenous drug abuse, and previous history of spinal surgery or injection. They can threaten the spinal cord by compressive effect, leading to sensory motor deficits and ultimately paralysis and death. Diagnosis may be a challenge due to the delayed presentation of nonspecific back pain or radicular pain such as chest pain or abdominal pain. We present a rare case on a patient with periumbilical pain, constipation, and urinary retention who was ultimately diagnosed with a paraspinal abscess extending into the epidural space from T1 to S2. He underwent decompressive laminectomy with incision and drainage of the abscesses. The patient made an excellent recovery postoperatively, and repeat magnetic resonance imaging at six weeks showed resolution of the abscess. PMID- 26770848 TI - The Myotonic Plot Thickens: Electrical Myotonia in Antimuscle-Specific Kinase Myasthenia Gravis. AB - Electrical myotonia is known to occur in a number of inherited and acquired disorders including myotonic dystrophies, channelopathies, and metabolic, toxic, and inflammatory myopathies. Yet, electrical myotonia in myasthenia gravis associated with antibodies against muscle-specific tyrosine kinase (MuSK) has not been previously reported. We describe two such patients, both of whom had a typical presentation of proximal muscle weakness with respiratory failure in the context of a significant electrodecrement in repetitive nerve stimulation. In both cases, concentric needle examination revealed electrical myotonia combined with myopathic motor unit morphology and early recruitment. These findings suggest that MuSK myasthenia should be included within the differential diagnosis of disorders with electrical myotonia. PMID- 26770849 TI - Herpes Simplex Viral Encephalitis Masquerading as a Classic Left MCA Stroke. AB - Objective. Stroke is a clinical diagnosis, with a history and physical examination significant for acute onset focal neurological symptoms and signs, often occurring in patients with known vascular risk factors and is frequently confirmed radiographically. Case Report. A 79-year-old right-handed woman, with a past medical history of hypertension, hyperlipidemia, and prior transient ischemic attack (TIA), presented with acute onset global aphasia and right hemiparesis, in the absence of fever or prodrome. This was initially diagnosed as a proximal left middle cerebral artery (MCA) stroke. However, CT perfusion failed to show evidence of reduced blood volume, and CT angiogram did not show evidence of a proximal vessel occlusion. Furthermore, MRI brain did not demonstrate any areas of restricted diffusion. EEG demonstrated left temporal periodic lateralized epileptiform discharges (PLEDs). The patient was empirically loaded with a bolus valproic acid and started on acyclovir, both intravenously. CSF examination demonstrated a pleocytosis and PCR confirmed the diagnosis of herpes simplex viral encephalitis (HSVE). Conclusions. HSVE classically presents in a nonspecific fashion with fever, headache, and altered mental status. However, acute focal neurological signs, mimicking stroke, are possible. A high degree of suspicion is required to institute appropriate therapy and decrease morbidity and mortality associated with HSVE. PMID- 26770850 TI - Metastatic Colorectal Cancer Resembling Severe Preeclampsia in Pregnancy. AB - Although colorectal cancer (CRC) is the third most common cancer in women, it is a rare malignancy in pregnancy. Symptoms of CRC such as fatigue, malaise, nausea, vomiting, rectal bleeding, anemia, altered bowel habits, and abdominal mass are often considered typical symptoms of pregnancy. Many cases of CRC are diagnosed in advanced stages due to missed warning signs of CRC, which may be misinterpreted as normal symptoms related to pregnancy. This report reviews 2 cases of CRC diagnosed within a 4-month interval at our institution. Both cases were initially thought to be atypical presentations of preeclampsia. Prenatal history, hospital course, and postpartum course were reviewed for both patients. CRC is often diagnosed at advanced stages in pregnancy. Common physiological symptoms of pregnancy should be scrutinized carefully and worked up appropriately, especially if symptoms remain persistent or increase in intensity or severity. PMID- 26770851 TI - Humerus Diaphysis Fracture in a Newborn during Vaginal Breech Delivery. AB - While most obstetricians are familiar with fracture of the clavicle in newborns during birth, an unlucky minority of obstetricians has encountered long-bone fractures in newborns as well. This complication is traumatic not only for the neonate, but also for the family and the obstetrician; it is also difficult to explain. Fortunately, the long-term prognosis for fracture of the long bones is excellent. Both vaginal and cesarean breech deliveries and maneuvers can be responsible for birth traumas, including long-bone fractures. This case report presents a newborn with breech presentation delivered vaginally that resulted in humerus diaphysis fracture. PMID- 26770852 TI - Conservative Management of Cesarean Scar Ectopic Pregnancy with Fetal Heart Activity and a Very High beta-hCG. AB - Cesarean scar ectopic pregnancy (CSP) is a rare type of ectopic pregnancy that is growing in incidence. The diagnosis of most CSP occurs when patients present in unstable conditions requiring surgical management and leading sometimes to hysterectomy. It has been shown that medical management is a safe option for early diagnosed hemodynamically stable CSP. However, no cases of CSP with beta hCG higher than 62,000 IU/L, conservatively treated, have been reported. We report the case of a 29-year-old patient who presented for her first prenatal visit at 13-week gestation and was diagnosed with CSP with present fetal heart tones and a quantitative beta-hCG of 144,337 IU/L. She was treated with bilateral uterine artery embolization and systemic methotrexate. Her beta-hCG significantly decreased and became undetectable within 10 weeks. We propose that patients with CSP with very high beta-hCG and fetal heart activity can be offered conservative or fertility preserving management. PMID- 26770853 TI - An Unusual Course of Metastatic Gastroesophageal Cancer. AB - We are reporting on a case of a 41-year-old woman who presented with metastatic gastroesophageal junction cancer and who achieved prolonged survival with a multimodal treatment approach. After initially experiencing robust response to chemotherapy, she was treated for distant recurrence with palliative radiation to the gastrohepatic and supraclavicular lymph nodes and subsequently, given her unusual near-complete response, with reirradiation to the abdomen with curative intent for residual disease. The case presented is unique due to the patient's atypical treatment course, including technically difficult reirradiation to the abdomen, and the resulting prolonged survival despite metastatic presentation. PMID- 26770854 TI - Arginine-Restricted Therapy Resistant Bilateral Macular Edema Associated with Gyrate Atrophy. AB - Introduction. Gyrate atrophy is a rare genetical metabolic disorder affecting vision. Here, we report a 9-year-old boy with gyrate atrophy associated with bilateral macular edema at the time of diagnosis and the effect of long term metabolic control on macular edema. Case Presentation. A 9-year-old boy presented with a complaint of low visual acuity (best corrected visual acuity: 20/80 in both eyes, refractive error: -12.00 D). Dilated fundus examination revealed multiple bilateral, sharply defined, and scalloped chorioretinal atrophy areas in the midperipheral and peripheral zone. Spectral-domain optical coherence tomography revealed bilateral cystoid macular edema in both eyes. Serum ornithine level was high (622 MUmol/L). An arginine-restricted diet reduced serum ornithine level (55 MUmol/L). However, visual findings including macular edema remained unchanged in 2 years of follow-up. Conclusion. Arginine-restricted diet did not improve macular edema in our patient with gyrate atrophy. A more comprehensive understanding of the underlying factors for macular edema will lead to the development of effective therapies. PMID- 26770855 TI - Bilateral Multifocal Choroidal Osteoma with Choroidal Neovascularization. AB - Choroidal osteoma has been reported to be unilateral in approximately 80% of cases diagnosed with this condition. Herein we report the clinical characteristics and multimodal imaging findings in a rare case of bilateral multifocal choroidal osteoma. A 32-year-old female presented with decreased visual acuity (VA) in the right eye (20/100), though she had normal VA (20/20) in the left eye. Ophthalmoscopy and multimodal imaging investigation revealed bilateral multifocal choroidal osteoma complicated by choroidal neovascularization (CNV) in the right eye. Following three injections of intravitreal bevacizumab (IVB) for CNV in the right eye, VA improved to 20/40. PMID- 26770856 TI - Visual Field Defect after Cardiac Surgery: The Striking Role of Interdisciplinary Collaboration. AB - Perioperative visual loss (POVL) is a potentially devastating complication that can occur following ocular or nonocular surgery. The leading causes of this disease are retinal vascular occlusions, ischemic optic neuropathies, and cortical blindness. POVL pathogenesis is strictly influenced by surgery, anesthesia, and patients' comorbidities. We report of a 55-year-old caucasian man who presented with complaints of sudden painless loss of vision and unilateral campimetric deficit. We recorded a preserved visual acuity but at fundus examination a bilateral ischemic optic neuropathy (ION) was suspected. Our hypothesis was supported by uncommon and peculiar visual field defects and a history of cardiovascular surgery shortly before was a striking data. When we examined his medical records we found strong accordance with what is reported in literature to be risk factors for postoperative ION development. He presented intraoperative hypotension, anemia, and hypothermia, he was older than 50 years, and surgery lasted for more than five hours. We are currently monitoring his visual acuity and visual fields which remain unchanged. As there is no proved therapy for such severe adverse events, we recommend intraoperative check of blood pressure, blood loss, and body temperature, associated with repeated eye checks and patients' interview. PMID- 26770857 TI - Ballistic Reconstruction of a Migrating Bullet in the Parapharyngeal Space. AB - A 21-year-old male suffering from severe throat pain after being hit by a bullet in Syria claimed that he was shot through his eye and that the bullet subsequently descended behind his throat. Even though the first medical report stated that this course is implausible, meticulous workup provided evidence that the bullet might have entered the parapharyngeal space in a more cranial position than the one it was found eight months later. Our case highlights that bullets are able to move within the body, rendering ballistic reconstruction difficult. However, after removal of the bullet the patient's symptoms completely resolved. PMID- 26770858 TI - Bilateral Sensorineural Hearing Loss and Polyneuropathy in a Patient with Sweet's Syndrome. AB - Sweet's syndrome is an inflammatory systemic disease which has been associated with various underlying causes. The disease can involve multiple areas of the body including the skin and neurological system. There have been only two cases which have described otological involvement. This report presents a patient who developed loss of hearing secondary to Sweet's syndrome after developing cutaneous involvement along with peripheral neuropathy. Despite the patient's skin and neuropathy noticing improvement with intravenous immunoglobulin and azathioprine, he required bilateral cochlear implants for partial recovery of his hearing loss. This case highlights the need to recognize Sweet's syndrome as a complicated disease process where the role of otolaryngologists is important in the multidisciplinary coordination of care in both diagnosis and treatment. PMID- 26770859 TI - A Large Extragnathic Keratocystic Odontogenic Tumour. AB - Odontogenic keratocysts (OKCs) are developmental cysts which occur typically in the jawbones. They present more commonly in the posterior mandible of young adults than the maxilla. OKCs have been reclassified under odontogenic tumours in 2005 by the WHO and have since been termed as keratocystic odontogenic tumours (KCOTs). Here we report a case of a recurrent buccal lesion in a 62-year-old man which was provisionally diagnosed as a space infection (buccal abscess) but surprisingly turned out to be a soft tissue KCOT in an unusual location on histopathologic examination. PMID- 26770860 TI - Single Stage Endovascular Treatment of a Type 2 Abernethy Malformation: Successful Nonsurgical Outcome in a Case Report. AB - Abernethy malformations are a rare collection of congenital hepatic portosystemic shunts. Our 19-year-old patient is with a type 2 Abernethy malformation elected permanent shunt closure following worsening dyspnea. This report details a single stage endovascular technique wherein shunt closure was achieved immediately by placement of an aortic endograft. At 5-month follow-up, the patient reported decreased shortness of breath. Furthermore, ultrasound investigation demonstrated a patent portal vein and right heart catheterization 6 months after procedure revealed decreased pulmonary hypertension relative to preprocedure values. This one step method may serve as an alternative treatment strategy to multistage endovascular closure techniques of type 2 Abernethy malformations. PMID- 26770861 TI - Imaging of Posterior Interosseous Neuropathy following Distal Biceps Repair: A Report of 3 Cases. AB - Three cases of PIN palsy following biceps repair are presented with clinical and imaging correlation. The imaging findings in these cases will be discussed and the orthopedic literature, as regards possible surgical approaches and technical factors believed to predispose to or prevent this complication, will be reviewed. It is important for radiologists to serve as consultants in these uncommon but sometimes devastating complications, helping to quickly and accurately recognize the imaging findings corresponding to the clinical symptoms and aiding the surgeon in diagnosis and treatment by identifying the possible causes and sites of nerve compression. PMID- 26770862 TI - Cervical Spinal Meningeal Melanocytoma Presenting as Intracranial Superficial Siderosis. AB - Meningeal melanocytoma is a rare pigmented tumor of the leptomeningeal melanocytes. This rare entity results in diagnostic difficulty in imaging unless clinical and histopathology correlation is performed. In this case report, we describe a case of meningeal melanocytoma of the cervical region presenting with superficial siderosis. Extensive neuroradiological examination is necessary to locate the source of the bleeding in such patients. Usually, the patient will be cured by the complete surgical excision of the lesion. PMID- 26770863 TI - Metastatic Tumor of the Spermatic Cord in Adults: A Case Report and Review. AB - Metastatic spermatic cord (SC) tumor is extremely rare. Recently, we experienced a case of late-onset metastatic SC tumor from cecal cancer. This case is a 68 year-old man presenting with a painless right SC mass. He had undergone a right hemicolectomy for cecal cancer 6 years ago. Radical orchiectomy and adjuvant chemotherapy with S-1 were performed. No recurrence was found after one year of follow-up. We identified a total of 25 cases, including our case, on a literature search via PubMed from January 2000 to April 2015. The most frequent primary sites of the tumors metastasizing to the SC were the stomach (8 cases, 32%) and the colon (8 cases, 32%), next the liver (2 cases, 8%), and kidney (2 cases, 8%). The majority of the cases underwent radical orchiectomy for the metastatic tumors of the SC. Over half of the cases received adjuvant interventions based on the regimens for the primary tumors. Prognosis in the patients with metastatic tumor of the SC was unfavorable except for late-onset metastasis. In patients with a mass in the SC and a history of neoplasm, especially in gastrointestinal tract, the possibility of metastasis from the primary cancer should be considered. PMID- 26770864 TI - Management of Recurrent Rectourethral Fistula by York Mason Posterior Transrectal Transsphincteric Approach. AB - Rectourethral fistula (RUF) may develop after ureterovesical and rectal intervention or radiation therapy (RT) rarely, but it is associated with significant morbidity and mortality. The patient will typically present with pneumaturia, faecaluria, and urinary drainage from the rectum. Diagnosis can be easily done with digital rectal examination, cystography, and urethrocystoscopy. Conservative supportive management of RUF does not appear to be successful in most patients, and management with surgical intervention remains the best treatment option. Several surgical techniques have been described including transabdominal, transanal, transperineal, combined abdominoperineal, anterior and posterior transsphincteric, transsacral, laparoscopic, robotic, and endoscopic minimally invasive approaches. There have been very few data about treatment of recurrent RUF. We would like to report the management of recurrent RUF following transurethral resection of prostate and RT for prostate carcinoma in an immunosuppressed, 75-year-old patient by York Mason posterior transrectal transsphincteric approach. PMID- 26770865 TI - CCR7 Receptor Expression in Mono-MAC-1 Cells: Modulation by Liver X Receptor alpha Activation and Prostaglandin E 2. AB - Cell migration via chemokine receptor CCR7 expression is an essential function of the immune system. We previously showed that prostaglandin E2 (PGE2), an important immunomodulatory molecule, increases CCR7 expression and function in monocytes. Here, we explore the role of the liver X receptor alpha (LXRalpha) activation on CCR7 expression in Mono-Mac-1 (MM-1) cells in the presence of PGE2. To do this, MM-1 cells were stimulated with the LXRalpha synthetic agonist T0901317 in the presence or absence of PGE2. CCR7 mRNA transcription was measured using quantitative RT-PCR and protein expression was examined using flow cytometry. CCR7 function was analyzed using migration assays in response to CCL19/CCL21, which are natural ligands for CCR7. Our results show that agonist mediated activation of LXRalpha in the presence of PGE2 increases CCR7 mRNA transcription and MM-1 cell migratory capacity in response to CCL19/21. In addition, our results demonstrate that engagement of the E-prostanoids 2 and 4 (EP2/EP4) receptors present on MM-1 cells is responsible for the observed increase in CCR7 mRNA expression and function during LXRalpha activation. Examination of monocyte migration in response to lipid derivatives such as PGE2 and oxysterols that are produced at sites of chronic inflammation would contribute to understanding the excessive monocyte migration that characterizes atherosclerosis. PMID- 26770866 TI - Trend Analysis of Malaria Occurrence in Wolaita Zone, Southern Ethiopia: Retrospective Cross-Sectional Study. AB - Background. Malaria is a major public health problem in Ethiopia. The trend of malaria occurrence remains unknown in the study area. This study is aimed at determining the last five years' trend of malaria occurrence from 2008/09 to 2012/13 in Wolaita Zone, Southern Ethiopia. Methods. A health facility-based retrospective study was conducted in Wolaita Zone from March to August, 2014. Five years' laboratory confirmed malaria record review was made from six health centers. Result. A total of 105,755 laboratory confirmed malaria cases were reported, with total slide positivity rate of 33.27% and mean annual occurrence of 21,151 cases. Malaria occurred with a fluctuating trend in the study area, with its peak occurring at the year 2011/12. Overall, no remarkable decline in the total laboratory confirmed malaria was observed in the last five years. P. falciparum was the predominantly reported species, accounting for 75,929 (71.80%) of cases. The highest slide positivity rate was observed in the age group of 5-14 years (40.5%) followed by 1-4 years (35.5%). Two malaria peak seasons occurred: one from September to December and the other from April to June. Conclusion. No remarkable decline in laboratory confirmed malaria in the last five years was observed. PMID- 26770867 TI - Diffusion Kurtosis Imaging of Substantia Nigra Is a Sensitive Method for Early Diagnosis and Disease Evaluation in Parkinson's Disease. AB - Background. To diagnose Parkinson disease (PD) in an early stage and accurately evaluate severity, it is important to develop a sensitive method for detecting structural changes in the substantia nigra (SN). Method. Seventy-two untreated patients with early PD and 72 healthy controls underwent diffusion tensor and diffusion kurtosis imaging. Regions of interest were drawn in the rostral, middle, and caudal SN by two blinded and independent raters. Mean kurtosis (MK) and fractional anisotropy in the SN were compared between the groups. Receiver operating characteristic (ROC) and Spearman correlation analyses were used to compare the diagnostic accuracy and correlate imaging findings with Hoehn-Yahr (H Y) staging and part III of the Unified Parkinson's Disease Rating Scale (UPDRS III). Result. MK in the SN was increased significantly in PD patients compared with healthy controls. The area under the ROC curve was 0.976 for MK in the SN (sensitivity, 0.944; specificity, 0.917). MK in the SN had a positive correlation with H-Y staging and UPDRS-III scores. Conclusion. Diffusion kurtosis imaging is a sensitive method for PD diagnosis and severity evaluation. MK in the SN is a potential biomarker for imaging studies of early PD that can be widely used in clinic. PMID- 26770868 TI - Medical Record Review to Differentiate between Idiopathic Parkinson's Disease and Parkinsonism: A Danish Record Linkage Study with 10 Years of Follow-Up. AB - Background. The electronic medical records provide new and unprecedented opportunities for large population-based and clinical studies if valid and reliable diagnoses can be obtained, to determine what information is needed to distinguish idiopathic PD from Parkinsonism in electronic medical records. Methods. Chart review of complete medical records of 2,446 patients with a hospital discharge diagnosis of PD, who, between 1996 and 2009, were registered in the Danish National Hospital Register as idiopathic PD. All patients were examined in neurology departments. Clinical features were abstracted from charts to determine Parkinsonian phenotypes and disease course, using predefined criteria for idiopathic PD. Results. Chart review verified that 2,068 (84.5%) patients met criteria for idiopathic PD. The most distinguishing features of idiopathic PD patients were asymmetric onset, and fewer atypical features at onset or follow-up compared to Parkinsonism, and the area under the curve (AUC) for these items alone is moderate (0.74-0.77) and the highest AUC (0.91) was achieved when using all clinical features recorded in addition to PD medication use and a follow-up of 5 years or more. Conclusion. To reduce disease misclassification, information extracted from medical record review with at least 5 years of follow-up after first diagnosis was key to improve diagnostic accuracy. PMID- 26770869 TI - EGCG Protects against 6-OHDA-Induced Neurotoxicity in a Cell Culture Model. AB - Background. Parkinson's disease (PD) is a progressive neurodegenerative disease that causes severe brain dopamine depletion. Disruption of iron metabolism may be involved in the PD progression. Objective. To test the protective effect of (-) epigallocatechin-3-gallate (EGCG) against 6-hydroxydopamine- (6-OHDA-) induced neurotoxicity by regulating iron metabolism in N27 cells. Methods. Protection by EGCG in N27 cells was assessed by SYTOX green assay, MTT, and caspase-3 activity. Iron regulatory gene and protein expression were measured by RT-PCR and Western blotting. Intracellular iron uptake was measured using (55)Fe. The EGCG protection was further tested in primary mesencephalic dopaminergic neurons by immunocytochemistry. Results. EGCG protected against 6-OHDA-induced cell toxicity. 6-OHDA treatment significantly (p < 0.05) increased divalent metal transporter-1 (DMT1) and hepcidin and decreased ferroportin 1 (Fpn1) level, whereas pretreatment with EGCG counteracted the effects. The increased (55)Fe (by 96%, p < 0.01) cell uptake confirmed the iron burden by 6-OHDA and was reduced by EGCG by 27% (p < 0.05), supporting the DMT1 results. Pretreatment with EGCG and 6 OHDA significantly increased (p < 0.0001) TH(+) cell count (~3-fold) and neurite length (~12-fold) compared to 6-OHDA alone in primary mesencephalic neurons. Conclusions. Pretreatment with EGCG protected against 6-OHDA-induced neurotoxicity by regulating genes and proteins involved in brain iron homeostasis, especially modulating hepcidin levels. PMID- 26770870 TI - Evaluation of Analgesic Effect of Caudal Epidural Tramadol, Tramadol-Lidocaine, and Lidocaine in Water Buffalo Calves (Bubalus bubalis). AB - Aim of this study was to compare the analgesic effect of tramadol and a combination of tramadol-lidocaine with that produced by lidocaine administration in the epidural space in buffalo calves. In a prospective randomized crossover study, ten male buffalo calves were used to compare the epidural analgesic effect of tramadol (1 mg/kg) and tramadol-lidocaine combination (0.5 mg/kg and 0.11 mg/kg, resp.) with that produced by 2% lidocaine (0.22 mg/kg). Loss of sensation was examined by pin-prick test. Onset time, duration, and degree of analgesia and ataxia were recorded after each treatment. Heart rate (HR), respiratory rate (RR), rectal temperature, and haematobiochemical parameters were recorded after all treatments. Time to onset and duration of analgesia, respectively, were as follows: tramadol 11 +/- 2 min and 208 +/- 15 min; tramadol-lidocaine 6 +/- 2 min and 168 +/- 9 min; lidocaine 4 +/- 1 min and 67 +/- 13 min. Onset time and duration were significantly longer with tramadol than the other treatments. Duration was significantly longer with tramadol-lidocaine than lidocaine. Ataxia was mildly observed in tramadol-lidocaine and was moderate in lidocaine. HR, RR, and rectal temperature did not differ significantly from baseline after any treatment. Haematobiochemical parameters returned to basal levels by 24 h after all treatments. This combination might be clinically useful to provide analgesia in buffalo for long-duration surgical procedures. PMID- 26770871 TI - Low Dose Perioperative Intravenous Tranexamic Acid in Patients Undergoing Total Knee Arthroplasty: A Double-Blind Randomized Placebo Controlled Clinical Trial. AB - Background and Objectives. The null hypothesis of this study was that TA has no effect on postsurgical bleeding in patients undergoing TKA. Methods. This study was a double-blind randomized trial. In the first group (T) patients received 500 mg of intravenous Tranexamic acid (TA) twice (once preoperatively and once 3 hours postoperatively) and in the second group (P) they received slow infusion of normal saline as placebo. The primary outcome of the study was the level of Hb 48 hours after surgery. Results. Hb levels 48 hours after surgery as the primary outcome were 10.92 +/- 0.97 and 10.23 +/- 0.98 (g/dL) in groups T and P, respectively, and the difference was statistically significant (P = 0.001). Statistically significant differences were also observed in Hb levels 6 and 24 hours after surgery, the drain output 48 hours after surgery, and the number of units of packed cells transfused between study groups (P < 0.05). There was no significant difference in duration of hospitalization between the study groups (P = n.s.). Conclusions. The low dose perioperative intravenous TA significantly reduces blood loss, requirement for blood transfusion, and drain output in patients undergoing TKA. However, duration of hospitalization did not change significantly. PMID- 26770872 TI - Role of mast cell in the late phase of contact hypersensitivity induced by trimellitic anhydride. AB - Mast cells are known as effector cells of IgE-mediated allergic responses, but role of mast cells in contact hypersensitivity (CHS) has been considered controversial. In this study, we investigated role of mast cell in trimellitic anhydride (TMA)-induced CHS. The mice were sensitized to TMA on the back and repeatedly challenged with TMA on the left ear at 1-week intervals. The ear after challenge showed biphasic responses. The repetition of TMA challenge shifted in time course of ear response and enlarged the extent of early and late phase reactions in proportion to the frequency of TMA challenges in C57BL/6 mice. In late phase reaction, peak of ear response by single challenge showed at 24 hours after challenge, but the peak by repeat challenges at 8 hours after the last challenge. Number of mast cells and eosinophils per unit area increased in proportion to frequency of TMA challenges. However, mast cell-deficient WBB6F1/J Kit(W)/Kit(W-v) mice developed the late phase reaction without the early phase reaction. The repetition of TMA challenge shifted in time course of ear response and enlarged the extent of ear response and the infiltration of eosinophils. The magnitude of these responses observed according to the frequency of the TMA challenge in mast cell-deficient WBB6F1/J-Kit(W)/Kit(W-v) mice was significantly lower than that in C57BL/6 mice. Also TMA elicited mast cell degranulation and histamine release from rat peritoneal mast cells in a concentration-dependent manner. Conclusively, TMA induces the early and late phase reactions in CHS, and mast cells may be required for TMA-induced CHS. PMID- 26770873 TI - Protective effects of kaempferol against cardiac sinus node dysfunction via CaMKII deoxidization. AB - Kaempferol exerts cardioprotective actions through incompletely understood mechanisms. This study investigated the molecular mechanisms underlying the cardioprotective effects of kaempferol in sinus node dysfunction (SND) heart. Here, we demonstrate that angiotensin II (Ang II) infusion causes SND through oxidized calmodulin kinase II (CaMKII). In contrast to this, kaempferol protects sinus node against Ang II-induced SND. Ang II evoked apoptosis with caspase-3 activation in sinus nodal cells. However, kaempferol lowered the CaMKII oxidization and the sinus nodal cell death. To block the CaMKII oxidization, gene of p47phox, a cytosolic subunit of NADPH oxidase, was deleted using Cas9 KO plasmid. In the absence of p47phox, sinus nodal cells were highly resistance to Ang II-induced apoptosis, suggesting that oxidized-CaMKII contributed to sinus nodal cell death. In Langendorff heart from Ang II infused mice, kaempferol preserved normal impulse formation at right atrium. These data suggested that kaempferol protects sinus node via inhibition of CaMKII oxidization and may be useful for preventing SND in high risk patients. PMID- 26770874 TI - A combinational effect of acetaminophen and oriental herbs on the regulation of inflammatory mediators in microglia cell line, BV2. AB - The mechanism of Western medicine that is commonly used for pain relief is well known. However, very little is known for oriental herbs, and even less is known for mixture of the two. We investigated the combinational effect of 3 kinds of oriental herbs, usually used for the control of headache, and acetaminophen to relieve headache in microglia cell line, BV2. Lipopolysaccharide (LPS) stimulation induced to produce nitrite and increased the expression of inflammation-related factors like inducible nitric oxide synthase and cyclooxygenase-2 (COX-2) in murine microglia cell line, BV2. Oriental herbs such as Angelica tenuissima, Angelica dahurica, and Scutellaria baicalensis reduced the production of nitric oxide and the expression of COX-2. Moreover, a treatment of acetaminophen combined with oriental herbs was more decreased the COX-2 expression, and its product, prostaglandin E2 production in BV2 cells. Therefore, a combined treatment of oriental herbs such as A. tenuissima, A. dahurica, and S. baicalensis and Western medicine like acetaminophen has a synergistic effect on the decrease of LPS-induced inflammation in microglia. PMID- 26770875 TI - The influence of substrate topography and biomaterial substance on skin wound healing. AB - Tissue engineering is a new field of which the main purpose is to regenerate and repair the damaged tissues. Scaffolds serve as three dimensional matrices for neo organogenesis and their substance can be biologic or synthetic. Natural polymers have good interactions with the cells and synthetic biomaterials are also highly useful in biomedical application because of their biocompatible properties. In addition to scaffold substance, surface properties of biomaterials have an important role in tissue engineering. In this study, we examined whether substrate substance is important for wound healing or its surface topography. Therefore, we fabricated two matrices, electrospun polycaprolactone (PCL) nanofibers and collagen/chitosan film, and implanted them to the same rat models. After 2 weeks, the sizes of healing wounds were measured and their cellular structures were evaluated by histochemistry and mmunohistochemistry. Histological staining showed a good level of cellularization and epidermis-dermis formation in PCL implant while no determinable epithelium was observed after 2 weeks in collagen-chitosan graft. Immunohistochemical study demonstrated the highly expressed pancytokeratin in PCL graft while its expression was weak in underdeveloped epidermis of collagen-chitosan implantation. In conclusion, this study suggested that PCL nanofibers with high surface area had a more ideal property than natural collagen-chitosan film, therefore the structure and topography of a matrix seemed to be more important in wound healing than its material substance. PMID- 26770876 TI - Haversian system of compact bone and comparison between endosteal and periosteal sides using three-dimensional reconstruction in rat. AB - The current model of compact bone is that of a system of Haversian (longitudinal) canals connected by Volkmann's (transverse) canals. Models based on either histology or microcomputed tomography do not accurately represent the morphologic detail and microstructure of this system, especially that of the canal networks and their spatial relationships. The aim of the present study was to demonstrate the morphologic pattern and network of the Haversian system and to compare endosteal and periosteal sides in rats using three-dimensional (3D) reconstruction. Ten Sprague-Dawley rats aged 8-10 weeks were used. The femurs were harvested from each rat and fixed, decalcified with 10% EDTA-2Na, serially sectioned at a thickness of 5 um, and then stained with hematoxylin and eosin. The serial sections were reconstructed three-dimensionally using Reconstruct software. The Haversian canals in the endosteal region were found to be large, highly interconnected, irregular, and close to neighboring canals. In contrast, the canals in the periosteal region were straight and small. This combined application of 3D reconstruction and histology examinations to the Haversian system has confirmed its microstructure, showing a branched network pattern on the endosteal side but not on the periosteal side. PMID- 26770877 TI - White matter plasticity in the cerebellum of elite basketball athletes. AB - Recent neuroimaging studies indicate that learning a novel motor skill induces plastic changes in the brain structures of both gray matter (GM) and white matter (WM) that are associated with a specific practice. We previously reported an increased volume of vermian lobules VI-VII (declive, folium, and tuber) in elite basketball athletes who require coordination for dribbling and shooting a ball, which awakened the central role of the cerebellum in motor coordination. However, the precise factor contributing to the increased volume was not determined. In the present study, we compared the volumes of the GM and WM in the sub-regions of the cerebellar vermis based on manual voxel analysis with the ImageJ program. We found significantly larger WM volumes of vermian lobules VI-VII (declive, folium, and tuber) in elite basketball athletes in response to long-term intensive motor learning. We suggest that the larger WM volumes of this region in elite basketball athletes represent a motor learning-induced plastic change, and that the WM of this region likely plays a critical role in coordination. This finding will contribute to gaining a deeper understanding of motor learning-evoked WM plasticity. PMID- 26770878 TI - Anatomical study of the nerve regeneration after selective neurectomy in the rabbit: clinical application for esthetic calf reduction. AB - The purposes of this study were therefore to characterize the degeneration and regeneration of nerves to the calf muscles after selective neurectomy, both macroscopically and microscopically, and to determine the incidence of such regeneration in a rabbit model. Seventy four New Zealand white rabbits were used. Selective neurectomy to the triceps surae muscles was performed, and the muscles were subsequently harvested and weighed 1-4 months postneurectomy. The gastrocnemius muscles were stained with Sihler's solution to enable the macroscopic observation of any nerve regeneration that may have occurred subsequent to neurectomy. The change in triceps surae muscle weight was measured along the time course of the experiment. After neurectomy, nerve degeneration was followed by regeneration in all cases. The weight of the triceps surae muscle decreased dramatically between completion of the neurectomy and 1 month postneurectomy, but increased thereafter. The nerve branches were weakly stained with Sihler's solution until 2 months postneurectomy, and then strongly stained after 3 months. The number of myelinated axons was decreased at 2 month after neurectomy compared to nonneurectomized controls, but then gradually increased thereafter. Although there are currently no reports on the incidence of recovery after calf reduction, it may be a very common occurrence in the clinical field based on our findings. The findings of this study provide fundamental anatomical and surgical information to aid planning and practice in calf-reduction surgery. PMID- 26770879 TI - Craniometric study for sex determination in a Thai population. AB - Sex determination is an important step in biological identification from skeletal remains, especially in forensic circumstances. Many authors suggested that the morphological study was more subjective than the metric. There are various craniometric studies in different populations. They revealed that there was population-specific for the sex discriminant equation derived from each population. Thus, the present study aimed to evaluate sexual dimorphism and develop the discriminant function from 200 Thai skulls. Twenty-five standard cranial measurements were examined. The results revealed that males' cranium were statistically significant larger than females' in all measurements (P<0.05), except for minimum breadth of nasal bone. Sexual dimorphism index also expressed relatively high male/female ratio indicating great sexual dimorphism. The best practical equation for sex determination with six measurements (maximum cranial length, bizygomatic breadth, biauricular breadth, nasal height, biorbital breadth and right mastoid length) was derived from a stepwise discriminant method. This equation with 90.6% accuracy (91.1% in male and 90.0% in female) can provide valuable application utilizing in sex determination from skull in a Thai population. PMID- 26770880 TI - Evaluation of the effectiveness of the new tooth wear measurement parameters. AB - Nowadays, there has been an increasing interest in the preservation of natural dentition and the proper occlusion related to tooth wear for quality of life. To overcome the problems of the existing qualitative tooth wear analysis method, virtual three-dimensional models have been used. This study was designed to develop and validate a new quantitative method using tooth wear measurement parameters with angles obtained from virtual vectors and planes of the three dimensional models. Sixteen parameters were evaluated in the virtual models of 20 students (7.57+/-1.55 years old) and 20 adults (56.85+/-6.34 years old). There were 12 angle and 4 height parameters, and the number of parameters measured from the virtual planes and vectors were 10 and 6, respectively. For each parameter, means and standard deviations were calculated, and an unpaired sample t test was performed to compare the young and the adult groups. Also, differences between the means were determined and expressed as percentages. The results were statistically significant between the two groups (P<0.001). In general, parameters using virtual vectors showed greater change than virtual plane. Although there were statistically significant differences among all parameters using virtual planes (P<0.001), the changes of the three angles were similar, except distolingual cusp angle. It was found that the parameters using virtual vectors were effective and tooth wear took place in both buccal and lingual cusps. Likewise, the validation of the new measurement parameters suggests that they can also be applied in the assessment of tooth wear related to dental biomaterials. PMID- 26770881 TI - Morphology and topography of the parietal emissary foramina in South Indians: an anatomical study. AB - The objectives of the present study were to study the prevalence of the parietal emissary vein in adult South Indian population and to study the distance of foramen from the sagittal suture. There were 58 adult human skulls in the present study which were available at the anatomy department of our institution. The study included 116 parietal bones which have been observed macroscopically for the number, prevalence and topography of the emissary foramen. The emissary foramen was present in 83 parietal bones (71.5%) of the present study. It was present at the junction between the middle 1/3 and posterior 1/3 region of the parietal bone. The foramen was observed solitary in 73 parietal bones (62.9%), double in 8 bones (6.9%), and triple in 2 parietal bones (1.7%). The foramen was not observed in 33 parietal bones (28.4%). The bilateral absence of parietal emissary foramen was seen in 7 skulls (12.1%). It was absent unilaterally in 19 skulls (32.7%). The accessory foramina were seen in only 8 skulls (13.8%). The mean distance of the foramen from the sagittal suture was 6.7+/-2.9 mm and 6.8+/ 2.8 mm on the right and left sides respectively. The prevalence of parietal emissary vein in the present study was 71.5%. The present study has observed important data about the morphology and morphometry of the parietal emissary vein in South Indian population. The identification of parietal emissary veins and accessory veins is important in the operation room to prevent the blood loss. PMID- 23867975 TI - The 6-Minute Walk Test and Person-Reported Outcomes in Boys with Duchenne Muscular Dystrophy and Typically Developing Controls: Longitudinal Comparisons and Clinically-Meaningful Changes Over One Year. AB - INTRODUCTION: Data is currently lacking anchoring a 30-meter longitudinal change in walking ability by 6-minute walk test (6MWT) in Duchenne muscular dystrophy as a minimal clinically important difference and "clinically meaningful" person reported outcomes (PROs) at differing levels of ambulatory ability. METHODS: We describe correlation between measures, 1-year change in measures, and correlation of 1-year changes between measures for the six-minute walk test (6MWT), 10-meter run/walk velocity, PedsQL and POSNA Pediatric Outcomes Data Collection Instrument (PODCI) in 24 4-12 year old. ambulatory DMD and 36 typical controls, and determine if minimal clinically important differences (MCID) of PROs contribute to different estimates of 6-minute walk distance (6MWD) change at differing levels of ability. RESULTS: PedsQL total and physical function and PODCI global, transfer/mobility and sports/physical function PROs demonstrated significant differences between DMD and controls (p<0.00001). In DMD, 6MWD and 10-meter run/walk velocity were correlated with PODCI domain scores, with the transfer/mobility scale showing the strongest relationship (r=0.79 and r=0.76). In DMD, 6MWD distance and 10-meter run/walk velocity weakly correlated with PedsQL domain scores. In DMD, 6MWD, 10-meter run/walk velocity, and PODCI global and transfer and basic mobility demonstrated significant one-year change and exceeded the amount of change representing MCID. In DMD, 6MWD change highly correlated with change in PODCI global and PODCI transfer/mobility scores (r=0.76 and r=0.93). PODCI global and PODCI transfer/mobility scales provided the best estimates of 6MWT performance. A "meaningful" 4.5 point change in a low PODCI transfer / basic mobility score of 30 to 34.5 was associated with a 5.6m 6MWD change from 150.3 to 155.9m. At PODCI levels closer to normative levels for healthy controls, the change in 6MWD distance associated with a "meaningful" change in PODCI scores was almost 46m. DISCUSSION: At lower levels of function, smaller increases in 6MWD result in meaningful change in quality of life (QoL) instrument scores. At higher levels of function, larger increases may be necessary to achieve the same QoL change score. PMID- 26770883 TI - Exploring the Neurochemical Basis of Alcohol Addiction-Related Behaviors: Translational Research. AB - This Editorial presents the position that translational research continues to play a vital role in the field of alcohol addiction research. Using diverse animal models that mimic fundamental features of the disease, tremendous progress has been made in our understanding of alcohol actions in the brain and in identifying key neurobiological adaptations that may contribute to the pathophysiology of alcohol addiction. Current translational research in this field is now focusing on identifying the causal mechanisms that drive the shift from recreational to abusive ethanol drinking behaviors. The relatively recent development and application of optogenetic and chemogenetic techniques is beginning to afford alcohol researchers with the opportunity to identify specific neuronal circuits that govern key elements of the addiction process. These advances are rapidly pointing the way toward novel neural targets for the development of more effective treatments for addictive disorders. PMID- 26770884 TI - Modeling The Bone Marrow Microenvironment's Influence on Leukemic Disease. PMID- 26770885 TI - Measuring Dyspnea and Perceived Exertion in Healthy Adults and with Respiratory Disease: New Pictorial Scales. AB - BACKGROUND: Dyspnea or perceived exertion during exercise is most commonly measured using Borg or visual analog scales, created for use in adults. In contrast, pictorial scales have been promoted for children due to skepticism concerning applicability of the said scales in pediatrics. We sought to validate our newly created, pictorial Dalhousie Dyspnea and Perceived Exertion Scales in adult populations and compare ratings with the Borg scale. METHODS: Dyspnea and perceived exertion ratings obtained with both modified Borg CR-10 and Dalhousie scales during maximal cycle exercise were compared in 24 healthy adults and 17 with various pulmonary disorders. Scale ratings for perceived exertion were plotted against work while ratings for dyspnea were plotted against ventilation using previously developed alternative models to simple power law. Goodness of fit was determined by lowest root-mean-square error or by corrected Akaike information criterion. RESULTS: Pictorial ratings of dyspnea and perceived exertion measured by both scale ratings rose as expected with increasing exercise intensity, and individual trajectories obtained by either scale were virtually superimposable in 90 % of subjects. In general, the lowest root-mean-square error or corrected Akaike information criterion was found with models which incorporated a time delay, defined as the fraction of maximum work or ventilation at which point a clear increase in ratings above resting level was reported. CONCLUSIONS: The Dalhousie Dyspnea and Exertion Scales offer an equally good alternative to the Borg scale for measuring dyspnea and perceived exertion in adults. PMID- 26770886 TI - Metallothionein's role in PCB126 induced hepatotoxicity and hepatic micronutrient disruption. AB - Polychlorinated biphenyls (PCBs), industrial chemicals and persistent environmental pollutants, are found in rural and urban settings. Rodent studies have shown that exposure to PCB126, a dioxin-like PCB, causes a significant disruption of hepatic micronutrient homeostasis and an increase in metallothionein (MT), an antioxidant protein and metal carrier. A MT knockout mouse strain was used to assess metallothionein's role in micronutrient disruption and overall hepatotoxicity. Twenty four 129S male mice (12 wild type (WT) and 12 MT knockout (MTKO)) were placed on a purified diet (AIN-93G) for 3 weeks to achieve hepatic metal equilibrium. Mice were then given a single IP injection, of either vehicle or 150 umol/kg PCB126 in vehicle. The animals were sacrificed 2 weeks later and organs processed for analysis. Liver histology, hepatic lipids, gene expression, micronutrient and ROS status were investigated. Liver weights, liver lipids, ROS, and hepatocyte vacuolation were increased with PCB126 exposure along with AhR responsive genes. The MTKO animals had more severe histological changes in the liver and elevated liver lipids than their wild type counterparts. Hepatic and renal metals levels (Cu, Zn, Se and Mn) were mostly reduced by PCB126 treatment. Renal micronutrients were more affected by PCB126 treatment in the MTKO animals. This research suggests that MT may not be the sole/primary cause of the metal disruption caused by PCB126 exposure in mice, but may provide protection against overall hepatotoxicity. PMID- 26770888 TI - Increase in Blood Glutathione and Erythrocyte Proteins Related to Glutathione Generation, Reduction and Utilization in African-American Old Women with Diabetes. AB - Data from this report demonstrate that the plasma and erythrocyte levels of total glutathione (TGSH) are significantly lower in nondiabetic old women than in their young counterparts, and significantly higher in diabetic patients than in age matched nondiabetic controls. The ratio of reduced glutathione (GSH) to oxidized glutathione (GSSG) declines with age and diabetes, and shows an order as follows: nondiabetic young > nondiabetic old > diabetic old women. In addition, advanced glycation end-products (AGEs) accumulates in RBCs obtained from diabetic patients but not in those from young and old nondiabetic controls. The erythrocyte levels of glutamate cysteine ligase catalytic subunit (GCLC), glucose-6-phosphate dehydrogenase (G6PD), glutathione reductase (GR), glutathione peroxidase-1 (GPx1), glutathione S-transferase-rho1 (GST-rho1) and glyoxalase I (Glo1) are comparable in nondiabetic young and old women, but significantly higher in diabetic patients than in age-matched nondiabetic controls. Oxidative stress has been suggested to upregulate the expression of these proteins. It is possible that increase in oxidative stress in diabetes, reflected by reduced GSH/GSSG ratio and accumulation of AGEs, upregulates the expression of proteins involved in glutathione synthesis, reduction and utilization in erythrocyte precursor cells, and that overexpression of GCLC is, at least partially, responsible for the increased TGSH in diabetes. PMID- 26770887 TI - Pbx4 is Required for the Temporal Onset of Zebrafish Myocardial Differentiation. AB - Proper control of the temporal onset of cellular differentiation is critical for regulating cell lineage decisions and morphogenesis during development. Pbx homeodomain transcription factors have emerged as important regulators of cellular differentiation. We previously showed, by using antisense morpholino knockdown, that Pbx factors are needed for the timely activation of myocardial differentiation in zebrafish. In order to gain further insight into the roles of Pbx factors in heart development, we show here that zebrafish pbx4 mutant embryos exhibit delayed onset of myocardial differentiation, such as delayed activation of tnnt2a expression in early cardiomyocytes in the anterior lateral plate mesoderm. We also observe delayed myocardial morphogenesis and dysmorphic patterning of the ventricle and atrium, consistent with our previous Pbx knock down studies. In addition, we find that pbx4 mutant larvae have aberrant outflow tracts and defective expression of the proepicardial marker tbx18. Finally, we present evidence for Pbx expression in cardiomyocyte precursors as well as heterogeneous Pbx expression among the pan-cytokeratin-expressing proepicardial cells near the developing ventricle. In summary, our data show that Pbx4 is required for the proper temporal activation of myocardial differentiation and establish a basis for studying additional roles of Pbx factors in heart development. PMID- 26770889 TI - Benefits of Physical Exercise for Individuals with Fragile X Syndrome in Humans. AB - Fragile X syndrome (FXS) is the most common known genetic cause of autism spectrum disorder, and is also linked to other neurologic and psychiatric disorders. The purpose of this review article is to examine a variety of recent studies on the correlation between physical exercise and autistic behavior in individuals with fragile X syndrome. Additionally, we discuss promising approaches for further investigation of the benefits of physical exercise for autism spectrum disorder (ASD) patients. A systematic search of the PubMed digital library database for pertinent articles published from 1995 to 2011 was conducted. Individuals with ASD who experience exercise tend to exhibit improvement in physical function. In addition, exercise promotes neurotrophic factors and boosts the growth of new brain cells. The collected review articles describe how physical exercise has particular effects on stereotypic behavior and cognition among ASD patients. Finally, physical exercise may benefit patients with autism spectrum disorder through the improvement of muscular strength for increased physical capability. PMID- 26770890 TI - Perception of Exercise Lifestyle as a Valid Tool for Prevention and Treatment of Depression in Rural Communities. AB - BACKGROUND: This study examines perception of exercise lifestyle prescription as a valid treatment for depression among rural patients at a primary care clinic in Texas. METHODS: The researchers created a depression and exercise survey completed by 104 patients ages 18 and up living in central, economically disadvantaged rural Texas. Logistic regression was used to analyze data obtained. RESULTS: There was a significant difference (p = 0.01) in perception of exercise as a valid treatment for depression as a function of demographic variables, however not as a function of exercise duration (p = 0.12) in the rural primary care clinic's patients. Even though it was not a statistically significant finding, there was a positive correlation found between the amount of exercise engaged in per day and the likelihood to have a positive perception of exercise prescription as a tool in depression prevention and treatment. CONCLUSION: Participants between ages 40 to 59 years old, female, and of Hispanic ethnicity independently are most likely to perceive exercise lifestyle as a valid treatment for depression. This is the first study to look specifically at patient perception of exercise as a valid treatment tool for depression not only in rural areas, but also in the nation. Findings from this pilot study may help healthcare service providers learn how to best incorporate exercise prescription into depression prevention and treatment in rural areas, leading to reducing depression epidemics. PMID- 26770891 TI - A Review of 21st Century Utility of a Biopsychosocial Model in United States Medical School Education. AB - BACKGROUND: Current medical practice is grounded in a biomedical model that fails to effectively address multifaceted lifestyle and morbidogenic environmental components that are the root causes of contemporary chronic diseases. Utilizing the biopsychosocial (BPS) model in medical school training may produce competent healthcare providers to meet the challenge of rising chronic illnesses that are a result of these factors. This study explored the current trend of research on the utility of the BPS model in medical education and examined medical school curricula that have explicitly adopted the BPS model. METHODS: A systematic review of peer-reviewed literature was conducted on the BPS model and medical education since the 1970s using multiple databases. Descriptive analysis was used to illustrate findings regarding the trends of the BPS model in medical education and its utility in specific medical schools in the United States. RESULTS: Major findings illustrated a growing trend in research on the BPS model in medical education since the 1970s with literature in this area most visible since 2000. The same trend was established for the incorporation of psychosocial or behavioral and social science components in medical education. From our peer reviewed literature search, only 5 medical schools featured utility of the BPS model in their curricula utilizing variable educational processes. CONCLUSION: Although literature regarding the BPS model in medical education is growing, the explicit utility of the BPS model in medical school is limited. Our findings can stimulate educational processes and research endeavors to advance medical education and medical practice to ensure that future doctors can meet the challenge of rising lifestyle and environmental associated illnesses. PMID- 26770892 TI - Obesity and Hypertension among School-going Adolescents in Peru. AB - BACKGROUND: Adolescent obesity and hypertension are global public health issues. The burden of adolescent obesity and hypertension in Peru is unclear. The aim of this study was to determine the prevalence of obesity and hypertension and their relationship among school-attending adolescents and to assess the need for health promoting school programs in the study area. METHODS: A cross-sectional school based survey was conducted in a randomly selected sample of 952 secondary school adolescents from 11 schools in Lima or Callao, Peru, in 2014. Weight, height, and blood pressure (BP) were measured and categorized. Obesity was defined as >= 95(th) percentile in body mass index (BMI) for age and sex. Hypertension was defined as average systolic blood pressure and/or diastolic blood pressure >=95(th) percentile in BP for sex, age, and height. Chi-square test and univariate logistic regressions were used at a 5% significance level to determine the relationship between BMI and BP category. RESULTS: The mean age of subjects was 14.6 years; 46.4% were boys and 53.6% were girls. The prevalence of overweight and obesity was 20.2% and 9.5% overall, 17.4% and 11.1% for boys, and 22.5% and 8.0% for girls, respectively. The prevalence of hypertension was 26.7% overall, 34.8% for boys, and 19.6% for girls. In both sexes, BMI was strongly associated with BP (p < 0.01). CONCLUSION: The prevalence of obesity and hypertension observed in the study area is relatively high. Overweight and obesity are strongly associated with BP status among adolescents. Health promoting school programs may reduce the burdens of obesity and hypertension among school-going adolescents. PMID- 26770893 TI - Analysis of Socio-demographics, Self-rated Health, Social Capital, and Happiness in a Medium-Sized Healthy City, Republic of Korea. AB - BACKGROUND: This study explores the relationships between social capital, self rated health, and happiness and suggests ways to improve the happiness level of a community. METHODS: The survey was conducted with 445 people using stratified random sampling in a medium-sized city in Korea. Collected information included socio-demographic characteristics, social capital, self-rated health, and happiness. RESULTS: Among the demographic characteristics, age had a statistically significant association with happiness level. People in their 40s (OR = 0.33, 95% CI = 0.13-0.88) and 50s (OR = 0.19, 95% CI = 0.06-0.57) were less happy than people of other ages. Married people (OR = 4.58, CI = 1.99-10.53) were more likely to have a high happiness level compared to unmarried people. Cognitive social capital (OR = 1.34, CI = 1.19-1.51) and self-rated health (OR = 2.22, CI = 1.59-3.09) were positively associated with happiness. CONCLUSION: The results suggest that social capital and level of health are determinants of subjective happiness. Public policies and programs for improving social capital are needed to support happiness among community residents. PMID- 26770894 TI - Effects of a Social Welfare Program for Health Promotion on Cardiovascular Risk Factors. AB - BACKGROUND: Socioeconomic status is closely associated with an individual's health status. However, there are few studies examining the role of exercise training as part of a community-based social welfare program in socially vulnerable groups. Given this, our aim was to measure whether long-term exercise training as a social welfare program affects the prevalence of depressive symptoms, metabolic syndrome and peripheral blood vessel condition among participants with low household income. METHODS: Twenty-nine adults and twenty two older adults were recruited into this study with non-radomized, pre/post-test design. The subjects underwent a combined training consisting of aerobic and muscle strengthening exercises for 6 months or more. Depressive symptoms were evaluated using the Beck Depression Inventory and the Korean version of Geriatric Depression Scale. Metabolic syndrome was defined according to the International Diabetes Federation criteria. Blood vessel condition was assessed using non invasive accelerated photoplethysmograph. RESULTS: Mean skeletal muscle mass increased after exercise-training, but body mass index and percent body fat were unchanged. Overall age-specific physical fitness and performance increased markedly among both adult and elderly subjects, respectively. The proportion of depressive symptoms was significantly reduced by 33% after exercise-training among all participants. The prevalence of individuals having metabolic syndrome was significantly reduced by 19.6% and the number of individual components of metabolic syndrome decreased after the exercise intervention. Among components of metabolic syndrome, waist circumference, HDL cholesterol and systolic blood pressure significantly improved. In addition, the proportions of moderate and severe arteriosclerotic progression significantly decreased. CONCLUSION: Long term exercise-training as a social welfare program is beneficial for health promotion and effective in simultaneously improving psychological and physiological health status in a low income population. This suggests that the development and expansion of an exercise intervention as a health-promoting welfare program are needed to address the inequality of exercise participation among socially vulnerable groups. PMID- 26770895 TI - Early Life Factors Influencing the Risk of Obesity. AB - The obesity epidemic is a worldwide problem. Factors predisposing to obesity include genetics, race, socioeconomic conditions, birth by cesarean section, and perinatal antibiotic use. High protein (HP) content in infant formulas has been identified as a potential culprit predisposing to rapid weight gain in the first few months of life and leading to later obesity. In a large multicountry study the effects of lower protein (LP) formula (1.77 and 2.2 g protein/100 kcal, before and after the 5th month, respectively) were compared to those of higher protein (2.9 and 4.4 g protein/100 kcal, respectively). Results indicated that at 24 months, the weight-for-length z score of infants in the LP formula group was 0.20 (0.06, 0.34) lower than that of the HP group and was similar to that of the breastfed reference group. The authors concluded that a HP content of infant formula is associated with higher weight in the first 2 years of life but has no effect on length. LP intake in infancy might diminish the later risk of overweight and obesity. At 6 years of age HP children had a significantly higher body mass index (by 0.51; 95% confidence interval [CI], 0.13-0.90; p=0.009) and a 2.43 (95% CI, 1.12-5.27; p=0.024) fold greater risk of becoming obese than those who received the LP. In conclusion, several factors may influence development of metabolic syndrome and obesity. Breastfeeding should always be encouraged. An overall reduction of protein intake in formula non breastfed infants seems to be an additional way to prevent obesity. PMID- 26770896 TI - Cyclic Vomiting Syndrome: A Functional Disorder. AB - Cyclic vomiting syndrome (CVS) is a functional disorder characterized by stereotypical episodes of intense vomiting separated by weeks to months. Although it can occur at any age, the most common age at presentation is 3-7 years. There is no gender predominance. The precise pathophysiology of CVS is not known but a strong association with migraine headaches, in the patient as well as the mother indicates that it may represent a mitochondriopathy. Studies have also suggested the role of an underlying autonomic neuropathy involving the sympathetic nervous system in its pathogenesis. CVS has known triggers in many individuals and avoiding these triggers can help prevent the onset of the episodes. It typically presents in four phases: a prodrome, vomiting phase, recovery phase and an asymptomatic phase until the next episode. Complications such as dehydration and hematemesis from Mallory Wise tear of the esophageal mucosa may occur in more severe cases. Blood and urine tests and abdominal imaging may be indicated depending upon the severity of symptoms. Brain magnetic resonance imaging and upper gastrointestinal endoscopy may also be indicated in certain circumstances. Management of an episode after it has started ('abortive treatment') includes keeping the patient in a dark and quiet room, intravenous hydration, ondansetron, sumatriptan, clonidine, and benzodiazepines. Prophylactic treatment includes cyproheptadine, propranolol and amitriptyline. No mortality has been reported as a direct result of CVS and many children outgrow it over time. A subset may develop other functional disorders like irritable bowel syndrome and migraine headaches. PMID- 26770897 TI - Maladaptive Behavior and Gastrointestinal Disorders in Children with Autism Spectrum Disorder. AB - PURPOSE: Various gastrointestinal factors may contribute to maladaptive behavior in children with autism spectrum disorders (ASD). To determine the association between maladaptive behavior in children with ASD and gastrointestinal symptoms such as severity, intestinal microbiota, inflammation, enterocyte damage, permeability and absorption of opioid peptides. METHODS: This observational cross sectional study compared children with ASD to healthy controls, aged 2-10 years. Maladaptive behavior was classified using the Approach Withdrawal Problems Composite subtest of the Pervasive Developmental Disorder Behavior Inventory. Dependent variables were gastrointestinal symptom severity index, fecal calprotectin, urinary D-lactate, urinary lactulose/mannitol excretion, urinary intestinal fatty acids binding protein (I-FABP) and urinary opioid peptide excretion. RESULTS: We did not find a significant difference between children with ASD with severe or mild maladaptive behavior and control subjects for gastrointestinal symptoms, fecal calprotectin, urinary D-lactate, and lactulose/mannitol ratio. Urinary opioid peptide excretion was absent in all children. Children with ASD with severe maladaptive behavior showed significantly higher urinary I-FABP levels compared to those with mild maladaptive behavior (p=0.019) and controls (p=0.015). CONCLUSION: In our series, maladaptive behavior in ASD children was not associated with gastrointestinal symptoms, intestinal inflammation (no difference in calprotectin), microbiota (no difference in urinary D-lactate) and intestinal permeability (no difference in lactulose/manitol ratio). ASD children with severe maladaptive behavior have significantly more enterocyte damage (increased urinary I-FABP) than ASD children with mild maladaptive behavior and normal children. PMID- 26770898 TI - Esophageal Bolus Transit in Newborns with Gastroesophageal Reflux Disease Symptoms: A Multichannel Intraluminal Impedance Study. AB - PURPOSE: The aim of this study was to evaluate bolus transit during esophageal swallow (ES) and gastroesophageal reflux (GER) events and to investigate the relationship between the characteristics of ES and GER events in a population of term and preterm newborns with symptoms of gastroesophageal reflux disease (GERD). METHODS: The study population consisted of term and preterm newborns referred to combined multichannel intraluminal impedance (MII) and pH monitoring for GERD symptoms. The frequency and characteristics of ES and GER events were assessed by two independent investigators. Statistical significance was set at p<0.05. RESULTS: Fifty-four newborns (23 preterm) were included in the analyses. Median bolus head advancing time corrected for esophageal length (BHATc) was shorter during mealtime than during the postprandial period (median, interquartile range): 0.20 (0.15-0.29) s/cm vs. 0.47 (0.39-0.64) s/cm, p<0.001. Median bolus presence time (BPT) was prolonged during mealtime: 4.71(3.49-6.27) s vs. 2.66 (1.82-3.73) s, p<0.001. Higher BHATc (p=0.03) and prolonged BPT (p<0.001) were observed in preterm newborns during the postprandial period. A significant positive correlation between BHATc and bolus clearance time was also observed (rho=0.33, p=0.016). CONCLUSION: The analysis of ES and GER events at the same time by MII provides useful information to better understand the physiopathology of GERD. In particular, the analysis of BHATc during the postprandial period could help clinicians identify newborns with prolonged esophageal clearance time due to impaired esophageal motility, which could allow for more accurate recommendations regarding further tests and treatment. PMID- 26770899 TI - Association between Gastric pH and Helicobacter pylori Infection in Children. AB - PURPOSE: To assess gastric pH and its relationship with urease-test positivity and histological findings in children with Helicobacter pylori infection. METHODS: Fasting gastric juices and endoscopic antral biopsy specimens were collected from 562 children and subjected to the urease test and histopathological examination. The subjects were divided into 3 age groups: 0-4, 5-9, and 10-15 years. The histopathological grade was assessed using the Updated Sydney System, while the gastric juice pH was determined using a pH meter. RESULTS: The median gastric juice pH did not differ significantly among the age groups (p=0.655). The proportion of individuals with gastric pH >4.0 was 1.3% in the 0-4 years group, 6.1% in the 5-9 years group, and 8.2% in 10-15 years (p=0.101). The proportions of moderate and severe chronic gastritis, active gastritis, and H. pylori infiltration increased with age (p<0.005). Urease-test positivity was higher in children with hypochlorhydria (77.8%) than in those with normal gastric pH (31.7%) (p<0.001). Chronic and active gastritis were more severe in the former than the latter (p<0.001), but the degree of H. pylori infiltration did not differ (20.9% vs. 38.9%; p=0.186). CONCLUSION: Gastric pH while fasting is normal in most children regardless of age. Urease-test positivity may be related to hypochlorhydria in children, and hypochlorhydria is in turn related to H. pylori infection. PMID- 26770900 TI - Clinical Manifestations and Treatment Outcomes of Eosinophilic Gastroenteritis in Children. AB - PURPOSE: The aim of the present study was to investigate the clinical features and outcome of eosinophilic gastroenteritis (EGE) in children. METHODS: Our study enrolled 24 children who were diagnosed with EGE from 1993 to 2014 at the Department of Pediatrics, Seoul National University Children's Hospital. The patients' clinical manifestations, treatments, and outcomes were reviewed from the medical records. RESULTS: The mean age at diagnosis was 5.3 years. Most patients had gastrointestinal symptoms including diarrhea (54.2%) and abdominal pain (45.8%). Peripheral eosinophilia was present in 91.7% of the patients. Thirteen patients (54.2%) showed anemia, and 15 patients (62.5%) had hypoalbuminemia. EGE was classified as mucosal, subserosal, or muscular in 75.0%, 20.8%, and 4.2% of cases, respectively. Three patients showed gastroduodenal ulcers upon endoscopic analysis. A history of allergy was reported in 13 patients, including atopic dermatitis, allergic rhinitis, and asthma. Five patients (20.8%) improved with food restrictions. Among the 19 patients treated with steroids, 11 (57.9%) discontinued steroid treatment without subsequent relapse, 4 (21.1%) relapsed after ceasing steroid treatment, and 4 (21.1%) showed no response to steroids. Two patients who were resistant to steroids underwent therapeutic surgery. The presence of gastroduodenal ulcers was significantly associated with relapse and steroid resistance. CONCLUSION: A high suspicion of EGE is warranted when children have nonspecific gastrointestinal symptoms and peripheral eosinophilia. Most patients improved with food restrictions or steroid treatment, although one-third of patients showed a relapse or steroid resistance. PMID- 26770901 TI - The Importance of Esophageal and Gastric Diseases as Causes of Chest Pain. AB - PURPOSE: Pediatric chest pain is considered to be idiopathic or caused by benign diseases. This study was to find out how much upper gastrointestinal (UGI) diseases are major causes of chest pain in pediatric patients. METHODS: The records of 75 children (42 boys and 33 girls, aged 3-17 years old) who have presented with mainly chest pain from January 1995 to March 2015 were retrospectively reviewed. Chest X-ray and electrocardiography (ECG) were performed in all aptients. Further cardiologic and gastrointestinal (GI) evaluations were performed in indicated patients. RESULTS: Chest pain was most common in the children of 6 and 9 to 14 years old. Esopha-gogastric diseases were unexpectedly the most common direct causes of the chest pain, the next are idiopathic, cardiac diseases, chest trauma, respiratory disease, and psychosomatic disease. Even though 21 showed abnormal ECG findings and 7 showed abnormalities on echocardiography, cardiac diseases were determined to be the direct causes only in 9. UGI endoscopy was performed in 57 cases, and esophago gastric diseases which thereafter were thought to be causative diseases were 48 cases. The mean age of the children with esophago-gastric diseases were different with marginal significance from that of the other children with chest pain not related with esophago-gastric diseases. All the 48 children diagnosed with treated with GI medicines based on the diagnosis, and 37 cases (77.1%) subsequently showed clinical improvement. CONCLUSION: Diagnostic approaches to find out esophageal and gastric diseases in children with chest pain are important as well as cardiac and respiratory investigations. PMID- 26770902 TI - Primary Sclerosing Cholangitis with Inflammatory Bowel Disease in Korean Children. AB - PURPOSE: Primary sclerosing cholangitis (PSC) is a rare condition that can be associated with inflammatory bowel disease (IBD). The aim of this study was to evaluate PSC and its association with IBD in children. METHODS: We retrospectively enrolled 13 pediatric patients (<18 years) with PSC treated at Asan Medical Center between June 1989 and December 2013. Clinical findings and long-term outcomes were investigated. During the same period, the incidence of PSC among IBD patients was evaluated among 600 Crohn disease (CD) and 210 ulcerative colitis (UC) patients. RESULTS: All 13 study patients diagnosed with PSC also presented with IBD. Eleven boys and two girls with a median age of 15.0 years old (9.0-17.8 years) were included. The cumulative incidence of PSC for UC was 5.7% (12 of 210) and 0.2% for CD (1 of 600), respectively. PSC occurred during follow-up for IBD for five patients (38.5%) whereas, IBD developed during follow-up for PSC for two patients (15.4%), and was diagnosed during the initial work-up for PSC for 6 patients (46.2%). For the 77.3 month median follow-up period, 9/13 patients (69.2%), neither the clinical symptoms nor blood test results worsened. Two cases (15.4%) developed liver cirrhosis and underwent liver transplantation. Among 13 PSC patients with IBD, two (15.4%) developed colorectal cancer, and no one developed cholangiocarcinoma. CONCLUSION: All patients with PSC in this study had associated IBD. The incidence of PSC was not rare compared to reports in adults. PSC should be considered during the management of IBD and vice versa in children. PMID- 26770903 TI - A Case of Post-Traumatic Pseudocyst in the Spleen Successfully Treated with Alcohol Sclerotherapy. AB - This report details a case of post-traumatic pseudocyst in the spleen that was successfully treated with sclerotherapy using ethanol. A sixteen-year-old boy visited our hospital for a follow-up examination of a splenic cyst. He had experienced blunt trauma to the abdomen three years prior to presentation. An abdominal computed tomography scan revealed a large cyst of the lower pole of the spleen. The cyst was 6.8*9.5*7.0 cm and conservative management was tried. A follow-up ultrasonographic examination three years later revealed that the size of the cyst was unchanged and another treatment was needed to prevent complications. One session of sclerosis with ethanol (90 mL of 99% ethanol) percutaneously was applied to the cyst. A follow-up after four months revealed that the cyst had completely resolved. PMID- 26770904 TI - Heterotopic Pancreas Presented as Duodenal Tumor with Obstruction. AB - Heterotopic pancreas (HP) is defined as pancreatic tissue lacking anatomic and vascular continuity with the main body of the pancreas. Most are asymptomatic, but can cause ulcer, bleeding, intussusception, and mechanical obstruction. Herein, we presented one case of HP presented as duodenal tumor causing duodenal obstruction. A 7-year-old girl visited the emergency room for abdominal pain with vomiting for 24 hours. Computed tomography and upper gastrointestinal series revealed a polypoid mass with short stalk in the 2nd portion of duodenum. We attempted an endoscopic removal. However, the lumen was nearly obstructed by the mass and the stalk was too broad and hard to excise. The mass was surgically removed via duodenotomy. It was confirmed as a HP with ductal and acini components (type 2 by Heinrich classification). Postoperatively, the patient has been well without any complication and recurrence. PMID- 26770905 TI - Mesalizine-Induced Acute Pancreatitis and Interstitial Pneumonitis in a Patient with Ulcerative Colitis. AB - Ulcerative colitis (UC) is a chronic idiopathic inflammatory bowel disease. Mesalizine for the first-line therapy of UC has adverse effects include pancreatitis, pneumonia and pericarditis. UC complicated by two coexisting conditions, however, is very rare. Moreover, drug-related pulmonary toxicity is particularly rare. An 11-year-old male patient was hospitalized for recurring upper abdominal pain after meals with vomiting, hematochezia and exertional dyspnea developing at 2 weeks of mesalizine therapy for UC. The serum level of lipase was elevated. Chest X-ray and thorax computed tomography showed interstitial pneumonitis. Mesalizine was discontinued and steroid therapy was initiated. Five days after admission, symptoms were resolved and mesalizine was resumed after a drop in amylase and lipase level. Symptoms returned the following day, however, accompanied by increased the serum levels of amylase and lipase. Mesalizine was discontinued again and recurring symptoms rapidly improved. PMID- 26770906 TI - Efficacy and safety evaluation of pentoxifylline associated with other antioxidants in medical treatment of Peyronie's disease: a case-control study. AB - Peyronie's disease (PD) is a chronic disorder involving the tunica albuginea surrounding the corpora cavernosa of the penis. A conservative treatment is indicated in the first stage of disease. The aim of this study was to assess the therapeutic impact and possible side effects of treatment with pentoxifylline (PTX) in combination with other antioxidants in 307 patients with early-stage PD. Patients were subdivided into three groups: A, B, and C. Both groups, A and B, comprising of 206 patients, underwent treatment, whereas Group C was the control group (n=101). Treatment lasted 6 months and included the following: Group A: PTX 400 mg twice a day + propolis 600 mg/d + blueberry 160 mg/d + vitamin E 600 mg/d + diclofenac 4% gel twice/a day + PTX 100 mg via perilesional penile injection/every other week (12 injections in all); Group B: the same treatment as Group A except for the penile PTX injections. After the 6-month treatment course, we obtained the following results: actual mean decrease in plaque volume -46.9% and -24.8% in Group A and B, respectively (P<0.0001); mean curvature reduction 10.1 degrees and -4.8 degrees , respectively (P,0.0001); resolution of pain in 67.6% and 67.2% of cases, respectively (P=0.961); recovery of normal penile rigidity in 56.09% and 23.5% of cases, respectively (P=0.005). After 6 months, progression of disease was observed in all patients belonging to Group C: plaque volume +123.3%; curvature +15.7 degrees ; no recovery of penile rigidity. The statistically significant results of our study show that multimodal treatment with PTX in association with other antioxidants and topical diclofenac is efficacious in treating early-stage PD. Furthermore, treatment proved to be more effective when PTX was administered both orally and by penile injection. No serious adverse effects occurred. PMID- 26770907 TI - A Rare Consequence of Chronic Graft Versus Host Disease - Peyronie's Disease. AB - Chronic graft versus host disease (GvHD) after allogeneic stem cell transplantation (SCT) may involve any organ system, but male genital involvement is rare. Peyronie's Disease (PD) is an acquired, localized fibrotic disorder of the tunica albuginea, which leads to penile deformity, pain, and eventually to erectile dysfunction. We report the case of a 52 year old African American male with Acute Myeloid Leukemia who underwent human leucocyte antigen (HLA) matched sibling allogeneic peripheral blood SCT. His post transplant course was complicated by development of acute and multi-organ chronic GvHD requiring prolonged immunosuppression. He developed progressive dorsal curvature of the penis with erections within 1 year of ultra low dose interleukin -2 (IL2) treatment for his chronic GvHD but concealed symptoms for several months. Color Doppler Duplex ultrasound evaluation of the erect penis revealed a 75-degree curvature and appropriate hemodynamic response to prostaglandin injection. He underwent successful incision and grafting of the penile plaque. There is no significant residual curvature and is now able to engage in intercourse. A strong temporal association between GVHD (or its treatment) and Peyronie's is documented here. Awareness of the possible link between PD and chronic GVHD is required in this era of rapid growth in numbers of SCT. PMID- 26770908 TI - Hesperidin Inhibits Vascular Formation by Blocking the AKT/mTOR Signaling Pathways. AB - Hesperidin has been shown to possess a potential inhibitory effect on vascular formation in endothelial cells. However, the fundamental mechanism for the anti angiogenic activity of hesperidin is not fully understood. In the present study, we evaluated whether hesperidin has anti-angiogenic effects in mouse embryonic stem cell (mES)-derived endothelial-like cells, and human umbilical vascular endothelial cells (HUVECs), and evaluated their mechanism via the AKT/mammalian target of rapamycin (mTOR) signaling pathway. The endothelial cells were treated with several doses of hesperidin (12.5, 25, 50, and 100 MUM) for 24 h. Cell viability and vascular formation were analyzed using the 3-(4,5-dimethylthiazol-2 yl)-2,5-diphenyltetrazolium bromide and tube formation assay, respectively. Alteration of the AKT/mTOR signaling in vascular formation was analyzed by western blot. In addition, a mouse aortic ring assay was used to determine the effect of hesperidin on vascular formation. There were no differences between the viability of mES-derived endothelial-like cells and HUVECs after hesperidin treatment. However, hesperidin significantly inhibited cell migration and tube formation of HUVECs (P<0.05) and suppressed sprouting of microvessels in the mouse aortic ring assay. Moreover, hesperidin suppressed the expression of AKT and mTOR in HUVECs. Taken together, these findings suggest that hesperidin inhibits vascular formation by blocking the AKT/mTOR signaling pathways. PMID- 26770909 TI - Microalgal Oil Supplementation Has an Anti-Obesity Effect in C57BL/6J Mice Fed a High Fat Diet. AB - This study investigated the impact of microalgal oil (MO) on body weight management in C57BL/6J mice. Obesity was induced for 8 weeks and animals were orally supplemented with the following for 8 additional weeks: beef tallow (BT), corn oil, fish oil (FO), microalgal oil (MO), or none, as a high fat diet control group (HD). A normal control group was fed with a normal diet. After completing the experiment, the FO and MO groups showed significant decreases in body weight gain, epididymal fat pad weights, serum triglycerides, and total cholesterol levels compared to the HD and BT groups. A lower mRNA expression level of lipid anabolic gene and higher levels of lipid catabolic genes were observed in both FO and MO groups. Serum insulin and leptin concentrations were lower in the MO group. These results indicated that microalgal oil has an anti-obesity effect that can combat high fat diet-induced obesity in mice. PMID- 26770910 TI - The Effect of L-Ornithine on the Phosphorylation of mTORC1 Downstream Targets in Rat Liver. AB - A non-protein amino acid, L-ornithine (Orn), has been shown to stimulate the urea cycle and tissue protein synthesis in the liver. The purpose of the current study was to assess whether Orn affects the mammalian target of rapamycin (mTOR) complex 1 (mTORC1) pathway, which is involved in protein synthesis. Primary cultured cells isolated from Wistar rat liver were incubated in an amino acid free medium, followed by addition of Orn for 3 h. The cell lysate was subjected to immunoblotting to evaluate the phosphorylation of downstream targets of mTORC1, including p70S6K, S6, and 4EBP1. To assess the involvement of mTORC1 for the effect of Orn, the cells were pretreated with the mTOR inhibitor rapamycin before the addition of Orn and the cell lysate was subjected to immunoblotting. We next examined whether the effects of Orn were exerted in vivo. Orn was orally administered to 18 h food-deprived rats, the blood and the livers were collected at 1 and 3 h after administration for immunoblotting. Orn treatment for primary cultured cells for 3 h enhanced the phosphorylation of p70S6K, S6, and 4EBP1. In addition, rapamycin blocked the effects of Orn completely (p70S6K and S6) or partially (4EBP1). The oral administration of Orn to the rat also augmented the phosphorylation of mTORC1 downstream targets notably in S6 at 1 h. Our findings demonstrate that Orn has the potential to induce the phosphorylation of downstream targets of mTORC1 in the rat liver. This may be mediated by the augmentation of mTORC1 activity. PMID- 26770911 TI - Hot Water Extract of Leather Carp (Cyprinus carpio nudus) Improves Exercise Performance in Mice. AB - The hot water extract of leather carp (Cyprinus carpio nudus) has been used as a nourishing tonic soup and as an aid for recovery from physical fatigue. In this study, we investigated the effect of leather carp extract on exercise performance in mice. Swimming endurance and forelimb grip strength were assessed following oral administration of the extract (once per day for 7 days) at a dose of 0.5 mg/10 MUL/g body weight. After 7 days, mice given the leather carp extract had significantly greater swimming endurance [105+/-18 s (P<0.05); 52% longer than day 0] and forelimb grip strength [1.18+/-0.05 Newton (P<0.01); 17% greater than day 0]. The extract increased muscle mass, but had little effect on body weight. Following the swimming exercise, blood glucose, glutathione peroxidase, and superoxide dismutase levels in extract-fed mice were significantly higher (145%, 131%, and 106%, respectively) than in the saline control group. Blood levels of high-density lipoprotein cholesterol were also significantly increased (128%) in mice given the extract compared to the controls. These results suggest that leather carp extract can improve physical exercise performance and prevent oxidative stress caused by exhaustive workouts. PMID- 26770912 TI - High Hydrostatic Pressure Extract of Red Ginseng Attenuates Inflammation in Rats with High-fat Diet Induced Obesity. AB - Chronic low-grade inflammation is associated with obesity. This study investigated effect of high hydrostatic pressure extract of red ginseng (HRG) on inflammation in rats with high-fat (HF) diet induced obesity. Male, Sprague Dawley rats (80~110 g) were randomly divided into two groups, and fed a 45% HF diet (HF) and a 45% HF diet containing 1.5% HRG (HF+HRG) for 14 weeks. At the end of the experiment, the serum leptin level was reduced by the HRG supplementation. The mRNA expression of genes related to adipogenesis including peroxisome proliferator-activated receptor-gamma and adipocyte protein 2 was down-regulated in the white adipose tissue (WAT). The mRNA levels of major inflammatory cytokines such as tumor necrosis factor-alpha, monocyte chemoattractant protein 1, and interleukin-6 were remarkably down-regulated by the HRG in WAT. These results suggest that HRG might be beneficial in ameliorating the inflammation associated health complications by suppressing adipogenic and pro-inflammatory gene expression. PMID- 26770913 TI - Effects of Rubus coreanus-Cheonggukjang on Bone Mineral Density and Bone Mineral Content in Growing Rats. AB - The purpose of the present study was to investigate the bone-conserving effects of Rubus coreanus-Cheonggukjang (RC-CGJ) supplemented with more intensified phytochemicals compared to general Cheonggukjang (CGJ) in growing rats. Eighteen rats were divided into 3 treatment groups (Control, CGJ, and RC-CGJ) and were given experimental diets for 9 weeks. All of the rats in this study were fed a AIN-93G-based diet. Both CGJ groups were fed with 33.1% CGJ and RC-CGJ powder, respectively. The results of this study indicate that weight gain, mean food intake, and food efficiency ratio were not significantly different by the experimental diets among all groups. Spine bone mineral density (BMD) and femur BMD were not significantly different by the experimental diets. Spine bone mineral content (BMC) was significantly higher in the RC-CGJ and CGJ groups than in the control group, regardless of CGJ type. The femur BMC of the CGJ supplemented group was significantly higher compared with the control group and the RC-CGJ group. Compared with the control group, spine BMD and femur BMD per weight were markedly increased in the RC-CGJ and CGJ group regardless of CGJ type. Also, spine BMC per weight was significantly higher in the RC-CGJ group than in the CGJ group. However, femur BMC per weight was significantly higher in the CGJ group than in the RC-CGJ group. It can be concluded that RC-CGJ and CGJ supplemented diets have more beneficial effects on spine and femur peak bone mass in growing rats. PMID- 26770914 TI - Mitigating Effect of Resveratrol on the Structural Changes of Mice Liver and Kidney Induced by Cadmium; A Stereological Study. AB - Exposure to cadmium (Cd) has harmful effects on the liver and kidney. Resveratrol (RES) is an herbal substance that functions as a protective mediator. This study aimed to investigate the effects of RES on the histology of liver and kidney in Cd-exposed mice. Male mice were divided into 4 groups daily receiving normal saline (1 mL normal saline/d), Cd (1 mg/kg/d), RES (20 mg/kg/d), and Cd plus RES, respectively. After 4 weeks, the liver and kidney components were evaluated using stereological methods. The total volume and number of hepatocytes, and volume of fibrous tissue were respectively increased by 34%, 58%, and a 3-fold in the Cd exposed mice in comparison to the control animals (P < 0.03). On the other hand, the volume of the main vasculature (sinusoids and central veins) was decreased by 36% in the Cd group compared to the control mice (P < 0.03). Considering the kidney, the results showed a 3-fold increase in the total glomeruli volume and a 7-fold increase in fibrous tissue in the Cd-treated group compared to the control mice (P < 0.03). After Cd treatment, a 32% reduction was observed in the volume and length of the proximal and distal convoluted tubules. RES-treatment alone did not induce any structural changes. In comparison to the Cd group, an increase in the normal components of the liver and kidney and a decrease in the formation of the fibrous and degenerated tissues were observed in the Cd+RES-treated mice (P < 0.03). PMID- 26770915 TI - Hydrocolloids Decrease the Digestibility of Corn Starch, Soy Protein, and Skim Milk and the Antioxidant Capacity of Grape Juice. AB - Hydrocolloids have many applications in foods including their use in dysphagia diets. We aimed to evaluate whether hydrocolloids in foods affect the digestibility of starch and protein, and their effects on antioxidant capacity. The thickening hydrocolloids: locust bean gum and carboxymethyl cellulose, and the gel-forming agents: agar agar, konjac-glucomannan, and Hot & Soft Plus were blended with corn starch and soy protein, skim milk, or grape juice and were examined for their in vitro-digestability by comparing the reducing sugar and trichloroacetic acid (TCA)-soluble peptide, for antioxidant capacity by total polyphenol contents and the 2,2-diphenyl-1-picrylhydrazyl radical scavenging activity. The hydrocolloids resulted in a decrease in starch digestibility with the gel-forming agents. Hydrocolloids diminished TCA-soluble peptides in skim milk compared to soy protein with the exception of locust bean gum and decreased free radical scavenging capacities and total phenolic contents in grape juice. Our findings may provide evidence for the use of hydro-colloids for people at risk of nutritional deficiencies such as dysphagia patients. PMID- 26770916 TI - Preparation of Yeast Hydrolysate Enriched in Cyclo-His-Pro (CHP) by Enzymatic Hydrolysis and Evaluation of Its Functionality. AB - In this study, we attempted to enrich cyclo-His-Pro (CHP) using enzymatic hydrolysis of yeast and to evaluate the functionality of yeast hydrolysate (YH) enriched CHP. Flavourzyme offered a better performance in enhancing CHP content than other proteases. The CHP enrichment conditions were optimized as follows: addition of 1% Flavourzyme, 48-h incubation at 60 degrees C, and pH 6.0. The CHP content significantly increased by 20-fold after ultra-filtration (UF). Maximal CHP translation was obtained after heating for 8 h at 50 degrees C and pH 7.0. YH showed poor foaming capacity between pH 3.0 to 9.0. The emulsifying activities of YHs were slightly higher at near acidic pH. Increase in heating temperature and time resulted in decreased CHP content. The results indicate that YH is more heat stable after UF. Therefore, the CHP in YH after UF can be used as a food additive with physiological CHP activity and high heat stability. PMID- 26770917 TI - Quality Characteristics and Quantification of Acetaldehyde and Methanol in Apple Wine Fermentation by Various Pre-Treatments of Mash. AB - The objective of this study was to compare the effects of adding lactic acid and pectinase, and chaptalization for the quality of apple wine and the production of hazardous compounds (methanol and acetaldehyde). The pH of all of the samples was below 4; therefore, mash seemed to be fermented without any issue. Total acidity was the highest in sample A due to lactic acid addition. Pre-treated groups (samples B, C, and D) showed higher total acidities than that of the control (P<0.05). Pre-treatments might influence the production of organic acids in apple wines. The control and pectinase added sample (sample B) had the lowest alcohol contents. Adding lactic acid produced more alcohol, and chaptalized samples produced more alcohol due to the addition of sugar. Adding pectinase with and without chaptalization was not effective for producing more alcohol. The control sample had significantly higher acetaldehyde content (2.39 mg/L) than the other samples (1.00~2.07 mg/L); therefore, pre-treatments for apple wine fermentation produced a lower amount of acetaldehyde. Among the pre-treated samples, samples C and D showed the lowest acetaldehyde content of 1.00 mg/L and 1.16 mg/L, respectively. On the other hand, a significantly higher amount of methanol was generated for sample A (1.03 mg/L) and sample D (1.22 mg/L) than that of the control (0.82 mg/L) (P<0.05). Adding lactic acid or chaptalization was effective in reducing methanol and acetaldehyde in apple wines. PMID- 26770918 TI - Anti-Obesity Effects of Starter Fermented Kimchi on 3T3-L1 Adipocytes. AB - The anti-obesity effects of starter (Leuconostoc mesenteroides+Lactobacillus plantarum) fermented kimchi on 3T3-L1 adipocyte were studied using naturally fermented kimchi (NK), a functional kimchi (FK, NK supplemented with green tea), and FK supplemented with added starters (FKS). Oil red O staining and cellular levels of triglyceride (TG) and glycerol were used to evaluate the in vitro anti obesity effects of these kimchis in 3T3-L1 cells. The expressions of adipogenesis/lipogenesis-related genes of peroxisome proliferator-active receptor (PPAR)-gamma, CCAAT/enhance-binding protein (C/EBP)-alpha, and fatty acid synthase (FAS) were determined by RT-PCR. Kimchis, especially FKS, markedly decreased TG levels and increased levels of intracellular glycerol and lipid lipolysis. In addition, FKS also reduced the mRNA levels of PPAR-gamma, C/EBP alpha, and FAS, which are related to adipogenesis/lipogenesis in 3T3-L1 cells. These results suggest the anti-obesity effects of FKS were to due to enhanced lipolysis and reduced adipogenesis/lipogenesis in 3T3-L1 adipocytes. PMID- 26770919 TI - Nitric oxide in liver fibrosis: The role of inducible nitric oxide synthase. AB - The inducible form of nitric oxide synthase (iNOS) is expressed in hepatic cells in pathological conditions. Its induction is involved in the development of liver fibrosis, and thus iNOS could be a therapeutic target for liver fibrosis. This review summarizes the role of iNOS in liver fibrosis, focusing on 1) iNOS biology, 2) iNOS-expressing liver cells, 3) iNOS-related therapeutic strategies, and 4) future directions. PMID- 26770921 TI - Transarterial chemoembolization using drug eluting beads for the treatment of hepatocellular carcinoma: Now and future. AB - Transarterial chemoembolization (TACE) using doxorubicin-eluting beads (DEBs) have been introduced as a novel device which ensures more sustained and tumor selective drug delivery and permanent embolization compared to conventional TACE with lipiodol. Studies highlighting the use of TACE with DEBs for the treatment of hepatocellular carcinoma (HCC) have shown similar or better results compared to conventional TACE with lipiodol. TACE with DEBs is increasingly being performed interchangeably with conventional TACE. This review assessed the characteristics, clinical outcomes and future direction of TACE with DEBs compared to conventional TACE. PMID- 26770920 TI - Imaging findings of mimickers of hepatocellular carcinoma. AB - Radiological imaging plays a crucial role in the diagnosis of hepatocellular carcinoma (HCC) as the noninvasive diagnosis of HCC in high-risk patients by typical imaging findings alone is widely adopted in major practice guidelines for HCC. While imaging techniques have markedly improved in detecting small liver lesions, they often detect incidental benign liver lesions and non-hepatocellular malignancy that can be misdiagnosed as HCC. The most common mimicker of HCC in cirrhotic liver is nontumorous arterioportal shunts that are seen as focal hypervascular liver lesions on dynamic contrast-enhanced cross-sectional imaging. Rapidly enhancing hemangiomas can be easily misdiagnosed as HCC especially on MR imaging with liver-specific contrast agent. Focal inflammatory liver lesions mimic HCC by demonstrating arterial-phase hypervascularity and subsequent washout on dynamic contrast-enhanced imaging. It is important to recognize the suggestive imaging findings for intrahepatic cholangiocarcinoma (CC) as the management of CC is largely different from that of HCC. There are other benign mimickers of HCC such as angiomyolipomas and focal nodular hyperplasia-like nodules. Recognition of their typical imaging findings can reduce false-positive HCC diagnosis. PMID- 26770922 TI - What we know about paracentesis induced circulatory dysfunction? PMID- 26770923 TI - Erectile dysfunction in patients with liver disease related to chronic hepatitis B. AB - BACKGROUND/AIMS: Despite sexual function making an important contribution to the quality of life, data on erectile function are relatively scant in patients with chronic liver disease. We evaluated the prevalence of and risk factors for erectile dysfunction (ED) in patients with liver disease related to hepatitis B, especially among those with chronic hepatitis B (CHB) or early-stage cirrhosis. METHODS: In total, 69 patients (35 with CHB and 34 with hepatitis-B-related liver cirrhosis [HBV-LC]) aged 40-59 years were analyzed. Child-Pugh classes of A and B were present in 30 (88.2%) and 4 (11.8%) of the patients with HBV-LC, respectively. The erectile function of the patients was evaluated using the Korean version of IIEF-5. RESULTS: The prevalence of any ED was 24.6% for all patients, and 8.6% and 41.2% for those with CHB and HBV-LC, respectively (P=0.002). While there was only one (2.9%) CHB patient for each stage of ED, mild, moderate, and severe ED stages were seen in three (8.8%), one (2.9%), and ten (29.4%) of the HBV-LC patients, respectively. Multiple regression analysis identified the type of liver disease (P=0.010), hypertension (P=0.022), score on the Beck Depression Inventory (P =0.044), and the serum albumin level (P=0.014) as significant independent factors for the presence of ED. CONCLUSIONS: The prevalence of ED was significantly higher in patients with early-stage HBV-LC than in those with CHB. Therefore, screening male patients with early viral cirrhosis for ED and providing appropriate support are needed, especially when the cirrhosis is accompanied by hypertension, depression, or a depressed level of serum albumin. PMID- 26770924 TI - Sofosbuvir-based therapy for patients with chronic hepatitis C: Early experience of its efficacy and safety in Korea. AB - BACKGROUND/AIMS: The previous standard treatment for chronic hepatitis C (CHC) patients, comprising a combination of pegylated interferon (IFN) and ribavirin, was associated with suboptimal efficacy and severe adverse reactions. A new era of direct-acting antivirals is now dawning in Korea. Early experience of applying sofosbuvir-based therapy to CHC patients in Korea is reported herein. METHODS: Data on efficacy and safety were collected for CHC patients treated with a combination of sofosbuvir plus ribavirin or sofosbuvir/ledipasvir with or without ribavirin. RESULTS: This retrospective study included 25 consecutive patients who received sofosbuvir-based therapy (19 with genotype 1b and 6 with genotype 2) at Seoul National University Hospital from May 2014 to April 2015. A virologic response was achieved at week 4 by 85.7% and 80% of the patients with genotypes 1b and 2, respectively. The HCV-RNA level decreased more slowly in IFN experienced than in treatment-naive patients with genotype 1b. However, the sustained virologic response at week 12 (SVR12) rate did not differ among these patients, and was as high as 100%. The presence of cirrhosis significantly increased the risk of a virologic response failure at week 4 (OR, 11.0; P=0.011) among patients with HCV genotype 1b. Only five patients (20%) experienced minor adverse events, including grade 1 fatigue and headache. The hemoglobin level decreased slightly after sofosbuvir-based therapy, but there was no case of premature discontinuation of this therapy. CONCLUSIONS: In a real clinical practice, sofosbuvir-based therapy for CHC patients in Korea achieved optimal antiviral efficacy with insignificant adverse events. Long-term follow-up data are warranted to ensure the sustained antiviral efficacy and long-term safety of sofosbuvir-based IFN-free therapy. PMID- 26770925 TI - The impact of paracentesis flow rate in patients with liver cirrhosis on the development of paracentesis induced circulatory dysfunction. AB - BACKGROUND/AIMS: Ascites is a dreadful complication of liver cirrhosis associated with short survival. Large volume paracentesis (LVP) is used to treat tense or refractory ascites. Paracentesis induced circulatory dysfunction (PICD) develops if no plasma expanders are given with ominous complications. To study the effect of ascites flow rate on PICD development. METHODS: Sixty patients with cirrhosis and tense ascites underwent LVP of 8 L were randomized into 3 equal groups of different flow rate extraction; group I (80 mL/minute), group II (180 mL/minute) and group III (270 mL/minute). Plasma renin activity (PRA) was measured baseline and on day six. PICD was defined as increase in PRA >50% of the pretreatment value. RESULTS: In group I through 3; the mean age was (52.5+/-9.4 vs. 56.4+/-8.5 vs. 55.8+/-7.1 years; P>0.05), mean arterial pressure (81.4+/-5.6 vs. 81.5+/-7 vs. 79.5+/-7.2 mmHg; P>0.05), MELD (17.6+/-4.1 vs. 15.8+/-4.1 vs. 14.7+/-4.5). Baseline PRA was comparable (1,366.0+/-1244.9 vs. 1,151.3+/-1,444.8 vs. 951.9+/ 1,088 pg/mL; P>0.05). There was no statistically significant (P>0.05) flow mediated changes (Delta) of creatinine (0.23+/-0.27 vs. 0.38+/-0.33 vs. 0.26+/ 0.18 mg/dL), MELD (1.25+/-5.72 vs. 1.70+/-2.18 vs. 1.45+/-2.21) or PRA (450.93+/ 614.10 vs. 394.61+/-954.64 vs. 629.51+/-1,116.46 pg/mL). PICD was detected in a similar frequency in the three groups (P>0.05). On univariate logistic analysis only female sex was a fairly significant PICD predictor (Wald 3.85, odds ratio 3.14; P=0.05). CONCLUSIONS: The ascites flow rate does not correlate with PICD development. PMID- 26770926 TI - Impact of hypothyroidism on the development of non-alcoholic fatty liver disease: A 4-year retrospective cohort study. AB - BACKGROUND/AIMS: Hypothyroidism is reported to contribute to the development of nonalcoholic fatty liver disease (NAFLD). We compared the risk of the development of NAFLD among three groups with different thyroid hormonal statuses (control, subclinical hypothyroidism, and overt hypothyroidism) in a 4-year retrospective cohort of Korean subjects. METHODS: Apparently healthy Korean subjects without NAFLD and aged 20-65 years were recruited (n=18,544) at health checkups performed in 2008. Annual health checkups were applied to the cohort for 4 consecutive years until December 2012. Based on their initial serum-free thyroxine (fT4) and thyroid-stimulating hormone (TSH) levels, they were classified into control, subclinical hypothyroidism (TSH >4.2 mIU/L, normal fT4), and overt hypothyroidism (TSH >4.2 mIU/L, fT4 <0.97 ng/dL) groups. NAFLD was diagnosed on the basis of ultrasonography findings. RESULTS: NAFLD developed in 2,348 of the 18,544 subjects, representing an overall incidence of 12.7%: 12.8%, 11.0%, 12.7% in the control, subclinical hypothyroidism, and overt hypothyroidism groups, respectively. The incidence of NAFLD did not differ significantly with the baseline thyroid hormonal status, even after multivariate adjustment (subclinical hypothyroidism group: hazard ratio [HR]=0.965, 95% confidence interval [CI]=0.814 1.143, P=0.67; overt hypothyroidism group: HR=1.255, 95% CI=0.830-1.899, P=0.28). CONCLUSIONS: Our results suggest that the subclinical and overt types of hypothyroidism are not related to an increased incidence of NAFLD. PMID- 26770927 TI - Effect of vitamin E in nonalcoholic fatty liver disease with metabolic syndrome: A propensity score-matched cohort study. AB - BACKGROUND/AIMS: Vitamin E improves the biochemical profiles and liver histology in nonalcoholic steatohepatitis, but the role of vitamin E is not clearly defined in the management of nonalcoholic fatty liver disease (NAFLD) which includes both simple steatosis and steatohepatitis. Co-morbid metabolic syndrome increases the probability of steatohepatitis in NAFLD. In this study, we aimed to determine the short-term effects of vitamin E and off-treatment durability of response in a propensity-score matched cohort of NAFLD patients with metabolic syndrome. METHODS: A retrospective cohort was constructed by retrieving 526 consecutive NAFLD patients from the electronic medical record data warehouse of a tertiary referral hospital in South Korea. Among them, 335 patients (63.7%) had metabolic syndrome and were eligible for vitamin E therapy. In order to assess the effect of vitamin E, propensity score matching was used by matching covariates between control patients (n=250) and patients who received vitamin E (n=85). RESULTS: The PS-matched vitamin E group (n=58) and control group (n=58) exhibited similar baseline metabolic profiles. After 6 months of vitamin E therapy, the mean ALT levels decreased significantly compared to PS-matched control (P<0.01). The changes in metabolic profiles (body weight, lipid and glucose levels) did not differ between control and vitamin E groups during the study period. CONCLUSIONS: Short-term vitamin E treatment significantly reduces ALT levels in NAFLD patients with metabolic syndrome, but metabolic profiles are not affected by vitamin E. PMID- 26770928 TI - Peliosis hepatis presenting with massive hepatomegaly in a patient with idiopathic thrombocytopenic purpura. AB - Peliosis hepatis is a rare condition that can cause hepatic hemorrhage, rupture, and ultimately liver failure. Several authors have reported that peliosis hepatis develops in association with chronic wasting disease or prolonged use of anabolic steroids or oral contraceptives. In this report we describe a case in which discontinuation of steroid therapy improved the condition of a patient with peliosis hepatis. Our patient was a 64-year-old woman with a history of long-term steroid treatment for idiopathic thrombocytopenic purpura . Her symptoms included abdominal pain and weight loss; the only finding of a physical examination was hepatomegaly. We performed computed tomography (CT) and magnetic resonance imaging (MRI) of the liver and a liver biopsy. Based on these findings plus clinical observations, she was diagnosed with peliosis hepatis and her steroid treatment was terminated. The patient recovered completely 3 months after steroid discontinuation, and remained stable over the following 6 months. PMID- 26770929 TI - Intrahepatic bile duct adenoma in a patient with chronic hepatitis B accompanied by elevation of alpha-fetoprotein. AB - A 51-year-old male patient with chronic hepatitis B was referred to our hospital due to a 1-cm liver nodule on ultrasonography. Alpha-fetoprotein (AFP) was slightly elevated. The nodule showed prolonged enhancement on dynamic liver magnetic resonance imaging and appeared as a hyperintensity on both diffusion weighted and T2-weighted imaging. The nodule was followed up because it was small and typical findings of hepatocellular carcinoma (HCC) were not observed in the dynamic imaging investigations. However, liver contrast-enhanced ultrasonography performed 1 month later showed enhancement during the arterial phase and definite washout during the delayed phase. Also, AFP had increased to over 200 ng/mL even though AST and ALT were decreased after administering an antiviral agent. He was presumptively diagnosed as HCC and underwent liver segmentectomy. Microscopy findings of the specimen indicated bile duct adenoma. After resection, the follow up AFP had decreased to within the normal range. This patient represents a case of bile duct adenoma with AFP elevation mimicking HCC on contrast-enhanced ultrasonography. PMID- 26770930 TI - Focal type of peliosis hepatis. PMID- 26770931 TI - Evolution of Phosphodiesterase-5 Inhibitors. PMID- 26770932 TI - Testosterone Replacement Therapy and Prostate Cancer Incidence. AB - While early studies demonstrated a positive association between testosterone and prostate cancer, evidence on the nature of the relationship has evolved with time and newer data. Studies examining links between baseline testosterone levels as well as testosterone therapy and incident prostate cancer, reveal a more complex relationship. Moreover, investigators have reported their initial experiences with supplementing testosterone in men with a history of both treated and untreated prostate cancer. PMID- 26770933 TI - Testosterone Replacement Therapy and Cardiovascular Risk: A Review. AB - Recent reports in the scientific and lay press have suggested that testosterone (T) replacement therapy (TRT) is likely to increase cardiovascular (CV) risk. In a final report released in 2015, the Food and Drug Administration (FDA) cautioned that prescribing T products is approved only for men who have low T levels due to primary or secondary hypogonadism resulting from problems within the testis, pituitary, or hypothalamus (e.g., genetic problems or damage from surgery, chemotherapy, or infection). In this report, the FDA emphasized that the benefits and safety of T medications have not been established for the treatment of low T levels due to aging, even if a man's symptoms seem to be related to low T. In this paper, we reviewed the available evidence on the association between TRT and CV risk. In particular, data from randomized controlled studies and information derived from observational and pharmacoepidemiological investigations were scrutinized. The data meta-analyzed here do not support any causal role between TRT and adverse CV events. This is especially true when hypogonadism is properly diagnosed and replacement therapy is correctly performed. Elevated hematocrit represents the most common adverse event related to TRT. Hence, it is important to monitor hematocrit at regular intervals in T-treated subjects in order to avoid potentially serious adverse events. PMID- 26770935 TI - Individualized Treatment Guidelines for Postpubertal Cryptorchidism. AB - Cryptorchidism is a well-known congenital anomaly in children. However, its diagnosis is often delayed for reasons including patient unawareness or denial of abnormal findings in the testis. Moreover, it has been difficult to establish an optimal treatment strategy for postpubertal cryptorchidism, given the small number of patients. Unlike cryptorchidism in children, postpubertal cryptorchidism is associated with an increased probability of neoplasms, which has led orchiectomy to be the recommended treatment. However, routine orchiectomy should be avoided in some cases due to quality-of-life issues and the potential risk of perioperative mortality. Based on a literature review, this study proposes individualized treatment guidelines for postpubertal cryptorchidism. PMID- 26770936 TI - Dyslipidemia Prevalence in Iranian Adult Men: The Impact of Population-Based Screening on the Detection of Undiagnosed Patients. AB - PURPOSE: Dyslipidemia has been established as one of the most important modifiable risk factors for cardiovascular disease. Due to the higher prevalence of dyslipidemia in males, this study aimed to estimate the prevalence of dyslipidemia in Iranian urban men. MATERIALS AND METHODS: A screening program was conducted in 845 Iranian men 25 years of age and older in 2014. A health interview survey was conducted to evaluate the prevalence of self-reported dyslipidemia and to collect demographic data, as well as serum lipid profile screening by a reference laboratory. Lipoprotein levels was categorized based on the Adult Treatment Panel III criteria and the data were analyzed using the chi square test and analysis of variance. RESULTS: The overall prevalence of dyslipidemia was 51.8%, and the prevalence of various forms of dyslipidemia was as follows: hypercholesterolemia (>=240 mg/dL), 11.4%; hyper-low-density lipoprotein cholesterol (>=160 mg/dL), 9.6%; hypertriglyceridemia (>=200 mg/dL), 25%; and hypo-high-density lipoprotein (HDL) cholesterol (<40 mg/dL), 34.3%. With the exception of hypo-HDL, all forms of dyslipidemia were significantly less common in men over 65 years of age (p<0.05). CONCLUSIONS: The prevalence of hypo HDL and hypertriglyceridemia was higher than expected in Iranian adult men, with half of men 25 years of age and older affected by at least one form of dyslipidemia. A large gap in primary and secondary care was observed, because nearly 80% of patients with dyslipidemia were unaware of their status. Urgent preventive programs and lifestyle changes are necessary to reduce the prevalence of cardiovascular risk factors. PMID- 26770934 TI - Smoking and Male Infertility: An Evidence-Based Review. AB - Many studies have reported that the contents of cigarette smoke negatively affect sperm parameters, seminal plasma, and various other fertility factors. Nevertheless, the actual effect of smoking on male fertility is not clear. The effect of smoking on semen parameters is based on the well-established biological finding that smoking increases the presence of reactive oxygen species, thereby resulting in oxidative stress (OS). OS has devastating effects on sperm parameters, such as viability and morphology, and impairs sperm function, hence reducing male fertility. However, not all studies have come to the same conclusions. This review sheds light upon the arguable association between smoking and male fertility and also assesses the impact of non-smoking routes of tobacco consumption on male infertility. It also highlights the evidence that links smoking with male infertility, including newly emerging genetic and epigenetic data, and discusses the clinical implications thereof. PMID- 26770937 TI - Associations of Self-Reported Erectile Function with Non-Invasive Measurements of Endothelial Function: A Preliminary Study. AB - PURPOSE: To evaluate the association of self-reported erectile function and endothelial function using the EndoPAT device. MATERIALS AND METHODS: We prospectively enrolled 76 men (age>=40 years) after obtaining a complete medical history and a self-reported questionnaire (International Index of Erectile Function-5 [IIEF-5], SEP Q2, Q3). Endothelial function was noninvasively measured with an EndoPAT 2000, recorded as the reactive hyperemia index (RHI), and analyzed according to the patients' baseline characteristics. RESULTS: The mean patient age and IIEF-5 score were 62.50+/-8.56 years and 11.20+/-6.36, respectively. In comparing the RHI according to erectile dysfunction (ED) risk factors, the RHI was significantly lower in older subjects (p=0.004). There was no difference in the RHI according to age, body mass index, waist circumference, obesity, smoking habit, or other comorbidities. When the subjects were divided into four groups according to the severity of ED, no statistical differences in the RHI value were found among the groups. There was no difference in IIEF-5 according to the RHI when categorized according to the normal cutoff value or quartile ranges. The second subdomain of IIEF-5 (erection firmness) was significantly correlated with the RHI value (R=0.309, p=0.007); however, this was not the case with the other IIEF-5 subdomains. Self-assessment showed a tendency toward a negative correlation with the RHI value (R=-0.202, p=0.080). CONCLUSIONS: The role of endothelial function measurement by the EndoPAT in the evaluation and management of ED patients remains inconclusive. However, further studies are needed to validate the role of endothelial function measurement, by the EndoPAT or any other device. PMID- 26770938 TI - Preoperative Urinary Retention Increased the Risk of Urinary Retention after Photoselective Vaporization of the Prostate. AB - PURPOSE: The aim of the present study was to evaluate preoperative acute urinary retention (AUR) as a factor affecting the outcomes of patients who underwent photoselective vaporization of the prostate (PVP), both in terms of overall effectiveness and the postoperative incidence of AUR. MATERIALS AND METHODS: Baseline prostate characteristics were obtained for patients who underwent PVP, including prostate-specific antigen (PSA) levels, transrectal ultrasound findings, voiding diary parameters, the International Prostate Symptoms Score (IPSS), and uroflowmetry parameters. These parameters were assessed two weeks, one month, three months, six months, and three years postoperatively. Subjects were divided into AUR and non-AUR groups based on the preoperative occurrence of AUR. RESULTS: Of the 476 patients, 91 had at least one episode of preoperative AUR. The AUR group was found to be significantly older and to have significantly higher PSA levels, lower body mass indices, and larger prostates. At one year of follow-up, the total IPSS was 7.6+/-6.8 in the AUR group and 11.4+/-8.2 in the non-AUR group, with the AUR group showing a more significant improvement. In the non-AUR group, 17 of the 385 patients (4.4%) experienced postoperative retention, compared to 16 of the 91 patients (17.6%) patients in the AUR group. CONCLUSIONS: Almost all patients exhibited improvements in subjective and objective voiding parameters following PVP, regardless of the presence of preoperative urinary retention. Patients with a preoperative history of AUR had a higher risk of postoperative retention. PMID- 26770939 TI - The Practicality of Targeted Prostate Biopsy Procedures on the Dominant Side of the Tumor Determined by Magnetic Resonance Imaging in Elderly Patients with High Serum Levels of Prostate-Specific Antigen. AB - PURPOSE: To examine the possibility of reducing the number of cores per prostate biopsy in elderly patients with high levels of prostate-specific antigen (PSA) without significantly lowering the detection rate of prostate cancer. MATERIALS AND METHODS: Two hundreds sixteen men with PSA levels >20 ng/mL who underwent prostate biopsies from May 2009 to April 2013 were retrospectively reviewed. With the help of magnetic resonance imaging (MRI), the laterality of the dominant tumor burden in patients was determined. The results of targeted biopsies were compared with those of conventional biopsy procedures. RESULTS: The mean age and PSA level were 79.5 years and 81.3 ng/mL, respectively, and the overall diagnostic rate of sextant biopsies was 81.9% (177/216). MRI was able to show the tumor burden in 189 of the 216 patients. The detection rate of transrectal ultrasonography (TRUS)-guided targeted biopsies was 87.3% (165/189). Detection rates were comparable with conventional biopsies (81.9% [177/216]) (p=0.23). Of the 177 men in whom the results of the sextant biopsy were positive, 12 men (6.8%) with PSA levels <29 ng/mL did not have any cancer cells according to targeted biopsies. However, all other patients were diagnosed with prostate cancer using the abovementioned techniques. CONCLUSIONS: We believe that TRUS guided targeted biopsies of the prostate in elderly men with high PSA levels could reduce the number of unnecessary cores per biopsy. However, a risk of detection loss remains. Therefore, we recommend that at least a sextant biopsy should be performed, even in elderly patients, in order to detect prostate cancer. PMID- 26770940 TI - Changes in Nocturia and Lower Urinary Tract Symptoms after Radical Prostatectomy. AB - PURPOSE: The goal of this study was to evaluate changes in nocturia and other lower urinary tract symptoms (LUTS) after laparoscopic radical prostatectomy (LRP) and robot-assisted laparoscopic radical prostatectomy (RALP). MATERIALS AND METHODS: We reviewed the medical records of 96 patients who underwent LRP or RALP for clinically localized prostate cancer and completed the International Prostate Symptom Score (IPSS) questionnaire, which provided a basis for assessing their symptoms. We also evaluated maximal flow rate and post-void residual urine volume over a follow-up period of at least 24 months. We divided the patients into three groups according to postoperative changes in the frequency of nocturia. RESULTS: Voiding symptoms significantly improved over the course of 24 months in patients who underwent LRP or RALP. However, most patients showed persistent or increased nocturia after LRP or RALP. Moreover, more than one third of the patients (33/96) presented with exacerbated nocturia (1.0+/-0.9 episodes of preoperative nocturia vs. 3.0+/-1.3 episodes of postoperative nocturia). Multiple regression analysis showed that preoperative IPSS storage sub-score had negative association with the nocturia after radical prostatectomy (p=0.005). However, patients' age, body mass index, preoperative prostate specific antigen, Gleason score, T-stage, and prostate volume had no association. CONCLUSIONS: The present study showed that nocturia was influenced by a range of factors, including other storage LUTS and the relief of bladder outlet obstruction after radical prostatectomy. Moreover, the preoperative storage symptoms are regarded as an important factor which influences the changes of nocturia after radical prostatectomy. PMID- 26770941 TI - Long-Term Safety and Longevity of a Mixture of Polymethyl Methacrylate and Cross Linked Dextran (Lipen-10(r)) after Penile Augmentation: Extension Study from Six to 18 Months of Follow-Up. AB - PURPOSE: The goal of this study was to investigate the long-term efficacy and safety of a mixture of polymethyl methacrylate (PMMA) and cross-linked dextran Lipen-10(r) used for penile augmentation under the physical impact generated during sexual intercourse. MATERIALS AND METHODS: From March 2010 to October 2011, a total of 20 patients with a mean age of 44 years (interquartile range, 20~70 years) who requested penile augmentation participated in this study. Lipen 10(r) filler is a mixture of 75% cross-linked dextran, 15% PMMA, and 10% hypromellose solution. With the patient in the supine position, Lipen-10(r) was injected into the subcutaneous tissue between the dartos fascia and Buck's fascia of the penis using a fanning technique. Penile length and circumference were measured before the procedure and six, 12, and 18 months after the procedure. Values were compared using the Student's t-test and the paired t-test. RESULTS: A total of 15 patients completed this study. The increases in circumference and length observed six months after the procedure were found to have been maintained without change at 12 and 18 months of follow-up. At 12 and 18 months of follow up, no abnormal findings were observed. Pelvic magnetic resonance imaging conducted at 18 months of follow-up showed no trace of the injected filler having migrated to other sites, and the volume was well maintained. CONCLUSIONS: Lipen 10(r), a mixture of PMMA and cross-linked dextran, showed good durability and tolerability over 18 months of follow-up during which the participants were sexually active. PMID- 26770942 TI - Impaired Physical Performance and Clinical Responses after a Recreational Bodybuilder's Self-Administration of Steroids: A Case Report. AB - We reported clinical and physical responses to 7 weeks of anabolic-androgenic steroid (AAS) self-administration in a male recreational bodybuilder. He was self administrating a total of 3,250 mg of testosterone when his previous and current clinical and physical trials records were revisited. Body shape, performance, and biochemistry results were clustered into three phases labeled PRE (before the self-use), POST I (immediately at the cessation of the 7-week administration), and POST II (12 weeks after the cessation). Elevated testosterone and estradiol levels were observed in the POST I phase, while hepatic and renal functions remained altered in the POST II phase. Body mass and body fat percentages increased throughout the three phases. When adjusted according to body mass, drops in aerobic and anaerobic power and capacity (2.1% to 12.9%) were observed across the phases. This case report shows that overall performance decreased when a bodybuilding practitioner self-administered AAS. PMID- 26770943 TI - Consortium for Improving Survival of Lymphoma (CISL): a model of multicenter collaboration for lymphoma studies in Korea. PMID- 26770944 TI - A multifaceted approach targeting NK cells for better treatment of cancer: focus on hematological malignancies. PMID- 26770945 TI - A T-cell/histiocyte-rich large B-cell lymphoma involving only the bone marrow. PMID- 26770946 TI - Follicular lymphoma in leukemic phase with unusual morphology at diagnosis. PMID- 26770947 TI - Hematopoietic stem cell expansion and generation: the ways to make a breakthrough. AB - Hematopoietic stem cell transplantation (HSCT) is the first field where human stem cell therapy was successful. Flooding interest on human stem cell therapy to cure previously incurable diseases is largely indebted to HSCT success. Allogeneic HSCT has been an important modality to cure various diseases including hematologic malignancies, various non-malignant hematologic diseases, primary immunodeficiency diseases, and inborn errors of metabolism, while autologous HSCT is generally performed to rescue bone marrow aplasia following high-dose chemotherapy for solid tumors or multiple myeloma. Recently, HSCs are also spotlighted in the field of regenerative medicine for the amelioration of symptoms caused by neurodegenerative diseases, heart diseases, and others. Although the demand for HSCs has been growing, their supply often fails to meet the demand of the patients needing transplant due to a lack of histocompatible donors or a limited cell number. This review focuses on the generation and large scale expansion of HSCs, which might overcome current limitations in the application of HSCs for clinical use. Furthermore, current proof of concept to replenish hematological homeostasis from non-hematological origin will be covered. PMID- 26770948 TI - Nationwide statistical analysis of myeloid malignancies in Korea: incidence and survival rate from 1999 to 2012. AB - BACKGROUND: Large-scale epidemiologic analysis for hematologic malignancies will be helpful to understand the trends in incidence and survival. METHODS: The Korea Central Cancer Registry (KCCR) updated the nationwide analysis on the incidence and survival of myeloid malignancies, from the Korean National Cancer Incidence Database between 1999 and 2012. Myeloid malignancies were classified based on the International Classification of Diseases for Oncology 3(rd) edition (ICD-O-3). RESULTS: Overall 3,771 cases of myeloid diseases, which was 1.7% of all cancers, were identified in 2012. The highest incidence of myeloid malignancies was observed in age 70s and male predominance was noted (1.3:1). Acute myeloid leukemia (AML) was the most frequent subtype, followed by myeloproliferative neoplasms (MPN), myelodysplastic syndrome (MDS) and MDS/MPN: age-standardized incidence rates (ASR) in 2012 for each disease were 2.02, 1.95, 1.13, and 0.12 per 100,000 persons, respectively. The ASR for all myeloid malignancies was increased from 3.31 in 1999 to 5.70 in 2012 with the annual percentage change (APC) of 5.4 %. Five-year relative survival rate (RS) for myeloid malignancies has gradually improved for decades. RS changed from 26.3% to 34.8% in AML, specifically from 51.6% to 69.6% in acute promyelocytic leukemia (APL) and from 23.8% to 29.9% in non-APL AML, between 1996-2000 and 2008-2012. RS also increased from 81.8% to 87.1% in MPN, with a significant improvement in CML (from 74.5% to 85.5%), and from 27.3% to 31.7% in MDS/MPN between 2001-2005 and 2008-2012. However, there was no survival improvement in MDS during the study period (45.6% in 2001-2005 to 44.4% in 2008-2012). CONCLUSION: This report updated the nationwide statistical analysis on myeloid malignancies since 2008, showing increasing incidence and improving trends in survival. PMID- 26770949 TI - Expression and functional roles of the chemokine receptor CXCR7 in acute myeloid leukemia cells. AB - BACKGROUND: The C-X-C chemokine receptor 7 (CXCR7) has been shown to be a decoy receptor for CXCR4 in certain cell types. We investigated the expression status and functional roles of CXCR7 in acute myeloid leukemia (AML) cells in vitro. METHODS: CXCR7 mRNA was knocked down in AML cells by using small interfering RNA (siRNA) technology, and subsequent biological alterations in the cells were evaluated in vitro. RESULTS: All AML cell lines examined in this study (U937, K562, KG1a, HL-60, and MO7e) and primary CD34(+) cells obtained from patients with AML expressed CXCR7 mRNA at various levels. Western blotting showed that all AML cells produced CXCR7. Furthermore, all AML cells expressed CXCR7 in both the cytoplasm and on the cell surface at various levels. Stromal cell-derived factor 1 (SDF-1; C-X-C motif ligand 12 (CXCL12)) induced internalization of cell surface CXCR7. However, neither hypoxia nor the examined hematopoietic growth factors (interleukin-1beta (IL-1beta), IL-3, IL-6, granulocyte-colony-stimulating factor, granulocyte, macrophage-colony-stimulating factor, and stem cell factor) and proinflammatory cytokines (interferon-gamma, transforming growth factor-beta, and tumor necrosis factor-alpha) were found to alter cell surface CXCR7 expression. The transfection of AML cells with CXCR4 siRNA, but not CXCR7 siRNA, significantly impaired the CXCL12-induced transmigration of the cells. The transfection of AML cells with CXCR7 siRNA did not affect the survival or proliferation of these cells. Knockdown of CXCR7, but not CXCR4, induced the upregulation of CXCL12 mRNA expression and CXCL12 production in AML cells. CONCLUSION: CXCR7 is involved in the regulation of autocrine CXCL12 in AML cells. PMID- 26770950 TI - Immunophenotypic markers in adult acute lymphoblastic leukemia: the prognostic significance of CD20 and TdT expression. AB - BACKGROUND: Efforts to overcome poor outcomes in patients with adult acute lymphoblastic leukemia (ALL) have focused on combining new therapeutic agents targeting immunophenotypic markers (IPMs) with classical cytotoxic agents; therefore, it is important to evaluate the clinical significance of IPMs. METHODS: Baseline characteristics and clinical outcomes of patients with adult ALL were retrospectively analyzed. The percentage of blasts expressing IPMs at diagnosis was measured by multicolor flow cytometry analysis. Samples in which >=20% of blasts expressed an IPM were considered positive. RESULTS: Among the total patient population (N=230), almost all (92%) were in first or second hematological complete remission (HCR) and 54% received allogeneic hematopoietic cell transplant (allo-HCT). Five-year hematologic relapse-free survival (HRFS) and overall survival (OS) rates were 36% and 39%, respectively, and 45.6% and 80.5% of patients were positive for the IPMs CD20 and terminal deoxynucleotidyl transferase (TdT), respectively. Expression of CD20, CD13, CD34, and TdT was associated with HRFS rate, and expression of CD20 and CD13 was associated with OS rate, as was the performance of allo-HCT. In multivariate analysis, positivity for CD20 (HRFS: hazard ratio [HR], 2.21, P<0.001; OS: HR, 1.63, P=0.015) and negativity for TdT (HRFS: HR, 2.30, P=0.001) were both significantly associated with outcomes. When patients were categorized into three subgroups according to positivity for CD20 and TdT, there were significant differences in HRFS and OS among the subgroups. CONCLUSION: Positivity for CD20 and TdT expression and clinical risk group were prognostic factors in adult ALL. PMID- 26770951 TI - The prognostic value of glucocorticoid receptors for adult acute lymphoblastic leukemia. AB - BACKGROUND: Therapeutic protocols used in adult acute lymphoblastic leukemia (ALL) are widely variable, and glucocorticoids (GCs) are essential components in ALL treatment. Therefore, this study aimed to evaluate the distribution of prominent glucocorticoid receptor (GR) gene polymorphic variants among adult ALL patients. We also investigated the association between GR messenger ribonucleic acid (mRNA) isoform expressions and the response to chemotherapy. METHODS: Fifty two newly diagnosed Philadelphia-negative adult ALL patients and 30 healthy control subjects were enrolled in this study. Genotyping was carried out using a polymerase chain reaction (PCR)-restriction fragment length polymorphism analysis. GR mRNA isoform expressions were assayed by quantitative real-time PCR. RESULTS: ALL patients in this study had a median age of 34 years (range, 18-75). GRalpha expression was associated with complete remission (P=0.03), while GRgamma mRNA expression was significantly higher in GC resistant patients (P=0.032) and in non-responders (P=0.019). However, there were no significant associations with GC resistance. The BclI polymorphic variant of the GR gene was the most frequent in adult ALL patients and was not associated with the GC response. Both higher GRalpha expression and lower GRgamma expression were associated with achievement of complete remission, while higher GRgamma expression was associated with GC resistance. CONCLUSION: Our data suggest that the level of GR isoform expression may be useful in predicting GC response, achievement of complete remission, and better event-free survival in ALL patients. However, further evaluation with a larger cohort of patients is warranted. PMID- 26770952 TI - Intraocular lymphoma in Korea: the Consortium for Improving Survival of Lymphoma (CISL) study. AB - BACKGROUND: Intraocular lymphoma (IOL) is a rare malignant lymphoma that most closely resembles a diffuse large B-cell lymphoma, and it is a subtype of primary central nervous system lymphoma (PCNSL). IOL is located inside the eye in the retina, uvea, and/or optic nerve. We retrospectively analyzed IOL patient data to identify treatment patterns and survival rates in Korea. METHODS: Cytological confirmation for a diagnosis of IOL was performed for all patients. The clinical data collected from medical records included Ann Arbor stage, International Prognostic Index, performance status, date of diagnosis, treatment modality and response, date of relapse, and date of last follow-up. RESULTS: Twenty patients who were diagnosed with IOL, between December 2007 and June 2014 at multiple centers in Korea, were included in the analysis. Four patients were diagnosed with IOL alone, not involving the CNS. Two patients with isolated IOL later developed PCNSL. Nine patients developed CNS lesions before the onset of ocular lymphoma. Five patients had simultaneous onset in the eye and CNS. Twelve patients were treated by intravitreal injection of methotrexate for IOL. The median progression-free survival (PFS) for patients was 19.7 months (95% CI, 8.7 30.7 mo). The estimated 3-year overall survival (OS) for all patients was 75.1%. CONCLUSION: Treatment for IOL patients included radiotherapy and intraocular chemotherapy. IOL patients showed favorable PFS and OS. These patients would require long-term follow-up to identify relapse and adverse effects of radiotherapy or intraocular chemotherapy. PMID- 26770953 TI - Immune tolerance induction in patients with severe hemophilia A with inhibitors. AB - BACKGROUND: Inhibitory antibodies to factor VIII (FVIII) are an important complication when managing patients with hemophilia A. Immune tolerance induction (ITI) has been regarded as a useful method for eradicating inhibitors. We report the results of a retrospective study in Korean patients with hemophilia A who underwent ITI. METHODS: We reviewed the records of patients with hemophilia A with inhibitors who underwent ITI from March 2004 to December 2014. ITI was started with FVIII concentrates at 100 IU/kg, 3 times per week. The dose of FVIII was reduced according to the inhibitor titer and recovery of FVIII. Inhibitor elimination was defined as the time taken to achieve a negative inhibitor assay with no anamnestic response and normal FVIII recovery and/or normal half-life. RESULTS: In total, 17 patients with severe hemophilia A were evaluated. Complete tolerance was achieved in 14 of 17 patients (83%). The mean peak inhibitor titer before ITI was 38.4 BU/mL. The mean treatment duration was 26.2 months. The mean duration between inhibitor detection and ITI was 5.1 years in the complete tolerance group and 10.8 years in the partial tolerance and failed group. CONCLUSION: This study shows that ITI can be an effective and well-tolerated method for eradicating inhibitors. Possible influencing factors for ITI success were age at the start of ITI treatment and duration after inhibitor detection. More research to provide further insight about other factors and conditions is needed. PMID- 26770954 TI - Complete remission in CD30-positive refractory extranodal NK/T-cell lymphoma with brentuximab vedotin. PMID- 26770955 TI - Primary bone lymphoma with multifocal osteolytic lesions: a rare case report with review of literature. PMID- 26770956 TI - Pre- and post-therapy (18)F-FDG PET/CT of a patient affected by non-HIV multicentric IgG4-related Castleman disease. PMID- 26770957 TI - Bilateral Parotid MALToma: a sure shot for radiation. PMID- 26770958 TI - Sickle cell-beta thalassemia with concomitant hemophilia A: a rare presentation. PMID- 26770959 TI - Hypothermia as a cause of death in British Columbia, 1998-2012: a descriptive assessment. AB - BACKGROUND: Hypothermia can result from exposure to cold or as a consequence of underlying physiologic vulnerabilities. Who, where, when and how British Columbians (and Canadians) die of hypothermia have received little research attention. The objective of this study was to describe the epidemiology of mortality due to hypothermia among residents of British Columbia. METHODS: We examined all records in the death registry of the British Columbia Vital Statistics Agency between 1998 and 2012 that had an underlying or contributing cause of death coded for hypothermia or exposure to excessive natural cold. RESULTS: Hypothermia or exposure to excessive natural cold was found to be the underlying or contributing cause in 384 deaths between 1998 and 2012. Mean age of decedents was 52 (SD 20.78) years and 73.2% were male. The annual death rate for hypothermia increased with age, ranging from 0.3 per 100 000 population among people aged 1-34 years to 1.6 per 100 000 population among those older than 75 years of age. The highest annual death rate occurred among older males (2.1 per 100 000 population) followed by older females (1.3 per 100 000 population). Although hypothermia-related deaths occurred year-round, 45.9% occurred during winter months (December, January and February) and, in particular, on days with lower temperatures (mean 0.56 degrees C). Use of alcohol (40.1%) and other psychoactive substances (22.7%) were the most common additional causes of death identified among deaths due to hypothermia. Areas of British Columbia with the lowest population density or lowest socioeconomic status were found to have the highest crude hypothermia-related mortality rates. INTERPRETATION: Our results showed that older people are at higher risk of hypothermia-related death. Among residents of British Columbia who died of hypothermia, the most frequent additional causes of death were alcohol and nonalcohol psychoactive substances. However, further assessment of both the occurrence and determinants of mortality due to hypothermia are needed to inform measures to reduce its impact. PMID- 26770960 TI - Maternal placental syndromes among women living with HIV in Ontario: a population based study. AB - BACKGROUND: Maternal placental syndromes are associated with adverse fetal outcomes and maternal cardiovascular disease. However, whether HIV infection increases the risk of maternal placental syndromes is unknown. Our objective was to compare the risk of maternal placental syndromes between women living with and without HIV infection in Ontario. METHODS: We conducted a population-based study using health administrative data from Ontario. We identified all pregnancies resulting in a live birth between Apr. 1, 2002, and Mar. 31, 2011; we identified women living with HIV using a validated case-finding algorithm. Our primary composite outcome was maternal placental syndromes, defined as a diagnosis of preeclampsia, eclampsia, placental abruption or placental infarction. We used generalized estimating equations with a logit link function to derive adjusted odds ratios (AORs) and 95% confidence intervals (CI) for the association between HIV infection and maternal placental syndromes. RESULTS: Data from 1 132 871 pregnancies were available for analysis; 634 (0.06%) of the pregnancies were in women living with HIV. After multivariable adjustment, we found no difference in the risk of maternal placental syndromes between women living with HIV and those without HIV infection (5.8% v. 5.6%; AOR 0.85 [95% CI 0.59-1.21]). An increased risk of maternal placental syndromes was associated with pre-existing diabetes (AOR 1.47 [95% CI 1.39-1.54]), pre-existing hypertension (AOR 4.28 [95% CI 4.15 4.42]) and chronic kidney disease (AOR 1.83 [95% CI 1.61-2.08]). INTERPRETATION: Women with HIV are not at increased risk of maternal placental syndromes. Our results underscore the importance of optimizing the management of comorbid illness associated with maternal placental syndromes during the prenatal period for all women, irrespective of HIV status. PMID- 26770961 TI - Readiness of hospital-based internists to embrace and discuss high-value care with patients and family members: a single-centre cross-sectional survey study. AB - BACKGROUND: Choosing Wisely Canada is a campaign that fosters conversations between physicians and patients about high-value health care. However, little is known about physicians' readiness to have these conversations. Our objective was to determine how ready practising internists were to embrace and openly address high-value care during conversations with patients or their families. METHODS: Practising internists in hospitals affiliated with McMaster University, Hamilton, Ontario, were invited to complete an electronic survey with 3 clinical scenarios: each had 3 low-value interventions that had been requested by the patient or family member. For each request, participants chose 1 of 3 statements reflecting how they would respond: a low-value statement agreeing to provide the intervention, an implicit high-value statement declining to provide the intervention without mentioning value or an explicit high-value statement declining to provide the intervention with mention of value. RESULTS: Forty-four of 62 eligible physicians (71.0% response rate) participated in the survey. High value statements were selected in 91% of cases. The implicit high-value statement was chosen more often than the explicit high-value statement (65.7% v. 25.5% of all responses, respectively; chi2 range 4.46-56.23, p < 0.05). INTERPRETATION: Physicians favoured high-value care but frequently chose not to explicitly address value in their statements. Physicians seemed ready to embrace high-value health care practice, although they were not ready to openly discuss it with patients and their families. PMID- 26770962 TI - Correction: A cross-sectional examination of medicinal substance abuse and use of nonmedicinal substances among Canadian youth: findings from the 2012-2013 Youth Smoking Survey. PMID- 26770963 TI - Operative versus nonoperative interventions for common fractures of the clavicle: a meta-analysis of randomized controlled trials. AB - BACKGROUND: The popularity of surgery for acute displaced midshaft clavicle fractures has been fuelled by early randomized controlled trials (RCTs) showing improved rates of radiographic union and perceived functional benefits compared with nonoperative approaches. We performed a meta-analysis to determine the effect of operative and nonoperative interventions on the risk of secondary operation and complications and on long-term function. METHODS: We search MEDLINE, Embase and the Cochrane Central Register of Controlled Trials for reports of relevant RCTs published to Mar. 7, 2014. Two reviewers assessed eligibility of potential reports and the risk of bias of included trials. The Grading of Recommendations Assessment, Development and Evaluation approach was used to summarize the quality of evidence for all outcomes. RESULTS: We included 15 RCTs (9 trials comparing operative and nonoperative interventions, 5 comparing implants for operative treatment, and 1 comparing nonoperative treatments). Nonoperative treatments did not differ from operative treatments in the risk of secondary operation (risk ratio [RR] 1.16, 95% confidence interval [CI] 0.58 to 2.35) or all complications (RR 0.90, 95% CI 0.55 to 1.50). One in 4 patients had a complication regardless of the treatment approach. Differences in functional outcomes, although smaller than the threshold for minimal important differences at 1 year, favoured operative interventions (standardized mean difference 0.38, 95% CI 0 to 0.75). Evidence for the type of implant or approach to nonoperative treatment remained inconclusive. INTERPRETATION: Current evidence does not support the routine use of internal fixation for the treatment of displaced midshaft clavicle fractures. Complication rates were high regardless of the treatment approach. PMID- 26770964 TI - Treatment for mild cognitive impairment: a systematic review and meta-analysis. AB - BACKGROUND: The effectiveness of treatments for mild cognitive impairment is uncertain. The aim of this review was to evaluate the effectiveness and harms of treatment for mild cognitive impairment in adults 65 years of age and older. METHODS: We searched MEDLINE, Embase and Cochrane Central (December 2012-December 2014); citations from 2 systematic reviews were considered for inclusion. We included randomized controlled trials involving community-dwelling adults aged 65 years and older with a diagnosis of mild cognitive impairment. Studies reporting on cognition, function, behaviour, global status, mortality and adverse events for treatment with pharmacologic and nonpharmacologic interventions were included. RESULTS: Seventeen studies were included. Cholinesterase inhibitor studies evaluating cognition (Alzheimer's Disease Assessment Scale, cognition subscale) showed no difference between intervention and control groups (mean difference [MD] -0.33, 95% CI -0.73 to 0.06]; one behavioural study showed no significant effect on cognition (Alzheimer's Disease Assessment Scale, cognition subscale) for the intervention group when compared to controls (MD -0.60, (95% CI -1.44 to 0.24), and one study on vitamin E showed no difference between intervention and control groups (MD 0.85, 95% CI -0.32 to 2.02). With the Mini Mental State Examination, cholinesterase inhibitors showed no difference between intervention and control groups (MD 0.17, 95% CI -0.13 to 0.47); behavioural studies showed a significant difference favouring intervention (MD 1.01, 95% CI 0.25 to 1.77), and studies of dietary supplements and/or vitamins showed no difference between intervention and control groups (MD 0.20, 95% CI -0.04 to 0.43). Pharmacologic studies showed no difference in serious adverse events (risk ratio 0.98, 95% CI 0.86 to 1.10). No serious adverse events were reported for nonpharmacologic interventions. INTERPRETATION: Treatment of mild cognitive impairment with cholinesterase inhibitors showed no benefit when compared with a control group. A small cognitive benefit was observed using behavioural therapies when compared with the control group. However, the clinical significance of this small benefit remains uncertain. The current evidence does not support the use of cholinesterase inhibitors for treating mild cognitive impairment, and future high quality research using a standardized approach is needed to affirm the finding of a small benefit on cognition that was observed for behavioural interventions. REGISTRATION: PROSPERO no. CRD42014015431. PMID- 26770965 TI - Trends in the coprescription of proton pump inhibitors with clopidogrel: an ecological analysis. AB - BACKGROUND: In early 2009, 2 observational studies and a US Food and Drug Administration (FDA) advisory addressed the drug interaction between proton pump inhibitors (PPIs) and clopidogrel. One study suggested that pantoprazole could be used safely in this setting, whereas the other study and the FDA advisory did not distinguish among PPIs. We examined trends in PPI prescribing among clopidogrel recipients in the period following these events. METHODS: We conducted a population-based time series analysis of Ontario residents aged 66 years or older for whom clopidogrel was prescribed between Apr. 1, 1999, and Sept. 30, 2013. We determined the proportion of clopidogrel recipients dispensed a PPI during each quarter and the proportions who received pantoprazole or other PPIs. The outcome of interest was change in the use of pantoprazole. RESULTS: In the final quarter of 2008, pantoprazole represented 23.7% of all PPI prescriptions dispensed to patients receiving clopidogrel. Following the publications and FDA advisory in early 2009, pantoprazole use increased substantially. By the end of 2009, this medication accounted for 52.5% of all PPI prescriptions issued to patients receiving clopidogrel; by the end of the study period, it accounted for 71.0% of all PPI prescriptions dispensed to such patients (p < 0. 001). We also observed a modest drop in overall PPI use among clopidogrel recipients beginning in early 2009. INTERPRETATION: In 2009, the prescribing of PPIs with clopidogrel changed substantially in Ontario, with pantoprazole rapidly becoming the most commonly prescribed agent in its class. However, a modest decline in overall PPI use also occurred that may reflect suboptimal translation of emerging drug safety information to clinical practice. PMID- 26770966 TI - Time trends in intracranial bleeding associated with direct oral anticoagulants: a 5-year cohort study. AB - BACKGROUND: Over the past 5 years, dabigatran, rivaroxaban and apixaban were approved for stroke prevention. Phase III studies have shown a lower risk of intracranial bleeding with these direct oral anticoagulants than with warfarin; however, there is a lack of real-life data to validate this. We analyzed time trends in atraumatic intracranial bleeding from 2009 to 2013 among patients prescribed oral anticoagulants and those not prescribed oral anticoagulants. METHODS: We used ICD-10-CA (enhanced Canadian version of the 10th revision of the International Statistical Classification of Diseases and Related Health Problems) codes to identify all patients with atraumatic intracranial bleeding who presented to our neurosurgical centre (serving a population of more than 1.2 million). Trained researchers extracted data on anticoagulant medications used in the week before diagnosis of the intracranial bleed. Provincial prescription data for oral anticoagulants were obtained from IMS Brogan CompuScript Market Dynamics. The primary outcome was the time trend in incident intracranial bleeds associated with oral anticoagulation during the period 2009-2013. The secondary outcomes were the time trend in intracranial bleeds not associated with oral anticoagulation and the provincial prescribing patterns for oral anticoagulants during the same period. RESULTS: A total of 2050 patients presented with atraumatic intracranial bleeds during the study period. Of the 371 (18%) prescribed an anticoagulant in the week before presentation, 335 were prescribed an oral anticoagulant. There was an increasing time trend in intracranial bleeding associated with oral anticoagulants (p = 0.009; 6 additional events per year) and in intracranial bleeding not associated with oral anticoagulation (p = 0.06). During 2013, prescriptions for warfarin decreased to 70% of all oral anticoagulant prescriptions in the province, whereas those for dabigatran and rivaroxaban increased to 17% and 12%, respectively. INTERPRETATION: We observed increasing time trends in intracranial bleeding, both associated with and not associated with oral anticoagulants, over the study period. Although aggregate provincial data showed increased prescribing of oral anticoagulants, other more likely explanations for our findings include an aging population or increasing frailty. PMID- 26770967 TI - Cost-effectiveness of clopidogrel, prasugrel and ticagrelor for dual antiplatelet therapy after acute coronary syndrome: a decision-analytic model. AB - BACKGROUND: The use of prasugrel or ticagrelor as part of dual antiplatelet therapy with acetylsalicylic acid after acute coronary syndrome (ACS) improves clinical outcomes relative to clopidogrel. The relative cost-effectiveness of these agents are unknown. We conducted an economic analysis evaluating 12 months of treatment with clopidogrel, prasugrel or ticagrelor after ACS. METHODS: We developed a fully probabilistic Markov cohort decision-analytic model using a lifetime horizon, from the perspective of the Ontario Ministry of Health and Long Term Care. The model incorporated risks of death, recurrent ACS, heart failure, major bleeding and other adverse effects of treatment. Data on probabilities and utilities were obtained from the published literature where available. The primary outcome was quality-adjusted life-years (QALYs). RESULTS: Treatment with clopidogrel was associated with the lowest effectiveness (7.41 QALYs, 95% confidence interval [CI] 1.05-14.79) and the lowest cost ($39 601, 95% CI $8434 $111 186). Ticagrelor treatment had an effectiveness of 7.50 QALYs (95% CI 1.13 14.84) at a cost of $40 649 (95% CI $9327-$111 881). The incremental cost effectiveness ratio (ICER) for ticagrelor relative to clopidogrel was $12 205 per QALY gained. Prasugrel had an ICER of $57 630 per QALY gained relative to clopidogrel. Ticagrelor was the preferred option in 90% of simulations at a willingness-to-pay threshold of $50 000 per QALY gained. INTERPRETATION: Ticagrelor was the most cost-effective agent when used as part of dual antiplatelet therapy after ACS. This conclusion was robust to wide variations in model parameters. PMID- 26770968 TI - Divergence of the bZIP Gene Family in Strawberry, Peach, and Apple Suggests Multiple Modes of Gene Evolution after Duplication. AB - The basic leucine zipper (bZIP) transcription factors are the most diverse members of dimerizing transcription factors. In the present study, 50, 116, and 47 bZIP genes were identified in Malus domestica (apple), Prunus persica (peach), and Fragaria vesca (strawberry), respectively. Species-specific duplication was the main contributor to the large number of bZIPs observed in apple. After WGD in apple genome, orthologous bZIP genes corresponding to strawberry on duplicated regions in apple genome were retained. However, in peach ancestor, these syntenic regions were quickly lost or deleted. Maybe the positive selection contributed to the expansion of clade S to adapt to the development and environment stresses. In addition, purifying selection was mainly responsible for bZIP sequence-specific DNA binding. The analysis of orthologous pairs between chromosomes indicates that these orthologs derived from one gene duplication located on one of the nine ancient chromosomes in the Rosaceae. The comparative analysis of bZIP genes in three species provides information on the evolutionary fate of bZIP genes in apple and peach after they diverged from strawberry. PMID- 26770969 TI - Computer Simulation and Analysis on Flow Characteristics and Distribution Patterns of Polymethylmethacrylate in Lumbar Vertebral Body and Vertebral Pedicle. AB - This study was designed to analyze the flow and distribution of polymethylmethacrylate (PMMA) in vertebral body through computer simulation. Cadaveric lumbar vertebrae were scanned through electron beam tomography (EBT). The data was imported into Mimics software to build computational model. Vertebral body center and junction of pedicle and vertebral body were chosen as injection points. Silicone oil with viscosity of 100,000 cSt matching with PMMA bone cement was chosen for injection. The flow and distribution of silicone oil were analyzed using Fluent software. In vertebral body, silicone oil formed a circle-like shape centered by injection point on transverse and longitudinal sections, finally forming a sphere-like shape as a whole. Silicone oil diffused along lateral and posterior walls forming a circle-like shape on transverse section centered by injection point in pedicle, eventually forming a sphere-like shape as a whole. This study demonstrated that silicone oil flowed and diffused into a circle-like shape centered by injection point and finally formed a sphere like shape as a whole in both vertebral body and pedicle. The flow and distribution of silicon oil in computational model could simulate PMMA distribution in vertebral body. It may provide theoretical evidence to reduce PMMA leakage risk during percutaneous vertebroplasty. PMID- 26770970 TI - Mitochondrial Dysfunction and Autophagy in Hepatic Ischemia/Reperfusion Injury. AB - Ischemia/reperfusion (I/R) injury remains a major complication of liver resection, transplantation, and hemorrhagic shock. Although the mechanisms that contribute to hepatic I/R are complex and diverse involving the interaction of cell injury in hepatocytes, immune cells, and endothelium, mitochondrial dysfunction is a cardinal event culminating in hepatic reperfusion injury. Mitochondrial autophagy, so-called mitophagy, is a key cellular process that regulates mitochondrial homeostasis and eliminates damaged mitochondria in a timely manner. Growing evidence accumulates that I/R injury is attributed to defective mitophagy. This review aims to summarize the current understanding of autophagy and its role in hepatic I/R injury and highlight the various therapeutic approaches that have been studied to ameliorate injury. PMID- 26770971 TI - Effluent Tenascin-C Levels Reflect Peritoneal Deterioration in Peritoneal Dialysis: MAJOR IN PD Study. AB - Peritoneal deterioration causing structural changes and functional decline is a major complication of peritoneal dialysis (PD). The aim of this study was to explore effluent biomarkers reflecting peritoneal deterioration. In an animal study, rats were intraperitoneally administered with PD fluids adding 20 mM methylglyoxal (MGO) or 20 mM formaldehyde (FA) every day for 21 days. In the MGO treated rats, tenascin-C (TN-C) levels in the peritoneal effluents were remarkably high and a cluster of TN-C-positive mesothelial cells with epithelial to-mesenchymal transition- (EMT-) like change excessively proliferated at the peritoneal surface, but not in the FA-treated rats. Effluent matrix metalloproteinase-2 (MMP-2) levels increased in both the MGO- and FA-treated rats. In a clinical study at 18 centers between 2006 and 2013, effluent TN-C and MMP-2 levels were quantified in 182 PD patients with end-stage renal disease. Peritoneal function was estimated using the peritoneal equilibration test (PET). From the PET results, the D/P Cr ratio was correlated with effluent levels of TN C (rho = 0.57, p < 0.001) and MMP-2 (rho = 0.73, p < 0.001). We suggest that TN-C in the effluents may be a diagnostic marker for peritoneal deterioration with EMT like change in mesothelial cells in PD. PMID- 26770972 TI - Identification of Extended-Spectrum beta-Lactamases Escherichia coli Strains Isolated from Market Garden Products and Irrigation Water in Benin. AB - The present study aimed at biochemical and molecular characterization of Escherichia coli strains isolated from horticultural products and irrigation water of Cotonou. The samples were collected from 12 market gardeners of 4 different sites. Rapid' E. coli medium was used for identification of E. coli strains and the antimicrobial susceptibility was performed by the agar disk diffusion method. The beta-lactamases production was sought by the liquid acidimetric method. The genes coding for beta-lactamases and toxins were identified by PCR method. The results revealed that about 34.95% of the analyzed samples were contaminated by E. coli. Cabbages were the most contaminated by E. coli (28.26%) in dry season. All isolated strains were resistant to amoxicillin. The penicillinase producing E. coli carried blaTEM (67.50%), blaSHV (10%), and blaCTX-M (22.50%) genes. The study revealed that the resistance genes such as SLTI (35.71%), SLTII (35.71%), ETEC (7.15%), and VTEC (21.43%) were carried. Openly to the found results and considering the importance of horticultural products in Beninese food habits, it is important to put several strategies aiming at a sanitary security by surveillance and sensitization of all the actors on the risks of some practices. PMID- 26770973 TI - Long-Term Outcomes of Cultivated Limbal Epithelial Transplantation: Evaluation and Comparison of Results in Children and Adults. AB - PURPOSE: To compare the long-term clinical outcomes of cultivated limbal epithelial transplantation (CLET) in children and adults with limbal stem cell deficiency. DESIGN: Retrospective case series. METHODS: Case records of patients with limbal stem cell deficiency (LSCD) who underwent CLET from April 2004 to December 2014 were studied. Outcome measures were compared in terms of anatomical success and visual improvement. Parameters for total anatomical success were avascular, epithelized, and clinically stable corneal surface without conjunctivalization, whereas partial anatomical success was considered when mild vascularization (sparing centre of cornea) and mild conjunctivalization were noted along with complete epithelization. RESULTS: A total of 62 cases underwent the CLET procedure: 38 (61.3%) were children and 24 (38.7%) were adults. Patients with unilateral LSCD (33 children and 21 adults) had autografts and those with bilateral LSCD (5 children and 3 adults) had allografts. Amongst the 54 autografts partial and total anatomical success were noted in 21.2% and 66.6% children, respectively, and 19.0% and 80.9% in adults, respectively (p value 0.23). Visual improvement of 1 line and >=2 lines was seen in 57.5% and 21.2% children, respectively, and 38% and 38% in adults, respectively (p value 0.31). CONCLUSION: Cultivated limbal epithelial transplantation gives good long-term results in patients with LSCD and the outcomes are comparable in children and adults. PMID- 26770975 TI - Experimental Analysis of the Mechanism of Hearing under Water. AB - The mechanism of human hearing under water is debated. Some suggest it is by air conduction (AC), others by bone conduction (BC), and others by a combination of AC and BC. A clinical bone vibrator applied to soft tissue sites on the head, neck, and thorax also elicits hearing by a mechanism called soft tissue conduction (STC) or nonosseous BC. The present study was designed to test whether underwater hearing at low intensities is by AC or by osseous BC based on bone vibrations or by nonosseous BC (STC). Thresholds of normal hearing participants to bone vibrator stimulation with their forehead in air were recorded and again when forehead and bone vibrator were under water. A vibrometer detected vibrations of a dry human skull in all similar conditions (in air and under water) but not when water was the intermediary between the sound source and the skull forehead. Therefore, the intensities required to induce vibrations of the dry skull in water were significantly higher than the underwater hearing thresholds of the participants, under conditions when hearing by AC and osseous BC is not likely. The results support the hypothesis that hearing under water at low sound intensities may be attributed to nonosseous BC (STC). PMID- 26770974 TI - Antibody-Based Assays for Phenotyping of Extracellular Vesicles. AB - Extracellular vesicles (EVs) are a heterogeneous population of membrane-enclosed vesicles. EVs are recognized as important players in cell-to-cell communication and are described to be involved in numerous biological and pathological processes. The fact that EVs are involved in the development and progression of several diseases has formed the basis for the use of EV analysis in a clinical setting. As the interest in EVs has increased immensely, multiple techniques have been developed aiming at characterizing these vesicles. These techniques characterize different features of EVs, like the size distribution, enumeration, protein composition, and the intravesicular cargo (e.g., RNA). This review focuses on techniques that exploit the specificity and sensitivity associated with antibody-based assays to characterize the protein phenotype of EVs. The protein phenotype of EVs can provide information on the functionality of the vesicles and may be used for identification of disease-related biomarkers. Thus, protein profiling of EVs holds great diagnostic and prognostic potential. PMID- 26770976 TI - Exploring the Link between the Components of Metabolic Syndrome and the Risk of Depression. AB - BACKGROUND: Metabolic syndrome (MetS) has been reported with an increased risk of depression. MetS was also associated with insulin resistance. This study aimed to evaluate whether MetS components might contribute to depression in participants with insulin resistance (IR) or not. METHODS: This study included 3,331 participants >=18 years in the NHANES 2009-2010. Depressive symptoms were assessed using the Patient Health Questionnaire-9 (PHQ-9). MetS components were measured using blood chemistry and body measurements. IR was identified using the homeostasis model assessment method. RESULTS: Predicted PHQ-9 scores significantly increased as the number of MetS components increased in patients with IR. The adjusted beta coefficients of the predicted PHQ-9 score with 2, 4, and 5 MetS components were 1.803, 2.081, and 3.048, respectively (P for trend < 0.05). Low HDL-C levels were significantly associated with higher predicted total PHQ-9 scores in fully adjusted models in the IR group (P < 0.05). CONCLUSION: The results indicated that the presence of a greater number of components of MetS was significantly associated with higher predicted total PHQ-9 scores in participants with IR. Among the components of MetS, the most apparent association was observed between low HDL and higher predicted total PHQ-9 scores. PMID- 26770977 TI - Natural Hirudin Increases Rat Flap Viability by Anti-Inflammation via PARs/p38/NF kappaB Pathway. AB - The present study aimed to evaluate the effect of natural hirudin on rat random skin flap viability and to determine the mechanism. Forty-eight rats were randomly divided into 2 groups. After the dorsal skin flap operation (3 cm * 10 cm in size), subcutaneous injections of 6 ATU hirudin were administered to group H (n = 24) every 12 h, while group C (n = 24) received an equal volume of 0.9% normal saline. Six rats from each group were euthanized 1, 2, 4, and 7 days after the operation. A full skin sample was collected from these rats to measure the p38-mitogen-activated protein kinase (p38-MAPK), phospho-p38- (Pp38-) MAPK, nuclear factor-kappaB (NF-kappaB) p65, phosphor-NF-kappaB (pNF-kappaB) p65, tumour necrosis factor- (TNF-) alpha, interleukin- (IL-) 6, and intercellular adhesion molecule- (ICAM-) 1 levels via western blot (WB) assays. The results showed that flap viability was significantly higher in the hirudin-treated group, which showed a reduced inflammatory response compared with the control group. The Pp38/p38, pNF-kappaB p65/NF-kappaB p65, TNF-alpha, IL-6, and ICAM-1 levels in the hirudin-treated group were lower than those in the control group. The results demonstrated that hirudin could improve random skin flap viability and suggested that this effect maybe occurs by blocking the thrombin/proteinase-activated receptors (PARs)/p38/NF-kappaB signalling pathway, thus decreasing the inflammatory response. PMID- 26770978 TI - Role of TLR4-Mediated PI3K/AKT/GSK-3beta Signaling Pathway in Apoptosis of Rat Hepatocytes. AB - We investigated the mechanism of the Toll-like receptor 4- (TLR4-) mediated PI3K/AKT/GSK-3beta signaling pathway in rat hepatocytes apoptosis induced by LPS. The cultured rat hepatocytes were treated with LPS alone or first pretreated with TLR4 inhibitor, AKT inhibitor, and GSK-3beta inhibitor, respectively, and then stimulated with the same dose of LPS. Cell viability, cell apoptotic rate, and apoptosis morphology were assessed; the level of P-AKT(Ser473), P-GSK 3beta(Ser9), and active Caspase-3 and the ratio of Bax/Bcl-2 were evaluated. The results indicated that cell viability decreased, while cell apoptotic rate increased with time after LPS stimulation. The expression of P-AKT(Ser473) and P GSK-3beta(Ser9) in the LPS group decreased compared with the control, while the level of active Caspase-3 and the ratio of Bax/Bcl-2 were significantly increased. These effects were attenuated by pretreatment with CLI-095. In addition, the apoptotic ratio decreased after pretreatment with LiCl but increased following pretreatment with LY294002. The expression of P-AKT(Ser473) further decreased following pretreatment with LY294002 and the expression of P GSK-3beta(Ser9) increased following pretreatment with LiCl. Moreover, pretreatment with CLI-095 weakened LPS-induced nuclear translocation of GSK 3beta. Our findings suggest that the TLR4-mediated PI3K/AKT/GSK-3beta signaling pathway is present in rat hepatocytes and participates in apoptosis of BRL-3A cells. PMID- 26770979 TI - Quantification of Outdoor Mobility by Use of Accelerometer-Measured Physical Behaviour. AB - Hip fractures in older persons are associated with both low levels of daily physical activity and loss of outdoor mobility. The aim was to investigate if accelerometer-based measures of physical behaviour can be used to determine if people undertake outdoor walking and to provide reference values for physical behaviour outcomes related to outdoor mobility. Older persons (n = 245), >=70 years, one year after hip fracture, participated. Six objective measures of physical behaviour collected by an activity monitor were compared with self reported outdoor mobility assessed with the Nottingham Extended ADL scale. All measures of time and length in upright periods were significantly lower in participants who reported not walking outdoors (p < 0.001). A set of cut-off points for the different physical behaviour variables was generated. Maximum length of upright events discriminated best between groups, with 31 minutes as a threshold to determine if a person is more likely to report that they walk outdoors (sensitivity: 0.805, specificity: 0.704, and AUC: 0.871) or 41 minutes or more to determine if a person is more likely to report outdoor walking on their own (AUC: 0.891). Physical behaviour variables from activity monitoring can provide information about patterns of physical behaviour related to outdoor activity performance. PMID- 26770980 TI - In Vivo Confocal Microscopy of the Human Cornea in the Assessment of Peripheral Neuropathy and Systemic Diseases. AB - In vivo confocal microscopy (IVCM) of the living human cornea offers the ability to perform repeated imaging without tissue damage. Studies using corneal IVCM have led to significant contributions to scientific and clinical knowledge of the living cornea in health and pathological states. Recently the application of corneal IVCM beyond ophthalmology to wider clinical and research fields has been demonstrated. Abnormalities of the corneal subbasal nerve plexus have been associated with many forms of peripheral neuropathy and Langerhans cells correlate with systemic inflammatory states. There is a rapidly growing evidence base investigating the use of corneal IVCM in many systemic conditions and a well established evidence base for IVCM imaging of the corneal subbasal plexus in diabetic peripheral neuropathy. This paper reviews the potential use of corneal IVCM in general clinical practice as a noninvasive method of assessing peripheral neuropathies, monitoring inflammatory states and clinical therapeutic response. PMID- 26770981 TI - Association of 2184AG Polymorphism in the RAGE Gene with Diabetic Nephropathy in Chinese Patients with Type 2 Diabetes. AB - OBJECTIVE: The interaction between advanced glycation end products and their cellular receptor (RAGE) has an important role in the pathogenesis of diabetic microvascular complications. The aim of this study was to investigate the relationship between the 2184A/G polymorphism in the RAGE gene and diabetic nephropathy in Chinese Han patients with type 2 diabetes mellitus. METHODS: A total of 868 patients with type 2 diabetes mellitus (486 without and 382 with diabetic nephropathy) were enrolled in this study. The genotype and allele frequencies of the 2184A/G polymorphism were detected using the polymerase chain reaction-restriction fragment-length polymorphism method. RESULTS: The G allele and AG + GG genotype frequencies in patients with diabetic nephropathy were significantly lower than those in patients without diabetic nephropathy (P = 0.001 and P = 0.005, resp.). After adjustments for possible confounders, multivariate logistic regression analyses showed that the 2184A/G polymorphism was independently associated with diabetic nephropathy (OR = 0.46, 95% CI: 0.22 0.92, P = 0.028). CONCLUSIONS: Our study indicated that the 2184A/G polymorphism in the RAGE gene was significantly associated with diabetic nephropathy in Chinese Han patients with type 2 diabetes. PMID- 26770982 TI - A Combination of Human Embryonic Stem Cell-Derived Pancreatic Endoderm Transplant with LDHA-Repressing miRNA Can Attenuate High-Fat Diet Induced Type II Diabetes in Mice. AB - Type II diabetes mellitus (T2D) is a chronic metabolic disorder that results from defects in both insulin secretion and insulin action. The deficit and dysfunction of insulin secreting beta-cell are signature symptom for T2D. Additionally, in pancreatic beta-cell, a small group of genes which are abundantly expressed in most other tissues are highly selectively repressed. Lactate dehydrogenase A (LDHA) is one of such genes. Upregulation of LDHA is found in both human T2D and rodent T2D models. In this study, we identified a LDHA-suppressing microRNA (hsa miR-590-3p) and used it together with human embryonic stem cell (hESC) derived pancreatic endoderm (PE) transplantation into a high-fat diet induced T2D mouse model. The procedure significantly improved glucose metabolism and other symptoms of T2D. Our findings support the potential T2D treatment using the combination of microRNA and hESC-differentiated PE cells. PMID- 26770983 TI - Effect of Acarbose on Long-Term Prognosis in Acute Coronary Syndromes Patients with Newly Diagnosed Impaired Glucose Tolerance. AB - OBJECTIVE: To investigate the effect of acarbose therapy on the long-term prognosis of patients with acute coronary syndromes (ACS) complicating newly diagnosed impaired glucose tolerance (IGT). METHODOLOGY: 135 patients hospitalized for ACS who had been newly diagnosed with IGT were randomly assigned to acarbose group (150 mg/day, n = 67) or control group (no acarbose, n = 68). All cases in each group were given the same elementary treatment. Mean follow-up was 2.3 years. The incidence of major adverse cardiovascular event (MACE) and carotid intima-middle thickness (CIMT) were statistically analyzed. RESULTS: During the mean follow-up of 2.3 years, the risk of recurrent MACE in acarbose group was decreased significantly compared with that in control group (26.67% versus 46.88%, P < 0.05); at the same time, thickening of the CIMT was significantly slower than the control group ((1.28 +/- 0.42) mm versus (1.51 +/- 0.64) mm, P < 0.05). CONCLUSIONS: Acarbose can effectively reduce the risk of MACE in ACS patients with newly diagnosed IGT, simultaneously retarding the progression of carotid intima-media thickness. PMID- 26770984 TI - Modulating DDAH/NOS Pathway to Discover Vasoprotective Insulin Sensitizers. AB - Insulin resistance syndrome (IRS) is a configuration of cardiovascular risk factors involved in the development of metabolic disorders including type 2 diabetes mellitus. In addition to diet, age, socioeconomic, and environmental factors, genetic factors that impair insulin signaling are centrally involved in the development and exacerbation of IRS. Genetic and pharmacological studies have demonstrated that the nitric oxide (NO) synthase (NOS) genes are critically involved in the regulation of insulin-mediated glucose disposal. The generation of NO by the NOS enzymes is known to contribute to vascular homeostasis including insulin-mediated skeletal muscle vasodilation and insulin sensitivity. By contrast, excessive inhibition of NOS enzymes by exogenous or endogenous factors is associated with insulin resistance (IR). Asymmetric dimethylarginine (ADMA) is an endogenous molecule that competitively inhibits all the NOS enzymes and contributes to metabolic perturbations including IR. The concentration of ADMA in plasma and tissue is enzymatically regulated by dimethylarginine dimethylaminohydrolase (DDAH), a widely expressed enzyme in the cardiovascular system. In preclinical studies, overexpression of DDAH has been shown to reduce ADMA levels, improve vascular compliance, and increase insulin sensitivity. This review discusses the feasibility of the NOS/DDAH pathway as a novel target to develop vasoprotective insulin sensitizers. PMID- 26770985 TI - Association of Haemostatic and Inflammatory Biomarkers with Nephropathy in Type 1 Diabetes Mellitus. AB - This study aimed at investigating the association between haemostatic biomarkers, proinflammatory, and anti-inflammatory cytokines with chronic kidney disease in type 1 diabetic patients. Patients were divided into two groups: with nephropathy (albuminuria >= 30 mg/g and/or GFR < 60 mL/min/1.73 m(2)), n = 65; and without nephropathy (albuminuria < 30 mg/g and GFR >= 60 mL/min/1.73 m(2)), n = 60. INF gamma, IL-6, IL-10, and TNF-alpha plasma levels were determined by flow cytometry. VWF, ADAMTS13 antigen, and D-Dimer plasma levels were determined by enzyme-linked immunosorbent assay and ADAMTS13 activity was assessed by fluorescence resonance energy transfer assay. Elevated levels of INF-gamma, VWF, ADAMTS13 antigen, D-Dimer, and reduced ADAMTS13 activity/antigen ratio were observed in patients with nephropathy as compared to those without nephropathy (P = 0.001, P < 0.001, P < 0.001, P < 0.001, and P < 0.001, resp.). Cytokines and haemostatic biomarkers remained associated with nephropathy after adjustments (use of statin, acetylsalicylic acid, angiotensin converting enzyme inhibitor, and angiotensin antagonist). INF-gamma, TNF-alpha, and IL-10 significantly correlated with haemostatic biomarkers. Inflammatory and hypercoagulability status are associated with nephropathy in type 1 diabetes mellitus and an interrelationship between them may play an important role in pathogenesis of diabetic nephropathy. PMID- 26770986 TI - Recent Insight in Islet Amyloid Polypeptide Morphology, Structure, Membrane Interaction, and Toxicity in Type 2 Diabetes. PMID- 26770987 TI - Nutrition and Physical Activity in Nonalcoholic Fatty Liver Disease. AB - Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide and it is associated with other medical conditions such as diabetes mellitus, metabolic syndrome, and obesity. The mechanisms of the underlying disease development and progression are not completely established and there is no consensus concerning the pharmacological treatment. In the gold standard treatment for NAFLD weight loss, dietary therapy, and physical activity are included. However, little scientific evidence is available on diet and/or physical activity and NAFLD specifically. Many dietary approaches such as Mediterranean and DASH diet are used for treatment of other cardiometabolic risk factors such as insulin resistance and type-2 diabetes mellitus (T2DM), but on the basis of its components their role in NAFLD has been discussed. In this review, the implications of current dietary and exercise approaches, including Brazilian and other guidelines, are discussed, with a focus on determining the optimal nonpharmacological treatment to prescribe for NAFLD. PMID- 26770989 TI - Psychological Aspects Related to Diabetes Mellitus. PMID- 26770988 TI - Subclinical Detection of Diabetic Cardiomyopathy with MicroRNAs: Challenges and Perspectives. AB - The prevalence of cardiac diabetic diseases has been increased around the world, being the most common cause of death and disability among diabetic patients. In particular, diabetic cardiomyopathy is characterized with a diastolic dysfunction and cardiac remodelling without signs of hypertension and coronary artery diseases. In an early stage, it is an asymptomatic disease; however, clinical studies demonstrate that diabetic myocardia are more vulnerable to injury derived by acute myocardial infarct and are the worst prognosis for rehabilitation. Currently, biochemical and imaging diagnostic methods are unable to detect subclinical manifestation of the disease (prior to diastolic dysfunction). In this review, we elaborately discuss the current scientific evidences to propose circulating microRNAs as promising biomarkers for early detection of diabetic cardiomyopathy and, then, to identify patients at high risk of diabetic cardiomyopathy development. Moreover, here we summarise the research strategies to identify miRNAs as potential biomarkers, present limitations, challenges, and future perspectives. PMID- 26770990 TI - Modulation Effect of Peroxisome Proliferator-Activated Receptor Agonists on Lipid Droplet Proteins in Liver. AB - Peroxisome proliferator-activated receptor (PPAR) agonists are used for treating hyperglycemia and type 2 diabetes. However, the mechanism of action of these agonists is still under investigation. The lipid droplet-associated proteins FSP27/CIDEC and LSDP5, regulated directly by PPARgamma and PPARalpha, are associated with hepatic steatosis and insulin sensitivity. Here, we evaluated the expression levels of FSP27/CIDEC and LSDP5 and the regulation of these proteins by consumption of a high-fat diet (HFD) or administration of PPAR agonists. Mice with diet-induced obesity were treated with the PPARgamma or PPARalpha agonist, pioglitazone or fenofibrate, respectively. Liver tissues from db/db diabetic mice and human were also collected. Interestingly, FSP27/CIEDC was expressed in mouse and human livers and was upregulated in obese C57BL/6J mice. Fenofibrate treatment decreased hepatic triglyceride (TG) content and FSP27/CIDEC protein expression in mice fed an HFD diet. In mice, LSDP5 was not detected, even in the context of insulin resistance or treatment with PPAR agonists. However, LSDP5 was highly expressed in humans, with elevated expression observed in the fatty liver. We concluded that fenofibrate greatly decreased hepatic TG content and FSP27/CIDEC protein expression in mice fed an HFD, suggesting a potential regulatory role for fenofibrate in the amelioration of hepatic steatosis. PMID- 26770991 TI - Assessment of Insulin Resistance in Subjects with Normal Glucose Tolerance, Hyperinsulinemia with Normal Blood Glucose Tolerance, Impaired Glucose Tolerance, and Newly Diagnosed Type 2 Diabetes (Prediabetes Insulin Resistance Research). AB - AIM: To evaluate the differences in insulin resistance (IR) among subjects with normal glucose tolerance (NGT), hyperinsulinemia with NGT (HINS), impaired glucose tolerance (IGT), and newly diagnosed type 2 diabetes mellitus (T2DM). METHODS: 5 NGT, 25 HINS, 25 IGT, and 25 T2DM subjects participated in this research. The hyperinsulinemic-euglycemic clamp technique (HECT) was performed in all of them to evaluate IR levels. The relative factors influencing IR were evaluated. The simple insulin sensitivity indices were calculated, and the correlation between each index and the M value was analyzed. RESULTS: The M values of NGT, HINS, IGT, and T2DM groups were 11.88 +/- 2.93 mg . kg(-1) . min( 1), 6.23 +/- 1.73 mg . kg(-1) . min(-1), 6.37 +/- 2.12 mg . kg(-1) . min(-1), and 6.19 +/- 1.89 mg . kg(-1) . min(-1), respectively. M values in HINS, IGT, and T2DM groups were lower than those in the NGT group (P = 0.005); however, the differences among the HINS, IGT, and T2DM groups were not statistically significant (P = 0.835). The independent factors influencing the M value were waistline and fasting insulin level (FINS). The simple insulin sensitivity indices, especially Matsuda and Gutt index, were significantly associated with the M value (P < 0.01). CONCLUSION: IR existed in the HINS, IGT, and T2DM groups, and IR levels were consistent in the three groups. The independent factors influencing IR were waistline and FINS. PMID- 26770992 TI - Characterization of Adsorbents for Cytokine Removal from Blood in an In Vitro Model. AB - INTRODUCTION: Cytokines are basic targets that have to be removed effectively in order to improve the patient's health status in treating severe inflammation, sepsis, and septic shock. Although there are different adsorbents commercially available, the success of their clinical use is limited. Here, we tested different adsorbents for their effective removal of cytokines from plasma and the resulting effect on endothelial cell activation. METHODS: The three polystyrene divinylbenzene (PS-DVB) based adsorbents Amberchrom CG161c and CG300m and a clinically approved haemoperfusion adsorbent (HAC) were studied with regard to cytokine removal in human blood. To induce cytokine release from leucocytes, human blood cells were stimulated with 1 ng/ml LPS for 4 hours. Plasma was separated and adsorption experiments in a dynamic model were performed. The effect of cytokine removal on endothelial cell activation was evaluated using a HUVEC-based cell culture model. The beneficial outcome was assessed by measuring ICAM-1, E-selectin, and secreted cytokines IL-8 and IL-6. Additionally the threshold concentration for HUVEC activation by TNF-alpha and IL-1beta was determined using this cell culture model. RESULTS: CG161c showed promising results in removing the investigated cytokines. Due to its pore size the adsorbent efficiently removed the key factor TNF-alpha, outperforming the commercially available adsorbents. The CG161c treatment reduced cytokine secretion and expression of cell adhesion molecules by HUVEC which underlines the importance of effective removal of TNF-alpha in inflammatory diseases. CONCLUSION: These results confirm the hypothesis that cytokine removal from the blood should approach physiological levels in order to reduce endothelial cell activation. PMID- 26770994 TI - Current Mathematical Models for Analyzing Anti-Malarial Antibody Data with an Eye to Malaria Elimination and Eradication. AB - The last decade has witnessed a steady reduction of the malaria burden worldwide. With various countries targeting disease elimination in the near future, the popular parasite infection or entomological inoculation rates are becoming less and less informative of the underlying malaria burden due to a reduced number of infected individuals or mosquitoes at the time of sampling. To overcome such problem, alternative measures based on antibodies against specific malaria antigens have gained recent interest in malaria epidemiology due to the possibility of estimating past disease exposure in absence of infected individuals. This paper aims then to review current mathematical models and corresponding statistical approaches used in antibody data analysis. The application of these models is illustrated with three data sets from Equatorial Guinea, Brazilian Amazonia region, and western Kenyan highlands. A brief discussion is also carried out on the future challenges of using these models in the context of malaria elimination. PMID- 26770993 TI - Reconciling the IPC and Two-Hit Models: Dissecting the Underlying Cellular and Molecular Mechanisms of Two Seemingly Opposing Frameworks. AB - Inflammatory cascades and mechanisms are ubiquitous during host responses to various types of insult. Biological models and interventional strategies have been devised as an effort to better understand and modulate inflammation-driven injuries. Amongst those the two-hit model stands as a plausible and intuitive framework that explains some of the most frequent clinical outcomes seen in injuries like trauma and sepsis. This model states that a first hit serves as a priming event upon which sequential insults can build on, culminating on maladaptive inflammatory responses. On a different front, ischemic preconditioning (IPC) has risen to light as a readily applicable tool for modulating the inflammatory response to ischemia and reperfusion. The idea is that mild ischemic insults, either remote or local, can cause organs and tissues to be more resilient to further ischemic insults. This seemingly contradictory role that the two models attribute to a first inflammatory hit, as priming in the former and protective in the latter, has set these two theories on opposing corners of the literature. The present review tries to reconcile both models by showing that, rather than debunking each other, each framework offers unique insights in understanding and modulating inflammation-related injuries. PMID- 26770995 TI - Impact of Tobacco Smoking and Type-2 Diabetes Mellitus on Public Health: A Cerebrovascular Perspective. PMID- 26770996 TI - Humoral response to EBV is associated with cortical atrophy and lesion burden in patients with MS. AB - OBJECTIVE: Because dysregulated Epstein-Barr virus (EBV)-infected B cells may induce meningeal inflammation, which contributes to cortical pathology in multiple sclerosis (MS), we investigated associations between antibody responses to EBV and development of cortical pathology in MS. METHODS: We included 539 patients with MS (369 with relapsing-remitting MS, 135 with secondary progressive MS, and 35 with primary progressive MS), 66 patients with clinically isolated syndrome (CIS), 63 patients with other neurologic diseases (OND), and 178 age- and sex-matched healthy controls (HC). All participants were scanned on 3T MRI. Serum samples were analyzed for IgG antibodies against EBV viral capsid antigen (VCA) and EBV nuclear antigen-1 (EBNA-1), and their quartiles were determined on the whole study sample. Differences between the study groups were assessed using analysis of covariance adjusted for multiple comparisons. RESULTS: More than 30% of patients with MS and CIS presented with the highest quartile of anti-EBV-VCA and -EBNA-1 status compared to <=10% of HC (p < 0.001). The figures were 9 (14.3%) and 7 (12.3%) for patients with OND. Patients with MS with the highest quartile of anti-EBV-VCA showed significantly increased T2 lesion volume (p = 0.001), T1 lesion number (p = 0.002), and T1 lesion volume (p = 0.04) and decreased gray matter (p = 0.041) and cortical (p = 0.043) volumes compared to patients with MS with lower quartiles. No significant differences of MRI outcomes in patients with CIS, patients with OND, and HC with lower or highest quartiles of anti-EBV-VCA and -EBNA-1 were detected. CONCLUSIONS: Humoral response to anti EBV-VCA and -EBNA-1 is associated with more advanced cortical atrophy, accumulation of chronic T1 black holes, and focal white matter lesions in patients with MS. PMID- 26770997 TI - Lipocalin-2 is increased in progressive multiple sclerosis and inhibits remyelination. AB - OBJECTIVE: We aimed to examine the regulation of lipocalin-2 (LCN2) in multiple sclerosis (MS) and its potential functional relevance with regard to myelination and neurodegeneration. METHODS: We determined LCN2 levels in 3 different studies: (1) in CSF and plasma from a case-control study comparing patients with MS (n = 147) with controls (n = 50) and patients with relapsing-remitting MS (n = 75) with patients with progressive MS (n = 72); (2) in CSF and brain tissue microdialysates from a case series of 7 patients with progressive MS; and (3) in CSF at baseline and 60 weeks after natalizumab treatment in a cohort study of 17 patients with progressive MS. Correlation to neurofilament light, a marker of neuroaxonal injury, was tested. The effect of LCN2 on myelination and neurodegeneration was studied in a rat in vitro neuroglial cell coculture model. RESULTS: Intrathecal production of LCN2 was increased predominantly in patients with progressive MS (p < 0.005 vs relapsing-remitting MS) and displayed a positive correlation to neurofilament light (p = 0.005). Levels of LCN2 in brain microdialysates were severalfold higher than in the CSF, suggesting local production in progressive MS. Treatment with natalizumab in progressive MS reduced LCN2 levels an average of 13% (p < 0.0001). LCN2 was found to inhibit remyelination in a dose-dependent manner in vitro. CONCLUSIONS: LCN2 production is predominantly increased in progressive MS. Although this moderate increase does not support the use of LCN2 as a biomarker, the correlation to neurofilament light and the inhibitory effect on remyelination suggest that LCN2 might contribute to neurodegeneration through myelination-dependent pathways. PMID- 26770998 TI - The severe side of the IgG4-related hypertrophic pachymeningitis disease spectrum. PMID- 26770999 TI - Undersampled Phase Retrieval with Outliers. AB - This paper proposes a general framework for reconstructing sparse images from undersampled (squared)-magnitude data corrupted with outliers and noise. This phase retrieval method uses a layered approach, combining repeated minimization of a convex majorizer (surrogate for a nonconvex objective function), and iterative optimization of that majorizer using a preconditioned variant of the alternating direction method of multipliers (ADMM). Since phase retrieval is nonconvex, this implementation uses multiple initial majorization vectors. The introduction of a robust 1-norm data fit term that is better adapted to outliers exploits the generality of this framework. The derivation also describes a normalization scheme for the regularization parameter and a known adaptive heuristic for the ADMM penalty parameter. Both 1D Monte Carlo tests and 2D image reconstruction simulations suggest the proposed framework, with the robust data fit term, reduces the reconstruction error for data corrupted with both outliers and additive noise, relative to competing algorithms having the same total computation. PMID- 26771000 TI - Diabetic Csf1op/op mice lacking macrophages are protected against the development of delayed gastric emptying. AB - BACKGROUND & AIMS: Diabetic gastroparesis is associated with changes in interstitial cells of Cajal (ICC), neurons and smooth muscle cells in both animal models and humans. Macrophages appear to be critical to the development of cellular damage that leads to delayed gastric emptying but the mechanisms involved are not well understood. Csf1op/op (Op/Op) mice lack biologically active Csf1, resulting in the absence of Csf1-dependent tissue macrophages. The aim of this study was to use Csf1op/op mice to determine the role of macrophages in the development of delayed gastric emptying. METHODS: Animals were injected with streptozotocin to make them diabetic. Gastric emptying was determined weekly. Immunohistochemistry was used to identify macrophages and ICC networks in the gastric muscular layers. Oxidative stress was measured by serum malondialdehyde (MDA) levels. Quantitative, reverse transcription PCR was used to measure levels of mRNA. RESULTS: Csf1op/op mice had normal ICC. With onset of diabetes both Csf1op/op and wild type Csf1+/+ mice developed increased levels of oxidative stress (75.8 +/- 9.1 and 41.2+/-13.6 nmol/mL MDA respectively). Wild type Csf1+/+ mice developed delayed gastric emptying after onset of diabetes (4/13) whereas no diabetic Csf1op/op mouse developed delayed gastric emptying (0/15, P=0.035). ICC were disrupted in diabetic wild type Csf1+/+ mice with delayed gastric emptying but remained normal in diabetic Csf1op/op mice. CONCLUSIONS: Cellular injury and development of delayed gastric emptying in diabetes requires the presence of muscle layer macrophages. Targeting macrophages may be an effective therapeutic option to prevent cellular damage and development of delayed gastric emptying in diabetes. PMID- 26771001 TI - Enteric glia mediate neuron death in colitis through purinergic pathways that require connexin-43 and nitric oxide. AB - BACKGROUND AND AIMS: The concept of enteric glia as regulators of intestinal homeostasis is slowly gaining acceptance as a central concept in neurogastroenterology. Yet how glia contribute to intestinal disease is still poorly understood. Purines generated during inflammation drive enteric neuron death by activating neuronal P2X7 purine receptors (P2X7R), triggering ATP release via neuronal pannexin-1 channels that subsequently recruits intracellular calcium ([Ca2+]i) responses in the surrounding enteric glia. We tested the hypothesis that the activation of enteric glia contributes to neuron death during inflammation. METHODS: We studied neuroinflammation in vivo using the 2,4 dinitrobenzenesulfonic acid model of colitis and in situ using whole-mount preparations of human and mouse intestine. Transgenic mice with a targeted deletion of glial connexin-43 (Cx43) [GFAP?CreERT2+/-/Cx43f/f ] were used to specifically disrupt glial signaling pathways. Mice deficient in inducible nitric oxide (NO) synthase (iNOS-/-) were used to study NO production. Protein expression and oxidative stress were measured using immunohistochemistry and in situ Ca2+ and NO imaging were used to monitor glial [Ca2+]i and [NO]i. RESULTS: Purinergic activation of enteric glia drove [Ca2+]i responses and enteric neuron death through a Cx43-dependent mechanism. Neurotoxic Cx43 activity, driven by NO production from glial iNOS, was required for neuron death. Glial Cx43 opening liberated ATP and Cx43-dependent ATP release was potentiated by NO. CONCLUSIONS: Our results show that the activation of glial cells in the context of neuroinflammation kills enteric neurons. Mediators of inflammation that include ATP and NO activate neurotoxic pathways that converge on glial Cx43 hemichannels. The glial response to inflammatory mediators might contribute to the development of motility disorders. PMID- 26771002 TI - Projected and Observed Aridity and Climate Change in the East Coast of South India under RCP 4.5. AB - In the purview of global warming, the present study attempts to project changes in climate and quantify the changes in aridity of two coastal districts in south India under the RCP 4.5 trajectory. Projected climate change output generated by RegCM 4.4 model, pertaining to 14 grid points located within the study area, was analyzed and processed for this purpose. The meteorological parameters temperature and precipitations were used to create De Martonne Aridity Index, to assess the spatial distribution of aridity. The original index values ranged from 13.7 to 16.4 mm/ degrees C, characterizing this area as a semidry climate. The outcome from the changed scenario analysis under RCP 4.5 showed that, during the end of the 21st century, the aridity may be increased more as the index values tend to reduce. The increasing trend in the drying phenomenon may be attributed to the rising of mean annual temperatures. PMID- 26771003 TI - A Focused Screen Identifies Antifolates with Activity on Mycobacterium tuberculosis. AB - Antifolates are widely used to treat several diseases but are not currently used in the first-line treatment of tuberculosis, despite evidence that some of these molecules can target Mycobacterium tuberculosis (Mtb) bacilli in vitro. To identify new antifolate candidates for animal-model efficacy studies of tuberculosis, we paired knowledge and tools developed in academia with the infrastructure and chemistry resources of a large pharmaceutical company. Together we curated a focused library of 2508 potential antifolates, which were then tested for activity against live Mtb. We identified 210 primary hits, confirmed the on-target activity of potent compounds, and now report the identification and characterization of 5 hit compounds, representative of 5 different chemical scaffolds. These antifolates have potent activity against Mtb and represent good starting points for improvement that could lead to in vivo efficacy studies. PMID- 26771004 TI - Using Computational Modeling To Optimize the Design of Antibodies That Trap Viruses in Mucus. AB - Immunoglobulin G (IgG) antibodies that trap viruses in cervicovaginal mucus (CVM) via adhesive interactions between IgG-Fc and mucins have recently emerged as a promising strategy to block vaginally transmitted infections. The array of IgG bound to a virus particle appears to trap the virus by making multiple weak affinity bonds to the fibrous mucins that form the mucus gel. However, the antibody characteristics that maximize virus trapping and minimize viral infectivity remain poorly understood. Toward this goal, we developed a mathematical model that takes into account physiologically relevant spatial dimensions and time scales, binding, and unbinding rates between IgG and virions and between IgG and mucins, as well as the respective diffusivities of virions and IgG in semen and CVM. We then systematically explored the IgG-antigen and IgG mucin binding and unbinding rates that minimize the flux of infectious HIV arriving at the vaginal epithelium. Surprisingly, contrary to common intuition that infectivity would drop monotonically with increasing affinities between IgG and HIV, and between IgG and mucins, our model suggests maximal trapping of HIV and minimal flux of HIV to the epithelium are achieved with IgG molecules that exhibit (i) rapid antigen binding (high kon) rather than very slow unbinding (low koff), that is, high-affinity binding to the virion, and (ii) relatively weak affinity with mucins. These results provide important insights into the design of more potent "mucotrapping" IgG for enhanced protection against vaginally transmitted infections. The model is adaptable to other pathogens, mucosal barriers, geometries, and kinetic and diffusional effects, providing a tool for hypothesis testing and producing quantitative insights into the dynamics of immune-mediated protection. PMID- 26771005 TI - Gradient-Modulated PETRA MRI. AB - Image blurring due to off-resonance and fast T 2* signal decay is a common issue in radial ultrashort echo time MRI sequences. One solution is to use a higher readout bandwidth, but this may be impractical for some techniques like pointwise encoding time reduction with radial acquisition (PETRA), which is a hybrid method of zero echo time and single point imaging techniques. Specifically, PETRA has severe specific absorption rate (SAR) and radiofrequency (RF) pulse peak power limitations when using higher bandwidths in human measurements. In this study, we introduce gradient modulation (GM) to PETRA to reduce image blurring artifacts while keeping SAR and RF peak power low. Tolerance of GM-PETRA to image blurring was evaluated in simulations and experiments by comparing with the conventional PETRA technique. We performed inner ear imaging of a healthy subject at 7T. GM PETRA showed significantly less image blurring due to off-resonance and fast T2* signal decay compared to PETRA. In in vivo imaging, GM-PETRA nicely captured complex structures of the inner ear such as the cochlea and semicircular canals. Gradient modulation can improve the PETRA image quality and mitigate SAR and RF peak power limitations without special hardware modification in clinical scanners. PMID- 26771006 TI - Potential for Early Fracture Risk Assessment in Patients with Metastatic Bone Disease using Parametric Response Mapping of CT Images. AB - Pathologic vertebral compression fractures (PVCF) cause significant morbidity in patients with bone metastases from breast cancer and other malignancies. Due to limitations of existing biochemical and imaging biomarkers, clinicians currently have no reliable metrics to identify patients with impending PVCF, impeding efforts to prevent this severe complication. To establish the feasibility of a new method for defining risk of PVCF, we retrospectively analyzed serial CT scans from five breast cancer patients using parametric response mapping (PRM) to quantify dynamic bone density changes that preceded an event. Vertebrae segmented from each scan were registered to vertebrae at the earliest time point (i.e. furthest from PVCF) and voxel classification accomplished using a predetermined threshold of change in HU values, resulting in relative volumes of increased (PRMHU+), decreased (PRMHU-), or unchanged (PRMHU0) attenuation. A total of seven PVCF were compared to un-diseased vertebrae in each patient serving as controls. Receiver operator curve (ROC) analysis identified optimal image acquisition and analysis times for group stratification. Bone density changes were visualized by an increasing trend in PRMHU+ as early as one year before fracture. PRMHU- demonstrated negligible changes over the course of the study. These observations were consistent with ROC results, showing poor performance of PRMHU- in stratifying PVCF versus control. As early as 6 months prior to PVCF, PRMHU+ was significantly larger (12.9 +/- 11.6%) compared to control vertebrae (2.3 +/- 2.5%), with an AUC of 0.918 from a receiver operator curve analysis. Mean HU changes were also significant between PVCF (+26.8 +/- 26.9%) and control (-2.2 +/ 22.0%) over the same period. PRM analysis of bone density changes using standard CT imaging was sensitive for spatially resolving bone remodeling which preceded structural failure in patients with breast cancer vertebral metastases. PMID- 26771007 TI - Fluorescence Lifetime Imaging of Apoptosis. AB - Genetically-encoded fluorescence resonance energy transfer (FRET) reporters are powerful tools to analyze cell signaling and function at single cell resolution in standard two-dimensional cell cultures, but these reporters rarely have been applied to three-dimensional environments. FRET interactions between donor and acceptor molecules typically are determined by changes in relative fluorescence intensities, but wavelength-dependent differences in absorption of light complicate this analysis method in three-dimensional settings. Here we report fluorescence lifetime imaging microscopy (FLIM) with phasor analysis, a method that displays fluorescence lifetimes on a pixel-wise basis in real time, to quantify apoptosis in breast cancer cells stably expressing a genetically encoded FRET reporter. This microscopic imaging technology allowed us to identify treatment-induced apoptosis in single breast cancer cells in environments ranging from two-dimensional cell culture, spheroids with cancer and bone marrow stromal cells, and living mice with orthotopic human breast cancer xenografts. Using this imaging strategy, we showed that combined metabolic therapy targeting glycolysis and glutamine pathways significantly reduced overall breast cancer metabolism and induced apoptosis. We also determined that distinct subpopulations of bone marrow stromal cells control resistance of breast cancer cells to chemotherapy, suggesting heterogeneity of treatment responses of malignant cells in different bone marrow niches. Overall, this study establishes FLIM with phasor analysis as an imaging tool for apoptosis in cell-based assays and living mice, enabling real time, cellular-level assessment of treatment efficacy and heterogeneity. PMID- 26771008 TI - Noise-Induced Neural Degeneration and Therapeutic Effect of Antioxidant Drugs. AB - The primary site of lesion induced by noise exposure is the hair cells in the organ of Corti and the primary neural degeneration occurs in synaptic terminals of cochlear nerve fibers and spiral ganglion cells. The cellular basis of noise induced hearing loss is oxidative stress, which refers to a severe disruption in the balance between the production of free radicals and antioxidant defense system in the cochlea by excessive production of free radicals induced by noise exposure. Oxidative stress has been identified by a variety of biomarkers to label free radical activity which include four-hydroxy-2-nonenal, nitrotyrosine, and malondialdehyde, and inducible nitric oxide synthase, cytochrome-C, and cascade-3, 8, 9. Furthermore, oxidative stress is contributing to the necrotic and apoptotic cell deaths in the cochlea. To counteract the known mechanisms of pathogenesis and oxidative stress induced by noise exposure, a variety of antioxidant drugs including oxygen-based antioxidants such as N-acetyl-L-cystein and acetyl-L-carnitine and nitrone-based antioxidants such as phenyl-N-tert butylnitrone (PBN), disufenton sodium, 4-hydroxy PBN, and 2, 4-disulfonyl PBN have been used in our laboratory. These antioxidant drugs were effective in preventing or treating noise-induced hearing loss. In combination with other antioxidants, antioxidant drugs showed a strong synergistic effect. Furthermore, successful use of antioxidant drugs depends on the optimal timing of treatment and the duration of treatment, which are highly related to the time window of free radical formation induced by noise exposure. PMID- 26771009 TI - Acoustic Change Complex: Clinical Implications. AB - The acoustic change complex (ACC) is a cortical auditory evoked potential elicited in response to a change in an ongoing sound. The characteristics and potential clinical implications of the ACC are reviewed in this article. The P1 N1-P2 recorded from the auditory cortex following presentation of an acoustic stimulus is believed to reflect the neural encoding of a sound signal, but this provides no information regarding sound discrimination. However, the neural processing underlying behavioral discrimination capacity can be measured by modifying the traditional methodology for recording the P1-N1-P2. When obtained in response to an acoustic change within an ongoing sound, the resulting waveform is referred to as the ACC. When elicited, the ACC indicates that the brain has detected changes within a sound and the patient has the neural capacity to discriminate the sounds. In fact, results of several studies have shown that the ACC amplitude increases with increasing magnitude of acoustic changes in intensity, spectrum, and gap duration. In addition, the ACC can be reliably recorded with good test-retest reliability not only from listeners with normal hearing but also from individuals with hearing loss, hearing aids, and cochlear implants. The ACC can be obtained even in the absence of attention, and requires relatively few stimulus presentations to record a response with a good signal-to noise ratio. Most importantly, the ACC shows reasonable agreement with behavioral measures. Therefore, these findings suggest that the ACC might represent a promising tool for the objective clinical evaluation of auditory discrimination and/or speech perception capacity. PMID- 26771010 TI - Relation between Phonological Processing, Auditory Processing and Speech Perception among Bilingual Poor Readers. AB - BACKGROUND AND OBJECTIVES: A deficit in phonological processing abilities has been hypothesized as a cause of reading deficits among poor readers, but the precise etiology of this deficit is still unknown. Many studies have investigated the relation of auditory processing and speech perception with phonological processing, while the relation between these are not well understood. Thus, the present study was carried out to investigate the relation between these abilities among poor readers. SUBJECTS AND METHODS: A total of 20 children between 7-12 years of age participated in the study. Among these 10 were typically developing children and 10 were poor readers. Auditory processing, speech perception in noise and phonological processing skills were assessed in both the groups. RESULTS: Auditory processing was not significantly different between children in both the groups. In contrast, phonological awareness, verbal short-term memory and rapid automatized naming, which reflect phonological processing, and speech perception in noise were found to be significantly affected in poor readers. In addition, the results showed a significant correlation between phonological processing and speech perception in noise. CONCLUSIONS: The present study found a significant relationship between speech perception in noise and phonological processing, while there was no relationship between auditory processing and phonological processing. This finding suggests that poor speech perception among poor readers may be one of the contributing factors for phonological processing deficits, which in turn leads to reading difficulties. PMID- 26771011 TI - Positive, Neutral, and Negative Connotations Associated with Social Representation of 'Hearing Loss' and 'Hearing Aids'. AB - BACKGROUND AND OBJECTIVES: In our previous studies we explored the social representation of hearing loss and hearing aids. In this study we aimed at exploring if the positive, neutral and negative connotations associated with the social representation of 'hearing loss' and 'hearing aids' for the same categories vary across countries. In addition, we also looked at if there is an association between connotations and demographic variables. SUBJECTS AND METHODS: A total of 404 individuals from four countries were asked to indicate the words and phrases that comes to mind when they think about 'hearing loss' and 'hearing aids'. They also indicated if the words and phrases they reported had positive, neutral or negative association, which were analyzed and reported in this paper. RESULTS: There are considerable differences among the countries in terms of positive, neutral and negative associations report for each category in relation to hearing loss and hearing aids. However, there is limited connection between demographic variables and connotations reported in different countries. CONCLUSIONS: These results suggesting that the social representation about the phenomenon hearing loss and hearing aids are relatively stable within respondents of each country. PMID- 26771012 TI - Influences of Diabetes on Hearing Recovery in Noise-Exposed Mice. AB - BACKGROUND AND OBJECTIVES: Many studies have reported an association between diabetes and hearing loss. However, these reports were mainly abstractive correlations between common hearing loss and the incidence of diabetes. Therefore, we evaluated the impact of diabetes on the occurrence of and recovery from noise-induced hearing loss. MATERIALS AND METHODS: We used 5-week-old C57BLKS/J-m wild type (+/+) and C57BLKS/J-db/db male mice as the control and diabetic groups, respectively. In one set of experiments, the hearing levels of control and diabetic mice were measured weekly for 7 weeks. In a second set of experiments, control and diabetic mice were exposed to broadband white noise of 110 dB SPL for 3 hours; hearing levels were analyzed before and immediately after exposure, 1, 3, and 5 days, and 1, 2, 3, and 4 weeks after the noise exposure. RESULTS: The hearing levels of the control group were better than those of the diabetic group at each weekly revision for 7 weeks at all auditory brainstem response frequencies (4, 8, 16, and 32 kHz). After noise exposure, both groups of mice showed an immediate increase in the hearing level threshold at all frequencies. Subsequent threshold recovery was seen in both groups with no difference in the hearing level recovery rates between the two groups. CONCLUSIONS: Hearing level with aging becomes significantly impaired earlier in diabetic mice but hearing recovery after noise exposure is similar between diabetic and control mice. PMID- 26771013 TI - Error Patterns Analysis of Hearing Aid and Cochlear Implant Users as a Function of Noise. AB - BACKGROUND AND OBJECTIVES: Not all impaired listeners may have the same speech perception ability although they will have similar pure-tone threshold and configuration. For this reason, the present study analyzes error patterns in the hearing-impaired compared to normal hearing (NH) listeners as a function of signal-to-noise ratio (SNR). SUBJECTS AND METHODS: Forty-four adults participated: 10 listeners with NH, 20 hearing aids (HA) users and 14 cochlear implants (CI) users. The Korean standardized monosyllables were presented as the stimuli in quiet and three different SNRs. Total error patterns were classified into types of substitution, omission, addition, fail, and no response, using stacked bar plots. RESULTS: Total error percent for the three groups significantly increased as the SNRs decreased. For error pattern analysis, the NH group showed substitution errors dominantly regardless of the SNRs compared to the other groups. Both the HA and CI groups had substitution errors that declined, while no response errors appeared as the SNRs increased. The CI group was characterized by lower substitution and higher fail errors than did the HA group. Substitutions of initial and final phonemes in the HA and CI groups were limited by place of articulation errors. However, the HA group had missed consonant place cues, such as formant transitions and stop consonant bursts, whereas the CI group usually had limited confusions of nasal consonants with low frequency characteristics. Interestingly, all three groups showed /k/ addition in the final phoneme, a trend that magnified as noise increased. CONCLUSIONS: The HA and CI groups had their unique error patterns even though the aided thresholds of the two groups were similar. We expect that the results of this study will focus on high error patterns in auditory training of hearing-impaired listeners, resulting in reducing those errors and improving their speech perception ability. PMID- 26771014 TI - Is Intratympanic Dexamathasone Injection Effective for the Treatment of Idiopathic Sudden Sensorineural Hearing Loss? AB - BACKGROUND AND OBJECTIVES: The purpose of this study is to identify the effectiveness of intratympanic (IT) steroids when used as an initial therapy in sudden sensorineural hearing loss (SSNHL), and when it is used as a salvage therapy in a refractory SSNHL. SUBJECTS AND METHODS: This retrospective study included 122 patients with SSNHL. First, patients were divided into three groups according to the initial treatment; IT steroid, systemic steroid and combined (systemic and IT steroid) groups. Second, patients were divided into two groups according to the salvage treatment in a refractory SSNHL; IT steroid and the control (non IT group). Fifty eight patients who did not respond to initial therapy were included in the second analysis. Hearing was assessed immediately before the treatment and 2 weeks, 4 weeks and 3 months after the treatments. Hearing recovery was defined as an improvement of >15 dB and the final hearing of 25-45 dB in the audiogram. RESULTS: When we analyzed the hearing recovery in initial treatment, the comparison of audiogram among three groups did not result in significantly different outcomes. There were no differences in the recovery rate in 2 and 4 weeks throughout all the frequencies. Also, the analysis of the salvage treatment demonstrated that neither IT steroid group nor control group was significantly effective in treating the refractory SSNHL. CONCLUSIONS: The results suggest that initial treatment of SSNHL with IT steroid alone is as effective as systemic steroid alone or a combination therapy. Also, salvage IT steroids for refractory SSNHL did not have any additional beneficial effects. PMID- 26771015 TI - Feasibility and Safety of Transcutaneous Vagus Nerve Stimulation Paired with Notched Music Therapy for the Treatment of Chronic Tinnitus. AB - BACKGROUND AND OBJECTIVES: A recent study demonstrated that tinnitus could be eliminated by vagus nerve stimulation (VNS) paired with notched sounds in a rat tinnitus model. The aims of this clinical study were to investigate the effects and safety of transcutaneous VNS (tVNS) by patch-type electrode paired with notched music for treating chronic tinnitus. SUBJECTS AND METHODS: Thirty patients with refractory chronic tinnitus for >12 months were included in this study. A patch-type electrode was attached to the auricular concha of the patient's left ear and tVNS was performed for 30 min (pulse rate 25 Hz, pulse width 200 us, and amplitude 1-10 mA) using a transcutaneous electric nerve stimulation eco2. During tVNS, the patients listened to notched music cleared of the frequency spectrum corresponding to the tinnitus with a 0.5 octave notch width. RESULTS: After 10 treatment sessions, 15/30 patients (50%) reported symptom relief in terms of a global improvement questionnaire. The mean tinnitus loudness (10-point scale) and the mean tinnitus awareness score (%) improved significantly from 6.32+/-2.06 to 5.16+/-1.52 and from 82.40+/-24.37% to 65.60+/ 28.15%, respectively (both p<0.05). None of the patients had any specific side effects, such as changes in heart rate or blood pressure. CONCLUSIONS: This study has demonstrated the feasibility and safety of tVNS paired with notched music therapy in patients with chronic tinnitus, with the use of a pad-type electrode attached to the auricular concha. PMID- 26771016 TI - Does Hearing Aid Use Increase the Likelihood of Cerumen Impaction? AB - BACKGROUND AND OBJECTIVES: Impacted cerumen is a common condition in adults. It is commonly believed that wearing hearing aids may increase the cerumen impaction, although no empirical evidence exist. The current study was aimed at studying if the use of hearing aids increase the likelihood of impaction of cerumen. SUBJECTS AND METHODS: The study used retrospective design. The study sample included 164 consecutive patients who were referred to cerumen clinic from Royal Glamorgan Hospital, Wales. Audiologist classified the cerumen impaction into four categories (i.e., no cerumen; non-occluding cerumen; occluding cerumen; and fully non-occluding cerumen and debris). Chi-square analysis was performed to study the association between hearing aid use and cerumen impaction. RESULTS: The current study results showed no association between hearing aid use and cerumen impaction. Also, there was no association between right/left ear and cerumen impaction. CONCLUSIONS: These results interesting and contrary to our assumption that hearing aid use increases the likelihood of cerumen impaction. More well controlled studies with prospective designs are needed to confirm if these results are accurate. PMID- 26771017 TI - Analysis of Bacterial Biofilms on a Cochlear Implant Following Methicillin Resistant Staphylococcus Aureus Infection. AB - To demonstrate biofilm formations on a cochlear implant magnet of a pediatric patient suffering from a methicillin-resistant Staphylococcus aureus (MRSA) infection. The appearance of biofilm colonies was analyzed on different magnet sections. The appearance of MRSA biofilms on the surface of an explanted cochlear implant was analyzed by scanning electron microscopy (SEM), focusing on the pattern of extracellular polymeric substances (EPS) within the biofilms. SEM revealed unique biofilms with a three-dimensional EPS complex and tower-like formations. Biofilm configurations changed from the margin to the center of the magnet. Biofilms were solitary and scattered at the margin; large and plate-like in the center; and stacked in layers, forming towers and water channels, in the middle region. After a MRSA infection, biofilm formations were observed on the surface of a magnet. Bacterial biofilms provide optimal conditions for bacterial growth and antibiotic resistance and can cause intractable infections that lead to device failure. PMID- 26771018 TI - A Case of Sudden Deafness with Intralabyrinthine Hemorrhage Intralabyrinthine Hemorrhage and Sudden Deafness. AB - Sudden hearing deterioration may occur in our population, but it is difficult to explain the exact pathophysiology and the cause. Magnetic resonance imaging (MRI) in sudden sensorineural hearing loss (SSNHL) is usually useful to evaluate neural lesions such as acoustic schwannoma and hemorrhage in labyrinth. Recently some cases of SSNHL caused by intralabyrintine hemorrhage were reported by the advance of MRI. In the case of intralabyrintine hemorrhage, MRI showed a hyperintense signal in the labyrinth on the pre-contrast and contrast enhanced T1-weighted image and relatively weak intensity on T2-weighted image. The prognosis SSNHL by intralabyrintine hemorrhage is generally known to be poor. We report a case of sudden deafness with intralabyrintine hemorrhage who has a history of anticoagulant administration, with a review of literature. PMID- 26771019 TI - Bilateral Sequential Pneumolabyrinth Resulting from Nose Blowing. AB - Pneumolabyrinth describes a condition with entrapped air in the labyrinth and usually occurs in temporal bone fractures that involve the otic capsule. While sporadic cases of bilateral pneumolabyrinth have been reported, cases lacking head trauma are very rare. We report the case of a 43-year-old man who had sudden hearing loss bilaterally after blowing his nose at an interval of 1 year. Although conservative management for the right ear and exploratory tympanotomy with sealing of the possible site of perilymphatic leakage in the left ear were performed, hearing outcome was poor in both ears. To our knowledge, this is the first case of bilateral pneumolabyrinth occurring as a result of nose blowing. PMID- 26771020 TI - Orientation of Turing-like Patterns by Morphogen Gradients and Tissue Anisotropies. AB - Patterning of periodic stripes during development requires mechanisms to control both stripe spacing and orientation. A number of models can explain how stripe spacing is controlled, including molecular mechanisms, such as Turing's reaction diffusion model, as well as cell-based and mechanical mechanisms. However, how stripe orientation is controlled in each of these cases is poorly understood. Here, we model stripe orientation using a simple, yet generic model of periodic patterning, with the aim of finding qualitative features of stripe orientation that are mechanism-independent. Our model predicts three qualitatively distinct classes of orientation mechanism: gradients in production rates, gradients in model parameters, and anisotropies (e.g. in diffusion or growth). We provide evidence that the results from our minimal model may also apply to more specific and complex models, revealing features of stripe orientation that may be common to a variety of biological systems. PMID- 26771021 TI - The Molecular Signatures Database (MSigDB) hallmark gene set collection. AB - The Molecular Signatures Database (MSigDB) is one of the most widely used and comprehensive databases of gene sets for performing gene set enrichment analysis. Since its creation, MSigDB has grown beyond its roots in metabolic disease and cancer to include >10,000 gene sets. These better represent a wider range of biological processes and diseases, but the utility of the database is reduced by increased redundancy across, and heterogeneity within, gene sets. To address this challenge, here we use a combination of automated approaches and expert curation to develop a collection of "hallmark" gene sets as part of MSigDB. Each hallmark in this collection consists of a "refined" gene set, derived from multiple "founder" sets, that conveys a specific biological state or process and displays coherent expression. The hallmarks effectively summarize most of the relevant information of the original founder sets and, by reducing both variation and redundancy, provide more refined and concise inputs for gene set enrichment analysis. PMID- 26771023 TI - Copper(II)-mediated regioselective N-arylation of pyrroles, indoles, pyrazoles and carbazole via dehydrogenative coupling. AB - A copper(II)-mediated regioselective N-arylation of azoles has been developed using 8-aminoquinoline amide as a directing group. This reaction shows a broad substrate scope with different azoles such as pyrroles, indoles, pyrazoles and carbazole with good yields. PMID- 26771024 TI - Nazarov cyclization of 1,4-pentadien-3-ols: preparation of cyclopenta[b]indoles and spiro[indene-1,4'-quinoline]s. AB - The first Lewis acid-catalyzed intramolecular interrupted Nazarov cyclization of 1,4-pentadien-3-ols is described. Using FeBr3 as the catalyst, a series of new substituted cyclopenta[b]indoles was prepared-through a sequence of Nazarov cyclization, nucleophilic amination, and isomerization-with good yields and high diastereo- and regioselectivities. A similar catalytic process was also developed for the synthesis of structurally interesting spiro[indene-1,4'-quinoline]s. PMID- 26771025 TI - Hydrophobicity-induced prestaining for protein detection in polyacrylamide gel electrophoresis. AB - An AIE fluorescent surfactant has been first used to prestain protein by ultrastrong hydrophobic interaction between fluorescent surfactants and proteins, distinguishing from the most widely used poststaining strategies by employing AIE molecules with weak hydrophobic characteristics. A mixture of proteins with variable molecular weights has been detected. PMID- 26771026 TI - Betaine mediated synthesis of annulated dihydrofurans from oxobis(methylthio)ketene acetals and N-butyl-N'-methyl ethane-1,2-diamine as precursors via NHC elimination. AB - First in situ generation of a betaine intermediate has been developed using two new precursors oxobis(methylthio)ketene acetals and N-butyl-N'-methyl ethane-1,2 diamine for the synthesis of annulated dihydrofurans. This protocol adds a new dimension for the formation of annulated dihydrofurans through a series of selective consecutive formation of C-C and C-O bonds after reacting with enone rings. This in situ generated betaine intermediate corresponds to deoxy-Breslow intermediates in the reaction via elimination of NHC. PMID- 26771027 TI - Ion flow in a zeolitic imidazolate framework results in ionic diode phenomena. AB - Ionic transport (for applications in nanofluidics or membranes) and "ionic diode" phenomena in a zeolitic imidazolate framework (ZIF-8) are investigated by directly growing the framework from aqueous Zn(2+) and 2-methylimidazole as an "asymmetric plug" into a 20 MUm diameter pore in a ca. 6 MUm thin poly-ethylene terephthalate (PET) film. PMID- 26771028 TI - Dimerization of a marginally stable disilenyl germylene to tricyclic systems: evidence for reversible NHC-coordination. AB - Tetrasiladigermatricyclohexanes in two isomeric forms (chair and doubly-bridged tetrahedron) are obtained by the reaction of MeLi with an alpha-chlorosilyl functionalized NHC-stabilized silagermenylidene. (29)Si NMR at low temperature proves the initial formation of a monomeric NHC-adduct of a disilenyl germylene followed by cyclisation to the isomeric heavy cyclopropene. Addition of an excess of NHC stabilizes the both intermediates and demonstrates the reversibility of rate-determining initial equilibria involving NHC dissociation. Finally, a mixture of two isomeric tricyclic Si4Ge2 species is obtained: at elevated temperature the chair isomer converts to the doubly edge-bridged tetrahedron. PMID- 26771029 TI - Where does methanol lose hydrogen to trigger steam reforming? A revisit of methanol dehydrogenation on the PdZn alloy model obtained from kinetic Monte Carlo simulations. AB - Pd/ZnO is a promising catalyst studied for methanol steam reforming (MSR) and the 1 : 1 PdZn alloy is demonstrated to be the active component. It is believed that MSR starts from methanol dehydrogenation to methoxy. Previous studies of methanol dehydrogenation on the ideal PdZn(111) surface show that methanol adsorbs weakly on the PdZn(111) surface and it is hard for methanol to transform into methoxy because of the high dehydrogenation barrier, indicating that the catalyst model is not appropriate for investigating the first step of MSR. Using the model derived from our recent kinetic Monte Carlo simulations, we examined the process CH3OH -> CH3O -> CH2O -> CHO -> CO. Compared with the ideal model, methanol adsorbs much more strongly and the barrier from CH3OH -> CH3O is much lower on the kMC model. On the other hand, the C-H bond breaking of CH3O, CH2O and CHO becomes harder. We show that co-adsorbed water is important for refreshing the active sites. The present study shows that the first MSR step most likely takes place on three-fold hollow sites formed by Zn atoms, and the inhomogeneity of the PdZn alloy may exert significant influences on reactions. PMID- 26771030 TI - A robust comparison of dynamical scenarios in a glass-forming liquid. AB - We use Bayesian inference methods to provide fresh insights into the sub nanosecond dynamics of glycerol, a prototypical glass-forming liquid. To this end, quasielastic neutron scattering data as a function of temperature have been analyzed using a minimal set of underlying physical assumptions. On the basis of this analysis, we establish the unambiguous presence of three distinct dynamical processes in glycerol, namely, translational diffusion of the molecular centre of mass and two additional localized and temperature-independent modes. The neutron data also provide access to the characteristic length scales associated with these motions in a model-independent manner, from which we conclude that the faster (slower) localized motions probe longer (shorter) length scales. Careful Bayesian analysis of the entire scattering law favors a heterogeneous scenario for the microscopic dynamics of glycerol, where molecules undergo either the faster and longer or the slower and shorter localized motions. PMID- 26771031 TI - Copper(II) complexes with peptides based on the second cell binding site of fibronectin: metal coordination and ligand exchange kinetics. AB - Copper(ii) complexes with short peptides based on the second cell binding site of fibronectin, PHSFN and PHSEN, have been characterized by potentiometric, UV-vis, CD, EPR and NMR spectroscopic methods. The histidine imidazole nitrogen is the anchoring site for the metal ion binding. Thermodynamic and spectroscopic evidence is given that the side chain oxygen donor atom of glutamyl residue in Ac PHSEN-NH2 is also involved in the binding up to physiological pH. To determine ligand exchange kinetic parameters after the imidazole nitrogen anchoring, proton relaxation enhancement NMR data have been collected for the two hydrogen atoms of the imidazole ring in the temperature range 293-315 K at pH 5.2 and globally treated within different kinetic models for ligand exchange. The best fitting model involves two steps. In the first one, which is slow, a water molecule disengages a carbonyl or a carboxylate group coordinated to the metal ion in the complex formed by PHSFN or PHSEN, respectively. This stage is one order of magnitude slower for PHSEN, due to entropic effects. In the second step, which is fast, the complex just formed exchanges with the ligand. In this step, no appreciable differences are found for the two cases examined. PMID- 26771032 TI - Potential energy surface of fluoroxene: experiment and theory. AB - The potential energy surface (PES) of the general anesthetic fluoroxene (2,2,2 trifluoroethyl vinyl ether) was probed in a supersonic jet expansion using broadband chirped-pulse Fourier transform microwave (CP-FTMW) spectroscopy and theoretical calculations. The PES is dominated by a single conformation, as other stable minima are shown to kinetically relax in the expansion to the global minimum. Consistently, the rotational spectrum reveals a single conformation. Fluoroxene adopts a CS heavy-atom planar skeleton structure in the gas phase, with a cis-trans conformation (cis for the CH2=CH-O-CH2- and trans for the =CH-O CH2-CF3 part). The sensitivity of a recently-built CP-FTMW spectrometer at the UPV/EHU is demonstrated by the detection of five isotopologues of fluoroxene in natural abundance, corresponding to the (13)C and (18)O monosubstituted species. The rS and r0 structures were determined and are in good agreement with theoretical predictions using the MP2, B3LYP and M06-2X methods. PMID- 26771033 TI - Designing voltage multipliers with nanofluidic diodes immersed in aqueous salt solutions. AB - Membranes with nanofluidic diodes allow the selective control of molecules in physiological salt solutions at ambient temperature. The electrical coupling of the membranes with conventional electronic elements such as capacitors suggests opportunities for the external monitoring of sensors and actuators. We demonstrate experimentally and theoretically the voltage multiplier functionality of simple electrical networks composed of membranes with conical nanopores coupled to load capacitors. The robust operation of half and full wave voltage multipliers is achieved in a broad range of experimental conditions (single pore and multipore membranes, electrolyte concentrations, voltage amplitudes, and solid-state capacitances). The designed voltage multipliers operate in the liquid state and can be used in sensing devices because different electrical, optical, and chemical inputs are known to modulate the individual nanofluidic diode resistances in the electrical network. PMID- 26771034 TI - Emission shaping in fluorescent proteins: role of electrostatics and pi-stacking. AB - For many decades, simulating the excited state properties of complex systems has been an intriguing but daunting task due to its high computational cost. Here, we apply molecular dynamics based techniques with interpolated potential energy surfaces toward calculating fluorescence spectra of the green fluorescent protein (GFP) and its variants in a statistically meaningful manner. With the GFP, we show that the diverse electrostatic tuning can shape the emission features in many different ways. By computationally modulating the electrostatic interactions between the chromophore phenoxy oxygen and its nearby residues, we demonstrate that we indeed can shift the emission to the blue or to the red side in a predictable manner. We rationalize the shifting effects of individual residues in the GFP based on the responses of both the adiabatic and the diabatic electronic states of the chromophore. We next exhibit that the yellow emitting variant, the Thr203Tyr mutant, generates changes in the electrostatic interactions and an additional pi-stacking interaction. These combined effects indeed induce a red shift to emit the fluorescence into the yellow region. With the series of demonstrations, we suggest that our approach can provide sound rationales and useful insights in understanding different responses of various fluorescent complexes, which may be helpful in designing new light emitting proteins and other related systems in future studies. PMID- 26771035 TI - The truth about the 1st cycle Coulombic efficiency of LiNi1/3Co1/3Mn1/3O2 (NCM) cathodes. AB - The 1st cycle Coulombic efficiency (CE) of LiNi1/3Co1/3Mn1/3O2 (NCM) at 4.6 V vs. Li/Li(+) has been extensively investigated in NCM/Li half cells. It could be proven that the major part of the observed overall specific capacity loss (in total 36.3 mA h g(-1)) is reversible and induced by kinetic limitations, namely an impeded lithiation reaction during discharge. A measure facilitating the lithiation reaction, i.e. a constant potential (CP) step at the discharge cut-off potential, results in an increase in specific discharge capacity of 22.1 mA h g( 1). This capacity increase during the CP step could be proven as a relithiation process by Li(+) content determination in NCM via an ICP-OES measurement. In addition, a specific capacity loss of approx. 4.2 mA h g(-1) could be determined as an intrinsic reaction to the NCM cathode material at room temperature (RT). In total, less than 10.0 mA h g(-1) (=28% of the overall capacity loss) can be attributed to irreversible reactions, mainly to irreversible structural changes of NCM. Thus, the impact of parasitic reactions, such as oxidative electrolyte decomposition, on the irreversible capacity is negligible and could also be proven by on-line MS. As a consequence, the determination of the amount of extracted Li(+) ("Li(+) extraction ratio") so far has been incorrect and must be calculated by the charge capacity (=delithiation amount) divided by the theoretical capacity. In a NCM/graphite full cell the relithiation amount during the constant voltage (CV) step is smaller than in the half cell, due to irreversible Li(+) loss at graphite. PMID- 26771037 TI - Influence of the central venous site on the transpulmonary thermodilution parameters in critically ill burn patients. AB - The aim of this study was to verify the measurement concordance of cardiac index (CI), extra-vascular lung water index (EVLWI) and global end diastolic volume index (GEDVI) with transpulmonary thermodilution (TPTD) between the jugular and femoral access with catheters inserted ipsilaterally in critically ill burn patients. Correlations were excellent and the concordance was good for the CI, EVLW and GEDVI (mean bias -0.11 L/min/m2, -0.3 mL/kg and -20 mL/m2 for CI, EVLW and GEDVI, respectively). We conclude that ipsilateral arterial and venous femoral and jugular measurement of TPTD parameters can be used interchangeably if catheters with different lengths on the femoral site are used. PMID- 26771038 TI - Quiz Corner - A comment. PMID- 26771039 TI - Quiz corner - A response. PMID- 26771036 TI - Simple bioconjugate chemistry serves great clinical advances: albumin as a versatile platform for diagnosis and precision therapy. AB - Albumin is the most abundant circulating protein in plasma and has recently emerged as a versatile protein carrier for drug targeting and for improving the pharmacokinetic profile of peptide or protein based drugs. Three drug delivery technologies related to albumin have been developed, which include the coupling of low-molecular weight drugs to exogenous or endogenous albumin, conjugating bioactive proteins by albumin fusion technology (AFT), and encapsulation of drugs into albumin nanoparticles. This review article starts with a brief introduction of human serum albumin (HSA), and then summarizes the mainstream chemical strategies of developing HSA binding molecules for coupling with drug molecules. Moreover, we also concisely condense the recent progress of the most important clinical applications of HSA-binding platforms, and specify the current challenges that need to be met for a bright future of HSA-binding. PMID- 26771040 TI - Author response. PMID- 26771041 TI - Author response. PMID- 26771042 TI - Reply to letter to the editor on: perinatal ischemic stroke: a five-year retrospective study in a level-III maternity. Einstein (Sao Paulo). 2015;13(1):65 71. PMID- 26771043 TI - Fieldwork: Extreme research. PMID- 26771044 TI - [Establishment of early warning system of malaria in Jiangsu Province V Es- tablishment of prevention and control system of imported falciparum malaria]. AB - OBJECTIVE: To establish a system of the prevention and control of imported falciparum malaria in Jiangsu Prov- ince and provide the new scientific basis for the prevention and control of imported falciparum malaria. METHODS: The data- bases for overseas labor companies and labors in Jiangsu Province were built and the health education was conducted to the overseas labors. The "1-3-7" elimination strategy was established. A weekly reporting system for malaria case details was es- tablished. A system for screening accompanies of imported malaria patients was established. RESULTS: At the end of 2013, the database of companies engaged in labor export was built and1 405 companies were incorporated into the database. The time interval between the symptom onset and the first health facility visit was reduced to 3.07 days in 2013. The time interval be- tween the first health facility visit to malaria diagnosis was reduced to 1.57 days in 2013. The rate of laboratory confirmation was increased to 100% in 2013, and there was a statistically significant difference among the rates of laboratory confirmation from 2009 to 2013 (chi2 = 36.35, P < 0.05). The proportion of severe imported falciparum malaria cases was decreased to 3.15% in 2013 and there was a statistically significant difference among the proportions of severe cases from 2009 to 2013 (chi2 = 301.16, P < 0.05). No death malaria case was reported in the whole province in 2013. CONCLUSION: Jiangsu Province has built a preliminary system of the prevention and control of imported falciparum malaria, which plays an important role in the prevention and control of overseas imported falciparum malaria. PMID- 26771045 TI - Editorial. PMID- 26771046 TI - Network science and the human brain: Using graph theory to understand the brain and one of its hubs, the amygdala, in health and disease. AB - Over the past 15 years, the emerging field of network science has revealed the key features of brain networks, which include small-world topology, the presence of highly connected hubs, and hierarchical modularity. The value of network studies of the brain is underscored by the range of network alterations that have been identified in neurological and psychiatric disorders, including epilepsy, depression, Alzheimer's disease, schizophrenia, and many others. Here we briefly summarize the concepts of graph theory that are used to quantify network properties and describe common experimental approaches for analysis of brain networks of structural and functional connectivity. These range from tract tracing to functional magnetic resonance imaging, diffusion tensor imaging, electroencephalography, and magnetoencephalography. We then summarize the major findings from the application of graph theory to nervous systems ranging from Caenorhabditis elegans to more complex primate brains, including man. Focusing, then, on studies involving the amygdala, a brain region that has attracted intense interest as a center for emotional processing, fear, and motivation, we discuss the features of the amygdala in brain networks for fear conditioning and emotional perception. Finally, to highlight the utility of graph theory for studying dysfunction of the amygdala in mental illness, we review data with regard to changes in the hub properties of the amygdala in brain networks of patients with depression. We suggest that network studies of the human brain may serve to focus attention on regions and connections that act as principal drivers and controllers of brain function in health and disease. PMID- 26771047 TI - A prospective audit of preprocedural fasting practices on a transplant ward: when fasting becomes starving. AB - AIMS AND OBJECTIVES: To investigate the prevalence and duration of preprocedural medically ordered fasting during a period of hospitalisation in an Australian population of patients with hepatic cirrhosis or following liver transplantation and to identify potential solutions to reduce fasting times. BACKGROUND: Protein energy malnutrition is a common finding in patients with hepatic cirrhosis and can impact significantly on survival and quality of life. Protein and energy requirements in patients with cirrhosis are higher than those of healthy individuals. A significant feature of cirrhosis is the induction of starvation metabolism following seven to eight hours of food deprivation. Many investigative and interventional procedures for patients with cirrhosis necessitate a period of fasting to comply with anaesthesia guidelines. DESIGN: An observational study of the fasting episodes for 34 hospitalised patients with hepatic cirrhosis or following liver transplantation. METHODS: Nutritional status was estimated using subjective global assessment and handgrip strength. The prevalence and duration of fasting practices for diagnostic or investigational procedures were estimated using electronic records and patient notes. RESULTS: Thirty-three patients (97%) were malnourished. Twenty-two patients (65%) were fasted during the observation period. There were 43 occasions of fasting with a median fasting time of 13.5 hours. On 40 occasions fasting times exceeded the maximum six-hour guideline recommended prior to the administration of anaesthesia by the majority of Anaesthesiology Societies. The majority of procedures (77%) requiring fasting occurred after midday. Eating breakfast on the day of the procedure reduced fasting time by 45%. CONCLUSIONS: Medically ordered preprocedural fasting times almost always exceed existing guidelines in this nutritionally compromised group. RELEVANCE TO CLINICAL PRACTICE: Adherence to fasting guidelines and eating breakfast before the procedure can reduce fasting times significantly and avoid the potential induction of starvation metabolism in this nutritionally at risk group. PMID- 26771048 TI - Facile Construction of Structurally Defined Porous Membranes from Supramolecular Hexakistriphenylamine Metallacycles through Electropolymerization. AB - The construction of well-controlled porous materials is very challenging. Herein, we report the successful preparation of structurally defined porous membranes based on hexakistriphenylamine metallacycles through electropolymerization. The newly designed porous materials were characterized by the typical cyclic voltammograms, XPS, SEM, and TEM investigations. Further investigations revealed that the metallacycle-based polymer films displayed a good size-selective molecular-sieving behavior. PMID- 26771049 TI - Highly Transparent Wafer-Scale Synthesis of Crystalline WS2 Nanoparticle Thin Film for Photodetector and Humidity-Sensing Applications. AB - In the present investigation, we report a one-step synthesis method of wafer scale highly crystalline tungsten disulfide (WS2) nanoparticle thin film by using a modified hot wire chemical vapor deposition (HW-CVD) technique. The average size of WS2 nanoparticle is found to be 25-40 nm over an entire 4 in. wafer of quartz substrate. The low-angle XRD data of WS2 nanoparticle shows the highly crystalline nature of sample along with orientation (002) direction. Furthermore, Raman spectroscopy shows two prominent phonon vibration modes of E(1)2g and A1g at ~356 and ~420 cm(-1), respectively, indicating high purity of material. The TEM analysis shows good crystalline quality of sample. The synthesized WS2 nanoparticle thin film based device shows good response to humidity and good photosensitivity along with good long-term stability of the device. It was found that the resistance of the films decreases with increasing relative humidity (RH). The maximum humidity sensitivity of 469% along with response time of ~12 s and recovery time of ~13 s were observed for the WS2 thin film humidity sensor device. In the case of photodetection, the response time of ~51 s and recovery time of ~88 s were observed with sensitivity ~137% under white light illumination. Our results open up several avenues to grow other transition metal dichalcogenide nanoparticle thin film for large-area nanoelectronics as well as industrial applications. PMID- 26771051 TI - Metformin Scavenges Methylglyoxal To Form a Novel Imidazolinone Metabolite in Humans. AB - Methylglyoxal (MG) is a highly reactive dicarbonyl compound involved in the formation of advanced glycation endproducts (AGE). Levels of MG are elevated in patients with type-2 diabetes mellitus (T2DM), and AGE have been implicated in the progression of diabetic complications. The antihyperglycemic drug metformin (MF) has been suggested to be a scavenger of MG. The present work examined and characterized unequivocally the resulting scavenged product from the metformin-MG reaction. The primary product was characterized by (1)H, (13)C, 2D-HSQC, and HMBC NMR and tandem mass spectrometry. X-ray diffraction analysis determined the structure of the metformin and MG-derived imidazolinone compound as (E)-1,1 dimethyl-2-(5-methyl-4-oxo-4,5-dihydro-1H-imidazol-2-yl)guanidine (IMZ). A LC MS/MS multiple reaction monitoring method was developed to detect and quantify the presence of IMZ in metformin-treated T2DM patients. Urine from >90 MF-treated T2DM patients was analyzed, with increased levels of MF directly correlating with elevations in IMZ. Urinary MF was detected in the range of 0.17 MUM to 23.0 mM, and simultaneous measurement of IMZ concentrations were in the range of 18.8 nM to 4.3 MUM. Since plasma concentrations of MG range from 40 nM to 4.5 MUM, the level of IMZ production may be of therapeutic significance. Thus, in addition to lowering hepatic gluconeogenesis, metformin also scavenges the highly reactive MG in vivo, thereby reducing potentially detrimental MG protein adducts, with subsequent reductions in diabetic complications. PMID- 26771052 TI - Light and Temperature Control of the Spin State of Bis(p-methoxyphenyl)carbene: A Magnetically Bistable Carbene. AB - Bis(p-methoxyphenyl)carbene is the first carbene that at cryogenic temperatures can be isolated in both its lowest energy singlet and triplet states. At 3 K, both states coexist indefinitely under these conditions. The carbene is investigated in argon matrices by IR, UV-vis, and X-band EPR spectroscopy and in MTHF glasses by W-band EPR and Q-band ENDOR spectroscopy. UV (365 nm) irradiation of the system results in formation of predominantly the triplet carbene, whereas visible (450 nm) light shifts the photostationary equilibrium toward the singlet state. Upon annealing at higher temperatures (>10 K), the triplet is converted to the singlet; however, cooling back to 3 K does not restore the triplet. Therefore, depending on matrix temperature and irradiation conditions, matrices containing predominantly the triplet or singlet carbene can be generated. Controlling the magnetic and chemical properties of carbenes by using light of different wavelengths might be of general interest for applications such as information storage and radical-initiated polymerization processes. PMID- 26771053 TI - Harnessing click detectors for the genuine characterization of light states. AB - The key requirement for harnessing the quantum properties of light is the capability to detect and count individual photons. Of particular interest are photon-number-resolving detectors, which allow one to determine whether a state of light is classical or genuinely quantum. Existing schemes for addressing this challenge rely on a proportional conversion of photons to electrons. As such, they are capable of correctly characterizing small photon fluxes, yet are limited by uncertainties in the conversion rate. In this work, we employ a divide-and conquer approach to infallibly discerning non-classicality of states of light. This is achieved by transforming the incident fields into uniform spatial distributions that readily lend themselves for characterization by standard on off detectors. Since the exact statistics of the light stream in multiplexed on off detectors are click statistics, our technique is freely scalable to accommodate-in principle-arbitrarily large photon fluxes. Our experiments pave the way towards genuine integrated photon-number-resolving detection for advanced on-chip photonic quantum networks. PMID- 26771054 TI - Database support for adaptation to climate change: An assessment of web-based portals across scales. AB - The widely recognized increase in greenhouse gas emissions is necessitating adaptation to a changing climate, and policies are being developed and implemented worldwide, across sectors, and between government scales globally. The aim of this article is to reflect on one of the major challenges: facilitating and sharing information on the next adaptation practices. Web portals (i.e., web sites) for disseminating information are important tools in meeting this challenge, and therefore, we assessed the characteristics of select major portals across multiple scales. We found that there is a rather limited number of case studies available in the portals-between 900 and 1000 in total with 95 that include cost information and 195 that include the participation of stakeholders globally. Portals are rarely cited by researchers, suggesting a suboptimal connection between the practical, policy-related, and scientific development of adaptation. The government portals often lack links on search results between US and European Union (EU) web sites, for example. With significant investments and policy development emerging in both the United States and the European Union, there is great potential to share information via portals. Moreover, there is the possibility of better connecting the practical adaptation experience from bottom-up projects to the science of adaptation. Integr Environ Assess Manag 2016;12:627-631. (c) 2016 SETAC. PMID- 26771055 TI - Medication Safety During Pregnancy: Improving Evidence-Based Practice. AB - Nearly 90% of women in the United States have taken medications during pregnancy. Medication exposures during pregnancy can result in adverse pregnancy and neonatal outcomes including birth defects, fetal loss, intrauterine growth restriction, prematurity, and longer-term neurodevelopmental outcomes. Advising pregnant women about the safety of medication use during pregnancy is complicated by a lack of data necessary to engage the woman in an informed discussion. Routinely, health care providers turn to the package insert, yet this information can be incomplete and can be based entirely on animal studies. Often, adequate safety data are not available. In a busy clinical setting, health care providers need to be able to quickly locate the most up-to-date information in order to counsel pregnant women concerned about medication exposure. Deciding where to locate the best available information is difficult, particularly when the needed information does not exist. Pregnancy registries are initiated to obtain more data about the safety of specific medication exposures during pregnancy; however, these studies are slow to produce meaningful information, and when they do, the information may not be readily available in a published form. Health care providers have valuable data in their everyday practice that can expand the knowledge base about medication safety during pregnancy. This review aims to discuss the limitations of the package insert regarding medication safety during pregnancy, highlight additional resources available to health care providers to inform practice, and communicate the importance of pregnancy registries for expanding knowledge about medication safety during pregnancy. PMID- 26771056 TI - A non-sense MCM9 mutation in a familial case of primary ovarian insufficiency. AB - Primary ovarian insufficiency (POI) results in an early loss of ovarian function, and remains idiopathic in about 80% of cases. Here, we have performed a complete genetic study of a consanguineous family with two POI cases. Linkage analysis and homozygosity mapping identified 12 homozygous regions with linkage, totalling 84 Mb. Whole-exome sequencing of the two patients and a non-affected sister allowed us to detect a homozygous causal variant in the MCM9 gene. The variant c.1483G>T [p.E495*], confirmed using Sanger sequencing, introduced a premature stop codon in coding exon 8 and is expected to lead to the loss of a functional protein. MCM9 belongs to a complex required for DNA repair by homologous recombination, and its impairment in mouse is known to induce meiotic recombination defects and oocyte degeneration. A previous study recently described two consanguineous families in which homozygous mutations of MCM9 were responsible for POI and short stature. Interestingly, the affected sisters in the family described here had a normal height. Altogether, our results provide the confirmation of the implication of MCM9 variants in POI and expand their phenotypic spectrum. PMID- 26771057 TI - Factors influencing change in clinical practice: A qualitative evaluation of the implementation of the quality improvement in colonoscopy study. AB - PURPOSE: The quality improvement in colonoscopy study was a region wide service improvement study to improve adenoma detection rate at colonoscopy by implementing evidence into routine colonoscopy practice. Implementing evidence into clinical practice can be challenging. The purpose of this paper is to perform a qualitative interview study to evaluate factors that influenced implementation within the study. DESIGN/METHODOLOGY/APPROACH: Semi-structured interviews were conducted with staff in endoscopy units taking part in the quality improvement in colonoscopy study, after study completion. Units and interviewees were purposefully sampled to ensure a range of experiences was represented. Interviews were conducted with 11 participants. FINDINGS: Key themes influencing uptake of the quality improvement in colonoscopy evidence bundle included time, study promotion, training, engagement, positive outcomes and modifications. Areas within themes were increased awareness of quality in colonoscopy (QIC), emphasis on withdrawal time and empowerment of endoscopy nurses to encourage the use of quality measures were positive outcomes of the study. The simple, visible study posters were reported as useful in aiding study promotion. Feedback sessions improved engagement. Challenges included difficulty arranging set-up meetings and engaging certain speciality groups. ORIGINALITY/VALUE: This evaluation suggests that methods to implement evidence into clinical practice should include identification and empowerment of team members who can positively influence engagement, simple, visible reminders and feedback. Emphasis on timing of meetings and strategies to engage speciality groups should also be given consideration. Qualitative evaluations can provide important insights into why quality improvement initiatives are successful or not, across different sites. PMID- 26771058 TI - Applying Lean Six Sigma to improve medication management. AB - PURPOSE: A significant proportion of veterans use dual care or health care services within and outside the Veterans Health Administration (VHA). In this study conducted at a VHA medical center in the USA, the authors used Lean Six Sigma principles to develop recommendations to eliminate wasteful processes and implement a more efficient and effective process to manage medications for dual care veteran patients. The purpose of this study is to: assess compliance with the VHA's dual care policy; collect data and describe the current process for co management of dual care veterans' medications; and draft recommendations to improve the current process for dual care medications co-management. DESIGN/METHODOLOGY/APPROACH: Input was obtained from the VHA patient care team members to draw a process map to describe the current process for filling a non VHA prescription at a VHA facility. Data were collected through surveys and direct observation to measure the current process and to develop recommendations to redesign and improve the process. FINDINGS: A key bottleneck in the process that was identified was the receipt of the non-VHA medical record which resulted in delays in filling prescriptions. The recommendations of this project focus on the four domains of: documentation of dual care; veteran education; process redesign; and outreach to community providers. RESEARCH LIMITATIONS/IMPLICATIONS: This case study describes the application of Lean Six Sigma principles in one urban Veterans Affairs Medical Center (VAMC) in the Mid-Western USA to solve a specific organizational quality problem. Therefore, the findings may not be generalizable to other organizations. PRACTICAL IMPLICATIONS: The Lean Six Sigma general principles applied in this project to develop recommendations to improve medication management for dual care veterans are applicable to any process improvement or redesign project and has valuable lessons for other VAMCs seeking to improve care for their dual care veteran patients. ORIGINALITY/VALUE: The findings of this project will be of value to VA providers and policy makers and health care managers who plan to apply Lean Six Sigma techniques in their organizations to improve the quality of care for their patients. PMID- 26771059 TI - Discharge against medical advice from a Tehran emergency department. AB - PURPOSE: The purpose of this paper is to identify the main reasons for discharge against medical advice (DAMA) in the emergency department (ED) of a teaching hospital in Tehran, Iran. DESIGN/METHODOLOGY/APPROACH: This cross-sectional study was conducted on all the patients who left the ED of a referral teaching hospital against medical advice (AMA) in 2008. A questionnaire was filled out for each patient to determine the reasons behind patient leaving AMA. FINDINGS: In total, 12.8 percent of the patients left the hospital AMA. Dissatisfaction with being observed in the ED, having a feeling of recovery and hospital personnel encouraging patients to leave the hospital were the main reasons for leaving the hospital AMA. PRACTICAL IMPLICATIONS: Like many other centers, the results showed that poor communication skill and work overload were the main contributing factors to DAMA. The center managed to improve patient satisfaction and thus lowered DAMA rates following this study. Considering the similarities reported in the reports and that of other studies, it could be concluded that policy makers in other centers can also benefit from the results to adopt effective approaches to reduce DAMA rate. ORIGINALITY/VALUE: To the knowledge no study has evaluated the rate and the reasons behind DAMA in the Iranian EDs. PMID- 26771060 TI - Measuring family satisfaction with inpatient rehabilitation care. AB - PURPOSE: The purpose of this paper is to investigate the psychometric characteristics of the Questionnaire of Family members' Satisfaction about the Rehabilitation (QFSR), a new questionnaire assessing the satisfaction of patients' families with the in-hospital rehabilitation service, i.e., the organizational procedure, medical treatment, relationship with nurses/other health workers, and outcome. DESIGN/METHODOLOGY/APPROACH: The QFSR (13 items) was administered to 1,226 (F=60.4 percent; mean age=57.4, SD 15 years) family members of patients admitted to two units for inpatient rehabilitation, i.e., cardiovascular and neuromotor. FINDINGS: Confirmatory factor analysis (CFA) confirmed the theoretical four-factor structure of the questionnaire in a subsample of 308 respondents randomly selected from the sample (SB chi2 (61)=57.4, p=0.61; RMSEA=0.0; 90 percent CI [0.0, 0.031], CFI=1.00). The remaining 708 respondents (393 relatives of cardiovascular unit inpatients and 315 relatives of neuromotor unit inpatients) were used to test measurement invariance between the groups of family members with patients in the two units. The configurial, scalar, and strict factorial invariance provided a good fit to the data. ORIGINALITY/VALUE: The QFSR, specifically developed to measure the satisfaction of family members of patients undergoing rehabilitation, appears to be a promising brief questionnaire that can provide important indications for continuous improvement in the delivery of healthcare. PMID- 26771061 TI - Hospital menu interventions: a systematic review of research. AB - PURPOSE: Most patients in developed countries solely depend on the hospital menu to order their food. The provision of menu choices to patients differs between facilities. The purpose of this paper is to determine which strategies that provide menu choices to patients are effective in improving clinical and non clinical outcomes in hospital. DESIGN/METHODOLOGY/APPROACH: Five databases were searched to identify relevant publications. Prospective research published in English with the menu as the primary intervention was included. Study eligibility was determined and risk of bias assessed. Outcome data were combined narratively due to absence of homogeneous study design and outcomes. FINDINGS: Of the 2,201 records screened, six studies met inclusion criteria. Standardised menu formatting and the spoken menu system were found to improve meal tray accuracy. The spoken menu and computerised interactive menu selector system enhanced aspects of patient satisfaction without cost increases. Descriptive menus may increase food consumption. Branding food items was not well supported by patients. One study rated positively for study quality with the remaining five studies receiving neutral quality ratings. RESEARCH LIMITATIONS/IMPLICATIONS: The small number of studies conducted on each intervention and the quality of the evidence made it difficult to establish a solid evidence base around providing menu choices to patients. Further research is needed on menu ordering systems, including spoken and visual menus, to determine their impact on outcomes in hospital. ORIGINALITY/VALUE: This review is first to examine the effectiveness of menu interventions in hospital. Hospital foodservice departments should consider these findings when reviewing local systems. PMID- 26771062 TI - Trans-disciplinary community groups: an initiative for improving healthcare. AB - PURPOSE: In the context of budget constraints and the current quality crisis facing UK healthcare, the purpose of this paper is to examine the use of trans disciplinary community groups (TCG)--an innovative and inexpensive initiative for improving patient care. DESIGN/METHODOLOGY/APPROACH: Using an action research study, TCG was implemented within a private healthcare firm for vulnerable adults. Qualitative data were gathered over 12 months from 33 participants using depth interviews and focus groups. FINDINGS: TCG led to improved patient activities and increased patient decision-making and confidence in self-advocacy. Key prerequisites were top management commitment, democratic leadership and employee empowerment. However, staff nurses resisted TCG because they were inclined to using managerial control and their own independent clinical judgements. RESEARCH LIMITATIONS/IMPLICATIONS: Whilst the findings from this study should not be generalized across all healthcare sectors, its results could be replicated in contexts where there is wide commitment to TCG and where managers adopt a democratic style of leadership. Researchers could take this study further by exploring the applicability of TCG in public healthcare organizations or other multi-disciplinary service contexts. PRACTICAL IMPLICATIONS: The findings of this research paper provide policy makers and healthcare managers with practical insights on TCG and the factors that are likely to obstruct and facilitate its implementation. ORIGINALITY/VALUE: Adopting TCG could enable healthcare managers to ameliorate their services with little or no extra cost, which is especially important in a budget constraint context and the current quality crisis facing UK healthcare. PMID- 26771063 TI - Maternity-care: measuring women's perceptions. AB - PURPOSE: Achieving maternity-care outcomes that align with women's needs, preferences and expectations is important but theoretically driven measures of women's satisfaction with their entire maternity-care experience do not appear to exist. The purpose of this paper is to outline the development of an instrument to assess women's perception of their entire maternity-care experience. DESIGN/METHODOLOGY/APPROACH: A questionnaire was developed on the basis of previous research and informed by a framework of standard service quality categories covering the spectrum of typical consumer concerns. A pilot survey with a sample of 195 women who had recent experience of birth was undertaken to establish valid and reliable scales pertaining to different stages of maternity care. Exploratory factor analysis was used to interpret scales and convergent validity was assessed using a modified version of the Client Satisfaction Questionnaire. FINDINGS: Nine theoretically informed, reliable and valid stand alone scales measuring the achievement of different dimensions of women's expectancies of public maternity care were developed. The study scales are intended for use in identifying some potential areas of focus for quality improvement in the delivery of maternity care. RESEARCH LIMITATIONS/IMPLICATIONS: Reliable and valid tools for monitoring the extent to which services respond to women's expectations of their entire maternity care form part of the broader toolkit required to adequately manage health-care quality. This study offers guidance on the make-up of such tools. ORIGINALITY/VALUE: The scales produced from this research offer a means to assess maternity care across the full continuum of care and are brief and easy to use. PMID- 26771064 TI - Relationship Between Diastolic Dysfunction and Atherosclerosis and Vascular Calcification in Hemodialysis Patients: Diagnostic Potential of the Cardio-Ankle Vascular Index. AB - Diastolic dysfunction (DD) commonly causes heart failure with preserved ejection fraction (EF). Here, we examine associations between DD severity and atherosclerosis/vascular calcification in hemodialysis patients. Echocardiography was performed on 101 patients undergoing hemodialysis therapy. Twelve patients (EF < 50% or chronic atrial fibrillation) were excluded; DD of the remaining 89 patients was classified into four grades. We then investigated the relationship between their DD grades and the cardio-ankle vascular index (CAVI), ankle brachial pressure index (ABI), toe-brachial pressure index (TBI), and aortic calcification area index (ACAI). Seventy-seven patients (86.5%) with EF >= 50% had DD. Associations with advanced age and comorbid diabetes mellitus and cardiovascular disease were observed. The CAVI, TBI, and ACAI, but not ABI, increased proportionally with DD grades. Thus, many hemodialysis patients developed DD, with systolic function maintained. Strong associations between DD grades and progression of both atherosclerosis and vascular calcification could be inferred. PMID- 26771065 TI - Proteomics Approach Identifies Factors Associated With the Response to Low Density Lipoprotein Apheresis Therapy in Patients With Steroid-Resistant Nephrotic Syndrome. AB - Low-density lipoprotein apheresis (LDL-A) has been shown to reduce proteinuria in a subgroup of nephrotic syndrome patients refractory to immunosuppressive therapy. Factors influencing the efficacy of LDL-A in nephrotic syndrome are completely unknown. Using a proteomics approach, we aimed to identify biological markers that predict the response to LDL-A in patients with steroid-resistant nephrotic syndrome (SRNS). Identification of plasma proteins bound to the dextran sulfate column at the first session of LDL-A was determined by mass spectrometry. To investigate biological factors associated with the response to LDL-A, we compared profiles of column-bound proteins between responders (defined by more than 50% reduction of proteinuria after the treatment) and non-responders by 2 dimensional gel electrophoresis (2-DE) coupled to mass spectrometry in seven patients with SRNS. Evaluation of proteins adsorbed to LDL-A column in patients with SRNS revealed the identity of 62 proteins, which included apolipoproteins, complement components, and serum amyloid P-component (SAP). Comparative analysis of the column-bound proteins between responders and non-responders by 2-DE demonstrated that apolipoprotein E (APOE) and SAP levels were increased in non responders as compared with responders. These results were confirmed by western blotting. Moreover, serum levels of APOE and SAP were significantly higher in the non-responder group than in the responder group by ELISA. Our data provide comprehensive analysis of proteins adsorbed by LDL-A in SRNS, and demonstrate that the serum levels of APOE and SAP may be used to predict the response to LDL A in these patients. PMID- 26771066 TI - Safety and Tolerability of Nafamostat Mesilate and Heparin as Anticoagulants in Leukocytapheresis for Ulcerative Colitis: Post Hoc Analysis of a Large-Scale, Prospective, Observational Study. AB - Nafamostat mesilate is the first anticoagulant of choice for leukocytapheresis (LCAP) with a Cellsorba E column for treating ulcerative colitis (UC). However, because of complications, mainly due to allergy to nafamostat mesilate, heparin may be used as a substitute. To evaluate the safety and tolerability of nafamostat mesilate and heparin as anticoagulants in LCAP for UC, we conducted post hoc analysis of data from a large-scale, prospective, observational study of LCAP, which was conducted at 116 medical facilities in Japan between May 2010 and December 2012. Of 832 patients included in this analysis, nafamostat mesilate and heparin were used in 676 (81.3%) and 113 (13.6%), respectively. There were no significant differences in the incidence of adverse reactions (8.6% vs. 7.1%) and intrafilter pressure increases (12.7% vs. 16.8%) between the nafamostat mesilate and heparin groups. Adverse reactions of hemorrhage or blood pressure decreases associated with heparin use were not observed. There were no significant differences in rates of clinical remission (69.1% vs. 68.1%) and mucosal healing (62.9% vs. 63.6%) between the nafamostat mesilate and heparin groups. Thus, the safety and tolerability were comparable in the nafamostat mesilate and heparin groups, indicating that both nafamostat mesilate and heparin can be well tolerated as anticoagulants in LCAP for UC. PMID- 26771067 TI - Progressive vascular remodelling, endothelial dysfunction and stiffness in mesenteric resistance arteries in a rodent model of chronic kidney disease. AB - Chronic kidney disease (CKD) and hypertension are co-morbid conditions both associated with altered resistance artery structure, biomechanics and function. We examined these characteristics in mesenteric artery together with renal function and systolic blood pressure (SBP) changes in the Lewis polycystic kidney (LPK) rat model of CKD. Animals were studied at early (6-weeks), intermediate (12 weeks), and late (18-weeks) time-points (n=21), relative to age-matched Lewis controls (n=29). At 12 and 18-weeks, LPK arteries exhibited eutrophic and hypertrophic inward remodelling characterised by thickened medial smooth muscle, decreased lumen diameter, and unchanged or increased media cross-sectional area, respectively. At these later time points, endothelium-dependent vasorelaxation was also compromised, associated with impaired endothelium-dependent hyperpolarisation and reduced nitric oxide synthase activity. Stiffness, elastic modulus/stress slopes and collagen/elastin ratios were increased in 6 and 18-week old-LPK, in contrast to greater arterial compliance at 12weeks. Multiple linear regression analysis highlighted SBP as the main predictor of wall-lumen ratio (r=0.536, P<0.001 n=46 pairs). Concentration-response curves revealed increased sensitivity to phenylephrine but not potassium chloride in 18-week-LPK. Our results indicate that impairment in LPK resistance vasculature is evident at 6weeks, and worsens with hypertension and progression of renal disease. PMID- 26771068 TI - Effects of Aloe barbadensis Mill. extract (AVH200(r)) on human blood T cell activity in vitro. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Aloe barbadensis Mill. (Aloe vera) is a widely used medicinal plant well reputed for its diverse therapeutic applications. It has been used for thousands of years in folk medicine to treat various conditions and the Aloe vera gel has been reported to possess anti-inflammatory as well as immunostimulatory and immunomodulatory properties. However, the mode of action is still unclear. AIM OF THE STUDY: The aim of this study was determine the effects of two well-defined A. barbadensis Mill. extracts AVH200(r) and AVE200 on human blood T cells in vitro. MATERIALS AND METHODS: Peripheral blood mononuclear cells (PBMC) from healthy donors were stimulated polyclonally in the presence or absence of AVH200(r) and AVE200. The T cell phenotype was investigated by flow cytometry, cell proliferation was determined by CFSE dye and thymidine assay, respectively and cytokine secretion was determined by MSD(r) Multi-Spot Assay system and ELISA. RESULTS: The presence of AVH200(r) resulted in a reduced expression of CD25 among CD3(+) T cells and suppression of T cell proliferation in a dose dependent manner. Furthermore, AVH200(r) reduced the expression of CD28 on CD3(+) T cells. AVH200(r) also reduced the secretion of IL-2, IFN-gamma and IL 17A in PBMC cultures. The AVH200(r) dose dependent reduction in T cell activation and proliferation recorded in the cell cultures was not due to apoptosis or cell death. Additionally, AVH200(r) was found to be more effective as compared to AVE200 in reducing T cell activation and proliferation. CONCLUSION: AVH200(r) has the potential to reduce the activation, proliferation and cytokine secretion of healthy human blood T cells. Our study suggests that AVH200(r) has a suppressive effect on human blood T cells in vitro. PMID- 26771069 TI - Estrogenic effects of Ficus umbellata Vahl. (Moraceae) extracts and their ability to alleviate some menopausal symptoms induced by ovariectomy in Wistar rats. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Ficus umbellata Vahl. (Moraceae) is a medicinal plant used in Cameroon to treat amenorrhea as well as other physiological disorders related to menopause. AIM OF STUDY: In order to justify scientifically its traditional use, the estrogen-like properties of the aqueous (AE) and methanol (MeOH) extracts of F. umbellata were investigated. MATERIAL AND METHODS: In vitro, the ability of different extracts of F. umbellata to activate estrogen receptors alpha (ERalpha) and beta (ERbeta) in cell-based reporter gene assays using human embryonic kidney (HEK293T) cells transfected with ERs was tested. In vivo, a 3-day uterotrophic assay and the capacity of the extracts to alleviate hot flushes in ovariectomized adult rats were tested. Using a bioassay-guided fractionation the major compound of F. umbellata was isolated and tested in vitro on HEK293T-ERalpha and ERbeta cells. RESULTS: AE and MeOH extracts significantly altered ERalpha as well as ERbeta activities. In vivo, both extracts significantly increase the uterine and vaginal epithelium thickness, and uterine total protein levels in a dose dependent manner. Interestingly, both extracts of F. umbellata at the dose of 100 mg/kg BW significantly decreased the total number, average duration as well as frequency of hot flushes in experimental rats compared to age-matched OVX controls. Finally, 7-methylumbelliferone, a coumarin was characterized as the major compound of F. umbellata; however this compound did not transactivate ERalpha as well ERbeta in vitro. CONCLUSION: These aforementioned results suggest that F. umbellata extracts as used by the traditional practitioner have estrogen-like effects and may alleviate some menopausal problems such as vaginal dryness and hot flushes. PMID- 26771070 TI - Terminalia arjuna bark extract improves diuresis and attenuates acute hypobaric hypoxia induced cerebral vascular leakage. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Terminalia arjuna (Roxb. ex DC.) Wight & Arn. (T. arjuna) has been widely used in the traditional ayurvedic system of medicine as a cardioprotectant and for acute and chronic renal diseases supporting its ethnopharmacological use. AIM OF THE STUDY: The present study aimed at evaluating the diuretic action of an alcoholic extract of T. arjuna and its possible use as a prophylactic to prevent vascular leakage during acute mountain sickness at high altitude. MATERIALS AND METHODS: Rats were exposed to hypobaric hypoxia simulated to an altitude of 27,000 ft. in a decompression chamber for 12h. T. arjuna bark extract was administered at a single dose of 150 mg/kg (p.o.) to male Sprague Dawley rats (200 +/- 20 g) 30 min prior to exposure. Total urine volume was measured during exposure to hypobaric hypoxia. The animals were then investigated for cerebral vascular leakage and serum concentration of sodium, potassium, renin, angiotensin-II, aldosterone and atrial natriuretic peptide (ANP). RESULTS: T. arjuna ameliorated acute hypobaric hypoxia induced decrease in glomerular filtration rate (p<0.5), increased total urine output (p<0.5) and prevented cerebral vascular leakage in hypoxic rats. T. arjuna treated animals also showed decrease in serum levels of renin (p<0.001) and angiotensin-II (p<0.5) as compared to placebo treated animals. Administration of T. arjuna attenuated acute hypobaric hypoxia induced oxidative stress, improved aldosterone levels and altered electrolyte balance in animals through ANP dependent mechanism. CONCLUSION: Results of the present study indicate towards diuretic potential of hydro-alcoholic extract of T. arjuna bark and provide evidence for its novel application as a prophylactic to attenuate acute hypobaric hypoxia induced cerebral vascular leakage through ANP mediated modulation of renin-angiotensin aldosterone system. PMID- 26771071 TI - Influence of platelet-derived growth factor on osseous remodeling properties of a variable-thread tapered dental implant in vivo. AB - OBJECTIVES: To evaluate the effect of platelet-derived growth factor (rhPDGF-BB) on the promotion of osteogenesis around variable-thread tapered implants in an animal model. MATERIAL AND METHODS: Twenty-four variable-thread tapered implants were inserted in the tibia of 12 rabbits. Twelve sites received additional rhPDGF BB released from a presoaked xenogenic bone block that was fixed supracrestally. Primary outcomes were bone-to-implant contact (BIC; in % +/- SD) and percentage of medullary bone fill around the implants (PMF; in % +/- SD) after 3 weeks (PDGF n = 6, no PDGF n = 6) and 6 weeks (PDGF n = 6, no PDGF n = 6). RESULTS: Considerable crestal and medullary bone remodeling could be found around all implants. After 3 weeks, both BIC and PMF values were higher in the no PDGF group (BIC: 63% +/- 10 with PDGF vs. 85% +/- 5 with no PDGF; PMF: 57% +/- 10 with PDGF vs. 74% +/- 4 with no PDGF). After 6 weeks, the BIC difference between the two groups was less distinct (BIC: 78% +/- 17 with PDGF vs. 72% +/- 25 with no PDGF), whereas the PDGF group showed higher PMF values (PMF: 77% +/- 5 with PDGF vs. 56% +/- 10 with no PDGF). CONCLUSIONS: The addition of rhPDGF-BB decreases early osseous crestal and medullar healing properties around dental implants. In a later phase, an increase in the cortical area as well as an increased medullar bone formation was seen. This response is likely to provide stronger secondary stability and stability in suboptimal situations involving poor-quality bone. PMID- 26771072 TI - Straightforward Synthesis, Electrochemical Properties, and Gel Formation of Thiacalix[n]thiophenes. AB - A facile synthetic approach toward thiacalix[n]thiophene homologues (n=4-6) is presented herein. Pd-catalyzed coupling of 2,5-dibromothiophene derivatives with stannyl sulfide gave various thiacalix[n]thiophenes in good yields. The optical and electrochemical properties of the produced cavitands were investigated. Furthermore, gelation was observed in some solvents. PMID- 26771073 TI - Effect of spatial constraints on Hardy-Weinberg equilibrium. AB - Panmixia is a key issue in maintaining genetic diversity, which facilitates evolutionary potential during environmental changes. Additionally, conservation biologists suggest the importance of avoiding small or subdivided populations, which are prone to losing genetic diversity. In this paper, computer simulations were performed to the genetic drift of neutral alleles in random mating populations with or without spatial constraints by randomly choosing a mate among the closest neighbours. The results demonstrated that the number of generations required for the neutral allele to become homozygous (Th) varied proportionally to the population size and also strongly correlated with spatial constraints. The average Th for populations of the same size with spatial constraints was approximately one-and-a-half times longer than without constraints. With spatial constraints, homozygous population clusters formed, which reduced local diversity but preserved global diversity. Therefore, panmixia might be harmful in preserving the genetic diversity of an entire population. The results also suggested that the gene flow or gene exchange among the subdivided populations must be carefully processed to restrict diseases transmission or death during transportation and to monitor the genetic diversity. The application of this concept to similar systems, such as information transfer among peers, is also discussed. PMID- 26771075 TI - A one-pot gold seed-assisted synthesis of gold/platinum wire nanoassemblies and their enhanced electrocatalytic activity for the oxidation of oxalic acid. AB - Three-dimensional (3D) noble metal nanoassemblies composed of one-dimensional (1D) nanowires have been attracting much interest due to the unique physical and chemical properties of 1D nanowires as well as the particular interconnected open pore structure of 3D nanoassemblies. In this work, well-defined Au/Pt wire nanoassemblies were synthesized by using a facile NaBH4 reduction method in the presence of a branched form of polyethyleneimine (PEI). A study of the growth mechanism indicated the morphology of the final product to be highly related to the molecular structure of the polymeric amine. Also, the preferred Pt-on-Pt deposition contributed to the formation of the 1D Pt nanowires. The Au/Pt wire nanoassemblies were functionalized with PEI at the same time that these nanoassemblies were synthesized due to the strong N-Pt bond. The chemically functionalized Au/Pt wire nanoassemblies exhibited better electrocatalytic activity for the electro-oxidation of oxalic acid than did commercial Pt black. PMID- 26771074 TI - Novel Methods of Determining Urinary Calculi Composition: Petrographic Thin Sectioning of Calculi and Nanoscale Flow Cytometry Urinalysis. AB - Accurate determination of urinary stone composition has significant bearing on understanding pathophysiology, choosing treatment modalities and preventing recurrence. A need exists for improved methods to determine stone composition. Urine of 31 patients with known renal calculi was examined with nanoscale flow cytometry and the calculi collected during surgery subsequently underwent petrographic thin sectioning with polarized and fluorescent microscopy. Fluorescently labeled bisphosphonate probes (Alendronate-fluorescein/Alendronate Cy5) were developed for nanoscale flow cytometry to enumerate nanocrystals that bound the fluorescent probes. Petrographic sections of stones were also imaged by fluorescent and polarized light microscopy with composition analysis correlated to alendronate +ve nanocrystal counts in corresponding urine samples. Urine samples from patients with Ca(2+) and Mg(2+) based calculi exhibited the highest alendronate +ve nanocrystal counts, ranging from 100-1000 nm in diameter. This novel urine based assay was in agreement with composition determined by petrographic thin sections with Alendronate probes. In some cases, high alendronate +ve nanocrystal counts indicated a Ca(2+) or Mg(2+) composition, as confirmed by petrographic analysis, overturning initial spectrophotometric diagnosis of stone composition. The combination of nanoscale flow cytometry and petrographic thin sections offer an alternative means for determining stone composition. Nanoscale flow cytometry of alendronate +ve nanocrystals alone may provide a high-throughput means of evaluating stone burden. PMID- 26771076 TI - A case study of school support and the psychological, emotional and behavioural consequences of HIV and AIDS on adolescents. AB - Various studies have reported a huge increase in the numbers of orphaned adolescents in Sub-Saharan Africa and its effects on their psychological, emotional and behavioural development. Yet, their needs are seldom recognised or adequately addressed in policy and programmes.This article uses a qualitative study to report the experiences of 11 orphaned adolescents (5 boys and 6 girls aged between 15 and 18 years) affected by HIV and AIDS in a secondary school (in Atteridgeville, Pretoria, South Africa) and the school support provided by them. The primary data-generation strategies were informal interviews and the Beck Youth Inventories-II (BYI-II) (adopted to measure the participants' level of emotional, behavioural and psychological problems). All interview transcriptions with the participants were thematically analysed. BYI-II data were subjected to T scores (in percentages) to know the participant's psychological, behavioural and emotional problems in order to compare it with their perceptions on the degree of support provided by the school. Result shows that participants have a high prevalence of psychological, behavioural and emotional problems and that the school support provided to them (teachers' support, the general school environment and the degree of discrimination, labelling and bullying that exists in the school) was not sufficient. The participants, however, reported a high level of support from the principal. In conclusion, we have suggested the urgent need for teachers to acquire and possess basic knowledge and skills in caring and paying attention to learners affected by HIV and AIDS and for government agencies and NGOs working with HIV-and AIDS-affected children, to focus on proposals that address the psychological, behavioural and emotional problems in such affected adolescents. PMID- 26771077 TI - The convergence of HIV/AIDS and customary tenure on women's access to land in rural Malawi. AB - This paper examines the convergence of HIV/AIDS and the social processes through which women access customary land in rural Malawi. Data were collected from focus group discussions with women in patrilineal and matrilineal communities. Women's land tenure is primarily determined through kinship group membership, customary inheritance practices and location of residence. In patrilineal communities, land is inherited through the male lineage and women access land through relationships with male members who are the rightful heirs. Conversely in matrilineal matrilocal communities, women as daughters directly inherit the land. This research found that in patrilineal communities, HIV/AIDS, gendered inequalities embedded in customary inheritance practices and resource shortages combine to affect women's access to land. HIV/AIDS may cause the termination of a woman's relationship with the access individual due to stigma or the individual's death. Termination of such relationships increases tenure insecurity for women accessing land in a community where they do not have inheritance rights. In contrast to the patrilineal patrilocal experience, research on matrilineal matrilocal communities demonstrates that where women are the inheritors of the land and have robust land tenure rights, they are not at risk of losing their access to land due to HIV/AIDS. PMID- 26771078 TI - The Prevalence of Autism Spectrum Disorders in West Pomeranian and Pomeranian Regions of Poland. AB - BACKGROUND: The prevalence of autism spectrum disorders (ASD) varies worldwide from 1.4/10 000 children in the Arabian Peninsula to 185/10 000 children of Asian population. In Europe, the highest prevalence has been observed in Sweden, while the lowest in Croatia (115/10 000 and 2-3/10 000, respectively). There have been no epidemiological studies on the prevalence of ASD in Polish population. The aim of our study was to assess the prevalence of ASD in children aged 0-16 years, inhabitants of West Pomeranian and Pomeranian regions. MATERIAL AND METHODS: In total, 2514 children (2038 males, 81.1%) were included. The estimates were based on the government registries, whereas data were obtained from Provincial Disability Services Commissions. RESULTS: The prevalence of ASD in children aged 0-16 years varies between two regions of Poland - 32/10 000 in West Pomeranian and 38/10 000 in Pomeranian region. CONCLUSIONS: The average prevalence of ASD was 35/10 000 children and was about 4-fold higher in males (P < 0.05). More studies are necessary. PMID- 26771079 TI - Sexual dimorphism in sister species of Leucoraja skate and its relationship to reproductive strategy and life history. AB - Instances of sexual dimorphism occur in a great variety of forms and manifestations. Most skates (Batoidea: Rajoidei) display some level of body shape dimorphism in which the pectoral fins of mature males develop to create a distinct bell-shaped body not found in females. This particular form of dimorphism is present in each of the sister species Leucoraja erinacea and Leucoraja ocellata, but differences between sexes are much greater in the former. In order to understand the nature and potential causes of pectoral dimorphism, we used geometric morphometrics to investigate allometry of fin shape in L. erinacea and L. ocellata and its relationship to the development of reproductive organs, based on previous work on the bonnethead shark, Sphyrna tiburo. We found that allometric trajectories of overall pectoral shape were different in both species of skate, but only L. erinacea varied significantly with respect to endoskeleton development. Male maturation was characterized by a number of sex-specific morphological changes, which appeared concurrently in developmental timing with elongation of cartilage-supported claspers. We suggest that external sexual dimorphism of pectoral fins in skates is a byproduct of skeletal growth needed for clasper development. Further, the magnitude of male shape change appears to be linked to the differential life histories of species. This work reports for the first time that pectoral dimorphism is a persistent feature in rajoid fishes, occurring in varying degrees across several genera. Lastly, our results suggest that pectoral morphology may be useful as a relative indicator of reproductive strategy in some species. PMID- 26771080 TI - Effect of sagittal plane mechanics on ACL strain during jump landing. AB - The relationships between non-contact anterior cruciate ligament injuries and the underlying biomechanics are still unclear, despite large quantities of academic research. The purpose of this research was to study anterior cruciate ligament strain during jump landing by investigating its correlation with sagittal plane kinetic/kinematic parameters and by creating an empirical model to estimate the maximum strain. Whole-body kinematics and ground reaction forces were measured from seven subjects performing single leg jump landing and were used to drive a musculoskeletal model that estimated lower limb muscle forces. These muscle forces and kinematics were then applied on five instrumented cadaver knees using a dynamic knee simulator system. Correlation analysis revealed that higher ground reaction force, lower hip flexion angle and higher hip extension moment among others were correlated with higher peak strain (p < 0.05). Multivariate regression analyses revealed that intrinsic anatomic factors account for most of the variance in strain. Among the extrinsic variables, hip and trunk flexion angles significantly contributed to the strain. The empirical relationship developed in this study could be used to predict the relative strain between jumps of a participant and may be beneficial in developing training programs designed to reduce an athlete's risk of injury. (c) 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:1636-1644, 2016. PMID- 26771081 TI - CART modulates the effects of levodopa in rat model of Parkinson's disease. AB - Parkinson's disease (PD) is an age-related disorder characterized by a progressive degeneration of dopaminergic neurons of substantia nigra (SN). The neuropeptide cocaine- and amphetamine-regulated transcript (CART) is known to closely interact with the dopamine system and regulate psychomotor activity. We screened the effectiveness of CART in reversing the symptoms of PD in a rat model. PD like condition was induced by administering 6-hydroxydopamine (6-OHDA) directly in the SN of the right side. Fifteen days later, intraperitoneal (IP) treatment with apomorphine hydrochloride to these rats, resulted in contralateral rotations in the rotation test chamber suggesting induction of PD-like symptoms. This action of apomorphine was significantly attenuated by intracerebroventricular (ICV) treatment with CART and potentiated by CART antibody. IP treatment with levodopa also produced contralateral rotation in PD induced rats, and showed anti-Parkinson-like action. Prior treatment with CART via ICV route potentiated the anti-Parkinsonian effects of levodopa, while CART antibody produced opposite effects. CART treatment per se, to PD induced rats produced ipsilateral rotations, suggesting that the peptide may promote the endogenous release of dopamine from intact neurons. While CART-immunoreactivity in arcuate nucleus, paraventricular nucleus, striatum, substantia nigra, ventral tegmental area and locus coeruleus was reduced in the PD induced rats, levodopa treatment restored the expression of CART-immunoreactivity in these nuclei. These results suggest that endogenous CART might closely interact with the dopamine containing SN-striatal pathway which is known to profoundly influence the motor system. The study underscores the importance of CART as a potential therapeutic agent in the treatment of PD. PMID- 26771083 TI - Magnetic phase separation in double layer ruthenates Ca3(Ru(1-x)Ti(x))2O7. AB - A phase transition from metallic AFM-b antiferromagnetic state to Mott insulating G-type antiferromagnetic (G-AFM) state was found in Ca3(Ru(1-x)Ti(x))2O7 at about x = 0.03 in our previous work. In the present, we focused on the study of the magnetic transition near the critical composition through detailed magnetization measurements. There is no intermediate magnetic phases between the AFM-b and G AFM states, which is in contrasted to manganites where a similar magnetic phase transition takes place through the presence of several intermediate magnetic phases. The AFM-b-to-G-AFM transition in Ca3(Ru(1-x)Ti(x))2O7 happens through a phase separation process in the 2-5% Ti range, whereas similar magnetic transitions in manganites are tuned by 50-70% chemical substitutions. We discussed the possible origin of such an unusual magnetic transition and compared with that in manganites. PMID- 26771082 TI - Architecture and Function of Mechanosensitive Membrane Protein Lattices. AB - Experiments have revealed that membrane proteins can form two-dimensional clusters with regular translational and orientational protein arrangements, which may allow cells to modulate protein function. However, the physical mechanisms yielding supramolecular organization and collective function of membrane proteins remain largely unknown. Here we show that bilayer-mediated elastic interactions between membrane proteins can yield regular and distinctive lattice architectures of protein clusters, and may provide a link between lattice architecture and lattice function. Using the mechanosensitive channel of large conductance (MscL) as a model system, we obtain relations between the shape of MscL and the supramolecular architecture of MscL lattices. We predict that the tetrameric and pentameric MscL symmetries observed in previous structural studies yield distinct lattice architectures of MscL clusters and that, in turn, these distinct MscL lattice architectures yield distinct lattice activation barriers. Our results suggest general physical mechanisms linking protein symmetry, the lattice architecture of membrane protein clusters, and the collective function of membrane protein lattices. PMID- 26771084 TI - Cell-Permeable Peptide Blocks TLR4 Signaling and Improves Islet Allograft Survival. AB - Toll-like receptor 4 (TLR4) activation in pancreatic beta cells activates aberrant islet graft cellular pathways and contributes to immune rejection in allogeneic islet transplantation. As an approach to overcoming this problem, we determined the capacity of a 33-amino acid peptide consisting of a protein transduction domain (PTD) from the Hph-1 virus and a fragment of the intracellular domain of TLR4 from the C3H mice (PTD-dnTLR4) to block TLR4 signaling and improve allogeneic islet survival in vitro and after transplantation. The efficacy of PTD-dnTLR4 in blocking TLR4 signaling was assessed in the Raw264.7 macrophage line, in the islets, and the betaTC3 cell line. In Raw264.7 cells, preculture with the peptide reduced LPS-induced NF kappaB activation and production of proinflammatory cytokines (IL-1beta, TNF alpha, iNOS, and IL-6). In islets and beta cells, preincubation with PTD-dnTLR4 suppressed LPS-induced TNF-alpha expression via inhibition of NF-kappaB activation and protected them from stress-induced cell death. In vivo, preincubation of BALB/c (H-2(d)) islets with PTD-dnTLR4 resulted in significantly longer survival than control islets in a streptozotocin-induced diabetes model (two of seven grafts survived long term >100 days). PTD-dnTLR4-treated grafts exhibited reduced expression of TNF-alpha and iNOS and reduced macrophage infiltration posttransplant. The data indicate that PTD-dnTLR4 blocked TLR4 signaling in both macrophages and beta cells, and prolonged allograft survival at least in part by suppressing inflammation and macrophage infiltration. This strategy for blocking TLR4 activity has potential utilization in the treatment of diseases where excessive TLR4 activation contributes to the pathologic cellular pathways such as islet transplantation. PMID- 26771085 TI - Wnt9a deficiency discloses a repressive role of Tcf7l2 on endocrine differentiation in the embryonic pancreas. AB - Transcriptional and signaling networks establish complex cross-regulatory interactions that drive cellular differentiation during development. Using microarrays we identified the gene encoding the ligand Wnt9a as a candidate target of Neurogenin3, a basic helix-loop-helix transcription factor that functions as a master regulator of pancreatic endocrine differentiation. Here we show that Wnt9a is expressed in the embryonic pancreas and that its deficiency enhances activation of the endocrine transcriptional program and increases the number of endocrine cells at birth. We identify the gene encoding the endocrine transcription factor Nkx2-2 as one of the most upregulated genes in Wnt9a-ablated pancreases and associate its activation to reduced expression of the Wnt effector Tcf7l2. Accordingly, in vitro studies confirm that Tcf7l2 represses activation of Nkx2-2 by Neurogenin3 and inhibits Nkx2-2 expression in differentiated beta cells. Further, we report that Tcf7l2 protein levels decline upon initiation of endocrine differentiation in vivo, disclosing the downregulation of this factor in the developing endocrine compartment. These findings highlight the notion that modulation of signalling cues by lineage-promoting factors is pivotal for controlling differentiation programs. PMID- 26771086 TI - The genetic basis of asymptomatic codon 8 frame-shift (HBB:c25_26delAA) beta(0) thalassaemia homozygotes. AB - Two 21-year old dizygotic twin men of Iraqi descent were homozygous for HBB codon 8, deletion of two nucleotides (-AA) frame-shift beta(0) -thalassaemia mutation (FSC8; HBB:c25_26delAA). Both were clinically well, had splenomegaly, and were never transfused. They had mild microcytic anaemia (Hb 120-130 g/l) and 98% of their haemoglobin was fetal haemoglobin (HbF). Both were carriers of Hph alpha thalassaemia mutation. On the three major HbF quantitative trait loci (QTL), the twins were homozygous for G>A HBG2 Xmn1 site at single nucleotide polymorphism (SNP) rs7482144, homozygous for 3-bp deletion HBS1L-MYB intergenic polymorphism (HMIP) at rs66650371, and heterozygous for the A>C BCL11A intron 2 polymorphism at rs766432. These findings were compared with those found in 22 other FSC8 homozygote patients: four presented with thalassaemia intermedia phenotype, and 18 were transfusion dependent. The inheritance of homozygosity for HMIP 3-bp deletion at rs66650371 and heterozygosity for Hph alpha-thalassaemia mutation was found in the twins and not found in any of the other 22 patients. Further studies are needed to uncover likely additional genetic variants that could contribute to the exceptionally high HbF levels and mild phenotype in these twins. PMID- 26771087 TI - Resilience, emotion processing and emotion expression among youth with type 1 diabetes. AB - : Poor adherence to self-care among youth with type-1 diabetes (YWD) can lead to significant long-term health problems. Negative diabetes-related emotions (NDRE) are common, and are significantly correlated with poor/deteriorating A1c. Resilient youth handle diabetes self-care challenges, such as adjusting for diabetes in public, better. Resiliency skills and perceptions include benefit finding (BF), fitting in with friends (FI), diabetes acceptance (DA), emotion processing (EP) and emotion expression (EE). First study goal: to verify structure of underlying measurement variables: NDRE, EP, EE, BF, DA, FI and comfort in adjusting for diabetes in public (CA) among youth 11-16 yr of age with diabetes. We also hypothesize: (i) YWD who engage in EP and EE will have higher levels of BF, FI, DA, (ii) EP and EE will moderate NDRE impact and (iii) higher levels of EP, EE, BF, FI and DA will be associated with higher CA. SUBJECTS: 243 summer diabetes campers between 11-16 yr of age. METHODS: Pre-camp survey. RESULTS: Measurement variables were verified. EP and EE to friends were positively associated with BF, FI and DA for most YWD. NDRE was negatively associated with FI and DA, and for YWD aged 14-16 yr with CA. FI was positively associated with CA. EE moderated the impact of NDRE on CA among youth 11-13 yr. R2 for CA in youth 14-16 yr was 48.2%, for 11-13 yr was 38.3%. DA was positively associated with CA for youth 14-16 yr. CONCLUSIONS: Resilience factors appear to influence CA either directly or indirectly. PMID- 26771088 TI - TP53 mutation in patients with high-risk acute myeloid leukaemia treated with allogeneic haematopoietic stem cell transplantation. AB - Treatment success in patients with acute myeloid leukaemia (AML) is heterogeneous. Cytogenetic and molecular alterations are strong prognostic factors, which have been used to individualize treatment. Here, we studied the impact of TP53 mutations on the outcome of AML patients with adverse cytogenetic risk treated with allogeneic haematopoietic stem cell transplantation (HSCT). Samples of 97 patients with AML and adverse-risk cytogenetics who had received a HSCT within three randomized trials were analysed. Complete sequencing of the TP53 coding region was performed using next generation sequencing. The median age was 51 years. Overall, TP53 mutations were found in 40 patients (41%). With a median follow up of 67 months, the three-year probabilities of overall survival (OS) and event-free survival for patients with TP53 wild type were 33% [95% confidence interval (CI), 21% to 45%] and 24% (95% CI, 13% to 35%) compared to 10% (95% CI, 0% to 19%) and 8% (95% CI, 0% to 16%) (P = 0.002 and P = 0.007) for those with mutated TP53, respectively. In multivariate analysis, the TP53 mutation status had a negative impact on OS (Hazard Ratio = 1.7; P = 0.066). Mutational analysis of TP53 might be an important additional tool to predict outcome after HSCT in patients with adverse karyotype AML. PMID- 26771089 TI - MapMaker and PathTracer for tracking carbon in genome-scale metabolic models. AB - Constraint-based reconstruction and analysis (COBRA) modeling results can be difficult to interpret given the large numbers of reactions in genome-scale models. While paths in metabolic networks can be found, existing methods are not easily combined with constraint-based approaches. To address this limitation, two tools (MapMaker and PathTracer) were developed to find paths (including cycles) between metabolites, where each step transfers carbon from reactant to product. MapMaker predicts carbon transfer maps (CTMs) between metabolites using only information on molecular formulae and reaction stoichiometry, effectively determining which reactants and products share carbon atoms. MapMaker correctly assigned CTMs for over 97% of the 2,251 reactions in an Escherichia coli metabolic model (iJO1366). Using CTMs as inputs, PathTracer finds paths between two metabolites. PathTracer was applied to iJO1366 to investigate the importance of using CTMs and COBRA constraints when enumerating paths, to find active and high flux paths in flux balance analysis (FBA) solutions, to identify paths for putrescine utilization, and to elucidate a potential CO2 fixation pathway in E. coli. These results illustrate how MapMaker and PathTracer can be used in combination with constraint-based models to identify feasible, active, and high flux paths between metabolites. PMID- 26771090 TI - Response to anti-VEGF-A treatment of endothelial cells in vitro. AB - This study was conducted to compare the effects of two anti-VEGF-A drugs, Ranibizumab and Aflibercept, on the expression and secretion of VEGFs family members, and on their influence in proliferation and migration of endothelial cells (HECV) in vitro. HECV cells were exposed 24 h (T1), 4 days (T2) and 6 days (T3) to Ranibizumab or Aflibercept at pharmacodynamically relevant concentrations (Ranibizumab: 12.5 MUg/ml and 125 MUg/ml; Aflibercept: 50 MUg/ml and 500 MUg/ml). Cell viability and then expression and secretion of VEGF-A, VEGF-B, VEGF-C and PlGF were evaluated respectively by Real Time-PCR and ELISA. Intracellular signaling activated by VEGF-A and VEGF-C was investigated evaluating phosphorylation of VEGFR2. Influence in would healing was evaluated through scratch assay. In general no differences were observed among the tested concentrations of anti-vegf drugs. Ranibizumab and Aflibercept did not affect HECV cell viability in all experimental times. At T1, Ranibizumab decreased mRNA levels of VEGF-A, induced VEGF-C secretion, abrogated phosphorylation of VEGFR2 stimulated by VEGF-A, and impaired ability of HECV cells to repair wound healing. Aflibercept decreased mRNA levels of VEGF-A, -B and PlGF; slightly increased basal level of phVEGFR2, and completely abrogated phosphorylation stimulated by VEGF-A and VEGF-C. No effects on secretion of VEGF-B and on would healing were observed after exposure to Aflibercept. Prolonged exposure to anti-VEGFs decreased expression and secretion of VEGF-A and VEGF-B, up-regulated VEGF-C mRNA levels and its secretion, and increased basal phosphorylation of VEGFR2. Acute treatment with Ranibizumab or Aflibercept evoked different responses on endothelial cells, however these differences were lost after prolonged exposure. Scratch test results suggest that treatment with Ranibizumab may be more effective than Aflibercept in reducing angiogenic potential of endothelial cells in vitro. PMID- 26771091 TI - Women's experiences during myocardial infarction: systematic review and meta ethnography. AB - AIMS AND OBJECTIVES: The aim of this review is to identify, analyse and synthesise existing knowledge concerning female experiences during myocardial infarction. BACKGROUND: There is a lack of knowledge about women's experiences during myocardial infarction, and a meta-synthesis is needed to synthesise existing evidence. DESIGN: A systematic review and meta-ethnography. METHOD: A systematic review was undertaken in September 2013. Four databases were searched. Grey literature and reference lists were screened for relevant studies. Four hundred and eighty-one papers were identified and 14 were included. The method of Noblit and Hare was used in the process of conducting this review and meta ethnography. RESULTS: Three themes were identified. 1. 'Feeling the changes in my body', 2. 'Understanding the changes in my body' and 3. 'Acting on the changes in my body'. The majority of women did not experience their body changes as being severe and threatening. Therefore, the women chose to wait or self-medicate before consulting others. The women who initially experienced the symptoms related to myocardial infarction as being severe and threatening, chose to consult others earlier than the majority of women. CONCLUSION: Women's experiences and interpretation of body symptoms during myocardial infarction vary. Most commonly women do not initially recognise their body symptoms as being severe and life threatening. The theory of Merleau-Ponty's 'current and habituated body' is relevant for explaining women's ways of understanding and acting on their body changes during myocardial infarction. RELEVANCE FOR CLINICAL PRACTICE: This review is relevant in a preventive and rehabilitating perspective for professionals working in health care. It helps professionals to understand women's experiences during myocardial infarction, optimises their ability to suspect myocardial infarction and teach women to react on these body changes. PMID- 26771092 TI - [Various States of Impaired Consciousness Observed from EEG]. PMID- 26771093 TI - [Description of the Microsurgical Anatomy and Intramedullary Tumor Resection in the Anterior Part of the Spinal Cord]. AB - During resection of an intramedullary spinal cord tumor, dissection of the ventro central part of the tumor is most difficult because of the close anatomical relationship between the spinal branches of central vessels to be preserved and the tumor feeding arteries. The central vessels run anteroposteriorly through the anterior median septum(AMS), and a pair comprising a central artery and vein forms a vascular bundle that runs into the spinal cord from the tip of the AMS. These vascular bundles are covered with thin folds of the AMS, named septal sleeves, until they enter the spinal cords. Furthermore, the feeding arteries of the tumor arising from the spinal branches of the central arteries at the tip of the AMS are contained in thick septal sleeves; these thick sleeves indicate the position of the feeding arteries to be excised. To control brisk bleeding from the stump of the feeding artery at the top of the AMS, pinpoint coagulation of the arterial stump under direct vision after debulking the tumor is desirable. When pinpoint hemostasis cannot be achieved, coagulation of the AMS including the bleeding artery to a depth of 1-2 mm is advisable. As central arteries run tortuously in the AMS, the direction of the coagulation should be inclined craniocaudally, although this may increase the risk of damaging the adjacent central vessels. Surgeons should be aware of the anatomical relationship between the AMS, the central vessels, and the tumor feeding arteries to perform safe detachment of the tumors in the ventral region. PMID- 26771094 TI - [Comprehensive Hybrid Strategy for Carotid Artery Stenosis with 8 Rules "Toyama Carotid 8"]. AB - In this paper, the preliminary results of carotid endarterectomy(CEA)and carotid artery stenting(CAS)for patients with carotid artery stenosis based on the 8 Rules "Toyama Carotid 8" are reported. This study included 104 patients who underwent CEA or CAS for carotid artery stenosis between March 2012 and January 2015. Toyama 8 Rules primarily recommend CEA and CAS for symptomatic and asymptomatic lesions, respectively. However, crossover of therapeutic options can be performed in patients at high surgical risk associated with CEA or CAS. Monitoring of platelet function is important prior to CAS. Internal shunting and near infrared spectroscopy monitoring are essential in CEA. Temporary cardiac pacing is essential in CAS. The choice of protection device and stent depends on the results of MR plaque imaging. Cerebral blood flow measurement is mandatory before and after CEA/CAS. Fifty-two CEAs and 52 CASs were performed for 55 symptomatic and 49 asymptomatic lesions. Crossover of therapeutic options was performed in 10(18%)of 55 symptomatic lesions and 7(14%)of 49 asymptomatic lesions. The 30-day morbidity rate was 1.9% in CEA and 1.9% in CAS. Postoperative diffusion-weighted magnetic resonance imaging showed fresh ischemic lesions in 5 patients who underwent CEA(10%)and 9 who underwent CAS(17%). Hyperperfusion syndrome occurred in one patient(1.0%). A management protocol for carotid artery stenosis needs to be established in hospitals to allow sharing of information and improvement in the short-term results of CEA / CAS for carotid artery stenosis. Further studies are warranted to evaluate the long-term outcome. PMID- 26771095 TI - [Efficacy of Stent-Assisted Coil Embolization for a Dissecting Aneurysm of the Cervical Internal Carotid Artery Caused by a Systemic Vascular Disease: A Case Report]. AB - Systemic vascular diseases such as fibromuscular dysplasia, Ehlers-Danlos syndrome, Marfan syndrome, and Behcet's disease are known to cause spontaneous dissecting aneurysms of the cervical internal carotid artery. These diseases are generally associated with vascular fragility; therefore, invasive treatments are avoided in many cases of dissecting aneurysms, and a conservative approach is used for the primary disease. Surgical or intravascular treatment may be chosen when aneurysms are progressive or are associated with a high risk of hemorrhage; however, there is no consensus on which treatment is better. We report a case of a dissecting aneurysm of the cervical internal carotid artery in a patient with suspected Behcet's disease, which was treated using stent-assisted coil embolization. A man in his 40's, with suspected Behcet's disease, presented with an enlarged dissecting aneurysm of the right cervical internal carotid artery. The lesion was present for approximately 10 years. We performed stent-assisted coil embolization for the lesion. Post-surgery, no aneurysms were detected with carotid artery echography. Our case report suggests that stent-assisted coil embolization is a promising treatment for dissecting aneurysms of the cervical internal carotid artery. In addition, the procedure demonstrates the utility of carotid artery echograms for examining recanalization after stent-assisted coil embolization. PMID- 26771096 TI - [Endoscopic Endonasal Transethmoidal Biopsy for IgG4-Related Intraorbital Pseudotumor:A Case Report]. AB - BACKGROUND: We experienced a case of intraorbital pseudotumor associated with IgG4-related disease, for which we successfully performed an endoscopic endonasal transethmoidal biopsy for the intraorbital pseudotumor as well as endoscopic sinus surgery for a refractory pansinusitis at the same time. CASE REPORT: A 59 year-old man was referred to our hospital because of an intraorbital mass lesion. MRI showed 2 mass lesions:a large intraconal lesion encasing the left optic nerve on the orbital apex, and a small extraconal lesion medial to the left medial rectus muscle extending into the anterior ethmoid canal. In addition, CT showed severe pansinusitis. A blood test showed a marked elevation of IgG4. IgG4-related pseudotumor was suspected, but IgG4-related MALT lymphoma was an alternative diagnosis, and a biopsy of the mass lesion was required. We successfully performed both, an endoscopic endonasal transethmoidal biopsy for the mass lesion and endoscopic sinus surgery for the refractory pansinusitis at the same time. The pathological diagnosis was an IgG4-related pseudotumor. CONCLUSION: Endoscopic endonasal transethmoidal biopsy is an effective and minimally invasive method for making a definitive diagnosis of IgG4-related intraorbital pseudotumor. Using this method, refractory pansinusitis frequently associated with this disease can be treated. For successful treatment, interdisciplinary decision making and collaborative team surgery are crucial. PMID- 26771097 TI - [Ruptured Dissecting Distal Superior Cerebellar Artery Aneurysm Successfully Treated with Coil Embolization: A Case Report]. AB - BACKGROUND: Ruptured dissecting superior cerebellar artery aneurysms are rare, and only 12 cases have been reported. We report a case of dissecting aneurysm of the distal superior cerebellar artery presenting with subarachnoid hemorrhage. CASE PRESENTATION: An 80-year-old man presented with a three-day history of headache and diplopia. CT revealed slight subarachnoid hemorrhage and CT angiography demonstrated a dissecting aneurysm located in the distal portion of the left superior cerebellar artery. Initially, we chose conservative therapy. Ten days later, the patient became drowsy. Repeat CT showed that the amount of the subarachnoid hematoma increased and the aneurysm enlarged. Emergent endovascular coil embolization with parent artery occlusion was performed successfully. Postoperative MRI revealed no infarction in the cerebellum or brain stem. Delayed ischemic deficits were not observed after treatment. CONCLUSION: Endovascular parent artery occlusion of the distal superior cerebellar artery is an effective method with low morbidity for treatment of ruptured dissecting distal superior cerebellar artery aneurysms. PMID- 26771098 TI - [Brain Abscess due to Infection with Dematiaceous Fungi Cladophialophora bantiana Associated with Hypogammaglobulinemia Following Gastrectomy: A Case Report]. AB - Dematiaceous fungi have melanin-like pigment in the cell wall and usually cause a variety of dermal infections in humans. Infections of the central nervous system(cerebral phaeohyphomycosis)are rare but serious, since they commonly occur in immunocompromized patients. A 76-year-old man was admitted with mild motor aphasia and underwent total excision of a mass in the left frontal lobe. With the postoperative diagnosis of brain abscess due to infection with dematiaceous fungi (C. bantiana) associated with hypogammaglobulinemia following gastrectomy, intravenous antifungal drugs including amphotericin B and fluconazole were administered. Regrowth of the abscess with intraventricular rupture was noted at about the 88th day after the initial surgery, and the patient underwent neuroendoscopic aspiration of the pus and placement of a ventricular drain. Following intraventricular administration of miconazole through ventricular drainage or an Ommaya reservoir, neuroradiological findings improved, but general and neurological conditions worsened. Further treatment was discontinued and the patient died 9 months after onset. The poor outcome in this patient is attributed to 1)intractability of dematiaceous fungi, 2)development of ventriculitis and the need for intraventricular administration of antifungal drugs, and 3)untreatable hypogammaglobulinemia following gastrectomy. PMID- 26771099 TI - [Update Knowledge for Brain Tumors(3)Astrocytic Tumors]. PMID- 26771100 TI - Economic consequences of workplace injuries in the United States: Findings from the National Longitudinal Survey of Youth (NLSY79). AB - BACKGROUND: This study explored economic consequences of work-related injuries using a longitudinal data source. METHODS: Data were from the National Longitudinal Survey of Youth, 1979 cohort (n = 12,686). Short-term consequences were measured when the injury was reported. "Difference-in-differences" approach was applied to estimate income and wealth disparities between injured and non injured workers before and after injury. Fixed effects models were used to identify variations over time. RESULTS: The annual earnings growth was $3,715 (in 2000 dollars) less for workers with DAFW injury and $1,152 less for workers with NDAFW injury compared to non-injured workers during a 10-year follow-up. Lost wages and disability following injury contributed to income loss for injured workers, but the loss was moderated by union membership. After controlling for confounders, income disparities persisted, but family wealth differences did not. CONCLUSIONS: Occupational injuries exacerbate income inequality. Efforts to reduce such disparities should include workplace safety and health enforcement. PMID- 26771102 TI - Engineering Hydrogen-Bonded Hexagonal Networks Built from Flexible 1,3,5 Trisubstituted Derivatives of Benzene. AB - 2,4-Diamino-1,3,5-triazinyl (DAT) groups are known to form N-H...N hydrogen bonds according to reliable patterns of self-association. In compounds 3a-c, three DAT groups are attached to trigonally substituted phenyl cores via identical flexible arms. Crystallization of compounds 3a-c produces robust networks in which each molecule is linked to its immediate neighbors by a total of 10-12 hydrogen bonds. In compound 3a, the DAT groups are designed to lie close to the plane of the phenyl core, thereby giving hydrogen-bonded sheets built from hexameric rosettes. In contrast, the more highly substituted phenyl cores of analogues 3b and 3c favor conformations in which the DAT groups are no longer coplanar, leading predictably to the formation of three-dimensional networks. In general, the nominally trigonal topologies of compounds 3a-c favor structures in which hexagonal networks are prominent, so they behave like trimesic acid despite their greater complexity and flexibility. The structures of all crystals incorporate open networks with significant fractions of volume accessible to guests (32-60%). Despite their flexibility, compounds 3a-c appear to be unable to assume conformations that pack efficiently and simultaneously allow the DAT groups to engage in normal hydrogen bonding. PMID- 26771101 TI - Individual, occupational, and workplace correlates of occupational health and safety vulnerability in a sample of Canadian workers. AB - OBJECTIVE: To describe OH&S vulnerability across a diverse sample of Canadian workers. METHODS: A survey was administered to 1,835 workers employed more than 15 hrs/week in workplaces with at least five employees. Adjusted logistic models were fitted for three specific and one overall measure of workplace vulnerability developed based on hazard exposure and access to protective OH&S policies and procedures, awareness of employment rights and responsibilities, and workplace empowerment. RESULTS: More than one third of the sample experienced some OH&S vulnerability. The type and magnitude of vulnerability varied by labor market sub group. Younger workers and those in smaller workplaces experienced significantly higher odds of multiple types of vulnerability. Temporary workers reported elevated odds of overall, awareness- and empowerment-related vulnerability, while respondents born outside of Canada had significantly higher odds of awareness vulnerability. CONCLUSION: Knowing how labor market sub-groups experience different types of vulnerability can inform better-tailored primary prevention interventions. PMID- 26771103 TI - A Bifunctional Thioether Linked Coumarin Appended Calix[4]arene Acquires Selectivity Toward Cu(2+) Sensing on Going from Solution to SAM on Gold. AB - A bifunctional calix[4]arene molecule bearing coumarin moiety on the lower rim and thioether moiety on the upper rim (L1), has been synthesized and well characterized by (1)H, (13)C NMR and mass spectrometry. Suitably functionalized coumarin moieties are well suited for selective recognition of various cations and anions. Among the 10 different metal ions studied, only Cu(2+) and Fe(3+) exhibit appreciable changes in the absorption spectra owing to the availability of functional moieties present at both the lower as well as the upper rim of free L1 in acetonitrile solution. To bring better selectivity, we blocked one of these functional moieties by coating on to a surface so that only the other one is exposed to the environment for sensing. Such a study carried out in the present case using the self-assembled monolayer (SAM) of L1 on Au(111) resulted in selective sensing of Cu(2+) over several other metal ions as studied by surface plasmon resonance (SPR). The SAM of L1 on Au(111) was confirmed by different techniques, such as grazing incidence FT-IR, contact angle measurement, cyclic voltammetry and scanning tunneling microscopy. Thus, L1 is proven to be a suitable sensor for Cu(2+) when attached to gold surface. PMID- 26771104 TI - alpha-Amino Aldehydes as Readily Available Chiral Aldehydes for Rh-Catalyzed Alkyne Hydroacylation. AB - Readily available alpha-amino aldehydes, incorporating a methylthiomethyl (MTM) protecting group on nitrogen, are shown to be efficient substrates in Rh catalyzed alkyne hydroacylation reactions. The reactions are performed under mild conditions, employing a small-bite-angle bis-phosphine ligand, allowing for good functional group tolerance with high stereospecificity. Amino aldehydes derived from glycine, alanine, valine, leucine, phenylalanine, isoleucine, serine, tryptophan, methionine, and cysteine were successfully employed, as was an enantiomerically enriched alpha-OMTM-aldehyde derived from phenyllactic acid. The synthetic utility of the alpha-amino enone products is demonstrated in a short enantioselective synthesis of the natural product sphingosine. PMID- 26771105 TI - Multigrid-Based Methodology for Implicit Solvation Models in Periodic DFT. AB - Continuum solvation models have become a widespread approach for the study of environmental effects in Density Functional Theory (DFT) methods. Adding solvation contributions mainly relies on the solution of the Generalized Poisson Equation (GPE) governing the behavior of the electrostatic potential of a system. Although multigrid methods are especially appropriate for the solution of partial differential equations, up to now, their use is not much extended in DFT-based codes because of their high memory requirements. In this Article, we report the implementation of an accelerated multigrid solver-based approach for the treatment of solvation effects in the Vienna ab initio Simulation Package (VASP). The stated implicit solvation model, named VASP-MGCM (VASP-Multigrid Continuum Model), uses an efficient and transferable algorithm for the product of sparse matrices that highly outperforms serial multigrid solvers. The calculated solvation free energies for a set of molecules, including neutral and ionic species, as well as adsorbed molecules on metallic surfaces, agree with experimental data and with simulation results obtained with other continuum models. PMID- 26771106 TI - Ultrafast Mid-Infrared Nanoscopy of Strained Vanadium Dioxide Nanobeams. AB - Long regarded as a model system for studying insulator-to-metal phase transitions, the correlated electron material vanadium dioxide (VO2) is now finding novel uses in device applications. Two of its most appealing aspects are its accessible transition temperature (~341 K) and its rich phase diagram. Strain can be used to selectively stabilize different VO2 insulating phases by tuning the competition between electron and lattice degrees of freedom. It can even break the mesoscopic spatial symmetry of the transition, leading to a quasiperiodic ordering of insulating and metallic nanodomains. Nanostructuring of strained VO2 could potentially yield unique components for future devices. However, the most spectacular property of VO2--its ultrafast transition--has not yet been studied on the length scale of its phase heterogeneity. Here, we use ultrafast near-field microscopy in the mid-infrared to study individual, strained VO2 nanobeams on the 10 nm scale. We reveal a previously unseen correlation between the local steady-state switching susceptibility and the local ultrafast response to below-threshold photoexcitation. These results suggest that it may be possible to tailor the local photoresponse of VO2 using strain and thereby realize new types of ultrafast nano-optical devices. PMID- 26771107 TI - Cell Penetrant Inhibitors of the KDM4 and KDM5 Families of Histone Lysine Demethylases. 1. 3-Amino-4-pyridine Carboxylate Derivatives. AB - Optimization of KDM6B (JMJD3) HTS hit 12 led to the identification of 3-((furan-2 ylmethyl)amino)pyridine-4-carboxylic acid 34 and 3-(((3-methylthiophen-2 yl)methyl)amino)pyridine-4-carboxylic acid 39 that are inhibitors of the KDM4 (JMJD2) family of histone lysine demethylases. Compounds 34 and 39 possess activity, IC50 <= 100 nM, in KDM4 family biochemical (RFMS) assays with >= 50 fold selectivity against KDM6B and activity in a mechanistic KDM4C cell imaging assay (IC50 = 6-8 MUM). Compounds 34 and 39 are also potent inhibitors of KDM5C (JARID1C) (RFMS IC50 = 100-125 nM). PMID- 26771108 TI - Synthesis and Pharmacology of Mono-, Di-, and Trialkyl-Substituted 7-Chloro-3,4 dihydro-2H-1,2,4-benzothiadiazine 1,1-Dioxides Combined with X-ray Structure Analysis to Understand the Unexpected Structure-Activity Relationship at AMPA Receptors. AB - Positive allosteric modulators of 2-amino-3-(3-hydroxy-5-methylisoxazol-4 yl)propionic acid (AMPA)-type ionotropic glutamate receptors are promising compounds for treatment of neurological disorders, for example, Alzheimer's disease. Here, we report synthesis and pharmacological evaluation of a series of mono-, di-, or trialkyl-substituted 7-chloro-3,4-dihydro-2H-1,2,4 benzothiadiazine 1,1-dioxides, comprising in total 16 new modulators. The trisubstituted compounds 7b, 7d, and 7e revealed potent activity (EC2* = 2.7-4.3 MUM; concentration of compound responsible for a 2-fold increase of the AMPA mediated response) as AMPA receptor potentiators in an in vitro cellular fluorescence assay (FLIPR). The 4-cyclopropyl compound 7f was found to be considerably less potent (EC2* = 60 MUM), in contrast to previously described 4 monoalkyl-substituted benzothiadiazine dioxides for which the cyclopropyl group constitutes the best choice of substituent. 7b was subjected to X-ray structural analysis in complex with the GluA2 ligand-binding domain. We propose an explanation of the unexpected structure-activity relationship of this new series of mono-, di-, and trialkyl-substituted 1,2,4-benzothiadiazine 1,1-dioxide compounds. The methyl substituent in the 3-position directs the binding mode of the 1,2,4-benzothiadiazine 1,1-dioxide (BTD) scaffold. When a methyl substituent is present in the 3-position of the BTD, additional methyl substituents in both the 2- and 4-positions increase potency, whereas introduction of a 4-cyclopropyl group does not enhance potency of 2,3,4-alkyl-substituted BTDs. A hydrogen bond donor in the 2-position of the BTD is not necessary for modulator potency. PMID- 26771109 TI - Binding of Divalent Cations to Polygalacturonate: A Mechanism Driven by the Hydration Water. AB - We have investigated the interactions between polygalacturonate (polyGal) and four divalent cations (M(2+) = Ba(2+), Ca(2+), Mg(2+), Zn(2+)) that differ in size and affinity for water. Our results evidence that M(2+)-polyGal interactions are intimately linked to the affinity of M(2+) for water. Mg(2+) interacts so strongly with water that it remains weakly bound to polyGal (polycondensation) by sharing water molecules from its first coordination shell with the carboxylate groups of polyGal. In contrast, the other cations form transient ionic pairs with polyGal by releasing preferentially one water molecule (for Zn(2+)) or two (for Ca(2+) and Ba(2+)), which corresponds to monodentate and bidentate binding modes with carboxylates, respectively. The mechanism for the binding of these three divalent cations to polyGal can be described by two steps: (i) monocomplexation and formation of point-like cross-links between polyGal chains (at low M(2+)/Gal molar ratios, R) and (ii) dimerization (at higher R). The threshold molar ratio, R*, between these two steps depends on the nature of divalent cations and is lower for calcium ions (R* < 0.1) than for zinc and barium ions (R* > 0.3). This difference may be explained by the intermediate affinity of Ca(2+) for water with respect to those of Zn(2+) and Ba(2+), which may induce the formation of cross links of intermediate flexibility. By comparison, the lower and higher flexibilities of the cross-links formed by Zn(2+) and Ba(2+), respectively, may shift the formation of dimers to higher molar ratios (R*). PMID- 26771110 TI - Bypassing Intestinal Sugar Enhancement of Sweet Appetite. AB - Intestinal sugar sensing has an appetite-stimulating action that enhances preferences for sweets. Han et al. (2016) report that duodenal-jejunal bypass surgery reduces sweet appetite by reducing sugar-induced dopamine release in the dorsal striatum. PMID- 26771111 TI - Can Insulin Production Suppress beta Cell Growth? AB - While insulin has mitogenic effects in many cell types, its effects on beta cells remain elusive. In this issue of Cell Metabolism, Szabat et al. (2015) genetically block insulin production in adult beta cells and show that this leads to a relief of ER stress, AKT activation, and increased beta cell proliferation. PMID- 26771112 TI - The NLRP1-IL18 Connection: A Stab in the Back of Obesity-Induced Inflammation. AB - IL-18 has been reported to counteract obesity and metabolic syndrome, though the underlying mechanisms remain unclear. In this issue, Masters and colleagues describe how NLRP1 inflammasome induces IL-18 production in fat, solving not only an important biological mechanism, but also opening the door for therapeutic approaches (Murphy et al., 2016). PMID- 26771113 TI - Dramatis Personae in beta-Cell Mass Regulation: Enter SerpinB1. AB - How is beta-cell mass adjusted to changes in the functional insulin requirements? The answer to this question is central to the understanding of the causes and (potentially) the therapy of type 2 diabetes. In this issue of Cell Metabolism, El Ouaamari et al. (2016) report that increased production of the protease inhibitor SerpinB1 in the liver links insulin resistance to stimulation of beta cell proliferation. PMID- 26771114 TI - Confounding Effects of Metformin on the Human Gut Microbiome in Type 2 Diabetes. AB - Type 2 diabetes (T2D) is associated with dysbiosis of the gut microbiota, though diabetes treatment regimens, including metformin, may confound the results. Forslund et al. (2015) identify distinct disease and drug signatures and highlight the importance of adjusting for treatment when investigating how T2D influences the human gut microbiome. PMID- 26771116 TI - Obesity and Cancer: The Oil that Feeds the Flame. AB - Although discussion of the obesity epidemic had become a cocktail party cliche, its impact on public health cannot be dismissed. In the past decade, cancer had joined the list of chronic debilitating diseases whose risk is substantially increased by hypernutrition. Here we discuss recent advances in understanding how obesity increases cancer risk and propose a unifying hypothesis according to which the major tumor-promoting mechanism triggered by hypernutrition is the indolent inflammation that takes place at particular organ sites, including liver, pancreas, and gastrointestinal tract. The mechanisms by which excessive fat deposition feeds this tumor-promoting inflammatory flame are diverse and tissue specific. PMID- 26771117 TI - Galectin-3 Is Associated with Restrictive Lung Disease and Interstitial Lung Abnormalities. AB - RATIONALE: Galectin-3 (Gal-3) has been implicated in the development of pulmonary fibrosis in experimental studies, and Gal-3 levels have been found to be elevated in small studies of human pulmonary fibrosis. OBJECTIVES: We sought to study whether circulating Gal-3 concentrations are elevated early in the course of pulmonary fibrosis. METHODS: We examined 2,596 Framingham Heart Study participants (mean age, 57 yr; 54% women; 14% current smokers) who underwent Gal 3 assessment using plasma samples and pulmonary function testing between 1995 and 1998. Of this sample, 1,148 underwent subsequent volumetric chest computed tomography. MEASUREMENTS AND MAIN RESULTS: Higher Gal-3 concentrations were associated with lower lung volumes (1.4% decrease in percentage of predicted FEV1 per 1 SD increase in log Gal-3; 95% confidence interval [CI], 0.8-2.0%; P < 0.001; 1.2% decrease in percentage of predicted FVC; 95% CI, 0.6-1.8%; P < 0.001) and decreased diffusing capacity of the lung for carbon monoxide (2.1% decrease; 95% CI, 1.3-2.9%; P < 0.001). These associations remained significant after multivariable adjustment (P <= 0.008 for all). Compared with the lowest quartile, participants in the highest Gal-3 quartile were more than twice as likely to have interstitial lung abnormalities visualized by computed tomography (multivariable adjusted odds ratio, 2.67; 95% CI, 1.49-4.76; P < 0.001). CONCLUSIONS: Elevated Gal-3 concentrations are associated with interstitial lung abnormalities coupled with a restrictive pattern, including decreased lung volumes and altered gas exchange. These findings suggest a potential role for Gal-3 in early stages of pulmonary fibrosis. PMID- 26771119 TI - Head Start Wellness Policy Intervention in Hawaii: A Project of the Children's Healthy Living Program. AB - BACKGROUND: The increased prevalence of childhood overweight and obesity across the United States and the Pacific has become a serious public health concern, with especially high prevalence among Native Hawaiian and Pacific Islander (NHPI) children. This study aimed to measure the effect of a Head Start (HS) policy intervention for childhood obesity prevention. METHODS: Twenty-three HS classrooms located in Hawaii participated in the trial of a 7-month policy intervention with HS teachers. Classroom- and child-level outcome assessments were conducted, including: the Environment and Policy Assessment and Observations (EPAO) of the classroom environment; plate waste observations to assess child intake of fruit and vegetables; and child growth. RESULTS: The intervention showed a positive and significant effect on classroom EPAO physical activity (PA) and EPAO total scores. Although mean BMI z-score (zBMI) increased at postintervention for both intervention (mean = 0.60; standard deviation [SD], 1.16; n = 114) and delayed-intervention groups (mean = 0.35; SD, 1.17; n = 132), change in zBMI was not significantly different between the groups (p = 0.50; p = 0.48). CONCLUSIONS: These findings contribute evidence on the potential for HS wellness policy to improve the PA environment of HS classrooms. More research is needed to link these policy changes to other child outcomes. PMID- 26771115 TI - The Emerging Hallmarks of Cancer Metabolism. AB - Tumorigenesis is dependent on the reprogramming of cellular metabolism as both direct and indirect consequence of oncogenic mutations. A common feature of cancer cell metabolism is the ability to acquire necessary nutrients from a frequently nutrient-poor environment and utilize these nutrients to both maintain viability and build new biomass. The alterations in intracellular and extracellular metabolites that can accompany cancer-associated metabolic reprogramming have profound effects on gene expression, cellular differentiation, and the tumor microenvironment. In this Perspective, we have organized known cancer-associated metabolic changes into six hallmarks: (1) deregulated uptake of glucose and amino acids, (2) use of opportunistic modes of nutrient acquisition, (3) use of glycolysis/TCA cycle intermediates for biosynthesis and NADPH production, (4) increased demand for nitrogen, (5) alterations in metabolite driven gene regulation, and (6) metabolic interactions with the microenvironment. While few tumors display all six hallmarks, most display several. The specific hallmarks exhibited by an individual tumor may ultimately contribute to better tumor classification and aid in directing treatment. PMID- 26771118 TI - Simultaneous conduction mapping and intracellular membrane potential recording in isolated atria. AB - We describe a novel approach for simultaneously determining regional differences in action potential (AP) morphology and tissue electrophysiological properties in isolated atria. The epicardial surface of rat atrial preparations was placed in contact with a multi-electrode array (9 * 10 silver chloride electrodes, 0.1 mm diameter and 0.1 mm pitch). A glass microelectrode (100 MOmega) was simultaneously inserted into the endocardial surface to record intracellular AP from either of 2 regions (A, B) during pacing from 2 opposite corners of the tissue. AP duration at 80% of repolarisation and its restitution curve was significantly different only in region A (p < 0.01) when AP was initiated at different stimulation sites. Alternans in AP duration and AP amplitude, and in conduction velocity were observed during 2 separate arrhythmic episodes. This approach of combining microelectrode array and intracellular membrane potential recording may provide new insights into arrhythmogenic mechanisms in animal models of cardiovascular disease. PMID- 26771120 TI - Myiasis in Dogs in the Greater Accra Region of Ghana. AB - Myiasis is the infestation of tissues of live vertebrate animals and humans with dipterous larvae. In sub-Saharan Africa, Cordylobia anthropohaga and Cordylobia rodhaini are known to be responsible for cutaneous myiasis in animals and humans. Human cases of myiasis, purportedly acquired in Ghana but diagnosed in other countries, have been reported; however, published data on its occurrence in animals in Ghana is unavailable. This study assessed the prevalence of canine myiasis among owned dogs in the Greater Accra region (GAR) of Ghana. A cross sectional study was conducted in the Greater Accra region of Ghana, selected for being the region with the highest estimated population density of owned dogs. Physical examination and demographic characteristics of the study dogs were assessed. Management of the dogs was assessed through a questionnaire administered to the dog owners. A total of 392 owned dogs were sampled. Twenty nine (7.4%) had cutaneous myiasis caused by C. rodhaini. In addition, one (0.2%) of the dogs had intestinal myiasis, with Dermatobia hominis as the offending larvae. Among the breeds of dogs with myiasis, the mongrel was most affected, with 24 (82.8%) out of the 29 cases. The mongrels, majority of which (24; 82.8%) were males, were left to roam freely in the community. Results from this study demonstrate that C. rodhaini and D. hominis are important causes of myiasis in owned dogs in the GAR of Ghana. Dogs could play a role in the spread of myiasis to humans, with its attendant public health implications. PMID- 26771121 TI - Coupled Cluster Evaluation of the Stability of Atmospheric Acid-Base Clusters with up to 10 Molecules. AB - We investigate the utilization of the domain local pair natural orbital coupled cluster (DLPNO-CCSD(T)) method for calculating binding energies of atmospherical molecular clusters. Applied to small complexes of atmospherical relevance we find that the DLPNO method significantly reduces the scatter in the binding energy, which is commonly present in DFT calculations. For medium sized clusters consisting of sulfuric acid and bases the DLPNO method yields a systematic underestimation of the binding energy compared to canonical coupled cluster results. The errors in the DFT binding energies appear to be more random, while the systematic nature of the DLPNO results allows the establishment of a scaling factor, to better mimic the canonical coupled cluster calculations. Based on the trends identified for the small and medium sized systems, we further extend the application of the DLPNO method to large acid - base clusters consisting of up to 10 molecules, which have previously been out of reach with accurate coupled cluster methods. Using the Atmospheric Cluster Dynamics Code (ACDC) we compare the sulfuric acid dimer formation based on the new DLPNO binding energies with previously published RI-CC2/aug-cc-pV(T+d)Z results. We also compare the simulated sulfuric acid dimer concentration as a function of the base concentration with measurement data from the CLOUD chamber and flow tube experiments. The DLPNO method, even after scaling, underpredicts the dimer concentration significantly. Reasons for this are discussed. PMID- 26771122 TI - Validation of Cognitive Structures: A Structural Equation Modeling Approach. AB - Determining sources of item difficulty and using them for selection or development of test items is a bridging task of psychometrics and cognitive psychology. A key problem in this task is the validation of hypothesized cognitive operations required for correct solution of test items. In previous research, the problem has been addressed frequently via use of the linear logistic test model for prediction of item difficulties. The validation procedure discussed in this article is alternatively based on structural equation modeling of cognitive subordination relationships between test items. The method is illustrated using scores of ninth graders on an algebra test where the structural equation model fit supports the cognitive model. Results obtained with the linear logistic test model for the algebra test are also used for comparative purposes. PMID- 26771123 TI - Recovery of Weak Common Factors by Maximum Likelihood and Ordinary Least Squares Estimation. AB - This article examines the relative performance of two commonly used methods of parameter estimation in factor analysis, maximum likelihood (ML) and ordinary least squares (OLS). It is shown that ML will sometimes fail to recover a known population factor structure when OLS succeeds. A simulation study was conducted in which two types of error (model and sampling error) were introduced separately and in combination into correlation matrices generated from known population structures with at least one relatively weak major domain factor. Simulated correlation matrices were factor analyzed using both ML and OLS, and recovery of the relatively weak factor(s) was assessed. In situations with a moderate amount of error, ML often failed to recover the weak factor while OLS succeeded. It is suggested that the correspondence between the assumptions inherent in each method regarding error and the actual nature of error in the data may affect the success of recovery of weak common factors. An example using empirical data is also presented. PMID- 26771124 TI - Full Maximum Likelihood Estimation of Polychoric and Polyserial Correlations With Missing Data. AB - This article develops a full maximum likelihood method for obtaining joint estimates of variances and correlations among continuous and polytomous variables with incomplete data which are missing at random with an ignorable missing mechanism. The approach for obtaining the maximum likelihood estimate of the covariance matrix is via a simple confirmatory analysis model with a fixed identity loading matrix and a fixed diagonal matrix with small of unique variances. A Monte Carlo Expectation-Maximization (MCEM) algorithm is constructed to obtain the solution, in which the E-step is approximated by observations simulated by the Gibbs sampler. Results from a simulation study and a real example are provided to illustrate the methodology. PMID- 26771125 TI - An Analysis of Meehl's MAXCOV-HITMAX Procedure for the Case of Dichotomous Indicators. AB - MAXCOV-HITMAX was invented by Paul Meehl for the detection of latent taxonic structures (i.e., structures in which the latent variable, _, is not continuously, but rather Bernoulli, distributed). It involves the examination of the shape of a certain conditional covariance function, and is based on Meehl's claims that: (R1) Given a latent taxonic structure, this conditional covariance function is single peaked; and that (R2), continuous latent structures produce a flat, rather than single-peaked, curve. While Meehl has recommended that continuous indicators be used as input into MAXCOV-HITMAX, the use of dichotomous indicators has become popular. The current work investigates whether (R1) and (R2) are true for the case of dichotomous indicators. The conclusions will be that, for dichotomous indicators: (a) (R1) is not true; (b) (R1) is made true given that there are a large number of indicators; and (c) (R2) is not true, certain unexceptional Rasch structures, for example, producing single-peaked curves. Implications are briefly discussed of these results for the case of MAXCOV-HITMAX with continuous indicators. PMID- 26771127 TI - Recognition of MBR Reviewers. PMID- 26771126 TI - 2001 Presidential Address: Working with Imperfect Models. AB - Since the early years of psychological research, investigators in psychology have made use of mathematical models of psychological phenomena. Models are now routinely used to represent and study cognitive processes, the structure of psychological measurements, the structure of correlational relationships among variables, the nature of change over time, and many other topics and phenomena of interest. All of these models, in their attempt to provide a parsimonious representation of psychological phenomena, are wrong to some degree and are thus implausible if taken literally. Such models simply cannot fully represent the complexities of the phenomena of interest and at best provide an approximation of the real world. This imperfection has implications for how we specify, estimate, and evaluate models, and how we interpret results of fitting models to data. Using factor analysis and structural equation models as a context, I examine some implications of model imperfection for our use of models, focusing on formal specification of models; the nature of parameters and parameter estimates; the relevance of discrepancy functions; the issue of sample size; the evaluation, development, and selection of models; and the conduct of simulation studies. The overall perspective is that our use and study of models should be guided by an understanding that our models are imperfect and cannot be made to be exactly correct. PMID- 26771128 TI - In Memoriam: UNMC Cancer Researcher, Dr. Sidney Mirvish, 1929-2015. PMID- 26771129 TI - Dihydropyrimidine based hydrazine dihydrochloride derivatives as potent urease inhibitors. AB - Four series of heterocyclic compounds 4-dihydropyrimidine-2-thiones 7-12 (series A), N,S-dimethyl-dihydropyrimidines 13-18 (series B), hydrazine derivatives of dihydropyrimidine 19-24 (series C), and tetrazolo dihydropyrimidine derivatives 25-30 (series D), were synthesized and evaluated for in vitro urease inhibitory activity. The series B-D were first time examined for urease inhibition. Series A and C were found to be significantly active with IC50 values between 34.7-42.9 and 15.0-26.0 MUM, respectively. The structure-activity relationship showed that the free S atom and hydrazine moiety are the key pharmacophores against urease enzyme. The kinetic studies of the active series A (7-12) and C (19-24) were carried out to determine their modes of inhibition and dissociation constants Ki. Compounds of series A (7-12) and series C (19-24) showed a mixed-type of inhibition with Ki values ranging between 15.76-25.66 and 14.63-29.42 MUM, respectively. The molecular docking results showed that all the active compounds of both series have significant binding interactions with the active sites specially Ni-ion of the urease enzyme. Cytotoxicity of all series A-D was also evaluated against mammalian mouse fibroblast 3T3 cell lines, and no toxicity was observed in cellular model. PMID- 26771130 TI - Determination of pinostilbene in rat plasma by LC-MS/MS: Application to a pharmacokinetic study. AB - Pinostilbene (3-methoxyresveratrol or trans-3,4'-dihydroxy-5-methoxystilbene) is a naturally occurring monomethylether analogue of resveratrol (trans-3,5,4' trihydroxystilbene) that exhibits various pharmacological activities. To further examine its medicinal potential, a sensitive LC-MS/MS method was developed and validated for the determination of pinostilbene in rat plasma. Heavy Isotope labelled resveratrol was used as an internal standard. The ESI was operated in its negative ion mode while pinostilbene and resveratrol were measured by multiple reaction monitoring (MRM) using precursor-to-product ion transitions of m/z 241->181 and m/z 233->191, respectively. This LC-MS/MS method had excellent selectivity, sensitivity (LLOQ=1ng/ml), accuracy (both intra- and interday analytical recovery within 100+/-15%) and precision (both intra- and interday RSD < 15%). The matrix effect was insignificant. The pharmacokinetics of pinostilbene was subsequently profiled in Sprague-Dawley rats. Upon intravenous administration (5 or 10mg/kg), pinostilbene displayed rapid clearance (Cl=129+/-42 or 107+/ 31ml/min/kg) and extremely short mean transit time (MTT=6.24+/-0.41 or 8.52+/ 1.38min). After oral dosing (50mg/kg), the bioavailability of pinostilbene was limited but highly erratic (F=1.87+/-2.67%). Pharmacokinetic comparison among pinostilbene, resveratrol and some resveratrol analogues suggested that stilbenes with meta-hydroxyl group(s) may be associated with metabolic instability and subsequently suffer from rapid clearance and low oral bioavailability. The information obtained from this study will facilitate further exploration on pinostilbene as well as other resveratrol analogues. PMID- 26771131 TI - Quantitative analysis of maytansinoid (DM1) in human serum by on-line solid phase extraction coupled with liquid chromatography tandem mass spectrometry - Method validation and its application to clinical samples. AB - A sensitive and specific method was developed and validated for the quantitation of maytansinoid (DM1) in human serum using on-line solid phase extraction (SPE) liquid chromatography-tandem mass spectrometry (LC-MS/MS). Because DM1 contains a free thiol moiety, likely to readily dimerize or react with other thiol containing molecules in serum, samples were pre-treated with a reducing agent [tris (2-carboxyethyl) phosphine] (TCEP) and further blocked with N ethylmaleimide (NEM). The resulting samples were diluted with acetonitrile prior to the on-line solid phase extraction (SPE) on a C18 cartridge. A C18 (150*4.6mm ID 3MUm particle size) column was used for chromatographic separation with a 10.0min HPLC gradient and DM1-NEM was detected in the selected reaction monitoring mode of a triple quadrupole mass spectrometer. DM1 concentrations were back-calculated from DM1-NEM amount found in the human serum samples. The quantitation range of the method was 0.200-200ng/mL when using 0.25mL serum. Within-run day precisions (n=6) were 0.9-4.4% and between-run day (3 days runs; n=18) precisions 2.5-5.6%. Method biases were between 3.5-14.5% across the whole calibration range. DM1-NEM exhibited sufficiently stability under all relevant analytical conditions and no DM1 losses from the ADC were observed. Finally, the assay was used for DM1 determination in human serum concentration after the intravenous administration of an investigational antibody drug conjugate (ADC) containing DM1 as payload. PMID- 26771132 TI - Discriminating nicotine and non-nicotine containing e-liquids using infrared spectroscopy. AB - In a few countries, including Belgium, nicotine-containing e-cigarettes and e liquids are considered medicines, and therefore cannot freely be sold, but should be distributed in a pharmacy. The fact that in the neighbouring countries these products are freely available, poses a problem for custom personnel, the more the nicotine content of the products is not always labelled, especially when they are bought through internet. Therefore there is a need for easy-to-use equipment and methods to perform a first on site screening of intercepted samples, both for border control as to check label compliance of the sample. The use of attenuated total reflectance-infrared spectroscopy (ATR-IR) and near infrared spectroscopy (NIR), combined with chemometrics was evaluated for the discrimination between nicotine containing and non-nicotine containing samples. It could be concluded that both ATR-IR and NIR could be used for the discrimination when combined with the appropriate chemometric techniques. The presented techniques do not need sample preparation and result in models with a minimum of false negative samples. If a large enough training set can be established the interpretation can be fully automated, making the presented approach suitable for on-site screening of e liquid samples. PMID- 26771133 TI - Characterization of forced degradation products and in silico toxicity prediction of Sofosbuvir: A novel HCV NS5B polymerase inhibitor. AB - Sofosbuvir is a direct acting antiviral medication used to treat Hepatitis C viral infection. The present study focuses on the degradation behavior of the drug under various stress conditions (hydrolysis, oxidative, thermal and photolytic) as per International Conference on Harmonization (ICH Q1A (R2)) guidelines. A high performance liquid chromatographic system (HPLC) was used to develop a selective, precise and accurate method for separating all the degradation products. The separation was achieved on a SunfireTM C18 (150mm*4.6mm*5MUm) stationary phase with a mobile phase of 10mM ammonium acetate (pH 5.0) buffer and acetonitrile in gradient elution mode. A quadrupole-time of flight mass analyzer equipped with an electrospray ionization technique was used to propose the structural information based on the MS/MS and accurate mass measurements. Seven degradation products were identified and characterised by LC ESI-QTOF-MS/MS. In silico toxicity of the drug and its degradation products was determined using TOPKAT and DEREK toxicity prediction softwares. The proposed method was validated as per the ICH Q2 guidelines. PMID- 26771134 TI - Analysis of bioactive components and pharmacokinetic study of herb-herb interactions in the traditional Chinese patent medicine Tongmai Yangxin Pill. AB - Tongmai Yangxin (TMYX) Pill is a traditional Chinese patent medicine, composed of eleven Chinese medicinal herbs. It has been used to treat coronary heart disease for several decades. In this study, six male Sprague-Dawley rats were dosed orally with TMYX methanol extract, and a serum pharmacochemistry technique was used to screen absorbed bioactive compounds by UPLC/Q-TOF-MS. By comparing MS spectra to the published literature data, 40 bioactive components were identified. The results indicated that almost 45% of the absorbed compounds were from Radix Glycyrrhizae (GC). Subsequently, a reliable HPLC method was used to determine the concentrations of liquiritin, liquiritigenin, isoliquiritigenin, glycyrrhizic acid, and glycyrrhetinic acid in rat plasma following oral administration of GC or the combination of GC and Ramulus Cinnamomi (GZ). The results showed that GZ enhanced the absorption of four bioactive components: liquiritigenin, isoliquiritigenin, glycyrrhizic acid, and glycyrrhetinic acid. The data demonstrate that herb combination in TMYX Pill exhibit a synergistic action. PMID- 26771135 TI - The Relationship Between Plasma Cytokine Levels and Response to Selective Serotonin Reuptake Inhibitor Treatment in Children and Adolescents with Depression and/or Anxiety Disorders. AB - OBJECTIVE: In adults there is growing evidence that antidepressant (AD) treatment results in a decline in inflammatory cytokines. This is the first report, to our knowledge, of the relationship between response to selective serotonin reuptake inhibitor (SSRI) treatment for anxiety and/or depression and cytokine levels in children and adolescents. METHODS: Forty-one patients who met Diagnostic and Statistical Manual for Mental Disorders, 4th ed. (DSM-IV) criteria for major depressive disorder (MDD) or anxiety disorders participated in study. Their ages ranged from 9 to 18 (14.12 +/- 2.30) years. The patients were treated with fluoxetine for 8 weeks. Plasma concentrations of tumor necrosis factor (TNF) alpha, interleukin (IL)-6, and IL-1beta were measured by enzyme linked immunosorbent assays (ELISA) before and after fluoxetine treatment. Clinical response was measured with several scales, including the Children's Depression Rating Scale-Revised (CDRS-R), the Beck Depression Inventory (BDI), and the Screen for Child Anxiety Related Emotional Disorders (SCARED) Results: The overall response rate was 56%. Antidepressant treatment significantly reduced TNF alpha levels (p = 0.037), with no significant changes in the levels of IL-6 and IL-1beta. All three proinflammatory cytokines were significantly (p < 0.05) higher in SSRI-refractory than in SSRI-responsive patients. CONCLUSIONS: Higher levels of TNF-alpha, IL-6, and IL-1beta might predict nonresponse to fluoxetine treatment in children. PMID- 26771136 TI - Hierarchical regulation of the genome: global changes in nucleosome organization potentiate genome response. AB - Nucleosome occupancy is critically important in regulating access to the eukaryotic genome. Few studies in human cells have measured genome-wide nucleosome distributions at high temporal resolution during a response to a common stimulus. We measured nucleosome distributions at high temporal resolution following Kaposi's-sarcoma-associated herpesvirus (KSHV) reactivation using our newly developed mTSS-seq technology, which maps nucleosome distribution at the transcription start sites (TSS) of all human genes. Nucleosomes underwent widespread changes in organization 24 hours after KSHV reactivation and returned to their basal nucleosomal architecture 48 hours after KSHV reactivation. The widespread changes consisted of an indiscriminate remodeling event resulting in the loss of nucleosome rotational phasing signals. Additionally, one in six TSSs in the human genome possessed nucleosomes that are translationally remodeled. 72% of the loci with translationally remodeled nucleosomes have nucleosomes that moved to positions encoded by the underlying DNA sequence. Finally we demonstrated that these widespread alterations in nucleosomal architecture potentiated regulatory factor binding. These descriptions of nucleosomal architecture changes provide a new framework for understanding the role of chromatin in the genomic response, and have allowed us to propose a hierarchical model for chromatin-based regulation of genome response. PMID- 26771137 TI - Novel CXCL13 transgenic mouse: inflammation drives pathogenic effect of CXCL13 in experimental myasthenia gravis. AB - Abnormal overexpression of CXCL13 is observed in many inflamed tissues and in particular in autoimmune diseases. Myasthenia gravis (MG) is a neuromuscular disease mainly mediated by anti-acetylcholine receptor autoantibodies. Thymic hyperplasia characterized by ectopic germinal centers (GCs) is a common feature in MG and is correlated with high levels of anti-AChR antibodies. We previously showed that the B-cell chemoattractant, CXCL13 is overexpressed by thymic epithelial cells in MG patients. We hypothesized that abnormal CXCL13 expression by the thymic epithelium triggered B-cell recruitment in MG. We therefore created a novel transgenic (Tg) mouse with a keratin 5 driven CXCL13 expression. The thymus of Tg mice overexpressed CXCL13 but did not trigger B-cell recruitment. However, in inflammatory conditions, induced by Poly(I:C), B cells strongly migrated to the thymus. Tg mice were also more susceptible to experimental autoimmune MG (EAMG) with stronger clinical signs, higher titers of anti-AChR antibodies, increased thymic B cells, and the development of germinal center-like structures. Consequently, this mouse model finally mimics the thymic pathology observed in human MG. Our data also demonstrated that inflammation is mandatory to reveal CXCL13 ability to recruit B cells and to induce tertiary lymphoid organ development. PMID- 26771138 TI - DNA demethylation caused by 5-Aza-2'-deoxycytidine induces mitotic alterations and aneuploidy. AB - Aneuploidy, the unbalanced number of chromosomes in a cell, is considered a prevalent form of genetic instability and is largely acknowledged as a condition implicated in tumorigenesis. Epigenetic alterations like DNA hypomethylation have been correlated with cancer initiation/progression. Furthermore, a growing body of evidence suggests the involvement of epigenome-wide disruption as a cause of global DNA hypomethylation in aneuploidy generation.Here, we report that the DNA hypomethylating drug 5-aza-2'-deoxycytidine (DAC), affects the correct ploidy of nearly diploid HCT-116 human cells by altering the methylation pattern of the chromosomes. Specifically, we show that a DAC-induced reduction of 5-Methyl Cytosine at the pericentromeric region of chromosomes correlates with aneuploidy and mitotic defects.Our results suggest that DNA hypomethylation leads to aneuploidy by altering the DNA methylation landscape at the centromere that is necessary to ensure proper chromosomes segregation by recruiting the proteins necessary to build up a functional kinetochore. PMID- 26771139 TI - Survivin inhibitor YM155 suppresses gastric cancer xenograft growth in mice without affecting normal tissues. AB - Survivin overexpression is associated with poor prognosis of human gastric cancer, and is a target for gastric cancer therapy. YM155 is originally identified as a specific inhibitor of survivin. In this study, we investigated the antitumor effect of YM155 on human gastric cancer. Our results showed that YM155 treatment significantly inhibited cell proliferation, reduced colony formation and induced apoptosis of gastric cancer cells in a dose-dependent manner. Accordingly, YM155 treatment significantly decreased survivin expression without affecting XIAP expression and increased the cleavage of apoptosis associated proteins caspase 3, 7, 8, 9. YM155 significantly inhibited sphere formation of gastric cancer cells, suppressed expansion and growth of the formed spheres (cancer stem cell-like cells, CSCs) and downregulated the protein levels of beta-catenin, c-Myc, Cyclin D1 and CD44 in gastric cancer cells. YM155 infusion at 5 mg/kg/day for 7 days markedly inhibited growth of gastric cancer xenograft in a nude mouse model. Immunohistochemistry staining and Western Blot showed that YM155 treatment inhibited expression of survivin and CD44, induced apoptosis and reduced CD44+ CSCs in xenograft tumor tissues in vivo. No obvious pathological changes were observed in organs (e.g. heart, liver, lung and kidney) in YM155-treated mice. Our results demonstrated that YM155 inhibits cell proliferation, induces cell apoptosis, reduces cancer stem cell expansion, and inhibits xenograft tumor growth in gastric cancer cells. Our results elucidate a new mechanism by which YM155 inhibits gastric cancer growth by inhibition of CSCs. YM155 may be a promising agent for gastric cancer treatment. PMID- 26771140 TI - CXCR2 signaling regulates KRAS(G12D)-induced autocrine growth of pancreatic cancer. AB - Pharmacological inhibition of RAS, the master regulator of pancreatic ductal adenocarcinoma (PDAC), continues to be a challenge. Mutations in various isoforms of RAS gene, including KRAS are known to upregulate CXC chemokines; however, their precise role in KRAS-driven pancreatic cancer remains unclear. In this report, we reveal a previously unidentified tumor cell-autonomous role of KRAS(G12D)-induced CXCR2 signaling in mediating growth of neoplastic PDAC cells. Progressively increasing expression of mCXCR2 and its ligands was detected in the malignant ductal cells of Pdx1-cre;LSL-Kras(G12D) mice. Knocking-down CXCR2 in KRAS(G12D)-bearing human pancreatic duct-derived cells demonstrated a significant decrease in the in vitro and in vivo tumor cell proliferation. Furthermore, CXCR2 antagonists showed selective growth inhibition of KRAS(G12D)-bearing cells in vitro. Intriguingly, both genetic and pharmacological inhibition of CXCR2 signaling in KRAS(G12D)-bearing pancreatic ductal cells reduced the levels of KRAS protein, strongly implying the presence of a KRAS-CXCR2 feed-forward loop. Together, these data demonstrate the role of CXCR2 signaling in KRAS(G12D) induced growth transformation and progression in PDAC. PMID- 26771141 TI - Acyl protein thioesterase 1 and 2 (APT-1, APT-2) inhibitors palmostatin B, ML348 and ML349 have different effects on NRAS mutant melanoma cells. AB - Oncogenic NRAS mutations are frequent in melanoma and lead to increased downstream signaling and uncontrolled cell proliferation. Since the direct inhibition of NRAS is not possible yet, modulators of NRAS posttranslational modifications have become an area of interest. Specifically, interfering with NRAS posttranslational palmitoylation/depalmitoylation cycle could disturb proper NRAS localization, and therefore decrease cell proliferation and downstream signaling. Here, we investigate the expression and function of NRAS depalmitoylating acyl protein thioesterases 1 and 2 (APT-1, APT-2) in a panel of NRAS mutant melanoma cells. First, we show that all melanoma cell lines examined express APT-1 and APT-2. Next, we show that siRNA mediated APT-1 and APT-2 knock down and that the specific APT-1 and -2 inhibitors ML348 and ML349 have no biologically significant effects in NRAS mutant melanoma cells. Finally, we test the dual APT-1 and APT-2 inhibitor palmostatin B and conclude that palmostatin B has effects on NRAS downstream signaling and cell viability in NRAS mutant melanoma cells, offering an interesting starting point for future studies. PMID- 26771142 TI - Comparative analyses of the chemical and sensory parameters and consumer preference of a semi-dried smoked meat product (cabanossi) produced with warthog (Phacochoerus africanus) and domestic pork meat. AB - The study compared the chemical and sensory characteristics and consumer preference of a semi-dried, cured meat product, cabanossi, produced with warthog meat and with domestic pork. The warthog and pork cabanossi had similar total moisture (59.0%+/-2.07 and 54.3%+/-1.26) and protein (26.3%+/-2.20 and 24.2%+/ 2.15) contents, while the warthog cabanossi was lower in total fat content (6.9%+/-1.01) compared to pork cabanossi (13.7%+/-1.77, P=0.007). Descriptive sensory analysis found that the warthog cabanossi appeared darker red (P=0.001) and less fatty (P=0.001), while the pork cabanossi had a higher overall pork flavour (P=0.001). There were no differences in consumer preference of the appearance and taste between the two types of cabanossi, while the majority of consumers (91%) supported the use of game meat in meat products. The study concluded that warthog meat can be used in processed products without compromising the associated technical or organoleptic properties. PMID- 26771143 TI - Intensive vs. free-range organic beef. A preference study through consumer liking and conjoint analysis. AB - This paper evaluates consumer liking and preferences towards organic beef from two production systems allowed by EU regulation: i) free-range and ii) intensive (fattened in feed-lot with organic feedstuff) as compared with conventionally produced beef. Data were obtained in April-May 2014 with a sample of 150 regular beef consumers who completed two tasks: firstly a sensory test where consumers tasted and rated the meats and secondly a conjoint analysis to study beef purchasing preferences. Willingness-to-pay for the different meats was also calculated from conjoint results. Results show that consumers preferred organic from-concentrate beef at sensory level while organic beef from animals fed on grass was preferred when process characteristics (i.e. farming system) or attributes perceived at the point of purchase (i.e. colour) were evaluated. It was also found that the price-premium for organic beef is over 40%, with organic fed-on grass beef preferred slightly over that fed-on-concentrate. PMID- 26771144 TI - Growth, carcass and meat quality traits in beef from Angus, Hereford and cross breed grazing steers, and their association with SNPs in genes related to fat deposition metabolism. AB - Grazing steers from Angus and Hereford breeds, their cross-breeds and a three-way cross-breed (Limousin * Angus-Hereford) were measured for growth, carcass and meat quality traits. Breed effects were studied, and the association of SNPs with fat deposition and fatty acid (FA) composition (leptin, melanocortin-4 receptor, stearoyl-CoA desaturase, FA synthase and thyroglobulin) was tested. Limousin cross-breed showed the greatest final body weight, ultrasound rib eye area, dressing percentage, carcass and leg length, and the lowest backfat thickness and intramuscular fat content. Genetic groups had similar pH, shear force, cooking loss, L* and b* and n-6:n-3 ratio. Meat from 1/2-Angus presented greater a* than Limousin cross-breed. Whereas Angus had the highest total SFA content, Hereford had the lowest total SFA and the highest total MUFA. Limousin cross-breed had greater content of several individual PUFAs, total PUFA, n-6 and n-3 FA than Angus and 1/2-Angus. Leptin and FA synthase were associated with some FAs, supporting their influence over fat metabolism for grazing animals. PMID- 26771145 TI - The TNF-alpha-308G/A Polymorphism is Not Associated with Ocular Chlamydia trachomatis Infection in Han Chinese Children. AB - OBJECTIVE: To investigate the association between the TNF-alpha-308G/A polymorphism and ocular chlamydia trachomatis (C. Trachomatis) infection among Han Chinese children. METHODS: 248 patients and 162 matched healthy controls were recruited. The diagnosis of ocular C. Trachomatis infection was given after clinical observation and latex immunochromatography tests. The TNF-alpha-308G/A polymorphism was genotyped by sequencing. RESULTS: No association was found between the TNF-alpha-308G/A polymorphism and ocular C. Trachomatis infection. CONCLUSIONS: The TNF-alpha-308A polymorphism is unlikely to play a major role in the risk for ocular C. Trachomatis in the Chinese population. PMID- 26771146 TI - Kinetic Separation and Asymmetric Reactions of Norcaradiene Cycloadducts: Facilitated Access via H2O-Accelerated Cycloaddition. AB - We exploit the Buchner reaction to access 1,2-disubstituted cyclohexadiene synthons (norcaradienes), which participate in H2O-accelerated cycloaddition with dieneophiles to provide cyclopropyl-fused [2.2.2]-bicyclooctene derivatives in good yields. Regioisomeric mixtures can be kinetically separated by exploiting different reaction rates in Diels-Alder reactions. Meso-Diels-Alder products may be enantioselectively desymmetrized, providing highly substituted cyclohexanes with up to seven contiguous stereocenters. PMID- 26771147 TI - Amino-Functionalized Ceramic Capillary Membranes for Controlled Virus Retention. AB - A straightforward chemical functionalization strategy using aminosilanes for high flux yttria-stabilized zirconia capillary membranes is presented (macroporous, d50 = 144 nm, open porosity =49%, membrane flux ~150 L/(m(2)hbar)). Three different aminosilanes with one, two or three amino groups per silane molecule, namely 3-aminopropyltriethoxysilane (APTES), N-(2-aminoethyl)-3 aminopropyltriethoxysilane (AE-APTES) and N-(3 trimethoxysilylpropyl)diethylenetriamine (TPDA), are used to generate the amino functionalized membranes. With a higher number of amino groups per silane molecule increased loading capacities between 0.44 and 1.01 accessible amino groups/nm(2) membrane are achieved. Streaming potential measurements confirm that the zeta-potential of the membrane surface is converted from negative (non functionalized) to positive (amino-functionalized). By operation in dead-end filtration mode using the model virus MS2 (diameter = 25 nm, IEP = 3.9) the virus retention capacity of the amino-functionalized membranes is significantly increased and log reduction values (LRVs) of up to 9.6 +/- 0.3 (TPDA) are obtained whereas a LRV < 0.3 is provided by the non-functionalized membranes. Long-term dead-end filtration experiments for 1 week reveal a high stability of immobilized aminosilanes (TPDA), being robust against leaching. By iterative backflushing with desorption buffer MS2-loaded membranes are successfully regenerated being reusable for a new filtration cycle. The presented functionalization platform is highly promising for controlled virus retention. PMID- 26771148 TI - Dyslexia and Substance Use in a University Undergraduate Population. AB - BACKGROUND: A number of cognitive deficits are associated with dyslexia. However, only a limited amount of research has been performed exploring a putative link between dyslexia and substance use. As substance use is thought to involve a cognitive component, it is possible that the pattern of substance use would be different for dyslexic participants, when compared to nondyslexic controls. During the current study, a guiding hypothesis was that people with dyslexia would demonstrate less substance use than nondyslexic controls. Theories of memory activation, automaticity, and attentional bias in substance use suggest that cognitive components of substance use are important in the development and maintenance of continued substance use and it is thought that, at least some of these components, would be impaired in a dyslexic population. OBJECTIVES: If the cognitive deficits displayed by dyslexics somehow impair the development of cognitive components of substance use, substance use for dyslexic participants may be less pronounced. This paper therefore examines this hypothesis by comparing substance use within dyslexic and nondyslexic participants, from an undergraduate population. METHODS: This was an exploratory questionnaire-based study. Dyslexic participants (n = 35) were compared to control participants (n = 62) on a series of questions designed to measure their substance use history. RESULTS: The results provided preliminary evidence of a difference between dyslexic and nondyslexic substance use. Dyslexics reported a substance use history that was significantly lower than nondyslexic controls. CONCLUSIONS/IMPORTANCE: These results are interpreted in terms of cognitive deficits within dyslexia and with reference to the cognitive model of substance use. PMID- 26771150 TI - Clinical manifestation and associated factors of seborrheic dermatitis in Korea. AB - Systematic investigations of clinical manifestation and factors associated with the severity of seborrheic dermatitis (SD) have rarely been reported in Asia. We investigated the clinical manifestation and associated factors of SD. Patients were asked to fill a self-questionnaire including symptom severity and aggravating factors. We evaluated objective severity and involved sites of SD. Patients were categorized into three groups; young age group (age <30), middle age group (30<= age <60), and old age group (age >=60) and we compared clinical features among them. RESULTS: Among 253 patients included, scalp was the most frequently involved site and the most frequently reported aggravating factor was psychological stress. Different age groups have distinct clinical features and severity. Severity of SD decreased with age and patients in the old age group had less frequent involvement of the lower face. Risk factors of scalp involvement were male gender, disease duration >=7 years and a history of acne. We investigated associated factors of SD and observed different clinical features between the age groups. We suggest that the adult form of SD can be categorized into three groups; young age SD, middle age SD and old age SD. PMID- 26771151 TI - Overexpression of LOXIN Protects Endothelial Progenitor Cells From Apoptosis Induced by Oxidized Low Density Lipoprotein. AB - Human endothelial progenitor cells (hEPC) are adult stem cells located in the bone marrow and peripheral blood. Studies have indicated that hEPC play an important role in the recovery and repair of injured endothelium, however, their quantity and functional capacity is reduced in several diseases including hypercholesterolemia. Recently, it has been demonstrated that hEPC express lectin like oxidized low-density lipoprotein receptor-1 (LOX-1) and its activation by oxidized low-density lipoprotein (ox-LDL) induces cellular dysfunction and apoptosis. This study aimed to investigate whether overexpression of LOXIN, a truncated isoform of LOX-1 that acts as a dominant negative, plays a protective role against ox-LDL-induced apoptosis in hEPC. Human endothelial progenitor cells exposed to ox-LDL showed a significant increase in LOX-1 expression, and apoptosis began at ox-LDL concentrations above 50 MUg/mL. All hEPC apoptosed at 200 MUg/mL ox-LDL. High LOXIN expression was generated using adenoviral systems in hEPC and SiHa cells transduced with 100 colony-forming units per cell. Transduced LOXIN localized to the plasma membrane and blocked ox-LDL uptake mediated by LOX-1. Overexpression of LOXIN protected hEPC from ox-LDL-induced apoptosis, and therefore maybe a novel way of improving hEPC function and quantity. These results suggest that adenoviral vectors of LOXIN may provide a possible treatment for diseases related to ox-LDL and vascular endothelium dysfunction, including atherosclerosis. PMID- 26771152 TI - Cocaine Constrictor Mechanisms of the Cerebral Vasculature. AB - Cocaine constriction of the cerebral vasculature is thought to contribute to the ischemia associated with cocaine use. However, the mechanisms whereby cocaine elicits relevant vasoconstriction remain elusive. Indeed, proposed intra- and intercellular mechanisms based on over 3 decades of ex vivo vascular studies are, for the most part, of questionable relevancy due to the generally low contractile efficacy of cocaine combined with the use of nonresistance-type vessels. Furthermore, the significance attached to mechanisms derived from in vivo animal studies may be limited by the inability to demonstrate cocaine-induced decreased cerebral blood flow, as observed in (awake) humans. Despite these apparent limitations, we surmise that the vasoconstriction relevant to cocaine-induced ischemia is elicited by inhibition of dilator and activation of constrictor pathways because of cocaine action on the neurovascular unit (neuron, astrocyte, and vessel) and on vessels outside the unit. Furthermore, previous cocaine exposure, that is, conditions present in human subjects, downregulates and sensitizes these dilator and constrictor pathways, respectively, thereby enhancing constriction to acute cocaine. Identification of specific intra- and intercellular mechanisms requires investigations in the isolated microvasculature and the neurovascular unit from species chronically exposed to cocaine and in which cocaine decreases cerebral blood flow. PMID- 26771153 TI - Safety and Efficacy of Switching From Clopidogrel to Prasugrel in Patients Undergoing Percutaneous Coronary Intervention: A Study-level Meta-analysis From 15 Studies. AB - BACKGROUND: There is poor evidence on clinical outcome of switching from clopidogrel to prasugrel in patients undergoing percutaneous coronary intervention. OBJECTIVES: Data on the topic are limited and we performed a study level meta-analysis to assess safety and efficacy of such strategy. METHODS: A total of 15 studies and 3974 patients were included. The following comparisons were performed: prasugrel switching versus prasugrel only therapy; and prasugrel switching versus clopidogrel only therapy. Outcome measures were overall bleeding, major bleeding, and major adverse cardiac events (MACE). RESULTS: There was no statistically significant increased bleeding risk in the prasugrel switching versus prasugrel only group [overall bleeding: OR 1.07, 95% confidence interval (CI), 0.69-1.66; P = 0.77; major bleeding: OR 0.69, 95% CI, 0.32-1.49; P = 0.34]; MACE rates were also comparable. Incidence of safety end points was similar in the prasugrel switching and clopidogrel only groups (overall bleeding: OR 1.27, 95% CI, 0.75-2.15; P = 0.37; major bleeding: OR 0.70, 95% CI, 0.29-1.68; P = 0.42); occurrence of MACE was 3.8% in the prasugrel switching versus 8.3% in the clopidogrel only group (P = 0.23). No statistically significant difference in the safety outcomes was present stratifying by clinical presentation. CONCLUSIONS: Switching from clopidogrel to prasugrel does not increase bleeding complications during follow-up of patients undergoing percutaneous coronary intervention; however, the strength of the data is not sufficient to make definitive clinical recommendations. PMID- 26771154 TI - Cytoprotective Effects of Oleanolic Acid in Human Umbilical Vascular Endothelial Cells is Mediated Via UCP2/ROS/Cytochrome C/AIF Pathway. AB - The aim of this study is to assess the potential protective effect of oleanolic acid (OA) against ox-LDL induced damage in human umbilical vascular endothelial cells (HUVECs) and investigate potential mechanism of action including antioxidative effects and inhibition of mitochondria apoptosis pathway. Cell counting kit 8 was used to evaluate the viability of HUVECs. 2', 7'-DCFH-DA staining and flow cytometry was used to assess the levels of intracellular reactive oxygen species in HUVECs. The protein expression levels of uncoupling protein 2, cytochrome C, and apoptosis induction factors were measured by western blotting. The results indicated that OA treatment alleviated ox-LDL induced cytotoxicity in HUVECs and ameliorated the reactive oxygen species levels. Western blotting results demonstrated that OA treatment increased the expression level of uncoupling protein 2 and decreased the release of cytochrome C and apoptosis induction factors from mitochondria to cytoplasm, suggesting inhibition of mitochondria apoptosis pathway. In conclusion, OA could protect HUVECs from ox LDL-induced cytotoxicity; its antioxidant property and inhibition of mitochondria apoptosis are likely crucial contributors. PMID- 26771155 TI - Musculoskeletal symptoms and associated risk factors among African hair braiders. AB - African hair braiders are potentially subject to work-related musculoskeletal disorders (WMSDs) because they perform repetitive hand motions for many hours a day together with prolonged standing and/or prolonged sitting. A complete enumeration of African hair braiders was attempted in Oklahoma City (OKC) and Dallas/Fort Worth (DFW). Braiders were identified through the channels they typically use to offer services to clients. Potential risk factors and symptoms of WMSDs were assessed using an oral interview. Participation rates were 95% (18/19) in OKC and 83% (83/101) in DFW. More than 75% of braiders reported discomfort in the fingers, wrist/hand, upper back, and lower back. In multivariate analysis, years worked as a braider but not age was a significant risk factor (p < 0.005) for reported pain in the wrist/hand, time spent sitting during the work day was found to be a significant predictor (p < 0.05) of upper back pain and lower back pain, and time spent sitting and time spent standing during the work day were both significant predictors (p < 0.05) of shoulder pain. Braiders in OKC, where licensing requirements were stricter, were significantly more likely than braiders in DFW to work at home (67% vs. 4%, p < 0.001) and to report pain in the lower leg (p < 0.005) and ankle/foot (p < 0.05). The close knit nature of the African hair braiding community makes it an appealing candidate for community-based participatory research aimed at further elucidating occupational health concerns and reducing risk. PMID- 26771156 TI - The diagnostic performance of ultrasonographic optic nerve sheath diameter and color Doppler indices of the ophthalmic arteries in detecting elevated intracranial pressure. AB - OBJECTIVES: To assess the diagnostic accuracy of ultrasonographic optic nerve sheath diameter (ONSD) measurement and color Doppler indices of the ophthalmic arteries in detecting elevated intracranial pressure (ICP). PATIENTS AND METHODS: A total 60 patients with (cases, n=30) and without (controls, n=30) acute clinical and computed tomographic findings of elevated ICP due to intracranial mass/hemorrhage were recruited from a teaching hospital. The mean binocular and maximum ultrasonographic ONSDs, as well as the mean binocular Doppler ultrasound waveform indices of the ophthalmic arteries including pulsatility index (PI), resistive index (RI), end-systolic velocity (ESV), peak systolic velocity (PSV) and end-diastolic velocity (EDV) were compared between the two groups. RESULTS: Compared to controls, the case group had significantly higher mean binocular ONSD (5.48 +/- 0.52 mm vs. 4.09 +/- 0.22 mm, p<0.001), maximum ONSD (5.63 +/- 0.55 mm vs. 4.16 +/- 0.23 mm, p<0.001), mean PI (1.53 +/- 0.16 vs. 1.45 +/- 0.20, p=0.01), and mean RI (0.76 +/- 0.07 vs. 0.73 +/- 0.04, p=0.01). The mean EDV, in contrast, was significantly higher in controls (8.55 +/- 3.09 m/s vs. 7.17 +/- 2.61 m/s, p=0.01). The two groups were comparable for the mean PSV (30.73 +/- 7.93 m/s in cases vs. 32.27 +/- 10.39 m/s in controls, p=0.36). Among the mentioned variables, the mean binocular ONSD was the most accurate parameter in detecting elevated ICP (sensitivity and specificity of 100%, cut-off point=4.53 mm). The Doppler indices were only moderately accurate (sensitivity: 56.7-60%, specificity: 63.3-76.7%). CONCLUSION: While the ultrasonographic mean binocular ONSD (>4.53 mm) was completely accurate in detecting elevated ICP, color Doppler indices of the ophthalmic arteries were of limited value. PMID- 26771160 TI - Toxicity of titanium dioxide nanoparticles on Pseudomonas putida. AB - The increasing use of engineered nanoparticles (NPs) in industrial and household applications will very likely lead to the release of such materials into the environment. As wastewater treatment plants (WWTPs) are usually the last barrier before the water is discharged into the environment, it is important to understand the effects of these materials in the biotreatment processes, since the results in the literature are usually contradictory. We proposed the use of flow cytometry (FC) technology to obtain conclusive results. Aqueous solutions of TiO2 nanoparticles (0-2 mg mL(-1)) were used to check its toxicity effect using Pseudomonas putida as simplified model of real sludge over room light. Physiological changes in P. putida from viable to viable but non-culturable cells were observed by flow cytometry in presence of TiO2. The damaged and dead cell concentrations were below 5% in all cases under study. Both FSC and SSC parameter increased with TiO2 dose dependent manner, indicating nanoparticles uptake by the bacteria. The biological removal of salicylic acid (SA) was also significantly impacted by the presence of TiO2 in the medium reducing the efficiency. The use of FC allows also to develop and fit segregated kinetic models, giving the impact of TiO2 nanoparticles in the physiological subpopulations growth and implications for SA removal. PMID- 26771161 TI - Rethinking the sustainability of Israel's irrigation practices in the Drylands. AB - Broad utilization of drip irrigation technologies in Israel has contributed to the 1600 percent increase in the value of produce grown by local farmers over the past sixty-five years. The recycling of 86% of Israeli sewage now provides 50% of the country's irrigation water and is the second, idiosyncratic component in Israel's strategy to overcome water scarcity and maintain agriculture in a dryland region. The sustainability of these two practices is evaluated in light of decades of experience and ongoing research by the local scientific community. The review confirms the dramatic advantages of drip irrigation over time, relative to flood, furrow and sprinkler irrigation and its significance as a central component in agricultural production, especially under arid conditions. In contrast, empirical findings increasingly report damage to soil and to crops from salinization caused by irrigation with effluents. To be environmentally and agriculturally sustainable over time, wastewater reuse programs must ensure extremely high quality treated effluents and ultimately seek the desalinization of recycled sewage. PMID- 26771162 TI - Enrichment and characterization of microbial consortia degrading soluble microbial products discharged from anaerobic methanogenic bioreactors. AB - Soluble microbial products (SMP) produced in bioprocesses have been known as a main cause to decrease treatment efficiency, lower effluent quality, and promote membrane fouling in water reclamation plants. In this study, biological degradation of SMP using selectively enriched microbial consortia in a down-flow hanging sponge (DHS) reactor was introduced to remove SMP discharged from anaerobic methanogenic reactors. On average, 68.9-87.5% SMP removal was achieved by the enriched microbial consortia in the DHS reactor for >800 days. The influent SMP fed to the DHS reactor exhibited a bimodal molecular weight (MW) distribution with 14-20 kDa and <4 kDa. Between these two types of SMP, the small MW SMP were biodegraded in the upper part of the reactor, together with most of the large MW SMP. Using 16S rRNA gene pyrosequencing technology, the microbial community composition and structure were characterized and correlated with operational factors, such as hydraulic retention time, organic loading rate, and removal of soluble chemical oxygen demand at different depths of the reactor, by performing network and redundancy analyses. The results revealed that Saprospiraceae was strongly correlated to the increasing SMP loading condition, indicating positive co-occurrences with neighboring bacterial populations. Different microbial diversity along with the depth of the reactor implies that stratified microbial communities could participate in the process of SMP degradation. Taken together, these observations indicate that the spatial and temporal variability of the enriched microbial community in the DHS reactor could effectively treat SMP with respect to changes in the operational factors. PMID- 26771163 TI - Regulation of VWF expression, and secretion in health and disease. AB - PURPOSE OF REVIEW: Von Willebrand factor (VWF) is a large multidomain, multimeric glycoprotein that plays an essential role in regulating the balance between blood clotting and bleeding. Aberrant VWF regulation can lead to a spectrum of diseases extending from bleeding disorders [Von Willebrand disease (VWD)] to aberrant thrombotic thrombocytopenic purpura (TTP). Understanding the biology of VWF expression and secretion is essential for developing novel targeted therapies for VWF-related hemostasis disorders. RECENT FINDINGS: A number of recent elegant in vitro and in-vivo studies will be highlighted, including the discovery of intronic splicing in the VWF gene, microRNA-regulated VWF gene expression, and syntaxin binding protein and autophagy mediated VWF secretion. Compared with the already established critical role of VWF in VWD and TTP pathophysiology, additional clinical studies have clarified and reinforced the association of elevated plasma levels of VWF with an increased risk of stroke, myocardial infarction, venous thrombosis, and diabetic thrombotic complications. Moreover, experimental mouse models of ischemic stroke and myocardial infarction have further supported VWF as a potential therapeutic target. SUMMARY: VWF biosynthesis, maturation, and secretion is a complex process, which mandates tight regulation. Significant progress has been made in our understandings of VWF expression and secretion and its association with thrombotic diseases, contributing to the development of novel targeting VWF drugs for prevention and treatment of deficient and enhanced hemostasis. PMID- 26771164 TI - Doxycycline plus ivermectin versus ivermectin alone for treatment of patients with onchocerciasis. AB - BACKGROUND: Onchocerciasis, also known as "river blindness," is a parasitic disease that is caused by infection from the filarial nematode (roundworm), Onchocerca volvulus. Nematodes are transmitted from person to person by blackflies of the Simulium genus, which usually breed in fast flowing streams and rivers. The disease is the second leading infectious cause of blindness in endemic areas.Ivermectin (a microfilaricide) is widely distributed to endemic populations for prevention and treatment of onchocerciasis. Doxycycline, an antibiotic, targets Wolbachia organisms that are crucial to the survival of adult onchocerca (macrofilaricide). Combined treatment with both drugs is believed to cause direct microfilarial death by ivermectin and indirect macrofilarial death by doxycycline. Long-term reduction in the numbers of microfilaria in the skin and eyes and in the numbers of adult worms in the body has the potential to reduce the transmission and occurrence of onchocercal eye disease. OBJECTIVES: The primary aim of this review was to assess the effectiveness of doxycycline plus ivermectin versus ivermectin alone for prevention and treatment of onchocerciasis. The secondary aim was to assess the effectiveness of doxycycline plus ivermectin versus ivermectin alone for prevention and treatment of onchocercal ocular lesions in communities co-endemic for onchocerciasis and Loa loa (loiasis) infection. SEARCH METHODS: We searched CENTRAL (which contains the Cochrane Eyes and Vision Trials Register) (Issue 7, 2015), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to July 2015), EMBASE (January 1980 to July 2015), PubMed (1948 to July 2015), Latin American and Caribbean Health Sciences Literature Database (LILACS) (1982 to July 2015), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com) (last searched 1 July 2014), ClinicalTrials.gov (www.clinicaltrials.gov) and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic search for trials. We last searched the electronic databases on 15 July 2015. SELECTION CRITERIA: We included randomized controlled trials (RCTs) that had compared doxycycline plus ivermectin versus ivermectin alone. Participants with or without one or more characteristic signs of ocular onchocerciasis resided in communities where onchocerciasis was endemic. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial eligibility and extracted data. We used standard methodological procedures as expected by Cochrane. MAIN RESULTS: We identified three RCTs including a total of 466 participants with a diagnosis of onchocerciasis. All trials compared doxycycline plus ivermectin versus ivermectin alone. One study investigated improvement in visual impairment at six-month follow-up; the other two studies measured microfilarial loads in skin snips to assess sustained effects of treatment at follow-up of 21 months or longer. The studies were conducted at various centers across three countries (Cameroon, Ghana, and Liberia). We judged all studies to be at overall high risk of bias because of inadequate randomization and lack of masking (one study), missing data (two studies), and selective outcome reporting (three studies).Only one study measured visual outcomes. This study reported uncertainty about the difference in the proportion of participants with improvement in visual impairment at six-month follow-up for doxycycline plus ivermectin compared with ivermectin alone (risk ratio (RR) 1.06, 95% confidence interval (95% CI) 0.80 to 1.39; 240 participants; very low-quality evidence). No participant in either group showed improvement in optic atrophy, chorioretinitis, or sclerosing keratitis at six-month follow-up. More participants in the doxycycline plus ivermectin group than in the ivermectin alone group showed improvement in iridocyclitis (RR 1.24, 95% CI 0.69 to 2.22) and punctate keratitis (RR 1.43, 95% CI 1.02 to 2.00) at six-month follow-up; however, we graded these results as very low quality.Two studies reported that a six-week course of doxycycline may result in Wolbachia depletion and macrofilaricidal and sterilizing activities in female Onchocerca worms; however, no analysis was possible because data were missing and incomplete (graded evidence as very low quality). Adverse events were reported in 16 of 135 (12%) participants in one of these studies and included itching, headaches, body pains, and vertigo; no difference between treatment groups was reported for any adverse event. The second study reported that one (1.3%) participant in the doxycycline plus ivermectin group had bloody diarrhea after treatment was initiated. AUTHORS' CONCLUSIONS: Available evidence on the effectiveness of doxycycline plus ivermectin compared with ivermectin alone in preventing and treating onchocerciasis is unclear. Limited evidence of very low quality from two studies indicates that a six-week course of doxycycline followed by ivermectin may result in more frequent macrofilaricidal and microfilaricidal activity and sterilization of female adult Onchocerca compared with ivermectin alone; however, effects on vision-related outcomes are uncertain. Future studies should consider the effectiveness of treatments in preventing visual acuity and visual field loss and their effects on anterior and posterior segment lesions, particularly chorioretinitis. These studies should report outcomes in a uniform and consistent manner at follow-up of three years or longer to allow detection of meaningful changes in vision-related outcomes. PMID- 26771165 TI - Frontal cortex gray matter volume alterations in pathological gambling occur independently from substance use disorder. AB - Neuroimaging in pathological gambling (PG) allows studying brain structure independent of pharmacological/neurotoxic effects occurring in substance addiction. Because of high comorbidity of PG with substance use disorder (SUD), first results on structural deficits in PG are controversial. The current investigation is the first to examine gray matter (GM) volume alterations in PG controlling for the impact of SUD by comparing non-comorbid (PGPURE ) and two comorbid (PGALCOHOL and PGPOLY ) groups. Two hundred and five individuals were included in the analysis: 107 patients diagnosed with PG and 98 healthy controls (HCs). We employed voxel-based morphometry to look for GM volume differences between the groups controlling for age, smoking and depression. GM decreases in the superior medial and orbital frontal cortex occur independently of substance use in PGPURE compared with HCs. The frontal pattern of GM decrease was comparable with PGALCOHOL group where additionally GM volume was decreased in the anterior cingulate but increased in the amygdala. Moreover, regions in PGALCOHOL + POLY with reduced GM volume were the medial frontal, anterior cingulate and occipital lobe regions. PGALCOHOL + POLY not only exhibited structural deficits in comparison with HCs but also relative to PGPURE in the precuneus and post central gyrus. We demonstrated specific frontal cortex GM deficits in PG without SUD comorbidities. Whereas some target regions reported in earlier studies might result from comorbid substance abuse, there seems to be a core set of frontal alterations associated with addicted gambling behaviour independent of toxic substance effects. PMID- 26771166 TI - Laparoscopic Surgery is Useful for Preventing Recurrence of Small Bowel Obstruction After Surgery for Postoperative Small Bowel Obstruction. AB - INTRODUCTION: Risk factors for recurrence postoperative small bowel obstruction in patients who have postoperative abdominal surgery remain unclear. MATERIALS AND METHODS: The study group comprised 123 patients who underwent surgery for ileus that developed after abdominal surgery from 1999 through 2013. There were 58 men (47%) and 65 women (53%), with a mean age of 63 years (range, 17 to 92 y). The following surgical procedures were performed: lower gastrointestinal surgery in 47 patients (39%), gynecologic surgery in 39 (32%), upper gastrointestinal surgery in 15 (12%), appendectomy in 9 (7%), cholecystectomy in 5 (4%), urologic surgery in 5 (4%), and repair of injuries caused by traffic accidents in 3 (2%). Laparoscopic surgery was performed in 75 patients (61%), and open surgery was done in 48 (39%). We examined the following 11 potential risk factors for recurrence of small bowel obstruction after surgery for ileus: sex, age, body mass index, the number of episodes of ileus, the number of previously performed operations, the presence or absence of radiotherapy, the previously used surgical technique, the current surgical technique (laparoscopic surgery, open surgery), operation time, bleeding volume, and the presence or absence of enterectomy. RESULTS: The median follow-up was 57 months (range, 7 to 185 mo). Laparoscopic surgery was switched to open surgery in 11 patients (18%). The reason for surgery for postoperative small bowel obstruction was adhesion to the midline incision in 36 patients (29%), band formation in 30 (24%), intrapelvic adhesion in 23 (19%), internal hernia in 13 (11%), small bowel adhesion in 20 (16%), and others in 1 (1%). Postoperative complications developed in 35 patients (28%): wound infection in 12 (10%), recurrence of postoperative small bowel obstruction in 12 (10%), paralytic ileus in 4 (3%), intra-abdominal abscess in 3 (2%), suture failure in 1 (1%), anastomotic bleeding in 1 (1%), enteritis in 1 (1%), and dysuria in 1 (1%). Enterectomy was performed in 42 patients (38%). On univariate analysis, 2 risk factors were significantly related to the recurrence of small bowel obstruction: open surgery (P=0.017) and bleeding volume (P=0.031). On multivariate analysis, open surgery was an independent risk factor for the recurrence of small bowel obstruction (odds ratio, 5.621; P=0.015). CONCLUSIONS: Open surgery was an independent risk factor for the recurrence of small bowel obstruction after abdominal surgery. In the future, laparoscopic surgery should be performed to prevent the recurrence of small bowel obstruction. PMID- 26771167 TI - Rice terpene synthase 24 (OsTPS24) encodes a jasmonate-responsive monoterpene synthase that produces an antibacterial gamma-terpinene against rice pathogen. AB - Rice is one of the most important crops worldwide and is widely used as a model plant for molecular studies of monocotyledonous species. The plant hormone jasmonic acid (JA) is involved in rice-pathogen interactions. In addition, volatile compounds, including terpenes, whose production is induced by JA, are known to be involved in the rice defense system. In this study, we analyzed the JA-induced terpene synthase OsTPS24 in rice. We found that OsTPS24 was localized in chloroplasts and produced a monoterpene, gamma-terpinene. The amount of gamma terpinene increased after JA treatment. gamma-Terpinene had significant antibacterial activity against Xanthomonas oryzae pv. oryzae (Xoo); however, it did not show significant antifungal activity against Magnaporthe oryzae. The antibacterial activity of the gamma-terpinene against Xoo was caused by damage to bacterial cell membranes. These results suggest that gamma-terpinene plays an important role in JA-induced resistance against Xoo, and that it functions as an antibacterial compound in rice. PMID- 26771168 TI - Streptococcus mutans biofilm transient viscoelastic fluid behaviour during high velocity microsprays. AB - Using high-speed imaging we assessed Streptococcus mutans biofilm-fluid interactions during exposure to a 60-ms microspray burst with a maximum exit velocity of 51m/s. S. mutans UA159 biofilms were grown for 72h on 10mm-length glass slides pre-conditioned with porcine gastric mucin. Biofilm stiffness was measured by performing uniaxial-compression tests. We developed an in-vitro interproximal model which allowed the parallel insertion of two biofilm-colonized slides separated by a distance of 1mm and enabled high-speed imaging of the removal process at the surface. S. mutans biofilms were exposed to either a water microspray or an air-only microburst. High-speed videos provided further insight into the mechanical behaviour of biofilms as complex liquids and into high-shear fluid-biofilm interaction. We documented biofilms extremely transient fluid behaviour when exposed to the high-velocity microsprays. The presence of time dependent recoil and residual deformation confirmed the pivotal role of viscoelasticity in biofilm removal. The air-only microburst was effective enough to remove some of the biofilm but created a smaller clearance zone underlying the importance of water and the air-water interface of drops moving over the solid surface in the removal process. Confocal and COMSTAT analysis showed the high velocity water microspray caused up to a 99.9% reduction in biofilm thickness, biomass and area coverage, within the impact area. PMID- 26771169 TI - Improving outcomes for people in mental health crisis: a rapid synthesis of the evidence for available models of care. AB - BACKGROUND: Crisis Concordat was established to improve outcomes for people experiencing a mental health crisis. The Crisis Concordat sets out four stages of the crisis care pathway: (1) access to support before crisis point; (2) urgent and emergency access to crisis care; (3) quality treatment and care in crisis; and (4) promoting recovery. OBJECTIVES: To evaluate the clinical effectiveness and cost-effectiveness of the models of care for improving outcomes at each stage of the care pathway. DATA SOURCES: Electronic databases were searched for guidelines, reviews and, where necessary, primary studies. The searches were performed on 25 and 26 June 2014 for NHS Evidence, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, NHS Economic Evaluation Database, and the Health Technology Assessment (HTA) and PROSPERO databases, and on 11 November 2014 for MEDLINE, PsycINFO and the Criminal Justice Abstracts databases. Relevant reports and reference lists of retrieved articles were scanned to identify additional studies. STUDY SELECTION: When guidelines covered a topic comprehensively, further literature was not assessed; however, where there were gaps, systematic reviews and then primary studies were assessed in order of priority. STUDY APPRAISAL AND SYNTHESIS METHODS: Systematic reviews were critically appraised using the Risk Of Bias In Systematic reviews assessment tool, trials were assessed using the Cochrane risk-of-bias tool, studies without a control group were assessed using the National Institute for Health and Care Excellence (NICE) prognostic studies tool and qualitative studies were assessed using the Critical Appraisal Skills Programme quality assessment tool. A narrative synthesis was conducted for each stage of the care pathway structured according to the type of care model assessed. The type and range of evidence identified precluded the use of meta-analysis. RESULTS AND LIMITATIONS: One review of reviews, six systematic reviews, nine guidelines and 15 primary studies were included. There was very limited evidence for access to support before crisis point. There was evidence of benefits for liaison psychiatry teams in improving service-related outcomes in emergency departments, but this was often limited by potential confounding in most studies. There was limited evidence regarding models to improve urgent and emergency access to crisis care to guide police officers in their Mental Health Act responsibilities. There was positive evidence on clinical effectiveness and cost-effectiveness of crisis resolution teams but variability in implementation. Current work from the Crisis resolution team Optimisation and RElapse prevention study aims to improve fidelity in delivering these models. Crisis houses and acute day hospital care are also currently recommended by NICE. There was a large evidence base on promoting recovery with a range of interventions recommended by NICE likely to be important in helping people stay well. CONCLUSIONS AND IMPLICATIONS: Most evidence was rated as low or very low quality, but this partly reflects the difficulty of conducting research into complex interventions for people in a mental health crisis and does not imply that all research was poorly conducted. However, there are currently important gaps in research for a number of stages of the crisis care pathway. Particular gaps in research on access to support before crisis point and urgent and emergency access to crisis care were found. In addition, more high-quality research is needed on the clinical effectiveness and cost effectiveness of mental health crisis care, including effective components of inpatient care, post-discharge transitional care and Community Mental Health Teams/intensive case management teams. STUDY REGISTRATION: This study is registered as PROSPERO CRD42014013279. FUNDING: The National Institute for Health Research HTA programme. PMID- 26771170 TI - Isoliquiritigenin ameliorates dextran sulfate sodium-induced colitis through the inhibition of MAPK pathway. AB - Isoliquiritigenin (isoLQ), a chalcone found in licorice, has shown a variety of biological activity including anti-inflammatory and antioxidative effects, and the distribution of isoLQ in gastrointestinal tract was higher than any other tissues. Thus, we evaluated whether or not isoLQ attenuated the dextran sulfate sodium (DSS)-induced colitis by observing the physiological changes (body weight loss, diarrhea, bleeding stool, overall disease activity index (DAI) scores, colon length), histopathological analysis and myeloperoxidase (MPO) activities of esophagus and colon. Also, the MAPK pathways including phosphorylation of ERK1/2, p38, and AKT, and the activation of NK-kappaB were evaluated in colon tissue. Interestingly, the reduction of body weight and colon length, increase of diarrhea, bloody stool, DAI scores and MPO activity, and histologic disturbances in DSS-induced colitis were recovered by isoLQ treatment. Also, isoLQ treatment suppressed the phosphorylation of ERK1/2 and p38, and the activation of NK-kappaB compared to those in DSS-induced colitis mice. In addition, the distributions of isoLQ in colon were relatively higher in DSS-induced colitis models. All of these results suggested that isoLQ has potential activity to ameliorate the DSS-induced colitis through the inhibition of MAPK pathway. PMID- 26771171 TI - Mesial temporal lobe epilepsy presenting with rising epigastric sensation as the only clinical symptom: a case report. AB - Mesial temporal lobe epilepsy is generally manifested as central nervous system disorder, emotional disturbances, and visceral discomfort. We present the case of an elderly male patient with mesial temporal lobe epilepsy presenting with rising epigastric sensation as the only manifestation. A 60-year-old male patient who had been regularly suffering from episodic epigastric sensations three to seven times every day was admitted to our hospital. 'Rising air' initiated from epigastria, ascending to his chest, and terminated in the throat. Brain MRI showed sclerosis of the right hippocampus and enlargement of the right temporal horn. Video electroencephalography showed that the seizure was associated with a high-amplitude spike and slow wave, originating from the right anterior temporal region and extending to the leads in the right hemisphere. Extensive gastrointestinal and cardiothoracic investigations showed no abnormality, and so an underlying seizure disorder was suspected. The patient was prescribed a low dose of carbamazepine of 200 mg daily and was discharged the next day. A repeat video electroencephalography confirmed the satisfactory efficacy of the treatment. During the follow-up period of 22 months, there was no reappearance of epilepsy. Primary physicians, especially gastroenterologists, should be acquainted with the manifestations of simple partial seizures to avoid any dispensable medical examinations, even maltreatments. PMID- 26771172 TI - Mast Cells Contribute to Radiation-Induced Vascular Hyperpermeability. AB - Induction of vascular hyperpermeability is one of the early vascular responses to radiation exposure and is considered to contribute to subsequent fibrosis and tissue injuries. However, the mechanism underlying radiation-induced hyperpermeability has not yet been clearly elucidated. Here, we provide experimental evidence indicating that mast cells contribute to the increase in vascular permeability for albumin in normal mouse skin after irradiation. Vascular permeability in the skin of C3H mice increased after 2, 15 and 50 Gy irradiation, peaked at 24 h after irradiation and gradually decreased thereafter to the baseline level within 3-10 days. Both the extent and duration of hyperpermeability were dose dependent. We found significant degranulation of mast cells in the skin after 15 Gy irradiation. To further investigate the role of mast cells in the radiation-induced increase in vascular permeability, we measured vascular permeability in the skin of mast cell-deficient mice (WW(v)) and their wild-type littermates at 24 h after irradiation. Vascular permeability in WW(v) mice did not change, whereas that in wild-type mice significantly increased after irradiation. There were no appreciable changes in the total tissue levels of vascular endothelial growth factor or endothelial nitric oxide synthase after 15 Gy irradiation and there was no detectable expression of inducible nitric oxide synthase. Collectively, these results show that exposure to radiation induces vascular hyperpermeability in a dose-dependent manner and that mast cells contribute to this process. PMID- 26771173 TI - A New Model for Biological Dose Assessment in Cases of Heterogeneous Exposures to Ionizing Radiation. AB - In biological dosimetry by dicentric analysis, an exposure to radiation is considered non-homogeneous if the dicentric cell distribution shows overdispersion with respect to Poisson distribution. Traditionally, when this occurs, all non-homogeneous exposures are considered as partial-body exposures, assuming that there is only a mixture of irradiated and nonirradiated cells. The methods to estimate the dose in the irradiated fraction and the initial fraction of irradiated cells are based on separating which part of the cells without aberrations comes from the nonirradiated or irradiated fractions. In this study we show a new approach based on a mixed Poisson model, which allows for a distinction to be made between partial and heterogeneous exposures. To validate this approach blood samples from two donors, a male and a female, irradiated at different doses, were mixed at a 1:1 proportion to simulate partial and heterogeneous exposures. The results show a good agreement between the observed proportion of male and female cells and the proportion estimated by the model. Additionally, a good agreement was observed between the delivered doses, the initial fraction of cells and the ones estimated by the model. This good agreement was also observed after very high-dose irradiation (up to 17 Gy), when the lymphocyte cultures were treated with caffeine. Based on these results, we propose the use of this mixed Poisson model for a more accurate assessment of non homogeneous exposures. PMID- 26771174 TI - Radiation Biology Irradiator Dose Verification Survey. AB - Interest in standardized dosimetry for radiobiological irradiators has expanded over the last decade. At a symposium held at NIST, "The Importance of Standardization of Dosimetry in Radiobiology", a set of 12 criteria necessary for adequate irradiation was developed by the authors. Here we report on our review of dosimetry methods from various peer-reviewed publications and found that none of them satisfied all 12 criteria set forth by the authors of the NIAD/NCI/NIST proceedings. The inadequate reporting of dosimetry methods in the literature raises questions regarding the accuracy of the dose delivered to animal test subjects and the resulting experimental results. For this reason, we investigated the level of accuracy of dose delivery in radiation biology studies. We performed an irradiator output verification study of 12 radiation biology laboratories (7 gamma and 5 X-ray units) using polymethyl methacrylate (PMMA) mouse phantoms and thermoluminescent dosimeters (TLDs) readouts at the University of Wisconsin Medical Radiation Research Center (UWMRRC). The laboratories housing each of these irradiators were asked to deliver specific doses to individual mouse phantoms. Simultaneously, mouse phantoms at the UWMRRC were irradiated with NIST traceable reference beams representative of the subject laboratories' beam energies. The irradiated mouse phantoms were returned from the various institutions to the UWMRRC and the TLDs were processed, with their measured dose response compared to the known dose response of the calibration phantom TLDs. Of the five facilities using X-ray irradiators, only one delivered an output within 5% of the target dose. The dose differences for the other four X-ray irradiators ranged from 12 to 42%. These results indicate the potential need for standardization of dose determination and additional oversight of radiobiology investigations. PMID- 26771175 TI - Adverse effects of long-term administration of fluvoxamine on haematology, blood biochemistry and fertility in male albino rats: a possible effect of cessation. AB - Fluvoxamine is recommended as first-line treatment for a number of obsessive compulsive disorders, anxiety disorders, social phobia, and post-traumatic stress disorder and panic disorder. The adverse effects of prolonged oral administration of fluvoxamine on haematology, biochemical parameters and fertility in male rats were evaluated in this study. Sixty adult male rats were allocated into 5 equal groups and orally treated with fluvoxamine 9 mg kg-1 b.wt. (low therapeutic dose, LTD) and 27 mg kg-1 b.wt. (high therapeutic dose, HTD), while the control rats received 0.5 ml distilled water for a period of 8 weeks. The 4th and 5th groups were gavaged with LTD and HTD of fluvoxamine for 8 weeks and then left untreated for another 8 weeks (recovery groups). HTD of fluvoxamine induced leukocytosis, lymphocytosis and monocytosis. LTD and HTD of fluvoxamine evoked hepatic, renal and cardiac dysfunction. Moreover, fluvoxamine treatment might lead to the risk of male infertility, which is indicated by its deleterious impacts on spermiogram and steroidogenesis hormones. They also induced oxidative stress, apoptosis in testicular tissue. Fortunately, the previous alterations were mostly reversed during the recovery period. PMID- 26771176 TI - Combined stereotactic biopsy and stepping-source interstitial irradiation of glioblastoma multiforme. AB - Patients diagnosed with glioblastoma multiforme receiving stereotactic biopsy only either due to tumor localization or impaired clinical status face a devastating prognosis with very short survival times. One strategy to provide an initial cytoreductive and palliative therapy at the time of the stereotactic biopsy is interstitial irradiation through the pre-defined trajectory of the biopsy channel. We designed a novel treatment planning system and evaluated the treatment potential of a fixed-source and a stepping-source algorithm for interstitial radiosurgery on non-spherical glioblastoma in direct adjacency to risk structures. Using both setups, we show that radiation doses delivered to 100% of the gross tumor volume shifts from sub-therapeutic (10-12 Gy) to sterilizing single doses (25-30 Gy) when using the stepping source algorithm due to improved sparing of organs-at-risk. Specifically, the maximum doses at the brain stem were 100% of the PTV dose when a fixed central source and 38% when a stepping-source algorithm was used. We also demonstrated precision of intracranial target points and stability of superficial and deep trajectories using both a phantom and a body donor study. Our setup now for the first time provides a basis for a clinical proof-of-concept trial and may widen palliation options for patients with limited life expectancy that should not undergo time consuming therapies. PMID- 26771177 TI - The Validity of a New Low-Dose Stereoradiography System to Perform 2D and 3D Knee Prosthetic Alignment Measurements. AB - INTRODUCTION: The EOS stereoradiography system has shown to provide reliable varus/valgus (VV) measurements of the lower limb in 2D (VV2D) and 3D (VV3D) after total knee arthroplasty (TKA). Validity of these measurements has not been investigated yet, therefore the purpose of this study was to determine validity of EOS VV2D and VV3D. METHODS: EOS images were made of a lower limb phantom containing a knee prosthesis, while varying VV angle from 15 degrees varus to 15 degrees valgus and flexion angle from 0 degrees to 20 degrees , and changing rotation from 20 degrees internal to 20 degrees external rotation. Differences between the actual VV position of the lower limb phantom and its position as measured on EOS 2D and 3D images were investigated. RESULTS: Rotation, flexion or VV angle alone had no major impact on VV2D or VV3D. Combination of VV angle and rotation with full extension did not show major differences in VV2D measurements either. Combination of flexion and rotation with a neutral VV angle showed variation of up to 7.4 degrees for VV2D; maximum variation for VV3D was only 1.5 degrees . A combination of the three variables showed an even greater distortion of VV2D, while VV3D stayed relatively constant. Maximum measurement difference between preset VV angle and VV2D was 9.8 degrees , while the difference with VV3D was only 1.9 degrees . The largest differences between the preset VV angle and VV2D were found when installing the leg in extreme angles, for example 15 degrees valgus, 20 degrees flexion and 20 degrees internal rotation. CONCLUSIONS: After TKA, EOS VV3D were more valid than VV2D, indicating that 3D measurements compensate for malpositioning during acquisition. Caution is warranted when measuring VV angle on a conventional radiograph of a knee with a flexion contracture, varus or valgus angle and/or rotation of the knee joint during acquisition. PMID- 26771178 TI - Leishmania infantum Asparagine Synthetase A Is Dispensable for Parasites Survival and Infectivity. AB - A growing interest in asparagine (Asn) metabolism has currently been observed in cancer and infection fields. Asparagine synthetase (AS) is responsible for the conversion of aspartate into Asn in an ATP-dependent manner, using ammonia or glutamine as a nitrogen source. There are two structurally distinct AS: the strictly ammonia dependent, type A, and the type B, which preferably uses glutamine. Absent in humans and present in trypanosomatids, AS-A was worthy of exploring as a potential drug target candidate. Appealingly, it was reported that AS-A was essential in Leishmania donovani, making it a promising drug target. In the work herein we demonstrate that Leishmania infantum AS-A, similarly to Trypanosoma spp. and L. donovani, is able to use both ammonia and glutamine as nitrogen donors. Moreover, we have successfully generated LiASA null mutants by targeted gene replacement in L. infantum, and these parasites do not display any significant growth or infectivity defect. Indeed, a severe impairment of in vitro growth was only observed when null mutants were cultured in asparagine limiting conditions. Altogether our results demonstrate that despite being important under asparagine limitation, LiAS-A is not essential for parasite survival, growth or infectivity in normal in vitro and in vivo conditions. Therefore we exclude AS-A as a suitable drug target against L. infantum parasites. PMID- 26771179 TI - Cytoskeletal Expression and Remodeling in Pluripotent Stem Cells. AB - Many emerging cell-based therapies are based on pluripotent stem cells, though complete understanding of the properties of these cells is lacking. In these cells, much is still unknown about the cytoskeletal network, which governs the mechanoresponse. The objective of this study was to determine the cytoskeletal state in undifferentiated pluripotent stem cells and remodeling with differentiation. Mouse embryonic stem cells (ESCs) and reprogrammed induced pluripotent stem cells (iPSCs), as well as the original un-reprogrammed embryonic fibroblasts (MEFs), were evaluated for expression of cytoskeletal markers. We found that pluripotent stem cells overall have a less developed cytoskeleton compared to fibroblasts. Gene and protein expression of smooth muscle cell actin, vimentin, lamin A, and nestin were markedly lower for ESCs than MEFs. Whereas, iPSC samples were heterogeneous with most cells expressing patterns of cytoskeletal proteins similar to ESCs with a small subpopulation similar to MEFs. This indicates that dedifferentiation during reprogramming is associated with cytoskeletal remodeling to a less developed state. In differentiation studies, it was found that shear stress-mediated differentiation resulted in an increase in expression of cytoskeletal intermediate filaments in ESCs, but not in iPSC samples. In the embryoid body model of spontaneous differentiation of pluripotent stem cells, however, both ESCs and iPSCs had similar gene expression for cytoskeletal proteins during early differentiation. With further differentiation, however, gene levels were significantly higher for iPSCs compared to ESCs. These results indicate that reprogrammed iPSCs more readily reacquire cytoskeletal proteins compared to the ESCs that need to form the network de novo. The strategic selection of the parental phenotype is thus critical not only in the context of reprogramming but also the ultimate functionality of the iPSC differentiated cell population. Overall, this increased characterization of the cytoskeleton in pluripotent stem cells will allow for the better understanding and design of stem cell-based therapies. PMID- 26771180 TI - Prediction of T Cell Epitopes from Leishmania major Potentially Excreted/Secreted Proteins Inducing Granzyme B Production. AB - Leishmania-specific cytotoxic T cell response is part of the acquired immune response developed against the parasite and contributes to resistance to reinfection. Herein, we have used an immune-informatic approach for the identification, among Leishmania major potentially excreted/secreted proteins previously described, those generating peptides that could be targeted by the cytotoxic immune response. Seventy-eight nonameric peptides that are predicted to be loaded by HLA-A*0201 molecule were generated and their binding capacity to HLA A2 was evaluated. These peptides were grouped into 20 pools and their immunogenicity was evaluated by in vitro stimulation of peripheral blood mononuclear cells from HLA-A2+-immune individuals with a history of zoonotic cutaneous leishmaniasis. Six peptides were identified according to their ability to elicit production of granzyme B. Furthermore, among these peptides 3 showed highest affinity to HLA-A*0201, one derived from an elongation factor 1-alpha and two from an unknown protein. These proteins could constitute potential vaccine candidates against leishmaniasis. PMID- 26771181 TI - Quality Saving Mechanisms of Mitochondria during Aging in a Fully Time-Dependent Computational Biophysical Model. AB - Mitochondria are essential for the energy production of eukaryotic cells. During aging mitochondria run through various processes which change their quality in terms of activity, health and metabolic supply. In recent years, many of these processes such as fission and fusion of mitochondria, mitophagy, mitochondrial biogenesis and energy consumption have been subject of research. Based on numerous experimental insights, it was possible to qualify mitochondrial behaviour in computational simulations. Here, we present a new biophysical model based on the approach of Figge et al. in 2012. We introduce exponential decay and growth laws for each mitochondrial process to derive its time-dependent probability during the aging of cells. All mitochondrial processes of the original model are mathematically and biophysically redefined and additional processes are implemented: Mitochondrial fission and fusion is separated into a metabolic outer-membrane part and a protein-related inner-membrane part, a quality-dependent threshold for mitophagy and mitochondrial biogenesis is introduced and processes for activity-dependent internal oxidative stress as well as mitochondrial repair mechanisms are newly included. Our findings reveal a decrease of mitochondrial quality and a fragmentation of the mitochondrial network during aging. Additionally, the model discloses a quality increasing mechanism due to the interplay of the mitophagy and biogenesis cycle and the fission and fusion cycle of mitochondria. It is revealed that decreased mitochondrial repair can be a quality saving process in aged cells. Furthermore, the model finds strategies to sustain the quality of the mitochondrial network in cells with high production rates of reactive oxygen species due to large energy demands. Hence, the model adds new insights to biophysical mechanisms of mitochondrial aging and provides novel understandings of the interdependency of mitochondrial processes. PMID- 26771182 TI - Embryo defective 14 encodes a plastid-targeted cGTPase essential for embryogenesis in maize. AB - The embryo defective (emb) mutants in maize genetically define a unique class of loci that is required for embryogenesis but not endosperm development, allowing dissection of two developmental processes of seed formation. Through characterization of the emb14 mutant, we report here that Emb14 gene encodes a circular permuted, YqeH class GTPase protein that likely functions in 30S ribosome formation in plastids. Loss of Emb14 function in the null mutant arrests embryogenesis at the early transition stage. Emb14 was cloned by transposon tagging and was confirmed by analysis of four alleles. Subcellular localization indicated that the EMB14 is targeted to chloroplasts. Recombinant EMB14 is shown to hydrolyze GTP in vitro (Km = 2.42 +/- 0.3 MUm). Emb14 was constitutively expressed in all tissues examined and high level of expression was found in transition stage embryos. Comparison of emb14 and WT indicated that loss of EMB14 function severely impairs accumulation of 16S rRNA and several plastid encoded ribosomal genes. We show that an EMB14 transgene complements the pale green, slow growth phenotype conditioned by mutations in AtNOA1, a closely related YqeH GTPase of Arabidopsis. Taken together, we propose that the EMB14/AtNOA1/YqeH class GTPases function in assembly of the 30S subunit of the chloroplast ribosome, and that this function is essential to embryogenesis in plants. PMID- 26771183 TI - Correction. AB - Combined correlation-based network and mQTL analyses efficiently identified loci for branched-chain amino acid, serine to threonine, and proline metabolism in tomato seeds Volume 81, Issue 1, 121-133, Article first published online: 16 December 2014In the article by Toubiana et al. (2015), the sub-headings for segments of introgression line (IL) in Table 2 were published incorrectly.The correct Table 2 is reproduced below. PMID- 26771184 TI - Impact of Mechanical Thrombectomy on the Organization of the Management of Acute Ischemic Stroke. AB - BACKGROUND: Several trials and meta-analyses have recently demonstrated the superiority of endovascular therapy over standard medical treatment in patients presenting with acute ischemic stroke. In order to offer the best possible treatment to a maximum number of patients, many stroke care networks probably have to be reorganized. After analyzing the reliability of data in the literature, an algorithm is suggested for a pre-hospital and in-hospital alert system to improve the timeliness of subsequent treatment: a drip-and-ship approach. SUMMARY: Five recent well-designed randomized studies have demonstrated the benefit of endovascular therapy associated with intravenous fibrinolysis by recombinant tissue plasminogen activator (rt-PA) for acute ischemic stroke with confirmation by recent meta-analyses. The keys for success are a very short time to reperfusion, within 6 h, a moderate to severe pre-treatment deficit (National Institute of Health around 17), cerebral imaging able to identify proximal large vessel occlusion in the anterior circulation, a limited infarct core and a reversible penumbra, the use of the most recent devices (stent retriever) and a procedure that avoids general anesthesia, which reduces blood pressure. To meet these goals, every country must build a national stroke infrastructure plan to offer the best possible treatment to all patients eligible for intravenous fibrinolysis and endovascular therapy. The plan may include the following actions: inform the population about the first symptoms of stroke, provide the call number to improve the timeliness of treatment, increase the number of comprehensive stroke centers, link these to secondary and primary stroke centers by telemedicine, teach and train paramedics, emergency doctors and radiologists to identify the stroke infarct, proximal large vessel occlusion and the infarct core quickly, train a new generation of endovascular radiologists to improve access to this therapy. KEY MESSAGE: After 20 years of rt-PA, this new evidence based therapy is a revolution in stroke medicine that will benefit patients. However, a new robust and multi-disciplinary care strategy is necessary to transfer the scientific data into clinical practice. It will require reorganization of the stroke infrastructure, which will include comprehensive stroke centers and secondary and primary stroke centers. The winners will be patients with severe stroke. PMID- 26771185 TI - Acetylshikonin from Zicao Prevents Obesity in Rats on a High-Fat Diet by Inhibiting Lipid Accumulation and Inducing Lipolysis. AB - Various drugs have been developed to treat obesity, but these have undesirable secondary effects, and an efficient but non-toxic anti-obesity drug from natural sources is desired. This study investigated the anti-obesity effects and mechanisms of action of acetylshikonin (AS)-which is used in traditional Chinese medicine-in rats on a high-fat diet (HFD). Rats were fed a normal diet or an HFD; the latter group was received no treatment or were treated with 100, 300, or 900 mg/kg AS extract by intragastric administration for 6 weeks. In addition, 3T3-L1 adipocytes were treated with AS and the effects on adipogenesis and lipolysis were evaluated by western blot analysis of adipogenic transcription factors and lipid-metabolizing enzyme levels and the phosphorylation status of protein kinase (PK) A and hormone-sensitive lipase (HSL). AS prevented HFD-induced obesity including reduction in body weight, white adipose tissue content, liver mass, and serum triglyceride and free fatty acid levels in rats. It also suppressed the expression of adipogenic differentiation transcription factors and decreased the expression of the adipocyte-specific proteins HSL and adipose triglyceride lipase (ATGL). Furthermore, AS treatment induced lipolysis, leading to the release of glycerol and increased in PKA and HSL phosphorylation. These findings demonstrate that AS has anti-obesity effects in a rat model and may be a safe treatment for obesity in humans. PMID- 26771186 TI - Transient Tear Film Dysfunction after Cataract Surgery in Diabetic Patients. AB - PURPOSE: Diabetes mellitus is an increasingly common systemic disease. Many diabetic patients seek cataract surgery for a better visual acuity. Unlike in the general population, the influence of cataract surgery on tear film function in diabetic patients remains elusive. The aim of this study was to evaluate the tear function in diabetic and nondiabetic patients following cataract surgery. METHODS: In this prospective, interventional case series, 174 diabetic patients without dry eye syndrome (DES) and 474 age-matched nondiabetic patients as control who underwent phacoemulsification were enrolled at two different eye centers between January 2011 and January 2013. Patients were followed up at baseline and at 7 days, 1 month, and 3 months postoperatively. Ocular symptom scores (Ocular Surface Disease Index, OSDI) and tear film function including tear film stability (tear film break-up time, TBUT), corneal epithelium integrity (corneal fluorescein staining, CFS), and tear secretion (Schirmer's I test, SIT) were evaluated. RESULTS: In total, 83.9% of the diabetic patients (146 cases with 185 eyes) and 89.0% of the nondiabetic patients (422 cases with 463 eyes) completed all check-ups after the interventions (P = 0.095). The incidence of DES was 17.1% in the diabetic patients and 8.1% in the nondiabetic patients at 7 days after cataract surgery. In the diabetic patients, the incidence of DES remained 4.8% at 1 month postoperatively and decreased to zero at 3 months after surgery. No DES was diagnosed in nondiabetic patients at either the 1-month or 3-month follow-up. Compared with the baseline, the diabetic patients had worse symptom scores and lower TBUT values at 7 days and 1 month but not at 3 months postoperatively. In the nondiabetic patients, symptom scores and TBUT values had returned to preoperative levels at 1-month check-up. CFS scores and SIT values did not change significantly postoperatively in either group (P = 0.916 and P = 0.964, respectively). CONCLUSIONS: Diabetic patients undergoing cataract surgery are prone to DES. Ocular symptoms and tear film stability are transiently worsened in diabetic patients and are restored more slowly than those in nondiabetic patients. PMID- 26771188 TI - Identification of a Novel Transcript and Regulatory Mechanism for Microsomal Triglyceride Transfer Protein. AB - Microsomal triglyceride transfer protein (MTP) is essential for the assembly of triglyceride-rich apolipoprotein B-containing lipoproteins. Previous studies in our laboratory identified a novel splice variant of MTP in mice that we named MTP B. MTP-B has a unique first exon (1B) located 2.7 kB upstream of the first exon (1A) for canonical MTP (MTP-A). The two mature isoforms, though nearly identical in sequence and function, have different tissue expression patterns. In this study we report the identification of a second MTP splice variant (MTP-C), which contains both exons 1B and 1A. MTP-C is expressed in all the tissues we tested. In cells transfected with MTP-C, protein expression was less than 15% of that found when the cells were transfected with MTP-A or MTP-B. In silico analysis of the 5'-UTR of MTP-C revealed seven ATGs upstream of the start site for MTP-A, which is the only viable start site in frame with the main coding sequence. One of those ATGs was located in the 5'-UTR for MTP-A. We generated reporter constructs in which the 5'-UTRs of MTP-A or MTP-C were inserted between an SV40 promoter and the coding sequence of the luciferase gene and transfected these constructs into HEK 293 cells. Luciferase activity was significantly reduced by the MTP-C 5'-UTR, but not by the MTP-A 5'-UTR. We conclude that alternative splicing plays a key role in regulating MTP expression by introducing unique 5' UTRs, which contain elements that alter translation efficiency, enabling the cell to optimize MTP levels and activity. PMID- 26771189 TI - Upregulated Cellular Expression of IL-17 by CD4+ T-Cells in Osteoporotic Postmenopausal Women. AB - AIM: The study aimed to investigate cellular expression of IL-17 by CD4+ T-cells in osteoporotic postmenopausal women. METHODS: We enrolled 25 postmenopausal women with osteoporosis (PostMO) and 25 postmenopausal women with normal bone mineral density measurements (PostM) to examine the production of IL-17, tumor necrosis factor alpha (TNFalpha) and receptor activator of nuclear factor x03BA; B ligand (RANKL) by CD4+ T-cells and IL-17, RORx03B3;t, TNFalpha and RANKL mRNA levels in CD4+ T-cells. Circulating concentrations of IL-17 along with IL-6, TNFalpha, RANKL and osteoprotegerin (OPG) were also determined. RESULTS: Osteoporotic postmenopausal women had higher serum concentrations of IL-17 (3.7 +/- 1.3 vs. 2.5 +/- 1.1 ng/ml, p = 0.042), IL-6 (158 +/- 56 vs. 105 +/- 39 pg/ml, p = 0.044), TNFalpha (138 +/- 41 vs. 74 +/- 11 pg/ml, p < 0.001) and OPG (1.7 +/- 0.4 vs. 1.3 +/- 0.4 ng/ml, p = 0.039) than healthy controls. The IL-17-producing CD4+ T-cells were higher in the PostMO group than in the PostM group (7.1 +/- 2.4 vs. 4.9 +/- 1.4%, p = 0.0015). Additionally, osteoporotic postmenopausal women had greater mRNA levels of IL-17 (3.5 +/- 2.9 vs. 1.2 +/- 1.0%, p = 0.019) and RORx03B3;t (5.7 +/- 2.5 vs. 2.2 +/- 1.0%, p < 0.001) in CD4+ T-cells than in healthy controls. CONCLUSIONS: Our findings implied that the upregulated production of IL-17 may play an important role in regulating bone loss in osteoporotic postmenopausal women. PMID- 26771190 TI - Correction: Evaluating Serum Markers for Hormone Receptor-Negative Breast Cancer. PMID- 26771187 TI - Early Regulation of Profibrotic Genes in Primary Human Cardiac Myocytes by Trypanosoma cruzi. AB - The molecular mechanisms of Trypanosoma cruzi induced cardiac fibrosis remains to be elucidated. Primary human cardiomyoctes (PHCM) exposed to invasive T. cruzi trypomastigotes were used for transcriptome profiling and downstream bioinformatic analysis to determine fibrotic-associated genes regulated early during infection process (0 to 120 minutes). The identification of early molecular host responses to T. cruzi infection can be exploited to delineate important molecular signatures that can be used for the classification of Chagasic patients at risk of developing heart disease. Our results show distinct gene network architecture with multiple gene networks modulated by the parasite with an incline towards progression to a fibrogenic phenotype. Early during infection, T. cruzi significantly upregulated transcription factors including activator protein 1 (AP1) transcription factor network components (including FOSB, FOS and JUNB), early growth response proteins 1 and 3 (EGR1, EGR3), and cytokines/chemokines (IL5, IL6, IL13, CCL11), which have all been implicated in the onset of fibrosis. The changes in our selected genes of interest did not all start at the same time point. The transcriptome microarray data, validated by quantitative Real-Time PCR, was also confirmed by immunoblotting and customized Enzyme Linked Immunosorbent Assays (ELISA) array showing significant increases in the protein expression levels of fibrogenic EGR1, SNAI1 and IL 6. Furthermore, phosphorylated SMAD2/3 which induces a fibrogenic phenotype is also upregulated accompanied by an increased nuclear translocation of JunB. Pathway analysis of the validated genes and phospho-proteins regulated by the parasite provides the very early fibrotic interactome operating when T. cruzi comes in contact with PHCM. The interactome architecture shows that the parasite induces both TGF-beta dependent and independent fibrotic pathways, providing an early molecular foundation for Chagasic cardiomyopathy. Examining the very early molecular events of T. cruzi cellular infection may provide disease biomarkers which will aid clinicians in patient assessment and identification of patient subpopulation at risk of developing Chagasic cardiomyopathy. PMID- 26771191 TI - 37,X/38,XY Mosaicism in a Cryptorchid Bengal Cat with Mullerian Duct Remnants. AB - A 23-month-old tomcat was referred to our clinic because of male behavioral problems, cryptorchidism, and an undefined intra-abdominal organ resembling a uterus. Ultrasonography and computed tomography showed 2 fluid-filled tubular structures dorsolaterally to the bladder and connected to the pelvic urethra. The cat was castrated, and the tubular structures were surgically removed. Histology identified them as Mullerian duct remnants. The testes were hypoplastic, the epididymes and deferent ducts were normal. Cytogenetic analyses revealed the presence of a mosaic 37,X/38,XY karyotype which explains the clinical findings. PMID- 26771192 TI - LEDGF/p75 Overexpression Attenuates Oxidative Stress-Induced Necrosis and Upregulates the Oxidoreductase ERP57/PDIA3/GRP58 in Prostate Cancer. AB - Prostate cancer (PCa) mortality is driven by highly aggressive tumors characterized by metastasis and resistance to therapy, and this aggressiveness is mediated by numerous factors, including activation of stress survival pathways in the pro-inflammatory tumor microenvironment. LEDGF/p75, also known as the DFS70 autoantigen, is a stress transcription co-activator implicated in cancer, HIV AIDS, and autoimmunity. This protein is targeted by autoantibodies in certain subsets of patients with PCa and inflammatory conditions, as well as in some apparently healthy individuals. LEDGF/p75 is overexpressed in PCa and other cancers, and promotes resistance to chemotherapy-induced cell death via the transactivation of survival proteins. We report in this study that overexpression of LEDGF/p75 in PCa cells attenuates oxidative stress-induced necrosis but not staurosporine-induced apoptosis. This finding was consistent with the observation that while LEDGF/p75 was robustly cleaved in apoptotic cells into a p65 fragment that lacks stress survival activity, it remained relatively intact in necrotic cells. Overexpression of LEDGF/p75 in PCa cells led to the upregulation of transcript and protein levels of the thiol-oxidoreductase ERp57 (also known as GRP58 and PDIA3), whereas its depletion led to ERp57 transcript downregulation. Chromatin immunoprecipitation and transcription reporter assays showed LEDGF/p75 binding to and transactivating the ERp57 promoter, respectively. Immunohistochemical analysis revealed significantly elevated co-expression of these two proteins in clinical prostate tumor tissues. Our results suggest that LEDGF/p75 is not an inhibitor of apoptosis but rather an antagonist of oxidative stress-induced necrosis, and that its overexpression in PCa leads to ERp57 upregulation. These findings are of significance in clarifying the role of the LEDGF/p75 stress survival pathway in PCa. PMID- 26771194 TI - A Practical Anodic and Cathodic Curve Intersection Model to Understand Multiple Corrosion Potentials of Fe-Based Glassy Alloys in OH- Contained Solutions. AB - A practical anodic and cathodic curve intersection model, which consisted of an apparent anodic curve and an imaginary cathodic line, was proposed to explain multiple corrosion potentials occurred in potentiodynamic polarization curves of Fe-based glassy alloys in alkaline solution. The apparent anodic curve was selected from the measured anodic curves. The imaginary cathodic line was obtained by linearly fitting the differences of anodic curves and can be moved evenly or rotated to predict the number and value of corrosion potentials. PMID- 26771193 TI - Differentiation of Human Induced-Pluripotent Stem Cells into Smooth-Muscle Cells: Two Novel Protocols. AB - Conventional protocols for differentiating human induced-pluripotent stem cells (hiPSCs) into smooth-muscle cells (SMCs) can be inefficient and generally fail to yield cells with a specific SMC phenotype (i.e., contractile or synthetic SMCs). Here, we present two novel hiPSC-SMC differentiation protocols that yield SMCs with predominantly contractile or synthetic phenotypes. Flow cytometry analyses of smooth-muscle actin (SMA) expression indicated that ~45% of the cells obtained with each protocol assumed an SMC phenotype, and that the populations could be purified to ~95% via metabolic selection. Assessments of cellular mRNA and/or protein levels indicated that SMA, myosin heavy chain II, collagen 1, calponin, transgelin, connexin 43, and vimentin expression in the SMCs obtained via the Contractile SMC protocol and in SMCs differentiated via a traditional protocol were similar, while SMCs produced via the Sythetic SMC protocol expressed less calponin, more collagen 1, and more connexin 43. Differences were also observed in functional assessments of the two SMC populations: the two-dimensional surface area of Contractile SMCs declined more extensively (to 12% versus 44% of original size) in response to carbachol treatment, while quantification of cell migration and proliferation were greater in Synthetic SMCs. Collectively, these data demonstrate that our novel differentiation protocols can efficiently generate SMCs from hiPSCs. PMID- 26771195 TI - Determining an Optimal Cutoff of Serum beta-Human Chorionic Gonadotropin for Assisting the Diagnosis of Intracranial Germinomas. AB - BACKGROUND: Beta (beta)-human chorionic gonadotropin (beta-HCG) is used to confirm the diagnosis and plan treatment of intracranial germinomas. However, the cutoff values of serum beta-HCG in diagnosis of intracranial germinomas reported in the literature are inconsistent. To establish an appropriate cutoff value of serum beta-HCG for diagnosis of intracranial germinomas, we retrospectively reviewed the records of intracranial tumor patients who received serum beta-HCG and alpha-fetoprotein (AFP) tests for diagnostic purposes at our hospital from 2005 to 2014. METHODS: A total of 93 intracranial germinomas and 289 intracranial non-germ cell tumors were included in this study. Receiver operating characteristic (ROC) analysis was used to evaluate the sensitivity and specificity of 3 cutoffs (0.1, 0.4, and 0.5 mIU/mL) for diagnosing intracranial germinomas. The serum beta-HCG level of intracranial germinoma patients was further analyzed to investigate the effect of metastasis status and tumor location on serum beta-HCG level. RESULTS: The area under the ROC curve was 0.81 (P < .001), suggesting beta-HCG is an effective marker. Of the 3 cutoff values, 0.1 mIU/mL possessed a highest sensitivity (66.67%) and good specificity (91%). Although there was no beta-HCG level difference between metastatic and non metastatic intracranial germinoma patients, the diagnostic rate of metastatic neurohypophyseal germinomas was significantly higher than that of its non metastatic counterpart (P < .05), implying that the location of the germinoma might need to be considered when beta-HCG is used as a marker to predict metastasis. CONCLUSIONS: Determining an optimal cutoff of serum beta-HCG is helpful for assisting the diagnosis of intracranial germinoma. PMID- 26771196 TI - In Search of a Cure for Sepsis: Taming the Monster in Critical Care Medicine. AB - In spite of over half a century of research, sepsis still constitutes a major problem in health care delivery. Although advances in research have significantly increased our knowledge of the pathogenesis of sepsis and resulted in better prognosis and improved survival outcome, sepsis still remains a major challenge in modern medicine with an increase in occurrence predicted and a huge socioeconomic burden. It is generally accepted that sepsis is due to an initial hyperinflammatory response. However, numerous efforts aimed at targeting the proinflammatory cytokine network have been largely unsuccessful and the search for novel potential therapeutic targets continues. Recent studies provide compelling evidence that dysregulated anti-inflammatory responses may also contribute to sepsis mortality. Our previous studies on the role of regulatory T cells and phosphoinositide 3-kinases in sepsis highlight immunological approaches that could be explored for sepsis therapy. In this article, we review the current and emerging concepts in sepsis, highlight novel potential therapeutic targets and immunological approaches for sepsis treatment and propose a biphasic treatment approach for management of the condition. PMID- 26771197 TI - Dissecting the Molecular Mechanism of Nucleotide-Dependent Activation of the KtrAB K+ Transporter. AB - KtrAB belongs to the Trk/Ktr/HKT superfamily of monovalent cation (K+ and Na+) transport proteins that closely resemble K+ channels. These proteins underlie a plethora of cellular functions that are crucial for environmental adaptation in plants, fungi, archaea, and bacteria. The activation mechanism of the Trk/Ktr/HKT proteins remains unknown. It has been shown that ATP stimulates the activity of KtrAB while ADP does not. Here, we present X-ray structural information on the KtrAB complex with bound ADP. A comparison with the KtrAB-ATP structure reveals conformational changes in the ring and in the membrane protein. In combination with a biochemical and functional analysis, we uncover how ligand-dependent changes in the KtrA ring are propagated to the KtrB membrane protein and conclude that, despite their structural similarity, the activation mechanism of KtrAB is markedly different from the activation mechanism of K+ channels. PMID- 26771198 TI - Balancing ballistic protection against physiological strain: evidence from laboratory and field trials. AB - This project was based on the premise that decisions concerning the ballistic protection provided to defence personnel should derive from an evaluation of the balance between protection level and its impact on physiological function, mobility, and operational capability. Civilians and soldiers participated in laboratory- and field-based studies in which ensembles providing five levels of ballistic protection were evaluated, each with progressive increases in protection, mass (3.4-11.0 kg), and surface-area coverage (0.25-0.52 m(2)). Physiological trials were conducted on volunteers (N = 8) in a laboratory, under hot-dry conditions simulating an urban patrol: walking at 4 km.h(-1) (90 min) and 6 km.h(-1) (30 min or to fatigue). Field-based trials were used to evaluate tactical battlefield movements (mobility) of soldiers (N = 31) under tropical conditions, and across functional tests of power, speed, agility, endurance, and balance. Finally, trials were conducted at a jungle training centre, with soldiers (N = 32) patrolling under tropical conditions (averaging 5 h). In the laboratory, work tolerance was reduced as protection increased, with deep-body temperature climbing relentlessly. However, the protective ensembles could be grouped into two equally stressful categories, each providing a different level of ballistic protection. This outcome was supported during the mobility trials, with the greatest performance decrement evident during fire and movement simulations, as the ensemble mass was increased (-2.12%.kg(-1)). The jungle patrol trials similarly supported this outcome. Therefore, although ballistic protection does increase physiological strain, this research has provided a basis on which to determine how that strain can be balanced against the mission specific level of required personal protection. PMID- 26771199 TI - Cu(OAc)2-Mediated Reaction of C60 with Ureas for the Preparation of Fulleroimidazolidinones. AB - The Cu(OAc)2-mediated intermolecular diamination reaction of C60 with ureas allows the concise and efficient preparation of fulleroimidazolidinones involving the cleavage of two N-H bonds and formation of two C-N bonds. Both dialkylated and diarylated fulleroimidazolidinones can be synthesized using this method. PMID- 26771200 TI - Harnessing the Cancer Radiation Therapy by Lanthanide-Doped Zinc Oxide Based Theranostic Nanoparticles. AB - In this paper, doping of europium (Eu) and gadolinium (Gd) as high-Z elements into zinc oxide (ZnO) nanoparticles (NPs) was designed to optimize restricted energy absorption from a conventional radiation therapy by X-ray. Gd/Eu-doped ZnO NPs with a size of 9 nm were synthesized by a chemical precipitation method. The cytotoxic effects of Eu/Gd-doped ZnO NPs were determined using MTT assay in L929, HeLa, and PC3 cell lines under dark conditions as well as exposure to ultraviolet, X-ray, and gamma radiation. Doped NPs at 20 MUg/mL concentration under an X-ray dose of 2 Gy were as efficient as 6 Gy X-ray radiation on untreated cells. It is thus suggested that the doped NPs may be used as photoinducers to increase the efficacy of X-rays within the cells, consequently, cancer cell death. The doped NPs also could reduce the received dose by normal cells around the tumor. Additionally, we evaluated the diagnostic efficacy of doped NPs as CT/MRI nanoprobes. Results showed an efficient theranostic nanoparticulate system for simultaneous CT/MR imaging and cancer treatment. PMID- 26771201 TI - Enhanced Single Seed Trait Predictions in Soybean (Glycine max) and Robust Calibration Model Transfer with Near-Infrared Reflectance Spectroscopy. AB - Single seed near-infrared reflectance (NIR) spectroscopy predicts soybean (Glycine max) seed quality traits of moisture, oil, and protein. We tested the accuracy of transferring calibrations between different single seed NIR analyzers of the same design by collecting NIR spectra and analytical trait data for globally diverse soybean germplasm. X-ray microcomputed tomography (MUCT) was used to collect seed density and shape traits to enhance the number of soybean traits that can be predicted from single seed NIR. Partial least-squares (PLS) regression gave accurate predictive models for oil, weight, volume, protein, and maximal cross-sectional area of the seed. PLS models for width, length, and density were not predictive. Although principal component analysis (PCA) of the NIR spectra showed that black seed coat color had significant signal, excluding black seeds from the calibrations did not impact model accuracies. Calibrations for oil and protein developed in this study as well as earlier calibrations for a separate NIR analyzer of the same design were used to test the ability to transfer PLS regressions between platforms. PLS models built from data collected on one NIR analyzer had minimal differences in accuracy when applied to spectra collected from a sister device. Model transfer was more robust when spectra were trimmed from 910 to 1679 nm to 955-1635 nm due to divergence of edge wavelengths between the two devices. The ability to transfer calibrations between similar single seed NIR spectrometers facilitates broader adoption of this high throughput, nondestructive, seed phenotyping technology. PMID- 26771202 TI - Urea-Functionalized Self-Assembled Molecular Prism for Heterogeneous Catalysis in Water. AB - Reaction of a ditopic urea "strut" (L1) with cis-(tmen)Pd(NO3)2 yielded a [3+3] self-assembled molecular triangle (T) [L1 = 1,4-di(4-pyridylureido)benzene; tmen = N,N,N',N'-tetramethylethane-1,2-diamine]. Replacing cis-(tmen)Pd(NO3)2 in the above reaction with an equimolar mixture of Pd(NO3)2 and a clip-type donor (L2) yielded a template-free multicomponent 3D trigonal prism (P) decorated with multiple urea moieties [L2 = 3,3'-(1H-1,2,4-triazole-3,5-diyl)dipyridine]. This prism (P) was characterized by NMR spectroscopy, and the structure was confirmed by X-ray crystallography. The P was employed as an effective hydrogen-bond-donor catalyst for Michael reactions of a series of water-insoluble nitro-olefins in an aqueous medium. The P showed better catalytic activity compared to the urea-based ligand L1 and the triangle T. Moreover, the confined nanospace of P in addition to large product outlet windows makes this 3D architecture a perfect molecular vessel to catalyze Diels-Alder reactions of 9-hydroxymethylanthracene with N substituted maleimide in the aqueous medium. The present results demonstrate new observations on catalytic aqueous Diels-Alder and Michael reactions in heterogeneous fashion employing a discrete 3D architecture of Pd(II). The prism was recycled by simple filtration and reused several times without significant loss of activity. PMID- 26771203 TI - Cell Penetrant Inhibitors of the KDM4 and KDM5 Families of Histone Lysine Demethylases. 2. Pyrido[3,4-d]pyrimidin-4(3H)-one Derivatives. AB - Following the discovery of cell penetrant pyridine-4-carboxylate inhibitors of the KDM4 (JMJD2) and KDM5 (JARID1) families of histone lysine demethylases (e.g., 1), further optimization led to the identification of non-carboxylate inhibitors derived from pyrido[3,4-d]pyrimidin-4(3H)-one. A number of exemplars such as compound 41 possess interesting activity profiles in KDM4C and KDM5C biochemical and target-specific, cellular mechanistic assays. PMID- 26771205 TI - Driving Forces for Oppositely Charged Polyion Association in Aqueous Solutions: Enthalpic, Entropic, but Not Electrostatic. AB - Driving forces for association between oppositely charged biological or synthetic polymers in aqueous solution have long been identified as electrostatic in origin. This attraction is broken down into an entropic component, due to loss of counterions, and an enthalpic component, stemming from Coulombic attraction between opposite charges. While the balance between entropic and enthalpic contributions shifts according to the conditions, the presence of exotherms or endotherms on mixing, though small, are viewed as signatures of Coulombic interactions which support theories of polyelectrolyte association rooted in continuum electrostatics. Here, a head-to-head comparison is made between mechanisms based on electrostatics and those based on specific ion pairing, or ion exchange. Using a Hofmeister series of counterions for a common polycation, poly(diallyldimethylammonium), enthalpy changes on association with poly(styrenesulfonate) are shown to derive from changes in water perturbation, revealed by Raman scattering studies of water O-H vibrations. The free energy for complexation is almost completely entropic over all salt concentrations. PMID- 26771204 TI - Semiempirical Quantum-Chemical Orthogonalization-Corrected Methods: Theory, Implementation, and Parameters. AB - Semiempirical orthogonalization-corrected methods (OM1, OM2, and OM3) go beyond the standard MNDO model by explicitly including additional interactions into the Fock matrix in an approximate manner (Pauli repulsion, penetration effects, and core-valence interactions), which yields systematic improvements both for ground state and excited-state properties. In this Article, we describe the underlying theoretical formalism of the OMx methods and their implementation in full detail, and we report all relevant OMx parameters for hydrogen, carbon, nitrogen, oxygen, and fluorine. For a standard set of mostly organic molecules commonly used in semiempirical method development, the OMx results are found to be superior to those from standard MNDO-type methods. Parametrized Grimme-type dispersion corrections can be added to OM2 and OM3 energies to provide a realistic treatment of noncovalent interaction energies, as demonstrated for the complexes in the S22 and S66*8 test sets. PMID- 26771206 TI - Black Phosphorus-Zinc Oxide Nanomaterial Heterojunction for p-n Diode and Junction Field-Effect Transistor. AB - Black phosphorus (BP) nanosheet is two-dimensional (2D) semiconductor with distinct band gap and attracting recent attention from researches because it has some similarity to gapless 2D semiconductor graphene in the following two aspects: single element (P) for its composition and quite high mobilities depending on its fabrication conditions. Apart from several electronic applications reported with BP nanosheet, here we report for the first time BP nanosheet-ZnO nanowire 2D-1D heterojunction applications for p-n diodes and BP gated junction field effect transistors (JFETs) with n-ZnO channel on glass. For these nanodevices, we take advantages of the mechanical flexibility of p-type conducting of BP and van der Waals junction interface between BP and ZnO. As a result, our BP-ZnO nanodimension p-n diode displays a high ON/OFF ratio of ~10(4) in static rectification and shows kilohertz dynamic rectification as well while ZnO nanowire channel JFET operations are nicely demonstrated by BP gate switching in both electrostatics and kilohertz dynamics. PMID- 26771207 TI - Equatorial atmospheric Kelvin waves during El Nino episodes and their effect on stratospheric QBO. AB - Equatorial atmospheric Kelvin waves are investigated during a positive El Nino Southern Oscillation (ENSO) episode using temperature data retrieved from GPS Radio Occultation (RO) observations of FORMOSAT-3/COSMIC during the period from August 2006 to December 2013. Enhanced Kelvin wave amplitudes are observed during the El Nino episode of 2009-2010 and it is also observed that these amplitudes correlate with the Nino 3.4 index and also with outgoing longwave radiation and trade wind index. This study indicates that the enhanced equatorial atmospheric Kelvin wave amplitudes might be produced by geophysical processes that were involved in the onset and development of the El Nino episode. Further, easterly winds above the tropopause during this period favored the vertically upward propagation of these waves that induced a fast descending westerly regime by the end of 2010, where the zero-wind line is observed to take only 5 months to descend from 10 to 50 hPa. The current study presents observational evidence of enhanced Kelvin wave amplitudes during El Nino that has affected the stratospheric quasi-biennial oscillation (QBO) through wave-mean flow interactions. Earlier El Nino episodes of 1987 and 1998 are also qualitatively investigated, using reanalysis data. It is found that there might have been an enhancement in the equatorial Kelvin wave amplitudes during almost all El Nino episodes, however, an effect of a fast descending westerly is observed in the QBO only when the ambient zonal winds in the lower stratosphere favor the upward propagation of the Kelvin waves and consequently they interact with the mean flow. This study indicates that the El Nino and QBO are not linearly related and wave mean flow interactions play a very important role in connecting these two geophysical phenomena. PMID- 26771208 TI - Mapping the groundwater vulnerability for pollution at the pan African scale. AB - We estimated vulnerability and pollution risk of groundwater at the pan-African scale. We therefore compiled the most recent continental scale information on soil, land use, geology, hydrogeology and climate in a Geographical Information System (GIS) at a resolution of 15 km * 15 km and at the scale of 1:60,000,000. The groundwater vulnerability map was constructed by means of the DRASTIC method. The map reveals that groundwater is highly vulnerable in Central and West Africa, where the watertable is very low. In addition, very low vulnerability is found in the large sedimentary basins of the African deserts where groundwater is situated in very deep aquifers. The groundwater pollution risk map is obtained by overlaying the DRASTIC vulnerability map with land use. The northern, central and western part of the African continent is dominated by high pollution risk classes and this is very strongly related to shallow groundwater systems and the development of agricultural activities. Subsequently, we performed a sensitivity analysis to evaluate the relative importance of each parameter on groundwater vulnerability and pollution risk. The sensitivity analysis indicated that the removal of the impact of vadose zone, the depth of the groundwater, the hydraulic conductivity and the net recharge causes a large variation in the mapped vulnerability and pollution risk. The mapping model was validated using nitrate concentration data of groundwater as a proxy of pollution risk. Pan-African concentration data were inferred from a meta-analysis of literature data. Results shows a good match between nitrate concentration and the groundwater pollution risk classes. The pan African assessment of groundwater vulnerability and pollution risk is expected to be of particular value for water policy and for designing groundwater resources management programs. We expect, however, that this assessment can be strongly improved when better pan African monitoring data related to groundwater pollution will be integrated in the assessment methodology. PMID- 26771210 TI - Dynamic Organization of Myristoylated Src in the Live Cell Plasma Membrane. AB - The spatial organization of lipid-anchored proteins in the plasma membrane directly influences cell signaling, but measuring such organization in situ is experimentally challenging. The canonical oncogene, c-Src, is a lipid anchored protein that plays a key role in integrin-mediated signal transduction within focal adhesions and cell-cell junctions. Because of its activity in specific plasma membrane regions, structural motifs within the protein have been hypothesized to play an important role in its subcellular localization. This study used a combination of time-resolved fluorescence fluctuation spectroscopy and super-resolution microscopy to quantify the dynamic organization of c-Src in live cell membranes. Pulsed-interleaved excitation fluorescence cross-correlation spectroscopy (PIE-FCCS) showed that a small fraction of c-Src transiently sorts into membrane clusters that are several times larger than the monomers. Photoactivated localization microscopy (PALM) confirmed that c-Src partitions into clusters with low probability and showed that the characteristic size of the clusters is 10-80 nm. Finally, time-resolved fluorescence anisotropy measurements were used to quantify the rotational mobility of c-Src to determine how it interacts with its local environment. Taken together, these results build a quantitative description of the mobility and clustering behavior of the c-Src nonreceptor tyrosine kinase in the live cell plasma membrane. PMID- 26771209 TI - Synthesis and Evaluation of [(18)F]RAGER: A First Generation Small-Molecule PET Radioligand Targeting the Receptor for Advanced Glycation Endproducts. AB - The receptor for advanced glycation endproducts (RAGE) is a 35 kDa transmembrane receptor that belongs to the immunoglobulin superfamily of cell surface molecules. Its role in Alzheimer's disease (AD) is complex, but it is thought to mediate influx of circulating amyloid-beta into the brain as well as amplify Abeta-induced pathogenic responses. RAGE is therefore of considerable interest as both a diagnostic and a therapeutic target in AD. Herein we report the synthesis and preliminary preclinical evaluation of [(18)F]RAGER, the first small molecule PET radiotracer for RAGE (Kd = 15 nM). Docking studies proposed a likely binding interaction between RAGE and RAGER, [(18)F]RAGER autoradiography showed colocalization with RAGE identified by immunohistochemistry in AD brain samples, and [(18)F]RAGER microPET confirmed CNS penetration and increased uptake in areas of the brain known to express RAGE. This first generation radiotracer represents initial proof-of-concept and a promising first step toward quantifying CNS RAGE activity using PET. However, there were high levels of nonspecific [(18)F]RAGER binding in vitro, likely due to its high log P (experimental log P = 3.5), and rapid metabolism of [(18)F]RAGER in rat liver microsome studies. Therefore, development of second generation ligands with improved imaging properties would be advantageous prior to anticipated translation into clinical PET imaging studies. PMID- 26771211 TI - Lithographic Microfabrication of a 16-Electrode Array on a Probe Tip for High Spatial Resolution Electrochemical Localization of Exocytosis. AB - We report the lithographic microfabrication of a movable thin film microelectrode array (MEA) probe consisting of 16 platinum band electrodes placed on top of a supporting borosilicate glass substrate. These 1.2 MUm wide electrodes were tightly packed and positioned parallel in two opposite rows within a 20 MUm * 25 MUm square area and with a distance less than 10 MUm from the edge of the glass substrate. We demonstrate the ability to control and place the probe in close proximity to the surface of adherent bovine chromaffin cells and to amperometrically record single exocytosis release events with high spatiotemporal resolution. The two-dimensional position of single exocytotic events occurring in the center gap area separating the two rows of MEA band electrodes and that were codetected by electrodes in both rows was determined by analysis of the fractional detection of catecholamine released between electrodes and exploiting random walk simulations. Hence, two-dimensional electrochemical imaging recording of exocytosis release between the electrodes within this area was achieved. Similarly, by modeling the current spikes codetected by parallel adjacent band electrodes positioned in the same electrode row, a one-dimensional imaging of exocytosis with submicrometer resolution was accomplished within the area. The one- and two-dimensional electrochemical imaging using the MEA probe allowed for high spatial resolution of exocytosis activity and revealed heterogeneous release of catecholamine at the chromaffin cell surface. PMID- 26771212 TI - Use of elephant grass (Pennisetum purpureum) acid hydrolysate for microbial oil production by Trichosporon cutaneum. AB - Elephant grass (Pennisetum purpureum) dilute acid hydrolysate contains 34.6 g/L total sugars. The potential of lipid production by oleaginous yeast Trichosporon cutaneum grown on elephant grass acid hydrolysate was investigated for the first time. During the fermentation process on the elephant grass acid hydrolysate, glucose, xylose, and arabinose could be well utilized as carbon sources by T. cutaneum. Interestingly, xylose was almost no use before glucose was consumed completely. This illustrated that simultaneous saccharification of xylose and glucose by T. cutaneum did not occur on elephant grass acid hydrolysate. The highest biomass, lipid content, lipid yield, and lipid coefficient of T. cutaneum were measured after the sixth day of fermentation and were 22.76 g/L, 24.0%, 5.46 g/L, and 16.1%, respectively. Therefore, elephant grass is a promising raw material for microbial oil production by T. cutaneum. PMID- 26771214 TI - Ranting in 2016: A Medical System in Crisis. PMID- 26771215 TI - Volatile organic compounds at two oil and natural gas production well pads in Colorado and Texas using passive samplers. AB - A pilot study was conducted in application of the U.S. Environmental Protection Agency (EPA) Methods 325A/B variant for monitoring volatile organic compounds (VOCs) near two oil and natural gas (ONG) production well pads in the Texas Barnett Shale formation and Colorado Denver-Julesburg Basin (DJB), along with a traffic-dominated site in downtown Denver, CO. As indicated in the EPA method, VOC concentrations were measured for 14-day sampling periods using passive diffusive tube samplers with Carbopack X sorbent at fenceline perimeter and other locations. VOCs were significantly higher at the DJB well pad versus the Barnett well pad and were likely due to higher production levels at the DJB well pad during the study. Benzene and toluene were significantly higher at the DJB well pad versus downtown Denver. Except for perchloroethylene, VOCs measured at passive sampler locations (PSs) along the perimeter of the Barnett well pad were significantly higher than PSs farther away. At the DJB well pad, most VOC concentrations, except perchloroethylene, were significantly higher prior to operational changes than after these changes were made. Though limited, the results suggest passive samplers are precise (duplicate precision usually <=10%) and that they can be useful to assess spatial gradients and operational conditions at well pad locations over time-integrated periods. IMPLICATIONS: Recently enacted EPA Methods 325A/B use passive-diffusive tube samplers to measure benzene at multiple fenceline locations at petrochemical refineries. This pilot study presents initial data demonstrating the utility of Methods 325A/B for monitoring at ONG facilities. Measurements revealed elevated concentrations reflective of production levels and spatial gradients of VOCs relative to source proximity at the Barnett well pad, as well as operational changes at the DJB well pad. Though limited, these findings indicate that Methods 325A/B can be useful in application to characterize VOCs at well pad boundaries. PMID- 26771216 TI - Content Validity for a Child Care Self-assessment Tool: Creating Healthy Eating Environments Scale (CHEERS). AB - The purpose of this project was to develop and content validate both a formative and summative self-assessment scale designed to measure the nutrition and physical activity environment in community-based child care programs. The study followed a mixed-method modified Ebel procedure. An expert group with qualifications in nutrition, physical activity, and child care were recruited for content validation. The survey was subjected to expert review through digital communication followed by a face-to-face validation meeting. To establish consensus for content validity beyond the standard error of proportion (P < 0.05) the content validity index (CVI) required was >=0.78. Of the initial 64 items, 44 scored an acceptable CVI for inclusion. The remaining items were discussed, missing concepts identified, and a final CVI employed to determine inclusion. The final tool included 62 items with 5 subscales: food served, healthy eating program planning, healthy eating environment, physical activity environment, and healthy body image environment. Content validation is an integral step in scale development that is often overlooked or poorly carried out. Initial content validity of this scale has been established and will be of value to researchers and practitioners interested in conducting healthy eating interventions in child care. PMID- 26771213 TI - Exome Array Analysis Identifies a Common Variant in IL27 Associated with Chronic Obstructive Pulmonary Disease. AB - RATIONALE: Chronic obstructive pulmonary disease (COPD) susceptibility is in part related to genetic variants. Most genetic studies have been focused on genome wide common variants without a specific focus on coding variants, but common and rare coding variants may also affect COPD susceptibility. OBJECTIVES: To identify coding variants associated with COPD. METHODS: We tested nonsynonymous, splice, and stop variants derived from the Illumina HumanExome array for association with COPD in five study populations enriched for COPD. We evaluated single variants with a minor allele frequency greater than 0.5% using logistic regression. Results were combined using a fixed effects meta-analysis. We replicated novel single-variant associations in three additional COPD cohorts. MEASUREMENTS AND MAIN RESULTS: We included 6,004 control subjects and 6,161 COPD cases across five cohorts for analysis. Our top result was rs16969968 (P = 1.7 * 10(-14)) in CHRNA5, a locus previously associated with COPD susceptibility and nicotine dependence. Additional top results were found in AGER, MMP3, and SERPINA1. A nonsynonymous variant, rs181206, in IL27 (P = 4.7 * 10(-6)) was just below the level of exome-wide significance but attained exome-wide significance (P = 5.7 * 10(-8)) when combined with results from other cohorts. Gene expression datasets revealed an association of rs181206 and the surrounding locus with expression of multiple genes; several were differentially expressed in COPD lung tissue, including TUFM. CONCLUSIONS: In an exome array analysis of COPD, we identified nonsynonymous variants at previously described loci and a novel exome-wide significant variant in IL27. This variant is at a locus previously described in genome-wide associations with diabetes, inflammatory bowel disease, and obesity and appears to affect genes potentially related to COPD pathogenesis. PMID- 26771217 TI - Efficacy of Antibody Delivery to the Retina and Optic Nerve by Topical Administration. AB - PURPOSE: The purpose of this study was to determine whether nonspecific and ICAM 1-specific IgG1 antibodies can accumulate in the rat retina following topical application, and to develop a model system to show that antibodies that reach the posterior segment retain their pharmacological properties. METHODS: Eye drops containing mouse IgG1 or anti-ICAM-1 and the permeation enhancer saponin were topically applied to the eyes of Lewis rats. Concentrations were determined in the retina and optic nerve up to 30 min later using ELISA assays. We also developed an in vitro model to assess the pharmacologic activity of topically delivered antibodies in the retina based on the requirement of human umbilical vein endothelial cells (HUVECs) for vascular endothelial growth factor (VEGF) for growth. Rat eyes were treated with anti-VEGF antibody in the same manner as above; their retinas, harvested shortly thereafter, were added to HUVECs cultured in VEGF-containing media. The effect of these retinal homogenates on HUVEC proliferation was then assessed. RESULTS: Significant concentrations of IgG1 were detected in the optic nerve (P < 0.001) and retina (P < 0.0001) following topical application. Anti-ICAM-1 antibody also accumulated in the retina after topical application, though levels were less than those seen with IgG1 probably owing to a lower starting concentration. Retinal homogenates from eyes treated with anti VEGF antibody significantly suppressed HUVEC proliferation (P < 0.0001). CONCLUSIONS: Our data support the contention that topically applied antibodies can accumulate in the posterior segment, and suggest they retain their pharmacological properties. PMID- 26771218 TI - Transovarial Transmission of Co-Existing Orientia tsutsugamushi Genotypes in Laboratory-Reared Leptotrombidium imphalum. AB - The co-evolution of Orientia tsutsugamushi and its vector/host Leptotrombidium mites is important for this bacterium to survive and exist in its environment. The data in this study demonstrated that O. tsutsugamushi has adapted to take advantage of the parasitic nature of the host's larval stage and thus increase its chance of transmission to a vertebrate host and potentially to other vector mites by increasing its density at the time of transmission. Our data demonstrated that during the larval stage the density of O. tsutsugamushi was at its highest level compared to other life stages (Kruskal-Wallis, p < 0.0001). We further revealed that the different O. tsutsugamushi 56-kDa type-specific antigen (TSA) genotypes within the mite were maintained and preserved during transovarial transmission from the Leptotrombidium imphalum, lines Li-3 and Li-5. No sequence difference of 56-kDa TSA gene (variable domain I-III, 765 bp) was observed between the UT302-like genotype found in mothers and their offspring (100% identity). However, one or two nonsynonymous mutations in the 56-kDa TSA gene were observed in the Karp-like genotypes found in the F1 offspring with a percent difference ranging from 0.13 to 0.26 for nucleotide sequences and from 0.39 to 0.78 for amino acid sequences. Additionally, the composition of co-existing O. tsutsugamushi genotypes was maintained in L. imphalum lines through transsovarial and transstadial transmission processes; however, the proportion of these genotypes in each stage varied (larva, nymph, adult). These results show some of the key characteristics of O. tsutsugamushi maintenance within and transmission among its vector/host L. imphalum. PMID- 26771219 TI - Structure, NMR and Electronic Spectra of [m.n]Paracyclophanes with Varying Bridges Lengths (m, n = 2-4). AB - Extending our earlier studies on cyclophanes, we here report the structure, chemical shifts, spin-spin coupling constants, absorption and emission properties of [m.n]paracyclophanes, m, n = 2-4, obtained using a combination of experimental and computational techniques. Accurate values of proton chemical shifts as well as of JHH for the bridges are determined. The experimental chemical shifts, coupling constants, absorption and emission wavelengths are satisfactorily reproduced using density functional theory calculations, using both the B3LYP and omegaB97X-D functionals. The geometries predicted using a functional that includes dispersion corrections (omegaB97X-D) are in a better agreement with available experimental values than those obtained using the B3LYP method. Up to 8 UV-vis absorption/emission bands have been observed (or anticipated in the region below 200 nm) and assigned on the basis of quantum-chemical calculations. Optimized excited-state geometries showed that the distances between the aromatic bridgehead carbon atoms of all the [m.n]paracyclophanes in the excited state decrease compared to the ground-state geometries by ca. 0.2-0.9 A, the largest being for [4.4]paracyclophane, though the rather large differences in the calculated emission wavelength compared to experiment cast some doubts on the accuracy of the excited-state geometries. PMID- 26771220 TI - A Comparative Study of Power and Sample Size Calculations for Multivariate General Linear Models. AB - Repeated measures and longitudinal studies arise often in social and behavioral science research. During the planning stage of such studies, the calculations of sample size are of particular interest to the investigators and should be an integral part of the research projects. In this article, we consider the power and sample size calculations for normal outcomes within the framework of multivariate general linear models that represent the most fundamental method for the analysis of repeated measures and longitudinal data. Direct extensions of the existing generalized estimating equation and likelihood-based approaches are presented. The major feature of the proposed modification is the accommodation of both fixed and random models. A child development example is provided to illustrate the usefulness of the methods. The adequacies of the sample size formulas are evaluated through Monte Carlo simulation study. PMID- 26771221 TI - Sample Size Tables for Correlation Analysis with Applications in Partial Correlation and Multiple Regression Analysis. AB - Tables for selecting sample size in correlation studies are presented. Some of the tables allow selection of sample size so that r (or r2, depending on the statistic the researcher plans to interpret) will be within a target interval around the population parameter with probability .95. The intervals are +/-.05, ±.10, ±.15, and ±.20 around the population parameter. Other tables allow selection of sample size to meet a target for power when conducting a .05 test of the null hypothesis that a correlation coefficient is zero. Applications of the tables in partial correlation and multiple regression analyses are discussed. SAS and SPSS computer programs are made available to permit researchers to select sample size for levels of accuracy, probabilities, and parameter values and for Type I error rates other than those used in constructing the tables. PMID- 26771222 TI - Assessing the Consequences of Using Self-report Data to Determine the Correlates of HIV Status: Conditional and Marginal Approaches. AB - This article examines whether relationships between individual characteristics and HIV status can be identified when self-report data are used as a proxy for HIV serotest results. The analyses use data obtained from HIV serotests and face to-face interviews with 7,256 out-of-treatment drug users in ten sites from 1992 to 1998. Relationships between 17 individual characteristics and HIV status (measured both by self-report and serotest results) were determined by (a) comparing and evaluating the fit of both standard and "nonstandard" loglinear models, and (b) evaluating the fit of marginal homogeneity models. The loglinear analyses showed that HIV serostatus was related to individual characteristics in 38 percent of the relationships. In most cases, the strength of the relationships between HIV status and individual characteristics did not differ when HIV status was measured with self-report data. PMID- 26771223 TI - Unrestricted Factor Analytic Procedures for Assessing Acquiescent Responding in Balanced, Theoretically Unidimensional Personality Scales. AB - This article describes and proposes an unrestricted factor analytic procedure to: (a) assess the dimensionality and structure of a balanced personality scale taking into account the potential effects of acquiescent responding, and (b) correct the individual trait estimates for acquiescence. The procedure can be considered as an extension of ten Berge's (1999) principal component-based approach, and is intended for scales that attempt to measure a single trait. First, the rationale of the procedure is described for the correlation and covariance cases, and the relations with an alternative restricted model are discussed. Next, additional criteria for supporting the proposed unrestricted solution are suggested. The procedure and the additional criteria are illustrated using empirical data. The usefulness of the procedure in applied personality measurement is discussed. PMID- 26771224 TI - Case-Deletion Diagnostics for Nonlinear Structural Equation Models. AB - In this article, a case-deletion procedure is proposed to detect influential observations in a nonlinear structural equation model. The key idea is to develop the diagnostic measures based on the conditional expectation of the complete-data log-likelihood function in the EM algorithm. An one-step pseudo approximation is proposed to reduce the computational burden. Building blocks in the diagnostic measures are computed via the observations generated by the MH algorithm. Results from a simulation study and an illustrative real example are presented. PMID- 26771225 TI - Factor Analysis at 100:Historical Developments and Future Directions. PMID- 26771226 TI - Controlled Study of Obesity Among Adolescents with Bipolar Disorder. AB - OBJECTIVE: Despite numerous studies regarding obesity (OB) in adult bipolar disorder (BP), there are few studies on this topic among adolescents. The current study attempts to extend the literature on prevalence and correlates of OB in adolescent BP by including control participants, and determining OB by direct measurement. METHODS: Participants were 75 treatment-seeking adolescents, ages 13 19 years, with BP-I, -II, or -not otherwise specified, and 47 adolescents without major psychiatric illness. Diagnoses and clinical characteristics were assessed using the Kiddie Schedule for Affective Disorders and Schizophrenia for School Age Children, Present and Lifetime version (KSADS-PL). Family psychiatric history was assessed using the Family History Screen. OB was defined as adjusted body mass index >=95th percentile. Variables associated with OB in univariate analyses informed variable selection for within-group logistic regression analysis among BP adolescents. RESULTS: BP participants had a significantly higher rate of OB (18%) compared to controls (4%; chi2 = 5.3; p = 0.02). BP remained a significant predictor for OB when controlling for race (odds ratio [OR] = 5.1, 95% confidence interval [CI] = 1.1-24.0, p = 0.04). In univariate analyses among BP adolescents, OB was significantly associated with suicide attempt, self-injurious behavior, and oppositional defiant disorder. In multivariable analyses, suicide attempt and antidepressants that were not selective serotonin reuptake inhibitors were significantly associated with OB. CONCLUSIONS: OB is excessively prevalent among adolescents with BP and is associated with proxies for illness severity, including suicide attempts. Additional research is warranted to identify strategies to prevent and treat OB among BP adolescents, and to elucidate processes underlying the elevated risk of suicide attempts. PMID- 26771227 TI - Mapping of Escherichia coli Sources Connected to Waterways in the Ruamahanga Catchment, New Zealand. AB - Rivers and streams in New Zealand are natural with free access and used by many people for swimming and fishing. However, pastoral farming with free grazing animals is a common land use in New Zealand and faecal microorganisms from them often end up in waterways. These microorganisms can seriously affect human and animal health if ingested. This paper describes spatial modeling using GIS of Escherichia coli sources in a large catchment (350 000 ha), the Ruamahanga. By examining the pathway of water over and through soils, it is possible to determine whether E. coli sources are connected to waterways or not. The map of E. coli sources connected to waterways provides useful context to those setting water quality limits. This approach avoids the complexity of modeling the fate and transport of E. coli in waterways, yet still permits the assessment of catchment-wide mitigation and best management practice. Fencing of waterways would minimize E. coli sources directly defecated to water and would reduce total E. coli sources by approximately 35%. Introduction of dung beetles would minimize sources connected to waterways by overland flow and would reduce total E. coli sources by approximately 35%. Construction of dairy effluent ponds would minimize sources connected to waterways through high bypass flow in soils and would reduce total E. coli sources by approximately 25%. PMID- 26771228 TI - One-Step Synthesis of Sulfonamides from N-Tosylhydrazones. AB - The first described reaction between N-tosylhydrazone and SO2 is reported to provide alkyl sulfonamides in the presence of various amines. In this procedurally simple method, hydrazones of both unsaturated aldehydes and ketones proceed in moderate to excellent yields. Primary and secondary aliphatic amines are accommodated in this reaction, which provides a novel route to sulfonamides. PMID- 26771229 TI - Omega-3 Polyunsaturated Fatty Acids Inhibited Tumor Growth via Preventing the Decrease of Genomic DNA Methylation in Colorectal Cancer Rats. AB - Omge-3 polyunsaturated fatty acids (PUFAs) exhibited significant effect in inhibiting various tumors. However, the mechanisms of its anticancer role have not been fully demonstrated. The declination of 5-methylcytosine (5 mC) was closely associated with poor prognosis of tumors. To explore whether omega-3 PUFAs influences on DNA methylation level in tumors, colorectal cancer (CRC) rat model were constructed using N-methyl phosphite nitrourea and omega-3 PUFAs were fed to part of the rats during tumor induction. The PUFAs contents in the rats of 3 experimental groups were measured using gas chromatography and 5 mC level were detected by liquid chromatography tandem mass spectrometry. The results showed that tumor incidence in omega-3 treated rats was much lower than in CRC model rats, which confirmed significant antitumor role of omega-3 PUFAs. Six PUFA members categorized to omega-3 and omega-6 families were quantified and the ratio of omega-6/omega-3 PUFAs was remarkably lower in omega-3 PUFAs treatment group than in CRC model group. 5 mC content in omega-3 PUFAs treated rats was higher than in CRC model rats, suggesting omega-3 PUFAs promoted 5 mC synthesis. Therefore, omega-3 PUFAs probably inhibited tumor growth via regulating DNA methylation process, which provided a novel anticancer mechanism of omega-3 PUFAs from epigenetic view. PMID- 26771230 TI - Moderate-intensity physical activity is independently associated with lower extremity muscle power in older women. AB - Skeletal muscle power is a salient determinant of physical function in older adults, but its relationship with habitual physical activity has not been well characterized. The aim of this study was to examine the association between moderate-intensity physical activity and lower-extremity muscle power in community-dwelling older women. Older women (n = 96, mean age = 73.9 +/- 5.6 years, mean body mass index = 26.5 +/- 4.7 kg/m(2)) underwent assessments for body composition via dual-energy X-ray absorptiometry and lower-extremity muscle power (watts) using the Nottingham power rig. The Community Health Activities Model Program for Seniors questionnaire was used to estimate weekly caloric expenditure in moderate-intensity physical activity (kcals/wk). Linear regression indicated that moderate-intensity physical activity was independently related to muscle power (standardized beta = 0.20, p = .03), and this relationship remained following adjustment for covariates. Analysis of covariance revealed that women in the highest tertile of volume of physical activity had significantly greater muscle power than those with the lowest volume (199.0 vs. 170.7 watts, p < .05). Moderate-intensity physical activity was independently associated with lower extremity muscle power in older women. Future intervention trials should determine if increasing habitual physical activity is associated with improvements in lower-extremity muscle power in older women. PMID- 26771231 TI - Human T-cell leukemia virus type 1-positive lymphomatoid papulosis. PMID- 26771232 TI - Dlx-2 and glutaminase upregulate epithelial-mesenchymal transition and glycolytic switch. AB - Most cancer cells depend on enhanced glucose and glutamine (Gln) metabolism for growth and survival. Oncogenic metabolism provides biosynthetic precursors for nucleotides, lipids, and amino acids; however, its specific roles in tumor progression are largely unknown. We previously showed that distal-less homeobox-2 (Dlx-2), a homeodomain transcription factor involved in embryonic and tumor development, induces glycolytic switch and epithelial-mesenchymal transition (EMT) by inducing Snail expression. Here we show that Dlx-2 also induces the expression of the crucial Gln metabolism enzyme glutaminase (GLS1), which converts Gln to glutamate. TGF-beta and Wnt induced GLS1 expression in a Dlx-2 dependent manner. GLS1 shRNA (shGLS1) suppressed in vivo tumor metastasis and growth. Inhibition of Gln metabolism by shGLS1, Gln deprivation, and Gln metabolism inhibitors (DON, 968 and BPTES) prevented Dlx-2-, TGF-beta-, Wnt-, and Snail-induced EMT and glycolytic switch. Finally, shDlx-2 and Gln metabolism inhibition decreased Snail mRNA levels through p53-dependent upregulation of Snail-targeting microRNAs. These results demonstrate that the Dlx-2/GLS1/Gln metabolism axis is an important regulator of TGF-beta/Wnt-induced, Snail dependent EMT, metastasis, and glycolytic switch. PMID- 26771233 TI - The probiotic Propionibacterium freudenreichii as a new adjuvant for TRAIL-based therapy in colorectal cancer. AB - TNF-Related Apoptosis-Inducing Ligand (TRAIL) is a well-known apoptosis inducer, which activates the extrinsic death pathway. TRAIL is pro-apoptotic on colon cancer cells, while not cytotoxic towards normal healthy cells. However, its clinical use is limited by cell resistance to cell death which occurs in approximately 50% of cancer cells. Short Chain Fatty Acids (SCFA) are also known to specifically induce apoptosis of cancer cells. In accordance, we have shown that food grade dairy propionibacteria induce intrinsic apoptosis of colon cancer cells, via the production and release of SCFA (propionate and acetate) acting on mitochondria. Here, we investigated possible synergistic effect between Propionibacterium freudenreichii and TRAIL. Indeed, we hypothesized that acting on both extrinsic and intrinsic death pathways may exert a synergistic pro apoptotic effect. Whole transcriptomic analysis demonstrated that propionibacterial supernatant or propionibacterial metabolites (propionate and acetate), in combination with TRAIL, increased pro-apoptotic gene expression (TRAIL-R2/DR5) and decreased anti-apoptotic gene expression (FLIP, XIAP) in HT29 human colon cancer cells. The revealed synergistic pro-apoptotic effect, depending on both death receptors (TRAIL-R1/DR4, TRAIL-R2/DR5) and caspases (caspase-8, -9 and -3) activation, was lethal on cancer cells but not on normal human intestinal epithelial cells (HIEC), and was inhibited by Bcl-2 expression. Finally, milk fermented by P. freudenreichii induced HT29 cells apoptosis and enhanced TRAIL cytotoxic activity, as did P. freudenreichii DMEM culture supernatants or its SCFA metabolites. These results open new perspectives for food grade P. freudenreichii-containing products in order to potentiate TRAIL based cancer therapy in colorectal cancer. PMID- 26771234 TI - BRAF inhibitor resistance enhances vulnerability to arginine deprivation in melanoma. AB - BRAF inhibitor (BRAFi) has been used for treatment of melanomas harboring V600E mutation. Despite a high initial response rate, resistance to BRAFi is inevitable. Here, we demonstrate that BRAFi-resistant (BR) melanomas are susceptible to arginine deprivation due to inability to initiate re-expression of argininosuccinate synthetase (ASS1, a key enzyme for arginine synthesis) as well as ineffective autophagy. Autophagy and ASS1 re-expression are known to protect melanoma cells from cell death upon arginine deprivation. When melanoma cells become BR cells by long-term in vitro incubation with BRAFi, c-Myc-mediated ASS1 re-expression and the levels of autophagy-associated proteins (AMPK-alpha1 and Atg5) are attenuated. Furthermore, our study uncovers that downregulation of deubiquitinase USP28 which results in more active c-Myc degradation via ubiquitin proteasome machinery is the primary mechanism for inability to re-express ASS1 upon arginine deprivation in BR cells. Overexpression of USP28 in BR cells enhances c-Myc expression and hence increases ASS1 transcription upon arginine deprivation, and consequently leads to cell survival. On the other hand, overexpression of Atg5 or AMPK-alpha1 in BR cells can redirect arginine deprivation-induced apoptosis toward autophagy. The xenograft models also confirm that BR tumors possess lower expression of ASS1 and are hypersensitive to arginine deprivation. These biochemical changes in BRAFi resistance which make them vulnerable to arginine deprivation can be exploited for the future treatment of BR melanoma patients. PMID- 26771235 TI - Tissue transglutaminase-2 promotes gastric cancer progression via the ERK1/2 pathway. AB - Gastric cancer (GC) is one of the most common tumors worldwide and involves extensive local tumor invasion, metastasis, and poor prognosis. Understanding mechanisms regulating progression of GC is necessary for developing effective therapeutic strategies. Tissue transglutaminase-2 (TG2), a multifunctional member of the transglutaminase family, has been shown to be critical for tumor initiation and progression. However, how TG2 promotes the progression of GC is unknown. We report that TG2 was highly expressed in GC tissues and positively associated with depth of tumor invasion and late TNM stage. With gain- and loss of-function approaches, we observed that TG2 promoted GC cell proliferation, migration, invasion, as well as tumorigenesis and peritoneal metastasis in vivo. These events were associated with the ERK1/2 pathway activation and an ERK1/2 inhibitor (U0126) inhibited cell proliferation, migration, and invasion induced by overexpression of TG2. In summary, TG2 contributes to tumorigenesis and progression of GC by activating the ERK1/2 signaling pathway and is a potential therapeutic target of metastatic gastric cancer. PMID- 26771238 TI - Long duration measurements of whole-body vibration exposures associated with surface coal mining equipment compared to previous short-duration measurements. AB - Previous measurements of whole-body vibration associated with earth-moving equipment at surface coal mines have highlighted the significance of the hazard. Considerable variability in measurement amplitudes, even within the same equipment type operated at the same site, has been noted. However, the measurements have previously been undertaken for relatively short durations. Fifty-nine measurements were collected from a range of earth-moving equipment in operation at a surface coal mine. Measurement durations ranged from 100-460 min (median = 340 min). The results indicate that the measurements previously observed are not an artifact of the relatively short durations and confirm that operators of dozers and off-road haul trucks, in particular, are frequently exposed to vertical whole-body vibration levels which lie within, or above, the Health Guidance Caution Zone defined by ISO2631.1. Further investigations are justified to identify opportunities for reducing operators' exposure to high amplitude vibrations. PMID- 26771236 TI - Artemisinin-derived dimer ART-838 potently inhibited human acute leukemias, persisted in vivo, and synergized with antileukemic drugs. AB - Artemisinins, endoperoxide-containing molecules, best known as antimalarials, have potent antineoplastic activity. The established antimalarial, artesunate (AS), and the novel artemisinin-derived trioxane diphenylphosphate dimer 838 (ART 838) inhibited growth of all 23 tested acute leukemia cell lines, reduced cell proliferation and clonogenicity, induced apoptosis, and increased intracellular levels of reactive oxygen species (ROS). ART-838 was 88-fold more potent that AS in vitro, inhibiting all leukemia cell lines at submicromolar concentrations. Both ART-838 and AS cooperated with several established antileukemic drugs and newer kinase inhibitors to inhibit leukemia cell growth. ART-838 had a longer plasma half-life than AS in immunodeficient NOD-SCID-IL2Rgnull (NSG) mice, remaining at effective antileukemic concentrations for >8h. Intermittent cycles of ART-838 inhibited growth of acute leukemia xenografts and primagrafts in NSG mice, at higher potency than AS. Based on these preclinical data, we propose that AS, with its established low toxicity and low cost, and ART-838, with its higher potency and longer persistence in vivo, should be further developed toward integration into antileukemic regimens. PMID- 26771237 TI - ZYG11A serves as an oncogene in non-small cell lung cancer and influences CCNE1 expression. AB - By analyzing The Cancer Genome Atlas (TCGA) database, we identified ZYG11A as a potential oncogene. We determined the expression of ZYG11A in NSCLC tissues and explored its clinical significance. And also evaluated the effects of ZYG11A on NSCLC cell proliferation, migration, and invasion both in vitro and in vivo. Our results show that ZYG11A is hyper-expressed in NSCLC tissues compared to adjacent normal tissues, and increased expression of ZYG11A is associated with a poor prognosis (HR: 2.489, 95%CI: 1.248-4.963, p = 0.010). ZYG11A knockdown induces cell cycle arrest and inhibits proliferation, migration, and invasion of NSCLC cells. ZYG11A knockdown also results in decreased expression of CCNE1. Over expression of CCNE1 in cells with ZYG11A knockdown restores their oncogenic activities. Our data suggest that ZYG11A may serve as a novel oncogene promoting tumorigenicity of NSCLC cells by inducing cell cycle alterations and increasing CCNE1 expression. PMID- 26771239 TI - Fundus Autofluorescence and SD-OCT Document Rapid Progression in Autosomal Dominant Vitreoretinochoroidopathy (ADVIRC) Associated with a c.256G > A Mutation in BEST1. AB - PURPOSE: To report the variability of clinical findings, rapid concentric progression, and successful treatment of macular edema in autosomal dominant vitreoretinochoroidopathy (ADVIRC) associated with a heterozygous c.256G > A missense mutation in the bestrophin-1 (BEST1) gene. METHODS: Three affected members of a four-generation ADVIRC family were examined with fundus autofluorescence (FAF), near-infrared autofluorescence (NIA) and spectral domain optical coherence tomography (SD-OCT). Direct sequence analysis of coding and flanking intronic regions of the BEST1 gene was performed. RESULTS: Disease manifestations presented with high variability with visual problems manifesting between 10 and 40 years of age. Two probands showed marked signs of peripheral degeneration, while this retinal area was not noticeably affected in the third. Cystoid macular edema was present in one proband, which responded to long-term treatment with topic dorzolamide with improved visual acuity. FAF and NIA revealed mid-peripheral retinal degeneration in areas that appeared normal on ophthalmoscopy. The full-field ERG was markedly reduced in two probands. Within a 5-year period a marked increase in concentric progression of degeneration including the posterior pole was documented with FAF, NIA and SD-OCT in one proband after the age of 63 years. Direct sequence analysis of the BEST1 gene revealed a heterozygous c.256G > A missense mutation in the three affected probands. CONCLUSION: The findings in this family emphasize the previously noted variability of clinical manifestations in BEST1-associated ADVIRC and the relevance of FAF and NIA imaging. Cystoid macular edema and vascular leakage can be successfully treated using dorzolamide. PMID- 26771240 TI - Neurocognitive Functioning and Treatment Outcome Following Detoxification Among Asian Alcohol-Dependent Inpatients. AB - BACKGROUND: The prevalence of alcohol use disorders in Asia is increasing and relapse among treated populations remains the norm, not the exception. The extent to which cognitive impairment influences clinical outcome remains unclear, with research dominated by studies of Caucasian populations. OBJECTIVES: This study examines behavioral and self-reported cognitive functioning in detoxified alcohol dependent (AD) patients in Singapore and its association with outcome. METHODS: The cognitive performance of 30 recently-detoxified AD inpatients and 30 demographically-matched controls was compared using visuospatial memory, working memory, set-shifting, planning and reflection impulsivity tests of the CANTAB(r), and self-reported dysexecutive symptoms and everyday cognitive difficulties. Patients' alcohol use and self-reported cognitive functioning were reassessed 3 months post-discharge. RESULTS: Compared to matched controls, AD inpatients exhibited significantly poorer fluid intelligence, visuospatial memory, working memory, set-shifting flexibility and planning/organization, but not reflection impulsivity. In support of Western studies, a significant proportion (three quarters) were "clinically impaired" on subtests. Significant reductions were observed in alcohol units, frequency and dependency scores at follow-up, though improvements in self-reported cognitive functioning were limited to abstainers. Baseline cognitive performance did not differentiate those who had abstained from alcohol and relapsed at follow-up. CONCLUSIONS/IMPORTANCE: Memory and executive functioning impairments were evident among Asian AD patients alongside self reported cognitive difficulties, thus cognitively demanding psychological interventions may have limited impact during early detoxification. Future studies can build on these findings, with larger samples and measurement of moderating and mediating factors to extend our understanding of how cognitive impairment influences outcome. PMID- 26771242 TI - Neural representation for object recognition in inferotemporal cortex. AB - We suggest that population representation of objects in inferotemporal cortex lie on a continuum between a purely structural, parts-based description and a purely holistic description. The intrinsic dimensionality of object representation is estimated to be around 100, perhaps with lower dimensionalities for object representations more toward the holistic end of the spectrum. Cognitive knowledge in the form of semantic information and task information feed back to inferotemporal cortex from perirhinal and prefrontal cortex respectively, providing high-level multimodal-based expectations that assist in the interpretation of object stimuli. Integration of object information across eye movements may also contribute to object recognition through a process of active vision. PMID- 26771241 TI - Compartmentalized Epidermal Activation of beta-Catenin Differentially Affects Lineage Reprogramming and Underlies Tumor Heterogeneity. AB - Wnt/beta-catenin activation in adult epidermis can induce new hair follicle formation and tumor development. We used lineage tracing to uncover the relative contribution of different stem cell populations. LGR6(+) and LRIG1(+) stem cells contributed to ectopic hair follicles formed in the sebaceous gland upon beta catenin activation, whereas LGR5(+) cells did not. Lgr6, but not Lrig1 or Lgr5, was expressed in a subpopulation of interfollicular epidermal cells that were competent to form new hair follicles. Oncogenic beta-catenin expression in LGR5(+) cells led to formation of pilomatricomas, while LRIG1(+) cells formed trichoadenomas and LGR6(+) cells formed dermatofibromas. Tumor formation was always accompanied by a local increase in dermal fibroblast density and transient extracellular matrix remodeling. However, each tumor had a distinct stromal signature in terms of immune cell infiltrate and expression of CD26 and CD44. We conclude that compartmentalization of epidermal stem cells underlies different responses to beta-catenin and skin tumor heterogeneity. PMID- 26771243 TI - Preliminary study on the variation of radon-222 inside greenhouse of Shouguang county, China. AB - Studies on radon have become the focus of indoor radiation. In this study, we chose greenhouse to be the study field, the research aims to: (1) explore the diurnal variation of radon concentration inside greenhouse in Shouguang county, China; (2) pre-analyze the relationship between radon concentration, temperature and relative humidity, and shed light on the radon behavior characteristic inside greenhouse; (3) verify the feasibility of calculating radon radiation dose by using short-period detected radon concentrations in typical months in Shouguang county. The following conclusions were drawn. Firstly, the average radon levels in typical months in Shouguang county are all much higher than that in ordinary dwellings in China, diurnal and seasonal variations in radon levels are observed inside greenhouse. Secondly, temperature and relative humidity may play a role indirectly through affecting soil moisture and other factors. The mechanism need to be further studied. Thirdly, radon concentrations detected in typical months are still useful in preliminary estimation of radon radiation dose for vegetable plant farmers in Shouguang county. PMID- 26771244 TI - The use of tree bark as long term biomonitor of (137)Cs deposition. AB - Airborne (137)Cs originated from the nuclear tests in the atmosphere and from the Chernobyl nuclear disaster was retained by the trees biomass and nowadays it can still be found in various concentrations in tree barks from Romania and other European countries. This study brings the first results of (137)Cs presence in tree bark from Romania on different considerations: (i) data dispersion in spruce and oak bark from NW, SW and central Romania, and the spatial variability of (137)Cs within oak and spruce bark from a natural protected forest area from Balvanyos area (Covasna County), known to be highly affected by the Chernobyl nuclear release; (ii) comparison of (137)Cs content in different tree bark species (oak, spruce, poplar and cherry); (iii) differences in (137)Cs concentrations with the bark depth layers and around the tree trunk; and (iv) comparison of mean (137)Cs values in spruce/oak bark from Romania with data from other European countries. PMID- 26771245 TI - Recent developments of 2-aminothiazoles in medicinal chemistry. AB - The 2-aminothiazole (2-AT) core is an active pharmacophore and used in medicinal chemistry and drug discovery research. A number of drugs with 2-AT core are in the market, e.g. Famotidine, Cefdinir, Meloxcam etc. Recently, 2-AT core has been explored for many more important therapeutic areas and identified new 2 aminothiazoles with anticancer, antitumor, antidiebatic and anticonvulsant activity. In this review, we discuss the newly identified and developed 2 aminothiazoles in recent years and their use in medicinal chemistry and pharmacology. PMID- 26771246 TI - Determination of fragrance content in perfume by Raman spectroscopy and multivariate calibration. AB - An alternative methodology is herein proposed for determination of fragrance content in perfumes and their classification according to the guidelines established by fine perfume manufacturers. The methodology is based on Raman spectroscopy associated with multivariate calibration, allowing the determination of fragrance content in a fast, nondestructive, and sustainable manner. The results were considered consistent with the conventional method, whose standard error of prediction values was lower than the 1.0%. This result indicates that the proposed technology is a feasible analytical tool for determination of the fragrance content in a hydro-alcoholic solution for use in manufacturing, quality control and regulatory agencies. PMID- 26771247 TI - Geometry-based vs. intensity-based medical image registration: A comparative study on 3D CT data. AB - Spatial alignment of Computed Tomography (CT) data sets is often required in numerous medical applications and it is usually achieved by applying conventional exhaustive registration techniques, which are mainly based on the intensity of the subject data sets. Those techniques consider the full range of data points composing the data, thus negatively affecting the required processing time. Alternatively, alignment can be performed using the correspondence of extracted data points from both sets. Moreover, various geometrical characteristics of those data points can be used, instead of their chromatic properties, for uniquely characterizing each point, by forming a specific geometrical descriptor. This paper presents a comparative study reviewing variations of geometry-based, descriptor-oriented registration techniques, as well as conventional, exhaustive, intensity-based methods for aligning three-dimensional (3D) CT data pairs. In this context, three general image registration frameworks were examined: a geometry-based methodology featuring three distinct geometrical descriptors, an intensity-based methodology using three different similarity metrics, as well as the commonly used Iterative Closest Point algorithm. All techniques were applied on a total of thirty 3D CT data pairs with both known and unknown initial spatial differences. After an extensive qualitative and quantitative assessment, it was concluded that the proposed geometry-based registration framework performed similarly to the examined exhaustive registration techniques. In addition, geometry-based methods dramatically improved processing time over conventional exhaustive registration. PMID- 26771248 TI - alpha/beta coiled coils. AB - Coiled coils are the best-understood protein fold, as their backbone structure can uniquely be described by parametric equations. This level of understanding has allowed their manipulation in unprecedented detail. They do not seem a likely source of surprises, yet we describe here the unexpected formation of a new type of fiber by the simple insertion of two or six residues into the underlying heptad repeat of a parallel, trimeric coiled coil. These insertions strain the supercoil to the breaking point, causing the local formation of short beta strands, which move the path of the chain by 120 degrees around the trimer axis. The result is an alpha/beta coiled coil, which retains only one backbone hydrogen bond per repeat unit from the parent coiled coil. Our results show that a substantially novel backbone structure is possible within the allowed regions of the Ramachandran space with only minor mutations to a known fold. PMID- 26771249 TI - Motion along the mental number line reveals shared representations for numerosity and space. AB - Perception of number and space are tightly intertwined. It has been proposed that this is due to 'cortical recycling', where numerosity processing takes over circuits originally processing space. Do such 'recycled' circuits retain their original functionality? Here, we investigate interactions between numerosity and motion direction, two functions that both localize to parietal cortex. We describe a new phenomenon in which visual motion direction adapts nonsymbolic numerosity perception, giving rise to a repulsive aftereffect: motion to the left adapts small numbers, leading to overestimation of numerosity, while motion to the right adapts large numbers, resulting in underestimation. The reference frame of this effect is spatiotopic. Together with the tuning properties of the effect this suggests that motion direction-numerosity cross-adaptation may occur in a homolog of area LIP. 'Cortical recycling' thus expands but does not obliterate the functions originally performed by the recycled circuit, allowing for shared computations across domains. PMID- 26771250 TI - Nucleus accumbens response to rewards and testosterone levels are related to alcohol use in adolescents and young adults. AB - During adolescence there is a normative increase in risk-taking behavior, which is reflected in, for example, increases in alcohol consumption. Prior research has demonstrated a link between testosterone and alcohol consumption, and between testosterone and neural responses to rewards. Yet, no study to date tested how testosterone levels and neural responses to rewards relate to and predict individual differences in alcohol use. The current study aimed to investigate this by assessing alcohol use, testosterone levels and neural responses to rewards in adolescents (12-17 years old) and young adults (18-26 years old). Participants were measured twice with a two-year interval between testing sessions. Cross-sectional analysis showed that at the second time point higher neural activity to rewards, but not testosterone levels, explained significant variance above age in reported alcohol use. Predictive analyses showed that, higher testosterone level at the first time point, but not neural activity to rewards at the first time point, was predictive of more alcohol use at the second time point. These results suggest that neural responses to rewards are correlated with current alcohol consumption, and that testosterone level is predictive of future alcohol consumption. These results are interpreted in the context of trajectory models of adolescent development. PMID- 26771252 TI - Long-acting octreotide as secondary prevention of chemotherapy-induced diarrhea: proof of concept. AB - BACKGROUND: The aim of this study is to investigate the role of Octreotide LAR in secondary prevention in patients with chemotherapy-induced diarrhea. METHODS: In this study, patients experiencing CID >= grade 2 received 30 mg long-acting octreotide as a monthly injection and the next chemotherapy dose was administrated with a 25% dose decrease. If no CID >= grade 2 occurred, subsequent chemotherapy doses were increased to the initial 100% values. The primary endpoint of the study was the diarrhea control rate (< grade 2) for patients receiving the optimal dose of chemotherapy for a minimum of 2 cycles. RESULTS: Twenty-nine patients were included. Ten patients experienced no improvement or ended the study very early after the first injection of octreotide LAR. Nineteen patients had a reduction in the grade of diarrhea after the first administration of Octreotide LAR and a reduced chemotherapy dose. Seven of them (24%) did not reach the end of the study because of disease progression (6) or lost in follow up (1). Ultimately 12 patients (41%) continued the study till the end. In ten of these twelve patients, there was a significant and persisting reduction of diarrhea while receiving full dose chemotherapy. CONCLUSION: This study suggests that monthly injections with long-acting octreotide might be used as a secondary prevention of chemotherapy-induced diarrhea. Its usefulness and optimal dosage in secondary prevention in combination with antidiarrheal agents needs further research. PMID- 26771255 TI - Statistical Primer for Athletic Trainers: The Difference Between Statistical and Clinical Meaningfulness. AB - OBJECTIVE: To explain statistical significance and clinical meaningfulness and to provide guidance in evaluating the clinical meaningfulness of a study. BACKGROUND: Understanding the results and statistics reported in original research remains a large challenge for many certified athletic trainers, which in turn, may be among the biggest barriers to integrating research into athletic training practice. DESCRIPTION: Statistical significance reflects the influence of chance on the outcome, whereas clinical meaningfulness reflects the degree to which the differences and relationships reported in a study are relevant to athletic training practice. As consumers of original research, athletic trainers must understand the core factors, most notably sample size, that influence statistical significance. RECOMMENDATIONS: To assist clinicians in evaluating the clinical meaningfulness of a research study, authors should provide the core elements necessary for interpreting statistical significance and discuss the clinical meaningfulness of statistically significant findings. PMID- 26771251 TI - Epigenome-Wide Assessment of DNA Methylation in the Placenta and Arsenic Exposure in the New Hampshire Birth Cohort Study (USA). AB - BACKGROUND: Arsenic is one of the most commonly encountered environmental toxicants, and research from model systems has suggested that one mode of its toxic activity may be through alterations in DNA methylation. In utero exposure to arsenic can affect fetal, newborn, and infant health, resulting in a range of phenotypic outcomes. OBJECTIVES: This study examined variation in placental DNA methylation and its relationship to arsenic exposure in 343 individuals enrolled in the New Hampshire Birth Cohort Study. METHODS: Linear regression models using a reference-free correction to account for cellular composition were employed to determine CpG loci affected by arsenic levels. RESULTS: Total arsenic measured in maternal urine during the second trimester was not associated with methylation in the placenta, whereas arsenic levels quantified through maternal toenail collected at birth were associated with methylation at a single CpG locus (p = 4.1 * 10-8). Placenta arsenic levels were associated with 163 differentially methylated loci (false discovery rate < 0.05), with 11 probes within the LYRM2 gene reaching genome-wide significance (p < 10-8). Measurement of LYRM2 mRNA levels indicated that methylation was weakly to moderately correlated with expression (r = 0.15, p < 0.06). In addition, we identified pathways suggesting changes in placental cell subpopulation proportions associated with arsenic exposure. CONCLUSIONS: These data demonstrate the potential for arsenic, even at levels commonly experienced in a U.S. population, to have effects on the DNA methylation status of specific genes in the placenta and thus supports a potentially novel mechanism for arsenic to affect long-term children's health. CITATION: Green BB, Karagas MR, Punshon T, Jackson BP, Robbins DJ, Houseman EA, Marsit CJ. 2016. Epigenome-wide assessment of DNA methylation in the placenta and arsenic exposure in the New Hampshire Birth Cohort Study (USA). Environ Health Perspect 124:1253-1260; http://dx.doi.org/10.1289/ehp.1510437. PMID- 26771256 TI - Gold-Catalyzed Concomitant [3 + 3] Cycloaddition/Cascade Heterocyclization of Enynones/Enynals with Azides Leading to Furanotriazines. AB - [Au]-catalyzed [3 + 3] cycloaddition reaction of enynones/enynals with azides, which allows the efficient regioselective synthesis of highly fused furo[3,4 d][1,2,3]triazines in good-to-excellent yields under mild conditions, has been developed. The synthetic utility of furanotriazines was exploited by oxidation with cerium ammonium nitrate (CAN) affording highly functionalized dihydrotriazines. Both furo[3,4-d][1,2,3]triazines and dihydrotriazines exhibit good fluorescence activity. PMID- 26771257 TI - Long-Term High-Temperature Stability of Functionalized Graphene Oxide Nanoplatelets in Arab-D and API Brine. AB - Partially reduced graphene oxide (prGO) was covalently functionalized with a zwitterionic polymer polyzwitterionic polymer to afford a composite material with excellent dispersibility and long-term stability in high salinity brines including standard API and Arab-D found in deep oil reservoirs. When heated at 90 degrees C, the dispersions remained stable in excess of 140 days. These results suggest the utility of imidazolium-based polymers for brine stabilization as well as the use of diazonium containing polymers for a "grafting-to" approach to nanocarbon functionalization. PMID- 26771258 TI - Tailoring Membrane Nanostructure and Charge Density for High Electrokinetic Energy Conversion Efficiency. AB - The electrokinetic energy conversion (EKEC) of hydraulic work directly into electrical energy has been investigated in charged polymeric membranes with different pore charge densities and characteristic diameters of the nanoporous network. The membranes were synthesized from blends of nitrocellulose and sulfonated polystyrene (SPS) and were comprehensively characterized with respect to structure, composition, and transport properties. It is shown that the SPS can be used as a sacrificial pore generation medium to tune the pore size and membrane porosity, which in turn highly affects the transport properties of the membranes. Furthermore, it is shown that very high EKEC efficiencies (>35%) are encountered in a rather narrow window of the properties of the nanoporous membrane network, that is, with pore diameters of ca. 10 nm and pore charge densities of 4.6 * 10(2) to 1.5 * 10(3) mol SO3(-) m(-3) for dilute solutions (0.03 M LiCl). The high absolute value of the efficiency combined with the determination of the optimal membrane morphology makes membrane-based EKEC devices a step closer to practical applications and high-performance membrane design less empirical. PMID- 26771259 TI - Can Holo NMR Chemical Shifts be Directly Used to Resolve RNA-Ligand Poses? AB - Using a set of machine learning based predictors that are capable of predicting ligand-induced shielding effects on (1)H and (13)C nonexchangeable nuclei, it was discovered that holo NMR chemical shifts can be used to resolve RNA-ligand poses. This was accomplished by quantitatively comparing measured and predicted holo chemical shifts in conformationally diverse "decoy" pools for three test cases and then, for each, comparing the native pose to the pose in the decoy pool that exhibited the lowest error. For three test cases, the poses in the decoy pools that exhibited the best agreement between measured and predicted holo chemical shifts were within 0.28, 1.12, and 2.38 A of the native poses. Interestingly, the predictors used in this study were trained on a database containing, only, apo RNA data. The agreement between the chemical shift-selected poses and the native NMR poses suggests that the predictors used in this study were able to "learn" general chemical shift-structure relationships from apo RNA data that could be used to account for ligand-induced shielding effects on RNA nuclei for the test cases studied. PMID- 26771260 TI - Tuning of Photoluminescence by Cation Nanosegregation in the (CaMg)(x)(NaSc)(1 x)Si2O6 Solid Solution. AB - Controlled photoluminescence tuning is important for the optimization and modification of phosphor materials. Herein we report an isostructural solid solution of (CaMg)x(NaSc)1-xSi2O6 (0 < x < 1) in which cation nanosegregation leads to the presence of two dilute Eu(2+) centers. The distinct nanodomains of isostructural (CaMg)Si2O6 and (NaSc)Si2O6 contain a proportional number of Eu(2+) ions with unique, independent spectroscopic signatures. Density functional theory calculations provided a theoretical understanding of the nanosegregation and indicated that the homogeneous solid solution is energetically unstable. It is shown that nanosegregation allows predictive control of color rendering and therefore provides a new method of phosphor development. PMID- 26771262 TI - Synthesis of Octabromoperylene Dianhydride and Diimides: Evidence of Halogen Bonding and Semiconducting Properties. AB - A facile synthesis of octabromoperylene-3,4,9,10-tetracarboxylic dianhydride (Br8 PDA) (1), its diimides (Br8-PDIs) (2a-e), and bis-, tris-, and tetra-amino substituted diimides (5a-c) with six, five, and four remaining substitutable Br atoms, respectively, is reported. Octabromination results in facile chemical/electrochemical reduction, radical anion formation, and red-shifted optical properties. For the first time, diverse halogen-bonding interactions were identified in the PDA/PDI, which along with the attractive electronic features enhance the electron-transport characteristics compared to the di-/tetra brominated PDIs (3/4). PMID- 26771261 TI - Semiempirical Quantum-Chemical Orthogonalization-Corrected Methods: Benchmarks for Ground-State Properties. AB - The semiempirical orthogonalization-corrected OMx methods (OM1, OM2, and OM3) go beyond the standard MNDO model by including additional interactions in the electronic structure calculation. When augmented with empirical dispersion corrections, the resulting OMx-Dn approaches offer a fast and robust treatment of noncovalent interactions. Here we evaluate the performance of the OMx and OMx-Dn methods for a variety of ground-state properties using a large and diverse collection of benchmark sets from the literature, with a total of 13035 original and derived reference data. Extensive comparisons are made with the results from established semiempirical methods (MNDO, AM1, PM3, PM6, and PM7) that also use the NDDO (neglect of diatomic differential overlap) integral approximation. Statistical evaluations show that the OMx and OMx-Dn methods outperform the other methods for most of the benchmark sets. PMID- 26771263 TI - Parathyroid carcinoma. AB - PURPOSE OF REVIEW: This article highlights recent advances in our understanding of the incidence, epidemiology, clinical presentation, evaluation, diagnosis, treatment, and prognosis of parathyroid carcinoma. RECENT FINDINGS: The prevalence of parathyroid carcinoma is approximately 0.005% of all cancers. Therefore, parathyroid carcinoma is one of the rarest malignancies known. Patients with parathyroid carcinoma present with clinical symptoms of hypercalcaemia as these cancers are usually hormonally functional. It is not uncommon that patients present with complications of profound hypercalcaemia because of an elevated parathyroid hormone. Parathyroid carcinoma is difficult to diagnose preoperatively unless patients present with metastatic disease. Serum calcium often exceeds 14 mg/dl and serum parathyroid hormone is significantly elevated commonly between three and 10 times of the upper limit. Fine needle aspiration is not recommended because of the risk of parathyromatosis. Treatment includes surgery as a primary form of therapy and this usually follows with postoperative radiotherapy, although its use remains controversial. SUMMARY: Patients with parathyroid carcinoma should undergo adequate surgical excision with an attempt of preserving vital structures such as the recurrent laryngeal nerve. Often en bloc resection of the ipsilateral thyroid lobe with comprehensive level VI dissection is required. Postoperative radiotherapy should be considered in most cases. PMID- 26771264 TI - Propofol Enhances Hemoglobin-Induced Cytotoxicity in Neurons. AB - BACKGROUND: It has been increasingly suggested that propofol protects against hypoxic-/ischemic-induced neuronal injury. As evidenced by hemorrhage-induced stroke, hemorrhage into the brain may also cause brain damage. Whether propofol protects against hemorrhage-induced brain damage remains unknown. Therefore, in this study, we investigated the effects of propofol on hemoglobin-induced cytotoxicity in cultured mouse cortical neurons. METHODS: Neurons were prepared from the cortex of embryonic 15-day-old mice. Hemoglobin was used to induce cytotoxicity in the neurons. The neurons were then treated with propofol for 4 hours. Cytotoxicity was determined by lactate dehydrogenase release assay. Caspase-3 activation was examined by Western blot analysis. Finally, the free radical scavenger U83836E was used to examine the potential involvement of oxidative stress in propofol's effects on hemoglobin-induced cytotoxicity. RESULTS: We found that treatment with hemoglobin induced cytotoxicity in the neurons. Propofol enhanced hemoglobin-induced cytotoxicity. Specifically, there was a significant difference in the amount of lactate dehydrogenase release between hemoglobin plus saline (19.84% +/- 5.38%) and hemoglobin plus propofol (35.79% +/- 4.41%) in mouse cortical neurons (P = 0.00058, Wilcoxon Mann-Whitney U test, n = 8 in the control group or the treatment group). U83836E did not attenuate the enhancing effects of propofol on hemoglobin-induced cytotoxicity in the neurons, and propofol did not significantly affect caspase-3 activation induced by hemoglobin. These data suggested that caspase-3 activation and oxidative stress might not be the underlying mechanisms by which propofol enhanced hemoglobin-induced cytotoxicity. Moreover, these data suggested that the neuroprotective effects of propofol would be dependent on the condition of the brain injury, which will need to be confirmed in future studies. CONCLUSIONS: These results from our current proof-of-concept study should promote more research in vitro and in vivo to develop better anesthesia care for patients with hemorrhagic stroke. PMID- 26771265 TI - A Randomized Controlled Trial to Determine the Effect of Depth of Anesthesia on Emergence Agitation in Children. AB - BACKGROUND: The cause of emergence agitation (EA) in children is unknown. Rapid emergence from inhaled anesthesia has been implicated because EA is more common with sevoflurane than with halothane. A dose-dependent effect of sevoflurane, which increases seizure-like electroencephalogram activity, has also been proposed. METHODS: To determine whether depth of anesthesia as measured by bispectral index (BIS) affects EA, 40 ASA physical status I to II children aged 2 to 8 years undergoing ophthalmic surgery were enrolled in a blinded randomized controlled trial of low-normal (40-45, deep) versus high-normal (55-60, light) anesthesia. To distinguish transient irritability from severe EA, the primary outcome was first-stage postanesthesia care unit (PACU I) peak Pediatric Assessment of Emergence Delirium (PAED) score, with secondary outcomes of PAED and Face, Legs, Activity, Cry, and Consolability scores at emergence, postoperative fentanyl dose, emergence time, and discharge time. Subjects received a standard anesthesia protocol with oral midazolam followed by mask induction with sevoflurane 8%, fentanyl 1 to 1.5 MUg/kg IV (then as needed), neuromuscular blockade, and endotracheal intubation. Providers titrated expired sevoflurane (in N2O 67%) from 0.5% to 3% to maintain BIS range. PAED, Richmond Agitation Sedation Scale, and Face, Legs, Activity, Cry, and Consolability scores were measured at emergence, at PACU I arrival, and during PACU I stay. RESULTS: There was little difference between the groups in the primary outcome, peak PACU I PAED score (light: 7.7 +/- 4.6; deep: 8.6 +/- 5.3; mean difference, 0.9; 95% confidence interval, 4.1 to -2.3; effect size, 0.18). Discharge times were similar between groups. Treatment for severe EA was rare. CONCLUSIONS: There was no significant effect of BIS-guided deep versus light anesthesia on severe EA. PMID- 26771266 TI - Early Endotracheal Tube Insertion with the GlideScope: A Randomized Controlled Trial. AB - BACKGROUND: The GlideScope videolaryngoscope is an intubating device routinely used by anesthesiologists for tracheal intubation. It is occasionally difficult to advance the endotracheal tube (ETT) into the trachea, despite a good view of the glottis. One technique that may be used when difficulty is encountered is to remove the GlideScope from the pharynx and introduce the ETT into the pharynx first, leaving it in place posteriorly while the GlideScope is inserted. Frequently, when the GlideScope is subsequently inserted, the ETT tip will then be in good view, resting near the glottis, and will easily advance into the trachea. In this randomized, single-blinded trial, we assessed whether orotracheal intubation with the GlideScope is faster and/or easier with the ETT first technique as a primary technique in elective patients. METHODS: One hundred sixty patients with normal-appearing airways who required elective orotracheal intubation were allocated randomly to intubation with insertion of the ETT or GlideScope into the oropharynx first. The primary outcome was time to intubation. The secondary outcomes were subjective ease of intubation (100-mm visual analog scale, 0 = easy; 100 = difficult), number of attempts/failures, incidence of oropharyngeal bleeding, and postoperative sore throat and/or vocal changes. RESULTS: Baseline demographics were similar between the 2 groups. Mean time to intubation was 48.2 +/- 17.1 seconds with the ETT-first technique and 51.5 +/- 21.8 seconds with the GlideScope-first technique (P = 0.30). The mean difference was 3.3 seconds in favor of the ETT-first technique (95% confidence interval, 2.9 to 9.6). The median ease of intubation using the visual analog scale was 13.3 mm (interquartile range, 5.3 to 21) with the ETT-first technique and 13.5 mm (interquartile range, 5.6 to 29.5) with the GlideScope-first technique (P = 0.30). The difference between the medians was -2.0 mm in favor of the ETT-first group (95% confidence interval, -1.5 to 6.0). There was no difference between groups for number of intubation attempts, incidence of oropharyngeal bleeding, laryngoscopic grade, sore throat, or vocal changes. CONCLUSIONS: In this study of GlideScope laryngoscopy, no statistically significant difference was observed in the time to intubate or the subjective ease of intubation whether the ETT or GlideScope was inserted into the oropharynx first. PMID- 26771267 TI - The Effect of Intravenous Dexamethasone on Sugammadex Reversal Time in Children Undergoing Adenotonsillectomy. AB - BACKGROUND: Dexamethasone has been shown to cause inhibition of sugammadex reversal in functionally innervated human muscle cells. In this prospective, double-blind, randomized, controlled study, we evaluated the effect of dexamethasone on the reversal time of sugammadex in children undergoing tonsillectomy and/or adenoidectomy. METHODS: We recruited 60 patients with ASA physical status I to II, between the ages of 3 and 8 years, scheduled for elective tonsillectomy and/or adenoidectomy. After the induction of anesthesia, patients in group D received IV dexamethasone at a dose of 0.5 mg/kg within a total volume of 5 mL saline, whereas patients in group S received only 5 mL IV saline as the control group. At the end of surgery, all patients were given a single bolus dose (2 mg/kg) of sugammadex at reappearance of T2. Demographic data, hemodynamic variables, time to recovery (a train-of-four ratio of 0.9), time to tracheal extubation, and adverse effects were recorded. RESULTS: There was no statistical significance between 2 groups in time to recovery and time to extubation. Time to recovery was 97.7 +/- 23.9 seconds in group D and 91.1 +/- 39.5 seconds in group S (P = 0.436; 95% confidence interval, -10.3 to 23.5). Time to extubation was 127.9 +/- 23.2 seconds and 123.8 +/- 38.7 seconds in group D and in group S, respectively (P = 0.612; 95% confidence interval, -11.9 to 20.05). CONCLUSIONS: IV dexamethasone, given after induction of anesthesia, at a dose of 0.5 mg/kg, does not substantively affect the reversal time of sugammadex in pediatric patients undergoing adenoidectomy and/or tonsillectomy. PMID- 26771268 TI - The Effects of Ketamine on Cognitive Function in Elderly Patients Undergoing Ophthalmic Surgery: A Pilot Study. AB - BACKGROUND: Acute postoperative cognitive dysfunction is characterized by neurocognitive dysfunction and confusion. In this study, we compared the cognitive status of a geriatric population undergoing ophthalmic surgery, as assessed by the Short Portable Mental Status Questionnaire (SPMSQ) before and after ketamine administration. METHODS: Eighty patients were enrolled and randomly assigned in a double-blind study to receive either ketamine (0.3 mg/kg dose) or physiologic solution (control group). Sixty-five (control, n = 32; ketamine, n = 33) patients completed the trial. Cognitive performance was assessed with an abbreviated version of the SPMSQ. Measurements of analgesia, sedation, intraocular pressure, and hemodynamic variables were recorded. RESULTS: With respect to cognitive performance, the baseline evaluation was similar for the control and ketamine groups. Postoperative evaluation showed an improvement only in the ketamine group. No increase in intraocular pressure or a secondary nystagmus was observed. The average dose of midazolam was higher in the control group, but the difference was not clinically significant. After surgery, analgesic behavior was better in the ketamine group than in the control group. There were no differences between groups in the sedation scale or in hemodynamic variables. CONCLUSIONS: The administration of 0.3 mg/kg ketamine during ophthalmic surgery in geriatric patients changed their cognitive status as assessed by the SPMSQ, decreased the required dose of anesthetics, and produced no increase in intraocular pressure or in hemodynamic variables. However, because the evaluation only analyzed the immediate effects of the administered drug, further research will be required to examine the impact of ketamine on the postoperative cognitive performance of geriatric patients before the drug can be formally recommended for this purpose. PMID- 26771269 TI - Central Nervous System-Toxic Lidocaine Concentrations Unmask L-Type Ca2+ Current Mediated Action Potentials in Rat Thalamocortical Neurons: An In Vitro Mechanism of Action Study. AB - BACKGROUND: High systemic lidocaine concentrations exert well-known toxic effects on the central nervous system (CNS), including seizures, coma, and death. The underlying mechanisms are still largely obscure, and the actions of lidocaine on supraspinal neurons have received comparatively little study. We recently found that lidocaine at clinically neurotoxic concentrations increases excitability mediated by Na-independent, high-threshold (HT) action potential spikes in rat thalamocortical neurons. Our goal in this study was to characterize these spikes and test the hypothesis that they are generated by HT Ca currents, previously implicated in neurotoxicity. We also sought to identify and isolate the specific underlying subtype of Ca current. METHODS: We investigated the actions of lidocaine in the CNS-toxic concentration range (100 MUM-1 mM) on ventrobasal thalamocortical neurons in rat brain slices in vitro, using whole-cell patch clamp recordings aided by differential interference contrast infrared videomicroscopy. Drugs were bath applied; action potentials were generated using current clamp protocols, and underlying currents were identified and isolated with ion channel blockers and electrolyte substitution. RESULTS: Lidocaine (100 MUM-1 mM) abolished Na-dependent tonic firing in all neurons tested (n = 46). However, in 39 of 46 (85%) neurons, lidocaine unmasked evoked HT action potentials with lower amplitudes and rates of de-/repolarization compared with control. These HT action potentials remained during the application of tetrodotoxin (600 nM), were blocked by Cd (50 MUM), and disappeared after superfusion with an extracellular solution deprived of Ca. These features implied that the unmasked potentials were generated by high-voltage-activated Ca channels and not by Na channels. Application of the L-type Ca channel blocker, nifedipine (5 MUM), completely blocked the HT potentials, whereas the N-type Ca channel blocker, omega-conotoxin GVIA (1 MUM), had little effect. CONCLUSIONS: At clinically CNS-toxic concentrations, lidocaine unmasked in thalamocortical neurons evoked HT action potentials mediated by the L-type Ca current while substantially suppressing Na-dependent excitability. On the basis of the known role of an increase in intracellular Ca in the pathogenesis of local anesthetic neurotoxicity, this novel action represents a plausible contributing candidate mechanism for lidocaine's CNS toxicity in vivo. PMID- 26771270 TI - An Evaluation of Ultrasound-Guided Adductor Canal Blockade for Postoperative Analgesia After Medial Unicondylar Knee Arthroplasty. AB - BACKGROUND: Unicondylar knee arthroplasty (UKA) is a commonly performed procedure with significant expected postoperative pain. Peripheral nerve blocks are 1 analgesic option, but some approaches may decrease quadriceps motor strength and interfere with early ambulation. In this study, we compared the analgesia provided by an adductor canal block (ACB) and a psoas compartment block (PCB) after UKA. We hypothesized that the ACB would provide equivalent analgesia, defined as a difference of <2 points on the pain scale (0-10 numeric rating scale [NRS]), at rest and with movement 6 hours after block placement. METHODS: One hundred fifty patients undergoing medial UKA were randomly assigned to receive either an ACB or a PCB with 0.25% bupivacaine, 5 MUg/mL epinephrine, and 1.67 MUg/mL clonidine. All patients received multimodal analgesics, sham blockade at the alternate site, and a posterior capsule injection during surgery. Patients and observers were blinded to treatment groups. The primary end points were NRS pain scores with rest and movement at 6 hours. Secondary end points included quadriceps muscle strength at 6 hours (0-5 [5 being full strength]; Medical Research Council scale) as well as NRS pain scores, opioid consumption, and opioid-related side effects over 24 hours. RESULTS: One hundred forty-seven patients were analyzed. Pain scores were equivalent at 6 hours with rest (ACB 1.0 +/- 2 vs PCB 1.1 +/- 2.2 [mean NRS +/- SD]; 95% confidence interval of mean difference, -0.8 to 0.6; P < 0.0001) and with movement (ACB 1.6 +/- 2.6 vs PCB 1.5 +/- 2.8; 95% confidence interval of mean difference, -0.8 to 0.9; P < 0.0001). In addition, pain scores at rest and with movement at 12, 18, and 24 hours were equivalent. Quadriceps motor strength was significantly increased in the ACB group (Medical Research Council scale score, 4.0 +/- 1.1 vs 2.5 +/- 1.3 [mean +/- SD]; P < 0.0001). No significant differences were found between groups for time to first analgesic or for cumulative opioid consumption at 6, 12, 18, or 24 hours. Other than an increase in the incidence of pruritus in the ACB group at 6 hours, there were no differences in opioid-related side effects. CONCLUSIONS: An ACB provides equivalent analgesia after medial UKA when compared with a PCB. In addition, the ACB caused significantly less motor weakness. An ACB should be considered for postoperative analgesia after medial UKA. PMID- 26771271 TI - The Gly16 Allele of the Gly16Arg Single-Nucleotide Polymorphism in the beta2 Adrenergic Receptor Gene Augments Perioperative Use of Vasopressors: A Retrospective Cohort Study. AB - BACKGROUND: Arterial hypotension is frequent in patients undergoing anesthesia and may aggravate the outcome. Common genetic variations may influence the cardiovascular response to anesthesia. In this retrospective cohort study, we tested whether variation in the gene encoding the beta2-adrenergic receptor (ADRB2) influences perioperative arterial blood pressure and consequently the use of vasopressors. METHODS: Five hundred seventy-one Danish Caucasians undergoing neurosurgery were genotyped for 5 marker single-nucleotide polymorphisms (SNPs) within ADRB2 (Gly16Arg, Gln27Glu, Thr164Ile, Arg175Arg, and Gly351Gly). A pairwise tagging principle was used to identify ADRB2 haplotypes. Mean arterial blood pressure (MAP) was recorded in the supine awake state and, together with administration of vasopressors (ephedrine and/or phenylephrine), for 30 minutes after induction of general anesthesia (sevoflurane/remifentanil or propofol/remifentanil). RESULTS: Four hundred thirteen (72%) patients received ephedrine and/or phenylephrine. Only baseline MAP (P < 0.001) and the Arg175Arg SNP (P = 0.01) were associated with nadir perioperative MAP. The Gly16Arg SNP but no other SNPs showed a trend toward an association with the amount of vasopressors used during anesthesia with Arg16 homozygotes receiving less ephedrine equivalents. The Arg16-Gln27-Thr164-Arg175-Gly351 haplotype was associated with approximately 13% lower vasopressor requirements than the most common Gly16-Glu27-Thr164-Arg175-Gly351 haplotype (P = 0.01). CONCLUSIONS: Gly16 carriers received larger amounts of vasopressor compared with Arg16 homozygotes. This corresponds to previous studies demonstrating that the Gly16 allele in ADRB2 is associated with vasodilation and high cardiac output. PMID- 26771272 TI - Update: Stroke guidelines. PMID- 26771273 TI - Drinking from the fire hose. PMID- 26771274 TI - Tuning the Morphology of Solution-Sheared P3HT:PCBM Films. AB - Organic bulk heterojunction (BHJ) solar cells are a promising alternative for future clean-energy applications. However, to become attractive for consumer applications, such as wearable, flexible, or semitransparent power-generating electronics, they need to be manufactured by high-throughput, low-cost, large area-capable printing techniques. However, most research reported on BHJ solar cells is conducted using spin coating, a single batch fabrication method, thus limiting the reported results to the research lab. In this work, we investigate the morphology of solution-sheared films for BHJ solar cell applications, using the widely studied model blend P3HT:PCBM. Solution shearing is a coating technique that is upscalable to industrial manufacturing processes and has demonstrated to yield record performance organic field-effect transistors. Using grazing incident small-angle X-ray scattering, grazing incident wide-angle X-ray scattering, and UV-vis spectroscopy, we investigate the influence of solvent, film drying time, and substrate temperature on P3HT aggregation, conjugation length, crystallite orientation, and PCBM domain size. One important finding of this study is that, in contrast to spin-coated films, the P3HT molecular orientation can be controlled by the substrate chemistry, with PEDOT: PSS substrates yielding face-on orientation at the substrate-film interface, an orientation highly favorable for organic solar cells. PMID- 26771275 TI - Computational Characterization of Defects in Metal-Organic Frameworks: Spontaneous and Water-Induced Point Defects in ZIF-8. AB - Zeolitic imidazolate frameworks (ZIFs) are an important class of porous crystalline metal-organic framework (MOF) materials that have attracted widespread attention for applications ranging from gas adsorption and separation to catalysis. Although the bulk crystal structures of MOFs are typically well characterized, comparatively little is known regarding MOF defect structures. Drawing on analogies with conventional silicon-based zeolites, we utilize computational methods to examine the structure and stability of putative point defect structures (including vacancies, substitutions, and "dangling" linkers) within the prototypical ZIF-8 structure. Considering both postsynthetic (gas phase) and synthetic (solution-phase) conditions, we find that several of the defect structures lie low in energy relative to the defect-free parent crystal, with barriers to defect formation that are large but surmountable under relevant temperatures. These results are consistent with prior experimental observations of ZIF stability and reactivity and suggest that defects may play an important role in influencing the long-term stability of MOFs under conditions that include exposure to water vapor and trace contaminants such as acid gases. PMID- 26771276 TI - Dual-Frequency Alternating Current Designer Waveform for Reliable Voltammetric Determination of Electrode Kinetics Approaching the Reversible Limit. AB - Alternating current (ac) voltammetry provides access to faster electrode kinetics than direct current (dc) methods. However, difficulties in ac and other methods arise when the heterogeneous electron-transfer rate constant (k(0)) approaches the reversible limit, because the voltammetric characteristics become insensitive to electrode kinetics. Thus, in this near-reversible regime, even small uncertainties associated with bulk concentration (C), diffusion coefficient (D), electrode area (A), and uncompensated resistance (Ru) can lead to significant systematic error in the determination of k(0). In this study, we have introduced a kinetically sensitive dual-frequency designer waveform into the Fourier transformed large-amplitude alternating current (FTAC) voltammetric method that is made up of two sine waves having the same amplitude but with different frequencies (e.g., 37 and 615 Hz) superimposed onto a dc ramp to quantify the close-to-reversible Fc(0/+) process (Fc = ferrocene) in two nonhaloaluminate ionic liquids. The concept is that from a single experiment the lower-frequency data set, collected on a time scale where the target process is reversible, can be used as an internal reference to calibrate A, D, C, and Ru. These calibrated values are then used to calculate k(0) from analysis of the harmonics of the higher-frequency data set, where the target process is quasi-reversible. With this approach, k(0) values of 0.28 and 0.11 cm.s(-1) have been obtained at a 50 MUm diameter platinum microdisk electrode for the close-to-diffusion-controlled Fc(0/+) process in two ionic liquids, 1-ethyl-3-methylimidazolium bis(trifluoromethanesulfonyl)imide and 1-butyl-3-methylimidazolium bis(trifluoromethanesulfonyl)imide, respectively. PMID- 26771277 TI - A novel technology coupling extraction and foam fractionation for separating the total saponins from Achyranthes bidentata. AB - A novel technology coupling extraction and foam fractionation was developed for separating the total saponins from Achyranthes bidentata. In the developed technology, the powder of A. bidentata was loaded in a nylon filter cloth pocket with bore diameter of 180 um. The pocket was fixed in the bulk liquid phase for continuously releasing saponins. Under the optimal conditions, the concentration and the extraction rate of the total saponins in the foamate by the developed technology were 73.5% and 416.2% higher than those by the traditional technology, respectively. The foamates obtained by the traditional technology and the developed technology were analyzed by ultraperformance liquid chromatography-mass spectrometry to determine their ingredients, and the results appeared that the developed technology exhibited a better performance for separating saponins than the traditional technology. The study is expected to develop a novel technology for cost effectively separating plant-derived materials with surface activity. PMID- 26771279 TI - Mobile Source Air Toxic Emissions. PMID- 26771278 TI - Airflow Limitation and Endothelial Dysfunction. Unrelated and Independent Predictors of Atherosclerosis. AB - RATIONALE: Lower FEV1 is associated with increased prevalence of atherosclerosis; however, causal mechanisms remain elusive. OBJECTIVES: To determine if systemic endothelial dysfunction mediates the association between reduced FEV1 and increased atherosclerosis. METHODS: Brachial artery endothelial function, pulmonary function, coronary artery calcium, and carotid plaque were assessed in 231 Pittsburgh SCCOR (Specialized Centers for Clinically Oriented Research) study participants; peripheral arterial endothelial function, pulmonary function, and coronary artery calcium were assessed in 328 HeartSCORE (Heart Strategies Concentrating on Risk Evaluation) study participants. MEASUREMENTS AND MAIN RESULTS: Lower FEV1 was independently associated with increased atherosclerosis in both cohorts (per 25% lower % predicted FEV1: odds ratio [OR], 1.76; 95% confidence interval [CI], 1.30-2.40; P < 0.001 for carotid plaque in SCCOR participants) (per 25% lower % predicted FEV1: OR, 1.35; 95% CI, 1.02-1.77; P = 0.03 for coronary artery calcium in HeartSCORE participants). Similarly, reduced endothelial function was independently associated with increased atherosclerosis in both cohorts (per SD lower endothelial function: OR, 1.30; 95% CI, 1.01-1.67; P = 0.04 for carotid plaque in SCCOR participants) (per SD lower endothelial function: OR, 1.38; 95% CI, 1.09-1.76; P = 0.008 and OR, 1.41; 95% CI, 1.07-1.86; P = 0.01 for coronary artery calcium in SCCOR and HeartSCORE participants, respectively). However, there was no association between endothelial dysfunction and FEV1, FEV1/FVC, low-attenuation area/visual emphysema, and diffusing capacity in SCCOR participants, and between endothelial dysfunction and FEV1 or FEV1/FVC in HeartSCORE participants (all P > 0.05). Adjusting the association between FEV1 and atherosclerosis for endothelial dysfunction had no impact. CONCLUSIONS: Endothelial dysfunction does not mediate the association between airflow limitation and atherosclerosis. Instead, airflow limitation and endothelial dysfunction seem to be unrelated and mutually independent predictors of atherosclerosis. PMID- 26771280 TI - Analytical management of SCR catalyst lifetimes and multipollutant performance. AB - Selective catalytic reduction (SCR) catalysts are deactivated by several mineral and metallic trace elements at highly variable rates determined by fuel quality and furnace firing conditions. With a loss in activity, NO is reduced over a longer inlet length of the SCR monolith, which leaves a shorter trailing section to sustain the most favorable conditions to oxidize Hg(0) and SO2. Since virtually no operating SCR was designed for Hg oxidation and since different monoliths are routinely combined as layers in particular units, the Hg oxidation performance of any SCR fleet is largely unmanaged. The analysis in this paper directly relates a measurement or manufacturer's forecast on the deterioration in NO reduction with age to corresponding estimates for oxidation of Hg(0). It accommodates any number of catalyst layers with grossly different properties, including materials from different manufacturers and different ages. In this paper, the analysis is applied to 16 full-scale SCRs in the Southern Company fleet to demonstrate that catalyst deactivation disrupts even the most prominent connections among the Hg(0) oxidation performance of commercial SCRs and the behavior of fresh catalysts at lab, pilot, and even full scale. IMPLICATIONS: Catalyst deactivation confounds even the most prominent connections among the Hg(0) oxidation performance of commercial SCRs and the behavior of fresh catalyst at lab, pilot, and even full scale. The halogen dependence has been emphasized throughout the literature on catalytic Hg(0) oxidation, based on a large database on fresh catalysts. But for deactivated catalysts in commercial SCRs, the number of layers is much more indicative of the Hg(0) oxidation performance, in that SCRs with four layers perform better than those with three layers, and so on. The new qualified conclusion is that Hg(0) oxidation is greater for progressively greater HCl concentrations only among SCRs with the same number of layers, even for an assortment of catalyst design specifications and operating conditions. PMID- 26771281 TI - Comprehension and Use of Nutrition Facts Tables among Adolescents and Young Adults in Canada. AB - PURPOSE: Limited evidence exists on the comprehension and use of Nutrition Facts tables (NFt) among adolescents and young adults. This study provides an account of how young people engage with, understand, and apply nutrition information on the current and modified versions of the NFt to compare and choose foods. METHODS: Participants aged 16-24 years (n = 26) were asked to "think aloud" while viewing either the current or 1 of 5 modified NFts and completing a behavioural task. The task included a questionnaire with 9 functional items requiring participants to define, compare, interpret, and manipulate serving size and percentage daily value (%DV) information on NFts. Semi-structured interviews were conducted to further probe thought processes and difficulties experienced in completing the task. RESULTS: Equal serving sizes on NFts improved ability to accurately compare nutrition information between products. Most participants could define %DV and believed it can be used to compare foods, yet some confusion persisted when interpreting %DVs and manipulating serving-size information on NFts. Where serving sizes were unequal, mathematical errors were often responsible for incorrect responses. CONCLUSIONS: Results reinforce the need for equal serving sizes on NFts of similar products and highlight young Canadians' confusion when using nutrition information on NFts. PMID- 26771282 TI - Oral Administration of Forskolin, Homotaurine, Carnosine, and Folic Acid in Patients with Primary Open Angle Glaucoma: Changes in Intraocular Pressure, Pattern Electroretinogram Amplitude, and Foveal Sensitivity. AB - PURPOSE: To evaluate the effects of a food supplement containing forskolin, homotaurine, carnosine, folic acid, vitamins B1, B2, B6, and magnesium in patients with primary open angle glaucoma (POAG) already in treatment and compensated by intraocular pressure (IOP)-lowering drugs, during a period of 12 months. METHODS: Twenty-two patients (44 eyes) with POAG, with their IOP compensated by topical drugs, were enrolled and randomly assigned to the food supplement or control treatment group. The additional food supplement treatment consisted of 2 tablets per day (1 in the morning, 1 in the evening) given for 1 year of a balanced association of homotaurine, Coleus forskohlii root extract, L carnosine, folic acid, vitamins B1, B2, B6, and magnesium. Pattern Electroretinogram (PERG) amplitude, foveal sensitivity obtained with the visual field analyzer frequency doubling technology, and IOP were detected at enrollment (T0), 3 months (T1), 6 months (T2), 9 months (T3), and 12 months (T4). RESULTS: We observed in treated patients a significant further decrease of IOP and an improvement of PERG amplitude at 6, 9, and 12 months, and foveal sensitivity at 12 months. All values remained substantially stable in control patients. CONCLUSIONS: The results of the present pilot study indicate that the components of the food supplement reach the eye in a detectable manner, as evidenced by the effects on the IOP. Moreover, they suggest a short-term neuroactive effect, as indicated by the improvement of PERG amplitude and foveal sensitivity in treated, but not in control patients. PMID- 26771284 TI - THE EFFECT OF TIME AND COHORT DIFFERENCES ON THE INTERPRETATION OF AGE CHANGES IN COGNITIVE BEHAVIOR. AB - The Primary Mental Abilities Test and the Test of Behavioral Rigidity were administered to 1060 Ss obtained by stratified-random sampling of the membership of a prepaid medical plan. Independent samples of 26 men and 26 women in each five-year interval in the age range from 21 to 76 years were tested in 1966 and 1963. Composite longitudinal and cross-sectional padients were constructed and examined for the effect of time and cohort differences. Time difference is defined as that component of change between two successive measurements within the same generation which is due t o environmental experience. Cohort difference is defined as the difference in scores obtained by successive generations when measured at the same age level. Positive cohort and time differences were found for most unspeeded tasks while negative cohort and time differences occurred for the speeded tasks. It was concluded that cross-sectional studies tend to overestimate decrement on unspeeded tasks due to the effect of increasingly favorable life experience or genetic improvement in the species. As a result, within generation decrements appear to be relatively small. Decrement on speeded tasks is under- estimated by the cross-sectional method for the opposite reasons; i.e., un- favorable life experience or decrease in ability over successive generations. The results of repeated measurement and independent random sampling methods for the short-term study of developmental change were compared and the adequacy of the latter approach seems substantiated. PMID- 26771283 TI - Prevalence and Phylogenetic Analysis of Orientia tsutsugamushi in Small Mammals in Hanoi, Vietnam. AB - Rodents are important reservoirs of many human pathogens transmitted via arthropod vectors. Arthropod-borne bacteria belonging to the family Rickettsiaceae cause acute febrile diseases in humans worldwide, but the real burdens of rickettsial diseases appear to be underestimated in Hanoi, Vietnam, because differential diagnosis on the basis of clinical signs and symptoms is confounded by the presence of other tropical infectious diseases with similar signs and symptoms. To know the prevalence of bacteria of the family Rickettsiaceae among small mammals in Hanoi, 519 animals thriving in the public places were captured and examined for the presence of bacterial sequences using duplex PCR. Nucleotide sequences specific for Orientia tsutsugamushi were detected in seven samples (1.3%). Out of seven animals, two were captured in a market, whereas five were in hospitals. None of the captured small mammals tested positive for the genus Rickettsia. The nucleotide sequence analysis of the genes encoding the 47-kDa high-temperature requirement A (47-kDa HtrA) and 56-kDa type specific antigen (TSA) showed that these seven isolates were indistinguishable from each other. O. tsutsugamushi isolated in this study was closely related phylogenetically to the Gilliam strain, which was originally isolated at the border of Assam and Burma, rather than to those isolated in the central to southern part of Vietnam. It should be emphasized that Vietnamese hospitals were heavily infested by small rodents and some of them harbored O. tsutsugamushi. Strict hygienic control should be implemented to mitigate the potential risk posed by O. tsutsugamushi in hospital settings. PMID- 26771285 TI - THE GENERALITY OF BEHAVIORAL DATA I: GENERALIZATION FROM OBSERVATIONS ON ONE OCCASION. AB - The results of two experiments designed to study the generalization potential in behavioral data are reported. Both experiments investigated the effect of variation of task and group composition on ratings of behavior based on direct observation of individuals in group situations. Experiment I under- took ratings of military conscripts and Experiment II undertook ratings of children seven years of age. One main result was obtained common to both experiments: When the situation variation encompassed both task and group composition simultaneously the relationship was random between ratings made independently by two teams of judges, after one observation instance for each team. The correlation was mostly of considerable size, when the situations in which the two teams made their observations were identical o r differed only in respect to task or group composition. PMID- 26771286 TI - HOMOGENEOUS DIMENSIONS OF PERSONALITY SCALE CONTENT. AB - Four alternatively worded true and false keyed and positively and negatively stated types of each of five item content sets were prepared. Items were chosen from the Play, Social Recognition, Exhibition, Cognitive Structure, and Autonomy dimensions in the Personality Research Form item pool on the basis of high content saturation, freedom from desirability bias, and moderate endorsement frequencies. Correlational and factor analytic results yielded consistent evidence that, contrary to certain previous results, content dimensions could be defined clearly and uniquely regardless of direction of wording effect. Content dimensions proved to be orthogonal to factors defined by response style marker scales for acquiescence and desirability. Stylistic consistencies derived from an adjective checklist were related to a desirability factor of to a factor identified as acquiescence to personality items. PMID- 26771287 TI - TECHNIQUE FOR MINIMIZING THE INSTRUMENTAL FACTOR. AB - A technique is described for using orthogonal factor scores to compare the item scores obtained from two or more media so as to minimize the instrumental factor problem. It is compared with the hypothesis matrix technique using the item scores of a behavior rating scale and a structured psychiatric interview scale. The direct factor score method proved to be more effective in several aspects, mainly because it yielded larger loadings and, therefore, resulted in the extraction of more and better delineated factors. PMID- 26771288 TI - DESCRIPTIVE FACTOR ANALYSIS. AB - -When a set of variables cannot be regarded as being drawn from a well defined population, the estimation of communalities, population parameters, and universe factors is not a rational undertaking. A descriptive factor analysis can be performed by weighting test vectors inversely as the components of total test variance unable to determine a test battery common factor. Such components are well defined and a descriptive factor analysis based on weighting by such components requires no assumptions about the population and no estimations of communalities ; it requires only that regressions be reasonably linear. PMID- 26771289 TI - ,SOME CHARACTERISTICS OF LATENT SCORES. AB - A number of multivariate psychometric models hypothesize that a data matrix of observed, scores equals the sum of two mutually orthogonal latent matrices. Relationships among latent and observed scores are investigated psychometrically using the concept of the general inverse. A number of previously unrecognized characteristics of the latent scores are thus brought to light. PMID- 26771290 TI - ORF3 of Hepatitis E Virus Inhibits the Expression of Proinflammatory Cytokines and Chemotactic Factors in LPS-Stimulated Human PMA-THP1 Cells by Inhibiting NF kappaB Pathway. AB - Hepatitis E virus (HEV) is one of the primary causative agents of acute hepatitis. It is noteworthy that HEV can develop chronic infection and even lead to liver cirrhosis; however, the mechanism has not been revealed. In this study, the ELISA assay was used to detect protein levels, and we found that HEV open reading frame 3 (ORF3) protein inhibited the expression of proinflammatory cytokines (tumor necrosis factor-alpha [TNF-alpha], interleukin [IL]-1beta, IL-6, IL-8, IL-12p40, and IL-18) and chemotactic factors (nitric oxide [NO], interferon inducible protein-10 (IP-10), macrophage inflammatory protein (MIP)-1alpha, monocyte chemoattractant protein-1 (MCP-1), granulocyte colony-stimulating factor (G-CSF), granulocyte macrophage colony-stimulating factor (GM-CSF)] in lipopolysaccharide (LPS)-stimulated human PMA-THP1 cells. Further study showed that mRNA and protein levels of pattern recognition receptors (PRRs), such as Toll-like receptor 4 (TLR4), TNF receptor-associated factor 6 (TRAF6), and nucleotide-binding oligomerization domain containing 2 (NOD2), decreased after infection of pLL3.7-ORF3 (pORF3); moreover, the inhibition produced corresponding upregulation of IkappaBalpha and downregulation of phosphorylated IkappaB kinase IKKE (p-IKKE) and phosphorylated nuclear factor (NF)-kappaB (p-NF-kappaB), but little variation was found in the concentration of IKKE and NF-kappaB. Taken together, our results demonstrated that HEV ORF3 attenuated LPS-induced cytokine production and chemotactic factors, predominantly by inhibiting various PRRs mediated NF-kappaB signaling pathways. The anti-inflammatory properties might be of great importance to clarify the role and mechanism of macrophages in chronic HEV infection and cirrhosis. PMID- 26771291 TI - Emotional Reactivity and Regulation Following Citalopram Therapy in Children and Adolescents with Anxiety Disorders. AB - OBJECTIVE: Emotional dysregulation is an important element in the pathophysiology of childhood anxiety disorders and can distinguish anxious subjects from controls. Treatment with selective serotonin inhibitors (SSRIs) has been found to lessen anxiety, but its effects on emotional reactivity and regulation are less documented. The aim of the study was to prospectively assess changes in emotional reactivity and regulation in response to citalopram in children and adolescents with anxiety disorders, with special focus on the mechanism of reappraisal. METHODS: The sample included 70 children and adolescents (38 boys, 32 girls) 10 17 years of age, divided into three groups: Those with anxiety disorder treated with citalopram for 8 weeks (n = 35); untreated subjects with anxiety disorder on the waiting list for cognitive behavioral therapy (CBT) (n = 15); and subjects without anxiety disorder (controls) (n = 20). Emotional reactivity and regulation (i.e., reappraisal), were assessed at baseline and after 8 weeks (follow-up) with validated computer-based instruments, Reactivity and Regulation-Situations (REAR S) and Reactivity and Regulation-Images (REAR-I). RESULTS: Citalopram-treated subjects showed significantly greater improvement in reappraisal ability than CBT waitlisted subjects. Improvement in the ability to reappraise threatening images correlated significantly with the decrease in anxiety. There was a decrease in negative emotional reactivity between assessments, which was positively correlated with clinical improvement. Higher intensity of baseline reactivity (on the REAR-S) predicted more severe symptoms at follow-up. CONCLUSIONS: Citalopram therapy improves reappraisal ability in children and adolescents with anxiety. However, the improvement in other examined emotional reactivity indices occurred in both medicated and waitlisted groups. It is possible that these findings may have implications for understanding the pathophysiology of anxiety in children and adolescents. PMID- 26771292 TI - Effects of Temperature and Trophic State on Degradation of Environmental DNA in Lake Water. AB - Degradation of environmental DNA (eDNA) in aquatic habitats can affect the interpretation of eDNA data and the ability to detect aquatic organisms. The effect of temperature and trophic state on the decay of Common Carp (Cyprinus carpio) eDNA was evaluated using lake water microcosms and quantitative PCR for a Common Carp-specific genetic marker in two experiments. The first experiment tested the effect of temperature on Common Carp eDNA decay. Common Carp eDNA exhibited exponential decay that increased with temperature. The slowest decay rate was observed at 5 degrees C, with a T90 value (time to 90% reduction from initial concentration) of 6.6 days, as opposed to ~1 day at higher temperatures. In a second experiment, decay was compared across waters from lakes of different trophic states. In this experiment, Common Carp eDNA exhibited biphasic exponential decay, characterized by rapid decay for 3-8 days followed by slow decay. Decay rate was slowest in dystrophic water and fastest in oligotrophic water, and decay rate was negatively correlated to dissolved organic carbon concentration. The overall rapid decay of eDNA and the effects of temperature and water quality should be considered in protocols for water sample storage and field sampling design. PMID- 26771293 TI - Access to Different Isomeric Dibenzoxazepinones through Copper-Catalyzed C-H Etherification and C-N Bond Construction with Controllable Smiles Rearrangement. AB - An efficient new way to access two regio-isomeric dibenzoxazepinones is reported from 8-aminoquinoline benzamides and 2-bromophenols. Through choice of conditions, the reaction proceeds either through a sequential C-H etherification and subsequent Goldberg reaction, both controlled by the aminoquinoline group and Cu(I), or via a C-H etherification and subsequent Smiles rearrangement promoted by Cu(II) and t-BuOK. The 8-aminoquinoline moiety, e.g., 8-amino-5 methoxyquinoline, is readily removable from the structures of dibenzoxazepinones under moderate conditions. PMID- 26771294 TI - Effect of Curcumin Supplementation During Radiotherapy on Oxidative Status of Patients with Prostate Cancer: A Double Blinded, Randomized, Placebo-Controlled Study. AB - Curcumin is an antioxidant agent with both radiosensitizing and radioprotective properties. The aim of the present study was to evaluate the effect of curcumin supplementation on oxidative status of patients with prostate cancer who undergo radiotherapy. Forty patients treated with radiotherapy for prostate cancer were randomized to the curcumin (CG, n = 20) or placebo group (PG, n = 20). They received curcumin (total 3 g/day) or placebo during external-beam radiation therapy of up to 74 Gy. Plasma total antioxidant capacity (TAC) and activity of superoxide dismutase (SOD), catalase, and glutathione peroxidase (GPx) were measured at baseline and 3 mo after radiotherapy completion. Analysis of covariance was used to compare the variables between groups following the intervention. Serum PSA levels and MRI/MRS images were investigated. In CG, TAC significantly increased (P < 0.001) and the activity of SOD decreased (P = 0.018) after radiotherapy compared with those at baseline. In CG, however, the activity of SOD had a significant reduction (P = 0.026) and TAC had a significant increase (P = 0.014) compared with those in PG. PSA levels were reduced to below 0.2 ng/ml in both groups, 3 mo after treatment, however, no significant differences were observed between the 2 groups regarding treatment outcomes. PMID- 26771295 TI - A case of granulomatous mastitis, erythema nodosum and oligoarthralgia in a pregnant woman with high serum granulocyte-colony-stimulating factor. PMID- 26771296 TI - Intraoperative Management of Increased Intraocular Pressure in a Patient with Glaucoma Undergoing Robotic Prostatectomy in Trendelenburg Position. PMID- 26771297 TI - Ultrasound-Guided Quadratus Lumborum Blocks: Definition of the Clinical Relevant Endpoint of Injection and the Safest Approach. PMID- 26771298 TI - In Response. PMID- 26771299 TI - Closely Related Syntopic Cytotypes of Astyanax taeniatus (Jenyns, 1842) from the Upper Piranga River, Upper Doce Basin in Southeastern Brazil. AB - Astyanax taeniatus occurs in coastal areas of southeastern Brazil, and it is very abundant in the Upper Doce River Basin. Our objective was to study C-, argyrophilic nucleolar organizer region (Ag-NOR) and fluorescent in situ hybridization (FISH) banding patterns using 5S, 18S, CA(15), and GA(15) repetitive DNA probes on a population of A. taeniatus present in the Piranga River, in the Doce Basin. Two syntopic cytotypes were found, both with 2n = 50: cytotype A (14m + 12sm + 16st + 8t) and cytotype B (10m + 14sm + 18st + 8t). In both cytotypes, heterochromatic blocks occurred in all the chromosomes; Ag-NOR sites were multiple, ranging from four to eight. The 5S rDNA probe marked eight chromosomes in both cytotypes, a unique condition within Astyanax, suggesting a recent divergence between these cytotypes. The 18S rDNA probe differed between the cytotypes, marking 10 and 8 chromosomes in cytotypes A and B, respectively. CA(15) and GA(15) FISH patterns were mainly subtelomeric, but CA(15) showed centromeric markings that were diagnostic for each cytotype. Although overall cytogenetic evidence suggests that these cytotypes are closely related, morphological and molecular data in progress will provide further hypothesis test on their phylogenetic relationship. PMID- 26771300 TI - Prevalence of toxigenic Penicillium species associated with poultry house in Telangana, India. AB - The prevalence of mycotoxigenic Penicillium species in poultry houses of Telangana, India, was studied during 4 seasons between June 2009 and May 2010. Fungi belonging to 13 genera, including Penicillium, comprising 43 species were collected using petri plates. Fourteen Penicillium species demonstrated varying degrees of mycotoxigenicity. Chemical and chromatographic analysis of the different poultry feed samples revealed 8 different mycotoxins with ochratoxin A (OTA) predominating. The mean contamination rate of OTA was 38%. OTA quantities ranged between 5.78 and 6.73 ug/kg-1, 10.13 and 14.23 ug/kg-1, and 12.33 and 15.20 ug/kg-1 in starter, broiler, and layer feeds, respectively. Statistically significant positive correlation between prevalence of Penicillium species and the monsoon, autumn, and spring seasons and negative correlation between prevalence and the autumn, spring, and summer seasons were observed. These findings may serve as risk exposure indicators and contribute toward the initiation of a sustainable control program. PMID- 26771301 TI - A Patient with Keratoconus, Nanophthalmos, Lipodermoids, and Pigmentary Retinopathy. AB - A 44-year-old male with no pertinent history other than poor vision for more than 25 years was examined. Best corrected visual acuity was 20/80 OD [MR: +14.25 +1.00 * 15 degrees ] and 20/200 OS [MR: +15.00 +1.50 * 175 degrees ]. Significant limitation in ocular movements and the presence of an orbital lipodermoid in the infero-temporal aspect of each eye were noted. Forced duction test was positive for the same directions of limitation indicating possible extraocular muscle fibrosis. Ophthalmoscopy was remarkable for the presence of peripheral bony spicules. Corneal topography was compatible with keratoconus (Kmax = 55.04D OD and 52.87D OS). A-scan revealed axial lengths of 16.96 mm OD and 16.32 mm OS, compatible with a diagnosis of nanophthalmos. OCT revealed diffuse macular thickening for both eyes with foveal thickness of 350 um OD and 353 um OS. Over the next 12 years the patient had stable visual acuity, manifest refractions and anterior segment examination. Ophthalmoscopy revealed only minimal progression of pigmentary changes. We report the first case of these simultaneous multiple findings which may refer to a possible syndromic association of congenital or early childhood onset. PMID- 26771302 TI - Structure and Long-Term Stability of Alkylphosphonic Acid Monolayers on SS316L Stainless Steel. AB - Surface modification of stainless steel (SS316L) to improve surface properties or durability is an important avenue of research, as SS316L is widely used in industry and science. We studied, therefore, the formation and stability of a series of organic monolayers on SS316L under industrially relevant conditions. These included acidic (pH 3), basic (pH 11), neutral (Milli-Q water), and physiological conditions [10 mM phosphate-buffered saline (PBS)], as well as dry heating (120 degrees C). SS316L was modified with alkylphosphonic acids of chain length (CH2)n with n varying between 3 and 18. While alkylphosphonic acids of all chain lengths formed self-assembled monolayers with hydrophobic properties, only monolayers of chain lengths 12-18 formed ordered monolayers, as evidenced by static water contact angle (SCA), X-ray photoelectron spectroscopy (XPS), atomic force microscopy (AFM), and infrared reflection absorption spectroscopy (IRRAS). A long-term stability study revealed the excellent stability of monolayers with chain lengths 12-18 for up to 30 days in acid, neutral, and physiological solutions, and for up to 7 days under dry heating. Under strong basic conditions a partial breakdown of the monolayer was observed, especially for the shorter chain lengths. Finally, the effect of multivalent surface attachment on monolayer stability was explored by means of a series of divalent bisphosphonic acids. PMID- 26771304 TI - Flexibility and Constraint in the Evolution of Gene Expression and Behavior. PMID- 26771303 TI - Commercial Ethyl Glucuronide (EtG) and Ethyl Sulfate (EtS) Testing is Not Vulnerable to Incidental Alcohol Exposure in Pregnant Women. AB - BACKGROUND: Ethyl Glucoronide (EtG) and Ethyl Sulfate (EtS) have shown promise as biomarkers for alcohol and may be sensitive enough for use with pregnant women in whom even low-level alcohol use is important. However, there have been reports of over-sensitivity of EtG and EtS to incidental exposure to sources such as alcohol based hand sanitizer. Further, few studies have evaluated these biomarkers among pregnant women, in whom the dynamics of these metabolites may differ. OBJECTIVES: This study evaluated whether commercial EtG-EtS testing was vulnerable to high levels of environmental exposure to alcohol in pregnant women. METHODS: Two separate samples of five nurses-one pregnant and the other postpartum, all of whom reported high levels of alcohol-based hand sanitizer use-provided urine samples before and 4-8 hours after rinsing with alcohol-based mouthwash and using hand sanitizer. The five pregnant nurses provided urine samples before, during, and after an 8-hour nursing shift, during which they repeatedly cleansed with alcohol-based hand sanitizer (mean 33.8 uses). The five postpartum nurses used hand sanitizer repeatedly between baseline and follow-up urine samples. RESULTS: No urine samples were positive for EtG-EtS at baseline or follow-up, despite use of mouthwash and-in the pregnant sample-heavy use of hand sanitizer (mean of 33.8 uses) throughout the 8-hour shift. CONCLUSIONS/IMPORTANCE: Current, commercially available EtG-EtS testing does not appear vulnerable to even heavy exposure to incidental sources of alcohol among pregnant and postpartum women. PMID- 26771305 TI - A Participatory Design Approach to Develop a Web-Based Self-Care Program Supporting Early Rehabilitation among Patients after Total Laryngectomy. AB - AIM: To develop a Web-based self-care program for patients after total laryngectomy according to a participatory design approach. METHODS: We conducted a needs assessment with laryngectomees (n = 9) and their partners (n = 3) by means of a focus group interview. In 4 focus group sessions, a requirement plan was formulated by a team of health care professionals (n = 10) and translated into a prototype. An e-health application was built including illustrated information on functional changes after total laryngectomy as well as video demonstrations of skills and exercises. Usability of the prototype was tested by end users (n = 4) and expert users (n = 10). Interviews were held to elicit the intention to use and the desired implementation strategy. RESULTS: Six main self care topics were identified: (1) nutrition, (2) tracheostomy care, (3) voice prosthesis care, (4) speech rehabilitation, (5) smell rehabilitation, and (6) mobility of head, neck, and shoulder muscles. Expert users expressed concerns regarding tailored exercises, indicated a positive intent to implement the intervention in routine care, and expressed a need for guidance when implementing the intervention. End users and expert users appreciated the content completeness and multimedia-based information built into the application. CONCLUSION: The participatory design is a valuable approach to develop a self-care program to help meet users' needs. PMID- 26771306 TI - The Role of Renal Progenitors in Renal Regeneration. AB - The adult kidney has a remarkable ability to survive injury and restore function despite a limited turnover of cells under physiologic conditions. This accounts both for the tubular and to a lesser extent for the glomerular compartment. It is an ongoing debate whether renal repair is carried out by self-duplication/de differentiation of mature resident renal cells, or by specialized renal progenitors residing in specific niches or by circulating bone marrow-derived stem cells. In this review, the existence of renal progenitor cells and their contribution for regeneration of the tubular and the glomerular compartment are discussed, highlighting landmark publications of recent years. PMID- 26771307 TI - Orally Active and Selective Tubulin Inhibitors as Anti-Trypanosome Agents. AB - OBJECTIVES: There is an urgent need to develop a safe, effective, orally active, and inexpensive therapy for African trypanosomiasis due to the drawbacks of current drugs. Selective tubulin inhibitors have the potential to be promising drug candidates for the treatment of this disease, which is based on the tubulin protein structural difference between mammalian and trypanosome cells. We propose to identify novel tubulin inhibitors from a compound library developed based on the lead compounds that selectively target trypanosomiasis. METHODS: We used Trypanosoma brucei brucei as the parasite model, and human normal kidney cells and mouse microphage cells as the host model. Growth rates of both trypanosomes and mammalian cells were determined as a means to screen compounds that selectively inhibit the proliferation of parasites. Furthermore, we examined the cell cycle profile of the parasite and compared tubulin polymerization dynamics before and after the treatment using identified compounds. Last, in vivo anti parasite activities of these compounds were determined in T. brucei-infected mice. RESULTS: Three compounds were selected that are 100 fold more effective against the growth of T. brucei cells than mammalian cells. These compounds caused cell cycle progression defects in T. brucei cells. Western analyses indicated that these compounds decreased tubulin polymerization in T. brucei cells. The in vivo investigation revealed that these compounds, when admitted orally, inhibited T. brucei cell proliferation in mouse blood. However, they were not potent enough to clear up the infection completely. CONCLUSIONS: These compounds are promising lead compounds as orally active agents for drug development of anti-trypanosome agents. A more detail structure activity relationship (SAR) was summarized that will be used to guide future lead optimization to improve the selectivity and potency of the current compounds. PMID- 26771309 TI - Awareness, Interest, and Preferences of Primary Care Providers in Using Point-of Care Cancer Screening Technology. AB - Well-developed point-of-care (POC) cancer screening tools have the potential to provide better cancer care to patients in both developed and developing countries. However, new medical technology will not be adopted by medical providers unless it addresses a population's existing needs and end-users' preferences. The goals of our study were to assess primary care providers' level of awareness, interest, and preferences in using POC cancer screening technology in their practice and to provide guidelines to biomedical engineers for future POC technology development. A total of 350 primary care providers completed a one time self-administered online survey, which took approximately 10 minutes to complete. A $50 Amazon gift card was given as an honorarium for the first 100 respondents to encourage participation. The description of POC cancer screening technology was provided in the beginning of the survey to ensure all participants had a basic understanding of what constitutes POC technology. More than half of the participants (57%) stated that they heard of the term "POC technology" for the first time when they took the survey. However, almost all of the participants (97%) stated they were either "very interested" (68%) or "somewhat interested" (29%) in using POC cancer screening technology in their practice. Demographic characteristics such as the length of being in the practice of medicine, the percentage of patients on Medicaid, and the average number of patients per day were not shown to be associated with the level of interest in using POC. These data show that there is a great interest in POC cancer screening technology utilization among this population of primary care providers and vast room for future investigations to further understand the interest and preferences in using POC cancer technology in practice. Ensuring that the benefits of new technology outweigh the costs will maximize the likelihood it will be used by medical providers and patients. PMID- 26771308 TI - Multiple Pathogens Including Potential New Species in Tick Vectors in Cote d'Ivoire. AB - BACKGROUND: Our study aimed to assess the presence of different pathogens in ticks collected in two regions in Cote d'Ivoire. METHODOLOGY/PRINCIPAL FINDINGS: Real-time PCR and standard PCR assays coupled to sequencing were used. Three hundred and seventy eight (378) ticks (170 Amblyomma variegatum, 161 Rhipicepalus microplus, 3 Rhipicephalus senegalensis, 27 Hyalomma truncatum, 16 Hyalomma marginatum rufipes, and 1 Hyalomma impressum) were identified and analyzed. We identified as pathogenic bacteria, Rickettsia africae in Am. variegatum (90%), Rh. microplus (10%) and Hyalomma spp. (9%), Rickettsia aeschlimannii in Hyalomma spp. (23%), Rickettsia massiliae in Rh. senegalensis (33%) as well as Coxiella burnetii in 0.2%, Borrelia sp. in 0.2%, Anaplasma centrale in 0.2%, Anaplasma marginale in 0.5%, and Ehrlichia ruminantium in 0.5% of all ticks. Potential new species of Borrelia, Anaplasma, and Wolbachia were detected. Candidatus Borrelia africana and Candidatus Borrelia ivorensis (detected in three ticks) are phylogenetically distant from both the relapsing fever group and Lyme disease group borreliae; both were detected in Am. variegatum. Four new genotypes of bacteria from the Anaplasmataceae family were identified, namely Candidatus Anaplasma ivorensis (detected in three ticks), Candidatus Ehrlichia urmitei (in nine ticks), Candidatus Ehrlichia rustica (in four ticks), and Candidatus Wolbachia ivorensis (in one tick). CONCLUSIONS/SIGNIFICANCE: For the first time, we demonstrate the presence of different pathogens such as R. aeschlimannii, C. burnetii, Borrelia sp., A. centrale, A. marginale, and E. ruminantium in ticks in Cote d'Ivoire as well as potential new species of unknown pathogenicity. PMID- 26771310 TI - Factors Influencing Aqueous Proinflammatory Cytokines and Growth Factors in Uveitic Glaucoma. AB - PURPOSE: To analyze the effects of factors on aqueous humor proinflammatory cytokine and growth factor levels in patients with uveitic glaucoma (UG). METHODS: In this cross-sectional study, we enrolled 143 participants: 1) UG patients (n = 39); 2) primary open-angle glaucoma (POAG) patients (n = 36); and 3) cataract surgery patients, as a comparative group (n = 68). Aqueous humor samples were obtained at the start of surgery. Aqueous cytokine levels were determined using a multiplex immunoassay (xMAP and the Human Cytokine/Chemokine Panel I). RESULTS: In UG cases, mean interleukin (IL)-6, IL-8, monocyte chemotactic protein (MCP)-1, tumor necrosis factor (TNF)-alpha, platelet-derived growth factor (PDGF)-AA, PDGF-AB/BB, and VEGF levels were 171.1, 214.5, 2791.7, 3.5, 23.9, 5.4, and 168.9 pg/mL, respectively, and were higher than those in cataract (non-glaucomatous) cases except PDGF. Levels of IL-6, MCP-1, and VEGF were higher in UG cases than in POAG cases. UG cases with a history of phacoemulsification displayed significantly higher levels of IL-6 (P = 0.0164), IL-8 (P = 0.0003), MCP-1 (P = 0.0465), and PDGF-AB/BB (P = 0.0062) compared to the phakic cases. The presence of cells in the anterior chamber was related to higher levels of IL-8 (P = 0.0002), TNF-alpha (P = 0.0037), and PDGF-AB/BB (P = 0.0009). The level of PDGF-AB/BB was higher in infectious uveitis than in non infectious uveitis (P = 0.0211). The level of transforming growth factor (TGF) beta2 was negatively correlated with the levels of MCP-1 (adjusted R2 = 0.28, t = -2.45, P = 0.031) and TNF-alpha (adjusted R2 = 0.27, t = -2.43, P = 0.032). CONCLUSION: A history of phacoemulsification, the presence of cells in the anterior chamber, and infectious uveitis were related to aqueous proinflammatory cytokine levels in patients with UG. TGF-beta2 might be an anti-inflammatory factor in aqueous humor of UG patients. PMID- 26771311 TI - Combined Healthy Lifestyle Is Inversely Associated with Psychological Disorders among Adults. AB - BACKGROUND AND AIMS: Joint association of lifestyle-related factors and mental health has been less studied in earlier studies, especially in Middle Eastern countries. This study aimed to examine how combinations of several lifestyle related factors related to depression and anxiety in a large group of middle-age Iranian population. METHODS: In a cross-sectional study on 3363 Iranian adults, a healthy lifestyle score was constructed by the use of data from dietary intakes, physical activity, smoking status, psychological distress and obesity. A dish based 106-item semi-quantitative validated food frequency questionnaire (FFQ), General Practice Physical Activity Questionnaire (GPPAQ), General Health Questionnaire (GHQ) and other pre-tested questionnaires were used to assess the components of healthy lifestyle score. The Hospital Anxiety and Depression Scale (HADS) was applied to screen for anxiety and depression. RESULTS: After adjustment for potential confounders, we found that individuals with the highest score of healthy lifestyle were 95% less likely to be anxious (OR: 0.05; 95% CI: 0.01-0.27) and 96% less likely to be depressed (OR: 0.04; 95% CI: 0.01-0.15), compared with those with the lowest score. In addition, non-smokers had lower odds of anxiety (OR: 0.64; 95% CI: 0.47-0.88) and depression (OR: 0.62; 95% CI: 0.48-0.81) compared with smokers. Individuals with low levels of psychological distress had expectedly lower odds of anxiety (OR: 0.13; 95% CI: 0.10-0.16) and depression (OR: 0.10; 95% CI: 0.08-0.12) than those with high levels. Individuals with a healthy diet had 29% lower odds of depression (OR: 0.71; 95% CI: 0.59 0.87) than those with a non-healthy diet. CONCLUSION: We found evidence indicating that healthy lifestyle score was associated with lower odds of anxiety and depression in this group of Iranian adults. Healthy diet, psychological distress, and smoking status were independent predictors of mental disorders. PMID- 26771313 TI - Estimates of prostate cancer burden in Italy. AB - Age-standardized incidence rates of prostate cancer (PC) sharply increased during the period 1990-2005 in Italian areas covered by cancer registries, while corresponding mortality rates remained nearly constant. The latest observations have reported on a reversal of the incidence trend with decreasing values after 2005. We provided incidence, mortality, and prevalence estimates at national and geographical area levels, together with time projections up to the year 2020. We applied the MIAMOD method, using as input national mortality data for the years 1970-2010 and population-based survival data for the period of diagnosis (1985 2002). We assumed relative survival of prostate cancer remained constant after the year of diagnosis (2005). The age-standardized incidence rates of PC were estimated to increase during the period 1984-2005, from 31 per 100,000 in 1984 to 93 per 100,000 in 2005. From 2005 onwards, the estimated rates declined to 71 in 2015 and to 62 in 2020. Age-standardized mortality rates slightly increased from 1970 up to about 19 per 100,000 in 1999 and then started to decrease with an estimated reduction of about 2.3% per year. Mortality projections indicated a continuing reduction, with a predicted age-standardized rate of about 12 per 100,000 in 2020. Prevalence was estimated to continuously increase up to a crude prevalence value of 1.2% in the year 2020. The results indicate that the epidemic peak of PC was reached around the year 2005 followed by declining incidence rates, while a substantial decrease in mortality, starting during the early 2000s, is expected to continue during the 2010s. PMID- 26771314 TI - Secular trends of HPV genotypes in invasive cervical cancer in Cali, Colombia 1950-1999. AB - Aim To estimate relative contribution and time trends of HPV types in cervical cancer in Cali, Colombia over a 50 years' period. METHODS: Paraffin blocks of 736 cervical cancer histological confirmed cases were retrieved from the pathology laboratory at Hospital Universitario del Valle (Cali, Colombia) and HPV genotyped using SPF10-PCR/DEIA/LiPA25 (version 1) assay. Marginal effect of age and year of diagnosis in secular trends of HPV type prevalence among HPV+ cases were assessed by robust Poisson regression analysis. RESULTS: 64.7% (95%CI: 59.9-69.2) of squamous cell carcinomas (SCCs) were attributed to HPV 16 and 18, 78.2% (95%CI: 74-82) to HPV 16, 18, 31, 33 and 45 and 84.8% (95%CI: 81-88.1) to HPV 16, 18, 31, 33, 45, 52 and 58 while ninety-three percent of adenocarcinomas (ADCs) were attributed to HPV 16, 18 and 45 only. The prevalence of specific HPV types did not change over the 50-year period. A significant downward trend of prevalence ratios of HPV16 (P=0.017) and alpha7 but HPV 18 (i.e., HPV 39, 45, 68, 70, P=0.024) with increasing age at diagnosis was observed. In contrast, the prevalence ratio to other HPV genotypes of alpha9 but HPV 16 genotypes (i.e., HPV 31, 33, 35, 52, 58, 67, P=0.002) increased with increasing age at diagnosis. CONCLUSION: No changes were observed in the relative contribution of HPV types in cervical cancer in Cali, Colombia during the 50 years. In this population, an HPV vaccine including the HPV 16, 18, 31, 33, 45, 52 and 58 genotypes may have the potential to prevent ~85% and 93% of SCC and ADC cases respectively. PMID- 26771312 TI - Co-Circulation of Canine Coronavirus I and IIa/b with High Prevalence and Genetic Diversity in Heilongjiang Province, Northeast China. AB - To trace the evolution of canine coronavirus (CCoV), 201 stool samples from diarrheic dogs in northeast China were subjected to reverse transcription polymerase chain reactions (RT-PCRs) targeting the partial M and S genes of CCoV, followed by an epidemiological analysis. M gene RT-PCRs showed that 28.36% (57/201) of the samples were positive for CCoV; of the 57 positive samples, CCoV I and CCoV-II accounted for 15.79% (9/57) and 84.21% (48/57), respectively. A sequence comparison of the partial M gene revealed nucleotide homologies of 88.4% 100% among the 57 CCoV strains, and 88.7%-96.2% identity between the 57 CCoV strains and the Chinese reference strain HF3. The CCoV-I and CCoV-II strains exhibited genetic diversity when compared with reference strains from China and other countries. The 57 CCoV strains exhibited high co-infection rates with canine kobuvirus (CaKV) (33.33%) and canine parvovirus-2 (CPV-2) (31.58%). The CCoV prevalence in diarrheic dogs differed significantly with immunization status, regions, seasons, and ages. Moreover, 28 S genes were amplified from the 57 CCoV-positive samples, including 26 CCoV-IIa strains, one CCoV-IIb strain, and one CCoV-I strain. A sequence comparison of the partial S gene revealed 86.3% 100% nucleotide identity among the 26 CCoV-IIa strains, and 89.6%-92.2% identity between the 26 CCoV-IIa strains and the Chinese reference strain V1. The 26 CCoV IIa strains showed genetic diversity when compared with reference strains from China and other countries. Our data provide evidence that CCoV-I, CCoV-IIa, and CCoV-IIb strains co-circulate in the diarrhoetic dogs in northeast China, high co infection rates with CaKV and CPV-2 were observed, and the CCoV-II strains exhibited high prevalence and genetic diversity. PMID- 26771315 TI - Screening of Pre-miRNA-155 Binding Peptides for Apoptosis Inducing Activity Using Peptide Microarrays. AB - MicroRNA-155, one of the most potent miRNAs that suppress apoptosis in human cancer, is overexpressed in numerous cancers, and it displays oncogenic activity. Peptide microarrays, constructed by immobilizing 185 peptides containing the C terminal hydrazide onto epoxide-derivatized glass slides, were employed to evaluate peptide binding properties of pre-miRNA-155 and to identify its binding peptides. Two peptides, which were identified based on the results of peptide microarray and in vitro Dicer inhibition studies, were found to inhibit generation of mature miRNA-155 catalyzed by Dicer and to enhance expression of miRNA-155 target genes in cells. In addition, the results of cell experiments indicate that peptide inhibitors promote apoptotic cell death via a caspase dependent pathway. Finally, observations made in NMR and molecular modeling studies suggest that a peptide inhibitor preferentially binds to the upper bulge and apical stem-loop region of pre-miRNA-155, thereby suppressing Dicer-mediated miRNA-155 processing. PMID- 26771316 TI - Pharmacokinetics of Amitriptyline HCl and Its Metabolites in Healthy African Grey Parrots ( Psittacus erithacus ) and Cockatoos (Cacatua Species). AB - Amitriptyline, a tricyclic antidepressant, is used clinically to treat feather destructive behavior in psittacine birds at a recommended dosage of 1-5 mg/kg PO q12-24h, which has been extrapolated from human medicine and based on anecdotal reports. The purpose of this pilot study was to describe the individual and population pharmacokinetic parameters of amitriptyline after a single oral dose at 1.5 mg/kg, 4.5 mg/kg, and 9 mg/kg in healthy African grey parrots ( Psittacus erithacus , n = 3) and cockatoos (Cacatua species, n = 3). Three birds received an initial 1.5 mg/kg oral dose, and blood samples were collected for 24 hours at fixed time intervals. Serum concentrations of amitriptyline and its metabolites were determined by polarized immunofluorescence. After determining the initial parameters and a 14-day washout period, 2 African grey parrots and 1 cockatoo received a single oral dose at 4.5 mg/kg, and 3 cockatoos and 1 African grey parrot received a single oral dose at 9 mg/kg. Concentrations reached the minimum therapeutic range reported in people (60 ng/mL) in 4 of 10 birds (4.5 and 9.0 mg/kg). Concentrations were within the toxic range in 1 African grey parrot (9 mg/kg), with regurgitation, ataxia, and dullness noted. Serum concentrations were nondetectable in 3 birds (1.5 and 4.5 mg/kg) and detectable but below the human therapeutic range in 3 birds (1.5 mg/kg and 9 mg/kg). Drug concentrations were continuing to increase at the end of the study (24 hours) in 1 bird. Elimination half-life varied from 1.6 to 91.2 hours. Population pharmacokinetics indicated significantly varied absorption, and elimination constants varied between species. Although amitriptyline appeared to be tolerated in most birds, disposition varies markedly among and within species, between the 2 genera, and within individual birds. The current recommended dosage of 1-5 mg/kg q12h in psittacine birds appears insufficient to achieve serum concentrations within the human therapeutic range and does not yield predictable concentrations. Results of this study suggest doses of up to 9 mg/kg may be necessary, although that dose may produce adverse events in some birds, and elimination half-life is sufficiently variable that dosing intervals are not predictable. Therapeutic drug monitoring combined with response to therapy is indicated to determine individual therapeutic ranges. PMID- 26771317 TI - Thromboelastography in Selected Avian Species. AB - Currently available assay methods and reagents are not optimized for evaluating avian hemostasis; therefore, assessing avian coagulopathies is challenging. Recently, thromboelastography (TEG), which measures the viscoelastic properties of blood, has been used clinically in mammalian species to diagnose and characterize hemostatic disorders. To evaluate TEG in healthy individuals of 6 avian species, we modified existing mammalian TEG protocols to allow analysis of citrated, avian whole-blood samples collected from scarlet ibis (Eudocimus ruber) (n = 13), American flamingos ( Phoenicopterus ruber ) (n = 13), helmeted Guinea fowl ( Numida meleagris ) (n = 12), Amazon parrots (Amazona species) (n = 9), Humboldt penguins ( Spheniscus humboldti ) (n = 6), and domestic chickens (n = 16). Activated partial thromboplastin time, prothrombin time, and fibrinogen were measured as a means of comparison. Regardless of the mode of activation, clot formation in the species studied was markedly delayed compared with mammals. Because of prolonged reaction time (14.7-52.7 minutes) with kaolin and diluted tissue factor, undiluted human tissue factor was used in all avian samples because it provided the shortest reaction time. Species differed significantly in reaction time (P = .007), clotting rate (P < .001), rate of clot formation (alpha angle; P < .001), and maximum amplitude (P < .001) values, indicating that species-specific reference intervals are necessary. Based on these results, TEG with specific reference intervals could prove useful in evaluating avian hemostatic disorders. PMID- 26771318 TI - Analysis of Arterial and Venous Blood Gases in Healthy Gyr Falcons ( Falco rusticolus ) Under Anesthesia. AB - Arterial and venous blood gas analysis is useful in the assessment of tissue oxygenation and ventilation and in diagnosis of metabolic and respiratory derangements. It can be performed with a relatively small volume of blood in avian patients under emergency situations. Arterial and venous blood gas analysis was performed in 30 healthy gyr falcons ( Falco rusticolus ) under anaesthesia to establish temperature-corrected reference intervals for arterial blood gas values and to compare them to temperature-corrected venous blood gas values with a portable point-of-care blood gas analyzer (i-STAT 1, Abbott Laboratories, Abbott Park, IL, USA). Statistically significant differences were observed between the temperature-corrected values of pH, partial pressure of carbon dioxide (Pco2), and partial pressure of oxygen (Po2) and the corresponding nontemperature corrected values of these parameters in both arterial and venous blood. Values of temperature-corrected pH, temperature-corrected Pco2, bicarbonate concentrations, and base excess of extra cellular fluid did not differ significantly between arterial and venous blood, suggesting that, in anesthetized gyr falcons, venous blood gas analysis can be used in place of arterial blood gas analysis in clinical situations. Values for hematocrit, measured by the point-of-care analyzer, were significantly lower compared with those obtained by the microhematocrit method. PMID- 26771319 TI - Pharmacokinetics of Short- and Long-acting Formulations of Oxytetracycline After Intramuscular Administration in Chickens. AB - Both short- and long-acting formulations of oxytetracycline are commonly used in veterinary medicine to treat animals infected with gram-negative and gram positive bacteria, rickettsiae, mycoplasma, and chlamydiae. To compare pharmacokinetics of short- and long-acting oxytetracycline in chickens, injectable formulations from the same pharmaceutical company were administered to healthy 6-week-old broiler chickens in accordance to the labeled instructions. Fourteen chickens were separated into 2 groups: chickens in group A (n = 7) were administered the short-acting formulation (10 mg/kg IM q24h) for 4 consecutive days, whereas those in group B (n = 7) were treated with a single dose (20 mg/kg IM) of the long-acting formulation. Blood samples were collected into heparinized tubes before and at 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 10, and 24 hours after initial treatment. Thereafter, blood samples were taken every 24 hours up to 120 hours. Plasma concentrations of oxytetracycline were determined by competitive enzyme linked immunoabsorbent assay, and pharmacokinetic parameters were obtained. Both formulations delivered therapeutic plasma concentrations of oxytetracycline for approximately 100% of their respective dosing intervals as recommended. However, considering the additional labor, patient stress, and mortalities associated with handling, in addition to rejection of the carcass due to tissue necrosis resulting from multiple injections, we recommend use of the long-acting instead of the short-acting injectable formulation in broiler chickens. PMID- 26771320 TI - Comparison of Hematologic and Biochemical Test Results in Blood Samples Obtained by Jugular Venipuncture Versus Nail Clip in Moluccan Cockatoos (Cacatua moluccensis). AB - In birds, blood samples are often collected from the jugular, medial metatarsal, and basilic vein. Samples are sometimes collected by toe nail clip, but concerns to avoid drawing blood from the nail include pain after nail clips for blood collection, potential differences in complete blood count (CBC) results, and potential contamination with uric acid values. To compare differences in biochemical and hematologic values in blood samples obtained by jugular venipuncture versus toenail clip, blood samples were collected from Moluccan cockatoos (Cacatua moluccensis) (N = 23) and sent to a commercial laboratory for routine CBCs and serum biochemical analysis. Results showed good agreement between venipuncture and nail clip blood samples in red blood cell count, packed cell volume, heterophil count and percentage, lymphocyte count and percentage, aspartate aminotransferase, chloride, creatine phosphokinase, glucose, lactate dehydrogenase, total protein, and uric acid values. Constant bias was found in values of bile acids, cholesterol, and hemoglobin. Proportional bias toward higher values in the jugular sample were found in total white blood cell (WBC) count and inorganic phosphorus. Serum calcium plots revealed a proportional bias toward higher values in the toe nail blood when values were increased. Results suggest some differences in WBC count, bile acids, calcium, cholesterol, hemoglobin, and phosphorus values between blood samples collected by jugular venipuncture and samples collected by toe nail clip, but the differences are mostly minor and, with the possible exception of inorganic phosphorus and marginally elevated or very low WBC counts, are unlikely to affect the use or interpretation of the avian blood panel. PMID- 26771321 TI - Health and Reproductive Assessment of Selected Puerto Rican Parrots ( Amazona vittata ) in Captivity. AB - The Puerto Rican parrot ( Amazona vittata ) has become an iconic and high-profile conservation species. The cornerstone of the recovery plan for this critically endangered species is an active captive breeding program, management of the wild population, and a long-term reintroduction program. In 2002, 40 adult Puerto Rican parrots that had not produced viable offspring were selected for reproductive assessment at 2 aviary populations in Puerto Rico (Iguaca and Rio Abajo), which are the only sources of parrots for release. The goal was to enhance reproductive potential and produce productive pairings in an attempt to augment the population growth and provide ample individuals for reintroduction. Seven Hispanolian Amazon parrots ( Amazona ventralis ) that were used as surrogate parents for the Puerto Rican parrots were also included in the study. This assessment included physical examination, endoscopic evaluation, hematologic and plasma biochemical profiles, viral screening, and hormonal assays. Results of general physical examination and hematologic and plasma biochemical testing revealed overall good health and condition of this subset of the population of Puerto Rican parrots; no major infectious diseases were found. Endoscopic examination also revealed overall good health and condition, especially of females. The apparent low fertility of male birds warrants further investigation. The findings helped to define causes of reproductive failure in the selected pairs and individual birds. New pairings resulting from the assessment helped to augment reproduction of this critically endangered species. PMID- 26771322 TI - Chronic T-cell Lymphocytic Leukemia in a Black Swan ( Cygnus atratus ): Diagnosis, Treatment, and Pathology. AB - An asymptomatic 14-year old, male black swan ( Cygnus atratus ) housed at a zoological institution was presented for routine preshipment examination. Hematologic findings indicated that the bird had a severe lymphocytic leukocytosis, consistent with chronic lymphocytic leukemia. Radiographs showed the presence of multiple soft tissue masses within the caudal coelomic cavity; ultrasound showed one mass to be an enlarged spleen, a cystic mass near the gonads, and a mass suspected to be associated with the ventriculus. Results of further antemortem diagnostics, including bone marrow aspiration, fine-needle aspirate cytology of the coelomic masses, and immunohistochemical staining confirmed T-cell leukemia with infiltration of the bone marrow and the spleen. The bird showed partial response to treatment with chlorambucil, lomustine, prednisone, l-asparaginase, and whole-body radiation, with neither evidence of adverse effects nor clinical signs of disease. Although the leukemia showed response, there was no evidence of remission at any point. The swan died 433 days after initial evaluation and initiation of therapy. Necropsy, histopathologic findings, and immunohistochemistry results confirmed extensive infiltration of multiple organs, including the liver, spleen, heart, lungs, and kidneys with neoplastic T-cell lymphocytes. PMID- 26771323 TI - Polyostotic Chondroblastic Osteosarcoma in a Kestrel ( Falco tinnunculus ). AB - We report a case of polyostotic chondroblastic osteosarcoma in a kestrel ( Falco tinnunculus ) admitted to the Wildlife Rehabilitation and Rescue Center (Naples, Italy). A consolidated fracture of the left tibiotarsus bone and a deviation of the limb were evident. After radiographic, cytologic, and histopathologic examinations, a diagnosis of polyostotic chondroblastic osteosarcoma was made. To our knowledge, this is the first report on polyostotic chondroblastic osteosarcoma in a kestrel. PMID- 26771324 TI - Lead Toxicosis in a Southern Ground Hornbill Bucorvus leadbeateri in South Africa. AB - The southern ground hornbill (Bucorvus leadbeateri) has been classified as globally vulnerable and, in South Africa, regionally endangered, with a negative population trend. Factors contributing to the population decline in South Africa are poisoning, electrocution, and illegal capture for trade, coupled with slow reproductive rates and extensive habitat requirements. Lead toxicosis is a previously undescribed threat for the population. An adult southern ground hornbill presented with acute lead toxicosis due to lead particles in the gizzard, which required intensive treatment. Two other hornbills were likely exposed. The source of the lead in these cases was likely a carcass of a porcupine that was killed with lead shot. This report highlights the importance of the use of lead-free ammunition within the habitat of the southern ground hornbill in South Africa. PMID- 26771326 TI - A New Look at the Endangered Species Act and Its Effects on Genetic Diversity. PMID- 26771327 TI - What Is Your Diagnosis? Leucocytozoonosis. PMID- 26771325 TI - Detection and Management of Air Sac Trematodes (Szidatitrema Species) in Captive Multispecies Avian Exhibits. AB - From 2 exhibits in a zoological collection, 2 juvenile fairy bluebirds ( Irena puella ) and 1 adult blue-grey tanager (Thraupis episcopus) died within 3 months of one another. The cause of death was attributed to air sac trematodes, which were identified as Szidatitrema species based on morphology of adult trematodes and miracidia isolated from a snail intermediate host. To determine the extent of trematodiasis in the collection, individual exhibits within the same building as the original presenting cases were assessed, with birds representing 27 avian species from 9 orders. Sampling consisted of individual (n = 244) and pooled same species group (n = 193) fecal examinations, and for some individuals, and tracheal swab (n = 106), resulting in a total of 543 samples. In addition, tracheal swabs were performed on 14 birds for comparative cytology, but no parasites were found. Flukes were positively identified in 4 tracheal swab samples (4%), 37 individual fecal samples (15%), and 52 of the group fecal samples (27%). When results of the swab method were compared with those of fecal examination, fecal testing was significantly associated (P < .001) with positive results. Based on these results, a screening process was instituted of 3- or 4 day combined fecal samples evaluated by both sedimentation and flotation techniques 2 weeks before outgoing shipments or intrazoo transfers of birds housed in exhibits known to have snail populations. Snail control methods also were initiated in all exhibits. Treatment with praziquantel was carried out on a case-by-case basis, and included oral, parenteral, and nebulized administration. Although control measures were expected to manage the infection and reduce distribution of the parasite to other collections, complete eradication of trematodes in the population is unlikely. PMID- 26771336 TI - Single Cesium Lead Halide Perovskite Nanocrystals at Low Temperature: Fast Single Photon Emission, Reduced Blinking, and Exciton Fine Structure. AB - Metal-halide semiconductors with perovskite crystal structure are attractive due to their facile solution processability, and have recently been harnessed very successfully for high-efficiency photovoltaics and bright light sources. Here, we show that at low temperature single colloidal cesium lead halide (CsPbX3, where X = Cl/Br) nanocrystals exhibit stable, narrow-band emission with suppressed blinking and small spectral diffusion. Photon antibunching demonstrates unambiguously nonclassical single-photon emission with radiative decay on the order of 250 ps, representing a significant acceleration compared to other common quantum emitters. High-resolution spectroscopy provides insight into the complex nature of the emission process such as the fine structure and charged exciton dynamics. PMID- 26771337 TI - Care around birth, infant and mother health and maternal health investments - Evidence from a nurse strike. AB - Care around birth may impact child and mother health and parental health investments. We exploit the 2008 national strike among Danish nurses to identify the effects of care around birth on infant and mother health (proxied by health care usage) and maternal investments in the health of their newborns. We use administrative data from the population register on 39,810 Danish births in the years 2007-2010 and complementary survey and municipal administrative data on 8288 births in the years 2007-2009 in a differences-in-differences framework. We show that the strike reduced the number of mothers' prenatal midwife consultations, their length of hospital stay at birth, and the number of home visits by trained nurses after hospital discharge. We find that this reduction in care around birth increased the number of child and mother general practitioner (GP) contacts in the first month. As we do not find strong effects of strike exposure on infant and mother GP contacts in the longer run, this result suggests that parents substitute one type of care for another. While we lack power to identify the effects of care around birth on hospital readmissions and diagnoses, our results for maternal health investments indicate that strike-exposed mothers especially those who lacked postnatal early home visits-are less likely to exclusively breastfeed their child at four months. Thus reduced care around birth may have persistent effects on treated children through its impact on parental investments. PMID- 26771339 TI - Target-organ damage and incident hypertension: the Korean genome and epidemiology study. AB - OBJECTIVE: Hypertension is associated with cardiovascular organ damage. However, data are scanty on whether individual forms or combinations of subclinical target organ damage (TOD) increase the risk of incident hypertension in nonhypertensive study participants. METHODS: A total of 1785 nonhypertensive participants from the fourth biennial examination (2007-2008) of the Korean Genome and Epidemiology Study were followed-up for four years. Echocardiographic left ventricular (LV) hypertrophy, LV diastolic dysfunction, increased carotid intima-media thickness (cIMT), and brachial-ankle pulse wave velocity (baPWV) were defined according to the current guidelines. RESULTS: During 4-year follow-up, 19.9% of participants developed hypertension. In multivariate Cox proportional hazards models, the adjusted hazard ratios for developing hypertension were 1.39, 1.66, 1.48, and 0.78 for higher values of the LV mass index, cIMT, baPWV, and tissue Doppler e' velocity, respectively (all P < 0.01). The hazard ratios for LV hypertrophy, LV diastolic dysfunction, cIMT >75th percentile, and baPWV >= 1400 cm/s were 1.61, 1.30, 1.86, and 2.07, respectively (all P < 0.05). Compared with participants without any TOD, those with combinations of TOD types had significantly greater risk for developing hypertension (hazard ratio = 2.12 and 3.98 for 1-2 and 3-4 TOD sites, respectively, all P < 0.001). CONCLUSION: In the nonhypertensive population, each subclinical form of TOD independently predicts incident hypertension. In addition, the combinations of various forms of TOD are associated with stepwise increases in the risk for developing hypertension. The results suggest that asymptomatic TOD does not always exist in an intermediate stage in the cardiovascular continuum. PMID- 26771338 TI - (Pro)renin receptor contributes to regulation of renal epithelial sodium channel. AB - BACKGROUND: Recent studies reported increased (Pro)renin receptor (PRR) expression during low-salt intake. We hypothesized that PRR plays a role in regulation of renal epithelial sodium channel (ENaC) through serum and glucocorticoid-inducible kinase isoform 1 (SGK-1)-neural precursor cell expressed, developmentally downregulated 4-2 (Nedd4-2) signaling pathway. METHOD: Male Sprague-Dawley rats on normal-sodium diet and mouse renal inner medullary collecting duct cells treated with NaCl at 130 mmol/l (normal salt), or 63 mmol/l (low salt) were studied. PRR and alpha-ENaC expressions were evaluated 1 week after right uninephrectomy and left renal interstitial administration of 5% dextrose, scramble shRNA, or PRR shRNA (n = 6 each treatment). RESULTS: In-vivo PRR shRNA significantly reduced expressions of PRR throughout the kidney and alpha-ENaC subunits in the renal medulla. In inner medullary collecting duct cells, low salt or angiotensin II (Ang II) augmented the mRNA and protein expressions of PRR (P < 0.05), SGK-1 (P < 0.05), and alpha-ENaC (P < 0.05). Low salt or Ang II increased the phosphorylation of Nedd4-2. In cells treated with low salt or Ang II, PRR siRNA significantly downregulated the mRNA and protein expressions of PRR (P < 0.05), SGK-1 (P < 0.05), and alpha-ENaC expression (P < 0.05). CONCLUSION: We conclude that PRR contributes to the regulation of alpha ENaC via SGK-1-Nedd4-2 signaling pathway. PMID- 26771340 TI - Eating frequency predicts new onset hypertension and the rate of progression of blood pressure, arterial stiffness, and wave reflections. AB - BACKGROUND: Cross-sectional evidence indicates that eating frequency correlates with blood pressure, hypertension, and related target organ damage. The aim of the present study was to prospectively assess eating frequency as a predictor of arteriosclerosis progression and new onset hypertension over a follow-up period of 5 years in adults without cardiovascular disease. METHODS: Eating frequency among other dietary parameters was evaluated in 115 nondiabetic study participants from a general population sample (54 +/- 9.1 years, 45 women) at a baseline visit. Metabolic parameters known to be associated with eating frequency, markers of arteriosclerosis, including augmentation index, pulse wave velocity, SBP, and DBP were evaluated in all volunteers at baseline and after a 5 year follow-up. RESULTS: By applying linear mixed models analysis, it was found that a high eating frequency at baseline significantly correlated with the rate of progression of pulse wave velocity (beta = 0.521, P = 0.004), augmentation index (beta = 0.503, P = 0.01), SBP (beta = 0.694, P < 0.001), and DBP (beta = 0.477, P = 0.009) and the incidence of new onset hypertension (odds ratio = 8.89, P < 0.001). After adjustment traditional cardiovascular risk factors, heart rate, homeostasis model assessment index of insulin resistance and total energy intake, the associations with augmentation index, SBP, DBP, and new onset hypertension remained significant. CONCLUSION: In a population of nondiabetic adults without cardiovascular disease, eating frequency is associated with the rate of progression of wave reflections, blood pressure and of new onset hypertension. Interventional studies should confirm these data and possibly further assess the utility of eating behavior in the prevention of new onset hypertension and related target organ damage. PMID- 26771341 TI - ATRQbeta-001 vaccine prevents atherosclerosis in apolipoprotein E-null mice. AB - OBJECTIVE: Angiotensin II (AngII) type 1 receptor (AT1R) blockers have been proved to reduce atherosclerosis. Previously, we have invented ATRQbeta-001 vaccine which showed a desirable blocking effect for AT1R. The purpose of this study was to investigate whether ATRQbeta-001 vaccine would prevent atherosclerosis in apolipoprotein E-null (ApoE-/-) mice. METHODS: Male ApoE-/- mice were administered with ATRQbeta-001 vaccine, Qbeta virus-like particles, valsartan or vehicle over a period of 24 weeks. In vitro, human coronary artery endothelial cells preincubated with the anti-ATR-001 antibody, the neutralization antibody or valsartan for 2 h, were treated with AngII for 24 h. Histological stain and molecule biology methods were used to assess the atheroprotective effect of the vaccine. RESULTS: ATRQbeta-001 vaccine significantly reduced the lesion area and promoted the stability of atherosclerotic plaque. Meanwhile, macrophage infiltration as well as the expressions of adhesion molecules and monocyte chemoattractant protein-1 was obviously decreased in the ATRQbeta-001 vaccine group. Additionally, the vaccine markedly reduced the apoptosis in the lesions of the ApoE-/- mice. In vitro, the anti-ATR-001 antibody inhibited endothelial apoptosis induced by AngII. Furthermore, ATRQbeta-001 vaccine exhibited a dramatical attenuation in the expressions of lectin-like oxidized low density lipoprotein receptor-1 and AT1R in the aortic. More importantly, compared with the valsartan group, no obvious feedback of the plasma renin-angiotensin system was elicited in the vaccine group. CONCLUSION: The results demonstrated that ATRQbeta-001 vaccine reduced the progression of atherosclerosis in ApoE-/- mice without obvious feedback of renin-angiotensin system. PMID- 26771342 TI - Relationship between aortic root size and glomerular filtration rate in hypertensive patients. AB - OBJECTIVE: Recent studies suggest that enlarged aortic root diameter (ARD) may predict cardiovascular events in absence of aneurysmatic alterations. Little is known about the influence of renal function on ARD. Our study was aimed to assess the relationships between glomerular filtration rate (GFR) and ARD in hypertensive subjects. METHODS: We enrolled 611 hypertensive individuals (mean age: 52 +/- 15 years; men 63%). ARD was measured by echocardiography at the level of Valsalva's sinuses using M-mode tracings. It was considered as absolute measure, normalized to body surface area (ARD/BSA) and indexed to height (ARD/H). GFR was estimated by the Chronic Kidney Disease Epidemiology Collaboration equation. The study population was categorized into seven groups: subjects without chronic kidney disease (no CKD) and subjects with increasing severity of CKD (1, 2, 3a, 3b, 4, 5), as proposed by the 2012 Kidney Disease: Improving Global Outcomes guidelines. RESULTS: ARD/BSA and ARD/H showed a stepwise increase from the group with normal renal function to the groups with increasing severity of CKD. GFR correlated significantly with ARD (r = -0.17), ARD/BSA (r = -0.43) and ARD/H (r = -0.35; all P < 0.001). The associations of GFR with ARD/BSA (beta = -0.26; P < 0.001) and ARD/H (beta = -0.13; P = 0.01) held in linear multiple regression analyses, after adjustment for various confounding factors. CONCLUSION: Our study seems to suggest that a reduced renal function may adversely influence ARD. This may contribute to explain the enhanced cardiovascular risk associated with renal insufficiency. PMID- 26771343 TI - Prevalence, awareness, and control of hypertension in elderly and very elderly in Poland: results of a cross-sectional representative survey. AB - OBJECTIVE: The aim of the study was to examine prevalence, awareness, and control of hypertension in elderly and very elderly in Poland. METHODS: The random sample of 4950 study participants aged 65 or more (age range 65-104 years), equally distributed in six age subgroups, and participated in cross-sectional, nationally representative survey PolSenior. During two separate visits, standardized interviews on awareness of hypertension as well as anthropometric measurements, blood pressure (BP) and heart rate readings were obtained. Hypertension was defined according to 2013 European Society of Hypertension/European Society of Cardiology Guidelines. RESULTS: Mean SBP was highest in men aged 75-79 years (148.3 mmHg) and in women aged 80-84 years (149.9 mmHg), and then steadily decreased, whereas DBP decreased steadily from age 65. Hypertension affected about 80% of septuagenarians. Its prevalence decreased with age to 67% in women and 60% in men aged 90 years or older. In nonagenarians, awareness of hypertension (72% in women and 61% in men) and percentage of treated study participants (64% of women and 54% of men) was the lowest. In contrast, among treated study participants proportion of well controlled (BP < 140/90 mmHg) was the highest in people older than 85 reaching 34% among nonagenarian women and 38% in men. CONCLUSIONS: The results show a reversed trend in prevalence and control of hypertension in people aged 80 years and older when compared with the younger elderly. As awareness and treatment of hypertension decreases with advanced age, it seems reasonable to extend screening programs and antihypertensive initiatives for the elderly and very elderly. PMID- 26771346 TI - The Challenge: How can we improve the quality of ecotoxicology research to increase relevance and use in regulatory decision making? PMID- 26771345 TI - Are harmful algal blooms becoming the greatest inland water quality threat to public health and aquatic ecosystems? AB - In this Focus article, the authors ask a seemingly simple question: Are harmful algal blooms (HABs) becoming the greatest inland water quality threat to public health and aquatic ecosystems? When HAB events require restrictions on fisheries, recreation, and drinking water uses of inland water bodies significant economic consequences result. Unfortunately, the magnitude, frequency, and duration of HABs in inland waters are poorly understood across spatiotemporal scales and differentially engaged among states, tribes, and territories. Harmful algal bloom impacts are not as predictable as those from conventional chemical contaminants, for which water quality assessment and management programs were primarily developed, because interactions among multiple natural and anthropogenic factors determine the likelihood and severity to which a HAB will occur in a specific water body. These forcing factors can also affect toxin production. Beyond site specific water quality degradation caused directly by HABs, the presence of HAB toxins can negatively influence routine surface water quality monitoring, assessment, and management practices. Harmful algal blooms present significant challenges for achieving water quality protection and restoration goals when these toxins confound interpretation of monitoring results and environmental quality standards implementation efforts for other chemicals and stressors. Whether HABs presently represent the greatest threat to inland water quality is debatable, though in inland waters of developed countries they typically cause more severe acute impacts to environmental quality than conventional chemical contamination events. The authors identify several timely research needs. Environmental toxicology, environmental chemistry, and risk-assessment expertise must interface with ecologists, engineers, and public health practitioners to engage the complexities of HAB assessment and management, to address the forcing factors for HAB formation, and to reduce the threats posed to inland surface water quality. PMID- 26771347 TI - In Response: An academic perspective. PMID- 26771348 TI - In Response: A Government perspective. PMID- 26771349 TI - In Response: Business perspective. PMID- 26771350 TI - Defining the role of omics in assessing ecosystem health: Perspectives from the Canadian environmental monitoring program. AB - Scientific reviews and studies continue to describe omics technologies as the next generation of tools for environmental monitoring, while cautioning that there are limitations and obstacles to overcome. However, omics has not yet transitioned into national environmental monitoring programs designed to assess ecosystem health. Using the example of the Canadian Environmental Effects Monitoring (EEM) program, the authors describe the steps that would be required for omics technologies to be included in such an established program. These steps include baseline collection of omics endpoints across different species and sites to generate a range of what is biologically normal within a particular ecosystem. Natural individual variability in the omes is not adequately characterized and is often not measured in the field, but is a key component to an environmental monitoring program, to determine the critical effect size or action threshold for management. Omics endpoints must develop a level of standardization, consistency, and rigor that will allow interpretation of the relevance of changes across broader scales. To date, population-level consequences of routinely measured endpoints such as reduced gonad size or intersex in fish is not entirely clear, and the significance of genome-wide molecular, proteome, or metabolic changes on organism or population health is further removed from the levels of ecological change traditionally managed. The present review is not intended to dismiss the idea that omics will play a future role in large-scale environmental monitoring studies, but rather outlines the necessary actions for its inclusion in regulatory monitoring programs focused on assessing ecosystem health. PMID- 26771351 TI - Development of Bipotent Cardiac/Skeletal Myogenic Progenitors from MESP1+ Mesoderm. AB - The branchiomeric skeletal muscles co-evolved with new chambers of the heart to enable predatory feeding in chordates. These co-evolved tissues develop from a common population in anterior splanchnic mesoderm, referred to as cardiopharyngeal mesoderm (CPM). The regulation and development of CPM are poorly understood. We describe an embryonic stem cell-based system in which MESP1 drives a PDGFRA+ population with dual cardiac and skeletal muscle differentiation potential, and gene expression resembling CPM. Using this system, we investigate the regulation of these bipotent progenitors, and find that cardiac specification is governed by an antagonistic TGFbeta-BMP axis, while skeletal muscle specification is enhanced by Rho kinase inhibition. We define transcriptional signatures of the first committed CPM-derived cardiac and skeletal myogenic progenitors, and discover surface markers to distinguish cardiac (PODXL+) from the skeletal muscle (CDH4+) CPM derivatives. These tools open an accessible window on this developmentally and evolutionarily important population. PMID- 26771352 TI - Overcoming Pluripotent Stem Cell Dependence on the Repair of Endogenous DNA Damage. AB - Pluripotent stem cells (PSCs) maintain a low mutation frequency compared with somatic cell types at least in part by preferentially utilizing error-free homologous recombination (HR) for DNA repair. Many endogenous metabolites cause DNA interstrand crosslinks, which are repaired by the Fanconi anemia (FA) pathway using HR. To determine the effect of failed repair of endogenous DNA lesions on PSC biology, we generated iPSCs harboring a conditional FA pathway. Upon FA pathway loss, iPSCs maintained pluripotency but underwent profound G2 arrest and apoptosis, whereas parental fibroblasts grew normally. Mechanistic studies revealed that G2-phase FA-deficient iPSCs possess large gammaH2AX-RAD51 foci indicative of accrued DNA damage, which correlated with activated DNA-damage signaling through CHK1. CHK1 inhibition specifically rescued the growth of FA deficient iPSCs for prolonged culture periods, surprisingly without stimulating excessive karyotypic abnormalities. These studies reveal that PSCs possess hyperactive CHK1 signaling that restricts their self-renewal in the absence of error-free DNA repair. PMID- 26771353 TI - Equine-Induced Pluripotent Stem Cells Retain Lineage Commitment Toward Myogenic and Chondrogenic Fates. AB - Induced pluripotent stem cells (iPSCs) hold great potential not only for human but also for veterinary purposes. The equine industry must often deal with health issues concerning muscle and cartilage, where comprehensive regenerative strategies are still missing. In this regard, a still open question is whether equine iPSCs differentiate toward muscle and cartilage, and whether donor cell type influences their differentiation potential. We addressed these questions through an isogenic system of equine iPSCs obtained from myogenic mesoangioblasts (MAB-iPSCs) and chondrogenic mesenchymal stem cells (MSC-iPSCs). Despite similar levels of pluripotency characteristics, the myogenic differentiation appeared enhanced in MAB-iPSCs. Conversely, the chondrogenic differentiation was augmented in MSC-iPSCs through both teratoma and in vitro differentiation assays. Thus, our data suggest that equine iPSCs can differentiate toward the myogenic and chondrogenic lineages, and can present a skewed differentiation potential in favor of the source cell lineage. PMID- 26771354 TI - BMP Sustains Embryonic Stem Cell Self-Renewal through Distinct Functions of Different Kruppel-like Factors. AB - Bone morphogenetic protein (BMP) signaling exerts paradoxical roles in pluripotent stem cells (PSCs); it sustains self-renewal of mouse embryonic stem cells (ESCs), while it induces differentiation in other PSCs, including human ESCs. Here, we revisit the roles of BMP-4 using mouse ESCs (mESCs) in naive and primed states. SMAD1 and SMAD5, which transduce BMP signals, recognize enhancer regions together with KLF4 and KLF5 in naive mESCs. KLF4 physically interacts with SMAD1 and suppresses its activity. Consistently, a subpopulation of cells with active BMP-SMAD can be ablated without disturbing the naive state of the culture. Moreover, Smad1/5 double-knockout mESCs stay in the naive state, indicating that the BMP-SMAD pathway is dispensable for it. In contrast, the MEK5 ERK5 pathway mediates BMP-4-induced self-renewal of mESCs by inducing Klf2, a critical factor for the ground state pluripotency. Our study illustrates that BMP exerts its self-renewing effect through distinct functions of different Kruppel like factors. PMID- 26771356 TI - High-Content Analysis of CRISPR-Cas9 Gene-Edited Human Embryonic Stem Cells. AB - CRISPR-Cas9 gene editing of human cells and tissues holds much promise to advance medicine and biology, but standard editing methods require weeks to months of reagent preparation and selection where much or all of the initial edited samples are destroyed during analysis. ArrayEdit, a simple approach utilizing surface modified multiwell plates containing one-pot transcribed single-guide RNAs, separates thousands of edited cell populations for automated, live, high-content imaging and analysis. The approach lowers the time and cost of gene editing and produces edited human embryonic stem cells at high efficiencies. Edited genes can be expressed in both pluripotent stem cells and differentiated cells. This preclinical platform adds important capabilities to observe editing and selection in situ within complex structures generated by human cells, ultimately enabling optical and other molecular perturbations in the editing workflow that could refine the specificity and versatility of gene editing. PMID- 26771367 TI - Parry-Romberg syndrome associated with contralateral cerebral atrophy. PMID- 26771357 TI - Identification of Distinct Breast Cancer Stem Cell Populations Based on Single Cell Analyses of Functionally Enriched Stem and Progenitor Pools. AB - The identification of breast cancer cell subpopulations featuring truly malignant stem cell qualities is a challenge due to the complexity of the disease and lack of general markers. By combining extensive single-cell gene expression profiling with three functional strategies for cancer stem cell enrichment including anchorage-independent culture, hypoxia, and analyses of low-proliferative, label retaining cells derived from mammospheres, we identified distinct stem cell clusters in breast cancer. Estrogen receptor (ER)alpha+ tumors featured a clear hierarchical organization with switch-like and gradual transitions between different clusters, illustrating how breast cancer cells transfer between discrete differentiation states in a sequential manner. ERalpha- breast cancer showed less prominent clustering but shared a quiescent cancer stem cell pool with ERalpha+ cancer. The cellular organization model was supported by single cell data from primary tumors. The findings allow us to understand the organization of breast cancers at the single-cell level, thereby permitting better identification and targeting of cancer stem cells. PMID- 26771368 TI - Correction. PMID- 26771355 TI - CD13 and ROR2 Permit Isolation of Highly Enriched Cardiac Mesoderm from Differentiating Human Embryonic Stem Cells. AB - The generation of tissue-specific cell types from human embryonic stem cells (hESCs) is critical for the development of future stem cell-based regenerative therapies. Here, we identify CD13 and ROR2 as cell-surface markers capable of selecting early cardiac mesoderm emerging during hESC differentiation. We demonstrate that the CD13+/ROR2+ population encompasses pre-cardiac mesoderm, which efficiently differentiates to all major cardiovascular lineages. We determined the engraftment potential of CD13+/ROR2+ in small (murine) and large (porcine) animal models, and demonstrated that CD13+/ROR2+ progenitors have the capacity to differentiate toward cardiomyocytes, fibroblasts, smooth muscle, and endothelial cells in vivo. Collectively, our data show that CD13 and ROR2 identify a cardiac lineage precursor pool that is capable of successful engraftment into the porcine heart. These markers represent valuable tools for further dissection of early human cardiac differentiation, and will enable a detailed assessment of human pluripotent stem cell-derived cardiac lineage cells for potential clinical applications. PMID- 26771369 TI - Psychometric properties of the Transitions from Foster Care Key Leader Survey. AB - This study summarizes the development and piloting of the Transitions from Foster Care Key Leader Survey (TFC-KLS), an instrument designed to measure change in systems serving young people transitioning from foster care to adulthood. The Jim Casey Youth Opportunity Initiative's logic model was used as a basis for instrument development. The instrument was piloted with 119 key leaders in six communities. Seven of eight latent scales performed well in psychometric testing. The relationships among the 24 measures of system change were explored. A CFA testing overall model fit was satisfactory following slight modifications. Finally, a test of inter-rater reliability between two raters did not find reliable reporting of service availability in a supplemental portion of the survey. The findings were generally positive and supported the validity and utility of the instrument for measuring system change, following some adaptations. Implications for the field are discussed. PMID- 26771370 TI - Percutaneous pedicle screw placement into a spinal segment previously treated with vertebroplasty: technical note. AB - Vertebral augmentation with cement has become a common procedure for the treatment of compression fractures, leading to a growing population who have had this procedure and are now in need of another spinal surgery. This technical note reports an undescribed method for placing pedicle screws through a previously cemented level. PMID- 26771371 TI - Disc nucleus fortification for lumbar degenerative disc disease: a biomechanical study. AB - OBJECTIVE Spinal stability is attributed in part to osteoligamentous structures, including the vertebral body, facets, intervertebral discs, and posterior elements. The materials in this study provide an opportunity to augment the degenerated nucleus without removing native disc material, a procedure introduced here as "fortification." The objective of this study was to determine the effect of nucleus fortification on lumbar disc biomechanics. METHODS The authors performed in vitro analysis of human cadaveric functional spinal units (FSUs), along with characterization and quantification of movement of the units using biomechanical data in intact, disc-only, and fortified specimens. The units underwent removal of all posterior elements and annulus and were fortified by injecting a biogel into the nucleus pulposus. Each specimen was subjected to load testing, range of motion (ROM) quantification, and disc bulge measurements. Optoelectric tracking was used to quantify disc bulge. These criteria were assessed in the intact, disc-only, and fortified treatments. RESULTS Disc-only FSUs resulted in increased ROM when compared with intact and fortified conditions. Fortification of the FSU resulted in partial restoration of normal ROM in the treatment groups. Analysis of hysteresis loops showed more linear response in the fortified groups when compared with the intact and disc-only groups. CONCLUSIONS Disc nucleus fortification increases linearity and decreases ROM. PMID- 26771372 TI - The 100 most-cited articles in spinal oncology. AB - OBJECTIVE The authors' objective was to identify the 100 most-cited research articles in the field of spinal oncology. METHODS The Thomson Reuters Web of Science service was queried for the years 1864-2015 without language restrictions. Articles were sorted in descending order of the number of times they were cited by other studies, and all titles and abstracts were screened to identify the research areas of the top 100 articles. Levels of evidence were assigned on the basis of the North American Spine Society criteria. RESULTS The authors identified the 100 most-cited articles in spinal oncology, which collectively had been cited 20,771 times at the time of this writing. The oldest article on this top 100 list had been published in 1931, and the most recent in 2008; the most prolific decade was the 1990s, with 34 articles on this list having been published during that period. There were 4 studies with Level I evidence, 3 with Level II evidence, 9 with Level III evidence, 70 with Level IV evidence, and 2 with Level V evidence; levels of evidence were not assigned to 12 studies because they were not on therapeutic, prognostic, or diagnostic topics. Thirty-one unique journals contributed to the 100 articles, with the Journal of Neurosurgery contributing most of the articles (n = 25). The specialties covered included neurosurgery, orthopedic surgery, neurology, radiation oncology, and pathology. Sixty-seven articles reported clinical outcomes. The most common country of article origin was the United States (n = 62), followed by Canada (n = 8) and France (n = 7). The most common topics were spinal metastases (n = 35), intramedullary tumors (n = 18), chordoma (n = 17), intradural tumors (n = 7), vertebroplasty/kyphoplasty (n = 7), primary bone tumors (n = 6), and others (n = 10). One researcher had authored 6 studies on the top 100 list, and 7 authors had 3 studies each on this list. CONCLUSIONS This study identified the 100 most-cited research articles in the area of spinal oncology. The studies highlighted the multidisciplinary and multimodal nature of spinal tumor management. Recognition of historical articles may guide future spinal oncology research. PMID- 26771373 TI - Lumbar paraspinal muscle morphometry and its correlations with demographic and radiological factors in adult isthmic spondylolisthesis: a retrospective review of 120 surgically managed cases. AB - OBJECTIVE The objective of this study was to assess the cross-sectional areas (CSAs) of lumbar paraspinal muscles in adults with isthmic spondylolisthesis (IS), to compare them with those in the normative population, and to evaluate their correlations with demographic factors and MRI changes in various spinal elements. METHODS The authors conducted a retrospective study of patients who had undergone posterior lumbar interbody fusion for IS, and 2 of the authors acting as independent observers calculated the CSAs of various lumbar paraspinal muscles (psoas, erector spinae [ES], multifidus [MF]) on preoperative axial T2-weighted MR images from the L-3 to L-5 vertebral levels and computed the CSAs as ratios with respect to the corresponding vertebral body areas. These values were then compared with those in an age- and sex-matched normative population and were analyzed with respect to age, sex, duration of symptoms, grade of listhesis, and various MRI changes at the level of the listhesis (pedicle signal change, disc degeneration, and facetal arthropathy). RESULTS Compared with values in normative controls, the mean CSA value for the ES muscle was significantly higher in the study cohort of 120 patients (p = 0.002), whereas that for the MF muscle was significantly lower (p = 0.009), and more so in the patients with PSC (p = 0.002). Magnetic resonance imaging signal change in the pedicle was seen in half of the patients, all of whom demonstrated a Type 2 change. Of the variables tested in a multivariate analysis, age independently predicted lower area values for all 3 muscles (p <= 0.001), whereas female sex predicted a lower mean psoas area value (p < 0.001). None of the other variables significantly predicted any of the muscle area values. A decrease in the mean MF muscle area value alone was associated with a significantly increased likelihood of a PSC (p = 0.039). CONCLUSIONS Compared with normative controls, patients with IS suffer selective atrophy of their MF muscle, whereas their ES muscle undergoes a compensatory hypertrophy. Advancing age has a detrimental effect on the areas of the lumbar PSMs, whereas female sex predisposes to a decreased psoas muscle area. Multifidus muscle atrophy correlates with PSC, indicating the role of this deep stabilizer in the biomechanical stability of spondylolisthetic spines. This may be of clinical significance in targeted physiotherapy programs during the conservative management of IS. PMID- 26771374 TI - A pilot study of the utility of a laboratory-based spinal fixation training program for neurosurgical residents. AB - OBJECTIVE Pedicle and lateral mass screw placement is technically demanding due to complex 3D spinal anatomy that is not easily visualized. Neurosurgical and orthopedic surgery residents must be properly trained in such procedures, which can be associated with significant complications and associated morbidity. Current training in pedicle and lateral mass screw placement involves didactic teaching and supervised placement in the operating room. The objective of this study was to assess whether teaching residents to place pedicle and lateral mass screws using navigation software, combined with practice using cadaveric specimens and Sawbones models, would improve screw placement accuracy. METHODS This was a single-blinded, prospective, randomized pilot study with 8 junior neurosurgical residents and 2 senior medical students with prior neurosurgery exposure. Both the study group and the level of training-matched control group (each group with 4 level of training-matched residents and 1 senior medical student) were exposed to a standardized didactic education regarding spinal anatomy and screw placement techniques. The study group was exposed to an additional pilot program that included a training session using navigation software combined with cadaveric specimens and accessibility to Sawbones models. RESULTS A statistically significant reduction in overall surgical error was observed in the study group compared with the control group (p = 0.04). Analysis by spinal region demonstrated a significant reduction in surgical error in the thoracic and lumbar regions in the study group compared with controls (p = 0.02 and p = 0.04, respectively). The study group also was observed to place screws more optimally in the cervical, thoracic, and lumbar regions (p = 0.02, p = 0.04, and p = 0.04, respectively). CONCLUSIONS Surgical resident education in pedicle and lateral mass screw placement is a priority for training programs. This study demonstrated that compared with a didactic-only training model, using navigation simulation with cadavers and Sawbones models significantly reduced the number of screw placement errors in a laboratory setting. PMID- 26771375 TI - Children's recantation of adult wrongdoing: An experimental investigation. AB - Child maltreatment cases often hinge on a child's word versus a defendant's word, making children's disclosures crucially important. There is considerable debate concerning why children recant allegations, and it is imperative to examine recantation experimentally. The purpose of this laboratory analogue investigation was to test (a) how often children recant true allegations of an adult's wrongdoing after disclosing and (b) whether children's age and caregiver supportiveness predict recantation. During an interactive event, 6- to 9-year olds witnessed an experimenter break a puppet and were asked to keep the transgression a secret. Children were then interviewed to elicit a disclosure of the transgression. Mothers were randomly assigned to react supportively or unsupportively to this disclosure, and children were interviewed again. We coded children's recantations (explicit denials of the broken puppet after disclosing) and changes in their forthcomingness (shifts from denial or claims of lack of knowledge/memory to disclosure and vice versa) in free recall and in response to focused questions about the transgression. Overall, 23.3% of the children recanted their prior disclosures (46% and 0% in the unsupportive and supportive conditions, respectively). No age differences in recantation rates emerged, but 8 and 9-year-olds were more likely than 6- and 7-year-olds to maintain their recantation throughout Interview 2. Children whose mothers reacted supportively to disclosure became more forthcoming in Interview 2, and those whose mothers reacted unsupportively became less forthcoming. Results advance theoretical understanding of how children disclose negative experiences, including sociomotivational influences on their reports, and have practical implications for the legal system. PMID- 26771376 TI - Prognostic Significance of KIT Mutations in Core-Binding Factor Acute Myeloid Leukemia: A Systematic Review and Meta-Analysis. AB - The prognostic significance of KIT mutations in core-binding factor acute myeloid leukemia (CBF-AML), including inv(16) and t(8;21) AML, is uncertain. We performed a systematic review and meta-analysis of the effect of KIT mutations on the complete remission (CR) and relapse rates and overall survival (OS) of CBF-AML. PubMed, Embase, Web of Science, and the Cochrane Library were searched and relevant studies were included. Negative effect was indicated on relapse risk of CBF-AML (RR [relative risk], 1.43; 95%CI [confidence interval], 1.20-1.70) and t(8;21) AML (RR, 1.70; 95% CI, 1.31-2.21), not on OS of CBF-AML (RR, 1.09; 95% CI, 0.97-1.23), CR (OR [odds ratio], 0.95; 95% CI, 0.52-1.74), relapse risk (RR, 1.12; 95% CI, 0.90-1.41) or OS (RR, 1.03; 95% CI, 0.90-1.18) of inv(16) AML. Subgroup analysis of t(8,21) AML showed negative effect of KIT mutations on CR (OR, 2.03; 95%CI: 1.02-4.05), relapse risk (RR, 1.89; 95%CI: 1.51-2.37) and OS (RR, 2.26; 95%CI: 1.35-3,78) of non-Caucasians, not on CR (OR, 0.61; 95%CI: 0.19 1.95) or OS (RR, 1.12; 95%CI: 0.90-1.40) of Caucasians. This study indicates KIT mutations in CBF-AML to be included in the initial routine diagnostic workup and stratification system of t(8,21) AML. Prospective large-scale clinical trials are warranted to evaluate these findings. PMID- 26771377 TI - Diagnosis and management of bile stone disease and its complications. AB - Bile stone disease is one of the most prevalent gastroenterological diseases with a considerable geographical and ethnic variation. Bile stones can be classified according their origin, their localization and their biochemical structure. Development and clinical expression depend on a complex interaction between congenital and acquired risk factors. Indeed, bile stones can be either asymptomatic, or cause biliary colic or complications such as acute cholecystitis, jaundice, cholangitis and acute pancreatitis. Diagnosis is based on a combination of clinical features, laboratory findings and imaging techniques and correct identification of symptomatic gallstone patients is essential before cholecystectomy. Transabdominal ultrasonography is the gold standard for the diagnosis of gallstones. However, endoscopic ultrasonography, magnetic resonance cholangiopancreatography and intraoperative cholangiography may also play a role in the diagnosis of bile stones. Management includes prevention measures against modifiable risk factors. Biliary colic and acute cholecystitis are common indications of laparoscopic cholecystectomy, while endoscopic retrograde cholangiopancreatography (ERCP) with endoscopic biliary sphincterotomy and stone extraction is the gold standard for the treatment of common bile duct (CBD) stones. Timing of ERCP and cholecystectomy are of critical importance in the management. Lithotripsy modalities are generally reserved for patients with technically difficult CBD stone removal. Percutaneous access combined with lithotripsy may be helpful for complicated intrahepatic stones. PMID- 26771378 TI - Ionic Liquids as Electrolytes for Electrochemical Double-Layer Capacitors: Structures that Optimize Specific Energy. AB - Key parameters that influence the specific energy of electrochemical double-layer capacitors (EDLCs) are the double-layer capacitance and the operating potential of the cell. The operating potential of the cell is generally limited by the electrochemical window of the electrolyte solution, that is, the range of applied voltages within which the electrolyte or solvent is not reduced or oxidized. Ionic liquids are of interest as electrolytes for EDLCs because they offer relatively wide potential windows. Here, we provide a systematic study of the influence of the physical properties of ionic liquid electrolytes on the electrochemical stability and electrochemical performance (double-layer capacitance, specific energy) of EDLCs that employ a mesoporous carbon model electrode with uniform, highly interconnected mesopores (3DOm carbon). Several ionic liquids with structurally diverse anions (tetrafluoroborate, trifluoromethanesulfonate, trifluoromethanesulfonimide) and cations (imidazolium, ammonium, pyridinium, piperidinium, and pyrrolidinium) were investigated. We show that the cation size has a significant effect on the electrolyte viscosity and conductivity, as well as the capacitance of EDLCs. Imidazolium- and pyridinium based ionic liquids provide the highest cell capacitance, and ammonium-based ionic liquids offer potential windows much larger than imidazolium and pyridinium ionic liquids. Increasing the chain length of the alkyl substituents in 1-alkyl-3 methylimidazolium trifluoromethanesulfonimide does not widen the potential window of the ionic liquid. We identified the ionic liquids that maximize the specific energies of EDLCs through the combined effects of their potential windows and the double-layer capacitance. The highest specific energies are obtained with ionic liquid electrolytes that possess moderate electrochemical stability, small ionic volumes, low viscosity, and hence high conductivity, the best performing ionic liquid tested being 1-ethyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide. PMID- 26771379 TI - Spatiotemporal Determinants of Urban Leptospirosis Transmission: Four-Year Prospective Cohort Study of Slum Residents in Brazil. AB - BACKGROUND: Rat-borne leptospirosis is an emerging zoonotic disease in urban slum settlements for which there are no adequate control measures. The challenge in elucidating risk factors and informing approaches for prevention is the complex and heterogeneous environment within slums, which vary at fine spatial scales and influence transmission of the bacterial agent. METHODOLOGY/PRINCIPAL FINDINGS: We performed a prospective study of 2,003 slum residents in the city of Salvador, Brazil during a four-year period (2003-2007) and used a spatiotemporal modelling approach to delineate the dynamics of leptospiral transmission. Household interviews and Geographical Information System surveys were performed annually to evaluate risk exposures and environmental transmission sources. We completed annual serosurveys to ascertain leptospiral infection based on serological evidence. Among the 1,730 (86%) individuals who completed at least one year of follow-up, the infection rate was 35.4 (95% CI, 30.7-40.6) per 1,000 annual follow-up events. Male gender, illiteracy, and age were independently associated with infection risk. Environmental risk factors included rat infestation (OR 1.46, 95% CI, 1.00-2.16), contact with mud (OR 1.57, 95% CI 1.17-2.17) and lower household elevation (OR 0.92 per 10m increase in elevation, 95% CI 0.82-1.04). The spatial distribution of infection risk was highly heterogeneous and varied across small scales. Fixed effects in the spatiotemporal model accounted for the majority of the spatial variation in risk, but there was a significant residual component that was best explained by the spatial random effect. Although infection risk varied between years, the spatial distribution of risk associated with fixed and random effects did not vary temporally. Specific "hot-spots" consistently had higher transmission risk during study years. CONCLUSIONS/SIGNIFICANCE: The risk for leptospiral infection in urban slums is determined in large part by structural features, both social and environmental. Our findings indicate that topographic factors such as household elevation and inadequate drainage increase risk by promoting contact with mud and suggest that the soil-water interface serves as the environmental reservoir for spillover transmission. The use of a spatiotemporal approach allowed the identification of geographic outliers with unexplained risk patterns. This approach, in addition to guiding targeted community-based interventions and identifying new hypotheses, may have general applicability towards addressing environmentally-transmitted diseases that have emerged in complex urban slum settings. PMID- 26771380 TI - The Hydroxyl at Position C1 of Genipin Is the Active Inhibitory Group that Affects Mitochondrial Uncoupling Protein 2 in Panc-1 Cells. AB - Genipin (GNP) effectively inhibits uncoupling protein 2 (UCP2), which regulates the leakage of protons across the inner mitochondrial membrane. UCP2 inhibition may induce pancreatic adenocarcinoma cell death by increasing reactive oxygen species (ROS) levels. In this study, the hydroxyls at positions C10 (10-OH) and C1 (1-OH) of GNP were hypothesized to be the active groups that cause these inhibitory effects. Four GNP derivatives in which the hydroxyl at position C10 or C1 was replaced with other chemical groups were synthesized and isolated. Differences in the inhibitory effects of GNP and its four derivatives on pancreatic carcinoma cell (Panc-1) proliferation were assessed. The effects of GNP and its derivatives on apoptosis, UCP2 inhibition and ROS production were also studied to explore the relationship between GNP's activity and its structure. The derivatives with 1-OH substitutions, geniposide (1-GNP1) and 1 ethyl-genipin (1-GNP2) lacked cytotoxic effects, while the other derivatives that retained 1-OH, 10-piv-genipin (10-GNP1) and 10-acetic acid-genipin (10-GNP2) exerted biological effects similar to those of GNP, even in the absence of 10-OH. Thus, 1-OH is the key functional group in the structure of GNP that is responsible for GNP's apoptotic effects. These cytotoxic effects involve the induction of Panc-1 cell apoptosis through UCP2 inhibition and subsequent ROS production. PMID- 26771381 TI - Discovery of Influenza A Virus Sequence Pairs and Their Combinations for Simultaneous Heterosubtypic Targeting that Hedge against Antiviral Resistance. AB - The multiple circulating human influenza A virus subtypes coupled with the perpetual genomic mutations and segment reassortment events challenge the development of effective therapeutics. The capacity to drug most RNAs motivates the investigation on viral RNA targets. 123,060 segment sequences from 35,938 strains of the most prevalent subtypes also infecting humans-H1N1, 2009 pandemic H1N1, H3N2, H5N1 and H7N9, were used to identify 1,183 conserved RNA target sequences (>=15-mer) in the internal segments. 100% theoretical coverage in simultaneous heterosubtypic targeting is achieved by pairing specific sequences from the same segment ("Duals") or from two segments ("Doubles"); 1,662 Duals and 28,463 Doubles identified. By combining specific Duals and/or Doubles to form a target graph wherein an edge connecting two vertices (target sequences) represents a Dual or Double, it is possible to hedge against antiviral resistance besides maintaining 100% heterosubtypic coverage. To evaluate the hedging potential, we define the hedge-factor as the minimum number of resistant target sequences that will render the graph to become resistant i.e. eliminate all the edges therein; a target sequence or a graph is considered resistant when it cannot achieve 100% heterosubtypic coverage. In an n-vertices graph (n >= 3), the hedge-factor is maximal (= n- 1) when it is a complete graph i.e. every distinct pair in a graph is either a Dual or Double. Computational analyses uncover an extensive number of complete graphs of different sizes. Monte Carlo simulations show that the mutation counts and time elapsed for a target graph to become resistant increase with the hedge-factor. Incidentally, target sequences which were reported to reduce virus titre in experiments are included in our target graphs. The identity of target sequence pairs for heterosubtypic targeting and their combinations for hedging antiviral resistance are useful toolkits to construct target graphs for different therapeutic objectives. PMID- 26771384 TI - Reducing Wildlife Damage with Cost-Effective Management Programmes. AB - Limiting the impact of wildlife damage in a cost effective manner requires an understanding of how control inputs change the occurrence of damage through their effect on animal density. Despite this, there are few studies linking wildlife management (control), with changes in animal abundance and prevailing levels of wildlife damage. We use the impact and management of wild pigs as a case study to demonstrate this linkage. Ground disturbance by wild pigs has become a conservation issue of global concern because of its potential effects on successional changes in vegetation structure and composition, habitat for other species, and functional soil properties. In this study, we used a 3-year pig control programme (ground hunting) undertaken in a temperate rainforest area of northern New Zealand to evaluate effects on pig abundance, and patterns and rates of ground disturbance and ground disturbance recovery and the cost effectiveness of differing control strategies. Control reduced pig densities by over a third of the estimated carrying capacity, but more than halved average prevailing ground disturbance. Rates of new ground disturbance accelerated with increasing pig density, while rates of ground disturbance recovery were not related to prevailing pig density. Stochastic simulation models based on the measured relationships between control, pig density and rate of ground disturbance and recovery indicated that control could reduce ground disturbance substantially. However, the rate at which prevailing ground disturbance was reduced diminished rapidly as more intense, and hence expensive, pig control regimes were simulated. The model produced in this study provides a framework that links conservation of indigenous ecological communities to control inputs through the reduction of wildlife damage and suggests that managers should consider carefully the marginal cost of higher investment in wildlife damage control, relative to its marginal conservation return. PMID- 26771382 TI - Associations between Retinal Markers of Microvascular Disease and Cognitive Impairment in Newly Diagnosed Type 2 Diabetes Mellitus: A Case Control Study. AB - OBJECTIVE: To investigate associations between retinal microvascular changes and cognitive impairment in newly diagnosed type 2 diabetes mellitus. DESIGN: Case control study. SETTING: A primary care cohort with newly diagnosed type 2 diabetes mellitus. METHODS: For this analysis, we compared 69 cases with lowest decile scores (for the cohort) on the Modified Telephone Interview for Cognitive Status and 68 controls randomly selected from the remainder of the cohort. Retinal images were rated and the following measures compared between cases and controls: retinal vessel calibre, arterio-venous ratio, retinal fractal dimension, and simple and curvature retinal vessel tortuosity. RESULTS: Total and venular (but not arteriolar) simple retinal vessel tortuosity levels were significantly higher in cases than controls (t = 2.45, p = 0.015; t = 2.53, p = 0.013 respectively). The associations persisted after adjustment for demographic factors, retinopathy, neuropathy, obesity and blood pressure. There were no other significant differences between cases and controls in retinal measures. CONCLUSIONS: A novel association was found between higher venular tortuosity and cognitive impairment in newly diagnosed type 2 diabetes mellitus. This might be accounted for by factors such as hypoxia, thrombus formation, increased vasoendothelial growth factor release and inflammation affecting both the visible retinal and the unobserved cerebral microvasculature. PMID- 26771385 TI - Molecular Cage Impregnated Palladium Nanoparticles: Efficient, Additive-Free Heterogeneous Catalysts for Cyanation of Aryl Halides. AB - Two shape-persistent covalent cages (CC1(r) and CC2(r)) have been devised from triphenyl amine-based trialdehydes and cyclohexane diamine building blocks utilizing the dynamic imine chemistry followed by imine bond reduction. The cage compounds have been characterized by several spectroscopic techniques which suggest that CC1(r) and CC2(r) are [2+3] and [8+12] self-assembled architectures, respectively. These state-of-the-art molecules have a porous interior and stable aromatic backbone with multiple palladium binding sites to engineer the controlled synthesis and stabilization of ultrafine palladium nanoparticles (PdNPs). As-synthesized cage-embedded PdNPs have been characterized by transmission electron microscopy (TEM), scanning electron microscopy (SEM), and powder X-ray diffraction (PXRD). Inductively coupled plasma optical emission spectrometry reveals that Pd@CC1(r) and Pd@CC2(r) have 40 and 25 wt% palladium loading, respectively. On the basis of TEM analysis, it has been estimated that as small as ~1.8 nm PdNPs could be stabilized inside the CC1(r), while larger CC2(r) could stabilize ~3.7 nm NPs. In contrast, reduction of palladium salts in the absence of the cages form structure less agglomerates. The well-dispersed cage-embedded NPs exhibit efficient catalytic performance in the cyanation of aryl halides under heterogeneous, additive-free condition. Moreover, these materials have excellent stability and recyclability without any agglomeration of PdNPs after several cycles. PMID- 26771383 TI - Impact of Mated Female Nonproductive Days in Breeding Herd after Porcine Epidemic Diarrhea Virus Outbreak. AB - Porcine epidemic diarrhea virus (PEDV) is an important pathogen that has a significant economic impact on the swine industry by imposing a high rate of mortality in suckling piglets. However, limited information on the productivity values of gilts and sows infected with PEDV is available. Here, we evaluate the productivity index in gilts and sows during the 1-year period before (19 January 2013 to 18 January 2014) and after (19 January 2014 to 18 January 2015) a PEDV outbreak from a 2000-sow breeding herd in Taiwan. The farrowing rate (FR), return rate (RR), total pigs born per litter (TB), pigs born alive per litter (BA), weaning pigs per litter (WPL), pre-weaning mortality, percentage of sows mated by 7 days after weaning, weaning to first service interval (WFSI), mated female nonproductive days (NPDs), replacement rate of sows and sow culling rate were compared using productive records. The FR (-9.6%), RR (+9.8%), TB (-1.6), BA ( 1.1), WPL (-1.1), sows mated by 7 days after weaning (-6.9%), WFSI (+0.8 days), NPDs (+6.9 days) and sow culling rate (+7.2%) were significantly different between the 1-year pre-PEDV outbreak period and the post-PEDV outbreak period. Impacts of the PEDV infection on the reproductive performance were more severe in pregnant gilts than in sows. In conclusion, these findings indicate that the outbreak of PEDV caused an increase in the rate of NPDs in breeding herds. PMID- 26771386 TI - Vasoactive enzymes and blood flow responses to passive and active exercise in peripheral arterial disease. AB - BACKGROUND: Peripheral arterial disease (PAD) is characterised by impaired leg blood flow, which contributes to claudication and reduced exercise capacity. This study investigated to what extent vasoactive enzymes might contribute to altered blood flow in PAD (Fontaine stage II). METHODS: We compared femoral artery blood flow during reactive hyperaemia, leg-extension exercise and passive leg movement, and determined the level of vasoactive enzymes in skeletal muscle samples from the vastus lateralis in PAD (n = 10, 68.5 +/- 6.5 years) and healthy controls (CON, n = 9, 62.1 +/- 12.3 years). Leg blood flow was measured with Doppler ultrasound and muscle protein levels of phosphorylated endothelial nitric oxide synthase, NADPH oxidase, cyclooxygenase 1 and 2, thromboxane synthase, and prostacyclin synthase were determined. RESULTS: Leg blood flow during the initial 90 s of passive leg movement (242 +/- 33 vs 441 +/- 75 ml min(-1), P = 0.03) and during reactive hyperaemia (423 +/- 100 vs 1255 +/- 175 ml min(-1), P = 0.002) was lower in PAD than CON, whereas no significant difference was observed for leg blood flow during exercise (1490 +/- 250 vs 1887 +/- 349 ml min(-1), P = 0.37). PAD had higher NADPH oxidase than CON (1.04 +/- 0.19 vs 0.50 +/- 0.06 AU, P = 0.02), with no differences for other enzymes. Leg blood flow during exercise was correlated with prostacyclin synthase (P = 0.001). CONCLUSION: Elevated NADPH oxidase indicates that oxidative stress may be a primary cause of low nitric oxide availability and impaired blood flow in PAD. PMID- 26771388 TI - Synthesis and Biological Evaluation of Well-Defined Poly(propylene fumarate) Oligomers and Their Use in 3D Printed Scaffolds. AB - A ring opening polymerization method for synthesizing oligomeric poly(propylene fumarate) (PPF) provides a rapid, and scalable method of synthesizing PPF with well-defined molecular mass, molecular mass distribution (Dm), and viscosity properties suitable for 3D printing. These properties will also reduce the amount of solvent necessary to ensure sufficient flow of material during 3D printing. MALDI mass spectrometry precisely shows the end group fidelity, and size exclusion chromatography (SEC) demonstrates narrow mass distributions (<1.6) of a series of low molecular mass oligomers (700-3000 Da). The corresponding intrinsic viscosities range from 0.0288 +/- 0.0009 dL/g to 0.0780 +/- 0.0022 dL/g. The oligomers were printed into scaffolds via established photochemical methods and standardized ISO 10993-5 testing shows that the 3D printed materials are nontoxic to both L929 mouse fibroblasts and human mesenchymal stem cells. PMID- 26771387 TI - Folate Deficiency Triggered Apoptosis of Synoviocytes: Role of Overproduction of Reactive Oxygen Species Generated via NADPH Oxidase/Mitochondrial Complex II and Calcium Perturbation. AB - Despite a plethora of literature has documented that osteoarthritis (OA) is veritably associated with oxidative stress-mediated chondrocyte death and matrix degradation, yet the possible involvement of synoviocyte abnormality as causative factor of OA has not been thoroughly investigated. For this reason, we conduct the current studies to insight into how synoviocytes could respond to an episode of folate-deprived (FD) condition. First, when HIG-82 synoviocytes were cultivated under FD condition, a time-dependent growth impediment was observed and the demise of these cells was demonstrated to be apoptotic in nature mediated through FD-evoked overproduction of reactive oxygen species (ROS) and drastically released of cytosolic calcium (Ca2+) concentrations. Next, we uncovered that FD evoked ROS overproduction could only be strongly suppressed by either mitochondrial complex II inhibitors (TTFA and carboxin) or NADPH oxidase (NOX) inhibitors (AEBSF and apocynin), but not by mitochondrial complex I inhibitor (rotenone) and mitochondrial complex III inhibitor (antimycin A). Interestingly, this selective inhibition of FD-evoked ROS by mitochondrial complex II and NOX inhibitors was found to correlate excellently with the suppression of cytosolic Ca2+ release and reduced the magnitude of the apoptotic TUNEL-positive cells. Taken together, we present the first evidence here that FD-triggered ROS overproduction in synoviocytes is originated from mitochondrial complex II and NOX. Both elevated ROS in tandem with cytosolic Ca2+ overload serve as final arbitrators for apoptotic lethality of synoviocytes cultivated under FD condition. Thus, folate supplementation may be beneficial to patients with OA. PMID- 26771389 TI - Oxyboration with and without a Catalyst: Borylated Isoxazoles via B-O sigma-Bond Addition. AB - Herein we report an oxyboration reaction with activated substrates that employs B O sigma bond additions to C-C pi bonds to form borylated isoxazoles, which are potential building blocks for drug discovery. Although this reaction can be effectively catalyzed by gold, it is the first example of uncatalyzed oxyboration of C-C pi bonds by B-O sigma bonds--and only the second example that is catalyzed. This oxyboration reaction is tolerant of groups incompatible with alternative lithiation/borylation and palladium-catalyzed C-H activation/borylation technologies for the synthesis of borylated isoxazoles. PMID- 26771390 TI - A Simple Method for Automated Equilibration Detection in Molecular Simulations. AB - Molecular simulations intended to compute equilibrium properties are often initiated from configurations that are highly atypical of equilibrium samples, a practice which can generate a distinct initial transient in mechanical observables computed from the simulation trajectory. Traditional practice in simulation data analysis recommends this initial portion be discarded to equilibration, but no simple, general, and automated procedure for this process exists. Here, we suggest a conceptually simple automated procedure that does not make strict assumptions about the distribution of the observable of interest in which the equilibration time is chosen to maximize the number of effectively uncorrelated samples in the production timespan used to compute equilibrium averages. We present a simple Python reference implementation of this procedure and demonstrate its utility on typical molecular simulation data. PMID- 26771391 TI - Sirt1-Positive Lymphocytes in Acute Cellular Cardiac Allograft Rejection: Contributor to Pathogenesis and a Therapeutic Target. AB - Cardiac allograft rejection remains a problem, despite advances with immunosuppressants. Understanding the mechanisms behind rejection is essential for developing targeted therapies. The goal of this investigation is to explore Sirtuin 1 (Sirt1) as a therapeutic target for cardiac allograft rejection. Thirteen endomyocardial biopsy specimens with acute cellular rejection (grade 2R or 3R) were selected. CD3, CD4, CD8, CD20, CD68, T-cell intracytoplasmic antigen (TIA-1), and Sirt1 expressions were determined by immunohistochemical stains. Comparison of Sirt1 expression was made with 10 cases of grade 0R and grade 1R. Quantitative image analysis was performed. There were 2 cases of grade 3R and 11 cases of grade 2R acute cellular rejection. Sirtuin 1 expression was present in the majority of mononuclear cells (median percentage, 73.5; interquartile range, 51.2-100%); staining was also observed in cardiomyocytes. Twelve of the 13 cases (92.3%) had an elevated CD8/FoxP3 ratio, coinciding with acute cellular rejection. Sirtuin 1 expression in the nuclei of FoxP3+ cells can lead to deacetylation and inactivation of FoxP3 rendering the T-suppressor cells inactive and promoting acute cellular rejection. The use of a Sirt1 inhibitor may be a therapeutic option in expanding the functionality of the FoxP3+ T-suppressor cells and moderating the severity of such rejection. PMID- 26771392 TI - Automated Rotational Percussion Bed and Bronchoscopy Improves Respiratory Mechanics and Oxygenation in ARDS Patients Supported with Extracorporeal Membrane Oxygenation. AB - Extracorporeal membrane oxygenation (ECMO) has been used to provide "lung rest" through the use of low tidal volume (6 ml/kg) and ultralow tidal volume (<6 ml/kg) ventilation in acute respiratory distress syndrome (ARDS). Low and ultralow tidal volume ventilation can result in low dynamic respiratory compliance and potentially increased retention of airway secretions. We present our experience using automated rotational percussion beds (ARPBs) and bronchoscopy in four ARDS patients to manage increased pulmonary secretions. These beds performed automated side-to-side tilt maneuver and intermittent chest wall percussion. Their use resulted in substantial reduction in peak and plateau pressures in two patients on volume control ventilation, while the driving pressures (inspiratory pressure) to attain the desired tidal volumes in patients on pressure control ventilation also decreased. In addition, mean partial pressure of oxygen in arterial blood (PaO2)/fraction of inspired oxygen (FiO2) ratio (109 pre-ARPB vs. 157 post-ARPB), positive end-expiratory pressure (10 cm H2O vs. 8 cm H2O), and FiO2 (0.88 vs. 0.52) improved after initiation of ARPB. The improvements in the respiratory mechanics and oxygenation helped us to initiate early ECMO weaning. Based on our experience, the use of chest physiotherapy, frequent body repositioning, and bronchoscopy may be helpful in the management of pulmonary secretions in patients supported with ECMO. PMID- 26771393 TI - Systemic Thrombolysis Versus Device Exchange for Pump Thrombosis Management: A Single-Center Experience. AB - In patients with left ventricular assist device (LVAD) implants, pump thrombosis is a potential life-threatening complication. In a retrospective data analysis, we compared clinical outcomes in 50 patients with HeartWare (HW) or HeartMate II implants undergoing device exchange (DEx; n = 21) or systemic thrombolysis (STL; n = 29) for pump thrombosis. Primary end-point was survival up to 90 days postintervention. Secondary end-points were the need for blood products postintervention, duration of intensive care unit stay, in-hospital stay, 90 day and 2 year therapy failure (the need for additional surgical or nonsurgical intervention because of pump thrombosis), and 2 year survival. Ninety-day survival was 89.3% in the STL group and 91.0% in the DEx group (p = 0.901). Compared with the DEx group, the average use of different blood products was lower (p < 0.001), and duration of intensive care unit stay and in-hospital stay tended to be shorter in the STL group (p values = 0.086 and 0.048, respectively). However, 90 day freedom from therapy failure was significantly lower in the STL group than in the DEx exchange group (p = 0.027) and so was 2 year freedom from therapy failure (p = 0.006). Two-year survival was comparable between groups (p = 0.267). Our data indicate that STL can be considered as a therapeutic option in LVAD patients with pump thrombosis. PMID- 26771394 TI - Total Artificial Heart, Augmented by Venovenous Extracorporeal Membrane Oxygenation. AB - Shortly after SynCardia total artificial heart (TAH) implant, venovenous extracorporeal membrane oxygenation (ECMO) via a 31 Fr Avalon cannula was used for profound hypoxic lung dysfunction. Immediately after starting ECMO, TAH flow increased by 1.5-2.0 L/min, presumably because of augmented TAH filling by the ECMO jet. PMID- 26771395 TI - Heart Transplant Survival Based on Recipient and Donor Risk Scoring: A UNOS Database Analysis. AB - Unlike the lung allocation score, currently, there is no quantitative scoring system available for patients on heart transplant waiting list. By using United Network for Organ Sharing (UNOS) data, we aim to generate a scoring system based on the recipient and donor risk factors to predict posttransplant survival. Available UNOS data were queried between 2005 and 2013 for heart transplant recipients aged >=18 years to create separate cox-proportional hazard models for recipient and donor risk scoring. On the basis of risk scores, recipients were divided into five groups and donors into three groups. Kaplan-Meier curves were used for survival. Total 17,131 patients had heart transplant within specified time period. Major factors within high-risk groups were body mass index > 30 kg/m (46%), mean pulmonary artery pressure >30 mmHg (65%), creatinine > 1.5 mg% (63%), bilirubin > 1.5 mg% (54%), noncontinuous-flow left ventricular assist devices (45%) for recipients and gender mismatch (81%) and ischemia time >4 hours (88%) for donors. Survival in recipient groups 1, 2, 3, 4, and 5 at 5 years was 81, 80, 77, 74, and 62%, respectively, and in donor groups 1, 2, and 3 at 5 years was 79, 77, and 70%, respectively (p < 0.001). Combining donor and recipient groups based on scoring showed acceptable survival in low-risk recipients with high-risk donor (75% at 5 years). A higher recipient and donor risk score are associated with worse long-term survival. A low-risk recipient transplanted with high-risk donor has acceptable survival at 5 years, but high-risk recipient combined with a high risk donor has marginal results. Using an objective scoring system could help get the best results when utilizing high-risk donors. PMID- 26771396 TI - In Vitro Validation of a Multiscale Patient-Specific Norwood Palliation Model. AB - In Norwood physiology, shunt size and the occurrence of coarctation can affect hemodynamics significantly. The aim of the study was to validate an in vitro model of the Norwood circulation against clinical measurements for patients presenting differing aortic morphologies. The mock circulatory system used coupled a lumped parameter network of the neonatal Norwood circulation with modified Blalock-Taussig (mBT) shunt with a three-dimensional aorta model. Five postoperative aortic arch anatomies of differing morphologies were reconstructed from imaging data, and the system was tuned to patient-specific clinical values. Experimentally measured flow rates and pressures were compared with clinical measurements. Time-based experimental and clinical pressure and flow signals within the aorta and pulmonary circulation branches agreed closely (0.72 < R < 0.95) for the five patients, whereas mean values within the systemic and pulmonary branches showed no significant differences (95% confidence interval). We validated an experimental multiscale model of the Norwood circulation with mBT shunt by showing it capable of reproducing clinical pressure and flow rates at various positions of the circulation with very good fidelity across a range of patient physiologies and morphologies. The multiscale aspect of the model provides a means to study variables in isolation with their effects both locally and at the system level. The model serves as a tool to further the understanding of the complex physiology of single-ventricle circulation. PMID- 26771397 TI - Prolonged Support Using a Percutaneous OxyRVAD in a Patient with End-Stage Lung Disease, Pulmonary Hypertension, and Right Cardiac Failure. AB - Options for cardiopulmonary support in patients with severe pulmonary hypertension (PH) that is not associated with left-sided heart failure are limited. We describe the novel use of prolonged percutaneous venovenous extracorporeal membrane oxygenation as a right ventricular assist device in a patient presenting with cardiogenic shock because of severe PH decompensation. PMID- 26771398 TI - Percutaneous Right Ventricular Assist Device Support in a Patient Supported by an LVAD. AB - Right ventricular failure requiring short-term mechanical support is a relatively common complication after left ventricular assist device (LVAD) implantation. Removal of the temporary right ventricular assist device (RVAD) generally requires a reoperative sternotomy. In this report, we describe an innovative percutaneous approach for placing an RVAD at the time of LVAD implantation using the Impella RP (Abiomed Inc.) that does not require reoperation for removal, as the Impella RP can be removed at the patient's bedside. PMID- 26771399 TI - Retrospective Observational Review of Percutaneous Cannulation for Extracorporeal Membrane Oxygenation. AB - Cannulation is a potentially complex event in the conduct of venovenous extracorporeal membrane oxygenation (VV-ECMO) for patients with severe respiratory failure. The purpose of this article is to describe our approach to cannulation and its complications. A single-center, retrospective, observational cohort, electronic note review study of patients commenced on VV-ECMO for severe respiratory failure. We identified 348 cannulae placed in 179 patients commenced on VV-ECMO from December 2011 to March 2015. All cannulations were successful. There were no deaths related to cannulation, and complications included one arterial injury, one cardiac tamponade, two cases of venous insufficiency, and five cannula site infections. Percutaneous cannulation for VV-ECMO can be achieved with a high degree of success and low complication rate by intensivists using ultrasound and fluoroscopic guidance. PMID- 26771401 TI - Effective Interventions to Reduce Sexually Transmitted Disease: Introduction to the Special Issue. PMID- 26771400 TI - A Visual Profile of Queensland Indigenous Children. AB - PURPOSE: Little is known about the prevalence of refractive error, binocular vision, and other visual conditions in Australian Indigenous children. This is important given the association of these visual conditions with reduced reading performance in the wider population, which may also contribute to the suboptimal reading performance reported in this population. The aim of this study was to develop a visual profile of Queensland Indigenous children. METHODS: Vision testing was performed on 595 primary schoolchildren in Queensland, Australia. Vision parameters measured included visual acuity, refractive error, color vision, nearpoint of convergence, horizontal heterophoria, fusional vergence range, accommodative facility, AC/A ratio, visual motor integration, and rapid automatized naming. Near heterophoria, nearpoint of convergence, and near fusional vergence range were used to classify convergence insufficiency (CI). RESULTS: Although refractive error (Indigenous, 10%; non-Indigenous, 16%; p = 0.04) and strabismus (Indigenous, 0%; non-Indigenous, 3%; p = 0.03) were significantly less common in Indigenous children, CI was twice as prevalent (Indigenous, 10%; non-Indigenous, 5%; p = 0.04). Reduced visual information processing skills were more common in Indigenous children (reduced visual motor integration [Indigenous, 28%; non-Indigenous, 16%; p < 0.01] and slower rapid automatized naming [Indigenous, 67%; non-Indigenous, 59%; p = 0.04]). The prevalence of visual impairment (reduced visual acuity) and color vision deficiency was similar between groups. CONCLUSIONS: Indigenous children have less refractive error and strabismus than their non-Indigenous peers. However, CI and reduced visual information processing skills were more common in this group. Given that vision screenings primarily target visual acuity assessment and strabismus detection, this is an important finding as many Indigenous children with CI and reduced visual information processing may be missed. Emphasis should be placed on identifying children with CI and reduced visual information processing given the potential effect of these conditions on school performance. PMID- 26771402 TI - The Expedited Partner Therapy Continuum: A Conceptual Framework to Guide Programmatic Efforts to Increase Partner Treatment. AB - BACKGROUND: Expedited partner therapy (EPT) is a partner treatment strategy wherein health care providers give patients antibiotics or a prescription to deliver to their sex partners as treatment, without an intervening medical evaluation. METHODS: We used PubMed and the Cochrane database to systematically identify published articles about EPT after 2006 and randomized controlled trials before that date; we also sought conference abstracts and unpublished data from 2013 to 2014. We described key steps in a hypothetical "EPT continuum," beginning with diagnosis of Chlamydia trachomatis or Neisseria gonorrhoeae in a patient and ending with treatment for the patient's sex partner(s) with EPT. All reports were abstracted for a set of defined measures and related interventions. RESULTS: We reviewed 100 published articles, unpublished data reports, and conference abstracts; 42 met the inclusion criteria and provided measures of the following: provider uptake and offer of EPT, patient acceptance and receipt of EPT, patient delivery of EPT to sex partners, and partner receipt of EPT and treatment. Implementation phase, populations, settings, and methodologies varied across reports. Providers' uptake and offer of EPT are rate-limiting steps in the EPT continuum and were the focus of all 5 programmatic interventions we identified. There were 7 population-based measures of patient receipt of EPT; however, several of the patient populations overlapped. CONCLUSIONS: A heterogenous body of literature describes EPT, and variation in study population, setting, and metrics limit generalizability. Programs seeking to increase partner treatment should focus their efforts on provider uptake and offer and should use population based measures to monitor EPT use. PMID- 26771403 TI - Classical Magnetic Dipole Moments for the Simulation of Vibrational Circular Dichroism by ab Initio Molecular Dynamics. AB - We present a new approach for calculating vibrational circular dichroism spectra by ab initio molecular dynamics. In the context of molecular dynamics, these spectra are given by the Fourier transform of the cross-correlation function of magnetic dipole moment and electric dipole moment. We obtain the magnetic dipole moment from the electric current density according to the classical definition. The electric current density is computed by solving a partial differential equation derived from the continuity equation and the condition that eddy currents should be absent. In combination with a radical Voronoi tessellation, this yields an individual magnetic dipole moment for each molecule in a bulk phase simulation. Using the chiral alcohol 2-butanol as an example, we show that experimental spectra are reproduced very well. Our approach requires knowing only the electron density in each simulation step, and it is not restricted to any particular electronic structure method. PMID- 26771404 TI - Development of a Neutralizing Monoclonal Antibody Against Porcine Epidemic Diarrhea Virus S1 Protein. AB - The truncated spike protein (S1, 390-789aa) of porcine epidemic diarrhea virus was expressed as a recombinant protein in Baculorvirus expression system. Female BALB/c mice were immunized with the purified recombinant S1 (rS1) protein and two monoclonal antibodies, designated 8A3A10 and 12C4G12, were generated by hybridoma technique. The two monoclonal antibodies specifically reacted with PEDV rS1 protein, as proven by Western blot and indirect immunofluorescence assay. 8A3A10 monoclonal antibody showed a neutralizing activity to PEDV, as demonstrated in the results of fluorescent focus neutralization assay. These two newly established monoclonal antibodies may work as a useful tool to study the pathogenic mechanisms of PED virus and to develop diagnostic reagents. PMID- 26771405 TI - On the Formal Differentiation of Traces and Determinants. AB - A compact notation for obtaining and handling matrices of partial derivatives is suggested in an attempt to generalize "symbolic vector differentiation" to matrices of independent variables. The proposed technique differs from methods advocated by Dwyer and MacPhail (1948) and Wrobleski (1963) in several respects, notably in a deliberate limitation on the classes of scalar functions considered: traces and determinants. To narrow interest to these two classes of scalar matrix functions allows one to invoke certain algebraic identities which simplifies the problem, because (a) the treatment of traces of products of matrices can be reduced to that of a few representatives of large equivalence classes of such products, all having the same formal derivative, and because (b) the more involved task of differentiating determinants of matrix products can be translated into the more amenable problem of differentiating the traces of such products. A number of illustrative examples are included in an attempt to show that the above limitation is not as serious as might at first appear, because traces and determinants apply to a wide range of psychometric and statistical problems. PMID- 26771406 TI - Illinois Classroom Assessment Profile: Development of the Instrument. AB - This article describes the development of a teacher rating scale that is sensitive to a select group of behavior disorders exhibited by children in the classroom. The scale, the Illinois Classroom Assessment Profile (ICAP), was developed to distinguish among behavioral dimensions representing sustained attention, impulsivity, conduct, fine motor coordination, and evaluative anxiety. The fact that disorders in these behaviors are observed in children diagnosed as hyperactive has served as the impetus for this research. The ICAP is intended to facilitate research investigating the effects of specific treatments on each of these behavioral dimensions. PMID- 26771407 TI - Efron's Bootstrap with Application to the Repeated Measures Design. AB - The traditional univariate ANOVA for the repeated measures or split-plot design, commonly used in the behavioral sciences, requires, in addition to the usual assumptions of error normality and variance homogeneity, that the covariance matrix for the repeated measures have a special form (Type H). Because detection of lack of compliance with these assumptions is problematic, this design is a good candidate for alternative analysis. This paper illustrates an application of Efron's bootstrap to the repeated measures design. While the bootstrap approach does not require parametric assumptions, it does utilize distributional information in the sample. By appropriately resampling from the data collected in a study, the bootstrap may determine quite accurate sampling distributions for estimators, effects, or contrasts of interest. PMID- 26771408 TI - Scaling Sociomatrices by Optimizing an Explicit Function: Correspondence Analysis of Binary Single Response Sociomatrices. AB - Most methods for detecting structure in sociometric data involve either continuous spatial representations (e.g. MDS) or discrete hierarchical clustering analysis (e.g. CONCOR). By producing either spatial or clustering representations, these methods can highlight only some of the theoretically interesting group structures. Correspondence analysis, in contrast, can provide either spatial or clustering representations by assigning spatial coordinates to minimize the distance between individuals linked by a sociometric relationship. These scales may then be used to identify individuals' locations in a multidimensional representation of a group's structure or to reorder the rows and columns of a sociomatrix. Unlike many other methods of sociometric analysis, the numerical methods of correspondence analysis also are well understood and the optimization of the goodness-of-fit measure allows an evaluation of a particular model of group structure. PMID- 26771409 TI - Multidimensional Scaling: A Possible Technique for Examining Male and Female Occupational Perceptions and Preferences. AB - Multidimensional scaling (MDS) was examined as a technique for examining the similarities and differences in career perceptions and preferences of males and females. In an exploratory study using grade 9 and 11 high school students and postgraduate teachers-in-training, the rationale of the technique is developed. The technique is non-reactive, applicable across the age-range tested, and productive of readily interpretable representations of internally organized, potentially causal, systems of interrelations. Some evidence was discussed concerning validity; brief comments were made comparing results to previous MDS studies. It was concluded that the method is suited to the study and understanding of gender-related changes in perceptions and preferences in response to educational programs and career counselling. PMID- 26771410 TI - A Comparison of Alternative Proposed Subscale Structures for MMPI Scale 2. AB - Scale 2 of the MMPI was subjected to confirmatory (Oblique Multiple Groups) factor analysis, following the procedures employed by Bernstein and Eveland (1982) in a related context. Various proposed subscale structures (those of Comrey, 1957; Harris & Lingoes, 1955; Weiner, 1948) were evaluated in two different populations: Job Applicants and Psychotherapy Outpatients. Particular effort was directed toward seeing how differences in item endorsement probability (response level) affect the item level structure of Scale 2 and, therefore, the proposed subscales. It was found that none of the proposed subscales explained the item level structure very well. The conclusion was that there is nothing to be gained by use of the proposed subscale systems compared to the use of Scale 2 as a whole. Although there is an apparently large set of factors present in Scale 2, these factors seem to reflect nonsubstantive aspects of item interrelationships. PMID- 26771411 TI - Is the Road to Precision Medicine in Chronic Lung Disease Paved with Degraded Chitin? PMID- 26771412 TI - The Challenge of Addressing Family Needs at the End of Life. PMID- 26771413 TI - Early-Life Exposures and Later Lung Function. Add Pollutants to the Mix. PMID- 26771414 TI - Broad Therapeutic Efficacy of Nintedanib in Idiopathic Pulmonary Fibrosis. PMID- 26771415 TI - Diagnosis of Post-extubation Stridor: Easier with Technology Support? PMID- 26771416 TI - Cigarette Smoking Induces Changes in Airway Epithelial Expression of Genes Associated with Monogenic Lung Disorders. PMID- 26771417 TI - Key Role of alpha-Toxin in Fatal Pneumonia Caused by Staphylococcus aureus Sequence Type 398. PMID- 26771418 TI - Written Asthma Action Plans: The Devil's in the Details. PMID- 26771419 TI - Written Action Asthma Plans: Not Such a Simple Issue in Subspecialist Care? PMID- 26771420 TI - Reply: "Written Asthma Action Plans: The Devil's in the Details" and "Written Action Asthma Plans: Not Such a Simple Issue in Subspecialist Care?". PMID- 26771421 TI - Erratum: Global Epidemiology of Pediatric Severe Sepsis: The Sepsis Prevalence, Outcomes, and Therapies Study. PMID- 26771422 TI - Work-Related Lung Diseases. PMID- 26771423 TI - Calcium Supplementation Does Not Contribute to Constipation in Healthy Women. AB - PURPOSE: It is commonly suggested that calcium supplementation contributes to constipation; however, little research has explored the effects of calcium supplementation on gut motility. METHODS: In an 8-week, randomized, double-blind, crossover pilot study, healthy females (n = 27, aged 43.0 +/- 10.6 years) received a split dose of 500 mg/d of elemental calcium from calcium carbonate or calcium phosphate each for 2 weeks, after a 2-week baseline and separated by a 2 week washout. Participants completed daily questionnaires of stool frequency, Bristol Stool Form Scale (BSFS), and supplement intake compliance. RESULTS: There were no differences among periods. Mean +/- SE stool frequency averaged 1.3 +/- 0.1 stools/d in each period. Participants reported 34%, 34%, 37%, and 29% of stools were indicative of slow transit or constipation (BSFS of 1 or 2) during baseline, calcium carbonate, calcium phosphate, and washout periods, respectively. Participants also reported from 6% to 10% of stools as fast transit or diarrhea (BSFS of 6 or 7) during the periods. CONCLUSION: This study suggests that neither calcium carbonate nor calcium phosphate, providing 500 mg/d of calcium, affects stool frequency or form. Although stool frequency was normal, the healthy females participating in the study experienced stools indicating slow (constipation) and fast (diarrhea) transit. PMID- 26771424 TI - Juggling Multiple Guidelines: A Woman's Heart in the Balance. AB - In 2011, the American Heart Association (AHA) issued the pivotal "Effectiveness based Guidelines for the Prevention of Cardiovascular Disease in Women-2011 Update." In the interim, multiple guidelines have dramatically altered recommendations for preventive cardiovascular care. This article addresses how I juggle these multiple guidelines in my clinical practice. In brief, my approach to risk stratification is to use the Pooled Cohort Equations, but I also routinely assess the risk factors unique to or predominant in women such as pregnancy complications and systemic autoimmune collagen vascular diseases. I follow the 2013 AHA/American College of Cardiology (ACC) Guidelines on Lifestyle Management to Reduce Cardiovascular Risk, but find value in the detailed aspects of physical activity recommendation in the 2011 Women's Guideline, including those for weight loss or weight loss maintenance. Based solely on epidemiological data, I consider a blood pressure (BP) of 120//80 mmHg ideal in women who remain asymptomatic at that level. I typically titrate BP therapy to 120-130/80-90 mmHg as tolerated. I endorse the current ACC/AHA recommendations for cholesterol management, but for my women patients older than age 75 who previously tolerated a high-intensity statin, I continue that medication or whatever statin they tolerated through age 75. For women older than age 75 with a recent acute atherosclerotic cardiovascular disease (ASCVD) event, a high-risk population, I follow the guideline for younger patients. As ASCVD events are becoming more common before 40 years of age, I screen younger women earlier when risk factors unique to or predominant in women are present. I incorporate sex-specific risk factors for stroke in the risk ascertainment component of women's medical records. With regard to depression, at minimum I perform screening for all women with coronary heart disease with a 2-item Patient Health Questionnaire (PHQ-2). For women with suspected ischemic heart disease, I adhere to the recommendations of the 2014 Consensus Statement of the AHA, "The Role of Noninvasive Testing in the Evaluation of Women with Suspected Ischemic Heart Disease." An unmet need remains an updated guideline on Prevention of Cardiovascular Disease in Women. PMID- 26771425 TI - Geographical Assessment of Rickettsioses in Indonesia. AB - To expand the documentation of rickettsioses in Indonesia, we conducted an ectoparasite and small mammal investigation involving four major islands: Java, Sumatra, Sulawesi, and Kalimantan. Coastal and highland regions on each island surveyed were chosen to represent different ecologies in Indonesia. Indication of the presence of Rickettsia spp. was evident in all areas sampled. Typhus group rickettsiae-specific antibodies had significantly higher prevalence among small mammals captured in Java compared to the other islands surveyed (78% in coastal and 50% in highland regions) and the prevalence of spotted fever group rickettsiae-specific antibodies was significantly higher in Kalimantan than the other islands investigated. Hosts and vectors were restricted by Rickettsia spp. but not by coastal or highland regions. Our findings expand the range in which rickettsial pathogens have been documented within the Indonesian archipelago and point to a significant risk to human health. PMID- 26771426 TI - Sample Size Planning for the Squared Multiple Correlation Coefficient: Accuracy in Parameter Estimation via Narrow Confidence Intervals. AB - Methods of sample size planning are developed from the accuracy in parameter approach in the multiple regression context in order to obtain a sufficiently narrow confidence interval for the population squared multiple correlation coefficient when regressors are random. Approximate and exact methods are developed that provide necessary sample size so that the expected width of the confidence interval will be sufficiently narrow. Modifications of these methods are then developed so that necessary sample size will lead to sufficiently narrow confidence intervals with no less than some desired degree of assurance. Computer routines have been developed and are included within the MBESS R package so that the methods discussed in the article can be implemented. The methods and computer routines are demonstrated using an empirical example linking innovation in the health services industry with previous innovation, personality factors, and group climate characteristics. PMID- 26771427 TI - Mutual Suppression: Comment on Paulhus et al. (2004). AB - Paulhus, Robins, Trzesniewski, and Tracy (Multivariate Behavioral Research, 2004 , 39, 305-328) suggested that the three types of two-predictor suppression situations-classical suppression, cooperative suppression, and net suppression- can all be considered special cases of mutual suppression, in that the magnitude of each of the two standardized partial regression coefficients exceeds the magnitude of its corresponding standardized bivariate regression coefficient. Classical suppression and cooperative suppression can be considered mutual suppression, but net suppression cannot. Hypothetical and empirical examples of net suppression in which the magnitude of the standardized partial regression coefficient for the suppressor variable is greater than, equal to, and less than the magnitude of its standardized bivariate regression coefficient are provided. The empirical examples were drawn from the social psychology literature relating psychological well-being outcomes to life aspirations. PMID- 26771428 TI - Reconsidering the Use of Autoregressive Latent Trajectory (ALT) Models. AB - The simultaneous estimation of autoregressive (simplex) structures and latent trajectories, so called ALT (autoregressive latent trajectory) models, is becoming an increasingly popular approach to the analysis of change. Although historically autoregressive (AR) and latent growth curve (LGC) models have been developed quite independently from each other, the underlying pattern of change is often highly similar. In this article it is shown that their integration rests on the strong assumption that neither the AR part nor the LGC part contains any misspecification. In practice, however, this assumption is often violated due to nonlinearity in the LGC part. As a consequence, the autoregressive (simplex) process incorrectly accounts for part of this nonlinearity, thus rendering any substantive interpretation of parameter estimates virtually impossible. Accordingly, researchers are advised to exercise extreme caution when using ALT models in practice. All arguments are illustrated by empirical data on skill acquisition, and a simulation study is provided to investigate the conditions and consequences of mistaking nonlinear growth curve patterns as autoregressive processes. PMID- 26771429 TI - SEM with Missing Data and Unknown Population Distributions Using Two-Stage ML: Theory and Its Application. AB - This article provides the theory and application of the 2-stage maximum likelihood (ML) procedure for structural equation modeling (SEM) with missing data. The validity of this procedure does not require the assumption of a normally distributed population. When the population is normally distributed and all missing data are missing at random (MAR), the direct ML procedure is nearly optimal for SEM with missing data. When missing data mechanisms are unknown, including auxiliary variables in the analysis will make the missing data mechanism more likely to be MAR. It is much easier to include auxiliary variables in the 2-stage ML than in the direct ML. Based on most recent developments for missing data with an unknown population distribution, the article first provides the least technical material on why the normal distribution-based ML generates consistent parameter estimates when the missing data mechanism is MAR. The article also provides sufficient conditions for the 2-stage ML to be a valid statistical procedure in the general case. For the application of the 2-stage ML, an SAS IML program is given to perform the first-stage analysis and EQS codes are provided to perform the second-stage analysis. An example with open- and closed book examination data is used to illustrate the application of the provided programs. One aim is for quantitative graduate students/applied psychometricians to understand the technical details for missing data analysis. Another aim is for applied researchers to use the method properly. PMID- 26771430 TI - Special MBR Section: SMEP Student Paper Competition Abstracts. PMID- 26771431 TI - Abstract: A Multi-Level Model of Individual Differences in Speed/Accuracy Tradeoff (SATin). AB - Individuals performing an experimental cognitive task have a choice whether to favor accuracy, speed, or weight them both equally. Models of speed/ accuracy tradeoff have been proposed in the assessment literature ( van der Linden, 2007 ) and experimental literature ( Ratcliff & Rouder, 1998 ). However, these models do not estimate individual differences in choice of speed/ accuracy tradeoff at between- and within-subjects levels. The top of Figure 1 presents the equations and path diagram for the SATin model. Individual differences in speed/ accuracy tradeoff will be modeled at two levels with, 1) variability in Tradeoff (between subject level, Level 2) and 2) variability in c (within-subject level, Level 1). An individual's Tradeoff factor score represents the individual's distributional position relative to others regarding whether they favor speed (values < 0), accuracy (values > 0), or neither (value = 0). A negative c indicates that the individual is trading off speed and accuracy for these particular trials, whereas a positive and zero c indicate the individual is not trading off. [Figure: see text] Panels 1 and 2 illustrate Simpson's paradox, where speed/ accuracy tradeoff occurs in opposing directions at between- and within-subject levels. This highlights the need for a multi-level model as the researcher would draw opposing conclusions by observing only one of these levels. Simulations studies compared the SATin model to a popular model in cognitive psychology that uses speed alone to estimate ability. SATin outperformed this model by accounting for substantially more variance in actual ability. PMID- 26771432 TI - Abstract: Parameter Influence In Structural Equation Models. AB - In applications of SEM, investigators obtain and interpret parameter estimates that are computed so as to produce optimal model fit in the sense that the obtained model fit would deteriorate to some degree if any of those estimates were changed. This property raises a question: to what extent would model fit deteriorate if parameter estimates were changed? And which parameters have the greatest influence on model fit? This is the idea of parameter influence. The present paper will cover two approaches to quantifying parameter influence. Both are based on the principle of likelihood displacement (LD), which quantifies influence as the discrepancy between the likelihood under the original model and the likelihood under the model in which a minor perturbation is imposed ( Cook, 1986 ). One existing approach for quantifying parameter influence is a vector approach ( Lee & Wang, 1996 ) that determines a vector in the parameter space such that altering parameter values simultaneously in this direction will cause maximum change in LD. We propose a new approach, called influence mapping for single parameters, that determines the change in model fit under perturbation of a single parameter holding other parameter estimates constant. An influential parameter is defined as one that produces large change in model fit under minor perturbation. Figure 1 illustrates results from this procedure for three different parameters in an empirical application. Flatter curves represent less influential parameters. Practical implications of the results are discussed. The relationship with statistical power in structural equation models is also discussed.[Figure: see text]. PMID- 26771433 TI - Abstract: Adequacy of Semiparametric Approximations for Growth Models with Nonnormal Random Effects. AB - Conventional growth models assume that the random effects describing individual trajectories are conditionally normal. In practice, this assumption may often be unrealistic. As an alternative, Nagin (2005) suggested a semiparametric group based approach (SPGA) which approximates an unknown, continuous distribution of individual trajectories with a mixture of group trajectories. Prior simulations ( Brame, Nagin, & Wasserman, 2006 ; Nagin, 2005 ) indicated that SPGA could generate nearly-unbiased estimates of means and variances of a nonnormal distribution of individual trajectories, as functions of group-trajectory estimates. However, these studies used few random effects-usually only a random intercept. Based on the analytical relationship between SPGA and adaptive quadrature, we hypothesized that SPGA's ability to approximate (a) random effect variances/covariances and (b) effects of time-invariant predictors of growth should deteriorate as the dimensionality of the random effects distribution increases. We expected this problem to be mitigated by correlations among the random effects (highly correlated random effects functioning as fewer dimensions) and sample size (larger N supporting more groups). We tested these hypotheses via simulation, varying the number of random effects (1, 2, or 3), correlation among the random effects (0 or .6), and N (250, 500). Results indicated that, as the number of random effects increased, SPGA approximations remained acceptable for fixed effects, but became increasingly negatively biased for random effect variances. Whereas correlated random effects and larger N reduced this underestimation, correlated random effects sometimes distorted recovery of predictor effects. To illustrate this underestimation, Figure 1 depicts SPGA's approximation of the intercept variance from a three correlated random effect generating model (N < eqid1 > 500). These results suggest SPGA approximations are inadequate for the nonnormal, high-dimensional distributions of individual trajectories often seen in practice.[Figure: see text]. PMID- 26771434 TI - Abstract: A Comparison of the Factor Mixture Model and Taxometric Procedures. AB - Taxometric procedures and the Factor Mixture Model (FMM) have a complimentary set of strengths and weaknesses. Both approaches purport to detect evidence of a latent class structure. Taxometric procedures, popular in psychiatric and psychopathology literature, make no assumptions beyond those needed to compute means and covariances. However, Taxometric procedures assume that observed items are uncorrelated within a class or taxon. This assumption is violated when there are individual differences in the trait underlying the items (i.e., severity differences within class). FMMs can model within-class covariance structures ranging from local independence to multidimensional within-class factor models and permits the specification of more than two classes. FMMs typically rely on normality assumptions for within-class factors and error terms. FMMs are highly parameterized and susceptible to misspecifications of the within-class covariance structure. The current study compared the Taxometric procedures MAXEIG and the Base-Rate Classification Technique to the FMM in their respective abilities to (1) correctly detect the two-class structure in simulated data, and to (2) correctly assign subjects to classes. Two class data were simulated under conditions of balanced and imbalanced relative class size, high and low class separation, and 1-factor and 2-factor within-class covariance structures. For the 2-factor data, simple and cross-loaded factor loading structures, and positive and negative factor correlations were considered. For the FMM, both correct and incorrect within-class factor structures were fit to the data. FMMs generally outperformed Taxometric procedures in terms of both class detection and in assigning subjects to classes. Imbalanced relative class size (e.g., a small minority class and a large majority class) negatively impacted both FMM and Taxometric performance while low class separation was much more problematic for Taxometric procedures than the FMM. Comparisons of alterative FMMs based on information criteria generally resulted in correct model choice but deteriorated when small class separation was combined with imbalanced relative class size. PMID- 26771435 TI - Abstract: Local Influence and Robust Methods for Mediation Models. AB - Mediation analysis investigates how certain variables mediate the effect of predictors on outcome variables. Existing studies of mediation models have been limited to normal theory maximum likelihood (ML) or least squares with normally distributed data. Because real data in the social and behavioral sciences are seldom normally distributed and often contain outliers, classical methods can result in biased and inefficient estimates, which lead to inaccurate or unreliable test of the meditated effect. The authors propose two approaches for better mediation analysis. One is to identify cases that strongly affect test results of mediation using local influence methods and robust methods. The other is to use robust methods for parameter estimation, and then test the mediated effect based on the robust estimates. Analytic details of both local influence and robust methods particular for mediation models were provided and one real data example was given. We first used local influence and robust methods to identify influential cases. Then, for the original data and the data with the identified influential cases removed, the mediated effect was tested using two estimation methods: normal theory ML and the robust method, crossing two tests of mediation: the Sobel (1982) test using information-based standard error (z I ) and sandwich-type standard error (z SW ). Results show that local influence and robust methods rank the influence of cases similarly, while the robust method is more objective. The widely used z I statistic is inflated when the distribution is heavy-tailed. Compared to normal theory ML, the robust method provides estimates with smaller standard errors and more reliable test. PMID- 26771436 TI - Association of N-Methyl-D-Aspartate receptor 2B Subunit (GRIN2B) polymorphism with earlier age at onset of withdrawal symptoms in Indian alcohol dependent subjects. AB - The associations of GRIN2B polymorphism (rs1806201) with alcohol withdrawal and related clinical parameters in alcohol dependent subjects were investigated. Cases were assessed using a semi-structured clinical pro forma for alcohol abuse and a questionnaire for family history of alcohol dependence and psychiatric disorders after obtaining informed consent. The study included alcohol dependent male cases (n = 220, age at onset of alcohol withdrawal symptoms = 32.4 +/- 8.8 y) recruited at the Center for Addiction Medicine, National Institute of Mental Health and Neurosciences, Bangalore, India. The controls comprised of healthy unrelated males (n = 183) who were ethnically matched and selected randomly. The polymorphism rs1806201 was analyzed by polymerase chain reaction and restriction fragment length polymorphism. The presence of T allele at this locus was significantly associated with lower age at onset of alcohol withdrawal symptoms (p = .005) among the cases. Mean age at onset of alcohol withdrawal symptoms in subjects who were T carriers was 31.4 +/- 8.5 y (n = 160) and non-T carriers was 35.2 +/- 9.0 y (n = 60). The SNP rs1806201 in GRIN2B may play an important role in genetic susceptibility to earlier age of withdrawal in alcohol dependent patients. PMID- 26771438 TI - Synthesis and Structural Studies of Gallium(III) and Iron(III) Hemicryptophane Complexes. AB - New gallium(III) and iron(III) endohedral complexes were obtained from a hemicryptophane ligand bearing suitable binding sites for octahedral metal coordination. The solid-state structures of the free host and of the complexes were determined by single-crystal X-ray diffraction analysis. The metal ion is linked to the hydrazone nitrogen and the phenolate oxygen atoms, yielding a distorted octahedral geometry around the encapsulated metal. The two isomorphous structures of the metal complexes reveal the exclusive formation of PDelta/MLambda enantiomeric pairs. PMID- 26771439 TI - Abstracts from the Society for Acupuncture Research 2015 International Conference Reaching Across Disciplines to Broaden the Acupuncture Research Network November 12-14, 2015 Boston, MA. PMID- 26771437 TI - The Effectiveness and Tolerability of Central Nervous System Stimulants in School Age Children with Attention-Deficit/Hyperactivity Disorder and Disruptive Mood Dysregulation Disorder Across Home and School. AB - OBJECTIVE: This study examines the effectiveness and tolerability of stimulants in children with attention-deficit/hyperactivity disorder (ADHD) and disruptive mood dysregulation disorder (DMDD). METHODS: To be eligible, participants had to meet Diagnostic and Statistical Manual of Mental Disorders, 4th ed., Text Revision (DSM-IV) criteria for the combined subtype of ADHD and National Institute of Mental Health (NIMH) severe mood dysregulation criteria. The Diagnostic and Statistical Manual of Mental Disorders, 5th ed. (DSM-V) DMDD criteria were retrospectively assessed after the study was completed. An open label medication trial lasting up to 6 weeks was completed to optimize the central nervous system (CNS) stimulant dose. Measures of affective symptoms, ADHD symptoms and other disruptive behaviors, impairment, and structured side effect ratings were collected before and after the medication trial. RESULTS: Optimization of stimulant medication was associated with a significant decline in depressive symptoms on the Childhood Depression Rating Score-Revised Scale (p<0.05, Cohen's d=0.61) and Mood Severity Index score (p<0.05, Cohen's d=0.55), but not in manic-like symptoms on the Young Mania Rating Scale. There was a significant reduction in ADHD (p<0.05, Cohen's d=0.95), oppositional defiant disorder (ODD) (p<0.05, Cohen's d=0.5), and conduct disorder (CD) symptoms (p<0.05, Cohen's d=0.65) as rated by parents. There was also a significant reduction in teacher-rated ADHD (p<0.05, Cohen's d=0.33) but not in ODD symptoms. Medications were well tolerated and there was no increase in side effect ratings seen with dose optimization. Significant improvement in functioning was reported by clinicians and parents (all p's<0.05), but youth still manifested appreciable impairment at end-point. CONCLUSIONS: CNS simulants were well tolerated by children with ADHD comorbid with a diagnosis of DMDD. CNS stimulants were associated with clinically significant reductions in externalizing symptoms, along with smaller improvements in mood. However, most participants still exhibited significant impairment, suggesting that additional treatments may be needed to optimize functioning. PMID- 26771442 TI - Theoretical Evidence for the Relevance of n(F) -> sigma*(C-X) (X = H, C, O, S) Stereoelectronic Interactions. AB - Theoretical calculations on r-1,c-3,c-5-trifluorocyclohexane (1), r-2,c-4,c-6 trifluoro-1,3,5-trioxane (2), and r-2,c-4,c-6-trifluoro-1,3,5-trithiane (3) confirm the importance of n(F) -> sigma*(C-Y)gem, where Y = H, C, O, S, hyperconjugative interactions; that is, contrary to common wisdom, fluorine is a good lone pair electron donor toward geminal sigma bonds. This conclusion is in line with the recent observations reported by O'Hagan and co-workers, who synthesized and examined all-cis 1,2,3,4,5,6-hexafluoro-cyclohexane (Nat. Chem. 2015, 7, 483-488). PMID- 26771441 TI - Mucosal lichen sclerosus/lichen planus overlap syndrome with cutaneous lesions of lichen sclerosus. PMID- 26771440 TI - Soy Isoflavone Genistein-Mediated Downregulation of miR-155 Contributes to the Anticancer Effects of Genistein. AB - We previously reported that dietary genistein inhibits mammary tumor growth and metastasis of the highly metastatic MDA-MB-435 cancer cells in immunocompromised mice. The purpose herein was to characterize the role of the novel oncogenic microRNA (miRNA) miR-155 in the anticancer effects of genistein in metastatic breast cancer. The effect of genistein was determined on breast cancer cell viability, apoptosis, and expression of miR-155 and its targets. At low physiologically relevant concentrations, genistein inhibits cell viability and induces apoptosis in metastatic MDA-MB-435 and Hs578t breast cancer cells, without affecting the viability of nonmetastatic MCF-7 breast cancer cells. In parallel with reduced cell viability, miR-155 is downregulated, whereas proapoptotic and anticell proliferative miR-155 targets FOXO3, PTEN, casein kinase, and p27 are upregulated in MDA-MB-435 and Hs578t cells in response to genistein treatment. However, miR-155 levels remain unchanged in response to genistein in the MCF-7 cells. Ectopic expression of miR-155 in MDA-MB-435 and Hs578t cells decreases the effects of genistein on cell viability and abrogates the effects of genistein on apoptosis and expression of proapoptotic genes. Therefore, genistein-mediated downregulation of miR-155 contributes to the anticancer effects of genistein in metastatic breast cancer. PMID- 26771443 TI - Changes in Treatment Patterns and Overall Survival in Patients With Early-Stage Non-Small Cell Lung Cancer in the United States After the Incorporation of Stereotactic Ablative Radiation Therapy: A Population-based Analysis. AB - PURPOSE: Technologic developments have made radiation therapy (RT) more effective and have introduced new treatment options, such as stereotactic ablative radiation therapy (SABR). This study sought to determine changes in practice patterns for treatment of stage IA non-small cell lung cancer (NSCLC) after the introduction of SABR into the United States. This population-based study also examined changes in survival during this time period for all patients and specifically for patients treated with RT, surgery, or observation. METHODS: We included patients in the Surveillance, Epidemiology, and End Results database diagnosed with stage IA NSCLC diagnosed between 2004 and 2012. Changes in treatment patterns were assessed. Outcomes were compared across 2 time periods: 2004 to 2008 (pre-SABR) and 2009 to 2012 (post-SABR). Kaplan-Meier and Cox regression were performed to compare overall survival (OS) for patients treated with surgery, RT, or observation. RESULTS: A total of 32,249 patients met the specified criteria. Comparing patients diagnosed in 2004 to those diagnosed in 2012, RT use increased from 13% to 29% (P<0.001), surgery use decreased from 76% to 61% (P<0.001), and patients observed decreased from 11% to 10% (P=0.3). There was no significant OS improvement in all patients or those patients who were observed; there were significant improvements in OS for patients treated with RT (hazard ratio=0.768; 95% confidence interval, 0.711-0.829) and those patients treated with surgery (hazard ratio=0.9; 95% confidence interval, 0.855-0.962). CONCLUSIONS: There has been an increase in RT utilization and decrease in surgical utilization after the incorporation of SABR by radiation oncologists within the United States. In addition, there has been an improvement in OS for patients treated with definitive RT for early-stage NSCLC between 2004 and 2012 that may be associated with increased utilization of SABR. PMID- 26771444 TI - Alternate Immersion in an External Glucose Solution Differentially Affects Blood Sugar Values in Older Versus Younger Zebrafish Adults. AB - Recently, zebrafish have been used to examine hyperglycemia-induced complications (retinopathy and neuropathy), as would occur in individuals with diabetes. Current models to induce hyperglycemia in zebrafish include glucose immersion and streptozotocin injections. Both are effective, although neither is reported to elevate blood sugar values for more than 1 month. In this article, we report differences in hyperglycemia induction and maintenance in young (4-11 months) versus old (1-3 years) zebrafish adults. In particular, older fish immersed in an alternating constant external glucose solution (2%) for 2 months displayed elevated blood glucose levels for the entire experimental duration. In contrast, younger adults displayed only transient hyperglycemia, suggesting the fish were acclimating to the glucose exposure protocol. However, modifying the immersion protocol to include a stepwise increasing glucose concentration (from 1% -> 2% >3%) resulted in maintained hyperglycemia in younger zebrafish adults for up to 2 months. Glucose-exposed younger fish collected after 8 weeks of exposure also displayed a significant decrease in wet weight. Taken together, these data suggest different susceptibilities to hyperglycemia in older and younger fish and that stepwise increasing glucose concentrations of 1% are required for maintenance of hyperglycemia in younger adults, with higher concentrations of glucose resulting in greater increases in blood sugar values. PMID- 26771446 TI - A Review of Methods for Detecting Tick-Borne Encephalitis Virus Infection in Tick, Animal, and Human Specimens. AB - Tick-borne encephalitis virus (TBEV) is the most important tick-transmitted arbovirus causing human disease in Europe and Asia. Over the past decades, the incidence of TBEV infection has significantly increased, with over 13,000 annual hospital referrals in endemic countries and cases emerging in previously unaffected regions. Specific detection of TBEV is required to diagnose suspected human cases or during surveillance of tick vectors and/or susceptible animal species. Widely used techniques for diagnosis comprise serological methods to detect viral antigens or antibodies and nucleic acid tests to detect viral RNA in target specimens. Moreover, virus isolation using susceptible cell lines or vertebrates, electron microscopy, or immunohistochemistry can also be employed on specific occasions. The purpose of this review is to compile and outline various approaches and techniques for detecting TBEV infection in ticks, wild animals, and humans. Specific sections for specimen collection and storage, nucleic acid testing, and serological assays cover various aspects of dynamics, performance characteristics, and utility in the diagnostic workup of suspected cases. Impact of immunoglobulin M testing and quantification, immunoglobulin G avidity, and real-time and quantitative polymerase chain reaction methods were overviewed with assay comparisons. Recent advances in serological assays to mitigate the impact of cross-reactions were further discussed along with the detailed interpretation of laboratory test results in human infections. PMID- 26771445 TI - Safety and efficacy of oral febuxostat for treatment of HLA-B*5801-negative gout: a randomized, open-label, multicentre, allopurinol-controlled study. AB - OBJECTIVES: This phase IIIB study compared the efficacy and safety of febuxostat and allopurinol in gout patients with or without tophi who were HLA-B*5801 negative. METHOD: Eligible patients were randomized to a febuxostat group (80 mg QD) or an allopurinol group (300 mg QD). Following an initial 2-week washout period, over the next 12 weeks we made five measurements of serum urate levels along with assessments of adverse events (AEs). RESULTS: Forty-three out of 152 screened subjects (28.3%) were ineligible either because of the presence of the HLA-B*5801 allele or for various other reasons. The febuxostat group (n = 54) and the allopurinol group (n = 55) had no significant differences in demographic or baseline characteristics. From week 2 to week 12, the febuxostat group had a significantly lower serum urate level than the allopurinol group (p <= 0.001 for all comparisons) and significantly more patients with serum urate levels less than 6.0 mg/dL. The serum urate levels of the febuxostat group declined by more than 40% from week 2 to week 12 and this decrease was greater than that in the allopurinol group (~30%). The two groups were similar in terms of AEs. CONCLUSIONS: Febuxostat was more effective than allopurinol in reducing the serum urate levels of Han Chinese patients with gout or tophaceous gout who were HLA B*5801 negative, without causing any serious skin reactions. Febuxostat should be considered for treatment of Han Chinese patients with gout who are HLA-B*5801 negative. PMID- 26771447 TI - Control of Cell Attachment and Spreading on Poly(acrylamide) Brushes with Varied Grafting Density. AB - To achieve spatial control of fibroblast cell attachment and spreading on a biocompatible polymer coating, the effect of poly(acrylamide) (PAAm) brushes with varied grafting density was investigated. The synthesis of the brushes was performed by surface-initiated atom transfer radical polymerization (SI-ATRP). Gold substrates were modified with binary self-assembled monolayers (SAMs) of an initiator and 16-mercaptohexadecanoic acid (MHDA) as an "inert" thiol to initiate the ATRP of AAm. By using different mixtures for the binary SAMs, a series of polymer brushes with varied grafting densities were prepared. The fractional coverage of surface bound initiator was determined by grazing incidence Fourier transform infrared (FTIR) spectroscopy, X-ray photoelectron spectroscopy (XPS), time-of-flight secondary ion mass spectrometry (ToF-SIMS), and contact angle measurements. A linear relationship between the Br/S ratio determined by XPS and ToF-SIMS versus the fraction of initiator on the surface determined by water contact angle measurements was observed. The varied initiation concentration on the gold substrates yielded PAAm brushes with different thicknesses, indicating a transition from mushroom to brush regimes with increasing grafting density. Thereby we achieved exquisite control of the degree of cell adhesion. Cell attachment experiments with NIH 3T3 fibroblast cells revealed cell spreading on PAAm brushes with low grafting densities (initiator fractional coverage <0.2) as well as a complete passivation by polymer brushes with higher grafting densities. PMID- 26771448 TI - Going forward with Ultrastructural Pathology. PMID- 26771449 TI - Lack of electron microscopy hinders correct renal biopsy diagnosis: A study from India. AB - Electron microscopy (EM) is performed routinely on all native kidney biopsies in the western world. However, in India, it is not regularly performed due to non availability and financial constraints. The aim of this prospective study was to evaluate the usefulness of routinely performing EM on native kidney biopsies. In order to eliminate selection bias, all consecutive native kidney biopsies were included in this study, provided they had adequate tissue for light, immunofluorescence (IF), and EM. The biopsies were reported on the basis of light and IF microscopy. EM was performed on each case by another pathologist who also independently reviewed the light microscopic slides and IF images. The findings were then reviewed to assess how the ultrastructural features contributed to the primary diagnosis and assigned to one of the following categories: 1. Crucial for diagnosis, 2. Important contribution, or 3. Not required. Of the 115 cases evaluated, EM was crucial in 12% of the cases. In 20% of the cases, it provided important confirmatory information and in the remaining 68% cases, EM was not considered required. This study supports the use of EM as a routine diagnostic tool in the evaluation of native kidney biopsies. There is an urgent need for availability and accessibility of EM in our country. PMID- 26771450 TI - Histiocytic differentiation in acute monocytic leukemia. AB - Myeloid histocytes of dendritic cells (DCs), Langerhans cells (LCs), and macrophages in varied tissues, as leukemic blasts in acute monoblastic and monocytic leukemia (AML-M5a and M5b), are derived from monocyte progenitors in bone marrow. Based on DC induction from hematopoietic stem cells, myeloid progenitors, and monocytes, and occasional expressions of histocyte-related antigens (HRAs) in M5, we presume some M5 cases share histiocytic phenotypes originally. To clarify the conception, 93 M5 cases were tested with antibodies for HRAs, CD1a, CD163, S100, fascin, and langerin by immunostaining, and their morphologic characteristics were studied by light and transmission electron microscopy. The study revealed that 23 M5 cases were positive for two or more kinds of HRAs and shared a serial of histocytic immunophenotype and morphologic features, which were closely associated with M5b subtype and expression of CD14 in M5. PMID- 26771451 TI - [Refractory Hoarseness In Granular Cell Tumor of the Vocal Cord]. PMID- 26771452 TI - Simultaneous Measurement of Breathing Kinematics and Surface Electromyography of Chest Wall Muscles during Maximum Performance and Speech Tasks in Children: Methodological Considerations. AB - OBJECTIVE: To develop a standardized paediatric protocol for acquiring simultaneous chest wall kinematics and surface electromyography (EMG) of chest wall muscles during maximum performance and speech tasks. PATIENTS AND METHODS: Eighteen healthy participants included: (a) a younger age group (n = 6; ages 4.0 6.5 years), (b) an older age group (n = 6; ages 7.0-10.5 years), and (c) an adult group (n = 8; ages 21-33 years). A child (age 10 years) with spastic-type cerebral palsy (CP) served as a 'proof of protocol feasibility'. Chest wall kinematics and surface EMGs (intercostals, rectus abdominus, external oblique, latissimus dorsi, and erector spinae) were acquired during maximum performance and speech tasks. RESULTS: Successful calibration of the EMG signal and reliable detection of muscle activation onset, offset, and amplitude relative to vital capacity and percent maximum voluntary contraction in children were demonstrated. Kinematic and surface EMG measurements were sensitive to non-speech and speech tasks, age, and neurological status (i.e. CP). CONCLUSION: The simultaneous measurement of kinematics and EMG of the chest wall muscle groups provides a more comprehensive description of speech breathing in children. This protocol can be used for the observation and interpretation of clinical outcomes seen in children with motor speech disorders following treatments that focus on increasing overall respiratory and vocal effort. PMID- 26771453 TI - Multiple Looser zones of osteomalacia in Byler disease with associated vitamin D deficiency, phosphaturia, and elevated FGF23. AB - INTRODUCTION: Byler disease (progressive familial intrahepatic cholestasis) is associated metabolic bone disease as a consequence of chronic malabsorption. CASE PRESENTATION: A 33-year-old man with decompensated liver disease secondary to Byler disease was referred to the orthopaedic department with progressive pain over this right proximal tibia. On examination, he had an antalgic gait. Tenderness was localised to the proximal tibia just distal to the tibial tubercle and bilateral foot swelling. Radiographs showed multiple stress fractures characteristic of Looser zones at various stages of healing in both tibia, metatarsals (third, fourth, and fifth on the right side, and second and fourth on the left) and left femur. Bone mineral density was extremely low. Subsequent investigations were consistent with severe osteomalacia due to a combination of vitamin D deficiency and phosphaturia with elevated fibroblast factor 23 (FGF23). A good clinical response was achieved following supplementation with calcium 1000mg and vitamin D 20MUg daily. DISCUSSION: Stress fractures are often associated with delay in diagnosis. Our patient presented to the orthopaedic service with multiple Looser zones that had not been previously detected. As expected, there was biochemical evidence of vitamin D deficiency. An unexpected finding was phosphaturia that was associated with marked elevation in FGF23, which has never been reported previously. CONCLUSION: Byler disease may result in Looser zones of osteomalacia due to chronic malabsorption. Renal phosphorus wasting as a consequence of unexplained marked elevation in FGF23 is thought to have contributed to the onset of osteomalacia. PMID- 26771454 TI - Preparation of a beta-Cyclodextrin-Based Open-Tubular Capillary Electrochromatography Column and Application for Enantioseparations of Ten Basic Drugs. AB - An open-tubular capillary electrochromatography column was prepared by chemically immobilized beta-cyclodextrin modified gold nanoparticles onto new surface with the prederivatization of (3-mercaptopropyl)-trimethoxysilane. The synthesized nanoparticles and the prepared column were characterized by transmission electron microscopy, scanning electron microscopy, infrared spectroscopy and ultraviolet visible spectroscopy. When the column was employed as the chiral stationary phase, no enantioselectivity was observed for ten model basic drugs. So beta cyclodextrin was added to the background electrolyte as chiral additive to expect a possible synergistic effect occurring and resulting in a better separation. Fortunately, significant improvement in enantioselectivity was obtained for ten pairs of drug enantiomers. Then, the effects of beta-cyclodextrin concentration and background electrolyte pH on the chiral separation were investigated. With the developed separation mode, all the enantiomers (except for venlafaxine) were baseline separated in resolutions of 4.49, 1.68, 1.88, 1.57, 2.52, 2.33, 3.24, 1.63 and 3.90 for zopiclone, chlorphenamine maleate, brompheniramine maleate, dioxopromethazine hydrochloride, carvedilol, homatropine hydrobromide, homatropine methylbromide, venlafaxine, sibutramine hydrochloride and terbutaline sulfate, respectively. Further, the possible separation mechanism involved was discussed. PMID- 26771455 TI - Phytoremediation of the organic Xenobiotic simazine by p450-1a2 transgenic Arabidopsis thaliana plants. AB - The potential use of human P450-transgenic plants for phytoremediation of pesticide contaminated soils was tested in laboratory and greenhouse experiments. The transgenic P450 CYP1A2 gene Arabidopsis thaliana plants metabolize number of herbicides, insecticides and industrial chemicals. The P450 isozymes CYP1A2 expressed in A. thaliana were examined regarding the herbicide simazine (SIM). Transgenic A. thaliana plants expressing CYP1A2 gene showed significant resistance to SIM supplemented either in plant growth medium or sprayed on foliar parts. The results showed that SIM produces harmful effect on both rosette diameter and primary root length of the wild type (WT) plants. In transgenic A. thaliana lines, the rosette diameter and primary root length were not affected by SIM concentrations used in this experiment. The results indicate that CYP1A2 can be used as a selectable marker for plant transformation, allowing efficient selection of transgenic lines in growth medium and/or in soil-grown plants. The transgenic A. thaliana plants exhibited a healthy growth using doses of up to 250 MUmol SIM treatments, while the non-transgenic A. thaliana plants were severely damaged with doses above 50 MUmol SIM treatments. The transgenic A. thaliana plants can be used as phytoremediator of environmental SIM contaminants. PMID- 26771456 TI - Gut Microbiota in Children Hospitalized with Oedematous and Non-Oedematous Severe Acute Malnutrition in Uganda. AB - BACKGROUND: Severe acute malnutrition (SAM) among children remains a major health problem in many developing countries. SAM manifests in both an oedematous and a non-oedematous form, with oedematous malnutrition in its most severe form also known as kwashiorkor. The pathogenesis of both types of malnutrition in children remains largely unknown, but gut microbiota (GM) dysbiosis has recently been linked to oedematous malnutrition. In the present study we aimed to assess whether GM composition differed between Ugandan children suffering from either oedematous or non-oedematous malnutrition. METHODOLOGY/PRINCIPAL FINDINGS: As part of an observational study among children hospitalized with SAM aged 6-24 months in Uganda, fecal samples were collected at admission. Total genomic DNA was extracted from fecal samples, and PCR amplification was performed followed by Denaturing Gradient Gel Electrophoresis (DGGE) and tag-encoded 16S rRNA gene targeted high throughput amplicon sequencing. Alpha and beta diversity measures were determined along with ANOVA mean relative abundance and G-test of independence followed by comparisons between groups. Of the 87 SAM children included, 62% suffered from oedematous malnutrition, 66% were boys and the mean age was 16.1 months. GM composition was found to differ between the two groups of children as determined by DGGE (p = 0.0317) and by high-throughput sequencing, with non-oedematous children having lower GM alpha diversity (p = 0.036). However, beta diversity analysis did not reveal larger differences between the GM of children with oedematous and non-oedematous SAM (ANOSIM analysis, weighted UniFrac, R = -0.0085, p = 0.584; unweighted UniFrac, R = 0.0719, p = 0.011). CONCLUSIONS/SIGNIFICANCE: Our results indicate that non-oedematous SAM children have lower GM diversity compared to oedematous SAM children, however no clear compositional differences were identified. PMID- 26771461 TI - Correction: Katanin Localization Requires Triplet Microtubules in Chlamydomonas reinhardtii. PMID- 26771460 TI - Cryptosporidium proliferans n. sp. (Apicomplexa: Cryptosporidiidae): Molecular and Biological Evidence of Cryptic Species within Gastric Cryptosporidium of Mammals. AB - The morphological, biological, and molecular characteristics of Cryptosporidium muris strain TS03 are described, and the species name Cryptosporidium proliferans n. sp. is proposed. Cryptosporidium proliferans obtained from a naturally infected East African mole rat (Tachyoryctes splendens) in Kenya was propagated under laboratory conditions in rodents (SCID mice and southern multimammate mice, Mastomys coucha) and used in experiments to examine oocyst morphology and transmission. DNA from the propagated C. proliferans isolate, and C. proliferans DNA isolated from the feces of an African buffalo (Syncerus caffer) in Central African Republic, a donkey (Equus africanus) in Algeria, and a domestic horse (Equus caballus) in the Czech Republic were used for phylogenetic analyses. Oocysts of C. proliferans are morphologically distinguishable from C. parvum and C. muris HZ206, measuring 6.8-8.8 (mean = 7.7 MUm) * 4.8-6.2 MUm (mean = 5.3) with a length to width ratio of 1.48 (n = 100). Experimental studies using an isolate originated from T. splendens have shown that the course of C. proliferans infection in rodent hosts differs from that of C. muris and C. andersoni. The prepatent period of 18-21 days post infection (DPI) for C. proliferans in southern multimammate mice (Mastomys coucha) was similar to that of C. andersoni and longer than the 6-8 DPI prepatent period for C. muris RN66 and HZ206 in the same host. Histopatologicaly, stomach glands of southern multimammate mice infected with C. proliferans were markedly dilated and filled with necrotic material, mucus, and numerous Cryptosporidium developmental stages. Epithelial cells of infected glands were atrophic, exhibited cuboidal or squamous metaplasia, and significantly proliferated into the lumen of the stomach, forming papillary structures. The epithelial height and stomach weight were six-fold greater than in non-infected controls. Phylogenetic analyses based on small subunit rRNA, Cryptosporidium oocyst wall protein, thrombospondin-related adhesive protein of Cryptosporidium-1, heat shock protein 70, actin, heat shock protein 90 (MS2), MS1, MS3, and M16 gene sequences revealed that C. proliferans is genetically distinct from C. muris and other previously described Cryptosporidium species. PMID- 26771462 TI - Impact of Helicopter Emergency Medical Service in Traumatized Patients: Which Patient Benefits Most? AB - INTRODUCTION: The Helicopter Emergency Medical Service (HEMS) was established for the prehospital trauma care of patients. Improved rescue times and increased coverage areas are discussed as specific advantages of HEMS. We recently found evidence that HEMS exerts beneficial effects on outcomes for severely injured patients. However, it still remains unknown which group of trauma patients might benefit most from HEMS rescue. Consequently, the unique aim of this study was to reveal which patients might benefit most from HEMS rescue. METHODS: Trauma patients (ISS >=9) primarily treated by HEMS or ground emergency medical services (GEMS) between 2002 and 2012 were analysed using the TraumaRegister DGU. A multivariate regression analysis was used to reveal the survival benefit between different trauma populations. RESULTS: The study included 52 281 trauma patients. Of these, 68.8% (35 974) were rescued by GEMS and 31.2% (16 307) by HEMS. HEMS patients were more severely injured compared to GEMS patients (ISS: HEMS 24.8+/ 13.5 vs. GEMS 21.7+/-18.0) and more frequently suffered traumatic shock (SBP sys <90mmHg: HEMS 18.3% vs. GEMS 14.8%). However, logistic regression analysis revealed that HEMS rescues resulted in an overall survival benefit compared to GEMS (OR 0.81, 95% CI [0.75-0.87], p<0.001, Nagelkerke's R squared 0.526, area under the ROC curve 0.922, 95% CI [0.919-0.925]). Analysis of specific subgroups demonstrated that patients aged older than 55 years (OR 0.62, 95% CI [0.50-0.77]) had the highest survival benefit after HEMS treatment. Furthermore, HEMS rescue had the most significant impact after 'low falls' (OR 0.68, 95% CI [0.55-0.84]) and in the case of minor severity injuries (ISS 9-15) (OR 0.66, 95% CI [0.49 0.88]). CONCLUSIONS: In general, trauma patients benefit from HEMS rescue with in hospital survival as the main outcome parameter. Focusing on special subgroups, middle aged and older patients, low-energy trauma, and minor severity injuries had the highest survival benefit when rescued by HEMS. Further studies are required to determine the potential reasons of this benefit. PMID- 26771469 TI - Vascular interventions in the elderly. PMID- 26771463 TI - A Factor Graph Approach to Automated GO Annotation. AB - As volume of genomic data grows, computational methods become essential for providing a first glimpse onto gene annotations. Automated Gene Ontology (GO) annotation methods based on hierarchical ensemble classification techniques are particularly interesting when interpretability of annotation results is a main concern. In these methods, raw GO-term predictions computed by base binary classifiers are leveraged by checking the consistency of predefined GO relationships. Both formal leveraging strategies, with main focus on annotation precision, and heuristic alternatives, with main focus on scalability issues, have been described in literature. In this contribution, a factor graph approach to the hierarchical ensemble formulation of the automated GO annotation problem is presented. In this formal framework, a core factor graph is first built based on the GO structure and then enriched to take into account the noisy nature of GO term predictions. Hence, starting from raw GO-term predictions, an iterative message passing algorithm between nodes of the factor graph is used to compute marginal probabilities of target GO-terms. Evaluations on Saccharomyces cerevisiae, Arabidopsis thaliana and Drosophila melanogaster protein sequences from the GO Molecular Function domain showed significant improvements over competing approaches, even when protein sequences were naively characterized by their physicochemical and secondary structure properties or when loose noisy annotation datasets were considered. Based on these promising results and using Arabidopsis thaliana annotation data, we extend our approach to the identification of most promising molecular function annotations for a set of proteins of unknown function in Solanum lycopersicum. PMID- 26771470 TI - Molecular and biological hallmarks of ageing. AB - BACKGROUND: Ageing is the inevitable time-dependent decline in physiological organ function that eventually leads to death. Age is a major risk factor for many of the most common medical conditions, such as cardiovascular disease, cancer, diabetes and Alzheimer's disease. This study reviews currently known hallmarks of ageing and their clinical implications. METHODS: A literature search of PubMed/MEDLINE was conducted covering the last decade. RESULTS: Average life expectancy has increased dramatically over the past century and is estimated to increase even further. Maximum longevity, however, appears unchanged, suggesting a universal limitation to the human organism. Understanding the underlying molecular processes of ageing and health decline may suggest interventions that, if used at an early age, can prevent, delay, alleviate or even reverse age related diseases. Hallmarks of ageing can be grouped into three main categories. The primary hallmarks cause damage to cellular functions: genomic instability, telomere attrition, epigenetic alterations and loss of proteostasis. These are followed by antagonistic responses to such damage: deregulated nutrient sensing, altered mitochondrial function and cellular senescence. Finally, integrative hallmarks are possible culprits of the clinical phenotype (stem cell exhaustion and altered intercellular communication), which ultimately contribute to the clinical effects of ageing as seen in physiological loss of reserve, organ decline and reduced function. CONCLUSION: The sum of these molecular hallmarks produces the clinical picture of the elderly surgical patient: frailty, sarcopenia, anaemia, poor nutrition and a blunted immune response system. Improved understanding of the ageing processes may give rise to new biomarkers of risk or prognosis, novel treatment targets and translational approaches across disciplines that may improve outcomes. PMID- 26771471 TI - Surgery for an ageing population. PMID- 26771472 TI - Elevated levels of Interleukin (IL)-33 induce bone pathology but absence of IL-33 does not negatively impact normal bone homeostasis. AB - Interleukin (IL)-33 is a member of the IL-1 family. IL-33 effects are mediated through its receptor, ST2 and IL-1RAcP, and its signaling induces the production of a number of pro-inflammatory mediators, including TNFalpha, IL-1beta, IL-6, and IFN-gamma. There are conflicting reports on the role of IL-33 in bone homeostasis, with some demonstrating a bone protective role for IL-33 whilst others show that IL-33 induces inflammatory arthritis with concurrent bone destruction. To better clarify the role IL-33 plays in bone biology in vivo, we studied IL-33 KO mice as well as mice in which the cytokine form of IL-33 was overexpressed. Mid-femur cortical bone mineral density (BMD) and bone strength were similar in the IL-33 KO mice compared to WT animals during the first 8months of life. However, in the absence of IL-33, we observed higher BMD in lumbar vertebrae and distal femur in female mice. In contrast, overexpression of IL-33 resulted in a marked and rapid reduction of bone volume, mineral density and strength. Moreover, this was associated with a robust increase in inflammatory cytokines (including IL-6 and IFN-gamma), suggesting the bone pathology could be a direct effect of IL-33 or an indirect effect due to the induction of other mediators. Furthermore, the detrimental bone effects were accompanied by increases in osteoclast number and the bone resorption marker of C-terminal telopeptide collagen-I (CTX-I). Together, these results demonstrate that absence of IL-33 has no negative consequences in normal bone homeostasis while high levels of circulating IL-33 contributes to pathological bone loss. PMID- 26771474 TI - Predictors of 30-Day Readmission for Pneumonia. AB - OBJECTIVE: This study examined data from 4 sources: number of hospital-acquired conditions, patient perception of care, quality outcome measures, and demographic data to explain variances associated with 30-day pneumonia readmission rates. BACKGROUND: Patients readmitted within 30 days for pneumonia increases the length of hospital stay by 7 to 9 days, increases crude mortality rate 30% to 70%, and costs of $40,000 or greater per patient. METHODS: Variances in outcomes measures associated with 30-day pneumonia readmissions from 577 nonfederal general hospitals in Massachusetts, California, and New York were analyzed using datasets from Hospital Consumer Assessment of Healthcare Providers and Systems, Centers of Medicare & Medicaid Services, Agency for Healthcare Research and Quality, and American Hospital Association. RESULTS: Three factors increased pneumonia readmission rates: poor nurse-patient communication, poor staff responsiveness to patient needs, and iatrogenic pneumothorax. Conversely, factors lowering pneumonia readmission rates included patients hospitalized in California, higher RN staffing, and higher proportions of nursing staff to total hospital personnel. CONCLUSION: Findings suggest lower nurse staffing, poor nurse-patient communication, and nurse responsiveness to patient needs contribute to increased pneumonia readmission rates. PMID- 26771475 TI - Reducing Medication Administration Errors in Acute and Critical Care: Multifaceted Pilot Program Targeting RN Awareness and Behaviors. AB - OBJECTIVE: The aim of this medication safety pilot program was to increase RN sensitivity to potential error risk, improve behaviors, and reduce observed medication administration errors (MAEs). BACKGROUND: MAEs are common and preventable and may lead to adverse drug events, costing the patient and organization. MAEs are low visibility, rarely intercepted, and underreported. METHODS: An interprofessional team used process improvement methodology to develop a human factors-based medication safety pilot program to address identified issues. An observational time-series design study monitored the effect of the program. RESULTS: After the program, error interception practices during administration increased, and some nurses reported using a mindfulness strategy to gain situational awareness before administration. Process behaviors were performed more consistently, and the risk of MAE decreased. Familiarity and complexity were identified as additional variables affecting MAE outcome. CONCLUSIONS: Strategies to support safe medication administration may reduce error and be of interest to nurse leaders. PMID- 26771476 TI - Residency for Transition Into Practice: An Essential Requirement for New Graduates From Basic RN Programs. AB - Nurse residency programs have been developed with the goal of helping newly licensed nurses successfully transition to independent practice. The authors propose that all newly licensed nurses hired in acute care hospitals be required to complete an accredited residency program. An evidence table examines the state of the science related to transition-to-practice programs and provides the basis for recommendations. PMID- 26771473 TI - Type 2 diabetes mellitus coincident with pulmonary or latent tuberculosis results in modulation of adipocytokines. AB - Type 2 diabetes mellitus (T2DM) is recognized as major risk factor for the progress of active pulmonary tuberculosis (PTB), although the mechanistic link between diabetes and tuberculosis remains poorly characterized. Moreover, the influence of poorly controlled diabetes on the baseline levels of adipocytokines in the context of tuberculosis has not been explored in detail. To characterize the influence of coexistent DM on adipocytokine levels in pulmonary or latent TB (LTB), we examined circulating levels of adipocytokines in the plasma of individuals with PTB-DM or LTB-DM and compared them with those without DM (PTB or LTB). PTB-DM or LTB-DM is characterized by diminished circulating levels of adiponectin and adipsin and/or heightened circulating levels of leptin, visfatin and PAI-1. In addition, adiponectin and adipsin exhibit a significant negative correlation, whereas leptin, visfatin and PAI-1 display a significant positive correlation with HbA1C levels and random blood glucose levels. Therefore, our data reveal that PTB-DM or LTB-DM is characterized by alterations in the systemic levels of adipocytokines, indicating that altered adipose tissue inflammation underlying Type 2 diabetes potentially contributes to pathogenesis of TB disease. PMID- 26771479 TI - Standing Up for Sticklebacks. AB - The morphology of the vertebrate skeleton exhibits tremendous plasticity in evolution, allowing adaptation to a wide variety of ecological niches and lifestyles. Indjeian et al. now uncover how the cis regulation of a gene controls skeletal variation in fish and might have contributed to the evolution of bipedalism in humans. PMID- 26771480 TI - A New aDENNDum to Genetics of Childhood Asthma. AB - Childhood asthma is typically associated with a polarized Th2 response to inhaled allergens and is influenced by genetics. Yang et al. show that the asthma susceptibility gene DENND1B controls cytokine production in Th2 lymphocytes by controlling the rate of TCR internalization and routing to endosomes, providing a molecular basis for how DENND1B contributes to asthma pathogenesis. PMID- 26771481 TI - Street View of the Cognitive Map. AB - To understand the origins of spatial navigational signals, Acharya et al. record the activity of hippocampal neurons in rats running in open two-dimensional environments in both the real world and in virtual reality. They find that a subset of hippocampal neurons have directional tuning that persists in virtual reality, where vestibular cues are absent. PMID- 26771482 TI - Shadow on the Plant: A Strategy to Exit. AB - The light spectrum perceived by plants is affected by crowding, which results in the shade avoidance syndrome (SAS). Findings presented by Pedmale et al. bring cryptochromes to the forefront of SAS and elucidate a fascinating molecular crosstalk between photoreceptor systems operating in different wavebands. PMID- 26771483 TI - The Heroes of CRISPR. AB - Three years ago, scientists reported that CRISPR technology can enable precise and efficient genome editing in living eukaryotic cells. Since then, the method has taken the scientific community by storm, with thousands of labs using it for applications from biomedicine to agriculture. Yet, the preceding 20-year journey- the discovery of a strange microbial repeat sequence; its recognition as an adaptive immune system; its biological characterization; and its repurposing for genome engineering--remains little known. This Perspective aims to fill in this backstory--the history of ideas and the stories of pioneers--and draw lessons about the remarkable ecosystem underlying scientific discovery. PMID- 26771484 TI - Biology and Applications of CRISPR Systems: Harnessing Nature's Toolbox for Genome Engineering. AB - Bacteria and archaea possess a range of defense mechanisms to combat plasmids and viral infections. Unique among these are the CRISPR-Cas (clustered regularly interspaced short palindromic repeats-CRISPR associated) systems, which provide adaptive immunity against foreign nucleic acids. CRISPR systems function by acquiring genetic records of invaders to facilitate robust interference upon reinfection. In this Review, we discuss recent advances in understanding the diverse mechanisms by which Cas proteins respond to foreign nucleic acids and how these systems have been harnessed for precision genome manipulation in a wide array of organisms. PMID- 26771485 TI - Cell-free DNA Comprises an In Vivo Nucleosome Footprint that Informs Its Tissues Of-Origin. AB - Nucleosome positioning varies between cell types. By deep sequencing cell-free DNA (cfDNA), isolated from circulating blood plasma, we generated maps of genome wide in vivo nucleosome occupancy and found that short cfDNA fragments harbor footprints of transcription factors. The cfDNA nucleosome occupancies correlate well with the nuclear architecture, gene structure, and expression observed in cells, suggesting that they could inform the cell type of origin. Nucleosome spacing inferred from cfDNA in healthy individuals correlates most strongly with epigenetic features of lymphoid and myeloid cells, consistent with hematopoietic cell death as the normal source of cfDNA. We build on this observation to show how nucleosome footprints can be used to infer cell types contributing to cfDNA in pathological states such as cancer. Since this strategy does not rely on genetic differences to distinguish between contributing tissues, it may enable the noninvasive monitoring of a much broader set of clinical conditions than currently possible. PMID- 26771486 TI - The Protease Ste24 Clears Clogged Translocons. AB - Translocation into the endoplasmic reticulum (ER) is the first step in the biogenesis of thousands of eukaryotic endomembrane proteins. Although functional ER translocation has been avidly studied, little is known about the quality control mechanisms that resolve faulty translocational states. One such faulty state is translocon clogging, in which the substrate fails to properly translocate and obstructs the translocon pore. To shed light on the machinery required to resolve clogging, we carried out a systematic screen in Saccharomyces cerevisiae that highlighted a role for the ER metalloprotease Ste24. We could demonstrate that Ste24 approaches the translocon upon clogging, and it interacts with and generates cleavage fragments of the clogged protein. Importantly, these functions are conserved in the human homolog, ZMPSTE24, although disease associated mutant forms of ZMPSTE24 fail to clear the translocon. These results shed light on a new and critical task of Ste24, which safeguards the essential process of translocation. PMID- 26771487 TI - Force Feedback Controls Motor Activity and Mechanical Properties of Self Assembling Branched Actin Networks. AB - Branched actin networks--created by the Arp2/3 complex, capping protein, and a nucleation promoting factor--generate and transmit forces required for many cellular processes, but their response to force is poorly understood. To address this, we assembled branched actin networks in vitro from purified components and used simultaneous fluorescence and atomic force microscopy to quantify their molecular composition and material properties under various forces. Remarkably, mechanical loading of these self-assembling materials increases their density, power, and efficiency. Microscopically, increased density reflects increased filament number and altered geometry but no change in average length. Macroscopically, increased density enhances network stiffness and resistance to mechanical failure beyond those of isotropic actin networks. These effects endow branched actin networks with memory of their mechanical history that shapes their material properties and motor activity. This work reveals intrinsic force feedback mechanisms by which mechanical resistance makes self-assembling actin networks stiffer, stronger, and more powerful. PMID- 26771488 TI - Integrins Form an Expanding Diffusional Barrier that Coordinates Phagocytosis. AB - Phagocytosis is initiated by lateral clustering of receptors, which in turn activates Src-family kinases (SFKs). Activation of SFKs requires depletion of tyrosine phosphatases from the area of particle engagement. We investigated how the major phosphatase CD45 is excluded from contact sites, using single-molecule tracking. The mobility of CD45 increased markedly upon engagement of Fcgamma receptors. While individual CD45 molecules moved randomly, they were displaced from the advancing phagocytic cup by an expanding diffusional barrier. By micropatterning IgG, the ligand of Fcgamma receptors, we found that the barrier extended well beyond the perimeter of the receptor-ligand engagement zone. Second messengers generated by Fcgamma receptors activated integrins, which formed an actin-tethered diffusion barrier that excluded CD45. The expanding integrin wave facilitates the zippering of Fcgamma receptors onto the target and integrates the information from sparse receptor-ligand complexes, coordinating the progression and ultimate closure of the phagocytic cup. PMID- 26771489 TI - WNT-SHH Antagonism Specifies and Expands Stem Cells prior to Niche Formation. AB - Adult stem cell (SC) maintenance and differentiation are known to depend on signals received from the niche. Here, however, we demonstrate a mechanism for SC specification and regulation that is niche independent. Using immunofluorescence, live imaging, genetics, cell-cycle analyses, in utero lentiviral transduction, and lineage-tracing, we show that in developing hair buds, SCs are born from asymmetric divisions that differentially display WNT and SHH signaling. Displaced WNT(lo) suprabasal daughters become SCs that respond to paracrine SHH and symmetrically expand. By contrast, basal daughters remain WNT(hi). They express but do not respond to SHH and hence maintain slow-cycling, asymmetric divisions. Over time, they become short-lived progenitors, generating differentiating daughters rather than SCs. Thus, in contrast to an established niche that harbors a fixed SC pool whose expelled progeny differentiate, asymmetric divisions first specify and displace early SCs into an environment conducive to expansion and later restrict their numbers by switching asymmetric fates. PMID- 26771490 TI - Nitric Oxide as a Switching Mechanism between Axon Degeneration and Regrowth during Developmental Remodeling. AB - During development, neurons switch among growth states, such as initial axon outgrowth, axon pruning, and regrowth. By studying the stereotypic remodeling of the Drosophila mushroom body (MB), we found that the heme-binding nuclear receptor E75 is dispensable for initial axon outgrowth of MB gamma neurons but is required for their developmental regrowth. Genetic experiments and pharmacological manipulations on ex-vivo-cultured brains indicate that neuronally generated nitric oxide (NO) promotes pruning but inhibits regrowth. We found that high NO levels inhibit the physical interaction between the E75 and UNF nuclear receptors, likely accounting for its repression of regrowth. Additionally, NO synthase (NOS) activity is downregulated at the onset of regrowth, at least partially, by short inhibitory NOS isoforms encoded within the NOS locus, indicating how NO production could be developmentally regulated. Taken together, these results suggest that NO signaling provides a switching mechanism between the degenerative and regenerative states of neuronal remodeling. PMID- 26771491 TI - Astrocytes Assemble Thalamocortical Synapses by Bridging NRX1alpha and NL1 via Hevin. AB - Proper establishment of synapses is critical for constructing functional circuits. Interactions between presynaptic neurexins and postsynaptic neuroligins coordinate the formation of synaptic adhesions. An isoform code determines the direct interactions of neurexins and neuroligins across the synapse. However, whether extracellular linker proteins can expand such a code is unknown. Using a combination of in vitro and in vivo approaches, we found that hevin, an astrocyte secreted synaptogenic protein, assembles glutamatergic synapses by bridging neurexin-1alpha and neuroligin-1B, two isoforms that do not interact with each other. Bridging of neurexin-1alpha and neuroligin-1B via hevin is critical for the formation and plasticity of thalamocortical connections in the developing visual cortex. These results show that astrocytes promote the formation of synapses by modulating neurexin/neuroligin adhesions through hevin secretion. Our findings also provide an important mechanistic insight into how mutations in these genes may lead to circuit dysfunction in diseases such as autism. PMID- 26771492 TI - Prefrontal Parvalbumin Neurons in Control of Attention. AB - While signatures of attention have been extensively studied in sensory systems, the neural sources and computations responsible for top-down control of attention are largely unknown. Using chronic recordings in mice, we found that fast-spiking parvalbumin (FS-PV) interneurons in medial prefrontal cortex (mPFC) uniformly show increased and sustained firing during goal-driven attentional processing, correlating to the level of attention. Elevated activity of FS-PV neurons on the timescale of seconds predicted successful execution of behavior. Successful allocation of attention was characterized by strong synchronization of FS-PV neurons, increased gamma oscillations, and phase locking of pyramidal firing. Phase-locked pyramidal neurons showed gamma-phase-dependent rate modulation during successful attentional processing. Optogenetic silencing of FS-PV neurons deteriorated attentional processing, while optogenetic synchronization of FS-PV neurons at gamma frequencies had pro-cognitive effects and improved goal-directed behavior. FS-PV neurons thus act as a functional unit coordinating the activity in the local mPFC circuit during goal-driven attentional processing. PMID- 26771493 TI - Restoration of Visual Function by Enhancing Conduction in Regenerated Axons. AB - Although a number of repair strategies have been shown to promote axon outgrowth following neuronal injury in the mammalian CNS, it remains unclear whether regenerated axons establish functional synapses and support behavior. Here, in both juvenile and adult mice, we show that either PTEN and SOCS3 co-deletion, or co-overexpression of osteopontin (OPN)/insulin-like growth factor 1 (IGF1)/ciliary neurotrophic factor (CNTF), induces regrowth of retinal axons and formation of functional synapses in the superior colliculus (SC) but not significant recovery of visual function. Further analyses suggest that regenerated axons fail to conduct action potentials from the eye to the SC due to lack of myelination. Consistent with this idea, administration of voltage-gated potassium channel blockers restores conduction and results in increased visual acuity. Thus, enhancing both regeneration and conduction effectively improves function after retinal axon injury. PMID- 26771495 TI - Ebola Viral Glycoprotein Bound to Its Endosomal Receptor Niemann-Pick C1. AB - Filoviruses, including Ebola and Marburg, cause fatal hemorrhagic fever in humans and primates. Understanding how these viruses enter host cells could help to develop effective therapeutics. An endosomal protein, Niemann-Pick C1 (NPC1), has been identified as a necessary entry receptor for this process, and priming of the viral glycoprotein (GP) to a fusion-competent state is a prerequisite for NPC1 binding. Here, we have determined the crystal structure of the primed GP (GPcl) of Ebola virus bound to domain C of NPC1 (NPC1-C) at a resolution of 2.3 A. NPC1-C utilizes two protruding loops to engage a hydrophobic cavity on head of GPcl. Upon enzymatic cleavage and NPC1-C binding, conformational change in the GPcl further affects the state of the internal fusion loop, triggering membrane fusion. Our data therefore provide structural insights into filovirus entry in the late endosome and the molecular basis for design of therapeutic inhibitors of viral entry. PMID- 26771494 TI - Extracellular Vesicles from Trypanosoma brucei Mediate Virulence Factor Transfer and Cause Host Anemia. AB - Intercellular communication between parasites and with host cells provides mechanisms for parasite development, immune evasion, and disease pathology. Bloodstream African trypanosomes produce membranous nanotubes that originate from the flagellar membrane and disassociate into free extracellular vesicles (EVs). Trypanosome EVs contain several flagellar proteins that contribute to virulence, and Trypanosoma brucei rhodesiense EVs contain the serum resistance-associated protein (SRA) necessary for human infectivity. T. b. rhodesiense EVs transfer SRA to non-human infectious trypanosomes, allowing evasion of human innate immunity. Trypanosome EVs can also fuse with mammalian erythrocytes, resulting in rapid erythrocyte clearance and anemia. These data indicate that trypanosome EVs are organelles mediating non-hereditary virulence factor transfer and causing host erythrocyte remodeling, inducing anemia. PMID- 26771496 TI - Generation and Application of Mouse-Rat Allodiploid Embryonic Stem Cells. AB - Mammalian interspecific hybrids provide unique advantages for mechanistic studies of speciation, gene expression regulation, and X chromosome inactivation (XCI) but are constrained by their limited natural resources. Previous artificially generated mammalian interspecific hybrid cells are usually tetraploids with unstable genomes and limited developmental abilities. Here, we report the generation of mouse-rat allodiploid embryonic stem cells (AdESCs) by fusing haploid ESCs of the two species. The AdESCs have a stable allodiploid genome and are capable of differentiating into all three germ layers and early-stage germ cells. Both the mouse and rat alleles have comparable contributions to the expression of most genes. We have proven AdESCs as a powerful tool to study the mechanisms regulating X chromosome inactivation and to identify X inactivation escaping genes, as well as to efficiently identify genes regulating phenotypic differences between species. A similar method could be used to create hybrid AdESCs of other distantly related species. PMID- 26771497 TI - Functional Genomic Landscape of Human Breast Cancer Drivers, Vulnerabilities, and Resistance. AB - Large-scale genomic studies have identified multiple somatic aberrations in breast cancer, including copy number alterations and point mutations. Still, identifying causal variants and emergent vulnerabilities that arise as a consequence of genetic alterations remain major challenges. We performed whole genome small hairpin RNA (shRNA) "dropout screens" on 77 breast cancer cell lines. Using a hierarchical linear regression algorithm to score our screen results and integrate them with accompanying detailed genetic and proteomic information, we identify vulnerabilities in breast cancer, including candidate "drivers," and reveal general functional genomic properties of cancer cells. Comparisons of gene essentiality with drug sensitivity data suggest potential resistance mechanisms, effects of existing anti-cancer drugs, and opportunities for combination therapy. Finally, we demonstrate the utility of this large dataset by identifying BRD4 as a potential target in luminal breast cancer and PIK3CA mutations as a resistance determinant for BET-inhibitors. PMID- 26771499 TI - SnapShot: SMC Protein Complexes Part I. AB - This first of two SnapShots on SMC proteins depicts the composition and architecture of SMC protein complexes and their regulators. Their roles at different stages of the cell cycle will appear in Part II. To view this SnapShot, open or download the PDF. PMID- 26771498 TI - A Proteome-wide Fission Yeast Interactome Reveals Network Evolution Principles from Yeasts to Human. AB - Here, we present FissionNet, a proteome-wide binary protein interactome for S. pombe, comprising 2,278 high-quality interactions, of which ~ 50% were previously not reported in any species. FissionNet unravels previously unreported interactions implicated in processes such as gene silencing and pre-mRNA splicing. We developed a rigorous network comparison framework that accounts for assay sensitivity and specificity, revealing extensive species-specific network rewiring between fission yeast, budding yeast, and human. Surprisingly, although genes are better conserved between the yeasts, S. pombe interactions are significantly better conserved in human than in S. cerevisiae. Our framework also reveals that different modes of gene duplication influence the extent to which paralogous proteins are functionally repurposed. Finally, cross-species interactome mapping demonstrates that coevolution of interacting proteins is remarkably prevalent, a result with important implications for studying human disease in model organisms. Overall, FissionNet is a valuable resource for understanding protein functions and their evolution. PMID- 26771500 TI - Diagnostic performance of the "MESACUP anti-Skin profile TEST". AB - BACKGROUND: The "MESACUP anti-Skin profile TEST" is a new, commercially available ELISA kit to detect circulating IgG autoantibodies against desmoglein 1, desmoglein 3, BP180, BP230, and type VII collagen, both simultaneously and more rapidly than previous assays. OBJECTIVES: The aim of this study was to evaluate the diagnostic accuracy of this kit for the diagnosis of pemphigus foliaceus, pemphigus vulgaris, bullous pemphigoid and epidermolysis bullosa acquisita. MATERIALS & METHODS: Dual-centre retrospective study in which 138 patients with autoimmune blistering diseases were compared to 40 controls RESULTS: Using the MESACUP anti-Skin profile TEST, both sensitivities and specificities for desmoglein 1, desmoglein 3, BP180, BP230, and type VII collagen autoantibodies were similar to those obtained using previous, specific ELISA systems and 88% of the results were concordant without any significant difference. CONCLUSION: The MESACUP anti-Skin profile TEST had a similar performance to previously produced ELISA systems. The novel kit can be used for rapid diagnosis of most common autoimmune blistering diseases and is especially suitable for identifying overlapping disorders. PMID- 26771501 TI - Corrigendum. PMID- 26771502 TI - Corrigendum. PMID- 26771503 TI - Corrigendum. PMID- 26771504 TI - Influence of the monomer structure and electrochemical parameters on the formation of nanotubes with parahydrophobic properties (high water adhesion) by a templateless electropolymerization process. AB - Controlling the formation of surface nanostructures and nanotubes in particular is extremely important for various applications in electronic devices for energy systems, biosensing but also for the control of water adhesion. Here, we use a direct (without template) electropolymerization process to produce vertically aligned nanotubes. Different monomers are tested as well as different solvents, electrolytes and electrodeposition methods. We show that naphtho[2,3-b]thieno[3,4 e][1,4]dioxine (NaphDOT) is the best monomer to obtain these nanotubes while dichloromethane has to be used as solvent for their formation. The surfaces with nanotubes display both extremely high apparent contact angles (theta(w)=142.7 degrees ) and high water adhesion even if the nanotubes are made of intrinsically hydrophilic polymers and are not densely packed. PMID- 26771505 TI - Photodegradation of dispersants in colloidal suspensions of pristine graphene. AB - We demonstrate that UV degradation can remove polymeric dispersants from the surface of colloidal pristine graphene. In particular, we investigated the irradiation of polyvinylpyrrolidone (PVP)-dispersed graphene in water; this polymer has been established as a versatile nanosheet dispersant for a range of solvents, and it undergoes photo-oxidative degradation when exposed to UV light. We find that the molecular weight of PVP decreases with irradiation time and subsequently desorbs from the graphene surface. This causes gradual destabilization of graphene and agglomeration in water. The amount of adsorbed PVP decreases by approximately 45% after 4 h of irradiation in comparison with the non-irradiated dispersion. At this point, the majority of the stable graphene nanosheets flocculate, likely because of insufficient surface coverage as indicated by thermogravimetric analysis. Graphene aggregates were characterized as a function of irradiation time by optical microscopy, UV-vis spectroscopy, Raman spectroscopy, and conductivity measurements; the data suggest that the agglomerates maintain a graphene-like (rather than graphite-like) structure. The effect is also observed for another graphene dispersant (sapogenin), which suggests that our findings can be generalized to the broader class of photodegradable dispersants. PMID- 26771506 TI - Layer-by-layer modification of high surface curvature nanoparticles with weak polyelectrolytes using a multiphase solvent precipitation process. AB - The layer-by-layer modification of ~5 nm mercaptocarboxylic acid stabilized gold nanoparticles was studied in an effort to illustrate effective means to overcome practical issues in handling and performing surface modification of such extremely small materials. To accomplish this, each layer deposition cycle was separated into a multi-step process wherein solution pH was controlled in two distinct phases of polyelectrolyte adsorption and centrifugation. Additionally, a solvent precipitation step was introduced to make processing more amenable by concentrating the sample and exchanging solution pH before ultracentrifugation. The pH-dependent assembly on gold nanoparticles was assessed after each layer deposition cycle by monitoring the plasmon peak absorbance location, surface charge, and the percentage of nanoparticles recovered. The selection of solution pH during the adsorption phase was found to be a critical parameter to enhance particle recovery and maximize surface charge when coating with weak polyelectrolytes. One bilayer was deposited with a high yield and the modified particles exhibited enhanced colloidal stability across a broad pH range and increased ionic strength. These findings support the adoption of this multi-step processing approach as an effective and generalizable approach to improve stability of high surface curvature particles. PMID- 26771507 TI - Polyaniline nanofibers as highly effective re-usable adsorbent for removal of reactive black 5 from aqueous solutions. AB - Polyaniline nanofibers (PANI NFs) with 50-80 nm in diameter were successfully prepared at room temperature (22 degrees C) using ferric chloride (FeCl3) as an oxidant via a simple rapid mixing polymerization method. The prepared PANI NFs were characterized by FE-SEM, HR-TEM, BET, ATR-FTIR and by Zeta potential measurement method. The adsorption of azo dye Reactive Black 5 (RB5) onto PANI NFs from aqueous solutions was investigated. Adsorption studies were carried out at different initial dye concentrations, initial solution pH and adsorbent doses. The kinetic data fitted well with the pseudo-second-order model while the equilibrium data were satisfactorily described by the Langmuir isotherm model. The Langmuir maximum adsorption capacity of RB5 at pH 6.0 was found to be 312.5, 389.1 and 434.7 mg/g at 25 degrees C, 35 degrees C and 45 degrees C, respectively. Thermodynamic parameters including the Gibbs free energy (DeltaG degrees ), enthalpy (DeltaH degrees ), and entropy (DeltaS degrees ) changes indicated that the adsorption of RB5 onto PANI NFs was feasible, spontaneous, and endothermic. Moreover, desorption experiments revealed that the PANI NFs can be reused effectively for five consecutive adsorption-desorption cycles without any loss of its original capacity. PMID- 26771508 TI - HER2 Targeted Breast Cancer Therapy with Switchable "Off/On" Multifunctional "Smart" Magnetic Polymer Core-Shell Nanocomposites. AB - Multifunctional magnetic polymer nanocombinations are gaining importance in cancer nanotheranostics due to their safety and their potential in delivering targeted functions. Herein, we report a novel multifunctional core-shell magnetic polymer therapeutic nanocomposites (NCs) exhibiting pH dependent "Off-On" release of drug against breast cancer cells. The NCs are intact in blood circulation ("Off" state), i.e., at physiological pH, whereas activated ("On" state) at intracellular acidic pH environment of the targeted breast cancer cells. The NCs are prepared by coating the cannonball (iron nanocore) with hydrophobic nanopockets of pH-responsive poly(d,l-lactic-co-glycolic acid) (PLGA) polymer nanoshell that allows efficient loading of therapeutics. Further, the nanocore polymer shell is stabilized by poly(vinylpyrrolidone) (PVP) and functionalized with a targeting HER2 ligand. The prepared Her-Fe3O4@PLGA-PVP nanocomposites facilitate packing of anticancer drug (Tamoxifen) without premature release in the bloodstream, recognizing the target cells through binding of Herceptin antibody to HER2, a cell surface receptor expressed by breast cancer cells to promote HER2 receptor mediated endocytosis and finally releasing the drug at the intracellular site of tumor cells ("On" state) to induce apoptosis. The therapeutic efficiency of hemo/cytocompatible NCs drug delivery system (DDS) in terms of targeted delivery and sustained release of therapeutic agent against breast cancer cells was substantiated by in vitro and in vivo studies. The multifunctional properties of Her-Tam-Fe3O4@PLGA-PVP NCs may open up new avenues in cancer therapy through overcoming the limitations of conventional cancer therapy. PMID- 26771509 TI - Suitability of Taxodium distichum for Afforesting the Littoral Zone of the Three Gorges Reservoir. AB - The littoral zone ecosystem of the Three Gorges Reservoir (TGR) has become significantly degraded by annual cycles of prolonged winter flooding and summer drought. For purposes of flood control and sediment management, the water level in the reservoir is lowered by 30 m during the summer monsoon season and raised again to 175 m above sea level each year at the end of the monsoon period. To explore an effective way to promote biodiversity and associated ecosystem services, we examined Taxodium distichum as a species for afforesting the littoral zone. Sapling growth variations were measured after two rounds of winter flooding. Dominant influence factors were determined by redundancy analysis. Herb community similarities between the experimental afforested areas and nearby control areas were assessed to detect the ecosystem influence of the experimental afforestation. 94.5% of saplings planted at elevations above 168 m survived. All measured growth indices (tree height, diameter at breast height, crown width and foliage density) decreased as the flood depth increased. Completely submerged saplings had a mean dieback height of -0.65 m. Greater initial foliage density led to increased tree height and stem diameter. Shannon-Wiener indices were not significantly different between plots in experimental and control areas, but the low similarity of herb communities between experimental and control areas (0.242 on average) suggested that afforestation would enrich plant community structure and improve littoral zone ecosystem stability. Because littoral zone afforestation provides several ecosystem services (habitat, carbon sink, water purification and landscaping), it is a promising revegetation model for the TGR. PMID- 26771510 TI - Role of robotic surgery in the management of deep infiltrating endometriosis. AB - Standard laparoscopy (SL) is the gold standard for endometriosis surgery including deep infiltrating endometriosis (DIE). DIE laparoscopic surgery can require complex surgical procedures performed by multidisciplinary surgical team. Robotic assisted laparoscopy (RAL) could offer technical advantages such as 3D vision, tremor filtration and better surgical ergonomy. RAL would be able to improve surgical performances compared to SL, decrease perioperative morbidity and decrease the risk of laparo-conversion. For these reasons, DIE could be one of the best indications for RAL in gynecologic surgery. Demonstrating the feasibility of RAL for DIE surgery, few series of cases have been already published. None of them have demonstrated differences in surgical outcomes. One randomized control trial comparing SL to RAL would be mandatory in order to define potential benefits of RAL for DIE surgery. PMID- 26771511 TI - Burkholderia pseudomallei: Its Detection in Soil and Seroprevalence in Bangladesh. AB - BACKGROUND: Melioidosis, caused by Burkholderia pseudomallei, is an endemic disease in Bangladesh. No systematic study has yet been done to detect the environmental source of the organism and its true extent in Bangladesh. The present study attempted to isolate B. pseudomallei in soil samples and to determine its seroprevalence in several districts in Bangladesh. METHODOLOGY AND RESULTS: Soil samples were collected from rural areas of four districts of Bangladesh from where culture confirmed melioidosis cases were detected earlier. Multiple soil samples, collected from 5-7 sampling points of 3-5 sites of each district, were cultured in Ashdown selective media. Suspected colonies of B. pseudomallei were identified by biochemical and serological test, and by polymerase chain reaction (PCR) using 16s rRNA specific primers. Blood samples were collected from 940 healthy individuals of four districts to determine anti- B. pseudomallei IgG antibody levels by indirect enzyme linked immunosorbent assay (ELISA) using sonicated crude antigen. Out of 179 soil samples, B. pseudomallei was isolated from two samples of Gazipur district which is located 58 km north of capital Dhaka city. Both the isolates were phenotypically identical, arabinose negative and showed specific 550bp band in PCR. Out of 940 blood samples, anti- B. pseudomallei IgG antibody, higher than the cut-off value (>0.8), was detected in 21.5% individuals. Seropositivity rate was 22.6%-30.8% in three districts from where melioidosis cases were detected earlier, compared to 9.8% in a district where no melioidosis case was either detected or reported (p<0.01). Seropositivity increased with the advancement of age from 5.3% to 30.4% among individuals aged 1-10 years and > 50 years respectively. The seropositivity rates were 26.0% and 20.6% in male and female respectively, while it was 20-27% among different occupational groups. No significant association was observed with gender (chi2 = 3.441, p = 0.064) or any occupational group (chi2 = 3.835, p = 0.280). CONCLUSION: This is the first study demonstrating the presence of B. pseudomallei in the environmental (soil) samples of Bangladesh. It also suggested that a large proportion of people, residing in these districts, were exposed to the organism. PMID- 26771512 TI - The Computerized Table Setting Test for Detecting Unilateral Neglect. AB - BACKGROUND: Patients with unilateral neglect fail to respond normally to stimuli on the left side. To facilitate the evaluation of unilateral spatial neglect, we developed a new application that runs on a tablet device and investigated its feasibility in stroke patients. METHODS: We made the computerized table setting test (CTST) to run on the tablet computer. Forty acute ischemic stroke patients (20 patients with right hemispheric infarction with neglect, 10 patients with right hemispheric infarction without neglect, and 10 patients with left hemispheric infarction) and 10 healthy controls were prospectively enrolled to validate the CTST. The test requires subjects to set a table by dragging 12 dishes located below the table on the tablet screen. The horizontal deviation of the 12 dishes from the midline of the table, the selection tendency measured by the sequence of the dish selection, and the elapsed time for table setting were calculated automatically. RESULTS: Parameters measured by the CTST were correlated with the results of conventional neglect tests. The horizontal deviation was significantly higher in patients with right hemispheric infarction with neglect compared with the other groups. The selection tendency and elapsed time also were significantly different in patients with right hemispheric infarction with neglect compared with the left hemispheric infarction and control groups, but were similar to those with right hemispheric infarction without neglect. CONCLUSIONS: The CTST is feasible to administer and comparable with conventional neglect tests. This new application may be useful for the initial diagnosis and follow-up of neglect patients. PMID- 26771513 TI - Spatiotemporal Evolution of Ebola Virus Disease at Sub-National Level during the 2014 West Africa Epidemic: Model Scrutiny and Data Meagreness. AB - BACKGROUND: The Ebola outbreak in West Africa has infected at least 27,443 individuals and killed 11,207, based on data until 24 June, 2015, released by the World Health Organization (WHO). This outbreak has been characterised by extensive geographic spread across the affected countries Guinea, Liberia and Sierra Leone, and by localized hotspots within these countries. The rapid recognition and quantitative assessment of localised areas of higher transmission can inform the optimal deployment of public health resources. METHODS: A variety of mathematical models have been used to estimate the evolution of this epidemic, and some have pointed out the importance of the spatial heterogeneity apparent from incidence maps. However, little is known about the district-level transmission. Given that many response decisions are taken at sub-national level, the current study aimed to investigate the spatial heterogeneity by using a different modelling framework, built on publicly available data at district level. Furthermore, we assessed whether this model could quantify the effect of intervention measures and provide predictions at a local level to guide public health action. We used a two-stage modelling approach: a) a flexible spatiotemporal growth model across all affected districts and b) a deterministic SEIR compartmental model per district whenever deemed appropriate. FINDINGS: Our estimates show substantial differences in the evolution of the outbreak in the various regions of Guinea, Liberia and Sierra Leone, illustrating the importance of monitoring the outbreak at district level. We also provide an estimate of the time-dependent district-specific effective reproduction number, as a quantitative measure to compare transmission between different districts and give input for informed decisions on control measures and resource allocation. Prediction and assessing the impact of control measures proved to be difficult without more accurate data. In conclusion, this study provides us a useful tool at district level for public health, and illustrates the importance of collecting and sharing data. PMID- 26771514 TI - Correction: Depletion of the Chromatin Looping Proteins CTCF and Cohesin Causes Chromatin Compaction: Insight into Chromatin Folding by Polymer Modelling. AB - [This corrects the article DOI: 10.1371/journal.pcbi.1003877.]. PMID- 26771516 TI - MiR-1303 Regulates Mycobacteria Induced Autophagy by Targeting Atg2B. AB - MicroRNAs are emerging post-transcriptional regulators of gene expressions in both innate immunity and adaptive immunity. In mycobacteria infection, autophagy plays an important role in innate defense mechanism and is tightly regulated by the autophagy-related proteins. Here, we show that Atg2B is involved in the regulation of mycobacteria-induced autophagy. MiR-1303, which function is not defined yet, is found to negatively regulate mycobacteria-induced Atg2B protein production, ultimately down-regulate mycobacteria-induced autophagy. MiR-1303 production is shown to be upregulated during BCG infection and its production is regulated by PI3K and NFkappaB. It is also demonstrated that miR-1303 targets putative target sites on Atg2B and possibly represses its translation. PMID- 26771517 TI - Responses of Wheat Yield, Macro- and Micro-Nutrients, and Heavy Metals in Soil and Wheat following the Application of Manure Compost on the North China Plain. AB - The recycling of livestock manure in cropping systems is considered to enhance soil fertility and crop productivity. However, there have been no systematic long term studies of the effects of manure application on soil and crop macro- and micro-nutrients, heavy metals, and crop yields in China, despite their great importance for sustainable crop production and food safety. Thus, we conducted field experiments in a typical cereal crop production area of the North China Plain to investigate the effects of compost manure application rates on wheat yield, as well as on the macro-/micro-nutrients and heavy metals contents of soil and wheat. We found that compost application increased the soil total N and the available K, Fe, Zn, and Mn concentrations, whereas the available P in soil was not affected, and the available Cu decreased. In general, compost application had no significant effects on the grain yield, biomass, and harvest index of winter wheat. However, during 2012 and 2013, the N concentration decreased by 9% and 18% in straw, and by 16% and 12% in grain, respectively. With compost application, the straw P concentration only increased in 2012 but the grain P generally increased, while the straw K concentration tended to decrease and the grain K concentration increased in 2013. Compost application generally increased the Fe and Zn concentrations in straw and grain, whereas the Cu and Mn concentrations decreased significantly compared with the control. The heavy metal concentrations increased at some compost application rates, but they were still within the safe range. The balances of the macro-and micro-nutrients indicated that the removal of nutrients by wheat was compensated for by the addition of compost, whereas the level of N decreased without the application of compost. The daily intake levels of micronutrients via the consumption of wheat grain were still lower than the recommended levels when sheep manure compost was applied, except for that of Mn. PMID- 26771515 TI - Direct Effect of Remifentanil and Glycine Contained in Ultiva(r) on Nociceptive Transmission in the Spinal Cord: In Vivo and Slice Patch Clamp Analyses. AB - BACKGROUND: Ultiva(r) is commonly administered intravenously for analgesia during general anaesthesia and its main constituent remifentanil is an ultra-short acting MU-opioid receptor agonist. Ultiva(r) is not approved for epidural or intrathecal use in clinical practice. Previous studies have reported that Ultiva(r) provokes opioid-induced hyperalgesia by interacting with spinal dorsal horn neurons. Ultiva(r) contains glycine, an inhibitory neurotransmitter but also an N-methyl-D-aspartate receptor co-activator. The presence of glycine in the formulation of Ultiva(r) potentially complicates its effects. We examined how Ultiva(r) directly affects nociceptive transmission in the spinal cord. METHODS: We made patch-clamp recordings from substantia gelatinosa (SG) neurons in the adult rat spinal dorsal horn in vivo and in spinal cord slices. We perfused Ultiva(r) onto the SG neurons and analysed its effects on the membrane potentials and synaptic responses activated by noxious mechanical stimuli. RESULTS: Bath application of Ultiva(r) hyperpolarized membrane potentials under current-clamp conditions and produced an outward current under voltage-clamp conditions. A barrage of excitatory postsynaptic currents (EPSCs) evoked by the stimuli was suppressed by Ultiva(r). Miniature EPSCs (mEPSCs) were depressed in frequency but not amplitude. Ultiva(r)-induced outward currents and suppression of mEPSCs were not inhibited by the MU-opioid receptor antagonist naloxone, but were inhibited by the glycine receptor antagonist strychnine. The Ultiva(r)-induced currents demonstrated a specific equilibrium potential similar to glycine. CONCLUSIONS: We found that intrathecal administration of Ultiva(r) to SG neurons hyperpolarized membrane potentials and depressed presynaptic glutamate release predominantly through the activation of glycine receptors. No Ultiva(r)-induced excitatory effects were observed in SG neurons. Our results suggest different analgesic mechanisms of Ultiva(r) between intrathecal and intravenous administrations. PMID- 26771518 TI - Antigen-Specific Binding of Multivalent Soluble Antigen Arrays Induces Receptor Clustering and Impedes B Cell Receptor Mediated Signaling. AB - A pressing need exists for autoimmune disease therapies that act in an antigen specific manner while avoiding global immunosuppression. Multivalent soluble antigen arrays (SAgAPLP:LABL), designed to induce tolerance to a specific multiple sclerosis autoantigen, consist of a flexible hyaluronic acid (HA) polymer backbone cografted with multiple copies of autoantigen peptide (PLP) and cell adhesion inhibitor peptide (LABL). Previous in vivo studies revealed copresentation of both signals on HA was necessary for therapeutic efficacy. To elucidate therapeutic cellular mechanisms, in vitro studies were performed in a model B cell system to evaluate binding and specificity. Compared to HA and HA arrays containing only grafted PLP or LABL, SAgAPLP:LABL displaying both PLP and LABL exhibited greatly enhanced B cell binding. Furthermore, the binding avidity of SAgAPLP:LABL was primarily driven by the PLP antigen, determined via flow cytometry competitive dissociation studies. Fluorescence microscopy showed SAgAPLP:LABL induced mature receptor clustering that was faster than other HA arrays with only one type of grafted peptide. SAgAPLP:LABL molecules also reduced and inhibited IgM-stimulated signaling as discerned by a calcium flux assay. The molecular mechanisms of enhanced antigen-specific binding, mature receptor clustering, and dampened signaling observed in B cells may contribute to SAgAPLP:LABL therapeutic efficacy. PMID- 26771519 TI - Passivation of PbS Quantum Dot Surface with l-Glutathione in Solid-State Quantum Dot-Sensitized Solar Cells. AB - Surface oxidation of quantum dots (QDs) is one of the biggest challenges in quantum dot-sensitized solar cells (QDSCs), because it introduces surface states that enhance electron-hole recombination and degrade device performance. Protection of QDs from surface oxidation by passivating the surface with organic or inorganic layers can be one way to overcome this issue. In this study, solid state QDSCs with a PbS QD absorber layer were prepared from thin mesoporous TiO2 layers by the successive ionic layer adsorption/reaction (SILAR) method. Spiro OMeTAD was used as the organic p-type hole transporting material (HTM). The effects on the solar cell performance of passivating the surface of the PbS QDs with the tripeptide l-glutathione (GSH) were investigated. Current-voltage characteristics and external quantum efficiency measurements of the solar cell devices showed that GSH-treatment of the QD-sensitized TiO2 electrodes more than doubled the short circuit current and conversion efficiency. Impedance spectroscopy, intensity-modulated photovoltage and photocurrent spectroscopy analysis of the devices revealed that the enhancement in solar cell performance of the GSH-treated cells originates from improved charge injection from PbS QDs into the conduction band of TiO2. Time-resolved photoluminescence decay measurements show that passivation of the surface of QDs with GSH ligands increases the exciton lifetime in the QDs. PMID- 26771521 TI - Protocol for the Evaluation of Speech Intelligibility in Dysarthrias: Evidence of Reliability and Validity. AB - BACKGROUND/AIMS: Studies about the reliability and validity of intelligibility measures are fundamental to direct their use and interpretation in both clinical and research settings. The present study assessed inter-rater reliability, internal consistency and criterion validity of scores for the sentence and word subtests of the Protocol for the Evaluation of Speech Intelligibility (PESI). METHODS: This study included 180 adult volunteers who were divided into three groups: 30 speakers with dysarthria, 30 control speakers and 120 listeners. Intelligibility scores were calculated according to the percentage of words correctly transcribed in each subtest: words in sentences and single words. RESULTS: The intelligibility measurements exhibited a high level of inter-rater reliability for sentences [intraclass correlation coefficient (ICC) = 0.94] and for single words (ICC = 0.96). The items from the single words subtest of the PESI revealed high internal consistency (Cronbach's alpha = 0.93). The measurement of intelligibility of sentences and single words had a high discriminatory power (0.82 and 0.95, respectively), with high sensitivity and specificity, particularly for scores in the single words subtest. CONCLUSION: This study provides preliminary evidence of the reliability and validity of the PESI. PMID- 26771522 TI - Efficacy and Safety of Fixed-Dose Perindopril Arginine/Amlodipine in Hypertensive Patients Not Adequately Controlled with Amlodipine 5 mg or Perindopril tert Butylamine 4 mg Monotherapy. AB - OBJECTIVES: To assess the blood pressure-lowering efficacy and tolerability of perindopril/amlodipine fixed-dose combinations in Chinese patients with mild-to moderate essential hypertension not adequately controlled with monotherapy alone. METHODS: In 2 separate double-blind studies, patients received a 4-week run-in monotherapy of amlodipine 5 mg or perindopril 4 mg, respectively. Those whose blood pressure was uncontrolled were then randomized to receive the fixed-dose combination of perindopril 5 mg/amlodipine 5 mg (Per/Amlo group) or remain on the monotherapy for 8 weeks. Patients who were uncontrolled at the week 8 (W8) visit were up-titrated for the Per/Amlo combination, or received additional treatment if on monotherapy, for a further 4 weeks. The main efficacy assessment was at 8 weeks. RESULTS: After 8 weeks, systolic blood pressure (SBP; primary criterion) was statistically significantly lower in the Per/Amlo group (vs. Amlo 5 mg, p = 0.0095; vs. Per 4 mg, p < 0.0001). Uncontrolled patients at W8 who received an up titration of the Per/Amlo combination showed a further SBP reduction. These changes were mirrored by reassuring reductions in diastolic blood pressure. The fixed-dose combinations were well tolerated. CONCLUSIONS: Single-pill combinations of perindopril and amlodipine provide hypertensive patients with a convenient and effective method of reducing blood pressure. PMID- 26771523 TI - From Crime to Disease: Laws on Infanticide in the Modern Era. AB - This is the third of three papers investigating the legislative history concerning infanticide. After Antiquity and the Middle Ages, this paper focuses on legislative reforms during the last 400 years. Despite dreadful punishment, the practice remained frequent until safe abortion became available. In the 17th century, the rate of executions of women for this crime was 1 per 100,000 inhabitants. The actual incidence greatly exceeded this figure. The death penalty failed to deter, and punishing fornication promoted rather than prevented infanticide. Well into the 18th century, severely malformed infants were killed. The lung flotation test, albeit unreliable, was used to save the mother from the death penalty. When the motives for infanticide - poverty, shame, despair, and preserving honour - became understood in the late 18th century, the image of the 'child murderess' changed, and infanticide shifted from constituting a capital crime to a privileged delict. Illegitimate pregnancy was no longer punished, and lying-in hospitals for pregnant unmarried women and foundling hospitals for their children were established. Specific infanticide laws were issued in Prussia in 1756, Britain in 1803, and France in 1811. Once psychosis and denial of pregnancy became understood, severe penalties were no longer issued. The justifications for lenient legislation included social circumstances, difficult proof, and curtailed protection of the newborn due to its illegitimacy, helplessness, and diminished awareness. Thoughts on the limited right to live of newborn infants are still hampering ethical decisions when the beginning and end of life are near each other. PMID- 26771520 TI - The plasma membrane as a capacitor for energy and metabolism. AB - When considering which components of the cell are the most critical to function and physiology, we naturally focus on the nucleus, the mitochondria that regulate energy and apoptotic signaling, or other organelles such as the endoplasmic reticulum, Golgi, ribosomes, etc. Few people will suggest that the membrane is the most critical element of a cell in terms of function and physiology. Those that consider the membrane critical will point to its obvious barrier function regulated by the lipid bilayer and numerous ion channels that regulate homeostatic gradients. What becomes evident upon closer inspection is that not all membranes are created equal and that there are lipid-rich microdomains that serve as platforms of signaling and a means of communication with the intracellular environment. In this review, we explore the evolution of membranes, focus on lipid-rich microdomains, and advance the novel concept that membranes serve as "capacitors for energy and metabolism." Within this framework, the membrane then is the primary and critical regulator of stress and disease adaptation of the cell. PMID- 26771524 TI - Expression and Polymorphism of Toll-Like Receptor 4 and Effect on NF-kappaB Mediated Inflammation in Colon Cancer Patients. AB - Our aim was to evaluate the association between the expression and the polymorphism of TLR4/NF-kappaB pathways and colon cancer. TLR4 (rs4986790, rs10759932, rs10759931 and rs2770150) were genotyped in blood samples from Colorectal patients and healthy controls. TLR4 and cytokines inflammatory expression were evaluated by real time PCR on 40 matching normal and colon tissues and the protein level by Immunohistochemistry. The high level of TLR4 expression in colon cancer tissues is mainly due to infections by bacteria in the human colon and leads to induction of an acute secretion of inflammatory cytokines mediated by NF-kappaB. Also, we report here a clear evidence for an association between TLR4 rs10759931 polymorphism (OR = 0.086, CI: 0.04-0.18, P = <0.00001). This polymorphism affects the entire population without being specific to either gender or to any age group. In contrast, the rs2770150 is associated with colon cancer in women aged over 50 years and is closely linked with the decreased levels of female sex hormones during the post-menopausal period (OR = 0.188, CI: 0.074-0.48, P = <0.00084). rs10759932 and rs4986790 appear to have any association with colon cancer. Our data suggest that TLR4 SNPs could possibly serve as biomarkers for decision making in colon cancer treatment. PMID- 26771526 TI - Effects of a powered air-purifying respirator intervention on indium exposure reduction and indium related biomarkers among ITO sputter target manufacturing workers. AB - This study aimed to evaluate the efficacy of powered air-purifying respirators (PAPRs) worn by the workers, and to investigate the effect of this application on exposure and preclinical effects in terms of workplace measuring and biomarker monitoring in ITO sputter target manufacturing plants and workers, respectively. Fifty-four workers were recruited and investigated from 2010-2012, during which PAPRs were provided to on-site workers in September 2011. Each worker completed questionnaires and provided blood and urine samples for analysis of biomarkers of indium exposure and preclinical effects. Area and personal indium air samples were randomly collected from selected worksites and from participants. The penetration percentage of the respirator (concentration inside respirator divided by concentration outside respirator) was 6.6%. Some biomarkers, such as S-In, SOD, GPx, GST, MDA, and TMOM, reflected the decrease in exposure and showed lower levels, after implementation of PAPRs. This study is the first to investigate the efficacy of PAPRs for reducing indium exposure. The measurement results clearly showed that the implementation of PAPRs reduces levels of indium-related biomarkers. These findings have practical applications for minimizing occupational exposure to indium and for managing the health of workers exposed to indium. PMID- 26771525 TI - The Influence of Efflux Pump Inhibitors on the Activity of Non-Antibiotic NSAIDS against Gram-Negative Rods. AB - BACKGROUND: Most patients with bacterial infections suffer from fever and various pains that require complex treatments with antibiotics, antipyretics, and analgaesics. The most common drugs used to relieve these symptoms are non steroidal anti-inflammatory drugs (NSAIDs), which are not typically considered antibiotics. Here, we investigate the effects of NSAIDs on bacterial susceptibility to antibiotics and the modulation of bacterial efflux pumps. METHODOLOGY: The activity of 12 NSAID active substances, paracetamol (acetaminophen), and eight relevant medicinal products was analyzed with or without pump inhibitors against 89 strains of Gram-negative rods by determining the MICs. Furthermore, the effects of NSAIDs on the susceptibility of clinical strains to antimicrobial agents with or without PAbetaN (Phe-Arg-beta naphtylamide) were measured. RESULTS: The MICs of diclofenac, mefenamic acid, ibuprofen, and naproxen, in the presence of PAbetaN, were significantly (>=4 fold) reduced, decreasing to 25-1600 mg/L, against the majority of the studied strains. In the case of acetylsalicylic acid only for 5 and 7 out of 12 strains of P. mirabilis and E. coli, respectively, a 4-fold increase in susceptibility in the presence of PAbetaN was observed. The presence of Aspirin resulted in a 4 fold increase in the MIC of ofloxacin against only two strains of E. coli among 48 tested clinical strains, which included species such as E. coli, K. pneumoniae, P. aeruginosa, and S. maltophilia. Besides, the medicinal products containing the following NSAIDs, diclofenac, mefenamic acid, ibuprofen, and naproxen, did not cause the decrease of clinical strains' susceptibility to antibiotics. CONCLUSIONS: The effects of PAbetaN on the susceptibility of bacteria to NSAIDs indicate that some NSAIDs are substrates for efflux pumps in Gram-negative rods. Morever, Aspirin probably induced efflux-mediated resistance to fluoroquinolones in a few E. coli strains. PMID- 26771528 TI - Correction: Epidemiological Changes in Leishmaniasis in Spain According to Hospitalization-Based Records, 1997-2011: Raising Awareness towards Leishmaniasis in Non-HIV Patients. PMID- 26771527 TI - Gigantism and Its Implications for the History of Life. AB - Gigantism-very large body size-is an ecologically important trait associated with competitive superiority. Although it has been studied in particular cases, the general conditions for the evolution and maintenance of gigantism remain obscure. I compiled sizes and dates for the largest species in 3 terrestrial and 7 marine trophic and habitat categories of animals from throughout the Phanerozoic. The largest species (global giants) in all categories are of post-Paleozoic age. Gigantism at this level appeared tens to hundreds of millions of years after mass extinctions and long after the origins of clades in which it evolved. Marine gigantism correlates with high planktic or seafloor productivity, but on land the correspondence between productivity and gigantism is weak at best. All global giants are aerobically active animals, not gentle giants with low metabolic demands. Oxygen concentration in the atmosphere correlates with gigantism in the Paleozoic but not thereafter, likely because of the elaboration of efficient gas exchange systems in clades containing giants. Although temperature and habitat size are important in the evolution of very large size in some cases, the most important (and rare) enabling circumstance is a highly developed ecological infrastructure in which essential resources are abundant and effectively recycled and reused, permitting activity levels to increase and setting the stage for gigantic animals to evolve. Gigantism as a hallmark of competitive superiority appears to have lost its luster on land after the Mesozoic in favor of alternative means of achieving dominance, especially including social organization and coordinated food-gathering. PMID- 26771529 TI - Surveillance of Rift Valley Fever Virus in Mosquito Vectors of the Republic of Korea. AB - Rift Valley fever (RVF) is an acute mosquito-borne viral zoonotic disease that affects mainly domestic ruminants and humans. RVF virus (RVFV) was first identified in Kenya in 1931 and was reported to be endemic in Africa but has recently spread to the Arabian Peninsula. With increasing climate change and globalization of trade in animals and animal products, there is great concern that the disease will spread worldwide to regions such as Europe, Asia, and the Americas. Although RVFV has not been reported in the Republic of Korea (ROK), the possibility of RVFV introduction is increasing because transmissible mosquito vectors are present and direct flights to Africa were added in 2012. For these reasons, we conducted a surveillance study to detect RVFV in mosquito vectors collected around the airport and harbor from 2012 to 2013. A total of 36,734 mosquitoes were collected and tested by real-time RT-PCR. A total of 1837 mosquito pools were used, and all were confirmed to be negative. This is the first report in the ROK concerning RVFV surveillance in mosquito vectors, and continuous surveillance will be conducted for the early warning of RVFV introduction. PMID- 26771530 TI - Effect of Graph Scale on Risky Choice: Evidence from Preference and Process in Decision-Making. AB - We investigate the effect of graph scale on risky choices. By (de)compressing the scale, we manipulate the relative physical distance between options on a given attribute in a coordinate graphical context. In Experiment 1, the risky choice changes as a function of the scale in the graph. In Experiment 2, we show that the type of graph scale also affects decision times. In Experiment 3, we examine the graph scale effect by using real money among students who have taken statistics courses. Consequently, the scale effects still appear even when we control the variations in calculation ability and increase the gravity with which participants view the consequence of their decisions. This finding is inconsistent with descriptive invariance of preference. The theoretical implications and practical applications of the findings are discussed. PMID- 26771531 TI - Characteristics of heavy metal transfer and their influencing factors in different soil-crop systems of the industrialization region, China. AB - Soil heavy metals and their bioaccumulation in agricultural products have attracted widespread concerns, yet the transfer and accumulation characteristics of heavy metals in different soil-crop systems was rarely investigated. Soil and crop samples were collected from the typical agricultural areas in the Yangtze River Delta region, China. The concentrations of Cu, Pb, Zn, Cd and Hg in the soils, roots and grains of rice (Oryza Sativa L.), wheat (Triticum L.) and canola (Brassica napus L.) were determined in this study. Transfer ability of heavy metals in soil-rice system was stronger than those in soil-wheat and soil-canola systems. The wheat showed a strong capacity to transfer Zn, Cu and Cd from root to the grain while canola presented a restricting effect to the intake of Cu and Cd. Soil pH and total organic matter were major factors influencing metal transfer from soil to rice, whereas soil Al2O3 contents presented a negative effect on heavy metal mobility in wheat and canola cultivation systems. The concentration of Zn and Cd in crop grains could well predicted according to the stepwise multiple linear regression models, which could help to quantitatively evaluate the ecologic risk of heavy metal accumulation in crops in the study area. PMID- 26771532 TI - In vitro dioxin-like potencies of HO- and MeO-PBDEs and inter-species sensitivity variation in birds. AB - Due to their bioaccumulative properties, hydroxylated and methoxylated polybrominated diphenyl ethers (HO-/MeO-PBDEs) may pose ecological risks to wild life, including birds. However, their toxicity potencies in avian species are largely unknown. In the present study, an avian AHR1 luciferase reporter gene (LRG) assay with luciferase probes from chicken, pheasant and quail was used to test activations of avian aryl hydrocarbon receptor (AHR)-mediated pathways by 19 HO- or MeO-PBDEs in different avian species. Species-specific relative potencies (RePs) of HO-/MeO-PBDEs to tetrachlorodibenzo-p-dioxin (TCDD) and relative sensitivities of various species to each chemical were estimated. The results indicated that the ReP of the most potent HO-/MeO-PBDEs, 5-Cl-6-HO-BDE-47, was 7.8*10(-4) for chicken, 1.1*10(-2) for pheasant, and 1.7*10(-1) for quail comparing to TCDD. In addition, it was found that avian species with the greatest sensitivity to TCDD did not always have the greatest sensitivity to HO-/MeO-PBDEs and vice versa. This study contributed to filling in the knowledge gap regarding the dioxin-like activity of HO-/MeO-PBDEs in birds, and provided beneficial information for the prioritization of HO-/MeO-PBDEs for further research. CAPSULE ABSTRACT: HO-/MeO-PBDEs activate avian AHR-mediated pathways in a congener- and species- specific manner. 5-Cl-6-HO-BDE-47 was the most potent among the nineteen HO-/MeO-PBDEs tested. PMID- 26771534 TI - Elastic Barrier Dynamical Freezing in Free Energy Calculations: A Way To Speed Up Nonequilibrium Molecular Dynamics Simulations by Orders of Magnitude. AB - An important issue concerning computer simulations addressed to free energy estimates via nonequilibrium work theorems, such as the Jarzynski equality [Phys. Rev. Lett. 1997, 78, 2690], is the computational effort required to achieve results with acceptable accuracy. In this respect, the dynamical freezing approach [Phys. Rev. E 2009, 80, 041124] has been shown to improve the efficiency of this kind of simulations, by blocking the dynamics of particles located outside an established mobility region. In this report, we show that dynamical freezing produces a systematic spurious decrease of the particle density inside the mobility region. As a consequence, the requirements to apply nonequilibrium work theorems are only approximately met. Starting from these considerations, we have developed a simulation scheme, called "elastic barrier dynamical freezing", according to which a stiff potential-energy barrier is enforced at the boundaries of the mobility region, preventing the particles from leaving this region of space during the nonequilibrium trajectories. The method, tested on the calculation of the distance-dependent free energy of a dimer immersed into a Lennard-Jones fluid, provides an accuracy comparable to the conventional steered molecular dynamics, with a computational speedup exceeding a few orders of magnitude. PMID- 26771533 TI - Characterization of a Gene Coding for the Complement System Component FB from Loxosceles laeta Spider Venom Glands. AB - The human complement system is composed of more than 30 proteins and many of these have conserved domains that allow tracing the phylogenetic evolution. The complement system seems to be initiated with the appearance of C3 and factor B (FB), the only components found in some protostomes and cnidarians, suggesting that the alternative pathway is the most ancient. Here, we present the characterization of an arachnid homologue of the human complement component FB from the spider Loxosceles laeta. This homologue, named Lox-FB, was identified from a total RNA L. laeta spider venom gland library and was amplified using RACE PCR techniques and specific primers. Analysis of the deduced amino acid sequence and the domain structure showed significant similarity to the vertebrate and invertebrate FB/C2 family proteins. Lox-FB has a classical domain organization composed of a control complement protein domain (CCP), a von Willebrand Factor domain (vWFA), and a serine protease domain (SP). The amino acids involved in Mg2+ metal ion dependent adhesion site (MIDAS) found in the vWFA domain in the vertebrate C2/FB proteins are well conserved; however, the classic catalytic triad present in the serine protease domain is not conserved in Lox-FB. Similarity and phylogenetic analyses indicated that Lox-FB shares a major identity (43%) and has a close evolutionary relationship with the third isoform of FB-like protein (FB-3) from the jumping spider Hasarius adansoni belonging to the Family Salcitidae. PMID- 26771537 TI - Promoting Photochemical Water Oxidation with Metallic Band Structures. AB - The development of economic water oxidation catalysts is a key step toward large scale water splitting. However, their current exploration remains empirical to a large extent. Elucidating the correlations between electronic properties and catalytic activity is crucial for deriving general and straightforward catalyst design principles. Herein, strongly correlated electronic systems with abundant and easily tunable electronic properties, namely La(1-x)Sr(x)BO3 perovskites and La(2-x)Sr(x)BO4 layered perovskites (B = Fe, Co, Ni, or Mn), were employed as model systems to identify favorable electronic structures for water oxidation. We established a direct correlation between the enhancement of catalytic activity and the insulator to metal transition through tuning the electronic properties of the target perovskite families via the La(3+)/Sr(2+) ratio. Their improved photochemical water oxidation performance was clearly linked to the increasingly metallic character. These electronic structure-activity relations provide a promising guideline for constructing efficient water oxidation catalysts. PMID- 26771536 TI - Disruptive Mood Dysregulation Disorder at Ages 13-18: Results from the National Comorbidity Survey-Adolescent Supplement. AB - OBJECTIVE: "Disruptive mood dysregulation disorder" (DMDD) has been introduced into the Diagnostic and Statistical Manual of Mental Disorders, 5th ed. but the utility of this new label and the clinical correlates of the children it describes are yet to be determined. METHODS: A proxy for the DMDD diagnosis was extracted from the National Comorbidity Survey - Adolescent Supplement (NCS-A) data on 6483 adolescents (51.4% female) including Composite International Diagnostic Interview (CIDI) diagnoses and measures of impaired functioning from the Sheehan Disability Scale. Cross tabulations and logistic regression were used to assess for prevalence and comorbidity. RESULTS: A total of 310 (5.26%) adolescents met the criteria for DMDD when diagnostic hierarchy and frequency of outbursts were not considered. At the low end of prevalence estimation, only nine adolescents (0.12%) met the most stringent proxy diagnosis, and they also met criteria for a number of comorbid disorders and functional impairment. The rates of comorbidity and functional impairment in adolescents with bipolar disorder were the same, irrespective of their meeting criteria for DMDD. CONCLUSIONS: The DMDD diagnosis captures a small group of adolescents with multiple other psychiatric and neurologic conditions. The specificity of this diagnostic label, therefore, at least in adolescents, remains an open question. PMID- 26771535 TI - SNARE-Mediated Cholesterol Movement to Mitochondria Supports Steroidogenesis in Rodent Cells. AB - Vesicular transport involving soluble N-ethylmaleimide sensitive factor attachment protein receptor (SNARE) proteins is known to be responsible for many major cellular activities. In steroidogenic tissues, chronic hormone stimulation results in increased expression of proteins involved in the steroidogenic pathway, whereas acute hormone stimulation prompts the rapid transfer of cholesterol to the inner mitochondrial membrane to be utilized as substrate for steroid hormone production. Several different pathways are involved in supplying cholesterol to mitochondria, but mobilization of stored cholesteryl esters appears to initially constitute the preferred source; however, the mechanisms mediating this cholesterol transfer are not fully understood. To study the potential contribution of SNARE proteins in steroidogenesis, we examined the expression levels of various SNARE proteins in response to hormone stimulation in steroidogenic tissues and cells and established an in vitro mitochondria reconstitution assay system to assess the contribution of various SNARE proteins on cholesterol delivery for steroidogenesis. Our results from reconstitution experiments along with knockdown studies in rat primary granulosa cells and in a Leydig cell line show that soluble N-ethylmaleimide sensitive factor attachment protein-alpha, synaptosomal-associated protein of 25 kDa, syntaxin-5, and syntaxin-17 facilitate the transport of cholesterol to mitochondria. Thus, although StAR is required for efficient cholesterol movement into mitochondria for steroidogenesis, specific SNAREs participate and are necessary to mediate cholesterol movement to mitochondria. PMID- 26771538 TI - Fabrication of a Homogeneous, Integrated, and Compact Film of Organic-Inorganic Hybrid Ni(en)3Ag2I4 with Near-Infrared Absorbance and Semiconducting Features. AB - The organic-inorganic hybrid crystal Ni(en)3Ag2I4 (where en represents 1,2 ethylenediamine) crystallizes in hexagonal space group P63, in which the AgI4(3-) tetrahedra connect into a diamondlike inorganic framework via sharing of the vertex and the Ni(en)3(2+) octahedra fill in the pores of the framework. UV-vis near-IR (NIR) spectroscopy disclosed that this hybrid shows intense NIR absorbance centered at ca. 870 nm, and the variable-temperature conductivity measurement revealed that the hybrid is a semiconductor with Ea = 0.46 eV. The electronic band structure of Ni(en)3Ag2I4 was calculated using the density functional theory method, indicating that the NIR absorbance arises from d-d transition within the Ni(2+) cation of Ni(en)3(2+). The homogeneous, compact, and transparent crystalline film of Ni(en)3Ag2I4 was fabricated via a secondary seed growth strategy, which has promising application in NIR devices. PMID- 26771539 TI - Health Behaviours and Awareness of Canada's Food Guide: A Population-based Study. AB - PURPOSE: Lifestyle behaviours among adults reporting awareness of Canada's Food Guide (CFG) are described. METHODS: Data from a cross-sectional survey of adults from Alberta were used to estimate the prevalence of reported health behaviours among respondents aware of the CFG. RESULTS: Respondents (n = 1044) reported general awareness of CFG (mean age 50.3 years; 54.2% female) of whom 82.2% reported awareness of specific CFG recommendations. Respondents reported frequently reading food labels (>58.0%), reading the number of calories (45.5%), the amount of sodium (49.5%), the amount of fat (46.7%), and the type of fat (45.5%) on the food label. Most respondents (90.0%) reported frequently selecting foods to promote health. Approximately one-third of the respondents (35.8%) reported frequently consuming >=5 portions of vegetables and fruit per day and regularly participating in physical activity (55.3%). Body weight was perceived as healthy by 63.4% of the respondents. Most engaged in 2 health behaviours frequently. Adjusting for important socio-demographic characteristics, those who reported frequently consuming >=5 portions of vegetables and fruit per day were more likely to engage in a second health behaviour outlined in CGF (OR: 23.6, 95% CI (16.2-34.4)). CONCLUSION: Awareness of CFG did not translate to positive health behaviours. More proactive population level strategies to support specific health behaviours as outlined in CFG might be warranted. PMID- 26771540 TI - alpha-Fluoroallenoate Synthesis via N-Heterocyclic Carbene-Catalyzed Fluorination Reaction of Alkynals. AB - The first catalytic alpha-fluoroallenoate synthesis is described. With a suitable combination of N-heterocyclic carbene precatalyst, base, and fluorine reagent, the reaction proceeded smoothly to yield a wide range of alpha-fluoroallenoates with excellent chemoselectivity. These substituted alpha-fluorinated allenoates have been synthesized for the first time, and they are versatile synthetic intermediates toward other useful fluorine-containing building blocks. PMID- 26771541 TI - Environmental Persistence and Infectivity of Oocysts of Two Species of Gregarines, Blabericola migrator and Blabericola cubensis (Apicomplexa: Eugregarinida: Blabericolidae), Parasitizing Blaberid Cockroaches (Dictyoptera: Blaberidae). AB - For apicomplexan parasites using an oral-fecal transmission route with significant environmental exposure, the environmental persistence and infectivity of the oocyst has a direct impact on local infection dynamics, including the ability to withstand extended periods without readily available hosts. Herein we quantify the environmental persistence and infectivity of the oocysts of 2 septate gregarine species at controlled temperature and humidity and demonstrate that they can persist over multiple generational time spans. Species of Blabericola generally complete their endogenous life cycles from oocyst to oocyst within 10 days. The median residual environmental oocyst lifetime for Blabericola oocysts in this study is 21-28 days, but a significant number of oocysts of Blabericola migrator persisted and remained infective in the environment for up to 39 days while those of Blabericola cubensis persisted and remained infective for up to 92 days. Although long-lived relative to their own generational time, the oocysts of Blabericola species infecting cockroaches are short-lived relative to gregarines infecting tenebrionid beetles. For these gregarines, oocysts can persist in the environment and remain infective for up to 787 days. Mechanistically, environmental persistence and infectivity are probably energy limited phenomena related to the amount of stored amylopectin and the basal metabolic rate of quiescent oocysts. PMID- 26771543 TI - Society for Acupuncture Research 2015 International Conference: Award-Winning Abstracts in Clinical and Basic Sciences. PMID- 26771542 TI - Calculating Stress: From Entropy to a Thermodynamic Concept of Health and Disease. AB - To date, contemporary science has lacked a satisfactory tool for the objective expression of stress. This text thus introduces a new-thermodynamically derived approach to stress measurement, based on entropy production in time and independent of the quality or modality of a given stressor or a combination thereof. Hereto, we propose a novel model of stress response based on thermodynamic modelling of entropy production, both in the tissues/organs and in regulatory feedbacks. Stress response is expressed in our model on the basis of stress entropic load (SEL), a variable we introduced previously; the mathematical expression of SEL, provided here for the first time, now allows us to describe the various states of a living system, including differentiating between states of health and disease. The resulting calculation of stress response regardless of the type of stressor(s) in question is thus poised to become an entirely new tool for predicting the development of a living system. PMID- 26771546 TI - Correction: Are Treatments More Effective than Placebos? A Systematic Review and Meta-Analysis. PMID- 26771544 TI - SLO BK Potassium Channels Couple Gap Junctions to Inhibition of Calcium Signaling in Olfactory Neuron Diversification. AB - The C. elegans AWC olfactory neuron pair communicates to specify asymmetric subtypes AWCOFF and AWCON in a stochastic manner. Intercellular communication between AWC and other neurons in a transient NSY-5 gap junction network antagonizes voltage-activated calcium channels, UNC-2 (CaV2) and EGL-19 (CaV1), in the AWCON cell, but how calcium signaling is downregulated by NSY-5 is only partly understood. Here, we show that voltage- and calcium-activated SLO BK potassium channels mediate gap junction signaling to inhibit calcium pathways for asymmetric AWC differentiation. Activation of vertebrate SLO-1 channels causes transient membrane hyperpolarization, which makes it an important negative feedback system for calcium entry through voltage-activated calcium channels. Consistent with the physiological roles of SLO-1, our genetic results suggest that slo-1 BK channels act downstream of NSY-5 gap junctions to inhibit calcium channel-mediated signaling in the specification of AWCON. We also show for the first time that slo-2 BK channels are important for AWC asymmetry and act redundantly with slo-1 to inhibit calcium signaling. In addition, nsy-5-dependent asymmetric expression of slo-1 and slo-2 in the AWCON neuron is necessary and sufficient for AWC asymmetry. SLO-1 and SLO-2 localize close to UNC-2 and EGL-19 in AWC, suggesting a role of possible functional coupling between SLO BK channels and voltage-activated calcium channels in AWC asymmetry. Furthermore, slo-1 and slo-2 regulate the localization of synaptic markers, UNC-2 and RAB-3, in AWC neurons to control AWC asymmetry. We also identify the requirement of bkip-1, which encodes a previously identified auxiliary subunit of SLO-1, for slo-1 and slo-2 function in AWC asymmetry. Together, these results provide an unprecedented molecular link between gap junctions and calcium pathways for terminal differentiation of olfactory neurons. PMID- 26771545 TI - Model-Based Geostatistical Mapping of the Prevalence of Onchocerca volvulus in West Africa. AB - BACKGROUND: The initial endemicity (pre-control prevalence) of onchocerciasis has been shown to be an important determinant of the feasibility of elimination by mass ivermectin distribution. We present the first geostatistical map of microfilarial prevalence in the former Onchocerciasis Control Programme in West Africa (OCP) before commencement of antivectorial and antiparasitic interventions. METHODS AND FINDINGS: Pre-control microfilarial prevalence data from 737 villages across the 11 constituent countries in the OCP epidemiological database were used as ground-truth data. These 737 data points, plus a set of statistically selected environmental covariates, were used in a Bayesian model based geostatistical (B-MBG) approach to generate a continuous surface (at pixel resolution of 5 km x 5km) of microfilarial prevalence in West Africa prior to the commencement of the OCP. Uncertainty in model predictions was measured using a suite of validation statistics, performed on bootstrap samples of held-out validation data. The mean Pearson's correlation between observed and estimated prevalence at validation locations was 0.693; the mean prediction error (average difference between observed and estimated values) was 0.77%, and the mean absolute prediction error (average magnitude of difference between observed and estimated values) was 12.2%. Within OCP boundaries, 17.8 million people were deemed to have been at risk, 7.55 million to have been infected, and mean microfilarial prevalence to have been 45% (range: 2-90%) in 1975. CONCLUSIONS AND SIGNIFICANCE: This is the first map of initial onchocerciasis prevalence in West Africa using B-MBG. Important environmental predictors of infection prevalence were identified and used in a model out-performing those without spatial random effects or environmental covariates. Results may be compared with recent epidemiological mapping efforts to find areas of persisting transmission. These methods may be extended to areas where data are sparse, and may be used to help inform the feasibility of elimination with current and novel tools. PMID- 26771548 TI - Mitigating the Impact of Bats in Historic Churches: The Response of Natterer's Bats Myotis nattereri to Artificial Roosts and Deterrence. AB - Bats frequently roost in historic churches, and these colonies are of considerable conservation value. Inside churches, bat droppings and urine can cause damage to the historic fabric of the building and to items of cultural significance. In extreme cases, large quantities of droppings can restrict the use of a church for worship and/or other community functions. In the United Kingdom, bats and their roosts are protected by law, and striking a balance between conserving the natural and cultural heritage can be a significant challenge. We investigated mitigation strategies that could be employed in churches and other historic buildings to alleviate problems caused by bats without adversely affecting their welfare or conservation status. We used a combination of artificial roost provision and deterrence at churches in Norfolk, England, where significant maternity colonies of Natterer's bats Myotis nattereri damage church features. Radio-tracking data and population modelling showed that excluding M. nattereri from churches is likely to have a negative impact on their welfare and conservation status, but that judicious use of deterrents, especially high intensity ultrasound, can mitigate problems caused by bats. We show that deterrence can be used to move bats humanely from specific roosting sites within a church and limit the spread of droppings and urine so that problems to congregations and damage to cultural heritage can be much reduced. In addition, construction of bespoke roost spaces within churches can allow bats to continue to roost within the fabric of the building without flying in the church interior. We highlight that deterrence has the potential to cause serious harm to M. nattereri populations if not used judiciously, and so the effects of deterrents will need careful monitoring, and their use needs strict regulation. PMID- 26771547 TI - Effect of Immunotherapy on Seizure Outcome in Patients with Autoimmune Encephalitis: A Prospective Observational Registry Study. AB - OBJECTIVE: To evaluate the seizure characteristics and outcome after immunotherapy in adult patients with autoimmune encephalitis (AE) and new-onset seizure. METHODS: Adult (age >=18 years) patients with AE and new-onset seizure who underwent immunotherapy and were followed-up for at least 6 months were included. Seizure frequency was evaluated at 2-4 weeks and 6 months after the onset of the initial immunotherapy and was categorized as "seizure remission", "> 50% seizure reduction", or "no change" based on the degree of its decrease. RESULTS: Forty-one AE patients who presented with new-onset seizure were analysed. At 2-4 weeks after the initial immunotherapy, 51.2% of the patients were seizure free, and 24.4% had significant seizure reduction. At 6 months, seizure remission was observed in 73.2% of the patients, although four patients died during hospitalization. Rituximab was used as a second-line immunotherapy in 12 patients who continued to have seizures despite the initial immunotherapy, and additional seizure remission was achieved in 66.6% of them. In particular, those who exhibited partial response to the initial immunotherapy had a better seizure outcome after rituximab, with low adverse events. CONCLUSION: AE frequently presented as seizure, but only 18.9% of the living patients suffered from seizure at 6 months after immunotherapy. Aggressive immunotherapy can improve seizure outcome in patients with AE. PMID- 26771550 TI - Cyclosporine for Dry Eye Associated With Nivolumab: A Case Progressing to Corneal Perforation. AB - PURPOSE: To present the clinical outcome of 2 cases of severe dry eye associated with Nivolumab, with 1 case progressing to corneal perforation. DESIGN: Case report. CASE 1: : A 58-year-old man with metastatic melanoma was referred for the management of severe bilateral dry eyes after undergoing his sixth cycle of Nivolumab. The right eye progressed to corneal perforation 4 weeks after referral, after which Nivolumab was discontinued. When metastatic disease recurred, Nivolumab was continued with an ocular surface stabilized with an intensive regimen that included topical cyclosporine. CASE 2: : A 46-year-old woman with metastatic melanoma was referred for severe dry eye symptoms around the timing of her third cycle of Nivolumab. Improvement of symptoms and surface staining was achieved with a regimen that included aggressive lubrication and topical cyclosporine. On follow-up after completing Nivolumab therapy, metastatic melanoma has remained regressed. CONCLUSIONS: Nivolumab can cause or worsen dry eye disease to the point of corneal perforation. Given that its antitumor effect is immune-mediated, therapies targeting ocular surface inflammation can be effective for stabilizing dry eye disease in patients who continue treatment with Nivolumab. PMID- 26771552 TI - Alternative Strategies for Cross-Validation of Covariance Structure Models. AB - Alternative strategies for two-sample cross-validation of covariance structure models are described and investigated. The strategies vary according to whether all (tight strategy) or some (partial strategy) of the model parameters are held constant when a calibration sample solution is re-fit to a validation sample covariance matrix. Justification is provided for three partial strategies. Conventional and alternative strategies for cross-validation are discussed as methods for evaluating overall discrepancy of a model fit to a particular sample, where overall discrepancy arises from the combined influences of discrepancy of approximation and discrepancy of estimation (Cudeck & Henly, 1991). Results of a sampling study using empirical data show that for tighter strategies simpler models are preferred in smaller samples. However, when partial cross-validation is employed, a more complex model may be supported even in a small sample. Implications for model comparison and evaluation, as well as the issues of model complexity and sample size are discussed. PMID- 26771551 TI - Quantifying Access Disparities in Response Plans. AB - Effective response planning and preparedness are critical to the health and well being of communities in the face of biological emergencies. Response plans involving mass prophylaxis may seem feasible when considering the choice of dispensing points within a region, overall population density, and estimated traffic demands. However, the plan may fail to serve particular vulnerable subpopulations, resulting in access disparities during emergency response. For a response plan to be effective, sufficient mitigation resources must be made accessible to target populations within short, federally-mandated time frames. A major challenge in response plan design is to establish a balance between the allocation of available resources and the provision of equal access to PODs for all individuals in a given geographic region. Limitations on the availability, granularity, and currency of data to identify vulnerable populations further complicate the planning process. To address these challenges and limitations, data driven methods to quantify vulnerabilities in the context of response plans have been developed and are explored in this article. PMID- 26771549 TI - The p70S6K Specific Inhibitor PF-4708671 Impedes Non-Small Cell Lung Cancer Growth. AB - BACKGROUND: As a serine/threonine protein kinase, p70S6K plays an important role in tumor cells. Evidence has revealed overexpression of p70S6K and phosphorylated p70S6K (p-p70S6K) in various tumor tissues, with these proteins identified as independent prognostic markers in non-small cell lung cancer (NSCLC). In this study, we explored the role of the p70S6K specific inhibitor PF-4708671 in NSCLC. METHODS: Three NSCLC cell lines (A549, SK-MES-1, and NCI-H460) were treated with PF-4708671 at five different concentrations, including 0.1MUM, 0.3MUM, 1MUM, 3MUM and 10MUM, and protein levels were determined by Western-blot. Then, PF-4708671's effects were assessed both in vitro (cell proliferation, apoptosis, cell cycle distribution, and invasion) and in vivo. RESULTS: The expression levels of p p70S6K and the downstream effector S6 were significantly reduced by PF-4708671. Diametrically opposite, the downstream protein levels of BAD, Caspase3 and ERK had increased after treatment with PF-4708671. In addition, PF-4708671 drastically inhibited cell proliferation and invasion ability in A549, SK-MES-1 and NCI-H460 cells in vitro, causing cell cycle arrest in G0-G1 phase. Limited effects of PF-4708671 were observed on apoptosis in the three NSCLC cell lines assessed. Importantly, PF-4708671 could inhibit tumorigenesis in nude mice in vivo. CONCLUSION: These findings demonstrated that the p70S6K specific inhibitor PF-4708671 has inhibitory effects on NSCLC tumorigenesis in vitro and in vivo. Therefore, P70S6K should be considered a new potential therapeutic target, and PF 470867 may be used as targeted drug for cancer treatment. PMID- 26771553 TI - Multiple Regression With Data Collected From Relatives: Testing Assumptions of the Model. AB - Multiple regression is a causal model of the relationship between sets of independent (X) and dependent (Y) variables. This model is extended to cover data collected from relatives, where the observations are not independent. If correct, the model permits appropriate statistical tests of regression coefficients in data collected from relatives. Across relative covariances, particularly across the independent and dependent variables may reject the basic regression model. Further extensions of the model are developed that permit tests of several assumptions implicit in multiple regression: (a) the assignment of variables as dependent or independent; (b) the relationship between X and Y variables is not due to some latent variable which causes variation in both; and (c) there is no reciprocal interaction between the X and the Y variables. Discrimination between these alternatives is especially strong if data are collected from more than one class of relative, which differ in their X and Y variable covariance structure. Data on Eysenck Extraversion, Neuroticism and CESD depression collected from twins are used as an illustrative example. PMID- 26771554 TI - Structural Equation Models of Factorial Invariance in Parallel Proportional Profiles and Oblique Confactor Problems. AB - Some problems of multiple group factor rotation based on Cattell's "parallel proportional profiles" and "confactor rotation" are described (see Cattell, 1944, 1966, 1972). Some relations between these classic ideas and contemporary practices in structural equation modeling (e.g., LISREL) are explored. We show how the Confactor approach: (a) is related to Meredith's (1964a) selection model, (b) can be a parsimonious model for multiple group factor analyses, and (c) how this model can be fitted using standard structural equation modeling techniques. We discuss several alternative structural modeling solutions, including (d) selection of a good reference variable solution, (e) rotation of the invariant orthogonal structure by standard rotation routines, and (f) higher-order, latent paths, and latent means structural model restrictions. Mathematical and statistical properties of these models are examined using Meredith's (1964b) four group problem fitted by Jdreskog and Sdrbom's (1979, 1985) LlSREL algorithm. The benefits and limitations of this structural modeling approach to oblique Confactor resolution are examined and opportunities for future research are discussed. PMID- 26771555 TI - Factor Analysis of Ipsative Measures. AB - lpsative measures are multiple measures, where the data are collected, or are modified, in such a way that all subject totals across the measures are equal. Much has been written about factor analysis with such data, however, no clear consensus has been reached regarding the suitability of ipsative measures for factor analysis. The purpose of the present article is to show analytically the fundamental problems that ipsative measures impose for factor analysis. The expected value of the correlation between ipsative measures is shown to equal - 1/ ( k - I), where k is the number of measures. The rank of the resulting correlation matrix is reduced by one to k - 1, and ipsativity alone produces k - 1 artifactual bipolar factors, which will obscure any actual interrelations among the measures. If the data are known to be ipsative or if the tell-tale signs of ipsativity are seen, factor analysis should not be done. PMID- 26771556 TI - Psychosocial resources and sleep disturbance before chemotherapy for gynecologic cancer. AB - Personal psychosocial resources (e.g., positive affect, social support, perceived mastery, meaning in life) are associated with better sleep in noncancer populations, but there have been few studies in cancer patients. The present study examined psychosocial resources and sleep in gynecological cancer patients. Before chemotherapy, 72 participants completed self-report measures of sleep and psychosocial resources; 63 also completed actigraphic monitoring. Subjective sleep was associated with positive affect, social support, perceived mastery, and meaning in life; objective sleep was associated with social support. Future studies should examine whether interventions to enhance psychosocial resources result in improved sleep in this population. PMID- 26771557 TI - Urotensin-IIReceptor Antagonist SB-710411 Protects Rat Heart against Ischemia Reperfusion Injury via RhoA/ROCK Pathway. AB - AIM: SB-710411 is a rat selective urotensin-II (U-II) receptor antagonist, which can block U-II-induced contraction of the aorta and inhibit U-II-induced myocardial fibrosis in rats. However, the effect of SB-710411 on myocardial ischemia-reperfusion (I/R) injury is unclear. The present study was designed to investigate whether SB-710411 has a protective effect on myocardial I/R injury in rats and the possible mechanisms. METHODS AND RESULTS: Myocardial I/R injury was induced by occluding the left anterior descending coronary artery in adult male Sprague-Dawley rats. Hemodynamic parameters, electrocardiogram (ECG), infarct size, histological alteration, lactate dehydrogenase (LDH), creatine phosphokinase-MB (CK-MB), cardiac troponin I (cTnI), RhoA, and the protein expressions of U-II receptor (UTR), ROCK1 and ROCK2 were evaluated. Cardiac I/R injury significantly up-regulated the expressions of UTR, ROCK1 and ROCK2 proteins in rat myocardium. SB-710411 1.0 and 2.0 MUg/kg significantly reduced cardiac I/R-induced the infarct size and histological damage in rat myocardium, markedly inhibited the changes of hemodynamic parameters and the increases of ST segment in ECG, the serum LDH and CK-MB activities and cTnI level in rats subjected to myocardial I/R injury. Furthermore, SB-710411 obviously prevented myocardial I/R-increased RhoA activity and UTR, ROCK1 and ROCK2 protein expressions. CONCLUSIONS: Our results indicate that cardiac I/R injury increases myocardial UTR expression, and SB-710411 has a potent protective effect on myocardial I/R injury in rats. The cardioprotection may be associated with the inhibition of UTR-RhoA/ROCK pathway. PMID- 26771558 TI - Editor's Note. PMID- 26771560 TI - Care of Women During Menopause. AB - We would like to introduce a new section in the Journal of Women's Health, the Clinical Update. Important studies are continually published in both this Journal and other medical publications. However, it is difficult for busy providers to stay current with the changing literature. The Clinical Update is designed to serve as a review of recently published, high-impact, and potentially practice changing journal articles, digested for our readers. The Clinical Update will be published on a quarterly basis. Each edition of the update will focus on a specific women's health topic, with planned topics to include menopause, sexual dysfunction, breast health, contraception, osteoporosis, and cardiovascular disease. PMID- 26771559 TI - A Report of the Women's Health Congress Workshop on The Health of Women of Color: A Critical Intersection at the Corner of Sex/Gender and Race/Ethnicity. AB - Women of color face unique health challenges that differ significantly from those of other women and men of color. To bring these issues to light, the National Institutes of Health (NIH) Office of Research on Women's Health sponsored a preconference workshop at the 23rd Annual Women's Health Congress, which was held in Washington, DC, in April 2015. The workshop featured presentations by NIH intramural and extramural scientists who provided insight on the disparities of a wide range of conditions, including cancer, cardiovascular disease, the risk of HIV infection, and disability in an aging population. In this study, we highlight the major points of each presentation and the ensuing discussion. PMID- 26771561 TI - Sprouting Buds of Zebrafish Research in Malaysia: First Malaysia Zebrafish Disease Model Workshop. AB - Zebrafish is gaining prominence as an important vertebrate model for investigating various human diseases. Zebrafish provides unique advantages such as optical clarity of embryos, high fecundity rate, and low cost of maintenance, making it a perfect complement to the murine model equivalent in biomedical research. Due to these advantages, researchers in Malaysia are starting to take notice and incorporate the zebrafish model into their research activities. However, zebrafish research in Malaysia is still in its infancy stage and many researchers still remain unaware of the full potential of the zebrafish model or have limited access to related tools and techniques that are widely utilized in many zebrafish laboratories worldwide. To overcome this, we organized the First Malaysia Zebrafish Disease Model Workshop in Malaysia that took place on 11th and 12th of November 2015. In this workshop, we showcased how the zebrafish model is being utilized in the biomedical field in international settings as well as in Malaysia. For this, notable international speakers and those from local universities known to be carrying out impactful research using zebrafish were invited to share some of the cutting edge techniques that are used in their laboratories that may one day be incorporated in the Malaysian scientific community. PMID- 26771562 TI - Multidimensional Geriatric Prognostic Index, Based on a Geriatric Assessment, for Long-Term Survival in Older Adults in Korea. AB - The patient's survival estimate is important for clinical decision-making, especially in frail patients with multimorbidities. We aimed to develop a multidimensional geriatric prognosis index (GPI) for 3- and 5-year mortality in community-dwelling elderly and to validate the GPI in a separate hospital-based population. The GPI was constructed using data for 988 participants in the Korean Longitudinal Study on Health and Aging (KLoSHA) and cross-validated with 1109 patients who underwent a geriatric assessment at the Seoul National University Bundang Hospital (SNUBH). The GPI, with a total possible score of 8, included age, gender, activities of daily living, instrumental activities of daily living, comorbidities, mood, cognitive function, and nutritional status. During the 5 year observation period, 179 KLoSHA participants (18.1%) and 340 SNUBH patients (30.7%) died. The c-indices for 3- and 5-year mortality were 0.78 and 0.80, respectively, in the KLoSHA group and 0.73 and 0.80, respectively, in the SNUBH group. Positive linear trends were observed for GPI scores and both 3- and 5-year mortality in both groups. In conclusions, using common components of a geriatric assessment, the GPI can stratify the risk of 3- and 5-year mortality in Korean elderly people both in the community and hospital. PMID- 26771563 TI - Effects of Line and Pillar Array Microengineered SiO2 Thin Films on the Osteogenic Differentiation of Human Bone Marrow-Derived Mesenchymal Stem Cells. AB - A primary goal in bone tissue engineering is the design of implants that induce controlled, guided, and rapid healing. The events that normally lead to the integration of an implant into bone and determine the performance of the device occur mainly at the tissue-implant interface. Topographical surface modification of a biomaterial might be an efficient tool for inducing stem cell osteogenic differentiation and replace the use of biochemical stimuli. The main goal of this work was to develop micropatterned bioactive silica thin films to induce the osteogenic differentiation of human bone marrow-derived mesenchymal stem cells (hMSCs) only through topographical stimuli. Line and pillar micropatterns were developed by a combination of sol-gel/soft lithography and characterized by scanning electron microscopy, atomic force microscopy, and contact angle measurements. hMSCs were cultured onto the microfabricated thin films and flat control for up to 21 days under basal conditions. The micropatterned groups induced levels of osteogenic differentiation and expression of osteoblast associated markers higher than those of the flat controls. Via comparison of the micropatterns, the pillars caused a stronger response of the osteogenic differentiation of hMSCs with a higher level of expression of osteoblast associated markers, ALP activity, and extracellular matrix mineralization after the cells had been cultured for 21 days. These findings suggest that specific microtopographic cues can direct hMSCs toward osteogenic differentiation. PMID- 26771564 TI - Using the Rasch Model to Measure the Extent to which Students Work Conceptually with Mathematics. AB - Differences between working conceptually and procedurally with mathematics are well documented. In short, working procedurally can be characterized as learning and applying rules without reason. Working conceptually, in contrast, means creating and applying a web of knowledge. To continue this line of research, an instrument that is able to measure the level of conceptual work, and that is based on the basic requirements of measurement, is desireable. As such, this paper presents a Rasch calibrated instrument that measures the extent to which students work conceptually with mathematics. From a sample of 133 student teachers and 185 Civil Engineering students, 20 items are concluded as being productive for measurement. PMID- 26771565 TI - Rasch Model Parameter Estimation via the Elastic Net. AB - In this paper we investigate the novel method, penalized joint maximum likelihood estimation (PJMLE), for estimating the parameters of the Rasch model (Rasch, 1960). Here we use joint maximum likelihood estimation (JMLE) along with elastic net penalization using the glmnet package (Friedman, Hastie, and Tibshirani, 2010) in R to obtain estimates for item difficulties and examinee abilities. Through simulation we compared the accuracy of PJMLE to conditional maximum likelihood estimation (CMLE), marginal maximum likelihood estimation (MMLE), and marginal Bayes modal estimation (MBME). We show that PJMLE successfully estimates parameters of a Rasch model when the number of items is greater than the number of examinees, which is a shortcoming of traditional estimation techniques. In addition, we further show that PJMLE performs similarly to traditional techniques when the number of examinees is greater than the number of assessment items without specifying a mixing distribution or a prior distribution. PMID- 26771566 TI - A Rasch Analysis of the KeyMath-3 Diagnostic Assessment. AB - Effectively assessing children's academic development can help school professionals make placement decisions and prepare appropriate instructional supports. The KeyMath-3 Diagnostic Assessment (Connolly, 2008) is a widely used assessment of children's mathematical abilities; however, despite much use, the measurement properties of the KeyMath-3 DA have not been examined, aside from the development and standardization phases. The current study conducted a Rasch analysis of the Basic Concepts content area of the KeyMath-3 DA in a diverse sample of 308 young children to assess the quality of the assessment. Rasch analytic procedures examined unidimensionality, item and person fit statistics, reliability, and item hierarchy. Misfitting items were further examined, and response patterns were modified. In general, results show that the Basic Concepts subscale is a good measure of the underlying construct of young children's understanding of the basic concepts in mathematics. Implications are discussed. PMID- 26771567 TI - Psychometric Properties of the Attitudes toward Physical Activity Scale: A Rasch Analysis Based on Data From Five Locations. AB - This article describes the development and validation of the Attitudes toward Physical Activity Scale (APAS) to measure the attitudes, beliefs, and self efficacy toward physical activity by children at the primary school level. The framework included: physical fitness, self-efficacy, personal best goal orientation in physical activity, interest in physical activity, importance of physical activity, benefits of physical activity, contributions of video exercise to learning in school subjects, contributions of video exercise to learning about health and environmental support. The sample comprised of 630 school students between grades 1 and 7 from five countries, namely Lithuania (29%), Poland (26%), Serbia (19%), Singapore (16%) and Zimbabwe (11%). Rasch analysis found empirical evidence in support of measurement validity of the APAS in terms of Rasch item reliabilities, unidimensionality, effectiveness of response categories, and absence of gender differential item functioning (DIF). The validation of the APAS according to the Rasch model meant that a dependable tool was established for gauging programme effectiveness of intervention programs on physical activity of primary school children in classroom settings at various geographical locations globally. PMID- 26771568 TI - Development and Analysis of a Scale for Meauring Teachers' Sense of Efficacy in Urban Schools (SEUS). AB - Research in teacher self-efficacy has a long history that can be traced back to Bandura (1986) and has been shown to be linked to teacher performance. This article presents evidence for teacher self-efficacy in urban schools, a construct that is separate from but related to the more general construct of teacher self efficacy. An instrument was developed and validated by a team of university faculty, urban teachers, and school administrators. The Teachers' Sense of Efficacy in Urban Schools (SEUS) is a 15-item instrument designed to address factors that are important for success in teaching in an urban environment, including working effectively with English language learners, students with disabilities, economically disadvantaged students, cultural diversity, literacy, technology, differentiation, and assessment data. The present study analyzes SEUS on multiple levels, using the Rasch partial credit model. PMID- 26771569 TI - Testing the Multidimensionality in Teacher Interpersonal Behavior: Validating the Questionnaire on Teacher Interaction Using the Rasch Measurement Model. AB - This study investigated the perceptions of 1235 students of their form teachers' interpersonal behaviors across 40 classrooms in 24 Singaporean secondary schools. The 32-item Questionnaire on Teacher Interaction (QTI) survey was administered to obtain the initial quantitative data of teacher behaviors perceived by the students in these classrooms. The eight scales of QTI are: Leadership, Helping/Friendly, Understanding, Student Responsibility/ Freedom, Uncertain, Dissatisfied, Admonishing, and Strict. The Rasch measurement model was used to estimate students' traits with respect to each subscale, and then to examine its proposed multidimensional structure. Findings demonstrate overall good fit of the responses with the Rasch model for each subscale. Findings also support the hypothesized relationships among the eight dimensions proposed for the QTI. PMID- 26771570 TI - Planning a Study for Testing the Rasch Model given Missing Values due to the use of Test-booklets. AB - Though calibration of an achievement test within a psychological and educational context is very often carried out by the Rasch model, data sampling is hardly designed according to statistical foundations. However, Kubinger, Rasch, and Yanagida (2009, 2011) suggested an approach for the determination of sample size according to a given Type-I and Type-II risk and a certain effect of model contradiction when testing the Rasch model. The approach uses a three-way analysis of variance design with mixed classification. For the while, their simulation studies deal with complete data, meaning every examinee is administered with all of the items of an item pool. The simulation study now presented in this paper deals with the practical relevant case, in particular for large-scale assessments, that item presentation happens to use several test booklets. As a consequence, there are missing values by design. Therefore, the question to be considered is, whether this approach works in this case as well. Besides the fact, that data are not normally distributed but there is a dichotomous variable (an examinee either solves an item or fails to solve it), only a single entry for each cell exists in the given three-way analysis of variance design, if at all, due to missing values. Hence, the obligatory test statistic's distribution may not be retained, in contrast to the case of having no missing values. The result of our simulation study, despite applying only to a very special scenario, is that this approach works, indeed: Whether test-booklets were used or every examinee is administered all of the items changes nothing in respect to the actual Type-I risk or to the power of the test, given almost the same amount of information of examinees per item. However, as the results are limited to a special scenario, we currently recommend any interested researcher to simulate the appropriate one in advance by him/herself. PMID- 26771571 TI - The Reliability and Validity of the Power-Load-Margin Inventory: A Rasch Analysis. AB - Margin is a function of the relationship of stress to strength. The greater the margin, the more likely students are able to successfully navigate academic structures. This study examined the psychometric properties of a newly created instrument designed to measure margin - the Power-Load-Margin Inventory (PLMI). The PLMI was created using eight domains: (A) Student's aptitude and ability, (B) Course structure, (C) External motivation, (D) Student health, (E) Instructor style, (F) Internal motivation, (G) Life opportunities, and (H) University support structure. A three-point response scale was used to measure the domains: (1) stress, (2) neither stress nor strength, and (3) strength. The PLMI was administered to 586 medical, dental, and pharmacy students. A Rasch rating scale model was used to examine the psychometric properties of the PLMI. The PLMI demonstrated acceptable psychometric properties for use with pharmacy, dental, and medical students. The PLMI's primary weakness was with the subscales' reliability. We attribute this to the small number of items per subscale. PMID- 26771572 TI - A Novel Mixture Model to Estimate the Time to Drug Effect Onset and Its Association with Covariates. AB - OBJECTIVE: Drugs take effect at different times in different individuals. Consequently, researchers seek to examine how the timing of the biological response to drugs may be affected by factors such as gender, genotypes, age, or baseline symptom scores. METHODS: Typically, studies measure symptoms immediately after the initiation of drug treatment and then at a sequence of later time points. In this study, we develop a statistical mixture model for analyzing such longitudinal data. Our method estimates the onset of drug effect and assesses the association between the probability distribution of the onset times and possible contributing factors. Our mixture model treats the timing of onset as missing for each individual but restricts it, for simplicity, to two possible onset points, early or late. To estimate the model, we use an expectation-maximization-based approach and provide the general formulas of the variance and covariance matrix for the estimated parameters. RESULTS: We evaluate the model's overall utility and performance via simulation studies. In addition, we illustrate its use by application to longitudinal data from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. The algorithm identified age and anxiety status as significant factors in affecting the onset distribution of citalopram (Celexa). PMID- 26771573 TI - Left Atrial Size and Function in a Canine Model of Chronic Atrial Fibrillation and Heart Failure. AB - BACKGROUND: Our aim was to assess how atrial fibrillation (AF) induction, chronicity, and RR interval irregularity affect left atrial (LA) function and size in the setting of underlying heart failure (HF), and to determine whether AF effects can be mitigated by vagal nerve stimulation (VNS). METHODS: HF was induced by 4-weeks of rapid ventricular pacing in 24 dogs. Subsequently, AF was induced and maintained by atrial pacing at 600 bpm. Dogs were randomized into control (n = 9) and VNS (n = 15) groups. In the VNS group, atrioventricular node fat pad stimulation (310 MUs, 20 Hz, 3-7 mA) was delivered continuously for 6 months. LA volume and LA strain data were calculated from bi-weekly echocardiograms. RESULTS: RR intervals decreased with HF in both groups (p = 0.001), and decreased further during AF in control group (p = 0.014), with a non significant increase in the VNS group during AF. LA size increased with HF (p<0.0001), with no additional increase during AF. LA strain decreased with HF (p = 0.025) and further decreased after induction of AF (p = 0.0001). LA strain decreased less (p = 0.001) in the VNS than in the control group. Beat-by-beat analysis showed a curvilinear increase of LA strain with longer preceding RR interval, (r = 0.45, p <0.0001) with LA strain 1.1% higher (p = 0.02) in the VNS treated animals, independent of preceding RR interval duration. The curvilinear relationship between ratio of preceding and pre-preceding RR intervals, and subsequent LA strain was weaker, (r = 0.28, p = 0.001). However, VNS-treated animals again had higher LA strain (by 2.2%, p = 0.002) independently of the ratio of preceding and pre-preceding RR intervals. CONCLUSIONS: In the underlying presence of pacing-induced HF, AF decreased LA strain, with little impact on LA size. LA strain depends on the preceding RR interval duration. PMID- 26771574 TI - Surfactant Protein A Enhances Constitutive Immune Functions of Clathrin Heavy Chain and Clathrin Adaptor Protein 2. AB - NF-kappaB transcription factors are key regulators of pulmonary inflammatory disorders and repair. Constitutive lung cell type- and microenvironment-specific NF-kappaB/inhibitor kappaBalpha (IkappaB-alpha) regulation, however, is poorly understood. Surfactant protein (SP)-A provides both a critical homeostatic and lung defense control, in part by immune instruction of alveolar macrophages (AMs) via clathrin-mediated endocytosis. The central endocytic proteins, clathrin heavy chain (CHC) and the clathrin adaptor protein (AP) complex AP2, have pivotal alternative roles in cellular homeostasis that are endocytosis independent. Here, we dissect endocytic from alternative functions of CHC, the alpha-subunit of AP2, and dynamin in basal and SP-A-modified LPS signaling of macrophages. As revealed by pharmacological inhibition and RNA interference in primary AMs and RAW264.7 macrophages, respectively, CHC and alpha-adaptin, but not dynamin, prevent IkappaB-alpha degradation and TNF-alpha release, independent of their canonical role in membrane trafficking. Kinetics studies employing confocal microscopy, Western analysis, and immunomagnetic sorting revealed that SP-A transiently enhances the basal protein expression of CHC and alpha-adaptin, depending on early activation of protein kinase CK2 (former casein kinase II) and Akt1 in primary AMs from rats, SP-A(+/+), and SP-A(-/-) mice, as well as in vivo when intratracheally administered to SP-A(+/+) mice. Constitutive immunomodulation by SP-A, but not SP-A-mediated inhibition of LPS-induced NF-kappaB activity and TNF alpha release, requires CHC, alpha-adaptin, and dynamin. Our data demonstrate that endocytic proteins constitutively restrict NF-kappaB activity in macrophages and provide evidence that SP-A enhances the immune regulatory capacity of these proteins, revealing a previously unknown pathway of microenvironment-specific NF kappaB regulation in the lung. PMID- 26771575 TI - The Prognosis of Nail Apparatus Melanoma: 20 Years of Experience from a Single Institute. AB - INTRODUCTION AND OBJECTIVES: Nail apparatus melanoma (NAM) is an uncommon tumor, especially in Caucasians. The prognosis of patients affected by NAM was analyzed and correlated with the histopathological criteria and the surgical management of the tumors. MATERIALS AND METHODS: We collected data regarding NAM referred to the Skin Cancer Unit of the Dermatology Department of the University of Bologna, from 1992 to January 2012. RESULTS: Out of 1,327 melanoma cases diagnosed between 1992 and 2012, 42 patients were affected by NAM (2.93%). All the patients were Caucasian. Two deceased patients with insufficient medical records and 1 woman with a personal history of breast cancer were excluded. Thirty-nine cases entered this study: 24 were women (67%) and 15 men (33%). The mean age at diagnosis of NAM was 57.3 years (range 29-88 years). Statistical analyses showed that prognosis was significantly correlated with the Breslow thickness (>=/<2 mm; p = 0.02), regression (p < 0.0001) and ulceration (p = 0.04). Regarding surgical management, Kaplan-Meier's test pointed out that performing functional surgery compared to disarticulation did not correlate with a better prognosis of patients (p = 0.08). CONCLUSIONS: In our experience, the surgical management (disarticulation with respect to functional surgical excision) did not influence the prognosis of NAM patients. The latter was affected by the histopathological characteristics (Breslow thickness, regression and mitoses) and location (fingers vs. foot). PMID- 26771576 TI - The New Combination Docetaxel, Prednisone and Curcumin in Patients with Castration-Resistant Prostate Cancer: A Pilot Phase II Study. AB - OBJECTIVES: Favorable phase I results justified this pilot phase II study to assess the efficacy of docetaxel/curcumin in patients with chemotherapy-naive metastatic castration-resistant prostate cancer (CRPC). METHODS: Thirty patients with progressing CRPC and a rising prostate-specific antigen (PSA) received docetaxel/prednisone in standard conditions for 6 cycles in combination with per os curcumin, 6,000 mg/day (day -4 to day +2 of docetaxel). The co-primary endpoint was the overall response rate determined by PSA and target assessments. An ancillary study assessed the seric values of chromogranin A (CgA) and neuron specific enolase (NSE). RESULTS: Twenty-six patients received the scheduled treatment, 2 progressed and 2 died before the end of treatment. A PSA response was observed in 59% of patients (14% of PSA normalization) and achieved within the first three cycles for 88% of responders. Partial response was reached for 40% of evaluable patients. The regimen was well tolerated, and no adverse event was attributed to curcumin. Twenty patients were 100% curcumin compliant. The PSA level and objective response rate were not correlated with the serum values of CgA and NSE. CONCLUSION: This study produced additional data on curcumin as a treatment for cancer, with a high response rate, good tolerability and patient acceptability, justifying the interest to conduct a randomized trial. PMID- 26771577 TI - Open Data in Global Environmental Research: The Belmont Forum's Open Data Survey. AB - This paper presents the findings of the Belmont Forum's survey on Open Data which targeted the global environmental research and data infrastructure community. It highlights users' perceptions of the term "open data", expectations of infrastructure functionalities, and barriers and enablers for the sharing of data. A wide range of good practice examples was pointed out by the respondents which demonstrates a substantial uptake of data sharing through e-infrastructures and a further need for enhancement and consolidation. Among all policy responses, funder policies seem to be the most important motivator. This supports the conclusion that stronger mandates will strengthen the case for data sharing. PMID- 26771579 TI - Accuracy in Parameter Estimation for the Root Mean Square Error of Approximation: Sample Size Planning for Narrow Confidence Intervals. AB - The root mean square error of approximation (RMSEA) is one of the most widely reported measures of misfit/fit in applications of structural equation modeling. When the RMSEA is of interest, so too should be the accompanying confidence interval. A narrow confidence interval reveals that the plausible parameter values are confined to a relatively small range at the specified level of confidence. The accuracy in parameter estimation approach to sample size planning is developed for the RMSEA so that the confidence interval for the population RMSEA will have a width whose expectation is sufficiently narrow. Analytic developments are shown to work well with a Monte Carlo simulation study. Freely available computer software is developed so that the methods discussed can be implemented. The methods are demonstrated for a repeated measures design where the way in which social relationships and initial depression influence coping strategies and later depression are examined. PMID- 26771580 TI - Fractals, Vigilance, and Adolescent Diabetes Management: A Case for When Regulation May Be Difficult to Measure With the Current Medical Standards. AB - Temporal patterning in blood glucose (BG) consistent with fractals-how BG follows a repetitive pattern through resolutions of time-was used to examine 2 different samples of adolescents with Type 1 diabetes (10-14 years). Sample 1 contained 10 adolescents with longtime series for accurate estimations of long-term dependencies associated with fractals. The second contained 94 adolescents measured multiple times daily over a 2-week period corresponding to psychosocial measures. In both samples, temporal dependencies in BG showed patterns consistent with fractals. In the second sample, temporal dependencies were associated with indicators of vigilant regulation including adolescents' higher anxiety, mothers' higher monitoring, and intrusive support. The existence of temporal dependencies in BG moderated the relationship between glycosylated hemoglobin (HbA1c) and indicators of low BG risk but not the relationship between HbA1c and high BG risk. These results show how a biomedical indicator may be susceptible to metric issues associated with fractals. PMID- 26771581 TI - Robust Mokken Scale Analysis by Means of the Forward Search Algorithm for Outlier Detection. AB - Exploratory Mokken scale analysis (MSA) is a popular method for identifying scales from larger sets of items. As with any statistical method, in MSA the presence of outliers in the data may result in biased results and wrong conclusions. The forward search algorithm is a robust diagnostic method for outlier detection, which we adapt here to identify outliers in MSA. This adaptation involves choices with respect to the algorithm's objective function, selection of items from samples without outliers, and scalability criteria to be used in the forward search algorithm. The application of the adapted forward search algorithm for MSA is demonstrated using real data. Recommendations are given for its use in practical scale analysis. PMID- 26771578 TI - A Spatial Framework for Understanding Population Structure and Admixture. AB - Geographic patterns of genetic variation within modern populations, produced by complex histories of migration, can be difficult to infer and visually summarize. A general consequence of geographically limited dispersal is that samples from nearby locations tend to be more closely related than samples from distant locations, and so genetic covariance often recapitulates geographic proximity. We use genome-wide polymorphism data to build "geogenetic maps," which, when applied to stationary populations, produces a map of the geographic positions of the populations, but with distances distorted to reflect historical rates of gene flow. In the underlying model, allele frequency covariance is a decreasing function of geogenetic distance, and nonlocal gene flow such as admixture can be identified as anomalously strong covariance over long distances. This admixture is explicitly co-estimated and depicted as arrows, from the source of admixture to the recipient, on the geogenetic map. We demonstrate the utility of this method on a circum-Tibetan sampling of the greenish warbler (Phylloscopus trochiloides), in which we find evidence for gene flow between the adjacent, terminal populations of the ring species. We also analyze a global sampling of human populations, for which we largely recover the geography of the sampling, with support for significant histories of admixture in many samples. This new tool for understanding and visualizing patterns of population structure is implemented in a Bayesian framework in the program SpaceMix. PMID- 26771583 TI - 2010 Tanaka Award Winner. PMID- 26771582 TI - A Systematic Review of Propensity Score Methods in the Social Sciences. AB - The use of propensity scores in psychological and educational research has been steadily increasing in the last 2 to 3 years. However, there are some common misconceptions about the use of different estimation techniques and conditioning choices in the context of propensity score analysis. In addition, reporting practices for propensity score analyses often lack important details that allow other researchers to confidently judge the appropriateness of reported analyses and potentially to replicate published findings. In this article we conduct a systematic literature review of a large number of published articles in major areas of social science that used propensity scores up until the fall of 2009. We identify common errors in estimation, conditioning, and reporting of propensity score analyses and suggest possible solutions. PMID- 26771584 TI - Recognition of MBR Reviewers. PMID- 26771585 TI - Correction: Evaluation of the Genetic Basis of Familial Aggregation of Pacemaker Implantation by a Large Next Generation Sequencing Panel. PMID- 26771586 TI - An Efficient Next Hop Selection Algorithm for Multi-Hop Body Area Networks. AB - Body Area Networks (BANs) consist of various sensors which gather patient's vital signs and deliver them to doctors. One of the most significant challenges faced, is the design of an energy-efficient next hop selection algorithm to satisfy Quality of Service (QoS) requirements for different healthcare applications. In this paper, a novel efficient next hop selection algorithm is proposed in multi hop BANs. This algorithm uses the minimum hop count and a link cost function jointly in each node to choose the best next hop node. The link cost function includes the residual energy, free buffer size, and the link reliability of the neighboring nodes, which is used to balance the energy consumption and to satisfy QoS requirements in terms of end to end delay and reliability. Extensive simulation experiments were performed to evaluate the efficiency of the proposed algorithm using the NS-2 simulator. Simulation results show that our proposed algorithm provides significant improvement in terms of energy consumption, number of packets forwarded, end to end delay and packet delivery ratio compared to the existing routing protocol. PMID- 26771587 TI - Airborne Petcoke Dust is a Major Source of Polycyclic Aromatic Hydrocarbons in the Athabasca Oil Sands Region. AB - Oil sands mining has been linked to increasing atmospheric deposition of polycyclic aromatic hydrocarbons (PAHs) in the Athabasca oil sands region (AOSR), but known sources cannot explain the quantity of PAHs in environmental samples. PAHs were measured in living Sphagnum moss (24 sites, n = 68), in sectioned peat cores (4 sites, n = 161), and snow (7 sites, n = 19) from ombrotrophic bogs in the AOSR. Prospective source samples were also analyzed, including petroleum coke (petcoke, from both delayed and fluid coking), fine tailings, oil sands ore, and naturally exposed bitumen. Average PAH concentrations in near-field moss (199 ng/g, n = 11) were significantly higher (p = 0.035) than in far-field moss (118 ng/g, n = 13), and increasing temporal trends were detected in three peat cores collected closest to industrial activity. A chemical mass-balance model estimated that delayed petcoke was the major source of PAHs to living moss, and among three peat core the contribution to PAHs from delayed petcoke increased over time, accounting for 45-95% of PAHs in contemporary layers. Petcoke was also estimated to be a major source of vanadium, nickel, and molybdenum. Scanning electron microscopy with energy-dispersive X-ray spectroscopy confirmed large petcoke particles (>10 MUm) in snow at near-field sites. Petcoke dust has not previously been considered in environmental impact assessments of oil sands upgrading, and improved dust control from growing stockpiles may mitigate future risks. PMID- 26771588 TI - The Prevalence of Tuberculosis in Zambia: Results from the First National TB Prevalence Survey, 2013-2014. AB - BACKGROUND: Tuberculosis in Zambia is a major public health problem, however the country does not have reliable baseline data on the TB prevalence for impact measurement; therefore it was among the priority countries identified by the World Health Organization to conduct a national TB prevalence survey. OBJECTIVE: To estimate the prevalence of tuberculosis among the adult Zambian population aged 15 years and above, in 2013-2014. METHODS: A cross-sectional population based survey was conducted in 66 clusters across all the 10 provinces of Zambia. Eligible participants aged 15 years and above were screened for TB symptoms, had a chest x-ray (CXR) performed and were offered an HIV test. Participants with TB symptoms and/or CXR abnormality underwent an in-depth interview and submitted one spot- and one morning sputum sample for smear microscopy and liquid culture. Digital data collection methods were used throughout the process. RESULTS: Of the 98,458 individuals who were enumerated, 54,830 (55.7%) were eligible to participate, and 46,099 (84.1%) participated. Of those who participated, 45,633/46,099 (99%) were screened by both symptom assessment and chest x-ray, while 466/46,099 (1.01%) were screened by interview only. 6,708 (14.6%) were eligible to submit sputum and 6,154/6,708 (91.7%) of them submitted at least one specimen for examination. MTB cases identified were 265/6,123 (4.3%). The estimated national adult prevalence of smear, culture and bacteriologically confirmed TB was 319/100,000 (232-406/100,000); 568/100,000 (440-697/100,000); and 638/100,000 (502-774/100,000) population, respectively. The risk of having TB was five times higher in the HIV positive than HIV negative individuals. The TB prevalence for all forms was estimated to be 455 /100,000 population for all age groups. CONCLUSION: The prevalence of tuberculosis in Zambia was higher than previously estimated. Innovative approaches are required to accelerate the control of TB. PMID- 26771589 TI - High Milk-Clotting Activity Expressed by the Newly Isolated Paenibacillus spp. Strain BD3526. AB - Paenibacillus spp. BD3526, a bacterium exhibiting a protein hydrolysis circle surrounded with an obvious precipitation zone on skim milk agar, was isolated from raw yak (Bos grunniens) milk collected in Tibet, China. Phylogenetic analysis based on 16S rRNA and whole genome sequence comparison indicated the isolate belong to the genus Paenibacillus. The strain BD3526 demonstrated strong ability to produce protease with milk clotting activity (MCA) in wheat bran broth. The protease with MCA was predominantly accumulated during the late exponential phase of growth. The proteolytic activity (PA) of the BD3526 protease was 1.33-fold higher than that of the commercial R. miehei coagulant. A maximum MCA (6470 +/- 281 SU mL(-1)) of the strain BD3526 was reached under optimal cultivation conditions. The protease with MCA was precipitated from the cultivated supernatant of wheat bran broth with ammonium sulfate and purified by anion-exchange chromatography. The molecular weight of the protease with MCA was determined as 35 kDa by sodium dodecyl sulfate-polyacrylamide gels electrophoresis (SDS-PAGE) and gelatin zymography. The cleavage site of the BD3526 protease with MCA in kappa-casein was located at the Met106-Ala107 bond, as determined by mass spectrometry analysis. PMID- 26771590 TI - Chemical Structure-Related Drug-Like Criteria of Global Approved Drugs. AB - The chemical structure of a drug determines its physicochemical properties, further determines its ADME/Tox properties, and ultimately affects its pharmacological activity. Medicinal chemists can regulate the pharmacological activity of drug molecules by modifying their structure. Ring systems and functional groups are important components of a drug. The proportion of non hydrocarbon atoms among non-hydrogen atoms reflects the heavy atoms proportion of a drug. The three factors have considerable potential for the assessment of the drug-like properties of organic molecules. However, to the best of our knowledge, there have been no studies to systematically analyze the simultaneous effects of the number of aromatic and non-aromatic rings, the number of some special functional groups and the proportion of heavy atoms on the drug-like properties of an organic molecule. To this end, the numbers of aromatic and non-aromatic rings, the numbers of some special functional groups and the heavy atoms proportion of 6891 global approved small drugs have been comprehensively analyzed. We first uncovered three important structure-related criteria closely related to drug-likeness, namely: (1) the best numbers of aromatic and non aromatic rings are 2 and 1, respectively; (2) the best functional groups of candidate drugs are usually -OH, -COOR and -COOH in turn, but not -CONHOH, -SH, CHO and -SO3H. In addition, the -F functional group is beneficial to CNS drugs, and -NH2 functional group is beneficial to anti-infective drugs and anti-cancer drugs; (3) the best R value intervals of candidate drugs are in the range of 0.05 0.50 (preferably 0.10-0.35), and R value of the candidate CNS drugs should be as small as possible in this interval. We envision that the three chemical structure related criteria may be applicable in a prospective manner for the identification of novel candidate drugs and will provide a theoretical foundation for designing new chemical entities with good drug-like properties. PMID- 26771591 TI - Role of Nitric Oxide and Hydrogen Sulfide in the Vasodilator Effect of Ursolic Acid and Uvaol from Black Cherry Prunus serotina Fruits. AB - The present research aimed to isolate the non-polar secondary metabolites that produce the vasodilator effects induced by the dichloromethane extract of Prunus serotina (P. serotina) fruits and to determine whether the NO/cGMP and the H2S/KATP channel pathways are involved in their mechanism of action. A bioactivity-directed fractionation of the dichloromethane extract of P. serotina fruits led to the isolation of ursolic acid and uvaol as the main non-polar vasodilator compounds. These compounds showed significant relaxant effect on rat aortic rings in an endothelium- and concentration-dependent manner, which was inhibited by NG-nitro-L-arginine methyl ester (L-NAME), DL-propargylglycine (PAG) and glibenclamide (Gli). Additionally, both triterpenes increased NO and H2S production in aortic tissue. Molecular docking studies showed that ursolic acid and uvaol are able to bind to endothelial NOS and CSE with high affinity for residues that form the oligomeric interface of both enzymes. These results suggest that the vasodilator effect produced by ursolic acid and uvaol contained in P. serotina fruits, involves activation of the NO/cGMP and H2S/KATP channel pathways, possibly through direct activation of NOS and CSE. PMID- 26771592 TI - Antibacterial Activity and Antibiotic-Enhancing Effects of Honeybee Venom against Methicillin-Resistant Staphylococcus aureus. AB - Methicillin-resistant Staphylococcus aureus (MRSA), along with other antibiotic resistant bacteria, has become a significant social and clinical problem. There is thus an urgent need to develop naturally bioactive compounds as alternatives to the few antibiotics that remain effective. Here we assessed the in vitro activities of bee venom (BV), alone or in combination with ampicillin, penicillin, gentamicin or vancomycin, on growth of MRSA strains. The antimicrobial activity of BV against MRSA strains was investigated using minimum inhibitory concentrations (MIC), minimum bactericidal concentrations (MBC) and a time-kill assay. Expression of atl which encodes murein hydrolase, a peptidoglycan-degrading enzyme involved in cell separation, was measured by reverse transcription-polymerase chain reaction. The MICs of BV were 0.085 ug/mL and 0.11 ug/mL against MRSA CCARM 3366 and MRSA CCARM 3708, respectively. The MBC of BV against MRSA 3366 was 0.106 ug/mL and that against MRSA 3708 was 0.14 ug/mL. The bactericidal activity of BV corresponded to a decrease of at least 3 log CFU/g cells. The combination of BV with ampicillin or penicillin yielded an inhibitory concentration index ranging from 0.631 to 1.002, indicating a partial and indifferent synergistic effect. Compared to ampicillin or penicillin, both MRSA strains were more susceptible to the combination of BV with gentamicin or vancomycin. The expression of atl gene was increased in MRSA 3366 treated with BV. These results suggest that BV exhibited antibacterial activity and antibiotic enhancing effects against MRSA strains. The atl gene was increased in MRSA exposed to BV, suggesting that cell division was interrupted. BV warrants further investigation as a natural antimicrobial agent and synergist of antibiotic activity. PMID- 26771593 TI - Identification of Selective ERRgamma Inverse Agonists. AB - GSK5182 (4) is currently one of the lead compounds for the development of estrogen-related receptor gamma (ERRgamma) inverse agonists. Here, we report the design, synthesis, pharmacological and in vitro absorption, distribution, metabolism, excretion, toxicity (ADMET) properties of a series of compounds related to 4. Starting from 4, a series of analogs were structurally modified and their ERRgamma inverse agonist activity was measured. A key pharmacophore feature of this novel class of ligands is the introduction of a heterocyclic group for A ring substitution in the core scaffold. Among the tested compounds, several of them are potent ERRgamma inverse agonists as determined by binding and functional assays. The most promising compound, 15g, had excellent binding selectivity over related subtypes (IC50 = 0.44, >10, >10, and 10 MUM at the ERRgamma, ERRalpha, ERRbeta, and ERalpha subtypes, respectively). Compound 15g also resulted in 95% transcriptional repression at a concentration of 10 MUM, while still maintaining an acceptable in vitro ADMET profile. This novel class of ERRgamma inverse agonists shows promise in the development of drugs targeting ERRgamma-related diseases. PMID- 26771594 TI - The Structure-Activity Relationship of the Antioxidant Peptides from Natural Proteins. AB - Peptides derived from dietary proteins, have been reported to display significant antioxidant activity, which may exert notably beneficial effects in promoting human health and in food processing. Recently, much research has focused on the generation, separation, purification and identification of novel peptides from various protein sources. Some researchers have tried to discover the structural characteristics of antioxidant peptides in order to lessen or avoid the tedious and aimless work involving the ongoing generated peptide preparation schemes. This review aims to summarize the current knowledge on the relationship between the structural features of peptides and their antioxidant activities. The relationship between the structure of the precursor proteins and their abilities to release antioxidant fragments will also be summarized and inferred. The preparation methods and antioxidant capacity evaluation assays of peptides and a prediction scheme of quantitative structure-activity relationship (QSAR) will also be pointed out and discussed. PMID- 26771595 TI - Screening a Small Library of Xanthones for Antitumor Activity and Identification of a Hit Compound which Induces Apoptosis. AB - Our previous work has described a library of thioxanthones designed to have dual activity as P-glycoprotein modulators and antitumor agents. Some of these compounds had shown a significant cell growth inhibitory activity towards leukemia cell lines, without affecting the growth of non-tumor human fibroblasts. However, their effect in cell lines derived from solid tumors has not been previously studied. The present work aimed at: (i) screening this small series of compounds from an in-house library, for their in vitro cell growth inhibitory activity in human tumor cell lines derived from solid tumors; and (ii) initiate a study of the effect of the most potent compound on apoptosis. The tumor cell growth inhibitory effect of 27 compounds was first analysed in different human tumor cell lines, allowing the identification of a hit compound, TXA1. Its hydrochloride salt TXA1.HCl was then synthesized, to improve solubility and bioavailability. Both TXA1 and TXA1.HCl inhibited the growth of MCF-7, NCI-H460, A375-C5, HeLa, 786-O, Caki-2 and AGS cell lines. The effect of TXA1.HCl in MCF-7 cells was found to be irreversible and was associated, at least in part, with an increase in cellular apoptosis. PMID- 26771596 TI - Low Temperature Soda-Oxygen Pulping of Bagasse. AB - Wood shortages, environmental pollution and high energy consumption remain major obstacles hindering the development of today's pulp and paper industry. Energy saving and environmental friendly pulping processes are still needed, especially for non-woody materials. In this study, soda-oxygen pulping of bagasse was investigated and a successful soda-oxygen pulping process for bagasse at 100 degrees C was established. The pulping parameters of choice were under active alkali charge of 23%, maximum cooking temperature 100 degrees C, time hold at maximum temperature 180 min, initial pressure of oxygen 0.6 MPa, MgSO4 charge 0.5%, and de-pithed bagasse consistency 12%. Properties of the resultant pulp were screened yield 60.9%, Kappa number 14, viscosity 766 dm3/kg, and brightness 63.7% ISO. Similar pulps were also obtained at 110 degrees C or 105 degrees C with a cooking time of 90 min. Compared with pulps obtained at higher temperatures (115-125 degrees C), this pulp had higher screened yield, brightness, and acceptable viscosity, while the delignification degree was moderate. These results indicated that soda-oxygen pulping at 100 degrees C, the lowest cooking temperature reported so far for soda-oxygen pulping, is a suitable process for making chemical pulp from bagasse. Pulping at lower temperature and using oxygen make it an environmental friendly and energy-saving pulping process. PMID- 26771597 TI - Selective and Efficient Generation of ortho-Brominated para-Substituted Phenols in ACS-Grade Methanol. AB - The mono ortho-bromination of phenolic building blocks by NBS has been achieved in short reaction times (15-20 min) using ACS-grade methanol as a solvent. The reactions can be conducted on phenol, naphthol and biphenol substrates, giving yields of >86% on gram scale. Excellent selectivity for the desired mono ortho brominated products is achieved in the presence of 10 mol % para-TsOH, and the reaction is shown to be tolerant of a range of substituents, including CH3, F, and NHBoc. PMID- 26771600 TI - Possible Immune Regulation of Natural Killer T Cells in a Murine Model of Metal Ion-Induced Allergic Contact Dermatitis. AB - Metal often causes delayed-type hypersensitivity reactions, which are possibly mediated by accumulating T cells in the inflamed skin, called irritant or allergic contact dermatitis. However, accumulating T cells during development of a metal allergy are poorly characterized because a suitable animal model is unavailable. We have previously established novel murine models of metal allergy and found accumulation of both metal-specific T cells and natural killer (NK) T cells in the inflamed skin. In our novel models of metal allergy, skin hypersensitivity responses were induced through repeated sensitizations by administration of metal chloride and lipopolysaccharide into the mouse groin followed by metal chloride challenge in the footpad. These models enabled us to investigate the precise mechanisms of the immune responses of metal allergy in the inflamed skin. In this review, we summarize the immune responses in several murine models of metal allergy and describe which antigen-specific responses occur in the inflamed skin during allergic contact dermatitis in terms of the T cell receptor. In addition, we consider the immune regulation of accumulated NK T cells in metal ion-induced allergic contact dermatitis. PMID- 26771598 TI - Obesity and Its Potential Effects on Antidepressant Treatment Outcomes in Patients with Depressive Disorders: A Literature Review. AB - Accumulating evidence regarding clinical, neurobiological, genetic, and environmental factors suggests a bidirectional link between obesity and depressive disorders. Although a few studies have investigated the link between obesity/excess body weight and the response to antidepressants in depressive disorders, the effect of weight on treatment response remains poorly understood. In this review, we summarized recent data regarding the relationship between the response to antidepressants and obesity/excess body weight in clinical studies of patients with depressive disorders. Although several studies indicated an association between obesity/excess body weight and poor antidepressant responses, it is difficult to draw definitive conclusions due to the variability of subject composition and methodological differences among studies. Especially, differences in sex, age and menopausal status, depressive symptom subtypes, and antidepressants administered may have caused inconsistencies in the results among studies. The relationship between obesity/excess body weight and antidepressant responses should be investigated further in high-powered studies addressing the differential effects on subject characteristics and treatment. Moreover, future research should focus on the roles of mediating factors, such as inflammatory markers and neurocognitive performance, which may alter the antidepressant treatment outcome in patients with comorbid obesity and depressive disorder. PMID- 26771599 TI - Insights into Mechanisms of Chronic Neurodegeneration. AB - Chronic neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and prion diseases are characterised by the accumulation of abnormal conformers of a host encoded protein in the central nervous system. The process leading to neurodegeneration is still poorly defined and thus development of early intervention strategies is challenging. Unique amongst these diseases are Transmissible Spongiform Encephalopathies (TSEs) or prion diseases, which have the ability to transmit between individuals. The infectious nature of these diseases has permitted in vivo and in vitro modelling of the time course of the disease process in a highly reproducible manner, thus early events can be defined. Recent evidence has demonstrated that the cell-to-cell spread of protein aggregates by a "prion-like mechanism" is common among the protein misfolding diseases. Thus, the TSE models may provide insights into disease mechanisms and testable hypotheses for disease intervention, applicable to a number of these chronic neurodegenerative diseases. PMID- 26771602 TI - Altered Pre-mRNA Splicing Caused by a Novel Intronic Mutation c.1443+5G>A in the Dihydropyrimidinase (DPYS) Gene. AB - Dihydropyrimidinase (DHP) deficiency is an autosomal recessive disease caused by mutations in the DPYS gene. Patients present with highly elevated levels of dihydrouracil and dihydrothymine in their urine, blood and cerebrospinal fluid. The analysis of the effect of mutations in DPYS on pre-mRNA splicing is hampered by the fact that DHP is primarily expressed in liver and kidney cells. The minigene approach can detect mRNA splicing aberrations using cells that do not express the endogenous mRNA. We have used a minigene-based approach to analyze the effects of a presumptive pre-mRNA splicing mutation in two newly identified Chinese pediatric patients with DHP deficiency. Mutation analysis of DPYS showed that both patients were compound heterozygous for a novel intronic mutation c.1443+5G>A in intron 8 and a previously described missense mutation c.1001A>G (p.Q334R) in exon 6. Wild-type and the mutated minigene constructs, containing exons 7, 8 and 9 of DPYS, yielded different splicing products after expression in HEK293 cells. The c.1443+5G>A mutation resulted in altered pre-mRNA splicing of the DPYS minigene construct with full skipping of exon 8. Analysis of the DHP crystal structure showed that the deletion of exon 8 severely affects folding, stability and homooligomerization of the enzyme as well as disruption of the catalytic site. Thus, the analysis suggests that the c.1443+5G>A mutation results in aberrant splicing of the pre-mRNA encoding DHP, underlying the DHP deficiency in two unrelated Chinese patients. PMID- 26771601 TI - Aneurysm miRNA Signature Differs, Depending on Disease Localization and Morphology. AB - Limited comprehension of aneurysm pathology has led to inconclusive results from clinical trials. miRNAs are key regulators of post-translational gene modification and are useful tools in elucidating key features of aneurysm pathogenesis in distinct entities of abdominal and popliteal aneurysms. Here, surgically harvested specimens from 19 abdominal aortic aneurysm (AAA) and 8 popliteal artery aneurysm (PAA) patients were analyzed for miRNA expression and histologically classified regarding extracellular matrix (ECM) remodeling and inflammation. DIANA-based computational target prediction and pathway enrichment analysis verified our results, as well as previous ones. miRNA-362, -19b-1, -194, -769, -21 and -550 were significantly down-regulated in AAA samples depending on degree of inflammation. Similar or inverse regulation was found for miR-769, 19b 1 and miR-550, -21, whereas miR-194 and -362 were unaltered in PAA. In situ hybridization verified higher expression of miR-550 and -21 in PAA compared to AAA and computational analysis for target genes and pathway enrichment affirmed signal transduction, cell-cell-interaction and cell degradation pathways, in line with previous results. Despite the vague role of miRNAs for potential diagnostic and treatment purposes, the number of candidates from tissue signature studies is increasing. Tissue morphology influences subsequent research, yet comparison of distinct entities of aneurysm disease can unravel core pathways. PMID- 26771603 TI - Post-Translational Modification and Secretion of Azelaic Acid Induced 1 (AZI1), a Hybrid Proline-Rich Protein from Arabidopsis. AB - Arabidopsis EARLI-type hybrid proline-rich proteins (HyPRPs) consist of a putative N-terminal secretion signal, a proline-rich domain (PRD), and a characteristic eight-cysteine-motif (8-CM). They have been implicated in biotic and abiotic stress responses. AZI1 is required for systemic acquired resistance and it has recently been identified as a target of the stress-induced mitogen activated protein kinase MPK3. AZI1 gel migration properties strongly indicate AZI1 to undergo major post-translational modifications. These occur in a stress independent manner and are unrelated to phosphorylation by MAPKs. As revealed by transient expression of AZI1 in Nicotiana benthamiana and Tropaeolum majus, the Arabidopsis protein is similarly modified in heterologous plant species. Proline rich regions, resembling arabinogalactan proteins point to a possible proline hydroxylation and subsequent O-glycosylation of AZI1. Consistently, inhibition of prolyl hydroxylase reduces its apparent protein size. AZI1 secretion was examined using Arabidopsis protoplasts and seedling exudates. Employing Agrobacterium mediated leaf infiltration of N. benthamiana, we attempted to assess long distance movement of AZI1. In summary, the data point to AZI1 being a partially secreted protein and a likely new member of the group of hydroxyproline-rich glycoproteins. Its dual location suggests AZI1 to exert both intra- and extracellular functions. PMID- 26771604 TI - Individualized Follow-up of Pregnant Women with Asymptomatic Autoimmune Thyroid Disease. AB - Maternal hormones are essential for the normal fetal development during pregnancy. Autoimmune thyroid disease is a frequent pathology in our iodine replete region. The aim of this study is to evaluate the occurrence of subclinical hypothyroidism (SCH) in cases with known autoimmune thyroid disease, which were in a euthyroid state prior to pregnancy, and to assess the association between supplemental treatments administered and the outcome of the pregnancy. The study is a prospective interventional controlled study. The two cohorts comprise the interventional group, consisting of 109 pregnant women with known autoimmune asymptomatic thyroid disease, without any levothyroxine (LT4) treatment and an aged-matched control group, with an unknown thyroid disease. After the pregnancy, a monthly evaluation of TSH, FT3, and FT4 was performed. Offspring evaluation was made at birth time. 88.8% of the women developed SCH in the first four weeks of pregnancy. Average LT4 doses increased as the pregnancy progressed. The monthly adjustment was 12.5 or 25 MUg. All SCH cases developed in the first trimester of pregnancy. There was no significant difference regarding the gestational week, weight, or length at birth between the interventional group and controls, when TSH values were in the optimal range, during the whole pregnancy. Premature birth was described in one case in the interventional group. PMID- 26771606 TI - Transactivation of Epidermal Growth Factor Receptor by G Protein-Coupled Receptors: Recent Progress, Challenges and Future Research. AB - Both G protein-coupled receptors (GPCRs) and receptor-tyrosine kinases (RTKs) regulate large signaling networks, control multiple cell functions and are implicated in many diseases including various cancers. Both of them are also the top therapeutic targets for disease treatment. The discovery of the cross-talk between GPCRs and RTKs connects these two vast signaling networks and complicates the already complicated signaling networks that regulate cell signaling and function. In this review, we focus on the transactivation of epidermal growth factor receptor (EGFR), a subfamily of RTKs, by GPCRs. Since the first report of EGFR transactivation by GPCR, significant progress has been made including the elucidation of the mechanisms underlying the transactivation. Here, we first provide a basic picture for GPCR, EGFR and EGFR transactivation by GPCR. We then discuss the progress made in the last five years and finally provided our view of the future challenge and future researches needed to overcome these challenges. PMID- 26771607 TI - Enrichment of Secondary Wastewater Sludge for Production of Hydrogen from Crude Glycerol and Comparative Evaluation of Mono-, Co- and Mixed-Culture Systems. AB - Anaerobic digestion using mixed-culture with broader choice of pretreatments for hydrogen (H2) production was investigated. Pretreatment of wastewater sludge by five methods, such as heat, acid, base, microwave and chloroform was conducted using crude glycerol (CG) as substrate. Results for heat treatment (100 degrees C for 15 min) showed the highest H2 production across the pretreatment methods with 15.18 +/- 0.26 mmol/L of medium at 30 degrees C in absence of complex media and nutrient solution. The heat-pretreated inoculum eliminated H2 consuming bacteria and produced twice as much as H2 as compared to other pretreatment methods. The fermentation conditions, such as CG concentration (1.23 to 24 g/L), percentage of inoculum size (InS) (1.23% to 24% v/v) along with initial pH (2.98 to 8.02) was tested using central composite design (CCD) with H2 production as response parameter. The maximum H2 production of 29.43 +/- 0.71 mmol/L obtained at optimum conditions of 20 g/L CG, 20% InS and pH 7. Symbiotic correlation of pH over CG and InS had a significant (p-value: 0.0011) contribution to H2 production. The mixed-culture possessed better natural acclimatization activity for degrading CG, at substrate inhibition concentration and provided efficient inoculum conditions in comparison to mono- and co-culture systems. The heat pretreatment step used across mixed-culture system is simple, cheap and industrially applicable in comparison to mono-/co-culture systems for H2 production. PMID- 26771605 TI - Survivin Modulates Squamous Cell Carcinoma-Derived Stem-Like Cell Proliferation, Viability and Tumor Formation in Vivo. AB - Squamous Cell Carcinoma-derived Stem-like Cells (SCC-SC) originate from alterations in keratinocyte stem cells (KSC) gene expression and sustain tumor development, invasion and recurrence. Since survivin, a KSC marker, is highly expressed in SCC-SC, we evaluate its role in SCC-SC cell growth and SCC models. Survivin silencing by siRNA decreases clonal growth of SCC keratinocytes and viability of total, rapidly adhering (RAD) and non-RAD (NRAD) cells from primary SCC. Similarly, survivin silencing reduces the expression of stem cell markers (OCT4, NOTCH1, CD133, beta1-integrin), while it increases the level of differentiation markers (K10, involucrin). Moreover, survivin silencing improves the malignant phenotype of SCC 3D-reconstruct, as demonstrated by reduced epidermal thickness, lower Ki-67 positive cell number, and decreased expression of MMP9 and psoriasin. Furthermore, survivin depletion by siRNA in Ras(G12V) IkappaBalpha-derived tumors leads to smaller tumor formation characterized by lower mitotic index and reduced expression of the tumor-associated marker HIF1alpha, VEGF and CD51. Therefore, our results indicate survivin as a key gene in regulating SCC cancer stem cell formation and cSCC development. PMID- 26771609 TI - Overexpression of PRL7D1 in Leydig Cells Causes Male Reproductive Dysfunction in Mice. AB - Prolactin family 7, subfamily d, member 1 (PRL7D1) is found in mouse placenta. Our recent work showed that PRL7D1 is also present in mouse testis Leydig cells, and the expression of PRL7D1 in the testis exhibits an age-related increase. In the present study, we generated transgenic mice with Leydig cell-specific PRL7D1 overexpression to explore its function during male reproduction. Prl7d1 male mice exhibited subfertility as reflected by reduced sperm counts and litter sizes. The testes from Prl7d1 transgenic mice appeared histologically normal, but the frequency of apoptotic germ cells was increased. Prl7d1 transgenic mice also had lower testosterone concentrations than wild-type mice. Mechanistic studies revealed that Prl7d1 transgenic mice have defects in the testicular expression of steroidogenic acute regulatory protein (STAR) and hydroxy-delta-5-steroid dehydrogenase, 3 beta- and steroid delta-isomerase cluster (HSD3B). Further studies revealed that PRL7D1 overexpression affected the expression of transferrin (TF) in Sertoli cells. These results suggest that PRL7D1 overexpression could lead to increased germ cell apoptosis and exert an inhibitory effect on testosterone production in Leydig cells by reducing the expression of certain steroidogenic-related genes. In addition, PRL7D1 appears to have important roles in the function of Sertoli cells, which, in turn, affects male fertility. We conclude that the expression level of PRL7D1 is associated with the reproductive function of male mice. PMID- 26771610 TI - Optimizing a Male Reproductive Aging Mouse Model by D-Galactose Injection. AB - The d-galactose (d-gal)-injected animal model, which is typically established by administering consecutive subcutaneous d-gal injections to animals for approximately six or eight weeks, has been frequently used for aging research. In addition, this animal model has been demonstrated to accelerate aging in the brain, kidneys, liver and blood cells. However, studies on aging in male reproductive organs that have used this animal model remain few. Therefore, the current study aimed to optimize a model of male reproductive aging by administering d-gal injections to male mice and to determine the possible mechanism expediting senescence processes during spermatogenesis. In this study, C57Bl/6 mice were randomized into five groups (each containing 8-10 mice according to the daily intraperitoneal injection of vehicle control or 100 or 200 mg/kg dosages of d-gal for a period of six or eight weeks). First, mice subjected to d-gal injections for six or eight weeks demonstrated considerably decreased superoxide dismutase activity in the serum and testis lysates compared to those in the control group. The lipid peroxidation in testis also increased in the d gal-injected groups. Furthermore, the d-gal-injected groups exhibited a decreased ratio of testis weight/body weight and sperm count compared to the control group. The percentages of both immotile sperm and abnormal sperm increased considerably in the d-gal-injected groups compared to those of the control group. To determine the genes influenced by the d-gal injection during murine spermatogenesis, a c DNA microarray was conducted to compare testicular RNA samples between the treated groups and the control group. The d-gal-injected groups exhibited RNA transcripts of nine spermatogenesis-related genes (Cycl2, Hk1, Pltp, Utp3, Cabyr, Zpbp2, Speer2, Csnka2ip and Katnb1) that were up- or down-regulated by at least two-fold compared to the control group. Several of these genes are critical for forming sperm-head morphologies or maintaining nuclear integration (e.g., cylicin, basic protein of sperm head cytoskeleton 2 (Cylc2), casein kinase 2, alpha prime interacting protein (Csnka2ip) and katanin p80 (WD40-containing) subunit B1 (Katnb1)). These results indicate that d-gal-injected mice are suitable for investigating male reproductive aging. PMID- 26771612 TI - Steady State Response Analysis of a Tubular Piezoelectric Print Head. AB - In recent years, inkjet technology has played an important role in industrial materials printing and various sensors fabrication, but the mechanisms of the inkjet print head should be researched more elaborately. The steady state deformation analysis of a tubular piezoelectric print head, which can be classified as a plane strain problem because the radii of the tubes are considerably smaller than the lengths, is discussed in this paper. The geometric structure and the boundary conditions are all axisymmetric, so a one-dimensional mathematical model is constructed. By solving the model, the deformation field and stress field, as well as the electric potential distribution of the piezoelectric tube and glass tube, are obtained. The results show that the deformations are on the nanometer scale, the hoop stress is larger than the radial stress on the whole, and the potential is not linearly distributed along the radial direction. An experiment is designed to validate these computations. A discussion of the effect of the tubes' thicknesses on the system deformation status is provided. PMID- 26771611 TI - Nonalcoholic Fatty Liver Disease: Pros and Cons of Histologic Systems of Evaluation. AB - The diagnostic phenotype of nonalcoholic fatty liver disease (NAFLD)--in particular, the most significant form in terms of prognosis, nonalcoholic steatohepatitis (NASH)--continues to rely on liver tissue evaluation, in spite of remarkable advances in non-invasive algorithms developed from serum-based tests and imaging-based or sonographically-based tests for fibrosis or liver stiffness. The most common tissue evaluation remains percutaneous liver biopsy; considerations given to the needle size and the location of the biopsy have the potential to yield the most representative tissue for evaluation. The pathologist's efforts are directed to not only global diagnosis, but also assessment of severity of injury. Just as in other forms of chronic liver disease, these assessments can be divided into necroinflammatory activity, and fibrosis with parenchymal remodeling, in order to separately analyze potentially reversible (grade) and non-reversible (stage) lesions. These concepts formed the bases for current methods of evaluating the lesions that collectively comprise the phenotypic spectra of NAFLD. Four extant methods have specific applications; there are pros and cons to each, and this forms the basis of the review. PMID- 26771613 TI - A New Approach to Detection of Systematic Errors in Secondary Substation Monitoring Equipment Based on Short Term Load Forecasting. AB - In recent years, Secondary Substations (SSs) are being provided with equipment that allows their full management. This is particularly useful not only for monitoring and planning purposes but also for detecting erroneous measurements, which could negatively affect the performance of the SS. On the other hand, load forecasting is extremely important since they help electricity companies to make crucial decisions regarding purchasing and generating electric power, load switching, and infrastructure development. In this regard, Short Term Load Forecasting (STLF) allows the electric power load to be predicted over an interval ranging from one hour to one week. However, important issues concerning error detection by employing STLF has not been specifically addressed until now. This paper proposes a novel STLF-based approach to the detection of gain and offset errors introduced by the measurement equipment. The implemented system has been tested against real power load data provided by electricity suppliers. Different gain and offset error levels are successfully detected. PMID- 26771614 TI - A Compact Fiber Inclinometer Using a Thin-Core Fiber with Incorporated an Air-Gap Microcavity Fiber Interferometer. AB - A compact fiber-optic inclinometer is proposed and experimentally demonstrated based on a Fabry-Perot interference (FFPI). The sensing head consists of a short segment of thin-core fiber (TCF) following with a piece of hollow-core fiber (HCF). High-order cladding modes have been excited because of core diameter mismatch. A clear interference spectrum has been obtained as the consequence of interference among the reflected core modes and cladding modes. Fringe contrast of the interference spectrum is highly sensitive to fiber bending with direction independence, and good linearity has been observed during the bending range from 1 degrees to 3 degrees with a sensitivity of 2.71 dB/deg. PMID- 26771608 TI - miRNAs Regulation and Its Role as Biomarkers in Endometriosis. AB - MicroRNAs (miRNAs) are small non-coding RNAs (18-22 nt) that function as modulators of gene expression. Since their discovery in 1993 in C. elegans, our knowledge about their biogenesis, function, and mechanism of action has increased enormously, especially in recent years, with the development of deep-sequencing technologies. New biogenesis pathways and sources of miRNAs are changing our concept about these molecules. The study of the miRNA contribution to pathological states is a field of great interest in research. Different groups have reported the implication of miRNAs in pathologies such as cancer, diabetes, cardiovascular, and gynecological diseases. It is also well-known that miRNAs are present in biofluids (plasma, serum, urine, semen, and menstrual blood) and have been proposed as ideal candidates as disease biomarkers. The goal of this review is to highlight the current knowledge in the field of miRNAs with a special emphasis to their role in endometriosis and the newest investigations addressing the use of miRNAs as biomarkers for this gynecological disease. PMID- 26771615 TI - Identification of Shearer Cutting Patterns Using Vibration Signals Based on a Least Squares Support Vector Machine with an Improved Fruit Fly Optimization Algorithm. AB - Shearers play an important role in fully mechanized coal mining face and accurately identifying their cutting pattern is very helpful for improving the automation level of shearers and ensuring the safety of coal mining. The least squares support vector machine (LSSVM) has been proven to offer strong potential in prediction and classification issues, particularly by employing an appropriate meta-heuristic algorithm to determine the values of its two parameters. However, these meta-heuristic algorithms have the drawbacks of being hard to understand and reaching the global optimal solution slowly. In this paper, an improved fly optimization algorithm (IFOA) to optimize the parameters of LSSVM was presented and the LSSVM coupled with IFOA (IFOA-LSSVM) was used to identify the shearer cutting pattern. The vibration acceleration signals of five cutting patterns were collected and the special state features were extracted based on the ensemble empirical mode decomposition (EEMD) and the kernel function. Some examples on the IFOA-LSSVM model were further presented and the results were compared with LSSVM, PSO-LSSVM, GA-LSSVM and FOA-LSSVM models in detail. The comparison results indicate that the proposed approach was feasible, efficient and outperformed the others. Finally, an industrial application example at the coal mining face was demonstrated to specify the effect of the proposed system. PMID- 26771616 TI - A Sensitivity Enhanced MWCNT/PDMS Tactile Sensor Using Micropillars and Low Energy Ar+ Ion Beam Treatment. AB - High sensitive flexible and wearable devices which can detect delicate touches have attracted considerable attentions from researchers for various promising applications. This research was aimed at enhancing the sensitivity of a MWCNT/PDMS piezoresistive tactile sensor through modification of its surface texture in the form of micropillars on MWCNT/PDMS film and subsequent low energy Ar+ ion beam treatment of the micropillars. The introduction of straight micropillars on the MWCNT/PDMS surface increased the sensitivity under gentle touch. Low energy ion beam treatment was performed to induce a stiff layer on the exposed surface of the micropillar structured MWCNT/PDMS film. The low energy ion bombardment stabilized the electrical properties of the MWCNT/PDMS surface and tuned the curvature of micropillars according to the treatment conditions. The straight micropillars which were treated by Ar+ ion with an incident angle of 0 degrees demonstrated the enhanced sensitivity under normal pressure and the curved micropillars which were treated with Ar+ ion with an incident angle of 60 degrees differentiated the direction of an applied shear pressure. The ion beam treatment on micropillar structured MWCNT/PDMS tactile sensors can thus be applied to reliable sensing under gentle touch with directional discrimination. PMID- 26771617 TI - Lead-Free Piezoelectric Diaphragm Biosensors Based on Micro-Machining Technology and Chemical Solution Deposition. AB - In this paper, we present a new approach to the fabrication of integrated silicon based piezoelectric diaphragm-type biosensors by using sodium potassium niobate silver niobate (0.82KNN-0.18AN) composite lead-free thin film as the piezoelectric layer. The piezoelectric diaphragms were designed and fabricated by micro-machining technology and chemical solution deposition. The fabricated device was very sensitive to the mass changes caused by various targets attached on the surface of diaphragm. The measured mass sensitivity value was about 931 Hz/MUg. Its good performance shows that the piezoelectric diaphragm biosensor can be used as a cost-effective platform for nucleic acid testing. PMID- 26771618 TI - A Virtual Blind Cane Using a Line Laser-Based Vision System and an Inertial Measurement Unit. AB - A virtual blind cane system for indoor application, including a camera, a line laser and an inertial measurement unit (IMU), is proposed in this paper. Working as a blind cane, the proposed system helps a blind person find the type of obstacle and the distance to it. The distance from the user to the obstacle is estimated by extracting the laser coordinate points on the obstacle, as well as tracking the system pointing angle. The paper provides a simple method to classify the obstacle's type by analyzing the laser intersection histogram. Real experimental results are presented to show the validity and accuracy of the proposed system. PMID- 26771619 TI - 3,1-Benzothiazines, 1,4-Benzodioxines and 1,4-Benzoxazines as Inhibitors of Matriptase-2: Outcome of a Focused Screening Approach. AB - The liver enzyme matriptase-2 is a multi-domain, transmembrane serine protease with an extracellular, C-terminal catalytic domain. Synthetic low-molecular weight inhibitors of matriptase-2 have potential as therapeutics to treat iron overload syndromes, in particular in patients with beta-thalassemia. A sub library of 64 compounds was screened for matriptase-2 inhibition and several active compounds were identified. (S)-Ethyl 2-(benzyl(3-((4 carbamidoylphenoxy)methyl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)amino)-2 oxoacetate ((S)-12) showed an IC50 value of less than 10 uM. Structure-activity relationships were discussed and proposals to design new matriptase-2 inhibitors were made. PMID- 26771620 TI - Cyanobacterial Metabolite Calothrixins: Recent Advances in Synthesis and Biological Evaluation. AB - The marine environment is host to unparalleled biological and chemical diversity, making it an attractive resource for the discovery of new therapeutics for a plethora of diseases. Compounds that are extracted from cyanobacteria are of special interest due to their unique structural scaffolds and capacity to produce potent pharmaceutical and biotechnological traits. Calothrixins A and B are two cyanobacterial metabolites with a structural assembly of quinoline, quinone, and indole pharmacophores. This review surveys recent advances in the synthesis and evaluation of the biological activities of calothrixins. Due to the low isolation yields from the marine source and the promise this scaffold holds for anticancer and antimicrobial drugs, organic and medicinal chemists around the world have embarked on developing efficient synthetic routes to produce calothrixins. Since the first review appeared in 2009, 11 novel syntheses of calothrixins have been published in the efforts to develop methods that contain fewer steps and higher yielding reactions. Calothrixins have shown their potential as topoisomerase I poisons for their cytotoxicity in cancer. They have also been observed to target various aspects of RNA synthesis in bacteria. Further investigation into the exact mechanism for their bioactivity is still required for many of its analogs. PMID- 26771621 TI - Five New Cytotoxic Metabolites from the Marine Fungus Neosartorya pseudofischeri. AB - The marine fungus Neosartorya pseudofischeri was isolated from Acanthaster planci from the South China Sea. In a preliminary bioactivity screening, the crude methanol extract of the fungal mycelia showed significant inhibitory activity against the Sf9 cell line from the fall armyworm Spodoptera frugiperda. Five novel compounds, including 5-olefin phenylpyropene A (1), 13 dehydroxylpyripyropene A (4), deacetylsesquiterpene (7), 5-formyl-6-hydroxy-8 isopropyl-2- naphthoic acid (9) and 6,8-dihydroxy-3-((1E,3E)-penta-1,3-dien-1 yl)isochroman-1-one (10), together with eleven known compounds, phenylpyropene A (2) and C (3), pyripyropene A (5), 7-deacetylpyripyropene A (6), (1S,2R,4aR,5R,8R,8aR)-1,8a-dihydroxy-2-acetoxy-3,8-dimethyl-5- (prop-1-en-2-yl) 1,2,4a, 5,6,7,8,8a-octahydronaphthalene (8), isochaetominine C (11), trichodermamide A (12), indolyl-3-acetic acid methyl ester (13), 1-acetyl-beta carboline (14), 1,2,3,4-tetrahydro-6-hydroxyl-2-methyl-l,3,4-trioxopyrazino[l,2 a]-indole (15) and fumiquinazoline F (16), were obtained. The structures of these compounds were determined mainly by MS and NMR data. The absolute configuration of 9 was assigned by the single-crystal X-ray diffraction studies. Compounds 1-11 and 15 showed significant cytotoxicity against the Sf9 cells from S. frugiperda. PMID- 26771622 TI - Changes in Depression and Stress after Release from a Tobacco-Free Prison in the United States. AB - Prior research has found high levels of depression and stress among persons who are incarcerated in the United States (U.S.). However, little is known about changes in depression and stress levels among inmates post-incarceration. The aim of this study was to examine changes in levels of depression and stress during and after incarceration in a tobacco-free facility. Questionnaires that included valid and reliable measures of depression and stress were completed by 208 male and female inmates approximately eight weeks before and three weeks after release from a northeastern U.S. prison. Although most inmates improved after prison, 30.8% had a worsening in levels of depression between baseline and the three-week follow-up. In addition, 29.8% had a worsening in levels of stress after release than during incarceration. While it is not surprising that the majority of inmates reported lower levels of depression and stress post-incarceration, a sizable minority had an increase in symptoms, suggesting that environmental stressors may be worse in the community than in prison for some inmates. Further research is needed to address depression and stress levels during and after incarceration in order for inmates to have a healthier transition back into the community and to prevent repeat incarcerations. PMID- 26771623 TI - Urban Natural Environments, Obesity, and Health-Related Quality of Life among Hispanic Children Living in Inner-City Neighborhoods. AB - Although a substantial body of literature has provided evidence supporting the positive effects of natural environments on well-being, little has been known about the specific spatial patterns of urban nature in promoting health-related quality of life (HRQOL) among children. This study assessed the association that the urban natural environment measured by landscape spatial patterns may have with obesity and HRQOL among Hispanic children. Ninety-two 4th and 5th grade students were recruited from Houston, Texas, and the Pediatric Quality of Life Inventory (PedsQL) was used to capture the children's HRQOL. The quality of urban natural environments was assessed by quantifying the landscape spatial patterns, using landscape indices generated by Geographic Information Systems and remote sensing. From the bivariate analyses, children's body mass index showed a significantly negative association with their HRQOL. After controlling for socio demographic factors, the results revealed that larger and more tree areas were positively correlated with children's HRQOL. In addition, those children living in areas with tree patches further apart from each other showed higher HRQOL. This research adds to the current multi-disciplinary area of research on environment-health relationships by investigating the roles of urban greeneries and linking their spatial structures with children's HRQOL. PMID- 26771624 TI - Cigarette Smoking and Electronic Cigarettes Use: A Meta-Analysis. AB - Increasing evidence indicates that cigarette smoking is a strong predictor of electronic cigarettes (e-cigarettes) use, particularly in adolescents, yet the effects has not be systematically reviewed and quantified. Relevant studies were retrieved by searching three databases up to June 2015. The meta-analysis results were presented as pooled odds ratios (ORs) with 95% confidence intervals (CIs) calculated by a random-effects model. Current smokers were more likely to use e cigarette currently (OR: 14.89, 95% CI: 7.70-28.78) and the probability was greater in adolescents than in adults (39.13 vs. 7.51). The probability of ever e cigarettes use was significantly increased in smokers (OR: 14.67, 95% CI: 11.04 19.49). Compared with ever smokers and adults, the probabilities were much greater in current smokers (16.10 vs. 9.47) and adolescents (15.19 vs. 14.30), respectively. Cigarette smoking increases the probability of e-cigarettes use, especially in current smokers and adolescents. PMID- 26771625 TI - The Use of Illegal Drugs and Infectious Contagious Diseases: Knowledge and Intervention among Dockworkers. AB - This study's objective was to analyze the use of illegal drugs by dockworkers and provide risk communication regarding the use of illegal drugs and test for infectious contagious diseases among dockworkers. This cross-sectional study including an intervention addressed to 232 dockworkers, who were individually interviewed, as well as communication of risk with testing for infectious contagious diseases for 93 dockworkers from a city in the interior of Rio Grande do Sul, Brazil. Poisson regression analysis was used. Twenty-nine workers reported the use of illegal drugs. Poisson regression indicated that being a wharfage worker, smoker, having a high income, and heavier workload increases the prevalence of the use of illegal drugs. During risk communication, two workers were diagnosed with hepatitis B (2.2%), three (3.2%) with hepatitis C, two (2.2%) with syphilis. None of the workers, though, had HIV. This study provides evidence that can motivate further research on the topic and also lead to treatment of individuals to improve work safety, productivity, and the health of workers. PMID- 26771627 TI - Back-Analyses of Landfill Instability Induced by High Water Level: Case Study of Shenzhen Landfill. AB - In June 2008, the Shenzhen landfill slope failed. This case is used as an example to study the deformation characteristics and failure mode of a slope induced by high water levels. An integrated monitoring system, including water level gauges, electronic total stations, and inclinometers, was used to monitor the slope failure process. The field measurements suggest that the landfill landslide was caused by a deep slip along the weak interface of the composite liner system at the base of the landfill. The high water level is considered to be the main factor that caused this failure. To calculate the relative interface shear displacements in the geosynthetic multilayer liner system, a series of numerical direct shear tests were carried out. Based on the numerical results, the composite lining system simplified and the centrifuge modeling technique was used to quantitatively evaluate the effect of water levels on landfill instability. PMID- 26771626 TI - Differences in Ambient Polycyclic Aromatic Hydrocarbon Concentrations between Streets and Alleys in New York City: Open Space vs. Semi-Closed Space. AB - BACKGROUND: Outdoor ambient polycyclic aromatic hydrocarbon (PAH) concentrations are variable throughout an urban environment. However, little is known about how variation in semivolatile and nonvolatile PAHs related to the built environment (open space vs. semi-closed space) contributes to differences in concentrations. METHODS: We simultaneously collected 14, two-week samples of PAHs from the outside of windows facing the front (adjacent to the street) open side of a New York City apartment building and the alley, semi-closed side of the same apartment unit between 2007 and 2012. We also analyzed samples of PAHs measured from 35 homes across Northern Manhattan and the Bronx, 17 from street facing windows with a median floor level of 4 (range 2-26) and 18 from alley-facing windows with a median floor level of 4 (range 1-15). RESULTS: Levels of nonvolatile ambient PAHs were significantly higher when measured from a window adjacent to a street (an open space), compared to a window 30 feet away, adjacent to an alley (a semi-closed space) (street geometric mean (GM) 1.32 ng/m3, arithmetic mean +/- standard deviation (AM +/- SD) 1.61 +/- 1.04 ng/m3; alley GM 1.10 ng/m3, AM +/- SD 1.37 +/- 0.94 ng/m3). In the neighborhood-wide comparison, nonvolatile PAHs were also significantly higher when measured adjacent to streets compared with adjacent to alley sides of apartment buildings (street GM 1.10 ng/m3, AM +/- SD 1.46 +/- 1.24 ng/m3; alley GM 0.61 ng/m3, AM +/- SD 0.81 +/- 0.80 ng/m3), but not semivolatile PAHs. CONCLUSIONS: Ambient PAHs, nonvolatile PAHs in particular, are significantly higher when measured from a window adjacent to a street compared to a window adjacent to an alley, despite both locations being relatively close to street traffic. This study highlights small-scale spatial variations in ambient PAH concentrations that may be related to the built environment (open space vs. semi-closed space) from which the samples are measured, as well as the relative distance from street traffic, that could impact accurate personal exposure assessments. PMID- 26771628 TI - The Impact of the 2008 Economic Crisis on Substance Use Patterns in the Countries of the European Union. AB - BACKGROUND: From 2008 on, a severe economic crisis (EC) has characterized the European Union (E.U.). However, changes in substance use behavioral patterns as a result of the economic crisis in Europe, have been poorly reflected upon, and underlying mechanisms remain to be identified; METHODS: In this review we explore and systematize the available data on the effect of the 2008 economic crisis on patterns of substance use and related disorders, within the E.U. countries; RESULTS: The results show that effects of the recession need to be differentiated. A number of studies point to reductions in population's overall substance use. In contrast, an increase in harmful use and negative effects is found within specific subgroups within the society. Risk factors include job-loss and long-term unemployment, and pre-existing vulnerabilities. Finally, our findings point to differences between types of substances in their response on economic crisis periods; CONCLUSIONS: the effects of the 2008 economic crisis on substance use patterns within countries of the European Union are two-sided. Next to a reduction in a population's overall substance use, a number of vulnerable subgroups experience serious negative effects. These groups are in need of specific attention and support, given that there is a real risk that they will continue to suffer negative health effects long after the economic downfall has formally been ended. PMID- 26771629 TI - A Two-Stage Method to Estimate the Contribution of Road Traffic to PM2.5 Concentrations in Beijing, China. AB - BACKGROUND: Fine particulate matters with aerodynamic diameters smaller than 2.5 micrometers (PM2.5) have been a critical environmental problem in China due to the rapid road vehicle growth in recent years. To date, most methods available to estimate traffic contributions to ambient PM2.5 concentration are often hampered by the need for collecting data on traffic volume, vehicle type and emission profile. OBJECTIVE: To develop a simplified and indirect method to estimate the contribution of traffic to PM2.5 concentration in Beijing, China. METHODS: Hourly PM2.5 concentration data, daily meteorological data and geographic information were collected at 35 air quality monitoring (AQM) stations in Beijing between 2013 and 2014. Based on the PM2.5 concentrations of different AQM station types, a two-stage method comprising a dispersion model and generalized additive mixed model (GAMM) was developed to estimate separately the traffic and non-traffic contributions to daily PM2.5 concentration. The geographical trend of PM2.5 concentrations was investigated using generalized linear mixed model. The temporal trend of PM2.5 and non-linear relationship between PM2.5 and meteorological conditions were assessed using GAMM. RESULTS: The medians of daily PM2.5 concentrations during 2013-2014 at 35 AQM stations in Beijing ranged from 40 to 92 MUg/m3. There was a significant increasing trend of PM2.5 concentration from north to south. The contributions of road traffic to daily PM2.5 concentrations ranged from 17.2% to 37.3% with an average 30%. The greatest contribution was found at AQM stations near busy roads. On average, the contribution of road traffic at urban stations was 14% higher than that at rural stations. CONCLUSIONS: Traffic emissions account for a substantial share of daily total PM2.5 concentrations in Beijing. Our two-stage method is a useful and convenient tool in ecological and epidemiological studies to estimate the traffic contribution to PM2.5 concentrations when there is limited information on vehicle number and types and emission profile. PMID- 26771630 TI - Defining the Enterovirus Diversity Landscape of a Fecal Sample: A Methodological Challenge? AB - Enteroviruses are a group of over 250 naked icosahedral virus serotypes that have been associated with clinical conditions that range from intrauterine enterovirus transmission withfataloutcome through encephalitis and meningitis, to paralysis. Classically, enterovirus detection was done by assaying for the development of the classic enterovirus-specific cytopathic effect in cell culture. Subsequently, the isolates were historically identified by a neutralization assay. More recently, identification has been done by reverse transcriptase-polymerase chain reaction (RT-PCR). However, in recent times, there is a move towards direct detection and identification of enteroviruses from clinical samples using the cell culture-independent RT semi-nested PCR (RT-snPCR) assay. This RT-snPCR procedure amplifies the VP1 gene, which is then sequenced and used for identification. However, while cell culture-based strategies tend to show a preponderance of certain enterovirus species depending on the cell lines included in the isolation protocol, the RT-snPCR strategies tilt in a different direction. Consequently, it is becoming apparent that the diversity observed in certain enterovirus species, e.g., enterovirus species B(EV-B), might not be because they are the most evolutionarily successful. Rather, it might stem from cell line specific bias accumulated over several years of use of the cell culture-dependent isolation protocols. Furthermore, it might also be a reflection of the impact of the relative genome concentration on the result of pan-enterovirus VP1 RT-snPCR screens used during the identification of cell culture isolates. This review highlights the impact of these two processes on the current diversity landscape of enteroviruses and the need to re-assess enterovirus detection and identification algorithms in a bid to better balance our understanding of the enterovirus diversity landscape. PMID- 26771631 TI - Features of the Antitumor Effect of Vaccinia Virus Lister Strain. AB - Oncolytic abilities of vaccinia virus (VACV) served as a basis for the development of various recombinants for treating cancer; however, "natural" oncolytic properties of the virus are not examined in detail. Our study was conducted to know how the genetically unmodified L-IVP strain of VACV produces its antitumor effect. Human A431 carcinoma xenografts in nude mice and murine Ehrlich carcinoma in C57Bl mice were used as targets for VACV, which was injected intratumorally. A set of virological methods, immunohistochemistry, light and electron microscopy was used in the study. We found that in mice bearing A431 carcinoma, the L-IVP strain was observed in visceral organs within two weeks, but rapidly disappeared from the blood. The L-IVP strain caused decrease of sizes in both tumors, however, in different ways. Direct cell destruction by replicating virus plays a main role in regression of A431 carcinoma xenografts, while in Ehrlich carcinoma, which poorly supported VACV replication, the virus induced decrease of mitoses by pushing tumor cells into S-phase of cell cycle. Our study showed that genetically unmodified VACV possesses at least two mechanisms of antitumor effect: direct destruction of tumor cells and suppression of mitoses in tumor cells. PMID- 26771632 TI - Effect of Folic Acid, Betaine, Vitamin B6, and Vitamin B12 on Homocysteine and Dimethylglycine Levels in Middle-Aged Men Drinking White Wine. AB - Moderate regular consumption of alcoholic beverages is believed to protect against atherosclerosis but can also increase homocysteine or dimethylglycine, which are putative risk factors for atherosclerosis. We aimed (1) to investigate the effect of alcohol consumption on vitamins and several metabolites involved in one-carbon metabolism; and (2) to find the most effective way of decreasing homocysteine during moderate alcohol consumption. METHODS: Male volunteers (n = 117) were randomly divided into five groups: the wine-only group (control, 375 mL of white wine daily for one month) and four groups combining wine consumption with one of the supplemented substances (folic acid, betaine, and vitamins B12 or B6). Significant lowering of homocysteine concentration after the drinking period was found in subjects with concurrent folate and betaine supplementation. Vitamin B12 and vitamin B6 supplementation did not lead to a statistically significant change in homocysteine. According to a multiple linear regression model, the homocysteine change in the wine-only group was mainly determined by the interaction between the higher baseline homocysteine concentration and the change in dimethylglycine levels. Folate and betaine can attenuate possible adverse effects of moderate alcohol consumption. Dimethylglycine should be interpreted together with data on alcohol consumption and homocysteine concentration. PMID- 26771633 TI - Research Priorities for Fertility and Conception Research as Identified by Multidisciplinary Health Care Practitioners and Researchers. AB - The Robinson Research Institute of the University of Adelaide convened a multidisciplinary group of n = 33 clinicians, researchers and representatives of government organisations on the 2 October 2014 for a workshop entitled "Promoting fertility and healthy conception. How do we generate greater reproductive health awareness?" The key aim of the workshop was to assess the body of knowledge that informs clinical practice and government policy, and to identify questions and additional information needed by health practitioners and government representatives working in the field of reproductive health and to frame future research and policy. The workshop identified topics that fell mostly into three categories: lifestyle-related, societal and biological factors. The lifestyle topics included nutrition and diet, exercise, obesity, shift work and other factors deemed to be modifiable at the level of the individual. The societal topics included discussions of matters that are structural, and resistant to change by individuals, including specific ethical issues, social disadvantage, government and educational policies. The biological factors are intrinsic physical states of the individual, and included many factors where there is a dense body of scientific knowledge which may not be readily accessible in less academic language. This workshop thus provided an opportunity to identify further actions that could be undertaken to meet the needs of diverse organisations and groups of professionals with an interest in human fertility. Since so many factors in our social and biological environment can impact fertility and preconception health, it is imperative to involve many disciplines or levels of government or societal organisations that have not traditionally been involved in this area. PMID- 26771634 TI - Consumption of Whole-Grain Bread and Risk of Colorectal Cancer among Norwegian Women (the NOWAC Study). AB - There is evidence that consumption of foods containing dietary fiber decreases the risk of colorectal cancer (CRC). Whole grains contain dietary fiber, as well as a range of micronutrients and bioactive compounds, but the association between the consumption of whole grains and the risk of CRC remains less studied. The aim of the present study was to investigate the association between whole-grain bread consumption and CRC incidence among Norwegian women, using data from a prospective cohort study (the Norwegian Women and Cancer Study). Dietary intake was estimated from the food-frequency questionnaires of 78,254 women in the cohort (median age: 55 years), and these women were then followed up for CRC incidence. During the 9 years of median follow-up, 795 women were diagnosed with CRC (316 proximal, 193 distal, 218 rectal). Associations between whole-grain bread consumption and the risk of CRC (including colorectal subsites) were investigated using Cox proportional hazards regression models. When compared to the low consumption group, the hazard ratio for CRC was 0.89 (95% confidence interval (CI): 0.72-1.09) for the high consumption group and 0.86 (95% CI: 0.72 1.02) for the medium consumption group in a multivariable model. Overall, no association between whole-grain bread consumption and CRC was found. PMID- 26771635 TI - In Vitro Bioaccessibility of Phenolic Acids from a Commercial Aleurone-Enriched Bread Compared to a Whole Grain Bread. AB - Wheat aleurone, due to its potentially higher bioaccessibility and bioavailability of micronutrients and phenolic acids, could represent a useful ingredient in the production of commonly consumed cereal-based food. The aim of the present study was to investigate the in vitro bioaccessibility of phenolic acids both from an aleurone-enriched bread and from a whole grain bread. The two bread samples were firstly characterized for the phenolic acid content. An in vitro digestion was then performed in order to evaluate the release of phenolic acids. The results obtained suggest that the bioaccessibility of the phenolic acids in the aleurone-enriched bread is higher than in the whole grain bread. These in vitro results suggest the potential use of aleurone in the production of foods, and this may represent an attractive possibility to vehicle nutritionally interesting components to consumers. PMID- 26771637 TI - Effect of Oat beta-Glucan Intake on Glycaemic Control and Insulin Sensitivity of Diabetic Patients: A Meta-Analysis of Randomized Controlled Trials. AB - Many individual studies on oat beta-glucan (OBG) confirmed its functionality in improving type 2 diabetes mellitus (T2DM), but disagreements were identified among those results. To derive a pooled estimate of these results, relevant articles, published before 5 September 2015, were collected from four electronic databases (Pubmed, Cochrane Library, Scopus, and Web of Science) and subjected to meta-analysis in the present work. In total, four articles, dealing with 350 T2DM patients combined, met the inclusion criteria. Compared to control, T2DM patients administrated OBG from 2.5 to 3.5 g/day for 3 to 8 weeks presented significantly lowered concentrations in fasting plasma glucose (FPG) by -0.52 (95% CI: -0.94, 0.10) mmol/L (p = 0.01) and glycosylated hemoglobin (HbA1c) by -0.21% (95% CI: 0.40, -0.02) (p = 0.03). However, OBG intake did not significantly lower the fasting plasma insulin (FPI) concentration. In conclusion, mediate-term OBG intake (3-8 weeks) favored the glycaemic control of T2DM patients but did not improve their insulin sensitivity. Regrettably, data upon the effects of long term OBG intake on glycaemic control and insulin sensitivity were scarce, which is of much importance and should be addressed in future research. PMID- 26771636 TI - Protection against Oxygen-Glucose Deprivation/Reperfusion Injury in Cortical Neurons by Combining Omega-3 Polyunsaturated Acid with Lyciumbarbarum Polysaccharide. AB - Ischemic stroke, characterized by the disturbance of the blood supply to the brain, is a severe worldwide health threat with high mortality and morbidity. However, there is no effective pharmacotherapy for ischemic injury. Currently, combined treatment is highly recommended for this devastating injury. In the present study, we investigated neuroprotective effects of the combination of omega-3 polyunsaturated fatty acids (omega-3 PUFAs) and Lyciumbarbarum polysaccharide (LBP) on cortical neurons using an in vitro ischemic model. Our study demonstrated that treatment with docosahexaenoic acid (DHA), a major component of the omega-3 PUFAs family, significantly inhibited the increase of intracellular Ca(2+) in cultured wild type (WT) cortical neurons subjected to oxygen-glucose deprivation/reperfusion (OGD/R) injury and promoted their survival compared with the vehicle-treated control. The protective effects were further confirmed in cultured neurons with high endogenous omega-3 PUFAs that were isolated from fat-1 mice, in that a higher survival rate was found in fat-1 neurons compared with wild-type neurons after OGD/R injury. Our study also found that treatment with LBP (50 mg/L) activated Trk-B signaling in cortical neurons and significantly attenuated OGD/R-induced cell apoptosis compared with the control. Notably, both combining LBP treatment with omega-3 PUFAs administration to WT neurons and adding LBP to fat-1 neurons showed enhanced effects on protecting cortical neurons against OGD/R injury via concurrently regulating the intracellular calcium overload and neurotrophic pathway. The results of the study suggest that omega-3 PUFAs and LBP are promising candidates for combined pharmacotherapy for ischemic stroke. PMID- 26771639 TI - The Effect of Co-Administration of Death Camas (Zigadenus spp.) and Low Larkspur (Delphinium spp.) in Cattle. AB - In many rangeland settings, there is more than one potential poisonous plant. Two poisonous plants that are often found growing simultaneously in the same location in North American rangelands are death camas (Zigadenus spp.) and low larkspur (Delphinium spp.). The objective of this study was to determine if co administration of death camas would exacerbate the toxicity of low larkspur in cattle. Cattle dosed with 2.0 g of death camas/kg BW showed slight frothing and lethargy, whereas cattle dosed with both death camas and low larkspur showed increased clinical signs of poisoning. Although qualitative differences in clinical signs of intoxication in cattle co-treated with death camas and low larkspur were observed, there were not any significant quantitative differences in heart rate or exercise-induced muscle fatigue. Co-treatment with death camas and low larkspur did not affect the serum zygacine kinetics, however, there was a difference in the larkspur alkaloid kinetics in the co-exposure group. Overall, the results from this study suggest that co-exposure to death camas and low larkspur is not significantly more toxic to cattle than exposure to the plants individually. The results from this study increase our knowledge and understanding regarding the acute toxicity of death camas and low larkspur in cattle. PMID- 26771638 TI - Preparative Separation of Main Ustilaginoidins from Rice False Smut Balls by High Speed Counter-Current Chromatography. AB - Ustilaginoidins are bis-naphtho-gamma-pyrone mycotoxins isolated from the rice false smut balls (FSBs) infected by the pathogen Villosiclava virens in rice spikelets on panicles. In order to obtain large amounts of pure ustilaginoidins to further evaluate their biological activities and functions, phytotoxicity on rice, security to human and animals as well as to accelerate their applications as pharmaceuticals, preparative high-speed counter-current chromatography (HSCCC) was successfully applied to the isolation and purification of seven bis-naphtho gamma-pyrone mycotoxins, namely ustilaginoidins A (1), G (2), B (3), H (4), I (5), C (6), and J (7) from the ethyl acetate crude extract of rice FSBs. Both 1 and 2 were prepared by HSCCC from the low-polarity fraction of the crude extract using the two-phase solvent system composed of n-hexane-ethyl acetate-methanol water at the volume ratio of 6.5:3.5:5.0:5.0. Similarly, 3, 4 and 5 were prepared from the medium-polarity fraction using the system at the volume ratio of 4.0:5.0:5.0:6.0, and 6 and 7 were prepared from the higher-polarity fraction using the system at volume ratio of 3.0:5.0:4.0:6.7. A total of 6.2 mg of 1, 5.1 mg of 2, 3.9 mg of 3, 1.2 mg of 4, 5.7 mg of 5, 3.5 mg of 6, and 6.1 mg of 7 with purities of 88%, 82%, 91%, 80%, 92%, 81% and 83%, respectively, were yielded from total 62 mg fraction samples in three independent HSCCC runs. The structures of the purified ustilaginoidins were characterized by means of physicochemical and spectrometric analysis. PMID- 26771640 TI - Incobotulinum Toxin-A Improves Post-Surgical and Post-Radiation Pain in Cancer Patients. AB - Cancer patients who undergo surgery or radiation can develop persistent focal pain at the site of radiation or surgery. Twelve patients who had surgery or radiation for local cancer and failed at least two analgesic medications for pain control were prospectively enrolled in a research protocol. Patients were injected up to 100 units of incobotulinum toxin A (IncoA) intramuscularly or subcutaneously depending on the type and location of pain (muscle cramp or neuropathic pain). Two patients passed away, one dropped out due to a skin reaction and another patient could not return for the follow up due to his poor general condition. All remaining 8 subjects (Age 31-70, 4 female) demonstrated significant improvement of Visual Analog Scale (VAS) (3 to 9 degrees, average 3.9 degrees) and reported significant satisfaction in Patients' Global Impression of Change scale (PGIC) (7 out of 8 reported the pain as much improved). Three of the 8 patients reported significant improvement of quality of life. PMID- 26771641 TI - Benefits of Minimal Access Surgery in Elderly Patients with Pelvic Cancer. AB - An increasing proportion of patients requiring treatment for malignancy are elderly, which has created new challenges for oncologic surgeons. Aging is associated with an increasing prevalence of frailty and comorbidities that may affect the outcome of surgical procedures. By decreasing complications and shortening length of hospital stay without affecting oncologic safety, surgery performed using the robot, rather than traditional laparotomy, improves the chances of a better outcome in our growing elderly populations. In addition to age, surgeons should take into account factors, such as frailty and comorbidities that correlate with outcome. PMID- 26771643 TI - The Effect of Stromal Integrin beta3-Deficiency on Two Different Tumors in Mice. AB - There is an increasing focus on the tumor microenvironment in carcinogenesis. Integrins are important receptors and adhesion molecules in this environment and have been shown to be involved in cell adhesion, proliferation, differentiation and migration. The present study aimed to evaluate the effect of stromal integrin beta3-deficiency on tumor growth, angiogenesis, interstitial fluid pressure (PIF), fibrosis and metastasis in a murine breast cancer (4T1) and a prostate tumor (RM11) model. We showed that stromal integrin beta3-deficiency led to an elevation in PIF that correlated to a shift towards thicker collagen fibrils in the 4T1 mammary tumor. In the RM11 prostate carcinoma model there was no effect of integrin beta3-deficiency on PIF and collagen fibril thickness. These findings support the notion that changes in the collagen scaffold influence PIF, and also indicate that there must be important crosstalk between the stroma and tumor cells, in a tumor cell line specific manner. Furthermore, stromal integrin beta3 deficiency had no effect on tumor growth or angiogenesis in both tumor models and no effect on lung metastasis in the 4T1 mammary tumor model. In conclusion, the stromal beta3 integrin influence PIF, possibly via its effect on the structure of the collagen network, in a tumor cell line dependent manner. PMID- 26771645 TI - Re-Use of Established Drugs for Anti-Metastatic Indications. AB - Most patients that die from cancer do not die due to the primary tumor but due to the development of metastases. However, there is currently still no drug on the market that specifically addresses and inhibits metastasis formation. This lack was, in the past, largely due to the lack of appropriate screening models, but recent developments have established such models and have provided evidence that tumor cell migration works as a surrogate for metastasis formation. Herein we deliver on several examples a rationale for not only testing novel cancer drugs by use of these screening assays, but also reconsider established drugs even of other fields of indication. PMID- 26771642 TI - Cell Proliferation in Neuroblastoma. AB - Neuroblastoma, the most common extracranial solid tumor of childhood, continues to carry a dismal prognosis for children diagnosed with advanced stage or relapsed disease. This review focuses upon factors responsible for cell proliferation in neuroblastoma including transcription factors, kinases, and regulators of the cell cycle. Novel therapeutic strategies directed toward these targets in neuroblastoma are discussed. PMID- 26771646 TI - The tRNA Elbow in Structure, Recognition and Evolution. AB - Prominent in the L-shaped three-dimensional structure of tRNAs is the "elbow" where their two orthogonal helical stacks meet. It has a conserved structure arising from the interaction of the terminal loops of the D- and T-stem-loops, and presents to solution a flat face of a tertiary base pair between the D- and T loops. In addition to the ribosome, which interacts with the elbow in all three of its tRNA binding sites, several cellular RNAs and many proteins are known to recognize the elbow. At least three classes of non-coding RNAs, namely 23S rRNA, ribonuclease P, and the T-box riboswitches, recognize the tRNA elbow employing an identical structural motif consisting of two interdigitated T-loops. In contrast, structural solutions to tRNA-elbow recognition by proteins are varied. Some enzymes responsible for post-transcriptional tRNA modification even disrupt the elbow structure in order to access their substrate nucleotides. The evolutionary origin of the elbow is mysterious, but, because it does not explicitly participate in the flow of genetic information, it has been proposed to be a late innovation. Regardless, it is biologically essential. Even some viruses that hijack the cellular machinery using tRNA decoys have convergently evolved near perfect mimics of the tRNA elbow. PMID- 26771647 TI - Traumatic Brain Injury in United States Operation Enduring Freedom/Operation Iraqi Freedom (OEF/OIF) Hispanic Veterans-A Review Using the PRISMA Method. AB - Traumatic brain injury (TBI) is commonly defined by Menon et al. as an "alteration of the brain function, or other evidence of brain pathology, caused by an external force." TBI can be caused by penetrating trauma to the head in which the magnitude of the injury is dependent on the magnitude of the forces that are applied to the head. The consequences of TBI can range from minimal to severe disability and even death. The major objectives of this systematic review are to survey the current literature on Operation Enduring Freedom (OEF) and Operation Iraqi Freedom (OIF) Hispanic veterans with TBI. To complete this analysis, the Preferred Reporting Items for Systematic Reviews and MetaAnalysis (PRISMA) identified 875 articles in common and retrieved a total of 34 articles that met the inclusion criteria, consisted of OEF/OIF Hispanic veterans, reported quantitative data, and were conducted with adult U.S. veterans living in the United States. Since TBI diagnosis was unclear in most articles, only five articles that used the VATBIST instrument were analyzed. The results suggested that there is a lack of research on OEF/OIF Hispanic veterans and Hispanic subgroups. Future studies need to be conducted to consider minority groups while analyzing data involving TBI. PMID- 26771644 TI - Stress Response Leading to Resistance in Glioblastoma-The Need for Innovative Radiotherapy (iRT) Concepts. AB - Glioblastoma (GBM) is the most common and most aggressive malignant primary brain tumor in adults. In spite of multimodal therapy concepts, consisting of surgery, radiotherapy and chemotherapy, the median survival, merely 15-18 months, is still poor. Mechanisms for resistance of GBM to radio(chemo)therapy are not fully understood yet and due to the genetic heterogeneity within the tumor including radiation-resistant tumor stem cells, there are several factors leading to therapy failure. Recent research revealed that, hypoxia during radiation and miRNAs may adversely affect the therapeutic response to radiotherapy. Further molecular alterations and prognostic markers like the DNA-repair protein O6 methylguanine-DNA methyltransferase (MGMT), anti-apoptotic molecular chaperones, and/or the activity of aldehyde dehydrogenase 1 (ALDH1) have also been identified to play a role in the sensitivity to cytostatic agents. Latest approaches in the field of radiotherapy to use particle irradiation or dose escalation strategies including modern molecular imaging, however, need further evaluation with regard to long-term outcome. In this review we focus on current information about the mechanisms and markers that mediate resistance to radio(chemo)therapy, and discuss the opportunities of Innovative Radiotherapy (iRT) concepts to improve treatment options for GBM patients. PMID- 26771648 TI - Emerging Transcriptional Mechanisms in the Regulation of Epithelial to Mesenchymal Transition and Cellular Plasticity in the Kidney. AB - Notwithstanding controversies over the role of epithelial to mesenchymal transition in the pathogenesis of renal disease, the last decade has witnessed a revolution in our understanding of the regulation of renal cell plasticity. Significant parallels undoubtedly exist between ontogenic processes and the initiation and propagation of damage in the diseased kidney as evidenced by the reactivation of developmental programmes of gene expression, in particular with respect to TGFbeta superfamily signaling. Indeed, multiple signaling pathways converge on a complex transcriptional regulatory nexus that additionally involves epigenetic activator and repressor mechanisms and microRNA regulatory networks that control renal cell plasticity. It is becoming increasingly apparent that differentiated cells can acquire an undifferentiated state akin to "stemness" which is leading us towards new models of complex cell behaviors and interactions. Here we discuss the latest findings that delineate new and novel interactions between this transcriptional regulatory network and highlight a hitherto poorly recognized role for the Polycomb Repressive Complex (PRC2) in the regulation of renal cell plasticity. A comprehensive understanding of how external stimuli interact with the epigenetic control of gene expression, in normal and diseased contexts, establishes a new therapeutic paradigm to promote the resolution of renal injury and regression of fibrosis. PMID- 26771650 TI - Application of Pre-Column Labeling Liquid Chromatography for Canine Plasma-Free Amino Acid Analysis. AB - Plasma-free amino acid (PFAA) levels are a useful metric for diagnosing cancer and providing a prognosis. However, the use of analysis of PFAA levels has been limited in the veterinary medicine field. We addressed the application of liquid chromatography (LC) using a pre-column labeling technique for analysis of canine PFAA levels. This method significantly shortened the analysis time relative to conventional methods. No diurnal fluctuations were detected at 9:00 AM in most PFAA levels, and food intake increased the levels of some PFAAs, including valine, leucine, tyrosine, phenylalanine, and proline. These results indicate that LC with pre-column labeling is useful for measuring canine PFAA levels, for which time of day and interval after food intake must be taken into consideration. PMID- 26771649 TI - Reversible Human TGF-beta Signal Shifting between Tumor Suppression and Fibro Carcinogenesis: Implications of Smad Phospho-Isoforms for Hepatic Epithelial Mesenchymal Transitions. AB - Epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET) are observed during both physiological liver wound healing and the pathological fibrotic/carcinogenic (fibro-carcinogenetic) process. TGF-beta and pro-inflammatory cytokine are considered to be the major factors accelerating liver fibrosis and promoting liver carcinogenesis. Smads, consisting of intermediate linker regions connecting Mad homology domains, act as the intracellular mediators of the TGF-beta signal transduction pathway. As the TGF beta receptors, c-Jun N-terminal kinase and cyclin-dependent kinase, differentially phosphorylate Smad2/3, we have generated numerous antibodies against linker (L) and C-terminal (C) phosphorylation sites in Smad2/3 and identified four types of phosphorylated forms: cytostatic COOH-terminally phosphorylated Smad3 (pSmad3C), mitogenic pSmad3L (Ser-213) signaling, fibrogenic pSmad2L (Ser-245/250/255)/C signaling and migratory pSmad2/3L (Thr-220/179)/C signaling. After acute liver injury, TGF-beta upregulates pSmad3C signaling and terminates pSmad3L (Ser-213)-mediated hepatocyte proliferation. TGF-beta and pro inflammatory cytokines cooperatively enhance collagen synthesis by upregulating pSmad2L (Thr-220)/C and pSmad3L (Thr-179)/C pathways in activated hepatic stellate cells. During chronic liver injuries, hepatocytes persistently affected by TGF-beta and pro-inflammatory cytokines eventually become pre-neoplastic hepatocytes. Both myofibroblasts and pre-neoplastic hepatocyte exhibit the same carcinogenic (mitogenic) pSmad3L (Ser-213) and fibrogenic pSmad2L (Ser 245/250/255)/C signaling, with acquisition of fibro-carcinogenic properties and increasing risk of hepatocellular carcinoma (HCC). Firstly, we review phospho Smad-isoform signalings in epithelial and mesenchymal cells in physiological and pathological conditions and then consider Smad linker phosphorylation as a potential target for pathological EMT during human fibro-carcinogenesis, because human Smad phospho-isoform signals can reverse from fibro-carcinogenesis to tumor suppression in a process of MET after therapy. PMID- 26771652 TI - Isolation of a Rickettsia slovaca-Like Agent from Dermacentor variabilis Ticks in Vero Cell Culture. AB - Rickettsia slovaca is transmitted by Dermacentor marginatus ticks, and is the causative agent of tick-borne lymphadenopathy and Dermacentor-borne necrosis erythema lymphadenopathy throughout Europe. It has not been found in New World ticks, nor have tick-borne lymphadenopathy or Dermacentor-borne necrosis erythema lymphadenopathy been reported in humans in the Americas. Here we describe the isolation of a R. slovaca-like agent from D. variabilis nymphs from a colony of ticks derived from field collected adults. PMID- 26771651 TI - Glutaminase Increases in Rat Dorsal Root Ganglion Neurons after Unilateral Adjuvant-Induced Hind Paw Inflammation. AB - Glutamate is a neurotransmitter used at both the peripheral and central terminals of nociceptive primary sensory neurons, yet little is known concerning regulation of glutamate metabolism during peripheral inflammation. Glutaminase (GLS) is an enzyme of the glutamate-glutamine cycle that converts glutamine into glutamate for neurotransmission and is implicated in producing elevated levels of glutamate in central and peripheral terminals. A potential mechanism for increased levels of glutamate is an elevation in GLS expression. We assessed GLS expression after unilateral hind paw inflammation by measuring GLS immunoreactivity (ir) with quantitative image analysis of L4 dorsal root ganglion (DRG) neurons after one, two, four, and eight days of adjuvant-induced arthritis (AIA) compared to saline injected controls. No significant elevation in GLS-ir occurred in the DRG ipsilateral to the inflamed hind paw after one or two days of AIA. After four days AIA, GLS-ir was elevated significantly in all sizes of DRG neurons. After eight days AIA, GLS-ir remained elevated in small (<400 um2), presumably nociceptive neurons. Western blot analysis of the L4 DRG at day four AIA confirmed the elevated GLS-ir. The present study indicates that GLS expression is increased in the chronic stage of inflammation and may be a target for chronic pain therapy. PMID- 26771655 TI - Synthesis of Benzothiadiazole Derivatives by Applying C-C Cross-Couplings. AB - The benzothiadiazole moiety has been extensively exploited as a building block in the syntheses of efficient organic semiconducting materials during the past decade. In this paper, parallel synthetic routes to benzothiadiazole derivatives, inspired by previous computational findings, are reported. The results presented here show that various C-C cross-couplings of benzothiadiazole, thiophene, and thiazole derivatives can be efficiently performed by applying Xantphos as a ligand of the catalyst system. Moreover, improved and convenient methods to synthesize important chemical building blocks, e.g., 4,7-dibromo-2,1,3 benzothiadiazole, in good to quantitative yields are presented. Additionally, the feasibility of Suzuki-Miyaura and direct coupling methods are compared in the synthesis of target benzothiadiazole derivatives. The computational characterization of the prepared benzothiadiazole derivatives shows that these compounds have planar molecular backbones and the possibility of intramolecular charge transfer upon excitation. The experimental electrochemical and spectroscopic studies reveal that although the compounds have similar electronic and optical properties in solution, they behave differently in solid state due to the different alkyl side-group substitutions in the molecular backbone. These benzothiadiazole derivatives can be potentially used as building blocks in the construction of more advanced small molecule organic semiconductors with acceptor donor-acceptor motifs. PMID- 26771654 TI - Molecular Detection and Identification of Spotted Fever Group Rickettsiae in Ticks Collected from the West Bank, Palestinian Territories. AB - BACKGROUND: Tick-borne rickettsioses are caused by obligate intracellular bacteria belonging to the spotted fever group (SFG) rickettsiae. Although Spotted Fever is prevalent in the Middle East, no reports for the presence of tick-borne pathogens are available or any studies on the epidemiology of this disease in the West Bank. We aimed to identify the circulating hard tick vectors and genetically characterize SFG Rickettsia species in ixodid ticks from the West Bank Palestinian territories. METHODOLOGY/PRINCIPAL FINDINGS: A total of 1,123 ixodid ticks belonging to eight species (Haemaphysalis parva, Haemaphysalis adleri, Rhipicephalus turanicus, Rhipicephalus sanguineus, Rhipicephalus bursa, Hyalomma dromedarii, Hyalomma aegyptium and Hyalomma impeltatum) were collected from goats, sheep, camels, dogs, a wolf, a horse and a tortoise in different localities throughout the West Bank during the period of January-April, 2014. A total of 867 ticks were screened for the presence of rickettsiae by PCR targeting a partial sequence of the ompA gene followed by sequence analysis. Two additional genes, 17 kDa and 16SrRNA were also targeted for further characterization of the detected Rickettsia species. Rickettsial DNA was detected in 148 out of the 867 (17%) tested ticks. The infection rates in Rh. turanicus, Rh. sanguineus, H. adleri, H. parva, H. dromedarii, and H. impeltatum ticks were 41.7, 11.6, 16.7, 16.2, 11.8 and 20%, respectively. None of the ticks, belonging to the species Rh. bursa and H. aegyptium, were infected. Four SFG rickettsiae were identified: Rickettsia massiliae, Rickettsia africae, Candidatus Rickettsia barbariae and Candidatus Rickettsia goldwasserii. SIGNIFICANCE: The results of this study demonstrate the geographic distribution of SFG rickettsiae and clearly indicate the presence of at least four of them in collected ticks. Palestinian clinicians should be aware of emerging tick-borne diseases in the West Bank, particularly infections due to R. massiliae and R. africae. PMID- 26771653 TI - The Use of Interferon Gamma Inducible Protein 10 as a Potential Biomarker in the Diagnosis of Latent Tuberculosis Infection in Uganda. AB - BACKGROUND: In the absence of a gold standard for the diagnosis of latent tuberculosis (TB) infection (LTBI), the current tests available for the diagnosis of LTBI are limited by their inability to differentiate between LTBI and active TB disease. We investigated IP-10 as a potential biomarker for LTBI among household contacts exposed to sputum positive active TB cases. METHODS: Active TB cases and contacts were recruited into a cohort with six months' follow-up. Contacts were tested for LTBI using QuantiFERON(r)-TB Gold In-Tube (QFN) assay and the tuberculin skin test (TST). Baseline supernatants from the QFN assay of 237 contacts and 102 active TB cases were analysed for Mycobacterium tuberculosis (MTB) specific and mitogen specific IP-10 responses. RESULTS: Contacts with LTBI (QFN+TST+) had the highest MTB specific IP-10 responses at baseline, compared to uninfected contacts (QFN-TST-) p<0.0001; and active cases, p = 0.01. Using a cut off of 8,239 pg/ml, MTB specific IP-10 was able to diagnose LTBI with a sensitivity of 87.1% (95% CI, 76.2-94.3) and specificity of 90.9% (95% CI, 81.3 96.6). MTB specific to mitogen specific IP-10 ratio was higher in HIV negative active TB cases, compared to HIV negative latently infected contacts, p = 0.0004. Concentrations of MTB specific IP-10 were higher in contacts with TST conversion (negative at baseline, positive at 6-months) than in those that were persistently TST negative, p = 0.001. CONCLUSION: IP-10 performed well in differentiating contacts with either latent or active TB from those who were uninfected but was not able to differentiate LTBI from active disease except when MTB specific to mitogen specific ratios were used in HIV negative adults. In addition, IP-10 had the potential to diagnose 'recent TB infection' in persons classified as having LTBI using the TST. Such individuals with strong IP-10 responses would likely benefit from chemoprophylaxis. PMID- 26771656 TI - Clinical Outcome and Predictive Factors in the Response to Splenectomy in Elderly Patients with Primary Immune Thrombocytopenia: A Multicenter Retrospective Study. AB - BACKGROUND: Because many physicians seem reluctant to recommend splenectomy for elderly patients with immune thrombocytopenia (ITP), we investigated the safety and efficacy of splenectomy and the predictive factors for response in these patients. METHODS: 184 patients with primary ITP were retrospectively analyzed based on age at splenectomy: an elderly group (>=60 years, n = 52) and a younger group (<60 years, n = 132). RESULTS: There was no difference in the response rate of elderly versus younger patients (80.7 vs. 80.3%, p = 0.466). Relapse (45.2 vs. 22.6%, p = 0.006), complications, and median postoperative stay (9.5 vs. 7 days, p = 0.019) were significantly higher in the elderly group. The 5-year relapse free survival of responders was 51.8% in the elderly group and 76.3% in the younger group (p = 0.002). Response to any treatment before splenectomy (HR 2.9, 95% CI: 1.24-6.80, p = 0.014) and platelet count on postoperative day 14 >=200 * 109/l (HR 31.43, 95% CI: 4.15-238.28, p = 0.001) were independent factors for a favorable response. CONCLUSIONS: Age >=60 years did not influence the response to splenectomy but was associated with increased relapse and postoperative complications. Splenectomy could provide a durable long-term response for elderly ITP patients. PMID- 26771657 TI - Enhancement of mRNA expression of survivin and human beta-defensin-3 in lesions of psoriasis vulgaris. AB - BACKGROUND: Suppression of apoptosis is one of the pathogenetic mechanisms for psoriasis vulgaris (PV). Survivin has the function of regulating cell division and inhibiting apoptosis. Patients with PV have an increased resistance to cutaneous infections. Human beta-defensin-3 (hBD-3) is a kind of antimicrobial peptide with antimicrobial activities. To assess and compare the transcript levels of survivin and hBD-3 in pairwise skin from PV. MATERIALS & METHODS: A total of 20 patients, 10 with mild PV and 10 with severe PV, and 10 healthy control donors were recruited in the study. Real-time PCR was conducted to determine survivin and hBD-3 mRNA expression in skin lesions and normal-appearing skin of PV patients, and normal skin of healthy controls. RESULTS: Compared with normal control skin, the survivin mRNA expression of normal-appearing skin in the mild PV group, lesions of the mild PV group and the severe PV group were significantly elevated (P<0.05). hBD-3 mRNA expression was statistically increased in both normal-appearing skin and in lesions in mild and severe PV groups, in contrast to normal skin (P<0.001). Significant differences of hBD-3 mRNA were also found between lesions and non-lesional skin in the mild PV group and severe PV group (P<0.05). Survivin mRNA levels were mildly correlated with hBD-3 mRNA levels (rs = 0.398; P<0.05) in skin lesions from 20 PV patients. CONCLUSION: Survivin and hBD-3 may be involved in the pathogenesis of psoriasis. PMID- 26771659 TI - A Simple and Low-Cost Monitoring System to Investigate Environmental Conditions in a Biological Research Laboratory. AB - Basic equipment such as incubation and refrigeration systems plays a critical role in nearly all aspects of the traditional biological research laboratory. Their proper functioning is therefore essential to ensure reliable and repeatable experimental results. Despite this fact, in many academic laboratories little attention is paid to validating and monitoring their function, primarily due to the cost and/or technical complexity of available commercial solutions. We have therefore developed a simple and low-cost monitoring system that combines a "Raspberry Pi" single-board computer with USB-connected sensor interfaces to track and log parameters such as temperature and pressure, and send email alert messages as appropriate. The system is controlled by open-source software, and we have also generated scripts to automate software setup so that no background in programming is required to install and use it. We have applied it to investigate the behaviour of our own equipment, and present here the results along with the details of the monitoring system used to obtain them. PMID- 26771658 TI - Comparative Functional Responses Predict the Invasiveness and Ecological Impacts of Alien Herbivorous Snails. AB - Understanding determinants of the invasiveness and ecological impacts of alien species is amongst the most sought-after and urgent research questions in ecology. Several studies have shown the value of comparing the functional responses (FRs) of alien and native predators towards native prey, however, the technique is under-explored with herbivorous alien species and as a predictor of invasiveness as distinct from ecological impact. Here, in China, we conducted a mesocosm experiment to compare the FRs among three herbivorous snail species: the golden apple snail, Pomacea canaliculata, a highly invasive and high impact alien listed in "100 of the World's Worst Invasive Alien Species"; Planorbarius corneus, a non-invasive, low impact alien; and the Chinese native snail, Bellamya aeruginosa, when feeding on four locally occurring plant species. Further, by using a numerical response equation, we modelled the population dynamics of the snail consumers. For standard FR parameters, we found that the invasive and damaging alien snail had the highest "attack rates" a, shortest "handling times" h and also the highest estimated maximum feeding rates, 1/hT, whereas the native species had the lowest attack rates, longest handling times and lowest maximum feeding rates. The non-invasive, low impact alien species had consistently intermediate FR parameters. The invasive alien species had higher population growth potential than the native snail species, whilst that of the non-invasive alien species was intermediate. Thus, while the comparative FR approach has been proposed as a reliable method for predicting the ecological impacts of invasive predators, our results further suggest that comparative FRs could extend to predict the invasiveness and ecological impacts of alien herbivores and should be explored in other taxa and trophic groups to determine the general utility of the approach. PMID- 26771660 TI - Impact of Endocrine Disruptors on the Thyroid Hormone System. AB - The thyroid hormone (TH) system plays a central role in central physiological processes of many species, including mammals and humans, ranging from growth and cell differentiation, energy metabolism, thermoregulation and phasing of hibernation or annual movements of migratory species, metamorphosis from larvae to adult forms, brain development, reproduction, or the cardiovascular system. Several chemicals are known to be TH-disrupting compounds (THDCs) and have been shown to interact with virtually all elements of TH homeostasis such as feedback mechanisms with the hypothalamus-pituitary axis, TH synthesis, TH storage and release from the thyroid gland, transport protein binding and TH distribution in tissues and organs, cellular TH uptake, intracellular TH metabolism, and TH receptor binding. Therefore, chemicals interfering with the TH homeostasis have the potential to interact with many of these important processes, and especially early-life stage exposure results in permanent alterations of tissue organization and homeostatic regulation of adaptive processes. This is not only of theoretical importance as the reported plasma concentrations of THDCs in human plasma fall well within the range of reported in vitro effect concentrations, and this is of even higher importance as the developing fetus and young children are in a sensitive developmental stage. PMID- 26771661 TI - Validation of the Serbian Version of Multiple Sclerosis Spasticity Scale 88 (MSSS 88). AB - OBJECTIVE: Multiple Sclerosis Spasticity Scale (MSSS)-88 has been developed for self-assessment of spasticity symptoms in patients with multiple sclerosis (MS). The objective of this study was to validate MSSS-88 and evaluate the psychometric properties in patients with MS in Serbia. METHODS: The study comprised 65 MS patients with spasticity. MSSS-88 consists of 88 items grouped in eight sections. Internal consistency of the MSSS-88SR subscales was determined using Cronbach's alpha coefficient. Test/retest reliability with an intra-class correlation coefficient (ICC) for each MSSS-88SR subscale was performed. Clinical validity of MSSS-88SR was determined by correlations with the Numeric Rating Scale (NRS) and the Modified Ashworth Scale (MAS). RESULTS: The range of Cronbach's alpha for all scales and ICC was 0.91-0.96 and 0.84-0.91, respectively. All ICCs were statistically significant (p<0.05). All evaluated subscales of MSSS-88 were significantly correlated with the NRS scale. The highest correlation coefficients were registered between the WL subscale and the EDSS and MAS, while the strongest relationship was observed between the MSS subscale and the NRS. CONCLUSION: The Serbian translated version of this instrument may be useful as a clinical measure for spasticity and functionality in patients with MS. PMID- 26771662 TI - Tuberculosis Infection in Early Childhood and the Association with HIV-exposure in HIV-uninfected Children in Rural Uganda. AB - BACKGROUND: In high tuberculosis (TB) burden countries, a significant proportion of the latent TB reservoir is established by the age 5 years. There are critical knowledge gaps in our understanding of the age-specific prevalence of TB infection and the influence of HIV exposure on TB infection in the first 5 years of life among HIV-uninfected children in sub-Saharan Africa. METHODS: We measured TB infection with the Quantiferon Gold-in-Tube (QFT) and tuberculin skin tests (TST) in 447 children <=60 months and their 284 HIV-infected and IV-uninfected mothers in rural Uganda. RESULTS: The overall prevalence of TB infection in children <=60 months by TST was 24% (95% confidence intervals [CI]: 19.9-27.9). The prevalence of TST positivity was highest among children in their first year of life (36%; 95% CI: 26.0-45.9) and declined with age to 19% at 36-60 months of age, chi test for trend P = 0.014. In contrast, 4% (95% CI: 1.9-5.87%) of children had a positive QFT, and there was no trend detected with age, P = 0.576. QFT positivity was detected as early as 5 months. HIV-exposed uninfected children had significantly higher odds of TB infection by QFT (odds ratio [OR]: 21.2; P = 0.008; 95% CI: 2.2-204.7) or positive TST or QFT (OR, 2.4; P = 0.020; 95% CI: 1.2 5.1) compared with HIV-unexposed uninfected children, adjusting for age, BCG vaccination and a positive maternal TST or QFT. CONCLUSIONS: An appreciable prevalence of TB infection was detected in early childhood. HIV-exposed uninfected children have a higher risk for TB infection compared with children born to HIV-uninfected mothers. PMID- 26771663 TI - Clinical Characterization of Children Presenting to the Hospital with Enterovirus D68 Infection During the 2014 Outbreak in St. Louis. AB - BACKGROUND: The largest known outbreak of enterovirus D68 (EV-D68) infections occurred during 2014. The goal of our study is to characterize the illness severity and clinical presentation of children infected with EV-D68 in comparison to non-EV-D68-human rhinoviruses/enteroviruses (HRV/EV). METHOD: Our study is a retrospective analysis of severity level, charges and length of stay of children who presented to St. Louis Children's Hospital from August 8, 2014 to October 31, 2014 and tested positive for EV-D68 in comparison to non-EV-D68-HRV/EV-infected patients. Chart review was performed for all EV-D68-infected patients and age and severity matched non-EV-D68-HRV/EV-infected patients. RESULT: There was a striking increase in hospital census in August of 2014 in our hospital with simultaneous increase in the number of patients with EV-D68 infection. There was no significant difference in severity of illness, length of stay or total charges between EV-D68-infected and non-EV-D68-HRV/EV-infected children. EV-D68 infection was characterized by presenting complaints of difficulty breathing (80%) and wheezing (67%) and by findings of tachypnea (65%), wheezing (71%) and retractions (65%) on examination. The most common interventions were albuterol (79%) and corticosteroid (68%) treatments, and the most common discharge diagnosis was asthma exacerbation (55%). CONCLUSION: EV-D68 caused a significant outbreak in 2014 with increased hospital admissions and associated increased charges. There was no significant difference in severity of illness caused by EV-D68 compared with non-EV-D68-HRV/EV infections suggesting that the impact from EV-D68 was because of increased number of infected children presenting to the hospital and not necessarily due to increased severity of illness. PMID- 26771664 TI - Chemopreventive Effects of Eryngium foetidum L. Leaves on COX-2 Reduction in Mice Induced Colorectal Carcinogenesis. AB - To investigate the potential effects of Eryngium foetidum Linn. leaves (EF) in colitis-induced colorectal carcinogenesis in mice by azoxymethane (AOM) and dextran sulfate sodium (DSS), 39 ICR male mice were studied and divided into 6 groups. The mice were received a modified AIN-76 diet in Group 1, whereas Group 2 was given an AOM, DSS, and AIN-76 diet. Groups 3 and 4 were fed with 0.8% and 3.2% freeze-dried EF with AIN-76 diets, for 5 wk. Groups 5 and 6 were fed with 0.8% and 3.2% EF diets for 5 wk during AOM/DSS administration. The mice were necropsied at Week 20 and their colons were collected. The results indicated that the incidences of tumors in Groups 2, 5, and 6 was 100%, 75%, and 88%, with multiplicities (mean +/-SE) of 3.75 +/-0.92, 2.38 +/- 0.96 and 4.25 +/- 0.79, respectively. Interestingly, there was a significant difference in COX-2 expression in mice received 3.2% EF in their diet, but the proliferative cell nuclear antigen index and iNOS protein expression were not significantly different. We concluded that EF at a dose level of 3.2% in their diet had a preventive effect on colorectal carcinogenesis via the proinflammatory cytokine, COX-2. PMID- 26771666 TI - Hypoglycemia: A Serious Complication for the Older Adult with Diabetes. AB - Hypoglycemic events range from mild to severe and occur at an increased rate among older adults with diabetes. Some diabetes medications increase the risk of hypoglycemia, as can inadequate nutrition, cognitive impairment, and other factors. While hypoglycemia can often be easily treated, the physiologic, sensory, and cognitive changes of aging can inhibit bodily mechanisms that produce warning symptoms of low blood glucose and impair the ability to recognize such symptoms when they occur. Severe hypoglycemic events in older adults can have devastating consequences. Nurses are well positioned to assess for hypoglycemia and to educate the growing population of older adults with type 2 diabetes on its prevention. PMID- 26771667 TI - Using Essential Oils to Enhance Nursing Practice and for Self-Care. AB - With the growing popularity of integrative medicine, essential oils have found their way back into health care. Essential oils provide a simple way to alleviate certain physical symptoms, promote emotional well-being, and provide comfort. This article, the last in a five-part series on holistic nursing, discusses the administration and common uses of essential oils; their reported benefits, potential risks, and contraindications; and the current state of associated research. The authors focus specifically on the inhalation, both direct and by diffusion, as well as the topical application of essential oils, providing guidance for their use in acute care, self-care, community nursing, and long-term care that will enable readers to incorporate this modality into nursing practice. PMID- 26771665 TI - Discovery of the First Potent and Selective Inhibitors of Human dCTP Pyrophosphatase 1. AB - The dCTPase pyrophosphatase 1 (dCTPase) regulates the intracellular nucleotide pool through hydrolytic degradation of canonical and noncanonical nucleotide triphosphates (dNTPs). dCTPase is highly expressed in multiple carcinomas and is associated with cancer cell stemness. Here we report on the development of the first potent and selective dCTPase inhibitors that enhance the cytotoxic effect of cytidine analogues in leukemia cells. Boronate 30 displays a promising in vitro ADME profile, including plasma and mouse microsomal half-lives, aqueous solubility, cell permeability and CYP inhibition, deeming it a suitable compound for in vivo studies. PMID- 26771668 TI - Prevalence, structure and correlates of anxiety-depression in boys with an autism spectrum disorder. AB - BACKGROUND: Comorbidity of anxiety and depression predicts impaired treatment outcomes, poor quality of life and increased suicide risk. No study has reported on a combined measure of anxiety-depression in boys with an Autism Spectrum Disorder. AIMS: To explore the prevalence, underlying factor structure and relationships between anxiety-depression, physiological stress and symptoms of Autism Spectrum Disorder (ASD). METHODS: 150 boys (aged 6-18 years; IQ M=94.9, range=73-132) with an ASD plus their parents (135 mothers, 15 fathers) completed scales about the boys' anxiety and depression, and the boys provided samples of their saliva in the morning and afternoon. Parents also completed the ASD Behaviour Checklist about the boys' ASD symptoms. RESULTS: The two sources of ratings were not significantly different for prevalence of anxiety-depression but the factor structures varied between the parents' and boys' responses, with a four-factor solution for the boys' ratings and a three-factor solution for the parents' ratings. There were also differences in the correlations between cortisol and anxiety-depression and between ASD symptoms and anxiety depression across the boys' and parents' data. CONCLUSIONS: Assessment of anxiety and depression comorbidity from parents and from children with an ASD themselves could provide a valuable adjunct datum when diagnosing ASD. PMID- 26771669 TI - Non-Steroidal Anti-Inflammatory Drug Use and Risk of Anastomotic Leakage after Anterior Resection: A Protocol-Based Study. AB - BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) have been introduced as opioid-sparing analgesics in colorectal surgery. However, recent research has implicated these drugs as risk factors for anastomotic dehiscence. METHODS: The Swedish Colorectal Cancer Registry was used to identify all patients operated with anterior resection for rectal cancer at centres that performed more than 25 abdominal operations per year, from 2007 to 2012, inclusive. The registry provided individual patient data on demographic variables and symptomatic anastomotic leakage. The patient exposure to NSAIDs was defined according to the protocol of the hospital at which the patient was operated. Logistic regression was employed to estimate ORs and 95% CIs, adjusting for confounders. RESULTS: The study cohort comprised 2,605 patients operated at 21 centres. In the NSAID group, 102/1,458 (7.0%) suffered an anastomotic leak, as compared to 124/1,023 (10.8%) in the non-NSAID group. With adjustment for confounding, patients treated at NSAID hospitals had a reduced risk of developing anastomotic leakage (OR 0.68; 95% CI 0.48-0.96). CONCLUSIONS: In this retrospective protocol-based study, NSAIDs did not increase the risk of anastomotic leakage after anterior resection for rectal cancer. The postoperative use of NSAIDs may not be detrimental, but more research is warranted. PMID- 26771670 TI - Netnography of Female Use of the Synthetic Growth Hormone CJC-1295: Pulses and Potions. AB - BACKGROUND: Communal online folk pharmacology fuels the drive for short cuts in attaining muscle enhancement, fat loss, and youthful skin. OBJECTIVES: The study used "netnography" to explore female use of CJC-1295, a synthetic growth hormone analogue from the perspectives contained in Internet forum activity. METHODS: A systematic Internet search was conducted using variation of the term "CJC-1295"; and combined with "forum." Ninety-six hits related to bodybuilding websites where CJC-1295 was mentioned. Following application of exclusion criteria to confine to female use and evidence of forum activity, 9 sites remained. These were searched internally for reference to CJC-1295. Twenty-three discussion threads relating to female use of CJC-1295 formed the end data set, and analyzed using the Empirical Phenomenological Psychological method. RESULTS: Forum users appeared well versed and experienced in the poly use of performance and image drug supplementation. Choice to use CJC-1295 centered on weight loss, muscle enhancement, youthful skin, improved sleep, and injury healing. Concerns were described relating to female consequences of use given gender variations in growth hormone pulses affecting estimation of dosage, cycling, and long-term consequences. CONCLUSIONS: Public health interventions should consider female self-medicating use of synthetic growth hormone within a repertoire of product supplementation, and related adverse health consequences. PMID- 26771671 TI - Biocatalytic Characterization of Human FMO5: Unearthing Baeyer-Villiger Reactions in Humans. AB - Flavin-containing mono-oxygenases are known as potent drug-metabolizing enzymes, providing complementary functions to the well-investigated cytochrome P450 mono oxygenases. While human FMO isoforms are typically involved in the oxidation of soft nucleophiles, the biocatalytic activity of human FMO5 (along its physiological role) has long remained unexplored. In this study, we demonstrate the atypical in vitro activity of human FMO5 as a Baeyer-Villiger mono-oxygenase on a broad range of substrates, revealing the first example to date of a human protein catalyzing such reactions. The isolated and purified protein was active on diverse carbonyl compounds, whereas soft nucleophiles were mostly non- or poorly reactive. The absence of the typical characteristic sequence motifs sets human FMO5 apart from all characterized Baeyer-Villiger mono-oxygenases so far. These findings open new perspectives in human oxidative metabolism. PMID- 26771672 TI - Parallel Mapping of Antibiotic Resistance Alleles in Escherichia coli. AB - Chemical genomics expands our understanding of microbial tolerance to inhibitory chemicals, but its scope is often limited by the throughput of genome-scale library construction and genotype-phenotype mapping. Here we report a method for rapid, parallel, and deep characterization of the response to antibiotics in Escherichia coli using a barcoded genome-scale library, next-generation sequencing, and streamlined bioinformatics software. The method provides quantitative growth data (over 200,000 measurements) and identifies contributing antimicrobial resistance and susceptibility alleles. Using multivariate analysis, we also find that subtle differences in the population responses resonate across multiple levels of functional hierarchy. Finally, we use machine learning to identify a unique allelic and proteomic fingerprint for each antibiotic. The method can be broadly applied to tolerance for any chemical from toxic metabolites to next-generation biofuels and antibiotics. PMID- 26771673 TI - Is Using the Strengths and Difficulties Questionnaire in a Community Sample the Optimal Way to Assess Mental Health Functioning? AB - An important characteristic of a screening tool is its discriminant ability or the measure's accuracy to distinguish between those with and without mental health problems. The current study examined the inter-rater agreement and screening concordance of the parent and teacher versions of SDQ at scale, subscale and item-levels, with the view of identifying the items that have the most informant discrepancies; and determining whether the concordance between parent and teacher reports on some items has the potential to influence decision making. Cross-sectional data from parent and teacher reports of the mental health functioning of a community sample of 299 students with and without disabilities from 75 different primary schools in Perth, Western Australia were analysed. The study found that: a) Intraclass correlations between parent and teacher ratings of children's mental health using the SDQ at person level was fair on individual child level; b) The SDQ only demonstrated clinical utility when there was agreement between teacher and parent reports using the possible or 90% dichotomisation system; and c) Three individual items had positive likelihood ratio scores indicating clinical utility. Of note was the finding that the negative likelihood ratio or likelihood of disregarding the absence of a condition when both parents and teachers rate the item as absent was not significant. Taken together, these findings suggest that the SDQ is not optimised for use in community samples and that further psychometric evaluation of the SDQ in this context is clearly warranted. PMID- 26771674 TI - The unmasking of 'junk' RNA reveals novel sRNAs: from processed RNA fragments to marooned riboswitches. AB - While the notion that RNAs can function as regulators dates back to early molecular studies of gene regulation of the lac operon, it is only over the last decade that the ubiquity and diversity of regulatory RNAs are being realized. Advancements in high throughput sequencing and the adoption of these approaches to rapidly sequence genomes and transcriptomes and to examine gene expression and RNA binding protein specificity have revealed an ever-expanding RNA world. In this review, we focus on recent studies revealing that RNA fragments cleaved from larger coding or noncoding RNAs can have regulatory functions. Additionally, we discuss examples of riboswitches that function in trans as mRNA or protein binding sRNAs, upending the traditional thinking that these are exclusively cis acting elements. PMID- 26771676 TI - Changes in Total Lesion Glycolysis Evaluated by Repeated F-18 FDG PET/CT as Prognostic Factor in Locally Advanced Esophageal Cancer Patients Treated with Preoperative Chemoradiotherapy. AB - AIMS: The present study was aimed to investigate whether volumetric parameters measured by sequential F-18 fluoro-D-glucose (F-18 FDG) positron emission tomography/computed tomography (PET/CT) could be used as prognostic factors in patients with locally advanced esophageal cancer (LAEC) who received preoperative chemoradiotherapy (CRT). METHODS: A total of 61 patients with LAEC were included in the current study. All patients were evaluated by F-18 FDG PET/CT before and after 46 Gy of radiotherapy with a concurrent cisplatin-based chemotherapy. Initial, second, and percent changes (Delta, %) of semiquantitative and volumetric parameters were used to calculate recurrence-free survival (RFS) and overall survival (OS). The median values of each parameter were used as cutoff values. The prognostic significance was assessed using univariate and multivariate Cox proportional hazard regression analyses. RESULTS: Cox proportional hazard regression analyses revealed that change in total lesion glycolysis (DeltaTLG) was a potent predictor of RFS and OS. Kaplan-Meier survival curves showed better prognosis in higher DeltaTLG. CONCLUSION: Our data suggest that DeltaTLG measured by sequential F-18 FDG PET/CT after preoperative CRT could provide prognostic information in LAEC patients. PMID- 26771675 TI - Maternal Exercise during Pregnancy Increases BDNF Levels and Cell Numbers in the Hippocampal Formation but Not in the Cerebral Cortex of Adult Rat Offspring. AB - Clinical evidence has shown that physical exercise during pregnancy may alter brain development and improve cognitive function of offspring. However, the mechanisms through which maternal exercise might promote such effects are not well understood. The present study examined levels of brain-derived neurotrophic factor (BDNF) and absolute cell numbers in the hippocampal formation and cerebral cortex of rat pups born from mothers exercised during pregnancy. Additionally, we evaluated the cognitive abilities of adult offspring in different behavioral paradigms (exploratory activity and habituation in open field tests, spatial memory in a water maze test, and aversive memory in a step-down inhibitory avoidance task). Results showed that maternal exercise during pregnancy increased BDNF levels and absolute numbers of neuronal and non-neuronal cells in the hippocampal formation of offspring. No differences in BDNF levels or cell numbers were detected in the cerebral cortex. It was also observed that offspring from exercised mothers exhibited better cognitive performance in nonassociative (habituation) and associative (spatial learning) mnemonic tasks than did offspring from sedentary mothers. Our findings indicate that maternal exercise during pregnancy enhances offspring cognitive function (habituation behavior and spatial learning) and increases BDNF levels and cell numbers in the hippocampal formation of offspring. PMID- 26771679 TI - Letter to the Editor: Suboccipital decompression without dural opening. PMID- 26771677 TI - False Negative NIPT Results: Risk Figures for Chromosomes 13, 18 and 21 Based on Chorionic Villi Results in 5967 Cases and Literature Review. AB - Non-invasive prenatal testing (NIPT) demonstrated a small chance for a false negative result. Since the "fetal" DNA in maternal blood originates from the cytotrophoblast of chorionic villi (CV), some false negative results will have a biological origin. Based on our experience with cytogenetic studies of CV, we tried to estimate this risk. 5967 CV samples of pregnancies at high risk for common aneuplodies were cytogenetically investigated in our centre between January 2000 and December 2011. All cases of fetal trisomy 13, 18 and 21 were retrospectively studied for the presence of a normal karyotype or mosaicism < 30% in short-term cultured (STC-) villi. 404 cases of trisomies 13, 18 and 21 were found amongst 5967 samples (6,8%). Of these 404 cases, 14 (3,7%) had a normal or low mosaic karyotype in STC-villi and therefore would potentially be missed with NIPT. It involved 2% (5/242) of all trisomy 21 cases and 7.3% (9/123) of all trisomy 18 cases. In 1:426 (14/5967) NIPT samples of patients at high risk for common aneuploidies, a trisomy 18 or 21 will potentially be missed due to the biological phenomenon of absence of the chromosome aberration in the cytotrophoblast. PMID- 26771678 TI - Changing Paradigm of Hemophilia Management: Extended Half-Life Factor Concentrates and Gene Therapy. AB - Management of hemophilia has evolved significantly in the last century-from recognition of the causative mechanism in the 1950s to commercially available clotting factor concentrates in the 1960s. Availability of lyophilized concentrates in the 1970s set the stage for home-based therapy, followed by introduction of virally attenuated plasma-derived, and then recombinant factor concentrates in the 1980s and 1990s, respectively. The subsequent years saw a paradigm shift in treatment goals from on-demand therapy to prophylactic factor replacement starting at an early age, to prevent hemarthrosis becoming the standard of care for patients with severe hemophilia. In the developed world, the increasing use of home-based prophylactic regimens has significantly improved the quality of life, and life expectancy of patients with severe hemophilia. Seminal developments in the past 5 years, including the commercial availability of extended half-life factor concentrates and the publication of successful results of gene therapy for patients with hemophilia B, promise to further revolutionize hemophilia care over the next few decades. In this review, we summarize the evolution of management for hemophilia, with a focus on extended half-life factor concentrates and gene therapy. PMID- 26771681 TI - Botulinum Toxin Type A for Relief of Intractable Pain After Face and Brow-Lift Surgery. PMID- 26771680 TI - A case of spinal epidural venous malformation with mediastinal extension: management with combined surgery and percutaneous sclerotherapy. AB - While spinal epidural arteriovenous malformations, fistulas, and shunts are well reported, the presence of a venous malformation in the spinal epidural space is a rare phenomenon. Herein, the authors report the clinical presentation, imaging findings, pathological features, and the outcome of surgical and percutaneous interventional management of a mediastinal and spinal epidural venous malformation in a young woman who presented clinically with neurogenic claudication from presumed venous hypertension precipitating the formation of a syrinx. The patient underwent a C6-T5 osteoplastic laminectomy for decompression of the spinal canal and subtotal resection of the epidural venous malformation, followed by percutaneous sclerotherapy of the mediastinal and residual anterior spinal venous malformation. She developed transient loss of dorsal column sensation, which returned to baseline within 3 weeks of the surgery. A 6-month postoperative MRI study revealed complete resolution of the syrinx and the mediastinal venous malformation. Twelve months after the surgery, the patient has had resolution of all neurological symptoms with the exception of her premorbid migraine headaches. A multidisciplinary approach with partial resection and the use of percutaneous sclerotherapy for the residual malformation can be used to successfully treat a complex venous malformation. PMID- 26771682 TI - Comparison of MITF and Melan-A Immunohistochemistry During Mohs Surgery for Lentigo Maligna-Type Melanoma In Situ and Lentigo Maligna Melanoma. AB - BACKGROUND: Mohs micrographic surgery (MMS) with frozen section immunohistochemistry is a treatment option for malignant melanoma in situ (MMIS) and lentigo maligna melanoma (LMM). Melan-A is a cytoplasmic melanocyte immunostain useful on frozen sections but may lack specificity. Microphthalmia transcription factor (MITF) is a more specific nuclear melanocyte immunostain less frequently used in MMS. OBJECTIVE: To quantify melanocyte density in chronic sun-damaged skin (CSDS), negative margin, and tumor from patients undergoing MMS for MMIS and LMM using MITF and melan-A. METHODS: Sixteen patients with MMIS or LMM had frozen sections from CSDS, negative margin, and 12 tumor samples, stained with MITF and melan-A. Melanocyte counts were performed. RESULTS: Chronic sun damaged skin mean melanocyte count (MMC) for MITF and melan-A was 9.8 and 13.7, respectively, (p < .001). Negative margin MMC for MITF and melan-A was 8.84 and 14.06, respectively, (p < .001). Tumor MMC for MITF and melan-A was 63.5 and 62.4, respectively. CONCLUSION: Although both MITF and melan-A facilitate the identification of tumor during MMS for MMIS and LMM, the apparent melanocyte density on tumor-free CSDS appears higher with melan-A than MITF. Microphthalmia transcription factor provides a crisp outline of melanocyte nuclei and is a useful alternative stain to melan-A for MMS of melanoma. PMID- 26771683 TI - The Accuracy of Ultrasonography on the Location of Lipomas in the Forehead. AB - BACKGROUND: Preoperative recognition of tumor plane is important to avoid surgical complications in surgeries involving the scalp. Ultrasonography is a useful diagnostic tool to detect the depth of tumor noninvasively. However, some findings are not always in accordance with the actual locations of lipomas, especially in the forehead. OBJECTS: To evaluate the accuracy of preoperative ultrasonographic findings for the location of lipomas in the forehead. MATERIALS AND METHODS: The study included 14 patients with lipomas in the forehead who all underwent preoperative ultrasonography and surgical excision of the lesions. The authors compared the diagnostic location of tumors by ultrasonography with the actual location in the surgical field. RESULTS: On ultrasonography, 10 of 14 cases were diagnosed as frontalis-associated lipomas. However, 13 cases were confirmed as frontalis-associated lipomas intraoperatively, and only 1 case as superficial lipoma, which did not correspond with the ultrasonographic finding. The ultrasonographic findings were accurate in 9 of 14 cases (64.3%). CONCLUSION: The accuracy of ultrasonography on the location of lipomas in the forehead is not as high as expected. Therefore, the surgeon must consider the possibility of deep lipoma even if a forehead lipoma is superficial in location on ultrasonography. PMID- 26771684 TI - A Review of the Association Between Parkinson Disease and Malignant Melanoma. AB - BACKGROUND: An association between melanoma and Parkinson disease (PD) has been hinted at in the neurology and oncology literature since the 1970s after the initiation of levodopa (L-DOPA) therapy for PD. Given that L-DOPA is a substrate in melanin synthesis, there existed a concern that this therapy might cause melanoma. OBJECTIVE: The objective was to research possible etiological links to explain the connection between PD and melanoma. METHODS: A PubMed and Google Scholar literature search was performed using access provided by the University of Minnesota biomedical library. RESULTS: Patients with PD have an overall decreased risk of cancer diagnoses. However, breast cancer and melanoma have an uncharacteristically high rate of co-occurrence with PD. Family history of melanoma and lighter hair and skin color confer a higher risk of developing PD, and having a first-degree relative with either disease conveys a significantly increased risk of developing the other. Other possible connections that have been explored include pigmentation genes in neural-derived cells, pesticides, MC1R polymorphisms, and abnormal cellular autophagy. CONCLUSION: Although a link between PD and melanoma exists, the etiology of this link continues to be elusive. Both PD and melanoma are likely multifactorial diseases involving genetic and environmental risk factors. PMID- 26771685 TI - Chronic Ulcer as a Complication of Gold Needle Implantation. PMID- 26771686 TI - Efficacy and Safety of Cross-Linked Carboxymethylcellulose Filler for Rejuvenation of the Lower Face: A 6-Month Prospective Open-Label Study. AB - BACKGROUND: Cross-linked carboxymethylcellulose (CMC) filler is a biosynthetic filler with very low antigenic risk. OBJECTIVE: To assess the efficacy and safety of CMC filler in the rejuvenation of the lower face. MATERIALS AND METHODS: Two hundred eighty-seven procedures were performed in 174 patients: 115 nasolabial folds, 86 marionette lines, 29 bar codes, 14 cheek rhytides, and 43 lip rejuvenations. Results were evaluated at 3 (T1) and 6 months (T2) with photographic evaluation, Global Aesthetic Improvement Scale (GAIS), Modified Fitzpatrick Wrinkle Scale (MFWS) for nasolabial folds, Marionette Lines Grading Scale (MLGS), and Medicis Lip Fullness Scale (LFS). RESULTS: GAIS was >=2 in >91.05% of patients both in T1 and T2. MFWS score significantly improved at T1 (86.9% class <=1, p < .001) and T2 (82.6% class <=1, p < .001); in all patients in T1 and T2, median amelioration of MLGS was 2 +/- 1 and there was a significant amelioration of at least 1 grade in LSF in both upper and lower lips. CONCLUSION: The use of CMC filler resulted in a significant and satisfactory amelioration of lower face aging signs with very low incidence of adverse events. Therefore, it should be considered a valid alternative to cross-linked hyaluronic acid fillers. PMID- 26771687 TI - Correlation of Local Structure and Diffusion Pathways in the Modulated Anisotropic Oxide Ion Conductor CeNbO(4.25). AB - CeNbO4.25 is reported to exhibit fast oxygen ion diffusion at moderate temperatures, making this the prototype of a new class of ion conductor with applications in a range of energy generation and storage devices. To date, the mechanism by which this ion transport is achieved has remained obscure, in part due to the long-range commensurately modulated structural motif. Here we show that CeNbO4.25 forms with a unit cell ~12 times larger than the stoichiometric tetragonal parent phase of CeNbO4 as a result of the helical ordering of Ce(3+) and Ce(4+) ions along z. Interstitial oxygen ion incorporation leads to a cooperative displacement of the surrounding oxygen species, creating interlayer "NbO6" connectivity by extending the oxygen coordination number to 7 and 8. Molecular dynamic simulations suggest that fast ion migration occurs predominantly within the xz plane. It is concluded that the oxide ion diffuses anisotropically, with the major migration mechanism being intralayer; however, when obstructed, oxygen can readily move to an adjacent layer along y via alternate lower energy barrier pathways. PMID- 26771688 TI - It's not too late: a proposal to standardize the terminology of "late-onset" cytomegalovirus infection and disease in solid organ transplant recipients. PMID- 26771689 TI - Chikungunya infection in a human immunodeficiency virus-infected kidney transplant recipient returning to Italy from the Dominican Republic. AB - Since December 2013, chikungunya virus (CHIKV) spread in many countries of the Western Hemisphere, and during the last year some cases of infected European travelers, coming back from the Caribbean, have been reported. The risk of acquiring severe travel-related illness is higher in immunocompromised subjects, such as patients with human immunodeficiency virus (HIV) infection or solid organ transplant recipients. We reported the first case, to our knowledge, of CHIKV infection in an HIV-infected kidney transplant recipient. PMID- 26771692 TI - Different-Sized Gold Nanoparticle Activator/Antigen Increases Dendritic Cells Accumulation in Liver-Draining Lymph Nodes and CD8+ T Cell Responses. AB - The lack of efficient antigen and activator delivery systems, as well as the restricted migration of dendritic cells (DCs) to secondary lymph organs, dramatically limits DC-based adoptive immunotherapy. We selected two spherical gold nanoparticle (AuNP)-based vehicles of optimal size for activator and antigen delivery. Their combination (termed the NanoAu-Cocktail) was associated with the dual targeting of CpG oligonucleotides (CpG-ODNs) and an OVA peptide (OVAp) to DC subcellular compartments, inducing enhanced antigen cross-presentation, upregulated expression of costimulatory molecules and elevated secretion of T helper1 cytokines. We demonstrated that the intravenously transfused NanoAu Cocktail pulsed DCs showed dramatically improved in vivo homing ability to lymphoid tissues and were settled in T cell area. Especially, by tissue distribution analysis, we found that more than 60% of lymphoid tissues-homing DCs accumulated in liver-draining lymph nodes (LLNs). The improved homing ability of NanoAu-Cocktail pulsed DCs was associated with the high expression of chemokine receptor 7 (CCR7) and rearrangement of the cytoskeletons. In addition, by antigen specific tetramers detection, NanoAu-Cocktail pulsed DCs were proved able to elicit strong antigen-specific CD8+ T cell responses, which provided enhanced protection from viral invasions. This study highlights the importance of codelivering antigen/adjuvant using different sized gold nanoparticles to improve DC homing and therapy. PMID- 26771693 TI - Creating Hierarchical Topographies on Fibrous Platforms Using Femtosecond Laser Ablation for Directing Myoblasts Behavior. AB - Developing an artificial extracellular matrix that closely mimics the native tissue microenvironment is important for use as both a cell culture platform for controlling cell fate and an in vitro model system for investigating the role of the cellular microenvironment. Electrospinning, one of the methods for fabricating structures that mimic the native ECM, is a promising technique for creating fibrous platforms. It is well-known that align or randomly distributed electrospun fibers provide cellular contact guidance in a single pattern. However, native tissues have hierarchical structures, i.e., topographies on the micro- and nanoscales, rather than a single structure. Thus, we fabricated randomly distributed nanofibrous (720 +/- 80 nm in diameter) platforms via a conventional electrospinning process, and then we generated microscale grooves using a femtosecond laser ablation process to develop engineered fibrous platforms with patterned hierarchical topographies. The engineered fibrous platforms can regulate cellular adhesive morphology, proliferation, and distinct distribution of focal adhesion proteins. Furthermore, confluent myoblasts cultured on the engineered fibrous platforms revealed that the direction of myotube assembly can be controlled. These results indicate that our engineered fibrous platforms may be useful tools in investigating the roles of nano- and microscale topographies in the communication between cells and ECM. PMID- 26771691 TI - Risk Factors for Insulin Resistance, Metabolic Syndrome, and Diabetes in 248 HFE C282Y Homozygotes Identified by Population Screening in the HEIRS Study. AB - BACKGROUND: We sought to identify risk factors for insulin resistance, metabolic syndrome (MetS), and diabetes mellitus in 248 non-Hispanic white HFE C282Y homozygotes identified by population screening. METHODS: We analyzed observations obtained prospectively in a postscreening examination: age; sex; body mass index (BMI); systolic/diastolic blood pressure; metacarpophalangeal (MP) joint hypertrophy; hepatomegaly; complete blood counts; alanine/aspartate aminotransferase levels; elevated C-reactive protein (>0.5 mg/dL); transferrin saturation; serum ferritin; homeostasis model assessment-insulin resistance (HOMA IR); and MetS. RESULTS: Twenty-six participants (10.5%) had diabetes diagnoses. A significant trend across HOMA-IR quartiles was observed only for blood neutrophils. Logistic regression on HOMA-IR fourth quartile revealed positive associations: age (P = 0.0002); male sex (P = 0.0022); and BMI (P < 0.0001). HOMA IR fourth quartile predicted MetS (P < 0.0001). Logistic regression on diabetes revealed positive associations: age (P = 0.0012); male sex (P = 0.0068); MP joint hypertrophy (P = 0.0167); neutrophils (P = 0.0342); and MetS (P = 0.0298). Serum ferritin did not predict HOMA-IR fourth quartile, MetS, or diabetes. CONCLUSIONS: In screening C282Y homozygotes, age, male sex, and BMI predicted HOMA-IR fourth quartile. HOMA-IR fourth quartile alone predicted MetS. Diabetes was associated with greater age, male sex, MP joint hypertrophy, greater blood neutrophil counts, and MetS. PMID- 26771694 TI - Physiologically Based Pharmacokinetic Model for Long-Circulating Inorganic Nanoparticles. AB - A physiologically based pharmacokinetic model was developed for accurately characterizing and predicting the in vivo fate of long-circulating inorganic nanoparticles (NPs). This model is built based on direct visualization of NP disposition details at the organ and cellular level. It was validated with multiple data sets, indicating robust inter-route and interspecies predictive capability. We suggest that the biodistribution of long-circulating inorganic NPs is determined by the uptake and release of NPs by phagocytic cells in target organs. PMID- 26771695 TI - [The importance of the mother archetype in our day's Hungary]. AB - The worsening demographic situation in our mother country as in Europe too call for the investigation of family life and the feminine role. We began the analysis of the developing problem with the investigation of the spirit of the age in which it appears. We examine the importance of the family life and the woman's role in the foundation of the future. We point out that in the archaic pattern of family life, the mother archetype functions as energy generator from the point of the family and the society. The children make it possible and necessary for the parents to live over again the whole process of human development. Through empathy they make possible the spontaneous corrective examination of the parents own deep psychological relational patterns. These make it certain that family life works psychologically as the source of energy, and workshop. PMID- 26771696 TI - [Neurobiological correlates of cognitive flexibility in ADHD - A systematic review of the literature]. AB - INTRODUCTION: Attention deficit hyperactivity disorder (ADHD) is one of the most commonly diagnosed childhood psychiatric disorders, which persists to adulthood in 30-50% of the cases. Previous studies have shown that cognitive flexibility, which means to switch between two different rules, that can be tested with task switching paradigms, is affected. Although poor performance in cognitive flexibility tests has been demostrated, the neurobiological background is only partly known. OBJECTIVE: The aim of our review was to examine the neurobiological background of impairment of cognitive flexibility in ADHD, with a specific focus on functional MRI (fMRI) and electrophysiological (electroencephalography, EEG) studies. METHODS: We searched MEDLINE, PubMed, and PsychInfo using the following keywords: 'ADHD', 'cognitive flexibility', 'set shifting', 'task switching', 'EEG', 'fMRI'. RESULTS: Compared to healthy controls, ADHD patients showed reduced activation in regions of the prefrontal and parietal lobe and in the basal ganglia. However in two studies, increased activation was also observed in specific regions of temporal lobe and in anterior cingulate cortex. Magnetoencephalographic results indicated that instead of an increased activity in medio-temporal lobe, ADHD patients showed an enhanced activation in the superior temporal gyrus and in the left inferior parietal lobe. CONCLUSIONS: Based on our review, patients with ADHD, as compared to healthy controls, showed reduced activation in brain regions associated with cognitive flexibility. Based on the differences in the spatial and temporal patterns of activation in the temporal lobe we conclude that ADHD patient engage different brain regions to resolve the conflicts caused by task switching. However, further studies are required to corroborate this conclusion. PMID- 26771697 TI - [Recovering helpers in the addiction treatment system in Hungary: an interpretative phenomenological analysis]. AB - INTRODUCTION: The work of recovering helpers who work in the addiction rehabilitation centres was studied. The aim was to investigate the process of addicts becoming recovering helpers, and to study what peer help means to them. METHODS: According to interpretative phenomenological analysis (IPA) design, subjects were selected, data were collected and analysed. SUBJECTS: 6 (5 males, 1 female), working as recovering helpers at least one year at addiction rehabilitation centres. Semi-structured life interviews were carried out and analysed according to IPA. RESULTS: Emerging themes from the interviews were identified and summarized, then interpreted as central themes: important periods and turning points of the life story interviews: the experience of psychoactive drugs use, the development of the addiction (which became " Turning Point No 1") then the "rock bottom" experience ("Turning Point No 2"). Then the experience of the helping process was examined: here four major themes were identified: the development of the recovering self and the helping self, the wounded helper and the skilled helper, the experience of the helping process. DISCUSSION: IPA was found to be a useful method for idiographic exploration of the development and the work of the recovering helpers. The work of the recovering helpers can be described as mentoring of the addict clients. Our experiences might be used for the training programs for recovering helpers as well as to adopt their professional role in addiction services. PMID- 26771698 TI - [Mindfulness-based interventions in psychotherapy and in rehabilitation]. AB - Mindfulness means paying attention in a particular way: on purpose, in the present moment in a nonjudgmental and nonreactive way. During the last years we can see a growing interest about this topic both in psychology both in medicine. Our article reviews the concept of mindfulness, the wide range of its effects (from genexpression to social connections) and the theoretical models of mindfulness. We shortly review the methods which explicitly focus on the improvement of the skill of mindfulness (Mindfulness Based Stress Reduction, Mindfulness Based Cognitive Therapy, Acceptance and Commitment Therapy) and the role of mindfulness in (oncological and neurological) rehabilitation. PMID- 26771699 TI - [Anti-N-methyl-D aspartate receptor encephalitis - guideline to the challenges of diagnosis and therapy]. AB - OBJECTIVE: Anti-N-methyl-D-Aspartate encephalitis is a recently diagnosed autoimmune disorder with increasing significance. During this disease antibodies are produced against the subunit of the NMDA receptor, which cause different symptoms, both psychiatric and neurological. The aim of this publication is to introduce this disease, to facilitate the diagnosis and to recommend therapeutical guideline. MATERIALS AND METHODS: In this review we summarized the relevant literature published between 2007 and 2015 giving emphasis on etiopathogenesis, diagnosis, differential diagnosis, treatment and prognosis. RESULTS: In the etiology an underlying tumor or a viral agent should be considered. During the disease we can discern 3 periods: first prodromal viral infections-like symptoms can be seen, 1-2 weeks later psychiatric symptoms, such as aggression, sleep and behavior disturbances appear. After that neurological symptoms (tonic-clonic convulsions, aphasia, catatonia, orofacial dyskinesia, autonom lability, altered mental state) are typical, and the patient's condition deteriorates. For the correct diagnosis it is necessary to detect antibodies against the NMDA receptor from the serum and the liquor. Steroids, immunoglobulins and plasmaheresis are the first-line therapies. If the disease is unresponsive, then as a second-line therapy anti-CD 20 (Rituximab) and cyclophosphamid can be useful. Most of the patients are improving without any neurological sequale with prompt detection and appropriate therapy. CONCLUSION: It is important to be familiar with the symptoms, diagnosis and therapy of this disease as a practicing clinician, especially as a psychiatrist or neurologist. 75 percentage of the patients are admitted to psychiatric departments first because of the leading symptoms. Autoimmune NMDA encephalitis is a reversible disease after early diagnosis and treatment. PMID- 26771700 TI - [MMPI-2 profiles in groups of systemic autoimmune disease - rheumatoid arthritis and systemic lupus erythematosus - patients]. AB - OBJECTIVE: Systemic autoimmune diseases like rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) are characterized by the alteration of immunological response, which can damage many organs and systems and result in a wide variety of clinical presentations. In addition to physical symptoms, psychiatric disorders are also common to many autoimmune diseases. Anxiety, depression, psychosis and cognitive deficits have the highest prevalence. The aim of this study was to display the degree of psychopathological symptoms in patients with RA and SLE. METHODS: Female inpatients with RA (N=68) and SLE (N=78) were recruited from the Rheumatology and Immunology Clinic of the University of Pecs and were asked to complete the Minnesota Multiphasic Personality Inventory-2 (MMPI-2) and a short demografical form. The clinical personality profiles of the patient groups were explored and compared with each other. RESULTS: High scores (above 64T) were detected on the Hypochondriasis (Hs), Depression (D) and Hysteria (Hy) scales in both groups. Besides, the participants performed elevated scores on the Masculinity-Feminity (Mf), Psychasthenia (Pt) and Social Introversion (Si) clinical scales. They scored in the elevated range on the Physical Malfunctioning, Subjective Depression, Lassitude-Malaise and Somatic Complaints subscales of the neurotic triad. No significant difference was found on the ten clinical scales between the SLE and RA patients. CONCLUSION: Characteristics of MMPI-2 profiles in SLE and RA patients seem to be the consequence of the disease and a common feature of chronic conditions. High scores on the neurotic triad scales may reflect the comorbid psychiatric disorders and the somatic symptoms alike, so further investigations with the revised Hungarian MMPI-2 are needed. PMID- 26771701 TI - Psychosis in adolescence - an anthropological approach. AB - Certain young men may react with psychosis to the Eriksonian developmental crisis of identity vs. role diffusion. In its symptomatology, this decompensation belongs to the category of schizophreniphorm psychoses, and may be reappearing within a given timeframe. This can be termed as a "psychosocial moratorium". Approached from a socio-anthropological viewpoint, in our culture deprived of myths and rites, these psychoses may be interpreted as analogous phenomena to initiation rites. The triad of segregation-liminality-reintegration may come useful in the therapeutic interpretation of these phenomena. PMID- 26771702 TI - Interactions Between Trypanosoma cruzi the Chagas Disease Parasite and Naturally Infected Wild Mepraia Vectors of Chile. AB - Chagas disease, which ranks among the world's most neglected diseases, is a chronic, systemic, parasitic infection caused by the protozoan Trypanosoma cruzi. Mepraia species are the wild vectors of this parasite in Chile. Host-parasite interactions can occur at several levels, such as co-speciation and ecological host fitting, among others. Thus, we are exploring the interactions between T. cruzi circulating in naturally infected Mepraia species in all areas endemic of Chile. We evaluated T. cruzi infection rates of 27 different haplotypes of the wild Mepraia species and identified their parasite genotypes using minicircle PCR amplification and hybridization tests with genotype-specific DNA probes. Infection rates were lower in northern Chile where Mepraia gajardoi circulates (10-35%); in central Chile, Mepraia spinolai is most abundant, and infection rates varied in space and time (0-55%). T. cruzi discrete typing units (DTUs) TcI, TcII, TcV, and Tc VI were detected. Mixed infections with two or more DTUs are frequently found in highly infected insects. T. cruzi DTUs have distinct, but not exclusive, ecological and epidemiological associations with their hosts. T. cruzi infection rates of M. spinolai were higher than in M. gajardoi, but the presence of mixed infection with more than one T. cruzi DTU was the same. The same T. cruzi DTUs (TcI, TcII, TcV, and TcVI) were found circulating in both vector species, even though TcI was not equally distributed. These results suggest that T. cruzi DTUs are not associated with any of the two genetically related vector species nor with the geographic area. The T. cruzi vectors interactions are discussed in terms of old and recent events. By exploring T. cruzi DTUs present in Mepraia haplotypes and species from northern to central Chile, we open the analysis on these invertebrate host-parasite interactions. PMID- 26771703 TI - Validation of PHPQoL, a Disease-Specific Quality-of-Life Questionnaire for Patients With Primary Hyperparathyroidism. AB - CONTEXT: Health-related quality of life (HRQoL) is impaired in primary hyperparathyroidism (PHPT) but instruments to specifically assess this are scarce. OBJECTIVE: Validate the new disease-specific Primary Hyperparathyroidism Quality of Life (PHPQoL) questionnaire in usual clinical practice. DESIGN: Observational, prospective, and multicenter. SETTING: Public hospital ambulatory care. PATIENTS: Patients with PHPT of both sexes, aged more than or equal to 18 years either initiated treatment for PHPT (group A) or had stable PHPT, not requiring therapy (group B). Patients in group A had at least one surgical criterion according to the 2009 Third International Workshop on Management of Asymptomatic PHPT. INTERVENTION: Sociodemographic, clinical, and HRQoL data (PHPQol, Short Form-36, Psychological Well-Being Index, and patients' self perceived health status) were collected. Group A underwent 4 evaluations (baseline, 3 +/- 1, 6 +/- 1, and 12 +/- 2 months after a therapeutic intervention) and group B 2, at baseline and 1 month later to assess test-retest reliability. RESULTS: A total of 182 patients were included (104 group A, 78 group B) with a mean age (SD) of 61.4 (12.1) years; 79.7% were women. Group A increased PHPQoL score (SD) (better HRQoL) (52 +/- 23 at baseline; 62 +/- 24 at 12 months; P < .001). At baseline, symptomatic patients had a lower PHPQoL score (worse) than asymptomatic ones (51 +/- 21 vs 68 +/- 21; P < .001). Correlations were seen between PHPQoL and Short Form-36, Psychological Well-Being Index, and self-perceived health status (P < .001). PHPQoL had good internal consistency (Cronbach's alpha = 0.80), test-retest reliability (group B, intraclass correlation coefficient > 0.80), and sensitivity to detect HQRoL changes over time. CONCLUSIONS: PHPQoL is a valid HRQoL measure to assess the impact of PHPT on health perception in clinical practice. PMID- 26771704 TI - MicroRNA Species in Follicular Fluid Associating With Polycystic Ovary Syndrome and Related Intermediary Phenotypes. AB - CONTEXT: Polycystic ovary syndrome (PCOS) has a largely unknown etiology and presents with a clinical heterogeneous patient group. Small noncoding microRNA (miRNA) might prove promising as biomarker candidates for PCOS patient stratification. Altered miRNA expression profiles have been observed in few studies. OBJECTIVE: The aim was to assess the miRNA expression profile in follicular fluid from PCOS patients and healthy, regularly cycling, matched controls. DESIGN AND SETTING: Experimental case-control study including 49 PCOS women (19 of which were hyperandrogenic and 30 normo-androgenic) and 21 healthy matched women all undergoing in vitro fertilization treatment. INTERVENTIONS AND MAIN OUTCOME: Anthropometric and relevant clinical baseline measurements were obtained. Relative expression of miRNA levels were estimated using miRNA quantitative PCR arrays and validated by quantitative RT-PCR. Correlation between miRNAs and clinical relevant measurements was estimated. RESULTS: PCOS women, both normo-androgenic and hyperandrogenic, had decreased levels of miR-24-3p, 29a, -151-3p, and -574-3p compared with controls. Furthermore, miR-518f-3p was differentially expressed within the PCOS group with high levels observed in the hyperandrogenic group compared with the normo-androgenic PCOS patients. Serum levels of total and free T were positively correlated with miR-518f-3p in PCOS subjects (P = .001). Distinction between PCOS and controls could be made using miR-151-3p alone with an area under the curve of 0.91 or a combination of four selected miRNAs (area under the curve, 0.93). Bioinformatic target analysis points to an involvement of these miRNAs in biological pathways involving regulation of cell proliferation, extracellular matrix, and processes in intermediary metabolism. CONCLUSION: Our study provides evidence that the miRNA expression profile in follicular fluid is altered in PCOS and indicates that specific follicular fluid miRNAs are associated with phenotypical traits of PCOS. An altered miRNA profile holds potentials for new methods of PCOS patient stratification and may contribute to and in part explain the heterogeneous nature found within PCOS women. PMID- 26771705 TI - Effects of the Internal Circadian System and Circadian Misalignment on Glucose Tolerance in Chronic Shift Workers. AB - CONTEXT: Shift work is a risk factor for diabetes. The separate effects of the endogenous circadian system and circadian misalignment (ie, misalignment between the central circadian pacemaker and 24-hour environmental/behavioral rhythms such as the light/dark and feeding/fasting cycles) on glucose tolerance in shift workers are unknown. OBJECTIVE: The objective of the study was to test the hypothesis that the endogenous circadian system and circadian misalignment separately affect glucose tolerance in shift workers, both independently from behavioral cycle effects. DESIGN: A randomized, crossover study with two 3-day laboratory visits. SETTING: Center for Clinical Investigation at Brigham and Women's Hospital. PATIENTS: Healthy chronic shift workers. INTERVENTION: The intervention included simulated night work comprised of 12-hour inverted behavioral and environmental cycles (circadian misalignment) or simulated day work (circadian alignment). MAIN OUTCOME MEASURES: Postprandial glucose and insulin responses to identical meals given at 8:00 am and 8:00 pm in both protocols. RESULTS: Postprandial glucose was 6.5% higher at 8:00 pm than 8:00 am (circadian phase effect), independent of behavioral effects (P = .0041). Circadian misalignment increased postprandial glucose by 5.6%, independent of behavioral and circadian effects (P = .0042). These variations in glucose tolerance appeared to be explained, at least in part, by different insulin mechanisms: during the biological evening by decreased pancreatic beta-cell function (18% lower early and late phase insulin; both P <= .011) and during circadian misalignment presumably by decreased insulin sensitivity (elevated postprandial glucose despite 10% higher late phase insulin; P = .015) without change in early-phase insulin (P = .38). CONCLUSIONS: Internal circadian time affects glucose tolerance in shift workers. Separately, circadian misalignment reduces glucose tolerance in shift workers, providing a mechanism to help explain the increased diabetes risk in shift workers. PMID- 26771706 TI - Prostate-Specific Membrane Antigen Is a Potential Antiangiogenic Target in Adrenocortical Carcinoma. AB - CONTEXT: Adrenocortical carcinoma (ACC) is a rare tumor type with a poor prognosis and few therapeutic options. OBJECTIVE: Assess prostate-specific membrane antigen (PSMA) expression as a potential novel therapeutic target for ACC. DESIGN: Expression of PSMA was evaluated in benign and malignant adrenal tumors and 1 patient with metastatic ACC. SETTING: This study took place at a tertiary referral center. PATIENTS: Fifty adrenal samples were evaluated, including 16 normal adrenal glands, 16 adrenocortical adenomas, 15 primary ACC, and 3 ACC metastases. MAIN OUTCOME MEASURES: Demographics, PSMA expression levels via real-time quantitative polymerase chain reaction and immunohistochemistry and whole-body positron emission tomography-computed tomography standardized uptake values for 1 patient. RESULTS: qPCR demonstrated an elevated level of PSMA in ACC relative to all benign tissues (P < .05). Immunohistochemistry localized PSMA expression to the neovasculature of ACC and confirmed overexpression of PSMA in ACC relative to benign tissues both in intensity and percentage of vessels stained (78% of ACC, 0% of normal adrenal, and 3.27% of adenoma-associated neovasculature; P < .001). Those with more than 25% PSMA-positive vessels were 33 times more likely to be malignant than benign (odds ratio, P < .001). Whole-body positron emission tomography-computed tomography imaging showed targeting of anti PSMA Zr89-J591 to 5/5 of the patient's multiple lung masses with an average measurement of 3.49 +/- 1.86 cm and a standardized uptake value of 1.4 +/- 0.65 relative to blood pool at 0.8 standardized uptake value. CONCLUSIONS: PSMA is significantly overexpressed in ACC neovasculature when compared with normal and benign adrenal tumors. PSMA expression can be used to image ACC metastases in vivo and may be considered as a potential diagnostic and therapeutic target in ACC. PMID- 26771707 TI - Nickel-Catalyzed Double Bond Transposition of Alkenyl Boronates for in Situ syn Selective Allylboration Reactions. AB - The transposition of a homoallyl pinacol boronic ester was realized by a highly reactive nickel-catalyst system comprising NiCl2(dppp), zinc powder, ZnI2, and Ph2PH. The in situ generated Z-crotyl pinacol boronic esters were reacted with various aldehydes to form syn-homoallylic alcohols in high diastereoselectivities. The present nickel-catalyzed reaction is complementary to the iridium-catalyzed transposition reported by Murakami leading to the corresponding anti-homoallylic alcohols. Also, the multiple transposition of pentenyl pinacol boronic ester was realized. PMID- 26771708 TI - Our Own Worst Enemy. PMID- 26771710 TI - Bub3 activation and inhibition of the APC/C. PMID- 26771711 TI - Reducing GWAS Complexity. AB - Genome-wide association studies (GWAS) have revealed numerous genomic 'hits' associated with complex phenotypes. In most cases these hits, along with surrogate genetic variation as measure by numerous single nucleotide polymorphisms (SNPs) that are in linkage disequilibrium, are not in coding genes making assignment of functionality or causality intractable. Here we propose that fine-mapping along with the matching of risk SNPs at chromatin biofeatures lessen this complexity by reducing the number of candidate functional/causal SNPs. For example, we show here that only on average 2 SNPs per prostate cancer risk locus are likely candidates for functionality/causality; we further propose that this manageable number should be taken forward in mechanistic studies. The candidate SNPs can be looked up for each prostate cancer risk region in 2 recent publications in 2015 (1,2) from our groups. PMID- 26771709 TI - Discovery of Highly Potent Inhibitors Targeting the Predominant Drug-Resistant S31N Mutant of the Influenza A Virus M2 Proton Channel. AB - With the emergence of highly pathogenic avian influenza (HPAI) H7N9 and H5N1 strains, there is a pressing need to develop direct-acting antivirals (DAAs) to combat such deadly viruses. The M2-S31N proton channel of the influenza A virus (A/M2) is one of the validated and most conserved proteins encoded by the current circulating influenza A viruses; thus, it represents a high-profile drug target for therapeutic intervention. We recently discovered a series of S31N inhibitors with the general structure of adamantyl-1-NH2(+)CH2-aryl, but they generally had poor physical properties and some showed toxicity in vitro. In this study, we sought to optimize both the adamantyl as well as the aryl/heteroaryl group. Several compounds from this study exhibited submicromolar EC50 values against S31N-containing A/WSN/33 influenza viruses in antiviral plaque reduction assays with a selectivity index greater than 100, indicating that these compounds are promising candidates for in-depth preclinical pharmacology. PMID- 26771712 TI - Mitochondrial dysfunction induces SESN2 gene expression through Activating Transcription Factor 4. AB - We found that inhibitors of mitochondrial respiratory chain complexes III (myxothiazol) and I (piericidin A) in some epithelial carcinoma cell lines induce transcription of the p53-responsive SESN2 gene that plays an important role in stress response and homeostatic regulation. However, the effect did not depend on p53 because i) there was no induction of p53 after the treatment with piericidin A; ii) after the treatment with myxothiazol the peak of SESN2 gene upregulation occurred as early as 5h, before the onset of p53 activation (13h); iii) a supplementation with uridine that abolishes the p53 activation in response to myxothiazol did not abrogate the induction of SESN2 transcripts; iv) in the p53 negative HCT116 p53 -/- cells SESN2 transcription could be also induced by myxothiazol. In response to the respiratory chain inhibitors we observed an induction of ATF4, the key transcription factor of the integrated stress response (ISR). We found that the induction of SESN2 transcripts could be prevented by the ISR inhibitory small molecule ISRIB. Also, by inhibiting or overexpressing ATF4 with specific shRNA or ATF4-expressing constructs, respectively, we have confirmed the role of ATF4 in the SESN2 gene upregulation induced by mitochondrial dysfunction. At a distance of 228 bp upstream from the SESN2 transcription start site we found a candidate sequence for the ATF4 binding site and confirmed its requirement for the induction of SESN2 in luciferase reporter experiments. We suggest that the upregulation of SESN2 by mitochondrial dysfunction provides a homeostatic feedback that attenuates biosynthetic processes during temporal losses of energy supply from mitochondria thereby assisting better adaptation and viability of cells in hostile environments. PMID- 26771713 TI - BCL10 is recruited to sites of DNA damage to facilitate DNA double-strand break repair. AB - Recent studies have found BCL10 can localize to the nucleus and that this is linked to tumor aggression and poorer prognosis. These studies suggest that BCL10 localization plays a novel role in the nucleus that may contribute to cellular transformation and carcinogenesis. In this study, we show that BCL10 functions as part of the DNA damage response (DDR). We found that BCL10 facilitates the rapid recruitment of RPA, BRCA1 and RAD51 to sites of DNA damage. Furthermore, we also found that ATM phosphorylates BCL10 in response to DNA damage. Functionally, BCL10 promoted DNA double-strand breaks repair, enhancing cell survival after DNA damage. Taken together our results suggest a novel role for BCL10 in the repair of DNA lesions. PMID- 26771715 TI - Calpain restrains the stem cells compartment in breast cancer. AB - CAPNS1 is essential for the stability and function of ubiquitous CAPN1 and CAPN2. Calpain modulates by proteolytic cleavage many cellular substrates and its activity is often deregulated in cancer cells, therefore calpain inhibition has been proposed as a therapeutical strategy for a number of malignancies. Here we show that CAPNS1 depletion is coupled to impairment of MCF7 and MCF10AT cell lines growth on plate and defective architecture of mammary acini derived from MCF10A cells. In soft agar CAPNS1 depletion leads to cell growth increase in MCF7, and decrease in MCF10AT cells. In both MCF7 and MCF10AT, CAPNS1 depletion leads to the enlargement of the stem cell compartment, as demonstrated by mammosphere formation assays and evaluation of stem cell markers by means of FACS and western blot analysis. Accordingly, activation of calpain by thapsigargin treatment leads to a decrease in the stem cell reservoir. The expansion of the cancer stem cell population in CAPNS1 depleted cells is coupled to a defective shift from symmetric to asymmetric division during mammosphere growth coupled to a decrease in NUMB protein level. PMID- 26771714 TI - MMSET is dynamically regulated during cell-cycle progression and promotes normal DNA replication. AB - The timely and precise duplication of cellular DNA is essential for maintaining genome integrity and is thus tightly-regulated. During mitosis and G1, the Origin Recognition Complex (ORC) binds to future replication origins, coordinating with multiple factors to load the minichromosome maintenance (MCM) complex onto future replication origins as part of the pre-replication complex (pre-RC). The pre-RC machinery, in turn, remains inactive until the subsequent S phase when it is required for replication fork formation, thereby initiating DNA replication. Multiple myeloma SET domain-containing protein (MMSET, a.k.a. WHSC1, NSD2) is a histone methyltransferase that is frequently overexpressed in aggressive cancers and is essential for normal human development. Several studies have suggested a role for MMSET in cell-cycle regulation; however, whether MMSET is itself regulated during cell-cycle progression has not been examined. In this study, we report that MMSET is degraded during S phase in a cullin-ring ligase 4-Cdt2 (CRL4(Cdt2)) and proteasome-dependent manner. Notably, we also report defects in DNA replication and a decreased association of pre-RC factors with chromatin in MMSET-depleted cells. Taken together, our results suggest a dynamic regulation of MMSET levels throughout the cell cycle, and further characterize the role of MMSET in DNA replication and cell-cycle progression. PMID- 26771718 TI - Short- and long-term evaluation of mandibular dental arch dimensional changes in patients treated with a lip bumper during mixed dentition followed by fixed appliances. AB - OBJECTIVE: To evaluate short- and long-term mandibular dental arch changes in patients treated with a lip bumper during the mixed dentition followed by fixed appliances, compared with a matched control sample. MATERIALS AND METHODS: Dental casts and lateral cephalograms obtained from 31 consecutively treated patients before (T0) and after (T1) lip bumper, after fixed appliances (T2), and a minimum of 3 years after fixed appliances (T3) were analyzed. The control group was matched as closely as possible. Arch width, arch perimeter, arch length, and incisor proclination were evaluated. Repeated measures ANOVA was used to analyze changes in measurements over all four time points between treatment and control groups. RESULTS: Arch widths and crowding were always significantly different except at T2-T1. At T1-T0, only crowding decreased 3.2 mm while intercanine, interpremolar, and intermolar widths increased by 3.8, 3.3, and 3.9 mm, respectively. Changes at T3-T2 showed a significant decrease of 2.1 mm for crowding and an increase of 3.5, 2.9, 2.7, and 0.8 mm for intercanine, interpremolar, and intermolar widths and arch perimeter, respectively. Finally, at T3-T0, the reduction in crowding of 5.03 mm was significant and clinically important in the treated group. The differences between intercanine, interpremolar, and intermolar widths were also significant (2.1, 3.8, and 3.6 mm, respectively). All those differences favored the treated group. CONCLUSIONS: Mandibular dental arch dimensions were significantly changed after lip bumper treatment. At follow-up, all arch widths were slightly decreased, generating an increase of 0.4 mm in crowding, considered clinically irrelevant. Overall changes remained stable after an average 6.3-year follow-up. PMID- 26771716 TI - Direct interactions with both p27 and Cdk2 regulate Spy1-mediated proliferation in vivo and in vitro. AB - Families of cyclin-like proteins have emerged that bind and activate cyclin dependent kinases (Cdk)s, directing the phosphorylation of noncanonical Cdk substrates. One of these proteins, Spy1, has demonstrated the unique ability to directly bind and activate both Cdk1 and Cdk2, as well as binding and promoting the degradation of at least one Cdk inhibitor, p27(Kip1). Spy1 accelerates somatic cell growth and proliferation and is implicated in a number of human cancers including the breast, brain and liver. Herein we isolate key residues mediating the direct interaction with p27. We use mutants of Spy1 to determine the physiological role of direct interactions with distinct binding partners Cdk2 and p27. We demonstrate that disrupting the direct interaction with either Spy1 binding partner decreased endogenous activity of Cdk2, as well as Spy1-mediated proliferation. However, only the direct interaction with p27 was essential for Spy1-mediated effects on p27 stability. In vivo neither mutation completely prevented tumorigenesis, although each mutation slowed the rate of Spy1-mediated tumorigenesis and decreased overall tumor volumes. This work supports the conclusion that direct interaction with both p27 and Cdk2 contribute to Spy1 mediated effects on cell growth. It is important to elucidate the dynamics of these interactions and to consider these data when assessing functional outcomes. PMID- 26771719 TI - New developments with drug-coated balloons. PMID- 26771720 TI - How does a drug-coated balloon work? Overview of coating techniques and their impact. AB - BACKGROUND: According to current understanding the drug-coated balloon (DCB) carries a sufficient dose of an effective antineoplastic agent, i.e. paclitaxel, to the target lesion. METHODS: Literature review and report on experimental studies simulating the access of coated balloons to the treatment site and studies in pigs. RESULTS: The drug adheres to the balloon membrane and is partially hidden below the folds which are wrapped around the shaft. Upon inflation solid paclitaxel particles are pushed into the vessel wall. Premature loss of paclitaxel and transfer to the vessel wall are controlled by the coating formulation which includes an inactive additive. Particles in the tissue dissolve slowly resulting in a terminal half-life of almost 2 months. The very low solubility of paclitaxel minimizes premature loss of the drug, dissolution, and elimination, while maximizing efficacy and tolerance are limited by the very low solubility of paclitaxel. From an exemplary DCB, approximately 10% of drug is lost before the target lesion is reached, 5-20% is transferred into the vessel wall and 10% remain on the balloon after withdrawal. The remainder of the drug is distributed in the general circulation. Inhibition of neointimal proliferation in animal models is reliable and as persistent as with drug-eluting stents. Histology reveals slight to moderate dose-dependent downstream effects without functional or clinical impairment. CONCLUSION: Paclitaxel continues to be the drug of choice, the dose varies between 2 and 3.5 ug/mm2 balloon surface. Neither animal experiments nor clinical trials have demonstrated problems in vessel segments treated with overlapping balloons. Future developments are expected to improve efficacy in additional disease conditions (e.g., calcified vessels) and vessel territories. PMID- 26771717 TI - Cyclin-dependent kinase-mediated phosphorylation of breast cancer metastasis suppressor 1 (BRMS1) affects cell migration. AB - Expression of Breast Cancer Metastasis Suppressor 1 (BRMS1) reduces the incidence of metastasis in many human cancers, without affecting tumorigenesis. BRMS1 carries out this function through several mechanisms, including regulation of gene expression by binding to the mSin3/histone deacetylase (HDAC) transcriptional repressor complex. In the present study, we show that BRMS1 is a novel substrate of Cyclin-Dependent Kinase 2 (CDK2) that is phosphorylated on serine 237 (S237). Although CDKs are known to regulate cell cycle progression, the mutation of BRMS1 on serine 237 did not affect cell cycle progression and proliferation of MDA-MB-231 breast cancer cells; however, their migration was affected. Phosphorylation of BRMS1 does not affect its association with the mSin3/HDAC transcriptional repressor complex or its transcriptional repressor activity. The serine 237 phosphorylation site is immediately proximal to a C terminal nuclear localization sequence that plays an important role in BRMS1 mediated metastasis suppression but phosphorylation does not control BRMS1 subcellular localization. Our studies demonstrate that CDK-mediated phosphorylation of BRMS1 regulates the migration of tumor cells. PMID- 26771721 TI - Drug-coated balloons: what is the evidence? AB - Having evolved at a rapid pace, the therapy options for percutaneous treatment of peripheral arterial disease in the lower limbs, especially percutaneous transluminal angioplasty in combination with stent-technology, are able to deliver a rate where at least 80% of the treated patients remain free from reintervention after the first years under ideal study conditions, meaning that defined and often restrict in- and exclusion criteria were fulfilled and mid-term dual platelet therapy is warranted. This is somewhat a huge leap when compared to the 50-60% in the 1980s and 1990s, but we now face an era of an increasingly demanding clientele, where the industry also strives to cover this final 20% with newer technologies. As recent studies with drug-eluting stents (DES) suggests, nowadays it is possible to achieve up to 90% patency in the short- and mid-term, but this comes accompanied by remarkably increased therapy costs, making it almost impossible to most centers to implant it as the standard therapy option. Trying to fill this gap between the low-patency of the plain old balloon angioplasty and the higher costs of the DES, drug-coated balloon technology has found its niche, knowing that reimbursement shows a broad variation across the countries and continents. PMID- 26771722 TI - Drug coated balloons below-the-knee: just too early? AB - Patients with infrapopliteal arterial disease are generally considered challenging due to the usual presence of multivessel atherosclerotic disease. Several treatment options have been used by different authors but none of them can be considered ideal. In the last few years drug coated balloons have gained popularity especially due to the extraordinary results in the femoro-popliteal region. Following the great success, physicians started to use this promising device also in the below-the-knee (BTK) region. The initial enthusiasm correlated to some studies is not confirmed by the largest randomized trial, IN.PACT Deep, comparing In.Pact DCB to standard PTA. This trial failed completely to show the superiority of drug coated balloon (DCB). The negative outcome was mainly correlated to safety issues with an amputation rate higher for the drug coated balloon when compared to the conventional balloon (8.8% DCB vs.3.6% PTA, P=0.08). A thorough evaluation has been performed to justify these negative outcomes, given the good results reported by other studies. But nowadays it is still difficult to find a clear explanation. Especially for this negative outcome and for the big difference, in term of results, between the different studies in the BTK region and also between the above and below the knee regions more trials are mandatory. PMID- 26771723 TI - What are the potential limitations of drug coated balloons and possible ways to overcome. AB - In several independent randomized clinical studies, it has been shown that drug coated balloons (DCBs) cause persistent clinically meaningful and statistically significant inhibition of restenosis in femoropopliteal arteries in comparison to percutaneous transluminal angioplasty with uncoated balloon catheters. The potential benefits of delivering an antiproliferative drug into the vessel wall using a balloon as transporter are manifold: 1) widespread applicability: balloon angioplasty is suitable for use in a wide range of lesions. The use of DCBs is technically less demanding and offers greater flexibility compared with stenting techniques. 2) Maintaining options: minimizing the use of durable implants is providing more options for following and complementary revascularization procedures; 3) proven efficacy: consistent, positive outcomes across studies and key subgroups have been demonstrated from the first preclinical studies to ongoing clinical trials. Beside the enthusiasm carried along with this novel technique and questioning if DCBs will become standard-of-care-therapy for the superficial femoral artery, the potential limitations have to be discussed. PMID- 26771724 TI - Carotid interventions (CEA and CAS) in acute stroke patients: which procedure on which patient. AB - Treatment of carotid bifurcation disease in patients presenting with acute stroke has been a controversial issue over the past four decades. Classically, patients were asked to wait four to six weeks before intervention was entertained in order for the brain to stabilize and the risks of intervention to be minimized. Unfortunately, up to 20% of patients will have a secondary event after their index event and the window of opportunity to save potentially salvageable ischemic tissue will be missed. Early reports had demonstrated poor results with intervention. However, more recently, institutions such as ours have demonstrated excellent results with early intervention in patients who present with stable mild to moderate stroke with an NIH stroke scale less than 15 and preferably less than 10, present with stroke and ipsilateral carotid artery lesion of 50% or greater. Also more recently, we have been aggressively treating patients with larger ulcerative plaques even if the stenosis approaches 50%. In our and others experiences, patients who are treated at institutions that have comprehensive stroke centers (CSCs) where they have a multidisciplinary system that consists of vascular surgeons, neuro interventionalists, stroke neurologists, specifically trained stroke nursing staff and a neuro intensive ICU have had optimal results. Early assessment, diagnosis of stroke with recognition of cause of embolization is mandatory but patient selection is extremely important; finding those patients who will benefit the most from urgent intervention. Most studies have demonstrated the benefit of carotid endarterectomy in these patients. More recent studies have demonstrated acceptable results with carotid stenting, especially in smaller lesions, those less than 1.2 centimeters. Early intervention should be avoided in most patients who are obtunded or with an NIH stroke scale greater than 15 or who do not have any "brain at risk" to salvage. These patients may be better served by being treated medically and the small group of patients that do have some improvement may benefit from interval intervention. PMID- 26771725 TI - Endovascular intracranial treatment of acute ischemic strokes. AB - Acute ischemic stroke (AIS) is the leading cause of long-term disability and the second cause of death worldwide. Intravenous (IV) tissue plasminogen activator (tPA) remains the only FDA-approved treatment for AIS. The use of IV tPA in AIS related to large-vessel occlusion (LVO) has shown low recanalization rates and poor clinical outcomes. Over the last decade, endovascular treatment has demonstrated safety and effectiveness in the management of LVO-associated AIS due to the evolution of endovascular techniques and technologies, beginning with intraarterial thrombolysis, aspiration, self-expanding intracranial stents, and now retrievable stents. With the recent publication of the results of five randomized controlled studies, mechanical thrombectomy in combination with IV tPA demonstrated significant radiographic and clinical benefit over traditional strategies with IV tPA alone. In light of these results, endovascular therapy has been placed at the forefront of stroke treatment, redefining the standard of care. This review presents the evolution of endovascular treatment of AIS resulting from LVO; provides an analysis of the initial and latest RCTs; and discusses the association between endovascular mechanical thrombectomy and clinical outcomes, functional outcomes, and rates of revascularization, intracranial hemorrhage, morbidity, and mortality. Finally, shortcomings of the recent technological advances, such as clot fragmentation, and potential solutions to overcome these drawbacks are presented. PMID- 26771726 TI - Acute stroke: balloon-tipped catheter in thrombectomy. AB - The management of acute stroke has changed in the recent past due to the superior results of thrombectomy in patients with occlusion of larger brain supplying arteries in comparison to intravenous thrombolysis. This progress is mainly based on the use of stent retrievers for thrombectomy. The combination of stent retrievers with balloon-tipped catheters has increased the efficacy of the procedure. PMID- 26771727 TI - Transcranial Doppler and diffusion-weighted magnetic resonance evaluation of cerebral embolization occurring during transfemoral carotid stenting with proximal flow blockage. AB - BACKGROUND: Transfemoral carotid artery stenting (CAS) with endovascular proximal flow blockage is deemed able to reduce the cerebral embolization observed during filter-protected CAS. We evaluated clinical outcome and intraoperative embolization rates, measured by diffusion-weighted magnetic resonance imaging (DW MRI) and transcranial Doppler monitoring, in a series of patients undergoing CAS with proximal flow blockage. METHODS: A series of 35 consecutive patients with symptomatic or asymptomatic internal carotid artery stenosis >=70% were included to undergo CAS with proximal flow blockage, obtained with the Mo.Ma system. All patients underwent preoperative and postoperative DW-MRI in order to detect new ischemic lesions. Of the 35 patients, 31 (89%) underwent intraoperative transcranial Doppler monitoring to record the microembolic signals (MES) produced during each procedure. RESULTS: The MoMa system was successfully used in 34 patients (technical success: 97%). Intolerance to balloon occlusion was observed in 4 patients (12%), but never compromised the completion of the procedure. No deaths or neurological events occurred in the postoperative period. DW-MRI disclosed 74 new ischemic lesions in 8 patients (8/34, 23.5%). All lesions except one were ipsilateral to the treated carotid artery. MES were detected in all procedures, with a mean number of 33.2+/-23.2 (range 3-103). In 20 procedures (20/31, 65%), MES were detected also during flow blockage (mean: 9.1+/-7; range 2 28). CONCLUSION: While achieving good technical and clinical results, CAS with proximal flow blockage is still accompanied by a non-negligible cerebral embolization. The detection of MES during ICA flow blockage suggests the need for a better selection of patients. PMID- 26771728 TI - Outcome of extensive descending aorta repair adopting present concepts of spinal cord preservation. AB - BACKGROUND: Preoperative radiological identification of the Adamkiewicz artery and intraoperative neurologic monitoring are known to be helpful for preventing paraplegia after thoracoabdominal aorta replacement. To answer whether they should be used routinely, we investigated the incidence of spinal cord ischemia after extensive descending aortic repair without using such modalities. METHODS: We retrospectively reviewed the outcome of 95 patients who underwent extensive descending thoracic (DTA) or thoracoabdominal aorta (TAA) repair without the Adamkiewicz artery identification or neurologic monitoring from 2006 through 2010. Spinal cord protection strategy consisted of distal aortic perfusion, cerebrospinal fluid drainage, mild hypothermia, and maintenance of hypertension (systolic>=120mmHg) through the second postoperative day. A few segmental arteries were empirically selected for reimplantation based on the size and the amount of backbleeding; overall 1.4 per patient, 0.3 for DTA, 1.4 for type I, 2.4 for type II, 0.9 for type III, and 0 for type IV TAA. RESULTS: Two patients died early after surgery. All the remaining patients awoke without paraplegia or paraparesis. Delayed deficit occurred in 7 patients (7.4%) after hypotensive events caused by sedation, bleeding, respiratory distress, or cardiac dysfunction. Three patients (3.2%) became permanently paraplegic and the other four recovered completely within 48 hours after cerebrospinal fluid drainage and elevation of systemic blood pressure. CONCLUSION: Even without the Adamkiewicz artery identification and neuromonitoring, the incidence of immediate paraplegia could be kept low by applying the strategy based on the modern concept of cord perfusion. The relatively high incidence of delayed deficit suggests the importance of postoperative hemodynamic management and prevention of cardiopulmonary complications. PMID- 26771729 TI - How to calculate the main aortic graft-diameter for a chimney-graft. AB - BACKGROUND: The aim of this paper was to present a mathematical model to calculate the required main aortic graft-diameter for parallel chimney-grafts. METHODS: Geometric approximation model, developed to allow for a standardized calculation of the main aortic graft-diameter determined by the aortic diameter and the diameter of the chimney-graft. RESULTS: We propose a mathematical formula using circular segments of the aorta and the chimney-graft and provide a table with recommended main aortic graft-diameters for single chimney-grafts of 6 and 8 mm. CONCLUSION: Geometric approximation can be used to calculate the required main aortic graft-diameter. For parallel running chimney-grafts a significant degree of oversizing is necessary to allow the main aortic body to surround the chimney and to prevent the occurrence of gutters, which may cause type-1 endoleaks. PMID- 26771730 TI - Abdominal aortic aneurysm. AB - Endovascular repair of abdominal aortic aneurysms has become a milestone in the treatment of patients with abdominal aortic aneurysm. Technological improvement allows treatment in more and more complex cases. This review summarizes all grafts available on the market. A complete review of most important trial on this topic is provided to the best of our knowledge, and technical tips and tricks for standard cases are also included. PMID- 26771731 TI - Endovascular treatment of an early arch aneurysm rupture after open thoracoabdominal aortic repair. AB - Optimal treatment for synchronous aortic aneurysms is still debated. Staged repair is advocated as the standard of care. Its disadvantage however is the consistent risk of rupture of the untreated aortic segment during recovery; moreover a considerable percentage of patients either refuse the second stage or is lost to follow-up. We present the case of a patient with a ruptured aortic arch aneurysm after open-surgery for a type III thoracoabdominal aortic aneurysm. Our therapeutic decision is described and discussed, with all the related advantages and disadvantages. PMID- 26771732 TI - Is low anticoagulation intensity more beneficial for patients with bileaflet mechanical mitral valves? A meta-analysis. AB - BACKGROUND: For the mitral valve replacement (MVR) using the lowest thrombogenic risk bileaflet valves (St. Jude Medical [St Paul, MN, USA], Carbomedics [Austin, TX, USA] and On-X [Austin, TX, USA]), excellent results can be achieved by adopting the anticoagulation intensity (median INR<2.5) which is lower than the recommended intensity (INR:2.5~3.5). Our aim was to provide a pooled estimate of potential benefit from clinical studies using low anticoagulation intensity and high intensity in these patients. METHODS: Relevant studies published before February 2014 were searched through a number of digital databases (MEDLINE, EMBASE, Cochrane Library, etc.). They were pooled by SPSS19.0 using the random effect method in three fields: occurrence rate of major thromboembolism, major hemorrhage and major total events. Fourteen studies with 3595 patients were included. The follow-up period was 12,846.6 patient-years. RESULTS: Pooled estimates indicated reduction in major hemorrhage (RR:0.420, 95%CI: 0.296~0.595, P<0.001) and major total events (RR: 0.738, 95%CI: 0.604~0.902, P=0.003) in the low intensity group. No difference was noted in major thromboembolism (RR: 1.045, 95%CI: 0.814~1.341, P=0.75). CONCLUSION: Compared with the recommended high intensity, low anticoagulation intensity (median INR<2.5) may be more beneficial for the MVR patients using the lowest thrombogenic risk bileaflet valves. We recommended an INR between 2.0 and 2.5, with a median INR of 2.3 for these MVR patients. PMID- 26771733 TI - Eptifibatide infusion versus placebo in high risk patients with non-ST segment elevation acute coronary syndromes managed with urgent coronary artery bypass graft surgery. A prospective multicenter randomized placebo-controlled clinical trial. AB - BACKGROUND: This randomized prospective clinical trial aimed to evaluate safety and efficacy of preoperative use of eptifibatide in high risk patients with non ST-segment elevation acute coronary syndrome (NSTE-ACS), requiring urgent coronary artery bypass graft surgery (CABG). METHODS: A total of 140 patients with NSTE-ACS eligible for urgent surgical revascularization received either eptifibatide (bolus plus infusion) 12-48 hours prior to surgery (N.=72 patients) or placebo (normal saline; N.=68 patients) followed by routinely administered enoxaparin and aspirin. Patients were regarded as unsuitable for percutaneous coronary intervention by the heart team. CABG was performed 4 hours after discontinuation of eptifibatide or placebo infusion. The primary end point was major adverse cardiac and cerebrovascular events (MACCE) defined as death, nonfatal myocardial infarction (MI), stroke and the need for rehospitalization due to recurrent ischemia at 12-month follow-up. Secondary endpoints included MACCE rate at 1 month, bleeding complications, platelet inhibition efficacy and correlation of platelet activity with MACCE rate. RESULTS: Cumulative one year MACCE rate was 35% vs. 14% in the control and treated group respectively (P=0.012). Mortality rate at 30 days follow-up was 10% vs. 3% (P=0.021) and was not changed at 12-month follow-up. There was a significant difference between both groups regarding perioperative MI (22% vs. 8%, P=0.03). The rates of stroke, blood loss and blood transfusion were similar in both groups. CONCLUSION: Preoperative use of eptifibatide vs. placebo is linked to significantly reduced 12-month MACCE rate in patients with NSTE-ACS requiring urgent CABG, while it simultaneously seems not to confer a greater risk of postoperative bleeding. PMID- 26771734 TI - Right miniparasternotomy may be a good minimally invasive alternative to full sternotomy for cardiac valve operations: a propensity-adjusted analysis. AB - BACKGROUND: Limited real-world data existed for mini-parasternotomy approach with good sample size in Asian cohorts and most previous studies were eclipsed by case heterogeneity. The goal of this study was to compare safety and quality outcomes of cardiac non-coronary valve operations by mini-parasternotomy and full sternotomy approaches on risk-adjusted basis. METHODS From our hospital database, we retrieved the cases of non-coronary valve operations from 1 January 2005 to 31 December 2012, including re-do, emergent, and combined procedures. Estimated EuroScore-II and propensity score for choosing mini-parasternotomy were adjusted for in the regression models on hospital mortality, complications (pneumonia, stroke, sepsis, etc.), and quality parameters (length of stay, ICU time, ventilator time, etc.). Non-complicated cases, defined as survival to discharge, ventilator use not over one week, and intensive care unit stay not over two weeks, were used for quality parameters. RESULTS: There were 283 mini parasternotomy and 177 full sternotomy cases. EuroScore-II differed significantly (medians 2.1 vs. 4.7, P<0.001). Propensity scores for choosing mini parasternotomy were higher with lower EuroScore-II (OR=0.91 per 1%, P<0.001), aortic regurgitation (OR=2.3, P=0.005), and aortic non-mitral valve disease (OR=3.9, P<0.001). Adjusted for propensity score and EuroScore-II, mini parasternotomy group had less pneumonia (OR=0.32, P=0.043), less sepsis (OR=0.31, P=0.045), and shorter non-complicated length of stay (coefficient=-7.2 (day), P<0.001) than full sternotomy group, whereas Kaplan-Meier survival, non complicated ICU time, non-complicated ventilator time, and 30-day mortality did not differ significantly. CONCLUSION: The propensity-adjusted analysis demonstrated encouraging safety and quality outcomes for mini-parasternotomy valve operation in carefully selected patients. PMID- 26771735 TI - Mitral valve replacement in the elderly is associated with low mortality and similar survival to the general population. AB - BACKGROUND: With the increase of elderly population, cardiologists and surgeons are faced with an increased incidence of mitral regurgitation. Most of these patients are denied surgery due to a misconceived perception of ominous surgical results. Our objective was to analyze early and late survival in elderly patients after mitral valve surgery in a center in which replacement is the procedure of choice. METHODS: We obtained clinical follow-up of patients older than 70 years who underwent first-time isolated replacement from January 2000 to January 2012. Observed survival was compared with expected survival in the general population of Uruguay. Independent predictors of operative mortality and survival were determined. RESULTS: A total of 127 patients were included. Global operative mortality was 9.4% (1.8% after year 2006 vs. 15.3% before 2006; P<0.05). Surgery performed before 2006, preoperative hematocrit and creatinine were independent predictors for operative mortality after multivariate analysis. 6-year survival was 70.2% for females (72.4% expected survival, P=ns) and 40.1% in males (63.5% expected survival, P<0.05). Independent predictors of survival were surgery performed before 2006 (HR=3.2) and female sex (HR=0.4). CONCLUSION: Mitral valve replacement is a feasible option for elderly patients with mitral valve disease in centers with lack expertise in valve repair. Actual surgical results provide low operative mortality and similar survival to general the population (mainly in females). PMID- 26771736 TI - The Effect of Childhood Supervisory Neglect on Emerging Adults' Drinking. AB - This study investigated the effect of childhood supervisory neglect on emerging adults' drinking. Child supervisory neglect is the most common form of child maltreatment in the United States, but few studies explore supervisory neglect separate from other forms of maltreatment among emerging adults, 18-25 years old. The study sample included (n = 11,117) emerging adults, 18-25 years old who participated in Waves I and III of the National Longitudinal Study of Adolescent Health (Add Health). We conducted separate analyses for male and female emerging adults, because they have different rates of alcohol consumption and alcohol risk behaviors. Our study used latent class analysis to understand how patterns of alcohol risk behaviors clustered together. For males, we found the following four classes: (1) multiple-risk drinkers, (2) moderate-risk drinkers, (3) binge drinkers, and (4) low-risk drinkers or abstainers. For females, we found the following three classes: (1) multiple-risk drinkers, (2) moderate-risk drinkers, and (3) low-risk drinkers or abstainers. For both males and females, supervisory neglect increased the odds of membership in the multiple-risk drinkers' class compared to the low-risk drinkers or abstainers' class. Single males who did not live with their parents, and who were white had increased odds of being in the multiple-risk drinkers. For females, being more educated, or in a serious romantic relationship increased the odds of membership in the multiple-risk drinkers' class. Practitioners should ask about histories of supervisory neglect among emerging adults who engage in alcohol risk behaviors. PMID- 26771737 TI - Heterogeneity of Treatment Response to Citalopram for Patients With Alzheimer's Disease With Aggression or Agitation: The CitAD Randomized Clinical Trial. AB - OBJECTIVE: Pharmacological treatments for agitation and aggression in patients with Alzheimer's disease have shown limited efficacy. The authors assessed the heterogeneity of response to citalopram in the Citalopram for Agitation in Alzheimer Disease (CitAD) study to identify individuals who may be helped or harmed. METHOD: In this double-blind parallel-group multicenter trial of 186 patients with Alzheimer's disease and clinically significant agitation, participants were randomly assigned to receive citalopram or placebo for 9 weeks, with the dosage titrated to 30 mg/day over the first 3 weeks. Five planned potential predictors of treatment outcome were assessed, along with six additional predictors. The authors then used a two-stage multivariate method to select the most likely predictors; grouped participants into 10 subgroups by their index scores; and estimated the citalopram treatment effect for each. RESULTS: Five covariates were likely predictors, and treatment effect was heterogeneous across the subgroups. Patients for whom citalopram was more effective were more likely to be outpatients, have the least cognitive impairment, have moderate agitation, and be within the middle age range (76-82 years). Patients for whom placebo was more effective were more likely to be in long-term care, have more severe cognitive impairment, have more severe agitation, and be treated with lorazepam. CONCLUSIONS: Considering several covariates together allowed the identification of responders. Those with moderate agitation and with lower levels of cognitive impairment were more likely to benefit from citalopram, and those with more severe agitation and greater cognitive impairment were at greater risk for adverse responses. Considering the dosages used and the association of citalopram with cardiac QT prolongation, use of this agent to treat agitation may be limited to a subgroup of people with dementia. PMID- 26771738 TI - Neural Circuitry of Impaired Emotion Regulation in Substance Use Disorders. AB - Impaired emotion regulation contributes to the development and severity of substance use disorders (substance disorders). This review summarizes the literature on alterations in emotion regulation neural circuitry in substance disorders, particularly in relation to disorders of negative affect (without substance disorder), and it presents promising areas of future research. Emotion regulation paradigms during functional magnetic resonance imaging are conceptualized into four dimensions: affect intensity and reactivity, affective modulation, cognitive modulation, and behavioral control. The neural circuitry associated with impaired emotion regulation is compared in individuals with and without substance disorders, with a focus on amygdala, insula, and prefrontal cortex activation and their functional and structural connectivity. Hypoactivation of the rostral anterior cingulate cortex/ventromedial prefrontal cortex (rACC/vmPFC) is the most consistent finding across studies, dimensions, and clinical populations (individuals with and without substance disorders). The same pattern is evident for regions in the cognitive control network (anterior cingulate and dorsal and ventrolateral prefrontal cortices) during cognitive modulation and behavioral control. These congruent findings are possibly related to attenuated functional and/or structural connectivity between the amygdala and insula and between the rACC/vmPFC and cognitive control network. Although increased amygdala and insula activation is associated with impaired emotion regulation in individuals without substance disorders, it is not consistently observed in substance disorders. Emotion regulation disturbances in substance disorders may therefore stem from impairments in prefrontal functioning, rather than excessive reactivity to emotional stimuli. Treatments for emotion regulation in individuals without substance disorders that normalize prefrontal functioning may offer greater efficacy for substance disorders than treatments that dampen reactivity. PMID- 26771741 TI - Pulpal Remineralisation of Artificial Residual Caries Lesions in vitro. AB - We assessed pulpal remineralisation of caries lesions in vitro. On the coronal aspect of human dentin discs (n = 70), artificial lesions [mineral loss x0394;Z (mean +/- SD) = 3,060 +/- 604 vol% * um] were induced, covered and pulpal surfaces exposed to pulpal fluid, remineralisation medium or water at pressures of 0, 1.47 or 2.94 kPa for 3 months. Mineral loss differences were assessed using transversal microradiography. No significant mineral gain occurred at 0 kPa and in samples exposed to water. At 1.47 and 2.94 kPa, pulpal and remineralisation fluid induced significant mineral gain [x0394;x0394;Z = 1,317 (25th/75th percentiles: 735/1,541) vol% * um; p < 0.001]. Pressure and fluid composition determined pulpal remineralisation in vitro. PMID- 26771739 TI - Effect of Hippocampal and Amygdala Connectivity on the Relationship Between Preschool Poverty and School-Age Depression. AB - OBJECTIVE: In this study, the authors tested the hypothesis that poverty experienced in early childhood, as measured by income-to-needs ratio, has an impact on functional brain connectivity at school age, which in turn mediates influences on child negative mood/depression. METHOD: Participants were from a prospective longitudinal study of emotion development. Preschoolers 3-5 years of age were originally ascertained from primary care and day care sites in the St. Louis area and then underwent annual behavioral assessments for up to 12 years. Healthy preschoolers and those with a history of depression symptoms underwent neuroimaging at school age. Using functional MRI, the authors examined whole brain resting-state functional connectivity with the left and right hippocampus and amygdala. RESULTS: Lower income-to-needs ratio at preschool age was associated with reduced connectivity between hippocampus and amygdala and a number of regions at school age, including the superior frontal cortex, lingual gyrus, posterior cingulate, and putamen. Lower income-to-needs ratio predicted greater negative mood/depression severity at school age, as did connectivity between the left hippocampus and the right superior frontal cortex and between the right amygdala and the right lingual gyrus. Connectivity mediated the relationship between income-to-needs ratio and negative mood/depression at the time of scanning. CONCLUSIONS: These findings suggest that poverty in early childhood, as assessed by at least one measure, may influence the development of hippocampal and amygdala connectivity in a manner leading to negative mood symptoms during later childhood. PMID- 26771740 TI - Novel Structural and Functional Motifs in cellulose synthase (CesA) Genes of Bread Wheat (Triticum aestivum, L.). AB - Cellulose is the primary determinant of mechanical strength in plant tissues. Late-season lodging is inversely related to the amount of cellulose in a unit length of the stem. Wheat is the most widely grown of all the crops globally, yet information on its CesA gene family is limited. We have identified 22 CesA genes from bread wheat, which include homoeologs from each of the three genomes, and named them as TaCesAXA, TaCesAXB or TaCesAXD, where X denotes the gene number and the last suffix stands for the respective genome. Sequence analyses of the CESA proteins from wheat and their orthologs from barley, maize, rice, and several dicot species (Arabidopsis, beet, cotton, poplar, potato, rose gum and soybean) revealed motifs unique to monocots (Poales) or dicots. Novel structural motifs CQIC and SVICEXWFA were identified, which distinguished the CESAs involved in the formation of primary and secondary cell wall (PCW and SCW) in all the species. We also identified several new motifs specific to monocots or dicots. The conserved motifs identified in this study possibly play functional roles specific to PCW or SCW formation. The new insights from this study advance our knowledge about the structure, function and evolution of the CesA family in plants in general and wheat in particular. This information will be useful in improving culm strength to reduce lodging or alter wall composition to improve biofuel production. PMID- 26771742 TI - Effect of Exercise Intensity on Spontaneous Physical Activity Energy Expenditure in Overweight Boys: A Crossover Study. AB - OBJECTIVE: Evaluate the effect of different exercise intensities on spontaneous physical activity energy expenditure in overweight adolescents. METHODS: A crossover study was developed with a control session, followed by moderate and vigorous exercise sessions, with six days of monitoring each. Twenty-four adolescents, 11-13 years old, male and overweight were selected. Spontaneous physical activity energy expenditure was assessed by accelerometers. Linear mixed effects models were used to evaluate the differences per session across time. RESULTS: Energy expenditure during the 1st hour was different between all three sessions, with averages of 82, 286 and 343 kcal to the control, moderate and vigorous sessions, respectively (p <0.001). The same pattern of difference in energy expenditure between the sessions remained after 24 hours (704 vs 970 vs 1056 kcal, p <0.001). However, energy expenditure during the six days indicates compensation from second to the sixth day, although small differences remained at the end of the 6-day period (5102 vs 5193 vs 5271 kcal, p <0.001). CONCLUSIONS: A single aerobic session seems to modify the spontaneous physical activities in overweight adolescents but still keeping the vigorous session with higher total energy expenditure during the follow-up period. Despite the observed compensatory effect, the greater energy expenditure observed in both moderate and vigorous exercise sessions indicates that physical activity should be recommended to promote an increased energy expenditure in adolescents. TRIAL REGISTRATION: ClinicalTrials.gov NCT 02272088. PMID- 26771744 TI - Simultaneous BK Polyomavirus (BKPyV)-associated nephropathy and hemorrhagic cystitis after living donor kidney transplantation. AB - BK polyomavirus (BKPyV) commonly reactivates after kidney transplantation, and can cause polyomavirus-associated nephropathy (PyVAN), whereas after allogeneic stem cell transplantation the most frequent manifestation of BKPyV is polyomavirus-associated hemorrhagic cystitis (PyVHC). Despite high-level BKPyV replication in both, the pathogenesis and manifestation of both BKPyV entities appears to differ substantially. We describe an unusual case of simultaneous PyVAN and PyVHC presenting with acute symptoms in a BKPyV-IgG positive recipient eight months after kidney transplantation from a haploidentical living donor, who was BKPyV-IgG negative. Symptoms of cystitis and viremia subsided rapidly after reduction of immunosuppression. PMID- 26771745 TI - Correction: A Leafhopper-Transmissible DNA Virus with Novel Evolutionary Lineage in the Family Geminiviridae Implicated in Grapevine Redleaf Disease by Next Generation Sequencing. PMID- 26771746 TI - Geometry Design Optimization of Functionally Graded Scaffolds for Bone Tissue Engineering: A Mechanobiological Approach. AB - Functionally Graded Scaffolds (FGSs) are porous biomaterials where porosity changes in space with a specific gradient. In spite of their wide use in bone tissue engineering, possible models that relate the scaffold gradient to the mechanical and biological requirements for the regeneration of the bony tissue are currently missing. In this study we attempt to bridge the gap by developing a mechanobiology-based optimization algorithm aimed to determine the optimal graded porosity distribution in FGSs. The algorithm combines the parametric finite element model of a FGS, a computational mechano-regulation model and a numerical optimization routine. For assigned boundary and loading conditions, the algorithm builds iteratively different scaffold geometry configurations with different porosity distributions until the best microstructure geometry is reached, i.e. the geometry that allows the amount of bone formation to be maximized. We tested different porosity distribution laws, loading conditions and scaffold Young's modulus values. For each combination of these variables, the explicit equation of the porosity distribution law-i.e the law that describes the pore dimensions in function of the spatial coordinates-was determined that allows the highest amounts of bone to be generated. The results show that the loading conditions affect significantly the optimal porosity distribution. For a pure compression loading, it was found that the pore dimensions are almost constant throughout the entire scaffold and using a FGS allows the formation of amounts of bone slightly larger than those obtainable with a homogeneous porosity scaffold. For a pure shear loading, instead, FGSs allow to significantly increase the bone formation compared to a homogeneous porosity scaffolds. Although experimental data is still necessary to properly relate the mechanical/biological environment to the scaffold microstructure, this model represents an important step towards optimizing geometry of functionally graded scaffolds based on mechanobiological criteria. PMID- 26771743 TI - Population Genetic Structure and Potential Incursion Pathways of the Bluetongue Virus Vector Culicoides brevitarsis (Diptera: Ceratopogonidae) in Australia. AB - Culicoides brevitarsis is a vector of the bluetongue virus (BTV), which infects sheep and cattle. It is an invasive species in Australia with an assumed Asian/South East Asian origin. Using one mitochondrial marker (i.e., part of the cytochrome oxidase subunit I gene) and six nuclear markers, we inferred population genetic structure and possible incursion pathways for Australian C. brevitarsis. Nine mitochondrial haplotypes, with low nucleotide sequence diversity (0.0-0.7%) among these, were identified in a sample of 70 individuals from seven sites. Both sets of markers revealed a homogeneous population structure, albeit with evidence of isolation by distance and two genetically distinct clusters distributed along a north-to-south cline. No evidence of a cryptic species complex was found. The geographical distribution of the mitochondrial haplotypes is consistent with at least two incursion pathways into Australia since the arrival of suitable livestock hosts. By contrast, 15 mitochondrial haplotypes, with up to four times greater nucleotide sequence diversity (0.0-2.9%) among these, were identified in a sample of 16 individuals of the endemic C. marksi (sampled from a site in South Australia and another in New South Wales). A phylogenetic tree inferred using the mitochondrial marker revealed that the Australian and Japanese samples of C. brevitarsis are as evolutionarily different from one another as some of the other Australian species (e.g., C. marksi, C. henryi, C. pallidothorax) are. The phylogenetic tree placed four of the species endemic to Australia (C. pallidothorax, C. bundyensis, C. marksi, C. henryi) in a clade, with a fifth such species (C. bunrooensis) sharing a common ancestor with that clade and a clade comprising two Japanese species (C. verbosus, C. kibunensis). PMID- 26771748 TI - Synthesis and photocatalytic properties of Palladium-loaded three dimensional flower-like anatase TiO2 with dominant {001} facets. AB - Palladium-loaded (Pd-loaded) anatase TiO2 with dominant {001} facets used as photocatalysts was prepared by a two-step process. Three dimensional flower-like structures of anatase TiO2 with exposed {001} facets were synthesized by solvothermal method, and then Pd nanoparticles were photodeposited onto the {101} surface of TiO2 by UV reduction. The resulting Pd/TiO2 was characterized by X-ray diffraction, scanning electron microscopy, transmission electron microscopy, X ray photoelectron spectroscopy, and UV-vis diffuse reflectance spectra. Characterization results indicated that the flower-like structures of anatase TiO2 were assembled by two dimensional nanosheets with a thickness of approximately 10nm and a length of approximately 1.0MUm. The Pd/TiO2 nanocomposites with improved visible-light-harvesting capability, high charge hole mobility, and low electron-hole recombination exhibited improved photocatalytic performance in degrading bisphenol A. This study provided new insights into the fabrication and practical application of high-performance photocatalysts in degrading organic pollutants. PMID- 26771747 TI - Epoch Analysis of On-Treatment Disability Progression Events over Time in the Tysabri Observational Program (TOP). AB - OBJECTIVE: To evaluate the effect of natalizumab on disability progression beyond 2 years of treatment in clinical practice. METHODS: Analyses included the 496 relapsing-remitting multiple sclerosis (RRMS) patients among 5122 patients in the Tysabri Observational Program (TOP) who had completed 4 continuous years of natalizumab treatment and had baseline (study enrollment) and postbaseline Expanded Disability Status Scale (EDSS) assessments. Proportions of patients with 6-month or 12-month confirmed >=1.0-point EDSS progression relative to baseline were compared in treatment months 1-24 and 25-48. Sensitivity analyses compared progression rates in months 13-24 and 25-36. RESULTS: Baseline characteristics appeared similar between the overall TOP population (N = 5122), patients who had completed 4 years of natalizumab treatment (n = 469), and patients eligible to complete 4 years in TOP who had discontinued natalizumab after 2 years of treatment (n = 514). Among 4-year completers, the proportion of patients with 6 month and 12-month confirmed EDSS progression decreased between months 1-24 and 25-48 of natalizumab treatment by 42% (from 10.9% to 6.3%; p < 0.01) and 52% (from 9.5% to 4.6%; p < 0.01), respectively. Few patients had 6-month or 12-month confirmed EDSS progression in both epochs (0.6% and 0.2%, respectively). Between months 13-24 and 25-36 of treatment, the proportion of patients with 6-month and 12-month confirmed EDSS progression decreased by 60% (from 7.5% to 3.0%; p < 0.01) and 58% (from 6.7% to 2.8%; p < 0.01), respectively. Significant reductions in disability progression events between months 13-24 and 25-36 were also observed in relapse-free patients. CONCLUSION: In this observational study, the disability progression rate decreased further beyond 2 years of natalizumab treatment. Patients who responded well and remained on continuous natalizumab therapy for over 4 years had sustained and potentially enhanced reductions in EDSS progression over time. PMID- 26771750 TI - Bromate removal from water by polypyrrole tailored activated carbon. AB - Bromate adsorption behavior and mechanism were examined on a novel adsorbent devised via depositing polypyrrole (Ppy) into the pores of nut shell-based activated carbon (NAC). This Ppy-tailored activated carbon (Ppy-NAC) hosted positively charged polypyrrole functionality that offered considerable sorption capacity for bromate. Specifically, the Ppy-NAC achieved a bromate loading of 62.5mg/g in the adsorption isotherm, 8.3 times higher than the pristine NAC. The adsorption isotherm data were fitted well by the Langmuir model, and the adsorption kinetics were described well by the pseudo-second-order equation. The occurrence of chloride ions in solution showed that Cl(-) exchanged with BrO3(-) during the adsorption process. The X-ray photoelectron spectroscopy (XPS) analysis and the detection of bromide in solution indicated that some of BrO3(-) were reduced to Br(-), and the produced bromide ions were released to the solution and adsorbed on the Ppy-NAC. The increase of oxygen-containing functional groups on Ppy-NAC after adsorption verified that the redox reaction occurred during the adsorption process. The mechanisms of bromate removal by the Ppy-NAC included ion exchange and reduction reaction of bromate on the Ppy-NAC surfaces. PMID- 26771749 TI - Inhibition of bacterial surface colonization by immobilized silver nanoparticles depends critically on the planktonic bacterial concentration. AB - Immobilization of antimicrobial silver nanoparticles (AgNPs) on surfaces has been proposed as a method to inhibit biofouling or as a possible route by which incidental releases of AgNPs may interfere with biofilms in the natural environment or in wastewater treatment. This study addresses the ability of planktonic Pseudomonas fluorescens bacteria to colonize surfaces with pre adsorbed AgNPs. The ability of the AgNP-coated surfaces to inhibit colonization was controlled by the dissolved silver in the system, with a strong dependence on the initial planktonic cell concentration in the suspension, i.e., a strong inoculum effect. This dependence was attributed to a decrease in dissolved silver ion bioavailability and toxicity caused by its binding to cells and/or cell byproducts. Therefore, when the initial cell concentration was high (~1*10(7)CFU/mL), an excess of silver binding capacity removed most of the free silver and allowed both planktonic growth and surface colonization directly on the AgNP-coated surface. When the initial cell concentration was low (~1*10(5)CFU/mL), 100% killing of the planktonic cell inoculum occurred and prevented colonization. When an intermediate initial inoculum concentration (~1*10(6)CFU/mL) was sufficiently large to prevent 100% killing of planktonic cells, even with 99.97% initial killing, the planktonic population recovered and bacteria colonized the AgNP-coated surface. In some conditions, colonization of AgNP-coated surfaces was enhanced relative to silver-free controls, and the bacteria demonstrated a preferential attachment to AgNP-coated, rather than bare, surface regions. The degree to which the bacterial concentration dictates whether or not surface-immobilized AgNPs can inhibit colonization has significant implications both for the design of antimicrobial surfaces and for the potential environmental impacts of AgNPs. PMID- 26771751 TI - [In Process Citation]. PMID- 26771752 TI - Approaches to Testing Interaction Effects Using Structural Equation Modeling Methodology. AB - Use of structural equation modeling (SEM) methodology to study interactive relationships among latent variables began with the work of Kenny and Judd (1984) who developed a method of testing interactions involving continuous latent variables by forming products of multiple indicator variables. Until recently, there has been considerable difficulty implementing the method in SEM programs. This article reviews a single indicator approach (Joreskog & Yang, 1996) and multiple indicator approaches (Jaccard & Wan, 1995; Ping, 1996) that simplify Kenny and Judd's method. An illustrative application using an empirical example examining the interactive effect of perceptions of competence and perceptions of autonomy on exercise intrinsic motivation is presented. Practical issues surrounding the use of these different approaches are discussed. PMID- 26771753 TI - A Multidimensional Scaling Model Accommodating Differential Stimulus Familiarity. AB - We introduce a multidimensional scaling procedure that attempts to derive a spatial representation of stimuli unconfounded by the effect of subjects' degrees of familiarity with these stimuli. The proposed model assumes that stimulus unfamiliarity produces a tendency for a subject to anchor his/her dissimilarity judgments towards a reference value on the response scale. The input data needed to perform such analyses are the degree of stimulus familiarity along with the dissimilarity judgments for all pairs of stimuli. In a Monte Carlo study, we investigate the extent to which the procedure recovers known parameters. Furthermore, empirical applications; of the model to positioning studies of magazines and banks in the Netherlands are provided. PMID- 26771754 TI - The TETRAD Project: Constraint Based Aids to Causal Model Specification. AB - The statistical community has brought logical rigor and mathematical precision to the problem of using data to make inferences about a model's parameter values. The TETRAD project, and related work in computer science and statistics, aims to apply those standards to the problem of using data and background knowledge to make inferences about a model's specification. We begin by drawing the analogy between parameter estimation and model specification search. We then describe how the specification of a structural equation model entails familiar constraints on the covariance matrix for all admissible values of its parameters; we survey results on the equivalence of structural equation models, and we discuss search strategies for model specification. We end by presenting several algorithms that are implemented in the TETRAD I1 program. PMID- 26771755 TI - TETRAD and SEM. PMID- 26771756 TI - Causal Independence and Faithfulness. PMID- 26771757 TI - Response to: The TETRAD Project: Constraint Based Aids to Causal Model Specification. PMID- 26771758 TI - The TETRAD Approach to Model Respecification. AB - The TETRAD project revives the tetrad analysis developed almost a century ago. Vanishing tetrads are overidentifying restrictions implied by the structure of a model. As such, it is possible to examine a model empirically by these constraints. Scheines, Spirtes, Glymour, Meek, & Richardson (1998) advocate using vanishing tetrads as a tool for automatic model searches. Despite the search algorithm proving to be superior to those from LISREL and EQS in an earlier report, it is argued that TETRAD II, the search program, is still a datamining procedure. It is important that substantive justifications should be given before, not after, a model is selected. This is impossible with any type of automatic, procedure for specification search. Researchers should take an active role in formulating alternative ' models rather than looking for a quick fix. Finally, the tetrad test developed by Bollen and Ting (1993) is discussed with its application for testing competing models or their components formulated in I advance. PMID- 26771759 TI - Reply to Comments. AB - We will respond to our commentators individually, but the order of our responses follows naturally from the issues they bring up. Judea Pearl describes SEM's unfortunate retreat from the clear causal semantics articulated by Sewall Wright (1921) and later by Haavelmo (1943) to the algebraic interpretation preferred more recently by econometricians. We agree with Pearl about the history and also the problem, namely that the algebraic interpretation is suitable for estimation but expressively too weak to even distinguish among competing causal claims. Here we try to elaborate on the distinction between the semantics of a causal SEM and the epistemological connections between statistical data, background knowledge, and causal structure. We argue that many modern critics of SEM make their hay by conflating this distinction. Having tried to make it clear, we then turn to the assumptions that give the epistemological issues their structure, namely the Causal Independence and Faithfulness assumptions. Jim Woodward questions these assumptions at length, especially the Causal Independence assumption, and we spend the second part of our response defending it. Phil Wood seems to accept the fundamental assumptions upon which TETRAD rests, and even the utility of tools like it, but he brings out a wide array of subtle difficulties that we have not had time to discuss, some of which we now cover. Kwok-fai Ting questions the utility of any specification search done by computer, and we attempt to address his concerns last. PMID- 26771760 TI - Baby-led Weaning: A Preliminary Investigation. AB - PURPOSE: To date, baby-led weaning (BLW) has not been examined in a Canadian population. This research investigated common BLW practices and compared associated knowledge and perceptions of practicing mothers and health care professionals (HCPs). METHODS: Sixty-five mothers practicing BLW and 33 HCPs were surveyed using 2 online questionnaires. Mothers were recruited through the Newfoundland and Labrador BLW Facebook page and HCPs via email at 2 regional health authorities. RESULTS: Mothers described BLW in terms of food shape and consistency (whole, solid); however, in practice, some mothers offered pureed foods such as infant cereals. More HCPs than mothers indicated choking, inadequate energy, and iron intake as concerns. Mothers relied on the Facebook page over HCPs for BLW information and support. Although all practicing mothers would recommend BLW to others, less than half (48.5%) of HCPs would support it in their practice. CONCLUSIONS: Mothers following BLW vary greatly in their experiences and adherence to BLW. They view the practice and its disadvantages very differently than HCPs. Although most HCPs were aware of BLW, few were familiar with specific practices. HCPs may benefit from a greater understanding of BLW to provide guidance to the growing number of mothers following this practice. PMID- 26771761 TI - Nuclear Magnetic Resonance Solution Structures of Lacticin Q and Aureocin A53 Reveal a Structural Motif Conserved among Leaderless Bacteriocins with Broad Spectrum Activity. AB - Lacticin Q (LnqQ) and aureocin A53 (AucA) are leaderless bacteriocins from Lactococcus lactis QU5 and Staphylococcus aureus A53, respectively. These bacteriocins are characterized by the absence of an N-terminal leader sequence and are active against a broad range of Gram-positive bacteria. LnqQ and AucA consist of 53 and 51 amino acids, respectively, and have 47% identical sequences. In this study, their three-dimensional structures were elucidated using solution nuclear magnetic resonance and were shown to consist of four alpha-helices that assume a very similar compact, globular overall fold (root-mean-square deviation of 1.7 A) with a highly cationic surface and a hydrophobic core. The structures of LnqQ and AucA resemble the shorter two-component leaderless bacteriocins, enterocins 7A and 7B, despite having low levels of sequence identity. Homology modeling revealed that the observed structural motif may be shared among leaderless bacteriocins with broad-spectrum activity against Gram-positive organisms. The elucidated structures of LnqQ and AucA also exhibit some resemblance to circular bacteriocins. Despite their similar overall fold, inhibition studies showed that LnqQ and AucA have different antimicrobial potency against the Gram-positive strains tested, suggesting that sequence disparities play a crucial role in their mechanisms of action. PMID- 26771762 TI - MicroRNA-103 suppresses tumor cell proliferation by targeting PDCD10 in prostate cancer. AB - BACKGROUND: It is known that microRNAs (miRNAs) are a class of small, non-coding RNAs that act as key regulators in various physiological and pathological processes. However, the regulatory mechanisms involving miRNAs in prostate cancer remain largely unknown. Here, we found that miR-103 is down-regulated in prostate cancer and closely associated with tumor proliferation and migration. Our objective was to explore the role of the miR-103 in prostate cancer. METHODS: In this study, we measured miR-103 level using real-time polymerase chain reaction in the human prostate cancer cell lines, including PC-3, LNCap, 22Rv1, DU145, and the normal prostate epithelium cell line RWPE-1, a total of 25 pairs of primary prostate cancer tissues and adjacent non-cancerous tissues (NCTs) were measured also. In addition, over-expression of miR-103 in prostate cancer cell lines to determine the role of miR-103 in prostate cancer. RESULTS: We found that miR-103 is down-regulated in prostate cancer and closely associated with tumor proliferation and migration. In addition, over-expression of miR-103 apparently inhibits prostate cancer cell proliferation and migration in vitro. Gain-of function in vitro experiments further show that miR-103 mimics significantly inhibited prostate cancer cell proliferation, invasion and increase the cell cycle in G1 phase, while promoted cell apoptosis. Subsequent dual-luciferase reporter assay identified one of the proto-oncogene PDCD10 as direct target of miR-103. CONCLUSIONS: Therefore, our data collectively demonstrate that miR-103 is a proto-oncogene miRNA that can suppress prostate cancer proliferation and migration by down-regulating the oncogene PDCD10, indicating that miR-103 may represent a new potential diagnostic and therapeutic target for prostate cancer treatment. PMID- 26771763 TI - Resistance of Amphiphilic Polysaccharides against Marine Fouling Organisms. AB - Amphiphilic coatings are promising candidates for fouling-release applications. As hydrophilic components, polysaccharides are interesting and environmentally benign building blocks. We used covalently coupled alginic acid (AA) and hyaluronic acid (HA) and postmodified them with a hydrophobic fluorinated amine. The surfaces showed good stability under marine conditions and fluorination led to a decreased uptake of Ca(2+) ions after modification. In single species settlement assays (bacteria, diatoms, barnacle cypris larvae), the modification decreased the settlement density and/or the adhesion strength of many of the tested species. Field studies supported findings of the laboratory experiments, as hydrophobic modification of AA and HA decreased diatom colonization. PMID- 26771765 TI - Reply to: postoperative intermediate care unit and life-threatening complications: How much and how are they linked? PMID- 26771764 TI - Plasma levels of chemokine ligand 20 and chemokine receptor 6 in patients with sepsis: A case control study. AB - BACKGROUND: Chemokine ligand 20 (CCL20) is a chemokine released by mainly liver and blood leucocytes. Particularly under pro-inflammatory circumstances it triggers chemotaxis of lymphocytes and dendritic cells via activating receptor chemokine receptor 6 (CCR6) that is specific to it. In experimental sepsis models, the chemokine-receptor pair has been identified as a potential pathophysiological axis affecting mortality. OBJECTIVE: Measurement of CCL20 and CCR6 plasma levels in septic patients compared with postsurgical, nonseptic patients. DESIGN: Case control study. SETTING: Surgical ICUs of the Department of Anaesthesiology, General Hospital of Vienna, Vienna, Austria. PATIENTS: Plasma levels were measured in 46 patients with sepsis, severe sepsis or septic shock according to current American College of Chest Physicians/Society of Critical Care Medicine criteria at the day of sepsis onset. Plasma levels in 36 postsurgical controls without sepsis admitted to the ICU were investigated. Plasma concentrations were determined by using commercially available ELISA kits. Data are given as median and interquartile range (IQR). MAIN OUTCOME MEASURES: CCL20 and CCR6 plasma levels. RESULTS: CCL20 plasma levels were significantly increased in the sepsis group: 220.9 pg ml (IQR, 72.8 to 540.1) compared with the ICU controls: 37.0 pg ml (IQR 6.5 to 83.6) (P < 0.0001). Significantly elevated CCR6 levels were found in the sepsis group: 2.47 ng ml (IQR 0.92 to 5.54) compared with the controls: 0.59 ng ml (IQR 0.17 to 1.48) (P < 0.0001). Both CCL20 and CCR6 correlated with the maximum sequential organ failure assessment score (CCL20: P < 0.0001, CCR6: P < 0.0001). Length of ICU admission depended significantly on the logarithm of CCR6 (P = 0.008) and sequential organ failure assessment maximum (P < 0.0001). CONCLUSION: There were early increased plasma concentrations of CCL20 and CCR6 in patients with sepsis. CCL20 and CCR6 correlate with severity of illness in ICU patients. Levels of CCR6 predicted the length of patients' admission. PMID- 26771766 TI - Chemical Structural Characteristics of HULIS and Other Fractionated Organic Matter in Urban Aerosols: Results from Mass Spectral and FT-IR Analysis. AB - The chemical characteristics of complex organic matter in atmospheric aerosols remain poorly understood. Water-insoluble organic matter (WISOM) and water soluble organic matter (WSOM) in the total suspended particulates collected in the city of Nagoya in summer/early autumn and winter were extracted using multiple solvents. Two fractions of humic-like substances, showing neutral and acidic behavior (HULIS-n and HULIS-a, respectively), and the remaining highly polar part (HP-WSOM) were fractionated from WSOM using solid phase extraction. The chemical structural characteristics and concentrations of the organic matter were investigated using mass spectrometry and Fourier transform infrared (FT-IR) spectroscopy. WISOM and HULIS-n had low O/C ratios (0.1 and 0.4, respectively) and accounted for a large fraction of the organics in aerosols (70%). HULIS-a and HP-WSOM had higher O/C ratios (0.7 and 1.0, respectively), and their concentrations in summer and early autumn were on average ~2 times higher than those in winter. The mass spectrum and FT-IR analyses suggest the following: (1) WISOM were high-molecular-weight aliphatics (primarily C27-C32) with small proportions of -CH3, -OH, and C?O groups; (2) HULIS-n was abundant in aliphatic structures and hydroxyl groups (primarily C9-C18) and by branched structures; (3) HULIS-a and HP-WSOM contained relatively large amounts of low-molecular-weight carboxylic acids and alcohols (primarily C4-C10); and (4) WISOM and HULIS-n were relatively abundant in amines and organic nitrates. PMID- 26771767 TI - NAC selectively inhibit cancer telomerase activity: A higher redox homeostasis threshold exists in cancer cells. AB - Telomerase activity controls telomere length, and this plays an important role in stem cells, aging and tumors. Antioxidant was shown to protect telomerase activity in normal cells but inhibit that in cancer cells, but the underlying mechanism is elusive. Here we found that 7721 hepatoma cells held a higher redox homeostasis threshold than L02 normal liver cells which caused 7721 cells to have a higher demand for ROS; MnSOD over-expression in 7721 decreased endogenous reactive oxygen species (ROS) and inhibited telomerase activity; Akt phosphorylation inhibitor and NAC both inhibited 7721 telomerase activity. The over-elimination of ROS by NAC resulted in the inhibition of Akt pathway. Our results suggest that ROS is involved in the regulation of cancer telomerase activity through Akt pathway. The different intracellular redox homeostasis and antioxidant system in normal cells and tumor cells may be the cause of the opposite effect on telomerase activity in response to NAC treatment. Our results provide a theoretical base of using antioxidants selectively inhibit cancer telomerase activity. Findings of the present study may provide insights into novel approaches for cancer treatment. PMID- 26771769 TI - Molecular Chaperones as Therapy for PFIC: Not So Fast! PMID- 26771768 TI - Prevalence of Functional Gastrointestinal Disorders in Schoolchildren in Ecuador. AB - The prevalence of functional gastrointestinal disorders (FGIDs) in children in Ecuador is unknown. We describe a survey study in 2 schools in Quito, Ecuador, using a Spanish translation of the Questionnaire on Pediatric Gastrointestinal Symptoms-Rome III Version (QPGS-RIII). A total of 417 children (51% boys) with a mean age of 12.0 years were included. FGIDs were present in 95 children (22.8%) and occurred in 25% of girls and in 20.7% of boys (P = 0.296). Functional defecation disorders were found in 12.0% of children, 9.4% had an abdominal pain related FGID and 3.8% was diagnosed with a vomiting or aerophagia FGID. PMID- 26771772 TI - DIMENSIONS OF PERSONALITY: I. CONJOINT FACTOR STRUCTURE OF GUILFORD AND CATTELL TRAIT MARKERS. AB - This is the first of three reports of a taxonomic investigation of person- ality based on a matrix of 600 personality questionnaire items represented equally by marker items derived from the personality trait systems developed by J. P. Guilford and R. B. Cattell. This report outlines the entire prsject (Sells, Demaree, and Will, 1968) and focuses on the factor structure of the total matrix with particular concern for the relative contributions and relations of the two sources. The second report will analyze in detail the separate factor structures found in the Guilford and Cattell trait markers, while the third will summarize the final factor identification, based on analyses of the total matrix and matrices representing the Guilford and Cattell systems. PMID- 26771770 TI - E-cadherin-mediated contact of endothelial progenitor cells with mesenchymal stem cells through beta-catenin signaling. AB - Mesenchymal stem cells (MSCs) and endothelial progenitor cells (EPCs) are attached to each other in the bone marrow (BM) cavity and in in vitro cultures, and this adhesion has important physiological significance. We demonstrated that cell proliferation could be promoted when MSCs were co-cultured with EPCs, which was beneficial to angiogenesis, tissue repair, and regeneration. The adhesion of MSCs and EPCs could promote the pluripotency of MSCs, particularly self-renewal and multi-differentiation to osteoblasts, chondrocytes, and adipocytes. This study focused on the mechanism of adhesion between EPCs and MSCs. The results showed that E-cadherin (E-cad) mediated the adhesion of MSCs and EPCs through the E-cad/beta-catenin signaling pathway. The E-cad of EPCs occupied a dominant position during this process, which activated and up-regulated the beta-catenin (beta-catenin) of MSCs to improve cohesion and exert their biological function. PMID- 26771771 TI - Mass and number size distributions of emitted particulates at five important operation units in a hazardous industrial waste incineration plant. AB - Past studies indicated particulates generated by waste incineration contain various hazardous compounds. The aerosol characteristics are very important for particulate hazard control and workers' protection. This study explores the detailed characteristics of emitted particulates from each important operation unit in a rotary kiln-based hazardous industrial waste incineration plant. A dust size analyzer (Grimm 1.109) and a scanning mobility particle sizer (SMPS) were used to measure the aerosol mass concentration, mass size distribution, and number size distribution at five operation units (S1-S5) during periods of normal operation, furnace shutdown, and annual maintenance. The place with the highest measured PM10 concentration was located at the area of fly ash discharge from air pollution control equipment (S5) during the period of normal operation. Fine particles (PM2.5) constituted the majority of the emitted particles from the incineration plant. The mass size distributions (elucidated) made it clear that the size of aerosols caused by the increased particulate mass, resulting from work activities, were mostly greater than 1.5 MUm. Whereas the number size distributions showed that the major diameters of particulates that caused the increase of particulate number concentrations, from work activities, were distributed in the sub micrometer range. The process of discharging fly ash from air pollution control equipment can significantly increase the emission of nanoparticles. The mass concentrations and size distributions of emitted particulates were different at each operation unit. This information is valuable for managers to take appropriate strategy to reduce the particulate emission and associated worker exposure. PMID- 26771773 TI - THE INTELLECT OF EAST AFRICAN STUDENTS. AB - The present experiment is intended to confirm my earlier findings, and to sustain the assumption that East African students' structure of mental difficulties is no different from that of students in the West. Seven factors were chosen for this study, each being represented by two Western reference tests. These Factors are: NFT; CFB; CFU; MSI; ESU; CMU and DSU. The battery was administered to two samples of students:-l04 Higher School Certificate boys (HSC) in secondary 5 land 6, and 165 Makerere University College Undergraduates (MUC). Principal components analysis was followed by orthogonal rotation using the Varimax solution. The seven factors were identifiable in both samples, tending to sustain the assumption that. the structure of mental abilities in East African students is similar to that in Western students. PMID- 26771774 TI - THE THERAPIST'S EXPERIENCE OF PSYCHOTHERAPY: SOME DIMENSIONS AND DETERMINANTS. AB - Eleven dimensions of therapists' experiences during psychotherapy ses- sions were derived, factor analytically, for a sample of 17 therapists. These therapists completed a standard questionnaire after each of 8 or more sessions with 31 female patients. In general, the 11 dimensions reflected various experiences of (a) being helpful towards patients, (b) attempting to deal with difSicult patients, (c) making non-therapeutic responses to patients, and (d) entrapment in personally distressing situations with patients. Personal-social characteristics of patients and therapists were examined as possible determinants of therapist experience. Among other characteristics, patients' employment and marital status, diagnosis and previous treatment, influenced certain therapist experience dimensions-as did therapists' profession, marital status, and personal psychotherapy. PMID- 26771775 TI - AFFECTIVE MEANING SYSTEMS: A MULTIVARIATE APPROACH. AB - A three-mode factor analysis was applied to the semantic differential ratings by 100 subjects of 20 concepts on 76 bipolar adjeotival scales. Four scale factors, five concept factors, and two subject factors emerged f m the analysis. On the basis of the interrelationships among these three types of factors it was concluded that different types of subjwts tend to utilize the basic scalar dimensions of meaning in different ways when applying khese scales across concepts. Further, thris differential application of scale dimen- sions varied with the class of concept being rated. PMID- 26771776 TI - CONSTRUCT VALIDATION OF THE COMREY PERSONALITY SCALES. AB - To investigate the construct validity of the Comrey Personality Scales, this personality test and a biographical data inventory inquiring about past and present life circumstances were administered to 209 volunteer U.C.L.A. students. Biographical data variables were correlated with scores on the eight personality scales. Personality scale score estimates by the authors, based on examination of the respondents' biographical data responses, were also correlated with actual scale scores. The personality scales which received the best confirmation were Social Conformity vs Rebelliousness and Orderliness vs. Lack of Compulsion. Support for the construct validity of the other personality scales varied from moderate to negligible. PMID- 26771777 TI - SUBMATRICES OF INTERASSOCIATIONS FOR SCORING INTERRELATEDNESS WITHIN MATRICES AS AN INDEX OF PSYCHOLOGICAL DISTURBANCE. AB - A method is given whereby a matrix of interassociations between individuals can be divided to yield a submatrix which can in turn be used to score the degree of interrelatedness of the parent matrix. The method can be appIied to determine the significance of .the difference between the inter- relatedness of two or more parent matrices. The method is applied to a small study of normal and distunbed subjects, and provides promising results. PMID- 26771778 TI - APPLICATION OF A MODEL OF CATEGORIZING BEHAVIOR. AB - A model for Latent Partition Analysis is proposed and two applications to data arising from sorting tasks are described. The model is based on a possible strategy which subjects might use in sorting a large number of stimuli. The first application is concerned with a judgmental classification of semantic differential scales in conhast to the usual type uf analysis based on responding with the scales to particular concepts. The second application is concerned with the classification by university students of a selection of student behaviors. PMID- 26771779 TI - SOME RESULTS RELATING TO THE CHOICE OF AN EXPERIMENTAL UNIT IN MULTlVARIATE RESEARCH. AB - Several analytic expressions are presented and discussed interms of differences which are to be expected between results obtained from applying the same multivariate analysis to data based on different experimental units. The 2 units considered are the individual observation and the group as a unit, i.e., some function, typically the mean, of the individual observations with in a group. It is demonstrated that certain statistical properties of the class of design matrices where this choice of units arises lead to substantial differences in the results and interpretations of multivariate analyses. This development provides a partial mathematical account for such observed differences as are frequently encountered in practice. PMID- 26771780 TI - Teamwork in the ICU--Do We Practice What We Preach? PMID- 26771781 TI - Randomized, Double-Blind, Placebo-Controlled Trial of Thiamine as a Metabolic Resuscitator in Septic Shock: A Pilot Study. AB - OBJECTIVE: To determine if intravenous thiamine would reduce lactate in patients with septic shock. DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: Two US hospitals. PATIENTS: Adult patients with septic shock and elevated (> 3 mmol/L) lactate between 2010 and 2014. INTERVENTIONS: Thiamine 200 mg or matching placebo twice daily for 7 days or until hospital discharge. MEASUREMENTS AND MAIN RESULTS: The primary outcome was lactate levels 24 hours after the first study dose. Of 715 patients meeting the inclusion criteria, 88 patients were enrolled and received study drug. There was no difference in the primary outcome of lactate levels at 24 hours after study start between the thiamine and placebo groups (median: 2.5 mmol/L [1.5, 3.4] vs. 2.6 mmol/L [1.6, 5.1], p = 0.40). There was no difference in secondary outcomes including time to shock reversal, severity of illness and mortality. 35% of the patients were thiamine deficient at baseline. In this predefined subgroup, those in the thiamine treatment group had statistically significantly lower lactate levels at 24 hours (median 2.1 mmol/L [1.4, 2.5] vs. 3.1 [1.9, 8.3], p = 0.03). There was a statistically significant decrease in mortality over time in those receiving thiamine in this subgroup (p = 0.047). CONCLUSION: Administration of thiamine did not improve lactate levels or other outcomes in the overall group of patients with septic shock and elevated lactate. In those with baseline thiamine deficiency, patients in the thiamine group had significantly lower lactate levels at 24 hours and a possible decrease in mortality over time. PMID- 26771783 TI - Value-Based Medicine: Dollars and Sense. AB - With ever-increasing total healthcare expenditures and expenditures on new pharmaceuticals, there is a temptation to enact relatively simple silo-based, cost-control measures such as attempts to control a burgeoning health-system medication budget by limiting physician and ultimately patient access to medications without considering cost-effectiveness or overall value. Such an approach with a singular focus on dollars does not make sense. The challenge is to think beyond a pure dollars approach in a specialty of health care where the high cost of care is acknowledged but the dynamics are not always understood. This will take a thoughtful, coordinated effort by a team of dedicated health professionals that includes a clinical pharmacist with expertise in optimal and comprehensive medication management. PMID- 26771784 TI - Postintensive Care Syndrome: Right Care, Right Now...and Later. PMID- 26771782 TI - Multicenter Comparison of Machine Learning Methods and Conventional Regression for Predicting Clinical Deterioration on the Wards. AB - OBJECTIVE: Machine learning methods are flexible prediction algorithms that may be more accurate than conventional regression. We compared the accuracy of different techniques for detecting clinical deterioration on the wards in a large, multicenter database. DESIGN: Observational cohort study. SETTING: Five hospitals, from November 2008 until January 2013. PATIENTS: Hospitalized ward patients INTERVENTIONS: None MEASUREMENTS AND MAIN RESULTS: Demographic variables, laboratory values, and vital signs were utilized in a discrete-time survival analysis framework to predict the combined outcome of cardiac arrest, intensive care unit transfer, or death. Two logistic regression models (one using linear predictor terms and a second utilizing restricted cubic splines) were compared to several different machine learning methods. The models were derived in the first 60% of the data by date and then validated in the next 40%. For model derivation, each event time window was matched to a non-event window. All models were compared to each other and to the Modified Early Warning score, a commonly cited early warning score, using the area under the receiver operating characteristic curve (AUC). A total of 269,999 patients were admitted, and 424 cardiac arrests, 13,188 intensive care unit transfers, and 2,840 deaths occurred in the study. In the validation dataset, the random forest model was the most accurate model (AUC, 0.80 [95% CI, 0.80-0.80]). The logistic regression model with spline predictors was more accurate than the model utilizing linear predictors (AUC, 0.77 vs 0.74; p < 0.01), and all models were more accurate than the MEWS (AUC, 0.70 [95% CI, 0.70-0.70]). CONCLUSIONS: In this multicenter study, we found that several machine learning methods more accurately predicted clinical deterioration than logistic regression. Use of detection algorithms derived from these techniques may result in improved identification of critically ill patients on the wards. PMID- 26771785 TI - The Future of Critical Care Medicine: Integration and Personalization. PMID- 26771786 TI - Guidelines for the Provision and Assessment of Nutrition Support Therapy in the Adult Critically Ill Patient: Society of Critical Care Medicine (SCCM) and American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.). PMID- 26771787 TI - Choosing the Duration of Therapy for Bacteremia: Keep Calm and Work With Your Infectious Disease and Antibiotic Stewardship Colleagues. PMID- 26771788 TI - Evaluating Tele-ICU Cost--An Imperfect Science. PMID- 26771789 TI - Is Interleukin-1 Receptor Blockade Ready for Prime Time in Patients With Severe Sepsis and Macrophage Activation Syndrome? PMID- 26771790 TI - Noninvasive Ventilation in Acute Hypoxemic Respiratory Failure: Songs of Love and Hate. PMID- 26771791 TI - Improved Outcomes in Critically Ill Patients With AIDS: How Does This Trend Continue? PMID- 26771792 TI - Heart Rate and the Post Cardiac Arrest Syndrome: Another Clue to Individualizing Care? PMID- 26771793 TI - Endotoxin: Back to the Future. PMID- 26771794 TI - Pulse Pressure Variations in Acute Respiratory Distress Syndrome: "Fifty Shades of Grey". PMID- 26771795 TI - Organ Donation: Circulatory Death, Brain Death, and the Eureka Effect. PMID- 26771796 TI - Neurotoxic Properties of Propofol Sedation Following Traumatic Brain Injury. PMID- 26771797 TI - Fibrinogen Measurement and Viscoelastic Technique Are Necessary to Define Acute Traumatic Coagulopathy. PMID- 26771798 TI - The authors reply. PMID- 26771799 TI - Staffing Ratios and Patient Outcomes: Looking Beyond Nurses, Doctors, and Survival at ICU Discharge. PMID- 26771800 TI - Patient Mortality Is Associated With Staff Resources and Workload in the ICU. PMID- 26771801 TI - The authors reply. PMID- 26771802 TI - Timing of Appropriate Antibiotics in Sepsis: How Much Does Each Hour Matter? PMID- 26771803 TI - The authors reply. PMID- 26771804 TI - Dopamine in Pediatric Fluid-Refractory Septic Shock: Too Early to Sound the Death Knell? PMID- 26771805 TI - The authors reply. PMID- 26771807 TI - Nurse-like cells impact on disease progression in chronic lymphocytic leukemia. PMID- 26771806 TI - miR-23b/SP1/c-myc forms a feed-forward loop supporting multiple myeloma cell growth. AB - Deregulated microRNA (miR)/transcription factor (TF)-based networks represent a hallmark of cancer. We report here a novel c-Myc/miR-23b/Sp1 feed-forward loop with a critical role in multiple myeloma (MM) and Waldenstrom's macroglobulinemia (WM) cell growth and survival. We have found miR-23b to be downregulated in MM and WM cells especially in the presence of components of the tumor bone marrow milieu. Promoter methylation is one mechanism of miR-23b suppression in myeloma. In gain-of-function studies using miR-23b mimics-transfected or in miR-23b-stably expressing MM and WM cell lines, we observed a significant decrease in cell proliferation and survival, along with induction of caspase-3/7 activity over time, thus supporting a tumor suppressor role for miR-23b. At the molecular level, miR-23b targeted Sp1 3'UTR and significantly reduced Sp1-driven nuclear factor-kappaB activity. Finally, c-Myc, an important oncogenic transcription factor known to stimulate MM cell proliferation, transcriptionally repressed miR 23b. Thus MYC-dependent miR-23b repression in myeloma cells may promote activation of oncogenic Sp1-mediated signaling, representing the first feed forward loop with critical growth and survival role in myeloma. PMID- 26771808 TI - Infectious complications in children with acute myeloid leukemia: decreased mortality in multicenter trial AML-BFM 2004. AB - Infections are an important cause for morbidity and mortality in pediatric acute myeloid leukemia (AML). We therefore characterized infectious complications in children treated according to the trial AML-BFM 2004. Patients with Down syndrome were excluded from the analysis. Data were gathered from the medical records in the hospital where the patients were treated. A total of 405 patients (203 girls; median age 8.4 years) experienced 1326 infections. Fever without identifiable source occurred in 56.1% of the patients and clinically and microbiologically documented infections in 17.5% and 32.4% of the patients, respectively. In all, 240 Gram-positive (112 viridans group streptococci) and 90 Gram-negative isolates were recovered from the bloodstream. Invasive fungal infection was diagnosed in 3% of the patients. Three children each died of Gram-negative bacteremia and invasive aspergillosis, respectively. As compared with the results of AML-BFM 93 with lower dose intensity, infection-related morbidity was slightly higher in AML BFM 2004 (3.3. versus 2.8 infections per patient), whereas infection-related mortality significantly decreased (1.5% versus 5.4%; P=0.003). Specific anti infective recommendations included in the treatment protocol, regular training courses for pediatric hematologists and increasing experience may be the reason for reduced infection-related mortality in children with AML. Further studies are needed to decrease infection-related morbidity. PMID- 26771809 TI - The Kyoto Prognostic Index for patients with diffuse large B-cell lymphoma in the rituximab era. PMID- 26771810 TI - Carfilzomib and the cardiorenal system in myeloma: an endothelial effect? AB - Carfilzomib (Cfz) has been associated with an ~5% incidence of unexplained and unpredictable cardiovascular toxicity in clinical trials. We therefore implemented a detailed, prospective, clinical cardiac and renal evaluation of 62 Cfz-treated myeloma patients, including serial blood pressure (BP), creatinine, troponin, NT-proBNP and pre- and post-treatment echocardiograms, including ejection fraction (EF), average global longitudinal strain and compliance. Pre treatment elevations in NT-proBNP and BP, as well as abnormal cardiac strain were common. A rise in NT-proBNP occurred frequently post-treatment often without corresponding cardiopulmonary symptoms. A rise in creatinine was common, lessened with hydration and often reversible. All patients had a normal EF pre-treatment. Five patients experienced a significant cardiac event (four decline in EF and one myocardial infarction), of which 2 (3.2%) were considered probably attributable to Cfz. None were rechallenged with Cfz. The ideal strategy for identifying patients at risk for cardiac events, and parameters by which to monitor for early toxicity have not been established; however, it appears baseline echocardiographic testing is not consistently predictive of toxicity. The toxicities observed suggest an endothelial mechanism and further clinical trials are needed to determine whether or not this represents a class effect or is Cfz specific. PMID- 26771811 TI - Prognostic interaction between ASXL1 and TET2 mutations in chronic myelomonocytic leukemia. AB - Mutations involving epigenetic regulators (TET2~60% and ASXL1~40%) and splicing components (SRSF2~50%) are frequent in chronic myelomonocytic leukemia (CMML). On a 27-gene targeted capture panel performed on 175 CMML patients (66% males, median age 70 years), common mutations included: TET2 46%, ASXL1 47%, SRSF2 45% and SETBP1 19%. A total of 172 (98%) patients had at least one mutation, 21 (12%) had 2, 24 (14%) had 3 and 30 (17%) had >3 mutations. In a univariate analysis, the presence of ASXL1 mutations (P=0.02) and the absence of TET2 mutations (P=0.03), adversely impacted survival; while the number of concurrent mutations had no impact (P=0.3). In a multivariable analysis that included hemoglobin, platelet count, absolute monocyte count and circulating immature myeloid cells (Mayo model), the presence of ASXL1 mutations (P=0.01) and absence of TET2 mutations (P=0.003) retained prognostic significance. Patients were stratified into four categories: ASXL1wt/TET2wt (n=56), ASXL1mut/TET2wt (n=31), ASXL1mut/TET2mut (n=50) and ASXL1wt/TET2mut (n=38). Survival data demonstrated a significant difference in favor of ASXL1wt/TET2mut (38 months; P=0.016), compared with those with ASXL1wt/TET2wt (19 months), ASXL1mut/TET2wt (21 months) and ASXL1mut/TET2mut (16 months) (P=0.3). We confirm the negative prognostic impact imparted by ASXL1 mutations and suggest a favorable impact from TET2 mutations in the absence of ASXL1 mutations. PMID- 26771812 TI - Karyotype complexity and prognosis in acute myeloid leukemia. AB - A complex aberrant karyotype consisting of multiple unrelated cytogenetic abnormalities is associated with poor prognosis in patients with acute myeloid leukemia (AML). The European Leukemia Net classification and the UK Medical Research Council recommendation provide prognostic categories that differ in the definition of unbalanced aberrations as well as the number of single aberrations. The aim of this study on 3526 AML patients was to redefine and validate a cutoff for karyotype complexity in AML with regard to adverse prognosis. Our study demonstrated that (1) patients with a pure hyperdiploid karyotype have an adverse risk irrespective of the number of chromosomal gains, (2) patients with translocation t(9;11)(p21~22;q23) have an intermediate risk independent of the number of additional aberrations, (3) patients with ?4 abnormalities have an adverse risk per se and (4) patients with three aberrations in the absence of abnormalities of strong influence (hyperdiploid karyotype, t(9;11)(p21~22;q23), CBF-AML, unique adverse-risk aberrations) have borderline intermediate/adverse risk with a reduced overall survival compared with patients with a normal karyotype. PMID- 26771813 TI - Significance of KIT exon 17 mutation depends on mutant level rather than positivity in core-binding factor acute myeloid leukemia. AB - KIT exon 17 mutation is a poor prognostic factor in core-binding factor acute myeloid leukemia. However, the mutation detection method used for risk assessment is not assigned. It is necessary to verify the analytical and clinical performance before applying new methods. Herein, we firstly applied a highly sensitive allele-specific, real-time quantitative PCR (AS-qPCR) assay to analyze KIT mutations, which demonstrated excellent sensitivity and specificity. Much higher incidence of KIT mutations (62.2%, 69/111) and prevalence of multiple mutations (43.5%, 30/69) were observed using AS-qPCR, which meant the existence of multiple KIT mutant subclones. The relative KIT mutant level was variable (median, 0.3 per control allele 100 copies, 0.002-532.7) and was divided into two groups: high (?10, n=26) and low (<10) mutant level. Interestingly, rather than mutation positivity, mutant level was found to be associated with clinical outcome. High mutant level showed significantly inferior overall survival (P=0.005) and event-free survival (P=0.03), whereas low level did not influence the prognosis. The follow-up data showed that the mutant level were along with fusion transcripts in the majority (n=29), but moved separately in some cases, including the loss of mutations (n=5) and selective proliferation of minor clones (n=2) at relapse. This study highlighted that the KIT mutation should be analyzed using sensitive and quantitative techniques and set a cutoff level for identifying the risk group. PMID- 26771814 TI - High expression of PTPN21 in B-cell non-Hodgkin's gastric lymphoma, a positive mediator of STAT5 activity. PMID- 26771815 TI - Serological Evidence for Schmallenberg Virus Infection in Sheep of Portugal, 2014. AB - Between November and December of 2014, a serosurvey was set up to evaluate the presence of Schmallenberg virus (SBV) antibodies in sheep of Portugal. Sera (n = 1068) were tested using an indirect enzyme linked immunosorbent assay (ID Screen((r)) Schmallenberg virus indirect, IDvet Innovative Diagnostics, Montpellier, France). The estimated occurrence of immunogobulin G (IgG) antibodies against SBV in sheep of Portugal was 12.8% (95% confidence interval 11.0-15.0%). This is the first study reporting the presence of SBV antibodies in sheep of Portugal. PMID- 26771816 TI - Intermittent hydrostatic pressure maintains and enhances the chondrogenic differentiation of cartilage progenitor cells cultivated in alginate beads. AB - The objective of this study was to explore the effects of intermittent hydrostatic pressure (IHP) on the chondrogenic differentiation of cartilage progenitor cells (CPCs) cultivated in alginate beads. CPCs were isolated from the knee joint cartilage of rabbits, and infrapatellar fat pad-derived stem cells (FPSCs) and chondrocytes (CCs) were included as the control cell types. Cells embedded in alginate beads were treated with IHP at 5 Mpa and 0.5 Hz for 4 h/day for 1, 2, or 4 weeks. The cells' migratory and proliferative capacities were evaluated using the scratch and Live/Dead assays, respectively. Hematoxylin and eosin staining, safranin O staining, and immunohistochemical staining were performed to determine the effects of IHP on the synthesis of extracellular matrix (ECM) proteins. Real-time polymerase chain reaction analysis was performed to measure the expression of genes related to chondrogenesis. The scratch and Live/Dead assays revealed that IHP significantly promoted the migration and proliferation of FPSCs and CPCs to different extents. The staining experiments showed greater production of cartilage ECM components (glycosaminoglycans and collagen II) by cells exposed to IHP, and the gene expression analysis demonstrated that IHP stimulated the expression of chondrocyte-related genes. Importantly, these effects of IHP were more prominent in CPCs than in FPSCs and CCs. Considering all of our experimental results combined, we conclude that CPCs demonstrated a stronger chondrogenic differentiation capacity than the FPSCs and CCs under stimulation with IHP. Thus, the use of CPCs, combined with mechanical stimulation, may represent a valuable strategy for cartilage tissue engineering. PMID- 26771823 TI - Selective Prenylation of Protected Phenols for Synthesis of Pawhuskin A Analogues. AB - Pawhuskin A is a prenylated stilbene that functions as an antagonist of the kappa opioid receptor. Analogues of this natural product bearing different placements of the prenyl group in the A-ring have shown selectivity for either the kappa or the delta receptors subtypes. This differential activity has drawn attention to regiospecific preparation of the C-2, C-5, and C-6 prenylated A-ring regioisomers. Through halogen metal exchange, advanced intermediates representing each of these regioisomers have been prepared, and the new C-6 intermediate has been converted to a new analogue of the natural stilbene. PMID- 26771824 TI - A Retrospective Investigation of Clozapine Treatment in Autistic and Nonautistic Children and Adolescents in an Inpatient Clinic in Turkey. AB - OBJECTIVE: The aim of this retrospective study is to examine the clinical outcomes and safety of clozapine in children and adolescents with schizophrenia or other psychotic disorders/autism spectrum disorder (ASD) or affective disorders. METHODS: The inpatient and outpatient files of all children and adolescents treated with clozapine over a period of 34 months (from October 2011 to July 2014) were reviewed. Demographic and clinical data were examined to describe clinical and metabolic findings, dosing, and tolerability of clozapine treatment in youth with schizophrenia, other psychotic disorders, ASD, or bipolar disorder. RESULTS: The 37 pediatric patients included 26 patients with schizophrenia or other psychotic disorders, 7 patients with ASD complicated by schizophrenia or other psychotic disorders or affective disorders, and 4 patients with ASD only. In all groups (n = 37) there was a significant reduction (p < 0.001) in Brief Psychiatric Rating Scale (BPRS) points after clozapine treatment during the inpatient period (38.78 +/- 27.75 days). In patients with schizophrenia or other psychotic disorders co-occurring with ASD or not (n = 31), there was a significant improvement in psychotic symptoms according to Positive and Negative Syndrome Scale (PANSS) total scores and subscores (p < 0.001). Of the 26 patients with schizophrenia or other psychotic disorders, 8 (30.8%) showed a positive response (>30% symptom reduction on BPRS). In patients with ASD complicated by schizophrenia or other psychotic disorders or bipolar disorders (n = 7), there was a significant reduction (p = 0.017) in BPRS scores after clozapine treatment. The discontinuation rate for clozapine was 10.8%, and the most frequently observed side effect was hypersalivation (54.1%). Neutropenia associated with clozapine was observed in only one patient (2.7%). CONCLUSIONS: Clozapine seems to be effective and safe in children and adolescents with schizophrenia or other psychotic disorders co-occuring with ASD or not. There is a need for further studies for determining the efficacy of clozapine in children and adolescents with bipolar affective disorder or ASD. PMID- 26771825 TI - Venous leg ulcers. AB - INTRODUCTION: Leg ulcers usually occur secondary to venous reflux or obstruction, but 20% of people with leg ulcers have arterial disease, with or without venous disorders. Between 1.5 and 3.0 in 1000 people have active leg ulcers. Prevalence increases with age to about 20 in 1000 people aged over 80 years. METHODS AND OUTCOMES: We conducted a systematic overview, aiming to answer the following clinical questions: What are the effects of treatments for venous leg ulcers? What are the effects of organisational interventions for venous leg ulcers? What are the effects of advice about self-help interventions in people receiving usual care for venous leg ulcers? What are the effects of interventions to prevent recurrence of venous leg ulcers? We searched: Medline, Embase, The Cochrane Library, and other important databases up to March 2014 (Clinical Evidence overviews are updated periodically; please check our website for the most up-to date version of this overview). RESULTS: At this update, searching of electronic databases retrieved 116 studies. After deduplication and removal of conference abstracts, 63 records were screened for inclusion in the overview. Appraisal of titles and abstracts led to the exclusion of 43 studies and the further review of 20 full publications. Of the 20 full articles evaluated, four systematic reviews were updated and four RCTs were added at this update. We performed a GRADE evaluation for 23 PICO combinations. CONCLUSIONS: In this systematic overview, we categorised the efficacy for 13 interventions based on information about the effectiveness and safety of advice to elevate leg, advice to keep leg active, compression stockings for prevention of recurrence, compression bandages and stockings to treat venous leg ulcers, laser treatment (low level), leg ulcer clinics, pentoxifylline, skin grafting, superficial vein surgery for prevention of recurrence, superficial vein surgery to treat venous leg ulcers, therapeutic ultrasound, and topical negative pressure. PMID- 26771827 TI - Satisfaction with treatment and health-related quality of life among patients with lichen planus: a web-based survey. PMID- 26771826 TI - Gpnmb Is a Potential Marker for the Visceral Pathology in Niemann-Pick Type C Disease. AB - Impaired function of NPC1 or NPC2 lysosomal proteins leads to the intracellular accumulation of unesterified cholesterol, the primary defect underlying Niemann Pick type C (NPC) disease. In addition, glycosphingolipids (GSLs) accumulate in lysosomes as well. Intralysosomal lipid accumulation triggers the activation of a set of genes, including potential biomarkers. Transcript levels of Gpnmb have been shown to be elevated in various tissues of an NPC mouse model. We speculated that Gpnmb could serve as a marker for visceral lipid accumulation in NPC disease. We report that Gpnmb expression is increased at protein level in macrophages in the viscera of Npc1nih/nih mice. Interestingly, soluble Gpnmb was also found to be increased in murine and NPC patient plasma. Exposure of RAW264.7 macrophages to the NPC-phenotype-inducing drug U18666A also upregulated Gpnmb expression. Inhibition of GSL synthesis with the glucosylceramide synthase (GCS) inhibitor N-butyl-1-deoxynojirimycin prevented U18666A-induced Gpnmb induction and secretion. In summary, we show that Gpnmb is upregulated in NPC mice and patients, most likely due to GSL accumulation. PMID- 26771828 TI - Depression, Sex and Gender Roles in Older Adult Populations: The International Mobility in Aging Study (IMIAS). AB - OBJECTIVES: To assess the associations between gender roles and depression in older men and women and whether gender roles are independent risk factors for depression. METHODS: International cross-sectional study of adults between 65 and 74 years old (n = 1,967). Depression was defined by a score of 16 or over in the Center for Epidemiologic Studies Depression Scale (CES-D). A validated 12-item Bem Sex Role Inventory (BSRI) was used to classify participants in gender roles (Masculine, Feminine, Androgynous, and Undifferentiated) using research site medians of femininity and masculinity as cut-off points. Poisson regressions were fitted to estimate the prevalence ratios (PR) of depression for each gender role compared to the masculine role, adjusting for sex, sufficiency of income, education, marital status, self-rated health, and chronic conditions. RESULTS: Among men, 31.2% were androgynous, 26% were masculine, 14.4% were feminine, and 28.4% were undifferentiated; among women, the corresponding percentages were 32.7%, 14.9%, 27%, and 25.4%. Both in men and in women, depressive symptoms (CES D>=16) were more prevalent in those endorsing the undifferentiated type, compared to masculine, feminine or androgynous groups. However, after adjusting for potential confounders, compared to the masculine group only those endorsing the androgynous role were 28% less likely to suffer from depression: PR of 0.72 (95% CI: 0.55-0.93). In fully adjusted models, prevalence rates of depression were not different from masculine participants in the two other gender groups of feminine and undifferentiated. CONCLUSIONS: Androgynous roles were associated with lower rates of depression in older adults, independently of being a man or a woman. PMID- 26771829 TI - Mutations of the Calcium Channel Gene cacophony Suppress Seizures in Drosophila. AB - Bang sensitive (BS) Drosophila mutants display characteristic seizure-like phenotypes resembling, in some aspects, those of human seizure disorders such as epilepsy. The BS mutant parabss1, caused by a gain-of-function mutation of the voltage-gated Na+ channel gene, is extremely seizure-sensitive with phenotypes that have proven difficult to ameliorate by anti-epileptic drug feeding or by seizure-suppressor mutation. It has been presented as a model for intractable human epilepsy. Here we show that cacophony (cacTS2), a mutation of the Drosophila presynaptic Ca++ channel alpha1 subunit gene, is a particularly potent seizure-suppressor mutation, reverting seizure-like phenotypes for parabss1 and other BS mutants. Seizure-like phenotypes for parabss1 may be suppressed by as much as 90% in double mutant combinations with cacTS2. Unexpectedly, we find that parabss1 also reciprocally suppresses cacTS2 seizure-like phenotypes. The cacTS2 mutant displays these seizure-like behaviors and spontaneous high-frequency action potential firing transiently after exposure to high temperature. We find that this seizure-like behavior in cacTS2 is ameliorated by 85% in double mutant combinations with parabss1. PMID- 26771830 TI - Data-Driven Engineering of Social Dynamics: Pattern Matching and Profit Maximization. AB - In this paper, we define a new problem related to social media, namely, the data driven engineering of social dynamics. More precisely, given a set of observations from the past, we aim at finding the best short-term intervention that can lead to predefined long-term outcomes. Toward this end, we propose a general formulation that covers two useful engineering tasks as special cases, namely, pattern matching and profit maximization. By incorporating a deep learning model, we derive a solution using convex relaxation and quadratic programming transformation. Moreover, we propose a data-driven evaluation method in place of the expensive field experiments. Using a Twitter dataset, we demonstrate the effectiveness of our dynamics engineering approach for both pattern matching and profit maximization, and study the multifaceted interplay among several important factors of dynamics engineering, such as solution validity, pattern-matching accuracy, and intervention cost. Finally, the method we propose is general enough to work with multi-dimensional time series, so it can potentially be used in many other applications. PMID- 26771831 TI - Splenic Leukocytes Traffic to the Thyroid and Produce a Novel TSHbeta Isoform during Acute Listeria monocytogenes Infection in Mice. AB - The thyroid stimulating hormone beta-subunit (TSHbeta) with TSHalpha form a glycoprotein hormone that is produced by the anterior pituitary in the hypothalamus-pituitary-thyroid (HPT) axis. Although TSHbeta has been known for many years to be made by cells of the immune system, the role of immune system TSH has remained unclear. Recent studies demonstrated that cells of the immune system produce a novel splice variant isoform of TSHbeta (TSHbetav), but little if any native TSHbeta. Here, we show that within three days of systemic infection of mice with Listeria monocytogenes, splenic leukocytes synthesized elevated levels of TSHbetav. This was accompanied by an influx of CD14+, Ly6C+, Ly6G+ cells into the thyroid of infected mice, and increased levels of intrathyroidal TSHbetav gene expression. Adoptive transfer of carboxyfluorescein succinimidyl ester (CFSE)-labeled splenic leukocytes from infected mice into non-infected mice migrated into the thyroid as early as forty-eight hours post-cell transfer, whereas CFSE-labeled cells from non-infected mice failed to traffic to the thyroid. These findings demonstrate for the first time that during bacterial infection peripheral leukocytes produce elevated levels of TSHbetav, and that spleen cells traffic to the thyroid where they produce TSHbetav intrathyroidally. PMID- 26771832 TI - Longitudinal Associations Between Preschool Disruptive Mood Dysregulation Disorder Symptoms and Neural Reactivity to Monetary Reward During Preadolescence. AB - OBJECTIVE: Reward-processing abnormalities are thought to be a key feature of various psychiatric disorders and may also play a role in disruptive mood dysregulation disorder (DMDD), a new diagnosis in DSM-5. In the current study, we used event-related potentials (ERP) sensitive to monetary gains (i.e., the reward positivity [RewP]) and losses (i.e., the N200) to examine associations between symptoms of DMDD during early childhood and later reward processing during preadolescence. METHODS: To assess early emerging DMDD symptoms in a large longitudinal community sample (n=373) of 3-year old children, we administered a diagnostic interview, Preschool Age Psychiatric Assessment (PAPA) with parents. At a later assessment, ~6 years later, children completed a monetary reward task while an electroencephalogram (EEG) was recorded. Children's lifetime history of psychopathology was also assessed at that time using Kiddie-Schedule of Affective Disorders and Schizophrenia (K-SADS) with the child and parent. RESULTS: Multiple regression analyses revealed that age 3 DMDD symptoms predicted an enhanced RewP to monetary rewards in preadolescence. This association is independent of demographics and lifetime history of symptoms of depression, any anxiety disorder, attention-deficit disorder, oppositional defiant disorder, or conduct disorder Conclusions: Early manifestations of DMDD in children as young as 3 years old predicted enhanced reward processing later in development. These findings add to the growing corpus of literature on the pathophysiology of DMDD, and underscore the predictive validity of preschool DMDD on a neural level. PMID- 26771833 TI - Identification of Algerian Field-Caught Phlebotomine Sand Fly Vectors by MALDI TOF MS. AB - BACKGROUND: Phlebotomine sand flies are known to transmit Leishmania parasites, bacteria and viruses that affect humans and animals in many countries worldwide. Precise sand fly identification is essential to prevent phlebotomine-borne diseases. Over the past two decades, progress in matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) has emerged as an accurate tool for arthropod identification. The objective of the present study was to investigate the usefulness of MALDI-TOF MS as a tool for identifying field-caught phlebotomine. METHODOLOGY/PRINCIPAL FINDINGS: Sand flies were captured in four sites in north Algeria. A subset was morphologically and genetically identified. Six species were found in these areas and a total of 28 stored frozen specimens were used for the creation of the reference spectrum database. The relevance of this original method for sand fly identification was validated by two successive blind tests including the morphological identification of 80 new specimens which were stored at -80 degrees C, and 292 unknown specimens, including engorged specimens, which were preserved under different conditions. Intra-species reproducibility and inter-species specificity of the protein profiles were obtained, allowing us to distinguish specimens at the gender level. Querying of the sand fly database using the MS spectra from the blind test groups revealed concordant results between morphological and MALDI-TOF MS identification. However, MS identification results were less efficient for specimens which were engorged or stored in alcohol. Identification of 362 phlebotomine sand flies, captured at four Algerian sites, by MALDI-TOF MS, revealed that the subgenus Larroussius was predominant at all the study sites, except for in M'sila where P. (Phlebotomus) papatasi was the only sand fly species detected. CONCLUSION: The present study highlights the application of MALDI-TOF MS for monitoring sand fly fauna captured in the field. The low cost, reliability and rapidity of MALDI-TOF MS analyses opens up new ways in the management of phlebotomine sand fly-borne diseases. PMID- 26771834 TI - Study of Graphene-based 2D-Heterostructure Device Fabricated by All-Dry Transfer Process. AB - We developed a technique for transferring graphene and hexagonal boron nitride (hBN) in dry conditions for fabrication of van der Waals heterostructures. The graphene layer was encapsulated between two hBN layers so that it was kept intact during fabrication of the device. For comparison, we also fabricated the devices containing graphene on SiO2/Si wafer and graphene on hBN. Electrical properties of the devices were investigated at room temperature. The mobility of the graphene on SiO2 devices and graphene on hBN devices were 15,000 and 37,000 cm(2) V(-1) s(-1), respectively, while the mobility of the sandwich structure device reached the highest value of ~100,000 cm(2) V(-1) s(-1), at room temperature. The electrical measurements of the samples were carried out in air and vacuum environments. We found that the electrical properties of the encapsulated graphene devices remained at a similar level both in a vacuum and in air, whereas the properties of the graphene without encapsulation were influenced by the external environment. PMID- 26771835 TI - Immunoglobulin Light-Chain Amyloidosis: From Basics to New Developments in Diagnosis, Prognosis and Therapy. AB - Immunoglobulin amyloid light-chain (AL) amyloidosis is the most common form of systemic amyloidosis, where the culprit amyloidogenic protein is immunoglobulin light chains produced by marrow clonal plasma cells. AL amyloidosis is an infrequent disease, and since presentation is variable and often nonspecific, diagnosis is often delayed. This results in cumulative organ damage and has a negative prognostic effect. AL amyloidosis can also be challenging on the diagnostic level, especially when demonstration of Congo red-positive tissue is not readily obtained. Since as many as 31 known amyloidogenic proteins have been identified to date, determination of the amyloid type is required. While several typing methods are available, mass spectrometry has become the gold standard for amyloid typing. Upon confirming the diagnosis of amyloidosis, a pursuit for organ involvement is essential, with a focus on heart involvement, even in the absence of suggestive symptoms for involvement, as this has both prognostic and treatment implications. Details regarding initial treatment options, including stem cell transplantation, are provided in this review. AL amyloidosis management requires a multidisciplinary approach with careful patient monitoring, as organ impairment has a major effect on morbidity and treatment tolerability until a response to treatment is achieved and recovery emerges. PMID- 26771836 TI - Adiabatic Nanofocusing in Hybrid Gap Plasmon Waveguides on the Silicon-on Insulator Platform. AB - We present an experimental demonstration of a new class of hybrid gap plasmon waveguides on the silicon-on-insulator (SOI) platform. Created by the hybridization of the plasmonic mode of a gap in a thin metal sheet and the transverse-electric (TE) photonic mode of an SOI slab, this waveguide is designed for efficient adiabatic nanofocusing simply by varying the gap width. For gap widths greater than 100 nm, the mode is primarily photonic in character and propagation lengths can be many tens of micrometers. For gap widths below 100 nm, the mode becomes plasmonic in character with field confinement predominantly within the gap region and with propagation lengths of a few microns. We estimate the electric field intensity enhancement in hybrid gap plasmon waveguide tapers at 1550 nm by three-photon absorption of selectively deposited CdSe/ZnS quantum dots within the gap. Here, we show electric field intensity enhancements of up to 167 +/- 26 for a 24 nm gap, proving the viability of low loss adiabatic nanofocusing on a commercially relevant photonics platform. PMID- 26771838 TI - Model Comparison for Breast Cancer Prognosis Based on Clinical Data. AB - We compared the performance of several prediction techniques for breast cancer prognosis, based on AU-ROC performance (Area Under ROC) for different prognosis periods. The analyzed dataset contained 1,981 patients and from an initial 25 variables, the 11 most common clinical predictors were retained. We compared eight models from a wide spectrum of predictive models, namely; Generalized Linear Model (GLM), GLM-Net, Partial Least Square (PLS), Support Vector Machines (SVM), Random Forests (RF), Neural Networks, k-Nearest Neighbors (k-NN) and Boosted Trees. In order to compare these models, paired t-test was applied on the model performance differences obtained from data resampling. Random Forests, Boosted Trees, Partial Least Square and GLMNet have superior overall performance, however they are only slightly higher than the other models. The comparative analysis also allowed us to define a relative variable importance as the average of variable importance from the different models. Two sets of variables are identified from this analysis. The first includes number of positive lymph nodes, tumor size, cancer grade and estrogen receptor, all has an important influence on model predictability. The second set incudes variables related to histological parameters and treatment types. The short term vs long term contribution of the clinical variables are also analyzed from the comparative models. From the various cancer treatment plans, the combination of Chemo/Radio therapy leads to the largest impact on cancer prognosis. PMID- 26771837 TI - System for Rapid, Precise Modulation of Intraocular Pressure, toward Minimally Invasive In Vivo Measurement of Intracranial Pressure. AB - Pathologic changes in intracranial pressure (ICP) are commonly observed in a variety of medical conditions, including traumatic brain injury, stroke, brain tumors, and glaucoma. However, current ICP measurement techniques are invasive, requiring a lumbar puncture or surgical insertion of a cannula into the cerebrospinal fluid (CSF)-filled ventricles of the brain. A potential alternative approach to ICP measurement leverages the unique anatomy of the central retinal vein, which is exposed to both intraocular pressure (IOP) and ICP as it travels inside the eye and through the optic nerve; manipulating IOP while observing changes in the natural pulsations of the central retinal vein could potentially provide an accurate, indirect measure of ICP. As a step toward implementing this technique, we describe the design, fabrication, and characterization of a system that is capable of manipulating IOP in vivo with <0.1 mmHg resolution and settling times less than 2 seconds. In vitro tests were carried out to characterize system performance. Then, as a proof of concept, we used the system to manipulate IOP in tree shrews (Tupaia belangeri) while video of the retinal vessels was recorded and the caliber of a selected vein was quantified. Modulating IOP using our system elicited a rapid change in the appearance of the retinal vein of interest: IOP was lowered from 10 to 3 mmHg, and retinal vein caliber sharply increased as IOP decreased from 7 to 5 mmHg. Another important feature of this technology is its capability to measure ocular compliance and outflow facility in vivo, as demonstrated in tree shrews. Collectively, these proof-of-concept demonstrations support the utility of this system to manipulate IOP for a variety of useful applications in ocular biomechanics, and provide a framework for further study of the mechanisms of retinal venous pulsation. PMID- 26771840 TI - Expression of programmed cell death-ligand 1 and its correlation with clinical outcomes in gliomas. AB - Programmed cell death-ligand 1(PD-L1) was expressed in various malignancies, and interaction with its receptor programmed cell death 1 (PD-1) often contributed to immune evasion of tumor cells. In this study, we explored the expression of PD-L1 and its correlation with clinical outcomes in gliomas. Clinicopathological data of 229 patients with gliomas was collected. PD-L1 expression was assessed by tissue-microarray-based immunohistochemistry. Over 5% of tumor cells with cytoplasm or membrane staining was defined as PD-L1 positive expression. The associations of clinicopathological features with overall survival (OS) and disease-free survival (DFS) were analyzed by univariate analysis and multivariate analysis was further performed by Cox regression model. PD-L1 positive expression was observed in 51.1% gliomas patients and no significant association was verified between PD-L1 expression and pathological grade in 229 gliomas patients. However, PD-L1 expression rate was 49.2%, 53.7% and 68.8% for grade II, III and IV in 161 patients with those >= 12 months of OS, respectively. Although no significant discrepancies was displayed, there was a certain degree of differences between PD-L1 expression and pathological grade (49.2% vs. 53.7% vs. 68.8%, P = 0.327). Univariate analysis showed that PD-L1 expression was significantly associated with poor OS in the patients with long-time survival or follow up (OS >= 12 months) (P = 0.018), especially in patients with grade IV (P = 0.019). Multivariate analysis revealed that a strong tendency towards statistical significance was found between PD-L1 expression and poor OS (P = 0.081). In gliomas patients with long-time survival or follow up, PD-L1 positive expression could indicate the poor prognosis and it is possible that immunotherapy targeting PD-L1 pathway needed to be determined in the further study. PMID- 26771839 TI - MiRNA-29a as a tumor suppressor mediates PRIMA-1Met-induced anti-myeloma activity by targeting c-Myc. AB - The proto-oncogene c-Myc plays substantial role in multiple myeloma (MM) pathogenesis and is considered a potential drug target. Here we provide evidence of a novel mechanism for PRIMA-1Met, a small molecule with anti-tumor activity in phase I/II clinical trial, showing that PRIMA-1Met induces apoptosis in MM cells by suppressing c-Myc and upregulating miRNA-29a. Our study further demonstrates that miRNA-29a functions as a tumor suppressor which targets c-Myc. The baseline expression of miR-29a was significantly lower in MM cell lines and MM patient samples compared to normal hematopoietic cells. In addition, ectopic expression of miRNA-29a or exposure to PRIMA-1Met reduced cell proliferation and induced apoptosis in MM cells. On the other hand, overexpression of c-Myc at least partially reverted the inhibitory effects of PRIMA-1Met or miRNA-29a overexpression suggesting the miRNA-29a/c-Myc axis mediates anti-myeloma effects of PRIMA-1Met. Importantly, intratumor delivery of miRNA-29a mimics induced regression of tumors in mouse xenograft model of MM and this effect synergized with PRIMA-1Met. Our study indicates that miRNA-29a is a tumor suppressor that plays an important role during PRIMA-1Met-induced apoptotic signaling by targeting c-Myc and provides the basis for novel therapeutic strategies using miRNA-29a mimics combined with PRIMA-1Met in MM. PMID- 26771841 TI - Transcriptomic profiling of urine extracellular vesicles reveals alterations of CDH3 in prostate cancer. AB - Extracellular vesicles (EV) are emerging structures with promising properties for intercellular communication. In addition, the characterization of EV in biofluids is an attractive source of non-invasive diagnostic, prognostic and predictive biomarkers. Here we show that urinary EV (uEV) from prostate cancer (PCa) patients exhibit genuine and differential physical and biological properties compared to benign prostate hyperplasia (BPH). Importantly, transcriptomics characterization of uEVs led us to define the decreased abundance of Cadherin 3, type 1 (CDH3) transcript in uEV from PCa patients. Tissue and cell line analysis strongly suggested that the status of CDH3 in uEVs is a distal reflection of changes in the expression of this cadherin in the prostate tumor. CDH3 was negatively regulated at the genomic, transcriptional, and epigenetic level in PCa. Our results reveal that uEVs could represent a non-invasive tool to inform about the molecular alterations in PCa. PMID- 26771842 TI - CD68 and interleukin 13, prospective immune markers for esophageal squamous cell carcinoma prognosis prediction. AB - PURPOSE: Oncology immunity was reported to play a key role in cancer development and progression, so we investigated the prediction role of several immune markers in esophageal squamous cell carcinoma (ESCC) patients after operation in this study. PATIENTS AND METHODS: 66 primary ESCC tumor tissues and four sets of tissue microarrays including 705 primary ESCC tumor tissues from four centers were collected and analyzed. Expressions of several immune markers in ESCC tumor tissue were detected with immunohistochemistry staining. Their distribution densities were analyzed with InFormTM 2.0.1 software. All statistic analyses were performed with SPSS16.0 and Stata version 10.0. RESULTS: Survival analyses assessed by Kaplan-Meier plots and log-rank tests demonstrated that densities of CD68 and interleukin 13 (IL-13) in tumor stroma were positively correlated with the overall survival of ESCC patients after operation (p < 0.01 for CD68, p < 0.001 for IL-13). Further, a model based on tumor stroma densities of CD68 and IL 13 was constructed and it could significantly classify patients with poor or good prognosis. This model could further identify high-risk group and low-risk group at the same Tumor lymph Nodes Metastases (TNM) stage. Lastly, a more accuracy model based on TNM stage, densities of CD68 and IL-13 was constructed to predict the prognosis of ESCC patient after operation. CONCLUSION: Combining the TNM staging system and densities of CD68 and IL-13 could substantially improve the prognosis prediction accuracy of ESCC patient after operation, which might be an excellent tool for selecting patients for individualized therapy in future. PMID- 26771843 TI - Decreased expression of B7-H3 reduces the glycolytic capacity and sensitizes breast cancer cells to AKT/mTOR inhibitors. AB - B7 family proteins are important immune response regulators, and can mediate oncogenic signaling and cancer development. We have used human triple-negative breast cancer cell lines with different expression levels of B7-H3 to evaluate its effects on the sensitivity to 22 different anticancer compounds in a drug screen. API-2 (triciribidine) and everolimus (RAD-001), two inhibitors that target the PI3K/AKT/mTOR pathway, showed enhanced inhibition of cell viability and proliferation in B7-H3 knockdown tumor cells compared to their B7-H3 expressing counterparts. Similar inhibition was seen in control cells treated with an anti-B7-H3 monoclonal antibody. In B7-H3 overexpressing cells, the effects of the two drugs were reduced, supported also by in vivo experiments in which B7-H3 overexpressing xenografts were less sensitive to everolimus than control tumors. In API-2 and everolimus-treated B7-H3 overexpressing cells, phospho-mTOR levels were decreased. However, phosphorylation of p70S6K was differentially regulated in B7-H3 cells treated with API-2 or everolimus, suggesting a different B7-H3-mediated mechanism downstream of mTOR. Both API-2 and everolimus decreased the glycolysis of the cells, whereas knockdown of B7-H3 decreased and B7-H3 overexpression increased the glycolytic capacity. In conclusion, we have unveiled a previously unknown relationship between B7-H3 expression and glycolytic capacity in tumor cells, and found that B7-H3 confers resistance to API-2 and everolimus. The results provide novel insights into the function of B7-H3 in cancer, and suggest that targeting of B7-H3 may be a novel alternative to improve current anticancer therapies. PMID- 26771845 TI - Detections of Yersinia pestis East of the Known Distribution of Active Plague in the United States. AB - We examined fleas collected from black-tailed prairie dog (Cynomys ludovicianus) burrows from 2009 through 2011 in five national park units east of the known distribution of active plague across the northern Great Plains for the presence of Yersinia pestis. Across all national park units, Oropsylla tuberculata and Oropsylla hirsuta were the most common fleas collected from prairie dog burrows, 42.4% and 56.9%, respectively, of the 3964 fleas collected from burrow swabbing. Using a nested PCR assay, we detected 200 Y. pestis-positive fleas from 3117 assays. In total, 6.4% of assayed fleas were Y. pestis positive and 13.9% of prairie dog burrows swabbed contained Y. pestis-positive fleas. Evidence of the presence of Y. pestis was observed at all national park units except Devils Tower National Monument in Wyoming. We detected the presence of Y. pestis without large die-offs, i.e., enzootic sylvatic plague, east of the known distribution of active plague and near the eastern edge of the present distribution of black tailed prairie dogs. This study, in combination with previous work suggests that sylvatic plague likely occurs across the range of black-tailed prairie dogs and should now be treated as endemic across this range. PMID- 26771844 TI - Nuclear translocation and activation of YAP by hypoxia contributes to the chemoresistance of SN38 in hepatocellular carcinoma cells. AB - Although hypoxia is a prominent feature contributing to the therapeutic resistance of hepatocellular carcinoma cells (HCC) against chemotherapeutic agents, including the Topoisomerase I inhibitor SN38, the underlying mechanism is not fully understood and its understanding remains a major clinical challenge. In the present study, we found that hypoxia-induced nuclear translocation and accumulation of YAP acted as a survival input to promote resistance to SN38 in HCC. The induction of YAP by hypoxia was not mediated by HIF-1alpha because manipulating the abundance of HIF-1alpha with CoCl2, exogenous expression, and RNA interference had no effect on the phosphorylation or total levels of YAP. The mevalonate-HMG-CoA reductase (HMGCR) pathway may modulate the YAP activation under hypoxia. Combined YAP inhibition using either siRNA or the HMGCR inhibitor statins together with SN38 treatment produced improved anti-cancer effects in HCC cells. The increased anti-cancer effect of the combined treatment with statins and irinotecan (the prodrug of SN-38) was further validated in a human HepG2 xenograft model of HCC in nude mice. Taken together, our findings identify YAP as a novel mediator of hypoxic-resistance to SN38. These results suggest that the administration of SN28 together with the suppression of YAP using statins is a promising strategy for enhancing the treatment response in HCC patients, particularly in advanced stage HCC cases presenting hypoxic resistance. PMID- 26771846 TI - A case of isolated amyloid light-chain amyloidosis of the radial nerve. AB - Peripheral nerve involvement may be the first sign of systemic amyloid light chain (AL) amyloidosis, a rare disease. Physical examination and electrodiagnostic testing are the mainstays of peripheral neuropathy evaluation at presentation. Sural nerve biopsy is performed in conjunction with serum and urine protein evaluation to differentiate between focal and systemic disease. Systemic disease is treated with a combination of chemotherapy, steroids, and stem cell transplantation. Isolated peripheral nerve disease is extremely rare. The authors here report the case of an 80-year-old woman who presented with progressive right upper-extremity weakness due to right radial neuropathy discovered upon electrodiagnostic testing. Magnetic resonance neurography (MRN) revealed a focal lesion within the right radial nerve. She underwent radial nerve exploration and excision of an intraneural mass consisting of amyloid on histopathology, with mass spectrometry analysis diagnostic for AL amyloidosis. Noninvasive testing and clinical history did not suggest systemic involvement. This unique case of isolated peripheral nerve AL amyloidosis in the absence of signs and symptoms of systemic disease is described, and the literature demonstrating peripheral nerve involvement in AL amyloidosis is reviewed. PMID- 26771847 TI - Endovascular management of internal carotid artery injuries secondary to endonasal surgery: case series and review of the literature. AB - OBJECTIVE Internal carotid artery (ICA) injury is a rare but severe complication of endonasal surgery. The authors describe their endovascular experience managing ICA injuries after transsphenoidal surgery; they review and summarize the current literature regarding endovascular techniques; and they propose a treatment algorithm based on the available evidence. METHODS A retrospective review of 576 transsphenoidal pituitary adenoma resections was performed. Cases of ICA injury occurring at our institution and transfers from other hospitals were evaluated. Endovascular treatments for ICA injury reported in the literature were also reviewed and summarized. RESULTS Seven cases were identified from the institutional cohort (mean age 46.3 years, mean follow-up 43.4 months [1-107 months]) that received endovascular treatment for ICA injury. Five injuries occurred at our institution (5 [0.9%] of 576), and 2 injuries occurred at outside hospitals. Three patients underwent ICA sacrifice by coil placement, 2 underwent lesion embolization (coil or stent-assisted coil placement), and 2 underwent endoluminal reconstruction (both with flow diversion devices). Review of the literature identified 98 cases of ICA injury treated with endovascular methods. Of the 105 total cases, 46 patients underwent ICA sacrifice, 28 underwent lesion embolization, and 31 underwent endoluminal reconstruction. Sacrifice of the ICA proved a durable solution in all cases; however, the rate of persistent neurological complications was relatively high (10 [21.7%] of 46). Lesion embolization was primarily performed by coil embolization without stenting (16 cases) and stent-assisted coiling (9 cases). Both techniques had a relatively high rate of at least some technical complication (6 [37.5%] of 16 and 5 [55.6%] of 9, respectively) and major technical complications (i.e., injury, new neurological deficit, or ICA sacrifice) (5 [31.3%] of 16 and 2 [22.2%] of 9, respectively). Endoluminal reconstruction was performed by covered stent (24 cases) and flow diverter (5 cases) placement. Covered stents showed a reasonably high rate of technical complications (10 [41.7%] of 24); however, 8 of these problems were resolved, leaving a small percentage with major technical complications (2 [8.3%] of 24). Flow diverter placement was also well tolerated, with only 1 minor technical complication. CONCLUSIONS Endovascular treatments including vessel sacrifice, coil embolization (with or without stent assistance), and endoluminal reconstruction offer a tailored approach to ICA injury management after endonasal surgery. Vessel sacrifice remains the definitive treatment for acute, uncontrolled bleeding; however, vessel preservation techniques should be considered carefully in select patients. Multiple factors including vascular anatomy, injury characteristics, and risk of dual antiplatelet therapy should guide best treatment, but more study is needed (particularly with flow diverters) to refine this decision-making process. Ideally, all endovascular treatment options should be available at institutions performing endonasal surgery. PMID- 26771848 TI - Genomic landscape of intracranial meningiomas. AB - Meningiomas are the most common primary intracranial neoplasms in adults. Current histopathological grading schemes do not consistently predict their natural history. Classic cytogenetic studies have disclosed a progressive course of chromosomal aberrations, especially in high-grade meningiomas. Furthermore, the recent application of unbiased next-generation sequencing approaches has implicated several novel genes whose mutations underlie a substantial percentage of meningiomas. These insights may serve to craft a molecular taxonomy for meningiomas and highlight putative therapeutic targets in a new era of rational biology-informed precision medicine. PMID- 26771849 TI - Tumor cell-specific chromosomal abnormality in the vascular endothelial cells of anaplastic oligodendroglioma. AB - OBJECTIVE 1p/19q co-deletion is a well-established tumor cell-specific chromosomal abnormality in oligodendroglial tumors. The endothelial cells (ECs) of oligodendroglial tumor vessels are considered to be normal cells that do not acquire mutations. METHODS A total of 30 samples from 16 male and 14 female patients (median age of 46.5 years) with a histological diagnosis of primary anaplastic oligodendroglioma (AO) were collected in the study. The immunofluorescence technique was used to identify vascular ECs, and the 1p/19q status was detected with fluorescence in situ hybridization. Kaplan-Meier plots were compared using the log-rank method. RESULTS The ECs in AO had a higher 1p36 (detected signal) deletion rate than 1q25 (reference signal) (p < 0.01) and a higher 19q13 (detected signal) deletion rate than 19p13 (reference signal) (p < 0.01). The survival analysis results showed that both the progression-free survival (PFS) and overall survival (OS) of the patients with 1p/19q-co-deleted ECs were significantly longer than those with 1p/19q-intact ECs (PFS, p < 0.001; OS, p < 0.001). This correlation was validated by an independent cohort. In addition, the Cox regression model revealed that 1p/19q co-deletion in ECs was an independent prognostic factor (HR 0.056 [95% CI 0.012-0.261], p < 0.001 for PFS; HR 0.061 [95% CI 0.013-0.280], p < 0.01 for OS). CONCLUSIONS 1p/19q co-deletion and polysomy can be also found in the ECs of AO, which suggests that the ECs are, in part, tumor related and reflect a novel aspect of tumor angiogenesis. PMID- 26771850 TI - Optic nerve sheath diameter as ICP marker. PMID- 26771851 TI - Electrical stimulation of the parahippocampal gyrus for prediction of posthippocampectomy verbal memory decline. AB - OBJECTIVE Epilepsy surgery is of known benefit for drug-resistant temporal lobe epilepsy (TLE); however, a certain number of patients suffer significant decline in verbal memory after hippocampectomy. To prevent this disabling complication, a reliable test for predicting postoperative memory decline is greatly desired. Therefore, the authors assessed the value of electrical stimulation of the parahippocampal gyrus (PHG) as a provocation test of verbal memory decline after hippocampectomy on the dominant side. METHODS Eleven right-handed, Japanese speaking patients with medically intractable left TLE participated in the study. Before surgery, they underwent provocative testing via electrical stimulation of the left PHG during a verbal encoding task. Their pre- and posthippocampectomy memory function was evaluated according to the Wechsler Memory Scale-Revised (WMS R) and/or Mini-Mental State Examination (MMSE) before and 6 months after surgery. The relationship between postsurgical memory decline and results of the provocative test was evaluated. RESULTS Left hippocampectomy was performed in 7 of the 11 patients. In 3 patients with a positive provocative recognition test, verbal memory function, as assessed by the WMS-R, decreased after hippocampectomy, whereas in 4 patients with a negative provocative recognition test, verbal memory function, as assessed by the WMS-R or MMSE, was preserved. CONCLUSIONS Results of the present study suggest that electrical stimulation of the PHG is a reliable provocative test to predict posthippocampectomy verbal memory decline. PMID- 26771852 TI - The long-term recurrence of Rathke's cleft cysts as predicted by histology but not by surgical procedure. AB - OBJECTIVE Patients with symptomatic Rathke's cleft cysts (RCCs) managed by surgical treatment often experience recurrence. The authors attempted to clarify the outcome of surgically treated RCCs over a long-term follow-up period. METHODS Ninety-one consecutive RCC patients with a follow-up period of more than 12 months (mean 80.2 months, range 12-297 months) were retrospectively studied. The authors examined the clinical features and postoperative course of patients who experienced a reaccumulation of cyst contents visible on MRI after the initial surgery, and they investigated data from the patients who underwent reoperation for symptomatic recurrent RCCs. RESULTS Reaccumulation of cyst contents occurred in 36 patients (39.6%). In 34 of these patients, a reaccumulation occurred in the first 5 years after surgery. The initial cysts in these patients were most often large, with squamous metaplasia in the cyst walls. Thirteen patients (14.3%) with recurrent symptoms underwent a reoperation, and 10 of the 13 patients had a reaccumulation of RCCs within the 1st year after surgery. The reoperations were performed in the 1st year (61.5%) or several years later (23.1%). Patients were likely to initially have had a visual disturbance and the cyst walls likely included squamous metaplasia. However, no association was observed between the incidence of reaccumulation/reoperation of RCCs and the surgical procedure for RCCs. CONCLUSIONS The reaccumulation rate of RCC is high in the long-term period, and it is associated with the histological findings but not with the surgical procedure. Long-term monitoring, for a period of at least 5 years, should therefore be conducted to identify and assess any RCC reaccumulation. PMID- 26771853 TI - Role of terminal and anastomotic circulation in the patency of arteries jailed by flow-diverting stents: animal flow model evaluation and preliminary results. AB - OBJECTIVE The authors describe herein the creation of an animal model capable of producing quantifiable data regarding blood flow rate and velocity modifications in terminal and anastomotic types of cerebrofacial circulation. They also present the preliminary results of a translational study aimed at investigating the role of terminal and anastomotic types of circulation in arterial branches jailed by flow-diverting stents as factors contributing to arterial patency or occlusion. METHODS Two Large White swine were used to validate a terminal-type arterial model at the level of the right ascending pharyngeal artery (APhA), created exclusively by endovascular means. Subsequently 4 Large White swine, allocated to 2 groups corresponding to the presence (Group B) or absence (Group A) of terminal type flow modification, underwent placement of flow-diverting stents. Blood flow rates and velocities were quantified using a dedicated time-resolved 3D phase contrast MRA sequence before and after stenting. Three months after stent placement, the stented arteries were evaluated with digital subtraction angiography (DSA) and scanning electron microscopy (SEM). Patent (circulating) ostia quantification was performed on the SEM images. RESULTS Terminal-type flow modification was feasible; an increase of 75.8% in mean blood velocities was observed in the right APhAs. The mean blood flow rate for Group A was 0.31 +/- 0.19 ml/sec (95% CI -1.39 to 2.01) before stenting and 0.21 +/- 0.07 ml/sec (95% CI -0.45 to 0.87) after stenting. The mean blood flow rate for Group B was 0.87 +/- 0.32 ml/sec (95% CI -1.98 to 3.73) before stenting and 0.76 +/- 0.13 ml/sec (95% CI -0.41 to 1.93) after stenting. Mean flow rates after stenting showed a statistically significant difference between Groups A and B (Welch test). Mean and maximal blood velocities were reduced in Group A cases and did not decrease in Group B cases. Control DSA and SEM findings showed near occlusion of the jailed APhAs in both cases of anastomotic circulation (mean patent ostium surface 32,776 MUm2) and patency in both cases of terminal-type circulation (mean patent ostium surface 422,334 MUm2). CONCLUSIONS Terminal-type arterial modification in swine APhAs is feasible. Sufficient data were acquired to perform an a priori analysis for further research. Flow diversion at the level of the APhA ostium resulted in significant stenosis in cases of anastomotic circulation, while sufficient patency was observed in terminal-type circulation. PMID- 26771854 TI - Microsurgical management of vestibular schwannoma after failed previous surgery. AB - OBJECTIVE Microsurgical treatment of recurrent vestibular schwannoma (VS) is difficult and poses specific challenges. The authors report their experience with 53 cases of surgically treated recurrent VS. Outcome of these tumors was compared to that of primarily operated on VS. Special attention was given to the facial nerve functional outcome. METHODS A retrospective analysis was performed of the patients who underwent surgery for recurrent VS at one institution from 2000 to 2013. The preoperative data, intraoperative findings, and outcome in terms of facial nerve function and improvement of the preoperative symptoms were analyzed and compared with those in a control group of 30 randomly selected patients with primarily operated on VS. A multivariate regression analysis was performed to test the factors that could affect the facial nerve outcome in each group. RESULTS Fifty-three consecutive patients underwent surgery for recurrent VS. Seventeen patients were previously operated on and received postoperative radiosurgery (Group A). Thirty-six patients were previously operated on but did not receive postoperative radiosurgery (Group B). The overall postoperative facial nerve function was significantly worse in Groups A and B in comparison with the control group (Group C). Interestingly, there was no significant difference in the facial nerve outcome among the 3 groups in patients who had good preoperative facial nerve function. The tumor size and the preoperative facial nerve function are variables that significantly affect the facial nerve outcome. Most of the patients showed improvement of the preoperative symptoms, such as trigeminal hypesthesia, gait disturbance, and headache. CONCLUSIONS Complete microsurgical tumor removal is the optimal management for patients with recurrent or regrowing VS. The procedure is safe, associated with favorable facial nerve outcome, and may also improve existing neurological symptoms. PMID- 26771855 TI - Eliminating unnecessary routine head CT scanning in neurologically intact mild traumatic brain injury patients: implementation and evaluation of a new protocol. AB - OBJECTIVE The utility of routine repeat head CT (HCT) scans in the management of minimal head injury (MHI) patients with an intracranial hemorrhage (ICH) has been questioned in multiple studies. All these studies analyzed this by obtaining a repeat HCT study, and none examined the effects of eliminating these routine HCT studies in neurologically intact patients. The authors' institution implemented a new "Neurologic Observation without Repeat HCT" (NORH) protocol with no repeat HCT scanning for patients admitted for MHI and ICH whose neurological status was maintained or improved to a Glasgow Coma Scale score of 15 at 24 hours after admission. This purpose of this study was to assess the outcomes and safety of this novel protocol. METHODS Records of patients who sustained blunt trauma MHI and an ICH and/or skull fracture on initial HCT between January 1, 2009, and December 31, 2012, were retrieved from the trauma registry of a Level I trauma center. The authors analyzed 95 patients in whom the NORH protocol was followed. Outcome measures included death, emergency department readmission, neurosurgical intervention, delayed repeat HCT, and length of stay. RESULTS The NORH protocol was followed for 95 patients; 83% of the patients were male, the average age was 38 +/- 16.0 years old, and the most common cause of trauma was assault (35%). Of the 95 patients in whom the NORH protocol was followed, 8 (8%) had a delayed repeat HCT study (> 24 hours) after admission, but none resulted in neurosurgical intervention because of progression of ICH. The average length of stay was 4 +/- 7.2 days. None of the patients were readmitted to the hospital. CONCLUSIONS Implementation of the NORH protocol (eliminating routine follow-up HCT) resulted in very low rates of delayed neurological deterioration, no late neurosurgical interventions resulting from ICH progression, very few emergency department revisits, and no readmissions. For a select group of MHI patients with ICH, the NORH protocol is safe and effective, and can reduce radiation exposure and costs. PMID- 26771856 TI - Predictors of infection after 754 cranioplasty operations and the value of intraoperative cultures for cryopreserved bone flaps. AB - OBJECTIVE The authors' aim was to report the largest study on predictors of infection after cranioplasty and to assess the predictive value of intraoperative bone flap cultures before cryopreservation. METHODS They retrospectively examined all cranioplasties performed between March 2004 and November 2014. Throughout this study period, the standard protocol during initial craniectomy was to obtain a culture swab of the extracted autologous bone flap (ABF)-prior to its placement in cytostorage-to screen for microbial contamination. Two consecutive protocols were employed for the use and interpretation of the intraoperative swab culture results: A) From March 2004 through June 2013, any culture-positive ABF (+ABF) was discarded and a custom synthetic prosthesis was implanted at the time of cranioplasty. B) From July 2013 through November 2014, any ABF with a skin flora organism was not discarded. Instead, cryopreservation was maintained and the +ABF was reimplanted after a 10-minute soak in bacitracin irrigation as well as a 3 minute soak in betadine. RESULTS Over the 10.75-year period, 754 cranioplasty procedures were performed. The median time from craniectomy to cranioplasty was 123 days. Median follow-up after cranioplasty was 237 days for protocol A and 225 days for protocol B. The overall infection rate after cranioplasty was 6.6% (50 cases) occurring at a median postoperative Day 31. Staphylococcus spp. were involved as the causative organisms in 60% of cases. Culture swabs taken at the time of initial craniectomy were available for 640 ABFs as 114 ABFs were not salvageable. One hundred twenty-six (20%) were culture positive. Eighty-nine +ABFs occurred during protocol A and were discarded in favor of a synthetic prosthesis at the time of cranioplasty, whereas 37 +ABFs occurred under protocol B and were reimplanted at the time of cranioplasty. Cranioplasty material did not affect the postcranioplasty infection rate. There was no significant difference in the infection rate among sterile ABFs (7%), +ABFs (8%), and synthetic prostheses (5.5%; p = 0.425). All 3 +ABF infections under protocol B were caused by organisms that differed from those in the original intraoperative bone culture from the initial craniectomy. A cranioplasty procedure <= 14 days after initial craniectomy was the only significant predictor of postcranioplasty infection (p = 0.007, HR 3.62). CONCLUSIONS Cranioplasty procedures should be performed at least 14 days after initial craniectomy to minimize infection risk. Obtaining intraoperative bone cultures at the time of craniectomy in the absence of clinical infection should be discontinued as the culture results were not a useful predictor of postcranioplasty infection and led to the unnecessary use of synthetic prostheses and increased health care costs. PMID- 26771857 TI - Techniques and long-term outcomes of cotton-clipping and cotton-augmentation strategies for management of cerebral aneurysms. AB - OBJECTIVE To address the challenges of microsurgically treating broad-based, frail, and otherwise complex aneurysms that are not amenable to direct clipping, alternative techniques have been developed. One such technique is to use cotton to augment clipping ("cotton-clipping" technique), which is also used to manage intraoperative aneurysm neck rupture, and another is to reinforce unclippable segments or remnants of aneurysm necks with cotton ("cotton-augmentation" technique). This study reviews the natural history of patients with aneurysms treated with cotton-clipping and cotton-augmentation techniques. METHODS The authors queried a database consisting of all patients with aneurysms treated at Barrow Neurological Institute in Phoenix, Arizona, between January 1, 2004, and December 31, 2014, to identify cases in which cotton-clipping or cotton augmentation strategies had been used. Management was categorized as the cotton clipping technique if cotton was used within the blades of the aneurysm clip and as the cotton-clipping technique if cotton was used to reinforce aneurysms or portions of the aneurysm that were unclippable due to the presence of perforators, atherosclerosis, or residual aneurysms. Data were reviewed to assess patient outcomes and annual rates of aneurysm recurrence or hemorrhage after the initial procedures were performed. RESULTS The authors identified 60 aneurysms treated with these techniques in 57 patients (18 patients with ruptured aneurysms and 39 patients with unruptured aneurysms) whose mean age was 53.1 years (median 55 years; range 24-72 years). Twenty-three aneurysms (11 cases of subarachnoid hemorrhage) were treated using cotton-clipping and 37 with cotton-augmentation techniques (7 cases of subarachnoid hemorrhage). In total, 18 patients presented with subarachnoid hemorrhage. The mean Glasgow Outcome Scale (GOS) score at the time of discharge was 4.4. At a mean follow-up of 60.9 +/- 35.6 months (median 70 months; range 10-126 months), the mean GOS score at last follow-up was 4.8. The total number of patient follow-up years was 289.4. During the follow-up period, none of the cotton-clipped aneurysms increased in size, changed in configuration, or rebled. None of the patients experienced early rebleeding. The annual hemorrhage rate for aneurysms treated with cotton-augmentation was 0.52% and the recurrence rate was 1.03% per year. For all patients in the study, the overall risk of hemorrhage was 0.35% per year and the annual recurrence rate was 0.69%. CONCLUSIONS Cotton-clipping is an effective and durable treatment strategy for intraoperative aneurysm rupture and for management of broad-based aneurysms. Cotton-augmentation can be safely used to manage unclippable or partially clipped intracranial aneurysms and affords protection from early aneurysm re-rupture and a relatively low rate of late rehemorrhage. PMID- 26771859 TI - Basic Insights into Tunable Graphene Hydrogenation. AB - The hydrogenation and deuteration of graphite with potassium intercalation compounds as starting materials were investigated in depth. Characterization of the reaction products (hydrogenated and deuterated graphene) was carried out by thermogravimetric analysis coupled with mass spectrometry (TG-MS) and statistical Raman spectroscopy (SRS) and microscopy (SRM). The results reveal that the choice of the hydrogen/deuterium source, the nature of the graphite (used as starting material), the potassium concentration in the intercalation compound, and the choice of the solvent have a great impact on the reaction outcome. Furthermore, it was possible to prove that both mono- and few-layer hydrogenated/deuterated graphene can be produced. PMID- 26771858 TI - Endolides A and B, Vasopressin and Serotonin-Receptor Interacting N-Methylated Peptides from the Sponge-Derived Fungus Stachylidium sp. AB - The marine-derived fungus Stachylidium sp. was isolated from the sponge Callyspongia sp. cf. C. flammea. Culture on a biomalt medium supplemented with sea salt led to the isolation of two new, most unusual N-methylated peptides, i.e., the tetrapeptides endolide A and B (1 and 2). Both of these contain the very rare amino acid 3-(3-furyl)-alanine. In radioligand binding assays endolide A (1) showed affinity to the vasopressin receptor 1A with a Ki of 7.04 MUM, whereas endolide B (2) exhibited no affinity to the latter receptor, but was selective toward the serotonin receptor 5HT2b with a Ki of 0.77 MUM. PMID- 26771860 TI - A CASE OF CHORIORETINOPATHY AS FIRST MANIFESTATION OF HODGKIN'S LYMPHOMA. AB - PURPOSE: To report a case of chorioretinopathy, which preceded diagnosis of Hodgkin's lymphoma. METHODS: Single patient case report. RESULTS: A 61-year-old woman with a history of breast cancer in remission and low-grade follicular lymphoma without criteria of high tumor burden presented with bilateral multifocal chorioretinopathy. The usual etiologies of chorioretinopathy were excluded, and subsequent onset of fever and back pain revealed the diagnosis of Hodgkin's lymphoma. The evolution of this case of ocular involvement was concordant with that of Hodgkin's lymphoma. CONCLUSION: The authors describe a case of Hodgkin's lymphoma postdating the onset of chorioretinopathy, emphasizing the need to research an underlying disorder when faced with any inflammatory intraocular disease, and the role of indocyanine green angiography in the diagnosis and follow-up of posterior uveitis. PMID- 26771862 TI - Controlling Proton Conductivity with Light: A Scheme Based on Photoacid Doping of Materials. AB - Transducing light energy to changes in material properties is central to a large range of functional materials, including those used in light harvesting. In conventional semiconductors, photoconductivity arises due to generation of mobile electrons or holes with light. Here we demonstrate, to our knowledge for the first time, an analogue of this effect for protons in an organic polymer solution and in water. We show that when a material is doped with photoacids, light excitation generates extra mobile protons that change the low-frequency conductivity of the material. We measure such change both in poly(ethylene glycol) (PEG) and in water sandwiched between two transparent electrodes and doped with a well-known photoacid 8-hydroxypyrene-1,3,6-trisulfonic acid (HPTS). The complex impedance of the material is measured over a range of 0.1 Hz-1 MHz in both the presence and absence of light, and it is found that shining light changes the low frequency impedance significantly. We model the impedance spectra of the material with a minimal circuit composed of a diffusive impedance (Warburg element), a parallel capacitance, and a resistance. Fitting the light and dark impedance spectra to the model reveals that light reduces the low-frequency diffusive impedance of the material, which is consistent with generation of extra free carriers by light. We further suggest that the light-induced conductivity change arises mainly due to those photoreleased protons that manage to escape the zone of influence of the parent ion and avoid recapture. Such escape is more likely in materials with larger diffusion coefficient for protons and shorter electrostatic screening lengths for the parent ion. This explanation is consistent with our observed differences in the photoconductivity of solution of HPTS in water and in PEG. We anticipate that this scheme can be employed in protonic circuits where direct transduction of energy from light to protonic gradients or protonic currents is necessary. This work will also serve as a basis for using photoacids as optical handles for characterizing the molecular mechanisms of conductivity in proton conducting materials. PMID- 26771861 TI - The Medicinal Chemistry of Dengue Virus. AB - The dengue virus and related flaviviruses are an increasing global health threat. In this perspective, we comment on and review medicinal chemistry efforts aimed at the prevention or treatment of dengue infections. We include target-based approaches aimed at viral or host factors and results from phenotypic screenings in cellular assay systems for viral replication. This perspective is limited to the discussion of results that provide explicit chemistry or structure-activity relationship (SAR), or appear to be of particular interest to the medicinal chemist for other reasons. The discovery and development efforts discussed here may at least partially be extrapolated toward other emerging flaviviral infections, such as West Nile virus. Therefore, this perspective, although not aimed at flaviviruses in general, should also be able to provide an overview of the medicinal chemistry of these closely related infectious agents. PMID- 26771864 TI - Role of p38 MAPK activation and mitochondrial cytochrome-c release in allicin induced apoptosis in SK-N-SH cells. AB - Here, we investigate the apoptotic effect of allicin, the predominant component of freshly crushed garlic, on neuroblastoma cells. In this paper, the authors have first assessed the effect of allicin on human neuroblastoma SK-N-SH cells and then investigated the underlying mechanism. The results indicate that allicin suppresses SK-N-SH cell growth in a dose-dependent and time-dependent manner and that 5 MUmol/l of allicin leads to a significant increase in apoptotic rate with annexin-V/PI double staining. Western blot analysis shows that treatment with allicin-induced apoptosis through activation of caspases-3 and 9. Phosphorylation of p38 MAPK contributes to allicin-induced apoptosis upstream of caspase activation. Using p38 MAPK inhibitor, the authors discovered that p38 MAPK activation subsequently induces the release of cytochrome-c from mitochondria into the cytosol. Taken together, the results demonstrate that allicin can activate the p38 MAPK pathway, which leads to mitochondrial release of cytochrome c, thus inducing SK-N-SH cell apoptosis. Overall, this study suggests that allicin may be used as one of the novel pharmacological treatment strategies in neuroblastoma. PMID- 26771863 TI - SLC1A1 Gene Variants and Normal Tension Glaucoma: An Association Study. AB - BACKGROUND: It has been hypothesized that dysfunction of the solute carrier family 1, member1 gene (SLC1A1), which encodes the glutamate aspartate transporter, may play a role in normal tension glaucoma. In this study we investigate whether SLC1A1 is associated with normal tension glaucoma in Japanese patients. METHODS: A total of 292 Japanese patients with normal tension glaucoma and 500 healthy control subjects were recruited. We genotyped 12 single nucleotide polymorphisms in SLC1A1. We also performed an imputation analysis to evaluate the potential association of un-genotyped SLC1A1 single-nucleotide polymorphisms, and 165 single-nucleotide polymorphisms were imputed. RESULTS: We observed an increased frequency of the G allele of rs10739062 in patients compared to controls (p = 0.043, OR = 1.25). The rs10739062 polymorphism exhibited a dominant effect: individuals with genotype GG and GC showed a 1.91 fold increase in risk compared to genotype CC (p = 0.0082). However, the statistical significance disappeared after Bonferroni correction for multiple testing (pc > 0.05). We did not find any significant association between any of the remaining 176 single-nucleotide polymorphisms and disease risk. CONCLUSIONS: Our study showed a lack of association between SLC1A1 variants and normal tension glaucoma in Japanese patients, suggesting that the SLC1A1 gene does not play a critical role in the development of the disorder in this patient population. However, further genetic studies with larger sample sizes are needed to clarify whether SLC1A1 may make some contribution that affects the risk of developing normal tension glaucoma. PMID- 26771865 TI - Efficacy and safety analysis of chemotherapy for advanced colitis-associated colorectal cancer in Japan. AB - Chemotherapy for advanced colitis-associated colorectal cancer (CAC) has been insufficiently evaluated. The goal of this study was to clarify the efficacy and safety of chemotherapy for CAC in Japan. CAC patients who were treated with chemotherapy between 2005 and 2015 were retrospectively examined. Twenty-nine patients (median age, 48 years; 23 men) were assessed. Eighteen patients had ulcerative colitis, and 11 had Crohn's disease. Three ulcerative colitis and four Crohn's disease patients were in the active disease phase. Primary tumors were located in the rectum/anus (n=16), the left colon (n=9), or the right colon (n=4). Palliative or adjuvant chemotherapy was performed in 13 and 16 patients, respectively. First-line palliative chemotherapy regimens were as follows: fluorouracil, leucovorin, and oxaliplatin (FOLFOX; n=6), FOLFOX+bevacizumab (n=3), and others (n=4). Adjuvant chemotherapy regimens were S-1 (n=7), oxaliplatin-based (n=4) and others (n=5). In palliative chemotherapy, the objective response rate was 15%, and the median progression-free survival and overall survival were 182 and 315 days, respectively. In adjuvant chemotherapy, the 5-year relapse-free survival rate was 78%. Grade 3/4 adverse events (AEs) were observed in 16 patients (55%). Active and remission inflammatory bowel disease patients suffered grade 3/4 nonhematological AEs at an incidence of 71 and 23%, respectively (P<0.01). Dose reduction was required in 11 patients (38%), eight of whom required it for hematological AEs. Adjuvant chemotherapy for CAC exhibited sufficient efficacy, whereas modest efficacy was shown for palliative chemotherapy for CAC. AEs, particularly nonhematological AEs, were closely associated with disease activity of colitis. PMID- 26771866 TI - How Locally Specific Factors May Impact the Delivery of HIV-Related Services to the Severely Mentally Ill in Washington, DC. PMID- 26771867 TI - Is a history of radiation therapy a contraindication for carotid surgery? AB - Advances in surgical and medical oncology have seen a significant increase in survival of patients suffering from head and neck malignancies. Many of these patients are treated with radiotherapy to the neck, including the cervical carotid artery. Cervical irradiation (CI) may induce carotid stenosis. Prior CI in association with carotid artery stenosis poses potential challenges, when revascularization is considered. As the focus of radiotherapy determines the level of the resultant obstruction it may be in a location that is difficult to reach surgically. Also scar tissue from CI may increase the risk of cranial nerve injury. Carotid angioplasty and stenting (CAS) may be an alternative for CEA in post CI cases. This manuscript aims to derive a treatment algorithm for post CI stenosis from the available literature, answering three questions: 1) do symptomatic post CI stenoses require revascularization?; 2) Do asymptomatic post CI stenoses require revascularization?; 3) What is the preferred revascularization modality? The answers to those questions are the following: 1) as several studies have shown the increased likelihood of stenosis after CI and its potential for embolic events, symptomatic stenosis should be treated; 2) patients after CI have a much greater chance of serious events from their malignancies than from their carotid disease, therefore most asymptomatic stenoses probably do not warrant revascularization; 3) CEA post CI carries less peri procedural risk than previously supposed and CAS is hampered by increased restenosis rates, so CEA should be the preferred treatment if feasible. An individual patient tailored approach for post CI carotid stenosis is warranted, the guideline being: "If symptomatic: revascularize; if possible: operate; if not: consider stenting". PMID- 26771868 TI - Management of in-stent restenosis in the superficial femoral artery. AB - This manuscript will describe of the process of in-stent restenosis and the histopathological changes involved. Moreover, it will provide an overview of the current status of the literature of the various therapeutic options that are available for the treatment of in-stent restenosis. PMID- 26771869 TI - Treatment options for postdissection aortic aneurysms. AB - Aortic dissection is one of the most devastating catastrophes that can affect the aorta. Surgical treatment is proposed only when complications such as rupture or malperfusion occur. No clear consensus has been reached regarding the best therapy to prevent aortic rupture after the acute phase. We have performed a thorough review of the most recent literature on the strategies to treat patients in the chronic phase of aortic dissection. PMID- 26771870 TI - Buprenorphine Maintenance Treatment of Opiate Dependence: Correlations Between Prescriber Beliefs and Practices. AB - BACKGROUND: Despite the existence of evidence-based guidelines, different prescriber practices around buprenorphine maintenance treatment (BMT) of opiate dependence exist. Moreover, certain prescriber beliefs may influence their practice patterns. OBJECTIVE: To understand community BMT practice patterns and discern their relationship to practitioner beliefs. METHOD: Survey of 30 local BMT prescribers about aspects of BMT, and analysis of correlations between practices and practitioner beliefs. RESULTS: Practitioners generally followed standard treatment guidelines, though the most-common maintenance dosages of BMT (4-12 mg) were lower than recommended by some studies. Endorsement of belief in a "spiritual basis" of addiction correlated with lower average BMT doses and less frequent endorsement of the belief that BMT-treated patients are "in recovery." CONCLUSIONS/IMPORTANCE: These data suggest that relatively standardized, longer term BMT of opiate dependence is accepted among the majority of surveyed prescribers, and certain provider beliefs about addiction may influence prescribing habits and attitudes. Future studies should: (1) assess these findings in larger samples; (2) examine how prescriber beliefs about addiction and BMT compare with those of other addiction treatment providers; and (3) ascertain whether individual prescriber beliefs influence patient outcomes. PMID- 26771871 TI - Stretch-induced Activation of Transforming Growth Factor-beta1 in Pulmonary Fibrosis. AB - RATIONALE: Recent findings suggesting transforming growth factor (TGF)-beta1 activation by mechanical stimuli in vitro raised the question of whether this phenomenon was relevant in vivo in the context of pulmonary fibrosis. OBJECTIVES: To explore the effect of mechanical stress on TGF-beta1 activation and its signaling pathway in rat and human fibrotic lung tissue using a novel ex vivo model. METHODS: Rat lung fibrosis was induced using transient gene expression of active TGF-beta1. Lungs were harvested at Day 14 or 21 and submitted to various stimuli in a tissue bath equipped with a force transducer and servo-controlled arm. MEASUREMENTS AND MAIN RESULTS: Fibrotic lung strips responded to tensile force by releasing active TGF-beta1 from latent stores with subsequent increase in tissue phospho-Smad2/3. In contrast, measurable active TGF-beta1 and phospho Smad2/3 were not induced by mechanical stress in nonfibrotic lungs. Protease inhibition did not affect the release of active TGF-beta1. A TGF-beta1 receptor inhibitor, Rho-associated protein kinase inhibitor, and alphav integrin inhibitor all attenuated mechanical stretch-induced phospho-Smad2/3 in fibrotic lung strips. Furthermore, the induction of phospho-Smad2/3 was enhanced in whole fibrotic rat lungs undergoing ventilation pressure challenge compared with control lungs. Last, tissue slices from human lung with usual interstitial pneumonia submitted to mechanical force showed an increase in TGF-beta1 activation and induction of phospho-Smad2/3 in contrast with human nonfibrotic lungs. CONCLUSIONS: Mechanical tissue stretch contributes to the development of pulmonary fibrosis via mechanotransduced activation of TGF-beta1 in rodent and human pulmonary fibrosis. PMID- 26771873 TI - The impact on health-related quality of life in the first 12 months: A randomised comparison of preoperative short-course radiation versus long-course chemoradiation for T3 rectal cancer (Trans-Tasman Radiation Oncology Group Trial 01.04). AB - PURPOSE: To assess health-related quality of life (HRQOL) in patients participating in a randomised trial of neoadjuvant short course radiation (SC) or long course chemoradiation (LC) for operable rectal cancer. PATIENTS AND METHODS: Eligible patients with T3N0-2M0 rectal cancer completed the European Organisation for Research and Treatment of Cancer quality of life questionnaire (QLQ-C30) and the colorectal cancer specific module (QLQ C38) at randomisation and 1, 2, 3, 6, 9 and 12 months later. RESULTS: Of 326 patients randomised, 297 (SC 143, LC 154) were eligible for completion of HRQOL questionnaires. Baseline scores were comparable across the SC and LC groups. Patients reported low scores on sexual functioning and sexual enjoyment. Defaecation problems were the worst of the symptoms at baseline. Surgery had the most profoundly negative effect on HRQOL, seen in both the SC and LC treatment groups to the same extent. The most severely affected domains were physical function and role function and the most severely affected symptoms were fatigue, pain, appetite, weight loss and male sexual problems. Most domains and symptoms returned to baseline levels by 12 months apart from body image, sexual enjoyment and male sexual problems. Future perspective was better than prior to treatment. CONCLUSION: There is no overall difference in HRQOL between SC and LC neoadjuvant treatment strategies, in the first 12 months, after surgery. In the immediate postoperative period HRQOL was adversely affected in both groups but for the most part was temporary. Some residual sexual functioning concerns persisted at 12 months. PMID- 26771874 TI - Synthetic cannabinoid 3-benzyl-5-[1-(2-pyrrolidin-1-ylethyl)-1H-indol-3-yl]-1,2,4 oxadiazole. The first detection in illicit market of new psychoactive substances. AB - We were the first to detect 3-benzyl-5-[1-(2-pyrrolidin-1-ylethyl)-1H-indol-3-yl] 1,2,4-oxadiazole (given name BzODZ-EPyr) as a new synthetic cannabinoid, in illegal market of new psychoactive compounds (NPS). The compound was known only from pharmaceutical literature so far. BzODZ-EPyr was identified by means of gas chromatography/mass spectrometry (GC/MS) including high resolution mass spectrometry (GC/HRMS), ultra-high performance liquid chromatography/high resolution tandem mass spectrometry (UHPLC/HRMS(2)), Fourier-transform infrared spectroscopy (FT-IR) and nuclear magnetic resonance spectroscopy (NMR) (1)H and (13)C. The peculiarities of mass-spectral fragmentation in experiments in electronic ionization (EI) and collision-induced dissociation (CID) modes were studied. Herewith we report analytical characteristics of BzODZ-EPyr enabling its (and possible analogues thereof) determination in criminal seizures. PMID- 26771872 TI - Predictive relevance of PD-L1 expression combined with CD8+ TIL density in stage III non-small cell lung cancer patients receiving concurrent chemoradiotherapy. AB - BACKGROUND: Expression of programmed cell death-ligand 1 (PD-L1) is known to be a mechanism whereby cancer can escape immune surveillance, but little is known about factors predictive of efficacy in patients with locally advanced non-small cell lung cancer (NSCLC). We investigated the predictive relevance of PD-L1 expression and CD8+ tumour-infiltrating lymphocytes (TILs) density in patients with locally advanced NSCLC receiving concurrent chemoradiotherapy (CCRT). METHODS: We retrospectively reviewed 74 consecutive patients with stage III NSCLC who had received CCRT. PD-L1 expression and CD8+ TIL density were evaluated by immunohistochemical analysis. RESULTS: Univariate and multivariate analyses demonstrated that CD8+ TIL density was an independent and significant predictive factor for progression-free survival (PFS) and OS, whereas PD-L1 expression was not correlated with PFS and OS. Sub-analysis revealed that the PD-L1+/CD8 low group had the shortest PFS (8.6 months, p = 0.02) and OS (13.9 months, p = 0.11), and that the PD-L1-/CD8 high group had the longest prognosis (median PFS and OS were not reached) by Kaplan-Meier curves of the four sub-groups. CONCLUSIONS: Among stage III NSCLC patients who received CCRT, there was a trend for poor survival in those who expressed PD-L1. Our analysis indicated that a combination of lack of PD-L1 expression and CD8+ TIL density was significantly associated with favourable survival in these patients. It is proposed that PD-L1 expression in combination with CD8+ TIL density could be a useful predictive biomarker in patients with stage III NSCLC. PMID- 26771875 TI - Golgi-Resident GTPase Rab30 Promotes the Biogenesis of Pathogen-Containing Autophagosomes. AB - Autophagy acts as a host-defense system against pathogenic microorganisms such as Group A Streptococcus (GAS). Autophagy is a membrane-mediated degradation system that is regulated by intracellular membrane trafficking regulators, including small GTPase Rab proteins. Here, we identified Rab30 as a novel regulator of GAS containing autophagosome-like vacuoles (GcAVs). We found that Rab30, a Golgi resident Rab, was recruited to GcAVs in response to autophagy induction by GAS infection in epithelial cells. Rab30 recruitment was dependent upon its GTPase activity. In addition, the knockdown of Rab30 expression significantly reduced GcAV formation efficiency and impaired intracellular GAS degradation. Rab30 normally functions to maintain the structural integrity of the Golgi complex, but GcAV formation occurred even when the Golgi apparatus was disrupted. Although Rab30 also colocalized with a starvation-induced autophagosome, Rab30 was not required for autophagosome formation during starvation. These results suggest that Rab30 mediates autophagy against GAS independently of its normal cellular role in the structural maintenance of the Golgi apparatus, and autophagosome biogenesis during bacterial infection involves specific Rab GTPases. PMID- 26771879 TI - Correction: Development and Internal Validation of a Predictive Model Including Pulse Oximetry for Hospitalization of Under-Five Children in Bangladesh. PMID- 26771878 TI - Lung Transplantation for Lymphangioleiomyomatosis in Japan. AB - BACKGROUND: Lung transplantation has been established as the definitive treatment option for patients with advanced lymphangioleiomyomatosis (LAM). However, the prognosis after registration and the circumstances of lung transplantation with sirolimus therapy have never been reported. METHODS: In this national survey, we analyzed data from 98 LAM patients registered for lung transplantation in the Japan Organ Transplantation Network. RESULTS: Transplantation was performed in 57 patients as of March 2014. Survival rate was 86.7% at 1 year, 82.5% at 3 years, 73.7% at 5 years, and 73.7% at 10 years. Of the 98 patients, 21 had an inactive status and received sirolimus more frequently than those with an active history (67% vs. 5%, p<0.001). Nine of twelve patients who remained inactive as of March 2014 initiated sirolimus before or while on a waiting list, and remained on sirolimus thereafter. Although the statistical analysis showed no statistically significant difference, the survival rate after registration tended to be better for lung transplant recipients than for those who awaited transplantation (p = 0.053). CONCLUSIONS: Lung transplantation is a satisfactory therapeutic option for advanced LAM, but the circumstances for pre-transplantation LAM patients are likely to alter with the use of sirolimus. PMID- 26771880 TI - PP1-Dependent Formin Bnr1 Dephosphorylation and Delocalization from a Cell Division Site. AB - Cell cycle ends with cytokinesis that is the physical separation of a cell into two daughter cells. For faithful cytokinesis, cells integrate multiple processes, such as actomyosin ring formation, contraction and plasma membrane closure, into coherent responses. Linear actin assembly by formins is essential for formation and maintenance of actomyosin ring. Although budding yeast's two formins, Bni1 and Bnr1, are known to switch their subcellular localization at the division site prior to cytokinesis, the underlying mechanisms were not completely understood. Here, we provide evidence showing that Bnr1 is dephosphorylated concomitant with its release from the division site. Impaired PP1/Glc7 activity delayed Bnr1 release and dephosphorylation, Bni1 recruitment and actomyosin ring formation at the division site. These results suggest the involvement of Glc7 in this regulation. Further, we identified Ref2 as the PP1 regulatory subunit responsible for this regulation. Taken together, Glc7 and Ref2 may have a role in actomyosin ring formation by modulating the localization of formins during cytokinesis. PMID- 26771881 TI - Dietary Intake among Grade 7 Students from Southwestern Ontario Attempting to Gain Weight. AB - PURPOSE: To describe dietary intake associated with intentional weight gain among grade 7 students. METHODS: Data were collected using the Waterloo web-based Eating Behaviour Questionnaire (WEB-Q) and measured heights/weights were taken to assess Body Mass Index (BMI). Dietary intake and the Canadian Healthy Eating Index-2009 were compared among participants who ate more to gain weight. RESULTS: Among 1015 participants, approximately 9% of participants were actively attempting to gain weight with more males than females (P < 0.001) and more underweight and normal weight than overweight/obese (P < 0.001) participants. Unadjusted analyses revealed that weight gainers versus non-weight gainers consumed more grain products (P < 0.001), meat and alternatives (P = 0.005), and other foods (P < 0.001), in addition to more total energy (P < 0.001). Although greater amounts of carbohydrates, fat, and protein were consumed among the weight gainers, no differences in the percentage of each macronutrient were observed once corrected for total energy intake. The adjusted model revealed that weight gainers were more likely to consume grain products in line with current recommendations, yet they were further from the recommendations for total fat intake. CONCLUSION: Health promotion strategies need to consider intentional weight gain among young adolescents to ensure that appropriate weight gaining strategies are being followed to avoid potential detrimental health effects. PMID- 26771876 TI - Systematic Identification and Characterization of Long Non-Coding RNAs in the Silkworm, Bombyx mori. AB - Long noncoding RNAs (lncRNAs) are emerging as important regulators in various biological processes. However, to date, no systematic characterization of lncRNAs has been reported in the silkworm Bombyx mori. In the present study, we generated eighteen RNA-seq datasets with relatively high depth. Using an in-house designed lncRNA identification pipeline, 11,810 lncRNAs were identified for 5,556 loci. Among these lncRNAs, 474 transcripts were intronic lncRNAs (ilncRNAs), 6,250 transcripts were intergenic lncRNAs (lincRNAs), and 5,086 were natural antisense lncRNAs (lncNATs). Compared with protein-coding mRNAs, silkworm lncRNAs are shorter in terms of full length but longer in terms of exon and intron length. In addition, lncRNAs exhibit a lower level of sequence conservation, more repeat sequences overlapped and higher tissue specificity than protein-coding mRNAs in the silkworm. We found that 69 lncRNA transcripts from 33 gene loci may function as miRNA precursors, and 104 lncRNA transcripts from 72 gene loci may act as competing endogenous RNAs (ceRNAs). In total, 49.47% of all gene loci (2,749/5,556) for which lncRNAs were identified showed sex-biased expression. Co expression network analysis resulted in 19 modules, 12 of which revealed relatively high tissue specificity. The highlighted darkgoldenrod module was specifically associated with middle and posterior silk glands, and the hub lncRNAs within this module were co-expressed with proteins involved in translation, translocation, and secretory processes, suggesting that these hub lncRNAs may function as regulators of the biosynthesis, translocation, and secretion of silk proteins. This study presents the first comprehensive genome wide analysis of silkworm lncRNAs and provides an invaluable resource for genetic, evolutionary, and genomic studies of B. mori. PMID- 26771882 TI - Male Courtship Pheromones Induce Cloacal Gaping in Female Newts (Salamandridae). AB - Pheromones are an important component of sexual communication in courting salamanders, but the number of species in which their use has been demonstrated with behavioral evidence remains limited. Here we developed a behavioral assay for demonstrating courtship pheromone use in the aquatically courting Iberian ribbed newt Pleurodeles waltl. By performing an in-depth study of the courtship behavior, we show that females invariably open their cloaca (cloacal gaping) before engaging in pinwheel behavior, the circling movement that is the prelude to spermatophore uptake. In contrast, cloacal gaping was not observed in failed courtships, where females escaped or displayed thanatosis. Since gaping mainly occurred during male amplexus and cloacal imposition, which is the obvious period of pheromone transfer, we next investigated whether male courtship water (i.e., water holding courtship pheromones) alone was able to induce this reaction in females. These tests showed that courtship water induced cloacal gaping significantly more than water, even in the absence of a male. Cloacal gaping thus provides a simple and robust test for demonstrating courtship pheromone use in the Iberian ribbed newt. Since opening the cloaca is an essential prerequisite for spermatophore pick-up in all internally fertilizing salamanders, we hypothesize that variations on this assay will also be useful in several other species. PMID- 26771883 TI - Is More Ever Too Much? The Number of Indicators per Factor in Confirmatory Factor Analysis. AB - We evaluated whether "more is ever too much" for the number of indicators (p) per factor (p/f) in confirmatory factor analysis by varying sample size (N = 50-1000) and p/f (2-12 items per factor) in 35,000 Monte Carlo solutions. For all N's, solution behavior steadily improved (more proper solutions, more accurate parameter estimates, greater reliability) with increasing p/f. There was a compensatory relation between N and p/f: large p/f compensated for small N and large N compensated for small p/f, but large-N and large-p/f was best. A bias in the behavior of the chi(2) was also demonstrated where apparent goodness of fit declined with increasing p/f ratios even though approximating models were "true". Fit was similar for proper and improper solutions, as were parameter estimates form improper solutions not involving offending estimates. We also used the 12 p/f data to construct 2, 3, 4, or 6 parcels of items (e.g., two parcels of 6 items per factor, three parcels of 4 items per factor, etc.), but the 12 indicator (nonparceled) solutions were somewhat better behaved. At least for conditions in our simulation study, traditional "rules" implying fewer indicators should be used for smaller N may be inappropriate and researchers should consider using more indicators per factor that is evident in current practice. PMID- 26771884 TI - A Comparison of Regression and Loading Weights for the Computation of Factor Scores. AB - An alternative strategy for computing factor scores was introduced and compared to a popular contemporary scoring procedure. The new strategy involved unit weighted composites of the standardized items that possessed salient factor score coefficients. Within the context of a sampling model, this strategy was shown to be superior to the common method of computing factor scores by unit-weighting and summing the standardized items with salient factor structure coefficients. Specifically, the new strategy produced factor scores that (a) captured a greater proportion of the true score variance of the factors, (b) were less confounded by true scores from factors other than those they were supposed to be estimates of, and (c) were less correlated with one another when the underlying factor structure was truly orthogonal. The implications of these findings were discussed within the context of two general applications of factor analysis, and practical recommendations were offered. PMID- 26771885 TI - An Efficient Metric Combinatorial Algorithm for Fitting Additive Trees. AB - A new combinatorial algorithm for fitting additive trees to proximity data is described. This algorithm, termed the "generalized triples" or GT method, proceeds by examining all triples of objects x,y,u in relation to the remaining set of objects to be clustered. For a given focal object, say x, the algorithm determines whether y or u is x's nearest neighbor using estimates derived from the distances of these objects to each other and the saved sums of distances of these objects to the remaining objects in the set. The result is a basic computational loop that is approximately order(n(3)). This idea is applied in a sequential agglomerative algorithm, with all pairs of objects that are mutual nearest neighbors (based on the above estimates) being joined at each stage. A simple version of the algorithm can be proven to find the correct solution if the dissimilarities matrix D actually satisfies the additive tree metric. The algorithm also works well on errorful data (i.e. data that cannot be modeled perfectly by an additive tree). A simulation study demonstrates that the GT algorithm works as effectively as the Sattath and Tversky algorithm (Corter, 1982; Sattath & Tversky, 1977) in terms of fit of the obtained solutions, and is faster for moderate- to large-sized data sets, especially in the presence of error. A second simulation study shows that the GT algorithm obtains comparable fits to De Soete's ( 1983) algorithm, with large savings in computation time. PMID- 26771886 TI - The Factor Structure of the WAIS-R: Replicability Across Age-Groups. AB - This article examines the factor structure of the Wechsler Adult Intelligence Scale- Revised across nine age groups using several methods of factor analysis, including reliable component analysis (RCA). RCA defines orthogonal components which have maximum reliability, and has several desirable properties which are discussed. Although the one- factor model (General Intelligence, or g), and the two-factor model (Verbal and Performance) of the WAIS-R are fairly well established. no such consensus has been reached regarding the three-factor model (Verbal Comprehension. Perceptual Organization, and Freedom from Distractibility). In the present study, g and Verbal and Performance factors were consistent across age groups for most methods of extraction, although somewhat different from the usual division. The three-factor model, however, was not consistently identified across age groups by any method, particularly with respect to Freedom from Distractibility. Meaningful interpretation of scores on this factor is therefore tenuous. RCA performed well, relative to most other methods, in identifying factors consistently across age groups and can provide useful and unique information. PMID- 26771887 TI - An Alternative Framework for Defining Mediation. AB - The present article provides an alternative framework for evaluating mediated relationships. From this perspective. a mediated process is a chain reaction, beginning with an independent variable that affects a mediator that in turn affects an outcome. The definition of mediation offered here, presented for stage sequences, states three conditions for establishing mediation: (a) the independent variable affects the probability of the sequence no mediator to mediator to outcome; (b) the independent variable affects the probability of a transition into the mediator stage; (c) the mediator affects the probability of a transition into the outcome stage at every level of the independent variable. This definition of mediation is compared and contrasted with the well-known definition of mediation for continuous variables discussed in Baron and Kenny (1986), Judd and Kenny (1981), and Kenny, Kashy, and Bolger (1997). The definition presented in this article emphasizes the intraindividual, time-ordered nature of mediation. PMID- 26771891 TI - Hierarchy of the Collective Effects in Water Clusters. AB - The results of dipole moment as well as of intra- and intermolecular bond order calculations indicate the big importance of collective electrostatic effects caused by the nonimmediate environment in liquid water models. It is also discussed how these collective effects are built up as consequences of the electrostatic and quantum chemical interactions in water clusters. PMID- 26771889 TI - Mucosal tissue pharmacokinetics of the integrase inhibitor raltegravir in a humanized mouse model: Implications for HIV pre-exposure prophylaxis. AB - Orally administered anti-retroviral drugs show considerable promise for HIV/AIDS pre-exposure prophylaxis (PrEP). For the success of these strategies, pharmacokinetic (PK) data defining the optimal concentration of the drug needed for protection in relevant mucosal exposure sites is essential. Here we employed a humanized mouse model to derive comprehensive PK data on the HIV integrase inhibitor raltegravir (RAL), a leading PrEP drug candidate. Under steady state conditions following oral dosing, plasma and multiple mucosal tissues were sampled simultaneously. RAL exhibited higher drug exposure in mucosal tissues relative to that in plasma with one log higher exposure in vaginal and rectal tissue and two logs higher exposure in intestinal mucosa reflecting the trends seen in the human studies. These data demonstrate the suitability of RAL for HIV PrEP and validate the utility of humanized mouse models for deriving important preclinical PK-PD data. PMID- 26771890 TI - OBESICA study: relationship between BMI and acute heart failure outcome. AB - OBJECTIVE: The objective of this study was to investigate the relationship between BMI and outcome of acute heart failure (AHF). METHODS: We carried out a secondary analysis of the Epidemiology of Acute Heart Failure in Emergency department Registry (prospective, multicenter registry following a cohort of AHF patients from 34 Spanish emergency departments). Follow-up was at 3 months and 1 year after enrolment over the telephone and included medical history review. We analyzed revisits to the emergency department and death in relation to BMI. Significant differences were analyzed using proportional risk models including data on demographic variables, basal status, the acute episode, and patient outcome. RESULTS: We included 1562 patients: low weight 1.3%, normal weight 26.1%, overweight 45.3%, obese 24.3%, and morbidly obese 3.1%. BMI was inversely associated with mortality (P<0.001) but not with revisit (P=0.70). Compared with patients with normal weight, the proportional risk of death among patients with low weight was increased [hazard ratio (HR) 1.75, 95% confidence interval (CI) 0.95-3.23], being reduced in overweight, obese and morbidly obese patients (HR 0.72, 95% CI 0.59-0.89; HR 0.75, 95% CI 0.58-0.96; and HR 0.42, 95% CI 0.20-0.85, respectively). These differences disappeared after adjusting the model for confounding factors and other predictive variables of mortality. CONCLUSION: BMI seems to be related to AHF and death, although this relationship disappeared on considering other prognostic factors and confounding variables. This finding limits the use of BMI by emergency physicians when estimating the risk of emergency department reconsultation or death in AHF patients. PMID- 26771888 TI - Key genes involved in the immune response are generally not associated with intraprostatic inflammation in men without a prostate cancer diagnosis: Results from the prostate cancer prevention trial. AB - BACKGROUND: We previously reported that both intraprostatic inflammation and SNPs in genes involved in the immune response are associated with prostate cancer risk and disease grade. In the present study, we evaluated the association between these SNPs and intraprostatic inflammation in men without a prostate cancer diagnosis. METHODS: Included in this cross-sectional study were 205 white controls from a case-control study nested in the placebo arm of the Prostate Cancer Prevention Trial. We analyzed inflammation data from the review of H&E stained prostate tissue sections from biopsies performed per protocol at the end of the trial irrespective of clinical indication, and data for 16 SNPs in key genes involved in the immune response (IL1beta, IL2, IL4, IL6, IL8, IL10, IL12(p40), IFNG, MSR1, RNASEL, TLR4, TNFA; 7 tagSNPs in IL10). Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) for the association between carrying at least one minor allele and having at least one biopsy core (of a mean of three reviewed) with inflammation. RESULTS: None of the SNPs evaluated was statistically significantly associated with having at least one core with inflammation. However, possible inverse associations were present for carrying the minor allele of rs2069762 (G) in IL2 (OR = 0.51, 95%CI 0.25-1.02); carrying two copies of the minor allele of rs1800871 (T) of IL10 (OR = 0.29, 95%CI 0.08-1.00); and carrying the minor allele of rs486907 (A) in RNASEL (OR = 0.52, 95%CI 0.26-1.06). After creating a genetic risk score from the three SNPs possibly associated with inflammation, the odds of inflammation increased with increasing number of risk alleles (P-trend = 0.008). CONCLUSION: While our findings do not generally support a cross-sectional link between individual SNPs in key genes involved in the immune response and intraprostatic inflammation in men without a prostate cancer diagnosis, they do suggest that some of these variants when in combination may be associated with intraprostatic inflammation in benign tissue. PMID- 26771892 TI - Optical Properties of Wintertime Aerosols from Residential Wood Burning in Fresno, CA: Results from DISCOVER-AQ 2013. AB - The optical properties, composition and sources of the wintertime aerosols in the San Joaquin Valley (SJV) were characterized through measurements made in Fresno, CA during the 2013 DISCOVER-AQ campaign. PM2.5 extinction and absorption coefficients were measured at 405, 532, and 870 nm along with refractory black carbon (rBC) size distributions and concentrations. BC absorption enhancements (Eabs) were measured using two methods, a thermodenuder and mass absorption coefficient method, which agreed well. Relatively large diurnal variations in the Eabs at 405 nm were observed, likely reflecting substantial nighttime emissions of wood burning organic aerosols (OA) from local residential heating. Comparably small diurnal variations and absolute nighttime values of Eabs were observed at the other wavelengths, suggesting limited mixing-driven enhancement. Positive matrix factorization analysis of OA mass spectra from an aerosol mass spectrometer resolved two types of biomass burning OA, which appeared to have different chemical composition and absorptivity. Brown carbon (BrC) absorption was estimated to contribute up to 30% to the total absorption at 405 nm at night but was negligible (<10%) during the day. Quantitative understanding of retrieved BrC optical properties could be improved with more explicit knowledge of the BC mixing state and the distribution of coating thicknesses. PMID- 26771893 TI - Measurement of driver calibration and the impact of feedback on drivers' estimates of performance. AB - Recent studies focused on driver calibration show that drivers are often miscalibrated, either over confident or under confident, and the magnitude of this miscalibration changes under different conditions. Previous work has demonstrated behavioral and performance benefits of feedback, yet these studies have not explicitly examined the issue of calibration. The objective of this study was to examine driver calibration, i.e., the degree to which drivers are accurately aware of their performance, and determine whether feedback alters driver calibration. Twenty-four drivers completed a series of driving tasks (pace clocks, traffic light, speed maintenance, and traffic cones) on a test track. Drivers drove three different blocks around the test track: (1) baseline block, where no participants received feedback; (2) feedback block, where half of the participants received performance feedback while the other half received no feedback; (3) a no feedback block, where no participants received feedback. Results indicated that across two different calibration measures, drivers were sufficiently calibrated to the pace clocks, traffic light, and traffic cone tasks. Drivers were not accurately aware of their performance regarding speed maintenance, though receiving feedback on this task improved calibration. Proper and accurate measurements of driver calibration are needed before designing performance feedback to improve calibration as these feedback systems may not always yield the intended results. PMID- 26771895 TI - Erratum. PMID- 26771894 TI - A 'test and treat' strategy for elevated wound protease activity for healing in venous leg ulcers. AB - BACKGROUND: Venous leg ulcers are a common and recurring type of complex wound. They can be painful, malodorous, prone to infection and slow to heal. Standard treatment includes compression therapy and a dressing. The use of protease modulating treatments for venous leg ulcers is increasing. These treatments are based on some evidence that a proportion of slow to heal ulcers have elevated protease activity in the wound. Point-of-care tests which aim to detect elevated protease activity are now available. A 'test and treat' strategy involves testing for elevated proteases and then using protease-modulating treatments in ulcers which show elevated protease levels. OBJECTIVES: To determine the effects on venous leg ulcer healing of a 'test and treat' strategy involving detection of high levels of wound protease activity and treatment with protease-modulating therapies, compared with alternative treatment strategies such as using the same treatment for all participants or using a different method of treatment selection. SEARCH METHODS: We searched the following electronic databases to identify reports of relevant randomised clinical trials: The Cochrane Wounds Group Specialised Register (January 2016), the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library) Issue 12, 2015); Ovid MEDLINE (1946 to January 2016); Ovid MEDLINE (In-Process & Other Non-Indexed Citations January 2016); Ovid EMBASE (1974 to January 2016); EBSCO CINAHL (1937 to January 2016). We also searched three clinical trials registers, reference lists and the websites of regulatory agencies. There were no restrictions with respect to language, date of publication or study setting. SELECTION CRITERIA: Published or unpublished RCTs which assessed a test and treat strategy for elevated protease activity in venous leg ulcers in adults compared with an alternative treatment strategy. The test and treat strategy needed to be the only systematic difference between the groups. DATA COLLECTION AND ANALYSIS: Two review authors independently performed study selection; we planned that two authors would also assess risk of bias and extract data. MAIN RESULTS: We did not identify any studies which met the inclusion criteria for this review. We identified one ongoing study; it was unclear whether this would be eligible for inclusion. AUTHORS' CONCLUSIONS: Currently there is no randomised evidence on the impact of a test and treat policy for protease levels on outcomes in people with venous leg ulcers. PMID- 26771896 TI - Predicting future protection of respirator users: Statistical approaches and practical implications. AB - The purpose of this article is to describe a statistical approach for predicting a respirator user's fit factor in the future based upon results from initial tests. A statistical prediction model was developed based upon joint distribution of multiple fit factor measurements over time obtained from linear mixed effect models. The model accounts for within-subject correlation as well as short-term (within one day) and longer-term variability. As an example of applying this approach, model parameters were estimated from a research study in which volunteers were trained by three different modalities to use one of two types of respirators. They underwent two quantitative fit tests at the initial session and two on the same day approximately six months later. The fitted models demonstrated correlation and gave the estimated distribution of future fit test results conditional on past results for an individual worker. This approach can be applied to establishing a criterion value for passing an initial fit test to provide reasonable likelihood that a worker will be adequately protected in the future; and to optimizing the repeat fit factor test intervals individually for each user for cost-effective testing. PMID- 26771897 TI - Inula Viscosa Extracts Induces Telomere Shortening and Apoptosis in Cancer Cells and Overcome Drug Resistance. AB - Telomerase is activated in human papillomavirus (HPV) positive cervical cancer and targeting telomeres offers a novel anticancer therapeutic strategy. In this study, the telomere targeting properties, the cytotoxic as well as the pro apoptotic effects of hexane (IV-HE) and dichloromethane (IV-DF) fractions from Inula viscosa L. extracts were investigated on human cervical HeLa and SiHa cancer cells. Our data demonstrate that IV-HE and IV-DF extracts were able to inhibit cell growth in HeLa and SiHa cells in a dose-dependent manner and studied resistant cell lines exhibited a resistance factor less than 2 when treated with the extracts. IV-HE and IV-DF extracts were able to inhibit telomerase activity and to induce telomere shortening as shown by telomeric repeat amplification protocol and TTAGGG telomere length assay, respectively. The sensitivity of fibroblasts to the extracts was increased when telomerase was expressed. Finally, IV-HE and IV-DF were able to induce apoptosis as evidenced by an increase in annexin-V labeling and caspase-3 activity. This study provides the first evidence that the IV-HE and IV-DF extracts from Inula viscosa L. target telomeres induce apoptosis and overcome drug resistance in tumor cells. Future studies will focus on the identification of the molecules involved in the anticancer activity. PMID- 26771898 TI - Novel therapies for severe Clostridium difficile colitis. AB - PURPOSE OF REVIEW: Clostridium difficile infection (CDI) is becoming a large healthcare burden with increasing incidence, high recurrence rates, and associated morbidity and mortality. Disease severity varies from mild to severe and complicated presentations. Current mainstays of therapy in severe CDI include: fluid resuscitation, support of organ dysfunction, discontinuation of inciting agents, and antibiotic treatment. RECENT FINDINGS: Recent focus on the impact of the microbiome and targeted therapies to reconstitute biodiversity may provide alternative therapeutic modalities with higher success and lower recurrence rates. Newer antibiotics are under development, along with targeted immunotherapies that attempt to neutralize pathogenic toxins. Alternative surgical options from traditional subtotal colectomy may provide a less morbid surgical option for those requiring intervention. SUMMARY: With further understanding of the pathogenesis and shortcomings of current therapies, the future of management of CDI may include a multimodal approach focusing on microbiota and immunologic therapies that could result in improved cure with reduced recurrence. PMID- 26771899 TI - Cross-Sectional Serosurvey and Risk Factors Associated with the Presence of Toxoplasma gondii Antibodies in Pigs in Greece. AB - INTRODUCTION: Toxoplasmosis is a worldwide reported zoonotic infection caused by the protozoon Toxoplasma gondii. Pigs may become infected by ingesting feed or water contaminated with cat faeces, by cannibalism, and/or by eating infected rodents. T. gondii infected edible tissues of pigs are a source of infection for humans. This study was undertaken to detect seropositivity of pigs against T. gondii and identify possible risk factors as well as to compare two serological methods. METHODS: A total of 609 blood samples were collected from 10% of the sows from 65 pig farms located in mainland Greece. Information about the geographical location, size, and biosecurity level of the herd was recorded. Samples were tested for the presence of antibodies against T. gondii employing the indirect fluorescent antibody test and the enzyme-linked immunosorbent assay. RESULTS: Twenty-six positive samples were detected (4.3%) in 17 out of the 65 farms tested (26.2%). The average seroprevalence in affected herds was 26.8% (95% confidence interval 21.0-32.6%). Among the categorical data evaluated, the biosecurity level (odds ratio 0.17, p < 0.01) and the geographical characteristics (odds ratio 13.55, p < 0.05) significantly affected the presence of toxoplasmosis in the herd. Toxoplasmosis was recorded in significantly higher percentages in mountainous farms as compared to lowlands (p < 0.05) and in those with poor biosecurity levels than in those with very good (p < 0.05). A very good agreement (kappa = 0.958) was observed between the two serological methods. CONCLUSION: The presence of antibodies in pigs is indirect information on the risk of the infection and an indication of the necessity of biosecurity measures to be taken in order to control infection at least in the areas at highest risk. PMID- 26771902 TI - Effects of long-term exposure to two fungicides, pyrimethanil and tebuconazole, on survival and life history traits of Italian tree frog (Hyla intermedia). AB - Over the last few years, the hazards associated with the extensive use of fungicides have become an issue of great concern but, at present, the effects of these substances on amphibians remain poorly understood. The goal of the present study was to assess the effects of two commonly used fungicides, tebuconazole and pyrimethanil, on Italian Tree Frog (Hyla intermedia), a species frequently found in agricultural areas. Tadpoles were exposed to fungicides from developmental Gosner stage 25 (GS 25) to completion of metamorphosis (GS 46) and the whole exposure period lasted 78 days. For both tested fungicides we used two concentrations (5 and 50MUg/L) that are comparable to those detected in surface waters, near agricultural fields. A variety of sublethal effects-on growth, development, behavior, and physiology-may be used for evaluating alterations induced by pollutants in amphibians. We estimated whether pyrimethanil and tebuconazole exposure impacted on H. intermedia life history traits. For this purpose, survival, growth, development, initiation of metamorphosis, success and size at metamorphosis, time to metamorphosis, and frequency of morphological abnormalities were evaluated. We showed, for all considered endpoints, that the exposure to tebuconazole exerts more harmful effects on H. intermedia than does exposure to pyrimethanil. Before the onset of metamorphic climax we showed, for both fungicides, that the low concentrations (5MUg/L) induced significantly greater effects than the higher ones (50MUg/L) on survival and deformity incidence. During the metamorphic climax, a complete reversal of this nonlinear trend takes place, and the percentage of animals initiating metamorphosis was reduced in fungicide-exposed groups in a concentration-dependent manner. Furthermore, a strong correlation emerged between fungicide exposure and the incidence of morphological abnormalities such as tail malformations, scoliosis, edema, mouth and limb deformities. Exposure to tested fungicides also caused a reduction in developmental rates just prior to the onset of metamorphic climax, which translated to a significant delay in timing of metamorphosis. We detected a drastic decrease in the success at metamorphosis in all exposed groups, compared to control group (86.25%). In fact, the percentage of survived larvae to GS 46, in the high and low concentrations, respectively, was only 22.5% and 36.25% in tebuconazole-exposed groups and 43.75% (50MUg/L) and 56.25% (5MUg/L) in pyrimethanil-exposed groups. Our findings underscore the hazardous properties of these two fungicides for non-target species in the context of ecotoxicological risk assessment. No published studies have addressed the long-term effects of tebuconazole and pyrimethanil on amphibians. To date, this is one of only a few studies documenting the effects of fungicide exposure over the whole larval development. PMID- 26771903 TI - Nurse practitioner and physician assistant students' knowledge, attitudes, and perspectives of chiropractic. AB - OBJECTIVE: The purpose of this study was to assess nurse practitioner (NP) and physician assistant (PA) students' views of chiropractic. As the role of these providers progresses in primary care settings, providers' views and knowledge of chiropractic will impact interprofessional collaboration and patient outcomes. Understanding how NP and PA students perceive chiropractic may be beneficial in building integrative health care systems. METHODS: This descriptive quantitative pilot study utilized a 56-item survey to examine attitudes, knowledge, and perspectives of NP and PA students in their 2nd year of graduate studies. Frequencies and binomial and multinomial logistic regression models were used to examine responses to survey totals. RESULTS: Ninety-two (97%) students completed the survey. There were conflicting results as to whether participants viewed chiropractic as mainstream or alternative. The majority of participants indicated lack of awareness regarding current scientific evidence for chiropractic and indicated a positive interest in learning more about the profession. Students who reported prior experience with chiropractic had higher attitude-positive responses compared to those without experience. Participants were found to have substantial knowledge deficits in relation to chiropractic treatments and scope of practice. CONCLUSION: The results of this study emphasize the need for increased integrative initiatives and chiropractic exposure in NP and PA education to enhance future interprofessional collaboration in health care. PMID- 26771904 TI - Estrogenic Activity of Mineral Oil Aromatic Hydrocarbons Used in Printing Inks. AB - The majority of printing inks are based on mineral oils (MOs) which contain complex mixtures of saturated and aromatic hydrocarbons. Consumer exposure to these oils occurs either through direct skin contacts or, more frequently, as a result of MO migration into the contents of food packaging that was made from recycled newspaper. Despite this ubiquitous and frequent exposure little is known about the potential toxicological effects, particularly with regard to the aromatic MO fractions. From a toxicological point of view the huge amount of alkylated and unsubstituted compounds therein is reason for concern as they can harbor genotoxicants as well as potential endocrine disruptors. The aim of this study was to assess both the genotoxic and estrogenic potential of MOs used in printing inks. Mineral oils with various aromatic hydrocarbon contents were tested using a battery of in vitro assays selected to address various endpoints such as estrogen-dependent cell proliferation, activation of estrogen receptor alpha or transcriptional induction of estrogenic target genes. In addition, the comet assay has been applied to test for genotoxicity. Out of 15 MOs tested, 10 were found to potentially act as xenoestrogens. For most of the oils the effects were clearly triggered by constituents of the aromatic hydrocarbon fraction. From 5 oils tested in the comet assay, 2 showed slight genotoxicity. Altogether it appears that MOs used in printing inks are potential endocrine disruptors and should thus be assessed carefully to what extent they might contribute to the total estrogenic burden in humans. PMID- 26771906 TI - Can We Use Antibodies to Chlamydia trachomatis as a Surveillance Tool for National Trachoma Control Programs? Results from a District Survey. AB - BACKGROUND: Trachoma is targeted for elimination by 2020. World Health Organization advises districts to undertake surveillance when follicular trachoma (TF) <5% in children 1-9 years and mass antibiotic administration has ceased. There is a question if other tools could be used for surveillance as well. We report data from a test for antibodies to C. trachomatis antigen pgp3 as a possible tool. METHODOLOGY: We randomly sampled 30 hamlets in Kilosa district, Tanzania, and randomly selected 50 children ages 1-9 per hamlet. The tarsal conjunctivae were graded for trachoma (TF), tested for C. trachomatis infection (Aptima Combo2 assay: Hologic, San Diego, CA), and a dried blood spot processed for antibodies to C. trachomatis pgp3 using a multiplex bead assay on a Luminex 100 platform. PRINCIPAL FINDINGS: The prevalence of trachoma (TF) was 0.4%, well below the <5% indicator for re-starting a program. Infection was also low, 1.1%. Of the 30 hamlets, 22 had neither infection nor TF. Antibody positivity overall was low, 7.5% and increased with age from 5.2% in 1-3 year olds, to 9.3% in 7-9 year olds (p = 0.015). In 16 of the 30 hamlets, no children ages 1-3 years had antibodies to pgp3. CONCLUSIONS: The antibody status of the 1-3 year olds indicates low cumulative exposure to infection during the surveillance period. Four years post MDA, there is no evidence for re-emergence of follicular trachoma. PMID- 26771905 TI - The LSH/DDM1 Homolog MUS-30 Is Required for Genome Stability, but Not for DNA Methylation in Neurospora crassa. AB - LSH/DDM1 enzymes are required for DNA methylation in higher eukaryotes and have poorly defined roles in genome maintenance in yeast, plants, and animals. The filamentous fungus Neurospora crassa is a tractable system that encodes a single LSH/DDM1 homolog (NCU06306). We report that the Neurospora LSH/DDM1 enzyme is encoded by mutagen sensitive-30 (mus-30), a locus identified in a genetic screen over 25 years ago. We show that MUS-30-deficient cells have normal DNA methylation, but are hypersensitive to DNA damaging agents. MUS-30 is a nuclear protein, consistent with its predicted role as a chromatin remodeling enzyme, and levels of MUS-30 are increased following DNA damage. MUS-30 co-purifies with Neurospora WDR76, a homolog of yeast Changed Mutation Rate-1 and mammalian WD40 repeat domain 76. Deletion of wdr76 rescued DNA damage-hypersensitivity of Deltamus-30 strains, demonstrating that the MUS-30-WDR76 interaction is functionally important. DNA damage-sensitivity of Deltamus-30 is partially suppressed by deletion of methyl adenine glycosylase-1, a component of the base excision repair machinery (BER); however, the rate of BER is not affected in Deltamus-30 strains. We found that MUS-30-deficient cells are not defective for DSB repair, and we observed a negative genetic interaction between Deltamus-30 and Deltamei-3, the Neurospora RAD51 homolog required for homologous recombination. Together, our findings suggest that MUS-30, an LSH/DDM1 homolog, is required to prevent DNA damage arising from toxic base excision repair intermediates. Overall, our study provides important new information about the functions of the LSH/DDM1 family of enzymes. PMID- 26771907 TI - Prenatal diagnosis of fetuses with increased nuchal translucency using an approach based on quantitative fluorescent polymerase chain reaction and genomic microarray. AB - OBJECTIVE: To assess the clinical value of prenatal diagnosis of fetuses with increased nuchal translucency (NT) using an approach based on quantitative fluorescent polymerase chain reaction (QF-PCR) and chromosomal microarray (CMA). STUDY DESIGN: From January 2013 to October 2014, we included 175 pregnancies with fetal NT >= 3.5mm at 11-13 weeks' gestation who received chorionic villus sampling. QF-PCR was first used to rapidly detect common aneuploidies. The cases with a normal QF-PCR result were analyzed by CMA. RESULTS: Of the 175 cases, common aneuploidies were detected by QF-PCR in 53 (30.2%) cases (30 cases of trisomy 21, 12 cases of monosomy X, 7 cases of trisomy 18, 3 cases of trisomy 13 and 1 case of 47, XXY). Among the 122 cases with a normal QF-PCR result, microarray detected additional pathogenic copy number variants (CNVs) in 5.7% (7/122) of cases. Four cases would have expected to be detectable by conventional karyotyping because of large deletions/duplications (>10 Mb), leaving three cases (2.5%; 3/118) with pathogenic CNVs only detectable by CMA. CONCLUSION: It is rational to use a diagnostic strategy in which CMA is preceded by the less expensive, rapid, QF-PCR to detect common aneuploidies. CMA allows detection of a number of pathogenic chromosomal aberrations in fetuses with a high NT. PMID- 26771908 TI - Low-molecular-weight heparin and aspirin in the prevention of recurrent early onset pre-eclampsia in women with antiphospholipid antibodies: the FRUIT-RCT. AB - OBJECTIVE: To examine whether combined treatment with low-molecular-weight heparin (LMWH) and aspirin reduces recurrent hypertensive disorders of pregnancy (HD: pre-eclampsia, eclampsia or HELLP syndrome) in women with antiphospholipid antibodies (aPLA) and a previous delivery for HD and/or small-for-gestational-age (SGA) birthweight before 34 weeks gestation. STUDY DESIGN: This multicentre randomised controlled trial was performed between December 2000 and December 2009. Women were recruited from all eight university and six non university/teaching hospitals in The Netherlands, two university hospitals in Australia and one university hospital in Sweden. Thirty two women with a previous delivery <34 weeks gestation with HD and/or SGA and aPLA were included before 12 weeks gestation. The intervention was daily LMWH with aspirin or aspirin alone. PRIMARY OUTCOMES: recurrent HD onset <34 weeks and recurrent HD irrespective of gestational age. Analysis by intention-to-treat. RESULTS: After an interim analysis, recruitment was ceased: accrual was low and the incidence of recurrent HD was far lower (3%) than expected (60%). The final analysis, performed on 32 women, shows no difference in the primary outcomes (LMWH and aspirin 0/16 versus aspirin only 1/16, risk difference 6.25% [CI -17 to 27%] for recurrent HD onset <34 weeks and 0/16 for LMWH and aspirin versus 2/16 for aspirin only, risk difference 12.5% [CI -15 to 35%] for HD irrespective of gestational age). CONCLUSION: In this population of women with aPLA, who had previously had an early delivery for HD and/or SGA prior to 34 weeks gestation, combined LMWH and aspirin treatment started before 12 weeks gestation in a subsequent pregnancy did not show reduction of onset of recurrent HD either <34 weeks gestation or irrespective of gestational age, compared with aspirin alone. PMID- 26771909 TI - Anesthetic Care for Orthopedic Patients: Is There a Potential for Differences in Care? AB - BACKGROUND: Differences in health care represent a major health policy issue. Despite increasing evidence on the mediating role of anesthesia type used for surgery on perioperative outcome, there is a lack of data on potential care differences in this field. The authors aimed to determine whether anesthesia practice (use of neuraxial anesthesia [NA] or peripheral nerve block [PNB]) differs by patient and hospital factors. METHODS: The authors extracted data on n = 1,062,152 hip and knee arthroplasty procedures from the Premier Perspective database (2006 to 2013). Multilevel multivariable logistic regression models measured associations (odds ratios [ORs] and 95% CIs) between patient/hospital factors and NA or PNB use. RESULTS: Of all patients, 22.2% (n = 236,083) received NA and 17.9% (n = 189,732) received PNB. Lower adjusted odds for receiving NA were seen for black patients (OR, 0.88; 95% CI, 0.86 to 0.91) and those on Medicaid (OR, 0.78; 95% CI, 0.74 to 0.82) or without insurance (OR, 0.89; 95% CI, 0.81 to 0.98). Furthermore, teaching hospitals (compared with nonteaching hospitals) had lower adjusted odds for NA utilization (OR, 0.35; 95% CI, 0.14 to 0.89). Although generally similar patterns were seen for PNB utilization, the main difference was that particularly Hispanic patients were less likely to receive PNB compared with white patients (OR, 0.60; 95% CI, 0.56 to 0.65). Sensitivity analyses generally validated our results. CONCLUSIONS: Significant differences exist in the provision of regional anesthetic care with factors such as race and insurance type being important determinants of anesthetic practice. Further and in-depth research is needed to fully assess the background of these differences. PMID- 26771910 TI - Inferior Vena Cava Ultrasonography before General Anesthesia Can Predict Hypotension after Induction. AB - BACKGROUND: Hypotension is a common side effect of general anesthesia induction, and when severe, it is related to adverse outcomes. Ultrasonography of inferior vena cava (IVC) is a reliable indicator of intravascular volume status. This study investigated whether preoperative ultrasound IVC measurements could predict hypotension after induction of anesthesia. METHODS: One hundred four adult patients, conforming to American Society of Anesthesiologists physical status I to III, scheduled for elective surgery after general anesthesia were recruited. Maximum IVC diameter (dIVCmax) and collapsibility index (CI) were measured preoperatively. Before induction, mean blood pressure (MBP) was recorded. After induction, MBP was recorded for 10 min after intubation. Hypotension was defined as greater than 30% decrease in MBP from baseline or MBP less than 60 mmHg. Receiver operating characteristic curve analysis with gray zone approach and regression analyses were used. RESULTS: IVC scanning was unsuccessful in 13.5% of patients. Data from 90 patients were analyzed. After induction, 42 patients developed hypotension. Areas (95% confidence interval) under the curves were 0.90 (0.82 to 0.95) for CI and 0.76 (0.66 to 0.84) for dIVCmax. The optimal cutoff values were 43% for CI and 1.8 cm for dIVCmax. The gray zone for CI was 38 to 43% and included 12% of patients and that for dIVCmax was 1.5 to 2.1 cm and included 59% of patients. After adjusting for other factors, it was found that CI was an independent predictor of hypotension with the odds ratio of 1.17 (1.09 to 1.26). CI was also positively associated with a percentage decrease in MBP (regression coefficient = 0.27). CONCLUSIONS: Preoperative ultrasound IVC CI measurement was a reliable predictor of hypotension after induction of general anesthesia, wherein CI greater than 43% was the threshold. PMID- 26771911 TI - Cautious Optimism: Can Preoperative Ultrasound Predict Postinduction Hypotension? PMID- 26771912 TI - Diastematomyelia: Split Cord Malformation. PMID- 26771914 TI - Aflatoxin B1, zearalenone and deoxynivalenol in feed ingredients and complete feed from central China. AB - Between 2012 and 2014, 2528 feed ingredient and complete feed samples were collected from central China. Numbers of 2083, 255 and 190 samples were analysed for aflatoxin B1 (AFB1), zearalenone (ZEN) and deoxynivalenol (DON), respectively, by high-performance liquid chromatography in combination with UV or fluorescence detection. The incidence rates of AFB1, ZEN and DON contamination of feed ingredients and complete feeds were 33.9%, 90.2% and 77.4%, respectively. The percentage of positive samples for AFB1 ranged from 13.1% to 97.1%. Cottonseed meal presented the most serious contamination by AFB1. ZEN and DON contamination levels of feeds ranged from 50% to 100%, indicating serious contamination over the studied 3-year period. This study demonstrates that AFB1, ZEN and DON contamination of feeds in central China is serious and differs over the years. Feeds are mostly contaminated with ZEN, followed by DON and AFB1. PMID- 26771915 TI - Rehabilitation, clinical outcome and return to sporting activities after posterolateral elbow instability: a systematic review. AB - BACKGROUND: The aim of this study was to systematically review the literature for rehabilitation concepts, clinical outcome and sporting performance after surgical or non- surgical treatment of Posterolateral Rotatory Instability of the elbow (PLRI). METHODS: In order to identify any published clinical study reporting on rehabilitation concepts and sporting performance following surgical or non surgical treatment of PLRI a systematic search in literature was conducted. Rehabilitation protocols were reviewed according to main rehabilitation protocol categories [bracing, range of motion (ROM), strengthening and return to sport (RTS)]. RESULTS: Seven articles, including 148 patients met the inclusion criteria. Lateral ulnar collateral ligament (LUCL) repair with sutures or suture anchors was reported in two studies. In four studies treatment was an isolated graft reconstruction and in one study a repair or graft reconstruction was performed. No study reporting on conservative treatment was found. Bracing with initially limiting ROM was declared in all studies. Duration of immobilization varied from one day to six weeks postoperative. Limitation of ROM to 30 degrees of elbow extension was reported in the majority of studies. Strengthening was allowed from six to eight weeks postoperative. Postoperative improvement in elbow range of motion was noted in all studies. CONCLUSION: Although there is agreement concerning bracing and limiting ROM following PLRI surgery there is currently no consensus in the rehabilitative- and conservative treatment modalities for patients with symptomatic PLRI. The majority of surgically treated patients with PLRI regain high acceptable results but further research is needed to determine the postoperative level of performance of these athletes. PMID- 26771916 TI - Patient-specific interface pressure case study at transradial prosthetic socket: comparison trials between ICRC polypropylene socket and air splint socket. AB - BACKGROUND: While considering how important the interface between the amputees with the prostheses socket, we have carried out research to compare the gradient pressure occur at the interface socket that may lead to the discomforting effects to the user using common ICRC polypropylene socket and air splint socket. DESIGN: Not Applicable SETTING: Not Applicable POPULATION: The subject was a 23 year old who suffered a traumatic defect on the right arm caused by higher electrical volt. METHODS: F-Socket sensors have been used to measure dynamic socket interface pressure for the transradial amputee wearer during static and dynamic movements. The printed circuit with a thickness of 0.18 mm is equipped between the socket and the surface of the residual limb. Two F-Socket sensor is required to cover the entire socket surface attached to the residual limb. The average of 10 trials made on prosthetic user using both type of sockets for static and dynamic movements was recorded. RESULTS: The pressure gradient shows that the circumference of the socket interface for the ICRC polypropylene socket gives the most pressure distributions to the amputees compared to the pressure gradient for the air splint socket. CONCLUSION: The pressure gradient for ICRC socket increased consistently when the user makes movements while for the air splint socket remain constantly. CLINICAL REHABILITATION IMPACT: The specific interface pressure occur at the socket interface help in determine the comfort and pain of the socket design and improve the correlation between the user and the prosthesis. PMID- 26771913 TI - A Randomized Controlled Trial Investigating the Effects of Neurofeedback, Methylphenidate, and Physical Activity on Event-Related Potentials in Children with Attention-Deficit/Hyperactivity Disorder. AB - OBJECTIVE: Electroencephalographic (EEG) neurofeedback (NF) is considered a nonpharmacological alternative for medication in attention-deficit/hyperactivity disorder (ADHD). Comparisons of the behavioral efficacy of NF and medication have produced inconsistent results. EEG measures can provide insight into treatment mechanisms, but have received little consideration. In this randomized controlled trial (RCT), effects of NF were compared with methylphenidate (MPH), and physical activity (PA) in children with ADHD on event-related potential (ERP) indices of response inhibition, which are involved in ADHD psychopathology. METHODS: Using a multicenter three way parallel group RCT design, 112 children with a Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV) (American Psychiatric Association 1994 ) diagnosis of ADHD, between 7 and 13 years of age, were initially included. NF training consisted of 30 sessions of theta/beta training at Cz over a 10 week period. PA training was a semiactive control group, matched in frequency and duration. MPH was titrated using a double-blind placebo controlled procedure in 6 weeks, followed by a stable dose for 4 weeks. ERP measures of response inhibition, N2 and P3, were available for 81 children at pre and postintervention (n = 32 NF, n = 25 MPH, n = 24 PA). RESULTS: Only the medication group showed a specific increase in P3 amplitude compared with NF (partial eta-squared [etap(2) ] = 0.121) and PA (etap(2) = 0.283), which was related to improved response inhibition. Source localization of medication effects on P3 amplitude indicated increased activation primarily in thalamic and striatal nuclei. CONCLUSIONS: This is the first study that simultaneously compared NF with stimulant treatment and a semiactive control group. Only stimulant treatment demonstrated specific improvements in brain function related to response inhibition. These results are in line with recent doubts on the efficacy and specificity of NF as treatment for ADHD. CLINICAL TRIALS REGISTRATION: Train Your Brain? Exercise and Neurofeedback Intervention for ADHD, https://clinicaltrials.gov/show/NCT01363544 , Ref. No. NCT01363544. PMID- 26771917 TI - Goal setting and strategies to enhance goal pursuit in adult rehabilitation: summary of a Cochrane systematic review and meta-analysis. AB - INTRODUCTION: Goal setting is considered an essential part of rehabilitation, but approaches to goal setting vary with no consensus regarding the best approach. The aim of this systematic review and meta-analysis was to assess the effects of goal setting and strategies to enhance the pursuit of goals on improving outcomes in adult rehabilitation. EVIDENCE ACQUISITION: We searched CENTRAL, MEDLINE, EMBASE, four other databases and three trial registries for randomized control trials (RCTs), cluster RCTs, or quasi-RCTs published before December 2013. Two reviewers independently screened all search results, then critically appraised and extracted data on all included studies. We identified 39 trials, which differed in clinical context, participant populations, research question related to goal use, and outcomes measured. Eighteen studies compared goal setting, with or without strategies to enhance goal pursuit, to no goal setting. EVIDENCE SYNTHESIS: These 18 studies provided very low-quality evidence for a moderate effect size that any type of goal setting is better than no goal setting for improving health-related quality of life or self-reported emotional status (N.=446, standard mean difference [SMD]=0.53, 95% confidence interval [CI]: 0.17 to 0.88), and very low-quality evidence of a large effect size for self-efficacy (N.=108, SMD=1.07, 95% CI: 0.64 to 1.49). Fourteen studies compared a structured approach to goal setting to "usual care" goal setting, where some goals may have been set but no structured approach was followed. These studies provided very low quality evidence for a small effect size that more structured goal setting results in higher patient self-efficacy (N.=134, SMD=0.37, 95% CI: 0.02 to 0.71). No conclusive evidence was found to support the notion that goal setting, or structured goal setting in comparison to "usual care" goal setting, changes outcomes for patients for measures of participation, activity, or engagement in rehabilitation programs. CONCLUSIONS: This review found a large and increasing amount of research being conducted on goal setting in rehabilitation. However, problems with study design and diversity in methods used means the quality of evidence to support estimated effect sizes is poor. Further research is highly likely to change reported estimates of effect size arising from goal setting in rehabilitation. PMID- 26771919 TI - New-onset psoriasis induced by rituximab therapy for non-Hodgkin lymphoma in a child. PMID- 26771920 TI - DDQ-Promoted Benzylic/Allylic sp(3) C-H Activation for the Stereoselective Intramolecular C-N Bond Formation: Applications to the Total Synthesis of (-) Codonopsinine, (+)-5-epi-Codonopsinine, (+)-Radicamine B, and (-)-Codonopsinol. AB - This is the first report on an intramolecular C-N bond formation of an amide tethered benzylic/allylic system using DDQ under neutral conditions which has been successfully applied to the total synthesis of naturally occurring pyrolidine alkaloids. The key steps for the synthesis of corresponding precursors involve Julia-Kociensky olefination/cross-metathesis and dihydroxylation reactions, and this methodology is also extended to the omega-unsaturated N sulfanilamide to furnish piperidines. PMID- 26771918 TI - The Neuroprotective Effect of Rapamycin as a Modulator of the mTOR-NF-kappaB Axis during Retinal Inflammation. AB - PURPOSE: The determination of the molecular mechanism underlying retinal pathogenesis and visual dysfunction during innate inflammation, and the treatment effect of rapamycin thereon. METHODS: The endotoxin-induced uveitis and retinitis mouse model was established by injecting lipopolysaccharide. The mice were subsequently treated with rapamycin, a mammalian target of rapamycin (mTOR) inhibitor. The rhodopsin mRNA and protein expression level in the retina and the photoreceptor outer segment (OS) length in immunohistochemical stainings were measured, and visual function was recorded by electroretinography. Inflammatory cytokines, their related molecules, mTOR, and LC3 levels were measured by real time PCR and/or immunoblotting. Leukocyte adhesion during inflammation was analyzed using concanavalin A lectin. RESULTS: The post-transcriptional reduction in the visual pigment of rod photoreceptor cells, rhodopsin, OS shortening, and rod photoreceptor cell dysfunction during inflammation were suppressed by rapamycin. Activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) and induction of inflammatory cytokines, such as interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1), and the activation of the downstream signaling protein, signal transducer and activator of transcription 3 (STAT3), which reduces rhodopsin in the retina during inflammation, were attenuated by rapamycin. Increased leukocyte adhesion was also attenuated by rapamycin. Interestingly, although mTOR activation was observed after NF-kappaB activation, mTOR inhibition suppressed NF-kappaB activation at the early phase, indicating that the basal level of activated mTOR was sufficient to activate NF kappaB in the retina. In addition, the inhibition of NF-kappaB suppressed mTOR activation, suggesting a positive feedback loop of mTOR and NF-kappaB during inflammation. The ratio of LC3II to LC3I, which reflects autophagy induction, was not changed by inflammation but was increased by rapamycin. CONCLUSIONS: Our results propose the potential use of rapamycin as a neuroprotective therapy to suppress local activated mTOR levels, related inflammatory molecules, and the subsequent visual dysfunction during retinal inflammation. PMID- 26771921 TI - Inorganic fouling of an anaerobic membrane bioreactor treating leachate from the organic fraction of municipal solid waste (OFMSW) and a polishing aerobic membrane bioreactor. AB - The treatment of leachate (Average TCOD=11.97 g/L, 14.4% soluble) from the organic fraction of municipal solid waste was investigated using a Submerged Anaerobic Membrane BioReactor (SAMBR), followed by an aerobic membrane bioreactor (AMBR) to polish this effluent. This paper investigated the exact nature and composition of the inorganic precipitate in each of the reactors in the process. The flux decreased due to precipitation of calcium as monohydrocalcite (CaCO3.H2O) containing traces of metals onto the SAMBR membrane because of high CO2 partial pressures. Precipitation of calcium in the AMBR was also observed due to a higher pH. In this case, phosphorus also precipitated with calcium in two different phases: the background layer contained calcium, oxygen, carbon and small amounts of phosphorus (2-6.7%), while flakes containing calcium, oxygen and higher amounts of phosphorus (10-17%) were probably hydroxyapatite (Ca5(PO4)3OH). PMID- 26771922 TI - Metabolic biotransformation of copper-benzo[a]pyrene combined pollutant on the cellular interface of Stenotrophomonas maltophilia. AB - Previous studies have confirmed that Stenotrophomonas maltophilia can bind an appreciable amount of Cu(II) and degrade BaP. However, the removal mechanisms of Cu(II) coexisted with BaP by S. maltophilia are still unclear. In this study, the micro-interaction of contaminants on the cellular surface was investigated. The results indicated that carboxyl groups played an important role in the binding of copper to the thallus and that the cell walls were the main adsorption sites. Nevertheless, these reactive groups had no obvious effect on the uptake of BaP. Instead, the disruption and modification of cell walls accelerated transportation of BaP across the membrane into cells. The observation of SEM-EDS confirmed that Cu(II) would be adsorbed and precipitated onto the cell surface but would also be removed by extracellular precipitation when BaP coexisted. And the XPS analysis reflected that part of Cu(II) bound onto biosorbents changed into Cu(I) and Cu. PMID- 26771923 TI - Direct membrane-carbonation photobioreactor producing photoautotrophic biomass via carbon dioxide transfer and nutrient removal. AB - An advanced-material photobioreactor, the direct membrane-carbonation photobioreactor (DMCPBR), was tested to investigate the impact of directly submerging a membrane carbonation (MC) module of hollow-fiber membranes inside the photobioreactor. Results demonstrate that the DMCPBR utilized over 90% of the supplied CO2 by matching the CO2 flux to the C demand of photoautotrophic biomass growth. The surface area of the submerged MC module was the key to control CO2 delivery and biomass productivity. Tracking the fate of supplied CO2 explained how the DMCPBR reduced loss of gaseous CO2 while matching the inorganic carbon (IC) demand to its supply. Accurate fate analysis required that the biomass associated C include soluble microbial products as a sink for captured CO2. With the CO2 supply matched to the photosynthetic demand, light attenuation limited the rate microalgal photosynthesis. The DMCPBR presents an opportunity to improve CO2-deliver efficiency and make microalgae a more effective strategy for C neutral resource recovery. PMID- 26771924 TI - Comparative evaluation of chemical and enzymatic saccharification of mixotrophically grown de-oiled microalgal biomass for reducing sugar production. AB - For the commercialization of microalgal based biofuels, utilization of de-oiled carbohydrate rich biomass is important. In the present study, chemo-enzymatic hydrolysis of mixotrophically grown Scenedesmus sp. CCNM 1077 de-oiled biomass is evaluated. Among the chemical hydrolysis, use of 0.5M HCl for 45 min at 121 degrees C resulted in highest saccharification yield of 37.87% w/w of de-oiled biomass. However, enzymatic hydrolysis using Viscozyme L at loading rate of 20 FBGU/g of de-oiled biomass, pH 5.5 and temperature 45 degrees C for 72 h resulted in saccharification yield of 43.44% w/w of de-oiled biomass. Further, 78% ethanol production efficiency was achieved with enzymatically hydrolyzed de-oiled biomass using yeast Saccharomyces cerevisiae ATCC 6793. These findings of the present study show application of mixotrophically grown de-oiled biomass of Scenedesmus sp. CCNM 1077 as promising feedstock for bioethanol production. PMID- 26771926 TI - Potential sources of microbial colonizers in an initial soil ecosystem after retreat of an alpine glacier. AB - Rapid disintegration of alpine glaciers has led to the formation of new terrain consisting of mineral debris colonized by microorganisms. Despite the importance of microbial pioneers in triggering the formation of terrestrial ecosystems, their sources (endogenous versus exogenous) and identities remain elusive. We used 454-pyrosequencing to characterize the bacterial and fungal communities in endogenous glacier habitats (ice, sub-, supraglacial sediments and glacier stream leaving the glacier forefront) and in atmospheric deposition (snow, rain and aeolian dust). We compared these microbial communities with those occurring in recently deglaciated barren soils before and after snow melt (snow-covered soil and barren soil). Atmospheric bacteria and fungi were dominated by plant epiphytic organisms and differed from endogenous glacier habitats and soils indicating that atmospheric input of microorganisms is not a major source of microbial pioneers in newly formed soils. We found, however, that bacterial communities in newly exposed soils resembled those of endogenous habitats, which suggests that bacterial pioneers originating from sub- and supraglacial sediments contributed to the colonization of newly exposed soils. Conversely, fungal communities differed between habitats suggesting a lower dispersal capability than bacteria. Yeasts putatively adapted to cold habitats characteristic of snow and supraglacial sediments were similar, despite the fact that these habitats were not spatially connected. These findings suggest that environmental filtering selects particular fungi in cold habitats. Atmospheric deposition provided important sources of dissolved organic C, nitrate and ammonium. Overall, microbial colonizers triggering soil development in alpine environments mainly originate from endogenous glacier habitats, whereas atmospheric deposition contributes to the establishment of microbial communities by providing sources of C and N. PMID- 26771927 TI - Geographic patterns of co-occurrence network topological features for soil microbiota at continental scale in eastern China. AB - Soil microbiota play a critical role in soil biogeochemical processes and have a profound effect on soil functions. Recent studies have revealed microbial co occurrence patterns in soil microbial communities, yet the geographic pattern of topological features in soil microbial co-occurrence networks at the continental scale are largely unknown. Here, we investigated the shifts of topological features in co-occurrence networks inferred from soil microbiota along a continental scale in eastern China. Integrating archaeal, bacterial and fungal community datasets, we inferred a meta-community co-occurrence network and analyzed node-level and network-level topological shifts associated with five climatic regions. Both node-level and network-level topological features revealed geographic patterns wherein microorganisms in the northern regions had closer relationships but had a lower interaction influence than those in the southern regions. We further identified topological differences associated with taxonomic groups and demonstrated that co-occurrence patterns were random for archaea and non-random for bacteria and fungi. Given that microbial interactions may contribute to soil functions more than species diversity, this geographic shift of topological features provides new insight into studying microbial biogeographic patterns, their organization and impacts on soil-associated function. PMID- 26771928 TI - Single-cell activity of freshwater aerobic anoxygenic phototrophic bacteria and their contribution to biomass production. AB - Aerobic anoxygenic phototrophic (AAP) bacteria are photoheterotrophs that despite their low abundances have been hypothesized to play an ecologically and biogeochemically important role in aquatic systems. Characterizing this role requires a better understanding of the in situ dynamics and activity of AAP bacteria. Here we provide the first assessment of the single-cell activity of freshwater AAP bacteria and their contribution to total bacterial production across lakes spanning a wide trophic gradient, and explore the role of light in regulating AAP activity. The proportion of cells that were active in leucine incorporation and the level of activity per cell were consistently higher for AAP than for bulk bacteria across lakes. As a result, AAP bacteria contributed disproportionately more to total bacterial production than to total bacterial abundance. Interestingly, although environmentally driven patterns in activity did not seem to differ largely between AAP and bulk bacteria, their response to light did, and exposure to light resulted in increases in the proportion of active AAP bacteria with no clear effect on their cell-specific activity. This suggests that light may play a role in the activation of AAP bacteria, enabling these photoheterotrophs to contribute more to the carbon cycle than suggested by their abundance. PMID- 26771929 TI - Shifts in diversity and function of lake bacterial communities upon glacier retreat. AB - Global climate change is causing a wastage of glaciers and threatening biodiversity in glacier-fed ecosystems. The high turbidity typically found in those ecosystems, which is caused by inorganic particles and result of the erosive activity of glaciers is a key environmental factor influencing temperature and light availability, as well as other factors in the water column. Once these lakes loose hydrological connectivity to glaciers and turn clear, the accompanying environmental changes could represent a potential bottleneck for the established local diversity with yet unknown functional consequences. Here, we study three lakes situated along a turbidity gradient as well as one clear unconnected lake and evaluate seasonal changes in their bacterial community composition and diversity. Further, we assess potential consequences for community functioning. Glacier runoff represented a diverse source community for the lakes and several taxa were able to colonize downstream turbid habitats, although they were not found in the clear lake. Operational taxonomic unit-based alpha diversity and phylogenetic diversity decreased along the turbidity gradient, but metabolic functional diversity was negatively related to turbidity. No evidence for multifunctional redundancy, which may allow communities to maintain functioning upon alterations in diversity, was found. Our study gives a first view on how glacier-fed lake bacterial communities are affected by the melting of glaciers and indicates that diversity and community composition significantly change when hydrological connectivity to the glacier is lost and lakes turn clear. PMID- 26771930 TI - Segregating metabolic processes into different microbial cells accelerates the consumption of inhibitory substrates. AB - Different microbial cell types typically specialize at performing different metabolic processes. A canonical example is substrate cross-feeding, where one cell type consumes a primary substrate into an intermediate and another cell type consumes the intermediate. While substrate cross-feeding is widely observed, its consequences on ecosystem processes is often unclear. How does substrate cross feeding affect the rate or extent of substrate consumption? We hypothesized that substrate cross-feeding eliminates competition between different enzymes and reduces the accumulation of growth-inhibiting intermediates, thus accelerating substrate consumption. We tested this hypothesis using isogenic mutants of the bacterium Pseudomonas stutzeri that either completely consume nitrate to dinitrogen gas or cross-feed the intermediate nitrite. We demonstrate that nitrite cross-feeding eliminates inter-enzyme competition and, in turn, reduces nitrite accumulation. We further demonstrate that nitrite cross-feeding accelerates substrate consumption, but only when nitrite has growth-inhibiting effects. Knowledge about inter-enzyme competition and the inhibitory effects of intermediates could therefore be important for deciding how to best segregate different metabolic processes into different microbial cell types to optimize a desired biotransformation. PMID- 26771932 TI - WHAT'S NEW IN SHOCK, FEBRUARY 2016? PMID- 26771933 TI - RECENT ADVANCES IN BIOMARKERS IN SEVERE BURNS. AB - The pathophysiology of burn injuries is tremendously complex. A thorough understanding is essential for correct treatment of the burned area and also to limit the appearance of organ dysfunction, which, in fact, is a key determinant of morbidity and mortality. In this context, research into biomarkers may play a major role. Biomarkers have traditionally been considered an important area of medical research: the measurement of certain biomarkers has led to a better understanding of pathophysiology, while others have been used either to assess the effectiveness of specific treatments or for prognostic purposes. Research into biomarkers may help to improve the prognosis of patients with severe burn injury. The aim of the present clinical review is to discuss new evidence of the value of biomarkers in this setting. PMID- 26771931 TI - Peat: home to novel syntrophic species that feed acetate- and hydrogen-scavenging methanogens. AB - Syntrophic bacteria drive the anaerobic degradation of certain fermentation products (e.g., butyrate, ethanol, propionate) to intermediary substrates (e.g., H2, formate, acetate) that yield methane at the ecosystem level. However, little is known about the in situ activities and identities of these syntrophs in peatlands, ecosystems that produce significant quantities of methane. The consumption of butyrate, ethanol or propionate by anoxic peat slurries at 5 and 15 degrees C yielded methane and CO2 as the sole accumulating products, indicating that the intermediates H2, formate and acetate were scavenged effectively by syntrophic methanogenic consortia. 16S rRNA stable isotope probing identified novel species/strains of Pelobacter and Syntrophomonas that syntrophically oxidized ethanol and butyrate, respectively. Propionate was syntrophically oxidized by novel species of Syntrophobacter and Smithella, genera that use different propionate-oxidizing pathways. Taxa not known for a syntrophic metabolism may have been involved in the oxidation of butyrate (Telmatospirillum related) and propionate (unclassified Bacteroidetes and unclassified Fibrobacteres). Gibbs free energies (DeltaGs) for syntrophic oxidations of ethanol and butyrate were more favorable than DeltaGs for syntrophic oxidation of propionate. As a result of the thermodynamic constraints, acetate transiently accumulated in ethanol and butyrate treatments but not in propionate treatments. Aceticlastic methanogens (Methanosarcina, Methanosaeta) appeared to outnumber hydrogenotrophic methanogens (Methanocella, Methanoregula), reinforcing the likely importance of aceticlastic methanogenesis to the overall production of methane. DeltaGs for acetogenesis from H2 to CO2 approximated to -20 kJ mol(-1) when acetate concentrations were low, indicating that acetogens may have contributed to the flow of carbon and reductant towards methane. PMID- 26771934 TI - IMPACT OF CONTINUOUS RENAL REPLACEMENT THERAPY INTENSITY ON SEPTIC ACUTE KIDNEY INJURY. AB - The intensity of continuous renal replacement therapy (CRRT) for acute kidney injury (AKI) has been evaluated, but recent randomized clinical trials have failed to demonstrate a beneficial impact of high intensity on the outcomes. High intensity might cause some detrimental results recognized recently as CRRT trauma. This study was undertaken to evaluate the association of CRRT intensity with mortality in a population of AKI patients treated with lower-intensity CRRT in Japan. A retrospective single-center cohort study enrolled 125 AKI patients treated with CRRT in mixed intensive care units of a university hospital in Japan. Subanalysis was conducted for septic and postsurgical AKI. The median value of the prescribed total effluent rate was 20.1 (interquartile range 15.3 27.1) mL/kg/h. Overall, univariate Cox regression analysis indicated no association of the CRRT intensity with the 60-day in-hospital mortality rate (hazard ratio 1.006, 95% confidence interval [CI] 0.991-1.018, P = 0.343). In subanalysis with the septic AKI patients, multivariate analysis revealed two factors associated independently with the 60-day mortality rate: the Sequential Organ Failure Assessment score at initiation of CRRT (hazard ratio 1.152, 95% CI 1.025-1.301, P = 0.0171) and the CRRT intensity (hazard ratio 1.024, 95% CI 1.004 1.042, P = 0.0195). The CRRT intensity was associated significantly with higher 60-day in-hospital mortality in septic AKI, suggesting that unknown detrimental effects of CRRT with high-intensity CRRT might worsen the outcomes in septic AKI patients. PMID- 26771935 TI - EPHA4-FC TREATMENT REDUCES ISCHEMIA/REPERFUSION-INDUCED INTESTINAL INJURY BY INHIBITING VASCULAR PERMEABILITY. AB - The inflammatory response is characterized by increased endothelial permeability, which permits the passage of fluid and inflammatory cells into interstitial spaces. The Eph/ephrin receptor ligand system plays a role in inflammation through a signaling cascade, which modifies Rho-GTPase activity. We hypothesized that blocking Eph/ephrin signaling using an EphA4-Fc would result in decreased inflammation and tissue injury in a model of ischemia/reperfusion (I/R) injury. Mice undergoing intestinal I/R pretreated with the EphA4-Fc had significantly reduced intestinal injury compared to mice injected with the control Fc. This reduction in I/R injury was accompanied by significantly reduced neutrophil infiltration, but did not affect intestinal inflammatory cytokine generation. Using microdialysis, we identified that intestinal I/R induced a marked increase in systemic vascular leakage, which was completely abrogated in EphA4-Fc-treated mice. Finally, we confirmed the direct role of Eph/ephrin signaling in endothelial leakage by demonstrating that EphA4-Fc inhibited tumor necrosis factor-alpha-induced vascular permeability in human umbilical vein endothelial cells. This study identifies that Eph/ephrin interaction induces proinflammatory signaling in vivo by inducing vascular leak and neutrophil infiltration, which results in tissue injury in intestinal I/R. Therefore, therapeutic targeting of Eph/ephrin interaction using inhibitors, such as EphA4-Fc, may be a novel method to prevent tissue injury in acute inflammation by influencing endothelial integrity and by controlling vascular leak. PMID- 26771936 TI - OXYGEN MITIGATES THE INFLAMMATORY RESPONSE IN A MODEL OF HEMORRHAGE AND ZYMOSAN INDUCED INFLAMMATION. AB - Sequential insults (hits) may change the inflammatory reaction that develops in response to separate single hits (e.g., injury, infection); however, their effects on the long-term clinical outcome are still only partially elucidated. Double-hit models are typically severe and fatal. We characterized in C57BL/6 mice a moderate double-hit model of hemorrhage (35%-40% of total blood volume) and resuscitation, followed by peritoneal injection of zymosan A that induced local and systemic inflammation with 58% mortality. This model allowed exploration of the inflammatory response over time in the surviving mice. We show that after 2 days, mice subjected to the double-hit model had elevated proinflammatory systemic and local peritoneal cytokine response (interleukin [IL] 1beta, tumor necrosis factor-alpha, IL-6) and moderately elevated anti inflammatory cytokines (IL-10, transforming growth factor-beta), compared with the single-hit and sham mice. However, this dynamically changed, and by day 7, proinflammatory cytokines were reduced, and anti-inflammatory cytokines were markedly (P < 0.05) elevated in the double-hit group. Mice in the double-hit group that inhaled 100% oxygen intermittently for 6 h every day exhibited markedly reduced serum proinflammatory cytokines as early as day 2 (P < 0.05), inhibited macrophage infiltration into the peritoneum (by 13-fold; P < 0.05), and substantially increased survival rates of 85% (P = 0.00144). Oxygen mitigates the inflammatory response and exerts a beneficial effect on survival in a double-hit model of hemorrhage and zymosan-induced inflammation. PMID- 26771937 TI - Adapting High-Resolution Respirometry to Glucose-Limited Steady State Mycelium of the Filamentous Fungus Penicillium ochrochloron: Method Development and Standardisation. AB - Fungal electron transport systems (ETS) are branched, involving alternative NADH dehydrogenases and an alternative terminal oxidase. These alternative respiratory enzymes were reported to play a role in pathogenesis, production of antibiotics and excretion of organic acids. The activity of these alternative respiratory enzymes strongly depends on environmental conditions. Functional analysis of fungal ETS under highly standardised conditions for cultivation, sample processing and respirometric assay are still lacking. We developed a highly standardised protocol to explore in vivo the ETS-and in particular the alternative oxidase-in Penicillium ochrochloron. This included cultivation in glucose-limited chemostat (to achieve a defined and reproducible physiological state), direct transfer without any manipulation of a broth sample to the respirometer (to maintain the physiological state in the respirometer as close as possible to that in the chemostat), and high-resolution respirometry (small sample volume and high measuring accuracy). This protocol was aimed at avoiding any changes in the physiological phenotype due to the high phenotypic plasticity of filamentous fungi. A stable oxygen consumption (< 5% change in 20 minutes) was only possible with glucose limited chemostat mycelium and a direct transfer of a broth sample into the respirometer. Steady state respiration was 29% below its maximum respiratory capacity. Additionally to a rotenone-sensitive complex I and most probably a functioning complex III, the ETS of P. ochrochloron also contained a cyanide-sensitive terminal oxidase (complex IV). Activity of alternative oxidase was present constitutively. The degree of inhibition strongly depended on the sequence of inhibitor addition. This suggested, as postulated for plants, that the alternative terminal oxidase was in dynamic equilibrium with complex IV-independent of the rate of electron flux. This means that the onset of activity does not depend on a complete saturation or inhibition of the cytochrome pathway. PMID- 26771939 TI - Annual trends in occurrence of submicron particles in ambient air and health risk posed by particle bound metals. AB - Risk analysis is highly important in toxicology and public health studies. Health risk related to exposure to toxic metals of PM1 was assessed. Concentrations of 13 heavy metals, adsorbed to submicron particulate matter PM1 were experimentally examined but only 12 metals were found at detectable levels inside IIT Kanpur campus in 2008-2009 for all months excluding June and October. A total of 90 samples collected for 8 h sampling time by a single stage round nozzle, grease impaction substrate based impactor type PM1 sampler were analysed by ICP-OES (Inductively Coupled Plasma Optical Emission Spectrometry). Results showed daily average PM1 concentration is 102.46 +/- 35.9 MUg/m(3) and metal concentration followed the trend: Ca > Fe > Mg > Zn > Pb > Cu > Cr > Ni > Se > Cd > V > As. Contamination level assessment using geo-accumulation index showed Ca, Fe and Mg exhibited non contamination whereas metals like Cr, Zn, As, Cd, Pb, Se, Ni and Cu exhibited ranges from moderate to extreme contamination. Ingestion is found to be the major exposure pathway for heavy metals. Non-carcinogenic health risk assessment for Pb, Cd and Cr (HI > 1) signified strong chances of adverse impact on children whereas adults are well under safe limit. Cancer Risk for adults and children followed the same decreasing order, Cr(VI)>Cd > Ni > As > Pb. It was found to be higher than permissible limits (10(-6)) for adults and children both. PMID- 26771938 TI - AXIN2 expression predicts prostate cancer recurrence and regulates invasion and tumor growth. AB - BACKGROUND: Treatment of prostate cancer (PCa) may be improved by identifying biological mechanisms of tumor growth that directly impact clinical disease progression. We investigated whether genes associated with a highly tumorigenic, drug resistant, progenitor phenotype impact PCa biology and recurrence. METHODS: Radical prostatectomy (RP) specimens (+/-disease recurrence, N = 276) were analyzed by qRT-PCR to quantify expression of genes associated with self-renewal, drug resistance, and tumorigenicity in prior studies. Associations between gene expression and PCa recurrence were confirmed by bootstrap internal validation and by external validation in independent cohorts (total N = 675) and in silico. siRNA knockdown and lentiviral overexpression were used to determine the effect of gene expression on PCa invasion, proliferation, and tumor growth. RESULTS: Four candidate genes were differentially expressed in PCa recurrence. Of these, low AXIN2 expression was internally validated in the discovery cohort. Validation in external cohorts and in silico demonstrated that low AXIN2 was independently associated with more aggressive PCa, biochemical recurrence, and metastasis-free survival after RP. Functionally, siRNA-mediated depletion of AXIN2 significantly increased invasiveness, proliferation, and tumor growth. Conversely, ectopic overexpression of AXIN2 significantly reduced invasiveness, proliferation, and tumor growth. CONCLUSIONS: Low AXIN2 expression was associated with PCa recurrence after RP in our test population as well as in external validation cohorts, and its expression levels in PCa cells significantly impacted invasiveness, proliferation, and tumor growth. Given these novel roles, further study of AXIN2 in PCa may yield promising new predictive and therapeutic strategies. PMID- 26771940 TI - Team-Based Learning for Nursing and Medical Students: Focus Group Results From an Interprofessional Education Project. AB - Past research indicates that inadequacies in health care delivery create substantial preventable quality issues that can be addressed through improving relationships among clinicians to decrease the negative effects on patient outcomes. The purpose of this article is to describe the implementation of an interprofessional education project with senior nursing and third-year medical students working in teams in a clinical setting. Results include data from focus groups conducted at the conclusion of the project. PMID- 26771941 TI - Implementation of a State Legislative Fellowship for Doctor of Nursing Practice Students. AB - Doctor of Nursing Practice (DNP) students need to be effective health policy leaders and contribute their expertise to legislative discussions. Nursing faculty have unique opportunities to prepare future DNP health policy leaders through legislative experiential learning opportunities. Yet, the creation of legislative fellowships can seem challenging. This article describes a state legislative fellowship based on Kolb's experiential learning theory and explores ways faculty can support DNP student preparation. PMID- 26771942 TI - Collaborative Testing as NCLEX Enrichment. PMID- 26771943 TI - Nursing Examinations: Promotion of Integrity and Prevention of Cheating. AB - Academic integrity is a concern in higher education. The authors describe the findings of a nursing faculty task force developed with the goal of reducing incidents of cheating on classroom examinations in a school of nursing. Following a review of the literature, a modified Delphi technique was used to prioritize the suggested strategies into recommendations for faculty to follow. The findings and recommendations from the task force are presented and serve as a guide for nursing faculty in implementing measures to promote academic integrity during classroom examinations. PMID- 26771944 TI - Survey of Nursing Faculty Preparation for Teaching About Autism Spectrum Disorders. AB - The prevalence of autism spectrum disorders (ASDs) has increased significantly in children and adults. Nursing faculty's ability to teach students about best practices in their care across the lifespan is important. This study explored nurse educators' perceived knowledge of, and levels of comfort in, their abilities to teach nursing students about nursing care of people with ASD. Strategies are proposed to incorporate competencies for care of people with ASD into nursing curricula. PMID- 26771945 TI - Chronic mild stress influences nerve growth factor through a matrix metalloproteinase-dependent mechanism. AB - Stress is generally a beneficial experience that motivates an organism to action to overcome the stressful challenge. In particular situations, when stress becomes chronic might be harmful and devastating. The hypothalamus is a critical coordinator of stress and the metabolic response; therefore, disruptions in this structure may be a significant cause of the hormonal and metabolic disturbances observed in depression. Chronic stress induces adverse changes in the morphology of neural cells that are often associated with a deficiency of neurotrophic factors (NTFs); additionally, many studies indicate that insufficient NTF synthesis may participate in the pathogenesis of depression. The aim of the present study was to determine the expression of the nerve growth factor (NGF) in the hypothalamus of male rats subjected to chronic mild stress (CMS) or to prenatal stress (PS) and to PS in combination with an acute stress event (AS). It has been found that chronic mild stress, but not prenatal stress, acute stress or a combination of PS with AS, decreased the concentration of the mature form of NGF (m-NGF) in the rat hypothalamus. A discrepancy between an increase in the Ngf mRNA and a decrease in the m-NGF levels suggested that chronic mild stress inhibited NGF maturation or enhanced the degradation of this factor. We have shown that NGF degradation in the hypothalamus of rats subjected to chronic mild stress is matrix metalloproteinase-dependent and related to an increase in the active forms of some metalloproteinases (MMP), including MMP2, MMP3, MMP9 and MMP13, while the NGF maturation process does not seem to be changed. We suggested that activated MMP2 and MMP9 potently cleave the mature but not the pro- form of NGF into biologically inactive products, which is the reason for m-NGF decomposition. In turn, the enhanced expression of Ngf in the hypothalamus of these rats is an attempt to overcome the reduced levels of m-NGF. Additionally, the decreased level of m-NGF together with the increased level of pro-NGF can decrease TrkA-mediated neuronal survival signalling and enhance the action of pro NGF on the p75(NTR) receptor, respectively, to evoke pro-apoptotic signalling. This hypothesis is supported by elevated levels of the caspase-3 mRNA in the hypothalamus of rats subjected to chronic mild stress. PMID- 26771946 TI - Oxytocin modulates behavioral and physiological responses to a stressor in marmoset monkeys. AB - Social isolation is a major source of stress and can lead to activation of the hypothalamic-pituitary-adrenal (HPA) axis. The presence of a close social partner can reduce the magnitude of the HPA-axis response during a stressor, a phenomenon known as social buffering. The oxytocin (OXT) system has been identified as one candidate for mediating social buffering due to its role in the facilitation of social bonding and the expression of prosocial behavior. The goal of the present study was to determine whether the OXT system contributes to social buffering of HPA-axis activity in response to stressor exposure in marmoset monkeys (Callithrix jacchus). Male and female marmosets experienced a standardized psychogenic stressor with and without their long-term mate under OXT-treatments (Pro(8)-OXT, Leu(8)-OXT, OXT antagonist, and saline); we assessed HPA-axis activity by measuring urinary cortisol across the stressor. We found that blocking, but not augmenting, the OXT system altered patterns of cortisol and proximity behavior in response to a stressor. We demonstrated that (1) the presence of a mate during a stressor significantly attenuated HPA-axis activity in female, but not male, marmosets; (2) male, but not female, marmosets treated with an OXT antagonist had significantly higher HPA-axis activity across the stressor than when they were treated with saline, suggesting that the OXT system may reduce the stressor-induced rise in cortisol levels; (3) male and female marmosets treated with an OXT antagonist spent significantly less time in close proximity to their mate during the first 30 min of the stressor than when they were treated with saline, suggesting that the OXT system may be important for the expression of partner-seeking behavior during a stressor. Thus, the OXT system and social context differentially influenced how the HPA-axis responded to a stressor in male and female marmosets, and may modulate HPA-axis activity by promoting the expression of proximity behavior with a close social partner. PMID- 26771948 TI - Abnormal default-mode network homogeneity and its correlations with personality in drug-naive somatization disorder at rest. AB - BACKGROUND: While the default-mode network (DMN) appears to play a crucial role in patients suffering from somatization disorder (SD), the abnormalities of the network homogeneity (NH) of the DMN in SD patients have been poorly explored. The aim of this study is to examine DMN NH using an NH approach in patients suffering from SD at rest and determine its correlations with personality as measured by the Eysenck Personality Questionnaire (EPQ). METHODS: A total of 25 drug-naive patients with SD and 28 sex-, age-, and education-matched healthy controls underwent functional magnetic resonance imaging scans at rest. The data were analyzed by an automated NH method. RESULTS: Patients showed increased NH in the left superior frontal gyrus and decreased NH in the bilateral precuneus. Moreover, a significantly negative correlation was observed between the NH values in the bilateral precuneus and the EPQ--Neuroticism scores. LIMITATIONS: The present study should be considered preliminary due to a lenient, uncorrected threshold of p<0.01. CONCLUSIONS: The results suggest that abnormal DMN NH exists in drug-naive SD and further highlight the importance of the DMN in the pathophysiology of SD. PMID- 26771949 TI - Substance use is a risk factor for violent behavior in male patients with bipolar disorder. AB - BACKGROUND: To determine the factors involved in violent behavior in patients with bipolar disorder (BD) and to investigate the relationship between violence and substance use disorder (SUD). METHODS: A sample of 100 male inpatients diagnosed with BD type I who were experiencing a current mood episode participated in the study. Violent behavior was defined as physical aggression against others. All patients were evaluated using the Young Mania Rating Scale (YMRS), Hamilton Depression Rating Scale (HDRS), Positive and Negative Syndrome Scale-positive subscale (PANSS-p), Barratt Impulsivity Scale-11 (BIS-11), Buss Perry Aggression Questionnaire (BPAQ) and Overt Aggression Scale (OAS). Lifetime SUD and current use of substances were evaluated. Logistic regression analysis was conducted to predict violent behavior. RESULTS: Current substance use (CSU) rather than lifetime SUD was found to be related to violent behavior in patients with BD, and CSU was associated with a threefold increase in the risk of violence. The rate of lifetime SUD in our sample was 59%, and the rate of CSU was 39%. The most commonly abused substances were cannabis and alcohol, followed by synthetic cannabinoids, in both groups of patients with lifetime SUD and CSU. Individuals abusing any substance were more likely to have a criminal record and history of incarceration than other patients. One of the most significant risk factors for violence was a previous history of violent behavior. LIMITATIONS: The sample was limited to male patients. Data on some participants' recent substance use from standard urine analysis was not obtained. The data on the use of synthetic cannabinoids was obtained from patients and their families owing to the lack of equipment for detecting synthetic cannabinoids using laboratory analysis. CONCLUSIONS: CSU appears to be a significant predictive factor in violent behavior in male patients. Further investigation of co-occurrence of violence with CSU and improvement in treatment strategies might reduce or prevent violence in patients with BD. PMID- 26771950 TI - Dietary magnesium intake and the incidence of depression: A 20-year follow-up study. AB - BACKGROUND: Depression is a major global public health concern. The aetiology of depression is partly unclear; however, intake of nutrients, such as magnesium, have been suggested to affect depressive symptoms and modify depression risk. METHODS: This research is a part of the Kuopio Ischemic Heart Disease Risk Factor (KIHD) Study, conducted on a sample of 2320 Eastern Finnish men aged 42-61 years old at the baseline. Magnesium intake was assessed by a 4-day food record. Hospital discharge diagnosis of unipolar depressive disorder was used as an outcome variable. RESULTS: Participants in the middle tertile of dietary magnesium intake had a statistically significantly decreased risk of getting a hospital discharge diagnosis of depression compared to participants in the lowest tertile of magnesium intake (HR 0.49, CI 0.25-0.95, P=0.035) in the prospective setting after multivariable adjustments. In addition, an inverse association between magnesium intake and the risk of depression was found when the combined middle and highest tertiles of magnesium intake were compared with the lowest tertile (HR 0.53, CI 0.29-0.95, P=0.033). LIMITATIONS: Our findings may not be generalizable to individuals below middle-age or women. Moreover, we were unable to consider cases with mild depression in the longitudinal setting. CONCLUSIONS: The results of this study suggest that magnesium intake may have an effect on the risk to develop depression. Further studies are needed to investigate whether sufficient magnesium intake could have implications for prevention or treatment of depression. PMID- 26771951 TI - Iron replacement therapy: do we need new guidelines? AB - PURPOSE OF REVIEW: Approximately, one-third of the world's population suffers from anemia, and at least half of these cases are because of iron deficiency. With the introduction of new intravenous iron preparations over the last decade, uncertainty has arisen when these compounds should be administered and under which circumstances oral therapy is still an appropriate and effective treatment. RECENT FINDINGS: Numerous guidelines are available, but none go into detail about therapeutic start and end points or how iron-deficiency anemia should be best treated depending on the underlying cause of iron deficiency or in regard to concomitant underlying or additional diseases. SUMMARY: The study points to major issues to be considered in revisions of future guidelines for the true optimal iron replacement therapy, including how to assess the need for treatment, when to start and when to stop treatment, when to follow-up for relapse, which dosage and type of therapy should be recommended or not recommended, and if some patients should not be treated. PMID- 26771947 TI - Changes in causal attributions and relationship representations: Are they specific or common mechanisms in the treatment of depression? AB - BACKGROUND: The goal of the study was to examine two central theory-driven mechanisms of change, causal attributions and relational representations, to account for symptomatic improvement in psychodynamic treatment and supportive clinical management, combined with either pharmacotherapy or placebo, in a randomized control trial (RCT) for depression. METHOD: We used data from an RCT for depression, which reported non-significant differences in outcome among patients (N=149) who received supportive-expressive psychotherapy (SET), clinical management combined with pharmacotherapy (CM+MED), or clinical management with placebo pill (CM+PBO) (Barber et al., 2012). Mechanism and outcome measures were administered at intake, mid-treatment, end of treatment, and at a 4-month follow up. RESULTS: Improvements in causal attributions and in relational representations were found across treatments. Changes in causal attributions did not predict subsequent symptomatic level when controlling for prior symptomatic level. In contrast, decrease in negative relational representations predicted subsequent symptom reduction across all treatments, and increase in positive relational representations predicted subsequent symptom reduction only in SET. LIMITATIONS: The study is limited by its moderate sample size. Additional studies are needed to examine the same questions using additional treatment orientations, such as cognitive treatments. CONCLUSIONS: Findings demonstrate that changes in negative relational representations may act as a common mechanism of change and precede symptom reduction across psychodynamic therapy and supportive case management combined with either pharmacotherapy or placebo, whereas an increase in positive relational representation may be a mechanism of change specific to psychodynamic therapy. PMID- 26771954 TI - Editorial. PMID- 26771957 TI - Bloodless cardiac surgery: a strategy for few or the future standard of care? PMID- 26771955 TI - Munc18-2 is required for Syntaxin 11 Localization on the Plasma Membrane in Cytotoxic T-Lymphocytes. AB - Cytotoxic T-lymphocytes (CTL) kill their targets by cytolytic granule secretion at the immunological synapse. The Sec/Munc protein, Munc18-2, and its binding partner Syntaxin 11 (STX11) are both required for granule secretion, with mutations in either leading to the primary immunodeficiency, Familial Haemophagocytic Lymphohistiocytosis (FHL4 and 5). Understanding how Munc18-2 and STX11 function in CTL has been hampered by not knowing the endogenous localization of these proteins. Using a novel FHL5 Munc18-2 mutation that results in loss of protein, cytotoxicity and degranulation together with CTL from an FHL4 patient lacking STX11, enabled us to localize endogenous STX11 and Munc18-2 in CTL. Munc18-2 localized predominantly to cytolytic granules with low levels associated with the plasma membrane where STX11 localized. Importantly, while Munc18-2 localization is unaffected by the absence of STX11 in FHL4 CTL, STX11 is lost from the plasma membrane in FHL5 CTL lacking Munc18-2. These findings support a role for Munc18-2 in chaperoning STX11 to the plasma membrane where the final fusion events involved in secretion occur. PMID- 26771958 TI - Making good policy decisions: a discipline we cannot afford to ignore. PMID- 26771959 TI - TRANSFUSION MEDICINE ILLUSTRATED. Heparin-induced thrombocytopenia: a cautionary tale. PMID- 26771961 TI - Erratum. PMID- 26771962 TI - Correction: Singlet lifetime measurements in an all-proton chemically equivalent spin system by hyperpolarization and weak spin lock transfers. AB - Correction for 'Singlet lifetime measurements in an all-proton chemically equivalent spin system by hyperpolarization and weak spin lock transfers' by Y. Zhang et al., Phys. Chem. Chem. Phys., 2015, 17, 24370-24375. PMID- 26771963 TI - PUFAs: Structures, Metabolism and Functions. AB - Polyunsaturated fatty acids (PUFAs) include two series of fatty acids: omega-6 and omega-3 series. PUFAs have amphiphatic properties: hydrophilic head and hydrophobic tail. Such structure and other properties of unsaturated fatty acids are responsible for exerting the following biological action: maintaining cell membrane fluidity, inhib- iting inflammatory processes, decreasing secretion of proinflammatory cytokines by monocytes/macrophages, decreasing susceptibility to ventricular rhythm disorders of the heart, improving functions of vascular endothe- lial cells, inhibiting blood platelet aggregation and decreasing triglyceride synthesis in the liver. In an organism, aracidonic acid (ARA) is converted to prostanoids series 2 (PGE2, PGI2, TXA2) and leukotrienes series 4 (LTB4, LTC4, LTD4) which are endowed with pro-inflammatory potential and are able to induce platelet aggregation and vasoconstriction. The metabolism of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) gives prostanoids series 3 (PGE3, PGI3, TXA3) and leukotrienes series 5 (LTB5, LTC5, LTD5); this group of eicosanoids shows anti-inflammatory, antiplatelet and antiarrhythmic properties. PMID- 26771964 TI - Orbital Opening Shape and Its Alphanumerical Classification. AB - BACKGROUND: Orbit is the one of the most complicated areas of the facial part of cranium. The anthropological analysis of the orbits comprises basic measurement characterizing their shape: width and height. Classic anthropometric methods used to measure the skull variability are burdened with mistakes resulting from construction of measuring devices as well as from researcher's experience. OBJECTIVES: The purpose of our research was to introduce a metric classification of the orbital opening. MATERIAL AND METHODS: The study was carried out on 184 skulls. In our study we suggest introducing a classification of the orbital opening shape by calculating a functional for the 15 categories of the orbit shape. Shape categories have been arranged following the increasing value of the functionals. Each shape category of the orbital opening, according to the Piasecki's descriptive classification, was assigned a letter from the alphabet. RESULTS: We have observed a greater number of symmetrical skulls in the female group (29.11%) than in the male (23.81%). In both groups the symmetry type AA was the most frequent, it corresponds to the value of functional comprised in the interval from 0 to 1,30. According to the Piasecki's descriptive classification it was the oval elongated type. CONCLUSIONS: Our alphanumerical classification based on the value of functional and on the orbit outline assigned to the value is an objective and useful method of the orbital opening shape analysis. PMID- 26771965 TI - Comparison of TaqMan Real-Time and Tetra-Primer ARMS PCR Techniques for Genotyping of Rs 8066560 Variant in Children and Adolescents with Metabolic Syndrome. AB - BACKGROUND: Single nucleotide polymorphisms (SNPs) are major contributors to susceptibility or resistance to various human diseases. Metabolic syndrome (MetS) is a collection of risk factors, including abdominal obesity, dyslipidemia and increased blood pressure. MetS is more common among Iranian children and adolescents in comparison to other ethnicities. Sterol regulatory element binding factors (SREBFs) involve in the regulation of carbohydrate and lipid metabolism. The tetra-primer amplification refractory mutation system PCR (tetra-primer ARMS PCR/T-ARMS-PCR) is a fast and economical means of assaying SNPs, requiring only PCR amplification and subsequent electrophoresis for the determination of genotypes. OBJECTIVES: This study aims to optimize and compare the results of tetra-primer ARMS-PCR for genotyping of rs8066560 in Iranian children and adolescents being afflicted with metabolic syndrome with the TaqMan assay. MATERIAL AND METHODS: In this study, a total of 50 individuals with 9-19 years of age, including 25 healthy subjects and 25 MetS cases were studied. The tetra primer ARMS-PCR was used to genotype the rs8066560. RESULTS: After PCR optimization, we could successfully detect the rs8066560 polymorphism in all the studied subjects. Furthermore, we observed complete concordance between tetra primer ARMS-PCR assay and TaqMan method's results. CONCLUSIONS: Tetra-primer ARMS PCR can be utilized as a cost-effective, rapid and reproducible method for SNP genotyping especially while performing large-scale epidemiological/association at studies. PMID- 26771966 TI - The Analgesic, Anti-Inflammatory and Anti-Pyretic Activities of Tinospora cordifolia. AB - BACKGROUND: Tinospora cordifolia (T. cordifolia) is a valuable resource due to its traditional uses in the treatment of pain, fever and inflammation, but no sufficient scientific literature is available online to confirm its traditional uses in these ailments. OBJECTIVES: This study was carried out to validate the traditional uses of T. cordifolia in treating pain, inflammation and pyrexia, using albino mice as an experimental animal model. MATERIAL AND METHODS: The analgesic effects of T. cordifolia extract were assessed by using the acetic acid induced writhing test, hot plate test and tail-flick test. The carrageenan test was performed to assess anti-inflammatory potential, and anti-pyretic activity was evaluated by the brewer's yeast-induced pyrexia method. RESULTS: The results showed that the T. cordifolia extract exhibited significant analgesic effects in a dose-dependent manner in the three pain models tested. The extract also exhibited significant anti-inflammatory effects in the carrageenan-induced inflammation test and antipyretic effects in the brewer's yeast-induced pyrexia test in dose-dependent manner compared to the effects observed in the control group animals. CONCLUSIONS: From the findings of the present study, it can be concluded that T. cordifolia extract has strong analgesic, anti-inflammatory and anti-pyretic effects. Further studies are required to investigate the therapeutic activities of the phytochemical constituents of T. cordifolia against pain, inflammation and pyrexia. PMID- 26771967 TI - Prognostic Implications of Discordant Results of Myocardial Perfusion Single Photon Emission Computed Tomography and Exercise ECG Test in Patients with Stable Angina. AB - BACKGROUND: ECG exercise treadmill test (ExT) and myocardial perfusion SPECT (single photon emission computed tomography) study are widely used for the non invasive evaluation of patients with coronary artery disease (CAD). OBJECTIVES: To assess long-term prognosis in patients with suspected or known coronary artery disease (CAD), in whom ECG exercise treadmill test (ExT) and myocardial perfusion single photon emission computed tomography (SPECT) provided discordant results are lacking. MATERIAL AND METHODS: Four hundred eighty three patients with suspected or known stable CAD underwent 99mTc-methoxyisobutylisonitrile SPECT and ExT. SPECT was considered positive (+) if inducible or mixed perfusion defects were detected. ExT was evaluated using widely accepted criteria. Based on the results of both examinations the patients were divided into 4 subgroups: group 1 SPECT (+) and ExT (+), group 2 - SPECT (+) and ExT (-), group 3 - SPECT (-) and ExT (+), group 4 - SPECT (-) and ExT (-). RESULTS: After a mean follow-up of 59 +/- 7 months, major cardiac events (cardiac death and nonfatal myocardial infarction combined) and revascularizations were more prevalent in groups 1 and 2 than in groups 3 and 4. However, the statistical significance (p <= 0.01) was reached only for the following differences: in major cardiac events - group 1 vs group 3 and group 1 vs group 4; in revascularizations - group 1 vs. group 3, group 1 vs. group 4 and group 2 vs group 4 and in cardiac hospitalizations - group 1 vs. group 4 and group 2 vs. group 4. CONCLUSIONS: Positive myocardial perfusion SPECT result is associated with similar clinical outcome irrespectively of ExT result in long-term follow-up. PMID- 26771968 TI - The Effects of Cigarette Smoking on the Tp-e Interval, Tp-e/QT Ratio and Tp-e/QTc Ratio. AB - BACKGROUND: Cigarette smoking increases the risk of sudden cardiac death. Smoking may predispose individuals to ventricular fibrillation and sudden cardiac death by altering ventricular repolarization and stimulating sympathetic nervous system activity. OBJECTIVES: The aim of the study was to investigate the instantaneous effects of smoking on ventricular repolarization. MATERIAL AND METHODS: The study included 47 healthy subjects; 24 long-term heavy smokers (10 women, mean age: 40 +/- 5 years) constituted the study group, and 23 non-smokers (10 women, mean age: 42 +/- 10 years) constituted the control group. ECGs were performed on all the subjects. The Tp-e interval, Tp-e/QT ratio and Tp-e/QTc ratio were measured and compared between the groups. RESULTS: There were no significant differences between smokers and nonsmokers in the basic clinical and echocardiographic variables (p > 0.05). The QT interval and QTc interval were similar in both groups. The Tp-e interval (p = 0.02) and Tpe/QT ratio (p = 0.001) were higher in the heavy smokers than in the non-smokers. The Tpe/QTc ratio (p = 0.001) was also higher in the smokers. Other ECG parameters were similar between the smokers and nonsmokers. CONCLUSIONS: The results show that chronic cigarette smoking is associated with a prolonged Tp-e interval, increased Tp-e/QT ratio and Tp-e/QTc ratio. These observations may indicate that there may be a relationship between smoking and altered ventricular repolarization. Abnormal ventricular repolarization values on an ECG may explain the increased cardiovascular event risk in long-term heavy cigarette smokers. PMID- 26771969 TI - Prolonged CRP Increase After Percutaneous Coronary Intervention Is Associated with High Thrombin Concentrations and Low Platelet' Response to Clopidogrel in Patients with Stable Angina. AB - BACKGROUND: Inflammation is involved in all stages of development of atherosclerotic plaques. Currently, percutaneous coronary intervention (PCI) is a widely used method of treatment of coronary artery disease (CAD) when combined with optimal medical therapy (OMT). However, there is still controversy over invasive versus optimal pharmacological treatment in stable CAD (SCAD). Systemic inflammatory response triggered by PCI may limit its effectiveness in patients with SCAD. OBJECTIVES: We aimed to evaluate plasma CRP and its relation to thrombin generation and platelet reactivity both early after the procedure and in a one-month observation following successful PCI with stent implantation, in patients with SCAD and OMT, including statins. MATERIAL AND METHODS: We conducted a prospective study, in which CRP, platelet activation, thrombin generation and time course of prothrombin activation were determined at baseline, 3-5 days and 30 days after successful PCI with stent implantation, in 50 consecutive patients with SCAD, on chronic statin therapy. RESULTS: Early after PCI CRP increased by 176% as compared with baseline (p < 0.001) and one-month after angioplasty CRP was still 54% higher than before the procedure (p = 0.002). In multivariate model prolonged increase in CRP 1 month after PCI was independently associated with P2Y12-reactivity index (PRI) (p = 0.04) and maximum concentration of thrombin (p = 0.003), both measured 30 days after the procedure. CONCLUSIONS: Post-procedural CRP increase, which persists at least one month in patients with SCAD, after elective PCI with stent implantation, is one of the main finding of our study. We demonstrated the relationship between prolonged post-PCI inflammatory reaction, reflected by elevated CRP, and increased thrombin generation and low platelets' response to clopidogrel, which may account for limited benefits of PCI in stable coronary patients. It may be advisable to assay post-procedural CRP in each patient with SCAD, who underwent PCI to predict those, with potentially low response to clopidogrel. PMID- 26771971 TI - Effects of Rivaroxaban Therapy on ROTEM Coagulation Parameters in Patients with Venous Thromboembolism. AB - BACKGROUND: Rivaroxaban (Xarelto) does not require routine coagulation monitoring; however, in certain clinical situations (overdose, drug accumulation, urgent surgery) measurement of its plasma concentration is highly recommended. Currently, there is no single hemostasis test that shows a direct correlation between rivaroxaban plasma levels and anticoagulant efficacy. OBJECTIVES: This study was intended to assess the value of ROTEM in determining rivaroxaban administration. MATERIAL AND METHODS: Thirteen patients with venous thromboembolism and 13 healthy volunteers were compared with regard to certain ROTEM parameters and anti-FXa activity. The tests were done before the administration of 20 mg rivaroxaban (i.e. 24 h after previous administration) and 2.5 h afterwards. RESULTS: The study group demonstrated residual activity of rivaroxaban in plasma (20 +/- 11.3 ng/mL) 24 h following the previous administration, which did not cause marked changes in clotting assays compared to controls. In the group, 2.5 h after rivaroxaban administration, prolongation of PT (PTratio 1.51 +/- 0.22), APTT (APPTratio: 1.30 +/- 0.14) and ROTEM CT (CTratio - EXTEM: 2.45 +/- 1.06, CTratio - INTEM: 1.32 +/- 0.21) were observed. The cut off values for particular tests were created to determine if the patient had achieved desirable anticoagulant effect after rivaroxaban administration. The mean anti-FXa values were significantly lower in patients before rivaroxaban dosing than after. CONCLUSIONS: PT demonstrated better diagnostic value than APTT in rivaroxaban administration. The ROTEM clotting time (CT) according to EXTEM may be used to determine the anticoagulation effect of rivaroxaban, but is not sensitive enough to measure the residual activity of this drug. PMID- 26771970 TI - Expression of Proinflammatory Factors, Proangiogenic Factors and Endostatin in Patients with Heart Failure and Different Grades of Collateral Circulation Development. AB - BACKGROUND: The process of collateral vessel maturation is stimulated by numerous factors affecting the endothelium and smooth muscle cells building the vessel wall. Looking for arteriogenesis stimulating factors means looking for a potential innovative heart failure treatment method in the patients unresponsive to traditional therapies. OBJECTIVES: The purpose of this study was to assess the changes in serum concentrations of pro-inflammatory factor IL-6, growth factors FGF (FGFa, FGFb, FGFbH), HGF, VEGF and endostatin in heart failure patients in relation to the coronary collaterals development stage. MATERIAL AND METHODS: This study included 22 patients with chronic heart failure NYHA II or III (mean age 62.5 +/- 11.6 years) and 8 control patients (mean age 58.4 +/- 10.7 years). Coronary angiography was performed and the presence and grade of collateral circulation was assessed by a four-level scale proposed by Rentrop and Cohen. The level of the studied factors was determined in the blood samples collected during the angiographic procedure. RESULTS: The concentration of IL-6 was significantly higher in the heart failure patients than in the control group (p < 0.001) and in NYHA III vs. NYHA II patients (p < 0.02). Patients with heart failure and collaterals grade 1 or 2 exhibited higher serum concentrations of FGFbH (from p < 0.03 to p < 0.01). The serum VEGF level in NYHA III patients was significantly higher than in NYHA II individuals (from p < 0.03 to p < 0.01). CONCLUSIONS: Higher levels of IL-6 and FGFbH were observed in patients with heart failure. Collaterals formation seems to be associated with the activation of pro inflammatory factors, growth factors and endostatin. PMID- 26771972 TI - Acquired von Willebrand Syndrome During the Course of Myelofibrosis: Analysis of 32 Cases. AB - BACKGROUND: Identification of patients with myelofibrosis being at increased risk of acquired von Willebrand syndrome (avWS) would likely facilitate individualization of treatment and improve its outcomes. OBJECTIVES: To determine the prevalence of avWS in patients with myelofibrosis, and to verify if individuals with and without this bleeding disorder differ in terms of their baseline clinical parameters. MATERIAL AND METHODS: The study included 32 consecutive patients with myelofibrosis. avWS was diagnosed on the basis of abnormally low levels of von Willebrand factor and other routine tests. Patients with and without concomitant avWS were compared in terms of their demographic characteristics, present and past medical histories and laboratory parameters. RESULTS: Concomitant avWS was found in 5 patients (15.6%). In 1/5 patients with avWS and in 8/27 persons without this bleeding disorder, myelofibrosis developed secondarily to polycythemia vera (n = 7) or essential thrombocytopenia (n = 2). As many as 4/5 individuals with avWS presented with clinical evidence of a bleeding disorder. The subjects with avWS differed from the remaining patients with myelofibrosis in terms of significantly lower activity of von Willebrand factor (vWF) and lower vWF to vWF antigen ratio. CONCLUSIONS: All patients with myelofibrosis should be routinely evaluated for avWS with the panel of specific tests. Further, avWS should be the primary suspicion in each patient with myelofibrosis in whom clinical evidence of a bleeding disorder has emerged. PMID- 26771973 TI - Risk Factors of Parathyroid Dysfunction in Elderly Patients with Chronic Kidney Disease Undergoing Hemodialysis. AB - BACKGROUND: Aberrant mineral metabolism and bone diseases, which are commonly seen in chronic kidney disease (CKD), have been considered to be the important causes of morbidity and decreased quality of life. OBJECTIVES: We aimed to investigate the characteristics of calcium-phosphorus metabolism abnormalities and parathyroid dysfunction in elderly patients with chronic kidney disease undergoing hemodialysis. MATERIAL AND METHODS: A total of 336 patients undergoing maintenance hemodialysis were divided into two age groups: elderly (>= 65 years) and non-elderly (< 65 years). Before dialysis, fasting blood samples were initially collected, then hemoglobin (Hb), serum creatinine (Scr), blood urea nitrogen (BUN), calcium, phosphorus, intact parathyroid hormone (iPTH), high sensitivity C-reactive protein (HsCRP) and albumin (Alb) were measured. Serums BUN, ultrafiltration volume, dialysis duration and body weight were measured after dialysis. Finally, well-established formulas were used to obtain the serum albumin corrected calcium (Ac-Ca) and urea removal index (Kt/V). RESULTS: Elderly patients accounted for 52.7% of our patients; essential hypertension accounted for 35.6% of the cause for chronic renal failure, followed by chronic glomerulonephritis (21.5%) and diabetes mellitus (19.8%) in the elderly group; while in the non-elderly group, 43.4% of the chronic renal failure was due to chronic glomerulonephritis, followed by diabetes mellitus (23.9%) and essential hypertension (12.6%). Significant differences were found in the dialysis duration, blood pressure, concentrations of serum BUN, Scr, P, iPTH, Alb, standard-protein nitrogen present rate (nPNA) and Hs-CRP between the 2 groups. The multiple logistic regression analysis showed that age, plasma phosphorus, albumin and nPNA were independent risk factors for secondary hyperparathyroidism in patients undergoing maintenance hemodialysis. CONCLUSIONS: We conclude that most elderly patients undergoing hemodialysis experience hyperparathyroidism. The risk factors may include age and malnutrition but need further investigation. PMID- 26771974 TI - Attenuate Synovial Fluid Uncarboxylated Matrix Gla-Protein (ucMGP) Concentrations Are Linked with Radiographic Progression in Knee Psteoarthritis. AB - BACKGROUND: Decreased serum and synovial fluid (SF) uncarboxylated matrix Gla protein (ucMGP) levels have been detected in OA patients. This study was carried out to investigate the association of serum and synovial fluid (SF) ucMGP levels with radiographic severity in knee OA patients. OBJECTIVES: This study was carried out to investigate the association of serum and synovial fluid (SF) ucMGP levels with radiographic severity in knee OA patients. MATERIAL AND METHODS: One hundred sewenty eight knee OA patients and 160 healthy controls among the outpatients in our hospital were enrolled in the study. Anteroposterior knee X ray plains were taken to evaluate the radiographic severity of the affected knee. The radiographic assessment of knee OA was performed according to the Kellgren Lawrence criteria. ucMGP levels in the serum and synovial fluid were examined utilizing enzyme-linked immunosorbent assay method (ELISA). RESULTS: The mean serum ucMGP levels of the knee OA patients was significantly lower than that of healthy controls [2603 (1919~3222) nmol/LVS 2811 (1926~3619) nmol/L, p = 0.045]. Synovial fluid (r = -0.479, p = 0.05) was negatively correlated with radiographic severity. CONCLUSIONS: In conclusion, this study revealed a significant decrease in the SF ucMGP levels of OA patients and illustrated a negative correlation of SF ucMGP levels with the extent of radiographic severity in patients with knee OA. The present findings indicate that ucMGP in SF might serve as a novel biomarker for assessing OA progression. PMID- 26771975 TI - Compression Anastomosis Clips Versus a Hand-Sewn Technique for Intestinal Anastomosis in Pigs. AB - BACKGROUND: Anastomotic dehiscence and leaks are major problems in gastrointestinal surgery and result in increased morbidity and mortality. The ideal device to create anastomoses should ensure good serosal apposition without requiring either transgression of the bowel wall or the presence of foreign material for an extended period of time. OBJECTIVES: The aim of this experimental study was to evaluate the safety and efficacy of a new compression anastomosis clip (CAC) for jejunojejunostomies and ileocolostomies by comparing CAC anastomoses with hand-sewn (HS) anastomoses in pigs in terms of healing, breaking strength and the time to create anastomoses. MATERIAL AND METHODS: The 11 pigs in the study underwent side-to-side CAC and HS jejunojejunostomies and ileocolostomies, for a total of 88 anastomoses. The pigs were sacrificed on postoperative day 5 (5 pigs) or 7 (6 pigs). Macroscopic, histopathological and breaking-strength examinations were performed. The time to create the anastomoses was recorded. RESULTS: Neither group had anastomotic complications such as leakage or obstruction. Macroscopic examination showed no statistically significant differences between the groups. In the CAC group, the healing process was characterized by a lesser inflammatory reaction (p < 0.05) and very thin scar tissue at the anastomotic line (less collagen deposition and better epithelial regeneration), while the HS group had a much thicker anastomotic line. The breaking strength was significantly greater in the CAC group compared with the HS group (p < 0.05). The anastomosis time was shorter in the CAC group than in the HS group (p < 0.01). CONCLUSIONS: Anastomosis using a CAC appears to be safe and less time-consuming than HS; it was also characterized by a good healing process with little inflammatory reaction and a high breaking strength compared with HS anastomosis. PMID- 26771976 TI - Diagnostic Value of Serological Tests Against Verotoxigenic Escherichia coli in Hemolytic Uremic Syndrome in Children. AB - BACKGROUND: Diarrhea-associated hemolytic uremic syndrome (HUS D+) caused by verotoxigenic E. coli strains (VTEC) is a major cause of acute kidney injury in children between 1 and 5 years of age. Because of the short presence of VTEC in the gastrointestinal tract as well as difficulties with the detection of the verotoxigenic strain, identification of HUS etiology might be challenging. OBJECTIVES: The aim of the study was to assess the clinical and diagnostic value of serological tests for specific antibodies against verotoxigenic strains of E. coli in patients with HUS. MATERIAL AND METHODS: Eight children aged 8 months - 7.1 years (mean 40 +/- 29 months) with symptoms of acute kidney injury, hemolytic anemia and thrombocytopenia observed after hemorrhagic diarrhea were included to the study. VTEC presence was detected in a stool culture with subsequent analysis of the ability to produce verotoxin and the presence of VT1 and VT2 as well as intimin and enterohemolysin genes. In addition, the presence of specific IgA, IgM and IgG antibodies against E. coli serogroups O26, O103, O104, O111, O121, O145 and O157 was measured using ELISA. RESULTS: In 3 subjects, VTEC O26, O157 and O104 serogroups were cultured in the stool and the specific IgA, IgM and IgG antibodies were detected. In 4 subjects, no VTEC strains were cultured, however, high titers of IgA, IgM and IgG antibodies against E. coli O26, O157 and O111 were detected. In a single patient, the negative results of bacteriological and serological analyses excluded VTEC etiology of HUS. CONCLUSIONS: A serological analysis of VTEC can confirm the result of stool culture for verotoxigenic E. coli strains and help to find the cause of HUS in case of negative results of a stool culture. PMID- 26771977 TI - The Quality of Imaging of the Carotid Body by the Standard Protocol for Computed Tomography Angiography of the Carotid Arteries. AB - BACKGROUND: The clinical significance of the carotid body (CB) has been increasing. Currently, research connected with the CB is focused on establishing the significance of chronically increased activity of the CB in the progression of heart failure and in the genesis of hypertension. Moreover, it has been suggested that cardiac hypertrophy may be associated with an increase in CB volume. OBJECTIVES: The aim of study was to assess the quality of imaging the CB by following the standard protocol for computed tomography angiography (CTA) of the carotid arteries. MATERIAL AND METHODS: The analysis includes 50 consecutive CTA examinations of the carotid arteries. A retrospective assessment of the quality of imaging both the right and left CB (rCB and lCB) was carried out for all the CTA examinations of the carotid arteries. RESULTS: The rCB was exposed in 62% and the lCB in 56% of the CTA examinations. None of the CTA examinations analyzed resulted in good or very good quality visualization of the CB. Only 22% of the CTA examinations provided a medium quality rCB image. An even lower ratio of medium-quality visualizations of the lCB was noted: only 14% of the analyzed examinations. In the male sample group, the CB was exposed significantly more often than in the female group. CONCLUSIONS: The standard protocol for CTA examinations of the carotid arteries appears to be insufficient for use in assessing the CB. PMID- 26771979 TI - Analysis of Chosen Variables Psychological Determining the Occurrence of Mood Disorders After Childbirth. AB - BACKGROUND: Psychological factors are one of many that contribute to the increased risk of a psychiatric disorder's occurrence after childbirth. OBJECTIVES: The aim of this work was to determine the relation between psychological variables, such as sense of self-efficacy and dispositional optimism, and the risk of mood disorder's occurrence in women after childbirth. MATERIAL AND METHODS: Two hundred eighty five women, who gave birth in the University Hospital no. 2 in Bydgoszcz, took part in the study. To measure the risk occurrence of mood disorder symptoms after childbirth the Edinburgh Postnatal Depression Scale (EDPS) was used. Obtaining a score of 12 or more points out of 30 on the Edinburgh Postnatal Depression Scale was an indicator of mood disorders. To study psychological variables the General Self-Efficacy Scale (GSES) and Life Orientation Test (LOT-R) were used. RESULTS: Twenty three point two percent of women obtained 12 or more points in the EDPS scale. The average result in GSES scale for all women who took part in the study was 30.80 and indicated a high estimation of women's own capabilities in dealing with new situations. Obtained results indicated a surprisingly small group of women with low estimation of their own capabilities (n = 15). However, negative correlation between EDPS and GSES parameters, on a statistically significant level (p < 0.0001) was found (r = 0.27). In the course of analysis of the results concerning optimism-pessimism dimension rated with LOT-R, the average result was calculated to be 15.6. In the same group, 61 women showed pessimistic tendencies, and 23 (34.8%) suffered from mood disorders. Scores obtained in EDPS negatively correlated with the results in LOT-R (r = -0.43) and are statistically significant (p < 0.0001). CONCLUSIONS: In the first week after childbirth, one fourth of women are in danger of the occurrence of mood disorders. There is a negative correlation between the sense of self-efficacy and dispositional optimism and risk of occurrence of mood disorders after childbirth. PMID- 26771978 TI - Head Trauma in Elderly Patients: Mechanisms of Injuries and CT Findings. AB - BACKGROUND: Head injuries in elderly people are a common cause of hospitalization at emergency departments. This group of patients is at high risk of post traumatic intracranial pathology, which is diagnosed by computed tomography (CT) scanning of the head. OBJECTIVES: The aim of this study was to determine the incidence and outcomes of head trauma in older people in different scenarios, on the basis of CT scan findings. MATERIAL AND METHODS: The study involved a retrospective analysis of medical records of patients treated in the Emergency Department of Copernicus Memorial Hospital in Lodz, Poland, between the years 2010-2012. Patients above 75 years old whose diagnoses were coded with ICD-10 codes S00-S09 were included in the study. The patients' age, gender, the mechanism and cause of injury, their Glasgow Coma Scale (GCS) score at admission and the results of their head CTs were analyzed. RESULTS: A total of 301 patients were included in the analysis. Intracranial abnormalities caused by trauma were detected in 24 patients (8%). Transient loss of consciousness (TLOC) was a cause of injury in 44 patients (14.6%) and was related to an increased risk of an abnormal CT scan result (OR 4.6, 95% CI, 1.2-18.4, p < 0.003). Other mechanisms related to an increased risk of post-traumatic intracranial pathology were high energy mechanisms of injury and unexplained falls. CONCLUSIONS: Ground-level falls are the most frequent mechanism of head trauma in older people. One of the most commonly identified mechanisms of a fall is TLOC. Head injuries due to TLOC entailed a high risk of intracranial pathology in the elderly population. The risk of trauma-related positive CT scans in patients with unexplained falls is high, and is similar to that observed in patients with TLOC. The highest risk of trauma-related positive CT scans is observed in patients who have suffered a high energy trauma. PMID- 26771980 TI - Polymorphisms of Toll-Like Receptor 4 as a Risk Factor for Periodontitis: Meta Analysis. AB - BACKGROUND: Toll-like receptors play an important role in the recognition of periopathogens. There are widely known polymorphisms of these receptors that may alter host susceptibility to periodontitis. OBJECTIVES: Evaluating the association of TLR4 polymorphisms (Asp299 and Thr399Ile) with the occurrence of periodontitis and its two clinical types: chronic (CP) and aggressive (AgP) among Caucasians. MATERIAL AND METHODS: A review of 4 electronic databases was made to identify studies that match the inclusion criteria for the meta-analysis and were published up to December 31, 2013. RESULTS: Fifteen studies met the inclusion criteria. For Asp299Gly polymorphism 1621 patients with periodontitis (1148 with CP and 473 with AgP) and 1755 individuals without clinical signs of periodontitis were included in the meta-analysis. The occurrence of polymorphism The 399Ile was evaluated among 1522 patients with periodontitis (1017 with CP and 505 with AgP) and 1461 subjects in the control group. The pooled OR with a random effects model for the Asp299Gly and chronic periodontitis was 1.35 (95% CI: 1.02-1.8, p = 0.038), indicating a possible association between this polymorphism and CP. Other published meta-analyzes showed no significant association between single nucleotide polymorphisms of TLR4 and periodontitis nor its clinical types. No publication bias was reported. CONCLUSIONS: Our meta-analysis showed statistically significant association between TLR4 Asp299Gly allele and increased susceptibility to chronic periodontitis. PMID- 26771981 TI - Evaluating Maxilla Bone Quality Through Clinical Investigation of Voxel Grey Scale Values from Cone-Beam Computed Tomography for Dental Use. AB - BACKGROUND: During the study the relative bone density thickness in maxilla was evaluated in 20 patients. OBJECTIVES: The aim of the study was to investigate relative bone density in maxilla by means of voxel value measurements. MATERIAL AND METHODS: The study comprised of 20 patients in whom cone beam computed tomography scans were made for diagnostic purposes. The horizontal scans of the maxilla were used for analysis. The measurements of density of both cortical plates and trabecular bone were taken in interdental spaces. To eliminate negative values a modified grey scale was introduced in which radiological density of the air was determined as "0". For every patient relative bone density was calculated separately for anterior and posterior maxilla. RESULTS: Mean values of relative radiological density for cortical plates and trabecular bone were 0.849 for palatal cortical plate, 0.8978 for vestibular cortical plate and 0.5988 for trabecular bone in anterior maxilla with standard deviation (SD) 0.0931 - 0.0971 - 0.1091 respectively. In posterior maxilla the mean values were 0.5274 for palatal cortical plate, 0.6047 for vestibular cortical plate and 0.3307 for trabecular bone with SD 0.1635 - 0.1515 - 0.126 respectively. The statistically significant difference (p < 0.001) was found for radiological density of dental alveolus in anterior and posterior maxilla. CONCLUSIONS: The mean of radiological densities of vestibular cortical plate is higher than that of palatal cortical plate. The mean radiological density of trabecular bone is * 2 lower than the mean radiological density of vestibular cortical plate in posterior region and * 1.5 lower in anterior region of the maxilla. The clinical use of CBCT radiological bone density measurement tool with modified grey scale voxel values creates possibility to evaluate the relative bone density of dental alveolus. PMID- 26771982 TI - Evaluation of a Home-Based Pulmonary Rehabilitation Program for Older Females Suffering from Bronchial Asthma. AB - BACKGROUND: Asthma is a disease that affects people of all ages worldwide. OBJECTIVES: The aim of the study was to evaluate the effectiveness of a home based pulmonary rehabilitation program, with one supervised session a week, for improvement of respiratory function, inspiratory muscle strength and physical fitness in older women suffering from asthma. MATERIAL AND METHODS: The study involved 10 female patients (mean age 70.8) with diagnosed bronchial asthma in the slight and moderate stage. Before the program started, all the patients were in a stable phase of the disease. All the patients carried out a respiratory function test based on measurement of the flow/volume loop assessing FVC, FEV1, FEV1/FVC, PEF, MEF50 and MEF25/75. An inspiratory muscle strength test (PImax) was also performed. Agility was assessed by the Fullerton Functional Fitness test, which consists of sitting down on/standing up from a chair, bicep curls with weights, upper and lower body flexibility trials, a complex coordination trial and a six minute walk test (6MWT) to assess the patients' exercise capacity. To evaluate health-related quality of life, the Saint George Respiratory Questionnaire (SGRQ) was completed, and the Hospital Anxiety and Depression Scale was used to diagnose any signs of anxiety or depression. The main part of the program consisted of eight two-minute whole body exercises separated by one-minute intervals. Statistical significance was determined by the Wilcoxon test. RESULTS: Almost all the respiratory function parameters, PImax, exercise tolerance, lower body flexibility trial and 6MWT improved significantly after following the program for eight weeks. Among the parameters measured by the questionnaires and scales, only the component of the SGRQ related to symptoms of the disease has significantly improved. CONCLUSIONS: The home-based pulmonary rehabilitation program significantly improved all respiratory function parameters. The patients' PImax scores also significantly improved. Among the physical fitness parameters, the 6MWT and lower body flexibility trials significantly improved. The home-based pulmonary rehabilitation program can be used effectively in patients suffering from bronchial asthma. PMID- 26771983 TI - The Pathogenesis and Diagnosis of Thromboangiitis obliterans: Is It Still a Mystery? AB - Thromboangiitis obliterans (TAO) is a rare disease of unknown etiology that results in the occlusion of limb arteries located distally to the elbow and knee. Despite the fact that more than one hundred years have passed since its first description, knowledge on the pathogenesis of TAO and precipitating factors is still limited. Due to a lack of decisive noninvasive diagnostic methods and geographical differences in the prevalence of this condition, data on TAO epidemiology also remains sparse. This review presents important evidence on the pathogenesis and the course of the condition, as well as diagnostic modalities, with a focus on differential diagnosis. Theories on the pathogenesis of TAO include the theory of an infectious disease, coagulation disorders and injury to vascular endothelium resulting in activation of the inflammatory response. Differential diagnosis should exclude thoracic outlet syndrome, blue toe syndrome, infectious endocarditis, popliteal entrapment syndrome, Takayasu disease, primary and secondary systemic vasculitis, antiphospholipid syndrome, infection with the anaerobic Clostridium sp. bacilli and some less common conditions. PMID- 26771985 TI - Heidelberg Edge Perimeter: The New Method of Perimetry. AB - Glaucoma is an optic nerve neuropathy associated with progressive visual field loss. One of the most frequent eye diseases these days, it is believed to have affected 60 million people worldwide in 2014. Various visual field examination methods are known, from the confrontational test to kinetic and static perimetry. The latest device to access the visual field is the Heidelberg Edge Perimeter (HEP). It is a flicker perimeter, but, unlike others of its kind, it uses a unique stimulus called FDF (Flicker Defined Form). A 5-grade round stimulus is created by reversing the phase of flickering black and white dots, thereby forming illusory outlines. The test uses randomly flickering points in medium illumination (50 cd/m2). The background remains the same during the whole test. Background luminance is 50 cd/m2, the marker showing time is 400 ms, and the frequency is 15 Hz. Current studies show that HEP can detect early visual field loss which remains invisible during a standard visual field test with standard automated perimetry. HEP might also prove useful in the early detection of other diseases connected with visual field loss, for example in neurology. PMID- 26771984 TI - The Dry Form of Age-Related Macular Degeneration (AMD): The Current Concepts of Pathogenesis and Prospects for Treatment. AB - Age-related macular degeneration (AMD) is a disease that causes varying degrees of blindness, which afflicts millions of adults in their later years. Preliminary changes occur during normal aging, but in some individuals the pathology leads to the development of AMD. The pathology seems to be a mixture of biochemical, cellular, and molecular events. Lipofuscinogenesis and early drusen genesis are in the early stages of AMD and their inhibition or reversal would dramatically increase the quality of vision in elderly people. The disease is characterized by abnormal extracellular deposits, known as drusen, which accumulate along the basal surface of the retinal pigmented epithelium RPE. Widespread drusen deposition is associated with retinal pigmented epithelial cell dysfunction and degeneration of the photoreceptors. Recent studies have shown that drusen contain a variety of immunomodulatory molecules, suggesting that the process of drusen formation involves local inflammatory events, including activation of the complement cascade. Molecular pathways involved in the etiology of this disease and the potential prospects of its treatment will be presented on the basis of the results of the current studies. PMID- 26771986 TI - Mycotic Infections of the Eye. AB - Fungal infections of the eye are an important cause of significant visual loss and blindness in some regions of the world, especially developing countries. Ocular mycoses remain a diagnostic and therapeutic challenge to the ophthalmologist. Corneal infection is the most frequent presentation, but the orbit, eyelids, lacrimal apparatus, conjunctiva, sclera and internal structures of the eye can also be affected. Candida spp., Fusarium spp. and Aspergillus spp. are the most frequently isolated organisms in fungal keratitis and in endophthalmitis. The difficulties posed by ocular mycoses are mainly related to establishing the clinical diagnosis, isolation of the fungal pathogen and effective local treatment, particularly in infections of the cornea. The critical issue in diagnosing fungal infection of the eye is microbiological identification of the etiologic agent in clinical samples. Early diagnosis and prompt treatment allow serious complications, including blindness, to be avoided. Local, systemic and even surgical treatment is applied in the therapy. PMID- 26771990 TI - The development of lurasidone for bipolar depression. AB - Bipolar disorder is a chronic, recurrent illness that ranks among the top 10 causes of disability in the developed world. As the illness progresses, major depressive episodes increasingly predominate. However, few treatment options are available that have demonstrated efficacy in the treatment of bipolar depression, either as monotherapy or adjunctive therapy in combination with mood stabilizers. Lurasidone is an atypical antipsychotic drug that was initially developed for the treatment of schizophrenia. Since no previous atypical antipsychotic development program had proceeded directly from work on schizophrenia to bipolar depression, the decision to focus on this indication represented an innovation in central nervous system drug development and was designed to address a clinically significant unmet need. The current review summarizes key results of a clinical development program undertaken to characterize the efficacy and safety of lurasidone in patients diagnosed with bipolar depression. Lurasidone is currently the only treatment for bipolar depression approved in the United States as both a monotherapy and an adjunctive therapy with lithium or valproate. The approval of lurasidone expands available treatment options for patients with bipolar depression and provides a therapy with an overall favorable risk-benefit profile. PMID- 26771991 TI - What Lies Behind Drug Shortages, the Consequences-and a Good Alternative. PMID- 26771987 TI - Evolutionary Novelty in a Butterfly Wing Pattern through Enhancer Shuffling. AB - An important goal in evolutionary biology is to understand the genetic changes underlying novel morphological structures. We investigated the origins of a complex wing pattern found among Amazonian Heliconius butterflies. Genome sequence data from 142 individuals across 17 species identified narrow regions associated with two distinct red colour pattern elements, dennis and ray. We hypothesise that these modules in non-coding sequence represent distinct cis regulatory loci that control expression of the transcription factor optix, which in turn controls red pattern variation across Heliconius. Phylogenetic analysis of the two elements demonstrated that they have distinct evolutionary histories and that novel adaptive morphological variation was created by shuffling these cis-regulatory modules through recombination between divergent lineages. In addition, recombination of modules into different combinations within species further contributes to diversity. Analysis of the timing of diversification in these two regions supports the hypothesis of introgression moving regulatory modules between species, rather than shared ancestral variation. The dennis phenotype introgressed into Heliconius melpomene at about the same time that ray originated in this group, while ray introgressed back into H. elevatus much more recently. We show that shuffling of existing enhancer elements both within and between species provides a mechanism for rapid diversification and generation of novel morphological combinations during adaptive radiation. PMID- 26771993 TI - Crossing the Border between Laboratory and Field: Bacterial Quorum Quenching for Anti-Biofouling Strategy in an MBR. AB - Quorum quenching (QQ) has recently been acknowledged to be a sustainable antifouling strategy and has been investigated widely using lab-scale membrane bioreactor (MBR) systems. This study attempted to bring this QQ-MBR closer to potential practical application. Two types of pilot-scale QQ-MBRs with QQ bacteria entrapping beads (QQ-beads) were installed and run at a wastewater treatment plant, feeding real municipal wastewater to test the systems' effectiveness for membrane fouling control and thus the amount of energy savings, even under harsh environmental conditions. The rate of transmembrane pressure (TMP) build-up was significantly mitigated in QQ-MBR compared to that in a conventional-MBR. Consequently, QQ-MBR can substantially reduce energy consumption by reducing coarse bubble aeration without compromising the effluent water quality. The addition of QQ-beads to a conventional MBR substantially affected the EPS concentrations, as well as microbial floc size in the mixed liquor. Furthermore, the QQ activity and mechanical stability of QQ-beads were well maintained for at least four months, indicating QQ-MBR has good potential for practical applications. PMID- 26771992 TI - Ultrasound Imaging Techniques for Spatiotemporal Characterization of Composition, Microstructure, and Mechanical Properties in Tissue Engineering. AB - Ultrasound techniques are increasingly being used to quantitatively characterize both native and engineered tissues. This review provides an overview and selected examples of the main techniques used in these applications. Grayscale imaging has been used to characterize extracellular matrix deposition, and quantitative ultrasound imaging based on the integrated backscatter coefficient has been applied to estimating cell concentrations and matrix morphology in tissue engineering. Spectral analysis has been employed to characterize the concentration and spatial distribution of mineral particles in a construct, as well as to monitor mineral deposition by cells over time. Ultrasound techniques have also been used to measure the mechanical properties of native and engineered tissues. Conventional ultrasound elasticity imaging and acoustic radiation force imaging have been applied to detect regions of altered stiffness within tissues. Sonorheometry and monitoring of steady-state excitation and recovery have been used to characterize viscoelastic properties of tissue using a single transducer to both deform and image the sample. Dual-mode ultrasound elastography uses separate ultrasound transducers to produce a more potent deformation force to microscale characterization of viscoelasticity of hydrogel constructs. These ultrasound-based techniques have high potential to impact the field of tissue engineering as they are further developed and their range of applications expands. PMID- 26771994 TI - Undiagnosed term intraligamentous pregnancy: A case report and literature review. PMID- 26771995 TI - Expanded Scope for JNEB! PMID- 26771996 TI - Nutrition Educators as Players in the 2016 International Year of .... PMID- 26772048 TI - World kidney day 2016 Averting the legacy of kidney disease--- focus on childhood. PMID- 26772049 TI - Is Kauppila method able to detect the progression of vascular calcification and predict cardiovascular events in patients undergoing hemodialysis? AB - BACKGROUND: Cardiovascular disease (CVD) is the main cause of death in hemodialysis (HD) patients. Vascular calcification (VC) is common in these patients. The main objective of this study was to evaluate if a semiquantitative radiographic method is able to detect VC progression in a prospective cohort of patients and predict the risk of cardiovascular events. Secondarily, we intend to identify predictors of the presence and progression of VC. METHODS: 49 patients undergoing HD for >= 90 days were included. At the beginning and after 12 months, the VC score (VCS) was determined by the Kauppila method, and clinical, nutritional, and laboratory markers were measured. The rates of fatal and nonfatal cardiovascular events were analyzed from months 13 to 24. RESULTS: Of 49 patients, 55.1% were male, 46.9% diabetic, and the mean age was 59.5 +/- 14.4 years. At the beginning of the follow-up, 65.3% of the patients exhibited VC with a median VCS of 4 points. The intracellular water was negatively associated with VC and its intensity. The presence of VC was the only independent predictor of VC progression. Among patients with VC, 17 showed rapid progression, and 15 showed slow progression. The VCS was independently associated with rapid progression, while DeltaCS (final VCS - initial VCS) was an independent predictor of cardiovascular events. CONCLUSIONS: The Kauppila method was able to detect VC, its progression, and predict cardiovascular events. These results suggest an association of VC with nutritional status. PMID- 26772050 TI - Prediction of all-cause death in hemodialysis patients using elevated postdialysis pulse wave velocity. AB - BACKGROUND: To identify the relationship between predialysis pulse wave velocity (PWV), postdialysis PWV during 1 hemodialysis (HD) session, and deaths in maintenance HD patients. METHODS: 43 patients were recruited. PWV was measured before and after one HD session and dialysis- related data were recorded. Clinical data such as blood pressure, blood lipids, and blood glucose, were carefully observed and managed in a 5-year follow-up. The association between all cause death, predialysis PWV, postdialysis PWV, change of PWV (DeltaPWV), and other related variables were analyzed. RESULTS: After 5 years, 17 patients (39.5%) died. Univariate Cox regression analysis showed that all-cause death of the patients significantly correlated with age, postdialysis PWV, and DeltaPWV. Multivariate Cox regression analysis revealed that postdialysis PWV was an independent predictor for all-cause death in these patients (HR: 1.377, 95% CI: 1.146 - 1.656, p = 0.001). CONCLUSION: Elevated postdialysis PWV significantly correlated with and was an independent predictor for all-cause death in maintenance HD patients. PMID- 26772051 TI - Effects of defined mixtures of persistent organic pollutants (POPs) on multiple cellular responses in the human hepatocarcinoma cell line, HepG2, using high content analysis screening. AB - Persistent organic pollutants (POPs) are toxic substances, highly resistant to environmental degradation, which can bio-accumulate and have long-range atmospheric transport potential. Most studies focus on single compound effects, however as humans are exposed to several POPs simultaneously, investigating exposure effects of real life POP mixtures on human health is necessary. A defined mixture of POPs was used, where the compound concentration reflected its contribution to the levels seen in Scandinavian human serum (total mix). Several sub mixtures representing different classes of POPs were also constructed. The perfluorinated (PFC) mixture contained six perfluorinated compounds, brominated (Br) mixture contained seven brominated compounds, chlorinated (Cl) mixture contained polychlorinated biphenyls and also p,p' dichlorodiphenyldichloroethylene, hexachlorobenzene, three chlordanes, three hexachlorocyclohexanes and dieldrin. Human hepatocarcinoma (HepG2) cells were used for 2h and 48h exposures to the seven mixtures and analysis on a CellInsightTM NXT High Content Screening platform. Multiple cytotoxic endpoints were investigated: cell number, nuclear intensity and area, mitochondrial mass and membrane potential (MMP) and reactive oxygen species (ROS). Both the Br and Cl mixtures induced ROS production but did not lead to apoptosis. The PFC mixture induced ROS production and likely induced cell apoptosis accompanied by the dissipation of MMP. Synergistic effects were evident for ROS induction when cells were exposed to the PFC+Br mixture in comparison to the effects of the individual mixtures. No significant effects were detected in the Br+Cl, PFC+Cl or total mixtures, which contain the same concentrations of chlorinated compounds as the Cl mixture plus additional compounds; highlighting the need for further exploration of POP mixtures in risk assessment. PMID- 26772052 TI - Back to the future. PMID- 26772053 TI - Assessing the prevalence of HIV, HBV, and HCV infection among people with severe mental illness. PMID- 26772054 TI - Psychological therapies for psychosis: a view from the hills. PMID- 26772055 TI - Psychiatric genetics: what's new in 2015? PMID- 26772056 TI - Neuroimaging in 2015: a turning point? PMID- 26772057 TI - Big data analytics and machine learning: 2015 and beyond. PMID- 26772058 TI - Global mental health in 2015: 95% implementation. PMID- 26772060 TI - Intensive community outreach for those at ultra high risk of psychosis: dilution, not solution--Authors' reply. PMID- 26772061 TI - Intensive community outreach for those at ultra high risk of psychosis: dilution, not solution. PMID- 26772062 TI - "Hotspots" and "copycats": a plea for more thoughtful language about suicide. PMID- 26772065 TI - Andre Tomlin: mental elf guru. PMID- 26772063 TI - "Hotspots" and "copycats": a plea for more thoughtful language about suicide- Authors' reply. PMID- 26772067 TI - The Simple Physical Activity Questionnaire. PMID- 26772066 TI - Mental health training for health workers in Africa: a systematic review. AB - Commitment to building mental health treatment capacity in Africa is increasing but little agreement exists on strategies to train health workers on mental health or evaluation of training efforts. We systematically reviewed published literature on interventions to train health-care workers in Africa on mental health. 37 studies met our inclusion criteria. Training outcomes focused on changes in knowledge and attitude, with few studies evaluating skill and practice and only two studies measuring clinical outcomes. Quality of study methodology was generally not high, with scarce follow-up data and use of control cohorts. Existing studies provide examples of many training and evaluation strategies, but evidence to draw conclusions about the efficacy of different training techniques is inadequate. Key knowledge gaps include development and testing of innovative educational strategies; development of standardised, competency-based learning objectives and outcome measures; and training that facilitates implementation of integrated mental health systems. African institutions need to be empowered to do research in these areas to encourage the development of best practices for the continent. PMID- 26772068 TI - A research agenda for childhood bullying. PMID- 26772069 TI - Prozac: better than well. PMID- 26772070 TI - Competitive tendering for offender care. PMID- 26772071 TI - Experimental Approaches to Study Endothelial Responses to Shear Stress. AB - SIGNIFICANCE: Shear stress controls multiple physiological processes in endothelial cells (ECs). RECENT ADVANCES: The response of ECs to shear has been studied using a range of in vitro and in vivo models. CRITICAL ISSUES: This article describes some of the experimental techniques that can be used to study endothelial responses to shear stress. It includes an appraisal of large animal, rodent, and zebrafish models of vascular mechanoresponsiveness. It also describes several bioreactors to apply flow to cells and physical methods to separate mechanoresponses from mass transport mechanisms. FUTURE DIRECTIONS: We conclude that combining in vitro and in vivo approaches can provide a detailed mechanistic view of vascular responses to force and that high-throughput systems are required for unbiased assessment of the function of shear-induced molecules. Antioxid. Redox Signal. 25, 389-400. PMID- 26772121 TI - A novel automated device for rapid nucleic acid extraction utilizing a zigzag motion of magnetic silica beads. AB - We report a novel automated device for nucleic acid extraction, which consists of a mechanical control system and a disposable cassette. The cassette is composed of a bottle, a capillary tube, and a chamber. After sample injection in the bottle, the sample is lysed, and nucleic acids are adsorbed on the surface of magnetic silica beads. These magnetic beads are transported and are vibrated through the washing reagents in the capillary tube under the control of the mechanical control system, and thus, the nucleic acid is purified without centrifugation. The purified nucleic acid is automatically extracted in 3 min for the polymerase chain reaction (PCR). The nucleic acid extraction is dependent on the transport speed and the vibration frequency of the magnetic beads, and optimizing these two parameters provided better PCR efficiency than the conventional manual procedure. There was no difference between the detection limits of our novel device and that of the conventional manual procedure. We have already developed the droplet-PCR machine, which can amplify and detect specific nucleic acids rapidly and automatically. Connecting the droplet-PCR machine to our novel automated extraction device enables PCR analysis within 15 min, and this system can be made available as a point-of-care testing in clinics as well as general hospitals. PMID- 26772122 TI - A review on recent developments for biomolecule separation at analytical scale using microfluidic devices. AB - Microfluidic devices with their inherent advantages like the ability to handle 10(-9) to 10(-18) L volume, multiplexing of microchannels, rapid analysis and on chip detection are proving to be efficient systems in various fields of life sciences. This review highlights articles published since 2010 that reports the use of microfluidic devices to separate biomolecules (DNA, RNA and proteins) using chromatography principles (size, charge, hydrophobicity and affinity) along with microchip capillary electrophoresis, isotachophoresis etc. A detailed overview of stationary phase materials and the approaches to incorporate them within the microchannels of microchips is provided as well as a brief overview of chemical methods to immobilize ligand(s). Furthermore, we review research articles that deal with microfluidic devices as analytical tools for biomolecule (DNA, RNA and protein) separation. PMID- 26772123 TI - Automation of static and dynamic non-dispersive liquid phase microextraction. Part 1: Approaches based on extractant drop-, plug-, film- and microflow formation. AB - Simplicity, effectiveness, swiftness, and environmental friendliness - these are the typical requirements for the state of the art development of green analytical techniques. Liquid phase microextraction (LPME) stands for a family of elegant sample pretreatment and analyte preconcentration techniques preserving these principles in numerous applications. By using only fractions of solvent and sample compared to classical liquid-liquid extraction, the extraction kinetics, the preconcentration factor, and the cost efficiency can be increased. Moreover, significant improvements can be made by automation, which is still a hot topic in analytical chemistry. This review surveys comprehensively and in two parts the developments of automation of non-dispersive LPME methodologies performed in static and dynamic modes. Their advantages and limitations and the reported analytical performances are discussed and put into perspective with the corresponding manual procedures. The automation strategies, techniques, and their operation advantages as well as their potentials are further described and discussed. In this first part, an introduction to LPME and their static and dynamic operation modes as well as their automation methodologies is given. The LPME techniques are classified according to the different approaches of protection of the extraction solvent using either a tip-like (needle/tube/rod) support (drop-based approaches), a wall support (film-based approaches), or microfluidic devices. In the second part, the LPME techniques based on porous supports for the extraction solvent such as membranes and porous media are overviewed. An outlook on future demands and perspectives in this promising area of analytical chemistry is finally given. PMID- 26772124 TI - Strengths and weaknesses of in-tube solid-phase microextraction: A scoping review. AB - In-tube solid-phase microextraction (in-tube SPME or IT-SPME) is a sample preparation technique which has demonstrated over time its ability to couple with liquid chromatography (LC), as well as its advantages as a miniaturized technique. However, the in-tube SPME perspectives in the forthcoming years depend on solutions that can be brought to the environmental, industrial, food and biomedical analysis. The purpose of this scoping review is to examine the strengths and weaknesses of this technique during the period 2009 to 2015 in order to identify research gaps that should be addressed in the future, as well as the tendencies that are meant to strengthen the technique. In terms of methodological aspects, this scoping review shows the in-tube SPME strengths in the coupling with LC (LC-mass spectrometry, capillary LC, ultra-high-pressure LC), in the new performances (magnetic IT-SPME and electrochemically controlled in-tube SPME) and in the wide range of development of coatings and capillaries. Concerning the applicability, most in-tube SPME studies (around 80%) carry out environmental and biomedical analyses, a lower number food analyses and few industrial analyses. Some promising studies in proteomics have been performed. The review makes a critical description of parameters used in the optimization of in-tube SPME methods, highlighting the importance of some of them (i.e. type of capillary coatings). Commercial capillaries in environmental analysis and laboratory-prepared capillaries in biomedical analysis have been employed with good results. The most consolidated configuration is in-valve mode, however the cycle mode configuration is frequently chosen for biomedical analysis. This scoping review revealed that some aspects such as the combination of in-tube SPME with other sample treatment techniques for the analysis of solid samples should be developed in depth in the near future. PMID- 26772125 TI - Investigation of kinetics and thermodynamics of DNA hybridization by means of 2-D fluorescence spectroscopy and soft/hard modeling techniques. AB - Reversible hybridization reaction plays a key role in fundamental biological processes, in many laboratory techniques, and also in DNA based sensing devices. Comprehensive investigation of this process is, therefore, essential for the development of more sophisticated applications. Kinetics and thermodynamics of the hybridization reaction, as a second order process, are systematically investigated with the aid of the soft and hard chemometric methods. Labeling two complementary 21 mer DNA single strands with FAM and Texas red fluorophores, enabled recording of the florescence excitation-emission matrices during the experiments which led to three-way data sets. The presence of fluorescence resonance energy transfer in excitation and emission modes and the closure in concentration mode, made the three-way data arrays rank deficient. To acquire primary chemical information, restricted Tucker3 as a soft method was employed. Herein a model-based method, hard restricted trilinear decomposition, is introduced for in depth analysis of rank deficient three-way data sets. By employing proposed hard method, the nonlinear model parameters as well as the correct profiles could be estimated. In addition, a simple constraint is presented to extract chemically reasonable output profiles regarding the core elements of restricted Tucker3 model. PMID- 26772126 TI - Sensitive and versatile electrogenerated chemiluminescence biosensing platform for protein kinase based on Ru(bpy)3(2+) functionalized gold nanoparticles mediated signal transduction. AB - A novel, sensitive and versatile electrogenerated chemiluminescence biosensing platform is developed for monitoring activity and inhibition of protein kinase based on Ru(bpy)3(2+) functionalized gold nanoparticles (Ru(bpy)3(2+)-AuNPs) mediated signal transduction. Ru(bpy)3(2+)-AuNPs were formed by functionalizing AuNPs with Ru(bpy)3(2+) through electrostatic interactions and were used as thiol versatile signal probe. Casein kinase II (CK2) and cAMP-dependent protein kinase (PKA), two classical protein kinase implicated in disease, were chosen as model protein kinases while a CK2-specific peptide (CRRRADDSDDDDD) and a PKA-specific peptide (CLRRASLG) were employed as molecular substrate for CK2 and PKA, respectively. The specific peptide was self-assembled onto the gold electrode via Au-S bond to form ECL biosensor. Upon thiophosphorylation of the peptide on the electrode in the presence of protein kinase and co-substrate adenosine-5'-(gamma thio)-triphosphate, Ru(bpy)3(2+)-AuNPs was assembled onto the thiophosphorylated peptides via Au-S bond. The Ru(bpy)3(2+)-AuNPs attached on electrode surface produce detectable ECL signal in the presence of coreactant tripropylamine. This strategy is promising for multiple protein kinase assay and kinase inhibitor profiling with high sensitivity, good selectivity and versatility. The ECL intensity is proportional to the activity of CK2 in the range of 0.01-0.5 unit/mL with a low detection limit of 0.008 unit/mL and to the activity of PKA in the range of 0.01-0.4 unit/mL with a detection limit of 0.005 unit/mL. Additionally, this assay was applied to the detection of CK2 in serum samples and the inhibition of CK2 and PKA. This work demonstrates that the developed ECL method can provide a sensitive and versatile platform for the detection of kinase activity and drug-screening. PMID- 26772127 TI - Fabrication of highly catalytic silver nanoclusters/graphene oxide nanocomposite as nanotag for sensitive electrochemical immunoassay. AB - Silver nanoclusters and graphene oxide nanocomposite (AgNCs/GRO) is synthesized and functionalized with detection antibody for highly sensitive electrochemical sensing of carcinoembryonic antigen (CEA), a model tumor marker involved in many cancers. AgNCs with large surface area and abundant amount of low-coordinated sites are synthesized with DNA as template and exhibit high catalytic activity towards the electrochemical reduction of H2O2. GRO is employed to assemble with AgNCs because it has large specific surface area, super electronic conductivity and strong pi-pi stacking interaction with the hydrophobic bases of DNA, which can further improve the catalytic ability of the AgNCs. Using AgNCs/GRO as signal amplification tag, an enzyme-free electrochemical immunosensing protocol is designed for the highly sensitive detection of CEA on the capture antibody functionalized immunosensing interface. Under optimal conditions, the designed immunosensor exhibits a wide linear range from 0.1 pg mL(-1) to 100 ng mL(-1) and a low limit of detection of 0.037 pg mL(-1). Practical sample analysis reveals the sensor has good accuracy and reproducibility, indicating the great application prospective of the AgNCs/GRO in fabricating highly sensitive immunosensors, which can be extended to the detection of various kinds of low abundance disease related proteins. PMID- 26772128 TI - Nanostructured cupric oxide electrode: An alternative to amperometric detection of carbohydrates in anion-exchange chromatography. AB - In this paper, a new and low cost copper/cupric oxide nanostructured electrode is presented as an alternative to the amperometric detection of carbohydrates in high-performance anion exchange chromatography. The modified copper electrodes were prepared by a simple and fast method which resulted in the obtainment of homogeneously distributed nanostructures adhered to the surface with controlled chemical nature. The results, when compared to conventional copper electrodes, exhibited considerable improvements in analytical results, including: 1) Better repeatability in consecutive glucose detections, in which the percent relative standard deviation improved from 15.1% to 0.279%. 2) Significant improvements in the stability of the baseline and a decrease of the stabilization time, going from several hours to approximately 15 min. 3) Considerable increase in the sensitivity towards glucose, from 5.02 nA min mg L(-1) to 25.5 nA min mg L(-1). 4) Improvements in the detectability with limits as low as 1.09 pmol. 5) Wide working range of concentrations (1 * 10(-2) to 1 * 10(4) mg L(-1)). 6) Good linearity with correlation coefficients greater than 0.998. 7) Possibility of detecting different molecules of carbohydrates (lactose, maltose, sucrose cellobiose, sorbitol, fructose, glucose, galactose, manose, arabitol, xylose, ribose and arabnose). In comparison to the electrode that is more employed for this type of application (gold electrode), the low cost, the possibility of detection at constant potential and the equivalent detection limits presented by the new electrode material introduced in this work emerge as characteristics that make this material a powerful alternative considering the detection of carbohydrates in anion exchange chromatography. PMID- 26772129 TI - Practical improvements in soil redox potential (Eh) measurement for characterisation of soil properties. Application for comparison of conventional and conservation agriculture cropping systems. AB - The soil redox potential (Eh) can provide essential information to characterise soil conditions. In practice, however, numerous problems may arise regarding: (i) Eh determination in soils, especially aerobic soils, e.g. variations in the instrumentation and methodology for Eh measurement, high spatial and temporal Eh variability in soils, irreversibility of the redox reaction at the surface electrode, chemical disequilibrium; and (ii) measurement interpretation. This study aimed at developing a standardised method for redox potential measurement in soils, in order to use Eh as a soil quality indicator. This paper presents practical improvements in soil Eh measurement, especially regarding the control of electromagnetic perturbations, electrode choice and preparation, soil sample preparation (drying procedure) and soil:water extraction rate. The repeatability and reproducibility of the measurement method developed are highlighted. The use of Eh corrected at pH7, pe+pH or rH2, which are equivalent notions, is proposed to facilitate interpretation of the results. The application of this Eh measurement method allows characterisation of soil conditions with sufficient repeatability, reproducibility and accuracy to demonstrate that conservation agriculture systems positively alter the protonic and electronic balance of soil as compared to conventional systems. PMID- 26772130 TI - Bovine serum albumin-Cu(II) hybrid nanoflowers: An effective adsorbent for solid phase extraction and slurry sampling flame atomic absorption spectrometric analysis of cadmium and lead in water, hair, food and cigarette samples. AB - Herein, the synthesis of bovine serum albumin-Cu(II) hybrid nanoflowers (BSA-NFs) through the building blocks of bovine serum albumin (BSA) and copper(II) ions in phosphate buffered saline (PBS) and their use as adsorbent for cadmium and lead ions are reported. The BSA-NFs, for the first time, were efficiently utilized as novel adsorbent for solid phase extraction (SPE) of cadmium and lead ions in water, food, cigarette and hair samples. The method is based on the separation and pre-concentration of Cd(II) and Pb(II) by BSA-NFs prior to determination by slurry analysis via flame atomic absorption spectrometry (FAAS). The analytes were adsorbed on BSA-NFs under the vortex mixing and then the ion-loaded slurry was separated and directly introduced into the flame AAS nebulizer by using a hand-made micro sample introduction system to eliminate a number of drawbacks. The effects of analytical key parameters, such as pH, amount of BSA-NFs, vortexing time, sample volume, and matrix effect of foreign ions on adsorbing of Cd(II) and Pb(II) were systematically investigated and optimized. The limits of detection (LODs) for Cd(II) and Pb(II) were calculated as 0.37 MUg L(-)(1) and 8.8 MUg L(-)(1), respectively. The relative standard deviation percentages (RSDs) (N = 5) for Cd(II) and Pb(II) were 7.2%, and 5.0%, respectively. The accuracy of the developed procedure was validated by the analysis of certified reference materials (TMDA-53.3 Fortified Water, TMDA-70 Fortified Water, SPS-WW2 Waste Water, NCSDC-73349 Bush Branches and Leaves) and by addition/recovery analysis. The quantitative recoveries were obtained for the analysis of certified reference materials and addition/recovery tests. The method was successfully applied to the analysis of cadmium and lead in water, food, cigarette and hair samples. PMID- 26772131 TI - Use of magnetic effervescent tablet-assisted ionic liquid dispersive liquid liquid microextraction to extract fungicides from environmental waters with the aid of experimental design methodology. AB - In this work, a novel effervescence-assisted microextraction technique was proposed for the detection of four fungicides. This method combines ionic liquid based dispersive liquid-liquid microextraction with the magnetic retrieval of the extractant. A magnetic effervescent tablet composed of Fe3O4 magnetic nanoparticles, sodium carbonate, sodium dihydrogen phosphate and 1-hexyl-3 methylimidazolium bis(trifluoromethanesulfonimide) was used for extractant dispersion and retrieval. The main factors affecting the extraction efficiency were screened by a Plackett-Burman design and optimized by a central composite design. Under the optimum conditions, good linearity was obtained for all analytes in pure water model and real water samples. Just for the pure water, the recoveries were between 84.6% and 112.8%, the limits of detection were between 0.02 and 0.10 MUg L(-1) and the intra-day precision and inter-day precision both are lower than 4.9%. This optimized method was successfully applied in the analysis of four fungicides (azoxystrobin, triazolone, cyprodinil, trifloxystrobin) in environmental water samples and the recoveries ranged between 70.7% and 105%. The procedure promising to be a time-saving, environmentally friendly, and efficient field sampling technique. PMID- 26772132 TI - Potential of atmospheric pressure chemical ionization source in gas chromatography tandem mass spectrometry for the screening of urinary exogenous androgenic anabolic steroids. AB - The atmospheric pressure chemical ionization (APCI) source for gas chromatography mass spectrometry analysis has been evaluated for the screening of 16 exogenous androgenic anabolic steroids (AAS) in urine. The sample treatment is based on the strategy currently applied in doping control laboratories i.e. enzymatic hydrolysis, liquid-liquid extraction (LLE) and derivatization to form the trimethylsilyl ether-trimethylsilyl enol ether (TMS) derivatives. These TMS derivatives are then analyzed by gas chromatography tandem mass spectrometry using a triple quadrupole instrument (GC-QqQ MS/MS) under selected reaction monitoring (SRM) mode. The APCI promotes soft ionization with very little fragmentation resulting, in most cases, in abundant [M + H](+) or [M + H 2TMSOH](+) ions, which can be chosen as precursor ions for the SRM transitions, improving in this way the selectivity and sensitivity of the method. Specificity of the transitions is also of great relevance, as the presence of endogenous compounds can affect the measurements when using the most abundant ions. The method has been qualitatively validated by spiking six different urine samples at two concentration levels each. Precision was generally satisfactory with RSD values below 25 and 15% at the low and high concentration level, respectively. Most the limits of detection (LOD) were below 0.5 ng mL(-1). Validation results were compared with the commonly used method based on the electron ionization (EI) source. EI analysis was found to be slightly more repeatable whereas lower LODs were found for APCI. In addition, the applicability of the developed method has been tested in samples collected after the administration of 4 chloromethandienone. The highest sensitivity of the APCI method for this compound, allowed to increase the period in which its administration can be detected. PMID- 26772134 TI - Highly photoluminescent MoO(x) quantum dots: Facile synthesis and application in off-on Pi sensing in lake water samples. AB - Molybdenum oxide (MoOx) is a well-studied transition-metal semiconductor material, and has a wider band gap than MoS2 which makes it become a promising versatile probe in a variety of fields, such as gas sensor, catalysis, energy storage ect. However, few MoOx nanomaterials possessing photoluminescence have been reported until now, not to mention the application as photoluminescent probes. Herein, a one-pot method is developed for facile synthesis of highly photoluminescent MoOx quantum dots (MoOx QDs) in which commercial molybdenum disulfide powder and hydrogen peroxide (H2O2) are involved as the precursor and oxidant, respectively. Compared with current synthesis methods, the proposed one has the advantages of rapid, one-pot, easily prepared, environment friendly as well as strong photoluminescence. The obtained MoOx QDs is further utilized as an efficient photoluminescent probe, and a new off-on sensor has been constructed for phosphate (Pi) determination in complicated lake water samples, attributed to the fact that the binding affinity of Eu(3+) ions to the oxygen atoms from Pi is much higher than that from the surface of MoOx QDs. Under the optimal conditions, a good linear relationship was found between the enhanced photoluminescence intensity and Pi concentration in the range of 0.1-160.0 MUM with the detection limit of 56 nM (3sigma/k). The first application of the photoluminescent MoOx nanomaterials for ion photochemical sensing will open the gate of employing MoOx nanomaterials as versatile probes in a variety of fields, such as chemi-/bio sensor, cell imaging, biomedical and so on. PMID- 26772133 TI - A competitive immunoassay for ultrasensitive detection of Hg(2+) in water, human serum and urine samples using immunochromatographic test based on surface enhanced Raman scattering. AB - An immunochromatographic test (ICT) strip was developed for ultrasensitive competitive immunoassay of Hg(2+). This strategy was achieved by combining the easy-operation and rapidity of ICT with the high sensitivity of surface-enhanced Raman scattering (SERS). Monoclonal antibody (mAb) against Hg(2+) and Raman active substance 4-mercaptobenzoic acid (MBA) dual labelled gold nanoparticles (GNPs) were prepared as an immunoprobe. The Raman scattering intensity of MBA on the test line of the ICT strip was measured for quantitative determination of Hg(2+). The ICT was able to directly detect Hg(2+) without complexing due to the specific recognition of the mAb with Hg(2+). The IC50 and limit of detection (LOD) of the assay for Hg(2+) detection were 0.12 ng mL(-1) and 0.45 pg mL(-1), respectively. There was no cross-reactivity (CR) of the assay with other nineteen ions and the ICT strips could be kept for 5 weeks without loss of activity. The recoveries of the assay for water, human serum and urine samples spiked with Hg(2+) were in range of 88.3-107.3% with the relative standard deviations (RSD) of 1.5-9.5% (n = 3). The proposed ICT was used for the detection of Hg(2+) in urine samples collected from Occupational Disease Hospital and the results were confirmed by cold-vapor atomic fluorescence spectroscopy (CV-AFS). The assay exhibited high sensitivity, selectivity, stability, precision and accuracy, demonstrating a promising method for the detection of trace amount of Hg(2+) in environmental water samples and biological serum and urine samples. PMID- 26772135 TI - Trypsin immobilization in ordered porous polymer membranes for effective protein digestion. AB - Fast and effective protein digestion is a vital process for mass spectrometry (MS) based protein analysis. This study introduces a porous polymer membrane enzyme reactor (PPMER) coupled to nanoflow liquid chromatography-tandem MS (nLC ESI-MS/MS) for on-line digestion and analysis of proteins. Poly (styrene-co maleic anhydride) (PS-co-MAn) was fabricated by the breath figure method to make a porous polymer membrane in which the MAn group was covalently bound to enzyme. Based on this strategy, microscale PPMER (MUPPMER) was constructed for on-line connection with the nLC-ESI-MS/MS system. Its capability for enzymatic digestion with bovine serum albumin (BSA) was evaluated with varied digestion periods. The on-line proteolysis of BSA and subsequent analysis with MUPPMER-nLC-ESI-MS/MS revealed that peptide sequence coverage increased from 10.3% (digestion time 10 min) to 89.1% (digestion time 30 min). MUPPMER can efficiently digest proteins due to the microscopic confinement effect, showing its potential application in fast protein identification and protease immobilization. Applications of on-line digestion using MUPPMER with human plasma and urinary proteome samples showed that the developed on-line method yielded equivalent or better performance in protein coverage and identified more membrane proteins than the in-solution method. This may be due to easy accommodation of hydrophobic membrane proteins within membrane pores. PMID- 26772136 TI - Development of a multiplex quantitative PCR assay for the analysis of human cytokine gene expression in influenza A virus-infected cells. AB - Cytokines are global mediators of cellular communications that are involved in broad array of biological processes, including the immunological and inflammatory mechanisms of virus-host interactions. Measuring the gene expression of simultaneously expressed cytokines is necessary for understanding the pathogenesis of many viral infections, including influenza. We developed a multiplex quantitative real-time PCR (qPCR) method for the detection of the following human cytokines: IL-1B, IL-2, IL-4, IL-6, IL-10, IL-12B, IL-18, IFN gamma and TNF. The assay consisted of three sets of multiple qPCRs; in each qPCR, three target cytokines and reference GAPDH genes were amplified. The assay provided a precise and sensitive quantification of cytokine gene expression with a 20fmol limit of detection and a 1.5% coefficient of variation. This method was successfully applied to cytokine profiling in epithelial A549 cells that were infected with A/California/07/09 (H1N1pdm2009) virus. PMID- 26772137 TI - Neurorehabilitation in Pakistan: Is Home Family Care Feasible? PMID- 26772138 TI - Challenges in oral drug delivery of antiretrovirals and the innovative strategies to overcome them. AB - Development of novel drug delivery systems (DDS) represents a promising opportunity to overcome the various bottlenecks associated with the chronic antiretroviral (ARV) therapy of the human immunodeficiency virus (HIV) infection. Oral drug delivery is the most convenient and simplest route of drug administration that involves the swallowing of a pharmaceutical compound with the intention of releasing it into the gastrointestinal tract. In oral delivery, drugs can be formulated in such a way that they are protected from digestive enzymes, acids, etc. and released in different regions of the small intestine and/or the colon. Not surprisingly, with the exception of the subcutaneous enfuvirtide, all the marketed ARVs are administered orally. However, conventional (marketed) and innovative (under investigation) oral delivery systems must overcome numerous challenges, including the acidic gastric environment, and the poor aqueous solubility and physicochemical instability of many of the approved ARVs. In addition, the mucus barrier can prevent penetration and subsequent absorption of the released drug, a phenomenon that leads to lower oral bioavailability and therapeutic concentration in plasma. Moreover, the frequent administration of the cocktail (ARVs are administered at least once a day) favors treatment interruption. To improve the oral performance of ARVs, the design and development of more efficient oral drug delivery systems are called for. The present review highlights various innovative research strategies adopted to overcome the limitations of the present treatment regimens and to enhance the efficacy of the oral ARV therapy in HIV. PMID- 26772139 TI - Direct measurement of molecular mobility and crystallisation of amorphous pharmaceuticals using terahertz spectroscopy. AB - Despite much effort in the area, no comprehensive understanding of the formation and behaviour of amorphous solids has yet been achieved. This severely limits the industrial application of such materials, including drug delivery where, in principle, amorphous solids have demonstrated their great usefulness in increasing the bioavailability of poorly aqueous soluble active pharmaceutical ingredients. Terahertz time-domain spectroscopy is a relatively novel analytical technique that can be used to measure the fast molecular dynamics of molecules with high accuracy in a non-contact and non-destructive fashion. Over the past decade a number of applications for the characterisation of amorphous drug molecules and formulations have been developed and it has been demonstrated how this technique can be used to determine the onset and strength in molecular mobility that underpins the crystallisation of amorphous drugs. In this review we provide an overview of the history, fundamentals and future perspective of pharmaceutical applications related to the terahertz dynamics of amorphous systems. PMID- 26772141 TI - [Opening new horizons at Radiologia]. PMID- 26772140 TI - Comparison of bleeding risks related to venous thromboembolism prophylaxis in laparoscopic vs open colorectal cancer surgery: a multicenter study in Japanese patients. AB - BACKGROUND: Venous thromboembolism is the most common preventable cause of hospital death. The objective of this study was to clarify risk factors for postoperative bleeding related to thromboprophylaxis after laparoscopic colorectal cancer surgery. METHODS: The study was conducted at 23 Japanese institutions and included patients with colorectal cancer who underwent laparoscopic or open surgery followed by fondaparinux treatment. We performed a retrospective analysis from a prospectively maintained database. We used multivariate analyses to evaluate clinical risk factors for prophylaxis-related bleeding events. RESULTS: After multivariate analysis, male gender, intraoperative blood loss of less than 25 mL, and a preoperative platelet count below 15 * 104/MUL were found to be independent risk factors in the laparoscopic surgery group. Only the preoperative platelet count was an independent risk factor in the open surgery group. CONCLUSIONS: Different prophylactic treatments for postoperative venous thromboembolism may be necessary in laparoscopic vs open surgery for colorectal cancer. PMID- 26772142 TI - Specific deletion of AMP-activated protein kinase (alpha1AMPK) in mouse Sertoli cells modifies germ cell quality. AB - The AMP-activated protein kinase (AMPK) is an important regulator of cellular energy homeostasis which plays a role in fertility. Complete disruption of the AMPK catalytic subunit alpha1 gene (alpha1AMPK KO) in male mice results in a decrease in litter size which is associated with the production of altered sperm morphology and motility. Because of the importance of Sertoli cells in the formation of germ cells, we have chosen to selectively disrupt alpha1AMPK only in the Sertoli cells in mice (Sc-alpha1AMPK-KO mice). Specific deletion of the alpha1AMPK gene in Sertoli cells resulted in a 25% reduction in male fertility associated with abnormal spermatozoa with a thin head. No clear alterations in testis morphology or modification in the number of Sertoli cells in vivo were observed, but a dysregulation in energy metabolism in Sertoli cells occurred. We have reported an increase in lactate production, in lipid droplets, and a reduction in ATP production in Sc-alpha1AMPK-KO Sertoli cells. These perturbations were associated with lower expression of mitochondrial markers (cytochrome c and PGC1-alpha). In addition another metabolic sensor, the deacetylase SIRT1, had a reduction in expression which is correlated with a decline in deacetylase activity. Finally, expression and localization of junctions forming the blood-testis barrier between Sertoli cells themselves and with germ cells were deregulated in Sc-alpha1AMPK-KO. In conclusion, these results suggest that dysregulation of the energy sensing machinery exclusively through disruption of alpha1AMPK in Sertoli cells translates to a reduction in the quality of germ cells and fertility. PMID- 26772143 TI - Can Internet-Based Sexual Health Services Increase Diagnoses of Sexually Transmitted Infections (STI)? Protocol for a Randomized Evaluation of an Internet Based STI Testing and Results Service. AB - BACKGROUND: Ensuring rapid access to high quality sexual health services is a key public health objective, both in the United Kingdom and internationally. Internet based testing services for sexually transmitted infections (STIs) are considered to be a promising way to achieve this goal. This study will evaluate a nascent online STI testing and results service in South East London, delivered alongside standard face-to-face STI testing services. OBJECTIVE: The aim of this study is to establish whether an online testing and results services can (1) increase diagnoses of STIs and (2) increase uptake of STI testing, when delivered alongside standard face-to-face STI testing services. METHODS: This is a single blind randomized controlled trial. We will recruit 3000 participants who meet the following eligibility criteria: 16-30 years of age, resident in the London boroughs of Lambeth and Southwark, having at least one sexual partner in the last 12 months, having access to the Internet and willing to take an STI test. People unable to provide informed consent and unable to read and understand English (the websites will be in English) will be excluded. Baseline data will be collected at enrolment. This includes participant contact details, demographic data (date of birth, gender, ethnicity, and sexual orientation), and sexual health behaviors (last STI test, service used at last STI test and number of sexual partners in the last 12 months). Once enrolled, participants will be randomly allocated either (1) to an online STI testing and results service (Sexual Health 24) offering postal self-administered STI kits for chlamydia, gonorrhoea, syphilis, and HIV; results via text message (short message service, SMS), except positive results for HIV, which will be delivered by phone; and direct referrals to local clinics for treatment or (2) to a conventional sexual health information website with signposting to local clinic-based sexual health services. Participants will be free to use any other interventions or services during the trial period. At 6 weeks from randomization we will collect self-reported follow-up data on service use, STI tests and results, treatment prescribed, and acceptability of STI testing services. We will also collect objective data from participating STI testing services on uptake of STI testing, STI diagnoses and treatment. We hypothesise that uptake of STI testing and STI diagnoses will be higher in the intervention arm. Our hypothesis is based on the assumption that the intervention is less time-consuming, more convenient, more private, and incur less stigma and embarrassment than face-to-face STI testing pathways. The primary outcome measure is diagnosis of any STI at 6 weeks from randomization and our co-primary outcome is completion of any STI test at 6 weeks from randomization. We define completion of a test, as samples returned, processed, and results delivered to the intervention and/or clinic settings. We will use risk ratios to calculate the effect of the intervention on our primary outcomes with 95% confidence intervals. All analyses will be based on the intention-to-treat (ITT) principle. RESULTS: This study is funded by Guy's and St Thomas' Charity and it has received ethical approval from NRES Committee London-Camberwell St Giles (Ref 14/LO/1477). Research and Development approval has been obtained from Kings College Hospital NHS Foundation Trust and Guy's and St Thomas' NHS Foundation Trust. Results are expected in June 2016. CONCLUSIONS: This study will provide evidence on the effectiveness of an online STI testing and results service in South East London. Our findings may also be generalizable to similar populations in the United Kingdom. TRIAL REGISTRATION: International Standard Randomized Controlled Trial Number (ISRCTN): 13354298; http://www.isrctn.com/ISRCTN13354298 (Archived by WebCite at http://www.webcitation.org/6d9xT2bPj). PMID- 26772145 TI - Feedback processing in children and adolescents: Is there a sensitivity for processing rewarding feedback? AB - Developmental studies indicate that children rely more on external feedback than adults. Some of these studies claim that they additionally show higher sensitivity toward positive feedback, while others find they preferably use negative feedback for learning. However, these studies typically did not disentangle feedback valence and expectancy, which might contribute to the controversial results. The present study aimed at examining the neurophysiological correlates of feedback processing in children (8-10 years) and adolescents (12-14 years) in a time estimation paradigm that allows separating the contribution of valence and expectancy. Our results show that in the feedback related negativity (FRN), an event-related potential (ERP) reflecting the fast initial processing of feedback stimuli, children and adolescents did not differentiate between unexpected positive and negative feedback. Thus, they did not show higher sensitivity to positive feedback. The FRN did also not differentiate between expected and unexpected feedback, as found for adults. In contrast, in a later processing stage mirrored in the P300 component of the ERP, children and adolescents processed the feedback's unexpectedness. Interestingly, adolescents with better behavioral adaptation (high-performers) also had a more frontal P300 expectancy effect. Thus, the recruitment of additional frontal brain regions might lead to better learning from feedback in adolescents. PMID- 26772144 TI - Speed-accuracy strategy regulations in prefrontal tumor patients. AB - The ability to flexibly switch between fast and accurate decisions is crucial in everyday life. Recent neuroimaging evidence suggested that left lateral prefrontal cortex plays a role in switching from a quick response strategy to an accurate one. However, the causal role of the left prefrontal cortex in this particular, non-verbal, strategy switch has never been demonstrated. To fill this gap, we administered a perceptual decision-making task to neuro-oncological prefrontal patients, in which the requirement to be quick or accurate changed randomly on a trial-by-trial basis. To directly assess hemispheric asymmetries in speed-accuracy regulation, patients were tested a few days before and a few days after surgical excision of a brain tumor involving either the left (N=13) or the right (N=12) lateral frontal brain region. A group of age- and education-matched healthy controls was also recruited. To gain more insight on the component processes implied in the task, performance data (accuracy and speed) were not only analyzed separately but also submitted to a diffusion model analysis. The main findings indicated that the left prefrontal patients were impaired in appropriately adopting stricter response criteria in speed-to-accuracy switching trials with respect to healthy controls and right prefrontal patients, who were not impaired in this condition. This study demonstrates that the prefrontal cortex in the left hemisphere is necessary for flexible behavioral regulations, in particular when setting stricter response criteria is required in order to successfully switch from a speedy strategy to an accurate one. PMID- 26772146 TI - Personality and cognitive profiles of a general synesthetic trait. AB - The recent sharp increase in studies on synesthesia has taught us a lot about this fascinating condition. Still, while we define synesthesia as 'the mixing of senses', the great majority of synesthesia studies focus on only one synesthesia type (in particular grapheme-color synesthesia). In this study, a large group of subjects are tested on the presence or absence of different types of synesthesia. Efforts to recruit a representative sample of the Dutch population, not related to or aware of synesthesia as a research topic, helped counter a selection bias or a self-report bias in our subject group. A sharp increase in synesthesia prevalence was found, at least partially due to including many different types of synesthesia in the synesthesia 'diagnoses'. The five synesthesia types reported in the Novich et al (2011) study were obtained; Colored Sequences, Colored Music, Colored Sensations, Spatial Sequences, Non-Visual Sequelae, as well as an additional synesthesia type, Sequence-Personality. No differences were found between synesthetes and non-synesthetes in education level, handedness, age, and sex. The synesthetes showed increased intelligence as compared with matched non synesthetes. This was a general effect rather than bound to a specific cognitive domain or to a specific (synesthesia-type to stimulus-material) relationship. The expected effect of increased "Openness" in synesthetes was obtained, as well as two unexpected effects in personality traits (increased "Neuroticism" and decreased "Conscientiousness"). We also found increased "Emotionality" (experiencing emotions) and increased "Fantasizing", but synesthetes did not differ in cognitive appraisal of emotions (identifying/analyzing/verbalizing of emotions). The personality and cognitive characteristics were found related to having synesthesia (in general) rather then to particular synesthesia subtypes. This supports the existence of a general synesthetic 'trait', over the notion of relatively independent 'types' of synesthesia. In further support, exploratory analyses showed that a measurement of synesthetic strength (number of subtypes of synesthesia) correlates with stronger findings (increased "Openness", "Fantasizing", and "Emotionality", and decreased "Conscientiousness"). In conclusion, results are in line with the notion of a general synesthetic 'trait', and this synesthetic trait is associated with particular personality traits and cognitive characteristics. PMID- 26772147 TI - Three-dimensional analysis of morphological changes in the malaria parasite infected red blood cell by serial block-face scanning electron microscopy. AB - The human malaria parasite, Plasmodium falciparum, exhibits morphological changes during the blood stage cycle in vertebrate hosts. Here, we used serial block-face scanning electron microscopy (SBF-SEM) to visualize the entire structures of P. falciparum-infected red blood cells (iRBCs) and to examine their morphological and volumetric changes at different stages. During developmental stages, the parasite forms Maurer's clefts and vesicles in the iRBC cytoplasm and knobs on the iRBC surface, and extensively remodels the iRBC structure for proliferation of the parasite. In our observations, the Maurer's clefts and vesicles in the P. falciparum-iRBCs, resembling the so-called tubovesicular network (TVN), were not connected to each other, and continuous membrane networks were not observed between the parasitophorous vacuole membrane (PVM) and the iRBC cytoplasmic membrane. In the volumetric analysis, the iRBC volume initially increased and then decreased to the end of the blood stage cycle. This suggests that it is necessary to absorb a substantial amount of nutrients from outside the iRBC during the initial stage, but to release waste materials from inside the iRBC at the multinucleate stage. Transportation of the materials may be through the iRBC membrane, rather than a special structure formed by the parasite, because there is no direct connection between the iRBC membrane and the parasite. These results provide new insights as to how the malaria parasite grows in the iRBC and remodels iRBC structure during developmental stages; these observation can serve as a baseline for further experiments on the effects of therapeutic agents on malaria. PMID- 26772148 TI - Crystal structure of Rv2258c from Mycobacterium tuberculosis H37Rv, an S-adenosyl l-methionine-dependent methyltransferase. AB - The Mycobacterium tuberculosis Rv2258c protein is an S-adenosyl-L-methionine (SAM)-dependent methyltransferase (MTase). Here, we have determined its crystal structure in three forms: a ligand-unbound form, a binary complex with sinefungin (SFG), and a binary complex with S-adenosyl-L-homocysteine (SAH). The monomer structure of Rv2258c consists of two domains which are linked by a long alpha helix. The N-terminal domain is essential for dimerization and the C-terminal domain has the Class I MTase fold. Rv2258c forms a homodimer in the crystal, with the N-terminal domains facing each other. It also exists as a homodimer in solution. A DALI structural similarity search with Rv2258c reveals that the overall structure of Rv2258c is very similar to small-molecule SAM-dependent MTases. Rv2258c interacts with the bound SFG (or SAH) in an extended conformation maintained by a network of hydrogen bonds and stacking interactions. Rv2258c has a relatively large hydrophobic cavity for binding of the methyl-accepting substrate, suggesting that bulky nonpolar molecules with aromatic rings might be targeted for methylation by Rv2258c in M. tuberculosis. However, the ligand binding specificity and the biological role of Rv2258c remain to be elucidated due to high variability of the amino acid residues defining the substrate-binding site. PMID- 26772149 TI - Risk of Recurrent Pancreatitis and Progression to Chronic Pancreatitis After a First Episode of Acute Pancreatitis. AB - BACKGROUND & AIMS: Patients with a first episode of acute pancreatitis can develop recurrent or chronic pancreatitis (CP). However, little is known about the incidence or risk factors for these events. METHODS: We performed a cross sectional study of 669 patients with a first episode of acute pancreatitis admitted to 15 Dutch hospitals from December 2003 through March 2007. We collected information on disease course, outpatient visits, and hospital readmissions, as well as results from imaging, laboratory, and histology studies. Standardized follow-up questionnaires were sent to all available patients to collect information on hospitalizations and interventions for pancreatic disease, abdominal pain, steatorrhea, diabetes mellitus, medications, and alcohol and tobacco use. Patients were followed up for a median time period of 57 months. Primary end points were recurrent pancreatitis and CP. Risk factors were evaluated using regression analysis. The cumulative risk was assessed using Kaplan-Meier analysis. RESULTS: Recurrent pancreatitis developed in 117 patients (17%), and CP occurred in 51 patients (7.6%). Recurrent pancreatitis developed in 12% of patients with biliary disease, 24% of patients with alcoholic etiology, and 25% of patients with disease of idiopathic or other etiologies; CP occurred in 3%, 16%, and 10% of these patients, respectively. Etiology, smoking, and necrotizing pancreatitis were independent risk factors for recurrent pancreatitis and CP. Acute Physiology and Chronic Health Evaluation II scores at admission also were associated independently with recurrent pancreatitis. The cumulative risk for recurrent pancreatitis over 5 years was highest among smokers at 40% (compared with 13% for nonsmokers). For alcohol abusers and current smokers, the cumulative risks for CP were similar-approximately 18%. In contrast, the cumulative risk of CP increased to 30% in patients who smoked and abused alcohol. CONCLUSIONS: Based on a retrospective analysis of patients admitted to Dutch hospitals, a first episode of acute pancreatitis leads to recurrent pancreatitis in 17% of patients, and almost 8% of patients progress to CP within 5 years. Progression was associated independently with alcoholic etiology, smoking, and a history of pancreatic necrosis. Smoking is the predominant risk factor for recurrent disease, whereas the combination of alcohol abuse and smoking produces the highest cumulative risk for chronic pancreatitis. PMID- 26772150 TI - Association Between VDR FokI Polymorphism and Intervertebral Disk Degeneration. AB - Intervertebral disk degeneration (IDD) is strongly associated with genetic predisposition and environmental susceptibility. Several studies been conducted to investigate the potential association between IDD and FokI polymorphism located in the gene encoding the vitamin D receptor (VDR), and inconsistent conclusions had been reached among different ethnic populations. In order to assess the association between the FokI polymorphism and the risk of IDD, we performed a comprehensive and systematic meta-analysis. Candidate articles were retrieved from PubMed, EMBASE, China National Knowledge Infrastructure (CNKI), and China Biology Medical (CBM) with strict inclusion criteria in January 2015. Among the 54 articles that were retrieved, only eight studies met the inclusion criteria. The pooled data analysis based on allele contrast, homozygote, heterozygote, dominant, and recessive models revealed no significant correlation between the FokI polymorphism and the risk of IDD. However, when stratified by ethnicity, significant associations were detected for Hispanics based on allele contrast (OR=1.395, 95% CI=1.059-1.836, P=0.018), homozygote (OR=1.849, 95% CI=1.001-3.416, P=0.049), heterozygote (OR=1.254, 95% CI=1.049-1.498, P=0.013), and dominant (OR=1.742, 95% CI=1.174-2.583, P=0.006) models, and for Asians using the dominant model (OR=1.293, 95% CI=1.025-1.632, P=0.030), whereas there is no significant association detected for Caucasians. In conclusion, FokI polymorphism is not generally associated with IDD, but there is increased risk for IDD in Hispanics and Asians carrying FokI allele T. PMID- 26772154 TI - LincRNAs and base modifications of p53 induced by arsenic methylation in workers. AB - Arsenic (As) metabolites could induce methylation changes of DNA and base modifications of p53, which play role in the toxicity of As. LincRNAs should play a key regulatory role in the p53 transcriptional response. There were 43 workers producing As trioxide, 36 workers who stopped exposure to As trioxide about 85 days ago, and 24 individuals as control group. Three As species in urine were measured, and primary and secondary methylation indexes, iAs%, MMA% and DMA% were calculated. RT-PCR was performed to detect the expression of 7 LincRNAs and the base modifications of exon 5, 6, 7, and 8 of p53. The concentrations of urinary As were high in workers. Compared to control group, significant changes for 5 LincRNAs in workers producing As trioxide were found (P < 0.05), and there were significant base modifications of p53 in workers came from the two plants (P < 0.05). There exist various correlations between different exon base modifications of p53 and expressions of LincRNAs (P < 0.05). The closely positive correlations between MMA/DMA and MEG3/TUG1/HOTAIR/MALAT1 were found, but negative correlation between DMA/MALAT1 and the base modifications of exon 7 and 8 of p53 were found also (P < 0.05). LincRNAs and base modifications of p53 could be induced by As, MALAT1 and the base modifications of exon 7 and 8 of p53 could play unique roles in epigenic changes. These findings suggest potentially widespread roles of p53 and relative RNAs in arsenic workers, which may be caused by As metabolism. PMID- 26772152 TI - Enzymatic and non-enzymatic functions of the lysyl oxidase family in bone. AB - Advances in the understanding of the biological roles of the lysyl oxidase family of enzyme proteins in bone structure and function are reviewed. This family of proteins is well-known as catalyzing the final reaction required for cross linking of collagens and elastin. Novel emerging roles for these proteins in the phenotypic development of progenitor cells and in angiogenesis are highlighted and which point to enzymatic and non-enzymatic roles for this family in bone development and homeostasis and in disease. The explosion of interest in the lysyl oxidase family in the cancer field highlights the need to have a better understanding of the functions of this protein family in normal and abnormal connective tissue homeostasis at fundamental molecular and cellular levels including in mineralized tissues. PMID- 26772153 TI - Molecular detection and genetic characterization of Toxoplasma gondii infection in sika deer (Cervus nippon) in China. AB - The objective of the present study was to investigate the prevalence and genetic characterization of Toxoplasma gondii infection in sika deer in China. During August 2014 to November 2014, a total of 450 tissue samples coming from 150 sika deer were collected to detect the T. gondii B1 gene using a nested PCR, and the positive samples were genotyped at 11 genetic markers (SAG1, 5'- and 3'-SAG2, alternative SAG2, SAG3, BTUB, GRA6, L358, PK1, c22-8, c29-2, and Apico) using multilocus polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technology. Seventeen of 150 sika deer (11.33%) were tested positive by nested PCR. Six DNA samples from the 17 positive samples were completely typed, in which 4 samples from lung tissues, and 2 from muscular tissues, were identified as ToxoDB Genotype #9 (http://toxodb.org/toxo/). The results of the present study revealed the existence of T. gondii infection in sika deer in China, which provided the information of T. gondii genetic diversity in this host species. This study also indicated that ToxoDB Genotype #9 has a wide distribution in sika deer that could be potential reservoirs for T. gondii transmission, which may pose a threat to human health. PMID- 26772151 TI - Stress-induced neuroinflammation is mediated by GSK3-dependent TLR4 signaling that promotes susceptibility to depression-like behavior. AB - Most psychiatric and neurological diseases are exacerbated by stress. Because this may partially result from stress-induced inflammation, we examined factors involved in this stress response. After a paradigm of inescapable foot shock stress that causes learned helplessness depression-like behavior, eighteen cytokines and chemokines increased in mouse hippocampus, peaking 6-12h after stress. A 24h prior pre-conditioning stress accelerated the rate of stress induced hippocampal cytokine and chemokine increases, with most reaching peak levels after 1-3h, often without altering the maximal levels. Toll-like receptor 4 (TLR4) was involved in this response because most stress-induced hippocampal cytokines and chemokines were attenuated in TLR4 knockout mice. Stress activated glycogen synthase kinase-3 (GSK3) in wild-type mouse hippocampus, but not in TLR4 knockout mice. Administration of the antidepressant fluoxetine or the GSK3 inhibitor TDZD-8 reduced the stress-induced increases of most hippocampal cytokines and chemokines. Stress increased hippocampal levels of the danger associated molecular pattern (DAMP) protein high mobility group box 1 (HMGB1), activated the inflammatory transcription factor NF-kappaB, and the NLRP3 inflammasome. Knockdown of HMGB1 blocked the acceleration of cytokine and chemokine increases in the hippocampus caused by two successive stresses. Fluoxetine treatment blocked stress-induced up-regulation of HMGB1 and subsequent NF-kappaB activation, whereas TDZD-8 administration attenuated NF-kappaB activation downstream of HMGB1. To test if stress-induced cytokines and chemokines contribute to depression-like behavior, the learned helplessness model was assessed. Antagonism of TNFalpha modestly reduced susceptibility to learned helplessness induction, whereas TLR4 knockout mice were resistant to learned helplessness. Thus, stress-induces a broad inflammatory response in mouse hippocampus that involves TLR4, GSK3, and downstream inflammatory signaling, and these stress responses contribute to susceptibility to depression-like behavior in mice. PMID- 26772156 TI - Protective effect of hyperoside against acetaminophen (APAP) induced liver injury through enhancement of APAP clearance. AB - Acetaminphen (APAP) overdose leads to severe hepatotoxicity. Apocynum venetum L. (A. venetum) possess potent hepatoprotective effect. Hyperoside is one of the major compounds exist in Apocynum venetum L. and might be a potential agent to protect against APAP-induce liver injury. In this study, we investigated the effect of hyperoside on APAP hepatotoxicity in mice. Mice were treated intragastrically with hyperoside (10, 50 or 100 mg/kg) for 3 days before APAP (300 mg/kg) injection. APAP alone caused severe liver injury characterized by significantly increased serum aminotransferase levels, hepatic malondialdehyde (MDA) and 3-nitrotyrosine (3-NT) formation, as well as liver superoxide dismutase (SOD), glutathione peroxidase (GPx) and glutathione (GSH) depletions. Hyperoside significantly attenuated APAP-induced liver damages in a dose dependent manner, and 100 mg/kg was the most effective dose. Further study confirmed that hyperoside was able to increase activities and mRNA expressions of uridine diphoshate glucuronosyltransferases (UGTs) and sulfotransferases (SULTs), as well as to inhibit CYP2E1 activities, and thereby suppressed toxic intermediate formation and promoted APAP hepatic detoxification. Nrf-2 activation might be involved in hyperoside induced up-regulation of phase II enzymes. Collectively, our data provide evidence that hyperoside protected the liver against APAP induced injury mainly by accelerating APAP harmless metabolism, implying that hyperoside can be considered as a potential natural hepatoprotective agent. PMID- 26772155 TI - ROS-mediated endoplasmic reticulum stress and mitochondrial dysfunction underlie apoptosis induced by resveratrol and arsenic trioxide in A549 cells. AB - Although it is well documented that endoplasmic reticulum (ER) stress and mitochondrial dysfunction are associated with apoptosis, little is known about whether they are involved in the apoptotic cell death induced by resveratrol and arsenic trioxide (ATO) combination. In this study, we identified a series of sensitization effects of resveratrol on human lung adenocarcinoma A549 cells to ATO treatment, with the combination index (CI) of resveratrol and ATO less than 1. Then, we demonstrated that ER stress was contributed to this synergistic effect, which was manifested by increased the expression levels of ER stress hallmarks, including 78-kDa glucose-regulated protein (GRP 78), caspase 12 and C/EBP-homologous protein (CHOP), In addition, mitochondrial dysfunction was observed after exposure of A549 cells to resveratrol or/and ATO, which was displayed by some alterations of mitochondria-related events, such as loss of mitochondrial membrane potential, cytochrome c release and changes of Bax and Bcl 2 expressions. Our results further demonstrated that resveratrol and ATO-induced ER stress and mitochondrial dysfunction were mediated by reactive oxygen species (ROS), showing that pre-treatment of N-acetyl-l-cysteine, a potent ROS scavenger, restored the ER stress and mitochondrial dysfunction in cells co-treated with resveratrol and ATO, thereby leading to the reduction of the apoptosis. Collectively, these results clearly suggest that ROS-mediated ER stress and mitochondrial dysfunction were involved in the apoptosis induced by resveratrol and ATO in A549 cells, which provides a novel insight into the molecular mechanisms of resveratrol-mediated ATO-sensitization. PMID- 26772157 TI - In vitro anticancer activity of Betulinic acid and derivatives thereof on equine melanoma cell lines from grey horses and in vivo safety assessment of the compound NVX-207 in two horses. AB - Betulinic acid, a pentacyclic triterpene, and its derivatives are promising compounds for cancer treatment in humans. Melanoma is not only a problem for humans but also for grey horses as they have a high potential of developing melanoma lesions coupled to the mutation causing their phenotype. Current chemotherapeutic treatment carries the risk of adverse health effects for the horse owner or the treating veterinarian by exposure to antineoplastic compounds. Most treatments have low prospects for systemic tumor regression. Thus, a new therapy is needed. In this in vitro study, Betulinic acid and its two derivatives B10 and NVX-207, both with an improved water solubility compared to Betulinic acid, were tested on two equine melanoma cell lines (MelDuWi and MellJess/HoMelZh) and human melanoma (A375) cell line. We could demonstrate that all three compounds especially NVX-207 show high cytotoxicity on both equine melanoma cell lines. The treatment with these compounds lead to externalization of phosphatidylserines on the cell membrane (AnnexinV-staining), DNA fragmentation (cell cycle analysis) and activation of initiator and effector caspases (Caspase assays). Our results indicate that the apoptosis is induced in the equine melanoma cells by all three compounds. Furthermore, we succeed in encapsulating the most active compound NVX-207 in 2-Hydroxyprolyl-beta cyclodextrine without a loss of its activity. This formulation can be used as a promising antitumor agent for treating grey horse melanoma. In a first tolerability evaluation in vivo the formulation was administered every one week for 19 consecutive weeks and well tolerated in two adult melanoma affected horses. PMID- 26772159 TI - Production of a soluble single-chain variable fragment antibody against okadaic acid and exploration of its specific binding. AB - Okadaic acid is a lipophilic marine algal toxin commonly responsible for diarrhetic shellfish poisoning (DSP). Outbreaks of DSP have been increasing and are of worldwide public health concern; therefore, there is a growing demand for more rapid, reliable, and economical analytical methods for the detection of this toxin. In this study, anti-okadaic acid single-chain variable fragment (scFv) genes were prepared by cloning heavy and light chain genes from hybridoma cells, followed by fusion of the chains via a linker peptide. An scFv-pLIP6/GN recombinant plasmid was constructed and transformed into Escherichia coli for expression, and the target scFv was identified with IC-CLEIA (chemiluminescent enzyme immunoassay). The IC15 was 0.012 +/- 0.02 MUg/L, and the IC50 was 0.25 +/- 0.03 MUg/L. The three-dimensional structure of the scFv was simulated with computer modeling, and okadaic acid was docked to the scFv model to obtain a putative structure of the binding complex. Two predicted critical amino acids, Ser32 and Thr187, were then mutated to verify this theoretical model. Both mutants exhibited significant loss of binding activity. These results help us to understand this specific scFv-antigen binding mechanism and provide guidance for affinity maturation of the antibody in vitro. The high-affinity scFv developed here also has potential for okadaic acid toxin detection. PMID- 26772158 TI - Phase II Study of Haploidentical Natural Killer Cell Infusion for Treatment of Relapsed or Persistent Myeloid Malignancies Following Allogeneic Hematopoietic Cell Transplantation. AB - We conducted a phase 2 study to determine the efficacy of HLA-haploidentical related donor natural killer (NK) cells after cyclophosphamide-based lymphodepletion in patients with relapsed or progressive acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS) following allogeneic hematopoietic cell transplantation (HCT). Eight patients (2 with MDS and 6 with AML) were treated with cyclophosphamide 50 mg/kg on day -3 and day -2 before infusion of NK cells isolated from a haploidentical related donor. One patient also received fludarabine 25 mg/m2/day for 4 days. Six doses of 1 million units of interleukin-2 (IL-2) were administered on alternating days beginning on day 1. The median number of NK cells infused was 10.6 * 10(6)/kg (range, 4.3 to 22.4 * 10(6)/kg), and the median number of CD3 cells infused was 2.1 * 10(3)/kg (range, 1.9 to 40 * 10(3)/kg). NK infusions were well tolerated, with a median time to neutrophil recovery of 19 days (range, 7 days to not achieved) and no incidence of graft-versus-host disease after NK infusion. One patient with AML and 1 patient with MDS achieved a complete response, but relapsed at 1.7 and 1.8 months, respectively. One patient with MDS experienced resolution of dysplastic features but persistence of clonal karyotype abnormalities; this patient was stable at 65 months after NK cell therapy. The median duration of survival was 12.9 months (range, 0.8 to 65.3 months). Chimerism analysis of CD3(-)/CD56(+) peripheral blood cells did not detect any circulating haploidentical NK cells after infusion. NK phenotyping was performed in 7 patients during and after IL-2 infusion. We found a slight trend toward greater expression of KIR2DL2/2DL3/2DS2 (5% versus 28%; P = .03) at 14 days in patients who survived longer than 6 months from NK cell infusion (n = 4) compared with those who died within 6 months of NK cell therapy (n = 3). In summary, our data support the safety of haploidentical NK cell infusion after allogeneic HCT. PMID- 26772160 TI - Design and development of high bioluminescent resonance energy transfer efficiency hybrid-imaging constructs. AB - Here we describe the design and construction of an imaging construct with high bioluminescent resonance energy transfer (BRET) efficiency that is composed of multiple quantum dots (QDs; lambdaem = 655 nm) self-assembled onto a bioluminescent protein, Renilla luciferase (Rluc). This is facilitated by the streptavidin-biotin interaction, allowing the facile formation of a hybrid imaging construct (HIC) comprising up to six QDs (acceptor) grafted onto a light emitting Rluc (donor) core. The resulting assembly of multiple acceptors surrounding a donor permits this construct to exhibit high resonance energy transfer efficiency (~64.8%). The HIC was characterized using fluorescence excitation anisotropy measurements and high-resolution transmission electron microscopy. To demonstrate the application of our construct, a generation-5 (G5) polyamidoamine dendrimer (PAMAM) nanocarrier was loaded with our HIC for in vitro and in vivo imaging. We envision that this design of multiple acceptors and bioluminescent donor will lead to the development of new BRET-based systems useful in sensing, imaging, and other bioanalytical applications. PMID- 26772161 TI - Cannabinoid receptor 1 ligands revisited: Pharmacological assessment in the ACTOne system. AB - In vitro cannabinoid pharmacology has evolved over time from simple receptor binding to include [(35)S]GTPgamma, beta-arrestin, and cAMP assays. Each assay has benefits and drawbacks; however, no single functional system has been used for high-throughput evaluation of compounds from binding to pharmacological functionality and antagonist assessment in a well-characterized human cell line. In this study, we evaluated and validated one system-ACTOne human embryonic kidney cells transfected with a cyclic nucleotide gated channel and cannabinoid receptor 1 (CB1)-and compared human CB1 affinity, functional, and antagonistic effects on cAMP with previously published results. The study was conducted on a diverse group of CB1 ligands, including endocannabinoids and related compounds, 2 AG, AEA, MAEA, and ACEA, the phytocannabinoid Delta(9) THC, and synthetic cannabinoids CP 55,940, WIN 55,212-2, SR 141716A, CP 945,598, and WIN 55,212-3. Our results were compared with literature values where human CB1 was used for affinity determination and cAMP was used as a functional readout. Here we report the first detailed evaluation of the ACTOne assay for the pharmacological evaluation of CB1 ligands. The results from the study reveal some interesting deviations from previously reported functional activities of the aforementioned ligands. PMID- 26772163 TI - Assessing the effect of manual physical activity on proximal hand phalanges using Hellenistic and modern skeletal samples from Greece. AB - In humans, physical activity is an important regulator of bone size. Furthermore, hand bones have been proposed as a potential avenue for assessing patterns of manual activity. However, there are very few studies presenting a metric comparison of proximal hand phalanges among different populations. Moreover, an osteoarchaeological approach to the manual activities performed by an ancient population is yet to be made. In this framework, this study aims at assessing and interpreting the metric variation in these bones between a documented modern Greek sample (20th century) and a Hellenistic sample from Demetrias (3rd-1st century BCE), in terms of size and sexual dimorphism. Ancient males were significantly larger than females for ten phalangeal measurements out of 35. Even though the degree of sexual dimorphism was lower in the Hellenistic material (the maximum sexual dimorphism observed - 12.46%) than in modern sample (the maximum observed - 21.19%), the ranking of rays and bone parts by sexual dimorphism was similar in both populations. No metric difference was observed between modern and ancient males, whereas ancient females were larger than modern females in seven dimensions (the maximum variation observed was 11.58%), which involved the bases and midshafts of phalanges. Given that these dimensions are affected by the degree of muscular recruitment for the formation of various hand grips, it is suggested that ancient females were involved in manual activities of greater grasping variance than modern females. Indeed, the historical and archaeological sources suggest that sexual distribution of labour in the Hellenistic society seems to explain the differences estimated between the sexes and the two populations under study. PMID- 26772162 TI - Nuclear magnetic resonance evidence for the dimer formation of beta amyloid peptide 1-42 in 1,1,1,3,3,3-hexafluoro-2-propanol. AB - Alzheimer's disease involves accumulation of senile plaques in which filamentous aggregates of amyloid beta (Abeta) peptides are deposited. Recent studies demonstrate that oligomerization pathways of Abeta peptides may be complicated. To understand the mechanisms of Abeta(1-42) oligomer formation in more detail, we have established a method to produce (15)N-labeled Abeta(1-42) suited for nuclear magnetic resonance (NMR) studies. For physicochemical studies, the starting protein material should be solely monomeric and all Abeta aggregates must be removed. Here, we succeeded in fractionating a "precipitation-resistant" fraction of Abeta(1-42) from an "aggregation-prone" fraction by high-performance liquid chromatography (HPLC), even from bacterially overexpressed Abeta(1-42). However, both Abeta(1-42) fractions after 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) treatment formed amyloid fibrils. This indicates that the "aggregation seed" was not completely monomerized during HFIP treatment. In addition, Abeta(1-42) dissolved in HFIP was found to display a monomer-dimer equilibrium, as shown by two-dimensional (1)H-(15)N NMR. We demonstrated that the initial concentration of Abeta during the HFIP pretreatment altered the kinetic profiles of Abeta fibril formation in a thioflavin T fluorescence assay. The findings described here should ensure reproducible results when studying the Abeta(1-42) peptide. PMID- 26772164 TI - A peculiar new virus-spermatozoon association in the bug Raphigaster nebulosa (Poda) (Heteroptera-Insecta). AB - The sperm of the heteropteran bug Raphigaster nebulosa (Poda) are of two types, differing in length and size of their flagella. The thicker sperm are shorter than the thinner ones and have large mitochondrial derivatives. The presence of virus particles associated with the plasma membrane of thinner sperm is described for the first time; thicker sperm are immune to virus infection. The fact that virus particles are present on thinner sperm only initiates considerations on the transmission of virus. PMID- 26772165 TI - High concentrations of H2O2 trigger hypertrophic cascade and phosphatase and tensin homologue (PTEN) glutathionylation in H9c2 cardiomyocytes. AB - Cardiac hypertrophy occurs in response to different stimuli and is mainly characterized by an enlargement of cardiomyocyte size. During hypertrophy, cardiomyocytes undergo not only radical changes of the cellular architecture but also activation of signaling cascades that counteract the atrophy genes. Experimental studies highlighted that chronic low concentrations of H2O2, induce a hypertrophic phenotype, while higher levels of H2O2 promote apoptosis. In this study, we explored the early and long-term hypertrophic effects of high concentrations of H2O2 on H9c2 rat cardiomyocytes. We found that 2-h stimulation with 200MUM H2O2 caused an early dramatic reduction of cell viability, accompanied, 5-days later, by increased cell size and up-regulation of atrial natriuretic peptide transcription. This hypertrophic phenotype is associated to increased Akt phosphorylation and a consequent reduction of the FOXO3a and atrogin-1 gene expression. Moreover, we observed that H2O2 caused the overexpression of miR-212/miR-132 cluster concomitantly to a down-regulation of PTEN transcript without changes in its protein expression. Noteworthy, we found that the treatment of cardiomyocytes with H2O2 further led to an increase of oxidized glutathione and glutathionylation of proteins, including PTEN. In conclusion, our results permit to reconstruct the molecular cascade triggering the cardiomyocyte hypertrophy upon high concentrations of H2O2. PMID- 26772166 TI - Reductions in neonatal listeriosis: "Collateral benefit" of Group B streptococcal prophylaxis? AB - OBJECTIVES: We tested the hypothesis that declines in Listeria monocytogenes in infants are related to declines in rates of early-onset Group B Streptococcus (GBS) infections associated with widespread prophylaxis using agents with Listeria activity. METHODS: We performed a retrospective cohort analysis using a national administrative database Pediatric Health Information System (PHIS). We searched for ICD-9 codes for Listeriosis in infants <30 days old and for early onset GBS infection of any kind in infants <5 days old during the study period. RESULTS: We identified 183 cases of Listeriosis in infants <30 days in the PHIS database from 1992 to 2013. We noted a statistically significant decline in case rates over the years studied: 4.78 cases per 10,000 admissions (1992-1995) to 2.24 (1996-2002) to 1.31 from (2003-2013) (p < 0.0001). Case rates of early-onset GBS dropped significantly over the study period: 30.10 cases per 1000 admissions (1992-1995) to 21.70 (1996-2002) to 18.57 (2003-2013) (p < 0.0001). There was a statistically significant correlation between yearly rates of Listeriosis and early-onset GBS (rho: 0.53; p = 0.01). CONCLUSIONS: These results support the hypothesis of a "collateral benefit" to widespread GBS prophylaxis and further support the position that empiric antibiotic regimens for febrile infants may no longer require Listeria activity. PMID- 26772167 TI - India needs to strengthen microbial disease surveillance strategies. PMID- 26772168 TI - Variation of Circulating Inflammatory Mediators in Staphylococcus aureus and Escherichia coli Bloodstream Infection. AB - BACKGROUND: The aim of this study was to examine the behavior of circulating inflammatory mediators and to exclude gram-positive from gram-negative bloodstream infections. Results may be helpful in selection of optimal specific antibiotic therapies. MATERIAL/METHODS: Mice (25-27 g) were randomized to 3 groups infected with Staphylococcus aureus (S. aureus) ATCC 25923, Escherichia coli (E. coli) ATCC 25922, or phosphate-buffered saline (PBS). The white blood cell count (WBC) and the concentrations of serum C-reactive protein (CRP), procalcitonin (PCT), interleukin (IL)-1alpha, IL-1beta, IL-6, IL-10, monocyte chemotactic protein-1 (MCP-1), and macrophage inflammatory protein-1alpha (MIP 1alpha) were detected in blood samples at different time intervals after intravenous tail injection. RESULTS: The results showed that compared to the control mice, infected animals exhibited significantly higher levels of all mediators after bacterial infection. Moreover, compared to the mice that received S. aureus, animals with E. coli infection showed significantly greater increases in serum IL-1alpha, IL-1beta, IL-6, MCP-1, and MIP-1alpha levels. CONCLUSIONS: These results suggest that the use of the analyzed serum markers at an early stage of bloodstream infection may give useful information for the clinician to distinguish gram-negative from gram-positive infections. PMID- 26772169 TI - Critical factors influencing physicians' intention to use computerized clinical practice guidelines: an integrative model of activity theory and the technology acceptance model. AB - BACKGROUND: With the widespread use of information communication technologies, computerized clinical practice guidelines are developed and considered as effective decision supporting tools in assisting the processes of clinical activities. However, the development of computerized clinical practice guidelines in Taiwan is still at the early stage and acceptance level among major users (physicians) of computerized clinical practice guidelines is not satisfactory. This study aims to investigate critical factors influencing physicians' intention to computerized clinical practice guideline use through an integrative model of activity theory and the technology acceptance model. METHODS: The survey methodology was employed to collect data from physicians of the investigated hospitals that have implemented computerized clinical practice guidelines. A total of 505 questionnaires were sent out, with 238 completed copies returned, indicating a valid response rate of 47.1 %. The collected data was then analyzed by structural equation modeling technique. RESULTS: The results showed that attitudes toward using computerized clinical practice guidelines (gamma = 0.451, p < 0.001), organizational support (gamma = 0.285, p < 0.001), perceived usefulness of computerized clinical practice guidelines (gamma = 0.219, p < 0.05), and social influence (gamma = 0.213, p < 0.05) were critical factors influencing physicians' intention to use computerized clinical practice guidelines, and these factors can explain 68.6 % of the variance in intention to use computerized clinical practice guidelines. CONCLUSIONS: This study confirmed that some subject (human) factors, environment (organization) factors, tool (technology) factors mentioned in the activity theory should be carefully considered when introducing computerized clinical practice guidelines. Managers should pay much attention on those identified factors and provide adequate resources and incentives to help the promotion and use of computerized clinical practice guidelines. Through the appropriate use of computerized clinical practice guidelines, the clinical benefits, particularly in improving quality of care and facilitating the clinical processes, will be realized. PMID- 26772170 TI - Facilitation of axon outgrowth via a Wnt5a-CaMKK-CaMKIalpha pathway during neuronal polarization. AB - BACKGROUND: Wnt5a, originally identified as a guidance cue for commissural axons, activates a non-canonical pathway critical for cortical axonal morphogenesis. The molecular signaling cascade underlying this event remains obscure. RESULTS: Through Ca(2+) imaging in acute embryonic cortical slices, we tested if radially migrating cortical excitatory neurons that already bore primitive axons were sensitive to Wnt5a. While Wnt5a only evoked brief Ca(2+) transients in immature neurons present in the intermediate zone (IZ), Wnt5a-induced Ca(2+) oscillations were sustained in neurons that migrated out to the cortical plate (CP). We wondered whether this early Wnt5a-Ca(2+) signaling during neuronal polarization has a morphogenetic consequence. During transition from round to polarized shape, Wnt5a administration to immature cultured cortical neurons specifically promoted axonal, but not dendritic, outgrowth. Pharmacological and genetic inhibition of the CaMKK-CaMKIalpha pathway abolished Wnt5a-induced axonal elongation, and rescue of CaMKIalpha in CaMKIalpha-knockdown neurons restored Wnt5a-mediated axon outgrowth. CONCLUSIONS: This study suggests that Wnt5a activates Ca(2+) signaling during a neuronal morphogenetic time window when axon outgrowth is critically facilitated. Furthermore, the CaMKK-CaMKIalpha cascade is required for the axonal growth effect of Wnt5a during neuronal polarization. PMID- 26772172 TI - Description of Sergentomyia phadangensis n. sp. (Diptera, Psychodidae) of Thailand. AB - BACKGROUND: Since 1996, there are emerging autochthonous cases of leishmaniasis in Thailand due to Leishmania "siamensis" and to L. martiniquensis explaining a recent interest for the sand fly fauna where Sergentomyia gemmea and Se. barraudi have been considered possible vectors in the country. METHODS: Field studies were undertaken in a cave of Phitsanulok Province, Thailand. Phlebotomine sandflies have been studied morphologically and some have been processed for molecular biology (sequencing of cytB rDNA). RESULTS: A new species of sand fly, belonging to the genus Sergentomyia: Se. phadangensis n. sp., is described. The association of the male and female is supported by the homology of the sequences of cytochrome b rDNA. CONCLUSIONS: The description of a new species in Thailand is of importance in view of the existence of autochthonous leishmaniases. PMID- 26772171 TI - Group-based exercise and cognitive-physical training in older adults with self reported cognitive complaints: The Multiple-Modality, Mind-Motor (M4) study protocol. AB - BACKGROUND: Dementia is associated with cognitive and functional deficits, and poses a significant personal, societal, and economic burden. Directing interventions towards older adults with self-reported cognitive complaints may provide the greatest impact on dementia incidence and prevalence. Risk factors for cognitive and functional deficits are multifactorial in nature; many are cardiovascular disease risk factors and are lifestyle-mediated. Evidence suggests that multiple-modality exercise programs can provide cognitive and functional benefits that extend beyond what can be achieved from cognitive, aerobic, or resistance training alone, and preliminary evidence suggests that novel mind motor interventions (i.e., Square Stepping Exercise; SSE) can benefit cognition and functional fitness. Nevertheless, it remains unclear whether multiple modality exercise combined with mind-motor interventions can benefit diverse cognitive and functional outcomes in older adults with cognitive complaints. METHODS/DESIGN: The Multiple-Modality, Mind-Motor (M4) study is a randomized controlled trial investigating the cognitive and functional impact of combined physical and cognitive training among community-dwelling adults with self reported cognitive complaints who are 55 years of age or older. Participants are randomized to a Multiple-Modality and Mind-Motor (M4) intervention group or a Multiple-Modality (M2) comparison group. Participants exercise for 60 minutes/day, 3-days/week for 24 weeks and are assessed at baseline, 24 weeks and 52 weeks. The primary outcome is global cognitive function at 24 weeks, derived from the Cambridge Brain Sciences computerized cognitive battery. Secondary outcomes are: i) global cognitive function at 52 weeks; ii) domain-specific cognitive function at 24 and 52 weeks; iii) mobility (gait characteristics under single and dual-task conditions and balance); and 3) vascular health (blood pressure and carotid arterial measurements). We will analyze data based on an intent-to-treat approach, using mixed models for repeated measurements. DISCUSSION: The design features of the M4 trial and the methods included to address previous limitations within cognitive and exercise research will be discussed. Results from the M4 trial will provide evidence of combined multiple modality and cognitive training among older adults with self-reported cognitive complaints on cognitive, mobility-related and vascular outcomes. TRIAL REGISTRATION: ClinicalTrials.gov NCT02136368. PMID- 26772173 TI - Reporting standards for guideline-based performance measures. AB - BACKGROUND: The Guidelines International Network (G-I-N) aims to promote high quality clinical guideline development and implementation. Guideline-based performance measures are a key implementation tool and are widely used internationally for quality improvement, quality assurance, and pay for performance in health care. There is, however, no international consensus on best methods for guideline-based performance measures. In order to address this issue, the G-I-N Performance Measures Working Group aimed to develop a set of consensus based reporting standards for guideline-based performance measure development and re-evaluation. METHODS: Methodology publications on guideline-based performance measures were identified from a systematic literature review and analyzed. Core criteria for the development and evaluation process of guideline-based performance measures were determined and refined into draft standards with an associated rationale and description of the evidence base. In a two-round Delphi process, the group members appraised and approved the draft standards. After the first round, the group met to discuss comments and revised the drafts accordingly. RESULTS: Twenty-one methodology publications were reviewed. The group reached strong consensus on nine reporting standards concerning: (1) selection of clinical guidelines, (2) extraction of clinical guideline recommendations, (3) description of the measure development process, (4) measure appraisal, (5) measure specification, (6) description of the intended use of the measure, (7) measure testing/validating, (8) measure review/re-evaluation, and (9) composition of the measure development panel. CONCLUSIONS: These proposed international reporting standards address core components of guideline-based performance measure development and re-evaluation. They are intended to contribute to international reporting harmonization and improvement of methods for performance measures. Further research is required regarding validity, acceptability, and practicality. PMID- 26772174 TI - "We're checking them out": Indigenous and non-Indigenous research participants' accounts of deciding to be involved in research. AB - BACKGROUND: It is important for researchers to understand the motivations and decision-making processes of participants who take part in their research. This enables robust informed consent and promotes research that meets the needs and expectations of the community. It is particularly vital when working with Indigenous communities, where there is a history of exploitative research practices. In this paper, we examine the accounts of Australian Indigenous and non-Indigenous research participants in terms of how and why they agree to take part in research. METHODS: A qualitative research approach was employed to undertake individual interviews with 36 research participants in Victoria, Australia. Eight participants identified as Indigenous and 28 were non Indigenous. Thematic analysis was used to interpret the data. RESULTS: There were stark differences between Indigenous and non-Indigenous research participants in terms of why and how they decided to participate in research. For Indigenous participants, taking part in research was primarily to benefit their communities rather than for personal interests. Indigenous participants often started from a position of caution, and showed a considered and deliberate process of decision making. In weighing up their decision to participate, some Indigenous participants clearly articulated what was valued in conducting research with Indigenous communities, for example, honesty, reciprocity, and respect; these values were explicitly used to assist their decision whether or not to participate. This was in contrast to non-Indigenous participants who took researchers' claims on face value, and for whom deciding to participate in research was relatively straightforward. The motivations to participate of non Indigenous participants were due to personal interests, a desire to help others, or trust in the medical practitioner who recruited them for the research project. CONCLUSION: Understanding research participants' motivations about taking part in research is important. This is particularly relevant for Indigenous communities where there is a reported history of research abuse leading to mistrust. This understanding can lead to research practice that is more respectful and responsive to the needs of Indigenous communities and abides by the values of Indigenous communities. Moreover it can lead to more ethical and respectful research practice for all. PMID- 26772175 TI - Downstream tests, treatments, and annual direct payments in older men cared for by primary care providers with high or low prostate-specific antigen screening rates using 100 percent Texas U.S. Medicare public insurance claims data: a retrospective cohort study. AB - BACKGROUND: All authorities recommend against prostate specific antigen (PSA) screening in men 75 years and older. However, some primary care physicians (PCPs) continue to have high rates of PSA, with large variation in testing. We assessed the tests, treatments, and payments for prostate cancer care in men aged 75 or older who have PCPs with high or low PSA testing rates. METHODS: We performed a retrospective cohort study using the 2010 Medicare beneficiaries aged 75 or older in Texas, United States who had no prostate cancer in 2007-2009 and had an identifiable PCP. We first identified high vs. low PSA testing PCPs, and then grouped older men in the two PCP groups. We determined health care visits to any provider and to urologists in office and outpatient settings. We estimated the direct medical payments for prostate cancer care for diagnostics, treatments and visits to providers in 2010-2011 using the generalized gamma model with log link function. RESULTS: In multilevel, multivariable analyses, 25.4% (n = 550) of PCPs had PSA testing rates in men aged 75 or older that were significantly higher than the mean rate of all 2,169 Texas PCPs; 29.4% (n = 638) had rates that were significantly lower. In all, 22,853 vs. 23,929 older men were cared for by PCPs with high vs. low testing rates. Older men cared for by high PSA rate PCPs were more likely to receive a PSA test (OR 3.64, 95% CI 3.48-3.80), a biopsy (OR 1.16, 95% CI 1.02-1.31), an ultrasound (OR 1.19, 95% CI 1.07-1.32) or any radiation treatment (OR 1.31, 95% CI 1.03-1.66) than men cared for by low PSA rate PCPs. Men with high PSA rate PCPs were 1.21 (95% CI 1.05-1.39) times more likely to have such outpatient visits. The average annual adjusted Medicare payments for prostate cancer care was $25.60 higher for patients cared for by PCPs with high PSA test rates. CONCLUSIONS: Older men seeing PCPs with high rates of PSA testing undergo more testing and treatments for prostate cancer, with higher Medicare insurance payments. Future studies are needed to delineate whether men seeing PCPs with low testing rates likely received PSA tests from other providers. PMID- 26772176 TI - Extended resection in pancreatic metastases: feasibility, frequency, and long term outcome: a retrospective analysis. AB - BACKGROUND: Metastases to the pancreas are rare, accounting for less then 2% of all pancreatic malignancies. However, both the benefit of extended tumor resection and the ideal oncological approach have not been established for such cases; therefore, we evaluated patients with metastasis to the pancreas who underwent pancreatic resection. METHODS: Between 1994 and 2012, 676 patients underwent pancreatic surgery in our institution. We retrospectively reviewed patients' medical records according to survival, and surgical and non-surgical complications. Student's t-test and the log-rank test were used for statistical analysis. RESULTS: Eighteen patients (2.7%) received resection for pancreatic metastases (12 multivisceral resections and 6 standard resections). The pancreatic metastases originated from renal cell carcinoma (n = 10), malignant melanoma (n = 2), neuroendocrine tumor of the ileum (n = 1), sarcoma (n = 1), colon cancer (n = 1), gallbladder cancer (n = 1), gastrointestinal stromal tumor (n = 1), and non-small cell lung cancer (n = 1). The median time between primary malignancy resection to metastasectomy was 83 months (range, 0-228 months). Minor surgical complications (Grade I-IIIa) occurred in six patients (33.3%) whereas major surgical complications (Grade IIIb-V) occurred in three patients (16.6%). No patients died during hospitalization. The median follow-up was 76 months (range, 10-165 months). One-year, 3-year and 5-year survival for standard resection versus multivisceral resection was 83, 50, and 56% versus 83, 66, and 50, respectively. Twelve patients died after a median of 26 months (range, 5-55 months). CONCLUSIONS: A surgical approach with curative intent is justified in select patients suffering from metastases to the pancreas and offers good long term survival. The resection of pancreatic metastases of different tumor types was associated with favorable morbidity and mortality when compared with resection of the primary pancreatic malignancies. Our findings also demonstrated that multivisceral resection was feasible, with acceptable long term outcomes, even though morbidity rates tended to be higher after multivisceral resection than after standard resection. PMID- 26772177 TI - Influences on eating: a qualitative study of adolescents in a periurban area in Lima, Peru. AB - BACKGROUND: Peruvian adolescents are at high nutritional risk, facing issues such as overweight and obesity, anemia, and pregnancy during a period of development. Research seeking to understand contextual factors that influence eating habits to inform the development of public health interventions is lacking in this population. This study aimed to understand socio-cultural influences on eating among adolescents in periurban Lima, Peru using qualitative methods. METHODS: Semi-structured interviews and pile sort activities were conducted with 14 adolescents 15-17 years. The interview was designed to elicit information on influences on eating habits at four levels: individual (intrapersonal), social environmental (interpersonal), physical environmental (community settings), and macrosystem (societal). The pile sort activity required adolescents to place cards with food images into groups and then to describe the characteristics of the foods placed in each group. Content analysis was used to identify predominant themes of influencing factors in interviews. Multidimensional scaling and hierarchical clustering analysis was completed with pile sort data. RESULTS: Individual influences on behavior included lack of financial resources to purchase food and concerns about body image. Nutrition-related knowledge also played a role; participants noted the importance of foods such as beans for anemia prevention. At the social environmental level, parents promoted healthy eating by providing advice on food selection and home-cooked meals. The physical environment also influenced intake, with foods available in schools being predominantly low-nutrient energy-dense. Macrosystem influences were evident, as adolescents used the Internet for nutrition information, which they viewed as credible. CONCLUSIONS: To address nutrition-related issues such as obesity and iron-deficiency anemia in Peruvian adolescents, further research is warranted to elucidate the roles of certain factors shaping behavior, particularly that of family, cited numerous times as having a positive influence. Addressing nutrition related issues such as obesity and iron-deficiency anemia in this population requires consideration of the effect of social and environmental factors in the context of adolescent lifestyles on behavior. Nutrition education messages for adolescents should consider the cultural perceptions and importance of particular foods, taking into account the diverse factors that influence eating behaviors. PMID- 26772179 TI - Situation awareness errors in anesthesia and critical care in 200 cases of a critical incident reporting system. AB - BACKGROUND: A loss of adequate Situation Awareness (SA) may play a major role in the genesis of critical incidents in anesthesia and critical care. This observational study aimed to determine the frequency of SA errors in cases of a critical incident reporting system (CIRS). METHODS: Two experts independently reviewed 200 cases from the German Anesthesia CIRS. For inclusion, reports had to be related to anesthesia or critical care for an individual patient and take place in an in-hospital setting. Based on the SA framework, the frequency of SA errors was determined. Representative cases were analyzed qualitatively to illustrate the role of SA for decision-making. RESULTS: SA errors were identified in 81.5%. Predominantly, errors occurred on the levels of perception (38.0%) and comprehension (31.5%). Errors on the level of projection played a minor role (12.0%). The qualitative analysis of selected cases illustrates the crucial role of SA for decision-making and performance. CONCLUSIONS: SA errors are very frequent in critical incidents reported in a CIRS. The SA taxonomy was suitable to provide mechanistic insights into the central role of SA for decision-making and thus, patient safety. PMID- 26772178 TI - svclassify: a method to establish benchmark structural variant calls. AB - BACKGROUND: The human genome contains variants ranging in size from small single nucleotide polymorphisms (SNPs) to large structural variants (SVs). High-quality benchmark small variant calls for the pilot National Institute of Standards and Technology (NIST) Reference Material (NA12878) have been developed by the Genome in a Bottle Consortium, but no similar high-quality benchmark SV calls exist for this genome. Since SV callers output highly discordant results, we developed methods to combine multiple forms of evidence from multiple sequencing technologies to classify candidate SVs into likely true or false positives. Our method (svclassify) calculates annotations from one or more aligned bam files from many high-throughput sequencing technologies, and then builds a one-class model using these annotations to classify candidate SVs as likely true or false positives. RESULTS: We first used pedigree analysis to develop a set of high confidence breakpoint-resolved large deletions. We then used svclassify to cluster and classify these deletions as well as a set of high-confidence deletions from the 1000 Genomes Project and a set of breakpoint-resolved complex insertions from Spiral Genetics. We find that likely SVs cluster separately from likely non-SVs based on our annotations, and that the SVs cluster into different types of deletions. We then developed a supervised one-class classification method that uses a training set of random non-SV regions to determine whether candidate SVs have abnormal annotations different from most of the genome. To test this classification method, we use our pedigree-based breakpoint-resolved SVs, SVs validated by the 1000 Genomes Project, and assembly-based breakpoint resolved insertions, along with semi-automated visualization using svviz. CONCLUSIONS: We find that candidate SVs with high scores from multiple technologies have high concordance with PCR validation and an orthogonal consensus method MetaSV (99.7 % concordant), and candidate SVs with low scores are questionable. We distribute a set of 2676 high-confidence deletions and 68 high-confidence insertions with high svclassify scores from these call sets for benchmarking SV callers. We expect these methods to be particularly useful for establishing high-confidence SV calls for benchmark samples that have been characterized by multiple technologies. PMID- 26772181 TI - Effect of maternal stress during pregnancy on the risk for preterm birth. AB - BACKGROUND: Preterm birth defined as birth prior to 37 weeks of gestation is caused by different risk factors and implies an increased risk for disease and early death for the child. The aim of the study was to investigate the effect of maternal stress during pregnancy on the risk of preterm birth. METHODS: A case control study that included 340 women; 168 women who gave birth preterm and 172 women who gave birth at term. Data were manually extracted from standardized medical records. If the medical record contained a psychiatric diagnosis or a self-reported stressor e.g., depression or anxiety the woman was considered to have been exposed to stress during pregnancy. Adjusted odds ratio (AOR) was used to calculate the attributable risk (AR) of maternal stress during pregnancy on preterm birth, both for the women exposed to stress during pregnancy (AR1 = (AOR 1)/AOR) and for the whole study population (AR2 = AR1*case fraction). RESULTS: Maternal stress during pregnancy was more common among women who gave birth preterm compared to women who gave birth at term (p <0.000, AOR 2.15 (CI = 1.18 3.92)). Among the women who experienced stress during pregnancy 54% gave birth preterm with stress as an attributable risk factor. Among all of the women the percentage was 23%. CONCLUSIONS: Stress seems to increase the risk of preterm birth. It is of great importance to identify and possibly alleviate the exposure to stress during pregnancy and by doing so try to decrease the preterm birth rate. PMID- 26772180 TI - Conceptual foundations of a palliative approach: a knowledge synthesis. AB - BACKGROUND: Much of what we understand about the design of healthcare systems to support care of the dying comes from our experiences with providing palliative care for dying cancer patients. It is increasingly recognized that in addition to cancer, high quality end of life care should be an integral part of care that is provided for those with other advancing chronic life-limiting conditions. A "palliative approach" has been articulated as one way of conceptualizing this care. However, there is a lack of conceptual clarity regarding the essential characteristics of a palliative approach to care. The goal of this research was to delineate the key characteristics of a palliative approach found in the empiric literature in order to establish conceptual clarity. METHODS: We conducted a knowledge synthesis of empirical peer-reviewed literature. Search terms pertaining to "palliative care" and "chronic life-limiting conditions" were identified. A comprehensive database search of 11 research databases for the intersection of these terms yielded 190,204 documents. A subsequent computer assisted approach using statistical predictive classification methods was used to identify relevant documents, resulting in a final yield of 91 studies. Narrative synthesis methods and thematic analysis were used to then identify and conceptualize key characteristics of a palliative approach. RESULTS: The following three overarching themes were conceptualized to delineate a palliative approach: (1) upstream orientation towards the needs of people who have life limiting conditions and their families, (2) adaptation of palliative care knowledge and expertise, (3) operationalization of a palliative approach through integration into systems and models of care that do not specialize in palliative care. CONCLUSION: Our findings provide much needed conceptual clarity regarding a palliative approach. Such clarity is of fundamental importance for the development of healthcare systems that facilitate the integration of a palliative approach in the care of people who have chronic life-limiting conditions. PMID- 26772183 TI - Pre-operative localization of solitary pulmonary nodules with computed tomography guided hook wire: report of 181 patients. AB - BACKGROUND: Video-assisted thoracic surgery (VATS) is currently performed to diagnose and treat solitary pulmonary nodules (SPN). However, the intra-operative identification of deep nodules can be challenging with VATS as the lung is difficult to palpate. The aim of the study was to report the utility and the results of pre-operative computed tomography (CT)-guided hook wire localization of SPN. METHODS: All records of the patients undergoing CT-guided hook wire localization prior to VATS resection for SPN between 2002 and 2013 were reviewed. The efficacy in localizing the nodule, hook wire complications, necessity to convert VATS to thoracotomy and the histology of SPN are reported. RESULTS: One hundred eighty-one patients (90 females, mean age 63 y, range 28-82 y) underwent 187 pulmonary resections after CT-guided hook wire localization. The mean SPN diameter was 10.3 mm (range: 4-29 mm). The mean distance of the lesion from the pleural surface was 11.6 mm (range: 0-45 mm). The mean time interval from hook wire insertion to VATS resection was 224 min (range 54-622 min). Hook wire complications included pneumothorax requiring chest tube drainage in 4 patients (2.1%) and mild parenchymal haemorrhage in 11 (5.9%) patients. Migration of the hook wire occurred in 7 patients (3.7%) although it did not affect the success of VATS resection (nodule location guided by the lung puncture site). Three patients underwent additional wedge resection by VATS during the same procedure because no lesion was identified in the surgical specimen. Conversion thoracotomy was required in 13 patients (7 %) for centrally localized lesions (6 patients) and pleural adhesions (7 patients). The mean operative time was 60 min (range 18-135 min). Pathological examination revealed a malignant lesion in 107 patients (59 %). The diagnostic yield was 98.3 %. CONCLUSION: VATS resection for SPN after CT guided hook wire localization for SPN is safe and allows for proper diagnosis with a low thoracotomy conversion rate. PMID- 26772182 TI - Nanoparticle-allergen interactions mediate human allergic responses: protein corona characterization and cellular responses. AB - BACKGROUND: Engineered nanomaterials (ENMs) interact with different biomolecules as soon as they are in contact, resulting in the formation of a biomolecule 'corona'. Hence, the 'corona' defines the biological identity of the ENMs and could affect the response of the immune system to ENM exposure. With up to 40 % of the world population suffering from type I allergy, a possible modulation of allergen effects by binding to ENMs is highly relevant with respect to work place and consumer safety. Therefore, the aim of this present study was to gain an insight into the interactions of gold nanoparticles with different seasonally and perennially occurring outdoor and indoor allergens. METHODS: Gold nanoparticles (AuNPs) were conjugated with the major allergens of birch pollen (Bet v 1), timothy grass pollen (Phl p 5) and house dust mite (Der p 1). The AuNP-allergen conjugates were characterized by means of TEM negative staining, dynamic light scattering (DLS), z-potential measurements and hyperspectral imaging. Furthermore, 3D models were constructed, based on the characterization data, to visualize the interaction between the allergens and the AuNPs surface. Differences in the activation of human basophil cells derived from birch/grass pollen- and house dust mite-allergic patients in response to free allergen and AuNP-allergen conjugates were determined using the basophil activation assay (BAT). Potential allergen corona replacement during BAT was controlled for using Western blotting. The protease activity of AuNP-Der p 1 conjugates compared to free Der p 1 was assessed, by an enzymatic activity assay and a cellular assay pertaining to lung type II alveolar epithelial cell tight junction integrity. RESULTS: The formation of a stable corona was found for all three allergens used. Our data suggest, that depending on the allergen, different effects are observed after binding to ENMs, including enhanced allergic responses against Der p 1 and also, for some patients, against Bet v 1. Moreover elevated protease activity of AuNP-Der p 1 conjugates compared to free Der p 1 was found. CONCLUSION: In summary, this study presents that conjugation of allergens to ENMs can modulate the human allergic response, and that protease activity can be increased. Graphical Abstract Cross-linking of IgE receptors and degranulation of human basophils due to epitope alignment of nanoparticle-coated allergens. PMID- 26772185 TI - Predictors of increasing injury severity across suspected recurrent episodes of non-accidental trauma: a retrospective cohort study. AB - BACKGROUND: Little is known about how the severity of injury changes with recurrent events of suspected non-accidental trauma (NAT). Our objective was to determine risk factors for escalating severity of injury in children with multiple events of suspected NAT. METHODS: This retrospective longitudinal cohort study included children from a pediatric Medicaid accountable care organization with >= 1 non-birth related episode containing an International Classification of Diseases, Ninth Revision, Clinical Modification or Current Procedural Terminology code for NAT or a skeletal survey between 2007 and 2011. Subsequent potential NAT events were defined as independent episodes with codes for either NAT, a skeletal survey, or injuries suspicious for abuse. Severity of injury was calculated using the New Injury Severity Score (NISS). Multivariable Cox proportional hazards regression modeling was used with results expressed as hazard ratios and 95 % confidence intervals. RESULTS: Of the 914 children with at least one suspected NAT event, 39 % had at least one suspected recurrent NAT event; 12 % had 2 events and 5 % had >= 3 events during follow-up. Factors associated with an increased risk for a recurrent episode of suspected NAT with higher NISS were living in a rural area (1.69, 1.02-2.78, p = 0.04) and having an open wound (2.12, 1.24-3.62, p = 0.006), or superficial injury (2.28, 1.31-3.98, p = 0.004). In contrast, a greater number of injuries was associated with a decreased risk for a recurrent episode of suspected NAT with higher NISS (p < 0.0001). CONCLUSIONS: Though limited by a lack of follow-up of children placed in out of home care, our results suggest that children with "minor" or less numerous injuries are either not reported to child protective services or not removed from the unsafe environment with either situation leading to subsequent events. The medical and child welfare systems need to better identify these potential victims of recurrent events.. PMID- 26772184 TI - Functional analysis of monoclonal antibodies against the Plasmodium falciparum PfEMP1-VarO adhesin. AB - BACKGROUND: Rosetting, namely the capacity of the Plasmodium falciparum-infected red blood cells to bind uninfected RBCs, is commonly observed in African children with severe malaria. Rosetting results from specific interactions between a subset of variant P. falciparum erythrocyte membrane protein 1 (PfEMP1) adhesins encoded by var genes, serum components and RBC receptors. Rosette formation is a redundant phenotype, as there exists more than one var gene encoding a rosette mediating PfEMP1 in each genome and hence a diverse array of underlying interactions. Moreover, field diversity creates a large panel of rosetting associated serotypes and studies with human immune sera indicate that surface reacting antibodies are essentially variant-specific. To gain better insight into the interactions involved in rosetting and map surface epitopes, a panel of monoclonal antibodies (mAbs) was investigated. METHODS: Monoclonal antibodies were isolated from mice immunized with PfEMP1-VarO recombinant domains. They were characterized using ELISA and reactivity with the native PfEMP1-VarO adhesin on immunoblots of reduced and unreduced extracts, as well as SDS-extracts of Palo Alto 89F5 VarO schizonts. Functionality was assessed using inhibition of Palo Alto 89F5 VarO rosette formation and disruption of Palo Alto 89F5 VarO rosettes. Competition ELISAs were performed with biotinylated antibodies against DBL1 to identify reactivity groups. Specificity of mAbs reacting with the DBL1 adhesion domain was explored using recombinant proteins carrying mutations abolishing RBC binding or binding to heparin, a potent inhibitor of rosette formation. RESULTS: Domain-specific, surface-reacting mAbs were obtained for four individual domains (DBL1, CIDR1, DBL2, DBL4). Monoclonal antibodies reacting with DBL1 potently inhibited the formation of rosettes and disrupted Palo Alto 89F5 VarO rosettes. Most surface-reactive mAbs and all mAbs interfering with rosetting reacted on parasite immunoblots with disulfide bond-dependent PfEMP1 epitopes. Based on competition ELISA and binding to mutant DBL1 domains, two distinct binding sites for rosette-disrupting mAbs were identified in close proximity to the RBC-binding site. CONCLUSIONS: Rosette-inhibitory antibodies bind to conformation-dependent epitopes located close to the RBC-binding site and distant from the heparin binding site. These results provide novel clues for a rational intervention strategy that targets rosetting. PMID- 26772187 TI - Realistic Instrumentation Platform for Active and Passive Optical Remote Sensing. AB - We describe the development of a novel versatile optical platform for active and passive remote sensing of environmental parameters. Applications include assessment of vegetation status and water quality. The system is also adapted for ecological studies, such as identification of flying insects including agricultural pests. The system is based on two mid-size amateur astronomy telescopes, continuous-wave diode lasers at different wavelengths ranging from violet to the near infrared, and detector facilities including quadrant photodiodes, two-dimensional and line scan charge-coupled device cameras, and a compact digital spectrometer. Application examples include remote Ramanlaser induced fluorescence monitoring of water quality at 120 m distance, and insect identification at kilometer ranges using the recorded wing beat frequency and its spectrum of overtones. Because of the low cost this developmental platform is very suitable for advanced research projects in developing countries and has, in fact, been multiplied during hands-on workshops and is now being used by a number of groups at African universities. PMID- 26772186 TI - Non-acidic activation of pain-related Acid-Sensing Ion Channel 3 by lipids. AB - Extracellular pH variations are seen as the principal endogenous signal that triggers activation of Acid-Sensing Ion Channels (ASICs), which are basically considered as proton sensors, and are involved in various processes associated with tissue acidification. Here, we show that human painful inflammatory exudates, displaying non-acidic pH, induce a slow constitutive activation of human ASIC3 channels. This effect is largely driven by lipids, and we identify lysophosphatidylcholine (LPC) and arachidonic acid (AA) as endogenous activators of ASIC3 in the absence of any extracellular acidification. The combination of LPC and AA evokes robust depolarizing current in DRG neurons at physiological pH 7.4, increases nociceptive C-fiber firing, and induces pain behavior in rats, effects that are all prevented by ASIC3 blockers. Lipid-induced pain is also significantly reduced in ASIC3 knockout mice. These findings open new perspectives on the roles of ASIC3 in the absence of tissue pH variation, as well as on the contribution of those channels to lipid-mediated signaling. PMID- 26772188 TI - Low blood levels of bicarbonate are linked to premature death in healthy older people, study shows. PMID- 26772190 TI - Production of biobutanol from cellulose hydrolysate by the Escherichia coli co culture system. AB - The commercialization of the n-butanol bioprocess is largely dependent on the price of feedstocks. Renewable cellulose appears to be an appealing feedstock. The microbial production of n-butanol still remains challenging because of the limited availability of intracellular NADH. To address this issue, an Escherichia coli strain carrying the clostridial CoA-dependent pathway was supplied with heterologous formate dehydrogenase. With the cellulose hydrolysate of rice straw, this single strain produced cellulosic biobutanol with a production yield at 35% of the theoretical and a productivity of 0.093 g L(-1) h(-1). In an alternative method, the production involved a co-culture system consisting of two separate strains provided with the full CoA-dependent pathway. This system achieved a production yield and productivity reaching 62.8% of the theoretical and 0.163 g L(-1) h(-1), respectively. The result indicates that the E. coli co-culture system is technically promising for the production of cellulosic biobutanol. PMID- 26772191 TI - India is at high risk from surge in cases of melioidosis, warn researchers. PMID- 26772189 TI - Epoxyeicosatrienoic acid analogue mitigates kidney injury in a rat model of radiation nephropathy. AB - Arachidonic acid is metabolized to epoxyeicosatrienoic acids (EETs) by CYP epoxygenases, and EETs are kidney protective in multiple pathologies. We determined the ability of an EET analogue, EET-A, to mitigate experimental radiation nephropathy. The kidney expression of the EET producing enzyme CYP2C11 was lower in rats that received total body irradiation (TBI rat) compared with non-irradiated control. At 12 weeks after TBI, the rats had higher systolic blood pressure and impaired renal afferent arteriolar function compared with control, and EET-A or captopril mitigated these abnormalities. The TBI rats had 3-fold higher blood urea nitrogen (BUN) compared with control, and EET-A or captopril decreased BUN by 40-60%. The urine albumin/creatinine ratio was increased 94-fold in TBI rats, and EET-A or captopril attenuated that increase by 60-90%. In TBI rats, nephrinuria was elevated 30-fold and EET-A or captopril decreased it by 50 90%. Renal interstitial fibrosis, tubular and glomerular injury were present in the TBI rats, and each was decreased by EET-A or captopril. We further demonstrated elevated renal parenchymal apoptosis in TBI rats, which was mitigated by EET-A or captopril. Additional studies revealed that captopril or EET-A mitigated renal apoptosis by acting on the p53/Fas/FasL (Fas ligand) apoptotic pathway. The present study demonstrates a novel EET analogue-based strategy for mitigation of experimental radiation nephropathy by improving renal afferent arteriolar function and by decreasing renal apoptosis. PMID- 26772192 TI - Effect of Synbiotic Therapy on Gut-Derived Uremic Toxins and the Intestinal Microbiome in Patients with CKD. PMID- 26772193 TI - Synbiotics Easing Renal Failure by Improving Gut Microbiology (SYNERGY): A Randomized Trial. AB - BACKGROUND AND OBJECTIVES: The generation of key uremic nephrovascular toxins, indoxyl sulfate (IS), and p-cresyl sulfate (PCS), is attributed to the dysbiotic gut microbiota in CKD. The aim of our study was to evaluate whether synbiotic (pre- and probiotic) therapy alters the gut microbiota and reduces serum concentrations of microbiome-generated uremic toxins, IS and PCS, in patients with CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Predialysis adult participants with CKD (eGFR=10-30 ml/min per 1.73 m(2)) were recruited between January 5, 2013 and November 12, 2013 to a randomized, double-blind, placebo controlled, crossover trial of synbiotic therapy over 6 weeks (4-week washout). The primary outcome was serum IS. Secondary outcomes included serum PCS, stool microbiota profile, eGFR, proteinuria-albuminuria, urinary kidney injury molecule 1, serum inflammatory biomarkers (IL-1beta, IL-6, IL-10, and TNF-alpha), serum oxidative stress biomarkers (F2-isoprostanes and glutathione peroxidase), serum LPS, patient-reported health, Gastrointestinal Symptom Score, and dietary intake. A prespecified subgroup analysis explored the effect of antibiotic use on treatment effect. RESULTS: Of 37 individuals randomized (age =69+/-10 years old; 57% men; eGFR=24+/-8 ml/min per 1.73 m(2)), 31 completed the study. Synbiotic therapy did not significantly reduce serum IS (-2 MUmol/L; 95% confidence interval [95% CI], -5 to 1 MUmol/L) but did significantly reduce serum PCS (-14 MUmol/L; 95% CI, -27 to -2 MUmol/L). Decreases in both PCS and IS concentrations were more pronounced in patients who did not receive antibiotics during the study (n=21; serum PCS, -25 MUmol/L; 95% CI, -38 to -12 MUmol/L; serum IS, -5 MUmol/L; 95% CI, -8 to -1 MUmol/L). Synbiotics also altered the stool microbiome, particularly with enrichment of Bifidobacterium and depletion of Ruminococcaceae. Except for an increase in albuminuria of 38 mg/24 h (P=0.03) in the synbiotic arm, no changes were observed in the other secondary outcomes. CONCLUSION: In patients with CKD, synbiotics did not significantly reduce serum IS but did decrease serum PCS and favorably modified the stool microbiome. Large-scale clinical trials are justified. PMID- 26772194 TI - Poly(ADP-ribosyl)ation of Methyl CpG Binding Domain Protein 2 Regulates Chromatin Structure. AB - The epigenetic information encoded in the genomic DNA methylation pattern is translated by methylcytosine binding proteins like MeCP2 into chromatin topology and structure and gene activity states. We have shown previously that the MeCP2 level increases during differentiation and that it causes large-scale chromatin reorganization, which is disturbed by MeCP2 Rett syndrome mutations. Phosphorylation and other posttranslational modifications of MeCP2 have been described recently to modulate its function. Here we show poly(ADP-ribosyl)ation of endogenous MeCP2 in mouse brain tissue. Consequently, we found that MeCP2 induced aggregation of pericentric heterochromatin and that its chromatin accumulation was enhanced in poly(ADP-ribose) polymerase (PARP) 1(-/-) compared with wild-type cells. We mapped the poly(ADP-ribosyl)ation domains and engineered MeCP2 mutation constructs to further analyze potential effects on DNA binding affinity and large-scale chromatin remodeling. Single or double deletion of the poly(ADP-ribosyl)ated regions and PARP inhibition increased the heterochromatin clustering ability of MeCP2. Increased chromatin clustering may reflect increased binding affinity. In agreement with this hypothesis, we found that PARP-1 deficiency significantly increased the chromatin binding affinity of MeCP2 in vivo. These data provide novel mechanistic insights into the regulation of MeCP2 mediated, higher-order chromatin architecture and suggest therapeutic opportunities to manipulate MeCP2 function. PMID- 26772195 TI - Parathyroidectomy or Calcimimetic to Treat Hypercalcemia after Kidney Transplantation? PMID- 26772196 TI - Assessment of megabase-scale somatic copy number variation using single-cell sequencing. AB - Megabase-scale copy number variants (CNVs) can have profound phenotypic consequences. Germline CNVs of this magnitude are associated with disease and experience negative selection. However, it is unknown whether organismal function requires that every cell maintain a balanced genome. It is possible that large somatic CNVs are tolerated or even positively selected. Single-cell sequencing is a useful tool for assessing somatic genomic heterogeneity, but its performance in CNV detection has not been rigorously tested. Here, we develop an approach that allows for reliable detection of megabase-scale CNVs in single somatic cells. We discover large CNVs in 8%-9% of cells across tissues and identify two recurrent CNVs. We conclude that large CNVs can be tolerated in subpopulations of cells, and particular CNVs are relatively prevalent within and across individuals. PMID- 26772198 TI - Neurogenic Fever. AB - Fever is a relatively common occurrence among patients in the intensive care setting. Although the most obvious and concerning etiology is sepsis, drug reactions, venous thromboembolism, and postsurgical fevers are all on the differential diagnosis. There is abundant evidence that fever is detrimental in acute neurologic injury. Worse outcomes are reported in acute stroke, subarachnoid hemorrhage, and traumatic brain injury. In addition to the various etiologies of fever in the intensive care setting, neurologic illness is a risk factor for neurogenic fevers. This primarily occurs in subarachnoid hemorrhage and traumatic brain injury, with hypothalamic injury being the proposed mechanism. Paroxysmal sympathetic hyperactivity is another source of hyperthermia commonly seen in the population with traumatic brain injury. This review focuses on the detrimental effects of fever on the neurologically injured as well as the risk factors and diagnosis of neurogenic fever. PMID- 26772197 TI - Mapping nucleosome positions using DNase-seq. AB - Although deoxyribonuclease I (DNase I) was used to probe the structure of the nucleosome in the 1960s and 1970s, in the current high-throughput sequencing era, DNase I has mainly been used to study genomic regions devoid of nucleosomes. Here, we reveal for the first time that DNase I can be used to precisely map the (translational) positions of in vivo nucleosomes genome-wide. Specifically, exploiting a distinctive DNase I cleavage profile within nucleosome-associated DNA--including a signature 10.3 base pair oscillation that corresponds to accessibility of the minor groove as DNA winds around the nucleosome--we develop a Bayes-factor-based method that can be used to map nucleosome positions along the genome. Compared to methods that require genetically modified histones, our DNase-based approach is easily applied in any organism, which we demonstrate by producing maps in yeast and human. Compared to micrococcal nuclease (MNase)-based methods that map nucleosomes based on cuts in linker regions, we utilize DNase I cuts both outside and within nucleosomal DNA; the oscillatory nature of the DNase I cleavage profile within nucleosomal DNA enables us to identify translational positioning details not apparent in MNase digestion of linker DNA. Because the oscillatory pattern corresponds to nucleosome rotational positioning, it also reveals the rotational context of transcription factor (TF) binding sites. We show that potential binding sites within nucleosome-associated DNA are often centered preferentially on an exposed major or minor groove. This preferential localization may modulate TF interaction with nucleosome-associated DNA as TFs search for binding sites. PMID- 26772199 TI - Antimicrobial Resistance in the Intensive Care Unit: A Focus on Gram-Negative Bacterial Infections. AB - Bacterial infections are a frequent cause of hospitalization, and nosocomial infections are an increasingly common condition, particularly within the acute/critical care setting. Infection control practices and new antimicrobial development have primarily focused on gram-positive bacteria; however, in recent years, the incidence of infections caused by gram-negative bacteria has risen considerably in intensive care units. Infections caused by multidrug-resistant (MDR) gram-negative organisms are associated with high morbidity and mortality, with significant direct and indirect costs resulting from prolonged hospitalizations due to antibiotic treatment failures. Of particular concern is the increasing prevalence of antimicrobial resistance to beta-lactam antibiotics (including carbapenems) among Pseudomonas aeruginosa and Acinetobacter baumannii and, recently, among pathogens of the Enterobacteriaceae family. Treatment options for infections caused by these pathogens are limited. Antimicrobial stewardship programs focus on optimizing the appropriate use of currently available antimicrobial agents with the goals of improving outcomes for patients with infections caused by MDR gram-negative organisms, slowing the progression of antimicrobial resistance, and reducing hospital costs. Newly approved treatment options are available, such as beta-lactam/beta-lactamase inhibitor combinations, which significantly extend the armamentarium against MDR gram-negative bacteria. PMID- 26772200 TI - Thyroid bud morphogenesis requires CDC42- and SHROOM3-dependent apical constriction. AB - Early development of the gut endoderm and its subsequent remodeling for the formation of organ buds are accompanied by changes to epithelial cell shape and polarity. Members of the Rho-related family of small GTPases and their interacting proteins play multiple roles in regulating epithelial morphogenesis. In this study we examined the role of Cdc42 in foregut development and organ bud formation. Ablation of Cdc42 in post-gastrulation mouse embryos resulted in a loss of apical-basal cell polarity and columnar epithelial morphology in the ventral pharyngeal endoderm, in conjunction with a loss of apical localization of the known CDC42 effector protein PARD6B. Cell viability but not proliferation in the foregut endoderm was impaired. Outgrowth of the liver, lung and thyroid buds was severely curtailed in Cdc42-deficient embryos. In particular, the thyroid bud epithelium did not display the apical constriction that normally occurs concurrently with the outgrowth of the bud into the underlying mesenchyme. SHROOM3, a protein that interacts with Rho GTPases and promotes apical constriction, was strongly expressed in the thyroid bud and its sub-cellular localization was disrupted in Cdc42-deficient embryos. In Shroom3 gene trap mutant embryos, the thyroid bud epithelium showed no apical constriction, while the bud continued to grow and protruded into the foregut lumen. Our findings indicate that Cdc42 is required for epithelial polarity and organization in the endoderm and for apical constriction in the thyroid bud. It is possible that the function of CDC42 is partly mediated by SHROOM3. PMID- 26772201 TI - Daily cycle in oxygen consumption by the sea anemone Nematostella vectensis Stephenson. AB - In bilaterian animals, the circadian clock is intimately involved in regulating energetic metabolism. Although cnidarians exhibit diel behavioral rhythms including cycles in locomotor activity, tentacle extension and spawning, daily cycles in cnidarian metabolism have not been described. To explore a possible circadian metabolic cycle, we maintained the anemone Nematostella vectensis in a 12 h light/dark cycle, a reversed light cycle, or in constant darkness. Oxygen consumption rates were measured at intervals using an optical oxygen meter. Respiration rates responded to entrainment with higher rates during light periods. During a second experiment with higher temporal resolution, respiration rates peaked late in the light period. The diel pattern could be detected after six days in constant darkness. Together, our results suggest that respiration rates in Nematostella exhibit a daily cycle that may be under circadian control and that the cycle in respiration rate is not driven by the previously described nocturnal increase in locomotor activity in this species. PMID- 26772202 TI - RON Nuclear Translocation under Hypoxia Potentiates Chemoresistance to DNA Double Strand Break-Inducing Anticancer Drugs. AB - Tumor hypoxia is associated with radioresistance, chemoresistance, and metastasis, which eventually lead to cancer progression and a poor patient prognosis. RON [also known as macrophage-stimulating protein receptor (MST1R)] belongs to the c-MET [also known as hepatocyte growth factor receptor (HGFR)] receptor tyrosine kinase (RTK) superfamily. To identify the interaction partners of RON nuclear translocation in response to hypoxia, the nuclear extract of TSGH8301 bladder cancer cells was immunoprecipitated for tandem mass profiling analysis. Nuclear RON interacted with adenosine triphosphate (ATP)-dependent DNA helicase 2 (Ku70) and DNA-dependent protein kinase catalytic subunit (DNA-PKcs) to activate nonhomologous end joining (NHEJ) DNA repair. The interaction was time dependent, extending 3 to 24 hours posthypoxia or until the components had been exposed to the chemotherapeutic drugs doxorubicin and epirubicin. Stable knockdown experiments in vitro suggest the importance of RON for the chemoresistance of cancer cells under hypoxia. In addition, the tyrosine kinase domain of nuclear RON is crucial for interaction with Ku70 under hypoxia. J82 cells transfected with RON showed a survival advantage in the presence of epirubicin and hypoxia. This suggests that nuclear RON activates NHEJ repair by interacting with Ku70/DNA-PKcs and inhibiting RON activity to increase cancer cell chemosensitivity. Mol Cancer Ther; 15(2); 276-86. (c)2016 AACR. PMID- 26772204 TI - Inhibition of Class I Histone Deacetylases 1 and 2 Promotes Urothelial Carcinoma Cell Death by Various Mechanisms. AB - Class I histone deacetylases HDAC1 and HDAC2 contribute to cell proliferation and are commonly upregulated in urothelial carcinoma. To evaluate whether specific inhibition of these enzymes might serve as an appropriate therapy for urothelial carcinoma, siRNA-mediated knockdown and specific pharmacologic inhibition of HDAC1 and HDAC2 were applied in urothelial carcinoma cell lines (UCC) with distinct HDAC1 and HDAC2 expression profiles. HDACs and response marker proteins were followed by Western blotting and qRT-PCR. Effects of class I HDAC suppression on UCCs were analyzed by viability, colony forming, and caspase-3/7 assays; flow cytometry, senescence and lactate dehydrogenase cytotoxicity assays; and immunofluorescence staining. Whereas single knockdowns of HDAC1 or HDAC2 were impeded by compensatory upregulation of the other isoenzyme, efficient double knockdown of HDAC1 and HDAC2 reduced proliferation by up to 80% and induced apoptosis-like cell death in all UCCs. Clonogenic growth was cell line- and HDAC dependently reduced, with double knockdown of HDAC1 and HDAC2 being usually most efficient. Class I HDAC-specific inhibitors, especially the more specific HDAC1/2 inhibitors romidepsin and givinostat, significantly reduced proliferation of all UCCs (IC50, 3.36 nmol/L-4.59 MUmol/L). Romidepsin and givinostat also significantly inhibited clonogenic growth of UCCs, with minor effects on nontumorigenic controls. Intriguingly, these compounds induced primarily S-phase disturbances and nonapoptotic cell death in UCCs. Thus, although both ways of inhibiting HDAC1/2 share mechanisms and efficaciously inhibit cell proliferation, their modes of action differ substantially. Regardless, combined inhibition of HDAC1/2 appears to represent a promising strategy for urothelial carcinoma therapy. Mol Cancer Ther; 15(2); 299-312. (c)2016 AACR. PMID- 26772203 TI - Target Identification in Small Cell Lung Cancer via Integrated Phenotypic Screening and Activity-Based Protein Profiling. AB - To overcome hurdles in identifying key kinases in small cell lung cancer (SCLC), we integrated a target-agnostic phenotypic screen of kinase inhibitors with target identification using activity-based protein profiling (ABPP) in which a desthiobiotin-ATP probe was used. We screened 21 SCLC cell lines with known c-MYC amplification status for alterations in viability using a chemical library of 235 small-molecule kinase inhibitors. One screen hit compound was interrogated with ABPP, and, through this approach, we reidentified Aurora kinase B as a critical kinase in MYC-amplified SCLC cells. We next extended the platform to a second compound that had activity in SCLC cell lines lacking c-MYC amplification and identified TANK-binding kinase 1, a kinase that affects cell viability, polo-like kinase-1 signaling, G2-M arrest, and apoptosis in SCLC cells lacking MYC amplification. These results demonstrate that phenotypic screening combined with ABPP can identify key disease drivers, suggesting that this approach, which combines new chemical probes and disease cell screens, has the potential to identify other important targets in other cancer types. Mol Cancer Ther; 15(2); 334-42. (c)2016 AACR. PMID- 26772205 TI - Mental Imagery in Depression: Phenomenology, Potential Mechanisms, and Treatment Implications. AB - Mental imagery is an experience like perception in the absence of a percept. It is a ubiquitous feature of human cognition, yet it has been relatively neglected in the etiology, maintenance, and treatment of depression. Imagery abnormalities in depression include an excess of intrusive negative mental imagery; impoverished positive imagery; bias for observer perspective imagery; and overgeneral memory, in which specific imagery is lacking. We consider the contribution of imagery dysfunctions to depressive psychopathology and implications for cognitive behavioral interventions. Treatment advances capitalizing on the representational format of imagery (as opposed to its content) are reviewed, including imagery rescripting, positive imagery generation, and memory specificity training. Consideration of mental imagery can contribute to clinical assessment and imagery-focused psychological therapeutic techniques and promote investigation of underlying mechanisms for treatment innovation. Research into mental imagery in depression is at an early stage. Work that bridges clinical psychology and neuroscience in the investigation of imagery related mechanisms is recommended. PMID- 26772207 TI - Diagnostic Issues and Controversies in DSM-5: Return of the False Positives Problem. AB - The fifth revision of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) was the most controversial in the manual's history. This review selectively surveys some of the most important changes in DSM-5, including structural/organizational changes, modifications of diagnostic criteria, and newly introduced categories. It analyzes why these changes led to such heated controversies, which included objections to the revision's process, its goals, and the content of altered criteria and new categories. The central focus is on disputes concerning the false positives problem of setting a valid boundary between disorder and normal variation. Finally, this review highlights key problems and issues that currently remain unresolved and need to be addressed in the future, including systematically identifying false positive weaknesses in criteria, distinguishing risk from disorder, including context in diagnostic criteria, clarifying how to handle fuzzy boundaries, and improving the guidelines for "other specified" diagnosis. PMID- 26772208 TI - Conducting Clinical Research Using Crowdsourced Convenience Samples. AB - Crowdsourcing has had a dramatic impact on the speed and scale at which scientific research can be conducted. Clinical scientists have particularly benefited from readily available research study participants and streamlined recruiting and payment systems afforded by Amazon Mechanical Turk (MTurk), a popular labor market for crowdsourcing workers. MTurk has been used in this capacity for more than five years. The popularity and novelty of the platform have spurred numerous methodological investigations, making it the most studied nonprobability sample available to researchers. This article summarizes what is known about MTurk sample composition and data quality with an emphasis on findings relevant to clinical psychological research. It then addresses methodological issues with using MTurk--many of which are common to other nonprobability samples but unfamiliar to clinical science researchers--and suggests concrete steps to avoid these issues or minimize their impact. PMID- 26772206 TI - Mental Health in Lesbian, Gay, Bisexual, and Transgender (LGBT) Youth. AB - Today's lesbian, gay, bisexual, and transgender (LGBT) youth come out at younger ages, and public support for LGBT issues has dramatically increased, so why do LGBT youth continue to be at high risk for compromised mental health? We provide an overview of the contemporary context for LGBT youth, followed by a review of current science on LGBT youth mental health. Research in the past decade has identified risk and protective factors for mental health, which point to promising directions for prevention, intervention, and treatment. Legal and policy successes have set the stage for advances in programs and practices that may foster LGBT youth mental health. Implications for clinical care are discussed, and important areas for new research and practice are identified. PMID- 26772209 TI - Suicide, Suicide Attempts, and Suicidal Ideation. AB - Suicidal behavior is a leading cause of death and disability worldwide. Fortunately, recent developments in suicide theory and research promise to meaningfully advance knowledge and prevention. One key development is the ideation-to-action framework, which stipulates that (a) the development of suicidal ideation and (b) the progression from ideation to suicide attempts are distinct phenomena with distinct explanations and predictors. A second key development is a growing body of research distinguishing factors that predict ideation from those that predict suicide attempts. For example, it is becoming clear that depression, hopelessness, most mental disorders, and even impulsivity predict ideation, but these factors struggle to distinguish those who have attempted suicide from those who have only considered suicide. Means restriction is also emerging as a highly effective way to block progression from ideation to attempt. A third key development is the proliferation of theories of suicide that are positioned within the ideation-to-action framework. These include the interpersonal theory, the integrated motivational-volitional model, and the three step theory. These perspectives can and should inform the next generation of suicide research and prevention. PMID- 26772210 TI - Paraphilias in the DSM-5. AB - This review summarizes and critically examines the changes in how the Diagnostic and Statistical Manual of Mental Disorders (DSM) characterizes paraphilias. Attention is paid to the diagnostic options that were included in DSM-5, the decision not to include criterion sets for two additional disorders (paraphilic coercive disorder and hypersexual behavior disorder), and the further decision not to modify the diagnosis of pedophilic to pedohebephilic disorder. The three most significant changes are (a) the move to distinguish paraphilias from paraphilic disorders (allowing unusual sexual interests to be studied by researchers but only regarded as disorders when they cause distress or dysfunction), (b) introducing criteria describing paraphilic disorders as being in remission (when they no longer cause distress or dysfunction), and (c) clarifying the relationship between behavior and paraphilias. Concerns are noted about the forensic use of diagnoses and the lack of funding for field trials in this revision of the DSM. Suggestions are given for future directions in order to further research efficacy and clinical diagnosis. PMID- 26772212 TI - Regulation of Immunity by Butyrophilins. AB - Butyrophilin molecules (commonly contracted to BTN), collectively take their name from the eponymous protein in cow's milk. They are considered to be members of the B7 family of costimulatory receptors, which includes B7.1 (CD80), B7.2 (CD86), and related molecules, such as PD-L1 (B7-H1, CD274), ICOS-L (CD275), and B7-H3 (CD276). These coreceptors modulate T cell responses upon antigen presentation by major histocompatibility complex and cognate alphabeta T cell receptor engagement. Molecules such as BTN3A1 (CD277), myelin oligodendrocyte glycoprotein, and mouse Skint1 and Btnl2, all members of the butyrophilin family, show greater structural and functional diversity than the canonical B7 receptors. Some butyrophilins mediate complex interactions between antigen-presenting cells and conventional alphabeta T cells, and others regulate the immune responses of specific gammadelta T cell subsets by mechanisms that have characteristics of both innate and adaptive immunity. PMID- 26772211 TI - Crystal Formation in Inflammation. AB - The formation and accumulation of crystalline material in tissues is a hallmark of many metabolic and inflammatory conditions. The discovery that the phase transition of physiologically soluble substances to their crystalline forms can be detected by the immune system and activate innate immune pathways has revolutionized our understanding of how crystals cause inflammation. It is now appreciated that crystals are part of the pathogenesis of numerous diseases, including gout, silicosis, asbestosis, and atherosclerosis. In this review we discuss current knowledge of the complex mechanisms of crystal formation in diseased tissues and their interplay with the nutrients, metabolites, and immune cells that account for crystal-induced inflammation. PMID- 26772307 TI - What can local and geographic population limits tell us about distributions? AB - PREMISE OF THE STUDY: Understanding the evolutionary and ecological factors that determine plant distributions is of primary importance in botanical research. These factors may vary in predictable ways across different spatial scales, and thus, we can leverage scale to reveal the underlying processes limiting plant distributions. METHODS: We review various research considerations across local and geographic scales, including the investigation of dispersal and habitat limitation, evolutionary factors, abiotic and biotic factors, and research logistics. We also present two case studies, slender monkeyflower (Mimulus leptaleus) and cut-leaf monkeyflower (Mimulus laciniatus), in the California Sierra Nevada. KEY RESULTS: At a local spatial scale (within 50 m), no seeds were produced from plants sown at sites located just beyond known patches of M. leptaleus, but within the species' geographic range. At a much broader spatial scale (kilometers), at the highest and lowest elevations of the species' range, we found greatly reduced abundance and fecundity in plants sown outside of the geographic range limits of M. laciniatus. CONCLUSIONS: These cases illustrate two contrasting spatial scales, yet agree in their illustration of strong habitat limitation. We end by discussing future avenues of research and by suggesting ways botanical researchers can frame their studies to maximize information gained on species requirements, distribution limits, and conservation among varying spatial scales. PMID- 26772270 TI - Fluid Flow Regulation of Revascularization and Cellular Organization in a Bioengineered Liver Platform. AB - OBJECTIVE: Modeling of human liver development, especially cellular organization and the mechanisms underlying it, is fundamental for studying liver organogenesis and congenital diseases, yet there are no reliable models that mimic these processes ex vivo. DESIGN: Using an organ engineering approach and relevant cell lines, we designed a perfusion system that delivers discrete mechanical forces inside an acellular liver extracellular matrix scaffold to study the effects of mechanical stimulation in hepatic tissue organization. RESULTS: We observed a fluid flow rate-dependent response in cell distribution within the liver scaffold. Next, we determined the role of nitric oxide (NO) as a mediator of fluid flow effects on endothelial cells. We observed impairment of both neovascularization and liver tissue organization in the presence of selective inhibition of endothelial NO synthase. Similar results were observed in bioengineered livers grown under static conditions. CONCLUSION: Overall, we were able to unveil the potential central role of discrete mechanical stimulation through the NO pathway in the revascularization and cellular organization of a bioengineered liver. Last, we propose that this organ bioengineering platform can contribute significantly to the identification of physiological mechanisms of liver organogenesis and regeneration and improve our ability to bioengineer livers for transplantation. PMID- 26772309 TI - The rise of evo-devo: Pan-American Society for Evolutionary Developmental Biology sets the stage. PMID- 26772308 TI - Project Baseline: An unprecedented resource to study plant evolution across space and time. AB - PREMISE OF THE STUDY: Project Baseline is a seed bank that offers an unprecedented opportunity to examine spatial and temporal dimensions of microevolution during an era of rapid environmental change. Over the upcoming 50 years, biologists will withdraw genetically representative samples of past populations from this time capsule of seeds and grow them contemporaneously with modern samples to detect any phenotypic and molecular evolution that has occurred during the intervening time. METHODS: We carefully developed this living genome bank using protocols to enhance its experimental value by collecting from multiple populations and species across a broad geographical range in sites that are likely to be preserved into the future. Seeds are accessioned with site and population data and are stored by maternal line under conditions that maximize seed longevity. This open-access resource will be available to researchers at regular intervals to evaluate contemporary evolution. KEY RESULTS: To date, the Project Baseline collection includes 100-200 maternal lines of each of 61 species collected from over 831 populations on sites that are likely to be preserved into the future across the United States (~78,000 maternal lines). Our strategically designed collection circumvents some problems that can cloud the results of "resurrection" studies involving naturally preserved or existing seed collections that are available fortuitously. CONCLUSIONS: The resurrection approach can be coupled with long-established and newer techniques over the next five decades to elucidate genetic change and thereby vastly improve our understanding of temporal and spatial changes in phenotype and the evolutionary processes underlying it. PMID- 26772310 TI - Evolutionary insights from studies of geographic variation: Contemporary variation and looking to the future. AB - In an age of rapid global change, it is imperative that we continue to improve our understanding of factors that govern genetic differentiation in plants to inform biologically reasonable predictions for the future and enlighten conservation and restoration practices. In this special issue, we have assembled a set of original research and reviews that employ diverse approaches, both classic and contemporary, to illuminate patterns of phenotypic and genetic variation, probe the underlying evolutionary processes that have contributed to these patterns, build predictive models, and test evolutionary hypotheses. Our goal was to underscore the unique insights that can be obtained through the complementary and distinct studies of plant populations across species' geographic ranges. PMID- 26772311 TI - Isotope Effects Reveal the Mechanism of Enamine Formation in l-Proline-Catalyzed alpha-Amination of Aldehydes. AB - The mechanism of l-proline-catalyzed alpha-amination of 3-phenylpropionaldehyde was studied using a combination of experimental kinetic isotope effects (KIEs) and theoretical calculations. Observation of a significant carbonyl (13)C KIE and a large primary alpha-deuterium KIE support rate-determining enamine formation. Theoretical predictions of KIEs exclude the widely accepted mechanism of enamine formation via intramolecular deprotonation of an iminium carboxylate intermediate. An E2 elimination mechanism catalyzed by a bifunctional base that directly forms an N-protonated enamine species from an oxazolidinone intermediate accounts for the experimental KIEs. These findings provide the first experimental picture of the transition-state geometry of enamine formation and clarify the role of oxazolidinones as nonparasitic intermediates in proline catalysis. PMID- 26772312 TI - Prehistoric hunter-gatherer population growth rates rival those of agriculturalists. PMID- 26772313 TI - Reckoning the moment of reckoning in spontaneous voluntary movement. PMID- 26772314 TI - A transcriptional signature of hub connectivity in the mouse connectome. AB - Connectivity is not distributed evenly throughout the brain. Instead, it is concentrated on a small number of highly connected neural elements that act as network hubs. Across different species and measurement scales, these hubs show dense interconnectivity, forming a core or "rich club" that integrates information across anatomically distributed neural systems. Here, we show that projections between connectivity hubs of the mouse brain are both central (i.e., they play an important role in neural communication) and costly (i.e., they extend over long anatomical distances) aspects of network organization that carry a distinctive genetic signature. Analyzing the neuronal connectivity of 213 brain regions and the transcriptional coupling, across 17,642 genes, between each pair of regions, we find that coupling is highest for pairs of connected hubs, intermediate for links between hubs and nonhubs, and lowest for connected pairs of nonhubs. The high transcriptional coupling associated with hub connectivity is driven by genes regulating the oxidative synthesis and metabolism of ATP--the primary energetic currency of neuronal communication. This genetic signature contrasts that identified for neuronal connectivity in general, which is driven by genes regulating neuronal, synaptic, and axonal structure and function. Our findings establish a direct link between molecular function and the large-scale topology of neuronal connectivity, showing that brain hubs display a tight coordination of gene expression, often over long anatomical distances, that is intimately related to the metabolic requirements of these highly active network elements. PMID- 26772315 TI - The brain's predictive prowess revealed in primary visual cortex. PMID- 26772316 TI - Sweet beginning for cancer stem cells. PMID- 26772388 TI - Lift performance and lumbar loading in standing and seated lifts. AB - This study investigated the effect of posture on lifting performance. Twenty three male soldiers lifted a loaded box onto a platform in standing and seated postures to determine their maximum lift capacity and maximum acceptable lift. Lift performance, trunk kinematics, lumbar loads, anthropometric and strength data were recorded. There was a significant main effect for lift effort but not for posture or the interaction. Effect sizes showed that lumbar compression forces did not differ between postures at lift initiation (Standing 5566.2 +/- 627.8 N; Seated 5584.0 +/- 16.0) but were higher in the standing posture (4045.7 +/- 408.3 N) when compared with the seated posture (3655.8 +/- 225.7 N) at lift completion. Anterior shear forces were higher in the standing posture at both lift initiation (Standing 519.4 +/- 104.4 N; Seated 224.2 +/- 9.4 N) and completion (Standing 183.3 +/- 62.5 N; Seated 71.0 +/- 24.2 N) and may have been a result of increased trunk flexion and a larger horizontal distance of the mass from the L5-S1 joint. Practitioner Summary: Differences between lift performance and lumbar forces in standing and seated lifts are unclear. Using a with-in subjects repeated measures design, we found no difference in lifted mass or lumbar compression force at lift initiation between standing and seated lifts. PMID- 26772389 TI - Reducing the length of postnatal hospital stay: implications for cost and quality of care. AB - BACKGROUND: UK health services are under pressure to make cost savings while maintaining quality of care. Typically reducing the length of time patients stay in hospital and increasing bed occupancy are advocated to achieve service efficiency. Around 800,000 women give birth in the UK each year making maternity care a high volume, high cost service. Although average length of stay on the postnatal ward has fallen substantially over the years there is pressure to make still further reductions. This paper explores and discusses the possible cost savings of further reductions in length of stay, the consequences for postnatal services in the community, and the impact on quality of care. METHOD: We draw on a range of pre-existing data sources including, national level routinely collected data, workforce planning data and data from national surveys of women's experience. Simulation and a financial model were used to estimate excess demand, work intensity and bed occupancy to explore the quantitative, organisational consequences of reducing the length of stay. These data are discussed in relation to findings of national surveys to draw inferences about potential impacts on cost and quality of care. DISCURSIVE ANALYSIS: Reducing the length of time women spend in hospital after birth implies that staff and bed numbers can be reduced. However, the cost savings may be reduced if quality and access to services are maintained. Admission and discharge procedures are relatively fixed and involve high cost, trained staff time. Furthermore, it is important to retain a sufficient bed contingency capacity to ensure a reasonable level of service. If quality of care is maintained, staffing and bed capacity cannot be simply reduced proportionately: reducing average length of stay on a typical postnatal ward by six hours or 17% would reduce costs by just 8%. This might still be a significant saving over a high volume service however, earlier discharge results in more women and babies with significant care needs at home. Quality and safety of care would also require corresponding increases in community based postnatal care. Simply reducing staffing in proportion to the length of stay increases the workload for each staff member resulting in poorer quality of care and increased staff stress. CONCLUSIONS: Many policy debates, such as that about the length of postnatal hospital-stay, demand consideration of multiple dimensions. This paper demonstrates how diverse data sources and techniques can be integrated to provide a more holistic analysis. Our study suggests that while earlier discharge from the postnatal ward may achievable, it may not generate all of the anticipated cost savings. Some useful savings may be realised but if staff and bed capacity are simply reduced in proportion to the length of stay, care quality may be compromised. PMID- 26772317 TI - Chronic Traumatic Encephalopathy: The Neuropathological Legacy of Traumatic Brain Injury. AB - Almost a century ago, the first clinical account of the punch-drunk syndrome emerged, describing chronic neurological and neuropsychiatric sequelae occurring in former boxers. Thereafter, throughout the twentieth century, further reports added to our understanding of the neuropathological consequences of a career in boxing, leading to descriptions of a distinct neurodegenerative pathology, termed dementia pugilistica. During the past decade, growing recognition of this pathology in autopsy studies of nonboxers who were exposed to repetitive, mild traumatic brain injury, or to a single, moderate or severe traumatic brain injury, has led to an awareness that it is exposure to traumatic brain injury that carries with it a risk of this neurodegenerative disease, not the sport or the circumstance in which the injury is sustained. Furthermore, the neuropathology of the neurodegeneration that occurs after traumatic brain injury, now termed chronic traumatic encephalopathy, is acknowledged as being a complex, mixed, but distinctive pathology, the detail of which is reviewed in this article. PMID- 26772392 TI - Lower expression of CADM1 and higher expression of MAL in Merkel cell carcinomas are associated with Merkel cell polyomavirus infection and better prognosis. AB - Merkel cell carcinoma (MCC) is a clinically aggressive neuroendocrine skin cancer; 80% of the cases are associated with the Merkel cell polyomavirus (MCPyV). We previously reported that MCPyV-negative MCCs have more irregular nuclei with abundant cytoplasm and significantly unfavorable outcomes than do MCPyV-positive MCCs. These results suggest that some cell adhesion or structural stabilization molecules are differently expressed depending on MCPyV infection status. Thus, we investigated the association of prognosis or MCPyV infection status in MCCs with cell adhesion molecule 1 (CADM1)/differentially expressed in adenocarcinoma of the lung protein 1 (DAL-1)/membrane protein, palmitoylated 3 (MPP3) tripartite complex and mal T-cell differentiation protein (MAL) expression, which play important roles in cell adhesion and oncogenesis and are related to cancer outcomes in various malignancies, to elucidate the role of these molecules. We analyzed the pathological and molecular characteristics of 26 MCPyV-positive and 15 MCPyV-negative MCCs. Univariate Cox regression analysis showed that advanced age (hazard ratio [HR], 8.249; P = .007) and high CADM1 expression (HR, 5.214; P = .012) were significantly unfavorable overall survival parameters, whereas MCPyV infection (HR, 0.043, P < .001) and lower MAL expression (HR, 0.273; P = .018) were significantly favorable. On multivariate analysis, only MCPyV infection was significantly favorable for overall survival (HR, 0.04; P = .005). Hypermethylation of CADM1, DAL-1, and MAL promoters was detected in 1 of 18, 15 of 27, and 1 of 13 cases, respectively. Double immunostaining for cytokeratin 20 and CADM1, DAL-1, or MAL showed that nonneoplastic Merkel cells expressed DAL-1 and MAL but not CADM1. This study revealed that MCPyV-negative MCCs significantly expressed higher CADM1 and lower MAL than MCPyV-positive MCCs; these expression levels were markedly related to unfavorable outcomes. These data will give us important insights to develop novel molecular target therapies for MCCs. PMID- 26772393 TI - An analysis of MYC and EBV in diffuse large B-cell lymphomas associated with angioimmunoblastic T-cell lymphoma and peripheral T-cell lymphoma not otherwise specified. AB - Composite diffuse large B-cell lymphomas (DLBCLs) with peripheral T-cell lymphomas (PTCLs) are rare co-occurrences with poorly understood pathologic features. Herein, we describe 15 distinct cases of DLBCL occurring in association with PTCL, including angioimmunoblastic T-cell lymphoma (AITL; n = 12) and PTCL, not otherwise specified (n = 3). Sheets of large B cells were seen in all cases, with Hodgkin/Reed-Sternberg-like (HRS-L) cells present in 6 cases. When compared to cases of AITL without DLBCL, HRS-L cells were more frequently seen in cases of AITL with DLBCL (P = .02). Epstein-Barr virus (EBV) expression was seen in 10 of 15 cases, and in those with HRS-L cells, EBV expression was detected invariably in at least a subset of the HRS-L cells. MYC gene rearrangements were consistently absent, although 6 of the 10 cases showed MYC overexpression by immunohistochemistry in the neoplastic B cells; a frequency significantly increased compared to other cases of DLBCL not associated with a T-cell lymphoma: 29 of 166 (P = .005). In addition, when MYC was overexpressed in DLBCL, it was also weakly present in the HRS-L cells. The increased and frequent morphologic presence of HRS-L cells in association with this composite lymphoma raises a possible link between their occurrence and DLBCLs in PTCLs; furthermore, the frequent detection of MYC protein expression and EBV infection in these cases suggests a possible role of these pathways in B-cell lymphomagenesis. PMID- 26772390 TI - Enhanced syphilis screening among HIV-positive men (ESSAHM): a study protocol for a clinic-randomized trial with stepped wedge design. AB - BACKGROUND: The current syphilis epidemic among urban men who have sex with men (MSM) has serious implications for those co-infected with human immunodeficiency virus (HIV). Routine and frequent syphilis screening has the potential to ensure early detection and treatment, minimize disease burden, and help control the ongoing spread of syphilis and HIV. We aim to enhance syphilis screening among HIV-positive men by conducting a clinic-based intervention that incorporates opt out syphilis testing into routine HIV laboratory evaluation for this population. Trial objectives are to determine the degree to which the intervention (1) increases the detection rate of untreated syphilis, (2) increases screening coverage, (3) increases screening frequency, and (4) reaches men at highest risk according to sexual behaviors. METHODS/DESIGN: The trial is a pragmatic, stepped wedge cluster-randomized controlled trial that introduces the intervention stepwise across four urban HIV clinics in Ontario, Canada. The intervention includes standing orders for syphilis serological testing whenever a male in HIV care undergoes HIV viral load testing, which typically occurs every 3-6 months. The control condition is the maintenance of current, provider-initiated syphilis testing practice. Approximately 3100 HIV-positive men will be followed over 30 months. Test results will be obtained from the centralized provincial laboratory in Ontario and will be supplemented by a standardized clinical worksheet and medical chart review at the clinics. Detailed clinical, psychosocial, and behavioral data is available for a subset of men receiving HIV care who are also participants of the province-wide Ontario HIV Treatment Network Cohort Study. Process evaluation plans include audit and feedback of compliance of the participating centers to identify potential barriers to the introduction of this type of practice into routine care. Health economic components include evaluation of the impact and cost-effectiveness of the intervention. DISCUSSION: This trial will be the first of its kind in Canada and will provide evidence regarding the feasibility, clinical effectiveness, and cost-effectiveness of a clinic-based intervention to improve syphilis screening among HIV-positive men. Involvement of knowledge users in all stages of trial design, conduct, and analysis will facilitate scale-up should the intervention be effective. TRIAL REGISTRATION: ClinicalTrials.gov NCT02019043. PMID- 26772391 TI - Hematopoietic stem cell transplantation for multiple sclerosis: is it a clinical reality? AB - Hematopoietic stem cell transplantation (HSCT) is a treatment paradigm that has long been utilized for cancers of the blood and bone marrow but has gained some traction as a treatment paradigm for multiple sclerosis (MS). Success in the treatment of patients with this approach has been reported primarily when strict inclusion criteria are imposed that have eventuated a more precise understanding of MS pathophysiology, thereby governing trial design. Moreover, enhancing the yield and purity of hematopoietic stem cells during isolation along with the utility of appropriate conditioning agents has provided a clearer foundation for clinical translation studies. To support this approach, preclinical data derived from animal models of MS, experimental autoimmune encephalomyelitis, have provided clear identification of multipotent stem cells that can reconstitute the immune system to override the autoimmune attack of the central nervous system. In this review, we will discuss the rationale of HSCT to treat MS by providing the benefits and complications of the clinically relevant protocols, the varying graft types, and conditioning regimens. However, we emphasize that future trials based on HSCT should be focused on specific therapeutic strategies to target and limit ongoing neurodegeneration and demyelination in progressive MS, in the hope that such treatment may serve a greater catchment of patient cohorts with potentially enhanced efficiency and lower toxicity. Despite these future ambitions, a proposed international multicenter, randomized clinical trial of HSCT should be governed by the best standard care of treatment, whereby MS patients are selected upon strict clinical course criteria and long-term follow up studies of patients from international registries are imposed to advocate HSCT as a therapeutic option in the management of MS. PMID- 26772394 TI - The utility of CDX2, GATA3, and DOG1 in the diagnosis of testicular neoplasms: an immunohistochemical study of 109 cases. AB - We identified 109 testicular tumors, including pure and mixed germ cell tumors and sex cord-stromal tumors, and conducted immunohistochemical staining for CDX2, DOG1, and GATA3 to address the potential utility of these readily available and commonly used markers in the evaluation of testicular tumors. Their expression has not been previously thoroughly examined in testicular germ cell tumors. The distribution, percentage, and intensity of positivity were assessed. CDX2 was positive in all yolk sac tumors, 25% of choriocarcinomas, 9% of seminomas, and 4% of embryonal carcinomas (sensitivity for yolk sac tumor, 100%; specificity, 89% [teratomas excluded]). CDX2 also stained glandular components within teratomas and identified inconspicuous yolk sac tumor components in 3 cases previously diagnosed as pure embryonal carcinoma. GATA3 was positive in all choriocarcinomas (sensitivity, 100%). Weak GATA3 immunostaining was also seen in 12% of yolk sac tumors and 2 of 2 primitive neuroectodermal tumors. DOG1 was negative in all tumors, but stained spermatocytes and spermatids and the luminal borders of the epididymis and rete testis of nonneoplastic testis. We conclude that CDX2 is a sensitive and relatively specific marker for yolk sac tumor among the nonteratomatous germ cell tumors. It may serve to screen for yolk sac tumor components often overlooked on hematoxylin and eosin-stained slides. GATA3 is helpful in the recognition of trophoblastic cells, especially of intermediate type. DOG1 is a sensitive marker for spermatocytes and needs to be further studied for its significance. PMID- 26772395 TI - CD3 immunohistochemical staining in diagnosis of lymphocytic colitis. AB - Microscopic colitis (MC) is a common cause of chronic watery diarrhea. Traditionally, MC encompasses the 2 subgroups lymphocytic colitis (LC) and collagenous colitis, but recently, an additional subgroup, MC incomplete, has been introduced. Distinguishing between the subgroups relies exclusively on histopathologic evaluation. In the present study, 4 pathologists evaluated 156 archived biopsies originally diagnosed as LC or LC incomplete (LCi). Each pathologist assigned a diagnosis of LC, LCi, or nonspecific inflammation to all cases at 2 independent assessments. At the first assessment, hematoxylin and eosin (HE) stainings were available. At the second assessment, a supplementary CD3 immunohistochemical staining was also available. The aim was to evaluate whether a supplementary CD3 would increase the diagnostic agreement among pathologists, and whether a CD3 stain would change the diagnosis based on HE staining only. After the complete assessment, the cases were divided into 3 groups, that is, full agreement, partial agreement, and disagreement. The CD3 staining increased the number of cases with full agreement from 60 to 78. One hundred thirty-one cases with agreement or partial diagnostic agreement based on HE + CD3 were compared with the HE diagnoses. In 44 (34%) of 131 cases, CD3 changed the diagnosis. Cases assigned to the LCi category based on HE were often changed by a supplementary CD3. Conclusively, it is recommended to use a CD3 before giving the histopathologic diagnosis of LCi. PMID- 26772396 TI - Undiagnosed fatal malignancy in adult autopsies: a 10-year retrospective study. AB - Autopsies reveal undiagnosed malignancies even in this era of modern diagnostic imaging and ancillary laboratory studies. The incidence of clinically undiagnosed malignancies related to primary cause of death in a university hospital setting has rarely been studied. Our objective was to determine the incidence of clinically undiagnosed fatal malignancies in an urban teaching hospital and to assess whether this incidence was influenced by the duration of hospital stay. We performed a retrospective analysis of consecutive adult hospital autopsies in which the primary cause of death was related to undiagnosed malignancy. The detailed autopsy report, clinical records, and relevant laboratory results from laboratory and hospital databases were reviewed. Eight hundred twenty-one adult autopsies were performed over 10 years. Sixty-nine clinically undiagnosed malignant neoplasms were found in 66 cases (8%). In 26 of these 66 cases, the undiagnosed malignant neoplasm was related to the primary cause of death (3.1%). The duration of hospital stay was less than 24 hours in 8 cases (30.7%), 2 to 7 days in 9 cases (34.6%), and greater than 7 days in 9 cases (34.6%). In 10 of these 26 cases (1.2%), there was suspicion of malignancy without definitive tissue diagnosis, and the average hospital stay was 4.9 days. In 16 (1.9%) of these 26 cases, malignancy was not clinically suspected, and the average hospital stay was 9.9 days. We conclude that despite the recent advances in diagnostic imaging and laboratory techniques, a subset of adult autopsies (3.1%) performed in an urban university hospital have clinically undiagnosed malignancy related to the primary cause of death. Malignancy was not clinically suspected in 1.9% of these cases. There is a need to conduct comprehensive "root cause" analysis in these cases for improvement of clinical care. PMID- 26772397 TI - The role of GATA3 in breast carcinomas: a review. AB - GATA3 is a zinc-binding transcription factor that regulates the differentiation of many human tissue types, including the mammary gland. In surgical pathology, immunohistochemistry for GATA3 is largely used to support urothelial or breast origin in a carcinoma of unknown origin. GATA3 is sensitive but not entirely specific in this setting. Although GATA3 labeling is highest in estrogen receptor positive carcinomas, it also labels estrogen receptor-negative carcinomas and thus has particular diagnostic utility in the setting of triple-negative breast carcinomas, which are typically negative for other mammary-specific markers. PMID- 26772398 TI - Decreased expression of autophagy protein LC3 and stemness (CD44+/CD24-/low) indicate poor prognosis in triple-negative breast cancer. AB - This study evaluated the prognostic value of expression of autophagy protein light chain 3 (LC3) and the prognostic value of coexpression of LC3 and stemness markers CD44+/CD24-/low in triple-negative breast cancer (TNBC). LC3 and LC3/CD44+/CD24-/low immunophenotypes in tumor tissues were evaluated by immunohistochemistry in 67 TNBC patients. LC3- was expressed in 30 (44.78%) cases. The LC3- phenotype revealed a significant negative association with overall survival in both univariate (P = .0006) and multivariate (P = .0153) analyses. LC3-/CD44+/CD24-/low phenotype was observed in 24 (35.82%) of 67 TNBC patients. According to Kaplan-Meier analysis, prognosis was significantly worse in tumors with LC3-/CD44+/CD24-/low phenotype (P = .0280). Multivariate analysis indicated that LC3-/CD44+/CD24-/low phenotype was a significant independent prognostic indicator of overall survival. These results suggest that LC3 suppresses TNBC in mature tumor cells and cancer stem cells (CSCs). In conclusion, this study suggests that CSCs are linked to progression of autophagy in TNBC. During the progression and development of TNBC, autophagy of CSCs/progenitor cells is low. LC3-/CD44+/CD24-/low immunophenotype indicates a highly aggressive TNBC subgroup associated with a poor prognosis. This study investigated that LC3 deficiency may restrain TNBC in mature tumor cells and CSCs. Therefore, a reasonable inference is that inducing autophagy may be an effective therapeutic strategy in TNBC. PMID- 26772399 TI - Cytogenetically confirmed low-grade fibromyxoid sarcoma arising from the tibia. AB - Low-grade fibromyxoid sarcoma is a rare soft tissue tumor with a benign histologic appearance but comparatively aggressive clinical course. These discrepant features make it extremely important to diagnose early so that appropriate management can be initiated. This diagnosis often hinges on the presence of the hallmark cytogenetic aberration, a balanced 7;16 translocation resulting in a FUS-CREB3L2 fusion gene. Although this neoplasm most commonly arises in the deep soft tissue of the lower extremities, it has been reported to arise from a wide variety of sites including intraabdominal and intracranial locations. Only 1 previous study has described low-grade fibromyxoid sarcoma as arising from a bony site; however, cytogenetic and immunohistochemical confirmation was not available at that time. Herein, we describe the first ever cytogenetically confirmed case of low-grade fibromyxoid sarcoma arising as a primary bone tumor in the tibia of a 35-year-old woman. PMID- 26772400 TI - Digital histologic analysis reveals morphometric patterns of age-related involution in breast epithelium and stroma. AB - Complete age-related regression of mammary epithelium, often termed postmenopausal involution, is associated with decreased breast cancer risk. However, most studies have qualitatively assessed involution. We quantitatively analyzed epithelium, stroma, and adipose tissue from histologically normal breast tissue of 454 patients in the Normal Breast Study. High-resolution digital images of normal breast hematoxylin and eosin-stained slides were partitioned into epithelium, adipose tissue, and nonfatty stroma. Percentage area and nuclei per unit area (nuclear density) were calculated for each component. Quantitative data were evaluated in association with age using linear regression and cubic spline models. Stromal area decreased (P = 0.0002), and adipose tissue area increased (P < 0.0001), with an approximate 0.7% change in area for each component, until age 55 years when these area measures reached a steady state. Although epithelial area did not show linear changes with age, epithelial nuclear density decreased linearly beginning in the third decade of life. No significant age-related trends were observed for stromal or adipose nuclear density. Digital image analysis offers a high-throughput method for quantitatively measuring tissue morphometry and for objectively assessing age-related changes in adipose tissue, stroma, and epithelium. Epithelial nuclear density is a quantitative measure of age-related breast involution that begins to decline in the early premenopausal period. PMID- 26772401 TI - Integrin alpha5 promotes tumor progression and is an independent unfavorable prognostic factor in esophageal squamous cell carcinoma. AB - The integrin family plays a major role in complex biological events such as differentiation, development, wound healing, and the altered adhesive and invasive properties of tumor cells. The expression and function of integrin alpha5 in esophageal squamous cell carcinoma (ESCC) are not clear. Here, by using tissue microarrays and immunohistochemical method, integrin alpha5 expression was retrospectively evaluated in 147 samples of human ESCC. Results showed that expression of integrin alpha5 was heterogeneous and varied from negative to intense expression in a membrane and cytoplasmic distribution manner. High expression of integrin alpha5 was significantly correlated with lymph node metastasis (P = .042) and tumor size (P = .042). Kaplan-Meier analysis revealed that high expression of integrin alpha5 was related to poor overall survival of ESCC patients (P = .018). Multivariate analysis suggested that integrin alpha5 expression status was an independent prognostic factor for ESCC (P = .003). Moreover, integrin alpha5 expression was associated with the survival of patients with lymph node metastasis (P = .020), but did not influence the survival of patients without lymph node metastasis. Finally, we found that RNAi-mediated knockdown of integrin alpha5 led to decreased growth, migration, and invasion of ESCC cells. Combined, integrin alpha5 might play important roles in the progression of ESCC. Integrin alpha5 is a novel biomarker to predict the prognosis of ESCC patients. PMID- 26772402 TI - Pathologic findings of follow-up surgical excision for radial scar on breast core needle biopsy. AB - The data regarding radial scar (RS) as a risk factor for breast cancer are conflicting, and it is unclear whether an excision is warranted for patients with RS identified on core needle biopsy (CNB). In this study, we investigated the follow-up excisional results for patients with RS on CNB with no history of or concurrent breast cancer or atypical proliferative lesions. The study cohort was composed of 403 such cases, and follow-up excision (FUE) was performed in 220 (54.6%). There was no significant difference in the radiologic findings in cases with and without FUE. Of the 220 cases with FUE, only 2 (0.9%) were upgraded to malignancy (1 invasive carcinoma and 1 ductal carcinoma in situ), whereas 44 cases (20.0%) were upgraded to atypical ductal hyperplasia and 13 cases (5.9%) to lobular neoplasia. Upgrades were associated with greater age but not with any other variable. This is one of the largest studies to evaluate excisional findings in patients with RS identified on CNB but no history of or concurrent breast cancer or atypical proliferative lesions, and the extremely low malignancy upgrade rate indicates that conservative follow-up with imaging rather than surgical excisions may be more appropriate for these patients. PMID- 26772403 TI - Pediatric cystic nephromas: distinctive features and frequent DICER1 mutations. AB - Cystic nephromas (CNs) are uncommon benign renal neoplasms that present with a bimodal age distribution, affecting either infants/young children or adult females. Although differences between these age groups have been suggested, large studies of pediatric CN have not been conducted. As a result, the nomenclature and diagnostic criteria for these lesions remain controversial. In addition, the morphological overlap seen between CN and cystic partially differentiated nephroblastoma (CPDN) can result in diagnostic dilemmas. This study reviews the morphologic and radiographic features of 44 pediatric CN prospectively enrolled on a Children's Oncology Group protocol from 2007 to 2013. Although the typical multicystic architecture with thin septa described in adult CN was present in all of our pediatric cases, differences were also identified. We report distinctive features that add to the morphological spectrum of CN in children. Of the 44 cases, 16 had been previously analyzed and reported for DICER1 mutation, and either loss of function or missense mutations or both were identified in 15 of 16. In contrast, we analyzed 10 cases of adult CN, and all were negative for DICER1 mutations; similarly, 6 CPDNs previously analyzed and reported were negative for DICER1 mutations. Therefore, the clinical, morphological, and genetic differences between pediatric and adult CN, as well as between CN and CPDN, suggest that these 3 lesions represent distinct entities. PMID- 26772404 TI - Clonality assessment of adenomatoid tumor supports its neoplastic nature. AB - Adenomatoid tumor is a relatively rare disease that predominantly involves male and female internal genital tracts. Although its clinical and pathologic features are well characterized, there is still controversy regarding its nature as a true neoplasm or a variant of mesothelial hyperplasia of a reactive nature. We sought to resolve this debate by investigating the clonality of uterine adenomatoid tumor from 13 female cases. The mesothelial cells and surrounding normal myometrium were precisely harvested using laser capture microdissection, and genomic DNA was extracted for clonal analysis by assessing the patterns of X chromosome inactivation. Fluorescent polymerase chain reaction amplification of a highly polymorphic short tandem repeat of the human androgen receptor (HUMARA) gene with and without methylation-sensitive restriction endonuclease HpaII digestion was performed on DNA extracted from mesothelial cells, using normal myometrium and male blood sample as controls. Of the 13 cases successfully amplified, all 10 informative cases showed concordant nonrandom X-chromosome inactivation pattern consistent with monoclonality. In comparison, surrounding normal myometrium showed a polyclonal pattern of X-chromosome inactivation, and male blood sample failed to be amplified after HpaII treatment. Our results demonstrate that adenomatoid tumor is a monoclonal disease favoring a neoplastic process. This neoplastic rather than reactive nature probably accounts for its frequently observed infiltrative growth pattern and the occurrence of diffuse adenomatoid tumor, especially when host immunity is compromised. Additional studies with larger sample sizes will be needed to conclusively prove our conclusion. PMID- 26772406 TI - One Hundred Years in the Making: The Global Tobacco Epidemic. AB - Today's global tobacco epidemic may represent one of the first instances of the globalization of a noninfectious cause of disease. This article focuses on the first century of the global tobacco epidemic and its current status, reviewing the current and projected future of the global tobacco epidemic and the steps that are in progress to end it. In the United States and many countries of Western Europe, tobacco consumption peaked during the 1960s and 1970s and declined as tobacco control programs were initiated, motivated by the evidence indicting smoking as a leading cause of disease. Despite this policy advancement and the subsequent reductions in tobacco consumption, the global tobacco epidemic continued to grow exponentially in the later years of the twentieth century, as the multinational companies sought new markets to replace those shrinking in high income countries. In response, between 2000 and 2004, the World Health Organization developed its first public health treaty, the Framework Convention on Tobacco Control, which entered into force in 2005. An accompanying package of interventions has been implemented. New approaches to tobacco control, including plain packaging and single representation of brands, have been implemented by Australia and Uruguay, respectively, but have been challenged by the tobacco industry. PMID- 26772408 TI - Antimicrobial Resistance, Food Safety, and One Health: The Need for Convergence. AB - Antimicrobial resistance is a complex, multifaceted, urgent global health problem. There is increasing concern about the emergence of multidrug-resistant superbugs. These superbugs result in infections responsive to treatment with few if any currently available antimicrobial agents, reviving memories of the preantibiotic era and evoking concerns about a postantibiotic era. Use of antibiotics exerts selective pressure on pathogens as well as on commensal organisms that are part of the normal flora of humans, animals, and the environment; this favors the emergence of resistant strains and sometimes involves the food supply. Addressing this urgent threat requires implementation of a multifaceted strategy that has been articulated in the past few years; implementation will require sustained political will, investment in systems and research, and a One Health approach involving improved communication, cooperation, and collaboration among the many professional disciplines and organizations with important roles to play at the intersection of human, animal, and environmental health. Priorities include strengthened human and animal health surveillance and monitoring for resistant organisms, antimicrobial stewardship programs, infection-control programs, development and approval of new antimicrobial agents, research on innovative therapeutic approaches, development of rapid diagnostic tests and new vaccines, and educational programs that target professional groups and the public. PMID- 26772407 TI - Identification of four squid species by quantitative real-time polymerase chain reaction. AB - Squids are distributed worldwide, including many species of commercial importance, and they are often made into varieties of flavor foods. The rapid identification methods for squid species especially their processed products, however, have not been well developed. In this study, quantitative real-time PCR (qPCR) systems based on specific primers and TaqMan probes have been established for rapid and accurate identification of four common squid species (Ommastrephes bartramii, Dosidicus gigas, Illex argentinus, Todarodes pacificus) in Chinese domestic market. After analyzing mitochondrial genes reported in GenBank, the mitochondrial cytochrome b (Cytb) gene was selected for O. bartramii detection, cytochrome c oxidase subunit I (COI) gene for D. gigas and T. Pacificus detection, ATPase subunit 6 (ATPase 6) gene for I. Argentinus detection, and 12S ribosomal RNA (12S rDNA) gene for designing Ommastrephidae-specific primers and probe. As a result, all the TaqMan systems are of good performance, and efficiency of each reaction was calculated by making standard curves. This method could detect target species either in single or mixed squid specimen, and it was applied to identify 12 squid processed products successfully. Thus, it would play an important role in fulfilling labeling regulations and squid fishery control. PMID- 26772405 TI - Addictions Neuroclinical Assessment: A Neuroscience-Based Framework for Addictive Disorders. AB - This article proposes a heuristic framework for the Addictions Neuroclinical Assessment that incorporates key functional domains derived from the neurocircuitry of addiction. We review how addictive disorders (ADs) are presently diagnosed and the need for new neuroclinical measures to differentiate patients who meet clinical criteria for addiction to the same agent while differing in etiology, prognosis, and treatment response. The need for a better understanding of the mechanisms provoking and maintaining addiction, as evidenced by the limitations of current treatments and within-diagnosis clinical heterogeneity, is articulated. In addition, recent changes in the nosology of ADs, challenges to current classification systems, and prior attempts to subtype individuals with ADs are described. Complementary initiatives, including the Research Domain Criteria project, that have established frameworks for the neuroscience of psychiatric disorders are discussed. Three domains-executive function, incentive salience, and negative emotionality-tied to different phases in the cycle of addiction form the core functional elements of ADs. Measurement of these domains in epidemiologic, genetic, clinical, and treatment studies will provide the underpinnings for an understanding of cross-population and temporal variation in addictions, shared mechanisms in addictive disorders, impact of changing environmental influences, and gene identification. Finally, we show that it is practical to implement such a deep neuroclinical assessment using a combination of neuroimaging and performance measures. Neuroclinical assessment is key to reconceptualizing the nosology of ADs on the basis of process and etiology, an advance that can lead to improved prevention and treatment. PMID- 26772409 TI - Bile Acid Modifications at the Microbe-Host Interface: Potential for Nutraceutical and Pharmaceutical Interventions in Host Health. AB - Bile acids have emerged as important signaling molecules in the host, as they interact either locally or systemically with specific cellular receptors, in particular the farnesoid X receptor (FXR) and TGR5. These signaling functions influence systemic lipid and cholesterol metabolism, energy metabolism, immune homeostasis, and intestinal electrolyte balance. Through defined enzymatic activities, the gut microbiota can significantly modify the signaling properties of bile acids and therefore can have an impact upon host health. Alterations to the gut microbiota that influence bile acid metabolism are associated with metabolic disease, obesity, diarrhea, inflammatory bowel disease (IBD), Clostridium difficile infection, colorectal cancer, and hepatocellular carcinoma. Here, we examine the regulation of this gut-microbiota-liver axis in the context of bile acid metabolism and indicate how this pathway represents an important target for the development of new nutraceutical (diet and/or probiotics) and targeted pharmaceutical interventions. PMID- 26772410 TI - Unraveling Anthocyanin Bioavailability for Human Health. AB - This review considers the bioavailability of health-protective anthocyanin pigments from foods, in light of the multiple molecular structures and complicated traffic patterns taken by anthocyanins both as flavonoid metabolites and as phenolic acid metabolites within the body. Anthocyanins have generally been considered to have notoriously poor bioavailability, based on the very low levels typically detected in routine human blood draws after ingestion. Although some investigations have assessed anthocyanin bioavailability solely based on the measurement of parent anthocyanins or phenolic acid breakdown products, more recent research has increasingly revealed the presence, qualitative diversity, relatively high concentrations, and tenacity of molecular intermediates of anthocyanins that retain the unique flavonoid C6-C3-C6 backbone structure. We argue that the persistence of anthocyanin metabolites suggests enterohepatic recycling, leading to prolonged residence time, and supports the notion that anthocyanins are far more bioavailable than previously suggested. PMID- 26772411 TI - CRISPR-Based Typing and Next-Generation Tracking Technologies. AB - Bacteria occur ubiquitously in nature and are broadly relevant throughout the food supply chain, with diverse and variable tolerance levels depending on their origin, biological role, and impact on the quality and safety of the product as well as on the health of the consumer. With increasing knowledge of and accessibility to the microbial composition of our environments, food supply, and host-associated microbiota, our understanding of and appreciation for the ratio of beneficial to undesirable bacteria are rapidly evolving. Therefore, there is a need for tools and technologies that allow definite, accurate, and high resolution identification and typing of various groups of bacteria that include beneficial microbes such as starter cultures and probiotics, innocuous commensals, and undesirable pathogens and spoilage organisms. During the transition from the current molecular biology-based PFGE (pulsed-field gel electrophoresis) gold standard to the increasingly accessible omics-level whole genome sequencing (WGS) N-gen standard, high-resolution technologies such as CRISPR-based genotyping constitute practical and powerful alternatives that provide valuable insights into genome microevolution and evolutionary trajectories. Indeed, several studies have shown potential for CRISPR-based typing of industrial starter cultures, health-promoting probiotic strains, animal commensal species, and problematic pathogens. Emerging CRISPR-based typing methods open new avenues for high-resolution typing of a broad range of bacteria and constitute a practical means for rapid tracking of a diversity of food associated microbes. PMID- 26772412 TI - Food Antioxidants: Chemical Insights at the Molecular Level. AB - In this review, we briefly summarize the reliability of the density functional theory (DFT)-based methods to accurately predict the main antioxidant properties and the reaction mechanisms involved in the free radical-scavenging reactions of chemical compounds present in food. The analyzed properties are the bond dissociation energies, in particular those involving OH bonds, electron transfer enthalpies, adiabatic ionization potentials, and proton affinities. The reaction mechanisms are hydrogen-atom transfer, proton-coupled electron transfer, radical adduct formation, single electron transfer, sequential electron proton transfer, proton-loss electron transfer, and proton-loss hydrogen-atom transfer. Furthermore, the chelating ability of these compounds and its role in decreasing or inhibiting the oxidative stress induced by Fe(III) and Cu(II) are considered. Comparisons between theoretical and experimental data confirm that modern theoretical tools are not only able to explain controversial experimental facts but also to predict chemical behavior. PMID- 26772413 TI - Metabolomic Technologies for Improving the Quality of Food: Practice and Promise. AB - It is now well documented that the diet has a significant impact on human health and well-being. However, the complete set of small molecule metabolites present in foods that make up the human diet and the role of food production systems in altering this food metabolome are still largely unknown. Metabolomic platforms that rely on nuclear magnetic resonance (NMR) and mass spectrometry (MS) analytical technologies are being employed to study the impact of agricultural practices, processing, and storage on the global chemical composition of food; to identify novel bioactive compounds; and for authentication and region-of-origin classifications. This review provides an overview of the current terminology, analytical methods, and compounds associated with metabolomic studies, and provides insight into the application of metabolomics to generate new knowledge that enables us to produce, preserve, and distribute high-quality foods for health promotion. PMID- 26772414 TI - Impact of Pathogen Population Heterogeneity and Stress-Resistant Variants on Food Safety. AB - This review elucidates the state-of-the-art knowledge about pathogen population heterogeneity and describes the genotypic and phenotypic analyses of persister subpopulations and stress-resistant variants. The molecular mechanisms underlying the generation of persister phenotypes and genetic variants are identified. Zooming in on Listeria monocytogenes, a comparative whole-genome sequence analysis of wild types and variants that enabled the identification of mutations in variants obtained after a single exposure to lethal food-relevant stresses is described. Genotypic and phenotypic features are compared to those for persistent strains isolated from food processing environments. Inactivation kinetics, models used for fitting, and the concept of kinetic modeling-based schemes for detection of variants are presented. Furthermore, robustness and fitness parameters of L. monocytogenes wild type and variants are used to model their performance in food chains. Finally, the impact of stress-resistant variants and persistence in food processing environments on food safety is discussed. PMID- 26772415 TI - Genomic Epidemiology: Whole-Genome-Sequencing-Powered Surveillance and Outbreak Investigation of Foodborne Bacterial Pathogens. AB - As we are approaching the twentieth anniversary of PulseNet, a network of public health and regulatory laboratories that has changed the landscape of foodborne illness surveillance through molecular subtyping, public health microbiology is undergoing another transformation brought about by so-called next-generation sequencing (NGS) technologies that have made whole-genome sequencing (WGS) of foodborne bacterial pathogens a realistic and superior alternative to traditional subtyping methods. Routine, real-time, and widespread application of WGS in food safety and public health is on the horizon. Technological, operational, and policy challenges are still present and being addressed by an international and multidisciplinary community of researchers, public health practitioners, and other stakeholders. PMID- 26772416 TI - Silencing of Paralemmin-3 Protects Mice from lipopolysaccharide-induced acute lung injury. AB - Excessive inflammatory response induced by lipopolysaccharide (LPS) plays a critical role in the development of acute lung injury (ALI). Paralemmin-3 (PALM3) is a novel protein that can modulate LPS-stimulated inflammatory responses in alveolar epithelial A549 cells. However, it remains unclear whether it is involved in the progression of ALI in vivo. Therefore, we studied the role of PALM3 in the pathogenesis of ALI induced by LPS. ALI was induced by LPS peritoneal injection in C57BL/6J mice. Lentivirus-mediated small interfering RNA (siRNA) targeting the mouse PALM3 gene and a negative control siRNA were intranasally administered to the mice. We found that the expression of PALM3 was up-regulated in the lung tissues obtained from the mouse model of LPS-induced ALI. The LPS-evoked inflammatory response (neutrophils and the concentrations of proinflammatory cytokines [IL-6, IL-1beta, TNF-alpha, MIP-2] in the bronchoalveolar lavage fluid [BALF]), histologic lung injury (lung injury score), permeability of the alveolar capillary barrier (lung wet/dry weight ratio and BALF protein concentration) and mortality rates were attenuated in the PALM3 siRNA-treated mice. These results indicate that PALM3 contributes to the development of ALI in mice challenged with LPS. Inhibiting PALM3 through the intranasal application of specific siRNA protected against LPS-induced ALI. PMID- 26772419 TI - Delirium Associated With Lidocaine Patch Administration: A Case Presentation. AB - Delirium is a common complication among hospitalized elderly individuals. Systemic analgesics are known precipitating factors for delirium. However, the risk from topical pain agents is not well documented. We report a case of a woman who developed delirium after the application of a lidocaine patch. Although lidocaine patches are generally perceived as safe, clinicians should be aware of delirium as a potential adverse effect, particularly in older patients. This report also highlights the role of a systematic approach of staff education, use of a standardized protocol, and interdisciplinary communication in the identification and management of delirium in acute rehabilitation facilities. PMID- 26772417 TI - Postponing the Hypoglycemic Response to Partial Hepatectomy Delays Mouse Liver Regeneration. AB - All serious liver injuries alter metabolism and initiate hepatic regeneration. Recent studies using partial hepatectomy (PH) and other experimental models of liver regeneration implicate the metabolic response to hepatic insufficiency as an important source of signals that promote regeneration. Based on these considerations, the analyses reported here were undertaken to assess the impact of interrupting the hypoglycemic response to PH on liver regeneration in mice. A regimen of parenteral dextrose infusion that delays PH-induced hypoglycemia for 14 hours after surgery was identified, and the hepatic regenerative response to PH was compared between dextrose-treated and control mice. The results showed that regenerative recovery of the liver was postponed in dextrose-infused mice (versus vehicle control) by an interval of time comparable to the delay in onset of PH-induced hypoglycemia. The regulation of specific liver regeneration promoting signals, including hepatic induction of cyclin D1 and S-phase kinase associated protein 2 expression and suppression of peroxisome proliferator activated receptor gamma and p27 expression, was also disrupted by dextrose infusion. These data support the hypothesis that alterations in metabolism that occur in response to hepatic insufficiency promote liver regeneration, and they define specific pro- and antiregenerative molecular targets whose regenerative regulation is postponed when PH-induced hypoglycemia is delayed. PMID- 26772418 TI - Situational but Not Dispositional Pain Catastrophizing Correlates With Early Postoperative Pain in Pain-Free Patients Before Surgery. AB - Pain catastrophizing may be assessed as a dispositional measure using a previous painful experience as a reference or as a situational measure using an actual ongoing pain as a reference. The latter has shown more robust correlations with pain-related outcomes; the relative influence of dispositional and situational pain catastrophizing remains unknown in relation to populations with no pain before surgery. Forty-two consecutive patients who underwent corrective surgery for funnel chest were asked to complete the Pain Catastrophizing Scale with reference to 1) a previous painful experience (dispositional pain catastrophizing), 2) experimental pain during a 2-minute cold pressor test (situational experimental pain catastrophizing), and 3) clinical pain 3 days after surgery (situational clinical pain catastrophizing) to investigate whether these measures predicted immediate pain intensity and unpleasantness in the early postoperative period. Thirty-four patients were available for analyses. Dispositional pain catastrophizing was unrelated to situational experimental and situational clinical pain catastrophizing and to postoperative pain and unpleasantness (P > .05). In contrast, the 2 situation-specific pain catastrophizing measures were strongly associated (rho = .59, P = .0002). In analyses adjusted for preoperative anxiety, depression, and cold pressor pain sensitivity, situational experimental and situational clinical pain catastrophizing correlated with postoperative movement-evoked pain (beta = 1.36, P = .01 and beta = 1.24, P = .02, respectively) and unpleasantness (beta = 1.32, P = .01 and beta = 1.36, P = .01, respectively). PERSPECTIVE: Pain catastrophizing should be captured in relation to specific painful events in otherwise healthy patients. Future studies might benefit from assessing situational pain catastrophizing to identify patients at risk for increased postoperative pain to optimize stratified pain treatment. PMID- 26772420 TI - A two-hit model of suicide-trait-related behaviors in the context of a schizophrenia-like phenotype: Distinct effects of lithium chloride and clozapine. AB - Schizophrenia patients show a high rate of premature mortality due to suicide. The pathophysiological mechanisms of these suicidal behaviors in schizophrenia do not appear to involve serotonergic neurotransmission as found in the general population. Our aim was to develop an in vivo model of schizophrenia presenting suicide-trait-related behaviors such as aggressiveness, impulsivity, anxiety and helplessness. We opted for a two-hit model: C57BL/6 dams were injected with polyI:C on gestational day 12. The pups were submitted to social isolation for 4weeks after weaning. During the last week of social isolation and 30min before behavioral testing, the mice received vehicle, lithium chloride or clozapine. Lithium chloride is well known for its suicide preventive effects in the non schizophrenic population, while clozapine is the antipsychotic with the best established suicide preventive effect. The two-hit model induced several schizophrenia-related and suicide-trait-related behaviors in male, but not female, mice. Additionally, lithium chloride improved prepulse inhibition, aggressiveness, impulsivity and anxiety-like behavior in socially isolated mice only, whereas clozapine prevented behavioral abnormalities mainly in mice prenatally exposed to polyI:C and submitted to isolated rearing. The distinct effects of lithium chloride and clozapine suggested that mice prenatally exposed to polyI:C and submitted to social isolation presented a distinct phenotype from that of mice submitted to social isolation only. Because diagnosing suicidal risk in patients is a challenge for psychiatrists given the lack of specific clinical predictors, our in vivo model could help in gaining a better understanding of the mechanisms underlying suicidal behavior in the context of schizophrenia. PMID- 26772421 TI - Asymmetry of righting reflexes in sea turtles and its behavioral correlates. AB - The righting responses, when the animal rights itself over one side of the body after been overturned on the back, are one of the simplest ways to test for laterality, especially in lower vertebrates. In anuran amphibians unilateral preferences in righting responses correlated to the degree of the use of alternating-limb (asynchronous) movements during locomotion. Turtles is one of the underrepresented vertebrate groups in the studies of laterality, while possess also different types of locomotion (with synchronous or asynchronous use of the contralateral limbs), which allows testing the hypothesis on functional relationship between the mode of locomotion and the strength of laterality. We studied two species of sea turtles, Green turtle (Chelonia mydas) and Olive Ridley turtle (Lepidochelys olivacea), which differ from the majority of other representatives of the order in that they mostly utilize synchronous locomotion, when all four limbs move simultaneously in strokes (scratching). In righting response tests turtles demonstrated individual and weak population level laterality, which differed in strength. The Green turtle was less lateralized with the majority of individuals being ambipreferent. The Olive Ridley turtle had a greater number of lateralized individuals and a greater average strength of laterality. Interspecies comparison to land tortoises, which use only asynchronous (alternating-limb) walking (crawling), confirmed the rule found in amphibians: the more asynchronous locomotion is used, the greater is the strength of laterality in righting. Hence, data from turtles and amphibians may represent a phenomenon common for all quadruped vertebrates. We also discuss possible biomechanical and neurological correlates of this evolutionary change in locomotory patterns and lateralization in sea turtles when adapting to sea life. PMID- 26772423 TI - A self-assembly peptide nanofibrous scaffold reduces inflammatory response and promotes functional recovery in a mouse model of intracerebral hemorrhage. AB - Self-assembly peptide nanofibrous scaffold (SAPNS), such as RADA16-I, has been shown to reduce acute brain injury and enhance functional recovery in rat intracerebral hemorrhage (ICH) models. The acidic property of RADA16-I, however, limits its application in patients. In the present study, by using a modified neutral SAPNS (the RADA16mix) in collagenase IV induced ICH mice, we detected there were less microglial and apoptotic cells in mice injected with RADA16mix, meanwhile, more cells survived in this group. In addition, behavioral tests indicated that mice treated with RADA16mix showed better functional recovery than RADA16-I. Local delivery of RADA16mix reduces acute brain injury by lowering the number of apoptotic cells, decreasing glial reaction, reducing inflammatory response and, therefore promotes functional recovery. Moreover, new nerve fibers have grown into this new SAPNS, which indicates RADA16mix is able to serve as a bridge for nerve fibers to grow through. FROM THE CLINICAL EDITOR: Acute brain injury, such as intracerebral hemorrhage is a serious problem. In this work, self assembly peptide nanofibrous scaffold (SAPNS) were tested in a rat model to aid functional recovery. Several items have been considered, such as histology, brain water content, hematoma volume, cell death and survival, inflammatory response, and nerve fiber growth. The positive data generated should pave the way towards better treatment options. PMID- 26772422 TI - Parameters affecting intracellular delivery of molecules using laser-activated carbon nanoparticles. AB - Previous studies showed that carbon nanoparticles exposed to nanosecond laser pulses cause intracellular uptake of molecules. In this study, prostate cancer cells incubated with carbon-black (CB) nanoparticles and fluorescent marker compounds were exposed to 10ns laser pulses at 1064nm wavelength, after which intracellular uptake was measured by flow cytometry. Calcein and dextran (150kDa) were delivered into >50% of cells, whereas larger dextrans (<=2000kDa) were taken up by ~10% of cells. Under all conditions studied, cell viability loss was minimal. Uptake also increased with increasing laser power, increasing CB nanoparticle concentration, increasing CB nanoparticle size and decreasing laser wavelength. CB nanoparticles enabled uptake better than gold nanoparticles or multi-walled carbon nanotubes under the conditions studied. Proof-of-principle experiments showed intracellular uptake by cells in vivo. We conclude that intracellular uptake of molecules using laser-activated CB nanoparticles provides a promising approach to deliver molecules into cells. FROM THE CLINICAL EDITOR: Delivery of drugs using nanoparticles as carriers is promising. The authors in this study investigated the use of laser-activated carbon nanoparticles to increase the cellular uptake of payloads in various parameters. The positive data generated should provide further platform for a new approach for intracellular delivery of molecules. PMID- 26772424 TI - Drug delivery system targeting advanced hepatocellular carcinoma: Current and future. AB - Hepatocellular carcinoma (HCC) has a fairly high morbidity and is notoriously difficult to treat due to long latent period before detection, multidrug resistance and severe drug-related adverse effects from chemotherapy. Targeted drug delivery systems (DDS) that can selectively deliver therapeutic drugs into tumor sites have demonstrated a great potential in cancer treatment, which could be utilized to resolve the limitations of conventional chemotherapy. Numerous preclinical studies of DDS have been published, but targeted DDS for HCC has yet to be made for practical clinical use. Since rational targeted DDS design should take cancer-specific properties into consideration, we have reviewed the biological and physicochemical properties of HCC extensively to provide a comprehensive understanding on HCC, and recent DDS studies on HCC, aiming to find some potential targeted DDSs for HCC treatment and a meaningful platform for further development of HCC treatments. FROM THE CLINICAL EDITOR: Hepatocellular carcinoma has a high incidence worldwide and is known to be multidrug resistant. Thus, intensive research is being carried out to find better chemotherapeutic agents as well as new drug delivery systems. In this article, the authors reviewed in depth the current challenges facing new drug designs and also outlined novel targeted drug delivery systems (DDS) in the fight against HCC. PMID- 26772425 TI - Amphotericin B-silver hybrid nanoparticles: synthesis, properties and antifungal activity. AB - High antifungal activity is reported, in comparison with commercially available products, of a novel hybrid system based on silver nanoparticles synthesized using a popular antifungal macrocyclic polyene amphotericin B (AmB) acting both as a reducing and stabilizing/capping agent. The synthesis reaction proceeds in an alkaline environment which prevents aggregation of AmB itself and promotes nanoparticle formation. The innovative approach produces monodisperse (PDI=0.05), AmB-coated silver nanoparticles (AmB-AgNPs) with the diameter ~7nm. The products were characterized using imaging (electron microscopy) and spectroscopic (UV-vis and infrared absorption, dynamic light scattering and Raman scattering) methods. The nanoparticles were tested against Candida albicans, Aspergillus niger and Fusarium culmorum species. For cytotoxicity studies CCD-841CoTr and THP-1 cell lines were used. Particularly high antifungal activity of AmB-AgNPs is interpreted as the result of synergy between the antifungal activity of amphotericin B and silver antimicrobial properties (Ag(+) ions release). FROM THE CLINICAL EDITOR: Amphotericin B (AmB) is a common agent used for the treatment against severe fungal infections. In this article, the authors described a new approach in using a combination of AmB and silver nanoparticles, in which the silver nanoparticles were synthesized and stabilized by AmB. Experimental data confirmed synergistic antifungal effects between amphotericin B and silver. This novel synthesis process could potentially be important in future drug development and fabrication. PMID- 26772426 TI - Structural requirements of mono- and multivalent L-selectin blocking aptamers for enhanced receptor inhibition in vitro and in vivo. AB - L-selectin mediates extravasation of leukocytes from blood into the surrounding tissue during inflammation and is therefore a therapeutical target in certain overwhelming immune reactions. In this study, we characterized an L-selectin specific blocking DNA aptamer with respect to nucleotide composition and target binding. Introduction of deletions and nucleotide exchanges resulted in an optimized DNA sequence but preservation of the IC50 in the low nanomolar range. The inhibitory potential was significantly increased when the aptamer was displayed as a di- and trimer connected via appropriate linker length. Similar to monoclonal antibodies, trimer yielded picomolar IC50 values in a competitive binding assay. In comparison to the monovalent aptamer, the trivalent assembly reduced PBMC interactions to L-selectin ligands 90-fold under shear and exerted superior inhibition of PBMC rolling in vivo. In conclusion, our work demonstrates the feasibility of optimizing aptamer sequences and shows that multivalent ligand presentation enables superior adhesion receptor targeting. FROM THE CLINICAL EDITOR: During inflammation, leukocytes extravasate from blood vessels under chemotaxic signals. The presence of L-selectin on endothelium acts as a mediator for the extravasation process. In this study, the authors investigated an L selectin specific blocking DNA aptamer in various forms, as inhibitors to leukocyte binding and extravasation. This new approach confirmed the potential use of aptamers in clinical setting. PMID- 26772427 TI - Polymer-lipid hybrid nanoparticles synchronize pharmacokinetics of co encapsulated doxorubicin-mitomycin C and enable their spatiotemporal co-delivery and local bioavailability in breast tumor. AB - Effective combination chemotherapy requires the delivery of drugs of synergism to tumor sites while sparing normal tissues. Herein we investigated whether coencapsulation of doxorubicin and mitomycin C within polymer-lipid hybrid nanoparticles (DMPLN) achieved this goal via ratiometric drugs in an orthotopic murine breast tumor model with nanocarrier-modified biodistribution, pharmacokinetics, local bioavailability and toxicity. Fluorescence imaging revealed quickened and extended tumor uptake but reduced cardiac accumulation of DMPLN. Quantitative drug analysis demonstrated prolonged systemic circulation, increased tumor accumulation and sustained synergistic ratios of doxorubicin and mitomycin C delivered by DMPLN over 24h. Higher levels of tumor cell apoptosis and reduced organ toxicity were obtained with DMPLN compared to free drug cocktails. DMPLN released DOX in tumors more efficiently than that from liposomal doxorubicin, as evidenced by a higher extent of the metabolite, doxorubicinol. These findings substantiate the importance of rational design of nanoparticles for synergistic drug combination therapy. FROM THE CLINICAL EDITOR: The treatment of cancer usually involves using combination chemotherapeutic agents. In adopting a nanomedicine approach, one can in theory design combination therapy consisting of drugs of synergistic activities, with the aim to target tumor specifically while minimizing systemic toxicity. The authors in this study provided evidence for this rational design by co-encapsulation of doxorubicin and mitomycin C within polymer-lipid hybrid nanoparticles (DMPLN) in a breast cancer model. PMID- 26772428 TI - Silk fibroin nanoparticles support in vitro sustained antibiotic release and osteogenesis on titanium surface. AB - Increasing amounts of metal-based implants are used for orthopedic or dental surgeries throughout the world. Still several implant-related problems such as inflammation, loosening and bacterial infection are prevalent. These problems stem from the immediate microbial contamination and failure of initial osteoblast adhesion. Additionally, bacterial infections can cause serious and life threatening conditions such as osteomyelitis. Here, antibiotic (gentamicin) loaded silk protein fibroin (non-mulberry silkworm, Antheraea mylitta) nanoparticles are fabricated and deposited over the titanium surface to achieve sustained drug release in vitro and to alter the surface nano-roughness. Based on the altered surface topography, chemistry and antibacterial activity, we conclude that the nanoparticle-deposited surfaces are superior for osteoblast adhesion, proliferation and differentiation in comparison to bare Ti. This method can be utilized as a cost-effective approach in implant modification. FROM THE CLINICAL EDITOR: Titanium-based implants are commonly used in the field of orthopedics or dentistry. Surface modification of an implant is vital to ensure osseointegration. In this article, the author investigated the use of silk protein fibroins for metal surface modification and also for drug delivery against bacteria. The encouraging data should provide a new method in terms of nanotechnology in the respective clinical fields. PMID- 26772429 TI - NIR-emitting chiral gold nanoclusters coated with gamma-cyclodextrin are pH sensitive: Application as biomarker. AB - Change in cellular pH due to onset of certain malfunctions needs to be tracked quickly so that treatment to cure such incidents may be started immediately. For example, microenvironment of a developing tumor is acidic due to high metabolic rate as well as low oxygen supply. Hence biomarkers that can sharply sense transition in pH could be of great use in the early detection of tumor formation. In the present work, a unique pH sensitive non-cytotoxic gold nanocluster based probe has been synthesized to precisely detect sharp change in biological pH. The gold nanoclusters were coated with dihydrolipoic acid incorporated gamma cyclodextrins. Measurements with steady state fluorometric changes reveal the sensibility of the probes through obvious wavelength shift depending on the changes in the microenvironment. The nanocluster based probe has been successfully applied to detect cancer cells with high precision. FROM THE CLINICAL EDITOR: Biomarkers sensitive to physiological environment have extensive uses in nanomedicines. pH sensitive ultrasmall gold nanoclusters coated with dihydrolipoic acid incorporated gamma-cyclodextrins indicate Changes in cellular pH, therefore certain malfunctions. The new biomarker could be useful to detect tumor calls. PMID- 26772431 TI - Challenges of clinical translation in nanomedicine: A qualitative study. AB - Clinical translation of breakthroughs in nanotechnology and nanomedicine is expected to significantly improve diagnostic tools and therapeutic modalities for various diseases. This will not only improve human health and well-being, but is also likely to reduce health care costs in the long run. However, clinical translation is a long, arduous, resource intensive process that requires priority setting, resource mobilization, successful national and international collaboration, and effective coordination between key stakeholders. The aim of this paper is to describe various challenges faced by the stakeholders involved in translational nanomedicine while planning and conducting first in human clinical trials. We draw on insights obtained from 46 in-depth qualitative interviews with key stakeholders from Europe and North America. FROM THE CLINICAL EDITOR: Translational research is a crucial step in bringing basic research into clinical reality. This is particularly important in a new field like nanomedicine. Clinical translation is a long and resource intensive process with difficulties along the way. In this article, the authors looked at the challenges faced by various parties in order to help identify ways to overcome these challenges. PMID- 26772430 TI - Subtumoral analysis of PRINT nanoparticle distribution reveals targeting variation based on cellular and particle properties. AB - The biological activity of nanoparticle-directed therapies critically depends on cellular targeting. We examined the subtumoral fate of Particle Replication in Non-Wetting Templates (PRINT) nanoparticles in a xenografted melanoma tumor model by multi-color flow cytometry and in vivo confocal tumor imaging. These approaches were compared with the typical method of whole-organ quantification by radiolabeling. In contrast to radioactivity based detection which demonstrated a linear dose-dependent accumulation in the organ, flow cytometry revealed that particle association with cancer cells became dose-independent with increased particle doses and that the majority of the nanoparticles in the tumor were associated with cancer cells despite a low fractional association. In vivo imaging demonstrated an inverse relationship between tumor cell association and other immune cells, likely macrophages. Finally, variation in particle size nonuniformly affected subtumoral association. This study demonstrates the importance of subtumoral targeting when assessing nanoparticle activity within tumors. FROM THE CLINICAL EDITOR: Particle Replication in Non-Wetting Templates (PRINT) technology allows the production of nanoparticles with uniform size. The authors in the study utilized PRINT-produced nanoparticles to investigate specific tumor uptake by multi-color flow cytometry and in vivo confocal tumor imaging. This approach allowed further in-depth correlation between nanoparticle properties and tumor cells and should improve future design. PMID- 26772432 TI - An analysis of nonlinear dynamics underlying neural activity related to auditory induction in the rat auditory cortex. AB - A sound interrupted by silence is perceived as discontinuous. However, when high intensity noise is inserted during the silence, the missing sound may be perceptually restored and be heard as uninterrupted. This illusory phenomenon is called auditory induction. Recent electrophysiological studies have revealed that auditory induction is associated with the primary auditory cortex (A1). Although experimental evidence has been accumulating, the neural mechanisms underlying auditory induction in A1 neurons are poorly understood. To elucidate this, we used both experimental and computational approaches. First, using an optical imaging method, we characterized population responses across auditory cortical fields to sound and identified five subfields in rats. Next, we examined neural population activity related to auditory induction with high temporal and spatial resolution in the rat auditory cortex (AC), including the A1 and several other AC subfields. Our imaging results showed that tone-burst stimuli interrupted by a silent gap elicited early phasic responses to the first tone and similar or smaller responses to the second tone following the gap. In contrast, tone stimuli interrupted by broadband noise (BN), considered to cause auditory induction, considerably suppressed or eliminated responses to the tone following the noise. Additionally, tone-burst stimuli that were interrupted by notched noise centered at the tone frequency, which is considered to decrease the strength of auditory induction, partially restored the second responses from the suppression caused by BN. To phenomenologically mimic the neural population activity in the A1 and thus investigate the mechanisms underlying auditory induction, we constructed a computational model from the periphery through the AC, including a nonlinear dynamical system. The computational model successively reproduced some of the above-mentioned experimental results. Therefore, our results suggest that a nonlinear, self-exciting system is a key element for qualitatively reproducing A1 population activity and to understand the underlying mechanisms. PMID- 26772433 TI - MaxiK channel interactome reveals its interaction with GABA transporter 3 and heat shock protein 60 in the mammalian brain. AB - Large conductance voltage and calcium-activated potassium (MaxiK) channels are activated by membrane depolarization and elevated cytosolic Ca(2+). In the brain, they localize to neurons and astrocytes, where they play roles such as resetting the membrane potential during an action potential, neurotransmitter release, and neurovascular coupling. MaxiK channels are known to associate with several modulatory proteins and accessory subunits, and each of these interactions can have distinct physiological consequences. To uncover new players in MaxiK channel brain physiology, we applied a directed proteomic approach and obtained MaxiK channel pore-forming alpha subunit brain interactome using specific antibodies. Controls included immunoprecipitations with rabbit immunoglobulin G (IgG) and with anti-MaxiK antibodies in wild type and MaxiK channel knockout mice (Kcnma1( /-)), respectively. We have found known and unreported interactive partners that localize to the plasma membrane, extracellular space, cytosol and intracellular organelles including mitochondria, nucleus, endoplasmic reticulum and Golgi apparatus. Localization of MaxiK channel to mitochondria was further confirmed using purified brain mitochondria colabeled with MitoTracker. Independent proof of MaxiK channel interaction with previously unidentified partners is given for GABA transporter 3 (GAT3) and heat shock protein 60 (HSP60). In human embryonic kidney 293 cells containing SV40 T-antigen (HEK293T) cells, both GAT3 and HSP60 coimmunoprecipitated and colocalized with MaxiK channel; colabeling was observed mainly at the cell periphery with GAT3 and intracellularly with HSP60 with protein proximity indices of ~ 0.6 and ~ 0.4, respectively. In rat primary hippocampal neurons, colocalization index was identical for GAT3 (~ 0.6) and slightly higher for HSP60 (~ 0.5) association with MaxiK channel. The results of this study provide a complete interactome of MaxiK channel the mouse brain, further establish the localization of MaxiK channel in the mouse brain mitochondria and demonstrate the interaction of MaxiK channel with GAT3 and HSP60 in neurons. The interaction of MaxiK channel with GAT3 opens the possibility of a role of MaxiK channel in GABA homeostasis and signaling. PMID- 26772434 TI - The discovery of immunoglobulin E. AB - The discovery of immunoglobulin E (IgE) was a breakthrough in the field of allergy and immunology. Our understanding of mechanisms of allergic reactions and the role of IgE in these disorders has paralleled to the discovery of treatment modalities for patients with allergy. The first clue to the existence of a substance responsible for hypersensitivity reactions was demonstrated in 1921 by Prausnitz and Kustner, and after four decades it was identified as an immunoglobulin subclass by Ishizakas and co-workers. In 1968, the WHO International Reference Centre for Immunoglobulins announced the presence of a fifth immunoglobulin isotype, IgE. PMID- 26772435 TI - IL-10 from marginal zone precursor B cells controls the differentiation of Th17, Tfh and Tfr cells in transplantation tolerance. AB - B cells are known to control CD4T cell differentiation in secondary lymphoid tissues. We hypothesized that IL-10 expression by marginal zone precursor (MZP) regulatory B cells controls the differentiation and positioning of effector and regulatory T cells during tolerization. Costimulatory blockade with donor specific transfusion (DST) and anti-CD40L mAb in C57BL/6 mice induced tolerance to allogeneic cardiac allograft. B cell depletion or IL-10 deficiency in B cells prevented tolerance, resulting in decreased follicular regulatory CD4(+) T cells (Tfr) and increased IL-21 expression by T follicular helper (Tfh) cells in the B cell and T cell zones. IL-21 acted with IL-6 to induce CCR6(+) Th17 that caused rejection. Deficiency or blockade of IL-6, IL-21, IL-21R, or CCR6 prevented B cell depletion-induced acute cellular rejection; while agonistic mCCL20-Ig induced rejection. Adoptive transfer of IL-10(+/+) MZP in tolerogen treated CD19 Cre(+/-):IL-10(fl/fl) mice rescued the localization of Tfh and Tfr cells in the B cell follicle and prevented allograft rejection. MZP B cell IL-10 is necessary for tolerance and controls the differentiation and position of Th17, Tfh and Tfr cells in secondary lymphoid tissues. This has implications for understanding tolerance induction and how B cell depletion may prevent tolerance. PMID- 26772436 TI - Negative impact of AQP-4 channel inhibition on survival of retinal ganglion cells and glutamate metabolism after crushing optic nerve. AB - The purpose of this study was to determine whether inhibition of aquaporin 4 (AQP4) is neuroprotective or neurodestructive after crushing the optic nerve of rats. The left optic nerves of rats were crushed, and TGN-020 (5.0 mg/kg, crush TGN-020) or its vehicle (DMSO, crush placebo) was injected intraperitoneally just after the crushing. As controls, the left optic nerves were exposed but not touched in other rats (sham controls). The retinal damages were determined by the density of retinal ganglion cells (RGCs) and the ratio of BAX/Bcl-2 on day 7. The glutamate level in the optic nerve on day 1 after the crushing was determined. The expressions of glutamine synthetase, glutamate-aspartate transporter (GLAST), and AQP4 were determined on day 3 by immunoblotting. The effects of AQP4 inhibition on the glutamate-induced changes of AQP4 expression and on the glutamate uptake were determined for optic nerve astrocytes in culture. The results showed that the density of RGCs was 2040 +/- 91.3 cells/mm(2) (n = 6) in the sham control, and it was significantly decreased to 1072 +/- 134.3 cells/mm(2) after crushing the optic nerve (P < 0.0001, crush placebo, n = 7; Fisher). An intraperitoneal injection of TGN-020 led to a further significant (P = 0.02, Fisher) decrease of the density of RGCs to 743 +/- 371 cells/mm(2) (crush TGN-020, n = 7). The mRNA level of BAX/Bcl-2 ratio was 0.37 +/- 0.05 in the sham control (n = 6) which was significantly increased to 0.88 +/- 0.10 after crushing the optic nerve (placebo crush, n = 7; P = 0.0001, Scheffe). TGN-020 also significantly increased the BAX/Bcl-2 ratio to 1.29 +/- 0.4 (n = 6) from the crush placebo group (P = 0.04, Scheffe). Immunoblotting showed similar changes in the protein levels. The glutamate level in the optic nerve was significantly increased to 53.7 +/- 6.0 MUM/mg/protein on day 1 (n = 4) from the sham control level of 45.9 +/- 3.1 MUM/mg/protein (n = 4; P = 0.04, t test). TGN-020 significantly (P < 0.05, Scheffe) depressed the expression of glutamate metabolism-related proteins on day 3. Exposure of cultured optic nerve astrocytes to glutamate (1.0 mM, n = 4) significantly increased the expression of AQP4 (P < 0.001, Scheffe) that was depressed by TGN-020 (100 nM, n = 4). In addition, glutamate uptake was inhibited by TGN-020 at 10 nM or higher. These results indicate that an inhibition of AQP4 enhances the loss of RGCs and retinal damages after crushing the optic nerve. Inhibition of AQP4 impairs glutamate metabolism which may account in part for these neurodestructive events. PMID- 26772437 TI - Dominant negative consequences of a hERG 1b-specific mutation associated with intrauterine fetal death. AB - The human ether-a-go-go related gene (hERG) encodes two subunits, hERG 1a and hERG 1b, that combine in vivo to conduct the rapid delayed rectifier potassium current (IKr). Reduced IKr slows cardiac action potential (AP) repolarization and is an underlying cause of cardiac arrhythmias associated with long QT syndrome (LQTS). Although the physiological importance of hERG 1b has been elucidated, the effects of hERG 1b disease mutations on cardiac IKr and AP behavior have not been described. To explore the disease mechanism of a 1b-specific mutation associated with a case of intrauterine fetal death, we examined the effects of the 1b-R25W mutation on total protein, trafficking and membrane current levels in HEK293 cells at physiological temperatures. By all measures the 1b-R25W mutation conferred diminished expression, and exerted a temperature-sensitive, dominant negative effect over the WT hERG 1a protein with which it was co-expressed. Membrane currents were reduced by 60% with no apparent effect on voltage dependence or deactivation kinetics. The dominant-negative effects of R25W were demonstrated in iPSC-CMs, where 1b-R25W transfection diminished native IKr compared to controls. R25W also slowed AP repolarization, and increased AP triangulation and variability in iPSC-CMs, reflecting cellular manifestations of pro-arrhythmia. These data demonstrate that R25W is a dominant-negative mutation with significant pathophysiological consequences, and provide the first direct link between hERG 1b mutation and cardiomyocyte dysfunction. PMID- 26772438 TI - The Popeye domain containing protein family--A novel class of cAMP effectors with important functions in multiple tissues. AB - Popeye domain containing (Popdc) proteins are a unique family, which combine several different properties and functions in a surprisingly complex fashion. They are expressed in multiple tissues and cell types, present in several subcellular compartments, interact with different classes of proteins, and are associated with a variety of physiological and pathophysiological processes. Moreover, Popdc proteins bind the second messenger cAMP with high affinity and it is thought that they act as a novel class of cAMP effector proteins. Here, we will review the most important findings about the Popdc family, which accumulated since its discovery about 15 years ago. We will be focussing on Popdc protein interaction and function in striated muscle tissue. However, as a full picture only emerges if all aspects are taken into account, we will also describe what is currently known about the role of Popdc proteins in epithelial cells and in various types of cancer, and discuss these findings with regard to their relevance for cardiac and skeletal muscle. PMID- 26772439 TI - Amyloid imaging using fluorine-19 magnetic resonance imaging ((19)F-MRI). AB - The formation of senile plaques followed by the deposition of amyloid-beta is the earliest pathological change in Alzheimer's disease. Thus, the detection of senile plaques remains the most important early diagnostic indicator of Alzheimer's disease. Amyloid imaging is a noninvasive technique for visualizing senile plaques in the brains of Alzheimer's patients using positron emission tomography (PET) or magnetic resonance imaging (MRI). Because fluorine-19 ((19)F) displays an intense nuclear magnetic resonance signal and is almost non-existent in the body, targets are detected with a higher signal-to-noise ratio using appropriate fluorinated contrast agents. The recent introduction of high-field MRI allows us to detect amyloid depositions in the brain of living mouse using (19)F-MRI. So far, at least three probes have been reported to detect amyloid deposition in the brain of transgenic mouse models of Alzheimer's disease; (E,E) 1-fluoro-2,5-bis-(3-hydroxycarbonyl-4-hydroxy)styrylbenzene (FSB), 1,7-bis(4' hydroxy-3'-trifluoromethoxyphenyl)-4-methoxycarbonylethyl-1,6-heptadiene3,5-dione (FMeC1, Shiga-Y5) and 6-(3',6',9',15',18',21'-heptaoxa-23',23',23' trifluorotricosanyloxy)-2-(4'-dimethylaminostyryl)benzoxazole (XP7, Shiga-X22). This review presents the recent advances in amyloid imaging using (19)F-MRI, including our own studies. PMID- 26772440 TI - Impact of Testosterone Replacement Therapy on Myocardial Infarction, Stroke, and Death in Men With Low Testosterone Concentrations in an Integrated Health Care System. AB - The aim of this study was to assess the effect of testosterone replacement therapy (TRT) on cardiovascular outcomes. Men (January 1, 1996, to December 31, 2011) with a low initial total testosterone concentration, a subsequent testosterone level, and >3 years of follow-up were studied. Levels were correlated with testosterone supplement use. The primary outcome was major adverse cardiovascular events (MACE), defined as a composite of death, nonfatal myocardial infarction, and stroke at 3 years. Multivariate adjusted hazard ratios (HRs) comparing groups of persistent low (<212 ng/dl, n = 801), normal (212 to 742 ng/dl, n = 2,241), and high (>742 ng/dl, n = 1,694) achieved testosterone were calculated by Cox hazard regression. A total of 4,736 men were studied. Three-year rates of MACE and death were 6.6% and 4.3%, respectively. Subjects supplemented to normal testosterone had reduced 3-year MACE (HR 0.74; 95% confidence interval [CI] 0.56 to 0.98, p = 0.04) compared to persistently low testosterone, driven primarily by death (HR 0.65, 95% CI 0.47 to 0.90). HRs for MI and stroke were 0.73 (95% CI 0.40 to 1.34), p = 0.32, and 1.11 (95% CI 0.54 to 2.28), p = 0.78, respectively. MACE was noninferior but not superior for high achieved testosterone with no benefit on MI and a trend to greater stroke risk. In conclusion, in a large general health care population, TRT to normal levels was associated with reduced MACE and death over 3 years but a stroke signal with high achieved levels suggests a conservative approach to TRT. PMID- 26772441 TI - Assessment of Valvular Disorders in Survivors of Hodgkin's Lymphoma Treated by Mediastinal Radiotherapy +/- Chemotherapy. AB - As the number of Hodgkin's lymphoma (HL) survivors grows, understanding long-term complications becomes more important. Mediastinal radiotherapy (MRT) seems to cause valvular disease, and the prevalence might increase during follow-up. In this cross-sectional study 82 HL survivors participated (52% men, mean age 47.8 years, 50 treated with MRT). Valvular disease was diagnosed by transthoracic echocardiography and compared between HL survivors treated with and without MRT. Univariate and multivariate logistic regression analysis was used to identify predictors for valvular disease. During a median follow-up of 13.4 years (range 2 to 39 years), >= mild valvular disease was present in 61.2% of HL survivors with MRT (n = 30), compared with 31.0% of HL survivors without MRT (n = 9; odds ratio [OR] 3.51, 95% CI 1.32 to 9.30, p = 0.01). In multivariate analysis, only current age remained predictive for >= mild valvular disease (OR 1.08 per year, 95% CI 1.01 to 1.14, p = 0.023). Aortic regurgitation (AR) was most prevalent and irradiated patients had significantly more >= mild AR (38.2% vs 6.8%, p = 0.007). Within the MRT subgroup, time after radiation of >15 years was associated with AR (OR 4.70, 95% CI 1.05 to 21.03, p = 0.043), after adjusting for current age and hypertension. Severe valvular disease was present in 24.5% of HL survivors with MRT compared with 3.4% without MRT (p = 0.016). Valvular surgery was performed in 9 HL survivors (18.0%) with MRT and in none without MRT. In conclusion, the prevalence of valvular disease in HL survivors treated with MRT is high and increases with time after irradiation. Long-time screening for valvular disease by transthoracic echocardiography might be worthwhile. PMID- 26772442 TI - Prognostic Value of Albuminuria on Cardiovascular Outcomes After Elective Percutaneous Coronary Intervention. AB - Albuminuria is the most widely evaluated marker of kidney damage. Many previous studies have demonstrated an association between the presence of albuminuria and increased cardiovascular events. However, there are limited data regarding the impact of albuminuria in patients requiring coronary revascularization. This study investigated whether the urinary albumin excretion rate could predict cardiovascular events in such a population. We enrolled 698 consecutive patients who underwent elective percutaneous coronary intervention. The baseline urinary albumin-to-creatinine ratio (ACR; mg/gCr) was measured and patients were divided into those with normoalbuminuria (ACR <30 mg/gCr), microalbuminuria (ACR 30 to 300 mg/gCr), or macroalbuminuria (ACR >300 mg/gCr). We collected data on the incidences of cardiac death and/or nonfatal myocardial infarction. We identified 389, 230, and 79 patients with normoalbuminuria, microalbuminuria, and macroalbuminuria, respectively. During follow-up (median: 1,564 days), 41 events occurred. The event-free survival rate was 89% in patients with macroalbuminuria, 92% in those with microalbuminuria, and 97% in those with normoalbuminuria, respectively (log-rank test p = 0.002). After adjustment for conventional risk factors, Cox analysis revealed hazard ratios for cardiac death and/or nonfatal myocardial infarction were 2.56 (95% CI 1.23 to 5.32, p = 0.01) in those with microalbuminuria and 4.02 (95% CI 1.59 to 10.12, p = 0.003) in those with macroalbuminuria compared with those with normoalbuminuria. In conclusion, an elevated urinary albumin excretion rate independently predicted adverse cardiovascular outcomes, with a gradual risk increase that progressed from microalbuminuria to macroalbuminuria in patients undergoing elective percutaneous coronary intervention. PMID- 26772443 TI - Intraindividual Variability and Association of Human Collateral Supply to Different Arterial Regions. AB - The intraindividual variability and association of human collateral functional supply to different arterial regions is unknown. The primary study end point was collateral flow index (CFI) as obtained in the coronary artery (CA), renal artery (RA), left superficial femoral artery (SFA), and left subclavian artery (SCA) of the same individual. CFI is the ratio between simultaneously recorded mean arterial occlusive pressure divided by mean aortic pressure both subtracted by mean central venous pressure. In 100 patients admitted for diagnostic coronary angiography, CFI was assessed in 3 arterial regions (CA, RA, and SFA), 13 patients underwent CFI measurements in all 4 territories. By quantitative coronary angiography, 82 patients had a stenosis <50% in diameter in the CA who underwent CFI measurement. CFI in the CA, RA, left SFA, and left SCA region amounted to 0.110 +/- 0.093, 0.119 +/- 0.082, 0.512 +/- 0.147, and 0.563 +/- 0.155, respectively (p <0.0001). There was a direct and linear correlation between CA and SFA CFI: CFI_SFA = 0.47 + 0.47CFI_CA (r(2) = 0.05; p = 0.0259). In patients with CFI values in all 4 arterial regions, an inverse linear relation between left SFA and left SCA CFI was observed: CFI_SCA = 0.91-0.67CFI_SFA (r(2) = 0.36; p = 0.0305). In conclusion, intraindividual, preexistent collateral function is widely varying between different arterial supply areas. On average, collateral flow ranges from approximately 12% in comparison to flow during arterial patency in the coronary and renal circulation to over 50% in the left SFA and left SCA, that is, circle of Willi's territory. CA and SFA CFIs are directly related to each other. PMID- 26772444 TI - Meta-Analysis of Risks for Short-Term Readmission in Patients With Heart Failure. AB - This investigation sought to quantify the risk factors for short-term readmission in patients with heart failure (HF). Electronic databases were systematically searched for studies reporting relative risk, odds ratio, and hazard ratio for the combined primary outcome of all-cause hospital readmission or all-cause mortality <=90 days from discharge of patients with HF. Clinical characteristics, study design, type and incidence of outcome, univariable effect sizes for each risk factor, and their associated 95% confidence intervals were extracted. Each univariable effect size was pooled and computed in a separate meta-analysis using random-effects models weighted by inverse variance. The frequency of significance of each risk factor in multivariable models was also assessed to confirm their independence. Sixty-nine studies (2,038,524 patients) were included and 144 factors were reported, including 32 reported more than twice. The significant associations of the combined primary outcome were chronic lung disease, chronic kidney disease, atherosclerotic vascular disease (peripheral, coronary, and cerebrovascular), diabetes, anemia, lower systolic blood pressure, previous admission, multidisciplinary treatment, and use of beta-blockade and angiotensin converting enzyme inhibition or angiotensin receptor blockade. In multivariable analyses, most of these variables remained independently associated with the combined primary outcome. However, age, male gender, black race, hypertension, dyslipidemia, smoking, atrial fibrillation, cancer, and uses of diuretics, aldosterone antagonists, and digoxin were not significant. In conclusion, noncardiovascular co-morbidities, poor physical condition, history of admission, and failure to use evidence-based medication are more strongly associated with 90 day readmission or death than standard risks in patients with HF. PMID- 26772445 TI - Towards continuous and real-time attention monitoring at work: reaction time versus brain response. AB - Continuous and objective measurement of the user attention state still represents a major challenge in the ergonomics research. Recently available wearable electroencephalography (EEG) opens new opportunities for objective and continuous evaluation of operators' attention, which may provide a new paradigm in ergonomics. In this study, wearable EEG was recorded during simulated assembly operation, with the aim to analyse P300 event-related potential component, which provides reliable information on attention processing. In parallel, reaction times (RTs) were recorded and the correlation between these two attention-related modalities was investigated. Negative correlation between P300 amplitudes and RTs has been observed on the group level (p < .001). However, on the individual level, the obtained correlations were not consistent. As a result, we propose the P300 amplitude for accurate attention monitoring in ergonomics research. On the other hand, no significant correlation between RTs and P300 latency was found on group, neither on individual level. Practitioner Summary: Ergonomic studies of assembly operations mainly investigated physical aspects, while mental states of the assemblers were not sufficiently addressed. Presented study aims at attention tracking, using realistic workplace replica. It is shown that drops in attention could be successfully traced only by direct brainwave observation, using wireless electroencephalographic measurements. PMID- 26772446 TI - First report of pyrethroid resistance in Rhipicephalus (Boophilus) annulatus larvae (Say, 1821) from Iran. AB - Rhipicephalus (Boophilus) annulatus is one of the most important hard ticks parasitizing cattle in northern Iran. The aim of this study was to evaluate pyrethroid resistance levels of this species from Nur County, northern Iran. The hard ticks were collected through a multistage cluster randomized sampling method from the study area and fully engorged female R. (B.) annulatus were reared in a controlled insectary until they produced larvae for bioassay. Seventeen populations of the hard ticks were bioassayed with cypermethrin and 12 populations with lambda-cyhalothrin using a modified larval packet test (LPT). Biochemical assays to measure the contents/activity of different enzyme groups including mixed function oxidases (MFOs), glutathione S-transferases (GSTs) and general esterases were performed. Population 75 showed a resistance ratio of 4.05 with cypermethrin when compared with the most susceptible field population 66 at the LC50 level. With lambda-cyhalothrin the resistance ratio based on LC50 was 3.67 when compared with the susceptible population. The results of biochemical assays demonstrated significantly elevated levels of GSTs and esterases in populations tested compared with the heterozygous susceptible filed population and a correlation coefficient of these enzymes was found in association to lambda cyhalothrin resistance. Based on the results, pyrethroid acaricides may operationally fail to control R. (B.) annulatus in North of Iran. This study is the first document of pyrethroid resistance in R. (B.) annulatus populations from Iran. PMID- 26772447 TI - Lectin-carbohydrate recognition mechanism of Plasmodium berghei in the midgut of malaria vector Anopheles stephensi using quantum dot as a new approach. AB - Potential targets of Plasmodium ookinetes at the mosquito midgut walls were investigated in relation to interfering malarial transmission. In this study, the essential application of Quantum Dots (QDs) was used to examine the interaction between Plasmodium berghei ookinetes and the Anopheles stephensi midgut, based on lectin-carbohydrate recognition. Two significant lectins were utilized to determine this interaction. Two QDs, cadmium telluride (CdTe)/CdS and cadmium selenide (CdSe)/CdS, were employed in staining Plasmodium ookinete to study its interaction in the midgut of the mosquito vector in vivo. Concurrently, two lectins, wheat germ agglutinin (WGA) and concanavalin A (Con A), were inadvertently exploited to mask lectin binding sites between ookinetes and mosquito midgut cells. The numbers of ookinetes in both lumen and epithelial cells were eventually counted, following adequate preparation of wax sections extracted from whole midgut, and subsequent examination using a differential interference contrast a fluorescence microscopic technique. Interestingly, we detected that neither of the QDs mutated ookinete invasion into the midgut cells of the investigated mosquitoes. QD staining of ookinetes remained permanent despite the effective embedding procedure. The massive binding potency of ookinetes to midgut cells of the cross-examined mosquitoes undoubtedly revealed that Con A did not interrupt ookinete penetration into the midgut wall. In contrast, WGA inhibited ookinete invasion into the midgut cells. The results proved that QD nanoparticles are biocompatible, non-toxic to P. berghei and stable to photobleaching. The QDs staining, which was successfully implemented for ookinete labelling, is a simple and effective tool which plays a crucial role in bioimaging including the study of parasite-vector interactions. PMID- 26772448 TI - Dynamics of expression of two vitellogenin genes in the Chagas' disease vector Triatoma infestans: Analysis throughout pre-vitellogenesis and vitellogenesis. AB - The reproductive success of all oviparous species depends on vitellogenin (Vg) biosynthesis and its accumulation in the developing oocytes. The expression levels of two Vg genes (Vg1 and Vg2) were analyzed by qPCR and western blot in fat body and ovaries of adult females, at different times after ecdysis (pre vitellogenic phase) and after blood feeding of females (vitellogenic phase). Vg genes were also evaluated in fat bodies of adult males as well as in female fifth instar nymphs. No trace of Vg mRNA was detected in adult males or in nymphs. Vg1 and Vg2 were expressed in the fat bodies and ovaries of adult females. The Vg genes start to be expressed slightly in both tissues of adult females during pre vitellogenesis. After blood feeding, Vg1 and Vg2 were up regulated and significant levels of Vg transcripts as well as protein expression were observed in fat bodies sampled throughout vitellogenesis. During this period however, the distribution patterns of Vg1 and Vg2 transcripts showed two peaks around early and advanced vitellogenesis (days 4 and 12 post-feeding, respectively). In the ovaries, levels of mRNAs increased from the day 10 post-blood feeding onwards. In addition, the immunofluorescence assays showed a strong signal for vitellin in the yolk bodies of terminal follicles of vitellogenic females. The involvement of fat body and ovary in the synthesis of Vg suggests different roles of Vgs in supporting the growth of oocytes. PMID- 26772449 TI - Household and personal factors are sources of heterogenity in intestinal parasite clearance among Mexican children 6-15 months of age supplemented with vitamin A and zinc. AB - A randomised, double-blind, placebo-controlled trial was carried out among Mexico children aged 6-15 months to determine how household characteristics modify vitamin A and zinc supplementation efficacy on Ascaris lumbricoides, Giardia intestinalis and Entamoeba histolytica/E. dispar infection durations. Children assigned to receive vitamin A every 2 months, a daily zinc supplement, a combined vitamin A-zinc supplement or a placebo were followed for 1 year. Parametric hazard models were fit to infection durations stratified by personal and household factors. Children supplemented with vitamin A and zinc combined from households lacking piped water and children in all three treatment arms from households with dirt floors had longer G. intestinalis and A. lumbricoides infection durations than their counterparts, respectively. Shorter E. histolytica/E.dispar durations were found among zinc-supplemented children of mothers who had <6 years of education and no indoor bathrooms. Heterogeneity in supplementation efficacy among children may reflect differences in exposure risk and baseline immune responses. PMID- 26772450 TI - The iTClamp in the management of prehospital haemorrhage. AB - INTRODUCTION: Bleeding remains a leading cause of death in trauma patients. The iTClamp is a temporary wound closure device designed to control external bleeding within seconds of injury. We describe our experience using this device on 10 patients in the prehospital environment. METHODS: We have implemented the iTClamp for prehospital use through our physician-staffed helicopter emergency medical service (HEMS). Indications were massive bleeding that could not be controlled with an ordinary compressive bandage or a haemostatic bandage. RESULTS: Ten patients were treated with the iTClamp. Seven patients had a severe head injury due to various traumas, one patient had a neck injury from a disk cutter, one patient had an open chest wound and one patient had an open femur fracture. After applying the iTClamp, bleeding was controlled in 90% of these patients (n=9), with complete cessation reported in 60% (n=6), partial cessation with adequate control reported in 30% (n=3); in one patient, the bleeding could not be controlled with the iTClamp alone. It took an average of 10s to apply the iTClamp, and the average usage satisfaction score was 7.7. CONCLUSION: We conclude that the iTClamp is a safe, fast and useful tool for stopping or controlling external blood loss in our series of prehospital patients. Further studies of the iTClamp are needed to determine which patients might benefit from this device. PMID- 26772451 TI - Use of giant-sized flow-through venous flap for simultaneous reconstruction of dual or multiple major arteries in salvage therapy for complex upper limb traumatic injury. AB - BACKGROUND/OBJECTIVES: Salvage repair after complex upper limb traumatic injury is surgically challenging due to underlying major arterial impairment with complicating a large-sized soft tissue defect. The purpose of this study was to evaluate the effectiveness and safety of using a giant-sized (>=100 cm(2)) flow through venous flap for reconstruction of dual or multiple forearm, metacarpal, or digital arteries after complex upper limb traumatic injury. METHODS: Seven patients were consecutively hospitalized for emergency salvage repair after complex upper limb traumatic injury between March 2012 and May 2014. The forearm and palmar artery defects were repaired using the calf great saphenous vein flap and the volar forearm venous flap, respectively. RESULTS: The flow-through venous flap ranged from 9.5 cm * 12.0 cm to 12.0 cm * 20.0 cm (mean, 158.4 cm(2)) in size. The flaps and affected limbs survived uneventfully in five patients, with one patient experiencing distal flap marginal necrosis and a second patient requiring amputation of the affected limb. Computed tomography angiography showed patent vessels in all patients. The mean total active motion of the repaired fingers was 199.5 degrees versus 258.8 degrees for the contralateral counterpart (77.1%). The sensory return was determined to be S2 in 2 patients, S3 in 3 patients and S3+ in 1 patient. The disability scores for the arm, shoulder, and hand ranged from 4.6-18.2 (mean, 11.3), and the mean Michigan hand outcomes questionnaire score was 7.8 +/- 0.9. CONCLUSIONS: The flow-through venous flap is an effective and safe treatment alternative for salvage therapy of a >=100-cm(2) complex upper limb traumatic injury with dual or multiple major arterial impairment. This technique allows simultaneous reconstruction of dual or multiple artery injuries and an extensive soft tissue defect. Serious surgical site infection remains a major safety concern and necessitates radical debridement in complicating cases. PMID- 26772452 TI - Splenic function after angioembolization for splenic trauma in children and adults: A systematic review. AB - PURPOSE: Splenic artery embolization (SAE), proximal or distal, is becoming the standard of care for traumatic splenic injury. Theoretically the immunological function of the spleen may be preserved, but this has not yet been proven. A parameter for measuring the remaining splenic function must therefore be determined in order to decide whether or not vaccinations and/or antibiotic prophylaxis are necessary to prevent an overwhelming post-splenectomy infection (OPSI). METHODS: A systematic review of the literature was performed July 2015 by searching the Embase and Medline databases. Articles were eligible if they described at least two trauma patients and the subject was splenic function. Description of procedure and/or success rate of SAE was not necessary for inclusion. Two reviewers independently assessed the eligibility and the quality of the articles and performed the data extraction. RESULTS: Twelve studies were included, eleven with adult patients and one focusing on children. All studies used different parameters to assess splenic function. None of them reported a OPSI after splenic embolization. Eleven studies found a preserved splenic function after SAE, in both adults and children. CONCLUSION: All but one studies on the long term effects of SAE indicate a preserved splenic function. However, there is still no single parameter or test available which can demonstrate that unequivocally. PMID- 26772475 TI - Histopathologic and metabolic effect of ursodeoxycholic acid treatment on PCOS rat model. AB - The aim of this study was to determine the effect of ursodeoxycholic acid (UDCA) treatment on a polycystic ovary syndrome (PCOS) rat model. Thirty-two female Wistar-Albino rats were randomly divided into four groups as follows - group 1: sham group (n: 8), group 2: letrozole-induced PCOS group (n: 8), group 3: letrozole-induced PCOS plus metformin-treated (500 mg/kg) group (n: 8) and group 4: letrozole-induced PCOS plus UDCA (150 mg/kg)-treated group (n: 8). Histopathologic examination of the ovaries, circulating estrone (E1), estradiol (E2), testosterone, androstenedione, glucose, insulin and lipid profiles were evaluated. Histopathologic examination results revealed that groups 3 and 4 had significantly lower cystic and atretic follicles compared to group 2. Besides, group 4 had significantly higher antral follicles than group 2 (8.5 +/- 2.9 versus 5.4 +/- 1.1; p: 0.001). Furthermore, total testosterone (4.9 +/- 2.8 versus 8.8 +/- 2.9; p= 0.004) and insulin levels were significantly lower in group 4 compared to group 2 (1.7 +/- 0.08 versus 2.1 +/- 0.5; p = 0.02). However, lipid parameters, E1, E2, glucose and HOMA-IR were comparable between the groups. Our study results demonstrated that UDCA therapy improves ovarian morphology and decreases total testosterone and insulin levels. PMID- 26772476 TI - Feeding rates affect stress and non-specific immune responses of juvenile blunt snout bream Megalobrama amblycephala subjected to hypoxia. AB - This study aimed to investigate the effects of feeding rates on stress response, innate immunity and hypoxia resistance of juvenile blunt snout bream Megalobrama amblycephala. Fish were randomly assigned to one of six feeding rates (2, 3, 4, 5, 6 and 7% of body weight/day) for 60 days. Then, fish were subjected to hypoxic conditions and haemato-immunological parameters were analyzed pre- and post challenge. Low feed ration resulted in decreased liver superoxide dismutase and catalase activities and reduced glutathione contents. Inadequate feeding also adversely affected the immune functions of fish, as was characterized by the relatively low haemato-immunological parameters (including alternative complement (ACH50), myeloperoxidase (MPO), plasma protein profiles and transferring) and high hypoxia-induced mortality. High feed ration did not lead to the improvement in antioxidant capability, immune responses and survival. In addition, plasma cortisol, glucose and transferrin levels as well as lysozyme activities all increased significantly after hypoxia challenge, whereas the opposite was true for plasma ACH50 and MPO activities as well as protein profiles in terms of hypoxia challenge. An interaction between feeding rate and hypoxia was also observed in plasma cortisol, glucose and protein profiles. In conclusion, a feeding rate of 4-5% of body weight/day is optimal to boost the innate immunity of juvenile blunt snout bream. Low ration resulted in decreased antioxidant capability, compromised immune functions and reduced hypoxia resistance, while over feeding did not benefit the health status. PMID- 26772478 TI - Phosphoinositide 3-kinase family in channel catfish and their regulated expression after bacterial infection. AB - The phosphoinositide-3-kinase (PI3Ks) family of lipid kinases is widely conserved from yeast to mammals. In this work, we identified a total of 14 members of the PI3Ks from the channel catfish genome and transcriptome and conducted phylogenetic and syntenic analyses of these genes. The expression profiles after infection with Edwardsiella ictaluri and Flavobacterium columnare were examined to determine the involvement of PI3Ks in immune responses after bacterial infection in catfish. The results indicated that PI3Ks genes including all of the catalytic subunit and several regulatory subunits genes were widely regulated after bacterial infection. The expression patterns were quite different when challenged with different bacteria. The PI3Ks were up-regulated rapidly at the early stage after ESC infection, but their induced expression was much slower, at the middle stage after columnaris infection. RNA-Seq datasets indicated that PI3K genes may be expressed at different levels in different catfish differing in their resistance levels against columnaris. Future studies are required to confirm and validate these observations. Taken together, this study indicated that PI3K genes may be involved as a part of the defense responses of catfish after infections, and they could be one of the determinants for disease resistance. PMID- 26772477 TI - An attenuated virus vaccine appears safe to the central nervous system of rainbow trout (Oncorhynchus mykiss) after intranasal delivery. AB - Nasal vaccines are very effective but the olfactory organ provides direct access of antigens to the brain. Infectious hematopoietic necrosis virus (IHNV) is known to cause high mortalities in salmonids. The purpose of this study is to evaluate the safety of a live attenuated IHNV nasal (I.N) vaccine in rainbow trout (Oncorhynchus mykiss). In the olfactory organ, the vaccine was detected 1 and 4 days after primary I.N vaccination but not in the intramuscular (i.m) or control groups. In the brain, IHNV was detected by RT-qPCR 4 and 21 days after i.m primary vaccination. One i.m and one I.N vaccinated trout were positive at days 4 and 28 days post-boost, respectively. Presence of IHNV in the brain of i.m vaccinated fish correlated with moderate increases in IL-1beta and TNF-alpha expression in this tissue. These results demonstrate that IHNV vaccine lasts for 4 days in the local nasal environment and that nasal vaccination appears to be safe to the CNS of rainbow trout. PMID- 26772479 TI - Immune response and protection in gibel carp, Carassius gibelio, after vaccination with beta-propiolactone inactivated cyprinid herpesvirus 2. AB - Herpesviral haematopoietic necrosis (HVHN) of gibel carp (Carassius gibelio) is a newly emerged infectious disease caused by cyprinid herpesvirus 2 (CyHV-2) and has caused huge economic losses in aquaculture operations. Currently, no effective methods are available for the control of the disease. In this study, beta-propiolactone inactivated cyprinid herpesvirus 2 (CyHV-2) vaccine was prepared, and the immune response and protection in cultured gibel carp after vaccination was thoroughly investigated. This included blood cell counting and classification, phagocytic activity, lysozyme and superoxide dismutase activity, neutralizing antibody titration, immune gene expression analysis, and determination of the relative percent survival in vaccinated gibel carp. The results of blood cell counts indicated that the numbers of the red and white blood cells in the peripheral blood of immunized gibel carp increased significantly at day 4 and day 7 after vaccination (p < 0.01). The differential leukocyte count of neutrophils and monocytes were significantly different compared to the control group at day 4 and 7 and the percentage of lymphocytes reached a peak at day 21. The phagocytic percentage and phagocytic index peaked at day 4 post-vaccination. The lysozyme activity and superoxide dismutase activity were significantly increased compared to the control group (p < 0.01). The serum neutralizing antibody titer peaked (203.03 +/- 13.44) at day 21. The qPCR analysis revealed that the expression of the immune genes interlukin 11 and complement component C3 were significantly up-regulated in the immunized group. The challenge test demonstrated that the immunized group had a relative survival rate of 71.4%. These results indicate that the inactivated CyHV-2 vaccine induced both non-specific and specific anti-viral immune responses that resulted in significant protection against HVHN disease and mortality in gibel carp. PMID- 26772480 TI - Sox3 binds to 11beta-hydroxysteroid dehydrogenase gene promoter suggesting transcriptional interaction in catfish. AB - In fishes, the expression of steroidogenic enzyme genes and their related transcription factors (TFs) are critical for the regulation of steroidogenesis and gonadal development. 11-KT is the potent androgen and hence, 11beta-hsd, enzyme involved in 11-KT production is important. Regulation of 11beta-hsd gene was never studied in any fishes. At first 11beta-hsd was cloned and recombinant protein was tested for enzyme activity prior to expression and promoter motif analysis. Expression changes revealed stage- and sex-dependent increase in the ontogenic studies. Further, 11beta-hsd expression was higher during spawning phase of reproductive cycle and was found to be gonadotropin inducible both in vivo and in vitro. ~2kb of 5' upstream region of 11beta-hsd, was cloned from catfish genomic DNA library and in silico promoter analysis revealed putative TF binding sites such as Sox3, Wt1, Pax2, Dmrt1 and Ad4BP/SF-1. Luciferase reporter assay using the sequential deletion constructs in human embryonic kidney and Chinese hamster ovary cells revealed considerable promoter activity of the constructs containing Sox3, but not with other motifs largely. Site-directed mutagenesis, Sox3 over expression, electrophoretic mobility shift and chromatin immunoprecipitation assays further substantiated the binding of Sox3 to its corresponding cis-acting element in the upstream promoter motif of 11beta-hsd. This is the first report to show that Sox3 binds to the 11beta-hsd gene promoter and transactivates to regulate male reproduction in a teleost. PMID- 26772481 TI - Understanding the molecular basis of agonist/antagonist mechanism of GPER1/GPR30 through structural and energetic analyses. AB - The G-protein coupled receptors (GPCRs) represent the largest superfamily of membrane proteins in charge to pass the cell signaling after binding with their cognate ligands to the cell interior. In breast cancer, a GPCR named GPER1 plays a key role in the process of growth and the proliferation of cancer cells. In a previous study, theoretical methods were applied to construct a model of GPER1, which later was submitted to molecular dynamics (MD) simulations to perform a docking calculation. Based on this preceding work, it is known that GPER1 is sensitive to structural differences in its binding site. However, due to the nature of that past study, conformational changes linked to the ligand binding were not observed. Therefore, in this study, in order to explore the conformational changes coupled to the agonist/antagonist binding, MD simulations of about 0.25MUs were performed for the free and bound states, summarizing 0.75MUs of MD simulation in total. For the bound states, one agonist (G-1) and antagonist (G-15) were chosen since is widely known that these two molecules cause an impact on GPER1 mobility. Based on the conformational ensemble generated through MD simulations, we found that despite G-1 and G-15 being stabilized by similar map of residues, the structural differences between both ligands impact the hydrogen bond pattern not only at the GPER1 binding site but also along the seven-helix bundle, causing significant differences in the conformational mobility along the extracellular and cytoplasmic domain, and to a lesser degree in the curvatures of helix 2, helix 3 and helix 7 between the free and bound states, which is in agreement with reported literature, and might be linked to microscopic characteristics of the activated-inactivated transition. Furthermore, binding free energy calculations using the MM/GBSA method for the bound states, followed by an alanine scanning analysis allowed us to identify some important residues for the complex stabilization. PMID- 26772523 TI - Effect of dietary nitrate supplementation on metabolic rate during rest and exercise in human: A systematic review and a meta-analysis. AB - BACKGROUND: Recent randomized controlled trials have suggested that dietary nitrate (NO3(-)), found in beetroot and other vegetables, and inorganic NO3(-) salts decrease metabolic rate under resting and exercise conditions. OBJECTIVE: Our aim was therefore to determine from a systematic review and meta-analysis whether dietary NO3(-) supplementation significantly reduces metabolic rate, expressed as oxygen uptake (VO2), under resting and exercise conditions in healthy humans and those with cardiorespiratory diseases. DESIGN: A systematic article search was performed on electronic databases (PubMed, Scopus and Web of Science) from February to March 2015. The inclusion criteria included 1) randomized controlled trials; 2) studies reporting the effect of NO3(-) on VO2 under resting and/or exercise conditions; 3) comparison between dietary NO3(-) supplementation and placebo. Random-effects models were used to calculate the pooled effect size. RESULTS: Twenty nine randomized placebo-controlled trials were included in the systematic review, and 26 of which were included in the meta analysis. Dietary NO3(-) supplementation significantly decreases VO2 during submaximal intensity exercise [-0.26 (95% IC: -0.38, -0.15), p < 0.01], but not in the sub-analysis of subjects with chronic diseases [-0.09 (95% IC: -0.50, 0.32), p = 0.67]. When data were separately analyzed by submaximal intensity domains, NO3(-) supplementation reduces VO2 during moderate [-0.29 (95% IC: 0.48,-0.10), p < 0.01] and heavy [-0.33 (95% IC: -0.54,-0.12), p < 0.01] intensity exercise. When the studies with the largest effects were excluded from the meta-analysis, there is a trend for a VO2 decrease under resting condition in dietary NO3(-) supplementation [-0.28 (95% IC: -0.62, 0.05), p = 0.10]. CONCLUSION: Dietary NO3(-) supplementation decreases VO2 during exercise performed in the moderate and heavy intensity domains in healthy subjects. The present meta-analysis did not show any significant effect of dietary NO3(-) supplementation on metabolic rate in subjects with chronic diseases, despite enhanced exercise tolerance. PMID- 26772524 TI - Cholesterol-based tethers and markers for model membranes investigation. AB - A series of new bifunctional cholesterol compounds for tethered bilayer membrane (tBLM) systems were synthesized and tested. The compounds containing cyclic disulfide group may be used as molecular anchors for phospholipid bilayers. Anchoring occurs through the insertion of the cholesterol moiety into the hydrophobic slab of the phospholipid layer, while the surface density of anchor molecules may be adjusted using disulfides terminated spacers. Five ethylene oxide segments between the disulfide group and the cholesteryl provide hydration of the layer separating solid support and model membrane. Another group of cholesterol derivatives described in this work contains either fluorescence probe or electroactive functional groups. We demonstrated the practical utility of these compounds for visualization of cholesterol extraction from and loading to tBLMs. We demonstrated that electroactive group containing cholesterol derivatives can be reconstituted either into vesicles or tBLMs. In both cases an electrochemical signal can be generated on electrodes from these probes. In general, the newly synthesized compound may be utilized in a variety of applications involving tethered bilayer systems and vesicles. PMID- 26772525 TI - Special issue on New Developments in Relatedness and Relationship Estimation. PMID- 26772526 TI - HPMA-based block copolymers promote differential drug delivery kinetics for hydrophobic and amphiphilic molecules. AB - We describe a method how polymeric nanoparticles stabilized with (2 hydroxypropyl)methacrylamide (HPMA)-based block copolymers are used as drug delivery systems for a fast release of hydrophobic and a controlled release of an amphiphilic molecule. The versatile method of the miniemulsion solvent evaporation technique was used to prepare polystyrene (PS) as well as poly-d/l lactide (PDLLA) nanoparticles. Covalently bound or physically adsorbed fluorescent dyes labeled the particles' core and their block copolymer corona. Confocal laser scanning microscopy (CLSM) in combination with flow cytometry measurements were applied to demonstrate the burst release of a fluorescent hydrophobic drug model without the necessity of nanoparticle uptake. In addition, CLSM studies and quantitative calculations using the image processing program Volocity(r) show the intracellular detachment of the amphiphilic block copolymer from the particles' core after uptake. Our findings offer the possibility to combine the advantages of a fast release for hydrophobic and a controlled release for an amphiphilic molecule therefore pointing to the possibility to a 'multi step and multi-site' targeting by one nanocarrier. STATEMENT OF SIGNIFICANCE: We describe thoroughly how different components of a nanocarrier end up in cells. This enables different cargos of a nanocarrier having a consecutive release and delivery of distinct components. Most interestingly we demonstrate individual kinetics of distinct components of such a system: first the release of a fluorescent hydrophobic drug model at contact with the cell membrane without the necessity of nanoparticle uptake. Secondly, the intracellular detachment of the amphiphilic block copolymer from the particles' core after uptake occurs. This offers the possibility to combine the advantages of a fast release for a hydrophobic substance at the time of interaction of the nanoparticle with the cell surface and a controlled release for an amphiphilic molecule later on therefore pointing to the possibility to a 'multi-step and multisite' targeting by one nanocarrier. We therefore feel that this could be used for many cellular systems where the combined and orchestrated delivery of components is prerequisite in order to obtain the highest efficiency. PMID- 26772527 TI - Fabrication of biomimetic vascular scaffolds for 3D tissue constructs using vascular corrosion casts. AB - Vascularization is among the most pressing technical challenges facing tissue engineering of 3D organs. While small engineered constructs can rely solely on vascular infiltration and diffusion from host tissues following implantation, larger avascular constructs do not survive long enough for vessel ingrowth to occur. To address this challenge, strategies for pre-vascularization of engineered constructs have been developed. Various biofabrication techniques have been utilized for pre-vascularization, but limitations exist with respect to the size and complexity of the resulting vessels. To this end, we developed a simple and novel fabrication method to create biomimetic microvascular scaffolds using vascular corrosion casting as a template for pre-vascularization of engineered tissue constructs. Gross and electron microscopic analysis demonstrates that polycaprolactone (PCL)-derived kidney vascular corrosion casts are able to capture the architecture of normal renal tissue and can serve as a sacrificial template for the creation of a collagen-based vascular scaffold. Histological analysis demonstrates that the collagen vascular scaffolds are biomimetic in structure and can be perfused, endothelialized, and embedded in hydrogel tissue constructs. Our scaffold creation method is simple, cost effective, and provides a biomimetic, tissue-specific option for pre-vascularization that is broadly applicable in tissue engineering. STATEMENT OF SIGNIFICANCE: Tissues in the body are vascularized to provide nutrients to the cells within the tissues and carry away waste, but creating tissue engineered constructs with functional vascular networks has been challenging. Current biofabrication techniques can incorporate blood vessel-like structures with straight or simple branching patterns into tissue constructs. Unfortunately, these techniques are expensive, complicated and create simplified versions of the complex vessel structures seen in native tissue. Our technique uses novel vascular corrosion casts of normal tissue as templates to create vascular scaffolds that are a copy of normal vessels. These vascular scaffolds can be easily incorporated into 3D tissue constructs. Our process is simple, inexpensive and inherently tissue-specific, making it widely applicable in the field of tissue engineering. PMID- 26772528 TI - Meeting the Growing Need for Pediatric Rehabilitation Medicine Physicians. AB - Disability in childhood is on the rise. In light of the national shortage of pediatric rehabilitation medicine physicians to provide care for the growing population of children with disabilities, the field of pediatric rehabilitation medicine should consider allowing pediatric trainees into pediatric rehabilitation medicine fellowships. There are concerns about how best to train these fellows. This commentary discusses the issues and concludes that training opportunities should be developed to allow pediatricians to become pediatric rehabilitation medicine physicians. PMID- 26772529 TI - Word Memory Test Predicts Recovery in Claimants With Work-Related Head Injury. AB - OBJECTIVE: To investigate the predictive validity of the Word Memory Test (WMT), a verbal memory neuropsychological test developed as a performance validity measure to assess memory, effort, and performance consistency. DESIGN: Cohort study with 1-year follow-up. SETTING: Workers' compensation rehabilitation facility. PARTICIPANTS: Participants included workers' compensation claimants with work-related head injury (N=188; mean age, 44y; 161 men [85.6%]). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Outcome measures for determining predictive validity included days to suspension of wage replacement benefits during the 1-year follow-up and work status at discharge in claimants undergoing rehabilitation. Analysis included multivariable Cox and logistic regression. RESULTS: Better WMT performance was significantly but weakly correlated with younger age (r=-.30), documented brain abnormality (r=.28), and loss of consciousness at the time of injury (r=.25). Claimants with documented brain abnormalities on diagnostic imaging scans performed better (~9%) on the WMT than those without brain abnormalities. The WMT predicted days receiving benefits (adjusted hazard ratio, 1.13; 95% confidence interval, 1.04-1.24) and work status outcome at program discharge (adjusted odds ratio, 1.62; 95% confidence interval, 1.13-2.34). CONCLUSIONS: Our results provide evidence for the predictive validity of the WMT in workers' compensation claimants. Younger claimants and those with more severe brain injuries performed better on the WMT. It may be that financial incentives or other factors related to the compensation claim affected the performance. PMID- 26772530 TI - May the fibrosis be with you: Is discoidin domain receptor 2 the receptor we have been looking for? AB - In a recent issue of Journal of Molecular and Cellular Cardiology, George et al. [1] identified discoidin domain receptor 2 (DDR2) as a positive modulator of collagen production in cardiac fibroblasts stimulated with angiotensin II (Ang II). DDR2 is a tyrosine kinase collagen receptor and is associated with pathological scarring of multiple organs; nevertheless, the functional role of DDR2 in the myocardium remains unclear. George et al. present evidence for the first time that Ang II induces cardiac fibrosis by enhancing DDR2 expression in cardiac fibroblasts via p38 mitogen activated protein kinase (p38 MAPK)-mediated activation of nuclear factor-kappaB (NF-kappaB). PMID- 26772531 TI - AMPK in cardiac fibrosis and repair: Actions beyond metabolic regulation. AB - Fibrosis is a general term encompassing a plethora of pathologies that span all systems and is marked by increased deposition of collagen. Injury of variable etiology gives rise to complex cascades involving several cell-types and molecular signals, leading to the excessive accumulation of extracellular matrix that promotes fibrosis and eventually leads to organ failure. Cardiac fibrosis is a dynamic process associated notably with ischemia, hypertrophy, volume- and pressure-overload, aging and diabetes mellitus. It has profoundly deleterious consequences on the normal architecture and functioning of the myocardium and is associated with considerable mortality and morbidity. The AMP-activated protein kinase (AMPK) is a ubiquitously expressed cellular energy sensor and an essential component of the adaptive response to cardiomyocyte stress that occurs during ischemia. Nevertheless, its actions extend well beyond its energy-regulating role and it appears to possess an essential role in regulating fibrosis of the myocardium. In this review paper, we will summarize the main elements and crucial players of cardiac fibrosis. In addition, we will provide an overview of the diverse roles of AMPK in the heart and discuss in detail its implication in cardiac fibrosis. Lastly, we will highlight the recently published literature concerning AMPK-targeting current therapy and novel strategies aiming to attenuate fibrosis. PMID- 26772532 TI - IL-10 for cardiac autophagy modulation: New direction in the pursuit of perfection. PMID- 26772533 TI - Acute myocardial infarction: susceptibility-weighted cardiac MRI for the detection of reperfusion haemorrhage at 1.5 T. AB - AIM: To assess whether susceptibility-weighted imaging (SWI) provides better image contrast for the detection of haemorrhagic ischaemia-reperfusion injury in the heart. MATERIALS AND METHODS: Thirty patients (all men; mean age 53 years) underwent cardiac magnetic resonance imaging (MRI) within 7 days of primary percutaneous intervention for acute ST elevation myocardial infarction (STEMI). Multiple gradient-echo T2* sequences with magnitude and phase reconstructions were acquired. A high-pass filtered phase map was used to create a mask for the SWI reconstructions. The difference in image contrast was assessed in those patients with microvascular obstruction. A mixed effects regression model was used to test the effect of echo time and reconstruction method on phase and contrast-to-noise ratio (CNR). Medians and interquartile ranges (IQR) are reported. RESULTS: T2* in haemorrhagic infarcts was shorter than in non haemorrhagic infarcts (33.5 ms [24.9-43] versus 49.9 ms [44.6-67.6]; p=0.0007). The effect of echo time on phase was significant (p<0.0001), as was the effect of haemorrhage on phase (p=0.0016). SWI reconstruction had a significant effect on the CNR at all echo times (echoes 1-5, p<0.0001; echo 6, p=0.01; echo 7, p=0.02). The median echo number at which haemorrhage was first visible was less for SWI compared to source images (echo 2 versus echo 5, p=0.0002). CONCLUSION: Cardiac SWI improves the contrast between myocardial haemorrhage and the surrounding tissue following STEMI and has potential as a new tool for identifying patients with ischaemia-reperfusion injury. PMID- 26772535 TI - How do the full-generation poly(amido)amine (PAMAM) dendrimers activate blood platelets? Platelet membrane zeta potential and other membrane-associated phenomena. AB - We explored the hypothesis that zeta potential altered by polycations affects blood platelet activation and reactivity, the phenomena associated with membrane lipid fluidity and platelet mitochondrial bioenergetics. PAMAM dendrimers generation- and dose-dependently enhanced zeta potential of platelets (from -10.7 mV to -4.3 mV). Increased expressions of activation markers, P-selectin and the active complex alphaIIbbeta3, as well as significantly enhanced fibrinogen binding occurred upon the in vitro incubation of blood platelets in the presence of PAMAMs G3 and G4 (resp. 62.1% and 69.4% vs. 1.4% and 2.7% in control for P selectin, P<0.0001). PAMAM dendrimers increased fluidity of platelet membrane lipid bilayer, while they did not affect platelet mitochondria respiration. Increased platelet activation and their responses to agonists in vitro were statistically associated with the revealed alterations in zeta potential. Our results support the hypothesis that polycation-mediated "neutralized" zeta potential may underlie the activating effects of PAMAMs on blood platelets. PMID- 26772534 TI - A UV-Raman spectrometry method for quality control of anticancer preparations: Results after 18 months of implementation in hospital pharmacy. AB - In France, chemotherapy preparation units of hospital pharmacy compound cytotoxic infusion bags adapted to each patient. The narrow therapeutic index of these preparations led us to implement qualitative and quantitative control for patients' safety. To this aim, we calibrated an equipment combining UV-vis spectrometry and Raman spectroscopy (QC Prep+) and monitored 14 different molecule-solvent combinations over a 18 months period. This rapid and specific method allowed the qualitative and quantitative analysis of 1 mL sample tests in less than 2 min. On 5742 anticancer preparations, we obtained accepted results with more than 99.4% solvent identification, 99.6% drug identification and only 1.52% of preparations not matching quantitative specifications (+/-15% of theoretical concentration). This quantitative control enabled us to pinpoint some critical points of production for two of the most common preparations. We thus updated the procedures of reconstitution and preparation, increasing the quality of final product. UV-Raman spectrometry is thus an effective tool to control chemotherapy infusions and to improve good practices of preparation. PMID- 26772536 TI - Continuous preparation of polymer coated drug crystals by solid hollow fiber membrane-based cooling crystallization. AB - A facile way to continuously coat drug crystals with a polymer is needed in controlled drug release. Conventional polymer coating methods have disadvantages: high energy consumption, low productivity, batch processing. A novel method for continuous polymer coating of drug crystals based on solid hollow fiber cooling crystallization (SHFCC) is introduced here. The drug acting as the host particle and the polymer for coating are Griseofulvin (GF) and Eudragit RL100, respectively. The polymer's cloud point temperature in its acetone solution was determined by UV spectrophotometry. An acetone solution of the polymer containing the drug in solution as well as undissolved drug crystals in suspension were pumped through the tube side of the SHFCC device; a cold liquid was circulated in the shell side to rapidly cool down the feed solution-suspension in the hollow fiber lumen. The polymer precipitated from the solution and coated the suspended crystals due to rapid temperature reduction and heterogeneous nucleation; crystals formed from the solution were also coated by the polymer. Characterizations by scanning electron microscopy, thermogravimetric analysis, laser diffraction spectroscopy, X-ray diffraction, Raman spectroscopy, and dissolution tests show that a uniformly coated, free-flowing drug/product can be obtained under appropriate operating conditions without losing the drug's pharmaceutical properties and controlled release characteristics. PMID- 26772537 TI - An acetyl-L-carnitine switch on mitochondrial dysfunction and rescue in the metabolomics study on aluminum oxide nanoparticles. AB - BACKGROUND: Due to the wide application of engineered aluminum oxide nanoparticles and increased aluminum containing particulate matter suspending in air, exposure of human to nano-scale aluminum oxide nanoparticles (Al2O3 NPs) is becoming inevitable. METHODS: In the present study, RNA microarray coupled with metabolomics analysis were used to uncover mechanisms underlying cellular responses to Al2O3 NPs and imply the potential rescue. RESULTS: We found that Al2O3 NPs significantly triggered down-regulation of mitochondria-related genes located in complex I, IV and V, which were involved in oxidative phosphorylation and neural degeneration pathways, in human bronchial epithelial (HBE) cells. Subsequent cell- and animal- based assays confirmed that Al2O3 NPs caused mitochondria-dependent apoptosis and oxidative stress either in vitro or in vivo, which were consistent with the trends of gene regulation. To rescue the Al2O3 NPs induced mitochondria dysfunction, disruption of small molecular metabolites of HBE were profiled using metabolomics analysis, which facilitates identification of potential antagonizer or supplement against nanoparticle-involved damages. Supplementation of an antioxidant, acetyl-L-carnitine, completely or partially restored the Al2O3 NPs modulated gene expression levels in mitochondrial complex I, IV and V. It further reduced apoptosis and oxidative damages in both Al2O3 NPs treated HBE cells and animal lung tissues. CONCLUSION: Thus, our results demonstrate the potential mechanism of respiratory system damages induced by Al2O3 NPs. Meanwhile, based on the metabolomics profiling, application of acetyl L-carnitine is suggested to ameliorate mitochondria dysfunction associated with Al2O3 NPs. PMID- 26772538 TI - The relationship between snoring and left ventricular hypertrophy of China: a cross-sectional study. AB - BACKGROUND: Population-based investigations studying the association between snoring and left ventricular hypertrophy (LVH) are lacking. Therefore, our study aims to investigate whether snoring is significantly associated with LVH, and to make clear the effect of varying degrees of snoring intensity on LVH. METHODS: A total of 10,139 participants were involved in this cross-sectional study. Snoring status and snoring intensity were evaluated by a structured questionnaire. LVH was defined as left ventricular mass index >= 51 g/m(2.7) for both men and women. RESULTS: The total prevalence of LVH was 10.0%. the prevalence increased significantly in snorers according to snoring intensity, including low (10.3%), normal (13.1%), strong (14.7%) and very strong (16.7%). After adjustment for age, race, gender, educational status, physical activity, annual income, current smoking status, current drinking status, sleep duration, hypertension, body mass index, waist circumference, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglyceride, total cholesterol and fasting plasma glucose, snoring (OR, 1.371; 95% CI, 1.147-1.637, P < 0.001) was significantly associated with LVH. In addition, among the four kinds of intensity of snoring, normal (OR, 1.436; 95% CI, 1.126-1.832, P = 0.004), strong (OR, 1.462; 95% CI, 1.124-1.902, P < 0.001) and very strong (OR, 1.813; 95% CI, 1.273-2.684, P < 0.001), rather than low (OR, 1.094; 95% CI, 0.834-1.434, P = 0.518) were significantly associated with LVH. CONCLUSIONS: Snoring is independently associated with LVH. What's more, with the rise in snoring intensity, snoring will exert an increasing effect on LVH. PMID- 26772539 TI - SB203580 increases G-CSF production via a stem-loop destabilizing element in the 3' untranslated region in macrophages independently of its effect on p38 MAPK activity. AB - BACKGROUND: Granulocyte-colony stimulating factor (G-CSF) is a major regulator of the production and survival of neutrophils. Regulation of G-CSF expression is complex and occurs at both transcription and post-transcription levels. Two distinct types of cis-acting elements in the 3' untranslated region (3'UTR) of G CSF mRNA have been identified as destabilizing elements; these consist of adenylate uridylate-rich elements (AUREs) and a stem-loop destabilizing element (SLDE). Regulation of the stability of mRNA by p38 mitogen-activated protein kinase (MAPK) has been indicated to be linked to AUREs in the 3'UTR. However, whether p38 MAPK is involved in the regulation of the stability of G-CSF mRNA has not been elucidated. This study investigated the effect of SB203580, an inhibitor of p38 MAPK, on the lipopolysaccharide-induced G-CSF expression in macrophages at the post-transcription level. RESULTS: Our study showed surprising results that SB203580 augmented the lipopolysaccharide-induced increase in the G-CSF mRNA levels in RAW264.7 mouse macrophages, mouse bone marrow-derived macrophages and in THP-1 human macrophages. This effect was also seen in p38alpha MAPK knockdown RAW264.7 cells, showing that it was not due to inhibition of p38 MAPK activity. In the presence of actinomycin D, the decay of G-CSF mRNA was slower in SB203580 treated cells than in control cells, showing that SB203580 increased the stability of G-CSF mRNA. Reporter genes containing luciferase with or without the 3'UTR of G-CSF were constructed and transfected into RAW264.7 cells and the results showed that the presence of the 3'UTR reduced the luciferase mRNA levels and luciferase activity. Furthermore, SB203580 increased the luciferase mRNA levels and activity in RAW264.7 cells transfected with the luciferase reporter containing the 3'UTR, but not in cells transfected with the luciferase reporter without the 3'UTR. Mutations of the highly conserved SLDE in the 3'UTR abolished these effects, showing that the SLDE was essential for the SB203580-induced increase in the stability of mRNA. CONCLUSIONS: SB203580 increases G-CSF expression in macrophages by increasing the stability of G-CSF mRNA via its 3'UTR, and the effect was not due to its inhibition of p38 MAPK activity. The results of this study also highlight a potential target for boosting endogenous production of G-CSF during neutropenia. PMID- 26772540 TI - The importance of reaming the posterior femoral cortex before inserting lengthening nails and calculation of the amount of reaming. AB - BACKGROUND: Lengthening nails have been used to correct limb length discrepancy caused by different etiologies, as well as for post-traumatic reasons. Two important lengthening nail-related complications are damage to the distraction mechanism and femoral fractures around the nail tip. As a result of the curved anatomy of the femur, straight nails impinge on the anterior cortex. Therefore, proper reshaping of the medullary canal to accommodate straight lengthening nails is crucial for the prevention of this problem. Reaming the dense posterior cortex is important when aiming to insert a lengthening nail without incurring anterior cortex nail tip impingement-related complications. Posterior femoral cortex over reaming is a solution to this situation. METHODS: Sixty patients received lengthening nails during 2008-2013, (ISKD, Fitbone, Precice). Posterior cortex rigid-reaming technique was used successfully in 45 retrograde femoral lengthening cases. The preoperatively planned posterior cortex amount was reamed until the impingement was overcome during the operation under fluoroscopic control for each case. Since the preoperative determination of posterior cortex reaming amount is time consuming and operator dependent, we evaluated the X-rays of the patients with computer software and conventional paper-based measurements. The effect of reaming the posterior cortical wall on the inclination of the nail tip to the anterior femoral cortex was detected with measurements on the preoperative and postoperative lateral femoral X-rays by using the CorelDRAW(r) Graphic Suite X6 software package (Corel, Inc., Ottawa, Ontario, Canada) software. On the same software, X-rays and the posterior reaming amount were also calculated. RESULTS: The mean age of the patients was 27 years (11-42), while the mean lengthening was 5.9 cm (2-14). The mean consolidation index was 1.05 (0.75 1.62), and the mean follow-up period was 31 months (range, 18-45 months). The mean distance of the osteotomy site to the intercondylar notch of the femur was 81.2 mm (+/- 16.92). The mean displacement of the nail tip position was 15.42 mm (+/- 4.77) on the measurements on the postoperative X-rays after nail insertion compared to the preoperative simulations on the templates. The mean posterior cortex reaming thickness was 3.68 mm (+/- 1.02). CONCLUSIONS: We derived a formula that allows the required amount of optimal posterior cortex reaming to be determined. No impingement-related complications or nail damage were observed. PMID- 26772542 TI - Impact of documentation on interpretation of administrative data. PMID- 26772541 TI - A novel APOC2 gene mutation identified in a Chinese patient with severe hypertriglyceridemia and recurrent pancreatitis. AB - BACKGROUND: The severe forms of hypertriglyceridemia are usually caused by genetic defects. In this study, we described a Chinese female with severe hypertriglyceridemia caused by a novel homozygous mutation in the APOC2 gene. METHODS: Lipid profiles of the pedigree were studied in detail. LPL and HL activity were also measured. The coding regions of 5 candidate genes (namely LPL, APOC2, APOA5, LMF1, and GPIHBP1) were sequenced using genomic DNA from peripheral leucocytes. The ApoE gene was also genotyped. RESULTS: Serum triglyceride level was extremely high in the proband, compared with other family members. Plasma LPL activity was also significantly reduced in the proband. Serum ApoCII was very low in the proband as well as in the heterozygous mutation carriers. A novel mutation (c.86A > CC) was identified on exon 3 [corrected] of the APOC2 gene, which converted the Asp [corrected] codon at position 29 into Ala, followed by a termination codon (TGA). CONCLUSIONS: This study presented the first case of ApoCII deficiency in the Chinese population, with a novel mutation c.86A > CC in the APOC2 gene identified. Serum ApoCII protein might be a useful screening test for identifying mutation carriers. PMID- 26772543 TI - De novo transcriptome assembly for the lobster Homarus americanus and characterization of differential gene expression across nervous system tissues. AB - BACKGROUND: The American lobster, Homarus americanus, is an important species as an economically valuable fishery, a key member in marine ecosystems, and a well studied model for central pattern generation, the neural networks that control rhythmic motor patterns. Despite multi-faceted scientific interest in this species, currently our genetic resources for the lobster are limited. In this study, we de novo assemble a transcriptome for Homarus americanus using central nervous system (CNS), muscle, and hybrid neurosecretory tissues and compare gene expression across these tissue types. In particular, we focus our analysis on genes relevant to central pattern generation and the identity of the neurons in a neural network, which is defined by combinations of genes distinguishing the neuronal behavior and phenotype, including ion channels, neurotransmitters, neuromodulators, receptors, transcription factors, and other gene products. RESULTS: Using samples from the central nervous system (brain, abdominal ganglia), abdominal muscle, and heart (cardiac ganglia, pericardial organs, muscle), we used RNA-Seq to characterize gene expression patterns across tissues types. We also compared control tissues with those challenged with the neuropeptide proctolin in vivo. Our transcriptome generated 34,813 transcripts with known protein annotations. Of these, 5,000-10,000 of annotated transcripts were significantly differentially expressed (DE) across tissue types. We found 421 transcripts for ion channels and identified receptors and/or proteins for over 20 different neurotransmitters and neuromodulators. Results indicated tissue specific expression of select neuromodulator (allostatin, myomodulin, octopamine, nitric oxide) and neurotransmitter (glutamate, acetylcholine) pathways. We also identify differential expression of ion channel families, including kainite family glutamate receptors, inward-rectifying K(+) (IRK) channels, and transient receptor potential (TRP) A family channels, across central pattern generating tissues. CONCLUSIONS: Our transcriptome-wide profiles of the rhythmic pattern generating abdominal and cardiac nervous systems in Homarus americanus reveal candidates for neuronal features that drive the production of motor output in these systems. PMID- 26772544 TI - Predictors of fibromyalgia: a population-based twin cohort study. AB - BACKGROUND: Fibromyalgia (FM) is a pain syndrome, the mechanisms and predictors of which are still unclear. We have earlier validated a set of FM-symptom questions for detecting possible FM in an epidemiological survey and thereby identified a cluster with "possible FM". This study explores prospectively predictors for membership of that FM-symptom cluster. METHODS: A population-based sample of 8343 subjects of the older Finnish Twin Cohort replied to health questionnaires in 1975, 1981, and 1990. Their answers to the set of FM-symptom questions in 1990 classified them in three latent classes (LC): LC1 with no or few symptoms, LC2 with some symptoms, and LC3 with many FM symptoms. We analysed putative predictors for these symptom classes using baseline (1975 and 1981) data on regional pain, headache, migraine, sleeping, body mass index (BMI), physical activity, smoking, and zygosity, adjusted for age, gender, and education. Those with a high likelihood of having fibromyalgia at baseline were excluded from the analysis. In the final multivariate regression model, regional pain, sleeping problems, and overweight were all predictors for membership in the class with many FM symptoms. RESULTS: The strongest non-genetic predictor was frequent headache (OR 8.6, CI 95% 3.8-19.2), followed by persistent back pain (OR 4.7, CI 95% 3.3-6.7) and persistent neck pain (OR 3.3, CI 95% 1.8-6.0). CONCLUSIONS: Regional pain, frequent headache, and persistent back or neck pain, sleeping problems, and overweight are predictors for having a cluster of symptoms consistent with fibromyalgia. PMID- 26772547 TI - Communication: Electrical rectification of C59N: The role of anchoring and doping sites. AB - Based on the nonequilibrium Green's function formalism and density-functional theory, we investigate the onset of electrical rectification in a single C59N molecule in conjunction with gold electrodes. Our calculations reveal that rectification is dependent upon the anchoring of the Au atom on C59N; when the Au electrode is singly bonded to a C atom (labeled here as A), the system does not exhibit rectification, whereas when the electrode is connected to the C-C bridge site between two hexagonal rings (labeled here as B), transmission asymmetry is observed, where the rectification ratio reaches up to 2.62 at +/-1 V depending on the N doping site relative to the anchoring site. Our analysis of the transmission mechanism shows that N doping of the B configuration causes rectification because more transmission channels are available for transmission in the B configuration than in the A configuration. PMID- 26772545 TI - Effects of stimulating interleukin -2/anti- interleukin -2 antibody complexes on renal cell carcinoma. AB - BACKGROUND: Current therapies for advanced renal cell carcinoma (RCC) have low cure rates or significant side effects. It has been reported that complexes composed of interleukin (IL)-2 and stimulating anti-IL-2 antibody (IL-2C) suppress malignant melanoma growth. We investigated whether it could have similar effects on RCC. METHODS: A syngeneic RCC model was established by subcutaneously injecting RENCA cells into BALB/c mice, which were administered IL-2C or phosphate-buffered saline every other day for 4 weeks. RCC size was measured serially, and its weight was assessed 4 weeks after RENCA injection. Immune cell infiltration into RCC lesions and spleen was assessed by flow cytometry and immunohistochemistry. RESULTS: IL-2C treatment increased the numbers of CD8(+) memory T and natural killer (NK) cells in healthy BALB/c mice (P < 0.01). In the spleen of RCC mice, IL-2C treatment also increased the number of CD8(+) memory T, NK cells, and macrophages as compared to PBS-treated controls (P < 0.01). The number of interferon-gamma- and IL-10-producing splenocytes increased and decreased, respectively after 4 weeks in the IL-2C-treated mice (P < 0.01). Tumor infiltrating immune cells including CD4(+) T, CD8(+) T, NK cells as well as macrophages were increased in IL-2C-treated mice than controls (P < 0.05). Pulmonary edema, the most serious side effect of IL-2 therapy, was not exacerbated by IL-2C treatment. However, IL-2C had insignificant inhibitory effect on RCC growth (P = 0.1756). CONCLUSIONS: IL-2C enhanced immune response without significant side effects; however, this activity was not sufficient to inhibit RCC growth in a syngeneic, murine model. PMID- 26772546 TI - IPLaminator: an ImageJ plugin for automated binning and quantification of retinal lamination. AB - BACKGROUND: Information in the brain is often segregated into spatially organized layers that reflect the function of the embedded circuits. This is perhaps best exemplified in the layering, or lamination, of the retinal inner plexiform layer (IPL). The neurites of the retinal ganglion, amacrine and bipolar cell subtypes that form synapses in the IPL are precisely organized in highly refined strata within the IPL. Studies focused on developmental organization and cell morphology often use this layered stratification to characterize cells and identify the function of genes in development of the retina. A current limitation to such analysis is the lack of standardized tools to quantitatively analyze this complex structure. Most previous work on neuron stratification in the IPL is qualitative and descriptive. RESULTS: In this study we report the development of an intuitive platform to rapidly and reproducibly assay IPL lamination. The novel ImageJ based software plugin we developed: IPLaminator, rapidly analyzes neurite stratification patterns in the retina and other neural tissues. A range of user options allows researchers to bin IPL stratification based on fixed points, such as the neurites of cholinergic amacrine cells, or to define a number of bins into which the IPL will be divided. Options to analyze tissues such as cortex were also added. Statistical analysis of the output then allows a quantitative value to be assigned to differences in laminar patterning observed in different models, genotypes or across developmental time. CONCLUSION: IPLaminator is an easy to use software application that will greatly speed and standardize quantification of neuron organization. PMID- 26772548 TI - Variational dynamics of the sub-Ohmic spin-boson model on the basis of multiple Davydov D1 states. AB - Dynamics of the sub-Ohmic spin-boson model is investigated by employing a multitude of the Davydov D1 trial states, also known as the multi-D1 Ansatz. Accuracy in dynamics simulations is improved significantly over the single D1 Ansatz, especially in the weak system-bath coupling regime. The reliability of the multi-D1 Ansatz for various coupling strengths and initial conditions is also systematically examined, with results compared closely with those of the hierarchy equations of motion and the path integral Monte Carlo approaches. In addition, a coherent-incoherent phase crossover in the nonequilibrium dynamics is studied through the multi-D1 Ansatz. The phase diagram is obtained with a critical point sc = 0.4. For sc < s < 1, the coherent-to-incoherent crossover occurs at a certain coupling strength, while the coherent state recurs at a much larger coupling strength. For s < sc, only the coherent phase exists. PMID- 26772549 TI - Molecular response properties in equation of motion coupled cluster theory: A time-dependent perspective. AB - Molecular response properties for ground and excited states and for transitions between these states are defined by solving the time-dependent Schrodinger equation for a molecular system in a field of a time-periodic perturbation. In equation of motion coupled cluster (EOM-CC) theory, molecular response properties are commonly obtained by replacing, in configuration interaction (CI) molecular response property expressions, the energies and eigenstates of the CI eigenvalue equation with the energies and eigenstates of the EOM-CC eigenvalue equation. We show here that EOM-CC molecular response properties are identical to the molecular response properties that are obtained in the coupled cluster configuration interaction (CC-CI) model, where the time-dependent Schrodinger equation is solved using an exponential (coupled cluster) parametrization to describe the unperturbed system and a linear (configuration interaction) parametrization to describe the time evolution of the unperturbed system. The equivalence between EOM-CC and CC-CI molecular response properties only holds when the CI molecular response property expressions-from which the EOM-CC expressions are derived-are determined using projection and not using the variational principle. In a previous article [F. Pawlowski, J. Olsen, and P. Jorgensen, J. Chem. Phys. 142, 114109 (2015)], it was stated that the equivalence between EOM-CC and CC-CI molecular response properties only held for a linear response function, whereas quadratic and higher order response functions were mistakenly said to differ in the two approaches. Proving the general equivalence between EOM-CC and CC-CI molecular response properties is a challenging task, that is undertaken in this article. Proving this equivalence not only corrects the previous incorrect statement but also first and foremost leads to a new, time dependent, perspective for understanding the basic assumptions on which the EOM CC molecular response property expressions are founded. Further, the equivalence between EOM-CC and CC-CI molecular response properties highlights how static molecular response properties can be obtained from finite-field EOM-CC energy calculations. PMID- 26772550 TI - Spectroscopic detectability of the molecular Aharonov-Bohm effect. AB - It is theoretically shown that the emission spectra from an excited Jahn-Teller state in which the ions undergo a forced periodic trajectory have an M-shaped form, directly due to the sign change by the Berry-phase factor. The presence of a weak spectral sideline is noted and the effects of a nonlinear vibronic coupling are calculated. Experimental verifications of the results, e.g., on R' centers in LiF, are proposed. The dip in the M-shaped emission line is a novel, and perhaps unique, spectroscopic manifestation of the "molecular Aharonov-Bohm effect." PMID- 26772552 TI - On the elimination of the electronic structure bottleneck in on the fly nonadiabatic dynamics for small to moderate sized (10-15 atom) molecules using fit diabatic representations based solely on ab initio electronic structure data: The photodissociation of phenol. AB - In this work, we demonstrate that for moderate sized systems, here a system with 13 atoms, global coupled potential energy surfaces defined for several electronic states over a wide energy range and for distinct regions of nuclear coordinate space characterized by distinct electron configurations, can be constructed with precise energetics and an excellent description of non-adiabatic interactions in all regions. This is accomplished using a recently reported algorithm for constructing quasi-diabatic representations, H(d), of adiabatic electronic states coupled by conical intersections. In this work, the algorithm is used to construct an H(d) to describe the photodissociation of phenol from its first and second excited electronic states. The representation treats all 33 internal degrees of freedom in an even handed manner. The ab initio adiabatic electronic structure data used to construct the fit are obtained exclusively from multireference configuration interaction with single and double excitation wave functions comprised of 88 * 10(6) configuration state functions, at geometries determined by quasi-classical trajectories. Since the algorithm uses energy gradients and derivative couplings in addition to electronic energies to construct H(d), data at only 7379 nuclear configurations are required to construct a representation, which describes all nuclear configurations involved in H atom photodissociation to produce the phenoxyl radical in its ground or first excited electronic state, with a mean unsigned energy error of 202.9 cm(-1) for electronic energies <60 000 cm(-1). PMID- 26772551 TI - Solvated molecular dynamics of LiCN isomerization: All-atom argon solvent versus a generalized Langevin bath. AB - The reaction rate rises and falls with increasing density or friction when a molecule is activated by collisions with the solvent particles. This so-called Kramers turnover has recently been observed in the isomerization reaction of LiCN in an argon bath. In this paper, we demonstrate by direct comparison with those results that a reduced-dimensional (generalized) Langevin description gives rise to similar reaction dynamics as the corresponding (computationally expensive) full molecular dynamics calculations. We show that the density distributions within the Langevin description are in direct agreement with the full molecular dynamics results and that the turnover in the reaction rates is reproduced qualitatively and quantitatively at different temperatures. PMID- 26772553 TI - A perturbation theoretic approach to the Riccati equation for the Floquet energies, spectral intensities, and cutoff energy of harmonic generation in photon emission from nonadiabatic electron-transfer dynamics driven by infrared CW laser fields. AB - A complicated yet interesting induced photon emission can take place by a nonadiabatic intramolecular electron transfer system like LiF under an intense CW laser [Y. Arasaki, S. Scheit, and K. Takatsuka, J. Chem. Phys. 138, 161103 (2013)]. Behind this phenomena, the crossing point between two potential energy curves of covalent and ionic natures in diabatic representation is forced to oscillate, since only the ionic potential curve is shifted significantly up and down repeatedly (called the Dynamical Stark effect). The wavepacket pumped initially to the excited covalent potential curve frequently encounters such a dynamically moving crossing point and thereby undergoes very complicated dynamics including wavepacket bifurcation and deformation. Intramolecular electron transfer thus driven by the coupling between nonadiabatic state-mixing and laser fields induces irregular photon emission. Here in this report we discuss the complicated spectral features of this kind of photon emission induced by infrared laser. In the low frequency domain, the photon emission is much more involved than those of ultraviolet/visible driving fields, since many field-dressed states are created on the ionic potential, which have their own classical turning points and crossing points with the covalent counterpart. To analyze the physics behind the phenomena, we develop a perturbation theoretic approach to the Riccati equation that is transformed from coupled first-order linear differential equations with periodic coefficients, which are supposed to produce the so-called Floquet states. We give mathematical expressions for the Floquet energies, frequencies, and intensities of the photon emission spectra, and the cutoff energy of their harmonic generation. Agreement between these approximate quantities and those estimated with full quantum calculations is found to be excellent. Furthermore, the present analysis provides with notions to facilitate deeper understanding for the physical and mathematical mechanisms of the present photon emission. PMID- 26772554 TI - Photoconductivities from band states and a dissipative electron dynamics: Si(111) without and with adsorbed Ag clusters. AB - A new general computational procedure is presented to obtain photoconductivities starting from atomic structures, combining ab initio electronic energy band states with populations from density matrix theory, and implemented for a specific set of materials based on Si crystalline slabs and their nanostructured surfaces without and with adsorbed Ag clusters. The procedure accounts for charge mobility in semiconductors in photoexcited states, and specifically electron and hole photomobilities at Si(111) surfaces with and without adsorbed Ag clusters using ab initio energy bands and orbitals generated from a generalized gradient functional, however with excited energy levels modified to provide correct bandgaps. Photoexcited state populations for each band and carrier type were generated using steady state solution of a reduced density matrix which includes dissipative medium effects. The present calculations provide photoexcited electronic populations and photoinduced mobilities resulting from applied electric fields and obtained from the change of driven electron energies with their electronic momentum. Extensive results for Si slabs with 8 layers, without and with adsorbed Ag clusters, show that the metal adsorbates lead to substantial increases in the photomobility and photoconductivity of electrons and holes. PMID- 26772555 TI - A theoretical investigation of the influence of gold nanosphere size on the decay and energy transfer rates and efficiencies of quantum emitters. AB - We present in this contribution a comprehensive investigation of the effect of the size of gold nanospheres on the decay and energy transfer rates of quantum systems placed close to these nanospheres. These phenomena have been investigated before, theoretically and experimentally, but no comprehensive study of the influence of the nanoparticle size on important dependences of the decay and energy transfer rates, such as the dependence on the donor-acceptor spectral overlap and the relative positions of the donor, acceptor, and nanoparticle, exists. As such, different accounts of the energy transfer mechanism have been presented in the literature. We perform an investigation of the energy transfer mechanisms between emitters and gold nanospheres and between donor-acceptor pairs in the presence of the gold nanospheres using a Green's tensor formalism, experimentally verified in our lab. We find that the energy transfer rate to small nanospheres is greatly enhanced, leading to a strong quenching of the emission of the emitter. When the nanosphere size is increased, it acts as an antenna, increasing the emission of the emitter. We also investigate the emission wavelength and intrinsic quantum yield dependence of the energy transfer to the nanosphere. As evidenced from the literature, the energy transfer process between the quantum system and the nanosphere can have a complicated distance dependence, with a r(-6) regime, characteristic of the Forster energy transfer mechanism, but also exhibiting other distance dependences. In the case of a donor-acceptor pair of quantum systems in the presence of a gold nanosphere, when the donor couples strongly to the nanosphere, acting as an enhanced dipole; the donor-acceptor energy transfer rate then follows a Forster trend, with an increased Forster radius. The coupling of the acceptor to the nanosphere has a different distance dependence. The angular dependence of the energy transfer efficiency between donor and acceptor exhibits a strong focusing effect and the same enhanced donor dipole character in different angular arrangements. The spectral overlap of the donor emission and acceptor absorption spectra shows that the energy transfer follows the near-field scattering efficiency, with a red-shift from the localized surface plasmon peak for small sphere sizes. PMID- 26772556 TI - Sparse maps--A systematic infrastructure for reduced-scaling electronic structure methods. II. Linear scaling domain based pair natural orbital coupled cluster theory. AB - Domain based local pair natural orbital coupled cluster theory with single-, double-, and perturbative triple excitations (DLPNO-CCSD(T)) is a highly efficient local correlation method. It is known to be accurate and robust and can be used in a black box fashion in order to obtain coupled cluster quality total energies for large molecules with several hundred atoms. While previous implementations showed near linear scaling up to a few hundred atoms, several nonlinear scaling steps limited the applicability of the method for very large systems. In this work, these limitations are overcome and a linear scaling DLPNO CCSD(T) method for closed shell systems is reported. The new implementation is based on the concept of sparse maps that was introduced in Part I of this series [P. Pinski, C. Riplinger, E. F. Valeev, and F. Neese, J. Chem. Phys. 143, 034108 (2015)]. Using the sparse map infrastructure, all essential computational steps (integral transformation and storage, initial guess, pair natural orbital construction, amplitude iterations, triples correction) are achieved in a linear scaling fashion. In addition, a number of additional algorithmic improvements are reported that lead to significant speedups of the method. The new, linear-scaling DLPNO-CCSD(T) implementation typically is 7 times faster than the previous implementation and consumes 4 times less disk space for large three-dimensional systems. For linear systems, the performance gains and memory savings are substantially larger. Calculations with more than 20 000 basis functions and 1000 atoms are reported in this work. In all cases, the time required for the coupled cluster step is comparable to or lower than for the preceding Hartree-Fock calculation, even if this is carried out with the efficient resolution-of-the identity and chain-of-spheres approximations. The new implementation even reduces the error in absolute correlation energies by about a factor of two, compared to the already accurate previous implementation. PMID- 26772557 TI - New insights into the nonadiabatic state population dynamics of model proton coupled electron transfer reactions from the mixed quantum-classical Liouville approach. AB - In a previous study [F. A. Shakib and G. Hanna, J. Chem. Phys. 141, 044122 (2014)], we investigated a model proton-coupled electron transfer (PCET) reaction via the mixed quantum-classical Liouville (MQCL) approach and found that the trajectories spend the majority of their time on the mean of two coherently coupled adiabatic potential energy surfaces. This suggested a need for mean surface evolution to accurately simulate observables related to ultrafast PCET processes. In this study, we simulate the time-dependent populations of the three lowest adiabatic states in the ET-PT (i.e., electron transfer preceding proton transfer) version of the same PCET model via the MQCL approach and compare them to the exact quantum results and those obtained via the fewest switches surface hopping (FSSH) approach. We find that the MQCL population profiles are in good agreement with the exact quantum results and show a significant improvement over the FSSH results. All of the mean surfaces are shown to play a direct role in the dynamics of the state populations. Interestingly, our results indicate that the population transfer to the second-excited state can be mediated by dynamics on the mean of the ground and second-excited state surfaces, as part of a sequence of nonadiabatic transitions that bypasses the first-excited state surface altogether. This is made possible through nonadiabatic transitions between different mean surfaces, which is the manifestation of coherence transfer in MQCL dynamics. We also investigate the effect of the strength of the coupling between the proton/electron and the solvent coordinate on the state population dynamics. Drastic changes in the population dynamics are observed, which can be understood in terms of the changes in the potential energy surfaces and the nonadiabatic couplings. Finally, we investigate the state population dynamics in the PT-ET (i.e., proton transfer preceding electron transfer) and concerted versions of the model. The PT-ET results confirm the participation of all of the mean surfaces, albeit in different proportions compared to the ET-PT case, while the concerted results indicate that the mean of the ground- and first-excited state surfaces only plays a role, due to the large energy gaps between the ground- and second excited state surfaces. PMID- 26772558 TI - A two-layer approach to the coupled coherent states method. AB - In this paper, a two-layer scheme is outlined for the coupled coherent states (CCS) method, dubbed two-layer CCS (2L-CCS). The theoretical framework is motivated by that of the multiconfigurational Ehrenfest method, where different dynamical descriptions are used for different subsystems of a quantum mechanical system. This leads to a flexible representation of the wavefunction, making the method particularly suited to the study of composite systems. It was tested on a 20-dimensional asymmetric system-bath tunnelling problem, with results compared to a benchmark calculation, as well as existing CCS, matching-pursuit/split operator Fourier transform, and configuration interaction expansion methods. The two-layer method was found to lead to improved short and long term propagation over standard CCS, alongside improved numerical efficiency and parallel scalability. These promising results provide impetus for future development of the method for on-the-fly direct dynamics calculations. PMID- 26772559 TI - New parallelizable schemes for integrating the Dissipative Particle Dynamics with Energy conservation. AB - This work presents new parallelizable numerical schemes for the integration of dissipative particle dynamics with energy conservation. So far, no numerical scheme introduced in the literature is able to correctly preserve the energy over long times and give rise to small errors on average properties for moderately small time steps, while being straightforwardly parallelizable. We present in this article two new methods, both straightforwardly parallelizable, allowing to correctly preserve the total energy of the system. We illustrate the accuracy and performance of these new schemes both on equilibrium and nonequilibrium parallel simulations. PMID- 26772560 TI - Non-Markovian dynamics of single- and two-qubit systems interacting with Gaussian and non-Gaussian fluctuating transverse environments. AB - We address the interaction of single- and two-qubit systems with an external transverse fluctuating field and analyze in detail the dynamical decoherence induced by Gaussian noise and random telegraph noise (RTN). Upon exploiting the exact RTN solution of the time-dependent von Neumann equation, we analyze in detail the behavior of quantum correlations and prove the non-Markovianity of the dynamical map in the full parameter range, i.e., for either fast or slow noise. The dynamics induced by Gaussian noise is studied numerically and compared to the RTN solution, showing the existence of (state dependent) regions of the parameter space where the two noises lead to very similar dynamics. We show that the effects of RTN noise and of Gaussian noise are different, i.e., the spectrum alone is not enough to summarize the noise effects, but the dynamics under the effect of one kind of noise may be simulated with high fidelity by the other one. PMID- 26772561 TI - Optimizing molecular properties using a relative index of thermodynamic stability and global optimization techniques. AB - We devised a global optimization (GO) strategy for optimizing molecular properties with respect to both geometry and chemical composition. A relative index of thermodynamic stability (RITS) is introduced to allow meaningful energy comparisons between different chemical species. We use the RITS by itself, or in combination with another calculated property, to create an objective function F to be minimized. Including the RITS in the definition of F ensures that the solutions have some degree of thermodynamic stability. We illustrate how the GO strategy works with three test applications, with F calculated in the framework of Kohn-Sham Density Functional Theory (KS-DFT) with the Perdew-Burke-Ernzerhof exchange-correlation. First, we searched the composition and configuration space of CmHnNpOq (m = 0-4, n = 0-10, p = 0-2, q = 0-2, and 2 <= m + n + p + q <= 12) for stable molecules. The GO discovered familiar molecules like N2, CO2, acetic acid, acetonitrile, ethane, and many others, after a small number (5000) of KS DFT energy evaluations. Second, we carried out a GO of the geometry of CumSnn (+) (m = 1, 2 and n = 9-12). A single GO run produced the same low-energy structures found in an earlier study where each CumSnn (+) species had been optimized separately. Finally, we searched bimetallic clusters AmBn (3 <= m + n <= 6, A,B= Li, Na, Al, Cu, Ag, In, Sn, Pb) for species and configurations having a low RITS and large highest occupied Molecular Orbital (MO) to lowest unoccupied MO energy gap (Eg). We found seven bimetallic clusters with Eg > 1.5 eV. PMID- 26772562 TI - Dynamical density functional theory for microswimmers. AB - Dynamical density functional theory (DDFT) has been successfully derived and applied to describe on one hand passive colloidal suspensions, including hydrodynamic interactions between individual particles. On the other hand, active "dry" crowds of self-propelled particles have been characterized using DDFT. Here, we go one essential step further and combine these two approaches. We establish a DDFT for active microswimmer suspensions. For this purpose, simple minimal model microswimmers are introduced. These microswimmers self-propel by setting the surrounding fluid into motion. They hydrodynamically interact with each other through their actively self-induced fluid flows and via the common "passive" hydrodynamic interactions. An effective soft steric repulsion is also taken into account. We derive the DDFT starting from common statistical approaches. Our DDFT is then tested and applied by characterizing a suspension of microswimmers, the motion of which is restricted to a plane within a three dimensional bulk fluid. Moreover, the swimmers are confined by a radially symmetric trapping potential. In certain parameter ranges, we find rotational symmetry breaking in combination with the formation of a "hydrodynamic pumping state," which has previously been observed in the literature as a result of particle-based simulations. An additional instability of this pumping state is revealed. PMID- 26772563 TI - A broadened classical master equation approach for nonadiabatic dynamics at metal surfaces: Beyond the weak molecule-metal coupling limit. AB - A broadened classical master equation (BCME) is proposed for modeling nonadiabatic dynamics for molecules near metal surfaces over a wide range of parameter values and with arbitrary initial conditions. Compared with a standard classical master equation-which is valid in the limit of weak molecule-metal couplings-this BCME should be valid for both weak and strong molecule-metal couplings. (The BCME can be mapped to a Fokker-Planck equation that captures level broadening correctly.) Finally, our BCME can be solved with a simple surface hopping algorithm; numerical tests of equilibrium and dynamical observables look very promising. PMID- 26772564 TI - Site-resolved multiple-quantum filtered correlations and distance measurements by magic-angle spinning NMR: Theory and applications to spins with weak to vanishing quadrupolar couplings. AB - We discuss and analyze four magic-angle spinning solid-state NMR methods that can be used to measure internuclear distances and to obtain correlation spectra between a spin I = 1/2 and a half-integer spin S > 1/2 having a small quadrupolar coupling constant. Three of the methods are based on the heteronuclear multiple quantum and single-quantum correlation experiments, that is, high rank tensors that involve the half spin and the quadrupolar spin are generated. Here, both zero and single-quantum coherence of the half spins are allowed and various coherence orders of the quadrupolar spin are generated, and filtered, via active recoupling of the dipolar interaction. As a result of generating coherence orders larger than one, the spectral resolution for the quadrupolar nucleus increases linearly with the coherence order. Since the formation of high rank tensors is independent of the existence of a finite quadrupolar interaction, these experiments are also suitable to materials in which there is high symmetry around the quadrupolar spin. A fourth experiment is based on the initial quadrupolar driven excitation of symmetric high order coherences (up to p = 2S, where S is the spin number) and subsequently generating by the heteronuclear dipolar interaction higher rank (l + 1 or higher) tensors that involve also the half spins. Due to the nature of this technique, it also provides information on the relative orientations of the quadrupolar and dipolar interaction tensors. For the ideal case in which the pulses are sufficiently strong with respect to other interactions, we derive analytical expressions for all experiments as well as for the transferred echo double resonance experiment involving a quadrupolar spin. We show by comparison of the fitting of simulations and the analytical expressions to experimental data that the analytical expressions are sufficiently accurate to provide experimental (7)Li-(13)C distances in a complex of lithium, glycine, and water. Discussion of the regime for which such an approach is valid is given. PMID- 26772565 TI - Resonance effects in elastic cross sections for electron scattering on pyrimidine: Experiment and theory. AB - We measured differential cross sections for elastic (rotationally integrated) electron scattering on pyrimidine, both as a function of angle up to 180(?) at electron energies of 1, 5, 10, and 20 eV and as a function of electron energy in the range 0.1-14 eV. The experimental results are compared to the results of the fixed-nuclei Schwinger variational and R-matrix theoretical methods, which reproduce satisfactorily the magnitudes and shapes of the experimental cross sections. The emphasis of the present work is on recording detailed excitation functions revealing resonances in the excitation process. Resonant structures are observed at 0.2, 0.7, and 4.35 eV and calculations for different symmetries confirm their assignment as the X(2)A2, A(2)B1, and B(2)B1 shape resonances. As a consequence of superposition of coherent resonant amplitudes with background scattering the B(2)B1 shape resonance appears as a peak, a dip, or a step function in the cross sections recorded as a function of energy at different scattering angles and this effect is satisfactorily reproduced by theory. The dip and peak contributions at different scattering angles partially compensate, making the resonance nearly invisible in the integral cross section. Vibrationally integrated cross sections were also measured at 1, 5, 10 and 20 eV and the question of whether the fixed-nuclei cross sections should be compared to vibrationally elastic or vibrationally integrated cross section is discussed. PMID- 26772566 TI - Absolute cross sections for electronic excitation of pyrimidine by electron impact. AB - We measured differential cross sections for electron-impact electronic excitation of pyrimidine, both as a function of electron energy up to 18 eV, and of scattering angle up to 180 degrees . The emphasis of the present work is on recording detailed excitation functions revealing resonances in the excitation process. The differential cross sections were summed to obtain integral cross sections. These are compared to results of R-matrix calculations, which successfully reproduce both the magnitude of the cross section and the major resonant features. Comparison of the experiment to the calculated contributions of different symmetries to the integral cross section permitted assignment of several features to specific core-excited resonances. Comparison of the resonant structure of pyrimidine with that of benzene revealed pronounced similarities and thus a dominant role of pi-pi(*) excited states and resonances. Electron energy loss spectra were measured as a preparation for the cross section measurements and vibrational structure was observed for some of the triplet states. A detailed analysis of the electronic excited states of pyrimidine is also presented. PMID- 26772568 TI - The contribution of the delayed ionization in strong-field nonsequential double ionization. AB - With the classical ensemble model, we have investigated the pulse-duration dependence of nonsequential double ionization (NSDI) over a wide range of laser intensity. The correlated electron momentum distributions are distinctly different for the few-cycle and multiple cycle pulses, which agree well with the previous experiments. Based on this agreement, we analyzed the underlying process for the pulse-duration dependence of the electron correlation by tracing the classical trajectories. Counterintuitively, our analysis shows that the recollision-induced excited states of NSDI could resist ionization in the strong laser field for a time much longer than one optical cycle even at very high intensities. For the multiple-cycle pulses, NSDI events with such a long time delay have significant contribution to the total NSDI yields, which is responsible for the pulse-duration dependence of the observed correlated patterns in the electron momentum distributions. PMID- 26772567 TI - Torsion-rotation-vibration effects in the ground and first excited states of methacrolein, a major atmospheric oxidation product of isoprene. AB - Methacrolein is a major oxidation product of isoprene emitted in the troposphere. New spectroscopy information is provided with the aim to allow unambiguous identification of this complex molecule, characterized by a large amplitude motion associated with the methyl top. State-of-the-art millimeter-wave spectroscopy experiments coupled to quantum chemical calculations have been performed. For the most stable s-trans conformer of atmospheric interest, the torsional and rotational structures have been characterized for the ground state, the first excited methyl torsional state (nu27), and the first excited skeletal torsional state (nu26). The inverse sequence of A and E tunneling sub-states as well as anomalous A-E splittings observed for the rotational lines of v26 = 1 state clearly indicates a coupling between methyl torsion and skeletal torsion. A comprehensive set of molecular parameters has been obtained. The far infrared spectrum of Durig et al. [Spectrochim. Acta, Part A 42, 89-103 (1986)] was reproduced, and a Fermi interaction between nu25 and 2nu27 was evidenced. PMID- 26772569 TI - Exciton interference revealed by energy dependent exciton transfer rate for ring structured molecular systems. AB - The quantum interference is an intrinsic phenomenon in quantum physics for photon and massive quantum particles. In principle, the quantum interference may also occur with quasi-particles, such as the exciton. In this study, we show how the exciton quantum interference can be significant in aggregates through theoretical simulations with hierarchical equations of motion. The systems under investigation are generalized donor-bridge-acceptor model aggregates with the donor consisting of six homogeneous sites assuming the nearest neighbor coupling. For the models with single-path bridge, the exciton transfer time only shows a weak excitation energy dependence. But models with double-path bridge have a new short transfer time scale and the excitation energy dependence of the exciton transfer time assumes clear peak structure which is detectable with today's nonlinear spectroscopy. This abnormality is attributed to the exciton quantum interference and the condition for a clear observation in experiment is also explored. PMID- 26772571 TI - Ab initio adiabatic and quasidiabatic potential energy surfaces of H(+) + CO system: A study of the ground and the first three excited electronic states. AB - The global ground and first three excited electronic state adiabatic as well as the corresponding quasidiabatic potential energy surfaces is reported as a function of nuclear geometries in the Jacobi coordinates (R->,r->,gamma) using Dunning's cc-pVTZ basis set at the internally contracted multi-reference (single and double) configuration interaction level of accuracy. Nonadiabatic couplings, arising out of relative motion of proton and the vibrational motion of CO, are also reported in terms of coupling potentials. The quasidiabatic potential energy surfaces and the coupling potentials have been obtained using the ab initio procedure [Simah et al., J. Chem. Phys. 111, 4523 (1999)] for the purpose of dynamics studies. PMID- 26772570 TI - Two-pulse control over double ionization pathways in CO2. AB - We visualize and control molecular dynamics taking place on intermediately populated states during different sequential double ionization pathways of CO2 using a sequence of two delayed laser pulses which exhibit different peak intensities. Measured yields of CO2 (2+) and of fragment pairs CO(+)/O(+) as a function of delay between the two pulses are weakly modulated by various vibronic dynamics taking place in CO2 (+). By Fourier analysis of the modulations we identify the dynamics and show that they can be assigned to merely two double ionization pathways. We demonstrate that by reversing the sequence of the two pulses it becomes possible to control the pathway which is taken across CO2 (+) towards the final state in CO2 (2+). A comparison between the yields of CO2 (2+) and CO(+)/O(+) reveals that the modulating vibronic dynamics oscillate out-of phase with each other, thus opening up opportunities for strong-field fragmentation control on extended time scales. PMID- 26772572 TI - Observations and analysis with the spline-based Rydberg-Klein-Rees approach for the 3(1)Sigmag(+) state of Rb2. AB - Ro-vibrational term values of the 3(1)Sigmag (+) state of (85,85)Rb2 and (85,87)Rb2 and resolved fluorescence spectra to the A(1)Sigmau (+) state are recorded following optical-optical double resonance excitation. The experimental data are heavily perturbed, and as a result, the standard analysis based on Dunham series representation of the energy levels fails. The analysis is done via modeling the adiabatic potential function with the Rydberg-Klein-Rees potential constructed from the generalized smoothing spline interpolation of the vibrational energies Gv and rotational constants Bv. PMID- 26772573 TI - Global triplet potential energy surfaces for the N2(X(1)Sigma) + O((3)P) -> NO(X(2)Pi) + N((4)S) reaction. AB - This work presents two global triplet potential energy surfaces (PESs) for the high-energy reaction N2(X(1)Sigma) + O((3)P) -> NO(X(2)Pi) + N((4)S)-in particular, for the lowest energy (3)A' and (3)A" PESs. In order to obtain the energies needed for fitting analytic surfaces, we carried out multireference configuration interaction (MRCI) calculations based on wave functions obtained from state-averaged complete active space self-consistent field calculations for 2280 geometries for the three lowest (3)A" states and for 2298 geometries for the three lowest (3)A' states. The lowest-energy (3)A' and (3)A" states at each of these geometries were then improved by applying the dynamically scaled external correlation (DSEC) method to all MRCI points, and the resulting DSEC energies were used for construction of the ground-state PES for each symmetry. The many body component of the DSEC energies for the three-dimensional (3)A' and (3)A" PESs was then least-squares fitted in terms of permutationally invariant polynomials in mixed exponential-Gaussian bond order variables. The global and local minima as well as the transition structures of both the (3)A' and the (3)A" analytic PES were explored. In agreement with previous work, we find that the reverse reaction is barrierless on the (3)A" surface along the minimum energy pathway. However, we have explored several new local minima and transition structures on the (3)A' PES. Furthermore, based on the newly found minima and transition structures, two independent reaction mechanisms have been illustrated for the reaction path on the (3)A' PES. The analytic surfaces may be used for dynamics calculations of electronically adiabatic reactive scattering and energy transfer. PMID- 26772574 TI - Potential energy surface of triplet N2O2. AB - We present a global ground-state triplet potential energy surface for the N2O2 system that is suitable for treating high-energy vibrational-rotational energy transfer and collision-induced dissociation. The surface is based on multi-state complete-active-space second-order perturbation theory/minimally augmented correlation-consistent polarized valence triple-zeta electronic structure calculations plus dynamically scaled external correlation. In the multireference calculations, the active space has 14 electrons in 12 orbitals. The calculations cover nine arrangements corresponding to dissociative diatom-diatom collisions of N2, O2, and nitric oxide (NO), the interaction of a triatomic molecule (N2O and NO2) with the fourth atom, and the interaction of a diatomic molecule with a single atom (i.e., the triatomic subsystems). The global ground-state potential energy surface was obtained by fitting the many-body interaction to 54 889 electronic structure data points with a fitting function that is a permutationally invariant polynomial in terms of bond-order functions of the six interatomic distances. PMID- 26772575 TI - Full empirical potential curves for the X(1)Sigma(+) and A(1)Pi states of CH(+) from a direct-potential-fit analysis. AB - All available "conventional" absorption/emission spectroscopic data have been combined with photodissociation data and translational spectroscopy data in a global analysis that yields analytic potential energy and Born-Oppenheimer breakdown functions for the X(1)Sigma(+) and A(1)Pi states of CH(+) and its isotopologues that reproduce all of the data (on average) within their assigned uncertainties. For the ground X(1)Sigma(+) state, this fully quantum mechanical "Direct-Potential-Fit" analysis yielded an improved empirical well depth of ??e = 34 362.8(3) cm(-1) and equilibrium bond length of re = 1.128 462 5 (58) A. For the A(1)Pi state, the resulting well depth and equilibrium bond length are ??e = 10 303.7(3) cm(-1) and re = 1.235 896 (14) A, while the electronic isotope shift from the hydride to the deuteride is DeltaTe = - 5.99(+/-0.08) cm(-1). PMID- 26772576 TI - Global analysis of the high temperature infrared emission spectrum of (12)CH4 in the dyad (nu2/nu4) region. AB - We report new assignments of vibration-rotation line positions of methane ((12)CH4) in the so-called dyad (nu2/nu4) region (1100-1500 cm(-1)), and the resulting update of the vibration-rotation effective model of methane, previously reported by Nikitin et al. [Phys. Chem. Chem. Phys. 15, 10071 (2013)], up to and including the tetradecad. High resolution (0.01 cm(-1)) emission spectra of methane have been recorded up to about 1400 K using the high-enthalpy source developed at Institut de Physique de Rennes associated with the Fourier transform spectrometer of the SOLEIL synchrotron facility (AILES beamline). Analysis of these spectra allowed extending rotational assignments in the well-known cold band (dyad-ground state (GS)) and related hot bands in the pentad-dyad system (3000 cm(-1)) up to Jmax = 30 and 29, respectively. In addition, 8512 new transitions belonging to the octad-pentad (up to J = 28) and tetradecad-octad (up to J = 21) hot band systems were successfully identified. As a result, the MeCaSDa database of methane was significantly improved. The line positions assigned in this work, together with the information available in the literature, were fitted using 1096 effective parameters with a dimensionless standard deviation sigma = 2.09. The root mean square deviations dRMS are 3.60 * 10(-3) cm(-1) for dyad-GS cold band, 4.47 *10(-3) cm(-1) for the pentad-dyad, 5.43 * 10( 3) cm(-1) for the octad-pentad, and 4.70 * 10(-3) cm(-1) for the tetradecad-octad hot bands. The resulting new line list will contribute to improve opacity and radiative transfer models for hot atmospheres, such as those of hot-Jupiter type exoplanets. PMID- 26772577 TI - Decomposition of cyclohexane ion induced by intense femtosecond laser fields by ion-trap time-of-flight mass spectrometry. AB - Decomposition of cyclohexane cations induced by intense femtosecond laser fields at the wavelength of 800 nm is investigated by ion-trap time-of-flight mass spectrometry in which cyclohexane cations C6H12 (+) stored in an ion trap are irradiated with intense femtosecond laser pulses and the generated fragment ions are recorded by time-of-flight mass spectrometry. The various fragment ion species, C5Hn (+) (n = 7, 9), C4Hn (+) (n = 5-8), C3Hn (+) (n = 3-7), C2Hn (+) (n = 2-6), and CH3 (+), identified in the mass spectra show that decomposition of C6H12 (+) proceeds efficiently by the photo-irradiation. From the laser intensity dependences of the yields of the fragment ion species, the numbers of photons required for producing the respective fragment ions are estimated. PMID- 26772578 TI - Theoretical analysis of the S2<-S0 vibronic spectrum of the 2-pyridone dimer. AB - The interplay between excitonic and vibronic coupling in hydrogen-bonded molecular dimers leads to complex spectral structures and other intriguing phenomena such as a quenching of the excitonic energy splitting. We recently extended our analysis from that of the quenching mechanism to the theoretical investigation of the complete vibronic spectrum for the ortho-cyanophenol dimer. We now apply the same approach to the vibronic spectrum of the 2-pyridone dimer and discuss the assignment of vibronic lines to gain insight into the underlying coupling mechanism. This is based on potential energy surfaces obtained at the RI CC2/aug-cc-pVTZ level. They are used for the dynamical analysis in the framework of a multi-mode vibronic coupling approach. The theoretical results based on the quadratic vibronic coupling model are found to be in good agreement with the experimental resonant two-photon ionization spectrum. PMID- 26772579 TI - Efficient measurement of point-to-set correlations and overlap fluctuations in glass-forming liquids. AB - Cavity point-to-set correlations are real-space tools to detect the roughening of the free-energy landscape that accompanies the dynamical slowdown of glass forming liquids. Measuring these correlations in model glass formers remains, however, a major computational challenge. Here, we develop a general parallel tempering method that provides orders-of-magnitude improvement for sampling and equilibrating configurations within cavities. We apply this improved scheme to the canonical Kob-Andersen binary Lennard-Jones model for temperatures down to the mode-coupling theory crossover. Most significant improvements are noted for small cavities, which have thus far been the most difficult to study. This methodological advance also enables us to study a broader range of physical observables associated with thermodynamic fluctuations. We measure the probability distribution of overlap fluctuations in cavities, which displays a non-trivial temperature evolution. The corresponding overlap susceptibility is found to provide a robust quantitative estimate of the point-to-set length scale requiring no fitting. By resolving spatial fluctuations of the overlap in the cavity, we also obtain quantitative information about the geometry of overlap fluctuations. We can thus examine in detail how the penetration length as well as its fluctuations evolve with temperature and cavity size. PMID- 26772580 TI - The "anomalous" dynamics of decahyroisoquinoline revisited. AB - Decahydroisoquinoline (DHIQ) appears to be a unique material-the only non associated, simple liquid with dynamics deviating from density scaling. To examine whether this anomaly is real, the density, rho, of DHIQ was measured at temperatures, T, as low as 214 K and pressures up to ~1.2 GPa. This enabled the equation of state (EoS) to be determined, without extrapolation, over the range of thermodynamic conditions for which the relaxation times had been reported. Using this less ambiguous EoS, we find that within the precision of the available relaxation times, the latter are a function of T/rho(3.9), contrary to previous reports. Thus, the behavior of DHIQ is unexceptional; similar to every non associated liquid tested to date, its dynamics comply with density scaling. PMID- 26772581 TI - Interfacial charge rearrangement and intermolecular interactions: Density functional theory study of free-base porphine adsorbed on Ag(111) and Cu(111). AB - We employ dispersion-corrected density-functional theory to study the adsorption of tetrapyrrole 2H-porphine (2H-P) at Cu(111) and Ag(111). Various contributions to adsorbate-substrate and adsorbate-adsorbate interactions are systematically extracted to analyze the self-assembly behavior of this basic building block to porphyrin-based metal-organic nanostructures. This analysis reveals a surprising importance of substrate-mediated van der Waals interactions between 2H-P molecules, in contrast to negligible direct dispersive interactions. The resulting net repulsive interactions rationalize the experimentally observed tendency for single molecule adsorption. PMID- 26772582 TI - Many-body effects and excitonic features in 2D biphenylene carbon. AB - The remarkable excitonic effects in low dimensional materials in connection to large binding energies of excitons are of great importance for research and technological applications such as in solar energy and quantum information processing as well as for fundamental investigations. In this study, the unique electronic and excitonic properties of the two dimensional carbon network biphenylene carbon were investigated with GW approach and the Bethe-Salpeter equation accounting for electron correlation effects and electron-hole interactions, respectively. Biphenylene carbon exhibits characteristic features including bright and dark excitons populating the optical gap of 0.52 eV and exciton binding energies of 530 meV as well as a technologically relevant intrinsic band gap of 1.05 eV. Biphenylene carbon's excitonic features, possibly tuned, suggest possible applications in the field of solar energy and quantum information technology in the future. PMID- 26772583 TI - Growth of metalloid aluminum clusters on graphene vacancies. AB - Ab initio simulations are used to show that graphene vacancy sites may offer a means of templated growth of metalloid aluminum clusters from their monohalide precursors. We present density functional theory and ab initio molecular dynamics simulations of the aluminum halide AlCl interacting with a graphene surface. Unlike a bare Al adatom, AlCl physisorbs weakly on vacancy-free graphene with little charge transfer and no hybridization with carbon orbitals. The barrier for diffusion of AlCl along the surface is negligible. Covalent bonding is seen only with vacancies and results in strong chemisorption and considerable distortion of the nearby lattice. Car-Parrinello molecular dynamics simulations of AlCl liquid around a graphene single vacancy show spontaneous metalloid cluster growth via a process of repeated insertion reactions. This suggests a means of templated cluster nucleation and growth on a carbon substrate and provides some confirmation for the role of a trivalent aluminum species in nucleating a ligated metalloid cluster from AlCl and AlBr solutions. PMID- 26772585 TI - Pattern formation in thin films of polymer solutions: Theory and simulations. AB - Self-assembly has been recognized as an efficient tool for generating a wide range of functional, chemically, or physically textured surfaces for applications in small scale devices. In this work, we investigate the stability of thin films of polymer solutions. For low concentrations of polymer in the solution, long length scale dewetting patterns are obtained with wavelength approximately few microns. Whereas, for concentrations above a critical value, bimodal dispersion curves are obtained with the dominant wavelength being up to two orders smaller than the usual dewetting length scale. We further show that the short wavelength corresponds to the phase separation in the film resulting in uniformly distributed high and low concentration regions. Interestingly, due to the solvent entropy, at very high concentration values of polymer, a re-entrant behaviour is observed with the dominant length scale now again corresponding to the dewetting wavelength. Thus, we show that the binary films of polymer solutions provide additional control parameters that can be utilized for generating functional textured surfaces for various applications. PMID- 26772584 TI - The mechanism of the emergence of distinct overstretched DNA states. AB - Although multiple overstretched DNA states were identified in experiments, the mechanism of the emergence of distinct states is still unclear. Molecular dynamics simulation is an ideal tool to clarify the mechanism, but the force loading rates in stretching achieved by conventional all-atom DNA models are much faster, which essentially affect overstretching states. We employed a modified coarse-grained DNA model with an unprecedented low loading rate in simulations to study the overstretching transitions of end-opened double-stranded DNA. We observed two-strand peeling off for DNA with low stability and the S-DNA with high stability under tension. By introducing a melting-forbidden model which prevents base-pair breaking, we still observed the overstretching transition induced by the formation of S-DNA due to the change of dihedral angle. Hence, we confirmed that the competition between the two strain-softening manners, i.e., base-pair breaking and dihedral angle variation, results in the emergence of distinct overstretched DNA states. PMID- 26772586 TI - Flexible polyelectrolyte chain in a strong electrolyte solution: Insight into equilibrium properties and force-extension behavior from mesoscale simulation. AB - Macromolecules with ionizable groups are ubiquitous in biological and synthetic systems. Due to the complex interaction between chain and electrostatic decorrelation lengths, both equilibrium properties and micro-mechanical response of dilute solutions of polyelectrolytes (PEs) are more complex than their neutral counterparts. In this work, the bead-rod micromechanical description of a chain is used to perform hi-fidelity Brownian dynamics simulation of dilute PE solutions to ascertain the self-similar equilibrium behavior of PE chains with various linear charge densities, scaling of the Kuhn step length (lE) with salt concentration cs and the force-extension behavior of the PE chain. In accord with earlier theoretical predictions, our results indicate that for a chain with n Kuhn segments, lE ~ cs (-0.5) as linear charge density approaches 1/n. Moreover, the constant force ensemble simulation results accurately predict the initial non linear force-extension region of PE chain recently measured via single chain experiments. Finally, inspired by Cohen's extraction of Warner's force law from the inverse Langevin force law, a novel numerical scheme is developed to extract a new elastic force law for real chains from our discrete set of force-extension data similar to Pade expansion, which accurately depicts the initial non-linear region where the total Kuhn length is less than the thermal screening length. PMID- 26772587 TI - Depletion-induced forces and crowding in polymer-nanoparticle mixtures: Role of polymer shape fluctuations and penetrability. AB - Depletion forces and macromolecular crowding govern the structure and function of biopolymers in biological cells and the properties of polymer nanocomposite materials. To isolate and analyze the influence of polymer shape fluctuations and penetrability on depletion-induced interactions and crowding by nanoparticles, we model polymers as effective penetrable ellipsoids, whose shapes fluctuate according to the probability distributions of the eigenvalues of the gyration tensor of an ideal random walk. Within this model, we apply Monte Carlo simulation methods to compute the depletion-induced potential of mean force between hard nanospheres and crowding-induced shape distributions of polymers in the protein limit, in which polymer coils can be easily penetrated by smaller nanospheres. By comparing depletion potentials from simulations of ellipsoidal and spherical polymer models with predictions of polymer field theory and free volume theory, we show that polymer depletion-induced interactions and crowding depend sensitively on polymer shapes and penetrability, with important implications for bulk thermodynamic phase behavior. PMID- 26772588 TI - Comment on "Fe2: As simple as a Herculean labour. Neutral (Fe2), cationic (Fe2(+)), and anionic (Fe2(-)) species" [J. Chem. Phys. 142, 244304 (2015)]. AB - A recent paper on Fe2 [A. Kalemos, J. Chem. Phys. 142, 244304 (2015)] critiqued our previous work on the system [Hoyer et al., J. Chem. Phys. 141, 204309 (2014)]. In this comment, we explain the nature of our previously reported potential energy curve for Fe2 and we discuss our computed properties for Fe2. Additionally, we fix a labeling error that was present in our previous work, although this error is unrelated to the main point of discussion. PMID- 26772589 TI - Response to "Comment on 'Fe2: As simple as a Herculean labour. Neutral (Fe2), cationic (Fe2(+)), and anionic (Fe2(-)) species"' [J. Chem. Phys. 144, 027101 (2016)]. PMID- 26772590 TI - Erratum: "Compressible generalized hybrid Monte Carlo" [J. Chem. Phys. 140, 174108 (2014)]. PMID- 26772591 TI - A scoping review on determinants of unmet need for family planning among women of reproductive age in low and middle income countries. AB - BACKGROUND: Poor access and low contraceptive prevalence are common to many Low- and Middle-Income Countries (LMICs). Unmet need for family planning (FP), defined as the proportion of women wishing to limit or postpone child birth, but not using contraception, has been central to reproductive health efforts for decades and still remains relevant for most policy makers and FP programs in LMICs. There is still a lag in contraceptive uptake across regions resulting in high unmet need due to various socioeconomic and cultural factors. In this mixed method scoping review we analyzed quantitative, qualitative and mixed method studies to summarize those factors influencing unmet need among women in LMICs. METHODS: We conducted our scoping review by employing mixed method approach. We included studies applying quantitative and qualitative methods retrieved from online data bases (PubMed, JSTOR, and Google Scholar). We also reviewed the indexes of journals specific to the field of reproductive health by using a set of keywords related to unmet contraception need, and non-contraception use in LMICs. RESULTS: We retrieved 283 articles and retained 34 articles meeting our inclusion criteria. Of these, 26 were quantitative studies and 8 qualitative studies. We found unmet need for FP to range between 20 % and 58% in most studies. Woman's age was negatively associated with total unmet need for FP, meaning as women get older the unmet need for FP decreases. The number of children was found to be a positively associated determinant for a woman's total unmet need. Also, woman's level of education was negatively associated--as a woman's education improves, her total unmet need decreases. Frequently reported reasons for non-contraception use were opposition from husband or husbands fear of infidelity, as well as woman's fear of side effects or other health concerns related to contraceptive methods. CONCLUSION: Factors associated with unmet need for FP and non contraception use were common across different LMIC settings. This suggests that women in LMICs face similar barriers to FP and that it is still necessary for reproductive health programs to identify FP interventions that more specifically tackle unmet need. PMID- 26772593 TI - Mental Health Interventions in the Workplace and Work Outcomes: A Best-Evidence Synthesis of Systematic Reviews. AB - BACKGROUND: Mental health issues in the workplace are a growing concern among organizations and policymakers, but it remains unclear what interventions are effective in preventing mental health problems and their associated organizational consequences. This synthesis reports on workplace mental health interventions that impact absenteeism, productivity and financial outcomes. OBJECTIVE: To determine the level of evidence supporting mental health interventions as valuable to work outcomes. METHODS: Databases were searched for systematic reviews between 2000 and 2012: Medline, EMBASE, the Cochrane Database of Systematic Reviews, DARE, CINAHL, PsycINFO and TRIP. Grey literature searches included health-evidence.ca, Rehab+, National Rehabilitation Information Center (NARIC), and Institute for Work and Health. The assessment of articles for inclusion criteria and methodological quality was conducted independently by two or more researchers, with differences resolved through consensus. RESULTS: The search resulted in 3363 titles, of which 3248 were excluded following title/abstract review, with 115 articles retrieved for full-text review. 14 articles finally met the inclusion criteria and are summarized in this synthesis. CONCLUSION: There is moderate evidence for the effectiveness of workplace mental health interventions on improved workplace outcomes. Certain types of programs, such as those incorporating both mental and physical health interventions, multicomponent mental health and/or psychosocial interventions, and exposure in vivo containing interventions for particular anxiety disorders had a greater level of research evidence to support their effectiveness. PMID- 26772592 TI - 3DIANA: 3D Domain Interaction Analysis: A Toolbox for Quaternary Structure Modeling. AB - Electron microscopy (EM) is experiencing a revolution with the advent of a new generation of Direct Electron Detectors, enabling a broad range of large and flexible structures to be resolved well below 1 nm resolution. Although EM techniques are evolving to the point of directly obtaining structural data at near-atomic resolution, for many molecules the attainable resolution might not be enough to propose high-resolution structural models. However, accessing information on atomic coordinates is a necessary step toward a deeper understanding of the molecular mechanisms that allow proteins to perform specific tasks. For that reason, methods for the integration of EM three-dimensional maps with x-ray and NMR structural data are being developed, a modeling task that is normally referred to as fitting, resulting in the so called hybrid models. In this work, we present a novel application-3DIANA-specially targeted to those cases in which the EM map resolution is medium or low and additional experimental structural information is scarce or even lacking. In this way, 3DIANA statistically evaluates proposed/potential contacts between protein domains, presents a complete catalog of both structurally resolved and predicted interacting regions involving these domains and, finally, suggests structural templates to model the interaction between them. The evaluation of the proposed interactions is computed with DIMERO, a new method that scores physical binding sites based on the topology of protein interaction networks, which has recently shown the capability to increase by 200% the number of domain-domain interactions predicted in interactomes as compared to previous approaches. The new application displays the information at a sequence and structural level and is accessible through a web browser or as a Chimera plugin at http://3diana.cnb.csic.es. PMID- 26772594 TI - The Effect of Atorvastatin on Preventing Noise-Induced Hearing Loss: An Experimental Study. AB - BACKGROUND: Noise-induced hearing loss (NIHL) is a common, irreversible occupational disease. Statins have recently been proposed to prevent NIHL. OBJECTIVE: To assess the effect of atorvastatin for the prevention of NIHL in rats. METHODS: In this experimental study, forty 2-3-month-old Wistar male rats were divided into 5 groups of 8 animals. 3 groups of rats received atorvastatin at doses of 5, 25, and 50 mg/kg daily for 14 days. The 4th group of rats received normal saline; another group was the control group. After 2 weeks of treatment, the rats were exposed to broad-band noise (125-20 000 Hz) at 110 dB-SPL intensity for 2 hours. Response amplitude of all ears at 5 frequencies was assessed by distortion product otoacoustic emissions (DP-OAE) at baseline, 2 hours, and 2 weeks after the exposure. RESULTS: Response amplitude was significantly decreased at all frequencies immediately after exposure to noise in all studied groups. The amplitude increased after 72 hours to a level higher than temporary threshold shift (TTS); this change was only significant in the group received 5 mg/kg atorvastatin. CONCLUSION: Low dose atorvastatin (5 mg/kg) used before exposure to noise can probably prevent NIHL in rats. This effect was not observed with higher doses of the drug. PMID- 26772595 TI - Assessment of Health Systems and Services Including Availability of Components for Mental Health Care in Industries of Kolar District, India. AB - BACKGROUND: Non-communicable diseases (NCDs) and psychological hazards are increasingly observed in industries, necessitating the need to strengthen industrial health systems to control the same. District level data on level of functioning of industrial health systems and services with special focus on systems available for mental health care is lacking in India. This information is vital to plan need-based interventions for system strengthening. OBJECTIVE: To assess the status of functioning of industrial health systems and services in Kolar district, India, with special focus on systems and services available for mental health care. METHODS: This cross-sectional study was undertaken between October and December 2014 on a stratified random sample of 69 industries located in Kolar, which were stratified proportionately by their hazardous nature. Interview and observation checklist were used to assess and classify functioning of industrial health systems and services including those available for mental health care. RESULTS: Occupational safety and health (OSH) policy was present in 56% and health insurance in 39% of the 69 industries assessed. Pre-placement and periodical medical examination were conducted in 23% of industries. Health systems and services in hazardous industries were functioning at less than 50% level of functioning. Health systems and services for mental health care were non existent. CONCLUSION: There is a need in Kolar district, India, to integrate the mental health components within existing industrial health systems, as per policy directives to implement setting based approaches in mental health programs. PMID- 26772596 TI - Assessment of the Personal Losses Suffered by Correctional Officers due to Burnout Syndrome. AB - BACKGROUND: Professional burnout is defined as a state of depletion and loss of motivation accompanied by different mental and physical symptoms. OBJECTIVE: To assess personal losses suffered by correctional officers due to burnout. METHODS: This cross-sectional study conducted between June and December 2012 included 201 correctional officers in two Bulgarian prisons. The mean age of the whole group was 41.2 (SD 8.0) years. The respondents was mostly male (56.7%), married (72.6%), had a secondary educational level (61.7%), and 76.1% of them had been in current prison work over 5 years. RESULTS: The demographic characteristics had no influence on the occurrence of burnout but there was a correlation between level of burnout and the number of sick-leaves, the need for medical help, and the expenses spent on medications. Officers affected by burnout took more sick-leaves and this affected adversely their remuneration as they lost 3.1% of their annual wages. Their expenses spent on user fees for medical services were 3 times higher. Their monthly expenses spent on medications were 3.14 times higher than those of people without the burnout syndrome. CONCLUSION: The high level of burnout has a negative personal economic effect on the prison employees. PMID- 26772598 TI - Adjustment Disorder as an Occupational Disease: Our Experience in Italy. PMID- 26772597 TI - Genotoxicity following Organophosphate Pesticides Exposure among Orang Asli Children Living in an Agricultural Island in Kuala Langat, Selangor, Malaysia. AB - BACKGROUND: Agriculture is an important sector for the Malaysian economy. The use of pesticides in agriculture is crucial due to its function in keeping the crops from harmful insects. Children living near agricultural fields are at risk of pesticide poisoning. OBJECTIVE: To evaluate the genotoxic risk among children who exposed to pesticides and measure DNA damage due to pesticides exposure. METHODS: In a cross-sectional study 180 Orang Asli Mah Meri children aged between 7 and 12 years were studied. They were all living in an agricultural island in Kuala Langat, Selangor, Malaysia. The data for this study were collected via modified validated questionnaire and food frequency questionnaire, which consisted of 131 food items. 6 urinary organophosphate metabolites were used as biomarkers for pesticides exposure. For genotoxic risk or genetic damage assessment, the level of DNA damage from exfoliated buccal mucosa cells was measured using the comet assay electrophoresis method. RESULTS: Out of 180 respondents, 84 (46.7%) showed positive traces of organophosphate metabolites in their urine. Children with detectable urinary pesticide had a longer tail length (median 43.5; IQR 30.9 to 68.1 MUm) than those with undetectable urinary pesticides (median 24.7; IQR 9.5 to 48.1 MUm). There was a significant association between the extent of DNA damage and the children's age, length of residence in the area, pesticides detection, and frequency of apple consumption. CONCLUSION: The organophosphate genotoxicity among children is associated with the amount of exposure (detectability of urinary pesticide) and length of residence in (exposure) the study area. PMID- 26772599 TI - Serum Neuron-Specific Enolase in Lead-Exposed Individuals. PMID- 26772601 TI - From positive screen to engagement in treatment: a preliminary study of the impact of a new model of care for prisoners with serious mental illness. AB - BACKGROUND: The high prevalence of serious mental illness (SMI) in prisons remains a challenge for mental health services. Many prisoners with SMI do not receive care. Screening tools have been developed but better detection has not translated to higher rates of treatment. In New Zealand a Prison Model of Care (PMOC) was developed by forensic mental health and correctional services to address this challenge. The PMOC broadened triggers for referrals to mental health teams. Referrals were triaged by mental health nurses leading to multidisciplinary team assessment within specified timeframes. This pathway for screening, referral and assessment was introduced within existing resources. METHOD: The PMOC was implemented across four prisons. An AB research design was used to explore the extent to which mentally ill prisoners were referred to and accepted by prison in-reach mental health teams and to determine the proportion of prison population receiving specialist mental health care. RESULTS: The number of prisoners in the study in the year before the PMOC (n = 9,349) was similar to the year after (n = 19,421). 24.6 % of prisoners were screened as per the PMOC in the post period. Referrals increased from 491 to 734 in the post period (Z = 7.23, p < 0.0001). A greater number of triage assessments occurred after the introduction of the PMOC (pre = 458; post = 613, Z = 4.74, p < 0.0001) leading to a significant increase in the numbers accepted onto in-reach caseloads (pre = 338; post = 426, Z = 3.16, p < 0.01). Numbers of triage assessments completed within specified time frames showed no statistically significant difference before or after implementation. The proportion of prison population on in-reach caseloads increased from 5.6 % in the pre period to 7.0 % in the year post implementation while diagnostic patterns did not change, indicating more prisoners with SMI were identified and engaged in treatment. CONCLUSIONS: The PMOC led to increased prisoner numbers across screening, referral, treatment and engagement. Gains were achieved without extra resources by consistent processes and improved clarity of professional roles and tasks. The PMOC described a more effective pathway to specialist care for people with SMI entering prison. PMID- 26772600 TI - mTORC2 sustains thermogenesis via Akt-induced glucose uptake and glycolysis in brown adipose tissue. AB - Activation of non-shivering thermogenesis (NST) in brown adipose tissue (BAT) has been proposed as an anti-obesity treatment. Moreover, cold-induced glucose uptake could normalize blood glucose levels in insulin-resistant patients. It is therefore important to identify novel regulators of NST and cold-induced glucose uptake. Mammalian target of rapamycin complex 2 (mTORC2) mediates insulin stimulated glucose uptake in metabolic tissues, but its role in NST is unknown. We show that mTORC2 is activated in brown adipocytes upon beta-adrenergic stimulation. Furthermore, mice lacking mTORC2 specifically in adipose tissue (AdRiKO mice) are hypothermic, display increased sensitivity to cold, and show impaired cold-induced glucose uptake and glycolysis. Restoration of glucose uptake in BAT by overexpression of hexokinase II or activated Akt2 was sufficient to increase body temperature and improve cold tolerance in AdRiKO mice. Thus, mTORC2 in BAT mediates temperature homeostasis via regulation of cold-induced glucose uptake. Our findings demonstrate the importance of glucose metabolism in temperature regulation. PMID- 26772602 TI - High-Efficient Transfection of Human Embryonic Stem Cells by Single-Cell Plating and Starvation. AB - Nowadays, the low efficiency of small interfering RNA (siRNA) or plasmid DNA (pDNA) transfection is a critical issue in genetic manipulation of human embryonic stem (hES) cells. Development of an efficient transfection method for delivery of siRNAs and plasmids into hES cells becomes more and more imperative. In this study, we tried to modify the traditional transfection protocol by introducing two crucial processes, single-cell plating and starvation, to increase the transfection efficiency in hES cells. Furthermore, we comparatively examined the transfection efficiency of some commercially available siRNA or pDNA transfection reagents in hES cells. Our results showed that the new developed method markedly enhanced the transfection efficiency without influencing the proliferation and pluripotency of hES cells. Lipofectamine RNAiMAX exhibited much higher siRNA transfection efficiency than the other reagents, and FuGENE HD was identified as the best suitable reagent for efficient pDNA transfection of hES cells among the tested reagents. PMID- 26772603 TI - Papillary fibroelastoma of the aortic valve in association with rheumatic heart disease: a case report. AB - BACKGROUND: Papillary fibroelastoma (PFE) is a rare primary cardiac neoplasm that is usually discovered incidentally at autopsy or during cardiac surgery. PFE combined with rheumatic heart disease (RHD) is extremely rare, and only a few cases have been reported. Additionally, the growth rate of the tumor is unknown. CASE PRESENTATION: Here, we present a very rare case of PFE of the aortic valve combined with RHD, which were identified in a female patient who survived for 5 years without surgical intervention, and who subsequently underwent successful surgical treatment. CONCLUSIONS: PFEs may be generally slow-growing tumors, however, the better treatment of choice may be surgery because it produces good curative effects with very low risk of complications, while preventing serious disease consequences. PMID- 26772604 TI - The association of serum procalcitonin and high-sensitivity C-reactive protein with pneumonia in elderly multimorbid patients with respiratory symptoms: retrospective cohort study. AB - BACKGROUND: Serum procalcitonin and high-sensitivity C-reactive protein (hs-CRP) elevations have been associated with pneumonia in adults. Our aim was to establish their diagnostic usefulness in a cohort of hospitalized multimorbid patients >=65 years old admitted to hospital with acute respiratory symptoms. METHODS: With a retrospective cohort study design, all multimorbid patients >=65 years-old with acute respiratory symptoms admitted to an internal medicine hospital ward in Italy from January to August 2013 were evaluated. Pneumonia diagnosis, comorbidities expressed through Cumulative Illness Rating Scale (CIRS), setting of living, length of stay, serum hs-CRP and procalcitonin at admission were collected for each patient. Data were analyzed with Mann-Whitney's U test and multivariate Cox logistic regression analysis. A Receiver Operating Characteristic (ROC) curve was used to verify each biomarker's association with pneumonia diagnosis. RESULTS: Four hundred fifty five patients (227 M) were included in the study, of whom 239 with pneumonia (138 M, mean age 80 +/- 13) and 216 without pneumonia (89 M, mean age 80 +/- 14). After adjustment for age and sex, median levels of hs-CRP were significantly higher in patients with pneumonia (116 mg/L, IQR 46.5-179.0, vs 22.5 mg/dl, IQR 6.9-84.4, p < 0.0001), while procalcitonin median levels were not (0.22 ng/ml IQR 0.12-0.87, vs 0.15 ng/ml, IQR 0.10-0.35, p = 0.08). The ROC analysis showed that, unlike procalcitonin, hs CRP values were predictive of pneumonia (AUC 0.76, 95% CI 0.72-0.79, p < 0.0001, cut-off value 61 mg/L), even after adjustment for possible confounders including nursing home residence and dementia. Serum hs-CRP levels >61 mg/L were independently associated with a 3.59-fold increased risk of pneumonia (OR 3.59, 95% CI 2.35-5.48, p < 0.0001). CONCLUSION: In elderly multimorbid patients who require hospital admission for respiratory symptoms, serum hs-CRP testing seems to be more useful than procalcitonin for guiding the diagnostic process when clinical suspicion of pneumonia is present. Procalcitonin testing might hence be not recommended in this setting. PMID- 26772605 TI - Time Sharing Between Robotics and Process Control: Validating a Model of Attention Switching. AB - OBJECTIVE: The aim of this study was to validate the strategic task overload management (STOM) model that predicts task switching when concurrence is impossible. BACKGROUND: The STOM model predicts that in overload, tasks will be switched to, to the extent that they are attractive on task attributes of high priority, interest, and salience and low difficulty. But more-difficult tasks are less likely to be switched away from once they are being performed. METHOD: In Experiment 1, participants performed four tasks of the Multi-Attribute Task Battery and provided task-switching data to inform the role of difficulty and priority. In Experiment 2, participants concurrently performed an environmental control task and a robotic arm simulation. Workload was varied by automation of arm movement and both the phases of environmental control and existence of decision support for fault management. Attention to the two tasks was measured using a head tracker. RESULTS: Experiment 1 revealed the lack of influence of task priority and confirmed the differing roles of task difficulty. In Experiment 2, the percentage attention allocation across the eight conditions was predicted by the STOM model when participants rated the four attributes. Model predictions were compared against empirical data and accounted for over 95% of variance in task allocation. More-difficult tasks were performed longer than easier tasks. Task priority does not influence allocation. CONCLUSIONS: The multiattribute decision model provided a good fit to the data. APPLICATIONS: The STOM model is useful for predicting cognitive tunneling given that human-in-the-loop simulation is time-consuming and expensive. PMID- 26772606 TI - Rating the quality of evidence is by necessity a matter of judgment. PMID- 26772607 TI - Current use was established and Cochrane guidance on selection of social theories for systematic reviews of complex interventions was developed. AB - OBJECTIVE: To identify examples of how social theories are used in systematic reviews of complex interventions to inform production of Cochrane guidance. STUDY DESIGN AND SETTING: Secondary analysis of published/unpublished examples of theories of social phenomena for use in reviews of complex interventions identified through scoping searches, engagement with key authors and methodologists supplemented by snowballing and reference searching. Theories were classified (low-level, mid-range, grand). RESULTS: Over 100 theories were identified with evidence of proliferation over the last 5 years. New low-level theories (tools, taxonomies, etc) have been developed for classifying and reporting complex interventions. Numerous mid-range theories are used; one example demonstrated how control theory had changed the review's findings. Review specific logic models are increasingly used, but these can be challenging to develop. New low-level and mid-range psychological theories of behavior change are evolving. No reviews using grand theory (e.g., feminist theory) were identified. We produced a searchable Wiki, Mendeley Inventory, and Cochrane guidance. CONCLUSIONS: Use of low-level theory is common and evolving; incorporation of mid-range theory is still the exception rather than the norm. Methodological work is needed to evaluate the contribution of theory. Choice of theory reflects personal preference; application of theory is a skilled endeavor. PMID- 26772608 TI - A calibration hierarchy for risk models was defined: from utopia to empirical data. AB - OBJECTIVE: Calibrated risk models are vital for valid decision support. We define four levels of calibration and describe implications for model development and external validation of predictions. STUDY DESIGN AND SETTING: We present results based on simulated data sets. RESULTS: A common definition of calibration is "having an event rate of R% among patients with a predicted risk of R%," which we refer to as "moderate calibration." Weaker forms of calibration only require the average predicted risk (mean calibration) or the average prediction effects (weak calibration) to be correct. "Strong calibration" requires that the event rate equals the predicted risk for every covariate pattern. This implies that the model is fully correct for the validation setting. We argue that this is unrealistic: the model type may be incorrect, the linear predictor is only asymptotically unbiased, and all nonlinear and interaction effects should be correctly modeled. In addition, we prove that moderate calibration guarantees nonharmful decision making. Finally, results indicate that a flexible assessment of calibration in small validation data sets is problematic. CONCLUSION: Strong calibration is desirable for individualized decision support but unrealistic and counter productive by stimulating the development of overly complex models. Model development and external validation should focus on moderate calibration. PMID- 26772609 TI - A guide for health professionals to interpret and use recommendations in guidelines developed with the GRADE approach. AB - An increasing number of organizations worldwide are using new and improved standards for developing trustworthy clinical guidelines. One of such approaches, developed by the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) working group, offers systematic and transparent guidance in moving from evidence to recommendations. The GRADE strategy concentrates on four factors: the balance between benefits and harms, the certainty of the evidence, values and preferences, and resource considerations. However, it also considers issues around feasibility, equity, and acceptability of recommendations. GRADE distinguishes two types of recommendations: strong and weak. Strong recommendations reflect a clear preference for one alternative and should apply to all or almost all patients, obviating the need for a careful review of the evidence with each patient. Weak recommendations are appropriate when there is a close balance between desirable and undesirable consequences of alternative management strategies, uncertainty regarding the effects of the alternatives, uncertainty or variability in patients' values and preferences, or questionable cost-effectiveness. Weak recommendations usually require accessing the underlying evidence and a shared decision-making approach. Clinicians using GRADE recommendations should understand the meaning of the strength of the recommendation, be able to critically appraise the recommendation, and apply trustworthy recommendations according to their strength. PMID- 26772610 TI - NHS organ registry considers new way to stop families over-ruling relatives' wish to donate. PMID- 26772612 TI - Long Receptor Residence Time of C26 Contributes to Super Agonist Activity at the Human beta2 Adrenoceptor. AB - Super agonists produce greater functional responses than endogenous agonists in the same assay, and their unique pharmacology is the subject of increasing interest and debate. We propose that receptor residence time and the duration of receptor signaling contribute to the pharmacology of super agonism. We have further characterized the novel beta2 adrenoceptor agonist C26 (7-[(R)-2-((1R,2R) 2-benzyloxycyclopentylamino)-1-hydroxyethyl]-4-hydroxybenzothiazolone), which displays higher intrinsic activity than the endogenous ligand adrenaline in cAMP accumulation, beta-arrestin-2 recruitment, and receptor internalization assays. C26 recruited beta-arrestin-2, and internalized the Green Fluorescent Protein (GFP)-taggedbeta2 adrenoceptor at a slow rate, with half-life (t1/2) values of 0.78 +/- 0.1 and 0.78 +/- 0.04 hours, respectively. This was compared with 0.31 +/- 0.04 and 0.34 +/- 0.01 hours for adrenaline-mediated beta-arrestin-2 recruitment and GFP-beta2 internalization, respectively. The slower rate for C26 resulted in levels of beta-arrestin-2 recruitment increasing up to 4-hour agonist incubation, at which point the intrinsic activity was determined to be 124.3 +/- 0.77% of the adrenaline response. In addition to slow functional kinetics, C26 displayed high affinity with extremely slow receptor dissociation kinetics, giving a receptor residence half-life of 32.7 minutes at 37 degrees C, which represents the slowest dissociation rate we have observed for any beta2 adrenoceptor agonist tested to date. In conclusion, we propose that the gradual accumulation of long-lived active receptor complexes contributes to the increased intrinsic activity of C26 over time. This highlights the need to consider the temporal aspects of agonist binding and signaling when characterizing ligands as super agonists. PMID- 26772611 TI - Risk of Secondary Injury in Younger Athletes After Anterior Cruciate Ligament Reconstruction: A Systematic Review and Meta-analysis. AB - BACKGROUND: Injury to the ipsilateral graft used for reconstruction of the anterior cruciate ligament (ACL) or a new injury to the contralateral ACL are disastrous outcomes after successful ACL reconstruction (ACLR), rehabilitation, and return to activity. Studies reporting ACL reinjury rates in younger active populations are emerging in the literature, but these data have not yet been comprehensively synthesized. PURPOSE: To provide a current review of the literature to evaluate age and activity level as the primary risk factors in reinjury after ACLR. STUDY DESIGN: Systematic review and meta-analysis. METHODS: A systematic review of the literature was conducted via searches in PubMed (1966 to July 2015) and EBSCO host (CINAHL, Medline, SPORTDiscus [1987 to July 2015]). After the search and consultation with experts and rating of study quality, 19 articles met inclusion for review and aggregation. Population demographic data and total reinjury (ipsilateral and contralateral) rate data were recorded from each individual study and combined using random-effects meta-analyses. Separate meta-analyses were conducted for the total population data as well as the following subsets: young age, return to sport, and young age + return to sport. RESULTS: Overall, the total second ACL reinjury rate was 15%, with an ipsilateral reinjury rate of 7% and contralateral injury rate of 8%. The secondary ACL injury rate (ipsilateral + contralateral) for patients younger than 25 years was 21%. The secondary ACL injury rate for athletes who return to a sport was also 20%. Combining these risk factors, athletes younger than 25 years who return to sport have a secondary ACL injury rate of 23%. CONCLUSION: This systematic review and meta-analysis demonstrates that younger age and a return to high level of activity are salient factors associated with secondary ACL injury. These combined data indicate that nearly 1 in 4 young athletic patients who sustain an ACL injury and return to high-risk sport will go on to sustain another ACL injury at some point in their career, and they will likely sustain it early in the return to-play period. The high rate of secondary injury in young athletes who return to sport after ACLR equates to a 30 to 40 times greater risk of an ACL injury compared with uninjured adolescents. These data indicate that activity modification, improved rehabilitation and return-to-play guidelines, and the use of integrative neuromuscular training may help athletes more safely reintegrate into sport and reduce second injury in this at-risk population. PMID- 26772614 TI - Corrigendum. AB - Volume 309, September 1, 2015. Williams JA, Ni HM, Ding Y, Ding WX. Parkin regulates mitophagy and mitochondrial function to protect against alcohol-induced liver injury and steatosis in mice. Am J Physiol Gastrointest Liver Physiol 309: G324-G340, 2015. First published July 9, 2015; doi:10.1152/ajpgi.00108.2015.Panels E and F of Fig. 3 were inadvertently omitted from this article as originally published. The corrected figure is as follows. PMID- 26772613 TI - Perspectives and experiences of new migrants on health screening in Sweden. AB - BACKGROUND: In Sweden, migrants from countries considered to have a high burden of certain infectious diseases are offered health screening to prevent the spread of these diseases, but also identify their health needs. However, very little is known about their experiences and perceptions about the screening process. This study aimed at exploring these perceptions and experiences in order to inform policy and clinical practice. METHOD: Using an interpretive description framework, 26 new migrants were interviewed between April and June 2013 in four Swedish counties. Thematic analysis was used to analyze data. RESULTS: The three themes developed include: new country, new practices; new requirements in the new country; and unmet needs and expectations. Participants described what it meant for them to come to a new country with a foreign language, new ways of communicating with caregivers/authorities and being offered health screening without clarification. Participants perceived health screening as a requirement from the authorities to be fulfilled by all newcomers but conceded that it benefits equally the host society and themselves. However, they also expressed concern over the involvement of the Migration Board staff and feared possible collaboration with health service to their detriment. They further stated that the screening program fell short of their expectations as it mainly focused on identifying infectious diseases and overlooked their actual health needs. Finally, they expressed frustration over delay in screening, poor living conditions in reception centers and the restrictive entitlement to care. CONCLUSIONS: Migrants are aware of their vulnerability and the need to undergo health screening though they view it as an official requirement. Thus, those who underwent the screening were more concerned about residency rather than the actual benefits of screening. The issues highlighted in this study may limit access to and uptake of the screening service, and compromise its effectiveness. To maximize the uptake: (1) linguistically and culturally adapted information is needed, (2) other screening approaches should be tried, (3) trained medical interpreters should be used, (4) a holistic and human right approach should be applied, (5) the involvement of migration staff should be reconsidered to avoid confusion and worries. Finally, to improve the effectiveness, (6) all migrants from targeted countries should be offered screening and efforts should be taken to improve the health literacy of migrants and the living conditions in reception centers. PMID- 26772616 TI - Doctors condemn closures at Sudanese teaching hospital. PMID- 26772615 TI - Down regulation of miR-18a, miR-21 and miR-221 genes in gastric cancer cell line by chrysin-loaded PLGA-PEG nanoparticles. AB - Chrysin were well-documented as having significant biological roles particularly cancer chemo-preventive activity. However, the poor water solubility of chrysin limited their bioavailability and biomedical applications. In this study, we encapsulate the chrysin into PLGA-PEG nanoparticles for local treatment. In regard to the amount of the drug load, IC50 was significant decreased in nanocapsulated chrysin in comparison with free chrysin. This was confirmed through decrease of miR-18a, miR-21, and miR-221 genes expression by real-time PCR. The results demonstrated that PLGA-PEG-chrysin complexes can be more effective than free chrysin. Therefore, PLGA-PEG can be a better nanocarrier for this kind of hydrophobic flavonoid. PMID- 26772618 TI - Spinal intradural metastasis via the brachial plexus. PMID- 26772619 TI - Pedicle thinning finding on X-ray imaging of the lumbar spine: a case of spinal conus dermoid cyst. PMID- 26772617 TI - Statistical considerations for a chronic bioassay study: Exposure to Decamethylcyclopentasiloxane (D5) and incidence of uterine endometrial adenocarcinomas in a 2-year inhalation study with Fischer rats. AB - Decamethylcyclopentasiloxane (D5) is a cyclic siloxane used in the production of industrial and consumer products. Four groups of 60 Fischer-344 female rats were analyzed for uterine endometrial adenocarcinoma (inhalation study with exposure levels in ppm/number of observed cases: 0/0, 10/1, 40/0, and 160/5) by exact regression (logistic, Poisson), the max poly-3 trend test, and a random effects probit model. When comparing the 160 ppm group to controls after 24 months, the incidence of adenocarcinomas was elevated (borderline significant); it was significant when all exposure levels were included. Four sets of (historical) control groups were formed, with varying heterogeneity. The effect of D5 was either significant or borderline significant when comparing all control sets to the 160 ppm group. When considering all exposure groups using any of the analysis methods, a significant effect was observed when the high dose group was included in the analysis; the effect was not significant when the high dose group was not included. The evidence tends to support the conclusion that D5 at the highest dose level (160 ppm) results in an increased incidence of adenocarcinomas. However, it is important to verify any potential effect through a biological investigation. PMID- 26772620 TI - Development of a molecular test of Paget's disease of bone. AB - Depending on populations, 15 to 40% of patients have a familial form of Paget's disease of bone (PDB), which is transmitted in an autosomal-dominant mode of inheritance with incomplete penetrance. To date, only SQSTM1 gene mutations have been linked to the disease. Several single nucleotide polymorphisms (SNPs) have been associated with PDB in patient non-carriers of SQSTM1 mutations, but they have minor size effects. The current clinical practice guidelines still recommend to measure total serum alkaline phosphatase (sALP) for PDB screening. However, genetic or bone biomarkers alone may lack sensitivity to detect PDB. Thus, the objective of this study was to develop a molecular test of PDB, combining genetic and bone biomarkers, in order to detect PDB, which is frequently asymptomatic. We genotyped 35 SNPs previously associated with PDB in 305 patients, and 292 healthy controls. In addition, serum levels of 14 bone biomarkers were assayed in 51 patients and 151 healthy controls. Bivariate and multivariate logistic regression models with adjustment for age and sex were fitted to search for a combination of SNPs and/or bone biomarkers that could best detect PDB in patient non-carriers of SQSTM1 mutations. First, a combination of five genetic markers gave rise to the highest area under the ROC curve (AUC) with 95% confidence interval [95% CI] of 0.731 [0.688; 0.773], which allowed us to detect 81.5% of patients with PDB. Second, a combination of two bone biomarkers had an AUC of 0.822 [0.726; 0.918], and was present in 81.5% of patients with PDB. Then, the combination of the five genetic markers and the two bone biomarkers increased the AUC up to 0.892 [0.833; 0.951], and detected 88.5% of patients with PDB. These results suggested that an algorithm integrating first a screen for SQSTM1 gene mutations, followed by either a genetic markers combination or a combined genetic and biochemical markers test in patients non-carrier of any SQSTM1 mutation, may detect the PDB phenotype better than biomarkers already available in the clinical practice. PMID- 26772621 TI - Different osteocalcin forms, markers of metabolic syndrome and anthropometric measures in children within the IDEFICS cohort. AB - OBJECTIVE: Osteocalcin (OC), an aboundant non-collagenous bone protein, is inversely associated with parameters of glucose metabolism. Interactions between bone tissue and energy metabolism have not been thoroughly investigated during childhood. This study investigated OC, metabolic parameters and anthropometric characteristics in normal weight and overweight/obese children. METHODS: This study comprised 108 (46 normal weight/62 overweight/obese) Swedish 2-9year old children. Anthropometric data, insulin, glucose, glycosylated haemoglobin (HbA1c), HOMA index, vitamin D, adiponectin, total OC, carboxylated OC (cOC) and undercarboxylated OC (ucOC) were analysed. RESULTS: No difference was found for total OC between the normal and overweight/obese groups, with a mean (+/-SD) value of 82.6 (+/-2.8) ng/mL and 77.0 (+/-2.4) ng/mL, (P=0.11), respectively. Overweight children had lower cOC levels, mean 69.1 (+/-2.2) ng/mL, vs. normal weight children, mean 75.6 (+/-2.5) ng/mL (P=0.03). The mean ucOC levels of 7.9 (+/-0.4) ng/mL in overweight children did not differ vs. normal weight children, mean level 7.0 (+/-0.4) ng/mL, (P=0.067). None of the three OC forms correlated with any of the measured parameters. CONCLUSIONS: The cOC levels were lower in overweight children. There was no correlation between the three OC forms and any of the measured anthropometric or metabolic parameters. OC has been suggested to have a possible metabolic role, but in general the current study in prepubertal children does not support the hypothesis of an association between OC and a positive metabolic profile. PMID- 26772622 TI - Dynamics of Cytosine Methylation in the Proximal Promoters of CYP3A4 and CYP3A7 in Pediatric and Prenatal Livers. AB - Members of the human CYP3A family of metabolizing enzymes exhibit developmental changes in expression whereby CYP3A7 is expressed in fetal tissues, followed by a transition to expression of CYP3A4 in the first months of life. Despite knowledge about the general pattern of CYP3A activity in human development, the mechanisms that regulate developmental expression remain poorly understood. Epigenetic changes, including cytosine methylation, have been suggested to play a role in the regulation of CYP3A expression. The objective of this study was to investigate changes in cytosine methylation of the CYP3A4 and CYP3A7 genes in human pediatric and prenatal livers. The methylation status of cytosine-phospho guanine dinucleotides was determined in 16 pediatric liver samples using methyl seq and confirmed by bisulfite sequencing of 48 pediatric and 34 prenatal liver samples. Samples were separated by age into five groups (prenatal, < 1 year of age, 1.8-6 years, 7-11 years, and 12-17 years). Methyl-seq anaylsis revealed that cytosines in the proximal promoter of CYP3A7 are hypomethylated in neonates compared with adolescents (P < 0.001). In contrast, a cytosine 383 base pair upstream of CYP3A4 is hypermethylated in liver samples from neonates compared with adolescents (P = 0.00001). Developmental changes in methylation of cytosines in the proximal promoters of CYP3A4 and CYP3A7 in pediatric livers were confirmed by bisulfite sequencing. In addition, the methylation status of cytosine in the CYP3A4 and CYP3A7 proximal promoters correlated with changes in developmental expression of mRNA for the two enzymes. PMID- 26772623 TI - The Role of Technology in Chronic Disease Care. AB - Chronic disease represents the epidemic of our time, present in half the adult population and responsible for 86% of United States (US) healthcare costs and 70% of deaths. The major chronic diseases are primarily due to health risk behaviors that are widely communicable across populations. As a nation, the US has performed poorly in managing chronic disease, in large part because of a failed delivery model of care. New opportunities exist as a result of recent advances in home-based wireless devices, apps and wearables, enabling health delivery systems to monitor disease metrics in near real time. These technologies provide a framework for patient engagement and a new model of care delivery utilizing integrated practice units, both of which are needed to navigate the healthcare needs of the 21st century. PMID- 26772624 TI - Rationale and study protocol for the Nursing Home Compare Plus (NHCPlus) randomized controlled trial: A personalized decision aid for patients transitioning from the hospital to a skilled-nursing facility. AB - BACKGROUND: Annually more than 3 million people are admitted to one of the 15,965 skilled nursing facilities (SNFs) in the United States, with 90% of admissions occurring from a hospital. Although the Centers for Medicare and Medicaid Services (CMS) publishes several internet-based report cards, including one for nursing homes (Nursing Home Compare, NHC), they are not widely used. This is due, in part, to the complexity of the information available and the fact that the choice of nursing homes is typically made while in the hospital without access to the web-based NHC. We developed Nursing Home Compare Plus (NHCPlus) to address these limitations and to improve the decision-making process. METHODS/DESIGN: This paper describes the design and rationale of a two-arm randomized controlled trial designed to test the effectiveness of NHCPlus compared to usual care only, in a sample of patients being discharged from the hospital to an SNF (N=229). Assessments were conducted within 24h prior to patient discharge and 30-days post discharge. Primary outcomes to be examined included the use of NHC, increased choice of nursing homes with better reported outcomes, and increased distance between patient/family residence and nursing home. Secondary outcomes included satisfaction with the decision to go to a nursing home, confidence in the choice of nursing home, and reduced hospital length of stay. DISCUSSION: NHCPlus is an innovative mobile application designed to allow patients to personalize their choice of nursing homes to meet their medical needs and preferences. The application to other quality report cards is discussed. PMID- 26772625 TI - Serotonin receptor antagonists increase fast ripple activity in rats treated with kainic acid. AB - Fast ripples (FR, 250-600 Hz) are field potentials that occur only in those areas capable of generating seizures, such as the hippocampus, and modulation of FR by serotonin has been reported. Therefore, we hypothesized that the receptor antagonists 5HT1A and 5HT2A, B, C will increase FR in rats treated with kainic acid (KA, 0.8 MUg/0.5 MUl). For this purpose, the intracranial EEG recordings of the hippocampus from animals treated with KA and the serotonin antagonists WAY100135 and ritanserin (dose 0.2mg/Kg, i.p) were analyzed. In addition, morphologic parameters were analyzed after staining samples with cresyl violet, Timm stain, NeuN and GFAP and observing immunofluorescence. The results showed an increase in the number of events of FR (p<0.0001) and duration of each FR event after the administration of WAY100135 (p<0.030). Additionally, there was an increase in the number of events of FR (p<0.0001) and amplitude of FR after ritanserin administration (p<0.014). In relation to changes in unspecified cells, there was a significant decrement in the width of the CA3 pyramidal layer of the hippocampus (p<0.001), and there were no significant changes in reactive glia and fiber sprouting. However, a slight gain of astrocytes marked with GFAP and larger astrocytes with more projections were observed. In conclusion, these results support the modulation of FR by serotonin with participation of the 5HT1A receptor as a possible mediator of the effect. However the exact mechanisms resulting in such effect is not known. PMID- 26772627 TI - Preconditioning of H2S inhalation protects against cerebral ischemia/reperfusion injury by induction of HSP70 through PI3K/Akt/Nrf2 pathway. AB - It is of great importance to protect the brain against cerebral ischemia and reperfusion (I/R) injury, which leads to excitotoxicity, redox imbalance, inflammation and apoptosis; however, there is currently no effective treatment. The present study aimed to investigate the effect of H2S preconditioning on cerebral I/R injury and its underlying mechanism. The results demonstrated that H2S preconditioning significantly prevented the development of neurological function abnormality, inflammation and oxidative injury in mice as well as cognitive impairment caused by cerebral I/R. H2S preconditioning also suppressed the apoptosis caused by cerebral I/R. Moreover, the protective effect of H2S preconditioning was found to involve heat shock protein 70 (HSP70), in which the PI3K/Akt/Nrf2 pathway was involved. The data showed that H2S preconditioning could protect mice against cerebral I/R injury by the induction of HSP70 and the PI3K/Akt/Nrf2 pathway. PMID- 26772626 TI - Involvement of BDNF/ERK signaling in spontaneous recovery from trimethyltin induced hippocampal neurotoxicity in mice. AB - Trimethyltin (TMT) toxicity causes histopathological damage in the hippocampus and induces seizure behaviors in mice. The lesions and symptoms recover spontaneously over time; however, little is known about the precise mechanisms underlying this recovery from TMT toxicity. We investigated changes in the brain derived neurotrophic factor/extracellular signal-regulated kinases (BDNF/ERK) signaling pathways in the mouse hippocampus following TMT toxicity. Mice (7 weeks old, C57BL/6) administered TMT (2.6 mg/kg intraperitoneally) showed acute and severe neurodegeneration with increased TUNEL-positive cells in the dentate gyrus (DG) of the hippocampus. The mRNA and protein levels of BDNF in the hippocampus were elevated by TMT treatment. Immunohistochemical analysis showed that TMT treatment markedly increased phosphorylated ERK1/2 expression in the mouse hippocampus 1-4 days after TMT treatment, although the intensity of ERK immunoreactivity in mossy fiber decreased at 1-8 days post-treatment. In addition, ERK-immunopositive cells were localized predominantly in doublecortin positive immature progenitor neurons in the DG. In primary cultured immature hippocampal neurons (4 days in vitro), BDNF treatment alleviated TMT-induced neurotoxicity, via activation of the ERK signaling pathway. Thus, we suggest that BDNF/ERK signaling pathways may be associated with cell differentiation and survival of immature progenitor neurons, and will eventually lead to spontaneous recovery in TMT-induced hippocampal neurodegeneration. PMID- 26772628 TI - Protective effects of aloin on oxygen and glucose deprivation-induced injury in PC12 cells. AB - The present study aims to determine whether aloin could protect cells from ischemic and reperfusion injury in vitro and to elucidate the related mechanisms. Oxygen and glucose deprivation model in PC12 cells was used in the present study. 2-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), lactate dehydrogenase (LDH) assay and Hoechst 33342 nuclear staining were used to evaluate the protective effects of aloin, at concentrations of 10, 20, or 40 MUg/mL in PC12 cells. PCR was applied to detect fluorescence caspase-3, Bax and Bcl-2 mRNA expression in PC12 cells. The contents of malondialdehyde (MDA), superoxide dismutase (SOD) activity were evaluated by biochemical method. The concentration of intracellular-free calcium [Ca(2+)]i, mitochondrial membrane potential (MMP) were determined to estimate the degree of neuronal damage. It was shown that aloin (10, 20, and 40 MUg/mL) significantly attenuated PC12 cells damage with characteristics of an increased injured cells absorbance of MTT and releases of LDH, decreasing cell apoptosis, and antagonizing decreases in SOD activity and increase in MDA level induced by OGD-reoxygenation. Meanwhile pretreatment with aloin significantly reduced injury-induced intracellular ROS, increased MMP (P<0.01), but it inhibited [Ca(2+)]i (P<0.01) elevation in a dose dependent manner. Furthermore, pre-treatment with aloin significantly up regulated Bcl-2 mRNA expression, down-regulated Bax mRNA expression and consequently activated caspase-3 mRNA expression in a dose-dependent manner. The results indicated that the protection of aloin on OGD-induced apoptosis in PC12 cells is associated with its suppression on OGD-induced oxidative stress and protection on mitochondrial function and inhibition of caspase activity. Alion could be a promising candidate in the development of a novel class of anti ischemic agent. PMID- 26772629 TI - Influence of the cortical midline structures on moral emotion and motivation in moral decision-making. AB - The present study aims to examine the relationship between the cortical midline structures (CMS), which have been regarded to be associated with selfhood, and moral decision making processes at the neural level. Traditional moral psychological studies have suggested the role of moral self as the moderator of moral cognition, so activity of moral self would present at the neural level. The present study examined the interaction between the CMS and other moral-related regions by conducting psycho-physiological interaction analysis of functional images acquired while 16 subjects were solving moral dilemmas. Furthermore, we performed Granger causality analysis to demonstrate the direction of influences between activities in the regions in moral decision-making. We first demonstrate there are significant positive interactions between two central CMS seed regions i.e., the medial prefrontal cortex (MPFC) and posterior cingulate cortex (PCC) and brain regions associated with moral functioning including the cerebellum, brainstem, midbrain, dorsolateral prefrontal cortex, orbitofrontal cortex and anterior insula (AI); on the other hand, the posterior insula (PI) showed significant negative interaction with the seed regions. Second, several significant Granger causality was found from CMS to insula regions particularly under the moral-personal condition. Furthermore, significant dominant influence from the AI to PI was reported. Moral psychological implications of these findings are discussed. The present study demonstrated the significant interaction and influence between the CMS and morality-related regions while subject were solving moral dilemmas. Given that, activity in the CMS is significantly involved in human moral functioning. PMID- 26772630 TI - The effect of pneumococcal conjugate vaccines on the incidence of invasive pneumococcal disease caused by ten non-vaccine serotypes in Denmark. AB - BACKGROUND: Surveillance data on invasive pneumococcal disease (IPD) in Denmark (1999-2014) was analysed regarding the incidence and age-distribution due to ten selected non-PCV serotypes (10-Non-PCV). The effect of PCV-7 and PCV-13 vaccines on the 10-Non-PCV IPD incidence was examined. METHODS: IPD cases caused by serotypes included in PCV-7, the additional six serotypes included in PCV-13 and 10-Non-PCV serotypes were identified (8, 9N, 11A, 12F, 15A, 22F, 24F, 20, 23B, 33F). The IPD incidence was stratified by three age groups: 0-4 years, 5-64 years and 65+ years. RESULTS: The predominant IPD cases were caused by serotypes that are not included in PCV-13 (71%), followed by the six additional PCV-13 serotypes. The IPD incidence of serotypes included in the PCV-7 decreased markedly after PCV-7 introduction but are still diagnosed at a low level. The IPD incidence for the 10-Non-PCV serotypes was low for age groups 0-4 years and 5-64 years but high for 65+ years. CONCLUSION: Future vaccinations of the young age group alone with a vaccine targeting some of the 10-Non-PCV serotypes may not elicit the desired effect on herd protection since these serotypes are primarily causing IPD among the elderly. Future pneumococcal vaccination strategies in Denmark may therefore need carriage studies in order to identify among whom the pneumococcal serotypes causing IPD are carried. PMID- 26772631 TI - Use of the nonavalent HPV vaccine in individuals previously fully or partially vaccinated with bivalent or quadrivalent HPV vaccines. AB - With the availability of the nonavalent human papillomavirus (HPV) vaccine, vaccinees, parents and healthcare providers need guidance on how to complete an immunization course started with the bi- or quadrivalent vaccine and whether to revaccinate individuals who have completed a full immunization course with the bi or quadrivalent vaccine. To answer these questions three parameters should be considered: age at the start of vaccination (9 to 14 years of age versus 15 years and older, the cut-off for 2 or 3 doses schedule), the number of doses already received and the time interval between doses. Based on a number of scenarios, we propose that the 9-valent vaccine can be used to complete an incomplete vaccination regimen or might be added to a previous completed schedule to extend protection. PMID- 26772632 TI - Metal based nanoparticles as cancer antigen delivery vehicles for macrophage based antitumor vaccine. AB - In the present study, we would like to evaluate the efficacy of modified metal oxide nanoparticles (NPs) as cancer antigen delivery vehicles for macrophage (MFs) based antitumor vaccine. The cobalt oxide nanoparticles (CoO NPs) were promising tools for delivery of antigens to antigen presenting cells and have induced an antitumor immune response. Synthesized CoO NPs were modified by N phosphonomethyliminodiacetic acid (PMIDA), facilitated the conjugation of lysate antigen, i.e. cancer antigen derived from lysis of cancer cells. The cancer cell lysate antigen conjugated PMIDA-CoO NPs (Ag-PMIDA-CoO NPs) successfully activated macrophage (MF) evident by the increasing the serum IFN-gamma and TNF-alpha level. Immunization of mice with the Ag-PMIDA-CoO NPs constructed an efficient immunological adjuvant induced anticancer IgG responses, and increased the antibody dependent cellular cytotoxicity (ADCC) response than only lysate antigen treated group to combat the cancer cell. The nanocomplexes enhanced the anticancer CD4(+)T cell response in mice. The result showed that Ag-PMIDA-CoO NPs can stimulate the immune responses over only lysate antigens, which are the most important findings in this study. These NP-mediated Ag deliveries may significantly improve the anticancer immune response by activating MFs and may act as adjuvant and will balance the pro-inflammatory and anti-inflammatory immunoresponse. The crosstalk between the activated MF with other immune competent cells will be monitored by measuring the cytokines which illustrate the total immunological network setups. PMID- 26772633 TI - Stability and efficacy of the 3'-UTR A4G-G5A variant of viral hemorrhagic septicemia virus (VHSV) as a live attenuated immersion VHSV vaccine in olive flounder (Paralichthys olivaceus). AB - Viral hemorrhagic septicemia virus (VHSV) is the causative agent of viral hemorrhagic septicemia in fish, a disease that affects a number of teleost fish species including olive flounder (Paralichthys olivaceus). In this study, we assessed the safety and efficacy of two recombinant attenuated VHSV strains, termed A4G-G5A and DeltaNV, with the purpose to select the most suitable vaccine strain. The virus strains were passaged in two commercially available cell lines, EPC and RTG-2, and the strains were also tested for residual virulence in zebrafish (Danio rerio). The A4G-G5A strain showed an attenuated growth profile in both the EPC and RTG-2 cell lines compared to wild-type (WT) VHSV (JF-09, genotype IVa), whereas the growth profile of DeltaNV was comparable to the WT strains in RTG-2 cells in contrast to EPC cells. Moreover, DeltaNV had higher residual virulence compared to A4G-G5A and was highly pathogenic to zebrafish. The A4G-G5A strain was chosen as vaccine candidate and tested for efficacy in in vivo fish studies in the target species, olive flounder, using an immersion vaccine scheme. Groups of fish were immunized with 10(2.5), 10(3.5), 10(4.5), and 10(5.5) TCID50/ml of A4G-G5A giving 5-13.3 cumulative percent mortality (CPM) post immunization. Immunization was followed by a challenge experiment using VHSV WT. The relative percent survival (RPS) in immunized groups ranged from 81.6% to 100%, correlating with vaccination dose. This study demonstrates that while strain A4G-G5A has retained some residual virulence it confers high level of protection in immunized olive flounder. PMID- 26772634 TI - Immunogenicity and efficacy of alphavirus-derived replicon vaccines for respiratory syncytial virus and human metapneumovirus in nonhuman primates. AB - Human respiratory syncytial virus (hRSV) and human metapneumovirus (hMPV) are major causes of illness among children, the elderly, and the immunocompromised. No vaccine has been licensed for protection against either of these viruses. We tested the ability of two Venezuelan equine encephalitis virus-based viral replicon particle (VEE-VRP) vaccines that express the hRSV or hMPV fusion (F) protein to confer protection against hRSV or hMPV in African green monkeys. Animals immunized with VEE-VRP vaccines developed RSV or MPV F-specific antibodies and serum neutralizing activity. Compared to control animals, immunized animals were better able to control viral load in the respiratory mucosa following challenge and had lower levels of viral genome in nasopharyngeal and bronchoalveolar lavage fluids. The high level of immunogenicity and protective efficacy induced by these vaccine candidates in nonhuman primates suggest that they hold promise for further development. PMID- 26772635 TI - Enduring changes in tonic GABAA receptor signaling in dentate granule cells after controlled cortical impact brain injury in mice. AB - Changes in functional GABAAR signaling in hippocampus have previously been evaluated using pre-clinical animal models of either diffuse brain injury or extreme focal brain injury that precludes measurement of cells located ipsilateral to injury. As a result, there is little information about the status of functional GABAAR signaling in dentate granule cells (DGCs) located ipsilateral to focal brain injury, where significant cellular changes have been documented. We used whole-cell patch-clamp recordings from hippocampal slices to measure changes in GABAARs in dentate granule cells (DGCs) at 1-2, 3-5, and 8-13 weeks after controlled cortical impact (CCI) brain injury. Synaptic and tonic GABAAR currents (ITonicGABA) were measured in DGCs at baseline conditions and during application of the GABAAR agonist 4,5,6,7-tetrahydroisoxazolo[5,4 c]pyridine-3-ol hydrochloride (THIP) to assess in the function of delta subunit containing GABAARs. DGCs ipsilateral to CCI exhibited no changes in the amplitude of resting ITonicGABA relative to DGCs after sham-injury or contralateral to CCI. In contrast, there was a significant reduction in the THIP-evoked ITonicGABA in DGCs ipsilateral to CCI at both time-points. Tonic GABAergic inhibition of DGCs ipsilateral to injury also exhibited reduced responsiveness to the neurosteroid THDOC. ITonicGABA in DGCs ipsilateral to CCI did not exhibit a change in sensitivity to L655,708, an inverse agonist with selectivity for alpha5 subunit containing GABAARs, suggesting a lack of functional change in GABAARs containing this subunit. At the 8-13 week time-point, gene expression of GABAAR subunits expected to contribute to ITonicGABA (i.e., alpha4, alpha5 and delta) was not significantly altered by CCI injury in isolated dentate gyrus. Collectively, these results demonstrate enduring functional changes in ITonicGABA in DGCs ipsilateral to focal brain injury that occur independent of altered gene expression. PMID- 26772636 TI - Differential effects of myelin basic protein-activated Th1 and Th2 cells on the local immune microenvironment of injured spinal cord. AB - Myelin basic protein (MBP) activated T cells (MBP-T) play an important role in the damage and repair process of the central nervous system (CNS). However, whether these cells play a beneficial or detrimental role is still a matter of debate. Although some studies showed that MBP-T cells are mainly helper T (Th) cells, their subtypes are still not very clear. One possible explanation for MBP T immunization leading to conflicting results may be the different subtypes of T cells are responsible for distinct effects. In this study, the Th1 and Th2 type MBP-T cells (MBP-Th1 and -Th2) were polarized in vitro, and their effects on the local immune microenvironment and tissue repair of spinal cord injury (SCI) after adoptive immunization were investigated. In MBP-Th1 cell transferred rats, the high levels of pro-inflammatory cells (Th1 cells and M1 macrophages) and cytokines (IFN-gamma, TNF-alpha, -beta, IL-1beta) were detected in the injured spinal cord; however, the anti-inflammatory cells (Th2 cells, regulatory T cells, and M2 macrophages) and cytokines (IL-4, -10, and -13) were found in MBP-Th2 cell transferred animals. MBP-Th2 cell transfer resulted in decreased lesion volume, increased myelination of axons, and preservation of neurons. This was accompanied by significant locomotor improvement. These results indicate that MBP-Th2 adoptive transfer has beneficial effects on the injured spinal cord, in which the increased number of Th2 cells may alter the local microenvironment from one primarily populated by Th1 and M1 cells to another dominated by Th2, Treg, and M2 cells and is conducive for SCI repair. PMID- 26772637 TI - Chronic stress regulates NG2+ cell maturation and myelination in the prefrontal cortex through induction of death receptor 6. AB - Chronic stress significantly affects neuron morphometry and function in the prefrontal cortex, a brain region controlling cognition and emotion. However, whether and how chronic stress regulates the maturation of NG2-expressing oligodendrocyte precursor cell (NG2(+) cell) and the importance of these changes remained unknown. Here, we report that exposing adult mice to chronic stress results in NG2(+) cell atrophy and myelination arrested in the medial prefrontal cortex (mPFC), and impaired mPFC-dependent functions. These alterations, are phenocopied by overexpression of death receptor 6 (DR6) in NG2(+) cell. Conversely, selectively silencing of DR6 in the NG2(+) cell can partly rescue NG2(+) cell atrophy and cognitive deficiency caused by chronic stress. We further demonstrate that myelination appears necessary for mPFC-dependent cognitive processes, as lysolecithin (LPC)-induced demyelination specifically in the mPFC is sufficient to cause these behavioral and cognitive impairments. Our results indicate that chronic stress impairs cognitive functions, at least in part, through modulation of NG2(+) cell maturation and myelination, and suggest that myelination is require for normal cognitive functions. PMID- 26772638 TI - Profiling the human hippocampal proteome at all pathologic stages of Alzheimer's disease. AB - INTRODUCTION: We performed a comprehensive quantitative proteomics study on human hippocampus tissue involving all Braak stages to assess changes in protein abundance over the various stages of Alzheimer's disease (AD). METHODS: Hippocampal subareas CA1 and subiculum of 40 cases were isolated using laser capture microdissection and analyzed using mass spectrometry. Immunoblotting and immunohistochemistry were used for validation. RESULTS: Over the Braak stages, an altered expression was found for 372 proteins including changes in levels of extracellular matrix components, and in calcium-dependent signaling proteins. Early changes were observed in levels of proteins related to cytoskeletal dynamics and synaptic components including an increase in RIMS1 and GRIK4. Several synaptic proteins, such as BSN, LIN7A, DLG2, -3, and -4, exhibit an early up, late-down expression pattern. DISCUSSION: This study provides new insight into AD-dependent changes in protein levels in the hippocampus during AD pathology, identifying potential novel therapeutic targets and biomarkers. PMID- 26772640 TI - Histopathologic and Ultrastructural Changes in Seminiferous Tubules of Adult Male Albino Rats Following Daily Administration of Different Doses of Tadalafil. AB - OBJECTIVE: To investigate the effect of chronic daily administration of different doses of tadalafil on the structure of the seminiferous tubules and on spermatogenesis. MATERIALS AND METHODS: Sixty adult male Wistar rats were included; they were divided into four groups: a control group (group I) and groups II, III, and IV that received daily tadalfil in doses of 0.45, 0.9, and 1.8 mg/kg for 12 weeks (equivalent to human doses of 5, 10, and 20 mg daily), respectively. The epididymis was processed for evaluation of sperm parameters, serum testosterone was measured, Johnsen score for rats was calculated, and testicular histopathological and ultrastructural examinations were performed. RESULTS: Serum testosterone was significantly lower in group IV than in groups I and II. Moreover, posttreatment values in group IV were significantly lower than pretreatment values. A significant decline in sperm motility and morphology was detected in groups III and IV compared to groups I and II. Sperm count was significantly lower in group IV compared to the other groups. Johnsen score was significantly lower in groups III and IV compared to groups I and II and in group IV compared to group III. In addition, histopathological and ultrastructural degenerative changes in rat testes were detected; these changes were dose dependent and increased with increasing the dose of tadalafil. CONCLUSION: Chronic daily oral administration of tadalafil to male albino rats demonstrates a dose-dependent alteration to testicular histology and semen parameters. The influence of these changes on the actual fertility of these animals remains to be determined. PMID- 26772639 TI - Endoscopic and Pathologic Characterization of Papillary Architecture in Struvite Stone Formers. AB - OBJECTIVE: To describe the endoscopic characteristics of renal papillae in struvite stone formers (SFs). MATERIALS AND METHODS: From 2009 to 2014, patients undergoing percutaneous nephrolithotomy were prospectively enrolled in our study. Endoscopic analysis and biopsy of papillae were performed to demonstrate the presence and percentage surface area (SA) of Randall's plaque or ductal plug. Comparison with idiopathic calcium oxalate (CaOx) SF and non-SF controls was performed. RESULTS: We identified 29 struvite SFs to compare with 90 idiopathic CaOx SFs and 17 controls. On endoscopic mapping, 28 struvite SFs (97%) demonstrated Randall's plaque and 9 (31%) had plugging. The average mean SA of Randall's plaque in struvite SF (1.5 +/- 1.4%) was less than CaOx SFs (3.7 +/- 4.3%, P = .0018) and similar to controls (1.7 +/- 2.7%, P = .76). Average mean plug SA was similar between struvite SFs, CaOx SFs, and controls. On metabolic assessment, 83% of struvite SFs had at least one urine abnormality, with urinary uric acid and oxalate levels significantly higher among struvite SFs compared to controls (P = .002). Despite lack of active urinary tract infection, interstitial inflammation was more prevalent in struvite SFs compared to CaOx SFs (43.5% vs 7.3%, P = .0001). CONCLUSIONS: Our findings suggest a limited role for Randall's plaque in struvite stone formation. Struvite SFs have less plaque formation than CaOx SFs, but demonstrate evidence of severe parenchymal inflammation compared to other SFs. The role of this prominent interstitial inflammation requires further study. PMID- 26772641 TI - The Prevalence and Association of Varicoceles on Male Patients With Benign Prostatic Hyperplasia/Lower Urinary Tract Symptoms. AB - OBJECTIVE: To investigate the association between the prevalence of varicocele and benign prostatic hyperplasia (BPH)/lower urinary tract symptoms (LUTS) in elder man in China. METHODS: A total of 831 BPH/LUTS outpatients who were 40 years or older were recruited. The patients' age, total prostatic volume (TPV), International Prostate Symptom Score, total prostate-specific antigen, nocturia, and body mass index were recorded. The presence and grade of varicocele were diagnosed by physical examination in combination with scrotal color Doppler. RESULTS: The total prevalence of varicocele was 53.0%. The prevalence values of varicoceles in patients were 40-49, 50-59, 60-69, 70-79 years old, and 80 or above were 43.0%, 42.4%, 54.0%, 59.5%, and 64.0%, respectively. When comparing with varicocele grade, TPV (P = .002) was found to be significantly different. Nocturia frequencies increased significantly in patients with varicocele (P < .01). There were no difference in terms of International Prostate Symptom Score, total prostate-specific antigen, and body mass index between patients with no varicocele and with grades 1, 2, and 3 varicoceles (P > .05). CONCLUSION: For elderly patients, the prevalence of varicocele shows an increasing trend with aging. Higher-grade varicoceles are associated with higher TPV and nocturia levels. Varicocele, which may be a factor that affects BPH/LUTS, cannot be overlooked. PMID- 26772642 TI - Pioglitazone Enhances Survival and Regeneration of Pelvic Ganglion Neurons After Cavernosal Nerve Injury. AB - OBJECTIVE: To investigate the effects of pioglitazone on pelvic ganglion neurons in a rat model of bilateral cavernosal nerve crush injury (BCNI), thereby elucidating the actions of pioglitazone in preventing post-prostatectomy neurogenic erectile dysfunction. METHODS: Sprague-Dawley rats aged 12 weeks were divided into four groups: (a) sham procedure, (b) BCNI, (c) BCNI + postsurgical pioglitazone, and (d) BCNI + pre and postsurgical pioglitazone (preventive therapy). Preoperative injection of Fluoro-Gold (FG) fluorescent tracer into the cavernosal tissue was performed for retrograde labeling of pelvic ganglion cells. Pelvic ganglia were resected at 2 weeks in all rats and processed for real-time polymerase chain reaction, immunohistochemistry, and Western blot to examine the expression of FG, neuronal nitric oxide synthase, beta-III tubulin, neurturin, and glial cell line-derived neurotrophic factor family receptor alpha-2 (GFRalpha2). RESULTS: Animals treated with pre- and postsurgical pioglitazone demonstrated increased staining for FG similar to sham levels. Gene expression of neuronal nitric oxide synthase, neurturin, GFRalpha2, and beta-III tubulin was also upregulated in the group receiving preventive therapy. CONCLUSION: Pioglitazone provides a protective effect on pelvic ganglion neurons after BCNI. PMID- 26772643 TI - Omissions in Urology Residency Training Regarding Sexual Dysfunction Subsequent to Prostate Cancer Treatment: Identifying a Need. AB - OBJECTIVE: To assess urology residents' current knowledge, practice, previous training, barriers, and training needs regarding prostate cancer treatment related sexual dysfunction. MATERIALS AND METHODS: A cross-sectional questionnaire study inventoried the practice patterns and training need of urology residents attending a national training course in June 2015. RESULTS: Of 101 urology residents throughout the Netherlands, 87 attended the training (response rate 100%). Median age was 32 years (range 28-38); 55.2% were woman. Regardless of the residency level, most trainees had never received education about sexual dysfunction (58.6%), reported a limited level of knowledge (48.3%), and indicated an evident need for training (69.4%). The majority did not feel competent to advise prostate cancer patients regarding the treatment of sexual dysfunction (55.2%). Almost all participants inquired about preoperative erectile dysfunction (89.7%), and always informed about treatment-related sexual dysfunction (88.5%). At follow-up, 63.9% of the residents routinely addressed sexual complaints again. More than half of the participants indicated that urology residency training does not provide sufficient education on sexual dysfunction (54.8%).Time constraint (67.1%) and lack of training (35.3%) were the most frequently mentioned barriers. CONCLUSION: Current urology residency does not pay sufficient attention to sexual communication skills and sexual dysfunction. The residents require more knowledge about and more practical training in sexual counseling. Findings support efforts to enhance the education of urology residents regarding prostate cancer treatment-related sexual dysfunction. PMID- 26772644 TI - Endoscopic Management of Urolithiasis in the Horseshoe Kidney. AB - OBJECTIVE: To assess the endourologic outcomes of patients diagnosed with a horseshoe kidney (HK) and symptomatic urolithiasis. METHODS: A retrospective review was performed of patients diagnosed with an HK who underwent endoscopic management from 2002 to present. RESULTS: We identified 45 patients with 64 stone bearing moieties who underwent 56 procedures, of which 31 (69%) were male. Mean age was 49.4 years (23-78) and mean stone size was 1.6 cm (0.2-5.7). Of the 64 moieties, 37 (58%) underwent percutaneous nephrolithotomy (PCNL), 25 (39%) underwent ureteroscopy (URS), and 2 (3%) underwent extracorporal shockwave lithotripsy (SWL). More than one access was utilized in 2 (5.7%) moieties undergoing PCNL. Additional procedures were required in 10 (28.5%) PCNL patients, of which 7 were URS, 2 were secondary PCNL, and 1 sandwich therapy with SWL and PCNL. Stone-free rate by moiety was 81.1% for PCNL, 84% for URS, and 50% for SWL. Postoperative complications occurred in 3 patients in the PCNL group, including readmission for pain and complicated urinary tract infection. With a mean follow up of 20.5 months (range 0-118 months), stone recurrence was noted in 7 (16%) patients with a total of 11 events. Calcium oxalate was the most common stone type and 20/24 (83%) of patients with metabolic evaluations were found to have at least one abnormality. CONCLUSION: After careful consideration of the anatomy, individuals with HK and symptomatic urolithiasis can be managed safely by a variety of endoscopic approaches with excellent outcomes; however, secondary procedures and recurrence are common. PMID- 26772645 TI - Growth of a Level III Vena Cava Tumor Thrombus Within 1 Month. AB - We describe a patient with rapid growth of a vena cava tumor thrombus from level I-II to level III within 1 month. This case illustrates that once the diagnosis of vena cava involvement is established in renal cell carcinoma, surgery should not be delayed without urgent reasons. PMID- 26772647 TI - Smoke and autoimmunity: The fire behind the disease. AB - The association between smoke habit and autoimmunity has been hypothesized a long time ago. Smoke has been found to play a pathogenic role in certain autoimmune disease as it may trigger the development of autoantibodies and act on pathogenic mechanism possibly related with an imbalance of the immune system. Indeed, both epidemiological studies and animal models have showed the potential deleterious effect caused by smoke. For instance, smoke, by provoking oxidative stress, may contribute to lupus disease by dysregulating DNA demethylation, upregulating immune genes, thereby leading to autoreactivity. Moreover, it can alter the lung microenvironment, facilitating infections, which, in turn, may trigger the development of an autoimmune condition. This, in turn, may result in a dysregulation of immune system leading to autoimmune phenomena. Not only cigarette smoke but also air pollution has been reported as being responsible for the development of autoimmunity. Large epidemiological studies are needed to further explore the accountability of smoking effect in the pathogenesis of autoimmune diseases. PMID- 26772648 TI - A reliable measure of footwear upper comfort enabled by an innovative sock equipped with textile pressure sensors. AB - Footwear comfort is essential and pressure distribution on the foot was shown as a relevant objective measurement to assess it. However, asperities on the foot sides, especially the metatarsals and the instep, make its evaluation difficult with available equipment. Thus, a sock equipped with textile pressure sensors was designed. Results from the mechanical tests showed a high linearity of the sensor response under incremental loadings and allowed to determine the regression equation to convert voltage values into pressure measurements. The sensor response was also highly repeatable and the creep under constant loading was low. Pressure measurements on human feet associated with a perception questionnaire exhibited that significant relationships existed between pressure and comfort perceived on the first, the third and the fifth metatarsals and top of the instep. Practitioner Summary: A sock equipped with textile sensors was validated for measuring the pressure on the foot top, medial and lateral sides to evaluate footwear comfort. This device may be relevant to help individuals with low sensitivity, such as children, elderly or neuropathic, to choose the shoes that fit the best. PMID- 26772649 TI - Symptomatic Graves' Disease After Autoimmune Hypothyroidism. PMID- 26772650 TI - Swinging Thyroid Function Test Results in a Young Woman. PMID- 26772651 TI - Systemic Inflammation Gone Awry: PASH Syndrome and Temporomandibular Joint Ankylosis. PMID- 26772653 TI - Bovine mastitis disease/pathogenicity: evidence of the potential role of microbial biofilms. AB - Bovine mastitis (BM) is a disease with high incidence worldwide and one of the most relevant bovine pathologies and the most costly to the dairy industry. BM is an inflammation of the udder and represents one of the most difficult veterinary diseases to control. Biofilm formation is considered a selective advantage for pathogens causing mastitis, facilitating bacterial persistence in the udder. In fact, recently some authors drew attention to the biofilm formation ability presented by several mastitis causing pathogens and to its possible relation with recurrent mastitis infections and with the increased resistance to antimicrobial agents and host immune defence system. Actually, up to now, several researchers reported the potential role of cells in this mode of growth in the previous facts mentioned. As a consequence of the presence of biofilms, the infection here focused is more difficult to treat and eradicate, making this problem a more relevant pressing issue. Thus, we believe that a deeper knowledge of these structures in mastitis can help to determine the best control strategy to be used in veterinary practice in order to reduce losses in the dairy industry and to ensure milk safety and quality. The aim of this paper was to review the existing research and consequently to provide an overview of the role of biofilms in BM infections. PMID- 26772654 TI - Disaggregation of lipopolysaccharide by albumin, hemoglobin or high-density lipoprotein, forming complexes that prime neutrophils for enhanced release of superoxide. AB - We studied the interaction of LPS with albumin, hemoglobin or high-density lipoprotein (HDL), and whether the interaction affected the activity of LPS on neutrophils. These proteins disaggregated LPS, depending upon temperature and LPS:protein ratio. Albumin-treated LPS was absorbed by immobilized anti-albumin antibody and was eluted with Triton X-100, indicating that LPS formed a hydrophobic complex with albumin. Rd mutant LPS was not disaggregated by the proteins, and did not form a complex with the proteins. But triethylamine-treated Rd mutant LPS formed complexes. When LPS was incubated with an equal concentration of albumin and with polymyxin B (PMXB), PMXB-LPS-protein three-way complexes were formed. After removal of PMXB, the complexes consisted of 11-15 LPS monomers bound to one albumin or hemoglobin molecule. LPS primed neutrophils for enhanced release of formyl peptide-stimulated superoxide, in a serum- and LPS binding protein (LBP)-dependent manner. Although LPS plus LBP alone did not prime neutrophils, albumin-, hemoglobin- or HDL-treated LPS primed neutrophils when added with LBP. Triethylamine-treated Rd mutant LPS primed neutrophils only when incubated with one of the proteins and with LBP. Thus, in addition to LBP, disaggregation and complex formation of LPS with one of these proteins is required for LPS to prime neutrophils. PMID- 26772655 TI - Patients' experiences and actions when describing pain after surgery--a critical incident technique analysis. AB - BACKGROUND: Postoperative pain assessment remains a significant problem in clinical care despite patients wanting to describe their pain and be treated as unique individuals. Deeper knowledge about variations in patients' experiences and actions could help healthcare professionals to improve pain management and could increase patients' participation in pain assessments. OBJECTIVE: The aim of this study was, through an examination of critical incidents, to describe patients' experiences and actions when needing to describe pain after surgery. METHODS: An explorative design involving the critical incident technique was used. Patients from one university and three county hospitals in both urban and rural areas were included. To ensure variation of patients a strategic sampling was made according to age, gender, education and surgery. A total of 25 patients who had undergone orthopaedic or general surgery was asked to participate in an interview, of whom three declined. FINDINGS: Pain experiences were described according to two main areas: "Patients' resources when in need of pain assessment" and "Ward resources for performing pain assessments". Patients were affected by their expectations and tolerance for pain. Ability to describe pain could be limited by a fear of coming into conflict with healthcare professionals or being perceived as whining. Furthermore, attitudes from healthcare professionals and their lack of adherence to procedures affected patients' ability to describe pain. Two main areas regarding actions emerged: "Patients used active strategies when needing to describe pain" and "Patients used passive strategies when needing to describe pain". Patients informed healthcare professionals about their pain and asked questions in order to make decisions about their pain situation. Selfcare was performed by distraction and avoiding pain or treating pain by themselves, while others were passive and endured pain or refrained from contact with healthcare professionals due to healthcare professionals' large work load. PMID- 26772656 TI - Psychometric comparison of single-item, short, and comprehensive depression screening measures in Korean young adults. AB - BACKGROUND: Integrating long depression-screening instruments into routine clinical practice and research studies is often impractical, necessitating short item if not single-item measures with comparable psychometric properties. OBJECTIVE: To examine whether single-item or short depression-screening measures are comparable to a comprehensive screening measure in reliability (i.e., internal consistency and test-retest reliability) and validity (i.e., convergent, concurrent, and predictive validity) in Korean young adults within a Classical Testing Theory framework. METHOD: A total of 458 students from six nursing colleges in South Korea completed three depression measures: the 20-item Center for Epidemiologic Studies-Depression screening instrument (CES-D; comprehensive measure); the five-item Profile of Mood States-Brief depression subscale (POMS-B depression subscale; short measure); a single-item Likert measure; and a single item numeric rating scale. Internal consistency reliability was tested by Cronbach's alpha and item-total correlations; test-retest reliability by intraclass correlation coefficient (ICC); convergent validity by correlation with the CES-D; concurrent validity by the correlation with perceived stress level and sleep quality; and predictive validity by receiver operating characteristic curve to predict the two groups with different depression levels. RESULTS: The POMS-B depression subscale was comparable to the comprehensive CES-D scale in internal consistency reliability (alpha=.85); test-retest reliability (ICC=.76); and convergent (r=.81 with CES-D), concurrent (r=.64 with perceived stress level, r=.34 with sleep quality), and predictive validity (area under the curve=.88). The two single-item options were not comparable to the comprehensive CES-D. CONCLUSION: The short POMS-B depression subscale shows an acceptable balance between practical clinical and research needs and psychometric quality. PMID- 26772652 TI - Role of Candida albicans secreted aspartyl protease Sap9 in interkingdom biofilm formation. AB - The fungus Candida albicans colonizes oral cavity surfaces and is carried by up to 60% of human populations. Biofilm development by C. albicans may be modulated by oral streptococci, such as Streptococcus gordonii, S. oralis or S. mutans, so as to augment pathogenicity. In this study we sought to determine if the cell wall-associated secreted aspartyl proteinase Sap9 was necessary for hyphal adhesin functions associated with biofilm community development. A sap9Delta mutant of C. albicans SC5314 formed biofilms that were flatter, and contained fewer blastospores and more hyphal filaments than the parent strain. This phenotypic difference was accentuated under flow (shear) conditions and in the presence of S. gordonii. Dual-species biofilms of C. albicans sap9Delta with S. oralis, S. sanguinis, S. parasanguinis, S. mutans and Enterococcus faecalis all contained more matted hyphae and more bacteria bound to substratum compared to C. albicans wild type. sap9Delta mutant hyphae showed significantly increased cell surface hydrophobicity, ~25% increased levels of binding C. albicans cell wall protein Als3, and reduced interaction with Eap1, implicating Sap9 in fungal cell cell recognition. These observations suggest that Sap9 is associated with protein receptor interactions between fungal cells, and with interkingdom communication in the formation of polymicrobial biofilm communities. PMID- 26772657 TI - Haploidization via Chromosome Elimination: Means and Mechanisms. AB - The ability to generate haploids and subsequently induce chromosome doubling significantly accelerates the crop breeding process. Haploids have been induced through the generation of plants from haploid tissues (in situ gynogenesis and androgenesis) and through the selective loss of a parental chromosome set via inter- or intraspecific hybridization. Here, we focus on the mechanisms responsible for this selective chromosome elimination. CENH3, a variant of the centromere-specific histone H3, has been exploited to create an efficient method of haploid induction, and we discuss this approach in some detail. Parallels have been drawn with chromosome-specific elimination, which occurs as a normal part of differentiation and sex determination in many plant and animal systems. PMID- 26772658 TI - Effects of dietary Lactobacillus plantarum B1 on growth performance, intestinal microbiota, and short chain fatty acid profiles in broiler chickens. AB - Two experiments were conducted to determine the effects of Lactobacillus plantarum B1 on broiler performance, cecal bacteria, and ileal and cecal short chain fatty acids (SCFA). The study also determined whether it was necessary to feed Lactobacillus throughout the entire growth period or if the beneficial effects could be obtained by supplementation during the starter or finisher period only. Experiment 1 was conducted with 72 broilers assigned to 2 treatments (N=6). One treatment was the basal diet (Con), and the other was the basal diet supplemented with 2*10(9) cfu/kg L. plantarum B1 (Wh). In experiment 2, 144 one day-old broilers were assigned to 4 treatments (N=6) including a basal diet (Con), the basal diet supplemented with 2*10(9) cfu/kgL. plantarum B1 during d one to 21 only (St), the basal diet supplemented with L. plantarum B1 during d 22 to 42 only (Fn), and, finally, the basal diet supplemented with L. plantarum B1 from d one to 42 (Wh). Experiment 1 showed that L. plantarum B1 enhanced broiler average daily gain (ADG) and feed conversion ratio (FCR). In experiment 2, during the starter period, broilers in the Wh and St treatments had higher ADG (P<0.05) than broilers in the Con and Fn, while during the finisher period, broilers in the Wh and Fn had higher ADG (P<0.01) and improved FCR (P<0.01) compared with broilers in the Con and St. On d 42, broilers in the Wh and Fn had decreased E. coli (P<0.05) and increased lactic acid bacteria (P<0.05) in their cecal digesta. L. plantarum B1 also increased (P<0.05) ileal mucosal sIgA as well as ileal and cecal SCFA. However, L. plantarum B1 had no effect on intestinal morphology. In conclusion,L. plantarum B1 plays a positive role in broilers. Supplementation during the finisher period or the entire growth period is superior to supplementation during the starter period only. PMID- 26772659 TI - Oral antibody to interleukin-10 reduces growth rate depression due to Eimeria spp. infection in broiler chickens. AB - Eimeria spp. must be controlled in floor-reared poultry to prevent the onset of coccidiosis. Here we use an oral antibody to chicken IL-10 to prevent growth depression due to Eimeria spp. infection. Egg antibody directed against an antigenic peptide of IL-10 was produced in laying hens and measured using an ELISA. In the first experiment, egg yolk powder containing antibody to chicken IL 10 (vlpramqt conjugate) (anti-IL-10 yolk powder) was fed at 3.4 g/kg feed to determine growth response following mixed Eimeria spp. challenge. Chicks were fed either anti-IL-10 antibodies or control antibodies and challenged (d3) with either sterile saline or a 10* attenuated Eimeria spp. vaccine. Control-fed and Eimeria-challenged chicks grew 8.8% slower than those challenged with saline (P < 0.04), whereas anti-IL-10-fed Eimeria challenged chicks were not different from untreated controls. In the second trial a dose response was performed with doses of either 0 (control antibody), 0.34-, or 3.4-g anti-IL-10 yolk powder/kg feed. Control-fed, Eimeria-challenged chicks grew 10.6% slower than control saline challenged chicks (P < 0.05); however, anti-IL-10-fed chicks fed either dose of anti-IL-10 were not different from saline-challenged chicks. Finally, the effect of anti-IL-10 on acquired immunity was investigated. Chicks were fed control or anti-IL-10 yolk powder and vaccinated with a 1* dose of Eimeria vaccine at d 3. After 14 d, antibody was removed from the diet. Chicks were either saline or 10* Eimeria challenged at d 17. We found that the anti-IL-10-fed chickens did not show a reduction in growth due to challenge; hence anti-IL-10 does not appear to affect adaptive immunity during the primary immunization. Overall, use of an antibody to IL-10 is a novel method in preventing adverse effects of Eimeria spp. infection in poultry. PMID- 26772660 TI - Formation of lysinoalanine in egg white under alkali treatment. AB - To investigate the formation mechanism of lysinoalanine (LAL) in eggs during the alkali treatment process, NaOH was used for the direct alkali treatment of egg white, ovalbumin, and amino acids; in addition, the amount of LAL formed during the alkali treatment process was measured. The results showed that the alkali treatment resulted in the formation of LAL in the egg white. The LAL content increased with increasing pH and temperature, with the LAL content first increasing and then leveling off with increasing time. The amount of LAL formed in the ovalbumin under the alkali treatment condition accounted for approximately 50.51% to 58.68% of the amount of LAL formed in the egg white. Thus, the LAL formed in the ovalbumin was the main source for the LAL in the egg white during the alkali treatment process. Under the alkali treatment condition, free L serine, L-cysteine, and L-cystine reacted with L-lysine to form LAL; therefore, they are the precursor amino acids of LAL formed in eggs during the alkali treatment process. PMID- 26772661 TI - Cranial Ultrasound as a First-Line Imaging Examination for Craniosynostosis. AB - BACKGROUND: Radiography, typically the first-line imaging study for diagnosis of craniosynostosis, exposes infants to ionizing radiation. We aimed to compare the accuracy of cranial ultrasound (CUS) with radiography for the diagnosis or exclusion of craniosynostosis. METHODS: Children aged 0 to 12 months who were assessed for craniosynostosis during 2011-2013 by using 4-view skull radiography and CUS of the sagittal, coronal, lambdoid, and metopic sutures were included in this prospective study. Institutional review board approval and parental informed consent were obtained. CUS and radiography were interpreted independently and blindly by 2 pediatric radiologists; conflicts were resolved in consensus. Sutures were characterized as closed, normal, or indeterminate. Correlation between CUS and radiography and interreader agreement were examined for each suture. RESULTS: A total of 126 children (82 boys, 64.5%) ages 8 to 343 days were included. All sutures were normal on CUS and radiography in 115 patients (93.7%); craniosynostosis of 1 suture was detected in 8 (6.3%, 5 sagittal, 2 metopic, 1 coronal). In 3 cases the metopic suture was closed (n = 2) or indeterminate on CUS (n = 1) but normally closed on radiography. CUS sensitivity was 100%, specificity 98% (95% confidence interval 94%-100%). Reader agreement was 100% for sagittal, coronal, and lambdoid sutures (kappa = 0.80); after consensus, disagreement remained on 3 metopic sutures. CONCLUSIONS: In this series, CUS could be safely used as a first-line imaging tool in the investigation of craniosynostosis, reducing the need for radiographs in young children. Additional assessment may be required for accurate assessment of the metopic suture. PMID- 26772662 TI - Pharmacologic Interventions for Infantile Hemangioma: A Meta-analysis. AB - CONTEXT: Infantile hemangiomas (IH) may be associated with significant functional impact. OBJECTIVE: The objective of this study was to meta-analyze studies of pharmacologic interventions for children with IH. DATA SOURCES: Data sources were Medline and other databases from 1982 to June 2015. STUDY SELECTION: Two reviewers assessed studies using predetermined inclusion criteria. DATA EXTRACTION: One reviewer extracted data with review by a second. RESULTS: We included 18 studies in a network meta-analysis assessing relative expected rates of IH clearance associated with beta-blockers and steroids. Oral propranolol had the largest mean estimate of expected clearance (95%; 95% Bayesian credible interval [BCI]: 88%-99%) relative to oral corticosteroids (43%, 95% BCI: 21%-66%) and control (6%, 95% BCI: 1%-11%). Strength of evidence (SOE) was high for propranolol's effects on reducing lesion size compared with observation/placebo. Corticosteroids demonstrated moderate effectiveness at reducing size/volume (moderate SOE for improvement in IH). SOE was low for effects of topical timolol versus placebo. LIMITATIONS: Methodologic limitations of available evidence may compromise SOE. Validity of meta-analytic estimates relies on the assumption of exchangeability among studies, conditional on effects of the intervention. Results rely on assumed lack of reporting bias. CONCLUSIONS: Propranolol is effective at reducing IH size compared with placebo, observation, and other treatments including steroids in most studies. Corticosteroids demonstrate moderate effectiveness at reducing IH size/volume. The meta-analysis estimates provide a relative ranking of anticipated rates of lesion clearance among treatments. Families and clinicians making treatment decisions should also factor in elements such as lesion size, location, number, and type, and patient and family preferences. PMID- 26772664 TI - Preventing Online Victimization: College Students' Views on Intervention and Prevention. AB - Facebook, Twitter, and other social networking sites have changed the way we interact online. Technological advances have also facilitated the emergence of cyberstalking and online harassment, a growing issue on college campuses. This study utilizes focus group data to examine college students' experiences with online harassment and cyberstalking. Students voiced concerns with online tracking, falsifying identities, and harassment. They also noted that incoming first-year students and those negotiating some of their first romantic relationships are especially vulnerable. In addition, students were asked to propose appropriate prevention, education, and intervention strategies at the college level. Surprisingly, many students recommended offline programs to battle this online problem. PMID- 26772663 TI - Stunting at 5 Years Among SGA Newborns. AB - OBJECTIVE: To compare risk of stunting at 5 years across etiological subgroups of small for gestational age (SGA) newborns. METHODS: We analyzed data of a subsample (N = 1100) of the Early Childhood Longitudinal Study-Birth Cohort. We defined SGA as birth weight <10th percentile, then classified subjects into etiological subgroups by each of 8 risk factors (ie, maternal prepregnancy underweight, short stature, smoking during pregnancy, alcohol use during pregnancy, inadequate gestational weight gain [GWG], hypertension, genital herpes infection, and multiple births) or by cooccurrence of 2 often intertwined risk factors (smoking and inadequate GWG). We defined stunting as 5 years height-for age z score below -2. We fitted logistic regression models to test whether the risk of stunting differed across SGA subgroups, adjusting for confounders. RESULTS: SGA subgroup with maternal short stature (odds ratio [OR] = 3.88; 95% confidence interval [CI] = 2.16-6.96) or inadequate GWG (OR = 2.18; 95% CI = 1.23 3.84) had higher risk of stunting at 5 years, compared with the SGA subgroup without the corresponding risk factor. SGA newborns with both maternal smoking and inadequate GWG during pregnancy had much higher risk of stunting at 5 years (OR = 3.10; 95% CI = 1.21-7.91), compared with SGA newborns without any of these 2 SGA risk factors. CONCLUSIONS: Etiological subgroups of SGA differed in risk of stunting at 5 years. SGA newborns of inadequate GWG mothers who smoke and SGA newborns of short mothers were at particularly high risk of stunting. PMID- 26772665 TI - Control, Norms, and Attitudes: Differences Between Students Who Do and Do Not Intervene as Bystanders to Sexual Assault. AB - Sexual assault is a major concern on the U.S. college campus. Engaging students as pro-social bystanders has become more common as a potentially effective mechanism for reducing the incidence of sexual assault and mitigating the harm of assaults that have already occurred. Understanding the influences of pro-social bystander behavior is imperative to developing effective programs, and the use of an evidence-based theoretical framework can help identify the differences between students who intervene and those who do not when presented with the opportunity. A sample of 815 undergraduate university students completed the Sexual Assault Bystander Behavior Questionnaire, a survey based on the theory of planned behavior (TPB) that investigates students' perceived behavioral control to intervene, subjective norms that support intervening, attitudes toward intervening, and intent to intervene in the future. Two-tailed t tests revealed interveners reported significantly greater perceived behavioral control than non interveners for eight of the 12 intervention behaviors, more supportive subjective norms than non-interveners for seven of the 12 intervention behaviors, more positive attitudes than non-interveners for only one of the 12 intervention behaviors, and greater intent to intervene in the future for six of the 12 intervention behaviors. Differences in the four TPB variables were not consistent for the 12 intervention behaviors. The use of a theoretical framework found to be effective in explaining-and changing-other health-related behaviors, and the inquiry into students' opportunities to intervene to compare against their reported intervention behaviors, is new to this body of literature and contributes to the understanding of the influences of pro-social bystander behavior. PMID- 26772666 TI - How Do Men Construct and Explain Men's Violence? AB - In this study, we examine men's constructions of violence and their explanations of their own violent behavior. Interviews were conducted with 12 adult men, employed in industrial and manual labor, regarding their associations with violence, their reasons for engaging in violent behavior, and their reasons for not engaging in violent behavior. Utilizing consensual qualitative research methodology, our findings indicated that men's constructions of violence and their justifications for engaging in violence were linked to their constructions of masculinity and what it meant to them to be a man. Results are discussed through the lenses of multiple gender-based theories and ultimately, deemed to demonstrate the most support for the notion of precarious manhood. Specifically, violence was viewed as necessary in particular situations to assert or maintain one's social status and sense of self as masculine when faced with threats to manhood status. Implications for psychological intervention and practice with men are discussed, including identifying positive alternatives to violence that preserve one's sense of self as masculine. PMID- 26772667 TI - Impact of hypovitaminosis D on clinical, hormonal and insulin sensitivity parameters in normal body mass index polycystic ovary syndrome women. AB - Earlier data on the relationship of 25 hydroxyvitamins (25OHD) levels with various components of polycystic ovary syndrome (PCOS) has been conflicting. We studied 122 normal body mass index (BMI) women with PCOS (cases) and 46 age and BMI-matched healthy women (controls) and assessed the impact of serum 25OHD levels on clinical, biochemical and insulin sensitivity parameters in these lean Indian women with PCOS. The mean age and BMI of the cases and controls were comparable. Mean serum 25OHD levels respectively were 10.1 +/- 9.9 and 7.9 +/- 6.8 ng/ml with 87.7% and 91.1% vitamin D (VD) deficient. No significant correlation was noted between 25OHD levels and clinical, biochemical and insulin sensitivity parameters except with the total testosterone levels (p = 0.007). Also, no significant difference in these parameters was observed once the PCOS women were stratified into various subgroups based on the serum 25OHD levels. We conclude that VD deficiency being common in normal BMI Indian women with or without PCOS does not seem to alter the metabolic phenotype in these women. PMID- 26772668 TI - High trait aggression in men is associated with low 5-HT levels, as indexed by 5 HT4 receptor binding. AB - Impulsive aggression has commonly been associated with a dysfunction of the serotonin (5-HT) system: many, but not all, studies point to an inverse relationship between 5-HT and aggression. As cerebral 5-HT4 receptor (5-HT4R) binding has recently been recognized as a proxy for stable brain levels of 5-HT, we here test the hypothesis in healthy men and women that brain 5-HT levels, as indexed by cerebral 5-HT4R, are inversely correlated with trait aggression and impulsivity. Sixty-one individuals (47 men) underwent positron emission tomography scanning with the radioligand [(11)C]SB207145 for quantification of brain 5-HT4R binding. The Buss-Perry Aggression Questionnaire (BPAQ) and the Barratt Impulsiveness Scale were used for assessment of trait aggression and trait impulsivity. Among male subjects, there was a positive correlation between global 5-HT4R and BPAQ total score (P = 0.037) as well as BPAQ physical aggression (P = 0.025). No main effect of global 5-HT4R on trait aggression or impulsivity was found in the mixed gender sample, but there was evidence for sex interaction effects in the relationship between global 5-HT4R and BPAQ physical aggression. In conclusion we found that low cerebral 5-HT levels, as indexed by 5 HT4R binding were associated with high trait aggression in males, but not in females. PMID- 26772669 TI - Co-ordinated structural and functional covariance in the adolescent brain underlies face processing performance. AB - Our ability to process complex social cues presented by faces improves during adolescence. Using multivariate analyses of neuroimaging data collected longitudinally from a sample of 38 adolescents (17 males) when they were 10, 11.5, 13 and 15 years old, we tested the possibility that there exists parallel variations in the structural and functional development of neural systems supporting face processing. By combining measures of task-related functional connectivity and brain morphology, we reveal that both the structural covariance and functional connectivity among 'distal' nodes of the face-processing network engaged by ambiguous faces increase during this age range. Furthermore, we show that the trajectory of increasing functional connectivity between the distal nodes occurs in tandem with the development of their structural covariance. This demonstrates a tight coupling between functional and structural maturation within the face-processing network. Finally, we demonstrate that increased functional connectivity is associated with age-related improvements of face-processing performance, particularly in females. We suggest that our findings reflect greater integration among distal elements of the neural systems supporting the processing of facial expressions. This, in turn, might facilitate an enhanced extraction of social information from faces during a time when greater importance is placed on social interactions. PMID- 26772670 TI - Evolution around the Red Sea: Systematics and biogeography of the agamid genus Pseudotrapelus (Squamata: Agamidae) from North Africa and Arabia. AB - Since the Oligocene, regions adjacent to the Red Sea have experienced major environmental changes, from tectonic movements and continuous geological activity to shifting climatic conditions. The effect of these events on the distribution and diversity of the regional biota is still poorly understood. Agamid members of the genus Pseudotrapelus are diurnal, arid-adapted lizards distributed around the Red Sea from north-eastern Africa, across the mountains and rocky plateaus of the Sinai and Arabian Peninsulas northwards to Syria. Despite recent taxonomic work and the interest in the group as a model for studying biogeographic and diversity patterns of the arid areas of North Africa and Arabia, its taxonomy is poorly understood and a comprehensive phylogeny is still lacking. In this study, we analyzed 92 Pseudotrapelus specimens from across the entire distribution range of the genus. We included all known species and subspecies, and sequenced them for mitochondrial (16S, ND4 and tRNAs) and nuclear (MC1R, c-mos) markers. This enabled us to obtain the first time-calibrated molecular phylogeny of the genus, using gene trees, species trees and coalescent-based methods for species delimitation. Our results revealed Pseudotrapelus as a monophyletic genus comprised of two major clades and six independently evolving lineages. These lineages correspond to the five currently recognized species and a sixth lineage relating to the synonymized P. neumanni. The subspecific validity of P. sinaitus werneri needs further assessment as it does not form a distinct cluster relative to P. s. sinaitus. The onset of Pseudotrapelus diversification is estimated to have occurred in Arabia during the late Miocene. Radiation has likely resulted from vicariance and dispersal events due to the continued geological instability, sea level fluctuations and climatic changes within the region. PMID- 26772721 TI - Genomic organization and expression of insulin receptors in grass carp, Ctenopharyngodon idellus. AB - Insulin receptors have been demonstrated to be involved in embryogenesis, food intake regulation and glucose metabolism in several fish, while more researchis needed for further understanding. In this study, the complete coding sequence (CDS) of insulin receptor a (insra) gene and insulin receptor b (insrb) gene in grass carp were obtained, the CDS were 4068 bp and 4514 bp in length, encoding 1355 aa protein and 1351 aa protein. Both of insra and insrb in grass carp showed high amino acid identities with other fish. Insra and insrb genes were widely expressed in all tested tissues with an overlapping but distinct expressions. The high levels of insra mRNA were distributed in hindgut and heart tissues. The insrb gene showed the highest expression levels in liver and hindgut. We also proved that two forms of grass carp insulin receptors participate in the regulation of blood glucose and might act differently. Phylogenetic analysis confirmed that different isoforms of fish insulin receptors are derived from two distinct genes, which was inconsistent with the generation of mammalian insulin receptors. Synteny analyses of insulin receptor genes showed that genes surrounding the insulin receptor genes were conserved in fish. Arhgef18, PEX11G, humanC19orf45 genes were highly conserved among mammal species. However, no conserved synteny was observed among fish, mammals, avians and amphibians. PMID- 26772722 TI - High-throughput measurement of 25-hydroxyvitamin D by LC-MS/MS with separation of the C3-epimer interference for pediatric populations. AB - BACKGROUND: Liquid chromatography-tandem mass spectrometry (LC-MS/MS) is widely used for the measurement of 25-hydroxyvitamin D3 (25OHD3) and 25-hydroxyvitamin D2 (25OHD2) in blood. However, the presence of 25OHD3 C3-epimer (3-epi-25OHD3) may cause interference and overestimation of the 25OHD3 level. We developed a rapid and simple assay for measurement of 25OHD that separates this interference and to investigate its impact on 25OHD3 measurement in adult and pediatric populations. METHODS: Sample preparation consisted of protein precipitation followed by solid-phase extraction with an LC run time of 4.8 min. Method comparison with another LC-MS/MS method of a major reference laboratory that does not separate the C3-epimer interference was performed using adult (n=52) and pediatric (n=40) samples. RESULTS: This method is free from significant ion suppression, carryover and interference. The assay can separate 25OHD3 from the 3 epi-25OHD3, and can measure 25OHD2 and 25OHD3 from 4.2 to 310.7 ng/ml and 5.2 to 311.1 ng/ml, respectively. Method comparison with a LC-MS method that does not separate the interference revealed biases of -0.15 and 4.54 for 25OHD3 measurement in adult and pediatric samples, respectively. CONCLUSION: A fast and simple LC-MS/MS method for quantification of 25OHD3 and 25OHD2 without 3-epi 25OHD3 interference was developed. This assay is required for accurate quantitation of 25OHD3 in pediatric samples and suitable for routine use in a high volume clinical laboratory. PMID- 26772671 TI - Calcium influx enhances neuropeptide activation of ecdysteroid hormone production by mosquito ovaries. AB - A critical step in mosquito reproduction is the ingestion of a blood meal from a vertebrate host. In mosquitoes like Aedes aegypti, blood feeding stimulates the release of ovary ecdysteroidogenic hormone (OEH) and insulin-like peptide 3 (ILP3). This induces the ovaries to produce ecdysteroid hormone (ECD), which then drives egg maturation. In many immature insects, prothoracicotropic hormone (PTTH) stimulates the prothoracic glands to produce ECD that directs molting and metamorphosis. The receptors for OEH, ILP3 and PTTH are different receptor tyrosine kinases with OEH and ILP3 signaling converging downstream in the insulin pathway and PTTH activating the mitogen-activated protein kinase pathway. Calcium (Ca(2+)) flux and cAMP have also been implicated in PTTH signaling, but the role of Ca(2+) in OEH, ILP3, and cAMP signaling in ovaries is unknown. Here, we assessed whether Ca(2+) flux affects OEH, ILP3, and cAMP activity in A. aegypti ovaries and also asked whether PTTH stimulated ovaries to produce ECD. Results indicated that Ca(2+) flux enhanced but was not essential for OEH or ILP3 activity, whereas cAMP signaling was dependent on Ca(2+) flux. Recombinant PTTH from Bombyx mori fully activated ECD production by B. mori PTGs, but exhibited no activity toward A. aegypti ovaries. Recombinant PTTH from A. aegypti also failed to stimulate either B. mori PTGs or A. aegypti ovaries to produce ECD. We discuss the implications of these results in the context of mosquito reproduction and ECD biosynthesis by insects generally. PMID- 26772723 TI - Gene variants at FTO, 9p21, and 2q36.3 are age-independently associated with myocardial infarction in Czech men. AB - AIM: Cardiovascular disease (CVD) is a major cause of morbidity and mortality in developed countries. This study aimed to confirm the effect of common putative CVD-associated gene variants (FTO rs17817449, KIF6 rs20455, 9p21 rs10757274 and 2q36.3 rs2943634) on CVD manifestation, and determine whether this effect differs between younger (< 50 years) and older CVD patients. METHODS: 1191 controls and 1889 MI patients were analyzed. All participants were Caucasian Czech males aged <65 years (532 were <50 years) who were examined at cardiology clinics in Prague, Czech Republic. Variants of FTO, 9p21, 2q36.3, and KIF-6 were genotyped using PCR RFLP or TaqMan assay. RESULTS: Variants of FTO (OR 1.48; 95% CI, 1.19-1.84 in a TT vs. GG comparison, p=0.0005); 9p21 (OR 1.74; 95% CI, 1.41-2.14 in an AA vs. GG comparison, p=0.0001); and 2q36.3 (OR 1.34; 95%CI, 1.09-1.65 in an AA vs. +C comparison, p=0.006) were significantly associated with MI in the male Czech population. In contrast, genotype frequencies of KIF-6 (rs20455) were the same in patients and controls (P=1.00). Nearly identical results were observed when a subset of young MI patients (N=532, aged <50 years) was analyzed. CONCLUSION: We confirmed the importance of determining FTO, 9p21, and 2q36.3 variants as part of the genetic determination of MI risk in the Czech male population. PMID- 26772724 TI - A fluorescent imaging assay of cast in renal disease based on graphene quantum dots and Fe3O4 nanoparticles. AB - BACKGROUND: Renal disease has become a global public health problem. Cast is a useful disease marker of kidney injury and renal failure. Hence, a cast-targeted fluorescent imaging assay is developed for the laboratory diagnosis of renal disease. METHODS: Firstly, graphene quantum dots (GQDs) were stripped from graphene oxide sheets and amine-modified. Then, anti-human IgG antibody was conjugated with Fe3O4 nanoparticles to identify the cast in urine. Furthermore, the modified GQDs were linked onto the surface of Fe3O4/anti-IgG nanocomposites. Lastly, this Fe3O4/GQD fluorescent probe was added into the sample to detect the cast through fluorescent imaging. RESULTS: Preliminary application of this probe in clinical detection showed that the common types of casts in urine (including RBC, WBC, fatty and granular casts) could be detected by this fluorescent imaging assay. The method has the advantages of fast speed, high sensitivity (lowest detection limit to 2 casts/ml), good selectivity, and wide linear range (2-2000 casts/ml). Regression analysis also showed that there was a good linear relationship (y=0.9495*+10.974, R(2)=0.9879) between the fluorescent counts and the casts in urine. CONCLUSION: This cast-targeted fluorescent imaging assay may be a potential method for the laboratory diagnosis of renal disease. PMID- 26772727 TI - The 6th International Conference on Analysis of Microbial Cells at the Single Cell Level, Retz, Austria, 19-22 July 2015. AB - The 6th International Conference on Analysis of Microbial Cells at the Single Cell Level, held in Retz, Austria from 19 to 22 July 2015, brought together experts from different areas working with bacterial, yeast and mammalian cell systems. The conference highlighted the importance of dissecting cell behaviour down to the single cell level, as analysis of mixed populations can obscure crucial cell-to-cell variations. The sessions covered advances in the fields of image analysis and microscopy, flow cytometry and cell sorting as well as bioinformatics, including recent developments and new applications of existing tools. In addition, a high speed poster slam session contributed to the lively discussions and exchange of expertise among academic and industrial researchers. PMID- 26772725 TI - A comparison of phosphospecific affinity reagents reveals the utility of recombinant Forkhead-associated domains in recognizing phosphothreonine containing peptides. AB - Phosphorylation is an important post-translational event that has a wide array of functional consequences. With advances in the ability of various technologies in revealing and mapping new phosphosites in proteins, it is equally important to develop affinity reagents that can monitor such post-translational modifications in eukaryotic cells. While monoclonal and polyclonal antibodies have been shown to be useful in assessing the phosphoproteome, we have expanded our efforts to exploit the Forkhead-associated 1 (FHA1) domain as scaffold for generating recombinant affinity reagents that recognize phosphothreonine-containing peptides. A phage display library of FHA1 variants was screened by affinity selection with 15 phosphothreonine-containing peptides corresponding to various human transcription factors and kinases, including human Myc, calmodulin dependent protein kinase II (CaMKII), and extracellular-signal regulated kinases 1 and 2 (ERK1/2). The library yielded binding variants against 10 targets (66% success rate); success was largely determined by what residue occurred at the +3 position (C-terminal) to the pThr moiety (i.e., pT+3). The FHA domains binding Myc, CaMKII, and ERK1/2 were characterized and compared against commercially available antibodies. All FHA domains were shown to be phosphorylation-dependent and phosphothreonine-specific in their binding, unlike several commercial monoclonal and polyclonal antibodies. Both the pThr and the residue at the pT+3 position were major factors in defining the specificity of the FHA domains. PMID- 26772726 TI - High precision quantification of human plasma proteins using the automated SISCAPA Immuno-MS workflow. AB - Efficient robotic workflows for trypsin digestion of human plasma and subsequent antibody-mediated peptide enrichment (the SISCAPA method) were developed with the goal of improving assay precision and throughput for multiplexed protein biomarker quantification. First, an 'addition only' tryptic digestion protocol was simplified from classical methods, eliminating the need for sample cleanup, while improving reproducibility, scalability and cost. Second, methods were developed to allow multiplexed enrichment and quantification of peptide surrogates of protein biomarkers representing a very broad range of concentrations and widely different molecular masses in human plasma. The total workflow coefficients of variation (including the 3 sequential steps of digestion, SISCAPA peptide enrichment and mass spectrometric analysis) for 5 proteotypic peptides measured in 6 replicates of each of 6 different samples repeated over 6 days averaged 3.4% within-run and 4.3% across all runs. An experiment to identify sources of variation in the workflow demonstrated that MRM measurement and tryptic digestion steps each had average CVs of ~2.7%. Because of the high purity of the peptide analytes enriched by antibody capture, the liquid chromatography step is minimized and in some cases eliminated altogether, enabling throughput levels consistent with requirements of large biomarker and clinical studies. PMID- 26772728 TI - Speract, a sea urchin egg peptide that regulates sperm motility, also stimulates sperm mitochondrial metabolism. AB - Sea urchin sperm have only one mitochondrion, that in addition to being the main source of energy, may modulate intracellular Ca(2+) concentration ([Ca(2+)]i) to regulate their motility and possibly the acrosome reaction. Speract is a decapeptide from the outer jelly layer of the Strongylocentrotus purpuratus egg that upon binding to its receptor in the sperm, stimulates sperm motility, respiration and ion fluxes, among other physiological events. Altering the sea urchin sperm mitochondrial function with specific inhibitors of this organelle, increases [Ca(2+)]i in an external Ca(2+) concentration ([Ca(2+)]ext)-dependent manner (Ardon, et al., 2009. BBActa 1787: 15), suggesting that the mitochondrion is involved in sperm [Ca(2+)]i homeostasis. To further understand the interrelationship between the mitochondrion and the speract responses, we measured mitochondrial membrane potential (DeltaPsi) and NADH levels. We found that the stimulation of sperm with speract depolarizes the mitochondrion and increases the levels of NADH. Surprisingly, these responses are independent of external Ca(2+) and are due to the increase in intracellular pH (pHi) induced by speract. Our findings indicate that speract, by regulating pHi, in addition to [Ca(2+)]i, may finely modulate mitochondrial metabolism to control motility and ensure that sperm reach the egg and fertilize it. PMID- 26772729 TI - Laparoscopic Nephrectomy as Outpatient Surgery. AB - PURPOSE: We tested the feasibility and safety of performing laparoscopic nephrectomy as outpatient surgery in patients with renal cancer. MATERIALS AND METHODS: We performed a prospective, multicenter, descriptive study between April 2014 and February 2015 with postoperative followup at 30 days. A total of 140 patients were diagnosed with renal cancer during this period, of whom 50 met study inclusion criteria and agreed to participate. Reasons for exclusion from analysis included planned partial nephrectomy in 35 patients, lived alone without adequate home support in 17, advanced age or significant comorbid conditions in 33 and refusal to participate in 5. Pain, nausea, fatigue, operative time, bleeding, postoperative care unit stay and hospital stay were assessed. Continuous variables were compared by the paired t-test and categorical variables were compared by the Fisher exact test. RESULTS: Mean age of the 35 males (70%) and 15 females (30%) treated with planned outpatient surgery was 59.8 years. Of the patients 46 (92%) were discharged home within the first 6 hours after surgery. Four patients (8%) could not be discharged due to wrong medication in 2, fatigue in 1 and intestinal injury in 1. None of the 46 patients discharged early were readmitted to the hospital. In 2 patients with wound infection oral antibiotic treatment achieved good results without rehospitalization. CONCLUSIONS: Laparoscopic nephrectomy may be performed as outpatient surgery in carefully selected patients who meet inclusion criteria, representing greater than 40% of candidates for the surgery. Our study demonstrates that outpatient nephrectomy may be done safely and does not require hospital readmission. PMID- 26772730 TI - A 3D-printed functioning anatomical human middle ear model. AB - The middle ear is a sophisticated and complex structure with a variety of functions, yet a delicate organ prone to injuries due to various reasons. Both, understanding and reconstructing its functions has always been an important topic for researchers from medical and technical background. Currently, human temporal bones are generally used as model for tests, experiments and validation of the numerical results. However, fresh human preparations are not always easily accessible and their mechanical properties vary with time and between individuals. Therefore we have built an anatomically based and functional middle ear model to serve as a reproducible test environment. Our middle ear model was manufactured with the aid of 3D-printing technology. We have segmented the essential functional elements from micro computed tomography data (MUCT) of a single temporal bone. The ossicles were 3D-printed by selective laser melting (SLM) and the soft tissues were casted with silicone rubber into 3D-printed molds. The ear canal, the tympanic cavity and the inner ear were artificially designed, but their design ensured the anatomically correct position of the tympanic membrane, ossicular ligaments and the oval window. For the determination of their auditory properties we have conducted two kinds of tests: measurement of the stapes footplate response to sound and tympanometry of the model. Our experiments regarding the sound transmission showed that the model has a similar behavior to a human middle ear. The transfer function has a resonance frequency at around 1 kHz, the stapes' response is almost constant for frequencies below the resonance and a roll-off is observed above the resonance. The tympanometry results show that the compliance of the middle ear model is similar to the compliance of a healthy human middle ear. We also present that we were able to manipulate the transmission behavior, so that healthy or pathological scenarios can be created. For this purpose we have built models with different mechanical properties by varying the hardness of the silicone rubber used for different structures, such as tympanic membrane, oval window and ossicle attachments in the range of Shore 10-40 A. This allowed us to set the transmission amplitudes in the plateau region higher, lower or within the tolerances of normal middle ears (Rosowski et al., 2007). Our results showed that it is possible to build an artificial model of the human middle ear by using 3D-printing technology in combination with silicone rubber molding. We were able to reproduce the anatomical shape of the middle ear's essential elements with high accuracy and also assemble them into a functioning middle ear model. The acoustic behavior of the model can be reproduced and manipulated by the choice of material. If the issues such as resonance of the casing and steep roll-off slope in higher frequencies can be solved, this model creates a reproducible environment for experiments and can be useful for the evaluation of prosthetic devices. PMID- 26772731 TI - First-in-human study and clinical case reports of the alveolar bone regeneration with the secretome from human mesenchymal stem cells. AB - BACKGROUND: Secreted growth factors and cytokines in the conditioned medium from bone marrow-derived mesenchymal stem cells (MSC-CM) have several effects on cell behavior. Our previous studies revealed that MSC-CM enhances bone regeneration by increasing cell mobilization, angiogenesis, and osteogenesis in vitro and in vivo. This clinical study was undertaken to evaluate the safety and use of MSC-CM for alveolar bone regeneration in eight patients who were diagnosed as needing bone augmentation prior to dental implant placement. METHODS: The protocol of this clinical study was approved by the ethics committee of Nagoya University Hospital. MSC-CM was prepared from conditioned medium from commercially available human bone marrow-derived MSCs. Patients were treated with beta-tricalcium phosphate (beta-TCP) or an atelocollagen sponge soaked with MSC-CM. Clinical and radiographic assessments were performed during the follow-up period. Histological assessments were also performed in some cases. Clinical and histological data from patients who underwent the SFE procedure without MSC-CM were also used retrospectively as reference controls. RESULTS: MSC-CM contained several cytokines such as insulin-like growth factor-1, vascular endothelial growth factor, transforming growth factor-beta1, and hepatocyte growth factor in relatively low amounts. No systemic or local complications were reported throughout the study. Radiographic evaluation revealed early bone formation in all cases. Histological evaluation also supported the radiographic findings. Furthermore, infiltration of inflammatory cells was scarce throughout the specimens. CONCLUSIONS: MSC-CM was used safely and with less inflammatory signs and appears to have great osteogenic potential for regenerative medicine of bone. This is the first in-human clinical study of alveolar bone regeneration using MSC CM. PMID- 26772732 TI - Development and validation of clinical performance assessment in simulated medical emergencies: an observational study. AB - BACKGROUND: Critical illness is a time-sensitive process which requires practitioners to process vast quantities of data and make decisions rapidly. We have developed a tool, the Checklist for Early Recognition and Treatment of Acute Illness (CERTAIN), aimed at enhancing care delivery in such situations. To determine the efficacy of CERTAIN and similar cognitive aids, we developed rubric for evaluating provider performance in a simulated medical resuscitation environments. METHODS: We recruited 18 clinicians with current valid ACLS certification for evaluation in three simulated medical scenarios designed to mimic typical medical decompensation events routinely experienced in clinical care. Subjects were stratified as experienced or novice based on prior critical care training. A checklist of critical actions was designed using face validity for each scenario to evaluate task completion and performance. Simulation sessions were video recorded and scored by two independent raters. Construct validity was assessed under the assumption that experienced clinicians should perform better than novice clinicians on each task. Reliability was assessed as percentage agreement, kappa statistics and Bland-Altman plots as appropriate. RESULTS: Eleven experts and seven novices completed evaluation. The overall agreement on common checklist item completion was 84.8 %. The overall model achieved face validity and was consistent with our construct, with experienced clinicians trending towards better performance compared to novices for accuracy and speed of task completion. CONCLUSIONS: A standardized video assessment tool has potential to provide a valid and reliable method to assess 12 performances of clinicians facing simulated medical emergencies. PMID- 26772733 TI - Th-17 regulatory cytokines inhibit corticosteroid induced airway structural cells apoptosis. AB - BACKGROUND: Although corticosteroid is a powerful anti-inflammatory drug that is used widely to control asthma, still severe asthmatics can develop steroid resistance. Airway fibroblasts are quite resistant to steroids during Idiopathic pulmonary fibrosis (IPF) and fibrosis in asthmatic lungs is not always controlled. Th-17 regulatory cytokine which are elevated in lung tissues of asthmatics were shown to enhance the survival of various types of cells. STAT factors are central to this anti-apoptotic function. However, it is not yet clear whether these cytokines contribute to steroid hypo-responsiveness in asthma. Therefore, in this study, we investigated the ability of Th-17 regulatory cytokines, specifically IL-21, IL22 and IL23, to protect structural airway cells against dexamethasone-induced apoptosis. METHODS: Primary human fibroblasts, ASM cells, and lung endothelial cells line were treated with IL-21, IL-22, and IL-23 cytokines before incubation with dexamethasone and the level of apoptosis was determined by measuring cellular Annexin-V using Flow cytometry. RESULTS: Our data indicated that treatment with Th-17 regulatory cytokines was effective in inhibiting induced apoptosis for both fibroblasts and endothelial cells but not ASM cells. STAT3 phosphorylation levels were also upregulated in fibroblasts and endothelial upon treatment with these cytokines. Interestingly, inhibiting STAT3 phosphorylation abrogated IL-21, IL-22, and IL-23 anti-apoptotic effect on fibroblasts and endothelial cells. CONCLUSIONS: This data suggest that Th-17 regulatory cytokines may play a critical role in regulating the survival of fibroblasts during asthma, IPF as well as other chronic lung inflammatory diseases leading to enhanced fibrosis. Accordingly, findings of this paper may pave the way for more extensive research on the role of these regulatory cytokines in fibrosis development in various chronic inflammatory diseases. PMID- 26772735 TI - Back-table procedure and auto-lung transplantation for locally advanced lung cancer: a case report. AB - BACKGROUND: To avoid a pneumonectomy and preserve the lung parenchyma, a bronchovascular double-sleeve plasty including an extended sleeve lobectomy is a good choice for locally advanced lung cancer. CASE PRESENTATION: We describe a case with lung adenocarcinoma enrolled in our new protocol for ex situ auto-lung transplantation following an en bloc pneumonectomy and back table procedure for central lung cancer. Following completion of the pneumonectomy, the excised lung was irrigated with a cold extracellular phosphate-buffered solution to protect the lung graft from ischemia-reperfusion injury during preparation of the graft of a right basal segment as a back-table procedure. CONCLUSION: Although auto lung transplantation is a complicated procedure, an en bloc pneumonectomy following a back table procedure makes preparation of the graft easy, while simultaneous mediastinal lymph node dissection by another surgeon shortens operation time. PMID- 26772734 TI - Correlation of KIT and PDGFRA mutational status with clinical benefit in patients with gastrointestinal stromal tumor treated with sunitinib in a worldwide treatment-use trial. AB - BACKGROUND: Several small studies indicated that the genotype of KIT or platelet derived growth factor receptor-alpha (PDGFRA) contributes in part to the level of clinical effectiveness of sunitinib in gastrointestinal stromal tumor (GIST) patients. This study aimed to correlate KIT and PDGFRA mutational status with clinical outcome metrics (progression-free survival [PFS], overall survival [OS], objective response rate [ORR]) in a larger international patient population. METHODS: This is a non-interventional, retrospective analysis in patients with imatinib-resistant or intolerant GIST who were treated in a worldwide, open-label treatment-use study (Study 1036; NCT00094029) in which sunitinib was administered at a starting dose of 50 mg/day on a 4-week-on, 2-week-off schedule. Molecular status was obtained in local laboratories with tumor samples obtained either pre imatinib, post-imatinib/pre-sunitinib, or post-sunitinib treatment, and all available data were used in the analyses regardless of collection time. The primary analysis compared PFS in patients with primary KIT exon 11 versus exon 9 mutations (using a 2-sided log-rank test) and secondary analyses compared OS (using the same test) and ORR (using a 2-sided Pearson chi(2) test) in the same molecular subgroups. RESULTS: Of the 1124 sunitinib-treated patients in the treatment-use study, 230 (20%) were included in this analysis, and baseline characteristics were similar between the two study populations. Median PFS was 7.1 months. A significantly better PFS was observed in patients with a primary mutation in KIT exon 9 (n = 42) compared to those with a primary mutation in exon 11 (n = 143; hazard ratio = 0.59; 95 % confidence interval, 0.39-0.89; P = 0.011), with median PFS times of 12.3 and 7.0 months, respectively. Similarly, longer OS and higher ORR were observed in patients with a primary KIT mutation in exon 9 versus exon 11. The data available were limited to investigate the effects of additional KIT or PDGFRA mutations on the efficacy of sunitinib treatment. CONCLUSIONS: This large retrospective analysis confirms the prognostic significance of KIT mutation status in patients with GIST. This analysis also confirms the effectiveness of sunitinib as a post-imatinib therapy, regardless of mutational status. TRIAL REGISTRATION: NCT01459757. PMID- 26772737 TI - Relevance of in vitro agar based screens to characterize the anti-fungal activities of bacterial endophyte communities. AB - BACKGROUND: Endophytes are microbes that inhabit internal plant tissues without causing disease. Plant microbial communities consist of large numbers of endophyte species. Understanding the functions of these endophytes is a major challenge. An important function of some endophytes is to suppress fungal pathogens. Typically, plant associated microbes are screened for anti-fungal activities in vitro using the high-throughput dual culture screen, but it is not clear whether this method correlates with the activities of these microbes in planta. Furthermore, it is not clear whether in vitro screening captures all of the microbes that show this activity inside plants. The objective of this study was to evaluate the relevance of the in vitro dual culture method for screening endophytes with anti-fungal activity. RESULTS: In parallel, 190 bacterial endophytes from the corn grass family (Zea) were screened for suppression of two fungal pathogens (Sclerotinia homoeocarpa and Rhizoctonia solani) using the in vitro dual culture method, and in planta using the model plant, creeping bentgrass. All endophytes that showed anti-fungal activity in planta against Sclerotinia homoeocarpa and Rhizoctonia solani (3 or 4 strains, respectively, out of 190), were captured in vitro. The in vitro and in planta screening results strongly correlated (r = 0.81 and r = 0.94 for the two pathogens, respectively). CONCLUSIONS: Evidence was gained here that the in vitro dual culture method is a relevant method for high throughput screening of plant endophyte communities for anti-fungal activity. In our study, the method captured all of the microbes that suppressed the corresponding pathogens in planta. PMID- 26772736 TI - PANasta Trial; Cattell Warren versus Blumgart techniques of panreatico jejunostomy following pancreato-duodenectomy: Study protocol for a randomized controlled trial. AB - BACKGROUND: Failure of the pancreatic remnant anastomosis to heal following pancreato-duodenectomy is a major cause of significant and life-threatening complications, notably a post-operative pancreatic fistula. Recently, non randomized trials have shown superiority of a most intuitive anastomosis (Blumgart technique), which involves both a duct-to-mucosa and a full-thickness pancreatic "U" stitch, in effect a mattress stitch, over a standard duct-mucosa technique (Cattell-Warren). The aim of this study is to examine if these findings remain within a randomized setting. METHODS/DESIGN: The PANasta trial is a randomized, double-blinded multi-center study, whose primary aim is to assess whether a Blumgart pancreatic anastomosis (trial intervention) is superior to a Cattell-Warren pancreatic anastomosis (control intervention), in terms of pancreatic fistula rates. Patients with suspected malignancy of the pancreatic head, in whom a pancreato-duodenectomy is recommended, would be recruited from several UK specialist regional centers. The hypothesis to be tested is that a Blumgart anastomosis will reduce fistula rate from 20 to 10 %. Subjects will be stratified by research site, pancreatic consistency and diameter of pancreatic duct; giving a sample size of 253 per group. The primary outcome measure is fistula rate at the pancreatico-jejunostomy. Secondary outcome measures are: entry into adjuvant therapy, mortality, surgical complications, non-surgical complications, hospital stay, cancer-specific quality of life and health economic assessments. Enrolled patients will undergo pancreatic resection and be randomized immediately prior to pancreatic reconstruction. The operation note will only record "anastomosis constructed as per PANasta trial randomization," thus the other members of the trial team and patient are blinded. An inbuilt internal pilot study will assess the ability to randomize patients, while the construction of an operative manual and review of operative photographs will maintain standardization of techniques. DISCUSSION: The PANasta trial will be the first multi-center randomized controlled trial (RCT) comparing two types of duct to-mucosa pancreatic anastomosis with surgical quality assurance. TRIAL REGISTRATION: ISRCTN52263879 . Date of registration 15 January 2015. PMID- 26772738 TI - Impact of B-type natriuretic peptide level on the risk of left atrial appendage thrombus in patients with nonvalvular atrial fibrillation: a prospective study. AB - BACKGROUND: The impact of B-type natriuretic peptide (BNP) level on the risk of left atrial appendage (LAA) thrombus in patients with nonvalvular atrial fibrillation (NVAF) has not been prospectively studied. METHODS: In two academic medical centers, we obtained BNP levels immediately prior to transesophageal echocardiogram performed to exclude LAA thrombus in patients with NVAF. RESULTS: Among 261 subjects (mean age 65 +/- 12 years; 30 % women) with NVAF, 17 (6.5 %) had LAA thrombus and 85 (32.6 %) had at least mild spontaneous echo contrast (SEC). Mean BNP level was significantly higher in patients with LAA thrombus [775 +/- 678 vs. 384 +/- 537, P = 0.001]. Receiver operator characteristics analysis demonstrated that BNP has a good discriminatory capacity for LAA thrombus (area under the curve, 0.74; 95 % confidence interval [CI], 0.63-0.85; P = 0.001); BNP >= 67 pg/mL was 100 % sensitive and 20 % specific for LAA thrombus. Multivariate logistic regression analysis demonstrated that BNP was not independently associated with LAA thrombus (odds-ratio, 1.05 per 100 pg/mL increment; CI, 0.99 1.12; P = 0.127) after adjusting for CHA2DS2-VASc score; while the latter was independently associated with LAA thrombus after adjusting for BNP level (odds ratio, 1.46 per CHA2DS2-VASc point; CI, 1.09-1.96; P = 0.011). Nonetheless, BNP was associated with SEC in univariate and multivariate analysis, after adjusting for the CHA2DS2-VASc score, (odds-ratio, 1.08; CI, 1.02-1.14; P = 0.005). CONCLUSIONS: BNP is predictive of SEC. However, it does not provide significant incremental value in the prediction of LAA thrombus. PMID- 26772740 TI - Rectal cancer project of the Spanish Association of Surgeons (Viking project): Past and future. PMID- 26772739 TI - The STAP-study: The (cost) effectiveness of custom made orthotic insoles in the treatment for plantar fasciopathy in general practice and sports medicine: design of a randomized controlled trial. AB - BACKGROUND: Plantar fasciopathy is a common cause of foot pain, accounting for 11 to 15% of all foot symptoms requiring professional care in adults. Although many patients have complete resolution of symptoms within 12 months, many patients wish to reduce this period as much as possible. Orthotic devices are a frequently applied option of treatment in daily practice, despite a lack of evidence on the effectiveness. Therefore, the objective is to study the (cost)-effectiveness of custom made insoles by a podiatrist, compared to placebo insoles and usual care in patients with plantar fasciopathy in general practice and sports medicine clinics. METHOD/DESIGN: This study is a multi-center three-armed participant and assessor-blinded randomized controlled trial with 6-months follow-up. Patients with plantar fasciopathy, with a minimum duration of complaints of 2 weeks and aged between 18 and 65, who visit their general practitioner or sport physician are eligible for inclusion. A total of 185 patients will be randomized into three parallel groups. One group will receive usual care by the general practitioner or sports physician alone, one group will be referred to a podiatrist and will receive a custom made insole, and one group will be referred to a podiatrist and will receive a placebo insole. The primary outcome will be the change from baseline to 12 weeks follow-up in pain severity at rest and during activity on a 0-10 numerical rating scale (NRS). Secondary outcomes include foot function (according to the Foot Function Index) at 6, 12 and 26 weeks, recovery (7-point Likert) at 6, 12 and 26 weeks, pain at rest and during activity (NRS) at 6 and 26 weeks and cost-effectiveness of the intervention at 26-weeks. Measurements will take place at baseline and at, 2, 4, 6, 12 and 26 weeks of follow-up. DISCUSSION: The treatment of plantar fasciopathy is a challenge for health care professionals. Orthotic devices are frequently applied, despite a lack of evidence of the effectiveness on patient reported outcome. The results of this randomized controlled trial will improve the evidence base for treating this troublesome condition in daily practice. TRIAL REGISTRATION: Dutch Trial Registration: NTR5346 . Date of registration: August 5(th) 2015. PMID- 26772741 TI - The clinical trial landscape in oncology and connectivity of somatic mutational profiles to targeted therapies. AB - BACKGROUND: Precision medicine in oncology relies on rapid associations between patient-specific variations and targeted therapeutic efficacy. Due to the advancement of genomic analysis, a vast literature characterizing cancer associated molecular aberrations and relative therapeutic relevance has been published. However, data are not uniformly reported or readily available, and accessing relevant information in a clinically acceptable time-frame is a daunting proposition, hampering connections between patients and appropriate therapeutic options. One important therapeutic avenue for oncology patients is through clinical trials. Accordingly, a global view into the availability of targeted clinical trials would provide insight into strengths and weaknesses and potentially enable research focus. However, data regarding the landscape of clinical trials in oncology is not readily available, and as a result, a comprehensive understanding of clinical trial availability is difficult. RESULTS: To support clinical decision-making, we have developed a data loader and mapper that connects sequence information from oncology patients to data stored in an in house database, the JAX Clinical Knowledgebase (JAX-CKB), which can be queried readily to access comprehensive data for clinical reporting via customized reporting queries. JAX-CKB functions as a repository to house expertly curated clinically relevant data surrounding our 358-gene panel, the JAX Cancer Treatment Profile (JAX CTP), and supports annotation of functional significance of molecular variants. Through queries of data housed in JAX-CKB, we have analyzed the landscape of clinical trials relevant to our 358-gene targeted sequencing panel to evaluate strengths and weaknesses in current molecular targeting in oncology. Through this analysis, we have identified patient indications, molecular aberrations, and targeted therapy classes that have strong or weak representation in clinical trials. CONCLUSIONS: Here, we describe the development and disseminate system methods for associating patient genomic sequence data with clinically relevant information, facilitating interpretation and providing a mechanism for informing therapeutic decision-making. Additionally, through customized queries, we have the capability to rapidly analyze the landscape of targeted therapies in clinical trials, enabling a unique view into current therapeutic availability in oncology. PMID- 26772742 TI - Growth of marine fungi on polymeric substrates. AB - BACKGROUND: Marine fungi are a diverse group of opportunistic and obligate organisms isolated from marine environments. These fungi are now often included in screens for novel metabolites, while less attention has been given to their production of hydrolytic enzymes. Most enzymes derived from marine microorganisms have been obtained from marine bacteria. The enzymes produced by marine fungi may have different properties than those derived from bacteria or from terrestrial fungi. Here we assess the growth of six filamentous marine fungi on a wide range of polymeric substrates as an indication of their general capacity to produce hydrolytic enzymes. RESULTS: Calcarisporium sp. KF525, Tritirachium sp. LF562, Bartalinia robillardoides LF550, Penicillium pinophilum LF458, Scopulariopsis brevicaulis LF580 and Pestalotiopsis sp. KF079 all grew on both casein and gelatin as N-source, indicating secretion of proteases. All species also grew on starch, laminarin, xylan, pectin and oil, indicating production of amylases, glucanases, xylanases, pectinases and lipases. Growth on cellulose occurred but was weaker than on xylan. All strains also grew to some extent on sulphated arabinogalactan, although only LF562 could utilise arabinose. Four strains grew on the sulphated ulvans, whereas only KF525 grew on agar or carrageenan. KF525 and LF562 showed limited growth on alginate. Although fucose was used as carbon source by several species, fucoidan did not support biomass production. CONCLUSIONS: Marine fungi could be excellent sources of a wide range of hydrolytic enzymes, including those able to hydrolyse various seaweed polymers. Although the native hosts may secrete only small amounts of these enzymes, the genes may provide a rich source of novel enzymes. PMID- 26772743 TI - A computational method for genotype calling in family-based sequencing data. AB - BACKGROUND: As sequencing technologies can help researchers detect common and rare variants across the human genome in many individuals, it is known that jointly calling genotypes across multiple individuals based on linkage disequilibrium (LD) can facilitate the analysis of low to modest coverage sequence data. However, genotype-calling methods for family-based sequence data, particularly for complex families beyond parent-offspring trios, are still lacking. RESULTS: In this study, first, we proposed an algorithm that considers both linkage disequilibrium (LD) patterns and familial transmission in nuclear and multi-generational families while retaining the computational efficiency. Second, we extended our method to incorporate external reference panels to analyze family-based sequence data with a small sample size. In simulation studies, we show that modeling multiple offspring can dramatically increase genotype calling accuracy and reduce phasing and Mendelian errors, especially at low to modest coverage. In addition, we show that using external panels can greatly facilitate genotype calling of sequencing data with a small number of individuals. We applied our method to a whole genome sequencing study of 1339 individuals at ~10X coverage from the Minnesota Center for Twin and Family Research. CONCLUSIONS: The aggregated results show that our methods significantly outperform existing ones that ignore family constraints or LD information. We anticipate that our method will be useful for many ongoing family-based sequencing projects. We have implemented our methods efficiently in a C++ program FamLDCaller, which is available from http://www.pitt.edu/~wec47/famldcaller.html. PMID- 26772744 TI - Performance of a core of transversal skills: self-perceptions of undergraduate medical students. AB - BACKGROUND: There is an increasingly growing trend towards integrating scientific research training into undergraduate medical education. Communication, research and organisational/learning skills are core competences acquired by scientific research activity. The aim of this study was to assess the perceived performance of a core of transversal skills, related with scientific research, by Portuguese medical students. METHODS: A cross-sectional study was conducted in 611 Portuguese students attending the first, fourth and sixth years of the medical course, during the same academic year. A validated questionnaire was applied for this purpose. RESULTS: Medical students felt confident regarding the majority of the analyzed transversal skills, particularly regarding team work capacity (72.7% perceived their own capacity as good). On the other hand, the perceived ability to manage information technology, time and to search literature was classified only as sufficient by many of them. The progression over the medical course and participation in research activities were associated with an increasing odds of a good perceived performance of skills such as writing skills (research activity: OR = 2.00; 95% CI: 1.34-2.97) and English proficiency (research activity: OR = 1.59; 95% CI: 1.06-2.38/final year medical students: OR = 3.63; 95% CI: 2.42 5.45). CONCLUSIONS: In this line, the early exposure to research activities along undergraduate medical education is an added value for students and the implementation of an integrated research program on medical curriculum should be considered. PMID- 26772745 TI - Multimodal image fusion with SIMS: Preprocessing with image registration. AB - In order to utilize complementary imaging techniques to supply higher resolution data for fusion with secondary ion mass spectrometry (SIMS) chemical images, there are a number of aspects that, if not given proper consideration, could produce results which are easy to misinterpret. One of the most critical aspects is that the two input images must be of the same exact analysis area. With the desire to explore new higher resolution data sources that exists outside of the mass spectrometer, this requirement becomes even more important. To ensure that two input images are of the same region, an implementation of the insight segmentation and registration toolkit (ITK) was developed to act as a preprocessing step before performing image fusion. This implementation of ITK allows for several degrees of movement between two input images to be accounted for, including translation, rotation, and scale transforms. First, the implementation was confirmed to accurately register two multimodal images by supplying a known transform. Once validated, two model systems, a copper mesh grid and a group of RAW 264.7 cells, were used to demonstrate the use of the ITK implementation to register a SIMS image with a microscopy image for the purpose of performing image fusion. PMID- 26772746 TI - Diverse Hormone Response Networks in 41 Independent Drosophila Cell Lines. AB - Steroid hormones induce cascades of gene activation and repression with transformative effects on cell fate . Steroid transduction plays a major role in the development and physiology of nearly all metazoan species, and in the progression of the most common forms of cancer. Despite the paramount importance of steroids in developmental and translational biology, a complete map of transcriptional response has not been developed for any hormone . In the case of 20-hydroxyecdysone (ecdysone) in Drosophila melanogaster, these trajectories range from apoptosis to immortalization. We mapped the ecdysone transduction network in a cohort of 41 cell lines, the largest such atlas yet assembled. We found that the early transcriptional response mirrors the distinctiveness of physiological origins: genes respond in restricted patterns, conditional on the expression levels of dozens of transcription factors. Only a small cohort of genes is constitutively modulated independent of initial cell state. Ecdysone responsive genes tend to organize into directional same-stranded units, with consecutive genes induced from the same strand. Here, we identify half of the ecdysone receptor heterodimer as the primary rate-limiting step in the response, and find that initial receptor isoform levels modulate the activated cohort of target transcription factors. This atlas of steroid response reveals organizing principles of gene regulation by a model type II nuclear receptor and lays the foundation for comprehensive and predictive understanding of the ecdysone transduction network in the fruit fly. PMID- 26772747 TI - Combinatorial Cis-regulation in Saccharomyces Species. AB - Transcriptional control of gene expression requires interactions between the cis regulatory elements (CREs) controlling gene promoters. We developed a sensitive computational method to identify CRE combinations with conserved spacing that does not require genome alignments. When applied to seven sensu stricto and sensu lato Saccharomyces species, 80% of the predicted interactions displayed some evidence of combinatorial transcriptional behavior in several existing datasets including: (1) chromatin immunoprecipitation data for colocalization of transcription factors, (2) gene expression data for coexpression of predicted regulatory targets, and (3) gene ontology databases for common pathway membership of predicted regulatory targets. We tested several predicted CRE interactions with chromatin immunoprecipitation experiments in a wild-type strain and strains in which a predicted cofactor was deleted. Our experiments confirmed that transcription factor (TF) occupancy at the promoters of the CRE combination target genes depends on the predicted cofactor while occupancy of other promoters is independent of the predicted cofactor. Our method has the additional advantage of identifying regulatory differences between species. By analyzing the S. cerevisiae and S. bayanus genomes, we identified differences in combinatorial cis regulation between the species and showed that the predicted changes in gene regulation explain several of the species-specific differences seen in gene expression datasets. In some instances, the same CRE combinations appear to regulate genes involved in distinct biological processes in the two different species. The results of this research demonstrate that (1) combinatorial cis regulation can be inferred by multi-genome analysis and (2) combinatorial cis regulation can explain differences in gene expression between species. PMID- 26772748 TI - The E2F-DP1 Transcription Factor Complex Regulates Centriole Duplication in Caenorhabditis elegans. AB - Centrioles play critical roles in the organization of microtubule-based structures, from the mitotic spindle to cilia and flagella. In order to properly execute their various functions, centrioles are subjected to stringent copy number control. Central to this control mechanism is a precise duplication event that takes place during S phase of the cell cycle and involves the assembly of a single daughter centriole in association with each mother centriole . Recent studies have revealed that posttranslational control of the master regulator Plk4/ZYG-1 kinase and its downstream effector SAS-6 is key to ensuring production of a single daughter centriole. In contrast, relatively little is known about how centriole duplication is regulated at a transcriptional level. Here we show that the transcription factor complex EFL-1-DPL-1 both positively and negatively controls centriole duplication in the Caenorhabditis elegans embryo. Specifically, we find that down regulation of EFL-1-DPL-1 can restore centriole duplication in a zyg-1 hypomorphic mutant and that suppression of the zyg-1 mutant phenotype is accompanied by an increase in SAS-6 protein levels. Further, we find evidence that EFL-1-DPL-1 promotes the transcription of zyg-1 and other centriole duplication genes. Our results provide evidence that in a single tissue type, EFL-1-DPL-1 sets the balance between positive and negative regulators of centriole assembly and thus may be part of a homeostatic mechanism that governs centriole assembly. PMID- 26772751 TI - Robust detection of heartbeats using association models from blood pressure and EEG signals. AB - BACKGROUNDS: The heartbeat is fundamental cardiac activity which is straightforwardly detected with a variety of measurement techniques for analyzing physiological signals. Unfortunately, unexpected noise or contaminated signals can distort or cut out electrocardiogram (ECG) signals in practice, misleading the heartbeat detectors to report a false heart rate or suspend itself for a considerable length of time in the worst case. To deal with the problem of unreliable heartbeat detection, PhysioNet/CinC suggests a challenge in 2014 for developing robust heart beat detectors using multimodal signals. METHODS: This article proposes a multimodal data association method that supplements ECG as a primary input signal with blood pressure (BP) and electroencephalogram (EEG) as complementary input signals when input signals are unreliable. If the current signal quality index (SQI) qualifies ECG as a reliable input signal, our method applies QRS detection to ECG and reports heartbeats. Otherwise, the current SQI selects the best supplementary input signal between BP and EEG after evaluating the current SQI of BP. When BP is chosen as a supplementary input signal, our association model between ECG and BP enables us to compute their regular intervals, detect characteristics BP signals, and estimate the locations of the heartbeat. When both ECG and BP are not qualified, our fusion method resorts to the association model between ECG and EEG that allows us to apply an adaptive filter to ECG and EEG, extract the QRS candidates, and report heartbeats. RESULTS: The proposed method achieved an overall score of 86.26 % for the test data when the input signals are unreliable. Our method outperformed the traditional method, which achieved 79.28 % using QRS detector and BP detector from PhysioNet. Our multimodal signal processing method outperforms the conventional unimodal method of taking ECG signals alone for both training and test data sets. CONCLUSIONS: To detect the heartbeat robustly, we have proposed a novel multimodal data association method of supplementing ECG with a variety of physiological signals and accounting for the patient-specific lag between different pulsatile signals and ECG. Multimodal signal detectors and data-fusion approaches such as those proposed in this article can reduce false alarms and improve patient monitoring. PMID- 26772749 TI - Identification and Characterization of Wor4, a New Transcriptional Regulator of White-Opaque Switching. AB - The human fungal pathogen Candida albicans can switch between two cell types, "white" and "opaque," each of which is heritable through many cell divisions. Switching between these two cell types is regulated by six transcriptional regulators that form a highly interconnected circuit with multiple feedback loops. Here, we identify a seventh regulator of white-opaque switching, which we have named Wor4. We show that ectopic expression of Wor4 is sufficient to drive switching from the white to the opaque cell type, and that deletion of Wor4 blocks switching from the white to the opaque cell type. A combination of ectopic expression and deletion experiments indicates that Wor4 is positioned upstream of Wor1, and that it is formally an activator of the opaque cell type. The combination of ectopic expression and deletion phenotypes for Wor4 is unique; none of the other six white-opaque regulators show this pattern. We determined the pattern of Wor4 binding across the genome by ChIP-seq and found it is highly correlated with that of Wor1 and Wor2, indicating that Wor4 is tightly integrated into the existing white-opaque regulatory circuit. We previously proposed that white-to-opaque switching relies on the activation of a complex circuit of feedback loops that remains excited through many cell divisions. The identification of a new, central regulator of white-opaque switching supports this idea by indicating that the white-opaque switching mechanism is considerably more complex than those controlling conventional, nonheritable patterns of gene expression. PMID- 26772750 TI - Major Improvements to the Heliconius melpomene Genome Assembly Used to Confirm 10 Chromosome Fusion Events in 6 Million Years of Butterfly Evolution. AB - The Heliconius butterflies are a widely studied adaptive radiation of 46 species spread across Central and South America, several of which are known to hybridize in the wild. Here, we present a substantially improved assembly of the Heliconius melpomene genome, developed using novel methods that should be applicable to improving other genome assemblies produced using short read sequencing. First, we whole-genome-sequenced a pedigree to produce a linkage map incorporating 99% of the genome. Second, we incorporated haplotype scaffolds extensively to produce a more complete haploid version of the draft genome. Third, we incorporated ~20x coverage of Pacific Biosciences sequencing, and scaffolded the haploid genome using an assembly of this long-read sequence. These improvements result in a genome of 795 scaffolds, 275 Mb in length, with an N50 length of 2.1 Mb, an N50 number of 34, and with 99% of the genome placed, and 84% anchored on chromosomes. We use the new genome assembly to confirm that the Heliconius genome underwent 10 chromosome fusions since the split with its sister genus Eueides, over a period of about 6 million yr. PMID- 26772753 TI - Schizophrenia-spectrum patients treated with long-acting injectable risperidone in real-life clinical settings: functional recovery in remitted versus stable, non-remitted patients (the EVeREST prospective observational cohort study). AB - BACKGROUND: Previous studies showed functional improvement in stable patients with schizophrenia treated with risperidone long-acting injection (LAI). We therefore re-investigated functional improvement with risperidone LAI in remitted patients, in comparison with stable patients. The study was conducted in real life conditions because of the high heterogeneity of the patients' situations. METHOD: This was a multi-centre, prospective observational cohort study involving adult schizophrenia-spectrum chronic patients who were previously treated with risperidone LAI for 6 months. Remission was evaluated using the consensus criteria proposed by the Remission in Schizophrenia Working Group (RSWG). The primary endpoint was global functioning (assessed with the Global Assessment of Functioning scale, GAF) after one year of treatment. Social functioning was a secondary outcome. RESULTS: The analysis included 1490 patients. Attrition rate was 9.1 % at the end of the study. 27.7 % of patients were in remission after one year of risperidone LAI treatment. The mean GAF rating score (62.5 +/- 1.5) was higher than the cut-off previously used to identify patients with satisfactory functioning (60) and significantly higher than the mean GAF score in stable, non remitted patients (48.3, p < 0.001). Social functioning was also high in remitted patients (21.0 +/- 3.6 vs. 17.2 +/- 3.7 in non-remitted patients, p < 0.001). CONCLUSION: The results clearly show that after one year of treatment with risperidone LAI, RSWG-remitted patients have a high level of global functioning, which is significantly higher than in stable, non-remitted patients. Social functioning was also higher in remitted patients as compared with stable, non remitted patients. PMID- 26772752 TI - FRET biosensors reveal AKAP-mediated shaping of subcellular PKA activity and a novel mode of Ca(2+)/PKA crosstalk. AB - Scaffold proteins play a critical role in cellular homeostasis by anchoring signaling enzymes in close proximity to downstream effectors. In addition to anchoring static enzyme complexes, some scaffold proteins also form dynamic signalosomes that can traffic to different subcellular compartments upon stimulation. Gravin (AKAP12), a multivalent scaffold, anchors PKA and other enzymes to the plasma membrane under basal conditions, but upon [Ca(2+)]i elevation, is rapidly redistributed to the cytosol. Because gravin redistribution also impacts PKA localization, we postulate that gravin acts as a calcium "switch" that modulates PKA-substrate interactions at the plasma membrane, thus facilitating a novel crosstalk mechanism between Ca(2+) and PKA-dependent pathways. To assess this, we measured the impact of gravin-V5/His expression on compartmentalized PKA activity using the FRET biosensor AKAR3 in cultured cells. Upon treatment with forskolin or isoproterenol, cells expressing gravin-V5/His showed elevated levels of plasma membrane PKA activity, but cytosolic PKA activity levels were reduced compared with control cells lacking gravin. This effect required both gravin interaction with PKA and localization at the plasma membrane. Pretreatment with calcium-elevating agents thapsigargin or ATP caused gravin redistribution away from the plasma membrane and prevented gravin from elevating PKA activity levels at the membrane. Importantly, this mode of Ca(2+)/PKA crosstalk was not observed in cells expressing a gravin mutant that resisted calcium-mediated redistribution from the cell periphery. These results reveal that gravin impacts subcellular PKA activity levels through the spatial targeting of PKA, and that calcium elevation modulates downstream beta adrenergic/PKA signaling through gravin redistribution, thus supporting the hypothesis that gravin mediates crosstalk between Ca(2+) and PKA-dependent signaling pathways. Based on these results, AKAP localization dynamics may represent an important paradigm for the regulation of cellular signaling networks. PMID- 26772754 TI - The effect of prior antithyroid drug use on delaying remission in high uptake Graves' disease following radioiodine ablation. AB - Antithyroid drugs (ATDs) have been shown to attenuate the effectiveness of radioiodine (radioiodine ablation, RIA) therapy in Graves' disease. We undertook a study to look at the impact of iodine uptakes on the outcome of (131)I therapy. To determine the effect of prior ATD use on the duration of time to achieve cure in patients with high vs intermediate uptake Graves' disease who received a fixed dose (15 mCi) of (131)I radioiodine. In a retrospective study of patients with Graves' disease, 475 patients who underwent RIA were followed-up on a two-monthly basis with thyroid function tests. Of the 123 patients with a documented preablation RAIU and consistent follow-up it was observed that 40 patients had an intermediate RAIU (10-30%) and 83 subjects had a distinctly increased uptake (>30%). Successful cure was defined as the elimination of thyrotoxicosis in the form of low free thyroxin and rising TSH levels. When a standard dose of 15 mCi (131)I was administered, a cure rate of 93% was achieved. The median duration of time to cure (TC) was 129 days. Surprisingly, a direct proportional linear relationship (R(2)=0.92) was established between time to cure and radioiodine uptake (TC> 3 0%=172days, TC10 - 3 0%=105 days, P<0.001). Patients who used ATD medications took a proportionately longer duration to achieve remission (TCNO ATD=102days, TCATD=253days, P<0.001). The effect of prior ATD therapy in delaying remission was amplified in the subset of patients with higher uptakes (TC> 3 0% + ATD=310days, TC> 3 0% + NO ATD=102days, P<0.001) compared to those with the intermediate uptakes (TC10 - 3 0% + ATD=126 days, TC10 - 3 0% + NO ATD=99 days, P<0.001). RIA, using a dose of 15 mCi achieved a high cure rate. Higher uptakes predicted longer time to achieve remission, with prior ATD use amplifying this effect. PMID- 26772756 TI - A Breakthrough: Macrophage-Directed Cancer Immunotherapy. AB - Successful immunotherapy of cancer is becoming a reality aided by the realization that macrophages play an important role in the growth or regression of tumors. Specifically, M2/repair-type macrophages predominate in human cancers and produce growth-promoting molecules that actively stimulate tumor growth in much the same way they help wounds heal. However, modulating M2/repair-type macrophages to M1/kill-type can slow or stop cancer growth. The effects involve direct activity of M1 kill-type as well as the ability of M1-type macrophages to stimulate Th1 type cytotoxic T cells and other effector cells. Macrophage responses can also predict cancer susceptibility; individuals with a high M1/kill to M2/repair ratio are less prone. That macrophages/innate immunity can be modulated to play a central role in directly or indirectly combating cancer is a breakthrough that seems likely to finally make successful immunotherapy of cancer a reality. PMID- 26772758 TI - Immigrants with dementia in Swedish residential care: an exploratory study of the experiences of their family members and Nursing staff. AB - BACKGROUND: Worldwide, there is a growing population of older people who develop dementia in a country other than that of their origin. When their dementia has reached an advanced stage, residential care is most often needed. People with dementia in Sweden are often cared for in group homes. For immigrants, this may mean a linguistically challenging care environment for both healthcare staff and the patients' family members. The aim of this study was to explore and describe the experiences of family members and professional caregivers regarding the care provided to immigrants with dementia in group homes in Sweden. METHODS: An exploratory, descriptive study with a qualitative approach was chosen. In-depth semi-structured interviews were conducted with nine professional caregivers and five family members of people with dementia with Finnish, Estonian, Hungarian and Ingrian backgrounds; all were chosen purposefully. All people with dementia had lost their Swedish language skills as their second language. The data was analysed using qualitative content analysis. RESULTS: Three main categories and seven subcategories were identified. The first main category: A new living situation comprised the subcategories: adjusting to new living arrangements and expectations regarding activities and traditional food at the group home, the second main category: Challenges in communication with the subcategories: limited communication between the immigrant with dementia and the Swedish-speaking nursing staff and the consequences of linguistic misunderstandings and nuanced communication in a common language and the third main category: The role of the family member at the group home with the subcategories: a link to the healthy life story of the family member with dementia and an expert and interpreter for the nursing staff. CONCLUSIONS: The family member played a crucial role in the lives of immigrants with dementia living in a group home by facilitating communication between the nursing staff and the PWD and also by making it possible for PWD to access the cultural activities they wanted and which professional caregivers were either not able to recognise as needed or could not deliver. PMID- 26772757 TI - Pitfalls in the management of isolated pulmonary Takayasu's arteritis after surgery: a case report of an experience during 34 months after a pulmonary artery graft replacement. AB - BACKGROUND: Several controversial matters still remain unresolved in the management of Takayasu's arteritis, especially after vascular intervention. First, a definitive diagnostic tool has not been established to assess disease activity correctly. Second, the optimal medical regimen has not been established to prevent restenosis of the vascular lesion. Surgical treatments have been rarely performed to relieve critical vascular stenosis in isolated pulmonary Takayasu's arteritis, but their postoperative courses on long-term follow-up periods have not been sufficiently reported. CASE PRESENTATION: A 48-year-old man underwent a successful graft replacement for severe right main pulmonary artery stenosis due to isolated pulmonary Takayasu's arteritis. The patient had remained asymptomatic with no clinical inflammatory signs under adequate anticoagulation therapy since then. However, stenosis of the prosthetic graft accompanied by marked pulmonary hypertension was detected 18 months after surgery. Anti inflammatory treatment with only 5 mg/day of oral prednisolone was then implemented, and the stenosis remained unchanged with the patient being stable for the next 16 months. CONCLUSIONS: This is the first published case report that describes the actual clinical course with a long-term follow-up period after surgery for isolated pulmonary Takayasu's arteritis, including images of the stenosed prosthetic graft. This case suggests that patients should be followed with multiple complementary diagnostic techniques on the assumption that restenosis is highly possible and unpredictable even after surgery. Besides, sufficient anti-inflammatory treatment should be applied as soon as possible after surgery no matter how inactive the disease appears to be, although its optimal regimen especially during the inactive inflammatory phase needs to be further established. PMID- 26772755 TI - DNA Hypomethylation and Histone Variant macroH2A1 Synergistically Attenuate Chemotherapy-Induced Senescence to Promote Hepatocellular Carcinoma Progression. AB - Aging is a major risk factor for progression of liver diseases to hepatocellular carcinoma (HCC). Cellular senescence contributes to age-related tissue dysfunction, but the epigenetic basis underlying drug-induced senescence remains unclear. macroH2A1, a variant of histone H2A, is a marker of senescence associated heterochromatic foci that synergizes with DNA methylation to silence tumor-suppressor genes in human fibroblasts. In this study, we investigated the relationship between macroH2A1 splice variants, macroH2A1.1 and macroH2A1.2, and liver carcinogenesis. We found that protein levels of both macroH2A1 isoforms were increased in the livers of very elderly rodents and humans, and were robust immunohistochemical markers of human cirrhosis and HCC. In response to the chemotherapeutic and DNA-demethylating agent 5-aza-deoxycytidine (5-aza-dC), transgenic expression of macroH2A1 isoforms in HCC cell lines prevented the emergence of a senescent-like phenotype and induced synergistic global DNA hypomethylation. Conversely, macroH2A1 depletion amplified the antiproliferative effects of 5-aza-dC in HCC cells, but failed to enhance senescence. Senescence associated secretory phenotype and whole-transcriptome analyses implicated the p38 MAPK/IL8 pathway in mediating macroH2A1-dependent escape of HCC cells from chemotherapy-induced senescence. Furthermore, chromatin immunoprecipitation sequencing revealed that this hepatic antisenescence state also required active transcription that could not be attributed to genomic occupancy of these histones. Collectively, our findings reveal a new mechanism by which drug-induced senescence is epigenetically regulated by macroH2A1 and DNA methylation and suggest macroH2A1 as a novel biomarker of hepatic senescence that could potentially predict prognosis and disease progression. PMID- 26772759 TI - Preparation of cryogel columns for depletion of hemoglobin from human blood. AB - In this study, we aimed to prepare the metal chelate affinity cryogels for the hemoglobin (Hb) depletion. Poly(2-hydroxyethyl methacrylate) (PHEMA) cryogels were selected as base matrix because of their blood compatibility, osmotic, chemical, and mechanical stability. Cryogels are also useful when working with the viscous samples such as blood, because of their interconnected macroporous structure. Iminodiacetic acid (IDA), the chelating agent, was covalently coupled with PHEMA cryogels after activation with the epichlorohydrin and then the Ni(II) ions were chelated to the IDA-bound cryogels. The depletion of the Hb from hemolysate was shown by SDS-PAGE. PMID- 26772760 TI - "In our stories": The perspectives of women living with HIV on an evidence-based group intervention. AB - A qualitative study among women living with HIV assessed the aspects of an evidence-based intervention targeting HIV transmission risk reduction (Women Involved in Life Learning from Other Women [WiLLOW]) that women valued and how their lives were impacted. Thirty-one women (80.6% African American) completed interviews. Women valued the personal stories and positive group dynamics (i.e. safety, trust, openness, getting feedback, bonding, and socializing). As a result of WiLLOW, women embraced a strong woman image, joined groups, changed behaviors, accepted their HIV status, became optimistic, and spoke up/advocated in their relationships and communities. Interventions for HIV-positive women may benefit from incorporating the sharing of stories in their curricula and factors that build positive group dynamics. PMID- 26772762 TI - Manufacturers failed to report infections from duodenoscopes, US investigation finds. PMID- 26772761 TI - Dopamine receptors participate in acquisition and consolidation of latent learning of spatial information in zebrafish (Danio rerio). AB - There is growing appreciation that various aspects of learning and memory are strongly influenced by dopamine neurotransmission, and that zebrafish hold particular promise in the study of neurotransmitter systems. In this study, we sought to investigate the effect of dopamine receptors on acquisition and consolidation of memory in zebrafish using a latent learning paradigm. To this end, fish were subjected to a 30 min training trial each day for 16 days during which fish were allowed to freely explore a complex maze with the left or right path blocked and without the presence of a reward. During 16 days fish were treated with dopaminergic agonists (apomorphine, SKF-38393, and quinpirole) and antagonists (SCH-23390 and eticlopride) before or after training trials. To assess cognitive performance of fish, a subsequent probe trial was performed on day 17 while all paths leading to a reward chamber were open and the maze now contained stimulus fish as a reward. Pre- and post-training exposure to apomorphine, SKF-38393, and quinpirole significantly impaired learning and memory in fish. In contrast, fish exposed to eticlopride before and after training exhibited improved performance in a latent learning task. Administration of SCH 23390 before training did not affect zebrafish learning ability, but produced significant memory enhancement when given after training trials. Taken together, these findings are the first indications that D1 and D2 receptors are critically involved in acquisition and consolidation of latent learning in zebrafish, with a more prominent role for D2 receptors. The current study opens the door to future studies to investigate the involvement of dopamine receptors in various aspects of cognitive processes. PMID- 26772763 TI - Understanding involvement in surgical orthopaedic randomized controlled trials: A qualitative study of patient and health professional views and experiences. AB - BACKGROUND: Factors influencing patients' motivations for enrolling in, and their experiences of, orthopaedic randomized controlled trials (RCTs) are not fully understood. Less is known about healthcare professionals' (HCP) experiences of RCT involvement. AIM: This study investigates patients' and HCPs' views and experiences of RCT participation and delivery to inform the planning of future RCTs. METHODS: Total hip or knee replacement patients (n = 24) participating in the single-center double-blind APEX RCTs of an intra-operative anesthetic intervention and HCPs (n = 15) involved in trial delivery were interviewed. Data were audio-recorded, transcribed, anonymized and thematically analyzed. RESULTS: Although altruistic reasons for RCT participation were common, patients also weighed up demands of the RCT with the potential benefits of taking part, demonstrating the complex and conditional nature of trial participation. HCPs were interested in RCT involvement as a means of contributing towards advances in medical knowledge and also considered the costs and benefits of RCT involvement. CONCLUSION: Patients and HCPs value involvement in RCTs that they see as relevant and of value, while imposing minimum burden. These findings have important implications for the design of methods to recruit patients to RCTs and for planning how an RCT might best interface with HCP clinical commitments. PMID- 26772764 TI - Patient and provider experience with a new model of care for primary hip and knee arthroplasties. AB - BACKGROUND: The orthopaedic program at a large academic teaching hospital introduced a quality initiative for the primary hip and knee arthroplasty population with the goal to reduce the overall length of stay (LOS) to less than 3 days while ensuring an efficient and exceptional patient experience. This article focuses on the process used to evaluate patient and provider satisfaction with the changes made to achieve a reduction in length of stay. METHOD: The initiative involved current and future process mapping, patient and staff education, a comprehensive mobility strategy, pain management pathways and an evaluation of the patient and provider experience. The goal to reduce LOS for both primary hip and knee arthroplasty surgery was achieved. CONCLUSION: The patients were satisfied with their overall experience including their LOS and preparedness for discharge home. PMID- 26772765 TI - Who cares? A critical discussion of the value of caring from a patient and healthcare professional perspective. AB - BACKGROUND: This study was undertaken in order to discover and illuminate the essential caring behaviours valued by both patients and staff in an orthopaedic setting within a district general hospital in the United Kingdom. OBJECTIVES: This descriptive study was undertaken in order to acquire a greater understanding of perceptions of caring from both patient and orthopaedic healthcare professional perspectives. METHODS: A sample of 30 patients and 53 healthcare professionals consisting of doctors, nurses, physiotherapists and occupational therapists were asked to complete the Caring Behaviours Inventory (CBI) questionnaire (Wolf et al., 1994). Data were analysed using descriptive and inferential statistics. RESULTS: The findings revealed both similarities and differences relating to the importance of positive caring behaviours exhibited during caring interactions. Healthcare professionals working in the orthopaedic setting acknowledged the value of similar positive caring behaviours to those of the patient group but ranked the importance of these differently. DISCUSSION: Several important insights into perceptions of caring have been gained. These relate to an overall understanding of the caring behaviours that are considered of importance to patients and healthcare professionals; the differences that exist between the caring perceptions of both groups and the factors which influence these perceptions. PMID- 26772766 TI - Meeting the demands of on-going metal-on-metal hip surveillance through nurse led services. AB - This paper discusses the implications following a recall of all metal-on-metal hip replacements by the Medicines and Healthcare products regulatory Agency (MHRA). Issues identified were the release of metal ions from the metal implants. These ions were found to seep into local tissues and cause reactions that destroyed muscle and bone leaving some patients with long term disability. At the centre surveillance was monitored by an extension of the current Nurse Led services using existing staff and resources. There were a significant number of patients that required monitoring and there were difficulties contacting these patients and ensuring that they understood the importance of attending a clinic. PMID- 26772768 TI - Metformin alleviates vascular calcification induced by vitamin D3 plus nicotine in rats via the AMPK pathway. PMID- 26772767 TI - Stimulation of calcium-sensing receptors induces endothelium-dependent vasorelaxations via nitric oxide production and activation of IKCa channels. AB - Stimulation of vascular calcium-sensing receptors (CaSRs) is reported to induce both constrictions and relaxations. However, cellular mechanisms involved in these responses remain unclear. The present study investigates the effect of stimulating CaSRs on vascular contractility and focuses on the role of the endothelium, nitric oxide (NO) and K(+) channels in these responses. In wire myography studies, increasing [Ca(2+)]o from 1mM to 6mM induced concentration dependent relaxations of methoxamine pre-contracted rabbit mesenteric arteries. [Ca(2+)]o-induced relaxations were dependent on a functional endothelium, and were inhibited by the negative allosteric CaSR modulator Calhex-231. [Ca(2+)]o induced relaxations were reduced by inhibitors of endothelial NO synthase, guanylate cyclase, and protein kinase G. CaSR activation also induced NO production in freshly isolated endothelial cells (ECs) in experiments using the fluorescent NO indicator DAF-FM. Pre-treatment with inhibitors of large (BKCa) and intermediate (IKCa) Ca(2+)-activated K(+) channels (iberiotoxin and charybdotoxin), and Kv7 channels (linopirdine) also reduced [Ca(2+)]o-induced vasorelaxations. Increasing [Ca(2+)]o also activated IKCa currents in perforated patch recordings of isolated mesenteric artery ECs. These findings indicate that stimulation of CaSRs induces endothelium-dependent vasorelaxations which are mediated by two separate pathways involving production of NO and activation of IKCa channels. NO stimulates PKG leading to BKCa activation in vascular smooth muscle cells, whereas IKCa activity contributes to endothelium-derived hyperpolarisations. PMID- 26772769 TI - Context, mechanisms and outcomes of integrated care for diabetes mellitus type 2: a systematic review. AB - BACKGROUND: Integrated care interventions for chronic conditions can lead to improved outcomes, but it is not clear when and why this is the case. This study aims to answer the following two research questions: First, what are the context, mechanisms and outcomes of integrated care for people with type 2 diabetes? Second, what are the relationships between context, mechanisms and outcomes of integrated care for people with type 2 diabetes? METHODS: A systematic literature search was conducted for the period 2003-2013 in Cochrane and PubMed. Articles were included when they focussed on integrated care and type 2 diabetes, and concerned empirical research analysing the implementation of an intervention. Data extraction was performed using a common data extraction table. The quality of the studies was assessed with the Mixed Methods Appraisal Tool. The CMO model (context + mechanism = outcome) was used to study the relationship between context factors (described by the barriers and facilitators encountered in the implementation process and categorised at the six levels of the Implementation Model), mechanisms (defined as intervention types and described by their number of Chronic Care Model (sub-)components) and outcomes (the intentional and unintentional effects triggered by mechanism and context). RESULTS: Thirty-two studies met the inclusion criteria. Most reported barriers to the implementation process were found at the organisational context level and most facilitators at the social context level. Due to the low number of articles reporting comparable quantitative outcome measures or in-depth qualitative information, it was not possible to make statements about the relationship between context, mechanisms and outcomes. CONCLUSIONS: Efficient resource allocation should entail increased investments at the organisational context level where most barriers are expected to occur. It is likely that investments at the social context level will also help to decrease the development of barriers at the organisational context level, especially by increasing staff involvement and satisfaction. If future research is to adequately inform practice and policy regarding the impact of these efforts on health outcomes, focus on the actual relationships between context, mechanisms and outcomes should be actively incorporated into study designs. PMID- 26772770 TI - Lower selfing rates in metallicolous populations than in non-metallicolous populations of the pseudometallophyte Noccaea caerulescens (Brassicaceae) in Southern France. AB - BACKGROUND AND AIMS: The pseudometallophyte Noccaea caerulescens is an excellent model to study evolutionary processes, as it grows both on normal and on heavy metal-rich, toxic soils. The evolution and demography of populations are critically impacted by mating system and, yet, information about the N. caerulescens mating system is limited. METHODS: Mean selfing rates were assessed using microsatellite loci and a robust estimation method (RMES) in five metallicolous and five non-metallicolous populations of N. caerulescens in Southern France, and this measure was replicated for two successive reproductive seasons. As a part of the study, the patterns of gene flow among populations were analysed. The mating system was then characterized at a fine spatial scale in three populations using the MLTR method on progeny arrays. KEY RESULTS: The results confirm that N. caerulescens has a mixed mating system, with selfing rates ranging from 0.2 to 0.5. Selfing rates did not vary much among populations within ecotypes, but were lower in the metallicolous than in the non metallicolous ecotype, in both seasons. Effective population size was also lower in non-metallicolous populations. Biparental inbreeding was null to moderate. Differentiation among populations was generally high, but neither ecotype nor isolation by distance explained it. CONCLUSIONS: The consequences of higher selfing rates on adaptation are expected to be weak to moderate in non metallicolous populations and they are expected to suffer less from inbreeding depression, compared to metallicolous populations. PMID- 26772772 TI - The Knoevenagel reaction of cyanoacetylhydrazine with pregnenolone: Synthesis of thiophene, thieno[2,3-d]pyrimidine, 1,2,4-triazole, pyran and pyridine derivatives with anti-inflammatory and anti-ulcer activities. AB - The reaction of pregnenolone with cyanoacetylhydrazine and ammonium acetate at 120 degrees C gave the Knoevenagel condensation product 3. The latter reacted with different reagents to give thiophene, thieno[2,3-d]pyrimidine, 1,2,4 triazole and pyran derivatives. The anti-inflammatory and anti-ulcer evaluations of the newly synthesized products were evaluated and the results showed that compounds 4, 8c, 10, 11, 13c, 15a, 15c, 17a, 17b, 17e, 18a and 18f possessed higher activity compared to the rest of the compounds. In addition to this, the toxicity of these active compounds was studied against shrimp larvae where compounds 15a, 15c and 18a showed non-toxicity against the tested organisms. PMID- 26772771 TI - Primary Care Providers' Views of Patient Portals: Interview Study of Perceived Benefits and Consequences. AB - BACKGROUND: The United States government is encouraging physicians to adopt patient portals-secure websites that allow patients to access their health information. For patient portals to recognize their full potential and improve patient care, health care providers' acceptance and encouragement of their use will be essential. However, little is known about provider concerns or views of patient portals. OBJECTIVE: We conducted this qualitative study to determine how administrators, clinic staff, and health care providers at practices serving a lower income adult population viewed patient portals in terms of their potential benefit, areas of concern, and hopes for the future. METHODS: We performed in depth interviews between October 2013 and June 2014 with 20 clinic personnel recruited from health centers in four North Carolina counties. Trained study personnel conducted individual interviews following an interviewer guide to elicit perceptions of the benefits and disadvantages of patient portals. Interviews were recorded and transcribed. Research team members reviewed transcribed interviews for major themes to construct a coding dictionary. Two researchers then coded each transcript with any coding discrepancies resolved through discussion. RESULTS: The interviews revealed that clinic personnel viewed patient portals as a mandated product that had potential to improve communication and enhance information sharing. However, they expressed many concerns including portals' potential to generate more work, confuse patients, alienate non-users, and increase health disparities. Clinic personnel expected few older and disadvantaged patients to use a portal. CONCLUSIONS: Given that clinic personnel have significant concerns about portals' unintended consequences, their uptake and impact on care may be limited. Future studies should examine ways portals can be implemented in practices to address providers' concerns and meet the needs of vulnerable populations. PMID- 26772773 TI - Redox Imbalance in Lung Cancer of Patients with Underlying Chronic Respiratory Conditions. AB - Chronic respiratory diseases such as obstructive pulmonary disease (COPD) and oxidative stress may underlie lung cancer (LC). We hypothesized that the profile of oxidative and antioxidant events may differ in lung tumors and blood compartments of patients with non-small cell LC (NSCLC) with and without COPD. Redox markers (immunoblotting, ELISA, chemiluminescence, 2D electrophoresis and proteomics) were analyzed in blood samples of 17 control subjects and 80 LC patients (59 LC-COPD and 21 LC) and lung specimens (tumor and nontumor) from those undergoing thoracotomy (35 patients: 23 LC-COPD and 12 LC). As smoking history was more prevalent in LC-COPD patients, these were further analyzed post hoc as heavy and moderate smokers (cutoff, 60 pack-years). Malondialdehyde (MDA) protein adducts and SOD1 levels were higher in tumor and nontumor samples of LC COPD than in LC. In tumors compared with nontumors, SOD2 protein content was greater, whereas catalase levels were decreased in both LC and LC-COPD patients. Blood superoxide anion levels, protein carbonylation and nitration were greater in LC and LC-COPD patients than in the controls, and in the latter patients compared with the former. Systemic superoxide anion, protein carbonyls and nitrotyrosine above specific cutoff values best identified underlying COPD among all patients. Smoking did not influence the study results. A differential expression profile of oxidative stress markers exists in blood and, to a lesser extent, in the tumors of LC-COPD patients. These findings suggest that systemic oxidative stress and lung antioxidants (potential biomarkers) may predispose patients with chronic respiratory diseases to a higher risk for LC. PMID- 26772774 TI - MECHANICAL VENTILATION AUGMENTS POLY(I:C)INDUCED LUNG INJURY VIA A WISP1-INTEGRIN beta3 DEPENDENT PATHWAY IN MICE. AB - Mechanical ventilation can improve hypoxemia, but can also cause the so-called ventilator-induced lung injury (VILI). Polyinosinic-polycytidylic acid (poly(I:C)), an analogue of natural double strand RNA virus, can induce lung inflammation. The purpose of this study was to determine whether moderate tidal volume mechanical ventilation (MTV) augments Poly(I:C)-induced lung injury, and if so, the mechanism responsible for it. Poly(I:C) (2MUg/g) were instilled intratracheally in C57BL/6J wide type (WT) mice. They were then randomized to MTV (10ml/kg tidal volume) or spontaneous breath. Lung tissues and bronchoalveolar lavage fluid (BALF) were collected 4h later for various measurements. Our results showed that MTV did not cause significant injury in normal lungs, but augmented Poly(I:C)-induced lung injury. The expression level of WNT-induced secreted protein 1 (WISP1) was consistent with lung injury, and the amplification of lung injury by MTV can be alleviated by anti-WISP1 antibody treatment. MTV further increased Poly(I:C)-induced integrin beta3 expression in the lung. And co immunoprecipitation (Co-IP) results suggested there was an interaction between WISP1 and beta3. WISP1 significantly increased Poly(I:C)-induced TNF-alpha production in macrophages isolated from WT mice but not in macrophages isolated from beta3 knock-out mice. Co-treatment with WISP1 and Poly(I:C) markedly increased the phosphorylation of extracellular signal-related kinase (ERK) in macrophages. Pretreating macrophages with an ERK inhibitor, U0126, dose dependently antagonized WISP's synergistic effect on Poly(I:C)-induced TNF-alpha release. In conclusion, MTV exaggerates Poly(I:C)-induced lung injury in a WISP1 and integrin beta3 dependent manner, involving, at least part, the activation of the ERK pathway. The WISP1-integrin beta3 pathway could be an important target for novel therapy. PMID- 26772775 TI - Purified and Recombinant Hemopexin: Protease Activity and Effect on Neutrophil Chemotaxis. AB - Infusion of the heme-binding protein hemopexin has been proposed as a novel approach to decrease heme-induced inflammation in settings of red blood cell breakdown, but questions have been raised as to possible side effects related to protease activity and inhibition of chemotaxis. We evaluated protease activity and effects on chemotaxis of purified plasma hemopexin obtained from multiple sources as well as a novel recombinant fusion protein Fc-hemopexin. Amidolytic assay was performed to measure the protease activity of several plasma-derived hemopexin and recombinant Fc-hemopexin. Hemopexin was added to the human monocyte culture in the presence of lipopolysaccharides (LPS), and also injected into mice intravenously (i.v.) 30 min before inducing neutrophil migration via intraperitoneal (i.p.) injection of thioglycolate. Control groups received the same amount of albumin. Protease activity varied widely between hemopexins. Recombinant Fc-hemopexin bound heme, inhibited the synergy of heme with LPS on tumor necrosis factor (TNF) production from monocytes, and had minor but detectable protease activity. There was no effect of any hemopexin preparation on chemotaxis, and purified hemopexin did not alter the migration of neutrophils into the peritoneal cavity of mice. Heme and LPS synergistically induced the release of LTB4 from human monocytes, and hemopexin blocked this release, as well as chemotaxis of neutrophils in response to activated monocyte supernatants. These results suggest that hemopexin does not directly affect chemotaxis through protease activity, but may decrease heme-driven chemotaxis and secondary inflammation by attenuating the induction of chemoattractants from monocytes. This property could be beneficial in some settings to control potentially damaging inflammation induced by heme. PMID- 26772776 TI - Cannabidiol Limits T Cell-Mediated Chronic Autoimmune Myocarditis: Implications to Autoimmune Disorders and Organ Transplantation. AB - Myocarditis is a major cause of heart failure and sudden cardiac death in young adults and adolescents. Many cases of myocarditis are associated with autoimmune processes in which cardiac myosin is a major autoantigen. Conventional immunosuppressive therapies often provide unsatisfactory results and are associated with adverse toxicities during the treatment of autoimmune myocarditis. Cannabidiol (CBD) is a nonpsychoactive constituent of marijuana that exerts antiinflammatory effects independent of classical cannabinoid receptors. Recently, 80 clinical trials have investigated the effects of CBD in various diseases from inflammatory bowel disease to graft versus host disease. CBD-based formulations are used for the management of multiple sclerosis in numerous countries, and CBD also received U.S. Food and Drug Administration approval for the treatment of refractory childhood epilepsy and glioblastoma multiforme. Herein, using a well-established mouse model of experimental autoimmune myocarditis (EAM) induced by immunization with cardiac myosin emmulsified in adjuvant resulting in T cell-mediated inflammation, cardiomyocyte cell death, fibrosis and myocardial dysfunction, we studied the potential beneficial effects of CBD. EAM was characterized by marked myocardial T-cell infiltration, profound inflammatory response and fibrosis (measured by quantitative real-time polymerase chain reaction, histology and immunohistochemistry analyses) accompanied by marked attenuation of both systolic and diastolic cardiac functions measured with a pressure-volume conductance catheter technique. Chronic treatment with CBD largely attenuated the CD3+ and CD4+ T cell-mediated inflammatory response and injury, myocardial fibrosis and cardiac dysfunction in mice. In conclusion, CBD may represent a promising novel treatment for managing autoimmune myocarditis and possibly other autoimmune disorders and organ transplantation. PMID- 26772779 TI - Bahraini doctor detained for Tweets needs legal and medical support, says BMA. PMID- 26772778 TI - The Effects of Volume-Controlled and Pressure-Controlled Ventilation on Lung Mechanics, Oxidative Stress, and Recovery in Gynecologic Laparoscopic Surgery. AB - STUDY OBJECTIVE: To compare ventilation variables, changes in oxidative stress, and the quality of recovery in 2 different ventilation strategies (volume controlled ventilation [VCV] and pressure-controlled ventilation [PCV]) during gynecologic laparoscopic surgery. DESIGN: A prospective randomized controlled trial (Canadian Task Force classification I). SETTING: One university teaching hospital in Taiwan. PATIENTS: Women scheduled for laparoscopic gynecologic surgery. INTERVENTIONS: Women were randomly assigned to receive either VCV or PCV during surgery. MEASUREMENTS AND MAIN RESULTS: Ventilation variables were recorded 1 minute before and 1 hour after pneumoperitoneum. Blood samples were collected for malondialdehyde measurement at 7 points: 1 minute before and 1 hour after pneumoperitoneum; 30, 60, 90, and 120 minutes after deflation; and 24 hours after surgery. Postoperative recovery was assessed by using a 9-item quality of recovery score at 24 hours after surgery. A total of 52 women randomly allocated to the VCV (n = 27) or PCV (n = 25) group completed the study. We found that after 1 hour of insufflation the PCV group had lower peak airway pressure (22.0 +/- 3.4 vs 26.6 +/- 4.1 cm H2O, p < .0001) and higher compliance (28.4 +/- 3.7 vs 24.1 +/- 3.3 mL/cm H2O, p < .0001) than the VCV group. In plasma levels of malondialdehyde, there were no significant differences between the 2 groups at 7 time points. The levels significantly increased in both groups after 1 hour of pneumoperitoneum and peaked at 2 hours after deflation. During postoperative recovery, lower scores were obtained at 24 hours after surgery compared with preoperative scores, but there were no significant differences between the 2 groups. CONCLUSION: PCV is an alternative ventilation mode in gynecologic laparoscopic surgery. However, PCV offered lower peak airway pressure and higher compliance than VCV but no advantages over VCV in oxidative stress or quality of recovery. PMID- 26772777 TI - Adenomyosis: What the Patient Needs. AB - A panel of experts in the field of endometriosis expressed their opinions on management options in a 28-year-old patient, attempting pregnancy for 1 year, with severe cyclic pelvic pain and with clinical examination and imaging techniques suggestive of adenomyosis. Many questions this paradigmatic patient may pose to the clinician are addressed, and all clinical scenarios are discussed. A decision algorithm derived from this discussion is also proposed. PMID- 26772780 TI - Individual trial analysis evidences clock and non-clock based conditioned suppression behaviors in rats. AB - We analyzed the temporal pattern of conditioned suppression of lever-pressing for food in rats conditioned with tone-shock pairings using either a 10 or 15s conditioned stimulus (CS)-unconditioned stimulus (US) interval with a CS duration that was three times the CS-US interval. The analysis of average suppression and of individual trials was performed during Probe CS-alone trials and when a short gap was inserted during the CS. The pattern of suppression followed the classical temporal rules: (1) scalar property, (2) a shift in peak suppression due to a gap, compatible with a Stop rule, (3) a three-state pattern of lever-pressing in individual trials, with abrupt start and stop of suppression. The peak of the average suppression curve, but not the middle time, was anticipatory to the programmed US time. The pattern of lever-pressing in individual trials unraveled two types of start of suppression behavior: a clock-based biphasic responding, with a burst of lever-pressing before suppression, and a non-clock based monophasic reduction of lever-pressing close to the CS onset. The non-clock based type of behavior may be responsible for the anticipatory peak time, and the biphasic pattern of lever-pressing may reflect the decision stage described in clock models. PMID- 26772781 TI - Preventing the recovery of extinguished ethanol tolerance. AB - There is substantial evidence that drug-paired cues become associated with drug effects. From a Pavlovian perspective, these cues act as conditioned stimuli and elicit conditioned compensatory responses that contribute to drug tolerance. Here we report two experiments with rats in which we studied the extinction of the associative tolerance to the ataxic effect of ethanol. Experiment 1 evaluated whether changes in the temporal and physical contexts after extinction training provoke recovery of the extinguished tolerance. The results showed successful extinction, spontaneous recovery and renewal of the extinguished tolerance, but no summation of renewal and spontaneous recovery. Experiment 2 evaluated whether using massive extinction trials and delivering extinction in multiple contexts attenuates the renewal effect. The results showed that both manipulations reduced renewal of the extinguished tolerance to the ataxic effect of ethanol; however, these manipulations used in combination did not appear to be more effective in reducing recovery than each by itself. The present results may help guide further research that evaluates behavioral ploys to prevent the recovery of extinguished responses. PMID- 26772782 TI - Direct costs and benefits of multiple mating: Are high female mating rates due to ejaculate replenishment? AB - Females often mate more than is necessary to ensure reproductive success even when they incur significant costs from doing so. Direct benefits are hypothesized to be the driving force of high female mating rates, yet species in which females only receive an ejaculate from their mate still realize increased fitness from multiple mating. Using the Texas field cricket, Gryllus texensis, we experimentally test the hypothesis that multiple mating via monandry or polyandry increases female fitness by replenishing ejaculates, thereby allowing females to produce more offspring for a longer period of time. We found that higher rates of female mating significantly increased lifetime fecundity and oviposition independent of whether females mated with one or two males. Further, although interactions with males significantly increased rates of injury or death, females that replenished ejaculates experienced an increased rate and duration of oviposition, demonstrating that the immediate benefits of multiple mating may greatly outweigh the long-term costs that mating poses to female condition and survival. We suggest that ejaculate replenishment is a driving factor of high mating rates in females that do not receive external direct benefits from mating and that a comparative study across taxa will provide additional insight into the role that ejaculate size plays in the evolution of female mating rates. PMID- 26772783 TI - Behavioral changes over time in post-traumatic stress disorder: Insights from a rat model of single prolonged stress. AB - Post-traumatic stress disorder (PTSD) is manifested as a persistent mental and emotional condition after potentially life-threatening events. Different animal models of PTSD have been developed for neuro-pathophysiology and pharmacological evaluations. A single prolonged stress (SPS) induced animal model has demonstrated to result in specific neuro-endocrinological dysregulation, and behavior abnormalities observed in PTSD. However, animal studies of PTSD have mostly been performed at one time point after SPS exposure. To better understand the development of PTSD-like behaviors in the SPS animal model, and to identify an optimal period of study, we examined depressive behavior, anxiety-like behavior, physical activity and body weight in SPS model rats for two weeks. Our results confirmed the SPS-induced PTSD-like behavior and physical activity observed in previous studies, and indicated that the most pronounced symptomatic behavior changes were observed on day 1 and 7 after SPS exposure, which may involve stress-induced acute hormone changes and unclear secondary neurobiological changes, respectively. These results provide a solid basis for further investigation into the neuro-pathophysiology of or neuropharmacology for PTSD using the SPS rat model. However, for chronic (pharmacological) studies longer than 7 days, a prolonged PTSD animal model should be developed, perhaps using enhanced stimulation. PMID- 26772784 TI - ER functions of oncogenes and tumor suppressors: Modulators of intracellular Ca(2+) signaling. AB - Intracellular Ca(2+) signals that arise from the endoplasmic reticulum (ER), the major intracellular Ca(2+)-storage organelle, impact several mitochondrial functions and dictate cell survival and cell death processes. Furthermore, alterations in Ca(2+) signaling in cancer cells promote survival and establish a high tolerance towards cell stress and damage, so that the on-going oncogenic stress does not result in the activation of cell death. Over the last years, the mechanisms underlying these oncogenic alterations in Ca(2+) signaling have started to emerge. An important aspect of this is the identification of several major oncogenes, including Bcl-2, Bcl-XL, Mcl-1, PKB/Akt, and Ras, and tumor suppressors, such as p53, PTEN, PML, BRCA1, and Beclin 1, as direct and critical regulators of Ca(2+)-transport systems located at the ER membranes, including IP3 receptors and SERCA Ca(2+) pumps. In this way, these proteins execute part of their function by controlling the ER-mitochondrial Ca(2+) fluxes, favoring either survival (oncogenes) or cell death (tumor suppressors). Oncogenic mutations, gene deletions or amplifications alter the expression and/or function of these proteins, thereby changing the delicate balance between oncogenes and tumor suppressors, impacting oncogenesis and favoring malignant cell function and behavior. In this review, we provided an integrated overview of the impact of the major oncogenes and tumor suppressors, often altered in cancer cells, on Ca(2+) signaling from the ER Ca(2+) stores. This article is part of a Special Issue entitled: Calcium and Cell Fate. Guest Editors: Jacques Haiech, Claus Heizmann, Joachim Krebs, Thierry Capiod and Olivier Mignen. PMID- 26772785 TI - Characterization, prediction and evolution of plant peroxisomal targeting signals type 1 (PTS1s). AB - Our knowledge of the proteome of plant peroxisomes and their functional plasticity is far from being complete, primarily due to major technical challenges in experimental proteome research of the fragile cell organelle. Several unexpected novel plant peroxisome functions, for instance in biotin and phylloquinone biosynthesis, have been uncovered recently. Nevertheless, very few regulatory and membrane proteins of plant peroxisomes have been identified and functionally described up to now. To define the matrix proteome of plant peroxisomes, computational methods have emerged as important powerful tools. Novel prediction approaches of high sensitivity and specificity have been developed for peroxisome targeting signals type 1 (PTS1) and have been validated by in vivo subcellular targeting analyses and thermodynamic binding studies with the cytosolic receptor, PEX5. Accordingly, the algorithms allow the correct prediction of many novel peroxisome-targeted proteins from plant genome sequences and the discovery of additional organelle functions. In this review, we provide an overview of methodologies, capabilities and accuracies of available prediction algorithms for PTS1 carrying proteins. We also summarize and discuss recent quantitative, structural and mechanistic information of the interaction of PEX5 with PTS1 carrying proteins in relation to in vivo import efficiency. With this knowledge, we develop a model of how proteins likely evolved peroxisomal targeting signals in the past and still nowadays, in which order the two import pathways might have evolved in the ancient eukaryotic cell, and how the secondary loss of the PTS2 pathway probably happened in specific organismal groups. PMID- 26772786 TI - Development of resazurin-based assay in 384-well format for high throughput whole cell screening of Trypanosoma brucei rhodesiense strain STIB 900 for the identification of potential anti-trypanosomal agents. AB - To accelerate the discovery of novel leads for the treatment of Human African Trypanosomiasis (HAT), it is necessary to have a simple, robust and cost effective assay to identify positive hits by high throughput whole cell screening. Most of the fluorescence assay was made in black plate however in this study the HTS assay developed in 384-well format using clear plate and black plate, for comparison. The HTS assay developed is simple, sensitive, reliable and reproducible in both types of plates. Assay robustness and reproducibility were determined under the optimized conditions in 384-well plate was well tolerated in the HTS assay, including percentage of coefficient of variation (% CV) of 4.68% and 4.74% in clear and black 384-well plate, signal-to-background ratio (S/B) of 12.75 in clear 384-well plate and 12.07 in black 384-well plate, Z' factor of 0.79 and 0.82 in clear 384-well plate and black 384-well plate, respectively and final concentration of 0.30% dimethylsulfoxide (DMSO) in both types of plate. Drug sensitivity was found to be comparable to the reported anti-trypanosomal assay in 96-well format. The reproducibility and sensitivity of this assay make it compliant to automated liquid handler use in HTS applications. PMID- 26772787 TI - Differential effects of co-administration of oxotremorine with SCH 23390 on impulsive choice in high-impulsive rats and low-impulsive rats. AB - The effect of acetylcholine on impulsive choice is thought to be due to interactions between cholinergic and dopaminergic systems, but this hypothesis has not been proven. This study investigated whether D1-like receptors were involved in the effects of the muscarinic cholinergic agonist oxotremorine on impulsive choice in high-impulsive rats (HI rats, n=8) and low-impulsive rats (LI rats, n=8) characterized by basal levels of impulsive choice in a delay discounting task. The results revealed that oxotremorine (0.05mg/kg) significantly increased the choice of the large reinforcer in HI rats, whereas decreased the choice of the large reinforcer in LI rats. The D1-like antagonist SCH 23390 produced significant reductions in the large-reinforcer choice in HI rats (0.01mg/kg) and LI rats (0.005, 0.0075, and 0.01mg/kg). SCH 23390 significantly inhibited the increase in the choice of the large reinforcer induced by oxotremorine (0.05mg/kg) in HI rats at doses of 0.005 and 0.0075mg/kg, but enhanced the effect of oxotremorine in LI rats only at the dose of 0.0075mg/kg. These findings suggested that D1-like receptors might be involved in the differential effects of oxotremorine on impulsive choice between HI rats and LI rats. PMID- 26772788 TI - Potential influence of in utero and early neonatal exposures on the later development of endometriosis. AB - OBJECTIVE: To investigate the possible correlation between maternal characteristics, in utero and early neonatal life exposures, and the development of endometriosis in adult life. DESIGN: Case-control study. SETTING: University hospital. PATIENT(S): A group of 161 patients with endometriosis and a control group of 230 women undergoing laparoscopy for benign adnexal diseases and free of endometriosis. INTERVENTION(S): All women included in the study were requested to answer a series of questions about their mothers' gestational data and on their own perinatal and early postnatal lives. MAIN OUTCOME MEASURE(S): Odds ratio, adjusted odds ratios, and 95% confidence intervals for the associations between maternal characteristics during the patient's pregnancy, in utero exposure to obstetrical and perinatal complications, and the type of feeding received during the neonatal period with the development of endometriosis in adult life. RESULT(S): Mothers of women with endometriosis were significantly more likely to be affected by endometriosis or uterine fibroids, with a higher incidence of smoking during pregnancy. Women with endometriosis were more frequently born prematurely, with a significantly lower birth weight, and their mothers experienced preeclampsia during their pregnancies more often than control subjects. They were also more frequently formula fed than breast fed in early life. However, only prematurity and formula feeding were retained in the multivariate analysis model. CONCLUSION(S): Among intrauterine and early neonatal exposures, prematurity and formula feeding were risk factors for the development of endometriosis in adult life. Further studies should evaluate the underlying biologic mechanisms. PMID- 26772789 TI - Is the resulting phenotype of an embryo with balanced X-autosome translocation, obtained by means of preimplantation genetic diagnosis, linked to the X inactivation pattern? AB - OBJECTIVE: To examine if a balanced female embryo with X-autosome translocation could, during its subsequent development, express an abnormal phenotype. DESIGN: Preimplantation genetic diagnosis (PGD) analysis on two female carriers with maternal inherited X-autosome translocations. SETTING: Infertility center and genetic laboratory in a public hospital. PATIENT(S): Two female patients carriers undergoing PGD for a balanced X-autosome translocations: patient 1 with 46,X,t(X;2)(q27;p15) and patient 2 with 46,X,t(X;22)(q28;q12.3). INTERVENTION(S): PGD for balanced X-autosome translocations. MAIN OUTCOME MEASURE(S): PGD outcomes, fluorescence in situ hybridization in biopsied embryos and meiotic segregation patterns analysis of embryos providing from X-autosome translocation carriers. RESULT(S): Controlled ovarian stimulation facilitated retrieval of a correct number of oocytes. One balanced embryo per patient was transferred and one developed, but the patient miscarried after 6 weeks of amenorrhea. In X autosome translocation carriers, balanced Y-bearing embryos are most often phenotypically normal and viable. An ambiguous phenotype exists in balanced X bearing embryos owing to the X inactivation mechanism. In 46,XX embryos issued from an alternate segregation, der(X) may be inactivated and partially spread transcriptional silencing into a translocated autosomal segment. Thus, the structural unbalanced genotype could be turned into a viable functional balanced one. It is relevant that a discontinuous silencing is observed with a partial and unpredictable inactivation of autosomal regions. Consequently, the resulting phenotype remains a mystery and is considered to be at risk of being an abnormal phenotype in the field of PGD. CONCLUSION(S): It is necessary to be cautious regarding to PGD management for this type of translocation, particularly in transferred female embryos. PMID- 26772791 TI - Reply. PMID- 26772792 TI - Preeclampsia: simplified or still miles to go? PMID- 26772793 TI - Posttest risk calculation following positive noninvasive prenatal screening using cell-free DNA in maternal plasma. AB - Noninvasive prenatal screening (NIPS) for fetal chromosome defects has high sensitivity and specificity but is not fully diagnostic. In response to a desire to provide more information to individual women with positive NIPS results, 2 online calculators have been developed to calculate posttest risk (PTR). Use of these calculators is critically reviewed. There is a mathematically dictated requirement for a precise estimate for the specificity to provide an accurate PTR. This is illustrated by showing that a 0.1% decrease in the value for specificities for trisomies 21, 18, and 13 can reduce the PTR from 79-64% for trisomy 21, 39-27% for trisomy 18, and 21-13% for trisomy 13, respectively. Use of the calculators assumes that sensitivity and specificity are constant for all women receiving the test but there is evidence that discordancy between screening results and true fetal karyotype is more common for older women. Use of an appropriate value for the prior risk is also important and for rare disorders there is considerable uncertainty regarding prevalence. For example, commonly used rates for trisomy 13, monosomy-X, triploidy, and 22q11.2 deletion syndrome can vary by >4-fold and this can translate into large differences in PTR. When screening for rare disorders, it may not be possible to provide a reliable PTR if there is uncertainty over the false-positive rate and/or prevalence. These limitations, per se, do not negate the value of screening for rare conditions. However, counselors need to carefully weigh the validity of PTR before presenting them to patients. Additional epidemiologic and NIPS outcome data are needed. PMID- 26772795 TI - Gender-specific diagnostic performance of a new high-sensitivity cardiac troponin I assay for detection of acute myocardial infarction. AB - BACKGROUND: The determination of cardiac troponin is essential for diagnosing myocardial infarction. A troponin I assay has recently been developed that provides the highest analytical sensitivity to date. METHODS: The analysis included 1560 patients with chest pain, of whom 1098 were diagnosed with non coronary chest pain, 189 with unstable angina pectoris and 273 with non-ST segment elevation myocardial infarction. The troponin I concentration was determined on admission (0 hours) and 3 hours later. The diagnostic algorithm incorporated troponin I elevation above the gender-specific 99th percentile as well as predefined relative or absolute 3-hour changes in the troponin I concentration (delta). RESULTS: The diagnostic criterion of troponin I above the 99th percentile resulted in a negative predictive value of 98.0% and 98.2% in men and women, respectively. For rule-in of non-ST-segment elevation myocardial infarction, the use of absolute deltas yielded higher positive predictive values and sensitivities compared to relative deltas. With detection rates of about 85% and 82% in men and women, respectively, non-ST-segment elevation myocardial infarction was diagnosed with a positive predictive value close to 84% in men and 80% in women. CONCLUSIONS: The investigational troponin I assay provides an excellent non-ST-segment elevation myocardial infarction rule out. With gender specific differences, the application of absolute changes in troponin concentration was superior to relative changes to rule in patients with non-ST segment elevation myocardial infarction. PMID- 26772790 TI - Preterm neonatal morbidity and mortality by gestational age: a contemporary cohort. AB - BACKGROUND: Although preterm birth <37 weeks' gestation is the leading cause of neonatal morbidity and mortality in the United States, the majority of data regarding preterm neonatal outcomes come from older studies, and many reports have been limited to only very preterm neonates. Delineation of neonatal outcomes by delivery gestational age is needed to further clarify the continuum of mortality and morbidity frequencies among preterm neonates. OBJECTIVE: We sought to describe the contemporary frequencies of neonatal death, neonatal morbidities, and neonatal length of stay across the spectrum of preterm gestational ages. STUDY DESIGN: This was a secondary analysis of an obstetric cohort of 115,502 women and their neonates who were born in 25 hospitals nationwide, 2008 through 2011. All liveborn nonanomalous singleton preterm (23.0-36.9 weeks of gestation) neonates were included in this analysis. The frequency of neonatal death, major neonatal morbidity (intraventricular hemorrhage grade III/IV, seizures, hypoxic ischemic encephalopathy, necrotizing enterocolitis stage II/III, bronchopulmonary dysplasia, persistent pulmonary hypertension), and minor neonatal morbidity (hypotension requiring treatment, intraventricular hemorrhage grade I/II, necrotizing enterocolitis stage I, respiratory distress syndrome, hyperbilirubinemia requiring treatment) were calculated by delivery gestational age; each neonate was classified once by the worst outcome for which criteria was met. RESULTS: In all, 8334 deliveries met inclusion criteria. There were 119 (1.4%) neonatal deaths. In all, 657 (7.9%) neonates had major morbidity, 3136 (37.6%) had minor morbidity, and 4422 (53.1%) survived without any of the studied morbidities. Deaths declined rapidly with each advancing week of gestation. This decline in death was accompanied by an increase in major neonatal morbidity, which peaked at 54.8% at 25 weeks of gestation. As frequencies of death and major neonatal morbidity fell, minor neonatal morbidity increased, peaking at 81.7% at 31 weeks of gestation. The frequency of all morbidities fell >32 weeks. After 25 weeks, neonatal length of hospital stay decreased significantly with each additional completed week of pregnancy; among babies delivered from 26-32 weeks of gestation, each additional week in utero reduced the subsequent length of neonatal hospitalization by a minimum of 8 days. The median postmenstrual age at discharge nadired around 36 weeks' postmenstrual age for babies born at 31-35 weeks of gestation. CONCLUSION: Our data show that there is a continuum of outcomes, with each additional week of gestation conferring survival benefit while reducing the length of initial hospitalization. These contemporary data can be useful for patient counseling regarding preterm outcomes. PMID- 26772796 TI - Comorbidity of Arithmetic and Reading Disorder. AB - The aim of the present study was to investigate the cognitive profiles of primary school children (age 82-133 months) on a battery of basic number processing and calculation tasks. The sample consisted of four groups matched for age and IQ: arithmetic disorder only (AD; n = 20), reading disorder only (RD; n = 40), a comorbid group ( n = 27), and an unimpaired control group ( n = 40). Multiple 2 (RD vs. No RD) * 2 (AD vs. No AD) factorial ANCOVAs showed that children with RD had selective impairments in counting and number transcoding efficiency. In contrast, children with AD performed poorly in most tasks, including symbolic and nonsymbolic magnitude comparisons, subitizing, number line estimation, number sets, number transcoding accuracy, and calculation. These findings provide further support that AD is characterized by multiple, heterogeneous underlying deficits. In contrast, RD is associated with specific number processing impairments only if tasks require verbal processing. Taken together, the results fully support the assumption of comorbid additivity of AD and RD. PMID- 26772797 TI - Microsatellite analysis of Saccharomyces uvarum diversity. AB - Considered as a sister species of Saccharomyces cerevisiae, S. uvarum is, to a lesser extent, an interesting species for fundamental and applied research studies. Despite its potential interest as a new gene pool for fermenting agents, the intraspecific molecular genetic diversity of this species is still poorly investigated. In this study, we report the use of nine microsatellite markers to describe S. uvarum genetic diversity and population structure among 108 isolates from various geographical and substrate origins (wine, cider and natural sources). Our combined microsatellite markers set allowed differentiating 89 genotypes. In contrast to S. cerevisiae genetic diversity, wild and human origin isolates were intertwined. A total of 75% of strains were proven to be homozygotes and estimated heterozygosity suggests a selfing rate above 0.95 for the different population tested here. From this point of view, the S. uvarum life cycle appears to be more closely related to S. paradoxus or S. cerevisiae of natural resources than S. cerevisiae wine isolates. Population structure could not be correlated to distinct geographic or technological origins, suggesting lower differentiation that may result from a large exchange between human and natural populations mediated by insects or human activities. PMID- 26772794 TI - Sex Differences in Animal Models: Focus on Addiction. AB - The purpose of this review is to discuss ways to think about and study sex differences in preclinical animal models. We use the framework of addiction, in which animal models have excellent face and construct validity, to illustrate the importance of considering sex differences. There are four types of sex differences: qualitative, quantitative, population, and mechanistic. A better understanding of the ways males and females can differ will help scientists design experiments to characterize better the presence or absence of sex differences in new phenomena that they are investigating. We have outlined major quantitative, population, and mechanistic sex differences in the addiction domain using a heuristic framework of the three established stages of the addiction cycle: binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation. Female rats, in general, acquire the self administration of drugs and alcohol more rapidly, escalate their drug taking with extended access more rapidly, show more motivational withdrawal, and (where tested in animal models of "craving") show greater reinstatement. The one exception is that female rats show less motivational withdrawal to alcohol. The bases for these quantitative sex differences appear to be both organizational, in that estradiol-treated neonatal animals show the male phenotype, and activational, in that the female phenotype depends on the effects of gonadal hormones. In animals, differences within the estrous cycle can be observed but are relatively minor. Such hormonal effects seem to be most prevalent during the acquisition of drug taking and less influential once compulsive drug taking is established and are linked largely to progesterone and estradiol. This review emphasizes not only significant differences in the phenotypes of females and males in the domain of addiction but emphasizes the paucity of data to date in our understanding of those differences. PMID- 26772798 TI - Expression of rotavirus VP6 protein: a comparison amongst Escherichia coli, Pichia pastoris and Hansenula polymorpha. AB - During this study. we successfully expressed a codon-optimized gene for rotavirus VP6 protein intracellularly in two methylotrophic yeasts, Pichia pastoris and Hansenula polymorpha, during methanol induction. Expressions were performed in shake flasks and subsequently scaled-up to 1.3 L bioreactors. The yields obtained in the yeasts were compared with that observed in Escherichia coli. Despite producing the lowest biomass levels of all the expression systems in shake flasks, the highest VP6 concentration was obtained with E. coli. In shake flasks, P. pastoris yielded higher volumetric levels of VP6 than H. polymorpha, but specific production of VP6 was approximately similar in both yeasts. In the controlled environment of bioreactors, yeast strains attained typical high cell densities, but also increased VP6 production compared to all shake flask cultures. Unlike in shake flask expressions, H. polymorpha outperformed both P. pastoris as well as E. coli during bioreactor cultivation. VP6 production was in all three expression systems growth-associated. In contrast to yeast expressions, bacterial expressed VP6 protein was found to be insoluble upon analysis. This is the first report of VP6 expressed in methylotrophic yeast and holds the promise for the inexpensive production of VP6 as a possible vaccine candidate or drug delivery mechanism. PMID- 26772799 TI - Tissue composition regulates distinct viscoelastic responses in auricular and articular cartilage. AB - It is well-accepted that articular (ART) cartilage composition and tissue architecture are intimately related to mechanical properties. On the other hand, very little information about other cartilage tissues is available, such as elastin-rich auricular (AUR) cartilage. While thorough investigation of ART cartilage has enhanced osteoarthritis research, ear cartilage reconstruction and tissue engineering (TE) could benefit in a similar way from in-depth analysis of AUR cartilage properties. This study aims to explore the constituent-function relationships of AUR cartilage, and how elastin influences mechanical behavior. Stress-relaxation indentation and tensile tests were performed on bovine ART and AUR cartilage. Elastase incubation was performed to simultaneously deplete elastin and sulfated glycosaminoglycans (sGAG), while hyaluronidase incubation was used to deplete sGAG-only, in order to systematically investigate matrix components in material behavior. ART and AUR cartilages showed different viscoelastic behaviors, with AUR cartilage exhibiting a more elastic behavior. Higher equilibrium properties and limited viscous dissipation of strain energy were observed in AUR cartilage, while ART cartilage exhibited a rapid viscous response and high resistance to instantaneous loading. In conclusion, loss of sGAG had no effect on auricular mechanics in contrast to articular cartilage where GAG loss clearly correlated with mechanical properties. Auricular cartilage without elastin lost all compressive mechanical integrity, whereas in articular cartilage this was provided by collagen. This work shows for the first time the involvement of elastin in the mechanical behavior of ear cartilage. In future, this data can be used in AUR cartilage TE efforts to support reproduction of tissue-specific mechanical properties. PMID- 26772800 TI - Membrane permeability during pressure ulcer formation: A computational model of dynamic competition between cytoskeletal damage and repair. AB - Pressure ulcers are debilitating wounds that arise frequently in people who have lost mobility. Mechanical stress, oxidative stress and ischemia-reperfusion injury are potential sources of damage during pressure ulcer formation, but cross talk between these sources has rarely been investigated. In vitro experiments with mechanically-induced cell damage previously demonstrated that non-lethal amounts of static cell deformation could induce myoblast membrane permeabilization. Permeabilization, in turn, has the potential to induce oxidative stress via leakage of calcium, myoglobin or alarmins. In this work, we constructed a hypothetical causal network of cellular-scale effects resulting from deformation and permeabilization, and we investigated the theoretical sensitivity of cell death toward various parameters and pathways of the model. Simulations showed that the survival/death outcome was particularly sensitive to the speed of membrane repair. The outcome was also sensitive to whether oxidative stress could decrease the speed of membrane repair. Finally, using the assumption that apoptosis and necrosis would have opposite effects on membrane leakage in dying cells, we showed that promoting apoptosis might under certain conditions have the paradoxical effect of decreasing, rather than increasing, total cell death. Our work illustrates that apoptosis may have hidden benefits at preventing spatial spread of death. More broadly, our work shows the importance of membrane repair dynamics and highlights the need for experiments to measure the effects of ischemia, apoptosis induction, and other co-occurring sources of cell stress toward the speed of membrane repair. PMID- 26772801 TI - Use of PRECIS ratings in the National Institutes of Health (NIH) Health Care Systems Research Collaboratory. AB - BACKGROUND: The National Institutes of Health (NIH) Health Care Systems Research Collaboratory (NIH Collaboratory) seeks to produce generalizable knowledge about the conduct of pragmatic research in health systems. This analysis applied the PRECIS-2 pragmatic trial criteria to five NIH Collaboratory pragmatic trials to better understand 1) the pragmatic aspects of the design and implementation of treatments delivered in real world settings and 2) the usability of the PRECIS-2 criteria for assessing pragmatic features across studies and across time. METHODS/DESIGN: Using the PRECIS-2 criteria, five pragmatic trials were each rated by eight raters. For each trial, we reviewed the original grant application and a required progress report written at the end of a 1-year planning period that included changes to the protocol or implementation approach. We calculated median scores and interrater reliability for each PRECIS domain and for the overall trial at both time points, as well as the differences in scores between the two time points. We also reviewed the rater comments associated with the scores. RESULTS: All five trials were rated to be more pragmatic than explanatory, with comments indicating that raters generally perceived them to closely mirror routine clinical care across multiple domains. The PRECIS-2 domains for which the trials were, on average, rated as most pragmatic on the 1 to 5 scale at the conclusion of the planning period included primary analysis (mean = 4.7 (range = 4.5 to 4.9)), recruitment (4.3 (3.6 to 4.8)), eligibility (4.1 (3.4 to 4.8)), setting (4.1 (4.0 to 4.4)), follow-up (4.1 (3.4 to 4.9)), and primary outcome (4.1 (3.5 to 4.9)). On average, the less pragmatic domains were organization (3.3 (2.6 to 4.4)), flexibility of intervention delivery (3.5 (2.1 4.5)), and flexibility of intervention adherence (3.8 (2.8-4.5)). Interrater agreement was modest but statistically significant for four trials (Gwet's AC1 statistic range 0.23 to 0.40) and the intraclass correlation coefficient ranged from 0.05 to 0.31. Rating challenges included assigning a single score for domains that may relate to both patients and care settings (that is, eligibility or recruitment) and determining to what extent aspects of complex research interventions differ from usual care. CONCLUSIONS: These five trials in diverse healthcare settings were rated as highly pragmatic using the PRECIS-2 criteria. Applying the tool generated insightful discussion about real-world design decisions but also highlighted challenges using the tool. PRECIS-2 raters would benefit from additional guidance about how to rate the interwoven patient and practice-level considerations that arise in pragmatic trials. TRIAL REGISTRATIONS: Clinicaltrials.gov trial registrations: NCT02019225 , NCT01742065 , NCT02015455 , NCT02113592 , NCT02063867 . PMID- 26772803 TI - Acute myocardial infarction, associated with the use of a synthetic adamantyl cannabinoid: a case report. AB - BACKGROUND: "Legal highs" are novel psychoactive substances that have evaded statutory control. Synthetic cannabinoid compounds with adamantane moieties have recently been identified, which have high potency at target receptors and are undetectable on conventional toxicology testing. However, little is known about any harmful effects, and their potential to cause serious ill health. We describe a case of myocardial infarction following the use of this class of drug. CASE PRESENTATION: We report the case of a 39-year-old man admitted after an out-of hospital cardiac arrest, in whom ECG and elevated cardiac enzymes confirmed ST elevation myocardial infarction. Normal coronary perfusion was restored after thrombectomy and coronary artery stenting. In the hours preceding his admission, the patient is known to have consumed the legal high product "Black Mamba". Subsequent urine testing confirmed the presence of an adamantyl-group synthetic cannabinoid, whilst cannabis, cocaine, amphetamines and other drugs of abuse were not detected. CONCLUSION: The use of legal highs is being increasingly recognised, but the chemical compositions and physiological effects of these drugs are poorly characterised and are continually changing. Synthetic cannabinoids, rarely identified on toxicological testing, can be linked to serious adverse cardiovascular events. This case highlights the importance of testing for novel psychoactive compounds, and recognising their potential to cause life-threatening conditions. PMID- 26772802 TI - A debate on working memory and cognitive control: can we learn about the treatment of substance use disorders from the neural correlates of anorexia nervosa? AB - BACKGROUND: Anorexia Nervosa (AN) is a debilitating, sometimes fatal eating disorder (ED) whereby restraint of appetite and emotion is concomitant with an inflexible, attention-to-detail perfectionist cognitive style and obsessive compulsive behaviour. Intriguingly, people with AN are less likely to engage in substance use, whereas those who suffer from an ED with a bingeing component are more vulnerable to substance use disorder (SUD). DISCUSSION: This insight into a beneficial consequence of appetite control in those with AN, which is shrouded by the many other unhealthy, excessive and deficit symptoms, may provide some clues as to how the brain could be trained to exert better, sustained control over appetitive and impulsive processes. Structural and functional brain imaging studies implicate the executive control network (ECN) and the salience network (SN) in the neuropathology of AN and SUD. Additionally, excessive employment of working memory (WM), alongside more prominent cognitive deficits may be utilised to cope with the experience of negative emotions and may account for aberrant brain function. WM enables mental rehearsal of cognitive strategies while regulating, restricting or avoiding neural responses associated with the SN. Therefore, high versus low WM capacity may be one of the factors that unites common cognitive and behavioural symptoms in those suffering from AN and SUD respectively. Furthermore, emerging evidence suggests that by evoking neural plasticity in the ECN and SN with WM training, improvements in neurocognitive function and cognitive control can be achieved. Thus, considering the neurocognitive processes of excessive appetite control and how it links to WM in AN may aid the application of adjunctive treatment for SUD. PMID- 26772804 TI - Assessing variability in results in systematic reviews of diagnostic studies. AB - BACKGROUND: To describe approaches used in systematic reviews of diagnostic test accuracy studies for assessing variability in estimates of accuracy between studies and to provide guidance in this area. METHODS: Meta-analyses of diagnostic test accuracy studies published between May and September 2012 were systematically identified. Information on how the variability in results was investigated was extracted. RESULTS: Of the 53 meta-analyses included in the review, most (n=48; 91%) presented variability in diagnostic accuracy estimates visually either through forest plots or ROC plots and the majority (n=40; 75%) presented a test or statistical measure for the variability. Twenty-eight reviews (53%) tested for variability beyond chance using Cochran's Q test and 31 (58%) reviews quantified it with I(2). 7 reviews (13%) presented between-study variance estimates (tau(2)) from random effects models and 3 of these presented a prediction interval or ellipse to facilitate interpretation. Half of all the meta analyses specified what was considered a significant amount of variability (n=24; 49%). CONCLUSIONS: Approaches to assessing variability in estimates of accuracy varied widely between diagnostic test accuracy reviews and there is room for improvement. We provide initial guidance, complemented by an overview of the currently available approaches. PMID- 26772805 TI - Deciphering transcriptional regulations coordinating the response to environmental changes. AB - BACKGROUND: Gene co-expression evidenced as a response to environmental changes has shown that transcriptional activity is coordinated, which pinpoints the role of transcriptional regulatory networks (TRNs). Nevertheless, the prediction of TRNs based on the affinity of transcription factors (TFs) with binding sites (BSs) generally produces an over-estimation of the observable TF/BS relations within the network and therefore many of the predicted relations are spurious. RESULTS: We present LOMBARDE, a bioinformatics method that extracts from a TRN determined from a set of predicted TF/BS affinities a subnetwork explaining a given set of observed co-expressions by choosing the TFs and BSs most likely to be involved in the co-regulation. LOMBARDE solves an optimization problem which selects confident paths within a given TRN that join a putative common regulator with two co-expressed genes via regulatory cascades. To evaluate the method, we used public data of Escherichia coli to produce a regulatory network that explained almost all observed co-expressions while using only 19 % of the input TF/BS affinities but including about 66 % of the independent experimentally validated regulations in the input data. When all known validated TF/BS affinities were integrated into the input data the precision of LOMBARDE increased significantly. The topological characteristics of the subnetwork that was obtained were similar to the characteristics described for known validated TRNs. CONCLUSIONS: LOMBARDE provides a useful modeling scheme for deciphering the regulatory mechanisms that underlie the phenotypic responses of an organism to environmental challenges. The method can become a reliable tool for further research on genome-scale transcriptional regulation studies. PMID- 26772806 TI - Gut microbiota lipopolysaccharide accelerates inflamm-aging in mice. AB - BACKGROUND: The constitutive inflammation that characterizes advanced age is termed inflamm-aging. This process is associated with age-related changes to immune homeostasis and gut microbiota. We investigated the relationship between aging and gut microbiota lipopolysaccharide (LPS)-inducible inflammation. RESULTS: A taxonomy-based analysis showed that aging resulted in increased prevalence of the phyla Firmicutes and Actinobacteria and a reduced prevalence of Bacteroidetes and Tenericutes, resulting in an increase in the Firmicutes to Bacteroidetes ratio. The levels of plasmatic and fecal lipopolysaccharides were higher in aged mice. Aging induced the expression of p16 and the activation of nuclear factor-kappa B (NF-kappaB) in the colon of aged mice. Interestingly, the expression level of sterile alpha-motif domain- and HD domain-containing protein 1 (SAMHD1) in the colon was higher in aged mice than in young mice, while cyclin dependent kinase-2 and cyclin E levels were lower in aged mice than in young mice. The lipopolysaccharide fraction of fecal lysates (LFL) from young or aged mice increased p16 and SAMHD1 expression and NF-kappaB activation in peritoneal macrophages from wild-type mice, in a TLR4-dependent manner. However, LFLs did not induce NF-kappaB activation and SAMHD1 expression in peritoneal macrophages from TLR4-deificent mice, whereas they significantly induced p16 expression. Nevertheless, p16 expression was induced more potently in macrophages from WT mice than in macrophages from TLR4-deficient mice. CONCLUSION: Aging increased p16 and SAMHD1 expression, gut microbiota LPS production, and NF-kappaB activation; thereby, signifying that gut microbiota LPS may accelerate inflamm aging and SAMHD1 may be an inflamm-aging marker. PMID- 26772807 TI - Effects of analogue insulin in multiple daily injection therapy of type 2 diabetes on postprandial glucose control and cardiac function compared to human insulin: a randomized controlled long-term study. AB - BACKGROUND: The prevention of cardiovascular disease, including diastolic cardiac dysfunction with its high prevalence and ominous prognosis, is a therapeutic challenge for patients with type 2 diabetes. Both short and long-acting insulin analogues (AI) have been shown to reduce glucose variability and provide potential benefit for cardiovascular disease although the effects on cardiac function have not yet been evaluated. This long-term, prospective, randomized controlled trial in patients with type 2 diabetes (T2D) tested the hypothesis that a multiple daily injection regimen (MDI) with AI improves postmeal glucose excursions in comparison to human insulin (HI) and that the effects of AI improve diastolic cardiac function. METHODS: For 36 months, MDI treatment in 109 T2D patients was adapted every 3 months (targets: fasting glucose <= 110 mg/dl, postmeal glucose <= 150 mg/dl) in both groups: AI (insulin detemir and insulin aspart, n = 61) and HI (NPH-insulin and regular HI, n = 48). Diastolic cardiac function (myocardial velocity E' using tissue Doppler imaging and the mitral inflow ratio E/A) and vascular function were assessed before and 2 h after a standardized breakfast (48 g carbohydrates). At baseline, both groups were comparable with regards to demographic, cardiac and metabolic data. Analysis of data included traditional statistics as well as the use of a multiple imputation technique shown in brackets [ ]. RESULTS: At 36 months, the primary endpoint, postmeal glucose, decreased by 20 +/- 62 mg/dl, p = 0.038 [p = 0.021] with AI and increased insignificantly with HI (inter-group p = 0.032 [p = 0.047]) to postmeal glucose levels of 161 +/- 39 with AI vs. 195 +/- 54 mg/dl with HI (inter-group p = 0.002 [p = 0.010]) whereas the levels of fasting glucose and HbA1c were comparable. With AI, postmeal E' improved by 0.6 +/- 1.4 cm/s, p = 0.009 [p = 0.002] and fasting E' by 0.4 +/- 1.4 cm/s, p = 0.069 [p = 0.013], however, E' remained unchanged with HI. These changes were consistent with those of the traditional parameter E/A. CONCLUSIONS: MDI with AI results in better postmeal glucose control compared to HI. The treatment with AI is associated with improved diastolic cardiac function. ClinicalTrials.gov (NTC00747409). PMID- 26772809 TI - Mapping and assessment of personal and professional development skills in a pharmacy curriculum. AB - BACKGROUND: Health sciences programs are increasingly expanding their curricula to bridge foundational scientific knowledge with needed skills to practice and patient care. The primary objectives of this study are to 1) assess whether the personal and professional development (PPD) subdomains (self-assessment, leadership, innovation and entrepreneurship, and professionalism) are integrated in a pharmacy curriculum; and 2) identify any gaps related to the subdomains' learning objectives. METHODS: Four different mapping activities were completed to create a comprehensive mapping plan regarding the integration of the PPD subdomains in the curriculum. The first mapping activity entailed matching the school's program educational outcomes (PEOs) to these subdomains (Step 1). Mapping of the enacted curriculum by faculty (Step 2) and learned curriculum by students (Step 3) were also completed in order to evaluate the integration of these subdomains in the curriculum. Finally, Step 4 involved mapping of the assessed curriculum by analyzing the progress of students on PPD-related competencies using standardized scoring rubrics and the correlation between students' and facultys' assessments with regard to matching competencies. The Cochrane's Q test and the Cohen's kappa coefficient were used in the statistical analysis of parametric data. RESULTS: The subdomains were found to be woven across curricular, co-curricular, and extra-curricular activities based on the four different mapping activities. Faculty and students agreed that the PPD competencies are integrated in the curriculum; provided example courses, experiences and activities; and identified areas of further improvements. The completed mapping activities drove the development of action plans for remediation of identified gaps in the curriculum. CONCLUSION: Mapping activities showed the sequential integration of the PPD skills at different depths and breadths in the curriculum. This study provides an example to health sciences schools on the incorporation of the PPD skills in their curricular, co-curricular and extra-curricular activities as current accreditation standards have directed Pharmacy programs to integrate and enforce them in their curricula. PMID- 26772808 TI - Integrative meta-analysis identifies microRNA-regulated networks in infantile hemangioma. AB - BACKGROUND: Hemangioma is a common benign tumor in the childhood; however our knowledge about the molecular mechanisms of hemangioma development and progression are still limited. Currently, microRNAs (miRNAs) have been shown as gene expression regulators with an important role in disease pathogenesis. Our goals were to identify miRNA-mRNA expression networks associated with infantile hemangioma. METHODS: We performed a meta-analysis of previously published gene expression datasets including 98 hemangioma samples. Deregulated genes were further used to identify microRNAs as potential regulators of gene expression in infantile hemangioma. Data were integrated using bioinformatics methods, and genes were mapped in proteins, which were then used to construct protein-protein interaction networks. RESULTS: Deregulated genes play roles in cell growth and differentiation, cell signaling, angiogenesis and vasculogenesis. Regulatory networks identified included microRNAs miR-9, miR-939 and let-7 family; these microRNAs showed the most number of interactions with deregulated genes in infantile hemangioma, suggesting that they may have an important role in the molecular mechanisms of disease. Additionally, results were used to identify drug gene interactions and druggable gene categories using Drug-Gene Interaction Database. We show that microRNAs and microRNA-target genes may be useful biomarkers for the development of novel therapeutic strategies for patients with infantile hemangioma. CONCLUSIONS: microRNA-regulated pathways may play a role in infantile hemangioma development and progression and may be potentially useful for future development of novel therapeutic strategies for patients with infantile hemangioma. PMID- 26772810 TI - Efficient generation of Rosa26 knock-in mice using CRISPR/Cas9 in C57BL/6 zygotes. AB - BACKGROUND: The CRISPR/Cas9 system is increasingly used for gene inactivation in mouse zygotes, but homology-directed mutagenesis and use of inbred embryos are less established. In particular, Rosa26 knock-in alleles for the insertion of transgenes in a genomic 'safe harbor' site, have not been produced. Here we applied CRISPR/Cas9 for the knock-in of 8-11 kb inserts into Rosa26 of C57BL/6 zygotes. RESULTS: We found that 10-20 % of live pups derived from microinjected zygotes were founder mutants, without apparent off-target effects, and up to 50 % knock-in embryos were recovered upon coinjection of Cas9 mRNA and protein. Using this approach, we established a new mouse line for the Cre/loxP-dependent expression of Cas9. CONCLUSIONS: Altogether, our protocols and resources support the fast and direct generation of new Rosa26 knock-in alleles and of Cas9 mediated in vivo gene editing in the widely used C57BL/6 inbred strain. PMID- 26772811 TI - Novel three-sinus enlargement technique for supravalvular aortic stenosis without aortic transection. AB - BACKGROUND: Although repair of a supravalvular aortic stenosis (SVAS) can be performed with low mortality rates, surgery for the complex form of SVAS continues to be associated with a high incidence of residual stenosis. CASE PRESENTATION: The patient was referred to our hospital at 1 month of age and was diagnosed with aortic valve stenosis (AS) by using echocardiography. Cardiac catheterization revealed moderate AS, and subsequent left ventriculography revealed discrete stenosis of the sino-tubular junction and a narrowed proximal ascending aorta. We performed a reconstructive operation for such heart defects involving novel three-sinus and ascending aorta enlargement without aortic root transection in a 6-month-old boy. CONCLUSION: Our novel three-sinus enlargement technique is suitable for treating each type of SVAS and is a useful method for a baby particularly less than 10 kg without disturbing the growth of the ascending aorta. PMID- 26772812 TI - DocOx (AIO-PK0106): a phase II trial of docetaxel and oxaliplatin as a second line systemic therapy in patients with advanced pancreatic ductal adenocarcinoma. AB - BACKGROUND: The current study was conducted to examine the activity of a docetaxel/oxaliplatin (DocOx) combination as second line treatment for advanced pancreatic ductal adenocarcinoma (Trial registration: NCT00690300. Registered June 2, 2008) METHODS: DocOx is a prospective, multi-center, single arm, phase II trial using docetaxel (75 mg/m(2), 60 min, d 1) and oxaliplatin (80 mg/m(2), 120 min, d 2) in 21-day cycles. The treatment period was scheduled for up to 8 cycles. Primary endpoint was tumor response according to RECIST 1.0. Secondary endpoints were progression free survival, overall survival, safety/toxicity, quality of life and clinical benefit. RESULTS: Data represent the intention to treat analysis of 44 patients with chemorefractory pancreatic cancer enrolled between 2008 and 2012 at five institutions in Germany. The primary endpoint of tumor response was achieved in 15.9% of the patients (7 partial remissions, no complete remission), with a disease control rate of 48% after the first two treatment cycles. Median progression free survival (PFS) was 1.82 months (CI 95% 1.5-3.96 months) and median overall survival (OS) was 10.1 months (CI 95% 5.1 14.1 months). CONCLUSIONS: This single-arm trial demonstrates that the combination of docetaxel and oxaliplatin yields promising results for the treatment of advanced pancreatic ductal adenocarcinoma patients. Selected patients had particular benefit from this treatment as indicated by long PFS and OS times. Even after 8 cycles of treatment with DocOx a partial response was observed in 2 patients and stable disease was observed in another 6 patients. The data obtained with the DocOx protocol compare well with other second line protocols such as OFF (oxaliplatin, 5-FU, leucovorin). The DocOx regimen could be an interesting option for patients who received gemcitabine as first line treatment for metastatic pancreatic cancer. PMID- 26772813 TI - Initial experience with 3D isotropic high-resolution 3 T MR arthrography of the wrist. AB - BACKGROUND: Our study was performed to evaluate the image quality of 3 T MR wrist arthrograms with attention to ulnar wrist structures, comparing image quality of isotropic 3D proton density fat suppressed turbo spin echo (PDFS TSE) sequence versus standard 2D 3 T sequences as well as comparison with 1.5 T MR arthrograms. METHODS: Eleven consecutive 3 T MR wrist arthrograms were performed and the following sequences evaluated: 3D isotropic PDFS, repetition time/echo time (TR/TE) 1400/28.3 ms, voxel size 0.35x0.35x0.35 mm, acquisition time 5 min; 2D coronal sequences with slice thickness 2 mm: T1 fat suppressed turbo spin echo (T1FS TSE) (TR/TE 600/20 ms); proton density (PD) TSE (TR/TE 3499/27 ms). A 1.5 T group of 18 studies with standard sequences were evaluated for comparison. All MR imaging followed fluoroscopically guided intra-articular injection of dilute gadolinium contrast. Qualitative assessment related to delineation of anatomic structures between 1.5 T and 3 T MR arthrograms was carried out using Mann Whitney test and the differences in delineation of anatomic structures among each sequence in 3 T group were analyzed with Wilcoxon signed-rank test. Quantitative assessment of mean relative signal intensity (SI) and relative contrast measurements was performed using Wilcoxon signed-rank test. RESULTS: Mean qualitative scores for 3 T sequences were significantly higher than 1.5 T (p < 0.01), with isotropic 3D PDFS sequence having highest mean qualitative scores (p < 0.05). Quantitative analysis demonstrated no significant difference in relative signal intensity among the 3 T sequences. Significant differences were found in relative contrast between fluid-bone and fluid-fat comparing 3D and 2D PDFS (p < 0.01). CONCLUSIONS: 3D isotropic PDFS sequence showed promise in both qualitative and quantitative assessment, suggesting this may be useful for MR wrist arthrograms at 3 T. Primary reasons for diagnostic potential include the ability to make reformations in any obliquity to follow the components of ulnar side wrist structures including triangular fibrocartilage complex. Additionally, isotropic imaging provides thinner slice thickness with less partial volume averaging allowing for identification of subtle injuries. PMID- 26772814 TI - Integrated sphingosine-1 phosphate signaling in the central nervous system: From physiological equilibrium to pathological damage. AB - Sphingosine-1 phosphate (S1P), a bioactive sphingolipid metabolite, plays an essential role in cellular homeostasis. It is well evidenced that enzymes responsible for S1P production, as well as S1P receptors are expressed in the central nervous system (CNS), implying that S1P may contribute to CNS physiology. In current review, we will present the current knowledge about developmental and neuromodulatory functions of S1P in the brain. Considering neuroprotective effects of S1P, we also review the relation between S1P and cellular autophagy, mitochondrial function, oxidative stress and apoptosis as well as molecular pathways underlying neuroprotective effects of S1P. Given these pivotal functions, in the last section, we will summarize latest findings about possible contribution of S1P dysregulation in neurological disorders like Alzheimer's disease and multiple sclerosis. PMID- 26772815 TI - CYP1B1 inhibition attenuates doxorubicin-induced cardiotoxicity through a mid chain HETEs-dependent mechanism. AB - Doxorubicin (DOX) has been reported to be a very potent and effective anticancer agent. However, clinical treatment with DOX has been greatly limited due to its cardiotoxicity. Furthermore, several studies have suggested a role for cytochrome P450 1B1 (CYP1B1) and mid-chain hydroxyeicosatetraenoic acids (mid-chain HETEs) in DOX-induced cardiac toxicity. Therefore, we hypothesized that DOX induced cardiotoxicity is mediated through the induction of CYP1B1 and its associated mid chain HETEs metabolite. To test our hypothesis, Sprague-Dawley rats and RL-14 cells were treated with DOX in the presence and absence of 2,3',4,5' tetramethoxystilbene (TMS), a selective CYP1B1 inhibitor. Thereafter, cardiotoxicity parameters were determined using echocardiography, histopathology, and gene expression. Further, the level of mid-chain HETEs was quantified using liquid chromatography-electron spray ionization-mass spectrometry. Our results showed that DOX induced cardiotoxicity in vivo and in vitro as evidenced by deleterious changes in echocardiography, histopathology, and hypertrophic markers. Importantly, the TMS significantly reversed these changes. Moreover, the DOX-induced cardiotoxicity was associated with a proportional increase in the formation of cardiac mid-chain HETEs both in vivo and in our cell culture model. Interestingly, the inhibition of cardiotoxicity by TMS was associated with a dramatic decrease in the formation of cardiac mid-chain HETEs suggesting a mid chain HETEs-dependent mechanism. Mechanistically, the protective effect of TMS against DOX-induced cardiotoxicity was mediated through the inhibition of mitogen activated protein kinases (MAPKs) and nuclear factor-kappaB (NF-kappaB). In conclusion, our study provides the first evidence that the inhibition of CYP1B1 and mid-chain HETE formation attenuate DOX-induced cardiotoxicity. PMID- 26772816 TI - Efficient biodegradation of chlorophenols in aqueous phase by magnetically immobilized aniline-degrading Rhodococcus rhodochrous strain. AB - BACKGROUND: Chlorophenols are environmental contaminants, which are highly toxic to living beings due to their carcinogenic, mutagenic and cytotoxic properties. Bacterial degradation has been considered a cost-effective and eco-friendly method of removing chlorophenols, compared to the traditional physical-chemical processes. RESULTS: In this study, we first developed an efficient process for the biodegradation of chlorophenols by magnetically immobilized Rhodococcus rhodochrous cells. R. rhodochrous DSM6263 degrades chlorophenols following the first step of hydroxylation at the ortho-positions of chlorophenolic rings. The cells immobilized by k-carrageenan with 9 g/L Fe3O4 nanoparticles could efficiently degrade 2-chlorophenol, 4-chlorophenol, 2,3-dichlorophenol and their mixture, which were even higher than those by free cells. The magnetically nanoparticle-immobilized cells could be used at least for six cycles. CONCLUSION: Given the much easier separation by an external magnetic field and high degradation efficiency, this study provides a promising technique for improving biocatalysts used in the bioremediation process for chlorophenols in wastewater. PMID- 26772817 TI - Policing, massive street drug testing and poly-substance use chaos in Georgia - a policy case study. AB - BACKGROUND: Since early 2000, intensive policing, wide scale street drug testing, and actions aimed at limiting the availability of specific drugs have been implemented in Georgia. Supporters of this approach argue that fear of drug testing and resulting punishment compels drug users to stop using and prevents youth from initiating drug use. It has been also stated that reduction in the availability of specific drugs should be seen as an indication of the overall success of counter-drug efforts. The aim of the current review is to describe the drug-related law enforcement response in Georgia and its impact on illicit drug consumption and drug-related harm. METHOD: We reviewed relevant literature that included peer-reviewed scientific articles, stand-alone research reports, annual drug situation reports, technical reports and program data. This was also supplemented by the review of relevant legislation and judicial practices for the twelve year period between 2002 and 2014. RESULTS: Every episode of reduced availability of any "traditional" injection drug was followed by the discovery/introduction of a new injection preparation. The pattern of drug consumption was normally driven by users' attempts to substitute their drug of choice through mixing together available alternative substances. Chaotic poly substance use and extensive utilization of home-made injection drugs, prepared from toxic precursors, became common. Massive random street drug testing had little or no effect on the prevalence of problem drug use. CONCLUSIONS: Intensive harassment of drug users and exclusive focus on reducing the availability of specific drugs did not result in reduction of the prevalence of injecting drug use. Repressive response of Georgian anti-drug authorities relied heavily on consumer sanctions, which led to shifts in drug users' behavior. In most cases, these shifts were associated with the introduction and use of new toxic preparations and subsequent harm to the physical and mental health of drug consumers. PMID- 26772818 TI - Evolutionary dynamics of a quantitative trait in a finite asexual population. AB - In finite populations, mutation limitation and genetic drift can hinder evolutionary diversification. We consider the evolution of a quantitative trait in an asexual population whose size can vary and depends explicitly on the trait. Previous work showed that evolutionary branching is certain ("deterministic branching") above a threshold population size, but uncertain ("stochastic branching") below it. Using the stationary distribution of the population's trait variance, we identify three qualitatively different sub-domains of "stochastic branching" and illustrate our results using a model of social evolution. We find that in very small populations, branching will almost never be observed; in intermediate populations, branching is intermittent, arising and disappearing over time; in larger populations, finally, branching is expected to occur and persist for substantial periods of time. Our study provides a clearer picture of the ecological conditions that facilitate the appearance and persistence of novel evolutionary lineages in the face of genetic drift. PMID- 26772819 TI - Anti-inflammatory therapies in TRAMP mice: delay in PCa progression. AB - The aim of this study was to characterize the structural and molecular biology as well as evaluate the immediate and late responses of prostatic cancer in the transgenic adenocarcinoma of the mouse prostate (TRAMP) model after treatment with goniothalamin (GTN) and celecoxib. The treated mice received GTN (150 mg/kg, gavage) or celecoxib (10 mg/kg, gavage) from 8 to 12 weeks of age. They were killed at different ages: the immediate-response groups at 12 weeks and the late response groups at 22 weeks. The ventral prostate was collected for light microscopy, immunohistochemistry, western blotting, TUNEL, and ELISA. Morphological analyses indicated that GTN treatment delayed the progression of prostatic adenocarcinoma, leading to a significant decrease of prostatic lesion frequency in both experimental period responses to this treatment, mainly high grade prostatic intraepithelial neoplasia and well-differentiated adenocarcinoma. Also, the celecoxib treatment showed a particular decrease in the proliferative processes (PCNA) in both the experimental periods. Despite celecoxib diminishing the COX2 and IGFR1 levels, GTN presented higher action spectrum considering the decrease of a greater molecular number involved in the proliferative and inflammatory processes in prostatic cancer. Goniothalamin attenuated the pro inflammatory response in TRAMP prostatic microenvironment, delaying prostate cancer (PCa) progression. Celecoxib treatment was efficient in the regulation of COX2 in the TRAMP mice, mainly in the advanced disease grade. Finally, we concluded that inflammatory process control in early grades of PCa was crucial for the downregulation of the signaling pathways involved in the proliferative processes in advanced cancer grades. PMID- 26772820 TI - Degrees of connectivity: Systems model for upstream risk assessment and mitigation. AB - There is growing recognition that in order to further improve safety performance, attention needs to be given beyond the immediate working conditions and worker actions. A systems approach to construction safety enables considering: multiple project elements simultaneously; connections between different elements; and all system elements affected by safety risk. This paper describes recent and current research to conceptualize a typical building project in terms of connections between workers, activities, and design elements, and to verify and analyze impacts of the design and worker interactions on worker safety. Prior research provides the basis for a network tying the design elements, construction activities, and work crews on a typical building project together along with the extent of interaction between each of the system elements in terms of safety. In conjunction with this systems approach, the researchers propose a concept for viewing and managing construction safety through four different types of connections, or "degrees of connectivity," between the different workers, activities, and design elements in the system. The degrees of connectivity are defined as: interacting with the design element during its construction (DoC #1); interacting with the design element in its final form to attach another component to it (DoC #2) or by working in the vicinity of it (DoC #3); and indirectly interacting with the design element through another worker (DoC #4). To support and verify the presence of the concept in practice, the researchers conducted a survey of construction personnel. The survey results confirm that the four different degrees of connectivity are present and felt during construction operations, and indicate that attention should be given to all design elements, activities, and workers to which a worker is "connected". According to the survey respondents, DoC's #1 and #2 are recognized as the most widely present on construction sites. Eighty percent of the respondents believe that the design element has a moderate or greater impact on worker safety while it is being constructed. These initial research steps provide the starting point for continuing study that aims to develop and demonstrate the degrees of connectivity concept linking workers and design elements, with the goal of understanding how to design a project and work operations in order to improve safety during construction. PMID- 26772821 TI - Leptin regulates energy metabolism in MCF-7 breast cancer cells. AB - Obesity is known to be a poorer prognosis factor for breast cancer in postmenopausal women. Among the diverse endocrine factors associated to obesity, leptin has received special attention since it promotes breast cancer cell growth and invasiveness, processes which force cells to adapt their metabolism to satisfy the increased demands of energy and biosynthetic intermediates. Taking this into account, our aim was to explore the effects of leptin in the metabolism of MCF-7 breast cancer cells. Polarographic analysis revealed that leptin increased oxygen consumption rate and cellular ATP levels were more dependent on mitochondrial oxidative metabolism in leptin-treated cells compared to the more glycolytic control cells. Experiments with selective inhibitors of glycolysis (2 DG), fatty acid oxidation (etomoxir) or aminoacid deprivation showed that ATP levels were more reliant on fatty acid oxidation. In agreement, levels of key proteins involved in lipid catabolism (FAT/CD36, CPT1, PPARalpha) and phosphorylation of the energy sensor AMPK were increased by leptin. Regarding glucose, cellular uptake was not affected by leptin, but lactate release was deeply repressed. Analysis of pyruvate dehydrogenase (PDH), lactate dehydrogenase (LDH) and pyruvate carboxylase (PC) together with the pentose-phosphate pathway enzyme glucose-6 phosphate dehydrogenase (G6PDH) revealed that leptin favors the use of glucose for biosynthesis. These results point towards a role of leptin in metabolic reprogramming, consisting of an enhanced use of glucose for biosynthesis and lipids for energy production. This metabolic adaptations induced by leptin may provide benefits for MCF-7 growth and give support to the reverse Warburg effect described in breast cancer. PMID- 26772822 TI - Effects of Neurexan (r) in an experimental acute stress setting--An explorative double-blind study in healthy volunteers. AB - AIMS: The objective of this study was to assess the efficacy profile of Nx4 (Neurexan (r)) in an acute experimental stress setting. An acute stress reaction is a biopsychological condition arising in response to an event that is individually regarded as emotionally stressful. Medications can mitigate stress perception and stress reactions, but may also have side effects. MATERIALS AND METHODS: Sixty-four healthy male and female volunteers participated in this prospective two-arm two-site study following an explorative randomized placebo controlled double-blind study design. Participants took six tablets of either Nx4 or placebo during a time period of 2.5h before exposure to an acute psychological stressor (Trier Social Stress Test), and were subsequently monitored for 1.5h. Subjective stress ratings as well as cardiovascular and neuroendocrine parameters were analyzed before and after stress exposure. KEY FINDINGS: All changes in primary and secondary efficacy parameters corresponded well with the experimental acute stress setting. Nx4 did not affect subjective stress ratings but significantly diminished stress-induced increases in salivary cortisol and plasma adrenaline. Nx4 was as safe as placebo and very well tolerated. SIGNIFICANCE: The results suggest an attenuated neuroendocrine stress response in healthy volunteers induced by Nx4. However, further investigations are needed to confirm these observations as well as to better understand why some parameters were affected while others were not. Future investigations should be extended to chronically stressed individuals with a greater disposition to experience stress in everyday life. ClinicalTrials.gov Identifier: NCT01703819. PMID- 26772824 TI - Alagebrium attenuates methylglyoxal induced oxidative stress and AGE formation in H9C2 cardiac myocytes. AB - AIM: Diabetes mellitus associated cardiovascular complications are a leading cause of morbidity and mortality worldwide. Methylglyoxal (MG) is a reactive ketoaldehyde and a byproduct of glucose metabolism and an inducer of advanced glycation endproducts (AGEs). Alagebrium (ALA) is an AGEs crosslink breaker, however, the effects of ALA on MG levels and its consequences in cultured rat cardiomyocytes are not known. The aim of the present study was to examine the effect of high glucose and MG on cultured rat cardiomyocytes and to investigate whether ALA could prevent any deleterious effects of high glucose and MG in these cells. MAIN METHODS: MG levels were determined by HPLC. The expression of different genes was measured by RT-PCR. Oxidative stress and AGEs formation was determined by DCF probe and immunocytochemistry respectively. KEY FINDINGS: High glucose- and MG treated- cardiomyocytes developed a significant increase in MG, and the expression for caspase-3, Bax, RAGE and NF-KB, which were all attenuated after pretreatment with ALA. A significant increase in reactive oxygen species generation and AGEs formation in high glucose- and MG treated- cultured cardiomyocytes was also observed, which was attenuated after pretreatment with ALA. SIGNIFICANCE: ALA may have a preventive role against the deleterious effects of high glucose and MG in the heart. Prevention of dicarbonyl-induced AGEs, by safer and specific scavengers of MG is an attractive therapeutic option. PMID- 26772823 TI - Cancer stem-like cell behavior in anaplastic thyroid cancer: A challenging dilemma. AB - AIMS: Anaplastic thyroid carcinoma (ATC) is an undifferentiated tumor of the thyroid which is characterized with poor prognosis, leading to its aggressive behavior and resistance to conventional therapies. Cancer stem cells (CSCs) are tumor cells that have self-renewal and clonal tumor initiation. Like other cancers, many studies have shown that ATC also has tumor cells with properties like stem cells. To evaluate the concept of cancer stem-like cell theory of ATC, we conducted this study to emphasize both on the concept of cancer stemness origin of these cells and target them for further therapeutic purposes. In the current study, we showed that two ATC cell lines, SW1736 and C643, have subpopulations (SP) that are similar to CSCs. MATERIALS AND METHODS: Using MACS technique, cells positive for CD133 were isolated and subsequently validated with flow cytometry. For further analysis, expression of some stemness markers was evaluated. KEY FINDINGS: ABCG2, CD133, and Sox2 were significantly up-regulated, while Nestin was down-regulated in CD133(pos) subpopulation compared to CD133(neg) cells. In contrast to previous reports that over-expression of Nestin was considered as a marker for thyroid CSCs, we noticed that expression of Nestin was declined in stem cell-like tumor cells, derived from ATC cell lines. SIGNIFICANCE: This study reconfirmed the concept of cancer stem-like cell identity of SW1736 and C643 cells. Indeed, the characterization of CSCs should not be merely based on surface markers. Cell origin and genetic background should be additionally considered on CSCs subpopulation of ATCs for therapeutics. PMID- 26772826 TI - [Accreditation in health care]. AB - Besides the rapid development of healing procedures and healthcare, efficiency of care, institutional performance and safe treatment are receiving more and more attention in the 21st century. Accreditation, a scientifically proven tool for improving patient safety, has been used effectively in healthcare for nearly a hundred years, but only started to spread worldwide since the 1990s. The support and active participation of medical staff are determining factors in operating and getting accross the nationally developed, upcoming Hungarian accreditation system. However, this active assistance cannot be expected without the participants' understanding of the basic goals and features of the system. The presence of the ISO certification in Hungary, well-known by healthcare professionals, further complicates the understanding and orientation among quality management and improvement systems. This paper aims to provide an overview of the history, goals, function and importance of healthcare accreditation, and its similarities and differences regarding ISO certification. PMID- 26772825 TI - [Management of multiple myeloma in Hungary in 2016]. AB - The last decade has witnessed a dramatic progress in the treatment of multiple myeloma. Both the chemotherapy protocols and the supportive therapy options have improved significantly since the publication of the previous Hungarian national guideline. An increasing proportion of patients now reach a durable response and cure became a potential option for some. The aim of the authors was to adapt the international guidelines to the specific circumstances of the Hungarian healthcare system in the light of the most recent developments. PMID- 26772827 TI - [Ten-year fracture risk by FRAX((r)) of women with osteoporosis attending osteoporosis care in Hungary]. AB - INTRODUCTION: Identification of patients with high fracture risk is a key-point in osteoporosis care. AIM: To assess the fracture risk among osteoporotic women attending osteoporosis care in Hungary. METHOD: A cross-sectional survey was conducted in 2009 in 11 centres among women with osteoporosis aged >=50 years. Main risk factors were recorded and 10-year fracture risk was calculated using the FRAX((r)) for Hungary. Health status was assessed by EQ VAS. RESULTS: 1301 patients with mean age of 68.5 (SD = 8.3) years and EQ VAS of 62.0 (SD = 17.2) participated, of whom 690 (53.0%) have already had previous fracture. Major osteoporotic and hip fracture FRAX((r)) scores were 20.1 (SD = 13.9) and 10.6 (SD = 12.5), respectively (by 10-year age groups, mean: 18.5/9.3; 16.2/6.7; 23/13.5; 28.9/18.3). Patients with previous fracture had significantly higher scores (p<0.05). CONCLUSIONS: Similar rate of patients attend osteoporosis care for primary and secondary prevention. FRAX((r)) score was higher than 7% in the majority of patients. The findings provide inputs for cost-effectiveness analyses and development of intervention thresholds in Hungary. PMID- 26772828 TI - [Successful direct thrombin inhibitor treatment of a left atrial appendage thrombus developed under rivaroxaban therapy]. AB - The authors present the history of a 62-year-old man on continuous rivaroxaban therapy who was scheduled for pulmonary vein isolation due to persistent atrial fibrillation. Preoperative transesophageal echocardiography detected the presence of left atrial appendage thrombus. Thrombophilia tests showed that the patient was heterozygous carrier of the methylene-tetrahydrofolate reductase gene mutation. The authors hypothesized that a direct thrombin inhibitor might exert a more appropriate effect against thrombosis in this case and, therefore, a switch to dabigatran was performed. After two months of anticoagulation with the direct thrombin inhibitor and folic acid supplementation the thrombus resolved. The authors underline that thrombus formation may develop in atrial fibrillation even if the patient is adequately treated with rivaroxaban. This case suggests, that methylene-tetrahydrofolate reductase gene mutation may modulate the efficacy of direct Xa factor inhibitors. According to this case history, dabigatran may be an effective therapeutic option in resolving established thrombus. PMID- 26772829 TI - [The Hungarian Royal Horthy Miklos University in Szeged opened 75 years ago]. PMID- 26772868 TI - Analysis of the healthcare process of patients with type 2 diabetes mellitus and associated comorbidity treated in Spain's National Health System: A perspective of medical professionals. IMAGINE study. AB - OBJECTIVES: To analyse the care received by patients with type 2 diabetes mellitus (DM2) and comorbidity in Spain's National Health System. PATIENTS AND METHODS: Cross-sectional study using an online survey. A total of 302 family physicians, internists and endocrinologists participated in the study. The participants were recruited voluntarily by their respective scientific societies and received no remuneration. RESULTS: Patients with DM2 and comorbidity are mostly treated in Primary Care (71.8%). Forty percent are referred to hospital care, mainly due to renal failure, poor glycaemic control and for a retinopathy assessment. Only 52% of those surveyed conducted medication reconciliation in the transition between healthcare levels. Fifty-eight percent reported conducting interconsultations, clinical meetings or consultancies between healthcare levels. The 3 main factors identified for improving the follow-up and control of DM2 with comorbidity were the multidisciplinary study (80.8%), the continuing education of health professionals (72.3%) and therapeutic education programmes (72%). A lack of time, a lack of qualified personnel for lifestyle interventions and organisational shortcomings were mentioned as the main obstacles for improving the care of these patients. CONCLUSIONS: Most patients with DM2 and comorbidity are treated in Primary Care. Promoting multidisciplinary care and training programmes for practitioners and patients can help improve the quality of care. Therapy reconciliation represents a priority area for improvement in this population. PMID- 26772870 TI - A negative allosteric modulator modulates GABAB-receptor signalling through GB2 subunits. AB - An gamma-aminobutyric acid type B (GABAB)-receptor mediates slow and prolonged synaptic inhibition in the central nervous system, which represents an interesting target for the treatment of various diseases and disorders of the central nervous system. To date, only one activator of the GABAB-receptor, baclofen, is on the market for the treatment of spasticity. Inhibitors of the GABAB-receptor, such as antagonists, show anti-absence seizure activity and pro cognitive properties. In a search for allosteric compounds of the GABAB-receptor, although several positive allosteric modulators have been developed, it is only recently that the first negative allosteric modulator (NAM), CLH304a (also named Compound 14), has been reported. In the present study, we provide further information on the mechanism of action of CLH304a, and also show the possibility of designing more NAMs, such as CLH391 and CLH393, based on the structure of CLH304a. First we show that CLH304a inhibits native GABAB-receptor activity in cultured cerebellar granular neurons. We then show that CLH304a has inverse agonist properties and non-competitively inhibits the effect of agonists, indicating that it binds at a different site to GABA. The GABAB-receptor is a mandatory heterodimer made of GB1 subunits, in which agonists bind, and GB2 subunits, which activate G-proteins. By using various combinations made up of wild-type and/or mutated GB1 and GB2 subunits, we show that CLH304a acts on the heptahelical domain of GB2 subunits. These data revealed the possibility of designing innovative NAMs acting in the heptahelical domain of the GB2 subunits, offering novel possibilities for therapeutic intervention based on GABAB-receptor inhibition. PMID- 26772872 TI - WHO confirms new case of Ebola in Sierra Leone. PMID- 26772869 TI - The effect of antiretroviral therapy on all-cause mortality, generalized to persons diagnosed with HIV in the USA, 2009-11. AB - BACKGROUND: Although antiretroviral therapy (ART) is known to be protective against HIV-related mortality, the expected magnitude of effect is unclear because existing estimates of the effect of ART may not directly generalize to recently HIV-diagnosed persons. METHODS: In this study, we estimated 5-year mortality risks for immediate versus no ART initiation among patients (n = 12,547) in the Centers for AIDS Research Network of Integrated Clinical Systems (CNICS) using the complement of adjusted Kaplan-Meier survival functions. We subsequently standardized estimates to persons diagnosed with HIV in the USA between 2009 and 2011, who were enumerated using national surveillance data. RESULTS: The 5-year mortality, had all patients in the CNICS immediately initiated ART, was 10.6% [95% confidence interval (CI): 9.3%, 11.9%] compared with 28.3% (95% CI: 19.1%, 37.5%) had ART initiation been delayed at least 5 years. The 5-year mortality risk difference due to ART among patients in the CNICS was -17.7% (95% CI: -27.0%, -8.4%). Based on methods for generalizing an estimate from a study sample to a different target population, the expected risk difference due to ART initiation among recently HIV-diagnosed persons in the USA was -19.1% (95% CI: -30.5%, -7.8%). CONCLUSIONS: Immediate ART initiation substantially lowers mortality among persons in the CNICS and this benefit is expected to be similar among persons recently diagnosed with HIV in the USA. We demonstrate a method by which concerns about generalizability can be addressed and evaluated quantitatively. PMID- 26772871 TI - The membrane topology of vitamin K epoxide reductase is conserved between human isoforms and the bacterial enzyme. AB - The membrane topology of vitamin K epoxide reductase (VKOR) is controversial with data supporting both a three transmembrane and a four transmembrane model. The positioning of the transmembrane domains and the loops between these domains is critical if we are to understand the mechanism of vitamin K oxidation and its recycling by members of the thioredoxin family of proteins and the mechanism of action of warfarin, an inhibitor of VKOR. Here we show that both mammalian VKOR isoforms adopt the same topology, with the large loop between transmembrane one and two facing the lumen of the endoplasmic reticulum (ER). We used a redox sensitive green fluorescent protein (GFP) fused to the N- or C-terminus to show that these regions face the cytosol, and introduction of glycosylation sites along with mixed disulfide formation with thioredoxin-like transmembrane protein (TMX) to demonstrate ER localization of the major loop. The topology is identical with the bacterial homologue from Synechococcussp., for which the structure and mechanism of recycling has been characterized. Our results provide a resolution to the membrane topology controversy and support previous results suggesting a role for members of the ER protein disulfide isomerase (PDI) family in recycling VKOR. PMID- 26772873 TI - Inferior frontal cortex activity is modulated by reward sensitivity and performance variability. AB - High reward sensitivity has been linked with motivational and cognitive disorders related with prefrontal and striatal brain function during inhibitory control. However, few studies have analyzed the interaction among reward sensitivity, task performance and neural activity. Participants (N=57) underwent fMRI while performing a Go/No-go task with Frequent-go (77.5%), Infrequent-go (11.25%) and No-go (11.25%) stimuli. Task-associated activity was found in inhibition-related brain regions, with different activity patterns for right and left inferior frontal gyri (IFG): right IFG responded more strongly to No-go stimuli, while left IFG responded similarly to all infrequent stimuli. Reward sensitivity correlated with omission errors in Go trials and reaction time (RT) variability, and with increased activity in right and left IFG for No-go and Infrequent-go stimuli compared with Frequent-go. Bilateral IFG activity was associated with RT variability, with reward sensitivity mediating this association. These results suggest that reward sensitivity modulates behavior and brain function during executive control. PMID- 26772875 TI - Outcomes of Air Injection Within 2 mm Inside a Deep Trephination for Deep Anterior Lamellar Keratoplasty in Eyes With Keratoconus. AB - PURPOSE: To evaluate the outcomes of a new technique for deep anterior lamellar keratoplasty (DALK) employing the injection of air up to 2 mm inside a deep trephination (intended within 100 MUm from the endothelial surface) obtained with a guarded trephine set by means of anterior segment optical coherence tomography (AS OCT). DESIGN: Retrospective, noncomparative, interventional case series. METHODS: The success rate and learning curve of pneumatic dissection in one clinical practice were analyzed in nonscarred keratoconic eyes undergoing a standardized DALK including 9-mm trephination intended to a depth within 100 MUm from the endothelial surface, based on the thinnest AS OCT measurement at this site; and injection of air through a cannula advanced 1-2 mm centripetally from the bottom of the trephination. Surgical parameters, success rate of pneumatic dissection, and complications were recorded. RESULTS: Eighty-eight eyes of 88 patients were included in the study. Pneumatic dissection succeeded in 75 of 88 eyes (85%). No significant correlation could be found between number of cases performed and success rate for this surgeon. Complications included loss of suction during trephination (n = 2, 2.3%) and perforation (n = 4, 4.6%). Conversion to penetrating keratoplasty was necessary in 1 case (1.1%). CONCLUSION: Setting an adjustable trephine to a depth within 100 MUm from the endothelial surface eliminates the need for reaching the central cornea for successful pneumatic dissection and substantially flattens the learning curve of DALK, while achieving a constant success rate above 80% and minimizing complications. PMID- 26772874 TI - Remission of Intermediate Uveitis: Incidence and Predictive Factors. AB - PURPOSE: To evaluate the incidence of remission among patients with intermediate uveitis; to identify factors potentially predictive of remission. DESIGN: Retrospective cohort study. METHODS: Involved eyes of patients with primary noninfectious intermediate uveitis at 4 academic ocular inflammation subspecialty practices, followed sufficiently long to meet the remission outcome definition, were studied retrospectively by standardized chart review data. Remission of intermediate uveitis was defined as a lack of inflammatory activity at >=2 visits spanning >=90 days in the absence of any corticosteroid or immunosuppressant medications. Factors potentially predictive of intermediate uveitis remission were evaluated using survival analysis. RESULTS: Among 849 eyes (of 510 patients) with intermediate uveitis followed over 1934 eye-years, the incidence of intermediate uveitis remission was 8.6/100 eye-years (95% confidence interval [CI], 7.4-10.1). Factors predictive of disease remission included prior pars plana vitrectomy (PPV) (hazard ratio [HR] [vs no PPV] = 2.39; 95% CI, 1.42-4.00), diagnosis of intermediate uveitis within the last year (HR [vs diagnosis >5 years ago] =3.82; 95% CI, 1.91-7.63), age >=45 years (HR [vs age <45 years] = 1.79; 95% CI, 1.03-3.11), female sex (HR = 1.61; 95% CI, 1.04-2.49), and Hispanic race/ethnicity (HR [vs white race] = 2.81; 95% CI, 1.23-6.41). Presence/absence of a systemic inflammatory disease, laterality of uveitis, and smoking status were not associated with differential incidence. CONCLUSIONS: Our results suggest that intermediate uveitis is a chronic disease with an overall low rate of remission. Recently diagnosed patients and older, female, and Hispanic patients were more likely to remit. With regard to management, pars plana vitrectomy was associated with increased probability of remission. PMID- 26772876 TI - Synthesis and evaluation of multivalent M2pep peptides for targeting alternatively activated M2 macrophages. AB - The tumor microenvironment in the majority of cancers is known to favor polarization of tumor-associated macrophages (TAMs) to alternatively activated M2 phenotype, promoting disease progression and reducing patient survival. Effective therapy targeting this M2 macrophage population is thus a promising adjuvant to approved cancer therapies. One of the challenges in targeting M2-like TAMs is a lack of high affinity targeting ligand with good selectivity over anti-tumor M1 like TAMs. We have previously identified an M2 macrophage-targeting peptide (M2pep) that binds preferentially to murine M2 macrophages and M2-like TAMs. A fusion peptide of M2pep with pro-apoptotic peptide KLA (M2pepKLA) was further used to reduce TAM population in vivo but high concentrations and frequent dosing were required due to low binding affinity of M2pep for M2 macrophage. The goal of this study was to develop more potent TAM depletion constructs by increasing the valency of both the M2pep targeting and KLA drug domains. Divalent and tetravalent displays of M2pep ([M2pep]2-Biotin and [M2pep]4-Biotin) were synthesized and evaluated for improvement in binding avidity to the murine macrophages. High avidity and selective binding of [M2pep]2-Biotin to M2 macrophages were achieved with at least 10-fold lower concentration than required for monovalent M2pep activity. Increasing M2pep valency to four, however, resulted in a reduction in both binding activity and selectivity. Surprisingly, both divalent and tetravalent M2pep, without conjugation of any cytotoxic drug cargo, exhibited M2 macrophage-selective toxicity not observed in monovalent M2pep treatment. We next synthesized divalent M2pep with monovalent and divalent KLA ([M2pep]2-[KLA] and [M2pep]2-[KLA]2) to evaluate its enhanced potency compared to M2pepKLA. While both constructs were significantly more toxic than M2pepKLA to primary, bone marrow-derived M2 macrophage, desired selectivity was retained only with [M2pep]2-[KLA]. Finally, we evaluated all multivalent M2pep and M2pepKLA analogs using a syngeneic CT-26 tumor cell suspension. In this setting, [M2pep]4-Biotin and [M2pep]2-[KLA]2 exhibited selective toxicity to both M2-like TAMs and malignant cells but not to M1-like TAMs. Therefore, these constructs are promising anti-cancer constructs with dual-modality mechanisms: malignant cell killing and TAM-based immunomodulation. PMID- 26772877 TI - Current applications of nanoparticles in infectious diseases. AB - For decades infections have been treated easily with drugs. However, in the 21st century, they may become lethal again owing to the development of antimicrobial resistance. Pathogens can become resistant by means of different mechanisms, such as increasing the time they spend in the intracellular environment, where drugs are unable to reach therapeutic levels. Moreover, drugs are also subject to certain problems that decrease their efficacy. This requires the use of high doses, and frequent administrations must be implemented, causing adverse side effects or toxicity. The use of nanoparticle systems can help to overcome such problems and increase drug efficacy. Accordingly, there is considerable current interest in their use as antimicrobial agents against different pathogens like bacteria, virus, fungi or parasites, multidrug-resistant strains and biofilms; as targeting vectors towards specific tissues; as vaccines and as theranostic systems. This review begins with an overview of the different types and characteristics of nanoparticles used to deliver drugs to the target, followed by a review of current research and clinical trials addressing the use of nanoparticles within the field of infectious diseases. PMID- 26772879 TI - Ergothioneine, an adaptive antioxidant for the protection of injured tissues? A hypothesis. AB - Ergothioneine (ET) is a diet-derived, thiolated derivative of histidine with antioxidant properties. Although ET is produced only by certain fungi and bacteria, it can be found at high concentrations in certain human and animal tissues and is absorbed through a specific, high affinity transporter (OCTN1). In liver, heart, joint and intestinal injury, elevated ET concentrations have been observed in injured tissues. The physiological role of ET remains unclear. We thus review current literature to generate a specific hypothesis: that the accumulation of ET in vivo is an adaptive mechanism, involving the regulated uptake and concentration of an exogenous natural compound to minimize oxidative damage. PMID- 26772880 TI - miR-367 promotes proliferation and invasion of hepatocellular carcinoma cells by negatively regulating PTEN. AB - MicroRNAs play important roles in the carcinogenesis of many types of cancers by inhibiting gene expression at posttranscriptional level. However, the roles of microRNAs in hepatocellular carcinoma, are still unclear. Here, we identified that miR-367 promotes hepatocellular carcinoma (HCC) cell proliferation by negatively regulates its target gene PTEN. The expression of miR-367 and PTEN are significantly inverse correlated in 35 HCC patients. In HCC cell line, CCK-8 proliferation assay indicated that the cell proliferation was promoted by miR 367, while miR-367 inhibitor significantly inhibited the cell proliferation. Transwell assay showed that miR-367 mimics significantly promoted the migration and invasion of HCC cells, whereas miR-367 inhibitors significantly reduced cell migration and invasion. Luciferase assays confirmed that miR-367 directly bound to the 3'untranslated region of PTEN, and western blotting showed that miR-367 suppressed the expression of PTEN at the protein levels. This study indicated that miR-367 negatively regulates PTEN and promotes proliferation and invasion of HCC cells. Thus, miR-367 may represent a potential therapeutic target for HCC intervention. PMID- 26772881 TI - Association analysis of the perturbation of interactions in biological pathways and anticancer drug activity. AB - Understanding how different genomic mutational landscapes in patients with cancer lead to different responses to anticancer drugs is an important challenge for realizing precision medicine for cancer. Many studies have analyzed the comprehensive anticancer drug-response profiles and genomic profiles of cancer cell lines to identify the relationship between the anticancer drug response and genomic alternations. However, few studies have focused on interpreting these profiles with a network perspective. In this work, we analyzed genomic alterations in cancer cell lines by considering which interactions in the signaling pathway were perturbed by mutations. With our interaction-centric approach, we identified novel interaction/drug response associations for two drugs (afatinib and ixabepilone) for which no gene-centric association could be found. When we compared the performance of classifiers for predicting the responses to 164 drugs, the classifiers trained with interaction-centric features outperformed the classifiers trained with gene-centric features, despite the smaller number of features (p-value = 2.0 * 10(-3)). By incorporating the interaction information from signaling pathways, we revealed associations between genomic alterations and drug responses that could be missed when using a gene centric approach. PMID- 26772882 TI - Basal transcription of APOBEC3G is regulated by USF1 gene in hepatocyte. AB - Apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3G (APOBEC3G, A3G) exert antiviral defense as an important factor of innate immunity. A variety of cytokines such as IFN-gamma,IL2,IL15,IL7 could induce the transcription of A3G. However, the regulation of other nuclear factor on the transcription of A3G have not been reported at the present. To gain new insights into the transcriptional regulation of this restriction factor, we cloned and characterized the promoter region of A3G and investigate the modulation of USF1 gene on the transcription of A3G. We identified a 232 bp region that was sufficient to regulate the activity of full promoter. Transcriptional start sites (TSS) were identified by the luciferase reporter assays of plasmids containing full or shorter fragments of the A3G promoter. The results demonstrated that the core promoter of A3G is located within the region -159/-84 relative to the TSS. Transcriptional activity of A3G core promoter regulated by USF1 was dependent on an E-box (located at position -91/-86 relative to the major TSS) and was abolished after mutation of this DNA element. USF1 gene can take part in basal transcription regulation of the human A3G gene in hepatocyte, and the identified E-box represented a binding site for the USF1. PMID- 26772883 TI - Involvement of rice histone deacetylase HDA705 in seed germination and in response to ABA and abiotic stresses. AB - Histone acetylation and deacetylation play crucial roles in the modification of chromatin structure and regulation of gene expression in eukaryotes. Histone acetyltransferases (HATs) and histone deacetylases (HDACs) assist to maintain the balance of chromatin acetylation status. Previous studies showed that plant HDACs are key regulators involved in response to development and stresses. In this study, we examined the expression pattern and function of HDA705, a member of the RPD3/HDA1-type HDAC in rice. Overexpression of HDA705 in rice decreased ABA and salt stress resistance during seed germination. Delayed seed germination of HDA705 overexpression lines was associated with down-regulated expression of GA biosynthetic genes and up-regulation of ABA biosynthetic genes. Moreover, overexpression of HDA705 in rice enhanced osmotic stress resistance during the seedling stage. Our findings demonstrate that HDA705 may play a role in regulating seed germination and the response to abiotic stresses in rice. PMID- 26772878 TI - Ligand-targeted theranostic nanomedicines against cancer. AB - Nanomedicines have significant potential for cancer treatment. Although the majority of nanomedicines currently tested in clinical trials utilize simple, biocompatible liposome-based nanocarriers, their widespread use is limited by non specificity and low target site concentration and thus, do not provide a substantial clinical advantage over conventional, systemic chemotherapy. In the past 20years, we have identified specific receptors expressed on the surfaces of tumor endothelial and perivascular cells, tumor cells, the extracellular matrix and stromal cells using combinatorial peptide libraries displayed on bacteriophage. These studies corroborate the notion that unique receptor proteins such as IL-11Ralpha, GRP78, EphA5, among others, are differentially overexpressed in tumors and present opportunities to deliver tumor-specific therapeutic drugs. By using peptides that bind to tumor-specific cell-surface receptors, therapeutic agents such as apoptotic peptides, suicide genes, imaging dyes or chemotherapeutics can be precisely and systemically delivered to reduce tumor growth in vivo, without harming healthy cells. Given the clinical applicability of peptide-based therapeutics, targeted delivery of nanocarriers loaded with therapeutic cargos seems plausible. We propose a modular design of a functionalized protocell in which a tumor-targeting moiety, such as a peptide or recombinant human antibody single chain variable fragment (scFv), is conjugated to a lipid bilayer surrounding a silica-based nanocarrier core containing a protected therapeutic cargo. The functionalized protocell can be tailored to a specific cancer subtype and treatment regimen by exchanging the tumor-targeting moiety and/or therapeutic cargo or used in combination to create unique, theranostic agents. In this review, we summarize the identification of tumor specific receptors through combinatorial phage display technology and the use of antibody display selection to identify recombinant human scFvs against these tumor-specific receptors. We compare the characteristics of different types of simple and complex nanocarriers, and discuss potential types of therapeutic cargos and conjugation strategies. The modular design of functionalized protocells may improve the efficacy and safety of nanomedicines for future cancer therapy. PMID- 26772885 TI - Microfluidic technology enhances the potential of human pluripotent stem cells. AB - Since the discovery of human somatic cell reprogramming, human induced pluripotent stem cells (hiPSC) have been increasingly recognized as the landmark for development of organs-on-chip. hiPSCs show a remarkable plasticity that is related to their ability to promptly respond to the surrounding environment. In vitro, the soluble culture microenvironment, with its critical balance between exogenous and cell-secreted factors, plays a great role in inducing hiPSC response, for both preserving pluripotency and controlling differentiation stages. Exploring the complexity of hiPSC microenvironment requires new experimental tools, as a tight control is limited within conventional culture dishes. Microfluidic technology is particularly attractive in hiPSC research because of its ability to mimic specific environmental cues by accurate control of soluble factors with high spatiotemporal resolution and in a high-throughput fashion. In this review, we highlight recent progress in hiPSC research enabled by microfluidic technology as well as new emerging scenarios. PMID- 26772884 TI - Direct measurement of catalase activity in living cells and tissue biopsies. AB - Spatiotemporal regulation of enzyme-substrate interactions governs the decision making steps in biological systems. Enzymes, being functional units of every living cell, contribute to the macromolecular stability of cell survival, proliferation and hence are vital windows to unraveling the biological complexity. Experimental measurements capturing this dynamics of enzyme-substrate interactions in real time add value to this understanding. Furthermore these measurements, upon validation in realistic biological specimens such as clinical biopsies - can further improve our capability in disease diagnostics and treatment monitoring. Towards this direction, we describe here a novel, high sensitive measurement system for measuring diffusion-limited enzyme-substrate kinetics in real time. Using catalase (enzyme) and hydrogen peroxide (substrate) as the example pair, we demonstrate that this system is capable of direct measurement of catalase activity in vitro and the measured kinetics follows the classical Michaelis-Menten reaction kinetics. We further demonstrate the system performance by measuring catalase activity in living cells and in very small amounts of liver biopsies (down to 1 MUg total protein). Catalase-specific enzyme activity is demonstrated by genetic and pharmacological tools. Finally we show the clinically-relevant diagnostic capability of our system by comparing the catalase activities in liver biopsies from young and old mouse (liver and serum) samples. We discuss the potential applicability of this system in clinical diagnostics as well as in intraoperative surgical settings. PMID- 26772886 TI - miR-1182 inhibits growth and mediates the chemosensitivity of bladder cancer by targeting hTERT. AB - microRNAs (miRNAs) have been demonstrated to contribute to tumor progression and metastasis and proposed to be key regulators of diverse biological processes. In this study, we report that miR-1182 is deregulated in bladder cancer tissues and cell lines. To characterize the role of miR-1182 in bladder cancer cells, we performed functional assays. The overexpression of miR-1182 significantly inhibits bladder cancer cell proliferation, colony formation, and invasion. Moreover, its up-regulation induced cell cycle arrest and apoptosis and mediated chemosensitivity to cisplatin in bladder cancer. Furthermore, a luciferase reporter assay and a rescue experiment indicated that miR-1182 directly targets hTERT by binding its 3'UTR. In conclusion, these results demonstrate that miR 1182 acts as a tumor suppressor and may be a potential biomarker for bladder cancer diagnosis and treatment. PMID- 26772887 TI - Cystathionine gamma-lyase(CSE)/hydrogen sulfide system is regulated by miR-216a and influences cholesterol efflux in macrophages via the PI3K/AKT/ABCA1 pathway. AB - This study was designed to evaluate whether CSE/H2S system, which is regulated by miR-216a, regulated ABCA1-mediated cholesterol efflux and cholesterol contents in THP-1 macrophages-derived foam cells. Our qPCR and western blotting results showed that CSE/H2S significantly up-regulated the expression of ATP-binding cassette transporter A1 (ABCA1) mRNA and protein via PI3K/AKT pathway in foam cells derived from human THP-1 macrophages. The miR-216a directly targeted 3' untranslated region of CSE. It significantly reduced CSE and ABCA1 expression, and also decreased the phosphorylation of PI3K and AKT. Additionally, cholesterol efflux decreased, and cholesterol levels increased in THP-1 macrophage-derived foam cells in response to treatment with miR-216a. Our study demonstrates that CSE/H2S system is regulated by miR-216a, and regulates ABCA1-mediated cholesterol efflux and cholesterol levels through the PI3K/AKT pathway. PMID- 26772888 TI - Telomere length in Parkinson's disease: A meta-analysis. AB - Parkinson's disease (PD) is a common and severe movement disorder. Differences in telomere length (TL) have been reported as possible risk factors for several neuropsychiatric disorders, including PD. Results from published studies for TL in PD are inconsistent, highlighting the need for a meta-analysis. In the current work, a meta-analysis of published studies for TL in PD was carried out. PubMed, Web of Science and Google Scholar databases were used to identify relevant articles that reported TL in groups of PD patients and controls. A random-effects model was used for meta-analytical procedures. The meta-analysis included eight primary studies, derived from populations of European and Asian descent, and did not show a significant difference in TL between 956 PD patients and 1284 controls (p value: 0.246). Our results show that there is no consistent evidence of shorter telomeres in PD patients and suggest the importance of future studies on TL and PD that analyze other populations and also include assessment of TL from different brain regions. PMID- 26772889 TI - A pilot study of EUS-guided through-the-needle forceps biopsy (with video). AB - BACKGROUND AND AIMS: In EUS-guided FNA (EUS-FNA), small-caliber needles are preferable for optimal cytologic yield, whereas large ones are preferable when histologic specimens are needed. Because of the rigidity and friction induced by its large caliber, however, technical limitation does exist in a 19-gauge FNA needle. Recent development of miniature biopsy forceps enables EUS-guided through the-needle forceps biopsy (EUS-TTNFB). The aim of this study is to evaluate safety and efficacy of EUS-TTNFB. METHODS: Eighteen sessions of EUS-TTNFB in 17 patients with solid lesions were performed by using a 0.75-mm biopsy forceps through a 19-gauge FNA needle. Technical feasibility, safety, and diagnostic yield of EUS-TTNFB were retrospectively studied. RESULTS: A total of 49 passes, a median of 3 passes per session, were performed, and the needle puncture, advancement and removal of the biopsy forceps, and subsequent EUS-FNA were technically successful in all patients. No adverse events were observed other than one case with hyperamylasemia without pancreatitis. Macroscopic histologic core by EUS-TTNFB was obtained at a rate of 71% per pass. The tissue acquisition rate by EUS-TTNFB alone was 67% per pass and 100% per session. When EUS-TTNFB and subsequent EUS-FNA were combined, the tissue acquisition rate was 94% per pass. The accuracy of combined EUS-TTNFB and EUS-FNA to diagnose malignancy was 88% per pass and 94% per session. With a single pass of EUS-TTNFB and EUS-FNA, the tissue acquisition rate was 89%, and the accuracy to diagnose malignancy was 83%. CONCLUSIONS: EUS-TTNFB was safe and technically feasible and provided additional tissue acquisition with a single puncture of a 19-gauge FNA needle. PMID- 26772890 TI - Peroral endoscopic myotomy: first human experience with a water-jet-assisted triangle knife. PMID- 26772892 TI - Endoscopic esophagopexy for treatment of a refractory esophago-cutaneous fistula. PMID- 26772891 TI - Rates and predictors of progression to esophageal carcinoma in a large population based Barrett's esophagus cohort. AB - BACKGROUND AND AIMS: Rates of progression to esophageal adenocarcinoma in subjects with Barrett's esophagus (BE) are lower than previously estimated. Identification of predictors of progression will enable risk stratification of BE subjects, potentially making current surveillance programs more efficient. We aimed to assess the potential of demographic and lifestyle factors, obesity, and medications in predicting progression in BE. METHODS: BE subjects were identified from the General Practice Research Database using validated diagnostic codes. BE subjects developing esophageal cancer (EC) 12 months after their index BE diagnosis were defined as progressors. Time-to-event analysis was used to assess the overall risk of progression to EC. Cox proportional hazards models and time varying marginal structural models were used to assess predictors of progression. RESULTS: Included in the analysis were 9660 BE patients. The mean age (SD) of the study subjects was 63 (13.5) years; 62.6% were men. One hundred three subjects (1.1%) progressed to EC. The mean (SD) follow-up since initial diagnosis was 4.8 (3.3) years. The incidence of EC was 2.23 per 1000 person-years of follow-up. Increasing age, male gender, and being overweight (body mass index, 25-29.9) were found to be independent predictors of progression. When time-varying models were used, proton pump inhibitor (PPI) and statin use were protective against progression. CONCLUSIONS: In this large population-based cohort of patients with BE, increasing age, male gender, and being overweight predicted progression to EC, whereas PPI and statin use were protective against EC development. These factors may aid in developing a risk score to predict the risk of progression and chemopreventive strategies in patients with BE. PMID- 26772893 TI - Laterally spreading tumor involving a colon diverticulum successfully resected by endoscopic submucosal dissection. PMID- 26772894 TI - Submucosal injection can facilitate biliary access in patients with periampullary diverticula. PMID- 26772895 TI - Growth and development and their environmental and biological determinants. AB - OBJECTIVE: To investigate child growth, cognitive/language development, and their environmental and biological determinants. METHODS: This was a cross-sectional, predictive correlation study with all 92 children aged 24-36 months who attended the municipal early childhood education network in a town in the Vale do Jequitinhonha region, in 2011. The socioeconomic profile was determined using the questionnaire of the Associacao Brasileira de Empresas de Pesquisa. The socio demographicand maternal and child health profiles were created through a self prepared questionnaire. The height-for-age indicator was selected to represent growth. Cognitive/language development was assessed through the Bayley Scale of Infant and Toddler Development. The quality of educational environments was assessed by Infant/Toddler Environment Scale; the home environment was assessed by the Home Observation for Measurement of the Environment. The neighborhood quality was determined by a self-prepared questionnaire. A multivariate linear regression analysis was performed. RESULTS: Families were predominantly from socioeconomic class D, with low parental education. The prevalence of stunted growth was 14.1%; cognitive and language development were below average at 28.6% and 28.3%, respectively. Educational institutions were classified as inadequate, and 69.6% of homes were classified as presenting a risk for development. Factors such as access to parks and pharmacies and perceived security received the worst score regarding neighborhood environment. Biological variables showed a greater association with growth and environmental variables with development. CONCLUSION: The results showed a high prevalence of stunting and below-average results for cognitive/language development among the participating children. Both environmental and biological factors were related to growth and development. However, biological variables showed a greater association with growth, whereas environmental variables were associated with development. PMID- 26772896 TI - [Ultrasound findings in rhabdomyolysis]. AB - BACKGROUND: Rhabdomyolysis is defined as skeletal muscle necrosis. Ultrasound assessment has recently become a useful tool for the diagnosis and monitoring of muscle diseases, including rhabdomyolysis. A case is presented on the ultrasound findings in a patient with rhabdomyolysis. OBJECTIVE: To highlight the importance of ultrasound as an essential part in the diagnosis in rhabdomyolysis, to describe the ultrasound findings, and review the literature. CLINICAL CASE: A 30 year-old with post-traumatic rhabdomyolysis of both thighs. Ultrasound was performed using a Philips Sparq model with a high-frequency linear transducer (5 10MHz), in low-dimensional scanning mode (2D), in longitudinal and transverse sections at the level of both thighs. The images obtained showed disorganisation of the orientation of the muscle fibres, ground glass image, thickening of the muscular fascia, and the presence of anechoic areas. CONCLUSIONS: Ultrasound is a useful tool in the evaluation of rhabdomyolysis. PMID- 26772897 TI - Applying quality by design principles to the small-scale preparation of the bone targeting therapeutic radiopharmaceutical rhenium-188-HEDP. AB - INTRODUCTION: Rhenium-188-HEDP ((188)Re-HEDP) is a therapeutic radiopharmaceutical for treatment of osteoblastic bone metastases. No standard procedure for the preparation of this radiopharmaceutical is available. Preparation conditions may influence the quality and in vivo behaviour of this product. In this study we investigate the effect of critical process parameters on product quality and stability of (188)Re-HEDP. METHODS: A stepwise approach was used, based on the quality by design (QbD) concept of the ICH Q8 (Pharmaceutical Development) guideline. Potential critical process conditions were identified. Variables tested were the elution volume, the freshness of the eluate, the reaction temperature and time, and the stability of the product upon dilution and storage. The impact of each variable on radiochemical purity was investigated. The acceptable ranges were established by boundary testing. RESULTS: With 2ml eluate, adequate radiochemical purity and stability were found. Nine ml eluate yielded a product that was less stable. Using eluate stored for 24h resulted in acceptable radiochemical purity. Complexation for 30min at room temperature, at 60 degrees C and at 100 degrees C generated appropriate and stable products. A complexation time of 10min at 90 degrees C was too short, whereas heating 60min resulted in products that passed quality control and were stable. Diluting the end product and storage at 32.5 degrees C resulted in notable decomposition. CONCLUSION: Two boundary tests, an elution volume of 9ml and a heating time of 10min, yielded products of inadequate quality or stability. The product was found to be instable after dilution or when stored above room temperature. Our findings show that our previously developed preparation method falls well within the proven acceptable ranges. Applying QbD principles is feasible and worthwhile for the small-scale preparation of radiopharmaceuticals. PMID- 26772898 TI - Chitosan-pectin hybrid nanoparticles prepared by coating and blending techniques. AB - The preparation of chitosan nanoparticles in combination with pectins, as additional mucoadhesive biopolymers, was investigated. Pectins from apple and from citrus fruit were considered; polygalacturonic acid was taken as a reference. Tripolyphosphate was used as an anionic cross-linker. Two different techniques were compared, namely the coating and the blending. Coated nanoparticles (NPs) in the ratio pectin:NPs from 2:1 to 5:1 evidenced that the size of NPs increased as the amount of pectin (both from apple and citrus fruit) was increased. In particular, for NPs coated with pectin from citrus fruit the size ranges from 200 to 260nm; while for NPs coated with pectin from apple the size ranges from 330 to 450nm. A minimum value of Z-potential around -35mV was obtained for the ratio pectin:NPs 4:1, while further addition of pectin did not decrease the Z-potential. Also blended NPs showed a dependence of the size on the ratio of the components: for a given ratio pectin:tripolyphosphate the size increases as the fraction of chitosan increases; for a low ratio chitosan:pectin a high amount of tripolyphosphate was needed to obtain a compact structure. The effect of the additional presence of loaded proteins in chitosan-pectin nanoparticles was also investigated, since proteins contribute to alter the electrostatic interactions among charged species. FT-IR and DSC characterization are presented to confirm the interactions between biopolymers. Finally, the biocompatibility of the used materials was assessed by the chorioallantoic membrane assay, confirming the safety of the materials. PMID- 26772900 TI - Molecular recognition of mRNA 5' cap by 3' poly(A)-specific ribonuclease (PARN) differs from interactions known for other cap-binding proteins. AB - The mRNA 5' cap structure plays a pivotal role in coordination of eukaryotic translation and mRNA degradation. Poly(A)-specific ribonuclease (PARN) is a dimeric exoribonuclease that efficiently degrades mRNA 3' poly(A) tails while also simultaneously interacting with the mRNA 5' cap. The cap binding amplifies the processivity of PARN action. We used surface plasmon resonance kinetic analysis, quantitative equilibrium fluorescence titrations and circular dichroism to study the cap binding properties of PARN. The molecular mechanism of 5' cap recognition by PARN has been demonstrated to differ from interactions seen for other known cap-binding proteins in that: i) the auxiliary biological function of 5' cap binding by the 3' degrading enzyme is accomplished by negative cooperativity of PARN dimer subunits; ii) non-coulombic interactions are major factors in the complex formation; and iii) PARN has versatile activity toward alternative forms of the cap. These characteristics contribute to stabilization of the PARN-cap complex needed for the deadenylation processivity. Our studies provide a consistent biophysical basis for elucidation of the processive mechanism of PARN-mediated 3' mRNA deadenylation and provide a new framework to interpret the role of the 5' cap in mRNA degradation. PMID- 26772899 TI - Differential Effects of Dexamethasone and Doxycycline on Inflammation and MMP Production in Murine Alkali-Burned Corneas Associated with Dry Eye. AB - Alkali burns to the cornea are among the most devastating injuries to the eye. The purpose of this study was to evaluate the effects of dexamethasone (Dex) or doxycycline (Doxy) on protease activity and corneal complications in a combined model (CM) of alkali burn and dry eye. C57BL/6 mice were subjected to the CM for 2 or 5 days (D). Mice were topically treated either with Dex (0.1%), Dox (0.025%) or vehicle QID and observed daily for appearance of corneal perforation. Quantitative real time PCR was performed to measure expression of inflammation cytokines and matrix metalloproteinases (MMPs) in whole cornea lysates. No perforations were observed in the Dex-treated corneas. All wounds in Doxy-treated corneas were closed 2D post-injury, and they had significantly lower corneal opacity scores at days 4 and 5 post-injury compared to BSS treatment. Dex-treated corneas had the lowest corneal opacity scores. Dex treatment significantly decreased expression of IL-1beta, IL-6, MMPs -1, -9, -13, and TIMP-1 after 2 days but increased levels of MMP-8, while Doxy treatment significantly decreased IL 1beta, IL-6, MMP-8, and -9, compared to vehicle. Decreased MMP-1, -9 and -13 immunoreactivity and gelatinolytic activity were seen in corneas treated with Doxy and Dex compared to vehicle. Increased neutrophil infiltration and myeloperoxidase activity was noted in the vehicle group compared to Dex 2 days post-injury. These findings demonstrate that early initiation of anti inflammatory therapy is very efficacious in preserving corneal clarity and facilitating wound healing, while modulating MMP production and suppressing neutrophil infiltration. PMID- 26772901 TI - Diagonal chromatography to study plant protein modifications. AB - An interesting asset of diagonal chromatography, which we have introduced for contemporary proteome research, is its high versatility concerning proteomic applications. Indeed, the peptide modification or sorting step that is required between consecutive peptide separations can easily be altered and thereby allows for the enrichment of specific, though different types of peptides. Here, we focus on the application of diagonal chromatography for the study of modifications of plant proteins. In particular, we show how diagonal chromatography allows for studying proteins processed by proteases, protein ubiquitination, and the oxidation of protein-bound methionines. We discuss the actual sorting steps needed for each of these applications and the obtained results. This article is part of a Special Issue entitled: Plant Proteomics--a bridge between fundamental processes and crop production, edited by Dr. Hans Peter Mock. PMID- 26772902 TI - Antifungal agents for preventing fungal infections in non-neutropenic critically ill patients. AB - BACKGROUND: Invasive fungal infections are important causes of morbidity and mortality among critically ill patients. Early institution of antifungal therapy is pivotal for mortality reduction. Starting a targeted antifungal therapy after culture positivity and fungi identification requires a long time. Therefore, alternative strategies (globally defined as 'untargeted antifungal treatments') for antifungal therapy institution in patients without proven microbiological evidence of fungal infections have been discussed by international guidelines. This review was originally published in 2006 and updated in 2016. This updated review provides additional evidence for the clinician dealing with suspicion of fungal infection in critically ill, non-neutropenic patients, taking into account recent findings in this field. OBJECTIVES: To assess the effects of untargeted treatment with any antifungal drug (either systemic or nonabsorbable) compared to placebo or no antifungal or any other antifungal drug (either systemic or nonabsorbable) in non-neutropenic, critically ill adults and children. We assessed effectiveness in terms of total (all-cause) mortality and incidence of proven invasive fungal infections as primary outcomes. SEARCH METHODS: We searched the following databases to February 2015: the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (OVID), and EMBASE (OVID). We also searched reference lists of identified studies and major reviews, abstracts of conference proceedings, scientific meetings and clinical trials registries. We contacted experts in the field, study authors and pharmaceutical companies as part of the search strategy. SELECTION CRITERIA: We included randomized controlled trials (RCTs) (irrespective of language or publication status) comparing the use of untargeted treatment with any antifungal drug (either systemic or nonabsorbable) to placebo, no antifungal, or another antifungal agent in non-neutropenic critically ill participants. DATA COLLECTION AND ANALYSIS: Three authors independently applied selection criteria, extracted data and assessed the risk of bias. We resolved any discrepancies by discussion. We synthesized data using the random-effects model and expressed the results as risk ratios (RR) with 95% confidence intervals. We assessed overall evidence quality using the GRADE approach. MAIN RESULTS: We included 22 studies (total of 2761 participants). Of those 22 studies, 12 were included in the original published review and 10 were newly identified. Eleven trials compared the use of fluconazole to placebo or no antifungal treatment. Three trials compared ketoconazole versus placebo. One trial compared anidulafungin with placebo. One trial compared caspofungin to placebo. Two trials compared micafungin to placebo. One trial compared amphotericin B to placebo. Two trials compared nystatin to placebo and one trial compared the effect of clotrimazole, ketoconazole, nystatin and no treatment. We found two new ongoing studies and four new studies awaiting classification. The RCTs included participants of both genders with wide age range, severity of critical illness and clinical characteristics. Funding sources from pharmaceutical companies were reported in 11 trials and one trial reported funding from a government agency. Most of the studies had an overall unclear risk of bias for key domains of this review (random sequence generation, allocation concealment, incomplete outcome data). Two studies had a high risk of bias for key domains. Regarding the other domains (blinding of participants and personnel, outcome assessment, selective reporting, other bias), most of the studies had a low or unclear risk but four studies had a high risk of bias.There was moderate grade evidence that untargeted antifungal treatment did not significantly reduce or increase total (all-cause) mortality (RR 0.93, 95% CI 0.79 to 1.09, P value = 0.36; participants = 2374; studies = 19). With regard to the outcome of proven invasive fungal infection, there was low grade evidence that untargeted antifungal treatment significantly reduced the risk (RR 0.57, 95% CI 0.39 to 0.83, P value = 0.0001; participants = 2024; studies = 17). The risk of fungal colonization was significantly reduced (RR 0.71, 95% CI 0.52 to 0.97, P value = 0.03; participants = 1030; studies = 12) but the quality of evidence was low. There was no difference in the risk of developing superficial fungal infection (RR 0.69, 95% CI 0.37 to 1.29, P value = 0.24; participants = 662; studies = 5; low grade of evidence) or in adverse events requiring cessation of treatment between the untargeted treatment group and the other group (RR 0.89, 95% CI 0.62 to 1.27, P value = 0.51; participants = 1691; studies = 11; low quality of evidence). The quality of evidence for the outcome of total (all-cause) mortality was moderate due to limitations in study design. The quality of evidence for the outcome of invasive fungal infection, superficial fungal infection, fungal colonization and adverse events requiring cessation of therapy was low due to limitations in study design, non-optimal total population size, risk of publication bias, and heterogeneity across studies. AUTHORS' CONCLUSIONS: There is moderate quality evidence that the use of untargeted antifungal treatment is not associated with a significant reduction in total (all-cause) mortality among critically ill, non-neutropenic adults and children compared to no antifungal treatment or placebo. The untargeted antifungal treatment may be associated with a reduction of invasive fungal infections but the quality of evidence is low, and both the heterogeneity and risk of publication bias is high.Further high-quality RCTs are needed to improve the strength of the evidence, especially for more recent and less studied drugs (e.g. echinocandins). Future trials should adopt standardized definitions for microbiological outcomes (e.g. invasive fungal infection, colonization) to reduce heterogeneity. Emergence of resistance to antifungal drugs should be considered as outcome in studies investigating the effects of untargeted antifungal treatment to balance risks and benefit. PMID- 26772903 TI - Development of a targeted selected ion monitoring assay for the elucidation of protease induced structural changes in cardiac troponin T. AB - Cardiac troponin T (cTnT) is a highly cardiospecific protein commonly used in the diagnosis of acute myocardial infarction (AMI), but is subject to proteolytic degradation upon its release in the circulation. In this study, a targeted mass spectrometry assay was developed to detect peptides which are differentially present within the different degradation products. cTnT was spiked in human serum and incubated at 37 degrees C to induce proteolytic degradation. Isolation and fractionation of cTnT and its fragments from serum were performed using immunoprecipitation and SDS-PAGE. Bands migrating to 37 kDa (intact cTnT), 29 kDa (primary fragment), and 19, 18, and 16kDa (secondary fragments) were excised, digested, and subsequently analysed using targeted selected ion monitoring on a UHPLC-coupled quadrupole-Orbitrap mass spectrometer. Sixteen precursor ions from a total of 11 peptides unique to cTnT were targeted. Precursor ions were detectable up until 1200 ng/L cTnT, which is a typical cTnT concentration after AMI. With tandem-MS and relative quantification, we proved the formation of cTnT fragments upon incubation in human serum and identified differentially present peptides in the fragment bands, indicative of N- and C-terminal proteolytic cleavage. These findings are of importance for the development of future cTnT assays, calibrators, and quality control samples. BIOLOGICAL SIGNIFICANCE: In this study we have developed a gel-based targeted mass spectrometry assay which is able to differentiate between different molecular forms of cTnT. The unravelling of the molecular presentation of cTnT in human serum is of importance in the field of clinical chemistry, where this highly specific and sensitive biomarker is being measured on a routinely basis in patient samples. Knowledge of the amino acid sequence of the different cTnT fragments may aid in the development of improved calibrators and quality control samples. In addition, different fragmentation patterns may be indicative of different underlying pathologies. New antibodies for future assays targeting specific areas of cTnT can thus be created based on this information. This assay will be used in future experiments to assess the fragmentation pattern of cTnT in serum of multiple patient groups in our laboratory. PMID- 26772904 TI - The impact of short-term depot-medroxyprogesterone acetate treatment on resting metabolic rate. AB - OBJECTIVE: This study examines the effect of a progestogen (depot medroxyprogesterone acetate, DMPA) on resting metabolic rate (RMR) in a cohort of young, normal-weight healthy women. We hypothesize an increase in RMR and nonshivering thermogenesis (NST) resulting in increased body temperature by DMPA. STUDY DESIGN: We performed a prospective cohort study in 13 subjects tested at baseline, 3 weeks and 9 weeks after 150 mg intramuscular DMPA administration. RMR was determined with indirect calorimetry. Secondary endpoints included changes in body mass index (BMI), body composition, temperature and serum levels of estradiol (E2), luteinizing hormone (LH), progesterone and MPA. RESULTS: The percent change in RMR from baseline to week 3 (9%) was significantly higher than the percent change from baseline to week 9 (1.6%) (p=.045). The greatest percent change from baseline to week 3 compared to baseline to week 9 was seen in women initiating DMPA in the luteal phase of the cycle. Hypothalamic-pituitary-ovarian axis was evident by decreases in E2, LH and progesterone. DMPA resulted in increased body temperature with a significant correlation between the change in body temperature and the change in RMR. No change in body composition was seen. CONCLUSIONS: RMR and NST increased in young healthy women with normal BMI 3 weeks after receiving the initial dose of 150 mg DMPA for contraception. The effect was augmented when the drug was administered during the luteal phase of the menstrual cycle. IMPLICATION: DMPA increases RMR and thermogenesis independent of changes in body mass. An increase in weight with chronic DMPA may result from a combination of hyperphagia and abnormal NST in predisposed individuals. PMID- 26772905 TI - Feasibility of radiolabeled small molecule permeability as a quantitative measure of microbicide candidate toxicity. AB - OBJECTIVE: To determine the feasibility of using quantitative changes in vaginal permeability to small molecules as a measure of candidate microbicide toxicity. STUDY DESIGN: Controlled, open-labeled, prospective study. Seven healthy women received a single vaginal dose of hydroxyethylcellulose gel (HEC), nonoxynol-9 (N 9) or K-Y Jelly. Each gel was radiolabeled with a small molecule ((99m)Tc-DTPA) followed by 12-h blood and urine collection. Pharmacokinetic (PK) parameters of (99m)Tc-DTPA were calculated to compare the impact of each gel on vaginal permeability. Each woman served as her own control. The Friedman test with post hoc Wilcoxon test was used to detect differences among the gels. RESULTS: Vaginal permeability of (99m)Tc-DTPA was highest for the N-9 radiolabel. N-9 plasma area under the concentration curve was 2.7-fold higher (p=.04), and peak concentration was threefold higher (p=.04) compared to HEC. There were no significant PK parameter differences between HEC and K-Y Jelly or between N-9 and K-Y Jelly. Cumulative dose-adjusted median (interquartile range) 12-h timed urine gamma activity was 66.70 * 10(-4)MUCi (27.90-152.00) following HEC dosing, 103.00 * 10( 4)MUCi (98.20-684.00) following N-9 gel dosing and 20.30 * 10(-4)MUCi (11.10 55.90) following K-Y gel dosing. The differences between urine HEC and K-Y Jelly (p=.047) and between N-9 and K-Y Jelly (p=.016) were statistically significant. CONCLUSIONS: It is feasible to measure differences in vaginal permeability among vaginal gels using a radiolabeled small molecule, though there are permeability differences that require a nuanced understanding of gel composition to interpret the results. IMPLICATIONS: Establishing the safety of both vehicle and active pharmaceutical ingredient is an essential task in microbicide development, to be determined as soon as possible. This study suggests that a combination of microbicide toxicity assessments, that is, cervicovaginal permeability, inspection and histopathology, may need to be studied simultaneously. PMID- 26772906 TI - United States family planning providers' knowledge of and attitudes towards preexposure prophylaxis for HIV prevention: a national survey. AB - OBJECTIVES: The Centers for Disease Control and Prevention defines HIV prevention as a core family planning service. The HIV community identified family planning visits as key encounters for women to access preexposure prophylaxis (PrEP) for HIV prevention. No studies explore US family planning providers' knowledge of and attitudes towards PrEP. We conducted a national survey of clinicians to understand barriers and facilitators to PrEP implementation in family planning. STUDY DESIGN: Family planning providers recruited via website postings, national meetings, and email completed an anonymous survey in 2015. Descriptive statistics were performed. RESULTS: Among 604 respondents, 495 were eligible for analysis and 342 were potential PrEP prescribers (physicians, nurse practitioners, midwives or physicians assistants). Among potential prescribers, 38% correctly defined PrEP [95% confidence interval (CI): 32.5-42.8], 37% correctly stated the efficacy of PrEP (95% CI: 32.0-42.4), and 36% chose the correct HIV test after a recent exposure (95% CI: 30.6-40.8). Characteristics of those who answered knowledge questions correctly included age less than 35 years, practicing in the Northeast or West, routinely offering HIV testing, providing rectal sexually transmitted infection screening or having seen any PrEP guidelines. Even among providers in the Northeast and West, the proportion of respondents answering questions correctly was less than 50%. Thirty-six percent of respondents had seen any PrEP guidelines. Providers identified lack of training as the main barrier to PrEP implementation; 87% wanted PrEP education. CONCLUSIONS: To offer comprehensive HIV prevention services, family planning providers urgently need training on PrEP and HIV testing. IMPLICATIONS: US family planning providers have limited knowledge about HIV PrEP and HIV testing, and report lack of provider training as the main barrier to PrEP provision. Provider education is needed to ensure that family planning clients access comprehensive HIV prevention methods. PMID- 26772907 TI - Identification and validation of reference genes for quantitative RT-PCR analysis of retinal pigment epithelium cells under hypoxia and/or hyperglycemia. AB - Retinal pigment epithelium (RPE) cell-based gene expression studies performed under hypoxia and/or hyperglycemia show huge potential for modeling cell responses in diabetic retinopathy, retinopathy of prematurity and other retinal diseases. However, normalization of gene expression on RPE cells under those conditions has commonly been done using either GAPDH or beta-actin as reference genes without any validation of their expression stability. Therefore, we aimed to establish a suitable set of reference genes for studies on RPE cells cultured under both normal culturing glucose and atmospheric oxygen tension (normoxia, 21%), under a low oxygen tension (hypoxia, 1%), under a high glucose growth medium (25 mmol/l) and under the combination of the two changed conditions above for distinct time points taking together from 24h to 7 days. Quantitative real time PCR (qRT-PCR) was applied on RNA obtained from a cell line, ARPE-19. Stability of 14 commonly used reference genes was assessed and ranked according to their stability values using the geNorm and NormFinder softwares with the aim to find the most stable expressed gene under all conditions. Our findings confirm that HPRT1, GUSB and PPIA are the most suitable reference genes for RPE cell gene expression experiments subjected to hypoxia and/or hyperglycemia. To emphasize the importance of selecting the most stably expressed reference genes for obtaining reliable results, mRNA expression levels of hypoxia induced factor 1alpha were analyzed vs the best reference genes, the worst ones and the most commonly used ones. These reference genes gave the most reliable normalization for comparative analyses of gene transcription under those conditions. PMID- 26772909 TI - MicroRNA expression profiles in response to drought stress in Sorghum bicolor. AB - The regulatory role of small non-coding RNAs that are 20-24 nucleotides in length has become the foremost area of research for biologists. A major class of small RNAs represented by the microRNAs (miRNAs), has been implicated in various aspects of plant development including leaf pattering, meristem function, root patterning etc. Recent findings support that miRNAs are regulated by drought and other abiotic stresses in various plant species. In this study, were report the expression profiling of 8 known abiotic stress deregulated miRNAs in 11 elite sorghum genotypes, under watered and drought conditions. Significant deregulation was observed with miR396, miR393, miR397-5p, miR166, miR167 and miR168. Among these, the expression levels of sbi-miR396 and sbi-miR398 were the highest in all the genotypes. The expression of sbi-miR396 was maximum in the grain sorghum HSD3226 under well-watered conditions and the profile shifted towards HSD3221 under drought stress. Forage accessions, N98 and Atlas, showed an opposite behavior in expression patterns of miR397-5p in drought physiologies. Such dynamic expression patterns could be indicative of prevailing drought tolerant mechanisms present in these sorghum accessions. This data provides insights into sorghum miRNAs which may have potential use in improving drought tolerance in sorghum and other cereal crops. PMID- 26772910 TI - A Group-Based Mobile Application to Increase Adherence in Exercise and Nutrition Programs: A Factorial Design Feasibility Study. AB - BACKGROUND: Novel methods of promoting self-monitoring and social support are needed to ensure long-term maintenance of behavior change. In this paper, we directly investigate the effects of group support in an exercise and nutrition program delivered by an mHealth application called Fittle. OBJECTIVE: Our first specific study aim was to explore whether social support improved adherence in wellness programs. Our second specific study aim was to assess whether media types (ePaper vs mobile) were associated with different levels of compliance and adherence to wellness programs. The third aim was to assess whether the use of an mHealth application led to positive changes to participants' eating behavior, physical activity, and stress level, compared to traditional paper-based programs. METHODS: A 2 * 2 (eg, Media: Mobile vs ePaper * Group Type: Team vs Solo) factorial design feasibility study was conducted. A sample of 124 volunteers who were interested in improving eating behavior, increasing physical activity, or reducing stress participated in this study. The study duration was 8 weeks. All groups were self-directed with no ongoing human input from the research team. RESULTS: Participants in ePaper conditions had higher attrition rates compared to participants in Mobile conditions, chi3(2)=9.96, P=.02 (N=124). Participants in Mobile conditions reported their compliance with a much higher frequency closer to the time of challenge activity completion (2-sample Kolmogorov-Smirnov test comparing distributions was highly significant-KS=0.33, P<.001 [N=63]). Participants in ePaper conditions had a much higher frequency of guessing while reporting as compared with those in Mobile conditions chi1(2)=25.25, P<.001 (N=63). Together, these findings suggest that the mobile app allowed a more accurate method to report and track health behaviors over a longer period than traditional ePaper-based diaries or log books. There was a significant difference in the overall compliance score for Mobile-Solo (Mean [SD] 0.30 [0.39]) and Mobile-Team (Mean [SD] 0.49 [0.35]) conditions (t50.82=1.94, P=.05). This suggests that working in a team increased participants' overall compliance within Fittle. Survival analysis showed that participants assigned to Team conditions are 66% more likely to engage longer with mHealth app-based intervention than those assigned to the Solo condition. Overall, participants across all groups reported some positive changes in eating behavior, physical activity, and stress level; however, participants in the Mobile-Solo condition reported higher perceived stress levels at the end of the study. CONCLUSIONS: The team-based Fittle app is an acceptable and feasible wellness behavior change intervention and a full randomized controlled trial to investigate the efficacy of such an intervention is warranted. PMID- 26772911 TI - Another Paradox? The Life Satisfaction of Older Hispanic Immigrants in the United States. AB - OBJECTIVE: To investigate disparities in life satisfaction among older Hispanic immigrants in the United States relative to their native-born Hispanic and non Hispanic White counterparts, and to identify factors associated with such disparities. METHOD: Cross-sectional data from 9,798 individuals age 60 and above from the Health and Retirement Study (HRS) were used to estimate ordinary least squares (OLS) regression models. RESULTS: Hispanic immigrants reported the highest levels of life satisfaction of all groups. Wealthier older adults, who were socially engaged, had social support, and experienced fewer functional limitations and lower exposure to discrimination, were more satisfied with their lives in the overall sample. Interaction effects revealed that although education was associated with greater life satisfaction only among non-Hispanic Whites, co residing with children was associated with greater life satisfaction only among Hispanics. DISCUSSION: Although older Hispanic immigrants had the least amount of socioeconomic resources of all groups in our study, they were the most satisfied with their lives. Possible explanations and directions for future research are discussed. PMID- 26772912 TI - Chitosan coating of red kiwifruit (Actinidia melanandra) for extending of the shelf life. AB - Commercial production of red kiwifruit (Actinidia melanandra) has been unsuccessful because of its short shelf life. Here in this study, we used chitosan to extend the shelf life of red kiwifruit berries. Chitosan (with 70-75% deacetylation degree and low molecular weight) was dissolved in acetic acid (at pH 2.0-2.3) to obtain gel material, which was used for coating of the fruit. The coated and uncoated samples were kept for 26 days at room temperature (20+/-2 degrees C). The changes in the weight loss, firmness, soluble solid content, total polyphenol content and ascorbic acid content were evaluated. All these findings showed that chitosan could be an effective coating material for berries of red kiwifruit to extend its short shelf life. PMID- 26772913 TI - Synthesis and characterisation of poly(acryalamide) grafted carboxymethyl xanthan gum copolymer. AB - In the present work, an unreported graft copolymer of carboxymethyl xanthan gum and acrylamide has been synthesised by free radical polymerisation in a nitrogen atmosphere using ammonium persulphate as an initiator. The optimum reaction conditions adopted for affording maximum percentage of grafting including its grafting efficiency were obtained by varying the concentration of carboxymethyl xanthan gum from 4 to 24 g dm(-3); ammonium persulphate from 5*10(-4) to 30*10( 4)mol dm(-3); acrylamide from 0.4 to 1.2 mol dm(-3); reaction temperature from 55 to 75 degrees C and reaction time from 30 to 90 min. The synthesised graft copolymer has been characterised by (1)H NMR, FTIR spectroscopy, X-ray diffraction measurement, thermal analysis, viscosity measurement and scanning electron microscopy. However, grafting of acrylamide onto carboxymethyl xanthan gum backbone enhanced its thermal stability. This graft copolymer might be well exploited globally as a potential carrier for drug delivery system. PMID- 26772908 TI - Epithelial sodium channel (ENaC) family: Phylogeny, structure-function, tissue distribution, and associated inherited diseases. AB - The epithelial sodium channel (ENaC) is composed of three homologous subunits and allows the flow of Na(+) ions across high resistance epithelia, maintaining body salt and water homeostasis. ENaC dependent reabsorption of Na(+) in the kidney tubules regulates extracellular fluid (ECF) volume and blood pressure by modulating osmolarity. In multi-ciliated cells, ENaC is located in cilia and plays an essential role in the regulation of epithelial surface liquid volume necessary for cilial transport of mucus and gametes in the respiratory and reproductive tracts respectively. The subunits that form ENaC (named as alpha, beta, gamma and delta, encoded by genes SCNN1A, SCNN1B, SCNN1G, and SCNN1D) are members of the ENaC/Degenerin superfamily. The earliest appearance of ENaC orthologs is in the genomes of the most ancient vertebrate taxon, Cyclostomata (jawless vertebrates) including lampreys, followed by earliest representatives of Gnathostomata (jawed vertebrates) including cartilaginous sharks. Among Euteleostomi (bony vertebrates), Actinopterygii (ray finned-fishes) branch has lost ENaC genes. Yet, most animals in the Sarcopterygii (lobe-finned fish) branch including Tetrapoda, amphibians and amniotes (lizards, crocodiles, birds, and mammals), have four ENaC paralogs. We compared the sequences of ENaC orthologs from 20 species and established criteria for the identification of ENaC orthologs and paralogs, and their distinction from other members of the ENaC/Degenerin superfamily, especially ASIC family. Differences between ENaCs and ASICs are summarized in view of their physiological functions and tissue distributions. Structural motifs that are conserved throughout vertebrate ENaCs are highlighted. We also present a comparative overview of the genotype-phenotype relationships in inherited diseases associated with ENaC mutations, including multisystem pseudohypoaldosteronism (PHA1B), Liddle syndrome, cystic fibrosis-like disease and essential hypertension. PMID- 26772914 TI - Exploring the effect of cellulose nanowhiskers isolated from oil palm biomass on polylactic acid properties. AB - In this work, polylactic acid (PLA) reinforced cellulose nanowhiskers (CNW) were prepared through solution casting technique. The CNW was first isolated from oil palm empty fruit bunch microcrystalline cellulose (OPEFB-MCC) by using 64% H2SO4 and was designated as CNW-S. The optical microscopy revealed that the large particle of OPEFB-MCC has been broken down by the hydrolysis treatment. The atomic force microscopy confirmed that the CNW-S obtained is in nanoscale dimension and appeared in individual rod-like character. The produced CNW-S was then incorporated with PLA at 1, 3, and 5 parts per hundred (phr) resins for the PLA-CNW-S nanocomposite production. The synthesized nanocomposites were then characterized by a mean of tensile properties and thermal stability. Interestingly to note that incorporating of 3 phr/CNW-S in PLA improved the tensile strength by 61%. Also, CNW-S loading showed a positive impact on the Young's modulus of PLA. The elongation at break (Eb) of nanocomposites, however, decreased with the addition of CNW-S. Field emission scanning electron microscopy and transmission electron microscopy revealed that the CNW-S dispersed well in PLA at lower filler loading before it started to agglomerate at higher CNW-S loading (5phr). The DSC analysis of the nanocomposites obtained showed that Tg,Tcc and Tm values of PLA were improved with CNW-S loading. The TGA analysis however, revealed that incopreated CNW-S in PLA effect the thermal stability (T10,T50 and Tmax) of nanocomposite, where it decrease linearly with CNW-S loading. PMID- 26772915 TI - Microencapsulation optimization of natural anthocyanins with maltodextrin, gum Arabic and gelatin. AB - The barberry (Berberis vulgaris) extract which is a rich source of anthocyanins was used for spray drying encapsulation with three different wall materials, i.e., combination of maltodextrin and gum Arabic (MD+GA), maltodextrin and gelatin (MD+GE), and maltodextrin (MD). Response Surface Methodology (RSM) was applied for optimization of microencapsulation efficiency and physical properties of encapsulated powders considering wall material type as well as different ratios of core to wall materials as independent variables. Physical characteristics of spray-dried powders were investigated by further analyses of moisture content, hygroscopicity, degree of caking, solubility, bulk and absolute density, porosity, flowability and microstructural evaluation of encapsulated powders. Our results indicated that samples produced with MD+GA as wall materials represented the highest process efficiency and best powder quality; the optimum conditions of microencapsulation process for barberry anthocyanins were found to be the wall material content and anthocyanin load of 24.54% and 13.82%, respectively. Under such conditions, the microencapsulation efficiency (ME) of anthocyanins could be as high as 92.83%. PMID- 26772916 TI - Tunable functional hydrogels formed from a versatile water-soluble chitosan. AB - A versatile water-soluble chitosan (WSC) was applied to construct two kinds of controllable functional hydrogels. Magnetic beads were prepared by physical cross linking WSC with sodium alginate, soaking particles with ferrous chloride and being subjected to self-oxidation. Magnetic character of the beads was tunable by simply changing the initial concentration of ferrous ions. The beads could bind compounds that contained different charges. Their adsorption capacities for coomassie brilliant blue, rhodamine and hemoglobin were 1, 0.5 and 2.3mg/g respectively. Another kind of functional hydrogel was prepared through radical cross-linking reaction between WSC and a macromonomer (PVAM) derived from well defined polyvinyl alcohol. The dynamic mechanical thermal analysis and thermogravimetric analysis results revealed that the mechanical strength and thermal stability of this hydrogel depended on the structure of PVAM. The capability to bind heavy metal ions of the hydrogel also relied on the structure of PVAM. The adsorption capacities of the hydrogels for Cu(2+) and Pb(2+) could reach 20.3 and 60.1mg/g respectively. PMID- 26772917 TI - Functional and cell proliferative properties of an exopolysaccharide produced by Nitratireductor sp. PRIM-31. AB - Exopolysaccharides (EPS) produced by bacteria are important source of natural biomolecules with therapeutic applications. In this study EPS produced by a strain PRIM-31 isolated from seawater from south west coast of India identified by 16S rRNA gene sequencing as Nitratireductor sp. was investigated for its biotechnological applications. The isolate produced 650 mg L(-1) EPS under optimum growth conditions. The purified EPS contained 58.3% carbohydrates with 7.08% uronic acid containing sugars, functional groups such as sulfate (2.68%) and trace amounts of proteins (0.65%). Molecular weight of the EPS was 90 kDa and monosaccharide composition was arabinose, glucose, xylose, glucuronic acid and galactose (6.6: 3.5: 2.1: 1.3: 1). The EPS displayed antioxidant activity in terms of total antioxidant capacity, ferric reducing power, scavenging of DPPH (IC50 390 MUg mL(-1)) and superoxide radicals (IC50 340 MUg mL(-1)). Cell proliferative activity of the EPS was evidenced by significant improvement in human dermal fibroblast (HDF) proliferation compared to control. Further, significant improvement (41%) in HDF cell migration was observed in in vitro scratch assay with EPS treatment. The EPS also showed antiproliferative activity against glioblastoma cells with an IC50 of 234.04 MUg mL(-1). These functional properties of the EPS prospect its biotechnological applications. PMID- 26772918 TI - PFTK1 regulates cell proliferation, migration and invasion in epithelial ovarian cancer. AB - PFTK1, also named Cyclin-Dependent Kinase 14 (CDK14), is a member of the cell division cycle 2 (CDC2)-related protein kinase family. It is a serine/threonine protein kinase involved in the regulation of cell cycle progression and cell proliferation. In this study, we investigated the role of PFTK1 in epithelial ovarian cancer (EOC) development. The expression of PFTK1 was detected by Western blot and immunohistochemistry staining, both of which demonstrated that PFTK1 was overexpressed in EOC tissues and cells. Statistical analysis showed the expression of PFTK1 was associated with multiple clinicopathological factors, including tumor grade, FIGO stage, lymph node metastatis, Ki-67 expression and predicted a poor prognosis of EOC patients. With in vitro studies we found that PFTK1 expression was decreased in serum-starved ovarian cancer cells, and progressively increased after serum-re-feeding. Knocking PFTK1 down by small interfering RNA (siRNA) significantly inhibited ovarian cancer cell proliferation, migration and invasion. Taken together, our study suggested that PFTK1 played an important role in ovarian cancer development. PMID- 26772919 TI - Effect of different isolation methods on structure and properties of lignin from valonea of Quercus variabilis. AB - Valonea of Quercus variabilis Blume, an abundant feedstock in China, can be used for tannin. However, there are little studies about lignin from this material. The present study aimed at lignin from the valonea: (1) Ethanol lignin (EL), alkali lignin (AL), milled wood lignin (MWL) and enzyme hydrolysis lignin (EHL) were prepared from the valonea of Q.variabilis Blume. (2) The effect of different isolation processes on the lignin chemical and physical features were studied by UV-vis, FT-IR, GPC, TG and (1)H NMR. (3) Antioxidant activities of four lignin preparations were evaluated by DPPH, ABTS and FRAP assays. The results showed that the valonea of Q. variabilis contained mass lignin and four lignin preparations were GSH-type with little differences. The MWL contained the least functional groups (1.75 mmol/g MeO, 0.87 mmol/g ArOH and 1.27 mmol/g AlkOH), the poorest thermostability (onset degradation temperature=111 degrees C, maximum rate of degradation=268 degrees C) and the highest antioxidant activity. The EHL had the highest molecular weight (Mw=1,429 g/mol; Mn=746.18 g/mol). This study provided a theoretical basis for the development and utilization of lignin from the valonea of Q. variabilis. PMID- 26772920 TI - Secretory expression, characterization and docking study of glucose-tolerant beta glucosidase from B. subtilis. AB - The thermostable, glucose tolerant beta-glucosidase gene (bgl) of Glycoside hydrolase family 1, isolated from Bacillus subtilis, was cloned and overexpressed in Escherichia coli. The bgl has open reading frame of 1,407 bp, encoding 469 amino acids with predicted molecular weight of 53 kDa. The recombinant protein (BGL) was purified 10.76 fold to homogeneity with specific activity of 54.04U/mg and recovery of 38.67%. The purified BGL was optimally active at pH 6.0 and temperature 60 degrees C. The enzyme retained more than 85% of maximum activity after 1h preincubation at 60 degrees C. The kinetic analysis indicated that BGL has highest catalytic efficiency (Kcat/Km) against p-nitrophenyl-beta-d xylopyranoside (654.58 mM(-1)s(-1)) followed by p-nitrophenyl-beta-d glucopyranoside (292.53 mM(-1)s(-1)) and p-nitrophenyl-beta-d-galactopyranoside (61.17 mM(-1)s(-1)). The Ki value for glucose and delta-gluconolactone was determined to be 1.9 mM and 0.018 mM, respectively. The BGL exhibited high tolerance against detergents and organic solvents. The homology modeling revealed that protein has 19 alpha-helices and 4 beta-sheets and adopted (alpha/beta)8 TIM barrel structure. Substrate docking and LigPlot analysis depicted the amino acids of active site involved in hydrogen bonding and hydrophobic interactions with substrates. The efficient BGL secretion with exploration of structural and functional relationship offer vistas for large scale production and various industrial applications. PMID- 26772921 TI - Exploitation of novel gum Prunus cerasoides as mucoadhesive beads for a controlled-release drug delivery. AB - The present study deals with the formulation of pH-sensitive mucoadhesive beads using natural gum isolated from Prunus cerasoides (PC) in combination with sodium alginate (SA) for the controlled release of diclofenac sodium (DS). PC and SA composite (PC-SA), DS loaded SA (DS-SA) and DS loaded PC-SA (DS-PC-SA) beads were prepared by ionotropic gelation method. The absence of interaction between DS and PC-SA was shown by FTIR, DSC and TGA analyses. The optimized DS-PC-SA formulation exhibited mucoadhesive property and the controlled release of DS was achieved 68% in 12h. The in vitro release kinetics follows zero order with anomalous diffusion mechanism. Therefore, the formulated mucoadhesive beads with the novel gum are preferable for the controlled release of DS by prolonging the residence time of the drug in the gastrointestinal tract, overcoming the problems associated with the immediate release dosage forms of DS. PMID- 26772922 TI - Management of Preschool Children with Recurrent Wheezing: Lessons from the NHLBI's Asthma Research Networks. AB - Recurrent wheezing in the preschool children is a common clinical problem, often associated with significant morbidity related to acute episodes. The management of these children has been complicated by a paucity of high-quality clinical trials in this age group. To fill this knowledge gap, National Heart, Lung, and Blood Institute's asthma research networks have performed a series of clinical trials in an effort to provide practitioners with guidance on appropriate management strategies. These studies establish daily inhaled corticosteroid (ICS) therapy in toddlers at high risk for subsequent asthma as an effective approach for the prevention of exacerbations and symptom reduction, but without evidence of disease-modifying properties. Additional studies have confirmed substantial heterogeneity in ICS response, in terms of both efficacy and effect on linear growth. Treatment with intermittent high-dose ICS was demonstrated to be an alternative approach to daily low-dose ICS for preventing severe exacerbations in toddlers with intermittent but significant wheeze and a positive modified asthma predictive index. This review details the findings and clinical implications derived from these studies, discuss the utility of biomarkers and the role of oral corticosteroids during acute exacerbations, and summarizes ongoing clinical trials in this age group. PMID- 26772924 TI - Should a Preschool Child with Acute Episodic Wheeze be Treated with Oral Corticosteroids? A Pro/Con Debate. AB - Traditionally, preschool-aged children with an acute wheezing episode have been treated with oral corticosteroids (OCSs) based on the efficacy of OCSs in older children and adolescents. However, this practice has been recently challenged based on the results of recent studies. The argument supporting the use of OCSs underscores the observation that many children with recurrent preschool wheezing develop atopic disease in early life which predicts both an increased risk to develop asthma in later life and response to OCS therapy. Further, review of the literature demonstrates heterogeneity of study designs, OCS dosage, interventions, study medication adherence, and settings and overall lack of predefined preschool wheezing phenotypes. The heterogeneity of these studies does not allow a definitive recommendation discouraging OCS use. Advocates against the use of OCSs in this population argue that most of studies investigating the efficacy of OCSs in acute episodic wheeze in preschool-aged children have not demonstrated beneficial effects. Moreover, repeated OCS bursts may be associated with adverse effects. Finally, both sides can agree that there is a significant need to conduct efficacy trials evaluating OCS treatment in preschool-aged children with recurrent wheezing targeted at phenotypes that would be expected to respond to OCSs. This article presents a summary of recent literature regarding the use of OCSs for acute episodic wheezing in preschool-aged children and a "pro" and "con" debate for such use. PMID- 26772923 TI - Severe Asthma in Children: Lessons Learned and Future Directions. AB - Severe asthma in children is a complicated and heterogeneous disorder that is extremely challenging to treat. Although most children with asthma derive clinical benefit from daily administration of low-to-medium-dose inhaled corticosteroid (ICS) therapy, a small subset of children with "severe" or "refractory" asthma require high doses of ICS and even systemic corticosteroids to maintain symptom control. These children with severe asthma are at increased risk for adverse outcomes including medication-related side effects and recurrent and life-threatening exacerbations that significantly impair quality of life. This review highlights findings on severe asthma in school-age children (age 6-17 years) from the National Heart, Lung and Blood Institute's Severe Asthma Research Program (SARP) over a 10-year period, between 2001 and 2011. Although SARP has advanced knowledge of the unique clinical, biological, and molecular attributes of severe asthma in children, considerable gaps remain for which additional studies are needed. PMID- 26772925 TI - Asthma in Childhood: Expression, Exacerbation, and Progression. PMID- 26772926 TI - A New Tool to Address an Asthma Research Gap. PMID- 26772927 TI - Asthma and Depression: It's Complicated. PMID- 26772928 TI - Improving Asthma Self-Management: Searching for Pearls of Wisdom. PMID- 26772929 TI - Sex differences in the risk of hospitalization among patients presenting to US emergency departments with asthma exacerbation, 2010-2012. PMID- 26772930 TI - Hypersensitivity Reactions, Dietary Supplements, and the Importance of the Case Report. PMID- 26772931 TI - When Cough Wheeze and Shortness of Breath Don't Equal Asthma. PMID- 26772932 TI - Venom Allergy. PMID- 26772933 TI - Omalizumab and Allergic Reactions. PMID- 26772934 TI - Reply. PMID- 26772935 TI - Post Cystoscopy Anaphylaxis. PMID- 26772936 TI - Routine Vaccinations in Diffuse Cutaneous Mastocytosis. PMID- 26772937 TI - Reply. PMID- 26772938 TI - Proprioception and Knee Arthroplasty: A Literature Review. AB - Proprioceptive mechanoreceptors provide neural feedback for position in space and are critical for three-dimensional interaction. Proprioception is decreased with osteoarthritis of the knees, which leads to increased risk of falling. As the prevalence of osteoarthritis increases so does the need for total knee arthroplasty (TKA), and knowing the effect of TKA on proprioception is essential. This article reviews the literature regarding proprioception and its relationship to balance, aging, osteoarthritis, and the effect of TKA on proprioception. Knee arthroplasty involving retention of the cruciate ligaments is also reviewed, as well the evidence of proprioception in the posterior cruciate ligament after TKA. PMID- 26772939 TI - Instability After Total Knee Arthroplasty. AB - Instability is one of the most common causes of failure after total knee arthroplasty. Although there are several contributing causes, surgical error and poor implant design selection contribute. For this reason, an accurate diagnosis is fundamental and is largely based on a thorough history and physical examination. In general, tibiofemoral instability can be classified into 3 different patterns: flexion instability, genu recurvatum, and extension instability. In this article, these 3 patterns are reviewed in greater depth. PMID- 26772940 TI - The Painful Total Knee Arthroplasty. AB - There are many causes of residual pain after total knee arthroplasty (TKA). Evaluation and management begins with a comprehensive history and physical examination, followed by radiographic evaluation of the replaced and adjacent joints, as well as previous films of the replaced joint. Further workup includes laboratory analysis, along with a synovial fluid aspirate to evaluate the white blood cell count with differential as well as culture. Advanced imaging modalities may be beneficial when the diagnosis remains unclear. Revision surgery is not advisable without a clear diagnosis, as it may be associated with poor results. PMID- 26772941 TI - Avoiding Hip Instability and Limb Length Discrepancy After Total Hip Arthroplasty. AB - Two complications after total hip arthroplasty (THA) are hip instability and limb length discrepancy; instability is a common indication for revision THA. The goal of a successful THA is to maximize impingement-free range of motion, recreate appropriate offset, and equalize limb length discrepancies to produce a pain-free and dynamically stable THA. In this article, the patient risk factors for dislocation and limb length discrepancy, key elements of the preoperative template, the anatomic landmarks for accurate component placement, the leg positions for soft tissue stability testing, and the management of postoperative instability are reviewed. PMID- 26772942 TI - Thromboembolic Disease After Orthopedic Trauma. AB - Orthopedic trauma results in systemic physiologic changes that predispose patients to venous thromboembolism (VTE). In the absence of prophylaxis, VTE incidence may be as high as 60%. Mechanical and pharmacologic thromboprophylaxis are effective in decreasing rates of VTE. Combined mechanical and pharmacologic thromboprophylaxis is more efficacious for decreasing VTE incidence than either regimen independently. If pharmacologic thromboprophylaxis is contraindicated, mechanical prophylaxis should be used. Patients with isolated lower extremity fractures who are ambulatory, or those with isolated upper extremity trauma, do not require pharmacologic prophylaxis in the absence of other VTE risk factors. PMID- 26772943 TI - Arthrofibrosis After Periarticular Fracture Fixation. AB - Arthrofibrosis after periarticular fractures can create clinically significant impairments in both the upper and lower extremities. The shoulder, elbow, and knee are particularly susceptible to the condition. Many risk factors for the development of arthrofibrosis cannot be controlled by the patient or surgeon. Early postoperative motion should be promoted whenever possible. Manipulations under anesthesia are effective for a period of time in certain fracture patterns, and open or arthroscopic surgical debridements should be reserved for the patient for whom nonoperative modalities fail and who has a clinically significant deficit. PMID- 26772944 TI - Impact of Infection on Fracture Fixation. AB - Surgical site infection can be a devastating complication that results in significant morbidity in patients who undergo operative fixation of fractures. Reducing the rate of infection and wound complications in high-risk trauma patients by giving early effective antibiotics, improving soft tissue management, and using antiseptic techniques is a common topic of discussion. Despite heightened awareness, there has not been a significant reduction in surgical site infection over the past 40 years. Patients should be treated aggressively to eliminate or suppress the infection, heal the fracture if there is a nonunion, and maintain the function of the patient. PMID- 26772945 TI - Nonunion of the Femur and Tibia: An Update. AB - Delayed union and nonunion of tibial and femoral shaft fractures are common orthopedic problems. Numerous publications address lower extremity long bone nonunions. This review presents current trends and recent literature on the evaluation and treatment of nonunions of the tibia and femur. New studies focused on tibial nonunion and femoral nonunion are reviewed. A section summarizing recent treatment of atypical femoral fractures associated with bisphosphonate therapy is also included. PMID- 26772946 TI - Complications of Pediatric Elbow Fractures. AB - Fractures about the elbow in children are common and varied. Both diagnosis and treatment can be challenging, and optimal treatment protocols continue to evolve with new research data. This article reviews common complications related to pediatric elbow fractures and presents recent literature to help guide treatment. PMID- 26772947 TI - Surgical Site Infections After Pediatric Spine Surgery. AB - Surgical site infection (SSI) after spinal deformity surgery is a complication in the pediatric population resulting in high morbidity and cost. Despite modern surgical techniques and preventative strategies, the incidence remains substantial, especially in the neuromuscular population. This review focuses on recent advancements in identification of risk factors, prevention, diagnosis, and treatment strategies for acute and delayed pediatric spine infections. It reviews recent literature, including the best practice guidelines for infection prevention in high-risk patients. Targets of additional research are highlighted to assess efficacy of current practices to further reduce risk of SSI in pediatric patients with spinal deformity. PMID- 26772948 TI - Complications After Surgical Treatment of Adolescent Idiopathic Scoliosis. AB - Even with current techniques and instrumentation, complications can occur after operative treatment of adolescent idiopathic scoliosis. The most dreaded complications-neurologic deficits-are relatively infrequent, occurring in 1% or less of patients. Nonneurologic deficits, such as infection, pseudarthrosis, curve progression, and proximal junctional kyphosis, are more frequent, but are much less likely to require reoperation or to cause poor functional outcomes. Understanding the potential complications of surgical treatment of pediatric spinal deformity is essential for surgical decision-making. PMID- 26772949 TI - Complications Related to the Treatment of Slipped Capital Femoral Epiphysis. AB - Slipped capital femoral epiphysis (SCFE) is a condition of the immature hip in which mechanical overload of the proximal femoral physis results in anterior and superior displacement of the femoral metaphysis relative to the epiphysis. The treatment of SCFE is surgical, as the natural history of nonsurgical treatment is slip progression and early arthritis. Despite advances in treatment, much controversy exists regarding the best treatment, and complication rates remain high. Complications include osteonecrosis, chondrolysis, SCFE-induced impingement, and related articular degeneration, fixation failure and deformity progression, growth disturbance of the proximal femur, and development of bilateral disease. PMID- 26772950 TI - Complications of Distal Radius Fixation. AB - Complications following any form of distal radius fixation remain prevalent. With an armamentarium of fixation options available to practicing surgeons, familiarity with the risks of newer plate technology as it compares with other conventional methods is crucial to optimizing surgical outcome and managing patient expectations. This article presents an updated review on complications following various forms of distal radius fixation. PMID- 26772951 TI - Complications of Carpal Tunnel Release. AB - Carpal tunnel release for compression of the median nerve at the wrist is one of the most common and successful procedures in hand surgery. Complications, though rare, are potentially devastating and may include intraoperative technical errors, postoperative infection and pain, and persistent or recurrent symptoms. Patients with continued complaints after carpal tunnel release should be carefully evaluated with detailed history and physical examination in addition to electrodiagnostic testing. For those with persistent or recurrent symptoms, a course of nonoperative management including splinting, injections, occupational therapy, and desensitization should be considered prior to revision surgery. PMID- 26772952 TI - Complications of Distal Biceps Repair. AB - Modern techniques to repair the distal biceps tendon include one-incision and 2 incision techniques that use transosseous sutures, suture anchors, interference screws, and/or cortical buttons to achieve a strong repair of the distal biceps brachii. Repair using these techniques has led to improved functional outcomes when compared with nonoperative treatment. Most complications consist of neuropraxic injuries to the lateral antebrachial cutaneous nerve, posterior interosseous nerve, stiffness and weakness with forearm rotation, heterotopic ossification, and wound infections. Although complications certainly affect outcomes, patients with distal biceps repairs report a high satisfaction rate after repair. PMID- 26772953 TI - Complications of Lateral Epicondylar Release. AB - Reported complication rates are low for lateral epicondylitis management, but the anatomic complexity of the elbow allows for possible catastrophic complication. This review documents complications associated with lateral epicondylar release: 67 studies reporting outcomes of lateral epicondylar release with open, percutaneous, or arthroscopic methods were reviewed and 6 case reports on specific complications associated with the procedure are included. Overall complication rate was 3.3%. For open procedures it was 4.3%, percutaneous procedures 1.9%, and arthroscopic procedures 1.1%. In higher-level studies directly comparing modalities, the complication rates were 1.3%, 0%, and 1.2%, respectively. PMID- 26772954 TI - Deep Vein Thrombosis in Foot and Ankle Surgery. AB - The routine use of venous thromboembolism prophylaxis in patients undergoing foot and ankle procedures is not well supported in the literature. Multiple studies draw conclusions from heterogeneous populations, and specific studies have small numbers of specific pathologic conditions. Depending on the study, recommendations for and against venous thromboembolism prophylaxis in foot and ankle surgery can be made. The identification of risk factors for venous thromboembolism is paramount in the decision making of postoperative venous thromboembolism prophylaxis. PMID- 26772955 TI - Common Complications in Orthopedics. PMID- 26772956 TI - Note from the Publisher. PMID- 26772957 TI - A germline predictive signature of response to platinum chemotherapy in esophageal cancer. AB - Platinum-based neoadjuvant therapy is the standard treatment for esophageal cancer (EC). At present, no reliable response markers exist, and patient therapeutic outcome is variable and very often unpredictable. The aim of this study was to understand the contribution of host constitutive DNA polymorphisms in discriminating between responder and nonresponder patients. DNA collected from 120 EC patients treated with platinum-based neoadjuvant chemotherapy was analyzed using drug metabolism enzymes and transporters (DMET) array platform that interrogates polymorphisms in 225 genes of drug metabolism and disposition. Four gene variants of DNA repair machinery, 2 in ERCC1 (rs11615; rs3212986), and 2 in XPD (rs1799793; rs13181) were also studied. Association analysis was performed with pTest software and corrected by permutation test. Predictive models of response were created using the receiver-operating characteristics curve approach and adjusted by the bootstrap procedure. Sixteen single nucleotide polymorphisms (SNPs) of the DMET array resulted significantly associated with either good or poor response; no association was found for the 4 variants mapping in DNA repair genes. The predictive power of 5 DMET SNPs mapping in ABCC2, ABCC3, CYP2A6, PPARG, and SLC7A8 genes was greater than that of clinical factors alone (area under the curve [AUC] = 0.74 vs 0.62). Interestingly, their combination with the clinical variables significantly increased the predictivity of the model (AUC = 0.78 vs 0.62, P = 0.0016). In conclusion, we identified a genetic signature of response to platinum-based neoadjuvant chemotherapy in EC patients. Our results also disclose the potential benefit of combining genetic and clinical variables for personalized EC management. PMID- 26772958 TI - Protein disulfide isomerase A3-specific Th1 effector cells infiltrate colon cancer tissue of patients with circulating anti-protein disulfide isomerase A3 autoantibodies. AB - To investigate novel colorectal cancer (CRC)-associated antigens that could be targets of humoral or cellular responses, we analyzed the reactivity of serum from a long-surviving CRC patient (for more than 100 months of follow-up) in clinical remission, by serologic proteome analysis. Two-dimensional Western blotting (2D-WB) and mass spectrometry analysis revealed a strong reactivity of this serum against protein disulfide isomerase A3 (PDIA3). Anti-PDIA3 antibodies are not a diagnostic marker of CRC, 2D-WB and Luminex analysis revealed that they were equally present in about 10% of sera from healthy subjects and CRC patients. Kaplan-Meier analysis of survival in CRC patient cohort, after 48 months of follow-up, showed a trend of higher survival in patients with increased levels of autoantibodies to PDIA3. Therefore, the interplay between the presence of these antibodies and T-cell response was investigated. Peripheral blood T cells from CRC patients with high immunoglobulin G (IgG) reactivity to PDIA3 also secreted interferon gamma (IFN-gamma) when stimulated in vitro with recombinant PDIA3, whereas those from CRC with low IgG reactivity to PDIA3 did not. PDIA3-pulsed dendritic cells efficiently induced proliferation and IFN-gamma production of autologous CD4(+) and CD8(+) T cells. Finally, ex vivo analysis of tumor infiltrating T lymphocytes from CRC patients with autoantibodies to PDIA3 revealed that PDIA3-specific Th1 effector cells accumulated in tumor tissue. These data indicate that the presence of autoantibodies to PDIA3 favors the development of an efficient and specific T-cell response against PDIA3 in CRC patients. These results may be relevant for the design of novel immunotherapeutic strategies in CRC patients. PMID- 26772959 TI - M10, a caspase cleavage product of the hepatocyte growth factor receptor, interacts with Smad2 and demonstrates antifibrotic properties in vitro and in vivo. AB - Hepatocyte growth factor receptor, also known as cellular mesenchymal-epithelial transition factor (c-MET, MET), is an important antifibrotic molecule that protects various tissues, including lung, from injury and fibrosis. The intracellular cytoplasmic tail of MET contains a caspase-3 recognition motif "DEVD-T" that on cleavage by caspase-3 generates a 10-amino acid peptide, TRPASFWETS, designated as "M10". M10 contains at its N-terminus the uncharged amino acid proline (P) directly after a cationic amino acid arginine (R) which favors the transport of the peptide through membranes. M10, when added to cell culture medium, remains in the cytoplasm and nuclei of cells for up to 24 hours. M10 effectively decreases collagen in both scleroderma and TGFbeta-stimulated normal lung and skin fibroblasts. M10 interacts with the Mad Homology 2 domain of Smad2 and inhibits TGFbeta-induced Smad2 phosphorylation, suggesting that the antifibrotic effects of M10 are mediated in part by counteracting Smad-dependent fibrogenic pathways. In the bleomycin murine model of pulmonary fibrosis, M10 noticeably reduced lung inflammation and fibrosis. Ashcroft fibrosis scores and lung collagen content were significantly lower in bleomycin-treated mice receiving M10 as compared with bleomycin-treated mice receiving scrambled peptide. We conclude that M10 peptide interacts with Smad2 and demonstrates strong antifibrotic effects in vitro and in vivo in an animal model of lung fibrosis and should be considered as a potential therapeutic agent for systemic sclerosis and other fibrosing diseases. PMID- 26772961 TI - A mixed-mode resin with tryptamine ligand for human serum albumin separation. AB - Mixed-mode chromatography (MMC) is a new technology that uses specially-designed ligands to improve the adsorption selectivity with multimodal protein-ligand interactions for protein separation. A new MMC resin TA-B-6FF with tryptamine as the functional ligand was prepared and used for human serum albumin (HSA) separation. Adsorption equilibria of plasma-derived HSA (pHSA) were investigated and compared with a commercial tryptophan-based resin (MX-Trp-650m), and the influence of pH and salt addition was studied. The results showed that weak acidic conditions (pH 5.0-7.0) were favorable for HSA adsorption. The maximum adsorption capacity of TA-B-6FF was 141.33mg/g at pH 5.0, which was two times higher than that of MX-Trp-650m. TA-B-6FF also showed better salt-tolerance than MX-Trp-650m. Moreover, TA-B-6FF was used to separate recombinant HSA (rHSA) from Pichia pastoris culture broth. The results indicated that rHSA could be directly captured by TA-B-6FF without dilution or pH adjustment. High purity (87.75%) of rHSA monomer could be obtained with a recovery of 98.53% through two-step elution process. Total content of rHSA monomer and degraded fragment was 99.75%, the removal of host cell proteins reached about 90%. The results demonstrate that new TA-B-6FF resin has a great potential for rHSA purification directly from the complex fermentation broth. PMID- 26772960 TI - Novel Wnt Regulator NEL-Like Molecule-1 Antagonizes Adipogenesis and Augments Osteogenesis Induced by Bone Morphogenetic Protein 2. AB - The differentiation factor NEL-like molecule-1 (NELL-1) has been reported as osteoinductive in multiple in vivo preclinical models. Bone morphogenetic protein (BMP)-2 is used clinically for skeletal repair, but in vivo administration can induce abnormal, adipose-filled, poor-quality bone. We demonstrate that NELL-1 combined with BMP2 significantly optimizes osteogenesis in a rodent femoral segmental defect model by minimizing the formation of BMP2-induced adipose-filled cystlike bone. In vitro studies using the mouse bone marrow stromal cell line M2 10B4 and human primary bone marrow stromal cells have confirmed that NELL-1 enhances BMP2-induced osteogenesis and inhibits BMP2-induced adipogenesis. Importantly, the ability of NELL-1 to direct BMP2-treated cells toward osteogenesis and away from adipogenesis requires intact canonical Wnt signaling. Overall, these studies establish the feasibility of combining NELL-1 with BMP2 to improve clinical bone regeneration and provide mechanistic insight into canonical Wnt pathway activity during NELL-1 and BMP2 osteogenesis. The novel abilities of NELL-1 to stimulate Wnt signaling and to repress adipogenesis may highlight new treatment approaches for bone loss in osteoporosis. PMID- 26772962 TI - Medicaid prescription limits: policy trends and comparative impact on utilization. AB - BACKGROUND: Medicaid programs face growing pressure to control spending. Despite evidence of clinical harms, states continue to impose policies limiting the number of reimbursable prescriptions (caps). We examined the recent use of prescription caps by Medicaid programs and the impact of policy implementation on prescription utilization. METHODS: We identified Medicaid cap policies from 2001 2010. We classified caps as applying to all prescriptions (overall caps) or only branded prescriptions (brand caps). Using state-level, aggregate prescription data, we developed interrupted time-series analyses to evaluate the impact of implementing overall caps and brand caps in a subset of states with data available before and after cap initiation. For overall caps, we examined the use of essential medications, which were classified as preventive or as providing symptomatic benefit. For brand caps, we examined the use of all branded drugs as well as branded and generic medications among classes with available generic replacements. RESULTS: The number of states with caps increased from 12 in 2001 to 20 in 2010. Overall cap implementation (n = 3) led to a 0.52% (p < 0.001) annual decrease in the proportion of essential prescriptions but no change in cost. For preventive essential medications, overall caps led to a 1.12% (p = 0.001) annual decrease in prescriptions (246,000 prescriptions annually) and a 1.20% (p < 0.001) decrease in spending (-$12.2 million annually), but no decrease in symptomatic essential medication use. Brand cap implementation (n = 6) led to an immediate 2.29% (p = 0.16) decrease in branded prescriptions and 1.26% (p = 0.025) decrease in spending. For medication classes with generic replacements, the decrease in branded prescriptions (0.74%, p = 0.003) approximately equaled the increase in generics (0.79%, p = 0.009), with estimated savings of $17.4 million. CONCLUSIONS: An increasing number of states are using prescription caps, with mixed results. Overall caps decreased the use of preventive but not symptomatic essential medications, suggesting that patients assign higher priority to agents providing symptomatic benefit when faced with reimbursement limits. Among medications with generic replacements, brand caps shifted usage from branded drugs to generics, with considerable savings. Future research should analyze the patient-level impact of these policies to measure clinical outcomes associated with these changes. PMID- 26772963 TI - The association of body image distortion with weight control behaviors, diet behaviors, physical activity, sadness, and suicidal ideation among Korean high school students: a cross-sectional study. AB - BACKGROUND: The identification of predictors for body image distortion would be an especially important first step in targeting a vulnerable population and developing a nutrition intervention program. We aimed to investigate the prevalence of body image distortion and the factors associated with body image distortion among Korean high school students. METHODS: We selected 20,264 normal weight high school students from the 10(th) Korea Youth Risk Behavior Web-based Survey using nationally representative data in 2014. With multivariate logistic regression, we assessed the association of body image distortion with individual demographic and socio-economic factors, weight control behaviors, and mental health characteristics. RESULTS: The over-estimation group of body weight status, compared with the correct estimation group, was significantly more likely to be a 3(rd) year high school student [adjusted odds ratio (AOR): 1.27, 95% confidence interval (CI): 1.16-1.39], to be female [AOR: 3.52, 95% CI: 3.25-3.81], to employ unhealthy weight control behaviors [AOR: 1.54, 95% CI: 1.37-1.72], and to have a sadness [AOR: 1.25, 95% CI: 1.16-1.35] and suicidal ideation [AOR: 1.20, 95% CI: 1.08-1.33]. The under-estimation group, compared with the correct estimation group, was significantly less likely to be female [AOR: 0.23, 95% CI: 0.21-0.25] and to employ unhealthy weight control behaviors [AOR: 0.50, 95% CI: 0.43-0.59] but were more likely to have a sadness [AOR: 1.12, 95% CI: 1.03-1.21] and suicidal ideation [AOR: 1.12, 95% CI: 1.00-1.25]. CONCLUSIONS: Not only the over estimation but also the under-estimation of body weight is prevalent among high school students in South Korea. Body image distortion was significantly associated with sadness and suicidal ideation. PMID- 26772964 TI - Subgroup analysis in MS trials. AB - Subgroup analysis is often conducted as a post-hoc evaluation of clinical trials. The aim of a subgroup analysis is the evaluation of the treatment effect that was tested in the trial, in a specific subgroups of patients. It can be run both on positive trials (to provide information about patients receiving the highest benefit from the treatment) and on negative trials (to test whether the treatment that had no effect on the overall population can be of any benefit in a specific subset of patients). A subgroup analysis is aimed at generating hypotheses for future research. Subgroup analyses have statistical challenges involving multiple testing and unplanned and low powered analyses; however the main issue, at least in subgroup analysis conducted so far in MS studies, seems to be related to the reporting and interpretation of results. In this viewpoint I will try to show the misleading ways of reporting subgroup analysis in MS trials, along with the correct approach based on an interaction test. PMID- 26772965 TI - Speeding up access to new drugs threatens evidence based medicine, says health economist. PMID- 26772966 TI - DNA aptamer selection in methanolic media: Adenine-aptamer as proof-of-concept. AB - The major objective of this study is to investigate the usefulness of aptamers as in situ detection tool in organic solvents, which are often used for environmental extraction. But two problems related to the use of methanol containing buffers have to be addressed. Firstly, the folding of nucleic acids can be impaired, because of weaker hydrogen bonding interactions. Secondly, the affinity of aptamers selected in aqueous buffers can be altered by the presence of methanol. Thus, in order to improve hydrophobicity of the DNA pool, nucleotide with hydrophobic modification 5-(octa1,7-diynyl)-2'-deoxyuridine (ODT) has been chosen instead of thymidine. As a proof of concept, an adenine aptamer operating in presence 25% of methanol has been selected. We have shown that the modified nucleotide is essential for target binding in organic media, in addition to essential structural pattern as proposed through analysing truncated sequences analysis. The strategy described in this paper offers preliminary insight on the adaptability of the implementation of aptamers as key instrument for in situ detection. It could be broaden to identify other aptamers directed against other chemical species after alcoholic extraction or for monitoring by-product traces in drugs production. PMID- 26772967 TI - Hydronephrosis: A Rare Presentation of Uterine Didelphys with Obstructed Hemivagina and Ipsilateral Renal Anomaly. AB - BACKGROUND: Obstructed hemivagina and ipsilateral renal anomaly syndrome is a Mullerian duct anomaly characterized by uterine didelphys, obstructed hemivagina, and ipsilateral renal anomalies. CASE: A 12-year-old girl with a history of right renal agenesis presented to the emergency department with abdominal pain, dysuria, and urinary retention. Imaging identified a uterine didelphys with a large obstructed right hemivagina compressing the left ureter, causing hydronephrosis. She underwent vaginal septum resection for curative treatment. SUMMARY AND CONCLUSION: In female patients who present with abdominal pain and a history of renal abnormalities, obstructed hemivagina and ipsilateral renal anomaly syndrome must be considered in the differential diagnosis. This consideration is important in preventing complications such as hydronephrosis seen in this patient. PMID- 26772968 TI - Species- and concentration-dependent differences of acetyl- and butyrylcholinesterase sensitivity to physostigmine and neostigmine. AB - Previous and more recent studies show that cholinesterase inhibitors (ChE-Is) are an important possibility for therapeutic intervention in Alzheimer's Disease, sepsis and other inflammatory syndromes. ChE-Is maintain high levels of acetylcholine (ACh) determining beneficial effects on the disease process. Despite numerous efforts to identify the appropriate choice of agents and dose of ChE-Is, a common protocol regarding concentration- and species-dependent differences in inhibitory potency (IC 50) of clinical relevant ChE-Is is still not available. To evaluate the in vitro sensitivity of Acetyl- and Butyrylcholinesterase (AChE, BChE), we compared the concentration-response effects of physostigmine and neostigmine on cholinesterases in whole blood from rat and human. A spectrophotometrical test system based on in vitro Ellman's reagent has been used to determine the kinetic properties of clinical relevant ChE-Is. In vitro, the enzyme activity of human AChE and BChE was inhibited in a concentration-dependent manner until a residual activity of 4-6% for AChE and 20 30% for BChE (IC 50 human AChE: 0.117 +/- 0.007 MUM physostigmine, 0.062 +/- 0.003 MUM neostigmine; IC 50 human BChE: 0.373 +/- 0.089 MUM neostigmine; 0.059 +/- 0.012 MUM physostigmine). The inhibition curve of rat BChE in contrast showed no concentration-dependency for physostigmine and neostigmine (87% residual activity even at high inhibitor concentrations). Rat AChE was inhibited in a concentration-dependent manner until a residual activity of 53%. The results suggest that cholinesterases from human and rat show marked species- and inhibitor-dependent differences in sensitivity to physostigmine and neostigmine. Knowledge of such differences may be critical in assessing the possible therapeutic effects of ChE-Is in both species and may guide researchers in the optimal design of future experiments regarding the application of ChE-Is. PMID- 26772969 TI - Abeta-mediated spine changes in the hippocampus are microtubule-dependent and can be reversed by a subnanomolar concentration of the microtubule-stabilizing agent epothilone D. AB - Dendritic spines represent the major postsynaptic input of excitatory synapses. Loss of spines and changes in their morphology correlate with cognitive impairment in Alzheimer's disease (AD) and are thought to occur early during pathology. Therapeutic intervention at a preclinical stage of AD to modify spine changes might thus be warranted. To follow the development and to potentially interfere with spine changes over time, we established a long term ex vivo model from organotypic cultures of the hippocampus from APP transgenic and control mice. The cultures exhibit spine loss in principal hippocampal neurons, which closely resembles the changes occurring in vivo, and spine morphology progressively changes from mushroom-shaped to stubby. We demonstrate that spine changes are completely reversed within few days after blocking amyloid-beta (Abeta) production with the gamma-secretase inhibitor DAPT. We show that the microtubule disrupting drug nocodazole leads to spine loss similar to Abeta expressing cultures and suppresses DAPT-mediated spine recovery in slices from APP transgenic mice. Finally, we report that epothilone D (EpoD) at a subnanomolar concentration, which slightly stabilizes microtubules in model neurons, completely reverses Abeta-induced spine loss and increases thin spine density. Taken together the data indicate that Abeta causes spine changes by microtubule destabilization and that spine recovery requires microtubule polymerization. Moreover, our results suggest that a low, subtoxic concentration of EpoD is sufficient to reduce spine loss during the preclinical stage of AD. PMID- 26772970 TI - Subtype-selective nicotinic acetylcholine receptor agonists can improve cognitive flexibility in an attentional set shifting task. AB - Nicotinic acetylcholine receptors (nAChRs) are considered to be viable targets to enhance cognition in patients diagnosed with schizophrenia. Activation of nAChRs with selective nicotinic receptor agonists may provide effective means to pharmacologically treat cognitive deficits observed in schizophrenia. Cognitive flexibility is one aspect of cognition, which can be assessed in a rodent model of the attentional set-shifting task (ASST). The aim of the present study was two fold, firstly, to evaluate the efficacy of a series of subtype selective nAChR agonists, such as those that target alpha7 and alpha4beta2 nAChR subtypes in non compromised rodents. Secondly, nicotine as a prototypic agonist was evaluated for its effects to restore attentional deficits produced by sub-chronic ketamine exposure in the ASST. Male hooded Lister rats underwent habituation, consisting of a simple odour and medium discrimination with subsequent assessment 24 h later. In experimentally naive rats, alpha7 subtype selective agonists, compound A and SSR180711 along with PNU-120596, an alpha7 positive allosteric modulator (PAM), were compared against the beta2* selective agonist, 5IA-85380. All compounds except for PNU-120596 were observed to significantly improve extra dimensional (ED) shift performance, nicotine, 5IA-85380 and SSR180711 further enhanced the final reversal (REV3) stage of the task. In another experiment, sub chronic ketamine treatment produced robust deficits during the ED and the REV3 stages of the discriminations; rodents required significantly more trials to reach criterion during these discriminations. These deficits were attenuated in rodents treated acutely with nicotine (0.1 mg/kg SC) 10 min prior to the ED shift. These results highlight the potential utility of targeting nAChRs to enhance cognitive flexibility, particularly the alpha7 and beta2* receptor subtypes. The improvement with nicotine was much greater in rodents that were impaired following the sub-chronic ketamine exposure suggesting a greater therapeutic opportunity to target nicotinic receptors for patients diagnosed with schizophrenia. PMID- 26772971 TI - Several wall-associated kinases participate positively and negatively in basal defense against rice blast fungus. AB - BACKGROUND: Receptor-like kinases are well-known to play key roles in disease resistance. Among them, the Wall-associated kinases (WAKs) have been shown to be positive regulators of fungal disease resistance in several plant species. WAK genes are often transcriptionally regulated during infection but the pathways involved in this regulation are not known. In rice, the OsWAK gene family is significantly amplified compared to Arabidopsis. The possibility that several WAKs participate in different ways to basal defense has not been addressed. Moreover, the direct requirement of rice OSWAK genes in regulating defense has not been explored. RESULTS: Here we show using rice (Oryza sativa) loss-of function mutants of four selected OsWAK genes, that individual OsWAKs are required for quantitative resistance to the rice blast fungus, Magnaporthe oryzae. While OsWAK14, OsWAK91 and OsWAK92 positively regulate quantitative resistance, OsWAK112d is a negative regulator of blast resistance. In addition, we show that the very early transcriptional regulation of the rice OsWAK genes is triggered by chitin and is partially under the control of the chitin receptor CEBiP. Finally, we show that OsWAK91 is required for H2O2 production and sufficient to enhance defense gene expression during infection. CONCLUSIONS: We conclude that the rice OsWAK genes studied are part of basal defense response, potentially mediated by chitin from fungal cell walls. This work also shows that some OsWAKs, like OsWAK112d, may act as negative regulators of disease resistance. PMID- 26772972 TI - Linking clinician interaction and coordination to clinical performance in Patient Aligned Care Teams. AB - BACKGROUND: Team coordination within clinical care settings is a critical component of effective patient care. Less is known about the extent, effectiveness, and impact of coordination activities among professionals within VA Patient-Aligned Care Teams (PACTs). This study will address these gaps by describing the specific, fundamental tasks and practices involved in PACT coordination, their impact on performance measures, and the role of coordination task complexity. METHODS/DESIGN: First, we will use a web-based survey of coordination practices among 1600 PACTs in the national VHA. Survey findings will characterize PACT coordination practices and assess their association with clinical performance measures. Functional job analysis, using 6-8 subject matter experts who are 3rd and 4th year residents in VA Primary Care rotations, will be utilized to identify the tasks involved in completing clinical performance measures to standard. From this, expert ratings of coordination complexity will be used to determine the level of coordinative complexity required for each of the clinical performance measures drawn from the VA External Peer Review Program (EPRP). For objective 3, data collected from the first two methods will evaluate the effect of clinical complexity on the relationships between measures of PACT coordination and their ratings on the clinical performance measures. DISCUSSION: Results from this study will support successful implementation of coordinated team-based work in clinical settings by providing knowledge regarding which aspects of care require the most complex levels of coordination and how specific coordination practices impact clinical performance. PMID- 26772973 TI - Oleanolic acid (OA) as an antileishmanial agent: Biological evaluation and in silico mechanistic insights. AB - Although a worldwide health problem, leishmaniasis is considered a highly neglected disease, lacking efficient and low toxic treatment. The efforts for new drug development are based on alternatives such as new uses for well-known drugs, in silico and synthetic studies and naturally derived compounds. Oleanolic acid (OA) is a pentacyclic triterpenoid widely distributed throughout the Plantae kingdom that displays several pharmacological activities. OA showed potent leishmancidal effects in different Leishmania species, both against promastigotes (IC(50 L. braziliensis) 30.47 +/- 6.35 MUM; IC(50 L. amazonensis) 40.46 +/- 14.21 MUM; IC(50 L. infantum) 65.93 +/- 15.12 MUM) and amastigotes (IC(50 L. braziliensis) 68.75 +/- 16.55 MUM; IC(50 L. amazonensis) 38.45 +/- 12.05 MUM; IC(50 L. infantum) 64.08 +/- 23.52 MUM), with low cytotoxicity against mouse peritoneal macrophages (CC(50) 235.80 +/- 36.95 MUM). Moreover, in silico studies performed to evaluate OA molecular properties and to elucidate the possible mechanism of action over the Leishmania enzyme sterol 14alpha-demethylase (CYP51) suggested that OA interacts efficiently with CYP51 and could inhibit the ergosterol synthesis pathway. Collectively, these data indicate that OA is a good candidate as leading compound for the development of a new leishmaniasis treatment. PMID- 26772974 TI - Unplanned revision spinal surgery within a week: a retrospective analysis of surgical causes. AB - BACKGROUND: The need for revision surgery after a spinal surgery can cause a variety of problems, including reduced quality of life for the patient, additional medical expenses, and patient-physician conflicts. The purpose of this study was to evaluate the causes of unplanned revision spinal surgery within a week after the initial surgery in order to identify the surgical issues most commonly associated with unplanned revision surgery. METHODS: We retrospectively reviewed the medical records of all patients at who received a spinal surgery at a regional medical center from July 2004 to April 2011 in order to identify those who required a revision surgery within one week of their initial surgery. Patients were excluded if they received a vertebroplasty, kyphoplasty, or nerve block surgery, because those surgeries are one-day surgeries that do not require hospital admission. In addition, patients with a primary diagnosis of wound infection were also excluded since reoperations for infection control can be expected. RESULTS: The overall incidence of unplanned revision spinal surgery during the time period covered by this review was 1.12% (116/10,350 patients). The most common surgical causes of reoperation were screw malposition (41 patients), symptomatic epidural hematoma (27 patients), and inadequate decompression (37 patients). Screw malposition was the most common complication, with an incidence rate of 0.82%. Screw instrumentation was significantly associated with revision surgery (p = 0.023), which suggests that this procedure carried a greater risk of requiring revision. The mean time interval to reoperation for epidural hematomas was significantly shorter than the intervals for other causes of revision spinal surgery (p < 0.001), which suggests that epidural hematoma was more emergent than other complications. Also, 25.93% of patients who underwent hematoma removal experienced residual sequelae; this percentage was significantly higher than for other surgical causes of revision spinal surgery (p = 0.013). CONCLUSIONS: The results suggest that to avoid the need for reoperation, screw malposition, inadequate decompression, and epidural hematoma are the key surgical complications to be guarded against. Accordingly, adequate decompression, epidural hematoma prevention, and proper pedicle screw placement may help reduce the incidence of revision surgery. PMID- 26772975 TI - Neuroprotective effects of bee venom phospholipase A2 in the 3xTg AD mouse model of Alzheimer's disease. AB - BACKGROUND: Alzheimer's disease (AD) is a severe neuroinflammatory disease. CD4(+)Foxp3(+) regulatory T cells (Tregs) modulate various inflammatory diseases via suppressing Th cell activation. There are increasing evidences that Tregs have beneficial roles in neurodegenerative diseases. Previously, we found the population of Treg cells was significantly increased by bee venom phospholipase A2 (bvPLA2) treatment in vivo and in vitro. METHODS: To examine the effects of bvPLA2 on AD, bvPLA2 was administered to 3xTg-AD mice, mouse model of Alzheimer's disease. The levels of amyloid beta (Abeta) deposits in the hippocampus, glucose metabolism in the brain, microglia activation, and CD4(+) T cell infiltration were analyzed to evaluate the neuroprotective effect of bvPLA2. RESULTS: bvPLA2 treatment significantly enhanced the cognitive function of the 3xTg-AD mice and increased glucose metabolism, as assessed with 18F-2 fluoro-2-deoxy-D-glucose ([F 18] FDG) positron emission tomography (PET). The levels of Abeta deposits in the hippocampus were dramatically decreased by bvPLA2 treatment. This neuroprotective effect of bvPLA2 was associated with microglial deactivation and reduction in CD4(+) T cell infiltration. Interestingly, the neuroprotective effects of bvPLA2 were abolished in Treg-depleted mice. CONCLUSIONS: The present studies strongly suggest that the increase of Treg population by bvPLA2 treatment might inhibit progression of AD in the 3xTg AD mice. PMID- 26772976 TI - Urinary alpha-1 antitrypsin and CD59 glycoprotein predict albuminuria development in hypertensive patients under chronic renin-angiotensin system suppression. AB - BACKGROUND: Hypertension is a multi-factorial disease of increasing prevalence and a major risk factor for cardiovascular mortality even in the presence of adequate treatment. Progression of cardiovascular disease (CVD) occurs frequently during chronic renin-angiotensin-system (RAS) suppression, and albuminuria is a marker of CV risk. High prevalence of albuminuria in treated hypertensive patients has been demonstrated, but there are no available markers able to predict evolution. The aim of this study was the identification of novel indicators of albuminuria progression measurable in urine of diabetic and non diabetic patients. METHODS: 1143 hypertensive patients under chronic treatment were followed for a minimum period of 3 years. Among them, 105 diabetic and non diabetic patients were selected and classified in three groups according to albuminuria development during follow-up: (a) patients with persistent normoalbuminuria; (b) patients developing de novo albuminuria; (c) patients with maintained albuminuria. Differential urine analysis was performed by 2D gel electrophoresis (2D-DIGE) and further confirmed by liquid chromatography-mass spectrometry. Non-parametric statistical tests were applied. RESULTS: CD59 glycoprotein and alpha-1 antitrypsin (AAT) resulted already altered in patients developing albuminuria de novo, with a similar response in those with maintained albuminuria. A prospective study in a sub-group of normoalbuminuric patients who were clinically followed up for at least 1 year from urine sampling, revealed CD59 and AAT proteins significantly varied in the urine collected from normoalbuminurics who will negatively progress, serving as predictors of future albuminuria development. CONCLUSIONS: CD59 and AAT proteins are significantly altered in hypertensive patients developing albuminuria. Interestingly, CD59 and AAT are able to predict, in normoalbuminuric individuals, who will develop albuminuria in the future, being potential predictors of vascular damage and CV risk. These findings contribute to early identify patients at risk of developing albuminuria even when this classical predictor is still in the normal range, constituting a novel strategy towards a prompt and more efficient therapeutic intervention with better outcome. PMID- 26772977 TI - Functional conservation of the apoptotic machinery from coral to man: the diverse and complex Bcl-2 and caspase repertoires of Acropora millepora. AB - BACKGROUND: Apoptotic cell death is a defining and ubiquitous characteristic of metazoans, but its evolutionary origins are unclear. Although Caenorhabditis and Drosophila played key roles in establishing the molecular bases of apoptosis, it is now clear that cell death pathways of these animals do not reflect ancestral characteristics. Conversely, recent work suggests that the apoptotic networks of cnidarians may be complex and vertebrate-like, hence characterization of the apoptotic complement of representatives of the basal cnidarian class Anthozoa will help us to understand the evolution of the vertebrate apoptotic network. RESULTS: We describe the Bcl-2 and caspase protein repertoires of the coral Acropora millepora, making use of the comprehensive transcriptomic data available for this species. Molecular phylogenetics indicates that some Acropora proteins are orthologs of specific mammalian pro-apoptotic Bcl-2 family members, but the relationships of other Bcl-2 and caspases are unclear. The pro- or anti-apoptotic activities of coral Bcl-2 proteins were investigated by expression in mammalian cells, and the results imply functional conservation of the effector/anti apoptotic machinery despite limited sequence conservation in the anti-apoptotic Bcl-2 proteins. A novel caspase type ("Caspase-X"), containing both inactive and active caspase domains, was identified in Acropora and appears to be restricted to corals. When expressed in mammalian cells, full-length caspase-X caused loss of viability, and a truncated version containing only the active domain was more effective in inducing cell death, suggesting that the inactive domain might modulate activity in the full-length protein. Structure prediction suggests that the active and inactive caspase domains in caspase-X are likely to interact, resulting in a structure resembling that of the active domain in procaspase-8 and the inactive caspase domain in the mammalian c-FLIP anti-apoptotic factor. CONCLUSIONS: The data presented here confirm that many of the basic mechanisms involved in both the intrinsic and extrinsic apoptotic pathways were in place in the common ancestor of cnidarians and bilaterians. With the identification of most or all of the repertoires of coral Bcl-2 and caspases, our results not only provide new perspectives on the evolution of apoptotic pathways, but also a framework for future experimental studies towards a complete understanding of coral bleaching mechanisms, in which apoptotic cell death might be involved. PMID- 26772978 TI - Lrp5/6 are required for cerebellar development and for suppressing TH expression in Purkinje cells via beta-catenin. AB - BACKGROUND: The cerebellum is responsible for coordinating motor functions and has a unique laminated architecture. Purkinje cells are inhibitory neurons and represent the only output from the cerebellar cortex. Tyrosine hydroxylase (TH) is the key enzyme for the synthesis of catecholamines, including dopamine and noradrenaline, and it is normally not expressed in cerebellar neurons. RESULTS: We report here that the low-density lipoprotein receptors (Lrp) 5 and 6, Wnt co receptors, are required for the development of the cerebellum and for suppressing ectopic TH expression in Purkinje cells. Simultaneous inactivation of Lrp 5 and 6 by Nestin-Cre results in defective lamination and foliation of the cerebellum during postnatal development. Surprisingly, TH is ectopically expressed by Purkinje cells, although they still keep its other neurochemical characteristics. These phenotypes are also observed in the cerebellum of GFAP-Cre;beta catenin(flox/flox) mice, and AAV2-Cre-mediated gene deletion leads to ectopic TH expression in Purkinje cells of beta-catenin(flox/flox) mice as well. CONCLUSIONS: Our results revealed a new role of the canonical Lrp5/6-beta-catenin pathway in regulating the morphogenesis of the cerebellum during postnatal development. PMID- 26772979 TI - Altered expression levels of occludin, claudin-1 and myosin light chain kinase in the common bile duct of pediatric patients with pancreaticobiliary maljunction. AB - BACKGROUND: In pancreaticobiliary maljunction (PBM), the sphincter of Oddi can not control bile and pancreatic juice flow, which may lead to two-way reflux of bile and pancreatic juice, thus causing chronic inflammation, thickening, fibrosis and metaplasia of the common bile duct wall. These pathophysiological changes have been linked to disruption of the epithelium barrier in the common bile duct. We hypothesized that the expression of tight junction-associated proteins may be dysregulated in the common bile duct in PBM. In the current study, we sought to analyze the expression of tight junction-associated proteins in the common bile duct epithelium of pediatric patients with PBM. METHODS: Specimens of the common bile duct were collected from 12 pediatric patients with PBM and 10 non-PBM controls. The expression of the tight junction-associated proteins occludin and claudin-1 in the epithelium was examined by immunohistochemistry. The Image-Pro Plus v. 6.0 image analysis software was used to calculate the mean qualifying score (MQS) of imunostained sections of common bile duct epithelium. Total protein extracts of common bile duct were analyzed by Western blotting assays to examine expression of occludin, claudin-1 and myosin light chain kinase (MLCK). Spearman correlation analysis was used to analyze the relation between MLCK and occludin, MLCK and claudin-1. RESULTS: Immunostained sections of the common bile duct epithelium showed significantly higher MQS in pediatric patients than controls for occludin (44.11 +/- 13.82 vs. 11.30 +/- 9.58, P = 0.0034) and claudin-1 (63.44 +/- 23.59 vs. 46.10 +/- 7.84, P = 0.0384). Western blotting also showed significantly higher expression of occludin, claudin 1 and MLCK in the common bile duct of patients than of controls (P = 0.0023, 0.0015, 0.0488). Spearman correlation analysis showed that MLCK expression correlated positively with the expression of occludin (r s = 0.61538, P = 0.0032) and claudin-1 (r s = 0.7972, P = 0.0019). CONCLUSIONS: Occludin and claudin-1 are up-regulated in the common bile duct epithelium of pediatric PBM patients. MLCK may be involved in the process of up-regulation of the tight junction-associated proteins in PBM. PMID- 26772980 TI - Excessive diagnostic testing in acute kidney injury. AB - BACKGROUND: The patterns, performance characteristics, and yield of diagnostic tests ordered for the evaluation of acute kidney injury (AKI) have not been rigorously evaluated. METHODS: We characterized the frequency of AKI diagnostic testing for urine, blood, radiology, and pathology tests in all adult inpatients who were admitted with or developed AKI (N = 4903 patients with 5731 AKI episodes) during a single calendar year. We assessed the frequency of abnormal test results overall and by AKI stage. We manually reviewed electronic medical records to evaluate the diagnostic yield of selected urine, blood, and radiology tests. Diagnostic yield of urine and blood tests was determined based on whether an abnormal test affected AKI diagnosis or management, whereas diagnostic yield of radiology tests was based on whether an abnormal test resulted in a procedural intervention. In sensitivity analyses we also evaluated appropriateness of testing using prespecified criteria. RESULTS: Frequency of testing increased with higher AKI stage for nearly all diagnostic tests, whereas frequency of detecting an abnormal result increased for some, but not all, tests. Frequency of detecting an abnormal result was highly variable across tests, ranging from 0 % for anti glomerular basement membrane testing to 71 % for urine protein testing. Many of the tests evaluated had low diagnostic yield. In particular, selected urine and blood tests were unlikely to impact AKI diagnosis or management, whereas radiology tests had greater clinical utility. CONCLUSIONS: In patients with AKI, many of the diagnostic tests performed, even when positive or abnormal, may have limited clinical utility. PMID- 26772982 TI - Postal recruitment and consent obtainment from index cases of narcolepsy. AB - BACKGROUND: Access to research volunteers may be hampered by low numbers of cases and few eligible participants for rare diseases in clinical settings. METHODS: We recruited volunteers and obtained informed consent by mail from narcolepsy cases in a case-control study, and here in we report feasibility, response rate, timeliness and cost. We invited index cases into the study by mail through their care-giving physicians then mailed study information and consent forms to cases that indicated interest in the study. RESULTS: Of the 33 index cases invited, 15 (45.0%) expressed interest in the study, and of those, 14 (93.3%) returned their signed informed consents by mail. The median number of days from invitation to consent return was 39, interquartile range = 45, and the cost per consent obtained from the recruited subjects was $ 23.61. CONCLUSION: In this setting, postal recruitment for biomedical research on rare conditions is feasible and time and cost effective. PMID- 26772981 TI - Aldosterone-producing adrenocortical carcinoma with prominent hepatic metastasis diagnosed by liver biopsy: a case report. AB - BACKGROUND: Aldosterone-producing adrenocortical carcinoma is a rare malignancy, which is usually diagnosed by histopathological examination of the excised tumor. In inoperable cases, aldosterone-producing ACC diagnosed by immunohistochemical staining of the metastatic tumor for Cytochrome P450 (CYP) 11beta has not previously been reported and even in that case staining for adrenocortical specific adrenal 4 binding protein/steroidogenic factor1 (Ad4BP/SF1) and steroidogenic enzymes has not been reported. CASE PRESENTATION: We report the case of a 67-year-old Japanese woman with aldosterone-producing adrenocortical carcinoma. Laboratory findings showed severe hypopotassemia. Endocrinological examination revealed an increased plasma aldosterone concentration and suppressed plasma renin activity. Plasma dehydroepiandrosterone sulfate (DHEA-S) was elevated. Diurnal variation in serum cortisol was lost and administration of 1 mg and 8 mg dexamethasone did not suppress serum cortisol levels. From the 24-h urine collection sample, urine aldosterone and urine cortisol levels were greatly increased. Therefore, autonomous excess production was observed for the three adrenal cortex hormones. Abdominal computed tomography and magnetic resonance imaging showed a right adrenal tumor and a huge liver tumor. Adrenocortical carcinoma with metastatic liver cancer was strongly suggested, however surgery could not be considered due to stage IV disease: the liver tumor was too large and cardiac ultrasonography indicated that her cardiac function was poor. Therefore, a liver biopsy was taken to properly determine the diagnosis. Immunohistochemical stains for Ad4BP/SF1 and steroidogenic enzymes were positive. Ad4BP/SF-1 was originally identified as a steroidogenic, tissue-specific transcription factor implicated in the expression of the steroidogenic CYP gene encoding cytochrome P450s. Hence we could diagnose the patient as having adrenocortical carcinoma with metastatic liver cancer. CONCLUSION: This rare case had severe hypopotassemia accompanied with not only increased cortisol and DHEA-S but also aldosterone. We reached the diagnosis of adrenocortical carcinoma with metastatic liver cancer based on positive immunohistochemical staining of Ad4BP/SF1 in the liver biopsy specimen. We have reported the first case of aldosterone-producing adrenocortical carcinoma diagnosed solely by immunohistochemical staining for adrenocortical-specific Ad4BP/SF1 and steroidogenic enzymes in a metastatic liver tumor. PMID- 26772984 TI - Adaptation to acute coronary syndrome-induced stress with lowering of testosterone: a possible survival factor. AB - OBJECTIVE: The objective of this study was to explore whether circulating testosterone (T) concentration is associated with the occurrence and risk for acute coronary syndromes (ACS). METHOD: This case-control study included male patients with acute myocardial infarction (AMI) (n=174) or unstable angina pectoris (UAP) (n=90) and healthy controls (n=238). Patients gave serum samples during the acute (n=264) and recovery (n=132) phases after a median of 10.5 months after the incident event. Secondary events (ACS or cardiovascular death) were registered during the following 6 years. RESULTS: During the acute phase, AMI and UAP patients had similar significantly reduced concentrations of serum testosterone in comparison to controls. Testosterone associated inversely with weight, the degree of inflammation (i.e. C-reactive protein concentration) and signs of a chronic infection. In a multiadjusted Cox regression, when compared to testosterone concentrations considered high-normal (14.91-34.0 nmol/l), low normal testosterone (9.26-14.90 nmol/l) in the acute phase predicted better prognosis for cardiovascular death rate with a hazard ratio (HR) of 0.17 (0.04 0.68, P=0.012). The increased testosterone concentrations after the recovery period did not associate with future cardiovascular disease events. CONCLUSION: Low-normal testosterone levels in the acute phase of ACS predicted better survival. The observation may indicate better adaptation to stress in survivors and warrants further study. PMID- 26772983 TI - A potent betulinic acid analogue ascertains an antagonistic mechanism between autophagy and proteasomal degradation pathway in HT-29 cells. AB - BACKGROUND: Betulinic acid (BA), a member of pentacyclic triterpenes has shown important biological activities like anti-bacterial, anti-malarial, anti inflammatory and most interestingly anticancer property. To overcome its poor aqueous solubility and low bioavailability, structural modifications of its functional groups are made to generate novel lead(s) having better efficacy and less toxicity than the parent compound. BA analogue, 2c was found most potent inhibitor of colon cancer cell line, HT-29 cells with IC50 value 14.9 MUM which is significantly lower than standard drug 5-fluorouracil as well as parent compound, Betulinic acid. We have studied another mode of PCD, autophagy which is one of the important constituent of cellular catabolic system as well as we also studied proteasomal degradation pathway to investigate whole catabolic pathway after exploration of 2c on HT-29 cells. METHODS: Mechanism of autophagic cell death was studied using fluorescent dye like acridine orange (AO) and monodansylcadaverin (MDC) staining by using fluorescence microscopy. Various autophagic protein expression levels were determined by Western Blotting, qRT-PCR and Immunostaining. Confocal Laser Scanning Microscopy (CLSM) was used to study the colocalization of various autophagic proteins. These were accompanied by formation of autophagic vacuoles as revealed by FACS and transmission electron microscopy (TEM). Proteasomal degradation pathway was studied by proteasome-GloTM assay systems using luminometer. RESULTS: The formation of autophagic vacuoles in HT-29 cells after 2c treatment was determined by fluorescence staining- confirming the occurrence of autophagy. In addition, 2c was found to alter expression levels of different autophagic proteins like Beclin-1, Atg 5, Atg 7, Atg 5-Atg 12, LC3B and autophagic adapter protein, p62. Furthermore we found the formation of autophagolysosome by colocalization of LAMP-1 with LC3B, LC3B with Lysosome, p62 with lysosome. Finally, as proteasomal degradation pathway downregulated after 2c treatment colocalization of ubiquitin with lysosome and LC3B with p62 was studied to confirm that protein degradation in autophagy induced HT-29 cells follows autolysosomal pathway. CONCLUSIONS: In summary, betulinic acid analogue, 2c was able to induce autophagy in HT-29 cells and as proteasomal degradation pathway downregulated after 2c treatment so protein degradation in autophagy induced HT-29 cells follows autolysosomal pathway. PMID- 26772985 TI - Quality of life, clinical outcomes and safety of early prophylactic levothyroxine administration in patients with Graves' hyperthyroidism undergoing radioiodine therapy: a randomized controlled study. AB - OBJECTIVE: While radioiodine therapy is commonly used for treating Graves' disease, a prolonged and clinical hypothyroidism may result in disabling symptoms leading to deterioration of quality of life (QoL) of patients. Introducing levothyroxine (LT4) treatment in the early post-therapeutic period may be an interesting approach to limit this phenomenon. METHODS: A multicenter, prospective, open-label randomized controlled trial enrolled 94 patients with Graves' hyperthyroidism randomly assigned to the experimental group (n=46) (group A: early prophylactic LT4 treatment) or the control group (n=48) (group B: standard follow-up). The primary endpoint was the 6-month QoL. The secondary endpoints were other QoL scores such as Graves' ophthalmopathy (GO) outcomes, thyroid function tests and safety. RESULTS: The primary endpoint at 6 months was achieved: the mental composite score (MCS) of Short Form 36 (SF-36) was significantly higher in group A compared to group B (P=0.009). Four other dimension scores of the SF-36 and four dimension scores of the thyroid-specific patient-reported outcome (ThyPRO) significantly differed between the two groups, indicating better QoL in group A. After adjustment for variables, the early LT4 administration strategy was found as an independent factor for only two scores of SF-36: the MCS and the general health (GH) score. There were no differences in GO, final thyroid status and changes in the anti-TSH receptor antibodies (TRAbs) levels between the two groups. No adverse cardiovascular event was reported. CONCLUSION: Early LT4 administration post-radioactive iodine (RAI) could represent a safe potential benefit for patients with regard to QoL. The optimal strategy taking into account administered RAI activities and LT4 treatment dosage and timing remains to be determined. PMID- 26772986 TI - Full-scale mesophilic biogas plants using manure as C-source: bacterial community shifts along the process cause changes in the abundance of resistance genes and mobile genetic elements. AB - The application of manure, typically harboring bacteria carrying resistance genes (RGs) and mobile genetic elements (MGEs), as co-substrate in biogas plants (BGPs) might be critical when digestates are used as fertilizers. In the present study, the relative abundance of RGs and MGEs in total community (TC-) DNA from manure, fermenters and digestate samples taken at eight full-scale BGPs co-fermenting manure were determined by real-time PCR. In addition, the bacterial community composition of all digestates as well as manure and fermenter material from one BGP (BGP3) was characterized by 454-pyrosequencing of 16S rRNA amplicons from TC DNA. Compared to respective input manures, relative abundances determined for sul1, sul2, tet(M), tet(Q), intI1, qacEDelta1, korB and traN were significantly lower in fermenters, whereas relative abundances of tet(W) were often higher in fermenters. The bacterial communities in all digestates were dominated by Firmicutes and Bacteroidetes while Proteobacteria were low in abundance and no Enterobacteriaceae were detected. High-throughput sequencing revealed shifts in bacterial communities during treatment for BGP3. Although in comparison to manure, digestate bacteria had lower relative abundances of RGs and MGEs except for tet(W), mesophilic BGPs seem not to be effective for prevention of the spread of RGs and MGEs via digestates into arable soils. PMID- 26772987 TI - Hemoglobin-induced neuronal degeneration in the hippocampus after neonatal intraventricular hemorrhage. AB - Neuronal degeneration following neonatal intraventricular hemorrhage (IVH) is incompletely understood. Understanding the mechanisms of degeneration and cell loss may point toward specific treatments to limit injury. We evaluated the role of hemoglobin (Hb) in cell death after intraventricular injection in neonatal rats. Hb was injected into the right lateral ventricle of post-natal day 7 rats. Rats exposed to anesthesia were used for controls. The CA-1 region of the hippocampus was analyzed via immunohistochemistry, hematoxylin and eosin (H&E) staining, Fluoro-Jade C staining, Western blots, and double-labeling stains. Compared to controls, intraventricular injection of Hb decreased hippocampal volume (27% decrease; p<0.05), induced neuronal loss (31% loss; p<0.01), and increased neuronal degeneration (2.7 fold increase; p<0.01), which were all significantly reduced with the iron chelator, deferoxamine. Hb upregulated p-JNK (1.8 fold increase; p<0.05) and increased expression of the Hb/haptoglobin endocytotic receptor CD163 in neurons in vivo and in vitro (cultured cortical neurons). Hb induced expression of the CD163 receptor, which co-localized with p JNK in hippocampal neurons, suggesting a potential pathway by which Hb enters the neuron to result in cell death. There were no differences in neuronal loss or degenerating neurons in Hb-injected animals that developed hydrocephalus versus those that did not. Intraventricular injection of Hb causes hippocampal neuronal degeneration and cell loss and increases brain p-JNK levels. p-JNK co-localized with the Hb/haptoglobin receptor CD163, suggesting a novel pathway by which Hb enters the neuron after IVH to result in cell death. PMID- 26772989 TI - EISL study (Estudio Internacional de Sibilancias en Lactantes): A global perspective of wheezing during the first year of life. PMID- 26772988 TI - Delayed application of the haematopoietic growth factors G-CSF/SCF and FL reduces neonatal excitotoxic brain injury. AB - BACKGROUND: Developmental brain injury results in cognitive and motor deficits in the preterm infant. Enhanced glutamate release and subsequent receptor activation are major pathogenetic factors. The effect of haematopoietic growth factors, such as granulocyte colony-stimulating factor (G-CSF), stem cell factor (SCF) and flt 3 ligand (FL) on neonatal brain injury is controversially discussed. Timing of treatment is known to be a crucial factor. Based on the hypothesis that an exacerbation of injury is caused by administration of substances in the acute phase, the objective of this study was to evaluate the effect of delayed administration of G-CSF/SCF and FL to protect against excitotoxic brain injury in vivo. METHODS: In an established neonatal mouse model of excitotoxic brain injury, we evaluated the effect of daily intraperitoneal doses of G-CSF/SCF or FL, starting 60 h after the excitotoxic insult. RESULTS: Intraperitoneal injections of G-CSF/SCF and FL, given 60 h after the excitotoxic insult, significantly reduced lesion size at postnatal days 10, 18 and 90. G-CSF/SCF treatment resulted in a decrease in apoptotic cell death indicated by reduced caspase-3 activation. G-CSF/SCF and FL treatment did not affect apoptosis inducing factor-dependent apoptosis or cell proliferation. CONCLUSION: We show that delayed systemic treatment with the haematopoietic growth factors G-CSF/SCF and FL protects against N-methyl-D-aspartate receptor-mediated developmental excitotoxic brain damage. Our results suggest that neuroprotective effects in this neonatal animal model of excitotoxic brain injury depend on the timing of drug administration after the insult. PMID- 26772990 TI - Evolution of DUF1313 family members across plant species and their association with maize photoperiod sensitivity. AB - Proteins of the DUF1313 family contain a highly conserved domain and are only found in plants; they play important roles in most plant functions. In this study, 269 DUF1313 genes from 81 photoautotrophic species were identified; they were classified into three major types based on the amino acid substitutions in the conserved region: IARV, I(S/T/F)(K/R)V, and IRRV. Phylogenic tree constructed from 51 DUF1313 genes from graminoids revealed three clades: A, B1, and B2. Clade B1 was found to have undergone episodic positive selection after a gene duplication event and included four amino acid sites under positive selection. The association between DUF1313 family members and traits investigated in maize indicated that three of four genes (GRMZM2G025646, GRMZM5G877647, GRMZM2G359322, and GRMZM2G382774) were associated with the target traits such as days to silking, days to tasselling, and plant height. The nucleotide diversity of the most primitive and highly conserved DUF1313 gene, ELF4-like4, was the highest in Tripsacum and the lowest in maize. Tajima's D and Fu and Li's D tests revealed that significant purifying selection had occurred in the coding sequence region of this DUF1313 gene in teosinte and maize. No significant signal was detected in the 5'-untranslated region of this gene in each of the three species (maize, teosinte, and Tripsacum) or in any gene regions of Tripsacum. Phylogenetic analyses revealed that the 103 accessions of maize, teosinte, and Tripsacum can be grouped into four clades based on the ELF4-like4 gene sequence similarity. Thus, this gene can be used to determine the relationships between maize and its relatives, and the DUF1313 family members and alleles identified in this study might be valuable genetic resources for molecular marker-assisted breeding in maize. PMID- 26772991 TI - A genomic view on epilepsy and autism candidate genes. AB - Epilepsy is a common complex disorder most frequently associated with psychiatric and neurological diseases. Massive parallel sequencing of individual or cohort genomes and exomes led the identification of several disease associated genes. We review here the candidate genes in epilepsy genetics with focus on exome and gene panel data. Together with the examination of brain expressed genes and post synaptic proteome the results show that: (1) Non-metabolic epilepsies and autism candidate genes tend to be AT-rich and (2) large transcript size and local AT richness are characteristic features of genes involved in developmental brain disorders and synaptic functions. These results point to the preferential location of core epilepsy and autism candidate genes in late replicating, GC-poor chromosomal regions (isochores). These results indicate that the genomic alterations leading to some brain disorders are confined to responsive chromatin areas harboring brain critical genes. PMID- 26772993 TI - Idelalisib Bolsters CLL Regimen. PMID- 26772992 TI - Enzymatic changes in myosin regulatory proteins may explain vasoplegia in terminally ill patients with sepsis. AB - The current study was conducted with the hypothesis that failure of maintenance of the vascular tone may be central to failure of the peripheral circulation and spiralling down of blood pressure in sepsis. Namely, we examined the balance between expression of myosin light chain (MLC) phosphatase and kinase, enzymes that regulate MLCs dephosphorylation and phosphorylation with a direct effect on pharmacomechanical coupling for smooth muscle relaxation and contraction respectively. Mechanical recordings and enzyme immunoassays of vascular smooth muscle lysates were used as the major methods to examine arterial biopsy samples from terminally ill sepsis patients. The results of the present study provide evidence that genomic alteration of expression of key regulatory proteins in vascular smooth muscles may be responsible for the relentless downhill course in sepsis. Down-regulation of myosin light chain kinase (MLCK) and up-regulation of MLCK may explain the loss of tone and failure to mount contractile response in vivo during circulation. The mechanical studies demonstrated the inability of the arteries to develop tone when stimulated by phenylephrine in vitro. The results of our study provide indirect hint that control of inflammation is a major therapeutic approach in sepsis, and may facilitate to ameliorate the progressive cardiovascular collapse. PMID- 26772994 TI - Histone H1 in gene expression and development. PMID- 26772995 TI - An Untranslated cis-Element Regulates the Accumulation of Multiple C4 Enzymes in Gynandropsis gynandra Mesophyll Cells. AB - C4 photosynthesis is a complex phenotype that allows more efficient carbon capture than the ancestral C3 pathway. In leaves of C4 species, hundreds of transcripts increase in abundance compared with C3 relatives and become restricted to mesophyll (M) or bundle sheath (BS) cells. However, no mechanism has been reported that regulates the compartmentation of multiple enzymes in M or BS cells. We examined mechanisms regulating CARBONIC ANHYDRASE4 (CA4) in C4 Gynandropsis gynandra. Increased abundance is directed by both the promoter region and introns of the G. gynandra gene. A nine-nucleotide motif located in the 5' untranslated region (UTR) is required for preferential accumulation of GUS in M cells. This element is present and functional in three additional 5' UTRs and six 3' UTRs where it determines accumulation of two isoforms of CA and pyruvate,orthophosphate dikinase in M cells. Although the GgCA4 5' UTR is sufficient to direct GUS accumulation in M cells, transcripts encoding GUS are abundant in both M and BS. Mutating the GgCA4 5' UTR abolishes enrichment of protein in M cells without affecting transcript abundance. The work identifies a mechanism that directs cell-preferential accumulation of multiple enzymes required for C4 photosynthesis. PMID- 26772997 TI - The adaptor protein Cindr regulates JNK activity to maintain epithelial sheet integrity. AB - Epithelia are essential barrier tissues that must be appropriately maintained for their correct function. To achieve this a plethora of protein interactions regulate epithelial cell number, structure and adhesion, and differentiation. Here we show that Cindr (the Drosophila Cin85 and Cd2ap ortholog) is required to maintain epithelial integrity. Reducing Cindr triggered cell delamination and movement. Most delaminating cells died. These behaviors were consistent with JNK activation previously associated with loss of epithelial integrity in response to ectopic oncogene activity. We confirmed a novel interaction between Cindr and Drosophila JNK (dJNK), which when perturbed caused inappropriate JNK signaling. Genetically reducing JNK signaling activity suppressed the effects of reducing Cindr. Furthermore, ectopic JNK signaling phenocopied loss of Cindr and was partially rescued by concomitant cindr over-expression. Thus, correct Cindr-dJNK stoichiometry is essential to maintain epithelial integrity and disturbing this balance may contribute to the pathogenesis of disease states, including cancer. PMID- 26772996 TI - Genome Reduction Uncovers a Large Dispensable Genome and Adaptive Role for Copy Number Variation in Asexually Propagated Solanum tuberosum. AB - Clonally reproducing plants have the potential to bear a significantly greater mutational load than sexually reproducing species. To investigate this possibility, we examined the breadth of genome-wide structural variation in a panel of monoploid/doubled monoploid clones generated from native populations of diploid potato (Solanum tuberosum), a highly heterozygous asexually propagated plant. As rare instances of purely homozygous clones, they provided an ideal set for determining the degree of structural variation tolerated by this species and deriving its minimal gene complement. Extensive copy number variation (CNV) was uncovered, impacting 219.8 Mb (30.2%) of the potato genome with nearly 30% of genes subject to at least partial duplication or deletion, revealing the highly heterogeneous nature of the potato genome. Dispensable genes (>7000) were associated with limited transcription and/or a recent evolutionary history, with lower deletion frequency observed in genes conserved across angiosperms. Association of CNV with plant adaptation was highlighted by enrichment in gene clusters encoding functions for environmental stress response, with gene duplication playing a part in species-specific expansions of stress-related gene families. This study revealed unique impacts of CNV in a species with asexual reproductive habits and how CNV may drive adaption through evolution of key stress pathways. PMID- 26772998 TI - Zfrp8 forms a complex with fragile-X mental retardation protein and regulates its localization and function. AB - Fragile-X syndrome is the most commonly inherited cause of autism and mental disabilities. The Fmr1 (Fragile-X Mental Retardation 1) gene is essential in humans and Drosophila for the maintenance of neural stem cells, and Fmr1 loss results in neurological and reproductive developmental defects in humans and flies. FMRP (Fragile-X Mental Retardation Protein) is a nucleo-cytoplasmic shuttling protein, involved in mRNA silencing and translational repression. Both Zfrp8 and Fmr1 have essential functions in the Drosophila ovary. In this study, we identified FMRP, Nufip (Nuclear Fragile-X Mental Retardation Protein interacting Protein) and Tral (Trailer Hitch) as components of a Zfrp8 protein complex. We show that Zfrp8 is required in the nucleus, and controls localization of FMRP in the cytoplasm. In addition, we demonstrate that Zfrp8 genetically interacts with Fmr1 and tral in an antagonistic manner. Zfrp8 and FMRP both control heterochromatin packaging, also in opposite ways. We propose that Zfrp8 functions as a chaperone, controlling protein complexes involved in RNA processing in the nucleus. PMID- 26773001 TI - Inverse probability weighting. PMID- 26773000 TI - CDX4 and retinoic acid interact to position the hindbrain-spinal cord transition. AB - The sub-division of the posterior-most territory of the neural plate results in the formation of two distinct neural structures, the hindbrain and the spinal cord. Although many of the molecular signals regulating the development of these individual structures have been elucidated, the mechanisms involved in delineating the boundary between the hindbrain and spinal cord remain elusive. Two molecules, retinoic acid (RA) and the Cdx4 transcription factor have been previously implicated as important regulators of hindbrain and spinal cord development, respectively. Here, we provide evidence that suggests multiple regulatory interactions occur between RA signaling and the Cdx4 transcription factor to establish the anterior-posterior (AP) position of the transition between the hindbrain and spinal cord. Using chemical inhibitors to alter RA concentrations and morpholinos to knock-down Cdx4 function in zebrafish, we show that Cdx4 acts to prevent RA degradation in the presumptive spinal cord domain by suppressing expression of the RA degradation enzyme, Cyp26a1. In the hindbrain, RA signaling modulates its own concentration by activating the expression of cyp26a1 and inhibiting the expansion of cdx4. Therefore, interactions between Cyp26a1 and Cdx4 modulate RA levels along the AP axis to segregate the posterior neural plate into the hindbrain and spinal cord territories. PMID- 26772999 TI - A quantitative method for defining high-arched palate using the Tcof1(+/-) mutant mouse as a model. AB - The palate functions as the roof of the mouth in mammals, separating the oral and nasal cavities. Its complex embryonic development and assembly poses unique susceptibilities to intrinsic and extrinsic disruptions. Such disruptions may cause failure of the developing palatal shelves to fuse along the midline resulting in a cleft. In other cases the palate may fuse at an arch, resulting in a vaulted oral cavity, termed high-arched palate. There are many models available for studying the pathogenesis of cleft palate but a relative paucity for high arched palate. One condition exhibiting either cleft palate or high-arched palate is Treacher Collins syndrome, a congenital disorder characterized by numerous craniofacial anomalies. We quantitatively analyzed palatal perturbations in the Tcof1(+/-) mouse model of Treacher Collins syndrome, which phenocopies the condition in humans. We discovered that 46% of Tcof1(+/-) mutant embryos and new born pups exhibit either soft clefts or full clefts. In addition, 17% of Tcof1(+/ ) mutants were found to exhibit high-arched palate, defined as two sigma above the corresponding wild-type population mean for height and angular based arch measurements. Furthermore, palatal shelf length and shelf width were decreased in all Tcof1(+/-) mutant embryos and pups compared to controls. Interestingly, these phenotypes were subsequently ameliorated through genetic inhibition of p53. The results of our study therefore provide a simple, reproducible and quantitative method for investigating models of high-arched palate. PMID- 26773002 TI - O-GlcNAcylation of master growth repressor DELLA by SECRET AGENT modulates multiple signaling pathways in Arabidopsis. AB - The DELLA family of transcription regulators functions as master growth repressors in plants by inhibiting phytohormone gibberellin (GA) signaling in response to developmental and environmental cues. DELLAs also play a central role in mediating cross-talk between GA and other signaling pathways via antagonistic direct interactions with key transcription factors. However, how these crucial protein-protein interactions can be dynamically regulated during plant development remains unclear. Here, we show that DELLAs are modified by the O linked N-acetylglucosamine (O-GlcNAc) transferase (OGT) SECRET AGENT (SEC) in Arabidopsis. O-GlcNAcylation of the DELLA protein REPRESSOR OF ga1-3 (RGA) inhibits RGA binding to four of its interactors-PHYTOCHROME-INTERACTING FACTOR3 (PIF3), PIF4, JASMONATE-ZIM DOMAIN1, and BRASSINAZOLE-RESISTANT1 (BZR1)-that are key regulators in light, jasmonate, and brassinosteroid signaling pathways, respectively. Consistent with this, the sec-null mutant displayed reduced responses to GA and brassinosteroid and showed decreased expression of several common target genes of DELLAs, BZR1, and PIFs. Our results reveal a direct role of OGT in repressing DELLA activity and indicate that O-GlcNAcylation of DELLAs provides a fine-tuning mechanism in coordinating multiple signaling activities during plant development. PMID- 26773003 TI - Rapid evolutionary turnover underlies conserved lncRNA-genome interactions. AB - Many long noncoding RNAs (lncRNAs) can regulate chromatin states, but the evolutionary origin and dynamics driving lncRNA-genome interactions are unclear. We adapted an integrative strategy that identifies lncRNA orthologs in different species despite limited sequence similarity, which is applicable to mammalian and insect lncRNAs. Analysis of the roX lncRNAs, which are essential for dosage compensation of the single X chromosome in Drosophila males, revealed 47 new roX orthologs in diverse Drosophilid species across ~40 million years of evolution. Genetic rescue by roX orthologs and engineered synthetic lncRNAs showed that altering the number of focal, repetitive RNA structures determines roX ortholog function. Genomic occupancy maps of roX RNAs in four species revealed conserved targeting of X chromosome neighborhoods but rapid turnover of individual binding sites. Many new roX-binding sites evolved from DNA encoding a pre-existing RNA splicing signal, effectively linking dosage compensation to transcribed genes. Thus, dynamic change in lncRNAs and their genomic targets underlies conserved and essential lncRNA-genome interactions. PMID- 26773004 TI - Combined deletion of cathepsin protease family members reveals compensatory mechanisms in cancer. AB - Proteases are important for regulating multiple tumorigenic processes, including angiogenesis, tumor growth, and invasion. Elevated protease expression is associated with poor patient prognosis across numerous tumor types. Several multigene protease families have been implicated in cancer, including cysteine cathepsins. However, whether individual family members have unique roles or are functionally redundant remains poorly understood. Here we demonstrate stage dependent effects of simultaneously deleting cathepsin B (CtsB) and CtsS in a murine pancreatic neuroendocrine tumor model. Early in tumorigenesis, the double knockout results in an additive reduction in angiogenic switching, whereas at late stages, several tumorigenic phenotypes are unexpectedly restored to wild type levels. We identified CtsZ, which is predominantly supplied by tumor associated macrophages, as the compensatory protease that regulates the acquired tumor-promoting functions of lesions deficient in both CtsB and CtsS. Thus, deletion of multiple cathepsins can lead to stage-dependent, compensatory mechanisms in the tumor microenvironment, which has potential implications for the clinical consideration of selective versus pan-family cathepsin inhibitors in cancer. PMID- 26773007 TI - Volume regulation and shape bifurcation in the cell nucleus. PMID- 26773005 TI - Prrx1 isoform switching regulates pancreatic cancer invasion and metastatic colonization. AB - The two major isoforms of the paired-related homeodomain transcription factor 1 (Prrx1), Prrx1a and Prrx1b, are involved in pancreatic development, pancreatitis, and carcinogenesis, although the biological role that these isoforms serve in the systemic dissemination of pancreatic ductal adenocarcinoma (PDAC) has not been investigated. An epithelial-mesenchymal transition (EMT) is believed to be important for primary tumor progression and dissemination, whereas a mesenchymal epithelial transition (MET) appears crucial for metastatic colonization. Here, we describe novel roles for both isoforms in the metastatic cascade using complementary in vitro and in vivo models. Prrx1b promotes invasion, tumor dedifferentiation, and EMT. In contrast, Prrx1a stimulates metastatic outgrowth in the liver, tumor differentiation, and MET. We further demonstrate that the switch from Prrx1b to Prrx1a governs EMT plasticity in both mouse models of PDAC and human PDAC. Last, we identify hepatocyte growth factor ( HGF) as a novel transcriptional target of Prrx1b. Targeted therapy of HGF in combination with gemcitabine in a preclinical model of PDAC reduces primary tumor volume and eliminates metastatic disease. Overall, we provide new insights into the isoform specific roles of Prrx1a and Prrx1b in primary PDAC formation, dissemination, and metastatic colonization, allowing for novel therapeutic strategies targeting EMT plasticity. PMID- 26773009 TI - Systematic Review: Interventions to Educate Children About Dog Safety and Prevent Pediatric Dog-Bite Injuries: A Meta-Analytic Review. AB - Objective: Dog-bite injury posits a significant threat to children globally. This review evaluated efficacy of cognitive/behavioral interventions for improving children's knowledge and behaviors around dogs. Methods: Manuscripts published before January 3, 2014 evaluating cognitive/behavioral interventions for dog-bite prevention among children <18 years of age were eligible for inclusion. Among 2,270 abstracts screened, 123 full texts were retrieved. Twelve studies were included in the qualitative synthesis; nine were included in the meta-analysis. Risk of bias and quality of evidence were evaluated. Results: Cognitive/behavioral interventions had a moderate effect in improving children's knowledge and a larger effect in improving children's behavior with dogs. The most effective intervention strategies were video for knowledge and instruction with live dogs for behaviors. Quality of evidence was poor. Conclusions: Cognitive/behavioral interventions have potential to improve both children's knowledge and behaviors around dogs. Future interventions should include multiple follow-ups on dog-bite rates from an international perspective using rigorous randomized controlled trials. PMID- 26773008 TI - Evolutionary Dynamics of the Leucine-Rich Repeat Receptor-Like Kinase (LRR-RLK) Subfamily in Angiosperms. AB - Gene duplications are an important factor in plant evolution, and lineage specific expanded (LSE) genes are of particular interest. Receptor-like kinases expanded massively in land plants, and leucine-rich repeat receptor-like kinases (LRR-RLK) constitute the largest receptor-like kinases family. Based on the phylogeny of 7,554 LRR-RLK genes from 31 fully sequenced flowering plant genomes, the complex evolutionary dynamics of this family was characterized in depth. We studied the involvement of selection during the expansion of this family among angiosperms. LRR-RLK subgroups harbor extremely contrasting rates of duplication, retention, or loss, and LSE copies are predominantly found in subgroups involved in environmental interactions. Expansion rates also differ significantly depending on the time when rounds of expansion or loss occurred on the angiosperm phylogenetic tree. Finally, using a dN/dS-based test in a phylogenetic framework, we searched for selection footprints on LSE and single-copy LRR-RLK genes. Selective constraint appeared to be globally relaxed at LSE genes, and codons under positive selection were detected in 50% of them. Moreover, the leucine-rich repeat domains, and specifically four amino acids in them, were found to be the main targets of positive selection. Here, we provide an extensive overview of the expansion and evolution of this very large gene family. PMID- 26773010 TI - Prebiotics, Fermentable Dietary Fiber, and Health Claims. AB - Since the 1970s, the positive effects of dietary fiber on health have increasingly been recognized. The collective term "dietary fiber" groups structures that have different physiologic effects. Since 1995, some dietary fibers have been denoted as prebiotics, implying a beneficial physiologic effect related to increasing numbers or activity of the gastrointestinal microbiota. Given the complex composition of the microbiota, the demonstration of such beneficial effects is difficult. In contrast, an exploration of the metabolites of dietary fiber formed as a result of its fermentation in the colon offers better perspectives for providing mechanistic links between fiber intake and health benefits. Positive outcomes of such studies hold the promise that claims describing specific health benefits can be granted. This would help bridge the "fiber gap"-that is, the considerable difference between recommended and actual fiber intakes by the average consumer. PMID- 26773011 TI - Choline, Its Potential Role in Nonalcoholic Fatty Liver Disease, and the Case for Human and Bacterial Genes. AB - Our understanding of the impact of poor hepatic choline/phosphatidylcholine availability in promoting the steatosis characteristic of human nonalcoholic fatty liver disease (NAFLD) has recently advanced and possibly relates to phosphatidylcholine/phosphatidylethanolamine concentrations in various, membranes as well as cholesterol dysregulation. A role for choline/phosphatidylcholine availability in the progression of NAFLD to liver injury and serious hepatic consequences in some individuals requires further elucidation. There are many reasons for poor choline/phosphatidylcholine availability in the liver, including low intake, estrogen status, and genetic polymorphisms affecting, in particular, the pathway for hepatic de novo phosphatidylcholine synthesis. In addition to free choline, phosphatidylcholine has been identified as a substrate for trimethylamine production by certain intestinal bacteria, thereby reducing host choline bioavailability and providing an additional link to the increased risk of cardiovascular disease faced by those with NAFLD. Thus human choline requirements are highly individualized and biomarkers of choline status derived from metabolomics studies are required to predict those at risk of NAFLD induced by choline deficiency and to provide a basis for human intervention trials. PMID- 26773012 TI - Potential of Dietary Non-Provitamin A Carotenoids in the Prevention and Treatment of Diabetic Microvascular Complications. AB - Diabetes is a chronic metabolic disease that affects a substantial part of the population around the world. Whether type I or type II, this disease has serious macro- and microvascular complications that constitute the primary cause of death in diabetic patients. Microvascular complications include diabetic retinopathy, nephropathy, and neuropathy. Although these complications are clinically and etiologically diverse, they share a common factor: glucose-induced damage. In the progression of diabetic complications, oxidative stress, inflammation, and the formation of glycation end products play an important role. Previous studies have shown that a healthy diet is vital in preventing these complications; in particular, the intake of antioxidants has been studied for their potential effect in ameliorating hyperglycemic injuries. Carotenoids are lipid-soluble pigments synthesized by plants, bacteria, and some kinds of algae that are responsible for the yellow, red, and orange colors in food. These compounds are part of the antioxidant machinery in plants and have also shown their efficacy in quenching free radicals, scavenging reactive oxygen species, modulating gene expression, and reducing inflammation in vitro and in vivo, showing that they can potentially be used as part of a preventive strategy for metabolic disorders, including diabetes and its related complications. This review highlights the potential protective effects of 4 non-provitamin A carotenoids--lutein, zeaxanthin, lycopene, and astaxanthin--in the development and progression of diabetic microvascular complications. PMID- 26773013 TI - Essential Nutrient Interactions: Does Low or Suboptimal Magnesium Status Interact with Vitamin D and/or Calcium Status? AB - Although much is known about magnesium, its interactions with calcium and vitamin D are less well studied. Magnesium intake is low in populations who consume modern processed-food diets. Low magnesium intake is associated with chronic diseases of global concern [e.g., cardiovascular disease (CVD), type 2 diabetes, metabolic syndrome, and skeletal disorders], as is low vitamin D status. No simple, reliable biomarker for whole-body magnesium status is currently available, which makes clinical assessment and interpretation of human magnesium research difficult. Between 1977 and 2012, US calcium intakes increased at a rate 2-2.5 times that of magnesium intakes, resulting in a dietary calcium to magnesium intake ratio of >3.0. Calcium to magnesium ratios <1.7 and >2.8 can be detrimental, and optimal ratios may be ~2.0. Background calcium to magnesium ratios can affect studies of either mineral alone. For example, US studies (background Ca:Mg >3.0) showed benefits of high dietary or supplemental magnesium for CVD, whereas similar Chinese studies (background Ca:Mg <1.7) showed increased risks of CVD. Oral vitamin D is widely recommended in US age-sex groups with low dietary magnesium. Magnesium is a cofactor for vitamin D biosynthesis, transport, and activation; and vitamin D and magnesium studies both showed associations with several of the same chronic diseases. Research on possible magnesium and vitamin D interactions in these human diseases is currently rare. Increasing calcium to magnesium intake ratios, coupled with calcium and vitamin D supplementation coincident with suboptimal magnesium intakes, may have unknown health implications. Interactions of low magnesium status with calcium and vitamin D, especially during supplementation, require further study. PMID- 26773014 TI - Red Raspberries and Their Bioactive Polyphenols: Cardiometabolic and Neuronal Health Links. AB - Diet is an essential factor that affects the risk of modern-day metabolic diseases, including cardiovascular disease, diabetes mellitus, obesity, and Alzheimer disease. The potential ability of certain foods and their bioactive compounds to reverse or prevent the progression of the pathogenic processes that underlie these diseases has attracted research attention. Red raspberries (Rubus idaeus L.) are unique berries with a rich history and nutrient and bioactive composition. They possess several essential micronutrients, dietary fibers, and polyphenolic components, especially ellagitannins and anthocyanins, the latter of which give them their distinctive red coloring. In vitro and in vivo studies have revealed various mechanisms through which anthocyanins and ellagitannins (via ellagic acid or their urolithin metabolites) and red raspberry extracts (or the entire fruit) could reduce the risk of or reverse metabolically associated pathophysiologies. To our knowledge, few studies in humans are available for evaluation. We review and summarize the available literature that assesses the health-promoting potential of red raspberries and select components in modulating metabolic disease risk, especially cardiovascular disease, diabetes mellitus, obesity, and Alzheimer disease-all of which share critical metabolic, oxidative, and inflammatory links. The body of research is growing and supports a potential role for red raspberries in reducing the risk of metabolically based chronic diseases. PMID- 26773016 TI - Dietary Patterns and Blood Pressure in Adults: A Systematic Review and Meta Analysis of Randomized Controlled Trials. AB - Hypertension is a major risk factor for developing cardiovascular disease, stroke, and kidney disease. To lower blood pressure (BP), several lifestyle changes are recommended such as weight loss, exercise, and following a healthy diet. Investigating the effect of single nutrients may have positive results, but food is consumed as part of a whole diet, resulting in nutrient interactions. The aim of this systematic review and meta-analysis was to assess the effect of dietary patterns on BP in adults. Studies that were published between January 1999 and June 2014 were retrieved using Scopus, Web of Science, and the MEDLINE database. Seventeen randomized controlled trials were included in the meta analysis. The results suggest that healthy dietary patterns such as the Dietary Approaches to Stop Hypertension diet, Nordic diet, and Mediterranean diet significantly lowered systolic BP and diastolic BP by 4.26 mm Hg and 2.38 mm Hg, respectively. These diets are rich in fruit, vegetables, whole grains, legumes, seeds, nuts, fish, and dairy and low in meat, sweets, and alcohol. Lifestyle factors such as exercise and weight loss in combination with dietary changes may also reduce BP. Further research is needed to establish the effect of dietary patterns on BP in different cultures other than those identified in this review. The review was registered on PROSPERO (International prospective register of systematic reviews) as CRD42015016272. PMID- 26773015 TI - Impact of Obesity and Metabolic Syndrome on Immunity. AB - Obesity is associated with metabolic disturbances that cause tissue stress and dysfunction. Obese individuals are at a greater risk for chronic disease and often present with clinical parameters of metabolic syndrome (MetS), insulin resistance, and systemic markers of chronic low-grade inflammation. It has been well established that cells of the immune system play an important role in the pathogenesis of obesity- and MetS-related chronic diseases, as evidenced by leukocyte activation and dysfunction in metabolic tissues such as adipose tissue, liver, pancreas, and the vasculature. However, recent findings have highlighted the substantial impact that obesity and MetS parameters have on immunity and pathogen defense, including the disruption of lymphoid tissue integrity; alterations in leukocyte development, phenotypes, and activity; and the coordination of innate and adaptive immune responses. These changes are associated with an overall negative impact on chronic disease progression, immunity from infection, and vaccine efficacy. This review presents an overview of the impact that obesity and MetS parameters have on immune system function. PMID- 26773017 TI - Can We Prevent Obesity-Related Metabolic Diseases by Dietary Modulation of the Gut Microbiota? AB - Obesity increases the risk of type 2 diabetes, cardiovascular diseases, and certain cancers, which are among the leading causes of death worldwide. Obesity and obesity-related metabolic diseases are characterized by specific alterations in the human gut microbiota. Experimental studies with gut microbiota transplantations in mice and in humans indicate that a specific gut microbiota composition can be the cause and not just the consequence of the obese state and metabolic disease, which suggests a potential for gut microbiota modulation in prevention and treatment of obesity-related metabolic diseases. In addition, dietary intervention studies have suggested that modulation of the gut microbiota can improve metabolic risk markers in humans, but a causal role of the gut microbiota in such studies has not yet been established. Here, we review and discuss the role of the gut microbiota in obesity-related metabolic diseases and the potential of dietary modulation of the gut microbiota in metabolic disease prevention and treatment. PMID- 26773019 TI - A Review of Cutoffs for Nutritional Biomarkers. AB - The nutritional status of an individual or population needs to be assessed through valid and reliable biomarkers. Cutoffs generally have an underlying relation to health status and are one of the important quantitative criteria against which biomarker outputs are compared. For this reason, cutoffs are integral for surveys, surveillance, screening, interventions, monitoring, and evaluation. Despite their importance, nutritional biomarker cutoffs have not been adequately addressed in the literature. Furthermore, the field has not reached a consensus on which cutoff to use for each biomarker, and different cutoffs are often used for the same biomarkers in published studies. This review provides a comprehensive overview of cutoffs related to nutritional biomarkers and highlights some of the high-priority research gaps and challenges of using micronutrient case studies. PMID- 26773018 TI - Human Milk Components Modulate Toll-Like Receptor-Mediated Inflammation. AB - Toll-like receptor (TLR) signaling is central to innate immunity. Aberrant expression of TLRs is found in neonatal inflammatory diseases. Several bioactive components of human milk modulate TLR expression and signaling pathways, including soluble toll-like receptors (sTLRs), soluble cluster of differentiation (sCD) 14, glycoproteins, small peptides, and oligosaccharides. Some milk components, such as sialyl (alpha2,3) lactose and lacto-N-fucopentaose III, are reported to increase TLR signaling; under some circumstances this might contribute toward immunologic balance. Human milk on the whole is strongly anti inflammatory, and contains abundant components that depress TLR signaling pathways: sTLR2 and sCD14 inhibit TLR2 signaling; sCD14, lactadherin, lactoferrin, and 2'-fucosyllactose attenuate TLR4 signaling; 3'-galactosyllactose inhibits TLR3 signaling, and beta-defensin 2 inhibits TLR7 signaling. Feeding human milk to neonates decreases their risk of sepsis and necrotizing enterocolitis. Thus, the TLR regulatory components found in human milk hold promise as benign oral prophylactic and therapeutic treatments for the many gastrointestinal inflammatory disorders mediated by abnormal TLR signaling. PMID- 26773020 TI - Update on NHANES Dietary Data: Focus on Collection, Release, Analytical Considerations, and Uses to Inform Public Policy. AB - NHANES is the cornerstone for national nutrition monitoring to inform nutrition and health policy. Nutritional assessment in NHANES is described with a focus on dietary data collection, analysis, and uses in nutrition monitoring. NHANES has been collecting thorough data on diet, nutritional status, and chronic disease in cross-sectional surveys with nationally representative samples since the early 1970s. Continuous data collection began in 1999 with public data release in 2-y cycles on ~10,000 participants. In 2002, the Continuing Survey of Food Intakes by Individuals and the NHANES dietary component were merged, forming a consolidated dietary data collection known as What We Eat in America; since then, 24-h recalls have been collected on 2 d using the USDA's Automated Multiple-Pass Method. Detailed and targeted food-frequency questionnaires have been collected in some NHANES cycles. Dietary supplement use data have been collected (in detail since 2007) so that total nutrient intakes can be described for the population. The continuous NHANES can adapt its content to address emerging public health needs and reflect federal priorities. Changes in data collection methods are made after expert input and validation/crossover studies. NHANES dietary data are used to describe intake of foods, nutrients, food groups, and dietary patterns by the US population and large sociodemographic groups to plan and evaluate nutrition programs and policies. Usual dietary intake distributions can be estimated after adjusting for day-to-day variation. NHANES remains open and flexible to incorporate improvements while maintaining data quality and providing timely data to track the nation's nutrition and health status. In summary, NHANES collects dietary data in the context of its broad, multipurpose goals; the strengths and limitations of these data are also discussed in this review. PMID- 26773022 TI - Sugars and Dental Caries: Evidence for Setting a Recommended Threshold for Intake. AB - Dental caries affects <=80% of the world's population with almost a quarter of US adults having untreated caries. Dental caries is costly to health care and negatively affects well-being. Dietary free sugars are the most important risk factor for dental caries. The WHO has issued guidelines that recommend intake of free sugars should provide <=10% of energy intake and suggest further reductions to <5% of energy to protect dental health throughout life. These recommendations were informed by a systematic review of the evidence pertaining to amount of sugars and dental caries risk, which showed evidence of moderate quality from cohort studies that limiting free sugars to <=10% of energy reduced, but did not eliminate, dental caries. Even low levels of dental caries in children are of concern because caries is a lifelong progressive and cumulative disease. The systematic review therefore explored if there were further benefits to dental health if the intake of free sugars was limited to <5% of energy. Available data were from ecologic studies and, although classified as being of low quality, showed lower dental caries when free sugar intake was <5% of energy compared with when it was >5% but <=10% of energy. The WHO recommendations are intended for use by policy makers as a benchmark when assessing intake of sugars by populations and as a driving force for policy change. Multiple strategies encompassing both upstream and downstream preventive approaches are now required to translate the recommendations into policy and practice. PMID- 26773023 TI - Magnesium. PMID- 26773024 TI - Scientific Report of the 2015 Dietary Guidelines Advisory Committee. Washington, DC: US Departments of Agriculture and Health and Human Services, 2015. PMID- 26773021 TI - Integration to Implementation and the Micronutrient Forum: A Coordinated Approach for Global Nutrition. Case Study Application: Safety and Effectiveness of Iron Interventions. AB - Paramount among the challenges to our ability to address the role of food and nutrition in health promotion and disease prevention is how to design and implement context-specific interventions and guidance. The Integration to Effective Implementation (I-to-I) concept is intended to address the complexities of the global health context through engagement of the continuum of stakeholders involved in the food and nutrition enterprise. The 2014 Micronutrient Forum (MNF) Global Conference held in Addis Ababa, Ethiopia, in June 2014 offered the opportunity to apply the I-to-I approach with the use of current concerns about the safety and effectiveness of interventions to prevent and treat iron deficiency (ID) as a case study. ID is associated with a range of adverse outcomes, especially in pregnant and nonpregnant women, infants, and primary school-age children. Strategies to combat ID include iron supplementation, multiple micronutrient powders, and food-based interventions to enhance dietary iron intake. Recent reports indicate potential increased adverse risks when iron is provided in areas with high infection burdens (e.g., malaria). This paradox has weakened iron intervention programs. Furthermore, the selection and interpretation of available biomarkers for assessing iron nutrition have been found to be compromised by the inflammatory process. These issues highlight the need for a comprehensive approach that considers basic biology, assessment, interventions, and how these can be translated into appropriate programs and policies. The application of the I-to-I with the use of the MNF offered an opportunity to explore how that might be achieved. PMID- 26773026 TI - Establishing Yourself as an Expert in Nutrition Science: Advice for Young Professionals. AB - In today's world in which there is a surplus of both scientists and online nutrition "experts," how do young professionals establish themselves? Becoming established as an expert requires selling yourself and your ideas to your colleagues and the general public by using effective communication skills. Helping young professionals develop these skills was the goal of a panel held at the ASN Scientific Sessions and Annual Meeting at Experimental Biology 2015. This panel featured a set of distinguished speakers who discussed techniques and strategies to enhance professional reputations centered around effectively leveraging communication platforms and opportunities to engage with colleagues. Early-career nutrition scientists can use the guidance provided by the panelists to improve their visibility and be a champion for themselves in order to establish themselves as experts in the field. PMID- 26773028 TI - Foreword. PMID- 26773029 TI - Vegetable and Fruit Acceptance during Infancy: Impact of Ontogeny, Genetics, and Early Experiences. AB - Many of the chronic illnesses that plague modern society derive in large part from poor food choices. Thus, it is not surprising that the Dietary Guidelines for Americans, aimed at the population >=2 y of age, recommends limiting consumption of salt, fat, and simple sugars, all of which have sensory properties that we humans find particularly palatable, and increasing the variety and contribution of fruits and vegetables in the diet, to promote health and prevent disease. Similar recommendations may soon be targeted at even younger Americans: the B-24 Project, led by the US Department of Health and Human Services and the USDA, is currently evaluating evidence to include infants and children from birth to 2 y of age in the dietary guidelines. This article reviews the underinvestigated behavioral phenomena surrounding how to introduce vegetables and fruits into infants' diets, for which there is much medical lore but, to our knowledge, little evidence-based research. Because the chemical senses are the major determinants of whether young children will accept a food (e.g., they eat only what they like), these senses take on even greater importance in understanding the bases for food choices in children. We focus on early life, in contrast with many other studies that attempt to modify food habits in older children and thus may miss sensitive periods that modulate long-term acceptance. Our review also takes into consideration ontogeny and sources of individual differences in taste perception, in particular, the role of genetic variation in bitter taste perception. PMID- 26773030 TI - Developmental and Environmental Influences on Young Children's Vegetable Preferences and Consumption. AB - Food intake patterns begin to be shaped at the earliest points in life. Early exposures and experiences are critical for the acceptance of some foods, particularly healthful foods such as vegetables, which often have a bitter component in their flavor profiles. In addition to repeated exposure to these foods, the quality and emotional tone of parent-child interactions are important in facilitating children's acceptance of vegetables. During early childhood, parents are challenged by children's developmental characteristics related to eating, such as the emergence of child neophobia, and by individual characteristics of the child that are more biologically based, including genetic predispositions to bitter taste and sensory sensitivities. Experimental studies consistently show that repeated exposure to novel and rejected familiar foods is the most powerful method to improve acceptance. However, the manner and persistence with which these exposures are performed are critical. Research investigating influences on children's vegetable acceptance and ingestion has focused on associations among availability, parent intakes, child neophobia, and the parental feeding response to children's reluctance to try and consume vegetables. Because young children's dietary intakes are low and below dietary recommendations, investigations have focused more on factors that impede children's vegetable acceptance, such as controlling feeding practices, than on positive influences. Research that addresses the multifaceted nature of these interactions among different levels of social-ecological environment, individual traits, parental feeding styles and practices, and socioeconomic influences and that uses longitudinal designs and complex statistical approaches is called for to ascertain more effective methods to improve children's vegetable acceptance. PMID- 26773031 TI - Physiology of Food Intake Control in Children. AB - The purpose of this review is to draw attention to the limited information available on food intake (FI) control in children and adolescents 7-17 y of age, which is essential for developing food policies and guidelines in this population. Although environmental factors have been the overwhelming focus of research on the causative factors of obesity, research focusing on the physiologic control of appetite in children and adolescents is a neglected area of research. To present this message, a review of FI regulation and the role of food and food components in signaling processes are followed by an examination of the role of hormones during puberty in intake regulation. To examine the interaction of environment and physiology on FI regulation, the effects of exercise, television programs, and food advertisements are discussed. In conclusion, although limited, this literature review supports a need for children and adolescents to be a greater focus of research that would lead to sound nutrition policies and actions to reduce chronic disease. A focus on the environment must be balanced with an understanding of physiologic and behavioral changes associated with this age group. PMID- 26773033 TI - Removing Potatoes from Children's Diets May Compromise Potassium Intake. AB - White potatoes are a forgotten source of nutrients. The goal of this study was to identify the nutritional implications of replacing a composite of white potatoes with a composite of vegetables commonly consumed by children aged 2-18 y (n = 3460) in a nationally representative sample. The NHANES 2005-2012 24-h dietary recall data were used to determine nutrient intake. Two replacement models were developed: one for potato consumers and another for those consuming vegetables other than potatoes. Analyses focused on 1) mean nutrient contributions per 1 cup equivalent vegetable composite (VC)/potato composite (PC) consumed by participants, and 2) mean daily nutrient intake when the nutrients per 1 cup equivalent PC replaced the nutrients per 1 cup equivalent VC. Covariate adjusted analysis was tested for statistical significance (P < 0.002). When 1 cup equivalent VC replaced 1 cup equivalent PC, significantly lower mean intakes were found for 20 of the 23 nutrients studied and higher mean intakes of total sugars, folate, and calcium. Differences were found including higher total intakes of monounsaturated fatty acids and potassium and lower total intakes of vitamins A and K. The percentage contribution of the PC to total daily nutrient intake was 6% for total energy, 8% for total fat, 5% for saturated fatty acids, 13% for dietary fiber, 4% for sodium, and 11% for potassium. Both composites contributed a variety of nutrients to the total diet; the consumption of white potatoes may be an important strategy to help meet the potassium recommendation. PMID- 26773032 TI - Nutrient Intakes and Vegetable and White Potato Consumption by Children Aged 1 to 3 Years. AB - In 2020, for the first time, the Dietary Guidelines for Americans will include recommendations for children from birth to age 24 mo. We examined average nutrient intakes as well as total vegetable and white potato (WP) consumption among children aged 1-3 y using day 1 dietary data from the NHANES 2009-2012 and the Food Patterns Equivalents Database 2009-2012. Appropriate survey weights were used to calculate average daily consumption of total vegetables and WPs, which included French-fried potatoes and chips, for boys and girls aged 1-3 y. We calculated mean intakes of selected nutrients of concern, including vitamin D, potassium, dietary fiber (DF), and calcium. We also examined intakes of selected nutrients by major food group. Average intakes of most nutrients, including calcium, by children aged 1-3 y exceeded Dietary Reference Intakes (DRIs). However, average intakes of potassium, DF, and vitamin D were 67%, 55%, and 49% of DRIs, respectively. Mean total vegetable intake was less than the recommendation of 1 cup/d. Boys and girls aged 1-3 y consumed an average of 0.58 cup equivalents of total vegetables on the day of the survey, which included 0.16 cups of WPs. Average vegetable consumption and mean intakes of potassium, DF, and vitamin D were far below recommendations. The consumption of all vegetables, particularly those that are excellent sources of potassium and DF, such as potatoes, should be encouraged. PMID- 26773034 TI - Nutrient Density and the Cost of Vegetables from Elementary School Lunches. AB - Vegetables are the major source of the dietary fiber, magnesium, potassium, and vitamins A and C that are crucial in the diets of children. This study assessed the nutrient content of vegetables offered through the National School Lunch Program and examined the relation between the overall nutrient density of vegetable subgroups and the costs of nutrients offered and wasted before and after the changes in school meal standards. Using data collected from 3 elementary schools before and after the changes in school meal standards, we found that vegetable plate waste increased from 52% to 58%. Plate waste for starchy vegetables, exclusive of potatoes, was relatively high compared with other subgroups; however, plate waste for white potatoes was the lowest among any type of vegetable. Energy density; cost per 100 g, per serving, and per 100 kcal; and percentage daily value were calculated and used to estimate nutrient density value and nutrient density per dollar. Cost per 100 kcal was highest for red/orange vegetables followed by dark green vegetables; however, nutrient density for red/orange vegetables was the highest in the group and provided the most nutrients per dollar compared with other subgroups. Given that many vegetables are less energy dense, measuring vegetable costs per 100 g and per serving by accounting for nutrient density perhaps is a better way of calculating the cost of vegetables in school meals. PMID- 26773035 TI - Next Steps for Science and Policy on Promoting Vegetable Consumption among US Infants and Young Children. AB - Vegetables are an important part of a healthy diet for infants and young children, but they are poorly accepted and underconsumed. This paper highlights major themes and research needs for understanding how to raise children to consume and enjoy vegetables as part of a healthful diet. A range of factors impedes US infants and young children from eating as many vegetables as experts consider optimal for child nutrition, health, and development. Barriers include biological and behavioral issues relating to infant and child development, household- and family-related barriers, obstacles in the larger community, economic limitations, and some government policies and programs. These barriers must be removed to encourage children to eat more vegetables. Research gaps also must be filled. We summarize the basic and applied research that is needed to craft more effective messages, devise strategies for parents and other child caretakers to take within households, develop action in the larger community, and modify some government policies and programs. PMID- 26773037 TI - The impact of multiple low-level BCR-ABL1 mutations on response to ponatinib. AB - The third-generation tyrosine kinase inhibitor (TKI) ponatinib shows activity against all common BCR-ABL1 single mutants, including the highly resistant BCR ABL1-T315I mutant, improving outcome for patients with refractory chronic myeloid leukemia (CML). However, responses are variable, and causal baseline factors have not been well-studied. The type and number of low-level BCR-ABL1 mutations present after imatinib resistance has prognostic significance for subsequent treatment with nilotinib or dasatinib as second-line therapy. We therefore investigated the impact of low-level mutations detected by sensitive mass spectrometry before ponatinib initiation (baseline) on treatment response in 363 TKI-resistant patients enrolled in the PONATINIB for Chronic Myeloid Leukemia Evaluation and Ph(+)Acute Lymphoblastic Leukemia trial, including 231 patients in chronic phase (CP-CML). Low-level mutations were detected in 53 patients (15%, including low-level T315I in 14 patients); most, however, did not undergo clonal expansion during ponatinib treatment and, moreover, no specific individual mutations were associated with inferior outcome. We demonstrate however, that the number of mutations detectable by mass spectrometry after TKI resistance is associated with response to ponatinib treatment and could be used to refine the therapeutic approach. Although CP-CML patients with T315I (63/231, 27%) had superior responses overall, those with multiple mutations detectable by mass spectrometry (20, 32%) had substantially inferior responses compared with those with T315I as the sole mutation detected (43, 68%). In contrast, for CP-CML patients without T315I, the inferior responses previously observed with nilotinib/dasatinib therapy for imatinib-resistant patients with multiple mutations were not seen with ponatinib treatment, suggesting that ponatinib may prove to be particularly advantageous for patients with multiple mutations detectable by mass spectrometry after TKI resistance. PMID- 26773036 TI - Deletion of Pten in CD45-expressing cells leads to development of T-cell lymphoblastic lymphoma but not myeloid malignancies. AB - Since its discovery in the late 1990s, Pten has turned out to be one of the most important tumor suppressor genes. Pten loss results in increased activation of the phosphatidylinositol 3-kinase/Akt signaling pathway, which is associated with increased proliferation, survival, and neoplastic growth. Here, we have addressed the effects of conditional deletion of Pten in hematopoietic cells by crossing Pten conditional knockout mice with a knock-in mouse expressing the Cre recombinase in the CD45 locus. CD45 is also known as leukocyte common antigen, and it is expressed in virtually all white cells and in hematopoietic stem cells. Using a reporter mouse, we demonstrate that CD45:Cre mouse displays recombinase activity in both myeloid and lymphoid cells. However, deletion of Pten in CD45 expressing cells induces development of T-cell acute lymphoblastic leukemia and lymphoma, but not other hematologic malignancies. PMID- 26773038 TI - N-linked glycan stabilization of the VWF A2 domain. AB - Shear forces in the blood trigger a conformational transition in the von Willebrand factor (VWF) A2 domain, from its native folded to an unfolded state, in which the cryptic scissile bond (Y1605-M1606) is exposed and can then be proteolysed by ADAMTS13. The conformational transition depends upon a Ca(2+)binding site and a vicinal cysteine disulfide bond. Glycosylation at N1574 has previously been suggested to modulate VWF A2 domain interaction with ADAMTS13 through steric hindrance by the bulky carbohydrate structure. We investigated how the N-linked glycans of the VWF A2 domain affect thermostability and regulate both the exposure of the ADAMTS13 binding sites and the scissile bond. We show by differential scanning fluorimetry that the N-linked glycans thermodynamically stabilize the VWF A2 domain. The essential component of the glycan structure is the first sugar residue (GlcNAc) at the N1574 attachment site. From its crystal structures, N1574-GlcNAc is predicted to form stabilizing intradomain interactions with Y1544 and nearby residues. Substitution of the surface-exposed Y1544 to aspartic acid is able to stabilize the domain in the absence of glycosylation and protect against ADAMTS13 proteolysis in both the VWF A2 domain and FLVWF. Glycan stabilization of the VWF A2 domain acts together with the Ca(2+)binding site and vicinal cysteine disulfide bond to control unfolding and ADAMTS13 proteolysis. PMID- 26773039 TI - B-cell survival and development controlled by the coordination of NF-kappaB family members RelB and cRel. AB - Targeted deletion of BAFF causes severe deficiency of splenic B cells. BAFF-R is commonly thought to signal to nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB)-inducing kinase dependent noncanonical NF-kappaB RelB. However, RelB-deficient mice have normal B-cell numbers. Recent studies showed that BAFF also signals to the canonical NF-kappaB pathway, and we found that both RelB and cRel are persistently activated, suggesting BAFF signaling coordinates both pathways to ensure robust B-cell development. Indeed, we report now that combined loss of these 2 NF-kappaB family members leads to impaired BAFF mediated survival and development in vitro. Although single deletion of RelB and cRel was dispensable for normal B-cell development, double knockout mice displayed an early B-cell developmental blockade and decreased mature B cells. Despite disorganized splenic architecture in Relb(-/-)cRel(-/-) mice, generation of mixed-mouse chimeras established the developmental phenotype to be B-cell intrinsic. Together, our results indicate that BAFF signals coordinate both RelB and cRel activities to ensure survival during peripheral B-cell maturation. PMID- 26773041 TI - Long-term follow-up of subtotal splenectomy for hereditary spherocytosis: a single-center study. PMID- 26773040 TI - Diffuse large B-cell lymphoma patient-derived xenograft models capture the molecular and biological heterogeneity of the disease. AB - Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease defined by transcriptional classifications, specific signaling and survival pathways, and multiple low-frequency genetic alterations. Preclinical model systems that capture the genetic and functional heterogeneity of DLBCL are urgently needed. Here, we generated and characterized a panel of large B-cell lymphoma (LBCL) patient-derived xenograft (PDX) models, including 8 that reflect the immunophenotypic, transcriptional, genetic, and functional heterogeneity of primary DLBCL and 1 that is a plasmablastic lymphoma. All LBCL PDX models were subjected to whole-transcriptome sequencing to classify cell of origin and consensus clustering classification (CCC) subtypes. Mutations and chromosomal rearrangements were evaluated by whole-exome sequencing with an extended bait set. Six of the 8 DLBCL models were activated B-cell (ABC)-type tumors that exhibited ABC-associated mutations such as MYD88, CD79B, CARD11, and PIM1. The remaining 2 DLBCL models were germinal B-cell type, with characteristic alterations of GNA13, CREBBP, and EZH2, and chromosomal translocations involving IgH and either BCL2 or MYC Only 25% of the DLBCL PDX models harbored inactivating TP53 mutations, whereas 75% exhibited copy number alterations of TP53 or its upstream modifier, CDKN2A, consistent with the reported incidence and type of p53 pathway alterations in primary DLBCL. By CCC criteria, 6 of 8 DLBCL PDX models were B-cell receptor (BCR)-type tumors that exhibited selective surface immunoglobulin expression and sensitivity to entospletinib, a recently developed spleen tyrosine kinase inhibitor. In summary, we have established and characterized faithful PDX models of DLBCL and demonstrated their usefulness in functional analyses of proximal BCR pathway inhibition. PMID- 26773042 TI - Polycomb-dependent epigenetic landscape in adult T-cell leukemia. AB - Adult T-cell leukemia-lymphoma (ATL) shows global gene expression alterations that confer cellular characteristics and unfavorable prognosis. However, molecular mechanisms of the sustained expression changes are largely unknown, because there is no study addressing the relationship between landscapes of the gene expression and epigenetic modifications. Here, we analyzed ATL epigenome and integrated it with transcriptome from primary ATL cells and those from corresponding normal CD4(+)T cells to decipher ATL-specific "epigenetic code" that was critical for cell identity. We found that polycomb-repressive complex 2 (PRC2)-mediated trimethylation at histone H3Lys27 (H3K27me3) was significantly and frequently reprogrammed at half of genes in ATL cells. A large proportion of the abnormal gene downregulation was detected at the early stage of disease progression and was explained by H3K27me3 accumulation. The global H3K27me3 alterations involved ATL-specific gene expression changes that included several tumor suppressors, transcription factors, epigenetic modifiers, miRNAs, and developmental genes, suggesting diverse outcomes by the PRC2-dependent hierarchical regulation. Interestingly, a key enzyme, EZH2, was sensitive to promiscuous signaling network including the NF-kappaB pathway and was functionally affected by human T-cell leukemia virus type I (HTLV-1) Tax. The Tax dependent immortalized cells showed H3K27me3 reprogramming that was significantly similar to that of ATL cells. Of note, a majority of the epigenetic silencing has occurred in leukemic cells from indolent ATL and also in HTLV-1-infected T cells from asymptomatic HTLV-1 carriers. Because pharmacologic inhibition of EZH2 reversed epigenetic disruption and selectively eliminated leukemic and HTLV-1 infected cells, targeting the epigenetic elements will hold great promise in treatment and prevention of the onset of ATL and HTLV-1-related diseases. PMID- 26773043 TI - Suppression of plasma hepcidin by venesection during steady-state hypoxia. PMID- 26773044 TI - Distinct GAB2 signaling pathways are essential for myeloid and lymphoid transformation and leukemogenesis by BCR-ABL1. AB - Tyrosine kinase inhibitors (TKIs) directed against BCR-ABL1, the product of the Philadelphia (Ph) chromosome, have revolutionized treatment of patients with chronic myeloid leukemia (CML). However, acquired resistance to TKIs is a significant clinical problem in CML, and TKI therapy is much less effective against Ph(+)B-cell acute lymphoblastic leukemia (B-ALL). BCR-ABL1, via phosphorylated Tyr177, recruits the adapter GRB2-associated binding protein 2 (GAB2) as part of a GRB2/GAB2 complex. We showed previously that GAB2 is essential for BCR-ABL1-evoked myeloid transformation in vitro. Using a genetic strategy and mouse models of CML and B-ALL, we show here that GAB2 is essential for myeloid and lymphoid leukemogenesis by BCR-ABL1. In the mouse model, recipients of BCR-ABL1-transducedGab2(-/-)bone marrow failed to develop CML-like myeloproliferative neoplasia. Leukemogenesis was restored by expression of GAB2 but not by GAB2 mutants lacking binding sites for its effectors phosphatidylinositol 3-kinase (PI3K) or SRC homology 2-containing phosphotyrosine phosphatase 2 (SHP2). GAB2 deficiency also attenuated BCR-ABL1-induced B-ALL, but only the SHP2 binding site was required. The SHP2 and PI3K binding sites were differentially required for signaling downstream of GAB2. Hence, GAB2 transmits critical transforming signals from Tyr177 to PI3K and SHP2 for CML pathogenesis, whereas only the GAB2-SHP2 pathway is essential for lymphoid leukemogenesis. Given that GAB2 is dispensable for normal hematopoiesis, GAB2 and its effectors PI3K and SHP2 represent promising targets for therapy in Ph(+)hematologic neoplasms. PMID- 26773045 TI - A lymphomagenic role for HIV beyond immune suppression? AB - Despite the immune reconstitution promoted by combined antiretroviral therapy (cART), lymphomas still represent the most common type of cancer in HIV-infected individuals. Cofactors related to immunodeficiency such as oncogenic viruses, chronic antigenic stimulation, and cytokine overproduction are thought to be the main drivers of HIV lymphomagenesis, although the current scenario does not convincingly explain the still-high incidence of lymphomas and the occurrence of peculiar lymphoma histotypes in HIV-infected patients under cART. Recent findings are challenging the current view of a mainly indirect role of HIV in lymphoma development and support the possibility that HIV may directly contribute to lymphomagenesis. In fact, mechanisms other than immune suppression involve biologic effects mediated by HIV products that are secreted and accumulate in lymphoid tissues, mainly within lymph node germinal centers. Notably, HIV infected patients with lymphomas, but not those not affected by these tumors, were recently shown to carry HIV p17 protein variants with enhanced B-cell clonogenic activity. HIV p17 protein variants were characterized by the presence of distinct insertions at the C-terminal region of the protein responsible for a structural destabilization and the acquisition of novel biologic properties. These data are changing the current paradigm assuming that HIV is only indirectly related to lymphomagenesis. Furthermore, these recent findings are consistent with a role of HIV as a critical microenvironmental factor promoting lymphoma development and pave the way for further studies that may lead to the design of more effective strategies for an early identification and improved control of lymphomas in the HIV setting. PMID- 26773046 TI - Dicer1-mediated miRNA processing shapes the mRNA profile and function of murine platelets. AB - Human platelets contain microRNAs (miRNAs) and miRNA processing machinery, but their contribution to platelet function remains incompletely understood. Here, we show that murine megakaryocyte (MK)-specific knockdown of Dicer1, the ribonuclease that cleaves miRNA precursors into mature miRNAs, reduces the level of the majority of miRNAs in platelets. This leads to altered platelet messenger RNA (mRNA) expression profiles and mild thrombocytopenia. Fibrinogen receptor subunits Itga2b (alphaIIb) and Itgb3 (beta3) mRNAs were among the differentially expressed transcripts that are increased in platelets lacking Dicer1. Argonaute 2 (Ago2), a member of the miRNA silencing complex, co-immunoprecipitated with alphaIIband beta3mRNAs in wild-type platelets. Furthermore, co immunoprecipitation experiments suggested reduced alphaIIb/beta3/Ago2 complexes in miRNA-deficient platelets. These results suggested that miRNAs regulate both integrin subunits. Subsequent 3' untranslated region luciferase reporter assays confirmed that the translation of both alphaIIband beta3mRNAs can be regulated by miRNAs miR-326, miR-128, miR-331, and miR-500. Consistent with these molecular changes, the deletion ofDicer1resulted in increased surface expression of integrins alphaIIband beta3, and enhanced platelet binding to fibrinogen in vivo and in vitro. Heightened platelet reactivity, shortened tail-bleeding time, and reduced survival following collagen/epinephrine-induced pulmonary embolism were also observed in Dicer1-deficient animals. CombinedPf4-cre-mediated deletion of Drosha and Dicer1 did not significantly exacerbate phenotypes observed in single Dicer1 knockout mice. In summary, these findings indicate that Dicer1-dependent generation of mature miRNAs in late-stage MKs and platelets modulates the expression of target mRNAs important for the hemostatic and thrombotic function of platelets. PMID- 26773047 TI - Genetics of Lipid-Storage Management in Caenorhabditis elegans Embryos. AB - Lipids play a pivotal role in embryogenesis as structural components of cellular membranes, as a source of energy, and as signaling molecules. On the basis of a collection of temperature-sensitive embryonic lethal mutants, a systematic database search, and a subsequent microscopic analysis of >300 interference RNA (RNAi)-treated/mutant worms, we identified a couple of evolutionary conserved genes associated with lipid storage in Caenorhabditis elegans embryos. The genes include cpl-1 (cathepsin L-like cysteine protease), ccz-1 (guanine nucleotide exchange factor subunit), and asm-3 (acid sphingomyelinase), which is closely related to the human Niemann-Pick disease-causing gene SMPD1. The respective mutant embryos accumulate enlarged droplets of neutral lipids (cpl-1) and yolk containing lipid droplets (ccz-1) or have larger genuine lipid droplets (asm-3). The asm-3 mutant embryos additionally showed an enhanced resistance against C band ultraviolet (UV-C) light. Herein we propose that cpl-1, ccz-1, and asm-3 are genes required for the processing of lipid-containing droplets in C. elegans embryos. Owing to the high levels of conservation, the identified genes are also useful in studies of embryonic lipid storage in other organisms. PMID- 26773048 TI - MicroRNA Biogenesis and Hedgehog-Patched Signaling Cooperate to Regulate an Important Developmental Transition in Granule Cell Development. AB - The Dicer1, Dcr-1 homolog (Drosophila) gene encodes a type III ribonuclease required for the canonical maturation and functioning of microRNAs (miRNAs). Subsets of miRNAs are known to regulate normal cerebellar granule cell development, in addition to the growth and progression of medulloblastoma, a neoplasm that often originates from granule cell precursors. Multiple independent studies have also demonstrated that deregulation of Sonic Hedgehog (Shh)-Patched (Ptch) signaling, through miRNAs, is causative of granule cell pathologies. In the present study, we investigated the genetic interplay between miRNA biogenesis and Shh-Ptch signaling in granule cells of the cerebellum by way of the Cre/lox recombination system in genetically engineered models of Mus musculus (mouse). We demonstrate that, although the miRNA biogenesis and Shh-Ptch-signaling pathways, respectively, regulate the opposing growth processes of cerebellar hypoplasia and hyperplasia leading to medulloblastoma, their concurrent deregulation was nonadditive and did not bring the growth phenotypes toward an expected equilibrium. Instead, mice developed either hypoplasia or medulloblastoma, but of a greater severity. Furthermore, some genotypes were bistable, whereby subsets of mice developed hypoplasia or medulloblastoma. This implies that miRNAs and Shh Ptch signaling regulate an important developmental transition in granule cells of the cerebellum. We also conclusively show that the Dicer1 gene encodes a haploinsufficient tumor suppressor gene for Ptch1-induced medulloblastoma, with the monoallielic loss of Dicer1 more severe than biallelic loss. These findings exemplify how genetic interplay between pathways may produce nonadditive effects with a substantial and unpredictable impact on biology. Furthermore, these findings suggest that the functional dosage of Dicer1 may nonadditively influence a wide range of Shh-Ptch-dependent pathologies. PMID- 26773049 TI - Small Heat Shock Proteins Are Novel Common Determinants of Alcohol and Nicotine Sensitivity in Caenorhabditis elegans. AB - Addiction to drugs is strongly determined by multiple genetic factors. Alcohol and nicotine produce distinct pharmacological effects within the nervous system through discrete molecular targets; yet, data from family and twin analyses support the existence of common genetic factors for addiction in general. The mechanisms underlying addiction, however, are poorly described and common genetic factors for alcohol and nicotine remain unidentified. We investigated the role that the heat shock transcription factor, HSF-1, and its downstream effectors played as common genetic modulators of sensitivity to addictive substances. Using Caenorhabditis elegans, an exemplary model organism with substance dose-dependent responses similar to mammals, we demonstrate that HSF-1 altered sensitivity to both alcohol and nicotine. Using a combination of a targeted RNAi screen of downstream factors and transgenic approaches we identified that these effects were contingent upon the constitutive neuronal expression of HSP-16.48, a small heat shock protein (HSP) homolog of human alpha-crystallin. Furthermore we demonstrated that the function of HSP-16.48 in drug sensitivity surprisingly was independent of chaperone activity during the heat shock stress response. Instead we identified a distinct domain within the N-terminal region of the HSP-16.48 protein that specified its function in comparison to related small HSPs. Our findings establish and characterize a novel genetic determinant underlying sensitivity to diverse addictive substances. PMID- 26773050 TI - FLAGS: A Flexible and Adaptive Association Test for Gene Sets Using Summary Statistics. AB - Genome-wide association studies (GWAS) have been widely used for identifying common variants associated with complex diseases. Despite remarkable success in uncovering many risk variants and providing novel insights into disease biology, genetic variants identified to date fail to explain the vast majority of the heritability for most complex diseases. One explanation is that there are still a large number of common variants that remain to be discovered, but their effect sizes are generally too small to be detected individually. Accordingly, gene set analysis of GWAS, which examines a group of functionally related genes, has been proposed as a complementary approach to single-marker analysis. Here, we propose a FL: exible and A: daptive test for G: ene S: ets (FLAGS), using summary statistics. Extensive simulations showed that this method has an appropriate type I error rate and outperforms existing methods with increased power. As a proof of principle, through real data analyses of Crohn's disease GWAS data and bipolar disorder GWAS meta-analysis results, we demonstrated the superior performance of FLAGS over several state-of-the-art association tests for gene sets. Our method allows for the more powerful application of gene set analysis to complex diseases, which will have broad use given that GWAS summary results are increasingly publicly available. PMID- 26773051 TI - DNA-DNA kissing complexes as a new tool for the assembly of DNA nanostructures. AB - Kissing-loop annealing of nucleic acids occurs in nature in several viruses and in prokaryotic replication, among other circumstances. Nucleobases of two nucleic acid strands (loops) interact with each other, although the two strands cannot wrap around each other completely because of the adjacent double-stranded regions (stems). In this study, we exploited DNA kissing-loop interaction for nanotechnological application. We functionalized the vertices of DNA tetrahedrons with DNA stem-loop sequences. The complementary loop sequence design allowed the hybridization of different tetrahedrons via kissing-loop interaction, which might be further exploited for nanotechnology applications like cargo transport and logical elements. Importantly, we were able to manipulate the stability of those kissing-loop complexes based on the choice and concentration of cations, the temperature and the number of complementary loops per tetrahedron either at the same or at different vertices. Moreover, variations in loop sequences allowed the characterization of necessary sequences within the loop as well as additional stability control of the kissing complexes. Therefore, the properties of the presented nanostructures make them an important tool for DNA nanotechnology. PMID- 26773052 TI - A short conserved motif in ALYREF directs cap- and EJC-dependent assembly of export complexes on spliced mRNAs. AB - The export of messenger RNAs (mRNAs) is the final of several nuclear posttranscriptional steps of gene expression. The formation of export-competent mRNPs involves the recruitment of export factors that are assumed to facilitate transport of the mature mRNAs. Using in vitro splicing assays, we show that a core set of export factors, including ALYREF, UAP56 and DDX39, readily associate with the spliced RNAs in an EJC (exon junction complex)- and cap-dependent manner. In order to elucidate how ALYREF and other export adaptors mediate mRNA export, we conducted a computational analysis and discovered four short, conserved, linear motifs present in RNA-binding proteins. We show that mutation in one of the new motifs (WxHD) in an unstructured region of ALYREF reduced RNA binding and abolished the interaction with eIF4A3 and CBP80. Additionally, the mutation impaired proper localization to nuclear speckles and export of a spliced reporter mRNA. Our results reveal important details of the orchestrated recruitment of export factors during the formation of export competent mRNPs. PMID- 26773053 TI - Overhang polarity of chromosomal double-strand breaks impacts kinetics and fidelity of yeast non-homologous end joining. AB - Non-homologous end joining (NHEJ) is the main repair pathway for DNA double strand breaks (DSBs) in cells with limited 5' resection. To better understand how overhang polarity of chromosomal DSBs affects NHEJ, we made site-specific 5' overhanging DSBs (5' DSBs) in yeast using an optimized zinc finger nuclease at an efficiency that approached HO-induced 3' DSB formation. When controlled for the extent of DSB formation, repair monitoring suggested that chromosomal 5' DSBs were rejoined more efficiently than 3' DSBs, consistent with a robust recruitment of NHEJ proteins to 5' DSBs. Ligation-mediated qPCR revealed that Mre11-Rad50 Xrs2 rapidly modified 5' DSBs and facilitated protection of 3' DSBs, likely through recognition of overhang polarity by the Mre11 nuclease. Next-generation sequencing revealed that NHEJ at 5' DSBs had a higher mutation frequency, and validated the differential requirement of Pol4 polymerase at 3' and 5' DSBs. The end processing enzyme Tdp1 did not impact joining fidelity at chromosomal 5' DSBs as in previous plasmid studies, although Tdp1 was recruited to only 5' DSBs in a Ku-independent manner. These results suggest distinct DSB handling based on overhang polarity that impacts NHEJ kinetics and fidelity through differential recruitment and action of DSB modifying enzymes. PMID- 26773054 TI - Unfolding the HIV-1 reverse transcriptase RNase H domain--how to lose a molecular tug-of-war. AB - Formation of the mature HIV-1 reverse transcriptase (RT) p66/p51 heterodimer requires subunit-specific processing of the p66/p66' homodimer precursor. Since the ribonuclease H (RH) domain contains an occult cleavage site located near its center, cleavage must occur either prior to folding or subsequent to unfolding. Recent NMR studies have identified a slow, subunit-specific RH domain unfolding process proposed to result from a residue tug-of-war between the polymerase and RH domains on the functionally inactive, p66' subunit. Here, we describe a structural comparison of the isolated RH domain with a domain swapped RH dimer that reveals several intrinsically destabilizing characteristics of the isolated domain that facilitate excursions of Tyr427 from its binding pocket and separation of helices B and D. These studies provide independent support for the subunit-selective RH domain unfolding pathway in which instability of the Tyr427 binding pocket facilitates its release followed by domain transfer, acting as a trigger for further RH domain destabilization and subsequent unfolding. As further support for this pathway, NMR studies demonstrate that addition of an RH active site-directed isoquinolone ligand retards the subunit-selective RH' domain unfolding behavior of the p66/p66' homodimer. This study demonstrates the feasibility of directly targeting RT maturation with therapeutics. PMID- 26773055 TI - p53 coordinates base excision repair to prevent genomic instability. AB - DNA constantly undergoes chemical modification due to endogenous and exogenous mutagens. The DNA base excision repair (BER) pathway is the frontline mechanism handling the majority of these lesions, and primarily involves a DNA incision and subsequent resealing step. It is imperative that these processes are extremely well-coordinated as unrepaired DNA single strand breaks (SSBs) can be converted to DNA double strand breaks during replication thus triggering genomic instability. However, the mechanism(s) governing the BER process are poorly understood. Here we show that accumulation of unrepaired SSBs triggers a p53/Sp1 dependent downregulation of APE1, the endonuclease responsible for the DNA incision during BER. Importantly, we demonstrate that impaired p53 function, a characteristic of many cancers, leads to a failure of the BER coordination mechanism, overexpression of APE1, accumulation of DNA strand breaks and results in genomic instability. Our data provide evidence for a previously unrecognized mechanism for coordination of BER by p53, and its dysfunction in p53-inactivated cells. PMID- 26773056 TI - Alternative splicing creates two new architectures for human tyrosyl-tRNA synthetase. AB - Many human tRNA synthetases evolved alternative functions outside of protein synthesis. These functions are associated with over 200 splice variants (SVs), most of which are catalytic nulls that engender new biology. While known to regulate non-translational activities, little is known about structures resulting from natural internal ablations of any protein. Here, we report analysis of two closely related, internally deleted, SVs of homodimeric human tyrosyl-tRNA synthetase (TyrRS). In spite of both variants ablating a portion of the catalytic core and dimer-interface contacts of native TyrRS, each folded into a distinct stable structure. Biochemical and nuclear magnetic resonance (NMR) analysis showed that the internal deletion of TyrRSDeltaE2-4 SV gave an alternative, neomorphic dimer interface 'orthogonal' to that of native TyrRS. In contrast, the internal C-terminal splice site of TyrRSDeltaE2-3 prevented either dimerization interface from forming, and yielded a predominantly monomeric protein. Unlike ubiquitous TyrRS, the neomorphs showed clear tissue preferences, which were distinct from each other. The results demonstrate a sophisticated structural plasticity of a human tRNA synthetase for architectural reorganizations that are preferentially elicited in specific tissues. PMID- 26773058 TI - CrossHub: a tool for multi-way analysis of The Cancer Genome Atlas (TCGA) in the context of gene expression regulation mechanisms. AB - The contribution of different mechanisms to the regulation of gene expression varies for different tissues and tumors. Complementation of predicted mRNA-miRNA and gene-transcription factor (TF) relationships with the results of expression correlation analyses derived for specific tumor types outlines the interactions with functional impact in the current biomaterial. We developed CrossHub software, which enables two-way identification of most possible TF-gene interactions: on the basis of ENCODE ChIP-Seq binding evidence or Jaspar prediction and co-expression according to the data of The Cancer Genome Atlas (TCGA) project, the largest cancer omics resource. Similarly, CrossHub identifies mRNA-miRNA pairs with predicted or validated binding sites (TargetScan, mirSVR, PicTar, DIANA microT, miRTarBase) and strong negative expression correlations. We observed partial consistency between ChIP-Seq or miRNA target predictions and gene-TF/miRNA co-expression, demonstrating a link between these indicators. Additionally, CrossHub expression-methylation correlation analysis can be used to identify hypermethylated CpG sites or regions with the greatest potential impact on gene expression. Thus, CrossHub is capable of outlining molecular portraits of a specific gene and determining the three most common sources of expression regulation: promoter/enhancer methylation, miRNA interference and TF-mediated activation or repression. CrossHub generates formatted Excel workbooks with the detailed results. CrossHub is freely available athttps://sourceforge.net/projects/crosshub/. PMID- 26773059 TI - Integration of multi-omics data of a genome-reduced bacterium: Prevalence of post transcriptional regulation and its correlation with protein abundances. AB - We developed a comprehensive resource for the genome-reduced bacterium Mycoplasma pneumoniae comprising 1748 consistently generated '-omics' data sets, and used it to quantify the power of antisense non-coding RNAs (ncRNAs), lysine acetylation, and protein phosphorylation in predicting protein abundance (11%, 24% and 8%, respectively). These factors taken together are four times more predictive of the proteome abundance than of mRNA abundance. In bacteria, post-translational modifications (PTMs) and ncRNA transcription were both found to increase with decreasing genomic GC-content and genome size. Thus, the evolutionary forces constraining genome size and GC-content modify the relative contributions of the different regulatory layers to proteome homeostasis, and impact more genomic and genetic features than previously appreciated. Indeed, these scaling principles will enable us to develop more informed approaches when engineering minimal synthetic genomes. PMID- 26773060 TI - G-quadruplexes as novel cis-elements controlling transcription during embryonic development. AB - G-quadruplexes are dynamic structures folded in G-rich single-stranded DNA regions. These structures have been recognized as a potential nucleic acid based mechanism for regulating multiple cellular processes such as replication, transcription and genomic maintenance. So far, their transcriptional role in vivo during vertebrate embryonic development has not yet been addressed. Here, we performed an in silico search to find conserved putative G-quadruplex sequences (PQSs) within proximal promoter regions of human, mouse and zebrafish developmental genes. Among the PQSs able to fold in vitro as G-quadruplex, those present in nog3, col2a1 and fzd5 promoters were selected for further studies. In cellulo studies revealed that the selected G-quadruplexes affected the transcription of luciferase controlled by the SV40 nonrelated promoter. G quadruplex disruption in vivo by microinjection in zebrafish embryos of either small ligands or DNA oligonucleotides complementary to the selected PQSs resulted in lower transcription of the targeted genes. Moreover, zebrafish embryos and larvae phenotypes caused by the presence of complementary oligonucleotides fully resembled those ones reported for nog3, col2a1 and fzd5 morphants. To our knowledge, this is the first work revealing in vivo the role of conserved G quadruplexes in the embryonic development, one of the most regulated processes of the vertebrates biology. PMID- 26773057 TI - Mechanism and regulation of the nonsense-mediated decay pathway. AB - The Nonsense-mediated mRNA decay (NMD) pathway selectively degrades mRNAs harboring premature termination codons (PTCs) but also regulates the abundance of a large number of cellular RNAs. The central role of NMD in the control of gene expression requires the existence of buffering mechanisms that tightly regulate the magnitude of this pathway. Here, we will focus on the mechanism of NMD with an emphasis on the role of RNA helicases in the transition from NMD complexes that recognize a PTC to those that promote mRNA decay. We will also review recent strategies aimed at uncovering novel trans-acting factors and their functional role in the NMD pathway. Finally, we will describe recent progress in the study of the physiological role of the NMD response. PMID- 26773061 TI - New players in heterochromatin silencing: histone variant H3.3 and the ATRX/DAXX chaperone. AB - A number of studies have demonstrated that various components of the ATRX/DAXX/Histone H3.3 complex are important for heterochromatin silencing at multiple genomic regions. We provide an overview of the individual components (ATRX, DAXX and/or H3.3) tested in each study and propose a model where the ATRX/DAXX chaperone complex deposits H3.3 to maintain the H3K9me3 modification at heterochromatin throughout the genome. PMID- 26773062 TI - Second test for Down's syndrome is recommended for NHS. PMID- 26773063 TI - The mental health benefits of employment: Results of a systematic meta-review. AB - OBJECTIVE: The literature on mental health in the workplace largely focuses on the negative impacts of work and how work may contribute to the development of mental disorders. The potential mental health benefits of employment have received less attention. METHOD: A systematic search of reviews or meta-analyses that consider the benefits of work in regards to mental health was undertaken using academic databases. All relevant reviews were subjected to a quality appraisal. RESULTS: Eleven reviews were identified as meeting the inclusion criteria, with four deemed to be of at least moderate quality. The available evidence supports the proposition that work can be beneficial for an employee's well-being, particularly if good-quality supervision is present and there are favourable workplace conditions. The benefits of work are most apparent when compared with the well-documented detrimental mental health effects of unemployment. CONCLUSIONS: The potential positive effects of good work and the role work can play in facilitating recovery from an illness and enhancing mental well-being need to be highlighted and promoted more widely. Future research should aim to further investigate what constitutes a 'good' workplace or a 'good' job in terms of mental health outcomes. PMID- 26773064 TI - Patients offered choices about psychological treatment have better outcomes, study shows. PMID- 26773066 TI - Csk/Src/EGFR signaling regulates migration of myofibroblasts and alveolarization. AB - Bronchopulmonary dysplasia (BPD) is characterized by premature alveolar developmental arrest. Antenatal exposure to inflammation inhibits lung morphogenesis, thus increasing the risk of developing BPD. Alveolar myofibroblasts are thought to migrate into the septal tips and elongate secondary septa during alveolarization. Here we found lipopolysaccharide (LPS) disrupted the directional migration of myofibroblasts and increased actin stress fiber expression and focal adhesion formation. In addition, COOH-terminal Src kinase (Csk) activity was downregulated in myofibroblasts treated with LPS, while activation of Src or epidermal growth factor receptor (EGFR) was upregulated by LPS treatment. Specifically, decreased Csk activity and increased activation of Src or EGFR was also observed in primary myofibroblasts isolated from newborn rat lungs with intra-amniotic LPS exposure, a model for BPD. Further investigation revealed that EGFR was involved in cell migration impairment induced by LPS, and Src inhibition blocked LPS-induced activation of EGFR or cell migration impairment. Csk silencing also resulted in EGFR activation and cell migration impairment. Besides, we found the effect of EGFR on myofibroblast migration was mediated through RhoA activation. EGFR inhibition alleviated the abnormal localization of myofibroblasts and improved alveolar development in antenatal LPS treated rats. Taken together, our data suggest that the Csk/Src/EGFR signaling pathway is critically involved in regulating directional migration of myofibroblasts and may contribute to arrested alveolar development in BPD. PMID- 26773067 TI - FGF9 and FGF18 in idiopathic pulmonary fibrosis promote survival and migration and inhibit myofibroblast differentiation of human lung fibroblasts in vitro. AB - Idiopathic pulmonary fibrosis (IPF) is characterized by an accumulation of extracellular matrix proteins and fibroblasts in the distal airways. Key developmental lung signaling pathways are reactivated in IPF. For instance, fibroblast growth factor 9 (FGF9) and FGF18, involved in epithelial-mesenchymal interactions, are critical for lung development. We evaluated the expression of FGF9, FGF18, and FGF receptors (FGFRs) in lung tissue from controls and IPF patients and assessed their effect on proliferation, survival, migration, and differentiation of control and IPF human lung fibroblasts (HLFs). FGF9, FGF18, and all FGFRs were present in the remodeled alveolar epithelium close to the fibroblast foci in IPF lungs. FGFR3 was generally detected in fibroblast foci by immunohistochemistry. In vitro, HLFs mainly expressed mesenchyme-associated FGFR isoforms (FGFR1c and FGFR3c) and FGFR4. FGF9 did not affect fibroblast proliferation, whereas FGF18 inhibited cell growth in control fibroblasts. FGF9 and FGF18 decreased Fas-ligand-induced apoptosis in control but not in IPF fibroblasts. FGF9 prevented transforming growth factor beta1-induced myofibroblast differentiation. FGF9 and FGF18 increased the migratory capacities of HLF, and FGF9 actively modulated matrix metalloproteinase activity. In addition, FGFR3 inhibition by small interfering RNA impacted p-ERK activation by FGF9 and FGF18 and their effects on differentiation and migration. These results identify FGF9 as an antiapoptotic and promigratory growth factor on HLF, maintaining fibroblasts in an undifferentiated state. The biological effects of FGF9 and FGF18 were partially driven by FGFR3. FGF18 was a less potent molecule. Both growth factors likely contribute to the fibrotic process in vivo. PMID- 26773065 TI - Cell-free hemoglobin: a novel mediator of acute lung injury. AB - Patients with the acute respiratory distress syndrome (ARDS) have elevated levels of cell-free hemoglobin (CFH) in the air space, but the contribution of CFH to the pathogenesis of acute lung injury is unknown. In the present study, we demonstrate that levels of CFH in the air space correlate with measures of alveolar-capillary barrier dysfunction in humans with ARDS (r = 0.89, P < 0.001) and in mice with ventilator-induced acute lung injury (r = 0.89, P < 0.001). To investigate the specific contribution of CFH to ARDS, we studied the impact of purified CFH in the mouse lung and on cultured mouse lung epithelial (MLE-12) cells. Intratracheal delivery of CFH in mice causes acute lung injury with air space inflammation and alveolar-capillary barrier disruption. Similarly, in MLE 12 cells, CFH increases proinflammatory cytokine expression and increases paracellular permeability as measured by electrical cell-substrate impedance sensing. Next, to determine whether these effects are mediated by the iron containing heme moiety of CFH, we treated mice with intratracheal hemin, the chloride salt of heme, and found that hemin was sufficient to increase alveolar permeability but failed to induce proinflammatory cytokine expression or epithelial cell injury. Together, these data identify CFH in the air space as a previously unrecognized driver of lung epithelial injury in human and experimental ARDS and suggest that CFH and hemin may contribute to ARDS through different mechanisms. Interventions targeting CFH and heme in the air space could provide a new therapeutic approach for ARDS. PMID- 26773070 TI - Advances in Mass Spectrometry Within Drug Discovery. PMID- 26773068 TI - Attenuation of airway smooth muscle contractility via flavonol-mediated inhibition of phospholipase-Cbeta. AB - Enhanced contractility of airway smooth muscle (ASM) is a major pathophysiological characteristic of asthma. Expanding the therapeutic armamentarium beyond beta-agonists that target ASM hypercontractility would substantially improve treatment options. Recent studies have identified naturally occurring phytochemicals as candidates for acute ASM relaxation. Several flavonoids were evaluated for their ability to acutely relax human and murine ASM ex vivo and murine airways in vivo and were evaluated for their ability to inhibit procontractile signaling pathways in human ASM (hASM) cells. Two members of the flavonol subfamily, galangin and fisetin, significantly relaxed acetylcholine-precontracted murine tracheal rings ex vivo (n = 4 and n = 5, respectively, P < 0.001). Galangin and fisetin also relaxed acetylcholine precontracted hASM strips ex vivo (n = 6-8, P < 0.001). Functional respiratory in vivo murine studies demonstrated that inhaled galangin attenuated the increase in lung resistance induced by inhaled methacholine (n = 6, P < 0.01). Both flavonols, galangin and fisetin, significantly inhibited purified phosphodiesterase-4 (PDE4) (n = 7, P < 0.05; n = 7, P < 0.05, respectively), and PLCbeta enzymes (n = 6, P < 0.001 and n = 6, P < 0.001, respectively) attenuated procontractile Gq agonists' increase in intracellular calcium (n = 11, P < 0.001), acetylcholine-induced increases in inositol phosphates, and CPI-17 phosphorylation (n = 9, P < 0.01) in hASM cells. The prorelaxant effect retained in these structurally similar flavonols provides a novel pharmacological method for dual inhibition of PLCbeta and PDE4 and therefore may serve as a potential treatment option for acute ASM constriction. PMID- 26773069 TI - Influence of AQP1 on cell adhesion, migration, and tumor sphere formation in malignant pleural mesothelioma is substratum- and histological-type dependent. AB - Malignant pleural mesothelioma (MPM) is an aggressive cancer. MPM cells express aquaporin-1 (AQP1) that in other cancers has been shown to participate in the tumor metastasis processes. However, in MPM patients AQP1 overexpression is an independent prognostic factor favoring survival. In this study we aimed at evaluating the role of AQP1 in cell adhesion, migration, and tumor sphere formation in nonmalignant mesothelial cells (MeT-5A) and in epithelioid (M14K) and sarcomatoid (ZL34) MPM cell lines. We used fibronectin (FN) or homologous cell-derived extracellular martrix (ECM) substratum to investigate the role of AQP1 in these experimental phenotypes, inhibiting AQP1 by 10(-5) M mercury chloride (MC). Deposited ECM during cell culture exhibited significant concentration differences among cell types. ZL34 cell adhesion was significantly higher than MeT-5A or M14K cells on FN and ECM. MeT-5A and M14K cell adhesion on FN was sensitive to AQP1 inhibition, whereas AQP1 inhibition on ECM was limited to M14K cells. Wound healing in ZL34 cells was significantly higher than MeT-5A and M14K cells on FN and ECM. AQP1 inhibition significantly lowered cell migration in ZL34 cells on FN and ECM. Sphere formation was not dependent on FN or ECM in the media. AQP1 inhibition in FN media reduced sphere formation in M14K cells, whereas, in ECM, all three cell types were sensitive to AQP1 inhibition. PMID- 26773071 TI - Bioaffinity Mass Spectrometry Screening. AB - Electrospray ionization Fourier transform ion cyclotron resonance mass spectrometry (ESI-FTICR-MS or ESI-FTMS) was used to screen 192 natural product extracts and a 659-member natural product-based fragment library for bindings to a potential malaria drug target, Plasmodium falciparum Rab11a (PfRab11a, PF13_0119). One natural product extract and 11 fragments showed binding activity. A new natural product, arborside E, was identified from the active extract of Psydrax montigena as a weak binder. Its binding activity and inhibitory activity against PfRab11a were confirmed by ESI-FTMS titration experiments and an orthogonal enzyme assay. PMID- 26773073 TI - Mortality and epilepsy: Can we identify those at higher risk? PMID- 26773072 TI - Vascular factors in suspected normal pressure hydrocephalus: A population-based study. AB - OBJECTIVE: We examined clinical and imaging findings of suspected idiopathic normal pressure hydrocephalus (iNPH) in relation to vascular risk factors and white matter lesions (WMLs), using a nested case-control design in a representative, population-based sample. METHODS: From a population-based sample, 1,235 persons aged 70 years or older were examined with CT of the brain between 1986 and 2000. We identified 55 persons with hydrocephalic ventricular enlargement, i.e., radiologic findings consistent with iNPH. Among these, 26 had clinical signs that fulfilled international guideline criteria for probable iNPH. These cases were labeled suspected iNPH. Each case was matched to 5 controls from the same sample, based on age, sex, and study cohort. Data on risk factors were obtained from clinical examinations and the Swedish Hospital Discharge Register. History of hypertension, diabetes mellitus (DM), smoking, overweight, history of coronary artery disease, stroke/TIA, and WMLs on CT were examined. Risk factors associated with iNPH with a p value <0.1 in chi2 tests were included in conditional logistic regression models. RESULTS: In the regression analyses, suspected iNPH was related to moderate to severe WMLs (odds ratio [OR] 5.2; 95% confidence interval [CI]: 1.5-17.6), while hydrocephalic ventricular enlargement was related to hypertension (OR 2.7; 95% CI: 1.1-6.8), moderate to severe WMLs (OR 6.5; 95% CI: 2.1-20.3), and DM (OR 4.3; 95% CI: 1.1-16.3). CONCLUSIONS: Hypertension, WMLs, and DM were related to clinical and imaging features of iNPH, suggesting that vascular mechanisms are involved in the pathophysiology. These findings might have implications for understanding disease mechanisms in iNPH and possibly prevention. PMID- 26773074 TI - Cause of death and predictors of mortality in a community-based cohort of people with epilepsy. AB - OBJECTIVE: The risk of premature mortality is increased in people with epilepsy. The reasons for this and how it may relate to epilepsy etiology remain unclear. METHODS: The National General Practice Study of Epilepsy is a prospective, community-based cohort that includes 558 people with recurrent unprovoked seizures of whom 34% died during almost 25 years of follow-up. We assessed the underlying and immediate causes of death and their relationship to epilepsy etiology. Psychiatric and somatic comorbidities of epilepsy as predictors of mortality were scrutinized using adjusted Cox proportional hazards models. RESULTS: The 3 most common underlying causes of death were noncerebral neoplasm, cardiovascular, and cerebrovascular disease, accounting for 59% (111/189) of deaths, while epilepsy-related causes (e.g., sudden unexplained death in epilepsy) accounted for 3% (6/189) of deaths. In 23% (43/189) of individuals, the underlying cause of death was directly related to the epilepsy etiology; this was significantly more likely if death occurred within 2 years of the index seizure (percent ratio 4.28 [95% confidence interval 2.63-6.97]). Specific comorbidities independently associated with increased risk of mortality were neoplasms (primary cerebral and noncerebral neoplasm), certain neurologic diseases, and substance abuse. CONCLUSIONS: Comorbid diseases are important causes of death, as well as predictors of premature mortality in epilepsy. There is an especially strong relationship between cause of death and epilepsy etiology in the first 2 years after the index seizure. Addressing these issues may help stem the tide of premature mortality in epilepsy. PMID- 26773075 TI - Is normal pressure hydrocephalus becoming less idiopathic? PMID- 26773076 TI - Low testosterone levels are associated with endothelial dysfunction in oophorectomized early postmenopausal women. AB - BACKGROUND: The actual consequences of low testosterone levels in women remain uncertain. OBJECTIVE: To assess endogenous testosterone influence on body composition, vascular and metabolic function in recent postmenopausal women. DESIGN: We studied 81 postmenopausal women under transdermal estradiol (E2) replacement therapy, 36 with bilateral oophorectomy (group O), and 45 controls (group C) through venous occlusion plethysmography, bioimpedance, DEXA, biochemical, hormonal, and inflammatory profile. RESULTS: Total testosterone level (TT) in group O was 11.0 (4.0-17.75) vs 23.0 (10.0-42.5) ng/dl in group C (P=0.001). Forearm blood flow, in ml/min/100 ml tissue, was lower in group O compared to group C at baseline (1.57 (1.05-2.47) vs 2.19 (1.59-2.66) P=0.036), following reactive hyperemia response (endothelium-dependent flow mediated dilatation, 3.44 (2.38-4.35) vs 4.3 (3.09-5.52), P=0.031) and following nitroglycerin (endothelium-independent dilation, 1.39 (0.99-1.7) vs 1.76 (1.15 2.0), P=0.025), with a positive correlation between TT and all parameters except for the reactive hyperemia response (r=0.233-0.312, P=0.036-0.004). The sVCAM1 levels were negatively correlated with TT (r=-0.320, P=0.005). E2 and other hormone levels, biochemical parameters and body composition did not differ between groups. Multiple linear regressions showed that the levels of TT, compared with other confounding variables, may explain the variation observed on endothelial parameters, with low explanatory power. CONCLUSION: The absence of ovarian testosterone production in recent postmenopausal oophorectomized women was associated with deleterious effects on endothelial function. PMID- 26773078 TI - JPEN Journal Club 18. Duplicate Publication. PMID- 26773077 TI - Guidelines for the Provision and Assessment of Nutrition Support Therapy in the Adult Critically Ill Patient: Society of Critical Care Medicine (SCCM) and American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.). PMID- 26773080 TI - Temperature Sensitivity Conferred by ligA Alleles from Psychrophilic Bacteria upon Substitution in Mesophilic Bacteria and a Yeast Species. AB - We have assembled a collection of 13 psychrophilic ligA alleles that can serve as genetic elements for engineering mesophiles to a temperature-sensitive (TS) phenotype. When these ligA alleles were substituted into Francisella novicida, they conferred a TS phenotype with restrictive temperatures between 33 and 39 degrees C. When the F. novicida ligA hybrid strains were plated above their restrictive temperatures, eight of them generated temperature-resistant variants. For two alleles, the mutations that led to temperature resistance clustered near the 5' end of the gene, and the mutations increased the predicted strength of the ribosome binding site at least 3-fold. Four F. novicida ligA hybrid strains generated no temperature-resistant variants at a detectable level. These results suggest that multiple mutations are needed to create temperature-resistant variants of these ligA gene products. One ligA allele was isolated from a Colwellia species that has a maximal growth temperature of 12 degrees C, and this allele supported growth of F. novicida only as a hybrid between the psychrophilic and the F. novicida ligA genes. However, the full psychrophilic gene alone supported the growth of Salmonella enterica, imparting a restrictive temperature of 27 degrees C. We also tested two ligA alleles from two Pseudoalteromonas strains for their ability to support the viability of a Saccharomyces cerevisiae strain that lacked its essential gene, CDC9, encoding an ATP-dependent DNA ligase. In both cases, the psychrophilic bacterial alleles supported yeast viability and their expression generated TS phenotypes. This collection of ligA alleles should be useful in engineering bacteria, and possibly eukaryotic microbes, to predictable TS phenotypes. PMID- 26773081 TI - DepR1, a TetR Family Transcriptional Regulator, Positively Regulates Daptomycin Production in an Industrial Producer, Streptomyces roseosporus SW0702. AB - Daptomycin is a potent cyclic lipopeptide antibiotic. It is widely used against various Gram-positive bacterial pathogens. Historically, a poor understanding of the transcriptional regulation of daptomycin biosynthesis has limited the options for targeted genetic engineering toward titer improvement. Here, we isolated a TetR family transcriptional regulator, DepR1, from the industrial producer Streptomyces roseosporus SW0702 using a biotinylated dptE promoter (dptEp) as a probe. The direct interaction between DepR1 and dptEp then was confirmed by electrophoretic mobility shift assays and DNase I footprinting assays. The deletion of depR1 led to a reduction in dptEp activity and the cessation of daptomycin production. The DeltadepR1 mutant produced less red pigment and failed to sporulate on R5 medium. This suggests that DepR1 plays a positive role in the control of morphological differentiation. Moreover, DepR1 was positively autoregulated by directly binding to its own promoter. This might account for the positive feedback regulation of daptomycin production. Based on these positive effects, genetic engineering by overexpression of depR1 raised daptomycin production and shortened the fermentation period both in flask and in fermentor. PMID- 26773082 TI - Characteristics of CTX-M Extended-Spectrum beta-Lactamase-Producing Escherichia coli Strains Isolated from Multiple Rivers in Southern Taiwan. AB - Extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli sequence type ST131 has emerged as the leading cause of community-acquired urinary tract infections and bacteremia worldwide. Whether environmental water is a potential reservoir of these strains remains unclear. River water samples were collected from 40 stations in southern Taiwan from February to August 2014. PCR assay and multilocus sequence typing (MLST) analysis were conducted to determine the CTX-M group and sequence type, respectively. In addition, we identified the seasonal frequency of ESBL-producing E. coli strains and their geographical relationship with runoffs from livestock and poultry farms between February and August 2014. ESBL-producing E. coli accounted for 30% of the 621 E. coli strains isolated from river water in southern Taiwan. ESBL-producing E. coli ST131 was not detected among the isolates. The most commonly detected strain was E. coli CTX-M group 9. Among the 92 isolates selected for MLST analysis, the most common ESBL-producing clonal complexes were ST10 and ST58. The proportion of ESBL-producing E. coli was significantly higher in areas with a lower river pollution index (P = 0.025) and regions with a large number of chickens being raised (P = 0.013). ESBL-producing E. coli strains were commonly isolated from river waters in southern Taiwan. The most commonly isolated ESBL-producing clonal complexes were ST10 and ST58, which were geographically related to chicken farms. ESBL-producing E. coli ST131, the major clone causing community-acquired infections in Taiwan and worldwide, was not detected in river waters. PMID- 26773083 TI - Responses of Saccharomyces cerevisiae Strains from Different Origins to Elevated Iron Concentrations. AB - Iron is an essential micronutrient for all eukaryotic organisms. However, the low solubility of ferric iron has tremendously increased the prevalence of iron deficiency anemia, especially in women and children, with dramatic consequences. Baker's yeast Saccharomyces cerevisiae is used as a model eukaryotic organism, a fermentative microorganism, and a feed supplement. In this report, we explore the genetic diversity of 123 wild and domestic strains of S. cerevisiae isolated from different geographical origins and sources to characterize how yeast cells respond to elevated iron concentrations in the environment. By using two different forms of iron, we selected and characterized both iron-sensitive and iron-resistant yeast strains. We observed that when the iron concentration in the medium increases, iron-sensitive strains accumulate iron more rapidly than iron resistant isolates. We observed that, consistent with excess iron leading to oxidative stress, the redox state of iron-sensitive strains was more oxidized than that of iron-resistant strains. Growth assays in the presence of different oxidative reagents ruled out that this phenotype was due to alterations in the general oxidative stress protection machinery. It was noteworthy that iron resistant strains were more sensitive to iron deficiency conditions than iron sensitive strains, which suggests that adaptation to either high or low iron is detrimental for the opposite condition. An initial gene expression analysis suggested that alterations in iron homeostasis genes could contribute to the different responses of distant iron-sensitive and iron-resistant yeast strains to elevated environmental iron levels. PMID- 26773084 TI - An Outer Membrane Protein Involved in the Uptake of Glucose Is Essential for Cytophaga hutchinsonii Cellulose Utilization. AB - Cytophaga hutchinsonii specializes in cellulose digestion by employing a collection of novel cell-associated proteins. Here, we identified a novel gene locus, CHU_1276, that is essential for C. hutchinsonii cellulose utilization. Disruption of CHU_1276 in C. hutchinsonii resulted in complete deficiency in cellulose degradation, as well as compromised assimilation of cellobiose or glucose at a low concentration. Further analysis showed that CHU_1276 was an outer membrane protein that could be induced by cellulose and low concentrations of glucose. Transcriptional profiling revealed that CHU_1276 exerted a profound effect on the genome-wide response to both glucose and Avicel and that the mutant lacking CHU_1276 displayed expression profiles very different from those of the wild-type strain under different culture conditions. Specifically, comparison of their transcriptional responses to cellulose led to the identification of a gene set potentially regulated by CHU_1276. These results suggest that CHU_1276 plays an essential role in cellulose utilization, probably by coordinating the extracellular hydrolysis of cellulose substrate with the intracellular uptake of the hydrolysis product in C. hutchinsonii. PMID- 26773086 TI - Discovery of Novel Haloalkane Dehalogenase Inhibitors. AB - Haloalkane dehalogenases (HLDs) have recently been discovered in a number of bacteria, including symbionts and pathogens of both plants and humans. However, the biological roles of HLDs in these organisms are unclear. The development of efficient HLD inhibitors serving as molecular probes to explore their function would represent an important step toward a better understanding of these interesting enzymes. Here we report the identification of inhibitors for this enzyme family using two different approaches. The first builds on the structures of the enzymes' known substrates and led to the discovery of less potent nonspecific HLD inhibitors. The second approach involved the virtual screening of 150,000 potential inhibitors against the crystal structure of an HLD from the human pathogen Mycobacterium tuberculosis H37Rv. The best inhibitor exhibited high specificity for the target structure, with an inhibition constant of 3 MUM and a molecular architecture that clearly differs from those of all known HLD substrates. The new inhibitors will be used to study the natural functions of HLDs in bacteria, to probe their mechanisms, and to achieve their stabilization. PMID- 26773085 TI - A TonB-Dependent Transporter Is Responsible for Methanobactin Uptake by Methylosinus trichosporium OB3b. AB - Methanobactin, a small modified polypeptide synthesized by methanotrophs for copper uptake, has been found to be chromosomally encoded. The gene encoding the polypeptide precursor of methanobactin, mbnA, is part of a gene cluster that also includes several genes encoding proteins of unknown function (but speculated to be involved in methanobactin formation) as well as mbnT, which encodes a TonB dependent transporter hypothesized to be responsible for methanobactin uptake. To determine if mbnT is truly responsible for methanobactin uptake, a knockout was constructed in Methylosinus trichosporium OB3b using marker exchange mutagenesis. The resulting M. trichosporium mbnT::Gm(r) mutant was found to be able to produce methanobactin but was unable to internalize it. Further, if this mutant was grown in the presence of copper and exogenous methanobactin, copper uptake was significantly reduced. Expression of mmoX and pmoA, encoding polypeptides of the soluble methane monooxygenase (sMMO) and particulate methane monooxygenase (pMMO), respectively, also changed significantly when methanobactin was added, which indicates that the mutant was unable to collect copper under these conditions. Copper uptake and gene expression, however, were not affected in wild type M. trichosporium OB3b, indicating that the TonB-dependent transporter encoded by mbnT is responsible for methanobactin uptake and that methanobactin is a key mechanism used by methanotrophs for copper uptake. When the mbnT::Gm(r) mutant was grown under a range of copper concentrations in the absence of methanobactin, however, the phenotype of the mutant was indistinguishable from that of wild-type M. trichosporium OB3b, indicating that this methanotroph has multiple mechanisms for copper uptake. PMID- 26773087 TI - Genome Analysis of the Fruiting Body-Forming Myxobacterium Chondromyces crocatus Reveals High Potential for Natural Product Biosynthesis. AB - Here, we report the complete genome sequence of the type strain of the myxobacterial genus Chondromyces, Chondromyces crocatus Cm c5. It presents one of the largest prokaryotic genomes featuring a single circular chromosome and no plasmids. Analysis revealed an enlarged set of tRNA genes, along with reduced pressure on preferred codon usage compared to that of other bacterial genomes. The large coding capacity and the plethora of encoded secondary metabolite biosynthetic gene clusters are in line with the capability of Cm c5 to produce an arsenal of antibacterial, antifungal, and cytotoxic compounds. Known pathways of the ajudazol, chondramide, chondrochloren, crocacin, crocapeptin, and thuggacin compound families are complemented by many more natural compound biosynthetic gene clusters in the chromosome. Whole-genome comparison of the fruiting-body forming type strain (Cm c5, DSM 14714) to an accustomed laboratory strain which has lost this ability (nonfruiting phenotype, Cm c5 fr-) revealed genetic changes in three loci. In addition to the low synteny found with the closest sequenced representative of the same family, Sorangium cellulosum, extensive genetic information duplication and broad application of eukaryotic-type signal transduction systems are hallmarks of this 11.3-Mbp prokaryotic genome. PMID- 26773091 TI - Commentary on: The Rise of Technology in Plastic Surgery Education: Is the Textbook Dead on Arrival (DOA)? PMID- 26773088 TI - Methodological Guidelines for Accurate Detection of Viruses in Wild Plant Species. AB - Ecological understanding of disease risk, emergence, and dynamics and of the efficacy of control strategies relies heavily on efficient tools for microorganism identification and characterization. Misdetection, such as the misclassification of infected hosts as healthy, can strongly bias estimates of disease prevalence and lead to inaccurate conclusions. In natural plant ecosystems, interest in assessing microbial dynamics is increasing exponentially, but guidelines for detection of microorganisms in wild plants remain limited, particularly so for plant viruses. To address this gap, we explored issues and solutions associated with virus detection by serological and molecular methods in noncrop plant species as applied to the globally important Barley yellow dwarf virus PAV (Luteoviridae), which infects wild native plants as well as crops. With enzyme-linked immunosorbent assays (ELISA), we demonstrate how virus detection in a perennial wild plant species may be much greater in stems than in leaves, although leaves are most commonly sampled, and may also vary among tillers within an individual, thereby highlighting the importance of designing effective sampling strategies. With reverse transcription-PCR (RT-PCR), we demonstrate how inhibitors in tissues of perennial wild hosts can suppress virus detection but can be overcome with methods and products that improve isolation and amplification of nucleic acids. These examples demonstrate the paramount importance of testing and validating survey designs and virus detection methods for noncrop plant communities to ensure accurate ecological surveys and reliable assumptions about virus dynamics in wild hosts. PMID- 26773092 TI - The Baker Gordon Educational Symposium at 50: A Tribute to the Legacy of Drs Thomas J. Baker and Howard L. Gordon. PMID- 26773090 TI - Perioperative Corticosteroids Reduce Short-Term Edema and Ecchymosis in Rhinoplasty: A Meta-Analysis. AB - BACKGROUND: A number of randomized controlled trials (RCTs) have investigated the role of perioperative corticosteroids in rhinoplasty. Each of these trials however has an insufficient sample sizes to reach definitive conclusions and detect harms. Three recent reviews have analyzed edema and ecchymosis outcomes following rhinoplasty; each arrived at a different conclusion and recommendation. OBJECTIVE: To estimate the effectiveness of systemic perioperative corticosteroid treatment compared to placebo for clinical outcomes in rhinoplasty using a methodologically rigorous meta-analysis. METHODS: Electronic databases were searched without language restriction. Included trials were randomized controlled trials of systemic perioperative corticosteroid treatment vs placebo in rhinoplasty evaluating at least one of: edema, ecchymosis, bleeding, cosmetic outcome, and patient satisfaction. The Cochrane risk of bias tool was applied to included trials, and the quality of evidence for each outcome was assessed using the GRADE approach. RESULTS: Analyses included 336 patients from eight trials. Perioperative corticosteroids reduced the worst edema (SMD: -1.03, 95%CI -1.30 to -0.76, P < .001) and ecchymosis (SMD: -0.78, 95%CI -1.09 to 0.47, P < .001) after rhinoplasty. At one day postoperative, a single dose of perioperative corticosteroid reduced edema (SMD -1.15, 95%CI -1.42 to -0.87, P < .001) and ecchymosis (SMD -0.79, 95%CI -1.05 to -0.52, P < .001). No clinical benefit in edema or ecchymosis was found seven days postoperatively, nor did intraoperative bleeding increase. CONCLUSIONS: There is high quality evidence to support perioperative systemic corticosteroid treatment in rhinoplasty to reduce short term edema and ecchymosis without increased intraoperative bleeding. These findings are not present at seven days. For future trials, we suggest evaluation of patient satisfaction, and correlation with long-term cosmetic outcome. LEVEL OF EVIDENCE 2: Therapeutic. PMID- 26773094 TI - Landmark Study: The Relation of Solar Radiation to Cancer Mortality in North America. PMID- 26773095 TI - Commentary on Huggins and Hodges: "Studies on Prostatic Cancer". PMID- 26773097 TI - Correction: A Modeling Approach to Explain Mutually Exclusive and Co-Occurring Genetic Alterations in Bladder Tumorigenesis. PMID- 26773096 TI - Obesity-Induced Colorectal Cancer Is Driven by Caloric Silencing of the Guanylin GUCY2C Paracrine Signaling Axis. AB - Obesity is a well-known risk factor for colorectal cancer but precisely how it influences risks of malignancy remains unclear. During colon cancer development in humans or animals, attenuation of the colonic cell surface receptor guanylyl cyclase C (GUCY2C) that occurs due to loss of its paracrine hormone ligand guanylin contributes universally to malignant progression. In this study, we explored a link between obesity and GUCY2C silencing in colorectal cancer. Using genetically engineered mice on different diets, we found that diet-induced obesity caused a loss of guanylin expression in the colon with subsequent GUCY2C silencing, epithelial dysfunction, and tumorigenesis. Mechanistic investigations revealed that obesity reversibly silenced guanylin expression through calorie dependent induction of endoplasmic reticulum stress and the unfolded protein response in intestinal epithelial cells. In transgenic mice, enforcing specific expression of guanylin in intestinal epithelial cells restored GUCY2C signaling, eliminating intestinal tumors associated with a high calorie diet. Our findings show how caloric suppression of the guanylin-GUCY2C signaling axis links obesity to negation of a universal tumor suppressor pathway in colorectal cancer, suggesting an opportunity to prevent colorectal cancer in obese patients through hormone replacement with the FDA-approved oral GUCY2C ligand linaclotide. PMID- 26773098 TI - Basolateral amygdala projections to ventral hippocampus modulate the consolidation of footshock, but not contextual, learning in rats. AB - The basolateral amygdala (BLA) modulates memory consolidation for a variety of types of learning, whereas other brain regions play more selective roles in specific kinds of learning suggesting a role for differential consolidation via distinct BLA pathways. The ventral hippocampus (VH), an efferent target of the BLA, has been suggested to selectively process emotion-related learning, yet whether the BLA -> VH pathway modulates memory consolidation, and does so in a learning-specific manner, is unknown. To address this issue, the BLA of male Sprague-Dawley rats was bilaterally transduced to express either ChR2(E123A) or eArchT3.0. Fiber optic probes were implanted in the VH to provide illumination of BLA axons. Rats then underwent a modified contextual fear conditioning task permitting separation of context and footshock learning. On day 1, rats received 3 min of pre-exposure to the apparatus. On day 2, rats were placed into the apparatus, received an immediate footshock, and quickly removed. Retention was tested on day 4. Optical stimulation of the BLA -> VH pathway following footshock, but not context, training using trains of 40-Hz light pulses enhanced retention. Continuous optical inhibition of this pathway for 15 min starting 25 min after footshock training impaired retention. These findings indicate that BLA -> VH projections influence the consolidation for footshock, but not context, learning of a modified CFC task and provide direct evidence that BLA projections to other brain regions modulate memory consolidation selectively depending on the kind of learning involved. PMID- 26773100 TI - Recovering and preventing loss of detailed memory: differential rates of forgetting for detail types in episodic memory. AB - Episodic memories undergo qualitative changes with time, but little is known about how different aspects of memory are affected. Different types of information in a memory, such as perceptual detail, and central themes, may be lost at different rates. In patients with medial temporal lobe damage, memory for perceptual details is severely impaired, while memory for central details is relatively spared. Given the sensitivity of memory to loss of details, the present study sought to investigate factors that mediate the forgetting of different types of information from naturalistic episodic memories in young healthy adults. The study investigated (1) time-dependent loss of "central" and "peripheral" details from episodic memories, (2) the effectiveness of cuing with reminders to reinstate memory details, and (3) the role of retrieval in preventing forgetting. Over the course of 7 d, memory for naturalistic events (film clips) underwent a time-dependent loss of peripheral details, while memory for central details (the core or gist of events) showed significantly less loss. Giving brief reminders of the clips just before retrieval reinstated memory for peripheral details, suggesting that loss of details is not always permanent, and may reflect both a storage and retrieval deficit. Furthermore, retrieving a memory shortly after it was encoded prevented loss of both central and peripheral details, thereby promoting retention over time. We consider the implications of these results for behavioral and neurobiological models of retention and forgetting. PMID- 26773101 TI - Inhibition of different histone acetyltransferases (HATs) uncovers transcription dependent and -independent acetylation-mediated mechanisms in memory formation. AB - Acetylation of histones changes the efficiency of the transcription processes and thus contributes to the formation of long-term memory (LTM). In our comparative study, we used two inhibitors to characterize the contribution of different histone acetyl transferases (HATs) to appetitive associative learning in the honeybee. For one we applied garcinol, an inhibitor of the HATs of the p300 (EP300 binding protein)/CBP (CREB-binding protein) family, and the HATs of the PCAF (p300/CBP-associated factor) family. As comparative agent we applied C646, a specific inhibitor that selectively blocks HATS of the p300/CBP family. Immunochemical analysis reveals differences in histone H3 acetylation in the honeybee brain, in response to the injection of either C646 or garcinol. Behavioral assessment reveals that the two drugs cause memory impairment of different nature when injected after associative conditioning: processes disturbed by garcinol are annihilated by the established transcription blocker actinomycin D and thus seem to require transcription processes. Actions of C646 are unaltered by actinomycin D, and thus seem to be independent of transcription. The outcome of our different approaches as summarized suggests that distinct HATs contribute to different acetylation-mediated processes in memory formation. We further deduce that the acetylation-mediated processes in memory formation comprise transcription-dependent and transcription-independent mechanisms. PMID- 26773099 TI - Targeted deletion of miR-132/-212 impairs memory and alters the hippocampal transcriptome. AB - miR-132 and miR-212 are structurally related microRNAs that have been found to exert powerful modulatory effects within the central nervous system (CNS). Notably, these microRNAs are tandomly processed from the same noncoding transcript, and share a common seed sequence: thus it has been difficult to assess the distinct contribution of each microRNA to gene expression within the CNS. Here, we employed a combination of conditional knockout and transgenic mouse models to examine the contribution of the miR-132/-212 gene locus to learning and memory, and then to assess the distinct effects that each microRNA has on hippocampal gene expression. Using a conditional deletion approach, we show that miR-132/-212 double-knockout mice exhibit significant cognitive deficits in spatial memory, recognition memory, and in tests of novel object recognition. Next, we utilized transgenic miR-132 and miR-212 overexpression mouse lines and the miR-132/-212 double-knockout line to explore the distinct effects of these two miRNAs on the transcriptional profile of the hippocampus. Illumina sequencing revealed that miR-132/-212 deletion increased the expression of 1138 genes; Venn analysis showed that 96 of these genes were also downregulated in mice overexpressing miR-132. Of the 58 genes that were decreased in animals overexpressing miR-212, only four of them were also increased in the knockout line. Functional gene ontology analysis of downregulated genes revealed significant enrichment of genes related to synaptic transmission, neuronal proliferation, and morphogenesis, processes known for their roles in learning, and memory formation. These data, coupled with previous studies, firmly establish a role for the miR-132/-212 gene locus as a key regulator of cognitive capacity. Further, although miR-132 and miR-212 share a seed sequence, these data indicate that these miRNAs do not exhibit strongly overlapping mRNA targeting profiles, thus indicating that these two genes may function in a complex, nonredundant manner to shape the transcriptional profile of the CNS. The dysregulation of miR 132/-212 expression could contribute to signaling mechanisms that are involved in an array of cognitive disorders. PMID- 26773103 TI - Monocytic Angiotensin and Endothelin Receptor Imbalance Modulate Secretion of the Profibrotic Chemokine Ligand 18. AB - OBJECTIVE: To assess monocytic expression and ratio of angiotensin and endothelin receptors in systemic sclerosis (SSc) and their functional relevance. METHODS: Receptor expression was measured by flow cytometry. Chemokine ligand 18 (CCL18) concentration in supernatants of peripheral blood mononuclear cells stimulated with immunoglobulin G was measured by ELISA. RESULTS: Monocytes of patients with SSc presented an increased angiotensin II Type 1 receptor (AT1R)/AT2R ratio compared with those of healthy donors. Patients with lung fibrosis and patients with high modified Rodnan skin score showed a reduced endothelin 1 Type A receptor (ETAR)/ETBR ratio. High AT1R/AT2R, but low ETAR/ETBR ratios corresponded to higher CCL18 secretion. CONCLUSION: Altered angiotensin and endothelin receptor ratios observed in SSc influence autoantibody-mediated effects such as secretion of profibrotic CCL18. PMID- 26773102 TI - The Incidence and Predictors of Infection in Psoriasis and Psoriatic Arthritis: Results from Longitudinal Observational Cohorts. AB - OBJECTIVE: To investigate the rate, type, characteristics, and predictors of infection in a cohort of patients with psoriatic arthritis (PsA) and a cohort of patients with psoriasis without arthritis (PsC). METHODS: A cohort of patients with PsA and a cohort of patients with PsC were followed according to a standard protocol and information on the occurrence of infections was recorded. The rate of infection was estimated by fitting an exponential model. A Weibull regression model was fitted to estimate the relative risk of first infection associated with a number of covariates. Risk factors for recurrent infections were investigated using generalized estimating equations. RESULTS: There were 498 and 74 infections reported among 695 and 509 patients with PsA and PsC, respectively, with an incidence rate of 19.6 per 100 person-years in the PsA cohort compared with 12.2 in the PsC cohort. The HR of the time to the first infection in PsA versus PsC was 1.6 (p = 0.002), and higher in patients treated with biologics versus nonbiologics at 1.56 (95% CI 1.22-2.00) in PsA and 1.50 (95% CI 0.64-3.54) in the PsC cohorts. Female sex and treatment with biologics were associated with infection in the PsA cohort, whereas a lower Psoriasis Area and Severity Index score and a higher Functional Comorbidity Index were associated with infection in the PsC cohort. Ultraviolet treatment was protective against infection in both cohorts. No difference in rates of hospitalization was found (p = 0.66). There were no infection-related deaths in either cohort. CONCLUSION: The incidence rate of infection was higher in the PsA than the PsC cohort and higher among patients treated with biologics. The data confirm the association between infection and biologic treatment in psoriatic disease. PMID- 26773104 TI - Improved Function and Reduced Pain after Swimming and Cycling Training in Patients with Osteoarthritis. AB - OBJECTIVE: Arthritis and its associated joint pain act as significant barriers for adults attempting to perform land-based physical activity. Swimming can be an ideal form of exercise for patients with arthritis. Yet there is no information on the efficacy of regular swimming exercise involving patients with arthritis. The effect of a swimming exercise intervention on joint pain, stiffness, and physical function was evaluated in patients with osteoarthritis (OA). METHODS: Using a randomized study design, 48 sedentary middle-aged and older adults with OA underwent 3 months of either swimming or cycling exercise training. Supervised exercise training was performed for 45 min/day, 3 days/week at 60-70% heart rate reserve for 12 weeks. The Western Ontario and McMaster Universities Arthritis Index was used to measure joint pain, stiffness, and physical limitation. RESULTS: After the exercise interventions, there were significant reductions in joint pain, stiffness, and physical limitation accompanied by increases in quality of life in both groups (all p < 0.05). Functional capacity as assessed by maximal handgrip strength, isokinetic knee extension and flexion power (15-30% increases), and the distance covered in the 6-min walk test increased (all p < 0.05) in both exercise groups. No differences were observed in the magnitude of improvements between swimming and cycling training. CONCLUSION: Regular swimming exercise reduced joint pain and stiffness associated with OA and improved muscle strength and functional capacity in middle-aged and older adults with OA. Additionally, the benefits of swimming exercise were similar to the more frequently prescribed land-based cycling training. TRIAL REGISTRATION: clinicaltrials.gov NCT01836380. PMID- 26773105 TI - Genetic Variants That Are Associated with Neuropsychiatric Systemic Lupus Erythematosus. AB - OBJECTIVE: While genetic risks have been implicated in systemic lupus erythematosus (SLE), the involvement of various genotypes in neuropsychiatric SLE (NPSLE) remains uncertain. The present metaanalysis aimed to combine data from different studies and evaluate the association between each genotype and the risk of developing NPSLE. METHODS: Studies were searched and retrieved from online databases (PubMed, EMBASE, BIOSIS, and ScienceDirect). Case-control studies were chosen if they reported genotype frequencies of the gamma Fc region (FCgammaR) receptors II-A, III-A, and III-B; tumor necrosis factor-alpha (TNF-alpha); mannan binding lectin (MBL); integrin alpha M (ITGAM); interleukin (IL) 1, IL-1beta, and IL-6; IL-10 promoter; and vitamin D genes. The OR were used to assess the strength of this association between patients with NPSLE and SLE. RESULTS: A total of 33 studies were considered in this metaanalysis. The results suggest that these genotypes demonstrated a significant association with NPSLE: the homozygous FCgammaR IIIa 158 FF genotype (OR 1.89, p = 0.03 for FF vs VV + FV), heterozygous FCgammaR IIIb NA1/2 genotype (OR 2.14, p = 0.03 for NA1/2 vs NA1/1; OR 1.81, p = 0.04 for NA1/2 vs NA1/1 + NA2/2), and homozygous ITGAM rs1143679 HH genotype (OR 3.39, p = 0.04 for HH vs RH; OR 3.11, p = 0.048 for HH vs RR + RH). Polymorphisms of the TNF-alpha, MBL2, IL-1, IL-1beta, IL-6, IL-10 promoter, and vitamin D receptor genes did not show a statistically significant association with the risk of developing NPSLE (p > 0.05). CONCLUSION: This metaanalysis indicates that polymorphisms in the pathways of immune complex clearance, such as the FcgammaRIIIa, FcgammaRIIIb, and ITGAM genotypes, are potential susceptibility genes for NPSLE. PMID- 26773106 TI - Development of System-level Performance Measures for Evaluation of Models of Care for Inflammatory Arthritis in Canada. AB - OBJECTIVE: To develop system-level performance measures for evaluating the care of patients with inflammatory arthritis (IA), including rheumatoid arthritis (RA), psoriatic arthritis, ankylosing spondylitis, and juvenile idiopathic arthritis. METHODS: This study involved several methodological phases. Over multiple rounds, various participants were asked to help define a set of candidate measurement themes. A systematic search was conducted of existing guidelines and measures. A set of 6 performance measures was defined and presented to 50 people, including patients with IA, rheumatologists, allied health professionals, and researchers using a 3-round, online, modified Delphi process. Participants rated the validity, feasibility, relevance, and likelihood of use of the measures. Measures with median ratings >= 7 for validity and relevance were included in the final set. RESULTS: Six performance measures were developed evaluating the following aspects of care, with each measure being applied separately for each type of IA except where specified: waiting times for rheumatology consultation for patients with new onset IA, percentage of patients with IA seen by a rheumatologist, percentage of patients with IA seen in yearly followup by a rheumatologist, percentage of patients with RA treated with a disease-modifying antirheumatic drug (DMARD), time to DMARD therapy in RA, and number of rheumatologists per capita. CONCLUSION: The first set of system-level performance measures for IA care in Canada has been developed with broad input. The measures focus on timely access to care and initiation of appropriate treatment for patients with IA, and are likely to be of interest to other arthritis care systems internationally. PMID- 26773107 TI - Characteristics Predicting Tuberculosis Risk under Tumor Necrosis Factor-alpha Inhibitors: Report from a Large Multicenter Cohort with High Background Prevalence. AB - OBJECTIVE: Screening strategies for latent tuberculosis (TB) before starting tumor necrosis factor (TNF)-alpha inhibitors have decreased the prevalence of TB among patients who are treated with these agents. However, despite vigilant screening, TB continues to be an important problem, especially in parts of the world with a high background TB prevalence. The aim of this study was to determine the factors related to TB among a large multicenter cohort of patients who were treated with anti-TNF. METHODS: Fifteen rheumatology centers participated in this study. Among the 10,434 patients who were treated with anti TNF between September 2002 and September 2012, 73 (0.69%) had developed TB. We described the demographic features and disease characteristics of these 73 patients and compared them to 7695 patients who were treated with anti-TNF, did not develop TB, and had complete data available. RESULTS: Among the 73 patients diagnosed with TB (39 men, 34 women, mean age 43.6 +/- 13 yrs), the most frequent diagnoses were ankylosing spondylitis (n = 38) and rheumatoid arthritis (n = 25). More than half of the patients had extrapulmonary TB (39/73, 53%). Six patients died (8.2%). In the logistic regression model, types of anti-TNF drugs [infliximab (IFX), OR 3.4, 95% CI 1.88-6.10, p = 0.001] and insufficient and irregular isoniazid use (< 9 mos; OR 3.15, 95% CI 1.43-6.9, p = 0.004) were independent predictors of TB development. CONCLUSION: Our results suggest that TB is an important complication of anti-TNF therapies in Turkey. TB chemoprophylaxis less than 9 months and the use of IFX therapy were independent risk factors for TB development. PMID- 26773108 TI - Improvement in Psoriasis Signs and Symptoms Assessed by the Psoriasis Symptom Inventory with Brodalumab Treatment in Patients with Psoriatic Arthritis. AB - OBJECTIVE: To evaluate the effect of brodalumab on psoriasis signs and symptoms assessed by the Psoriasis Symptom Inventory (PSI) in patients with psoriatic arthritis (PsA). METHODS: This prespecified analysis of a phase II study (NCT01516957) evaluated patients with active PsA and psoriasis-affected body surface area >= 3%, randomized to brodalumab (140 or 280 mg) or placebo every 2 weeks (Q2W) for 12 weeks with loading dose at Week 1. At Week 12, patients entering an open-label extension received brodalumab 280 mg Q2W. The PSI measures 8 psoriasis signs and symptoms: itch, redness, scaling, burning, stinging, cracking, flaking, and pain. PSI response is defined as total PSI <= 8 (range 0 32), each item <= 1 (range 0-4). PSI scores were assessed at weeks 12 and 24. RESULTS: There were 107 eligible patients. At Week 12, mean improvement in PSI scores was 7.8, 11.2, and 1.5 in brodalumab 140 mg, 280 mg, and placebo groups, respectively; by Week 24, improvement was 10.2, 12.4, and 11.7. At Week 12, 75.0%, 81.8%, and 16.7% of patients receiving brodalumab 140 mg, 280 mg, and placebo, respectively, achieved PSI response; improvement was sustained through Week 24, when 83.9% of prior placebo recipients achieved response. At Week 12, 25.0%, 36.4%, and 2.8% of patients receiving brodalumab 140 mg, 280 mg, and placebo, respectively, achieved PSI 0. Percentages improved through Week 24: 40.0% brodalumab 140 mg, 42.9% brodalumab 280 mg, and 48.4% placebo. CONCLUSION: Significantly more brodalumab-treated patients with PsA achieved patient-reported improvements in psoriasis signs and symptoms than did those receiving placebo. Improvements were comparable between brodalumab groups. PMID- 26773109 TI - Clinical Features, Morbidity, and Risk Factors of Intestinal Pseudo-obstruction in Systemic Lupus Erythematosus: A Retrospective Case-control Study. AB - OBJECTIVE: To analyze the epidemiology, clinical characteristics, and risk factors for systemic lupus erythematosus-related intestinal pseudo-obstruction (SLE-IPO). METHODS: We retrospectively examined 85 patients with SLE with IPO as the case group and 255 randomly matched patients with SLE without any gastrointestinal manifestations as the control group, out of 4331 inpatients at the Peking Union Medical College Hospital (PUMCH) from 2003 to 2014. RESULTS: Over the last 11 years at PUMCH, the prevalence of IPO in patients with SLE was 1.96% and the in-hospital fatality rate was 7.1%. Of these patients, 57.6% presented with IPO as the initial affected system of SLE, and the rate of misdiagnosis was about 78%. Pyeloureterectasis was the most common complication (58.9%) in patients with SLE-IPO and the incidence of biliary tract dilation was 7.1%. Patients with SLE with IPO were always diagnosed at an earlier stage of SLE with a higher frequency of hematological disturbance, polyserositis, and hypocomplementemia. Pyeloureterectasis, hypocomplementemia, and elevated C reactive protein levels in serum were independent risk factors for IPO in SLE disease. Patients with SLE-IPO with long IPO duration and those diagnosed during late stages of SLE or concurrent with pyeloureterectasis and megacholedochus always had an unfavorable outcome. CONCLUSION: IPO is a rare complication, but commonly presents as the initial affected system of SLE, which can lead to a difficult diagnosis and delayed treatment. SLE-IPO occurrence concomitantly with pyeloureterectasis and megacholedochus showed a severe clinical situation in our cohort. Thus, patients with SLE-IPO with systemic smooth muscular involvement should be diagnosed early and treated aggressively. PMID- 26773110 TI - The Framingham Score and the Systematic Coronary Risk Evaluation at Low Cutoff Values Are Useful Surrogate Markers of High-risk Subclinical Atherosclerosis in Patients with Rheumatoid Arthritis. AB - OBJECTIVE: We determined the performance of the Framingham score and the Systematic COronary Risk Evaluation (SCORE) in assessing high-risk atherosclerosis in patients with rheumatoid arthritis (RA). METHODS: We assembled 330 cases without established cardiovascular disease (CVD), diabetes, and moderate or severe chronic kidney disease among 451 consecutive Spanish patients who underwent CVD risk screening and carotid ultrasound-determined plaque assessment. The findings were validated in 90 black and 97 white African patients. RESULTS: When sensitivity for the Framingham score was set at 80% in receiver-operator curve analysis [area under the curve (AUC) = 0.799], the corresponding cutoff value and specificity were 7.3% and 63%, respectively. At a specificity of 80%, the cutoff value and sensitivity were 10.8% and 65%, respectively. When sensitivity for SCORE (AUC = 0.747) was set at 80%, the cutoff value and specificity were 0.5% and 58%, respectively. At a specificity of 80%, the cutoff value and sensitivity were 1.5% and 50%, respectively. Upon applying a cutoff value of 7.3% for the Framingham and 0.5% for SCORE in African white patients with RA, the corresponding sensitivities and specificities were 67% and 72%, and 67% and 55%, respectively. CVD risk equations did not discriminate between black African patients with and without plaque (AUC = 0.544 and 0.549 for Framingham score and SCORE, respectively). CONCLUSION: The Framingham score and SCORE at markedly low cutoff values of 7.3% to 10.8% and 0.5% to 1.5%, respectively, can usefully estimate plaque presence in RA. Effective population specific CVD risk assessment strategies are needed in black African patients with RA. PMID- 26773111 TI - Incremental Costs for Psoriasis and Psoriatic Arthritis in a Population-based Cohort in Southern Sweden: Is It All Psoriasis-attributable Morbidity? AB - OBJECTIVE: To estimate incremental costs for patients with psoriasis/psoriatic arthritis (PsO/PsA) compared to population-based referents free from PsO/PsA and estimate costs attributable specifically to PsO/PsA. METHODS: Patients were identified by International Classification of Diseases, 10th ed., codes for PsO/PsA using information from 1998 to 2007 in the Skane Healthcare Register, covering healthcare use for the population of the Skane region of Sweden. For each patient, 3 population-based referents were selected. Data were retrieved from Swedish registers on healthcare, drugs, and productivity loss. The human capital method was used to value productivity losses. Mean annual costs for 2008 to 2011 were assessed from a societal perspective. RESULTS: We identified 15,283 patients fulfilling the inclusion criteria for PsO [n = 12,562, 50% women, mean age (SD) 52 (21) yrs] or PsA [n = 2721, 56% women, mean age 54 (16) yrs] and included 45,849 referents. Mean annual cost per patient with PsO/PsA was 55% higher compared to referents: ?10,500 vs ?6700. The cost was 97% higher for PsA compared to PsO. Costs due to productivity losses represented the largest share of total costs, ranging from 52% for PsO to 60% for PsA. Biological drug costs represented 10% of the costs for PsA and 1.6% for PsO. The proportion of cost identified as attributable to PsO/PsA problems was greatest among the patients with PsA (drug costs 71% and healthcare costs 31%). CONCLUSION: Annual mean incremental societal cost per patient was highest for PsA, mainly because of productivity losses and biological treatment. A minor fraction of the costs were identified as attributable to PsO/PsA specifically, indicating an increased morbidity in these patients that needs to be further investigated. PMID- 26773112 TI - Physical and Mental Functioning in Patients with Established Rheumatoid Arthritis over an 11-year Followup Period: The Role of Specific Comorbidities. AB - OBJECTIVE: To investigate the longterm association of a wide range of comorbidities with physical and mental functioning in patients with rheumatoid arthritis (RA). METHODS: Longitudinal data over a period of 11 years were collected from 882 patients with RA. Somatic comorbidity and comorbid depression were measured at baseline, with a questionnaire including 20 chronic diseases and with the Center for Epidemiologic Depression Scale, respectively. Physical functioning was measured at 5 timepoints with a disease-specific measure [Health Assessment Questionnaire (HAQ)] and a generic measure [physical scales of the Medical Outcomes Study Short Form-36 (SF-36)]. Mental functioning was measured with the mental scales of the SF-36. To determine the association of baseline specific comorbidities with functioning over time, we performed longitudinal analyses. RESULTS: At baseline, 72% percent of the patients were women, mean age +/- SD was 59.3 +/- 14.8 years, median RA disease duration was 5.0 years, and 68% had >= 1 comorbid condition. The effect of comorbid conditions was more apparent when physical functioning was measured with SF-36, a disease-generic measure, compared with the HAQ, a disease-specific measure. Circulatory conditions and depression were associated (p < 0.05) with worse physical functioning according to the HAQ. Respiratory conditions, musculoskeletal conditions, cancer, and depression were associated (p < 0.05) with worse physical functioning according to the SF-36. Respiratory conditions and depression were associated with worse mental functioning. CONCLUSION: Patients with specific comorbid conditions have an increased risk of low functioning in the long term. Targeted attention for these specific comorbid conditions by clinicians is recommended. PMID- 26773113 TI - A Prospective Study Investigating Prediagnostic Leukocyte Telomere Length and Risk of Developing Rheumatoid Arthritis in Women. AB - OBJECTIVE: To prospectively examine the association between leukocyte telomere length (LTL) and subsequent rheumatoid arthritis (RA) development in women. METHODS: Using a case-control design nested within the prospective Nurses' Health Study (NHS), NHS II (NHSII), and Women's Health Study (WHS), each validated case of RA with a prediagnostic blood sample was matched to 3 controls by cohort, age, menopausal status, postmenopausal hormone therapy, and blood collection covariates. We measured telomere length in genomic DNA extracted from stored buffy coat samples using quantitative PCR. We used unconditional logistic regression to determine OR and 95% CI, and random-effects metaanalysis to combine study results. RESULTS: In total, we analyzed 296 incident RA cases and 827 matched controls. Mean age of diagnosis among women who developed RA was 60.5 in NHS/NHSII and 61.3 in WHS. Metaanalysis demonstrated that longer prediagnostic LTL was associated with increased RA risk when women in the longest versus shortest LTL tertile were compared (OR 1.51, 95% CI 1.03-2.23, Pheterogeneity = 0.27). However, statistically significant between-study heterogeneity was observed for the intermediate tertile category (Pheterogeneity = 0.008). We did not observe heterogeneity by menopausal status, inflammatory cytokine levels, age at diagnosis, age at blood collection, body mass index, seropositivity, or HLA DRbeta1 shared epitope status. CONCLUSION: Our results do not support an involvement for short LTL preceding RA development. PMID- 26773114 TI - Path Analysis Identifies Receptor Activator of Nuclear Factor-kappaB Ligand, Osteoprotegerin, and Sclerostin as Potential Mediators of the Tophus-bone Erosion Relationship in Gout. AB - OBJECTIVE: To determine the relationship between tophus, erosion and bone remodeling factors in gout. METHODS: Computed tomography bone erosion and circulating bone factors were measured in adults with tophaceous gout. Multiple regression modeling and path analysis were used to determine predictors of erosion. RESULTS: Tophus number, Maori or Pacific ethnicity, creatinine, receptor activator of nuclear factor-kappaB ligand (RANKL), osteoprotegerin (OPG), and sclerostin were independently associated with erosion. Path analysis showed a direct effect of tophus number on erosion, partially mediated through OPG, RANKL, and sclerostin. CONCLUSION: Tophus number is strongly associated with bone erosion in gout. Circulating RANKL, OPG, and sclerostin are potential mediators of tophus-related erosion. PMID- 26773115 TI - Predictors of Incident Seizure in Systemic Lupus Erythematosus. AB - OBJECTIVE: The risk factors for incident seizures in systemic lupus erythematosus (SLE) were prospectively determined in a cohort study. METHODS: A total of 2203 patients with SLE followed longitudinally in the Hopkins Lupus Cohort were analyzed. Demographic variables, clinical manifestations, laboratory tests, and SLE disease activity were recorded at each quarterly visit. Adjusted estimates of association of risk factors for onset of seizure were derived using pooled logistic regression. We examined incident seizures in 3 ways: at the time of diagnosis, more than 45 days after the diagnosis of SLE, and after cohort entry. RESULTS: Of 2203 patients with no history of seizure prior to SLE diagnosis, 157 (7.13%) had the first seizure occurrence at the time of (37 patients, 1.68%) or after diagnosis (120 patients, 5.45%) of SLE. The risk of seizure occurring around the time of SLE diagnosis was higher in patients with a history of malar rash (p = 0.002), proteinuria (p = 0.004), and psychosis (p < 0.001). Multivariable analysis of the first seizure occurring after the diagnosis of SLE showed that history of low C3 (p = 0.0078), psychosis (p < 0.0001), cranial or peripheral neuropathy (p = 0.0043), anti-Sm antibody (p = 0.0551), renal involvement (p = 0.0177), and current corticosteroid dose (p < 0.0001) were independently associated with a higher incidence of seizure. Disease activity was not predictive after adjusting for corticosteroids. CONCLUSION: Risk of seizure after diagnosis of SLE is increased in those patients with prior psychosis, neuropathy, proteinuria, anti-Sm, low C3, and use of corticosteroids. PMID- 26773116 TI - Novel Composite Radiographic Score for Longitudinal Observational Studies of Psoriatic Arthritis: A Proof-of-concept Study. AB - OBJECTIVE: To devise a feasible composite radiographic score for use in observational studies of psoriatic arthritis (PsA). METHODS: Radiographs from 50 patients with PsA were evaluated with the PsA-modified Sharp, Sharp/van der Heijde (SvdH), and Ratingen scores. Data reductions were made to devise a concise score. RESULTS: The Reductive X-ray Score for Psoriatic Arthritis (ReXSPA) required the assessment of only 22 joints (117 points), including erosion, joint space narrowing, and osteoproliferation in the hands and feet. The ReXSPA accounted for 80% of change detected with the SvdH score. CONCLUSION: We report a proof-of-concept radiographic score for observational studies derived though data reduction. PMID- 26773118 TI - Examining the Minimal Important Difference of Patient-reported Outcome Measures for Individuals with Knee Osteoarthritis: A Model Using the Knee Injury and Osteoarthritis Outcome Score. AB - OBJECTIVE: To examine the influence of different analytical methods, baseline covariates, followup periods, and anchor questions when establishing a minimal important difference (MID) for individuals with knee osteoarthritis (OA). Second, to propose MID for improving and worsening on the Knee injury and Osteoarthritis Outcome Score (KOOS). METHODS: Retrospective analysis of prospectively collected data from 272 patients with knee OA undergoing a multidisciplinary nonsurgical management strategy. The magnitude and rate of change as well as the influence of baseline covariates were examined for 5 KOOS subscales over 52 weeks. The MID for improving and worsening were investigated using 4 anchor-based methods. RESULTS: Waitlisted for joint replacement and exhibiting unilateral/bilateral symptoms influenced change in KOOS over time. Generally, low correlations between anchors and KOOS change scores limited calculations of MID; thus, they were only proposed for the pain, activities of daily living, and quality of life subscales. The method used to calculate the MID influenced the cutpoint; however, the type of anchor question only influenced the MID when analyzed with a particular mean change method. Depending on patient and clinical characteristics, the subscale, and the analytical approach used, the MID for KOOS improvement ranged from an absolute change of -1.5 to 20.6 points and worsening ranged from -19.17 to 8.5 points. CONCLUSION: MID vary with patient and clinical characteristics, KOOS subscale, and analytical approach. Provided the anchor question is relevant to the patient-reported outcome and baseline status is considered, the anchor does not appear to influence the MID for improvement or worsening when using some anchor-based methods. PMID- 26773117 TI - Longterm Efficacy of an Antipneumococcal Polysaccharide Vaccine among Patients with Autoimmune Inflammatory Rheumatic Diseases. AB - OBJECTIVE: To estimate the longterm humoral response of an antipneumococcal polysaccharide vaccine (PPSV23) in patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), ankylosing spondylitis (AS), or inflammatory bowel disease (IBD)-associated spondyloarthropathy (SpA), and the effect of demographic and clinical factors and treatment on the longterm efficacy of the vaccine. METHODS: A total of 145 consecutive patients treated with biologics [tumor necrosis factor-alpha (TNF-alpha) or interleukin 6 (IL-6) receptor inhibitors] or methotrexate (MTX) participated in this study. Fifteen were excluded because of absent information regarding their vaccination status (n = 9) or because of technical problems in obtaining their serum sample (n = 6). They were diagnosed with RA (n = 63, 48.5%), PsA (n = 29, 22.3%), AS (n = 28, 21.5%), or IBD associated SpA (n = 3, 2.3%). Their mean age was 54.6 years, and 61.5% were women. Data were collected on the timing of vaccination, demographic and clinical characteristics, and treatment, and patients' serum antipneumococcal antibody levels were tested. RESULTS: Two-thirds of the patients (67.7%) had received PPSV23 45 months (mean) earlier. Treatment included TNF-alpha inhibitors (73.9%), IL-6 receptor inhibitors (13.1%), or MTX without a biological treatment (13%). The uptake of vaccination was significantly higher in the older population (> 65 yrs). Vaccinated patients had significantly higher antibody levels compared with vaccine-naive patients. The antibody levels had been preserved after 10 years. MTX use, but not biologics, was associated with significantly lower antibody levels. CONCLUSION: The longterm efficacy of the PPSV23 vaccination seems to be preserved among patients with RA, PsA, AS, and IBD-associated SpA for at least 10 years. Efficacy is slightly impaired by MTX, but it is not affected by biologics. These findings suggest that revaccination after 5 years might not be needed for all, and testing the antibody titers should be considered to identify those who may benefit from revaccination. PMID- 26773119 TI - Severe Intracranial Involvement in Giant Cell Arteritis: 5 Cases and Literature Review. AB - OBJECTIVE: Involvement of intracranial arteries in giant cell arteritis (GCA) is rare. We describe the neurologic complications of intracranial GCA (IC GCA) and available treatment options. METHODS: We describe 5 IC GCA cases from 3 Canadian vasculitis centers and review the literature. We searched English-language publications reporting similar patients meeting American College of Rheumatology (ACR) criteria for GCA and having intracranial artery involvement diagnosed by autopsy, magnetic resonance angiography, computed tomography angiography, or conventional angiography. RESULTS: All 5 cases of IC GCA met ACR criteria for GCA; 4 cases had a temporal artery biopsy that was consistent with GCA. All cases experienced cerebrovascular accident(s). Arteritis involved the following vessels: intracranial internal carotid (n = 1), vertebrobasilar arteries (n = 1), or both (n = 3). All cases received aspirin and oral prednisone (preceded by intravenous methylprednisone in 3 cases), combined with an immunosuppressant in 4 cases. All patients survived; 2 had complete neurological recovery, 3 had residual neurologic sequelae. The literature review included 42 cases from 28 publications. The clinical features of the reported cases were similar to those of our 5 cases. However, mortality was 100% in untreated cases (n = 2), 58% in those treated with corticosteroid alone (n = 31), and 40% in those treated with corticosteroid and an immunosuppressant (n = 10). CONCLUSION: IC GCA appears to be associated with neurologic complications and mortality. In some cases corticosteroid alone was not sufficient to prevent neurologic complications. The role of additional immunosuppressive agents needs further investigation. PMID- 26773121 TI - Mycophenolate Mofetil in Nonrenal Manifestations of Systemic Lupus Erythematosus: An Observational Cohort Study. AB - OBJECTIVE: Mycophenolate mofetil (MMF), along with corticosteroids, is considered as the standard of care in lupus nephritis (LN); however, little is known regarding its efficacy in extrarenal manifestations of systemic lupus erythematosus (SLE). We aimed to determine its effectiveness in nonrenal SLE. METHODS: One hundred seventy-seven patients with SLE were enrolled; 105 for whom MMF was introduced for active LN (mean age 35.6 +/- 10.7 yrs, mean disease duration 8.9 +/- 7.8 yrs) and 72 for extrarenal manifestations (mean age 38.6 +/- 11.7 yrs, mean disease duration 11.7 +/- 9.2 yrs). The main indication for MMF initiation was based on the respective SLE Disease Activity Index element that was present at that time. Patients were subdivided according to the major nonrenal manifestation. Improvement was defined as the absence of the initial clinical or laboratory manifestation after 6 and 12 months. RESULTS: Cumulatively, the initial clinical manifestation or hematological abnormality was resolved in 42/72 nonrenal patients (58.3%) after 6 months and in 45/72 (62.5%) after 12 months. Corticosteroid dose was reduced in 44/72 patients (61.1%, p < 0.001, mean dose 18.4 +/- 12.6 mg/day at baseline to 12.1 +/- 9.0 mg/day after 12 mos, p < 0.05). In renal patients, 40 (38.1%) had complete resolution of the extrarenal manifestation after 6 months, while 53 (50.5%) achieved complete response after 12 months. Prednisone dose was reduced in 73/105 patients (69.5%) after 12 months (mean dose 29.2 +/- 16.6 mg/day at baseline to 15.3 +/- 9.7 mg/day, p < 0.001). CONCLUSION: MMF seems to be an efficacious alternative in refractory to standard of care nonrenal manifestations of SLE in the long term, allowing for disease activity control and significant reduction in corticosteroid dose. PMID- 26773122 TI - Venous and Arterial Thrombotic Events in Systemic Lupus Erythematosus. AB - OBJECTIVE: The incidence of thrombosis in patients with systemic lupus erythematosus (SLE) is 25 to 50-fold higher than in the general population; we aimed to define the characteristics of venous thrombotic events (VTE) and arterial thrombotic events (ATE) to identify the patients at highest risk. METHODS: The study included 219 patients with recent-onset SLE. At baseline, standardized medical history and laboratory tests were done. Followup visits occurred quarterly, and information about damage accrual, comorbidities, and cardiovascular risk factors was updated annually. Main outcome was development of TE after SLE diagnosis. RESULTS: Thirty-five patients (16%) developed TE (27 VTE, 8 ATE) during 5.21 years of followup; incidence rate 31/1000 patient-years. Most events (57%) developed within the first year of diagnosis, and 69% were not associated with lupus anticoagulant (LAC), determined with 1 method. VTE developed earlier than ATE (2.0 vs 57.5 mos, p = 0.02). In the multivariate analysis, variables preceding VTE included cutaneous vasculitis, nephrotic syndrome, dose of prednisone, and LAC in combination with anti-RNP/Sm antibodies (p < 0.03). Patients with ATE were older (median age 44 vs 29 yrs, p = 0.04), smokers, and had hypertension, diabetes mellitus, dyslipidemia, at least 2 traditional risk factors, nephrotic syndrome, chronic damage, and a higher cumulative dose of prednisone (p < 0.05). LAC in combination with anti-RNP/Sm antibodies was associated with VTE and improved the accuracy for predicting it. CONCLUSION: Our study suggests that in SLE, VTE and ATE have different risk factors. Understanding these differences is helpful for identifying patients at highest risk. The use of LAC plus anti-RNP/Sm for predicting VTE deserves further study. PMID- 26773123 TI - Regulation of NF-kappaB circuitry by a component of the nucleosome remodeling and deacetylase complex controls inflammatory response homeostasis. PMID- 26773124 TI - Stimulation of inducible nitric oxide by hepatitis B virus transactivator protein HBx requires MTA1 coregulator. PMID- 26773125 TI - Src subfamily kinases regulate nuclear export and degradation of transcription factor Nrf2 to swtich off Nrf2-mediated antioxidant activation of cytoprotective gene expression. PMID- 26773126 TI - Prothymosin-alpha mediates nuclear import of the INrf2/Cul3.Rbx1 complex to degrade nuclear Nrf2. PMID- 26773127 TI - Phosphorylation and dephosphorylation of tyrosine 141 regulate stability and degradation of INrf2. A novel mechanism in Nrf2 activation. PMID- 26773128 TI - The small GTPase RALA controls c-Jun N-terminal kinase-mediated FOXO activation by regulation of a JIP1 scaffold complex. PMID- 26773129 TI - Poly(ADP-ribosyl)ation of FOXP3 protein mediated by PARP-1 regulates the function of regulatory T cells. PMID- 26773120 TI - High Kellgren-Lawrence Grade and Bone Marrow Lesions Predict Worsening Rates of Radiographic Joint Space Narrowing; The SEKOIA Study. AB - OBJECTIVE: Determinants of radiographic progression in osteoarthritis (OA) are poorly understood. We investigated which features on baseline magnetic resonance imaging (MRI) acted as predictors of change in joint space width (JSW). METHODS: A total of 559 men and women over the age of 50 years with clinical knee OA [Kellgren-Lawrence (KL) grade 2-3] were recruited to the placebo arm of the SEKOIA study (98 centers; 18 countries). Minimal tibiofemoral joint space and KL grade on plain radiograph of the knee were assessed at baseline and at yearly followup up to 3 years. In a subset, serial knee MRI examinations were performed. Individuals with a bone marrow lesion (BML) >= grade 2 at the tibiofemoral joint at baseline were classified as BML-positive. Relationships between change in JSW and risk factors were assessed using linear regression. RESULTS: The mean age of study participants was 62.8 (SD 7.5) years and 73% were female; 38.6% had BML. Mean baseline JSW was 3.65 mm. This reduced by 0.18 (0.30) mm/year in men and 0.13 (0.23) mm/year in women. Those with BML had a significantly higher rate of annualized change in JSW; this relationship remained robust after adjustment for age, sex, and baseline KL grade [beta = -0.10 (95% CI -0.18, -0.02) mm/yr]. Age, sex, baseline KL grade, and other MRI findings did not influence the rate of change in JSW. CONCLUSION: The rate of change in JSW was similar in men and women. BML on knee MRI predicted the rate of radiographic change in JSW. This relationship was independent of age, sex, and baseline KL grade. PMID- 26773130 TI - Dynamic imaging of pancreatic nuclear factor kappaB (NF-kappaB) activation in live mice using adeno-associated virus (AAV) infusion and bioluminescence. PMID- 26773132 TI - SIRAH tools: mapping, backmapping and visualization of coarse-grained models. AB - Coarse-grained (CG) models reduce the cost of molecular dynamics simulations keeping the essence of molecular interactions. Still, the diversity of CG representations (sizes, connectivity, naming, etc.) hampers the handling and visualization of such models. SIRAH Tools comprises a set of utilities to convert all-atoms coordinates to arbitrary residue-based CG schemes, write GROMACS' topological information at any resolution into PSF format and a VMD plugin to visualize, analyze and retrieve pseudo-atomistic information from CG trajectories performed with the SIRAH force field. These tools facilitate the use of intricate CG force fields outside the small developer's community. AVAILABILITY AND IMPLEMENTATION: Different utilities of SIRAH Tools are written in Perl, Tcl, or R. Documentation and source codes are freely distributed at http://www.sirahff.com CONTACT: : mmachado@pasteur.edu.uy or spantano@pasteur.edu.uy. PMID- 26773131 TI - FINEMAP: efficient variable selection using summary data from genome-wide association studies. AB - MOTIVATION: The goal of fine-mapping in genomic regions associated with complex diseases and traits is to identify causal variants that point to molecular mechanisms behind the associations. Recent fine-mapping methods using summary data from genome-wide association studies rely on exhaustive search through all possible causal configurations, which is computationally expensive. RESULTS: We introduce FINEMAP, a software package to efficiently explore a set of the most important causal configurations of the region via a shotgun stochastic search algorithm. We show that FINEMAP produces accurate results in a fraction of processing time of existing approaches and is therefore a promising tool for analyzing growing amounts of data produced in genome-wide association studies and emerging sequencing projects. AVAILABILITY AND IMPLEMENTATION: FINEMAP v1.0 is freely available for Mac OS X and Linux at http://www.christianbenner.com CONTACT: : christian.benner@helsinki.fi or matti.pirinen@helsinki.fi. PMID- 26773133 TI - Antifungal activities of diphenyl diselenide and ebselen alone and in combination with antifungal agents against Fusarium spp. AB - Herein, we describe the in vitro activity of a combination of the organoselenium compounds diphenyl diselenide and ebselen alone and in combination with amphotericin B, caspofungin, itraconazole, and voriconazole against 25 clinical isolates of Fusarium spp. For this analysis, we used the broth microdilution method based on the M38-A2 technique and checkerboard microdilution method. Diphenyl diselenide (MIC range = 4-32 MUg/ml) and ebselen (MIC range = 2-8 MUg/ml) showed in vitro activity against the isolates tested. The most effective combinations were (synergism rates): ebselen + amphotericin B (88%), ebselen + voriconazole (80%), diphenyl diselenide + amphotericin B (72%), and diphenyl diselenide + voriconazole (64%). Combination with caspofungin resulted in low rates of synergism: ebselen + caspofungin, 36%, and diphenyl diselenide + caspofungin, 28%; combination with itraconazole demonstrated indifferent interactions. Antagonistic effects were not observed for any of the combinations tested. Our findings suggest that the antifungal potential of diphenyl diselenide and ebselen deserves further investigation in in vivo experimental models, especially in combination with amphotericin B and voriconazole. PMID- 26773134 TI - Aspergillus tubingensis: a major filamentous fungus found in the airways of patients with lung disease. AB - The black Aspergillus group comprises A. niger and 18 other species, which are morphologically indistinguishable. Among this species subset, A. tubingensis, described in less than 30 human cases before 2014, is primarily isolated from ear, nose, and throat samples. Recently, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry has emerged as a powerful technique to identify microbes in diagnostic settings. We applied this method to identify 1,720 filamentous fungi routinely isolated from clinical samples our laboratory over a two-year study period. Accordingly, we found 85 isolates of A. niger, 58 of A. tubingensis, and six other black Aspergillus (4 A. carbonarius and 2 A. japonicus). A. tubingensis was the fifth most frequent mold isolated in our mycology laboratory, primarily isolated from respiratory samples (40/58 isolates). In this study, we mainly aimed to describe the clinical pattern of Aspergillus tubingensisWe analyzed the clinical features of the patients in whom A. tubingensis had been isolated from 40 respiratory samples. Thirty patients suffered from cystic fibrosis, chronic obstructive pulmonary disease or other types of chronic respiratory failure. Strikingly, 20 patients were experiencing respiratory acute exacerbation at the time the sample was collected. Antifungal susceptibility testing of 36 A. tubingensis isolates showed lower amphotericin B MICs (P < 10(-4)) and higher itraconazole and voriconazole MICs (P < 10(-4) and P = .0331, respectively) compared with 36 A. niger isolates. Further studies are required to better establish the role that this fungus plays in human diseases, especially in the context of cystic fibrosis and chronic pulmonary diseases. PMID- 26773136 TI - Classic Spotlight: a Very Pleiotropic Mutant. PMID- 26773135 TI - Comprehensive analysis of the skin fungal microbiota of astronauts during a half year stay at the International Space Station. AB - The International Space Station (ISS) is a huge manned construct located approximately 400 km above the earth and is inhabited by astronauts performing space experiments. Because the station is within a closed microgravity environment, the astronauts are subject to consistent stress. This study analyzed the temporal changes in the skin fungal microbiota of 10 astronauts using pyrosequencing and quantitative PCR assay before, during, and after their stay in the ISS. Lipophilic skin fungi, Malassezia predominated most samples regardless of the collection period, body site (cheek or chest), or subject. During their stay in the ISS, the level of Malassezia colonization changed by 7.6- +/- 7.5 fold (mean +/- standard deviation) and 9.5- +/- 24.2-fold in cheek and chest samples, respectively. At the species level, M. restricta, M. globosa, and M. sympodialis were more abundant. In the chest samples, the ratio of M. restricta to all Malassezia species increased, whereas it did not change considerably in cheek samples. Fungal diversity was reduced, and the ratio of Malassezia to all fungal colonization increased during the astronauts' stay at the ISS. The ascomycetous yeast Cyberlindnera jadinii was detected in abundance in the in flight sample of 5 of the 10 astronauts. The microorganism may have incidentally adhered to the skin during the preflight period and persisted on the skin thereafter. This observation suggests the ability of a specific or uncommon microorganism to proliferate in a closed environment. Our study is the first to reveal temporal changes in the skin fungal microbiota of ISS astronauts. These findings will provide information useful for maintaining the health of astronauts staying in the space environment for long periods and for preventing infection due to the human skin microbiota. PMID- 26773137 TI - Classic Spotlight: the Awesome Power of Conjugation. PMID- 26773141 TI - Pro- and Anti-Inflammatory Role of ChemR23 Signaling in Pollutant-Induced Inflammatory Lung Responses. AB - Inhalation of traffic-related particulate matter (e.g., diesel exhaust particles [DEPs]) is associated with acute inflammatory responses in the lung, and it promotes the development and aggravation of allergic airway diseases. We previously demonstrated that exposure to DEP was associated with increased recruitment and maturation of monocytes and conventional dendritic cells (DCs), resulting in TH2 polarization. Monocytes and immature DCs express the G-protein coupled receptor chemR23, which binds the chemoattractant chemerin. Using chemR23 knockout (KO) and corresponding wild-type (WT) mice, we determined the role of chemR23 signaling in response to acute exposure to DEPs and in response to DEP enhanced house dust mite (HDM)-induced allergic airway inflammation. Exposure to DEP alone, as well as combined exposure to DEP plus HDM, elevated the levels of chemerin in the bronchoalveolar lavage fluid of WT mice. In response to acute exposure to DEPs, monocytes and monocyte-derived DCs accumulated in the lungs of WT mice, but this response was significantly attenuated in chemR23 KO mice. Concomitant exposure to DEP plus HDM resulted in allergic airway inflammation with increased eosinophilia, goblet cell metaplasia, and TH2 cytokine production in WT mice, which was further enhanced in chemR23 KO mice. In conclusion, we demonstrated an opposing role for chemR23 signaling depending on the context of DEP-induced inflammation. The chemR23 axis showed proinflammatory properties in a model of DEP-induced acute lung inflammation, in contrast to anti-inflammatory effects in a model of DEP-enhanced allergic airway inflammation. PMID- 26773142 TI - gammadelta T Cells Protect the Liver and Lungs of Mice from Autoimmunity Induced by Scurfy Lymphocytes. AB - gammadelta T cells have been shown to have immunoregulatory functions in several experimental autoimmune models. A mutation of the Foxp3 gene leads to the absence of regulatory T cells (Tregs) and a fatal systemic autoimmune disease in scurfy mice. Transfer of scurfy lymphocytes to RAG deficient (RAG(-/-)) recipients reproduces the inflammatory phenotype of the scurfy donor, including hepatitis and pneumonitis. In this study, we show that TCRalpha(-/-) recipients, which lack alphabeta T cells but have gammadelta T cells and B cells, are significantly protected from the hepatitis and pneumonitis, but not the dermatitis, induced by adoptive transfer of scurfy lymphocytes. Cotransfer of gammadelta T cells, but not B cells, prevented hepatitis and pneumonitis in RAG(-/-) recipients of scurfy lymphocytes. gammadelta T cells in the TCRalpha(-/-) recipients of scurfy cells markedly expanded and expressed a highly activated (CD62L(lo)CD44(hi)) phenotype. The activated gammadelta T cells expressed high levels of CD39 and NKG2D on their cell surface. A high frequency of scurfy T cells in TCRalpha(-/-) recipients produced IL-10, suggesting that gammadelta T cells may enhance suppressor cytokine production from scurfy T cells in TCRalpha(-/-) recipients. This study indicates that gammadelta T cells may contribute to the maintenance of immunological homeostasis by suppressing autoreactive T cells in liver and lung. PMID- 26773143 TI - Fatty Acid Amide Hydrolase Regulates Peripheral B Cell Receptor Revision, Polyreactivity, and B1 Cells in Lupus. AB - C57BL/6 mice bearing the Sle2(z) lupus-susceptibility congenic interval on chromosome 4 display high titers of polyclonal autoantibodies with generalized B cell hyperactivity, hallmarks of systemic lupus erythematosus. In B6.Sle2(z)HEL(Ig).sHEL BCR-transgenic mice, Sle2(z) did not breach central tolerance, but it led to heightened expression of endogenous Ig H and L chains in splenic B cells, upregulation of RAG, and serological polyreactivity, suggestive of excessive receptor revision. Fatty acid amide hydrolase (FAAH), a gene in the minimal subcongenic interval generated through recombinant mapping, was found to be upregulated in Sle2(z) B cells by microarray analysis, Western blot, and functional assays. Pharmacological inhibition of FAAH reversed the increase in receptor revision, RAG expression, and polyreactive autoantibodies in lupus-prone mice. These studies indicate that increased peripheral BCR revision, or selective peripheral expansion of BCR-revised B cells, may lead to systemic autoimmunity and that FAAH is a lupus-susceptibility gene that might regulate this process. PMID- 26773144 TI - Loss of Peripheral Protection in Pancreatic Islets by Proteolysis-Driven Impairment of VTCN1 (B7-H4) Presentation Is Associated with the Development of Autoimmune Diabetes. AB - Ag-specific activation of T cells is an essential process in the control of effector immune responses. Defects in T cell activation, particularly in the costimulation step, have been associated with many autoimmune conditions, including type 1 diabetes (T1D). Recently, we demonstrated that the phenotype of impaired negative costimulation, due to reduced levels of V-set domain-containing T cell activation inhibitor 1 (VTCN1) protein on APCs, is shared between diabetes susceptible NOD mice and human T1D patients. In this study, we show that a similar process takes place in the target organ, as both alpha and beta cells within pancreatic islets gradually lose their VTCN1 protein during autoimmune diabetes development despite upregulation of the VTCN1 gene. Diminishment of functional islet cells' VTCN1 is caused by the active proteolysis by metalloproteinase N-arginine dibasic convertase 1 (NRD1) and leads to the significant induction of proliferation and cytokine production by diabetogenic T cells. Inhibition of NRD1 activity, alternatively, stabilizes VTCN1 and dulls the anti-islet T cell responses. Therefore, we suggest a general endogenous mechanism of defective VTCN1 negative costimulation, which affects both lymphoid and peripheral target tissues during T1D progression and results in aggressive anti islet T cell responses. This mechanism is tied to upregulation of NRD1 expression and likely acts in two synergistic proteolytic modes: cell-intrinsic intracellular and cell-extrinsic systemic. Our results highlight an importance of VTCN1 stabilization on cell surfaces for the restoration of altered balance of immune control during T1D. PMID- 26773146 TI - Swift and Strong NK Cell Responses Protect 129 Mice against High-Dose Influenza Virus Infection. AB - It is generally unclear what roles NK cells play during influenza virus infection with regard to different host genetic backgrounds. In this study, we show that in six inbred mouse strains, NK cells play an important protective role only in 129 mice during high-dose influenza A H1N1 virus infection. Swift and strong NK cell responses efficiently control early pulmonary viral replication in 129 mice, providing survival privilege. In addition, we identified that early activation of TLRs and RIG-I signaling in 129 mice resulted in quick production of type 1 IFNs and inflammatory cytokines, which are important reasons for the swift kinetics of NK cell responses post influenza virus infection. Thus, under different microenvironments, NK cells play differential roles against viral infections. The kinetics and magnitude of NK cell responses correlate with the distinct roles that NK cells play against influenza virus infections. Thus, our works further our understandings about the complex role of NK cells during influenza virus infection. PMID- 26773145 TI - Cutting Edge: CD99 Is a Novel Therapeutic Target for Control of T Cell-Mediated Central Nervous System Autoimmune Disease. AB - Leukocyte trafficking into the CNS is a prominent feature driving the immunopathogenesis of multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis. Blocking the recruitment of inflammatory leukocytes into the CNS represents an exploitable therapeutic target; however, the adhesion molecules that specifically regulate the step of leukocyte diapedesis into the CNS remain poorly understood. We report that CD99 is critical for lymphocyte transmigration without affecting adhesion in a human blood-brain barrier model. CD99 blockade in vivo ameliorated experimental autoimmune encephalomyelitis and decreased the accumulation of CNS inflammatory infiltrates, including dendritic cells, B cells, and CD4(+) and CD8(+) T cells. Anti-CD99 therapy was effective when administered after the onset of disease symptoms and blocked relapse when administered therapeutically after disease symptoms had recurred. These findings underscore an important role for CD99 in the pathogenesis of CNS autoimmunity and suggest that it may serve as a novel therapeutic target for controlling neuroinflammation. PMID- 26773147 TI - Vaccine Induction of Lymph Node-Resident Simian Immunodeficiency Virus Env Specific T Follicular Helper Cells in Rhesus Macaques. AB - Measurement of Ag-specific T follicular helper (TFH) cell activity in rhesus macaques has not previously been reported. Given that rhesus macaques are the animal model of choice for evaluating protective efficacy of HIV/SIV vaccine candidates and that TFH cells play a pivotal role in aiding B cell maturation, quantifying vaccine induction of HIV/SIV-specific TFH cells would greatly benefit vaccine development. In this study, we quantified SIV Env-specific IL-21 producing TFH cells for the first time, to our knowledge, in a nonhuman primate vaccine study. Macaques were primed twice mucosally with adenovirus 5 host range mutant recombinants encoding SIV Env, Rev, Gag, and Nef followed by two i.m. boosts with monomeric SIV gp120 or oligomeric SIV gp140 proteins. At 2 wk after the second protein boost, we obtained lymph node biopsy specimens and quantified the frequency of total and SIV Env-specific IL-21(+) TFH cells and total germinal center B cells, the size and number of germinal centers, and the frequency of SIV specific Ab-secreting cells in B cell zones. Multiple correlation analyses established the importance of TFH for development of B cell responses in systemic and mucosally localized compartments, including blood, bone marrow, and rectum. Our results suggest that the SIV-specific TFH cells, initially induced by replicating adenovirus-recombinant priming, are long lived. The multiple correlations of SIV Env-specific TFH cells with systemic and mucosal SIV-specific B cell responses indicate that this cell population should be further investigated in HIV vaccine development as a novel correlate of immunity. PMID- 26773148 TI - Inducible Expression of CXCL1 within the Central Nervous System Amplifies Viral Induced Demyelination. AB - The functional role of the ELR(+) chemokine CXCL1 in host defense and disease following infection of the CNS with the neurotropic JHM strain of mouse hepatitis virus (JHMV) was examined. Mice in which expression of CXCL1 is under the control of a tetracycline-inducible promoter active within glial fibrillary acidic protein-positive cells were generated and this allowed for selectively increasing CNS expression of CXCL1 in response to JHMV infection and evaluating the effects on neuroinflammation, control of viral replication, and demyelination. Inducible expression of CNS-derived CXCL1 resulted in increased levels of CXCL1 protein within the serum, brain, and spinal cord that correlated with increased frequency of Ly6G(+)CD11b(+) neutrophils present within the CNS. Elevated levels of CXCL1 did not influence the generation of virus-specific T cells, and there was no difference in control of JHMV replication compared with control mice, indicating that T cell infiltration into the CNS is CXCL1-independent. Sustained CXCL1 expression within the CNS resulted in increased mortality that correlated with elevated neutrophil infiltration, diminished numbers of mature oligodendrocytes, and an increase in the severity of demyelination. Neutrophil ablation in CXCL1 transgenic mice reduced the severity of demyelination in mice, arguing for a role for these cells in white matter damage. Collectively, these findings illustrate that sustained CXCL1 expression amplifies the severity of white matter damage and that neutrophils can contribute to this process in a model of viral-induced neurologic disease. PMID- 26773150 TI - NK Cell-Specific Gata3 Ablation Identifies the Maturation Program Required for Bone Marrow Exit and Control of Proliferation. AB - NK cells are innate lymphocytes capable of eliciting an innate immune response to pathogens. NK cells develop and become mature in the bone marrow (BM) before they migrate out to peripheral organs. Although the developmental program leading to mature NK cells has been studied in the context of several transcription factors, the stage-specific role of GATA3 in NK cell development has been incompletely understood. Using NKp46-Cre-Gata3(fl/fl) mice in which Gata3 deficiency was induced as early as the immature stage of NK cell differentiation, we demonstrated that GATA3 is required for the NK cell maturation beyond the CD27 single-positive stage and is indispensable for the maintenance of liver-resident NK cells. The frequencies of NK cells from NKp46-Cre-Gata3(fl/fl) mice were found higher in the BM but lower in peripheral organs compared with control littermates, indicating that GATA3 controls the maturation program required for BM egress. Despite the defect in maturation, upon murine CMV infection, NK cells from NKp46-Cre-Gata3(fl/fl) mice expanded vigorously, achieving NK cell frequencies surpassing those in controls and therefore provided comparable protection. The heightened proliferation of NK cells from NKp46-Cre-Gata3(fl/fl) mice was cell intrinsic and associated with enhanced upregulation of CD25 expression. Taken together, our results demonstrate that GATA3 is a critical regulator for NK cell terminal maturation and egress out of the BM and that immature NK cells present in the periphery of NKp46-Cre-Gata3(fl/fl) mice can rapidly expand and provide a reservoir of NK cells capable of mounting an efficient cytotoxic response upon virus infection. PMID- 26773149 TI - A Novel Factor H-Fc Chimeric Immunotherapeutic Molecule against Neisseria gonorrhoeae. AB - Neisseria gonorrhoeae, the causative agent of the sexually transmitted infection gonorrhea, has developed resistance to almost every conventional antibiotic. There is an urgent need to develop novel therapies against gonorrhea. Many pathogens, including N. gonorrhoeae, bind the complement inhibitor factor H (FH) to evade complement-dependent killing. Sialylation of gonococcal lipooligosaccharide, as occurs in vivo, augments binding of human FH through its domains 18-20 (FH18-20). We explored the use of fusing FH18-20 with IgG Fc (FH18 20/Fc) to create a novel anti-infective immunotherapeutic. FH18-20 also binds to select host glycosaminoglycans to limit unwanted complement activation on host cells. To identify mutation(s) in FH18-20 that eliminated complement activation on host cells, yet maintained binding to N. gonorrhoeae, we created four mutations in domains 19 or 20 described in atypical hemolytic uremic syndrome that prevented binding of mutated fH to human erythrocytes. One of the mutant proteins (D to G at position 1119 in domain 19; FHD1119G/Fc) facilitated complement-dependent killing of gonococci similar to unmodified FH18-20/Fc but, unlike FH18-20/Fc, did not lyse human erythrocytes. FHD1119G/Fc bound to all (100%) of 15 sialylated clinical N. gonorrhoeae isolates tested (including three contemporary ceftriaxone-resistant strains), mediated complement-dependent killing of 10 of 15 (67%) strains, and enhanced C3 deposition (>=10-fold above baseline levels) on each of the five isolates not directly killed by complement. FHD1119G/Fc facilitated opsonophagocytic killing of a serum-resistant strain by human polymorphonuclear neutrophils. FHD1119G/Fc administered intravaginally significantly reduced the duration and burden of gonococcal infection in the mouse vaginal colonization model. FHD1119G/Fc represents a novel immunotherapeutic against multidrug-resistant N. gonorrhoeae. PMID- 26773152 TI - Depletion of CD8+ T Cells Exacerbates CD4+ T Cell-Induced Monocyte-to-Fibroblast Transition in Renal Fibrosis. AB - Bone marrow-derived monocyte-to-fibroblast transition is a key step in renal fibrosis pathogenesis, which is regulated by the inflammatory microenvironment. However, the mechanism by which the inflammatory microenvironment regulates this transition is not fully understood. In this study, we examined how the CD8(+) T cell/IFN-gamma microenvironment regulates the monocyte-to-fibroblast transition in renal fibrosis. Genetic ablation of CD8 promoted a monocyte-to-fibroblast transition and increased renal interstitial fibrosis, whereas reconstitution of CD8 knockout (KO) mice with CD8(+) T cells decreased fibrosis. However, depletion of CD4(+) T cells in CD8 KO mice also reduced fibrosis. To elucidate the role of CD4(+) T cells in mediating CD8-regulated monocyte-to-fibroblast transition, CD4(+) T cells were isolated from obstructed kidneys of CD8 KO or wild-type mice. CD4(+) T cells isolated from CD8 KO obstructed kidney expressed more IL-4 and GATA3 and less IFN-gamma and T-bet and showed increased monocyte-to-fibroblast transition in vitro compared with those isolated from wild-type obstructed kidney. To examine the role of IFN-gamma-expressing CD8(+) T cells, we reconstituted CD8 KO mice with CD8(+) T cells isolated from IFN-gamma KO mice. The IFN-gamma KO CD8(+) cells had no effect on IL-4, GATA3, IFN-gamma, and T-bet mRNA expression in obstructed kidneys or renal fibrosis. Taken together, our findings identify the axis of CD8(+) T cells and IFN-gamma-CD4(+) T cells as an important microenvironment for the monocyte-to-fibroblast transition, which negatively regulates renal fibrosis. PMID- 26773151 TI - CD28 Deficiency Enhances Type I IFN Production by Murine Plasmacytoid Dendritic Cells. AB - Type I IFNs (IFN-I) are key innate mediators that create a profound antiviral state and orchestrate the activation of almost all immune cells. Plasmacytoid dendritic cells (pDCs) are the most powerful IFN-I-producing cells and play important roles during viral infections, cancer, and autoimmune diseases. By comparing gene expression profiles of murine pDCs and conventional DCs, we found that CD28, a prototypic T cell stimulatory receptor, was highly expressed in pDCs. Strikingly, CD28 acted as a negative regulator of pDC IFN-I production upon TLR stimulation but did not affect pDC survival or maturation. Importantly, cell intrinsic CD28 expression restrained pDC (and systemic) IFN-I production during in vivo RNA and DNA viral infections, limiting antiviral responses and enhancing viral growth early after exposure. Finally, CD28 also downregulated IFN-I response upon skin injury. Our study identified a new pDC regulatory mechanism by which the same CD28 molecule that promotes stimulation in most cells that express it is co-opted to negatively regulate pDC IFN-I production and limit innate responses. PMID- 26773153 TI - p52 Overexpression Increases Epithelial Apoptosis, Enhances Lung Injury, and Reduces Survival after Lipopolysaccharide Treatment. AB - Although numerous studies have demonstrated a critical role for canonical NF kappaB signaling in inflammation and disease, the function of the noncanonical NF kappaB pathway remains ill-defined. In lung tissue from patients with acute respiratory distress syndrome, we identified increased expression of the noncanonical pathway component p100/p52. To investigate the effects of p52 expression in vivo, we generated a novel transgenic mouse model with inducible expression of p52 in Clara cell secretory protein-expressing airway epithelial cells. Although p52 overexpression alone did not cause significant inflammation, p52 overexpression caused increased lung inflammation, injury, and mortality following intratracheal delivery of Escherichia coli LPS. No differences in cytokine/chemokine expression were measured between p52-overexpressing mice and controls, but increased apoptosis of Clara cell secretory protein-positive airway epithelial cells was observed in transgenic mice after LPS stimulation. In vitro studies in lung epithelial cells showed that p52 overexpression reduced cell survival and increased the expression of several proapoptotic genes during cellular stress. Collectively, these studies demonstrate a novel role for p52 in cell survival/apoptosis of airway epithelial cells and implicate noncanonical NF kappaB signaling in the pathogenesis of acute respiratory distress syndrome. PMID- 26773155 TI - Phosphatidylinositol 4-Phosphate 5-Kinase beta Controls Recruitment of Lipid Rafts into the Immunological Synapse. AB - Phosphatidylinositol 4,5-biphosphate (PIP2) is critical for T lymphocyte activation serving as a substrate for the generation of second messengers and the remodeling of actin cytoskeleton necessary for the clustering of lipid rafts, TCR, and costimulatory receptors toward the T:APC interface. Spatiotemporal analysis of PIP2 synthesis in T lymphocytes suggested that distinct isoforms of the main PIP2-generating enzyme, phosphatidylinositol 4-phosphate 5-kinase (PIP5K), play a differential role on the basis of their distinct localization. In this study, we analyze the contribution of PIP5Kbeta to T cell activation and show that CD28 induces the recruitment of PIP5Kbeta to the immunological synapse, where it regulates filamin A and lipid raft accumulation, as well as T cell activation, in a nonredundant manner. Finally, we found that Vav1 and the C terminal 83 aa of PIP5Kbeta are pivotal for the PIP5Kbeta regulatory functions in response to CD28 stimulation. PMID- 26773154 TI - Fluvastatin Suppresses Mast Cell and Basophil IgE Responses: Genotype-Dependent Effects. AB - Mast cell (MC)- and basophil-associated inflammatory diseases are a considerable burden to society. A significant portion of patients have symptoms despite standard-of-care therapy. Statins, used to lower serum cholesterol, have immune modulating activities. We tested the in vitro and in vivo effects of statins on IgE-mediated MC and basophil activation. Fluvastatin showed the most significant inhibitory effects of the six statins tested, suppressing IgE-induced cytokine secretion among mouse MCs and basophils. The effects of fluvastatin were reversed by mevalonic acid or geranylgeranyl pyrophosphatase, and mimicked by geranylgeranyl transferase inhibition. Fluvastatin selectively suppressed key FcepsilonRI signaling pathways, including Akt and ERK. Although MCs and basophils from the C57BL/6J mouse strain were responsive to fluvastatin, those from 129/SvImJ mice were completely resistant. Resistance correlated with fluvastatin induced upregulation of the statin target HMG-CoA reductase. Human MC cultures from eight donors showed a wide range of fluvastatin responsiveness. These data demonstrate that fluvastatin is a potent suppressor of IgE-mediated MC activation, acting at least partly via blockade of geranyl lipid production downstream of HMG-CoA reductase. Importantly, consideration of statin use for treating MC-associated disease needs to incorporate genetic background effects, which can yield drug resistance. PMID- 26773156 TI - C1q Modulates the Response to TLR7 Stimulation by Pristane-Primed Macrophages: Implications for Pristane-Induced Lupus. AB - The complement component C1q is known to play a controversial role in the pathogenesis of systemic lupus erythematosus, but the underlying mechanisms remain poorly understood. Intraperitoneal injection of pristane induces a lupus like syndrome whose pathogenesis implicates the secretion of type I IFN by CD11b(+) Ly6C(high) inflammatory monocytes in a TLR7-dependent fashion. C1q was also shown to influence the secretion of IFN-alpha. In this study, we explored whether C1q deficiency could affect pristane-induced lupus. Surprisingly, C1qa(-/ ) mice developed lower titers of circulating Abs and milder arthritis compared with the controls. In keeping with the clinical scores, 2 wk after pristane injection the peritoneal recruitment of CD11b(+) Ly6C(high) inflammatory monocytes in C1qa(-/-) mice was impaired. Furthermore, C1q-deficient pristane primed resident peritoneal macrophages secreted significantly less CCL3, CCL2, CXCL1, and IL-6 when stimulated in vitro with TLR7 ligand. Replenishing C1q in vivo during the pristane-priming phase rectified this defect. Conversely, pristane-primed macrophages from C3-deficient mice did not show impaired cytokine production. These findings demonstrate that C1q deficiency impairs the TLR7 dependent chemokine production by pristane-primed peritoneal macrophages and suggest that C1q, and not C3, is involved in the handling of pristane by phagocytic cells, which is required to trigger disease in this model. PMID- 26773158 TI - Potential Role of the Formation of Tunneling Nanotubes in HIV-1 Spread in Macrophages. AB - Tunneling nanotubes (TNTs), the long membrane extensions connecting distant cells, have emerged as a novel form of cell-to-cell communication. However, it is not fully understood how and to what extent TNTs contribute to intercellular spread of pathogens including HIV-1. In this study, we show that HIV-1 promotes TNT formation per se via its protein Nef and a cellular protein M-Sec, which appears to mediate approximately half of viral spread among monocyte-derived macrophages (MDMs). A small compound that inhibits M-Sec-induced TNT formation reduced HIV-1 production by almost half in MDMs. Such inhibition was not observed with Nef-deficient mutant HIV-1 that fails to promote TNT formation and replicates less efficiently than the wild-type HIV-1 in MDMs. The TNT inhibitor sensitive/Nef-promoting viral production was also observed in a T cell line ectopically expressing M-Sec, but not in another M-Sec(-) T cell line. Our results suggest the importance of TNTs in HIV-1 spread among MDMs and might answer the long-standing question how Nef promotes HIV-1 production in a cell type-specific manner. PMID- 26773157 TI - Kras Is Critical for B Cell Lymphopoiesis. AB - The three major Ras members, Kras, Hras, and Nras, are highly homologous and individual Ras genes can have distinct biological functions. Embryonic lethality of Kras-deficient mice precludes study of the biological functions of this Ras family member. In this study, we generated and examined mice with hematopoietic specific deletion of Kras and bone marrow (BM) chimeric mice with B cell-specific targeted deletion of Kras. Hematopoietic-specific deletion of Kras impaired early B cell development at the pre-B cell stage and late B cell maturation, resulting in the reduction of BM pre-, immature, and mature B cells and peripheral follicular, marginal zone, and B1 mature B cells. In contrast, Kras deficiency did not affect T cell development. Studies of BM chimeric mice with B cell specific deletion of Kras demonstrated that Kras deficiency intrinsically impaired B cell development. Kras deficiency reduced BCR-induced B cell proliferation and survival. Furthermore, Kras deficiency specifically impaired pre-BCR- and BCR-induced activation of the Raf-1/MEK/ERK pathway in pre-B and mature B cells, respectively. Thus, Kras is the unique Ras family member that plays a critical role in early B cell development and late B cell maturation through controlling the Raf-1/MEK/ERK pathway. PMID- 26773159 TI - Ecdysone Titer Determined by 3DE-3beta-Reductase Enhances the Immune Response in the Silkworm. AB - Although recent studies have demonstrated that 20-hydroxyecdysone (20E), one of the two most important hormones for development, could promote the insect innate immune response, how insects regulate 20E titer to affect the immunity after suffering pathogen attack remains unknown. In this study, to our knowledge, we first found that 20E titer was significantly elevated after bacterial infection in the domesticated silkworm, Bombyx mori. Furthermore, the elevated 20E enhanced the silkworm innate immune system against invading bacteria via ecdysone receptor. During immune response, the expression of the silkworm 3 dehydroecdysone-3beta-reductase (3DE-3beta-reductase) that converts 3DE released from prothoracic glands into ecdysone was induced. RNA interference experiments suggested that 3DE-3beta-reductase is essential to upregulate the 20E titer after bacterial infection. The rescue experiments showed that injection with the recombinant 3DE-3beta-reductase protein can significantly elevate the 20E concentration and modulate the expressions of the silkworm immune-related genes. Taken together, 20E titer determined by 3DE-3beta-reductase enhances the silkworm defense against the bacterial infection. Thus, our findings reveal an important role of the 20E synthesis pathway from 3DE in enhancing the silkworm immune response and have profound implications for the understanding of interaction mechanisms between insect hormone and immunity. PMID- 26773160 TI - Multiplexed peptide analysis for kinetic measurements of major human apolipoproteins by LC/MS/MS. AB - A multiplexed assay was developed by MS to analyze, in a single run, six major human Apos involved in lipoprotein metabolism: ApoA-I, ApoA-II, ApoB100, ApoC-II, ApoC-III, and ApoE. This method was validated in vivo in six subjects who received a 14 h constant infusion of [5,5,5-(2)H3]L-leucine at 10 MUM/kg/h. Plasma lipoprotein fractions were isolated from collected blood samples and were digested with trypsin. Proteotypic peptides were subsequently analyzed by LC/MS/MS. Enrichment measurement data were compared with those obtained by the standard method using GC/MS. The required time to obtain the LC/MS/MS data was less than that needed for GC/MS. The enrichments from both methods were correlated for ApoA-I (r = 0.994; P < 0.0001) and ApoB100 (r = 0.999; P < 0.0001), and the Bland-Altman plot confirmed the similarity of the two methods. Intra- and inter-assay variability calculated for the six Apos of interest did not exceed 10.7 and 12.5%, respectively, and kinetic parameters were similar and/or in agreement with previously reported data. Therefore, LC/MS/MS can be considered as a useful tool for human Apo kinetic studies using stable isotopes. PMID- 26773163 TI - Angiotensin System Inhibitors in Renal Cell Carcinoma--Letter. PMID- 26773164 TI - Mixture of Alum--Naloxone and Alum--Naltrexone as a novel adjuvant elicits immune responses for Toxoplasma gondii lysate antigen in BALB /c mice. AB - Toxoplasma gondii (T. gondii) is an obligate intracellular parasite. Treatment of the infection induced by this parasite is not straightforward due to the toxic side effects of the available drugs. Vaccine development could be a solution to this problem. In the present study, T.gondii Lysate Antigen (TLA), as a model vaccine, in combination with the Alum-NLT (Aluminum phosphate-Naltrexone) and Alum-NLX (Aluminum phosphate-Naloxone) were evaluated for immunization BALB/c. 147 female BALB/c mice which were divided into seven groups of 21, were allocated to immunization experiments. The first group was selected as the negative control group, followed by the second, third, fourth, fifth, sixth and seventh groups which were immunized with Vac, Vac-Alum, Vac-NLX, Vac-NLT, Vac-Alum-NLX, Vac-Alum NLT, respectively. Ten days after the final immunization, mice in all groups were divided into three groups for evaluating cellular immune responses, measuring the delayed-type hypersensitivity responses (DTHs) and evaluating survival. The DTH and cellular immune responses showed that in mice immunized with the TLA vaccine combined with the Alum-NLT mixture, the efficacy improved by increasing the production of Interleukin-5(IL-5) and Interferon gamma. This consequently shifted the immune responses toward a Th1 profile by increasing the IFN-gamma/IL-5 ratios. In challenge experiments, immunized mice with the Alum-NLT-Vac mixture survived for a longer period of time which indicated an improvement in protective immunity against T. gondii. Administration of the Alum-NLT mixture adjuvant in combination with TLA vaccine enhanced the cellular immunity by shifting the immune response to a Th1 pattern. This shift to the Th1 pattern plays an important role in the induction of cellular. PMID- 26773162 TI - Quantitative Imaging in Cancer Clinical Trials. AB - As anticancer therapies designed to target specific molecular pathways have been developed, it has become critical to develop methods to assess the response induced by such agents. Although traditional, anatomic CT, and MRI examinations are useful in many settings, increasing evidence suggests that these methods cannot answer the fundamental biologic and physiologic questions essential for assessment and, eventually, prediction of treatment response in the clinical trial setting, especially in the critical period soon after treatment is initiated. To optimally apply advances in quantitative imaging methods to trials of targeted cancer therapy, new infrastructure improvements are needed that incorporate these emerging techniques into the settings where they are most likely to have impact. In this review, we first elucidate the needs for therapeutic response assessment in the era of molecularly targeted therapy and describe how quantitative imaging can most effectively provide scientifically and clinically relevant data. We then describe the tools and methods required to apply quantitative imaging and provide concrete examples of work making these advances practically available for routine application in clinical trials. We conclude by proposing strategies to surmount barriers to wider incorporation of these quantitative imaging methods into clinical trials and, eventually, clinical practice. Our goal is to encourage and guide the oncology community to deploy standardized quantitative imaging techniques in clinical trials to further personalize care for cancer patients and to provide a more efficient path for the development of improved targeted therapies. PMID- 26773165 TI - In vitro and in vivo action of terpinen-4-ol, gamma-terpinene, and alpha terpinene against Trypanosoma evansi. AB - This study aimed to evaluate the susceptibility in vitro and in vivo of Trypanosoma evansi to terpinen-4-ol, gamma-terpinene and alpha-terpinene, the three main compounds of tea tree oil (Melaleuca alternifolia) with known efficacy in the treatment of trypanosomosis. In vitro, a trypanocidal effect of terpinen-4 ol, gamma-terpinene, and alpha-terpinene was observed when used alone or associated at 0.5, 1 and 2% concentrations i.e., the alpha-terpinene showed a faster trypanocidal effect when compared to chemotherapy (diminazene aceturate - D.A.). In vivo studies were performed in two experiments: I and II where experiment I used T. evansi infected mice treated with terpinen-4-ol, gamma terpinene and alpha-terpinene alone (at a dose of 1.0 mL kg(-1)) or associated (two compounds, dose of 0.5 mL kg(-1) of each compound; tree compounds, dose of 0.335 mL kg(-1) of each compound); Treatment with alpha-terpinene was able to extend animal longevity, but showed no curative efficacy. In experiment II, T. evansi infected mice were treated with D.A. associate with alpha-terpinene, where a curative efficacy of 57.14% was found, a much better result when D.A. was used alone (14.28%). In summary, alpha-terpinene associated with D.A. can be used as an alternative treatment for T. evansi infection. The compound alpha-terpinene from M. alternifolia essential oil is the one responsible for the trypanocidal effect, a fact confirmed by in vitro results and the increased longevity observed on treated mice. PMID- 26773166 TI - TGF-beta1 levels and intraocular tissue alterations in mice infected with a virulent type I RH Toxoplasma gondii strain. AB - Toxoplasmosis is generally self-limiting in healthy adults but it may cause toxoplasmic retinochoroiditis in cases of congenital infection leading to blindness. The importance of host genetics in determining disease severity in ocular toxoplasmosis has been shown in different inbred mouse strains using low virulence toxoplasma strain. In this study, we studied intraocular immune response and tissue alterations in the genetically resistant BALB/c and susceptible MF1 mice infected with a virulent type I RH Toxoplasma gondii strain by intravitreal route. We observed a significant up-regulation of IFN-gamma and TNF-alpha to >2200 pg/ml and >300 pg/ml respectively in the blood of both BALB/c and MF1mice during the early stages of post intraocular infection (p < 0.01) but the levels dropped sharply to normal during the late stages of the infection on day 26. The cytokine levels detected were higher in the MF1 mice compared with the BALB/c mice and a relatively higher levels were observed in the aqueous humour (AqH) than in the blood of both group of mice. The TGF-beta1 level in the blood and AqH of BALB/c mice remained low throughout the infection period compared with MF1 mice which showed gradual increase to 50 pg/ml in the blood and AqH during the early stages of infection which then further increased 2-fold-132 pg/ml on day 11 (p < 0.01) and remained high till the last day of observation on day 26 except that the TGF-beta1 level in AqH dropped sharply to normal level. In summary, our results support that TGF-beta1 may down-regulate the effector functions of anti-Toxoplasma cellular immunity during acute toxoplasmosis. We document that a mild Th1 pro-inflammatory response in the BALB/c mice with high IFN-gamma and TNF-alpha and, low TGF-beta1 levels during the early stages of infection may have contributed to an effective cellular immune response leading to lower morbidity, mortality and less ocular tissue damage. However in the MF1 mice, a significantly high TGF-beta1 level in the blood as well as in the AqH during the acute intra-ocular toxoplasma infection may have adversely interfered with an effective cellular immune response leading to an increased mortality and extensive ocular tissue damage with parasite tachyzoites observed in the pigment epithelium layers. PMID- 26773168 TI - An anaesthesia information management system as a tool for a quality assurance program: 10years of experience. AB - INTRODUCTION: Anaesthesia Information Management Systems (AIMS) generate large amounts of data, which might be useful for quality assurance programs. This study was designed to highlight the multiple contributions of our AIMS system in extracting quality indicators over a period of 10years. METHODS: The study was conducted from 2002 to 2011. Two methods were used to extract anaesthesia indicators: the manual extraction of individual files for monitoring neuromuscular relaxation and structured query language (SQL) extraction for other indicators which were postoperative nausea and vomiting (PONV), pain, sedation scores, pain-related medications, scores and postoperative hypothermia. For each indicator, a program of information/meetings and adaptation/suggestions for operating room and PACU personnel was initiated to improve quality assurance, while data were extracted each year. RESULTS: The study included 77,573 patients. The mean overall completeness of data for the initial years ranged from 55 to 85% and was indicator-dependent, which then improved to 95% completeness for the last 5years. The incidence of neuromuscular monitoring was initially 67% and then increased to 95% (P<0.05). The rate of pharmacological reversal remained around 53% throughout the study. Regarding SQL data, an improvement of severe postoperative pain and PONV scores was observed throughout the study, while mild postoperative hypothermia remained a challenge, despite efforts for improvement. DISCUSSION: The AIMS system permitted the follow-up of certain indicators through manual sampling and many more via SQL extraction in a sustained and non-time consuming way across years. However, it requires competent and especially dedicated resources to handle the database. PMID- 26773167 TI - Does angiogenesis play a role in the establishment of mesial temporal lobe epilepsy? AB - Mesial temporal lobe epilepsy (MTLE) is a focal epileptic disorder that is frequently associated with hippocampal sclerosis. This study investigated whether blocking angiogenesis prevents the development of seizures and hippocampal atrophy in the pilocarpine rat model of MTLE. To block angiogenesis, a subset of animals were given sunitinib orally. Continuous video recordings were performed to identify seizures. Brains were then extracted and sectioned, and hippocampal surfaces and angiogenesis were assessed. After a latent period of 6.6 +/- 2.6 days, the sham-treated pilocarpine rats presented convulsive seizures, while the pilocarpine rats treated with sunitinib did not develop seizures. Sham-treated pilocarpine rats but not sunitinib-treated pilocarpine rats had significantly smaller hippocampi. Endothelial cell counts in sham-treated pilocarpine rats were significantly greater than in controls and sunitinib-treated pilocarpine rats. Blocking angiogenesis immediately following the initial insult in this animal model prevented thus angiogenesis and hippocampal atrophy and averted the development of clinical seizures. PMID- 26773169 TI - Calcium/calmodulin-dependent protein kinase IV: A multifunctional enzyme and potential therapeutic target. AB - The calcium/calmodulin-dependent protein kinase IV (CAMKIV) belongs to the serine/threonine protein kinase family, and is primarily involved in transcriptional regulation in lymphocytes, neurons and male germ cells. CAMKIV operates the signaling cascade and regulates activity of several transcription activators by phosphorylation, which in turn plays pivotal roles in immune response, inflammation and memory consolidation. In this review, we tried to focus on different aspects of CAMKIV to understand the significance of this protein in the biological system. This enzyme is associated with varieties of disorders such as cerebral hypoxia, azoospermia, endometrial and ovarian cancer, systemic lupus, etc., and hence it is considered as a potential therapeutic target. Structure of CAMKIV is comprised of five distinct domains in which kinase domain is responsible for enzyme activity. CAMKIV is involved in varieties of cellular functions such as regulation of gene expression, T-cell maturation, regulation of survival phase of dendritic cells, bone growth and metabolism, memory consolidation, sperm motility, regulation of microtubule dynamics, cell cycle progression and apoptosis. In this review, we performed an extensive analysis on structure, function and regulation of CAMKIV and associated diseases. PMID- 26773170 TI - Mass spectrometric detection of the amino acid sequence polymorphism of the hepatitis C virus antigen. AB - A method for detection and identification of the hepatitis C virus antigen (HCVcoreAg) in human serum with consideration for possible amino acid substitutions is proposed. The method is based on a combination of biospecific capturing and concentrating of the target protein on the surface of the chip for atomic force microscope (AFM chip) with subsequent protein identification by tandem mass spectrometric (MS/MS) analysis. Biospecific AFM-capturing of viral particles containing HCVcoreAg from serum samples was performed by use of AFM chips with monoclonal antibodies (anti-HCVcore) covalently immobilized on the surface. Biospecific complexes were registered and counted by AFM. Further MS/MS analysis allowed to reliably identify the HCVcoreAg in the complexes formed on the AFM chip surface. Analysis of MS/MS spectra, with the account taken of the possible polymorphisms in the amino acid sequence of the HCVcoreAg, enabled us to increase the number of identified peptides. PMID- 26773171 TI - Do glucagonomas always produce glucagon? AB - Pancreatic islet alpha-cell tumours that overexpress proglucagon are typically associated with the glucagonoma syndrome, a rare disease entity characterised by necrolytic migratory erythema, impaired glucose tolerance, thromboembolic complications and psychiatric disturbances. Paraneoplastic phenomena associated with enteric overexpression of proglucagon-derived peptides are less well recognized and include gastrointestinal dysfunction and hyperinsulinaemic hypoglycaemia. The diverse clinical manifestations associated with glucagon expressing tumours can be explained, in part, by the repertoire of tumorally secreted peptides liberated through differential post-translational processing of tumour-derived proglucagon. Proglucagon-expressing tumours may be divided into two broad biochemical subtypes defined by either secretion of glucagon or GLP-1, GLP-2 and the glucagon-containing peptides, glicentin and oxyntomodulin, due to an islet alpha-cell or enteroendocrine L-cell pattern of proglucagon processing, respectively. In the current review we provide an updated overview of the clinical presentation of proglucagon-expressing tumours in relation to known physiological actions of proglucagon-derived peptides and suggest that detailed biochemical characterisation of the peptide repertoire secreted from these tumours may provide new opportunities for diagnosis and clinical management. PMID- 26773172 TI - The mouse prostate: a basic anatomical and histological guideline. AB - Despite substantial similarities in embryological, cellular and molecular biology features, human and mouse prostates differ in organ morphology and tissue architecture. Thus, a clear understanding of the anatomy and histology of the mouse prostate is essential for the identification of urogenital phenotypes in genetically engineered mice, as well as for the study of the etiology, development, and treatment of human prostatic diseases for which mouse models are used. The purpose of this manuscript is to provide a brief guide for the dissection of the mouse prostate and the identification of its different lobes and histology, to both basic researchers and medical pathologists who are unfamiliar with mouse tissues. PMID- 26773173 TI - Modulation of iron metabolism by iron chelation regulates intracellular calcium and increases sensitivity to doxorubicin. AB - Increased intracellular iron levels can both promote cell proliferation and death, as such; iron has a "two-sided effect" in the delicate balance of human health. Though the role of iron in the development of cancer remains unclear, investigations of iron chelators as anti-tumor agents have revealed promising results. Here, we investigated the influence of iron and desferrioxamine (DFO), the iron chelating agent on intracellular calcium in a human leukemia cell line, K562. Iron uptake is associated with increased reactive oxygen species (ROS) generation. Therefore, we showed that iron also caused dose-dependent ROS generation in K562 cells. The measurement of intracellular calcium was determined using Furo-2 with a fluorescence spectrophotometer. The iron delivery process to the cytoplasmic iron pool was examined by monitoring the fluorescence of cells loaded with calcein-acetoxymethyl. Our data showed that iron increased intracellular calcium, and this response was 8 times higher when cells were incubated with DFO. K562 cells with DFO caused a 3.5 times increase of intracellular calcium in the presence of doxorubicin (DOX). In conclusion, DFO induces intracellular calcium and increases their sensitivity to DOX, a chemotherapeutic agent. PMID- 26773174 TI - Higher serum lipids and oxidative stress in patients with normal tension glaucoma, but not pseudoexfoliative glaucoma. AB - This study entailed a cross-examination of oxidant/antioxidant balance, high density lipoprotein (HDL)-linked paraoxonase 1 (PON1) phenotypes, and levels of serum routine lipids among patients with normal tension glaucoma (NTG) or pseudoexfoliative glaucoma (PEXG) compared with healthy control groups. We aimed to investigate the links between oxidative stress (OS), HDL-related antioxidant enzyme activities and dyslipidemia in distinct subtypes of glaucoma. The study included 32 patients with NTG, 31 patients with PEXG, and 40 control subjects. Levels of PON1 and arylesterase enzymatic activity, total oxidant status (TOS), and total antioxidant status were measured by spectrophotometry and OS indexes (OSI) were calculated. The phenotype distribution of PON1 was determined using the dual substrate method. Blood serum levels of HDL, low-density lipoprotein, total cholesterol (TC), and triglyceride (TG) were measured. The TOS and OSI values in the NTG group were significantly higher compared with the other groups (both p < 0.01). The phenotype distribution found in the glaucoma and control groups were NTG: QQ, 59.4%; QR, 37.5%; RR, 3.1%; PEXG: QQ, 45.1%; QR, 48.4%; RR, 6.5%; and in the control group: QQ, 42.5%; QR, 50.0%; RR, 7.5%. Serum TC levels were significantly higher than the control in both NTG and PEXG groups, whereas TG was significantly higher in NTG only (p < 0.01 and p < 0.02, respectively). Hyperlipidemia, OS and variations in phenotype distribution of PON1 may play a role in the pathogenesis of different types of glaucoma. PMID- 26773175 TI - Impacts of N-Butylphthalide on expression of growth factors in rats with focal cerebral ischemia. AB - This study investigates the impacts of n-butylphthalide (NBP) on the expression of vascular endothelial growth factor (VEGF) and transforming growth factor-beta1 (TGF-beta1) in rats with focal cerebral ischemia. The thread embolization method was used to prepare the rat model of cerebral ischemia-reperfusion (CIR). The animals were divided into a sham operation group, a model control group and NBP treatment group. The NBP group was orally administered 25 mg/kg NBP twice a day after the surgery. The immunohistochemistry and reverse transcription-polymerase chain reaction were performed to observe the protein and mRNA expressions of VEGF and TGF-beta 16 hours, 1 day and 2 days after inducing CIR. The mRNA and protein expressions of VEGF and TGF-beta1 in the model control group and the NBP treatment group were all increased after CIR, and those of the NBP treatment group at each post-CIR time point were higher than the model control group (p < 0.01). After CIR, the expressions of VEGF and TGF-beta1 increased, suggesting that VEGF and TGF-beta1 exhibited protective effects towards the ischemic brain injuries, and that NBP could upregulate the expressions of VEGF and TGF-beta1 in the peri-infarcted area, thus possibly protecting the ischemic brain tissues through this mechanism. PMID- 26773176 TI - The role of Six1 signaling in paclitaxel-dependent apoptosis in MCF-7 cell line. AB - The resistance of cancer cells to chemotherapeutic agents represents the main problem in cancer treatment. Despite intensive research, mechanisms of resistance have not yet been fully elucidated. Six1 signaling has an important role in the expansion of progenitor cell populations during early embryogenesis. Six1 gene overexpression has been strongly associated with aggressiveness, invasiveness, and poor prognosis of different cancers. In this study, we investigated the role of Six1 signaling in resistance of MCF-7 breast cancer cells to taxanes. We first established in vitro paclitaxel-resistant MCF-7 breast cancer cells. Morphological modifications in paclitaxel-resistant cells were examined via light microscopic images and fluorescence-activated cell sorting analysis. Applying quantitative real-time polymerase chain reaction, we measured Six1, B-cell lymphoma/leukemia(BCL-2), BAX, and P53 mRNA expression levels in both non resistant and resistant cells. Resistant cells were developed from the parent MCF 7 cells by applying increasing concentrations of paclitaxel up to 64 nM. The inhibitory concentration 50% value in resistant cells increased from 3.5 +/- 0.03 to 511 +/- 10.22 nM (p = 0.015). In paclitaxel-resistant cells, there was a significant increase in Six1 and BCL-2 mRNA levels (p = 0.0007) with a marked decrease in pro-apoptotic Bax mRNA expression level (p = 0.03); however, there was no significant change in P53 expression (p = 0.025). Our results suggest that identifying cancer patients with high Six1 expression and then inhibition of Six1 signaling can improve the efficiency of chemotherapeutic agents in the induction of apoptosis. PMID- 26773177 TI - Influence of bone mineral density and hip geometry on the different types of hip fracture. AB - The aim of this study was to assess the influence of bone mineral density and hip geometry on the fragility fracture of femoral neck and trochanteric region. There were 95 menopausal females of age >= 50 years with fragility fracture of hip, including 55 cases of femoral neck fracture and 40 cases of trochanteric fracture. Another 63 non-fractured females with normal bone mineral density (BMD) were chosen as control. BMD, hip axis length, neck-shaft angle and structural parameters including cross surface area, cortical thickness and buckling ratio were detected and compared. Compared with control group, the patients with femoral neck fracture or trochanteric fractures had significantly lower BMD of femoral neck, as well as lower cross surface area and cortical thickness and higher buckling ratio in femoral neck and trochanteric region. There were no significant differences of BMD and structural parameters in the femoral neck fracture group and intertrochanteric fracture group. Hip axis length and neck shaft angle were not significantly different among three groups. The significant changes of BMD and proximal femur geometry were present in the fragility fracture of femoral neck and trochanteric region. The different types of hip fractures cannot be explained by these changes. PMID- 26773178 TI - G-protein-coupled estrogen receptor-30 gene polymorphisms are associated with uterine leiomyoma risk. AB - The G-protein-coupled estrogen receptor (GPR30, GPER-1) is a member of the G protein-coupled receptor 1 family and is expressed significantly in uterine leiomyomas. To understand the relationship between GPR30 single nucleotide polymorphisms and the risk of leiomyoma, we measured the follicle-stimulating hormone (FSH) and estradiol (E2) levels of 78 perimenopausal healthy women and 111 perimenopausal women with leiomyomas. The participants' leiomyoma number and volume were recorded. DNA was extracted from whole blood with a GeneJET Genomic DNA Purification Kit. An amplification-refractory mutation system polymerase chain reaction approach was used for genotyping of the GPR30 gene (rs3808350, rs3808351, and rs11544331). The differences in genotype and allele frequencies between the leiomyoma and control groups were calculated using the chi-square (chi2) and Fischer's exact test. The median FSH level was higher in controls (63 vs. 10 IU/L, p=0.000), whereas the median E2 level was higher in the leiomyoma group (84 vs. 9.1 pg/mL, p=0.000). The G allele of rs3808351 and the GG genotype of both the rs3808350 and rs3808351 polymorphisms and the GGC haplotype increased the risk of developing leiomyoma. There was no significant difference in genotype frequencies or leiomyoma volume. However, the GG genotype of the GPR30 rs3808351 polymorphism and G allele of the GPR30 rs3808351 polymorphism were associated with the risk of having a single leiomyoma. Our results suggest that the presence of the GG genotype of the GPR30 rs3808351 polymorphism and the G allele of the GPR30 rs3808351 polymorphism affect the characteristics and development of leiomyomas in the Turkish population. PMID- 26773179 TI - Cholesteryl ester transfer protein gene polymorphism (I405V) and premature coronary artery disease in an Iranian population. AB - The effect of human cholesteryl ester transfer protein (CETP) expression on atherogenesis is still under debate. The rs5882 (I405V) polymorphism affect CETP function. We aimed to examine the relationship between the rs5882 polymorphism and the risk of angiographically determined coronary artery disease (CAD). To define premature CAD (PCAD), an age cutoff of 55 years for women and 45 years for men was used. An age- and sex-matched case-control study was conducted in 560 patients with newly diagnosed angiographically documented PCAD (>=50% luminal stenosis of any coronary vessel) and an equal number of control patients with normal coronary arteries (no luminal stenosis at coronary arteries). The severity of CAD was determined by vessel score and Gensini score. A real-time polymerase chain reaction (PCR) and high resolution melting analysis were used to distinguish between genotypes. The I405V genotype distributions were not statistically different in CAD and non-CAD groups in univariate and multivariable adjusted logistic regression analyzes. The median and inter-quartile range for Gensini score was not significantly different among the AA (43, 24 to 73), AG (40, 20 to 66), and GG (45, 25 to 72) genotypes (p = 0.097). Furthermore, the distribution of vessel score did not statistically differ between these genotypes (p = 0.691). Our results suggest that there is no significant association between CETP I405V polymorphism and the risk of PCAD presence and severity. Larger prospective studies are needed to investigate such associations in different populations. PMID- 26773180 TI - Nod-like receptor protein 3 inflammasome activation by Escherichia coli RNA induces transforming growth factor beta 1 secretion in hepatic stellate cells. AB - Nod-like receptor protein 3 (NLRP3) inflammasome has been implicated in alcoholic liver disease. Chronic alcohol consumption enhances gut permeability and causes microbial translocation. The present study explored the activation of the NLRP3 inflammasome by Escherichia coli RNA in hepatic stellate cells (HSCs), and the potential role of NLRP3 inflammasome in hepatic fibrosis. E. coli RNA transfection induced HSC-T6 cells to secrete and express mature interleukin-1 beta (IL-1beta), which was abolished by NLRP3 siRNA pretreatment. In addition, E. coli RNA transfection enhanced caspase-1 expression, whereas reduced caspase-1 precursor (pro-caspase-1) expression. E. coli RNA-stimulated transforming growth factor beta 1 (TGF-beta1) overproduction in HSC-T6 cells, which was blocked by recombinant IL-1 receptor antagonist (rIL-1Ra) or nuclear factor kappaB inhibitor BAY 11-7082. Furthermore, E. coli RNA-induced overexpression of pro-fibrogenic factors was suppressed by rIL-1Ra or TGF-beta receptor inhibitor A83-01. These results demonstrate that E. coli RNA can stimulate NLRP3 inflammasome activation, which leads to excessive production of pro-fibrogenic factors, suggesting that NLRP3 inflammasome activation in HSCs may play a role in hepatic fibrosis. PMID- 26773181 TI - The use of Matrix-assisted laser desorption ionization-time of flight mass spectrometry in the identification of Francisella tularensis. AB - Francisella tularensis is the cause of the zoonotic disease tularemia and is classified among highly pathogenic bacteria (HPB) due to its low infection dose and potential for airborne transmission. In the case of HBP, there is a pressing need for rapid, accurate and reliable identification. Phenotypic identification of Francisella species is inappropriate for clinical microbiology laboratories because it is time-consuming, hazardous and subject to variable interpretation. Matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) was recently evaluated as a useful tool for the rapid identification of a variety of microorganisms. In this study, we evaluated the use of MALDI-TOF MS for the rapid identification of Francisella tularensis and differentiation of its subspecies. Using national collection of Francisella isolates from the National Tularemia Reference Laboratory (Public Health Institute of Turkey, Ankara), a total of 75 clinical isolates were investigated by species and subspecies-specific polymerase chain reaction (PCR) test and MALDI TOF MS. All isolates were originally identified as F. tularensis subsp. holarctica due to RD1 subspecies-specific PCR result. For all isolates MALDI-TOF MS provided results in concordance with subspecies-specific PCR analysis. Although PCR-based methods are effective in identifying Francisella species, they are labor-intensive and take longer periods of time to obtain the results when compared with MALDI-TOF MS. MALDI-TOF MS appeared to be a rapid, reliable and cost-effective identification technique for Francisella spp. Shorter analysis time and low cost make this an appealing new option in microbiology laboratories. PMID- 26773182 TI - Prevalence of and risk factors for high-risk human papillomavirus infection: a population-based study from Hetian, Xinjiang, China. AB - Human papillomavirus (HPV) infection contributes to most cases of cervical cancer, and HPV genotypes exhibit different distributions according to geographic region. This study evaluates the prevalence of HPV infection in Hetian Prefecture, Xinjiang, and establishes risk factors associated with high-risk HPV (HR-HPV) genotypes in this region. In this cross-sectional, population-based study, 883 healthy women 15-54 years of age were enrolled. All participants completed a questionnaire regarding sociocultural and sexual activity characteristics. Visual inspections with acetic acid, colposcopies and biopsies were performed using the Preventive Oncology International microbiopsy protocol for pathological diagnosis. Cervical epithelial tissue specimens were collected and tested for HPV using linear array assays. According to the results of HR-HPV infection status, individuals infected with HR-HPV were classified into one group, and the remaining individuals were classified into the control group. The risk factors for HR-HPF infection were analyzed. The participants included 66 women (7.47%) with HR-HPV, 10 women (1.13%) with low-risk HPV, and 14 women (1.59%) with HPV of unknown risk. The five most prevalent types of HR-HPV were HPV-16 (0.31%), HPV-51 (0.08%), HPV-31 (0.07%), HPV-58 (0.07%), and HPV-39 (0.06%). Vulvovaginal ulcers and vulvovaginal inflammation were found in 190 participants (21.52%) and 256 participants (28.99%), respectively. The HR-HPV and control groups significantly differed with respect to age at first marriage, number of marriages, and the presence of vulvovaginal ulcers and vulvovaginal inflammation (p<0.05). Based on this study, an immunization strategy targeting HPV-16 should be prioritized in Hetian Prefecture. These findings contribute to the understanding of HPV infection. PMID- 26773183 TI - Comparison of three different regimens against Helicobacter pylori as a first line treatment: A randomized clinical trial. AB - Treatments with bismuth-containing quadruple therapy (QT), sequential therapy (ST), or concomitant therapy (CT) have been proposed as empirical first-line regimens for Helicobacter pylori. We compared the efficacy and tolerability of 10 days bismuth-containing quadruple QT, 10 days ST, and 10 days CT with as first line treatments for H. pylori in a randomized crossover study. The subjects were randomly divided into three groups. The first 130 patients were treated with rabeprazole, bismuth potassium citrate, metronidazole, and tetracycline for 10 days. The second 130 patients in the sequential group were treated with rabeprazole and amoxicillin for 5 days, and then rabeprazole, clarithromycin, and metronidazole for an additional 5 days. The last 130 patients in the concomitant group were treated with rabeprazole, amoxicillin, clarithromycin, and metronidazole for 10 days. H. pylori eradication was confirmed by urea breath test at 6 weeks. The primary outcome was eradication rates of first-line treatment by intention to treat and per protocol (PP) analyzes. There was no difference between the average ages and the male/female ratio of the groups. The PP analysis was performed on 121, 119, and 118 patients in the QT, ST, and CT groups, respectively. In the PP analysis, the successful eradication 94.2% (114/121), 95.0% (113/119), and 95.8% (113/118) the QT, ST, and CT groups, respectively. There was no significant difference among the three groups (p = 0.86). 10 days QT, ST, and CT are highly effective as empirical first-line therapies for H. pylori in the region with high clarithromycin resistance. PMID- 26773184 TI - The association between brain natriuretic peptide and tissue Doppler parameters in children with hypertrophic cardiomyopathy. AB - In this study, we investigated the association between brain natriuretic peptide (BNP) levels and tissue Doppler imaging measurements and also screening for deadly mutations in patients with hypertrophic cardiomyopathy (HCM). We enrolled 20 patients diagnosed with HCM (age:10.7+/-5 years (1-17), 85% male, weight:42.25+/-23.10 kg, height:141.80+/-32.45 cm) and 20 age, gender and body weight-matched control subjects. We performed electrocardiography, transthoracic echocardiography, and tissue Doppler echocardiography in each group, as well as genetic tests (for Arg403Gln, Arg453Cys, Arg719Trp and Arg719Gln mutations in MYH7 Exons 13, 14, 19) and BNP in the patients. The patients were divided into two groups according to the presence (Group 1) or absence (Group 2) of left ventricular (LV) outflow tract obstruction. QTc dispersion and the LV ejection fraction and left atrial (LA) volume index were increased in Group 1. The LA volume index and the mitral and septal E/Ea ratio and septum Z-score were increased while the mitral lateral annulus and septal annulus Ea wave velocities and the mitral and tricuspid E/A ratio were decreased in patients with high levels of BNP compared to those with normal BNP levels. There were no mutations that are associated with increased risk of sudden death found in patients included in this study. In the light of our data, we conclude that such parameters BNP levels above the 98 pg/mL, septal thickness Z-score ?6, and higher mitral and septal E/Ea ratios can be used for management of patients with HCM according to life-threatening conditions. PMID- 26773185 TI - Remifentanil-induced preconditioning has cross-talk with A1 and A2B adenosine receptors in ischemic-reperfused rat heart. AB - The purpose of this study was to determine whether there is a cross-talk between opioid receptors (OPRs) and adenosine receptors (ADRs) in remifentanil preconditioning (R-Pre) and, if so, to investigate the types of ADRs involved in the cross-talk. Isolated rat hearts received 30 min of regional ischemia followed by 2 hr of reperfusion. OPR and ADR antagonists were perfused from 10 min before R-Pre until the end of R-Pre. The heart rate, left ventricular developed pressure (LVDP),velocity of contraction (+dP/dtmax), and coronary flow (CF) were recorded. The area at risk and area of necrosis were measured. After reperfusion, the LVDP, +dP/dtmax,and CF showed a significant increase in the R-Pre group compared with the control group (no intervention before or after regional ischemia). These increases in the R-Pre group were blocked by naloxone, a nonspecific ADR antagonist, an A1 ADR antagonist, and an A2B ADR antagonist. The infarct size was reduced significantly in the R-Pre group compared with the control group. The infarct-reducing effect in the R-Pre group was blocked by naloxone, the nonspecific ADR antagonist, the A1 ADR antagonist, and the A2B ADR antagonist. The results of this study demonstrate that there is cross-talk between ADRs and OPRs in R-Pre and that A1 ADR and A2B ADR appear to be involved in the cross talk. PMID- 26773186 TI - Fecal calprotectin is associated with disease activity in patients with ankylosing spondylitis. AB - Calprotectin is one of the major antimicrobial S100 leucocyte proteins. Serum calprotectin levels are associated with certain inflammatory diseases such as rheumatoid arthritis, systemic lupus erythematosus and inflammatory bowel disease. The aim of this study was to investigate serum and fecal calprotectin levels in patients with ankylosing spondylitis (AS) and show their potential relations to the clinical findings of the disease. Fifty-one patients fulfilling the New York criteria of AS and 43 healthy age- and gender-matched volunteers were included in the study. Physical and locomotor system examinations were performed and history data were obtained for all patients. Disease activity parameters were assessed together with anthropometric parameters. Routine laboratory examinations and genetic testing (HLA-B27) were performed. Serum calprotectin levels and fecal calprotectin levels were measured by an enzyme linked immunosorbent assay. The mean age of the patients was 41.5 years, the mean duration of the disease was 8.6 years, and the delay in diagnosis was 4.2 years. Serum calprotectin levels were similar in both AS patients and in the control group (p=0.233). Serum calprotectin level was correlated with Bath AS disease activity index (BASDAI) and Bath AS functional index (BASFI) (p=0.001, p=0.002, respectively). A higher level of fecal calprotectin was detected in AS patients when compared with the control group. A statistically significant correlation between fecal calprotectin level and BASDAI, BASFI, C-reactive protein and Erythrocyte sedimentation rate were detected (p=0.002, p=0.005, p=0.001, p=0.002, respectively). The results indicated that fecal calprotectin levels were associated with AS disease findings and activity parameters. Calprotectin is a vital disease activity biomarker for AS and may have an important role in the pathogenesis of the disease. Multi-centered prospective studies are needed in order to provide further insight. PMID- 26773187 TI - Efficacy of laparoscopic transversus abdominis plane block for elective laparoscopic cholecystectomy in elderly patients. AB - Transversus abdominis plane (TAP) block technique seems to offer one of the most efficient methods for a local pain control. Our aim is to demonstrate the effectiveness and safety of TAP block for post-operative pain control under laparoscopic vision in elderly patients during laparoscopic cholecystectomy. The patients aged more than 65 years old, who had cholecystectomy due to symptomatic cholelithiasis, were retrospectively evaluated. The patients that were operated under general anesthesia + laparoscopic TAP block and those who were operated only under only general anesthesia were compared according to their' age and gender, comorbidities, American Society of Anesthesiologists scores, visual analog scale (VAS) for pain and length of stay in the hospital. Median (+/ interquartile range) values of post-operative 24th-hour-VAS for pain was found consecutively 2 (+/-1-3) in TAP block + group and 3 (+/-2-5) in TAP block - group. The median post-operative 24th-hour-VAS value in overall patients was three. Patients' VAS values were higher in the TAP block - group with a statistically significant difference (p = 0.001). Furthermore, no statistically significant difference was found for other parameters in two groups. The laparoscopic-guided TAP block can easily be performed and has potential for lower visceral injury risk and shorter operational time. Efficacy, safety and other advantages (analgesic requirements, etc.) make it an ideal abdominal field block in elderly patients. PMID- 26773188 TI - Tocilizumab inhibits neuronal cell apoptosis and activates STAT3 in cerebral infarction rat model. AB - Cerebral infarction is a severe hypoxic ischemic necrosis with accelerated neuronal cell apoptosis in the brain. As a monoclonal antibody against interleukin 6, tocilizumab (TCZ) is widely used in immune diseases, whose function in cerebral infarction has not been studied. This study aims to reveal the role of TCZ in regulating neuronal cell apoptosis in cerebral infarction. The cerebral infarction rat model was constructed by middle cerebral artery occlusion and treated with TCZ. Cell apoptosis in hippocampus and cortex of the brain was examined with TUNEL method. Rat neuronal cells cultured in oxygen-glucose deprivation (OGD) conditions and treated with TCZ were used to compare cell viability and apoptosis. Apoptosis-related factors including B-cell lymphoma extra large (Bcl-xL) and Caspase 3, as well as the phosphorylated signal transducer and activator of transcription 3 (p-STAT3) in brain cortex were analyzed from the protein level. Results indicated that TCZ treatment could significantly prevent the promoted cell apoptosis caused by cerebral infarction or OGD (P < 0.05 or P < 0.01). In brain cortex of the rat model, TCZ up-regulated Bcl-xL and down-regulated Caspase 3, consistent with the inhibited cell apoptosis. It also promoted tyrosine 705 phosphorylation of STAT3, which might be the potential regulatory mechanism of TCZ in neuronal cells. This study provided evidence for the protective role of TCZ against neuronal cell apoptosis in cerebral infarction. Based on these fundamental data, TCZ is a promising option for treating cerebral infarction, but further investigations on related mechanisms are still necessary. PMID- 26773189 TI - Ukrain (NSC 631570) ameliorates intestinal ischemia-reperfusion-induced acute lung injury by reducing oxidative stress. AB - Intestinal ischemia-reperfusion (I/R) causes severe destruction in remote organs. Lung damage is a frequently seen complication after intestinal I/R. Ukrain (NSC 631570) is a synthetic thiophosphate derivative of alkaloids from the extract of the celandine (Chelidonium majus L.) plant. We investigated the effect of Ukrain in animals with lung injury induced by intestinal I/R. Adult male Spraque-Dawley rats were randomly divided into four groups: control, Ukrain, I/R, I/R with Ukrain. Before intestinal I/R was induced, Ukrain was administered intraperitoneally at a dose of 7.0 mg/body weight. After 1 h ischemia and 2 h reperfusion period, lung tissues were excised. Tissue levels of total oxidative status (TOS), total antioxidant status (TAS) were measured and oxidative stress indices (OSI) were calculated. Lung tissues were also examined histopathologically. TOS and OSI levels markedly increased and TAS levels decreased in the I/R group compared to the control group (P < 0.05). TOS and OSI levels markedly decreased and TAS levels increased in the I/R with Ukrain group compared with the group subjected to IR only (P < 0.05). Severe hemorrhage, alveolar septal thickening, and leukocyte infiltration were observed in the I/R group. In the I/R with Ukrain group, morphologic changes occurring as a result of lung damage attenuated and histopathological scores reduced compared to the I/R group (P < 0.05). Our results suggest that Ukrain pretreatment could reduce lung injury induced by intestinal I/R induced via anti-inflammatory and antioxidant effects. PMID- 26773190 TI - Elevation of HLA-G-expressing DC-10 cells in patients with gastric cancer. AB - DC-10 is a distinct subset of human tolerogenic dendritic cells (DCs) which express high levels of human leukocyte antigen-G (HLA-G). DC-10 could induce adaptive type 1 regulatory T cells through the IL-10 dependent ILT4/HLA-G signaling pathway. However, the significance of DC-10 in malignancies remains unclear. In this study, the frequency and mean fluorescence intensity (MFI) of HLA-G+ DC-10 in the peripheral blood of 124 patients with gastric cancer (GC) and 130 normal controls was analyzed with flow cytometry. Plasma sHLA-G was analyzed with ELISA. Results showed both the percentages of peripheral HLA-G+ DC-10 (median: 0.13% vs 0.01%; p<0.01) and MFI of HLA-G on these cells (median: 310.0 vs 91.5; p<0.01) were dramatically increased in GC patients than in normal controls. The frequency of HLA-G+ DC-10 in GC patients was strongly relative to the tumor grade (p=0.021). sHLA-G levels in GC patients were significantly higher than in healthy controls (median: 85.80U/ml vs 61.20U/ml; p<0.01). There was no significant correlation between the percentage of DC-10 and plasma sHLA-G (p>0.05). However, the increased HLA-G+ DC-10, HLA-G MFI and plasma sHLA-G in patients with gastric cancer could be a diagnostic factor with the area under the ROC curve with 0.947 (p<0.01), 0.882 (p<0.01) and 0.700 (p<0.01) respectively. Given the immune tolerant function of DC-10 could play, the increased DC-10 might play an important role in immune suppression for patients with gastric cancer, while more studies are necessary to illustrate the clinical relevance of DC-10 in cancer patients. PMID- 26773192 TI - Vascular endothelial growth factor pathway in endometriosis: genetic variants and plasma biomarkers. AB - OBJECTIVE: To study single nucleotide polymorphisms (SNPs) involved in angiogenesis (VEGF, PLGF, VEGFR1, VEGFR2, HIF-1alpha) and plasma levels of the corresponding proteins (VEGF, PLGF, sVEGFR1, sVEGFR2) in women with and without endometriosis. DESIGN: Allele frequencies of vascular endothelial growth factor (VEGF) pathway SNPs and plasma levels of the corresponding proteins were investigated in patients with endometriosis and in controls. SETTING: University hospital. PATIENT(S): Samples of DNA from 1,931 Caucasian patients were included (1,109 patients with endometriosis and 822 controls). An additional study group included 973 DNA samples from volunteers, self-reported to be healthy without laparoscopic evaluation. INTERVENTION(S): Women who underwent a laparoscopy for subfertility and/or pain and healthy volunteers without laparoscopic evaluation. MAIN OUTCOME MEASURE(S): Functional SNPs of the VEGF, VEGFR1, VEGFR2, HIF-1alpha genes and Hap Map tagging SNPs of the PLGF gene were genotyped by using iPLEX technology on a Sequenom MassArray and TaqMan SNP Genotyping Assay. The VEGF levels were determined in ethylenediaminetetraacetic acid plasma samples by using Bio-Plex Protein Array System. PLGF, sVEGFR1, and sVEGFR2 levels were measured in ethylenediaminetetraacetic acid plasma samples by using ELISA Quantikine kits. RESULT(S): A significant association was found between the rs2268613 polymorphism in the PLGF gene and PLGF plasma levels. In all study subjects, women with the AA variant of the rs2268613 PLGF gene had significantly lower PLGF plasma levels (median [interquartile range] 9.36 [8.19-10.43] pg/mL) than those with the AG variant (12.1 [11.81-20.84] pg/mL; P(a)=.0085, P(b)=.04), both before and after multiple testing. Plasma levels of VEGF were elevated in endometriosis patients (especially in minimal-mild endometriosis during the menstrual cycle phase) compared with laparoscopic controls but had a moderate diagnostic performance (area under the curve, 0.73) in this discovery dataset. At a cut-off plasma level of VEGF >3.88 pg/mL, minimal-mild stages of endometriosis were diagnosed with a sensitivity of 74% and a specificity of 80% during the menstrual phase of cycle. The associations between the presence of endometriosis and SNPs in PLGF (rs2268614), HIF-1alpha (rs11549465), and VEGFR1 (rs9582036) genes lost statistical significance after multiple testing. CONCLUSION(S): Genetic variants in the PLGF rs2268613 gene may influence plasma levels of the corresponding protein. Plasma levels of VEGF were elevated in endometriosis patients compared with controls. The associations between the presence of endometriosis and SNPs in PLGF (rs2268614), HIF-1alpha (rs11549465), and VEGFR1 (rs9582036) genes lost statistical significance after multiple testing. PMID- 26773191 TI - Differences in infant feeding practices by mode of conception in a United States cohort. AB - OBJECTIVE: To identify associations between fertility treatment use (assisted reproductive technologies, ovulation induction, and artificial insemination) and subsequent infant feeding practices. DESIGN: The Upstate KIDS population-based cohort enrolled mothers who delivered live births in New York (2008-2010), sampling on fertility treatment and plurality. SETTING: Not applicable. PATIENT(S): Data regarding singletons and one randomly selected infant between twins were used. INTERVENTION(S): Not applicable. MAIN OUTCOME MEASURE(S): Mothers reported breast feeding and formula feeding practices at 4, 8, and 12 months postpartum. Modified Poisson regression was used to compare risks for feeding practices by mode of conception. Marginal structural models were used to estimate the controlled direct effects of fertility treatment on feeding, independent of preterm birth. RESULT(S): Among 4,591 mothers, 1,361 (30%) conceived with the use of fertility treatments. Mothers who used fertility treatments were less likely to breast feed to 12 months after birth and were more likely to provide formula, solids, and juice by 4 months than mothers who did not conceive with treatments. Fertility treatment remained associated with breast feeding cessation and formula feeding in mediation analyses, suggesting that preterm birth does not fully explain these associations. CONCLUSION(S): Women who conceived with the use of fertility treatments were less likely to breast feed later in infancy and were more likely to provide formula, solids, and juice earlier in infancy. Our analyses accounted for confounding and preterm birth, but other contributing factors may include difficulties feeding twins or workplace breast feeding accommodations. PMID- 26773193 TI - Oocyte vitrification for elective fertility preservation: lessons for patient counseling. PMID- 26773194 TI - Reconstructive tubal microsurgery and assisted reproductive technology. PMID- 26773195 TI - Unilateral giant hypertrophy of the lamina and spinous process of the C5 vertebra presenting with chronic cervical pain. PMID- 26773196 TI - Sacral epidural chordoma. PMID- 26773197 TI - A response to Jepsen et al. (2016). AB - Important findings, e.g. in ecology, should be questioned and debated. Our findings that defoliating looper outbreaks travel as waves across Europe and the response here to such a questioning could be a start of a debate (photo: winter moth carterpillar). PMID- 26773199 TI - (II) Physiological profiling of an endogenous peptide in the basal forebrain: Age related bioactivity and blockade with a novel modulator. AB - Previous studies have suggested that neurodegeneration is an aberrant form of development, mediated by a novel peptide from the C-terminus of acetylcholinesterase (AChE). Using voltage-sensitive dye imaging we have investigated the effects of a synthetic version of this peptide in the in vitro rat basal forebrain, a key site of degeneration in Alzheimer's disease. The brain slice preparation enables direct visualisation in real-time of sub-second meso scale neuronal coalitions ('Neuronal Assemblies') that serve as a powerful index of brain functional activity. Here we show that (1) assemblies are site-specific in their activity profile with the cortex displaying a significantly more extensive network activity than the sub-cortical basal forebrain; (2) there is an age-dependency, in both cortical and sub-cortical sites, with the younger brain (p14 rats) exhibiting more conspicuous assemblies over space and time compared to their older counterparts (p35-40 rats). (3) AChE-derived peptide significantly modulates the dynamics of neuronal assemblies in the basal forebrain of the p14 rat with the degree of modulation negatively correlated with age, (4) the differential in assembly size with age parallels the level of endogenous peptide in the brain, which also declines with maturity, and (5) this effect is completely reversed by a cyclised variant of AChE-peptide, 'NBP14'. These observations are attributed to an enhanced calcium entry that, according to developmental stage, could be either trophic or toxic, and as such may provide insight into the basic neurodegenerative process as well as an eventual therapeutic intervention. PMID- 26773198 TI - Functional regulation of PI3K-associated signaling in the accumbens by binge alcohol drinking in male but not female mice. AB - It is well established that binge alcohol consumption produces alterations in Group 1 metabotropic glutamate receptors (mGlus) and related signaling cascades in the nucleus accumbens (NAC) of adult male mice, but female and adolescent mice have not been examined. Thus, the first set of studies determined whether repeated binge alcohol consumption produced similar alterations in protein and mRNA levels of Group 1 mGlu-associated signaling molecules in the NAC of male and female adult and adolescent mice. The adult (9 weeks) and adolescent (4 weeks) C57BL/6J mice were exposed to 7 binge alcohol sessions every 3rd day while controls drank water. Repeated binge alcohol consumption produced sexually divergent changes in protein levels and mRNA expression for Group 1 mGlus and downstream signaling molecules in the NAC, but there was no effect of age. Binge alcohol intake decreased mGlu5 levels in females, whereas it decreased indices of phosphoinositide 3-kinase (PI3K), mammalian target of rapamycin (mTOR), 4E binding protein 1, and p70 ribosomal protein S6 kinase in males. Expression of genes encoding mGlu1, mGlu5, the NR2A subunit of the NMDA receptor, and Homer2 were all decreased by binge alcohol consumption in males, while females were relatively resistant (only phosphoinositide-dependent protein kinase 1 was decreased). The functional implication of these differences was investigated in a separate study by inhibiting mTOR in the NAC (via infusions of rapamycin) before binge drinking sessions. Rapamycin (50 and 100 ng/side) significantly decreased binge alcohol consumption in males, while consumption in females was unaffected. Altogether these results highlight that mTOR signaling in the NAC was necessary to maintain binge alcohol consumption only in male mice and that binge drinking recruits sexually divergent signaling cascades downstream of PI3K and presumably, Group 1 mGlus. Importantly, these findings emphasize that sex should be considered in the development of potential pharmacotherapeutic targets. PMID- 26773200 TI - D5 receptor agonist 027075 promotes cognitive function recovery and neurogenesis in a Abeta1-42-induced mouse model. AB - In this study, a high throughput screening system was set up to identify D5 receptor agonists-027075. Then, a series of behavior tests were used to evaluate the beneficial effects of 027075 in Abeta1-42-induced mice model including morris water maze, passive avoidance, active avoidance, open field and step-down test. The neuroprotective effect of 027075 was assessed by a high content screening in vitro. In behavior tests, the cognitive function impairment caused by Abeta1-42 was significantly ameliorated by 027075 in a dose-dependent manner. 027075 (8 mg/kg) significantly prolonged the time spent in the target quadrant when compared to the model group in morris water maze test. The latency was significantly increased and the number of errors was decreased in both passives avoidance task and step down test when compared to the model group. In active avoidance and open field test, latency, stimulation time, number of errors were significantly reduced, while number of avoidance and line crossing and central distance were increased by 027075 (8 mg/kg). All the results above was significantly reversed by 027075-H + SCH39166 (5 mg/kg) when compared to 027075-H (8 mg/kg). The neuroprotective effect of 027075 was demonstrated by promotion of cell differentiation and extension of neurite length. But the effects were abrogated by the specific D1/D5 antagonist, SCH39166. These results indicate that D5 receptor might be used as an ideal target for the treatment of AD and its agonists might become a new AD drugs in the future. PMID- 26773201 TI - Dynamic mass redistribution reveals diverging importance of PDZ-ligands for G protein-coupled receptor pharmacodynamics. AB - G protein-coupled receptors (GPCRs) are essential membrane proteins that facilitate cell-to-cell communication and co-ordinate physiological processes. At least 30 human GPCRs contain a Type I PSD-95/DLG/Zo-1 (PDZ) ligand in their distal C-terminal domain; this four amino acid motif of X-[S/T]-X-[phi] sequence facilitates interactions with PDZ domain-containing proteins. Because PDZ protein interactions have profound effects on GPCR ligand pharmacology, cellular localization, signal-transduction effector coupling and duration of activity, we analyzed the importance of Type I PDZ ligands for the function of 23 full-length and PDZ-ligand truncated (DeltaPDZ) human GPCRs in cultured human cells. SNAP epitope tag polyacrylamide gel electrophoresis revealed most Type I PDZ GPCRs exist as both monomers and multimers; removal of the PDZ ligand played minimal role in multimer formation. Additionally, SNAP-cell surface staining indicated removal of the PDZ ligand had minimal effects on plasma membrane localization for most GPCRs examined. Label-free dynamic mass redistribution functional responses, however, revealed diverging effects of the PDZ ligand. While no clear trend was observed across all GPCRs tested or even within receptor families, a subset of GPCRs displayed diminished agonist efficacy in the absence of a PDZ ligand (i.e. HT2RB, ADRB1), whereas others demonstrated enhanced agonist efficacies (i.e. LPAR2, SSTR5). These results demonstrate the utility of label-free functional assays to tease apart the contributions of conserved protein interaction domains for GPCR signal-transduction coupling in cultured cells. PMID- 26773203 TI - The contribution of pathways initiated via the Gq?11 G-protein family to atrial fibrillation. AB - Atrial fibrillation is the commonest cardiac arrhythmia and leads to significant clinical morbidity and mortality. It has a complex pathophysiology but is often initiated by atrial ectopic beats and because of atrial remodelling once it occurs it can become established. Thus therapeutic interventions designed to prevent the initial occurrence of the arrhythmia are particularly needed. At the cellular level, these ectopic beats arise because of abnormal calcium release events from the sarcoplasmic reticulum leading to an inward current mediated by the sodium-calcium exchanger. There has been considerable interest in this over the last few years largely focused on the ryanodine receptor and related signalling pathways. However, atrial myocytes also possess a well-developed inositol trisphosphate (IP3) dependent calcium release system and this has been less studied. In this review we focus on pathways and molecules that couple via the Gq?11 family of G-proteins including regulators of G-protein signalling that may influence IP3 mediated calcium release and atrial fibrillation. PMID- 26773204 TI - Post-bariatric abdominoplasty resulting in wound infection and dehiscence Conservative treatment with medical grade honey: A case report and review of literature. AB - INTRODUCTION: Wound complications in post-bariatric patients undergoing body contouring surgery after massive weight loss are not uncommon and often, surgical debridement or conservative management is necessary. Honey is one of the most ancient remedies for wound care and it is also considered to possess debriding effects. Current research has demonstrated promising results showing that honey can improve wound granulation and epithelialization, reduce exudate and shorten healing times. METHODS: This case report has been reported in line with the CARE criteria. PRESENTATION OF CASE: A 40 year-old female suffered wound infection and dehiscence after undergoing post-bariatric abdominoplasty. The patient was not interested in surgical revision and split skin grafting. Therefore, conservative wound treatment with topical Manuka honey was instituted resulting in significant clinical improvement and effective healing concurrently with good patient satisfaction. DISCUSSION: Surgical wound complications in post-bariatric patients undergoing abdominoplasty are common and often require surgical revision or conservative wound treatment. No previous publication has addressed outpatient treatment of post-bariatric abdominoplasty wound complications with medical grade honey. CONCLUSION: Although more research is needed for definitive conclusions of honey's efficacy, it is safe and as presented in our case, it may under certain circumstances reduce the need of surgical wound debridement and serve as a remedy for conservative treatment. PMID- 26773205 TI - A rare anomaly of left renal vein drainage into the left common iliac vein: A case report. AB - INTRODUCTION: Herein, we describe a case of sigmoid colon cancer with a rare anomaly of the left renal vein located between the inferior mesenteric artery (IMA) and the left common iliac artery. CASE PRESENTATION: A 57-year-old woman with sigmoid colon cancer underwent three-dimensional computed tomography angiography for a preoperative assessment; the results revealed a rare variant of the left renal vein. There were two left renal veins: one retroaortically drained into the inferior vena cava, and the other was located between the IMA and the left common iliac artery and drained into the left common iliac vein. Laparoscopic sigmoid colectomy was performed safely while carefully avoiding any injury to the left renal vein located posterior to the IMA. DISCUSSION: Several variations of the left renal vein have been reported, such as retroaortic or circumaortic left renal veins. The variants of renal vessels, which are frequently overlooked in the preoperative assessment, is rarely affected in colorectal surgery. However, if the surgeon is unaware of such renal vessel anomalies, an injury can occur, resulting in severe bleeding. CONCLUSION: It is important that surgeons identify retroperitoneal vessel variants before performing colorectal surgery. PMID- 26773206 TI - Dispositional Anxiety and Frontal-Midline Theta: On the Modulatory Influence of Sex and Situational Threat. AB - In their adaptive control hypothesis, Cavanagh and Shackman (2015) recently claimed that dispositional anxiety is correlated with frontal-midline theta (FMtheta) as a generic "need for control" signal of the anterior midcingulate cortex. Here, we tested this assumption, also considering potential modulatory influences of anticipatory threat and individuals' sex. In a nonclinical sample of 168 participants (84 women), electroencephalogram was recorded while individuals performed a simple two-choice task. Half of the participants were assigned to a threat anticipation condition (anticipation of public speaking), whereas the other half was assigned to a control condition. State anxiety was monitored across the experiment. Dispositional anxiety was assessed by self report scales, which were completed before individuals came to the laboratory. Target stimuli in the two-choice task induced a transient increase in FMtheta power that was subject to an interaction of dispositional anxiety, sex, and experimental group. Only in women who anticipated public speaking did we observe a substantial positive relation between dispositional anxiety and general FMtheta power. Our results indicate that the link between dispositional anxiety and FMtheta is not universal but rather depends on complex interactions of individuals' sex and situational threat. PMID- 26773202 TI - UGT genotyping in belinostat dosing. AB - Certain genetic polymorphisms of UDP glucuronosyltransferase 1 family, polypeptide A1 (UGT1A1) can reduce gene expression (*28, *60, *93) or activity (*6), thereby altering the pharmacokinetics, pharmacodynamics, and the risk of toxicities of UGT1A1 substrates, of which irinotecan is a widely-described example. This review presents an overview of the clinical effects of UGT1A1 polymorphisms on the pharmacology of UGT1A1 substrates, with a special focus on the novel histone deacetylase inhibitor belinostat. Belinostat, approved for the treatment of peripheral T-cell lymphoma, is primarily glucuronidated by UGT1A1. Recent preclinical and clinical data showed that UGT1A1*28 was associated with reduced glucuronidation in human liver microsomes, while in a retrospective analysis of a Phase I trial with patients receiving belinostat UGT1A1*60 was predominantly associated with increased belinostat plasma concentrations. Furthermore, both UGT1A1*28 and *60 variants were associated with increased incidence of thrombocytopenia and neutropenia. Using population pharmacokinetic analysis a 33% dose reduction has been proposed for patients carrying UGT1A1 variant alleles. Clinical effects of this genotype-based dosing recommendation is currently prospectively being investigated. Overall, the data suggest that UGT1A1 genotyping is useful for improving belinostat therapy. PMID- 26773207 TI - Letter to the Editor. PMID- 26773208 TI - The xanthophyll cycle pigments, violaxanthin and zeaxanthin, modulate molecular organization of the photosynthetic antenna complex LHCII. AB - The effect of violaxanthin and zeaxanthin, two main carotenoids of the xanthophyll cycle, on molecular organization of LHCII, the principal photosynthetic antenna complex of plants, was studied in a model system based on lipid-protein membranes, by means of analysis of 77 K chlorophyll a fluorescence and "native" electrophoresis. Violaxanthin was found to promote trimeric organization of LHCII, contrary to zeaxanthin which was found to destabilize trimeric structures. Moreover, violaxanthin was found to induce decomposition of oligomeric LHCII structures formed in the lipid phase and characterized by the fluorescence emission band at 715 nm. Both pigments promoted formation of two component supramolecular structures of LHCII and xanthophylls. The violaxanthin stabilized structures were composed mostly of LHCII trimers while, the zeaxanthin stabilized supramolecular structures of LHCII showed more complex organization which depended periodically on the xanthophyll content. The effect of the xanthophyll cycle pigments on molecular organization of LHCII was analyzed based on the results of molecular modeling and discussed in terms of a physiological meaning of this mechanism. Supramolecular structures of LHCII stabilized by violaxanthin, prevent uncontrolled oligomerization of LHCII, potentially leading to excitation quenching, therefore can be considered as structures protecting the photosynthetic apparatus against energy loses at low light intensities. PMID- 26773209 TI - Explaining the relationship between number line estimation and mathematical achievement: The role of visuomotor integration and visuospatial skills. AB - Performance on number line tasks, typically used as a measure of numerical representations, are reliably related to children's mathematical achievement. However, recent debate has questioned what precisely performance on the number line estimation task measures. Specifically, there has been a suggestion that this task may measure not only numerical representations but also proportional judgment skills; if this is the case, then individual differences in visuospatial skills, not just the precision of numerical representations, may explain the relationship between number line estimation and mathematical achievement. The current study investigated the relationships among visuospatial skills, visuomotor integration, number line estimation, and mathematical achievement. In total, 77 children were assessed using a number line estimation task, a standardized measure of mathematical achievement, and tests of visuospatial skills and visuomotor integration. The majority of measures were significantly correlated. In addition, the relationship between one metric from the number line estimation task (R(2)LIN) and mathematical achievement was fully explained by visuomotor integration and visuospatial skill competency. These results have important implications for understanding what the number line task measures as well as the choice of number line metric for research purposes. PMID- 26773210 TI - New C-methylated flavonoids and alpha-pyrone derivative from roots of Talinum triangulare growing in Nigeria. AB - The first chemical examination of roots of the traditionally used medicinal plant Talinum triangulare (Portulacaceae) from Nigeria led to the isolation of two new C-methylated flavonoids, 5,6-dimethoxy-7-hydroxy-8-methyl-flavone (1), 5,6 dimethoxy-8-methyl-2-phenyl-7H-1-benzopyran-7-one (2), and one new alpha-pyrone derivative, 4-methoxy-6-(2-hydroxy-4-phenylbutyl)-2H-pyran-2-one (3), along with thirteen known compounds, including nine amides (4-12), indole-3-carboxylic acid (13), p-hydroxy benzoic acid (14), and two steroids (15-16). Their structures were elucidated by extensive spectroscopic measurements including 1D, 2D NMR, MS, and by comparison with the literature. All isolated compounds were screened for their cytotoxic and antifungal activities. However, none of them showed significant activity. PMID- 26773212 TI - MicroRNAs: Non-coding fine tuners of receptor tyrosine kinase signalling in cancer. AB - Emerging evidence point to a crucial role for non-coding RNAs in modulating homeostatic signaling under physiological and pathological conditions. MicroRNAs, the best-characterized non-coding RNAs to date, can exquisitely integrate spatial and temporal signals in complex networks, thereby confer specificity and sensitivity to tissue response to changes in the microenvironment. MicroRNAs appear as preferential partners for Receptor Tyrosine Kinases (RTKs) in mediating signaling under stress conditions. Stress signaling can be especially relevant to disease. Here we focus on the ability of microRNAs to mediate RTK signaling in cancer, by acting as both tumor suppressors and oncogenes. We will provide a few general examples of microRNAs modulating specific tumorigenic functions downstream of RTK signaling and integrate oncogenic signals from multiple RTKs. A special focus will be devoted to epidermal growth factor receptor (EGFR) signaling, a system offering relatively rich information. We will explore the role of selected microRNAs as bidirectional modulators of EGFR functions in cancer cells. In addition, we will present the emerging evidence for microRNAs being specifically modulated by oncogenic EGFR mutants and we will discuss how this impinges on EGFRmut driven chemoresistance, which fits into the tumor heterogeneity-driven cancer progression. Finally, we discuss how other non-coding RNA species are emerging as important modulators of cancer progression and why the scenario depicted herein is destined to become increasingly complex in the future. PMID- 26773213 TI - Resetting the epigenome for heart regeneration. AB - In contrast to adults, recent evidence suggests that neonatal mice are able to regenerate following cardiac injury. This regenerative capacity is reliant on robust induction of cardiomyocyte proliferation, which is required for faithful regeneration of the heart following injury. However, cardiac regenerative potential is lost as cardiomyocytes mature and permanently withdraw from the cell cycle shortly after birth. Recently, a handful of factors responsible for the regenerative disparity between the adult and neonatal heart have been identified, but the proliferative response of adult cardiomyocytes following modulation of these factors rarely reaches neonatal levels. The inefficient re-induction of proliferation in adult cardiomyocytes may be due to the epigenetic landscape, which drastically changes during cardiac development and maturation. In this review, we provide an overview of the role of epigenetic modifiers in developmental processes related to cardiac regeneration. We propose an epigenetic framework for heart regeneration whereby adult cardiomyocyte identity requires resetting to a neonatal-like state to facilitate cell cycle re-entry and regeneration following cardiac injury. PMID- 26773211 TI - Feedback regulation of G protein-coupled receptor signaling by GRKs and arrestins. AB - GPCRs are ubiquitous in mammalian cells and present intricate mechanisms for cellular signaling and communication. Mechanistically, GPCR signaling was identified to occur vectorially through heterotrimeric G proteins that are negatively regulated by GRK and arrestin effectors. Emerging evidence highlights additional roles for GRK and Arrestin partners, and establishes the existence of interconnected feedback pathways that collectively define GPCR signaling. GPCRs influence cellular dynamics and can mediate pathologic development, such as cancer and cardiovascular remolding. Hence, a better understanding of their overall signal regulation is of great translational interest and research continues to exploit the pharmacologic potential for modulating their activity. PMID- 26773214 TI - Too much of a good thing: regulated depletion of c-di-AMP in the bacterial cytoplasm. AB - Bacteria that synthesize c-di-AMP also encode several mechanisms for controlling c-di-AMP levels within the cytoplasm. One major class of phosphodiesterases comprises GdpP and DhhP homologs, which degrade c-di-AMP into the linear molecule 5'-pApA or AMP by the DHH-DHHA1 domain. The other major class comprises PgpH homologs, which degrade c-di-AMP by the HD domain. Both GdpP and PgpH harbor sensory domains, likely to regulate c-di-AMP hydrolysis activity in response to signal input. As another possible mechanism for controlling cytoplasmic c-di-AMP levels, bacteria also secrete c-di-AMP via multidrug resistance transporters, as demonstrated for Listeria monocytogenes. Mutants that accumulate high c-di-AMP levels, by deletion of phosphodiesterases or multidrug resistance transporters, exhibit aberrant physiology, growth defects, and attenuated virulence in infection. PMID- 26773215 TI - A Systematic Review of Animal-Assisted Therapy on Psychosocial Outcomes in People with Intellectual Disability. AB - The aim of the study was to review the literature on animal assisted therapy (AAT) in people with intellectual disabilities (ID) measuring psychosocial outcomes (behavioural, social, cognitive and emotional). Quantitative studies were found through a systematic search that identified studies using AAT in people with ID and measuring psychosocial outcomes (behavioural, cognitive, emotional and social). The quality of studies was assessed using a standardised tool and rated as strong, moderate or weak. Only published articles from peer reviewed journals were included. No language or age restrictions were applied. Over half of the included studies were identified outside standard database searches (e.g. hand searching reference lists from included articles, references from AAT websites and using Google Scholar and a Grey Literature Database). Ten studies were included in the final review; two were rated as moderate quality and eight were rated as weak quality. Overall there was a positive improvement reported from studies for all psychosocial outcomes (with some cognitive, behavioural, social, emotional components reaching statistical significance p <= 0.01). Despite having no age restrictions, the included studies had participants that were mainly children and adolescents, in particular favouring male participants, which may limit generalisation. More rigorous methodology is required to improve the quality of future studies including in the main multicentre randomised designs and improved reporting according to CONSORT criteria. Further research should expand to include adults with ID and specific disorders such as challenging behaviour or mental illness. PMID- 26773216 TI - Specific language impairment and developmental dyslexia: What are the boundaries? Data from Greek children. AB - This study examines the significance (between-groups comparisons) and frequency (within-group analyses) of deficits in developmental dyslexia (DD, mainly deficits in decoding and phonemic awareness), specific language impairment (SLI, mainly deficits in listening comprehension), or both (mainly deficits in phonological short-term memory [STM]). Participants included two groups of children who had received a diagnosis of either SLI (N=15) or DD (N=15). For the between-groups comparison, the groups were matched pairwise on nonverbal IQ to 30 chronological age controls (CAC) and 30 reading level controls (RLC). For the within-group analyses, the participants were compared to 91 CACs and 63 RLCs. We developed tasks not used for the diagnoses to assess phonological skills (decoding, phonemic awareness, phonological STM) and non-phonological skills (listening and reading comprehension). SLI children scored lower than both DD children and RLCs on tasks assessing listening and reading comprehension, and lower than RLCs on phonological STM and phonemic awareness. Within-group comparisons showed that a higher proportion of SLI than DD children presented severe deficits in the same four domains. The opposite pattern was found for decoding skills (7 SLI children with a severe deficit, versus 13 in the DD group). These findings are discussed in the light of models explaining the overlap between SLI and DD. They highlight the need to assess both phonological and non-phonological skills in SLI and DD children, using both between- and within-groups designs. PMID- 26773217 TI - The role of social cognition and prosocial behaviour in relation to the socio emotional functioning of primary aged children with specific language impairment. AB - BACKGROUND AND AIMS: Children with language impairments often experience difficulties with their socio-emotional functioning and poorly developed prosocial behaviour. However, the nature of the association between language impairment and difficulties with socio-emotional functioning remains unclear. The social cognition skills of a group of primary-aged children (6-11 years old) with Specific Language Impairment (SLI) were examined in relation to their teachers' ratings of socio-emotional functioning. SAMPLE: Forty-two children with SLI were individually matched with 42 children for chronological age and non-verbal cognitive ability, and 42 children for receptive language ability. The children all attended mainstream primary schools or one Language Unit. METHODS: Four aspects of social cognition were directly assessed: emotion identification, emotion labelling, inferring the causes of emotions, and knowledge of conflict resolution strategies. The children's socio-emotional functioning was assessed using the Strengths and Difficulties questionnaire (SDQ), a standardised measure, completed by their teachers. Associations between children's performance on tasks of social cognition and children's socio-emotional functioning were explored. RESULTS: Significant group differences were found for all social cognition tasks. The SLI group was rated to experience significantly more problems with socio emotional functioning by their teachers than both control groups, indicating problems with all aspects of socio-emotional functioning. Social cognition and prosocial behaviour, but not language ability, predicted teacher-rated behavioural, emotional and social difficulties for the SLI group. CONCLUSION: The results challenge current understanding of socio-emotional functioning in children with SLI by pointing to the crucial role of social cognition and prosocial behaviour. Factors other than expressive and receptive language play a role in the socio-emotional functioning of children with SLI. PMID- 26773219 TI - Application of CdSe quantum dots for the direct detection of TNT. AB - CdSe quantum dots were synthesized through a simple, green organic-phase method. Paraffin was used as the reaction solvent and a reducing agent, oleic acid was the reaction ligand, and oleyl amine was the stabilizer. Based on the phenomenon of TNT quenched oil-soluble CdSe quantum dot fluorescence, a simple, fast, and direct method of TNT detection was established. Under optimum conditions, the degree of fluorescence quenching of oil-soluble CdSe quantum dots had a good linear correlation with TNT concentration in the 1.0*10(-7)-5.0*10(-5) mol/L range, and the correlation coefficient was 0.9990. TNT detection limit was 2.1*10(-8)mol/L. The method was successfully used to determine TNT-explosion dust samples, results were satisfactory. The fluorescence quenching mechanism of oil soluble CdSe quantum dots by TNT was also discussed. PMID- 26773218 TI - A regional method for craniofacial reconstruction based on coordinate adjustments and a new fusion strategy. AB - Craniofacial reconstruction recreates a facial outlook from the cranium based on the relationship between the face and the skull to assist identification. But craniofacial structures are very complex, and this relationship is not the same in different craniofacial regions. Several regional methods have recently been proposed, these methods segmented the face and skull into regions, and the relationship of each region is then learned independently, after that, facial regions for a given skull are estimated and finally glued together to generate a face. Most of these regional methods use vertex coordinates to represent the regions, and they define a uniform coordinate system for all of the regions. Consequently, the inconsistence in the positions of regions between different individuals is not eliminated before learning the relationships between the face and skull regions, and this reduces the accuracy of the craniofacial reconstruction. In order to solve this problem, an improved regional method is proposed in this paper involving two types of coordinate adjustments. One is the global coordinate adjustment performed on the skulls and faces with the purpose to eliminate the inconsistence of position and pose of the heads; the other is the local coordinate adjustment performed on the skull and face regions with the purpose to eliminate the inconsistence of position of these regions. After these two coordinate adjustments, partial least squares regression (PLSR) is used to estimate the relationship between the face region and the skull region. In order to obtain a more accurate reconstruction, a new fusion strategy is also proposed in the paper to maintain the reconstructed feature regions when gluing the facial regions together. This is based on the observation that the feature regions usually have less reconstruction errors compared to rest of the face. The results demonstrate that the coordinate adjustments and the new fusion strategy can significantly improve the craniofacial reconstructions. PMID- 26773220 TI - Right heart ischemia in cases of sepsis. AB - Data from the literature suggest that cases of sepsis complicated by right ventricular (RV) dysfunction have poorer prognosis. In these cases progressive hypoperfusion associated to increasing, injury-related, pulmonary vascular resistance account for RV ischemia. In the present analysis, we wanted to evaluate whether prevalent RV cardiac ischemic damage could be detected in a series of fatal sepsis cases. We retrospectively investigated 20 cases of sepsis that underwent forensic autopsy (study group-11?, 9?, mean age 57 years) and compared them to a group of 20 cases of hanging (hanging group-4 ?, 16 ?, mean age 44 years) as well as to a group of 20 cases of myocardial infarction (MI group-9 ?, 11 ?, mean age 65 years), as examples of cardiac damage due to global hypoxia during agony and ischemic damage, respectively. We performed immunohistochemistry with the antibodies anti-fibronectin and C5b-9. The reactions were semiquantitively classified and the groups were compared. In 30% of the cases of sepsis prevalent RV ischemic damage could be detected with the antibody anti-fibronectin. This expression was significantly different from that observed in cases of MI (p=0.028) and hanging (p<0.001). Our study showed that, in cases of fatal sepsis, prevalent RV ischemic damage occurred in a substantial minority of cases. PMID- 26773221 TI - Evidence based decontamination protocols for the removal of external Delta9 tetrahydrocannabinol (THC) from contaminated hair. AB - External contamination can cause false positive results in forensic hair testing for drugs of abuse and is therefore a major concern when hair evidence is used in court. Current literature about decontamination strategies is mainly focused on external cocaine contamination and no consensus on the best decontamination procedure for hair samples containing cannabinoids has been reached so far. In this study, different protocols with solvents, both organic as well as aqueous, were tested on blank and drug user hair for their performance on removing external cannabis contamination originating from either smoke or indirect contact with cannabis plant material. Smoke contamination was mimicked by exposing hair samples to smoke from a cannabis cigarette and indirect contact contamination by handling hair with cannabis contaminated gloves or hands. Delta9 tetrahydrocannabinol (THC) levels in the hair samples and wash solvents were determined using liquid chromatography tandem mass spectrometry (LC-MS/MS) analysis. Aqueous surfactant solutions removed more THC contamination compared to water, but much less than organic solvents. Methanol, dichloromethane and chloroform were most efficient in removing THC contamination. Due to its lower environmental impact, methanol was chosen as the preferred decontamination solvent. After testing of different sequential wash steps on externally contaminated blank hair, three protocols performed equally well, removing all normal level and more than 99% of unrealistically high levels of external cannabis contamination. Thorough testing on cannabis users' hair, both as such and after deliberate contamination, showed that using these protocols all contamination could be washed from the hair while no incorporated THC was removed from truly positive samples. The present study provides detailed scientific evidence in support of the recommendations of the Society of Hair Testing: a protocol using a single methanol wash followed by a single aqueous SDS solution wash, followed by a Milli-Q water rinsing step, is suggested as the preferred decontamination protocol to remove external cannabis contamination from hair while preserving the incorporated compounds. PMID- 26773222 TI - Determination of safety margins for whole blood concentrations of alcohol and nineteen drugs in driving under the influence cases. AB - Legislative limits for driving under the influence of 20 non-alcohol drugs were introduced in Norway in February 2012. Per se limits corresponding to blood alcohol concentrations (BAC) of 0.2g/kg were established for 20 psychoactive drugs, and limits for graded sanctions corresponding to BACs of 0.5 and 1.2g/kg were determined for 13 of these drugs. This new legislation made it possible for the courts to make sentences based on the analytical results, similar to the situation for alcohol. To ensure that the reported concentration is as least as high as the true concentration, with a 99% safety level, safety margins had to be calculated for each of the substances. Diazepam, tetrahydrocannabinol (THC) and alcohol were used as model substances to establish a new model for estimating the safety margins. The model was compared with a previous used model established several years ago, by a similar yet much simpler model, and they were found to be in agreement. The measurement uncertainties depend on the standard batch used, the work list and the measurements' replicate. A Bayesian modelling approach was used to determine the parameters in the model, using a dataset of 4700 diazepam positive specimens and 5400 THC positive specimens. Different safety margins were considered for low and high concentration levels of diazepam (<=2MUM (0.6mg/L) and >2MUM) and THC (<=0.01MUM (0.003mg/L) and >0.01MUM). The safety margins were for diazepam 19.5% (<=2MUM) and 34% (>2MUM), for THC 19.5% (<=0.01MUM) and 24.9% (>0.01MUM). Concentration dependent safety margins for BAC were based on a dataset of 29500 alcohol positive specimens, and were in the range 10.4% (0.1g/kg) to 4.0% (4.0g/kg) at a 99% safety level. A simplified approach was used to establish safety margins for the compounds amphetamine, MDMA, methamphetamine, alprazolam, phenazepam, flunitrazepam, clonazepam, nitrazepam, oxazepam, buprenorphine, GHB, methadone, ketamine, cocaine, morphine, zolpidem and zopiclone. The safety margins for these drugs were in the range 34-41%. PMID- 26773223 TI - Accuracy of Cameriere's third molar maturity index in assessing legal adulthood on Serbian population. AB - At the moment, a large number of asylum seekers from the Middle East are passing through Serbia. Most of them do not have identification documents. Also, the past wars in the Balkan region have left many unidentified victims and missing persons. From a legal point of view, it is crucial to determine whether a person is a minor or an adult (>=18 years of age). In recent years, methods based on the third molar development have been used for this purpose. The present article aims to verify the third molar maturity index (I3M) based on the correlation between the chronological age and normalized measures of the open apices and height of the third mandibular molar. The sample consisted of 598 panoramic radiographs (290 males and 299 females) from 13 to 24 years of age. The cut-off value of I3M=0.08 was used to discriminate adults and minors. The results demonstrated high sensitivity (0.96, 0.86) and specificity (0.94, 0.98) in males and females, respectively. The proportion of correctly classified individuals was 0.95 in males and 0.91 in females. In conclusion, the suggested value of I3M=0.08 can be used on Serbian population with high accuracy. PMID- 26773224 TI - State of the art in bile analysis in forensic toxicology. AB - In forensic toxicology, alternative matrices to blood are useful in case of limited, unavailable or unusable blood sample, suspected postmortem redistribution or long drug intake-to-sampling interval. The present article provides an update on the state of knowledge for the use of bile in forensic toxicology, through a review of the Medline literature from 1970 to May 2015. Bile physiology and technical aspects of analysis (sampling, storage, sample preparation and analytical methods) are reported, to highlight specificities and consequences from an analytical and interpretative point of view. A table summarizes cause of death and quantification in bile and blood of 133 compounds from more than 200 case reports, providing a useful tool for forensic physicians and toxicologists involved in interpreting bile analysis. Qualitative and quantitative interpretation is discussed. As bile/blood concentration ratios are high for numerous molecules or metabolites, bile is a matrix of choice for screening when blood concentrations are low or non-detectable: e.g., cases of weak exposure or long intake-to-death interval. Quantitative applications have been little investigated, but small molecules with low bile/blood concentration ratios seem to be good candidates for quantitative bile-based interpretation. Further experimental data on the mechanism and properties of biliary extraction of xenobiotics of forensic interest are required to improve quantitative interpretation. PMID- 26773225 TI - Secular trend in the maturation of permanent teeth in a sample of Turkish children over the past 30 years. AB - This study was performed to evaluate the influence of secular trends on dental maturation among Turkish children over the past 30 years. Orthopantomograms of 757 (385 boys, 372 girls) Turkish children born in the 1980s, 1990s, and 2000s were evaluated. Three groups were formed based on decade with five subgroups by age from 9 to 13 years old for each gender. The number of samples in each age group and gender were matched. The mandibular left seven permanent teeth were evaluated based on formation stage to determine the overall dental maturity score. The groups were compared based on decade and gender. The Bonferroni corrected Mann-Whitney U test and Kruskal-Wallis tests were used for statistical evaluation. Among 11-, 12-, and 13-year-olds born in the 2000s, girls exhibited significantly more mature dentition than did boys (p<0.01, p<0.05, and p<0.05, respectively). Twelve-year-old girls born in the 1990s and 2000s exhibited significantly more mature dentition than did girls born in the 1980s (p<0.01). Girls generally exhibited more mature dentition than boys. No significant positive secular trends in dental maturity were observed from the 1980s through the 2000s. Dental maturation among Turkish children was not affected by a secular trend. PMID- 26773227 TI - The determination of alpha- and beta-thujone in human serum - Simple analysis of absinthe congener substance. AB - Absinthe is a strong spirit beverage, mostly green in color, containing besides ethyl alcohol (main component), alcoholic macerate of wormwood and other plants such as star anise and fennel seed. Due to the potential risks associated with the presence of alpha- and beta-thujone many countries have implemented strict rules limiting the content of these congeners in alcohol products. The presented paper describes a simple and sensitive method for the determination of alpha- and beta-thujone in human serum using Solid Phase Extraction as a sample preparation method combined with GC/MS analysis. The procedure involves the protein precipitation process, which generally degrades the protein-analyte complex, and SPE isolation of thujone from the examined materials. The described method is characterized by a low LOD and a very high recovery of the analytes. The present method for the estimation of alpha- and beta-thujone concentration in human fluids after the consumption of alcoholic beverages and other foods containing the substance is applicable in forensic and clinical toxicology because of its simplicity and rapidness with high sensitivity. PMID- 26773226 TI - Simulated radioactive decontamination of biological samples using a portable DNA extraction instrument for rapid DNA profiling. AB - A portable DNA extraction instrument was evaluated for its ability to decontaminate blood and saliva samples deposited on different surfaces (metal, plastic and glass) contaminated with stable isotopes of cobalt (Co), cesium (Cs), and strontium (Sr) as equivalents to their radiogenic (60)Co, (137)Cs, and (90)Sr isotopes, respectively, that could be released during a nuclear weapon accident or a radiological dispersal device (RDD) detonation. Despite the very high contamination levels tested in this study, successful removal of greater than 99.996% of the Co, Cs, Sr contaminants was achieved based on inductively coupled plasma-mass spectrometry (ICP-MS) and neutron activation analyses carried out on all liquids (including DNA eluates) and solid waste produced during automated DNA extraction. The remaining amounts of Co, Cs and Sr in the DNA eluates, when converted to dose rates (corresponding to (60)Co, (137)Cs and (90)Sr), were determined to be below the recommended dose limits for the general public in most of the scenarios tested. The presence of Co, Cs and Sr contaminants in the cell lysates had no adverse impact on the binding of DNA onto the magnetic DNA IQTM beads. DNA yields were similar to uncontaminated controls. The remaining Co, Cs and Sr in the DNA eluates did not interfere with real-time PCR DNA quantification. In addition, the quality of the AmpFlSTR((r)) Identifiler((r)) profiles derived in 26min using an accelerated protocol was very good and comparable to controls. This study emphasizes the use of an accelerated process involving a portable DNA extraction instrument to significantly reduce radioactive dose rates to allow contaminated samples to be processed safely in a forensic mobile laboratory to expedite the identification of individuals potentially involved in the dispersal of nuclear or other radioactive materials. PMID- 26773228 TI - Preservation and storage of prepared ballistic gelatine. AB - The use of ballistic gelatine, generally accepted as a human muscle tissue simulant in wound ballistic studies, might be improved by adding a preservative (Methyl 4-hydroxybenzoate) which inhibits microbial growth. This study shows that replacing a part of the gelatine powder by the preservative does not significantly alter the penetration depth of projectiles. Storing prepared blocks of ballistic gelatine over time decreased the penetration depth of projectiles. Storage of prepared gelatine for 4 week already showed a significant effect on the penetration depth of projectiles. PMID- 26773229 TI - Profiling the decomposition odour at the grave surface before and after probing. AB - Human remains detection (HRD) dogs are recognised as a valuable and non-invasive search method for remains concealed in many different environments, including clandestine graves. However, the search for buried remains can be a challenging task as minimal odour may be available at the grave surface for detection by the dogs. Handlers often use a soil probe during these searches in an attempt to increase the amount of odour available for detection, but soil probing is considered an invasive search technique. The aim of this study was to determine whether the soil probe assists with increasing the abundance of volatile organic compounds (VOCs) available at the grave surface. A proof-of-concept method was developed using porcine remains to collect VOCs within the grave without disturbing the burial environment, and to compare their abundance at the grave surface before and after probing. Detection and identification of the VOC profiles required the use of comprehensive two-dimensional gas chromatography time-of-flight mass spectrometry (GC*GC-TOFMS) due to its superior sensitivity and selectivity for decomposition odour profiling. The abundance of decomposition VOCs was consistently higher within the grave environment compared to the grave surface, except when the grave surface had been disturbed, confirming the reduced availability of odour at the grave surface. Although probing appeared to increase the abundance of VOCs at the grave surface on many of the sampling days, there were no clear trends identified across the study and no direct relationships with the environmental variables measured. Typically, the decomposition VOCs that were most prevalent in the grave soil were the same VOCs detected at the grave surface, whereas the trace VOCs detected in these environments varied throughout the post-burial period. This study highlighted that probing the soil can assist with releasing decomposition VOCs but is likely correlated to environmental and burial variables which require further study. The use of a soil probe to assist HRD dogs should not be disregarded but should only follow the use of non-invasive methods if deemed appropriate. PMID- 26773230 TI - Protein turnover analysis in Salmonella Typhimurium during infection by dynamic SILAC, Topograph, and quantitative proteomics. AB - Protein turnover affects protein abundance and phenotypes. Comprehensive investigation of protein turnover dynamics has the potential to provide substantial information about gene expression. Here we report a large-scale protein turnover study in Salmonella Typhimurium during infection by quantitative proteomics. Murine macrophage-like RAW 264.7 cells were infected with SILAC labeled Salmonella. Bacterial cells were extracted after 0, 30, 60, 120, and 240 min. Mass spectrometry analyses yielded information about Salmonella protein turnover dynamics and a software program named Topograph was used for the calculation of protein half lives. The half lives of 311 proteins from intracellular Salmonella were obtained. For bacteria cultured in control medium (DMEM), the half lives for 870 proteins were obtained. The calculated median of protein half lives was 69.13 and 99.30 min for the infection group and the DMEM group, respectively, indicating an elevated protein turnover at the initial stage of infection. Gene ontology analyses revealed that a number of protein functional groups were significantly regulated by infection, including proteins involved in ribosome, periplasmic space, cellular amino acid metabolic process, ion binding, and catalytic activity. The half lives of proteins involved in purine metabolism pathway were found to be significantly shortened during infection. PMID- 26773231 TI - The Current State of Silicone-Based Dielectric Elastomer Transducers. AB - Silicone elastomers are promising materials for dielectric elastomer transducers (DETs) due to their superior properties such as high efficiency, reliability and fast response times. DETs consist of thin elastomer films sandwiched between compliant electrodes, and they constitute an interesting class of transducer due to their inherent lightweight and potentially large strains. For the field to progress towards industrial implementation, a leap in material development is required, specifically targeting longer lifetime and higher energy densities to provide more efficient transduction at lower driving voltages. In this review, the current state of silicone elastomers for DETs is summarised and critically discussed, including commercial elastomers, composites, polymer blends, grafted elastomers and complex network structures. For future developments in the field it is essential that all aspects of the elastomer are taken into account, namely dielectric losses, lifetime and the very often ignored polymer network integrity and stability. PMID- 26773232 TI - Characterization and application of two RANK-specific antibodies with different biological activities. AB - Antibodies play an important role in therapy and investigative biomedical research. The TNF-family member Receptor Activator of NF-kappaB (RANK) is known for its role in bone homeostasis and is increasingly recognized as a central player in immune regulation and epithelial cell activation. However, the study of RANK biology has been hampered by missing or insufficient characterization of high affinity tools that recognize RANK. Here, we present a careful description and comparison of two antibodies, RANK-02 obtained by phage display (Newa, 2014 [1]) and R12-31 generated by immunization (Kamijo, 2006 [2]). We found that both antibodies recognized mouse RANK with high affinity, while RANK-02 and R12-31 recognized human RANK with high and lower affinities, respectively. Using a cell apoptosis assay based on stimulation of a RANK:Fas fusion protein, and a cellular NF-kappaB signaling assay, we showed that R12-31 was agonist for both species. R12-31 interfered little or not at all with the binding of RANKL to RANK, in contrast to RANK-02 that efficiently prevented this interaction. Depending on the assay and species, RANK-02 was either a weak agonist or a partial antagonist of RANK. Both antibodies recognized human Langerhans cells, previously shown to express RANK, while dermal dendritic cells were poorly labeled. In vivo R12-31 agonist activity was demonstrated by its ability to induce the formation of intestinal villous microfold cells in mice. This characterization of two monoclonal antibodies should now allow better evaluation of their application as therapeutic reagents and investigative tools. PMID- 26773234 TI - Automated measurement of parameters related to the deformities of lower limbs based on x-rays images. AB - Measurement of the deformation of the lower limbs in the current standard full limb X-rays images presents significant challenges to radiologists and orthopedists. The precision of these measurements is deteriorated because of inexact positioning of the leg during image acquisition, problems with selecting reliable anatomical landmarks in projective X-ray images, and inevitable errors of manual measurements. The influence of the random errors resulting from the last two factors on the precision of the measurement can be reduced if an automated measurement method is used instead of a manual one. In the paper a framework for an automated measurement of various metric and angular quantities used in the description of the lower extremity deformation in full-limb frontal X ray images is described. The results of automated measurements are compared with manual measurements. These results demonstrate that an automated method can be a valuable alternative to the manual measurements. PMID- 26773233 TI - Advances in free-energy-based simulations of protein folding and ligand binding. AB - Free-energy-based simulations are increasingly providing the narratives about the structures, dynamics and biological mechanisms that constitute the fabric of protein science. Here, we review two recent successes. It is becoming practical: first, to fold small proteins with free-energy methods without knowing substructures and second, to compute ligand-protein binding affinities, not just their binding poses. Over the past 40 years, the timescales that can be simulated by atomistic MD are doubling every 1.3 years--which is faster than Moore's law. Thus, these advances are not simply due to the availability of faster computers. Force fields, solvation models and simulation methodology have kept pace with computing advancements, and are now quite good. At the tip of the spear recently are GPU-based computing, improved fast-solvation methods, continued advances in force fields, and conformational sampling methods that harness external information. PMID- 26773235 TI - Mechanism of isoniazid-induced hepatotoxicity: then and now. AB - Isoniazid (INH) remains a mainstay for the treatment of tuberculosis despite the fact that it can cause liver failure. Previous mechanistic hypotheses have classified this type of drug-induced liver injury (DILI) as 'metabolic idiosyncrasy' which was thought not to involve an immune response and was mainly due to the bioactivation of the acetylhydrazine metabolite. However, more recent studies support an alternative hypothesis, specifically, that INH itself is directly bioactivated to a reactive metabolite, which in some patients leads to an immune response and liver injury. Furthermore, there appear to be two phenotypes of INH-induced liver injury. Most cases involve mild liver injury, which resolves with immune tolerance, while other cases appear to have a more severe phenotype that is associated with the production of anti-drug/anti-CYP P450 antibodies and can progress to liver failure. PMID- 26773236 TI - Cortical trajectories during adolescence in preterm born teenagers with very low birthweight. AB - While cross-sectional neuroimaging studies on cortical development predict reductions in cortical volume (surface area and thickness) during adolescence, this is the first study to undertake a longitudinal assessment of cortical surface area changes across the continuous cortical surface during this period. We studied the developmental dynamics of cortical surface area and thickness in adolescents and young adults (aged 15-20) born with very low birth weight (VLBW; <1500 g) as well as in term-born controls. Previous studies have demonstrated brain structural abnormalities in cortical morphology, as well as long-term motor, cognitive and behavioral impairments, in adolescents and young adults with VLBW, but the developmental dynamics throughout adolescence have not been fully explored. T1-weighted MRI scans from 51 VLBW (27 scanned twice) and 79 term-born adolescents (37 scanned twice) were used to reconstruct the cortical surface and produce longitudinal estimates of cortical surface area and cortical thickness. Linear mixed model analyses were performed, and the main effects of time and group, as well as time * group interaction effects, were investigated. In both groups, cortical surface area decreased up to 5% in some regions, and cortical thickness up to 8%, over the five-year period. The most affected regions were located on the lateral aspect of the hemispheres, in posterior temporal, parietal and to some extent frontal regions. There was no significant interaction between time and group for either morphometry variable. In conclusion, cortical thickness decreases from 15 to 20 years of age, in a similar fashion in the clinical and control groups. Moreover, we show for the first time that developmental trajectories of cortical surface area in preterm and term-born adolescents do not diverge during adolescence. PMID- 26773237 TI - Recognizing and identifying people: A neuropsychological review. AB - Recognizing people is a classic example of a cognitive function that involves multiple processing stages and parallel routes of information. Neuropsychological data have provided important evidence for models of this process, particularly from case reports; however, the quality and extent of the data varies widely between studies. In this review we first discuss the requirements and logical basis of the types of neuropsychological evidence to support conclusions about the modules in this process. We then survey the adequacy of the current body of reports to address two key issues. First is the question of which cognitive operation generates a sense of familiarity: the current debate revolves around whether familiarity arises in modality-specific recognition units or later amodal processes. Key evidence on this point comes from the search for dissociations between familiarity for faces, voices and names. The second question is whether lesions can differentially affect the abilities to link diverse sources of person information (e.g., face, voice, name, biographic data). Dissociations of these linkages may favor a 'distributed-only' model of the organization of semantic knowledge, whereas a 'person-hub' model would predict uniform impairments of all linkages. While we conclude that there is reasonable evidence for dissociations in name, voice and face familiarity in regards to the first question, the evidence for or against dissociated linkages between information stores in regards to the second question is tenuous at best. We identify deficiencies in the current literature that should motivate and inform the design of future studies. PMID- 26773238 TI - Impact of Contrast Dose Reduction on Incidence of Acute Kidney Injury (AKI) Among Patients Undergoing PCI: A Modeling Study. AB - OBJECTIVE: Acute kidney injury is a common complication associated with angiography and percutaneous coronary intervention (PCI). Increasing doses of contrast are associated with an increase in the likelihood of AKI. The objective of our study was to estimate projected reduction in the burden of AKI in association with varying degrees of contrast media dose reduction among patients undergoing PCI. METHODS: We assessed the relationship between contrast volume to creatinine clearance among consecutive patients undergoing PCI in the state of Michigan between January 2010 and September 2013. Computational modeling was used to estimate the anticipated reduction in risk of AKI across varying degrees of reduction in contrast volume. RESULTS: The risk of AKI was significantly and substantially increased in patients in whom the contrast dose exceeded 2.99 times the creatinine clearance. The benefit of contrast dose reduction was most evident in those at greater predicted risk of AKI. An across the board 30% reduction in contrast dose would be expected to prevent one-eighth of AKI cases, although clinical benefits could also be anticipated with smaller dose reductions. CONCLUSION: Our study provides estimates of reduction in AKI that could be achieved with contrast dose reduction in clinical practice. These data should help guide planning of clinical trials and the application of contrast-saving strategies to routine clinical practice. PMID- 26773239 TI - Predictors and Outcomes of Side-Branch Occlusion in Coronary Chronic Total Occlusion Interventions. AB - OBJECTIVES: We investigated whether side-branch loss during chronic total occlusion (CTO) percutaneous coronary intervention (PCI) could adversely impact clinical outcomes. BACKGROUND: Side-branch occlusion during PCI has been associated with periprocedural myocardial infarction and higher incidence of major adverse cardiac event (MACE), but has received limited study in CTO-PCI. METHODS: We retrospectively reviewed the medical records and coronary angiograms for 109 consecutive CTOPCI cases performed at our institution during 2012 and 2013. Post-PCI patency of >=1 mm diameter side branches and associated clinical outcomes were assessed. RESULTS: Mean age was 65 +/- 8 years and 99.1% of the patients were men. The CTO target vessel was the right coronary artery (54%), circumflex (26%), and left anterior descending artery (20%). Side-branch loss occurred in 28 cases (25.7%) due to antegrade dissection/reentry (n = 9), retrograde dissection/reentry (n = 5), stenting over the branch (n = 12), and dissection during antegrade crossing attempts (n = 2). Recanalization of the occluded side branch was pursued in 8 cases (28.6%) and was successful in 4 patients. Patients with side-branch loss had higher post-PCI increase in CK-MB levels (8.4 ng/mL [interquartile range, 2.7-33.5 ng/mL] vs 1.8 ng/mL [interquartile range, 0.025-6.775 ng/mL]; P<.001) and higher 12-month incidence of all-cause death (17.3% vs 2.8%; P=.02) and cardiovascular death (7.4% vs 0.0%; P=.02). CONCLUSIONS: Side-branch loss occurs in approximately 1 in 4 CTO-PCIs and is associated with higher risk for periprocedural myocardial infarction and higher mortality. PMID- 26773240 TI - Mitral Annuloplasty Device Implantation for Non-Surgical Treatment of Mitral Regurgitation: Clinical Experience After the Approval Studies. AB - BACKGROUND AND AIMS: One option for interventional treatment of secondary mitral regurgitation is the placement of an indirect mitral annuloplasty device (Carillon Mitral Contour System) cinching the mitral annulus to facilitate coaptation of the mitral leaflets. The aim of this study is to evaluate the implantation success and hemodynamic results. METHODS AND RESULTS: Seventeen consecutive patients (11 females, 6 males) suffering from moderate to severe secondary mitral regurgitation (40% ischemic, 59% non-ischemic) received a Carillon Mitral Contour System device, which was evaluated prospectively in a single-center setting. The mean procedure time was 95.5 +/- 2.1 minutes, fluoroscopy time was 13.1 +/- 6.1 minutes, and the amount of contrast dye was 120.6 +/- 39.3 mL. The mitral regurgitation grade was reduced from 2.8 +/- 2.4 to 1.9 +/- 0.8 acutely (P<.01), with an additional improvement seen after 3 months to 1.5 +/- 0.75 (P<.01 to baseline). In 41.2% of patients, acute reduction of coronary artery flow was seen and managed with a stepwise approach: (1) intracoronary nitroglycerin was administered; (2) release of device tension; (3) a new device was changed and placed at a different location; and (4) the device was left in place and a stent was implanted in the coronary artery. Only 1 patient (5.8%) could not receive the device due to coronary compression. No periprocedural myocardial infarction occurred. CONCLUSION: Indirect mitral annuloplasty is feasible outside of controlled trials, and is associated with successful improvement of mitral regurgitation. Although coronary compromise needs to be addressed as part of the implantation procedure, this issue limits implantation of the device in only a small percentage of cases. PMID- 26773241 TI - First trimester pregnancy-associated plasma protein-A and birth weight. AB - OBJECTIVE: To evaluate first trimester pregnancy-associated plasma protein-A (PAPP-A) and birth weight percentile. STUDY DESIGN: Included were women who underwent first trimester prenatal screening through the California Prenatal Screening Program with expected dates of delivery between August 2009 and December 2010, linked birth certificate and hospital discharge records, known birth weight, and no chromosomal abnormality (n=134.105). PAPP-A results were reported as multiples of the median. The frequency of small or large for gestational age (SGA, <=10%; LGA, >=90%) versus appropriately grown for gestational age birth was examined by PAPP-A percentile. Patterns were studied by gestational age at delivery. Relative risks (RRs) and their 95% confidence intervals were adjusted for race/ethnicity. RESULTS: Women with PAPP-A <=10th percentile and an infant born after 32 weeks were increasingly more likely to have an SGA infant (adjRRs 1.5-4.6) as the PAPP-A percentile declined, and were increasingly less like to have an LGA infant born at term (adjRRs 0.5-0.7) compared to women with PAPP-A measurement >10th to <90th percentile. PAPP-A >=90th percentile was protective for SGA among infants born after 32 weeks gestation (adjRRs 0.3-0.7) and was associated with LGA among infants born at term (adjRRs 1.2-8.2). CONCLUSION: Women with PAPP-A <=10th percentile are more likely to have an SGA infant at all gestational ages. PAPP-A >=90th percentile is protective against SGA and is associated with an increased risk of LGA for infants born after 32 weeks gestation. PMID- 26773242 TI - Parenthood and separation in couples 6 years after their first infertility consultation. AB - OBJECTIVE: To evaluate the percentage of couples achieving parenthood and the rate of separation 6 years after their first consultation for infertility. STUDY DESIGN: Epidemiological study in the reproductive medicine department of a French university hospital. All first consulting couples (FCC) who had their first infertility consultation in the department in 2007 were contacted by phone and asked to respond to a questionnaire concerning their infertility treatments, parenthood and marital status 6 years after their first consultation. RESULTS: Of the 685 FCC, 94 could not be contacted, 34 refused to respond and 557 (86%) answered the questionnaire. Of 557 FCC who have responded, 361 (65%) have achieved parenthood: 166 (46%) after treatment, 98 (27%) after spontaneous conception, 38 (11%) after both spontaneous and treatment-induced conception and 59 (16%) through adoption. Parenthood was not influenced either by the causes or duration of infertility. Separation occurred in 53 (9.5%) of FCC, mainly in those without any children (28% vs 4% in FCC with at least one child; P<.0001). CONCLUSION: Six years after their primary consultation, 25% of couples remained childless and 28% of them were separated. PMID- 26773243 TI - Postpartum hemorrhage: guidelines for clinical practice from the French College of Gynaecologists and Obstetricians (CNGOF): in collaboration with the French Society of Anesthesiology and Intensive Care (SFAR). AB - Postpartum haemorrhage (PPH) is defined as blood loss >=500mL after delivery and severe PPH as blood loss >=1000mL, regardless of the route of delivery (professional consensus). The preventive administration of uterotonic agents just after delivery is effective in reducing the incidence of PPH and its systematic use is recommended, regardless of the route of delivery (Grade A). Oxytocin is the first-line prophylactic drug, regardless of the route of delivery (Grade A); a slowly dose of 5 or 10 IU can be administered (Grade A) either IV or IM (professional consensus). After vaginal delivery, routine cord drainage (Grade B), controlled cord traction (Grade A), uterine massage (Grade A), and routine bladder voiding (professional consensus) are not systematically recommended for PPH prevention. After caesarean delivery, placental delivery by controlled cord traction is recommended (grade B). The routine use of a collector bag to assess postpartum blood loss at vaginal delivery is not systematically recommended (Grade B), since the incidence of severe PPH is not affected by this intervention. In cases of overt PPH after vaginal delivery, placement of a blood collection bag is recommended (professional consensus). The initial treatment of PPH consists in a manual uterine examination, together with antibiotic prophylaxis, careful visual assessment of the lower genital tract, a uterine massage, and the administration of 5-10 IU oxytocin injected slowly IV or IM, followed by a maintenance infusion not to exceed a cumulative dose of 40IU (professional consensus). If oxytocin fails to control the bleeding, the administration of sulprostone is recommended within 30minutes of the PPH diagnosis (Grade C). Intrauterine balloon tamponade can be performed if sulprostone fails and before recourse to either surgery or interventional radiology (professional consensus). Fluid resuscitation is recommended for PPH persistent after first line uterotonics, or if clinical signs of severity (Grade B). The objective of RBC transfusion is to maintain a haemoglobin concentration (Hb) >8g/dL. During active haemorrhaging, it is desirable to maintain a fibrinogen level >=2g/L (professional consensus). RBC, fibrinogen and fresh frozen plasma (FFP) may be administered without awaiting laboratory results (professional consensus). Tranexamic acid may be used at a dose of 1 g, renewable once if ineffective the first time in the treatment of PPH when bleeding persists after sulprostone administration (professional consensus), even though its clinical value has not yet been demonstrated in obstetric settings. It is recommended to prevent and treat hypothermia in women with PPH by warming infusion solutions and blood products and by active skin warming (Grade C). Oxygen administration is recommended in women with severe PPH (professional consensus). If PPH is not controlled by pharmacological treatments and possibly intra-uterine balloon, invasive treatments by arterial embolization or surgery are recommended (Grade C). No technique for conservative surgery is favoured over any other (professional consensus). Hospital-to-hospital transfer of a woman with a PPH for embolization is possible once hemoperitoneum is ruled out and if the patient's hemodynamic condition so allows (professional consensus). PMID- 26773244 TI - Caspase activity and oxidative stress of granulosa cells are associated with the viability and developmental potential of vitrified immature oocytes. AB - OBJECTIVE: The aim of this study is to determine whether caspase activity and oxidative stress of granulosa cells are associated with the viability and developmental potential of vitrified immature oocytes. STUDY DESIGN: Oocytes from mice were exposed to genistein or/and Z-VAD-FMK with or without vitrification. Ultrastructural alterations of granulosa cells in vitrified immature oocytes were observed. Moreover, the level of superoxide dismutase (SOD) in granulosa cells, incidence of apoptotic follicles, the viability of vitrified-warmed oocytes and their subsequent developmental competence were measured. RESULTS: Ultrastructural alterations of granulosa cells vitrified in the presence of genistein or Z-VAD FMK were slighter than that of granulosa cells vitrified in the absence of genistein or Z-VAD-FMK. The incidence of apoptotic follicles vitrified in the presence of genistein or Z-VAD-FMK was significantly lower than that of immature oocytes vitrified in the absence of genistein or Z-VAD-FMK, whereas, the level of SOD in granulosa cells, the viability and developmental competence of immature oocytes vitrified in the presence of genistein or Z-VAD-FMK were significantly higher than that of immature oocytes vitrified in the absence of genistein or Z VAD-FMK. CONCLUSION: Both antioxidant (genistein) and caspase inhibition (Z-VAD FMK) improve the viability and developmental competence of vitrified immature oocytes. Genistein is superior to Z-VAD-FMK in improving the efficacy of immature oocyte vitrification. PMID- 26773245 TI - Unfair discrimination in prenatal aneuploidy screening using cell-free DNA? AB - Non-invasive prenatal testing on the basis of cell-free DNA of placental origin (NIPT) changed the landscape of prenatal care and is seen as superior to all other up to now implemented prenatal screening procedures - at least in the high risk population. NIPT has spread almost worldwide commercially, but only in a few countries the costs of NIPT are covered by insurance companies. Such financial barriers in prenatal testing can lead to significant restrictions to the average range of opportunities of pregnant women and couples, which on an intersubjective level can be defined as unfair discrimination and on an individual level weakens reproductive autonomy. Given that enabling reproductive autonomy is the main ethical justification for offering prenatal (genetic) testing, these barriers are not only an issue of justice in health care, but are potentially counteracting the primary purpose of these testing procedures. PMID- 26773246 TI - Carbetocin compared to oxytocin in emergency cesarean section: a randomized trial. AB - OBJECTIVE: To evaluate the uterotonic effect of carbetocin compared with oxytocin in emergency cesarean delivery. STUDY DESIGN: Participants were randomized to intravenous bolus injection of 100mcg carbetocin or 10IU oxytocin after cesarean delivery of the baby. The primary outcome is any additional uterotonic which may be administered by the blinded provider for perceived inadequate uterine tone with or without hemorrhage in the first 24hours after delivery. Secondary outcomes include operating time, perioperative blood loss, change in hemoglobin and hematocrit levels, blood transfusion and reoperation for postpartum hemorrhage. RESULTS: Additional uterotonic rates were 107/276 (38.8%) vs. 155/271 (57.2%) [RR 0.68 95% CI 0.57-0.81 p<0.001; NNTb 6 95% CI 3.8-9.8], mean operating time 45.9+/-16.0 vs. 44.5+/-13.1minutes p=0.26, mean blood loss 458+/-258 vs. 446+/-281ml p=0.6, severe postpartum hemorrhage (>=1000ml) rates 15/276 (5.4%) vs. 10/271 (3.7%) p=0.33 and blood transfusion rates 6/276 (2.2%) vs. 10/271 (3.7%); p=0.30 for carbetocin and oxytocin arms respectively. There was only one case of re-operation (oxytocin arm). In the cases that needed additional uterotonic 98% (257/262) was started intraoperatively and in 89% (234/262) the only additional uterotonic administered was an oxytocin infusion over 6hours. CONCLUSION: Fewer women in the carbetocin arm needed additional uterotonics but perioperative blood loss, severe postpartum hemorrhage, blood transfusion and operating time were not different. PMID- 26773247 TI - Effects of omega-3 fatty acids in prevention of early preterm delivery: a systematic review and meta-analysis of randomized studies. AB - OBJECTIVE: Preterm birth continues to be the one of the leading causes of infant deaths worldwide. There is a need for effective, easily available, safe and acceptable interventions to prevent preterm delivery, especially before 34 weeks of gestation. Omega-3 fatty acids such as EPA (eicosapentanoic acid) and DHA (docosahexanoic acid) are available as over the counter nutritional supplements, and are taken by women to improve pregnancy outcomes, without any clear recommendations. We undertook a systematic review to assess the effects of omega 3 fatty acids on early (<34 weeks) and any (<37 weeks) preterm delivery. METHODS: We searched MEDLINE, EMBASE and Cochrane Library from inception to 2014 without any language restrictions. Study selection, quality assessment and data extraction were done by two independent reviewers. Results were summarized as relative risks and 95% confidence intervals for dichotomous outcomes and mean differences for continuous outcomes. RESULTS: Of the nine included trials (5980 women), six (4193 women) evaluated the effects of omega-3 fatty acids on early preterm delivery. The risk of early preterm delivery was reduced by 58% (RR 0.42; 95% CI 0.27-0.66; I(2)=0%; p=0.0002) and any preterm delivery by 17% (RR 0.83; 95% CI 0.70-0.98; I(2)=0%; p=0.03) with the intervention. There was a significant increase in the mean gestational age by 1.95 weeks (95% CI 0.42-3.48 weeks; I(2)=0.47; p=0.01) and mean birth weight by 122.1g (95% CI 47.4-196.8; I(2)=0.84; p=0.001) in the intervention group compared to the controls. Subgroup analysis showed no significant differences in the effects between the groups according to the risk status, dose and timing of the intervention. CONCLUSION: Omega-3 fatty acids are effective in preventing early and any preterm delivery. The intervention is simple and easily available and has the potential to influence population based strategies in the prevention of preterm birth. PMID- 26773248 TI - Does anal sphincter injury preclude subsequent vaginal delivery? AB - OBJECTIVE: To assess continence and anal sphincter integrity during a subsequent pregnancy and delivery in women known to have a previous anal sphincter injury. DESIGN: Prospective observational study. SETTING: The National Maternity Hospital, Dublin, Ireland. POPULATION: Antenatal patients with a documented obstetric anal sphincter injury at a previous delivery. METHODS: Women underwent symptom scoring, endoanal ultrasound and manometry. MAIN OUTCOME MEASURES: Recommended and actual mode of delivery, continence scores and endoanal ultrasound findings after index delivery. RESULTS: 557 women were studied. 293 (53%) had no symptoms of faecal incontinence, 189 (34%) had mild symptoms and 75 (13%) moderate or severe symptoms. 408 (73%) had an endoanal ultrasound. 383(94%) had a normal or small (<1 quadrant) defect in the internal anal sphincter and 390 (96%) had a scar or small (<1e quadrant) defect in the external anal sphincter. 393 (70%) delivered vaginally. 164 (30%) were delivered by caesarean section. 197/557 (35%) returned for follow-up. There was no significant change in continence following either vaginal or caesarean delivery. 20 (5.1%) women had a recognised second anal sphincter tear during vaginal delivery. CONCLUSIONS: The majority of women who sustain a third degree tear have minimal or no symptoms of faecal incontinence when assessed antenatally in a subsequent pregnancy. 70% go on to have a vaginal delivery, with little impact on faecal continence. These findings provide reassurance for patients and clinicians about the safety of vaginal delivery following anal sphincter injury in appropriately selected patients. PMID- 26773249 TI - Screening LGI1 in a cohort of 26 lateral temporal lobe epilepsy patients with auditory aura from Turkey detects a novel de novo mutation. AB - Autosomal dominant lateral temporal lobe epilepsy (ADLTE) is an autosomal dominant epileptic syndrome characterized by focal seizures with auditory or aphasic symptoms. The same phenotype is also observed in a sporadic form of lateral temporal lobe epilepsy (LTLE), namely idiopathic partial epilepsy with auditory features (IPEAF). Heterozygous mutations in LGI1 account for up to 50% of ADLTE families and only rarely observed in IPEAF cases. In this study, we analysed a cohort of 26 individuals with LTLE diagnosed according to the following criteria: focal epilepsy with auditory aura and absence of cerebral lesions on brain MRI. All patients underwent clinical, neuroradiological and electroencephalography examinations and afterwards they were screened for mutations in LGI1 gene. The single LGI1 mutation identified in this study is a novel missense variant (NM_005097.2: c.1013T>C; p.Phe338Ser) observed de novo in a sporadic patient. This is the first study involving clinical analysis of a LTLE cohort from Turkey and genetic contribution of LGI1 to ADLTE phenotype. Identification of rare LGI1 gene mutations in sporadic cases supports diagnosis as ADTLE and draws attention to potential familial clustering of ADTLE in suggestive generations, which is especially important for genetic counselling. PMID- 26773251 TI - Mandibular sexual dimorphism analysis in CBCT scans. AB - The aim of this study was to evaluate sexual dimorphism using anthropometric measurements on mandibular images obtained by cone beam computed tomography (CBCT). The sample consisted of 160 CT scans collected from a Brazilian population (74 males, 86 females) aged 18-60 years. The CBCT images were analyzed by five reviewers. Six measurements (ramus length, gonion-gnathion length, minimum ramus breadth, gonial angle, bicondylar breadth, and bigonial breadth) were collected for the sexual prediction analysis. For the statistical analysis, intraclass correlation was used to evaluate intra- and inter-reviewers, analysis of variance was used to compare the mean values of these measurements, binary logistic regression equations were created to predict sex. Using these four variables, the rate of correct sex classification was 95.1%. After, the discriminant function was used to validate the formula built. Accuracy of 93.33% and 94.74% was found for estimating male and females, respectively. Thus, the formula developed in this study can be used for sex estimation in forensic settings. PMID- 26773250 TI - The hippocampus participates in a pharmacological rat model of absence seizures. AB - OBJECTIVE: Using the gamma-butyrolactone (GBL) model of absence seizures in Long Evans rats, this study investigated if 2.5-6 Hz paroxysmal discharges (PDs) induced by GBL were synchronized among the thalamocortical system and the hippocampus, and whether inactivation of the hippocampus affected PDs. METHODS: Local field potentials were recorded by chronically implanted depth electrodes in the neocortex (frontal, parietal, visual), ventrolateral thalamus and dorsal hippocampal CA1 area. In separate experiments, multiple unit recordings were made at the hippocampal CA1 pyramidal cell layer, or the mid-septotemporal hippocampus was inactivated by local infusion of GABAA receptor agonist muscimol. RESULTS: As PDs developed following GBL injection, coherence of local field potentials at 2.5 6 Hz increased between the hippocampus and thalamus, and between the hippocampus and the neocortex. Hippocampal theta rhythm was disrupted when GBL induced immobility in the rats. The probability of hippocampal multiple unit firing significantly increased at 40-80 ms prior to the negative peak of thalamic PDs. Coherence between hippocampal multiple unit activity and thalamic field potentials at 2.5-6 Hz was significantly increased after GBL injection. Muscimol infusion to inactivate the mid-septotemporal hippocampus, as compared to saline infusion, significantly decreased the peak frequency of the PDs induced by GBL, decreased 30-120 Hz hippocampal gamma power, and hastened the transition of PDs to 1-2 Hz slow waves. SIGNIFICANCE: During GBL induced 2.5-6 Hz PDs, a hallmark of absence seizure, increased synchronization between the hippocampus and the thalamocortical network was indicated by frequency and temporal correlation analysis. These results suggest that the hippocampus was entrained by thalamocortical activity in the present model of absence seizures. Prolonged synchronization of the hippocampus may result in synaptic alterations that may explain the cognitive and memory deficits in some patients with absence seizures and absence status epilepticus. PMID- 26773252 TI - Effect of single or combined chemical and natural antimicrobial interventions on Escherichia coli O157:H7, total microbiota and color of packaged spinach and lettuce. AB - Aqueous extract of Origanum vulgare (oregano), sodium hypochlorite (60 and 300 ppm of free chlorine), Citrox(r) (containing citric acid and phenolic compounds [bioflavonoids] as active ingredients), vinegar, lactic acid, and double combinations of Citrox, lactic acid and oregano were evaluated against Escherichia coli O157:H7 and total mesophilic microbiota on fresh-cut spinach and lettuce and for their impact on color of treated vegetables. Spinach and lettuce leaves were inoculated with E. coli O157:H7 to a level of 5-6 log CFU/g and immersed in washing solutions for 2 or 5 min at 20 degrees C, followed by rinsing with ice water (30s). Bacterial populations on vegetables were enumerated immediately after washing and after storage of the samples at 5 degrees C for 7 days under 20% CO2: 80% N2. No significant post-washing microbial reductions were achieved by chlorinated water, whereas after storage total microbiota was increased by 2.4 log CFU/g on lettuce. Vinegar wash was the most effective treatment causing E. coli O157:H7 reductions of 1.8-4.3 log CFU/g. During storage, pathogen was further decreased to below the detection limit level (<2 log CFU/g) and total microbiota exhibited the highest reductions compared to other treatments. Lactic acid reduced pathogen by 1.6-3.7 log CFU/g after washing; however levels of total microbiota increased by up to 2 log CFU/g on packaged lettuce during storage. Washing lettuce samples with oregano for 2 min resulted in 2.1 log CFU/g reduction of E. coli O157:H7. When Citrox was combined with oregano, 3.7-4.0 log CFU/g reduction was achieved on spinach and lettuce samples, with no significant effect on color parameters. Additionally, rinsing with ice water after decontamination treatments contributed to maintenance of color of the treated vegetables. In conclusion, the results indicated that vinegar, lactic acid or oregano aqueous extract alone or in combination, as alternative washing solutions to chlorine, may be effectively used to control E. coli O157:H7 and sustain acceptable appearance of fresh cut spinach and lettuce. PMID- 26773253 TI - Effectiveness of superheated steam for inactivation of Escherichia coli O157:H7, Salmonella Typhimurium, Salmonella Enteritidis phage type 30, and Listeria monocytogenes on almonds and pistachios. AB - This study was undertaken to evaluate the effectiveness of superheated steam (SHS) on the inactivation of Escherichia coli O157:H7, Salmonella Typhimurium, Salmonella Enteritidis phage type (PT) 30 and Listeria monocytogenes on almonds and in-shell pistachios and to determine the effect of superheated steam heating on quality by measuring color and texture changes. Almonds and in-shell pistachios inoculated with four foodborne pathogens were treated with saturated steam (SS) at 100 degrees C and SHS at 125, 150, 175, and 200 degrees C for various times. Exposure of almonds and pistachios to SHS for 15 or 30s at 200 degrees C achieved >5l og reductions among all tested pathogens without causing significant changes in color values or texture parameters (P>0.05). For both almonds and pistachios, acid and peroxide values (PV) following SS and SHS treatment for up to 15s and 30s, respectively, were within the acceptable range (PV<1.0 meq/kg). These results show that thermal application of 200 degrees C SHS treatment for 15s and 30s did not affect the quality of almonds and pistachios, respectively. Therefore, SHS treatment is a very promising alternative technology for the tree nuts industry by improving inactivation of foodborne pathogens on almonds and pistachios while simultaneously reducing processing time. PMID- 26773254 TI - Stability of active prophages in industrial Lactococcus lactis strains in the presence of heat, acid, osmotic, oxidative and antibiotic stressors. AB - Lactococcus lactis is a starter bacterium commonly used in cheese making where it has an important role in acid-mediated curd formation as well as the development of flavour compounds. Industrial L. lactis strains can harbour one or more inducible prophages which when induced can affect cell growth and possibly lead to cell lysis. This is undesirable during growth and fermentation, but can beneficially lead to faster release of enzymes during cheese ripening. Lactococci can encounter multiple stress inducing conditions during the production of cheese, such as low and high temperatures, low pH, high osmotic pressure and long term incubation. In this study, we tested the effect of these industrial stressors on prophage induction in two cheese making L. lactis subsp. cremoris strains (ASCC890049 and ASCC890310) as well as the laboratory strain L. lactis MG1363. Firstly, in order to identify inducible prophages in these strains we exposed them to the prophage inducing chemical mitomycin C (MMC) for 1 and 2h and then subjected the total genomic DNA to next-generation Illumina sequencing. Mapping of sequence reads back to the genome sequences revealed regions which contained a much higher fold coverage indicating DNA replication. These regions were amplified by up to 332-fold per cell (relative to the control tufA gene) and were identified as having similarities to different subgroups of P335 phages including MG-5, TP901-1, ul36.k1, bIL286, TP712 and BK5-T. Next, quantitative PCR was used to confirm the strong induction of prophages by MMC and then determine the copy number of the inducible prophages following exposure to various growth inhibitory levels of HCl, lactic acid, high temperature, NaCl, hydrogen peroxide and bacitracin. With the exception of a slight induction (2 to 4-fold) with hydrogen peroxide and long-term incubation after 21days in one industrial strain, none of the other stressors induced prophage DNA replication. These findings show that the repression system that maintains prophages in the dormant state in cheese making lactococcal strains is very tight and that several stressors encountered singularly are not predicted to be major inducers of prophage activation. PMID- 26773255 TI - Occurrence and molecular characterisation of Vibrio parahaemolyticus in crustaceans commercialised in Venice area, Italy. AB - Infections due to the pathogenic human vibrios, Vibrio parahaemolyticus, Vibrio cholerae and Vibrio vulnificus, are mainly associated with consumption of raw or partially cooked bivalve molluscs. At present, little is known about the presence of Vibrio species in crustaceans and the risk of vibriosis associated with the consumption of these products. The aim of the present study was to evaluate the prevalence and concentration of the main pathogenic Vibrio spp. in samples of crustaceans (n=143) commonly eaten in Italy, taking into account the effects of different variables such as crustacean species, storage conditions and geographic origin. Subsequently, the potential pathogenicity of V. parahaemolyticus strains isolated from crustaceans (n=88) was investigated, considering the classic virulence factors (tdh and trh genes) and four genes coding for relevant proteins of the type III secretion systems 2 (T3SS2alpha and T3SS2beta). In this study, the presence of V. cholerae and V. vulnificus was never detected, whereas 40 samples (28%) were positive for V. parahaemolyticus with an overall prevalence of 41% in refrigerated products and 8% in frozen products. The highest prevalence and average contamination levels were detected in Crangon crangon (prevalence 58% and median value 3400 MPN/g) and in products from the northern Adriatic Sea (35%), with the samples from the northern Venetian Lagoon reaching a median value of 1375 MPN/g. While genetic analysis confirmed absence of the tdh gene, three of the isolates contained the trh gene and, simultaneously, the T3SS2beta genes. Moreover three possibly clonal tdh-negative/trh-negative isolates carried the T3SS2alpha apparatus. The detection of both T3SS2alpha and T3SS2beta apparatuses in V. parahaemolyticus strains isolated from crustaceans emphasised the importance of considering new genetic markers associated with virulence besides the classical factors. Moreover this study represents the first report dealing with Vibrio spp. in crustaceans in Italy, and it may provide useful information for the development of sanitary surveillance plans to prevent the risk of vibriosis in seafood consumers. PMID- 26773256 TI - Virulence gene expression, adhesion and invasion of Campylobacter jejuni exposed to oxidative stress (H2O2). AB - Studies were undertaken to investigate the effect of oxidative stress conditions (exposure to hydrogen peroxide, H2O2) on [1] the expression of 14 Campylobacter jejuni virulence-associated genes associated with motility and/or invasion (flaA, flaB, flhA, flhB, ciaB, iamA), adhesion (cadF), cytotoxin production (cdtA, cdtB, cdtC) as well as some of the regulators of these genes (rpoN, fliA, luxS, cj1000), in 10 C. jejuni strains (5 poultry and 5 human) and [2] the ability of these cells to adhere to and invade Caco-2 cells. Using 16S rRNA as the reference gene (preliminary research demonstrated that this gene was stably expressed), the expression of the 14 virulence associated genes was investigated under normal and oxidative stress conditions using reverse transcription PCR. A Caco-2 cell tissue culture assay was used to examine adhesion and invasion. The response to oxidative stress was strain-dependent. Two strains showed significant (p<0.05) up or down regulation in 7 of the 14 genes tested, while only 1-2 genes were affected in the remaining strains. Expression of cadF was significantly (p<0.05) changed in all strains, cdt B in 4 strains and cj1000 in 3 strains. Expression of the remaining genes was either unaffected or significantly altered in 1-2 strains. NCTC 11168 completely lost the ability to adhere to and invade Caco-2 cells. One other strain also demonstrated reduced adherence while two others were unable to invade Caco-2 cells after exposure to oxidative stress conditions. In contrast strain 7, a poultry isolate, showed increased invasion. It was concluded that oxidative stress affects expression of C. jejuni virulence genes in a strain dependent manner, CadF may have a secondary survival function and the cdtB gene may have a different promoter than cdtA and cdtC. PMID- 26773258 TI - Patient-reported outcome measures in neurodisability: fit for purpose or scope for improvement? PMID- 26773259 TI - Inflammation in meconium aspiration syndrome-One of many heads of the hydra. PMID- 26773260 TI - A new rhodamine-based colorimetric chemosensor for naked-eye detection of Cu(2+) in aqueous solution. AB - A new colorimetric probe 1 based on rhodamine B lactam was developed for naked eye detection of Cu(2+). The optical feature of 1 for Cu(2+) was investigated by UV-vis absorption spectroscopy. Upon the addition of Cu(2+), the 1 displayed a distinct color change from colorless to pink, which can be directly detected by the naked eye. The stoichiometry of 1 to Cu(2+) complex was found to be 1:1 and the naked-eye detection limit was determined as low as 2 MUM. The results suggest that the probe 1 may provide a convenient method for visual detection of Cu(2+) with high sensitivity. PMID- 26773261 TI - Exploring the binding mechanism of 5-hydroxy-3',4',7-trimethoxyflavone with bovine serum albumin: Spectroscopic and computational approach. AB - The current study was carried out to investigate the binding mechanism of a potential flavonoid compound 5-hydroxy-3',4',7-trimethoxyflavone (HTMF) with bovine serum albumin (BSA) using ultraviolet-visible, fluorescence, circular dichroism (CD) spectral measurements along with molecular docking and molecular dynamics (MD) simulation. It was confirmed from fluorescence spectra that the intrinsic fluorescence of BSA was robustly quenched by HTMF through a static quenching mechanism. The number of binding sites (n) for HTMF binding on BSA was found to be about one. The thermodynamic parameters estimated from the van't Hoff plot specified that hydrophobic force was the predominant force in the HTMF-BSA complex and there also exist hydrogen bonds and electrostatic interactions. The effect of HTMF on the BSA conformation examined using CD studies revealed that there is a decrease in the helical content of BSA upon HTMF interaction. The results of molecular docking study shed light on the binding mode which exposed that HTMF bind within the hydrophobic pocket of the subdomain IIIA of BSA. The stability of HTMF-BSA complex with respect to free protein was analyzed from the molecular dynamic studies. The electronic structure analysis of HTMF was achieved by using density functional theory (DFT) calculations at B3LYP/6-31G** level to support its antioxidant role. The results of computational analysis are in good consistence with the experimental data and the present findings suggested that HTMF exhibits a good binding propensity to BSA protein which will be helpful for the drug design. PMID- 26773257 TI - Hippocampal 5-HT7 receptors signal phosphorylation of the GluA1 subunit to facilitate AMPA receptor mediated-neurotransmission in vitro and in vivo. AB - BACKGROUND AND PURPOSE: The 5-HT7 receptor is a GPCR that is the target of a broad range of antidepressant and antipsychotic drugs. Various studies have demonstrated an ability of the 5-HT7 receptor to modulate glutamatergic neurotransmission and cognitive processes although the potential impact upon AMPA receptors has not been investigated directly. The purposes of the present study were to investigate a direct modulation of the GluA1 AMPA receptor subunit and determine how this might influence AMPA receptor function. EXPERIMENTAL APPROACH: The influence of pharmacological manipulation of the 5-HT7 receptor system upon phosphorylation of GluA1 subunits was assessed by Western blotting of fractionated proteins from hippocampal neurones in culture (or proteins resident at the neurone surface) and the functional impact assessed by electrophysiological recordings in rat hippocampus in vitro and in vivo. KEY RESULTS: 5-HT7 receptor activation increased cAMP and relative pCREB levels in cultures of rat hippocampal neurones along with an increase in phosphorylation (Ser845) of the GluA1 AMPA receptor subunit evident in whole neurone extracts and within the neurone surface compartment. Electrophysiological recordings in rat hippocampus demonstrated a 5-HT7 receptor-mediated increase in AMPA receptor mediated neurotransmission in vitro and in vivo. CONCLUSIONS AND IMPLICATIONS: The 5-HT7 receptor-mediated phosphorylation of the GluA1 AMPA receptor provides a molecular mechanism consistent with the 5-HT7 receptor-mediated increase in AMPA receptor-mediated neurotransmission. PMID- 26773262 TI - X-ray diffraction and Raman spectroscopy study of white decorations on tricolored ceramics from Northwestern Argentina. AB - White virgules, commas, and dot designs on tricolored ceramics are sporadically found in different archaeological sites located in Northwestern Argentina area, as Puna and Quebrada de Humahuaca. This decorating style has been reported in several articles, but few previous archaeometric studies have been carried out on the pigment composition. Fragments from Puna and Quebrada archaeological sites, belonging to Regional Development Period (900-1430 AD), were analyzed by X-ray diffraction and Raman spectroscopy in order to characterize the pigments employed. Red and black pigments are based on iron and manganese oxides, as it has been extensively reported for the NW Argentina area. White pigments from white virgules, comma, and dot designs have shown different composition. Hydroxyapatite was found in samples from Doncellas site (North Puna region), and calcium and calcium-magnesium containing compounds, as vaterite and dolomite, along with titanium containing compounds were detected on samples from Abralaite (Central Puna region) and Gasoducto (Quebrada de Humahuaca region). It has been concluded that pigment composition is not characteristic of a unique region. PMID- 26773263 TI - A combined TD-DFT and spectroscopic investigation of the solute-solvent interactions of efavirenz. AB - Efavirenz, commercially known as Sustiva(r) or Stocrin(r), is a first-line antiretroviral treatment for HIV/AIDS. The clinical efficacy of efavirenz is, however, hindered by its solubility. We sought to investigate the solute-solvent effects of efavirenz by means of a combined qualitative study implementing UV visible spectrophotometry, (1)H NMR spectroscopy and time-dependent density functional theory (TD-DFT) calculations. The UV spectrum displayed two main absorbance maxima, band I and band II at 246-260 and 291-295 nm, respectively. A general bathochromic shift was noticed from the non-polar solvent cyclohexane to the most polar solvent DMSO (~13.69 nm) in band I and a smaller bathochromic (~2.17 nm) and hyperchromic shift was observed in band II. We propose that these observations are due to the role of the amino (NH) and carbonyl (CO) functionalities which induce charge-transfer and intra- and inter-molecular hydrogen bonding. The aromatic and amine protons showed the most deshielded effects in the observed chemical shifts (delta) in the more polar DMSO-d6 solvent relative to CDCl3. The (1)H NMR chemical shifts observed are due to the increased delocalization of the lone pair electrons of the amino nitrogen with increased polarity of the more polar DMSO solvent. The theoretical reproduction of the UV and (1)H NMR spectra by means of TD-DFT is in good agreement with the experimental results. PMID- 26773265 TI - Conformation analysis of 1",4"-Dispirocyclohexane-6,6'-bis(benzothiazoline): Combined IR, Raman, XRD and DFT approach. AB - The subject of the study is the structure and conformation of 1",4"-Dispiro cyclohexane-6,6'-bis(benzothiazoline), a dispiro compound that has a cyclohexyl ring flanked by two benzothiazoline rings on either side. Using single crystal X ray diffraction measurements, Infra-red absorption, and Raman spectroscopy techniques, it is found that the central cyclohexyl ring assumes the chair conformation and the sulfur, nitrogen atoms in both the benzothiazole rings are in the trans configurations. The experimental findings are further corroborated by geometry optimization and frequency calculations at B3LYP/6-311++G** level of theory using Gaussian 09 suite of program. PMID- 26773264 TI - An approach combining real-time release testing with near-infrared spectroscopy to improve quality control efficiency of Rhizoma paridis. AB - Raw material examination is a critical process in the industrial production of traditional Chinese medicine (TCM); high accuracy and minimal time consumption are both required. In this study, near-infrared (NIR) spectroscopy was applied to improve the quality control efficiency of Rhizoma paridis. Partial least squares regression (PLSR) was first used to develop quantitative calibration models, and the discriminant analysis model was established to qualitatively discriminate the qualified samples from the unqualified samples. These two established NIR models were applied for real-time release testing (RTRT) of R. paridis. R. paridis saponins (RPS)>=0.6% and moisture <=12% were used as the quantitative releasing criteria of RTRT according to the Chinese Pharmacopoeia. Qualified samples classified by the discriminant analysis model were deemed to meet the qualitative releasing criterion of RTRT. Using the established quantitative model, 24 samples were allowed to be released to the subsequent production processes with 100% accuracy. For the qualitative RTRT analysis, three samples were misclassified as the unqualified class and were released unsuccessfully, the accuracy of the qualitative RTRT was 90%. Therefore, the quantitative RTRT was more feasible for actual manufacturing processes. Based on this study, a rapid and effective quantitative NIR spectroscopic method was proposed for the RTRT of R. paridis. The combination of RTRT and NIR spectroscopy could be a potential tool to improve the quality control efficiency of R. paridis. PMID- 26773266 TI - Characterization of adsorption and electronic excited states of quercetin on titanium dioxide nanoparticles. AB - Adsorption of quercetin on colloidal titanium dioxide nanoparticles in ethanol and its excited-state electronic structure were investigated by means of electronic and vibrational spectroscopies. The changes in electronic charge redistribution as reflected by the dipole moment difference, ?MU, between the ground and excited electronic states were measured with electroabsorption spectroscopy and analyzed using results of TD DFT computations. Adsorption of quercetin causes a red shift of its absorption spectrum. Raman spectra of quercetin analyzed with reference to analogous data for morin indicate binding of quercetin through the hydroxy groups of the catechol moiety. The difference dipole moment, which is 5.5D in free quercetin, increases to 11.8D in opposite direction in adsorbed quercetin, and is associated with charge-transfer to the Ti atom. The computed transition energy, intensity, vector DeltaMU and molecular orbitals involved in the electronic transition at different molecular configurations indicate a bidentate chelating mode of binding of quercetin. PMID- 26773267 TI - Cancrinite from nepheline syenite (mariupolite) of the Oktiabrski massif, SE Ukraine, and its growth history. AB - Secondary cancrinite, (Na5.88K<0.01)?5.88(Ca0.62 Fe0.01Mn0.01Zn<0.01 Mg<0.01)?0.64[Si6.44Al 5.56O24](CO3)0.67(OH)0.26(F<0.01,Cl<0.01).2.04H2O), was found as accessory component of mariupolite (albite-aegirine nepheline syenite) from the Oktiabrski massif in the Donbass (SE Ukraine). It probably crystallized from a subsolidus reaction involving nepheline (and sodalite?) and calcite dissolved in the aqueous-carbonic fluid at the maximum temperature of 930 degrees C, decreasing to hydrothermal conditions. It is depleted in sodium, calcium and carbon, what results in the occurrence of vacant positions at both cationic and anionic sites. Ca-deficient cancrinite crystallized from the same hydrothermal Si-undersaturated fluids enriched in the ions such as Na(+), Ca(2+), Cl(-), F(-), HCO3(-), which formed calcite, sodalite, natrolite and fluorite. It has dark-red CL colours with patchy zoning, what indicates the variable/diverse fluid composition during its formation. In the CL spectrum of cancrinite only one broad emission band at 410 nm is observed, which can be attributed to O* center (the recombination of a free electron with an O(-) hole center). The formation of secondary CO3-rich species, i.e. cancrinite and calcite in mariupolite suggests that redox conditions in the Oktiabrski massif were oxidizing at the postmagmatic stage. PMID- 26773269 TI - Biopreservation of RBCs for in vitro Plasmodium falciparum culture. PMID- 26773271 TI - Drug development from the bench to the pharmacy: with special reference to dipeptidyl peptidase-4 inhibitor development. AB - The dipeptidyl peptidase-4 (DPP-4) inhibitor concept is an example of prospective drug design and development based upon a distinct endocrine hypothesis. The design of enzyme inhibitors is a pragmatic approach to drug design; being compatible with the identification and optimization of small molecules that have properties commensurate with oral administration, as well as acceptable drug metabolism, distribution and elimination characteristics. Glucagon-like peptide 1 (GLP-1), a hormone with a spectrum of favourable metabolic actions, including glucose-dependent stimulation of insulin and inhibition of glucagon secretion, provided the endocrine basis from which the idea of using DPP-4 inhibitors as anti-diabetic agents was developed. The origin of the DPP-4 inhibitor concept was inspired by the angiotensin-converting enzyme inhibitor approach, which succeeded in establishing a class of extensively used therapeutic agents for the treatment of cardiovascular disorders. PMID- 26773268 TI - Causes and consequences of limitations in visual working memory. AB - Recent methodological and conceptual advances have led to a fundamental reappraisal of the nature of visual working memory (WM). A large corpus of evidence now suggests that there might not be a hard limit on the number of items that can be stored. Instead, WM may be better captured by a highly limited--but flexible--resource model. More resource can be allocated to prioritized items but, crucially, at a cost of reduced recall precision for other stored items. Expectations may modulate resource distribution, for example, through neural oscillations in the alpha band increasing inhibition of irrelevant cortical regions. Our understanding of the neural architecture of WM is also undergoing radical revision. Whereas the prefrontal cortex has previously dominated research endeavors, other cortical regions, such as early visual areas, are now considered to make an essential contribution, for example holding one or more items in a privileged state or "focus of attention" within WM. By contrast, the striatum is increasingly viewed as crucial in determining why and how items are gated into memory, while the hippocampus, it has controversially been argued, might be critical in the formation of temporally resilient conjunctions across features of stored items in WM. PMID- 26773272 TI - Dental implant surgery in patients in treatment by dabigatran. AB - OBJECTIVES: The aim of this study was to evaluate the incidence of bleeding complications after dental implant placement in patients in treatment by the oral anticoagulant dabigatran following a specific protocol. MATERIAL AND METHODS: Seventy-one patients were divided into two groups: 29 had been taking dabigatran for over 6 months (150 mg orally every 12 h) before implant surgery (dabigatran group) and a control group consisting of 42 healthy subjects. Patients were treated in an outpatient setting. All subjects received dental implants in different positions, dabigatran group patients 12 h after the last dose of dabigatran. Nonabsorbable sutures were used and patients were given gauzes impregnated with tranexamic acid 5% to bite on for 30-60 min. Dabigatran patients resumed medication 8 h after the procedure, resuming usual dosage (every 12 h) the day after surgery. RESULTS: Two dabigatran patients and two control patients presented slight bleeding the day after surgery. Bleeding was managed with gauzes impregnated with tranexamic acid. No statistically significant differences (P = 0.542) were found in relation to bleeding episodes between the groups, with a relative risk of 0.675 based on the pooled groups and a 95% confidence interval of 0.090-5.088. CONCLUSIONS: Dental implant surgery in patients taking dabigatran can be performed safely providing 12 h have passed since the last dose and local hemostatic measures are applied. Normal dosage can be resumed 8 h after implant surgery. PMID- 26773270 TI - Germination and early plant development of ten plant species exposed to titanium dioxide and cerium oxide nanoparticles. AB - Ten agronomic plant species were exposed to different concentrations of nano titanium dioxide (nTiO2 ) or nano-cerium oxide (nCeO2 ) (0 MUg/mL, 250 MUg/mL, 500 MUg/mL, and 1000 MUg/mL) to examine potential effects on germination and early seedling development. The authors modified a standard test protocol developed for soluble chemicals (OPPTS 850.4200) to determine if such an approach might be useful for screening engineered nanomaterials (ENMs) and whether there were differences in response across a range of commercially important plant species to 2 common metal oxide ENMs. Eight of 10 species responded to nTiO2 , and 5 species responded to nCeO2 . Overall, it appeared that early root growth may be a more sensitive indicator of potential effects from ENM exposure than germination. The observed effects did not always relate to the exposure concentration, indicating that mass-based concentration may not fully explain the developmental effects of these 2 ENMs. The results suggest that nTiO2 and nCeO2 have different effects on early plant growth of agronomic species, with unknown effects at later stages of the life cycle. In addition, standard germination tests, which are commonly used for toxicity screening of new materials, may not detect the subtle but potentially more important changes associated with early growth and development in terrestrial plants. Environ Toxicol Chem 2016;35:2223 2229. Published 2016 Wiley Periodicals Inc. on behalf of SETAC. This article is a US Government work and, as such, is in the public domain in the United States of America. PMID- 26773273 TI - Homo- and Heterodinuclear Ir and Rh Imine-functionalized Protic NHC Complexes: Synthetic, Structural Studies, and Tautomerization/Metallotropism Insights. AB - The influence of the potentially chelating imino group of imine-functionalized Ir and Rh imidazole complexes on the formation of functionalized protic N heterocyclic carbene (pNHC) complexes by tautomerization/metallotropism sequences was investigated. Chloride abstraction in [Ir(cod)Cl{C3 H3N2 (DippN=CMe) kappaN3}] (1 a) (cod=1,5-cyclooctadiene, Dipp=2,6-diisopropylphenyl) with TlPF6 gave [Ir(cod){C3 H3N2 (DippN=CMe)-kappa(2) (C2,Nimine )}](+) [PF6 ](-) (3 a(+) [PF6 ](-)). Plausible mechanisms for the tautomerization of complex 1 a to 3 a(+) [PF6 ](-) involving C2-H bond activation either in 1 a or in [Ir(cod){C3 H3 N2 (DippN=CMe)-kappaN3}2](+) [PF6 ](-) (6 a(+) [PF6 ](-)) were postulated. Addition of PR3 to complex 3 a(+) [PF6 ](-) afforded the eighteen-valence-electron complexes [Ir(cod)(PR3){C3 H3N2 (DippN=CMe)-kappa(2) (C2,Nimine )}](+) [PF6 ](-) (7 a(+) [PF6 ](-) (R=Ph) and 7 b(+) [PF6 ](-) (R=Me)). In contrast to Ir, chloride abstraction from [Rh(cod)Cl{C3H3N2 (DippN=CMe)-kappaN3}] (1 b) at room temperature afforded [Rh(cod){C3 H3N2 (DippN=CMe)-kappaN3}2](+) [PF6 ](-) (6 b(+) [PF6 ](-)) and [Rh(cod){C3 H3N2 (DippN=CMe)-kappa(2) (C2,Nimine )}](+) [PF6 ](-) (3 b(+) [PF6 ](-) ) (minor); the reaction yielded exclusively the latter product in toluene at 110 degrees C. Double metallation of the azole ring (at both the C2 and the N3 atom) was also achieved: [Ir2 (cod)2 Cl{MU-C3H2N2 (DippN=CMe) kappa(2) (C2,Nimine ),kappaN3}] (10) and the heterodinuclear complex [IrRh(cod)2 Cl{MU-C3H2N2 (DippN=CMe)-kappa(2) (C2,Nimine ),kappaN3}] (12) were fully characterized. The structures of complexes 1 b, 3 b(+) [PF6 ](-) , 6 a(+) [PF6 ]( ) , 7 a(+) [PF6 ](-), [Ir(cod){C3HN2 (DippN=CMe)(DippN=CH)(Me)-kappa(2) (N3,Nimine )}](+) [PF6 ](-) (9(+) [PF6 ](-)), 10? Et2 O?toluene, [Ir2 (CO)4 Cl{MU C3H2N2 (DippN=CMe)-kappa(2) (C2,Nimine ),kappaN3}] (11), and 12?2 THF were determined by X-ray diffraction. PMID- 26773276 TI - The effect of different application timings of hyperbaric oxygen treatment on nerve regeneration in rats. AB - BACKGROUND: The aim of the study was to determine the effect of different application timings of hyperbaric oxygen treatment (HBO) on nerve regeneration in rats. MATERIALS AND METHODS: A total of forty 12-week-old female Wistar albino rats were used. The sciatic nerve was transected. The nerve ends were then realigned and repaired using standard microsurgical techniques. Animals were randomly assigned to four groups: 1) No hyperbaric oxygen, sectioned and repaired; 2) HBO started at postoperative first hour, sectioned and repaired; 3) HBO started at postoperative first week, sectioned, and repaired; and 4) HBO started at postoperative second week, sectioned, and repaired. All rats in all groups were evaluated with gait analysis at 8 and 16 weeks postoperatively. Sciatic function index was calculated. Sciatic nerve samples were taken after gait analysis at 16th week. Foreign body reaction, the intensity of the inflammatory cells and types, repair-associated vascular proliferation in the field, axonal vacuolar degeneration of the fibers from the cut line transition density and switching layout, and myelinization density with perineural sheath were evaluated histopathologically. RESULTS: At the 16th week, group 2 demonstrated the best gait analysis results. Gait analysis was better for group 3 than groups 1 and 4 (P < 0.05). No significant differences were observed among the groups in inflammation (P > 0.05). Fibrosis was statistically less in group 2 than that in other groups (P < 0.05); however, no significant differences were observed among groups 1, 3, and 4 (P > 0.05). CONCLUSIONS: Our results suggest that initiating HBO early after nerve repair will make a positive impact on recovery. (c) 2016 Wiley Periodicals, Inc. Microsurgery 36:586-592, 2016. PMID- 26773277 TI - Introducing Dunaliella LIP promoter containing light-inducible motifs improves transgenic expression in Chlamydomonas reinhardtii. AB - Promoter of the light-inducible protein gene (LIP) of Dunaliella was recently isolated in our laboratory. The aim of this work is to find the light-inducible motif in the Dunaliella LIP promoter and verify its regulatory motif with a Gaussia luciferase reporter gene transformed in Chlamydomonas reinhardtii. 400 bp upstream to the translational start site of the Dunaliella LIP gene was gradually truncated and analyzed for the luciferase expression. Furthermore, this promoter comprising duplicated or triplicated light-responsive motifs was tested for its augmentation of light response. Two putative light-responsive motifs, GT-1 binding motif and sequences over-represented in light-repressed promoters (SORLIP) located in the 200 bp LIP promoter fragment were analyzed for their light responsibility. It is turned out that SORLIP was responsible for the light inducible activity. With the copy number of SORLIP up to three showed stronger high light response compared with the native LIP promoter fragment. Therefore, we found a light-responsive DNA motif operating in Chlamydomonas and confirm a synthetic promoter including this motif displayed light inducibility in heterologously transformed green algae for the first time. This light-inducible expression system will be applied to various area of algal research including algal biotechnology. PMID- 26773279 TI - Socioeconomic position and incidence of colorectal cancer in the Swedish population. AB - BACKGROUND: The association between socioeconomic position and incidence of colorectal cancer is inconsistent and differs by global region. We aimed to clarify this association in the Swedish population. METHODS: We conducted a population-based open cohort study using data from Swedish national registers. We included all individuals, aged >=30 years, residing in Sweden between 1993 and 2010. Socioeconomic position was indicated by (1) highest educational level (five groups), and (2) disposable income (quintiles). We used Poisson regression to estimate incidence rate ratios (IRR) and 95% confidence intervals (95% CI) of colon and rectal cancer, and colon and rectal dysplasia. RESULTS: In total, 97,827,817 person-years were accumulated and 82,686 cases of colorectal cancer were diagnosed. Compared to men with 'higher secondary' education, the adjusted IRRs (95% CI) of rectal cancer in men with 'primary or less', 'lower secondary', 'lower university' or 'higher university' education were: 1.06 (1.00, 1.11), 1.05 (0.99, 1.10), 0.96 (0.89, 1.03), and 0.92 (0.86, 0.98), respectively. In women, the corresponding figures were: 1.04 (0.95, 1.14), 1.03 (0.94, 1.13), 0.92 (0.82, 1.02) and 0.92 (0.82, 1.02). Disposable income was not associated with rectal cancer incidence. Adjusted IRRs of colon cancer did not differ between levels of education or disposable income overall or for specific colon sub-sites. Neither education nor disposable income was consistently associated with incidence of colon or rectal dysplasia. CONCLUSIONS: Prevention strategies for colon cancer should be applicable to individuals regardless of their socioeconomic position. However, factors conferred by education, e.g., health awareness, may be important for approaches aiming to reduce inequalities in incidence of rectal cancer. Further evaluation of cancer prevention and health promotion strategies among less educated groups is warranted. PMID- 26773280 TI - Comparison of a commercial blood cross-matching kit to the standard laboratory method for establishing blood transfusion compatibility in dogs. AB - OBJECTIVE: To evaluate the accuracy of a commercial blood transfusion cross-match kit when compared to the standard laboratory method for establishing blood transfusion compatibility. DESIGN: A prospective observational in intro study performed from July 2009 to July 2013. SETTING: Private referral veterinary center. ANIMALS: Ten healthy dogs, 11 anemic dogs, and 24 previously transfused dogs. INTERVENTIONS: None. MEASUREMENT AND MAIN RESULTS: Forty-five dogs were enrolled in a prospective study in order to compare the standard blood transfusion cross-match technique to a commercial blood transfusion cross matching kit. These dogs were divided into 3 different groups that included 10 healthy dogs (control group), 11 anemic dogs in need of a blood transfusion, and 24 sick dogs that were previously transfused. Thirty-five dogs diagnosed with anemia secondary to multiple disease processes were cross-matched using both techniques. All dogs cross-matched via the kit had a compatible major and minor result, whereas 16 dogs out of 45 (35%) had an incompatible cross-match result when the standard laboratory technique was performed. The average time to perform the commercial kit was 15 minutes and this was 3 times shorter than the manual cross-match laboratory technique that averaged 45-50 minutes to complete. CONCLUSIONS: While the gel-based cross-match kit is quicker and less technically demanding than standard laboratory cross-match procedures, microagglutination and low-grade hemolysis are difficult to identify by using the gel-based kits. This could result in transfusion reactions if the gel-based kits are used as the sole determinant of blood compatibility prior to transfusion. Based on our results, the standard manual cross-match technique remains the gold standard test to determine blood transfusion compatibility. PMID- 26773281 TI - COMPUTED TOMOGRAPHIC APPEARANCE OF THE TEMPOROMANDIBULAR JOINT IN 1018 ASYMPTOMATIC HORSES: A MULTI-INSTITUTION STUDY. AB - Published descriptions of nonseptic arthritis of the equine temporomandibular joint (TMJ) are rare and large studies investigating variations in the TMJ for asymptomatic horses are lacking. The objectives of this cross-sectional, retrospective, multi-institutional study were to describe anatomical variations in the TMJ detected using computed tomography (CT) in an equid population asymptomatic for TMJ disease and determine whether these variations were associated with patient signalment, reason for CT examination, or CT slice width. Medical records at eight hospitals were searched for horses that had head/neck CT scans and no clinical signs of TMJ disease. Age, breed, sex, clinical presentation, and CT slice width data were recorded. Alterations in CT contour and density of the mandibular condyles, mandibular fossae, and TMJ intra articular discs were described for each horse. Generalized logistic regression was used to test associations between anatomical variations and horse age. A total of 1018 horses were sampled. Anatomical variations were found in TMJ CT images for 40% of horses and 29% of joints. These were dichotomous with regard to age. Horses <1 year old commonly had alterations in the shape and density of the mandibular condyle. Older horses commonly had spherical hypodensities within the mandibular condyles consistent with bone cysts; and hyperdense regions of the intra-articular disc consistent with dystrophic mineralization. Findings indicated that TMJ anatomic variations were common in CT images of younger and older horses asymptomatic for TMJ disease. Future studies are needed to more definitively characterize these CT variations using gross pathology and histopathology. PMID- 26773282 TI - Time to burn (calories)? The impact of retirement on physical activity among mature Americans. AB - Physical activity is crucial for maintaining and improving health, especially at advanced ages. While retirement increases the amount of time available for physical activity, there is only limited evidence regarding the causal effect of retirement on recommended levels of physical activity. Addressing this gap in the literature, we use data from the U.S. Health and Retirement Study to estimate the causal impact of retirement on meeting the federal government's 2008 Physical Activity Guidelines for Americans. Using official early and normal retirement ages as instruments for retirement, our causal IV analyses suggest significant positive effects of retirement on meeting the Guidelines. These effects are robust with regard to the treatment of unobserved individual-specific heterogeneity, the measurement of guideline compliance, the definition of retirement and respondents' health insurance status. We also show that the effects of retirement on physical activity are larger for persons with higher levels of education and wealth. PMID- 26773284 TI - The role of microRNA in myelodysplastic syndromes: beyond DNA methylation and histone modification. AB - Myelodysplastic syndromes (MDS) are heterogeneous group of hematologic disorders of mostly elderly and based on distinct clinical phenotypes. Current paradigm of their pathogenesis relies on somatic gene mutations combined with the predisposing defective osteohematopoietic niche, but due to the breakout in epigenetic research scientific focus has steered toward two most common epigenetic modifications: methylation mechanisms and histone modification. At the same time, relatively few studies have been undertaken regarding the third epigenetic pathway - microRNAs - in MDS. The main aim of this review is to provide the basics of microRNA biology and function in oncogenesis, showing the complexity of mechanisms behind this single-stranded 22 nucleotides long RNA molecule, with further focus on its implication in MDS pathology and clinical context. By extensive literature search, we have shown enough evidence for their deregulation in MDS. However, few studies have addressed the issue on pathogenic events in MDS and its association with specific microRNAs. Preliminary research in clinical setting has shown the possible utility of microRNAs in terms of prognosis and therapy, although we are only beginning to understand various implications of microRNAs in MDS and further extensive research is warranted to answer multiple questions arising from interconnection of this epigenetic mechanism in MDS. PMID- 26773283 TI - Gut-derived cholecystokinin contributes to visceral hypersensitivity via nerve growth factor-dependent neurite outgrowth. AB - BACKGROUND AND AIM: Irritable bowel syndrome is characterized by abdominal pain and altered bowel habits and may occur following stressful events or infectious gastroenteritis such as giardiasis. Recent findings revealed a link between cholecystokinin (CCK), neurotrophin synthesis, and intestinal hyperalgesia. The aim was to investigate the role of CCK in visceral hypersensitivity using mouse models challenged with a bout of infection with Giardia lamblia or psychological stress, either alone or in combination. METHODS: Abdominal pain was evaluated by visceromoter response to colorectal distension. Nerve fibers in intestinal tissues were stained using immunohistochemistry (PGP9.5). Human neuroblastoma SH SY5Y cells incubated with bacterial-free mouse gut supernatant or recombinant CCK 8S were assessed for neurite outgrowth and nerve growth factor (NGF) production. RESULTS: Intestinal hypersensitivity was induced by either stress or Giardia infection, and a trend of increased pain was seen following dual stimuli. Increased CCK levels and PGP9.5 immunoreactivity were found in colonic mucosa of mice following stress and/or infection. Inhibitors to the CCK-A receptor (L 364718) or CCK-B receptor (L-365260) blocked visceral hypersensitivity caused by stress, but not when induced by giardiasis. Nerve fiber elongation and NGF synthesis were observed in SH-SY5Y cells after incubation with colonic supernatants from mice given the dual stimuli, or after treatment with CCK-8S. Increased nerve fiber length by colonic supernatant and CCK-8S was attenuated by L-365260 or neutralizing anti-NGF. CONCLUSIONS: This new model successfully recapitulates intestinal hypernociception induced by stress or Giardia. Colonic CCK contributes to visceral hypersensitivity caused by stress, but not by Giardia, partly via NGF-dependent neurite outgrowth. PMID- 26773278 TI - Prospective association of liver function biomarkers with development of hepatobiliary cancers. AB - INTRODUCTION: Serum liver biomarkers (gamma-glutamyl transferase, GGT; alanine aminotransferase, ALT; aspartate aminotransferase, AST; alkaline phosphatase, ALP; total bilirubin) are used as indicators of liver disease, but there is currently little data on their prospective association with risk of hepatobiliary cancers. METHODS: A nested-case control study was conducted within the prospective EPIC cohort (>520,000 participants, 10 European countries). After a mean 7.5 mean years of follow-up, 121 hepatocellular carcinoma (HCC), 34 intrahepatic bile duct (IHBC) and 131 gallbladder and biliary tract (GBTC) cases were identified and matched to 2 controls each. Circulating biomarkers were measured in serum taken at recruitment into the cohort, prior to cancer diagnosis. Multivariable adjusted conditional logistic regression was used to calculate odds ratios and 95% confidence intervals (OR; 95%CI). RESULTS: In multivariable models, 1SD increase of each log-transformed biomarker was positively associated with HCC risk (OR(GGT)=4.23, 95%CI:2.72-6.59; OR(ALP)=3.43, 95%CI:2.31-5.10;OR(AST)=3.00, 95%CI:2.04-4.42; OR(ALT)=2.69, 95%CI:1.89-3.84; OR(Bilirubin)=2.25, 95%CI:1.58-3.20). Each liver enzyme (OR(GGT)=4.98; 95%CI:1.75 14.17; OR(AST)=3.10, 95%CI:1.04-9.30; OR(ALT)=2.86, 95%CI:1.26-6.48, OR(ALP)=2.31, 95%CI:1.10-4.86) but not bilirubin (OR(Bilirubin)=1.46,95%CI:0.85 2.51) showed a significant association with IHBC. Only ALP was significantly associated with GBTC risk (OR(ALP)=1.59, 95%CI:1.20-2.09). CONCLUSION: This study shows positive associations between circulating liver biomarkers in sera collected prior to cancer diagnoses and the risks of developing HCC or IHBC, but not GBTC. PMID- 26773286 TI - Quetiapine for Intensive Care Unit Delirium: The Evidence Remains Weak. PMID- 26773289 TI - Medical Savings Account balance and outpatient utilization: Evidence from Guangzhou, China. AB - Medical Savings Account (MSA) is a financing instrument designed to reduce consumer-side moral hazards. The Urban Employee Basic Medical Insurance (UEBMI) scheme in China has an MSA component in addition to a Social Risk-pooling Fund. This study examines the association between MSA balance and outpatient utilization in Guangzhou, China, and determines MSA's impact on utilization under different circumstances. It also seeks to ascertain whether MSA has achieved its intended functions of "Cost-containment", "Saving for the future" and "Enabling utilization". The first group of 114,657 MSA account-holders, including both employees and retirees, who consistently insured with UEBMI from 2002 to 2007, are selected for this study. A two-part model is employed to estimate the effect of the MSA balance on the probability of outpatient services utilization and on the level of outpatient expenditure. Results show that MSA balance is significantly associated with the likelihood of using outpatient services as well as the level of outpatient expenditure. The association is a non-linear U-shaped relationship for working individuals, and an inverted U-shaped relationship for the retirees. The observed U-shaped relationship for working individuals implies that at lower MSA balance levels, a negative balance-expenditure relation exits, while at higher MSA balance levels, the relationship is positive--suggesting possible improper utilization when MSA balance reaches high levels. Setting a maximum MSA balance limit and/or allowing enrollees to use MSA funds to purchase private insurance appears to be desirable. The observed inverted U-shaped relationship for retirees suggests that many retirees have to spend whatever funds they have in their MSA for outpatient care, but the less healthy individuals are able to shift the spending to inpatient care which is mainly financed by the Social Risk-pooling Fund. The results of this study also affirm the usefulness of MSA in performing its intended functions. PMID- 26773287 TI - A Bifunctional Electrocatalyst for Oxygen Evolution and Oxygen Reduction Reactions in Water. AB - Oxygen reduction and water oxidation are two key processes in fuel cell applications. The oxidation of water to dioxygen is a 4 H(+)/4 e(-) process, while oxygen can be fully reduced to water by a 4 e(-)/4 H(+) process or partially reduced by fewer electrons to reactive oxygen species such as H2O2 and O2(-). We demonstrate that a novel manganese corrole complex behaves as a bifunctional catalyst for both the electrocatalytic generation of dioxygen as well as the reduction of dioxygen in aqueous media. Furthermore, our combined kinetic, spectroscopic, and electrochemical study of manganese corroles adsorbed on different electrode materials (down to a submolecular level) reveals mechanistic details of the oxygen evolution and reduction processes. PMID- 26773290 TI - Does retirement (really) lead to worse health among European men and women across all educational levels? AB - OBJECTIVES: Whereas the view that retirement would have negative effects on health is widespread, many existing studies may be biased because they do not sufficiently take into account the issue of reverse causation. Using a large longitudinal dataset for twelve Western European countries, this study uses an instrumental variables approach to assess effects of retirement on health. METHODS: Longitudinal data for the years 2009-2012 for 75,722 men and 63,911 women from twelve Western European countries are derived from the European Union Statistics on Income and Living Conditions. Health outcomes used in this study are self-rated health, activity limitations and chronic conditions. Country- and sex-specific early- and full-pension ages are used as instruments. Models were stratified by sex as well as educational levels to assess potential effect heterogeneity. RESULTS: Results obtained from conventional random-effects models suggest that retired men and women have higher chances of reporting bad self rated health, activity limitations as well as chronic conditions. However, using an instrumental variables (IV) approach the results suggest that retirement can lead to health improvements in self-reported health as well as activity limitations among men and women. The health improvements associated with retirement among men and women exist across all educational levels. DISCUSSION: Contrary to several previous studies, the results suggest that retirement may have health preserving effects. The positive effects of retirement and health exist for low as well as high educated men and women. PMID- 26773288 TI - Executive functioning deficits in children with neurofibromatosis type 1: The influence of intellectual and social functioning. AB - The aim of this study was to provide a broad picture of Executive Functioning (EF) in NF1 children, while taking into account their lower average IQ and increased Autism Spectrum Disorder (ASD) symptoms. This was done by administering an extended battery of tasks and questionnaires, designed to reduce task impurity, that measures five EF domains (inhibition, cognitive flexibility, working memory, generativity and planning) in a laboratory setting and in daily life. Data are presented for 42 age- and gender-matched NF1, 52 typically developing, and 52 ASD children (8-18 years). Our results indicated that although EF is highly influenced by IQ and severity of ASD symptoms, EF deficits seem to be a core feature of NF1 and not merely a secondary effect of a lower IQ and/or increased ASD symptoms. However, additional research is needed to confirm these findings. PMID- 26773291 TI - Participants' use of enacted scenes in research interviews: A method for reflexive analysis in health and social care. AB - In our study of a workforce intervention within a health and social care context we found that participants who took part in longitudinal research interviews were commonly enacting scenes from their work during one-to-one interviews. Scenes were defined as portions of the interviews in which participants directly quoted the speech of at least two actors. Our analysis in this paper focuses on these enacted scenes, and compares the content of them before and after the intervention. We found that, whilst the tensions between consistency and change, and change management, were common topics for scene enactment in both pre and post-intervention data, following the intervention participants were much more likely to present themselves as active agents in that change. Post-intervention enacted scenes also showed participants' reports of taking a service user perspective, and a focus on their interactions with service users that had been absent from pre-intervention data. In addition, descriptions of positive feeling and emotions were present in the post-intervention enacted scenes. We suggest that this analysis confirms the importance of enacted scenes as an analytic resource, and that this importance goes beyond their utility in identifying the impact of this specific intervention. Given the congruence between the themes prominent in enacted scenes, and those which emerged from a more extensive qualitative analysis of these data, we argue that enacted scenes may also be of wider methodological importance. The possibility of using scene enactment as an approach to the validation of inductive analysis in health and social care settings could provide a useful methodological resource in settings where longitudinal ethnographic observation of frontline care staff is impossible or impractical. PMID- 26773292 TI - Effects of reduced cost-sharing on children's health: Evidence from Japan. AB - Although childhood health status is widely recognized as an important determinant for future achievement and health, there are few studies on the impact of patient cost-sharing on children's health. This paper investigates whether reduced cost sharing leads to an improvement of health status among preschool and school-age children in Japan, exploiting regional disparities in expansions of municipality level subsidy programs for out-of-pocket expenditure. With the eligibility for this subsidy program, known as the Medical Subsidy for Children and Infants (MSCI), the coinsurance rate generally decreases from 30% or 20% to zero for outpatient health care services and drug prescriptions. In order to uncover the impact of this program, I conducted an original survey of all municipalities in Japan to understand the time-series evolution of the eligible age for the MSCI in October 2013 (weighted response rate = 75%), and the probability of being eligible for the MSCI was then calculated by the age, prefecture of residence, and year. These probabilities were matched to children's health data from the Comprehensive Survey of Living Conditions from 1995 to 2010. The results show that eligibility for the MSCI improves subjective measures of health status among preschool children (n = 115,019). However, I find no such improvement among school-age children (n = 133,855). In addition, MSCI eligibility does not reduce hospitalization among either preschool or school-age children. Taken together, this study finds no discernible effects on health among school-age children, suggesting recent rapid expansions of the MSCI for this age group have not been associated with the improvement of health status. PMID- 26773294 TI - Pragmatic prevention, permanent solution: Women's experiences with hysterectomy in rural India. AB - Hysterectomy appears to be on the rise amongst low-income, rural women in India as routine treatment for gynaecological ailments. This paper explores the individual, household, socio-economic and health system factors that influenced women's decisions to undergo hysterectomy in rural Gujarat, with a focus on women's perspectives. Interviews were conducted with 35 rural, low-income women who had undergone hysterectomy, local gynaecologists and other key informants, alongside observation of daily life and health-related activities. Inductive, open coding was conducted within a framework analysis to identify thematic influences on the decision to undergo hysterectomy. Women underwent hysterectomy at an average age of 36, as treatment for typically severe gynaecological ailments. I argue that women, faced with embedded social inequality in the form of gender biases, lack of labour security and a maternal-centric health system, demonstrated pragmatic agency in their decision to remove the uterus. When they experienced gynaecological ailments, most sought two to three opinions and negotiated financial and logistical concerns. The health system offered few non invasive services for non-maternal health issues. Moreover, women and health care providers believed there is limited utility of the uterus beyond childbearing. Women's responsibilities as caretakers, workers and producers drove them to seek permanent solutions that would secure their long-term work and health security. Thus, hysterectomy emerged as a normalised treatment for gynaecological ailments, particularly for low-income women with limited resources or awareness of potential side effects. In this setting, hysterectomy reflects the power structures and social inequalities in which women negotiated medical treatment- and the need to reverse a culture of permanent solutions for low-income women. PMID- 26773293 TI - Capability deprivation of people with Alzheimer's disease: An empirical analysis using a national survey. AB - How can one assess the quality of life of older people--particularly those with Alzheimer's disease--from the point of view of their opportunities to do valued things in life? This paper is an attempt to answer this question using as a theoretical framework the capability approach. We use data collected on 8841 individuals above 60 living in France (the 2008 Disability and Health Household Survey) and propose a latent variable modelling framework to analyse their capabilities in two fundamental dimensions: freedom to perform self-care activities and freedom to participate in the life of the household. Our results show that living as a couple, having children, being mobile and having access to local shops, health facilities and public services enhance both capabilities. Age, household size and male gender (for one of the two capabilities) act as impediments while the number of impairments reduces both capabilities. We find that people with Alzheimer's disease have a lower level and a smaller range of capabilities (freedom) when compared to those without, even when the latter have several impairments. Hence they need a special attention in policy-making. PMID- 26773295 TI - Place-based perceptions of the impacts of fracking along the Marcellus Shale. AB - We examined community perspectives and experiences with fracking in Doddridge County, West Virginia, USA as part of a larger assessment to investigate the potential health impacts associated with fracking in neighboring Maryland, USA. In November 2013, we held two focus groups with community residents who had been impacted by fracking operations and conducted field observations in the impacted areas. Employing grounded theory, we conducted qualitative analysis to explore emergent themes related to direct and indirect health impacts of fracking. Three components of experience were identified, including (a) meanings of place and identity, (b) transforming relationships, and (c) perceptions of environmental and health impacts. Our findings indicate that fracking contributes to a disruption in residents' sense of place and social identity, generating widespread social stress. Although community residents acknowledged the potential for economic growth brought about by fracking, rapid transformations in meanings of place and social identity influenced residents' perceptions of environmental and health impacts. Our findings suggest that in order to have a more complete understanding of the health impacts of fracking, future work must consider the complex linkages between social disruption, environmental impacts, and health outcomes through critical engagements with communities undergoing energy development. PMID- 26773297 TI - Interleukin-1 and inflammasomes in alcoholic liver disease/acute alcoholic hepatitis and nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. AB - Both alcoholic liver disease (ALD) and nonalcoholic fatty liver disease are characterized by massive lipid accumulation in the liver accompanied by inflammation, fibrosis, cirrhosis, and hepatocellular carcinoma in a substantial subgroup of patients. At several stages in these diseases, mediators of the immune system, such as cytokines or inflammasomes, are crucially involved. In ALD, chronic ethanol exposure sensitizes Kupffer cells to activation by lipopolysaccharides through Toll-like receptors, e.g., Toll-like receptor 4. This sensitization enhances the production of various proinflammatory cytokines such as interleukin-1 (IL-1) and tumor necrosis factor-alpha, thereby contributing to hepatocyte dysfunction, necrosis, and apoptosis and the generation of extracellular matrix proteins leading to fibrosis/cirrhosis. Indeed, neutralization of IL-1 by IL-1 receptor antagonist has recently been shown to potently prevent liver injury in murine models of ALD. As IL-1 is clearly linked to key clinical symptoms of acute alcoholic hepatitis such as fever, neutrophilia, and wasting, interfering with the IL-1 pathway might be an attractive treatment strategy in the future. An important role for IL-1-type cytokines and certain inflammasomes has also been demonstrated in murine models of nonalcoholic fatty liver disease. IL-1-type cytokines can regulate hepatic steatosis; the NLR family pyrin domain containing 3 inflammasome is critically involved in metabolic dysregulation. CONCLUSION: IL-1 cytokine family members and various inflammasomes mediate different aspects of both ALD and nonalcoholic fatty liver disease. (Hepatology 2016;64:955-965). PMID- 26773296 TI - Food insufficiency, depression, and the modifying role of social support: Evidence from a population-based, prospective cohort of pregnant women in peri urban South Africa. AB - RATIONALE: Food insecurity has emerged as an important, and potentially modifiable, risk factor for depression. Few studies have brought longitudinal data to bear on investigating this association in sub-Saharan Africa. OBJECTIVE: To estimate the association between food insufficiency and depression symptom severity, and to determine the extent to which any observed associations were modified by social support. METHODS AND RESULTS: We conducted a secondary analysis of population-based, longitudinal data collected from 1238 pregnant women during a three-year cluster-randomized trial of a home visiting intervention in Cape Town, South Africa. Surveys were conducted at baseline, 6 months, 18 months, and 36 months (85% retention). A validated, single-item food insufficiency measure inquired about the number of days of hunger in the past week. Depression symptom severity was measured using the Xhosa version of the 10 item Edinburgh Postnatal Depression Scale. In multivariable regression models with cluster-correlated robust estimates of variance, lagged food insufficiency had a strong and statistically significant association with depression symptom severity (beta = 0.70; 95% CI, 0.46-0.94), suggesting a 6.5% relative difference in depression symptom severity per day of hunger. In stratified analyses, food insufficiency had a statistically significant association with depression only among women with low levels of instrumental support. Using quantile regression, we found that the adverse impacts of food insufficiency were experienced to a greater degree by women in the upper end of the conditional distribution of depression symptom severity. Estimates from fixed-effects regression models and fixed-effects quantile regression models, accounting for unobserved confounding by time-invariant characteristics, were similar. CONCLUSIONS: Food insufficiency was associated with depression symptom severity, particularly for women in the upper end of the conditional depression distribution. Instrumental social support buffered women against the adverse impacts of food insufficiency. PMID- 26773298 TI - Assessment of platelet-derived thrombogenicity with the total thrombus-formation analysis system in coronary artery disease patients receiving antiplatelet therapy. AB - BACKGROUND: Accurate evaluation of thrombogenicity helps to prevent thrombosis and excessive bleeding. The total thrombus-formation analysis system (T-TAS) was developed for quantitative analysis of platelet thrombus formation by the use of microchips with thrombogenic surfaces (collagen, platelet chip [PL-chip]; collagen plus tissue factor, atherome chip [AR-chip]). We examined the utility of the T-TAS in the assessment of the efficacy of antiplatelet therapy in patients with coronary artery disease (CAD). METHODS AND RESULTS: In this cross-sectional study, 372 consecutive patients admitted to the cardiovascular department were divided into three groups: patients not receiving any antiplatelet therapy (control, n = 56), patients receiving aspirin only (n = 69), and patients receiving aspirin and clopidogrel (n = 149). Blood samples were used for the T TAS to measure the platelet thrombus-formation area under the curve (AUC) at various shear rates (1500 s(-1) [PL18 -AUC10 ] and 2000 s(-1) [PL24 -AUC10 ] for the PL-chip; 300 s(-1) [AR10 -AUC30 ] for the AR-chip). The on-clopidogrel platelet aggregation was measured by the use of P2Y12 reaction units (PRUs) with the VerifyNow system. The mean PL24 -AUC10 levels were 358 +/- 111 (+/- standard deviation) (95% confidence interval [CI] 328.9-387.1) in the control group, 256 +/- 108 (95% CI 230.5-281.5) in the aspirin group, and 113 +/- 91 (95% CI 98.4 127.6) in the aspirin/clopidogrel group. In the aspirin/clopidogrel group, the PL24 -AUC10 was higher in poor metabolizers (PMs) with cytochrome P450 2C19(CYP2C19) polymorphisms (152 +/- 112, 95% CI 103.4-200.6) than in the non-PM group (87 +/- 74, 95% CI 73.8-100.2). CONCLUSIONS: Our findings suggest that the PL24 -AUC10 level measured by the T-TAS is a potentially suitable index for the assessment of antiplatelet therapy in CAD patients. PMID- 26773299 TI - Superresolution microscopy with transient binding. AB - For single-molecule localization based superresolution, the concentration of fluorescent labels has to be thinned out. This is commonly achieved by photophysically or photochemically deactivating subsets of molecules. Alternatively, apparent switching of molecules can be achieved by transient binding of fluorescent labels. Here, a diffusing dye yields bright fluorescent spots when binding to the structure of interest. As the binding interaction is weak, the labeling is reversible and the dye ligand construct diffuses back into solution. This approach of achieving superresolution by transient binding (STB) is reviewed in this manuscript. Different realizations of STB are discussed and compared to other localization-based superresolution modalities. We propose the development of labeling strategies that will make STB a highly versatile tool for superresolution microscopy at highest resolution. PMID- 26773300 TI - Membrane platforms for biological nanopore sensing and sequencing. AB - In the past two decades, biological nanopores have been developed and explored for use in sensing applications as a result of their exquisite sensitivity and easily engineered, reproducible, and economically manufactured structures. Nanopore sensing has been shown to differentiate between highly similar analytes, measure polymer size, detect the presence of specific genes, and rapidly sequence nucleic acids translocating through the pore. Devices featuring protein nanopores have been limited in part by the membrane support containing the nanopore, the shortcomings of which have been addressed in recent work developing new materials, approaches, and apparatus resulting in membrane platforms featuring automatability and increased robustness, lifetime, and measurement throughput. PMID- 26773301 TI - RNA nanomedicines: the next generation drugs? AB - RNA therapeutics could represent the next generation personalized medicine. The variety of RNA molecules that can inhibit the expression of any mRNA using, for example, RNA interference (RNAi) strategies, or increase the expression of a given protein using modified mRNA together with new gene editing strategies open new avenues for manipulating the fate of diseased cells while leaving healthy cells untouched. In addition, these therapeutic RNA molecules can maximize the treatment of diseases and minimize its adverse effects. Yet, the promise of RNA therapeutics is hindered by the lack of efficient delivery strategies to selectively target these molecules into specific cells. Herein, we will focus on the challenges and opportunities of the delivery of therapeutic RNAi molecules into cancer cells with special emphasis on solid tumors. Solid tumors represent more than 80 percent of cancers and some are very challenging to treat, not merely due to physiological barriers but also since the tumor microenvironment (TME) is a complex milieu of accessory cells besides the cancerous cells. In this review, we will highlight various limiting factors to successful delivery, current clinical achievements and future outlook focusing on RNAi therapeutics to the TME. PMID- 26773302 TI - Nanotransporters for drug delivery. AB - Soluble nanotransporters for drugs can be profiled for targeted delivery particularly to maximize the efficacy of highly potent drugs while minimizing off target effects. This article outlines on the use of biological carrier molecules with a focus on albumin, various drug linkers for site specific release of the drug payload from the nanotransporter and strategies to combine these in various ways to meet different drug delivery demands particularly the optimization of the payload per nanotransporter. PMID- 26773303 TI - DNA nanotechnology and fluorescence applications. AB - Structural DNA nanotechnology allow researchers to use the unique molecular recognition properties of DNA strands to construct nanoscale objects with almost arbitrary complexity in two and three dimensions. Abstracted as molecular breadboards, DNA nanostructures enable nanometer-precise placement of guest molecules such as proteins, fluorophores, or nanoparticles. These assemblies can be used to study biological phenomena with unprecedented control over number, spacing, and molecular identity. Here, we give a general introduction to structural DNA nanotechnology and more specifically discuss applications of DNA nanostructures in the field of fluorescence and plasmonics. PMID- 26773304 TI - Bio-inspired antifouling approaches: the quest towards non-toxic and non-biocidal materials. AB - Biofouling is an undesirable process in which organisms and their by-products encrust a surface. Antifouling solutions are of great importance since biofouling has negative effects on numerous species, ecosystems, and areas including water treatment facilities, health-care systems, and marine devices. Many useful solutions have been developed in the last few decades. However, with the emergence of environmental issues, the search for new promising non-toxic materials has expanded. One approach tries to mimic natural antifouling surfaces and relies on mechanisms of action derived from nature. Since these materials are based on natural systems, they are mostly biocompatible and more efficient against complex fouling. In this review, we cover the latest advances in the field of antifouling materials. We specifically focus on biomaterials that are based on the chemical and physical behavior of biological systems. PMID- 26773305 TI - Fabrication of a High-Quality, Porous, Surface-Confined Covalent Organic Framework on a Reactive Metal Surface. AB - A major goal of heterogeneous catalysis is to optimize catalytic selectivity. Selectivity is often limited by the fact that most heterogeneous catalysts possess sites with a range of reactivities, resulting in the formation of unwanted by-products. The construction of surface-confined covalent organic frameworks (sCOFs) on catalytically active surfaces is a desirable strategy, as pores can be tailored to operate as catalytic nanoreactors. Direct modification of reactive surfaces is impractical, because the strong molecule-surface interaction precludes monomer diffusion and formation of extended architectures. Herein, we describe a protocol for the formation of a high-quality sCOF on a Pd rich surface by first fabricating a porous sCOF through Ullmann coupling on a Au rich bimetallic surface on Pd(111). Once the sCOF has formed, thermal processing induces a Pd-rich surface while preserving the integrity of the sCOF architecture, as evidenced by scanning tunneling microscopy and titration of Pd sites through CO adsorption. PMID- 26773306 TI - Aspalathin, a dihydrochalcone C-glucoside, protects H9c2 cardiomyocytes against high glucose induced shifts in substrate preference and apoptosis. AB - SCOPE: Energy deprivation in the myocardium is associated with impaired heart function. This study aims to investigate if aspalathin (ASP) can ameliorate hyperglycemic-induced shift in substrate preference and protect the myocardium against cell apoptosis. METHODS AND RESULTS: H9c2 cells were exposed to, either normal (5.5 mM) or high (33 mM) glucose concentrations for 48 h. Thereafter, cells exposed to 33 mM glucose were treated with metformin (1 MUM) or ASP (1 MUM), as well as a combination of metformin and ASP for 6 h. In vitro studies revealed that ASP improved glucose metabolism by decreasing fatty acid uptake and subsequent beta-oxidation through the decreased expression of adenosine monophosphate-activated protein kinase threonine 172 (pAMPK (Thr172)) and carnitine palmitoyltransferase 1 (CPT1), while increasing acetyl-CoA carboxylase (ACC) and glucose transporter 4 (GLUT4) expression. ASP inhibited high glucose induced loss of membrane potential in H9c2 cells as observed by an increase in 5' ,6,6'-tetrachloro-1,1',3,3' -tetraethylbenzimidazolyl-carbocyanine iodide (JC-1) ratio (orange?red fluorescence) and decreased apoptosis by reducing intracellular reactive oxygen species and DNA nick formation, while increasing glutathione, superoxide dismutase, uncoupling protein 2 (UCP2), and Bcl-2?Bax ratio. CONCLUSION: Our study provides evidence that ASP increases glucose oxidation and modulates fatty acid utilization producing a favorable substrate shift in H9c2 cardiomyocytes exposed to high glucose. Such a favorable shift will be of importance in the protection of cardiomyocytes in the diabetic heart. PMID- 26773308 TI - Feasibility of self-performed urine pregnancy testing for follow-up after medical abortion. AB - OBJECTIVES: Medical termination of pregnancy (MToP) follow-up can be simplified by combining a clinical assessment with blood and urine human chorionic gonadotropin (hCG) measurements, the later using a low sensitivity urinary pregnancy (LSUP) testing. This study aimed to describe follow-up modalities of MToP in real-life conditions, and assess the benefit of a self-performed urine semiquantitative test in the follow-up of MToP and its feasibility, acceptability and user-friendliness as well as the women capacity to interpret it correctly. Concordance between qualitative results from LSUP test and quantitative values from the blood hCG measurement was also assessed. STUDY DESIGN: From May to November 2013, we conducted a national, prospective, observational study with 17 centres offering MToP. Pregnant women with at least 63 days of amenorrhea (DA) requesting MToP were recruited during a consultation visit for medical abortion. RESULTS: A total of 322 women were included (mean age: 28.1 +/- 6.4 years). The mean term of pregnancy at the time of MToP was 44.1 +/- 6.2 DA. Two regimens were mostly used: 200 and 600 mg mifepristone followed by 800 MUg of misoprostol (51.5 and 33.3% of patients, respectively). 82.0% of women attended the follow-up visit (N=264), 5.0% were reached by phone and 13.0% were lost to follow-up. 86.2% of women performed blood and urine measurements, as requested, on the same day (+/- one day). The MToP success rate was 93.6% of women. There were two ongoing pregnancies (0.7%) and 16 retained products of conception (5.7%). The overall concordance between urine and blood hCG levels was estimated at 94.5% CI95% [90.2%; 97.4%]. According to the physician's opinion, a majority of women (89.6%) read the urine test correctly. Self-performing the LSUP test at home was found reassuring for 39.9% of women, and satisfactory for 25.8% of them, but 2.8% considered it to be alarming and 11.8% unsettling. CONCLUSION: In our study, a self-performed LSUP test showed good concordance with blood test and appeared to be relevant, efficient and safe for women to monitor MToP success. PMID- 26773307 TI - Effect of imatinib on growth of experimental endometriosis in rats. AB - OBJECTIVE: Currently, medical and surgical treatment options for endometriosis are limited due to suboptimal efficacy, and also safety and tolerance issues. Long-term use of gonadotrophin-releasing hormone analogs, androgenes, and the danazol, which are widely used drugs for endometriosis, is usually not possible due to their suboptimal safety and tolerance profile. The lack of an effective, tolerable and safe treatment option for endometriosis makes animal models of experimental endometriosis necessary to study candidate drugs. The aim of this study was to investigate the efficacy of imatinib on the experimental endometriosis in a rat model. STUDY DESIGN: Endometriosis was induced by autotransplantation of uterine tissue into the peritoneal cavity. Twenty-four rats, which had visually confirmed endometriotic implants on subsequent laparotomy, were randomized into three groups to receive imatinib (25mg/kg/day, p.o.), anastrozole (0.004 mg/day, p.o.), or normal saline (0.1 mL, i.p.) for 14 days. After removal of endometriotic tissue and H & E staining, endometriosis score was determined according to a semiquantitative histological classification. Also, immunostaining with primary antibodies including VEGF, CD117, and Bax were used for immunohistochemical (IHC) examination. RESULTS: Both anastrozole and imatinib suppressed the growth of endometriotic tissue and reduced the number of ovarian follicles. Although the difference was not statistically significant, imatinib was less effective than anastrozole for treatment of endometriosis. CONCLUSION: Imatinib effectively treats experimental endometriosis by its inhibitor effects on angiogenesis and cell proliferation. PMID- 26773309 TI - Differences in psychophysical well-being and signs of depression in couples undergoing their first consultation for assisted reproduction technology (ART): an Italian pilot study. AB - OBJECTIVE: The data we refer to belong to a longitudinal research project starting at the first contact of individual couples with the Infertility Unity; they were then followed-up till pregnancy or failure of treatments. The study aims at investigating in depth the emotional state of patients admitted for first consultation. Specifically, we investigated the emotional state of the two members of an infertile couple, considering also their biomedical and socio demographic characteristics. STUDY DESIGN: This is a cross-sectional study evaluating a consecutive series of 309 couples, consulting for the first time our Infertility Unit for a multidisciplinary diagnostic evaluation in relation to their infertility. The multidisciplinary equip is composed of a gynaecologist, an andrologist and a clinical psychologist. Two standardized instruments were administered by the clinical psychologist to the two members of the couple: the Edinburgh Depression Scale (EDS) and the General Health Questionnaire-form 12 (GHQ-12), for screening of non-somatic signs of depression and psychophysical well-being, respectively. Couples were eligible for the study if they had not received any prior ART treatment in our Unit and were able to read and understand Italian. In addition, they had to agree to provide informed consent for the study. RESULTS: We obtained a response in 62% of all eligible couples. There were two major unexpected findings: CONCLUSION: Psychological and counselling services dedicated to ART should consider also socio-demographic data and always specifically consider gender differences, not only a couple's psychology and its dynamics. PMID- 26773310 TI - Hematologic malignancies in South Africa 2000-2006: analysis of data reported to the National Cancer Registry. AB - Little is known about the incidence patterns of hematologic malignancies in Sub Saharan Africa, including South Africa. We estimated incidence rates of pathology confirmed adult cases of leukemia, myeloma and related diseases (myeloma), Hodgkin lymphoma (HL), and non-Hodgkin lymphoma (NHL) reported to the National Cancer Registry of South Africa (NCR) between 2000 and 2006, by age, gender, and population group (Black, White, Coloured, Asian/Indian). Gender-specific age standardized rates were calculated overall and by population group and incidence rate ratios (IRRs) were estimated using Poisson regression models. Between 2000 and 2006, there were 14662 cases of leukemia, myeloma, HL, and NHL reported to the registry. Incidence rates of reported hematologic malignancies were generally 20-50% higher among males than females. Our analyses suggested marked differences in the rates of reported hematologic malignancies by population group which were most pronounced when comparing the White versus Black population groups (IRRs ranging from 1.6 for myeloma to 3.8 for HL for males and females combined). Challenges related to diagnosis and reporting of cancers may play a role in the patterns observed by population group while the set-up of the NCR (pathology based) could lead to some degree of under-ascertainment in all groups. This is the first country-wide report of the incidence of hematologic malignancies in South Africa. Despite challenges, it is important to analyze and report available national cancer incidence data to raise awareness of the cancer burden and to characterize patterns by demographic characteristics so as ultimately to improve the provision of cancer-related health care. PMID- 26773311 TI - Experimental Testing of Water Disinfection Models under Varying Hydraulic and Kinetic Conditions. AB - The concomitant effects of hydraulics and reaction kinetics on the disinfection efficiency (DE) of Chlorine Contact Tank (CCT) setups were experimentally assessed, to test the predictive-ability of first order kinetics models: Chick Watson (C-W), C-t rule and Wehner-Wilhelm (W-W). Prototype tests were conducted using river water characterised for quality parameters, chlorine demand and inactivation rates of total and thermotolerant coliform. Poor, average and superior CCT baffling conditions were assessed by tracer experimentation and for their DE under three chlorine dosages. The models' DE predictive-ability was comparable and high for superior baffling, but decreased differently with the hydraulic efficiency (maximum errors of +15.3% with W-W, +26.0% with C-W and 36.6% with C-t). The positive bias shown by W-W renders it unsafe for CCT design, so the results favoured the C-t rule as the preferred analytical tool of comparable complexity. Potential refinements to these models that could lead to operational savings are identified. PMID- 26773312 TI - Self-Perception of Aging and Satisfaction With Children's Support. AB - Objectives: Those with self-beliefs in negative aging may desire a stronger support network to buffer against potential threats and may hence see their current network as less than adequate. This study investigated whether negative self-perception of aging is associated with increased dissatisfaction with children's support. Method: Six hundred and forty Chinese older adults with at least one child and a total of 2,108 adult children rated the degree of support received from each child individually and the degree to which it met their expectation. Additionally, the participants responded to measures of self perception of aging (both positive and negative), neuroticism, instrumental activities of daily living, chronic illnesses, financial strain, and living status. The multilevel dataset was analyzed using mixed-effects regression. Results: Individuals who had a more negative self-perception of aging, who were younger, who lived alone, and who had fewer children provided lower support satisfaction ratings after support received from children was controlled for. Positive self-perception of aging was unrelated to support satisfaction. Neuroticism did not account for the relationship between negative self-perception of aging and support satisfaction. Discussion: A negative self-perception of aging may create vulnerability to intergenerational tension that puts older people at risk of adverse psychological and physical health outcomes. PMID- 26773313 TI - Age-related Decline in Case-Marker Processing and its Relation to Working Memory Capacity. AB - Objectives: Purposes of the current study were to investigate whether age-related decline emerged in a case-marker assignment task (CMAT) and to explore the relationship between working-memory (WM) capacity and case-marker processing. Method: A total of 121 individuals participated in the study with 62 younger adults and 59 elderly adults. All were administered a CMAT that consisted of active and passive constructions with canonical and noncanonical word-order conditions. A composite measure of WM tasks served as an index of participants' WM capacity. Results: The older group performed worse than the younger group, and the noncanonical word order elicited worse performance than the canonical condition. The older group demonstrated greater difficulty in case-marker processing under the canonical condition and passive construction. Regression results revealed that age, education, and sentence type were the best predictors to account for performance on the CMAT. Discussion: The canonicity of word order and passive construction were critical factors related to decline in abilities in a case-marker assignment. The combination of age, education, and sentence type factors accounted for overall performance on case-marker processing. Results indicated the crucial necessity to find a cognitively and linguistically demanding condition that elicits aging effects most efficiently, considering language-specific syntactic features. PMID- 26773314 TI - Extracellular Matrix Stiffness Controls VEGF Signaling and Processing in Endothelial Cells. AB - Vascular endothelial growth factor A (VEGF) drives endothelial cell maintenance and angiogenesis. Endothelial cell behavior is altered by the stiffness of the substrate the cells are attached to suggesting that VEGF activity might be influenced by the mechanical cellular environment. We hypothesized that extracellular matrix (ECM) stiffness modifies VEGF-cell-matrix tethering leading to altered VEGF processing and signaling. We analyzed VEGF binding, internalization, and signaling as a function of substrate stiffness in endothelial cells cultured on fibronectin (Fn) linked polyacrylamide gels. Cell produced extracellular matrices on the softest substrates were least capable of binding VEGF, but the cells exhibited enhanced VEGF internalization and signaling compared to cells on all other substrates. Inhibiting VEGF-matrix binding with sucrose octasulfate decreased cell-internalization of VEGF and, inversely, heparin pre-treatment to enhance Fn-matrix binding of VEGF increased cell internalization of VEGF regardless of matrix stiffness. beta1 integrins, which connect cells to Fn, modulated VEGF uptake in a stiffness dependent fashion. Cells on hard surfaces showed decreased levels of activated beta1 and inhibition of beta1 integrin resulted in a greater proportional decrease in VEGF internalization than in cells on softer matrices. Extracellular matrix binding is necessary for VEGF internalization. Stiffness modifies the coordinated actions of VEGF-matrix binding and beta1 integrin binding/activation, which together are critical for VEGF internalization. This study provides insight into how the microenvironment may influence tissue regeneration and response to injury and disease. J. Cell. Physiol. 231: 2026-2039, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26773315 TI - Curcumin prevents paracetamol-induced liver mitochondrial alterations. AB - OBJECTIVE: In the present study was evaluated if curcumin is able to attenuate paracetamol (PCM)-induced mitochondrial alterations in liver of mice. METHODS: Mice (n = 5-6/group) received curcumin (35, 50 or 100 mg/kg bw) 90 min before PCM injection (350 mg/kg bw). Plasma activity of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) was measured; histological analyses were done; and measurement of mitochondrial oxygen consumption, mitochondrial membrane potential, ATP synthesis, aconitase activity and activity of respiratory complexes was carried out. KEY FINDINGS: Curcumin prevented in a dose-dependent manner PCM-induced liver damage. Curcumin (100 mg/kg) attenuated PCM-induced liver histological damage (damaged hepatocytes from 28.3 +/- 7.7 to 8.3 +/- 0.7%) and increment in plasma ALT (from 2300 +/- 150 to 690 +/- 28 U/l) and AST (from 1603 +/- 43 to 379 +/- 22 U/l) activity. Moreover, curcumin attenuated the decrease in oxygen consumption using either succinate or malate/glutamate as substrates (evaluated by state 3, respiratory control ratio, uncoupled respiration and adenosine diphosphate/oxygen ratio), in membrane potential, in ATP synthesis, in aconitase activity and in the activity of respiratory complexes I, III and IV. CONCLUSIONS: These results indicate that the protective effect of curcumin in PCM-induced hepatotoxicity is associated with attenuation of mitochondrial dysfunction. PMID- 26773316 TI - Inhibition by Seeds of Phalaris canariensis Extracts of Key Enzymes Linked to Obesity. AB - CONTEXT: Obesity and its associated diseases are an increasing problem around the world. One hyperglycemic remedy is reduction of glucose absorption performed by suppressing digestion of carbohydrates and lipids through the use of inhibitors. Phalaris canariensis (P canariensis) is a species belonging to the Graminaceae family and is used in traditional medicine in Mexico for treatment of diabetes and obesity. OBJECTIVE: The aim of the study was to evaluate the effects of different extracts of the seeds of P canariensis on enzymes metabolizing fat and carbohydrates, obtained using 3 solvents. DESIGN: The seeds of P canariensis were extracted using hexane (ALH), chloroform (ALC), and methanol (ALM) and were investigated for their antiobesity potential. SETTING: This research was conducted in the Laboratory of Research of Natural Products in the School of Chemical Engineering at the National Polytechnic Institute and in the Research Laboratory of Enzymology in the National School of Biological Sciences. OUTCOME MEASURES: Different concentrations of the extracts were used to study the inhibition of enzymatic activity by porcine pancreatic alpha-amylase, with carbose as a positive control. The inhibitory activity of alpha-glucosidase was determined using the standard method with bovine serum albumin (BSA). Pancreatic lipase (PL) activity was measured by absorbance at 412 nm, and the data obtained were compared with orlistat. The PL activity was assessed using a second method measuring the rate of release of oleic acid from triolein. Lipoprotein lipase (LPL) activity was measured by released (3H)-oleic acid. Lipolytic activity in cultured, mouse, 3T3-Ll adipocytes was used as a measure of hormone-sensitive lipase activity. The inhibitory activity of rat intestinal sucrase was determined by measuring the glucose released. A Caco-2 cell assay determined the content of free glucose. RESULTS: The ALH extract of P canariensis showed potent inhibitory activity with IC50 values of 2.13 and 1.25 mg/mL as compared with alpha-amylase and alpha-glucosidase, respectively, and produced inhibition in rat intestinal sucrose. Further, the ALM extract showed significantly inhibitory effects against PL, LPL, and lipolysis of 3T3-LI adipocytes. CONCLUSIONS: The results provide evidence for the effects of the seeds of P canariensis for a retarded absorption of carbohydrates and lipids through the inhibition of enzymes that are related to obesity and diabetes mellitus type 2. PMID- 26773317 TI - Canary Seed in Diabetes: Sweet Harmony? PMID- 26773318 TI - Preliminary Measurement of Electromagnetic Fields and Microdischarges From the Human Body. AB - CONTEXT: From 1978-1999, a large number of experts and scholars in China tested and analyzed the external qi of qigong (ie, the electrical signals [ES] released from human practitioners). Development of negatives from some tests had revealed the existence of speckles on the films. In 1998, the current research team analyzed some of the negatives that had been exposed to the ES. OBJECTIVE: The current research team intended to test for the presence of ES in qigong using the dielectric-barrier discharge (DBD) method. DESIGN: The study design involved 2 measurements: electromagnetic test of a open, placebo-controlled methodology and an optical test of single-blinded open, placebo-controlled methodology. SETTING: The study occurred in Taiyuan, Suzhou, and Shenzhen (China) as well as in Hong Kong. PARTICIPANTS: Participants were 10 qigong masters and practitioners and 5 nonpractitioners from 4 cities. INTERVENTION: In the ES test, the practitioners released ES and the nonpractitioners simulated the release of ES, using 2 channels. Any ambient disturbance was recorded on both channels. For the photo file, the practitioner or nonpractitioner could press his or her palm onto 1 envelope that contained film or could hold his or her palm a certain distance (5 30 cm) above the envelope to release ES or simulate its release, respectively. OUTCOME MEASURES: An oscilloscope, current probes, and photo negatives were used to acquire >50,000 images. A type of discharged electromagnetic field (EMF), with a frequency of approximately 0.3-200 MHz, was recorded. RESULTS: The microdischarge pulses were positive, with a pulse width from 2-100 ns and with a total charge of approximately 0.001-0.2 nC. Many speckles could also be clearly seen in the photo negatives. Within the context of DBD theory, the speckles could be individual footprints of a barrier discharge for which the human skin acts as a barrier layer. Thus, the study measured reproducible field energy or an EMF and microdischarges. CONCLUSIONS: ES were measured; then EMFs with a frequency of approximately 0.3-200 MHz and microdischarge pulses were recorded. Within the context of DBD theory, those results suggest that the microdischarge may act as a barrier discharge to which the human skin forms a barrier layer. PMID- 26773319 TI - Efficacy of Theta Binaural Beats for the Treatment of Chronic Pain. AB - CONTEXT: According to the National Institutes of Health, in 2011, chronic pain affected from approximately 10% to >50% of the adult population in the United States, with a cost of $61 billion to US businesses annually. OBJECTIVE: The pilot study assessed the effects that an external, audio, neural stimulus of theta binaural beats (TBB) had on returning the brain neurosignature for chronic pain to homeostasis. METHODS: The quantitative, experimental, repeated-measures crossover study compared the results of 2 interventions in 2 time-order sequences. An a priori analysis indicated a sample size of 28 participants was needed for a 2-way repeated-measures analysis of variance (ANOVA). SETTING: The study was conducted in Richmond, VA, USA, with participants recruited from the financial sector. PARTICIPANTS: Thirty-six US adults with various types of chronic pain, and with a median age of 47 y, ranging in ages from 26-69 y, participated in the study. The study experienced 4 dropouts. INTERVENTION: Participants listened to 2 recordings-one using TBB at 6 Hz (TBB intervention) and one using a placebo of a nonbinaural beat tone of 300 Hz (sham intervention) for 20 min daily. Both interventions lasted 14 successive days each, with some participants hearing the TBB intervention first and the sham intervention second and some hearing them in the reverse order. Participants listened to the interventions via a Web site on the Internet or via a compact disc. Interviews were conducted either in person or telephonically with e-mail support. OUTCOME MEASURES: Using the West Haven-Yale Multidimensional Pain Inventory (MPI), potential changes in perceived severity of chronic pain were measured (1) at baseline; (2) after the first test at 14 d, either TBB or sham intervention; and (3) after the second test at 28 d-either TBB or sham intervention. The analysis compared the average mean for pretest and first and second posttest scores. RESULTS: The analysis indicated a large main effect for the TBB intervention in reducing perceived pain severity, P<.001 (F2,60=84.98, r=0.74). Although the TBB and the placebo interventions both reduced the pain scores, a post hoc Bonferroni correction that compared pairs of MPI scores found a 77% larger drop in the mean for the TBB intervention, from M=4.60 at pretest to M=2.74 at the end of both TBB periods than in the mean for the sham intervention, with a change from M=4.60 at pretest to M=4.17 at the end of both sham periods. CONCLUSIONS: The results supported the hypothesis that an external audio protocol of TBB was effective in reducing perceived pain severity for participants. PMID- 26773320 TI - Yoga-based Psychotherapy Groups for Boys Exposed to Trauma in Urban Settings. AB - BACKGROUND: Children who experience abuse and neglect and are exposed to adverse life events are at risk of developing emotional and behavioral problems. They may display variable internalizing and externalizing symptoms, such as posttraumatic stress, depression, anxiety, low self-esteem, and aggression. Yoga may be able to regulate body-brain pathways that cause stress following traumatic experiences, thereby reducing adverse mental and physical sequelae. OBJECTIVE: The objective of this preliminary study is to examine changes in functioning following meetings of a yoga-based psychotherapy group (YBPG) for boys with a history of interpersonal trauma exposure. METHODS/DESIGN: The study was a prospective, intervention cohort study. SETTING: The study occurred at an urban-based mental health center focusing on treatment of children exposed to interpersonal trauma in their communities and families. PARTICIPANTS: Participants were 10 boys, aged 8-12 y, who primarily were African-Americans (70%) and who had a history of trauma. INTERVENTION: The YBPG was a 12-wk, yoga-based, group therapy, integrated with mental health treatment that was trauma informed and evidence-based. OUTCOME MEASURES: Measures of attendance and interpersonal functioning-the Behavioral and Emotional Rating Scale 2 (BERS-2) and patient satisfaction surveys-were collected. The pre- and post-YBPG, paired t test; Wilcoxon's signed rank test; and effect sizes were calculated to assess change in interpersonal functioning following the YBPG, as reported by the parents and children. RESULTS: The BERS-2 scores yielded clinically and statistically significant mean improvements on the parents' ratings of participants' (1) Interpersonal Strength, Intrapersonal Strength, and Family Involvement scores, with mean improvements on those subscales being 1.4 (P=.007), 1.9 (P=.012), and 1.4 (P=.045) points, respectively; and (2) Strength Index scores, with a mean improvement of 8.7 (P=.004). The effect size was in the large range. In addition to significant improvements posttreatment, the parents' mean rating score of their children's functioning was closer but still lower than the children's self-reports on all subscales. The attendance rate for the YBPG was among the highest for group therapies at the center. CONCLUSIONS: The study provided preliminary evidence for the feasibility of YBPG as an effective intervention for boys exposed to trauma in urban settings. PMID- 26773321 TI - Physiotherapy and a Homeopathic Complex for Chronic Low-back Pain Due to Osteoarthritis: A Randomized, Controlled Pilot Study. AB - CONTEXT: Osteoarthritis (OA) is a common cause of chronic low-back pain (CLBP) and can be managed with drug therapy and physiotherapy. Homeopathic remedies may assist managing OA; however, research that supports their effectiveness is limited. OBJECTIVES: The study aimed to investigate the efficacy of a homeopathic complex in combination with physiotherapy in treating CLBP due to OA. DESIGN: The study was a 6-wk, randomized, double-blind, placebo-controlled pilot. SETTING: The study took place in a private physiotherapy practice in Gauteng, South Africa. PARTICIPANTS: The participants were 30 males and females, aged 45-75 y, who were receiving physiotherapy treatment for OA of the lumbar spine from a therapist in private practice. INTERVENTIONS: The intervention and control groups both received standard physiotherapy treatment-massage, thermal therapy, and joint mobilization-every 2 wk. In addition, the treatment group received a homeopathic complex-6cH each of Arnica montana, Bryonia alba, Causticum, Kalmia latifolia, Rhus toxicodendron, and Calcarea fluorica. The control group a received a placebo. OUTCOME MEASURES: The primary measure was a visual analogue scale (VAS) for pain. Secondary outcome measures included the Oswestry Disability Index (ODI), an evaluation of each patient's range of motion (ROM) of the lumbar spine, and a determination of each patient's need for pain medication. RESULTS: Intergroup analysis revealed that the treatment group significantly outperformed the control group with regard to pain, daily functioning, and ROM. No difference existed between the groups, however, in the need for conventional pain medication. CONCLUSIONS: The study was too small to be conclusive, but results suggest the homeopathic complex, together with physiotherapy, can significantly improve symptoms associated with CLBP due to OA. PMID- 26773322 TI - Acupuncture and Trigger Point Injections for Fibromyalgia: East-West Medicine Case Report. AB - Fibromyalgia is a clinical syndrome characterized by chronic widespread pain that is often accompanied by >=1 concomitant symptoms (eg, fatigue, poor sleep, cognitive alterations, and mood disturbances). In 2005, an estimated 5 million people in the United States suffered from fibromyalgia, and its growing effect on health-related quality of life is substantial. An increasingly popular hypothesis proposes that noxious, peripheral sensory input might contribute to the initiation and perpetuation of the diffuse pain seen in patients with fibromyalgia. That theory has led to the evaluation of multiple interventions to stimulate distal areas as a means to modulate the peripheral and central nervous systems. It has been the authors' experiences that the combination of trigger point injections and acupuncture provides improved clinical outcomes. In the current article, the authors present a case report of a patient with fibromyalgia who was successfully treated with an integrative approach that combined acupuncture with trigger point injections. PMID- 26773323 TI - Position-dependent interactions of Y-box protein 2 (YBX2) with mRNA enable mRNA storage in round spermatids by repressing mRNA translation and blocking translation-dependent mRNA decay. AB - Many mRNAs encoding proteins needed for the construction of the specialized organelles of spermatozoa are stored as translationally repressed, free messenger ribonucleoproteins in round spermatids, to be actively translated in elongating and elongated spermatids. The factors that repress translation in round spermatids, however, have been elusive. Two lines of evidence implicate the highly abundant and well-known translational repressor, Y-box protein 2 (YBX2), as a critical factor: First, protamine 1 (Prm1) and sperm-mitochondria cysteine rich protein (Smcp) mRNAs are prematurely recruited onto polysomes in Ybx2 knockout mouse round spermatids. Second, mutations in 3' untranslated region (3'UTR) cis-elements that abrogate YBX2 binding activate translation of Prm1 and Smcp mRNAs in round spermatids of transgenic mice. The abundance of YBX2 and its affinity for variable sequences, however, raise questions of how YBX2 targets specific mRNAs for repression. Mutations to the Prm1 and Smcp mRNAs in transgenic mice reveal that strong repression in round spermatids requires YBX2 binding sites located near the 3' ends of their 3'UTRs as locating the same sites in upstream positions produce negligible repression. This location-dependence implies that the assembly of repressive complexes is nucleated by adjacent cis elements that enable cooperative interactions of YBX2 with co-factors. The available data suggest that, in vertebrates, YBX2 has the important role of coordinating the storage of translationally repressed mRNAs in round spermatids by inhibiting translational activity and the degradation of transcripts via translation-dependent deadenylation. These insights should facilitiate future experiments designed to unravel how YBX2 targets mRNAs for repression in round spermatids and how mutations in the YBX2 gene cause infertility in humans. Mol. Reprod. Dev. 83: 190-207, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26773324 TI - Isolation and characterization of mimosine, 3, 4 DHP and 2, 3 DHP degrading bacteria from a commercial rumen inoculum. AB - The presence of the toxic amino acid mimosine in Leucaena leucocephala restricts its use as a protein source for ruminants. Rumen bacteria degrade mimosine to 3,4 and 2,3-dihydroxypyridine (DHP), which remain toxic. Synergistes jonesii is believed to be the main bacterium responsible for degradation of these toxic compounds but other bacteria may also be involved. In this study, a commercial inoculum provided by the Queensland's Department of Agriculture, Fisheries, and Forestry was screened for isolation and characterization of mimosine, 3,4- and 2,3-DHP degrading bacterial strains. A new medium for screening of 2,3-DHP degrading bacteria was developed. Molecular and biochemical approaches used in this study revealed four bacterial isolates - Streptococcus lutetiensis, Clostridium butyricum, Lactobacillus vitulinus, and Butyrivibrio fibrisolvens - to be able to completely degrade mimosine within 7 days of incubation. It was also observed that C. butyricum and L. vitulinus were able to partially degrade 2,3-DHP within 12 days of incubation, while S. lutetiensis, was able to fully degrade both 3,4 and 2,3 DHP. Collectively, we concluded that S. jonesii is not the sole bacterium responsible for detoxification of Leucaena. Comprehensive screening of rumen fluid of cattle grazing on Leucaena pastures is needed to identify additional mimosine-detoxifying bacteria and contribute to development of more effective inoculums to be used by farmers against Leucaena toxicity. PMID- 26773326 TI - What does selective motor control of the upper extremity in cerebral palsy tell us? PMID- 26773325 TI - Safety, pharmacokinetics and pharmacodynamics of the anti-hepcidin Spiegelmer lexaptepid pegol in healthy subjects. AB - BACKGROUND AND PURPOSE: Anaemia of chronic disease is characterized by impaired erythropoiesis due to functional iron deficiency, often caused by excessive hepcidin. Lexaptepid pegol, a pegylated structured l-oligoribonucleotide, binds and inactivates hepcidin. EXPERIMENTAL APPROACH: We conducted a placebo controlled study on the safety, pharmacokinetics and pharmacodynamics of lexaptepid after single and repeated i.v. and s.c. administration to 64 healthy subjects at doses from 0.3 to 4.8 mg.kg(-1) . KEY RESULTS: After treatment with lexaptepid, serum iron concentration and transferrin increased dose-dependently. Iron increased from approximately 20 MUmol.L(-1) at baseline by 67% at 8 h after i.v. infusion of 1.2 mg.kg(-1) lexaptepid. The pharmacokinetics showed dose proportional increases in peak plasma concentrations and moderately over proportional increases in systemic exposure. Lexaptepid had no effect on hepcidin production or anti-drug antibodies. Treatment with lexaptepid was generally safe and well tolerated, with mild and transient transaminase increases at doses >=2.4 mg.kg(-1) and with local injection site reactions after s.c. but not after i.v. administration. CONCLUSIONS AND IMPLICATIONS: Lexaptepid pegol inhibited hepcidin and dose-dependently raised serum iron and transferrin saturation. The compound is being further developed to treat anaemia of chronic disease. PMID- 26773327 TI - Favorable outcome of children and adolescents undergoing lung transplantation at a European adult center in the new era. AB - Lung transplantation (LTx) is an accepted therapy in children with end-stage lung diseases. Pediatric-specific experience is considered important in pediatric LTx. We present our institutional experience and its outcome since the year 2000, asking whether different treatment strategies produce comparable outcomes in pediatric lung transplant recipients at our predominantly adult center. This is a retrospective analysis of children and adolescents aged <=20 years, undergoing LTx between January 2001 and December 2013. Minimum follow-up was 12 months. Primary endpoints were re-transplantation or death. We performed 33 lung transplant procedures in 29 patients. Survival 1 month post-operatively was 96.6%, at 3 months 93.1% and at 12 months 82.8%, respectively. At the end of our follow up, 72.4% of our pediatric cohort was still alive - median post-transplant survival was 59 months (range 0-159). 72.4% of the children were transplanted with support of extracorporeal membrane oxygenation (ECMO), size-reduced donor grafts were used in 69.0%. The differences between post-transplant survival of the "non-ECMO-group" versus the "ECMO-group" (137 vs. 28 months, P=0.7) and "full size" versus "size-reduced bilateral transplants" (61 vs. 28 months, P = 0.7) were not significant, though. There were no anastomotic complications, also not in size-reduced lungs. Our results are well comparable to the international data and show excellent short- and mid-term outcomes. We advocate ECMO-bridge to be considered as a valuable treatment option to prolong time on the waiting list in highly selected patients, as well as size reduction and lobar transplants as a strong strategy to increase the donor pool and reduce donor-recipient size mismatches. Pediatr Pulmonol. 2016;51:1222-1228. (c) 2016 Wiley Periodicals, Inc. PMID- 26773328 TI - The functional relationship between hematopoietic stem cells and developing T lymphocytes. AB - In contrast to all other blood and immune cells, T lymphocytes do not develop in the bone marrow (BM), but in the specialized microenvironment provided by the thymus. Similar to the other lineages, however, all T cells arise from multipotent hematopoietic stem cells (HSCs) that reside in the BM. Not all HSCs give rise to T cells; but how many and what kind of developmental checkpoints are located along this intricate differentiation path is the subject of intense research. Traditionally, this process has been studied almost exclusively using mouse cells, but recent advances in immunodeficient mouse models, high-speed cell sorting, lentiviral transduction protocols, and deep sequencing techniques have allowed these questions to be addressed using human cells. Here we review the process of thymic seeding by BM-derived cells and T cell commitment in humans, discussing recent insights into the clonal composition of the thymus and the definition of developmental checkpoints, on the basis of insights from human severe combined immunodeficiency patients. PMID- 26773329 TI - The problem of pulmonary embolism diagnosis in pregnancy. PMID- 26773330 TI - Sensory function assessment of the human male lower urinary tract using current perception thresholds. AB - AIMS: To evaluate the feasibility and reliability of current perception threshold (CPT) measurement for sensory assessment of distinct locations in the male lower urinary tract (LUT). METHODS: Twelve male subjects (>18 years) without LUT symptoms or medical comorbidities were eligible. CPTs were determined twice (interval: 7-20 days) at the bladder dome, trigone and the proximal, membranous, and distal urethra. Square wave electrical stimulation of 3 Hz/0.2 ms and 0.5 Hz/1 ms was applied using a transurethral 8F catheter placed under fluoroscopic control. Bladder volume was kept constant (60 mL) using a second 10F catheter. Repetitive measurements and reliability were assessed by analysis of variance (ANOVA) and intraclass correlation coefficient (ICC). RESULTS: The ANOVA revealed significant main effects for stimulation site (P = 0.008) and type of stimulation (P < 0.001) with lower CPTs for 0.5 Hz/1 ms compared to 3 Hz/0.2 ms. There was no significant effect for visit number (P = 0.061). CPTs were higher for bladder dome than for proximal (0.5 Hz/1 ms: P = 0.022; 3 Hz/0.2 ms: P = 0.022) and distal urethra (0.5 Hz/1 ms: P = 0.026; 3 Hz/0.2 ms: P = 0.030). Reliability of CPT measurements was excellent to good (ICC = 0.67-0.96) except for the bladder dome (5 Hz/1 ms: ICC = 0.45; 3 Hz/0.2 ms: ICC = 0.20) and distal urethra (3 Hz/0.2 ms: ICC = 0.57). CONCLUSIONS: CPTs can be reliably detected at different LUT locations. However, alert and compliant subjects are essential. CPTs of LUT may become a complementary assessment method providing information on responsiveness and sensitivity of afferent LUT nerves. This is especially relevant for urethral afferents, which are not covered by standard urodynamic investigations. Neurourol. Urodynam. 36:469-473, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 26773331 TI - Glucose test provenance recording in UK primary care: was that fasted or random? AB - AIMS: To describe the proportion of glucose tests with unrecorded provenance in routine primary care data and identify the impact on clinical practice. METHODS: A cross-sectional analysis was conducted of blood glucose measurements from the Royal College of General Practitioner Research and Surveillance Centre database, which includes primary care records from >100 practices across England and Wales. All blood glucose results recorded during 2013 were identified. Tests were grouped by provenance (fasting, oral glucose tolerance test, random, none specified and other). A clinical audit in a single primary care practice was also performed to identify the impact of failing to record glucose provenance on diabetes diagnosis. RESULTS: A total of 2 137 098 people were included in the cross-sectional analysis. Of 203 350 recorded glucose measurements the majority (117 893; 58%) did not have any provenance information. The most commonly reported provenance was fasting glucose (75 044; 37%). The distribution of glucose values where provenance was not recorded was most similar to that of fasting samples. The glucose measurements of 256 people with diabetes in the audit practice (size 11 514 people) were analysed. The initial glucose measurement had no provenance information in 164 cases (64.1%). A clinician questioned the provenance of a result in 41 cases (16.0%); of these, 14 (34.1%) required repeating. Lack of provenance led to delays in the diagnosis of diabetes [median (range) 30 (3-614) days]. CONCLUSIONS: The recording of glucose provenance in UK primary care could be improved. Failure to record provenance causes unnecessary repeated testing, delayed diagnosis and wasted clinician time. PMID- 26773332 TI - Altered mechanical interaction between rat plantar flexors due to changes in intermuscular connectivity. AB - Connective tissue formation following muscle injury and remedial surgery may involve changes in the stiffness and configuration of the connective tissues linking adjacent muscles. We investigated changes in mechanical interaction of muscles by implanting either a tissue-integrating mesh (n = 8) or an adhesion barrier (n = 8) to respectively increase or decrease the intermuscular connectivity between soleus muscle (SO) and the lateral gastrocnemius and plantaris complex (LG+PL) of the rat. As a measure of mechanical interaction, changes in SO tendon forces and proximal-distal LG+PL force differences in response to lengthening LG+PL proximally were assessed 1 and 2 weeks post surgery. The extent of mechanical interaction was doubled 1 week post implantation of the tissue-integrating mesh compared to an unaffected compartment (n = 8), and was more than four times higher 2 weeks post-surgery. This was found only for maximally activated muscles, but not when passive. Implanting the adhesion barrier did not result in a reduction of the mechanical interaction between these muscles. Our findings indicate that the ratio of force transmitted via myofascial, rather than myotendinous pathways, can increase substantially when the connectivity between muscles is enhanced. This improves our understanding of the consequences of connective tissue formation at the muscle boundary on skeletal muscle function. PMID- 26773333 TI - Advances on the Determination of the Astatine Pourbaix Diagram: Predomination of AtO(OH)2 (-) over At(-) in Basic Conditions. AB - It is generally assumed that astatide (At(-) ) is the predominant astatine species in basic aqueous media. This assumption is questioned in non-complexing and non-reductive aqueous solutions by means of high-pressure anion-exchange chromatography. Contrary to what is usually believed, astatide is found to be a minor species at pH=11. A different species, which also bears a single negative charge, becomes predominant when the pH is increased beyond 7. Using competition experiments, an equilibrium constant value of 10(-6.9) has been determined for the formation of this species from AtO(OH) with the exchange of one proton. The identification of this species, AtO(OH)2 (-) , is achieved through relativistic quantum mechanical calculations, which rule out the significant formation of the AtO2 (-) species, while leading to a hydrolysis constant of AtO(OH) in excellent agreement with experiment when the AtO(OH)2 (-) species is considered. Beyond the completion of the Pourbaix diagram of astatine, this new information is of interest for the development of (211) At radiolabeling protocols. PMID- 26773334 TI - Perfusion of the diep flaps: A systematic review with meta-analysis. AB - PURPOSE: Perfusion zones of the deep inferior epigastric perforator (DIEP) flap aid surgeons in estimating approximate tissue territory with reliable perfusion. Since the Hartrampf perfusion zone was developed, it has been modified continuously; however controversies remain regarding whether the recent perfusion models can satisfy current anatomical and clinical evidence. We conducted a comprehensive review of previous studies to synthesize relevant knowledge and critically reappraise current perfusion models. METHODS: All anatomical and clinical studies that investigated perfusion of DIEP flaps were searched, yielding 21 studies suitable for review. A meta-analysis was conducted when sufficient data were provided. RESULTS: The perforators had unpredictable subcutaneous courses and were preferentially directed laterally. The medial and lateral perforators showed different characteristics in terms of branching pattern, orientation, and linking vessels between them. Ex-vivo perfusion findings suggested that medial perforators favored Hartrampf zone II rather than zone III and perfused the entire abdomen frequently, whereas the lateral perforators favored zone III and their perfusion territories were limited primarily to the hemi-abdomen. In the meta-analysis based on the clinical perfusion studies, zone III had significantly higher perfusion than zone II (P = 0.04) and these tendencies remained in both medial and lateral perforator-based flaps. CONCLUSIONS: Considerable discrepancies were found between findings of ex vivo and clinical perfusion studies. A thorough review of existing knowledge based on the perforasome concept explained these discrepancies satisfactorily and revealed unsolved issues of the current perfusion models. Flap perfusion clearly varies widely individually; however, this review will help with surgical planning and decision making. (c) 2016 Wiley Periodicals, Inc. Microsurgery, 38:98-108, 2018. PMID- 26773335 TI - Racemization of undesired enantiomers: Immobilization of mandelate racemase and application in a fixed bed reactor. AB - Production of optically pure products can be based on simple unselective synthesis of racemic mixtures combined with a subsequent separation of the enantiomers; however, this approach suffers from a 50% yield limitation which can be overcome by racemization of the undesired enantiomer and recycling. Application of biocatalyst for the racemization steps offers an attractive option for high-yield manufacturing of commercially valuable compounds. Our work focuses on exploiting the potential of racemization with immobilized mandelate racemase. Immobilization of crude mandelate racemase via covalent attachment was optimized for two supports: Eupergit((r)) CM and CNBr-activated Sepharose 4 Fast Flow. To allow coupling of enzymatic reaction with enantioselective chromatography, a mobile phase composition compatible with both processes was used in enzymatic reactor. Kinetic parameters obtained analyzing experiments carried out in a batch reactor could be successfully used to predict fixed-bed reactor performance. The applicability of the immobilized enzyme and the determined kinetic parameters were validated in transient experiments recording responses to pulse injections of R-mandelic acid. The approach investigated can be used for futher design and optimization of high yield combined resolution processes. The characterized fixed bed enzymatic reactor can be integrated e.g. with chromatographic single- or multicolumn steps in various configurations. PMID- 26773337 TI - Multipotency of melanoblasts isolated from murine skin depends on the Notch signal. AB - BACKGROUND: Melanoblasts (MBs), derived from neural crest cells, only differentiate into melanocytes (Ms) in vivo. We previously showed that MBs isolated from mouse skin were multipotent, generating neurons (Ns) and glial cells (Gs) together with Ms. Using Sox10-IRES-Venus mice and mouse embryonic stem cells, we investigated how MBs expressed their multipotency. RESULTS: MBs generated colonies containing Ns, Gs, and Ms in the presence of ST2 stromal cells, but they generated only M colonies when incubated with keratinocytes or ST2 culture supernatant, thus showing that MBs required contact with ST2 stromal cells for expression of their multipotency. Notch signaling was shown to be one of the important cues for the maintenance and differentiation of MBs through cell cell contact. When Notch signaling was inhibited, MBs mainly generated colonies that contained just one type of cells, Ns, Gs, or Ms; the number of colonies containing two or three types of cells markedly decreased even on ST2 stromal cells, showing restriction of their differentiation potency. Whereas when Notch signaling was activated, the number of colonies containing two or three types of cells increased, indicating that their multipotency had been maintained. CONCLUSIONS: Our results demonstrate that Notch signaling played novel roles in MB multipotency. PMID- 26773338 TI - The conserved genetic background for pluteus arm development in brittle stars and sea urchin. AB - Echinoderm pluteus larvae are considered a classical example of convergent evolution that occurred in sea urchins and brittle stars. Several genes are known to be involved in the development of pluteus arms in sea urchins, including fgfA, pax2/5/8, pea3, otp, wnt5, and tet. To determine whether the convergent evolution of larval arms also involves these genes in brittle stars, their expression patterns were determined in brittle star. We found that all genes showed similar expression in the arms of ophiopluteus to that seen in echinopluteus, suggesting that convergent evolution of pluteus arms occurred by recruitment of a similar set of genes. This may be explained by our observation that some of these genes are also expressed in the spine rudiment of direct-type development sea urchins. We propose an evolutionary scenario wherein the pluteus arms of both echinopluteus and ophiopluteus were acquired by independent co-options of the genetic module responsible for the projection of the adult skeleton. PMID- 26773339 TI - Endocrine and paracrine regulation of meiotic cell cycle progression in teleost oocytes: cAMP at the centre of complex intra-oocyte signalling events. AB - Participation of major endocrine and/or local autocrine/paracrine factors and potential interplay between apparently disparate intra-oocyte signalling events during maintenance and withdrawal of meiotic prophase arrest has been an area of active research in recent years. Studies on oocyte maturation have contributed substantially in the discovery of some of the most important biochemical and cellular events like functional significance of novel membrane-associated steroid receptors, elucidation of maturation promoting factor (MPF), cytostatic factor (CSF) and other signalling cascades that entrain the cell cycle clock to hormonal stimuli. While follicular estrogen has largely been implicated in maintenance of prophase arrest, involvement of maturational steroid and membrane progestin receptor in resumption of meiotic G2-M1 transition in piscine oocytes has been shown earlier. Moreover, detection of ovarian IGF system, maturational gonadotropin stimulation of IGF ligands and potential synergism between maturational steroid and IGF1 in zebrafish oocytes are most recent advancements. Though endocrine/paracrine regulation of cyclic nucleotide-mediated signalling events in meiotic cell cycle progression is well established, involvement of PI3K/Akt signalling cascade has also been reported in fish, amphibian and mammalian oocytes. The major objective of this overview is to describe how fish oocytes maintain high cAMP/PKA activity and how steroid- and/or growth factor mediated signalling cascade regulate this pathway for the withdrawal of meiotic arrest. Moreover, special emphasis is placed on some recent findings on interaction of PKA with some of the MPF-regulating components (e.g., synthesis of cyclin B or MEK/MAPK signalling cascade) for the maintenance of prophase arrest. PMID- 26773340 TI - Estradiol and testosterone modulate the tissue-specific expression of ghrelin, ghs-r, goat and nucb2 in goldfish. AB - Ghrelin, and nesfatin-1 (encoded by nucleobindin2/nucb2) are two metabolic peptides with multiple biological effects in vertebrates. While sex steroids are known to regulate endogenous ghrelin and NUCB2 in mammals, such actions by steroids in fish remain unknown. This study aimed to determine whether estradiol (E2) and testosterone (T) affects the expression of preproghrelin, ghrelin/growth hormone secretagogue receptor (GHS-R), ghrelin O-acyl transferase (GOAT) and NUCB2 in goldfish (Carassius auratus). First, a dose-response assay was performed in which fish were intraperitoneally (ip) implanted with pellets containing 25, 50 or 100 MUg/g body weight (BW) of E2 or T. It was found that sex steroids (100 MUg/g BW) administered for 2.5 days achieved the highest E2 or T in circulation. In a second experiment, fish were ip implanted with pellets containing 100 MUg/g BW of E2, T or without hormone (control). RT-qPCR analyses at 2.5 days post administration show that gut preproghrelin and GOAT expression was upregulated by both E2 and T treatments, while the same effect was observed for GHS-R only in the pituitary. Both treatments also reduced hypothalamic preproghrelin mRNA expression. NUCB2 expression was increased in the forebrain of T treated group and reduced in the gut and pituitary under both treatments. These results show for the first time a modulation of preproghrelin and nucb2/nesfatin-1 by sex steroids in fish. The interaction between sex steroids and genes implicated in both metabolism and reproduction might help meeting the reproduction dependent energy demands in fish. PMID- 26773341 TI - Responsibility and hand washing behaviour. AB - BACKGROUND AND OBJECTIVES: Recent research suggests that compulsions persist due to a self-perpetuating mechanism of poor memory confidence and repetition. However, most of this work has examined checking compulsions and findings may not generalize well to washing compulsions. This study examined the role of responsibility in the persistence of washing behaviour. METHODS: Hand washing was examined in undergraduates (n = 80) high and low in contamination fears (CF) under conditions of high or low responsibility (RL). Wash duration and number of visits to objects/locations key to the wash (e.g., soap) were examined. RESULTS: Overvalued responsibility predicted washing duration across groups. Neither wash duration nor number of visits was associated with memory for the wash. Wash duration predicted post-wash certainty that the wash had prevented harm, but only in the high CF group, and that effect varied according to RL: longer wash duration predicted greater certainty under conditions of low RL but predicted less certainty under conditions of high RL. Greater repetition predicted poorer sensory confidence, but only in the high CF group under high RL conditions. LIMITATIONS: The data were collected in an analogue sample of modest size. Replication in a clinical sample is required. CONCLUSIONS: Self-perpetuating mechanisms identified in perseverative checking seem to also be present in perseverative washing, but only under conditions of high responsibility. Sensory confidence may be more important to perseverative washing than memory confidence. More research is required to understand self-perpetuating mechanisms at play when washing to under conditions of high responsibility. PMID- 26773343 TI - Exposure to chlorpyrifos increases neutral lipid accumulation with accompanying increased de novo lipogenesis and decreased triglyceride secretion in McArdle RH7777 hepatoma cells. AB - Hepatic steatosis is associated with hepatic insulin resistance as well as hypertriglyceridemia. Recent studies have determined exposure to organophosphate (OP) pesticides can cause dyslipidemia and hepatic steatosis. However, the mechanisms through which OPs induced hepatic steatosis are not completely understood. Therefore, the current study was designed to determine if direct exposure to an OP insecticide, chlorpyrifos (CPS), could promote hepatic steatosis and identify putative mechanisms of CPS-induced steatosis. To determine if CPS exposure increased intracellular lipid accumulation, McA-RH7777 cells were incubated with CPS for 48 h then lipid accumulation was determined by Oil Red O staining. Exposure to CPS significantly increased neutral lipid accumulation in a concentration-dependent manner. This increase in Oil Red O staining appears to be due to increased intracellular triglyceride accumulation. In addition to increasing neutral lipid accumulation under normal growth conditions, exposure to CPS increased free fatty acid-induced intracellular neutral lipid accumulation. CPS induced increases in intracellular neutral lipid/triglyceride accumulation appear to be due to increased extracellular free fatty acid accumulation, increased de novo lipogenesis, and decreased fatty acidinduced triglyceride secretion. In summary, the present studies indicate exposure to CPS can have a direct effect on the hepatocyte to promote hepatic steatosis by increasing intracellular lipid/triglyceride accumulation through increased extracellular free fatty acid accumulation, increased hepatic de novo lipogenesis, and decreased triglyceride efflux. PMID- 26773342 TI - Sustained smoking abstinence is associated with reductions in smoking-specific experiential avoidance among treatment-seeking smokers. AB - BACKGROUND AND OBJECTIVES: Smoking-specific experiential avoidance is related to the maintenance of cigarette smoking. However, it is unclear whether sustained smoking abstinence is associated with subsequent reductions in smoking-specific experiential avoidance. METHODS: Daily smokers (n = 149) underwent a cessation attempt in the context of a 4-session smoking cessation treatment trial. Participants provided biochemical verification of smoking status at 1 week, 2 weeks, and 1 Month post-quit day. Smoking-specific experiential avoidance was assessed per the Avoidance and Inflexibility Scale (AIS) - the total score and two factor scores were examined at 1 Month post-quit day as a function of abstinence status. Two path models were conducted and included participant sex, treatment condition, and pre-cessation nicotine dependence, smoking-specific experiential avoidance, and presence of emotional disorders as covariates. RESULTS: After adjusting for covariates, sustained smoking abstinence was associated with a reduction in the AIS total score at Month 1 post-quit (beta = .45, p < .001). Sustained smoking abstinence was associated with reductions across both facets of experiential avoidance -- smoking-related thoughts and feelings (beta = -.44, p < .001) and internal bodily sensations (beta = -.41, p < .001). LIMITATIONS: Biochemical verification of smoking status was confirmed only at three time points post-quit day, and continued abstinence throughout the one month post-quitting period is not fully known. CONCLUSIONS: Sustained smoking abstinence may contribute to reductions in smoking-specific experiential avoidance. Findings add to the research documenting the relevance of experiential avoidance in various processes of smoking (including smoking abstinence). PMID- 26773344 TI - Pharmacokinetic-pharmacodynamic analyses of antihypertensive drugs, nifedipine and propranolol, in spontaneously hypertensive rats to investigate characteristics of effect and side effects. AB - To investigate the relationship between the pharmacokinetics (PK) and effects and/or side-effects of nifedipine and propranolol, simultaneous examination of their PK and pharmacodynamics (PD), namely blood pressure (BP), heart rate (HR), and QT interval (QT), were assessed in spontaneously hypertensive rats as a disease model. Drugs were infused intravenously for 30 min, then plasma PK and hemodynamic effects were monitored. After general two-compartmental analysis was applied to the plasma data, PD parameters were calculated by fitting the data to PK-PD models. After nifedipine administration, the maximal hypotensive effect appeared about 10 min after starting the infusion, then BP started to elevate although the plasma concentration increased, supposedly because of a negative feedback mechanism generated from the homeostatic mechanism. After propranolol administration, HR decreased by half, and this bradycardic effect was greater than that with nifedipine. Wide variation in QT was observed when the propranolol concentration exceeded 700 ng/mL. This variation may have been caused by arrhythmia. Prolongation of QT with propranolol was greater than that with nifedipine, and bradycardia was slower than the concentration increase and QT prolongation. The characteristically designed PK-PD model incorporating a negative feedback system could be adequately and simultaneously fitted to both observed effect and side-effects. PMID- 26773345 TI - Fall prevention intervention technologies: A conceptual framework and survey of the state of the art. AB - In recent years, an ever increasing range of technology-based applications have been developed with the goal of assisting in the delivery of more effective and efficient fall prevention interventions. Whilst there have been a number of studies that have surveyed technologies for a particular sub-domain of fall prevention, there is no existing research which surveys the full spectrum of falls prevention interventions and characterises the range of technologies that have augmented this landscape. This study presents a conceptual framework and survey of the state of the art of technology-based fall prevention systems which is derived from a systematic template analysis of studies presented in contemporary research literature. The framework proposes four broad categories of fall prevention intervention system: Pre-fall prevention; Post-fall prevention; Fall injury prevention; Cross-fall prevention. Other categories include, Application type, Technology deployment platform, Information sources, Deployment environment, User interface type, and Collaborative function. After presenting the conceptual framework, a detailed survey of the state of the art is presented as a function of the proposed framework. A number of research challenges emerge as a result of surveying the research literature, which include a need for: new systems that focus on overcoming extrinsic falls risk factors; systems that support the environmental risk assessment process; systems that enable patients and practitioners to develop more collaborative relationships and engage in shared decision making during falls risk assessment and prevention activities. In response to these challenges, recommendations and future research directions are proposed to overcome each respective challenge. PMID- 26773347 TI - Risk Factors for Treatment Failure With the Adjustable Transobturator Male System Incontinence Device: Who Will Succeed, Who Will Fail? Results of a Multicenter Study. AB - OBJECTIVE: To identify risk factors for treatment failure of men with the adjustable transobturator male system (ATOMS) for treating stress urinary incontinence (SUI). PATIENTS AND METHODS: Sixty-two patients with SUI after prostate surgery were provided with an ATOMS. The self-defined criteria for treatment failure (implant removal [A], no improvement or >=3 pads/24 hours [B], and no improvement or >=150 mL urine loss/24 hours [C]) were compared to anamnestic, clinical, and time-specific parameters: age, Charlson comorbidity index (CCI), urine culture (UC), previous ineffective implants, body mass index, radiotherapy, renal function (serum creatinine), smoker status, urethral strictures, SUI severity, surgery time, time to and season at implantation, and port system application. RESULTS: After a median follow-up of 17.7 months, 9 ATOMS (15%) were removed due to infection (8) or dysfunction (1); 23% and 16% had treatment failure of criteria B and C. Dry rate/overall success rate was 61%/87%. Age alone was no risk factor but the CCI and a positive UC were univariate significant predictors of the criteria A, B, and C. Besides, previous devices and renal failure were significantly associated with implant removal (A) and SUI severity with criterion C. In multivariate analysis, previous devices (P = .0163), positive UC (P = .0190), and SUI severity (P = .0123) were the strongest predictors of A, B, and C, respectively. CONCLUSION: A poor CCI, preoperative positive UC, severe SUI, and previous implants lead to more treatment failure and removal. Age, body mass index, radiotherapy, urethral strictures, current smoking, time-specific parameters, seasonality, and port system application did not influence the outcome. PMID- 26773348 TI - Well-differentiated Papillary Mesothelioma of the Tunica Vaginalis. AB - A 39-year-old man presented with painless scrotal swelling for 2 months. He denied any asbestos exposure but worked with wall and ceiling plaster. Physical exam revealed a large right scrotum which transilluminated. Scrotal ultrasonography revealed a large right hydrocele and a polypoidal mass along the anterior wall of the scrotum. Magnetic resonance imaging of the abdomen and computed tomography of the chest showed no metastases. He underwent a right inguinal scrotal exploration and wide excision of tunica vaginalis and a partial epididymectomy. Pathology revealed well-differentiated papillary mesothelioma of the tunica vaginalis. The patient had an uneventful recovery. PMID- 26773346 TI - Systemic DNA damage responses in aging and diseases. AB - The genome is constantly attacked by a variety of genotoxic insults. The causal role for DNA damage in aging and cancer is exemplified by genetic defects in DNA repair that underlie a broad spectrum of acute and chronic human disorders that are characterized by developmental abnormalities, premature aging, and cancer predisposition. The disease symptoms are typically tissue-specific with uncertain genotype-phenotype correlation. The cellular DNA damage response (DDR) has been extensively investigated ever since yeast geneticists discovered DNA damage checkpoint mechanisms, several decades ago. In recent years, it has become apparent that not only cell-autonomous but also systemic DNA damage responses determine the outcome of genome instability in organisms. Understanding the mechanisms of non-cell-autonomous DNA damage responses will provide important new insights into the role of genome instability in human aging and a host of diseases including cancer and might better explain the complex phenotypes caused by genome instability. PMID- 26773349 TI - Prostate-specific Antigen Mass Density--A Measure Predicting Prostate Cancer Volume and Accounting for Overweight and Obesity-related Prostate-specific Antigen Hemodilution. AB - OBJECTIVE: To test prostate-specific antigen mass density (PSAMD) as a predictor of total tumor volume (TTV) at radical prostatectomy (RP). METHODS: We conducted a detailed pathologic analysis of 469 RP from men with NCCN low-risk prostate cancer who had Gleason score of 3 + 3 = 6 (grade group 1) at RP. We then compared the ability of PSA, PSA density (PSAD), PSA mass (PSAM-absolute amount of PSA in patient's circulation), and PSAM density (PSAM divided by prostate weight without seminal vesicles) to predict TTV at RP. PSAM was calculated by multiplying plasma volume (estimated body surface [weight, kg(0.425) * height, m(0.72) * 0.007184] * 1.67) by PSA. Performance of the above measures in different BMI categories was assessed. Kruskal-Wallis test was used to compare the means and Spearman's rank correlation coefficient to assess the correlations. RESULTS: The 469 men were normal weight (n = 129), overweight (n = 253), and obese (n = 87). Mean age of the patients' was 57.4 years and PSA of 4.53 ng/ml. Increase of prostate weight with body mass index (BMI) was reflected in PSAM (both P <.001) but not in other measures. BMI did not correlate with TTV and PSA. Among PSA, PSAD, PSAM, and PSAMD, PSAMD had the highest correlation with TTV (r = 0.336; P <.001). Prostate weight had stronger (negative) association with PSAMD (r = -0.394; <.001) than TTV. CONCLUSION: PSAMD is the biochemical measure with the best correlation with TTV at RP. Unlike other measures, it is not affected by BMI-related hemodilution. Thresholds should be established to use this more objective measure clinically in surveillance algorithms and in planning radical prostatectomy. PMID- 26773350 TI - Pre-Existing Mature Oligodendrocytes Do Not Contribute to Remyelination following Toxin-Induced Spinal Cord Demyelination. AB - Remyelination is the regenerative response to demyelination. Although the oligodendrocyte progenitor is established as the major source of remyelinating cells, there is no conclusive evidence on whether mature, differentiated oligodendrocytes can also contribute to remyelination. Using two different inducible myelin-CreER mouse strains in which mature oligodendrocytes were prelabeled by the expression of membrane-bound Green fluorescent protein, we found that after focal spinal cord demyelination, the surrounding surviving labeled oligodendrocytes did not proliferate but remained at a consistent density. Furthermore, existing (prelabeled) oligodendrocytes showed no evidence of incorporation or migration into the lesioned area, or of process extension from the peripheral margins into the lesion. Thus, mature oligodendrocytes do not normally contribute to remyelination and are therefore not a promising target for regenerative therapy. PMID- 26773352 TI - A biophysical characterization of the interaction of a hepatitis C virus membranotropic peptide with micelles. AB - Membrane fusion is a highly regulated process that allows enveloped viruses to enter cells and replicate. Viral glycoproteins trigger membrane fusion by means of internal sequences known as fusion peptides. The hepatitis C virus (HCV) genome encodes the envelope glycoproteins E1 and E2, but their specific roles in the fusion step and the localization of the fusion peptide remain uncharacterized. Here, we studied the biophysics of the interactions between the glycoprotein E2 peptide HCV421-445 and four different micellar systems providing ionic, non-ionic and zwitterionic surfaces to investigate the importance of electrostatic interactions for peptide-membrane binding. Circular dichroism, fluorescence spectroscopy and calorimetry were used to characterize peptide micelle interactions and structural changes. Fluorescence quenching showed that HCV421-445 interacts with SDS or CTAB ionic, n-OGP non-ionic and DPC zwitterionic micelles. The indole ring of Trp seems to anchor the peptide in micelles. Trp residues seem to be more deeply inserted in ionic and non-ionic micelles where peptide interactions are more stable than with DPC zwitterionic micelles. The interaction with zwitterionic micelles appears to occur at the surface. Both interaction types are exothermic because of peptide-micelle interactions and a gain of secondary structure in the helical conformation. HCV421-445 interacts with detergent monomers and micelles. Peptide-micelle interaction is pH independent. HCV421-445 interacts with membranes, promoting aggregation and coalescence of vesicles with content leakage, suggesting that HCV421-445 may participate in membrane fusion. This structural characterization contributes to our understanding of the molecular process that promotes fusion, which is important in the further development of new antiviral therapies. PMID- 26773351 TI - Kupffer Cell Transplantation in Mice for Elucidating Monocyte/Macrophage Biology and for Potential in Cell or Gene Therapy. AB - Kupffer cells (KC) play major roles in immunity and tissue injury or repair. Because recapitulation of KC biology and function within liver will allow superior insights into their functional repertoire, we studied the efficacy of the cell transplantation approach for this purpose. Mouse KC were isolated from donor livers, characterized, and transplanted into syngeneic recipients. To promote cell engraftment through impairments in native KC, recipients were preconditioned with gadolinium chloride. The targeting, fate, and functionality of transplanted cells were evaluated. The findings indicated that transplanted KC engrafted and survived in recipient livers throughout the study period of 3 months. Transplanted KC expressed macrophage functions, including phagocytosis and cytokine expression, with or without genetic modifications using lentiviral vectors. This permitted studies of whether transplanted KC could affect outcomes in the context of acetaminophen hepatotoxicity or hepatic ischemia-reperfusion injury. Transplanted KC exerted beneficial effects in these injury settings. The benefits resulted from cytoprotective factors including vascular endothelial growth factor. In conclusion, transplanted adult KC were successfully targeted and engrafted in the liver with retention of innate immune and tissue repair functions over the long term. This will provide excellent opportunities to address critical aspects in the biogenesis, fate, and function of KC within their native liver microenvironment and to develop the cell and gene therapy potential of KC transplantation. PMID- 26773353 TI - Multi-walled carbon nanotubes (MWCNTs) lead to growth retardation, antioxidant depletion, and activation of the ERK signaling pathway but decrease copper bioavailability in the monogonont rotifer (Brachionus koreanus). AB - To examine the toxic effects of multi-walled carbon nanotubes (MWCNTs) in the marine environment, we first exposed the monogonont rotifer (Brachionus koreanus) to MWCNTs in the presence of copper. The acute toxicity of copper decreased significantly with a decrease in copper bioavailability resulting from MWCNT exposure. Furthermore, we examined the effects of MWCNT exposure on reproductive capacity, population growth rate, growth patterns, antioxidant systems, and mitogen-activated protein kinase (MAPK) activation. Reproductive capacity, population growth rate, and body growth rate were significantly suppressed in B. koreanus in response to 1.3-4mg/L MWCNT exposure. Furthermore, MWCNTs induced the generation of reactive oxygen species (ROS) and decreased the antioxidant enzymatic activities of catalase (CAT) and glutathione reductase (GR). However, the enzymatic activity of glutathione S-transferase (GST) was up-regulated after a 24 h-exposure to 100mg/L MWCNTs. Exposure to 100mg/L MCWNTs induced extracellular signal-regulated kinase (ERK) activation in B. koreanus, suggesting that p-ERK may mediate the adverse effects of MWCNTs in B. koreanus via the MAPK signaling pathway. Our results provide insight into the mechanistic basis of the ecotoxicological effects of MWCNTs in the marine environment. PMID- 26773354 TI - Responses of the aquatic midge Chironomus riparius to DEET exposure. AB - N,N-diethyl-3-methylbenzamide (DEET) is the active ingredient of many commercial insect repellents. Despite being detected worldwide in effluents, surface water and groundwater, there is still limited information on DEET's toxicity toward non target aquatic invertebrates. Thus, our main objective was to assess the effects of DEET in the life cycle of Chironomus riparius and assess its biochemical effects. Laboratory assays showed that DEET reduced developmental rates (reduced larval growth, delayed emergence) of C. riparius larvae and also caused a decrease in the size of adult midges. Concerning the biochemical responses, a short exposure to DEET caused no effects in lipid peroxidation, despite the significant inhibition of catalase and glutathione-S-transferase activities and of total glutathione contents. Moreover, inhibition of acetylcholinesterase activity was also observed showing neurotoxic effects. Environmental risk assessment of insect repellents is needed. Our results showed moderate toxicity of DEET toward C. riparius, however, due to their mode of action, indirect ecological effects of DEET and of other insect repellents cannot be excluded and should be evaluated. PMID- 26773356 TI - Some Reflections on IBM Watson and on Women's Health. PMID- 26773355 TI - Molecular cloning of the sex-related gene PSI in Bemisia tabaci and its alternative splicing properties. AB - The P-element somatic inhibitor (PSI) is gene known to regulate the transcription of doublesex (dsx) when transformer (tra) is absent in Bombyx mori. In this study, we identified and characterized a PSI homolog in Bemisia tabaci (BtPSI). BtPSI cDNA had a total length of 5700 bp and contained a predicted open reading frame (ORF) of 2208 nucleotides encoding for 735 amino acids. Multiple sequence alignments of the common regions of PSI proteins from B. tabaci and five other insect species revealed a high degree of sequence conservation. BtPSI is expressed in all stages of B. tabaci development, and expression did not significantly differ between female and male adult. A total of 92 BtPSI isoforms (78 in female and 22 in male) were identified, and a marker indicating the female specific form was found. These results increase the understanding of genes that may determine sex in B. tabaci and provide a foundation for research on the sex determination mechanism in this insect. PMID- 26773357 TI - Occurrence and ecological risk assessment of fluoroquinolone antibiotics in hospital waste of Lahore, Pakistan. AB - In the present study, wastewater and sludge samples of two major hospitals of Lahore, Pakistan were analyzed by developing an HPLC-UV method for the possible occurrence of five frequently used fluoroquinolone antibiotics i.e. ofloxacin, ciprofloxacin, sparfloxacin, moxifloxacin and gemifloxacin. The highest detected concentration was for moxifloxacin in both wastewater (224 MUg/L) and sludge samples (219 MUg/kg. The highest concentration of ofloxacin, ciprofloxacin, sparfloxacin and gemifloxacin were found to be 66, 18, 58 and 0.2 MUg/L respectively. Risk quotient (RQ) was also calculated based on maximum measured concentrations and the RQ values were very high particularly for ofloxacin and ciprofloxacin. The maximum RQ values for ofloxacin against Vibrio fisheri, Pseudomonas putida, fish, Daphnia, Green algae and Pseudokirchneriella subcapitata were 3300, 66,000, 124, 46, 3300 and 6000, respectively. In case of ciprofloxacin, RQ values were found to be 1750 and 3500 against green algae and Microcystis aeruginosa, respectively. PMID- 26773359 TI - Di(2-ethylhexyl) phthalate exacerbates non-alcoholic fatty liver in rats and its potential mechanisms. AB - Di(2-ethylhexyl) phthalate (DEHP) may be responsible for inducing alterations similar to those encountered in nonalcoholic fatty liver disease (NAFLD). The aim of the present study was to investigate the detrimental effects and possible mechanisms of DEHP on fatty liver rats directly through triggering the disorder of liver lipid metabolism or indirectly by hepatotoxic effect. Considering these effects, DEHP may play a significant role in the pathogenesis of NAFLD. In this study, high-fat diet was used to induce NAFLD in rats for eight weeks. DEHP treated groups received (0.05, 5, 500 mg/kg daily, respectively) dose by gavage during the whole experiment period. Our results indicated that the detrimental effects of DEHP on high-fat diet induced NAFLDs were mediated via increasing lipid accumulation in the liver and causing lipid peroxidation and inflammation. PMID- 26773358 TI - Protective effects of carnosine alone and together with alpha-tocopherol on lipopolysaccharide (LPS) plus ethanol-induced liver injury. AB - The aim of this study was to investigate the effect of carnosine (CAR) alone and together with vitamin E (Vit E) on alcoholic steatohepatitis (ASH) in rats. ASH was induced by ethanol (3 times; 5 g/kg; 12 h intervals, via gavage), followed by a single dose of lipopolysaccharide (LPS; 10 mg/kg; i.p.). CAR (250 mg/kg; i.p.) and Vit E (200 mg D-alpha-tocopherol/kg; via gavage) were administered 30 min before and 90 min after the LPS injection. CAR treatment lowered high serum transaminase activities together with hepatic histopathologic improvements in rats with ASH. Reactive oxygen species formation, malondialdehyde levels, myeloperoxidase activities and transforming growth factor beta1 (TGF-beta1) and collagen 1alpha1 (COL1A1) expressions were observed to decrease. These improvements were more remarkable in CAR plus Vit E-treated rats. Our results indicate that CAR may be effective in suppressing proinflammatory, prooxidant, and profibrotic factors in the liver of rats with ASH. PMID- 26773360 TI - Exposure to fipronil elevates systolic blood pressure and disturbs related biomarkers in plasma of rats. AB - Recent reports show that fipronil affects non-target organisms, including environmental species populations and potentially humans. We aimed to examine if fipronil exposure affects the systolic blood pressure and related biomarkers. Thus, fipronil was orally administered to rats (30 mg/kg/day) during 15 days (Fipronil group) or physiological solution (Control group). While fipronil increased significantly the systolic blood pressure (158+/-13 mmHg), no significant changes were observed in Control group (127+/-3 mmHg). Significantly, higher levels of fipronil in plasma were observed in Fipronil group (0.46+/-0.09 MUg/mL versus 0.17+/-0.11 MUg/mL in Control group). Fipronil group showed lower weight gain compared with Control group. While fipronil resulted in higher concentrations of endothelin-1, reduced antioxidant capacity and lower levels of circulating matrix metalloproteinase 2 (MMP-2) and nitric oxide (NO) metabolites compared to Control group, no alteration was observed in serum biomarkers of renal and hepatic/biliary functional abilities. Therefore, this study suggests that fipronil causes hypertension and endothelin-1 plays a key role. Also, these findings suggest that reductions of both MMP-2 and NO may contribute with the elevation of systolic blood pressure observed with fipronil. PMID- 26773361 TI - Molecular and biochemical evidence on the protection of cardiomyocytes from phosphine-induced oxidative stress, mitochondrial dysfunction and apoptosis by acetyl-L-carnitine. AB - The aim of the present study was to investigate the efficacy of acetyl-L carnitine (ALCAR) on pathologic changes of mitochondrial respiratory chain activity, ATP production, oxidative stress, and cellular apoptosis/necrosis induced by aluminum phosphide (AlP) poisoning. The study groups included: the Sham that received almond oil only; the AlP that received oral LD50 dose of aluminum; the AC-100, AC-200, and AC-300 which received concurrent oral LD50 dose of AlP and single 100, 200, and 300 mg/kg of ALCAR by intraperitoneal injection. After 24 h, the rats were sacrificed; the heart and blood sample were taken for measurement of biochemical and mitochondrial factors. The results specified that ALCAR significantly attenuated the oxidative stress (elevated ROS and plasma iron levels) caused by AlP poisoning. ALCAR also increased the activity of cytochrome oxidase, which in turn amplified ATP production. Furthermore, flow cytometric assays and caspase activity indicated that ALCAR prohibited AlP-induced apoptosis in cardiomyocytes. PMID- 26773362 TI - Glyphosate induces neurotoxicity in zebrafish. AB - Glyphosate based herbicides (GBH) like Roundup((r)) are used extensively in agriculture as well as in urban and rural settings as a broad spectrum herbicide. Its mechanism of action was thought to be specific only to plants and thus considered safe and non-toxic. However, mounting evidence suggests that GBHs may not be as safe as once thought as initial studies in frogs suggest that GBHs may be teratogenic. Here we utilize the zebrafish vertebrate model system to study early effects of glyphosate exposure using technical grade glyphosate and the Roundup((r)) Classic formulation. We find morphological abnormalities including cephalic and eye reductions and a loss of delineated brain ventricles. Concomitant with structural changes in the developing brain, using in situ hybridization analysis, we detect decreases in genes expressed in the eye, fore and midbrain regions of the brain including pax2, pax6, otx2 and ephA4. However, we do not detect changes in hindbrain expression domains of ephA4 nor exclusive hindbrain markers krox-20 and hoxb1a. Additionally, using a Retinoic Acid (RA) mediated reporter transgenic, we detect no alterations in the RA expression domains in the hindbrain and spinal cord, but do detect a loss of expression in the retina. We conclude that glyphosate and the Roundup((r)) formulation is developmentally toxic to the forebrain and midbrain but does not affect the hindbrain after 24 h exposure. PMID- 26773363 TI - Curcumin and beta-caryophellene attenuate cadmium quantum dots induced oxidative stress and lethality in Caenorhabditis elegans model system. AB - Curcumin (CUR) and beta-caryophellene (BCP) are well known bioactive phytomolecules which are known to reduce oxidative stress in living organisms. Therefore, the present study was envisaged to explore the possible effects of CUR and BCP in suppression of cadmium quantum dots (CdTe QDs) induced toxicity in Caenorhabditis elegans. CdTe QD are luminescent nanoparticles extensively exploited for in vivo imaging, but long term bioaccumulation confer deleterious effects on living organisms. The 24-h LC50 and LC100 of CdTe QD were found to be 18.40 MUg/ml and 100 MUg/ml respectively. The CdTe QD exposure elevated HSP-16.2 expression mediating induction of the stress response. The CdTe QD lethality was due to increment in ROS and decline in SOD and GST expression. The present study demonstrates improved survival in BCP (50 MUM) and CUR (20 MUM) treated worms by over 60% (P<0.01) and 50% (P<0.029) in CdTe QD (100 MUg/ml) exposed worms. Furthermore, BCP and CUR attenuate oxidative stress triggered by QD. The present study for the first time demonstrates CdTe QD toxicity remediation via BCP and CUR. The future investigations can unravel underlying protective effects of phytomolceules for remediating cyotoxicolgical effects of QDs. PMID- 26773364 TI - Lovastatin induces platelet apoptosis. AB - Statins are widely used in the prevention of atherosclerosis and treatment of coronary artery disease because of pleiotropic effects on thrombosis. Thrombocytopenia and hemorrhage occurred in some statin-treated patients, but the reason remains unclear. In the current study, we show that lovastatin dose dependently induces depolarization of mitochondrial inner transmembrane potential, leading to up-regulation of Bak, down-regulation of Bcl-XL, and activation of caspase-3/8/9. Lovastatin treatment did not increase the surface expression of P-selectin or PAC-1 binding but led to strongly reduced collagen- and thrombin-induced platelet aggregation. The integrin alphaIIbbeta3 antagonist, RGDS, inhibited lovastatin-induced apoptosis in both human platelets and Chinese hamster ovary (CHO) cells stably expressing integrin alphaIIbbeta3. The number of circulating platelets in mice was significantly reduced after intraperitoneal injections with lovastatin. Taken together, these data indicate that lovastatin induced caspase-dependent platelet apoptosis. Lovastatin does not incur platelet activation, whereas impairs platelet function and reduces circulating platelets in vivo, suggesting the possible pathogenesis of thrombocytopenia and hemorrhage in patients treated with statins. PMID- 26773366 TI - Prolonged hyperinsulinemia affects metabolic signal transduction markers in a tissue specific manner. AB - Insulin dysregulation is common in horses although the mechanisms of metabolic dysfunction are poorly understood. We hypothesized that insulin signaling in striated (cardiac and skeletal) muscle and lamellae may be mediated through different receptors as a result of receptor content, and that transcriptional regulation of downstream signal transduction and glucose transport may also differ between tissues sites during hyperinsulinemia. Archived samples from horses treated with a prolonged insulin infusion or a balanced electrolyte solution were used. All treated horses developed marked hyperinsulinemia and clinical laminitis. Protein expression was compared across tissues for the insulin receptor and insulin-like growth factor 1 receptor (IGF-1R) by immunoblotting. Gene expression of metabolic insulin-signaling markers (insulin receptor substrate 1, Akt2, and glycogen synthase kinase 3 beta [GSK-3beta]) and glucose transport (basal glucose transporter 1 and insulin-sensitive glucose transporter 4) was evaluated using real-time reverse transcription polymerase chain reaction. Lamellar tissue contained significantly more IGF-1R protein than skeletal muscle, indicating the potential significance of IGF-1R signaling for this tissue. Gene expression of the selected markers of insulin signaling and glucose transport in skeletal muscle and lamellar tissues was unaffected by prolonged hyperinsulinemia. In contrast, the significant upregulation of Akt2, GSK-3beta, GLUT1, and GLUT4 gene expression in cardiac tissue suggested that the prolonged hyperinsulinemia induced an increase in insulin sensitivity and a transcriptional activation of glucose transport. Responses to insulin are tissue specific, and extrapolation of data across tissue sites is inappropriate. PMID- 26773367 TI - Stimulation of regressing subordinate follicles of wave 2 with a gonadotropin product in heifers. AB - The recovery of regressing wave-2 subordinate follicles was studied by treating heifers with a gonadotropin product that had about 84% and 16% of follicle stimulating hormone and luteinizing hormone activity, respectively. A treated group (n = 8) received a single dose of 50 mg (2.5 mL) of the gonadotropin product, and a control group (n = 8) received 2.5 mL of saline vehicle. The group assignment of heifers was not known to the ultrasonographer who tracked the follicles and measured follicle diameters. Follicle measurements began on the day of expected follicle deviation in wave 2 (largest follicle closest to 8.5 mm), and treatment (hour 0) was given on Day 13.4 +/- 0.2 (Day 0 = ovulation) when the dominant follicles of waves 1 and 2 were 14.1 +/- 0.3 mm and 10.7 +/- 0.1 mm, respectively. Subordinate follicles of wave 2 that had regressed to a 3-mm category (3.0-3.9 mm) or 4-mm category by hour 0 decreased in diameter for at least 48 h before hour 0, whereas follicles that were in the 5-mm or 6-mm categories at hour 0 did not change significantly in diameter during the previous 48 h. About 55% of the follicles that had regressed to the 3-mm and 4-mm categories at hour 0% and 78% of the follicles in the 5-mm and 6-mm categories increased in diameter after gonadotropin treatment, whereas follicles in the control group continued to decrease (regress) in diameter. The follicles for each of the 4 diameter categories were greater (P < 0.05) in diameter 9 h after treatment in the treated group than in the control group. The dominant follicle of wave 1 and the largest subordinate follicle of wave 2 in the treated group also increased in diameter so that diameter was greater (P < 0.05) than in the controls at hour 9. The results demonstrated that subordinate follicles of wave 2 that had decreased in diameter (regressed) for at least 48 h retained the capability to recover as indicated by a diameter increase when exposed to a gonadotropin product. PMID- 26773365 TI - Changes in brain ribonuclease (BRB) messenger RNA in granulosa cells (GCs) of dominant vs subordinate ovarian follicles of cattle and the regulation of BRB gene expression in bovine GCs. AB - Brain ribonuclease (BRB) is a member of the ribonuclease A superfamily that is constitutively expressed in a range of tissues and is the functional homolog of human ribonuclease 1. This study was designed to characterize BRB gene expression in granulosa cells (GCs) during development of bovine dominant ovarian follicles and to determine the hormonal regulation of BRB in GCs. Estrous cycles of Holstein cows (n = 18) were synchronized, and cows were ovariectomized on either day 3 to 4 or day 5 to 6 after ovulation during dominant follicle growth and selection. Ovaries were collected, follicular fluid (FFL) was aspirated, and GCs were collected for RNA isolation and quantitative polymerase chain reaction. Follicles were categorized as small (1-5 mm; pooled per ovary), medium (5-8 mm; individually collected), or large (8.1-17 mm; individually collected) based on surface diameter. Estradiol (E2) and progesterone (P4) levels were measured by radioimmunoassay (RIA) in FFL. Abundance of BRB messenger RNA (mRNA) in GCs was 8.6- to 11.8-fold greater (P < 0.05) in small (n = 31), medium (n = 66), and large (n = 33) subordinate E2-inactive (FFL E2 < P4) follicles than in large (n = 16) dominant E2-active (FFL E2 > P4) follicles. In the largest 4 follicles, GCs BRB mRNA abundance was negatively correlated (P < 0.01) with FFL E2 (r = -0.65) and E2:P4 ratio (r = -0.46). In experiment 2, GCs from large (8-22 mm diameter) and small (1-5 mm diameter) follicles were treated with insulin-like growth factor 1 (IGF1; 0 or 30 ng/mL) and/or tumor necrosis factor alpha (0 or 30 ng/mL); IGF1 increased (P < 0.05) BRB mRNA abundance, and tumor necrosis factor alpha decreased (P < 0.001) the IGF1-induced BRB mRNA abundance in large-follicle GCs. In experiment 3 to 6, E2, follicle-stimulating hormone, fibroblast growth factor 9, cortisol, wingless 3A, or sonic hedgehog did not affect (P > 0.10) abundance of BRB mRNA in GCs; thyroxine and luteinizing hormone increased (P < 0.05), whereas prostaglandin E2 (PGE2) decreased (P < 0.05) BRB mRNA abundance in small-follicle GCs. Treatment of small-follicle GCs with recombinant human RNase1 increased (P < 0.05) GCs numbers and E2 production. In conclusion, BRB is a hormonally and developmentally regulated gene in bovine GCs and may regulate E2 production during follicular growth in cattle. PMID- 26773368 TI - Systemic effect of follicle-stimulating hormone and intraovarian effect of the corpus luteum on complete regression vs recovery of regressing wave-2 follicles in heifers. AB - Each subordinate of the second follicular wave (wave 2) was monitored, and the outcome was classified as fully regressed (decreased in diameter to 2 mm) or recovered (decreased initially and then increased to become a growing follicle of the subsequent wave 1). The changing diameter of each follicle after emergence at 2 mm and plasma concentration of follicle-stimulating hormone were determined every 12 h from the day of ovulation (Day 0) to 4 d after the subsequent ovulation in heifers with 2 follicular waves per interovulatory interval (n = 10). The number and percentage of wave-2 subordinates that initially regressed and then recovered (7.2 +/- 1.0 follicles; 33.2 +/- 5.1%) were less (P < 0.0008) than the number and percentage that completely regressed (15.0 +/- 1.7; 66.8 +/- 5.1%). Follicles that later recovered initially reached maximal diameter on a later day (P < 0.0001) after emergence at 2 mm (4.3 +/- 0.2 d) and at a larger (P < 0.0001) diameter (5.8 +/- 0.2 mm) than follicles that completely regressed (3.2 +/- 0.1 d; 4.7 +/- 0.1 mm). The follicle-stimulating hormone surge that stimulated wave 2 began earlier and was more sustained in a subgroup with a high percentage of recovered follicles (61%) than in a subgroup with a low percentage (24%). Recovery began on Day -1.0 +/- 0.1 when the follicles had regressed to 3.7 +/- 0.1 mm. Diameter of subordinate follicles on Day -6 or before the expected days of luteolysis was greater (P < 0.05) when in the corpus luteum (CL) ovary than when in the non-CL ovary. During expected luteolysis, more follicles (P < 0.008) per ovary continued to regress when ipsilateral to the CL (9.2 +/- 1.1 follicles) than when contralateral (5.8 +/- 1.1), and more follicles (P < 0.02) recovered from regression when contralateral to the CL (5.0 +/- 0.8) than when ipsilateral (2.2 +/- 0.6). The hypothesis that the CL has a local effect on the development, regression, and recovery of the subordinate follicles of wave 2 was supported. PMID- 26773369 TI - Defective secretion of Prostaglandin F2alpha during development of idiopathic persistent corpus luteum in mares. AB - Five mares that developed idiopathic persistent corpus luteum (PCL) were compared with 5 mares with apparently normal interovulatory intervals (IOIs). Progesterone (P4) and a metabolite of prostaglandin F2alpha (PGFM) were assayed daily beginning on the day of ovulation (Day 0). Transition between the end of an initial progressive P4 increase and the beginning of a gradual decrease in P4 occurred on mean Day 6. The gradual decrease in P4 between Days 6 and 12 was less (approached significance, P < 0.06) in the PCL group than in the IOI group. The P4 concentration on Day 12 (before luteolysis in IOI group) was greater (P < 0.05) in the PCL group than in the IOI group. In a post hoc comparison, an interaction (P < 0.04) of group by day for Days 4 to 7 indicated that the end of the progressive increase in P4 was temporally associated with a transient increase in concentration of PGFM in IOI mares but not in PCL mares. Complete luteolysis (P4 < 1 ng/mL) occurred in the IOI mares on Days 13 to 15. Partial luteolysis (mean P4 decrease, 62%) occurred in 3 of the 5 PCL mares. Normalization to the day at the end of the most pronounced P4 decrease in the IOI mares and in the 3 PCL mares with partial luteolysis resulted in a day-by-group interaction (P < 0.05) for PGFM concentration. The interaction was partly from lower PGFM concentration on the day at the end of the pronounced P4 decrease in the 3 PCL mares than in the IOI mares. The peak of a transient PGFM increase and the day at the end of the most pronounced decrease in P4 were synchronized in each IOI mare but not in any of the 3 PCL mares. In the other 2 PCL mares, partial luteolysis did not occur, and a transient increase in PGFM was not apparent. Results tentatively indicated that the relationship between P4 and PGFM may be altered as early as Day 6 in PCL mares and supported the hypothesis that prostaglandin F2alpha secretion is defective in mares with idiopathic PCL. PMID- 26773370 TI - The hypothalamo-pituitary-adrenal (HPA) axis in sheep is attenuated during lactation in response to psychosocial and predator stress. AB - Activation of the hypothalamo-pituitary-adrenal (HPA) axis by psychosocial stress is attenuated during lactation. We tested the hypothesis that lactating ewes will have attenuated HPA axis responses to isolation and restraint but will have greater responses to predator stress in the form of barking dogs. We imposed two 4 h stressors: psychosocial stress (isolation and restraint of ewes) and predator stress (barking dogs). Blood was collected intravenous every 10 min from nonlactating ewes (n = 6), lactating ewes with lambs present but not able to be suckled (n = 6), and lactating ewes with lambs present and able to be suckled (n = 6). Plasma cortisol and oxytocin were measured. For nonlactating ewes, cortisol increased (P < 0.01) in response to both stressors, and these increases were greater (P < 0.01) than that in the lactating animals. For lactating ewes with lambs present but unable to be suckled, cortisol increased (P < 0.05) in response to both stressors with a greater response to barking dogs (P < 0.05). For lactating ewes with lambs present and able to be suckled, cortisol increased (P < 0.01) in response to barking dogs only. Plasma oxytocin was greater (P < 0.01) in lactating ewes than in nonlactating ewes and did not change in response to the stressors. In conclusion, lactating ewes are likely to have a greater HPA axis response to a stressor that may be perceived to threaten the welfare of themselves and/or their offspring. The role of oxytocin in attenuation of the HPA axis to stress in sheep is unclear from the current research and requires further investigation. PMID- 26773371 TI - Genetic variants in the HER2 gene: Influence on HER2 overexpression and loss of heterozygosity in breast cancer. AB - Human epidermal growth factor receptor 2 (HER2) overexpression in breast cancer is an indicator of poor prognosis and is the pre-requisite for treatment with the agents targeting this member of the epidermal growth factor receptor family. In order to determine the influence of these common single-nucleotide polymorphisms (SNPs) in the HER2 gene, genomic DNA was obtained from 361 patients with breast cancer, aged between 29 and 82 years. Samples of tumour tissue were obtained from 241 (66%) patients and material for extraction of DNA is isolated from surrounding normal tissue by laser capture microdissection. Genotyping was performed using the Taqman fluorogenic 5' nuclease assay. Of the 360 patients with definitive determination of HER2 status, 49% were positive. The Ile655Val SNP had no influence on the frequency of HER2 expression. However, the proline allele of the Ala1170Pro SNP was associated with a higher frequency of HER2 overexpression (56% versus 43%, p = 0.015). Where the germline genotype was homozygous, the tumour genotype was identical in every case and for both SNPs. In HER2-positive tumours, heterozygosity was maintained in only 15% and 18% of the Ile655Val and Ala1170Pro SNPs, respectively. This was lower than in the HER2 negative tumours (46% and 43%, respectively). Normal breast tissue (n = 23) retained the germline genotype in all but one case. The underlying link between the Ala1170Pro SNP and HER2 positivity is not known, nor is the significance of HER2 overexpression and loss of heterozygosity in breast cancer. However, these results illustrate the complexity of HER2 genotype and overexpression in this disease. PMID- 26773372 TI - Electrochemical and bio-sensing platform based on a novel 3D Cu nano flowers/layered MoS2 composite. AB - A novel 3D nano-flower-like Cu/multi-layer molybdenum disulfide composite (CuNFs/MoS2) modified glassy carbon electrode (GCE) has been successfully constructed. It was a highly sensitive and selective non-enzymatic hydrogen peroxide (H2O2) and glucose biosensor. The morphology of the obtained CuNFs-MoS2 nano-particles was investigated with the use of a scanning electron microscopy (SEM), transmission electron microscopy (TEM), X-ray diffraction (XRD) and energy dispersive X-ray spectroscopy (EDS). The physicochemical properties of the modified electrode were characterized at each of the construction stages with the use of an electrochemical impedance spectroscopy (EIS) and cyclic voltammetry (CV) techniques. The new sensor combined the advantages of MoS2 and CuNFs, and exhibited high electro-catalytic activity toward H2O2 and glucose. Quantitative analysis of H2O2 and glucose was carried out with the use of the amperometric i-t method. Linear ranges were obtained between 0.04-1.88 MUM and 1.88-35.6 MUM for H2O2 and 1-20 MUM and 20-70 MUM for glucose, and their corresponding limits of detection (LOD) were 0.021 MUM and 0.32 MUM. This novel sensor was successfully applied for the quantitative analysis of H2O2 in tap water and glucose in human serum samples. PMID- 26773374 TI - Development of a highly specific and sensitive cadmium and lead microbial biosensor using synthetic CadC-T7 genetic circuitry. AB - Multiple copies of a cadC homolog encoding a heavy metal-responsive transcription factor were found in the genome of a bacterium isolated from ocean sediment, and the heavy metal responses of the encoded proteins were characterized using a fluorescence reporter assay. Each CadC regulator exhibited distinct specificity in response to heavy metal ions, indicating their potential use as modular heavy metal biosensors. Next, we constructed CadC-controlled T7 RNA transcription systems for intracellular signal amplification, i.e., higher sensitivity. Flow cytometry revealed that cadmium and lead ions could be recognized specifically by CadC-T7 biosensors, which could be combined with a microfluidic platform to generate heavy metal biosensor devices with increased sensitivity. Our results demonstrate the successful development of synthetic CadC-T7 genetic circuitry for use in improved heavy metal biosensor microfluidic devices. PMID- 26773373 TI - Long period fiber grating based sensor for the detection of triacylglycerides. AB - In this paper, stable, label free enzyme based sensor using long period fiber grating (LPG) is described for the detection of triacylglycerides. A stable covalent binding technique for lipase enzyme immobilization on an optical fiber is reported. An active and stable attachment of the functional group of the enzyme on the fiber surface is achieved using this method. Enzyme immobilization is confirmed by Scanning Electron Microscopy (SEM) and Raman Spectroscopy. The stability is confirmed by lipase p-nitrophenyl palmitate (PNP) assay. In contrast to widely used amperometric based biosensor, where a number of enzymes are required, only one enzyme, namely, lipase is required in our sensor. The sensor shows optimum response within one minute at a temperature of 37 degrees C and pH of 7.4. The sensor is based on the shift in resonance wavelength of the LPG transmission spectrum due to the interaction of triacylglycerides with the enzyme. The biosensor is highly specific towards triacylglycerides and is unaffected by the presence of many other interfering substances in serum. Interaction between the bio-molecules and the long period grating surface is also modeled theoretically using a four layer model for the LPG fiber with the bio recognition layer and the results obtained are consistent with experimentally obtained results. The sensor shows a high sensitivity of 0.5 nm/mM and a low detection limit of 17.71 mg/dl for the physiological range of triacylglycerides in human blood. PMID- 26773375 TI - Changes of global gene expression and secondary metabolite accumulation during light-dependent Aspergillus nidulans development. AB - Fungal development and secondary metabolite production are coordinated by regulatory complexes as the trimeric velvet complex. Light accelerates asexual but decreases sexual development of the filamentous fungus Aspergillus nidulans. Changes in gene expression and secondary metabolite accumulation in response to environmental stimuli have been the focus of many studies, but a comprehensive comparison during entire development is lacking. We compared snapshots of transcript and metabolite profiles during fungal development in dark or light. Overall 2.014 genes corresponding to 19% of the genome were differentially expressed when submerged vegetative hyphae were compared to surface development. Differentiation was preferentially asexual in light or preferentially sexual connected to delayed asexual development in dark. Light induces significantly gene expression within the first 24-48h after the transfer to surfaces. Many light induced genes are also expressed in dark after a delay of up to two days, which might be required for preparation of enhanced sexual development. Darkness results in a massive transcriptional reprogramming causing a peak of lipid derived fungal pheromone synthesis (psi factors) during early sexual development and the expression of genes for cell-wall degradation presumably to mobilize the energy for sexual differentiation. Accumulation of secondary metabolites like antitumoral terrequinone A or like emericellamide start under light conditions, whereas the mycotoxin sterigmatocystin or asperthecin and emodin appear under dark conditions during sexual development. Amino acid synthesis and pool rapidly drop after 72-96h in dark. Subsequent initiation of apoptotic cell-death pathways in darkness happens significantly later than in light. This illustrates that fungal adaptation in differentiation and secondary metabolite production to light conditions requires the reprogramming of one fifth of the potential of its genome. PMID- 26773376 TI - Effects of inorganic salts on denitrifying granular sludge: The acute toxicity and working mechanisms. AB - It is highly significant to investigate the toxicity of inorganic salts to denitrifying granular sludge (DGS) and its mechanism since the application of high-rate denitrification is seriously limited in the treatment of saline nitrogen-rich wastewaters. The batch experiments showed that the IC50 (half inhibition concentration) and LC50 (half lethal concentration) of NaCl, Na2SO4 and Na3PO4 on DGS were 11.46, 21.72, 7.46 g/L and 77.35, 100.58, 67.92 g/L respectively. Based on the analysis of specific denitrifying activity, the live cell percentage, the cell structure, and the DNA leakage, the toxicity of low salinity was ascribed to the inhibition of denitrifying activity and the toxicity of high salinity was ascribed to both the inhibition of denitrifying activity and the lethality of denitrifying cell. PMID- 26773377 TI - Cultivation of Spirulina maxima in medium supplemented with sugarcane vinasse. AB - The feasibility of sugarcane vinasse as supplement in growth medium of Spirulina maxima was investigated. The cell was cultivated under autotrophic (no vinasse, 70 MUmol photons m(-2) s(-1)), heterotrophic (no light, culture medium supplemented with vinasse at 0.1% v/v and 1.0% v/v) and mixotrophic conditions (70 MUmol photons m(-2) s(-1), vinasse at 0.1% v/v and 1.0% v/v). These preliminary results suggested a cyclic two-stage cultivation - CTSC, with autotrophic condition during light phase of the photoperiod (12 h, 70-200 MUmol photons m(-2) s(-1)) and heterotrophic condition during dark phase (12h, 3.0% v/v vinasse). The adopted CTSC strategy consisted in three cycles with 75% withdrawal of suspension and reposition of medium containing 3.0% v/v vinasse, separated by autotrophic rest periods of few days between cycles. Results show an increase of biomass concentration between 0.495 g L(-1) and 0.609 g L(-1) at the 7th day of each cycle and high protein content (between 74.3% and 77.3% w/w). PMID- 26773378 TI - Enhancing the growth rate and astaxanthin yield of Haematococcus pluvialis by nuclear irradiation and high concentration of carbon dioxide stress. AB - Unicellular green microalgae Haematococcus pluvialis was mutated with (60)Co gamma irradiation to promote growth rate and increase astaxanthin yield under high concentration of CO2 stress. The average specific growth rate of H. pluvialis mutated with 4000 Gy gamma-ray irradiation was increased by 15% compared with the original strain with air aeration. The mutant grew best with 6% CO2 (the maximum specific growth rate was 0.60/d) when it was cultured with high concentrations of CO2 (2-10%). The peak biomass productivity (0.16 g/L/d) of the mutant cultured with 6% CO2 was 82% higher than that of the mutant with air. The astaxanthin yield and lipid content of the mutant induced with 6% CO2 and high light (108 MUmol photons m(-2) s(-1)) increased to 46.0mg/L and 45.9%, which were 2.4 and 1.3 times higher than those of the wild-type strain, respectively. PMID- 26773379 TI - dsRNA-ended genomes in orthobunyavirus particles and infected cells. AB - dsRNA-ended genome RNPs accumulate during LaCrosse bunyavirus infection. The possible significance of these dsRNA structures for orthobunyavirus replication and survival are discussed. PMID- 26773381 TI - Specific binding of Fusarium graminearum Hex1 protein to untranslated regions of the genomic RNA of Fusarium graminearum virus 1 correlates with increased accumulation of both strands of viral RNA. AB - The HEX1 gene of Fusarium graminearum was previously reported to be required for the efficient accumulation of Fusarium graminearum virus 1 (FgV1) RNA in its host. To investigate the molecular mechanism underlying the production of FgHEX1 and the replication of FgV1 viral RNA, we conducted electrophoretic mobility shift assays (EMSA) with recombinant FgHex1 protein and RNA sequences derived from various regions of FgV1 genomic RNA. These analyses demonstrated that FgHex1 and both the 5'- and 3'-untranslated regions of plus-strand FgV1 RNA formed complexes. To determine whether FgHex1 protein affects FgV1 replication, we quantified accumulation viral RNAs in protoplasts and showed that both (+)- and ( )-strands of FgV1 RNAs were increased in the over-expression mutant and decreased in the deletion mutant. These results indicate that the FgHex1 functions in the synthesis of both strands of FgV1 RNA and therefore in FgV1 replication probably by specifically binding to the FgV1 genomic RNA. PMID- 26773380 TI - The eIF4AIII RNA helicase is a critical determinant of human cytomegalovirus replication. AB - Human cytomegalovirus (HCMV) was recently shown to encode a large number of spliced mRNAs. While the nuclear export of unspliced viral transcripts has been extensively studied, the role of host mRNA export factors in HCMV mRNA trafficking remains poorly defined. We found that the eIF4AIII RNA helicase, a component of the exon junction complex, was necessary for efficient virus replication. Depletion of eIF4AIII limited viral DNA accumulation, export of viral mRNAs from the nucleus, and the production of progeny virus. However eIF4AIII was dispensable for the association of viral transcripts with ribosomes. We found that pateamine A, a natural compound that inhibits both eIF4AI/II and eIF4AIII, has potent antiviral activity and inhibits HCMV replication throughout the virus lytic cycle. Our results demonstrate that eIF4AIII is required for efficient HCMV replication, and suggest that eIF4A family helicases may be a new class of targets for the development of host-directed antiviral therapeutics. PMID- 26773382 TI - The acidic C-terminus of vaccinia virus I3 single-strand binding protein promotes proper assembly of DNA-protein complexes. AB - The vaccinia virus I3L gene encodes a single-stranded DNA binding protein (SSB) that is essential for virus DNA replication and is conserved in all Chordopoxviruses. The I3 protein contains a negatively charged C-terminal tail that is a common feature of SSBs. Such acidic tails are critical for SSB dependent replication, recombination and repair. We cloned and purified variants of the I3 protein, along with a homolog from molluscum contagiosum virus, and tested how the acidic tail affected DNA-protein interactions. Deleting the C terminus of I3 enhanced the affinity for single-stranded DNA cellulose and gel shift analyses showed that it also altered the migration of I3-DNA complexes in agarose gels. Microinjecting an antibody against I3 into vaccinia-infected cells also selectively inhibited virus replication. We suggest that this domain promotes cooperative binding of I3 to DNA in a way that would maintain an open DNA configuration around a replication site. PMID- 26773383 TI - Epstein-Barr virus glycoprotein gM can interact with the cellular protein p32 and knockdown of p32 impairs virus. AB - The Epstein-Barr virus glycoprotein complex gMgN has been implicated in assembly and release of fully enveloped virus, although the precise role that it plays has not been elucidated. We report here that the long predicted cytoplasmic tail of gM is not required for complex formation and that it interacts with the cellular protein p32, which has been reported to be involved in nuclear egress of human cytomegalovirus and herpes simplex virus. Although redistribution of p32 and colocalization with gM was not observed in virus infected cells, knockdown of p32 expression by siRNA or lentivirus-delivered shRNA recapitulated the phenotype of a virus lacking expression of gNgM. A proportion of virus released from cells sedimented with characteristics of virus lacking an intact envelope and there was an increase in virus trapped in nuclear condensed chromatin. The observations suggest the possibility that p32 may also be involved in nuclear egress of Epstein-Barr virus. PMID- 26773384 TI - Screening a yeast library of temperature-sensitive mutants reveals a role for actin in tombusvirus RNA recombination. AB - Genetic recombination in RNA viruses drives the evolutionary arms race with host's antiviral strategies and recombination also facilitates adaptation of viruses to new hosts. In this paper, the authors used tombusvirus and a temperature-sensitive (ts) mutant library of yeast to identify 40 host proteins affecting viral recombination in yeast model host. Subsequent detailed analysis with two identified actin-related proteins, Act1p and Arp3p, has revealed that the wt actin network helps TBSV to maintain low level viral recombination. Pharmacological inhibition of actin in plant protoplasts confirmed the role of the actin network in tombusvirus recombination. An in vitro approach revealed the altered activity of the tombusvirus replicase in the presence of mutated Act1p. The authors show more efficient recruitment of a cellular DEAD-box helicase, which enhances tombusvirus recombination, into the membrane-bound replicase in Act1p mutant yeast. Overall, this work shows that the actin network affects tombusvirus recombination in yeast and plant cells. PMID- 26773385 TI - Genomic characterization and comparison of seven Myoviridae bacteriophage infecting Bacillus thuringiensis. AB - Bacillus thuringiensis Kurstaki, a bacterium that is a source of biopesticides and a safe simulant for pathogenic Bacillus species, was used to isolate seven unique bacteriophages. The phage genomes were sequenced and ranged in size from 158,100 to 163,019 bp encoding 290-299 genes, and the GC content of ~38% was similar to that of the host bacterium. All phages had terminal repeats 2-3 kb long. Three of the phages encoded tRNAs and three contained a self-splicing intron in the DNA polymerase gene. They were categorized as a single cluster (>60% nucleotide conservation) containing three subclusters (>80% nucleotide conservation), supported by genomic synteny and phylogenetic analysis. Considering the published genomes of phages that infect the genus Bacillus and noting the ability of many of the Bacillus cereus group phages to infect multiple species, a clustering system based on gene content is proposed. PMID- 26773386 TI - Suppression of type I interferon production by porcine epidemic diarrhea virus and degradation of CREB-binding protein by nsp1. AB - Type I interferons (IFN-alpha/beta) are the major components of the innate immune response of hosts, and in turn many viruses have evolved to modulate the host response during infection. We found that the IFN-beta production was significantly suppressed during PEDV infection in cells. To identify viral IFN antagonists and to study their suppressive function, viral coding sequences for the entire structural and nonstructural proteins were cloned and expressed. Of 16 PEDV nonstructural proteins (nsps), nsp1, nsp3, nsp7, nsp14, nsp15 and nsp16 were found to inhibit the IFN-beta and IRF3 promoter activities. The sole accessory protein ORF3, structure protein envelope (E), membrane (M), and nucleocapsid (N) protein were also shown to inhibit such activities. PEDV nsp1 did not interfere the IRF3 phosphorylation and nuclear translocation but interrupted the enhanceosome assembly of IRF3 and CREB-binding protein (CBP) by degrading CBP. A further study showed that the CBP degradation by nsp1 was proteasome-dependent. Our data demonstrate that PEDV modulates the host innate immune responses by degrading CBP and suppressing ISGs expression. PMID- 26773387 TI - Discovery and characterisation of a new insect-specific bunyavirus from Culex mosquitoes captured in northern Australia. AB - Insect-specific viruses belonging to significant arboviral families have recently been discovered. These viruses appear to be maintained within the insect population without the requirement for replication in a vertebrate host. Mosquitoes collected from Badu Island in the Torres Strait in 2003 were analysed for insect-specific viruses. A novel bunyavirus was isolated in high prevalence from Culex spp. The new virus, provisionally called Badu virus (BADUV), replicated in mosquito cells of both Culex and Aedes origin, but failed to replicate in vertebrate cells. Genomic sequencing revealed that the virus was distinct from sequenced bunyavirus isolates reported to date, but phylogenetically clustered most closely with recently discovered mosquito-borne, insect-specific bunyaviruses in the newly proposed Goukovirus genus. The detection of a functional furin cleavage motif upstream of the two glycoproteins in the M segment-encoded polyprotein suggests that BADUV may employ a unique strategy to process the virion glycoproteins. PMID- 26773389 TI - Molecular pharming - VLPs made in plants. AB - Plant-based expression offers a safe, inexpensive and potentially limitless way to produce therapeutics in a quick and flexible manner. Plants require only simple inorganic nutrients, water, carbon dioxide and sunlight for efficient growth. Virus-like particles (VLPs) are convincing look-alikes of viruses but without carrying infectious genomic material. However, they can still elicit a very potent immune response which makes them ideal vaccine candidates. In this review the different methods of plant expression are described together with the most recent developments in the field of transiently-expressed plant-made VLPs. PMID- 26773388 TI - A new perspective on microbial landscapes within food production. AB - High-throughput, 'next-generation' sequencing tools offer many exciting new possibilities for food research. From investigating microbial dynamics within food fermentations to the ecosystem of the food-processing built environment, amplicon sequencing, metagenomics, and transcriptomics present novel applications for exploring microbial communities in, on, and around our foods. This review discusses the many uses of these tools for food-related and food facility-related research and highlights where they may yield nuanced insight into the microbial world of food production systems. PMID- 26773390 TI - Antibiotic resistance genes and human bacterial pathogens: Co-occurrence, removal, and enrichment in municipal sewage sludge digesters. AB - Understanding which/how antibiotic resistance genes (ARGs) contribute to increased acquisition of resistance by pathogens in aquatic environments are challenges of profound significance. We explored the co-occurrence and removal versus enrichment of ARGs and human bacterial pathogens (HBPs) in municipal sewage sludge digesters. We combined metagenomic detection of a wide spectrum of 323 ARGs and 83 HBPs with a correlation-based statistical approach and charted a network of their co-occurrence relationships. The results indicate that most ARGs and a minor proportion of HBPs (mainly Collinsella aerofaciens, Streptococcus salivarius and Gordonia bronchialis) could not be removed by anaerobic digestion, revealing a biological risk of post-digestion sludge in disseminating antibiotic resistance and pathogenicity. Moreover, preferential co-occurrence patterns were evident within one ARG type (e.g., multidrug, beta-lactam, and aminoglycoside) and between two different ARG types (i.e., aminoglycoside and beta-lactam), possibly implicating co-effects of antibiotic selection pressure and co resistance on shaping antibiotic resistome in sewage sludge. Unlike beta-lactam resistance genes, ARGs of multidrug and macrolide-lincosamide-streptogramin tended to co-occur more with HBPs. Strikingly, we presented evidence that the most straightforward biological origin of an ARG-species co-occurring event is a hosting relationship. Furthermore, a significant and robust HBP-species co occurrence correlation provides a proper scenario for nominating HBP indicators (e.g., Bifidobacterium spp. are perfect indicators of C. aerofaciens; r = 0.92 0.99 and P-values < 0.01). Combined, this study demonstrates a creative and effective network-based metagenomic approach for exploring ARG hosts and HBP indicators and assessing ARGs acquisition by HBPs in human-impacted environments where ARGs and HBPs may co-thrive. PMID- 26773391 TI - In memory of Gianfranco Menestrina. PMID- 26773392 TI - Risk evaluation of the Arctic environmental POP exposure based on critical body residue and critical daily dose using captive Greenland sledge dogs (Canis familiaris) as surrogate species. AB - The risk from POP (persistent organic pollutant) exposure and subsequent reproductive, immunotoxic and liver histopathological effects was evaluated in a classical parallel trial on Greenland sledge dogs (Canis familiaris) fed contaminated minke whale (Balaenoptera acutorostrata) blubber. First the critical body residues (CBRs) were estimated using the physiologically-based pharmacokinetic (PBPK) model for seven POP compounds based on rat critical daily doses (CDDs). These were then compared with the actual daily oral POP doses (DD) and body residues (BR) in the sledge dogs by calculating risk quotients (RQDD: DD/CDD; RQBR: BR/CBR; >=1 indicates risk). The results showed that risk quotients for reproductive, immunotoxic and liver histopathological effects were significantly lowest in the control group (p<0.01) while risk quotients based on daily doses (RQDD) were significantly lower than RQs based on body residues (RQBR) (all p<0.01). RQBR in the exposed group ranged from 1.0-12 for reproductive and immunotoxic effects while those for liver histopathological effects ranged from 0.7-3.0. PCBs (polychlorinated biphenyls) and chlordanes were the dominant driver behind high immune and reproductive RQs while dieldrin was the most important factor behind RQs for liver histopathology. Principal component analyses and Spearman rank correlation analyses showed that complement and cellular immune parameters were significantly negative correlated with RQBR (all p<0.05) while logistic regression showed that RQDD had a significant effect on the number of born cups (p=0.03). No significantly relations were found between RQs and hormone concentrations, number of gestations, antibody titres or liver histopathology. These results confirm previous studies showing that POP exposure negatively impacts steroid hormones, various immune parameters, as well as liver histopathology in sledge dogs. It is also clear that RQBR is the best reflector of health effects from POP exposure and that it is especially accurate in predicting immune and reproductive effects. We recommend that PBPK modelled (CBR) and RQBR should be used in the assessment of POP exposure and health effects in Arctic top predators. PMID- 26773393 TI - Short-term fluctuations in personal black carbon exposure are associated with rapid changes in carotid arterial stiffening. AB - BACKGROUND: Vascular changes may underpin the association between airborne black carbon (BC) and cardiovascular events. Accurate assessment of personal exposure is a major challenge in epidemiological research. BC concentrations are strongly related to time-activity patterns, which is particularly relevant when investigating short-term effects. We investigated associations between arterial stiffness and personal short-term BC exposure. METHODS: This panel study included 54 healthy adults (92% women, mean age 40.7years). BC exposure was monitored individually with a micro-aethalometer during one workweek. Functional and structural properties of the carotid artery were examined ultrasonographically on two separate days. The effect of different short-term personal BC exposure windows (1, 2, 4, 6, 8, 24 and 48h before the ultrasound examination) on carotid artery stiffness was estimated using mixed models while adjusting for other known correlates of arterial stiffness. RESULTS: Median personal BC exposures within the same day ranged from 599.8 to 728.9ng/m(3) and were associated with carotid arterial stiffness measures. Young's elastic modulus and pulse wave velocity, both measures of stiffness, were positively associated with BC exposure, while the distensibility and compliance coefficient, measures of elasticity, were negatively associated with BC exposure. The strongest associations were observed with BC exposure 8h before the clinical examination. For each 100ng/m(3) increase in exposure within this time window, Young's elastic modulus increased by 2.38% (95% CI: 0.81 to 3.97; P=0.0033), while the distensibility coefficient decreased by 2.27% (95% CI: -3.62 to -0.92; P=0.0008). CONCLUSIONS: Short-term elevations in personal BC exposure, even within hours, are associated with increased arterial stiffness. This response may reflect a pathway by which air pollution triggers cardiovascular events. PMID- 26773394 TI - Spatial and temporal associations of road traffic noise and air pollution in London: Implications for epidemiological studies. AB - Road traffic gives rise to noise and air pollution exposures, both of which are associated with adverse health effects especially for cardiovascular disease, but mechanisms may differ. Understanding the variability in correlations between these pollutants is essential to understand better their separate and joint effects on human health. We explored associations between modelled noise and air pollutants using different spatial units and area characteristics in London in 2003-2010. We modelled annual average exposures to road traffic noise (LAeq,24h, Lden, LAeq,16h, Lnight) for ~190,000 postcode centroids in London using the UK Calculation of Road Traffic Noise (CRTN) method. We used a dispersion model (KCLurban) to model nitrogen dioxide, nitrogen oxide, ozone, total and the traffic-only component of particulate matter <=2.5MUm and <=10MUm. We analysed noise and air pollution correlations at the postcode level (~50 people), postcodes stratified by London Boroughs (~240,000 people), neighbourhoods (Lower layer Super Output Areas) (~1600 people), 1km grid squares, air pollution tertiles, 50m, 100m and 200m in distance from major roads and by deprivation tertiles. Across all London postcodes, we observed overall moderate correlations between modelled noise and air pollution that were stable over time (Spearman's rho range: |0.34-0.55|). Correlations, however, varied considerably depending on the spatial unit: largest ranges were seen in neighbourhoods and 1km grid squares (both Spearman's rho range: |0.01-0.87|) and was less for Boroughs (Spearman's rho range: |0.21-0.78|). There was little difference in correlations between exposure tertiles, distance from road or deprivation tertiles. Associations between noise and air pollution at the relevant geographical unit of analysis need to be carefully considered in any epidemiological analysis, in particular in complex urban areas. Low correlations near roads, however, suggest that independent effects of road noise and traffic-related air pollution can be reliably determined within London. PMID- 26773395 TI - Determination of parabens and benzophenone-type UV filters in human placenta. First description of the existence of benzyl paraben and benzophenone-4. AB - UV filters and parabens (PBs) are chemicals used in daily personal care and hygiene products to protect materials and humans from the adverse effects of UV radiation and to preserve the integrity of the formulation, respectively. Several studies highlight their widespread environmental occurrence and endocrine disrupting effects. However, little is known about human exposure to these compounds. The objective of this study was to investigate the exposure of human embryos and foetuses to endocrine disrupting UV filters and PBs. Placentas from volunteer mothers in Barcelona were collected at delivery after informed, written consent by the pregnant women. UV filters and parabens were analysed by liquid chromatography-tandem mass spectrometry. The excellent performance of the method allowed measuring the target compounds in human placental tissue at low ng/g fresh weight level. The detection frequency of the selected compounds was in the range 17-100%. Benzophenone-1, methyl paraben, butyl paraben and benzyl paraben were detected in all samples. The highest measured concentration corresponded to methyl paraben, 11.77ng/g fresh weight. Reported concentrations of benzophenone-4 and benzyl paraben constitute the first evidence about their accumulation in placenta. The results obtained corroborate that foetuses are exposed to a wide diversity of UV filters and PBs via the placenta. PMID- 26773396 TI - A new integrated in silico strategy for the assessment and prioritization of persistence of chemicals under REACH. AB - The fact that chemicals can be recalcitrant and persist in the environment arouses concern since their effects may seriously harm human and environmental health.We compiled three datasets containing half-life (HL) data on sediment, soil and water compartments in order to build in silico models and, finally, an integrated strategy for predicting persistence to be used within the EU legislation Registration, Evaluation, Authorisation and restriction of CHemicals (REACH). After splitting the datasets into training (80%) and test sets (20%), we developed models for each compartment using the k-nearest neighbor algorithm (k NN). Accuracy was higher than 0.79 and 0.76 respectively in the training and test sets for all three compartments. To support the k-NN predictions, we identified some structural alerts, using SARpy software, with a high-true positive percentage in the test set and some chemical classes related to persistence using the software IstChemFeat. All these results were combined to build an integratedmodel and to reach to an overall conclusion (based on assessment and reliability) on the persistenceof the substance. The results on the external validation set were very encouraging and support the idea that this tool can be used successfully for regulatory purposes and to prioritize substances. PMID- 26773397 TI - Are Chinese consumers at risk due to exposure to metals in crayfish? A bioaccessibility-adjusted probabilistic risk assessment. AB - Freshwater crayfish, the world's third largest crustacean species, has been reported to accumulate high levels of metals, while the current knowledge of potential risk associated with crayfish consumption lags behind that of finfish. We provide the first estimate of human health risk associated with crayfish (Procambarus clarkii) consumption in China, the world's largest producer and consumer of crayfish. We performed Monte Carlo Simulation on a standard risk model parameterized with local data on metal concentrations, bioaccessibility (phi), crayfish consumption rate, and consumer body mass. Bioaccessibility of metals in crayfish was found to be variable (68-95%) and metal-specific, suggesting a potential influence of metal bioaccessibility on effective metal intake. However, sensitivity analysis suggested risk of metals via crayfish consumption was predominantly explained by consumption rate (explaining >92% of total risk estimate variability), rather than metals concentration, bioaccessibility, or body mass. Mean metal concentrations (As, Cd, Cu, Ni, Pb, Se and Zn) in surveyed crayfish samples from 12 provinces in China conformed to national safety standards. However, risk calculation of phi-modified hazard quotient (HQ) and hazard index (HI) suggested that crayfish metals may pose a health risk for very high rate consumers, with a HI of over 24 for the highest rate consumers. Additionally, the phi-modified increased lifetime risk (ILTR) for carcinogenic effects due to the presence of As was above the acceptable level (10(-5)) for both the median (ILTR=2.5*10(-5)) and 90th percentile (ILTR=1.8*10( 4)), highlighting the relatively high risk of As in crayfish. Our results suggest a need to consider crayfish when assessing human dietary exposure to metals and associated health risks, especially for high crayfish-consuming populations, such as in China, USA and Sweden. PMID- 26773398 TI - Early adversity, hypocortisolism, and behavior problems at school entry: A study of internationally adopted children. AB - The hypothalamic-pituitary-adrenal (HPA) axis is influenced by early life adversity; however, less is known about the potential for recovery following marked improvements in care. The present study examined longitudinal changes in children's cortisol reactivity in the laboratory (4 assessments over 2 years) after adoption. Post-institutionalized (N=65) and post-foster care children (N=49) demonstrated blunted reactivity relative to non-adopted peers (N=53). Furthermore, post-institutionalized children exhibited no evidence of expected adaptation to repeated sessions in the 2 years following adoption. As evidenced by blunted cortisol reactivity, flatter diurnal slope, and lower home morning cortisol, we found support for hypocortisolism among children experiencing adverse early care. Hypocortisolism served as a mediator between adversity and teacher-reported attention and externalizing problems during kindergarten. Early adversity appears to contribute to the down-regulation of the HPA axis under both basal and stress conditions. PMID- 26773399 TI - BDNF val(66)met genotype shows distinct associations with the acoustic startle reflex and the cortisol stress response in young adults and children. AB - Brain Derived Neurotrophic Factor (BDNF) is a crucial regulator of neuronal development, organization and function and the val(66)met polymorphism in the BDNF gene has been associated with several (endo-) phenotypes of cognitive and affective processing. The BDNF met allele is considered a risk factor for anxiety and fear related phenotypes although findings are not entirely consistent. Here, the impact of BDNF val(66)met on two parameters of anxiety and stress was investigated in a series of studies. Acoustic startle responses were assessed in three adult samples (N1=117, N2=104, N3=116) as well as a children sample (N4=123). Cortisol increase in response to the Trier Social Stress Test (TSST) was measured in one adult sample (N3) and in the children sample (N4). The BDNF met allele was associated with enhanced cortisol responses in young adults (p=0.039) and children (p=0.013). On the contrary, BDNF met allele carriers showed a reduced acoustic startle response which reached significance in most samples (N1: p=0.004; N2: p=0.045; N3: n.s., N4: p=0.043) pointing to differential effects of BDNF val(66)met on distinct endophenotypes of anxiety and stress-related responses. However, small effect sizes suggest substantial additional genetic as well as environmental contributors. PMID- 26773401 TI - Splitting hair for cortisol? Associations of socio-economic status, ethnicity, hair color, gender and other child characteristics with hair cortisol and cortisone. AB - The aim of this study was to examine associations of SES and ethnicity with hair cortisol and cortisone and to identify potential child and family characteristics that can assist in choosing covariates and potential confounders for analyses involving hair cortisol and cortisone concentrations. Hair samples were collected in 2484 6-year-old children from the Generation R Study, a prospective cohort in Rotterdam, the Netherlands. Measurements for cortisol and cortisone were used as the outcome in regression analyses. Predictors were SES, ethnicity, hair color and child characteristics such as birthweight, gestational age at birth, BMI, disease, allergy, and medication use. Lower family income, more children to be supported by this income, higher BMI and darker hair color were associated with higher hair cortisol and cortisone levels. Boys also showed higher levels. Ethnicity (Dutch and North European descent) was related to lower levels. High amounts of sun in the month of hair collection was related to higher levels of cortisone only. More recent hair washing was related to lower levels of cortisol and cortisone. Gestational age at birth, birth weight, age, medication use, hair washing frequency, educational level of the mother, marital status of the mother, disease and allergy were not associated with cortisol or cortisone levels. Our results serve as a starting point for choosing covariates and confounders in studies of substantive predictors or outcomes. Gender, BMI, income, the number of persons in a household, ethnicity, hair color and recency of hair washing are strongly suggested to take into account. PMID- 26773402 TI - Major changes in the sphingophospholipidome of HDL in non-diabetic patients with metabolic syndrome. AB - OBJECTIVE: Phospholipids and sphingolipids play a critical role in the protective effects of HDL against atherosclerosis. These properties are impaired in patients with metabolic syndrome, before the development of diabetes. We thus investigated whether HDL from patients with metabolic syndrome but normal fasting glycaemia present abnormalities in their sphingophospholipid profile. METHODS: Using liquid chromatography/tandem mass spectrometry, we quantified the different species of the main phospholipids and sphingolipids in the HDL2 and HDL3 from 26 obese patients with metabolic syndrome but normal fasting glycaemia and 50 controls. RESULTS: Phosphatidylcholines, when expressed as the relative amount compared with total phospholipids and sphingolipids, were similar in both HDL2 and HDL3 in the two groups. Lysophosphatidylcholines were 41% (p = 0.0002) and 86% (p < 0.0001) higher in HDL2 and HDL3, respectively, from patients with metabolic syndrome than in those from controls. Phosphatidylinositols were also higher in HDL2 and HDL3 (respectively, +60 and + 103% (p < 0.0001)). In contrast, both HDL2 and HDL3 from patients with metabolic syndrome showed lower proportions of phosphatidylethanolamine-based plasmalogens (respectively -78 and -73%, p < 0.0001), phosphatidylcholine-based plasmalogens (respectively -44 and -53%, p < 0.0001), d18:1-sphingosine-1-phosphate (respectively -52 and -38%, p < 0.0001) and sphingomyelins (respectively -19% (p < 0.0001) and -24% (p = 0.0006)), than did controls. Moreover, we observed a decrease in C18:2 fatty acid-containing phospholipids and an increase in C20:4 fatty acid-containing phospholipids. CONCLUSION: The sphingophospholipidome of HDL from normoglycaemic obese patients with metabolic syndrome is profoundly modified, before the dysregulation of glycaemia. Most of the changes observed have pejorative effect in terms of vascular protection. PMID- 26773400 TI - Hypothalamic-pituitary-adrenal axis response to acute psychosocial stress: Effects of biological sex and circulating sex hormones. AB - Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis influences the risk for developing stress-related disorders. Sex-dependent differences in the HPA axis stress response are believed to contribute to the different prevalence rates of stress-related disorders found in men and women. However, studies examining the HPA axis stress response have shown mixed support for sex differences, and the role of endogenous sex hormones on HPA axis response has not been adequately examined in humans. This study utilized the largest sample size to date to analyze the effects of biological sex and sex hormones on HPA axis social stress responses. Healthy, 18- to 30- year-old community volunteers (N=282) completed the Trier Social Stress Test (TSST), a widely used and well validated stress-induction laboratory procedure. All women (n=135) were tested during the follicular phase of their menstrual cycle (when progesterone levels are most similar to men). Adrenocorticotropic hormone (ACTH) and cortisol measures were collected at multiple points throughout pre- and post-TSST. Testosterone and progesterone (in men) and progesterone and estradiol (in women) were determined pre-TSST. Following the TSST, men had greater ACTH and cortisol levels than women. Men had steeper baseline-to-peak and peak-to-end ACTH and cortisol response slopes than women; there was a trend for more cortisol responders among men than women. Testosterone negatively correlated with salivary cortisol response in men, while progesterone negatively correlated with ACTH and cortisol responses in women. These data confirm that men show more robust activation of the HPA axis response to the TSST than do women in the follicular phase of the menstrual cycle. Testosterone results suggest an inhibitory effect on HPA axis reactivity in men. Progesterone results suggest an inhibitory effect on HPA axis reactivity in women. Future work is needed to explain why men mount a greater ACTH and cortisol response to the TSST than do women during the follicular phase of the menstrual cycle. PMID- 26773407 TI - Duration of ovarian hormone exposure and gynecological cancer risk in Korean women: the Korean Heart Study. AB - BACKGROUND: Although reproductive and hormonal factors - such as early menarche and late menopause - have been reported as independent risk factors for cancer, few studies have examined these factors in East Asian populations. METHODS: We performed a large prospective cohort study of 66,466 women. Ovarian hormone exposure was defined as length of time between menarche and menopause. Incidence rates for breast, ovarian, endometrial and cervical cancers were examined separately in relation to reproductive lifespan defined as age at menopause minus age at menarche. Multivariable adjusted hazard ratios (HRs) with 95% confidence intervals (95% CIs) were calculated using the Cox proportional hazards model. RESULTS: Women with early menarche were at increased risk for developing breast cancer (HR, 1.57, 95% CI, 1.17-2.10) for age at menarche <=12 years compared to women with age at menarche >=17 years. Women with late age at menopause (>=52 years) had increased risks for cancers of the breast (HR, 1.59, 95%CI, 1.11-2.28) and ovary (HR, 3.22, 95% CI, 1.09-9.55) compared to women with early menopause (<=45 years of age). Women with longer duration of ovarian hormone exposure (>=40 years) were at increased risk for developing breast cancer (HR, 2.23, 95% CI, 1.35-3.68) as well as endometrial cancer (p for trend, 0.0209). CONCLUSIONS: We showed that longer reproductive spans are associated with an increased risk of breast and endometrial cancer in Korean women. PMID- 26773408 TI - Skeletal Mineralization Deficits and Impaired Biogenesis and Function of Chondrocyte-Derived Matrix Vesicles in Phospho1(-/-) and Phospho1/Pi t1 Double Knockout Mice. AB - We have previously shown that ablation of either the Phospho1 or Alpl gene, encoding PHOSPHO1 and tissue-nonspecific alkaline phosphatase (TNAP) respectively, lead to hyperosteoidosis, but that their chondrocyte-derived and osteoblast-derived matrix vesicles (MVs) are able to initiate mineralization. In contrast, the double ablation of Phospho1 and Alpl completely abolish initiation and progression of skeletal mineralization. We argued that MVs initiate mineralization by a dual mechanism: PHOSPHO1-mediated intravesicular generation of inorganic phosphate (Pi ) and phosphate transporter-mediated influx of Pi . To test this hypothesis, we generated mice with col2a1-driven Cre-mediated ablation of Slc20a1, hereafter referred to as Pi t1, alone or in combination with a Phospho1 gene deletion. Pi t1(col2/col2) mice did not show any major phenotypic abnormalities, whereas severe skeletal deformities were observed in the [Phospho1(-/-) ; Pi t1(col2/col2) ] double knockout mice that were more pronounced than those observed in the Phospho1(-/-) mice. Histological analysis of [Phospho1(-/-) ; Pi t1(col2/col2) ] bones showed growth plate abnormalities with a shorter hypertrophic chondrocyte zone and extensive hyperosteoidosis. The [Phospho1(-/-) ; Pi t1(col2/col2) ] skeleton displayed significant decreases in BV/TV%, trabecular number, and bone mineral density, as well as decreased stiffness, decreased strength, and increased postyield deflection compared to Phospho1(-/-) mice. Using atomic force microscopy we found that ~80% of [Phospho1(-/-) ; Pi t1(col2/col2) ] MVs were devoid of mineral in comparison to ~50% for the Phospho1(-/-) MVs and ~25% for the WT and Pi t1(col2/col2) MVs. We also found a significant decrease in the number of MVs produced by both Phospho1( /-) and [Phospho1(-/-) ; Pi t1(col2/col2) ] chondrocytes. These data support the involvement of phosphate transporter 1, hereafter referred to as Pi T-1, in the initiation of skeletal mineralization and provide compelling evidence that PHOSPHO1 function is involved in MV biogenesis. (c) 2016 American Society for Bone and Mineral Research. PMID- 26773409 TI - Outcome of patients with systemic light chain amyloidosis with concurrent renal and cardiac involvement. AB - Cardiac involvement in systemic light chain amyloidosis (AL) is generally associated with a worse outcome, especially if other organs are also involved. We sought to determine whether concurrent cardiac and renal involvement were associated with a worse outcome than either organ alone. We identified 129 patients with AL, who received high-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (auto-HCT) at our institution between 1997 and 2014. Ninety-nine patients had either renal (group 1: n = 62, 62%), cardiac (group 2: n = 20, 20%), or both cardiac and renal (group 3: n = 17, 17%) involvement. The overall hematological response rate (CR+VGPR+PR) post-auto-HCT in groups 1, 2, and 3 was 69%, 74% and 82%, respectively (P = 0.62). Overall, organ response in groups 1, 2, and 3 was 39%, 42%, and 70%, respectively. The median PFS from auto-HCT in groups 1, 2, and 3 was not reached (NR), 13.3 and 21 months, respectively (P = 0.02). The median OS in groups 1, 2, and 3 was 120, 46, and 60 months, respectively (P = 0.1). In conclusion, median PFS and OS in patients with concurrent cardiac and renal AL were comparable to patients with cardiac AL only, but worse than patients with renal AL. PMID- 26773412 TI - Prediction of oral appliance treatment outcomes in obstructive sleep apnea: A systematic review. AB - While oral appliances (OA) have demonstrated good efficacy in patients ranging from mild to severe levels of obstructive sleep apnea (OSA), this form of treatment is not completely effective in all patients. As a successful treatment response is not dependent solely on apnea hypopnea index severity, the prediction of OA treatment efficacy is of key importance for efficient disease management. This systematic review aims to investigate the accuracy of a variety of clinical and experimental tests for predicting OA treatment outcomes in OSA. A systematic literature review was conducted and the quality of the selected studies was assessed using the quality assessment of diagnostic accuracy studies (QUADAS-2) tool. Some 17 studies involving various prediction methods were included in this review. The predictive accuracy varied depending on the definitions of treatment success used as well as the type of index test. The studies with the best predictive accuracy and lowest risk of bias and concerns of applicability used a multisensor catheter. While a remotely controlled mandibular positioner study showed high accuracy, there was a high risk of bias. The available information on the validity of predictive index tests is very useful in clinical practice and allows for greater disease management efficiency. PMID- 26773413 TI - Tyrosinase versus Catechol Oxidase: One Asparagine Makes the Difference. AB - Tyrosinases mediate the ortho-hydroxylation and two-electron oxidation of monophenols to ortho-quinones. Catechol oxidases only catalyze the oxidation of diphenols. Although it is of significant interest, the origin of the functional discrimination between tyrosinases and catechol oxidases has been unclear. Recently, it has been postulated that a glutamate and an asparagine bind and activate a conserved water molecule towards deprotonation of monophenols. Here we demonstrate for the first time that a polyphenoloxidase, which exhibits only diphenolase activity, can be transformed to a tyrosinase by mutation to introduce an asparagine. The asparagine and a conserved glutamate are necessary to properly orient the conserved water in order to abstract a proton from the monophenol. These results provide direct evidence for the crucial importance of a proton shuttle for tyrosinase activity of type 3 copper proteins, allowing a consistent understanding of their different chemical reactivities. PMID- 26773414 TI - Aggressive behavior in humans: Genes and pathways identified through association studies. AB - Aggressive behavior has both genetic and environmental components. Many association studies have been performed to identify genetic factors underlying aggressive behaviors in humans. In this review we summarize the previous work performed in this field, considering both candidate gene (CGAS) and genome-wide association studies (GWAS), excluding those performed in samples where the primary diagnosis is a psychiatric or neurological disorder other than an aggression-related phenotype. Subsequently, we have studied the enrichment of pathways and functions in GWAS data. The results of our searches show that most CGAS have identified associations with genes involved in dopaminergic and serotonergic neurotransmission and in hormone regulation. On the other hand, GWAS have not yet identified genome-wide significant associations, but top nominal findings are related to several signaling pathways, such as axon guidance or estrogen receptor signaling, and also to neurodevelopmental processes and synaptic plasticity. Future studies should use larger samples, homogeneous phenotypes and standardized measurements to identify genes that underlie aggressive behaviors in humans. (c) 2016 Wiley Periodicals, Inc. PMID- 26773416 TI - Reply. PMID- 26773415 TI - Comparison of Radiofrequency Catheter Ablation Between Asymptomatic and Symptomatic Persistent Atrial Fibrillation: A Propensity Score Matched Analysis. AB - BACKGROUND: Whether patients with asymptomatic atrial fibrillation (AF) could benefit from radiofrequency catheter ablation (RFCA) remains unclear. This study aimed to compare the outcomes of RFCA between asymptomatic and symptomatic AF. METHODS: Sixty-six patients with asymptomatic persistent AF who underwent the primary ablation for AF were enrolled; 132 patients with symptomatic persistent AF were matched using propensity score matching. All patients underwent circumferential pulmonary vein isolation in combination with linear ablation using AF termination as the primary procedural endpoint. RESULTS: Sinus rhythm (SR) was restored by ablation in 18 (27.3%) patients in the asymptomatic group and 93 (70.5%) in the symptomatic group (P < 0.001). Combined with intravenous infusion of ibutilide (1 mg), the numbers were 45 (68.2%) and 116 (87.8%), respectively (P = 0.001). At 1-year follow-up, SR was present in 23 (34.8%) patients in the asymptomatic group and 78 (59.1%) in the symptomatic group without any antiarrhythmic medication after a single procedure (P = 0.001). Of the 43 patients experiencing recurrence in the asymptomatic group, 16 (37.2%) had recurrent atrial tachycardia (AT)-related symptoms. Multivariate analysis showed that asymptomatic AF was independently associated with AF failed to be terminated by ablation (OR: 7.1; 95% CI: 3.4 to 14.9; P < 0.001) and recurrence (OR: 2.2; 95% CI: 1.1 to 4.4; P = 0.018). Patients with asymptomatic AF showed less improvement in quality of life postablation than those with symptoms. CONCLUSION: Current catheter ablation techniques showed worse outcomes in asymptomatic AF patients than in those with symptoms. Recurrent AT could cause significant symptoms in previously asymptomatic patients. PMID- 26773411 TI - Selection of internal standards for accurate quantification of complex lipid species in biological extracts by electrospray ionization mass spectrometry-What, how and why? AB - Lipidomics is rapidly expanding because of the great facilitation of recent advances in, and novel applications of, electrospray ionization mass spectrometry techniques. The greatest demands have been for successful quantification of lipid classes, subclasses, and individual molecular species in biological samples at acceptable accuracy. This review addresses the selection of internal standards in different methods for accurate quantification of individual lipid species. The principles of quantification with electrospray ionization mass spectrometry are first discussed to recognize the essentials for quantification. The basics of different lipidomics approaches are overviewed to understand the variables that need to be considered for accurate quantification. The factors that affect accurate quantification are extensively discussed, and the solutions to resolve these factors are proposed-largely through addition of internal standards. Finally, selection of internal standards for different methods is discussed in detail to address the issues of what, how, and why related to internal standards. We believe that thorough discussion of the topics related to internal standards should aid in quantitative analysis of lipid classes, subclasses, and individual molecular species and should have big impacts on advances in lipidomics. (c) 2016 Wiley Periodicals, Inc. Mass Spec Rev 36:693-714, 2017. PMID- 26773417 TI - Effectiveness of a Technology-Based Intervention to Teach Evidence-Based Practice: The EBR Tool. AB - BACKGROUND: As the world becomes increasingly digital, advances in technology have changed how students access evidence-based information. Research suggests that students overestimate their ability to locate quality online research and lack the skills needed to evaluate the scientific literature. Clinical nurses report relying on personal experience to answer clinical questions rather than searching evidence-based sources. To address the problem, a web-based, evidence based research (EBR) tool that is usable from a computer, smartphone, or iPad was developed and tested. The purpose of the EBR tool is to guide students through the basic steps needed to locate and critically appraise the online scientific literature while linking users to quality electronic resources to support evidence-based practice (EBP). METHODS: Testing of the tool took place in a mixed method, quasi-experimental, and two-population randomized controlled trial (RCT) design in a U.S. and Middle East university. RESULTS: A statistically significant improvement in overall research skills was supported in the quasi-experimental nursing student group and RCT nutrition student group using the EBR tool. A statistically significant proportional difference was supported in the RCT nutrition and PharmD intervention groups in participants' ability to distinguish the credibility of online source materials compared with controls. The majority of participants could correctly apply PICOTS to a case study when using the tool. CONCLUSIONS: The data from this preliminary study suggests that the EBR tool enhanced student overall research skills and selected EBP skills while generating data for assessment of learning outcomes. LINKING EVIDENCE TO ACTION: The EBR tool places evidence-based resources at the fingertips of users by addressing some of the most commonly cited barriers to research utilization while exposing users to information and online literacy standards of practice, meeting a growing need within nursing curricula. PMID- 26773418 TI - Bilateral salpingectomy can reduce the risk of ovarian cancer in the general population: A meta-analysis. AB - BACKGROUND: The results of recent studies have suggested that high-grade serous ovarian cancer predominantly arises within the fallopian tubes. The reduction of ovarian cancer (OC) risk in women with a history of bilateral salpingectomy (BS) has been reported. We performed a meta-analysis to determine the impact of BS in preventing OC in the general population. METHODS: We searched the PubMed, MEDLINE, and EMBASE databases and CENTRAL in the Cochrane Library for all English language articles published up to January 2015, using the key words 'ovarian cancer' and 'bilateral salpingectomy.' Odds ratios (ORs) and their 95% confidence intervals (95% CIs) were calculated by standard meta-analysis techniques. RESULTS: Of the 77 studies retrieved, three were included in this meta-analysis, including one cohort study and two population-based case-control studies with 3509 patients who underwent BS and 5,655,702 controls who did not undergo salpingectomy. Over the combined study period, 29 of the 3509 BS patients developed OC compared with 44,006 of the 5,655,702 without salpingectomy. The meta-analysis results based on the fixed effects model revealed a significant decrease in the risk of OC occurrence in the patients who underwent BS relative to the controls (OR=0.51, 95% CI 0.35-0.75, I(2)=0%). This pattern was also observed in subgroup analysis for the study type. CONCLUSIONS: Our results suggest that removal of the fallopian tubes is an effective measure to reduce OC risk in the general population. Therefore, prophylactic bilateral salpingectomy should be considered for women who require hysterectomy with benign indications or sterilisation procedures. PMID- 26773419 TI - Disparities in melanoma incidence and mortality in South-Eastern Europe: Increasing incidence and divergent mortality patterns. Is progress around the corner? AB - INTRODUCTION: Most countries in South-Eastern Europe (SEE) have lower incidence, but higher mortality rates of malignant melanoma (MM) of the skin compared to North-Western Europe (NWE). We explored trends in MM incidence and mortality in SEE countries by sex and age and compared them with the trends in NWE. METHODS: We obtained data on incident cases and deaths from MM (ICD-10 code C43) from 11 population-based cancer registries in Bosnia and Herzegovina, Bulgaria, Croatia, Cyprus, Czech Republic, Malta, Romania, Serbia, Slovakia, Slovenia and Turkey. We calculated age-specific rates for 25-49 ('young'), 50-69 ('middle aged') and 70+ years ('older') and estimated the average annual percent of change in incidence and mortality trends 2000-2010 according to age group and sex, using joinpoint regression analysis. FINDINGS: The incidence rates of MM across the region were uniformly increasing. Significant increases in mortality rates were observed in middle aged men in Serbia and Bulgaria, middle aged women in Slovenia, older men in the Czech Republic, Serbia and Turkey, and older women in Slovenia and Serbia. INTERPRETATION: While MM incidence rates were still increasing across SEE, mortality trends diverged and were less favourable than in NWE. Empowering cancer registration and improving the quality of incidence and mortality data will be essential for monitoring progress in MM control. In the context of prevention of melanoma, disparities in early detection appear to be widening the gap between SEE and NWE, while the provision of care to patients with advanced disease is likely to prove a challenge for regional healthcare budgets. PMID- 26773421 TI - Ovarian cancer in Lynch syndrome; a systematic review. AB - OBJECTIVE: The aim was to systematically review the characteristics of ovarian cancer in women with Lynch syndrome (LS) and evaluate the role of surveillance in detection of ovarian cancer in LS. METHODS: All studies between 1979 and 2015 of women with ovarian cancer and LS or at 50% risk of LS were evaluated. Two reviewers independently evaluated eligible studies and extracted data on age at diagnosis, histological type, FIGO stage, and way of detection according to pre specified criteria. The studies were assessed for quality using the Newcastle Ottawa quality assessment scales. RESULTS: The quality score of the 49 identified studies was at least 6 out of 8 and provide clinical information on 747 LS women with ovarian cancer. The mean age at diagnosis was 45.3 (range 19-82) years. Most frequent mutations were MSH2 (47%) and MLH1 (38%). Histopathological data were available for 445 women. The most frequently reported histological type was mixed type (mucinous/endometrioid/clear cell carcinomas) (n = 136; 31%). Most tumours (281, 65%) were diagnosed at an early stage (FIGO I/II). Six studies evaluating the effect of surveillance of ovarian cancer, reported that seven of 22 (32%) ovarian cancers were found during surveillance, 6/7 (86%) were detected at an early stage. CONCLUSION: This systematic review describes that ovarian cancer in women with LS has a wide age-range of onset, is often diagnosed at an early stage with frequently endometrioid/clear cell histology. Data about the role of surveillance in detection of ovarian cancer in women with LS are scarce however detection at an early stage seems possible. PMID- 26773420 TI - Cyclophosphamide pharmacokinetics and pharmacogenetics in children with B-cell non-Hodgkin's lymphoma. AB - INTRODUCTION: Variation in cyclophosphamide pharmacokinetics and metabolism has been highlighted as a factor that may impact on clinical outcome in various tumour types. The current study in children with B-cell non-Hodgkin's lymphoma (NHL) was designed to corroborate previous findings in a large prospective study incorporating genotype for common polymorphisms known to influence cyclophosphamide pharmacology. METHODS: A total of 644 plasma samples collected over a 5 year period, from 49 B-cell NHL patients <= 18 years receiving cyclophosphamide (250 mg/m(2)), were used to characterise a population pharmacokinetic model. Polymorphisms in genes including CYP2B6 and CYP2C19 were analysed. RESULTS: A two-compartment model provided the best fit of the population analysis. The mean cyclophosphamide clearance value following dose 1 was significantly lower than following dose 5 (1.83 +/- 1.07 versus 3.68 +/- 1.43 L/h/m(2), respectively; mean +/- standard deviation from empirical Bayes estimates; P < 0.001). The presence of at least one CYP2B6*6 variant allele was associated with a lower cyclophosphamide clearance following both dose 1 (1.54 +/ 0.11 L/h/m(2) versus 2.20 +/- 0.31 L/h/m(2), P = 0.033) and dose 5 (3.12 +/- 0.17 L/h/m(2) versus 4.35 +/- 0.37 L/h/m(2), P = 0.0028), as compared to homozygous wild-type patients. No pharmacokinetic parameters investigated were shown to have a significant influence on progression free survival. CONCLUSION: The results do not support previous findings of a link between cyclophosphamide pharmacokinetics or metabolism and disease recurrence in childhood B-cell NHL. While CYP2B6 genotype was shown to influence pharmacokinetics, there was no clear impact on clinical outcome. PMID- 26773422 TI - Social deprivation in patients requiring pelvic exenterative surgery. AB - AIM: Pelvic exenteration is an aggressive operation for locally advanced rectal cancer. Social deprivation has been shown to reduce life expectancy and has been linked to a poorer outcome in patients with colorectal cancer. The aim of this study was to analyse the effect of social deprivation scores on the outcome in these complex patients. METHOD: A retrospective review of all patients undergoing pelvic exenteration for primary rectal cancer between 2006 and 2014 was performed. Deprivation scores were calculated for all patients using the Welsh Index of Multiple Deprivation. Patients were then grouped into quartiles, from Q1 (most deprived) to Q4 (least deprived). The primary outcome measure was 5-year survival. RESULTS: In all, 120 patients were included (65 female) with a median age of 64 (31-90) years. No differences between quartiles were identified for neoadjuvant therapy (P = 0.687) or type of exenteration (P = 0.690). The median length of stay was significantly higher in the most deprived groups (Q1-Q2; P = 0.023). There was a significant difference in survival between the groups, with lowest 5-year survival rates (53%) in the most deprived quartile (Q1) (P = 0.015). CONCLUSION: Social deprivation is significantly associated with postoperative length of stay and survival in patients undergoing pelvic exenteration for primary rectal cancer. PMID- 26773424 TI - Form of phytosterols and food matrix in which they are incorporated modulate their incorporation into mixed micelles and impact cholesterol micellarization. AB - SCOPE: The ability of different plant sterols/stanols (PS) mixtures, which differed in the degree of B-ring saturation and aliphatic side chain structure and saturation, to reduce cholesterol (CH) micellarization was explored. METHODS AND RESULTS: Experiments were performed using an in vitro digestion model, synthetic mixed micelles, and pure porcine pancreatic lipases. Sterols were measured by GC-FID. The ability of PS to reduce CH micellarization was dependent on the form of PS and on the type of delivery matrix (low-fat yogurt or olive oil). Long-chain PS esters delivered in the yogurt matrix, and medium chain PS esters delivered in olive oil provided the greatest reduction in CH micellarization. In yogurt, the ability to impair CH micellarization was inversely related (rho = -0.41, p < 0.0005) to PS melting point. In olive oil, the more hydrophobic PS mixtures, i.e. those rich in long-chain PS esters, had the lower ability to impair CH micellarization. CONCLUSIONS: Different forms of PS have a different ability to impair CH micellarization. This ability depends on the transfer efficiency of PS from the food matrix to the micelle, which in turn depends on the melting point and the hydrophobicity of PS and on the delivery food matrix. PMID- 26773425 TI - Social and environmental factors drive variation in plant and bird communities across urban greenspace in Sydney, Australia. AB - We examined whether environmental or social factors alone, or a combination of social-ecological factors were more effective at explaining patterns in plant and bird assemblages across urban greenspaces. Thirty publicly accessible, passive recreation greenspaces provided by municipal councils (i.e. city parks) were surveyed in a highly urbanised city - Sydney, Australia. Plant communities were influenced most by topography and park management approach, and to a lesser extent by land-use history. Greenspaces with greater topographic variation and that were co-managed with local citizen groups hosted higher plant species richness and abundance. Bird species richness within greenspaces increased with increasing distance from the central business district and decreasing distance from freshwater. Bird abundance was best explained by a combination of social ecological factors, with abundance increasing with increasing site (greenspace) age, increasing percent concrete groundcover of a site and increasing proximity to the central business district. We identified a group of 'rare city parks', dissimilar in ecological composition that hosted more complex and species rich plant communities compared to 'common city parks'. We suggest this difference is likely because rare city parks received management and maintenance input from local citizen groups, whereas common city parks were managed and maintained exclusively by local councils. How different social factors, such as management approach and ongoing maintenance, are linked to the ecology of urban greenspaces are key areas for future investigation to help create sustainable urban landscapes that provide maximum benefits to urban residents. PMID- 26773423 TI - A review of hair product use on breast cancer risk in African American women. AB - The incidence rate of breast cancer for African American women has recently converged with that of non-Hispanic White women in the United States, although African Americans have a higher mortality rate due to this disease. Although most research exploring health disparities associated with this phenomenon has focused on differences between women based on biology and behavior, both the academic and lay communities have begun to explore the potential role of environmental exposure to estrogen and endocrine disrupting chemicals (EDCs). This study reviews the current state of the science associating one such means of exposure, hair products containing EDCs, with breast cancer risk in African American women. We found a growing body of evidence linking: (1) environmental estrogen and EDC exposures to breast cancer risk, (2) the presence of such chemicals in personal care products, including hair products, and (3) the use of certain hair products with potential breast cancer risk in African Americans. At the same time, there is also increasing concern in the lay community about this risk. These results indicate the need for additional research, and the opportunity to benefit from strategic partnerships in community-collaborative approaches in order to better understand the potential "cost of beauty." PMID- 26773426 TI - A review on paint sludge from automotive industries: Generation, characteristics and management. AB - The automotive manufacturing process results in the consumption of several natural sources and the generation of various types of wastes. The primary source of hazardous wastes at an automotive manufacturing plant is the painting process, and the major waste fraction is paint sludge, which is classified with EU waste code of 080113* implying hazardous characteristics. The amount of the paint sludge generated increases every year with the worldwide increase in the car production. The characteristics of the paint sludge, which mainly designate the management route, are mainly determined by the type of the paint used, application technique employed, and the chemicals applied such as flocculants, detackifiers, pH boosters, antifoam agents, and biocides as well as the dewatering techniques preferred. Major routes for the disposal of the paint sludges are incineration as hazardous waste or combustion at cement kilns. Because of high dissolved organic carbon content of the paint, the paint sludge cannot be accepted by landfills according to European Union Legislations. More investigations are needed in the field of paint sludge recycling such as recycling it as a new paint or as other formulations, or making use of the sludge for the production of construction materials. Research on the applicability of the paint sludge in composting and biogasification can also be useful. Ongoing research is currently being conducted on new application techniques to increase the effectiveness of paint transfer, which helps to prevent the generation of paint sludge. Advancements in paint and coating chemistry such as the reduction in the coating layers with its thickness also help to decrease the level of paint sludge generation. Investigations on the effects of the chemicals on the recycling potential of paint sludges and consideration of these effects by the chemical manufacturer companies would be extremely important. This review presents the formation of paint sludge, the factors affecting its characteristics, common disposal routes, the findings of the field trips to automotive manufacturing plants in Turkey, and a summary of the characterization findings of the paint sludge samples from a plant in Turkey. PMID- 26773427 TI - Suitability of the microbial community composition and function in a semiarid mine soil for assessing phytomanagement practices based on mycorrhizal inoculation and amendment addition. AB - The recovery of species composition and functions of soil microbial community of degraded lands is crucial in order to guarantee the long-term self-sustainability of the ecosystems. A field experiment was carried out to test the influence of combining fermented sugar beet residue (SBR) addition and inoculation with the arbuscular mycorrhizal (AM) fungus Funneliformis mosseae on the plant growth parameters and microbial community composition and function in the rhizosphere of two autochthonous plant species (Dorycnium pentaphyllum L. and Asteriscus maritimus L.) growing in a semiarid soil contaminated by heavy metals. We analysed the phospholipid fatty acids (PLFAs), neutral lipids fatty acids (NLFAs) and enzyme activities to study the soil microbial community composition and function, respectively. The combined treatment was not effective for increasing plant growth. The SBR promoted the growth of both plant species, whilst the AM fungus was effective only for D. pentaphyllum. The effect of the treatments on plant growth was linked to shifts in the rhizosphere microbial community composition and function. The highest increase in dehydrogenase and beta glucosidase activities was recorded in SBR-amended soil. The SBR increased the abundance of marker PLFAs for saprophytic fungi, Gram+ and Gram- bacteria and actinobacteria, whereas the AM fungus enhanced the abundance of AM fungi-related NLFA and marker PLFAs for Gram- bacteria. Measurement of the soil microbial community composition and function was useful to assess the success of phytomanagement technologies in a semiarid, contaminated soil. PMID- 26773429 TI - The effects of feedstock pre-treatment and pyrolysis temperature on the production of biochar from the green seaweed Ulva. AB - Green seaweeds from the genus Ulva are a promising feedstock for the production of biochar for carbon (C) sequestration and soil amelioration. Ulva can be cultivated in waste water from land-based aquaculture and Ulva blooms ("green tides") strand millions of tons of biomass on coastal areas of Europe and China each year. The conversion of Ulva into biochar could recycle C and nutrients from eutrophic water into agricultural production. We produce biochar from Ulva ohnoi, cultivated in waste water from an aquaculture facility, and characterize its suitability for C sequestration and soil amelioration through bio-chemical analyses and plant growth experiments. Two biomass pre-treatments (fresh water rinsing to reduce salt, and pelletisation to increase density) were crossed with four pyrolysis temperatures (300-750 degrees C). Biomass rinsing decreased the ash and increased the C content of the resulting biochar. However, biochar produced from un-rinsed biomass had a higher proportion of fixed C and a higher yield. C sequestration decreased with increasing pyrolysis temperatures due to the combination of lower yield and lower total C content of biochar produced at high temperatures. Biochar produced from un-rinsed biomass at 300 degrees C had the greatest gravimetric C sequestration (110-120 g stable C kg(-1) seaweed). Biochar produced from un-pelletised Ulva enhanced plant growth three-fold in low fertility soils when the temperature of pyrolysis was less than 450 degrees C. The reduced effectiveness of the high-temperature biochars (>450 degrees C) was due to a lower N and higher salt content. Soil ameliorated with biochar produced from pelletised biomass had suppressed plant germination and growth. The most effective biochar for C sequestration and soil amelioration was produced from un rinsed and un-pelletised Ulva at 300 degrees C. The green tide that occurs annually along the Shandong coastline in China generates sufficient biomass (200,000 tons dry weight) to ameliorate 12,500 ha of soil, sequester 15,000 t C and recycle 5500 t N into agriculture. We provide clear parameters for biochar production to enable the beneficial use of this biomass. PMID- 26773428 TI - Monitoring of selected non-ionic surfactants in river water by liquid chromatography-tandem mass spectrometry. AB - Alcohol ethoxylates (AEs) are a significant component of the non-ionic surfactant (NS) flux discharged into surface water. Due to the polydispersity of the majority of NS, they are easily recognizable by their 'fingerprints', i.e. a series of mass peaks which differ by m/z = 44, namely the m/z of a single oxyethylene subunit. Dodecanol ethoxylates (C12EOx) represent AEs from both renewable and petrochemical sources. Therefore, C12Ex are suitable fingerprints of NS in the aquatic environment. The aim of this work was to develop an LC-MS/MS method suitable for AE monitoring in river water. River water samples taken from the River Warta in Poznan (Poland) were extracted with ethyl acetate, evaporated, reconstituted in the mobile phase and processed by the LC - Multistage MS procedure (LC-MS/MS) using optimum multiple reaction monitoring (MRM). The method of multiple standard additions was used for the evaluation of each AE fingerprint concentration. The concentration of C12EOx having 2-9 oxyethylene subunits was determined. Standards for higher C12EOx are not yet available. The developed method offers an LOD of between 1 and 9 ng L(-1), and is suitable for the monitoring of NS fingerprints in river water. The range of C12EO2-9 concentrations determined in the River Warta varied within two orders of magnitude in all cases. The lowest determined concentration was 17 +/- 1 ng L( 1), while the highest was 2.6 +/- 0.14 MUg L(-1). The total concentration of C12EO2-C12EO9 homologues varied between 1.4 and 11.2 MUg L(-1). A relatively high concentration of short-chained homologues (2-5 oxyethylene subunits) was observed in the investigated river water. This provides evidence of a biodegradation pathway involving the gradual shortening of the AE oxyethylene chain. Distinct evidence was also obtained of unregulated NS discharges into the river. PMID- 26773430 TI - Barrage fishponds: Reduction of pesticide concentration peaks and associated risk of adverse ecological effects in headwater streams. AB - Constructed wetlands have been suggested as pesticide risk mitigation measures. Yet, in many agricultural areas, ponds or shallow lakes are already present and may contribute to the control of non-point source contamination by pesticides. In order to test this hypothesis, we investigated the influence of extensively managed barrage fishponds (n = 3) on the dissolved concentrations of 100 pesticides in headwater streams over the course of a year. Among the 100 pesticides, 50 different substances were detected upstream and 48 downstream. Highest measured concentration upstream was 26.5 MUg/L (2-methyl-4 chlorophenoxyacetic acid, MCPA) and 5.19 MUg/L (isoproturon) downstream. Fishponds were found to reduce peak exposure levels as high pesticide concentrations (defined here as >= 1 MUg/L) generally decreased by more than 90% between upstream and downstream sampling sites. The measured concentrations in the investigated streams were compared to laboratory toxicity data for standard test organisms (algae, invertebrates and fish) using the toxic unit approach. When considering the threshold levels set by the European Union within the first tier risk assessment procedure for pesticide registration (commission regulation (EU) N degrees 546/2011), regulatory threshold exceedances were observed for 22 pesticides upstream from fishponds and for 9 pesticides downstream. Therefore, the investigated barrage fishponds contributed to the reduction of pesticide peak concentrations and potential risk of adverse effects for downstream ecosystems. PMID- 26773431 TI - Municipal water reuse for urban agriculture in Namibia: Modeling nutrient and salt flows as impacted by sanitation user behavior. AB - Adequate sanitation, wastewater treatment and irrigation infrastructure often lacks in urban areas of developing countries. While treated, nutrient-rich reuse water is a precious resource for crop production in dry regions, excessive salinity might harm the crops. The aim of this study was to quantify, from a system perspective, the nutrient and salt flows a new infrastructure connecting water supply, sanitation, wastewater treatment and nutrient-rich water reuse for the irrigation of agriculture, from a system perspective. For this, we developed and applied a quantitative assessment method to understand the benefits and to support the management of the new water infrastructure in an urban area in semi arid Namibia. The nutrient and salt flows, as affected by sanitation user behavior, were quantified by mathematical material flow analysis that accounts for the low availability of suitable and certain data in developing countries, by including data ranges and by assessing the effects of different assumptions in cases. Also the nutrient and leaching requirements of a crop scheme were calculated. We found that, with ideal sanitation use, 100% of nutrients and salts are reclaimed and the slightly saline reuse water is sufficient to fertigate 10 m(2)/cap/yr (90% uncertainty interval 7-12 m(2)/cap/yr). However, only 50% of the P contained in human excreta could be finally used for crop nutrition. During the pilot phase fewer sanitation users than expected used slightly more water per capita, used the toilets less frequently and practiced open defecation more frequently. Therefore, it was only possible to reclaim about 85% of nutrients from human excreta, the reuse water was non-saline and contained less nutrient so that the P was the limiting factor for crop fertigation. To reclaim all nutrients from human excreta and fertigate a larger agricultural area, sanitation user behavior needs to be improved. The results and the methodology of this study can be generalized and used worldwide in other semi-arid regions requiring irrigation for agriculture as well as urban areas in developing countries with inadequate sanitation infrastructure. PMID- 26773432 TI - Studies on sustainability of simulated constructed wetland system for treatment of urban waste: Design and operation. AB - New system configurations and wide range of treatability make constructed wetland (CW) as an eco-sustainable on-site approach of waste management. Keeping this view into consideration, a novel configured three-stage simulated CW was designed to study its performance efficiency and relative importance of plants and substrate in purification processes. Two species of submerged plant i.e., Potamogeton crispus and Hydrilla verticillata were selected for this study. After 6 months of establishment, operation and maintenance of simulated wetland, enhanced reduction in physicochemical parameters was observed, which was maximum in the planted CW. The percentage removal (%) of the pollutants in three-stage mesocosms was; conductivity (60.42%), TDS (67.27%), TSS (86.10%), BOD (87.81%), NO3-N (81.28%) and PO4-P (83.54%) at 72 h of retention time. Submerged macrophyte used in simulated wetlands showed a significant time dependent accumulation of toxic metals (p <= 0.05). P. crispus accumulated the highest Mn (86.36 MUg g(-1) dw) in its tissue followed by Cr (54.16 MUg g(-1) dw), Pb (31.56 MUg g(-1) dw), Zn (28.06 MUg g(-1) dw) and Cu (25.76 MUg g(-1) dw), respectively. In the case of H. verticillata, it was Zn (45.29), Mn (42.64), Pb (22.62), Cu (18.09) and Cr (16.31 MUg g(-1) dw). Thus, results suggest that the application of simulated CW tackles the water pollution problem more efficiently and could be exploited in small community level as alternative and cost effective tools of phytoremediation. PMID- 26773433 TI - Agronomic characteristics of five different urban waste digestates. AB - The use of digestate in agriculture is an efficient way to recycle materials and to decrease the use of mineral fertilizers. The agronomic characteristics of the digestates can promote plant growth and soil properties after digestate fertilization but also harmful effects can arise due to digestate quality, e.g. pH, organic matter and heavy metal content. The objective of this study was to evaluate the differences and similarities in agronomic characteristics and the value of five urban waste digestates from different biogas plants treating either food waste, organic fraction of organic solid waste or a mixture of waste activated sludge and vegetable waste. The digestate agronomic characteristics were studied with chemical analyses and the availability of nutrients was also assessed with growth experiments and soil mineralization tests. All studied urban digestates produced 5-30% higher ryegrass yields compared to a control mineral fertilizer with a similar inorganic nitrogen concentration, while the feedstock source affected the agronomic value. Food waste and organic fraction of municipal solid waste digestates were characterized by high agronomic value due to the availability of nutrients and low heavy metal load. Waste-activated sludge as part of the feedstock mixture, however, increased the heavy metal content and reduced nitrogen availability to the plant, thus reducing the fertilizer value of the digestate. PMID- 26773434 TI - Novel biosorbent with high adsorption capacity prepared by chemical modification of white pine (Pinus durangensis) sawdust. Adsorption of Pb(II) from aqueous solutions. AB - The natural sawdust (NS) from white pine (Pinus durangensis) was chemically modified by a hydrothermal procedure using citric, malonic and tartaric acids. The adsorption capacity of modified sawdust (MS) towards Pb(II) was considerably enhanced due to the introduction of carboxylic groups on the surface of MS during the modification, and the adsorption capacity was almost linearly dependent on the concentration of carboxylic sites. The NS surface was acidic, and the MS surface became more acidic after the modification. At T = 25 degrees C and pH = 5, the maximum adsorption capacity of the optimal MS towards Pb(II) was 304 mg/g, which is exceptionally high compared to NS and other MS reported previously. The adsorption capacity of MS was considerably reduced from 304 to 154 mg/g by decreasing the solution pH from 5 to 3 due to electrostatic interactions. The adsorption of Pb(II) on MS was reversible at pH = 2, but not at pH = 5. The contribution percentage of ion exchange to the overall adsorption capacity ranged from 70 to 99% and 10-66% at the initial pH of 3 and 5, respectively. Hence, the adsorption of Pb(II) on MS was mainly due to ion exchange at pH = 3 and to both ion exchange and electrostatic attraction at pH = 5. PMID- 26773435 TI - Altered fMRI resting-state connectivity in individuals with fibromyalgia on acute pain stimulation. AB - BACKGROUND: Fibromyalgia is a chronic widespread pain condition, with patients commonly reporting other symptoms such as sleep difficulties, memory complaints and fatigue. The use of magnetic resonance imaging (MRI) in fibromyalgia has allowed for the detection of neural abnormalities, with alterations in brain activation elicited by experimental pain and alterations in resting state connectivity related to clinical pain. METHODS: In this study, we sought to monitor state changes in resting brain connectivity following experimental pressure pain in fibromyalgia patients and healthy controls. Twelve fibromyalgia patients and 15 healthy controls were studied by applying discrete pressure stimuli to the thumbnail bed during MRI. Resting-state functional MRI scanning was performed before and immediately following experimental pressure pain. We investigated changes in functional connectivity to the thalamus and the insular cortex. RESULTS: Acute pressure pain increased insula connectivity to the anterior cingulate and the hippocampus. Additionally, we observed increased thalamic connectivity to the precuneus/posterior cingulate cortex, a known part of the default mode network, in patients but not in controls. This connectivity was correlated with changes in clinical pain. CONCLUSIONS: These data reporting changes in resting-state brain activity following a noxious stimulus suggest that the acute painful stimuli may contribute to the alteration of the neural signature of chronic pain. WHAT DOES THIS STUDY/ADD?: In this study acute pain application shows an echo in functional connectivity and clinical pain changes in chronic pain. PMID- 26773436 TI - Conversion of Prostate Adenocarcinoma to Small Cell Carcinoma-Like by Reprogramming. AB - The lineage relationship between prostate adenocarcinoma and small cell carcinoma was studied by using the LuCaP family of xenografts established from primary neoplasm to metastasis. Expression of four stem cell transcription factor (TF) genes, LIN28A, NANOG, POU5F1, SOX2, were analyzed in the LuCaP lines. These genes, when force expressed in differentiated cells, can reprogram the recipients into stem-like induced pluripotent stem (iPS) cells. Most LuCaP lines expressed POU5F1, while LuCaP 145.1, representative of small cell carcinoma, expressed all four. Through transcriptome database query, many small cell carcinoma genes were also found in stem cells. To test the hypothesis that prostate cancer progression from "differentiated" adenocarcinoma to "undifferentiated" small cell carcinoma could involve re-expression of stem cell genes, the four TF genes were transduced via lentiviral vectors into five adenocarcinoma LuCaP lines-70CR, 73CR, 86.2, 92, 105CR-as done in iPS cell reprogramming. The resultant cells from these five transductions displayed a morphology of small size and dark appearing unlike the parentals. Transcriptome analysis of LuCaP 70CR* ("*" to denote transfected progeny) revealed a unique gene expression close to that of LuCaP 145.1. In a prostate principal components analysis space based on cell-type transcriptomes, the different LuCaP transcriptome datapoints were aligned to suggest a possible ordered sequence of expression changes from the differentiated luminal-like adenocarcinoma cell types to the less differentiated, more stem-like small cell carcinoma types, and LuCaP 70CR*. Prostate cancer progression can thus be molecularly characterized by loss of differentiation with re-expression of stem cell genes. J. Cell. Physiol. 231: 2040-2047, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26773437 TI - Benzimidazole-Based Quinazolines: In Vitro Evaluation, Quantitative Structure Activity Relationship, and Molecular Modeling as Aurora Kinase Inhibitors. AB - A series of benzimidazole-based quinazoline derivatives with different substitutions of primary and secondary amines at the C2 position (1-12) were evaluated for their Aurora kinase inhibitory activities. All compounds except for 3 and 6 showed good activity against Aurora kinase inhibitors, with IC50 values in the range of 0.035-0.532 MUM. The ligand efficiency (LE) of the compounds with Aurora A kinase was also determined. The structure-activity relationship and the quantitative structure-activity relationship revealed that the Aurora inhibitory activities of these derivatives primarily depend on the different substitutions of the amine present at the C2 position of the quinazoline core. Molecular docking studies in the active binding site also provided theoretical support for the experimental biological data acquired. The current study identifies a novel class of Aurora kinase inhibitors, which can further be used for the treatment of cancer. PMID- 26773438 TI - Antioxidant properties in a non-polar environment of difluoromethyl bioisosteres of methyl hydroxycinnamates. AB - OBJECTIVES: Many natural antioxidants have poor pharmacokinetic properties that impair their therapeutic use. For hydroxycinnamic acids (HCAs) and other phenolic antioxidants, their major drawback is their low lipophilicity and a rapid metabolism. The difluoromethyl group may be considered as a 'lipophilic hydroxyl' due to its hydrogen bond donor and acceptor properties; this prompted us to assess it as a bioisosteric replacement of a phenolic hydroxyl for increasing the lipophilicity of HCAs. METHODS: Six difluoromethyl-substituted methyl cinnamates (4a-c, 5a-c) related to caffeic acid were synthesized and their antioxidant activity evaluated by chemical (FRAP, DPPH scavenging, inhibition of beta carotene bleaching, at 1-200 MUm), electrochemical (differential pulse voltammetry, cyclic voltammetry) and cell-based (inhibition of lipid peroxidation in erythrocytes, at 1 and 50 MUm) assays. KEY FNDINGS: Analogues 4a-c and 5a-c were inactive in FRAP and DPPH assays and only those containing a free phenolic hydroxyl (4a and 5a) exhibited electrochemical activity although with high redox potentials. Compounds 4a,b and 5a,b were active in the inhibition of beta carotene bleaching assay and all analogues inhibited lipid peroxidation in the human erythrocytes assay. CONCLUSIONS: Lipophilic difluoromethyl-substituted cinnamic esters retain radical scavenging capabilities that prove useful to confer antioxidant properties in a non-polar environment. PMID- 26773439 TI - ALK-rearranged renal cell carcinomas in children. AB - Knowledge of the clinicopathological and molecular spectrum of pediatric renal cell carcinomas (RCC) remains limited, and approximately 16%-24% of these neoplasms cannot be classified into specific subtypes. In this review of 168 pediatric RCC prospectively registered on Children's Oncology Group AREN03B2 protocol, six RCC (3.5%) that demonstrated a unique epithelioid morphology and a peculiar immunophenotypic profile that includes expression of ALK, TFE3, and retention of INI1 was identified. Further investigation revealed ALK rearrangements in all cases, manifested molecularly by fusion transcripts of either VCL-ALK (3 patients all with sickle cell trait which had been previously reported) or TPM3-ALK (3 patients, none with sickle cell trait). Based on the shared unique morphologic, immunophenotypic, and genetic features, it was proposed that these neoplasms belonged to a distinct subgroup of RCC frequently occurring in pediatric patients, which they have termed as ALK-rearranged RCC. Importantly, additional therapeutic options may be available for these patients. PMID- 26773440 TI - Hemin induces mitophagy in a leukemic erythroblast cell line. AB - BACKGROUND INFORMATION: In eukaryotic cells, autophagy is considered a lysosomal catabolic process which participates in the degradation of intracellular components in a vacuolar structure termed autolysosome. This pathway plays a significant role in the erythropoiesis process, contributing to the clearance of some organelles (such as mitochondria) that are not necessary in the mature red blood cells. Nevertheless, the role of autophagy in erythrocyte maturation has not been fully established. RESULTS: Here, we have demonstrated that hemin (a physiological erythroid maturation stimulator) is able to induce the expression of critical autophagic genes (i.e., Map1a1b (LC3), Beclin-1 gen, Atg5) in an erythroleukemia cell type. We have also shown that hemin increased the size of autophagic vacuoles which were labelled with LC3 and the degradative lysosomal marker dye quenched-bovine serum albumin. In addition, we have determined by Western blot a rise in the lipidated form of the autophagic protein LC3 (i.e., LC3-II) upon hemin treatment. Moreover, we provide evidence that hemin induces mitochondrial membrane depolarisation and that mitochondria sequestration by autophagy requires the active form of the NIX protein. CONCLUSIONS: We have found that the physiological erythroid maturation stimulator hemin is able to induce mitophagy in K562 cells, and that the autophagy adaptor NIX is necessary for mitophagy progression. K562 cells have been used as a relevant model to determine the possible therapeutic role of new differentiating compounds. SIGNIFICANCE: It has been proposed that autophagy induction is a feasible new therapeutic key in fighting cancer. Our results suggest that hemin is favoring erythroid maturation by inducing an autophagic response in K562 cells, being a possible therapeutic candidate that may help in the chronic myelogenous leukemia (CML) treatment. PMID- 26773441 TI - Clinicopathologic characteristics and treatment of marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma). AB - Extranodal marginal zone lymphoma of the mucosa-associated lymphoid tissue (MALT lymphoma) accounts for 7% to 8% of newly diagnosed lymphomas. Because of its association with infectious causes, such as Helicobacter pylori (HP) or Chlamydophila psittaci (CP), and autoimmune diseases, it has become the paradigm of an antigen-driven malignancy. MALT lymphoma usually displays an indolent course, and watch-and-wait strategies are justified initially in a certain percentage of patients. In patients with gastric MALT lymphoma or ocular adnexal MALT lymphoma, antibiotic therapy against HP or CP, respectively, is the first line management of choice, resulting in lymphoma response rates from 75% to 80% after HP eradication and from 33% to 65% after antibiotic therapy for CP. In patients who have localized disease that is refractory to antibiotics, radiation is widely applied in various centers with excellent local control, whereas systemic therapies are increasingly being applied, at least in Europe, because of the potentially systemic nature of the disease. Therefore, the objective of this review is to briefly summarize the clinicopathologic characteristics of this distinct type of lymphoma along with current data on management strategies. PMID- 26773442 TI - Use of standardized outcome measures should be common place in the clinical care of children with cerebral palsy: why isn't it? PMID- 26773443 TI - Improving food intake in persons living with dementia. AB - Persons living with dementia have many health concerns, including poor nutritional states. This narrative review provides an overview of the literature on nutritional status in persons diagnosed with a dementing illness or condition. Poor food intake is a primary mechanism for malnutrition, and there are many reasons why poor food intake occurs, especially in the middle and later stages of the dementing illness. Research suggests a variety of interventions to improve food intake, and thus nutritional status and quality of life, in persons with dementia. For family care partners, education programs have been the focus, while a range of intervention activities have been the focus in residential care, from tableware changes to retraining of self-feeding. It is likely that complex interventions are required to more fully address the issue of poor food intake, and future research needs to focus on diverse components. Specifically, modifying the psychosocial aspects of mealtimes is proposed as a means of improving food intake and quality of life and, to date, is a neglected area of intervention development and research. PMID- 26773444 TI - Advances in therapy for Philadelphia-positive acute lymphoblastic leukaemia of childhood and adolescence. AB - The presence of the BCR/ABL1 fusion gene in childhood acute lymphoblastic leukaemia (ALL) is a rare finding and has been an adverse prognostic factor associated with a high risk of therapeutic failure. The current key components of treatment are intensive polychemotherapy and a BCR/ABL1 kinase domain inhibitor. This treatment approach has been applied in a few clinical trials by paediatric leukaemia study groups. Thus, this subtype of ALL serves as the first model system for truly targeted treatment. The role of haematopoietic stem cell transplantation (HSCT) is increasingly called into question, at least in a favourable, though not yet clearly defined, subset of patients. Currently, the choice of the most effective tyrosine kinase inhibitor is not yet settled, in particular, in view of potential reduction of overall treatment intensity. PMID- 26773445 TI - Chondrocyte cultures from human proximal interphalangeal finger joints. AB - Osteoarthritis (OA) of the hand is a common disease resulting in pain and impaired function. The pathogenesis of hand OA (HOA) is elusive and models to study it have not been described. Chondrocyte culture has been essential to understand cartilage degeneration, which is a hallmark of OA. We investigated the feasibility of human chondrocyte culture derived from proximal interphalangeal (PIP) finger joints. Hyaline cartilage of the PIP and knee joints was obtained from human cadavers. Chondrocytes harvested up to 236 h after death of the donors were viable and expressed chondrocyte-specific genes. Gene expression comparing chondrocytes from PIP and knee joints using Affymetrix GeneChip arrays resulted in a unique PIP-specific gene expression pattern. Genes involved in developmental processes including the WNT pathway were differentially expressed between the joints. These findings suggest that our knowledge on chondrocyte biology derived mainly from knee and hip joints may not apply to chondrocytes of the PIP joints and some of the distinctive features of HOA may be caused by the specific properties of PIP chondrocytes. Chondrocyte culture of PIP cartilage is a novel tool to study cartilage degeneration in HOA. (c) 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:1569-1575, 2016. PMID- 26773446 TI - Safety and efficacy of insulin degludec/insulin aspart with bolus mealtime insulin aspart compared with standard basal-bolus treatment in people with Type 1 diabetes: 1-year results from a randomized clinical trial (BOOST(r) T1). AB - AIMS: To evaluate the long-term safety and efficacy of a simplified basal-bolus regimen of once-daily insulin degludec/insulin aspart (IDegAsp) with additional IAsp vs. a standard basal-bolus insulin regimen of insulin detemir (IDet) with IAsp in adults with Type 1 diabetes. METHODS: This was an open-label trial comprising a 26-week core phase followed by a 26-week extension phase. Participants were randomized to IDegAsp once daily at the main meal and IAsp at remaining meals (IDegAsp+IAsp), or IDet (once or twice daily) and IAsp at all meals (IDet+IAsp). Insulins were titrated to target plasma glucose of < 5 mmol/l (< 90 mg/dl) at pre-breakfast (IDegAsp and IDet) and at pre-meal (IAsp). RESULTS: After 52 weeks, the overall confirmed hypoglycaemia rate was 31.8 episodes/patient-years of exposure (PYE) with IDegAsp+Asp and 36.7 episodes/PYE with IDet+IAsp, and the rate of nocturnal confirmed hypoglycaemia was significantly lower with IDegAsp+Asp than with IDet+IAsp (3.1 vs. 5.4 episodes/PYE, respectively; P < 0.05). Adverse event rates were comparable between groups. Mean HbA1c decreased from baseline by 0.7% (IDegAsp+IAsp) and 0.6% (IDet+IAsp), achieving 60 or 61 mmol/mol (7.6% or 7.7%, respectively), at Week 52. The mean total daily insulin dose was lower with IDegAsp+IAsp than with IDet+IAsp (ratio: 0.87; 95% CI 0.79-0.95; P = 0.0026). CONCLUSIONS: Once-daily treatment with IDegAsp and IAsp as bolus insulin for remaining meals was associated with significantly lower risk of nocturnal confirmed hypoglycaemia, improved glycaemic control and showed non-inferiority compared with IDet+IAsp, the standard of care in Type 1 diabetes. PMID- 26773447 TI - Inhibition of complement component C5 prevents clotting in an ex vivo model of xenogeneic activation of coagulation. AB - BACKGROUND: Xenogeneic thrombotic microangiopathy (TMA) and acute vascular rejection (AVR) prevent long-term survival of porcine xenografts after transplantation into non-human primates. Preformed xenoreactive natural antibodies (XNA) cause endothelial damage and activate the complement system. Mechanisms of xenogeneic coagulation and platelet activation are only poorly characterized. METHODS: A microfluidic flow chamber was used to study platelet activation and thrombus formation of human platelet-rich plasma (PRP) upon perfusion over wild-type (WT) or alpha-1,3- galactosyltransferase knockout (GTKO) and human CD46 (hCD46) transgenic porcine aortic endothelial cells (PAEC). Activation of plasma coagulation (thrombin-anti-thrombin complex; TAT) and complement (C3a, C5a) was studied in human platelet-free plasma (PFP) after co incubation with PAEC. The activation of PAEC (E-Selectin, tissue factor, ICAM-1, ICAM-2, VCAM-1) was studied after incubation with human serum. Eculizumab (200 MUg/ml) was used to inhibit terminal complement activation in all experiments. RESULTS: WT-PAEC perfused with human PRP showed thrombus formation at different shear rates (3 dyn/cm(2) : 23 +/- 10%; 10 dyn/cm(2) : 17 +/- 10% of flow chamber viewing field). GTKO/hCD46 PAEC exhibited reduced, but not fully prevented thrombus formation (3 dyn/cm(2) : 12 +/- 12%). Porcine PRP caused little or no thrombus formation (3.0 +/- 4% and 0.5 +/- 0.9%, respectively). Flow cytometry of human platelets after perfusion over WT-PAEC revealed an increase in platelet CD62P expression (29.5 +/- 3%), compared to non-perfused PRP (7 +/- 2%) or PRP running through empty flow chambers (12.7 +/- 0.3%). Incubation of human PFP with PAEC resulted in an increase of TAT that correlated with C5a activation. Specific inhibition of complement by eculizumab prevented thrombus formation (WT-PAEC: 1.6 +/- 2% at 3 dyn/cm(2) and 0.24 +/- 0.33% at 10 dyn/cm(2) , GTKO/hCD46 PAEC: 0.2 +/- 0.3% at 3 dyn/cm(2) ) as well as activation of coagulation and platelets. Induction of endothelial E-Selectin and VCAM-1 in WT-PAEC upon incubation with human serum was significantly reduced by eculizumab. Eculizumab did not reduce thrombin generation capacity of human PRP or normal platelet aggregation. CONCLUSION: Thrombus formation in this ex vivo model of xenogeneic TMA was closely linked with complement activation. Specific inhibition of complement C5 by eculizumab prevented endothelial cell activation, but also coagulation and platelet activation without compromising thrombin generation capacity of human blood or normal platelet function. PMID- 26773448 TI - Real-Time Chemical Analysis of E-Cigarette Aerosols By Means Of Secondary Electrospray Ionization Mass Spectrometry. AB - Chemical analysis of aerosols collected from electronic cigarettes (ECs) has shown that these devices produce vapors that contain harmful and potentially harmful compounds. Conventional analytical methods used for the analysis of electronic cigarettes do not reflect the actual composition of the aerosols generated because they usually neglect the changes in the chemical composition that occur during the aerosol generation process and after collection. The aim of this work was to develop and apply a method for the real-time analysis of electronic cigarette aerosols, based on the secondary electrospray ionization technique coupled to high-resolution mass spectrometry, by mimicking the "vaping" process. Electronic cigarette aerosols were successfully analyzed and quantitative differences were found between the liquids and aerosols. Thanks to the high sensitivity shown by this method, more than 250 chemical substances were detected in the aerosols, some of them showing a high correlation with the operating power of the electronic cigarettes. The method also allows proper quantification of several chemical components such as alkaloids and flavor compounds. PMID- 26773449 TI - Right Heart Involvement in Patients with Sarcoidosis. AB - The left ventricle (LV) is affected in 20-25% of patients with sarcoidosis and its involvement is associated with morbidity and mortality. However, effects of sarcoidosis on the right ventricle (RV) are not well documented. Our aims were to investigate the prevalence of RV dysfunction in patients with sarcoidosis and determine whether it is predominantly associated with direct cardiac involvement, severity of lung disease, or pulmonary hypertension (PH). We identified 50 patients with biopsy-proven extra-cardiac sarcoidosis and preserved LV function, who underwent echocardiography, pulmonary function (PF) testing, and cardiovascular magnetic resonance. RV function was quantified by free wall longitudinal strain. Tricuspid valve Doppler and estimated right atrial pressure were used to estimate systolic pulmonary artery pressure. Myocardial late gadolinium enhancement was considered diagnostic for cardiac sarcoidosis and assumed to involve both ventricles. Of the 50 patients, 28 (56%) had RV dysfunction, 4 with poorly defined PF status. Of the remaining 24 patients, 16 (67%) had lung disease, 8 (33%) had PH, and 10 (42%) had LV involvement. Ten patients had greater than one of these findings, and 4 had all 3. In contrast, in 4/24 patients (17%), RV dysfunction could not be explained by these mechanisms, despite severely reduced RV strain. In conclusion, RV dysfunction is common in patients with sarcoidosis and is usually associated with either direct LV involvement, lung disease, or PH, but may occur in the absence of these mechanisms, suggesting the possibility of isolated RV involvement and underscoring the need for imaging protocols that would include RV strain analysis. PMID- 26773450 TI - Graphene oxide surface blocking agents can increase the DNA biosensor sensitivity. AB - Graphene oxide adsorbs single-strand fluorescent probe DNA, and the adsorbed probe can be desorbed by adding the complementary target DNA. Using this method, many biosensor studies have been carried out. We recently proposed a two-step mechanism for this sensing reaction: non-specific probe displacement followed by hybridization in the solution. Only about one out of six added target DNA is hybridized with the adsorbed probe to generate signal, leading to relatively low sensitivity. In this work, we aim to test whether surface blocking agents can minimize non-specific target adsorption and increase hybridization efficiency. Over ten blocking agents (polymers, surfactants, and DNA) were screened based on their effect on probe DNA adsorption and target DNA induced probe desorption. DNA oligonucleotides show significant and controllable enhancement in sensor sensitivity. The effect of DNA length and sequence was systematically investigated. Under optimized conditions, the sensor sensitivity was enhanced by nearly 10-fold. Using the same blocking method, sensitivity enhancement of other targets was also achieved, including adenosine and Hg(2+) with DNA aptamer probes. This reported surface blocking strategy can generally improve graphene oxide and potentially other surface adsorption based biosensors for metal ions, small molecules, and DNA. PMID- 26773453 TI - Proper Notch activity is necessary for the establishment of proximal cells and differentiation of intermediate, distal, and connecting tubule in Xenopus pronephros development. AB - BACKGROUND: Notch signaling in pronephros development has been shown to regulate establishment of glomus and proximal tubule, but how Notch signal works on competency of pronephric anlagen during the generation of pronephric components remains to be understood. RESULTS: We investigated how components of pronephros (glomus, proximal tubule, intermediate tubule, distal tubule, and connecting tubule) were generated in Xenopus embryos by timed overactivation and suppression of Notch signaling. Notch activation resulted in expansion of the glomus and disruption of the proximal tubule formation. Inhibition of Notch signaling reduced expression of wt1 and XSMP-30. In addition, when Notch signaling was overactivated at stage 20 on, intermediate, distal, and connecting tubule markers, gremlin and clcnkb, were decreased while Notch down-regulation increased gremlin and clcnkb. Similar changes were observed with segmental markers, cldn19, cldn14, and rhcg on activation or inhibition of Notch. Although Notch did not affect the expression of pan-pronephric progenitor marker, pax2, its activation inhibited lumen formation in the pronephros. CONCLUSIONS: Notch signal is essential for glomus and proximal tubule development and inhibition of Notch is critical for the differentiation of the intermediate, distal, and connecting tubule. PMID- 26773454 TI - Fully-automated, chemiluminescence IgA and IgG anti-tissue transglutaminase (tTG) antibodies serum assays for the screening of celiac disease. AB - AIM: Celiac disease (CD) is a systemic immune-mediated enteropathy sustained by gluten ingestion in genetically susceptible subjects. The European Society for Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) has recently revised the diagnostic criteria, emphasizing the crucial role of serological testing in the diagnosis of this condition. This study was hence aimed to evaluate a new chemiluminescence assay for measuring anti-transglutaminase (tTG) and anti-endomysium (EMA) antibodies in a general population of unselected outpatients. MATERIALS AND METHODS: The IgA and IgG anti-tissue transglutaminase (tTG) antibodies (Quanta Flash(r) IgA and Quanta Flash(r) IgG tTG, Inova Diagnostics, San Diego, CA, USA) were measured with the fully-automated BIO FLASH(r) analyzer (Inova Diagnostics) in serum samples of 727 consecutive patients without a diagnosis of CD. Data were compared with those of anti endomysium antibody (EmA) obtained in the same population. RESULTS: A total of 96.4% samples display a negative concordance (anti-tTG negative and EMA negative), O% were positive for EMA and negative for anti-tTG IgA and IgG, 3.6% were both positive for tTG IgA and EMA, whereas 0.6% displayed discordant results (positive for anti-tTG and negative for EMA). The concordance (99%) and inter rater agreement (Kappa Statistics, 0.943; p<0.001) between anti-tTG IgA and EmA antibodies were excellent, with sensitivity and specificity of 99% and 100%, respectively. CONCLUSION: The results of this study show that Quanta Flash(r) IgA assay alone may be regarded as a reliable approach for screening of CD, with no need to perform EMA detection. PMID- 26773455 TI - Incorporation of fluorescein conjugated function-spacer-lipid constructs into the red blood cell membrane facilitates detection of labeled cells for the duration of ex-vivo storage. AB - The contribution of ex-vivo storage duration of packed red blood cells (PRBC) to patient outcomes and transfusion-related immunomodulation (TRIM) remains a broadly debated area in transfusion medicine. KodeTM Technology with fluorescein conjugated function-spacer-lipid (FSL-FLRO4) constructs is a tool that can aid in vitro visualization and tracking of red blood cells (RBC) during routine storage. FSL-FLRO4 is incorporated into the RBC membrane without altering cell function. In this study, we explore the suitability of this technology to label clinical grade PRBC and to determine if the label would be retained during ex-vivo storage. Firstly, to confirm feasibility and assess the limit of detection of FSL FLRO4 on PRBC at date of expiry (42 days post-collection), we tracked the binding of FSL-FLRO4 on PRBC at weekly intervals during routine storage. Over the time course, all cells remained labelled with FSL-FLRO4, although a decrease in the intensity of labelling was observed (P<0.0001). We then further investigated differences in FSL-FLRO4 labelling during RBC storage by labelling separated light-young and dense-old RBC from the same PRBC unit. There were no differences in the capacity of FSL-FLRO4 to label these different RBC subsets. Together, these data demonstrate that FSL-FLRO4 is a suitable reagent for labelling PRBC at any point during routine storage. This technology will facilitate the development of immunoassays and transfusion models focused on addressing the mechanisms involved in TRIM. PMID- 26773456 TI - The future of Evo-Devo: the inaugural meeting of the Pan American Society for evolutionary developmental biology. AB - What is the future of evolutionary developmental biology? This question and more were discussed at the inaugural meeting for the Pan American Society for Evolutionary Developmental Biology, held August 5-9, 2015, in Berkeley, California, USA. More than 300 participants attended the first meeting of the new society, representing the current diversity of Evo-Devo. Speakers came from throughout the Americas, presenting work using an impressive range of study systems, techniques, and approaches. Current research draws from themes including the role of gene regulatory networks, plasticity and the role of the environment, novelty, population genetics, and regeneration, using new and emerging techniques as well as traditional tools. Multiple workshops and a discussion session covered subjects both practical and theoretical, providing an opportunity for members to discuss the current challenges and future directions for Evo-Devo. The excitement and discussion generated over the course of the meeting demonstrates the current dynamism of the field, suggesting that the future of Evo-Devo is bright indeed. PMID- 26773457 TI - Minimum dominating set-based methods for analyzing biological networks. AB - The fast increase of 'multi-omics' data does not only pose a computational challenge for its analysis but also requires novel algorithmic methodologies to identify complex biological patterns and decipher the ultimate roots of human disorders. To that end, the massive integration of omics data with disease phenotypes is offering a new window into the cell functionality. The minimum dominating set (MDS) approach has rapidly emerged as a promising algorithmic method to analyze complex biological networks integrated with human disorders, which can be composed of a variety of omics data, from proteomics and transcriptomics to metabolomics. Here we review the main theoretical foundations of the methodology and the key algorithms, and examine the recent applications in which biological systems are analyzed by using the MDS approach. PMID- 26773458 TI - COPD subtypes identified by network-based clustering of blood gene expression. AB - One of the most common smoking-related diseases, chronic obstructive pulmonary disease (COPD), results from a dysregulated, multi-tissue inflammatory response to cigarette smoke. We hypothesized that systemic inflammatory signals in genome wide blood gene expression can identify clinically important COPD-related disease subtypes, and we leveraged pre-existing gene interaction networks to guide unsupervised clustering of blood microarray expression data. Using network informed non-negative matrix factorization, we analyzed genome-wide blood gene expression from 229 former smokers in the ECLIPSE Study, and we identified novel, clinically relevant molecular subtypes of COPD. These network-informed clusters were more stable and more strongly associated with measures of lung structure and function than clusters derived from a network-naive approach, and they were associated with subtype-specific enrichment for inflammatory and protein catabolic pathways. These clusters were successfully reproduced in an independent sample of 135 smokers from the COPDGene Study. PMID- 26773459 TI - A quantitative cell modeling and wound-healing analysis based on the Electric Cell-substrate Impedance Sensing (ECIS) method. AB - In this paper, a quantitative modeling and wound-healing analysis of fibroblast and human keratinocyte cells is presented. Our study was conducted using a continuous cellular impedance monitoring technique, dubbed Electric Cell substrate Impedance Sensing (ECIS). In fact, we have constructed a mathematical model for quantitatively analyzing the cultured cell growth using the time series data directly derived by ECIS in a previous work. In this study, the applicability of our model into the keratinocyte cell growth modeling analysis was assessed first. In addition, an electrical "wound-healing" assay was used as a means to evaluate the healing process of keratinocyte cells at a variety of pressures. Two innovative and new-defined indicators, dubbed cell power and cell electroactivity, respectively, were developed for quantitatively characterizing the biophysical behavior of cells. We then employed the wavelet transform method to perform a multi-scale analysis so the cell power and cell electroactivity across multiple observational time scales may be captured. Numerical results indicated that our model can well fit the data measured from the keratinocyte cell culture for cell growth modeling analysis. Also, the results produced by our quantitative analysis showed that the wound healing process was the fastest at the negative pressure of 125mmHg, which consistently agreed with the qualitative analysis results reported in previous works. PMID- 26773461 TI - Comparison of Arthroscopic Lavage and Needle Lavage Techniques, and Lavage Volume on the Recovery of Colored Microspheres From the Tarsocrural Joints of Cadaver Horses. AB - OBJECTIVE: To quantify recovery of colored microspheres from normal cadaver tarsocrural joints using arthroscopic or needle lavage with 1-5 L of fluid. STUDY DESIGN: Ex vivo experimental study. ANIMALS: Adult Quarter Horse cadavers (n = 8). METHODS: After euthanasia, 1.5 * 10(6) colored microspheres were injected into each tarsocrural joint. Each joint was randomly assigned to receive lavage (5 L 0.9% NaCl) with an arthroscope (dorsomedial arthroscope and dorsolateral egress cannula) or three 14 g needles (dorsomedial ingress, dorsolateral, and plantarolateral egress). Egress fluid from each liter was collected separately over time and the number of microspheres present in each recovered liter determined by spectrophotometry. RESULTS: A significant interaction was present between treatment group and liter of fluid (P < .01). The number of microspheres recovered in the first liter of lavage fluid was significantly higher in the needle lavage group than in the arthroscopic lavage group (P < .01). For both groups, the number of microspheres recovered in the first liter of lavage fluid represented a majority of the total microspheres collected and was significantly different from each subsequent liter collected (P < .01). The number of microspheres recovered did not differ between liters 2, 3, 4, and 5 within or between treatment groups. CONCLUSION: In this model, tarsocrural lavage with three 14 g needles was more effective at removing colored microspheres from the joint than arthroscopic lavage, suggesting that the number or placement of portals present may be more important than portal size and flow rate. No difference in microsphere recovery was seen with lavage volumes >1 L. PMID- 26773460 TI - Comparative study of demineralized collagen degradation determined by hydroxyproline assay and microscopic depth measurement. AB - INTRODUCTION: Quantification of collagen degradation is an important parameter to evaluate dentin caries progression or the efficacy of caries prevention aid. The aim of this study was to validate the simple light microscopic technique (LM) to evaluate collagen degradation by comparing with hydroxyproline assay technique (HPN). MATERIALS AND METHODS: Bovine root dentin blocks were embedded in acrylic resin, polished and covered with nail varnish except a 1.5 * 2.5mm window. The specimens were demineralized in acetate buffer (pH 4.3) for 3 days to create incipient lesions and were exposed to collagenase enzyme for 6, 9 and 16 h. The specimens were sectioned into thin sections (200-220 MUm) to measure the degraded depth of collagen matrix by LM. The enzyme solutions were allocated to HPN assay using the simplified chloramines-T method. Correlation between LM and HPN was evaluated by Pearson correlation analysis. Anti-collagen degradation efficacy of 0.12% chlorhexidine (CHX) was evaluated by LM. RESULT: The depths of the degraded collagen and amount of hydroxyproline in 3 exposure periods were 27.8 +/- 3.8 MUm and 28.7 +/- 4.2 MUg for 6h, 48.1 +/- 8.6 MUm and 45.3 +/- 6.1 MUg for 9h, and 74.2 +/- 9.7 MUm and 71.3 +/- 8.0 MUg for 16 h, respectively. A significantly positive correlation (r=0.94, CI: 0.88-0.97, p<0.0001) was observed between LM and HPN and incubation time showed a linear correlation with amount of collagen degradation (R(2)=0.92). The CHX group (28.6 +/- 3.3 MUm) showed significantly lower collagen degradation than that of control group (53.1 +/- 7.8 MUm: p<0.01). CONCLUSION: The LM might be a reliable and simplified method to evaluate collagen degradation. PMID- 26773462 TI - Ligand-lipid and ligand-core affinity control the interaction of gold nanoparticles with artificial lipid bilayers and cell membranes. AB - Interactions between nanoparticles (NPs) and biomembranes depend on the physicochemical properties of the NPs, such as size and surface charge. Here we report on the size-dependent interaction of gold nanoparticles (AuNPs), stabilized with ligands differing in charge, i.e. sodium 3 (diphenylphosphino)benzene sulfonate (TPPMS) and sodium 3,3',3" triphenylphosphine sulfonate (TPPTS), respectively, with artificial membranes (black lipid membranes; BLMs) and HeLa cells. The TPPTS-stabilized AuNPs affect BLMs at lower size than TPPMS-stabilized ones. On HeLa cells we found decreasing cytotoxicity with increasing particle size, however, with an overall lower cytotoxicity for TPPTS-stabilized AuNPs. We attribute size-dependent BLM properties as well as reduced cytotoxicity of TPPTS-stabilized AuNPs to weaker shielding of the AuNP core when stabilized with TPPTS. We hypothesize that the partially unshielded hydrophobic gold core can embed into the hydrophobic membrane interior. Thereby we demonstrate that ligand-dependent cytotoxicity of NP can occur even when the NPs are not translocated through the membrane. FROM THE CLINICAL EDITOR: The use of nanoparticles (NPs) in the clinical setting means that there will be interactions between NPs and cell membranes. The authors investigated the underlying processes concerning cellular uptake and potential toxicity of gold nanoparticles (AuNPs) using particles with ligands different sizes and charges. The findings should further enhance existing knowledge on future design of safer NPs in the clinic. PMID- 26773464 TI - Influence of 3D printed porous architecture on mesenchymal stem cell enrichment and differentiation. AB - The interactions between cells and an underlying biomaterial are important for the promotion of cell adhesion, proliferation, and function. Mesenchymal stem cells (MSCs) have great clinical potential as they are an adult stem cell population capable of multilineage differentiation. The relationship between MSC behavior and several material properties including substrate stiffness and pore size are well investigated, but there has been little research on the influence of porous architecture in a three-dimensional scaffold with a well-controlled architecture. Here, we investigate the impact of two different three dimensionally printed, pore geometries on the enrichment and differentiation of MSCs. 3D printed scaffolds with ordered cubic pore geometry were supportive of MSC enrichment from unprocessed bone marrow, resulting in cell surface marker expression that was comparable to typical adhesion to tissue culture polystyrene, the gold standard for MSC culture. Results also show that scaffolds fabricated with ordered cubic pores significantly increase the gene expression of MSCs undergoing adipogenesis and chondrogenesis, when compared to scaffolds with ordered cylindrical pores. However, at the protein expression level, these differences were modest. For MSCs undergoing osteogenesis, gene expression results suggest that cylindrical pores may initially increase early osteogenic marker expression, while protein level expression at later timepoints is increased for scaffolds with ordered cubic pores. Taken together, these results suggest that 3D printed scaffolds with ordered cubic pores could be a suitable culture system for single-step MSC enrichment and differentiation. STATEMENT OF SIGNIFICANCE: Mesenchymal stem cells (MSCs) have great therapeutic potential, as they are capable of multilineage differentiation. MSC behavior, including lineage commitment, may be influenced by biomaterial properties including substrate stiffness and pore size. With three-dimensional (3D) printing, we can investigate these relationships in 3D culture systems. Here, we fabricated scaffolds with two different well-controlled pore geometries, and investigated the impact on MSC enrichment and differentiation. Results show that scaffolds with ordered cubic pore geometry were supportive of both MSC enrichment from unprocessed bone marrow as well as MSC differentiation, resulting in increased gene expression during adipogenesis and chondrogenesis. These results suggest that 3D printed scaffolds with ordered cubic pores could be a suitable culture system for single-step MSC enrichment and differentiation. PMID- 26773463 TI - Long-term, feeder-free maintenance of human embryonic stem cells by mussel inspired adhesive heparin and collagen type I. AB - For practical applications of human embryonic stem cells (hESCs) in regenerative medicine, hESCs should be cultured on a large scale, and at the same time their properties have to be maintained in a controllable manner. Here, we report a chemically defined, scalable culture platform involving co-immobilization of heparin-catechol (HepC) and collagen type-1 (Col) for the long-term maintenance (>18 passages) of hESCs in a feeder-free condition. This platform utilizes a wet adhesive, mussel-inspired heparin-catechol conjugate as a key component. We hypothesized that the heparin's affinity toward a wide range of proteins, might support undifferentiated in vitro growth of hESC. In fact, on the HepC-coated substrate, most hESC clumps were adhered (~78% at passage 2 (P2)) and expressed pluripotency markers (Fig. 2). Although HepC alone wasn't able to support long term maintenance of hESCs in a feeder-free system due to decrease in the adhesion rate of hESCs on HepC coating (~ 44% at P4) during the repeated passaging processes, we found that when collagen type I was co-immobilized in the process of HepC coating, the long-term maintenance (passage 18 or more) of hESCs could be achieved with 100% adhesion efficiency (Fig. 4). One remarkable observation is that hESCs on collagen type-I underwent spontaneous differentiation after P6 (Fig. 3), which implied co-immobilized HepC played a role to suppress differentiation of hESCs. This study suggests that unlike the previous studies using proteins, peptides, or synthetic polymers, a polysaccharide, heparin, can be used as a cost-effective component for chemically defined, feeder-free culture of hESC. STATEMENT OF SIGNIFICANCE: Towards practical applications of human embryonic stem cells (hESCs) in regenerative medicine, hESCs should be cultured on a large scale, and their pluripotent property has to be maintained in a controllable manner. To address these issues, studies that develop chemically defined culture substrates have been explored to replace the widely used, complex, and undefined culture materials represented by Matrigel. Most reports have focused on utilizing proteins, peptides and/or synthetic polymers. However, there have not yet been studies on using polysaccharides as two-dimensional coating materials to potentially replace Matrigel coating. Here, we report that heparin is an effective polysaccharide for the feeder-free, two dimensional culture of hESCs. Our study implies that use of polysaccharides or a polysaccharide/ECM combination can be a new, alternative design principle for hESC culture systems. PMID- 26773465 TI - Decreased emotional reactivity of rats exposed to repeated phase shifts of light dark cycle. AB - Disturbed light-dark (LD) cycles are associated with circadian disruption of physiological and behavioural rhythms and in turn with an increased risk of disease development. However, direct causal links and underlying mechanisms leading to negative health consequences still need to be revealed. In the present study, we exposed male Wistar rats to repeated phase shifts of LD cycle and analysed their ability to cope with mild emotional stressors. In experiment 1, rats were submitted to either a regular 12:12 LD cycle (CTRL rats) or 8-h phase delay shifts applied every 2days for 5weeks (SHIFT rats). Subsequently, the behaviour was examined in the open-field, black-white box and elevated plus maze tests. In experiment 2, changes in blood pressure (BP), heart rate (HR) as well as the activity of autonomic nervous system were measured in telemeterised rats in response to open-field and black-white box tests before and after 5-week exposure to shifted LD regime. Locomotor activity was consistently higher in SHIFT than CTRL rats in in the open-field and black-white box tests. Interestingly, in the elevated plus maze, SHIFT rats displayed increased risk assessment and decreased grooming compared to CTRL rats. Anxiety measures were affected only in the black-white box, where SHIFT rats displayed reduced anxiety like behaviour compared to CTRL rats. Differences in behavioural reactivity between SHIFT and CTRL rats did not correspond with BP and HR changes. However, exposure to phase shifts increased the sympathovagal reactivity in the black white box. Together, our results demonstrated that disturbed LD conditions decreased emotional reactivity of rats and affected their ability to cope with emotional stressors denoting an additional risk mechanism linking disrupted circadian organisation to adverse health effects. PMID- 26773466 TI - Physiological evidence of interpersonal dynamics in a cooperative production task. AB - Recent research suggests that shared behavioral dynamics during interpersonal interaction are indicative of subjective and objective outcomes of the interaction, such as feelings of rapport and success of performance. The role of shared physiological dynamics to quantify interpersonal interaction, however, has received comparatively little attention. In the present study, we investigate the coordination dynamics of multiple psychophysiological measures and their utility in capturing emotional dynamics in teams. We use data from an experiment where teams of three people built origami boats together in an assembly-line manner while their heart rate, skin conductance, and facial muscle activity were recorded. Our results show that physiological synchrony of skin conductance measures and eletromyographic measures of the corrugator supercilii develops spontaneously among team members during this cooperative production task. Moreover, high team synchrony is found indicative of team cohesion, while low team synchrony is found indicative of a teams' decision to adopt a new behavior across multiple production sessions. We conclude that team-level measures of synchrony offer new and complementary information compared to measures of individual levels of physiological activity. PMID- 26773467 TI - Low calorie sweeteners: Science and controversy: Conference proceedings. PMID- 26773468 TI - The GSK3-MAP1B pathway controls neurite branching and microtubule dynamics. AB - The microtubule-associated protein MAP1B plays a key role in axon regeneration. We investigated the role of GSK3-mediated MAP1B phosphorylation in local fine tuning of neurite branching and the underlying microtubule (MT) dynamics. In wildtype adult dorsal root ganglia (DRG) neurons, MAP1B phosphorylation is locally reduced at branching points, and branching dynamics from growth cones and distal neurite shafts is increased upon GSK3 inhibition. While map1b-/- neurites, that display increased branching, are not affected by GSK3 inhibition, transfection of map1b-/- neurons with full-length map1b-cDNA restores the wildtype branching phenotype, demonstrating that MAP1B is a key effector downstream of GSK3. Experiments in mutant mice lacking tyrosinated MTs indicate a preferential association of phospho-MAP1B with tyrosinated MTs. Interestingly, inhibition of GSK3-mediated MAP1B phosphorylation in map1b-cDNA-transfected fibroblasts protects both tyrosinated and acetylated MTs from nocodazole-induced depolymerization, while detyrosinated MTs are less abundant in the presence of MAP1B. Our data thus provide new insight into the molecular link between GSK3, MAP1B, neurite branching and MT stability regulation. We suggest that, at branching points, MAP1B undergoes a fine regulation of both its phosphorylation and sub-cellular amounts, in order to modulate the local balance between acetylated, detyrosinated, and tyrosinated microtubule pools. PMID- 26773469 TI - Proposed pathway and mechanism of vascularized lymph node flaps. AB - OBJECTIVE: To investigate the pump mechanism and pathway of lymph transit in vascularized lymph node flaps. BACKGROUND: Microsurgical treatment of lymphedema with vascularized lymph node transfer can improve signs and symptoms of disease, but the pathways and mechanisms of these flaps warrant further exploration. METHODS: (Animal model) 72 flaps were raised in 18 rats: 36 groin flaps contained lymph nodes (LN), 36 deep inferior epigastric artery perforator flaps did not (non-LN). Indocyanine green (ICG) was added into normal saline (NS), 1%, 3%, 5%, 7% and 10% albumin. Three rats were assigned to each group. LN and non-LN flaps were submerged in solution and surveyed for venous fluorescence. In the 7% albumin and NS groups, volumetric change of solution was measured. (Human model) A similar experiment was performed in humans using five submental LN flaps. RESULTS: (Animal model) Fluorescence was detected in the venous pedicle of LN flaps submerged in 5%, 7% and 10% albumin, and half of flaps submerged in 3% albumin. Fluorescence was not detected in LN node flaps submerged in ICG containing NS or 1% albumin solution. Fluorescence was not detected in non-LN flaps. There was greater volume reduction with LN flaps than non-LN flaps (p<0.001). (Human model) Fluorescence was detected in the venous pedicle of all flaps immersed in lymph. CONCLUSIONS: ICG fluorescence was detected in the venous pedicle of rat and human LN flaps submerged in lymph or albumin when the concentration was greater than 3%. Based on these results, a pathway for lymphatic uptake is presented. PMID- 26773470 TI - Racial disparities in survival in malignant germ cell tumors of the ovary. AB - OBJECTIVE: To investigate racial disparities with respect to adjuvant treatment and survival in patients presenting with malignant ovarian germ cell tumors (OGCT). METHODS: The National Cancer Database (NCDB) was used to identify women diagnosed with OGCT. Demographic data were abstracted, including stratification by race and histology. Standard univariate and multivariate analyses using logistic regression were performed to describe predictors of adjuvant treatment. Kaplan-Meier and Cox proportional hazards survival methods were used to evaluate racial differences in survival between African American (AA) and white (W) women. RESULTS: The study population included 2196 patients, with 1654 (75.3%) W and 328 (14.9%) AA women. Histologic distribution varied significantly by race (p<0.0001), but neither age nor stage at presentation showed racial differences (p=0.086 and p=0.209, respectively). AA received more chemotherapy than W (W: 54.6%, AA: 65.5%, p=0.008), but in multivariate analysis there was no statistically significant difference in any adjuvant treatment modality. Despite similar treatment, and independent of histology, survival varied significantly by race with 91% (CI 0.89-0.93) five year survival in W patients compared to 84% five year survival in AA (CI 0.8-0.89) (p=0.02). These disparities were most pronounced in advanced stage disease, with 5 year survival of 84% (CI 0.79-0.89) in W compared to 61% (CI 0.48-0.78) for AA in stage III (p=0.0002), and 54% (CI 0.42-0.68) compared to 14% (CI 0.03-0.71) for stage IV (p=0.05). CONCLUSIONS: AA with OGCT have significantly worse 5 year survival when compared to W patients despite similar rates and modalities of adjuvant treatment. PMID- 26773471 TI - Changing characteristics of statin-related cIMT trials from 1988 to 2006. AB - OBJECTIVES: Changes in cIMT have not been consistently correlated with cardiovascular risk reduction in clinical studies. The variability of carotid intima media thickness (cIMT) changes in published statin LDL-C-lowering studies in relation to various baseline and study characteristics was assessed. METHODS: This was an exploratory analysis of study-level data pooled from statin-treatment arms of 13 studies conducted during 1988-2006. Baseline mean common carotid artery (CCA)/cIMT, maximum mean CCA/cIMT and LDL-C levels, and annualized cIMT changes were estimated for the overall studies, those conducted before/after 2000, and in risk-based subgroups. Potential relationships between prespecified covariates and cIMT changes were assessed. RESULTS: Baseline mean CCA/cIMT and LDL-C levels were higher in the combined studies conducted before year 2000 (0.8521 mm) than after 2000 (0.7458 mm), and somewhat higher in study populations of patients with coronary heart disease risk and those with greater LDL-C reductions. Mean CCA/cIMT changes were also larger for the studies conducted before 2000 (-0.0119 mm/year) than after 2000 (-0.0013 mm/year). Notably, studies conducted before 2000 were of longer duration (>= 2 years) than after 2000 (<2 years). Heterogeneity in cIMT change was attributed to baseline and study-design characteristics. Longer study duration and greater LDL-C reductions were significantly related to larger annualized cIMT changes. Maximum cIMT results were similar. CONCLUSION: Baseline cIMT and LDL-C levels were lower, and cIMT changes were smaller in statin cIMT trials conducted after 2000 than those before 2000. These trends are consistent with increased treatment and control of high LDL-C levels over recent years in clinical practice, and may influence the results of cIMT studies. PMID- 26773474 TI - Another emerging disease: Swine Enteric Coronaviruses. PMID- 26773472 TI - Case-based educational intervention to assess change in providers' knowledge and attitudes towards the 2013 American College of Cardiology/American Heart Association Cholesterol Management Guideline. AB - OBJECTIVE: Prior studies have shown provider-level knowledge gaps regarding the 2013 American College of Cardiology/American Heart Association guideline on the treatment of cholesterol and concerns about 10-year atherosclerotic cardiovascular disease (ASCVD) risk estimation. The effect of an educational intervention to mitigate knowledge gaps is unknown. METHODS: We developed a questionnaire and administered it to providers before (pre-training) and after (post-training) a case-based educational intervention across 6 sites in Texas. The intervention highlighted the key recommendations of the 2013 guideline and the differences from the prior guideline mainly using clinical-vignettes. Several practice pertinent items were also discussed. RESULTS: Most participants were providers-in-training (78%) in internal medicine (68%). Compared to pre-training, the post-training metrics were: 43% vs. 82% for providers' ability to identify 4 statin benefit groups; 47% vs. 97% for their awareness of the ASCVD risk threshold of >= 7.5% to initiate discussion about risks/benefits of statin therapy; 9% vs. 40% for awareness of differences between the Framingham and the ASCVD risk estimator; 26% vs. 78% for awareness of the definition of statin intensity; 35% vs. 62% for using a repeat lipid panel to document treatment response and adherence; and 46% vs. 81% for confidence in using the ASCVD risk estimator, respectively. CONCLUSIONS: A case-based educational intervention was associated with significant increase in providers' knowledge towards the 2013 cholesterol guideline, which could be related to the engaging nature of our intervention, using practice pertinent information and clinical vignettes. Such interventions could be useful in effective dissemination of the cholesterol guideline. PMID- 26773473 TI - Decreased phosphatidylcholine plasmalogens--A putative novel lipid signature in patients with stable coronary artery disease and acute myocardial infarction. AB - OBJECTIVE: Glycerophospholipids and sphingolipids are structurally heterogeneous due to differences in the O- and N-linked fatty acids and head groups. Sphingolipids also show a heterogeneity in their sphingoid base composition which up to now has been little appreciated. The aim of this study was to investigate the association of certain glycerophospholipid and sphingolipid species with stable coronary artery disease (CAD) and acute myocardial infarction (AMI). METHODS: The lipid profile in plasma from patients with stable CAD (n = 18) or AMI (n = 17) was compared to healthy subjects (n = 14). Sixty five glycerophospholipid and sphingolipid species were quantified by LC-MS. The relative distribution of these lipids into lipoprotein fractions was analyzed. RESULTS: In the CAD cohort, 45 glycerophospholipid and sphingolipid species were significantly lower compared to healthy controls. In the AMI group, 42 glycerophospholipid and sphingolipid species were reduced. Four PC plasmalogens (PC33:1, PC33:2, PC33:3 and PC35:3) showed the most significant difference. Out of eleven analyzed sphingoid bases, four were lower in the CAD and six in the AMI group. Sphingosine-1-phosphate (S1P) levels were reduced in the AMI group whereas an atypical C16:1 S1P was lower in both groups. Phosphatidylcholine and sphingomyelin species were exclusively present in lipoprotein particles, whereas lysophosphatidylcholines were mainly found in the lipoprotein-free fraction. The observed differences were not explained by the use of statins as confirmed in a second, independent cohort. CONCLUSIONS: Reduced levels of four PC plasmalogens (PC33:1, PC33:2, PC33:3 and PC35:3) were identified as a putatively novel lipid signature for CAD and AMI. PMID- 26773475 TI - Changes in biochemical compounds in flesh and peel from Prunus persica fruits grown in Tunisia during two maturation stages. AB - Plants can synthesize tens to hundreds of thousands of primary and secondary metabolites with diverse biological properties and functions. Fatty acids (FA), phenolic compounds (PC) and volatile compounds (VC) of flesh and peel from three Prunus persica cultivars were evaluated at the Regional Centre of Agricultural Research--Experimental Farm (Sidi Bouzid, Tunisia) during two maturation stages. Palmitic, oleic and linoleic acids are the most abundant FA in Prunus persica cultivars. A genetic effect on FA composition was observed throughout the two sampling periods. Peel was rich in oleic acid with the highest content (31.3% on total FA) in 'O'Henry' cultivar at the commercial ripening date; flesh was rich in linoleic acid with the highest content (44.7% on total FA) in 'Sweet Cap' cultivar at the full ripening date. The monounsaturated/polyunsaturated fatty acids ratios were higher in the commercial ripe than in the full ripe fruits. The analysis of the composition of the VC led to the characterization of 98 different compounds, showing a very high variability among the cultivars. The full ripe fruit (peel and flesh) exhibited the highest total number of terpenoids. Commercial ripe peels were richest in the percentage of hydrocarbons. Comparing cultivars, 'Sweet Cap' cultivar showed the lowest contents of alcohols in peel and flesh of full ripe fruit but highest in peel of commercial ripe fruit, and lowest content of aldehydes in peel and flesh of commercial ripe fruit but highest in peel of ripe ones and the highest ones of lactones. Among PC, the highest contents were observed for o-diphenols and the values showed varietal influence. Total phenols contents decreased during ripening process (p < 0.05) in both peel and flesh tissues, except found for 'Sweet Cap' cultivar. In conclusion, to achieve better FA composition and greater VC and PC production of the peach fruit, P. persica cultivars should be harvested at the commercial ripening date. PMID- 26773476 TI - Why We Should Take a Closer Look at Gestures. PMID- 26773477 TI - How dynein and dynactin transport cargos: a structural perspective. AB - Recent structures of the dynein motor in three different conformations reveal how it uses ATP hydrolysis to move along microtubules. Attention is now turning to how cytoplasmic dynein-1 and dynactin act together to carry cargos. Cryo-electron microscopy (cryo-EM) has revealed the structure of dynactin and how it binds dynein in the presence of a cargo adaptor protein Bicaudal-D2 (BICD2). Future questions will include how dynein-1 transports so many different cargos and how the 2.4MDa dynein/dynactin transport machine is regulated. PMID- 26773478 TI - Protein sequence design and its applications. AB - Design of proteins has far-reaching potentials in diverse areas that span repurposing of the protein scaffold for reactions and substrates that they were not naturally meant for, to catching a glimpse of the ephemeral proteins that nature might have sampled during evolution. These non-natural proteins, either in synthesized or virtual form have opened the scope for the design of entities that not only rival their natural counterparts but also offer a chance to visualize the protein space continuum that might help to relate proteins and understand their associations. Here, we review the recent advances in protein engineering and design, in multiple areas, with a view to drawing attention to their future potential. PMID- 26773479 TI - Bone sialoprotein keratan sulfate proteoglycan (BSP-KSPG) and FGF-23 are important physiological components of medullary bone. AB - Medullary bone is a specialized bone found in the marrow cavity of laying birds. It provides a significant contribution to the calcium supply for egg shell formation. Medullary bone is distinguished from cortical bone by the presence of large amounts of a keratan sulfate proteoglycan (KSPG). The aims of the present experiment are to confirm the identity of the core protein of KSPG, identify a marker of medullary bone metabolism, and determine whether changes in keratan sulfate (KS) concentration in blood are associated with the egg-laying cycle. Using two different isolation techniques- one specific for bone and another for blood- we have identified bone sialoprotein (BSP) to be the core protein of this KSPG. We also determined that the amount of keratan sulfate (KS) in laying hen blood fluctuates in synchrony with the egg-laying cycle, and thus can serve as a specific marker for medullary bone metabolism. During the course of this investigation, we also found FGF-23 (phosphatonin) to be expressed in medullary bone, in synchrony with the egg-laying cycle. Western blotting was used to demonstrate the presence of this peptide in both laying hen blood and medullary bone extracts. The importance of FGF-23 (phosphatonin) and parathyroid hormone in normalizing the dramatic changes in plasma calcium and phosphorus during the 24h egg-laying cycle is discussed. PMID- 26773480 TI - Molecular and functional characterization of the vitellogenin receptor in oriental river prawn, Macrobrachium nipponense. AB - A complementary DNA (cDNA) that encodes the vitellogenin receptor (VgR) in the oriental river prawn, Macrobrachium nipponense, was cloned using expressed sequence tag analysis and a rapid amplification of cDNA ends approach. The coding region consists of 5920 base pairs (bp) that encode a 1902 amino acid protein, with a predicted molecular mass of 209 kDa. The coding region is flanked by a 45 bp 5'-untranslated region (UTR) and a 166 bp 3'-UTR. The deduced amino acid sequence of the M. nipponense VgR cDNA had typically conserved domains, such as an extracellular, lipoprotein-binding domain, epidermal growth factor-like and O glycosylation domains, a transmembrane domain and a short C-terminal, cytosolic tail. Quantitative real-time PCR (qPCR) indicated that Mn-VgR is highly expressed in the female ovary. Expression analysis by qPCR demonstrated the larval and ovarian developmental stage-specific expression pattern. As the ovaries developed, the expression level of Mn-VgR gradually increased during the reproductive cycle (stage I), to reach a peak in stage III. Levels then dropped as a new development cycle was entered after reproduction molting. Eyestalk ablation led to a significant increase in the expression of Mn-VgR during the ovarian development stages (P<0.05), when compared with the eyestalk-intact group. The investigation revealed that eyestalk ablation initially affected Mn VgR expression and then influenced vitellogenesis. In adult females, VgR RNA interference (RNAi) dramatically delayed the maturation of the ovary, in accordance with the gonad somatic index. In addition, Mn-VgR RNAi led to vitellin depletion in the oocytes and the accumulation of vitellin in the hepatopancreas. PMID- 26773482 TI - A theoretical approach to using faecal indicator data to model norovirus concentration in surface water for QMRA: Glomma River, Norway. AB - Monitoring of faecal indicator organisms, such as Escherichia coli, in environmental and drinking waters is inadequate for the protection public health, primarily due to the poor relationship between E. coli and the occurrence of human pathogens, especially viruses, in environmental samples. Nevertheless, measurements of faecal indicator organisms within the risk based approach, can provide valuable information related to the magnitude and variability of faecal contamination, and hence provide insight into the expected level of potential pathogen contamination. In this study, a modelling approach is presented that estimates the concentration of norovirus in surface water relying on indicator monitoring data, combined with specific assumptions regarding the source of faecal contamination. The model is applied to a case study on drinking water treatment intake from the Glomma River in Norway. Norovirus concentrations were estimated in two sewage sources discharging into the river upstream of the drinking water offtake, and at the source water intake itself. The characteristics of the assumed source of faecal contamination, including the norovirus prevalence in the community, the size of the contributing population and the relative treatment efficacy for indicators and pathogens in the sewage treatment plant, influenced the magnitude and variability in the estimated norovirus concentration in surface waters. The modelling exercise presented is not intended to replace pathogen enumeration from environmental samples, but rather is proposed as a complement to better understand the sources and drivers of viruses in surface waters. The approach has the potential to inform sampling regimes by identifying when the best time would be to collect environmental samples; fill in the gaps between sparse datasets; and potentially extrapolate existing datasets in order to model rarer events such as an outbreak in the contributing population. In addition, and perhaps most universally, in the absence of pathogen data, this approach can be used as a first step to predict the source water pathogen concentration under different contamination scenarios for the purpose of quantifying microbial risks. PMID- 26773481 TI - Predicting the drying properties of sludge based on hydrothermal treatment under subcritical conditions. AB - The effects of hydrothermal treatment on the drying properties of sludge were determined. Sludge was hydrothermally treated at 180-260 degrees C for 0.5-5 h using NaOH and HCl as additives to influence reaction conditions. Untreated sludge and attained hydrochar samples were then dried under identical conditions with a laboratory microdryer and an X-ray microtomograph was used to follow changes in sample dimensions. The effective moisture diffusivities of sludge and hydrochar samples were determined and the effect of process conditions on respective mean diffusivities evaluated using multiple linear regression. Based on the results the drying time of untreated sludge decreased from approximately 80 min to 37-59 min for sludge hydrochar. Drying of untreated sludge was governed by the falling rate period where drying flux decreased continuously as a function of sludge moisture content due to heat and mass transfer limitations and sample shrinkage. Hydrothermal treatment increased the drying flux of sludge hydrochar and decreased the effect of internal heat and mass transfer limitations and sample shrinkage especially at higher treatment temperatures. The determined effective moisture diffusivities of sludge and hydrochar increased as a function of decreasing moisture content and the mean diffusivity of untreated sludge (8.56.10(-9) m(2) s(-1)) and sludge hydrochar (12.7-27.5.10(-9) m(2) s(-1)) were found statistically different. The attained regression model indicated that treatment temperature governed the mean diffusivity of hydrochar, as the effects of NaOH and HCl were statistically insignificant. The attained results enabled prediction of sludge drying properties through mean moisture diffusivity based on hydrothermal treatment conditions. PMID- 26773483 TI - Integrated forward osmosis-membrane distillation process for human urine treatment. AB - This study demonstrated a forward osmosis-membrane distillation (FO-MD) hybrid system for real human urine treatment. A series of NaCl solutions at different concentrations were adopted for draw solutions in FO process, which were also the feed solutions of MD process. To establish a stable and continuous integrated FO MD system, individual FO process with different NaCl concentrations and individual direct contact membrane distillation (DCMD) process with different feed temperatures were firstly investigated separately. Four stable equilibrium conditions were obtained from matching the water transfer rates of individual FO and MD processes. It was found that the integrated system is stable and sustainable when the water transfer rate of FO subsystem is equal to that of MD subsystem. The rejections to main contaminants in human urine were also investigated. Although individual FO process had relatively high rejection to Total Organic Carbon (TOC), Total Nitrogen (TN) and Ammonium Nitrogen (NH4(+)-N) in human urine, these contaminants could also accumulate in draw solution after long term performance. The MD process provided an effective rejection to contaminants in draw solution after FO process and the integrated system revealed nearly complete rejection to TOC, TN and NH4(+)-N. This work provided a potential treatment process for human urine in some fields such as water regeneration in space station and water or nutrient recovery from source-separated urine. PMID- 26773484 TI - Viral persistence in surface and drinking water: Suitability of PCR pre-treatment with intercalating dyes. AB - After many outbreaks of enteric virus associated with consumption of drinking water, the study of enteric viruses in water has increased significantly in recent years. In order to better understand the dynamics of enteric viruses in environmental water and the associated viral risk, it is necessary to estimate viral persistence in different conditions. In this study, two representative models of human enteric viruses, adenovirus 41 (AdV 41) and coxsackievirus B2 (CV B2), were used to evaluate the persistence of enteric viruses in environmental water. The persistence of infectious particles, encapsidated genomes and free nucleic acids of AdV 41 and CV-B2 was evaluated in drinking water and surface water at different temperatures (4 degrees C, 20 degrees C and 37 degrees C). The infectivity of AdV 41 and CV-B2 persisted for at least 25 days, whatever the water temperature, and for more than 70 days at 4 degrees C and 20 degrees C, in both drinking and surface water. Encapsidated genomes persisted beyond 70 days, whatever the water temperature. Free nucleic acids (i.e. without capsid) also were able to persist for at least 16 days in drinking and surface water. The usefulness of a detection method based on an intercalating dye pre-treatment, which specifically targets preserved particles, was investigated for the discrimination of free and encapsidated genomes and it was compared to virus infectivity. Further, the resistance of AdV 41 and CV-B2 against two major disinfection treatments applied in drinking water plants (UV and chlorination) was evaluated. Even after the application of UV rays and chlorine at high doses (400 mJ/cm(2) and 10 mg.min/L, respectively), viral genomes were still detected with molecular biology methods. Although the intercalating dye pre-treatment had little use for the detection of the effects of UV treatment, it was useful in the case of treatment by chlorination and less than 1 log10 difference in the results was found as compared to the infectivity measurements. Finally, for the first time, the suitability of intercalating dye pre-treatment for the estimation of the quality of the water produced by treatment plants was demonstrated using samples from four drinking-water plants and two rivers. Although 55% (27/49) of drinking water samples were positive for enteric viruses using molecular detection, none of the samples were positive when the intercalating dye pre treatment method was used. This could indicate that the viruses that were detected are not infectious. PMID- 26773485 TI - Removal of aqueous nC60 fullerene from water by low pressure membrane filtration. AB - The potential environmental and health risks of engineered nanoparticles such as buckminsterfullerene C60 in water require their removal during the production of drinking water. We present a study focusing on (i) the removal mechanism and (ii) the elucidation of the role of the membrane pore size during removal of nC60 fullerene nanoparticle suspensions in dead-end microfiltration and ultrafiltration mimicking separation in real industrial water treatment plants. Membranes were selected with pore sizes ranging from 18 nm to 500 nm to determine the significance of the nC60 to membrane pore size ratio and the adsorption affinity between nC60 and membrane material during filtration. Experiments were carried out with a dead-end bench-scale system operated at constant flux conditions including a hydraulic backwash cleaning procedure. nC60 nanoparticles can be efficiently removed by low pressure membrane technology with smaller and, unexpectedly, also by mostly similar or larger pores than the particle size, although the nC60 filtration behaviour appeared to be different. The nC60 size to membrane pore size ratio and the ratio of the cake-layer deposition resistance to the clean membrane resistance, both play an important role on the nC60 filtration behaviour and on the efficiency of the backwash procedure recovering the initial membrane filtration conditions. These results become specifically significant in the context of drinking water production, for which they provide relevant information for an accurate selection between membrane processes and operational parameters for the removal of nC60 in the drinking water treatment. PMID- 26773486 TI - Fingerprinting the reactive toxicity pathways of 50 drinking water disinfection by-products. AB - A set of nine in vitro cellular bioassays indicative of different stages of the cellular toxicity pathway was applied to 50 disinfection by-products (DBPs) to obtain a better understanding of the commonalities and differences in the molecular mechanisms of reactive toxicity of DBPs. An Eschericia coli test battery revealed reactivity towards proteins/peptides for 64% of the compounds. 98% activated the NRf2-mediated oxidative stress response and 68% induced an adaptive stress response to genotoxic effects as indicated by the activation of the tumor suppressor protein p53. All DBPs reactive towards DNA in the E. coli assay and activating p53 also induced oxidative stress, confirming earlier studies that the latter could trigger DBP's carcinogenicity. The energy of the lowest unoccupied molecular orbital ELUMO as reactivity descriptor was linearly correlated with oxidative stress induction for trihalomethanes (r(2)=0.98) and haloacetamides (r(2)=0.58), indicating that potency of these DBPs is connected to electrophilicity. However, the descriptive power was poor for haloacetic acids (HAAs) and haloacetonitriles (r(2) (<) 0.06). For HAAs, we additionally accounted for speciation by including the acidity constant with ELUMO in a two-parameter multiple linear regression model. This increased r(2) to >0.80, indicating that HAAs' potency is connected to both, electrophilicity and speciation. Based on the activation of oxidative stress response and the soft electrophilic character of most tested DBPs we hypothesize that indirect genotoxicity-e.g., through oxidative stress induction and/or enzyme inhibition-is more plausible than direct DNA damage for most investigated DBPs. The results provide not only a mechanistic understanding of the cellular effects of DBPs but the effect concentrations may also serve to evaluate mixture effects of DBPs in water samples. PMID- 26773487 TI - Efficacy of dental unit waterlines disinfectants on a polymicrobial biofilm. AB - Due to their high surface-volume ratio, their laminar flow and frequent stagnation periods, dental unit waterlines (DUWL) foster the attachment of microorganisms and the development of biofilm, resulting in the continuous contamination of the outlet water from dental units; this contamination may be responsible for a potential risk of infection due to the exposure of patients and medical staff to droplet inhalation or splashed water. In this study, the anti biofilm activity of three disinfectants recommended by dental unit manufacturers Calbenium((c)), Oxygenal 6((c)) and Sterispray((c)) - was evaluated. A dynamic model simulating DUWL conditions was developed and polymicrobial biofilms containing bacteria (Pseudomonas aeruginosa), fungi (Candida albicans) and Free Living Amoeba (FLA: Vermamoeba vermiformis) were allowed to form. The ability of disinfectants to reduce biofilm formation or to eradicate an already formed biofilm was evaluated. Results showed the various effects of the tested disinfectants according to their composition, concentration and the targeted species. V. vermiformis was resistant to disinfectants, regardless of the tested concentrations and the concentrations recommended by manufacturers were not the most appropriate. Results also showed that Calbenium((c)) was the most effective disinfectant to reduce already formed biofilms; its maximum efficiency was observed from 0.5% on both P. aeruginosa and C. albicans compared to 2 and 3% respectively for Sterispray((c)). The maximum efficiency of Oxygenal((c)) was observed from 3% on P. aeruginosa but Oxygenal((c)) was unable to totally eliminate C. albicans in the tested conditions, contrary to other disinfectants. Calbenium((c)) was able to prevent biofilm formation efficiently even if it displayed no prophylactic activity against V. vermiformis. Overall, the FLA survival may contribute to maintaining other species. Finally the tested disinfectants were partially active against sessile microorganisms and more suitable concentrations could be used to increase their efficacy. Their use in a prophylactic rather than curative way should be recommended. PMID- 26773488 TI - Development and characterization of 3D-printed feed spacers for spiral wound membrane systems. AB - Feed spacers are important for the impact of biofouling on the performance of spiral-wound reverse osmosis (RO) and nanofiltration (NF) membrane systems. The objective of this study was to propose a strategy for developing, characterizing, and testing of feed spacers by numerical modeling, three-dimensional (3D) printing of feed spacers and experimental membrane fouling simulator (MFS) studies. The results of numerical modeling on the hydrodynamic behavior of various feed spacer geometries suggested that the impact of spacers on hydrodynamics and biofouling can be improved. A good agreement was found for the modeled and measured relationship between linear flow velocity and pressure drop for feed spacers with the same geometry, indicating that modeling can serve as the first step in spacer characterization. An experimental comparison study of a feed spacer currently applied in practice and a 3D printed feed spacer with the same geometry showed (i) similar hydrodynamic behavior, (ii) similar pressure drop development with time and (iii) similar biomass accumulation during MFS biofouling studies, indicating that 3D printing technology is an alternative strategy for development of thin feed spacers with a complex geometry. Based on the numerical modeling results, a modified feed spacer with low pressure drop was selected for 3D printing. The comparison study of the feed spacer from practice and the modified geometry 3D printed feed spacer established that the 3D printed spacer had (i) a lower pressure drop during hydrodynamic testing, (ii) a lower pressure drop increase in time with the same accumulated biomass amount, indicating that modifying feed spacer geometries can reduce the impact of accumulated biomass on membrane performance. The combination of numerical modeling of feed spacers and experimental testing of 3D printed feed spacers is a promising strategy (rapid, low cost and representative) to develop advanced feed spacers aiming to reduce the impact of biofilm formation on membrane performance and to improve the cleanability of spiral-wound NF and RO membrane systems. The proposed strategy may also be suitable to develop spacers in e.g. forward osmosis (FO), reverse electrodialysis (RED), membrane distillation (MD), and electrodeionisation (EDI) membrane systems. PMID- 26773489 TI - Theoretical investigation on the kinetics and mechanisms of hydroxyl radical induced transformation of parabens and its consequences for toxicity: Influence of alkyl-chain length. AB - As emerging organic contaminants (EOCs), the ubiquitous presence of preservative parabens in water causes a serious environmental concern. Hydroxyl radical ((*)OH) is a strong oxidant that can degrade EOCs through photochemistry in surface water environments as well as in advanced oxidation processes (AOPs). To better understand the degradation mechanisms, kinetics, and products toxicity of the preservative parabens in aquatic environments and AOPs, the (*)OH-initiated degradation reactions of the four parabens were investigated systematically using a computational approach. The four studied parabens with increase of alkyl-chain length were methylparaben (MPB), ethylparaben (EPB), propylparaben (PPB), and dibutylparaben (BPB). Results showed that the four parabens can be initially attacked by (*)OH through (*)OH-addition and H-abstraction routes. The (*)OH addition route was more important for the degradation of shorter alkyl-chain parabens like MPB and EPB, while the H-abstraction route was predominant for the degradation of parabens with longer alkyl-chain for example PPB and BPB. In assessing the aquatic toxicity of parabens and their degradation products using the model calculations, the products of the (*)OH-addition route were found to be more toxic to green algae than original parabens. Although all degradation products were less toxic to daphnia and fish than corresponding parental parabens, they could be still harmful to these aquatic organisms. Furthermore, as alkyl-chain length increased, the ecotoxicity of parabens and their degradation products was found to be also increased. PMID- 26773490 TI - Post-treatment of refinery wastewater effluent using a combination of AOPs (H2O2 photolysis and catalytic wet peroxide oxidation) for possible water reuse. Comparison of low and medium pressure lamp performance. AB - The main aim of this work was to study the feasibility of multi-barrier treatment (MBT) consisting of filtration, hydrogen peroxide photolysis (H2O2/UVC) and catalytic wet peroxide oxidation (CWPO) for post-treatment of petroleum refinery effluent. Also the possibility of water reuse or safe discharge was considered. The performance of MBT using medium (MP) and low (LP) pressure lamps was compared as well as operation and maintenance (O&M) cost. Decomposition of organic compounds was followed by means of gas chromatography-mass spectrometry (GC-MS), total organic carbon (TOC) and chemical oxygen demand (COD) analysis. After filtration step (25 MUm) turbidity and concentration of suspended solids decreased by 92% and 80%, respectively. During H2O2/UVC process with LP lamp at optimal conditions (H2O2:TOC ratio 8 and UVC dose received by water 5.28 WUVC s cm(-2)) removal of phenolic compounds, TOC and COD was 100%, 52.3% and 84.3%, respectively. Complete elimination of phenolic compounds, 47.6% of TOC and 91% of COD was achieved during H2O2/UVC process with MP lamp at optimal conditions (H2O2:TOC ratio 5, UVC dose received by water 6.57 WUVC s cm(-2)). In order to compare performance of H2O2/UVC treatment with different experimental set up, the UVC dose required for removal of mg L(-1) of COD was suggested as a parameter and successfully applied. The hydrophilicity of H2O2/UVC effluent significantly increased which in turn enhanced the oxidation of organic compounds during CWPO step. After H2O2/UVC treatment with LP and MP lamps residual H2O2 concentration was 160 mg L(-1) and 96.5 mg L(-1), respectively. Remaining H2O2 was fully consumed during subsequent CWPO step (6 and 3.5 min of contact time for LP and MP, respectively). Total TOC and COD removal after MBT was 94.7% and 92.2% (using LP lamp) and 89.6% and 95%, (using MP lamp), respectively. The O&M cost for MBT with LP lamp was estimated to be 0.44 ? m(-3) while with MP lamp it was nearly five times higher. Toxicity assessment was performed using two marine species (Vibrio fischeri and Paracentrotus lividus sea-urchin) after each treatment step. The highest toxicity was attributed to H2O2/UVC effluent for both tested species. After MBT a drastic decrease of toxicity was achieved. PMID- 26773491 TI - The benefits of powdered activated carbon recirculation for micropollutant removal in advanced wastewater treatment. AB - PAC adsorption is a widespread option for the removal of organic micropollutants (OMP) from secondary effluent. For an optimal exploitation of the adsorption capacity, PAC recirculation is nowadays a common practice, although the mechanistic interrelations of the complex recirculation process are not fully resolved. In this work, extensive multi-stage batch adsorption testing with repeated PAC and coagulant dosage was performed to evaluate the continuous-flow recirculation system. Partly loaded PAC showed a distinct amount of remaining capacity, as OMP and DOC removals considerably increased with each additional adsorption stage. At a low PAC dose of 10 mg PAC L(-1), removals of benzotriazole and carbamazepine were shown to rise from <40% in the first stage up to >80% in the 11th stage at 30 min adsorption time per stage. At a high PAC dose of 30 mg PAC L(-1), OMP and DOC removals were significantly higher and reached 98% (for benzotriazole and carbamazepine) after 11 stages. Coagulant dosage showed no influence on OMP removal, whereas a major part of DOC removal can be attributed to coagulation. Multi-stage adsorption is particularly beneficial for small PAC doses and significant PAC savings are feasible. A new model approach for predicting multi-stage OMP adsorption on the basis of a single-stage adsorption experiment was developed. It proved to predict OMP removals and PAC loadings accurately and thus contributes towards understanding the PAC recirculation process. PMID- 26773492 TI - Removal of organic micro-pollutants (phenol, aniline and nitrobenzene) via forward osmosis (FO) process: Evaluation of FO as an alternative method to reverse osmosis (RO). AB - In this study, we have explored and compared the effectiveness of using (1) lab fabricated forward osmosis (FO) membranes under both FO and reverse osmosis (RO) modes and (2) commercially available RO membranes under the RO mode for the removal of organic micro-pollutants. The lab-fabricated FO membranes are thin film composite (TFC) membranes consisting of a polyamide layer and a porous substrate cast from three different materials; namely, Matrimid, polyethersulfone (PESU) and sulfonated polyphenylene sulfone (sPPSU). The results show that the FO mode is superior to the RO mode in the removal of phenol, aniline and nitrobenzene from wastewater. The rejections of all three TFC membranes to all the three organic micro-pollutants under the FO processes are higher than 72% and can be even higher than 90% for aniline when a 1000 ppm aromatic aqueous solution and 1 M NaCl are employed as feeds. These performances outperform the results obtained from themselves and commercially available RO membranes under the RO mode. In addition, the rejection can be maintained even when treating a more concentrated feed solution (2000 ppm). The removal performance can be further enhanced by using a more concentrated draw solution (2 M). The water flux is almost doubled, and the rejection increment can reach up to 17%. Moreover, it was observed that annealing as a post-treatment would help compact the membrane selective layer and further enhance the separating efficiency. The obtained organic micro-pollutant rejections and water fluxes under various feasible operating conditions indicate that the FO process has potential to be a viable treatment for wastewater containing organic micro-pollutants. PMID- 26773493 TI - Comparison of the in-house made Carba-NP and Blue-Carba tests: Considerations for better detection of carbapenemase-producing Enterobacteriaceae. AB - The in-house Carba-NP and Blue-Carba tests were compared using 30 carbapenemase- and 33 non-producing Enterobacteriaceae. Tests were read by three operators. 100% sensitivity was reported for both tests, but Carba-NP was slightly more specific than Blue-Carba (98.9% vs. 91.7%). We describe potential sources of error during tests' preparation and reading. PMID- 26773494 TI - Aggregation induced emission from alpha-napthoflavone microstructures and its cyto-toxicity. AB - alpha-Napthoflavone (ANF) microstructures of various morphologies were synthesized using reprecipitation method. Sodium Dodecyl Sulfate (SDS) was used as morphology directing agent. The morphologies of the particles were characterized using optical and scanning electron microscopy (SEM). Single crystal data of ANF suggests that the aromatic units of ANF are in parallel slipped conformation in its aggregated form. Photophysical properties of aggregated ANF hydrosol were studied using UV-Vis absorption, steady state and time resolved spectroscopy. Red shift and broadening of UV-Vis spectra of ANF hydrosol are explained due to strong pi-pi and H-pi interactions among the neighboring ANF molecules within the aggregated microstructures. Though ANF is non-luminescent in good solvent, a strong emission is observed in its aggregated state. This aggregation induced emission (AIE) has been explained due to restriction of intramoleculer rotation and large amplitude vibrational modes of ANF in its aggregated state. Our Photophysical study also reveals that AIE effect decreases after an optimum concentration of ANF and this has been explained due to softening of crystal lattice. Cytotoxicity of ANF hydrosol was examined to get an idea of the toxic level of this hydrosol toward cultured normal human cells. It is observed that ANF hydrosol may draw beneficial effect in biological application as it has no higher toxic activity but has antioxidant property. PMID- 26773495 TI - 4SC-202 activates ASK1-dependent mitochondrial apoptosis pathway to inhibit hepatocellular carcinoma cells. AB - The aim of the present study is to investigate the potential anti-hepatocellular carcinoma (HCC) cell activity by 4SC-202, a novel class I HDAC inhibitor (HDACi). The associated signaling mechanisms were also analyzed. We showed that 4SC-202 treatment induced potent cytotoxic and proliferation-inhibitory activities against established HCC cell lines (HepG2, HepB3, SMMC-7721) and patient-derived primary HCC cells. Further, adding 4SC-202 in HCC cells activated mitochondrial apoptosis pathway, which was evidenced by mitochondrial permeability transition pore (mPTP) opening, cytochrome C cytosol release and caspase-3/-9 activation. Inhibition of this apoptosis pathway, by caspase-3/-9 inhibitors, mPTP blockers, or by shRNA-mediated knockdown of cyclophilin-D (Cyp-D, a key component of mPTP), significantly attenuated 4SC-202-induced HCC cell death and apoptosis. Reversely, over-expression of Cyp-D enhanced 4SC-202's sensitivity in HCC cells. Further studies showed that 4SC-202 induced apoptosis signal-regulating kinase 1 (ASK1) activation, causing it translocation to mitochondria and physical association with Cyp-D. This mitochondrial ASK1-Cyp-D complexation appeared required for mediating 4SC-202-induced apoptosis activation. ASK1 stable knockdown by targeted shRNAs largely inhibited 4SC-202-induced mPTP opening, cytochrome C release, and following HCC cell apoptotic death. Together, we suggest that 4SC-202 activates ASK1-dependent mitochondrial apoptosis pathway to potently inhibit human HCC cells. PMID- 26773497 TI - MiR-328 suppresses the survival of esophageal cancer cells by targeting PLCE1. AB - Esophageal cancer (EC) is the sixth leading cause of death worldwide. Recent studies have highlighted the vital role of microRNAs (miRNAs) in EC development and diagnosis. In our study, qPCR analysis showed that miRNA-328 was expressed at significantly low levels in EC109 and EC9706 cells. The results also showed that overexpression of miR-328 by lentivirus-mediated gene transfer markedly inhibited cell proliferation and invasion, and enhanced apoptosis; whereas, inhibition of miR-328 significantly promoted cell proliferation and invasion, and suppressed apoptosis in EC109 and EC9706 cells. Dual-luciferase reporter assay confirmed that miR-328 directly targeted phospholipase C epsilon 1 (PLCE1) by binding to target sequences in the 3'-UTR. qPCR and Western blot analysis showed that the PLCE1 was overexpressed in EC109 and EC9706 cells. Additionally, we found that miR-328 overexpression decreased PLCE1 mRNA and protein levels, while miR-328 inhibition enhanced the PLCE1 expression. Further analysis showed that PLCE1 overexpression rescued the inhibitory effect of miR-328 on cell proliferation and invasion, and repressed the promotive effect of miR-328 on cell apoptosis. In conclusion, our results suggest that miR-328 suppresses the survival of EC cells by regulating PLCE1 expression, which might be a potential therapeutic method for EC. PMID- 26773496 TI - Induction of MITF expression in human cholangiocarcinoma cells and hepatocellular carcinoma cells by cyclopamine, an inhibitor of the Hedgehog signaling. AB - Microphthalmia-associated transcription factor (MITF) is a key regulator of differentiation of melanocytes and retinal pigment epithelial cells, but it also has functions in non-pigment cells. MITF consists of multiple isoforms, including widely expressed MITF-A and MITF-H. In the present study, we explored the potential role played by the Hedgehog signaling on MITF expression in two common types of primary liver cancer, using human cholangiocarcinoma cell lines, the KKU 100 and HuCCT1, along with the HepG2 human hepatocellular carcinoma cell line. Importantly, cholangiocarcinoma is characterized by the activated Hedgehog signaling. Here we show that MITF-A mRNA is predominantly expressed in all three human liver cancer cell lines examined. Moreover, cyclopamine, an inhibitor of the Hedgehog signalling, increased the expression levels of MITF proteins in HuCCT1 and HepG2 cells, but not in KKU-100 cells, suggesting that MITF expression may be down-regulated in some liver cancer cases. PMID- 26773498 TI - SRSF3 represses the expression of PDCD4 protein by coordinated regulation of alternative splicing, export and translation. AB - Gene expression is regulated at multiple steps, such as transcription, splicing, export, degradation and translation. Considering diverse roles of SR proteins, we determined whether the tumor-related splicing factor SRSF3 regulates the expression of the tumor-suppressor protein, PDCD4, at multiple steps. As we have reported previously, knockdown of SRSF3 increased the PDCD4 protein level in SW480 colon cancer cells. More interestingly, here we showed that the alternative splicing and the nuclear export of minor isoforms of pdcd4 mRNA were repressed by SRSF3, but the translation step was unaffected. In contrast, only the translation step of the major isoform of pdcd4 mRNA was repressed by SRSF3. Therefore, overexpression of SRSF3 might be relevant to the repression of all isoforms of PDCD4 protein levels in most types of cancer cell. We propose that SRSF3 could act as a coordinator of the expression of PDCD4 protein via two mechanisms on two alternatively spliced mRNA isoforms. PMID- 26773499 TI - Neuroprotective effect of sulfated polysaccharide isolated from sea cucumber Stichopus japonicus on 6-OHDA-induced death in SH-SY5Y through inhibition of MAPK and NF-kappaB and activation of PI3K/Akt signaling pathways. AB - The purpose of this study is to investigate the protective effect and molecular mechanism of the sulfated polysaccharide (SJP) isolated from the sea cucumber Stichopus japonicus against 6-OHDA-induced toxicity in SH-SY5Y cells. The results showed that SJP could protect SH-SY5Y cells against 6-OHDA-induced cell injury. We found that SJP effectively improves cell viability, decreases LDH leakage, and reverses morphological damage. Moreover, SJP significantly increases SOD activity but decreases MDA levels and ROS generation. Effect of SJP on 6-OHDA-induced cell death in SH-SY5Y cells is associated with an arrest in the G1/S phase of the cell cycle and inhibits the expression of Cyclin D3. 6-OHDA-induced intracellular generation of ROS and mitochondrial dysfunctions, release of cytochrome c, imbalance of Bax/Bcl-2, cleaved caspase-9/caspase-9 and cleaved caspase-3/caspase 3 ratio, and p-p53 activation were strikingly attenuated by SJP pretreatment. Meanwhile, SJP counteracted NF-kappaB activation, thereby preventing up regulation of iNOS and intracellular NO release. The data provide the first evidence that SJP protects SH-SY5Y cells against 6-OHDA toxicity possibly by inhibiting MAPK and NF-kappaB and activating PI3K/Akt signaling pathways. Thus, SJP is a candidate for further evaluation of its protective effects against neurodegeneration in PD. PMID- 26773500 TI - Human Gb3/CD77 synthase reveals specificity toward two or four different acceptors depending on amino acid at position 211, creating P(k), P1 and NOR blood group antigens. AB - Human Gb3/CD77 synthase (alpha1,4-galactosyltransferase, P(k) synthase), encoded by A4GALT gene, is known for synthesis of Gal(alpha1-4)Gal moiety in globotriaosylceramide (Gb3Cer, CD77, P(k) blood group antigen), a glycosphingolipid of the globo series. Recently, it was shown that c.631C > G mutation in A4GALT, which causes p.Q211E substitution in the open reading frame of the enzyme, broadens the enzyme specificity, making it able also to synthesize Gal(alpha1-4)GalNAc moiety, which constitutes the defining terminal disaccharide of the NOR antigen (carried by two glycosphingolipids: NOR1 and NOR2). Terminal Gal(alpha1-4)Gal disaccharide is also present in another glycosphingolipid blood group antigen, called P1, which together with P(k) and NOR comprises the P1PK blood group system. Despite several attempts, it was never clearly shown that P1 antigen is synthesized by Gb3/CD77 synthase, leaving open an alternative hypothesis that there are two homologous alpha1,4-galactosyltransferases in humans. In this study, using recombinant Gb3/CD77 synthase produced in insect cells, we show that the consensus enzyme synthesizes both the P(k) and P1 antigens, while its p.Q211E variant additionally synthesizes the NOR antigen. This is the first direct biochemical evidence that Gb3/CD77 synthase is able to synthesize two different glycosphingolipid antigens: P(k) and P1, and when p.Q211E substitution is present, the NOR antigen is also synthesized. PMID- 26773501 TI - Excess Cdt1 inhibits nascent strand elongation by repressing the progression of replication forks in Xenopus egg extracts. AB - Cdt1 is a protein essential for initiation of DNA replication; it recruits MCM helicase, a core component of the replicative DNA helicase, onto replication origins. In our previous study, we showed that addition of excess Cdt1 inhibits nascent strand elongation during DNA replication in Xenopus egg extracts. In the present study, we investigated the mechanism behind the inhibitory effect of Cdt1. We found that addition of recombinant Cdt1 inhibited nascent DNA synthesis in a reinitiation-independent manner. To identify the mechanism by which Cdt1 inhibits nascent strand elongation, the effect of Cdt1 on loading of Mcm4 and Rpa70 onto chromatin was examined. The results showed that Cdt1 suppressed the excessive Rpa70 binding caused by extensive, aphidicolin-induced DNA unwinding; this unwinding occurs between stalled DNA polymerases and advancing replication forks. These findings suggested that excess Cdt1 suppressed the progression of replication forks. PMID- 26773502 TI - Up-regulation of FGF23 release by aldosterone. AB - The fibroblast growth factor (FGF23) plasma level is high in cardiac and renal failure and is associated with poor clinical prognosis of these disorders. Both diseases are paralleled by hyperaldosteronism. Excessive FGF23 levels and hyperaldosteronism are further observed in Klotho-deficient mice. The present study explored a putative aldosterone sensitivity of Fgf23 transcription and secretion the putative involvement of the aldosterone sensitive serum & glucocorticoid inducible kinase SGK1, SGK1 sensitive transcription factor NFkappaB and store operated Ca(2+) entry (SOCE). Serum FGF23 levels were determined by ELISA in mice following sham treatment or exposure to deoxycorticosterone acetate (DOCA) or salt depletion. In osteoblastic UMR106 cells transcript levels were quantified by qRT-PCR, cytosolic Ca(2+) concentration utilizing Fura-2-fluorescence, and SOCE from Ca(2+) entry following store depletion by thapsigargin. As a result, DOCA treatment and salt depletion of mice elevated the serum C-terminal FGF23 concentration. In UMR106 cells aldosterone enhanced and spironolactone decreased SOCE. Aldosterone further increased Fgf23 transcript levels in UMR106 cells, an effect reversed by mineralocorticoid receptor blockers spironolactone and eplerenone, SGK1 inhibitor EMD638683, NFkappaB-inhibitor withaferin A, and Ca(2+) channel blocker YM58483. In conclusion, Fgf23 expression is up-regulated by aldosterone, an effect sensitive to SGK1, NFkappaB and store-operated Ca(2+) entry. PMID- 26773503 TI - Eukaryotic translation initiation factor 5A (eIF5A) is essential for HIF-1alpha activation in hypoxia. AB - The eukaryotic initiation factor 5A (eIF5A) is an essential protein involved in translation elongation and cell proliferation. eIF5A undergoes several post translational modifications including hypusination and acetylation. Hypusination is indispensable for the function of eIF5A. On the other hand, the precise function of acetylation remains unknown, but it may render the protein inactive since hypusination blocks acetylation. Here, we report that acetylation of eIF5A increases under hypoxia. During extended hypoxic periods an increase in the level of eIF5A acetylation correlated with a decrease in HIF-1alpha, suggesting involvement of eIF5A activity in HIF-1alpha expression under hypoxia. Indeed, suppression of eIF5A by siRNA oligo-mediated knockdown or treatment with GC7, a deoxyhypusine synthase inhibitor, led to significant reduction of HIF-1alpha activity. Furthermore, knockdown of eIF5A or GC7 treatment reduced tumor spheroid formation with a concomitant decrease in HIF-1alpha expression. Our results suggest that functional, hypusinated eIF5A is necessary for HIF-1alpha expression during hypoxia and that eIF5A is an attractive target for cancer therapy. PMID- 26773504 TI - TROP2 overexpression promotes proliferation and invasion of lung adenocarcinoma cells. AB - Recent studies suggest that the human trophoblast cell-surface antigen TROP2 is highly expressed in a number of tumours and is correlated with poor prognosis. However, its role in non-small cell lung carcinoma (NSCLC) remains largely unknown. Here we examined TROP2 expression by immunohistochemistry in a series of 68 patients with adenocarcinoma (ADC). We found significantly elevated TROP2 expression in ADC tissues compared with normal lung tissues (P < 0.05), and TROP2 overexpression was significantly associated with TNM (tumour, node, metastasis) stage (P = 0.012), lymph node metastasis (P = 0.038), and histologic grade (P = 0.013). Kaplan-Meier survival analysis revealed that high TROP2 expression correlated with poor prognosis (P = 0.046). Multivariate analysis revealed that TROP2 expression was an independent prognostic marker for overall survival of ADC patients. Moreover, TROP2 overexpression enhanced cell proliferation, migration, and invasion in the NSCLC cell line A549, whereas knockdown of TROP2 induced apoptosis and impaired proliferation, migration, and invasion in the PC-9 cells. Altogether, our data suggest that TROP2 plays an important role in promoting ADC and may represent a novel prognostic biomarker and therapeutic target for the disease. PMID- 26773506 TI - Enhanced glucose tolerance by intravascularly administered piceatannol in freely moving healthy rats. AB - Piceatannol is a phytochemical in the seeds of passion fruit that has a hypoglycemic effect when orally administered. To elucidate the contribution of intact and metabolites of piceatannol after gastro-intestinal absorption to hypoglycemic effect, we examined the influence of piceatannol and isorhapontigenin on blood glucose concentrations during fasting and glucose tolerance tests by administering them intravascularly to freely moving healthy rats. We found that intravascularly administered piceatannol reduced the blood glucose concentrations during both fasting and glucose tolerance tests, but isorhapontigenin did not during either of them. Furthermore, we found that piceatannol increased the insulinogenic index during glucose tolerance tests and that piceatannol had no influence on insulin sensitivity by performing hyperinsulinemic euglycemic clamping tests. These results suggest that piceatannol orally intaken may enhance glucose tolerance by the effect of intact piceatannol through enhanced early-phase secretion of insulin. Therefore, oral intake of piceatannol might contribute to proper control of postprandial glycemic excursions in healthy subjects. PMID- 26773505 TI - Galactose-1 phosphate uridylyltransferase (GalT) gene: A novel positive regulator of the PI3K/Akt signaling pathway in mouse fibroblasts. AB - The vital importance of the Leloir pathway of galactose metabolism has been repeatedly demonstrated by various uni-/multicellular model organisms, as well human patients who have inherited deficiencies of the key GAL enzymes. Yet, other than the obvious links to the glycolytic pathway and glycan biosynthetic pathways, little is known about how this metabolic pathway interacts with the rest of the metabolic and signaling networks. In this study, we compared the growth and the expression levels of the key components of the PI3K/Akt growth signaling pathway in primary fibroblasts derived from normal and galactose-1 phosphate uridylyltransferase (GalT)-deficient mice, the latter exhibited a subfertility phenotype in adult females and growth restriction in both sexes. The growth potential and the protein levels of the pAkt(Thr308), pAkt(Ser473), pan Akt, pPdk1, and Hsp90 proteins were significantly reduced by 62.5%, 60.3%, 66%, 66%, and 50%, respectively in the GalT-deficient cells. Reduced expression of phosphorylated Akt proteins in the mutant cells led to diminished phosphorylation of Gsk-3beta (-74%). Protein expression of BiP and pPten were 276% and 176% higher respectively in cells with GalT-deficiency. Of the 24 genes interrogated using QIAGEN RT(2) Profiler PCR Custom Arrays, the mRNA abundance of Akt1, Pdpk1, Hsp90aa1 and Pi3kca genes were significantly reduced at least 2.03-, 1.37-, 2.45 , and 1.78-fold respectively in mutant fibroblasts. Both serum-fasted normal and GalT-deficient cells responded to Igf-1-induced activation of Akt phosphorylation at +15 min, but the mutant cells have lower phosphorylation levels. The steady state protein abundance of Igf-1 receptor was also significantly reduced in mutant cells. Our results thus demonstrated that GalT deficiency can effect down regulation of the PI3K/Akt growth signaling pathway in mouse fibroblasts through distinct mechanisms targeting both gene and protein expression levels. PMID- 26773507 TI - Desorption kinetics of cesium from Fukushima soils. AB - Understanding the behaviors of Cs(+) in soils is crucial for evaluation of the impacts of disposal of soils contaminated by radiocesium, (137)Cs. The desorption rate of Cs(+) evaluated in relatively short periods of time may not be adequate for such a purpose. In this study, we investigated long-term desorption kinetics of (137)Cs and (133)Cs from soils collected in Fukushima Prefecture by batch desorption experiments in the presence of cation exchange resin as a sorbent. The sorbent can keep the concentration of Cs(+) in the aqueous phase low and prevent re-sorption of desorbed Cs(+). Up to 60% of (137)Cs was desorbed after 139 d in dilute KCl media, which was larger than the desorption by conventional short-term extraction with 1 M ammonium acetate. Desorption of (137)Cs continued even after this period. It was also found that high concentration of K(+) prevented desorption of Cs(+) in the initial stage of desorption, but the effect was alleviated with time. The desorbed fraction of stable Cs was smaller than that of (137)Cs. This indicated that (137)Cs may gradually move to more stable states in soils. The half-life of (137)Cs desorption from the slowest sorption site was estimated to be at least two years by a three-site desorption model. PMID- 26773508 TI - A new version of the ERICA tool to facilitate impact assessments of radioactivity on wild plants and animals. AB - A new version of the ERICA Tool (version 1.2) was released in November 2014; this constitutes the first major update of the Tool since release in 2007. The key features of the update are presented in this article. Of particular note are new transfer databases extracted from an international compilation of concentration ratios (CRwo-media) and the modification of 'extrapolation' approaches used to select transfer data in cases where information is not available. Bayesian updating approaches have been used in some cases to draw on relevant information that would otherwise have been excluded in the process of deriving CRwo-media statistics. All of these efforts have in turn led to the requirement to update Environmental Media Concentration Limits (EMCLs) used in Tier 1 assessments. Some of the significant changes with regard to EMCLs are highlighted. PMID- 26773509 TI - Recovery of NORM from scales generated by oil extraction. AB - Scales, containing naturally occurring radioactive materials (NORM), are a major problem in oil production that lead to costly remediation and disposal programmes. In view of environmental protection, radio and chemical characterisation is an essential step prior to waste treatment. This study focuses on developing of a protocol to recover (226)Ra and (210)Pb from scales produced by petroleum industry. X-ray diffractograms of the scales indicated the presence of barite-strontium (Ba0.75Sr0.25SO4) and hokutolite (Ba0.69Pb0.31SO4) as main minerals. Quartz, galena and Ca2Al2SiO6(OH)2 or sphalerite and iron oxide were found in minor quantities. Incineration to 600 degrees C followed by enclosed-digestion and acid-treatment gave complete digestion. Using (133)Ba and (210)Pb tracers as internal standards gave recovery ranged 87-91% for (226)Ra and ca. 100% for (210)Pb. Radium was finally dissolved in concentrated sulphuric acid, while (210)Pb dissolved in the former solution as well as in 8 M nitric acid. Dissolving the scales would provide better estimation of their radionuclides contents, facilitate the determination of their chemical composition, and make it possible to recycle NORM wastes in terms of radionuclides production. PMID- 26773510 TI - Role of natural organic matter on iodine and (239)(,240)Pu distribution and mobility in environmental samples from the northwestern Fukushima Prefecture, Japan. AB - In order to assess how environmental factors are affecting the distribution and migration of radioiodine and plutonium that were emitted from the Fukushima Dai ichi Nuclear Power Plant (FDNPP) accident, we quantified iodine and (239,240)Pu concentration changes in soil samples with different land uses (urban, paddy, deciduous forest and coniferous forest), as well as iodine speciation in surface water and rainwater. Sampling locations were 53-63 km northwest of the FDNPP within a 75-km radius, in close proximity of each other. A ranking of the land uses by their surface soil (<4 cm) stable (127)I concentrations was coniferous forest > deciduous forest > urban > paddy, and (239,240)Pu concentrations ranked as deciduous forest > coniferous forest > paddy >= urban. Both were quite distinct from that of (134)Cs and (137)Cs: urban > coniferous forest > deciduous forest > paddy, indicating differences in their sources, deposition phases, and biogeochemical behavior in these soil systems. Although stable (127)I might not have fully equilibrated with Fukushima-derived (129)I, it likely still works as a proxy for the long-term fate of (129)I. Surficial soil (127)I content was well correlated to soil organic matter (SOM) content, regardless of land use type, suggesting that SOM might be an important factor affecting iodine biogeochemistry. Other soil chemical properties, such as Eh and pH, had strong correlations to soil (127)I content, but only within a given land use (e.g., within urban soils). Organic carbon (OC) concentrations and Eh were positively, and pH was negatively correlated to (127)I concentrations in surface water and rain samples. It is also noticeable that (127)I in the wet deposition was concentrated in both the deciduous and coniferous forest throughfall and stemfall water, respectively, comparing to the bulk rainwater. Further, both forest throughfall and stemflow water consisted exclusively of organo-iodine, suggesting all inorganic iodine in the original bulk deposition (~ 28.6% of total iodine) have been completely converted to organo-iodine. Fukushima-derived (239,240)Pu was detectable at a distance ~ 61 km away, NW of FDNPP. However, it is confined to the litter layer, even three years after the FDNPP accident-derived emissions. Plutonium-239,240 activities were significantly correlated with soil OC and nitrogen contents, indicating Pu may be associated with nitrogen-containing SOM, similar to what has been observed at other locations in the United States. Together, these finding suggest that natural organic matter (NOM) plays a key role in affecting the fate and transport of I and Pu and may warrant greater consideration for predicting long-term stewardship of contaminated areas and evaluating various remediation options in Japan. PMID- 26773511 TI - Sediment dynamics and heavy metal pollution history of the Cruhlig Lake (Danube Delta, Romania). AB - This is the first study reporting recent sedimentation rates data (e.g. the past 120-150 years) for the Cruhlig Lake situated in the Danube Delta. The aim of this study is to analyse the recent sedimentation rates using the (210)Pb dating method and identifying the heavy metal pollutants and their variability in time. Five sediment cores were taken with a gravity corer and - after drying the sliced samples-physical parameters, organic material and inorganic carbon content were determined. The total (210)Pb content was measured via (210)Po by alpha spectrometry, while supported (210)Pb was measured by (226)Ra (trough short life (222)Rn daughters) with HPGe detectors. Heavy metals were determined by ICP-MS; from the 64 measured elements, only exceeding values of Al, As, Cd, Co, Cs, Cr, Cu, Fe, Hg, K, Li, Mg, Mn, Ni, Pb and Zn are discussed. After applying the CRS model, ages and sedimentation rates were calculated. The average sedimentation rate of the Cruhlig Lake is 0.21 +/- 0.02 g/cm(2)y, Minimum values (0.05 +/- 0.003 g/cm(2)y) are registered along the eastern shoreline of the lake before 1913, while maximum values are recorded due to the flooding in 2006 in the western side (1.34 +/- 0.12 g/cm(2)y). Recent sedimentation rates divide the lake into three areas: the secluded eastern near shore part (0.63 +/- 0.07 g/cm(2)y), the centre of the lake (0.92 +/- 0.05 g/cm(2)y) and the dynamic western area, where most sediment transport takes place (1.13 +/- 0.01 g/cm(2)y). The sedimentation pattern proves this lake to be very sensitive to fluvial discharge fluctuations. The building of the Iron Gate dams (1972 and 1985) had a negative impact on the sedimentation decreasing it with 58.74%, while after 1989 these values grew 2.25 times. The lake received a quantity of sediment rich in heavy metals in 1992 +/- 3 y, which settled mostly on the eastern part. Values for Cd, Co, Cr, Hg, Pb and Zn are up to five times higher in 1980 +/- 5 y in the eastern part of the lake, while Cd, Co, Cr and Ni are twice as high as the values measured for the marine substrate. Values of As show increasing of up to 150% in 2006 +/- 2 y throughout the whole surface of the lake. PMID- 26773512 TI - Tritium dynamics in soils and plants grown under three irrigation regimes at a tritium processing facility in Canada. AB - The dynamics of tritium released from nuclear facilities as tritiated water (HTO) have been studied extensively with results incorporated into regulatory assessment models. These models typically estimate organically bound tritium (OBT) for calculating public dose as OBT itself is rarely measured. Higher than expected OBT/HTO ratios in plants and soils are an emerging issue that is not well understood. To support the improvement of models, an experimental garden was set up in 2012 at a tritium processing facility in Pembroke, Ontario to characterize the circumstances under which high OBT/HTO ratios may arise. Soils and plants were sampled weekly to coincide with detailed air and stack monitoring. The design included a plot of native grass/soil, contrasted with sod and vegetables grown in barrels with commercial topsoil under natural rain and either low or high tritium irrigation water. Air monitoring indicated that the plume was present infrequently at concentrations of up to about 100 Bq/m(3) (the garden was not in a major wind sector). Mean air concentrations during the day on workdays (HTO 10.3 Bq/m(3), HT 5.8 Bq/m(3)) were higher than at other times (0.7 2.6 Bq/m(3)). Mean Tissue Free Water Tritium (TFWT) in plants and soils and OBT/HTO ratios were only very weakly or not at all correlated with releases on a weekly basis. TFWT was equal in soils and plants and in above and below ground parts of vegetables. OBT/HTO ratios in above ground parts of vegetables were above one when the main source of tritium was from high tritium irrigation water (1.5-1.8). Ratios were below one in below ground parts of vegetables when irrigated with high tritium water (0.4-0.6) and above one in vegetables rain-fed or irrigated with low tritium water (1.3-2.8). In contrast, OBT/HTO ratios were very high (9.0-13.5) when the source of tritium was mainly from the atmosphere. TFWT varied considerably through time as a result of SRBT's operations; OBT/HTO ratios showed no clear temporal pattern in above or below ground plant parts. Native soil after ~20 years of operations at SRBT had high initial OBT that persisted through the growing season; little OBT formed in garden plot soil during experiments. High OBT in native soil appeared to be a signature of higher past releases at SRBT. This phenomenon was confirmed in soils obtained at another processing facility in Canada with a similar history. The insights into variation in OBT/HTO ratios found here are of regulatory interest and should be incorporated in assessment models to aid in the design of relevant environmental monitoring programs for OBT. PMID- 26773513 TI - The inhibitory effects of potassium chloride versus potassium silicate application on (137)Cs uptake by rice. AB - After the accident at the Fukushima Dai-ichi Nuclear Power Plant owned by the Tokyo Electric Power Company on 11 March 2011, potassium fertilizer was applied to agricultural fields in the southern Tohoku and northern Kanto regions of Japan to reduce the uptake of radiocesium by crops. In this study, we examined the effects of two types of potassium fertilizers, potassium chloride (a readily available potassium fertilizer) and potassium silicate (a slow-release potassium fertilizer), as well as a split application of potassium, on the accumulation of (137)Cs by rice plants in two pot experiments. The (137)Cs concentrations in the brown rice and in the above-ground plants were significantly lower after potassium chloride application than after potassium silicate application. The potassium ion (K(+)) concentrations in soil solutions sampled 9 and 21 d after transplanting were significantly higher for the potassium chloride application than for the potassium silicate application. The K(+) concentrations in soil solutions observed in the application of potassium silicate were similar to those in the treatment when no potassium was applied. This finding indicates that the application of potassium silicate did not sufficiently increase the available K(+) for rice plants in the soil, which led to a greater uptake of (137)Cs after the potassium silicate application than after the application of potassium chloride. The (137)Cs concentration in brown rice was higher in the split application of potassium fertilizer with the second application at the full heading stage than that without split application and the split application with the second application before heading. PMID- 26773515 TI - Effects of a ketogenic diet on ADHD-like behavior in dogs with idiopathic epilepsy. AB - OBJECTIVES: Epilepsy in humans and rodent models of epilepsy can be associated with behavioral comorbidities including an increased prevalence of attention deficit/hyperactivity disorder (ADHD). Attention-deficit/hyperactivity disorder symptoms and seizure frequency have been successfully reduced in humans and rodents using a ketogenic diet (KD). The aims of this study were (i) to describe the behavioral profile of dogs with idiopathic epilepsy (IE) while on a standardized nonketogenic placebo diet, to determine whether ADHD-like behaviors are present, and (ii) to examine the effect of a ketogenic medium chain triglyceride diet (MCTD) on the behavioral profile of dogs with idiopathic epilepsy (IE) compared with the standardized placebo control diet, including ADHD like behaviors. METHODS: A 6-month prospective, randomized, double-blinded, placebo-controlled, crossover dietary trial comparing the effects of the MCTD with a standardized placebo diet on canine behavior was carried out. Dogs diagnosed with IE, with a seizure frequency of at least 3 seizures in the past 3months (n=21), were fed the MCTD or placebo diet for 3months and were then switched to the alternative diet for 3months. Owners completed a validated behavioral questionnaire to measure 11 defined behavioral factors at the end of each diet period to report their dogs' behavior, with three specific behaviors hypothesized to be related to ADHD: excitability, chasing, and trainability. RESULTS: The highest scoring behavioral factors in the placebo and MCTD periods were excitability (mean+/-SE: 1.910+/-0.127) and chasing (mean+/-SE: 1.824+/ 0.210). A markedly lower trainability score (mean+/-SE: 0.437+/-0.125) than that of previously studied canine populations was observed. The MCTD resulted in a significant improvement in the ADHD-related behavioral factor chasing and a reduction in stranger-directed fear (p<0.05) compared with the placebo diet. The latter effect may be attributed to previously described anxiolytic effects of a KD. CONCLUSIONS: These data support the supposition that dogs with IE may exhibit behaviors that resemble ADHD symptoms seen in humans and rodent models of epilepsy and that a MCTD may be able to improve some of these behaviors, along with potentially anxiolytic effects. PMID- 26773516 TI - Discussing sexual health in patients with epilepsy: Clinicians don't ask, patients sometimes tell! PMID- 26773518 TI - Fertility in premenopausal women post autologous stem cell transplant with BEAM conditioning. AB - There is currently minimal data on fertility outcomes in premenopausal women undergoing autologous stem cell transplant (ASCT) with carmustine, etoposide, cytarabine and melphalan (BEAM) conditioning. A retrospective analysis of fertility outcomes in premenopausal females aged between 18 and 40 yr who underwent BEAM/ASCT for lymphoma between 1995 and 2011 was performed at four transplant centres. Of 41 premenopausal women who underwent BEAM conditioning, 25 met the inclusion criteria with the main exclusion criterion being inadequate documentation. Eighteen had Hodgkin lymphoma, and seven had non-Hodgkin lymphoma. Median number of chemotherapy regimens pretransplant was 2 (1-3). Seventeen women (68%) with a median age at transplant of 25 yr (range 17-33) recovered their menses. The comparative group without recovery was older with a median age of 34 yr (range 20-40) (P = 0.007). Ten patients, with a median age at transplant of 22 yr (range 17-30), had 15 naturally conceived pregnancies. Chemotherapy regimens and lymphoma type did not obviously influence the incidence of menses recovery or conception. The incidence of recovery of menses and fertility in premenopausal women undergoing BEAM/ASCT for lymphoma is substantial. Younger age at transplant correlates with superior fertility outcomes. PMID- 26773517 TI - IRS-1 Functions as a Molecular Scaffold to Coordinate IGF-I/IGFBP-2 Signaling During Osteoblast Differentiation. AB - Insulin like growth factor I (IGF-I) and insulin like growth factor binding protein-2 (IGFBP-2) function coordinately to stimulate AKT and osteoblast differentiation. IGFBP-2 binding to receptor protein tyrosine phosphatase beta (RPTPbeta) stimulates polymerization and inactivation of phosphatase activity. Because phosphatase and tensin homolog (PTEN) is the primary target of RPTPbeta, this leads to enhanced PTEN tyrosine phosphorylation and inactivation. However RPTPbeta inactivation also requires IGF-I receptor activation. The current studies were undertaken to determine the mechanism by which IGF-I mediates changes in RPTPbeta function in osteoblasts. IGFBP-2/IGF-I stimulated vimentin binding to RPTPbeta and this was required for RPTPbeta polymerization. Vimentin serine phosphorylation mediated its binding to RPTPbeta and PKCzeta was identified as the kinase that phosphorylated vimentin. To determine the mechanism underlying IGF-I stimulation of PKCzeta-mediated vimentin phosphorylation, we focused on insulin receptor substrate-1 (IRS-1). IGF-I stimulated IRS-1 phosphorylation and recruitment of PKCzeta and vimentin to phospho-IRS-1. IRS-1 immunoprecipitates containing PKCzeta and vimentin were used to confirm that activated PKCzeta directly phosphorylated vimentin. PKCzeta does not contain a SH 2 domain that is required to bind to phospho-IRS-1. To determine the mechanism of PKCzeta recruitment we analyzed the role of p62 (a PKCzeta binding protein) that contains a SH2 domain. Exposure to differentiation medium plus IGF-I stimulated PKCzeta/p62 association. Subsequent analysis showed the p62/PKCzeta complex was co-recruited to IRS-1. Peptides that disrupted p62/PKCzeta or p62/IRS-1 inhibited IGF-I/IGFBP-2 stimulated PKCzeta activation, vimentin phosphorylation, PTEN tyrosine phosphorylation, AKT activation, and osteoblast differentiation. The importance of these signaling events for differentiation was confirmed in primary mouse calvarial osteoblasts. These results demonstrate the cooperative interaction between RPTPbeta and the IGF-I receptor leading to a coordinated series of signaling events that are required for osteoblast differentiation. Our findings emphasize the important role IRS-1 plays in modulating these signaling events and confirm its essential role in facilitating osteoblast differentiation. (c) 2016 American Society for Bone and Mineral Research. PMID- 26773522 TI - Being Met as marked - patients' experiences of being infected with community acquired methicillin-resistant Staphylococcus aureus (MRSA). AB - BACKGROUND: It is known that patients who acquired methicillin-resistant Staphylococcus aureus (MRSA) in hospitals suffer and feel as plague. Moreover, the patient interaction with nurses and physicians is described as frightening. Little is known about patient experiences after having acquired CA-MRSA concerning care and everyday life. AIM: To reveal and interpret otherwise healthy patients' lived experiences of receiving care and their everyday life after having acquired community MRSA (CA-MRSA). METHODS: A phenomenological hermeneutic approach guided by Ricouer was conducted. Interviews with twelve patients were transcribed verbatim into a text. The text was analysed in three phases: naive understanding, structural analysis and comprehensive understanding to reveal a possible being in the world. In this study, this referred to what it means to be infected with CA-MRSA. RESULTS: The findings indicate that patients who acquired MRSA experience a changed body image. They suffer from ignorant and frightened behavior from healthcare workers, social contacts, and also of being bullied by colleagues. Despite this, patients assume great responsibility for protecting others. However, knowledgeable staff alleviate suffering and bring peace of mind to the patients. CONCLUSIONS: Preventing patient's feelings of being a pest, an outsider living with fear, requires urgent education and understanding about resistant bacteria and how to meet an infected patient. The results describing patients, affected with MRSA, may contribute and touch the readers to better understanding of patient's changed body image and suffering and how to mitigate these feelings. PMID- 26773523 TI - A multi-dimensional experiment for characterization of pore structure heterogeneity using NMR. AB - In a liquid saturated porous sample the spatial inhomogeneous internal magnetic field in general depends on the strength of the static magnetic field, the differences in magnetic susceptibilities, but also on the geometry of the porous network. To thoroughly investigate how the internal field can be used to determine various properties of the porous structure, we present a novel multi dimensional NMR experiment that enables us to measure several dynamic correlations in one experiment, and where all of the correlations involve the internal magnetic field and its dependence on the geometry of the porous network. (Correlations: internal gradient - pore size, internal gradient - magnetic susceptibility difference, internal gradient - longitudinal relaxation, longitudinal relaxation - magnetic susceptibility difference.) It is always a spatial average of the internal magnetic field, or one of the related properties, that is measured, which is important to take into consideration when analyzing the obtained results. We demonstrate how these correlations can be an indicator for pore structure heterogeneity, and focus in particular on how the effect from spatial averaging can be evaluated and taken into account in the different cases. PMID- 26773524 TI - Efficient high-resolution RF pulse design applied to simultaneous multi-slice excitation. AB - RF pulse design via optimal control is typically based on gradient and quasi Newton approaches and therefore suffers from slow convergence. We present a flexible and highly efficient method that uses exact second-order information within a globally convergent trust-region CG-Newton method to yield an improved convergence rate. The approach is applied to the design of RF pulses for single- and simultaneous multi-slice (SMS) excitation and validated using phantom and in vivo experiments on a 3T scanner using a modified gradient echo sequence. PMID- 26773525 TI - A fast field-cycling device for high-resolution NMR: Design and application to spin relaxation and hyperpolarization experiments. AB - A device for performing fast magnetic field-cycling NMR experiments is described. A key feature of this setup is that it combines fast switching of the external magnetic field and high-resolution NMR detection. The field-cycling method is based on precise mechanical positioning of the NMR probe with the mounted sample in the inhomogeneous fringe field of the spectrometer magnet. The device enables field variation over several decades (from 100MUT up to 7T) within less than 0.3s; progress in NMR probe design provides NMR linewidths of about 10(-3)ppm. The experimental method is very versatile and enables site-specific studies of spin relaxation (NMRD, LLSs) and spin hyperpolarization (DNP, CIDNP, and SABRE) at variable magnetic field and at variable temperature. Experimental examples of such studies are demonstrated; advantages of the experimental method are described and existing challenges in the field are outlined. PMID- 26773526 TI - SPIDYAN, a MATLAB library for simulating pulse EPR experiments with arbitrary waveform excitation. AB - Frequency-swept chirp pulses, created with arbitrary waveform generators (AWGs), can achieve inversion over a range of several hundreds of MHz. Such passage pulses provide defined flip angles and increase sensitivity. The fact that spectra are not excited at once, but single transitions are passed one after another, can cause new effects in established pulse EPR sequences. We developed a MATLAB library for simulation of pulse EPR, which is especially suited for modeling spin dynamics in ultra-wideband (UWB) EPR experiments, but can also be used for other experiments and NMR. At present the command line controlled SPin DYnamics ANalysis (SPIDYAN) package supports one-spin and two-spin systems with arbitrary spin quantum numbers. By providing the program with appropriate spin operators and Hamiltonian matrices any spin system is accessible, with limits set only by available memory and computation time. Any pulse sequence using rectangular and linearly or variable-rate frequency-swept chirp pulses, including phase cycling can be quickly created. To keep track of spin evolution the user can choose from a vast variety of detection operators, including transition selective operators. If relaxation effects can be neglected, the program solves the Liouville-von Neumann equation and propagates spin density matrices. In the other cases SPIDYAN uses the quantum mechanical master equation and Liouvillians for propagation. In order to consider the resonator response function, which on the scale of UWB excitation limits bandwidth, the program includes a simple RLC circuit model. Another subroutine can compute waveforms that, for a given resonator, maintain a constant critical adiabaticity factor over the excitation band. Computational efficiency is enhanced by precomputing propagator lookup tables for the whole set of AWG output levels. The features of the software library are discussed and demonstrated with spin-echo and population transfer simulations. PMID- 26773527 TI - Relative merits of rCW(A) and XiX heteronuclear spin decoupling in solid-state magic-angle-spinning NMR spectroscopy: A bimodal Floquet analysis. AB - We present a bimodal Floquet analysis of the recently introduced refocused continuous wave (rCW) solid-state NMR heteronuclear dipolar decoupling method and compare it with the similar looking X-inverse X (XiX) scheme. The description is formulated in the rf interaction frame and is valid for both finite and ideal pi pulse rCW irradiation that forms the refocusing element in the rCW scheme. The effective heteronuclear dipolar coupling Hamiltonian up to first order is described. The analysis delineates the difference between the two sequences to different orders of their Hamiltonians for both diagonal and off-diagonal parts. All the resonance conditions observed in experiments and simulations have been characterised and their influence on residual line broadening is highlighted. The theoretical comparison substantiates the numerical simulations and experimental results to a large extent. PMID- 26773514 TI - Adolescent neurobiological susceptibility to social context. AB - Adolescence has been characterized as a period of heightened sensitivity to social contexts. However, adolescents vary in how their social contexts affect them. According to neurobiological susceptibility models, endogenous, biological factors confer some individuals, relative to others, with greater susceptibility to environmental influences, whereby more susceptible individuals fare the best or worst of all individuals, depending on the environment encountered (e.g., high vs. low parental warmth). Until recently, research guided by these theoretical frameworks has not incorporated direct measures of brain structure or function to index this sensitivity. Drawing on prevailing models of adolescent neurodevelopment and a growing number of neuroimaging studies on the interrelations among social contexts, the brain, and developmental outcomes, we review research that supports the idea of adolescent neurobiological susceptibility to social context for understanding why and how adolescents differ in development and well-being. We propose that adolescent development is shaped by brain-based individual differences in sensitivity to social contexts - be they positive or negative - such as those created through relationships with parents/caregivers and peers. Ultimately, we recommend that future research measure brain function and structure to operationalize susceptibility factors that moderate the influence of social contexts on developmental outcomes. PMID- 26773528 TI - Microtesla NMR J-coupling spectroscopy with an unshielded atomic magnetometer. AB - We present experimental data and theoretical interpretation of NMR spectra of remotely magnetized samples, detected in an unshielded environment by means of a differential atomic magnetometer. The measurements are performed in an ultra-low field at an intermediate regime, where the J-coupling and the Zeeman energies have comparable values and produce rather complex line sets, which are satisfactorily interpreted. PMID- 26773529 TI - Anisotropy of spin-spin and spin-lattice relaxation times in liquids entrapped in nanocavities: Application to MRI study of biological systems. AB - Spin-spin and spin-lattice relaxations in liquid or gas entrapped in nanosized ellipsoidal cavities with different orientation ordering are theoretically investigated. The model is flexible in order to be applied to explain experimental results in cavities with various forms, from very prolate up to oblate ones, and different degree of ordering of nanocavities. In the framework of the considered model, the dipole-dipole interaction is determined by a single coupling constant, which depends on the form, size, and orientation of the cavity and number of nuclear spins in the cavity. It was shown that the transverse and longitudinal relaxation rates differently depend on the angle between the external magnetic field and cavity main axis. The calculation results for the local dipolar field, transverse and longitudinal relaxation times explain the angular dependencies observed in MRI experiments with biological objects: cartilage and tendon. Microstructure of these tissues can be characterized by the standard deviation of the Gaussian distribution of fibril orientations. The comparison of the theoretical and experimental results shows that the value of the standard deviation obtained at the matching of the calculation to experimental results can be used as a parameter characterizing the disorder in the biological sample. PMID- 26773530 TI - Molecular-Curvature-Induced Spontaneous Formation of Curved and Concentric Lamellae through Nucleation. AB - Spontaneous formation of concentric lamellae was observed in self-assembling giant surfactants consisting of a fluorinated polyhedral oligomeric silsesquioxane (FPOSS) head and flexible polymer tail(s). Owing to the asymmetrical sizes of the head and tail blocks and the rectangular molecular interface, the giant surfactants assumed a truncated-wedge-like molecular shape, which induced morphological curvature during self-assembly, thus resulting in the formation of curved and concentric lamellae. These curved/concentric lamellae were observed in FPOSS-based giant surfactants with different architectures and compositions. The spontaneous curvature formation not only promotes our fundamental understanding of assembly principles, but also provides a promising and efficient approach to the fabrication of a wide range of high-performance devices. PMID- 26773533 TI - A GC-FID method for quantitative analysis of N,N-carbonyldiimidazole. AB - N,N-Carbonyldiimidazole (CDI), a common synthetic reagent used in commercial scale pharmaceutical synthesis, is known to be sensitive to hydrolysis from ambient moisture. This liability demands a simple, robust analytical method to quantitatively determine reagent quality to ensure reproducible performance in chemical reactions. This work describes a protocol for a rapid GC-FID based analysis of CDI. PMID- 26773531 TI - Replication study of 34 common SNPs associated with prostate cancer in the Romanian population. AB - Prostate cancer is the third-most common form of cancer in men in Romania. The Romanian unscreened population represents a good sample to study common genetic risk variants. However, a comprehensive analysis has not been conducted yet. Here, we report our replication efforts in a Romanian population of 979 cases and 1027 controls, for potential association of 34 literature-reported single nucleotide polymorphisms (SNPs) with prostate cancer. We also examined whether any SNP was differentially associated with tumour grade or stage at diagnosis, with disease aggressiveness, and with the levels of PSA (prostate specific antigen). In the allelic analysis, we replicated the previously reported risk for 19 loci on 4q24, 6q25.3, 7p15.2, 8q24.21, 10q11.23, 10q26.13, 11p15.5, 11q13.2, 11q13.3. Statistically significant associations were replicated for other six SNPs only with a particular disease phenotype: low-grade tumour and low PSA levels (rs1512268), high PSA levels (rs401681 and rs11649743), less aggressive cancers (rs1465618, rs721048, rs17021918). The strongest association of our tested SNP's with PSA in controls was for rs2735839, with 29% increase for each copy of the major allele G, consistent with previous results. Our results suggest that rs4962416, previously associated only with prostate cancer, is also associated with PSA levels, with 12% increase for each copy of the minor allele C. The study enabled the replication of the effect for the majority of previously reported genetic variants in a set of clinically relevant prostate cancers. This is the first replication study on these loci, known to associate with prostate cancer, in a Romanian population. PMID- 26773532 TI - Vaginal Inflammation: Association between Leukocyte Concentration and Levels of Immune Mediators. AB - PROBLEM: A wide variety of mediators are involved in inflammatory processes. However, the identity of those participating in vaginal immune responses has not been established. We correlated extracellular matrix metalloproteinase inducer (EMMPRIN), matrix metalloproteinase-8 (MMP-8), hyaluronan (HA), hyaluronidase-1 (Hyal-1), human beta-defensin-2 (hBD2), and neutrophil gelatinase-associated lipocalin (NGAL) concentrations with the extent of leukocyte infiltration into the vagina and suggest their participation in vaginal inflammation. METHODS OF STUDY: Vaginal fluid was obtained from 233 women seen at the outpatient clinic in the Department of Obstetrics and Gynecology at Campinas University, Brazil. The magnitude of vaginal inflammation was determined by the leukocyte count on vaginal smears and categorized as no inflammation (0 leukocytes/field), moderate inflammation (1-4 leukocytes/field), and intense inflammation (>4 leukocytes/field). Concentrations of EMMPRIN, MMP-8, HA, Hyal-1, hBD2, and NGAL were determined in vaginal fluid by ELISA. RESULTS: EMMPRIN, MMP-8, HA, hBD2, and NGAL concentration increased with elevated leukocyte numbers (P < 0.05), while Hyal-1 did not. EMMPRIN concentrations were correlated with HA and MMP-8 levels. CONCLUSION: EMMPRIN, MMP-8, HA, beta-defensin, and NGAL are elevated in women with vaginal inflammation. PMID- 26773534 TI - Simultaneous determination of domperidone and Itopride in pharmaceuticals and human plasma using RP-HPLC/UV detection: Method development, validation and application of the method in in-vivo evaluation of fast dispersible tablets. AB - Domperidone and Itopride are pro-kinetic agents, regulating the gastric motility and are commonly prescribed as anti emetic drugs. In the present study a simple, rapid and sensitive RP-HPLC/UV method was developed for simultaneous determination of Domperidone and Itopride in pharmaceutical samples and human plasma, using Tenofavir as internal standard. Experimental conditions were optimized and method was validated according to the standard guidelines. Combination of water (pH 3.0) and acetonitrile (65:35 v/v) was used as mobile phase, pumped at the flow rate of 1.5 ml/min. Detector wavelength was set at 210 nm and column oven temperature was 40oC. Unlike conventional liquid-liquid extraction, simple precipitation technique was applied for drug extraction from human plasma using acetonitrile for deprotienation. The method showed adequate separation of both the analytes and best resolution was achieved using Hypersil BDS C8 column (150 mm * 4.6 mm, 5 MUm). The method was quite linear in the range of 20-600 ng/ml. Recovery of the method was 92.31% and 89.82% for Domperidone and Itopride, respectively. Retention time of both the analytes and internal standard was below 15 min. The lower limit of detection (LLOD) and lower limit of quantification (LLOQ) for Domperidone were 5 and 10 ng/ml while for Itopride was 12 and 15 ng/ml, respectively. The developed method was successfully applied for in-vivo analysis of fast dispersible tablets of Domperidone in healthy human volunteer. The proposed method was a part of formulation development study and was efficiently applied for determination of the two drugs in various pharmaceutical products and human plasma. PMID- 26773535 TI - Establishment and comparison of three novel methods for the determination of the photodynamic therapy agent 2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide-a (HPPH) in human serum. AB - 2-[1-Hexyloxyethyl]-2-devinyl pyropheophorbide-a (HPPH) is a second-generation photosensitizer that has been applied in clinical studies of photodynamic therapy for a variety of malignant lesions. Based on the differences in selectivity and labour intensity, three novel methods - fluorescence detection coupled with high performance liquid chromatography (LC-FLD), LC-tandem mass spectrometry (LC MS/MS) and fluorescence-based microplate reader methods - were developed for the determination of HPPH in human serum, which allowed comparison of fluorescence and MS platform for HPPH quantification. All three methods have been validated and successfully applied to support the clinical pharmacokinetic study of HPPH. The concentrations measured by LC-FLD matched those by LC-MS/MS with a correlation coefficient (r=0.994) and coefficient of determination (r(2)=0.989). Data consistency was also found between the measurements of microplate reader and LC-MS/MS with a correlation coefficient (r=0.999) and coefficient of determination (r(2)=0.998), indicating that fluorescence assay, the low cost alternative with a relatively poorer selectivity, is clearly suitable for the quantification of HPPH. Calibration curves in the methods of LC-FLD and microplate reader were linear (r?0.998) over the concentration range from 50 to 5000 ng/mL, and linearity was obtained over the concentration range from 5 to 1000 ng/mL in the LC-MS/MS method. Compared with the other two methods, the fluorescence-based microplate reader method with proven high selectivity should be strongly recommended because of obvious advantages such as the lowest labour intensity, the lowest instrument cost, a better sensitivity than LC-FLD and the very rapid determination of large number of samples (24 samples/40 s). PMID- 26773536 TI - Fast separation of triterpenoid saponins using supercritical fluid chromatography coupled with single quadrupole mass spectrometry. AB - Triterpenoid saponins (TSs) are the most important components of some traditional Chinese medicines (TCMs) and have exhibited valuable pharmacological properties. In this study, a rapid and efficient method was developed for the separation of kudinosides, stauntosides and ginsenosides using supercritical fluid chromatography coupled with single quadrupole mass spectrometry (SFC-MS). The separation conditions for the selected TSs were carefully optimized after the initial screening of eight stationary phases. The best compromise for all compounds in terms of chromatographic performance and MS sensitivity was obtained when water (5-10%) and formic acid (0.05%) were added to the supercritical carbon dioxide/MeOH mobile phase. Beside the composition of the mobile phase, the nature of the make-up solvent for interfacing SFC with MS was also evaluated. Compared to reversed phase liquid chromatography, the SFC approach showed higher resolution and shorter running time. The developed SFC-MS methods were successfully applied to the separation and identification of TSs present in Ilex latifolia Thunb., Panax quinquefolius L. and Panax ginseng C.A. Meyer. These results suggest that this SFC-MS approach could be employed as a useful tool for the quality assessment of natural products containing TSs as active components. PMID- 26773537 TI - Effects of ion source operating parameters on direct analysis in real time of 18 active components from traditional Chinese medicine. AB - Direct analysis in real time mass spectrometry (DART-MS) provides a new analytical method for traditional Chinese medicine (TCM). The present study investigated the effects of key ion source operating parameters on DART-MS analysis of various TCM active components. A total of 18 active components, including phenylpropanoids, alkaloids, saponins, flavones, volatile oils, and glycosides, were examined. For each substance, the peak area and signal-to-noise of its characteristic ions under different reagent gases and heater temperatures were compared. Based on the comparison, the relationships among chemical structures, ion source parameters and instrument responses were revealed. Finally, some suggestions about choosing reagent gas and heater temperature were proposed for types of TCM active substance, which offered a reference for the application of DART-MS on TCM analysis. PMID- 26773539 TI - The Effectiveness of Neck Stretching Exercises Following Total Thyroidectomy on Reducing Neck Pain and Disability: A Randomized Controlled Trial. AB - BACKGROUND: Although there are a limited number of studies showing effects of neck stretching exercises following a thyroidectomy in reducing neck discomfort symptoms, no study has specifically dealt with and examined the effect of neck stretching exercises on neck pain and disability. OBJECTIVE: To analyze the effect of neck stretching exercises, following a total thyroidectomy, on reducing neck pain and disability. METHODS: A randomized controlled trial was conducted. The participants were randomly assigned either to the stretching exercise group (n = 40) or to the control group (n = 40). The stretching exercise group learned the neck stretching exercises immediately after total thyroidectomy. The effects of the stretching exercises on the participants' neck pain and disability, neck sensitivity, pain with neck movements as well as on wound healing, were evaluated at the end of the first week and at 1 month following surgery. RESULTS: When comparing neck pain and disability scale (NPDS) scores, neck sensitivity and pain with neck movement before thyroidectomy, after 1 week and after 1-month time points, it was found that patients experienced significantly less pain and disability in the stretching exercise group than the control group (p < .001). At the end of the first week, the NPDS scores (mean [SD] = 8.82 [12.23] vs. 30.28 [12.09]), neck sensitivity scores (median [IR] = 0 [.75] vs. 2.00 [4.0]) and pain levels with neck movements (median [IR] = 0 [2.0] vs. 3.5 [5.75]) of the stretching exercise group were significantly lower than those of the control group. However, there was no significant difference between the groups with regard to the scores at the 1-month evaluation (p > .05). LINKING EVIDENCE TO ACTION: Neck stretching exercises done immediately after a total thyroidectomy reduce short-term neck pain and disability symptoms. PMID- 26773538 TI - Adjunctive Chinese Herbal Medicine therapy improves survival of patients with chronic myeloid leukemia: a nationwide population-based cohort study. AB - Despite good clinical results of current drugs, a good reason still exists to search for additional therapies for the management of Chronic Myeloid Leukemia (CML). Chinese Herbal Medicine (CHM) has thus far been overlooked by researchers and no data exists on the subject. We studied the impact of adjunctive CHM on the disease course of CML, using mortality as the major outcome measurement. We used the Taiwanese National Health Insurance Research Database to perform a nationwide population-based cohort study. Our study included CML patients diagnosed between 2000 and 2010. We matched groups according to age, sex, Charlson Comorbidity Index (CCI) score and use of imatinib, and compared the Hazard Ratios (HR) of CHM group and non-CHM users, as well as characterized trends of prescriptions used for treating CML. 1371 patients were diagnosed with CML in the years examined, of which 466 were included in to this study. We found that the HR of CHM group was significantly lower compared to non-CHM groups (0.32, 95% CI 0.22-0.48, P < 0.0001). We also established that this association between reduced HR was dose dependent, and the longer CHM users received prescriptions, the lower the HR (P < 0.01). We also analyzed the most commonly used herbal products as well as the HR associated to their use, thus providing future research candidates. Our results supply a strong reason to assume that when administered by properly trained physicians, CHM may have a substantial positive impact on the management of CML. PMID- 26773541 TI - Natural allelic variations of TCS1 play a crucial role in caffeine biosynthesis of tea plant and its related species. AB - Tea caffeine synthase 1 (TCS1) is an enzyme that catalyzes the methylation of N-3 and N-1 and considered to be the most critical enzyme in the caffeine biosynthetic pathway of tea plant. This study shows that TCS1 has six types of allelic variations, namely, TCS1a, TCS1b, TCS1c, TCS1d, TCS1e, and TCS1f, with a 252 bp insertion/deletion mutation in the 5'-untranslated region. Among tea plant and its related species, TCS1a is the predominant allele, and TCS1b-f are the rare alleles that mainly appear in few wild germplasms. The full-length cDNA sequences of three new alleles, namely, TCS1d, TCS1e, and TCS1f, were isolated from specific germplasms, and all of recombinant proteins have higher caffeine synthase (CS, EC 2.1.1.160) activity than theobromine synthase (TS, EC 2.1.1.159). Amino acid residue 269 is responsible for the difference in TCS activity and substrate recognition, which was demonstrated by using site-directed mutagenesis experiments. Furthermore, natural variations in TCS1 change the transcription levels. There are two molecular mechanisms controlling the caffeine biosynthesis in low-caffeine-accumulating tea germplasms, i.e., TCS1 allele with low transcription level or its encoded protein with only TS activity. Allelic variations of TCS1 play a crucial role in caffeine biosynthesis. Taken together, our work provides valuable foundation for a comprehensive understanding of the mechanism of caffeine biosynthesis in section Thea plants and useful guidance for effective breeding. PMID- 26773540 TI - Heterologous complementation studies reveal the solute transport profiles of a two-member nucleobase cation symporter 1 (NCS1) family in Physcomitrella patens. AB - As part of an evolution-function analysis, two nucleobase cation symporter 1 (NCS1) from the moss Physcomitrella patens (PpNCS1A and PpNCS1B) are examined- the first such analysis of nucleobase transporters from early land plants. The solute specificity profiles for the moss NCS1 were determined through heterologous expression, growth and radiolabeled uptake experiments in NCS1 deficient Saccharomyces cerevisiae. Both PpNCS1A and 1B, share the same profiles as high affinity transporters of adenine and transport uracil, guanine, 8 azaguanine, 8-azaadenine, cytosine, 5-fluorocytosine, hypoxanthine, and xanthine. Despite sharing the same solute specificity profile, PpNCS1A and PpNCS1B move nucleobase compounds with different efficiencies. The broad nucleobase transport profile of PpNCS1A and 1B differs from the recently-characterized Viridiplantae NCS1 in breadth, revealing a flexibility in solute interactions with NCS1 across plant evolution. PMID- 26773542 TI - Spatial and temporal distribution of genes involved in polyamine metabolism during tomato fruit development. AB - Polyamines are organic compounds involved in various biological roles in plants, including cell growth and organ development. In the present study, the expression profile, the accumulation of free polyamines and the transcript localisation of the genes involved in Put metabolism, such as Ornithine decarboxylase (ODC), Arginine decarboxylase (ADC) and copper containing Amine oxidase (CuAO), were examined during Solanum lycopersicum cv. Chiou fruit development and maturation. Moreover, the expression of genes coding for enzymes involved in higher polyamine metabolism, including Spermidine synthase (SPDS), Spermine synthase (SPMS), S adenosylmethionine decarboxylase (SAMDC) and Polyamine oxidase (PAO), were studied. Most genes participating in PAs biosynthesis and metabolism exhibited an increased accumulation of transcripts at the early stages of fruit development. In contrast, CuAO and SPMS were mostly expressed later, during the development stages of the fruits where a massive increase in fruit volume occurs, while the SPDS1 gene exhibited a rather constant expression with a peak at the red ripe stage. Although Put, Spd and Spm were all exhibited decreasing levels in developing immature fruits, Put levels maxed late during fruit ripening. In contrast to Put both Spd and Spm levels continue to decrease gradually until full ripening. It is worth noticing that in situ RNA-RNA hybridisation is reported for the first time in tomato fruits. The localisation of ADC2, ODC1 and CuAO gene transcripts at tissues such as the locular parenchyma and the vascular bundles fruits, supports the theory that all genes involved in Put biosynthesis and catabolism are mostly expressed in fast growing tissues. The relatively high expression levels of CuAO at the ImG4 stage of fruit development (fruits with a diameter of 3 cm), mature green and breaker stages could possibly be attributed to the implication of polyamines in physiological processes taking place during fruit ripening. PMID- 26773543 TI - Histone acetylation influences the transcriptional activation of POX in Beta vulgaris L. and Beta maritima L. under salt stress. AB - Acetylation of histone proteins is a type of chromatin modification which facilitates the activation of genes. Recent studies brought up the importance of this reversible and rapid process for the regulation of gene expression especially in plant defense against a variety of environmental stresses. Deciphering the exact mechanisms of chromatin modifications under abiotic stress conditions is important for improving crop plants' performance and yield. In a previous study we compared the salt stress responses of Beta vulgaris (sugar beet) and Beta maritima (wild beet). In accordance with those results we suggested that chromatin remodeling can be an active process in the regulation of genes related to salt stress tolerance of these plants. Therefore we performed ChIP assay in control and salt stressed (250 and 500 mM NaCl) plants and compared the enrichment of acetylation in the associated chromatin sites. We found that the transcriptional activation of one peroxidase (POX) encoding gene was associated with the elevated levels of acetylation in H3K9 and H3K27 sites. The acetylation patterns were remarkably different between two species in which the highest acetylation levels were found at H3K9 and H3K27 in wild beet and sugar beet respectively. PMID- 26773544 TI - Leaf malate and succinate accumulation are out of phase throughout the development of the CAM plant Ananas comosus. AB - In plants with Crassulacean Acid Metabolism (CAM), organic acids, mainly malate are crucial intermediates for carbon fixation. In this research we studied the circadian oscillations of three organic anions (malate, citrate, and succinate) in Ananas comosus, assessing the effect of season and plant development stage. Seasonal and plant development dependencies were observed. The circadian oscillations of malate and citrate were typical of CAM pathways reported in the literature. Citrate content was quite stable (25-30 MUmol g(-1) FW) along the day, with a seasonal effect. Succinate was shown to have both diurnal and seasonal oscillations and also a correlation with malate, since it accumulated during the afternoon when malate content was normally at a minimum, suggesting a possible mechanistic effect between both anions in CAM and/or respiratory metabolisms. PMID- 26773545 TI - Modification of oil and glucosinolate content in canola seeds with altered expression of Brassica napus LEAFY COTYLEDON1. AB - Over the last few decades, research focusing on canola (Brassica napus L.) seed oil content and composition has expanded. Oil production and accumulation are influenced by genes participating in embryo and seed development. The Arabidopsis LEAFY COTYLEDON1 (LEC1) is a well characterized regulator of embryo development that also enhances the expression of genes involved in fatty acid (FA) synthesis. B. napus lines over-expressing or down-regulating BnLEC1 were successfully generated by Agrobacterium-mediated transformation. The constitutive expression of BnLEC1 in B. napus var. Polo, increased seed oil content by 7-16%, while the down-regulation of BnLEC1 in B. napus var. Topas reduced oil content by 9-12%. Experimental manipulation of BnLEC1 caused transcriptional changes in enzymes participating in sucrose metabolism, glycolysis, and FA biosynthesis, suggesting an enhanced carbon flux towards FA biosynthesis in tissues over-expressing BnLEC1. The increase in oil content induced by BnLEC1 was not accompanied by alterations in FA composition, oil nutritional value or glucosinolate (GLS) levels. Suppression of BnLEC1 reduced seed oil accumulation and elevated the level of GLS possibly through the transcriptional regulation of BnST5a (Sulphotransferase5a), the last GLS biosynthetic enzyme. Collectively, these findings demonstrate that experimental alterations of BnLEC1 expression can be used to influence oil production and quality in B. napus. PMID- 26773546 TI - Liver mortality attributable to chronic hepatitis C virus infection in Denmark and Scotland--using spontaneous resolvers as the benchmark comparator. AB - Liver mortality among individuals with chronic hepatitis C (CHC) infection is common, but the relative contribution of CHC per se versus adverse health behaviors is uncertain. We explored data on spontaneous resolvers of hepatitis C virus (HCV) as a benchmark group to uncover the independent contribution of CHC on liver mortality. Using national HCV diagnosis and mortality registers from Denmark and Scotland, we calculated the liver mortality rate (LMR) for persons diagnosed with CHC infection (LMRchronic ) and spontaneously resolved infection (LMRresolved ), according to subgroups defined by age, sex, and drug use. Through these mortality rates, we determined subgroup-specific attributable fractions (AFs), defined as (LMRchronic - LMRresolved )/LMRchronic , and then calculated the total attributable fraction (TAF) as a weighted average of these AFs. Thus, the TAF represents the overall fraction (where 0.00 = not attributable at all; and 1.00 = entirely attributable) of liver mortality attributable to CHC in the diagnosed population. Our cohort comprised 7,005 and 21,729 persons diagnosed with HCV antibodies in Denmark and Scotland, respectively. Mean follow-up duration was 6.3-6.9 years. The TAF increased stepwise with age. It was lowest for death occurring at <45 years of age (0.21 in Denmark; 0.26 in Scotland), higher for death occurring at 45-59 years (0.69 in Denmark; 0.69 in Scotland), and highest for death at 60+years (0.92 in Denmark; 0.75 in Scotland). Overall, the TAF was 0.66 (95% confidence interval [CI]: 0.55-0.78) in Denmark and 0.55 (95% CI: 0.44-0.66) in Scotland. CONCLUSIONS: In Denmark and Scotland, the majority of liver death in the CHC-diagnosed population can be attributed to CHC nevertheless, an appreciable fraction cannot, cautioning that liver mortality in this population is a compound problem that can be reduced, but not solved, through antiviral therapy alone. PMID- 26773547 TI - Risk factors associated with portomesenteric venous thrombosis in patients undergoing restorative proctocolectomy for medically refractory ulcerative colitis. AB - AIM: Data on risk factors for portomesenteric venous thrombosis (PMVT) following abdominal surgery for ulcerative colitis (UC) are limited. The aim of this study was to investigate factors associated with PMVT after surgical treatment for UC. METHOD: Patients who underwent restorative proctocolectomy (RPC) and ileal pouch anal anastomosis (IPAA) including diverting ileostomy closure for medically refractory UC were identified from a prospectively maintained database. Patient related, disease-related and treatment-related variables were collected. Univariable and multivariable analyses were performed to assess factors associated with PMVT. RESULTS: Of the 521 patients completing surgical treatment for UC between 2006 and 2012, symptomatic PMVT occurred in 36 (7%), which resulted in a significantly increased hospital stay (P < 0.001). Patients developing PMVT were younger (P = 0.014), had a lower preoperative albumin level (P = 0.037) and were more likely to have been taking steroids within 1 month before surgery (P = 0.006). The combined incidence of PMVT was comparable between patients having a three-stage and two-stage management (6% vs. 8%, P = 0.43), but the relative incidence of PMVT after RPC + IPAA was 8%, significantly higher than the 4% after total abdominal colectomy (TAC) (P = 0.005) and the 2% after subsequent completion proctectomy (CP) + IPAA (P = 0.038). Multivariate analysis confirmed that RPC + IPAA was associated with a significantly greater risk of PMVT than CP + IPAA (OR = 4.9, P = 0.003) or TAC (OR = 3.5, P = 0.011). Preoperative steroid use was an independent factor for PMVT (OR = 5.8, P = 0.006). CONCLUSION: Steroid use 1 month before surgery is associated with an increased risk of PMVT. A staged restorative proctocolectomy does not increase the overall incidence of PMVT. PMID- 26773550 TI - Proteogenomics of rare taxonomic phyla: A prospective treasure trove of protein coding genes. AB - Sustainable innovations in sequencing technologies have resulted in a torrent of microbial genome sequencing projects. However, the prokaryotic genomes sequenced so far are unequally distributed along their phylogenetic tree; few phyla contain the majority, the rest only a few representatives. Accurate genome annotation lags far behind genome sequencing. While automated computational prediction, aided by comparative genomics, remains a popular choice for genome annotation, substantial fraction of these annotations are erroneous. Proteogenomics utilizes protein level experimental observations to annotate protein coding genes on a genome wide scale. Benefits of proteogenomics include discovery and correction of gene annotations regardless of their phylogenetic conservation. This not only allows detection of common, conserved proteins but also the discovery of protein products of rare genes that may be horizontally transferred or taxonomy specific. Chances of encountering such genes are more in rare phyla that comprise a small number of complete genome sequences. We collated all bacterial and archaeal proteogenomic studies carried out to date and reviewed them in the context of genome sequencing projects. Here, we present a comprehensive list of microbial proteogenomic studies, their taxonomic distribution, and also urge for targeted proteogenomics of underexplored taxa to build an extensive reference of protein coding genes. PMID- 26773555 TI - Ruthenium-based nitric oxide-donating and carbon monoxide-donating molecules. AB - OBJECTIVES: Over the past few years, the use of metallocomplexes for medical purposes has considerably grown. Because of its favourable characteristics, ruthenium has taken a significant place in this expanding field of research. Several ruthenium-containing metal compounds have been developed as delivery agents of physiological important molecules such as nitric oxide (NO) and carbon monoxide (CO). KEY FINDINGS: This review focuses on the (vaso)relaxant capacity of ruthenium-based NO-donating and CO-donating molecules in view of their potential usefulness in the treatment of cardiovascular diseases and erectile dysfunction. SUMMARY: Ruthenium seems to be a valuable candidate for the design of NO-donating and CO-donating molecules. To date, ruthenium remains of interest in drug research as the search for new alternatives is still necessary. PMID- 26773556 TI - Fatigue toughness of irradiated vitamin E/UHMWPE blends. AB - Radiation cross-linked ultrahigh molecular weight polyethylenes (UHMWPEs) have become the standard-of-care in total joint replacements (TJR) in the last decade because of their superior wear resistance in comparison with previously used "conventional" gamma sterilized UHMWPE. Some first generation radiation cross linked UHMWPEs were stabilized against oxidation by post-irradiation melting, which significantly reduced their fatigue crack propagation resistance or fatigue toughness. Second generation cross-linked UHMWPEs incorporated instead an antioxidant such as vitamin E, eliminating the need for melting. In this study, we investigated the fatigue crack propagation resistance and the impact toughness of vitamin E-blended and radiation cross-linked UHMWPEs as a function of vitamin E concentration and radiation dose. Both properties were strongly dependent on the cross-link density and they showed a good correlation with each other (R(2) = 0.89). (c) 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:1514-1520, 2016. PMID- 26773558 TI - Peptidoglycan microarray as a novel tool to explore protein-ligand recognition. AB - Peptidoglycan is a giant bag-shaped molecule essential for bacterial cell shape and resistance to osmotic stresses. The activity of a large number of bacterial surface proteins involved in cell growth and division requires binding to this macromolecule. Recognition of peptidoglycan by immune effectors is also crucial for the establishment of the immune response against pathogens. The availability of pure and chemically defined peptidoglycan fragments is a major technical bottleneck that has precluded systematic studies of the mechanisms underpinning protein-mediated peptidoglycan recognition. Here, we report a microarray strategy suitable to carry out comprehensive studies to characterize proteins peptidoglycan interactions. We describe a method to introduce a functional group on peptidoglycan fragments allowing their stable immobilization on amorphous carbon chip plates to minimize nonspecific binding. Such peptidoglycan microarrays were used with a model peptidoglycan binding protein-the human peptidoglycan recognition protein-S (hPGRP-S). We propose that this strategy could be implemented to carry out high-throughput analyses to study peptidoglycan binding proteins. (c) 2016 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 106: 422-429, 2016. PMID- 26773557 TI - Insulin degludec/insulin aspart once daily in Type 2 diabetes: a comparison of simple or stepwise titration algorithms (BOOST(r) : SIMPLE USE). AB - AIMS: To compare the efficacy and safety of two titration algorithms for insulin degludec/insulin aspart (IDegAsp) administered once daily with metformin in participants with insulin-naive Type 2 diabetes mellitus. METHODS: This open label, parallel-group, 26-week, multicentre, treat-to-target trial, randomly allocated participants (1:1) to two titration arms. The Simple algorithm titrated IDegAsp twice weekly based on a single pre-breakfast self-monitored plasma glucose (SMPG) measurement. The Stepwise algorithm titrated IDegAsp once weekly based on the lowest of three consecutive pre-breakfast SMPG measurements. In both groups, IDegAsp once daily was titrated to pre-breakfast plasma glucose values of 4.0-5.0 mmol/l. Primary endpoint was change from baseline in HbA1c (%) after 26 weeks. RESULTS: Change in HbA1c at Week 26 was IDegAspSimple -14.6 mmol/mol ( 1.3%) (to 52.4 mmol/mol; 6.9%) and IDegAspStepwise -11.9 mmol/mol (-1.1%) (to 54.7 mmol/mol; 7.2%). The estimated between-group treatment difference was -1.97 mmol/mol [95% confidence interval (CI) -4.1, 0.2] (-0.2%, 95% CI -0.4, 0.02), confirming the non-inferiority of IDegAspSimple to IDegAspStepwise (non inferiority limit of <= 0.4%). Mean reduction in fasting plasma glucose and 8 point SMPG profiles were similar between groups. Rates of confirmed hypoglycaemia were lower for IDegAspStepwise [2.1 per patient years of exposure (PYE)] vs. IDegAspSimple (3.3 PYE) (estimated rate ratio IDegAspSimple /IDegAspStepwise 1.8; 95% CI 1.1, 2.9). Nocturnal hypoglycaemia rates were similar between groups. No severe hypoglycaemic events were reported. CONCLUSIONS: In participants with insulin-naive Type 2 diabetes mellitus, the IDegAspSimple titration algorithm improved HbA1c levels as effectively as a Stepwise titration algorithm. Hypoglycaemia rates were lower in the Stepwise arm. PMID- 26773559 TI - Differential Neuronal Plasticity of Dental Pulp Stem Cells From Exfoliated Deciduous and Permanent Teeth Towards Dopaminergic Neurons. AB - Based on early occurrence in chronological age, stem-cells from human exfoliated deciduous teeth (SHED) has been reported to possess better differentiation potential toward certain cell-lineage in comparison to stem-cells from adult teeth (DPSCs). Whether this same property between them extends for the yield of functional central nervous system neurons is still not evaluated. Hence, we aim to assess the neuronal plasticity of SHED in comparison to DPSCs toward dopaminergic-neurons and further, if the difference is reflected in a differential expression of sonic-hedgehog (SHH)-receptors and basal-expressions of tyrosine-hydroxylase [TH; through cAMP levels]. Human SHED and DPSCs were exposed to midbrain-cues [SHH, fibroblast growth-factor8, and basic fibroblast growth-factor], and their molecular, immunophenotypical, and functional characterization was performed at different time-points of induction. Though SHED and DPSCs spontaneously expressed early-neuronal and neural-crest marker in their naive state, only SHED expressed a high basal-expression of TH. The upregulation of dopaminergic transcription-factors Nurr1, Engrailed1, and Pitx3 was more pronounced in DPSCs. The yield of TH-expressing cells decreased from 49.8% to 32.16% in SHED while it increased from 8.09% to 77.47% in DPSCs. Dopamine release and intracellular-Ca(2+) influx upon stimulation (KCl and ATP) was higher in induced DPSCs. Significantly lower-expression of SHH-receptors was noted in naive SHED than DPSCs, which may explain the differential neuronal plasticity. In addition, unlike DPSCs, SHED showed a down-regulation of cyclic adenosine monophosphate (cAMP) upon exposure to SHH; possibly another contributor to the lesser differentiation-potential. Our data clearly demonstrates for the first time that DPSCs possess superior neuronal plasticity toward dopaminergic-neurons than SHED; influenced by higher SHH-receptor and lower basal TH expression. J. Cell. Physiol. 231: 2048-2063, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26773562 TI - Atypical myopathy - insights on pathogenesis. PMID- 26773563 TI - Levanase from Bacillus subtilis hydrolyses beta-2,6 fructosyl bonds in bacterial levans and in grass fructans. AB - A Levanase, LevB, from Bacillus subtilis 168, was expressed as a His6-tagged protein in Escherichia coli. The enzyme was purified and characterised for its activity and substrate specificity. LevB has a pH optimum of 6.0-6.5 and a maximum observed specific activity of 3 U mg(-1) using levan from Erwinia herbicola as substrate. Hydrolysis products were analysed by HPAEC, TLC, and NMR using chicory root inulin, mixed linkage fructans purified from ryegrass (Lolium perenne) and levan from E. herbicola as substrates. This revealed that LevB is an endolevanase that selectively cleaves the (beta-2,6) fructosyl bonds and does not hydrolyse inulin. Ryegrass fructans and bacterial levan was hydrolysed partially releasing oligosaccharides, but together with exoinulinase, LevB hydrolysed both ryegrass fructans and bacterial levan to near completion. We suggest that LevB can be used as a tool to achieve more structural information on complex fructans and to achieve complete degradation and quantification of mixed linkage fructans. PMID- 26773564 TI - Diagnostic accuracy of endoscopic features of pediatric acute gastrointestinal graft-versus-host disease. AB - BACKGROUND AND AIM: Acute gastrointestinal graft-versus-host disease (GI-GVHD) is a major cause of morbidity and mortality after hematopoietic stem cell transplantation (HSCT). There are very few studies on specific endoscopic findings in pediatric acute GI-GVHD. The aim of this retrospective case-control study was to elucidate the characteristic endoscopic findings in pediatric acute GI-GVHD that improve the diagnostic accuracy of endoscopy. METHODS: All consecutive patients under 18 years of age who underwent allogeneic HSCT in Kyoto University Hospital from May 2003 to October 2014 were identified retrospectively. Patients who underwent GI endoscopy as a result of sustained GI symptoms were identified. Intestinal villous patterns were evaluated by magnification endoscopy with the water-immersion technique. The patients were diagnosed with acute GI-GVHD and non-GVHD on the basis of biopsy histology. Endoscopic findings of the two groups were compared. RESULTS: Of the 171 patients who underwent HSCT, 30 underwent GI endoscopy. Of these, 17 and nine were diagnosed with acute GI-GVHD and non-GVHD, respectively. Compared with non-GVHD, acute GI-GVHD was associated significantly more often with short blunt villi in the duodenum (P = 0.013), variable defect villi and short blunt villi in the ileum (P = 0.009 and 0.035, respectively), and edema, erosion, and tortoiseshell like mucosae in the colon (P = 0.017, 0.023, and 0.017, respectively). CONCLUSION: Pediatric acute GI-GVHD was associated with several characteristic features on magnifying endoscopy with the water-immersion technique. These features will be useful for endoscopic diagnosis of pediatric acute GI-GVHD. PMID- 26773561 TI - On using ethical principles of community-engaged research in translational science. AB - The transfer of new discoveries into both clinical practice and the wider community calls for reliance on interdisciplinary translational teams that include researchers with different areas of expertise, representatives of health care systems and community organizations, and patients. Engaging new stakeholders in research, however, calls for a reconsideration or expansion of the meaning of ethics in translational research. We explored expert opinion on the applicability of ethical principles commonly practiced in community-engaged research (CEnR) to translational research. To do so, we conducted 2 online, modified-Delphi panels with 63 expert stakeholders who iteratively rated and discussed 9 ethical principles commonly used in CEnR in terms of their importance and feasibility for use in translational research. The RAND/UCLA appropriateness method was used to analyze the data and determine agreement and disagreement among participating experts. Both panels agreed that ethical translational research should be "grounded in trust." Although the academic panel endorsed "culturally appropriate" and "forthcoming with community about study risks and benefits," the mixed academic-community panel endorsed "scientifically valid" and "ready to involve community in interpretation and dissemination" as important and feasible principles of ethical translational research. These findings suggest that in addition to protecting human subjects, contemporary translational science models need to account for the interests of, and owe ethical obligations to, members of the investigative team and the community at large. PMID- 26773560 TI - Establishing and maintaining cell polarity with mRNA localization in Drosophila. AB - How cell polarity is established and maintained is an important question in diverse biological contexts. Molecular mechanisms used to localize polarity proteins to distinct domains are likely context-dependent and provide a feedback loop in order to maintain polarity. One such mechanism is the localized translation of mRNAs encoding polarity proteins, which will be the focus of this review and may play a more important role in the establishment and maintenance of polarity than is currently known. Localized translation of mRNAs encoding polarity proteins can be used to establish polarity in response to an external signal, and to maintain polarity by local production of polarity determinants. The importance of this mechanism is illustrated by recent findings, including orb2-dependent localized translation of aPKC mRNA at the apical end of elongating spermatid tails in the Drosophila testis, and the apical localization of stardust A mRNA in Drosophila follicle and embryonic epithelia. PMID- 26773566 TI - Supramolecular Porphyrin-Based Metal-Organic Frameworks with Fullerenes: Crystal Structures and Preferential Intercalation of C70. AB - The syntheses and characterization of two new porphyrin-based metal-organic frameworks (P-MOFs), through the complexation of 5,10,15,20-tetra-4-pyridyl-21 H,23 H-porphine (H2 TPyP) and copper(II) acetate (CuAcO) in the presence of the fullerenes C60 or C70 are reported. Complex 1 was synthesized in conjunction with C60 , and this reaction produced a two-dimensional (2D) porous structure with the composition CuAcO-CuTPyP?m-dichlorobenzene (m-DCB), in which C60 molecules were not intercalated. Complex 2 was synthesized in the presence of C70 , generating a three-dimensional (3D) porous structure, in which C70 was intercalated, with the composition CuAcO-CuTPyP?C70 ?m-DCB?CHCl3 . The structures of these materials were determined by X-ray diffraction to identify the supramolecular interactions that lead to 2D and 3D crystal packing motifs. When a combination of C60 and C70 was employed, C70 was found to be preferentially intercalated between the porphyrins. PMID- 26773565 TI - Electrophoretic separation method for membrane pore-forming proteins in multilayer lipid membranes. AB - In this paper, we report on a novel electrophoretic separation and analysis method for membrane pore-forming proteins in multilayer lipid membranes (MLMs) in order to overcome the problems related to current separation and analysis methods of membrane proteins, and to obtain a high-performance separation method on the basis of specific properties of the lipid membranes. We constructed MLMs, and subsequently characterized membrane pore-forming protein behavior in MLMs. Through the use of these MLMs, we were able to successfully separate and analyze membrane pore-forming proteins in MLMs. To the best of our knowledge, this research is the first example of membrane pore-forming protein separation in lipid membranes. Our method can be expected to be applied for the separation and analysis of other membrane proteins including intrinsic membrane proteins and to result in high-performance by utilizing the specific properties of lipid membranes. PMID- 26773567 TI - Individual and joint effects of risk factors for onset widespread pain and obesity - a population-based prospective cohort study. AB - BACKGROUND: Widespread musculoskeletal pain (WSP) and obesity frequently co-occur and may have shared risk factors. We aimed to investigate whether four dichotomized risk factors individually or jointly increase the risk for the onset of WSP and onset of obesity. METHODS: Persons aged 34-76 years in 2004 living in Ullensaker municipality, Norway, responded to questionnaires in 2004 and 2010 (n = 1553). Using causal interaction analyses, we examined whether baseline obesity and WSP, poor sleep quality, mental distress and poor physical fitness jointly increased the risk of new onset WSP (>=3 pain sites leading to disability the last year) and new onset obesity (self-reported BMI >=30 kg/m(2) ) in persons without WSP (n = 1270) or without obesity (n = 1300) at baseline respectively. RESULTS: The mean (SD) age was 51 (12.1) years and 56% were female. The incidence of WSP and obesity were 9.1% and 5.4%. Mental distress and poor sleep quality individually and jointly with poor physical fitness increased WSP onset risk (relative excess risk due to interaction [RERI] = 1.90, 95% CI, 0.39-3.42 and RERI = 1.43, 95% CI, 0.10-2.76). Poor physical fitness individually increased the risk for new onset obesity, and baseline WSP and poor sleep quality jointly (RERI = 1.87, 95% CI, 0.49-3.24). The presence of more risk factors was dose dependently associated with onset WSP and to a lesser extent with onset obesity. CONCLUSION: The onset of WSP and the onset of obesity were results of joint effects of exposures. Poor physical fitness was a key covariate in increasing the risk for both conditions. WHAT DOES THIS STUDY ADD?: In a general population, the new onset of widespread pain and new onset of obesity were results of joint effects of risk factors and particularly poor physical fitness. The study may aid in the identification of patients at risk of future disability. PMID- 26773568 TI - Ezh2 regulates the Lin28/let-7 pathway to restrict activation of fetal gene signature in adult hematopoietic stem cells. AB - Fetal liver hematopoietic stem cells (HSCs) seed bone marrow (BM) and undergo reprograming into adult-type HSCs that are largely quiescent and restricted in their self-renewal activity. Here we report that in the absence of the polycomb group gene Ezh2, a cohort of fetal-specific genes, including let-7 target genes, were activated in BM hematopoietic stem/progenitor cells (HSPCs), leading to acquisition of fetal phenotypes by BM HSPCs, such as enhanced self-renewal activity and production of fetal-type lymphocytes. The Lin28b/let-7 pathway determines developmentally timed changes in HSPC programs. Of note, many of the fetal-specific let-7 target genes, including Lin28, appear to be transcriptionally repressed by Ezh2-mediated H3K27me3 in BM HSPCs, and Ezh2 loss results in their ectopic expression, particularly in hematologic malignancies that develop in the absence of Ezh2. These findings suggest that Ezh2 cooperates with let-7 microRNAs in silencing the fetal gene signature in BM HSPCs and restricts their transformation. PMID- 26773570 TI - Left Ventricular End-Systolic Eccentricity Index for Assessment of Pulmonary Hypertension in Infants. AB - BACKGROUND: Pulmonary hypertension (PH) is a common problem in the neonatal intensive care unit and is associated with significant morbidity and mortality. The aim of this study was to identify a quantitative echocardiographic marker of septal curvature that can be used to accurately identify PH in NICU infants with concern for PH. METHODS: Echocardiograms of infants who were prematurely born and infants with persistent pulmonary hypertension of the newborn were performed using a defined protocol for evaluation of PH. Qualitative assessment by a single pediatric cardiologist was used as a reference standard. Qualitative and quantitative parameters of right ventricular (RV) size, pressure, and function were documented. Left ventricular end-systolic eccentricity index (EI) was defined as the ratio of the anterior-inferior and septal-posterolateral cavity dimensions at the mid-ventricular level. RESULTS: A total of 216 infants at risk for PH were included in this study. One hundred forty-three (66%) had an interpretable tricuspid regurgitation jet velocity. While systolic septal flattening was recognized at EIs >= 1.15, more than half-systemic RV pressure became apparent at EIs >= 1.3. Unlike qualitative assessment of septal flattening, there was high inter-observer agreement for EIs. Quantitative parameters of RV systolic function were impaired only at EIs >= 1.3. CONCLUSIONS: We suggest that EIs should be incorporated into routine protocols when there is a concern for PH in neonates. This may lead to a more reliable assessment of PH and may reduce inter-observer variability. Correlation of EIs with invasive hemodynamic data is needed to validate our results. PMID- 26773569 TI - Evolving insights into the synergy between erythropoietin and thrombopoietin and the bipotent erythroid/megakaryocytic progenitor cell. AB - Although the synergy between erythropoietin and thrombopoietin has previously been pointed out, the clonal demonstration of a human bipotent erythroid/megakaryocytic progenitor (MEP) was first published in Experimental Hematology (Papayannopoulou T, Brice M, Farrer D, Kaushansky K. Exp Hematol. 1996;24:660-669) and later in the same year in Blood (Debili N, Coulombel L, Croisille L, et al. Blood. 1996;88:1284-1296). This demonstration, and the fact that both bipotent and monopotent erythroid or megakaryocytic progenitors co express markers of both lineages and respond to both lineage-specific transcription factors, has provided a background for the extensive use of MEP assessment by fluorescence-activated cell sorting in many subsequent studies. Beyond this, the demonstration of shared regulatory elements and the presence of single mutations affecting both lineages have inspired further studies to decipher how the shift in transcription factor networks occurs from one lineage to the other. Furthermore, in addition to shared effects, erythropoietin and thrombopoietin have additional independent effects. Most notable for thrombopoietin is its effect on hematopoietic stem cells illustrated by in vitro and in vivo approaches. PMID- 26773572 TI - Treatment of muscle-invasive bladder cancer: A systematic review. AB - There is uncertainty regarding the use of bladder-sparing alternatives to standard radical cystectomy, optimal lymph node dissection techniques, and optimal chemotherapeutic regimens. This study was conducted to systematically review the benefits and harms of bladder-sparing therapies, lymph node dissection, and systemic chemotherapy for patients with clinically localized muscle-invasive bladder cancer. Systematic literature searches of MEDLINE (from 1990 through October 2014), the Cochrane databases, reference lists, and the ClinicalTrials.gov Web site were performed. A total of 41 articles were selected for review. Bladder-sparing therapies were found to be associated with worse survival compared with radical cystectomy, although the studies had serious methodological shortcomings, findings were inconsistent, and only a few studies evaluated currently recommended techniques. More extensive lymph node dissection might be more effective than less extensive dissection at improving survival and decreasing local disease recurrence, but there were methodological shortcomings and some inconsistency. Six randomized trials found cisplatin-based combination neoadjuvant chemotherapy to be associated with a decreased mortality risk versus cystectomy alone. Four randomized trials found adjuvant chemotherapy to be associated with decreased mortality versus cystectomy alone, but none of these trials reported a statistically significant effect. There was insufficient evidence to determine optimal chemotherapeutic regimens. PMID- 26773573 TI - VariOtator, a Software Tool for Variation Annotation with the Variation Ontology. AB - The Variation Ontology (VariO) is used for describing and annotating types, effects, consequences, and mechanisms of variations. To facilitate easy and consistent annotations, the online application VariOtator was developed. For variation type annotations, VariOtator is fully automated, accepting variant descriptions in Human Genome Variation Society (HGVS) format, and generating VariO terms, either with or without full lineage, that is, all parent terms. When a coding DNA variant description with a reference sequence is provided, VariOtator checks the description first with Mutalyzer and then generates the predicted RNA and protein descriptions with their respective VariO annotations. For the other sublevels, function, structure, and property, annotations cannot be automated, and VariOtator generates annotation based on provided details. For VariO terms relating to structure and property, one can use attribute terms as modifiers and evidence code terms for annotating experimental evidence. There is an online batch version, and stand-alone batch versions to be used with a Leiden Open Variation Database (LOVD) download file. A SOAP Web service allows client programs to access VariOtator programmatically. Thus, systematic variation effect and type annotations can be efficiently generated to allow easy use and integration of variations and their consequences. PMID- 26773571 TI - HRAS mutation prevalence and associated expression patterns in pheochromocytoma. AB - Pheochromocytomas (PCC) and abdominal paragangliomas (PGL) display a highly diverse genetic background and recent gene expression profiling studies have shown that PCC and PGL (together PPGL) alter either kinase signaling pathways or the pseudo-hypoxia response pathway dependent of the genetic composition. Recurrent mutations in the Harvey rat sarcoma viral oncogene homolog (HRAS) have recently been verified in sporadic PPGLs. In order to further establish the HRAS mutation frequency and to characterize the associated expression profiles of HRAS mutated tumors, 156 PPGLs for exon 2 and 3 hotspot mutations in the HRAS gene was screened, and compared with microarray-based gene expression profiles for 93 of the cases. The activating HRAS mutations G13R, Q61R, and Q61K were found in 10/142 PCC (7.0%) and a Q61L mutation was revealed in 1/14 PGL (7.1%). All HRAS mutated cases included in the mRNA expression profiling grouped in Cluster 2, and 21 transcripts were identified as altered when comparing the mutated tumors with 91 HRAS wild-type PPGL. Somatic HRAS mutations were not revealed in cases with known PPGL susceptibility gene mutations and all HRAS mutated cases were benign. The HRAS mutation prevalence of all PPGL published up to date is 5.2% (49/950), and 8.8% (48/548) among cases without a known PPGL susceptibility gene mutation. The findings support a role of HRAS mutations as a somatic driver event in benign PPGL without other known susceptibility gene mutations. HRAS mutated PPGL cluster together with NF1- and RET-mutated tumors associated with activation of kinase signaling pathways. PMID- 26773574 TI - The assessment of thrombotic markers utilizing ionic versus non-ionic contrast during coronary angiography and intervention trial. AB - OBJECTIVE: To determine how two different types of iodinated contrast media (CM), low-osmolar ionic dimer ioxaglate (Hexabrix) and iso-osmolar non-ionic dimer iodixanol (Visipaque), affect multiple indices of hemostasis. BACKGROUND: In vitro models demonstrate differential effects of ionic and non-ionic CM on markers of hemostasis. METHODS: This blinded endpoint trial randomized 100 patients to ioxaglate or iodixanol. The primary endpoint was change in endogenous thrombin potential (ETP) following diagnostic angiography. Secondary endpoints included change in markers of fibrinolysis [tissue plasminogen activator (tPA) and plasminogen activator inhibitor 1 (PAI-1)] and platelet aggregation following diagnostic angiography and percutaneous coronary intervention (PCI) with bivalirudin. Data are presented as median [interquartile range]. RESULTS: ETP significantly decreased after diagnostic angiography in both ioxaglate (baseline 1810 nM*minute [1540-2089] to post-angiography 649 nM*minute [314-1347], p < 0.001) and iodixanol groups (baseline 1682 nM*minute [1534-2147] to post angiography 681 nM*minute [229-1237], p < 0.001), but the decrease was not different between CM (p = 0.70). There was a significant increase in ETP during PCI (n = 45), despite the use of bivalirudin, suggesting a prothrombotic effect of PCI (post-angiography 764 nM*minute [286-1283] to post-PCI 1081 nM*minute [668 1552], p = 0.02). There were no significant differential effects on tPA, PAI-1, and markers of platelet activity. CONCLUSION: There were no significant differential effects between ioxaglate and iodixanol. Both CM led to significant reductions in thrombin generation and no significant effects on fibrinolytic activity or platelet activity, thereby contributing to a favorable antithrombotic milieu. (c) 2016 Wiley Periodicals, Inc. PMID- 26773575 TI - c.376G>A mutation in WFS1 gene causes Wolfram syndrome without deafness. AB - Wolfram syndrome is one of the rare autosomal recessive, progressive, neurodegenerative disorders, characterized by diabetes mellitus and optic atrophy. Several other features are observed in patients including deafness, ataxia, and peripheral neuropathy. A gene called WFS1 is identified on chromosome 4p, responsible for Wolfram syndrome. We investigated a family consisted of parents and 8 children, which 5 of them have been diagnosed for Wolfram syndrome. WFS1 gene in all family members was sequenced for causative mutations. A mutation (c.376G>A, p.A126T) was found in all affected members in homozygous state and in both parents in heterozygous state. The bioinformatics analysis showed the deleterious effects of this nucleotide change on the structure and function of the protein product. As all of the patients in the family showed the homozygote mutation, and parents were both heterozygote, this mutation is probably the cause of the disease. We identified this mutation in homozygous state for the first time as Wolfram syndrome causation. We also showed that this mutation probably doesn't cause deafness in affected individuals. PMID- 26773576 TI - A family with the Arg103Pro mutation in the NEUROD1 gene detected by next generation sequencing - Clinical characteristics of mutation carriers. AB - Until now only a few families with early onset autosomal diabetes due to the NEUROD1 gene mutations have been identified. Moreover, only some of them meet strict MODY (maturity-onset diabetes of the young) criteria. Next-generation sequencing (NGS) provides an opportunity to detect more pathogenic mutations in this gene. Here, we evaluated the segregation of the Arg103Pro mutation in the NEUROD1 gene in a pedigree in which it was detected, and described the clinical characteristics of the mutation carriers. METHODS: We included 156 diabetic probands of MODY families, among them 52 patients earlier tested for GCK-MODY and/or HNF1A-MODY by Sanger sequencing with negative results. Genetic testing was performed by targeted NGS sequencing using a panel of 28 monogenic diabetes genes. RESULTS: As detected by NGS, one patient had the missense Arg103Pro (CGC/CCC) mutation in the gene NEUROD1 changing the amino-acid structure of the DNA binding domain of this transcription factor. We confirmed this sequence difference by Sanger sequencing. This family had previously been tested with negative results for HNF1A gene mutations. 17 additional members of this family were invited for further testing. We confirmed the presence of the mutation in 11 subjects. Seven adult mutation carriers (all but one) from three generations had been already diagnosed with diabetes. There were 3 individuals with the Arg103Pro mutation diagnosed before the age of 30 years in the family. The range of age of the four unaffected mutation carriers (3 minors and 1 adult) was 3-48 years. Interestingly, one mutation carrier had a history of transient neonatal hypoglycemia, of which the clinical course resembled episodes typical for HNF4A MODY. CONCLUSIONS: We report a family with autosomal dominant diabetes related to a new NEUROD1 mutation, one of very few meeting MODY criteria. The use of the NGS method will facilitate identification of more families with rare forms of MODY. PMID- 26773578 TI - Characterization of immunoglobulins through analysis of N-glycopeptides by MALDI TOF MS. AB - The aim of this report is to emphasize the role, usefulness and power of matrix assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) in the analysis of glycoforms of antibodies (Abs) through their proteolytic glycopeptides. Abs are complex biomolecules in which glycans hold determinant properties and thus need to be thoroughly characterized following Ab production by recombinant methods or Ab collection from human/animal serum or tissue. In spite of the great robustness of MALDI-TOF MS in terms of tolerance to impurities, the analysis of Abs and Ab components using this technique requires extensive sample preparation involving all or some of chromatography, solid phase extraction, enzymatic modification, and chemical derivatization. This report focuses on a monoclonal Ab produced in cell culture, as well as on a polyclonal human immunoglobulin (Ig) G obtained commercially and a polyclonal porcine IgG obtained from serum. A method is first provided to separate Ab protein chain components (light chains, heavy chains) by gel electrophoresis, which is useful for instance for protein-A eluates of Igs either from cell culture or biological samples. This allows for in-gel proteolytic digestion of the protein gel band(s) of choice for further MS characterization. Also discussed is the more conventional in-solution overnight digestion method used here with each of two proteolytic enzymes, i.e. trypsin and chymotrypsin. The overnight method is in turn compared with a much faster approach, that of digesting Abs with trypsin or chymotrypsin through the action of microwave heating. For method comparison, glycopeptides are fractionated from digestion mixtures using mostly C-18 cartridges for simplicity, although this enrichment procedure is also compared with other published procedures. The advantages of MALDI tandem mass spectrometry are highlighted for glycopeptide analysis, and lastly an esterification method applied to glycopeptides is discussed for retention of sialic acid residues on peptide acidic glycoforms. PMID- 26773579 TI - [Muscular dystrophies: From Duchenne to Becker]. PMID- 26773577 TI - An Open Letter to the Food and Drug Administration Regarding the Use of Morcellation Procedures in Women Having Surgery for Presumed Uterine Myomas. PMID- 26773580 TI - [Genetic counseling in dystrophinopathies]. AB - Genetic counseling in dystrophinopathies makes it possible to diagnose carriers, assess the risk for descendents, and discuss the different possibilities for having a boy without the disease: prenatal diagnosis, preimplantation diagnosis, ovocyte donation, and adoption. The different stages of each proposal are detailed. Prenatal diagnosis and preimplantation diagnosis can occur only within a highly defined legal framework. Invasive prenatal diagnosis in particular brings up the risk of miscarriage or termination of pregnancy for medical reasons. Preimplantation diagnosis is the study of the genetic characteristics of a 3-day-old embryo. It is proposed to couples who risk transmitting a particularly serious genetic disease to their child as an alternative to prenatal diagnosis. It requires turning to medically assisted reproduction for couples who do not necessarily present sterility problems. Preimplantation diagnosis requires a highly committed clinical and biological multidisciplinary team. It is very stressful for couples, both physically and psychologically. Technological advances (new-generation sequencing) suggests that noninvasive prenatal diagnosis may be possible in the years to come. PMID- 26773581 TI - [Duchenne muscular dystrophy pathophysiology]. AB - Dystrophin is a large cytoskeletal protein located at the plasma membrane in both muscle and non-muscle tissues, which mediates interactions between the cytoskeleton, cell membrane, and extracellular matrix. Dystrophin is a key component of multiprotein complexes (dystrophin- associated glycoprotein complex, or DGC). It is also involved in many intracellular cascades affecting membrane proteins such as calcium channels, or various signalisation pathways. In Duchenne Muscular Dystrophy, both dystrophin and DGC proteins are missing. This induces excessive membrane fragility and permeability, dysregulation of calcium homeostasis, oxidative damage, which in turn favour muscle cell necrosis. The latter is initially followed by regeneration. With age, the regenerative capacity of the muscles appears to be exhausted and muscle fibres are gradually replaced by connective and adipose tissue. PMID- 26773582 TI - [Diagnosis and natural history of Duchenne muscular dystrophy]. AB - Duchenne myopathy is today the most frequently encountered progressive muscular dystrophy in children, with an inexorable, progressive development to death in the third decade. Improvement in survival is related to improvement in orthopaedic management, early screening of cardiac and respiratory complications, but no curative therapy can be applied today beyond recent pharmacogenetic advances. This diagnosis is raised with evidence of proximal muscular deficit beginning after an interval free of symptoms lasting from 1 to several years. Muscular dystrophy's mechanism is suggested by a significant increase in CK (creatine kinase) and confirmed by muscle biopsy. The clinical motor and cognitive heterogeneity of this disease and its natural history need to be well known because it conditions future therapeutic trials. Identification of outcome measures such as the 6-minute walk test, the MFM score, manual muscle testing musculaire, or biomarkers is indispensable for patient follow-up and collaborative studies. PMID- 26773583 TI - [Genetics and molecular aspects of dystrophinopathies]. AB - Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are caused by mutations in the DMD gene that encodes the cytoskeletal protein, dystrophin. Dystrophinopathies are inherited in an X-linked recessive manner. Due to the tremendous size of the gene (2.2 megabases), the DMD locus has a high spontaneous mutation rate, and one third of sporadic cases of DMD are due to a de novo mutation. There are seven tissue-specific promoters in the gene. The skeletal muscular transcript contains 79 exons and encode the full-length protein (427 kDa) located at the inner face of the sarcolemma of muscle fibers. DMD gene mutations are highly heterogeneous. Large rearrangements (deletions or duplications of one or more exons) are most frequently involved while point mutations account for 20 %-30 % of cases. A survey of current strategies of molecular diagnosis is presented here. In particular, the role of muscle biopsy (for dystrophin and RNA analyses) in the diagnosis of dystrophinopathies is discussed. In more than 90 % of cases, the clinical severity is correlated with the impact of the mutations on the reading frame and the expression of the dystrophin (absence or residual amount of mutated protein). Various mechanisms contribute to the exceptions. Besides the clinical interest for the patient, the identification of the mutation allows accurate genetic counseling in the familles, and is a necessary prerequisite for the inclusion of the patient in the genotype-based clinical trials. PMID- 26773584 TI - [Specific features of Becker Muscular Dystrophy patients and female carriers of Duchenne Muscular Dystrophy]. AB - Becker muscular dystrophy (BMD) was first described in 1955 and linked to the DMD gene in 1987. Compared to Duchenne muscular dystrophy (DMD), clinical onset of BMD usually occurs after the age of 12 and wheelchair is required after the age of 16. BMD is characterized by generalized weakness first affecting limb girdle muscles, hypertrophy of the calves and cardiomyopathy in males. Some patients have only mild symptoms such as cramps or elevated serum creatine kinases (SCK) throughout all their lives. SCK levels are usually elevated. Muscle biopsy (immunohistochemistry or immunoblotting) shows a dystrophic pattern with abnormal dystrophin staining. Diagnosis is confirmed by DMD gene sequencing. Deletions or duplications of one or several exons are identified in the majority of cases. A multidisciplinary approach is recommended for the care management of these patients with a particular attention to the cardiomyopathy, which is typically responsible for death but can be prevented by specific treatment. X-linked dilated cardiomyopathies linked to DMD gene are a phenotypic continuum of BMD. Some female carriers of DMD mutations exhibit clinical symptoms of variable severity, often milder and beginning later than in males. The cardiomyopathy is the most frequent feature that should be especially monitored in these patients. Genetic counselling should be systematically proposed. PMID- 26773585 TI - [Cardiac involvement in dystrophinopathies]. AB - Dystrophinopathies may be associated with dilated cardiomyopathy, characterized by an impairment of left ventricular ejection fraction and potentially complicated by clinical heart failure. Conduction system disease and supraventricular or ventricular arrhythmias may also be present. The prevalence of cardiomyopathy is extremely high in Duchenne muscular dystrophy, intermediate in Becker dystrophy, and lower in female carriers. Cardiac follow-up is indicated in any patient with a mutation in the dystrophin gene, based on electrocardiogram and echocardiography, and must be closer, at least on a yearly basis, in patients with the highest cardiac risk. Systematic cardiac workups allow an earlier diagnosis of cardiac involvement and a prompt treatment. First-line treatments are angiotensin-converting-enzyme inhibitors and other heart failure treatments, which must be systematically initiated at the age of 10 years or earlier in Duchenne muscular dystrophy and regarding the identification of cardiac abnormalities in any patient with other dystrophinopathies. PMID- 26773586 TI - [Functional and orthopaedic aspects of dystrophinopathies]. AB - Although the clinical picture and the natural progression of Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) differ, borderline forms exist. Classical orthopaedic treatment is based on self-rehabilitation (by the parents and the patient), physical therapy, posture alignment with orthotics, ergotherapy to set up technical aides, notably positioning in an electric wheelchair to provide more satisfactory autonomy. The functional aspect predominates over pure orthopaedics. Although surgical indications have evolved for the lower limbs, pelvic-spinal arthrodesis for treatment of scoliosis remains the reference treatment, but the methods have evolved since the advent of corticotherapy for DMD. Corticotherapy slows the progression of motor deficits, the age at which walking ability is lost is delayed (shifting from 10 years to 13 14 years depending on the studies), scoliosis progresses later, respiratory insufficiency is better controlled, and therefore survival is prolonged (between 20 and 40 years). However, although this functional aspect seems to respond better to the progress in overall treatment, it also results from a multidisciplinary approach to the disease. Nevertheless, assessment is required, not at a time t as reflected by the scales currently in use, but during daily activities as proposed by qualitative and quantitative monitoring seeking to model nyctohemeral functional motor skills. The principle is to characterize the type of activity (sitting, standing, lying down, walking), its duration, its intensity (walking speed), its frequency (number of activity changes, number of walking episodes), and their sequence (temporal sequence, organization of activity variation). The goal is to identify the variety of functional motor skills and their occurrence over time to determine whether treatment contributes a functional benefit and whether this benefit is put into practice daily. PMID- 26773587 TI - [Respiratory and intensive care aspects of muscular dystrophies]. AB - Among the various myopathies, Duchenne muscular dystrophy represents the myopathy with the most stereotypical respiratory evolution. This progressive respiratory failure is going to develop in a parallel way of motor deficit, conducting patients to mechanical ventilation at the end of their second decade. In the absence of curative therapeutics, respiratory cares like home ventilation and prevention of respiratory complications, in a systematic and organized way, allowed to decrease the morbidity and the mortality of these patients. It is not exceptional to meet patients with life expectancy of which overtakes about forty. Besides axial stabilization, cough assistance techniques and swallowing disorders management need to be associated to mechanical ventilation. Invasive techniques of ventilation as tracheostomy keep their place in this pathology even if alternative techniques allowing full day non-invasive ventilation were generalized these last years. PMID- 26773588 TI - [Central manifestations of dystrophinopathies]. AB - The dystrophin gene involved in Duchenne and Becker muscular dystrophy is expressed in three main tissues resulting in clinical manifestations: skeletal muscle, heart and central nervous system. The 6 different existing dystrophins in the brain may play a role in the maturation and plasticity of neuronal synapses in particular by their functions in clustering and stabilization of different receptors at the post synaptic membrane. The possibility of an intellectual deficiency in Duchenne muscular dystrophy is known from the original description by Duchenne himself. Current data are in line with a constant cognitive impairment with a Gaussian curve shifted intellectual quotient (IQ) at -1 standard deviation from the standard population with an average IQ around 80. Clinical manifestations suggestive of a central nervous system involvement can affect all dystrophinopathies, including isolated central presentations without myopathic sign. The phenotypic spectrum appears broader and more subtle than non specific intellectual deficiency. The isolated or shared involvement of specific cognitive functions is possible (memory functions, executive functions, attention) with or without intellectual deficiency. Autism spectrum disorders are also among the encountered events. In clinical practice, it seems worth to ask for a measurement of serum creatine kinase (CK) in these different situations, keeping in mind that pure forms of central dystrophinopathies with a normal CK level have been recently reported. PMID- 26773589 TI - [The basic concept of therapeutic approaches for DMD]. AB - Duchenne muscular dystrophy (DMD) is the most frequent hereditary neuromuscular disorder in childhood. Over the past 30 years, increasingly better standards of care have considerably improved the quality of life as well as the life expectancy of DMD patients. Despite such progress in disease management, DMD remains a devastating disorder with continuous decline of motor and cardiac function. Until recently, corticosteroids were the only treatment available to slow down, however modestly, disease progression. Importantly, novel innovative therapeutic approaches are currently being developed. This review discusses the rational and underlying molecular mechanism of these novel strategies as well as the progress made by recent clinical trials. Importantly, these new therapeutic advances bear the potential to profoundly modify the disease course of DMD. PMID- 26773590 TI - [Principles of multidisciplinary management of Duchenne muscular dystrophy]. AB - Given the gradual progression observed in Duchenne muscular dystrophy, organization of care in multidisciplinary consultations is essential for optimal management of the different aspects of the disease. Drawing up a care plan is always preceded by a specific consultation for the announcement of the diagnosis with both the parents and the child. Explaining to the child the origin of his problems with simple words, telling him that why he experienced a particular symptom has been understood, is a fundamental step. The child needs to receive the information at different times of the disease following the rhythms of the disease stages, with an appropriate lead time. With the progress achieved in managing this disease, more than 90% of these children now live into adulthood. The switch from pediatric consultations to adult consultations, marking the transition from childhood management at adulthood, is a major challenge in the organization of care. Although today death occurs most often in adulthood, some children die in childhood. For the majority of teams who care for children, whatever the initial pathology may be, the notion of care continuity and accompaniment from the announcement of the disease to the terminal phase is essential. Increasing numbers of therapeutic trials have been developed over the past few years aiming to investigate children with DMD. However, they must not neglect the overall management of these patients and provide the best accompaniment possible. PMID- 26773594 TI - Observation of Main-Group Tricarbonyls [B(CO)3 ] and [C(CO)3 ](+) Featuring a Tilted One-Electron Donor Carbonyl Ligand. AB - A combined experimental and theoretical study on the main-group tricarbonyls [B(CO)3 ] in solid noble-gas matrices and [C(CO)3 ](+) in the gas phase is presented. The molecules are identified by comparing the experimental and theoretical IR spectra and the vibrational shifts of nuclear isotopes. Quantum chemical ab initio studies suggest that the two isoelectronic species possess a tilted eta(1) (MU1 -CO)-bonded carbonyl ligand, which serves as an unprecedented one-electron donor ligand. Thus, the central atoms in both complexes still retain an 8-electron configuration. A thorough analysis of the bonding situation gives quantitative information about the donor and acceptor properties of the different carbonyl ligands. The linearly bonded CO ligands are classical two-electron donors that display classical sigma-donation and pi-back-donation following the Dewar-Chatt-Duncanson model. The tilted CO ligand is a formal one-electron donor that is bonded by sigma-donation and pi-back-donation that involves the singly occupied orbital of the radical fragments [B(CO)2 ] and [C(CO)2 ](+) . PMID- 26773595 TI - Mainly subarachnoid amyloid angiopathy with pseudotumoral course. PMID- 26773596 TI - Palliative Care in Heart Failure. AB - Heart failure (HF) is a leading cause of morbidity and mortality worldwide, with limited curative options. Palliative care is a holistic, symptom based approach to patients that has been proven to improve the quality of life for both patients and their caregivers. In this review we will summarize the epidemiology of end stage HF and the data supporting the use of palliative care in this patient population. We will also review basic principles of palliative care as they apply to caring for end stage patients. PMID- 26773597 TI - Evaluation of the efficiency and safety in cosmetic products. AB - Chemicals used in cosmetics have to interact with enzymes for beneficial or destroy purpose after they enter in our body. Active sections of enzymes that catalyze reactions have three dimensions and they are active optically. When these limitations of catalytic sections are considered, it may be considered that defining geometric specifications of chemical materials and functional groups they contain may contribute on safety evaluations of cosmetic products. In this study, defining similarities and differences of geometric structures of chemicals that are prohibited to be used in cosmetic products and chemical that are allowed to be used by using group theory and analyze of functional groups that are often encountered in these chemicals are aimed. Molecule formulas related to chemical material of, 276 pieces chemicals that are prohibited to be used in cosmetic products and 65 pieces chemicals that are allowed, are used as the material. Two and three-dimension structures of these formulas are drawn and types and quantity of functional groups they contain are defined. And as a method, freeware (Free Trial) version of "Chem-BioOffice Ultra 13.0 Suite" chemical drawing program to draw two and three-dimension of formulas, "Campus-Licensed" version that are provided for use by our university of "Autodesk 3DS Max" for three-dimension drawings are used. In order to analyze geometric specifications of drawn molecules according to Group Theory and define type and quantity of available functional groups, Excel applications developed by Prof. Dr. Yasar Demir are used. PMID- 26773591 TI - Potentially diagnostic electron paramagnetic resonance spectra elucidate the underlying mechanism of mitochondrial dysfunction in the deoxyguanosine kinase deficient rat model of a genetic mitochondrial DNA depletion syndrome. AB - A novel rat model for a well-characterized human mitochondrial disease, mitochondrial DNA depletion syndrome with associated deoxyguanosine kinase (DGUOK) deficiency, is described. The rat model recapitulates the pathologic and biochemical signatures of the human disease. The application of electron paramagnetic (spin) resonance (EPR) spectroscopy to the identification and characterization of respiratory chain abnormalities in the mitochondria from freshly frozen tissue of the mitochondrial disease model rat is introduced. EPR is shown to be a sensitive technique for detecting mitochondrial functional abnormalities in situ and, here, is particularly useful in characterizing the redox state changes and oxidative stress that can result from depressed expression and/or diminished specific activity of the distinct respiratory chain complexes. As EPR requires no sample preparation or non-physiological reagents, it provides information on the status of the mitochondrion as it was in the functioning state. On its own, this information is of use in identifying respiratory chain dysfunction; in conjunction with other techniques, the information from EPR shows how the respiratory chain is affected at the molecular level by the dysfunction. It is proposed that EPR has a role in mechanistic pathophysiological studies of mitochondrial disease and could be used to study the impact of new treatment modalities or as an additional diagnostic tool. PMID- 26773598 TI - Characterization of a food-based enteric coating for capsules and its compatibility with an alternative sealing method. AB - Efficiency of a new protein-based enteric coating for capsules was studied. Coating physical-chemical properties were compared to those obtained from a well known methacrylate-based enteric coating (Eudragit). Swelling in simulated gastric fluid (SGF) was 20 times higher than for Eudragit films. Mechanical properties (elastic modulus, elongation and puncture strength at break) were comparable to those measured from a standard Eudragit formulation. Pilot-scale coating trials were performed following three methods: using a standard spray-gun configuration, using a HPC-based seal-coat prior to enteric coating and using an "inverted" spray-gun configuration. The effect of these methods on capsules sealing and in vitro gastric performance was studied. In vitro tests were performed following the two USP official methods: disintegration and dissolution. Inverted gun configuration and HPC-sealing showed the highest sealing efficiency and the best in vitro performance. Capsules with a weight gain of 14-16% generally passed all USP tests (no disintegration evidence after 60 min in SGF; release below 10% after 2h of experiments in SGF). However, in some cases, slight differences between results obtained from dissolution and disintegration tests were pointed out. This work demonstrates the potential of a protein-based enteric coating and underlines the importance of capsules sealing. PMID- 26773599 TI - Hydrophobic ion pairing of a minocycline/Ca(2+)/AOT complex for preparation of drug-loaded PLGA nanoparticles with improved sustained release. AB - Polymeric nanoparticles is an established and efficient means to achieve controlled release of drugs. Incorporation of minocycline, an antibiotic with anti-inflammatory and neuroprotective properties, into biodegradable nanoparticles may therefore provide an efficient means to combat foreign body reactions to implanted electrodes in the brain. However, minocycline is commonly associated with poor encapsulation efficiencies and/or fast release rates due to its high solubility in water. Moreover, minocycline is unstable under conditions of low and high pH, heat and exposure to light, which exacerbate the challenges of encapsulation. In this work drug loaded PLGA nanoparticles were prepared by a modified emulsification-solvent-diffusion technique and characterized for size, drug encapsulation and in vitro drug release. A novel hydrophobic ion pair complex of minocycline, Ca(2+) ions and the anionic surfactant AOT was developed to protect minocycline from degradation and prolong its release. The optimized formulation resulted in particle sizes around 220 nm with an entrapment efficiency of 43% and showed drug release over 30 days in artificial cerebrospinal fluid. The present results constitute a substantial increase in release time compared to what has hitherto been achieved for minocycline and indicate that such particles might provide useful for sustained drug delivery in the CNS. PMID- 26773601 TI - Role of scavenger receptors in peptide-based delivery of plasmid DNA across a blood-brain barrier model. AB - Receptor-mediated transcytosis remains a major route for drug delivery across the blood-brain barrier (BBB). PepFect 32 (PF32), a peptide-based vector modified with targeting ligand (Angiopep-2) binding to low-density lipoprotein receptor related protein-1 (LRP-1), was previously found to be a promising vector for plasmid delivery across an in vitro model of the BBB. Cellular uptake of PF32/plasmid DNA (pDNA) complexes was speculated the internalization via LRP-1 receptor. In this study, we prove that PF32/pDNA nanocomplexes are not only transported into brain endothelial cells via LRP-1 receptor-mediated endocytosis, but also via scavenger receptor class A and B (SCARA3, SCARA5, and SR-BI) mediated endocytosis. SCARA3, SCARA5, and SR-BI are found to be expressed in the brain endothelial cells. Inhibition of these receptors leads to a reduction of the transfection. In conclusion, this study shows that scavenger receptors also play an essential role in the cellular uptake of the PF32/pDNA nanocomplexes. PMID- 26773600 TI - Next generation of buccadhesive excipient: Preactivated carboxymethyl cellulose. AB - AIM: Assessment of preactivated carboxymethyl cellulose as potential excipient for buccal drug delivery. METHODS: Firstly, carboxymethyl cellulose (CMC) and cysteine (SH) were covalently coupled via amide bond formation to obtain thiolated carboxymethyl cellulose (CMC-SH). Further, preactivated carboxymethyl cellulose (CMC-S-S-MNA) was obtained by preactivation with 2-mercaptonicotinic acid (MNA). Sulforhodamine 101 (SRH101) was used as a model drug for permeation study through buccal mucosa. CMC-S-S-MNA was evaluated with respect to mucoadhesive and permeation enhancing effect and cytotoxicity. RESULTS: Thiolated carboxymethyl cellulose exhibited a total amount of 112.46 +/- 0.46 thiol groups. CMC-S-S-MNA exhibited around 50% of preactivated thiol groups. The preactivated polymer showed no toxic effect. Furthermore, compared to unmodified CMC, CMC-S-S MNA revealed 3.0-fold improved mucoadhesive properties according to the rotating cylinder method and 8.8-fold enhancement in mucoadhesiveness by tensile assay, respectively. CONCLUSION: Preactivated carboxymethyl cellulose fulfills the requirements as potential excipient of being mucoadhesive and permeation enhancing for the buccal drug delivery. PMID- 26773604 TI - Sleep deprivation produces feelings of vicarious agency. AB - A variety of self-related psychological constructs are supported by the fundamental ability to accurately sense either self-agency or lack of agency in some action or outcome. Agency judgments are typically studied in individuals who are well-rested and mentally-fresh; however, in our increasingly fast-paced world, such judgments often need to be made while in less optimal states. Here, we studied the effect of being in one such non-optimal state - when sleep deprived - on judgments of agency. We found that 24h of total sleep deprivation elevated agency ratings on trials designed to produce a strong sense of non agency. These data provide the first evidence that physiological state variables can affect agency processing in the normal population. PMID- 26773602 TI - Roles of phosphodiesterases in the regulation of the cardiac cyclic nucleotide cross-talk signaling network. AB - The balanced signaling between the two cyclic nucleotides (cNs) cAMP and cGMP plays a critical role in regulating cardiac contractility. Their degradation is controlled by distinctly regulated phosphodiesterase isoenzymes (PDEs), which in turn are also regulated by these cNs. As a result, PDEs facilitate communication between the beta-adrenergic and Nitric Oxide (NO)/cGMP/Protein Kinase G (PKG) signaling pathways, which regulate the synthesis of cAMP and cGMP respectively. The phenomena in which the cAMP and cGMP pathways influence the dynamics of each other are collectively referred to as cN cross-talk. However, the cross-talk response and the individual roles of each PDE isoenzyme in shaping this response remain to be fully characterized. We have developed a computational model of the cN cross-talk network that mechanistically integrates the beta-adrenergic and NO/cGMP/PKG pathways via regulation of PDEs by both cNs. The individual model components and the integrated network model replicate experimentally observed activation-response relationships and temporal dynamics. The model predicts that, due to compensatory interactions between PDEs, NO stimulation in the presence of sub-maximal beta-adrenergic stimulation results in an increase in cytosolic cAMP accumulation and corresponding increases in PKA-I and PKA-II activation; however, the potentiation is small in magnitude compared to that of NO activation of the NO/cGMP/PKG pathway. In a reciprocal manner, beta-adrenergic stimulation in the presence of sub-maximal NO stimulation results in modest cGMP elevation and corresponding increase in PKG activation. In addition, we demonstrate that PDE2 hydrolyzes increasing amounts of cAMP with increasing levels of beta-adrenergic stimulation, and hydrolyzes increasing amounts of cGMP with decreasing levels of NO stimulation. Finally, we show that PDE2 compensates for inhibition of PDE5 both in terms of cGMP and cAMP dynamics, leading to cGMP elevation and increased PKG activation, while maintaining whole-cell beta-adrenergic responses similar to that prior to PDE5 inhibition. By defining and quantifying reactions comprising cN cross-talk, the model characterizes the cross-talk response and reveals the underlying mechanisms of PDEs in this non-linear, tightly-coupled reaction system. PMID- 26773605 TI - Clinical and epidemiological features of respiratory virus infections in preschool children over two consecutive influenza seasons in southern Brazil. AB - This study reports the results of a systematic screening for respiratory viruses in pediatric outpatients from an emergency department (ED) in southern Brazil during two consecutive influenza seasons. Children eligible for enrollment in this study were aged 24-59 months and presented with acute respiratory symptoms and fever. Naso- and oropharyngeal swabs were collected and multiplex reverse transcription PCR (RT-PCR) was performed to identify the respiratory viruses involved. In total, 492 children were included in this study: 248 in 2010 and 244 in 2011. In 2010, 136 samples (55%) were found to be positive for at least one virus and the most frequently detected viruses were human rhinovirus (HRV) (18%), adenovirus (AdV) (13%), and human coronavirus (CoV) (5%). In 2011, 158 samples (65%) were found to be positive for at least one virus, and the most frequently detected were HRV (29%), AdV (12%), and enterovirus (9%). Further, the presence of asthma (OR, 3.17; 95% CI, 1.86-5.46) was independently associated with HRV infection, whereas fever was associated with AdV (OR, 3.86; 95% CI, 1.31-16.52) and influenza infections (OR, 3.74; 95% CI, 1.26-16.06). Ten patients (2%) were diagnosed with pneumonia, and six of these tested positive for viral infection (4 HRV, 1 RSV, and 1 AdV). Thus, this study identified the most common respiratory viruses found in preschool children in the study region and demonstrated their high frequency, highlighting the need for improved data collection, and case management in order to stimulate preventive measures against these infections. J. Med. Virol. 88:1325-1333, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26773606 TI - Long-term operation of biological activated carbon pre-treatment for microfiltration of secondary effluent: Correlation between the organic foulants and fouling potential. AB - The impact of long-term (>2 years) biological activated carbon (BAC) treatment for mitigating organic fouling in the microfiltration of biologically treated secondary effluent was investigated. Correlation between the organic constituents and hydraulic filtration resistance was investigated to identify the major components responsible for fouling. Over two years operation, the removal efficiency for dissolved organic carbon (DOC) by the BAC treatment was fairly consistent (30 +/- 3%), although the reduction in UVA254 gradually decreased from 56 to 34%. BAC treatment effectively decreased the organic foulants in the effluent and so contributed to the mitigation of membrane fouling as shown by reduction in the unified membrane fouling index (UMFI). BAC consistently removed biopolymers whereas the removal of humic substances decreased from 52 to 25% after two years of BAC operation, and thus led to a gradual decrease in UMFI reduction efficiency from 78 to 43%. This was due to gradual reduction in adsorption capacity of the activated carbon as confirmed by analysis of its pore size distribution. Hence humics also played an important role in membrane fouling. However, there was a good correlation between protein and carbohydrate contents with hydraulically reversible and irreversible filtration resistance, compared with UVA254, turbidity and DOC. Although the mitigation of membrane fouling decreased over time, this study demonstrated that the long-term use of BAC pre-treatment of biologically treated secondary effluent prior to microfiltration has potential to reduce the need for frequent chemical cleaning and so increase membrane life span. PMID- 26773608 TI - Modulating self-assembly behavior of a salt-free peptide amphiphile (PA) and zwitterionic surfactant mixed system. AB - A salt-free surfactant system formed by a peptide amphiphile with short headgroup (PA,C16-GK-3) and a zwitterionic surfactant (dodecyldimethylamine oxide, C12DMAO) in water has been systematically investigated. The microstructures and properties of C16-GK-3/C12DMAO mixed system were characterized using a combination of microscopic, scattering and spectroscopic techniques, including transmission electron microscopy (TEM), field emission-scanning electron microscopy (FE-SEM), atomic force microscopy (AFM), Fourier transform infrared (FT-IR), circular dichroism (CD) and rheological measurements. Rich phase transitions have been observed by adjusting the concentration of C16-GK-3. Investigation of the hydrogels of C16-GK-3/C12DMAO with TEM, SEM and AFM showed that all of these hydrogels form nanobelts. The nanobelt formation is performed in a hierarchical manner: beta-sheet peptides and C12DMAO first interact each other to form small aggregates, which then arrange themselves to form one dimensional (1D) left handed ribbons. The ribbons further aggregated into flat and rigid nanobelts. We proposed a mechanism to interpret the self-assembly process according to the specific peptide structure as well as multiple equilibria between the hydrogen bonding interactions between the headgroups of C16-GK-3, between C12DMAO molecules and the headgroups of C16-GK-3, chirality of the amino acid residues and hydrophobic interactions of the alkyl chains. PMID- 26773609 TI - Methane adsorption on porous nano-silica in the presence of water: An experimental and ab initio study. AB - This study investigated the effects of silanol groups and water content on methane adsorption on hydrophilic nano-silica H-380 through experiments and ab initio calculations. Fourier transform infrared (FTIR) spectroscopy was used to confirm the presence of silanol groups on the solid surface, and the pore size distribution between 0 and 40nm was determined using CO2 and N2 sorption experiments. Ab initio MP2 and complete basis set model (CBS-4) calculations were performed to optimize four different silica surfaces with and without silanol groups using different basis sets. The theoretical calculations and experiments indicated that the adsorption of methane slightly decreased when the water content was low. As the water content increased from 29.03wt% to 40.54wt%, the confined water molecules (water within the pores) promoted the adsorption of CH4 by forming deeper adsorption potential energy wells, thus rendering the system more stable. The experimental isotherms at 308.15-318.15K were obtained over a wide range of water contents up to 75.05wt%. The experimental data are consistent with the theoretical analysis, indicating an increase in the adsorption of CH4 as the water content increased from 39.75wt% to 50.35wt%. Additionally, the adsorption of CH4 sharply decreased when the water content was greater than 63.12wt%. This study contributes essential data on methane-confined H2O interactions on nano-silica surfaces to the scientific literature. PMID- 26773607 TI - Highly efficient nuclear delivery of anti-cancer drugs using a bio-functionalized reduced graphene oxide. AB - Targeted drug delivery has become important, attractive and challenging in biomedical science and applications. Anti-HER2 antibody-conjugated poly-l-lysine functionalized reduced graphene oxide (anti-HER2-rGO-PLL) nanocarriers were prepared to efficiently deliver doxorubicin targeting at the nucleus of HER2 over expressing cancer cells. The polycationic PLL was first covalently grafted to graphene oxide (GO) nanosheets followed by reduction to obtain rGO-PLL with high drug loading and good colloidal stability. The anti-HER2 antibodies were subsequently conjugated to the amino groups of PLL to achieve excellent cell uptake capability. Cellular uptake of anti-HER2-rGO-PLL into MCF7/HER2 cells is significantly higher than that of rGO-PLL due to the specific targeting of anti HER2 to HER2 overexpressing breast cancer cells. Additionally the anti-HER2-rGO PLL enables a fast accumulation of DOX inside the nucleus, its subcellular site of action. In vitro cytotoxicity measurements clearly reveal a seven fold improvement in the anticancer efficacy for anti-HER2-rGO-PLL/DOX in comparison to rGO-PLL/DOX. The enhanced anticancer efficacy could be ascribed to the different intracellular DOX distributions resulted from the different internalization routes that are energy-dependent macropinocytosis and energy-independent direct penetration by anti-HER2-rGO-PLL and rGO-PLL, respectively. The results demonstrate that anti-HER2 conjugated rGO-PLL developed is a promising vehicle for efficient nuclear delivery of chemotherapeutic agents to HER2 over-expressing tumours. PMID- 26773603 TI - Nutrient-sensing mTORC1: Integration of metabolic and autophagic signals. AB - The ability of adult cardiomyocytes to regenerate is limited, and irreversible loss by cell death plays a crucial role in heart diseases. Autophagy is an evolutionarily conserved cellular catabolic process through which long-lived proteins and damaged organelles are targeted for lysosomal degradation. Autophagy is important in cardiac homeostasis and can serve as a protective mechanism by providing an energy source, especially in the face of sustained starvation. Cellular metabolism is closely associated with cell survival, and recent evidence suggests that metabolic and autophagic signaling pathways exhibit a high degree of crosstalk and are functionally interdependent. In this review, we discuss recent progress in our understanding of regulation of autophagy and its crosstalk with metabolic signaling, with a focus on the nutrient-sensing mTOR complex 1 (mTORC1) pathway. PMID- 26773610 TI - Probing microenvironment of micelle and albumin using diethyl 6 (dimethylamino)naphthalene-2,3-dicarboxylate: An electroneutral solvatochromic fluorescent probe. AB - Synthesis, single-crystal X-ray characterization, and spectroscopic investigation of small, non-charged diethyl 6-(dimethylamino)naphthalene-2,3-dicarboxylate (DMNDC) by UV-Visible, steady-state, and time-resolved fluorescence reveal a series of interesting photophysical properties originating from the intrinsic intramolecular charge transfer (ICT) state, leading to diverse applications. Stokes shift, lifetime, and emission maxima of DMNDC show a very good correlation with ET(30) solvent polarity scale for a series of different polarity solvents, confirms that it has very good environment sensitivity. Furthermore, this dye has been found to be an exceptionally suitable probe for determining Critical Micelle Concentration (CMC) and probing self-organization processes of five different type of surfactant with structural diversity. A 20-60nm blue shift in emission maxima accompanied by a large fluorescence lifetime enhancement (ca. 23ns) was observed upon relocation of DMNDC into a hydrophobic microenvironment. Along with this, the small size, electroneutrality, pH stability, and excellent solvatochromic fluorescent properties are employed for deciphering the number of hydrophobic binding pockets with strong affinity and their local microenvironment present in Bovine Serum Albumin (BSA). PMID- 26773611 TI - A facile approach for synthesizing Fe-based layered double hydroxides with high purity and its exfoliation. AB - Transition metal (e.g., Fe, Co, Ni)-based layered double hydroxides (LDHs) and their exfoliated nanosheets have great potential applications due to their redox and magnetic properties. Here we report a facile approach for the preparation of Co-Fe LDHs with good crystallinity and high purity. The proposed approach includes two steps: (1) The mixed divalent metal (e.g., Co(2+), Fe(2+)) hydroxides were first synthesized using a homogeneous precipitation without piping N2 into the system; hexamethylenetetramine (HMT) was the hydrolysis agent providing OH(-), and hydroxylamine hydrochloride (HAH) was used as both a reducing and a complexing reagent. (2) Then the as-prepared hydroxides were slowly oxidated by air and simultaneously intercalated by CO3(2-) to form CO3 intercalated LDHs. The Co-Fe LDHs were roundly characterized by XRD, SEM, EDX and FT-IR. The effect of HAH on the morphology and structure of the Co-Fe LDHs was also studied. The magnetism of Co-Fe LDHs at room temperature was investigated and the results showed that the LDHs displayed a low saturation magnetization value of 6.3emug(-1), suggesting that the purity of the products was very high. In addition, the intercalated CO3(2-) in the Co-Fe LDHs could be successfully exchanged with other anions such as Cl(-) and ClO4(-). Furthermore, the exchanged LDHs could be exfoliated in formamide. This work establishes a new method for the synthesis of Fe-based LDHs with good crystallinity and high purity under mild conditions, and can accelerate the development of applications using these layered materials. PMID- 26773612 TI - Mechanism of the cathodic process coupled to the oxidation of iron monosulfide by dissolved oxygen. AB - This study investigated the mechanism of iron monosulfide (FeS) oxidation by dissolved oxygen (O2(aq)). Synthetic FeS was reacted with O2(aq) for 6days and at 25 degrees C. We have characterized the initial and reacted FeS surface using Scanning Electron Microscopy coupled with Energy Dispersive X-ray (SEM/EDX) analysis, Raman spectroscopy and Fourier transform infrared spectroscopy (FTIR). It was found that during the aqueous oxidation of FeS new solid phases (disulfide, polysulfide, elemental sulfur, ferric oxyhydroxides and Fe3O4) develop on the mineral surface. The results of potentiodynamic polarization experiments show that after 2days of FeS electrode immersion in oxygen bearing solution (OBS) at initial pH 5.1 and 25 degrees C the modulus of cathodic Tafel slopes dramatically decreases, from 393mV/dec to 86mV/dec. This decrease is ascribed to the change of the mechanism of electron transfer from cathodic sites to O2 (mechanism of cathodic process). The oxidation current densities (jox) indicate that mineral oxidative dissolution is not inhibited by pH increase up to 6.7. Another conclusion, which emerges from the analysis of jox, is that the dissolved Fe(3+) does not intermediate the aqueous oxidation of FeS. The results of electrochemical impedance spectroscopy (EIS) show that after 2days of contact between electrode and OBS the properties of FeS/water interface change. From the analysis of the EIS, FTIR spectroscopy, Raman spectroscopy and SEM/EDX data we can conclude that the change of FeS/water interface properties accompanies the formation of new solid phases on the mineral surface. The new characteristics of the surface layer and FeS/water interface do not cause the inhibition of mineral oxidation. PMID- 26773613 TI - Polymer grafted magnetic nanoparticles for delivery of anticancer drug at lower pH and elevated temperature. AB - Efficient and controlled delivery of therapeutics to tumor cells is one of the important issues in cancer therapy. In the present work, a series of pH- and temperature-responsive polymer grafted iron oxide nanoparticles were prepared by simple coupling of aminated iron oxide nanoparticle with poly(N isopropylacrylamide-ran-poly(ethylene glycol) methyl ether acrylate)-block poly(acrylic acid) (P(NIPA-r-PEGMEA)-b-PAA). For this, three water soluble block polymers were prepared via reversible addition fragmentation transfer (RAFT) polymerization technique. At first, three different block copolymers were prepared by polymerizing mixture of NIPA and PEGMEA (with varying mole ratio) in presence of poly(tert-butyl acrylate) (PtBA) macro chain transfer agent. Subsequently, P(NIPA-r-PEGMEA)-b-PAA copolymers were synthesized by hydrolyzing tert-butyl acrylate groups of the P(NIPA-r-PEGMEA)-b-PtBA copolymers. The resulting polymers were then grafted to iron oxide nanoparticles, and these functionalized nanoparticles were thoroughly characterized by X-ray diffraction (XRD), thermogravimetric analysis (TGA), zeta potential measurements, transmission electron microscopy (TEM), field emission scanning electron microscopy (FESEM), vibrating sample magnetometer (VSM) and Fourier transform infrared spectroscopy (FTIR). Doxorubicin (DOX), an anti-cancer drug, was loaded into the polymer coated nanoparticles and its release behavior was subsequently studied at different pH and temperatures. The drug release pattern revealed a sustained release of DOX preferentially at the desired lysosomal pH of cancer cells (pH 5.0) and slightly above the physiological temperature depending upon the composition of the copolymers. The potential anticancer activity of the polymer grafted DOX loaded nanoparticles were established by MTT assay and apoptosis study of cervical cancer ME 180cells in presence of the nanoparticles. Thus, these particles can be utilized for controlled delivery of anticancer drugs at the desired lysosomal pH and/or by slightly heating the cells using magnetic hyperthermia. PMID- 26773614 TI - Aggregation-induced emission from gold nanoclusters for use as a luminescence enhanced nanosensor to detect trace amounts of silver ions. AB - Several research have reported that silver ions (Ag(+)) could enhance the photoluminescence of some kinds of gold nanoclusters (AuNCs), and redox reaction involved mechanisms were recognized as the main reason to cause such phenomenon. However, in this work, we found that Ag(+) could enhance the luminescence of aggregation-induced emission gold nanoclusters (AIE-AuNCs) without valence state change. Upon addition of Ag(+), the luminescence of AIE-AuNCs enhanced instantly by 7.2 times with a red-shift of emission peak and a complete restoration of luminescence features was observed when Ag(+) was removed. A cost-effective, rapid-response, highly sensitive and selective method to detect trace amount of Ag(+) has thereby been established using AIE-AuNCs as a nanosensor. This analytical method exhibited a linear range of 0.5nM-20MUM with a limit of detection of 0.2nM and it showed great promise for Ag(+) monitoring in environmental water. PMID- 26773615 TI - Leprosy: Between biblical descriptions to advances in immunology and diagnostic techniques. PMID- 26773616 TI - Leprosy in the Bible. AB - For many years, the biblical term tzaraat has referred to leprosy. In fact, the disease or diseases described under this name have no relationship to leprosy, as it was known in the Middle Ages or today; moreover, the term referred not only to skin disease, but also to the state of the ritual impurity and punishment for the sins. Although the real nature of tzaraat remains unknown, the differential diagnosis might include the following: Psoriasis, seborrheic dermatitis, favus, dermatophyte infections, nummular dermatitis, atopic dermatitis, pityriasis rosea, crusted scabies, syphilis, impetigo, sycosis barbae, alopecia areata, furuncles, scabies, neurodermatitis, scarlet fever, lupus erythematosus, lichen sclerosus et atrophicus, folliculitis decalvans, morphea, sarcoidosis, and lichen planopilaris. Leprosy became interchangeable with the biblical leprosy due to two inaccurate translations: The Hebrew tzaraat was first translated into Greek as leprosy in the sixth century, and later, the word leprosy was translated into Arabic as lepra in the ninth century. PMID- 26773617 TI - Leprosy: Social implications from antiquity to the present. AB - One of the most important dermatologic diseases from the sociologic viewpoint has been leprosy. Those with leprosy were isolated, excluded from society, and stigmatized. Such a stigma indicates the strong feeling that a leprosy patient is shameful and should not be accepted by society. During the first millennium, leprosy was rapidly inscribed in the system of religious prohibitions-the disease was a punishment by God for wrongdoing, and the disease was associated with the lower spheres of the society. Social perception of leprosy gradually changed during the time of Crusades. The care for lepers became a Christian obligation, and celebrating Holy Masses as for the dead was forsaken. The sick were forced to stay at leprosaria, particularly from the 14th through the 19th centuries when fear of leprosy was at a high point. Admission to a leprosarium was mandatory not only for patients with leprosy but also even those suspected of having the disease. PMID- 26773618 TI - Misericordia and leprosy in the 20th century. AB - Leprosy, which in particular affects poor people of developing countries, was also a challenge for social and charitable activities. This was possible due to the engagement of "great community workers," people who devoted their professional and family life, passions, and their own material goods to conduct socio-medical activities among leprosy affected persons. This contribution discusses the work of the lepro-activists of international fame, Albert Schweitzer and Mother Teresa of Calcutta, as well as those who are less well known, Wanda Maria Blenska and Marian Zelazek. PMID- 26773619 TI - Leprosy as a multilayered biosocial phenomenon: The comparison of institutional responses and illness narratives of an endemic disease in Brazil and an imported disease in Portugal. AB - This paper questions the relation between human health and society from the case study of leprosy. To discuss the cultural and social mediator factors of both the experience of leprosy and outcomes of medical practices, it examines the biomedical twist in the dialectic between citizenship and public good that aimed to turn leprosy into a disease like any other, with the advent of multidrug therapy during the 1980s. Such analysis is based on a multisited ethnography, developed between 2008 and 2013 in two divergent contexts from the global South and North: Brazil, which remains the country in the world with the highest relative cases of leprosy, and Portugal, in which leprosy has become an imported disease. The main results of this research point to the limits of a pharmaceuticalized governmentality of leprosy and to heterogeneous medicalization's processes, which evince the determinacy of historical intersections between the State and civil society, as well as the corollaries of the former in medical care. This paper concludes with an analysis of the partition between biomedical cure and the healing of leprosy, which unveils the intermediation of institutional and extrainstitutional factors in access to health and in the cure of leprosy. It is finally argued that such intermediation requires a public health approach that might resocialize leprosy through a paradigmatic shift toward intersectoral and participatory operational strategies. PMID- 26773620 TI - Epidemiologic trends of leprosy for the 21st century. AB - Major gaps still exist in the knowledge about leprosy, particularly with regard to how it spreads. Leprosy epidemiology remains complicated due to the specific characteristics of Mycobacterium leprae. To describe epidemiologic trends for the 21st century, the first part of this paper gives an overview of the epidemiology of leprosy, followed by past trends and the present situation of new-case detection as a proxy of the incidence. The third part, regarding predicted epidemiologic trends for the 21st century, elaborates on the main topic of this paper. With limited diagnostic tools to detect infection with M leprae, other methods are necessary to estimate trends in incidence and transmission. A computer program has been developed for modeling the transmission and control of leprosy (SIMLEP). The effect of failure to sustain early case detection beyond 2005 on leprosy incidence and case detection is shown. Important unanswered questions are whether the incubation period is contagious and how rapid close contacts of leprosy patients are infected. As long as such key questions remain unanswered, it will be difficult to estimate the impact of control strategies on the transmission of M leprae on resulting disease incidence. In the meantime we can expect that the global new-case detection trends will stay more or less stable or only decrease slightly for many years to come. There is a need of new preventive interventions to change this situation and reduce the incidence of leprosy in the 21st century. PMID- 26773621 TI - History of chemotherapy of leprosy. AB - Chemotherapy of leprosy over the past 70 years has passed through several phases, from sulfones, to clofazimine, and to highly bactericidal drugs like rifampicin. The use particularly of the more potent drugs in effective combinations and the development of standard multidrug therapy regimens have made a huge difference in the successful treatment of leprosy as well as in reducing tremendously the prevalence of leprosy globally. A major contributing factor to development of better drugs and drug combinations has been the introduction of the mouse footpad model to evaluate the in vivo activity of drugs against Mycobacterium leprae. The World Health Organization has recommended multidrug therapy, which has been used to treat more than 15 million patients in the last 30 years and has set an excellent record with regard to its very high rate of cure, very low occurrence of relapse, and very rare occurrence of drug resistance. PMID- 26773622 TI - Leprosy type 1 reaction (formerly reversal reaction). AB - Nerve damage leading to impairment and permanent disability is the major problem in the course of a leprosy infection. Most of the damage occurs during two types of leprosy reactions, type 1 reaction (T1R) and type 2 reaction (T2R). Timely and adequate treatment may prevent this damage. Particular T1R reactions, however, are often diagnosed too late and are even missed. Clinical symptoms and warning signs are therefore covered, as are the immunology and pathophysiology of nerve damage. The differences between upgrading and downgrading, old terms but still relevant, are explained. Methods to detect reactions and to monitor their treatment are given. Triggering factors, the mechanisms of the reactions, including autoimmunity, and the presence of physical compression are discussed. Treatment over the years is placed in its context, and based on this information a treatment schedule is recommended. PMID- 26773623 TI - Assessing nerves in leprosy. AB - Leprosy neuropathy is dependent on the patient's immune response and expresses itself as a focal or multifocal neuropathy with asymmetric involvement. Leprosy neuropathy evolves chronically but recurrently develops periods of exacerbation during type 1 or type 2 reactions, leading to acute neuropathy. Nerve enlargement leading to entrapment syndromes is also a common manifestation. Pain may be either of inflammatory or neuropathic origin. A thorough and detailed evaluation is mandatory for adequate patient follow-up, including nerve palpation, pain assessment, graded sensory mapping, muscle power testing, and autonomic evaluation. Nerve conduction studies are a sensitive tool for nerve dysfunction, including new lesions during reaction periods or development of entrapment syndromes. Nerve ultrasonography is also a very promising method for nerve evaluation in leprosy. The authors propose a composite nerve clinical score for nerve function assessment that can be useful for longitudinal evaluation. PMID- 26773624 TI - Neuropathic pain in leprosy. AB - Nerve impairment is a key clinical aspect of leprosy and may present the distribution of mononeuropathy or multiple nerve trunks, small cutaneous nerve fibers, and free nerve endings. The clinical range of leprosy is determined by individual cell-mediated immune response to infection that also may play a role in different types of pain syndromes in leprosy. Previous studies reported a high prevalence of neuropathic pain in leprosy. In an Ethiopian study with 48 patients, pure nociceptive pain was experienced by 43% of patients and pure neuropathic pain (NeP) by 11% of patients. In an Indian study, 21.8% of leprosy patients had pain with neuropathic characteristics. These rates underlie the need to develop tools for the early diagnosis and detection of infection and its complications, such as nerve damage and pain. In a larger sample with leprosy associated NeP (n = 90), we have applied the Douleur Neuropathique en 4 questions (DN4) and found sensitivity = 97.1% and specificity = 57.9%. The high sensitivity of this tool in leprosy patients suggests that it could be a valuable tool to screen for neuropathic pain in this population and could be used as part of health care programs aimed at detecting, treating, and rehabilitating leprosy in endemic areas. PMID- 26773625 TI - Rehabilitation of leprosy-affected people: An overview. AB - Leprosy is mainly a disease of the skin and nerves. The involvement of nerves may lead to impairments that have, contributed to the fact that leprosy is often still seen as a disease to be feared. In non-leprosy-endemic Western countries, beliefs continue to prevail about the inevitability of deformities and the lack of a cure. I review the pathogenesis of deformity and to present a discourse on how deformities can, to a very large extent, be prevented and corrected. PMID- 26773626 TI - Imaging techniques in leprosy clinics. AB - Leprosy is the most common treatable peripheral nerve disorder worldwide, with periods of acute neuritis leading to functional impairment of limbs and stigmatizing deformities. The nerve involvement in leprosy reactions, if recognized early and promptly treated with steroids and nerve release surgery, can be reversible. Currently, the nerve assessment in leprosy relies mainly on clinical assessment and nerve conduction studies. High-resolution ultrasonography (HRUS) of peripheral nerves is finding wider application in the differential diagnosis of peripheral neuropathy. HRUS provides a noninvasive tool that gives information on location and degree of nerve enlargement, nerve morphologic alterations, echo texture, fascicular pattern, and vascularity of the nerve, which mirrors the histologic changes. HRUS is amenable to studying structural changes in nerve sites that cannot be biopsied for histopathologic examination and is more cost effective than magnetic resonance imaging. So far other there are only five studies available on the sonographic findings in leprosy. These findings are reviewed and the technique of HRUS is described in this paper, with a recommendation of a standard protocol and proforma. PMID- 26773627 TI - Drug-resistant M leprae. AB - Dapsone was used as a single drug to treat leprosy, and secondary resistance soon developed, greatly reducing its effectiveness. Multidrug therapy has been used successfully since 1982, and until now, only a few sporadic cases of rifampicin resistance have been reported. Surveillance is needed to make sure that chemotherapy for leprosy remains effective for the foreseeable future. This review is based on reports from the annual drug resistance surveillance meetings convened by the World Health Organization and related literature. Very few cases of rifampicin resistance are currently known globally, except for a small group of cases in a former leprosy colony in Brazil. A low level of ofloxacin resistance has been found, especially in India. A larger number of patient samples should be tested each year. The results give grounds for cautious optimism, although the number of samples tested should be significantly increased. Possible foci of rifampicin resistance near former leprosy colonies in Brazil should be further investigated. PMID- 26773628 TI - Advances in leprosy immunology and the field application: A gap to bridge. AB - Advances concerning the hosts' immune response to Mycobacterium leprae infection have focused on elucidating the immune pathomechanisms involved, with the hope that predictive diagnostic and prognostic parameters (biomarkers) for field use would emerge; however, improvements in our understanding of the immunologic responses to this complex disease have, to date, somewhat failed to provide the effective and robust methods for improving its predictive diagnosis in the field situation, particularly in those patients suffering from paucibacillary disease. In this contribution we have attempted to review some of the advances both in the immunology and immunopathology of leprosy, and also highlight the limited clusters of immune parameters that are now available. Most importantly, we point out the limitations that still prevail in the provision of effective biomarkers in the field situation for either: (1) the diagnosis of indeterminate disease, (2) predictive diagnosis of individuals developing reactional states, (3) monitoring efficacy of treatment, or (4) monitoring treatment of reactional states. PMID- 26773629 TI - Genetics of leprosy: Expected-and unexpected-developments and perspectives. AB - A solid body of evidence produced over decades of intense research supports the hypothesis that leprosy phenotypes are largely dependent on the genetic characteristics of the host. The early evidence of a major gene effect controlling susceptibility to leprosy came from studies of familial aggregation, twins, and complex segregation analysis. Later, linkage and association analysis, first applied to the investigation of candidate genes and chromosomal regions and more recently, to genome-wide scans, have revealed several HLA and non-HLA gene variants as risk factors for leprosy phenotypes such as disease per se, its clinical forms, and leprosy reactions. In addition, powerful, hypothesis-free strategies such as genome-wide association studies have led to an exciting, unexpected development: Leprosy susceptibility genes seem to be shared with Crohn's and Parkinson's disease. Today, a major challenge is to find the exact variants causing the biological effect underlying the genetic associations. New technologies, such as Next Generation Sequencing-that allows, for the first time, the cost- and time-effective sequencing of a complete human genome-hold the promise to reveal such variants; thus, strategies can be developed to study the functional impact of these variants in the context of infection, hopefully leading to the development of new targets for leprosy treatment and prevention. PMID- 26773630 TI - Medicolegal issues. AB - The legal landscape in dermatology is constantly evolving. Dermatologists should nurture strong physician-patient relationships with proper informed consent and stay abreast of legal issues as they pertain to today's practice of medicine. Medicolegal issues that have risen to the forefront include wrong-site surgery, delegation of procedures to nonphysician operators, and compounding of medications. Additionally, although the marriage of health care and technology has facilitated our practice of medicine, it has opened doors to new medicolegal pitfalls associated with the use of electronic medical records, teledermatology, and even social media. This contribution will highlight some of the common medicolegal issues in dermatology along with recommendations to minimize exposure to litigation. PMID- 26773631 TI - Patient expectations and performance measures in dermatologic surgery. AB - Patient satisfaction has increasingly played an important role in quality-of-care reforms and health care delivery. In dermatologic surgery, patient expectations of procedures and the outcomes are important determinants of satisfaction. Identification of the patient's met and unmet expectations through patient reported outcome measures may enable a better understanding of the patient's perspective and improve communication and the delivery of care. Performance measures report on the quality of care being delivered. Performance measures currently being implemented into dermatologic practices may have a role in demonstrating the "quality" of dermatologic surgery procedures in the near future. PMID- 26773632 TI - Myelodysplastic syndromes with single neutropenia or thrombocytopenia are rarely refractory cytopenias with unilineage dysplasia by World Health Organization 2008 criteria and have favourable prognosis. PMID- 26773634 TI - Endoscopy of the "brain": the next frontier in gastroenterology. PMID- 26773633 TI - Eosinophilic esophagitis: search for noninvasive techniques for long-term monitoring. PMID- 26773635 TI - EUS-guided pancreatic duct drainage by using a novel self-expandable stent in patients with obstructive pancreatic pain: a step in the right direction! PMID- 26773636 TI - EUS-guided biliary rendezvous: slow, hesitant, baby steps forward. PMID- 26773637 TI - Antireflux metallic biliary stents: Where do we stand? PMID- 26773638 TI - Diverticular stigmata of recent hemorrhage: find one, probe one, treat one. PMID- 26773639 TI - Double endoscopic bypass by using lumen-apposing stents (with videos). PMID- 26773640 TI - Over-the-scope clip treatment of refractory peptic ulcer bleeding. PMID- 26773641 TI - Hilar stenting for malignant biliary obstruction. PMID- 26773642 TI - Reviewing the reviewers: critical appraisal of "Effect of intragastric injection of botulinum toxin A for the treatment of obesity: a meta-analysis and meta regression". PMID- 26773643 TI - Response. PMID- 26773644 TI - Development and validation of real-time simulation of X-ray imaging with respiratory motion. AB - We present a framework that combines evolutionary optimisation, soft tissue modelling and ray tracing on GPU to simultaneously compute the respiratory motion and X-ray imaging in real-time. Our aim is to provide validated building blocks with high fidelity to closely match both the human physiology and the physics of X-rays. A CPU-based set of algorithms is presented to model organ behaviours during respiration. Soft tissue deformation is computed with an extension of the Chain Mail method. Rigid elements move according to kinematic laws. A GPU-based surface rendering method is proposed to compute the X-ray image using the Beer Lambert law. It is provided as an open-source library. A quantitative validation study is provided to objectively assess the accuracy of both components: (i) the respiration against anatomical data, and (ii) the X-ray against the Beer-Lambert law and the results of Monte Carlo simulations. Our implementation can be used in various applications, such as interactive medical virtual environment to train percutaneous transhepatic cholangiography in interventional radiology, 2D/3D registration, computation of digitally reconstructed radiograph, simulation of 4D sinograms to test tomography reconstruction tools. PMID- 26773645 TI - Influence of bio-lubricants on the orthodontic friction. AB - The Friction force of Stainless Steel (SS) and Nickel-Titanium (Ni-Ti) rectangular archwires against stainless steel brackets was investigated. Two types of brackets were used namely: Self-ligating brackets (SLB) and conventional brackets (CB). The friction tests were conducted on an adequate developed device under dry and lubricated conditions. Human saliva, olive oil, Aloe Vera oil, sesame oil and sunflower oil were used as bio-lubricants. The friction force was examined as a function of the ligation method and oil temperature. It is found that under oil lubrication, the friction behavior in the archwire/bracket assembly were the best. The SLB ligation was better than the conventional ligation system. The enhancement of the frictional behavior with natural oils was linked to their main components: fatty acids. PMID- 26773646 TI - Tribocorrosion behavior of biofunctional titanium oxide films produced by micro arc oxidation: Synergism and mechanisms. AB - Dental implants, inserted into the oral cavity, are subjected to a synergistic interaction of wear and corrosion (tribocorrosion), which may lead to implant failures. The objective of this study was to investigate the tribocorrosion behavior of Ti oxide films produced by micro-arc oxidation (MAO) under oral environment simulation. MAO was conducted under different conditions as electrolyte composition: Ca/P (0.3M/0.02M or 0.1M/0.03M) incorporated with/without Ag (0.62g/L) or Si (0.04M); and treatment duration (5 and 10min). Non-coated and sandblasted samples were used as controls. The surfaces morphology, topography and chemical composition were assessed to understand surface properties. ANOVA and Tukey's HSD tests were used (alpha=0.05). Biofunctional porous oxide layers were obtained. Higher Ca/P produced larger porous and harder coatings when compared to non-coated group (p<0.001), due to the presence of rutile crystalline structure. The total mass loss (Kwc), which includes mass loss due to wear (Kw) and that due to corrosion (Kc) were determined. The dominant wear regime was found for higher Ca/P groups (Kc/Kw~0.05) and a mechanism of wear-corrosion for controls and lower Ca/P groups (Kc/Kw~0.11). The group treated for 10min and enriched with Ag presented the lowest Kwc (p<0.05). Overall, MAO process was able to produce biofunctional oxide films with improved surface features, working as tribocorrosion resistant surfaces. PMID- 26773647 TI - Manufacturing of high-strength Ni-free Co-Cr-Mo alloy rods via cold swaging. AB - The strengthening of biomedical metallic materials is crucial to increasing component durability in biomedical applications. In this study, we employ cold swaging as a strengthening method for Ni-free Co-Cr-Mo alloy rods and examine its effect on the resultant microstructures and mechanical properties. N is added to the alloy to improve the cold deformability, and a maximum reduction in area (r) of 42.6% is successfully obtained via cold swaging. The rod strength and ductility increase and decrease, respectively, with increasing cold-swaging reduction r. Further, the 0.2% proof stress at r=42.6% eventually reaches 1900MPa, which is superior to that obtained for the other strengthening methods proposed to date. Such significant strengthening resulting from the cold-swaging process may be derived from extremely large work hardening due to a strain induced gamma (fcc)->epsilon (hcp) martensitic transformation, with the resultant intersecting epsilon-martensite plates causing local strain accumulation at the interfaces. The lattice defects (dislocations/stacking faults) inside the epsilon phase also likely contribute to the overall strength. However, excessive application of strain during the cold-swaging process results in a severe loss in ductility. The feasibility of cold swaging for the manufacture of high-strength Co-Cr-Mo alloy rods is discussed. PMID- 26773648 TI - Degradation of Zr-based bulk metallic glasses used in load-bearing implants: A tribocorrosion appraisal. AB - Owing to the amorphous structure, Bulk Metallic Glasses (BMGs) have been demonstrating attractive properties for potential biomedical applications. In the present work, the degradation mechanisms of Zr-based BMGs with nominal compositions Zr55Cu30Ni5Al10 and Zr65Cu18Ni7Al10 as potential load-bearing implant material were investigated in a tribocorrosion environment. The composition-dependent micro-mechanical and tribological properties of the two BMGs were evaluated prior to the tribocorrosion tests. The sample Zr65-BMG with a higher Zr content exhibited increased plasticity but relatively reduced wear resistance during the ball-on-disc tests. Both BMGs experienced abrasive wear after the dry wear test under the load of 2N. The cross-sectional subsurface structure of the wear track was examined by Focused Ion Beam (FIB). The electrochemical properties of the BMGs in simulated body fluid were evaluated by means of potentiodynamic polarization and X-ray Photoelectron Spectroscopy (XPS). The spontaneous passivation of Zr-based BMGs in Phosphate Buffer Saline solution was mainly attributed to the highly concentrated zirconium cation (Zr(4+)) in the passive film. The tribocorrosion performance of the BMGs was investigated using a reciprocating tribometer equipped with an electrochemical cell. The more passive nature of the Zr65-BMG had consequently a negative influence on its tribocorrosion resistance, which induced the wear-accelerated corrosion and eventually speeded-up the degradation process. It has been revealed the galvanic coupling was established between the depassivated wear track and the surrounding passive area, which is the main degradation mechanism for the passive Zr65-BMG subjected to the tribocorrosion environment. PMID- 26773649 TI - Mechanical and electrochemical characterisation of new Ti-Mo-Nb-Zr alloys for biomedical applications. AB - The development and characterisation of new metallic biomaterials that contain non-toxic and non-allergic elements but possess low elastic modulus and low biodegradation rates, has become a topic of serious investigation in orthopaedic implant application. The lowering of elastic modulus and improving of corrosion resistance can be achieved by specific chemical alloying and super-elasticity effects, associated with a stress-induced phase transformation from the BCC metastable beta phase to the orthorhombic alpha" martensite. Using this framework, this paper focuses on the effect of Nb and/or Zr micro-additions on the elastic modulus/yield strength balance and discusses microstructure, and the mechanical and electrochemical behaviour of four new beta-Ti-8Mo-xNb-xZr (x=2-5) alloys, using tensile tests, X-ray diffraction, SEM characterisation, ultrasound technique and potentiodynamic polarisation methods. The results reveal that the alloys exhibit a pronounced microstructural sensitivity response, with alloying elements and excellent agreement between beta-stability and high mechanical strength, with increasing Nb additions. Although all the alloys possess excellent corrosion resistance and low Young's modulus, Ti-8Mo-4Nb-2Zr alloy, which consists of beta+alpha'' phases, exhibits a low Young modulus of 35GPa, which is lower than those of the commercial alloys already used in biomedical implantation. The significant corrosion resistance, nontoxicity and better mechanical compatibility are properties pertinent to preventing stress shielding and bone resorption in orthopaedic implant applications. PMID- 26773650 TI - Simultaneous microstructural and mechanical characterization of human corneas at increasing pressure. AB - The cornea, through its shape, is the main contributor to the eye's focusing power. Pathological alterations of the cornea strongly affect the eye power. To improve treatments, complex biomechanical models have been developed based on the architecture and mechanical properties of the collagen network in the stroma, the main layer of the cornea. However, direct investigations of the structure of the stroma, as well as its link to the mechanical response, remained limited. We propose here an original set up, associating nonlinear optical imaging and mechanical testing. By using polarization resolved Second Harmonic signals, we simultaneously quantified micrometer (orientation of the collagen lamellae) and nanometer (local disorder within lamellae) scale corneal organization. We showed that the organization of the lamellae changes along the stroma thickness. Then, we measured simultaneously the deformation on the epithelial side of the cornea and the reorientation of the collagen lamellae for increasing intraocular pressure levels, from physiological ones to pathological ones. We showed that the observed deformation is not correlated to initial orientation, but to the reorganization of the lamellae in the stroma. Our results, by providing a direct multi-scale observation, will be useful for the development of more accurate biomechanical models. PMID- 26773651 TI - An accelerated buoyancy adhesion assay combined with 3-D morphometric analysis for assessing osteoblast adhesion on microgrooved substrata. AB - An accelerated negative buoyancy method has been developed to assess cell adhesion strength. This method has been used in conjunction with 3-D morphometric analysis to understand the effects of surface topology on cell response. Aligned micro-grooved surface topographies (with a range of groove depths) were produced on stainless steel 316L substrates by laser ablation. An investigation was carried out on the effect of the micro-grooved surface topography on cell adhesion strength, cell and nucleus volumes, cell phenotypic expression and attachment patterns. Increased hydrophobicity and anisotropic wettability was observed on surfaces with deeper grooves. A reduction was noted in cell volume, projected areas and adhesion sites for deeper grooves, linked to lower cell proliferation and differentiation rates and also to reduced adhesion strength. The results suggest that the centrifugation assay combined with three-dimensional cell morphometric analysis has considerable potential for obtaining improved understanding of the cell/substrate interface. PMID- 26773653 TI - Three-dimensional microscopic deformation measurements on cellular solids. AB - The increasing interest in small-scale problems demands novel experimental protocols providing dense sets of 3D deformation data of complex shaped microstructures. Obtaining such information is particularly significant for the study of natural and engineered cellular solids for which experimental data collected at macro scale and describing the global mechanical response provide only limited information on their function/structure relationship. Cellular solids, in fact, due their superior mechanical performances to a unique arrangement of the bulk material properties (i.e. anisotropy and heterogeneity) and cell structural features (i.e. pores shape, size and distribution) at the micro- and nano-scales. To address the need for full-field experimental data down to the cell level, this paper proposes a single-camera stereo-Digital Image Correlation (DIC) system that makes use of a wedge prism in series to a telecentric lens for performing surface shape and deformation measurements on microstructures in three dimensions. Although the system possesses a limited measurement volume (FOV~2.8*4.3mm(2), error-free DOF ~1mm), large surface areas of cellular samples can be accurately covered by employing a sequential image capturing scheme followed by an optimization-based mosaicing procedure. The basic principles of the proposed method together with the results of the benchmarking of its metrological performances and error analysis are here reported and discussed in detail. Finally, the potential utility of this method is illustrated with micro-resolution three-dimensional measurements on a 3D printed honeycomb and on a block sample of a Luffa sponge under compression. PMID- 26773652 TI - Differences between buccal and lingual bone quality and quantity of peri-implant regions. AB - The objective of the current study was to examine whether peri-implant bone tissue properties are different between the buccal and lingual regions treated by growth factors. Four dental implant groups were used: titanium (Ti) implants, alumina-blasted zirconia implants (ATZ-N), alumina-blasted zirconia implants with demineralized bone matrix (DBM) (ATZ-D), and alumina-blasted zirconia implants with rhBMP-2 (ATZ-B). These implants were placed in mandibles of six male dogs. Nanoindentation elastic modulus (E) and plastic hardness (H) were measured for the buccal and lingual bone tissues adjacent and away from the implants at 3 and 6 weeks post-implantation. A total of 2281 indentations were conducted for 48 placed implants. The peri-implant buccal region had less bone quantity resulting from lower height and narrower width of bone tissue than the lingual region. Buccal bone tissues had significant greater mean values of E and H than lingual bone tissues at each distance and healing period (p<0.007). Nearly all implant treatment groups displayed lower mean values of the E at the lingual bone tissues than at the buccal bone tissues (p<0.046) although the difference was not significant for the Ti implant group (p=0.758). The DBM and rhBMP-2 treatments stimulated more peri-implant bone remodeling at the lingual region, producing more immature new bone tissues with lower E than at the buccal region. This finding suggests that the growth factor treatments to the zirconia implant system may help balance the quantity and quality differences between the peri-implant bone tissues. PMID- 26773654 TI - Bacterial diversity in oil-polluted marine coastal sediments. AB - Marine environments harbour a persistent microbial seed which can be shaped by changes of the environmental conditions such as contamination by petroleum components. Oil spills, together with small but continuous discharges of oil from transportation and recreational activities, are important sources of hydrocarbon pollution within the marine realm. Consequently, prokaryotic communities have become well pre-adapted toward oil pollution, and many microorganisms that are exposed to its presence develop an active degradative response. The natural attenuation of oil pollutants, as has been demonstrated in many sites, is modulated according to the intrinsic environmental properties such as the availability of terminal electron acceptors and elemental nutrients, together with the degree of pollution and the type of hydrocarbon fractions present. Whilst dynamics in the bacterial communities in the aerobic zones of coastal sediments are well characterized and the key players in hydrocarbon biodegradation have been identified, the subtidal ecology of the anaerobic community is still not well understood. However, current data suggest common patterns of response in these ecosystems. PMID- 26773655 TI - Comparison of non-sequential sets of protein residues. AB - A methodology for performing sequence-free comparison of functional sites in protein structures is introduced. The method is based on a new notion of similarity among superimposed groups of amino acid residues that evaluates both geometry and physico-chemical properties. The method is specifically designed to handle disconnected and sparsely distributed sets of residues. A genetic algorithm is employed to find the superimposition of protein segments that maximizes their similarity. The method was evaluated by performing an all-to-all comparison on two separate sets of ligand-binding sites, comprising 47 protein FAD (Flavin-Adenine Dinucleotide) and 64 protein-NAD (Nicotinamide-Adenine Dinucleotide) complexes, and comparing the results with those of an existing sequence-based structural alignment tool (TM-Align). The quality of the two methodologies is judged by the methods' capacity to, among other, correctly predict the similarities in the protein-ligand contact patterns of each pair of binding sites. The results show that using a sequence-free method significantly improves over the sequence-based one, resulting in 23 significant binding-site homologies being detected by the new method but ignored by the sequence-based one. PMID- 26773656 TI - Adjustments of serine proteases of Daphnia pulex in response to temperature changes. AB - Elevated temperatures considerably challenge aquatic invertebrates, and enhanced energy metabolism and protein turnover require adjustments of digestion. In Daphnia, the serine proteases chymotrypsin and trypsin represent the major proteolytic enzymes. Daphnia pulex acclimated to different temperature conditions or subjected to acute heat stress showed increased expression level of serine proteases with rising temperatures. Transcripts of trypsin isoforms were always present in higher amounts than observed for chymotrypsin. Additionally, trypsin isoform transcripts were induced by elevated temperatures to a larger extent. Correspondingly, trypsin activity dominated in cold-acclimated animals. However, the enzymatic activity of chymotrypsin increased at elevated temperatures, whereas trypsin activity slightly decreased, resulting in a shift to dominating chymotrypsin activity in warm-acclimated animals. Zymograms revealed eight bands with proteolytic activity in the range of 20 to 86 kDa. The single bands were assigned to trypsin or chymotrypsin activity applying specific inhibitors or from casein cleavage products identified by mass spectrometric analysis. The total amount of proteolytic activity was elevated with acclimation temperature increase and showed a transient decrease under acute heat stress. The contribution of the different isoforms to protein digestion indicated induction of chymotrypsin with increasing acclimation temperature. For trypsin, the share of one isoform decreased with elevated temperature, while another isoform was enhanced. Thus differential expression of serine proteases was observed in response to chronic and acute temperature changes. The observed phenotypic plasticity adjusts the set of active proteases to the altered needs of protein metabolism optimizing protein digestion for the temperature conditions experienced in the habitat. PMID- 26773657 TI - Chemosensory proteins of the eastern honeybee, Apis cerana: Identification, tissue distribution and olfactory related functional characterization. AB - Chemosensory proteins (CSPs), a class of small soluble proteins, are thought to be involved in insect chemoreceptive behavior. Here, six CSP genes, AcerCSP1-6 from Apis cerana, were cloned and characterized from worker bees' antennae. Results revealed that the AcerCSPs' amino acid sequences shared high similarity with the homologous genes of Apis mellifera, but low similarity with other insect species. Compared with corresponding CSPs of A. mellifera, AcerCSPs (1, 3, 4, and 6) exhibit quite similar gene expression profiling. On the contrary, AcerCSP2 showed a higher expression level in the forager antennae and legs than CSP2 of A. mellifera. Furthermore, AcerCSP5 was not specifically expressed in larvae, unlike CSP5 of A. mellifera. In a ligand-binding assay, AcerCSP1 and AcerCSP2, which exhibited the highest expression in antennae of A. cerana, had a stronger affinity with candidate floral chemicals and pheromones than AcerCSP4, the results of which was supported by docking analysis, suggesting that the relevance of them with A. cerana olfactory functions. Taken together, these results suggest that despite the quasi-similarity of protein sequences between A. cerana and A. mellifera, differences in tissue expression and functional characteristics between the two species still exist, indicating that homologous proteins potentially perform different tasks even in related species. PMID- 26773658 TI - Yield of emergent neuroimaging in children with new-onset seizure and status epilepticus. AB - PURPOSE: To determine the yield of emergent neuroimaging among children with new onset seizures presenting with status epilepticus. METHOD: We performed a cross sectional study of children seen at a single ED between 1995 and 2012 with new onset seizure presenting with status epilepticus. We defined status epilepticus as a single seizure or multiple seizures without regaining consciousness lasting 30 min or longer. Our primary outcome was urgent or emergent intracranial pathology identified on neuroimaging. We categorized neuroimaging results as emergent if they would have changed acute management as assessed by a blinded neuroradiologist and neurologist. To ensure abnormalities were not missed, we review neuroimaging results for 30 days following the initial episode of SE. RESULTS: We included 177 children presenting with new-onset seizure with status epilepticus, of whom 170 (96%) had neuroimaging performed. Abnormal findings were identified on neuroimaging in 64/177 (36%, 95% confidence interval 29-43%) children with 15 (8.5%, 95% confidence interval 5.2-14%) children having urgent or emergent pathology. Four (27%) of the 15 children with urgent or emergent findings had a normal non-contrast computed tomography scan and a subsequently abnormal magnetic resonance image. Longer seizure duration and older age were associated with urgent or emergent intracranial pathology. CONCLUSION: A substantial minority of children with new-onset seizures presenting with status epilepticus have urgent or emergent intracranial pathology identified on neuroimaging. Clinicians should strongly consider emergent neuroimaging in these children. Magnetic resonance imaging is the preferred imaging modality when available and safe. PMID- 26773659 TI - Injectable dual-gelling cell-laden composite hydrogels for bone tissue engineering. AB - The present work investigated the osteogenic potential of injectable, dual thermally and chemically gelable composite hydrogels for mesenchymal stem cell (MSC) delivery in vitro and in vivo. Composite hydrogels comprising copolymer macromers of N-isopropylacrylamide were fabricated through the incorporation of gelatin microparticles (GMPs) as enzymatically digestible porogens and sites for cellular attachment. High and low polymer content hydrogels with and without GMP loading were shown to successfully encapsulate viable MSCs and maintain their survival over 28 days in vitro. GMP incorporation was also shown to modulate alkaline phosphatase production, but enhanced hydrogel mineralization along with higher polymer content even in the absence of cells. Moreover, the regenerative capacity of 2 mm thick hydrogels with GMPs only, MSCs only, or GMPs and MSCs was evaluated in vivo in an 8 mm rat critical size cranial defect for 4 and 12 weeks. GMP incorporation led to enhanced bony bridging and mineralization within the defect at each timepoint, and direct bone-implant contact as determined by microcomputed tomography and histological scoring, respectively. Encapsulation of both GMPs and MSCs enabled hydrogel degradation leading to significant tissue infiltration and osteoid formation. The results suggest that these injectable, dual-gelling cell-laden composite hydrogels can facilitate bone ingrowth and integration, warranting further investigation for bone tissue engineering. PMID- 26773661 TI - In vivo tissue has non-linear rheological behavior distinct from 3D biomimetic hydrogels, as determined by AMOTIV microscopy. AB - Variation in matrix elasticity has been shown to determine cell fate in both differentiation and development of malignant phenotype. The tissue microenvironment provides complex biochemical and biophysical signals in part due to the architectural heterogeneities found in extracellular matrices (ECMs). Three dimensional cell cultures can partially mimic in vivo tissue architecture, but to truly understand the role of viscoelasticity on cell fate, we must first determine in vivo tissue mechanical properties to improve in vitro models. We employed Active Microrheology by Optical Trapping InVivo (AMOTIV), using in situ calibration to measure in vivo zebrafish tissue mechanics. Previously used trap calibration methods overestimate complex moduli by ~ 2-20 fold compared to AMOTIV. Applying differential microscale stresses and strains showed that hyaluronic acid (HA) gels display semi-flexible polymer behavior, while laminin rich ECM hydrogels display flexible polymer behavior. In contrast, zebrafish tissues displayed different moduli at different stresses, with higher power law exponents at lower stresses, indicating that living tissue has greater stress dependence than the 3D hydrogels examined. To our knowledge, this work is the first vertebrate tissue rheological characterization performed in vivo. Our fundamental observations are important for the development and refinement of in vitro platforms. PMID- 26773660 TI - Knockdown of TNF-alpha by DNAzyme gold nanoparticles as an anti-inflammatory therapy for myocardial infarction. AB - In this study, we used deoxyribozyme (DNAzyme) functionalized gold nanoparticles (AuNPs) to catalytically silence tumor necrosis factor-alpha (TNF-alpha) in vivo as a potential therapeutic for myocardial infarction (MI). Using primary macrophages as a model, we demonstrated 50% knockdown of TNF-alpha, which was not attainable using Lipofectamine-based approaches. Local injection of DNAzyme conjugated to gold particles (AuNPs) in the rat myocardium yielded TNF-alpha knockdown efficiencies of 50%, which resulted in significant anti-inflammatory effects and improvement in acute cardiac function following MI. Our results represent the first example showing the use of DNAzyme AuNP conjugates in vivo for viable delivery and gene regulation. This is significant as TNF-alpha is a multibillion dollar drug target implicated in many inflammatory-mediated disorders, thus underscoring the potential impact of DNAzyme-conjugated AuNPs. PMID- 26773662 TI - Local delivery of a carbohydrate analog for reducing arthritic inflammation and rebuilding cartilage. AB - Osteoarthritis (OA) is a degenerative joint disease characterized by articular cartilage degradation. Because OA has a multifactorial nature and complex interrelationship of the individual elements of a whole joint, there is a need for comprehensive therapeutic approaches for cartilage tissue engineering, which simultaneously address multiple aspects of disease etiology. In this work, we investigated a multifunctional carbohydrate-based drug candidate, tri butanoylated N-acetyl-D-galactosamine analog (3,4,6-O-Bu3GalNAc) that induced cartilage tissue production by human mesenchymal stem cells (hMSCs) and human OA chondrocytes by modulating Wnt/beta-catenin signaling activity. The dual effects promoted chondrogenesis of human MSC and reduced inflammation of human OA chondrocytes in in vitro cultures. Translating these findings in vivo, we evaluated therapeutic effect of 3,4,6-O-Bu3GalNAc on the rat model of posttraumatic OA when delivered via local intra-articular sustained-release delivery using microparticles and found this method to be efficacious in preventing OA progression. These results show that 3,4,6-O-Bu3GalNAc, a disease modifying OA drug candidate, has promising therapeutic potential for articular cartilage repair. PMID- 26773664 TI - AMP-guided tumour-specific nanoparticle delivery via adenosine A1 receptor. AB - Active targeting-ligands have been increasingly used to functionalize nanoparticles for tumour-specific clinical applications. Here we utilize nucleotide adenosine 5'-monophosphate (AMP) as a novel ligand to functionalize polymer-based fluorescent nanoparticles (NPs) for tumour-targeted imaging. We demonstrate that AMP-conjugated NPs (NPs-AMP) efficiently bind to and are following internalized into colon cancer cell CW-2 and breast cancer cell MDA-MB 468 in vitro. RNA interference and inhibitor assays reveal that the targeting effects mainly rely on the specific binding of AMP to adenosine A1 receptor (A1R), which is greatly up-regulated in cancer cells than in matched normal cells. More importantly, NPs-AMP specifically accumulate in the tumour site of colon and breast tumour xenografts and are further internalized into the tumour cells in vivo via tail vein injection, confirming that the high in vitro specificity of AMP can be successfully translated into the in vivo efficacy. Furthermore, NPs-AMP exhibit an active tumour-targeting behaviour in various colon and breast cancer cells, which is positively related to the up-regulation level of A1R in cancer cells, suggesting that AMP potentially suits for more extensive A1R-overexpressing cancer models. This work establishes AMP to be a novel tumour-targeting ligand and provides a promising strategy for future diagnostic or therapeutic applications. PMID- 26773663 TI - Injectable hydrogel promotes early survival of induced pluripotent stem cell derived oligodendrocytes and attenuates longterm teratoma formation in a spinal cord injury model. AB - Transplantation of pluripotent stem cells and their differentiated progeny has the potential to preserve or regenerate functional pathways and improve function after central nervous system injury. However, their utility has been hampered by poor survival and the potential to form tumors. Peptide-modified biomaterials influence cell adhesion, survival and differentiation in vitro, but their effectiveness in vivo remains uncertain. We synthesized a peptide-modified, minimally invasive, injectable hydrogel comprised of hyaluronan and methylcellulose to enhance the survival and differentiation of human induced pluripotent stem cell-derived oligodendrocyte progenitor cells. Cells were transplanted subacutely after a moderate clip compression rat spinal cord injury. The hydrogel, modified with the RGD peptide and platelet-derived growth factor (PDGF-A), promoted early survival and integration of grafted cells. However, prolific teratoma formation was evident when cells were transplanted in media at longer survival times, indicating that either this cell line or the way in which it was cultured is unsuitable for human use. Interestingly, teratoma formation was attenuated when cells were transplanted in the hydrogel, where most cells differentiated to a glial phenotype. Thus, this hydrogel promoted cell survival and integration, and attenuated teratoma formation by promoting cell differentiation. PMID- 26773665 TI - Hollow mesoporous silica nanoparticles facilitated drug delivery via cascade pH stimuli in tumor microenvironment for tumor therapy. AB - To efficiently deliver anti-cancer drug to tumor site and reduce its toxic side effects on normal tissues, a polyethylene glycol (PEG) shielding and tumor microenvironment triggering cascade pH-responsive hollow mesoporous silica nanoparticles (HMSNs) drug delivery system was fabricated. 3-(3, 4 dihydroxyphenyl) propionic acid (DHPA) functionalized beta-cyclodextrin (beta-CD) was grafted onto the surfaces of HMSNs via boronic acid-catechol ester bonds. Then, PEG conjugated adamantane (Ada) was anchored on HMSNs-beta-CD nanocarrier via host-gust interaction. Various techniques proved the successful fabrication of the system. The in vitro tests confirmed that the system was biocompatible. After the system permeating into tumor via enhanced permeability and retention (EPR) effect, the benzoic-imine bonds between the PEG and Ada were cleaved under weak acid condition in tumor microenvironment (pH 6.8), while the dissociated PEG protective layer facilitating cellular uptake of HMSNs system. Subsequently, the boronic acid-catechol ester bonds linkers further hydrolyzed under even low endosomal pH (4.5-6.5) condition for intracellular drug delivery, leading to efficient cell apoptosis. The in vivo results demonstrated that drug loaded HMSNs significantly inhibited tumor growth while only with minimal toxic side effects. The strategy provides new insight into the development of new generation of drug delivery carriers triggering by tumor microenvironment. PMID- 26773666 TI - Acidity-responsive gene delivery for "superfast" nuclear translocation and transfection with high efficiency. AB - In principle, not only efficient but rapid transfection is required since it can maximize the bioavailability of vector-carried gene prior to the cellular excretion. However, the "rapid" goal has been paid few attentions so far in the research field of vector-aided transfection. As a pioneering attempt, the present study designed a lysosome-targeting acidity-responsive nanoassembly as gene vectors, which proved the amazing potency to mediate the "Superfast" transnuclear gene transport and gene transfection with high efficiency in vitro and in vivo. The nanoassembly was constructed on the pH-reversible covalent boronic acid-diol coupling between 1,3-diol-rich oligoethylenimine (OEI-EHDO) and phenylboronic acid modified cholesterol (Chol-PBA). The rapid and efficient nuclei-tropic delivery and transfection was demonstrated to highly rely on the lysosome-acidity induced assembly destruction followed by the easy liberation of gene payloads inside cells. The nanoassembly-mediated transfection at 8 h can afford the outcome even comparable to that achieved at 48 h by the golden standard of PEI25k, and the transfection efficiency can still remain at a high level during 48 h. In contrast, time-dependent efficiency enhancement was identified for the transfections using PEI25k and OEI-EHDO as delivery vectors. Moreover, owing to the hydroxyl-rich surface, this delivery nanosystem presented strong tolerance to the serum-induced transfection inhibition that frequently occurred for the polycationic gene vectors such as PEI25k. The in vitro and in vivo results manifested the low toxicity of this bio-decomposable nanoassembly. PMID- 26773667 TI - Mitochondrial electron transport chain identified as a novel molecular target of SPIO nanoparticles mediated cancer-specific cytotoxicity. AB - Superparamagnetic iron oxide nanoparticles (SPIONs) are highly cytotoxic and target cancer cells with high specificity; however, the mechanism by which SPIONs induce cancer cell-specific cytotoxicity remains unclear. Herein, the molecular mechanism of SPION-induced cancer cell-specific cytotoxicity to cancer cells is clarified through DNA microarray and bioinformatics analyses. SPIONs can interference with the mitochondrial electron transport chain (METC) in cancer cells, which further affects the production of ATP, mitochondrial membrane potential, and microdistribution of calcium, and induces cell apoptosis. Additionally, SPIONs induce the formation of reactive oxygen species in mitochondria; these reactive oxygen species trigger cancer-specific cytotoxicity due to the lower antioxidative capacity of cancer cells. Moreover, the DNA microarray and gene ontology analyses revealed that SPIONs elevate the expression of metallothioneins in both normal and cancer cells but decrease the expression of METC genes in cancer cells. Overall, these results suggest that SPIONs induce cancer cell death by targeting the METC, which is helpful for designing anti cancer nanotheranostics and evaluating the safety of future nanomedicines. PMID- 26773669 TI - Topological design and additive manufacturing of porous metals for bone scaffolds and orthopaedic implants: A review. AB - One of the critical issues in orthopaedic regenerative medicine is the design of bone scaffolds and implants that replicate the biomechanical properties of the host bones. Porous metals have found themselves to be suitable candidates for repairing or replacing the damaged bones since their stiffness and porosity can be adjusted on demands. Another advantage of porous metals lies in their open space for the in-growth of bone tissue, hence accelerating the osseointegration process. The fabrication of porous metals has been extensively explored over decades, however only limited controls over the internal architecture can be achieved by the conventional processes. Recent advances in additive manufacturing have provided unprecedented opportunities for producing complex structures to meet the increasing demands for implants with customized mechanical performance. At the same time, topology optimization techniques have been developed to enable the internal architecture of porous metals to be designed to achieve specified mechanical properties at will. Thus implants designed via the topology optimization approach and produced by additive manufacturing are of great interest. This paper reviews the state-of-the-art of topological design and manufacturing processes of various types of porous metals, in particular for titanium alloys, biodegradable metals and shape memory alloys. This review also identifies the limitations of current techniques and addresses the directions for future investigations. PMID- 26773670 TI - Composite core-and-skirt collagen hydrogels with differential degradation for corneal therapeutic applications. AB - Scarcity of donor tissue to treat corneal blindness and the need to deliver stem cells or pharmacologic agents to ensure corneal graft survival are major challenges. Here, new composite collagen-based hydrogels are developed as implants to restore corneal transparency while serving as a possible reservoir for cells and drugs. The composite hydrogels have a centrally transparent core and embedded peripheral skirt of adjustable transparency and degradability, with the skirt exhibiting faster degradation in vitro. Both core and skirt supported human epithelial cell populations in vitro and the skirt merged homogeneously with the core material to smoothly distribute a mechanical load in vitro. After in vivo transplantation in rabbit corneas over three months, composites maintained overall corneal shape and integrity, while skirt degradation could be tracked in vivo and non-invasively due to partial opacity. Skirt degradation was associated with partial collagen breakdown, thinning, and migration of host stromal cells and macrophages, while the central core maintained integrity and transparency as host cells migrated and nerves regenerated. IMPACT: This study indicates the feasibility of a collagen-based composite hydrogel to maintain corneal stability and transparency while providing a degradable peripheral reservoir for cell or substance release. PMID- 26773668 TI - Influence of sulfur content on bone formation and antibacterial ability of sulfonated PEEK. AB - Polyetheretherketone (PEEK) is desirable in orthopedic and dental applications because its mechanical properties are similar to those of natural bones but the bioinertness and inferior osteoconduction of PEEK have hampered many clinical applications. In this work, PEEK is sulfonated by concentrated sulfuric acid to fabricate a three-dimensional (3D) network. A hydrothermal treatment is subsequently conducted to remove the residues and the temperature is adjusted to obtain different sulfur concentrations. In vitro cell proliferation and real-time PCR analyses disclose enhanced proliferation and osteogenic differentiation of rat bone mesenchymal stem cells (rBMSCs) on the samples with small sulfur concentrations. The in vitro antibacterial evaluation reveals that all the sulfonated samples possess excellent resistance against Staphylococcus aureus and Escherichia coli. The in vivo rat femur implantation model is adopted and X-ray, micro-CT, and histological analyses indicate that not only the premeditated injected bacteria cells are sterilized, but also new bone forms around the samples with small sulfur concentrations. The in vitro and in vivo results reveal that the samples subjected to the hydrothermal treatment to remove excess sulfur have better osseointegration and antibacterial ability and PEEK modified by sulfonation and hydrothermal treatment is promising in orthopedic and dental applications. PMID- 26773671 TI - Testing the effects of a disgust placebo with eye tracking. AB - Previous neuroimaging research showed that a disgust placebo (inert pill presented with the verbal suggestion of disgust relief) reduced visual cortex activation during the viewing of disgust-inducing images. In order to investigate whether this effect of automatic emotion regulation was associated with changed visual scanning patterns of the pictures, we conducted two eye tracking experiments. In the first study, 23 women underwent a retest design during which they passively viewed images depicting disgusting, fear-eliciting, neutral items and fractals both with, and without a placebo. The placebo provoked a substantial decrease in experienced disgust. Although none of the recorded eye movement parameters (number of fixations, fixation duration, saccade amplitude, blinking rate) showed placebo-related changes, placebo effects were suggested by an analysis of spatial fixation patterns. In the second study, which focused on attentional (dis)engagement, 46 women looked at two pictures which were presented side-by-side on the screen. These picture pairs (disgust-neutral, neutral neutral) were once viewed with and once without a placebo. The placebo again provoked a marked decrease of experienced disgust and enhanced the number of fixations for disgusting images. This change might reflect a greater willingness of the participants to view these stimuli while on the placebo. PMID- 26773673 TI - 24-hour rhythmicity of seizures in refractory focal epilepsy. AB - The occurrence of seizures in specific types of epilepsies can follow a 24-hour nonuniform or nonrandom pattern. We described the 24-hour pattern of clinical seizures in patients with focal refractory epilepsy who underwent video electroencephalography monitoring. Only patients who were candidates for epilepsy surgery with an unequivocal seizure focus were included in the study. A total of 544 seizures from 123 consecutive patients were analyzed. Specific time of seizures were distributed along 3- or 4-hour time blocks or bins throughout the 24-hour period. The mean age of the subjects was 37.7 years, with standard deviation of 11.5 years, median of 37. The majority were females (70/56%). The majority of patients had a seizure focus located in the mesial temporal lobe (102/83%) and in the neocortical temporal lobe (13/11%). The remaining patients had a seizure focus located in the extratemporal lobe (8/6%). The most common etiology was mesial temporal sclerosis (86/69.9%). Nonuniform seizure distribution was observed in seizures arising from the temporal lobe (mesial temporal lobe and neocortical temporal lobe), with two peaks found in both 3- and 4-hour bins: 10:00-13:00/16:00-19:00 and 08:00-12:00/16:00-20:00 respectively (p=0.004). No specific 24-hour pattern was identified in seizures from extratemporal location. The 24-hour rhythmicity of seizure distribution is recognized in certain types of epilepsy, but studies on the topic are scarce. Their replication and validation is therefore needed. Our study confirms the bimodal pattern of temporal lobe epilepsy independently of the nature of the lesion. However, peak times differ between different studies, suggesting that the ambient, rhythmic exogenous factors or environmental/social zeitgebers, may modulate the 24-hour rhythmicity of seizures. Characterization of these 24-hour patterns of seizure occurrence can influence diagnosis and treatment in selected types of epilepsy, such as the case of temporal lobe epilepsy, the most common drug-resistant epilepsy. PMID- 26773672 TI - Effect of motivational interviewing on quality of life in patients with epilepsy. AB - OBJECTIVE: In this study, the effect of motivational interviewing on quality of life was evaluated in patients with epilepsy. METHODS: Fifty-six patients with epilepsy in a clinical trial were randomly assigned to intervention and control groups. Motivational interviewing during 5 sessions was applied for the intervention group, and the control group received health-care services. Quality of-life questionnaire in epilepsy (QOLIE-89) was applied as pre- and posttest for both groups. Before and two months after intervention, both groups were assessed. Data were analyzed by independent t-test, Chi-square test, and paired t-test. RESULTS: The data analysis showed that mean score of the QOLIE-89 was 38.94+/ 8.55 and 70.90+/-7.99 in the intervention group before and after the intervention, respectfully, and 44.59+/-12.27 and 36.52+/-7.16 in the control group sequentially. The intervention group showed a significant score increase in their quality of life (p<0.001), whereas the control group had a score decrease (p<0.001). CONCLUSION: Motivational interviewing approach could be used as an effective intervention method for improving patients' quality of life. PMID- 26773674 TI - Neuropsychological profiles and outcomes in children with new onset frontal lobe epilepsy. AB - Frontal lobe epilepsy (FLE) is the second most frequent type of localization related epilepsy, and it may impact neurocognitive functioning with high variability. The prevalence of neurocognitive impairment in affected children remains poorly defined. This report outlines the neuropsychological profiles and outcomes in children with new onset FLE, and the impact of epilepsy-related factors, such as seizure frequency and antiepileptic drug (AED) load, on the neurocognitive development. Twenty-three consecutive children (15 males and 8 females) with newly diagnosed cryptogenic FLE were enrolled; median age at epilepsy onset was 7 years (6-9.6 years). They underwent clinical and laboratory evaluation and neuropsychological assessment before starting AED treatment (time 0) and after one year of treatment (time 1). Twenty age-matched patients affected by idiopathic generalized epilepsy (10 male and 10 females) and eighteen age matched healthy subjects (9 males and 9 females) were enrolled as controls and underwent the same assessment. All patients with FLE showed a significant difference in almost all assessed cognitive domains compared with controls, mainly in frontal functions and memory. At time 1, patients were divided into two groups according to epilepsy-related factors: group 1 (9 patients) with persisting seizures despite AED polytherapy, and group 2 (14 patients) with good seizure control in monotherapy. A significant difference was highlighted in almost all subtests in group 1 compared with group 2, both at time 0 and at time 1. In children with FLE showing a broad range of neurocognitive impairments, the epilepsy-related factors mostly related to a worse neurocognitive outcome are poor seizure control and the use of AED polytherapy, suggesting that epileptic discharges may have a negative impact on the functioning of the involved cerebral regions. PMID- 26773675 TI - Preliminary evidence for gender effects of levetiracetam monotherapy duration on bone health of patients with epilepsy. AB - Enzyme-inducing antiepileptic drugs AEDs have adverse effects on bone mineral density (BMD), whereas studies on levetiracetam (LEV), a nonenzyme-inducing agent, have showed conflicting results. The aim of this study was to further elucidate the role of LEV in bone health. A sample of forty-six patients with epilepsy (mean age: 35.7 years, range: 20.2-64.2 years, 39.1% males) on LEV monotherapy for at least one year (range: 1.5-14.5 years, median 5.5 years) underwent femoral neck (FN) and lumbar spine (LS) BMD measurements. The T- and Z scores were calculated. Results showed that 15.2% of the patients were identified with osteopenia and none with osteoporosis. Pearson's correlations revealed a negative but not significant association of LEV duration with bone-related measurements (range of rhos: from -0.004 to -0.23), except for LS T-scores. In terms of FN BMD measurements, Z-scores, and T-scores, longer LEV therapy duration had adverse but not significant effects on bone health after adjusting for age and gender. With regard to LS BMD measurements, Z-scores, and T-scores, men taking LEV for at least 5.5 years had better, although not significant, bone health compared with men with shorter LEV exposure, after adjusting for age. The opposite was found in women, although differences did not reach significance. These preliminary results are indicative of a differential effect of LEV therapy duration in men and women, which could presumably account for the incongruity of the already published studies. Also, LS assessments were more sensitive to these gender differences. Future larger studies should validate these results. PMID- 26773676 TI - Ketogenic diet effects on neurobehavioral development of children with intractable epilepsy: A prospective study. AB - OBJECTIVE: This study aimed to determine the impact of a ketogenic diet (KD) on neurobehavioral development when used to treat children with intractable epilepsy, confirming the efficacy of the KD, as well as the correlation between early electroencephalography (EEG) changes in the early stage with treatment efficacy. METHODS: We enrolled 42 children who were starting treatment for intractable epilepsy with the classic KD protocol. The total development quotient as well as the development quotients for adaptability, gross motor movements, fine motor movements, language, and individual-social interaction on the Gesell developmental scales were assessed before and after 3, 6, 12, and 18 months of KD treatment. The efficacy assessment was based on changes in seizure frequency after KD as recorded by the parents. We conducted 24-h video-EEG before and after 1 month of KD treatment. RESULTS: Developmental quotients of five energy regions in the Gesell developmental scales assessment were used to compare adaptability (P1=0.000), gross motor movements (P2=0.010), and fine motor movements (P3=0.000); the results showed significant differences. After KD treatment at different time points, 69.0%, 54.8%, 40.5%, and 33.3% patients, respectively, achieved a >=50% reduction in seizure frequency. The reduction of epileptiform discharges in the awake state after 1 month of KD treatment correlated with the efficacy after 3 months of KD treatment. CONCLUSIONS: Ketogenic diet treatment tends to be associated with improved neurobehavioral development, and more significant improvement can be obtained with prolonged treatment. The KD is safe and effective in treating children with intractable epilepsy. Early EEG changes correlate with clinical efficacy, to a certain degree. PMID- 26773677 TI - Time course evaluation of behavioral impairments in the pilocarpine model of epilepsy. AB - Epilepsy is a brain function disorder characterized by unpredictable and recurrent seizures. The majority of patients with temporal lobe epilepsy (TLE), which is the most common type of epilepsy, have to live not only with seizures but also with behavioral alterations, including anxiety, psychosis, depression, and impaired cognitive functioning. The pilocarpine model has been recognized as an animal model of TLE. However, there are few studies addressing behavioral alterations in the maturation phase when evaluating the time course of the epileptogenic process after pilocarpine administration. Therefore, the present work was designed to analyze the neurobehavioral impairments of male adult Wistar rats during maturation and chronic phases in the pilocarpine model of epilepsy. Behavioral tests included: open-field tasks, olfactory discrimination, social recognition, elevated plus maze, and the forced swimming test. The main behavioral alterations observed in both maturation and chronic phases of the pilocarpine model were olfactory and short-term social memory deficits and decrease in the immobility time in the forced swimming test. Moreover, increased anxiety-like responses were only observed in the maturation phase. These findings indicate that early behavioral impairments can be observed in the pilocarpine model during the maturation phase, and these behavioral deficits also occur during the acquired epilepsy (chronic phase). Several of the neurobehavioral impairments that are associated with epilepsy in humans were observed in the pilocarpine-treated rats, thus, rendering this animal model a useful tool to study neuroprotective strategies as well as neurobiological and psychopathological mechanisms associated with epileptogenesis. PMID- 26773678 TI - Reappraisal of epileptic pain as a rare symptom of seizures. AB - PURPOSE: To draw attention to epileptic pain which is a rare seizure symptom mostly causing wrong diagnosis and delayed treatment. We present nine patients in whom pain was a prominent initial or early ictal symptom. METHODS: We reviewed the records of 4736 patients, and found nine patients who had pain as an aura or an early prominent symptom of their seizures. Seizure semiology, EEG, and cranial imaging features were evaluated retrospectively. RESULTS: Age at seizure onset ranged from 6 months to 50 years, and the mean age during the study was 37.7+/ 11.9 years. Pain was predominantly peripherally localized in four patients, whereas cephalic pain was detected in three patients, and abdominal pain was detected in two patients. Electroencephalography (EEG) revealed epileptic abnormalities on the temporoparietal and frontotemporal regions in three patients each. Photosensitive generalized epileptic discharges were detected in one and diffuse background slowing in the remaining two other patients. Electroencephalography abnormalities were lateralized to the contralateral site of the pain in four patients with strictly localized pain. Three patients revealed no abnormality on the cranial MR imaging, whereas others showed different types of abnormality such as heterotopias (n:1), mesial temporal lobe atrophy (n:1), white and gray matter sequela lesions (n:1), diffuse white matter lesion (n:1), chronic encephalomalacia and gliosis (n:1), and perivascular space dilatation (n:1). CONCLUSION: Epileptic pain is a neglected, but important, semiologic symptom with localization and lateralization value in the patients with somatosensorial seizures of parietal as well as temporal lobe origin. It occurs mainly as peripherally localized, cephalic, or abdominal pain and is usually associated with a symptomatic etiology. Awareness of epileptic pain is important to avoid misdiagnosis and delayed treatment. PMID- 26773679 TI - Felt and enacted stigma in elderly persons with epilepsy: A qualitative approach. AB - Stigma is a common psychological consequence of chronic diseases, including epilepsy; however, little research has been done to determine the effect of stigma on persons with epilepsy, especially the elderly. We interviewed 57 older adults with epilepsy to discover the extent and consequences of, and reasons for, epilepsy-related stigma in their lives. Felt stigma was more frequently reported than enacted stigma, with over 70% having experienced this form of stigma. Participants described ignorance and fear of the disease as the foundation of epilepsy-related stigma. The most common response to stigmatizing events was a decrease in epilepsy disclosure to family or friends. Results from this study could inform interventions designed for elderly persons with epilepsy and their support networks, as well as educational campaigns for the general public. PMID- 26773680 TI - Use of antiepileptic drugs during pregnancy and lactation: Type of information provided by searching Google. AB - Surveys among women with epilepsy (WWE) show that they receive their essential pregnancy-related information from many sources, including the internet. Our aim was to assess the types of websites provided by searching Google for the use of four antiepileptic drugs (AEDs) during pregnancy and lactation. The search was performed on 40 computers used by health-care professionals, on 40 computers used by nonhealth-care professionals, and on 5 computers used by WWE in Israel and on 8 computers used by nonhealth-care professionals in the U.S. On each computer, a Google search was conducted for term combinations that included one AED name ("carbamazepine","valproic acid", "lamotrigine", "levetiracetam", or "Keppra") and "Pregnancy", "Lactation", or "Breastfeeding". The top three and top ten websites retrieved in every search were mapped (a total of 45 and 150 websites, respectively, from each computer). Across all searches in English, on both U.S. and Israeli computers, the majority of websites listed among the first three and first ten results were those of independent health portals. The representation of the Epilepsy Foundation website was 10% or less, and only a few results were obtained from the NIH's general public-oriented MedlinePlus. In Hebrew, results included almost exclusively Israeli or Hebrew-translated websites. As in English, results from public-oriented, professionally-written websites in Hebrew accounted for less than 50% of entries. Overall, the availability of readable and high quality information on AEDs used by pregnant and breastfeeding women is limited. Guiding patients towards accurate web resources can help them navigate among the huge amount of available online information. PMID- 26773681 TI - Infodemiology of status epilepticus: A systematic validation of the Google Trends based search queries. AB - People increasingly use Google looking for health-related information. We previously demonstrated that in English-speaking countries most people use this search engine to obtain information on status epilepticus (SE) definition, types/subtypes, and treatment. Now, we aimed at providing a quantitative analysis of SE-related web queries. This analysis represents an advancement, with respect to what was already previously discussed, in that the Google Trends (GT) algorithm has been further refined and correlational analyses have been carried out to validate the GT-based query volumes. Google Trends-based SE-related query volumes were well correlated with information concerning causes and pharmacological and nonpharmacological treatments. Google Trends can provide both researchers and clinicians with data on realities and contexts that are generally overlooked and underexplored by classic epidemiology. In this way, GT can foster new epidemiological studies in the field and can complement traditional epidemiological tools. PMID- 26773682 TI - Parental-reported pain insensitivity in Dup15q. AB - Parents of children with chromosome 15q duplication syndrome (Dup15q) have anecdotally reported high pain threshold as a feature of the disorder. The purpose of this study was to document parental-reported estimates of the frequency of high pain tolerance and the stimuli that fail to evoke a normal pain response. We sent an online survey to 840 families with children with Dup15q to explore the frequency and clinical manifestations of high pain threshold. There were 216 respondents (25.7%). A high pain threshold was reported in 87% of children at some time. There was a trend (p=0.06) for high pain threshold to be more commonly observed among children with the isodicentric (85.6%) and other genetic variants (95%) than interstitial (69.6%) duplications. There was no association between reports of high pain threshold and reports of an intellectual disability (91% of cases), autism spectrum disorder (83% of cases), or self injurious behavior (40% of cases). Reports included many dramatic cases such as severe burns, broken bones, and electrical traumas, which were associated with little or no evidence of a painful stimulus. A high pain threshold is reported in other disorders associated with intellectual disability and autism; the underlying mechanism in Dup15q and other disorders remains undefined. PMID- 26773683 TI - Subjective and objective characteristics of altered consciousness during epileptic seizures. AB - BACKGROUND: Conscious states are inner states and processes of awareness. These states are by definition subjective. METHODS: We analyzed subjective and objective characteristics of alteration of consciousness (AOC) during epileptic seizures, including its involvement in both the level of awareness and subjective content of consciousness. We evaluated AOC using the Consciousness Seizure Scale, the Ictal Consciousness Inventory, and a new structured survey developed by our group: the Seizure Perception Survey, which incorporates patients' subjective experiences before and after they watch a video-electroencephalographic recording of their own seizure. RESULTS: We included 35 patients (105 seizures) with drug resistant epilepsy. Most seizures caused profound AOC. The content of consciousness was lower during temporal seizures with profound AOC. We uncovered a correlation between the subjective perception and objective duration of a seizure using the Seizure Perception Survey regarding memory; the patients had a better recall of ictal onset during wakefulness regardless of the epileptogenic zone, laterality, or magnitude of AOC. Nonetheless, the recovery of memory at the end of a seizure took more time in patients who showed greater AOC, less vivid content of consciousness, or a longer seizure. For 85% of the patients, this was the first time they were able to view their own seizures. The majority of the patients requested to view them again because this procedure allowed them to compare the recordings with their own memories and emotions during a seizure and to verify the real duration of the seizure. DISCUSSION: Alteration of consciousness is one of the most dramatic clinical manifestations of epilepsy. Usually, practitioners or relatives assume that the patients with AOC may not have any knowledge on their seizures. In this study, however, we found that most patients with AOC had a fairly accurate perception of the duration of a seizure and retained their memory of ictal onset. In contrast, for the majority of the patients, watching their own seizure was an extremely positive experience, and most patients stated that they were surprised as well as glad to view what really happened, without expressing negative opinions. Inclusion of subjective characteristics of AOC into the analysis yielded complete assessment of various dimensions of consciousness and therefore allowed us to gain a more detailed understanding of consciousness. PMID- 26773684 TI - Socioeconomic status influences time to surgery and surgical outcome in pediatric epilepsy surgery. AB - The aims of this study were to evaluate the influence of socioeconomic status (SES) on time-to-surgery (TTS) and surgical outcome in children with treatment resistant epilepsy in a universal health care system. The cohort consisted of children who had undergone resective epilepsy surgery between 2001 and 2013 in Canada. The patients' postal codes were linked to Statistics Canada National Household Survey data to obtain dissemination area income, which was used to infer SES. Time-to-surgery was defined as the interval from date of epilepsy onset to date of surgery. Seizure outcome was classified using ILAE classification. The associations between SES and TTS, as well as SES and surgical outcome, were assessed. Two hundred eighty-four children who had epilepsy surgery were included. Patients in the lowest income quintile had a significantly higher TTS relative to the highest income quintile (beta=0.121, p=0.044). There were no significant associations between income quintiles and seizure-free surgical outcome (odds ratio (OR)=0.746-1.494, all p>0.05). However, patients in the lowest income quintile had a significantly lower odds of an improvement in seizure frequency relative to the highest income quintile (OR=0.262, p=0.046). The TTS was not uniform across SES in spite of the existence of a universal health care system. This finding highlights the need to address social and economic barriers for epilepsy surgery to improve access to this potentially curative treatment. Those with lower SES had lower likelihood of improvement in seizure control following epilepsy surgery and may require additional support including social and financial support to mitigate the discrepancies in seizure control following surgery between SES levels. PMID- 26773685 TI - The development of pragmatic skills in children after hemispherotomy: Contribution from left and right hemispheres. AB - PURPOSE: Hemispherotomy (H) is the standard treatment used to cure hemispheric epileptic syndromes in childhood. The postoperative linguistic profile involves hemispheric specialization processes and developmental cognitive plasticity. This research concerns pragmatic aspects of language as a tool for communication which involves both linguistic and extralinguistic communication in context. Our aim was to analyze whether any correlation exists with age at surgery and side of surgery on pragmatic skills following H. METHOD: Forty children who underwent H (23 females, 16 right H) were evaluated at a mean age of 12.8 years (+/-2.6) with two receptive tasks (oral comprehension and syntactic judgment), the Children's Communication Checklist (CCC) rating scale, and the Behavioral Rating Inventory of Executive Function (BRIEF) questionnaire in order to evaluate the role of executive functions on pragmatic skills. Children operated on before the age of 18 months were considered the "early" group (5 right H and 9 left H), while those operated on later were called the "late" group (11 right H and 15 left H). KEY FINDINGS: The whole group had significant deficits in all three measures. We demonstrated a statistically significant crossed interaction between the side of H and the age at H with pragmatic language impairments (F(1,36)=17.48; p=.0002) and disorders in executive function (F(1,36)=5.80; p=.021) in left early H and in right late H patients. These findings are consistent with the previous studies of pragmatic language impairments concerning adolescents and adults with right hemisphere damage and emphasize the contribution of structural language in the early stage of verbal communication. SIGNIFICANCE: These results emphasize for the first time that hemispherotomized children have pragmatic language impairments that are independent of receptive language. Our findings are congruent with the recent theory on pragmatic language development in childhood with evidence of a participation of the left hemisphere at the early age followed by right hemispheric specialization and involvement of executive functions, independently of receptive language. PMID- 26773686 TI - Understanding the burden of idiopathic generalized epilepsy in the United States, Europe, and Brazil: An analysis from the National Health and Wellness Survey. AB - The aim of this study was to understand the current burden of primary generalized tonic-clonic seizures (PGTCS) associated with idiopathic generalized epilepsy (IGE) as a function of seizure frequency. We analyzed data for (IGE) as a proxy measure of PGTCS. Little is known about the quality of life (QoL), health utility, productivity, healthcare resource utilization (HRU), and cost burden of PGTCS or IGE. Patients were identified from the US (2011, 2012, & 2013), 5EU (2011 & 2013), and Brazil (2011 & 2012) National Health and Wellness Survey, a nationally representative, internet-based survey of adults (18+ years). Patients that self-reported a diagnosis of IGE were categorized into seizure frequencies of: >=1 seizure per week, 1-3 seizures per month, 1-4 seizures per year, or <1 seizure per year. QoL was measured using the SF-36v2 Mental (MCS) and Physical Component Summary (PCS) scores, health utilities with the SF-6D, productivity with the Work Productivity and Activity Impairment (WPAI) questionnaire, and HRU as reported in the past six months. Unit costs were estimated from the literature and multiplied against HRU values to calculate direct costs and WPAI values to calculate indirect costs. Generalized linear regression was utilized to examine the relationship between seizure frequency and each measure of burden with adjustment for covariates. Out of the general population surveyed, IGE was self reported in 782 of 176,093 (US), 172 of 30,000 (UK), 106 of 30,001 (Germany), 87 of 30,000 (France), 31 of 12,011 (Spain), 22 of 17,500 (Italy), and 34 of 24,000 (Brazil). Persistent seizures (>=1 per year) were reported in over 40% of patients with IGE (10-15% with >=1 seizure per week, 10-15% with 1-3 seizures per month, 20-25% with 1-4 seizures per year). Over 75% were treated with antiepileptic drugs (AEDs). Compared with those having <1 seizure per year (reference group), patients in the two most frequent seizure categories reported worse MCS and PCS scores. Patients in the three highest seizure frequency groups consistently reported worse health utility scores, and greater presenteeism (attending work while not physically or mentally capable of working), overall work impairment, activity impairment, HRU, indirect costs, and direct costs than the reference group. Despite the availability of AEDs during the year surveyed, a substantial number of patients experienced persistent seizures. Increasing seizure frequency was clearly associated with worse outcomes. The burden of PGTCS and IGE may be proportionally reduced by newer AEDs which may increase the proportion of seizure-free patients or shift more patients into lower seizure frequency categories. PMID- 26773687 TI - Intracerebroventricular application of S100B selectively impairs pial arteriolar dilating function in rats. AB - S100B is an astrocyte-derived protein that can act through the receptor for advanced glycation endproducts (RAGE) to mediate either "trophic" or "toxic" responses. Its levels increase in many neurological conditions with associated microvascular dysregulation, such as subarachnoid hemorrhage (SAH) and traumatic brain injury. The role of S100B in the pathogenesis of microvasculopathy has not been addressed. This study was designed to examine whether S100B alters pial arteriolar vasodilating function. Rats were randomized to receive (1) artificial cerebrospinal fluid (aCSF), (2) exogenous S100B, and (3) exogenous S100B+the decoy soluble RAGE (sRAGE). S100B was infused intracerebroventricularly (icv) using an osmotic pump and its levels in the CSF were adjusted to achieve a concentration similar to what we observed in SAH. After 48 h of continuous icv infusion, a cranial window/intravital microscopy was applied to animals for evaluation of pial arteriolar dilating responses to sciatic nerve stimulation (SNS), hypercapnia, and topical suffusion of vasodilators including acetylcholine (ACh), s-nitroso-N-acetyl penicillamine (SNAP), or adenosine (ADO). Pial arteriolar dilating responses were calculated as the percentage change of arteriolar diameter in relation to baseline. The continuous S100B infusion for 48 h was associated with reduced responses to the neuronal-dependent vasodilator SNS (p<0.05) and the endothelial-dependent vasodilator ACh (p<0.05), compared to controls. The inhibitory effects of S100B were prevented by sRAGE. On the other hand, S100B did not alter the responses elicited by vascular smooth muscle cell dependent vasodilators, namely hypercapnia, SNAP, or ADO. These findings indicate that S100B regulates neuronal and endothelial dependent cerebral arteriolar dilation and suggest that this phenomenon is mediated through RAGE-associated pathways. PMID- 26773689 TI - Functional connectivity predictors and mechanisms of cognitive behavioural therapies: A systematic review with recommendations. AB - OBJECTIVE: While there is now strong evidence that psychological therapies can alter the activity of individual brain regions, their impact on the functional integration between regions has not yet been systematically evaluated. This area is important given that brain dysconnectivity has been implicated across almost all psychiatric disorders. Accordingly, we sought to establish connectivity predictors and mechanisms of effective psychological therapies. We further establish whether connectivity changes represent normalisation of disorder pathophysiology or compensatory changes. METHOD: We reviewed studies examining structural and functional connectivity longitudinally as either a predictor or outcome variable of successful psychological therapies across psychiatric disorders. RESULTS: Fifteen studies met our inclusion criteria. All but three related to cognitive behavioural therapy. Of these, five assessed resting state, nine probed affective processing and one probed cognitive processing. Twelve studies reported evidence of functional connectivity as a significant predictor or outcome of cognitive behavioural therapy, with prefronto-limbic circuitry most commonly implicated. Only six studies included healthy participants, limiting direct inferences about normalisation as opposed to compensatory changes. Anxiety disorders were overrepresented, totalling 13 of the studies reviewed. No studies examined structural connectivity or utilised analyses allowing the directionality of functional connectivity to be inferred. CONCLUSION: While the evidence base is still in its infancy for other therapy approaches, there was clearer evidence that functional connectivity both predicts and is altered by cognitive behavioural therapy. Connections from prefrontal cortex appear especially key, perhaps given their role in cognitive appraisal of lower order affective, motivational and cognitive processes. A number of recommendations are made for this rapidly developing literature. PMID- 26773690 TI - Childhood adversities: Social support, premorbid functioning and social outcome in first-episode psychosis and a matched case-control group. AB - OBJECTIVE: The establishment of childhood adversities as risk factors for non affective psychosis has derived a need to consider alternative interpretations of several psychosis-related factors. This paper sought to examine premorbid adjustment trajectories and social outcome factors in relation to childhood adversities. Perceived support has been found to decrease the risk of post traumatic stress disorder, and we wished to compare perceived support in people with first-episode psychosis to non-clinical control persons and explore its relation to childhood adversities. METHOD: Every individual presenting with a non affective first-episode psychosis (F20-29, except F21) in Region Zealand over a 2 year period was approached for participation and the 101 consenting participants were matched to 101 people with no psychiatric disorders. Comprehensive demographic data were collected. Assessment instruments included the Premorbid Assessment Scale, the Global Assessment of Functioning scale and the Childhood Trauma Questionnaire. The latter represented the childhood adversities in addition to parental separation and institutionalization. RESULTS: There were no associations between number of childhood adversities and different social or academic premorbid trajectories. Those with more adversities had lower global functioning the year prior to treatment start and reported lower rates of perceived support during childhood along with less current face-to-face contact with family members. Lack of peer support remained a significant predictor of psychosis when adversities were adjusted for; peer support diminished the risk of psychosis caused by childhood adversities by 10%. CONCLUSION: Childhood adversities may not predict specific premorbid trajectories, but have an effect on global functioning when the psychosis has begun. Perceived support, especially from peers, may be important in the development of psychosis, and those with more adversities may represent a vulnerable subgroup who need more assistance to increase and maintain supportive networks. PMID- 26773688 TI - Norepinephrine at the nexus of arousal, motivation and relapse. AB - Arousal plays a critical role in cognitive, affective and motivational processes. Consistent with this, the dysregulation of arousal-related neural systems is implicated in a variety of psychiatric disorders, including addiction. Noradrenergic systems exert potent arousal-enhancing actions that involve signaling at alpha1- and beta-noradrenergic receptors within a distributed network of subcortical regions. The majority of research into noradrenergic modulation of arousal has focused on the nucleus locus coeruleus. Nevertheless, anatomical studies demonstrate that multiple noradrenergic nuclei innervate subcortical arousal-related regions, providing a substrate for differential regulation of arousal across these distinct noradrenergic nuclei. The arousal promoting actions of psychostimulants and other drugs of abuse contribute to their widespread abuse. Moreover, relapse can be triggered by a variety of arousal-promoting events, including stress and re-exposure to drugs of abuse. Evidence has long-indicated that norepinephrine plays an important role in relapse. Recent observations suggest that noradrenergic signaling elicits affectively-neutral arousal that is sufficient to reinstate drug seeking. Collectively, these observations indicate that norepinephrine plays a key role in the interaction between arousal, motivation, and relapse. This article is part of a Special Issue entitled SI: Noradrenergic System. PMID- 26773691 TI - Caffeine may enhance orthodontic tooth movement through increasing osteoclastogenesis induced by periodontal ligament cells under compression. AB - OBJECTIVE: Caffeine is the kernel component of coffee and has multiple effects on bone metabolism. Here we aimed to investigate the effects of caffeine intake on orthodontic tooth movement (OTM). DESIGN: (1) In the in vivo study, two groups comprising 15 randomly assigned rats each underwent orthodontic treatment. One group ingested caffeine at 25mg/kg body weight per day and the other, plain water. After 3 weeks, the degree of tooth movement and effect on the periodontium were assessed. (2) In the in vitro study, we established a model mimicking the essential bioprocess of OTM, which contained a periodontal ligament tissue model (PDLtm), and a co-culture system of osteoblasts (OBs) and osteoclast precursors (pre-OCs). After being subjected to static compressive force with or without caffeine administration, the conditioned media from the PDLtm were used for the OB/pre-OC co-cultures to induce osteoclastogenesis. RESULTS: (1) In vivo, the caffeine group displayed a significantly greater rate of tooth movement than the control. The alveolar bone mineral density and bone volume fraction were similar between the two groups; however, immunohistochemical staining showed that the caffeine group had significantly more TRAP(+) osteoclasts and higher RANKL expression in the compressed periodontium. (2) In vitro, caffeine at 0.01mM significantly enhanced the compression-induced expression of RANKL and COX-2, as well as prostaglandin E2 production in the PDLtm. Furthermore, the "caffeine+compression"-conditioned media induced significantly more TRAP(+) OC formation when compared with compression alone. CONCLUSIONS: Daily intake of caffeine, at least at some specific dosage, may enhance OTM through increasing osteoclastogenesis. PMID- 26773692 TI - Attitudes towards people with intellectual disability in the UK and Libya: A cross-cultural comparison. AB - BACKGROUND: The attitude of the general population towards people with intellectual disability (ID) provides important background for policy development. Furthermore, because of changes in attitudes across cultures, it is vital to ground policy development for each country in data from that country. AIMS: This paper aimed to undertake a cross-cultural study, investigating attitudes to people with ID in Libya in the year 2011, and to compare the Libyan data with those for the UK. METHODS AND PROCEDURES: This paper provides a cross cultural analysis of attitudes to people with ID, using a questionnaire study of three groups in Libya and in the UK: science students, psychology students and professionals in ID support. The questionnaire used was the established Community Living Attitude Scales for Mental Retardation (CLAS-MR). OUTCOMES AND RESULTS: In terms of the four CLAS-MR sub-scales, the Libyan sample showed significantly less favourable scores on Empowerment, Similarity and Exclusion than the UK sample, but no significant difference on the Sheltering sub-scale. Within-country analysis indicated no main effects of gender on all four sub-scales in Libya and the UK. CONCLUSIONS: This study is the first to undertake quantitative analysis of attitudes to people with ID in Libya. The attitudes were in general less favourable than in the UK and other Western countries, but showed similarities with studies of attitudes to people with ID in Pakistan. PMID- 26773693 TI - Examining accommodation effects for equity by overcoming a methodological challenge of sparse data. AB - BACKGROUND: As accommodation itself is an equity issue in varied contexts in and beyond education (e.g., the provision of assistive technology, extended time, or read-aloud), it is critical to examine the equitability of accommodation policies and practices by examining their effects on student performance. AIMS: This study sought to assess the effectiveness of thirty-one bundled accommodations for students with learning disabilities, emotional or behavioral disorders, or multiple exceptionalities writing a provincial literacy test in Ontario, Canada. METHODS AND PROCEDURES: We employed quantitative methods of log-linear analysis and odds ratio to examine the data. To analyze sparse data, we compared three different adjustment methods to meet this methodological challenge. OUTCOMES AND RESULTS: Our findings suggest that the problems with sparse data can be overcome by an adjustment method. We also found that the likelihood of achieving the provincial standards may differ among students with special needs depending on whether they did or did not receive certain combinations of accommodations for the literacy test. CONCLUSIONS AND IMPLICATIONS: We recommend that education stakeholders review the accommodations that produced significant differential effects to address the concerns regarding whether the test results were interpreted validly and fairly for students with special needs. PMID- 26773694 TI - Developmental trajectories of pitch-related music skills in children with Williams syndrome. AB - The study of music cognition in Williams syndrome (WS) has resulted in theoretical debates regarding cognitive modularity and development. However, no research has previously investigated the development of music skills in this population. In this study, we used the cross-sectional developmental trajectories approach to assess the development of pitch-related music skills in children with WS compared with typically developing (TD) peers. Thus, we evaluated the role of change over time on pitch-related music skills and the developmental relationships between music skills and different cognitive areas. In the TD children, the pitch-related music skills improved with chronological age and cognitive development. In the children with WS, developmental relationships were only found between several pitch-related music skills and specific cognitive processes. We also found non-systematic relationships between chronological age and the pitch-related music skills, stabilization in the level reached in music when cognitive development was considered, and uneven associations between cognitive and music skills. In addition, the TD and WS groups differed in their patterns of pitch-related music skill development. These results suggest that the development of pitch-related music skills in children with WS is atypical. Our findings stand in contrast with the views that claim innate modularity for music in WS; rather, they are consistent with neuroconstructivist accounts. PMID- 26773695 TI - Effectiveness of the revision to FMVSS 301: FARS and NASS-CDS analysis of fatalities and severe injuries in rear impacts. AB - PURPOSE: This study investigated the change in the fatality and severe injury risks in rear impacts with vehicle model years (MY) grouped prior to, during the phase-in and after the revision to FMVSS 301. METHODS: FARS and NASS-CDS data were used to determine the injury risks of non-ejected occupants in light vehicles involving non-rollover, rear impacts. The data were analyzed by MY groups: 1996-2001, 2002-2007 and 2008+ to represent the years prior to, during the phase-in and post-revision phase-in of FMVSS 301. The 1996-2013 FARS data were analyzed for rear crashes defined by the initial crash direction (IMPACT1) and direction with most damage (IMPACT2) to the rear. Fatality risk was determined by the number of fatally injured occupants per all occupants with known injury status. The 1994-2013 NASS-CDS was analyzed for rear crashes defined by the damage area variable. The risk of severe injury (MAIS 4+F) was determined as the number of occupants with MAIS 4+F injury per all occupants with known injury status. The distribution of rear crashes was determined by impact location and crash severity. NASS-CDS electronic cases with 2008+ MY vehicles were analyzed to evaluate the vehicle and occupant performance. RESULTS: The fatality risk was 20.6% in the 1996-2001, 17.3% in the 2002-2007 and 15.0% in the 2008+ MY vehicles using FARS with the initial crash direction variable (IMPACT1) to the rear. There was a 27.1% reduction in risk with post-FMVSS 301 vehicles 2008+ MY. The risk was 19.0%, 15.4% and 12.8% with the most damage variable (IMPACT2) to the rear. There was 32.8% reduction in risk with 2008+ MY vehicles. The NASS-CDS analysis showed that the risk of severe injury (MAIS 4+F) was 0.27+/-0.05% for 1996-2001, 0.30+/-0.13% for 2002-2007 and 0.08+/-0.04% for 2008+ MY year vehicles. There was a 70.2% reduction in the risk for severe injury with 2008+ MY vehicles. The NASS-CDS case review of MAIS 4+F injury in rear impacts of 2008+ MY vehicles that comply with the revised FMVSS 301 indicated that the crashes were very severe and generally involved significant 2nd row intrusion. CONCLUSIONS: The revision to FMVSS 301 has effectively reduced the risks for fatal and severe injury in vehicles compliant with the revision (2008+ MY). The reduction was 27.1 32.8% in fatality risk using FARS data and 70.2% in severe injury risk using the NASS-CDS when compared to vehicles prior to the phase-in of the revised FMVSS 301 (1996-2001 MY vehicles). It is not possible to parse the effects of other design changes in seats and restraint systems that also increased safety over the study years. PMID- 26773696 TI - Driver views on speed and enforcement. AB - This paper reports on the results of a drivers' survey regarding the effects of speed cameras for speed enforcement in Israel. The survey was part of a larger study that accompanied the introduction of digital speed cameras. Speed camera deployment started in 2011, and till the end of 2013 twenty-one cameras were deployed in interurban road sections. Yearly surveys were taken between 2010 and 2013 in 9 gas stations near speed camera installation sites in order to capture drivers' opinions about speed and enforcement. Overall, 1993 drivers were interviewed. In terms of admitted speed behavior, 38% of the drivers in 2010, 21% in 2011, 13% in 2012 and 11% in 2013 reported that their driving speed was above the perceived posted speed limit. The proportion of drivers indicating some speed camera influence on driving decreased over the years. In addition, the majority of drivers (61%) predicted positive impact of speed cameras on safety. This result did not change significantly over the years. The main stated explanation for speed limit violations was time pressure, while the main stated explanation for respecting the posted speed was enforcement, rather than safety concerns. Linear regression and sigmoidal models were applied to describe the linkage between the reported driving speed (dependent) and the perceived posted speed (independent). The sigmoidal model fitted the data better, especially at high levels of the perceived posted speeds. That is, although the perceived posted speed increased, at some point the actual driving speed levels off (asymptote) and did not increase. Moreover, we found that the upper asymptote of the sigmoidal model decreased over the years: from 113.22 (SE=18.84)km/h in 2010 to 88.92 (SE=1.55)km/h in 2013. A wide variance in perceived speed limits suggest that drivers may not know what the speed limits really are. PMID- 26773697 TI - Frontal lobe dementia syndrome as a first manifestation of primary angiitis of the central nervous system (PACNS). AB - This case presents a clinical course of a frontal lobe dysexecutive syndrome with dementia caused by a primary angiitis of the central nervous system (PACNS) of exclusively very small vessels. An isolated frontal lobe dementia syndrome as a primary manifestation of PACNS highlights the diverse clinical manifestations of the disease. The patient presented with a progressive cognitive decline with loss of memory, disinhibited behavior, inappropriate affect and frontal release signs. The diagnostic workup essentially revealed a lymphocytic pleocytosis in the cerebrospinal fluid and a generalized cortical atrophy without any vascular abnormalities. To grasp a diagnosis for this enigmatic clinical picture of a frontal lobe syndrome with signs of inflammation we targeted a tissue-based diagnosis. A brain biopsy gave the decisive hint towards a microvasculitis. Although the histopathologic picture showed peculiarities, a destruction of the vascular bed of very small vessels by lymphocytic infiltration was evident. Our case illustrates an uncommon clinical picture of a PACNS and points to shortcomings of the current histopathologic criteria if only very small vessels are involved. PMID- 26773698 TI - Neurodegeneration with brain iron accumulation presenting motor trick and impaired motor cortical plasticity. PMID- 26773699 TI - Surgery for "Long-term epilepsy associated tumors (LEATs)": Seizure outcome and its predictors. AB - OBJECTIVES: "Long-term epilepsy associated tumors (LEATs)" by definition are tumors primarily causing drug-resistant seizures for two years or more. They include low-grade glial and glioneuronal tumors with normal life expectancy. We studied a large cohort of patients with LEATs who underwent surgery through our epilepsy program. PATIENTS & METHODS: From 1998-2011, 105 patients with LEATs underwent surgery in our center. We utilized their data archived in a prospective registry to evaluate their electro-clinical-imaging characteristics affecting the long-term seizure outcome. RESULTS: Of 105 patients (age 3-50 years), mean age at surgery was 20 years and mean pre-surgical duration of epilepsy was 10.9 years. 66 (62.8%) had secondary generalized seizures. 82 had temporal tumors, 23 had extra temporal (13 frontal, 3 parietal, 2 occipital and 5 multilobar lesions) and four had associated hippocampal sclerosis. The interictal discharges and ictal onset were concordant to the lesion in 82 (78%) and 98 (93%) patients respectively. Lesionectomy and/or adjoining corticectomy or temporal lobectomy was done. Ganglioglioma was the most dominant pathological substrate in 61 (58%). During a mean follow-up of 7.5 years (range 3-16 years), 78/105 (74.2%) were seizure-free and 45 (57.4%) were totally off drugs. Secondary generalized seizures (p-0.02), temporal location of tumor (p-0.008) and spikes in third month post-operative EEG (p-0.03) caused unfavorable seizure outcome. A pre-surgical duration of epilepsy of more than 6.6 years caused less than optimal surgical outcome CONCLUSIONS: Early surgery should be considered a priority in LEATs. Presence of secondary generalized seizures is the single most important predictor of a poor seizure outcome. PMID- 26773700 TI - Olfactory dysfunction in behavioral variant frontotemporal dementia. AB - OBJECTIVE: Several neurodegenerative disorders show olfactory dysfunction. In patients with frontotemporal dementia (FTD), olfactory impairment is probably due to the involvement of the temporal and orbitofrontal lobes. We hypothesized that due to the disrupted areas in FTD, there would be an impairment in smell identification, differentiation and association. Moreover, we hypothesized that there would be a correlation between the severity of FTD and the severity of odor dysfunction. METHODS: In the current study, we compared odor identification, discrimination and association of nine patients with behavioral variant FTD with eleven healthy controls using the Brief Smell Identification Test and the Odor Perception and Semantics Battery. RESULTS: The results showed significant differences in the odor association test, but not in the identification or discrimination test. There was no correlation between disease severity and the performance in the odor tests. CONCLUSION: We showed impairment of odor association that is most likely due to disruption of specific associative areas involved in olfactory processing. Specifically, we propose that the impairment may well be due to disrupted areas in the temporal lobe and amygdala. PMID- 26773701 TI - Two approaches for treating upper thoracic spinal tuberculosis with neurological deficits in the elderly: A retrospective case-control study. AB - OBJECTIVE: The current study compared clinical outcomes of two diverse therapeutic strategies for upper thoracic (T1-4) spinal tuberculosis with neurological deficits in elderly patients. METHODS: A retrospective analysis was performed on 18 cases undergoing single-stage posterior transpedicular decompression, debridement, interbody fusion, and instrumentation (Group A). Sixteen cases underwent single- or two-stage anterior debridement, bone grafting, and posterior instrumentation (Group B). The clinical and radiographic results for these patients were analyzed and compared. RESULTS: Patients were followed up for an average of 40.9 +/- 4.0 months (range 36-48 months). Results demonstrated that the average operative duration, blood loss, hospital stays, and operative complication rate were lesser for Group A than for Group B. The average fusion time was 8.1 +/- 1.5 months and 7.8 +/- 2.9 months in Groups A and B, respectively (p>0.05). Cobb's angles were significantly corrected after surgical management, but loss of correction occurred in both groups. All patients had significant postoperative neurological improvement. CONCLUSIONS: Single-stage posterior transpedicular debridement, decompression, interbody fusion and instrumentation might be a better surgical treatment compared with combined posterior and anterior approaches. Such techniques may result in fewer complications and a better quality of life for elderly patients. PMID- 26773703 TI - Screening mammography: There is a golden mammoth in the room! PMID- 26773702 TI - Serum Beta Hydroxybutyrate Concentrations in Cats with Chronic Kidney Disease, Hyperthyroidism, or Hepatic Lipidosis. AB - BACKGROUND: Ketones, including beta hydroxybutyrate (BHB), are produced in conditions of negative energy balance and decreased glucose utilization. Serum BHB concentrations in cats are poorly characterized in diseases other than diabetes mellitus. HYPOTHESIS: Serum BHB concentrations will be increased in cats with chronic kidney disease (CKD), hyperthyroidism (HT), or hepatic lipidosis (HL). ANIMALS: Twenty-eight client-owned cats with CKD, 34 cats with HT, and 15 cats with HL; 43 healthy cats. METHODS: Prospective observational study. Serum BHB concentrations were measured at admission in cats with CKD, HT, and HL, for comparison with a reference interval established using healthy cats. Results of dipstick urine ketone measurement, when available, were compared to BHB measurement. RESULTS: Beta hydroxybutyrate was above the reference interval (<0.11 mmol/L) in 6/28 cats (21%) with CKD, 7/34 cats (20%) with HT, and 11/15 cats (73%) with HL, significantly exceeding the expected 2.5% above the reference interval for healthy cats (P < .001 for all groups). Elevations were mild in CKD and HT groups (median BHB 0.1 mmol/L for both groups, 80th percentile 0.12 and 0.11 mmol/L, respectively), but more marked in HL cats (median BHB 0.2 mmol/L, 80th percentile 0.84 mmol/L). None of 11 cats with increased serum BHB concentration having urine dipstick analysis performed within 24 h of sampling for BHB were ketonuric. CONCLUSIONS AND CLINICAL IMPORTANCE: Increases in serum BHB concentrations occur in cats with CKD, HT, and HL, and might provide an useful index of catabolism. PMID- 26773704 TI - Generational status, neighborhood context, and mother-child resemblance in dietary quality in Mexican-origin families. AB - Children of immigrants in the United States often grow up in very different nutrition environments than their parents. As a result, parent-child concordance in diet may be particularly weak in immigrant families. Yet, little is known about parent-child dietary resemblance in immigrant families and how local contexts shape it. This study uses data from the 1999/2000-2009/2010 Continuous National Health and Nutrition Examination Survey to examine mother-child resemblance in dietary quality in Mexican-origin families in the United States. We investigate how immigrant generational status and neighborhood context shape the association between mothers' and children's dietary quality. We find that mother-child resemblance in dietary quality is weaker for first-generation children relative to third-generation children. However, residence in an immigrant enclave strengthens the mother-child association in dietary quality for first-generation children. Findings offer a unique within-family perspective of immigrant health. Results suggest that the healthy eating advantage of Mexican immigrant mothers may not be sustained across family generations and that Mexican immigrant mothers may face unique challenges in promoting healthy eating among their children. PMID- 26773706 TI - Thrombophilic risk of individuals with rare compound factor V Leiden and prothrombin G20210A polymorphisms: an international case series of 100 individuals. AB - The risk of thrombosis in individuals with rare compound thrombophilias, homozygous factor V Leiden (FVL) plus heterozygous prothrombin G20210A (PTM), homozygous PTM plus heterozygous FVL, and homozygous FVL plus homozygous PTM, is unknown. We identified, worldwide, individuals with these compound thrombophilias, predominantly through mailing members of the International Society on Thrombosis and Haemostasis. Physicians were sent a clinical questionnaire. Confirmatory copies of the genetic results were obtained. One hundred individuals were enrolled; 58% were female. Seventy-one individuals had a venous thrombosis (includes superficial and deep vein thrombosis, and pulmonary embolism), 4 had an arterial thrombosis and 6 had both. Nineteen individuals had never had a thrombotic event. Thrombosis-free survival curves demonstrated that 50% of individuals had experienced a thrombotic event by 35 yrs of age, while 50% had a first venous thromboembolic event (VTE; includes all venous thrombosis except superficial thrombosis) by 41 yrs of age; 38.2% of first VTEs were unprovoked. 37% of patients had at least one VTE recurrence. Seventy percent of first pregnancies carried to term and not treated with anticoagulation were thrombosis-free. In conclusion, patients with these rare compound thrombophilias are not exceedingly thrombogenic, even though they have a substantial risk for VTE. PMID- 26773708 TI - Instrument translation and initial psychometric evaluation of the Danish Body Image Quality of Life Inventory. AB - RATIONALE AND OBJECTIVES: Negative body perception has been reported in a number of patient populations. No instrument in Danish for measuring body image-related concerns has been available. Without such an instrument, understanding of the phenomenon in Danish-speaking populations is limited. The purpose of the study was thus to translate and validate a Danish version of the Body Image Quality of Life Inventory (BIQLI), in order to obtain a valid instrument applicable for healthcare research. METHODS: The study consisted of two phases: (i) instrument adaptation, including forward and back translation, expert committee comparisons and cognitive interviewing, and (ii) empirical testing of the Danish version (BIQLI-DA) with subsequent psychometric evaluation. Hypothesised correlations to other measures, including body mass index (BMI), Medical Outcome Short Form-8 (SF 8), Patient Health Questionnaire-9 (PHQ-9), General Anxiety Disorder-7 and Symptom Check List-90-Revised (SCL-90-R(r) ) were tested. In addition, exploratory factor structure analysis (EFA) and internal consistency on item and scale level were performed. RESULTS AND STUDY LIMITATIONS: The adapted instrument was found to be semantically sound, yet concerns about face validity did arise through cognitive interviews. Danish college students (n = 189, 65 men, Mage = 21.1 years) participated in the piloting of the BIQLI-DA. Convergent construct validity was demonstrated through associations to related constructs. Exploratory factor analysis revealed a potential subscale structure. Finally, results showed a high internal consistency (Cronbach's alpha = 0.92). Support for the validity of the BIQLI-DA might have been strengthened by repeating cognitive interviews after layout alterations, by piloting the instrument on a larger sample. CONCLUSIONS: This study demonstrated tentative support for the validity of the Danish Body Image Quality of Life (BIQLI-DA) and found the measure to be reliable in terms of internal consistency. Further exploration of response processes and construct validity is needed. PMID- 26773705 TI - The physiological impacts of wealth shocks in late life: Evidence from the Great Recession. AB - Given documented links between individual socioeconomic status (SES) and health, it is likely that-in addition to its impacts on individuals' wallets and bank accounts-the Great Recession also took a toll on individuals' disease and mortality risk. Exploiting a quasi-natural experiment design, this study utilizes nationally representative, longitudinal data from the National Social Life, Health, and Aging Project (NSHAP) (2005-2011) (N = 930) and individual fixed effects models to examine how household-level wealth shocks experienced during the Great Recession relate to changes in biophysiological functioning in older adults. Results indicate that wealth shocks significantly predicted changes in physiological functioning, such that losses in net worth from the pre-to the post Recession period were associated with increases in systolic blood pressure and C reactive protein over the six year period. Further, while the association between wealth shocks and changes in blood pressure was unattenuated with the inclusion of other indicators of SES, psychosocial well-being, and health behaviors in analytic models, we document some evidence of mediation in the association between changes in wealth and changes in C-reactive protein, which suggests specificity in the social and biophysiological mechanisms relating wealth shocks and health at older ages. Linking macro-level conditions, meso-level household environments, and micro-level biological processes, this study provides new insights into the mechanisms through which economic inequality contributes to disease and mortality risk in late life. PMID- 26773709 TI - Stable Boron Peroxides with a Subporphyrinato Ligand. AB - Subporphyrin B-peroxides have been synthesized in good yields by acid-catalyzed exchange reactions of subporphyrin B-methoxide with the corresponding hydroperoxides. Thermal dimerization of the subporphyrin B-hydroperoxide provided the peroxo-bridged bis(subporphyrin) quantitatively. These subporphyrin B peroxides are fairly stable under ambient conditions, which allowed their isolation and full characterization as the first examples of structurally authenticated boron hydroperoxides, acyclic boron organylperoxides, and neutral peroxo-bridged diboron species. The subporphyrin B-peroxides thus prepared were investigated through their crystal structures, IR spectra, and cyclic voltammograms as well as by DFT calculations. The subporphyrin B-hydroperoxide oxidizes triphenylphosphine quantitatively to triphenylphosphine oxide. PMID- 26773707 TI - CD200 expression in human cultured bone marrow mesenchymal stem cells is induced by pro-osteogenic and pro-inflammatory cues. AB - Similar to other adult tissue stem/progenitor cells, bone marrow mesenchymal stem/stromal cells (BM MSCs) exhibit heterogeneity at the phenotypic level and in terms of proliferation and differentiation potential. In this study such a heterogeneity was reflected by the CD200 protein. We thus characterized CD200(pos) cells sorted from whole BM MSC cultures and we investigated the molecular mechanisms regulating CD200 expression. After sorting, measurement of lineage markers showed that the osteoblastic genes RUNX2 and DLX5 were up regulated in CD200(pos) cells compared to CD200(neg) fraction. At the functional level, CD200(pos) cells were prone to mineralize the extra-cellular matrix in vitro after sole addition of phosphates. In addition, osteogenic cues generated by bone morphogenetic protein 4 (BMP4) or BMP7 strongly induced CD200 expression. These data suggest that CD200 expression is related to commitment/differentiation towards the osteoblastic lineage. Immunohistochemistry of trephine bone marrow biopsies further corroborates the osteoblastic fate of CD200(pos) cells. However, when dexamethasone was used to direct osteogenic differentiation in vitro, CD200 was consistently down-regulated. As dexamethasone has anti-inflammatory properties, we assessed the effects of different immunological stimuli on CD200 expression. The pro-inflammatory cytokines interleukin-1beta and tumour necrosis factor-alpha increased CD200 membrane expression but down-regulated osteoblastic gene expression suggesting an additional regulatory pathway of CD200 expression. Surprisingly, whatever the context, i.e. pro-inflammatory or pro-osteogenic, CD200 expression was down-regulated when nuclear-factor (NF)-kappaB was inhibited by chemical or adenoviral agents. In conclusion, CD200 expression by cultured BM MSCs can be induced by both osteogenic and pro-inflammatory cytokines through the same pathway: NF-kappaB. PMID- 26773710 TI - Cancer stem cells: a metastasizing menace! AB - Cancer is one of the leading causes of death worldwide, and is estimated to be a reason of death of more than 18 billion people in the coming 5 years. Progress has been made in diagnosis and treatment of cancer; however, a sound understanding of the underlying cell biology still remains an unsolved mystery. Current treatments include a combination of radiation, surgery, and/or chemotherapy. However, these treatments are not a complete cure, aimed simply at shrinking the tumor and in majority of cases, there is a relapse of tumor. Several evidences suggest the presence of cancer stem cells (CSCs) or tumor initiating stem-like cells, a small population of cells present in the tumor, capable of self-renewal and generation of differentiated progeny. The presence of these CSCs can be attributed to the failure of cancer treatments as these cells are believed to exhibit therapy resistance. As a result, increasing attention has been given to CSC research to resolve the therapeutic problems related to cancer. Progress in this field of research has led to the development of novel strategies to treat several malignancies and has become a hot topic of discussion. In this review, we will briefly focus on the main characteristics, therapeutic implications, and perspectives of CSCs in cancer therapy. PMID- 26773711 TI - Optical Coherence Tomography for the Detection of Remote Optic Neuritis in Multiple Sclerosis. AB - BACKGROUND AND PURPOSE: Evidence of remote optic neuritis is often used to support a diagnosis of multiple sclerosis (MS). Optical coherence tomography (OCT) can provide qualitative and quantitative data on the retina, where the effects of optic neuritis can be seen. Our aim was to determine whether there is a quantitative difference in retinal structures in eyes with optic neuritis compared with those without, and which measures were best able to discriminate eyes with a history of optic neuritis from nonoptic neuritis eyes in MS patients. METHODS: We performed a prospective cohort study of 30 MS-optic neuritis patients, 22 MS-nonoptic neuritis patients, and 24 healthy participants. Patients underwent visual acuity testing and OCT imaging. Retinal measurements were compared across groups. OCT measurements and visual acuities were analyzed for their ability to discriminate between optic neuritis and nonoptic neuritis eyes. RESULTS: Optic neuritis eyes exhibited a thinner peripapillary retinal nerve fiber layer, papillomacular bundle, and ganglion cell + inner plexiform layer thicknesses compared to MS eyes without optic neuritis and healthy controls. Papillomacular bundle thickness was the best model to discriminate between eyes with optic neuritis and nonoptic neuritis eyes in MS patients. Visual acuity alone yielded rather poor models. CONCLUSIONS: Optic neuritis is associated with thinning in multiple regions of the retina. Optic neuritis eyes can be differentiated most accurately from nonoptic neuritis eyes using OCT. Our work suggests a potential role for OCT in documenting a remote history of optic neuritis to corroborate a diagnosis of MS. PMID- 26773712 TI - Feasibility of Administering High-Dose (131) I-MIBG Therapy to Children with High Risk Neuroblastoma Without Lead-Lined Rooms. AB - BACKGROUND: Although (131) I-metaiodobenzylguanidine ((131) I-MIBG) therapy is increasingly used for children with high-risk neuroblastoma, a paucity of lead lined rooms limits its wider use. We implemented radiation safety procedures to comply with New York City Department of Health and Mental Hygiene regulations for therapeutic radioisotopes and administered (131) I-MIBG using rolling lead shields. PROCEDURE: Patients received 0.67 GBq (18 mCi)/kg/dose (131) I-MIBG on an IRB-approved protocol (NCT00107289). Radiation safety procedures included private room with installation of rolling lead shields to maintain area dose rates <=0.02 mSv/hr outside the room, patient isolation until dose rate <0.07 mSv/hr at 1 m, and retention of a urinary catheter with collection of urine in lead boxes. Parents were permitted in the patient's room behind lead shields, trained in radiation safety principles, and given real-time radiation monitors. RESULTS: Records on 16 (131) I-MIBG infusions among 10 patients (age 2-11 years) were reviewed. Mean +/- standard deviation (131) I-MIBG administered was 17.67 +/ 11.14 (range: 6.11-40.59) GBq. Mean maximum dose rates outside treatment rooms were 0.013 +/- 0.008 mSv/hr. Median time-to-discharge was 3 days post-(131) I MIBG. Exposure of medical staff and parents was below regulatory limits. Cumulative whole-body dose received by the physician, nurse, and radiation safety officer during treatment was 0.098 +/- 0.058, 0.056 +/- 0.045, 0.055 +/- 0.050 mSv, respectively. Cumulative exposure to parents was 0.978 +/- 0.579 mSv. Estimated annual radiation exposure for inpatient nurses was 0.096 +/- 0.034 mSv/nurse. Thyroid bioassay scans on all medical personnel showed less than detectable activity. Contamination surveys were <200 dpm/100 cm(2) . CONCLUSIONS: The use of rolling lead shields and implementation of specific radiation safety procedures allows administration of high-dose (131) I-MIBG and may broaden its use without dedicated lead-lined rooms. PMID- 26773713 TI - A pilot study of operational tolerance with a regulatory T-cell-based cell therapy in living donor liver transplantation. AB - Potent immunosuppressive drugs have significantly improved early patient survival after liver transplantation (LT). However, long-term results remain unsatisfactory because of adverse events that are largely associated with lifelong immunosuppression. To solve this problem, different strategies have been undertaken to induce operational tolerance, for example, maintenance of normal graft function and histology without immunosuppressive therapy, but have achieved limited success. In this pilot study, we aimed to induce tolerance using a novel regulatory T-cell-based cell therapy in living donor LT. Adoptive transfer of an ex vivo-generated regulatory T-cell-enriched cell product was conducted in 10 consecutive adult patients early post-LT. Cells were generated using a 2-week coculture of recipient lymphocytes with irradiated donor cells in the presence of anti-CD80/86 monoclonal antibodies. Immunosuppressive agents were tapered from 6 months, reduced every 3 months, and completely discontinued by 18 months. After the culture, the generated cells displayed cell-number-dependent donor-specific inhibition in the mixed lymphocyte reaction. Infusion of these cells caused no significant adverse events. Currently, all patients are well with normal graft function and histology. Seven patients have completed successful weaning and cessation of immunosuppressive agents. At present, they have been drug free for 16-33 months; 4 patients have been drug free for more than 24 months. The other 3 recipients with autoimmune liver diseases developed mild rejection during weaning and then resumed conventional low-dose immunotherapy. CONCLUSIONS: A cell therapy using an ex vivo-generated regulatory T-cell-enriched cell product is safe and effective for drug minimization and operational tolerance induction in living donor liver recipients with nonimmunological liver diseases. (Hepatology 2016;64:632-643). PMID- 26773714 TI - Comparison of corneal degeneration and calcific band keratopathy from 2000 to 2013 in 69 horses. AB - OBJECTIVE: To compare signalment, presentation, treatment, and outcome in horses diagnosed with corneal degeneration (CD) or calcific band keratopathy (CBK) at a referral hospital. ANIMALS STUDIED: Sixty-nine horses (87 eyes) diagnosed with either CD or CBK. PROCEDURES: Medical records of horses diagnosed with CD or CBK at the University of California-Davis Veterinary Medical Teaching Hospital (UCD VMTH) between 2000 and 2013 were reviewed. Signalment, concurrent ophthalmic diagnoses, previous therapies, diagnostic tests, systemic diagnoses, treatment, follow-up, and outcomes were compared between horses diagnosed with CD or CBK. Age, breed, and gender were compared between the CD/CBK and UCD-VMTH populations. RESULTS: Thirty-three horses (42 eyes) and 36 horses (45 eyes) were diagnosed with CD and CBK, respectively. Horses with CD or CBK were significantly older (P < 0.001) than the UCD-VMTH population with a median age of 16 or 18 years, respectively. Appaloosas were significantly overrepresented in the CD/CBK population (33%) in comparison with the UCD-VMTH population (1.8%, P < 0.001). Equine recurrent uveitis was concurrently diagnosed in 67% and 84% of horses with CD or CBK, respectively. Pituitary pars intermedia dysfunction (PPID) was diagnosed significantly less often in horses with CD vs. CBK (P = 0.03). Chemical chelation with ethylenediaminetetraacetic acid was performed significantly less frequently in horses diagnosed with CD (7.1%) vs. CBK (31.1% of eyes) (P = 0.012). CONCLUSIONS: Despite some differences, equine CD and CBK are relatively similar conditions and may represent a continuum of disease severity. Horses with PPID should be monitored closely for corneal disease including CBK. PMID- 26773715 TI - Gelatin Nanoparticles with Enhanced Affinity for Calcium Phosphate. AB - Gelatin nanoparticles can be tuned with respect to their drug loading efficiency, degradation rate, and release kinetics, which renders these drug carriers highly suitable for a wide variety of biomedical applications. The ease of functionalization has rendered gelatin an interesting candidate material to introduce specific motifs for selective targeting to specific organs, but gelatin nanoparticles have not yet been modified to increase their affinity to mineralized tissue. By means of conjugating bone-targeting alendronate to biocompatible gelatin nanoparticles, a simple method is developed for the preparation of gelatin nanoparticles which exhibit strong affinity to mineralized surfaces. It has been shown that the degree of alendronate functionalization can be tuned by controlling the glutaraldehyde crosslinking density, the molar ratio between alendronate and glutaraldehyde, as well as the pH of the conjugation reaction. Moreover, it has been shown that the affinity of gelatin nanoparticles to calcium phosphate increases considerably upon functionalization with alendronate. In summary, gelatin nanoparticles have been developed, which exhibit great potential for use in bone-specific drug delivery and regenerative medicine. PMID- 26773716 TI - Deciphering CD137 (4-1BB) signaling in T-cell costimulation for translation into successful cancer immunotherapy. AB - CD137 (4-1BB, TNF-receptor superfamily 9) is a surface glycoprotein of the TNFR family which can be induced on a variety of leukocyte subsets. On T and NK cells, CD137 is expressed following activation and, if ligated by its natural ligand (CD137L), conveys polyubiquitination-mediated signals via TNF receptor associated factor 2 that inhibit apoptosis, while enhancing proliferation and effector functions. CD137 thus behaves as a bona fide inducible costimulatory molecule. These functional properties of CD137 can be exploited in cancer immunotherapy by systemic administration of agonist monoclonal antibodies, which increase anticancer CTLs and enhance NK-cell-mediated antibody-dependent cell-mediated cytotoxicity. Reportedly, anti-CD137 mAb and adoptive T-cell therapy strongly synergize, since (i) CD137 expression can be used to select the T cells endowed with the best activities against the tumor, (ii) costimulation of the lymphocyte cultures to be used in adoptive T-cell therapy can be done with CD137 agonist antibodies or CD137L, and (iii) synergistic effects upon coadministration of T cells and antibodies are readily observed in mouse models. Furthermore, the signaling cytoplasmic tail of CD137 is a key component of anti-CD19 chimeric antigen receptors that are used to redirect T cells against leukemia and lymphoma in the clinic. Ongoing phase II clinical trials with agonist antibodies and the presence of CD137 sequence in these successful chimeric antigen receptors highlight the importance of CD137 in oncoimmunology. PMID- 26773717 TI - Preparation of extended release solid dispersion formulations of tacrolimus using ethylcellulose and hydroxypropylmethylcellulose by solvent evaporation method. AB - OBJECTIVES: Tacrolimus is a poorly water-soluble compound that is used to prevent allograft rejection. We aimed to prepare an extended release formulation of tacrolimus to achieve both an extended release profile and improved solubility of tacrolimus. METHODS: Extended release granules (ERG) of tacrolimus were prepared with lactose, ethylcellulose (EC) and hydroxypropylmethylcellulose (HPMC) via the solvent evaporation method. KEY FINDINGS: In an in vitro release study, ERG had an extended release profile, and the release rate of tacrolimus was regulated by the quantity of lactose, EC and HPMC in the formulation. HPMC-containing ERG successfully enhanced and maintained supersaturation of tacrolimus even after 24 h in a supersaturated release study. In contrast, the extent of supersaturation rapidly decreased after 4 h and the concentration nearly reached the same level as that of crystalline tacrolimus at 24 h for ERG without HPMC. In vivo absorption characteristics were compared between ERGs and immediate release (IR) formulation of tacrolimus. Successful and sustained absorption of tacrolimus without reducing bioavailability compared with IR formulation was observed for ERG. CONCLUSIONS: These results suggest the feasibility of combining an EC-based formulation with solid dispersion utilizing HPMC for the extended release of oral formulations and sustained absorption of tacrolimus. PMID- 26773718 TI - Cadaveric gait simulation reproduces foot and ankle kinematics from population specific inputs. AB - Cadaveric gait simulation allows researchers to directly investigate biomechanical consequences of surgeries using invasive measurement techniques. However, it is unclear if foot and ankle kinematics that are population-specific are reproduced using these devices. Therefore, we assessed foot and ankle kinematics produced in a cadaveric gait simulator during the stance phase of gait in a set of five cadaveric feet. Tibial motions and ground reaction forces previously collected in vivo in a group of healthy adults were applied as inputs parameters. In vitro foot and ankle kinematics were acquired and directly compared to population-specific in vivo kinematics of the same healthy adults from which input parameters were acquired. Analyses were completed using cross correlation to determine the similarities in kinematic profiles and joint ranges of motion were calculated to determine absolute differences in kinematics. Ankle, subtalar, and talonavicular in vitro joint kinematics were positively correlated to in vivo joint kinematics (rxy = 0.57-0.87). Further, in vivo and in vitro foot and ankle kinematics demonstrated similar amounts of within-group variability (rxy = 0.50-0.85 and rxy = 0.72-0.76, respectively). Our findings demonstrate that cadaveric gait simulation techniques reproduce population specific foot and ankle kinematics, providing a valuable research tool for testing surgical treatments of foot and ankle maladies. (c) 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:1663-1668, 2016. PMID- 26773719 TI - Association of aerobic fitness level with exercise-induced hypoglycaemia in Type 1 diabetes. AB - AIM: To determine the impact of physical fitness level on hypoglycaemia risk during exercise in people with Type 1 diabetes. METHODS: A total of 44 patients [34 adults (aged 22-70 years) and 10 adolescents (aged 12-18 years)] with Type 1 diabetes, treated with insulin pump therapy, underwent a standardized exercise session. Cardiorespiratory fitness (maximum oxygen uptake) was measured and classified, based on established norms for age and sex, into either poor (< 25th percentile) or good fitness level (> 25th percentile). Plasma glucose levels were measured every 10 min, each patient performed physical activity at 60% maximum oxygen uptake either on a treadmill for 1 h or on a bicycle for 30 min. Frequency of hypoglycaemia (plasma glucose < 4 mmol/l) and decline in plasma glucose levels during exercise were assessed. RESULTS: In all, 23 patients had a good exercise fitness level. Hypoglycaemic events occurred in 17/23 patients (74.0%) in the good fitness level group compared with 8/21 patients (38.0%) in the poor fitness level group (P = 0.02). Both groups had similar pre-exercise plasma glucose levels. The plasma glucose values during exercise in the good fitness level group compared with the poor fitness level group were: plasma glucose nadir 3.9 +/- 1.6 vs 5.5 +/- 2.4 mmol/l (P = 0.01) and plasma glucose change -4.6 +/- 3.4 vs. -2.1 +/- 3.1 mmol/l (P = 0.01). The correlation between the plasma glucose nadir and maximum oxygen uptake was r = -0.38 (P = 0.01). CONCLUSIONS: Patients with good fitness level seem to be more prone to hypoglycaemia during exercise. This could be the result of better insulin sensitivity and the fact that they tend to exercise at greater work thresholds. These results are a step toward a better understanding of the association between physical fitness and exercise-induced hypoglycaemia. PMID- 26773720 TI - The impact of phospholipids and phospholipid removal on bioanalytical method performance. AB - Phospholipids (PLs) are a component of cellmembranes, biological fluids and tissues. These compounds are problematic for the bioanalytical chemist, especially when PLs are not the analytes of interest. PL interference with bioanalysis highly impacts reverse-phase chromatographic methods coupled with mass spectrometric detection. Phospholipids are strongly retained on hydrophobic columns, and can cause significant ionization suppression in the mass spectrometer, as they outcompete analyte molecules for ionization. Strategies for improving analyte detection in the presence of PLs are reviewed, including in analysis modifications and sample preparation strategies. Removal of interfering PLs prior to analysis seems to be most effective atmoderating thematrix effects fromthese endogenous cellular components, and has the potential to simplify chromatography and improve column lifetime. Products targeted at PL removal for sample pre-treatment, as well as products that combine multiplemodes of sample preparation (i.e. Hybrid SPE), show significant promise inmediating the effect on PL interference in bioanalysis. PMID- 26773721 TI - Transcription Factors and Medium Suitable for Initiating the Differentiation of Human-Induced Pluripotent Stem Cells to the Hepatocyte Lineage. AB - Transcription factors and culture media were investigated to determine the condition to initiate the differentiation of human-induced pluripotent stem (iPS) cells most efficiently. The expression of genes in human adult liver was compared with that in 201B7 cells (iPS cells) using cDNA microarray analysis. Episomal plasmids expressing transcription factors were constructed. 201B7 cells were transfected with the episomal plasmids and cultured in ReproFF (feeder-free media maintaining pluripotency), Leibovitz-15 (L15), William's E (WE), or Dulbecco's modified Eagle medium/Nutrient F-12 Ham (DF12) for 7 days. RNA was isolated and subjected to real-time quantitative PCR to analyze the expression of alpha-feto protein (AFP) and albumin. cDNA microarray analysis revealed 16 transcription factors that were upregulated in human adult liver relative to that in 201B7 cells. Episomal plasmids expressing these 16 genes were transfected into 201B7 cells. CCAAT/enhancer-binding protein alpha (CEBPA), CCAAT/enhancer-binding protein beta (CEBPB), forkhead box A1 (FOXA1), and forkhead box A3 (FOXA3) up regulated AFP and down-regulated Nanog. These four genes were further analyzed. The expression of AFP and albumin was the highest in 201B7 cells transfected with the combination of CEBPA, CEBPB, FOXA1, and FOXA3 and cultured in WE. The combination of CEBPA, CEBPB, FOXA1, and FOXA3 was suitable for 201B7 cells to initiate differentiation to the hepatocyte lineage and WE was the most suitable medium for culture after transfection. J. Cell. Biochem. 117: 2001-2009, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26773722 TI - Gait in Parkinson's disease: A visuo-cognitive challenge. AB - Vision and cognition have both been related to gait impairment in Parkinson's disease (PD) through separate strands of research. The cumulative and interactive effect of both (which we term visuo-cognition) has not been previously investigated and little is known about the influence of cognition on vision with respect to gait. Understanding the role of vision, cognition and visuo-cognition in gait in PD is critical for data interpretation and to infer and test underlying mechanisms. The purpose of this comprehensive narrative review was to examine the interdependent and interactive role of cognition and vision in gait in PD and older adults. Evidence from a broad range of research disciplines was reviewed and summarised. A key finding was that attention appears to play a pivotal role in mediating gait, cognition and vision, and should be considered emphatically in future research in this field. PMID- 26773723 TI - Sex effects on inflammatory and neurodegenerative processes in multiple sclerosis. AB - Clinical observations in human autoimmune diseases such as multiple sclerosis (MS) suggest a pivotal role of sex-related factors in the etiopathogenesis. These include a female preponderance in MS incidence and an increasing sex bias over time, a parent-of-origin effect in MS inheritance, and the protective effect of pregnancy on disease activity. The complex interplay of factors contributing to these clinical phenomena, however, is incompletely understood and may include sex hormones as well as genetic or epigenetic sex differences. While genetic and hormonal effects are impossible to study independently in humans, novel mouse models have started to unravel the cause-effect relationship between individual sex-related factors and autoimmunity. Here, we present the evidence for mechanisms underlying sex differences in the immune system and the central nervous system (CNS) and how these might help to explain some of the clinically observed sex differences in MS. A better understanding of the molecular underpinnings may ultimately help to devise sex-specific treatment strategies as well as highlight novel avenues for therapy in both sexes. PMID- 26773724 TI - Extranodal NK/T-cell lymphoma, nasal type, manifesting as rapidly progressive dementia without any mass or enhancing brain lesion. AB - Among the many potential etiologies for rapidly progressive dementia (RPD), primary central nervous system extranodal NK/T-cell lymphoma, nasal-type (ENKL) is a rare entity. We present the first reported case of autopsy-proven RPD due to ENKL without any mass or enhancing lesion of the brain. A 54-year-old immunocompetent man presented with RPD, myoclonus and ataxia. The mini-mental state examination (MMSE) score was 22/30. His brain MRI revealed progressive brain atrophy without gadolinium enhancement or mass lesion. Five months after the initial evaluation, cognitive impairment further worsened with an MMSE score of 3/30. At the advanced stage, lumbar MRI showed swollen cauda equina with gadolinium enhancement. The number of Epstein-Barr virus (EBV) DNA in cerebrospinal fluid had gradually increased. Twelve months after onset, the patient died of respiratory failure. Pathological findings revealed that lymphoma cells had diffusely invaded the meninges, parenchyma of the brain, spinal cord and cauda equina. Cells were positive for CD3, CD56 and EBV-encoded small RNAs and negative for CD20. No evidence of malignancy was identified in the visceral organs. This report indicates that ENKL should be recognized as one of the rare causes of RPD. Early testing for EBV-DNA in cerebrospinal fluid and imaging of cauda equina would be useful diagnostic tools. PMID- 26773725 TI - On two-liquid AC electroosmotic system for thin films. AB - Lab-on-chip devices employ EOF for transportation and mixing of liquids. However, when a steady (DC) electric field is applied to the liquids, there are undesirable effects such as degradation of sample, electrolysis, bubble formation, etc. due to large magnitude of electric potential required to generate the flow. These effects can be averted by using a time-periodic or AC electric field. Transport and mixing of nonconductive liquids remain a problem even with this technique. In the present study, a two-liquid system bounded by two rigid plates, which act as substrates, is considered. The potential distribution is derived by assuming a Boltzmann charge distribution and using the Debye-Huckel linearization. Analytical solution of this time-periodic system shows some effects of viscosity ratio and permittivity ratio on the velocity profile. Interfacial electrostatics is also found to play a significant role in deciding velocity gradients at the interface. High frequency of the applied electric field is observed to generate an approximately static velocity profile away from the Electric Double Layer (EDL). PMID- 26773726 TI - Causal effects of threat and challenge appraisals on coping and pain perception. AB - BACKGROUND: Numerous studies have found appraisals of pain as a source of potential threat or tissue damage influence pain perception and coping. Conversely, causal effects of challenge appraisals reflecting potential future benefits of bearing pain have received little attention. This experiment was designed to elucidate effects of appraising laboratory pain as a source of potential threat and challenge on pain perception and coping. METHODS: Before engaging in a cold pressor test (CPT), young adult women (N = 112) and men (N = 49) were randomly assigned to one of three conditions: a higher threat group in which participants read an orienting passage describing symptoms and consequences of frostbite (pain as a signal for nociception), a lower threat group in which participants read about CPT safety (pain independent of nociception) or a challenge appraisal group in which participants read a passage describing how persistence in the face of discomfort predicts future life success and satisfaction. RESULTS: The higher threat group had lower pain tolerance and catastrophized more during the task than lower threat and challenge appraisal groups. Conversely, the challenge appraisal group reported using more cognitive strategies (ignoring, diverting attention, coping self-statements) in managing pain than either threat group. Structural equation modelling indicated paths of subjective threat and challenge appraisals with pain tolerance were fully mediated by individual differences in reported cognitive coping and/or pain catastrophizing. CONCLUSIONS: Findings underscore causal effects of pain appraisals on coping responses and pain perception. WHAT DOES THIS STUDY ADD?: Effects of challenge appraisals of pain as a source of potential future growth or development have not been considered in experimental pain research. Causal effects of primary appraisals of laboratory pain as a source of potential threat and challenge were elucidated in relation to pain perception and coping. PMID- 26773727 TI - Chitosan-Assisted Crystallization and Film Forming of Perovskite Crystals through Biomineralization. AB - Biomimetic mineralization is a powerful approach for the synthesis of advanced composite materials with hierarchical organization and controlled structure. Herein, chitosan was introduced into a perovskite precursor solution as a biopolymer additive to control the crystallization and to improve the morphology and film-forming properties of a perovskite film by way of biomineralization. The biopolymer additive was able to control the size and morphology of the perovskite crystals and helped to form smooth films. The mechanism of chitosan-mediated nucleation and growth of the perovskite crystals was explored. As a possible application, the chitosan-perovskite composite film was introduced into a planar heterojunction solar cell and increased power conversion efficiency relative to that observed for the pristine perovskite film was achieved. The biomimetic mineralization method proposed in this study provides an alternative way of preparing perovskite crystals with well-controlled morphology and properties and extends the applications of perovskite crystals in photoelectronic fields, including planar-heterojunction solar cells. PMID- 26773728 TI - Rosiglitazone pretreatment protects against lipopolysaccharide-induced fetal demise through inhibiting placental inflammation. AB - Peroxisome proliferator-activated receptor (PPAR)-gamma is highly expressed in human and rodent placentas. Nevertheless, its function remains obscure. The present study investigated the effects of rosiglitazone, a PPAR-gamma agonist, on LPS-induced fetal death. All pregnant mice except controls were intraperitoneally injected with LPS (150 MUg/kg) daily from gestational day (GD)15 to GD17. As expected, maternal LPS injection caused placental inflammation and resulted in 63.6% fetal death in dams that completed the pregnancy. Interestingly, LPS induced fetal mortality was reduced to 16.0% when pregnant mice were pretreated with RSG. Additional experiment showed that rosiglitazone pretreatment inhibited LPS-induced expressions of tumor necrosis factor (Tnf)-alpha, interleukin (Il) 1beta, Il-6, macrophage inflammatory protein (Mip)-2 and keratinocyte-derived chemokine (Kc) in mouse placenta. Although rosiglitazone had little effect on LPS evoked elevation of IL-10 in amniotic fluid, it alleviated LPS-evoked release of TNF-alpha and MIP-2 in amniotic fluid. Further analysis showed that pretreatment with rosiglitazone, which activated placental PPAR-gamma signaling, simultaneously suppressed LPS-evoked nuclear factor kappa B (NF-kappaB) activation and blocked nuclear translocation of NF-kappaB p65 and p50 subunits in trophoblast giant cells of the labyrinth layer. These results provide a mechanistic explanation for PPAR-gamma-mediated anti-inflammatory activity in the placentas. Overall, the present study provides additional evidence for roles of PPAR-gamma as an important regulator of placental inflammation. PMID- 26773729 TI - The endocannabinoid system in the human granulosa cell line KGN. AB - Ovarian steroidogenesis is embedded in a sensitive network of regulatory mechanisms crucial for human fertility. The endocannabinoid system (ECS) represents an intrinsic modulating system involved in the regulation of endocrine functions. In the present study we characterized the ECS in the human granulosa cell line KGN and its impact on gonadotropin sensitivity and steroid hormone synthesis under basal and FSH-stimulated conditions. Expression studies were performed and estradiol was measured. CB1, CB2, DAGL, FAAH, GPR55, MAGL, NAPE-PLD and TRPV1 were expressed without FSH-dependent effects. Treatment with selective cannabinoid receptor agonists reduced basal but not FSH-stimulated estradiol and CYP19. Progesterone was not altered by ECS manipulation. CB1 agonist changed the expression of miRNAs associated with granulosa cell function, e.g. miR-23a, miR 24, miR-181a and miR-320a. Present data indicate a modulating role of the intrinsic ovarian ECS in the regulation of estradiol synthesis. PMID- 26773730 TI - Up-regulation of the Ang II/AT1 receptor may compensate for the loss of gastric antrum ICC via the PI3k/Akt signaling pathway in STZ-induced diabetic mice. AB - The classic renin-angiotensin system (RAS) is a complex system in which angiotensin II (Ang II) has been identified as an important endogenous regulator that influences both smooth muscle contraction and cell growth. Although a local RAS is known to exist in the gastrointestinal tract, it is unclear whether Ang II is involved in the loss of gastric interstitial cells of Cajal (ICC) in diabetic mice. The present study was designed to investigate the effect of Ang II on ICC survival in streptozotocin (STZ)-induced diabetic mice. Western blot, immunofluorescence, isometric muscle recording, enzyme-linked immunosorbent assay (ELISA) and a cell counting kit-8 were used in this research. Our results demonstrate that the c-Kit and membrane-bound stem cell factor (mSCF) protein expression levels in gastric smooth muscle were decreased in STZ-induced diabetic mice. However, the angiotensin receptor type 1 (AT1R) expression levels in gastric smooth muscle and angiotensin-converting enzyme (ACE) expression levels in gastric mucosa were increased. The effect of Ang II on the tonic contraction of gastric smooth muscle was potentiated in diabetic mice, and the plasma Ang II level was enhanced. Ang II increased mSCF expression, cell proliferation, and Akt Ser473 phosphorylation in cultured gastric smooth muscle cells (GSMCs). These effects were reduced by specific inhibitors ZD7155 (an AT1R antagonist) and LY294002 (a PI3-kinase inhibitor). Our results suggest that Ang II increases mSCF expression and cell proliferation in cultured GSMCs in a PI3K/Akt signaling dependent manner. ACE and AT1R up-regulation in the stomach may help compensate for ICC loss in STZ-induced diabetic mice. PMID- 26773731 TI - 1H NMR-based metabolomics study on the physiological variations during the rat pregnancy process. AB - In this study, NMR-based metabolomics in combination with multivariate pattern recognition technologies were employed to evaluate the physiological variations in the Wistar rats' plasma that are induced by pregnancy on the gestational days (GDs) 11, 14, 17 and 20. Untargeted metabolomics analysis revealed some possible mechanism of physiological effects for healthy pregnancies and showed a metabolic trajectory during pregnancy process. The levels of 24 metabolites were found to change significantly throughout pregnancy in maternal plasma. These metabolite changes involved in varied kinds of metabolic pathways including synthesis of biological substances, microbial metabolism in diverse environments, protein digestion and absorption, carbohydrate metabolism, digestion and absorption, mineral absorption, and ATP (Adenosine Triphosphate)-binding cassette transporters (ABC transporters). The substantial cores of all the metabolic pathways are promoting fetal growth and development and regulating maternal physiological state. This work showed relevant metabolic pathways perturbation in the maternal plasma due to normal pregnancy and provided the physical basis of time-dependent metabolic trajectory against which disease-related maternal physiological responses may be better understood in future studies. PMID- 26773732 TI - Sonic hedgehog improves ischemia-induced neovascularization by enhancing endothelial progenitor cell function in type 1 diabetes. AB - The Sonic hedgehog (Shh) pathway is downregulated in type 1 diabetes, and it has been reported that augmentation of this pathway may alleviate diabetic complications. However, the cellular mechanisms underlying these protective effects are poorly understood. Recent studies indicate that impaired function of endothelial progenitor cells (EPCs) may contribute to cardiovascular problems in diabetes. We hypothesized that impaired Shh signaling contribute to endothelial progenitor cell dysfunction and that activating the Shh signaling pathway may rescue EPC function and promote diabetic neovascularization. Adult male C57/B6 mice and streptozotocin (STZ)-induced type 1 diabetic mice were used. Gli1 and Ptc1 protein levels were reduced in EPCs from diabetic mice, indicating inhibition of the Shh signaling pathway. EPC migration, tube formation ability, and mobilization were impaired in diabetic mice compared with non-diabetic controls (p < 0.05 vs control), and all were improved by in vivo administration of the Shh pathway receptor agonist SAG (p < 0.05 vs diabetes). SAG significantly increased capillary density and blood perfusion in the ischemic hindlimbs of diabetic mice (p < 0.05 vs diabetes). The AKT activity was lower in EPCs from diabetic mice than those from non-diabetic controls (p < 0.05 vs control). This decreased AKT activity led to an increased GSK-3beta activity and degradation of the Shh pathway transcription factor Gli1/Gli2. SAG significantly increased the activity of AKT in EPCs. Our data clearly demonstrate that an impaired Shh pathway mediated by the AKT/GSK-3beta pathway can contribute to EPC dysfunction in diabetes and thus activating the Shh signaling pathway can restore both the number and function of EPCs and increase neovascularization in type 1 diabetic mice. PMID- 26773733 TI - Estimating the impact of better management of glycaemic control in adults with Type 1 and Type 2 diabetes on the number of clinical complications and the associated financial benefit. AB - AIM: To estimate potential cost avoidance through modest and achievable improvements in glycaemic control in adults with Type 1 or Type 2 diabetes mellitus in the UK healthcare system. METHODS: The IMS Core Diabetes Model was used to examine the impact of improved glycaemic control (indicated by reduction in HbA1c level), in a representative cohort of adults with Type 1 or Type 2 diabetes. The cumulative incidence of microvascular and macrovascular complications was modelled across 5-year periods to a 25-year time horizon. Complication costs were applied to the data to estimate potential accrued cost avoidance. RESULTS: Significant cost avoidance of ~L340 m is apparent in the first 5 years, increasing to ~L5.5bn after 25 years of sustained improvement in control. The overwhelming majority of cost avoidance arises from reductions in microvascular complications. In people with Type 1 diabetes the greatest cost avoidance comes from a reduction in renal disease (74% of cost avoidance), while in people with Type 2 diabetes it is generated by a reduction in foot ulcers, amputations and neuropathy: 57% cost avoidance). Greater cost reduction is accrued more rapidly in people with higher starting HbA1c levels. CONCLUSION: Modest improvements in glycaemic control generate significant reductions in the incidence and, therefore, cost of microvascular complications in people with Type 1 or Type 2 diabetes. This study provides clear support for the premise that prioritized and sustained investment in early and better intervention can provide concrete financial benefits in both the short and longer term. PMID- 26773734 TI - Frequent BCOR aberrations in extranodal NK/T-Cell lymphoma, nasal type. AB - Extranodal natural killer/T cell lymphoma (ENKTL) is a rare subtype of lymphoma. Recurrent mutations in the JAK-STAT pathway, recently reported in ENKTL cases, are interesting in terms of both pathogenesis and inhibitor therapy. However, the frequencies of these mutations are low and variable among reports, and other pathognomonic mutations in ENKTL remain to be elucidated. In the present study, targeted capture sequencing of 602 cancer-related genes from 25 frozen ENKTL samples was performed, 11 of which were matched to normal samples. Several recurrent somatic mutations involving BCOR (32%), TP53 (16%), DDX3X (12%), FAT4 (8%), NRAS (8%), MLL3 (12%), and MIR17HG (8%) were identified. The pattern of BCOR aberrations (1 nonsense and 5 frame-shift mutations, a mutation leading to a splicing error, and gene loss) suggested that loss of function of BCOR was the functionally important outcome of such changes. The literature was reviewed and the public data on BCOR aberrations was reanalyzed and it was found that the aberrations were frequently found in myeloid neoplasms, but, interestingly, were highly specific to ENKTL among lymphoid malignancies. Given the high frequency and pattern of aberration, BCOR is likely to play an important role in ENKTL pathogenesis as a tumor suppressor gene. PMID- 26773736 TI - Esthetic Evaluation of Anterior Single-Tooth Implants with Different Abutment Designs-Patients' Satisfaction Compared to Dentists' Observations. AB - PURPOSE: To correlate patients' satisfaction and dentists' observations regarding two abutment designs used for single crowns in the esthetic zone: a divergent one (control) and a curved one (experimental), with special emphasis on muco-gingival esthetics. MATERIALS AND METHODS: Twenty-six patients with nonadjacent missing teeth in the esthetic zone were enrolled in a randomized clinical trial (within subject comparison). Two implants placed in each were restored using abutments of different geometry. Patients' appreciation was assessed on a visual analog scale (VAS) by recording answers to three questions, and dentists' appreciation was determined by means of the Pink Esthetic Score (PES) at T0 (crown cementation, baseline) and at T12 (1 year post-cementation). ANOVA with post hoc analysis was used to identify differences between groups and at different moments in time. Pearson correlations were calculated between all variables, both at T0 and at T12. RESULTS: No statistically significant differences were found at any time between the control and experimental abutment design, either for the PES or for the VAS score. PES slightly improved after 1 year, as did the VAS rating related to functioning with the implant-crown compared to the natural teeth. All PES and VAS scores demonstrated highly significant correlation. Both patient satisfaction and professional appreciation of muco-gingival conditions after single implant treatment in the esthetic zone were high; however, the curved, experimental abutment design performed no better than the conventional, divergent type. CONCLUSION: Curved abutment design does not significantly impact crown or gingival esthetics as assessed by PES and VAS scored by dentists and patients, respectively. PMID- 26773737 TI - Blood Pressure Effects of Yoga, Alone or in Combination With Lifestyle Measures: Results of the Lifestyle Modification and Blood Pressure Study (LIMBS). AB - The authors conducted a study to assess the effects of yoga on blood pressure (BP). Patients were randomized to yoga (Blood Pressure Education Program [BPEP]), or a combined program (COMBO). Ambulatory BP was measured at baseline and at 12 and 24 weeks. Data are presented for all enrolled patients (n=137) and for completers only (n=90). Systolic BP (SBP) and diastolic BP (DBP) were significantly decreased within all groups at 12 and 24 weeks (P<.001) for enrolled patients and completers. SBP was significantly reduced in the yoga and COMBO groups as compared with the BPEP group at 12 weeks in all enrolled and completers. SBP differences were no longer significant at 24 weeks between groups in all enrolled patients; however, there was a greater reduction in SBP at 24 weeks in completers favoring BPEP over yoga. No differences in DBP between groups or in BP between the yoga and COMBO groups were present. The authors did not observe an additive benefit from combining yoga with BPEP measures. Reasons for this are unclear at this time. BP lowering with yoga, however, was similar to that achieved with lifestyle measures. PMID- 26773738 TI - Transgenic barley overexpressing a cytokinin dehydrogenase gene shows greater tolerance to drought stress. AB - Together with auxins, cytokinins are the main plant hormones involved in many different physiological processes. Given this knowledge, cytokinin levels can be manipulated by genetic modification in order to improve agronomic parameters of cereals in relation to, for example, morphology, yield, and tolerance to various stresses. The barley (Hordeum vulgare) cultivar Golden Promise was transformed using the cytokinin dehydrogenase 1 gene from Arabidopsis thaliana (AtCKX1) under the control of mild root-specific beta-glucosidase promoter from maize. Increased cytokinin degradation activity was observed positively to affect the number and length of lateral roots. The impact on morphology depended upon the recombinant protein's subcellular compartmentation. While assumed cytosolic and vacuolar targeting of AtCKX1 had negligible effect on shoot growth, secretion of AtCKX1 protein to the apoplast had a negative effect on development of the aerial part and yield. Upon the application of severe drought stress, all transgenic genotypes maintained higher water content and showed better growth and yield parameters during revitalization. Higher tolerance to drought stress was most caused by altered root morphology resulting in better dehydration avoidance. PMID- 26773735 TI - Anxiety, pain, and nausea during the treatment of standard-risk childhood acute lymphoblastic leukemia: A prospective, longitudinal study from the Children's Oncology Group. AB - BACKGROUND: This prospective study describes the procedure-related anxiety, treatment-related anxiety, pain, and nausea experienced by children with standard risk acute lymphoblastic leukemia (ALL) during the first year of treatment. METHODS: This study was undertaken at 31 Children's Oncology Group (COG) sites. Eligible children who were 2 to 9.99 years old were enrolled in a COG trial for patients with newly diagnosed standard-risk ALL from 2005 to 2009. Parents completed a demographic survey at the baseline and the Pediatric Quality of Life Inventory 3.0 Cancer Module (proxy version) and the General Functioning Scale of the Family Assessment Device 1, 6, and 12 months after the diagnosis. The association between patient-related (age, sex, ethnicity, and treatment), parent related (marital status and education), and family-related factors (functioning, income, and size) and symptom scores was evaluated. RESULTS: The mean scores for procedure-related anxiety, treatment-related anxiety, and pain improved during the first year of treatment (P < .0389). The mean nausea score was poorer 6 months after the diagnosis in comparison with the other assessments (P = .0085). A younger age at diagnosis was associated with significantly worse procedure related anxiety (P = .004). An older age (P = .0002) and assignment to the intensified consolidation study arm (P = .02) were associated with significantly worse nausea. CONCLUSIONS: Children with ALL experienced decreasing treatment related anxiety, procedure-related anxiety, and pain during the first year of treatment. In comparison with scores at 1 and 12 months, nausea was worse 6 months after the diagnosis. Minimization of procedure-related anxiety in younger children and improved nausea control in older children and those receiving more intensified treatment should be prioritized. PMID- 26773739 TI - Characterization by mass cytometry of different methods for the preparation of muscle mononuclear cells. AB - Biological processes that are mediated by cell-cell interactions in heterogeneous populations are best approached by methods that have single cell resolution. Most of these methods rely on the preparation, from solid tissues, of cell suspensions by enzymatic digestion, followed by analysis of single cell reactivity to an antibody panel that allows the discrimination of cell populations and characterization of their activation state. Thus for any specific biological problem, both efficient and at the same time mild, protocols for cell separation, together with tissue specific panels of antibodies, need to be developed and optimized. Here we characterize an antibody panel that permits the discrimination of mononuclear muscle cell populations by mass cytometry and use it to characterize the cell populations obtained by three different cell extraction procedures from muscle fibers. We show that our panel of antibodies, albeit limited and incomplete, is sufficient to discriminate most of the mononuclear muscle cell populations and that each cell extraction method yields heterogeneous cell populations with a different relative abundance of the distinct cell types. PMID- 26773740 TI - Examining Treatment Outcomes with Erlotinib in Patients with Advanced Non-Small Cell Lung Cancer Whose Tumors Harbor Uncommon EGFR Mutations. AB - INTRODUCTION: Exon 19 deletions and the exon 21 L858R mutation of the epidermal growth factor receptor gene (EGFR) predict activity of EGFR tyrosine kinase inhibitors, including erlotinib; however, the ability of less common EGFR mutations to predict efficacy of erlotinib is unclear. METHODS: The efficacy of erlotinib in individual patients with rare EGFR mutations from the MERIT, SATURN, TITAN, TRUST, ATLAS, BeTa, and FASTACT-2 trials was analyzed and compared with data from the literature. RESULTS: In the patients tested for biomarkers, the frequency of rare mutations identified here ranged from 1.7% (eight of 467) in the SATURN study to 7.4% (27 of 364) in ATLAS. Some rare mutations were associated with greater clinical benefit from EGFR tyrosine kinase inhibitor therapy or improved prognosis independent of treatment, whereas others appeared to have a poorer prognosis. In particular, exon 18 G719 mutations, exon 19 K757R and E746G mutations, the exon 20 S768I mutation, and the exon 21 G836S mutation appeared to confer a good outcome with erlotinib treatment, whereas exon 18 S720I showed a particularly poor outcome. Owing to the small number of patients with each mutation, however, it is difficult to confirm whether these rare mutations do indeed confer sensitivity or resistance to erlotinib. CONCLUSIONS: Erlotinib can have different efficacy depending on the specific EGFR mutation. More research is needed to create a central database such as the My Cancer Genome database of rare mutations to definitively confirm whether these mutations are activating, resistant, or neutral. PMID- 26773741 TI - Population-Based Patterns of Surgical Care for Stage IIIA NSCLC in the Netherlands between 2010 and 2013. AB - INTRODUCTION: Current guidelines include both induction therapy plus an operation and chemoradiotherapy (CRT) as options for clinical stage IIIA (cIIIA) non-small cell lung cancer (NSCLC) after multidisciplinary evaluation. We explored the use of operations for cIIIA NSCLC in the Netherlands. METHODS: Data about the primary treatment of patients with cIIIA NSCLC (according to the seventh edition of the Tumour, Node, and Metastasis Classification of Malignant Tumours) between 2010 and 2013 were extracted from the Netherlands Cancer Registry. Mortality information was obtained from the automated civil registry. RESULTS: A total of 4816 patients with cIIIA NSCLC (stage cN2, 3240 [67%]; stage T4, 1252 [26%]) were identified. CRT was used in 45% of patients and an operation was a component of treatment in 15%, with 28% of the latter having induction therapy. The 4-year survival rate was highest with induction therapy plus an operation (51%), followed by an operation plus adjuvant therapy (39%) and CRT (27%). Patients receiving induction therapy plus an operation were younger than those receiving CRT (median age 60 versus 66 years). The 30- and 90-day postoperative mortality rates after induction therapy plus lobectomy were 0.6% and 3.7% compared with 4.2% and 12.5% after induction therapy plus bilobectomy or pneumonectomy. Factors associated with poorer survival after induction therapy plus an operation were age older than 69 years, histological findings of nonsquamous cell carcinoma, and bilobectomy or pneumonectomy. Pathological stage IIIA NSCLC was present in only 51% of patients with cIIIA NSCLC who underwent an operation with or without adjuvant therapy, and the disease was of a lower stage in most of the remaining patients. CONCLUSIONS: In the Netherlands between 2010 and 2013, 15% of patients with cIIIA NSCLC received an operation, with the minority of these patients receiving induction therapy. In those receiving induction therapy, 90-day mortality after bilobectomy or pneumonectomy was more than three times higher than that for lobectomy. The discrepancy between clinical and pathological stage in patients receiving an upfront operation merits further investigation. PMID- 26773743 TI - Expression of spinach ferredoxin-thioredoxin reductase using tandem T7 promoters and application of the purified protein for in vitro light-dependent thioredoxin reduction system. AB - Thioredoxins (Trxs) regulate the activity of target proteins in the chloroplast redox regulatory system. In vivo, a disulfide bond within Trxs is reduced by photochemically generated electrons via ferredoxin (Fd) and ferredoxin thioredoxin reductase (FTR: EC 1.8.7.2). FTR is an alphabeta-heterodimer, and the beta-subunit has a 4Fe-4S cluster that is indispensable for the electron transfer from Fd to Trxs. Reconstitution of the light-dependent Fd/Trx system, including FTR, is required for the biochemical characterization of the Trx-dependent reduction pathway in the chloroplasts. In this study, we generated functional FTR by simultaneously expressing FTR-alpha and -beta subunits under the control of tandem T7 promoters in Escherichia coli, and purifying the resulting FTR complex protein. The purified FTR complex exhibited spectroscopic absorption at 410 nm, indicating that it contained the Fe-S cluster. Modification of the expression system and simplification of the purification steps resulted in improved FTR complex yields compared to those obtained in previous studies. Furthermore, the light-dependent Trx-reduction system was reconstituted by using Fd, the purified FTR, and intact thylakoids. PMID- 26773744 TI - Establishment of a novel method without sequence modification for developing NoV P particle-based chimeric vaccines. AB - The Norovirus (NoV) P particle (PP) is a subviral particle formed by 24 copies of the protruding (P) domain of the capsid protein. Each P domain has three surface loops that can be used for foreign antigen presentation. Hence, PPs have been demonstrated to be an excellent platform for vaccine development against many pathogens. However, current processes for preparing those chimeric PP vaccines vary and would change the original sequence of the PP. A detailed strategy also has not been reported for inserting a foreign antigen into all three loops. In order to develop a novel method for preparing distinct types of PP-based protein vaccines, we created two restriction enzyme sites (EagI and KpnI) in the P domain by site-directed mutagenesis without changing its original sequence. A synthesized gene with three copies of the Alzheimer's disease (AD) immunogen Abeta1-6 was then incorporated in loop2 of the P domain. Additionally, a synthesized gene with one copy of Abeta1-6 was inserted into each loop of the P domain. Furthermore, two recombinant proteins PP-3 copy-Abeta1-6-loop2 and PP-1 copy-Abeta1-6-loop123 were successfully purified without affecting PP formation. Particle size analysis and TEM observations demonstrated that the two chimeric P particles were still able to form 24-mer nanoparticles. Moreover, the two chimeric PP-based AD vaccines could both efficiently elicit strong immune responses in the mouse model. In conclusion, we have successfully established a novel method for preparing vaccines based on the NoV PP which would not affect PP sequence and function. PMID- 26773742 TI - Highly efficient recombinant production and purification of streptococcal cysteine protease streptopain with increased enzymatic activity. AB - Streptococcus pyogenes produces the cysteine protease streptopain (SpeB) as a critical virulence factor for pathogenesis. Despite having first been described seventy years ago, this protease still holds mysteries which are being investigated today. Streptopain can cleave a wide range of human proteins, including immunoglobulins, the complement activation system, chemokines, and structural proteins. Due to the broad activity of streptopain, it has been challenging to elucidate the functional results of its action and precise mechanisms for its contribution to S. pyogenes pathogenesis. To better study streptopain, several expression and purification schemes have been developed. These methods originally involved isolation from S. pyogenes culture but were more recently expanded to include recombinant Escherichia coli expression systems. While substantially easier to implement, the latter recombinant approach can prove challenging to reproduce, often resulting in mostly insoluble protein and poor purification yields. After extensive optimization of a wide range of expression and purification conditions, we applied the autoinduction method of protein expression and developed a two-step column purification scheme that reliably produces large amounts of purified soluble and highly active streptopain. This method reproducibly yielded 3 mg of streptopain from 50 mL of expression culture at >95% purity, with an activity of 5306 +/- 315 U/mg, and no remaining affinity tags or artifacts from recombinant expression. This improved method therefore enables the facile production of the important virulence factor streptopain at higher yields, with no purification scars that might bias functional studies, and with an 8.1-fold increased enzymatic activity compared to previously described procedures. PMID- 26773745 TI - Expression, purification and crystallization of human kynurenine aminotransferase 2 exploiting a highly optimized codon set. AB - Kynurenine aminotransferase (KAT) is a pyridoxal-5'-phosphate (PLP) dependent enzyme that catalyses kynurenine (KYN) to kynurenic acid (KYNA), a neuroactive product in the tryptophan metabolic pathway. Evidence suggests that abnormal levels of KYNA are involved in many neurodegenerative diseases such as Parkinson's disease, Huntington's disease, Alzheimer's disease and schizophrenia. Reducing KYNA production through inhibiting kynurenine aminotransferase 2 (KAT2) would be a promising approach to understanding and treating the related neurological and mental disorders. In this study we used an optimized codon sequence to overexpress histidine-tagged human KAT2 (hKAT2) using an Escherichia coli expression system. After a single step of Ni-NTA based purification the purified protein (>95%) was confirmed to be active by an HPLC based activity assay and was crystallized using the hanging-drop vapour diffusion method. The crystal system represents a novel space group, and a complete X-ray diffraction data set was collected to 1.83 A resolution, and higher resolution data than for any reported native human KAT2 structure. The optimised method of protein production provides a fast and reliable technique to generate large quantities of active human KAT2 suitable for future small-molecule lead compound screening and structural design work. PMID- 26773746 TI - A Jonah-like chymotrypsin from the therapeutic maggot Lucilia sericata plays a role in wound debridement and coagulation. AB - Lucilia sericata larvae are used in maggot debridement therapy, a traditional wound healing approach that has recently been approved for the treatment of chronic wounds. Maggot excretion products (MEP) contain many different proteases that promote disinfection, debridement and the acceleration of wound healing, e.g. by activating the host contact phase/intrinsic pathway of coagulation. In order to characterise relevant procoagulant proteases, we analysed MEP and identified a chymotrypsin-like serine protease with similarities to Jonah proteases from Drosophila melanogaster and a chymotrypsin from Lucilia cuprina. A recombinant form of the L. sericata Jonah chymotrypsin was produced in Escherichia coli. The activated enzyme (Jonahm) had a pH optimum of 8.0 and a temperature optimum of 37 degrees C, based on the cleavage of the chromogenic peptide s-7388 and casein. Jonahm reduced the clotting time of human plasma even in the absence of the endogenous protease kallikrein, factor XI or factor XII and digested the extracellular matrix proteins fibronectin, laminin and collagen IV, suggesting a potential mechanism of wound debridement. Based on these characteristics, the novel L. sericata chymotrypsin-like serine protease appears to be an ideal candidate for the development of topical drugs for wound healing applications. PMID- 26773749 TI - Design and Sensing Properties of a Self-Assembled Supramolecular Oligomer. AB - Invited for the cover of this issue is the group of Jonathan L. Sessler at the University of Texas at Austin. The image depicts the controlled self-assembly of electron rich and electron deficient components to create stimulus responsive oligomeric ensemble that functions as a sensor system for nitroaromatic explosives. Read the full text of the article at 10.1002/chem.201503701. PMID- 26773750 TI - In human T cells mifepristone antagonizes glucocorticoid non-genomic rapid responses in terms of Na(+)/H(+)-exchange 1 activity, but not ezrin/radixin/moesin phosphorylation. AB - Glucocorticoids (GCs) and progesterone have been employed as immunosuppressive agents during pregnancy for many years. Intracellular acidification by GCs is due to a rapid non-genomic inhibition of membrane Na(+)/H(+)-exchange 1 (NHE1) activity and is followed by immunosuppression of PHA-stimulated proliferation. NHE1 is tethered to the cortical actin cytoskeleton through ezrin/radixin/moesin (ERM) proteins within lipid rafts; these regulate cell shape, migration and resistance to apoptosis. We explored whether mifepristone (RU486), an antagonist of GCs in T cells, is able to completely block rapid non-genomic responses, namely NHE1 activity and the phosphorylation C-terminal residues of ERM proteins at threonine (cp-ERM). GCs stimulate a rapid non-genomic cp-ERM response in cells within 5min. RU486 antagonized the GC-induced rapid decrease in NHE1 activity, and arrested PHA-stimulated T cells at G0/G1 phase but had no effect on the rapid increase in cp-ERM, which persisted for 24h. However, the cp-ERM response was blocked by staurosporine in both resting and GC stimulated cells. The results of RU486 antagonized the GC induced rapid decrease in NHE1 ion transport activity, but not the increase cp-ERM. This suggests that RU486 in T cells exerts its antagonistic effects at NHE1 containing plasma membrane sites and not where cp ERM links lipid rafts to cortical cytoskeletons. PMID- 26773751 TI - The hippocampus may be more susceptible to environmental noise than the auditory cortex. AB - Noise exposure can cause structural and functional problem in the auditory cortex (AC) and hippocampus, the two brain regions in the auditory and non-auditory systems respectively. The aim of the present study was to explore which one of these two brain regions may be more susceptible to environmental noise. The AC and hippocampus of mice were separated following 1 or 3 weeks exposure to moderate noise (80 dB SPL, 2 h/day). The levels of oxidative stress and tau phosphorylation were then measured to evaluate the effects by noise. Results showed significant peroxidation and tau hyperphosphorylation in the hippocampus with 1 week of noise exposure. However, the AC did not show significant changes until exposure for 3 weeks. These data suggest that although the hippocampus and AC were affected by moderate noise exposure, the hippocampus in the non-auditory system may have been more vulnerable to environmental noise than the AC. PMID- 26773752 TI - Auditory and visual 3D virtual reality therapy as a new treatment for chronic subjective tinnitus: Results of a randomized controlled trial. AB - BACKGROUND: Subjective tinnitus (ST) is a frequent audiologic condition that still requires effective treatment. This study aimed at evaluating two therapeutic approaches: Virtual Reality (VR) immersion in auditory and visual 3D environments and Cognitive Behaviour Therapy (CBT). METHODS: This open, randomized and therapeutic equivalence trial used bilateral testing of VR versus CBT. Adult patients displaying unilateral or predominantly unilateral ST, and fulfilling inclusion criteria were included after giving their written informed consent. We measured the different therapeutic effect by comparing the mean scores of validated questionnaires and visual analog scales, pre and post protocol. Equivalence was established if both strategies did not differ for more than a predetermined limit. We used univariate and multivariate analysis adjusted on baseline values to assess treatment efficacy. In addition of this trial, purely exploratory comparison to a waiting list group (WL) was provided. RESULTS: Between August, 2009 and November, 2011, 148 of 162 screened patients were enrolled (VR n = 61, CBT n = 58, WL n = 29). These groups did not differ at baseline for demographic data. Three month after the end of the treatment, we didn't find any difference between VR and CBT groups either for tinnitus severity (p = 0.99) or tinnitus handicap (p = 0.36). CONCLUSION: VR appears to be at least as effective as CBT in unilateral ST patients. PMID- 26773753 TI - Effects of quasi-steady-state reduction on biophysical models with oscillations. AB - Many biophysical models have the property that some variables in the model evolve much faster than others. A common step in the analysis of such systems is to simplify the model by assuming that the fastest variables equilibrate instantaneously, an approach that is known as quasi-steady state reduction (QSSR). QSSR is intuitively satisfying but is not always mathematically justified, with problems known to arise, for instance, in some cases in which the full model has oscillatory solutions; in this case, the simplified version of the model may have significantly different dynamics to the full model. This paper focusses on the effect of QSSR on models in which oscillatory solutions arise via one or more Hopf bifurcations. We first illustrate the problems that can arise by applying QSSR to a selection of well-known models. We then categorize Hopf bifurcations according to whether they involve fast variables, slow variables or a mixture of both, and show that Hopf bifurcations that involve only slow variables are not affected by QSSR, Hopf bifurcations that involve fast and slow variables (i.e., singular Hopf bifurcations) are generically preserved under QSSR so long as a fast variable is kept in the simplified system, and Hopf bifurcations that primarily involve fast variables may be eliminated by QSSR. Finally, we present some guidelines for the application of QSSR if one wishes to use the method while minimising the risk of inadvertently destroying essential features of the original model. PMID- 26773754 TI - Gender-specific neuromuscular adaptations to unloading in isolated rat soleus muscles. AB - INTRODUCTION: The potential of gender to affect unloading-induced neuromuscular adaptations was investigated. METHODS: Twenty male and 20 female rats were assigned to control (CTL), or unloaded (UL) conditions. After 2 weeks of unloading, soleus muscles were removed, and neuromuscular function was assessed during a train of alternating indirect (neural) and direct (muscle) stimuli. RESULTS: In rested muscle, strength showed significant (P <= 0.05) main effects for gender (male > female) and treatment (CTL > UL). By the end of the testing protocol, when muscles showed fatigue, gender-related and treatment-related differences in strength had disappeared. Neuromuscular transmission efficiency and strength suffered a greater decline during the testing protocol in males than females. Unloaded male muscles displayed greater contractile velocity than female muscles both when rested and fatigued. CONCLUSIONS: Gender affected unloading induced neuromuscular adaptations. The greater strength of rested male muscles was due to greater muscle mass and neuromuscular transmission efficiency. Muscle Nerve 54: 300-307, 2016. PMID- 26773756 TI - Prolonged clot lysis time increases the risk of a first but not recurrent venous thrombosis. AB - The role of the fibrinolytic system in the development of venous thrombosis (VT) is unclear. We studied the risk of first and recurrent VT associated with reduced fibrinolysis, as measured by clot lysis time (CLT). We also studied the relationship between CLT and thrombin generation to determine if any relationship between CLT and VT was affected by thrombin generation. Analyses were performed in the Thrombophilia Hypercoagulability Environmental risk for Venous Thromboembolism Study, a two-centre population-based case-control study, including 579 patients and 338 controls, with patients followed from the event to determine incidence of recurrent VT. Hypofibrinolysis was associated with a 1.8 fold increased risk of a first VT [95% confidence interval (CI) 1.2-2.7]. Adjustment for sex, age, study location and Endogenous Thrombin Potential (ETP) did not change the result. The risk of VT was 2.9-fold increased when the 90th percentiles of prolonged CLT and high ETP were combined, with the highest risk for unprovoked first events (Odds Ratio = 4.2, 95% CI 1.3-13.5). In the follow-up study the Hazard Ratio for a recurrent VT associated with hypofibrinolysis was 1.5 (95% CI 0.9-2.6). A weak dose response effect was observed in relation to prolongation of CLT and recurrent VT. Although hypofibrinolysis constitutes a risk factor for a first VT, an association with recurrence is, at best, weak. PMID- 26773755 TI - Synthesis and tyrosinase inhibition activity of trans-stilbene derivatives. AB - Synthesis of a focussed library of trans-stilbene compounds through Wittig and other base catalysed condensation reactions is presented. The synthesized stilbenes were screened for their inhibitory potential against murine tyrosinase activity to explore the structure activity relationship (SAR). Presence of electron withdrawing group (-CN) at the double bond and hydroxyl group or halogen atom especially at para-position on the aromatic rings was found to significantly elevate the inhibitory activity. Among all the compounds screened, compounds 2, 6, 8, 10, 11, 15 and 21 were found to exhibit appreciable inhibitory activity. Compound 21 ((E)-2,3-bis(4-Hydroxyphenyl)acryonitrile) was found to be the most active with an IC50 value of 5.06 MUM which is less than half of the value 10.78 MUM observed for resveratrol (common standard used in murine tyrosinase activity studies) under similar conditions. The results obtained from the present study reveal structural/functional group sensitivity for the tyrosinase inhibitory activity of stilbenoid moieties and are expected to be very helpful for the design and synthesis of novel, selective and effective tyrosinase inhibitors. PMID- 26773757 TI - Anaerobic microbial dehalogenation of organohalides-state of the art and remediation strategies. AB - Contamination and remediation of groundwater with halogenated organics and understanding of involved microbial reactions still poses a challenge. Over the last years, research in anaerobic microbial dehalogenation has advanced in many aspects providing information about the reaction, physiology of microorganisms as well as approaches to investigate the activity of microorganisms in situ. Recently published crystal structures of reductive dehalogenases (Rdh), heterologous expression systems and advanced analytical, proteomic and stable isotope approaches allow addressing the overall reaction and specific enzymes as well as co-factors involved during anaerobic microbial dehalogenation. In addition to Dehalococcoides spp., Dehalobacter and Dehalogenimonas strains have been recognized as important and versatile organohalide respirers. Together, these provide perspectives for integrated concepts allowing to improve and monitor in situ biodegradation. PMID- 26773758 TI - Combining microbial production with chemical upgrading. AB - This review presents developments in the chemical processing of fermentation derived compounds, focusing on ethanol, lactic acid, 2,3-butanediol and the acetone-butanol-ethanol mixture. We examine pathways from these products to biologically-derived drop-in fuels, polymers, as well as commodity chemicals, highlighting the role of homogeneous and heterogeneous catalysts in the development of green processes for the production of fuels and high-value-added compounds from biomass. PMID- 26773760 TI - Systemic prostacyclin and thromboxane production in obstructive sleep apnea. AB - PURPOSE: Obstructive sleep apnea increases the risk of cardiovascular diseases. Alternations in prostacyclin and thromboxane concentrations and balance could constitute one of mechanisms linking sleep apnea and cardiovascular events. Thus we aimed to assess the concentrations of 6-keto-prostaglandin F1alpha (6-keto PGF1alpha) (metabolite of prostacyclin) and thromboxane B2 (TXB2) (metabolite of thromboxane A2) in urine and blood of obstructive sleep apnea patients and controls (snoring subjects with otherwise normal polysomnogram). MATERIAL AND METHODS: Overnight urine and morning blood samples were taken from subjects and controls at baseline and in sleep apnea group during continuous positive airway pressure (CPAP) treatment. Samples were analyzed using mass chromatography/gas spectrometry. RESULTS: We analyzed data from 26 obstructive sleep apnea subjects (mean apnea-hypopnea index 45.4+/-17.3) and 22 well-matched controls. At baseline sleep apnea patients, when compared to controls, have higher 6-keto-PGF1alpha in urine (0.89+/-0.15 vs 0.34+/-0.06, p=0.01) and blood (24.49+/-1.54 vs 19.70+/ 1.77, p=0.04). TXB2 levels in urine and blood were not different across groups. CPAP treatment significantly decreased 6-keto-PGF1alpha in urine (0.92+/-0.17 vs 0.22+/-0.10, p=0.04), but not in blood. TXB2 levels during CPAP treatment did not change significantly. CONCLUSIONS: These results suggest augmented systemic prostacyclin production in obstructive sleep apnea patients, which potentially could constitute a protective mechanism against detrimental effects of sleep apnea. PMID- 26773762 TI - Prognostic significance of mitral regurgitation in long-term all-cause mortality in patients aged >=80 years with acute coronary syndrome. [Int J Cardiol. 2014, 176(2):340-5]. PMID- 26773761 TI - Comparison of second- and first-generation drug eluting stent for percutaneous coronary chronic total occlusion intervention. AB - BACKGROUND: The performance of contemporary second-generation drug-eluting stents (DESs) for percutaneous chronic total occlusion (CTO) intervention is not well established. The present study compared the efficacy and safety outcomes of second-generation DESs with those of first-generation DESs in CTO-percutaneous coronary intervention (PCI). METHODS: This retrospective analysis included 1049 consecutive CTO patients who underwent successful DES implantation (first generation; 487 vs. second-generation; 562 patients) between March 2003 and August 2014. The primary endpoint was the composite of all-cause death, Q-wave myocardial infarction (MI), or target-vessel revascularization (TVR). RESULTS: During a follow-up of 3 years, the primary endpoint incidence was 10.1% for second- and 7.7% for first-generation DES (p=0.30). After multivariable adjustment, there was no significant difference between these groups in terms of the risk of composite of death, Q-wave MI, or TVR (Hazard ratio [HR] 1.42, 95% confidence interval [CI] 0.88-2.28, p=0.15) nor in the individual risks of death (adjusted HR 1.33, 95% CI 0.69-2.56, p=0.39), Q-wave MI (adjusted HR 1.15, 95% CI 0.30-4.47, p=0.84) and TVR (adjusted HR 1.06, 95% CI 0.52-2.15, p=0.87). The incidence of definite/probable stent thrombosis was relatively low (0.5% vs.0.9%, p=0.17) throughout the follow-up period. CONCLUSION: The 3-year clinical outcomes of patients treated with second-generation DESs are comparable to those treated with first-generation DESs for CTO-PCI. PMID- 26773759 TI - PRPH2/RDS and ROM-1: Historical context, current views and future considerations. AB - Peripherin 2 (PRPH2), also known as RDS (retinal degeneration slow) is a photoreceptor specific glycoprotein which is essential for normal photoreceptor health and vision. PRPH2/RDS is necessary for the proper formation of both rod and cone photoreceptor outer segments, the organelle specialized for visual transduction. When PRPH2/RDS is defective or absent, outer segments become disorganized or fail to form entirely and the photoreceptors subsequently degenerate. Multiple PRPH2/RDS disease-causing mutations have been found in humans, and they are associated with various blinding diseases of the retina such as macular degeneration and retinitis pigmentosa, the vast majority of which are inherited dominantly, though recessive LCA and digenic RP have also been associated with RDS mutations. Since its initial discovery, the scientific community has dedicated a considerable amount of effort to understanding the molecular function and disease mechanisms of PRPH2/RDS. This work has led to an understanding of how the PRPH2/RDS molecule assembles into complexes and functions as a necessary part of the machinery that forms new outer segment discs, as well as leading to fundamental discoveries about the mechanisms that underlie OS biogenesis. Here we discuss PRPH2/RDS-associated research and how experimental results have driven the understanding of the PRPH2/RDS protein and its role in human disease. PMID- 26773764 TI - Invasive vagal nerve stimulation causes delayed autonomic dysregulation: A case report. PMID- 26773763 TI - Evaluation of contraceptive methods in women with congenital heart disease in Germany, Hungary and Japan. AB - AIMS: For women with congenital heart defects (CHD), pregnancy may pose a health risk. Sexually active women with CHD without the desire for own children or for whom pregnancy would imply considerable health risks require adequate counselling regarding appropriate contraception. This study gathers data on the contraceptive behaviour of women with CHD from three different cultural regions. METHODS AND RESULTS: 634 women with CHD from Germany, Hungary and Japan were surveyed regarding contraception and contraceptive methods (CM) used. The patients were divided into groups according to different criteria such as pregnancy associated cardiovascular risk or "safety" of the contraceptive methods used. 59% of the study participants had already gained experience with CM. The average age at the first time of use was 18.4 years; the German patients were significantly younger at the first time of using a CM than those from Hungary and Japan. Overall the condom was the method used the most (38%), followed by oral contraceptives (30%) and coitus interruptus (11%). The range of CM used in Japan was much smaller than that in Germany or Hungary. Unsafe contraceptives were currently, or had previously been used, by 29% of the surveyed patients (Germany: 25%, Hungary: 37%, Japan: 32%). CONCLUSION: Most women with CHD use CM. There are differences between the participating countries. Adequate contraceptive counselling of women with CHD requires considering the individual characteristics of each patient, including potential contraindications. For choosing an appropriate CM, both the methods' "safety", as well as the maternal cardiovascular risk, are important. PMID- 26773765 TI - Risk factors of mortality after surgical correction of ventricular septal defect following myocardial infarction: Retrospective analysis and review of the literature. AB - BACKGROUND: Rupture of the ventricular septum following acute myocardial infarction (AMI) is an uncommon but serious complication, usually leading to congestive heart failure and cardiogenic shock. Surgical repair is the only definitive treatment for this condition. METHODS: We review our experience of surgical repair of post-infarction ventricular septal defects (VSDs), analyze the associated risk factors and outcomes, and do a complete review of the literature. A retrospective study was performed on 34 consecutive patients who had undergone surgical repair for VSDs following AMI from December 1991 to July 2014. Preoperative, clinical and echocardiographic variables were studied by uni-and multivariate analyses. RESULTS: Mortality was analyzed for the entire group of patients. Mean age was 69 +/- 7 years with 44% women. VSDs were anterior in 11 (32%) and posterior in 23 (68%) patients. A majority, 24 (71%) patients were in cardiogenic shock. Median interval from myocardial infarction to VSDs repair was 7 days. The 30 days operative mortality was 65%. Mortality within the posterior VSDs group was 74% and the anterior VSDs group was 46% (P=0.14). Concomitant coronary artery bypass graft (CABG) did not influence early or late survival. Multivariate analysis identified older age (HR=1.11, P=0.0001) and shorter time between AMI and surgery (HR=0.90, P=0.015) as independent predictors of 30-day and long-term mortality. CONCLUSION: In conclusion, surgical repair of post-AMI VSDs carries a high operative mortality. An algorithm of treatment for the management of these patients is suggested. PMID- 26773766 TI - Three cases of hepatocellular carcinoma in Fontan patients: Review of the literature and suggestions for hepatic screening. AB - The Fontan procedure has been used since 1971 as a palliative treatment for various (functionally) univentricular hearts. The systemic venous blood flows passively to the pulmonary arteries, without passing through a functional ventricle. This results in chronic systemic venous congestion, which may lead to liver fibrosis, cirrhosis and hepatocellular carcinoma. This review discusses possible screening modalities for liver fibrosis and cirrhosis in the Fontan population and proposes a screening protocol. We suggest starting screening for progression of fibrosis and cirrhosis in collaboration with the hepatologist circa 10 years after Fontan completion. The screening programme will consist of a yearly evaluation of liver laboratory tests in conjunction with imaging of the liver with ultrasound or MRI every two years. In case of liver fibrosis or cirrhosis, (reversible) causes should be ruled out (e.g. obstruction in the Fontan circuit). In case of severe fibrosis or cirrhosis, other complications of portal hypertension should be evaluated and screening for hepatocellular carcinoma is required on a regular (6-12 months) basis. As regards hepatocellular carcinoma, treatment should be discussed in a multidisciplinary team, before deciding a treatment modality. PMID- 26773767 TI - PEGylated and targeted extracellular vesicles display enhanced cell specificity and circulation time. AB - Extracellular vesicles (EVs) are increasingly being recognized as candidate drug delivery systems due to their ability to functionally transfer biological cargo between cells. However, the therapeutic applicability of EVs may be limited due to a lack of cell-targeting specificity and rapid clearance of exogenous EVs from the circulation. In order to improve EV characteristics for drug delivery to tumor cells, we have developed a novel method for decorating EVs with targeting ligands conjugated to polyethylene glycol (PEG). Nanobodies specific for the epidermal growth factor receptor (EGFR) were conjugated to phospholipid (DMPE) PEG derivatives to prepare nanobody-PEG-micelles. When micelles were mixed with EVs derived from Neuro2A cells or platelets, a temperature-dependent transfer of nanobody-PEG-lipids to the EV membranes was observed, indicative of a 'post insertion' mechanism. This process did not affect EV morphology, size distribution, or protein composition. After introduction of PEG-conjugated control nanobodies to EVs, cellular binding was compromised due to the shielding properties of PEG. However, specific binding to EGFR-overexpressing tumor cells was dramatically increased when EGFR-specific nanobodies were employed. Moreover, whereas unmodified EVs were rapidly cleared from the circulation within 10min after intravenous injection in mice, EVs modified with nanobody-PEG-lipids were still detectable in plasma for longer than 60min post-injection. In conclusion, we propose post-insertion as a novel technique to confer targeting capacity to isolated EVs, circumventing the requirement to modify EV-secreting cells. Importantly, insertion of ligand-conjugated PEG-derivatized phospholipids in EV membranes equips EVs with improved cell specificity and prolonged circulation times, potentially increasing EV accumulation in targeted tissues and improving cargo delivery. PMID- 26773768 TI - Targeting collagen for diagnostic imaging and therapeutic delivery. AB - As the most abundant protein in mammals and a major structural component in extracellular matrix, collagen holds a pivotal role in tissue development and maintaining the homeostasis of our body. Persistent disruption to the balance between collagen production and degradation can cause a variety of diseases, some of which can be fatal. Collagen remodeling can lead to either an overproduction of collagen which can cause excessive collagen accumulation in organs, common to fibrosis, or uncontrolled degradation of collagen seen in degenerative diseases such as arthritis. Therefore, the ability to monitor the state of collagen is crucial for determining the presence and progression of numerous diseases. This review discusses the implications of collagen remodeling and its detection methods with specific focus on targeting native collagens as well as denatured collagens. It aims to help researchers understand the pathobiology of collagen related diseases and create novel collagen targeting therapeutics and imaging modalities for biomedical applications. PMID- 26773769 TI - Recent advances of semiconducting polymer nanoparticles in in vivo molecular imaging. AB - Semiconducting polymer nanoparticles (SPNs) emerge as attractive molecular imaging nanoagents in living animals because of their excellent optical properties including large absorption coefficients, tunable optical properties and controllable dimensions, high photostability, and the use of organic and biologically inert components without toxic metals. This review summarizes the recent advances of these new organic nanoparticles in in vivo molecular imaging. The in vivo biocompatibility of SPNs is discussed first in details, followed by examples of their applications ranging from sentinel lymph node mapping and tumor imaging to long-term cell tracking, to drug toxicity and bacterial infection imaging for fluorescence, bioluminescence, chemiluminescence and photoacoustic imaging in living animals. The utility of SPNs for designing smart activatable probes for real-time in vivo imaging is also discussed. PMID- 26773770 TI - Comparison of immunomodulatory properties of mannose-binding lectins from Canavalia brasiliensis and Cratylia argentea in a mice model of Salmonella infection. AB - The immunomodulatory properties of mannose-binding lectins ConBr (Canavalia brasiliensis) and CFL (Cratylia argentea) were investigated comparatively in a model of Salmonella infection. The lectins were intraperitoneally (i.p.) administered to mice daily for three days before the bacterial challenge with Salmonella enterica Ser. Typhimurium (0.2 mL i.p.; 10(7) CFU/mL). In vivo assays have shown that both lectins induced a significant leukocyte infiltration into the peritoneal cavity of uninfected mice, which was higher in the CFL group 3 days post-infection. Total and differential cell counts in the bloodstreams have shown uninfected animals pretreated with ConBr and CFL exhibited accentuated lymphopenia. Conversely, there was an increasing population of lymphocytes following 3 days post-infection in mice pretreated with both lectins. In addition, the bacterial burden was significantly reduced into the peritoneal cavity, bloodstreams, spleen and the liver in these mice. The lectins did not induce the release of pro- or anti-inflammatory cytokines into the peritoneal fluid of uninfected animals. However, following infection, the release of TNF alpha and IL-10 in the peritoneal fluid were down-regulated in mice pretreated with both lectins whereas IL-1 was only reduced in mice pretreated with ConBr. Uninfected animals pretreated with CFL exhibited high nitric oxide (NO) content in the peritoneal fluid, which was decreased after infection in comparison to ConBr group. The lectins did not alter the serum levels of NO in uninfected mice but treatments with ConBr significantly reduced the NO content in infected animals in comparison to CFL group 24h after the bacterial challenge. Survival experiments have shown survival rates ranging from 70% to 100% in mice that received CFL or ConBr. On the other hand, untreated mice (PBS group) died 1-6 days after infection. We conclude that ConBr and CFL are prospective phytotherapeutics capable of modulate the cascade of pro-inflammatory plus regulatory cytokines and nitric oxide release derived from systemic infections. PMID- 26773771 TI - meso-Dihydroguaiaretic acid attenuates airway inflammation and mucus hypersecretion in an ovalbumin-induced murine model of asthma. AB - meso-Dihydroguaiaretic acid (MDGA), which is a dibenzylbutane lignin isolated from the ethyl acetate fraction of Saururus chinensis, has various biological activities, including anti-oxidative, anti-inflammatory, anti-bacterial, and neuroprotective effects. However, no report has examined the potential anti asthmatic activity of MDGA. In this study, we evaluated the protective effects of MDGA on asthmatic responses, particularly airway inflammation and mucus hypersecretion in an ovalbumin (OVA)-induced murine model of asthma. Intragastric administration of MDGA significantly lowered the productions of interleukin (IL) 4, IL-5, IL-13, tumor necrosis-alpha (TNF-alpha), eotaxin, monocyte chemoattractant protein-1 (MCP-1), vascular cell adhesion molecule-1 (VCAM-1), and immunoglobulin (Ig)E in bronchoalveolar lavage fluid (BALF), plasma, or lung tissues. Histological studies showed that MDGA inhibited OVA-induced inflammatory cell infiltration and mucus production in the respiratory tract. Moreover, MDGA markedly attenuated the OVA-induced activations of nuclear factor kappa B (NF kappaB), extracellular-signal-regulated kinases 1/2 (ERK1/2), and p38 mitogen activated protein kinase (p38 MAPK). Together, these results suggest that MDGA effectively inhibits airway inflammation and mucus hypersecretion by downregulating the levels of T helper 2 (Th2) cytokines, chemokines, and adhesion molecules, and inhibiting the activations of NF-kappaB and MAPKs. PMID- 26773772 TI - A fully human monoclonal antibody targeting PD-L1 with potent anti-tumor activity. AB - BACKGROUND: Programmed cell death ligand-1 (PD-L1) with its receptor PD-1 pathway is overactivated in many tumors. Inhibiting the interaction of PD-L1 and PD-1 is an attractive strategy to restore tumor-specific T cell immunity for tumor therapy. METHODS: A fully human anti-PD-L1 monoclonal antibody (mAb) B60-55 was identified by yeast surface display. The affinity, specificity, activity, and efficacy of mAb B60-55 were investigated in vitro or in vivo. RESULTS: mAb B60-55 (purity >99%) could bind to PD-L1 that is expressed on HEK293 cells with a dissociation constant of 0.2 nM, and specifically bind to human or cynomolgus macaque PD-L1 without a cross-reaction with murine PD-L1. Moreover, mAb B60-55 is an antagonistic antibody, which can block PD-L1 binding to its receptors, including PD-1 (PDCD1) and B7.1 (CD80). In vitro assays demonstrated the ability of mAb B60-55 to enhance T cell responses and cytokine production in the mixed lymphocyte reaction. In vivo studies showed that administration of mAb B60-55 exhibited a potent antitumor activity toward tumor cell carcinoma xenograft, with a mean half-life of 177.9h in cynomolgus monkeys. CONCLUSION: mAb B60-55 is a potential candidate for clinical development in cancer treatment. PMID- 26773773 TI - Combined treatment with low dose prednisone and escin improves the anti-arthritic effect in experimental arthritis. AB - The present study was aimed at investigating whether low dose oral prednisone combined with escin could inhibit the progression of adjuvant-induced arthritis (AIA) in rats. Adjuvant arthritis was induced in SD rats began day 1 for 28 days. Prednisone at doses of 2, 10 mg/kg/day alone or escin at doses of 5, 10 mg/kg/day alone, or prednisone at dose of 2 mg/kg/day with escin at doses of 5 or 10 mg/kg/day were given to different groups of rats intragastrically from day 13 to 28 respectively. Paw swelling, arthritic index, histological and radiographic changes were assessed to evaluate the anti-arthritic effect. Weight growth, spleen and thymus indexes were also calculated. Serum samples were collected for estimation of pro-inflammatory cytokines. Rats developed erosive arthritis of the hind paw when immunized with adjuvant. Prednisone 2 mg/kg combined with escin 5 or 10 mg/kg significantly inhibited the paw swelling. Histopathological and radiographic analysis showed a marked decrease of synovial inflammatory infiltration, synovial hyperplasia and bone erosion by combination therapy, which also markedly suppressed the expression of tumor necrosis factor-alpha (TNF alpha), interleukin-1beta (IL-1beta) and interleukin-6 (IL-6). No significant changes were found in monotherapy group except prednisone 10 mg/kg group. Furthermore, combined treatment rescued some of GCs' adverse effects evidenced by increase in body weight and decrease in index of spleen compared with untreated AIA rats. In conclusion, the combination therapy possessed synergistic anti arthritic efficacy and reduced adverse effect, which may play a role in the management of human RA. PMID- 26773774 TI - Effects of support surface and optic flow on step-like movements in pre-crawling and crawling infants. AB - Step-like movements were examined in pre-crawling (n=9) and crawling (n=9) 6-13 month-old infants in the air and on a surface in response to a static pattern or optic flows that moved toward or away from the infant. Infants completed six 60-s trials. A significant interaction between locomotor status and support condition revealed that pre-crawling infants made more step-like movements in the air than on a rigid surface. In contrast, crawling infants made an equivalent number of step-like movements in the air and on the surface. Optic flow did not influence the number of step-like movements made by infants. The pre-crawling infant finding is consistent with a finding in a previous study in which two month-old infants were shown to step more in the air than on the ground. This finding is discussed relative to the idea that the infant stepping pattern disappears because the legs become too heavy to lift. PMID- 26773775 TI - Association between 25-hydroxyvitamin D and inflammatory biomarker levels in a cross-sectional population-based study, Sao Paulo, Brazil. AB - Besides the classic vitamin D function on bone homeostasis, there are bodies of evidence showing that adequate status of vitamin D can modulate inflammation. We hypothesized that higher plasma levels of 25-hydroxyvitamin D (25[OH]D) would correlate with lower plasma levels of proinflammatory cytokines, acute-phase proteins, and soluble adhesion molecules and higher plasma levels of anti inflammatory cytokines. We included all adults (age, 20-59 years) of the population-based, cross-sectional study, Health Survey-Sao Paulo, conducted in Sao Paulo (Brazil) in the study (n = 281). Anthropometric parameters, blood pressure measurements, and a fasting blood sample were collected by trained fieldworkers. Serum 25(OH)D concentration, plasma inflammatory biomarker levels (C-reactive protein, interleukin [IL]-1beta, IL-6, IL-8, IL-10, tumor necrosis factor [TNF] alpha, IL-12p70, adiponectin, monocyte chemoattractant protein-1, soluble intercellular adhesion molecule-1, and soluble vascular cell adhesion molecule-1), and plasma blood lipid parameters were evaluated. The prevalence of vitamin D inadequacy (<50 nmol/L) was 65.5%. Inadequate participants were younger, with lower body mass index (BMI), systolic and diastolic blood pressures, triglyceride, and total cholesterol levels as well as low-density lipoprotein cholesterol, compared with individuals adequate for vitamin D status. After adjustment, plasma concentration of soluble intercellular adhesion molecule 1 was statistically higher among adequate participants. Stratifying for BMI categories, a negative association was observed between plasma IL-6 and TNF-alpha levels and serum 25(OH)D concentration in normal-weight participants, whereas a negative association was detected between plasma adiponectin level and serum 25(OH)D concentration in overweight participants. The present findings suggest that BMI interacts with serum 25(OH)D levels, modulating inflammatory response and affecting plasma IL-6, TNF-alpha, and adiponectin levels. These data indicate that BMI plays a determinant role in the vitamin D-inflammation axis. PMID- 26773776 TI - The effect of the paraoxonase 1 (PON1) T(-107)C polymorphism on serum PON1 activity in women is dependent on fatty acid intake. AB - Paraoxonase 1 (PON1) is an enzyme that prevents the peroxidation of lipoprotein and cell membranes. Our hypothesis is that the effect of the PON1 T(-107)C polymorphism on serum PON1 activity in healthy adult women is dependent on their fatty acid intake profile. This study included women (n = 39) who completed a food frequency questionnaire. Fatty acid intake was estimated based on the interview and a nutrient reference table. Blood samples were collected for genotyping and to measure serum PON1 activity. Serum PON1 activity was different among genotypes and was higher for women of the CC genotype (P < .001). Women in the study were categorized in 2 groups according to the median nutrient intake. Overall, there was a difference (P < .05) in serum PON1 activity between the CC and TT genotypes in women ingesting either above or below the median total fat, saturated fatty acids, monounsaturated fatty acids, polyunsaturated fatty acids, omega 3 (n-3) and omega 6 (n-6; P < .05). However, genotype effects on serum PON1 activity were not observed in women ingesting below the median (15:1) ratio of n 6/n-3 (P > .05) but were observed in women ingesting above the ratio of n-6/n-3 (P < .05). This is partly because women of the CC genotype had decreased PON1 activity when ingesting a lower ratio of n-6/n-3 diet (P < .05), while women of the TT genotype had increased PON1 activity (P < .05). In conclusion, the overall presence of the C allele was associated with increased serum PON1 activity, although a diet with high saturated fatty acid or a low ratio of n-6/n-3 reduced PON1 activity in women with the CC genotype. PMID- 26773777 TI - Green tea catechins prevent low-density lipoprotein oxidation via their accumulation in low-density lipoprotein particles in humans. AB - Green tea is rich in polyphenols, including catechins which have antioxidant activities and are considered to have beneficial effects on cardiovascular health. In the present study, we investigated the effects of green tea catechins on low-density lipoprotein (LDL) oxidation in vitro and in human studies to test the hypothesis that catechins are incorporated into LDL particles and exert antioxidant properties. In a randomized, placebo-controlled, double-blind, crossover trial, 19 healthy men ingested green tea extract (GTE) in the form of capsules at a dose of 1 g total catechin, of which most (>99%) was the gallated type. At 1 hour after ingestion, marked increases of the plasma concentrations of (-)-epigallocatechin gallate and (-)-epicatechin gallate were observed. Accordingly, the plasma total antioxidant capacity was increased, and the LDL oxidizability was significantly reduced by the ingestion of GTE. We found that gallated catechins were incorporated into LDL particles in nonconjugated forms after the incubation of GTE with plasma in vitro. Moreover, the catechin incorporated LDL was highly resistant to radical-induced oxidation in vitro. An additional human study with 5 healthy women confirmed that GTE intake sufficiently increased the concentration of gallated catechins, mainly in nonconjugated forms in LDL particles, and reduced the oxidizability of LDL. In conclusion, green tea catechins are rapidly incorporated into LDL particles and play a role in reducing LDL oxidation in humans, which suggests that taking green tea catechins is effective in reducing atherosclerosis risk associated with oxidative stress. PMID- 26773779 TI - Neuroprotective effects of the Phellinus linteus ethyl acetate extract against H2O2-induced apoptotic cell death of SK-N-MC cells. AB - Numerous studies have suggested that neuronal cells are protected against oxidative stress-induced cell damage by antioxidants, such as polyphenolic compounds. Phellinus linteus (PL) has traditionally been used to treat various symptoms in East Asian countries. In the present study, we prepared an ethyl acetate extract from the fruiting bodies of PL (PLEA) using hot water extraction, ethanol precipitation, and ethyl acetate extraction. The PLEA contained polyphenols as its major chemical component, and thus, we predicted that it may exhibit antioxidant and neuroprotective effects against oxidative stress. The results showed that the pretreatment of human brain neuroblastoma SK-N-MC cells with the PLEA (0.1-5 MUg/mL) significantly and dose-dependently reduced the cytotoxicity of H2O2 and the intracellular ROS levels and enhanced the expression of HO-1 (heme oxygenase-1) and antioxidant enzymes, such as CAT (catalase), GPx-1 (glutathione peroxidase-1), and SOD-1 and -2 (superoxide dismutase-1 and -2). The PLEA also directly scavenged free radicals. PLEA pretreatment also significantly attenuated DNA fragmentation and suppressed the mRNA expression and activation of mitogen-activated protein kinases extracellular signal-regulated kinase, c-Jun N terminal kinase, and p38 kinase, which are induced by oxidative stress and lead to cell death. PLEA pretreatment inhibited the activation of the apoptosis related proteins caspase-3 and poly (ADP-ribose) polymerase. These results demonstrate that the PLEA has neuroprotective effects against oxidative stress (H2O2)-induced neuronal cell death via its antioxidant and anti-apoptotic properties. PLEA should be investigated in an in vivo model on its potential to prevent or ameliorate neurodegenerative disease. PMID- 26773780 TI - Improvements in recall and food choices using a graphical method to deliver information of select nutrients. AB - Consumers have difficulty using nutrition information. We hypothesized that graphically delivering information of select nutrients relative to a target would allow individuals to process information in time-constrained settings more effectively than numerical information. Objectives of the study were to determine the efficacy of the graphical method in (1) improving memory of nutrient information and (2) improving consumer purchasing behavior in a restaurant. Values of fiber and protein per calorie were 2-dimensionally plotted alongside a target box. First, a randomized cued recall experiment was conducted (n=63). Recall accuracy of nutrition information improved by up to 43% when shown graphically instead of numerically. Second, the impact of graphical nutrition signposting on diner choices was tested in a cafeteria. Saturated fat and sodium information was also presented using color coding. Nutrient content of meals (n=362) was compared between 3 signposting phases: graphical, nutrition facts panels (NFP), or no nutrition label. Graphical signposting improved nutrient content of purchases in the intended direction, whereas NFP had no effect compared with the baseline. Calories ordered from total meals, entrees, and sides were significantly less during graphical signposting than no-label and NFP periods. For total meal and entrees, protein per calorie purchased was significantly higher and saturated fat significantly lower during graphical signposting than the other phases. Graphical signposting remained a predictor of calories and protein per calorie purchased in regression modeling. These findings demonstrate that graphically presenting nutrition information makes that information more available for decision making and influences behavior change in a realistic setting. PMID- 26773778 TI - Dietary supplementation with purified citrus limonin glucoside does not alter ex vivo functions of circulating T lymphocytes or monocytes in overweight/obese human adults. AB - Overweight/obesity is associated with chronic inflammation and impairs both innate and adaptive immune responses. Limonoids found in citrus fruits decreased cell proliferation and inflammation in animal studies. We hypothesized that limonin glucoside (LG) supplementation in vivo will decrease the ex vivo proliferation of T cells and the production of inflammatory cytokines by monocytes and T cells. In a double-blind, randomized, cross-over study, 10 overweight/obese human subjects were served purified LG or placebo drinks for 56 days each to determine the effects of LG on immune cell functions. The percentage of CD14+CD36+ cells in whole blood was analyzed by flow cytometry. Peripheral blood mononuclear cells were isolated and activated with CD3 plus CD28 antibodies (T-lymphocyte activation) or lipopolysaccharide (monocyte activation). Interferon gamma, tumor necrosis factor alpha, interleukin (IL) 2, IL-4, and IL-10 were measured in supernatants from activated T cells. Supernatants from activated monocytes were analyzed for the production of tumor necrosis factor alpha, IL 1beta, and IL-6. Peripheral blood mononuclear cells were prestained with PKH dye and activated with CD3 plus CD28 antibodies to determine the proliferative responses of CD4+ and CD8+ T lymphocytes by flow cytometry. No differences were observed for CD14+CD36+ monocyte populations, T-cell proliferation, or the production of T cell and monocyte cytokines between the 2 treatments. Thus, LG supplementation in vivo did not affect ex vivo functions of T cells and monocytes, whereas it decreased several circulating markers of hepatic inflammation as we previously reported. PMID- 26773781 TI - Chokeberry attenuates the expression of genes related to de novo lipogenesis in the hepatocytes of mice with nonalcoholic fatty liver disease. AB - Nonalcoholic fatty liver disease (NAFLD), which is characterized by steatosis, is a major public health concern. Previous studies have shown that chokeberry has anti-inflammatory, antimutagenic, hepatoprotective, cardioprotective, and antidiabetic effects. In this study, we hypothesized that chokeberry powder can attenuate the expression of genes related to de novo lipogenesis and the triglyceride levels in the hepatocytes of mice with high-fat diet-induced NAFLD. After coadministering chokeberry powder for 8weeks (0.5% and 1% powder) with a high-fat diet, mice that consumed chokeberry powder diets, regardless of the dose, had significantly lower liver triglyceride levels than control mice that were fed a high-fat diet (P=.0145 and P<.0012, respectively). Compared with mice that were fed a high-fat diet, mice that were given 1% chokeberry powder exhibited significantly decreased mRNA expression of sterol regulatory element binding protein (P=.009) and acetyl-CoA carboxylase (P=.0032) in the liver. Compared with mice in the control group, fatty acid synthase (FAS) expression significantly increased in the mice that were fed a high-fat diet, but both chokeberry powder-treated groups had significantly decreased FAS expression (P=.0157 and P<.0001, respectively). The size of the fat droplets was decreased in the livers of the chokeberry-supplemented groups. In summary, the administration of chokeberry powder may help attenuate high-fat diet-induced NAFLD by regulating the expression levels of sterol regulatory element-binding protein, acetyl-CoA carboxylase, and FAS and by decreasing the size of the fat droplets in the liver. PMID- 26773782 TI - Multiple differences between patients who initiate fish oil supplementation post myocardial infarction and those who do not: the TRIUMPH Study. AB - The utility of fish oil supplements (FOS) in patients who survive an acute myocardial infarction (MI) remains controversial, with randomized trials showing less benefit than observational studies would suggest. The differences in the characteristics of MI patients who use FOS in routine clinical care are unknown but may help explain this discrepancy. We used data from a 24-site registry study in which extensive information was available on 4340 MI patients at admission and 1, 6, and 12 months postdischarge. After excluding those using FOS at admission (n = 651), those who died before the 1-month follow-up visit (n = 63), and those with missing data at 1 month (n = 1228), 2398 remained. Of them, 377 (16%) started FOS within 1 month of their MI. We analyzed 53 patient characteristics associated with FOS use. We observed differences (P < .001) in 20 demographic, socioeconomic, treatment, disease severity, and health status domains. The FOS users were more likely than nonusers to be white, married, financially secure, highly educated, and eating fish. They also had a higher ejection fraction at discharge, were more likely to have had in-hospital percutaneous coronary interventions, and were more likely to have participated in cardiac rehabilitation programs. The FOS users were less likely to have a history of diabetes, alcohol abuse, stroke, MI, and angina. In conclusion, post-MI patients who initiate FOS within 1 month of discharge in routine clinical practice differ substantially from those who do not. These differences are strongly associated with a better post-MI prognosis and may illuminate several sources of unmeasured confounding in observational studies. PMID- 26773784 TI - Diet quality improves for parents and children when almonds are incorporated into their daily diet: a randomized, crossover study. AB - The health benefits of nuts may, in part, be due to the fiber that provides substrate for the maintenance of a healthy and diverse microbiota. We hypothesized that consuming almonds would benefit immune status through improving diet quality and modulation of microbiota composition in parents and their children, while improving gastrointestinal function. In a crossover trial, 29 parents (35 +/- 0.6 years) and their children (n = 29; 4 +/- 0.2 years; pairs) consumed 1.5 and 0.5 oz, respectively, of almonds and/or almond butter or control (no almonds) for 3 weeks followed by 4-week washouts. Parents completed daily questionnaires of stool frequency and compliance with nut intake. The Gastrointestinal Symptom Response Scale was administered weekly. Participants provided stools for microbiota analysis and saliva for secretory immunoglobulin A. Serum antioxidant/proinflammatory balance was determined in parents. From weekly dietary recalls (Automated Self-Administered 24-Hour Dietary Recall), nutrient and energy intake were assessed and Healthy Eating Index-2010 scores were calculated. Consuming almonds increased total Healthy Eating Index score from 53.7 +/- 1.8 to 61.4 +/- 1.4 (parents) and 53.7 +/- 2.6 to 61.4 +/- 2.2 (children; P < .001). Minimal changes in gastrointestinal symptoms and no change in stool frequency were noted with the almond intervention. Microbiota was stable at the phylum and family level, but genus-level changes occurred with nut intake, especially in children. No differences were observed for immune markers. Although higher intakes of almonds or longer interventions may be needed to demonstrate effects on immune status, a moderate intake of almonds improves diet quality in adults and their young children and modulates microbiota composition. PMID- 26773783 TI - Low serum 25-hydroxyvitamin D concentrations are associated with total adiposity of children in the United States: National Health and Examination Survey 2005 to 2006. AB - A negative association between serum 25-hydroxyvitamn D (25[OH]D) concentrations and adiposity has been found in adults. We hypothesized that serum 25(OH)D concentrations of children would correlate positively with vitamin D intake and correlate negatively with adiposity measures. Using a nationally representative sample of children aged 6 to 18 years from the National Health and Nutrition Examination Survey 2005-2006 (n = 2492), serum 25(OH)D concentrations were compared with measures of adiposity (weight, waist circumference [WC], WC-to height ratio, body mass index, skinfold thickness, and percent body fat). Based on Endocrine Society's serum 25(OH)D concentration criteria, 26.9% +/- 2.3% of the children were vitamin D deficient (<20 ng/mL) and 26.5% +/- 2.6% had sufficient levels (>=30 ng/mL). Controlling for age, sex, ethnicity, and income, linear regression analysis indicated that dietary vitamin D intake was positively associated with serum 25(OH)D levels (P < .05) and markers of adiposity were negatively associated with serum 25(OH)D levels: WC, WC-to-height ratio, body mass index, and triceps skinfold thickness (P < .05). A subgroup analysis (n = 2086; 8-18 years) of body fat, fat mass index, and percent body fat measured by dual-energy x-ray absorptiometry also was negatively associated with serum 25(OH)D levels (P < .05). When standardized beta coefficients were compared, strength of the inverse relationship to serum 25(OH)D concentrations was very similar for several adiposity measures. In conclusion, risk of a vitamin D deficiency was fairly common among children based on Endocrine Society criteria and low serum 25(OH)D concentrations were strongly associated with increased adiposity in children. PMID- 26773785 TI - Adzuki bean ameliorates hepatic lipogenesis and proinflammatory mediator expression in mice fed a high-cholesterol and high-fat diet to induce nonalcoholic fatty liver disease. AB - Nonalcoholic fatty liver disease (NAFLD) is a simple steatosis, in which fat accumulates more than 5% in the liver, and regarded as most common liver diseases worldwide. Because NAFLD can be developed to severe liver disease and correlated with metabolic disease, its importance is currently emphasized. Occurrence of NAFLD is strongly related to dietary patterns and lifestyles; therefore, the suggestion of physiologically beneficial food is essential. Based on these, adzuki beans containing anthocyanin, catechin, and adzukisaponin are suggested as a health-beneficial food. Moreover, the effects of adzuki beans on metabolic improvement are not well established through the in vivo studies. Therefore, this study hypothesized that adzuki beans can alleviate lipid accumulation and oxidative stress-mediated inflammation in high-cholesterol and high-fat diet induced NALFD mice. To demonstrate its effects, 6-week-old C57BL/6 male mice were allocated into 4 groups and fed a normal diet (ND), a high-cholesterol and high fat diet (HCD), and HCD with 10% and 20% adzuki bean for 10 weeks. The result shows that fasting blood glucose, serum and hepatic triglyceride and cholesterol levels, and antioxidative enzyme activity ameliorated in the adzuki bean groups (P < .05). The transcriptional factors of hepatic lipogenesis, such as adiponectin, AMP-activated protein kinase alpha, sterol regulatory element binding protein 1c, fatty acid synthase, carnitine palmitoyltransferase 1, 3 hydroxy-3-methyl-glutaryl-CoA reductase, and apolipoprotein B, as well as proinflammatory mediators, such as tumor necrosis factor alpha, nuclear factor kappaB, and caspase-3, improved in both experimental groups (P < .05). These results suggested that adzuki beans attenuate lipid accumulation and oxidative stress-induced inflammation by suppressing hepatic messenger RNA expression of lipogenic and inflammatory mediators in NAFLD. PMID- 26773787 TI - Sparse deconvolution method for ultrasound images based on automatic estimation of reference signals. AB - Sparse deconvolution is widely used in the field of non-destructive testing (NDT) for improving the temporal resolution. Generally, the reference signals involved in sparse deconvolution are measured from the reflection echoes of standard plane block, which cannot accurately describe the acoustic properties at different spatial positions. Therefore, the performance of sparse deconvolution will deteriorate, due to the deviations in reference signals. Meanwhile, it is inconvenient for automatic ultrasonic NDT using manual measurement of reference signals. To overcome these disadvantages, a modified sparse deconvolution based on automatic estimation of reference signals is proposed in this paper. By estimating the reference signals, the deviations would be alleviated and the accuracy of sparse deconvolution is therefore improved. Based on the automatic estimation of reference signals, regional sparse deconvolution is achievable by decomposing the whole B-scan image into small regions of interest (ROI), and the image dimensionality is significantly reduced. Since the computation time of proposed method has a power dependence on the signal length, the computation efficiency is therefore improved significantly with this strategy. The performance of proposed method is demonstrated using immersion measurement of scattering targets and steel block with side-drilled holes. The results verify that the proposed method is able to maintain the vertical resolution enhancement and noise-suppression capabilities in different scenarios. PMID- 26773786 TI - Normal vitamin D levels and bone mineral density among children with inborn errors of metabolism consuming medical food-based diets. AB - A higher incidence of osteopenia is observed among children with inherited metabolic disorders (inborn errors of metabolism, or IEMs) who consume medical food-based diets that restrict natural vitamin D-containing food sources. We evaluated the vitamin D status of children with IEMs who live in the Pacific Northwest with limited sun exposure and determined whether bone mineral density (BMD) in children with phenylketonuria (PKU), the most common IEM, correlated with diet or biochemical markers of bone metabolism. We hypothesized that children with IEMs would have lower serum vitamin D concentrations than controls and that some children with PKU would have reduced bone mineralization. A retrospective record review of 88 patients with IEMs, and 445 children on unrestricted diets (controls) found the 25-hydroxyvitamin D concentrations were normal and not significantly different between groups (IEM patients, 27.1 +/- 10.9; controls, 27.6 +/- 11.2). Normal BMD at the hip or spine (-2 0.05). The changes in soft tissue pontic height (PHC) amounted to a loss in the height of 0.34 mm (SD = 0.5) and 0.35 mm (0.2) for AG and CG, respectively. The mean VC amounted to a loss of 5.31 mm(3) (+/-1.1) (AG) and 4.32 mm(3) (+/-1.7) (CG). None of the changes between BL and 5-FU in volumetric and linear measurements, including TT and mean mesial and distal abutment height changes (mAHC and dAHC), reached statistically significant differences between AG and CG (P > 0.05). However the changes in linear measurements from BL to 5-FU were significant in all parameters for both groups (P < 0.01). CONCLUSION: At an observational period of 5 years, pontic sites with or without grafting under FDPs demonstrated similar dimensional stability. CLINICAL RELEVANCE: Pontic sites with or without grafting are volumetrically stable over 5 years. PMID- 26773801 TI - Multifaceted ability of naturally occurring polyphenols against metastatic cancer. AB - Although cancer metastases are known to be the main cause of cancer-related deaths, truly effective antimetastatic therapeutics remain scarce in clinical practice. Naturally occurring polyphenols are the most abundant antioxidants in human diets. Many of them possess chemopreventive and chemotherapeutic properties against various types of cancer. Recent advances in understanding the molecular pathways that mediate cancer development and progression have led to an increase of interest in preclinical investigations on the mechanisms underlying anticancer activity of polyphenols. In particular, an increasing number of preclinical studies using cultured cells and animal models have demonstrated the inhibitory effects of polyphenols on tumour cell invasion and metastasis, thereby highlighting the potential of polyphenols against metastatic cancer. This review specifically addresses growing evidence of the capability of polyphenols to impair the invasion and migration of tumour cells through a diverse set of mechanisms, including downregulation of expression of matrix metalloproteinases, modulation of regulators of epithelial-mesenchymal transition, interference with Met signalling, inhibition of nuclear factor-kappa B mediated transcription, and so on. Given that metastasis occurs through a multistep process in which each step is regulated by a complex network of signalling pathways, the multi-function and multi-target characteristics of polyphenols render those promising candidates for effective adjuvant therapy against metastatic cancer. PMID- 26773802 TI - An Integrative Analysis of the Narcissistic Personality Inventory and the Hypomanic Personality Scale: Implications for Construct Validity. AB - The primary goal of this study was to explicate the construct validity of the Narcissistic Personality Inventory (NPI) and the Hypomanic Personality Scale (HPS) by examining their relations both to each other and to measures of personality and psychopathology in a community sample ( N = 255). Structural evidence indicates that the NPI is defined by Leadership/Authority, Grandiose Exhibitionism, and Entitlement/Exploitativeness factors, whereas the HPS is characterized by specific dimensions reflecting Social Vitality, Mood Volatility, and Excitement. Our results establish that (a) factor-based subscales from these instruments display divergent patterns of relations that are obscured when relying exclusively on total scores and (b) some NPI and HPS subscales more clearly tap content specifically relevant to narcissism and mania, respectively, than others. In particular, our findings challenge the construct validity of the NPI Leadership/Authority and HPS Social Vitality subscales, which appear to assess overlapping assertiveness content that is largely adaptive in nature. PMID- 26773803 TI - Development and Validation of the Five-by-Five Resilience Scale. AB - This article introduces a new measure of resilience and five related protective factors. The Five-by-Five Resilience Scale (5*5RS) is developed on the basis of theoretical and empirical considerations. Two samples ( N = 475 and N = 613) are used to assess the factor structure, reliability, convergent validity, and criterion-related validity of the 5*5RS. Confirmatory factor analysis supports a bifactor model. The 5*5RS demonstrates adequate internal consistency as evidenced by Cronbach's alpha and empirical reliability estimates. The 5*5RS correlates positively with the Connor-Davidson Resilience Scale (CD-RISC), a commonly used measure of resilience. The 5*5RS exhibits similar criterion-related validity to the CD-RISC as evidenced by positive correlations with satisfaction with life, meaning in life, and secure attachment style as well as negative correlations with rumination and anxious or avoidant attachment styles. 5*5RS scores are positively correlated with healthy behaviors such as exercise and negatively correlated with sleep difficulty and symptomology of anxiety and depression. The 5*5RS incrementally explains variance in some criteria above and beyond the CD RISC. Item responses are modeled using the graded response model. Information estimates demonstrate the ability of the 5*5RS to assess individuals within at least one standard deviation of the mean on relevant latent traits. PMID- 26773805 TI - Pure Erythroid Leukemia Mimicking Ewing Sarcoma/Primitive Neuroectodermal Tumor in an Infant. AB - Pure erythroid leukemia (PEL) is a rare type of acute myeloid leukemia (AML) with a very aggressive clinical course. Presentation as a myeloid/erythroid sarcoma is exceedingly rare. We describe an infantile PEL presenting as a multifocal myeloid sarcoma, clinically and pathologically mimicking Ewing sarcoma/PNET family of tumors. The patient died 8 weeks after the initial presentation due to widespread disease. Our case shows that PEL needs to be considered in the differential diagnosis of small round blue cell tumors in infancy. A meticulous workup including immunohistochemistry, flow cytometry, molecular, and cytogenetic studies was required to reach the diagnosis. PMID- 26773806 TI - Cryptosporidium Infection Risk: Results of New Dose-Response Modeling. AB - Cryptosporidium human dose-response data from seven species/isolates are used to investigate six models of varying complexity that estimate infection probability as a function of dose. Previous models attempt to explicitly account for virulence differences among C. parvum isolates, using three or six species/isolates. Four (two new) models assume species/isolate differences are insignificant and three of these (all but exponential) allow for variable human susceptibility. These three human-focused models (fractional Poisson, exponential with immunity and beta-Poisson) are relatively simple yet fit the data significantly better than the more complex isolate-focused models. Among these three, the one-parameter fractional Poisson model is the simplest but assumes that all Cryptosporidium oocysts used in the studies were capable of initiating infection. The exponential with immunity model does not require such an assumption and includes the fractional Poisson as a special case. The fractional Poisson model is an upper bound of the exponential with immunity model and applies when all oocysts are capable of initiating infection. The beta Poisson model does not allow an immune human subpopulation; thus infection probability approaches 100% as dose becomes huge. All three of these models predict significantly (>10x) greater risk at the low doses that consumers might receive if exposed through drinking water or other environmental exposure (e.g., 72% vs. 4% infection probability for a one oocyst dose) than previously predicted. This new insight into Cryptosporidium risk suggests additional inactivation and removal via treatment may be needed to meet any specified risk target, such as a suggested 10-4 annual risk of Cryptosporidium infection. PMID- 26773804 TI - The effect of comorbidity on the use of adjuvant chemotherapy and type of regimen for curatively resected stage III colon cancer patients. AB - Postsurgical chemotherapy is guideline-recommended therapy for stage III colon cancer patients. Factors associated with patients not receiving adjuvant chemotherapy were identified in numerous studies; comorbidity was recognized as an important factor besides patient's age. We assessed the association between comorbidity and the use of adjuvant chemotherapy and type of chemotherapy regimen. Stage III colon cancer patients who underwent surgical resection were obtained from ten Centers for Disease Control and Prevention (CDC)-NPCR Specialized Registries which participated in the Comparative Effectiveness Research (CER) project. Comorbidity was classified into no comorbidity recorded, Charlson, non-Charlson comorbidities, number, and severity of Charlson comorbidity. Pearson chi-square test and multivariable logistic regression were employed. Of 3180 resected stage III colon cancer patients, 64% received adjuvant chemotherapy. After adjusting for patient's demographic and tumor characteristics, there were no significant differences in receipt of chemotherapy between Charlson and non-Charlson comorbidity. However, patients who had two or more Charlson comorbidities or had moderate to severe disease were significantly less likely to have chemotherapy (ORs 0.69 [95% CI, 0.51-0.92] and 0.62 [95% CI, 0.42-0.91], respectively) when compared with those with non-Charlson comorbidity. In addition, those with moderate or severe comorbidities were more likely to receive single chemotherapy agent (P < 0.0001). Capecitabine and FOLFOX were the most common single- and multi-agent regimens regardless of type of comorbidity grouping. Both the number and severity of comorbidity were significantly associated with receipt of guideline-recommended chemotherapy and type of agent in stage III resected colon cancer patients. Better personalized care based on individual patient's condition ought to be recognized. PMID- 26773807 TI - Endoplasmic Reticulum (ER)-Targeted, Galectin-Mediated Retrograde Transport by Using a HaloTag Carrier Protein. AB - Investigations into metabolic processes within the cell have often relied on genetic methods such as forced expression and knockout or knockdown techniques. An alternative approach would be introducing a molecule into the desired location inside the cell. To translocate compounds from outside cells into the endoplasmic reticulum (ER), we constructed a delivery carrier protein. This comprised N terminal galectin-1 for cell-surface binding (G1), a protease cleavable sequence (ps), a HaloTag domain for attaching exogenous compounds (Halo), and a C-terminal KDEL sequence for ER retention. Fluorescently labeled G1-ps-Halo-KDEL passed through the Golgi apparatus and reached the ER. By using Man9 GlcNAc2 -BODIPY as a cargo compound, the carrier protein was also delivered into the ER with concomitant processing of mannose to Man5,6, by the ER-resident alpha1,2 mannosidase. G1-ps-Halo-KDEL might serve as a new type of delivery carrier protein to direct compounds into the ER. PMID- 26773808 TI - Time to optimise and enforce training in interpretation of intrapartum cardiotocograph. PMID- 26773810 TI - The Arabidopsis glutamate receptor-like gene GLR3.6 controls root development by repressing the Kip-related protein gene KRP4. AB - In Arabidopsis, 20 genes encode putative glutamate receptor-like proteins (AtGLRs). However, the functions of most genes are unknown. In this study, our results revealed that loss of function of AtGLR3.6 (atglr3.6-1) leads to reduced primary root growth and fewer lateral roots, whereas AtGLR3.6 overexpression induced both primary and lateral root growth. The glr3.6-1 mutant exhibited a smaller root meristem size compared with the wild type, indicating that AtGLR3.6 controls root meristem size. In addition, atglr3.6-1 roots show a decreased mitotic activity accounting for the reduced root meristem size. Furthermore, expression of a gene encoding a cell cycle inhibitor, the cyclin-dependent kinase (CDK) inhibitor Kip-related protein 4 (KRP4), was significantly up-regulated in the mutant and down-regulated in AtGLR3.6-overexpressing roots, suggesting a role for KRP4 in AtGLR3.6-mediated root meristem maintenance. Importantly, the atglr3.6-1 mutant recovered most of its root growth when KRP4 expression is down regulated, whereas elevated KRP4 expression in AtGLR3.6-overexpressing plants phenocopied the wild-type root growth, implying an underlying relationship between AtGLR3.6 and KRP4 genes. Cytosolic Ca(2+) elevation is reduced in atglr3.6-1 roots, suggesting impaired calcium signaling. Moreover, calcium treatment reduced the level of KRP4 and hence induced root growth. Collectively, we reveal that AtGLR3.6 is required for primary and lateral root development, and KRP4 functions as a downstream signaling element in Arabidopsis thaliana. PMID- 26773811 TI - Biocatalysts from alkaloid producing plants. AB - Metabolic pathways leading to benzylisoquinoline and monoterpene indole alkaloids in plants are revealing remarkable new reactions. Understanding of the enzymes involved in alkaloid biosynthesis provides access to a variety of applications in biocatalysis and bioengineering. In chemo-enzymatic settings, plant biocatalysts can transform medically important scaffolds. Additionally, synthetic biologists are taking alkaloid pathways as templates to assemble pathways in microorganisms that are tailored to the needs of medicinal chemistry. In light of these many recent discoveries, it is expected that plants will continue to be a source of novel biocatalysts for the foreseeable future. PMID- 26773809 TI - Evolution by gene duplication of Medicago truncatula PISTILLATA-like transcription factors. AB - PISTILLATA (PI) is a member of the B-function MADS-box gene family, which controls the identity of both petals and stamens in Arabidopsis thaliana. In Medicago truncatula (Mt), there are two PI-like paralogs, known as MtPI and MtNGL9. These genes differ in their expression patterns, but it is not known whether their functions have also diverged. Describing the evolution of certain duplicated genes, such as transcription factors, remains a challenge owing to the complex expression patterns and functional divergence between the gene copies. Here, we report a number of functional studies, including analyses of gene expression, protein-protein interactions, and reverse genetic approaches designed to demonstrate the respective contributions of each M. truncatula PI-like paralog to the B-function in this species. Also, we have integrated molecular evolution approaches to determine the mode of evolution of Mt PI-like genes after duplication. Our results demonstrate that MtPI functions as a master regulator of B-function in M. truncatula, maintaining the overall ancestral function, while MtNGL9 does not seem to have a role in this regard, suggesting that the pseudogenization could be the functional evolutionary fate for this gene. However, we provide evidence that purifying selection is the primary evolutionary force acting on this paralog, pinpointing the conservation of its biochemical function and, alternatively, the acquisition of a new role for this gene. PMID- 26773812 TI - Inhibition of human anthracycline reductases by emodin - A possible remedy for anthracycline resistance. AB - The clinical application of anthracyclines, like daunorubicin and doxorubicin, is limited by two factors: dose-related cardiotoxicity and drug resistance. Both have been linked to reductive metabolism of the parent drug to their metabolites daunorubicinol and doxorubicinol, respectively. These metabolites show significantly less anti-neoplastic properties as their parent drugs and accumulate in cardiac tissue leading to chronic cardiotoxicity. Therefore, we aimed to identify novel and potent natural inhibitors for anthracycline reductases, which enhance the anticancer effect of anthracyclines by preventing the development of anthracycline resistance. Human enzymes responsible for the reductive metabolism of daunorubicin were tested for their sensitivity towards anthrachinones, in particular emodin and anthraflavic acid. Intense inhibition kinetic data for the most effective daunorubicin reductases, including IC50- and Ki-values, the mode of inhibition, as well as molecular docking, were compiled. Subsequently, a cytotoxicity profile and the ability of emodin to reverse daunorubicin resistance were determined using multiresistant A549 lung cancer and HepG2 liver cancer cells. Emodin potently inhibited the four main human daunorubicin reductases in vitro. Further, we could demonstrate that emodin is able to synergistically sensitize human cancer cells towards daunorubicin at clinically relevant concentrations. Therefore, emodin may yield the potential to enhance the therapeutic effectiveness of anthracyclines by preventing anthracycline resistance via inhibition of the anthracycline reductases. In symphony with its known pharmacological properties, emodin might be a compound of particular interest in the management of anthracycline chemotherapy efficacy and their adverse effects. PMID- 26773814 TI - Low-dose pembrolizumab induced remission in patients with refractory classical Hodgkin lymphoma. PMID- 26773815 TI - The genetic basis of color-related local adaptation in a ring-like colonization around the Mediterranean. AB - Uncovering the genetic basis of phenotypic variation and the population history under which it established is key to understand the trajectories along which local adaptation evolves. Here, we investigated the genetic basis and evolutionary history of a clinal plumage color polymorphism in European barn owls (Tyto alba). Our results suggest that barn owls colonized the Western Palearctic in a ring-like manner around the Mediterranean and meet in secondary contact in Greece. Rufous coloration appears to be linked to a recently evolved nonsynonymous-derived variant of the melanocortin 1 receptor (MC1R) gene, which according to quantitative genetic analyses evolved under local adaptation during or following the colonization of Central Europe. Admixture patterns and linkage disequilibrium between the neutral genetic background and color found exclusively within the secondary contact zone suggest limited introgression at secondary contact. These results from a system reminiscent of ring species provide a striking example of how local adaptation can evolve from derived genetic variation. PMID- 26773816 TI - Generalized evaluation of environmental radioactivity measurements with UncertRadio Part II: Methods with linear unfolding. AB - For the software UncertRadio (UR), designed for a generalized evaluation of environmental radioactivity measurements, the evaluation procedure is given if least squares-fitting is involved. UR is then applied to the simultaneous detection of Strontium-89 and Strontium-90. This method is easily extendable over recent approaches based on the evaluation of two measurements, i.e. on two unknowns with two equations. The evaluation within UR includes ISO 11929 decision thresholds and detection limits. The propagation of distributions with MC simulation is described. PMID- 26773817 TI - Measurement of the (211)Pb half-life using recoil atoms from (219)Rn decay. AB - The radioactive half-life of (211)Pb was measured, by alpha-particle counting of samples of radiochemically pure (211)Pb in equilibrium with its alpha-emitting progeny, (211)Bi and (211)Po. The samples were prepared by the collection of (215)Po recoil atoms from the decay of the (219)Rn decay progeny produced from a (223)Ra sample onto stainless steel discs. The radioactive decay of the (211)Pb was measured utilising a 2pi proportional counter operating on the alpha plateau. A half-life of 36.164 (13)min was determined, which is in agreement with currently available literature. A full uncertainty budget is presented. A recommended half-life of T1/2((211)Pb)=36.161 (17)min has been evaluated from the current literature values. PMID- 26773813 TI - Understanding the immunogenicity and antigenicity of nanomaterials: Past, present and future. AB - Nanoparticle immunogenicity and antigenicity have been under investigation for many years. During the past decade, significant progress has been made in understanding what makes a nanoparticle immunogenic, how immune cells respond to nanoparticles, what consequences of nanoparticle-specific antibody formation exist and how they challenge the application of nanoparticles for drug delivery. Moreover, it has been recognized that accidental contamination of therapeutic protein formulations with nanosized particulate materials may contribute to the immunogenicity of this type of biotechnology products. While the immunological properties of engineered nanomaterials and their application as vaccine carriers and adjuvants have been given substantial consideration in the current literature, little attention has been paid to nanoparticle immuno- and antigenicity. To fill in this gap, we herein provide an overview of this subject to highlight the current state of the field, review past and present research, and discuss future research directions. PMID- 26773818 TI - A simulation study on angular and micro pattern effects in GEM detectors. AB - A useful approach for the enhancement of thermal neutrons detection has been reported here. This technique, based on the angular and micro pattern effects, has been developed and applied to the boron-coated ((10)B) Gas Electron multiplier (GEM) detector. In the angular effect case, as a general rule, the detector device is turned at an angle which improves the device response per unit area of the detector. While for the latter case, a regular pattern in the form of micrometer deep grooves is fabricated onto the converter coating, consequently it enhances the capture probability of the detector. For the current study, both of these techniques using a (10)B-coated GEM detector have been simulated for low energy neutrons. For the evaluation of detector response thermal neutrons in the energy ranges from 25meV to 100meV were transported onto the detector surface. For this work, FLUKA MC code has been utilized. The output in both cases has been estimated as a function of incident thermal neutron energies. By employing both techniques, the angle and the micro pattern dependent efficiencies for (10)B coated GEM detectors are presented, which indicate an improved efficiency response of the device. We anticipate that by using these modifications can lead a further forward step in the development and improvement of thermal neutron detection technology. PMID- 26773819 TI - Development of a (170)Tm source for mercury monitoring studies in humans using XRF. AB - The goals of the present study were to develop a (170)Tm radioisotope and generate a K XRF spectrum of mercury. Thulium foil and thulium oxide powder were both tested for impurities and the latter was found to be a better prospect for further studies. The (170)Tm radioisotope was developed from thulium oxide powder following the method of disolution and absorption. A suitable source holder and collimator were also designed based on Monte Carlo simulations. Using the radioisotope thus developed, a mercury XRF spectrum was successfully generated. PMID- 26773820 TI - Palliative treatment of metastatic bone pain with radiopharmaceuticals: A perspective beyond Strontium-89 and Samarium-153. AB - PURPOSE: The present review article aims to provide an overview of the available radionuclides for palliative treatment of bone metastases beyond (89)Sr and (153)Sm. In addition, it aims to review and summarize the clinical outcomes associated with the palliative treatment of bone metastases using different radiopharmaceuticals. MATERIALS AND METHODS: A literature search was conducted on Science Direct and PubMed databases (1990 - 2015). The following search terms were combined in order to obtain relevant results: "bone", "metastases", "palliative", "care", "therapy", "treatment", "radiotherapy", "review", "radiopharmaceutical", "phosphorus-32", "strontium-89", "yttrium-90", "tin-117m", "samarium-153", "holmium-166", "thulium-170", "lutetium-177", "rhenium-186", "rhenium-188" and "radium-223". Studies were included if they provided information regarding the clinical outcomes. RESULTS AND CONCLUSIONS: A comparative analysis of the measured therapeutic response of different radiopharmaceuticals, based on previously published data, suggests that there is a lack of substantial differences in palliative efficacy among radiopharmaceuticals. However, when the comparative analysis adds factors such as patient's life expectancy, radionuclides' physical characteristics (e.g. tissue penetration range and half-life) and health economics to guide the rational selection of a radiopharmaceutical for palliative treatment of bone metastases, (177)Lu and (188)Re-labeled radiopharmaceuticals appear to be the most suitable radiopharmaceuticals for treatment of small and medium/large size bone lesions, respectively. PMID- 26773821 TI - Efficiency calibration and minimum detectable activity concentration of a real time UAV airborne sensor system with two gamma spectrometers. AB - A small-sized UAV (NH-UAV) airborne system with two gamma spectrometers (LaBr3 detector and HPGe detector) was developed to monitor activity concentration in serious nuclear accidents, such as the Fukushima nuclear accident. The efficiency calibration and determination of minimum detectable activity concentration (MDAC) of the specific system were studied by MC simulations at different flight altitudes, different horizontal distances from the detection position to the source term center and different source term sizes. Both air and ground radiation were considered in the models. The results obtained may provide instructive suggestions for in-situ radioactivity measurements of NH-UAV. PMID- 26773822 TI - Excitation functions for (d,x) reactions on (133)Cs up to Ed=40MeV. AB - In the frame of a systematic study of excitation functions of deuteron induced reactions the excitation functions of the (133)Cs(d,x)(133m,133mg,131mg)Ba,(134,)(132)Cs and (12)(9m)Xe nuclear reactions were measured up to 40MeV deuteron energies by using the stacked foil irradiation technique and gamma-ray spectroscopy of activated samples. The results were compared with calculations performed with the theoretical nuclear reaction codes ALICE-IPPE-D, EMPIRE II-D and TALYS calculation listed in the TENDL-2014 library. A moderate agreement was obtained. Based on the integral yields deduced from our measured cross sections, production of (131)Cs via the (133)Cs(d,4n)(131)Ba >(131)Cs reaction and (133)Ba via (133)Cs(d,2n) reactions is discussed in comparison with other charged particle production routes. PMID- 26773823 TI - Cancer care cost trends in the United States: 1998 to 2012. AB - BACKGROUND: The authors examine trends in spending on cancer from 1998 through 2012, including cancer care costs, prevalence, and cases by payer, and discuss the results within the context of a prior analysis and recent health policy and programmatic changes. METHODS: Condition-specific distribution of expenditures from the Medical Expenditure Panel Survey, supplemented with results from the National Nursing Home Survey and other data sources, was used as the basis for allocating the Personal Health Care components of the National Health Expenditure Accounts among conditions. RESULTS: Cancer care expenditures grew at an annualized rate of 2.9% from 1998 to 2012. The share of expenditures for hospital based care declined to a low of 48% during 2007 through 2009. Professional and clinical services' shares declined substantially between 2007 to 2009 and 2010 to 2012 when the hospital share increased. Treated prevalence decreased for all payers between the first and last study periods with the exception of private payers (11.2% increase). Out-of-pocket expenditures declined to 4.7%, whereas Medicare's share increased slightly. Medication expenditures increased, notably within retail and mail order settings. CONCLUSIONS: The previous rapid growth of cancer prevalence and expenditures has now slowed, most remarkably since the 2007 recession. Out-of-pocket expenses for cancer treatment continue to decline, most recently reaching the lowest point in 25 years. In addition, the early effects of Affordable Care Act expansion can be observed in the decline of treated prevalence in the Medicaid population as the demographics of Medicaid enrollees change. PMID- 26773824 TI - Multi-view L2-SVM and its multi-view core vector machine. AB - In this paper, a novel L2-SVM based classifier Multi-view L2-SVM is proposed to address multi-view classification tasks. The proposed Multi-view L2-SVM classifier does not have any bias in its objective function and hence has the flexibility like MU-SVC in the sense that the number of the yielded support vectors can be controlled by a pre-specified parameter. The proposed Multi-view L2-SVM classifier can make full use of the coherence and the difference of different views through imposing the consensus among multiple views to improve the overall classification performance. Besides, based on the generalized core vector machine GCVM, the proposed Multi-view L2-SVM classifier is extended into its GCVM version MvCVM which can realize its fast training on large scale multi view datasets, with its asymptotic linear time complexity with the sample size and its space complexity independent of the sample size. Our experimental results demonstrated the effectiveness of the proposed Multi-view L2-SVM classifier for small scale multi-view datasets and the proposed MvCVM classifier for large scale multi-view datasets. PMID- 26773825 TI - Parameterising User Uptake in Economic Evaluations: The role of discrete choice experiments. AB - Model-based economic evaluations of new interventions have shown that user behaviour (uptake) is a critical driver of overall impact achieved. However, early economic evaluations, prior to introduction, often rely on assumed levels of uptake based on expert opinion or uptake of similar interventions. In addition to the likely uncertainty surrounding these uptake assumptions, they also do not allow for uptake to be a function of product, intervention, or user characteristics. This letter proposes using uptake projections from discrete choice experiments (DCE) to better parameterize uptake and substitution in cost effectiveness models. A simple impact model is developed and illustrated using an example from the HIV prevention field in South Africa. Comparison between the conventional approach and the DCE-based approach shows that, in our example, DCE based impact predictions varied by up to 50% from conventional estimates and provided far more nuanced projections. In the absence of observed uptake data and to model the effect of variations in intervention characteristics, DCE-based uptake predictions are likely to greatly improve models parameterizing uptake solely based on expert opinion. This is particularly important for global and national level decision making around introducing new and probably more expensive interventions, particularly where resources are most constrained. PMID- 26773826 TI - Optimum bolus wizard settings in insulin pumps in children with Type 1 diabetes. AB - AIM: To evaluate current insulin pump settings in an optimally regulated paediatric population using bolus wizard. METHODS: We used a retrospective study design to analyse data from 124 children on insulin pump therapy who had optimum HbA1c levels [< 59 mmol/mol (< 7.5%)] and no history of severe hypoglycaemic events. Bolus wizard settings were used to calculate the insulin to carbohydrate factors and insulin sensitivity factors. Multiple regression analysis was used to analyse the variables associated with the calculation factors. RESULTS: Insulin to carbohydrate factor varied from 276 in the youngest group to 424 in the oldest group, and increased according to age. Insulin sensitivity factor was highest in the group aged 6 to < 12 years, with a value of 125. Age, amount of carbohydrates, number of boluses per day and insulin per kg were all significantly associated with both calculation factors. Furthermore, duration of insulin pump treatment was significantly associated with insulin sensitivity factor and percentage bolus/basal was significantly associated with insulin to carbohydrate factor. Gender, diabetes duration and BMI were not associated with any of the calculation factors. CONCLUSION: Optimum insulin pump settings at pump initiation depend on both insulin requirements and use of the pump. Settings need to be individualized because the standardized calculation factors are not constant for children. There is a need to develop specific age- and insulin dose dependent calculation factors. PMID- 26773827 TI - First genetic characterization of rotavirus C in Russia. AB - Rotaviruses C (RVC) cause sporadic cases and outbreaks of diarrhea in humans and animals worldwide. The aim of this study was to monitor RVC during a surveillance study of sporadic cases of viral gastroenteritis in the Novosibirsk and Omsk regions of Russia from 2006 to 2011. A total of 2144 stool samples from children and adults hospitalized with acute gastroenteritis were tested for RVC by RT-PCR. Sixteen RVC-positive stool samples were detected at a rate of 0.6% (13/2037) in children and 2.8% (3/107) in adults. The low detection rate suggested that RVC infection was an uncommon cause of hospitalization in Russia. The complete VP7, VP4, VP6, and NSP4 gene sequences were determined. It was found that RVCs with at least two different genome backgrounds circulated in Siberia. VP4, VP6, and NSP4 gene sequences of most Russian RVC strains clustered with South Asian strains, while the VP7 gene showed a closer relationship to European strains. Meanwhile, only VP4 and NSP4 sequences of the strain Omsk08-386 clustered with South Asian strains, while its VP6 and VP7 sequences clustered with European strains. This is the first genetic characterization of Russian RVC strains and the first report on the prevalence of RVC in the Asian part of Russia. PMID- 26773828 TI - Serogroup, virulence, and molecular traits of Vibrio parahaemolyticus isolated from clinical and cockle sources in northeastern Thailand. AB - Vibrio parahaemolyticus is responsible for seafood-borne gastroenteritis worldwide. Isolates of V. parahaemolyticus from clinical samples (n=74) and cockles (Anadara granosa) (n=74) in Thailand were analyzed by serotyping, determination of virulence and related marker genes present, response to antimicrobial agents, and genetic relatedness. Serological analysis revealed 31 different serotypes, 10 of which occurred among both clinical and cockle samples. The clinical isolates commonly included the pandemic serogroup O3:K6, while a few of the cockle isolates exhibited likely pandemic serovariants such as O3:KUT and O4:KUT, but not O3:K6. The pandemic (orf8 gene-positive) strains were more frequently found among clinical isolates (78.4%) than cockle isolates (28.4%) (p<0.001). Likewise, the virulence and related marker genes were more commonly detected among clinical than cockle isolates; i.e., tdh gene (93.2% versus 29.7%), vcrD2 (97.3% versus 23.0%), vopB2 (89.2% versus 13.5%), vopT (98.6% versus 36.5%) (all p<0.001) and trh (10.8% versus 1.4%) (p<0.05). Pulsed-field gel electrophoresis of NotI-digested genomic DNA of 41 randomly selected V. parahaemolyticus isolates representing different serotypes produced 33 pulsotypes that formed 5 different clusters (clonal complexes) (A-E) in a dendrogram. Vibrio parahaemolyticus O3:K6 and likely related pandemic serotypes were especially common among the numerous clinical isolates in cluster C, suggesting a close clonal link among many of these isolates. Most clinical and cockle isolates were resistant to ampicillin. This study indicates that O3:K6 and its likely serovariants based on the PFGE clusters, are causative agents. Seafoods such as cockles potentially serve as a source of virulent V. parahaemolyticus, but further work is required to identify possible additional sources. PMID- 26773829 TI - Six-minute walk test predicts all-cause mortality and technique failure in ambulatory peritoneal dialysis patients. AB - AIM: This study investigated the associated factors of 6-min walk test (6MWT) and its predictive value of outcome in patients undergoing peritoneal dialysis (PD). METHODS: This is a single centre prospective observational cohort study. Stable ambulatory PD patients in our centre between 1 May 2010 and 30 April 2011 were enrolled in this study. All included subjects performed 6MWT, and 6-min walk distances (6MWDs) were recorded. Patients were divided into two groups according to 6MWD and prospectively followed up until death, cessation of PD or to the end of the study (30 September 2012). RESULTS: A total of 145 patients were enrolled, including 63 (43%) males. Multiple stepwise regression showed that age (beta = 0.295, P = 0.001), diastolic blood pressure (DBP) (beta = 0.292, P = 0.001), left ventricular ejection fraction (LVEF) (beta = 0.198, P = 0.019) were independently associated with lower 6MWD. By the end of the study, six (8%) patients died in long 6MWD group while 15 (20%) died in the short 6MWD group, a significantly lower patient survival was observed in short 6MWD group (Log-rank = 4.983, P = 0.026). Patients with short 6MWD also showed inferior technique survival (Log rank = 4.838, P = 0.028). There was no significant difference in peritonitis-free survival between the two groups (Log-rank = 0.801, P = 0.371). However, more patients in short 6MWD group had been transferred to hemodialysis due to peritonitis (25% vs 4.2%, P = 0.013). CONCLUSION: Age, diastolic blood pressure, LVEF are independent associated factors of 6MWD in patients undergoing PD. Having the advantages of easy applicability and safety, 6MWT may be proposed as an important predictor of outcome in ambulatory PD patients. PMID- 26773830 TI - Copper phytoremediation potential of Calandula officinalis L. and the role of antioxidant enzymes in metal tolerance. AB - Cu phytoremediation potential of an ornamental plant, Calandula officinalis, was explored in terms of growth responses, photosynthetic activities and antioxidant enzymes such as SOD, CAT and GPX. The results showed that this plant had high Cu tolerance of up to 400 mg/kg, which is far above the phytotoxic range for non hyperaccumulators. It grew normally in soils at all the doses (150-400 mg/kg) without showing external signs of phytotoxicity. At 150 mg/kg, flowering was augmented; root and shoot biomass, root lengths and leaf soluble protein contents remained same as that of the control. However, chlorophyll and carotenoid pigment contents declined significantly along with significant elevations in lipid peroxidation, at all the doses. Elevations of antioxidant enzymes reflected stress as well as probable mitigation of reactive oxygen species due to Cu stress. Except for the highest conc. (400 mg/kg), leaf accumulation of Cu was higher than root accumulations. The Cu accumulation peaked at 300 mg/kg Cu in soil, with leaf and root accumulations to be respectively, 4675 and 3995 ug/g dry wt., far more than the minimum of 1000 ug/g dry wt. for a Cu hyperaccumulator. The plant root at all the doses tolerated Cu, with the tolerance index ranging from 94-62.7. The soil to plant metal uptake capacity, indicated by extraction coefficient and the root to shoot translocation, indicated by translocation factor, at all the doses of Cu were >1, pointed towards efficient phytoremediation potential. PMID- 26773831 TI - Human Arsenic exposure via dust across the different ecological zones of Pakistan. AB - The present study aims to assess the arsenic (As) levels into dust samples and its implications for human health, of four ecological zones of Pakistan, which included northern frozen mountains (FMZ), lower Himalyian wet mountains (WMZ), alluvial riverine plains (ARZ), and low lying agricultural areas (LLZ). Human nail samples (N=180) of general population were also collected from the similar areas and all the samples were analysed by using ICP-MS. In general the higher levels (p<0.05) in paired dust and human nail samples were observed from ARZ and LLZ than those of other mountainous areas (i.e., WMZ and FMZ), respectively. Current results suggested that elevated As concentrations were associated to both natural, (e.g. geogenic influences) and anthropogenic sources. Linear regression model values indicated that As levels into dust samples were associated with altitude (r(2)=0.23), soil carbonate carbon density (SCC; r(2)=0.33), and population density (PD; r(2)=0.25). The relationship of paired dust and nail samples was also investigated and associations were found for As-nail and soil organic carbon density (SOC; r(2)=0.49) and SCC (r(2)=0.19) in each studied zone, evidencing the dust exposure as an important source of arsenic contamination in Pakistan. Risk estimation reflected higher hazard index (HI) values of non carcinogenic risk (HI>1) for children populations in all areas (except FMZ), and for adults in LLZ (0.74) and ARZ (0.55), suggesting that caution should be paid about the dust exposure. Similarly, carcinogenic risk assessment also highlighted potential threats to the residents of LLZ and ARZ, as in few cases (5-10%) the values exceeded the range of US-EPA threshold limits (10(-6)-10(-4)). PMID- 26773832 TI - Phytotoxicity of veterinary antibiotics to seed germination and root elongation of crops. AB - Large quantities of veterinary antibiotics (VAs) are being used worldwide in agricultural fields through wastewater irrigation and manure application. They cause damages to the ecosystem when discharged into the environment, but there is a lack of information on their toxicity to plants and animals. This study evaluated the phytotoxic effects of five major VAs, namely tetracycline (TC), sulfamethazine (SMZ), norfloxacin (NOR), erythromycin (ERY) and chloramphenicol (CAP), on seed germination and root elongation in lettuce, tomato, carrot and cucumber, and investigated the relationship between their physicochemical properties and phytotoxicities. Results show that these compounds significantly inhibited root elongation (p<0.05), the most sensitive endpoint for the phytotoxicity test. TC was associated with the highest level of toxicity, followed by NOR, ERY, SMZ and CAP. Regarding crop species, lettuce was found to be sensitive to most of the VAs. The median effect concentration (EC50) of TC, SMZ, NOR, ERY and CAP to lettuce was 14.4, 157, 49.4, 68.8 and 204 mg/L, respectively. A quantitative structure-activity relationship (QSAR) model has been established based on the measured data. It is evident that hydrophobicity was the most important factor governing the phytotoxicity of these compounds to seeds, which could be explained by the polar narcosis mechanism. Lettuce is considered a good biomarker for VAs in the environment. According to the derived equation, phytotoxicities of selected VA compounds on different crops can be calculated, which could be applicable to other VAs. Environmental risks of VAs were summarized based on the phytotoxicity results and other persistent factors. PMID- 26773833 TI - Extrapolating between toxicity endpoints of metal oxide nanoparticles: Predicting toxicity to Escherichia coli and human keratinocyte cell line (HaCaT) with Nano QTTR. AB - Synthesis of novel nanoparticles should always be accompanied by a comprehensive assessment of risk to human health and to ecosystem. Application of in silico models is encouraged by regulatory authorities to fill the data gaps related to the properties of nanoparticles affecting the environment and human health. Interspecies toxicity correlations provide a tool for estimation of contaminant's sensitivity with known levels of uncertainty for a diverse pool of species. We propose here first interspecies cytotoxicity correlation models between Escherichia coli (prokaryotic system) and human keratinocyte cell line (HaCaT) (eukaryotic system) to assess the discriminatory features for cytotoxicity of metal oxide nanoparticles. The nano-QTTR models can be employed for extrapolating cytotoxicity to E. coli and human keratinocyte cell line (HaCaT) for metal nanoparticles when the data for the other species are available. Informative illustrations of the contributing mechanisms of toxic action of the metal oxide nanoparticles to the HaCaT cell line as well as to the E. coli are identified from the developed nano quantitative toxicity-toxicity relationship (nano-QTTR) models. PMID- 26773834 TI - Polyamine and nitric oxide crosstalk: Antagonistic effects on cadmium toxicity in mung bean plants through upregulating the metal detoxification, antioxidant defense and methylglyoxal detoxification systems. AB - Cadmium (Cd) contamination is a serious agricultural and environmental hazard. The study investigates cross-protection roles of putrescine (Put, 0.2 mM) and nitric oxide (sodium nitroprusside; SNP, 1 mM) in conferring Cd (CdCl2, 1.5 mM) tolerance in mung bean (Vigna radiata L. cv. BARI Mung-2) seedlings. Cadmium stress increased root and shoot Cd content, reduced growth, destroyed chlorophyll (chl), modulated proline (Pro) and reduced leaf relative water content (RWC), increased oxidative damage [lipid peroxidation, H2O2 content, O2(?-) generation rate, lipoxygenase (LOX) activity], methylglyoxal (MG) toxicity. Put and/or SNP reduced Cd uptake, increasd phytochelatin (PC) content, reduced oxidative damage enhancing non-enzymatic antioxidants (AsA and GSH) and activities of enzymes [superoxide dismutase (SOD), catalase (CAT), ascorbate peroxidase (APX), dehydroascorbate reductase (DHAR), glutathione reductase (GR), glutathione S transferase (GST), and glutathione peroxidase (GPX)]. Exogenous Put and/or SNP modulated endogenous polyamines, PAs (putrescine, Put; spermidine, Spd; spermine, Spm), and NO; improved glyoxalase system in detoxifying MG and improved physiology and growth where combined application showed better effects which designates possible crosstalk between NO and PAs to confer Cd-toxicity tolerance. PMID- 26773835 TI - Bioaccumulation of nickel by E. sativa and role of plant growth promoting rhizobacteria (PGPRs) under nickel stress. AB - Phytoremediation potential of plants can be enhanced in association with microbes. Further, many plant growth-promoting rhizobacteria can improve growth under stress. The present study was conducted to investigate the effect of Pseudomonas putida (P. putida) on nickel (Ni) uptake and on growth of Eruca sativa (E. sativa). Three different levels of Ni (low; 150 ug/g, medium; 250 ug/g and high; 500 ug/g) were applied to the soil containing E. sativa seedlings, with or without P. putida. Ni-toxicity was measured by metamorphic parameters including shoot length, root length, biomass, chlorophyll and proline and Ni contents. Inoculation with P. putida increased 34% and 41% in root and shoot length and 38% and 24% in fresh, dry weight respectively, as compared to non inoculated plants. Similarly, Ni uptake increased by up to 46% following P. putida inoculation as compared to non-inoculated plants. Indole acetic acid, siderophore and 1-aminocyclopropane-1-carboxylate deaminase (ACCD) activity in the growing media enhanced growth and Ni uptake in E. sativa. The present results offer insight on Plant Growth Promoting Rhizobacteria (PGPR), such as P. putida, for the potential to enhance the plant growth by inhibiting the adverse effects of Ni in E. sativa. PMID- 26773836 TI - Variation in copper effects on kairomone-mediated responses in Daphnia pulicaria. AB - Chemical signals play an integral role in many predator-prey relationships but their effectiveness can be altered by environmental conditions. Prey species can detect predator kairomones, which induce anti-predator defenses. An example of this predator-prey relationship exists between Daphnia spp. and Chaoborus spp.; however, when living in water contaminated with low concentrations of copper (Cu) Daphnia can fail to respond to Chaoborus kairomone and, in turn, become more susceptible to predation. This has implications for Daphnia living in regions with Cu contamination, such as areas where mining activity has resulted in increased levels of metals in the surrounding lakes. We examined kairomone mediated responses of multiple Daphnia pulicaria clones obtained from 8 lakes in Ontario, Canada, in the absence and presence of environmentally-relevant Cu concentrations. Life history traits and morphological anti-predator defenses were assessed using neonates collected from mothers that were exposed to kairomone and Cu treatments. We found that kairomone-mediated responses and Cu-tolerance varied among D. pulicaria clones. Clones exposed to kairomone, in the absence of Cu additions, had diverse responses, including larger neonates, delayed reproduction, or altered brood size relative to no-kairomone controls. These kairomone-induced responses act as antipredator defense strategies against Chaoborus by preventing predation or stabilizing population growth. When exposed to Cu, two clones were able to respond to kairomone, while four clones no longer induced a response to kairomone. This variation in non-lethal effects of Cu on aquatic organisms suggests that toxicity tests should incorporate multiple genotypes and include predator-prey interactions. PMID- 26773837 TI - Air-borne xylene degradation by Bougainvillea buttiana and the role of epiphytic bacteria in the degradation. AB - The efficiency of xylene removal from contaminated air by thirteen perennial plants was studied. The results showed that Bougainvillea buttiana had the highest xylene removal efficiency. Different parts of B. buttiana such as stems, epicuticular waxes, and plant stomata (including microorganism-associated plant leaves) can uptake xylene 53.1+/-1.9%, 32.3+/-0.9, and 14.6+/-0.0%, respectively. Metabolite products found in treated plants may result from stress or defense compounds triggered by exposure to xylene. Moreover, possible degradation products in B. buttiana stems were analyzed after treatment with xylene at 100 ppm. Various metabolites in B. buttiana stems such as 2,6-dimethoxyphenol, 4 hydroxy-3,5-dimethoxy benzoic acid, 1-isopropyl-4-methylbenzene, p-tolualdehyde, 2,5-dimethoxy-4-methylbenzaldehyde, 2,4-dihydroxy-2,5-dimethyl-3(2H)-furanone, 3 methyl-2-butenal, dihydroxy acetone, propanedial, and many organic acids are related to the xylene degradation pathway. In addition, microorganism-associated B. buttiana leaves especially Enterobacter cloacae LSRC11, Staphylococcus sp. A1 and Pseudomonas aeruginosa enhanced the plant resulting in quicker xylene removal. PMID- 26773839 TI - Detachable Palatal Ramp of Teeth to Improve Comfort in a Completely Edentulous Patient with a Segmentally Resected Mandible. AB - The rehabilitation of a completely edentulous patient with segmental resection of the mandible (without osseous reconstruction) poses a considerable challenge to the restoring prosthodontist. Due to the absence of natural teeth in both arches, it is difficult to correct the mandibular deviation with the aid of guidance prostheses. Prosthetic management of such patients usually consists of a maxillary complete denture and mandibular segmental denture occluding in the deviated position itself. An additional ramp or row of denture teeth is placed on the palatal surface of the maxillary denture to facilitate this; however, patient comfort levels (during functions such as phonation) are found to be adversely impacted due to the encroachment of the tongue space by the position of the ramp. This report describes an innovative technique to overcome this problem by fabrication of a detachable ramp of additional denture teeth in the maxillary denture. The patient could wear the denture comfortably without the palatal ramp throughout the day and could attach the palatal ramp while eating. PMID- 26773838 TI - Particulate matter cytotoxicity in cultured SH-SY5Y cells is modulated by simvastatin: Toxicological assessment for oxidative damage. AB - Epidemiological studies have shown a positive correlation between environmental particulate matter and adverse health effects. In particular, residual oil fly ash (ROFA) induces inflammation and reactive oxygen species (ROS), exerting not only local, but also systemic adverse effects. Previously, in an experimental animal model, we found that simvastatin (Sv) pretreatment was effective in preventing ROFA induced lung inflammation. Herein, using the human neuroblastoma SH-SY5Y cell line as a neurotoxicity in vitro model, we studied the potential Sv protective effect on ROFA cytotoxicity. We evaluated cell viability by the MTT assay, superoxide anion generation by NBT test, Nrf2 activation by immunofluorescence, apoptosis by cleaved-PARP and active-caspase 3 expressions, and senescence by beta-galactosidase activity. SH-SY5Y cells exposed to ROFA (10 and 50MUg/ml) for 24h showed decreased cell viability, increased superoxide anion generation, apoptosis and senescence. Pretreatment with Sv (1MUM) for 6 days, restored cell viability to basal levels, reduced ROFA-induced O2(-) generation as well as the number of apoptotic and senescent cells. Sv pretreatment stimulated the basal and ROFA-induced levels of Nrf2 nuclear translocation suggesting that activation of the cellular antioxidant defense system prevented particle-induced oxidative stress. In parallel, rescue experiments with mevalonate did not modify the effects of SV pretreatment in any of the parameters evaluated in this study. We conclude that simvastatin may provide neuroprotection against air particulate matter-induced neurotoxicity independently of its ability to inhibit cholesterol synthesis. PMID- 26773840 TI - Body weight-supported training in Becker and limb girdle 2I muscular dystrophy. AB - INTRODUCTION: We studied the functional effects of combined strength and aerobic anti-gravity training in severely affected patients with Becker and Limb-Girdle muscular dystrophies. METHODS: Eight patients performed 10-week progressive combined strength (squats, calf raises, lunges) and aerobic (walk/run, jogging in place or high knee-lift) training 3 times/week in a lower-body positive pressure environment. Closed-kinetic-chain leg muscle strength, isometric knee strength, rate of force development (RFD), and reaction time were evaluated. RESULTS: Baseline data indicated an intact neural activation pattern but showed compromised muscle contractile properties. Training (compliance 91%) improved functional leg muscle strength. Squat series performance increased 30%, calf raises 45%, and lunges 23%. CONCLUSIONS: Anti-gravity training improved closed kinetic-chain leg muscle strength despite no changes in isometric knee extension strength and absolute RFD. The improved closed-kinetic-chain performance may relate to neural adaptation involving motor learning and/or improved muscle strength of other muscles than the weak knee extensors. Muscle Nerve 54: 239-243, 2016. PMID- 26773841 TI - Initial evidence for the link between activities and health: Associations between a balance of activities, functioning and serum levels of cytokines and C-reactive protein. AB - Growing evidence shows interrelations of psychological factors, neurological and immunological processes. Therefore, constructs like a balance of activities, the so called "occupational balance", could also have biological correlates. The aim of this study was to investigate potential associations between occupational balance, functioning, cytokines and C-reactive protein (CRP) in patients suffering from a chronic inflammatory disease like rheumatoid arthritis (RA) and healthy people. Moreover, we wanted to explore potential differences in gender and employment status. A descriptive study in patients with RA and healthy people was conducted using the Occupational Balance-Questionnaire (OB-Quest) and the Short-Form 36 Health Survey (SF-36). Serum levels of cytokines, such as interleukin 6 (IL-6) and 8 (IL-8), interferon alpha (INFalpha), tumour necrosis factor alpha (TNFalpha), rheumatoid factor (RF) and of CRP were measured. Descriptive statistics, as well as Mann-Whitney U tests and Spearmen's rank correlation coefficients (rs) were calculated. One-hundred-thirty-two patients with RA and 76 healthy people participated. Occupational balance was associated with functioning, cytokines and CRP. The strongest associations were identified in the unemployed healthy-people sample with cytokines and CRP being within the normal range. For example, the OB-Quest item challenging activities was associated with IL-8 (rs=-0.63, p=0.04) and the SF-36 sub-scale bodily pain was associated with IFNalpha (rs=-0.69, p=0.02). The items rest and sleep (rs=-0.71, p=0.01) and variety of different activities (rs=-0.74, p<0.01) correlated with the SF-36 sub-scale social functioning. Employed and unemployed people differed in their age and CRP levels. Additionally, gender differences were found in two OB-Quest items in that fewer women were able to adapt their activities to changing living conditions and fewer men were overstressed. In conclusion, we found preliminary biological evidence for the link between occupation and health in that the concepts encompassed in the construct of occupational balance were associated with functioning, cytokines and CRP. PMID- 26773842 TI - Hole-Transporting Materials Based on Twisted Bimesitylenes for Stable Perovskite Solar Cells with High Efficiency. AB - A new class of hole-transport materials (HTMs) based on the bimesitylene core designed for mesoporous perovskite solar cells is introduced. Devices fabricated using two of these derivatives yield higher open-circuit voltage values than the commonly used spiro-OMeTAD. Power conversion efficiency (PCE) values of up to 12.11% are obtained in perovskite-based devices using these new HTMs. The stability of the device made using the highest performing HTM (P1) is improved compared with spiro-OMeTAD as evidenced through long-term stability tests over 1000 h. PMID- 26773843 TI - Wild plants, pregnancy, and the food-medicine continuum in the southern regions of Ghana and Benin. AB - ETHNOPHARMACOLOGICAL RELEVANCE: In West Africa, women utilize wild plant species to maintain and enhance their health throughout the duration of pregnancy. These plants are a culturally resilient and financially accessible form of nourishment for pregnant women in the region, many of whom are malnourished, yet studies that identify both the nutritional and medicinal properties of these plants are limited. AIM OF THE STUDY: The objective of this study was to analyze women's knowledge of plants consumed in pregnancy in the southern regions of Ghana and Benin from a food-medicine continuum perspective. MATERIALS AND METHODS: We gathered data in two fieldwork periods in West Africa (Ghana 2010 and Benin 2011) through herbal market surveys and 56 questionnaires with women and then conducted a literature review on known properties of the plants. RESULTS: Ghanaian women reported consuming wild greens such as iron-rich Nephrolepis biserrata and tree barks such as protein-rich Ricinodendron heudelotii in a soup based on the African oil palm fruit (Elaeis guineensis), a source of fatty acids. In Benin, participants frequently reported ingesting plants during pregnancy in the form of herbal teas. Commonly cited species included Securidaca longipedunculata, Dichapetalum madagascariense, and Schwenckia americana. Several of the plants demonstrated antioxidant, anti-malarial and anti-inflammatory activity in pharmacological studies, yet the majority has incomplete nutritional and pharmacological profiles. In total, informants cited 105 species that were consumed during pregnancy. Although Ghanaian and Beninese women mentioned different species and different forms of consumption, in both countries women cited "strengthening" as the most common motivation to consume wild plants during pregnancy. Strengthening is a concept that resonates within the food-medicine continuum, bridging the local diet and herbal pharmacopoeia of women's plant use during pregnancy. CONCLUSIONS: Ethnobotanical studies of this nature highlight the multidimensional use of plants and can improve health and nutritional programs in the region. PMID- 26773845 TI - CJD and Scrapie Require Agent-Associated Nucleic Acids for Infection. AB - Unlike Alzheimer's and most other neurodegenerative diseases, Transmissible Spongiform Encephalopathies (TSEs) are all caused by actively replicating infectious particles of viral size and density. Different strain-specific TSE agents cause CJD, kuru, scrapie and BSE, and all behave as latent viruses that evade adaptive immune responses and can persist for years in lymphoreticular tissues. A foreign viral structure with a nucleic acid genome best explains these TSE strains and their endemic and epidemic spread in susceptible species. Nevertheless, it is widely believed that host prion protein (PrP), without any genetic material, encodes all these strains. We developed rapid infectivity assays that allowed us to reproducibly isolate infectious particles where >85% of the starting titer separated from the majority of host components, including PrP. Remarkably, digestion of all forms of PrP did not reduce brain particle titers. To ask if TSE agents, as other viruses, require nucleic acids, we exposed high titer FU-CJD and 22L scrapie particles to potent nucleases. Both agent-strains were propagated in GT1 neuronal cells to avoid interference by complex degenerative brain changes that can impede nuclease digestions. After exposure to nucleases that are active in sarkosyl, infectivity of both agents was reproducibly reduced by >=99%. No gold-stained host proteins or any form of PrP were visibly altered by these nucleases. In contrast, co-purifying protected mitochondrial DNA and circular SPHINX DNAs were destroyed. These findings demonstrate that TSE agents require protected genetic material to infect their hosts, and should reopen investigation of essential agent nucleic acids. J. Cell. Biochem. 117: 1947-1958, 2016. (c) 2016 Wiley Periodicals, Inc. PMID- 26773844 TI - Studies on medicinal herbs for cognitive enhancement based on the text mining of Dongeuibogam and preliminary evaluation of its effects. AB - ETHNOPHARMACOLOGICAL RELEVANCE: In literature on Korean medicine, Dongeuibogam (Treasured Mirror of Eastern Medicine), published in 1613, represents the overall results of the traditional medicines of North-East Asia based on prior medicinal literature of this region. We utilized this medicinal literature by text mining to establish a list of candidate herbs for cognitive enhancement in the elderly and then performed an evaluation of their effects. MATERIALS AND METHODS: Text mining was performed for selection of candidate herbs. Cell viability was determined in HT22 hippocampal cells and immunohistochemistry and behavioral analysis was performed in a kainic acid (KA) mice model in order to observe alterations of hippocampal cells and cognition. RESULTS: Twenty four herbs for cognitive enhancement in the elderly were selected by text mining of Dongeuibogam. In HT22 cells, pretreatment with 3 candidate herbs resulted in significantly reduced glutamate-induced cell death. Panax ginseng was the most neuroprotective herb against glutamate-induced cell death. In the hippocampus of a KA mice model, pretreatment with 11 candidate herbs resulted in suppression of caspase-3 expression. Treatment with 7 candidate herbs resulted in significantly enhanced expression levels of phosphorylated cAMP response element binding protein. Number of proliferated cells indicated by BrdU labeling was increased by treatment with 10 candidate herbs. Schisandra chinensis was the most effective herb against cell death and proliferation of progenitor cells and Rehmannia glutinosa in neuroprotection in the hippocampus of a KA mice model. In a KA mice model, we confirmed improved spatial and short memory by treatment with the 3 most effective candidate herbs and these recovered functions were involved in a higher number of newly formed neurons from progenitor cells in the hippocampus. CONCLUSIONS: These established herbs and their combinations identified by text mining technique and evaluation for effectiveness may have value in further experimental and clinical applications for cognitive enhancement in the elderly. PMID- 26773847 TI - Patterns and frequencies of acquired and constitutional uniparental isodisomies in pediatric and adult B-cell precursor acute lymphoblastic leukemia. AB - Single nucleotide polymorphism (SNP) arrays are increasingly being used in clinical routine for genetic analysis of pediatric B-cell precursor acute lymphoblastic leukemias (BCP ALL). Because constitutional DNA is not readily available as a control at the time of diagnosis, it is important to be able to distinguish between acquired and constitutional aberrations in a diagnostic setting. In the present study we focused on uniparental isodisomies (UPIDs). SNP array analyses of 143 pediatric and 38 adult B-cell precursor acute lymphoblastic leukemias and matched remission samples revealed acquired whole chromosome or segmental UPIDs (wUPIDs, sUPIDs) in 32 cases (18%), without any age- or gender related frequency differences. Acquired sUPIDs were larger than the constitutional ones (mean 35.3 Mb vs. 10.7 Mb; P < 0.0001) and were more often terminally located in the chromosomes (69% vs. 4.5%; P < 0.0001). Chromosomes 3, 5, and 9 were most often involved in acquired wUPIDs, whilst recurrent acquired sUPIDs targeted 6p, 9p, 9q, and 14q. The majority (56%) of sUPID9p was associated with homozygous CDKN2A deletions. In pediatric ALL, all wUPIDs were found in high hyperdiploid (51-67 chromosomes) cases and an extended analysis, also including unmatched diagnostic samples, revealed a higher frequency of wUPID-positivity in higher modal number (56-67 chromosomes) than in lower modal number (51-55 chromosomes) high hyperdiploid cases (34% vs. 11%; P = 0.04), suggesting different underlying mechanisms of formation of these subtypes of high hyperdiploidy. (c) 2016 Wiley Periodicals, Inc. PMID- 26773846 TI - Thiazole Orange Dimers in DNA: Fluorescent Base Substitutions with Hybridization Readout. AB - By using (S)-2-amino-1,3-propanediol as a linker, thiazole orange (TO) was incorporated in a dimeric form into DNA. The green fluorescence (lambda=530 nm) of the intrastrand TO dimer is quenched, whereas the interstrand TO dimer shows a characteristic redshifted orange emission (lambda=585 nm). Steady-state optical spectroscopic methods reveal that the TO dimer fluorescence is independent of the sequential base contexts. Time-resolved pump-probe measurements and excitation spectra reveal the coexistence of conformations, including mainly stacked TO dimers and partially unstacked ones, which yield exciton and excimer contributions to the fluorescence, respectively. The helicity of the DNA framework distorts the excitonic coupling. In particular, the interstrand TO dimer could be regarded as an excitonically interacting base pair with fluorescence readout for DNA hybridization. Finally, the use of this fluorescent readout was representatively demonstrated in molecular beacons. PMID- 26773849 TI - Diversity, frequency, and geographic distribution of facultative bacterial endosymbionts in introduced aphid pests. AB - Facultative bacterial endosymbionts in insects have been under intense study during the last years. Endosymbionts can modify the insect's phenotype, conferring adaptive advantages under environmental stress. This seems particularly relevant for a group of worldwide agricultural aphid pests, because endosymbionts modify key fitness-related traits, including host plant use, protection against natural enemies and heat tolerance. Aimed to understand the role of facultative endosymbionts on the success of introduced aphid pests, the distribution and abundance of 5 facultative endosymbionts (Hamiltonella defensa, Regiella insecticola, Serratia symbiotica, Rickettsia and Spiroplasma) were studied and compared in 4 cereal aphids (Sitobion avenae, Diuraphis noxia, Metopolophium dirhodum and Schizaphis graminium) and in the pea aphid Acyrthosiphon pisum complex from 2 agroclimatic zones in Chile. Overall, infections with facultative endosymbionts exhibited a highly variable and characteristic pattern depending on the aphid species/host race and geographic zone, which could explain the success of aphid pest populations after their introduction. While S. symbiotica and H. defensa were the most frequent endosymbionts carried by the A. pisum pea-race and A. pisum alfalfa-race aphids, respectively, the most frequent facultative endosymbiont carried by all cereal aphids was R. insecticola. Interestingly, a highly variable composition of endosymbionts carried by S. avenae was also observed between agroclimatic zones, suggesting that endosymbionts are responding differentially to abiotic variables (temperature and precipitations). In addition, our findings constitute the first report of bacterial endosymbionts in cereal aphid species not screened before, and also the first report of aphid endosymbionts in Chile. PMID- 26773851 TI - Competition between hydrogen and halogen bonding in halogenated 1-methyluracil: Water systems. AB - The competition between hydrogen- and halogen-bonding interactions in complexes of 5-halogenated 1-methyluracil (XmU; X = F, Cl, Br, I, or At) with one or two water molecules in the binding region between C5-X and C4=O4 is investigated with M06-2X/6-31+G(d). In the singly-hydrated systems, the water molecule forms a hydrogen bond with C4=O4 for all halogens, whereas structures with a halogen bond between the water oxygen and C5-X exist only for X = Br, I, and At. Structures with two waters forming a bridge between C4=O and C5-X (through hydrogen- and halogen-bonding interactions) exist for all halogens except F. The absence of a halogen-bonded structure in singly-hydrated ClmU is therefore attributed to the competing hydrogen-bonding interaction with C4=O4. The halogen-bond angle in the doubly-hydrated structures (150-160 degrees ) is far from the expected linearity of halogen bonds, indicating that significantly non-linear halogen bonds may exist in complex environments with competing interactions. PMID- 26773852 TI - Selective binding and magnetic separation of histidine-tagged proteins using Fe3O4/Cu-apatite nanoparticles. AB - Hierarchical Fe3O4@Cu-apatite nanoparticles (NPs) were synthesized via a facile hydrothermal method. The Fe3O4 cores present spherical shape and have a mean diameter of 300nm, and the Cu-apatite shell with thickness of about 50nm is composed of a large number of sheets. Using the high affinity of Cu(2+) on the surface toward histidine tags, the Fe3O4@Cu-apatite NPs can be applied to enrich and magnetically separate histidine tagged (His-tagged) proteins directly from the mixture of lysed cells. Research results indicated that the Fe3O4@Cu-apatite NPs presented negligible nonspecific protein adsorption and high protein binding ability. PMID- 26773853 TI - Maternal Outcomes in Birth Centers: An Integrative Review of the Literature. AB - INTRODUCTION: The birth center, a relatively recent innovation in maternity care, is an increasingly popular location of birth. The purpose of this integrative literature review is to assess the research on maternal outcomes from birth center care. METHODS: Using methods by Whittemore and Knafl, we conducted an integrative review of studies of birth centers published in English since 1980. Twenty-three quantitative sources and 9 qualitative sources describing maternal outcomes of birth center care were reviewed and synthesized. RESULTS: Outcomes for women receiving birth care were positive. Spontaneous vaginal birth rates and perineal integrity were higher for women beginning care in a birth center compared to women in hospital care. Rates of cesarean birth were also lower for women planning birth center care. Transfer rates are difficult to compare across studies, but antepartum transfer rates ranged from 13% to 27.2%. Intrapartum transfer rates ranged from 11.6% to 37.4%, and from 11.6% to 16.5% in studies published from 2011 to 2013. Nulliparous women had higher rates of transfer than multiparous women. Few severe maternal outcomes and no maternal deaths were reported in any studies. Women were satisfied with the comprehensive, personalized care that they received from birth centers. DISCUSSION: Quantitative studies reviewed included more than 84,300 women. The heterogeneity of the studies and variations of practice limit generalization of findings. However, even with multisite studies enrolling a variety of birth centers and practice changes over time, the consistency of positive outcomes supports this model of care. Policy makers in the United States should consider supporting the birth center model as a means of improving maternal outcomes. PMID- 26773848 TI - Diffusion MRI in early cancer therapeutic response assessment. AB - Imaging biomarkers for the predictive assessment of treatment response in patients with cancer earlier than standard tumor volumetric metrics would provide new opportunities to individualize therapy. Diffusion-weighted MRI (DW-MRI), highly sensitive to microenvironmental alterations at the cellular level, has been evaluated extensively as a technique for the generation of quantitative and early imaging biomarkers of therapeutic response and clinical outcome. First demonstrated in a rodent tumor model, subsequent studies have shown that DW-MRI can be applied to many different solid tumors for the detection of changes in cellularity as measured indirectly by an increase in the apparent diffusion coefficient (ADC) of water molecules within the lesion. The introduction of quantitative DW-MRI into the treatment management of patients with cancer may aid physicians to individualize therapy, thereby minimizing unnecessary systemic toxicity associated with ineffective therapies, saving valuable time, reducing patient care costs and ultimately improving clinical outcome. This review covers the theoretical basis behind the application of DW-MRI to monitor therapeutic response in cancer, the analytical techniques used and the results obtained from various clinical studies that have demonstrated the efficacy of DW-MRI for the prediction of cancer treatment response. Copyright (c) 2016 John Wiley & Sons, Ltd. PMID- 26773854 TI - Fresh from the Ornamental Garden: Hips of Selected Rose Cultivars Rich in Phytonutrients. AB - Morphological parameters (size, weight, color), the content of sugars, organic acids, lycopene, beta-carotene, and phenolics were determined in hips of Rosa canina (RCA), Rosa sweginzowii (RSW), Rosa rugosa (RUG), and selected ornamental Rosa cultivars Fru Dagmar Hastrup (FDH), Repandia (REP), Veilchenblau (RVB), Aloha (RAL), Bonica (BON), and Golden Gate (RGG). Although traditionally used RCA hips contained the highest amount of cyanidin-3-glucoside (83 MUg/g DW) and were the reddest (h degrees = 17.5), they did not stand out in other analyzed parameters. RGG climber had the biggest hips (8.86 g), which also contained highest sugar levels (50.9 g/100 g DW). RAL stood out as the cultivar rich in organic acids (33.9 g/100 g DW), mainly because of high quinic acid content (17.6 g/100g DW). FDH and RSW hips were characterized by particularly high ascorbic acid levels (4325 mg/100 g DW and 4711 mg/100 g DW). Other ornamental cultivars contained low amounts of ascorbic acid compared to the analyzed species. The phenolic profile was species/cultivars-specific. The greatest diversity of phenolic compounds was detected in RUG and FDH hips (55 and 54 different tentatively identified compounds with HPLC/MS). Flavanols represented the main phenolic class in most of the investigated species/cultivars and RGG hips contained the highest amount of catechin and proanthocyandin derivatives (15855 MUg/g DW). Altogether RAL hips contained the highest quantity of phenolics (44746 MUg/g DW) mainly due to high levels of hydrolysable tannins compared to other species/cultivars. Although small, hips of BON and REP were most abundant regarding beta-carotene and lycopene content, respectively. PMID- 26773850 TI - The potential roles for adipose tissue in peripheral nerve regeneration. AB - INTRODUCTION: This review summarizes current understanding about the role of adipose-derived tissues in peripheral nerve regeneration and discusses potential advances that would translate this approach into the clinic. METHODS: We searched PubMed for in vivo, experimental studies on the regenerative effects of adipose derived tissues on peripheral nerve injuries. We summarized the methods and results for the 42 experiments. RESULTS: Adipose-derived tissues enhanced peripheral nerve regeneration in 86% of the experiments. Ninety-five percent evaluated purified, cultured, or differentiated adipose tissue. These approaches have regulatory and scaling burdens, restricting clinical usage. Only one experiment tested the ability of adipose tissue to enhance nerve regeneration in conjunction with nerve autografts, the clinical gold standard. CONCLUSION: Scientific studies illustrate that adipose-derived tissues enhance regeneration of peripheral nerves. Before this approach achieves clinical acceptance, fat processing must become automated and regulatory approval achieved. Animal studies using whole fat grafts are greatly needed for clinical translation. PMID- 26773855 TI - Colloidal carriers for extended absorption window of furosemide. AB - OBJECTIVES: The aim was to investigate the potential of self-microemulsifying drug delivery systems (SMEDDS) and niosomes as carriers for widening the gastrointestinal absorption window of furosemide (model acidic drug). METHODS: The drug was incorporated in SMEDDS and was encapsulated into niosomes. The intestinal absorption was monitored at two anatomical sites (duodenum and jejuno ileum). This employed in situ rabbit intestinal perfusion technique. KEY FINDINGS: Perfusion of drug solution (control) revealed poor intestinal permeability with per cent fraction absorbed (%Fa) from the duodenum and jejuno ileum being 1.3 and 0.6 % per cm, respectively. Formulation of furosemide as SMEDDS increased the %Fa from the duodenum and jejuno-ileum to reach 1.7 and 1 % per cm, respectively. Niosomal encapsulation increased the %Fa from duodenum and jejuno-ileum to record 1.9 and 1.2 % per cm, respectively. The increase in the %Fa was also revealed as a reduction in the length required for 95 % absorption of the drug which was reduced from 557.2 to 245.8 cm and to 279.8 cm after delivery as niosomes or SMEDDS, respectively, in case of jejuno-ileum. The same trend was recorded with the duodenum. CONCLUSION: The recorded results highlighted the potential for SMEDDS and niosomes for widening the absorption window of acidic drugs after oral administration. PMID- 26773856 TI - High proportion of CD95(+) and CD38(+) in cultured CD8(+) T cells predicts acute rejection and infection, respectively, in kidney recipients. AB - The aim of this study was to find noninvasive T-cell markers able to predict rejection or infection risk after kidney transplantation. We prospectively examined T-lymphocyte subsets after cell culture stimulation (according to CD38, CD69, CD95, CD40L, and CD25 expression) in 79 first graft recipients from four centers, before and after transplantation. Patients were followed up for one year. Patients who rejected within month-1 (n=10) showed high pre-transplantation and week-1 post-transplantation percentages of CD95(+), in CD4(+) and CD8(+) T cells (P<0.001 for all comparisons). These biomarkers conferred independent risk for early rejection (HR:5.05, P=0.061 and HR:75.31, P=0.004; respectively). The cut-off values were able to accurately discriminate between rejectors and non rejectors and Kaplan-Meier curves showed significantly different free-of rejection time rates (P<0.005). Patients who rejected after the month-1 (n=4) had a higher percentage of post-transplantation CD69(+) in CD8(+) T-cells than non rejectors (P=0.002). Finally, patients with infection (n=41) previously showed higher percentage of CD38(+) in CD8(+) T-cells at all post-transplantation times evaluated, being this increase more marked in viral infections. A cut-off of 59% CD38(+) in CD8(+) T-cells at week-1, week-2 and month-2 reached 100% sensitivity for the detection of subsequent viral infections. In conclusion, predictive biomarkers of rejection and infection risk after transplantation were detected that could be useful for the personalized care of kidney recipients. PMID- 26773857 TI - Metabolic acidosis aggravates experimental acute kidney injury. AB - AIMS: Ischemia/reperfusion (I/R) injury and metabolic acidosis (MA) are two critical conditions that may simultaneously occur in clinical practice. The result of this combination can be harmful to the kidneys, but this issue has not been thoroughly investigated. The present study evaluated the influence of low systemic pH on various parameters of kidney function in rats that were subjected to an experimental model of renal I/R injury. MAIN METHODS: Metabolic acidosis was induced in male Wistar rats by ingesting ammonium chloride (NH4Cl) in tap water, beginning 2 days before ischemic insult and maintained during the entire study. Ischemia/reperfusion was induced by clamping both renal arteries for 45 min, followed by 48 h of reperfusion. Four groups were studied: control (subjected to sham surgery, n=8), I/R (n=8), metabolic acidosis (MA; 0.28 M NH4Cl solution and sham surgery, n=6), and MA+I/R (0.28 M NH4Cl solution plus I/R, n=9). KEY FINDINGS: Compared with I/R rats, MA+I/R rats exhibited higher mortality (50 vs. 11%, p=0.03), significant reductions of blood pH, plasma bicarbonate (pBic), and standard base excess (SBE), with a severe decline in the glomerular filtration rate and tubular function. Microscopic tubular injury signals were detected. Immunofluorescence revealed that the combination of MA and I/R markedly increased nuclear factor kappaB (NF-kappaB) and heme-oxygenase 1 (HO 1), but it did not interfere with the decrease in endothelial nitric oxide synthase (eNOS) expression that was caused by I/R injury. SIGNIFICANCE: Acute ischemic kidney injury is exacerbated by acidic conditions. PMID- 26773859 TI - Identification and characterization of immune-related microRNAs in blunt snout bream, Megalobrama amblycephala. AB - MicroRNAs (miRNAs) play vital roles in diverse biological processes, including in immune response. Blunt snout bream (Megalobrama amblycephala) is a prevalent and important commercial endemic freshwater fish species in China's intensive polyculture systems. To identify immune-related miRNAs of M. amblycephala, two small RNA (sRNA) libraries from immune tissues with or without lipopolysaccharide (LPS) stimulation were constructed and sequenced using the high-throughput sequencing technology. Totally, 16,425,543 and 15,076,813 raw reads, corresponding to 14,156,755 and 13,445,869 clean reads, were obtained in the normal and infected libraries, respectively. A total of 324 miRNAs, including 218 known miRNAs and 106 putative novel miRNAs were identified by bioinformatic analysis. We analyzed differentially expressed miRNAs between two libraries using pairwise comparison. 113 (34.88%) miRNAs were found to be significantly differentially expressed between two libraries, with 63 (55.75%) exhibiting elevated expression in LPS stimulation sample. Thereinto, a number of known miRNAs were identified immune-related. Real-time quantitative PCR (RT-qPCR) were implemented for 12 miRNAs of two samples, and agreement was confirmed between the sequencing and RT-qPCR data. Target genes likely regulated by these differentially expressed miRNAs were predicted using computational prediction. The functional annotation of target genes by Gene Ontology enrichment (GO) and Kyoto Encyclopedia of Genes and Genomes pathway analysis (KEGG) indicated that a majority of differential miRNAs might involved in immune response. To our knowledge, this is the first comprehensive study of miRNAs in response to LPS stimulation in M. amblycephala, even in fish. These results deepened our understanding of the role of miRNAs in the intricate host's immune system, and should be useful to develop new control strategies for host immune defense against various bacterial invasions in M. amblycephala. PMID- 26773858 TI - Ornithine is a key mediator in hyperphosphatemia-mediated human umbilical vein endothelial cell apoptosis: Insights gained from metabolomics. AB - AIMS: Hyperphosphatemia is associated with accelerated vascular endothelial dysfunction in patients with chronic kidney disease (CKD). The purpose of this study is to investigate the molecular mechanisms underlying hyperphosphatemia caused endothelial dysfunction. MAIN METHODS: The metabolic fingerprinting of human umbilical vein endothelial cells (HUVECs) subjected to hyperphosphatemia was characterized using an integrated metabolomics approach. HUVECs cultured in physiologically simulated hyperphosphatemia with or without phosphonoformic acid, a sodium-dependent phosphate transporter inhibitor (N=6) were collected for metabolomics analysis. Multivariate principle component analysis and partial least squares discriminant analysis were applied to analyze the metabolic data. The key metabolites were confirmed by quantitative analysis using liquid chromatography coupled with tandem mass spectrometer (LC-MS/MS). KEY FINDINGS: 36 metabolites were significantly altered in HUVECs following the challenges of hyperphosphatemia mimic, involving several metabolic pathways (all P<0.05). Among them, ornithine increased significantly in the HUVECs mediated by hyperphosphatemia mimic, and its levels positively correlated with cell apoptosis rate (r=0.674, P=0.002), and several additional metabolites in multiple metabolic pathways. The changes in the levels of ornithine and other several metabolites were supported by subsequent quantitative analyses using LC-MS/MS. Further study demonstrated that the increase in ornithine level may result from the increased expression of arginase 2 in HUVECs, which mediates the hydrolysis of arginine to form ornithine. SIGNIFICANCE: This is the first study demonstrating ornithine a key molecule mediating hyperphosphatemia-induced apoptosis of ECs. Arginase 2 may be a therapeutic target for hyperphosphatemia-associated cardiovascular events. PMID- 26773862 TI - Time to Make a Call? The Ethics of Mandatory Reporting. PMID- 26773860 TI - Sensing parasites: Proteomic and advanced bio-detection alternatives. AB - Parasitic diseases have a great impact in human and animal health. The gold standard for the diagnosis of the majority of parasitic infections is still conventional microscopy, which presents important limitations in terms of sensitivity and specificity and commonly requires highly trained technicians. More accurate molecular-based diagnostic tools are needed for the implementation of early detection, effective treatments and massive screenings with high throughput capacities. In this respect, sensitive and affordable devices could greatly impact on sustainable control programmes which exist against parasitic diseases, especially in low income settings. Proteomics and nanotechnology approaches are valuable tools for sensing pathogens and host alteration signatures within microfluidic detection platforms. These new devices might provide novel solutions to fight parasitic diseases. Newly described specific parasite derived products with immune-modulatory properties have been postulated as the best candidates for the early and accurate detection of parasitic infections as well as for the blockage of parasite development. This review provides the most recent methodological and technological advances with great potential for bio-sensing parasites in their hosts, showing the newest opportunities offered by modern "-omics" and platforms for parasite detection and control. PMID- 26773864 TI - Berberine up-regulates the BDNF expression in hippocampus and attenuates corticosterone-induced depressive-like behavior in mice. AB - Depression is increasingly become a global public healthy problem. This study was to investigate whether berberine could attenuate the depressive-like behavior induced by repeated corticosterone injection and explore the possible mechanisms. The present results showed that exogenous corticosterone injection caused depressive-like behaviors in mice, such as decreased sucrose intake in sucrose preference test (SPT) and increased immobility time in forced swimming test (FST). These behavioral alterations were accompanying with the decreased BDNF mRNA and protein levels in hippocampus and the elevated serum corticosterone levels. Treatment with berberine prevented these changes above. Our findings confirmed the antidepressant-like effect of berberine and suggested its mechanisms might be partially mediated by up-regulation of BDNF in hippocampus. PMID- 26773863 TI - Analytical Validation of a Personalized Medicine APOL1 Genotyping Assay for Nondiabetic Chronic Kidney Disease Risk Assessment. AB - The incidence of chronic kidney disease (CKD) varies by ancestry, with African Americans (AA) having a threefold to fourfold higher rate than whites. Notably, two APOL1 alleles, termed G1 [c.(1072A>G; 1200T>G)] and G2 (c.1212_1217del6), are strongly associated with higher rates of nondiabetic CKD and an increased risk for hypertensive end-stage renal disease. This has prompted the opportunity to implement APOL1 testing to identify at-risk patients and modify other risk factors to reduce the progression of CKD to end-stage renal disease. We developed an APOL1 genotyping assay using multiplex allele-specific primer extension, and validated using 58 positive and negative controls. Genotyping results were completely concordant with Sanger sequencing, and both triplicate interrun and intrarun genotyping results were completely concordant. Multiethnic APOL1 allele frequencies were also determined by genotyping 7059 AA, Hispanic, and Asian individuals from the New York City metropolitan area. The AA, Hispanic, and Asian APOL1 G1 and G2 allele frequencies were 0.22 and 0.13, 0.037 and 0.025, and 0.013 and 0.004, respectively. Notably, approximately 14% of the AA population carried two risk alleles and are at increased risk for CKD, compared with <1% of the Hispanic and Asian populations. This novel APOL1 genotyping assay is robust and highly accurate, and represents one of the first personalized medicine clinical genetic tests for disease risk prediction. PMID- 26773866 TI - Electroacupuncture regulate hypothalamic-pituitary-adrenal axis and enhance hippocampal serotonin system in a rat model of depression. AB - Hypothalamic-pituitary-adrenal (HPA) axis has been implicated in the pathogenesis of depression. Dysfunction of the hippocampal serotonin (5-hydroxytryptamine, 5 HT) system has been shown to be a key factor in depression. There is growing evidence that electro-acupuncture (EA) has antidepressant-like effect. However, the effect of EA on HPA axis and hippocampal serotonin system remains unknown. In our study, we investigated the antidepressant-like effect and mechanism of EA for depression rat models. Depression in rats was induced by chronic unpredictable mild stress (CUMS). EA treatment was administered once daily to CUMS rats for 14 days. The acupoints (ST36, bilateral and CV4) were selected. Untreated CUMS rats and normal rats were used as controls. Behavioral tests including forced swim test and open-field test were performed to evaluate the antidepressant effects of EA treatment. Hypothalamic corticotropin-releasing hormone (CRH) mRNA, plasma adrenocorticotropic hormone (ACTH) and corticosterone (CORT) were estimated as indices of HPA axis activity. Enzyme linked immunosorbent assay (ELISA) was performed to determine the concentrations of 5-HT in the hippocampus. Real-time PCR(RT-PCR)and Western blot were respectively used to detect the mRNA and protein levels of 5-hydroxytryptamine 1A receptor (5-HT1AR) in the hippocampus. Our results showed that EA treatment reversed the behavioral deficiency induced by CUMS in rats. EA treatment decreased CRH mRNA expression in the hypothalamic, and ACTH and CORT level in plasma, and markedly increased 5-HT concentration, 5-HT1AR (mRNA and protein) expression in the hippocampus. These results indicated that EA treatment could act on depression by modulating HPA axis and enhancing hippocampal 5-HT/5-HT1AR in CUMS Rats. PMID- 26773865 TI - Role of the neural pathway from hindbrain to hypothalamus in the regulation of energy homeostasis in rats. AB - Recent evidence suggests that neural pathways from the hindbrain to the hypothalamus are important for informing the hypothalamus of the body's condition with regard to energy metabolism. Here we examined energy metabolism in rats with transections of the midbrain that severed the neural pathway from the hindbrain to the hypothalamus, and then investigated the levels of various molecules associated with control of energy metabolism in these rats. Food intake and body weight were higher in the midbrain-transected rats than in sham-operated rats. In addition, the midbrain-transected rats showed insulin resistance and hyperleptinemia. Furthermore, the hypothalamic mRNA levels of anorectic proopiomelanocortin and cocaine- and amphetamine-related transcript were significantly lower in midbrain-transected rats than in sham-operated rats. Our findings elucidate the mechanisms of food intake and energy balance from the perspective of multifactorial regulatory systems that underlie functions such as neurohormonal integration. PMID- 26773867 TI - Des-acyl ghrelin prevents heatstroke-like symptoms in rats exposed to high temperature and high humidity. AB - We have shown previously that des-acyl ghrelin decreases body temperature in rats through activation of the parasympathetic nervous system. Here we investigated whether des-acyl ghrelin ameliorates heatstroke in rats exposed to high temperature. Peripheral administration of des-acyl ghrelin significantly attenuated hyperthermia induced by exposure to high-temperature (35 degrees C) together with high humidity (70-80%). Although biochemical analysis revealed that exposure to high temperature significantly increased hematocrit and the serum levels of aspartate amino transferase (AST), alanine transaminase (ALT), blood urea nitrogen (BUN), creatinine and electrolytes (Na(+), K(+), Cl(-)), most of these heatstroke-associated reactions were significantly reduced by treatment with des-acyl ghrelin. The level of des-acyl ghrelin in plasma was also found to be significantly increased under high-temperature conditions. These results suggest that des-acyl ghrelin could be useful for preventing heatstroke under high temperature condition. PMID- 26773868 TI - Experimental infection of the digeneans to some congeneric snail species radiated in a single water system: Relative importance of local evolution and phylogenetic constraint. AB - To determine the relative importance of local adaptation caused by host-parasite coevolution and resource tracking by the parasites, the susceptibility of the freshwater snail genus Semisulcospira to the digenean parasite genus Genarchopsis was investigated experimentally. Four snail species endemic to the Lake Biwa system in Japan and two non-endemic species were investigated. All but one species was also tested for local variation in susceptibility. Parasites were obtained from Takashima (mix population of Genarchopsis gigi and Genarchopsis chubuensis) and Nagahama (G. chubuensis). In endemic Semisulcospira, closely related specie pairs (Semisulcospira habei and Semisulcospira niponica, Semisulcospira decipiens and Semisulcospira nakasekoae) showed similar susceptibilities to parasites from both localities. S. habei and S. niponica were highly susceptible to parasites from Takashima, but were resistant to parasites from Nagahama. S. decipiens and S. nakasekoae showed moderate susceptibility to parasites from both localities. None of the endemic snail species showed a clear local variation in susceptibility. These results show that the susceptibility of endemic Semisulcospira to Genarchopsis is conservative and can be regarded as an example of resource-tracking. One of the non-endemic snails, Semisulcospira libertina, showed local variation in susceptibility. This variation was not related to the sympatry of the parasites used for the experimental infection, suggesting that it was not the result of local adaptation by parasites. PMID- 26773869 TI - Carbonyl stress phenomena during chronic infection with Opisthorchis felineus. AB - Infection with the fish borne liver fluke Opisthorchis felineus is common in the Eastern Europe (Ukraine, European part of Russia), Northern Asia (Siberia) and Central Asia (Northern Kazakhstan). Better understanding of the molecular pathogenesis of the biliary tract and liver during chronic opisthorchiasis can be expected to improve protection against and management of complications of this disease. We hypothesize that infection with O. felineus associates with formation of methylglyoxal and carbonyl stress in the liver and hence here we investigated the glyoxalase system and the receptor for advanced glycated end products (RAGE) in the liver of hamsters infected with this liver fluke. Expression of mRNA encoding glyoxalase 1 decreased at 8weeks of the infection and catalytic activity as well decreased at 8 and 12weeks after infection, and the expression of the glyoxalase 2 decreased until 36week post-infection, which associated with the decreasing activity of the enzyme at 8 and 12weeks post-infection. Glutathione levels in infected livers had decreased at week 8, whereas up-regulation of RAGE at mRNA levels was seen for the extended duration of the experimental infection of the hamsters. This outcome supported the notion of hepatic dicarbonyl stress during chronic opisthorchiasis. The inhibition of the glyoxalase system and accumulation of methylglyoxal at the early stages of the infection may underpin development of insulin resistance during opisthorchiasis. PMID- 26773870 TI - The role of Fc-receptors in the uptake and transport of therapeutic antibodies in the retinal pigment epithelium. AB - In the ophthalmological clinic, intravitreally applied antibodies or Fc containing fusion proteins are frequently used, but the biology and pharmacokinetics of these therapeutics in the retina are not well understood. We have previously shown intracellular uptake of Fc-containing molecules in RPE cells. In this study, we investigated the involvement of Fc-receptors, both Fcgamma-receptors and the neonatal Fc-receptor (FcRn) in the uptake and intracellular trafficking of the VEGF-antagonists bevacizumab, aflibercept and the anti-CD20 antibody rituximab in three different model systems, primary porcine RPE cells, ARPE-19 cells and porcine RPE/choroid explants. The expression of Fcgamma-receptors was tested in primary porcine RPE cells, and the expression of Fcgamma-receptors I and II could be shown in RT-PCR and qRT-PCR, while the expression of FcRn was additionally confirmed in Western blot and immunocytochemistry. All three compounds, bevacizumab, rituximab and aflibercept, were taken up into the cells and displayed a characteristic time-dependent pattern, as shown in Western blot and immunohistochemistry. The uptake was not altered by the inhibition of Fcgamma-receptors using different inhibitors (TruStain FcX, genistein, R406). However, the inhibition of FcRn with an antagonistic antibody reduced intracellular IgG in porcine RPE cells (rituximab) and ARPE-19 cells (bevacizumab, rituximab). Colocalisations between the tested compounds and myosin7a could be found. In addition, limited colocalization with FcRn and the tested compounds, as well as triple localization between compound, FcRn and myosin7a could be detected, indicating a role of myosin7a in FcRn mediated transport. However, the colocalizations are restricted to small fractions of the Fc-containing compounds. Furthermore, the FcRn is mainly found in the membrane section, where only minute amounts of the Fc-containing compounds are seen, suggesting a limited interaction. An apical to choroidal transport of IgG through the RPE/choroid can be found in RPE/choroid explants. Inhibition of FcRn increases the amount of bevacizumab found on the choroidal side, suggesting a role of FcRn in the recycling of bevacizumab. In conclusion, our data indicate a role for FcRn, but not Fcgamma-receptors, in the uptake and transport of Fc containing molecules in the RPE and indicate a recycling function of FcRn in the retina. PMID- 26773871 TI - Impact of lifestyle intervention in primary prevention of Type 2 diabetes did not differ by baseline age and BMI among Asian-Indian people with impaired glucose tolerance. AB - AIM: To investigate whether the effectiveness of lifestyle interventions on the incidence of diabetes was influenced by the baseline age and BMI of the Asian Indian participants with prediabetes. METHODS: Pooled data, obtained from two of our Indian Diabetes Prevention Programmes (2006, n=236 and 2013, n=473; total N=709) which had similar baseline characteristics and intervention principles, were analysed. For the present secondary analysis we dichotomously categorized the participants' baseline age (<45 and >=45 years) and BMI (<25.0 and >= 25.0 kg/m2 ). Glycaemic status was ascertained at 6-monthly intervals by oral glucose tolerance tests. The incidence rates of diabetes and relative risk reduction in both the intervention and the control group were calculated for categories of baseline age and BMI. Interactions between the intervention and baseline age and BMI on diabetes risk were also analysed. RESULTS: Incident diabetes was diagnosed in 227 of the total 709 participants (32.0%) [control group 139 participants (38.8%) vs intervention group 88 participants (24.2%)] during the median follow up period of 2 years. The overall relative risk reduction was 35.4% (95% CI 19.3 48.3). Lifestyle intervention was equally effective in both age groups [relative risk reduction in those aged <45 years: 43.7% (95% CI 19.8-60.5) and in those aged >= 45 years: 28.9% (95% CI 5.3-46.6) P for interaction = 0.52] and in categories of BMI [BMI <25 kg/m2 : 36.1% (95% CI 9.5-54.9); and BMI >= 25 kg/m2 : 34.8% (95% CI 12.9-51.2); P for interaction = 0.95]. CONCLUSIONS: In Asian-Indian individuals with prediabetes, the effectiveness of lifestyle intervention was not modified by baseline age and BMI. PMID- 26773872 TI - Synthesis and structure elucidation of new MU-oxamido-bridged dicopper(II) complex with in vitro anticancer activity: A combined study from experiment verification and docking calculation on DNA/protein-binding property. AB - A new oxamido-bridged dicopper(II) complex with formula of [Cu2(deap)(pic)2], where H2deap and pic represent N,N'-bis[3-(diethylamino)propyl]oxamide and picrate, respectively, was synthesized and characterized by elemental analyses, molar conductance measurements, IR and electronic spectral study, and single crystal X-ray diffraction. The crystal structure analyses revealed that the two copper(II) atoms in the dicopper(II) complex are bridged by the trans-deap(2-) ligand with the distances of 5.2116(17)A, and the coordination environment around the copper(II) atoms can be described as a square-planar geometry. Hydrogen bonding and pi-pi stacking interactions link the dicopper(II) complex into a three-dimensional infinite network. The DNA/protein-binding properties of the complex are investigated by molecular docking and experimental assays. The results indicate that the dicopper(II) complex can interact with HS-DNA in the mode of intercalation and effectively quench the intrinsic fluorescence of protein BSA by 1:1 binding with the most possible binding site in the proximity of Trp134. The in vitro anticancer activities suggest that the complex is active against the selected tumor cell lines, and IC50 values for SMMC-7721 and HepG2 are lower than cisplatin. The effects of the electron density distribution of the terminal ligand and the chelate ring arrangement around copper(II) ions bridged by symmetric N,N'-bis(substituted)oxamides on DNA/BSA-binding ability and in vitro anticancer activity are preliminarily discussed. PMID- 26773873 TI - The novel triterpenoid RTA 408 protects human retinal pigment epithelial cells against H2O2-induced cell injury via NF-E2-related factor 2 (Nrf2) activation. AB - Oxidative stress-induced retinal pigment epithelial (RPE) cell damage is an important factor in the pathogenesis of age-related macular degeneration (AMD). Previous studies have shown that RTA 408, a synthetic triterpenoid compound, potently activates Nrf2. This study aimed to investigate the protective effects of RTA 408 in cultured RPE cells during oxidative stress and to determine the effects of RTA 408 on Nrf2 and its downstream target genes. Primary human RPE cells were pretreated with RTA 408 and then incubated in 200MUM H2O2 for 6h. Cell viability was measured with the WST-8 assay. Apoptosis was quantitatively measured by annexin V/propidium iodide (PI) double staining and Hoechst 33342 fluorescent staining. Reduced (GSH) and oxidized glutathione (GSSG) were measured using colorimetric assays. Nrf2 activation and its downstream effects on phase II enzymes were examined by Western blot. Treatment of RPE cells with nanomolar ranges (10 and 100nM) of RTA 408 markedly attenuated H2O2-induced viability loss and apoptosis. RTA 408 pretreatment significantly protected cells from oxidative stress-induced GSH loss, GSSG formation and decreased ROS production. RTA 408 activated Nrf2 and increased the expression of its downstream genes, such as HO 1, NQO1, SOD2, catalase, Grx1, and Trx1. Consequently, the enzyme activities of NQO1, Grx1, and Trx1 were fully protected by RTA 408 pretreatment under oxidative stress. Moreover, knockdown of Nrf2 by siRNA significantly reduced the cytoprotective effects of RTA 408. In conclusion, our data suggest that RTA 408 protect primary human RPE cells from oxidative stress-induced damage by activating Nrf2 and its downstream genes. PMID- 26773876 TI - Transsphincteric tumor resection in case of a pararectal solitary fibrous tumor. AB - Transsphincteric resection of rectal tumors was first described about 120 years ago. Nowadays, this approach faded into obscurity due to standardized guidelines and practice in surgical oncology including lymphadenectomy, mesorectal excision and radical dissection of veins. However, transsphincteric resection seems reasonable in some cases, especially if an abdominal approach can be avoided. In the following, we will present and describe the technique of the transsphincteric approach with its variations in rectal surgery in the case of a rare pararectal tumor. PMID- 26773874 TI - Protein S-glutathionlyation links energy metabolism to redox signaling in mitochondria. AB - At its core mitochondrial function relies on redox reactions. Electrons stripped from nutrients are used to form NADH and NADPH, electron carriers that are similar in structure but support different functions. NADH supports ATP production but also generates reactive oxygen species (ROS), superoxide (O2(.-)) and hydrogen peroxide (H2O2). NADH-driven ROS production is counterbalanced by NADPH which maintains antioxidants in an active state. Mitochondria rely on a redox buffering network composed of reduced glutathione (GSH) and peroxiredoxins (Prx) to quench ROS generated by nutrient metabolism. As H2O2 is quenched, NADPH is expended to reactivate antioxidant networks and reset the redox environment. Thus, the mitochondrial redox environment is in a constant state of flux reflecting changes in nutrient and ROS metabolism. Changes in redox environment can modulate protein function through oxidation of protein cysteine thiols. Typically cysteine oxidation is considered to be mediated by H2O2 which oxidizes protein thiols (SH) forming sulfenic acid (SOH). However, problems begin to emerge when one critically evaluates the regulatory function of SOH. Indeed SOH formation is slow, non-specific, and once formed SOH reacts rapidly with a variety of molecules. By contrast, protein S-glutathionylation (PGlu) reactions involve the conjugation and removal of glutathione moieties from modifiable cysteine residues. PGlu reactions are driven by fluctuations in the availability of GSH and oxidized glutathione (GSSG) and thus should be exquisitely sensitive to changes ROS flux due to shifts in the glutathione pool in response to varying H2O2 availability. Here, we propose that energy metabolism-linked redox signals originating from mitochondria are mediated indirectly by H2O2 through the GSH redox buffering network in and outside mitochondria. This proposal is based on several observations that have shown that unlike other redox modifications PGlu reactions fulfill the requisite criteria to serve as an effective posttranslational modification that controls protein function. PMID- 26773875 TI - Arthroscopic correction for concomitant cam impingement in a patient with idiopathic osteonecrosis of the femoral head: A case report. AB - A 53-year-old man presented with pain in the right hip. Radiological examination showed idiopathic osteonecrosis of the femoral head (ONFH) combined with a cam lesion. Findings on physical examination were consistent for femoroacetabular impingement. At surgery, we performed isolated arthroscopic correction for the cam lesion but did not use other treatment options such as hip arthroplasty or osteotomies for the ONFH. At the latest follow-up evaluation 3 years after surgery, findings indicted a satisfactory outcome, with a Harris hip score of 93.2 (compared with 76.4 before surgery), no joint-space narrowing, and no collapse of the femoral head. It is important to accurately diagnose the status of idiopathic ONFH and to consider another possible pathogenesis when a patient with idiopathic ONFH has hip pain even without femoral-head collapse. PMID- 26773877 TI - Pericardio-diaphragmatic rupture following blunt abdominal trauma: Case report and review of literature. AB - INTRODUCTION: Traumatic diaphragmatic rupture (TDR) occurs in 0-5% of patients with major blunt thoraco-abdominal trauma, in most of them on the left side, and an early correct diagnosis is made in less than half of the cases (Meyers and McCabe, 1993; Ball et al., 1982). PRESENTATION OF THE CASE: We report a case of a forty-eight years old man who had a pericardio-diaphragmatic rupture after a high velocity blunt abdominal trauma that was diagnosed and treated successfully. DISCUSSION: Pericardio-diaphragmatic rupture (PDR) is an uncommon problem that poses a diagnostic challenge to surgeons. The incidence of PDR is between 0.2% and 3.3% of cases with TDR (Sharma, 1999 [3]). CONCLUSION: PDR should be suspected in any patient with high velocity thoraco-abdominal trauma. Early diagnosis is essential and needs a high index of suspicion. Early Management is important in decreasing morbidity and mortality. PMID- 26773878 TI - Coexistence of malignant phyllodes tumor and her2-positive locally advanced breast cancer in distinct breasts: A case report. AB - INTRODUCTION: Phyllodes tumor of the breast is a rare biphasic neoplasm, accounting for less than 1% of all breast tumors. Coexistence of phyllodes tumor and breast cancer in distinct breasts is extremely rare. CASE PRESENTATION: A 47 year-old Japanese woman presented with bilateral breast lumps. A HER2-positive, unresectable invasive carcinoma in the right breast and fibroadenoma in the left were diagnosed via core needle biopsy. During chemotherapy with anti-HER2 therapy, the breast cancer shrank quickly, while the left breast lump suddenly enlarged. Under a diagnosis of malignant neoplasm of the breast, left mastectomy was performed. Malignant phyllodes tumor was diagnosed by postoperative histological examination and recurred in multiple areas as early as 2 months after surgery. DISCUSSION: Only 10 cases of coexisting phyllodes tumor and breast cancer in distinct breasts have been reported in the English literature. Phyllodes tumor associated with breast cancer in distinct breasts tends to be malignant. This is the first case of phyllodes tumor rapidly enlarging during anti-HER2 chemotherapy for locally advanced HER2-positive breast cancer. CONCLUSION: Even during effective treatment of advanced or recurrent breast cancer, attention should also be paid to the contralateral breast for the possible association of a second malignancy such as phyllodes tumor. PMID- 26773879 TI - Microfluidic immunomagnetic cell separation from whole blood. AB - Immunomagnetic-based separation has become a viable technique for the separation of cells and biomolecules. Here we report on the design and analysis of a simple and efficient microfluidic device for high throughput and high efficiency capture of cells tagged with magnetic particles. This is made possible by using a microfluidic chip integrated with customized arrays of permanent magnets capable of creating large magnetic field gradients, which determine the effective capturing of the tagged cells. This method is based on manipulating the cells which are under the influence of a combination of magnetic and fluid dynamic forces in a fluid under laminar flow through a microfluidic chip. A finite element analysis (FEA) model is developed to analyze the cell separation process and predict its behavior, which is validated subsequently by the experimental results. The magnetic field gradients created by various arrangements of magnetic arrays have been simulated using FEA and the influence of these field gradients on cell separation has been studied with the design of our microfluidic chip. The proof-of-concept for the proposed technique is demonstrated by capturing white blood cells (WBCs) from whole human blood. CD45-conjugated magnetic particles were added into whole blood samples to label WBCs and the mixture was flown through our microfluidic device to separate the labeled cells. After the separation process, the remaining WBCs in the elute were counted to determine the capture efficiency, and it was found that more than 99.9% WBCs have been successfully separated from whole blood. The proposed design can be used for positive selection as well as for negative enrichment of rare cells. PMID- 26773880 TI - Determination of residual dextran sulfate in protein products by SEC-HPLC. AB - Dextran sulfate is a polyanionic derivative of dextran, produced by esterification of dextran with chlorosulphonic acid. Dextran sulfate with an average molecular weight of 8000Da can be added to the cell culture to inhibit binding of proteins to cells, increasing cellular growth and productivity. Residual dextran sulfate levels must be monitored during the purification process development to insure clearance. A size-exclusion chromatography based HPLC assay has been developed for the separation and quantitation of dextran sulfate in a highly concentrated purified protein drug substance sample. Trichloroacetic acid (TCA) was used to precipitate the protein and separate the dextran sulfate. Detection and quantitation of dextran sulfate was achieved by post column reaction with dimethylene blue to form a metachromatic complex that absorbs visible light at 530nm. The quantitation limit (LOQ) was determined to be 1.5MUg/mL dextran sulfate in high concentration protein samples. PMID- 26773881 TI - Simultaneous quantification of 5 main components of Psoralea corylifolia L. in rats' plasma by utilizing ultra high pressure liquid chromatography tandem mass spectrometry. AB - Psoralea corylifolia L. has long been used in traditional Chinese medicine for treating and preventing many diseases. A group of flavonoid components are regarded as the active principals within the seeds. In this research, a rapid, accurate and sensitive ultra high pressure liquid chromatography tandem mass spectrometry (UHPLC/MS/MS) method has been established for simultaneous quantification of its 5 main components, namely, neobavaisoflavone, bavachin, isobavachalcone, bavachinin and corylifol A in rats' plasma after the rats were orally administrated with Buguzhi extract. Negative ion electrospray mode was applied in the detection process. Multiple reactions monitoring (MRM) mode was utilized for simultaneous quantitative analyzing of neobavaisoflavone (m/z 321.1 >m/z 265.1), bavachin (m/z 323.1->m/z 119.0), isobavachalcone (m/z 323.2->m/z 119.0), bavachinin (m/z 337.2->m/z 119.0), corylifol A (m/z 389.2->m/z 277.0) and liquiritigenin (Internal Standard, m/z 255.1->m/z 119.0). Chromatographic separation of the above mentioned components was conducted on a Waters BEH-C18 column (100 mm*2.1mm, 1.7MUm) with gradient elution system at flow rate of 0.3mL/min. The mobile phase was composed of acetonitrile and 0.1% formic acid solution. The lower limit of quantification (LLOQ) for each of the above analytes was 0.5ng/mL. Each of the analytes exhibited good linearity within the concentration range of 0.5-100ng/mL. The method was fully validated for its selectivity, accuracy, precision, stability, matrix effect and extraction recovery. The validated method has been successfully applied for simultaneous determination of the 5 flavonoids in rat plasma for the first time. PMID- 26773882 TI - Comprehensive validation of a liquid chromatography-tandem mass spectrometry method for the confirmation of chloramphenicol in urine including stability of the glucuronide conjugate and efficiency of deconjugation. AB - This paper describes a method to reveal the illegal use of chloramphenicol (CAP) in animals intended for human consumption based on the detection of free CAP and chloramphenicol-glucuronide (CAP-glu) in urine. It details the different steps of the method, including hydrolysis of CAP-glu, extraction and cleanup with molecularly imprinted polymers and detection by LC-MS/MS, as well as the validation design. The efficiency of chloramphenicol release during the hydrolysis step and the stability of CAP-glu in urine samples stored at -20 degrees C were also investigated. These verifications were important to ensure the method's suitability for checking CAP misuse in veterinary medicine. Validation results were fully compliant with the qualitative and quantitative criteria required by European regulations. Intraday relative standard deviations were all below 7.5%, while interday relative standard deviations were below 6.9%. Recoveries lay between 93.3 and 104.6%. Purification appears very effective since no matrix effect was demonstrated. CAP-glu was found to be stable for at least 3 months, and the mean recovery following deconjugation was assessed to be 79.4%. The decision limits (CCa) were all found to be lower than 0.1MUg/kg. PMID- 26773883 TI - A stability-indicating HPLC method for simultaneous determination of morphine and naltrexone. AB - This study developed a stability-indicating reversed-phase HPLC method for the simultaneous determination of morphine sulfate and naltrexone hydrochloride content in bulk, Solid dosage forms and in-vitro dissolution samples to support product development and quality control efforts. Chromatographic separation of the pharmaceutical compound was achieved on a perfectSilTM MZ C18 column (250*4.6mm, 5MUm) with an isocratic mobile phase composed of a mixture of acetate buffer (10mM, pH 4, containing 0.1% of 1-heptanesulfonic acid sodium salt) and acetonitrile with 80/20 at a flow rate of 1.5mlmin(-1). Both analytes were quantified using a photodiode array detector set at a wavelength of 280nm and column temperature was set to 30 degrees C. naltrexone, morphine and a mixture of the two were subjected to thermal, peroxide, acid, base and photolytic degradation and their peak homogeneity was obtained using a photodiode array detector, demonstrating the specificity of method. These pharmaceuticals were spiked in biological fluid to examine method selectivity. The method was validated for system suitability, linearity, accuracy, precision, detection and quantification limits and robustness and was found it is acceptable in range of 2 250MUgml(-1) for morphine and 4-100MUgml(-1) for naltrexone. PMID- 26773884 TI - Determination of metabolites of di(2-ethylhexyl) terephthalate (DEHTP) in human urine by HPLC-MS/MS with on-line clean-up. AB - Di(2-ethylhexyl) terephthalate (DEHTP) is used as a substitute for ortho phthalate based plasticizers like di(2-ethylhexyl) phthalate (DEHP) which are discussed and regulated due to their reproductive toxicity. We developed a fast and rugged method to quantify side chain oxidized monoesters of DEHTP in human urine, namely 5OH-MEHTP, 5oxo-MEHTP, 2cx-MMHTP and 5cx-MEPTP. Sample preparation was kept simple with enzymatic deconjugation and a two column assembly for on line sample clean up. Metabolites were identified with authentic standards and quantified via isotope dilution LC-MS/MS. The limit of quantification was 0.2MUg/L for 5cx-MEPTP and 5oxo-MEHTP, 0.3MUg/L for 5OH-MEHTP and 0.4MUg/L for 2cx-MMHTP. Accuracy (relative recovery: 95.8-111%) and precision (relative standard deviation: <7%) were highly acceptable. In a pilot biomonitoring study with 34 volunteers (aged 25-61 (median 42), 20 female and 14 male) not known to be occupationally exposed to DEHTP, we could detect 5cx-MEPTP above the limit of quantification in 94% of the samples (median: 0.9MUg/L, maximum: 38.7MUg/L). The other metabolites investigated were detected at a lower rate and at lower concentration levels (5oxo-MEHTP: 21%, maximum: 1.8MUg/L; 5OH-MEHTP: 18%, maximum: 3.4MUg/L; 2cx-MMHTP: 9%, maximum: 0.9MUg/L). All target analytes can be regarded as promising and specific urinary biomarkers for DEHTP exposure. With this method we provide a basis for quantitatively investigating the human metabolism of DEHTP and for performing exposure and risk assessments in the general population and the working environment. PMID- 26773885 TI - Quantitation of anacetrapib, stable-isotope labeled-anacetrapib (microdose), and four metabolites in human plasma using liquid chromatography tandem mass spectrometry. AB - An ultra-high performance liquid chromatography/tandem mass spectrometry (UPLC MS/MS) method for the simultaneous determination of (4S,5R)-5-[3,5-bis (trifluoromethyl)phenyl]-3-{[4'-fluoro-5'-isopropyl-2'-methoxy-4 (trifluoromethyl)biphenyl-2-yl] methyl}-4-methyl-1,3-oxazolidin-2-one (anacetrapib, I) and [(13)C5(15)N]-anacetrapib, II in human plasma has been developed to support a clinical study to determine the absolute bioavailability of I. The analytes and the stable-isotope labeled internal standard ([(13)C7(15)N(2)H7]-anacetrapib, III) were extracted from 100MUL of human plasma by liquid-liquid extraction using 20/80 isopropyl alcohol/hexane (v/v). The chromatographic separation of the analytes was achieved using Waters BEH Shield RP 18 (50*2.1mm*1.7MUm) column and mobile phase gradient of 0.1% formic acid in water (Solvent A) and 0.1% formic acid in acetonitrile (Solvent B) at 0.6mL/min flow rate. The MS/MS detection was performed on AB Sciex 5000 or AB 5500 in positive electrospray ionization mode, operated in selected reaction monitoring mode. The assay was validated in the concentration range 1-2000ng/mL for I; and a lower curve range, 0.025-50ng/mL for II. In addition to the absolute bioavailability determination, it was desired to better elucidate the pharmacokinetic behavior of several hydroxylated metabolites of I. Toward this end, two exploratory assays for the hydroxy metabolites of I were qualified in the concentration range 0.5-500ng/mL. All metabolites were separated on a Supelco Ascentis Express Phenyl-Hexyl (50*2.1mm, 2.7MUm) column. Metabolite M4 was analyzed in the negative mode with a mobile phase consisting of a gradient mixture of water (A) and acetonitrile (B). The other three metabolites, M1-M3 were analyzed in the positive mode using a mobile phase gradient of water with 0.1% formic acid (A) and acetonitrile with 0.1% formic acid (B). The assays were utilized to support a clinical study in which a microdosing approach was used to determine the pharmacokinetics of anacetrapib and its metabolites. PMID- 26773886 TI - Simultaneous determination of tedizolid and linezolid in rat plasma by ultra performance liquid chromatography tandem mass spectrometry and its application to a pharmacokinetic study. AB - A sensitive and rapid ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method was developed to determine tedizolid and linezolid in rat plasma simultaneously. Chromatographic separation was carried out on an Acquity UPLC BEH C18 column and mass spectrometric analysis was performed using a XEVO TQD triple quadruple mass spectrometer coupled with an electrospray ionization (ESI) source in the positive ion mode. Multiple reaction monitoring (MRM) mode was used for quantification using target fragment ions m/z 371.4->343.2 for tedizolid, and m/z 338.3->56.1 for linezolid. This assay method has been fully validated in terms of selectivity, linearity, recovery and matrix effect, accuracy, precision and stability. The linearity of this method was found to be within the concentration range of 5-5000ng/mL for tedizolid, and 10 10,000ng/mL for linezolid in rat plasma, respectively. Only 3.0min was needed for an analytical run. This assay was used to support a preclinical study where multiple oral doses were administered to rats to investigate the pharmacokinetics of tedizolid and linezolid. PMID- 26773888 TI - Preparative separation of sesamin and sesamolin from defatted sesame meal via centrifugal partition chromatography with consecutive sample injection. AB - A preparative separation method using consecutive sample injection centrifugal partition chromatography (CPC) was developed to obtain sesamin and sesamolin from defatted sesame meal extracts. A two-phase solvent system consisting of n-hexane ethyl acetate-methanol-water (8:2:8:2, v/v) was applied in reversed-phase mode (descending mode). Preliminary experiments with an SCPC-100 (column volume: 100mL) were performed to select the appropriate two-phase solvent system and sample injection times; these parameters were then used with an SCPC-1000 (column volume: 1000mL) in a 10-fold scale-up preparative run. A sample containing 3g of crude extract was consecutively injected four times onto the SCPC-1000, which yielded 328mg of sesamin and 168mg of sesamolin. These compounds were analyzed by high-performance liquid chromatography and determined to have purities of 95.6% and 93.9%, respectively. Sesamin and sesamolin (30MUM) increased antioxidant response element (ARE) luciferase activity 2.6-fold and 1.9-fold, respectively. PMID- 26773889 TI - Capillary electrophoresis of RNA in hydroxyethylcellulose polymer with various molecular weights. AB - Recent research demonstrates that large numbers of long noncoding RNAs (lncRNAs) in mammals exhibit indices of functionality, and thus analysis of longer RNAs is of great significance. In the present work, we investigated the effect of molecular weight on the separation performance of long RNA by capillary electrophoresis (CE). Results demonstrate that (1) low molecular weight of hydroxyethylcellulose (HEC) (90k) favors the separation of short RNA (<1000 nt). The resolution for short RNA was improved and the migration time was linearly extended with the increase of polymer concentration. (2) In the longer chain HEC (250k, 720k and 1300k), the resolution for the small RNA fragment (<1000 nt) became better as the polymer concentration increased, whereas the resolution for the large ones (>3000 nt) deteriorated. (3) Based on logarithmic plot, there exist two migration regimes for RNA in short chain HEC (90k), three regimes in moderate chain HEC (250k and 720k), and four regimes in the long chain HEC (1300k). Such a systematic investigation of long RNAs may be useful for research on lncRNAs in the length range of 100-10,000 nt. PMID- 26773887 TI - Separation and preparation of 6-gingerol from molecular distillation residue of Yunnan ginger rhizomes by high-speed counter-current chromatography and the antioxidant activity of ginger oils in vitro. AB - Molecular distillation residue (MD-R) from ginger had the most total phenol content of 247.6mg gallic acid equivalents per gram (GAE/g) among the ginger oils. High-speed counter-current chromatography (HSCCC) technique in semi preparative scale was successfully performed in separation and purification of 6 gingerol from MD-R by using a two-phase solvent system composed of n-hexane-ethyl acetate-methanol-water (10:2:5:7, v/v/v/v). The target compound was isolated, collected, purified by HSCCC in the head-tail mode, and then analyzed by HPLC. A total of 90.38+/-0.53mg 6-gingerol was obtained from 600mg MD-R, with purity of 99.6%. In addition, the structural identification of 6-gingerol was performed by EI/MS, (1)H NMR and (13)C NMR. Moreover, the orders of antioxidant activity were vitamin E (VE)>supercritical fluid extraction oleoresin (SFE-O)=MD-R=6 gingerol>molecular distillation essential oil (MD-EO) and butylated hydroxytoluene (BHT)=VE>6-gingerol>MD-R=SFE-O>MD-EO, respectively in 2,2-diphenyl 1-picrylhydrazyl radical (DPPH) scavenging and beta-Carotene bleaching. PMID- 26773890 TI - Determination of manassantin B in rat plasma using a high performance liquid chromatography with fluorescence detection and its quantitative application to pharmacokinetic study. AB - A simple, sensitive, rapid, and reproducible analytical method of manassantin B in rat plasma by high performance liquid chromatography with fluorescence detection (HPLC-FL) was developed for its application to pharmacokinetic study in rats. Valsartan (VST) was used as an internal standard (IS) in this quantitative analytical method. Manassantin B and VST were extracted by simple and efficient protein precipitation method. Manassantin B was detected at 282/322nm (excitation/emission) wavelengths using FL detector. The chromatographic separation was obtained with reverse phase C18 column and the mobile phase composed of potassium phosphate buffer containing 0.025% trifluoroacetic acid (pH 2.5; 5mM) and acetonitrile including 0.025% trifluoroacetic acid (20:80, v/v) at 1.0mL/min flow rate. The linearity was established at 25.0-10000ng/mL and the lower limit of detection (LLOD) was 7ng/mL. The intra- and inter-day accuracy and precision values of manassantin B were within+/-15% of the theroretical values and <9% from the nominal concentrations, respectively. Accuracy and precision values of manassantin B after stability tests were also within the acceptable ranges. Developed assay was also successfully applied to pharmacokinetic study after intravenous administration of manassantin B in rats. PMID- 26773891 TI - Trace determination of antibacterial pharmaceuticals in fishes by microwave assisted extraction and solid-phase purification combined with dispersive liquid liquid microextraction followed by ultra-high performance liquid chromatography tandem mass spectrometry. AB - A novel pretreatment method involving microwave-assisted extraction and solid phase purification combined with dispersive liquid-liquid microextraction (MAE SPP-DLLME) followed by ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) was established for the simultaneous determination of six antibacterial pharmaceuticals including metronidazole, tinidazole, chloramphenicol, thiamphenicol, malachite green and crystal violet. The conditions of MAE were optimized using an orthogonal design and the optimal conditions were found to be 8mL for acetonitrile, 50 degrees C for 5min. Then, neutral alumina column was employed in the solid-phase purification. Finally, the critical parameters affecting DLLME, including selection of extraction and dispersive solvent, adjustment of pH, salt concentration, extraction time, were investigated by single factor study. Under optimum conditions, good linearities (r>0.9991) and satisfied recoveries (Recoveries>87.0%, relative standard deviation (RSD)<6.3%) were observed for all of the target analytes. The limits of detection and quantification were 4.54-101.3pgkg(-1) and 18.02-349.1pgkg(-1), respectively. Intra-day and inter-day RSDs were all lower than 3.6%. An obvious reduction in matrix effect was observed by this method compared with microwave assisted extraction followed by purification. The established method was sensitive, rapid, accurate and employable to simultaneously determine target analytes in farmed fish, river fish and marine fish. PMID- 26773892 TI - Development of a matrix solid-phase dispersion extraction combined with high performance liquid chromatography for determination of five lignans from the Schisandra chinensis. AB - A method based on a simplified sample extraction by matrix solid phase dispersion (MSPD) followed by HPLC determination is validated for analysis of five lignans in Schisandra chinensis. The MSPD parameters that affect the extraction efficiency of lignans from S. chinensis were examined and optimized. The optimal extraction conditions were determined to be that silica gel was used as dispersing sorbent, the ratio of silica gel to sample mass was selected to be 2:1, and 4mL of methanol was used as elution solvent. The method recoveries were determined to be from 92.25 to 101.17% and the RSDs from 1.3 to 4.9%. The extraction yields of five lignans obtained by the MSPD were higher than those of traditional reflux and sonication extraction with reduced requirements on sample, solvent and time. In addition, the optimized method was applied for analyzing five real S. chinensis samples obtained from different cultivated areas. PMID- 26773893 TI - Cell membrane chromatography coupled with UHPLC-ESI-MS/MS method to screen target components from Peucedanum praeruptorum Dunn acting on alpha1A adrenergic receptor. AB - Peucedanum praeruptorum Dunn (BaiHuaQianHu in Chinese) is a traditional Chinese medicine that has a long history of use in China. In this study, HEK 293 alpha1A adrenergic cell membrane chromatography was coupled with UHPLC-ESI-MS/MS and successfully used to identify active components from Peucedanum praeruptorum Dunn. Paeruptorin A, paeruptorin B, and paeruptorin C were identified with alpha1A adrenergic receptor activity. Pharmacological assays showed that tamsulosin hydrochloride, paeruptorin A, paeruptorin B, and paeruptorin C in concentrations of 1*10(-8) to 1*10(-4)mol/mL could relax prostate strips pre contracted with adrenalin in a concentration dependent manner. Therefore, the HEK293 alpha1A cell membrane chromatography coupled UHPLC-ESI-MS/MS system may be a potentially useful drug discovery method for screening for medicinal herbal components with alpha1A adrenergic receptor inhibitory activity. PMID- 26773894 TI - Fast and sensitive quantification of human liver cytosolic lithocholic acid sulfation using ultra-high performance liquid chromatography-tandem mass spectrometry. AB - Detoxification of lithocholic acid (LCA) to lithocholic acid sulfate (LCA-S) is catalyzed by sulfotransferases, mainly SULT2A1. We developed and validated an ultra-high performance liquid chromatography-tandem mass spectrometric (UPLC MS/MS) method to quantify human liver cytosolic-dependent LCA sulfation. Chromatographic separation was achieved on an UPLC C18 column (2.1*50mm, 1.7MUm) and a gradient elution of 0.1% formic acid in water and acetonitrile. Negative electrospray ionization with multiple reaction monitoring (MRM) mode was used to quantify LCA-S (455.3->97.0) and cholic acid (407.2->343.3; internal standard). The retention time was 3.51min for LCA-S and 3.08min for cholic acid. The lower limit of quantification of LCA-S was 0.5nM (or 0.23ng/ml in 400MUl total volume) and the assay was linear from 0.2 to 200pmol. Intra-day and inter-day accuracy and precision were <14%. The quality control samples were stable at room temperature for 4h, 4 degrees C for 24h, -20 degrees C for 14 days, and after three freeze-thaw cycles. The matrix (20-100MUg cytosolic protein) did not affect LCA-S quantification. This is the first UPLC-MS/MS method applied to optimization of the human liver cytosolic LCA sulfation assay. The optimal levels of MgCl2 and 3'-phosphoadenosine 5'-phosphosulfate (PAPS) cofactor were 2.5mM and 20MUM, respectively. Addition of reducing agents (2-mercaptoethanol and DL dithiothreitol) did not affect LCA-S formation. Human liver cytosolic LCA sulfation was linear with 20-100MUg of cytosolic protein and 5-30min incubation time. This UPLC-MS/MS approach offers a specific, sensitive, fast, and direct approach for quantifying human liver cytosolic LCA sulfation. PMID- 26773896 TI - The AAOMS Informational Campaign - Is it Succeeding? PMID- 26773895 TI - Comparative UPLC-QTOF-MS-based metabolomics and bioactivities analyses of Garcinia oblongifolia. AB - Garcinia oblongifolia Champ. ex Benth. (Clusiaceae) is a well-known medicinal plant from southern China, with edible fruits. However, the phytochemistry and bioactivity of the different plant parts of G. oblongifolia have not been studied extensively. Comparative metabolic profiling and bioactivities of the leaf, branch, and fruit of G. oblongifolia were investigated. A total of 40 compounds such as biflavonoids, xanthones, and benzophenones were identified using UPLC QTOF-MS and MS(E), including 15 compounds reported for the first time from this species. Heatmap analyses found that benzophenones, xanthones, and biflavonoids were predominately found in branches, with benzophenones present in relatively high concentrations in all three plant parts. Xanthones were found to have limited distribution in fruit while biflavonoids were present at only low levels in leaves. In addition, the cytotoxic (MCF-7 breast cancer cell line) and antioxidant (ABTS and DPPH chemical tests) activities of the crude extracts of G. oblongifolia indicate that the branch extract exhibits greater bioactivity than either the leaf or the fruit extracts. Orthogonal partial least squares discriminate analysis was used to find 12 marker compounds, mainly xanthones, from the branches, including well-known antioxidants and cytotoxic agents. These G. oblongifolia results revealed that the variation in metabolite profiles can be correlated to the differences in bioactivity of the three plant parts investigated. This UPLC-QTOF-MS strategy can be useful to identify bioactive constituents expressed differentially in the various plant parts of a single species. PMID- 26773897 TI - "Just dreaming of them": The Berlin Project for Primary Prevention of Child Sexual Abuse by Juveniles (PPJ). AB - The Berlin Project for Primary Prevention of Child Sexual Abuse by Juveniles (PPJ) offers diagnostic and therapeutic help to 12-to-18-year-old juveniles with a sexual preference for the prepubescent and/or early pubescent body of children and who apply for treatment on a voluntary basis. The project goal is to prevent primary or recurrent child sexual abuse as well as primary or recurrent use of child abuse images. Treatment aims to enable affected juveniles to obtain control over their conflictual sexual behaviors. In the present article, the origin of the PPJ; its main approach, including the conception of a media campaign; as well as results from the first year of a three-year study are presented. Further, initial characterizations of juveniles taking part in the project for the first 12 months are provided. The results confirmed that the group of 12-to-18-year-old juveniles with a sexual preference for prepubescent and/or early pubescent minors exists as a target group for primary preventive measures and that they can be assessed for their sexual preferences. PMID- 26773898 TI - Weight status and bullying behaviors among Chinese school-aged children. AB - This study was to examine the relationship between measured weight status and three experiences as victims, bullies and bully-victims. The participants were 10,587 Chinese school-aged students (girls: 5,527, boys: 5,060) who ranged in age from 7 to 18 years old. Height and weight were measured. Bullying behavior was obtained by one-to-one interview in 7-10 years older students and group administered surveys in 11-18 years older students. The results showed that, obese girls were more likely to be victimized (OR=1.73, CI: 1.16-2.59) compared to normal students. For boys, obesity was not associated with victimization, but obese boys (OR=1.45, CI: 1.04-2.03), especially 7-13 years old boys (OR=1.98, CI: 1.35-2.90) were more likely to bully others; obese boys also were more likely to be victim/bullies (OR=1.67, CI: 1.05-2.64). Weight victimization in Chinese school-aged children is not as common as in the west countries, but obese girls clearly realize more victimization, and obese younger boys show obvious aggression. Related departments should provide specific intervention for school bullying according students' weight status, age and gender. PMID- 26773899 TI - Measuring euthymia within the Neuroticism Scale from the NEO Personality Inventory: A Mokken analysis of the Norwegian general population study for scalability. AB - BACKGROUND: Whereas the Eysenck Neuroticism Scale only contains items covering negative mental health to measure dysthymia, the NEO Personality Inventory (NEO PI) contains neuroticism items covering both negative mental health and positive mental health (or euthymia). The consequence of wording items both positively and negatively within the NEO-PI has never been psychometrically investigated. The aim of this study was to perform a validation analysis of the NEO-PI neuroticism scale. METHODS: Using a Norwegian general population study we examined the structure of the negatively and positively formulated items by principal component analysis (PCA). The scalability of the identified two groups of euthymia versus dysthymia items was examined by Mokken analysis. RESULTS: With a response rate of 90%, 1082 individuals with a completed NEO-PI were available. The PCA identified the neuroticism scale as the most distinct where 14 items had acceptable loadings for the euthymia subscale, another 14 items for the dysthymia subscale. However, the Mokken analysis coefficient of homogeneity only found acceptable scalability for the euthymia subscale. LIMITATIONS: A comparison with the Eysenck Neuroticism Scale was not performed. CONCLUSION: The NEO-PI neuroticism scale contains two subscales consisting of items worded in an opposite direction where only the positive euthymia items have an acceptable scalability. PMID- 26773900 TI - Cannabis use, depression and anxiety: A 3-year prospective population-based study. AB - BACKGROUND: Whether or not cannabis use may increase the risk for depression and/or anxiety is not clear. For one thing, it has not been possible to draw a definitive conclusion regarding the direction of causality, i.e. whether cannabis use increases the risk for depression/anxiety or vice versa. This study aimed at examining possible associations between cannabis use, depression and anxiety, using all three measures as both exposure and outcome. METHODS: Data were obtained from a longitudinal cohort study comprising 8598 Swedish men and women, aged 20-64, with a three-year-follow-up. RESULTS: Adjusted for sex and age, cannabis use at baseline was associated with an increased relative risk (RR) for depression and anxiety at follow-up, with RR=1.22 [1.06-1.42 Cl 95%] for depression and RR=1.38 [1.26-1.50 Cl 95%] for anxiety. Adjusted for all confounders (alcohol and illicit drug use, education, family tension, place of upbringing), the associations were no longer statistically significant; RR=0.99 [0.82-1.17 Cl 95%] for depression and RR=1.09 [0.98-1.20 Cl 95%] for anxiety. Age adjusted, reporting depression or anxiety at baseline increased the risk of cannabis onset at follow-up three years later; RR=1.62 [1.28-2.03 CI 95%] and RR=1.63 [1.28-2.08 CI 95%] respectively. However, adjusted for other illicit drug use the associations were no longer statistically significant. LIMITATIONS: Lack of information on frequency of cannabis use and of age of initiation of use. CONCLUSIONS: We found no longitudinal associations between cannabis use and incidence of depression/anxiety, or between depression/anxiety and later cannabis use onset. PMID- 26773902 TI - Depressive symptomatology and the influence of the behavioral avoidance and activation: A gender-specific investigation. AB - BACKGROUND: Depression is a highly prevalent disorder which is usually considered as differentially experienced depending on gender. Behavioral theories of depression pinpoint the importance of the behavioral avoidance in the maintenance of depression. However, little is known about the specific impact of the behavioral avoidance and activation on each depressive symptom as well as on gender differences on the behavioral features of depression. METHODS: This study's aim was two-fold: (1) to assess the presence of gender differences on the BDI-II; (2) to investigate the respective predictive value of behavioral avoidance and of behavioral activation on each depressive symptom assessed by the BDI-II depending on gender. Community adults and adults attending mental healthcare composed the sample. RESULTS: Results showed differences in symptomatology profiles depending on gender (e.g. higher scores of sadness, self criticalness in women, higher scores of past failure and loss of pleasure in men). Behavioral avoidance positively predicted almost all depressive symptoms in women and in men while behavioral activation negatively predicted almost all symptoms in both gender. Nevertheless, the strengths of these relationships were different for some symptoms (e.g. pessimism). LIMITATIONS: The use of self-report instruments; the lack of assessment of causal or precipitating factors of the depressive symptomatology; the higher number of women in the sample. CONCLUSIONS: Results are discussed with respect to previous findings and present clinical implications: (1) to underline the relevance of the combination of gender specific assessment tools; (2) to highlight the need of tailored psychological intervention. PMID- 26773903 TI - Biodiversity patterns of soil ciliates along salinity gradients. AB - We evaluated ciliate diversity in saline soils with a salinity range from 6.5 to 65 psu by the morphological method of the Ludox-quantitative protargol stain (QPS) and the molecular techniques of ciliate-specific clone library and denaturing gradient gel electrophoresis. No active ciliates could be detected with the Ludox-QPS method, while high molecular diversity of ciliates was found. The highest ciliate molecular diversity was obtained from the soil at salinity of 8.9 psu, moderate diversity was found at salinity of 6.5 psu, and the diversity sharply decreased at salinity of 50.5 psu. By contrast, the number of ciliate classes clearly decreased with increasing soil salinity: six, five, four and two classes from sites with salinity of 6.5 psu, 8.9 psu, 29.5 psu and 50.5 psu, respectively. Ciliate diversity pattern is different from that of bacteria, whose diversity is also high in extremely saline environments. Meanwhile, the composition of ciliate community was significantly different along salinity gradient. Colpodea and Oligohymenophorea were diverse in soils at salinity less than 29.5 psu, while absent in soils with salinity above 50.5 psu. BIOENV analysis indicated soil salinity and water content were the main factors regulating the distribution of ciliates in saline soils. PMID- 26773901 TI - Identifying a clinical signature of suicidality among patients with mood disorders: A pilot study using a machine learning approach. AB - OBJECTIVE: A growing body of evidence has put forward clinical risk factors associated with patients with mood disorders that attempt suicide. However, what is not known is how to integrate clinical variables into a clinically useful tool in order to estimate the probability of an individual patient attempting suicide. METHOD: A total of 144 patients with mood disorders were included. Clinical variables associated with suicide attempts among patients with mood disorders and demographic variables were used to 'train' a machine learning algorithm. The resulting algorithm was utilized in identifying novel or 'unseen' individual subjects as either suicide attempters or non-attempters. Three machine learning algorithms were implemented and evaluated. RESULTS: All algorithms distinguished individual suicide attempters from non-attempters with prediction accuracy ranging between 65% and 72% (p<0.05). In particular, the relevance vector machine (RVM) algorithm correctly predicted 103 out of 144 subjects translating into 72% accuracy (72.1% sensitivity and 71.3% specificity) and an area under the curve of 0.77 (p<0.0001). The most relevant predictor variables in distinguishing attempters from non-attempters included previous hospitalizations for depression, a history of psychosis, cocaine dependence and post-traumatic stress disorder (PTSD) comorbidity. CONCLUSION: Risk for suicide attempt among patients with mood disorders can be estimated at an individual subject level by incorporating both demographic and clinical variables. Future studies should examine the performance of this model in other populations and its subsequent utility in facilitating selection of interventions to prevent suicide. PMID- 26773905 TI - Bottom-up versus top-down effects on ciliate community composition in four eutrophic lakes (China). AB - Previous studies have shown that ciliate plankton is generally controlled by food resources (e.g., algae) and predators (e.g., metazooplankton). Among lakes with similar trophic levels but different distributions of phyto- and metazooplankton, the main forces acting on ciliate assemblages may be different. We investigated the relationship between ciliate communities and bottom-up versus top-down variables based on a survey of four subtropical eutrophic lakes (China). Two of the lakes (Chaohu, Taihu) are located on the Mid-lower Yangtze Plain near sea level, and the other two (Dianchi, Xingyunhu) on the Yunnan-Kweichow Plateau at 1700 m above sea level. Blooms of cyanobacteria developed during summer in Lakes Chaohu and Taihu and throughout the year in Lakes Dianchi and Xingyunhu. Ciliate functional feeding groups differed significantly between lakes. The results of canonical correspondence analysis (CCA) and variation partitioning showed that cyanobacteria significantly influence ciliate species, whereas 'edible' algae (cryptophytes, diatoms) and cladocerans were the important variables in explaining the ciliate community structure of Lakes Dianchi and Xingyunhu compared with Lakes Taihu and Chaohu. Our results highlight the importance of consistent cyanobacterial blooms in shaping the ciliate community in subtropical eutrophic shallow lakes by interacting with top-down and bottom-up factors. PMID- 26773904 TI - Ciliate communities and hidden biodiversity in freshwater biotopes of the Pistoia province (Tuscany, Italy). AB - Ciliates are essential components of aquatic environments, playing a pivotal role in microbial loops. Thus, the composition and dynamics of ciliate communities have been subjected to intense studying. Morphological methods have been traditionally employed, until the development of next-generation sequencing recently allowed to explore the topic with exclusively molecular techniques. However, the results of the two approaches are hardly comparable, and the pictures they offer can be quite different. This may be due, among other reasons, to two factors: (1) morphological descriptions may miss a large portion of "hidden biodiversity" (including rare species and resistance forms) that is detected instead by molecular methods; (2) identification errors may arise due to difficulties in recognizing microbial taxa without in-depth analyses. In this survey of freshwater systems of the Pistoia province (Tuscany, Italy) we address both issues, trying to quantify the hidden diversity through prolonged observations of differentially treated sample aliquots, combining morphological identification with Sanger sequencing. We provide the first insights into the ciliate fauna of this area presenting results that are suitable for future comparisons thanks to their multidisciplinary origin, and supply the first molecular data on well-known taxa such as Linostomella and Disematostoma. PMID- 26773906 TI - The effects of levomilnacipran ER in adult patients with first-episode, highly recurrent, or chronic MDD. AB - BACKGROUND: Major depressive disorder (MDD) can be challenging to manage due its variable and episodic nature. Post hoc analyses were conducted on five studies (NCT00969709, NCT01377194, NCT00969150, NCT01034462, EudraCT:2006-002404-34) to evaluate the efficacy of levomilnacipran extended-release (ER) in patients with different MDD episode histories. METHODS: Adults with MDD were randomized to double-blind treatment with levomilnacipran ER (40-120mg/d) or placebo. Three subgroups were identified: first-episode (n=494); highly recurrent (>=3 major depressive episodes; n=1954); and chronic (current episode duration >=2 years; n=218). Mean changes from baseline to end of study (Week 8 [US studies], Week 10 [non-US study]) in Montgomery-Asberg Depression Rating Scale (MADRS), 17-item Hamilton Depression Rating Scale (HAMD17), and Sheehan Disability Scale (SDS) total scores were analyzed in each subgroup. MADRS response, defined as >=50% total score improvement from baseline to Week 8/10, was also analyzed. RESULTS: Least squares mean differences (LSMDs) between treatment groups indicated significantly greater improvements with levomilnacipran ER versus placebo in MADRS (first-episode, -2.5; highly recurrent, -3.0; chronic, -4.9; all P<.05) and HAMD17 (first-episode, -2.1; highly recurrent, -1.6; chronic, -2.6; all P<.05) total scores. LSMDs for SDS total score were statistically significant in the first-episode and highly recurrent MDD subgroups (both subgroups, -2.3; P<.01). MADRS response rate was significantly higher with levomilnacipran ER versus placebo in all three subgroups (first-episode, 44.5% versus 35.0%; highly recurrent, 44.3% versus 33.5%; 36.8% versus 22.0%; all P<.05). LIMITATIONS: MDD subgroups were defined post hoc; none of the studies were prospectively designed to evaluate outcomes in these subgroups. Other limitations include lack of active comparators and variability of dose/duration due to data being pooled from multiple clinical trials. CONCLUSIONS: Results suggest that levomilnacipran ER improves depression symptoms and functional impairment in adult patients with different histories of MDD episodes. PMID- 26773908 TI - Anxiety symptom interpretation: A potential mechanism explaining the cardiorespiratory fitness-anxiety relationship. AB - BACKGROUND: Higher cardiorespiratory fitness is associated with lower trait anxiety, but research has not examined whether fitness is associated with state anxiety levels and the interpretation of these symptoms. The aim of this paper was to (1) reexamine the association between cardiorespiratory fitness and general anxiety and (2) examine anxiety intensity and perceptions of these symptoms prior to an acute psychological stress task. METHODS: Participants (N=185; 81% female; Mage=18.04, SD=0.43 years) completed a 10-minute Paced Serial Addition Test. General anxiety was assessed using the anxiety subscale of the Hospital Anxiety Depression Scale. Cognitive and somatic anxiety intensity and perceptions of symptoms was assessed immediately prior to the acute psychological stress task using the Immediate Anxiety Measures Scale. Cardiorespiratory fitness was calculated using a validated standardized formula. RESULTS: Higher levels of cardiorespiratory fitness were associated with lower levels of general anxiety. Path analysis supported a model whereby perceptions of anxiety symptoms mediated the relationship between cardiorespiratory fitness and levels of anxiety experienced during the stress task; results remained significant after adjusting for general anxiety levels. Specifically, higher levels of cardiorespiratory fitness were positively associated with more positive perceptions of anxiety symptoms and lower levels of state anxiety. LIMITATIONS: A standard formula rather than maximal testing was used to assess cardiorespiratory fitness, self report questionnaires were used to assess anxiety, and the study was cross sectional in design. CONCLUSIONS: Results suggest a potential mechanism explaining how cardiorespiratory fitness can reduce anxiety levels. PMID- 26773907 TI - The temporal course and clinical correlates of subjective impulsivity in bipolar disorder as revealed through ecological momentary assessment. AB - BACKGROUND: Impulsivity is frequently linked with bipolar disorder and is associated with mania and negative outcomes. The temporal dynamics of subjective impulsivity are unclear, in particular whether impulsivity precedes or follows changes in positive or negative affect. METHODS: A total of 41 outpatients with bipolar disorder (I or II) were provided with mobile devices for 11 weeks and completed twice-daily surveys about affective states and subjective impulsivity. We examined the association between aggregate subjective impulsivity with baseline global cognitive function, suicide risk ratings, and medication adherence, as well as concurrent and lagged associations with momentary positive and negative affect ratings. RESULTS: A total of 2902 ratings were available across study subjects. Higher aggregate mean ratings of impulsivity were associated with worse baseline global cognitive function, prior suicide attempts, and self-reported problems with medication adherence, as well as more severe manic (but not depressive) symptoms. Time-lagged models indicated that greater negative affect, but not positive affect, predicted subsequent increases in subjective impulsivity, which, in turn, predicted diminished positive affect. LIMITATIONS: Other measures of impulsivity with which to validate subjective ratings were unavailable and the sample was restricted to generally clinically stable outpatients. CONCLUSIONS: Subjective impulsivity as measured by daily monitoring was associated with worse cognitive function and self-rated medication adherence, and higher suicide risk ratings. Impulsivity may be a maladaptive strategy to regulate negative affect in bipolar disorder. PMID- 26773909 TI - Gender differences in depression and pain: A two year follow-up study of the Survey of Health, Ageing and Retirement in Europe. AB - BACKGROUND: The longitudinal association of depression and pain according to gender was investigated using a population-based sample from 13 European countries. METHODS: The study population was taken from waves 4-5 of the Survey of Health, Ageing and Retirement in Europe. The sample consisted of 22,280 participants >=50 years, who were interviewed at baseline, and after two years. Regression models for each gender were used to assess the variables associated with depression and pain incidence and persistence. RESULTS: Prevalences of depression, pain, and depression-pain co-occurrence, were higher in women than in men (depression: 34.5% vs. 20.3%; OR=2.1; 95% CI=1.9-2.2; pain: 60.2% vs. 53.5%; OR=1.3; 95% CI=1.2-1.4; co-occurrence 25.3% vs. 14.0%; OR=2.3; 95% CI=2.2-2.6). Treated baseline pain in women (OR=1.6; 95% CI=1.3-2.0), and treated/untreated pain in men (untreated OR=1.3; 95% CI=1.1-1.7; treated OR=2.0; 95% CI=1.5-2.7), were associated with incident depression. Untreated baseline depression was associated with incident pain (women OR=1.3; 95% CI=1.1-1.7; men OR=1.8; 95% CI=1.3-2.6), and with persistent pain only in women (OR=1.3; 95% CI=1.1-1.6). LIMITATIONS: We lack information on pain severity, and the consumption of analgesics was used as a proxy. We lack information on antidepressants and anxiolytics consumption separately. Participants were interviewed twice in two years, and pain/depression at both interviews were considered persistent although they may have relapsed and recurred. CONCLUSIONS: Treated baseline pain is a risk factor for incident depression in both genders; untreated baseline pain is a risk factor only in men. Treating depression at baseline may protect from developing pain in both genders, and in women, it may also protect from pain persistence. PMID- 26773911 TI - Employment status, employment functioning, and barriers to employment among VA primary care patients. AB - BACKGROUND: Prior research found lower employment rates among working-aged patients who use the VA than among non-Veterans or Veterans who do not use the VA, with the lowest reported employment rates among VA patients with mental disorders. This study assessed employment status, employment functioning, and barriers to employment among VA patients treated in primary care settings, and examined how depression and anxiety were associated with these outcomes. METHODS: The sample included 287 VA patients treated in primary care in a large Midwestern VA Medical Center. Bivariate and multivariable analyses were conducted examining associations between socio-demographic and clinical predictors of six employment domains, including: employment status, job search self-efficacy, work performance, concerns about job loss among employed Veterans, and employment barriers and likelihood of job seeking among not employed Veterans. RESULTS: 54% of respondents were employed, 36% were not employed, and 10% were economically inactive. In adjusted analyses, participants with depression or anxiety (43%) were less likely to be employed, had lower job search self-efficacy, had lower levels of work performance, and reported more employment barriers. Depression and anxiety were not associated with perceived likelihood of job loss among employed or likelihood of job seeking among not employed. LIMITATIONS: Single VA primary care clinic; cross-sectional study. DISCUSSION: Employment rates are low among working-aged VA primary care patients, particularly those with mental health conditions. Offering primary care interventions to patients that address mental health issues, job search self-efficacy, and work performance may be important in improving health, work, and economic outcomes. PMID- 26773912 TI - An investigation of the role of intolerance of uncertainty in hoarding symptoms. AB - BACKGROUND: Hoarding disorder (HD) is a common, debilitating mental illness and public health burden. Understanding the factors that contribute to hoarding is critical for identifying treatment targets. As a relatively new diagnostic entity, this research remains in its initial stages. Intolerance of uncertainty (IU) is thought to be a vulnerability factor for generalized anxiety disorder (GAD) and obsessive-compulsive disorder (OCD), and may also be relevant to HD. We investigated the possible association between IU and hoarding in two sets of analyses. METHOD: First, we administered self-report measures of IU and hoarding symptoms to unscreened undergraduate students (N=456) and used regressions to probe their association controlling for relevant covariates. Second, in a clinical sample, we compared IU across groups of patients with HD (N=26), GAD (N=26), OCD (N=51), other anxiety disorders (N=91) and healthy controls (N=29). RESULTS: In the student sample, IU predicted hoarding symptoms above and beyond relevant covariates, including hoarding-related beliefs. In the clinical sample, HD patients evidenced greater IU relative to healthy individuals and the mixed anxiety group, and comparable levels of IU to the GAD and OCD groups. LIMITATIONS: This study relied exclusively on self-report questionnaires and a cross-sectional design. CONCLUSIONS: IU is associated with hoarding behavior and, as we discuss, conceptual models might benefit from the study of IU as a potentially contributing factor. Directions for future research are discussed. PMID- 26773910 TI - Graph-theoretical analysis of resting-state fMRI in pediatric obsessive compulsive disorder. AB - BACKGROUND: fMRI graph theory reveals resting-state brain networks, but has never been used in pediatric OCD. METHODS: Whole-brain resting-state fMRI was acquired at 3T from 21 children with OCD and 20 age-matched healthy controls. BOLD connectivity was analyzed yielding global and local graph-theory metrics across 100 child-based functional nodes. We also compared local metrics between groups in frontopolar, supplementary motor, and sensorimotor cortices, regions implicated in recent neuroimaging and/or brain stimulation treatment studies in OCD. RESULTS: As in adults, the global metric small-worldness was significantly (P<0.05) lower in patients than controls, by 13.5% (%mean difference=100%X(OCD mean - control mean)/control mean). This suggests less efficient information transfer in patients. In addition, modularity was lower in OCD (15.1%, P<0.01), suggesting less granular - or differently organized - functional brain parcellation. Higher clustering coefficients (23.9-32.4%, P<0.05) were observed in patients in frontopolar, supplementary motor, sensorimotor, and cortices with lower betweenness centrality (-63.6%, P<0.01) at one frontopolar site. These findings are consistent with more locally intensive connectivity or less interaction with other brain regions at these sites. LIMITATIONS: Relatively large node size; relatively small sample size, comorbidities in some patients. CONCLUSIONS: Pediatric OCD patients demonstrate aberrant global and local resting state network connectivity topologies compared to healthy children. Local results accord with recent views of OCD as a disorder with sensorimotor component. PMID- 26773913 TI - Systematic review of research on railway and urban transit system suicides. AB - INTRODUCTION: We critically review research on railway suicides to inform suicide prevention initiatives and future studies, including who is at risk and why, and behaviours at track locations. METHOD: Literature was identified from Scopus, Web of Science, Google Scholar and our documentation centre, and contacting 71 railway companies, resulting in 716 articles and eight unpublished reports, with 94 having empirical data on 55 unique studies. Research quality was critically assessed. RESULTS: The quality of studies varies greatly with frequent shortcomings: no justification of sample size, lacking information on the reliability and validity of measures, no explanation nor theoretical understanding of findings. Railway suicides resemble closely people who use other methods, although they tend to be younger. As with other suicide methods, mental health problems are likely to be present. Railway suicide attempters usually die, but most urban transportation systems attempters survive. Railway suicides are rarely impulsive; people usually go to the railway for the purpose of killing themselves. Hotspots have been the focus of some prevention measures. We know little about why people choose railway suicide, but studies of survivors suggest they often thought they would have an immediate, certain and painless death. Media reports on railway suicides can increase their incidence. CONCLUSIONS: Most research focuses on the incidence and characteristics of events and attempters. Research has not shown that railway suicides are different from suicides by other means. Better quality research is needed, particularly studies that investigate why people use railways to kill themselves and how railway suicides can be effectively prevented, as well as more evaluations of prevention programmes. Because of significant variations by country and region in characteristics of railway suicides, prevention programmes should conduct a local assessment of the characteristics of attempters and incidents. PRACTICAL IMPLICATIONS: We need more research on indicators of suicide risk in attempters on railway property, and studies of how suicidal people on railway property are prevented from suicide. Changing beliefs and attitudes about railway suicides, reducing media reports, offering help onsite, controlling access at hotspots and better staff training in mental health facilities near tracks are promising prevention strategies. However, local specificities must be considered in planning prevention strategies. PMID- 26773914 TI - PTPRR regulates ERK dephosphorylation in depression mice model. AB - BACKGROUND: The Protein tyrosine phosphatase receptor type R (PTPRR), which regulates the dephosphorylation of the downstream mitogen-activated protein kinase (MAPK) steering cell proliferation, apoptosis and synaptic plasticity, may be involved in the pathogenesis of depression. METHODS: Lentiviral vectors were utilized to express the PTPRR constitutively in the hippocampal dentate gyrus (DG) of mice before or after chronic mild stress. Behavior tests, MAPK levels, neuronal apoptosis and cell proliferation in the hippocampal DG were examined. RESULTS: Without chronic mild stress (CMS), the lenti-shPTPRR mice showed shorter immobility time in the tail suspension test than controls, while the lenti-PTPRR mice exhibited significantly less sucrose intake and increased immobility time in the forced swim tests than control mice, indicating increased prodepressant-like effects of PTPRR in lenti-PTPRR mice. Similarly, under CMS, the lenti-shPTPRR mice had more sucrose intake, shorter immobility time in the forced swim test and tail suspension test compared to controls, and lenti-PTPRR mice had less sucrose intake and longer immobility time in forced swim test and tail suspension test, exhibiting increased susceptibility to depressive-like behaviors and greater sensitivity to CMS. Besides, the Phospho-ERK1/2(p-ERK) had significant lower phosphorylation in lenti-PTPRR group and higher expression in lenti-shPTPRR group, both without CMS. The Lenti-PTPRR mice exposed to CMS had significant lower p-ERK, and the lenti-shPTPRR mice exposed to CMS had significant higher p ERK and lower p-P38. Moreover, there were more cells underwent apoptosis in lenti PTPRR group ,with and without CMS. In cell proliferation, less BrdU positive cells were observed in lenti-PTPRR mice than controls. CONCLUSION: The site specific lentiviral injections resulted in the PTPRR over-expression in the hippocampal DG and subsequent increased ERK dephosphorylation, which leads to more neuron apoptosis, less cell proliferation, depression onset and increased sensitivity to CMS. PTPRR/ERK pathway could be potential target for depression therapy. PMID- 26773915 TI - The relationship between rumination, posttraumatic stress disorder, and posttraumatic growth among Chinese adolescents after earthquake: A longitudinal study. AB - BACKGROUND: Posttraumatic stress disorder (PTSD) and posttraumatic growth (PTG) can coexist in individuals following traumatic experiences, and cognitive pathways to PTSD and PTG can be different. Nevertheless, to date, no study using the longitudinal-design has examine the cognitive process of PTSD and PTG, nor has the specific causal relation between cognitive factors and PTSD/PTG been clarified in the aftermath of disaster. Therefore, the aim of this study was to extend previous study from a longitudinal perspective, and further examine the possible cognitive mechanism of PTSD and PTG in a long-time frame after earthquake. METHODS: 310 middle school students in Lushan County were assessed using the Event-Related Rumination Inventory, the Post-Traumatic Growth Inventory and the Child PTSD Symptom Scale at 6 months (T1), 12 months (T2) and 18 months (T3) after the Ya'an earthquake. RESULTS: Intrusive rumination at T2 partly mediated the relationship of intrusive rumination at T1 to PTSD but not PTG at T3. Deliberate rumination at T2 did not mediate the relationship of intrusive rumination at T1 and PTG/PTSD at T3 but completely mediated the relation of intrusive rumination at T2 and PTSD/PTG at T3. LIMITATIONS: All variables were measured by self-report scales. CONCLUSIONS: Intrusive rumination at T1 had an effect on PTSD but not PTG at T3 through intrusive rumination at T2, and it could affect PTSD and PTG at T3 through deliberate rumination at T2. These results suggest that PTSD and PTG are influenced by different mechanisms and that intrusive rumination leads to PTSD, whereas deliberate rumination elicits PTG in a long time after trauma. PMID- 26773916 TI - Altered functioning of the HPA axis in depressed postpartum women. AB - BACKGROUND: The present study aimed to evaluate the relationship between the functioning of the hypothalamic-pituitary-adrenal (HPA) axis and major depressive episodes in the remote postpartum period. METHODS: The sample (mean age, 28.0+/ 5.3 years) consisted of 37 depressed postpartum women (DPP), 42 euthymic postpartum women (EPP) and 25 non-postpartum healthy women (HC). Salivary cortisol samples were collected immediately after awakening and 30min, 3 and 12h later, at approximately the sixth month postpartum (mean, 169.6+/-60.3 days). RESULTS: Differences in cortisol levels were observed at awakening (DPPEPP=HC). The relative increment in the cortisol awakening response (CARi%) was significantly higher in HC (113.5+/-94.3) than in EPP (63.1+/-69.8) and DPP (32.2+/-49.6). The relative reduction in diurnal variation (DVr%) was lower in DPP (56.5+/-41.8) than in EPP (75.6+/-22.4) and HC (75.1+/-13.0). LIMITATIONS: The main limitation was cortisol collection on a single day and without measurement at midnight. CONCLUSIONS: Our findings suggest that the remote postpartum period involves attenuation of HPA axis reactivity; this dysregulation is more pronounced in the presence of DPP, which is associated with a reduction in cortisol diurnal variation. Abnormalities in the neuroendocrine system related to stress processing, present even several months after delivery, can represent vulnerability to mental disorders. Thus, improvements in the mental health care of postpartum women are needed. PMID- 26773917 TI - Impact of physical exercise on catechol-O-methyltransferase activity in depressive patients: A preliminary communication. AB - BACKGROUND: Catechol-O-methyltransferase (COMT) is a catabolic enzyme involved in the degradation of bioactive molecules including the neurotransmitters epinephrine, norepinephrine, and dopamine. Higher COMT activity in depressive patients in comparison to non-depressed individuals has been reported. The effect of aerobic exercise on depressive patients has been studied and a number of researchers and clinicians believe it to be effective in the treatment of depression and to be involved in several molecular underlying mechanisms. However, the effect of physical exercise on this enzyme activity is unknown, and it remains to be elucidated if chronic exercise changes COMT activity. This randomized control trial evaluates the effects of chronic exercise on peripheral COMT (S-COMT) activity in women with depressive disorder. METHODS: Fourteen women (aged: 51.4+/-10.5 years) diagnosed with depression (according to International Classification of Diseases-10) were randomized to one of two groups: pharmacotherapy plus physical exercise (n=7) or only pharmacotherapy (n=7). The aerobic exercise program was supervised, lasting between 45-50min/session, three times/week for 16 weeks. Erythrocyte soluble COMT were assessed prior to and after the exercise program. RESULTS: Exercise group when compared to a control group presented a significant decrease (p=0.02, r=-0.535) in S-COMT activity between baseline and post-intervention. LIMITATIONS: These data are preliminary outcomes from a small sample and should be replicated. CONCLUSIONS: Chronic exercise therapy combined with pharmacotherapy leads to significant decrease in S COMT activity. Our results provide evidence that exercise interferes with S-COMT activity, a molecular mechanism involved in depression. PMID- 26773919 TI - The role of environmental exposures as risk factors for bipolar disorder: A systematic review of longitudinal studies. AB - BACKGROUND: The role of environmental risk factors in the development of bipolar disorder (BD) is not well characterized. We evaluate the prevalence, duration, and predictive value of environmental exposures for BD in longitudinal studies. METHODS: We conducted a systematic search of PubMed, Scopus and PsychINFO databases until April 01, 2015, using the following words in combination: prenatal exposure; maternal exposure; trauma; childhood abuse; alcoholism; cannabis; smoking; cocaine; central stimulants; opioids; uv light; pollution; global warming; vitamin d AND bipolar disorder. Additional references were obtained through cross-referencing. We included (1) longitudinal cohort studies or case-control studies nested within longitudinal designs; (2) studies of subjects without lifetime BD diagnoses at initial assessment and a diagnosis of BD at follow-up by clinical or structured assessment. Familial-risk studies were excluded. We tabulated details of study-design, exposure, diagnostic criteria, risk of bipolar disorder expressed as odd ratio (OR), relative risk (RR) or hazard ratio (HR). RESULTS: Of 2119 studies found, 22 met inclusion criteria. Risk factors identified can be grouped in 3 clusters: neurodevelopment (maternal influenza during pregnancy; indicators of fetal development), substances (cannabis, cocaine, other drugs - opioids, tranquilizers, stimulants, sedatives), physical/psychological stress (parental loss, adversities, abuses, brain injury). LIMITATIONS: Heterogeneity of designs and methodology prevented the use of meta analysis of the findings; studies did not provide sensitivity, specificity and predictive value of the risk factors identified; case-control studies classify cases based on diagnostic membership, but do not control for familial or genetic liability; methods for determining the exposures varied among studies. CONCLUSION: Only preliminary evidence exists that exposure to viral infection, substances or trauma increase the likelihood of BD. Given the limited data available, the specificity, sensitivity and predictive value could not be computed. As exposures are sometimes amenable to prevention, further research is needed. PMID- 26773918 TI - The association of an inability to form and maintain close relationships due to a medical condition with anxiety and depressive disorders. AB - BACKGROUND: While low social support is a risk factor for mental illness, anxiety and depression's relationship with social impairment specifically resulting from a medical condition is poorly understood. We hypothesize that when a medical illness makes it difficult for people to form and maintain close relationships with others, they will be at increased risk for anxiety and depression. METHODS: Two nationally representative surveys, the National Comorbidity Survey Replication and National Latino and Asian American Study, included 6805 adults with at least one medical illness and information on social impairment attributed to a medical condition. The Composite International Diagnostic Interview evaluated a 12-month history of anxiety and depressive disorders. RESULTS: 8.2% of our sample had at least moderate difficulty in forming and maintaining close relationships due to a medical condition. In bivariate analyses, younger age, Latino ethnicity, less education, worse financial status, more chronic illnesses, physical health and discomfort, and problems with mobility, home management, and self-care were associated with this social impairment. In multivariable analyses accounting for possible confounders, there was a dose-dependent relationship between social impairment and the prevalence of anxiety and depression. LIMITATIONS: Data are cross-sectional and our analyses are therefore unable to determine cause-and-effect relationships. CONCLUSIONS: Among adults with one or more medical conditions, social impairment attributed to medical illness was associated with a significantly greater odds of anxiety and depression. Further clarification of this relationship could inform more targeted, personalized interventions to prevent and/or alleviate mental illness in those with chronic medical conditions. PMID- 26773920 TI - Suicide in Serbia. AB - BACKGROUND: Suicide remains a significant public health problem worldwide. The aim of this study was to assess the mortality trend of suicide in Serbia for the years 1991-2014. METHODS: Data on persons who died of suicide and self-inflicted injury (site codes E950-E959 revision 9 and X60-X84 revision 10 of the International Classification of Diseases to classify death, injury and cause of death) were obtained from the Statistical Office of the Republic of Serbia. The age standardized rate was calculated by direct method (per 100,000 persons, using Segi's World population as standard population). Average annual percentage change (AAPC) with the corresponding 95% confidence interval (CI) was computed for trend using the joinpoint regression analysis. RESULTS: Total 33,930 (24,016 men and 9914 women) suicide deaths occurred in Serbia during the observed period, with the average annual age-standardized mortality rate being 12.7 per 100,000 inhabitants (19.5 per 100,000 in men and 6.7 per 100,000 in women). Suicide mortality in all age groups was higher among men than women. In both genders, suicide rates were highest in the oldest age group. Significantly decreased trend in suicide mortality was recorded continuously from 1991 to 2014 (AAPC=-1.9%, 95%CI -2.2 to -1.6). The most frequently used suicide method in both genders was hanging, strangulation or suffocation with 61.2% off all suicides. Changes in mortality rates were significant both for suicide by firearms, air guns and explosives (AAPC=-1.5% (AAPC=-1.5% in men and -3.1%-3.1% in women) and for suicide by hanging, strangulation, and suffocation (AAPC=-1.2% (AAPC=-1.2% in men and -3.0%-3.0% in women). In men, nonsignificant increase in suicide by firearms, air guns and explosives observed during the period 1991-1997 (by +6.1% per year) was followed by a significant decrease until 2014 (by -3.1% per year). The significantly increased mortality in suicide by firearms, air guns, and explosives was observed in older men (aged 40-69 years and 80 years and over). LIMITATIONS: The low rate of autopsies in Serbia, as well as the accuracy, reliability and comparability of the suicide mortality data is always a question. CONCLUSIONS: Downward trend in suicide mortality occurred in Serbia in last two decades. However, suicide rates are still very high in Serbia compared with the rates of suicides in developed countries. Particularly worrisome is the increase in mortality in older men, especially due to firearm suicides, air rifles, and explosives. Thus, additional efforts in the prevention of suicide are very important. PMID- 26773921 TI - Mortality and life expectancy in persons with severe unipolar depression. AB - BACKGROUND: Depression is a common psychiatric disorder, with a lifetime prevalence of 10-15% in the Danish population. Although depression is associated with excess mortality, it is not yet understood how this affects life expectancy. Our aim was to examine mortality rates and life expectancy in patients with unipolar depression compared to the general population, and to assess the impact of comorbid somatic illness and substance abuse. METHODS: We followed a Danish population-based cohort from 1995-2013 (N=5,103,699). The cohort included all residents in Denmark during the study period. Mortality rate ratios (MRRs) and life expectancy in persons with unipolar depression were calculated using survival analysis techniques. RESULTS: The overall MRR was 2.07 (95% Confidence Interval (CI): 2.05-2.09) in people with a previous unipolar depression diagnosis compared to the general Danish population. This excess mortality translated into a reduced life expectancy of 14.0 years in men and 10.1 years in women (assuming onset at age 15). The MRR was highest for death due to suicide and accidents (MRR: 4.66; 95% CI: 4.53-4.79), but the absolute number of deaths was highest for natural causes. CONCLUSION: People with unipolar depression have a significant shorter life expectancy, especially men. PMID- 26773922 TI - The association between peer victimization, PTSD, and dissociation in child victims of sexual abuse. AB - BACKGROUND: Sexually abused children present a host of psychological difficulties, including dissociation and post-traumatic stress (PTSD) symptoms. Negative repercussions associated with sexual abuse may interfere with children's ability to interact competently with their peers, and might put them at risk for peer victimization. The aims of the study were 1) to describe peer victimization experiences of sexually abused children using a multi-informant approach (self, parents, teachers), and 2) to examine if peer victimization experiences are associated with clinical levels of PTSD and dissociation after controlling for relevant variables. METHOD: Participants were 158 children (104 girls and 54 boys; Mean age=9.10) and their non-offending parents consulting after the disclosure of sexual abuse. Children, parents, and teachers completed a measure assessing peer victimization (Self-Report Victimization Scale). Measures of trauma-related symptoms (PTSD and dissociation) were used as outcome variables. RESULTS: More than half (60%) of sexually abused children reported being picked on, 51% reported sustaining verbal victimization and a third (35%) physical victimization by peers in the school context. Inter-informant agreement was higher between parents and teachers than between self-reports and adults' reports. Peer victimization experiences increased the odds by up to three-fold for clinical levels of dissociation and PTSD symptoms. LIMITATIONS: Our findings are based on cross-sectional data, and therefore, causal relationships cannot be inferred. No control group was included in the study. CONCLUSIONS: Results have significant relevance for prevention and intervention. Clinicians should include assessment of peer victimization experiences when evaluating sexually abused school-aged children. Prevention initiatives in terms of peer victimization could indirectly prevent worsening of symptoms in abused children. PMID- 26773923 TI - Depression-related treatment and costs in Germany: Do they change with comorbidity? A claims data analysis. AB - BACKGROUND: Existing diverse bottom-up estimations of direct costs associated with depression in Germany motivated a detailed patient-level analysis of depression-related treatment (DRT), -costs (DRC) and Comorbidity. METHODS: A large sickness fund's claims data was used to retrospectively identify patients aged 18-65 years with new-onset depression treatment between January 1st and February 15th 2010, and follow them until December 31st 2010, describe DRT, estimate associated DRC, and predict DRC with a generalised linear model. RESULTS: A total of 18,139 patients were analysed. Mean direct DRC were ?783. Predictors of DRC regarding psychiatric comorbidities were: "Delusion, psychotic disorders and personality disorders" (DRC-ratio 1.72), "Alcohol/drug addiction" (1.82), "abuse of alcohol/drugs" (1.57). Predictors of DRC regarding medical comorbidities were: "Rheumatoid arthritis" (0.77), "atherosclerosis" (0.65), "pregnancy" (0.66), and "Osteoarthritis" (1.87). Of all patients, 60.8% received their most intense/specialised DRT from a general practitioner, a medical specialist (23.7%), a psychotherapist (8.0%), a medical specialist and psychotherapist (2.9%), or in hospital (4.6%). Serious psychiatric comorbidity nearly tripled depression-related hospitalisation rates. LIMITATIONS: Seasonal affective disorder and missing psychiatric outpatient clinic data must be considered. CONCLUSIONS: Estimated DRC are significantly below the assessment of the German national guideline. Differing definitions of observation period and cost attribution might explain differing German DRC results. Signs of hospital psychiatric comorbidity bias indicate overestimation of hospital DRC. Identified associations of DRC with certain medical diseases in older adults warrant further research. Up to one quarter of patients with severe depression diagnosis might lack specialist treatment. PMID- 26773924 TI - Differential effects of GLP-1 receptor agonist on foam cell formation in monocytes between non-obese and obese subjects. AB - OBJECTIVE: Monocytes/macrophages (Mphi) transform into foam cells in the presence of oxidized-LDL (ox-LDL), releasing inflammatory mediators. The antiatherogenic role of a dipeptidyl peptidase-4 inhibitor is mediated, in part, through improving the unbalance of inflammatory (M1)/anti-inflammatory (M2) phenotypes in monocytes. In this study, we examined differential regulation of glucagon-like peptide-1 receptor (GLP-1R) signaling for antiatherogenesis in monocytes/Mphi from normal-weight control subjects and obese patients. METHODS: We evaluated the effects of exendin-4 (Ex-4), a GLP-1R agonist, on ox-LDL-stimulated foam cell formation, M1/M2 cytokine production, and organelle change in primary monocytes from control subjects and obese patients and human monocytic THP-1-derived Mphi as well. RESULTS: Here we report that Ex-4 suppressed foam cell formation and M1 cytokine expression and, interestingly, induced indicators of autophagy in ox-LDL stimulated monocytes from control subjects. The suppressing effects on foam cell formation by Ex-4 were reversed by a cAMP inhibitor. In contrast to control subjects, Ex-4 did not induce indicators of autophagy, but did induce foam cell formation and M1 cytokine expression in monocytes from obese patients. GLP-1R expression level was comparable between control subjects and obese patients. The effects of Ex-4 on inducing indicators of autophagy and suppressing foam cell formation were observed in THP-1 Mphi. CONCLUSIONS: These data suggest that GLP 1R signaling induces autophagy, thereby suppressing foam cell formation in non obese subjects. In obese patients, GLP-1R stimulation increased foam cell formation and IL-6, TNF-alpha, and IL-1beta production. Such altered signaling in monocytes of obese patients may be involved in the development of atherosclerosis. PMID- 26773925 TI - Glutathione peroxidase-1 gene (GPX1) variants, oxidative stress and risk of kidney complications in people with type 1 diabetes. AB - BACKGROUND AND AIM: Glutathione peroxidase (GPX) is a class of antioxidant enzymes that catalyze the reduction of hydrogen peroxide to water. GPX1 is the most abundant isoform and is expressed in all kidney cells. Isoprostane and advanced oxidation protein products (AOPP) were identified as markers of oxidative stress in patients with kidney disease. We investigated associations of GPX1 genotypes with kidney complications, and with plasma concentrations of isoprostane and AOPP in type 1 diabetic patients. METHODS: Four SNPs in the GPX1 gene region were genotyped in SURGENE (n=340; 10-year follow-up); GENEDIAB (n=461) and GENESIS (n=584) cohorts of type 1 diabetic patients. Subsets of GENEDIAB (n=237) and GENESIS (n=466) participants were followed up for 9 and 5years, respectively. Plasma concentrations of isoprostane and AOPP were measured at baseline in GENEDIAB. Hazard ratios (HR) were estimated for incidence of kidney complications. RESULTS: In SURGENE, 98 renal events (new cases of microalbuminuria or progression to more severe stage of diabetic nephropathy) occurred during follow-up. The minor T-allele of rs3448 was associated with the incidence of renal events (HR 1.81, 95% CI 1.16-2.84, p=0.008). In GENESIS/GENEDIAB pooled study, end stage renal disease (ESRD) occurred during follow-up in 52 individuals. The same variant was associated with the incidence of ESRD (HR 3.34, 95% CI, 1.69-6.98, p=0.0004). The variant was also associated with higher plasma isoprostane concentration in GENEDIAB cohort: 2.02+/-0.12 (TT+CT) vs 1.75+/-0.13 (CC) ng/mL (p=0.009), and with higher plasma AOPP in the subset of participants with the baseline history of ESRD (TT+CT 67+/-6 vs CC 48+/ 6MUmol/L, p=0.006). CONCLUSIONS: The minor T-allele of rs3448 was associated with kidney complications (incidences of microalbuminuria, renal events and ESRD) in patients with type 1 diabetes. The risk allele was associated with higher plasma concentrations of isoprostane and AOPP. Our results are consistent with the implication of GPX1 in the mechanism of renal protection against oxidative stress in type 1 diabetic patients. PMID- 26773926 TI - Metformin-associated lactic acidosis: Current perspectives on causes and risk. AB - Although metformin has become a drug of choice for the treatment of type 2 diabetes mellitus, some patients may not receive it owing to the risk of lactic acidosis. Metformin, along with other drugs in the biguanide class, increases plasma lactate levels in a plasma concentration-dependent manner by inhibiting mitochondrial respiration predominantly in the liver. Elevated plasma metformin concentrations (as occur in individuals with renal impairment) and a secondary event or condition that further disrupts lactate production or clearance (e.g., cirrhosis, sepsis, or hypoperfusion), are typically necessary to cause metformin associated lactic acidosis (MALA). As these secondary events may be unpredictable and the mortality rate for MALA approaches 50%, metformin has been contraindicated in moderate and severe renal impairment since its FDA approval in patients with normal renal function or mild renal insufficiency to minimize the potential for toxic metformin levels and MALA. However, the reported incidence of lactic acidosis in clinical practice has proved to be very low (<10 cases per 100,000 patient-years). Several groups have suggested that current renal function cutoffs for metformin are too conservative, thus depriving a substantial number of type 2 diabetes patients from the potential benefit of metformin therapy. On the other hand, the success of metformin as the first-line diabetes therapy may be a direct consequence of conservative labeling, the absence of which could have led to excess patient risk and eventual withdrawal from the market, as happened with earlier biguanide therapies. An investigational delayed-release metformin currently under development could potentially provide a treatment option for patients with renal impairment pending the results of future studies. This literature-based review provides an update on the impact of renal function and other conditions on metformin plasma levels and the risk of MALA in patients with type 2 diabetes. PMID- 26773927 TI - Wnt signaling pathway in cardiac fibrosis: New insights and directions. AB - OBJECTIVE: Wnt signaling pathway significantly participates in cardiac fibrosis and CFs activation. Therefore, we reviewed current evidence on the new perspectives and biological association between Wnt signaling pathway and cardiac fibrosis. DESIGN AND METHODS: A PubMed database search was performed for studies of Wnt signaling pathway in cardiac fibrosis and CFs activation. RESULTS: Numerous studies have shown that the Wnt signaling pathway significantly participates in cardiac fibrosis pathogenesis. The aim of this review is to describe the present knowledge about the Wnt signaling pathway significantly participating in cardiac fibrosis and CFs activation, and look ahead on new perspectives of Wnt signaling pathway research. Moreover, we will discuss the different insights that interact with the Wnt signaling pathway-regulated cardiac fibrosis. The Wnt proteins are glycoproteins that bind to the Fz receptors on the cell surface, which lead to several important biological functions, such as cell differentiation and proliferation. There are several signals among the characterized pathways of cardiac fibrosis, including Wnt/beta-catenin signaling. In this review, new insight into the Wnt signaling pathway in cardiac fibrosis pathogenesis is discussed, with special emphasis on Wnt/beta-catenin. CONCLUSION: It seems reasonable to suggest the potential targets of Wnt signaling pathway and it can be developed as a therapeutic target for cardiac fibrosis. PMID- 26773928 TI - Treatment with atorvastatin attenuates progression of insulin resistance and pancreatic fibrosis in the Otsuka Long-Evans Tokushima fatty rats. AB - PURPOSE: The effects of statins on insulin resistance (IR) and type 2 diabetes mellitus (T2DM) are still controversial and its effects on pancreatic fibrosis are poorly defined. The purpose of this study is to examine the effects of atorvastatin on these issues using the Otsuka Long-Evans Tokushima Fatty (OLETF) rat, an animal model of IR, T2DM and pancreatic fibrosis. METHODS: Male OLETF rats were divided into 2 groups at 6weeks of age. The first group received a standard diet until the end of experimental period at age 28weeks. The second group was given a diet containing 0.05% atorvastatin from 6weeks of age, before the onset of IR and pancreatic fibrosis. The age-matched Long-Evans Tokushima Otsuka rats without presence of IR, T2DM and pancreatic fibrosis, received a standard diet and were used as a normal control. RESULTS: Atorvastatin slightly decreased serum fasting glucose and insulin levels, but significantly improved index of IR compared with the untreated OLETF rats. In addition, atorvastatin markedly decreased transforming growth factor-beta1 mRNA expression, myeloperoxidase activity and proportion of fibrotic area, and elevated superoxide dismutase activity in the pancreas compared with the untreated OLETF rats. CONCLUSIONS: These findings suggest that atorvastatin exerts favorable influence on progression of IR and pancreatic inflammation and fibrosis via pleiotropic effect such as anti-oxidative property. PMID- 26773929 TI - Testosterone deprivation has neither additive nor synergistic effects with obesity on the cognitive impairment in orchiectomized and/or obese male rats. AB - OBJECTIVE: Previous studies demonstrated a correlation between cognitive decline and either testosterone deprivation or obesity. However, the effect of obesity combined with testosterone deprivation on cognitive function has not been investigated. This study investigated the effects of obesity on brain insulin sensitivity, brain mitochondrial function, hippocampal synaptic plasticity and cognitive function in testosterone-deprived male rats. MATERIALS/METHODS: Male Wistar rats were divided into sham-operated (control) and bilateral orchiectomized (ORX) groups. Rats in each group were further divided into two subgroups to receive either a normal diet (ND) or a high fat diet (HFD) for 4, 8 or 12weeks. Blood samples were collected to determine metabolic parameters. Cognitive function was tested using the Morris Water Maze Test. At the end of the study, brains were removed to investigate brain insulin sensitivity, brain mitochondrial function and hippocampal synaptic plasticity. RESULTS: Both control obese and ORX-obese rats developed peripheral insulin resistance at week eight, and brain insulin resistance as well as brain mitochondrial dysfunction at week 12. However, the ORX-obese rats developed cognitive impairment and decreased hippocampal synaptic plasticity beginning at week eight, whereas the control obese rats developed these impairments later at week 12. Although both peripheral and brain insulin resistance were not observed in both the control-lean and ORX lean rats, impaired cognition and decreased hippocampal synaptic plasticity were found in the ORX-lean rats beginning at week eight. CONCLUSION: These findings suggest that testosterone deprivation has neither additive nor synergistic effects over obesity in the development of cognitive dysfunction in orchiectomized-obese male rats. PMID- 26773930 TI - Baseline glycemic status and mortality in 241,499 Korean metropolitan subjects: A Kangbuk Samsung Health Study. AB - OBJECTIVE: Diabetes and prediabetes subjects have increased risk for mortality. We analyzed the mortality risk due to all causes, cardiovascular disease (CVD) and cancer in Korean subjects participating in a health-screening program according to baseline glycemic status and HbA1c levels. MATERIALS/METHODS: Among 241,499 participants of a health-screening program between 2005 and 2012, the risk of death from all causes, CVD, and cancer was calculated based on the baseline glycemic status (normoglycemia, prediabetes, and diabetes) and HbA1c levels. Uncontrolled diabetes was defined as HbA1c>=7.0%. Vital status and confirmation of the cause of death were based on the analysis of death certificate records from the National Death Index. RESULTS: During 923,343.1 person-years of follow-up, 877 participants died. The multivariable-adjusted hazard ratios (HR) of subjects with controlled and uncontrolled diabetes to normoglycemic subjects for all-cause mortality were 1.58 (95% CI 1.24-2.03) and 2.26 (95% CI 1.78-2.86), respectively. The HRs of subjects with controlled and uncontrolled diabetes to normoglycemic subjects for mortality due to cancer were 1.75 (95% CI 1.23-2.48) and 1.67 (95% CI 1.13-2.45). However, glycemic status was not significantly associated with the risk of mortality due to CVD. The subjects with HbA1c higher than 6.5% showed more than 2-fold increased risk for all-cause mortality and the subjects with HbA1c lower than 5.2% showed increased HR (1.45, 95% CI 1.06-1.97) compared with those with HbA1c of 5.5% in subjects not taking anti-diabetic medications. CONCLUSIONS: Mortality risk from all causes and cancer significantly increased in diabetes subjects regardless of the glucose control status. In subjects not taking anti-diabetic medications, both high and low HbA1c resulted in increased risk for all-cause mortality. PMID- 26773931 TI - Type 2 diabetes mitigation in the diabetic Goto-Kakizaki rat by elevated bile acids following a common-bile-duct surgery. AB - OBJECTIVE: Elevated plasma bile acids after bariatric surgery are thought to explain type 2 diabetes mellitus (T2DM) remission. Bile acids can bind to and activate the nuclear receptor farnesoid-X receptor (FXR) by regulating lipid and glucose metabolism. We performed a surgical procedure (ligation of the common bile duct and external biliary drainage [LBD]) in the diabetic Goto-Kakizaki (GK) rat in order to investigate its effect on bile acids metabolism and T2DM mitigation. MATERIAL/METHODS: LBD surgery and sham control surgery were performed on diabetic GK rats. The concentrations of total bile acids and blood glucose were analyzed by an automatic analyzer. Intraperitoneal glucose tolerance test (IPGTT) and insulin tolerance test (ITT) were used to monitor blood glucose level. Expression of genes involved in bile acid metabolism (FXR, CYP7A, et al.) and glycolipid metabolism (G6Pase, PEPCK, et al) was analyzed using qRT-PCR. The protein levels of pAKT, AKT and pGSK3beta were tested by western blot. The morphological alterations of the liver and epididymal fat were monitored by H&E staining. RESULTS: LBD increased plasma total bile acids, improved hepatic insulin sensitivity, and eventually mitigated T2DM, whereas food intake and body weight were unaltered. Post-LBD, the levels of total bile acids were elevated from 24.80+/-7.12 to 61.44+/-6.40 and the concentration of fast blood glucose was decreased from 204.7+/-11.06mg/dL to 109.3+/-5.4mg/dL. IPGTT and ITT showed that LBD operation improved insulin sensitivity in GK rats. Clusters of FXR signaling target genes were altered in the liver, such as FXR, CYP7A, G6Pase and PEPCK. These contributed to sustained bile acid homeostasis, and they ameliorated hepatic endoplasmic reticulum (ER) stress, increased energy expenditure, and reduced gluconeogenesis, resulting in a substantial improvement in hepatic insulin sensitivity. LBD also significantly reduced epididymal fat tissue and decreased the size of adipocytes. CONCLUSION: These results demonstrate that the elevated bile acids observed in LBD-operated GK rats link insulin sensitivity improvement to T2DM mitigation, recapitulating the metabolic effects of bariatric surgery. Our investigation establishes a model for a focused study of bile acids in the context of bariatric surgery that may contribute to the identification of therapeutics for T2DM. PMID- 26773932 TI - Soluble DPP-4 up-regulates toll-like receptors and augments inflammatory reactions, which are ameliorated by vildagliptin or mannose-6-phosphate. AB - OBJECTIVE: Studies have shown that dipeptidyl peptidase-4 (DPP-4) inhibitors have anti-inflammatory effects. Soluble DPP-4 (sDPP-4) has been considered as an adipokine of which actions need to be further characterized. METHODS: We investigated the pro-inflammatory actions of sDPP-4 and the anti-inflammatory effects of DPP-4 inhibition, using vildagliptin, as an enzymatic inhibitor, and mannose-6-phosphate (M6P) as a competitive binding inhibitor. RESULTS: In lipopolysaccharide (LPS)-stimulated RAW264.7 cells, vildagliptin suppressed the increased expression of inducible nitric oxide synthase (iNOS) and phosphorylated JNK (pJNK), activation of the NF-kappaB pathway, and the resultant NO and proinflammatory cytokine production. Although sDPP-4 alone did not affect the protein level of iNOS or pJNK or the production of NO in RAW264.7 cells, it did amplify iNOS expression, NO responses, and proinflammatory cytokine production in LPS-stimulated RAW264 cells. As a probable mechanism, we found that sDPP-4 caused dose-dependent increases in the expression levels of toll-like receptor 4 (TLR4) and TLR2 in RAW264.7 cells, and that these alterations were inhibited by vildagliptin, M6P, or bisindolylmaleimide II, a protein kinase C inhibitor. Either vildagliptin or M6P suppressed iNOS expression and NO and cytokine production in LPS+DPP-4-co-stimulated macrophages, while combined treatment of the co-stimulated cells with both agents had increased anti-inflammatory effects compared with either treatment alone. Intravenous injection of sDPP-4 to C57BL/6J mice increased the expression of both TLRs in kidney and white adipose tissues. CONCLUSION: Our findings suggest that sDPP-4 enhances inflammatory actions via TLR pathway, while DPP-4 inhibition with either an enzymatic or binding inhibitor has anti-inflammatory effects. PMID- 26773933 TI - Anti-inflammatory effects of the hydroxycarboxylic acid receptor 2. AB - The hydroxycarboxylic acid receptors (HCA1-3) are a family of G-protein-coupled receptors that are critical for sensing endogenous intermediates of metabolism. All three receptors are predominantly expressed on adipocytes and mediate anti lipolytic effects. In addition to adipocytes, HCA2 is highly expressed on immune cells, including macrophages, monocytes, neutrophils and dermal dendritic cells, among other cell types. The endogenous ligand for HCA2 is beta-hydroxybutyrate (beta-OHB), a ketone body produced by the liver through beta-oxidation when an individual is in a negative energy balance. Recent studies demonstrate that HCA2 mediates profound anti-inflammatory effects in a variety of tissues, indicating that HCA2 may be an important therapeutic target for treating inflammatory disease processes. This review summarizes the roles of HCA2 on inflammation in a number of tissues and clinical states. PMID- 26773934 TI - The SGLT2 inhibitor empagliflozin improves insulin sensitivity in db/db mice both as monotherapy and in combination with linagliptin. AB - AIMS: Combining different drug classes to improve glycemic control is one treatment strategy for type 2 diabetes. The effects on insulin sensitivity of long-term treatment with the sodium glucose co-transporter 2 (SGLT2) inhibitor empagliflozin alone or co-administered with the dipeptidyl peptidase-4 inhibitor linagliptin (both approved antidiabetes drugs) were investigated in mice using euglycemic-hyperinsulinemic clamps. MATERIALS AND METHODS: db/db mice (n=15/group) were treated for 8weeks with 10mg/kg/day empagliflozin monotherapy, 10mg/kg/day empagliflozin plus 3mg/kg/day linagliptin combination therapy, or 3mg/kg/day linagliptin monotherapy. At the end of the study, euglycemic hyperinsulinemic clamp studies were performed 4days after the last dose of treatment. RESULTS: HbA1c and 2-hour fasting glucose concentrations were improved with empagliflozin monotherapy and combination therapy compared with vehicle and linagliptin monotherapy. During the clamp, glucose disposal rates increased and hepatic glucose production decreased with empagliflozin monotherapy and combination therapy compared with vehicle and linagliptin monotherapy. Glucose uptake in liver and kidney was higher with empagliflozin monotherapy and combination therapy compared with vehicle; glucose uptake into both muscle and adipose tissue was only affected by linagliptin treatment. Empagliflozin and combination therapy altered the expression of genes involved in the inflammatory response, fatty acid synthesis and oxidation. CONCLUSIONS: These findings suggest that the insulin-sensitizing effects of SGLT2 inhibition contribute to improvements in glycemic control in insulin-resistant states. PMID- 26773935 TI - Facilitative glucose transporters: Implications for cancer detection, prognosis and treatment. AB - It is long recognized that cancer cells display increased glucose uptake and metabolism. In a rate-limiting step for glucose metabolism, the glucose transporter (GLUT) proteins facilitate glucose uptake across the plasma membrane. Fourteen members of the GLUT protein family have been identified in humans. This review describes the major characteristics of each member of the GLUT family and highlights evidence of abnormal expression in tumors and cancer cells. The regulation of GLUTs by key proliferation and pro-survival pathways including the phosphatidylinositol 3-kinase (PI3K)-Akt, hypoxia-inducible factor-1 (HIF-1), Ras, c-Myc and p53 pathways is discussed. The clinical utility of GLUT expression in cancer has been recognized and evidence regarding the use of GLUTs as prognostic or predictive biomarkers is presented. GLUTs represent attractive targets for cancer therapy and this review summarizes recent studies in which GLUT1, GLUT3, GLUT5 and others are inhibited to decrease cancer growth. PMID- 26773936 TI - On fuzzy semantic similarity measure for DNA coding. AB - A coding measure scheme numerically translates the DNA sequence to a time domain signal for protein coding regions identification. A number of coding measure schemes based on numerology, geometry, fixed mapping, statistical characteristics and chemical attributes of nucleotides have been proposed in recent decades. Such coding measure schemes lack the biologically meaningful aspects of nucleotide data and hence do not significantly discriminate coding regions from non-coding regions. This paper presents a novel fuzzy semantic similarity measure (FSSM) coding scheme centering on FSSM codons' clustering and genetic code context of nucleotides. Certain natural characteristics of nucleotides i.e. appearance as a unique combination of triplets, preserving special structure and occurrence, and ability to own and share density distributions in codons have been exploited in FSSM. The nucleotides' fuzzy behaviors, semantic similarities and defuzzification based on the center of gravity of nucleotides revealed a strong correlation between nucleotides in codons. The proposed FSSM coding scheme attains a significant enhancement in coding regions identification i.e. 36-133% as compared to other existing coding measure schemes tested over more than 250 benchmarked and randomly taken DNA datasets of different organisms. PMID- 26773937 TI - Mining frequent biological sequences based on bitmap without candidate sequence generation. AB - Biological sequences carry a lot of important genetic information of organisms. Furthermore, there is an inheritance law related to protein function and structure which is useful for applications such as disease prediction. Frequent sequence mining is a core technique for association rule discovery, but existing algorithms suffer from low efficiency or poor error rate because biological sequences differ from general sequences with more characteristics. In this paper, an algorithm for mining Frequent Biological Sequence based on Bitmap, FBSB, is proposed. FBSB uses bitmaps as the simple data structure and transforms each row into a quicksort list QS-list for sequence growth. For the continuity and accuracy requirement of biological sequence mining, tested sequences used during the mining process of FBSB are real ones instead of generated candidates, and all the frequent sequences can be mined without any errors. Comparing with other algorithms, the experimental results show that FBSB can achieve a better performance on both run time and scalability. PMID- 26773938 TI - Pharmacophore-based screening targeted at upregulated FN1, MMP-9, APP reveals therapeutic compounds for nasopharyngeal carcinoma. AB - Nasopharyngeal carcinoma (NpC) is rare in the west but common in Southeast Asia and only a few other locations. With the limited geographic incidence, it is relatively under-studied. It also has as co-determinant the Epstein-Barr virus (EBV), which may adapt to NpC therapies, so not only must a therapeutic compound be found, the discovery process must be rapid, to cope with the changing basis of the EBV. An R-based computer workbench, Mendel, was developed so biologists could quickly upload genomic data, pre-process them, and identify upregulated and downregulated genes. Mendel was used on 10 control and 31 diseased cell lines to discover 3 differentially expressed genes (DEGs) that meet thresholds on fold changes, 3-clique membership, pathway constraints, and druggability. From the DEGs, we conducted a pharmacophore-based screening of 22,723,923 compounds using protein-protein interaction anchor-residue clusters as binding sites. Of the 4 hits, 3 passed all the ADME-Tox tests. These 3 hit compounds, 6-(4 iminiocyclohexa-2,5-dien-1-ylidene)-4-(thiazol-2-ylcarbamoyl)-1H-pyrimidine-2 thiolate, 1-[4-[2-[(3R)-3-hydroxy-2-oxo-indolin-3-yl]acetyl]phenyl]-3-phenyl urea, and (2R)-N4-[4-(1-piperidyl)cyclohexyl]morpholine-2,4-dicarboxamide have predicted pIC50 values superior to the current drugs fluorouracil (5-FU) and taxotere, which have side effects and face EBV drug resistance. PMID- 26773939 TI - Large-scale CFD simulations of the transitional and turbulent regime for the large human airways during rapid inhalation. AB - The dynamics of unsteady flow in the human large airways during a rapid inhalation were investigated using highly detailed large-scale computational fluid dynamics on a subject-specific geometry. The simulations were performed to resolve all the spatial and temporal scales of the flow, thanks to the use of massive computational resources. A highly parallel finite element code was used, running on two supercomputers, solving the transient incompressible Navier-Stokes equations on unstructured meshes. Given that the finest mesh contained 350 million elements, the study sets a precedent for large-scale simulations of the respiratory system, proposing an analysis strategy for mean flow, fluctuations and wall shear stresses on a rapid and short inhalation (a so-called sniff). The geometry used encompasses the exterior face and the airways from the nasal cavity, through the trachea and up to the third lung bifurcation; it was derived from a contrast-enhanced computed tomography (CT) scan of a 48-year-old male. The transient inflow produces complex flows over a wide range of Reynolds numbers (Re). Thanks to the high fidelity simulations, many features involving the flow transition were observed, with the level of turbulence clearly higher in the throat than in the nose. Spectral analysis revealed turbulent characteristics persisting downstream of the glottis, and were captured even with a medium mesh resolution. However a fine mesh resolution was found necessary in the nasal cavity to observe transitional features. This work indicates the potential of large-scale simulations to further understanding of airway physiological mechanics, which is essential to guide clinical diagnosis; better understanding of the flow also has implications for the design of interventions such as aerosol drug delivery. PMID- 26773940 TI - Functional segmentation of dynamic PET studies: Open source implementation and validation of a leader-follower-based algorithm. AB - We present a novel segmentation algorithm for dynamic PET studies that groups pixels according to the similarity of their time-activity curves. METHODS: Sixteen mice bearing a human tumor cell line xenograft (CH-157MN) were imaged with three different (68)Ga-DOTA-peptides (DOTANOC, DOTATATE, DOTATOC) using a small animal PET-CT scanner. Regional activities (input function and tumor) were obtained after manual delineation of regions of interest over the image. The algorithm was implemented under the jClustering framework and used to extract the same regional activities as in the manual approach. The volume of distribution in the tumor was computed using the Logan linear method. A Kruskal-Wallis test was used to investigate significant differences between the manually and automatically obtained volumes of distribution. RESULTS: The algorithm successfully segmented all the studies. No significant differences were found for the same tracer across different segmentation methods. Manual delineation revealed significant differences between DOTANOC and the other two tracers (DOTANOC - DOTATATE, p=0.020; DOTANOC - DOTATOC, p=0.033). Similar differences were found using the leader-follower algorithm. CONCLUSION: An open implementation of a novel segmentation method for dynamic PET studies is presented and validated in rodent studies. It successfully replicated the manual results obtained in small-animal studies, thus making it a reliable substitute for this task and, potentially, for other dynamic segmentation procedures. PMID- 26773942 TI - Application of robust Generalised Cross-Validation to the inverse problem of electrocardiology. AB - Robust Generalised Cross-Validation was proposed recently as a method for determining near optimal regularisation parameters in inverse problems. It was introduced to overcome a problem with the regular Generalised Cross-Validation method in which the function that is minimised to obtain the regularisation parameter often has a broad, flat minimum, resulting in a poor estimate for the parameter. The robust method defines a new function to be minimised which has a narrower minimum, but at the expense of introducing a new parameter called the robustness parameter. In this study, the Robust Generalised Cross-Validation method is applied to the inverse problem of electrocardiology. It is demonstrated that, for realistic situations, the robustness parameter can be set to zero. With this choice of robustness parameter, it is shown that the robust method is able to obtain estimates of the regularisation parameter in the inverse problem of electrocardiology that are comparable to, or better than, many of the standard methods that are applied to this inverse problem. PMID- 26773941 TI - Rapid development of image analysis research tools: Bridging the gap between researcher and clinician with pyOsiriX. AB - We present pyOsiriX, a plugin built for the already popular dicom viewer OsiriX that provides users the ability to extend the functionality of OsiriX through simple Python scripts. This approach allows users to integrate the many cutting edge scientific/image-processing libraries created for Python into a powerful DICOM visualisation package that is intuitive to use and already familiar to many clinical researchers. Using pyOsiriX we hope to bridge the apparent gap between basic imaging scientists and clinical practice in a research setting and thus accelerate the development of advanced clinical image processing. We provide arguments for the use of Python as a robust scripting language for incorporation into larger software solutions, outline the structure of pyOsiriX and how it may be used to extend the functionality of OsiriX, and we provide three case studies that exemplify its utility. For our first case study we use pyOsiriX to provide a tool for smooth histogram display of voxel values within a user-defined region of interest (ROI) in OsiriX. We used a kernel density estimation (KDE) method available in Python using the scikit-learn library, where the total number of lines of Python code required to generate this tool was 22. Our second example presents a scheme for segmentation of the skeleton from CT datasets. We have demonstrated that good segmentation can be achieved for two example CT studies by using a combination of Python libraries including scikit-learn, scikit-image, SimpleITK and matplotlib. Furthermore, this segmentation method was incorporated into an automatic analysis of quantitative PET-CT in a patient with bone metastases from primary prostate cancer. This enabled repeatable statistical evaluation of PET uptake values for each lesion, before and after treatment, providing estaimes maximum and median standardised uptake values (SUVmax and SUVmed respectively). Following treatment we observed a reduction in lesion volume, SUVmax and SUVmed for all lesions, in agreement with a reduction in concurrent measures of serum prostate-specific antigen (PSA). PMID- 26773943 TI - Segmentation and optical flow estimation in cardiac CT sequences based on a spatiotemporal PDM with a correction scheme and the Hermite transform. AB - PURPOSE: The left ventricle and the myocardium are two of the most important parts of the heart used for cardiac evaluation. In this work a novel framework that combines two methods to isolate and display functional characteristics of the heart using sequences of cardiac computed tomography (CT) is proposed. A shape extraction method, which includes a new segmentation correction scheme, is performed jointly with a motion estimation approach. METHODS: For the segmentation task we built a Spatiotemporal Point Distribution Model (STPDM) that encodes spatial and temporal variability of the heart structures. Intensity and gradient information guide the STPDM. We present a novel method to correct segmentation errors obtained with the STPDM. It consists of a deformable scheme that combines three types of image features: local histograms, gradients and binary patterns. A bio-inspired image representation model based on the Hermite transform is used for motion estimation. The segmentation allows isolating the structure of interest while the motion estimation can be used to characterize the movement of the complete heart muscle. RESULTS: The work is evaluated with several sequences of cardiac CT. The left ventricle was used for evaluation. Several metrics were used to validate the proposed framework. The efficiency of our method is also demonstrated by comparing with other techniques. CONCLUSION: The implemented tool can enable physicians to better identify mechanical problems. The new correction scheme substantially improves the segmentation performance. Reported results demonstrate that this work is a promising technique for heart mechanical assessment. PMID- 26773944 TI - Age and gender effects on 15 platelet phenotypes in a Spanish population. AB - INTRODUCTION: Several studies have analysed the platelet parameters in human blood, nevertheless there are no extensive analyses on the less common platelet phenotypes. The main objective of our study is to evaluate the age and gender effects on 15 platelet phenotypes. METHODS: We studied 804 individuals, ranging in age from 2 to 93 years, included in the Genetic Analysis of Idiopathic Thrombophilia 2 (GAIT 2) Project. The 15 platelet phenotypes analysed were the platelets counts, platelet volumes, plateletcrits, immature platelet fraction (IPF) and platelet function assay (PFA). A regression-based method was used to evaluate the age and gender effects on these phenotypes. RESULTS: Our results were consistent with the previously reported results regarding platelet counts and plateletcrit (PCT). They showed a decrease with increasing age. The mean platelet volume (MPV), platelet distribution width (PDW) and platelet-large cell ratio (P-LCR) increased with age, but did not present any gender effect. All the IPF phenotypes increased with age, whereas the PFA phenotypes did not show any relation to age or gender. DISCUSSION: To sum up, our study provides a comprehensive analysis of the age and gender effects on the platelet phenotypes in a family-base sample. Our results suggest more reasonable age stratification into two distinct groups: childhood, ranging from 2 to 12 years, and the mature group, from 13 to 93 years. Moreover, the PFA phenotypes were maintained constant while the platelet counts, the MPV and IPF levels vary with age. PMID- 26773945 TI - Techno-economic evaluation of a complete bioprocess for 2,3-butanediol production from renewable resources. AB - This study presents the techno-economic evaluation of 2,3-butanediol (BDO) production via fermentation using glycerol, sucrose and sugarcane molasses as carbon sources. Literature-cited experimental data were used to design the fermentation stage, whereas downstream separation of BDO was based on reactive extraction of BDO employing an aldehyde to convert BDO into an acetal that is immiscible with water. The selected downstream process can be used in all fermentations employed. Sensitivity analysis was carried out targeting the estimation of the minimum selling price (MSP) of BDO at different plant capacities and raw material purchase costs. In all cases, the MSP of BDO is higher than 1 $/kg that is considered as the target in order to characterize a fermentation product as platform chemical. The complex nutrient supplements, the raw material market price and the fermentation efficiency were identified as the major reasons for the relatively high MSP observed. PMID- 26773946 TI - Thermal decomposition and gasification of biomass pyrolysis gases using a hot bed of waste derived pyrolysis char. AB - Chars produced from the pyrolysis of different waste materials have been investigated in terms of their use as a catalyst for the catalytic cracking of biomass pyrolysis gases during the two-stage pyrolysis-gasification of biomass. The chars were produced from the pyrolysis of waste tyres, refused derived fuel and biomass in the form of date stones. The results showed that the hydrocarbon tar yields decreased significantly with all the char materials used in comparison to the non-char catalytic experiments. For example, at a cracking temperature of 800 degrees C, the total product hydrocarbon tar yield decreased by 70% with tyre char, 50% with RDF char and 9% with biomass date stones char compared to that without char. There was a consequent increase in total gas yield. Analysis of the tar composition showed that the content of phenolic compounds decreased and polycyclic aromatic hydrocarbons increased in the product tar at higher char temperatures. PMID- 26773947 TI - Strain variation in microalgal lipid production during mixotrophic growth with glycerol. AB - Algal cultivation at high latitudes is challenged by the relatively low annual solar flux. One possible scenario to overcome this limitation is the use of mixotrophic growth to potentially boost biomass and lipid production. Here the effect of glycerol addition on the growth and lipid production by twelve indigenous microalgae was examined. The results show that there is considerable strain dependent variation in the maximum growth rate under mixotrophic conditions with the addition of glycerol causing in some cases up to a 2.4-fold increase in growth rate and a up to a 1.9-fold increase in biomass. In addition, glycerol increased total lipid production 40-60% in some strains. These results also show the value in screening culture collections for desired traits independent of strain identification since here one (PCH02) of the five Chlorella strains showed a large increase in lipid with glycerol. PMID- 26773948 TI - Saccharification of ozonated sugarcane bagasse using enzymes from Myceliophthora thermophila JCP 1-4 for sugars release and ethanol production. AB - The saccharification of ozonated sugarcane bagasse (SCB) by enzymes from Myceliophthora thermophila JCP 1-4 was studied. Fungal enzymes provided slightly higher sugar release than commercial enzymes, working at 50 degrees C. Sugar release increased with temperature increase. Kinetic studies showed remarkable glucose release (4.99 g/L, 3%w/w dry matter) at 60 degrees C, 8 h of hydrolysis, using an enzyme load of 10 FPU (filter paper unit). FPase and beta-glucosidase activities increased during saccharification (284% and 270%, respectively). No further significant improvement on glucose release was observed increasing the enzyme load above 7.5 FPU per g of cellulose. Higher dry matter contents increased sugars release, but not yields. The fermentation of hydrolysates by Saccharomyces cerevisiae provided glucose-to-ethanol conversions around to 63%. PMID- 26773949 TI - Enhanced methane production from microalgal biomass by anaerobic bio pretreatment. AB - Anaerobic digestion (AD) of microalgal biomass is one of the most energy efficient technologies to convert microalgae to biofuels. In order to improve the biogas productivity, breaking up the tough and rigid cell wall of microalgae by pretreatment is necessary. In this work, Bacillus licheniformis, a facultative anaerobic bacterial with hydrolytic and acidogenic activities, was adopted to pretreat Chlorella sp. In the established pretreatment process, pure bacterial culture (0%, 1%, 2%, 4%, 8%, v/v) were used to pretreat Chlorella sp. under anaerobic condition at 37 degrees C for 60 h. The soluble chemical oxygen demands (SCOD) content was increased by 16.4-43.4%, while volatile fatty acids (VFAs) were improved by 17.3-44.2%. Furthermore, enhancement of methane production (9.2 22.7%) was also observed in subsequent AD. The results indicated that the more dosages of bacteria were used to pretreat the microalgal biomass in the range of 1-8%, the more methane was produced. PMID- 26773950 TI - Kinetic parameters of red pepper waste as biomass to solid biofuel. AB - This work aimed to study the kinetic of thermal degradation of red pepper waste as solid biofuel to bioenergy production. The thermal degradation experiments were conducted at three heating rates, 5 degrees C/min, 7.5 degrees C/min and 10 degrees C/min in a thermogravimetric analyzer and oxidative atmosphere. The kinetic analysis was carried out applying the isoconversional model of Ozawa Flynn-Wall. The activation energy was considerate low and varied 29.49-147.25k J/mol. The enthalpies revealed the energy difference between the reagent and the activated complex agreed with activation energies, the values of the pre exponential factor indicated empirical first order reactions, Gibbs free energy varied from 71.77 kJ/mol to 207.03 kJ/mol and the changes of entropies had negative values, indicating that the degree of disorder of products formed through bond dissociations was lower than initial reactants. The calorific value was 19.5 MJ/kg, considered a relevant result for bioenergy production. PMID- 26773951 TI - Performance evaluation of the sulfur-redox-reaction-activated up-flow anaerobic sludge blanket and down-flow hanging sponge anaerobic/anoxic sequencing batch reactor system for municipal sewage treatment. AB - A sulfur-redox-reaction-activated up-flow anaerobic sludge blanket (UASB) and down-flow hanging sponge (DHS) system, combined with an anaerobic/anoxic sequencing batch reactor (A2SBR), has been used for municipal sewage treatment for over 2 years. The present system achieved a removal rate of 95+/-14% for BOD, 74+/-22% for total nitrogen, and 78+/-25% for total phosphorus, including low water temperature conditions. Sludge conversion rates during the operational period were 0.016 and 0.218 g-VSS g-COD-removed(-1) for the UASB, and DHS, respectively, which are similar to a conventional UASB-DHS system, which is not used of sulfur-redox-reaction, for sewage treatment. Using the sulfur-redox reaction made advanced treatment of municipal wastewater with minimal sludge generation possible, even in winter. Furthermore, the occurrence of a unique phenomenon, known as the anaerobic sulfur oxidation reaction, was confirmed in the UASB reactor under the winter season. PMID- 26773952 TI - A life cycle assessment and economic analysis of the Scum-to-Biodiesel technology in wastewater treatment plants. AB - This study used life cycle assessment and technical economic analysis tools in evaluating a novel Scum-to-Biodiesel technology and compares the technology with scum digestion and combustion processes. The key variables that control environmental and economic performance are identified and discussed. The results show that all impacts examined for the Scum-to-Biodiesel technology are below zero indicating significant environmental benefits could be drawn from it. Of the three technologies examined, the Scum-to-Biodiesel technology has the best environmental performance in fossil fuel depletion, GHG emissions, and eutrophication, whereas combustion has the best performance on acidification. Of all process inputs assessed, process heat, glycerol, and methanol uses had the highest impacts, much more than any other inputs considered. The Scum-to Biodiesel technology also makes higher revenue than other technologies. The diesel price is a key variable for its economic performance. The research demonstrates the feasibility and benefits in developing Scum-to-Biodiesel technology in wastewater treatment facilities. PMID- 26773954 TI - Selective simplification and reinforcement of microbial community in autothermal thermophilic aerobic digestion to enhancing stabilization process of sewage sludge by conditioning with ferric nitrate. AB - The effect of ferric nitrate on microbial community and enhancement of stabilization process for sewage sludge was investigated in autothermal thermophilic aerobic digestion. The disinhibition of volatile fatty acids (VFA) was obtained with alteration of individual VFA concentration order. Bacterial taxonomic identification by 454 high-throughput pyrosequencing found the dominant phylum Proteobacteria in non-dosing group was converted to phylum Firmicutes in dosing group after ferric nitrate added and simplification of bacteria phylotypes was achieved. The preponderant Tepidiphilus sp. vanished, and Symbiobacterium sp. and Tepidimicrobium sp. were the most advantageous phylotypes with conditioning of ferric nitrate. Consequently, biodegradable substances in dissolved organic matters increased, which contributed to the favorable environment for microbial metabolism and resulted in acceleration of sludge stabilization. Ultimately, higher stabilization level was achieved as ratio of soluble chemical oxygen demand to total chemical oxygen demand (TCOD) decreased while TCOD reduced as well in dosing group comparing to non-dosing group. PMID- 26773953 TI - Effects of fertilizer application and dry/wet processing of Miscanthus x giganteus on bioethanol production. AB - The effects of wet and dry processing of miscanthus on bioethanol production using simultaneous saccharification and fermentation (SSF) process were investigated, with wet samples showing higher ethanol yields than dry samples. Miscanthus grown with no fertilizer, with fertilizer and with swine manure were sampled for analysis. Wet-fractionation was used to separate miscanthus into solid and liquid fractions. Dilute sulfuric acid pretreatment was employed and the SSF process was performed with saccharomyces cerevisiae and a cocktail of enzymes at 35 degrees C. After pretreatment, cellulose compositions of biomass of the wet samples increased from 61.0-67.0% to 77.0-87.0%, which were higher than the compositions of dry samples. The highest theoretical ethanol yield of 88.0% was realized for wet processed pretreated miscanthus, grown with swine manure. Changes to the morphology and chemical composition of the biomass samples after pretreatment, such as crystallinity reduction, were observed using SEM and FTIR. These changes improved ethanol production. PMID- 26773955 TI - Redox zones stratification and the microbial community characteristics in a periphyton bioreactor. AB - Bioremediation techniques based on microorganisms have been widely applied to treat polluted surface water, but the efficiencies have been limited, especially in deep and static waters. Microbial aggregates, known as periphyton, were introduced into a tank bioreactor to improve pollutants removal and a periphyton bioreactor with an 84 cm column was built to investigate microbe-wastewater interactions. Periphyton greatly improved water quality and produced a distinct stratification in the water column into five redox zones with slight overlaps. From top to bottom these were: oxygen reduction, nitrate reduction, iron reduction, sulfate reduction and methanogenic zone. Periphyton communities had high species diversities (767-947 OTUs) with the facultative zone (middle layer) having higher species richness and functional diversity than the aerobic (top layer) and anaerobic zones (bottom layer). A good knowledge of interactions between periphyton and water column stratification could benefit from integration of periphyton to improve bioremediation of deep and static water. PMID- 26773956 TI - A biotechnological process efficiently co-produces two high value-added products, glucose and xylooligosaccharides, from sugarcane bagasse. AB - In this study, a co-production of two high value-added products, glucose and xylooligosaccharides (XOS), was investigated by utilizing sugarcane bagasse (SB) within a multi-product bio-refinery framework optimized by Box-Behnken design based response surface methodology. The developed process resulted in a maximum cellulose conversion of xylan-removed SB, 98.69+/-1.30%, and a maximum extracted SB xylan conversion into XOS (xylobiose and xylotriose) of 57.36+/-0.79% that was the highest SB xylan conversion reported in the literature, employing cellulase from Penicillium oxalicum EU2106 and recombinant endo-beta-1,4-xylanase in Pichia pastoris. Consequently, a mass balance analysis showed that the maximum yields of glucose and XOS were 34.43+/-0.32g and 5.96+/-0.09 g per 100 g raw SB. Overall, this described process may be a preferred option for the comprehensive utilization of SB. PMID- 26773957 TI - Use of magnetic nanoparticles to enhance bioethanol production in syngas fermentation. AB - The effect of two types of nanoparticles on the enhancement of bioethanol production in syngas fermentation by Clostridium ljungdahlii was examined. Methyl functionalized silica and methyl-functionalized cobalt ferrite-silica (CoFe2O4@SiO2-CH3) nanoparticles were used to improve syngas-water mass transfer. Of these, CoFe2O4@SiO2-CH3 nanoparticles showed better enhancement of syngas mass transfer. The nanoparticles were recovered using a magnet and reused five times to evaluate reusability, and it was confirmed that their capability for mass transfer enhancement was maintained. Both types of nanoparticles were applied to syngas fermentation, and production of biomass, ethanol, and acetic acid was enhanced. CoFe2O4@SiO2-CH3 nanoparticles were more efficient for the productivity of syngas fermentation due to improved syngas mass transfer. The biomass, ethanol, and acetic acid production compared to a control were increased by 227.6%, 213.5%, and 59.6%, respectively by addition of CoFe2O4@SiO2-CH3 nanoparticles. The reusability of the nanoparticles was confirmed by reuse of recovered nanoparticles for fermentation. PMID- 26773958 TI - Pellets valorization of waste biomass harvested by coagulation of freshwater algae. AB - There is a comparison of different coagulants: calcium chloride (20, 60, 120 and 180 mg/L); sodium alginate (10 and 20 mg/L) and tannins of Eucalyptus globulus bark (10 and 20 mg/L) in order to make the most of each method. The results show that 20 mg/L of tannin achieved a recovery efficiency of 95.35+/-1.16, sodium alginate 90.49+/-0.53 and 84.04+/-2.29 for calcium chloride. Taking into account the economic side of the coagulants, obtaining tannins is a profitable process. Bark is waste biomass obtained in the forestry process; therefore it does not involve extra costs. Finally, the feasibility of making pellets from harvested algae was studied, and the results suggest that waste biomass pellets may be used as fuel in boilers in a mixture <54% with other waste sources as Eucalyptus g. branches. PMID- 26773959 TI - Fast microwave-assisted catalytic co-pyrolysis of corn stover and scum for bio oil production with CaO and HZSM-5 as the catalyst. AB - This study investigated fast microwave-assisted catalytic co-pyrolysis of corn stover and scum for bio-oil production with CaO and HZSM-5 as the catalyst. Effects of reaction temperature, CaO/HZSM-5 ratio, and corn stover/scum ratio on co-pyrolysis product fractional yields and selectivity were investigated. Results showed that co-pyrolysis temperature was selected as 550 degrees C, which provides the maximum bio-oil and aromatic yields. Mixed CaO and HZSM-5 catalyst with the weight ratio of 1:4 increased the aromatic yield to 35.77 wt.% of feedstock, which was 17% higher than that with HZSM-5 alone. Scum as the hydrogen donor, had a significant synergistic effect with corn stover to promote the production of bio-oil and aromatic hydrocarbons when the H/C(eff) value exceeded 1. The maximum yield of aromatic hydrocarbons (29.3 wt.%) were obtained when the optimal corn stover to scum ratio was 1:2. PMID- 26773960 TI - beta-glucan restores tumor-educated dendritic cell maturation to enhance antitumor immune responses. AB - Tumors can induce the generation and accumulation of immunosuppressive cells such as myeloid-derived suppressor cells (MDSCs) in a tumor microenvironment, contributing to tumor escape from immunological attack. Although dendritic cell based cancer vaccines can initiate antitumor immune responses, tumor-educated dendritic cells (TEDCs) involved in the tolerance induction have attracted much attention recently. In this study, we investigated the effect of beta-glucan on TEDCs and found that beta-glucan treatment could promote the maturation and migration of TEDCs and that the suppressive function of TEDCs was significantly decreased. Treatment with beta-glucan drastically decreased the levels of regulatory T (Treg) cells but increased the infiltration of macrophages, granulocytes and DCs in tumor masses, thus elicited Th1 differentiation and cytotoxic T-lymphocyte responses and led to a delay in tumor progression. These findings reveal that beta-glucan can inhibit the regulatory function of TEDCs, therefore revealing a novel function for beta-glucan in immunotherapy and suggesting its potential clinical benefit. beta-Glucan directly abrogated tumor educated dendritic cells-associated immune suppression, promoted Th1 differentiation and cytotoxic T-lymphocyte priming and improved antitumor responses. PMID- 26773961 TI - Enantiomeric Separations of Pyriproxyfen and its Six Chiral Metabolites by High Performance Liquid Chromatography. AB - Pyriproxyfen is a chiral insecticide, and over 10 metabolites have been identified in the environment. In this work the separations of the enantiomers of pyriproxyfen and its six chiral metabolites were studied by high-performance liquid chromatography (HPLC). Both normal phase and reverse phase were applied using the chiral columns Chiralpak IA, Chiralpak IB, Chiralpak IC, Chiralcel OD, Chiralcel OD-RH, Chiralpak AY-H, Chiralpak AD-H, Chiracel OJ-H, (R,R)-Whelk-O 1, and Lux Cellulose-3. The effects of the chromatographic parameters such as mobile phase composition and temperature on the separations were investigated and the enantiomers were identified with an optical rotation detector. The enantiomers of these targets could obtain complete separations (resolution factor Rs > 1.5) on Chiralpak IA, Chiralpak IB, Chiralcel OD, Chiralpak AY-H, or Chiracel OJ-H under normal conditions. Chiralcel OJ-H showed the best chiral separation results with n-hexane as mobile phase and isopropanol (IPA) as modifier. The simultaneous enantiomeric separation of pyriproxyfen and four chiral metabolites was achieved on Chiralcel OJ-H under optimized condition: n-hexane/isopropanol = 80/20, 15 degrees C, flow rate of 0.8 ml/min, and UV detection at 230 nm. The enantiomers of pyriproxyfen and the metabolites , , and obtained complete separations on Chiralpak IA, Chiralpak IC, and Lux Cellulose-3 under reverse phase using acetonitrile/water as the mobile phase. The retention factors (k) and selectivity factors (alpha) decreased with increasing temperature, and the separations were better under low temperature in most cases. The work is of significance for the investigation of the environmental behaviors of pyriproxyfen on an enantiomeric level. PMID- 26773962 TI - Comparative study of treatment for distal radius fractures with two different palmar locking plates. AB - Few randomized trials have shown how the placement of a palmar locking plate affects outcomes. The purpose of this study was to compare clinical and radiological outcomes of fixation using locking plates with different concepts for placement relative to the watershed line in a prospective randomized trial. Sixty-four patients with a displaced distal radius fracture were divided into two groups according to the plates used for fixation: distal-type (AcuLoc(TM), Group A) and proximal-type (VariAx(TM), Group V). Wrist function including the range of motion and grip strength was compared at 1, 2, 3 and 6 months postoperatively. Loss of reduction was assessed radiologically. Both groups demonstrated overall satisfactory function at 6 months with no significant difference found between the groups. Minimal loss of reduction was demonstrated in both groups. Internal fixation using the palmar locking plates with two different placements provided satisfactory outcomes at 6-month follow-up, but our results indicate that plates placed distal to the watershed line may delay recovery of wrist motion. PMID- 26773963 TI - Highly Fluorescent and Photostable Polymeric Nanofibers as Scaffolds for Cell Interfacing and Long-Term Tracking. AB - Highly fluorescent polymeric nanofibers fabricated via electrospinning of PCL-DPP PCL (photostable polycaprolactones-di(thiophene-2-yl)-diketopyrrolopyrrole photostable polycaprolactones) and commercial PCL mixture show superior photostability and cytocompatibility for long-term tracking of cell-substrate interaction. As a proof of concept, these PCL-DPP-PCL nanofibers enable clear visualization of intricate cell-substrate interactions such as oligodendrocyte myelination. PMID- 26773965 TI - Expanding the ocular phenotype of 14q terminal deletions: A novel presentation of microphthalmia and coloboma in ring 14 syndrome with associated 14q32.31 deletion and review of the literature. AB - A variety of ocular anomalies have been described in the rare ring 14 and 14q terminal deletion syndromes, yet the character, prevalence, and extent of these anomalies are not well defined. Identification of these ocular anomalies can be central to providing diagnoses and facilitating optimal individual patient management. We report a child with a 14q32.31 terminal deletion and ring chromosome formation, presenting with severe visual impairment secondary to significant bilateral coloboma and microphthalmia. This patient is compared to previously reported patients with similar ocular findings and deletion sizes to further refine a locus for coloboma in the 14q terminal region. Those with ring formation and linear deletions are compared and the possibility of ring formation affecting the proximal 14q region is discussed. This report highlights the severity of ocular anomalies that can be associated with ring 14 and 14q terminal deletion syndromes and reveals the limited documentation of ocular examination in these two related syndromes. This suggests that many children with these genetic changes do not undergo an ophthalmology examination as part of their clinical assessment, yet it is only when this evaluation becomes routine that the true prevalence and extent of ocular involvement can be defined. This report therefore advocates for a thorough ophthalmological exam in children with ring 14 or 14q terminal deletion syndrome. PMID- 26773964 TI - CYP3A5 polymorphism affects the increase in CYP3A activity after living kidney transplantation in patients with end stage renal disease. AB - AIMS: It has been reported that cytochrome P450 (CYP)3A activity increases significantly in patients with end stage renal disease (ESRD) after kidney transplantation, with wide interindividual variability in the degree of increase. The aim of this study was to evaluate the influence of CYP3A5 polymorphism on the increase in CYP3A activity after living kidney transplantation, by measuring the plasma concentration of 4beta-hydroxycholesterol. METHODS: This prospective study recruited 22 patients with ESRD who underwent a first living kidney allograft transplantation, comprising 12 patients with CYP3A5*1 allele (CYP3A5*1/*1 or *1/*3) and 10 patients without CYP3A5*1 allele (CYP3A5*3/*3). RESULTS: No significant difference in estimated glomerular filtration rate over time was observed between patients with the CYP3A5*1 allele and patients without the CYP3A5*1 allele, suggesting that the degrees of recovery in renal function after living kidney transplantation were similar in the two groups. However, plasma concentrations of 4beta-hydroxycholesterol on days 90 (57.1 +/- 13.4 vs. 39.5 +/- 10.8 ng ml(-1)) and 180 (55.0 +/- 14.5 vs. 42.4 +/- 12.6 ng ml(-1)) after living kidney transplantation were significantly higher in the presence of the CYP3A5*1 allele than in the absence of the CYP3A5*1 allele [P = 0.0034 (95% confidence interval of difference 6.55, 28.6) and P = 0.043 (95% confidence interval of difference 0.47, 24.8), respectively], suggesting that CYP3A activity may increase markedly associated with recovery of renal function in patients with the CYP3A5*1 allele. CONCLUSIONS: These findings suggest that the presence of the CYP3A5*1 allele contributes to marked elevation of CYP3A activity associated with recovery of renal function after kidney transplantation. PMID- 26773966 TI - Cerebral palsy: the obstetrician is 'off the hook'...almost. PMID- 26773968 TI - Liver Transplantation From Uncontrolled DCD Donors: It's Time to Go Back to Basics. PMID- 26773967 TI - Shared cultural knowledge: Effects of music on young children's social preferences. AB - Adults use cultural markers to discern the structure of the social landscape. Such markers may also influence the social preferences of young children, who tend to conform to their own group and prefer others who do so. However, the forces that propel these preferences are unknown. Here, we use social preferences based on music to investigate these forces in four- and five-year-old children. First, we establish that children prefer other children whose favorite songs are familiar to them. Then we show that this effect depends on shared knowledge: children both prefer others who know songs they themselves know, and avoid others who know songs they do not know, irrespective of the target children's liking of the songs. These results suggest that young children have a remarkably selective sensitivity to shared cultural knowledge. Shared knowledge may be a powerful determinant of children's social preferences, both because it underpins effective communication and because it is conveyed by others through social interactions and therefore can serve as a marker of social group identity. PMID- 26773970 TI - Influence of evisceration time and carcass ageing conditions on wild venison quality. Preliminary study. AB - The influence of common carcass preparation practices of wild red deer on the physicochemical, microbiological and sensory quality of venison was assessed by varying evisceration time and ageing method. Deer were head shot; half were eviscerated 30 min and the other half 4 h post mortem. In both groups (n=18), 6 carcasses were skinned immediately after evisceration and aged for 24 h; 6 were aged unskinned for 24 h and 6 were aged unskinned for 72 h at 10 degrees C. Ageing method had a significant effect on the sensory quality of venison loin; unskinned ageing was associated with an increase of odour and taste intensity, and higher scores for gamey and sweet/caramel flavours. Carcasses aged for 72 h displayed darker and tender meat, but increased aerobic bacterial counts. Evisceration time had less influence on loin quality, although off-flavours were more often detected in deer eviscerated 4h post mortem. PMID- 26773971 TI - Consumers' segmentation based on the acceptability of meat from entire male pigs with different boar taint levels in four European countries: France, Italy, Spain and United Kingdom. AB - Two consumer studies were conducted to know the acceptability of pork with different boar taint levels: test 1 performed in Spain (n=126) and United Kingdom (n=146), and test 2 performed in France (n=139) and Italy (n=140). Each test had 3 types of pork: 'Female meat', 'Low boar tainted meat', and a third type was 'Medium boar tainted meat' or 'High boar tainted meat'. Three main clusters were identified on the basis of 'How delicious do you find this meat?': 1-Pork lovers, 2-Boar meat lovers, 3-Reject boar tainted meat. Additionally, in test 2, a fourth cluster was identified: 'Reject low tainted meat'. A group of 16.2-38.2% of consumers rejected meat from boars, and another group of 12.4-21.7% rated the meat with medium or high levels of boar taint better than the meat from females, identifying a niche for meat from medium and high levels of boar taint, and suggesting the need to select carcasses on the basis of boar taint. PMID- 26773972 TI - Effect of rigor temperature, ageing and display time on the meat quality and lipid oxidative stability of hot boned beef Semimembranosus muscle. AB - The effects of rigor temperature (5, 15, 20 and 25 degrees C), ageing (3, 7, 14, and 21 days) and display time on meat quality and lipid oxidative stability of hot boned beef M. Semimembranosus (SM) muscle were investigated. Ultimate pH (pH(u)) was rapidly attained at higher rigor temperatures. Electrical conductivity increased with rigor temperature (p<0.001). Tenderness, purge and cooking losses were not affected by rigor temperature; however purge loss and tenderness increased with ageing (p<0.01). Lightness (L*) and redness (a*) of the SM increased as rigor temperature increased (p<0.01). Lipid oxidation was assessed using (1)H NMR where changes in aliphatic to olefinic (R(ao)) and diallylmethylene (R(ad)) proton ratios can be rapidly monitored. R(ad), R(ao), PUFA and TBARS were not affected by rigor temperature, however ageing and display increased lipid oxidation (p<0.05). This study shows that rigor temperature manipulation of hot boned beef SM muscle does not have adverse effects on lipid oxidation. PMID- 26773969 TI - Responses to the Human Intruder Test are related to hair cortisol phenotype and sex in rhesus macaques (Macaca mulatta). AB - Measurement of cortisol in hair provides a chronic index of hypothalamic pituitary-adrenal (HPA) axis activity and has been applied to assessments of temperament (stable behavioral differences between individuals). However, the extent to which chronically high HPA axis activity relates to a correspondingly high degree of behavioral reactivity is as yet unknown. Therefore, the goal of the present experiment was to assess the relationship between hair cortisol and a reactive temperament. We administered the Human Intruder Test (HIT) twice to 145 (80 male) rhesus macaques (Macaca mulatta) in order to assess behavioral reactivity. The HIT presents monkeys with an unfamiliar experimenter and is composed of a Baseline phase (no intruder) followed by three experimental phases in which the orientation of the intruder changes (Profile, Stare, Back). Behavioral responses to the test were videotaped and behaviors thought to reflect a reactive response to the intruder were scored for duration. Hair samples collected within +/-1 month of the first HIT session were analyzed for cortisol by enzyme immunoassay. Subjects were assigned to three groups based on hair cortisol concentration: high, intermediate, and low cortisol phenotypes. Monkeys with the high cortisol phenotype were more reactive to the presence of the intruder than those with the low cortisol phenotype: they were more aggressive, scratched more, and spent more time in the back half of the cage. Males yawned significantly more while females spent more time immobile and in the back of the cage. Overall, monkeys with higher hair cortisol demonstrated an exaggerated response to the presence of the human intruder, supporting a relationship between high levels of chronic HPA axis activity and a reactive temperament. These results indicate that high levels of HPA axis activity, which may result from either genetic variation or environmental stress, correspond with heightened behavioral responses to a stressful experience. Am. J. Primatol. 79:e22526, 2017. (c) 2016 Wiley Periodicals, Inc. PMID- 26773973 TI - Engineering of bacterial exotoxins for highly efficient and receptor-specific intracellular delivery of diverse cargos. AB - The intracellular delivery of proteins with high efficiency in a receptor specific manner is of great significance in molecular medicine and biotechnology, but remains a challenge. Herein, we present the development of a highly efficient and receptor-specific delivery platform for protein cargos by combining the receptor binding domain of Escherichia coli Shiga-like toxin and the translocation domain of Pseudomonas aeruginosa exotoxin A. We demonstrated the utility and efficiency of the delivery platform by showing a cytosolic delivery of diverse proteins both in vitro and in vivo in a receptor-specific manner. In particular, the delivery system was shown to be effective for targeting an intracellular protein and consequently suppressing the tumor growth in xenograft mice. The present platform can be widely used for intracellular delivery of diverse functional macromolecules with high efficiency in a receptor-specific manner. Biotechnol. Bioeng. 2016;113: 1639-1646. (c) 2016 Wiley Periodicals, Inc. PMID- 26773975 TI - The role of oxidative and inflammatory stress and persistent viral infections in immunosenescence. AB - Immunosenescence involves age-related remodeling changes in the organization of lymphoid organs and functionality of immune cells, which have been associated with increased morbidity and mortality The pace of immunosenescence is modulated, however, by both intrinsic and extrinsic factors. Here, we review the mechanisms by which some factors, like the oxidative stress and certain chronic viral infections, may modulate the ageing immune system. Mounting evidence indicates that human cytomegalovirus (CMV) drives the expansion of late-differentiated T cells with an inflammatory profile. This would add to the "inflammaging" phenomenon, characterized by a low-grade inflammatory state, importantly involved in the etiology of several age-related diseases. We discuss that age-related oxidative stress is associated with chronic inflammation, and the oxidation inflammation theory of ageing is summarized. According to this theory, the ageing process is a chronic oxidative and inflammatory stress, leading to damage of cell components, including proteins, lipids and DNA, and contributing to the age related decline of physiological functions. Moreover oxi-inflamm-aging is associated with immunosenescence, which could be involved in the rate of ageing of individuals. PMID- 26773976 TI - Platypnea-Orthodeoxia Syndrome: From Gastroesophageal Reflux to Hypoxemia. PMID- 26773977 TI - Symptom Severity of Restless Legs Syndrome Predicts Its Clinical Course. AB - OBJECTIVE: This study examines the clinical course of restless legs syndrome according to its severity and factors associated with the remission of restless legs syndrome symptoms. METHODS: The remission or persistence of restless legs syndrome symptoms was investigated by considering patients with restless legs syndrome at the sleep clinic of Seoul National University Bundang Hospital. All subjects were observed for at least 18 months, and an incidence of remission was defined as having no restless legs syndrome symptoms for at least 1 year. Restless legs syndrome severity was evaluated by the International Restless Legs Syndrome Study Group Rating Scale. RESULTS: A total of 306 patients participated in this study. Over the observation periods of 4.1 +/- 1.6 years, the cumulative incidence of remission is 32.5% (95% confidence interval [CI], 27.0-38.0) and decreased with baseline restless legs syndrome severity (P < .001): 60% (95% CI, 44.9-75.1), 44% (95% CI, 34.4-53.6), and 16.7% (95% CI, 10.6-22.8) in mild, moderate, and severe to very severe restless legs syndrome cases, respectively. Most cases of remission (82/96) were observed within 1 year, and the remission occurred sooner for mild restless legs syndrome. The hazard ratios of remission by Cox proportional hazards model were lower for moderate (0.556; 95% CI, 0.340 0.909) and severe to very severe (0.193; 95% CI, 0.108-0.343) restless legs syndrome than for mild restless legs syndrome. The remission incidence was lower for those patients who had a family history of restless legs syndrome and were older at restless legs syndrome diagnosis. CONCLUSIONS: Mild restless legs syndrome severity, no family history, and young age at restless legs syndrome diagnosis were significant predictors of restless legs syndrome remission. More than 80% of patients with severe restless legs syndrome showed a chronic clinical course. PMID- 26773978 TI - Long-term prospective cohort study on dental implants: clinical and microbiological parameters. AB - OBJECTIVE: The aim of the present prospective cohort study is to evaluate clinical and microbiological data of dental implants after at least 8 years of follow-up. MATERIAL AND METHODS: A total of 110 patients and 232 implants were included at baseline and followed during 1 year. Fifty-two patients and 108 implants could be evaluated at the final examination. Clinical and microbiological data were taken at baseline, 1 year and at least 8 years. RESULTS: The mean follow-up time was 10.8 +/- 1.7 years. Plaque index was, respectively, 0.50 +/- 0.50 at baseline, 0.50 +/- 0.50 at 1 year and 0.33 +/- 0.67 at >=8 years. Gingival index was, respectively, 1.08 +/- 0.19 at baseline, 1.01 +/- 0.39 at 1 year and 0.22 +/- 0.47 at >=8 years. Sulcular bleeding index was, respectively, 0.17 +/- 0.22 at baseline, 0.11 +/- 0.33 at 1 year and 0.17 +/ 0.22 at >=8 years. Probing depth was, respectively, 2.67 +/- 0.75 at baseline, 3.00 +/- 0.83 at 1 year and 2.74 +/- 1.00 at >=8 years. Clinical attachment level was, respectively, 3.75 +/- 1.17 at baseline, 4.00 +/- 1.06 at 1 year and 4.00 +/ 1.17 at >=8 years. Peri-implant mucositis was detected around 60.2% of implants in 73.1% of patients, while peri-implantitis was affecting 12% of implants in 15.4% of patients. Some bacteria species were associated with worsened clinical parameters. CONCLUSIONS: About 69.4% of implants (75/108) and 67.3% of the patients (35/52) were considered as success in the present prospective cohort study after a mean follow-up of 10.8 years. Microbial follow-up may help to identify patients at risk for peri-implant disease. PMID- 26773979 TI - Imaging Cancer Cells Expressing the Folate Receptor with Carbon Dots Produced from Folic Acid. AB - Development of new imaging tools for cancer cells in vitro and in vitro is important for advancing cancer research, elucidating drug effects upon cancer cells, and studying cellular processes. We showed that fluorescent carbon dots (C dots) synthesized from folic acid can serve as an effective vehicle for imaging cancer cells expressing the folate receptor on their surface. The C-dots, synthesized through a simple one-step process from folic acid as the carbon source, exhibited selectivity towards cancer cells displaying the folate receptor, making such cells easily distinguishable in fluorescence microscopy imaging. Biophysical measurements and competition experiments both confirmed the specific targeting and enhanced uptake of C-dots by the folate receptor expressing cells. The folic acid-derived C-dots were not cytotoxic, and their use in bioimaging applications could aid biological studies of cancer cells, identification of agonists/antagonists, and cancer diagnostics. PMID- 26773980 TI - Low back pain with radicular symptoms as a presentation of hereditary neuropathy with liability to pressure palsies: the diagnostic challenge of an atypical presentation. PMID- 26773981 TI - Intraventricular Glioblastomas. AB - BACKGROUND AND IMPORTANCE: Although glioblastoma is the most common primary brain tumor, primary intraventricular locations are extremely rare; only 21 cases have been reported to date. METHODS: A retrospectively acquired database of all intracranial glioblastomas treated in 2 different neurosurgical departments during the last 10 years was queried. Patients with histologically proven intraventricular glioblastomas were included in the study. RESULTS: Eight patients were identified as having a histologically confirmed intraventricular glioblastoma. Patient age at diagnosis ranged from 6 to 74 years (mean 29.6 years) and the male/female ratio was 5:3. Increased intracranial pressure due to hydrocephalus was the main cause of the clinical manifestations. The tumor was located within the lateral ventricle in 6 cases and the anterior third ventricle in 2 others. Gross total tumor excision was achieved in 3 patients, whereas the surgical resection was subtotal in 4 cases and a surgical biopsy was performed in 1 patient. Postoperative adjuvant therapies were administered in 5 patients. Median survival time was 32.1 months, and 3 patients were alive at the end of study. All of them had isocitrate dehydrogenase-mutated tumors. CONCLUSIONS: Intraventricular glioblastoma is extremely rare and can affect younger individuals including children. This malignant tumor should be included in the differential diagnosis of intraventricular lesions, especially in the lateral ventricles. Radical surgical resection can be associated with remarkable disease free survival, especially in isocitrate dehydrogenase-mutated tumors. Because recurrence virtually is unavoidable, long-term follow-up is mandatory. PMID- 26773982 TI - Protection Device Made of a Modified Syringe for Muscle Protection During Cranial Perforation: Technical Note. AB - In neurosurgical procedures, avoiding damage of surrounding tissues such as muscle and periosteum during a craniotomy is important for esthetic and other reasons. We devised a protection tool by using an amputated syringe barrel to cover the perforating drill and protect temporal muscle damage. This device made it possible to prevent damage to surrounding tissues, such as the muscle and periosteum, during cranial perforation. This method could be useful as it is cost effective, simple, and versatile. PMID- 26773983 TI - Early Versus Delayed Surgical Decompression of Spinal Cord after Traumatic Cervical Spinal Cord Injury: A Cost-Utility Analysis. AB - OBJECTIVE: This cost-utility analysis was undertaken to compare early (<=24 hours since trauma) versus delayed surgical decompression of spinal cord to determine which approach is more cost effective in the management of patients with acute traumatic cervical spinal cord injury (SCI). METHODS: This study includes the patients enrolled into the Surgical Timing in Acute Spinal Cord Injury Study (STASCIS) and admitted at Toronto Western Hospital. Cases were grouped into patients with motor complete SCI and individuals with motor incomplete SCI. A cost-utility analysis was performed for each group of patients by the use of data for the first 6 months after SCI. The perspective of a public health care insurer was adopted. Costs were estimated in 2014 U.S. dollars. Utilities were estimated from the STASCIS. RESULTS: The baseline analysis indicates early spinal decompression is more cost-effective approach compared with the delayed spinal decompression. When we considered the delayed spinal decompression as the baseline strategy, the incremental cost-effectiveness ratio analysis revealed a saving of US$ 58,368,024.12 per quality-adjusted life years gained for patients with complete SCI and a saving of US$ 536,217.33 per quality-adjusted life years gained in patients with incomplete SCI for the early spinal decompression. The probabilistic analysis confirmed the early-decompression strategy as more cost effective than the delayed-decompression approach, even though there is no clearly dominant strategy. CONCLUSIONS: The results of this economic analysis suggests that early decompression of spinal cord was more cost effective than delayed surgical decompression in the management of patients with motor complete and incomplete SCI, even though no strategy was clearly dominant. PMID- 26773984 TI - Epidemiology of depression at Traditional Chinese Medicine Hospital in Shanghai, China. AB - BACKGROUND: Though Chinese Traditional Medicine (TCM) is one of the most important parts of health care system in China, studies on the epidemiology of depression in TCM are scarce and mental health issues in TCM have been neglected for longtime. METHODS: This was an interview-based survey. The prevalence of depression and suicidal risk in outpatients at a TCM hospital was identified by a one-stage diagnosing process using the Mini International Neuropsychiatric Interview. Associated risk factors, role impairment, and service utility were also assessed. RESULTS: A total of 2000 outpatients aged from 18 to 65years completed the survey with a response rate of 87.0%. The estimated prevalence of major depressive disorder was 13.2% for lifetime and 4.9% for current. No significant gender differences were found. Depression was more common in patients who lacked social support, experienced family economic burden and health burden, and underwent negative life events, poor self-rated health, or with moderate/severe sleep problem than in their correspondents; all with statistical significance (OR: 1.83-6.82). Patients with depression reported a mean of 82.7days and 99.3days of sick leave due to their physical and mental condition, respectively, which was much longer than those without depression (24.8days and 25.8days, respectively). Only 30.0% of patients with depression sought professional help from psychiatrists/psychologists or used antidepressants. LIMITATIONS: The recall bias could not be ruled out in this study and could have led to an underestimation of true prevalence and the unmet need for treatment. Since this study was cross-sectional, the causal relationships between sociodemographic factors and depression cannot be determined. CONCLUSIONS: Depression is common at TCM hospitals. The impairments due to depression are striking, and unmet needs for treatment are pervasive. Consequently, mental health services in TCM should not be neglected any longer. PMID- 26773985 TI - The effect of cigarette smoking on vitamin D level and depression in male patients with acute ischemic stroke. AB - OBJECTIVE: The association between low vitamin D levels and depression has been well documented in nonstroke subjects. Accumulating evidence shows that low vitamin D levels may be also associated with depression post stroke. Cigarette smoking was associated with lower vitamin D levels. The purposes of this study were to compare vitamin D levels in smokers to nonsmokers and examine the association between vitamin D levels and depression symptoms in patients with acute ischemic stroke. MATERIALS AND METHODS: Serum levels of 25-hydroxyvitamin D [25(OH)D] were measured in 194 males within 24h after admission: 116 smokers and 78 nonsmokers. Depression symptoms were assessed with the 17-item Hamilton Depression Scale (HAMD-17). Patients with the HAMD-17 score >7 were identified to have depression symptoms. RESULTS: The chi-square test showed that the frequency of depression in the smoker group was 23.3% (27/116), which was significantly higher than that in the nonsmoker group (11.5%=9/78), with an odds ratios (OR) of 2.33 (95% CI: 1.03-5.27; chi(2)=4.25, df=1, p=0.039, phi=0.15). Vitamin D levels were significantly lower in smokers than in nonsmokers (52.4+/-20.8 vs 61.7+/ 19.2; F=9.88, p=0.002), with an effect size of 0.05 (etap(2)). Patients with depression symptoms showed lower vitamin D levels than those with no depression symptoms (49.2+/-19.6 vs 57.7+/-20.6; F=5.03, p=0.03), with an effect size of 0.03 (etap(2)). CONCLUSION: Higher rates of depression in smokers with acute ischemic stroke may be associated with lower vitamin D levels induced by smoking. PMID- 26773986 TI - Psychometric properties of the DY-BOCS in a Turkish sample of children and adolescents. AB - BACKGROUND: Dimensional Yale-Brown Obsessive-Compulsive Scale (DY-BOCS) is a promising scale for assessing frequency and severity of symptom dimensions. The main objective of the study was to assess the psychometric properties of the DY BOCS in a large sample of children and adolescents from Turkey. METHODS: We studied 143 children and adolescents, 7-18years, with well characterized DSM-IV-R OCD, ascertained from seven collaborating university or state hospital sites. We compared the DY-BOCS scores with the Children's Yale-Brown Obsessive-Compulsive Scale (CY-BOCS), the Children's Depression Inventory (CDI), the Yale Global Tic Severity Scale (YGTSS) and the Child Behavior Checklist 6-18years (CBCL 6-18). RESULTS: The internal consistency of the DY-BOCS symptom dimensions and inter rater agreement of component scores were excellent. The agreement between global DY-BOCS score and the total CY-BOCS score was highly significant (Pearson's r=0.55, p<0.0001). Severity scores for individual symptom dimensions were independent of one another, only modestly correlating with the global ratings, and were also differentially related to ratings of depression, anxiety and tic severity. CONCLUSION: The DY-BOCS is a reliable and valid instrument for assessing multiple aspects of OCD symptom severity in children and adolescents from Turkey. PMID- 26773988 TI - Non-suicidal self-injury and suicidal thoughts and behaviors in heterosexual and sexual minority young adults. AB - OBJECTIVE: Despite consistently greater rates of non-suicidal self-injury (NSSI) and suicidal thoughts and behaviors (STBs; i.e., suicidal ideation, method/plan, and attempts) in lesbian, gay, and bisexual (LGB) individuals, prevalence, characteristics, and relations between these dangerous thoughts and behaviors are equivocal. The present study sought to examine and compare the rates of NSSI and STBs in a large sample of sexual minority and majority young adults. METHODS: Participants were 12,422 college students (ages 18-29; 57.3% female) who self reported demographic characteristics, NSSI frequency, the number of NSSI forms used, the number of NSSI functions, as well as STB history (i.e., ideation, method/plan, and attempts). Each participant's degree of SA was assessed via a 7 point scale (i.e., K0-K6) from Alfred Kinsey's research of sexual attraction and sexual experiences. This scale was collapsed to create five categories of SA: exclusively other SA (K0), mostly other SA (K1/2), equally other and same SA (K3), mostly same SA (K4/5), and exclusively same SA (K6). RESULTS: Consistent with previous research, we found that being a sexual minority young adult was associated with significantly higher odds of STBs compared to being a heterosexual young adult. In addition, compared to the exclusively other SA group (K0), being in the mostly other SA group (K1/2), equally other and same SA group (K3), or mostly same SA group (K4/5) was associated with significantly higher odds of NSSI engagement. Among those with NSSI, we found that the number of NSSI forms was significantly associated with suicide attempts, but was not associated with either suicidal ideation or suicide method/plan in the mostly other SA group (K1/2) or in the equally other and same SA group (K3). We also found a significant curvilinear relation between NSSI frequency and STBs in the mostly other SA group (K1/2) and between NSSI frequency and suicide method/plan and attempt in the exclusively other SA group (K0). In addition, we revealed specificity with regard to the relation between the number of lifetime NSSI episodes and risk for STBs among the equally other and same SA (K3), mostly same SA (K4/5), and exclusively same SA (K6) groups. CONCLUSION: Our findings suggest that among sexual minority young adults, equally other and same SA individuals may be at higher risk of NSSI and STBs than their sexual minority counterparts. In addition, these findings extend previous research by suggesting that the relations between NSSI frequency, number of forms, and number of functions and STBs might vary according to SA. A multi-theory based explanation is provided to explain the key findings and the study implications are discussed. PMID- 26773989 TI - Anomalous self-experiences and their relationship with symptoms, neuro-cognition, and functioning in at-risk adolescents and young adults. AB - Empirical and theoretical studies support the notion that anomalous self experience (ASE) may constitute a phenotypic aspect of vulnerability to schizophrenia, but there are no studies examining the relationship of ASE with other clinical risk factors in a sample of ultra-high risk (UHR) subjects. The aim of the present study was to explore the relationship between ASE, prodromal symptoms, neurocognition, and global functioning in a sample of 45 UHR adolescents and young adults (age range 15-25years) at first contact with Public Mental Health Services. Prodromal symptoms and global functioning were assessed through the SIPS interview. ASE was evaluated through the Examination of Anomalous Self-Experience (EASE); for neurocognition, we utilized a battery of tests examining seven cognitive domains as recommended by the Measurement And Treatment Research to Improve Cognition in Schizophrenia. In the UHR group, higher levels in two domains of the EASE (stream of consciousness and self awareness) were found in comparison with help-seeking subjects. Correlational analysis corrected for possible confounding variables showed a strong association (p>0.001) between higher EASE scores and global functioning. A principal factor analysis with Varimax rotation yielded a two-factor solution, jointly accounting for 70.58% of the total variance in the UHR sample. The first factor was comprised of SOPS domains, while the second was comprised of EASE-total, EASE-10, and GAF variables. Our findings provide support for the notion that disorders of self-experience are present early in schizophrenia and are related to global functioning. As such, they may constitute a potential marker of risk supplementing the UHR approach. PMID- 26773987 TI - The effect of community stress and problems on psychopathology: A structural equation modeling study. AB - This research aimed to estimate the effect of perceived social factors in the community stress and problems on the residents' psychopathology such as depression and suicidal behaviors. Subjects of this study were the informants (N=1618) in a psychological autopsy (PA) study with a case-control design. We interviewed two informants (a family member and a close friend) for 392 suicides and 416 living controls, which came from 16 rural counties randomly selected from three provinces of China. Community stress and problems were measured by the WHO SUPRE-MISS scale. Depression was measured by CES-D scale, and suicidal behavior was assessed by NCS-R scale. Multivariable liner and logistic regression models and the Structural Equation Modeling (SEM) were applied to probe the correlation of the depression and the suicidal behaviors with some major demographic variables as covariates. It was found that community stress and problems were directly associated with rural Chinese residents' depression (Path coefficient=0.127, P<0.001). There was no direct correlation between community stress and problem and suicidal behaviors, but community stress and problem can affect suicidal behaviors indirectly through depression. The path coefficient between depression and suicidal behaviors was 0.975. The current study predicts a new research viewpoint, that is, the depression is the intermediate between community stress and problem and suicidal behaviors. It might be an effective route to prevent depression directly and suicidal behaviors indirectly by reducing the community stress and problems. PMID- 26773990 TI - Heroin craving and its correlations with clinical outcome indicators in people with heroin dependence receiving methadone maintenance treatment. AB - BACKGROUND: Craving for substance use has been added as one of the diagnostic criteria of substance use disorders in DSM-5. However, further research is necessary to examine and expand the clinical potential of craving in the assessment and treatment for heroin users. This study aimed to examine the psychometrics of the Desire for Drug Questionnaire-Chinese Mandarin version (DDQ CM) and its clinical utility of assessing craving for heroin measured among heroin users with methadone maintenance treatment (MMT). METHOD: Self-reported craving for heroin use was measured on the DDQ-CM and visual analog scale among 314 intravenous heroin users receiving MMT. Self-reported heroin dependence, attitude toward heroin use, readiness to change heroin use, and depression were collected. RESULTS: The results found that although the original three-factor model was acceptable for applying the DDQ-CM for heroin users with MMT, only the concurrent validity of the subscales of Desire and Intention and Negative Reinforcement was supported but not that of Control. Meanwhile, the levels of craving on the subscales of Desire and Intention and of Negative Reinforcement on the DDQ-CM were positively associated with the levels of heroin dependence, positive and negative attitudes toward heroin use, and depression, but negatively associated with readiness to change heroin use. CONCLUSIONS: This study supported the application of the subscales of Desire and Intention and Negative Reinforcement on the DDQ-CM to measure heroin craving in Taiwanese-Chinese heroin users and supported the clinical implication of craving in heroin users with MMT. PMID- 26773992 TI - Associations of symptoms, neurocognition, and metacognition with insight in schizophrenia spectrum disorders. AB - Many persons with schizophrenia experience poor insight and, as a result, are at risk for treatment non-adherence and numerous negative outcomes. However, to date, the etiology of poor insight has not yet been fully elucidated. One recent theory concerning the roots of poor insight in schizophrenia has proposed that it may result, in part, from impairments in metacognition, or the capacity to think about thinking. The present study thus aims to examine whether metacognition is associated with insight even after controlling for the effects of psychiatric symptomatology and neurocognition. In this study, 95 adults with a schizophrenia spectrum disorder were assessed on measures of insight (i.e., awareness of symptoms, treatment needs, and illness consequences), psychiatric symptoms (i.e., positive symptoms, negative symptoms, and general psychopathology), neurocognitive functions (i.e., executive function, memory, and attention), and metacognitive capacities (i.e., self-reflectivity and theory of mind). Univariate correlations followed by stepwise multiple regressions, which controlled for symptoms and neurocognition, indicated that both self-reflectivity and theory of mind were significantly linked with awareness of symptoms; theory of mind was linked with awareness of treatment needs; and self-reflectivity was linked with awareness of illness consequences. Importantly, these findings suggest that metacognitive capacities may be related to insight independent of concurrent psychiatric symptoms and neurocognitive deficits. Moreover, awareness of different facets of the illness may require contributions from different components of metacognition. Future research should investigate how existing metacognitive skill training programs could potentially be tailored, or modified, to help persons with schizophrenia to develop and enhance insight. PMID- 26773991 TI - Demographic and clinical characteristics associated with comorbid cannabis use disorders (CUDs) in hospitalized patients with bipolar I disorder. AB - BACKGROUND: Published data suggest that cannabis use is associated with several negative consequences for individuals with bipolar disorder (BD), including new manic episode onset, psychosis, and functional disability. Yet much less is known about cannabis use disorders (CUDs) in this population, especially in more acutely symptomatic groups. METHODS: To evaluate correlates of CUD comorbidity in BD, a retrospective chart review was conducted for 230 adult patients with bipolar I disorder (BDI) who were admitted to a university-affiliated private psychiatric hospital. Using a computer algorithm, a hospital administrator extracted relevant demographic and clinical data from the electronic medical record for analysis. RESULTS: Thirty-six (16%) had a comorbid CUD. CUD comorbidity was significantly associated with younger age, manic/mixed episode polarity, presence of psychotic features, and comorbid nicotine dependence, alcohol use disorder (AUD), and other substance use disorders, but was associated with decreased likelihood of anxiety disorder comorbidity. With the exception of manic/mixed polarity and AUD comorbidity, results from multivariate analyses controlling for the presence of other SUDs were consistent with univariate findings. CONCLUSION: Patients with BD and comorbid CUDs appear to be a complex population with need for enhanced clinical monitoring. Given increasing public acceptance of cannabis use, and the limited availability of evidenced-based interventions targeted toward CUDs in BD, psychoeducation and other treatment development efforts appear to be warranted. PMID- 26773993 TI - Reactions of Oklahoma City bombing survivors to media coverage of the September 11, 2001, attacks. AB - OBJECTIVE: This study explored the effects of media coverage of a terrorist incident in individuals remote from the location of a major attack who had directly experienced a prior terrorist incident. METHOD: Directly-exposed survivors of the 1995 Oklahoma City bombing, initially studied six months after the incident, and indirectly-affected Oklahoma City community residents were assessed two to seven months after the September 11, 2001, attacks. Survivors were assessed for a diagnosis of bombing-related posttraumatic stress disorder (PTSD) at index and follow up, and emotional reactions and September 11 media behavior were assessed in all participants. RESULTS: Among the three investigated forms of media (television, radio, and newspaper), only television viewing was associated with 9/11-related posttraumatic stress reactions. Exposure to the Oklahoma City bombing was associated with greater arousal in relation to the September 11 attacks, and among survivors, having developed bombing-related PTSD was associated with higher scores on all three September 11 posttraumatic stress response clusters (intrusion, avoidance, and arousal). Although time spent watching television coverage of the September 11 attacks and fear-related discontinuation of media contact were not associated with Oklahoma City bombing exposure, discontinuing September 11 media contact due to fear was associated with avoidance/numbing in the full sample and in the analysis restricted to the bombing survivors. CONCLUSION: Surviving a prior terrorist incident and developing PTSD in relation to that incident may predispose individuals to adverse reactions to media coverage of a future terrorist attack. PMID- 26773995 TI - Symptom accommodation, trichotillomania-by-proxy, and interpersonal functioning in trichotillomania (hair-pulling disorder). AB - OBJECTIVE: This study investigated relationship functioning in trichotillomania (TTM) as well as specific interpersonal behaviors that have received little attention in TTM research, including by-proxy pulling, symptom accommodation, and self-disclosure. The objective was to contribute data for future development of components of treatment that focus on interpersonal functioning. METHODS: Data were collected through survey about relationships and related difficulties among adults who endorsed criteria consistent with DSM-5 criteria for TTM (n=670). RESULTS: Consistent with our hypotheses, TTM symptom severity was correlated negatively with relationship satisfaction and perceived social support, positively with perceived criticism, perceived risk in intimacy, and social interaction anxiety, though these correlations were small (absolute values r=.08 to .17). Approximately one-quarter of survey respondents had not told their closest friend about their trichotillomania, and one-fifth had not told their spouse or long-term romantic partner. TTM-by-proxy urges were reported by 54% of participants, and 37% of participants reported having actually pulled hair from other people, with the most common proxies specified as significant others (51%), parents (13%), friends (8%), siblings (8%), children (7%) and pets (5%). Higher levels of TTM-by-proxy urges were associated with "focused" pulling (d=.37) and perfectionistic thinking (d=.16 to .20), yet current by-proxy urges were not associated with, functional impairment. A small minority of individuals (7%) reported having asked other people to pull hair for them (78% of these requests were granted); there was increased endorsement of "focused" pulling among these individuals. The people who participants asked to pull hairs for them included significant others (66%), mothers (20%), siblings (11%), friends (9%) and one's children (9%). CONCLUSION: More than one-third of respondents had pulled hair from others, 7% had asked others to pull their hair, and sizable minorities kept TTM secret from their closest friends or even spouse/partners. Clinical levels of social interaction anxiety were endorsed by 51% of the sample. Understanding these interpersonal experiences more fully could improve our understanding of relationship functioning in TTM and guide efforts to individualize treatment for adults with TTM. PMID- 26773994 TI - Identifying a physical indicator of suicide risk: Non-suicidal self-injury scars predict suicidal ideation and suicide attempts. AB - BACKGROUND: Suicide risk is challenging to quantify due to reliance on self report, which is limited by individuals' lack of insight and the desire to conceal such intentions. Non-suicidal self-injury (NSSI) is one of the most robust predictors of suicidal ideation (SI) and suicide attempts (SA). Although NSSI often leads to permanent scarring, which can be assessed by objective physical examination, no research has examined whether scarring denotes tangible risk for SI and SA. The present study examined whether NSSI scar presence and number predict current SI and SA history. Further, we examined whether brooding would exacerbate the effects of NSSI scarring on SI or SA. METHODS: Young adults (N=231; M=21.24 years; 78% female) completed self-report questionnaires assessing SA history, frequency of NSSI, presence/number of NSSI scars, brooding, current depressive symptoms, and SI. RESULTS: NSSI scar presence and number predicted current SI and SA history after controlling for current depressive symptoms. Moreover, scar presence and number predicted current SI over and above the effects of SA history and NSSI frequency, method, and medical severity. Further, NSSI scar presence and number predicted SI more strongly among individuals with greater levels of brooding than among individuals with lower levels of brooding. CONCLUSIONS: The presence and number of NSSI scars are objective physical indicators of risk for SI and SAs. Brooding may further heighten the risk of SI for individuals bearing NSSI scars. PMID- 26773996 TI - Temperaments in completed suicides: Are they different from those in suicide attempters and controls? AB - BACKGROUND: Temperaments in completed suicides have never been assessed whereas there is substantial research on temperaments in attempted suicides and psychiatric patients. METHODS: The significant others of 18 completed suicides participated in this study in order to provide an assessment of temperaments, hopelessness, depression and the suicide risk of their loved ones. The data were compared with data from 244 psychiatric patients of whom 83 had attempted suicide in the previous month. The following instruments were used: the Temperament Evaluation of Memphis, Pisa, Paris and San Diego-auto questionnaire (TEMPS-A), the Beck Hopelessness Scale (BHS), the Gotland Scale for Male Depression (GSMD), and the Mini International Neuropsychiatric Interview (MINI) module for assessing suicide risk. RESULTS: Individuals who died by suicide more frequently had scores of 9 or higher on the BHS and higher MINI suicide risk scores compared with patients with mood disorders who had not attempted suicide in the previous month. Completed suicides also had lower scores on the TEMPS-A Cyclothymia and Anxiety scales and on the MINI suicide risk scale than mood disorder patients with a recent suicide attempt. LIMITATIONS: Proxy assessment of variables through survivors can result in underestimation of psychiatric morbidity and other parameters investigated, and limits the generalization of our results CONCLUSIONS: Our study adds information about temperamental subtypes and other variables in completed suicides and points to their difference from attempted suicides and non-suicidal psychiatric patients. PMID- 26773997 TI - Characteristics of motivation and their impacts on the functional outcomes in patients with schizophrenia. AB - BACKGROUND: Deficits of motivation have been considered to be a core feature of schizophrenia, and recent studies have begun to reveal the biological and psychological characteristics and mechanisms underlying the deficits in motivation in schizophrenia patients. The aims of the present study were to investigate the characteristics of motivation in schizophrenia patients using the General Causality Orientations Scale (GCOS), and the impacts of motivational orientations on the functional outcomes in schizophrenia patients. METHODS: A total of 53 outpatients with schizophrenia and 38 healthy controls were recruited for this study. The GCOS was used to assess individual tendencies in respect of three different motivational orientations: the autonomy, controlled, and impersonal orientations, corresponding to intrinsic motivation, extrinsic motivation, and amotivation, respectively. The cognitive functioning, psychiatric symptoms, social functioning, and quality of life of the subjects were also assessed. RESULTS: The score for autonomy orientation was significantly lower in the patient group than that in the control group, while no significant differences were found between the two groups in respect of the scores for the other two orientations. The autonomy orientation was associated with various clinical variables, and regression analysis identified as one of the variables with the highest predictive accuracy for social functioning. CONCLUSIONS: Intrinsic motivation measured by the GCOS in schizophrenia patients was significantly lower than that in healthy controls. The deficits of intrinsic motivation were broadly associated with the clinical features and were a determinant of social functioning. Development of treatments for enhancing intrinsic motivation would be essential for functional recovery in schizophrenia patients. PMID- 26773998 TI - Motivation and Pleasure Scale-Self-Report (MAP-SR): Validation of the German version of a self-report measure for screening negative symptoms in schizophrenia. AB - OBJECTIVES: Validated self-report instruments could provide a time efficient screening method for negative symptoms in people with schizophrenia. The aim of this study was to examine the psychometric properties of a German version of the Motivation and Pleasure Scale-Self-Report (MAP-SR) which is based on the Clinical Assessment Interview for Negative Symptoms (CAINS). METHODS: In- and outpatients (N=50) with schizophrenia or schizoaffective disorder were assessed with standardized interviews and questionnaires on negative and positive symptoms and general psychopathology in schizophrenia, depression, and global functioning. RESULTS: The German version of the MAP-SR showed high internal consistency. Convergent validity was supported by significant correlations between the MAP-SR with the experience sub-scale of the CAINS and the negative symptom sub-scale of the Positive and Negative Syndrome Scale. The MAP-SR also exhibited discriminant validity indicated by its non-significant correlations with positive symptoms and general psychopathology, which is in line with the findings for the original version of the MAP-SR. However, the MAP-SR correlated moderately with depression. CONCLUSION: The German MAP-SR appears to be a valid and suitable diagnostic tool for the identification of negative symptoms in schizophrenia. PMID- 26773999 TI - Sexual dysfunction and its impact on quality of life in Chinese patients with schizophrenia treated in primary care. AB - PURPOSE: Sexual dysfunction in schizophrenia patients is common. In China, maintenance treatment for clinically stable patients with schizophrenia is usually provided by primary care physicians. Illness- or treatment-related sexual dysfunction in this patient population has been never studied. This study describes the prevalence and correlates of sexual dysfunction and its impact on quality of life (QOL) in patients with schizophrenia treated in primary care in China. METHOD: A total of 607 patients with schizophrenia treated in 22 randomly selected primary care services in China formed the study sample. Patients' socio demographic and clinical characteristics including sexual function and QOL were recorded using a standardized protocol and data collection. RESULTS: Sexual dysfunction was present in 69.9% of all patients; 60.7% in males and 80.6% in females. Multiple logistic regression analysis revealed that female gender, being single, older age and use of first-generation antipsychotics were independently and significantly associated with more sexual dysfunction accounting for 23.5% of its variance (P<0.001). Unexpectedly, sexual dysfunction was not associated with lower QOL. CONCLUSIONS: High rate of sexual dysfunction was reported in the majority of patients with schizophrenia treated in primary care in China. Given its negative impact on social adjustment, QOL and treatment adherence, efforts should be made to address sexual dysfunction in this patient population. PMID- 26774000 TI - Accuracy of the number of previous episodes reported by patients with bipolar disorder. AB - BACKGROUND: The number of previous episodes in patients with BD is a variable widely used for both clinical and research purposes. The aim of this study was to compare the number of episodes retrospectively reported by euthymic BD subjects with that registered by their psychiatrists during a follow-up period. METHODS: Fifty euthymic patients with BD and more than 2years of follow-up were retrospectively asked in a standardized fashion about the number of hypomanic/manic and depressive episodes suffered during that period. Patient reported outcomes were compared with the number of episodes registered by psychiatrists in a life chart during the same period. RESULTS: The mean follow-up of patients was 66.70months. There was a mean difference of 2.74 episodes between reports of patients' and psychiatrists' reports during the complete follow-up period; Intraclass correlation coefficient was 0.40 (CI95%=0.15-0.61). This difference increased with the duration of the follow-up period (R=0.33, p=0.023) and with the number of episodes occurred during that (R=0.32, p=0.023). The difference between patient-reported and clinician-rated in the number of depressive during the follow-up period was more pronounced in BDII than in BDI (Z=-2.47, p=0.014), and it correlated with the number of previous depressive episodes at baseline (R=0.28, p=0.047) and subclinical depressive symptoms (R=0.41, p=0.003). CONCLUSIONS: The number of previous episodes referred by patients with BD is not an accurate measure of the true number of episodes suffered. The theoretical and practical implications of these findings are discussed. PMID- 26774001 TI - Compulsive buying in university students: its prevalence and relationships with materialism, psychological distress symptoms, and subjective well-being. AB - BACKGROUND: Compulsive buying has become a severe problem among young people. The prominent role that psychological variables play in this phenomenon support their consideration in establishing a risk profile for compulsive buying that serves as a guide for the development of prevention and treatment programs with guarantees of effectiveness. However, there are only a small number of studies in existence which have explored the compulsive buying prevalence among students, and none of them have been conducted in a Mediterranean country. OBJECTIVES: This study aims to estimate the compulsive buying prevalence in a sample of university students from the region of Galicia (Spain). We also intend to determine if statistically significant differences exist between compulsive buyers and non-compulsive buyers in relation with gender, materialistic values, psychological distress symptoms and subjective well-being. Lastly, the clarification of which of the determinants examined represent risk or protection factors for compulsive buying constitutes another important objective of this paper. METHODS: A total sample of 1448 university students participated in this study. They answered a battery of self reports assessing gender, compulsive buying propensity, materialism, distress symptomatology, and well-being. Participants were initially classified as either compulsive buyers or non-compulsive buyers. Both groups were compared for the aforementioned variables through chi-square testing or variance analyses. Then, a multivariate logistic regression analysis was conducted to determine which of these determinants make up a risk profile for compulsive buying. RESULTS: The estimated prevalence of compulsive buying in the sample of university students considered was 7.4%. Statistically significant differences between compulsive buyers and non-compulsive buyers were detected for gender, and each and every one of the psychological variables explored. Specifically, it was confirmed that compulsive buyers obtained significantly higher scores in materialism's dimensions of importance, success, and happiness, and in the psychological distress symptoms of anxiety, depression, obsession-compulsion, hostility, and somatization. On the contrary, they presented significantly lower levels in self esteem, life satisfaction, and optimism. Results of the logistic regression analysis confirmed that high scores in the importance dimension of materialism, in combination with the experiencing of symptoms of anxiety, depression, obsession-compulsion, hostility, and somatization, would constitute risk factors in relation with this phenomenon, and high levels of life satisfaction would act as a protection factor as for compulsive buying in the sample of students considered. CONCLUSIONS: Current findings revealed that 7.4% of the large sample of Spanish university students considered were classified as compulsive buyers. Additionally, it was confirmed that while materialism and psychological distress symptoms would represent vulnerability determinants increasing the propensity for compulsive buying, the high scores in life satisfaction would act to decrease the likelihood of becoming a compulsive buyer. Accordingly, our results suggested that prevention and intervention efforts in relation with compulsive buying among young people should include specific components aimed at the reduction of the importance assigned to money and possessions, and also at the relief of psychological distress symptoms. PMID- 26774002 TI - Recurrent unipolar mania: A comparative, cross-sectional study. AB - INTRODUCTION: A significant number of patients experience recurrent episodes of mania without depressive episodes. Evidence from the available literature suggests that these patients differ from typical "bipolar" or "manic-depressive" patients, but results have been inconsistent. The current study aims to add to this literature by comparing the demographic, clinical and risk factor profiles of patients with recurrent mania with and without depression. METHODS: 66 patients with a diagnosis of bipolar I disorder were divided into "unipolar mania" (recurrent mania alone, MA) and "bipolar" (both mania and depression, MD) sub-groups. Comorbid diagnoses were assessed using the Mini International Neuropsychiatric Interview (MINI), and genetic and environmental risk factors were explored using the Diagnostic Interview for Genetic Studies (DIGS), Childhood Trauma Questionnaire (CTQ), and an additional questionnaire designed for the purpose of the study. Differences between the MA and MD groups in terms of demographic variables, clinical profile, comorbidities and antecedent risk factors were explored. RESULTS: Patients with both mania and depression had higher frequencies of lifetime suicide attempts, antidepressant treatment, and catatonic symptoms. There was some evidence of an association between overcrowding in childhood and the presence of depressive episodes. No other differences in demographic, clinical or risk factor variables could be found between the two groups. DISCUSSION: Our results are consistent with the view that unipolar mania is not a distinctive disorder, or even a distinctive subtype of bipolar disorder. However, this conclusion is provisional as it is based only on clinical and demographic data. PMID- 26774003 TI - Development and validity of a very short form of the Eating Disorder Inventory. AB - INTRODUCTION: The main objective of the present series of studies was to develop and validate a 16-item very short form of the Eating Disorder Inventory (EDI-VS) for use as a short assessment tool in large-scale comprehensive or longitudinal studies, as well as in-depth idiographic studies. METHOD: The EDI-VS was developed, and validated, through a series of five studies based on independent community samples including a total of 1372 French adolescents. RESULTS: The results supported the reliability, content validity, factor validity, convergent validity, and criterion-related validity of the EDI-VS. CONCLUSIONS: The EDI-VS comprises 16 items assessing the eight original dimensions of the conceptual model for the EDI. Recommendations for future practice and research on the EDI-VS are outlined. PMID- 26774004 TI - Brain-derived neurotrophic factor serum levels in heroin-dependent patients after 26weeks of withdrawal. AB - BACKGROUND: Brain-derived neurotrophic factor (BDNF) has been implicated in the pathophysiology of heroin dependence. BDNF expression is dramatically changed during drug withdrawal, and is associated with drug withdrawal syndrome. This study aimed to explore (1) alterations of BDNF serum levels in heroin-dependent patients after long term abstinence; and (2) the association between BDNF serum levels and protracted withdrawal syndrome. METHOD: Fifty-three male heroin dependent patients and fifty-two gender-matched healthy controls were enrolled in this study. We measured BDNF serum levels at baseline and 26 weeks after heroin abstinence. Moreover, protracted withdrawal symptoms, depression and anxiety symptoms were measured by Protracted Withdrawal Symptoms of Heroin-dependent patients (PWSHA), Self-rating Depression Scale (SDS) and Self-rating Anxiety Scale (SAS), respectively. RESULT: We found that baseline BDNF serum levels were significantly lower in heroin-dependent patients compared to controls (p<0.01). There was also a significantly difference in BDNF serum levels among heroin dependent patients at baseline and 26-week follow-up (p<0.01). The BDNF serum levels were not associated with age, BMI, years of education, age of initial use, or duration of use. Of the clinical symptoms measured, the change in BDNF serum levels from baseline to 26-week follow-up was negatively associated with the change in PWSHA scores (r = -0.44, p<0.01, see Table 2 and Figure 2 for details). CONCLUSION: The results show that the BDNF serum levels in heroin-dependent patients are lower than those of healthy controls at baseline and increased after 26 weeks of abstinence, although the BDNF serum levels are still lower than those of the healthy controls. A negative correlation between the change in BDNF serum levels and protracted withdrawal symptoms was found but needs to be confirmed in further study. The results revealed that BDNF serum level is worth paying attention to in order to further investigate the possibility of it being a biomarker of treatment outcome for opiate dependence. PMID- 26774006 TI - The Changing Profile of Helicobacter pylori Antibiotic Resistance in Singapore: A 15-Year Study. AB - BACKGROUND: Antibiotic resistance is an important cause of H. pylori treatment failure. This study aimed to examine the change in H. pylori antibiotic resistance profile in Singapore over the course of 15 years. MATERIALS AND METHODS: The study period was from 2000 to 2014. Gastric mucosal biopsies obtained from H. pylori-positive patients were cultured. Antibiotic susceptibility to metronidazole, clarithromycin, levofloxacin, tetracycline, and amoxicillin was tested. The change in resistance rates over time was analyzed. RESULTS: A total of 708 H. pylori isolates were cultured. There was a significant increase in resistance rates for metronidazole (2000-2002: 24.8%; 2012-2014: 48.2%; p < .001), clarithromycin (2000-2002: 7.9%; 2012-2014: 17.1%; p = .022), and levofloxacin (2000-2002: 5%; 2012-2014: 14.7%; p = .007). The resistance rates for tetracycline (2000-2002: 5%; 2012-2014: 7.6%) and amoxicillin (2000 2002: 3%; 2012-2014: 4.4%) remained stable. Increase in dual (2000-2002: 6.9%; 2012-2014: 9.4%; p = .479) and triple antibiotic resistance rates (2000-2002: 0; 2012-2014: 7.6%; p < .001) were observed. Overall, the most common dual and triple resistance patterns were metronidazole/clarithromycin (4.4%) and metronidazole/clarithromycin/levofloxacin (1.8%), respectively. CONCLUSIONS: Over 15 years, H. pylori resistance rates to metronidazole, clarithromycin and levofloxacin had increased. There was increased resistance to multiple antibiotics. PMID- 26774005 TI - Uric acid is released in the brain during seizure activity and increases severity of seizures in a mouse model for acute limbic seizures. AB - Recent evidence points at an important role of endogenous cell-damage induced pro inflammatory molecules in the generation of epileptic seizures. Uric acid, under the form of monosodium urate crystals, has shown to have pro-inflammatory properties in the body, but less is known about its role in seizure generation. This study aimed to unravel the contribution of uric acid to seizure generation in a mouse model for acute limbic seizures. We measured extracellular levels of uric acid in the brain and modulated them using complementary pharmacological and genetic tools. Local extracellular uric acid levels increased three to four times during acute limbic seizures and peaked between 50 and 100 min after kainic acid infusion. Manipulating uric acid levels through administration of allopurinol or knock-out of urate oxidase significantly altered the number of generalized seizures, decreasing and increasing them by a twofold respectively. Taken together, our results consistently show that uric acid is released during limbic seizures and suggest that uric acid facilitates seizure generalization. PMID- 26774007 TI - Predisposing and Precipitating Factors for Dissociation During Labor in a Cohort Study of Posttraumatic Stress Disorder and Childbearing Outcomes. AB - INTRODUCTION: Peritraumatic dissociation is an important predictor of posttraumatic stress disorder (PTSD), depression, and impaired bonding following childbirth. The purpose of this study was to follow up on an earlier finding that peritraumatic dissociation in labor was associated with adverse postpartum outcomes by identifying predictors of dissociation in labor. METHODS: This analysis used data from a prospective cohort study of primiparous women from southeast Michigan. There were 564 women included in the analysis; the primary outcome measure was the Peritraumatic Dissociative Experiences Questionnaire (PDEQ) score measuring dissociation during labor. RESULTS: The prevalence of dissociation in labor for this sample was 7.4%. Important predictors of dissociation in labor included both predisposing (eg, childhood maltreatment trauma, preexisting psychopathology) and precipitating (eg, perception of care, negative appraisal of labor) factors. Overall, these predictors explained 14.7% of variance in PDEQ score. In 3 separate, simple linear regression models, the PDEQ score explained 20% of variance in postpartum PTSD, 13% of variance in postpartum depression, and 9% of variance in impaired bonding. DISCUSSION: Women with maltreatment history and PTSD are at risk to be retraumatized or overwhelmed by birth and to dissociate. Although it would be optimal to assess for dissociative coping prenatally, assessing with the PDEQ following birth could contribute to evaluation of risk for postpartum psychopathology. PMID- 26774008 TI - Development of a Health Screening Package Under the Universal Health Coverage: The Role of Health Technology Assessment. AB - This study reports the systematic development of a population-based health screening package for all Thai people under the universal health coverage (UHC). To determine major disease areas and health problems for which health screening could mitigate health burden, a consultation process was conducted in a systematic, participatory, and evidence-based manner that involved 41 stakeholders in a half-day workshop. Twelve diseases/health problems were identified during the discussion. Subsequently, health technology assessments, including systematic review and meta-analysis of health benefits as well as economic evaluations and budget impact analyses of corresponding population-based screening interventions, were completed. The results led to advice against elements of current clinical practice, such as annual chest X-rays and particular blood tests (e.g. kidney function test), and indicated that the introduction of certain new population-based health screening programs, such as for chronic hepatitis B, would provide substantial health and economic benefits to the Thais. The final results were presented to a wide group of stakeholders, including decision-makers at the Ministry of Public Health and the public health insurance schemes, to verify and validate the findings and policy recommendations. The package has been endorsed by the Thai UHC Benefit Package Committee for implementation in fiscal year 2016. PMID- 26774009 TI - Expression of p38 mitogen-activated protein kinase (p38MAPK) and pathological change in intussusception. AB - BACKGROUND: The aim of this study was to develop a mouse model and further assess the pathological changes associated with the expression of p38mitogen-activated protein kinase (p38MAPK) in intussusception. METHODS: Sixty-two adult Balb/C mice were used. A longitudinal incision was made in the middle rectus muscle in the body cavity. The ileum was intussuscepted into the colon. Measurements were taken at the onset of intussusception and at 5, 15, 30, 60, and 120 min. Mucosal impairment was assessed on microscopy. Ten of the intussuscepted mice were used as an ischemia-reperfusion (I/R) model. Immunohistochemistry was used to assess expression of p38MAPK in the I/R model and pediatric patients specimens of intussusception. RESULTS: The intussusception model was successfully established in 46 mice. After 15 min, vascular compromise became visible in these 46 mice. Over time, vascular function worsened. There were significant differences in microscopy injury score in the intestinal mucosa between the 15 min and 30 min groups (P = 0.0006), 30 min and 60 min groups (P = 0.0046), and the 60 min and 120 min groups (P = 0.0050). There was no significant difference between the 5 min and 15 min groups (P = 0.0597). p38MAPK was expressed strongly in pediatric specimens of intussusception. Immunostained sections of intestinal epithelium had significantly higher mean quick score for p38MAPK in the intussusception I/R model group than in the intussusception group and controls (P = 0.0130). On each two-group comparison there was a significant difference between groups (all P < 0.01; Fig. ). CONCLUSIONS: The present mouse model can be used to assess the dynamic pathological changes associated with intussusception. I/R is associated with upregulation of p38MAPK in intussusception. PMID- 26774012 TI - Guidelines for genomic array analysis in acquired haematological neoplastic disorders. AB - Genetic profiling is important for disease evaluation and prediction of prognosis or responsiveness to therapy in neoplasia. Microarray technologies, including array comparative genomic hybridization and single-nucleotide polymorphism detecting arrays, have in recent years been introduced into the diagnostic setting for specific types of haematological malignancies and solid tumours. It can be used as a complementary test or depending on the neoplasia investigated, also as a standalone test. However, comprehensive and readable presentation of frequently identified complex genomic profiles remains challenging. To assist diagnostic laboratories, standardization and minimum criteria for clinical interpretation and reporting of acquired genomic abnormalities detected through arrays in neoplastic disorders are presented. PMID- 26774010 TI - Validation of two-channel sequencing-by-synthesis for noninvasive prenatal testing of fetal whole and partial chromosome aberrations. AB - OBJECTIVE: To validate Illumina's two-channel NextSeq 500 sequencing system for noninvasive prenatal testing (NIPT) of fetal whole chromosome and partial aberrations. METHODS: A total of 162 plasma samples, previously sequenced for NIPT on a SOLiD 5500xl platform, were sequenced on the NextSeq 500 using 75-bp single-end sequencing, followed by analysis using the WISECONDOR algorithm. RESULTS: For whole chromosome aneuploidy detection, all samples were classified correctly (in total 3* T13, 3* T18, 8* T21 and 145* euploid). Three partial aberrations (36-Mb terminal loss of 5p, 14-Mb gain on 18p and 33-Mb terminal loss of 13q) were also correctly identified. Fetal fractions in 34 male samples sequenced on both the SOLiD 5500xl and NextSeq 500 platform showed no significant difference. To test robustness, two sample sets, containing both euploid and aneuploid samples, were sequenced on different NextSeq 500 machines, revealing identical results. With unchanged laboratory flow, the NIPT turnaround time could be reduced from 15-16 calendar days to 7-8 calendar days, after switching from the SOLiD 5500xl to the NextSeq 500 platform. CONCLUSIONS: The NextSeq 500 platform can be used for NIPT to detect both whole and partial chromosome aberrations. It has fast turnaround times and is suitable for mid-sized laboratories. PMID- 26774011 TI - Induction of regulatory T cells: A role for probiotics and prebiotics to suppress autoimmunity. AB - Regulatory T cells (Tregs) are comprised of a heterogeneous population of cells that play a vital role in suppressing inflammation and maintaining immune tolerance. Given the crucial role of Tregs in maintaining immune homeostasis, it is probably not surprising that many microbial species and their metabolites have the potential to induce Tregs. There is now great interest in the therapeutic potential of probiotics and prebiotics based strategies for a range of autoimmune disorders. This review will summarise recent findings concerning the role of probiotics and prebiotics in induction of Tregs to ameliorate the autoimmune conditions. In addition, the article is focused to explain the different mechanisms of Treg induction and function by these probiotics and prebiotics, based on the available studies till date. The article further proposes that induction of Tregs by probiotics and prebiotics could lead to the development of new therapeutic approach towards curbing the autoimmune response and as an alternative to detrimental immunosuppressive drugs. PMID- 26774013 TI - Diabetic ketoacidosis in an adolescent and young adult population in the UK in 2014: a national survey comparison of management in paediatric and adult settings. AB - AIMS: To assess the management of diabetic ketoacidosis in young people, which differs in the UK between paediatric and adult services, and to evaluate outcomes and extent to which national guidelines are used. METHODS: A standardized questionnaire was sent to all paediatric and adult diabetes services in England, requesting details of all diabetic ketoacidosis admissions in young people aged > 14 years in paediatric services ('paediatric' patients), and in young adults up to the age of 22 years in adult services ('adult' patients). RESULTS: A total of 64 adult patients aged <= 22 years (mean age 19.2 years) were reported, of whom seven were aged between 10 and 16 years. A total of 71 paediatric patients were reported [mean (range) age 14.9 (11-18) years]. We found that 85% of paediatric and 69% of adult patients were treated according to national guidelines, 99% of paediatric and 89% of adult patients were treated with 0.9% saline and fixed-rate insulin infusions and 16% of adult patients received an insulin bolus. Insulin treatment was initiated later in paediatric patients than in adult patients (100 vs 39 min; P < 0.001). In 23% of adult patients and 8.8% of paediatric patients, potassium levels were < 3.5 mmol/l (P < 0.005). The lowest mean potassium levels were 3.8 mmol/l in paediatric and 3.5 mmol/l in adult patients (P < 0.005). Hypoglycaemia occurred in 42.3% of paediatric and 36% of adult patients. Time to resolution was similar in paediatric and adult patients (16.0 vs 18.2 h), as was duration of hospital stay (2.35 vs 2.53 days). CONCLUSIONS: Young people were treated according to national guidelines, but the quality of monitoring was variable in both paediatric and adult settings. The incidence of hypoglycaemia and hypokalaemia was unacceptably high. PMID- 26774014 TI - Basal insulin intensification in type 2 diabetes: a key role for GLP-1 receptor agonists. PMID- 26774015 TI - GLP-1 RAs as compared to prandial insulin after failure of basal insulin in type 2 diabetes: lessons from the 4B and Get-Goal DUO 2 trials. AB - The add-on of a prandial (short-acting) GLP-1 RA to basal insulin in subjects with T2DM who fail to control A1C on basal insulin, stems from the physiological principles of post-prandial glucose homeostasis, and it is based on evidence from clinical trials. The 4B and GetGoal DUO 2 studies are the first to establish in head-to-head comparison, the efficacy and safety of short-acting GLP-1 RAs vs prandial insulin, when added-on to basal insulin glargine. In the 4B study (exenatide 2/d vs lispro 3/d) exenatide demonstrated similar efficacy vs lispro in reducing A1C to ~7.2%. However, exenatide reduced also body weight and hypoglycemia incidence as compared to lispro. In GetGoal DUO 2, the head-to-head comparison was between lixisenatide 1/d vs glulisine either 1/d (at the main meal, basal-plus) or 3/d (basal-bolus). Like in 4B, in GetGoal DUO 2 the A1C decreased to similar values with lixisenatide or glulisine 1/d (~7.2%), or glulisine 3/d (~7.0%). Again, as in the 4B, body weight and hypoglycemia incidence were lower with lixisenatide. In both studies a similar percentage of subjects reached the A1C <7.0% on GLP-1 RA or prandial insulin. A higher percentage of subjects reported adverse events on GLP-1 RAs, primarily gastrointestinal related. The studies 4B and GetGoal DUO 2 suggest that after failure of basal insulin in T2DM, the add-on of prandial GLP-1 RA is as effective as prandial insulin in lowering A1C, with added benefits of reducing body weight and risk for hypoglycemia. In addition, the GLP-1 RA + basal insulin is a simpler therapeutic option as compared to basal-plus and basal-bolus regimens. PMID- 26774016 TI - Options for intensification of basal insulin in type 2 diabetes: Premeal insulin or short-acting GLP-1 receptor agonists? AB - Type 2 diabetes is an evolutive disease with a progressive defect of beta-cell insulin secretion. This characteristic points to a need for treatment that takes into account such a natural history. When oral antidiabetic drugs fail to achieve the patient's target HbA1c level, basal insulin treatment is usually initiated and titrated in association with oral drugs to manage fasting hyperglycaemia. Over a period of time, it is enough to simply achieve the HbA1c target. However, when even a good fasting blood glucose level is no longer sufficient to control overall glycaemia, then prandial treatment must be combined with the titrated basal insulin to deal with the postprandial hyperglycaemia responsible for the elevation of HbA1c. Of the different therapeutic options now available for this, rapid-acting insulins and GLP-1 receptor agonists (RAs) can be used. Rapid-acting insulins can be added either at each meal, achieving full insulin supplementation with a basal-bolus regimen, or at the main meal only as a "basal-plus" regimen. Compared with the full basal-bolus, the basal-plus strategy is associated with fewer injections, yet provides similar efficacy in terms of HbA1c improvement, but with less weight gain and lower hypoglycaemic risk. As for GLP-1 RAs, numerous studies, and especially those using short-acting GLP-1 RAs, have demonstrated more pronounced effects on postprandial hyperglycaemia, good complementary effects with basal insulin, and significant improvement of HbA1c with no weight gain and a low risk of hypoglycaemia. Similarly, direct and indirect comparisons of the use of rapid-acting insulins and GLP-1 RAs to intensify basal insulin have shown comparable efficacy in terms of HbA1c control, but with less weight gain and fewer hypoglycaemic episodes with GLP-1 RAs. PMID- 26774017 TI - Pleiotropic effects of insulin and GLP-1 receptor agonists: Potential benefits of the association. AB - The combination of basal insulin and glucagon-like peptide-1 receptor agonists (GLP-1RAs) is an emerging option for patients with type 2 diabetes (T2D). GLP 1RAs have been shown to improve glycaemic control with a low risk of hypoglycaemia and to promote body weight loss. However, GLP-1 receptors (GLP-1Rs) are widely expressed in extrapancreatic tissues and could sustain pleiotropic actions of GLP-1RAs beyond glycaemic control. The underlying molecular mechanisms maintaining these extrapancreatic actions of GLP-1 are complex, and involve GLP 1R signalling in both the brain and several peripheral tissues. The present review focuses specifically on the role of GLP-1RAs in the cardiovascular system and liver. Preclinical data in rodents and pilot studies in humans suggest that GLP-1RAs may have potential beneficial effects on heart function, blood pressure, postprandial lipaemia, liver steatosis and non-alcoholic steatohepatitis (NASH). Long-term studies are now warranted to determine the safety and clinical relevance of the association between insulin and GLP-1RAs in T2D. PMID- 26774018 TI - Physiological aspects of the combination of insulin and GLP-1 in the regulation of blood glucose control. AB - Combining insulin with glucagon-like peptide-1 (GLP-1) receptor agonists or dipeptidyl peptidase-4 (DPP-4) inhibitors as glucose-lowering therapy for type 2 diabetes is a promising strategy that has gained considerable interest over the past few years. One advantage of this combination is the complementary mechanistic actions of insulin and GLP-1. Insulin increases glucose utilization and retards hepatic glucose production through direct actions in muscle, adipose tissue and the liver. On the other hand, GLP-1 stimulates insulin secretion, inhibits glucagon secretion and retards gastric emptying. Combining these effects results in powerful reductions in both fasting and postprandial glucose through diminished glucose entry into the bloodstream after food consumption, reduced hepatic production of glucose and increased glucose utilization. In addition, GLP 1 receptor agonists induce satiety, leading to decreases in food intakes and body weight, thereby preventing the weight gain often seen with insulin therapy. Clinical trials have verified that these physiological effects as a result of combining insulin with GLP-1 receptor agonists or DPP-4 inhibitors can indeed result in improved glycaemia, with limited risks of hypoglycaemia and weight gain. PMID- 26774019 TI - Postprandial and basal hyperglycaemia in type 2 diabetes: Contributions to overall glucose exposure and diabetic complications. AB - Both postprandial and fasting (basal) hyperglycaemia contribute to overall hyperglycaemia (ambient hyperglycaemia) in type 2 diabetes (T2D). Postprandial glucose is the main contributor in fairly well controlled individuals, whereas basal hyperglycaemia becomes the preponderant contributor in poorly controlled patients. A more generally acceptable description of the contribution of postprandial glucose is to simply say that the absolute impact of postprandial glucose to HbA1c remains constant at approximately 1% across the entire HbA1c spectrum of non-insulin-treated patients with T2D. While epidemiological and pathophysiological studies seem to indicate that excessive postprandial glucose excursions play a role in or are predictors of cardiovascular diseases, there is still currently a lack of clinical evidence that correcting post-meal hyperglycaemia can improve clinical outcomes. However, even in the absence of consensus, there are many reasons for thinking that excessive postprandial glucose might be an independent risk factor for diabetic complications as it contributes to both overall glucose exposure and glycaemic variability, especially in those who have HbA1c levels < 7.5-8%. Given that excessive glucose fluctuations from peaks to nadirs activate oxidative stress, it seems reasonable to consider that a key player in the pathogenesis of diabetic complications, according to the latest IDF guidelines, is post-meal glucose, thereby warranting its assessment and treatment when found at abnormally elevated levels. Nevertheless, healthcare professionals should bear in mind that targeting both post-meal and basal plasma glucose, giving equal consideration to both of them, is probably the best strategy for achieving optimal glycaemic control and thus preventing or reducing the risk of diabetic complications. PMID- 26774020 TI - Sticks and stones may break some bones. PMID- 26774022 TI - Increase in c-Fos and Arc protein in retrosplenial cortex after memory-improving lateral hypothalamic electrical stimulation treatment. AB - Post-training Intracranial self-stimulation (ICSS) of the lateral hypothalamus (LH), a kind of rewarding deep-brain stimulation, potentiates learning and memory and increases c-Fos protein expression in specific memory-related brain regions. In a previous study, Aldavert-Vera et al. (2013) reported that post-acquisition LH-ICSS improved 48 h retention of a delay two-way active avoidance conditioning (TWAA) and induced c-Fos expression increase in CA3 at 90 min after administration. Nevertheless, this c-Fos induction was only observed after the acquisition session and not after the retention test at 48 h, when the ICSS improving effect was observed on memory. This current study aims to examine the hypothesis that post-training ICSS treatment may stimulate c-Fos expression at the time of the TWAA retention test in retrosplenial cortex (RSC), a hippocampus related brain region more closely related with long-lasting memory storage. Effects of ICSS on Arc protein, a marker of memory-associated synaptic plasticity, were also measured by immunohistochemistry in granular and agranular RSC. The most innovative results are that the ICSS treatment potentiates the c Fos induction across TWAA conditions (no conditioning, acquisition and retention), specifically in layer V of the granular RSC, along with increases of Arc protein levels in the granular but not in agranular areas of RSC ipsilaterally few hours after ICSS. This leads us to suggest that plasticity related protein activation in the granular RSC could be involved in the positive modulatory effects of ICSS on TWAA memory consolidation, opening a new approach for future research in ICSS memory facilitation. PMID- 26774023 TI - The effects of prolonged administration of norepinephrine reuptake inhibitors on long-term potentiation in dentate gyrus, and on tests of spatial and object recognition memory in rats. AB - Phasic norepinephrine (NE) release events are involved in arousal, novelty detection and in plasticity processes underlying learning and memory in mammalian systems. Although the effects of phasic NE release events on plasticity and memory are prevalently documented, it is less understood what effects chronic NE reuptake inhibition and sustained increases in noradrenergic tone, might have on plasticity and cognitive processes in rodent models of learning and memory. This study investigates the effects of chronic NE reuptake inhibition on hippocampal plasticity and memory in rats. Rats were administered NE reuptake inhibitors (NRIs) desipramine (DMI; 0, 3, or 7.5mg/kg/day) or nortriptyline (NTP; 0, 10 or 20mg/kg/day) in drinking water. Long-term potentiation (LTP; 200 Hz) of the perforant path-dentate gyrus evoked potential was examined in urethane anesthetized rats after 30-32 days of DMI treatment. Short- (4-h) and long-term (24-h) spatial memory was tested in separate rats administered 0 or 7.5mg/kg/day DMI (25-30 days) using a two-trial spatial memory test. Additionally, the effects of chronically administered DMI and NTP were tested in rats using a two-trial, Object Recognition Test (ORT) at 2- and 24-h after 45 and 60 days of drug administration. Rats administered 3 or 7.5mg/kg/day DMI had attenuated LTP of the EPSP slope but not the population spike at the perforant path-dentate gyrus synapse. Short- and long-term memory for objects is differentially disrupted in rats after prolonged administration of DMI and NTP. Rats that were administered 7.5mg/kg/day DMI showed decreased memory for a two-trial spatial task when tested at 4-h. In the novel ORT, rats receiving 0 or 7.5mg/kg/day DMI showed a preference for the arm containing a Novel object when tested at both 2- and 24-h demonstrating both short- and long-term memory retention of the Familiar object. Rats that received either dose of NTP or 3mg/kg/day DMI showed impaired memory at 2-h, however this impairment was largely reversed at 24-h. Animals in the high dose NTP (20mg/kg/day) group were impaired at both short- and long-term intervals. Activity levels, used as an index of location memory during the ORT, demonstrated that rats receiving DMI were again impaired at retaining memory for location. DMI dose-dependently disrupts LTP in the dentate gyrus of anesthetized rats and also disrupts memory for tests of spatial memory when administered for long periods. PMID- 26774024 TI - TGF-beta Signaling in Cancer. AB - The transforming growth factor-beta (TGF-beta) is a family of structurally related proteins that comprises of TGF-beta, activins/inhibins, and bone morphogenic proteins (BMPs). Members of the TGF-beta family control numerous cellular functions including proliferation, apoptosis, differentiation, epithelial-mesenchymal transition (EMT), and migration. The first identified member, TGF-beta is implicated in several human diseases, such as vascular diseases, autoimmune disorders, and carcinogenesis. Activation of the TGF-beta receptor by its ligands induces the phosphorylation of serine/threonine residues and triggers phosphorylation of the intracellular effectors, SMADs. Upon activation, SMAD proteins translocate to the nucleus and induce transcription of their target genes, regulating several cellular functions. TGF-beta dysregulation has been implicated in carcinogenesis. In early stages of cancer, TGF-beta exhibits tumor suppressive effects by inhibiting cell cycle progression and promoting apoptosis. However, in late stages TGF-beta exerts tumor promoting effects, increasing tumor invasiveness, and metastasis. Furthermore, the TGF-beta signaling pathway communicates with other signaling pathways in a synergistic or antagonistic manner and regulates cellular functions. Elevated TGF-beta activity has been associated with poor clinical outcome. Given the pivotal role of TGF beta in tumor progression, this pathway is an attractive target for cancer therapy. Several therapeutic tools such as TGF-beta antibodies, antisense oligonucleotides, and small molecules inhibitors of TGF-beta receptor-1 (TGF betaR1) have shown immense potential to inhibit TGF-beta signaling. Finally, in the interest of developing future therapies, further studies are warranted to identify novel points of convergence of TGF-beta with other signaling pathways and oncogenic factors in the tumor microenvironment. PMID- 26774021 TI - Effects of new-generation inhibitors of the calcium-activated chloride channel anoctamin 1 on slow waves in the gastrointestinal tract. AB - BACKGROUND AND PURPOSE: High-throughput screening of compound libraries using genetically encoded fluorescent biosensors has identified several second generation. low MW inhibitors of the calcium-activated chloride channel anoctamin 1 (CaCC/Ano1). Here we have (i) examined the effects of these Ano1 inhibitors on gastric and intestinal pacemaker activity; (ii) compared the effects of these inhibitors with those of the more classical CaCC inhibitor, 5-nitro-2-(3 phenylpropylalanine) benzoate (NPPB); (ii) examined the mode of action of these compounds on the waveform of pacemaker activity; and (iii) compared differences in the sensitivity between gastric and intestinal pacemaker activity to the Ano1 inhibitors. EXPERIMENTAL APPROACH: Using intracellular microelectrode recordings of gastric and intestinal muscle preparations from C57BL/6 mice, the dose dependent effects of Ano1 inhibitors were examined on spontaneous electrical slow waves. KEY RESULTS: The efficacy of second-generation Ano1 inhibitors on gastric and intestinal pacemaker activity differed significantly. Antral slow waves were more sensitive to these inhibitors than intestinal slow waves. CaCCinh -A01 and benzbromarone were the most potent at inhibiting slow waves in both muscle preparations and more potent than NPPB. Dichlorophene and hexachlorophene were equally potent at inhibiting slow waves. Surprisingly, slow waves were relatively insensitive to T16Ainh -A01 in both preparations. CONCLUSIONS AND IMPLICATIONS: We have identified several second-generation Ano1 inhibitors, blocking gastric and intestinal pacemaker activity. Different sensitivities to Ano1 inhibitors between stomach and intestine suggest the possibility of different splice variants in these two organs or the involvement of other conductances in the generation and propagation of pacemaker activity in these tissues. PMID- 26774026 TI - How Many Water Molecules Does it Take to Dissociate HCl? AB - The potential energy surfaces of the HCl(H2O)n (n is the number of water molecules) clusters are systematically explored using density functional theory and high-level ab initio computations. On the basis of electronic energies, the number of water molecules needed for HCl dissociation is four as reported by some experimental groups. However, this number is five owing to the inclusion of entropic factors. Wiberg bond indices are calculated and analyzed, and the results provide a quadratic correlation and classification of clusters according to the nondissociated, partially dissociated, and fully dissociated character of the H-Cl bond. Our computations show that if temperature is not controlled during the experiment, the values obtained for the dipole moment (or for any measurable property) are susceptible to change, providing a different picture of the number of water molecules needed for HCl dissociation in a nanoscopic droplet. PMID- 26774025 TI - Clinical performance of the Food and Drug Administration-Approved high-risk HPV test for the detection of high-grade cervicovaginal lesions. AB - BACKGROUND: In recent years, high-risk human papillomavirus (hrHPV) testing for triaging atypical squamous cells of undetermined significance and cotesting with cytology have been implemented in clinical practice. However, clinical data for primary screening with human papillomavirus (HPV) testing alone are currently lacking. METHODS: This study retrospectively reviewed the correlation of cytology, histology, and hrHPV testing through the use of a cytology laboratory quality assurance database with 130,648 Papanicolaou (Pap) tests interpreted at Houston BioReference Laboratories and Houston Methodist Hospital between March 1, 2013 and June 30, 2014. Among the 47,499 patients who had undergone cytology-HPV cotesting, 1654 underwent follow-up biopsies. RESULTS: The sensitivities of the hrHPV and Pap tests were 80.8% and 81.2%, respectively, for detecting any type of cervicovaginal dysplasia and 91.3% and 90.9%, respectively, for high-grade cervicovaginal lesions. For biopsy-confirmed high-grade cervicovaginal lesions (cervical intraepithelial neoplasia grade 2+, adenocarcinoma in situ, or carcinoma; n = 253), the false-negative rates for hrHPV and Pap tests were 8.7% and 9.1%, respectively. The false-negative rate for cytology-hrHPV cotesting was only 1.2%. CONCLUSIONS: In clinical practice, the hrHPV test alone is not significantly superior to the Pap test as a primary screening method for cervicovaginal lesions. The false-negative rate of the hrHPV test in detecting biopsy-confirmed high-grade cervicovaginal lesions is comparable to the rate of the Pap test. Women with cytology and hrHPV cotesting, however, have a significantly lower false-negative rate than those undergoing either test alone. Currently, cytology-HPV cotesting remains the best strategy for detecting high grade cervicovaginal lesions. Cancer Cytopathol 2016;124:317-23. (c) 2016 American Cancer Society. PMID- 26774027 TI - A method to determine insulin responsiveness in synaptosomes isolated from frozen brain tissue. AB - BACKGROUND: Studying the insulin signaling response at the synapse is an important approach to understand molecular mechanisms involved in disease-related neurodegenerative processes. NEW METHOD: We developed a method for studying the insulin responsiveness at the synaptic level by isolating functional synaptosomes from fresh or frozen tissue and exposing them to insulin in the presence of ATP (a critical step) to detect insulin receptor (IR) activation. RESULTS: We performed an ATP dose-response curve, insulin dose-response curve, and insulin response time course to optimize this method. We also demonstrated that our protocol reflects the degree of insulin responsiveness in vivo by using an animal model of known insulin resistance, AtENPP1-Tg mice. COMPARISON WITH EXISTING METHOD(S): This method is advantageous over other methods detecting IR in total brain homogenates due to the ability to detect IR response without confounding contributions from other cell areas and cell types also expressing IR. Furthermore, ex vivo insulin stimulation can be compared to baseline synaptosomes obtained from the same animal which improves reliability and statistical power while decreasing the number of animals required to perform individual experiments. CONCLUSIONS: We have developed a reliable, efficient method to measure insulin-driven ex vivo phosphorylation of the synaptosomal insulin receptor that can reliably reflect the pre-existing insulin responsiveness status in the CNS of the animal. To the best of our knowledge, this is the first evidence of stimulation of isolated synaptosomes with insulin and a promising new technique to study the synaptic CNS insulin responsiveness under physiological or disease conditions. PMID- 26774028 TI - On high-pass filter artifacts (they're real) and baseline correction (it's a good idea) in ERP/ERMF analysis. PMID- 26774029 TI - High-pass filters and baseline correction in M/EEG analysis. Commentary on: "How inappropriate high-pass filters can produce artefacts and incorrect conclusions in ERP studies of language and cognition". AB - Tanner et al. (2015. Psychophysiology, 52(8), 1009. doi: 10.1111/psyp.12437) convincingly demonstrate how a late deflection like the N400 or the P600 is reflected into both earlier and later latencies by the application of high-pass filters with cutoff frequencies higher than 0.1Hz. It nicely underlines the importance of test-wise application of filters with different parameters to electrophysiological data to identify such unwanted filter effects. In general, we agree with their approach and conclusions, particularly with the notions that the application of a high-pass filter is reasonable if it improves the signal-to noise ratio (SNR) of the signal of interest, and that low frequency signals may carry important information. However, we disagree in two aspects: First, the test data of Tanner et al. are not optimally suited to demonstrate the benefits of high-pass filtering as they are only minimally contaminated by low frequency noise, and second, the standard baseline correction for particular applications in M/EEG data analysis should be replaced with high-pass filtering-as recommended by Widmann et al. (2015. J Neurosci Methods, 250, 46. doi: 10.1016/j.jneumeth.2014.08.002). PMID- 26774030 TI - Cerebrovascular pathology during the progression of experimental Alzheimer's disease. AB - Clinical and experimental evidence point to a possible role of cerebrovascular dysfunction in Alzheimer's disease (AD). The 5xFAD mouse model of AD expresses human amyloid precursor protein and presenilin genes with mutations found in AD patients. It remains unknown whether amyloid deposition driven by these mutations is associated with cerebrovascular changes. 5xFAD and wild type mice (2 to 12months old; M2 to M12) were used. Thinned skull in vivo 2-photon microscopy was used to determine Abeta accumulation on leptomeningeal or superficial cortical vessels over time. Parenchymal microvascular damage was assessed using FITC microangiography. Collagen-IV and CD31 were used to stain basal lamina and endothelial cells. Methoxy-XO4, Thioflavin-S or 6E10 were used to visualize Abeta accumulation in living mice or in fixed brain tissues. Positioning of reactive IBA1 microglia and GFAP astrocytes at the vasculature was rendered using confocal microscopy. Platelet-derived growth factor receptor beta (PDGFRbeta) staining was used to visualize perivascular pericytes. In vivo 2-photon microscopy revealed Methoxy-XO4(+) amyloid perivascular deposits on leptomeningeal and penetrating cortical vessels in 5xFAD mice, typical of cerebral amyloid angiopathy (CAA). Amyloid deposits were visible in vivo at M3 and aggravated over time. Progressive microvascular damage was concomitant to parenchymal Abeta plaque accumulation in 5xFAD mice. Microvascular inflammation in 5xFAD mice presented with sporadic FITC albumin leakages at M4 becoming more prevalent at M9 and M12. 3D colocalization showed inflammatory IBA1(+) microglia proximal to microvascular FITC-albumin leaks. The number of perivascular PDGFRbeta(+) pericytes was significantly decreased at M4 in the fronto-parietal cortices, with a trend decrease observed in the other structures. At M9-M12, PDGFRbeta(+) pericytes displayed hypertrophic perivascular ramifications contiguous to reactive microglia. Cerebral amyloid angiopathy and microvascular inflammation occur in 5xFAD mice concomitantly to parenchymal plaque deposition. The prospect of cerebrovascular pharmacology in AD is discussed. PMID- 26774032 TI - Benefit of a fish incision to counteract the external constricting ring in autologous breast reconstruction. PMID- 26774033 TI - An iterative approach for compound detection in an unknown pharmaceutical drug product: Application on Raman microscopy. AB - Raman chemical imaging provides both spectral and spatial information on a pharmaceutical drug product. Even if the main objective of chemical imaging is to obtain distribution maps of each formulation compound, identification of pure signals in a mixture dataset remains of huge interest. In this work, an iterative approach is proposed to identify the compounds in a pharmaceutical drug product, assuming that the chemical composition of the product is not known by the analyst and that a low dose compound can be present in the studied medicine. The proposed approach uses a spectral library, spectral distances and orthogonal projections to iteratively detect pure compounds of a tablet. Since the proposed method is not based on variance decomposition, it should be well adapted for a drug product which contains a low dose product, interpreted as a compound located in few pixels and with low spectral contributions. The method is tested on a tablet specifically manufactured for this study with one active pharmaceutical ingredient and five excipients. A spectral library, constituted of 24 pure pharmaceutical compounds, is used as a reference spectral database. Pure spectra of active and excipients, including a modification of the crystalline form and a low dose compound, are iteratively detected. Once the pure spectra are identified, multivariate curve resolution-alternating least squares process is performed on the data to provide distribution maps of each compound in the studied sample. Distributions of the two crystalline forms of active and the five excipients were in accordance with the theoretical formulation. PMID- 26774034 TI - A simple and sensitive UHPLC-MS/MS method for quantification of buddlejasaponin IV in rat plasma and its application to a pharmacokinetic study. AB - Buddlejasaponin IV (BS-IV), a natural triterpene saponin isolated from several herbal plants, has drawn a lot of attention for its anti-inflammatory, antinociceptive, antihyperlipidemia, and antitumor activities. In this study, a simple and sensitive method for determination of BS-IV in rat plasma was developed for the first time, using ultra-high performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS). Tenacissoside I was used as an internal standard (IS). Separation was achieved on an Agilent Extend-C18 column with gradient elution using methanol-water as mobile phase at a flow rate of 400MUL/min. A triple quadrupole mass spectrometer operating in the positive/negative ion-switching electrospray ionization mode with selection reaction monitoring (SRM) was used to determine BS-IV and IS transitions of 941.4 >779.5 and 815.5->755.5, respectively. The lower limit of quantification was 3.00ng/mL with a linear range of 3.0-3000ng/mL. The intra- and inter-day precisions were both <=10.4% for BS-IV, and the average intra- and inter-day accuracies ranged from -7.2% to 6.7%. The validated assay was successfully applied to a pharmacokinetic study of BS-IV following oral administration of 3, 6, 12mg/kg and an intravenous administration of 0.9mg/kg to rats. PMID- 26774035 TI - Synthesis and biological evaluation of fluorinated 1,5-diarylpyrrole-3 alkoxyethyl ether derivatives as selective COX-2 inhibitors endowed with anti inflammatory activity. AB - A series of substituted 1,5-diarylpyrrole-3-alkoxyethyl ethers were previously synthesized and the potential anti-inflammatory and antinociceptive activities of these compounds were evaluated in vivo. The compounds displayed a very good activity against both carrageenan-induced hyperalgesia and oedema in the rat paw test. Therefore, in a very preliminary test, compounds (8a,b) showed antiproliferative activity in the HaCaT (aneuploid immortal keratinocyte from adult human skin) cell models. On these basis, our research continued with the synthesis of fluorinated derivatives (8c,d, 9b-d, and 10b-d) with the aim of improving the pharmacokinetic profile of the previous active compounds. Substitution of a hydrogen atom by a fluorine atom may change the conformational preferences of the molecules due to stereoelectronic effects and also fluorine atom may be able to exert the metabolic obstruction reducing the "first-pass effect". Compound 10b exhibited a prominent in vivo anti-inflammatory and antinociceptive activities, in addition its antiproliferative power in an in vitro model of human skin cancer is herein described. PMID- 26774036 TI - New approach towards the synthesis of selenosemicarbazones, useful compounds for Chagas' disease. AB - Herein, we describe a new approach towards the synthesis of selenosemicarbazones. The reaction involves an O-Se exchange of semicarbazones using Ishihara reagent. Eleven selenosemicarbazones were prepared using this methodology, with low to moderate yields. Among the prepared compounds the m-bromo phenyl methyl derivative 1b was selected to be evaluated in vivo, in a murine model of acute Chagas' disease. Compound 1b 10 mg/kg bw/day reduced 50% of parasitaemia profile compared with the control group, but was less effective than Benznidazole (50 mg/kg bw/day reduced 90%) and toxic. These studies are important to guide future Chagas drug design. PMID- 26774037 TI - Neuroprotective profile of pyridothiazepines with blocking activity of the mitochondrial Na(+)/Ca(2+) exchanger. AB - The mitochondrial Na(+)/Ca(2+) exchanger plays an important role in the control of cytosolic Ca(2+) cycling in excitable cells, essential for the regulation of a plethora of Ca(2+)-dependent physio-pathological events, such as apoptosis in the presence of a Ca(2+) overload. There are very few pharmacological tools available to study both physiological and pathological implications of the mitochondrial Na(+)/Ca(2+) exchanger, where the benzothiazepine CGP37157 is the best-known ligand, used since the 1980s. However, it is not an efficient blocker and lacks of selectivity, as also blocks several other cellular Ca(2+) transporters. Moreover, CGP37157 is a very lipophilic drug, showing very poor water solubility, what has hindered its therapeutic use. Attempting to improve its pharmacokinetic profile as well as its potency and selectivity, we herein describe the synthesis of new CGP37157 analogs, where the benzene-fused ring has been replaced by a pyridine. On top of a better water solubility and lower log P value, some of these new pyridothiazepine derivatives also presented a higher capacity to regulate the mitochondrial Ca(2+) clearance, while keeping the neuroprotective properties presented in the head compound CGP37157. PMID- 26774038 TI - Flavonoid derivatives as selective ABCC1 modulators: Synthesis and functional characterization. AB - A series of chromones, bearing substituted amino groups or N-substituted carboxamide moieties in position 2, was synthesized and characterized in cellular assays for modulation of the ABC transporters ABCC1 (MDCKII-MRP1 cells), ABCB1 (Kb-V1 cells) and ABCG2 (MCF-7/Topo cells). The most potent ABCC1 modulators identified among these flavonoid-type compounds were comparable to the reference compound reversan regarding potency, but superior in terms of selectivity concerning ABCB1 and ABCG2 (2-[4-(Benzo[c][1,2,5]oxadiazol-5-ylmethyl)piperazin-1 yl]-5,7-dimethoxy-4H-chromen-4-one (51): ABCC1, IC50 11.3 MUM; inactive at ABCB1 and ABCG2). Compound 51 was as effective as reversan in reverting ABCC1-mediated resistance to cytostatics in MDCKII-MRP1 cells and proved to be stable in mouse plasma and cell culture medium. Modulators, such as compound 51, are of potential value as pharmacological tools for the investigation of the (patho)physiological role of ABCC1. PMID- 26774031 TI - Electronic cigarettes: what are they and what do they do? AB - Electronic cigarettes (ECIGs) use electricity to power a heating element that aerosolizes a liquid containing solvents, flavorants, and the dependence producing drug nicotine for user inhalation. ECIGs have evolved rapidly in the past 8 years, and the changes in product design and liquid constituents affect the resulting toxicant yield in the aerosol and delivery to the user. This rapid evolution has been accompanied by dramatic increases in ECIG use prevalence in many countries among adults and, especially, adolescents in the United States. The increased prevalence of ECIGs that deliver nicotine and other toxicants to users' lungs drives a rapidly growing research effort. This review highlights the most recent information regarding the design of ECIGs and their liquid and aerosol constituents, the epidemiology of ECIG use among adolescents and adults (including correlates of ECIG use), and preclinical and clinical research regarding ECIG effects. The current literature suggests a strong rationale for an empirical regulatory approach toward ECIGs that balances any potential ECIG mediated decreases in health risks for smokers who use them as substitutes for tobacco cigarettes against any increased risks for nonsmokers who may be attracted to them. PMID- 26774039 TI - Determination of critical nucleation number for a single nucleation amyloid-beta aggregation model. AB - Aggregates of amyloid-beta (Abeta) peptide are known to be the key pathological agents in Alzheimer disease (AD). Abeta aggregates to form large, insoluble fibrils that deposit as senile plaques in AD brains. The process of aggregation is nucleation-dependent in which the formation of a nucleus is the rate-limiting step, and controls the physiochemical fate of the aggregates formed. Therefore, understanding the properties of nucleus and pre-nucleation events will be significant in reducing the existing knowledge-gap in AD pathogenesis. In this report, we have determined the plausible range of critical nucleation number (n(*)), the number of monomers associated within the nucleus for a homogenous aggregation model with single unique nucleation event, by two independent methods: A reduced-order stability analysis and ordinary differential equation based numerical analysis, supported by experimental biophysics. The results establish that the most likely range of n(*) is between 7 and 14 and within, this range, n(*) = 12 closely supports the experimental data. These numbers are in agreement with those previously reported, and importantly, the report establishes a new modeling framework using two independent approaches towards a convergent solution in modeling complex aggregation reactions. Our model also suggests that the formation of large protofibrils is dependent on the nature of n(*), further supporting the idea that pre-nucleation events are significant in controlling the fate of larger aggregates formed. This report has re-opened an old problem with a new perspective and holds promise towards revealing the molecular events in amyloid pathologies in the future. PMID- 26774041 TI - Effect of exposure to aggressive stimuli on aggressive driving behavior at pedestrian crossings at unmarked roadways. AB - BACKGROUND: Aggressive driving, influenced by the proneness of driving aggression, angry state and provoking situation, is adversely affecting traffic safety especially in developing countries where pedestrians frequently cross an unmarked crosswalk. Exposure to aggressive stimuli causes driving anger and aggressive driving behaviors, but the exposure effect on higher and lower aggression drivers and their cumulative changes under successive exposures need more investigation. OBJECTIVES: An experiment was conducted to examine (1) driving behaviors of individuals with higher and lower aggressive driving traits when approaching pedestrian crossings at unmarked roadways with and without aggressive provocation; and (2) cumulative changes of driving performance under repeated provocations. METHOD: We conducted a driving simulator study with 50 participants. Trait of aggressive driving served as a between-subjects variable: participants with an Aggressive Driving Scale (ADS) total score of 30 or more (for men) or 23 or more (for women) were regarded as higher aggressive drivers; lower aggressive drivers were those individuals whose ADS total scores were 21 or less (for men) or 13 or less (for women). Exposure to aggressive stimuli (provoked vs. non-provoked condition) served as a within-subjects variable. Several aspects of the participants' minimum driving speed, lateral distance from a simulated pedestrian, lateral deviation, and subjective measures were collected. RESULTS: We found that drivers with higher aggressive driving traits were more likely to feel irritated and fail to give way for pedestrians and drove closer to pedestrians when exposed to sustained honking and improper passing compared to the non-provoked condition. This trait*state interaction only occurred when pedestrians crossed the street from the right roadway edge line. In addition, we observed an accumulation effect of exposure to aggressive stimuli on driver's aggressive behaviors at pedestrian crossings. CONCLUSIONS: Environmental design, law enforcement, and educational campaign may have practical value for reducing pedestrian and driver conflicts at unmarked roadways. PMID- 26774040 TI - Berberine treatment attenuates the palmitate-mediated inhibition of glucose uptake and consumption through increased 1,2,3-triacyl-sn-glycerol synthesis and accumulation in H9c2 cardiomyocytes. AB - Dysfunction of lipid metabolism and accumulation of 1,2-diacyl-sn-glycerol (DAG) may be a key factor in the development of insulin resistance in type 2 diabetes. Berberine (BBR) is an isoquinoline alkaloid extract that has shown promise as a hypoglycemic agent in the management of diabetes in animal and human studies. However, its mechanism of action is not well understood. To determine the effect of BBR on lipid synthesis and its relationship to insulin resistance in H9c2 cardiomyocytes, we measured neutral lipid and phospholipid synthesis and their relationship to glucose uptake. Compared with controls, BBR treatment stimulated 2-[1,2-(3)H(N)]deoxy-D-glucose uptake and consumption in palmitate-mediated insulin resistant H9c2 cells. The mechanism was though an increase in protein kinase B (AKT) activity and GLUT-4 glucose transporter expression. DAG accumulated in palmitate-mediated insulin resistant H9c2 cells and treatment with BBR reduced this DAG accumulation and increased accumulation of 1,2,3-triacyl-sn glycerol (TAG) compared to controls. Treatment of palmitate-mediated insulin resistant H9c2 cells with BBR increased [1,3-(3)H]glycerol and [1-(14)C]glucose incorporation into TAG and reduced their incorporation into DAG compared to control. In addition, BBR treatment of these cells increased [1-(14)C]palmitic acid incorporation into TAG and decreased its incorporation into DAG compared to controls. BBR treatment did not alter phosphatidylcholine or phosphatidylethanolamine synthesis. The mechanism for the BBR-mediated decreased precursor incorporation into DAG and increased incorporation into TAG in palmitate-incubated cells was an increase in DAG acyltransferase-2 activity and its expression and a decrease in TAG hydrolysis. Thus, BBR treatment attenuates palmitate-induced reduction in glucose uptake and consumption, in part, through reduction in cellular DAG levels and accumulation of TAG in H9c2 cells. PMID- 26774042 TI - Driving with pets and motor vehicle collision involvement among older drivers: A prospective population-based study. AB - OBJECTIVE: Distracted driving is a major cause of motor vehicle collision (MVC) involvement. Pets have been identified as potential distraction to drivers, particularly in the front. This type of distraction could be worse for those with impairment in the cognitive aspects of visual processing. The purpose of this study is to evaluate the association between driving with pets and rates of motor vehicle collision involvement in a cohort of older drivers. METHODS: A three-year prospective study was conducted in a population-based sample of 2000 licensed drivers aged 70 years and older. At the baseline visit, a trained interviewer asked participants about pet ownership, whether they drive with pets, how frequently, and where the pet sits in the vehicle. Motor vehicle collision (MVC) involvement during the three-year study period was obtained from the Alabama Department of Public Safety. At-fault status was determined by the police officer who arrived on the scene. Participants were followed until the earliest of death, driving cessation, or end of the study period. Poisson regression was used to calculate crude and adjusted rate ratios (RR) examining the association between pet ownership, presence of a pet in a vehicle, frequency of driving with a pet, and location of the pet inside with vehicle with any and at-fault MVC involvement. We examined whether the associations differed by higher order visual processing impairment status, as measured by Useful Field of View, Trails B, and Motor-free Visual Perception Test. RESULTS: Rates of crash involvement were similar for older adults who have ever driven with a pet compared to those who never drove with their pet (RR=1.15, 95% CI 0.76-1.75). Drivers who reported always or sometimes driving with their pet had higher MVC rates compared to pet owners who never drive with a pet, but this association was not statistically significant (RR=1.39, 95% CI 0.86-2.24). In terms of location, those reporting having a pet frequently ride in the front of the vehicle had similar rates of MVC involvement compared to those who did not drive with a pet in the front. A similar pattern of results was observed for at-fault MVCs. This association was not modified by visual processing impairment status. CONCLUSION: The current study demonstrates a positive but non-significant association between frequently driving with pets and MVC involvement. More research is needed, particularly on restraint use and whether the pet was in the car at the time of the crash, to help characterize the public safety benefit of regulations on driving with pets. PMID- 26774043 TI - Could cytokine levels in the peri-implant crevicular fluid be used to distinguish between healthy implants and implants with peri-implantitis? A systematic review. AB - BACKGROUND AND OBJECTIVE: Despite investigative efforts to identify the levels of different types of cytokines in the peri-implant crevicular fluid (PICF), the efficacy of these biomarkers in assisting the diagnosis of peri-implantitis is still undetermined. This systematic review aimed to answer the following question: "Could cytokine levels in the PICF be used to distinguish between healthy implants and implants with peri-implantitis?" MATERIAL AND METHODS: This review was conducted and reported in accordance with the PRISMA statement. The MEDLINE and EMBASE databases were searched from 1990 up to and including March 2015, using MeSH terms and other keywords. Additional publications were searched using a hand search of reference lists of relevant studies. Titles and abstracts were screened and papers that fulfilled eligibility criteria were assessed. RESULTS: Out of 1212 titles, 18 studies reporting the levels of nine different cytokines were included. Proinflammatory cytokines [interleukin (IL)-1beta, IL-6, IL-12, IL-17 and tumor necrosis factor-alpha) were the cytokines studied most commonly, followed by anti-inflammatory cytokines (IL-4 and IL-10), osteoclastogenesis-related cytokines (RANKL) and chemokines (IL-8). Nine studies reported statistically significantly higher levels of proinflammatory cytokines in the PICF of implants with peri-implantitis than in the PICF of healthy implants. Most studies did not find any significant differences in the PICF levels of anti-inflammatory cytokines and RANKL between healthy implants and implants with peri-implantitis. IL-8 was the only chemokine studied and its levels did not differ significantly between healthy and diseased implants. The studies differed greatly in the manner in which they reported the results (e.g. concentrations or total amounts) and in the exclusion of confounders, such as smoking. CONCLUSION: The results of this systematic review indicate moderate evidence in the literature to support that implants with peri-implantitis present higher levels of proinflammatory cytokines in the PICF than do healthy implants. Evidence regarding the PICF levels of anti-inflammatory cytokines, osteoclastogenesis-related cytokines and chemokines as possible predictors of peri-implantitis is too limited. PMID- 26774045 TI - EGb761 protects against Abeta1-42 oligomer-induced cell damage via endoplasmic reticulum stress activation and Hsp70 protein expression increase in SH-SY5Y cells. AB - Studies have shown that misfolded proteins and endoplasmic reticulum (ER) stress play pivotal roles in the progression of Alzheimer's disease (AD). It has also been reported that ER stress is considered to be a common mediator of apoptosis in neurodegenerative disorders like AD. However, the precise mechanisms leading to neuronal cell death caused by ER stress in AD remain unclear. Hsp70, the major inducible form of the heat shock protein family, functions at the level of chaperone-mediated protein folding. Enhanced expression of Hsp70 suppresses the neurotoxicity caused by protein misfolding. EGb761, an accepted traditional Chinese medicine used to treat AD, was used here to examine the molecular mechanism underlying its protective effect on ER stress and Hsp70. Our study shows that pretreatment with EGb761 overcomes the neurotoxicity of the Abeta1-42 oligomer by increasing Hsp70, Grp78, IRE1alpha and pAkt expression in a dose dependent manner and significantly decreases cell apoptosis-related protein expression. Our findings suggest that the neuroprotective effect of EGb761 is related to ER stress activation and increased Hsp70 expression, and subsequent activation of Akt. However, the effect of EGb761 on these processes is not direct. PMID- 26774047 TI - A thousand ways to say 'Delicious!'-Categorizing expressions of deliciousness from restaurant reviews on the social network site Yelp. AB - This study explored expressions of deliciousness-one of the main reasons people make specific food choices over others-from restaurant reviews on Yelp, a popular social network site. Through qualitative content analysis of 205 reviews from 41 food establishments in Hawaii, we found 8 main categories of expressions of deliciousness. These eight main categories created by both concept-driven and data-driven strategies are Sense, Culinary Affair, Matter of Heart, Health, Testimonial and Endorsement, Personal Signature, Consumer, and Restaurant. Each main category was further subcategorized. This meaningful categorization might contribute to healthier eating by helping policy makers and food companies craft effective strategies for healthy eating schemes, healthy menu items, or healthy food products. Marketers of any food product can also increase their market share by utilizing these categories, subcategories, and their underlying concepts in the planning stage. Detailed examples of nudging and social marketing campaigns inspired by our findings were provided. Moreover, social network sites can better serve health conscious and hedonic consumers by personalization through improved algorithms inspired by these categories. PMID- 26774046 TI - Evaluation of inter-batch differences in stem-cell derived neurons. AB - Differentiated cells retain the genetic information of the donor but the extent to which phenotypic differences between donors or batches of differentiated cells are explained by variation introduced during the differentiation process is not fully understood. In this study, we evaluated four separate batches of commercially available neurons originating from the same iPSCs to investigate whether the differentiation process used in manufacturing iPSCs to neurons affected genome-wide gene expression and modified cytosines, or neuronal sensitivity to drugs. No significant changes in gene expression, as measured by RNA-Seq, or cytosine modification levels, as measured by the Illumina 450K arrays, were observed between batches relative to changes over time. As expected, neurotoxic chemotherapeutics affected neuronal outgrowth, but no inter-batch differences were observed in sensitivity to paclitaxel, vincristine and cisplatin. As a testament to the utility of the model for studies of neuropathy, we observed that genes involved in neuropathy had relatively higher expression levels in these samples across different time points. Our results suggest that the process used to differentiate iPSCs into neurons is consistent, resulting in minimal intra-individual variability across batches. Therefore, this model is reasonable for studies of human neuropathy, druggable targets to prevent neuropathy, and other neurological diseases. PMID- 26774048 TI - Comprehensive analysis of RHD splicing transcripts reveals the molecular basis for the weak anti-D reactivity of Del -red blood cells. AB - BACKGROUND: Of the Rh blood type, Del is a rare variant that elicits the weakest anti-D reactivity. In this study, we revisit the genetic changes of Del allele and characterise the RHD splicing transcripts to realise the molecular basis of Del formation in the Taiwanese population. STUDY DESIGN AND METHODS: The RHD exons from Del and D-positive individuals were amplified by polymerase chain reaction (PCR) using different primer pairs followed by sequencing analyses. In addition, full-length RHD transcripts were reversed transcribed and amplified by nested-PCR. The type and frequency of the RHD splicing transcripts were analysed after sequencing the PCR products that were subcloned into a cloning vector. RESULTS: All Del individuals had a characteristic 1227G>A mutation. No deletion of the exon sequences was found. At least nine types of RHD splicing transcripts including exons 7/8/9 deletion, 7/9 deletion, 8/9 deletion, 9 deletion, 2/3/7/9 deletion, 2/3/7/8/9 deletion, exons 7/8/9 deletion with replacement of exon 3 with RHCE exon 3, exon 9 deletion with cryptic insertion of 170 bp of intron 7 and exons 7/8/9 deletion with cryptic insertion of 117 bp of intron 3 were identified in the Del -RBC. These aberrant splicing transcripts led to production of frame shift or truncated D antigen. Notably, no full-length RHD transcript was identified in the Del -RBC. CONCLUSION: The RHD 1227G>A mutation contributes to the molecular basis of Del phenotype in the Taiwanese population. The point mutation results in aberrant frame shift or exon deletion transcripts and generates D protein with weak antigen presenting function. PMID- 26774049 TI - A methodology concern of the meta-analysis of antiviral therapy for chronic hepatitis B virus infection in adults. PMID- 26774050 TI - Aquaporin-4 mediates communication between astrocyte and microglia: Implications of neuroinflammation in experimental Parkinson's disease. AB - Aquaporin-4 (AQP4), a water-selective membrane transport protein, is up-regulated in astrocytes in various inflammatory lesions, including Parkinson disease (PD). However, the exact functional roles of AQP4 in neuroinflammation remain unknown. In the present study, we investigated how AQP4 participates in the neuroinflammation of PD using AQP4 knockout (KO) mice and astrocyte-microglial co cultures. We found that AQP4 KO mice exhibited increased basal and inducible canonical NF-kappaB activity, and showed significantly enhanced gliosis (astrocytosis and microgliosis) in chronic MPTP (1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine)/probenecid PD models, companying with the increase in the production of IL-1beta and TNF-alpha in the midbrain. Similarly, AQP4 deficiency augmented the activation of the NF-kappaB pathway and the production of IL-1beta and TNF-alpha in midbrain astrocyte cultures treated with MPP(+) (1-methyl-4 phenylpyridinium). Furthermore, AQP4 deficiency promoted activation of microglial cells in the co-cultured system. Our data provide the first evidence that AQP4 modulates astrocyte-to-microglia communication in neuroinflammation, although its effect on astrocyte inflammatory activation remains to be explored. PMID- 26774051 TI - Prenatal maternal lipopolysaccharide administration leads to age- and region specific oxidative stress in the early developmental stage in offspring. AB - Prenatal exposure to lipopolysaccharide (LPS) has been exploited to simulate brain disorder in animal model. Prenatal LPS-exposure has shown elevated levels of pro-inflammatory cytokines in the early stages of the postnatal period. This study determines the effect of prenatal LPS-exposure on oxidative stress (OS) in the distinct brain regions in the early postnatal stages. LPS (50 MUg/kg, i.p.) and water for injection (100 MUl, i.p.) were given to the experimental (n=5) and control (n=5) group of pregnant Swiss albino mice respectively on gestational day (GD)-16 and 17. Animals were decapitated on postnatal day (PnD) - 1, 7, 14 and 21 to assay levels of oxidative markers from 6 distinct brain regions. When compared with the control, prenatal LPS-exposure alters levels of OS markers: (i) on PnD 1, glutathione (GSH) level is raised and superoxide dismutase (SOD) activity is dropped, (ii) on PnD-7, advanced oxidation of protein product (AOPP) level is elevated, (iii) on PnD-14, lipid peroxidation (MDA) and activity of catalase (CAT) are enhanced, (iv) on PnD-21, increased MDA continued. The hippocampus (HC) and cerebellum (CB) were mostly susceptible to OS in the early postnatal development. Levels of MDA and activity of CAT enzyme were increased on PnD-14 in the cortex, HC and CB. Except MDA, all OS markers recovered and returned to the level of control animals on PnD-21. Taken together, these results suggest that prenatal LPS-exposure induces age- and region-specific OS in the early postnatal stage. PMID- 26774052 TI - Deciphering the aggregation mechanism of bacteria (Shewanella oneidensis MR1) in the presence of polyethyleneimine: Effects of the exopolymeric superstructure and polymer molecular weight. AB - Aggregation tests between bacteria and Polyethyleneimine (PEI) of low (600g/mol) and high (750,000g/mol) molecular weight were performed in order to address the physico-chemical mechanisms underlying the interactions between cationic polymer and bacterial membranes. The selected strain, Schewanella oneidensis MR-1, produces a lipopolysaccharide (LPS) of various lengths depending on the growth conditions. Optical density, bioaggregate size, electrophoretic mobility measurements, TEM and AFM observations, and cell lysis tests (crystal violet release), were collected to describe the PEI-mediated aggregation of LPS-O antigen-free and LPS-O-antigen-decorated bacteria. The results show that PEI of low molecular weight (600g/mol) fails to aggregate bacteria, whereas PEIs of higher molecular weight (60,000 and 750,000g/mol) lead to flocculation at low polymer concentrations. In addition, the LPS-O antigen bacterial superstructure is shown to act as a protective barrier, thus delaying the harmful effects of the cationic polymer. Despite this protection, the interaction of bacterial membranes with increasing concentrations of PEI leads to a series of deleterious processes including biosurface modification (peeling, membrane permeabilization and/or lysis), aggregation of bacterial cells, and complexation of PEI with both released biosurface fragments and cytoplasmic residues issued from lysis. PMID- 26774053 TI - Agreement of skin test with IL-4 production and CD40L expression by T cells upon immunotherapy of subjects with systemic reactions to Hymenoptera stings. AB - Venom immunotherapy is the only curative intervention for subjects with Hymenoptera venom allergy who suffering systemic reactions upon bee or wasp stings. Venom immunotherapy can restore normal immunity against venom allergens, as well as providing to allergic subjects a lifetime tolerance against venoms. Nevertheless, it is necessary using safety assays to monitoring the development of tolerance in the VIT protocols to avoid fatal anaphylactic reactions. The purpose of this study was to assess the modifications in several markers of tolerance induction in subjects with Hymenoptera venom allergy undergoing immunotherapy. The studies were performed at baseline time and after six month of VIT. Intradermal skin tests, basophil activation tests, specific IgE levels; and the T-cell markers (IL-4 and IFN-gamma producing cells; and expression of the surface activation markers CD40L and CTLA-4) were assayed. At six month of immunotherapy all parameters studied had significant alterations. All decreased, except the IFN-gamma producing cells. In addition, modifications in intradermal skin test showed a significant correlation with both, CD40L expression on CD4 T lymphocytes (p=0.043) and IL-4 producing T lymphocytes (p=0.012). Neither basophil activation test nor serum levels of sIgE demonstrated any correlation with the immunological parameters studied nor among them. These results suggest that both IL-4 production and CD40L expression could be two good indicators of the beneficial effects of venom immunotherapy which translate into skin tests. PMID- 26774054 TI - Generation and characterization of recombinant bivalent fusion protein r-Cpib for immunotherapy against Clostridium perfringens beta and iota toxemia. AB - Clostridium perfringens beta (CPB) and iota (CPI) toxaemias result in some of the most lethal forms of haemorrhagic and necrotic enteritis and sudden death syndrome affecting especially neonates. While CPB enterotoxemia is one of the most common forms of clostridial enterotoxemia, CPI enterotoxemia though putatively considered to be rare is an emerging cause of concern. The similarities in clinical manifestation, gross and histopathology findings of both types of toxaemias coupled to the infrequency of CPI toxaemia might lead to symptomatic misidentification with Type C resulting in therapeutic failure due to habitual administration of CPB anti-toxin which is ineffective against CPI. Therefore in the present study, to generate a composite anti-toxin capable of neutralizing both toxaemias, a novel bivalent chimera r-Cpib was constructed by splicing the non-toxic C terminal binding regions of CPB and CPI, via a flexible glycine linker (G4S) by overlap-extension PCR. The fusion protein was characterized for its therapeutic abilities toward CPI and CPB toxin neutralizations. The r-Cpib was found to be non-toxic and could competitively inhibit binding of CPB to host cell receptors thereby reducing its cytotoxicity. Immunization of mice with r-Cpib generated specific antibodies capable of neutralizing the above toxaemias both in vitro and in vivo. Caco-2 cells exposed to a mixture of anti-r-Cpib sera and native CPI or CPB, displayed significantly superior protection against the respective toxins while passive challenge of mice with a similar mixture resulted in 83 and 91% protection against CPI and CPB respectively. Alternatively, mice exposed to a mixture of sham sera and native toxins died within 2-3 days. This work thus demonstrates r-Cpib as a novel bivalent fusion protein capable of efficient immunotherapy against C. perfringens CPI and CPB toxaemia. PMID- 26774056 TI - Cross-Species Application of SNP Chips is Not Suitable for Identifying Runs of Homozygosity. AB - Cross-species application of single-nucleotide polymorphism (SNP) chips is a valid, relatively cost-effective alternative to the high-throughput sequencing methods generally required to obtain a genome-wide sampling of polymorphisms. Kharzinova et al. (2015) examined the applicability of SNP chips developed in domestic bovids (cattle and sheep) to a semi-wild cervid (reindeer). The ancestors of bovids and cervids diverged between 20 and 30 million years ago (Hassanin and Douzery 2003; Bibi et al. 2013). Empirical work has shown that for a SNP chip developed in a bovid and applied to a cervid species, approximately 50% genotype success with 1% of the loci being polymorphic is expected (Miller et al. 2012). The genotyping of Kharzinova et al. (2015) follows this pattern; however, these data are not appropriate for identifying runs of homozygosity (ROH) and can be problematic for estimating linkage disequilibrium (LD) and we caution readers in this regard. PMID- 26774055 TI - Absence of ethnic differences in the pharmacokinetics of moxifloxacin, simvastatin, and meloxicam among three East Asian populations and Caucasians. AB - AIM: To examine whether strict control of clinical trial conditions could reduce apparent differences of pharmacokinetic (PK) parameters among ethnic groups. METHODS: Open-label, single dose PK studies of moxifloxacin, simvastatin and meloxicam were conducted in healthy male subjects from three East Asian populations (Japanese, Chinese and Koreans) and one Caucasian population as a control. These three drugs were selected because differences in PK parameters have been reported, even though the backgrounds of these East Asian populations are similar. Moxifloxacin (400 mg) was administered orally to 20 subjects, and plasma and urine levels of moxifloxacin and its metabolite (M2) were measured. Simvastatin (20 mg) was given to 40 subjects, and plasma levels of simvastatin and simvastatin acid were measured. Meloxicam (7.5 mg) was given to 30 subjects and its plasma concentration was determined. Intrinsic factors (polymorphism of UGT1A1 for moxifloxacin, SLCO1B1 for simvastatin, and CYP2C9 for meloxicam) were also examined. RESULTS: AUCinf values for moxifloxacin, simvastatin and meloxicam showed no significant differences among the East Asian groups. Cmax values of moxifloxacin and simvastatin, but not meloxicam, showed significant differences. There were no significant differences of data for M2 or simvastatin acid. Genetic analysis identified significant differences in the frequencies of relevant polymorphisms, but these differences did not affect the PK parameters observed. CONCLUSIONS: Although there were some differences in PK parameters among the three East Asian groups, the present study performed under strictly controlled conditions did not reproduce the major ethnic differences observed in previous studies. PMID- 26774057 TI - Genetic Conservation of Phosphine Resistance in the Rice Weevil Sitophilus oryzae (L.). AB - High levels of resistance to phosphine in the rice weevil Sitophilus oryzae have been detected in Asian countries including China and Vietnam, however there is limited knowledge of the genetic mechanism of resistance in these strains. We find that the genetic basis of strong phosphine resistance is conserved between strains of S. oryzae from China, Vietnam, and Australia. Each of 4 strongly resistant strains has an identical amino acid variant in the encoded dihydrolipoamide dehydrogenase (DLD) enzyme that was previously identified as a resistance factor in Rhyzopertha dominica and Tribolium castaneum. The unique amino acid substitution, Asparagine > Threonine (N505T) of all strongly resistant S. oryzae corresponds to the position of an Asparagine > Histidine variant (N506H) that was previously reported in strongly resistant R. dominica. Progeny (F16 and F18) from 2 independent crosses showed absolute linkage of N505T to the strong resistance phenotype, indicating that if N505T was not itself the resistance variant that it resided within 1 or 2 genes of the resistance factor. Non-complementation between the strains confirmed the shared genetic basis of strong resistance, which was supported by the very similar level of resistance between the strains, with LC50 values ranging from 0.20 to 0.36 mg L(-1) for a 48 h exposure at 25 degrees C. Thus, the mechanism of high-level resistance to phosphine is strongly conserved between R. dominica, T. castaneum and S. oryzae. A fitness cost associated with strongly resistant allele was observed in segregating populations in the absence of selection. PMID- 26774058 TI - Mitochondrial DNA Variation in Southeastern Pre-Columbian Canids. AB - The taxonomic status of the red wolf (Canis rufus) is heavily debated, but could be clarified by examining historic specimens from the southeastern United States. We analyzed mitochondrial DNA (mtDNA) from 3 ancient (350-1900 year olds) putative wolf samples excavated from middens and sinkholes within the historic red wolf range. We detected 3 unique mtDNA haplotypes, which grouped with the coyote mtDNA clade, suggesting that the canids inhabiting southeastern North America prior to human colonization from Europe were either coyotes, which would vastly expand historic coyote distributions, an ancient coyote-wolf hybrid, or a North American evolved red wolf lineage related to coyotes. Should the red wolf prove to be a distinct species, our results support the idea of either an ancient hybrid origin for red wolves or a shared common ancestor between coyotes and red wolves. PMID- 26774059 TI - Plastome Mutations and Recombination Events in Barley Chloroplast Mutator Seedlings. AB - The barley chloroplast mutator (cpm) is an allele of a nuclear gene that when homozygous induces several types of cytoplasmically inherited chlorophyll deficiencies. In this work, a plastome Targeting Induced Local Lesions in Genomes (TILLING) strategy based on mismatch digestion was used on families that carried the cpm genotype through many generations. Extensive scanning of 33 plastome genes and a few intergenic regions was conducted. Numerous polymorphisms were detected on both genic and intergenic regions. The detected polymorphisms can be accounted for by at least 61 independent mutational events. The vast majority of the polymorphisms originated in substitutions and small indels (insertions/deletions) in microsatellites. The rpl23 and the rps16 genes were the most polymorphic. Interestingly, the variation observed in the rpl23 gene consisted of several combinations of 5 different one nucleotide polymorphisms. Besides, 4 large indels that have direct repeats at both ends were also observed, which appear to be originated from recombinational events. The cpm mutation spectrum suggests that the CPM gene product is probably involved in plastome mismatch repair. The numerous subtle molecular changes that were localized in a wide range of plastome sites show the cpm as a valuable source of plastome variability for plant research and/or plant breeding. Moreover, the cpm mutant appears to be an interesting experimental material for investigating the mechanisms responsible for maintaining the stability of plant organelle DNA. PMID- 26774060 TI - Genetic Diversity of the Two Commercial Tetraploid Cotton Species in the Gossypium Diversity Reference Set. AB - A diversity reference set has been constructed for the Gossypium accessions in the US National Cotton Germplasm Collection to facilitate more extensive evaluation and utilization of accessions held in the Collection. A set of 105 mapped simple sequence repeat markers was used to study the allelic diversity of 1933 tetraploid Gossypium accessions representative of the range of diversity of the improved and wild accessions of G. hirsutum and G. barbadense. The reference set contained 410 G. barbadense accessions and 1523 G. hirsutum accessions. Observed numbers of polymorphic and private bands indicated a greater diversity in G. hirsutum as compared to G. barbadense as well as in wild-type accessions as compared to improved accessions in both species. The markers clearly differentiated the 2 species. Patterns of diversity within species were observed but not clearly delineated, with much overlap occurring between races and regions of origin for wild accessions and between historical and geographic breeding pools for cultivated accessions. Although the percentage of accessions showing introgression was higher among wild accessions than cultivars in both species, the average level of introgression within individual accessions, as indicated by species-specific bands, was much higher in wild accessions of G. hirsutum than in wild accessions of G. barbadense. The average level of introgression within individual accessions was higher in improved G. barbadense cultivars than in G. hirsutum cultivars. This molecular characterization reveals the levels and distributions of genetic diversity that will allow for better exploration and utilization of cotton genetic resources. PMID- 26774062 TI - Introduction: Historiography and the philosophy of the sciences. PMID- 26774061 TI - Genome-Wide Association Study of a Varroa-Specific Defense Behavior in Honeybees (Apis mellifera). AB - Honey bees are exposed to many damaging pathogens and parasites. The most devastating is Varroa destructor, which mainly affects the brood. A promising approach for preventing its spread is to breed Varroa-resistant honey bees. One trait that has been shown to provide significant resistance against the Varroa mite is hygienic behavior, which is a behavioral response of honeybee workers to brood diseases in general. Here, we report the use of an Affymetrix 44K SNP array to analyze SNPs associated with detection and uncapping of Varroa-parasitized brood by individual worker bees (Apis mellifera). For this study, 22 000 individually labeled bees were video-monitored and a sample of 122 cases and 122 controls was collected and analyzed to determine the dependence/independence of SNP genotypes from hygienic and nonhygienic behavior on a genome-wide scale. After false-discovery rate correction of the P values, 6 SNP markers had highly significant associations with the trait investigated (alpha < 0.01). Inspection of the genomic regions around these SNPs led to the discovery of putative candidate genes. PMID- 26774063 TI - Historicism and the failure of HPS. AB - This paper suggests that the failure to integrate history and philosophy of science properly may be explained by incompatible metaphysics implied by these fields. Historians and sociologists tend to be historicists, who assume that all objects of research are variable in principle, while philosophers look for permanent and essential qualities. I analyse, how the historicists and essentialist approaches differ with regard to the research objects of general history, history of science and science itself. The implied historicism makes some radical pronouncements by Latour on ontological variance understandable. I will also consider, whether there could be something like a historicist philosophy of science. The historicisation of the natural world proves most challenging, but both certain traditional disciplines and some recent advances in physical and life sciences indicate compatibility with historicism. One should note that historicism does not alter how 'truth' is understood. Historicism does not question the reality of objects either; only their eternality. PMID- 26774064 TI - Inevitability, contingency, and epistemic humility. AB - This paper offers an epistemological framework for the debate about whether the results of scientific enquiry are inevitable or contingent. I argue in Sections 2 and 3 that inevitabilist stances are doubly guilty of epistemic hubris--a lack of epistemic humility--and that the real question concerns the scope and strength of our contingentism. The latter stages of the paper-Sections 4 and 5-address some epistemological and historiographical worries and sketch some examples of deep contingencies to guide further debate. I conclude by affirming that the concept of epistemic humility can usefully inform critical reflection on the contingency of the sciences and the practice of history of science. PMID- 26774065 TI - "Exploratory experimentation" as a probe into the relation between historiography and philosophy of science. AB - This essay utilizes the concept "exploratory experimentation" as a probe into the relation between historiography and philosophy of science. The essay traces the emergence of the historiographical concept "exploratory experimentation" in the late 1990s. The reconstruction of the early discussions about exploratory experimentation shows that the introduction of the concept had unintended consequences: Initially designed to debunk philosophical ideas about theory testing, the concept "exploratory experimentation" quickly exposed the poverty of our conceptual tools for the analysis of experimental practice. Looking back at a number of detailed analyses of experimental research, we can now appreciate that the concept of exploratory experimentation is too vague and too elusive to fill the desideratum whose existence it revealed. PMID- 26774066 TI - Viewing past science from the point of view of present science, thereby illuminating both: Philosophy versus experiment in the work of Robert Boyle. AB - The seventeenth century witnessed the replacement of an Aristotelian worldview by a mechanical one. It also witnessed the beginnings of significant experimental enquiry. Alerted by the fact that the methods involved in the latter, but not in the former, resemble those employed in later science, I argue the historical case that the emergence of the mechanical worldview and the emergence of science were not closely related and that it was the latter that was to develop into science as we have come to know it. The details are explored in the context of the philosophical and experimental work of Robert Boyle and the relationship between them. PMID- 26774067 TI - Immanent philosophy of X. AB - In this paper I examine the relationship between historians, philosophers and sociologists of science, and indeed scientists themselves. I argue that (i) they co-habit a shared intellectual territory (science and its past); and (ii) they should be able to do so peacefully, and with mutual respect, even if they disagree radically about how to describe the methods and results of science. I then go on to explore some of the challenges to mutually respectful cohabitation between history, philosophy and sociology of science. I conclude by identifying a familiar kind of project in the philosophy of science which seeks to explore the worldview of a particular scientific discipline, and argue that it too has a right to explore the shared territory even though some historians and sociologists may find it methodologically suspect. PMID- 26774068 TI - Introduction: Scientific knowledge of the deep past. PMID- 26774069 TI - Testing hypotheses in macroevolution. AB - Experimental manipulation of microevolution (changes in frequency of heritable traits in populations) has shed much light on evolutionary processes. But many evolutionary processes occur on scales that are not amenable to experimental manipulation. Indeed, one of the reasons that macroevolution (changes in biodiversity over time, space and lineages) has sometimes been a controversial topic is that processes underlying the generation of biological diversity generally operate at scales that are not open to direct observation or manipulation. Macroevolutionary hypotheses can be tested by using them to generate predictions then asking whether observations from the biological world match those predictions. Each study that identifies significant correlations between evolutionary events, processes or outcomes can generate new predictions that can be further tested with different datasets, allowing a cumulative process that may narrow down on plausible explanations, or lead to rejection of other explanations as inconsistent or unsupported. A similar approach can be taken even for unique events, for example by comparing patterns in different regions, lineages, or time periods. I will illustrate the promise and pitfalls of these approaches using a range of examples, and discuss the problems of inferring causality from significant evolutionary associations. PMID- 26774071 TI - Histories of molecules: Reconciling the past. AB - Molecular data and methods have become centrally important to evolutionary analysis, largely because they have enabled global phylogenetic reconstructions of the relationships between organisms in the tree of life. Often, however, molecular stories conflict dramatically with morphology-based histories of lineages. The evolutionary origin of animal groups provides one such case. In other instances, different molecular analyses have so far proved irreconcilable. The ancient and major divergence of eukaryotes from prokaryotic ancestors is an example of this sort of problem. Efforts to overcome these conflicts highlight the role models play in phylogenetic reconstruction. One crucial model is the molecular clock; another is that of 'simple-to-complex' modification. I will examine animal and eukaryote evolution against a backdrop of increasing methodological sophistication in molecular phylogeny, and conclude with some reflections on the nature of historical science in the molecular era of phylogeny. PMID- 26774070 TI - A second look at the colors of the dinosaurs. AB - In earlier work, I predicted that we would probably not be able to determine the colors of the dinosaurs. I lost this epistemic bet against science in dramatic fashion when scientists discovered that it is possible to draw inferences about dinosaur coloration based on the microstructure of fossil feathers (Vinther et al., 2008). This paper is an exercise in philosophical error analysis. I examine this episode with two questions in mind. First, does this case lend any support to epistemic optimism about historical science? Second, under what conditions is it rational to make predictions about what questions scientists will or will not be able answer? In reply to the first question, I argue that the recent work on the colors of the dinosaurs matters less to the debate about the epistemology of historical science than it might seem. In reply to the second question, I argue that it is difficult to specify a policy that would rule out the failed bet without also being too conservative. PMID- 26774072 TI - Ethnographic analogy, the comparative method, and archaeological special pleading. AB - Ethnographic analogy, the use of comparative data from anthropology to inform reconstructions of past human societies, has a troubled history. Archaeologists often express concern about, or outright reject, the practice--and sometimes do so in problematically general terms. This is odd, as (or so I argue) the use of comparative data in archaeology is the same pattern of reasoning as the 'comparative method' in biology, which is a well-developed and robust set of inferences which play a central role in discovering the biological past. In pointing out this continuity, I argue that there is no 'special pleading' on the part of archaeologists in this regard: biologists must overcome analogous epistemic difficulties in their use of comparative data. I then go on to emphasize the local, empirically tractable ways in which particular ethnographic analogies may be licensed. PMID- 26774074 TI - Development of Implant Stability Quotient values of implants placed with simultaneous sinus floor elevation - results of a prospective study with 109 implants. AB - OBJECTIVES: In patients with implant placement and simultaneous sinus floor elevation (SFE), healing periods of 6 months have been the standard of care for more than 25 years. The primary objective of this prospective case series study was to determine what percentage of implants placed with SFE reach a threshold Implant Stability Quotient (ISQ) of >=70 after 8 weeks of healing using Resonance Frequency Analysis (RFA). MATERIAL AND METHODS: A total of 109 dental implants were placed in 97 patients. SFE was carried out with a lateral window approach and a mixture of autogenous bone chips and deproteinized bovine bone mineral (DBBM). Titanium screw-type, tissue-level implants with a chemically modified SLA surface were used. ISQ values were measured after implant insertion (ISQBL ) and after 8 weeks of healing (ISQ8 wk ). Patients showing ISQ8 wk >= 70 subsequently underwent restoration. Implants with an ISQ value < 70 were recalled at 2-week intervals. RESULTS: The ISQ at baseline had a mean value of 68.3 (SD +/- 9.8). At 8 weeks, the mean ISQ value was 73.6 (SD +/- 6.4). This increase was statistically significant (P < 0.001). An ISQ8 wk value >=70 was observed for 91 implants (83%). One implant (0.9%) with a peri-implant infection and severe bone loss at 8 weeks was considered an early failure. CONCLUSIONS: This study showed that 83% of implants reached the threshold level of ISQ >= 70 after 8 weeks, allowing an early loading protocol. The early failure rate was considered low with 0.9%. The RFA technology is a suitable method to objectively monitor implant stability longitudinally. PMID- 26774076 TI - In vitro metabolism of methiocarb and carbaryl in rats, and its effect on their estrogenic and antiandrogenic activities. AB - In this work, we examined the metabolism of the carbamate insecticides methiocarb and carbaryl by rat liver microsomes and plasma, and its effect on their endocrine-disrupting activities. Methiocarb and carbaryl were not enzymatically hydrolyzed by rat liver microsomes, but were hydrolyzed by rat plasma, mainly to methylthio-3,5-xylenol (MX) and 1-naphthol, respectively. When methiocarb was incubated with rat liver microsomes in the presence of NADPH, methiocarb sulfoxide was formed. The hydrolysis product, MX, was also oxidized to the sulfoxide, 3,5-dimethyl-4-(methylsulfinyl)phenol (SP), by rat liver microsomes in the presence of NADPH. These oxidase activities were catalyzed by cytochrome P450 and flavin-containing monooxygenase. Methiocarb and carbaryl both exhibited estrogen receptor alpha (ERalpha) and ERbeta agonistic activity. MX and 1 naphthol showed similar activities, but methiocarb sulfoxide and SP showed markedly decreased activities. On the other hand, methiocarb and carbaryl exhibited potent antiandrogenic activity in the concentration range of 1*10(-6) 3*10(-5) M. Their hydrolysis products, MX, and 1-naphthol also showed high activity, equivalent to that of flutamide. However, methiocarb sulfoxide and SP showed relatively low activity. Thus, hydrolysis of methiocarb and carbaryl and oxidation of methiocarb to the sulfoxide markedly modified the estrogenic and antiandrogenic activities of methiocarb and carbaryl. PMID- 26774073 TI - Sex differences in the association between neck circumference and asthma. AB - INTRODUCTION: The association between obesity and asthma control/quality of life commonly relies on body mass index (BMI) as the anthropomorphic measure. Due to limitations of BMI and the existence of alternative measures, such as neck circumference (NC), we examined the association between NC and asthma control/quality of life, with particular attention to male-female differences. MATERIALS AND METHODS: The AsthMaP-2 Project is an observational study of youth with physician-diagnosed asthma. NC was stratified according to age- and sex specific cutoffs and associated with asthma control (via Asthma Control Test [ACT]) and quality of life (via Integrated Therapeutics Group [ITG]-Asthma Short Form). RESULTS: The mean +/- SD age was 11.9 +/- 3.6 years, and 53% were male (N = 116). The mean BMI percentile was at the 71 +/- 28 percentile. Thirty-one participants (27%) met criteria for high NC. Males with high NC had significantly worse asthma control (P = 0.02) and lower quality of life than those with low NC. No similar association was found for females and the proportion of variability in ACT and ITG was best explained by BMI percentile. Conversely, for males, the proportion of variability in these scores explained by NC was larger than BMI percentile alone (Cohen's f(2) = 0.04-0.09, a small to medium effect size). DISCUSSION: Among male youth with asthma, combined use of NC and BMI percentile explained asthma control and quality of life better than BMI alone. Future studies of asthma should include measurement of NC and other anthropogenic measures of regional adiposity to clarify sex differences in asthma. Pediatr Pulmonol. 2016; 51:893-900. (c) 2016 Wiley Periodicals, Inc. PMID- 26774075 TI - Grafting of gallic acid onto chitosan nano particles enhances antioxidant activities in vitro and protects against ochratoxin A toxicity in catfish (Clarias gariepinus). AB - This study aimed to prepare and characterize enzymatic modified chitosan nanoparticles (CSNPs) with gallic acid (GA) or octyl gallate (OG) to optimize its potential in human application and to evaluate their protective role against ochrtoxin A (OTA) toxicity in catfish. The modified CSNPs have average size around 90 nm with positive charge and high scavenging activity especially GA CSNPs. In the in vivo study, catfish were divided into 8 groups and treated for 3 weeks as follow: the control group, OTA-treated group (1 mg/kg b.w.), the groups treated with CSNPs, GA-CSNPs or OG-CSNPs (280 mg/kg b.w.) anole or in combination with OTA. Blood, liver and kidney samples were collected for different analyses. OTA induced a significant biochemical disturbances accompanied with oxidative stress in liver and kidney, histological changes and increase DNA fragmentation in the kidney. Co-treatment with OTA plus the different CSNPs resulted in a significant improvement in all tested parameters and histological picture of the kidney. This improvement was more pronounced in the group treated with GA-CSNPs. It could be concluded that grafting of GA or its ester improved the properties of CSNPs. Moreover, GA-CSNPs showed strong scavenging properties than OG-CSNPs due to the blocking of carboxyl groups responsible of the scavenging activity in OG. PMID- 26774077 TI - 5q14.3 deletion neurocutaneous syndrome: Contiguous gene syndrome caused by simultaneous deletion of RASA1 and MEF2C: A progressive disease. AB - We report the case of a young girl who was presented with complex clinical symptoms caused by the deletion of contiguous genes: RASA1 and MEF2C, located on chromosome 5q14.3. Specifically, the diagnosis of her skin disorder and vascular malformations involving central nervous system is consistent with a RASopathy. The child's neurological manifestations are observed in most patients suffering from 5q14.3 by deletion or mutation of the MEF2C gene. A review of the literature allowed us to conclude that the contiguous deletion of genes RASA1 and MEF2C fulfills the criteria for the diagnosis of a Neurocutaneous syndrome as proposed by Carr et al. [2011]. We also assessed the penetrance of RASA1 and clinical manifestations of MEF2C according to the type of deletion. This child described presents the complete symptomatology of both deleted genes. We would also like to highlight the progression of the disorder. PMID- 26774078 TI - Continental-scale travelling waves in forest geometrids in Europe: an evaluation of the evidence. AB - A recent paper claims the existence of one of the most large-scale travelling waves ever recorded for any animal population. Here we address why conceptual and methodological pitfalls may have served to exaggerate or even impose the spatial patterns reported. Photo credit: Jane U. Jepsen. PMID- 26774079 TI - Late spontaneous resolution of persistent molar pregnancy. AB - OBJECTIVE: To determine the outcome of women with persistently raised but falling human chorionic gonadotrophin (hCG) levels 6 months after surgical evacuation of a molar pregnancy. DESIGN: An 11-year retrospective review. SETTING: The United Kingdom supra-regional trophoblastic disease treatment centres at Weston Park Hospital (Sheffield) and Charing Cross Hospital (London). POPULATION: Women with raised but falling serum human chorionic gonadotrophin (hCG) levels 6 months after evacuation of a molar pregnancy. METHODS: Retrospective case note review of eligible women identified by the electronic databases held at each supra-regional centre. MAIN OUTCOME MEASURES: The proportion of women that attain normal hCG levels spontaneously without chemotherapy. In addition, rates of gestational trophoblastic neoplasia (GTN), drug resistance, disease relapse and overall survival are reported. RESULTS: Thirty-five women with molar pregnancy and raised but falling serum hCG levels continued surveillance 6 months after evacuation. Levels of hCG in 30 of the patients (86%) fell to normal levels spontaneously. One woman defaulted follow up prior to hCG normalisation (3%) and the remaining four women (11%) were treated with chemotherapy due to a plateau or rise in serum hCG levels indicating GTN. All treated women were successfully salvaged by either first (n = 1) or second line (n = 2) chemotherapy or found to have persistently raised low level hCG of uncertain clinical relevance (n = 1). No women developed relapsed disease and overall survival was 100%. CONCLUSIONS: Women with a molar pregnancy and a raised but falling hCG level beyond 6 months from uterine evacuation can be safely observed with regular hCG monitoring and can usually avoid potentially toxic chemotherapy. TWEETABLE ABSTRACT: Women with treated molar pregnancy may avoid chemotherapy if 6-month hCG levels are raised but falling. PMID- 26774080 TI - Effects of the isoflavone prunetin on gut health and stress response in male Drosophila melanogaster. AB - The traditional Asian diet is rich in fruits, vegetables and soy, the latter representing a significant source of dietary isoflavones. The isoflavone prunetin was recently identified to improve intestinal epithelial barrier function in vitro and to ameliorate general survival and overall health state in vivo in male Drosophila melanogaster. However, the prunetin-mediated health benefits in the fruit fly were ascertained under standard living conditions. As the loss of intestinal integrity is closely related to a reduction in Drosophila lifespan and barrier dysfunction increases with age, effects on prunetin-modulated gut health under oxidative or pathogenic stress provocation remain to be elucidated. In this study, male adult D. melanogaster were administered either a prunetin or a control diet. Gut-derived junction protein expression and pathogen-induced antimicrobial peptide expressions as well as the stem cell proliferation in the gut were evaluated. Furthermore, survival following exposure to hydrogen peroxide was assessed. Prunetin ingestion did not attenuate bacterial infection and did not protect flies from oxidative stress. Intestinal mRNA expression levels of adherence and septate junction proteins as well as the stem cell proliferation were not altered by prunetin intake. Prunetin does not improve the resistance of flies against severe injuring, exogenous stress and therefore seems to function in a preventive rather than a therapeutic approach since the health-promoting benefits appear to be exclusively restricted to normal living circumstances. PMID- 26774082 TI - Electrochemistry of Layered Graphitic Carbon Nitride Synthesised from Various Precursors: Searching for Catalytic Effects. AB - Graphitic carbon nitride (g-C3 N4 ), synthesised by pyrolysis of different precursors (dicyandiamide, melamine and urea) under varying reaction conditions (air and nitrogen gas) is subjected to electrochemical studies for the elucidation of the inherent catalytic efficiency of the pristine material. Contrary to popular belief, pristine g-C3 N4 shows negligible, if any, enhancement in its electrochemical behaviour in this comprehensive study. Voltammetric analysis reveals g-C3 N4 to display similar catalytic efficiency to the unmodified glassy carbon electrode surface on which the bulk material was deposited. This highlights the non-catalytic nature of the pristine material and challenges the feasibility of using g-C3 N4 as a heterogeneous catalyst to deliver numerous promised applications. PMID- 26774081 TI - Plasma lipid oxidation induced by peroxynitrite, hypochlorite, lipoxygenase and peroxyl radicals and its inhibition by antioxidants as assessed by diphenyl-1 pyrenylphosphine. AB - Lipid oxidation has been implicated in the pathogenesis of many diseases. Lipids are oxidized in vivo by several different oxidants to give diverse products, in general lipid hydroperoxides as the major primary product. In the present study, the production of lipid hydroperoxides in the oxidation of mouse plasma induced by multiple oxidants was measured using diphenyl-1-pyrenylphosphine (DPPP) as a probe. DPPP itself is not fluorescent, but it reacts with lipid hydroperoxides stochiometrically to give highly fluorescent DPPP oxide and lipid hydroxides. The production of lipid hydroperoxides could be followed continuously in the oxidation of plasma induced by peroxynitrite, hypochlorite, 15-lipoxygenase, and peroxyl radicals with a microplate reader. A clear lag phase was observed in the plasma oxidation mediated by aqueous peroxyl radicals and peroxynitrite, but not in the oxidation induced by hypochlorite and lipoxygenase. The effects of several antioxidants against lipid oxidation induced by the above oxidants were assessed. The efficacy of antioxidants was dependent markedly on the type of oxidants. alpha-Tocopherol exerted potent antioxidant effects against peroxyl radical mediated lipid peroxidation, but it did not inhibit lipid oxidation induced by peroxynitrite, hypochlorite, and 15-lipoxygenase efficiently, suggesting that multiple antioxidants with different selectivities are required for the inhibition of plasma lipid oxidation in vivo. This is a novel, simple and most high throughput method to follow plasma lipid oxidation induced by different oxidants and also to assess the antioxidant effects in biologically relevant settings. PMID- 26774083 TI - Glycative stress from advanced glycation end products (AGEs) and dicarbonyls: An emerging biological factor in cancer onset and progression. AB - In recent years, glycative stress from exogenous or endogenous advanced glycation end products (AGEs) and highly reactive dicarbonyls has gained great attention for its putative effects on cancer development. AGEs are a group of compounds formed from the complex chemical reaction of reducing sugars with compounds containing an amino group. AGEs bind to and activate the receptor for AGEs (RAGE), which is a predominant modulator of inflammation-associated cancer, and AGEs induce reactive oxygen species that are an important regulator of the hallmarks of cancer. Dicarbonyls, which are formed during glycolysis, lipid oxidation, or protein degradation, include glyoxal, methylglyoxal, and 3 deoxyglucosone and are regarded as major precursors of AGEs. These dicarbonyls not only fuel the AGE pool in living organisms but also evoke carbonyl stress, which may contribute to the carbonylative damage of carbohydrates, lipids, proteins, or DNA. Carbonylative damage then leads to many lesions, some of which are implicated in the pathogenesis of cancer. In this review, studies regarding the effects of AGEs and dicarbonyls on cancer onset or progression are systematically discussed, and the utilization of AGE inhibitors and dicarbonyl scavengers in cancer therapy are noted. PMID- 26774084 TI - Persistent GnRH receptor activation in pituitary alphaT3-1 cells analyzed with a label-free technology. AB - The gonadotropin-releasing hormone (GnRH) receptor is a drug target for certain hormone-dependent diseases such as prostate cancer. In this study, we examined the activation profiles of the endogenous ligand, GnRH and a well-known marketed analog, buserelin using a label-free assay in pituitary alphaT3-1 cells with endogenous GnRH receptor expression. This whole cell impedance-based technology allows for the real-time measurement of morphological cellular changes. Both agonists dose-dependently decreased the impedance as a result of GnRH receptor activation with potencies of 9.3 +/- 0.1 (pEC50 value, buserelin) and 7.8 +/- 0.06 (pEC50 value, GnRH). Subsequently, GnRH receptor activation was completely abolished with a selective Galphaq inhibitor, thereby confirming the Galphaq coupling of the GnRH receptor in pituitary alphaT3-1 cells. Additionally, we observed continued responses after agonist stimulation of alphaT3-1 cells indicating long-lasting cellular effects. Wash-out experiments demonstrated that the long-lasting effects induced by GnRH were most likely caused by rebinding since over 70% of the original response was abolished after wash-out. In contrast, a long receptor residence time was responsible for the prolonged effects caused by buserelin, with over 70% of the original response remaining after wash-out. In summary, we validated that impedance-based label-free technology is suited for studying receptor-mediated activation in cell lines endogenously expressing the target of interest. Moreover, this real-time monitoring allows the examination of binding kinetics and its influence on receptor activation at a cellular level. PMID- 26774085 TI - A fluorescence resonance energy transfer (FRET) based "Turn-On" nanofluorescence sensor using a nitrogen-doped carbon dot-hexagonal cobalt oxyhydroxide nanosheet architecture and application to alpha-glucosidase inhibitor screening. AB - The medicines targeted at alpha-glucosidase played an important role in anti diabetes and anti-HIV therapy. Unfortunately, the method based on fluorescent assay strategy for alpha-glucosidase inhibitor screening remains poorly investigated. In this study, a novel "Turn On" fluorescence sensor platform has been developed for trace alpha-glucosidase inhibitor screening from natural medicines. Firstly, carbon dots were prepared by one-pot synthesis and used as the signal output. Combining with the carbon dots, cobalt oxyhydroxide (CoOOH) nanoflakes were employed to build the fluorescence resonance energy transfer (FRET) based sensor platform. Secondly, L-ascorbic acid-2-O-alpha-D glucopyranosyl (AAG) was innovatively introduced as alpha-glucosidase substrate. With hydrolysis of AAG by alpha-glucosidase, ascorbic acids (AA) were released that can rapidly reduce CoOOH nanoflakes to Co(2+), and then FRET was stopped accompanying with the fluorescence recovery of CDs. The sensor platform was ultrasensitive to AA with a detection limit of 5 nM, ensuring the sensitive monitoring of enzyme activity. Acarbose was used as the inhibitor model and its inhibition rate is proportional to the logarithm of concentration in range of 10( 9)-10(-3)M with the correlation coefficient of R(2)=0.996, and an ultralow limit of detection of ~1*10(-9)M was obtained. The inhibiting ability of seven compounds isolated from natural medicines was also evaluated. The constructed sensor platform was proven to be sensitive and selective as well as cost effective, facile and reliable, making it promising as a candidate for trace alpha-glucosidase inhibitor screening. PMID- 26774086 TI - Quantitative nanoimmunosensor based on dark-field illumination with enhanced sensitivity and on-off switching using scattering signals. AB - A nanoimmunosensor based on wavelength-dependent dark-field illumination with enhanced sensitivity was used to detect a disease-related protein molecule at zeptomolar (zM) concentrations. The assay platform of 100-nm gold nanospots could be selectively acquired using the wavelength-dependence of enhanced scattering signals from antibody-conjugated plasmonic silver nanoparticles (NPs) with on-off switching using optical filters. Detection of human thyroid-stimulating hormone (hTSH) at a sensitivity of 100 zM, which corresponds to 1-2 molecules per gold spot, was possible within a linear range of 100 zM-100 fM (R=0.9968). A significantly enhanced sensitivity (~4-fold) was achieved with enhanced dark field illumination compared to using a total internal reflection fluorescence immunosensor. Immunoreactions were confirmed via optical axial-slicing based on the spectral characteristics of two plasmonic NPs. This method of using wavelength-dependent dark-field illumination had an enhanced sensitivity and a wide, linear dynamic range of 100 zM-100 fM, and was an effective tool for quantitatively detecting a single molecule on a nanobiochip for molecular diagnostics. PMID- 26774087 TI - Bacteria detection based on its blockage effect on silicon nanopore array. AB - Bacteria detection plays an important role in the guarantee of food and water safety. This work proposed a new sensing strategy for the rapid detection of bacteria based on its blockage effect on nanopore array, which was prepared from electrochemically etched silicon. With the assistance of microfluidic technology, the nanopore array attached with Escherichia coli antibody can selectively and rapidly capture E. coli bacteria, resulting in the decrease of pore accessibility. The signal of pore blockage can be measured by in-direct Fourier Transformed Reflectometric Interference Spectroscopy (FT-RIS). The pore blockage signal has a linear relationship with the logarithm of bacterial density in aqueous sample within the range from 10(3) to 10(7)cfuml(-1). Due to the specific interaction between the antibody and target bacteria, only the E. coli sample displayed significant pore blockage effect, whereas the non-target bacteria, Nox and P17, almost did not show any pore blockage effect. The strategy established in this work might be pervasively applied in the rapid detection of target bacteria and cell in a label-free manner. PMID- 26774088 TI - A highly sensitive biosensor for tumor maker alpha fetoprotein based on poly(ethylene glycol) doped conducting polymer PEDOT. AB - Biocompatible polymers, such as poly(ethylene glycol) (PEG), are of great significance in the development of bio-interfaces and biosensors, as they possess excellent biocompatibility and are easy for modification. A novel highly biocompatible polymer composite was synthesized herein through electrochemical polymerization of the conducting polymer poly(3,4-ethylenedioxythiophene) (PEDOT) and a PEG derivative, 4-arm PEG terminated with thiol groups. The electrodeposited conducting polymer composite of PEG doped PEDOT (PEDOT/PEG) exhibited flake-like nanostructure, large surface area and outstanding stability. In order to further immobilize antibodies, gold nanoparticles (AuNPs) were introduced to the PEDOT/PEG composite surface through their unique interaction with the thiol groups. AuNPs modified PEDOT/PEG provided a desirable support for the immobilization of various biomolecules such as antibodies for alpha fetoprotein (AFP), a vital tumor biomarker for liver cancer. The fabricated AFP biosensor demonstrated favorable selectivity, high sensitivity, and ultralow detection limit. Furthermore, owing to the presence of PEG polymers that are highly hydrophilic, such AuNPs/PEDOT/PEG based AFP biosensor also exhibited good anti-fouling ability, and it was capable of assaying target AFP in 10% (V/V) human serum samples, indicating highly feasible potential for clinical diagnosis. PMID- 26774090 TI - Sensitive colorimetric detection of K(I) using catalytically active gold nanoparticles triggered signal amplification. AB - In this work, we report a simple, ultrasensitive, and feasible colorimetric assay for metal ion (K(+), used as a model) via inherent peroxidase-like enzymatic amplification strategy of gold nanoparticles (AuNPs). It is shown that peroxidase like activity of AuNPs can be improved dramatically by its surface activation with target-specific aptamer molecules. Whereas when the target exists, the aptamers leave the surface of AuNPs in a target concentration-dependent manner, resulting in a decrease of the nanoenzymatic catalytic ability of AuNPs. Thus, K(+) can be quantified in the presence of AuNPs by using a colorimetric sensing probe (3,3',5,5'-tetramethylbenzidine). The color change of the solution is relevant to the dose of the target, and this can be achieved with the naked eyes and monitored by UV-vis spectrometry. A linear dependence between the absorbance and target K(+) concentration is obtained under optimal conditions in the range from 0. 1 nM to 1 MUM with a detection limit (LOD) of 0.06 nM estimated at the 3Sblank level. The sensitivity displays to be 2-9 orders of magnitude better than those of other K(+) detection methods. This sensing strategy may in principle be universally applicable for the detection of a range of environmental or biomedical molecules of interest. PMID- 26774091 TI - Molecular beacon-based enzyme-free strategy for amplified DNA detection. AB - We report an enzyme-free, sensitive strategy for DNA detections through fluorescence amplification. The sensing method employs molecular beacons (MBs) and two single-stranded helper DNA probes. In the presence of a DNA target, it binds and opens an MB. This triggers the hybridizations between the MB and helper probes, and consequently releases the DNA target, which becomes available to react with another MB and enhances the fluorescence emission of the MBs. The detection limit of the proposed strategy is 0.58 pM, which is about 3 orders of magnitude better than the conventional MB-based method. This method is also fast and exhibits good selectivity. It is superior to previous MB-based amplification approaches employing enzymes or nanomaterials. PMID- 26774089 TI - Photoluminescence detection of 2,4,6-trinitrotoluene (TNT) binding on diatom frustule biosilica functionalized with an anti-TNT monoclonal antibody fragment. AB - A selective and label-free biosensor for detection of the explosive compound 2,4,6-trinitrotoluene (TNT) in aqueous solution was developed based on the principle of photoluminescence quenching of upon immunocomplex formation with antibody-functionalized diatom frustule biosilica. The diatom frustule is an intricately nanostructured, highly porous biogenic silica material derived from the shells of microscopic algae called diatoms. This material emits strong visible blue photoluminescence (PL) upon UV excitation. PL-active frustule biosilica was isolated from cultured cells of the marine diatom Pinnularia sp. and functionalized with a single chain variable fragment (scFv) derived from an anti-TNT monoclonal antibody. When TNT was bound to the anti-TNT scFv functionalized diatom frustule biosilica, the PL emission from the biosilica was partially quenched due to the electrophilic nature of the nitro (-NO2) groups on the TNT molecule. The dose-response curve for immunocomplex formation of TNT on the scFv-functionalized diatom frustule biosilica had a half-saturation binding constant of 6.4 +/- 2.4.10(-8)M and statistically-significant measured detection limit of 3.5.10(-8)M. The binding and detection were selective for TNT and TNB (trinitrobenzene) but not RDX (hexahydro-1,3,5-trinitro-1,3,5-triazine) or 2,6 DNT (2,6-dinitrotoluene). PMID- 26774092 TI - Conducting polymer and its composite materials based electrochemical sensor for Nicotinamide Adenine Dinucleotide (NADH). AB - Nicotinamide Adenine Dinucleotide (NADH) is an important coenzyme in the human body that participates in many metabolic reactions. The impact of abnormal concentrations of NADH significantly causes different diseases in human body. Electrochemical detection of NADH using bare electrode is a challenging task especially in the presence of main electroactive interferences such as ascorbic acid (AA), uric acid (UA) and dopamine (DA). Modified electrodes have been widely explored to overcome the problems of poor sensitivity and selectivity occurred from bare electrodes. This review gives an overview on the progress of using conducting polymers, polyelectrolyte and its composites (co-polymer, carbonaceous, metal, metal oxide and clay) based modified electrodes for the sensing of NADH. In addition, developments on the fabrication of numerous conducting polymer composites based modified electrodes are clearly described. PMID- 26774093 TI - A ratiometric fluorescent probe for hyaluronidase detection via hyaluronan induced formation of red-light emitting excimers. AB - Hyaluronidase (HAase), which is involved in various physiological and pathological processes, can selectively degrade hyaluronan (HA) into small fragments, and it has been reported as a diagnostic and prognostic biomarker for bladder cancer. Herein, a facile ratiometric fluorescent sensing system for HAase has been developed, which is based on hyaluronan-induced formation of red-light emitting excimers and can realize sensitive detection of HAase with a detection limit of 0.007 U/mL. A positively-charged pyrene analog (N-Py) has been synthesized and then mixed with the negatively-charged HA, due to electrostatic interaction between the two components, aggregation along with the N-Py excimers readily form which emits red light. While in the presence of HAase, the enzyme catalyzes the hydrolysis of HA into small fragments, which in turn triggers disassembly of excimers; consequently the N-Py excimer emission turns into monomer emission. The emission ratio resulted from the excimer-monomer transition can be used as the sensing signal for detecting HAase. The probe features visible light excitation and red light emission (excimer), which is conducive to reducing possible interference from autofluorescence of biological samples. Furthermore, the assay system can be successfully used to determine HAase in human urine samples with satisfactory accuracy. This strategy may provide a suitable sensitive and accurate assay for HAase as well as an effective approach for developing fluorescent ratiometric assays for other enzymes. PMID- 26774094 TI - Standoff detection of explosives and buried landmines using fluorescent bacterial sensor cells. AB - A standoff detection scheme for buried landmines and concealed explosive charges is presented. The detection procedure consists of the following: Live bacterial sensor strains, genetically engineered to produce a dose-dependent amount of green fluorescent protein (GFP) in the presence of explosives' vapors, are encapsulated and spread on the suspected area. The fluorescence produced by the bacteria in response to traces of the explosive material in their microenvironment is remotely detected by a phase-locked optoelectronic sampling system. This scheme enables fast direct access to a large minefield area, while obviating the need to endanger personnel and equipment. Moreover, the employment of phase locking detection efficiently isolates the bacterial sensors' fluorescent output from the background optical signals. This facilitates the application of bacterial sensors in an outdoor environment, where control of background illumination is not possible. Using this system, we demonstrate standoff detection of 2,4-DNT both in aqueous solution and when buried in soil, by sensor bacteria either in liquid culture or agar-immobilized, respectively, at a distance of 50 m in a realistic optically noisy environment. PMID- 26774095 TI - Electrochemical sensing of nuclear matrix protein 22 in urine with molecularly imprinted poly(ethylene-co-vinyl alcohol) coated zinc oxide nanorod arrays for clinical studies of bladder cancer diagnosis. AB - In 1996 and 2000, the US Food and Drug Administration (FDA) approved the use of Nuclear matrix protein 22 (NMP22) as a monitoring tool for predicting the recurrence/clearing of bladder cancer, and for screening undiagnosed individuals who have symptoms of, or are at risk for, that disease. The fabrication of electrodes for sensing NMP22 and their integration with a portable potentiostat in a homecare system may have great value. This work describes a sensing element comprised of molecularly imprinted polymers (MIPs) for the specific recognition of NMP22 target molecules. Zinc oxide (ZnO) nanorods (214 +/- 45 nm in diameter and 1.08 +/- 0.11 MUm long) were hydrothermally grown on the sensing electrodes to increase the surface area to be coated with MIPs. A portable potentiostat was assembled and a data acquisition (DAQ) card and the Labview program were utilized to monitor electrochemical reaction to sense NMP22 in urine samples. Finally, in phase 0 clinical trials, measurements were made of samples from a few patients with bladder cancer using the NMP22 MIP-coated ZnO nanorods electrodes that were integrated into a portable potentiostat, revealing NMP 22 concentrations in the range 128 +/- 19 to 588 +/- 53 ng/mL. PMID- 26774096 TI - Effect of electric impulse for improved energy generation in mediatorless dual chamber microbial fuel cell through electroevolution of Escherichia coli. AB - The main emphasis of this study is to understand the electroactive behavior of a microbe in microbial fuel cell (MFC) under specific selection pressure. This study explores potential of a non-electrogenic microbe for power production in a mediatorless MFC under the influence of a specific stress. Electric pulse of specific magnitude has been applied to Escherichia coli cells in a MFC and compared the results with unpulsed (control) MFC. Maximum power density of 187.77 mW/m(2) and 284.44 mW/m(2) for the control and experimental MFC has been observed at corresponding current density of 1444.44 mA/m(2) and 1777.77 mA/m(2). The results show improved performance for the pulsed (experimental) system, despite of initial downfall with respect to the control system. This suggests bacterial adaptation against electrical pulses which leads to evolution of an efficient electrogen. This observation is further confirmed by analyzing the results of Cyclic Voltammetry (CV), Scanning Electron Microscopy (SEM) Electrochemical Impedence Spectroscopy (EIS), enlightening different attributes like electrochemical property, bacterial morphology and impedance. The study is focused on development of a microbial fuel cell catalysed by E. coli, through triggering electroactive property in the microbe by exposing it to external stress. This study is unique in nature as it is mediatorless, economical and describes about a new method of natural bacterial evolution. PMID- 26774097 TI - What is your diagnosis? Clitoral mass in a dog. PMID- 26774098 TI - Factors affecting peak height variability for short tandem repeat data. AB - In forensic DNA analysis a DNA extract is amplified using polymerase chain reaction (PCR), separated using capillary electrophoresis and the resulting DNA products are detected using fluorescence. Sampling variation occurs when the DNA molecules are aliquotted during the PCR setup stage and this translates to variability in peak heights in the resultant electropherogram or between electropherograms generated from a DNA extract. Beyond the variability caused by sampling variation it has been observed that there are factors in generating the DNA profile that can contribute to the magnitude of variability observed, most notably the number of PCR cycles. In this study we investigate a number of factors in the generation of a DNA profile to determine which contribute to levels of peak height variability. PMID- 26774099 TI - Developmental validation of the PowerPlex((r)) Fusion 6C System. AB - The PowerPlex((r)) Fusion 6C System is a 27-locus, six-dye, multiplex that includes all markers in the expanded CODIS core loci and increases overlap with STR database standards throughout the world. Additionally, it contains two, rapidly mutating, Y-STRs and is capable of both casework and database workflows, including direct amplification. A multi-laboratory developmental validation study was performed on the PowerPlex((r)) Fusion 6C System. Here, we report the results of that study which followed SWGDAM guidelines and includes data for: species specificity, sensitivity, stability, precision, reproducibility and repeatability, case-type samples, concordance, stutter, DNA mixtures, and PCR based procedures. Where appropriate we report data from both extracted DNA samples and direct amplification samples from various substrates and collection devices. Samples from all studies were separated on both Applied Biosystems 3500 series and 6-dye capable 3130 series Genetic Analyzers and data is reported for each. Together, the data validate the design and demonstrate the performance of the PowerPlex((r)) Fusion 6C System. PMID- 26774100 TI - Developmental validation of the Quantifiler((r)) HP and Trio Kits for human DNA quantification in forensic samples. AB - The quantification of human genomic DNA is a necessary first step in the DNA casework sample analysis workflow. DNA quantification determines optimal sample input amounts for subsequent STR (short tandem repeat) genotyping procedures, as well as being a useful screening tool to identify samples most likely to provide probative genotypic evidence. To better mesh with the capabilities of newest generation STR analysis assays, the Quantifiler((r)) HP and Quantifiler((r)) Trio DNA Quantification Kits were designed for greater detection sensitivity and more robust performance with samples that contain PCR inhibitors or degraded DNA. The new DNA quantification kits use multiplex TaqMan((r)) assay-based fluorescent probe technology to simultaneously quantify up to three human genomic targets, allowing samples to be assessed for total human DNA, male contributor (i.e., Y chromosome) DNA, as well as a determination of DNA degradation state. The Quantifiler HP and Trio Kits use multiple-copy loci to allow for significantly improved sensitivity compared to earlier-generation kits that employ single-copy target loci. The kits' improved performance provides better predictive ability for results with downstream, newest-generation STR assays, and their shortened time-to-result allows more efficient integration into the forensic casework analysis workflow. PMID- 26774101 TI - High-quality mtDNA control region sequences from 680 individuals sampled across the Netherlands to establish a national forensic mtDNA reference database. AB - The use of mitochondrial DNA (mtDNA) for maternal lineage identification often marks the last resort when investigating forensic and missing-person cases involving highly degraded biological materials. As with all comparative DNA testing, a match between evidence and reference sample requires a statistical interpretation, for which high-quality mtDNA population frequency data are crucial. Here, we determined, under high quality standards, the complete mtDNA control-region sequences of 680 individuals from across the Netherlands sampled at 54 sites, covering the entire country with 10 geographic sub-regions. The complete mtDNA control region (nucleotide positions 16,024-16,569 and 1-576) was amplified with two PCR primers and sequenced with ten different sequencing primers using the EMPOP protocol. Haplotype diversity of the entire sample set was very high at 99.63% and, accordingly, the random-match probability was 0.37%. No population substructure within the Netherlands was detected with our dataset. Phylogenetic analyses were performed to determine mtDNA haplogroups. Inclusion of these high-quality data in the EMPOP database (accession number: EMP00666) will improve its overall data content and geographic coverage in the interest of all EMPOP users worldwide. Moreover, this dataset will serve as (the start of) a national reference database for mtDNA applications in forensic and missing person casework in the Netherlands. PMID- 26774102 TI - The rules of tool incorporation: Tool morpho-functional & sensori-motor constraints. AB - Previous studies showed that using tools modifies the agent's body and space representation. However, it is still not clear which rules govern those remapping processes. Here, we studied the differential role played by the morpho-functional characteristics of a tool and the sensori-motor constraints that a tool imposes on the hand. To do so, we asked a group of participants to reach and grasp an object using, in different conditions, two different tools: Pliers, to be acted upon by the index and thumb fingertips, and Sticks, taped to the same two digits. The two tools were equivalent in terms of morpho-functional characteristics, providing index finger and thumb with the same amount of elongation. Crucially, however, they imposed different sensori-motor constraints on the acting fingers. We measured and compared the kinematic profile of free-hand movements performed before and after the use of both devices. As predicted on the basis of their equivalent morpho-functional characteristics, both tools induced similar changes in the fingers (but not the arm) kinematics compatible with the hand being represented as bigger. Furthermore, the different sensori-motor constraints imposed by Pliers and Sticks over the hand, induced differential updates of the hand representation. In particular, the Sticks selectively affected the kinematics of the two fingers they were taped on, whereas Pliers had a more global effect, affecting the kinematics of hand movements not performed during the use of the tool. These results suggest that tool-use induces a rapid update of the hand representation in the brain, not only on the basis of the morpho functional characteristics of the tool, but also depending on the specific sensori-motor constraints imposed by the tool. PMID- 26774104 TI - Free versus anchored numerical estimation: A unified approach. AB - Children's number-line estimation has produced a lively debate about representational change, supported by apparently incompatible data regarding descriptive adequacy of logarithmic (Opfer, Siegler, & Young, 2011) and cyclic power models (Slusser, Santiago, & Barth, 2013). To test whether methodological differences might explain discrepant findings, we created a fully crossed 2*2 design and assigned 96 children to one of four cells. In the design, we crossed anchoring (free, anchored) and sampling (over-, even-), which were candidate factors to explain discrepant findings. In three conditions (free/over-sampling, free/even-sampling, and anchored/over-sampling), the majority of children provided estimates better fit by the logarithmic than cyclic power function. In the last condition (anchored/even-sampling), the reverse was found. Results suggest that logarithmically-compressed numerical estimates do not depend on sampling, that the fit of cyclic power functions to children's estimates is likely an effect of anchors, and that a mixed log/linear model provides a useful model for both free and anchored numerical estimation. PMID- 26774103 TI - Estimations of object frequency are frequently overestimated. AB - Real-world scenes are complex but lawful: blenders are more likely to be found in kitchens than beaches, and elephants are not generally found inside homes. Research over the past 40years has demonstrated that contextual associations influence object recognition, change eye movement distributions, and modulate brain activity. However, the majority of these studies choose object-scene pairs from experimenters' intuitions because the statistical relationships between objects and scenes had yet to be systematically quantified. How do intuitive estimations compare to actual object frequencies? Across six experiments, observers estimated the frequency with which an object is found in a particular environment, such as the frequency of "mug" in an office. Estimated frequencies were compared to observed frequencies in two fully labeled scene databases (Greene, 2013). Although inter-observer similarity was high, observers systematically overestimated object frequency by an average of 32% across experiments. Altogether, these results speak to the richness of scene schemata and to the necessity of measuring object frequencies. PMID- 26774105 TI - The PI3K/Akt pathway is involved in procyanidin-mediated suppression of human colorectal cancer cell growth. AB - Colorectal cancer (CRC) has the third highest incidence worldwide. Epidemiological studies showed that the consumption of fruit and vegetables containing procyanidins (PCA), polymers of flavan-3-ols, is associated with lower CRC risk. However, the molecular mechanisms supporting this positive association are unclear. This study investigated the capacity of PCA with different degrees of polymerization to reduce CRC cell growth, characterizing the underlying mechanisms. Compared to the monomer ((-)-epicatechin) and the trimer, the hexamer (Hex) was the most active at reducing CRC cell viability. Hex caused a concentration- (2.5-50 MUM) and time- (24-72 h) dependent decrease in the viability of six human CRC cell lines in culture. Hex caused CRC apoptotic Caco-2 cell death within 24 h, as evidenced by caspase 3 and caspase 9 activation, DNA fragmentation, and changes in nuclear morphology/staining. Hex-induced apoptosis occurs through the mitochondrial pathway, as evidenced by an increased Bad mitochondrial translocation, and cytochrome c release from the mitochondria to the cytosol. Hex also arrested the Caco-2 cell cycle at G2 /M phase and upregulated genes involved in autophagy. Mechanistically, in Caco-2 cells Hex inhibited the PI3K/Akt signaling pathway, causing the downstream downregulation of proteins involved in the regulation of cell survival (Bad, GSK-3beta). Accordingly, the Akt inhibitor MKK-2206 decreased Bad and GSK-3beta phosphorylation. MKK-2206 decreased cell growth, having an additive effect with Hex. In conclusion, our results show that large PCA can inhibit CRC cell growth via the Akt kinase pathway, demonstrating a mechanism to explain the epidemiological evidence linking PCA-rich diets with lower CRC risk. (c) 2016 Wiley Periodicals, Inc. PMID- 26774106 TI - Methodological Issues to Consider When Collecting Data to Estimate Poverty Impact in Economic Evaluations in Low-income and Middle-income Countries. AB - Out-of-pocket spending is increasingly recognized as an important barrier to accessing health care, particularly in low-income and middle-income countries (LMICs) where a large portion of health expenditure comes from out-of-pocket payments. Emerging universal healthcare policies prioritize reduction of poverty impact such as catastrophic and impoverishing healthcare expenditure. Poverty impact is therefore increasingly evaluated alongside and within economic evaluations to estimate the impact of specific health interventions on poverty. However, data collection for these metrics can be challenging in intervention based contexts in LMICs because of study design and practical limitations. Using a set of case studies, this letter identifies methodological challenges in collecting patient cost data in LMIC contexts. These components are presented in a framework to encourage researchers to consider the implications of differing approaches in data collection and to report their approach in a standardized and transparent way. PMID- 26774108 TI - Identifying the risk of compassion fatigue, improving compassion satisfaction and building resilience in emergency medicine. PMID- 26774107 TI - Health literacy, associated lifestyle and demographic factors in adult population of an English city: a cross-sectional survey. AB - BACKGROUND: Lower health literacy is a public health issue that follows a social gradient, potentially reinforcing existing health inequalities. However, levels of health literacy in particular populations can be unclear and are a key to identifying effective public health interventions. This research examined health literacy levels in Stoke-on-Trent, where 31.2% of the population live in areas classified amongst the 10% most deprived in England. METHODS: A cross-sectional survey using the Newest Vital Sign examined associations with demographic factors, lifestyle behaviours, Internet use and self-rated health. The sample (n = 1046) took account of variance in levels of health literacy by age, educational attainment and deprivation. Bivariate logistic regression and multivariate logistic regression were used to estimate associations with health literacy when adjusted for other demographic factors and lifestyle behaviours. RESULTS: Nine hundred and seventy-two respondents completed the health literacy measure (93%): 277 (28.5%) scored low, 228 (23.5%) scored marginal and 467 (48.0%) scored adequate. Associations with higher rates of limited health literacy included older age, lower educational level, lower income, perceived poor health and lack of access to the Internet. CONCLUSIONS: Given the complexity of factors influencing health literacy interdisciplinary approaches across health and social care and the voluntary sector are essential in identifying and developing appropriate interventions. PMID- 26774109 TI - Aetiological spectrum of benign gastric outlet obstruction in India: new trends. AB - There is a paucity of data on the spectrum of benign gastric outlet obstruction in India. Our aim was to evaluate its spectrum and to identify the subgroup which would be most amenable to endoscopic therapy. We studied 64 patients whose aetiology revealed in approximately equal proportions: corrosive injury; gastroduodenal tuberculosis (TB); and peptic ulcer disease. The median number of endoscopic dilations required was two for TB, four for peptic ulcer disease and five for corrosive injury. Gastroduodenal TB and corrosive injury appear now to be more, or at least as, common as peptic ulcer disease as causes of benign gastric outlet obstruction in India. Gastroduodenal TB responds best to endoscopic therapy. PMID- 26774110 TI - Helicobacter pylori infection in dyspeptic patients in an industrial belt of India. AB - The present study is done to study different aspects of Helicobacter pylori (H. pylori) such as its prevalence, association with upper gastrointestinal pathology, diagnosis and treatment outcome. Gastric antral biopsy and serology for H. pylori was done for all dyspeptic patients. Histopathology, gram stain and biopsy urease test was done from the gastric biopsy specimen. The prevalence of H. pylori infection was 58.8%. The sensitivity, specificity, positive and negative predictive value for histopathology was 96.9%, 100%, 100% and 95.8%, respectively; for biopsy urease test 80.4%, 100%, 100% and 78.2%, respectively; for gram stain 85.6%, 97.1%, 97.6% and 82.5%, respectively, and for serology 94.8%, 77.9%, 86% and 91.4%, respectively. Mostly peptic ulcer and duodenitis cases followed by chronic active gastritis were associated with H. pylori infection. Repeat biopsy revealed eradication of H. pylori in 90.7% cases. In dyspeptic patients, endoscopic biopsy not only detects H. pylori infection, but also reveals different gastric pathologies. PMID- 26774111 TI - Hyperuricaemia in patients with type 2 diabetes in a tertiary healthcare centre in sub-Saharan Africa: prevalence and determinants. AB - Hyperuricaemia in type 2 diabetes mellitus (T2DM) has been less well investigated in sub-Saharan Africans. Our study of 438 patients found that alcohol intake, body mass index >=25 kg/m2, hydrochlorothiazide use, statin use, diabetic retinopathy and glomerular filtration rate <60 mL/min/1.73m2 were independently positively associated with hyperuricaemia; whereas smoking reduced this risk. Hyperuricaemia is strongly associated with some modifiable factors, diabetic complications and certain drugs. Our results suggest that further studies should evaluate the potential cost-benefit of screening for hyperuricaemia in type 2 diabetes. PMID- 26774112 TI - A randomised controlled trial comparing 30 mL and 80 mL in Foley catheter for induction of labour after previous Caesarean section. AB - Inducing labour with a Foley balloon catheter rather than using oxytocin or prostaglandins is considered to be less risky if the uterus is scarred.1 It is not known if more fluid in the balloon is more effective without being more dangerous. Volumes of 80 mL and 30 mL were compared in 154 eligible women. Mode of delivery, duration of labour and delivery within 24 h were similar in both groups. However, the second group required oxytocin more frequently. Though more scar dehiscences occurred in the first group, the difference was not significant. PMID- 26774113 TI - Bevacizumab safety in Japanese patients with colorectal cancer. AB - BACKGROUND: Bevacizumab (Avastin((r))) was approved in Japan in April 2007 for patients with advanced or metastatic colorectal cancer. To address the limited clinical experience in Japanese patients, a post-approval surveillance study was undertaken in bevacizumab-treated patients in Japan. METHODS: Bevacizumab (5 or 10 mg/kg every 2 weeks) was administered with chemotherapy; patients were observed for 26 weeks from initiation of treatment. The primary objective was to investigate the incidence of adverse drug reactions, particularly those of interest for bevacizumab. Univariate and multivariate analyses were performed to identify potential risk factors for adverse drug reactions. RESULTS: In total, 2712 patients were registered and 2696 patients were included in the safety analysis. Hypertension (13.1%), hemorrhage (10.5%) and proteinuria (4.5%) were the most common adverse drug reaction. The incidences of serious adverse drug reactions were low: gastrointestinal perforation occurred in 0.9% of patients, hemorrhage in 1.3%, arterial thromboembolic events in 0.3%, venous thromboembolic events in 1.3% and wound-healing complications in 0.4%. The incidence of bevacizumab-specific adverse drug reactions was not influenced by the bevacizumab dose. Multivariate analyses identified risk factors for the following adverse drug reactions: hypertension (prior/concurrent hypertension); tumor-associated bleeding (performance status, prior/concomitant anticoagulant or nonsteroidal anti-inflammatory drug use); proteinuria (sex, performance status, prior/concurrent diabetes and proteinuria); gastrointestinal perforation (primary tumor in situ, concurrent nonsteroidal anti-inflammatory drug use); venous thromboembolic event (treatment stage, port insertion). CONCLUSIONS: The safety profile of bevacizumab-containing regimens in this Japanese population was comparable with studies performed in Western countries. Bevacizumab is generally well tolerated in Japanese patients with advanced or metastatic colorectal cancer. PMID- 26774114 TI - A Comparative Pharmacokinetic Study of Myrislignan by UHPLC-MS After Oral Administration of a Monomer and Myristica fragrans Extract to Rats. AB - An ultra-high performance liquid chromatography coupled with mass spectrometry (UHPLC-MS) method was developed and validated to quantify myrislignan in rat plasma using podophyllotoxin as an internal standard (IS). The chromatographic separation of myrislignan and IS was performed on a 3.0 um Hypersil C18 column (50 mm * 4.6 mm) with methanol and water containing 0.1% acetic acid (80:20, v/v) as the mobile phase at a flow rate of 0.3 mL/min. An electrospray ionization was used in the positive selective-ion monitoring mode for the target ions at m/z 397 and m/z 437 for the quantification of myrislignan and IS. The total run time was 3.6 min for each run. The calibration curve was linear over the range of 0.75-300 ng/mL (r> 0.995) with the lower limit of quantitation at 0.75 ng/mL. Intra- and interday precision was below 11.49%, and the mean accuracy ranged from -9.75 to 7.45%. The proposed method was successfully applied to evaluate the pharmacokinetic properties of myrislignan after oral administration of the myrislignan monomer and Myristica fragrans extract in rats. Statistical analyses indicate that the pharmacokinetic properties of myrislignan in rats have significant differences between two groups. PMID- 26774116 TI - Association of Self-Rated Health in Midlife With Mortality and Old Age Frailty: A 26-Year Follow-Up of Initially Healthy Men. AB - BACKGROUND: The aim was to investigate the relationship between self-rated health (SRH) in healthy midlife, mortality, and frailty in old age. METHODS: In 1974, male volunteers for a primary prevention trial in the Helsinki Businessmen Study (mean age 47 years, n = 1,753) reported SRH using a five-step scale (1 = "very good," n = 124; 2 = "fairly good," n = 862; 3 = "average," n = 706; 4 = "fairly poor," or 5 = "very poor"; in the analyses, 4 and 5 were combined as "poor", n = 61). In 2000 (mean age 73 years), the survivors were assessed using a questionnaire including the RAND-36/SF-36 health-related quality of life instrument. Simplified self-reported criteria were used to define phenotypic prefrailty and frailty. Mortality was retrieved from national registers. RESULTS: During the 26-year follow-up, 410 men had died. Frailty status was assessed in 81.0% (n = 1,088) of survivors: 434 (39.9%), 552 (50.7%), and 102 (9.4%) were classified as not frail, prefrail, and frail, respectively. With fairly good SRH as reference, and adjusted for cardiovascular risk in midlife and comorbidity in old age, midlife SRH was related to mortality in a J-shaped fashion: significant increase with both very good and poor SRH. In similar analyses, average SRH in midlife (n = 425) was related to prefrailty (odds ratio: 1.52, 95% confidence interval: 1.14-2.04) and poor SRH (n = 31) both to prefrailty (odds ratio: 3.56, 95% confidence interval: 1.16-10.9) and frailty (odds ratio: 8.38, 95% confidence interval: 2.32-30.3) in old age. CONCLUSIONS: SRH in clinically healthy midlife among volunteers of a primary prevention trial was related to the development of both prefrailty and frailty in old age, independent of baseline cardiovascular risk and later comorbidity. PMID- 26774115 TI - Effect of vitamin B12 and folic acid supplementation on biomarkers of endothelial function and inflammation among elderly individuals with hyperhomocysteinemia. AB - B-vitamin trials failed to demonstrate beneficial effects on cardiovascular outcomes, but hyperhomocysteinemia still stands out as an independent cardiovascular risk factor, particularly in elderly individuals. B-vitamins may influence early vascular dysfunction, such as endothelial dysfunction, or may have adverse effects, for example on inflammation. We investigated the effect of B-vitamins on endothelial function and inflammation within an interventional study. This study was conducted within the framework of the B-PROOF trial, which included 2919 hyperhomocysteinemic elderly individuals, who received daily vitamin B12 (500 MUg) and folic acid (400 MUg) or placebo for 2 years. Using an electrochemiluminescence platform, we measured intercellular adhesion molecule 1 (ICAM-1), vascular adhesion molecule 1 (VCAM-1), serum amyloid A (SAA), vascular endothelial growth factor (VEGF) and C-reactive protein (CRP) at baseline and follow-up in a subsample of 522 participants (271 intervention group; 251 placebo). Treatment effects were analyzed with ANCOVA. The participants had a mean age of 72 years, and 55% of them were male. At the 2-year follow-up, B vitamins did not change the ICAM-1 (+36% change in the intervention group versus +32% change in the placebo group; p = 0.72), VCAM-1 (+27% vs +25%; p = 0.39), VEGF (-1% vs +4%; p = 0.40), SAA (+34% vs +38%; p = 0.85) or CRP levels (+26% vs +36%; p = 0.70) as compared to placebo. In conclusion, in elderly patients with hyperhomocysteinemia, vitamin B12 and folic acid are unlikely to influence either endothelial function or low-grade systemic inflammation. ClinicalTrials.gov Identifier: NCT00696514. PMID- 26774117 TI - Circulating Concentrations of Growth Differentiation Factor 11 Are Heritable and Correlate With Life Span. AB - Growth differentiation factor 11 (GDF11) is member of the transforming growth factor beta (TGF-beta) superfamily of proteins. Circulating GDF11 concentrations appear to decline with age, and its depletion is associated with cardiac hypertrophy and other morbidities. Knowledge of GDF11 regulation is limited, and the effects of natural genetic variation on GDF11 levels are currently undefined. We tested whether genetic background determines serum GDF11 concentrations using two classical inbred mouse strains: C57BL/6J (B6) and BALB/cByJ (BALB). B6 mice exhibited significantly higher GDF11 levels than BALB mice, and these strain differences were consistent throughout the life span. Overall, interactions between age and genetic background determined GDF11 concentrations, which were unaffected by sex. We then surveyed a panel of 22 genetically diverse inbred mouse strains and discovered a sixfold range in GDF11 levels at middle age. We estimated that 74.52% of phenotypic variation in GDF11 levels was attributable to genetic background. We used the Mouse Phenome Database to screen for phenotypes that correlate with GDF11. Interestingly, GDF11 levels predicted median strain life spans. This study revealed high heritability of GDF11 levels. Furthermore, our correlative data suggest that GDF11 may serve as a novel predictor of mammalian life span. PMID- 26774118 TI - Impact of Chronic Conditions and Multimorbidity on the Disability Burden in the Older Population in Belgium. AB - BACKGROUND: The increase in longevity along with a high prevalence of chronic conditions contribute to increased disability burden. Despite the high occurrence of multimorbidity observed in advanced ages, most studies are restricted to the investigation of individual diseases. In this study, we assessed the impact of chronic conditions and multimorbidity on the disability burden in the older population in Belgium. METHODS: Data from 9,482 participants in the 2001, 2004, or 2008 Belgian Health Interview Surveys aged 55 years or older were analyzed. Disability was defined based on the Global Activity Limitation Indicator (GALI). To attribute disability to single chronic conditions and disease pairs, a multiple additive hazard model was fitted. RESULTS: Musculoskeletal conditions (45.3%), chronic respiratory diseases (11.2%), and cardiovascular diseases (10.2%) diseases were the most frequent conditions. Cardiovascular diseases, the co-occurrence of chronic respiratory diseases and depression, neurological diseases, cancer, and the combination of diabetes and cardiovascular diseases were the top five disabling conditions. The disability prevalence in the older population in Belgium was 35.6% (confidence interval =35.0; 36.2%). The most important contributors to the disability burden were musculoskeletal, cardiovascular, and chronic respiratory diseases. CONCLUSIONS: The present findings provide a deeper understanding of the role of chronic conditions and multimorbidity on the disability burden in the older population in Belgium. Although the disease pairs showed a low contribution to the disability burden, their occurrence presented a high impact on disability. Prevention strategies to tackle disability should target the main contributors to the disability burden and the most disabling conditions/disease pairs, especially in the clinical practice. PMID- 26774119 TI - Advance chromatin extraction improves capture performance of protein A affinity chromatography. AB - Practical effects of advance chromatin removal on performance of protein A affinity chromatography were evaluated using a caprylic acid-allantoin-based extraction method. Lacking this treatment, the practice of increasing loading residence time to increase capacity was shown to increase host protein contamination of the eluted IgG. Advance chromatin extraction suspended that compromise. Protein A ligand leakage from columns loaded with chromatin-extracted harvest was half the level observed on protein A columns loaded with non extracted harvest. Columns loaded with chromatin-extracted harvest were cleaned more effectively by 50-100mM NaOH than columns loaded with non-extracted harvest that were cleaned with 250-500mM NaOH. Two protein A media with IgG capacities in excess of 50g/L were loaded with chromatin-extracted harvest, washed with 2.0M NaCl before elution, and the eluted IgG fraction titrated to pH 5.5 before microfiltration. Host protein contamination in the filtrate was reduced to <1ppm, DNA to <1ppb, protein A leakage to 0.5ppm, and aggregates to 1.0%. Caprylic acid and allantoin were both reduced below 5ppm. Step recovery of IgG was 99.4%. Addition of a single polishing step reduced residual protein A beneath the level of detection and aggregates to <0.1%. Overall process recovery including chromatin extraction was 90%. PMID- 26774120 TI - Selective elimination of the free fatty acid fraction from esterified fatty acids in rat plasma through chemical derivatization and immobilization on amino functionalized silica nano-particles. AB - A high throughput and low cost approach to separate free fatty acids (FFAs) from phospholipid and acylglycerols (esterified fatty acids, EFAs) has been demonstrated, which may be widely used as a sample preparation method in the metabolomics and lipid research. The optimal conditions for FFAs reacting with N hydroxysuccinimide (NHS) only need 10min at room temperature to obtain a 93.5% yield of FFAs-NHS ester. The rest 6% FFA transformed into N-cyclohexyl-fatty acid amide which is stable to methyl esterification adopted for fatty acids analysis. 10min are taken for FFAs-NHS ester to react with amino functionalized silica nanoparticles to immobilize the FFAs. The separation of FFAs from EFAs could be carried out readily by centrifugation. The whole process including derivatization, immobilization, and centrifugation takes less than 40min. Much more accurate fatty acids composition of rat plasma EFAs could be obtained by this approach than the previous reported methods. PMID- 26774121 TI - Normal-phase liquid chromatography-atmospheric-pressure photoionization-mass spectrometry analysis of cholesterol and phytosterol oxidation products. AB - During thermal processing of sterols, complex mixtures of sterol oxidation products may be formed. Here, a new method for the separation and detection of such products is described. The method is based on normal-phase liquid chromatography (NPLC) for separation and atmospheric-pressure photoionization mass spectrometry (APPI-MS) for detection. The method was optimized using commercial cholesterol oxidation products and tested on an experimentally derived mixture of phytosterol oxidation products. The investigated parameters include solvent and dopant selection, dopant concentration, polar modifiers, the type of stationary phase, and flow rate. Best chromatographic separation and highest sensitivity were achieved using a diol-bonded silica column, employing a solvent system consisting of hexane and isopropanol. The dopant of choice was chlorobenzene, added post-column to the solvent stream at 10% of the flow rate. The developed NPLC-APPI-MS method proved to be a valuable tool for the separation and detection of sterol oxidation products. PMID- 26774122 TI - Development and characterization of the alpha3beta4alpha5 nicotinic receptor cellular membrane affinity chromatography column and its application for on line screening of plant extracts. AB - The alpha3beta4alpha5 nAChR has been recently shown to be a useful target for smoking cessation pharmacotherapies. Herein, we report on the development and characterization of the alpha3beta4alpha5 nicotinic receptor column by frontal displacement chromatography. The binding affinity of the nicotine and minor alkaloids found in tobacco smoke condensates were determined for both the alpha3beta4 and alpha3beta4alpha5 nicotinic receptors. It was demonstrated that while no subtype selectivity was observed for nicotine and nornicotine, anabasine was selective for the alpha3beta4alpha5 nicotinic receptor. The non-competitive inhibitor binding site was also studied and it was demonstrated while mecamylamine was not selective between subtypes, buproprion showed subtype selectivity for the alpha3beta4 nicotinic receptor. The application of this methodology to complex mixtures was then carried out by screening aqueous alcoholic solutions of targeted plant extracts, including Lycopodium clavatum L. (Lycopodiaceae) and Trigonella foenum graecum L. (Fabaceae) against both the alpha3beta4 and alpha3beta4alpha5 nAChRs. PMID- 26774124 TI - Repeal of the Michigan helmet law: the evolving clinical impact. AB - BACKGROUND: Michigan repealed a 35-year mandatory helmet law in April 2012. We examined the impact of this legislation on a level 1 trauma center. METHODS: A retrospective cohort study comparing the 7-month period before and the 3 motorcycle seasons after the helmet law repeal. RESULTS: A total of 345 patients were included in the study. Nonhelmeted riders increased from 7% to 28% after the repeal. Nonhelmeted crash scene fatalities were higher after the repeal (14% vs 68%). The nonhelmeted cohort had significantly higher in-patient mortality (10% vs 3%), injury severity score (19 vs 14.5) and abbreviated injury scale head (2.2 vs 1.3). Non-helmeted riders also had increased alcohol use, intensive care unit length of stay and need for mechanical ventilation. The median hospital cost for the non-helmeted cohort was higher (P < .05). CONCLUSIONS: The impact of the Michigan helmet law repeal continues to evolve. Three years after this legislative change, we are now observing increased injury severity score, higher in-patient mortality, and worse neurologic injury. PMID- 26774125 TI - Response to "Moral considerations in non-EXIT airway management". PMID- 26774123 TI - Predictive factors for colonic resection in patients less than 49 years with symptomatic diverticular disease. AB - BACKGROUND: Diverticular disease is a condition strongly associated with low fiber intake and obesity. There have been reports of an increasing incidence in younger individuals ranging from 12% to 21% of all cases. The aim of this study was to evaluate the management of complicated diverticular disease in patients less than 49 years and attempt to identify factors predictive of a more virulent course. METHODS: An analysis of a prospectively updated database of all patients admitted with a primary diagnosis of acute diverticulitis from 2005 to 2013 was performed. Data collected included age, length of stay, inflammatory markers on admission, use of computed tomography (CT), and Hinchey Classification. SPSS version 22 was used for statistical analysis, and a P value of .05 or less was considered significant. RESULTS: A total of 120 (54 female and 66 male) patients less than 49 (28 to 49, 42.1) years were noted to have a diagnosis of acute diverticulitis. Twelve patients (10%) required colonic resection for complicated diverticulitis. Histological evaluation revealed 5 cases of stricture, 2 obstruction, and 5 perforations. On multivariate analysis, predictors of operative intervention and/or colonic resection included, (hazard ratio [95% confidence interval]) patients aged 40 to 49 years (.92 [.9 to .95]) and elevated C-reactive protein on index admission (1.4 [1.32 to 1.54]). Females were less likely to undergo colonic resection compared with males (1.18 [1.15 to 1.2]). Median length of stay was 4 days (1 to 48) for patients managed nonoperatively and 13 days (5 to 27) for those who underwent surgery. CONCLUSIONS: Most younger patients with acute diverticulitis can be treated successfully by conservative means. However, a proportion of patients require aggressive surgical management. PMID- 26774126 TI - The comparison of caffeic acid and caffeic acid phenethyl ester against cisplatin induced hair cell damage. PMID- 26774127 TI - Comparison of CT and chemical-shift MRI for differentiating thymoma from non thymomatous conditions in myasthenia gravis: value of qualitative and quantitative assessment. AB - AIM: To evaluate the usefulness of computed tomography (CT) and chemical-shift magnetic resonance imaging (MRI) in patients with myasthenia gravis (MG) for differentiating thymoma (THY) from thymic lymphoid hyperplasia (TLH) and normal thymus (NT), and to determine which technique is more accurate. MATERIALS AND METHODS: Eighty-three patients with generalised MG who underwent surgery were divided into the TLH/NT group (A; 65 patients) and THY group (B; 24 patients). Differences in qualitative characteristics and quantitative data (CT: radiodensity in Hounsfield units; MRI: signal intensity index [SII]) between groups were tested using Fisher's exact test and Student's t-test. Logistic regression models were estimated for both qualitative and quantitative analyses. At quantitative analysis, discrimination abilities were determined according to the area under the receiver operating characteristic (ROC) curve (AUROC) with computation of optimal cut-off points. The diagnostic accuracies of CT and MRI were compared using McNemar's test. RESULTS: At qualitative assessment, MRI had higher accuracy than CT (96.4%, 80/83 and 86.7%, 72/83, respectively). At quantitative analysis, both the radiodensity and SII were significantly different between groups (p<0.0001). For CT, at quantitative assessment, the AUROC of the radiodensity in discriminating between groups was 0.904 (optimal cut-off point, 20 HU) with an accuracy of 77.1% (64/83). For MRI, the AUROC of the SII was 0.989 (optimal cut-off point, 7.766%) with an accuracy of 96.4% (80/83), which was significantly higher than CT (p<0.0001). By using optimal cut-off points for cases with an erroneous diagnosis at qualitative assessment, accuracy improved both for CT (89.2%, 74/83) and MRI (97.6%, 81/83). CONCLUSION: Quantitative analysis is useful in evaluating patients with MG and improves the diagnostic accuracy of CT and MRI based on qualitative assessment. Chemical-shift MRI is more reliable than CT in differentiating THYs from non-thymomatous conditions. PMID- 26774128 TI - Hybrid Structural Analysis of the Arp2/3 Regulator Arpin Identifies Its Acidic Tail as a Primary Binding Epitope. AB - Arpin is a newly discovered regulator of actin polymerization at the cell leading edge, which steers cell migration by exerting a negative control on the Arp2/3 complex. Arpin proteins have an acidic tail homologous to the acidic motif of the VCA domain of nucleation-promoting factors (NPFs). This tail is predicted to compete with the VCA of NPFs for binding to the Arp2/3 complex, thereby mitigating activation and/or tethering of the complex to sites of actin branching. Here, we investigated the structure of full-length Arpin using synchrotron small-angle X-ray scattering, and of its acidic tail in complex with an ankyrin repeats domain using X-ray crystallography. The data were combined in a hybrid model in which the acidic tail extends from the globular core as a linear peptide and forms a primary epitope that is readily accessible in unbound Arpin and suffices to tether Arpin to interacting proteins with high affinity. PMID- 26774129 TI - A Naturally Occurring Peptide with an Elementary Single Disulfide-Directed beta Hairpin Fold. AB - Certain peptide folds, owing to a combination of intrinsic stability and resilience to amino acid substitutions, are particularly effective for the display of diverse functional groups. Such "privileged scaffolds" are valuable as starting points for the engineering of new bioactive molecules. We have identified a precursor peptide expressed in the venom gland of the marine snail Conus victoriae, which appears to belong to a hitherto undescribed class of molluscan neuropeptides. Mass spectrometry matching with the venom confirmed the complete mature peptide sequence as a 31-residue peptide with a single disulfide bond. Solution structure determination revealed a unique peptide fold that we have designated the single disulfide-directed beta hairpin (SDH). The SDH fold is highly resistant to thermal denaturation and forms the core of several other multiple disulfide-containing peptide folds, including the inhibitor cystine knot. This elementary fold may offer a valuable starting point for the design and engineering of new bioactive peptides. PMID- 26774130 TI - Fire enhances solubility of biogenic silica. AB - Changing fire regimes in response to climate change are likely to have significant effects on terrestrial ecosystems and biogeochemical cycles. While effects of fire on some nutrient cycles have been quite well-studied, little attention has been paid to the silicon cycle. We used an alkaline continuous extraction to examine changes in the quantity and characteristics of alkaline extractable Si (AlkExSi) after applying two burning treatments (no heating, 350 degrees C and 550 degrees C) to three types of organic soil material (from spruce forest, beech forest and a commercial peat). The total AlkExSi measured was 25.1+/-2.1mgg-1 and 15.4+/-0.9mgg-1 for spruce and beech respectively, and 1.2+/ 0.5mgg-1 for peat. The alkaline extraction parameters confirm a purely biogenic AlkExSi source in untreated spruce and beech organic soil material samples. Organic soil material of beech forest had two biogenic silica pools, differing in reactivity during alkaline extraction. Burning severely alters the alkaline dissolution parameters suggesting a significant crystallization of biogenic Si (BSi) with increased burning severity. Additionally, dissolution experiments carried out in rain water showed that fire increased the solubility of BSi by a factor of 40 and 20 in the case of the spruce and beech organic soil material respectively. The extent of enhanced Si solubility appears to be a trade-off function between organic matter losses and degree of crystallization. The burned soils could provide a strong and immediate Si source for the environment. In situ ecosystem characteristics that affect the uptake-leaching balance will determine the fate of the dissolved Si. Ecosystems low in BSi, like Sphagnum peatland, will not show drastic alteration in the Si cycle due to fire. PMID- 26774131 TI - Effects of grain size and structural heterogeneity on the transport and retention of nano-TiO2 in saturated porous media. AB - Accurately predicting the fate and transport of nano-TiO2 in porous media is critical to assess its environmental impact. This study was designed to understand the effects of gain size and structural heterogeneity under different ionic strength (IS) on the fate and transport of nano-TiO2 in saturated porous media. In the columns packed homogenously with sand of different grain sizes (920, 550, 390, and 275MUm), the transport of nano-TiO2 decreased when the IS increased from 0.1 to 1 or 10mM. For all the three IS conditions, the retention of the nano-TiO2 particles in the columns increased when the gain size decreased, and the mobility of the nano-TiO2 was the lowest in the sand at size of 275MUm with recovery rates of 0.30% to 1.72%. The mass recovery rates of TiO2 in other homogeneous columns were higher and ranged from 0.37% to 59.9%. Structural heterogeneity created two flow domains for the retention and transport of nano TiO2 particles in the saturated porous media. The fast-flow domain dominated the flow and transport processes of the nano-TiO2 in the heterogeneous columns under the tested conditions. As a result, the transport of nano-TiO2 in the heterogeneous porous media was faster and higher than that in the homogeneous columns under similar experimental conditions. Because of the dominance of the fast-flow domain, the recovery rates of the nano-TiO2 in the heterogeneous columns were similar and ranged from 59.8% to 66.9%. These results reflected the importance of preferential flow to the fate and transport of nano-TiO2 particle in porous media. Simulations from a two-domain model matched the experimental breakthrough curves very well. PMID- 26774132 TI - Twenty years of research on water management issues in the Danube Macro-region - past developments and future directions. AB - The Danube River-Danube Delta-Black Sea (DBS) region has witnessed major political, social and economic changes during the past three decades, which have profoundly affected the riverine, coastal and marine systems, their water management situation and the development of related research programmes. We reviewed the research activities in the DBS system of the past twenty years to determine the main funding bodies and to assess key research areas and how they varied over time and geographic region. As data basis we used a metadatabase filled with 478 projects addressing environmental and water management issues in the Danube River Basin, covering also the Danube Delta and the north-western Black Sea. As overall outcome extensive research efforts in the field of water management could be proven for the past two decades, despite the tumultuous times of political and economic transformations. One of the main findings was that EU funded projects played a key role for the development of transboundary research collaboration and were also the scientifically most productive one's. Historically, nutrient pollution was the main problem addressed, shifting to pollution in a broader sense and hydromorphological alterations in recent years. The newly arising challenges of climate change impacts and sediment management became important research questions in the last years, too. Most research was performed in the thematic field of navigation, followed by restoration and biodiversity issues. To meet all of the already identified and newly emerging challenges in the DBS System, cross-border and integrated (river-delta-sea) research activities are of major importance and have to be further promoted. We thus suggest drawing up a regional DBS Research Agenda linked to key challenges in water management to strengthen research collaboration and advance targeted scientific projects, an approach fostering also the scientific capacity in the region. PMID- 26774133 TI - Estimating the leakage contribution of phosphate dosed drinking water to environmental phosphorus pollution at the national-scale. AB - Understanding sources of phosphorus (P) to the environment is critical for the management of freshwater and marine ecosystems. Phosphate is added at water treatment works for a variety of reasons: to reduce pipe corrosion, to lower dissolved lead and copper concentrations at customer's taps and to reduce the formation of iron and manganese precipitates which can lead to deterioration in the aesthetic quality of water. However, the spatial distribution of leakage into the environment of phosphate added to mains water for plumbosolvency control has not been quantified to date. Using water company leakage rates, leak susceptibility and road network mapping, we quantify the total flux of P from leaking water mains in England and Wales at a 1km grid scale. This is validated against reported leaks for the UKs largest water utility. For 2014, we estimate the total flux of P from leaking mains to the environment to be c. 1.2ktP/year. Spatially, P flux is concentrated in urban areas where pipe density is highest, with major cities acting as a significant source of P (e.g. London into the Thames, with potentially 30% of total flux). The model suggests the majority (69%) of the P flux is likely to be to surface water. This is due to leakage susceptibility being a function of soil corrosivity and shrink-swell behaviour which are both controlled by presence of low-permeability clays. The location of major cities such as London close to the coast results in a potentially significant flux of P from mains leakage to estuarine environments. The contribution of leakage of phosphate dosed mains water should be considered in future source apportionment and ecosystem management. The methodology presented is generic and can be applied in other countries where phosphate dosing is undertaken or used prior to dosing during investment planning. PMID- 26774134 TI - Imposex in Nassarius nitidus (Jeffreys, 1867) as a possible investigative tool to monitor butyltin contamination according to the Water Framework Directive: A case study in the Venice Lagoon (Italy). AB - Butyltin (TBT, DBT, and MBT) effects on molluscs, especially endocrine disruption in bivalves and gastropods, have been widely investigated. Imposex, the superimposition of male characters onto female gonochoristic Caenogastropods, is the most studied biological effect of TBT. TBT compounds are among the priority hazardous substances within Directives 2000/60/EC (WFD) and 2008/105/EC. The Environmental Quality Standards (EQSs) set by the WFD for TBT are quite difficult to quantify by means of chemical analysis, without the use of expensive and high performance methods. Assuming that EQSs set for TBT were derived from evidence of imposex development at very low concentrations, this specific biomarker could be used as an indirect measure of assessing levels of bioavailable BTs. Therefore, this study aims to validate the use of imposex development as an investigative tool to monitor the bioavailable fraction of BTs within the WFD, by comparing imposex levels and BT concentrations in Nassarius nitidus from the Venice Lagoon. BT concentrations and imposex levels in N. nitidus, collected in 2013, had decreased when compared to previous studies in the same area. Both VDSI and RPLI correlated positively with BT body burden in females, confirming that imposex is a valid tool to monitor bioavailable BTs. However, TBT is still a matter of concern in the Venice Lagoon, as TBT concentrations were still higher than its degradation products suggesting recent fresh TBT inputs in the studied area. To propose imposex levels as an indicator of the impact of BTs within the WFD, classification class boundaries and Ecological Quality Ratios were introduced. As a preliminary attempt, imposex levels were also compared to the OSPAR Commission EcoQOs which linked imposex levels in Nassarius reticulatus with TBT concentrations in water. Based on this comparison the degree of imposex development in the Venice Lagoon suggested that TBT concentrations in water should be over the EQS-AA concentration and, at one site, also over the EQS-MAC. From all the results obtained in this work, it appears that imposex evaluation in N. reticulatus could give information about the ecological status regarding BT compounds under the WFD and also be used to monitor their effects and support chemical analyses until more sensitive methods become available. PMID- 26774135 TI - Systematic MRI in NF1 children under six years of age for the diagnosis of optic pathway gliomas. Study and outcome of a French cohort. AB - BACKGROUND/PURPOSE: Optic pathway glioma (OPG) is the most common central nervous system tumor in children with neurofibromatosis type 1 (NF1), affecting 15-20% of patients. We reviewed the medical records of children systematically screened by ophthalmologic and MRI examinations to determine the influence of screening on the therapeutic management of children with OPG. METHODS: Data were collected on 306 newly diagnosed cases screened with systematic MRI from January 2001 to July 2007. In the OPG group, we distinguished the asymptomatic or symptomatic groups according to their initial status. RESULTS: Forty-five patients had confirmed OPG (14.7%). Thirty-six patients (80%) were asymptomatic and nine (20%) were symptomatic at the time of diagnosis with visual symptoms in six cases. The average age at OPG diagnosis was 3.4 years with six patients (13%) over six years old. Average follow-up was 7.7 years. Progression was observed in 16 cases (35%). Most patient conditions were managed conservatively (87%). Six children (13%) were treated with chemotherapy due to worsening visual function. All of these children had severe or mild visual impairment at the end of follow-up. CONCLUSION: Our study does not support a clear benefit of systematic MRI screening in NF1 children under six years old. Systematic neuroimaging in our study did not influence therapeutic management. Although OPG diagnosis was made early, treatment with chemotherapy did not improve the final visual outcome. If MRI remains the best tool for the diagnosis of cerebral and spinal pathologies in the NF1 population, our current study questions the usefulness of systematic MRI screening for OPG diagnosis. Conversely, this study suggests that the indication of neuroimaging should be dictated by the results of annual clinical and ophthalmological assessments. PMID- 26774136 TI - WITHDRAWN: Patients with lung cancer: Are electronic cigarettes harmful, useful? AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 26774137 TI - Endosialin: molecular and functional links to tumor angiogenesis. AB - Endosialin, alternatively named tumor endothelial marker 1 (TEM1) or CD248, is a bulk transmembrane glycoprotein expressed both in developing and adult tissues undergoing active physiological or pathological angiogenesis. Endosialin is often overexpressed in tumors, particularly in stromal cells and in vessels-covering pericytes, and its transcription is induced by hypoxia via HIF-2 transcription factor. Based on the expression pattern, molecular characteristics and phenotypes of genetic models, endosialin has been proposed to function as a receptor implicated in sprouting angiogenesis, vasculogenesis and/or pruning of vessels. Here we provide an overview of the recent knowledge linking endosialin to diverse aspects of angiogenesis. Based on data-mining, our experimental data and available literature, we suggest that endosialin cross-talks with both pro- and anti-angiogenic signals and ECM components, and participates in dynamic vascular remodeling, which facilitates tumor growth. Tumor-selective targeting of endosialin may therefore contribute to improvement of existing anti-angiogenic therapies. PMID- 26774138 TI - Role of pericytes in angiogenesis: focus on cancer angiogenesis and anti angiogenic therapy. AB - Pericytes, a kind of mural cells for microcirculation, are critical for vascular development and function. Although current studies indicate that PDGF/PDGFR-beta, Ang/Tie2, TGF-beta involve in the regulation of pericytes recruitment, the mechanisms governing pericytes migration and regulating angiogenesis, especially in cancers, have not been fully clear. Many evidences have showed that cancer vessels are characterized by abnormal pericyte coverage and altered pericytes endothelial cells interactions, which contribute to the metastasis and progress of cancers. Therefore pericyte-targeting tend to be a promising anticancer therapy. Here we discuss the roles of pericytes in vasculatures and the effects of pericyte-targeting in anticancer treatment. PMID- 26774139 TI - Chidamide and 5-flurouracil show a synergistic antitumor effect on human colon cancer xenografts in nude mice. AB - Chidamide is a novel histone deacetylase (HDAC) inhibitor that increases the acetylation of histone H3 by inhibiting the activity of HDAC1 and HDAC2. We previously found that treatment of human colon cancer cells with chidamide led to cell apoptosis and cell cycle arrest at G0/1 phase in vitro. The present study extended the observations in vivo and explored the underlying molecular mechanisms. In nude mice bearing human colon cancer LoVo cell xenografts, chidamide alone or in combination with 5-flurouracil (5-Fu) reduced the expression of HDAC1 and HDAC2, accompanied with increased acetylation of histone H3. Chidamide alone inhibited the tumor growth and induce cell apoptosis in tumor bearing mice. Combined treatment of chidamide with 5-Fu enhanced the anti-tumor activity of 5-Fu. Western blotting analysis showed that chidamide alone or in combination with 5-Fu upregulated the expressions of cleaved Caspase-3 and cleaved poly-ADP (adenosine diphosphate)-ribose polymerase (PARP). In addition, chidamide alone or in combination with 5-Fu increased the p53, phosphorylated-p53 (p-p53), p21 and gammaH2AX levels, but suppressed cyclin dependent kinase 4 (CDK4) expression in tumor cells. Chidamide alone or in combination with 5-Fu down regulated the expressions of p-AKT, p-mammalian target of rapamycin (mTOR), p-p70S6K, p-Raf, and p44/42 mitogen activated protein kinase (Erk1/2), indicating the blockage of these signaling pathways. The results demonstrated that chidamide alone or in combination with 5-Fu exerted anti-tumor activity in nude mice bearing human colon cancer LoVo cell xenografts, and several signaling pathways might be involved in the chidamide-induced tumor growth inhibition and tumor cell apoptosis. PMID- 26774140 TI - Adenosine inhibits migration, invasion and induces apoptosis of human cervical cancer cells. AB - Extracellular adenosine is a key signaling molecule which mediates immune suppression, angiogenesis, and regulates cancer cells growth. The effect of adenosine on cervical cancer cells migration and invasion has not been well studied. In the current study, we used Hela and SiHa cell lines to evaluate the effects of adenosine on cervical cancer cells migration, invasion, and apoptosis. The results showed that adenosine treatment inhibited the migration and invasion activities of Hela and SiHa cells. Moreover, by determining the expression of molecules which were involved in epithelial to mesenchymal transition (EMT) progress, we found that epithelial marker E-cadherin was significantly increased in response to adenosine treatment, while the mesenchymal markers including N cadherin and fibronectin were decreased. These data suggested that adenosine inhibited cervical cancer cells via repressing the EMT progress. The flow cytometry analysis showed that adenosine could also induce cervical cancer cell apoptosis, which mechanism was further confirmed by investigating the expression levels of apoptosis related molecules, via activating mitochondrial apoptosis pathway. These data might suggest that adenosine could be used as an agent for the treatment of cervical cancer. PMID- 26774141 TI - Pan-cancer methylation and expression profiling of adenocarcinomas revealed epigenetic silencing in the WNT signaling pathway. AB - Adenocarcinomas are tumors of glandular characteristics. While tissues of common origins have been known to undergo similar epigenetic changes, it is unclear whether adenocarcinomas of different cancer types would exhibit similar DNA methylation and epigenetic regulation profiles. Herein, we studied global methylation and mRNA expression levels in 1214 lung, prostate, colon, and rectal cancer samples from The Cancer Genome Atlas (TCGA). We identified 602 candidate epigenetically silenced genes shared across these cancer types, and 835 associated CpG sites. The shared candidate genes are enriched in developmental processes. Specifically, 15 of these genes were found in the WNT signaling pathway (enrichment test p-value=1.53x10-6). Notably, the subset of silenced WNT pathway genes in each sample may be different, and both WNT activating or inhibiting genes could be suppressed. Clustering analysis showed that each tumor type contained a similar hyper-methylated subset of samples showing strong epigenetic silencing in the WNT pathway genes, and other fractions of samples expressing subset of the genes. Overall, our results showed that aberration in epigenetic regulation of the WNT signaling pathway is a common signature in adenocarcinomas. PMID- 26774142 TI - Discovery of signature genes in gastric cancer associated with prognosis. AB - Gene expression profiles of gastric cancer (GC) were analyzed with bioinformatics tools to identify signature genes associated with prognosis. Four gene expression data sets (accession number: GSE2685, GSE30727, GSE38932 and GSE26253) were downloaded from Gene Expression Omnibus. Differentially expressed genes (DEGs) were screened out using significance analysis of microarrays (SAM) algorithm. P value 1 were set as the threshold. A co-expression network was constructed for the GC-related genes with package WGCNA of R. Modules were disclosed with WGCNA algorithm. Survival-related signature genes were screened out via COX single variable regression.A total of 3210 GC-related genes were identified from the 3 data sets. Significantly enriched GO biological process terms included cell death, cell proliferation, apoptosis, response to hormone and phosphorylation. Pathways like viral carcinogenesis, metabolism, EBV viral infection, and PI3K-AKT signaling pathway were significantly over-represented in the DEGs. A gene co expression network including 2414 genes was constructed, from which 7 modules were revealed. A total of 17 genes were identified as signature genes, such as DAB2, ALDH2, CD58, CITED2, BNIP3L, SLC43A2, FAU and COL5A1.Many signature genes associated with prognosis of GC were identified in present study, some of which have been implicated in the pathogenesis of GC. These findings could not only improve the knowledge about GC, but also provide clues for clinical treatments. PMID- 26774143 TI - Anti-tumor role of Bacillus subtilis fmbJ-derived fengycin on human colon cancer HT29 cell line. AB - To explore the potential clinical anti-tumor roles of Bacillus subtilis fmbJ derived fengycin on cell growth and apoptosis in colon cancer HT29 cell line.Fengycin was extracted from Bacillus subtilis fmbJ and detected using HPLC. The effects of different concentration of fengycin on colon cell HT29 cell activity at different time points were analyzed using MTT assay. ROS level in colon HT29 cells affected by fengycin was detected using DCFH-DA method, followed by measuring the effects of fengycin on HT29 cell apoptosis and cell cycle by flow cytometry. The effects of fengycin on Bax/Bcl-2, CDK4/cyclin D1, Caspase-6 and Caspase-3 expressions in HT29 cells were analyzed using western blot. Also, mRNA levels of Bax/Bcl-2 and CDK4/cyclin D1 in HT29 cells affected by fengycin were analyzed using qRT-PCR.Compared with controlss, 20 MUg/mL of fengycin performed an inhibit role on HT29 cell growth of at 3 day (P<0.05), and high dose of fengycin showed more excellent effect on inhibiting HT29 cell growth with time increasing. Besides, fengycin could induce HT29 cell apoptosis and affect the cell cycle arrest at G1. ROS level in HT29 cells treated by fengycin was significantly increased compared with that in control group (P<0.05). Western blot analysis showed that after being treated with fengycin, Bax, Caspase-3, and Caspase-6 expressions were increased, however, Bcl-2, and CDK4/cyclin D1 expressions were decreased (P<0.05).Our study suggested that fengycin may play certain inhibit roles in the development and progression of colon cancer through involving in the cell apoptosis and cell cycle processes by targeting the Bax/Bcl 2 pathway. PMID- 26774144 TI - H19 serves as a diagnostic biomarker and up-regulation of H19 expression contributes to poor prognosis in patients with gastric cancer. AB - Emerging evidences indicate that dysregulated long noncoding RNAs (lncRNAs) are implicated in cancer tumorigenesis and progression and might be used as diagnosis and prognosis biomarker, or potential therapeutic targets. LncRNA H19 has been reported to be upregulated in diverse human cancers; however, its clinical significance in gastric cancer (GC) remains elusive. Expression levels of H19 in 128 pairs of GC and adjacent normal tissues, GC cell lines and GC juices compared to their corresponding controls were detected by real-time quantitative polymerase chain reaction (qPCR) assay. A receiver operating characteristic (ROC) curve and Kaplan-Meier analysis were constructed to evaluate the diagnostic and prognostic values. Univariate and multivariate analysis were performed using the Cox proportional hazard analysis. H19 expression was remarkably increased in GC tissues and cell lines compared with that in the normal control, and its up regulation was significantly correlated to invasion depth (P < 0.001), advanced TNM stage (P = 0.002) and regional lymph nodes metastasis (P < 0.001) in GC. H19 levels were robust in differentiating GC tissues from controls [area under the curve (AUC) = 0.697; 95% confidence interval (CI) = 0.636-0.752, p<0.01]. Kaplan Meier analysis demonstrated that increased H19 expression contributed to poor overall survival (P = 0.017) and disease-free survival (P = 0.024) of patients. A multivariate survival analysis also indicated that H19 could be an independent prognostic marker. The levels of H19 in gastric juice from gastric patients were significantly higher than those from normal subjects (P = 0.034). Furthermore, knockdown of H19 expression by siRNA could inhibit cell migration and invasion in GC cells partly via regulating E-cadherin protein expression. H19 might serve as a promising biomarker for early detection and prognosis prediction of GC. PMID- 26774145 TI - Claudin-1, -3, -4 and -7 gene expression analyses in canine prostate carcinoma and mammary tissue derived cell lines. AB - Claudins (CLDNs) are transmembrane proteins localised in the cell membrane of epithelial cells composing a structural and functional component of the tight junction protein complexes. In canine tumors deregulations of the CLDN expression patterns were described immunohistochemically. Targeting of claudin proteins has further been evaluated to establish novel therapeutic approaches by directed claudin binding. Precondition for the development of claudin targeting approaches in canine cells is the possibility to characterise claudin expression specifically and the availability of claudin positive cell lines. Herein PCR/qPCR assays were established allowing a rapid qualitative and quantitative characterisation of CLDN-1, -3, -4 and -7 gene expression in canine cell lines and tissues. Further commercially available antibodies were used to verify CLDN gene expression on protein level by Western blots. The developed assays were used to analyse six canine cell lines derived from mammary and prostate tissue for their CLDN-1, -3, -4 and -7 expressions. The canine cell line DT08/40 (prostate transitional cell carcinoma) was used for the establishment of specific CLDNs -1, -3, -4 and -7PCR/qPCR. The designed assays were verified by amplicon cloning and sequencing. Gene expressions were verified on protein level by Western blot. Additionally further cell lines were analysed for their CLDN-1, -3, -4 and -7 expression on mRNA and protein level (mammary derived cell lines: MTH53A (non neoplastic), ZMTH3 (adenoma), MTH52C (carcinoma); prostate derived cell lines: DT08/46 and CT1258 (both adenocarcinoma).The screened cell lines showed expression for the CLDNs as follows: DT08/46 and DT08/40: CLDN-1, -3, -4 and -7 positive; CT1258: CLDN-1, -3, -4 and -7 negative; ZMTH3 and MTH52C: CLDN-1 and -7 positive, CLDN-3 and -4 negative; MTH53A: CLDN-1, -3 and -4 negative, CLDN-7 positive. Western blot analyses reflect the detected CLDN-1, -3, -4 and -7 expressions in the analysed cell lines. The established CLDN-1, -3, -4 and -7 PCR/qPCR assays allow a qualitative and quantitative characterisation of canine CLDN gene expression. Characterisation of CLDN expression in six canine cell lines led to the identification of two canine prostate tissue derived CLDN expressing cell lines. These cell lines serve as candidates for further research on CLDN-based functional and therapeutic approaches. PMID- 26774146 TI - The value of SHOX2 methylation test in peripheral blood samples used for the differential diagnosis of lung cancer and other lung disorders. AB - Methylation of the cytosine residues within the CpG dinucleotides plays an important role in the fundamental cellular processes, human diseases and even cancer. The DNA methylation represents a very stable sign and therefore may be used as a valuable marker for cancer screening. Epigenetic cancer biomarkers are independent of classical morphology and thus show extensive potential to overcome the limitations of cytology. Several epigenetic cancer markers have been reported to be detectable in body fluids such as bronchial aspirate, sputum, plasma and serum.Short stature homeobox gene 2 (SHOX2) encodes a homeo-domain transcription factor, which has been identified as a close homologue of the SHOX gene and both genes are involved in skeletogenesis and heart development. Methylation of SHOX2 gene has been shown to be present at high prevalence in carcinomas of lung, however may also be used to identify other tumour entities.In the presented study, we have compared suitability of two types of material associated with lung cancer for the detection of SHOX2 methylation. We have confirmed that methylation of SHOX2 gene represents reliable marker of lung malignancies. The parallel tests in the blood plasma revealed that it may represent a good alternative material for testing of the SHOX2 methylation, making the test available to patients who are unable to undergo bronchoscopy. PMID- 26774147 TI - Expression of lipid metabolism-related proteins in breast phyllodes tumors. AB - The aim of this study was to investigate the expression of lipid metabolism related proteins and the implications thereof in phyllodes tumor (PT) of the breast. A tissue microarray (TMA) was constructed using paraffin blocks from 194 PT patient tissue samples. Immunohistochemical staining for lipid metabolism related proteins, namely hormone-sensitive lipase (HSL), perilipin 2, fatty-acid binding proteins 4 (FABP4), carnitine palmitoyltransferase-1 (CPT-1), acyl-CoA oxidase 1 (ACOX-1), and fatty acid synthase (FASN) was performed, and the immunohistochemical staining results were analyzed with respect to clinicopathologic parameters. The numbers of benign, borderline, and malignant PTs were 151, 27, and 16, respectively. The expression of HSL, perilipin 2, FABP4, CPT-1, and FASN in stromal components was higher in higher grade tumors. On univariate analysis, shorter disease-free survival (DFS) was associated with stromal perilipin 2 positivity (p<0.001) and stromal CPT-1 positivity (p=0.004). Shorter overall survival (OS) was associated with stromal perilipin 2 positivity (p<0.001), stromal FABP4 positivity (p<0.001), stromal CPT-1 positivity (p=0.004), and stromal FASN positivity (p<0.001). Multivariate Cox analysis revealed that stromal perilipin 2 positivity (hazard ratio=31.693, 95% CI: 1.341 748.8, p=0.032) was an independent factor for shorter DFS. In conclusion, higher expressions of HSL, perilipin 2, FABP4, CPT-1 and FASN in the stromal component were observed in higher grade PT. PMID- 26774148 TI - Genetic risk factors of cisplatin induced ototoxicity in adult patients. AB - Ototoxicity is an important adverse effect of using Cisplatin (cis diamminedichloroplatinum) (CDDP) as a form of chemotherapy. The clinical picture of CDDP induced ototoxicity includes perceptive hearing impairment (reversible or permanent) and tinnitus. Ototoxicity manifests with considerable variability between patients. The objective of this prospective study was to investigate a possible genetic background to this variability. We assessed ototoxicity induced by therapeutic doses of CDDP in adult patients with germinative testicular tumors, or other tumors treated with an identical CDDP dosage scheme. Audiological examination before, during and after the treatment has shown deterioration in hearing; first in the high-frequencies and with increased CDDP cumulative doses, impairment in other frequencies as well. Occurrence of tinnitus was not dependent on the administered dose of CDDP, or the other risk factors examined in this study. The association of CDDP induced ototoxicity with genetic polymorphisms in candidate genes was examined. Our study has demonstrated an association of early onset of CDDP induced ototoxicity with the presence of two copies of GSTT1 gene (p=0,009) and with T allele of rs9332377 polymorphism in COMT gene (p=0,001). PMID- 26774149 TI - Treatment of locally advanced pancreatic cancer by percutaneous and intraoperative irreversible electroporation: general hospital cancer center experience. AB - The aim of this study was to evaluate the safety of irreversible electroporation (IRE) and the outcome of patients undergoing IRE of locally advanced pancreatic cancer (PC). Twenty-one patients with unresectable PC underwent open (n=19) or percutaneous (n=2) IRE of the tumor using the Nanoknife system with two electrodes that were repositioned several times to affect the whole mass. The size of the tumor was 39+/-10mm with a range from 21 to 65mm. Five patients underwent neoadjuvant chemotherapy and seven patients were treated with chemotherapy after IRE. Complications occurred in five patients, which resulted in prolongation of the average hospital stay from 10 to 34 days. There was no mortality in the first postoperative month. Median survival after IRE was 10.2 months compared to 9.3 months in a matched cohort (hazard ratio = .54, p = .053). The quality of life was declining slowly. 81% of time after IRE the Karnofsky performance status was >=70 and sharp decline occurred approximately 8 weeks before death.In conclusion, IRE is a safe palliative treatment option for a percentage of patients with locally advanced pancreatic carcinoma. The patients treated with open IRE lived a decent life until 8 weeks before their death. We believe that IRE of pancreatic carcinoma can be regarded as an option, if imaging or explorative laparotomy show that R0 resection in not possible. PMID- 26774150 TI - Overexpression of filamin-A protein is associated with aggressive phenotype and poor survival outcomes in NSCLC patients treated with platinum-based combination chemotherapy. AB - An actin-binding protein filamin A connects the actin filament network to cell membrane receptors, and acts as a scaffold for various signaling pathways related to cancer growth and progression. Recently, it has been reported that filamin A is required for efficient regulation of early stages of DNA repair process. Moreover, some in vitro studies showed that the overexpression of filamin A determines resistance to various cytotoxic drugs, including cisplatin. We aimed to analyse the expression of filamin A protein in resected NSCLC (Non Small Cell Lung Cancer) specimens, to investigate the association of the level of filamin A protein expression and other clinicopathological features, and possible relationship between the expression of filamin A and survival outcome in NSCLC patients, treated with platinum-based combination chemotherapy. We performed filamin A protein immunohistochemistry on formalin-fixed and paraffin-embedded (FFPE) tissue sections from 135 NSCLC patients, using EP2405Y antibody against C terminus of filamin A. Cytoplasmic, membranous and nuclear positivity of filamin A was evaluated semi-quantitatively and correlated with available clinicopathological data. Patients were divided into two groups for survival analysis (I group - patients treated with adjuvant platinum-based chemotherapy, II group - patients with surgical treatment only). We found significant positive correlation between filamin A protein expression and NSCLC stage (r=0.249; p<0,05), presence of lymph node (N)(r=0.205; p<0,05) and distant metastases (M) (r=0.332; P<0.01). Increased filamin A protein expression was significantly related with poor survival outcomes in patients with adjuvant platinum-based chemotherapy: OS (HR=1.005, 95%CI[1.000;1.010], p=0.037), DFS (HR=1.004, 95%CI [1.001:1.008], p=0,017). Multivariate Cox proportional hazards regression analysis also showed that overexpression of filamin A represents an independent risk factor for disease relapse, in addition to tumor size, stage, and metastases status (HR=1.723, 95%CI [1.021:2.909], p<0.05). Thus, filamin A expression might be a new prognostic marker in patients with NSCLC. PMID- 26774151 TI - Prognostic significance of thymidylate synthase (TS) expression in cutaneous malignant melanoma. AB - Thymidylate synthase (TS) plays an essential role in the pathogenesis and development of cancer, and TS-targeting agents have been widely used against different types of cancers. However, it remains still unclear whether or not TS is expressed in malignant melanoma. We conducted the clinicopathological study to investigate the prognostic significance of TS expression in cutaneous malignant melanoma. Ninety-nine patients with surgically resected cutaneous malignant melanoma were assessed. Tumor sections were stained by immunohistochemistry for TS, Ki-67, and microvessel density (MVD) determined by CD34. TS was positively expressed in 26% (26 out of 99). The expression of TS was significantly associated with T factor, cell proliferation (Ki-67) and MVD (CD34). By Spearman's rank test, TS expression was significantly correlated with Ki67 and CD34. By univariate analysis, ulceration, disease stage, TS, Ki-67 and CD34 had a significant relationship with survival. Multivariate analysis confirmed that TS was an independent prognostic factor for poor prognosis of cutaneous malignant melanoma. The positive expression of TS could be a useful marker for predicting poor prognosis in patients with cutaneous malignant melanoma, and TS-targeting agents may be worth trying for the treatment of this dismal disease. PMID- 26774152 TI - Clinical efficacy of type-B ultrasound-guided intraperitoneal hyperthermic chemoperfusion combined with systemic chemotherapy in advanced gastric cancer patients with malignant ascites. AB - OBJECTIVES: To evaluate the clinical efficacy of systemic chemotherapy combined with intraperitoneal hyperthermic perfusion in advanced gastric cancer patients with malignant ascites. PATIENTS AND METHODS: Forty-eight gastric cancer patients with malignant ascites who were admitted to our hospital were selected and randomly divided into the hyperthermic perfusion and control groups. The control group only received systemic chemotherapy, and the hyperthermic perfusion group received systemic chemotherapy combined with intraperitoneal hyperthermic chemoperfusion. The therapeutic efficacy, the survival time and the associated toxicity were determined for the two groups. RESULTS: The efficacy was significantly higher in the hyperthermic perfusion group (85.7%) than in the control group (30.0%) (P 0.05). The median progression-free survival (PFS) was significantly longer in the hyperthermic perfusion group (12 months) compared with the control group (6 months) (P < 0.05). The median overall survival (OS) was significantly longer in the hyperthermic perfusion group (21 months) compared with the control group (9 months) (P < 0.05). There was a significantly higher 1 year survival rate in the hyperthermic perfusion group (89.3%) than in the control group (36.4%) (P < 0.05); however, there was no significant difference in the 3-year survival rate (10.7% vs. 10.0%). The Karnofsky Performance Status (KPS) score in the hyperthermic perfusion group increased significantly from 62.8 +/- 1.84 to 74.3 +/- 5.0 after hyperthermic chemoperfusion (P < 0.05). CONCLUSION: Systemic chemotherapy combined with intraperitoneal hyperthermic perfusion exhibited significant clinical efficacy in advanced gastric cancer patients with malignant ascites, helped control ascites, improved the quality of life and extended PFS and OS. This treatment regimen is worth promoting. PMID- 26774153 TI - CyberKnife stereotactic radiosurgery and stereotactic ablative radiation therapy of patients with prostate cancer bone metastases. AB - The aim of the study was to evaluate the effectiveness and toxicity of CyberKnife (CK) stereotactic radiosurgery (SRS) and stereotactic ablative radiation therapy (SABR) of patients with prostate cancer bone metastases. Analysis of prognostic and predictive factors was also performed. Material consisted of 51 patients with 71 bone oligometastases treated using CK SRS/SABR. In half of the patients single lesion was treated, in half 2-5 lesions. Median PSA concentration at the time of metastasis detection was 5.75 ng/ml. Total dose of 6-45Gy (median 20) was delivered with 1-5 fractions of 6-15 Gy (median 9). Biologic equivalent dose (BED) (alpha/beta=1.6) over 100 Gy was delivered to 45 lesions (63%) in 38 patients (75%). In statistical analysis Kaplan-Meier method, log-rank test and the Cox proportional hazard model were used. One-, two- and three-year overall survival (OS) was 90%, 76% and 70%, respectively. All patients having PSA concentration lower that 1 ng/ml at last control lived at least three years. One , two- and three- year local control (LC) was 97%, 70% and 30%. Patients with PSA below 20 ng/ml at the time of metastasis detection had better local control of lesions and lower PSA at the last control. Median of PSA concentration after CK based SRS/SABR remains stable during first 12 months of follow-up, dropped during the next months and at last control was comparable to initial level. Median PSA at last control in patients without disease progression was 1.67ng/ml and 20 patients had PSA below 1.0ng/ml. At the last control 59% of patients had no other metastases. Rapid pain decrease was observed in analysed group and during each control about 90% of patients had pain relief. No major toxicity was observed, 3 patients suffered from fracture of irradiated bone.SRS/SABR of prostate cancer bone oligometastases provides good LC of lesions, excellent pain control without additional toxicity. Patients with PSA concentration below 20ng/ml at the time of metastasis detection have better LC and PSA concentration response. PMID- 26774154 TI - Metabolic activity of breast cancer metastatic lesions on positron emission tomography/computed tomography: comparison with histological and biological characteristics of primary tumor. AB - Higher intensity of FDG uptake on PET/CT in primary tumor is seen in patients with IDC compared to ILC, also in high grade tumours, tumours with negative ER and higher Ki67 values, while data are inconsistent in case of relation between primary tumor's PgR and HER2 expression with its metabolic activity levels. On account of the lack of studies that include research of breast cancer metastatic lesion metabolism level and its relation to tumor histology and biology, our goal was to investigate the association of metastatic lesions' glucose metabolism level on PET/CT with different histological and biological characteristics of primary tumor. In a total number of N=100 patients, highest SUVmax values for each patient were used in testing difference between metastatic metabolic activity in patients with different tumor histology, grade, ER, PgR and HER2 status, subtype, as well in testing relation of Ki67 index to metastasis' metabolism level. In testing difference between histological types of breast cancer, SUVmax values were also compared separately for each specific anatomical site (regional and distant lymph nodes, bones and liver). No difference was found regarding metastatic SUVmax values in patients with primary IDC (n=55, median SUVmax 9.70) and ILC (n=34, median SUVmax 7.20) independently of anatomic site, and for each of analysed sites separately. No difference was found as well between SUVmax detected in metastasis in patients with different grade (grade II: n=58, median SUVmax 7.70; grade III: n=12, median SUVmax 10.20), ER (59 positive, median SUVmax 8.50; 22 negative, median SUVmax 8.05), PgR (55 positive, median SUVmax 8.50; 23 negative, median SUVmax 7.80), and HER2 (14 positive, median SUVmax 6.84; 51 negative, median SUVmax 8.63) expression in primary tumor, and between patients with different tumor subtype. Ki67 was also not associated with tumor metastatic SUVmax values (n=11, rs = -0.21, p=0.53). We conclude that there is no association of primary breast cancer histological type, grade, ER, PgR, HER2 and Ki67 expression with metabolic activity in metastasis detected on PET/CT. PMID- 26774155 TI - A two kinase-gene signature model using CDK2 and PAK4 expression predicts poor outcome in non-small cell lung cancers. AB - Risk classification on the basis of specific genomic features can lead to more precise tailoring of treatment for cancer patients. Kinases are potential therapeutic targets and survival factors, but the predictive prognostic potentials of multi-kinase genes have seldom been investigated. In this study, with publicly available microarray data of non-small cell lung cancers (NSCLC), we identified two kinase genes cyclin-dependent kinase 2 (CDK2) and p21 protein (Cdc42/Rac)-activated kinase 4 (PAK4) significantly associated with poor outcome. Then we present a combined gene signature model using CDK2 and PAK4 that can stratify disease poor outcome independently of standard clinical prognostic factors. Next, the predictive robustness of this 2-gene classifier was in silico confirmed in an independent microarray dataset, and experimentally validated in a lung cancer cohort by immunohistochemistry. Therefore, in this study, we demonstrated that the CDK2-PAK4 kinase signature may be a useful prognostic indicator and potential target for NSCLC. We also propose that poor outcome subgroup stratified by this classifier may benefit from the recently developed CDK2 and PAK4 inhibitors. PMID- 26774156 TI - Production of extended-spectrum beta-lactamases and the potential indirect pathogenic role of Prevotella isolates from the cystic fibrosis respiratory microbiota. AB - Extended-spectrum beta-lactamase (ESBL) production and the prevalence of the beta lactamase-encoding gene blaTEM were determined in Prevotella isolates (n=50) cultured from the respiratory tract of adults and young people with cystic fibrosis (CF). Time-kill studies were used to investigate the concept of passive antibiotic resistance and to ascertain whether a beta-lactamase-positive Prevotella isolate can protect a recognised CF pathogen from the action of ceftazidime in vitro. The results indicated that approximately three-quarters (38/50; 76%) of Prevotella isolates produced ESBLs. Isolates positive for ESBL production had higher minimum inhibitory concentrations (MICs) of beta-lactam antibiotics compared with isolates negative for production of ESBLs (P<0.001). The blaTEM gene was detected more frequently in CF Prevotella isolates from paediatric patients compared with isolates from adults (P=0.002), with sequence analysis demonstrating that 21/22 (95%) partial blaTEM genes detected were identical to blaTEM-116. Furthermore, a beta-lactamase-positive Prevotella isolate protected Pseudomonas aeruginosa from the antimicrobial effects of ceftazidime (P=0.03). Prevotella isolated from the CF respiratory microbiota produce ESBLs and may influence the pathogenesis of chronic lung infection via indirect methods, including shielding recognised pathogens from the action of ceftazidime. PMID- 26774158 TI - Evaluation of antibiotic resistance to orally administrable antibiotics in staphylococcal bone and joint infections in one of the largest university hospitals in Germany: is there a role for fusidic acid? AB - Bone and joint infections (BJIs) are often difficult to treat. Staphylococcus spp. is the major pathogen causing these infections, which is often associated with biofilm formation on prosthetic materials. Therapeutic measures are complex, ranging from surgical intervention to initial intravenous and supportive long term oral antibiotic therapy. The options for oral antimicrobial therapy are limited, mainly due to the resistance profile of the causative pathogen and the unfavourable pharmacodynamic and pharmacokinetic properties of most antibiotics in biofilm. Data analysis over a 5-year period was performed on staphylococci isolated from BJI patients in the Orthopaedic Department of the University Hospital Heidelberg (Heidelberg, Germany) to assess the plausibility of fusidic acid (FA)-based alternative oral treatment regimens. Six percent of BJIs were caused by meticillin-resistant Staphylococcus aureus (MRSA), and multiresistance was common. Over 75% of MRSA in BJIs were resistant to the commonly used rifampicin (RIF)-based combinations. Resistance to FA-based combinations was high. However, over 80% were susceptible to the combination RIF+FA. In coagulase negative staphylococci, resistance to RIF-based combinations was similar to FA based combinations. Almost two-thirds of the isolates tested were susceptible to RIF+FA. These data suggest FA as a possible option as a substitution for RIF or as a combination companion in case of resistance or unavailability. PMID- 26774157 TI - Implementation hurdles of an interactive, integrated, point-of-care computerised decision support system for hospital antibiotic prescription. AB - Antimicrobial stewardship is used to combat antimicrobial resistance. In Singapore, a tertiary hospital has integrated a computerised decision support system, called Antibiotic Resistance Utilisation and Surveillance-Control (ARUSC), into the electronic inpatient prescribing system. ARUSC is launched either by the physician to seek guidance for an infectious disease condition or via auto-trigger when restricted antibiotics are prescribed. This paper describes the implementation of ARUSC over three phases from 1 May 2011 to 30 April 2013, compared factors between ARUSC launches via auto-trigger and for guidance, examined factors associated with acceptance of ARUSC recommendations, and assessed user acceptability. During the study period, a monthly average of 9072 antibiotic prescriptions was made, of which 2370 (26.1%) involved ARUSC launches. Launches via auto-trigger comprised 48.1% of ARUSC launches. In phase 1, 23% of ARUSC launches were completed. This rose to 38% in phase 2, then 87% in phase 3, as escapes from the ARUSC programme were sequentially disabled. Amongst completed launches for guidance, 89% of ARUSC recommendations were accepted versus 40% amongst completed launches via auto-trigger. Amongst ARUSC launches for guidance, being from a medical department [adjusted odds ratio (aOR)=1.20, 95% confidence interval (CI) 1.04-1.37] and ARUSC launch during on-call (aOR=1.81, 95% CI 1.61 2.05) were independently associated with acceptance of ARUSC recommendations. Junior physicians found ARUSC useful. Senior physicians found ARUSC reliable but admitted to having preferences for antibiotics that may conflict with ARUSC. Hospital-wide implementation of ARUSC encountered hurdles from physicians. With modifications, the completion rate improved. PMID- 26774159 TI - Simultaneous Multi-plane Imaging of Neural Circuits. AB - Recording the activity of large populations of neurons is an important step toward understanding the emergent function of neural circuits. Here we present a simple holographic method to simultaneously perform two-photon calcium imaging of neuronal populations across multiple areas and layers of mouse cortex in vivo. We use prior knowledge of neuronal locations, activity sparsity, and a constrained nonnegative matrix factorization algorithm to extract signals from neurons imaged simultaneously and located in different focal planes or fields of view. Our laser multiplexing approach is simple and fast, and could be used as a general method to image the activity of neural circuits in three dimensions across multiple areas in the brain. PMID- 26774160 TI - Simultaneous Denoising, Deconvolution, and Demixing of Calcium Imaging Data. AB - We present a modular approach for analyzing calcium imaging recordings of large neuronal ensembles. Our goal is to simultaneously identify the locations of the neurons, demix spatially overlapping components, and denoise and deconvolve the spiking activity from the slow dynamics of the calcium indicator. Our approach relies on a constrained nonnegative matrix factorization that expresses the spatiotemporal fluorescence activity as the product of a spatial matrix that encodes the spatial footprint of each neuron in the optical field and a temporal matrix that characterizes the calcium concentration of each neuron over time. This framework is combined with a novel constrained deconvolution approach that extracts estimates of neural activity from fluorescence traces, to create a spatiotemporal processing algorithm that requires minimal parameter tuning. We demonstrate the general applicability of our method by applying it to in vitro and in vivo multi-neuronal imaging data, whole-brain light-sheet imaging data, and dendritic imaging data. PMID- 26774163 TI - May maternal lifestyle have an impact on neonatal glucose levels? AB - Neonatal glucose levels correlate negatively with umbilical cord levels of C peptide, a polypeptide secreted with insulin. In other words, neonatal hypoglycemia results from excessive insulin secretion from fetal/neonatal beta cells. Given that insulin causes fat to be stored rather than to be used for energy, one would expect that chronic hyperinsulinemia would result in large-for gestational-age neonates. The finding that many small-for-gestational-age neonates have hypoglycemia suggests that the stimulus for insulin production occurs close to delivery. We postulated that a potent stimulation of maternal insulin production close to delivery would also provide a potent stimulus for fetal and neonatal insulin production, causing neonatal hypoglycemia. This study has evaluated 155 mothers with markers of excessive insulin production (such as acanthosis or grade III obesity), or with situations characterized by increased insulin requirements (such as an invasive bacterial infection or use of systemic corticosteroid within a week before delivery; or sedentariness or high carbohydrate intake within 24h before delivery) and their 158 neonates who were screened for glycemic levels at 1, 2 and 4h after birth. The minimum glucose level was correlated to the maternal parameters, and to classical predictors of neonatal hypoglycemia, such as low-birth weight and preterm delivery. The only independent predictors were sedentariness and high-carbohydrate intake within 24h before delivery. The risk of neonatal hypoglycemia increased five-fold with sedentariness, 11-fold with high-carbohydrate intake, and 329-fold with both risk factors. The risk of neonatal hypoglycemia seems to be highly influenced by maternal lifestyle within 24h before delivery. Controlled randomized trials may help determine whether a controlled carbohydrate diet combined with regular physical activity close to delivery can prevent neonatal hypoglycemia and all its severe complications to the newborn. PMID- 26774164 TI - The year that was. PMID- 26774162 TI - Spatial Sequence Coding Differs during Slow and Fast Gamma Rhythms in the Hippocampus. AB - Spatiotemporal trajectories are coded by "theta sequences," ordered series of hippocampal place cell spikes that reflect the order of behavioral experiences. Theta sequences are thought to be organized by co-occurring gamma rhythms (~25 100 Hz). However, how sequences of locations are represented during distinct slow (~25-55 Hz) and fast (~60-100 Hz) gamma subtypes remains poorly understood. We found that slow gamma-associated theta sequences activated on a compressed timescale and represented relatively long paths extending ahead of the current location. Fast gamma-associated theta sequences more closely followed an animal's actual location in real time. When slow gamma occurred, sequences of locations were represented across successive slow gamma phases. Conversely, fast gamma phase coding of spatial sequences was not observed. These findings suggest that slow gamma promotes activation of temporally compressed representations of upcoming trajectories, whereas fast gamma supports coding of ongoing trajectories in real time. PMID- 26774161 TI - NMDA Receptors Enhance Spontaneous Activity and Promote Neuronal Survival in the Developing Cochlea. AB - Spontaneous bursts of activity in developing sensory pathways promote maturation of neurons, refinement of neuronal connections, and assembly of appropriate functional networks. In the developing auditory system, inner hair cells (IHCs) spontaneously fire Ca(2+) spikes, each of which is transformed into a mini-burst of action potentials in spiral ganglion neurons (SGNs). Here we show that NMDARs are expressed in SGN dendritic terminals and play a critical role during transmission of activity from IHCs to SGNs before hearing onset. NMDAR activation enhances glutamate-mediated Ca(2+) influx at dendritic terminals, promotes repetitive firing of individual SGNs in response to each synaptic event, and enhances coincident activity of neighboring SGNs that will eventually encode similar frequencies of sound. Loss of NMDAR signaling from SGNs reduced their survival both in vivo and in vitro, revealing that spontaneous activity in the prehearing cochlea promotes maturation of auditory circuitry through periodic activation of NMDARs in SGNs. PMID- 26774165 TI - Delirium after surgical and transcatheter aortic valve replacement is associated with increased mortality. AB - OBJECTIVE: The purpose of this study was to determine the incidence and clinical significance of postoperative delirium (PD) in patients with aortic stenosis undergoing surgical aortic valve replacement (SAVR) or transcatheter aortic valve replacement (TAVR). METHOD: Between 2010 and 2013, 427 patients underwent TAVR (n = 168) or SAVR (n = 259) and were screened for PD using the Confusion Assessment Method for the Intensive Care Unit. The incidence of PD in both treatment groups was determined and its association with morbidity and mortality was retrospectively compared. RESULTS: PD occurred in 135 patients (32%) with a similar incidence between SAVR (33% [86 out of 259]) and TAVR (29% [49 out of 168]) (P = .40). TAVR by transfemoral approach had the lowest incidence of PD compared with SAVR (18% vs 33%; P = .025) or TAVR when performed by alternative access techniques (18% vs 35%; P = .02). Delirium was associated with longer initial intensive care unit stay (70 vs 27 hours), intensive care unit readmission (10% [14 out of 135] vs 2% [6 out of 292]), and longer hospital stay (8 vs 6 days) (P < .001 for all). PD was associated with increased mortality at 30 days (7% vs 1%; P < .001) and 1 year (21% vs 8%; P < .001). After multivariable adjustment, PD remained associated with increased 1-year mortality (hazard ratio, 3.02; 95% confidence interval, 1.75-5.23; P < .001). There was no interaction between PD and aortic valve replacement approach with respect to 1 year mortality (P = .12). Among propensity-matched patients (n = 170), SAVR treated patients had a higher incidence of PD than TAVR-treated patients (51% vs 29%; P = .004). CONCLUSIONS: PD occurs commonly after SAVR and TAVR and is associated with increased morbidity and mortality. Given the high incidence of PD and its associated adverse outcomes, further studies are needed to minimize PD and potentially improve patient outcomes. PMID- 26774167 TI - The "minimalist approach" for transfemoral transcatheter aortic valve replacement: Should we land at an airport without a fire department? PMID- 26774166 TI - Proinflammatory gene expression in patients undergoing mitral valve surgery and maze ablation for atrial fibrillation. AB - OBJECTIVE: It is difficult to achieve rhythm control in patients with long standing persistent atrial fibrillation (AF). The radiofrequency maze procedure is an effective means in curing AF with a variable recurrence rate depending on patient characteristics and AF duration. In these patients, the characteristics of the atrial substrate have not been well investigated. Because the inflammatory process has been shown to be important in the pathogenesis of AF, we sought to characterize the proinflammatory gene expression in left atria obtained from patients with AF undergoing mitral valve surgery combined with the maze procedure to distinguish the changes associated with AF and its recurrence after the surgical ablation. METHODS: Left atrial appendages from 35 patients receiving mitral valve surgery were used for study. Ten patients had sinus rhythm (SR) and 25 patients had persistent AF for more than 1 year and underwent the maze procedure. Among the AF patients, 13 patients remained in SR (AF-SR) and 12 patients had recurrent AF during the 1-year clinical follow-up (AF-AF). The nCounter Human Inflammation Array (NanoString Technologies, Seattle, Wash) was used for evaluating proinflammatory gene expression. Quantitative polymerase chain reaction, Western blot, and immunohistochemistry were applied for studying messenger RNA and protein expression. RESULTS: Of 144 expressed proinflammatory genes, the inflammation array analysis revealed that 32 genes were differentially expressed between AF (including AF-SR and AF-AF) and SR. Thirteen genes were differentially expressed between AF-SR and AF-AF. The array and quantitative polymerase chain reaction produced parallel results in analyzing the expression of particular genes. Concordant with the gene expression difference between AF and SR patients, rapid pacing increased the expressions of SHC1, RHOA, PDGFA, and TRAF2 in HL-1 myocytes, implicating a causative effect of tachyarrhythmia on these genes. Compared with AF-SR, AF-AF expressed more intense oxidative stress, upregulations of collagen, transforming growth factor beta 1, and intranuclear nuclear factor of activated T-cells. Regression analysis showed that increased left atrial diameter was associated with the expression of RHOA and STAT1. CONCLUSIONS: Differential expression profiles of proflammatory genes were presented between SR and AF and between maintained SR and recurrent AF after the maze procedure. The identified inflammatory molecules associated with AF and failed surgical ablation may provide clues for developing new potential therapeutic targets to improve AF rhythm control. PMID- 26774169 TI - Multidisciplinary risk assessment and treatment: The evolution of triage. PMID- 26774168 TI - Long-term results after surgical treatment of paravalvular leak in the aortic and mitral position. AB - OBJECTIVES: The aim of this study was to determine immediate results and long term outcomes after surgical management of paravalvular leak (PVL). METHODS: Between 1995 and 2012, a total of 190 patients underwent primary surgical repair (n = 142) or valve replacement (n = 48) for a PVL at our institution. The PVL was mild in 6 (3%) patients, moderate in 85 (45%), moderate to severe in 84 (44%), and severe in 15 (8%). Among these, 120 (63%) had PVL in the mitral position, 63 (33%) had PVL in the aortic position, and 7 (4%) had PVL in both valves. Mean follow-up was 5.3 +/- 4.6 years. RESULTS: Mean age at surgery was 63 +/- 12 years (64% men). Operative mortality occurred in 13 (7%) patients (10 [8%] in mitral; 2 [3%] in aortic; and 1 [14%] in double valve procedures). Survival at 1, 5, and 10 years was 85% +/- 3%, 73% +/- 4%, and 56% +/- 5%, respectively. The cumulative incidence of PVL recurrence was 3% +/- 1%, 14% +/- 3%, and 32% +/- 6%, at 1, 5, and 10 years, respectively. The number of previous surgeries was a predictor of survival and PVL recurrence. Freedom from New York Heart Association class >=III was 96% +/- 2%, 82% +/- 4%, and 58% +/- 6%, at 1, 5, and 10 years, respectively. The freedom from rehospitalization for heart failure was 92% +/- 2%, 83% +/- 4%, and 67% +/- 6%, at 1, 5, and 10 years. CONCLUSIONS: Surgical treatment of PVL resulted in acceptable outcomes. Nevertheless, the continued risk of PVL recurrence is higher in patients who have had multiple previous surgeries. More studies are needed to compare these results with the transcatheter PVL reduction technique. PMID- 26774170 TI - Discussion. PMID- 26774172 TI - Impact of cardiopulmonary resuscitation duration on survival from paramedic witnessed out-of-hospital cardiac arrests: An observational study. AB - BACKGROUND: Resuscitation guidelines often recommend ongoing cardiopulmonary resuscitation (CPR) efforts to hospital for out-of-hospital cardiac arrests (OHCA) witnessed by emergency medical service (EMS) personnel. In this study, we examine the relationship between EMS CPR duration and survival to hospital discharge in EMS witnessed OHCA patients. METHODS: Between January 2003 and December 2011, 1035 adult EMS witnessed arrests of presumed cardiac aetiology were included from the Victorian Ambulance Cardiac Arrest Registry. CPR duration was defined as the total sum of prehospital CPR time in minutes. Adjusted logistic regression analyses were used to assess the impact of EMS CPR duration on survival to hospital discharge. RESULTS: 382 (37.3%) patients were discharged alive. The median CPR duration was 12 min (95% CI: 11-13) overall, but was higher in non-survivors compared to survivors (24 min vs. 2 min, p<0.001). The 99th percentile CPR duration in patients surviving to hospital discharge differed by the initial rhythm of arrest: 32 min (95% CI: 27-44) overall, 32 min (95% CI: 23 44) for ventricular fibrillation and pulseless ventricular tachycardia (VF/VT), 34 min (95% CI: 30-34) for pulseless electrical activity (PEA), and 28 min (95% CI: 21-28) for asystole. There were no survivors after 44 min for all rhythms. After adjusting for prehospital confounders, every minute increase in CPR duration was associated with a 13% reduction in the odds of survival to hospital discharge (OR 0.87, 95% CI: 0.84-0.89, p<0.001). The multivariable model predicted no chance of survival at or after a CPR duration of 48 min for VF/VT patients, 47 min for PEA patients and 45 min for asystole patients. CONCLUSION: Resuscitation efforts exceeding 32 min yielded less than 1% of survivors from EMS witnessed OHCA. On the basis of this data, EMS witnessed OHCA patients may benefit from ongoing CPR efforts up to 48 min in duration. PMID- 26774171 TI - Cyclophilin B enhances HIV-1 infection. AB - Cyclophilin B (CypB) is a member of the immunophilin family and intracellular chaperone. It predominantly localizes to the ER, but also contains a nuclear localization signal and is secreted from cells. CypB has been shown to interact with the Gag protein of human immunodeficiency type 1 (HIV-1). Several proteomic and genetic studies identified it as a potential factor involved in HIV replication. Herein, we show that over-expression of CypB enhances HIV infection by increasing nuclear import of viral DNA. This enhancement was unaffected by cyclosporine treatment and requires the N-terminus of the protein. The N-terminus contains an ER leader sequence, putative nuclear localization signal, and is required for secretion. Deletion of the N-terminus resulted in mislocalization from the ER and suppression of HIV infection. Passive transfer experiments showed that secreted CypB did not impact HIV infection. Combined, these experiments show that intracellular CypB modulates a pathway of HIV nuclear import. PMID- 26774173 TI - Termination of resuscitation in the prehospital setting: A comparison of decisions in clinical practice vs. recommendations of a termination rule. AB - BACKGROUND: Of the proposed algorithms that provide guidance for in-field termination of resuscitation (TOR) decisions, the guidelines for cardiopulmonary resuscitation (CPR) refer to the basic and advanced life support (ALS)-TOR rules. To assess the potential consequences of implementation of the ALS-TOR rule, we performed a case-by-case evaluation of our in-field termination decisions and assessed the corresponding recommendations of the ALS-TOR rule. METHODS: Cohort of non-traumatic out-of-hospital cardiac arrest (OHCA)-patients who were resuscitated by the ALS-practising emergency medical service (EMS) in the Nijmegen area (2008-2011). The ALS-TOR rule recommends termination in case all following criteria are met: unwitnessed arrest, no bystander CPR, no shock delivery, no return of spontaneous circulation (ROSC). RESULTS: Of the 598 cases reviewed, resuscitative efforts were terminated in the field in 46% and 15% survived to discharge. The ALS-TOR rule would have recommended in-field termination in only 6% of patients, due to high percentages of witnessed arrests (73%) and bystander CPR (54%). In current practice, absence of ROSC was the most important determinant of termination [aOR 35.6 (95% CI 18.3-69.3)]. Weaker associations were found for: unwitnessed and non-public arrests, non-shockable initial rhythms and longer EMS-response times. CONCLUSION: While designed to optimise hospital transportations, application of the ALS-TOR rule would almost double our hospital transportation rate to over 90% of OHCA-cases due to the favourable arrest circumstances in our region. Prior to implementation of the ALS TOR rule, local evaluation of the potential consequences for the efficiency of triage is to be recommended and initiatives to improve field-triage for ALS-based EMS-systems are eagerly awaited. PMID- 26774174 TI - Prognostication of cardiac arrest survivors using low apparent diffusion coefficient cluster volume. AB - INTRODUCTION: We developed a new neuroprognostication method for cardiac arrest (CA) using the relative volume of the most dominant cluster of low apparent diffusion coefficient (ADC) voxels and tested its performance in a multicenter setting. METHODS: Adult (>15 years) out-of-hospital CA patients from three different facilities who underwent an MRI 12h after resuscitation were retrospectively analyzed. Patients with unknown long-term prognosis or poor baseline neurologic function were excluded. Average ADCs (mean and median), LADCV (relative volume of low-ADC voxels) and DC-LADCV (relative volume of most dominant cluster of low-ADC voxels) were extracted using different thresholds between 400 and 800 * 10(-6) mm(2) s(-1) at 10 * 10(-6) mm(2) s(-1) intervals. Area under the receiver operating characteristic curve (AUROC) and sensitivity for poor outcome (6-month cerebral performance category score >2) while maintaining 100% specificity were measured. RESULTS: 110 patients were analyzed. Average ADCs showed fair performance with an AUROC of 0.822 (95% confidence interval [CI], 0.744-0.900) for the mean and 0.799 (95% CI, 0.716-0.882) for the median. LADCV showed better performance with a higher AUROC (maximum, 0.925) in an ADC threshold range of 400 to 690 * 10(-6) mm(2) s(-1). DC-LADCV showed the best performance with a higher AUROC (maximum, 0.955) compared with LADCV in an ADC threshold range of 600 to 680 * 10(-6) mm(2) s(-1). DC-LADCV had a high sensitivity for poor outcomes (>80%) in a wide threshold range from 400 to 580 * 10(-6) mm(2) s(-1) with a maximum of 89.2%. CONCLUSIONS: Quantitative analysis using DC-LADCV showed impressive performance in determining the prognosis of out of-hospital CA patients in a multicenter setting. PMID- 26774175 TI - Effect of therapeutic hypothermia on the outcomes after out-of-hospital cardiac arrest according to initial ECG rhythm and witnessed status: A nationwide observational interaction analysis. AB - BACKGROUND: The use of mild therapeutic hypothermia (TH) in out-of-hospital cardiac arrest (OHCA) with shockable rhythms is recommended and widely used. However, it is unclear whether TH is associated with better outcomes in non shockable rhythms. METHODS: This is a retrospective observational study using a national OHCA cohort database composed of emergency medical services (EMS) and hospital data. We included adult EMS-treated OHCA patients of presumed cardiac etiology who were admitted to the hospital during Jan. 2008 to Dec. 2013. Patients without hospital outcome data were excluded. The primary outcome was good neurological outcome at discharge; secondary outcome was survival to discharge. The primary exposure was TH. We compared outcomes between TH and non TH groups using multivariable logistic regression, adjusting for individual and Utstein factors. Interactions of initial ECG rhythm and witnessed status on the effect of TH on outcomes were tested. RESULTS: There were 11,256 patients in the final analysis. TH was performed in 1703 patients (15.1%). Neurological outcome was better in TH (23.5%) than non-TH (15.0%) (Adjusted OR=1.25, 95% CI 1.05 1.48). The effect of TH on the odds for good neurological outcome was highest in the witnessed PEA group (Adjusted OR=3.91, 95% CI 1.87-8.14). Survival to discharge was significantly higher in the TH group (55.1%) than non-TH (35.9%) (Adjusted OR=1.76, 95% CI 1.56-2.00). CONCLUSIONS: In a nationwide observational study, TH is associated with better neurological outcome and higher survival to discharge. The effect of TH is greatest in witnessed OHCA patients with PEA as the initial ECG rhythm. PMID- 26774176 TI - Plasma cell mastitis in women with rheumatoid arthritis treated with TNFalpha antagonists: Report of 2 cases. PMID- 26774177 TI - Sicca symptoms are associated with similar fatigue, anxiety, depression, and quality-of-life impairments in patients with and without primary Sjogren's syndrome. AB - OBJECTIVE: To compare quality of life (QoL), depression, anxiety, and fatigue in prospectively included patients with primary Sjogren's syndrome (pSS) or with sicca but no diagnosis of Sjogren's syndrome. METHODS: Patients undergoing a multidisciplinary evaluation at a single university center in Brest, France, for suspected pSS and having sicca symptoms were included prospectively between November 2006 and December 2013. The same standardized investigations were performed in all patients. pSS and sicca not due to pSS diagnoses were based on evaluating physician opinion. Each patient completed three validated questionnaires on QoL (SF-36), fatigue (MFI), depression and anxiety (HADS). RESULTS: Of the 95 included patients, 55 (57.9%) had pSS and 40 (42.1%) had sicca without pSS. Gender distribution, age, disease duration, and sicca symptoms were similar in the two groups. The pSS group had a significantly higher proportion of patients with abnormal objective tests for dryness (Schirmer's test and salivary flow rate). The SF-36, HADS, and MFI scores were similarly altered in the two groups. Anxiety was more common than depression in both groups. The most affected domains were vitality in the SF-36 and general/physical fatigue in the MFI. Extraglandular systemic involvement was not a major determinant of QoL alteration in patients with pSS. CONCLUSIONS: Sicca symptoms are associated with severe alterations in SF-36, HADS, and MFI scores regardless of objective test abnormalities and pSS diagnosis. Anxiety is more common than depression and should be taken into account when managing all patients with sicca symptoms. PMID- 26774178 TI - Hepatic Transmembrane 6 Superfamily Member 2 Regulates Cholesterol Metabolism in Mice. AB - BACKGROUND & AIMS: The rs58542926 C>T variant of the transmembrane 6 superfamily member 2 gene (TM6SF2), encoding an E167K amino acid substitution, has been correlated with reduced total cholesterol (TC) and cardiovascular disease. However, little is known about the role of TM6SF2 in metabolism. We investigated the long-term effects of altered TM6SF2 levels in cholesterol metabolism. METHODS: C57BL/6 mice (controls), mice that expressed TM6SF2 specifically in the liver, and mice with CRISPR/Cas9-mediated knockout of Tm6sf2 were fed chow or high-fat diets. Blood samples were collected from all mice and plasma levels of TC, low-density lipoprotein cholesterol (LDL-c), high-density lipoprotein cholesterol, and triglycerides were measured. Liver tissues were collected and analyzed by histology, real-time polymerase chain reaction, and immunoblot assays. Adenovirus vectors were used to express transgenes in cultured Hep3B hepatocytes. RESULTS: Liver-specific expression of TM6SF2 increased plasma levels of TC and LDL-c, compared with controls, and altered liver expression of genes that regulate cholesterol metabolism. Tm6sf2-knockout mice had decreased plasma levels of TC and LDL-c, compared with controls, and consistent changes in expression of genes that regulate cholesterol metabolism. Expression of TM6SF2 promoted cholesterol biosynthesis in hepatocytes. CONCLUSIONS: TM6SF2 regulates cholesterol metabolism in mice and might be a therapeutic target for cardiovascular disease. PMID- 26774179 TI - Addition of Simvastatin to Standard Therapy for the Prevention of Variceal Rebleeding Does Not Reduce Rebleeding but Increases Survival in Patients With Cirrhosis. AB - BACKGROUND & AIMS: The combination of beta-blockers and band ligation is the standard approach to prevent variceal rebleeding, but bleeding recurs and mortality is high. The lipid-lowering drug simvastatin decreases portal pressure, improves hepatocellular function, and might reduce liver fibrosis. We assessed whether adding simvastatin to standard therapy could reduce rebleeding and death after variceal bleeding in patients with cirrhosis. METHODS: We performed a multicenter, double-blind, parallel trial of 158 patients with cirrhosis receiving standard prophylaxis to prevent rebleeding (a beta-blocker and band ligation) in Spain from October 2010 through October 2013. Within 10 days of bleeding, subjects were randomly assigned, but stratified by Child-Pugh class of A or B vs C, to groups given simvastatin (20 mg/d the first 15 days, 40 mg/d thereafter; n = 69) or placebo (n = 78). Patients were followed for as long as 24 months. The primary end point was a composite of rebleeding and death, and main secondary end points were the individual components of the composite (death and rebleeding). RESULTS: The primary end point was met by 30 of 78 patients in the placebo group and 22 of 69 in the simvastatin group (P = .423). Seventeen patients in the placebo group died (22%) vs 6 patients in the simvastatin group (9%) (hazard ratio for adding simvastatin to therapy = 0.39; 95% confidence interval: 0.15-0.99; P = .030). Simvastatin did not increase survival of patients with Child-Pugh class C cirrhosis. Rebleeding occurred in 28% of patients in the placebo group and 25% in the simvastatin group (P = .583). Serious adverse events occurred in 53% of patients in the placebo group and 49% in the simvastatin group (P = .752); the percentages of serious adverse events related to therapy were 11% in the placebo group vs 8% in the in the simvastatin group (P = .599). Two patients in the simvastatin group, each with advanced liver disease, developed rhabdomyolysis. CONCLUSIONS: In a randomized controlled trial, addition of simvastatin to standard therapy did not reduce rebleeding, but was associated with a survival benefit for patients with Child-Pugh class A or B cirrhosis. Survival was not the primary end point of the study, so these results require validation. The incidence of rhabdomyolysis in patients receiving 40 mg/d simvastatin was higher than expected. European Clinical Trial Database ID: EUDRACT 2009-016500-24; ClinicalTrials.gov ID: NCT01095185. PMID- 26774182 TI - Metabolic capacities of common carp (Cyprinus carpio) following combined exposures to copper and environmental hypoxia. AB - In aquatic ecosystems, a decline in water O2 level is the main factor that can release heavy metal ions from top sediment layer. Therefore, hypoxia in turn, and in association with heavy metals might provide undesirable environment and impairs physiological functions of aquatic animals. To address this, metabolic capacities, including standard metabolic rate (SMR), maximum metabolic rate (MMR), aerobic scope (AS) and factorial aerobic scope (FAS) of common carp were determined following exposures to different levels of water-borne Cu(2+) as well as hypoxia. Treatments for Cu(2+) were included: 100% (acute), 50% (sub-lethal) and 10% (chronic) of LC50-96h for immediately, 24h and 7 days exposures respectively. Hypoxia treatments were assigned as acute for immediately, sub lethal for 24h and chronic for 7 days. Combined effects of treatments were also considered as acute Cu(2+)+hypoxia, sub-lethal Cu(2+)+hypoxia and chronic Cu(2+)+hypoxia. While SMR of carp was reduced by chronic hypoxia, significant (P<0.05) increase was observed during acute hypoxia, as compared with control. The MMR and AS were significantly reduced (P<0.05) following all hypoxia treatments. The acute and chronic Cu(2+) treatments showed significant (P<0.05) increases in SMR and MMR values. All acute and sub-lethal combined treatments showed significant (P<0.05) reductions in SMR, MMR and AS values, whilst chronic combined treatments showed generally increasing trends for MMR and AS. PCrit was relatively reduced following all treatments except for acute and sub-lethal Cu(2+)-treated fish that showed higher value (P<0.05) and no change respectively. Although all Cu(2+) treatments increased the number of mucus cell, hypoxia treatments did not show any remarkable differences when compared with control group. In general, the results of present study reveal that hypoxia acts as limiting stressor whilst Cu(2+) do act as loading stressors in the case of common carp metabolism. The interactive exposures mostly showing a synergist effect in all metabolic capacities with an exception for chronic treatments. PMID- 26774181 TI - The ontogeny of ethanol aversion. AB - Recent work has suggested separate developmental periods within the broader framework of adolescence, with data suggesting distinct alterations and vulnerabilities within these intervals. While previous research has suggested reduced sensitivity to the aversive effects of alcohol in adolescence relative to adults, a more detailed ontogeny of this effect has yet to be conducted. The adolescent brain undergoes significant transitions throughout adolescence, including in regions linked with drug reward and aversion. The current study aimed to determine the ontogeny of ethanol aversion by utilizing a conditioned taste aversion procedure at six different ages to test the hypothesis that the transitions into, through, and out of adolescence are associated with ontogenetic alterations in sensitivity to the aversive properties of ethanol. Non-deprived animals given Boost(r) as the conditioned stimulus (CS) were used in Experiment 1, whereas Experiment 2 used water-restricted animals provided with a saccharin/sucrose solution as the CS. In both experiments, an attenuated sensitivity to the aversive properties of ethanol was evident in adolescents compared to adults, although more age differences were apparent in water deprived animals than when a highly palatable CS was given to ad libitum animals. Overall, the data suggest an attenuated sensitivity to the aversive properties of ethanol that is most pronounced during pre- and early adolescence, declining thereafter to reach the enhanced aversive sensitivity of adults. PMID- 26774183 TI - Maintenance of a fully functional digestive system during hibernation in the European hamster, a food-storing hibernator. AB - Some small mammals limit energy expenditure during winter conditions through torpor bouts, which are characterized by a decrease in body temperature and metabolic rate. Individuals arise periodically from torpor to restore critical functions requiring euthermia. Although most of the species involved do not feed during hibernation and rely on body reserves to fulfil energy requirements (fat storing species), others hoard food in a burrow (food-storing species) and can feed during interbout euthermy. Whereas fat-storing species undergo a marked atrophy of the digestive tract, food-storing species have to maintain a functional digestive system during hibernation. Our study aimed to evaluate the absorption capacities of a food-storing species, the European hamster, throughout the annual cycle. In vivo intestinal perfusions were conducted in different groups of hamsters (n=5) during the different life periods, namely before hibernation, in torpor, during interbout euthermy, and during summer rest. The triglyceride, non-esterified free fatty acid, starch, glucose and protein composition of the perfusate was evaluated before and after the 1h perfusion of a closed intestinal loop. Triglyceride, starch and protein hydrolysis rates were similar in hibernating (torpid and euthermic) and non-hibernating hamsters. Intestinal absorption of free fatty acid was also similar in all groups. However, glucose uptake rate was higher during hibernation than during the summer. In contrast with fat-storing species, the intestinal absorption capacities of food storing species are fully maintained during hibernation to optimize nutrient assimilation during short interbout euthermy. In particular, glucose uptake rate is increased during hibernation to restore glycaemia and ensure glucose-dependent pathways. PMID- 26774184 TI - The effect of aerobic exercise and starvation on growth performance and postprandial metabolic response in juvenile southern catfish (Silurus meridionalis). AB - To investigate the effects of aerobic exercise and starvation on growth performance, postprandial metabolic response and their interaction in a sedentary fish species, either satiation-fed or starved juvenile southern catfish (Silurus meridionalis) were exercised at 25 degrees C under three water velocities, i.e., nearly still water (control), 1 body length (bl) s(-1) and 2 bl s(-1), for eight weeks. Then, the feed intake (FI), food conversion efficiency (FCE), specific growth rate (SGR), morphological parameters, resting MO2 (MO2rest) and postprandial MO2 responses of the experimental fish were measured. Exercise at a low velocity (1 bl s(-1)) showed no effect on any growth performance parameter, whereas exercise at a high velocity (2 bl s(-1)) exhibited higher FI but similar SGR due to the extra energy expenditure from swimming and consequent decreased FCE. Starvation led to a significant body mass loss, whereas the effect intensified in both exercise groups. Exercise resulted in improved cardio respiratory capacity, as indicated by increased gill and heart indexes, whereas it exhibited no effect on resting and postprandial metabolism in S. meridionalis. The starved fish displayed significantly larger heart, gill and digestive tract indexes compared with the feeding fish, suggesting selective maintenance of cardio-respiratory and digestive function in this fish species during starvation. However, starved fish still exhibited impaired digestive performance, as evidenced by the prolonged duration and low postprandial metabolic increase, and this effect was further exacerbated in both the 1 and 2 bl s(-1) exercise groups. These data suggest the following: (1) aerobic exercise produced no improvement in growth performance but may have led to the impairment of growth under insufficient food conditions; (2) the mass of different organs and tissues responded differently to aerobic exercise and starvation due to the different physiological roles they play; and (3) aerobic exercise had no effect on the postprandial metabolic response under a "normal feeding" situation, whereas it may have resulted in the impairment of the digestive capacity when food availability was low due to the competition of energy and oxygen under unfavorable conditions in juvenile S. meridionalis. PMID- 26774180 TI - Organoid Models of Human Gastrointestinal Development and Disease. AB - We have greatly advanced our ability to grow a diverse range of tissue-derived and pluripotent stem cell-derived gastrointestinal (GI) tissues in vitro. These systems, broadly referred to as organoids, have allowed the field to move away from the often nonphysiological, transformed cell lines that have been used for decades in GI research. Organoids are derived from primary tissues and have the capacity for long-term growth. They contain varying levels of cellular complexity and physiological similarity to native organ systems. We review the latest discoveries from studies of tissue-derived and pluripotent stem cell-derived intestinal, gastric, esophageal, liver, and pancreatic organoids. These studies have provided important insights into GI development, tissue homeostasis, and disease and might be used to develop personalized medicines. PMID- 26774185 TI - Is salivary gland function altered in noninsulin-dependent diabetes mellitus and obesity-insulin resistance? AB - Salivary gland dysfunction in several systemic diseases has been shown to decrease the quality of life in patients. In non-insulin dependent diabetes mellitus (NIDDM), inadequate salivary gland function has been evidenced to closely associate with this abnormal glycemic control condition. Although several studies demonstrated that NIDDM has a positive correlation with impaired salivary gland function, including decreased salivary flow rate, some studies demonstrated contradictory findings. Moreover, the changes of the salivary gland function in pre-diabetic stage known as insulin resistance are still unclear. The aim of this review is to comprehensively summarize the current evidence from in vitro, in vivo and clinical studies regarding the relationship between NIDDM and salivary gland function, as well as the correlation between obesity and salivary gland function. Consistent findings as well as controversial reports and the mechanistic insights regarding the effect of NIDDM and obesity-insulin resistance on salivary gland function are also presented and discussed. PMID- 26774187 TI - Facial discrimination in body dysmorphic, obsessive-compulsive and social anxiety disorders. AB - Body dysmorphic disorder (BDD) is characterized by preoccupation with perceived flaws in one's own appearance. Several risk factors such as aesthetic perceptual sensitivity have been proposed to explain BDD's unique symptomatology. Although research on facial discrimination is limited so far, the few existing studies have produced mixed results. Thus, the purpose of this study was to further examine facial discrimination in BDD. We administered a facial discrimination paradigm, which allows to assess the ability to identify slight to strong facial changes (e.g., hair loss, acne) when presented with an original (unmodified) facial image, relative to a changed (modified) facial image. The experiment was administered in individuals with BDD, social anxiety disorder, obsessive compulsive disorder, and mentally healthy controls (32 per group, respectively). Overall, groups did not differ with respect to their ability to correctly identify facial aberrations when presented with other people's faces. Our findings do not support the hypothesis of enhanced general aesthetic perceptual sensitivity in individuals with (vs. without) BDD. PMID- 26774186 TI - Biomechanical and biochemical outcomes of porcine temporomandibular joint disc deformation. AB - OBJECTIVE: The structure-function relationship in the healthy temporomandibular joint (TMJ) disc has been well established, however the changes in dysfunctional joints has yet to be systematically evaluated. Due to the poor understanding of the etiology of temporomandibular disorders (TMDs) this study evaluated naturally occurring degenerative remodeling in aged female porcine temporomandibular joint (TMJ) discs in order to gain insight into the progression and effects on possible treatment strategies of TMDs. DESIGN: Surface and regional biomechanical and biochemical properties of discal tissues were determined in grossly deformed (>=Wilkes Stage 3) and morphologically normal (<=Wilkes Stage 2) TMJ discs. RESULTS: Compared to normal disc structure the deformed discs lacked a smooth biconcave shape and characteristic ECM organization. Reduction in tensile biomechanical integrity and increased compressive stiffness and cellularity was found in deformed discs. Regionally, the posterior and intermediate zones of the disc were most frequently affected along with the inferior surface. CONCLUSIONS: The frequency of degeneration observed on the inferior surface of the disc (predominantly posterior), suggests that a disruption in the disc-condyle relationship likely contributes to the progression of joint dysfunction more than the temporodiscal relationship. As such, the inferior joint space may be an important consideration in early clinical diagnosis and treatment of TMDs, as it is overlooked in techniques performed in the upper joint space, including arthroscopy and arthrocentesis. Furthermore, permanent damage to the disc mechanical properties would limit the ability to successfully reposition deformed discs, highlighting the importance of emerging therapies such as tissue engineering. PMID- 26774188 TI - Religiosity in young adolescents with auditory vocal hallucinations. AB - The current exploratory study examined the associations between auditory vocal hallucinations (AVH) and delusions and religiosity in young adolescents. 337 children from a population-based case-control study with and without AVH, were assessed after five years at age 12 and 13, on the presence and appraisal of AVH, delusions and religiosity. AVH status (persistent, remittent, incident or control) was examined in relationship to religiosity. Results demonstrated a non linear association between AVH and religiosity. Moderately religious adolescents were more likely to report AVH than non-religious adolescents (O.R.=2.6). Prospectively, moderately religious adolescents were more likely to have recently developed AVH than non-religious adolescents (O.R.=3.6) and strongly religious adolescents (O.R.=7.9). Of the adolescents reporting voices in this sample (16.3%), more than half reported positive voices. Religious beliefs were often described as supportive, useful or neutral (82%), regardless of the level of religiosity, for both adolescents with and without AVH. Co-occurrence of AVH and delusions, and severity of AVH were not related to religiosity. The present findings suggest there may be a non-linear association between religiosity and hearing voices in young adolescents. A speculative explanation may be that religious practices were adopted in response to AVH as a method of coping. PMID- 26774189 TI - Serum soluble urokinase-type plasminogen activator receptor levels in male patients with acute exacerbation of schizophrenia. AB - Inflammatory abnormalities have been shown in the pathogenesis of schizophrenia. Soluble urokinase-type plasminogen activator receptor (suPAR) is a protein that is measurable in the circulating blood and reflects the inflammation in the body. We aimed to investigate serum suPAR levels in patients with schizophrenia who were in acute state and to compare with healthy controls. Forty five patients and 43 healthy controls were included in the study. We found no significant difference in suPAR levels between patients and controls, suggesting that suPAR as an inflammatory marker does not have a role in the inflammatory process of acute schizophrenia. PMID- 26774190 TI - Blood lead, parental marital status and the risk of attention deficit/hyperactivity disorder in elementary school children: A longitudinal study. AB - The aim of this study was to investigate the blood lead level and parental marital status that might influence the development of attention deficit/hyperactivity disorder (ADHD) symptoms in school-aged children. The participants in the survey included elementary school children, and they were followed up biennially. The participants' parents or caregivers were administered a questionnaire including ADHD rating scale. Among 2967 who were not suspected to have ADHD at baseline survey, 2195 children who took follow-up test for ADHD were evaluated. The incidence rate of suspected ADHD was 5.0% (107 cases) during the two years of the follow-up period. The geometric mean blood lead level was 1.56MUg/dL. Relative risk ratio for ADHD was estimated using logistic regression analysis. After adjustment for potential confounders, ADHD developed more frequently in children with blood lead levels of >2.17MUg/dL (highest quartile) (RR 1.552, 95% CI 1.002-2.403) and in children with a single parent (RR 1.805, 95% CI 1.002-3.254). The RR was 3.567 (95% CI 1.595-7.980) in children with relatively high blood lead levels (>2.17MUg/dL) from single-parent families, compared with those with low blood lead and a two-parent family. The ADHD risk in association with blood lead level was modified by family status. PMID- 26774191 TI - Effects of anthropogenic heavy metal contamination on litter decomposition in streams - A meta-analysis. AB - Many streams worldwide are affected by heavy metal contamination, mostly due to past and present mining activities. Here we present a meta-analysis of 38 studies (reporting 133 cases) published between 1978 and 2014 that reported the effects of heavy metal contamination on the decomposition of terrestrial litter in running waters. Overall, heavy metal contamination significantly inhibited litter decomposition. The effect was stronger for laboratory than for field studies, likely due to better control of confounding variables in the former, antagonistic interactions between metals and other environmental variables in the latter or differences in metal identity and concentration between studies. For laboratory studies, only copper + zinc mixtures significantly inhibited litter decomposition, while no significant effects were found for silver, aluminum, cadmium or zinc considered individually. For field studies, coal and metal mine drainage strongly inhibited litter decomposition, while drainage from motorways had no significant effects. The effect of coal mine drainage did not depend on drainage pH. Coal mine drainage negatively affected leaf litter decomposition independently of leaf litter identity; no significant effect was found for wood decomposition, but sample size was low. Considering metal mine drainage, arsenic mines had a stronger negative effect on leaf litter decomposition than gold or pyrite mines. Metal mine drainage significantly inhibited leaf litter decomposition driven by both microbes and invertebrates, independently of leaf litter identity; no significant effect was found for microbially driven decomposition, but sample size was low. Overall, mine drainage negatively affects leaf litter decomposition, likely through negative effects on invertebrates. PMID- 26774192 TI - The cause of brachial plexopathy in robot-assisted transaxillary thyroidectomy-A neurophysiological investigation. AB - OBJECTIVES/HYPOTHESIS: During robot-assisted transaxillary thyroidectomy, the patient's arm is maintained in an overhead flexed position for a prolonged time, which poses a risk of postoperative brachial plexopathy. The aim of the study was to identify the causes of brachial plexopathy and to assess the benefit of intraoperative neurophysiological monitoring (IONM) in preventing positional brachial plexopathy in this setting. STUDY DESIGN: Retrospective case series. METHODS: The computerized database of a tertiary medical center was searched for all consecutive patients who underwent robot-assisted transaxillary thyroidectomy between 2012 and 2014. Clinical, operative, and outcome parameters were collected from the medical files. Findings were compared between patients operated with and without IONM. RESULTS: The cohort included 30 patients, 14 operated with IONM and 16 without. Three events of impending brachial plexopathy were detected in the monitored group. The monitored group had significantly better shoulder movement (P = .003), a lower rate of hypoesthesia (P = .011), less pain (P = .001) in the early postoperative period than the nonmonitored group and higher quality of life in the early postoperative period (P = .012). The monitored group was significantly younger than the nonmonitored one (P = .02) and had a significantly larger diameter of thyroid nodule than the nonmonitored group (P = .043). CONCLUSIONS: IONM during robot-assisted transaxillary thyroidectomy may improve short-term postoperative pain and shoulder movement and longer-term quality of life. LEVEL OF EVIDENCE: 4 Laryngoscope, 126:2187-2193, 2016. PMID- 26774193 TI - Retrospective Multicenter Study Investigating the Role of Targeted Next Generation Sequencing of Selected Cancer Genes in Mucinous Adenocarcinoma of the Lung. AB - INTRODUCTION: Mucin-rich lung adenocarcinomas (ADCs), namely mucinous and colloid ADCs, are classified as ADC variants according to the World Health Organization 2015 classification. A correlation between morphological patterns and mutational status of these rare entities is not well established. METHODS: We investigated the mutational profile of mucin-rich lung ADCs in correlation with histopathological and morphological features with the goal of identifying biological tumor characteristics of potential prognostic and therapeutic interest. A series of 54 surgically resected primary mucinous lung ADC samples were retrospectively analyzed for clinicopathological characteristics and by targeted next-generation sequencing. RESULTS: Fifty cases were invasive mucinous ADCs (32 pure and 18 mixed) and four were colloid-predominant ADCs. Invasive mucinous ADC cases with a pure mucinous pattern were associated with a lower risk of vascular invasion (p = 0.01), absence of signet ring cells (p = 0.03), negative nodal status (p = 0.006), and early clinical stage (p = 0.02). The most prevalent mutations involved the Kirsten rat sarcoma viral oncogene homolog gene (KRAS) and tumor protein p53 gene (TP53). Most mutations clustered in the mitogen activated protein/protein kinase B pathway and in the p53/DNA repair pathway. A few uncommon epidermal growth factor receptor gene (EGFR) mutations were found. A correlation between a higher number of mutations and favorable clinical outcome was seen (p < 0.001). CONCLUSIONS: Our data showed that mucinous ADCs have peculiar pathological and molecular features that might suggest the need for a differentially tailored therapeutic approach compared with that to conventional lung ADC. PMID- 26774194 TI - Long-term performance evaluation of down-flow hanging sponge reactor regarding nitrification in a full-scale experiment in India. AB - The first full-scale down-flow hanging sponge (DHS) reactor applied to post treatment of effluent from an upflow anaerobic sludge blanket (UASB) reactor for the treatment of municipal sewage was evaluated, with emphasis on nitrification. The full-scale DHS reactor was successfully operated at a hydraulic retention time of 1.5h for over 1800 days in India. The DHS reactor produced effluent with 6 mg L(-1) ammonium nitrogen, corresponding to 79% removal efficiency. The total nitrogen removal by the DHS reactor was 65%. The high process performance of the DHS reactor was supported by its distinctive characteristics of (1) high dissolved oxygen of 5.4 mg L(-1) in the DHS effluent without forced ventilation, (2) dense retained sludge in the range of 23-46 gVSS Lsponge(-1), and (3) adequate sludge activity of 52 mgN gVSS(-1) day(-1) for nitrification. The full scale experiment has proven that the DHS reactor has practical applicability to developing countries. PMID- 26774195 TI - Resveratrol for breast cancer prevention and therapy: Preclinical evidence and molecular mechanisms. AB - Globally, breast cancer is the most frequently diagnosed cancer among women. The major unresolved problems with metastatic breast cancer is recurrence after receiving objective response to chemotherapy, drug-induced side effects of first line chemotherapy and delayed response to second line of treatment. Unfortunately, very few options are available as third line treatment. It is clear that under such circumstances there is an urgent need for new and effective drugs. Phytochemicals are among the most promising chemopreventive treatment options for the management of cancer. Resveratrol (3,5,4'-trihydroxy-trans stilbene), a non-flavonoid polyphenol present in several dietary sources, including grapes, berries, soy beans, pomegranate and peanuts, has been shown to possess a wide range of health benefits through its effect on a plethora of molecular targets.The present review encompasses the role of resveratrol and its natural/synthetic analogue in the light of their efficacy against tumor cell proliferation, metastasis, epigenetic alterations and for induction of apoptosis as well as sensitization toward chemotherapeutic drugs in various in vitro and in vivo models of breast cancer. The roles of resveratrol as a phytoestrogen, an aromatase inhibitor and in stem cell therapy as well as adjuvent treatment are also discussed. This review explores the full potential of resveratrol in breast cancer prevention and treatment with current limitations, challenges and future directions of research. PMID- 26774196 TI - MicroRNAs in cholangiopathies: Potential diagnostic and therapeutic tools. AB - Cholangiopathies are the group of diseases targeting the bile duct epithelial cells (i.e. cholangiocytes). These disorders arise from different etiologies and represent a current diagnostic, prognostic and therapeutic challenge. Different molecular mechanisms participate in the development and progression of each type of biliary disease. However, microRNA deregulation is a common central event occurring in all of them that plays a key role in their pathogenesis. MicroRNAs are highly stable small non-coding RNAs present in cells, extracellular microvesicles and biofluids, representing valuable diagnostic tools and potential targets for therapy. In the following sections, the most novel and significant discoveries in this field are summarized and their potential clinical value is highlighted. PMID- 26774197 TI - [Painful tic convulsif: Case series and literature review]. AB - BACKGROUND: The coexistence of hemifacial spasm and trigeminal neuralgia, a clinical entity known as painful tic convulsive, was first described in 1910. It is an uncommon condition that is worthy of interest in neurosurgical practice, because of its common pathophysiology mechanism: Neuro-vascular compression in most of the cases. OBJECTIVE: To present 2 cases of painful tic convulsive that received treatment at our institution, and to give a brief review of the existing literature related to this. The benefits of micro-surgical decompression and the most common medical therapy used (botulin toxin) are also presented. CLINICAL CASES: Two cases of typical painful tic convulsive are described, showing representative slices of magnetic resonance imaging corresponding to the aetiology of each case, as well as a description of the surgical technique employed in our institution. The immediate relief of symptomatology, and the clinical condition at one-year follow-up in each case is described. A brief review of the literature on this condition is presented. CONCLUSION: This very rare neurological entity represents less than 1% of rhizopathies and in a large proportion of cases it is caused by vascular compression, attributed to an aberrant dolichoectatic course of the vertebro-basilar complex. The standard modality of treatment is micro-vascular surgical decompression, which has shown greater effectiveness and control of symptoms in the long-term. However medical treatment, which includes percutaneous infiltration of botulinum toxin, has produced similar results at medium-term in the control of each individual clinical manifestation, but it must be considered as an alternative in the choice of treatment. PMID- 26774198 TI - Brain Volumes at Term-Equivalent Age in Preterm Infants: Imaging Biomarkers for Neurodevelopmental Outcome through Early School Age. AB - OBJECTIVE: To evaluate the relationship between brain volumes at term and neurodevelopmental outcome through early school age in preterm infants. STUDY DESIGN: One hundred twelve preterm infants (born mean gestational age 28.6 +/- 1.7 weeks) were studied prospectively with magnetic resonance imaging (imaged at mean 41.6 +/- 1.0 weeks). T2- and T1-weighted images were automatically segmented, and volumes of 6 tissue types were related to neurodevelopmental outcome assessed using the Bayley Scales of Infant and Toddler Development, Third Edition (cognitive, fine, and gross motor scores) at 24 months corrected age (n = 112), Griffiths Mental Development Scales (developmental quotient) at age 3.5 years (n = 98), Movement Assessment Battery for Children, Second Edition (n = 85), and Wechsler Preschool and Primary Scale of Intelligence, Third Edition at age 5.5 years (n = 44). Corrections were made for intracranial volume, maternal education, and severe brain lesions. RESULTS: Ventricular volumes were negatively related to neurodevelopmental outcome at age 24 months and 3.5 years, as well as processing speed at age 5.5 years. Unmyelinated white matter (UWM) volume was positively associated with motor outcome at 24 months and with processing speed at age 5.5 years. Cortical gray matter (CGM) volume demonstrated a negative association with motor performance and cognition at 24 months and with developmental quotient at age 3.5 years. Cerebellar volume was positively related to cognition at these time points. Adjustment for brain lesions attenuated the relations between cerebellar and CGM volumes and cognition. CONCLUSIONS: Brain volumes of ventricles, UWM, CGM, and cerebellum may serve as biomarkers for neurodevelopmental outcome in preterm infants. The relationship between larger CGM volumes and adverse neurodevelopment may reflect disturbances in neuronal and/or axonal migration at the UWM-CGM boundary and warrants further investigation. PMID- 26774199 TI - Hydroxyethyl Starch 130/0.4 and the Risk of Acute Kidney Injury After Cardiopulmonary Bypass: A Single-Center Retrospective Study. AB - OBJECTIVES: To investigate whether using hydroxyethyl starch (HES) 130/0.4 as a pump prime and for intraoperative fluid therapy is associated with postoperative acute kidney injury (AKI) after adult cardiac surgery. DESIGN: Retrospective observational study. SETTING: University hospital, single center. PARTICIPANTS: Six hundred six adult patients who underwent on-pump cardiac surgery between April 2013 and June 2014 were included. INTERVENTIONS: Until July 2013, balanced HES 130/0.4 (Volulyte((r)), Fresenius Kabi AG, Bad Homburg, Germany) was used both as a pump prime (1,500 mL) and for intraoperative fluid therapy (1,000 mL). From August 2013, HES was replaced entirely by a balanced crystalloid solution (Plasma-Lyte A, Baxter, Lessines, Belgium). MEASUREMENTS AND MAIN RESULTS: The primary endpoint was the incidence of postoperative AKI during the first 48 postoperative hours, determined using the Acute Kidney Injury Network classification. Secondary outcomes included kidney function at postoperative day 7, postoperative dialysis or hemofiltration, postoperative pulmonary complications, lengths of intensive care unit and hospital stays, postoperative fluid balance and urinary output, surgical revision for bleeding, and 30-day mortality. Multivariable logistic regression was used to adjust for confounders. AKI occurred in 9.5% of crystalloid patients and in 21.5% of HES patients. Patients who received HES were about twice as likely to develop postoperative AKI as those treated with crystalloids (adjusted OR 2.26; 95% CI, 1.40-3.80; p = 0.02). HES patients also had a significantly more positive fluid balance and a lower urinary output during the first 48 postoperative hours. The incidence of surgical revision for bleeding was greater in the HES group (4.6% v 1.4%, p = 0.02). CONCLUSION: This study suggested that using balanced HES 130/0.4 as a pump prime and for intraoperative fluid therapy in adult patients undergoing on-pump cardiac surgery was associated with a greater incidence of AKI during the early postoperative period. PMID- 26774200 TI - A Case of Fatal Bleeding Following Emergency Surgery on an Ascending Aorta Intramural Hematoma in a Patient Taking Dabigatran. PMID- 26774202 TI - Biomarkers in the diagnosis and study of psychogenic nonepileptic seizures: A systematic review. AB - OBJECTIVE: Video electroencephalography (vEEG) is the gold-standard method for diagnosing psychogenic nonepileptic seizures (PNES), but such assessment is expensive, unavailable in many centers, requires prolonged hospitalization, and many times is unable to capture an actual seizure episode. This paper systematically reviews other non-vEEG candidate biomarkers that may facilitate both diagnosis and study of PNES as differentiated from epileptic seizures (ES). METHODS: PubMed database was searched to identify articles between 1980 and 2015 (inclusion: adult PNES population with or without controls, English language; exclusion: review articles, meta-analyses, single case reports). RESULTS: A total of 49 studies were examined, including neuroimaging, autonomic nervous system, prolactin, other (non-prolactin) hormonal, enzyme, and miscellaneous marker studies. Functional MRI studies have shown PNES is hyperlinked with dissociation and emotional dysregulation centers in the brain, although conflicting findings are seen across studies and none used psychiatric comparators. Heart rate variability suggests increased vagal tone in PNES when compared to ES. Prolactin is elevated in ES but not PNES, although shows low diagnostic sensitivity. Postictal cortisol and creatine kinase are nonspecific. Other miscellaneous biomarkers (neuron specific enolase, brain derived neurotropic factor, ghrelin, leptin, leukocytosis) showed no conclusive evidence of utility. Many studies are limited by lack of psychiatric comparators, size, and other methodological issues. CONCLUSION: No single biomarker successfully differentiates PNES from ES; in fact, PNES is only diagnosed via the negation of ES. Clinical assessment and rigorous investigation of psychosocial variables specific to PNES remain critical, and subtyping of PNES is warranted. Future investigational and clinical imperatives are discussed. PMID- 26774201 TI - Results of a Phase II Trial of Carboplatin, Pemetrexed, and Bevacizumab for the Treatment of Never or Former/Light Smoking Patients With Stage IV Non-Small Cell Lung Cancer. AB - INTRODUCTION: Bevacizumab- and pemetrexed-based therapies have demonstrated activity in patients with non-small-cell lung cancer (NSCLC) and nonsquamous histologic features. Patients with history of never or light smoking might derive greater benefit from these therapies. PATIENTS AND METHODS: The included patients had stage IIIB (malignant pleural effusion) or IV NSCLC with nonsquamous histologic features, adequate organ function, no contraindications to bevacizumab, and no previous cytotoxic therapy. The patients had also never smoked or had smoked <= 10 pack years and had quit >= 1 year before enrollment. The patients had received 4 cycles of carboplatin (area under the curve, 6), pemetrexed 500 mg/m(2), and bevacizumab 15 mg/kg. Patients without disease progression initiated maintenance therapy with pemetrexed and bevacizumab. A single-arm phase II trial with the primary endpoint of progression-free survival (PFS) was performed. The secondary endpoints were the objective response rate (ORR), overall survival (OS), and toxicity. RESULTS: From March 2010 to November 2013, 38 eligible patients were enrolled and treated in the trial. The most common histologic type was adenocarcinoma (97%). Most of the patients were women (66%) and never smokers (63%). The median PFS was 12.6 months (95% confidence interval [CI], 8.0-23.9 months). The ORR and OS were 47% (95% CI, 31%-64%) and 20.3 months (95% CI, 15.8-30.5 months). The grade 3 or 4 toxicities occurring at rate of >= 10% were neutropenia (18%), anemia (16%), fatigue (16%), hypertension (16%), and thrombocytopenia (11%). CONCLUSION: The combination of the carboplatin, pemetrexed, and bevacizumab demonstrated activity with acceptable toxicity in patients with a clinical history of never or light smoking. PMID- 26774203 TI - Different spontaneous breathing trials in patients with atrial fibrillation. PMID- 26774204 TI - Reply to the Letter: Different spontaneous breathing trials in patients with atrial fibrillation. PMID- 26774205 TI - Endotherapy is effective for pancreatic ductal disruption: A dual center experience. AB - BACKGROUND AND STUDY AIMS: Pancreatic duct (PD) disruptions occur as a result of different etiologies and can be managed medically, endoscopically, or surgically. The aim of this study was to provide an evaluation on the efficacy of endotherapy for treatment of PD disruption in a large cohort of patients and identify factors that predict successful treatment outcome. PATIENTS AND METHODS: We retrospectively evaluated consecutive patients who underwent endoscopic retrograde pancreatography (ERP) for transpapillary pancreatic stent placement for PD disruption from 2008 to 2013 at two tertiary referral institutions. PD disruption was defined as extravasation of contrast from the pancreatic duct as seen on ERP. Therapeutic success was defined by resolution of PD leak on ERP, clinical, and/or imaging evaluation. RESULTS: We evaluated 107 patients (58% male, mean age 53 years) with PD disruption. Etiologies of PD disruption were acute pancreatitis (36%), post-operative (31%), chronic pancreatitis (29%), and trauma (4%). PD disruption was successfully bridged by a stent in 45 (44%) patients. Two patients developed post-sphincterotomy bleeding, two had stent migration, and two patients died as a result of post-ERP related complications. Placement of a PD stent was successful in 103/107 (96%) patients. Therapeutic success was achieved in 80/107 (75%) patients. Non-acute pancreatitis etiologies and absence of complete duct disruption were independent predictors of therapeutic success. CONCLUSIONS: Endoscopic therapy using a transpapillary stent for PD disruption is safe and effective. Absence of complete duct disruption and non-AP etiologies determine a favorable endoscopic outcome. PMID- 26774206 TI - Synergistic Survival: A New Phenomenon Connected to Adverse Events of First-Line Sunitinib Treatment in Advanced Renal Cell Carcinoma. AB - BACKGROUND: The aim was to assess the relationship between treatment efficacy and adverse events (AEs) for patients with advanced renal cell carcinoma treated with first-line sunitinib. PATIENTS AND METHODS: 274 patients were treated with sunitinib (50 mg/d, 4-weeks-on and 2-weeks-off schedule). Physical and laboratory evaluations were done every sixth week. AEs were diagnosed at every visit. Clinical response was assessed every 3 months. The objective response rate (ORR), median progression-free (mPFS) and median overall survival (mOS) and AEs were evaluated. Besides chi(2) and log rank tests, multivariate Cox regression analysis and for synergism 1-sided t tests were used. RESULTS: The ORR was 25%. After a median follow-up of 32 months, the mPFS and mOS were 9 and 19 months, respectively. Hypertension, diarrhea, hypothyroidism, mucositis, hand-foot syndrome (HFS), skin toxicity, and leukopenia were the most frequent treatment associated AEs. Significantly longer (P < .01) mPFS and mOS were observed when hypertension, diarrhea, HFS, hypothyroidism, skin toxicity, or leukopenia occurred. A statistically significant synergistic effect of the listed AEs was observed for progression-free survival (P < .001) and overall survival (P < .001). Multivariate analysis revealed that besides the prognostic category, the higher number of AEs (3-6 vs. 0-2) was an independent marker of longer mPFS (24 vs. 5 months, respectively; P < .001) and mOS (51 vs. 9 months, respectively; P < .001). CONCLUSION: Results of this study provide evidence for the synergistically enhanced efficacy of sunitinib treatment in patients who present multiple AEs. These AEs are diagnosed routinely and their coexistence can help physicians to predict which group of patients would benefit the most from first-line sunitinib treatment. PMID- 26774207 TI - Urine TMPRSS2: ERG Fusion Transcript as a Biomarker for Prostate Cancer: Literature Review. AB - Prostate cancer (PCa) is one of the most common male malignancies. Serum prostate specific antigen (PSA) is one of the most valuable biomarkers in tumor biology and remains the standard marker in detecting and monitoring PCa. However, the high number of serum PSA false positive and false negative results make the identification of novel biomarkers extremely welcome to improve our diagnostic accuracy in detecting PCa and distinguishing the aggressive from the indolent ones. In this study, we analyzed the current role of urinary gene fusion transcripts involving v-ets erythroblastosis virus E26 oncogene homolog, commonly known as ERG, and the androgen-regulated gene transmembrane protease, serine 2 (TMPRSS2), as a biomarker for PCa. Used as a single marker, urinary TMPRSS2:ERG has low sensitivity but high specificity. However, its combination with the other urinary marker PCa antigen 3 (PCA3) has been reported to provide high specificity and sensitivity. Finally, a commercially available assay combining serum PSA with urinary PCA3 and TMPRSS2:ERG provides a 90% specificity and 80% sensitivity in diagnosing PCa. Urinary TMPRSS2:ERG also seems to be indicative of PCa aggressiveness upon biopsy. Should these findings be confirmed in larger studies, urinary TMPRSS2:ERG might become a valuable test not only for diagnosing PCa but also for distinguishing the aggressive tumors from the indolent ones. PMID- 26774208 TI - Estrogens, inflammation and cognition. AB - The effects of estrogens are pleiotropic, affecting multiple bodily systems. Changes from the body's natural fluctuating levels of estrogens, through surgical removal of the ovaries, natural menopause, or the administration of exogenous estrogens to menopausal women have been independently linked to an altered immune profile, and changes to cognitive processes. Here, we propose that inflammation may mediate the relationship between low levels of estrogens and cognitive decline. In order to determine what is known about this connection, we review the literature on the cognitive effects of decreased estrogens due to oophorectomy or natural menopause, decreased estrogens' role on inflammation--both peripherally and in the brain--and the relationship between inflammation and cognition. While this review demonstrates that much is unknown about the intersection between estrogens, cognition, inflammation, we propose that there is an important interaction between these literatures. PMID- 26774209 TI - These two are different. Yes, they're the same: Choice blindness for facial identity. AB - We examined the manipulability of face identity judgements by combining a sorting task for unfamiliar faces with a standard test of choice blindness. In Experiment 1, 50 participants completed a sorting task and then justified grouping specific pairs of photos together or apart. On manipulated trials, the presented pairings were different from those the participants had actually produced. Detection rates for these identity manipulations were strikingly low (~21%). Moreover, participants readily provided justifications for identity decisions that they had not made, typically referring to specific facial features. Experiment 2 was conducted along similar lines and confirmed that lower task difficulty and higher confidence in one's face identity judgements increase detection rates. We conclude that observers can easily be led to believe that they made identity judgements they did not make. As well as underscoring the fragility of unfamiliar face matching, our findings have implications for identity judgements in legal settings. PMID- 26774210 TI - Parietal theta burst TMS: Functional fractionation observed during bistable perception not evident in attention tasks. AB - When visual input is ambiguous, perception spontaneously alternates between interpretations: bistable perception. Studies have identified two distinct sites near the right intraparietal sulcus where inhibitory transcranial magnetic stimulation (TMS) affects the frequency of occurrence of these alternations, but strikingly with opposite directions of effect for the two sites. Lesion and TMS studies on spatial and sustained attention have also indicated a parcellation of right parietal cortex, into areas serving distinct attentional functions. We used the exact TMS procedure previously employed to affect bistable perception, yet measured its effect on spatial and sustained attention tasks. Although there was a trend for TMS to affect performance, trends were consistently similar for both parietal sites, with no indication of opposite effects. We interpret this as signifying that the previously observed parietal fractionation of function regarding the perception of ambiguous stimuli is not due to TMS-induced modification of spatial or sustained attention. PMID- 26774211 TI - Predicting recycling behaviour: Comparison of a linear regression model and a fuzzy logic model. AB - In this paper we demonstrate that fuzzy logic can provide a better tool for predicting recycling behaviour than the customarily used linear regression. To show this, we take a set of empirical data on recycling behaviour (N=664), which we randomly divide into two halves. The first half is used to estimate a linear regression model of recycling behaviour, and to develop a fuzzy logic model of recycling behaviour. As the first comparison, the fit of both models to the data included in estimation of the models (N=332) is evaluated. As the second comparison, predictive accuracy of both models for "new" cases (hold-out data not included in building the models, N=332) is assessed. In both cases, the fuzzy logic model significantly outperforms the regression model in terms of fit. To conclude, when accurate predictions of recycling and possibly other environmental behaviours are needed, fuzzy logic modelling seems to be a promising technique. PMID- 26774212 TI - Resveratrol-induced autophagy promotes survival and attenuates doxorubicin induced cardiotoxicity. AB - Resveratrol (RSV) has many biological effects, including antitumor and antiviral activities, and vascular protection. Recent studies have suggested that RSV exerts its antitumor effects through induction of autophagy by an unknown mechanism. Doxorubicin (DOX) is a wide spectrum antitumor drug, but its clinical application is limited by its cardiotoxicity. This study evaluated whether the manipulation of autophagy could attenuate the cardiotoxic effects of DOX in vitro as well as in a rat model of DOX-induced cardiotoxicity. We found that DOX induced H9C2 cell apoptosis by inhibiting AMPK activation and promoting pro apoptotic protein expression through p38MAPK/p53 signaling. RSV-treated H9C2 cells showed increased autophagy through the AMPK/mTOR/Ulk1 pathway. When DOX and RSV were combined, apoptosis was decreased, despite a slight increase in the autophagy ratio. The same result was observed in the rat model of DOX-induced cardiotoxicity. Injection with DOX or RSV alone, or in combination, for a week, resulted in a reduced apoptotic ratio in the combination group compared with the DOX alone group. Our results strongly indicate that this co-treatment strategy with RSV can attenuate the cardiotoxic effects of DOX. Our findings may have important clinical implications. PMID- 26774213 TI - A higher frequency of CD4(+)CXCR5(+) T follicular helper cells in patients with newly diagnosed Henoch-Schonlein purpura nephritis. AB - T follicular helper (TFH) cells play an important role in the humoral immune responses. The aim of this study was to examine the frequency of different subsets of CD4(+)CXCR5(+) TFH cells and B cells in patients with new-onset Henoch Schonlein purpura nephritis (HSPN). The numbers of different subsets of CD4(+)CXCR5(+) TFH cells, B cells and the constituents of serum cytokines were detected in a total of 25 patients with newly diagnosed HSPN before and after treatment, and in 14 healthy controls (HC). The potential connection of these cells with the clinical characteristics in HSPN patients was analyzed. The numbers of circulating CD4(+)CXCR5(+), CD4(+)CXCR5(+)ICOS(+) and CD4(+)CXCR5(+)PD 1(+) TFH cells, CD86(+)CD19(+), CD38(+)CD19(+) B cells and serum IL-2, IL-4, IL 17A, IL-21 and IFN-gamma were significantly higher in HSPN patients (p<0.05) than in HC. Before and after treatment the numbers of CD4(+)CXCR5(+) TFH cells were negatively correlated with the values of eGFR (r=-0.7162, p<0.05; r=-0.732, p<0.05, respectively). Similarly the numbers of CD4(+)CXCR5(+)PD-1(+) TFH cells were negatively correlated with 24-h urinary proteins (r=-0.4013, p<0.05; r= 0.7857, p<0.05, respectively), and the numbers of CD4(+)CXCR5(+)ICOS(+) TFH cells were positively correlated with the levels of serum IL-21 (r=0.5186, p<0.05; r=0.8503, p<0.05, respectively) and 24-h urinary protein (r=0.6045, p<0.05; r=0.833, p<0.05, respectively) in these patients, regardless of treatment. Following treatment the numbers of CD4(+)CXCR5(+), CD4(+)CXCR5(+)PD-1(+), and CD4(+)CXCR5(+)ICOS(+) TFH cells, as well as serum levels of IL-21 were significantly reduced, however IL-4 levels were noticeably increased (p<0.05). A higher frequency of circulating CD4(+)CXCR5(+) TFH cells existed in patients with HSPN and may be a viable therapeutic target. PMID- 26774214 TI - Interactions of a class IIb bacteriocin with a model lipid bilayer, investigated through molecular dynamics simulations. AB - The emergence of antibiotic resistant microorganisms poses an alarming threat to global health. Antimicrobial peptides (AMPs) are considered a possible effective alternative to conventional antibiotic therapies. An understanding of the mechanism of action of AMPs is needed in order to better control and optimize their bactericidal activity. Plantaricin EF is a heterodimeric AMP, consisting of two peptides Plantaricin E (PlnE) and Plantaricin F (PlnF). We studied the behavior of these peptides on the surface of a model lipid bilayer. We identified the residues that facilitate peptide-peptide interactions. We also identified residues that mediate interactions of the dimer with the membrane. PlnE interacts with the membrane through amino acids at both its termini, while only the N terminus of PlnF approaches the membrane. By comparing the activity of single site mutants of the two-peptide bacteriocin and the simulations of the bacteriocin on the surface of a model lipid bilayer, structure activity relationships are proposed. These studies allow us to generate hypotheses that relate biophysical interactions observed in simulations with the experimentally measured activity. We find that single-site amino acid substitutions result in markedly stronger antimicrobial activity when they strengthen the interactions between the two peptides, while, concomitantly, they weaken peptide-membrane association. This effect is more pronounced in the case of the PlnE mutant (G20A), which interacts the strongest with PlnF and the weakest with the membrane while displaying the highest activity. PMID- 26774215 TI - Functional characterization of solute carrier (SLC) 26/sulfate permease (SulP) proteins in membrane mimetic systems. AB - Solute carrier (SLC) 26 or sulfate permease (SulP) anion transporters, belong to a phylogenetically ancient family of secondary active transporters. Members of the family are involved in several human genetic diseases and cell physiological processes. Despite their importance, the substrates for transport by this family of proteins have been poorly characterized. In this study, recombinant StmYchM/DauA, a SulP from Salmonella typhimurium was purified to homogeneity and functionally characterized. StmYchM/DauA was found to be a dimer in solution as determined by size exclusion chromatography coupled to multiple angle light scattering. We report a functional characterization of the SulP proteins in two membrane mimetic systems and reveal a dual nature of anionic substrates for SulP. StmYchM/DauA functionally incorporated into nanodiscs could bind fumarate with millimolar affinities (KD = 4.6 +/- 0.29 mM) as detected by intrinsic tryptophan fluorescence quench studies. In contrast, electrophysiological experiments performed in reconstituted liposomes indicate a strong bicarbonate transport in the presence of chloride but no detectable electrogenic fumarate transport. We hence suggest that while SulP acts as an electrogenic bicarbonate transporter, fumarate may serve as substrate under different conditions indicating multiple functions of SulP. PMID- 26774216 TI - Changes in the distribution of radiocesium in the wood of Japanese cedar trees from 2011 to 2013. AB - The changes in the distribution of (137)Cs in the wood of Japanese cedar (Cryptomeria japonica) trunks within three years after the Fukushima Dai-ichi Nuclear Power Plant (FDNP) accident in 2011 were investigated. Thirteen trees were felled to collect samples at 6 forests in 2 regions of the Fukushima prefecture. The radial distribution of (137)Cs in the wood was measured at different heights. Profiles of (137)Cs distribution in the wood changed considerably from 2011 to 2013, and the process of (137)Cs distribution change in the wood was clarified. From 2011 to 2012, the active transportation from sapwood to heartwood and the radial diffusion in heartwood proceeded quickly, and the radial (137)Cs distribution differed according to the vertical positon of trees. From 2012 to 2013, the vertical diffusion of (137)Cs from the treetop to the ground, probably caused by the gradient of (137)Cs concentration in the trunk, was observed. Eventually, the radial (137)Cs distributions were nearly identical at any vertical positions in 2013. Our results suggested that the active transportation from sapwood to heartwood and the vertical and radial diffusion in heartwood proceeded according to the vertical position of the tree and (137)Cs distribution in the wood approached the equilibrium state within three years after the accident. PMID- 26774217 TI - The effect of childhood bilectalism and multilingualism on executive control. AB - Several investigations report a positive effect of childhood bilingualism on executive control (EC). An issue that has remained largely unexamined is the role of the typological distance between the languages spoken by bilinguals. In the present study we focus on children who grow up with Cypriot Greek and Standard Modern Greek, two closely related varieties that differ from each other on all levels of language analysis (vocabulary, pronunciation, grammar). We compare the EC performance of such bilectal children to that of English-Greek multilingual children in Cyprus and Standard Modern Greek-speaking monolingual children in Greece. A principal component analysis on six indicators of EC revealed two distinct factors, which we interpreted as representing working memory and inhibition. Multilingual and bilectal children exhibited an advantage over monolinguals that was evident across EC factors and emerged only after statistically controlling for their lower language proficiency. These results demonstrate that similar EC advantages as previously reported for 'true' bilingual speakers can be found in bilectal children, which suggests that minimal typological distance between the varieties spoken by a child suffices to give rise to advantages in EC. They further indicate that the effect of speaking more than one language or dialect on EC performance is located across the EC system without a particular component being selectively affected. This has implications for models of the locus of the bilingual advantage in EC performance. Finally, they show that the emergence of EC advantages in bilinguals is moderated by the level of their language proficiency. PMID- 26774218 TI - Findings questioning the involvement of Sigma-1 receptor in the uptake of anisamide-decorated particles. AB - Anisamide is a small benzamide previously suggested as a tumor-targeting ligand for nanocarriers and it has been shown to enhance tumor uptake in vitro as well as in vivo when grafted on the nanoparticle surface. Anisamide has been hypothesized to interact with the Sigma-1 receptor, based on the binding of larger benzamides, which contain anisamide in their structure, to this receptor. However, the interaction between anisamide and Sigma-1 receptor has never been thoroughly studied. We developed fluorescent PEGylated particles decorated with anisamide, which were preferentially taken up in vitro by melanoma cells compared to macrophages. The anisamide-decorated particles were used to study their interaction with the Sigma-1 receptor. The absence of competition of Sigma-1 receptor ligands for the particle uptake was a first indication that the receptor might not be involved in the uptake process. In addition, the extent of particle uptake did not correlate with the levels of cellular expression of Sigma-1 receptor in the cell models tested. Immunostaining of the receptor on melanoma cells revealed intracellular localization, indirectly excluding the possibility of anisamide binding to the receptor when grafted on the particles. All these data question the previously suggested Sigma-1 receptor-mediated uptake of the anisamide-decorated particles, a finding which may have an impact on the use of anisamide as a targeting ligand. PMID- 26774219 TI - Layered double hydroxides as effective carrier for anticancer drugs and tailoring of release rate through interlayer anions. AB - Hydrophobic anticancer drug, raloxifene hydrochloride (RH) is intercalated into a series of magnesium aluminum layered double hydroxides (LDHs) with various charge density anions through ion exchange technique for controlled drug delivery. The particle nature of the LDH in presence of drug is determined through electron microscopy and surface morphology. The release of drug from the RH intercalated LDHs was made very fast or sustained by altering the exchangeable anions followed by the modified Freundlich and parabolic diffusion models. The drug release rate is explained from the interactions between the drug and LDHs along with order disorder structure of drug intercalated LDHs. Nitrate bound LDH exhibits greater interaction with drug and sustained drug delivery against the loosely interacted phosphate bound LDH-drug, which shows fast release. Cell viability through MTT assay suggests drug intercalated LDHs as better drug delivery vehicle for cancer cell line against poor bioavailability of the pure drug. In vivo study with mice indicates the differential tumor healing which becomes fast for greater drug release system but the body weight index clearly hints at damaged organ in the case of fast release system. Histopathological experiment confirms the damaged liver of the mice treated either with pure drug or phosphate bound LDH-drug, fast release system, vis-a-vis normal liver cell morphology for sluggish drug release system with steady healing rate of tumor. These observations clearly demonstrate that nitrate bound LDH nanoparticle is a potential drug delivery vehicle for anticancer drugs without any side effect. PMID- 26774220 TI - Intranasal delivery of bFGF with nanoliposomes enhances in vivo neuroprotection and neural injury recovery in a rodent stroke model. AB - Basic fibroblast growth factor (bFGF) may protect stroke patients from cerebral ischemia-reperfusion (I/R) injury. In this study, we report the intranasal use of novel nanoliposomes for the brain delivery of bFGF in a rat model of cerebral I/R. Compared with free bFGF, nanoliposomal therapy was able to significantly improve bFGF accumulation in brain tissues (p<0.05) including the most affected ischemic penumbra regions (e.g. hippocampus, pallium). After intranasal bFGF nanoliposomal treatment for 3 consecutive days, functional recovery as indicated by improved neurologic deficit score and spontaneous locomotor activity was observed, and the stroke infarct volume was nearly halved (p<0.001) which persisted after 21days. These neuroprotective effects could be blocked by the PI3 K/Akt inhibitor LY294002, indicating the involvement of PI3-K/Akt activation in the therapeutic action. Overall, our results support the intranasal use of nanoliposomal bFGF as an efficient, non-invasive means to bypass the blood-brain barrier for ischemic stroke treatment. PMID- 26774221 TI - Induction of broad immunity by thermostabilised vaccines incorporated in dissolvable microneedles using novel fabrication methods. AB - Dissolvable microneedle (DMN) patches for immunization have multiple benefits, including vaccine stability and ease-of-use. However, conventional DMN fabrication methods have several drawbacks. Here we describe a novel, microfluidic, drop dispensing-based dissolvable microneedle production method that overcomes these issues. Uniquely, heterogeneous arrays, consisting of microneedles of diverse composition, can be easily produced on the same patch. Robustness of the process was demonstrated by incorporating and stabilizing adenovirus and MVA vaccines. Clinically-available trivalent inactivated influenza vaccine (TIV) in DMN patches is fully stable for greater than 6months at 40 degrees C. Immunization using low dose TIV-loaded DMN patches induced significantly higher antibody responses compared to intramuscular-based immunization in mice. TIV-loaded patches also induced a broader, heterosubtypic neutralizing antibody response. By addressing issues that will be faced in large scale fill-finish DMN fabrication processes and demonstrating superior thermostable characteristics and immunogenicity, this study progresses the translation of this microneedle platform to eventual clinical deployment. PMID- 26774222 TI - Controlled release of a microencapsulated arduous semi-hydrophobic active from coatings: Superhydrophilic polyelectrolyte shells as globally rate-determining barriers. AB - Polymethylmethacrylate-based microcapsules containing the antimicrobial agent 2-n octyl-4-isothiazolin-3-one (OIT) decorated by an anchored polyelectrolyte brush consisting of an amphiphilic diblock copolymer of polymethylmethacrylate-block poly(sodium methacrylate) type have been formulated via a coacervation technique. The polyelectrolyte brush surface provided the microcapsule with a high and stable surface charge density. This enabled further surface modification of the colloidal particle with a thin and dense polyelectrolyte multilayer using the layer-by-layer technique. The addition of the highly charged and hydrophilic polyelectrolyte multilayer assembled on the microcapsule surface resulted in a considerable decrease of the release rate of the encapsulated OIT in aqueous suspension, corresponding to a 40 times reduction of the effective OIT diffusion coefficient in the polymethylmethacrylate matrix. Moreover, the release of encapsulated or freely dispersed OIT from coatings as a function of the matrix density was evaluated and analyzed within the framework of applied diffusion models. Encapsulation of OIT in polyelectrolyte multilayer composite microcapsules was found to significantly prolong the release and render the release rate more or less independent of the matrix density. In addition, the long-term antimicrobial properties of the coatings were evaluated in terms of their susceptibility for biofouling using the fungus and common biofouler Aspergillus niger as model organism. The results clearly demonstrated that the use of encapsulated OIT gave a significantly prolonged surface protection and allowed for the determination of the critical surface flux. The polyelectrolyte multilayer has therefore been recognized as the rate-determining barrier for OIT. The matrix density has a minor influence on the release rate of encapsulated OIT from these microcapsules and this concept may very well be expanded to cover a broad range of hydrophobic and semi-hydrophobic biocides. PMID- 26774223 TI - Acoustic Cluster Therapy (ACT) - pre-clinical proof of principle for local drug delivery and enhanced uptake. AB - Proof of principle for local drug delivery with Acoustic Cluster Therapy (ACT) was demonstrated in a human prostate adenocarcinoma growing in athymic mice, using near infrared (NIR) dyes as model molecules. A dispersion of negatively charged microbubble/positively charged microdroplet clusters are injected i.v., activated within the target pathology by diagnostic ultrasound (US), undergo an ensuing liquid-to-gas phase shift and transiently deposit 20-30MUm large bubbles in the microvasculature, occluding blood flow for ~5-10min. Further application of low frequency US induces biomechanical effects that increase the vascular permeability, leading to a locally enhanced extravasation of components from the vascular compartment (e.g., released or co-administered drugs). Results demonstrated deposition of activated bubbles in tumor vasculature. Following ACT treatment, a significant and tumor specific increase in the uptake of a co administered macromolecular NIR dye was shown. In addition, ACT compound loaded with a lipophilic NIR dye to the microdroplet component was shown to facilitate local release and tumor specific uptake. Whereas the mechanisms behind the observed increased and tumor specific uptake are not fully elucidated, it is demonstrated that the ACT concept can be applied as a versatile technique for targeted drug delivery. PMID- 26774224 TI - Nanoparticle-liver interactions: Cellular uptake and hepatobiliary elimination. AB - 30-99% of administered nanoparticles will accumulate and sequester in the liver after administration into the body. This results in reduced delivery to the targeted diseased tissue and potentially leads to increased toxicity at the hepatic cellular level. This review article focuses on the inter- and intra cellular interaction between nanoparticles and hepatic cells, the elimination mechanism of nanoparticles through the hepatobiliary system, and current strategies to manipulate liver sequestration. The ability to solve the "nanoparticle-liver" interaction is critical to the clinical translation of nanotechnology for diagnosing and treating cancer, diabetes, cardiovascular disorders, and other diseases. PMID- 26774225 TI - Big tobacco, E-cigarettes, and a road to the smoking endgame. AB - The provision of the extraordinarily deadly product of cigarettes is dominated by a small number of large and incredibly profitable shareholder owned companies that are focussed on cigarettes. The legal duty of their managers to maximise shareholder wealth means that such companies vigorously fight any new public health measures that have the potential to disrupt their massive profit making, and have the resources to do so. Protecting the public health is therefore made a lot more difficult and expensive. We suggest that one way to counter this would be to actively design future tobacco control policies so that tobacco companies face mechanisms and incentives to develop in such a way that they no longer achieve the greatest shareholder value by focusing on cigarettes. A proper tobacco diversification and exit strategy for the shareholders of the profit seeking tobacco industry would protect the public health by addressing the current addiction to the continuation of the cigarette market. The increasing popularity of e-cigarettes presents a particular opportunity in this regard, and we therefore suggest a possible policy response in order to start discussion in this area. PMID- 26774226 TI - Healthcare satisfaction in older and younger patients with cancer. AB - OBJECTIVE: Although older patients represent the most rapidly growing segment of the oncology population, clinical care is guided by very little data on patient reported outcomes, particularly satisfaction with healthcare. Using a large cancer center registry, we sought to describe factors associated with satisfaction with care for older and younger oncology patients. METHODS: Data were collected through the University of North Carolina Health Registry Cancer Survivorship Cohort. Satisfaction was measured with the Patient Satisfaction Questionnaire Short Form. Quality of life (QOL) measures included were the Promis Global short form and the Functional Assessment of Cancer Therapy General (FACT G). RESULTS: A total of 2385 patients were included. 460 (20%) were aged 70 and above (older group). Older patients reported significantly higher levels of satisfaction in domains of time spent with doctor (scores 3.84 versus 3.73 p=0.03) and financial aspects (scores 4.03 versus 3.44 p<0.001) compared to younger patients. In multivariable analysis, higher QOL scores and higher self reported ECOG performance status were associated with higher satisfaction scores. African American race was associated with lower satisfaction scores in all age groups. QOL was more closely correlated with satisfaction in older patients compared to younger patients. CONCLUSIONS: Older patients with cancer report higher levels of satisfaction with care, in part due to lesser financial burden of care. Better QOL is associated with satisfaction with care in older patients. Use of patient-reported outcomes such as patient satisfaction may help improve patient-centered geriatric oncology care. PMID- 26774227 TI - High homocysteine and epistasis between MTHFR and APOE: association with cognitive performance in the elderly. AB - High total homocysteine (tHcy) is associated with cognitive impairment in the elderly. The impact of high tHcy on different cognitive domains deserves further investigation, as does the role of the C677T polymorphism of the 5,10 methylenetetrahydrofolate reductase (MTHFR) gene. A cross-sectional analysis of 903 subjects from the population-based "InveCe.Ab" study was performed. The participants had no psychosis or active neurological disorders. They underwent a neuropsychological assessment. Principal component analysis allowed cognitive performance to be condensed into two components: executive functions and memory. Novel components were evaluated for association with tHcy, controlling for potential confounders. Regression models showed that high serum tHcy was associated with lower executive functions, but not with memory. MTHFR C677T TT was associated with higher tHcy but did not affect cognitive performance per se. However, when combined with the apolipoprotein E (APOE)-epsilon4 allele, it was a risk factor for lower executive performance, independently of tHcy levels. In summary, high tHcy per se, or MTHFR C677T TT in combination with the APOE epsilon4 allele, might be associated primarily with executive dysfunctions rather than memory loss. PMID- 26774228 TI - Decreased bioavailability of nitric oxide in aorta from ovariectomized senescent mice. Role of cyclooxygenase. AB - This study investigates the effects of aging and/or ovariectomy on vascular reactivity to thromboxane A2 (TXA2) receptor stimulation with U46619, and the modulation by nitric oxide (NO) and cyclooxygenase (COX) in aorta from female senescence-accelerated mice (SAMP8) and from senescence resistant mice (SAMR1). Five-month-old female SAMR1 and SAMP8 were divided into three groups: sham operated, ovariectomized and ovariectomized plus estradiol. Twenty-eight days after surgery, thoracic aortic rings were mounted for isometric recording of tension and concentration-response curves for U46619 (10(-10)-3 * 10(-7) M) were performed in the absence and in the presence of the NO synthase inhibitor N(G) nitro-L-arginine methyl ester (L-NAME, 10(-4) M) and/or COX inhibitor indomethacin (10(-5)M). Vascular superoxide production was detected by dihydroethidium staining on sections of thoracic aorta. NO bioavailability in response to U46619 was suppressed by estrogen withdrawn in young and senescent mice and was restored by the administration of estradiol. In the presence of indomethacin, contractions to U46619 decreased in all groups indicating an aging- and estrogen-dependent modulation of contractile prostanoids. The simultaneous incubation of L-NAME and indomethacin did not change the maximal responses and sensitivities to TXA2 in any group in comparison with untreated aortic segments. The superoxide generation induced by TXA2 was greater in aorta from SAMP8 than in SAMR1. Moreover, in ovariectomized groups superoxide production was further increased and treatment with 17beta-estradiol reverted the effects of the ovariectomy. Inhibition of COX with indomethacin prevented the U46619-induced increase in superoxide formation. Our results indicate that NO bioavailability in response to TP receptor activation is both estrogen- and aging-dependent. TXA2 induced contractions are partially mediated by COX activation. Both aging and ovariectomy enhanced COX-dependent component of the TXA2-induced contraction. It is noteworthy that in the absence of estrogen, COX inhibition induces an increase of NO bioavailability. Therefore, in senescent female mice with an experimental menopause, TP-receptor stimulation is responsible for COX activation and enhanced superoxide generation, which may result in reduced NO bioavailability. These effects were reversed by estrogen administration. PMID- 26774229 TI - Myocardial Fractional Flow Reserve Measurement Using Contrast Media as a First Line Assessment of Coronary Lesions in Current Practice. AB - BACKGROUND: Fractional flow reserve (FFR) measurement requires adenosine injection. However, adenosine can induce conductive and rhythmic complications, or be contraindicated in some patients. Contrast-induced hyperemia could provide a simple first-line method (contrast-enhanced FFR; cFFR) to assess coronary lesions. In this study we evaluated the accuracy of cFFR to predict lesion significance. METHODS: This prospective study included 104 patients with 138 coronary lesions. Each stenosis was evaluated using resting distal coronary pressure to aortic pressure ratio (Pd/Pa) measurements using intracoronary iodixanol (cFFR) and adenosine (FFR) injection. An FFR value <= 0.8 defined a significant lesion. RESULTS: Dose-ranging analysis (n = 12 lesions) showed that 10 mL iodixanol was required to obtain the lowest cFFR value. Intermeasurement reproducibility of cFFR (n = 18 lesions) showed limited variability and small mean estimated bias (0.001 +/- 0.014). Values of cFFR and FFR were highly correlated in a first series of n = 36 lesions (r = 0.9; P < 0.001). Receiver operating characteristic curve analysis showed an excellent accuracy of cFFR cutoff value of <= 0.85 in predicting FFR value <= 0.80 (area under the curve, 0.94; 95% confidence interval, 0.90-0.98; sensitivity, 95%; specificity, 73%). This threshold was then tested prospectively in an independent cohort of n = 72 lesions. A cFFR value <= 0.85 correctly identified hemodynamically significant lesions with a sensitivity of 100%, specificity of 78%, positive predictive value of 78%, and negative predictive value of 100%. CONCLUSIONS: cFFR is reproducible and can be achieved with usual volumes of contrast. A cFFR threshold value of 0.85 provides excellent sensitivity and negative predictive value in coronary artery stenosis. PMID- 26774230 TI - Isolated Partial Congenital Absence of the Pericardium: A Familial Presentation. AB - Congenital defects of the pericardium are uncommon heart abnormalities. Most of the patients are asymptomatic and are usually diagnosed incidentally. Complications are more common in partial absence than in complete absence of the pericardium; thus, this congenital defect should be identified because of the associated risk of sudden death. We report the first mention in the literature, to our knowledge, of a 3-generation familial presentation of isolated congenital partial absence of the pericardium with similar physical examination and radiological findings. PMID- 26774231 TI - Preprocedure Anemia Management Decreases Transfusion Rates in Patients Undergoing Transcatheter Aortic Valve Implantation. AB - BACKGROUND: Periprocedural blood transfusions are associated with long-term mortality in patients undergoing transcatheter aortic valve implantation (TAVI). We sought to assess the impact of a preoperative blood conservation approach in treating anemia and preventing blood transfusions in patients undergoing TAVI. METHODS: Our cohort consisted of all patients evaluated in our structural heart clinic between January 1, 2012 and December 31, 2014. From March 2013, all anemic TAVI candidates were referred to the blood conservation clinic (BCC). We evaluated the effectiveness of the program to increase hemoglobin levels and to decrease the blood transfusion rates in the TAVI cohort. A multivariable logistic regression model was used to evaluate the association of being assessed by the BCC with receipt of a blood transfusion. RESULTS: The cohort included 239 patients, 62% of whom were anemic. Beginning in March 2013, 60 patients were evaluated in the BCC and treated with intravenous/oral iron or subcutaneous epoetin alfa, or both. Patients who underwent blood conservation had a significant increase in hemoglobin levels from 10.8 +/- 1.1 g/dL to 11.8 +/- 1.2 g/dL (P < 0.001). Implementation of the BCC was associated with a substantial decrease in the average blood transfusion rate from 33.3% before program initiation to 15.3% after implementation (P < 0.001). After adjusting for baseline hemoglobin values and comorbidities, being assessed at the BCC was strongly associated with a reduction in the need for transfusion (odds ratio, 0.28; 95% confidence interval, 0.11-0.69; P = 0.006). CONCLUSIONS: Preprocedural anemia management was successful in improving hemoglobin levels in anemic patients and in decreasing transfusion rates in TAVI. PMID- 26774232 TI - In-Stent Restenosis Caused by a Calcified Nodule: A Novel Pattern of Neoatherosclerosis. AB - Neoatherosclerosis has been described as a cause of in-stent restenosis (ISR), particularly in patients treated with drug-eluting stents (DESs). Although neoatherosclerosis may present as calcified plaques, the occurrence of a "calcified nodule" within the stent has not been previously reported. We describe optical coherence tomographic findings in a patient presenting with a calcified nodule causing "undilatable" ISR 2 years after implantation of a DES. The clinical and technical implications of this novel pattern of neoatherosclerosis are discussed. PMID- 26774233 TI - Cardiopulmonary Exercise Testing and Outcomes in Women With Heart Failure Examining the "Female Advantage". PMID- 26774234 TI - Are We Endangering Hypertensive Patients by Overzealous Treatment That Induces Diastolic Hypotension? A SPRINT to the Answer? PMID- 26774235 TI - Values and Preferences of Physicians and Patients With Nonvalvular Atrial Fibrillation Who Receive Oral Anticoagulation Therapy for Stroke Prevention. AB - BACKGROUND: Real-world data on patients' and physicians' values related to the use of oral anticoagulant (OAC) therapy for stroke prevention in patients with nonvalvular atrial fibrillation are currently lacking. We sought to assess the values, preferences, and experience of patients who receive OAC therapy, and of physicians who prescribe OAC therapy. METHODS: A national survey of randomly selected patients (n = 266) and physicians (n = 178) was conducted between May and September 2014. Each was asked to evaluate the importance of individual OAC attributes and identify which of 2 medication profiles they would prefer (individual attributes were progressively modified to determine which were the most valued and/or influenced treatment choice). Medication adherence and prescription practice was also assessed. RESULTS: The preferences of patients and physicians regarding OAC therapy differed but largely focused on characteristics related to safety and, to a lesser extent, efficacy. When based solely on the basis of the attribute profile (blinded to the specific agent), physicians were more likely to select apixaban (61%), whereas patients showed no significant preference among apixaban, rivaroxaban, and warfarin. Despite this, 49% of physicians spontaneously stated rivaroxaban as their preferred agent (vs 25% apixaban). Patients prescribed and taking once daily medications (rivaroxaban or warfarin) showed better compliance with their OAC therapy (approximately 30% of twice daily medications being taken once daily, with significantly more missed doses compared with once daily medications). CONCLUSIONS: Real-world prescriptions do not reflect reported values, which suggests that other factors influence patient-physician decision-making around OAC therapy. Data on self reported adherence to OAC therapy and discordance in the use of OACs from prescribed regimens are concerning and warrant further investigation. PMID- 26774236 TI - Analysis and visualization of intracardiac electrograms in diagnosis and research: Concept and application of KaPAVIE. AB - BACKGROUND AND OBJECTIVE: Progress in biomedical engineering has improved the hardware available for diagnosis and treatment of cardiac arrhythmias. But although huge amounts of intracardiac electrograms (EGMs) can be acquired during electrophysiological examinations, there is still a lack of software aiding diagnosis. The development of novel algorithms for the automated analysis of EGMs has proven difficult, due to the highly interdisciplinary nature of this task and hampered data access in clinical systems. Thus we developed a software platform, which allows rapid implementation of new algorithms, verification of their functionality and suitable visualization for discussion in the clinical environment. METHODS: A software for visualization was developed in Qt5 and C++ utilizing the class library of VTK. The algorithms for signal analysis were implemented in MATLAB. Clinical data for analysis was exported from electroanatomical mapping systems. RESULTS: The visualization software KaPAVIE (Karlsruhe Platform for Analysis and Visualization of Intracardiac Electrograms) was implemented and tested on several clinical datasets. Both common and novel algorithms were implemented which address important clinical questions in diagnosis of different arrhythmias. It proved useful in discussions with clinicians due to its interactive and user-friendly design. Time after export from the clinical mapping system to visualization is below 5min. CONCLUSION: KaPAVIE(2) is a powerful platform for the development of novel algorithms in the clinical environment. Simultaneous and interactive visualization of measured EGM data and the results of analysis will aid diagnosis and help understanding the underlying mechanisms of complex arrhythmias like atrial fibrillation. PMID- 26774237 TI - A new e-learning platform for radiology education (RadEd). AB - One of the key elements of e-learning platforms is the content provided to the students. Content creation is a time demanding task that requires teachers to prepare material taking into account that it will be accessed on-line. Moreover, the teacher is restricted by the functionalities provided by the e-learning platforms. In contexts such as radiology where images have a key role, the required functionalities are still more specific and difficult to be provided by these platforms. Our purpose is to create a framework to make teacher's tasks easier, specially when he has to deal with contents where images have a main role. In this paper, we present RadEd, a new web-based teaching framework that integrates a smart editor to create case-based exercises that support image interaction such as changing the window width and the grey scale used to render the image, taking measurements on the image, attaching labels to images and selecting parts of the images, amongst others. It also provides functionalities to prepare courses with different topics, exercises and theory material, and also functionalities to control students' work. Different experts have used RadEd and all of them have considered it a very useful and valuable tool to prepare courses where radiological images are the main component. RadEd provides teachers functionalities to prepare more realistic cases and students the ability to make a more specific diagnosis. PMID- 26774238 TI - Aid decision algorithms to estimate the risk in congenital heart surgery. AB - BACKGROUND AND OBJECTIVE: In this paper, we have tested the suitability of using different artificial intelligence-based algorithms for decision support when classifying the risk of congenital heart surgery. In this sense, classification of those surgical risks provides enormous benefits as the a priori estimation of surgical outcomes depending on either the type of disease or the type of repair, and other elements that influence the final result. This preventive estimation may help to avoid future complications, or even death. METHODS: We have evaluated four machine learning algorithms to achieve our objective: multilayer perceptron, self-organizing map, radial basis function networks and decision trees. The architectures implemented have the aim of classifying among three types of surgical risk: low complexity, medium complexity and high complexity. RESULTS: Accuracy outcomes achieved range between 80% and 99%, being the multilayer perceptron method the one that offered a higher hit ratio. CONCLUSIONS: According to the results, it is feasible to develop a clinical decision support system using the evaluated algorithms. Such system would help cardiology specialists, paediatricians and surgeons to forecast the level of risk related to a congenital heart disease surgery. PMID- 26774239 TI - Colistin resistance gene mcr-1 and pHNSHP45 plasmid in human isolates of Escherichia coli and Klebsiella pneumoniae. PMID- 26774240 TI - Possible genetic events producing colistin resistance gene mcr-1. PMID- 26774241 TI - Combination therapies for malaria are failing--what next? PMID- 26774242 TI - Colistin resistance gene mcr-1 in extended-spectrum beta-lactamase-producing and carbapenemase-producing Gram-negative bacteria in Germany. PMID- 26774244 TI - Co-occurrence of extended spectrum beta lactamase and MCR-1 encoding genes on plasmids. PMID- 26774245 TI - Investigation of a plasmid genome database for colistin-resistance gene mcr-1. PMID- 26774243 TI - Dihydroartemisinin-piperaquine resistance in Plasmodium falciparum malaria in Cambodia: a multisite prospective cohort study. AB - BACKGROUND: Artemisinin resistance in Plasmodium falciparum threatens to reduce the efficacy of artemisinin combination therapies (ACTs), thus compromising global efforts to eliminate malaria. Recent treatment failures with dihydroartemisinin-piperaquine, the current first-line ACT in Cambodia, suggest that piperaquine resistance may be emerging in this country. We explored the relation between artemisinin resistance and dihydroartemisinin-piperaquine failures, and sought to confirm the presence of piperaquine-resistant P falciparum infections in Cambodia. METHODS: In this prospective cohort study, we enrolled patients aged 2-65 years with uncomplicated P falciparum malaria in three Cambodian provinces: Pursat, Preah Vihear, and Ratanakiri. Participants were given standard 3-day courses of dihydroartemisinin-piperaquine. Peripheral blood parasite densities were measured until parasites cleared and then weekly to 63 days. The primary outcome was recrudescent P falciparum parasitaemia within 63 days. We measured piperaquine plasma concentrations at baseline, 7 days, and day of recrudescence. We assessed phenotypic and genotypic markers of drug resistance in parasite isolates. The study is registered with ClinicalTrials.gov, number NCT01736319. FINDINGS: Between Sept 4, 2012, and Dec 31, 2013, we enrolled 241 participants. In Pursat, where artemisinin resistance is entrenched, 37 (46%) of 81 patients had parasite recrudescence. In Preah Vihear, where artemisinin resistance is emerging, ten (16%) of 63 patients had recrudescence and in Ratanakiri, where artemisinin resistance is rare, one (2%) of 60 patients did. Patients with recrudescent P falciparum infections were more likely to have detectable piperaquine plasma concentrations at baseline compared with non recrudescent patients, but did not differ significantly in age, initial parasite density, or piperaquine plasma concentrations at 7 days. Recrudescent parasites had a higher prevalence of kelch13 mutations, higher piperaquine 50% inhibitory concentration (IC50) values, and lower mefloquine IC50 values; none had multiple pfmdr1 copies, a genetic marker of mefloquine resistance. INTERPRETATION: Dihydroartemisinin-piperaquine failures are caused by both artemisinin and piperaquine resistance, and commonly occur in places where dihydroartemisinin piperaquine has been used in the private sector. In Cambodia, artesunate plus mefloquine may be a viable option to treat dihydroartemisinin-piperaquine failures, and a more effective first-line ACT in areas where dihydroartemisinin piperaquine failures are common. The use of single low-dose primaquine to eliminate circulating gametocytes is needed in areas where artemisinin and ACT resistance is prevalent. FUNDING: National Institute of Allergy and Infectious Diseases. PMID- 26774246 TI - Plasmid-mediated carbapenem and colistin resistance in a clinical isolate of Escherichia coli. PMID- 26774247 TI - Colistin resistance gene mcr-1 harboured on a multidrug resistant plasmid. PMID- 26774248 TI - Colistin-resistant Escherichia coli harbouring mcr-1 isolated from food animals in Hanoi, Vietnam. PMID- 26774249 TI - Assessing the evidentiary value of smokeless powder comparisons. AB - Gas chromatography-electron ionization-mass spectrometry (GC-EI-MS) and physical characteristics data for 726 smokeless reloading powders were analyzed by pairwise comparisons of samples comprising the same product and different products. Pairwise comparisons were restricted to samples having matching kernel shape, color, presence or absence of a perforation and measurements. Discrete results were analyzed for same and different products having matching chemical composition determined from a list of 13 organic components. A continuous score based likelihood ratio was determined for same and different product comparisons using the Fisher transform of the Pearson correlation between the total ion spectra of the compared samples. Probability distributions for same product and different product comparisons appeared bimodal and were modeled with kernel density distributions. In the discrete and continuous data comparisons, the likelihood ratios for probabilities conditioned on same shape, color, presence/absence of perforation and size were found to provide relatively limited support for either the proposition of same product or different product. Further restricting the pairwise comparisons to samples belonging to the same cluster, as determined by agglomerative hierarchical cluster analysis, provided probability distributions for same product and different product comparisons that were more normal, but did not improve the resulting likelihood ratios. These results inform the forensic analyst regarding the evidentiary value of database search results and direct comparisons of recovered and control samples of smokeless powders. PMID- 26774250 TI - Automatic forensic analysis of automotive paints using optical microscopy. AB - The timely identification of vehicles involved in an accident, such as a hit-and run situation, bears great importance in forensics. To this end, procedures have been defined for analyzing car paint samples that combine techniques such as visual analysis and Fourier transform infrared spectroscopy. This work proposes a new methodology in order to automate the visual analysis using image retrieval. Specifically, color and texture information is extracted from a microscopic image of a recovered paint sample, and this information is then compared with the same features for a database of paint types, resulting in a shortlist of candidate paints. In order to demonstrate the operation of the methodology, a test database has been set up and two retrieval experiments have been performed. The first experiment quantifies the performance of the procedure for retrieving exact matches, while the second experiment emulates the real-life situation of paint samples that experience changes in color and texture over time. PMID- 26774251 TI - Analytical assessment of woven fabrics under vertical stabbing - The role of protective clothing. AB - Knives are being used more commonly in street fights and muggings. Therefore, this work presents an analytical model for woven fabrics under vertical stabbing loads. The model is based on energy method and the fabric is assumed to be unidirectional comprised of N layers. Thus, the ultimate stab resistance of fabric was determined based on structural parameters of fabric and geometrical characteristics of blade. Moreover, protective clothing is nowadays considered as a strategic branch in technical textile industry. The main idea of the present work is improving the stab resistance of woven textiles by using metal coating method. In the final, a series of vertical stabbing tests were conducted on cotton, polyester and polyamide fabrics. Consequently, it was found that the model predicts with a good accuracy the ultimate stab resistance of the sample fabrics. PMID- 26774252 TI - Synthesis, antimicrobial evaluation and molecular modeling of 5 hydroxyisoquinolinium salt series; the effect of the hydroxyl moiety. AB - In the present paper, we describe the synthesis of a new group of 5 hydroxyisoquinolinium salts with different lengths of alkyl side-chain (C10-C18), and their chromatographic analysis and biological assay for in vitro activity against bacterial and fungal strains. We compare the lipophilicity and efficacy of hydroxylated isoquinolinium salts with the previously published (non hydroxylated) isoquinolinium salts from the point of view of antibacterial and antifungal versatility and cytotoxic safety. Compound 11 (C18) had to be excluded from the testing due to its low solubility. Compounds 9 and 10 (C14, C16) showed only moderate efficacy against G+ bacteria, notably with excellent potency against Staphyloccocus aureus, but no effect against G- bacteria. In contrast, non-hydroxylated isoquinolinium salts showed excellent antimicrobial efficacy within the whole series, particularly 14 (C14) against G+ strains and 15 (C16) against fungi. The electronic properties and desolvation energies of 5 hydroxyisoquinolinium and isoquinolinium salts were studied by quantum-chemistry calculations employing B3LYP/6-311++G(d,p) method and an implicit water-solvent simulation model (SCRF). Despite the positive mesomeric effect of the hydroxyl moiety reducing the electron density of the quaternary nitrogen, it is probably the higher lipophilicity and lower desolvation energy of isoquinolinium salts, which is responsible for enhanced antimicrobial versatility and efficacy. PMID- 26774253 TI - Synthesis and evaluation of styrylpyran fluorophores for noninvasive detection of cerebral beta-amyloid deposits. AB - The development of amyloid-specific fluorophores allows the visualization of cerebral beta-amyloid deposits using optical imaging technology. In the present study, a series of smart styrylpyran fluorophores with compact donor-acceptor architecture were designed and evaluated for noninvasive detection of cerebral beta-amyloid deposits. Spectral behavior of the fluorophores changed significantly (optical turn-on) upon binding to beta-amyloid aggregates. Computational studies were conducted to correlate the experimental Kd values with calculated binding energies, speculating the relationship between fluorophore structure and beta-amyloid affinity. In vivo studies demonstrated that PAD-2 could discriminate APP/PS1 transgenic mice from wild type controls, with specific labeling of cerebral beta-amyloid deposits confirmed by ex vivo observation. Collectively, these styrylpyran fluorophores could provide a new scaffold for the development of optical imaging probes targeting cerebral beta-amyloid deposits. PMID- 26774255 TI - Autochthonous Cryptosporidium cuniculus infection in Spain: First report in a symptomatic paediatric patient from Madrid. PMID- 26774254 TI - [Ebola virus disease: Update]. AB - The first known Ebola outbreak occurred in 1976. Since then, 24 limited outbreaks had been reported in Central Africa, but never affecting more than 425 persons. The current outbreak in Western Africa is the largest in history with 28,220 reported cases and 11,291 deaths. The magnitude of the epidemic has caused worldwide alarm. For the first time, evacuated patients were treated outside Africa, and secondary cases have occurred in Spain and the United States. Since the start of the current epidemic, our knowledge about the epidemiology, clinical picture, laboratory findings, and virology of Ebola virus disease has considerably expanded. For the first time, experimental treatment has been tried, and there have been spectacular advances in vaccine development. A review is presented of these advances in the knowledge of Ebola virus disease. PMID- 26774257 TI - Severity assessment of intracranial large artery stenosis by pressure gradient measurements: A feasibility study. AB - BACKGROUND: Fractional flow reserve (FFR)-guided revascularization strategy is popular in coronary intervention. However, the feasibility of assessing stenotic severity in intracranial large arteries using pressure gradient measurements still remains unclear. METHODS: Between March 2013 and May 2014, 12 consecutive patients with intracranial large artery stenosis (including intracranial internal carotid artery, middle cerebral M1 segment, intracranial vertebral artery, and basilar artery) were enrolled in this study. The trans-stenotic pressure gradient was measured before and/or after percutaneous transluminal angioplasty and stenting (PTAS), and was then compared with percent diameter stenosis. A Pd /Pa cut-off of <=0.70 was used to guide stenting of hemodynamically significant stenoses. The device-related and procedure-related serious adverse events and recurrent cerebral ischemic events were recorded. RESULTS: The target vessel could be reached in all cases. No technical complications occurred due to the specific study protocol. Excellent pressure signals were obtained in all patients. For seven patients who performed PTAS, the mean pre-procedural pressure gradient decreased from 59.0 +/- 17.2 to 13.3 +/- 13.6 mm Hg after the procedure (P < 0.01). Only one patient who refused stenting experienced a TIA event in the ipsilateral MCA territory. No recurrent ischemic event was observed in other patients. CONCLUSION: Mean trans-stenotic pressure gradients can be safely and easily measured with a 0.014-inch fluid-filled guide wire in intracranial large arteries. (c) 2016 Wiley Periodicals, Inc. PMID- 26774256 TI - [Prevalence and risk factors for extended-spectrum beta-lactamase-producing Escherichia coli causing community-onset urinary tract infections in Colombia]. AB - INTRODUCTION: Urinary tract infections (UTI) are common in the community. However, information of resistant isolates in this context is limited in Latin America. This study aims to determine the prevalence and risk factors associated with community-onset UTI (CO-UTI) caused by extended-spectrum beta-lactamase (ESBL)-Producing Escherichia coli in Colombia. MATERIALS AND METHODS: A case control study was conducted between August and December of 2011 in three Colombian tertiary-care institutions. All patients who were admitted to the Emergency Department with a probable diagnosis of CO-UTI were invited to participate. All participating patients were asked for a urine sample. ESBL confirmatory test, antibiotic susceptibility, and molecular epidemiology were performed in these E.coli isolates (Real Time-PCR for bla genes, repetitive element palindromic PCR [rep-PCR], multilocus sequence typing [MLST] and virulence factors by PCR). Clinical and epidemiological information was recorded, and a statistical analysis was performed. RESULTS: Of the 2124 recruited patients, 629 had a positive urine culture, 431 of which grew E.coli; 54 were positive for ESBL, of which 29 were CTX-M-15. The majority of ESBL isolates were susceptible to ertapenem, phosphomycin and amikacin. Complicated UTI was strongly associated with ESBL-producing E.coli infections (OR=3.89; 95%CI: 1.10-13.89; P=.03). CTX-M-15-producing E.coli showed 10 different pulsotypes, 65% were PT1 or PT4, and corresponded to ST131. Most of these isolates had 8 out of the 9 analysed virulence factors. DISCUSSION: E.coli harbouring blaCTX-M-15 associated with ST131 is still frequent in Colombia. The presence of complicated CO-UTI increases the risk of ESBL-producing E.coli, and must be taken into account in order to provide an adequate empirical therapy. PMID- 26774258 TI - Developmental changes in the influence of conventional and instrumental cues on over-imitation in 3- to 6-year-old children. AB - Previous studies have shown that children in the preschool period are fastidious imitators who copy models with such high levels of fidelity that task efficiency may be compromised. This over-imitative tendency, and the pervasive nature of it, has led to many explorations and theoretical interpretations of this behavior, including social, causal, and conventional explanations. In support of the conventional account, recent research has shown that children are more likely to over-imitate when the task is framed using conventional verbal cues than when it is framed using instrumental verbal cues. The aim of the current study was to determine whether 3- to 6-year-old children (N=185, mean age=60 months) would over-imitate when presented with instrumental and conventional verbal cues, which varied only minimally and were more directly comparable between instrumental and conventional contexts than those used in previous studies. In addition to varying the overall context, we also varied the instrumental prompt used such that the cues provided ranged in the extent to which they provided explicit instruction to omit the irrelevant actions. Counter to our predictions, and the high levels of over-imitation witnessed in previous studies, the older children frequently over imitated irrespective of the context provided, whereas the youngest children over imitated selectively, including the irrelevant actions only when the task was presented in a conventional frame. We propose that the age differences found following an instrumental presentation are a result of the youngest children being more open to the motivation of learning the causality of the task, whereas the older children were more strongly motivated to adopt a social convention. PMID- 26774259 TI - Integrating across episodes: Investigating the long-term accessibility of self derived knowledge in 4-year-old children. AB - Semantic memory, defined as our store of knowledge about the world, provides representational support for all of our higher order cognitive functions. As such, it is crucial that the contents of semantic memory remain accessible over time. Although memory for knowledge learned through direct observation has been investigated previously, we know very little about the retention of knowledge derived through integration of information acquired across separate learning episodes. The current research investigated cross-episode integration in 4-year old children. Participants were presented with novel facts via distinct story episodes and tested for knowledge extension through cross-episode integration as well as for retention of the information over a 1-week delay. In Experiment 1, children retained the self-derived knowledge over the delay, although performance was primarily evidenced in a forced-choice format. In Experiment 2, we sought to facilitate the accessibility and robustness of self-derived knowledge by providing a verbal reminder after the delay. The accessibility of self-derived knowledge increased irrespective of whether participants successfully demonstrated knowledge of the integration facts during the first visit. The results suggest that knowledge extended through integration remains accessible after delays even in a population where this learning process is less robust. The findings also demonstrate the facilitative effect of reminders on the accessibility and further extension of knowledge over extended time periods. PMID- 26774262 TI - Use of strong anion exchange resins for the removal of perfluoroalkylated substances from contaminated drinking water in batch and continuous pilot plants. AB - In recent years abnormally high levels of perfluoroalkylated substances (PFAS) have been detected both in surface and underground water sampled in an area covering approximately 150 square kilometers in the Veneto region (Italy) indicating the presence of a pollution point source (fluorochemicals production plant). Adsorption on granular activated carbon is an emergency measure which is poorly effective requiring frequent replacement. This work focuses on the application of three strong anion exchange resins (Purolite(r) A520E, A600E and A532E) for the removal of traces of PFOA, PFOS, PFBA and PFBS (concentration of hundreds of ng L(-1)) from drinking water. This technology is attractive for the possibility of reusing resins after an in-situ regeneration step. A strong relationship between the hydrophobicity of the exchange functional group of the resin and its capacity in removing PFAS exists. A600E (non hydrophobic) and A520E (fairly hydrophobic) show a reduced sorption capacity compared to A532E (highly hydrophobic). While A600E and A520E can be regenerated with solvent-less dilute solutions of non-toxic NH4Cl and NH4OH, A532E requires concentrated solutions of methanol or ethanol and 1% NH4Cl and for the sake of this work it was regarded as non-regenerable. The volume of regeneration effluents requiring incineration can be efficiently reduced by more than 96.5% by using reverse osmosis coupled with under-vacuum evaporation. Transmission electron analysis on saturated resins showed that large molecular macro-aggregates of PFAS can form in the intraparticle pores of resin indicating that ion exchange is not the only mechanism involved in PFAS removal. PMID- 26774261 TI - DAS steered therapy in clinical practice; cross-sectional results from the METEOR database. AB - BACKGROUND: Little is known on how well targeted treatment, for instance targeting towards low DAS, is implemented in clinical practice. Our aim was to evaluate treatment adjustments in response to DAS in RA patients in clinical practice. METHODS: We used data from one referral centre, multiple rheumatologists, from the METEOR database. Generalized Estimating Equations (GEE) were used to assess whether in case of non-low disease activity (DAS > 2.4) treatment intensifications in DMARD therapy occurred ((change or increase in dose or number of DMARDs, including synthetic (s)DMARDs, biologic (b)DMARDs and corticosteroids compared to the visit before)). Determinants of not intensifying the treatment when DAS > 2.4 were investigated using GEE. RESULTS: Five thousand one hundred fifty-seven registered visits of 1202 patients were available for the analyses. A DAS > 2.4 was weakly (OR: 1.19; 95% CI 1.07-1.33) associated with a treatment intensification. In 69% (n = 3577) of the visits patients were in low disease activity. In 66% (n = 1028) of the visits with DAS > 2.4 treatment was not intensified. These patients had a higher tender joint count and received more often methotrexate plus a bDMARD, or csDMARD monotherapy, as compared to patients that received treatment intensification. CONCLUSION: In the majority of visits in the METEOR database patients were already in a state of low disease activity, reflecting appropriate treatment intensity. When DAS was greater than 2.4, treatment was often not intensified due to high tender joint count or specific treatment combinations. This data suggest that while aiming for low DAS, physicians per patient weigh whether all DAS elements indicate disease activity or will respond to DMARD adjustment or not, and make treatment decisions accordingly. PMID- 26774260 TI - Autoantibody signatures defined by serological proteome analysis in sera from patients with cholangiocarcinoma. AB - BACKGROUND: The challenging diagnosis and poor prognosis of cholangiocarcinoma require the determination of biomarkers. Autoantibodies could be used in the clinic as diagnostic markers for the early detection of tumours. By proteomic approaches, several autoantibodies were proposed as potential markers. We tried in this study, to perform a serological proteome analysis, using various antigenic substrates, including tumours and human liver. METHODS: Sera from patients (n = 13) and healthy donors (n = 10) were probed on immunoblots performed using 2-dimensionally separated proteins from cholangiocarcinoma cell lines (CCLP1 and CCSW1), from the liver of healthy subject and interestingly, from tumour and adjacent non-tumour liver tissues from five patients with cholangiocarcinoma and tested with their corresponding serum. Spots of interest were identified using mass spectrometry and classified according gene ontology analysis. RESULTS: A comparison of the whole immunoblotting patterns given by cholangiocarcinoma sera against those obtained with normal control sera enabled the definition of 862 spots. Forty-five different proteins were further analysed, corresponding to (1) spots stained with more than four of 13 (30 %) sera tested with the CCLP1 or the CCSW1 cell line and with the normal liver, and (2) to spots immunoreactive with at least two of the five sera probed with their tumour and non-tumour counter-part of cholangiocarcinoma. Immunoreactive proteins with catalytic activity as molecular function were detected at rates of 93 and 64 % in liver from healthy subjects or cholangiocarcinoma non-tumour tissues respectively, compared to 43, 33, 33 % in tumour tissues, or CCSW1 and CCLP1 cell lines. A second pattern was represented by structural proteins with rates of 7 and 7 % in normal liver or non-tumour tissues compared to 14, 33 and 67 % in tumour tissue, CCSW1 or CCLP1 cell lines. Proteins with a binding function were detected at rates of 7 % in non-tumour tissue and 14 % in tumour tissue. Using the extracted tumour tissue, serotransferrin was targeted by all cholangiocarcinoma-related sera. CONCLUSIONS: Immunological patterns depended on the type of antigen substrate used; i.e. tumour versus non tumour specimens. Nevertheless, a combination of multiple autoantibodies tested with the most appropriate substrate might be more sensitive and specific for the diagnosis of cholangiocarcinoma. PMID- 26774263 TI - Impact of natural organic matter properties on the kinetics of suspended ion exchange process. AB - Removal kinetics of four standard organic matter isolates under the application of strongly basic ion exchange resins (IEX) in suspended mode was studied under commercial application conditions. Suwannee River natural organic matter (SRNOM), SR fulvic acid (SRFA), and Pony Lake fulvic acid (PLFA) were greatly removed (>90%) and highly preferred by IEX resins (alpha > 5, over Cl(-), and HCO3(-)) while SR humic acid (SRHA) was the least preferred organic structure among the four isolates studied (alpha ~ 1). Moreover, the efficacy of removal for fulvic acids (i.e., SRFA, PLFA) was consistent over consecutive reuse of IEX resins (i.e., loading cycles) whereas it decreased for SRNOM and SRHA over the course of operation. The stoichiometric correlation between the chloride released from the resins as a result of organic molecules uptake indicated that ion exchange was the dominant mechanism. Results obtained indicated that molecular weight and charge density of isolates played a major role in the performance of ion exchange process for organic matter removal. Furthermore, various empirical and physical models were evaluated using the experimental data and pore diffusion was found to be the rate-liming step during the uptake of organic matters; hence, it was used as the appropriate model to predict the kinetics of removal. Consequently, free liquid diffusivities and effective pore diffusion coefficients of organic molecules were estimated and findings were in agreement with the literature data that were obtained from spectrophotometric methods. PMID- 26774264 TI - Removal of the pesticides imazalil and tebuconazole in saturated constructed wetland mesocosms. AB - The aim of this study was to investigate the removal of the pesticides imazalil and tebuconazole at realistic concentration levels (10 and 100 MUg L(-1)) in saturated constructed wetland (CW) mesocosms planted with five wetland plant species (Typha latifolia, Phragmites australis, Iris pseudacorus, Juncus effusus and Berula erecta) at different hydraulic loading rates during summer and winter. The removal of imazalil and tebuconazole was not influenced by the influent concentration, but the removal efficiency for both compounds was lower in winter than in summer. Planted mesocosms had significantly higher removal efficiencies than the unplanted controls only in summer. The first-order kinetics model fitted the tebuconazole removal in all mesocosms, and the reaction rate constants varied by plant species and season (0.1-0.7 d(-1) in winter and 0.6-2.9 d(-1) in summer). For imazalil, the first-order kinetics model fitted the removal only in mesocosms planted with Phragmites australis (k = 1.2 +/- 0.4 d(-1)) and in the unplanted control (k = 1.2 +/- 0.5 d(-1) in both summer and winter). The removal of imazalil and tebuconazole by sorption to the bed substrate and plant uptake were low, suggesting a high rate of metabolization in the saturated CW mesocosms. The removal of imazalil and tebuconazole correlated with the rate of evapotranspiration and the removal of nutrients (N and P) during summer and with the DO/oxygen saturation during winter. This reveals two possible metabolization pathways: degradation inside the plant tissue after uptake and plant-stimulated microbial degradation in the bed substrate. Furthermore, the results indicate that nitrifying bacteria may play an active role in the biodegradation of these pesticides. PMID- 26774265 TI - FRAX597, a PAK1 inhibitor, synergistically reduces pancreatic cancer growth when combined with gemcitabine. AB - BACKGROUND: Pancreatic ductal adenocarcinoma remains one of the most lethal of all solid tumours. Treatment options are limited and gemcitabine-based chemotherapy remains the standard of care. Although growing evidence shows that p21-activated kinase 1 (PAK1) plays a crucial role in pancreatic cancer, its role has not been fully elucidated. This study aimed to characterise the expression and functional relevance of PAK1 in pancreatic cancer. METHODS: PAK1 expression was measured in pancreatic cancer specimens by immunohistochemistry and in pancreatic cancer cell lines by western blotting. The effect of inhibition of PAK1 by either shRNA knock-down (KD), or by a selective inhibitor, FRAX597, alone or in combination with gemcitabine, on cell proliferation and migration/invasion was measured by thymidine uptake and Boyden chamber assays, respectively. The effect on tumour growth and survival was assessed in orthotopic murine models. RESULTS: PAK1 was expressed in all human pancreatic cancer samples tested, an7d was upregulated in all pancreatic cancer cell lines tested. PAK1 KD inhibited pancreatic cancer cell growth and survival, and increased sensitivity to gemcitabine treatment. AKT activity and HIF1alpha expression were also inhibited. FRAX597 inhibited pancreatic cancer cell proliferation, survival, and migration/invasion. When combined with gemcitabine, FRAX597 synergistically inhibited pancreatic cancer proliferation in vitro and inhibited tumour growth in vivo. CONCLUSIONS: These results implicate PAK1 as a regulator of pancreatic cancer cell growth and survival. Combination of a PAK1 inhibitor such as FRAX597 with cytotoxic chemotherapy deserves further study as a novel therapeutic approach to pancreatic cancer treatment. PMID- 26774266 TI - Ki-67 prognostic and therapeutic decision driven marker for pancreatic neuroendocrine neoplasms (PNENs): A systematic review. AB - BACKGROUND: We systematically evaluate the current evidence regarding Ki-67 as a prognostic factor in pancreatic neuroendocrine neoplasms to evaluate the differences of this marker in primary tumors and in distant metastases as well as the values of Ki-67 obtained by fine needle aspiration and by histology. METHODS: The literature search was carried out using the MEDLINE/PubMed database, and only papers published in the last 10 years were selected. RESULTS: The pancreatic tissue suitable for Ki-67 evaluation was obtained from surgical specimens in the majority of the studies. There was a concordance of 83% between preoperative and postoperative Ki-67 evaluation. Pooling the data of the studies which compared the Ki-67 values obtained in both cytological and surgical specimens, we found that they were not related. The assessment of Ki-67 was manual in the majority of the papers considered for this review. In order to eliminate manual counting, several imaging methods have been developed but none of them are routinely used at present. Twenty-two studies also explored the role of Ki-67 utilized as a prognostic marker for pancreatic neuroendocrine neoplasms and the majority of them showed that Ki-67 is a good prognostic marker of disease progression. Three studies explored the Ki-67 value in metastatic sites and one study demonstrated that, in metachronous and synchronous liver metastases, there was no significant variation in the index of proliferation. CONCLUSIONS: Ki-67 is a reliable prognostic marker for pancreatic neuroendocrine neoplasms. PMID- 26774267 TI - Renal carnitine excretion following abstinence after chronic drinking. AB - PURPOSE: Carnitine participates in the metabolism of lipids and cognitive activity. Excessive consumption of alcohol disturbes renal tubular canalicules, that increases urinary excretion of carnitine and its esters. The study evaluates restoration of the urinary free- and total carnitine as well as acylcarnitine excretion after chronic drinking and during the 49-days of controlled abstinence. MATERIALS/METHODS: In 32 patients (6?; 26?), 26-60 years old, 2-30 years of alcohol dependence: 75-700g of pure alcohol (166+/-94g) of alcohol daily consumption, 2-360 (35+/-67) days of intoxication and 1.25+/-0.8 days of abstinence at admission, we determined urinary free (FC) and total carnitine (TC) as well as acylcarnitine (AC) and acylcarnitine/free carnitine ratio (AC/FC) at admission (T0), after 30 (T30) and 49 (T49) days of the controlled abstinence. RESULTS: At T0 excretion of FC, TC and AC as well as AC/FC ratio were significantly higher as compared to the control group. After 30- and 49-days of abstinence, excretion of FC and TC decreased to the level of control group with an exception of the AC and AC/FC ratio at T30 that remained significantly increased. CONCLUSION: 30 days for the FC and TC and 49 days of abstinence for the AC and AC/FC ratio was sufficient to normalize urinary excretion of the carnitines. PMID- 26774268 TI - Assessment of TNFA polymorphisms at positions -857 and -863 in Polish peptic ulcer patients. AB - PURPOSE: Peptic ulceration connected with chronic inflammation in gastrointestinal mucosa could be induced by Helicobacter pylori infection. Tumor necrosis factor alpha (TNF-alpha) encoded by TNFA gene is a key mediator in the inflammation process. There are several polymorphisms in the promoter of TNFA influencing its transcriptional activity. -857C>T (rs1799724) and -863C>A (rs1800630) substitutions may be responsible for increased TNFA transcription and TNF-alpha production. The association of these two polymorphisms with peptic ulceration and the development of H. pylori infection in peptic ulcer patients in Poles were evaluated. MATERIAL AND METHODS: Polymorphisms were assessed by PCR RFLP in 203 peptic ulcer patients. H. pylori infection was confirmed by rapid urease test. The results of genotyping were compared with those obtained for 248 healthy Polish individuals. RESULTS: There were no significant differences in genotype and allele frequencies for both investigated polymorphisms between peptic ulcer patients and healthy individuals. No associations between frequencies of particular genotypes and alleles for both SNPs and the presence of H. pylori infection in peptic ulcer patients and in subgroups of peptic ulcer women and men were confirmed. CONCLUSIONS: The investigated SNPs are not risk factors for peptic ulcer development. They are not risk factors for H. pylori infection in ulcer patients. PMID- 26774269 TI - Low-tech, high impact: care for premature neonates in a district hospital in Burundi. A way forward to decrease neonatal mortality. AB - BACKGROUND: Death among premature neonates contributes significantly to neonatal mortality which in turn represents approximately 40% of paediatric mortality. Care for premature neonates is usually provided at the tertiary care level, and premature infants in rural areas often remain bereft of care. Here, we describe the characteristics and outcomes of premature neonates admitted to neonatal services in a district hospital in rural Burundi that also provided comprehensive emergency obstetric care. These services included a Neonatal Intensive Care Unit (NICU) and Kangaroo Mother Care (KMC) ward, and did not rely on high-tech interventions or specialist medical staff. METHODS: A retrospective descriptive study, using routine programme data of neonates (born at <32 weeks and 32-36 weeks of gestation), admitted to the NICU and/or KMC at Kabezi District Hospital. RESULTS: 437 premature babies were admitted to the neonatal services; of these, 134 (31%) were born at <32 weeks, and 236 (54%) at 32-36 weeks. There were 67 (15%) with an unknown gestational age but with a clinical diagnosis of prematurity. Survival rates at hospital discharge were 62% for the <32 weeks and 87% for the 32-36 weeks groups; compared to respectively 30 and 50% in the literature on neonates in low- and middle-income countries. Cause of death was categorised, non-specifically, as "Conditions associated with prematurity/low birth weight" for 90% of the <32 weeks and 40% of the 32-36 weeks of gestation groups. CONCLUSIONS: Our study shows for the first time that providing neonatal care for premature babies is feasible at a district level in a resource-limited setting in Africa. High survival rates were observed, even in the absence of high tech equipment or specialist neonatal physician staff. We suggest that these results were achieved through staff training, standardised protocols, simple but essential equipment, provision of complementary NICU and KMC units, and integration of the neonatal services with emergency obstetric care. This approach has the potential to considerably reduce overall neonatal mortality. PMID- 26774270 TI - Assessment of k-mer spectrum applicability for metagenomic dissimilarity analysis. AB - BACKGROUND: A rapidly increasing flow of genomic data requires the development of efficient methods for obtaining its compact representation. Feature extraction facilitates classification, clustering and model analysis for testing and refining biological hypotheses. "Shotgun" metagenome is an analytically challenging type of genomic data - containing sequences of all genes from the totality of a complex microbial community. Recently, researchers started to analyze metagenomes using reference-free methods based on the analysis of oligonucleotides (k-mers) frequency spectrum previously applied to isolated genomes. However, little is known about their correlation with the existing approaches for metagenomic feature extraction, as well as the limits of applicability. Here we evaluated a metagenomic pairwise dissimilarity measure based on short k-mer spectrum using the example of human gut microbiota, a biomedically significant object of study. RESULTS: We developed a method for calculating pairwise dissimilarity (beta-diversity) of "shotgun" metagenomes based on short k-mer spectra (5 <= k <= 11). The method was validated on simulated metagenomes and further applied to a large collection of human gut metagenomes from the populations of the world (n=281). The k-mer spectrum-based measure was found to behave similarly to one based on mapping to a reference gene catalog, but different from one using a genome catalog. This difference turned out to be associated with a significant presence of viral reads in a number of metagenomes. Simulations showed limited impact of bacterial genetic variability as well as sequencing errors on k-mer spectra. Specific differences between the datasets from individual populations were identified. CONCLUSIONS: Our approach allows rapid estimation of pairwise dissimilarity between metagenomes. Though we applied this technique to gut microbiota, it should be useful for arbitrary metagenomes, even metagenomes with novel microbiota. Dissimilarity measure based on k-mer spectrum provides a wider perspective in comparison with the ones based on the alignment against reference sequence sets. It helps not to miss possible outstanding features of metagenomic composition, particularly related to the presence of an unknown bacteria, virus or eukaryote, as well as to technical artifacts (sample contamination, reads of non-biological origin, etc.) at the early stages of bioinformatic analysis. Our method is complementary to reference based approaches and can be easily integrated into metagenomic analysis pipelines. PMID- 26774273 TI - Pathological Characterization of an Outbreak of Porcine Reproductive and Respiratory Syndrome in Northern Vietnam. AB - In 2007, a highly pathogenic porcine reproductive and respiratory syndrome virus (HP-PRRSV) emerged in Vietnam and spread to nearly all regions of the country by 2010. Ten representative pigs of different age groups, infected naturally with HP PRRSV in northern Vietnam in 2010, were used to characterize the pathological features of the infection. Infection was confirmed using reverse transcriptase polymerase chain reaction and viral isolation. The clinical signs and gross findings in these pigs included high fever (>40.2 degrees C), red skin, blue ears, anorexia, respiratory distress, diarrhoea, haemorrhagic pleurisy and lymphadenopathy. Reproductive failure was the main clinical feature in sows. PRRSV infection-associated microscopical lung and lymph node lesions were observed frequently, regardless of age of the animals. Lung lesions were characterized by interstitial pneumonia and were occasionally associated with haemorrhage and fluid exudation following alveolar collapse. Lymph nodes exhibited characteristic haemorrhage and apoptosis, lymphocytic depletion and disorganization secondary to fibrosis and capillary formation. Haematoxylin and eosin staining or caspase-3 immunohistochemistry revealed apoptosis induction in various tissues and organs, particularly the lymph nodes and lungs. Primarily haemorrhagic microscopical lesions were observed commonly in other organs including the spleen, liver, heart and kidney. Immunohistochemical examination revealed HP-PRRS antigen in the lung, lymph node, liver and kidney macrophages, and lung and kidney epithelial cells. Pigs infected naturally with HP-PRRS in the field have multisystemic disease characterized by marked apoptotic cell death. PMID- 26774271 TI - Saccharomyces cerevisiae Forms D-2-Hydroxyglutarate and Couples Its Degradation to D-Lactate Formation via a Cytosolic Transhydrogenase. AB - The D or L form of 2-hydroxyglutarate (2HG) accumulates in certain rare neurometabolic disorders, and high D-2-hydroxyglutarate (D-2HG) levels are also found in several types of cancer. Although 2HG has been detected in Saccharomyces cerevisiae, its metabolism in yeast has remained largely unexplored. Here, we show that S. cerevisiae actively forms the D enantiomer of 2HG. Accordingly, the S. cerevisiae genome encodes two homologs of the human D-2HG dehydrogenase: Dld2, which, as its human homolog, is a mitochondrial protein, and the cytosolic protein Dld3. Intriguingly, we found that a dld3Delta knock-out strain accumulates millimolar levels of D-2HG, whereas a dld2Delta knock-out strain displayed only very moderate increases in D-2HG. Recombinant Dld2 and Dld3, both currently annotated as D-lactate dehydrogenases, efficiently oxidized D-2HG to alpha-ketoglutarate. Depletion of D-lactate levels in the dld3Delta, but not in the dld2Delta mutant, led to the discovery of a new type of enzymatic activity, carried by Dld3, to convert D-2HG to alpha-ketoglutarate, namely an FAD-dependent transhydrogenase activity using pyruvate as a hydrogen acceptor. We also provide evidence that Ser3 and Ser33, which are primarily known for oxidizing 3 phosphoglycerate in the main serine biosynthesis pathway, in addition reduce alpha-ketoglutarate to D-2HG using NADH and represent major intracellular sources of D-2HG in yeast. Based on our observations, we propose that D-2HG is mainly formed and degraded in the cytosol of S. cerevisiae cells in a process that couples D-2HG metabolism to the shuttling of reducing equivalents from cytosolic NADH to the mitochondrial respiratory chain via the D-lactate dehydrogenase Dld1. PMID- 26774274 TI - Assessment of Mycoplasma hyopneumoniae-induced Pneumonia using Different Lung Lesion Scoring Systems: a Comparative Review. AB - Mycoplasma hyopneumoniae is the primary aetiological agent of swine enzootic pneumonia (EP) and one of the major contributors to the porcine respiratory disease complex (PRDC). Gross lung lesions in pigs affected by EP consist of cranioventral pulmonary consolidation (CVPC), usually distributed bilaterally in the apical, intermediate, accessory and cranial parts of the diaphragmatic lobes. Several lung scoring methods are currently in place for the evaluation of CVPC. The aims of this study were (1) to review the lung lesion scoring systems used to assess pneumonia associated with M. hyopneumoniae infection, and (2) to evaluate eight of these scoring systems by applying them to the lungs of 76 pigs with experimentally-induced M. hyopneumoniae pneumonia. A significant correlation between all lung lesion scoring systems was observed and the coefficients of determination in a regression analysis were very high between each pair-wise comparison, except for a unique scoring system based on image analysis. A formula of equivalence between lung scoring methods was developed in order to compare the results obtained with these methods. The present review provides a basis for comparison (even retrospectively) of lesions evaluated using different lung scoring systems. PMID- 26774272 TI - Biochemical Roles for Conserved Residues in the Bacterial Fatty Acid-binding Protein Family. AB - Fatty acid kinase (Fak) is a ubiquitous Gram-positive bacterial enzyme consisting of an ATP-binding protein (FakA) that phosphorylates the fatty acid bound to FakB. In Staphylococcus aureus, Fak is a global regulator of virulence factor transcription and is essential for the activation of exogenous fatty acids for incorporation into phospholipids. The 1.2-A x-ray structure of S. aureus FakB2, activity assays, solution studies, site-directed mutagenesis, and in vivo complementation were used to define the functions of the five conserved residues that define the FakB protein family (Pfam02645). The fatty acid tail is buried within the protein, and the exposed carboxyl group is bound by a Ser-93-fatty acid carboxyl-Thr-61-His-266 hydrogen bond network. The guanidinium of the invariant Arg-170 is positioned to potentially interact with a bound acylphosphate. The reduced thermal denaturation temperatures of the T61A, S93A, and H266A FakB2 mutants illustrate the importance of the hydrogen bond network in protein stability. The FakB2 T61A, S93A, and H266A mutants are 1000-fold less active in the Fak assay, and the R170A mutant is completely inactive. All FakB2 mutants form FakA(FakB2)2 complexes except FakB2(R202A), which is deficient in FakA binding. Allelic replacement shows that strains expressing FakB2 mutants are defective in fatty acid incorporation into phospholipids and virulence gene transcription. These conserved residues are likely to perform the same critical functions in all bacterial fatty acid-binding proteins. PMID- 26774275 TI - Reproductive Market Values Explain Post-reproductive Lifespans in Men. AB - Post-reproductive lifespans (PRLSs) of men vary across traditional societies. We argue that if sexual selection operates on male age-dependent resource availability (or 'reproductive market values') the result is variation in male late-life reproduction across subsistence systems. This perspective highlights the uniqueness of PRLS in both women and men. PMID- 26774276 TI - Effects on All-cause Mortality and Cardiovascular Outcomes in Patients With Type 2 Diabetes by Comparing Insulin With Oral Hypoglycemic Agent Therapy: A Meta analysis of Randomized Controlled Trials. AB - PURPOSE: Retrospective, case-control studies and prospective randomized controlled trials (RCTs) on insulin treatment for diabetic patients yielded contradictory mortality and cardiovascular outcomes. We aimed to evaluate the effects of insulin versus oral hypoglycemic agents (OHAs) on all-cause mortality and cardiovascular outcomes in patients with type 2 diabetes (T2D). METHODS: We searched Medline, Embase, Cochrane Central Register of Controlled Trials, Chinese Biological Medicine Database, China National Knowledge Infrastructure, Chinese Technical Periodicals, and Wanfang Data, up to July 10, 2015, for RCTs on insulin and OHAs that assessed all-cause mortality and/or cardiovascular death as primary end points. We derived pooled risk ratios (RRs) as summary statistics. RESULTS: Three trials were included in which 7649 patients received insulin and 8322 received OHAs, with mean (SD) diabetes duration of 5.0 (6.2) and 4.4 (5.9) years, respectively. Insulin did not differ from OHAs in all-cause mortality (RR = 1.00; 95% CI, 0.93-1.07), cardiovascular death (RR = 1.00; 95% CI, 0.91-1.09), myocardial infarction (RR = 1.04; 95% CI, 0.93-1.16), angina (RR = 0.97; 95% CI, 0.88-1.06), sudden death (RR = 1.02; 95% CI, 0.66-1.56), or stroke (RR = 1.01; 95% CI, 0.88-1.15). Insulin reduced the risk of heart failure compared with OHAs (RR = 0.87; 95% CI, 0.75-0.99). In the subgroup of secondary prevention of cardiovascular diseases (CVDs) or very high risk of CVDs, insulin did not differ from OHAs in all-cause mortality (RR = 0.99; 95% CI, 0.92-1.07), cardiovascular death (RR = 0.99; 95% CI, 0.90-1.09), myocardial infarction (RR = 1.01; 95% CI, 0.88-1.15), heart failure (RR = 0.69; 95% CI, 0.34-1.40), or stroke (RR = 1.05; 95% CI, 0.90-1.21). IMPLICATIONS: Insulin did not provide a clear benefit over OHAs in all-cause mortality or cardiovascular outcomes in the patients with T2D. Insulin therapy has many shortcomings, including inconvenience (injection, strict blood glucose monitoring), hypoglycemia, and obvious weight gain. Thus, we conclude that no robust evidence supports the active use of insulin for this population at present. PMID- 26774277 TI - Septic shock due to Saccharomyces boulardii. PMID- 26774278 TI - Streptococcus pneumoniae appendicitis and bacteremia in an immunocompetent adult. PMID- 26774279 TI - Compulsivity in obsessive-compulsive disorder and addictions. AB - Compulsive behaviors are driven by repetitive urges and typically involve the experience of limited voluntary control over these urges, a diminished ability to delay or inhibit these behaviors, and a tendency to perform repetitive acts in a habitual or stereotyped manner. Compulsivity is not only a central characteristic of obsessive-compulsive disorder (OCD) but is also crucial to addiction. Based on this analogy, OCD has been proposed to be part of the concept of behavioral addiction along with other non-drug-related disorders that share compulsivity, such as pathological gambling, skin-picking, trichotillomania and compulsive eating. In this review, we investigate the neurobiological overlap between compulsivity in substance-use disorders, OCD and behavioral addictions as a validation for the construct of compulsivity that could be adopted in the Research Domain Criteria (RDoC). The reviewed data suggest that compulsivity in OCD and addictions is related to impaired reward and punishment processing with attenuated dopamine release in the ventral striatum, negative reinforcement in limbic systems, cognitive and behavioral inflexibility with diminished serotonergic prefrontal control, and habitual responding with imbalances between ventral and dorsal frontostriatal recruitment. Frontostriatal abnormalities of compulsivity are promising targets for neuromodulation and other interventions for OCD and addictions. We conclude that compulsivity encompasses many of the RDoC constructs in a trans-diagnostic fashion with a common brain circuit dysfunction that can help identifying appropriate prevention and treatment targets. PMID- 26774280 TI - Zinc supplementation in rats impairs hippocampal-dependent memory consolidation and dampens post-traumatic recollection of stressful event. AB - Zinc is a trace element important for synaptic plasticity, learning and memory. Zinc deficiency, both during pregnancy and after birth, impairs cognitive performance and, in addition to memory deficits, also results in alterations of attention, activity, neuropsychological behavior and motor development. The effects of zinc supplementation on cognition, particularly in the adult, are less clear. We demonstrate here in adult rats, that 4 week-long zinc supplementation given by drinking water, and approximately doubling normal daily intake, strongly impairs consolidation of hippocampal-dependent memory, tested through contextual fear conditioning and inhibitory avoidance. Furthermore, the same treatment started after memory consolidation of training for the same behavioral tests, substantially dampens the recall of the stressful event occurred 4 weeks before. A molecular correlate of the amnesic effect of zinc supplementation is represented by a dysregulated function of GSK-3beta in the hippocampus, a kinase that participates in memory processes. The possible relevance of these data for humans, in particular regarding post-traumatic stress disorders, is discussed in view of future investigation. PMID- 26774281 TI - The Lipid Kinase PI5P4Kbeta Is an Intracellular GTP Sensor for Metabolism and Tumorigenesis. AB - While cellular GTP concentration dramatically changes in response to an organism's cellular status, whether it serves as a metabolic cue for biological signaling remains elusive due to the lack of molecular identification of GTP sensors. Here we report that PI5P4Kbeta, a phosphoinositide kinase that regulates PI(5)P levels, detects GTP concentration and converts them into lipid second messenger signaling. Biochemical analyses show that PI5P4Kbeta preferentially utilizes GTP, rather than ATP, for PI(5)P phosphorylation, and its activity reflects changes in direct proportion to the physiological GTP concentration. Structural and biological analyses reveal that the GTP-sensing activity of PI5P4Kbeta is critical for metabolic adaptation and tumorigenesis. These results demonstrate that PI5P4Kbeta is the missing GTP sensor and that GTP concentration functions as a metabolic cue via PI5P4Kbeta. The critical role of the GTP-sensing activity of PI5P4Kbeta in cancer signifies this lipid kinase as a cancer therapeutic target. PMID- 26774282 TI - Serine Metabolism Supports the Methionine Cycle and DNA/RNA Methylation through De Novo ATP Synthesis in Cancer Cells. AB - Crosstalk between cellular metabolism and the epigenome regulates epigenetic and metabolic homeostasis and normal cell behavior. Changes in cancer cell metabolism can directly impact epigenetic regulation and promote transformation. Here we analyzed the contribution of methionine and serine metabolism to methylation of DNA and RNA. Serine can contribute to this pathway by providing one-carbon units to regenerate methionine from homocysteine. While we observed this contribution under methionine-depleted conditions, unexpectedly, we found that serine supported the methionine cycle in the presence and absence of methionine through de novo ATP synthesis. Serine starvation increased the methionine/S-adenosyl methionine ratio, decreasing the transfer of methyl groups to DNA and RNA. While serine starvation dramatically decreased ATP levels, this was accompanied by lower AMP and did not activate AMPK. This work highlights the difference between ATP turnover and new ATP synthesis and defines a vital function of nucleotide synthesis beyond making nucleic acids. PMID- 26774283 TI - TRF2-Mediated Control of Telomere DNA Topology as a Mechanism for Chromosome-End Protection. AB - The shelterin proteins protect telomeres against activation of the DNA damage checkpoints and recombinational repair. We show here that a dimer of the shelterin subunit TRF2 wraps ~ 90 bp of DNA through several lysine and arginine residues localized around its homodimerization domain. The expression of a wrapping-deficient TRF2 mutant, named Top-less, alters telomeric DNA topology, decreases the number of terminal loops (t-loops), and triggers the ATM checkpoint, while still protecting telomeres against non-homologous end joining (NHEJ). In Top-less cells, the protection against NHEJ is alleviated if the expression of the TRF2-interacting protein RAP1 is reduced. We conclude that a distinctive topological state of telomeric DNA, controlled by the TRF2-dependent DNA wrapping and linked to t-loop formation, inhibits both ATM activation and NHEJ. The presence of RAP1 at telomeres appears as a backup mechanism to prevent NHEJ when topology-mediated telomere protection is impaired. PMID- 26774284 TI - Visualizing the Path of DNA through Proteins Using DREEM Imaging. AB - Many cellular functions require the assembly of multiprotein-DNA complexes. A growing area of structural biology aims to characterize these dynamic structures by combining atomic-resolution crystal structures with lower-resolution data from techniques that provide distributions of species, such as small-angle X-ray scattering, electron microscopy, and atomic force microscopy (AFM). A significant limitation in these combinatorial methods is localization of the DNA within the multiprotein complex. Here, we combine AFM with an electrostatic force microscopy (EFM) method to develop an exquisitely sensitive dual-resonance-frequency enhanced EFM (DREEM) capable of resolving DNA within protein-DNA complexes. Imaging of nucleosomes and DNA mismatch repair complexes demonstrates that DREEM can reveal both the path of the DNA wrapping around histones and the path of DNA as it passes through both single proteins and multiprotein complexes. Finally, DREEM imaging requires only minor modifications of many existing commercial AFMs, making the technique readily available. PMID- 26774285 TI - HELB Is a Feedback Inhibitor of DNA End Resection. AB - DNA double-strand break repair by homologous recombination is initiated by the formation of 3' single-stranded DNA (ssDNA) overhangs by a process termed end resection. Although much focus has been given to the decision to initiate resection, little is known of the mechanisms that regulate the ongoing formation of ssDNA tails. Here we report that DNA helicase B (HELB) underpins a feedback inhibition mechanism that curtails resection. HELB is recruited to ssDNA by interacting with RPA and uses its 5'-3' ssDNA translocase activity to inhibit EXO1 and BLM-DNA2, the nucleases catalyzing resection. HELB acts independently of 53BP1 and is exported from the nucleus as cells approach S phase, concomitant with the upregulation of resection. Consistent with its role as a resection antagonist, loss of HELB results in PARP inhibitor resistance in BRCA1-deficient tumor cells. We conclude that mammalian DNA end resection triggers its own inhibition via the recruitment of HELB. PMID- 26774287 TI - Identification of estrogen receptor alpha ligands with virtual screening techniques. AB - Utilization of computer-aided molecular discovery methods in virtual screening (VS) is a cost-effective approach to identify novel bioactive small molecules. Unfortunately, no universal VS strategy can guarantee high hit rates for all biological targets, but each target requires distinct, fine-tuned solutions. Here, we have studied in retrospective manner the effectiveness and usefulness of common pharmacophore hypothesis, molecular docking and negative image-based screening as potential VS tools for a widely applied drug discovery target, estrogen receptor alpha (ERalpha). The comparison of the methods helps to demonstrate the differences in their ability to identify active molecules. For example, structure-based methods identified an already known active ligand from the widely-used bechmarking decoy molecule set. Although prospective VS against one commercially available database with around 100,000 drug-like molecules did not retrieve many testworthy hits, one novel hit molecule with pIC50 value of 6.6, was identified. Furthermore, our small in-house compound collection of easy to-synthesize molecules was virtually screened against ERalpha, yielding to five hit candidates, which were found to be active in vitro having pIC50 values from 5.5 to 6.5. PMID- 26774288 TI - High nuclear expression of Twist1 in the skeletal extramedullary disease of myeloma patients predicts inferior survival. AB - The aim of the study was to investigate the expression of epithelial to mesenchymal transition (EMT)-inducing transcription factors, including Twist1 and ZEB1, in skeletal extramedullary disease (EMD) of multiple myeloma (MM) patients and to clarify the effects on clinical outcomes. The expression of Twist1 and ZEB1 in the bone marrow (BM) and the masses of skeletal EMD from 70 MM cases with skeletal EMD and 30 MM patients without skeletal EMD were determined by immunohistochemistry. The results demonstrated that the percentage of high nuclear staining for Twist1 was 24.3% (17/70) in skeletal EMD, which was significantly higher than in the BM of these patients as well as those without skeletal EMD (P=0.030 and P=0.011). The microvessel density (MVD, P=0.004) was significantly higher in patients with high nuclear expression of Twist1 (Twist1 high) than in those with low expression. Patients with Twist1-high experienced a lower rate of progression-free survival (PFS, 11.8% vs. 35.0%, P=0.000) and overall survival (OS, 52.5% vs. 83.7%, P=0.001) compared to those with low expression. Multivariate analysis showed that Twist1-high was independently associated with inferior PFS (HR=2.161; 95%CI: 1.116-4.183; P=0.022) and OS (HR=3.111; 95%CI: 1.114-8.685; P=0.030). We concluded that Twist1-high is associated with a poor prognosis and may be correlated with angiogenesis in the skeletal EMD of MM patients. PMID- 26774289 TI - The stem cell renewal and DNA damage response pathways are frequently altered in fibroepithelial tumors of breast in Indian patients. AB - Genetic and epigenetic alterations in genes associated with distinct cellular pathways were checked in fibroepithelial tumors, including fibroadenomas, benign and malignant phyllode and atypical ductal hyperplasia. A panel of 22 genes associated with different cellular pathways such as stem cell renewal (Wnt and Hedgehog), DNA damage response [homologous recombination (HR), mismatch repair (MMR) and nucleotide excision repair (NER)] and cell proliferation signaling pathway were tested. Alterations (genetic/epigenetic) of the genes associated with Wnt signaling pathway were detected in 100% (20/20) of the breast tumors for at least one out of the six Wnt antagonists tested. Frequent molecular alterations (57-64%) were detected in HR and MMR pathway and low frequency of alterations (8-25%) were seen in cell-proliferation and cell signaling pathways showing a differential pattern of alterations in different tumor types. The patterns of alterations, in particular the epigenetic alterations, differed little from that seen previously in breast carcinoma cells, suggesting epigenetic alterations to be an early event in the development of the tumors. In gene ontology analysis, it was evident that Wnt signaling pathway [GO: 0030111, Kegg: 04310], cell proliferation pathway [GO: 0008285] and pathways in cancer [Kegg: 05200] were significantly enriched by differentially altered genes in fibroadenoma and phyllode tumor types. All these results may provide a new breakthrough in early diagnosis, prognosis and treatment of these tumors. PMID- 26774286 TI - FBXW7 Facilitates Nonhomologous End-Joining via K63-Linked Polyubiquitylation of XRCC4. AB - FBXW7 is a haploinsufficient tumor suppressor with loss-of-function mutations occurring in human cancers. FBXW7 inactivation causes genomic instability, but the mechanism remains elusive. Here we show that FBXW7 facilitates nonhomologous end-joining (NHEJ) repair and that FBXW7 depletion causes radiosensitization. In response to ionizing radiation, ATM phosphorylates FBXW7 at serine 26 to recruit it to DNA double-strand break (DSB) sites, whereas activated DNA-PKcs phosphorylates XRCC4 at serines 325/326, which promotes binding of XRCC4 to FBXW7. SCF(FBXW7) E3 ligase then promotes polyubiquitylation of XRCC4 at lysine 296 via lysine 63 linkage for enhanced association with the Ku70/80 complex to facilitate NHEJ repair. Consistent with these findings, a small-molecule inhibitor that abrogates XRCC4 polyubiquitylation reduces NHEJ repair. Our study demonstrates one mechanism by which FBXW7 contributes to genome integrity and implies that inactivated FBXW7 in human cancers could be a strategy for increasing the efficacy of radiotherapy. PMID- 26774290 TI - Assessment of the circumferential margins, extraprostatic extension and Gleason score in radical prostatectomy specimens: Comparison of a partial embedding method with supplemental total inclusion of peripheral tissues. AB - BACKGROUND: Recent data suggest that up to 21% of positive circumferential margins (PCM) and 47% of extraprostatic extension (EPE) samples may be missed when partial embedding methods are employed. Kim and colleagues (2009) suggested that total inclusion of the periphery (3mm rim) of the prostate prevented the failure to detect PCM and EPE. DESIGN: Radical prostatectomy specimen (n=148) slides were reviewed after adoption of a protocol that included a ~3 mm rim of peripheral tissues. We evaluated whether the analysis of supplemental slides of prostate periphery changed margin status, presence of EPE, Gleason score and extent of PCM and EPE. RESULTS: Partial sampling resulted in missing 29% of PCM and 20% of EPE without using data from the supplemental slides of prostate periphery. Changes from focal to extensive disease were found in 11/21 (52%) cases of positive circumferential margins and in 5/13 (38%) cases of extraprostatic extension. Changes in the Gleason score were uncommon. CONCLUSIONS: These results indicate the importance of including all the prostate peripheral tissue for microscopic analysis when partial embedding methods are adopted. PMID- 26774291 TI - The dual systems model: Review, reappraisal, and reaffirmation. AB - According to the dual systems perspective, risk taking peaks during adolescence because activation of an early-maturing socioemotional-incentive processing system amplifies adolescents' affinity for exciting, pleasurable, and novel activities at a time when a still immature cognitive control system is not yet strong enough to consistently restrain potentially hazardous impulses. We review evidence from both the psychological and neuroimaging literatures that has emerged since 2008, when this perspective was originally articulated. Although there are occasional exceptions to the general trends, studies show that, as predicted, psychological and neural manifestations of reward sensitivity increase between childhood and adolescence, peak sometime during the late teen years, and decline thereafter, whereas psychological and neural reflections of better cognitive control increase gradually and linearly throughout adolescence and into the early 20s. While some forms of real-world risky behavior peak at a later age than predicted, this likely reflects differential opportunities for risk-taking in late adolescence and young adulthood, rather than neurobiological differences that make this age group more reckless. Although it is admittedly an oversimplification, as a heuristic device, the dual systems model provides a far more accurate account of adolescent risk taking than prior models that have attributed adolescent recklessness to cognitive deficiencies. PMID- 26774292 TI - Oriented cell division affects the global stress and cell packing geometry of a monolayer under stretch. AB - Cell division plays a vital role in tissue morphogenesis and homeostasis, and the division plane is crucial for cell fate. For isolated cells, extensive studies show that the orientation of divisions is sensitive to cell shape and the direction of extrinsic mechanical forces. However, it is poorly understood that how the cell divides within a cell monolayer and how the local stress change, due to the division, affects the global stress of epithelial monolayers. Here, we use the vertex dynamics models to investigate the effects of division orientation on the configurations and mechanics of a cell monolayer under stretch. We examine three scenarios of the divisions: dividing along the stretch axis, dividing along the geometric long axis of cells, and dividing at a random angle. It is found that the division along the long cell axis can induce the minimal energy difference, and the global stress of the monolayer after stretch releases more rapidly in this case. Moreover, the long-axis division can result in more random cell orientations and more isotropic cell shapes within the monolayer, comparing with other two cases. This study helps understand the division orientation of cells within a monolayer under mechanical stimuli, and may shed light on linking individual cell's behaviors to the global mechanics and patterns of tissues. PMID- 26774293 TI - Evolving Issues in Heart Failure Management. PMID- 26774294 TI - A case of cutaneous Paecilomyces formosus infection in an extremely premature infant. AB - BACKGROUND: Many types of weak pathogenic microorganisms often cause opportunistic infections in extremely preterm infants. Paecilomyces formosus is one such opportunistic fungus that can lead to a serious infection. Here, we report the clinical course of P. formosus infection in an extremely preterm infant. CASE PRESENTATION: An extremely preterm male infant was born at 23 weeks of gestation. Six days after birth, he developed yellowish-brown nodules on the skin of the back extending to the buttocks. P. formosus was identified by culture of samples from the cutaneous lesions. We treated the infection with intravenous micafungin and lanoconazole ointment application. The skin lesions improved dramatically and healed without scar tissue formation. CONCLUSION: Neonatologists should consider opportunistic P. formosus infections. This is the first report to describe that micafungin is effective for P. formosus cutaneous infection in extremely premature infants. PMID- 26774295 TI - Source composition and seasonal variation of particulate trace element fluxes in Prydz Bay, East Antarctica. AB - Particulate fluxes of trace elements (Al, Fe, Mn, Cu, Pb, Zn, Cd and Co) in the polynya area of Prydz Bay were measured using time series sediment trap lasting from December 16th 2010 to December 16th 2011. The comparison of annual fluxes from different regions, the seasonality and sources of trace element, and their association with organic matters were investigated. The fluxes of Cu, Zn and Cd in the polynya area of Prydz Bay are dominated by marine biogenic sources. Their similar seasonality with the export of biological materials (biogenic silica, organic carbon, and calcite carbonate) is strongly related to the ice coverage and biological production. Mineral debris derived from Antarctic continent is suggested to account for the particulate fluxes of Al, Fe, Mn, Pb and Co in the polynya. Their seasonal variations are most likely controlled by ice melting and freezing process. Furthermore, their fluxes are also influenced by scavenging onto biogenic material for Pb and uptake by phytoplankton for Co. The excess fluxes of Cu, Zn and Cd have good relationship with organic carbon export. The coupling patterns are mainly regulated by source composition of trace elements and non-lithogenic input from atmospheric deposition or upwelling, and partly influenced by biological uptake process. PMID- 26774296 TI - Effects of Nosema ceranae and thiametoxam in Apis mellifera: A comparative study in Africanized and Carniolan honey bees. AB - Multiple stressors, such as chemicals and pathogens, are likely to be detrimental for the health and lifespan of Apis mellifera, a bee species frequently exposed to both factors in the field and inside hives. The main objective of the present study was to evaluate comparatively the health of Carniolan and Africanized honey bees (AHB) co-exposed to thiamethoxam and Nosema ceranae (N. ceranae) spores. Newly-emerged worker honey bees were exposed solely with different sublethal doses of thiamethoxam (2% and 0.2% of LD50 for AHB), which could be consumed by bees under field conditions. Toxicity tests for the Carniolan bees were performed, and the LD50 of thiamethoxam for Carniolan honey bees was 7.86 ng bee( 1). Immunohistological analyses were also performed to detect cell death in the midgut of thiamethoxam and/or N. ceranae treated bees. Thiamethoxam exposure had no negative impact on Nosema development in experimental conditions, but it clearly inhibited cell death in the midgut of thiamethoxam and Nosema-exposed bees, as demonstrated by immunohistochemical data. Indeed, thiamethoxam exposure only had a minor synergistic toxic effect on midgut tissue when applied as a low dose simultaneously with N. ceranae to AHB and Carniolan honey bees, in comparison with the effect caused by both stressors separately. Our data provides insights into the effects of the neonicotenoid thiamethoxam on the AHB and Carniolan honey bee life span, as well as the effects of simultaneous application of thiamethoxam and N. ceranae spores to honey bees. PMID- 26774297 TI - As(III) removal and speciation of Fe (Oxyhydr)oxides during simultaneous oxidation of As(III) and Fe(II). AB - Abiotic oxidation of Fe(II) is an important pathway in the formation of Fe (oxyhydr)oxides. However, how can As(III) affect the oxidation rate of Fe(II) and the speciation of Fe (oxyhydr)oxides, and what's the extent of the newly formed Fe (oxyhydr)oxides on the removal of aqueous arsenic are still poorly understood. Oxidation of Fe(II) under neutral pH conditions was therefore investigated under different molar ratios of As:Fe. Our results suggest that co-existence of aqueous As(III) significantly slows down the oxidation rate of Fe(II). Speciation of Fe (oxyhydr)oxides is dependent on pH and As:Fe ratios. At pH 6.0, formation of lepidocrocite and goethite is apparently inhibited at low As:Fe ratios, and ferric arsenate is favored at high As:Fe ratios. At pH 7.0, lepidocrocite gradually degenerates with the increasing As:Fe ratios. At pH 8.0, arsenite significantly inhibits the development of magnetite and favors a formation of lepidocrocite. XPS analysis further reveals that more than half of As(III) is oxidized to As(V) at pH 6.0 and 7.0, whereas at pH 8.0, the rapid oxidation of Fe(II) as well as the rapid formation of Fe (oxyhydr)oxides facilitate a rapid removal of dissolved As(III) before its further oxidation to As(V). PMID- 26774298 TI - Effects of fluoride and aluminum on expressions of StAR and P450scc of related steroidogenesis in guinea pigs' testis. AB - A lot of studies have shown that fluoride and aluminum have toxic effect on male reproductive system, but the mechanism of which and the interaction between fluoride and aluminum is still unknown. This study investigated the effects of fluoride (NaF) or/and aluminum (AlCl3) on serum testosterone level, gene and protein expression levels of Steroidogenic Acute Regulatory Protein (StAR) and Cytochrome P450 cholesterol side chain cleavage enzyme (P450scc) in the testes of guinea pigs. Fifty-two guinea pigs were divided randomly into four groups (Control, HiF, HiAl and HiF + HiAl). Fluoride (150 mg NaF/L) or/and aluminum (300 mg AlCl3/L) were orally administrated to male guinea pigs for 13 weeks. The results showed that F and Al reduced number and elevated abnormal ratio of sperm. Meanwhile, the concentrations of serum testosterone in all experimental groups were decreased. P450scc protein expression was significantly reduced in all treatment groups, and StAR expression was decreased remarkably in HiF group and HiF + HiAl group. The levels of StAR mRNA in three groups were reduced by 53.9%, 21.4% and 33.4%, respectively, while the expressions of P450scc mRNA were reduced by 67.8%, 17.0% and 47.8%. Therefore, we concluded that F induced the reduction in testosterone and sperm amount, and thus in lower fertility, which might occur as a consequence of depressed StAR and P450scc mRNA expression. There were no synergistic effects between F and Al, instead, Al weakened the toxicity of F to some extents. The results indicated that Al had antagonism effects on F. PMID- 26774299 TI - Mobilization of soil-borne arsenic by three common organic acids: Dosage and time effects. AB - A batch experiment was conducted to investigate the mobilization of soil-borne arsenic by three common low-molecular-weight organic acids with a focus on dosage and time effects. The results show that oxalic acid behaved differently from citric acid and malic acid in terms of mobilizing As that was bound to iron compounds. At an equivalent molar concentration, reactions between oxalic acid and soil-borne Fe were kinetically more favourable, as compared to those between either citric acid or malic acid and the soil-borne Fe. It was found that reductive dissolution of soil-borne Fe played a more important role in liberating As, as compared to non-reductive reactions. Prior to the 7th day of the experiment, As mobility increased with increasing dose of oxalic acid while there was no significant difference (P > 0.05) in mobilized As among the treatments with different doses of citric acid or malic acid. The dosage effect on soil borne As mobilization in the citric acid and malic acid treatments became clear only after the 7th day of the experiment. Soluble Ca present in the soils could cause re-immobilization of As by competing with solution-borne Fe for available organic ligands to form practically insoluble organic compounds of calcium (i.e. calcium oxalate). This resulted in transformation of highly soluble organic complexes of iron (i.e. iron oxalate complexes) into slightly soluble organic compounds of iron (i.e. iron oxalate) or free ferric ion, which then reacted with the solution-borne arsenate ions to form practically insoluble iron arsenates in the latter part of the experiment. PMID- 26774300 TI - Effects of Cr(III) and Cr(VI) on nitrification inhibition as determined by SOUR, function-specific gene expression and 16S rRNA sequence analysis of wastewater nitrifying enrichments. AB - The effect of Cr(III) and Cr(VI) on nitrification was examined with samples from nitrifying enrichment cultures using three different approaches: by measuring substrate (ammonia) specific oxygen uptake rates (SOUR), by using RT-qPCR to quantify the transcripts of functional genes involved in nitrification, and by analysis of 16S rRNA sequences to determine changes in structure and activity of the microbial communities. The nitrifying bioreactor was operated as a continuous reactor with a 24 h hydraulic retention time. The samples were exposed in batch vessels to Cr(III) (10-300 mg/L) and Cr(VI) (1-30 mg/L) for a period of 12 h. There was considerable decrease in SOUR with increasing dosages for both Cr(III) and Cr(VI), however Cr(VI) was more inhibitory than Cr(III). Based on the RT-qPCR data, there was reduction in the transcript levels of amoA and hao for increasing Cr(III) dosage, which corresponded well with the ammonia oxidation activity measured via SOUR. For Cr(VI) exposure, there was comparatively little reduction in amoA expression while hao expression decreased for 1-3 mg/L Cr(VI) and increased at 30 mg/L Cr(VI). While Nitrosomonas spp. were the dominant bacteria in the bioreactor, based on 16S rRNA sequencing, there was a considerable reduction in Nitrosomonas activity upon exposure to 300 mg/L Cr(III). In contrast, a relatively small reduction in activity was observed at 30 mg/L Cr(VI) loading. Our data that suggest that both Cr(III) and Cr(VI) were inhibitory to nitrification at concentrations near the high end of industrial effluent concentrations. PMID- 26774301 TI - A permeable reactive barrier (PRB) media sequence for the remediation of heavy metal and hydrocarbon contaminated water: A field assessment at Casey Station, Antarctica. AB - A field trial was conducted at Casey Station, Antarctica to assess the suitability of a permeable reactive barrier (PRB) media sequence for the remediation of sites containing both hydrocarbon and heavy metal contamination. An existing PRB was modified to assess a sequence consisting of three sections: (i) Nutrient release/hydrocarbon sorption using ZeoProTM and granular activated carbon; (ii) Phosphorus and heavy metal capture by granular iron and sand; (iii) Nutrient and excess iron capture by zeolite. The media sequence achieved a greater phosphorus removal capacity than previous Antarctic PRB configurations installed on site. Phosphorus concentrations were reduced during flow through the iron/sand section and iron concentrations were reduced within the zeolite section. However, non-ideal flow was detected during a tracer test and supported by analysis of media and liquid samples from the second summer of operation. Results indicate that the PRB media sequence trialled might be appropriate for other locations, especially less environmentally challenging contaminated sites. PMID- 26774302 TI - Fur: A non-invasive approach to monitor metal exposure in bats. AB - This paper presents a novel assessment of the use of fur as a non-invasive proxy to biomonitor metal contamination in insectivorous bats. Concentrations of metals (cadmium, copper, lead and zinc) were measured using ICP-MS in tissues (kidneys, liver, stomach and stomach content, bones and fur) obtained from 193 Pipistrellus pipistrellus/pygmaeus bats. The bats were collected across a gradient of metal pollution in England and Wales. The utility of small samples of fur as an indicator of metal exposure from the environment was demonstrated with strong relationships obtained between the concentrations of non-essential metals in fur with concentrations in stomach content, kidneys, liver and bones. Stronger relationships were observed for non-essential metals than for essential metals. Fur analyses might therefore be a useful non-invasive proxy for understanding recent, as well as long term and chronic, metal exposure of live animals. The use of fur may provide valuable information on the level of endogenous metal exposure and contamination of bat populations and communities. PMID- 26774303 TI - Discrimination of excess toxicity from baseline level for ionizable compounds: Effect of pH. AB - The toxic effect can be affected by pH in water through affecting the degree of ionization of ionizable compounds. Wrong classification of mode of action can be made from the apparent toxicities. In this paper, the toxicity data of 61 compounds to Daphnia magna determined at three pH values were used to investigate the effect of pH on the discrimination of excess toxicity. The results show that the apparent toxicities are significantly less than the baseline level. Analysis on the effect of pH on bioconcentration factor (BCF) shows that the log BCF values are significantly over-estimated for the strongly ionizable compounds, leading to the apparent toxicities greatly less than the baseline toxicities and the toxic ratios greatly less than zero. A theoretical equation between the apparent toxicities and pH has been developed basing on the critical body residue (CBR). The apparent toxicities are non-linearly related to pH, but linearly to fraction of unionized form. The determined apparent toxicities are well fitted with the toxicities predicted by the equation. The toxicities in the unionized form calculated from the equation are close to, or greater than the baseline level for almost all the strongly ionizable compounds, which are very different from the apparent toxicities. The studied ionizable compounds can be either classified as baseline, less inert or reactive compounds in D. magna toxicity. Some ionizable compounds do not exhibit excess toxicity at a certain pH, due not to their poor reactivity with target molecules, but because of the ionization in water. PMID- 26774305 TI - Evaluation of the reactivity of exhaust from various biodiesel blends as a measure of possible oxidative effects: A concern for human exposure. AB - Diesel exhaust particles (DEP) are a major constituent of ambient air pollution and are associated with various adverse health effects, posing a major safety and public health concern in ambient and occupational environments. The effects of DEP from various biodiesel blends on biological systems was investigated using glutathione (GSH) as a marker of possible oxidative effects, based on the decrease in the concentration of GSH at physiological pH. The fluorophoric agent 2,3-naphthalenedicarboxaldehyde (NDA) was used as a selective probe of GSH in the presence of any likely interferents via fluorescence detection. Three different polar solvents (acetonitrile, methanol and water) were used to extract DEP generated during the combustion of different biodiesel blends (5%-99%). Oxidation of GSH to the disulfide (GSSG) was confirmed using electrospray ionization mass spectrometry. A decrease in the concentration of GSH was observed in the presence of DEP extracts from all of the biodiesel blends studied, with reaction rates that depend on the biodiesel blend. Interestingly the reactivity peaked at 50% biodiesel (B50) rather than decreasing monotonically with increased biodiesel content, as was expected. Organic solvent DEP extracts showed wider variations in reactivity with GSH, with methanol extracts giving the largest decrease in GSH concentrations. This may imply a more organic nature of the oxidants in the biodiesel exhaust. It is therefore important to consider ways of reducing concentrations of organic components in biodiesel exhaust that can cause different toxic activity before any blend is offered as a preferred alternative to petroleum diesel fuel. PMID- 26774304 TI - Hydroxylated polychlorinated biphenyls in human sera from adolescents and their mothers living in two U.S. Midwestern communities. AB - Hydroxylated polychlorinated biphenyls (OH-PCBs) have been detected in human specimens and some are suspected as being more toxic than their parent compounds. We compared 58 OH-PCB congeners (in 51 chromatographic peaks) in serum samples from participants in the AESOP Study, a longitudinal cohort study of adolescents and their mothers living in urban and rural areas in the United States. We hypothesized that adolescents would have lower levels of OH-PCBs than their mothers and that serum concentration of OH-PCBs would be stable over a 3-year period. We found statistically significant differences in total OH-PCBs between age groups in both East Chicago (p = 0.001) and Columbus Junction (p < 0.001), with adolescents having lower concentrations than their mothers. We observed that lower-chlorinated OH-PCBs were rarely detected, suggesting that they are not retained in serum and/or rapidly biotransformed into other forms. Twelve OH-PCBs, including several that are rarely reported (4,4'-diOH-PCB 202, 4'-OH-PCB 208, and 4-OH-PCB 163) were detected in over 60% of participants. Lastly, from repeated measures within subject serum for three OH-PCBs, concentrations of 4-OH-PCB 107 and 4-OH-PCB 187 changed significantly over three years of the study. PMID- 26774306 TI - Health risks of children's cumulative and aggregative exposure to metals and metalloids in a typical urban environment in China. AB - Rapid development of industrialization and urbanization results in serious environmental contamination by metal(loid)s, which would consequently cause deleterious health effects to the exposed people through multi-pathways. Therefore, total health risk assessment for the population in urban environment is very important. Unfortunately, few studies to date investigate the cumulative health risks of metal(loid)s through aggregative pathways in Children who are often susceptible population. 12 metal(loid)s including Lead(Pb), Cadmium(Cd), Arsenic(As), Chromium(Cr), Zinc(Zn), Copper(Cu), Nickel(Ni), Manganese(Mn), Cobalt(Co), Selenium(Se), Antimony(Se) and Vanadium(V), were analyzed in PM10, drinking water, food, soil and indoor dust in this study. The cumulative and aggregative risks of these metal(loid)s among the local children were then evaluated on a field sampling and questionnaire-survey basis. The results showed that the environments were heavily polluted by metal(loid)s. For most metal(loid)s, food ingestion accounted for more than 80% of the total daily exposure dose. The non-cancer risks were up to 30 times higher than the acceptable level due to the food ingestion via Pb, Cr, Cu, Zn, As, Se, Cd and Sb, and the PM10 inhalation via Cr and Mn. While, the cancer risks were mainly attributed to Cr via food ingestion and As via food and dust ingestion, and approximately 100 times of the maximum acceptable level of 1.0 * 10(-4). The study highlights the cumulative and aggregative exposure assessment, instead of pollutant investigation to evaluate the potential health risks and emphasizes concerns to improve indoor hygienic and environmental quality and to decrease the potential harmful health effects of children living in urban area. PMID- 26774307 TI - Effect of soil washing with only chelators or combining with ferric chloride on soil heavy metal removal and phytoavailability: Field experiments. AB - In a field experiment on multi-metal contaminated soil, we investigated the efficiency of Cd, Pb, Zn, and Cu removal by only mixture of chelators (MC) or combining with FeCl3. After washing treatment, a co-cropping system was performed for heavy metals to be extracted by Sedum alfredii and to produce safe food from Zea mays. We analyzed the concentration of heavy metals in groundwater to evaluate the leashing risk of soil washing with FeCl3 and MC. Results showed that addition of FeCl3 was favorable to the removal of heavy metals in the topsoil. Metal leaching occurred mainly in rain season during the first co-cropping. The removal rates of Cd, Zn, Pb, and Cu in topsoil were 28%, 53%, 41%, and 21% with washing by FeCl3+MC after first harvest. The application of FeCl3 reduced the yield of S. alfredii and increased the metals concentration of Z. mays in first harvest. However, after amending soil, the metals concentration of Z. mays in FeCl3+MC treatment were similar to that only washing by MC. The grains and shoots of Z. mays were safe for use in feed production. Soil washing did not worsen groundwater contamination during the study period. But the concentration of Cd in groundwater was higher than the limit value of Standard concentrations for Groundwater IV. This study suggests that soil washing using FeCl3 and MC for the remediation of multi-metal contaminated soil is potential feasibility. However, the subsequent measure to improve the washed soil environment for planting crop is considered. PMID- 26774308 TI - Effects of lead on growth, photosynthetic characteristics and production of reactive oxygen species of two freshwater green algae. AB - In the natural environment, heavy metal contamination can occur as long-term pollution of sites or as pulses of pollutants from wastewater disposal. In this study two freshwater green algae, Chlorella sp. FleB1 and Scenedesmus YaA6, were isolated from lead-polluted water samples and the effects of 24 h vs 4 and 8 d exposure of cultures to lead on growth, photosynthetic physiology and production of reactive oxygen species (ROS) of these algae were investigated. In Chlorella sp. FleB1, there was agreement between lead impacts on chlorophyll content, photosynthesis and growth in most case. However, in Scenedesmus acutus YaA6 growth was inhibited at lower lead concentrations (0.03-0.87 * 10(-9) M), under which ROS, measured by 2',7' dichlorodihydrofluorescein diacetate fluorescence, were 4.5 fold higher than in controls but photosynthesis was not affected, implying that ROS had played a role in the growth inhibition that did not involve direct effects on photosynthesis. Effects of short-term (5 h, 24 h) vs long-term (4 d and 8 d) exposure to lead were also compared between the two algae. The results contribute to our understanding of the mechanisms of lead toxicity to algae. PMID- 26774309 TI - Sources and fate of mercury pollution in Almaden mining district (Spain): Evidences from mercury isotopic compositions in sediments and lichens. AB - Variations in mercury (Hg) isotopic compositions have been scarcely investigated until now in the Almaden mining district (Spain), which is one of the most impacted Hg areas worldwide. In this work, we explore and compare Hg isotopic signatures in sediments and lichens from Almaden mining district and its surroundings in order to identify and trace Hg aquatic and atmospheric contamination sources. No statistically significant mass independent fractionation was observed in sediments, while negative Delta(201)Hg values from 0.12 to -0.210/00 (2SD = 0.060/00) were found in lichens. A large range of delta(202)Hg values were reported in sediments, from -1.86 +/- 0.210/00 in La Serena Reservoir sites far away from the pollution sources to delta(202)Hg values close to zero in sediments directly influenced by Almaden mining district, whereas lichens presented delta(202)Hg values from -1.95 to -0.400/00 (2SD = 0.150/00). A dilution or mixing trend in Hg isotope signatures versus the distance to the mine was found in sediments along the Valdeazogues River-La Serena Reservoir system and in lichens. This suggests that Hg isotope fingerprints in these samples are providing a direct assessment of Hg inputs and exposure from the mining district, and potential information on diffuse atmospheric contamination and/or geochemical alteration processes in less contaminated sites over the entire hydrosystem. This study confirms the applicability of Hg isotope signatures in lichens and sediments as an effective and complementary tool for tracing aquatic and atmospheric Hg contamination sources and a better constraint of the spatial and temporal fate of Hg released by recent or ancient mining activities. PMID- 26774310 TI - Nanomineralogy in the real world: A perspective on nanoparticles in the environmental impacts of coal fire. AB - Detailed geochemistry similarities between the burning coal cleaning rejects (BCCRs) and non-anthropogenic geological environments are outlined here. While no visible flames were detected, this research revealed that auto-combustion existed in the studied area for many years. The occurrence of several amorphous phases, mullite, hematite and many other Al/Fe-minerals formed by high temperature was found. Bad disposal of coal-dump wastes represents significant environmental concerns due to their potential influence on atmosphere, river sediments, soils and as well as on the surface and groundwater in the surroundings of these areas. The present work using multi-analytical techniques were performed to provide an improved understanding of the complex processes related with sulphide-rich coal waste oxidation, spontaneous combustion and newmineral creation. It recording huge numbers of rare minerals with alunite, montmorillonite, szmolnockite, halotrichite, coquimbite and copiapite at the BCCRs. The information presented the presence of abundant amorphous Si-Al-Fe-Ti as (oxy-)hydroxides and Fe hydro/oxides with goethite and hematite with various degrees of crystallinity, containing potential hazardous elements (PHEs), such as Cu, Cr, Hf, Hg, Mo, Ni, Se, Pb, Th, U, Zr, and others. Most of the nano-particles and ultra-fine particles found in the burned coal-dump wastes are the same as those commonly associated with coal cleaning rejects, in which oxidation of sulphides plays an important impact to environment and subsequently animal and human health. PMID- 26774311 TI - Bioaccessibility of arsenic and cadmium assessed for in vitro bioaccessibility in spiked soils and their interaction during the Unified BARGE Method (UBM) extraction. AB - Recent decades have seen a growing popularity of in vitro bioaccessibility being utilised as a screening tool in human health risk assessment. However the existing bioaccessibility studies only focus on single contaminant. Considering human are likely to ingest multi-contaminants, these contaminants could interact within human gastrointestinal tract which may lead to an increase or decrease in bioaccessibility. In this study, seven different types of soil were spiked with arsenic (As) or cadmium (Cd) and aged for one year. The effects of soil properties on the bioaccessibility were examined. Moreover, the interaction between As and Cd in simulated human digestive system was studied by mixing As spiked soil with Cd-spiked soil of the same type during bioaccessibility test. Results shows the bioaccessibility of As ranged from 40 +/- 2.8 to 95 +/- 1.3% in the gastric phase and 16 +/- 2.0 to 96 +/- 0.8% in the intestinal phase whilst a significant difference was observed between Cd gastric bioaccessibility (72 +/- 4.3 to 99 +/- 0.8%) and intestinal bioaccessibility (6.2 +/- 0.3 to 45 +/- 2.7%). Organic carbon, iron oxide and aluminium oxide were key parameters influencing the bioaccessibility of As (gastric and intestinal phases) and Cd (intestinal phase). No interactions between As and Cd during bioaccessibility test were observed in any soils, which indicates As and Cd may age independently and did not interact while being solubilised during bioaccessibility test. Thus additive effect may be proposed when estimating the bioaccessibility of mixtures of independently-aged As and Cd in soils. PMID- 26774312 TI - Effect of different post space irrigation procedures on the bond strength of a fiber post attached with a self-adhesive resin cement. AB - STATEMENT OF PROBLEM: The effects of different post space irrigation procedures on the bond strength of a self-adhesive resin cement to the root canal dentin are still unclear. PURPOSE: The purpose of this in vitro study was to evaluate the effects of alternative post space irrigation procedures on the cement strengths of posts attached with a self-adhesive resin cement. MATERIAL AND METHODS: Forty single-rooted teeth were selected, and after root canal preparation and obturation, post spaces were prepared. The teeth were divided into 4 groups corresponding to the post space irrigation procedure and treated as follows: the distilled water (DW) group (control) received 15 mL of distilled water; the NaOCl+ethylenediaminetetraacetic acid (EDTA) group was treated with 5 mL of 5.25% NaOCl, 5 mL of 17% EDTA, and 5 mL of distilled water; the chlorhexidine (CHX) group was treated with 15 mL of 2% chlorhexidine solution; and the phosphoric acid (PA) group treatment consisted of etching the walls of the prepared post holes with 35% phosphoric acid. Fiber posts were attached with a self-adhesive resin cement, and specimens were cut horizontally for push-out testing. The statistical evaluation consisted of 1-way ANOVA with the post hoc Tukey honest significant differences test (alpha=.05). RESULTS: The NaOCl+EDTA treatment yielded a significantly higher bond strength than those used in the other 3 groups (P=.003). No statistically significant differences were found among any of the other groups, as different root regions showed similar bond strength values (P>.05). CONCLUSIONS: The results showed that EDTA in combination with NaOCl could be advantageous for post space irrigation when fiber posts are bonded with a self-adhesive resin cement. PMID- 26774313 TI - In vitro evaluation of the marginal integrity of CAD/CAM interim crowns. AB - STATEMENT OF PROBLEM: The accuracy of interim crowns made with computer-aided design and computer-aided manufacturing (CAD/CAM) systems has not been well investigated. PURPOSE: The purpose of this in vitro study was to evaluate the marginal integrity of interim crowns made by CAD/CAM compared with that of conventional polymethylmethacrylate (PMMA) crowns. MATERIAL AND METHODS: A dentoform mandibular left second premolar was prepared for a ceramic crown and scanned for the fabrication of 60 stereolithical resin dies, half of which were scanned to fabricate 15 Telio CAD-CEREC and 15 Paradigm MZ100-E4D-E4D crowns. Fifteen Caulk and 15 Jet interim crowns were made on the remaining resin dies. All crowns were cemented with Tempgrip under a 17.8-N load, thermocycled for 1000 cycles, placed in 0.5% acid fuschin for 24 hours, and embedded in epoxy resin before sectioning from the mid-buccal to mid-lingual surface. The marginal discrepancy was measured using a traveling microscope, and dye penetration was measured as a percentage of the overall length under the crown. RESULTS: The mean vertical marginal discrepancy of the conventionally made interim crowns was greater than for the CAD/CAM crowns (P=.006), while no difference was found for the horizontal component (P=.276). The mean vertical marginal discrepancy at the facial surface of the Caulk crowns was significantly greater than that of the other 3 types of interim crowns (P<.001). At the facial margin, the mean horizontal component of the Telio crowns was significantly larger than that of the other 3 types, with no difference at the lingual margins (P=.150). The mean percentage dye penetration for the Paradigm MZ100-E4D crowns was significantly greater and for Jet crowns significantly smaller than for the other 3 crowns (P<.001). However, the mean percentage dye penetration was significantly correlated with the vertical and horizontal marginal discrepancies of the Jet interim crowns at the facial surface and with the horizontal marginal discrepancies of the Caulk interim crowns at the lingual surface (P<.01 in each instance). CONCLUSIONS: A significantly smaller vertical marginal discrepancy was found with the interim crowns fabricated by CAD/CAM as compared with PMMA crowns; however, this difference was not observed for the horizontal component. The percentage dye penetration was correlated with vertical and horizontal discrepancies at the facial surface for the Jet interim crowns and with horizontal discrepancies at the lingual surface for the Caulk interim crowns. PMID- 26774314 TI - Fixed dental prostheses with vertical tooth preparations without finish lines: A report of two patients. AB - Tooth abutments can be prepared to receive fixed dental prostheses with different types of finish lines. The literature reports different complications arising from tooth preparation techniques, including gingival recession. Vertical preparation without a finish line is a technique whereby the abutments are prepared by introducing a diamond rotary instrument into the sulcus to eliminate the cementoenamel junction and to create a new prosthetic cementoenamel junction determined by the prosthetic margin. This article describes 2 patients whose dental abutments were prepared to receive ceramic restorations using vertical preparation without a finish line. PMID- 26774315 TI - Fabrication technique for a custom face mask for the treatment of obstructive sleep apnea. AB - The development of the positive airway pressure custom mask (TAP-PAP CM) has changed the treatment of obstructive sleep apnea. The TAP-PAP CM is used in continuous positive airway pressure therapy (CPAP) and is fabricated from the impression of the face. This mask is then connected to a post screwed into the mechanism of the TAP3 (Thornton Anterior Positioner) oral appliance. This strapless CPAP face mask features an efficient and stable CPAP interface with mandibular stabilization (Hybrid Therapy). A technique with a 2-stage polyvinyl siloxane face impression is described that offers improvements over the established single-stage face impression. This 2-stage impression technique eliminates problems inherent in the single-stage face impression, including voids, compressed tissue, inadequate borders, and a rushed experience due to the setting time of the single stage. The result is a custom mask with an improved seal to the CPAP device. PMID- 26774316 TI - Fabricating a tooth- and implant-supported maxillary obturator for a patient after maxillectomy with computer-guided surgery and CAD/CAM technology: A clinical report. AB - An obturator prosthesis with insufficient retention and support may be improved with implant placement. However, implant surgery in patients after maxillary tumor resection can be complicated because of limited visibility and anatomic complexity. Therefore, computer-guided surgery can be advantageous even for experienced surgeons. In this clinical report, the use of computer-guided surgery is described for implant placement using a bone-supported surgical template for a patient with maxillary defects. The prosthetic procedure was facilitated and simplified by using computer-aided design/computer-aided manufacture (CAD/CAM) technology. Oral function and phonetics were restored using a tooth- and implant supported obturator prosthesis. No clinical symptoms and no radiographic signs of significant bone loss around the implants were found at a 3-year follow-up. The treatment approach presented here can be a viable option for patients with insufficient remaining zygomatic bone after a hemimaxillectomy. PMID- 26774317 TI - Simplified custom impression post for implant-supported restorations. AB - The esthetic outcome of an implant-supported restoration is greatly influenced by the relationship between the contours of the definitive prosthesis and the periimplant tissues. In this clinical technique, an implant analog holder and autopolymerizing acrylic resin were used to accurately register the soft-tissue transition zone created by the interim restoration and transfer it to the impression post during the definitive impression. PMID- 26774319 TI - Integrating conventional and CAD/CAM digital techniques for establishing canine protected articulation: A clinical report. AB - Canine protected articulation is widely accepted for patients requiring extensive oral rehabilitation. Computer-aided design and computer-aided manufacturing (CAD/CAM) restorations have been primarily designed in occlusion at the maximum intercuspal position. Designing a virtual articulator that is capable of accepting excursive occlusal records and duplicating the mandibular movements is a challenge for CAD/CAM technology. Modifying tooth shape using composite resin trial restorations to produce esthetic results and later scanning the modified teeth to create milled crowns is becoming a popular use of the CAD/CAM technology. This report describes a technique that combines conventional and CAD/CAM prosthodontic techniques for milling crowns for canine teeth that are designed to establish or improve canine protected articulation. This technique involves designing and fabricating interim restorations based on diagnostic waxing, scanning the designs intraorally, and storing them in software as pretreatment digital records. The scanned designs are then applied to the digital representation of the prepared teeth to fabricate the definitive restorations. PMID- 26774318 TI - Trueness of milled prostheses according to number of ball-end mill burs. AB - STATEMENT OF PROBLEM: Making a computer-aided design/computer-aided manufacturing (CAD/CAM) prosthesis with a milling machine often requires 2 (2- and 1-mm diameter) or 3 (2-, 1-, and 0.6-mm diameter) burs; however, using 3 burs can reduce time effectiveness and increase cost. Studies evaluating the trueness of prostheses made with 2 and 3 burs are lacking. PURPOSE: The purpose of this in vitro study was to evaluate the 3-dimensional trueness of crown prostheses made using 2 and 3 ball-end mill burs in the milling process. MATERIAL AND METHODS: The abutment die of the maxillary right first molar for ceramic crowns was designed with computer-aided design software. After the crown prosthesis design was completed, polyurethane blocks were milled using 2 and 3 burs with a 5-axis milling machine. The outer and inner surfaces of the milled crown prostheses were scanned with a dental scanner. The inner part was separated into a marginal part and an internal part using 3-dimensional evaluation software. The 3-dimensional trueness of the prostheses milled with 2 or 3 burs was compared. RESULTS: No significant differences in trueness were found for the inner or internal parts of the prosthesis (P>.05). However, the outer and marginal parts of the prosthesis did show significant differences in trueness (P<.05). CONCLUSIONS: Milling the marginal part of the inner prosthesis was better with 2 burs, whereas milling the outer part was better with 3 burs. PMID- 26774320 TI - Factors influencing the progression of noncarious cervical lesions: A 5-year prospective clinical evaluation. AB - STATEMENT OF PROBLEM: The etiology (chemical, friction, abfraction) of noncarious cervical lesion (NCCL) progression is poorly understood. PURPOSE: The purpose of this 5-year prospective clinical trial was to measure the relationship between NCCLs and various etiologic factors. MATERIAL AND METHODS: After review board approval, 29 participants with NCCLs were enrolled. Polyvinyl siloxane impressions were made of each NCCL, and casts were poured at baseline, 1, 2, and 5 years. The casts were scanned with a noncontact profilometer, and 1-, 2-, and 5 year scans were superimposed over baseline scans to measure volumetric change in NCCLs. T-scan and Fujifilm Prescale films were used to record relative and absolute occlusal forces on teeth with NCCLs at the 5-year recall. Participant diet, medical condition, toothbrushing, and adverse oral habit questionnaires were given at the 5-year recall. Occlusal analysis was completed on mounted casts to determine the presence of wear facets and group function. Volumetric lesion progression from 1 to 5 years was correlated to absolute and relative occlusal force using mixed model analysis. The Kruskall-Wallis and Mann-Whitney analyses compared lesion progression with diet, medical condition, toothbrushing, adverse oral habits, wear facets, and group function. RESULTS: The NCCL progression rate over 5 years was 1.50 +/-0.92 mm(3)/yr. The rate of progression of NCCLs was related to mean occlusal stress (P=.011) and relative occlusal force (P=.032) in maximum intercuspation position. No difference was seen in NCCL progression between participants with any other factors. CONCLUSION: Heavy occlusal forces play a significant role in the progression of NCCLs. PMID- 26774321 TI - Minimum intervention in restorative dentistry with V-shaped facial and palatal ceramic veneers: A clinical report. AB - The esthetic and functional rehabilitation of worn anterior teeth should follow the principles of minimally invasive dentistry. When dental wear occurs at both the facial and palatal surfaces, the sandwich approach of reconstructing eroded anterior teeth with palatal followed by facial veneers is a straightforward treatment that preserves sound dental structure. PMID- 26774323 TI - Complete denture fabrication supported by CAD/CAM. AB - The inclusion of computer-aided design/computer-aided manufacturing (CAD/CAM) technology into complete denture fabrication facilitates the procedures. The presented workflow for complete denture fabrication combines conventional and digitally supported treatment steps for improving dental care. With the presented technique, the registration of the occlusal plane, the determination of the ideal lip support, and the verification of the maxillomandibular relationship record are considered. PMID- 26774322 TI - Reliability of retrievable cemented implant-supported prostheses. AB - STATEMENT OF PROBLEM: One of the disadvantages of a cemented implant restoration is the potential difficulty of retrieving it. The restoration may be destroyed during removal. PURPOSE: The purpose of this retrospective clinical study was to assess the long-term survival rates of cemented posterior metal ceramic implant supported prostheses (ISPs) with a metal screw access hole. MATERIAL AND METHODS: During a 12-year period, 274 cemented ISPs with an abutment screw access hole in the metal framework were assessed and served as the study group, and 119 conventional cemented ISPs (without access hole) served as the control group. Participants were followed every 6 months in the first year and once a year subsequently. Ceramic fracture, screw loosening, and refabrication were the prosthetic outcome parameters evaluated at the recall. The Pearson Chi square and Fisher exact test were used to compare the outcome parameters between the control and study groups. RESULTS: A total of 1005 implants and 393 ISPs were evaluated. Ceramic fracture occurred in 6.6% of the ISPs (6.2% test and 7.6% control). Screw loosening occurred in 3.28% of the test group and 3.36% of the control group. Refabrication of ISPs was done in 2.79% of all restorations, (1.45% test and 6.72% control [P=.012]). CONCLUSIONS: Within the limits of this study, preparing cemented ISPs with a screw access hole in the metal framework improves ISP survival rates over time and lowers the cost of maintenance without increasing the risk for porcelain fracture or screw loosening. PMID- 26774325 TI - Multiple response optimization of a liquid chromatographic method for determination of fluoroquinolone and nitroimidazole antimicrobials in serum and urine. AB - OBJECTIVES: Development and validation of a sensitive, selective and robust SPE assisted HPLC method for the quantification of fluoroquinolones and nitroimidazoles in human serum and urine using design of experiments methodology. DESIGN AND METHODS: Design of experiments was employed for method optimization (Box-Behnken design) and robustness testing (Plackett-Burman design). Sample preparation involved a simple solid phase extraction, which offered a satisfactory recovery (>=94%). Analytes were separated on a phenyl hexyl column with mobile phase comprising water, acetonitrile and triethyl amine in ratio of 74:26:0.15 v/v, with a flow rate of 1.1mL/min. RESULTS: Calibration curves were linear over selected range (>=0.995) for all the analytes. The method was sensitive with detection limits of 0.06-0.16MUg/mL in serum and urine samples. Inter and intra-day precision data (in terms of %RSD) was found to be less than 7%. Stability studies were carried out to assess freeze thaw, short term and long term stability and all analytes were found to be stable. The method was successfully applied for determination of antimicrobial drugs in spiked serum and urine. CONCLUSION: The obtained results corroborated the potential of the proposed method for determination of all the four antimicrobial drugs in therapeutic drug monitoring, bioequivalence and drug-drug interaction studies. PMID- 26774324 TI - Systolic pressure response to voluntary apnea predicts sympathetic tone in obstructive sleep apnea as a clinically useful index. AB - The present investigation tested the hypotheses that systolic arterial pressure (SAP) responses to voluntary apnea (a) serve as a surrogate of sympathetic nerve activity (SNA), (b) can distinguish Obstructive Sleep Apnea (OSA) patients from control subjects and (c) can document autonomic effects of treatment. 9 OSA and 10 control subjects were recruited in a laboratory study; 44 OSA subjects and 78 control subjects were recruited in a clinical study; and 21 untreated OSA subjects and 14 well-treated OSA subjects were recruited into a treatment study. Each subject performed hypoxic and room air voluntary apneas in triplicate. Muscle SNA (MSNA) and continuous AP were measured during each apnea in the laboratory study, while systolic arterial pressure (SAP) responses were measured continuously and by standard auscultation in the clinical and treatment studies. OSA subjects exhibited increased mean arterial pressure (MAP), SAP and MSNA responses to hypoxic apnea (all P<0.01) and the SAP response highly correlated with the MSNA response (R(2)=0.72, P<0.001). Clinical assessment confirmed that OSA subjects exhibited markedly elevated SAP responses (P<0.01), while treated OSA subjects had a decreased SAP response to apnea (P<0.04) compared to poorly treated subjects. These data indicate that (a) OSA subjects exhibit increased pressor and MSNA responses to apnea, and that (b) voluntary apnea may be a clinically useful assessment tool of autonomic dysregulation and treatment efficacy in OSA. PMID- 26774326 TI - Bisalbuminaemia due to novel mutation at a critical residue involved in recycling; Albumin Lyon (510His->Arg). AB - OBJECTIVES: To define the underlying cause of bisalbuminaemia in an individual presenting with spontaneous venous thrombosis. METHOD: Plasma was examined by electrospray time-of-flight mass spectrometry (TOF MS) to assess albumin mutations and to quantify variant expression level. Tryptic peptide mapping and DNA sequencing were used to precisely define the mutation. RESULTS: Whole protein MS indicated a 19Da increase in the mass of 50% of the albumin molecules suggesting a His->Arg substitution. A novel heterozygous 510His->Arg mutation was identified by peptide mass mapping and confirmed by DNA sequencing of exon 12 of the albumin gene. CONCLUSION: The nature and location of the mutation suggest it would have no direct influence on haemostasis through altered warfarin binding or increased fibrinogen attachment and it appears to be incidental to the thrombotic phenotype. However the highly conserved His510 residue is recognised as being of critical importance in albumin recycling through interaction with its savaging neonatal Fc receptor. The normal albumin level of 41.1g/l and the coequal expression of albumin Lyon demonstrate that the conservative 510His->Arg substitution does not interfere with the pH dependant capture and release of albumin by the receptor. PMID- 26774328 TI - Surface mobility of molecular glasses and its importance in physical stability. AB - Amorphous molecular materials (molecular glasses) are useful for drug delivery, bio-preservation and organic electronics. A central issue in developing amorphous materials is the stability against crystallization and other transformations that can compromise material performance. We review recent progress in understanding the stability of molecular glasses, particularly the role for surface mobility. Surface diffusion in molecular glasses can be vastly faster than bulk diffusion. This high surface mobility enables fast crystal growth on the free surface. In this process, surface crystals grow upward and laterally, with the lateral growth rate being roughly proportional to surface diffusivity. Surface mobility also influences bulk crystal growth as the process can create fracture and free surfaces. During vapor deposition, surface mobility allows efficient equilibration of newly deposited molecules, producing low-energy, high-density glasses that are equivalent to liquid-cooled glasses aged for thousands of years. Free surfaces can accelerate chemical degradation of proteins. Measures for inhibiting surface-facilitated transformations include minimizing free surfaces, applying surface coatings, and preventing fracture. PMID- 26774327 TI - Decision support systems for personalized and participative radiation oncology. AB - A paradigm shift from current population based medicine to personalized and participative medicine is underway. This transition is being supported by the development of clinical decision support systems based on prediction models of treatment outcome. In radiation oncology, these models 'learn' using advanced and innovative information technologies (ideally in a distributed fashion - please watch the animation: http://youtu.be/ZDJFOxpwqEA) from all available/appropriate medical data (clinical, treatment, imaging, biological/genetic, etc.) to achieve the highest possible accuracy with respect to prediction of tumor response and normal tissue toxicity. In this position paper, we deliver an overview of the factors that are associated with outcome in radiation oncology and discuss the methodology behind the development of accurate prediction models, which is a multi-faceted process. Subsequent to initial development/validation and clinical introduction, decision support systems should be constantly re-evaluated (through quality assurance procedures) in different patient datasets in order to refine and re-optimize the models, ensuring the continuous utility of the models. In the reasonably near future, decision support systems will be fully integrated within the clinic, with data and knowledge being shared in a standardized, dynamic, and potentially global manner enabling truly personalized and participative medicine. PMID- 26774330 TI - Zika and microcephaly: causation, correlation, or coincidence? PMID- 26774329 TI - Recombinant murine toxin from Yersinia pestis shows high toxicity and beta adrenergic blocking activity in mice. AB - Yersinia pestis murine toxin (Ymt) encoded on pMT1 is a 61-kDa protein, a member of the phospholipase D superfamily, which is found in all the domains of life. It is considered to be an intracellular protein required for the survival of Y. pestis in the midgut of the flea, but the exact role of Ymt in the pathogenesis of Y. pestis has not been clarified. Purified Ymt is highly toxic to mice and rats, but the exact mechanism of the animals' death is unclear. Here, we prepared a recombinant Ymt in Escherichia coli BL21 cells, and determined its toxicity and activity. We demonstrated that recombinant Ymt was as toxic to mice as the native protein when administered via the intraperitoneal or intravenous route, and inhibited the elevation of blood sugar caused by adrenaline. We also demonstrated that recombinant Ymt was highly toxic to mice when administered via the muscular or subcutaneous route. We also show that the multiple organ congestion or hemorrhage caused by Ymt poisoning may explain the death of the mice. PMID- 26774331 TI - Autophagy and viral diseases transmitted by Aedes aegypti and Aedes albopictus. AB - Despite a long battle that was started by Oswaldo Cruz more than a century ago, in 1903, Brazil still struggles to fight Aedes aegypti and Aedes albopictus, the mosquito vectors of dengue virus (DENV), Chikungynya virus (CHIKV) and Zika virus (ZIKV). Dengue fever has been a serious public health problem in Brazil for decades, with recurrent epidemic outbreaks occurring during summers. In 2015, until November, 1,534,932 possible cases were reported to the Ministry of Healthv. More recently, the less studied CHIKV and ZIKV have gained attention because of a dramatic increase in their incidence (around 400% for CHIKV) and the association of ZIKV infection with a 11-fold increase in the number of cases of microcephaly from 2014 to 2015 in northeast Brazil (1761 cases until December 2015). The symptoms of these three infections are very similar, which complicates the diagnosis. These include fever, headache, nausea, fatigue, and joint pain. In some cases, DENV infection develops into dengue hemorrhagic fever, a life threatening condition characterized by bleeding and decreases in platelet numbers in the blood. As for CHIKV, the most important complication is joint pain, which can last for months. PMID- 26774332 TI - Characterization of IgA1 protease as a surface protective antigen of Streptococcus suis serotype 2. AB - IgA1 protease of Streptococcus suis serotype 2 (SS2) has been proven to be relative with virulence and immunogenicity, however, its protective efficacy remained to be evaluated. The present study found evidence that immunization with purified recombinant IgA1 protease (600-1926aa) could induce high IgG antibody titers and could confer complete protection against a challenge with a lethal dose of SS2 in a mouse model. In addition, our findings confirmed that the IgA1 protease distributes on the surface of SS2. Therefore, the present study identified the virulence-associated protein, IgA1 protease, as a novel surface protective antigen of SS2. PMID- 26774333 TI - Neutralization breadth and potency of serum derived from recently human immunodeficiency virus type 1-infected Thai individuals. AB - Neutralizing antibody responses play important roles in controlling several viral infections including human immunodeficiency virus type 1 (HIV-1). Potent and broad neutralizing antibody responses have been reported in some HIV-1-infected individuals; therefore, elucidating the mechanisms underlying neutralizing antibody responses will provide important information for the development of anti HIV-1 vaccines. We herein performed a comparative study on the neutralization breadth and potency of serum samples collected from Thai individuals recently and chronically infected with HIV-1. Neutralization tests using a series of envelope glycoproteins (Env)-recombinant viruses revealed that although several serum samples derived from recently infected individuals did not show any HIV-1 specific neutralizing activity, the remaining serum samples exhibited neutralizing activity not only for recombinant viruses with CRF01_AE Env, but also for viruses with subtypes B and C Env. Furthermore, some serum samples derived from recently infected individuals showed the neutralization potency. Our results may provide a deeper insight into the characteristics of neutralizing antibody responses that develop during the course of HIV-1 infection among individuals in Thailand. PMID- 26774334 TI - Suppression of host PTEN gene expression for Leishmania donovani survival in Indian visceral leishmaniasis. AB - Lipid phosphatase, PTEN is amongst the host gene actively involved in determining disease susceptibility. Expression of pten and other genes in vicinity egr1 &4e bp1 were evaluated in splenic tissue before and after treatment in visceral leishmaniasis patients. Lower expression of egr1 in correlation with pten suppressed 4e-bp1 gene in active cases. The higher levels of pten mRNA expression post treatment confirmed its role in effective clearance of Leishmania. Therefore, it is hypothesized that lower mRNA expression of pten is due to suppression of egr1 activates PI3K signaling bestowing host the ability to cope up infection and continue its normal metabolic machinery. PMID- 26774335 TI - Lonely planet: Multicellular organisms. PMID- 26774336 TI - Reply. PMID- 26774337 TI - Nicotine induces mitochondrial fission through mitofusin degradation in human multipotent embryonic carcinoma cells. AB - Nicotine is considered to contribute to the health risks associated with cigarette smoking. Nicotine exerts its cellular functions by acting on nicotinic acetylcholine receptors (nAChRs), and adversely affects normal embryonic development. However, nicotine toxicity has not been elucidated in human embryonic stage. In the present study, we examined the cytotoxic effects of nicotine in human multipotent embryonal carcinoma cell line NT2/D1. We found that exposure to 10 MUM nicotine decreased intracellular ATP levels and inhibited proliferation of NT2/D1 cells. Because nicotine suppressed energy production, which is a critical mitochondrial function, we further assessed the effects of nicotine on mitochondrial dynamics. Staining with MitoTracker revealed that 10 MUM nicotine induced mitochondrial fragmentation. The levels of the mitochondrial fusion proteins, mitofusins 1 and 2, were also reduced in cells exposed to nicotine. These nicotine effects were blocked by treatment with mecamylamine, a nonselective nAChR antagonist. These data suggest that nicotine degrades mitofusin in NT2/D1 cells and thus induces mitochondrial dysfunction and cell growth inhibition in a nAChR-dependent manner. Thus, mitochondrial function in embryonic cells could be used to assess the developmental toxicity of chemicals. PMID- 26774338 TI - The replication foci targeting sequence (RFTS) of DNMT1 functions as a potent histone H3 binding domain regulated by autoinhibition. AB - DNA methyltransferase 1 (DNMT1) plays an essential role in propagation of the DNA methylation pattern to daughter cells. The replication foci targeting sequence (RFTS) of DNMT1 is required for the recruitment of DNMT1 to DNA methylation sites through direct binding to ubiquitylated histone H3 mediated by UHRF1 (Ubiquitin like containing PHD and RING finger domains 1). Recently, it has been reported that the RFTS plugs the catalytic pocket of DNMT1 in an intermediated manner and inhibits its DNA methyltransferase activity. However, it is unclear whether this binding affects RFTS function in terms of recruitment to DNA methylation sites. Using Xenopus egg extracts, we demonstrate here that abrogation of the interaction between the RFTS and the catalytic center of DNMT1, by deletion of the C-terminal portion or disruption of the hydrogen bond, results in non ubiquitylated histone H3 binding and abnormal accumulation of DNMT1 on the chromatin. Interestingly, DNMT1 mutants identified in patients with a neurodegenerative disease, ADCA-DN, bound to non-ubiquitylated histone H3 and accumulated on chromatin during S phase in Xenopus egg extracts. These results suggest that the interaction between the RFTS and the catalytic center of DNMT1 serves as an autoinhibitory mechanism for suppressing the histone H3 binding of DNMT1 and ensuring the accurate recruitment of DNMT1 to sites of DNA methylation. The autoinhibitory mechanism may play an important role in the regulation of gene expression in neurogenesis. PMID- 26774339 TI - The DJ-1 superfamily members YhbO and YajL from Escherichia coli repair proteins from glycation by methylglyoxal and glyoxal. AB - YhbO and YajL belong to the PfpI/Hsp31/DJ-1 superfamily. Both proteins are involved in protection against environmental stresses. Here, we show that, like DJ-1 and Hsp31, they repair glyoxal- and methylglyoxal-glycated proteins. YhbO and YajL repair glycated serum albumin, collagen, glyceraldehyde-3-phosphate dehydrogenase, and fructose biphosphate aldolase. Bacterial extracts from deglycase mutants display increased glycation levels, whereas deglycase overexpression decreases protein glycation. Moreover, yhbO and yajL mutants display decreased viability in methylglyoxal- or glucose-containing media. Finally, the apparent glyoxalase activities of YhbO and YajL reflect their deglycase activities. PMID- 26774340 TI - Stoichiometry of ATP hydrolysis and chlorophyllide formation of dark-operative protochlorophyllide oxidoreductase from Rhodobacter capsulatus. AB - Dark-operative protochlorophyllide (Pchlide) oxidoreductase (DPOR) is a nitrogenase-like enzyme catalyzing a reduction of the C17 = C18 double bond of Pchlide to form chlorophyllide a (Chlide) in bacteriochlorophyll biosynthesis. DPOR consists of an ATP-dependent reductase component, L-protein (a BchL dimer), and a catalytic component, NB-protein (a BchN-BchB heterotetramer). The L-protein transfers electrons to the NB-protein to reduce Pchlide, which is coupled with ATP hydrolysis. Here we determined the stoichiometry of ATP hydrolysis and the Chlide formation of DPOR. The minimal ratio of ATP to Chlide (ATP/2e(-)) was 4, which coincides with that of nitrogenase. The ratio increases with increasing molar ratio of L-protein to NB-protein. This profile differs from that of nitrogenase. These results suggest that DPOR has a specific intrinsic property, while retaining the common features shared with nitrogenase. PMID- 26774341 TI - Single octapeptide deletion selectively processes a pathogenic prion protein mutant on the cell surface. AB - The number of octapeptide repeats has been considered to correlate with clinical and pathogenic phenotypes of prion diseases resulting from aberrant metabolism of prion protein (PrP). However, it is still poorly understood how this motif affects PrP metabolism. Here, we discover homozygous single octapeptide repeat deletion mutation in the PRNP gene encoding PrP in HeLa cells. The level of PrP proves to be unaffected by this mutation alone, but selectively reduced by additional pathogenic mutations within internal hydrophobic region of PrP. The pattern and relative amount of newly synthesized A117V mutant is unaffected, whereas the mutant appears to be differentially distributed and processed on the cell surface by single octapeptide deletion. This study provides an insight into a novel mutant-specific metabolism of PrP on the cell surface. PMID- 26774342 TI - High inorganic phosphate causes DNMT1 phosphorylation and subsequent fibrotic fibroblast activation. AB - Phosphate is an essential constituent of critical cellular functions including energy metabolism, nucleic acid synthesis and phosphorylation-dependent cell signaling. Increased plasma phosphate levels are an independent risk factor for lowered life-expectancy as well as for heart and kidney failure. Nevertheless, direct cellular effects of elevated phosphate concentrations within the microenvironment are poorly understood and have been largely neglected in favor of phosphor-regulatory hormones. Because interstitial fibrosis is the common determinant of chronic progressive kidney disease, and because fibroblasts are major mediators of fibrogenesis, we here explored the effect of high extracellular phosphate levels on renal fibroblasts. We demonstrate that high inorganic phosphate directly induces fibrotic fibroblast activation associated with increased proliferative activity, increased expression of alpha-smooth muscle actin and increased synthesis of type I collagen. We further demonstrate that such fibroblast activation is dependent on phosphate influx, aberrant phosphorylation of DNA methyltransferase DNMT1 and aberrant CpG island promoter methylation. In summary, our studies demonstrate that elevated phosphate concentrations induce pro-fibrotic fibroblast activation independent of phospho regulatory hormones. PMID- 26774343 TI - Kazinol-E is a specific inhibitor of ERK that suppresses the enrichment of a breast cancer stem-like cell population. AB - Growing evidence shows that cancer stem-like cells (CSLCs) contribute to breast cancer recurrence and to its resistance to conventional therapies. The extracellular signal-regulated kinase (ERK) signaling pathway is a major determinant in the control of diverse cellular processes, including the maintenance of CSLCs. In this study, we found that Kazinol-E, an antioxidant flavan from Broussonetia kazinoki, decreased the CSLC population of a breast cancer cell line, MCF7. The CSLC population, characterized by CD44 high/CD24 low expression or by high Aldehyde dehydrogenase 1 activity, was decreased by a concentration of Kazinol-E that did not affect the growth of bulk-cultured MCF7 cells. Kazinol-E did not decrease EGF-induced ERK phosphorylation in CSLCs, but did block the phosphorylation of an ERK substrate, p90RSK2, at Thr359/Ser363. We further demonstrated that EGF-induced ERK activity was blocked by Kazinol-E in a wild-type K-Ras-expressing non-small cell lung cancer cell line H226B. An in vitro kinase assay with purified ERK1 and p90RSK2 as its substrate demonstrated a direct inhibition of ERK activity by Kazinol E. Additionally, a the molecular docking study provided putative binding modes of Kazinol-E into the ATP binding pocket of ERK1 Collectively, these results suggest that Kazinol-E is a direct inhibitor of ERK1, and more studies are warranted to develop this reagent for therapeutic breast CSLC targeting. PMID- 26774344 TI - Ubiquitin ligase Fbw7 restricts the replication of hepatitis C virus by targeting NS5B for ubiquitination and degradation. AB - The nonstructural protein 5B (NS5B) of hepatitis C virus (HCV) is an RNA dependent RNA polymerase (RdRp) and responsible for replicating the whole HCV genome with help of viral and cellular proteins. However, how cellular factors influence NS5B and, in turn, regulating HCV replication are still poorly defined. The well known tumor suppressor Fbw7, a component of E3 ubiquitin ligase SCF(Fbw7), targets oncoproteins or cellular regulatory proteins for ubiquitin mediated degradation through a highly conserved binding site called a Cdc4 phosphodegron (CPD). But little is known about whether Fbw7 plays a role in regulation of viral proteins. In this study, we revealed that the conserved CPD is shared by NS5B of almost all genotype of HCV and our data demonstrated that NS5B is a bona fide substrate of Fbw7. Forced expression of Fbw7 promoted the ubiquination of NS5B and negatively regulated its turnover in the proteasome dependent manner. We further revealed the interaction between NS5B and Fbw7, which resulted in the relocation of Fbw7 from nucleus to cytoplasm. During HCV replication, ectopic expression of Fbw7 could strongly down-regulate NS5B level and consequently inhibited the virus replication. When endogenous Fbw7 was knocked down, both NS5B protein abundance and HCV replication were remarkably up regulated. The results provide more insights into the interplay of HCV and cellular factors and shed light on molecular mechanisms of HCV replication and pathogenesis. PMID- 26774346 TI - Photochemical changes in water accommodated fractions of MC252 and surrogate oil created during solar exposure as determined by FT-ICR MS. AB - To determine effects of photochemical weathering of petroleum, surrogate and Macondo (MC252) crude oils were exposed to solar radiation during the formation of Water Accommodated Fractions (WAFs) in sterile seawater. Samples were incubated in either unfiltered sunlight, with ultraviolet radiation blocked (Photosynthetically Active Radiation [PAR] only), or in darkness. WAFs were collected at two time points over the course of a week. Fourier Transform Ion Cyclotron Resonance Mass Spectrometry (FT-ICR MS) analyses of water soluble species formed during exposure to sunlight were compared for the different treatments. Photochemical alterations resulted in differences in compound class distributions. In general, surrogate oil was photo-oxidized across a wider carbon number range compared to MC252. While photochemical differences were observed between MC252 and surrogate oils, microbial production in seawater responded similarly to both WAFs from both types of oils with the majority of the inhibition resulting from oil exposure to visible light. PMID- 26774345 TI - Sensory Plasticity in Human Motor Learning. AB - There is accumulating evidence from behavioral, neurophysiological, and neuroimaging studies that the acquisition of motor skills involves both perceptual and motor learning. Perceptual learning alters movements, motor learning, and motor networks of the brain. Motor learning changes perceptual function and the sensory circuits of the brain. Here, we review studies of both human limb movement and speech that indicate that plasticity in sensory and motor systems is reciprocally linked. Taken together, this points to an approach to motor learning in which perceptual learning and sensory plasticity have a fundamental role. PMID- 26774348 TI - Long-Term Response After Surgery and Adjuvant Chemoradiation for T4 Mucinous Adenocarcinoma of the Bladder: A Case Report and Review of the Literature. PMID- 26774347 TI - Survival Outcomes in Men Undergoing Radical Prostatectomy After Primary Radiation Treatment for Adenocarcinoma of the Prostate. AB - PURPOSE: Salvage radical prostatectomy (SRP) is a treatment modality for patients with radio-recurrent prostate cancer but is currently underutilized. We analyzed the survival outcomes in patients receiving SRP for radio-recurrent prostate cancer. The secondary outcome was effect of lymph node dissection on survival following SRP. MATERIALS AND METHODS: The Surveillance, Epidemiology, and End Results (SEER) 18 registry was used to identify patients that underwent radical prostatectomy between 1988 and 2010. Search identified 2628 patients with prostate cancer that underwent surgery after radiation. Following exclusion, 364 patients remained. Endpoints included overall survival (OS) and cancer-specific survival (CSS). Effect of pelvic lymph node dissection (PLND) status and number of nodes retrieved were also studied. Kaplan-Meier analysis, log-rank tests, and Cox-proportional hazard models were used, and P < .05 was considered to be significant. RESULTS: OS was 77.5% at 10 years and 37.3% at 20 years; CSS was 88.6% at 10 years and 72.7% at 20 years. The hazard of mortality was higher in men who did not undergo PLND with a hazard ratio of 1.4 for OS (P = .2) and 2.7 for CSS (P = .01). No significant increase in OS or CC was seen with increasing number of lymph nodes retrieved. Some limitations are inherent to the SEER database and include the lack of hormone manipulation status and PSA data. CONCLUSIONS: Excellent long-term survival can be achieved with SRP. PLND improves CSS but increasing nodal yield does not significantly improve survival. Small sample sizes limit the overall power of this study. PMID- 26774349 TI - Placebo-Induced Severe Diarrhea in a Patient With Metastatic Castration-Resistant Prostate Cancer Participating in a Double-Blind, Randomized, Phase III International Trial. PMID- 26774350 TI - Aggressive Angiomyxoma as a Rare Differential Diagnosis of Enlargement of the Scrotum. PMID- 26774352 TI - High-throughput Imaging as a versatile and unbiased discovery tool. PMID- 26774351 TI - Proteome changes in rainbow trout (Oncorhynchus mykiss) fertilized eggs as an effect of triploidization heat-shock treatment. AB - The aim of the present study was to explore proteome changes in rainbow trout (Oncorhynchus mykiss) fertilized eggs as an effect of triploidization heat-shock treatment. Eggs and milt were taken from eight females and six males. The gametes were pooled to minimize the individual differences. After insemination, the eggs were incubated at 10 degrees C for 10min. Half of the fertilized eggs were then subjected to heat shock for 10min submerged in a 28 degrees C water bath to induce triploidy. The remainder were incubated normally and used as diploid controls. Three batches of eggs were randomly selected from each group and were incubated at 10-11 degrees C under the same environmental conditions in hatchery troughs until the fry stage. Triplicate samples of 30 eggs (10 eggs per trough) from each group were randomly selected 1.5h post-fertilization for proteome extraction. Egg proteins were analyzed using two-dimensional electrophoresis (2 DE) and MALDI-TOF/TOF mass spectrometry. Based on the results from the statistical analyses, 15 protein spots were found to decrease significantly in abundance in heat-shock treated group and were selected for identification. Out of 15 protein spots showing altered abundance, 14 spots were successfully identified. All of the egg proteins identified in our study were related to vitellogenin (vtg). Decreased abundance of vitellogenin in heat-shock treated eggs in our study may either be explained by (i) higher utilization of vtg as an effect of increased cell size in triploids or (ii) changed metabolism in response to heat-shock stress and (iii) diffusion of vtg through chorion due to incidence of egg shell damage. Decreased abundance of vitellogenin in heat-shock treated eggs was associated with reduced early survival rates and lowered growth performance of triploid fish. PMID- 26774354 TI - Assessments of histologic changes after peroral endoscopic myotomy. PMID- 26774353 TI - Clinical impact of endoscopic clip closure of perforations during endoscopic submucosal dissection for colorectal tumors. AB - BACKGROUND AND AIMS: Despite advances in endoscopic submucosal dissection (ESD), perforation can still occur. The purpose of this study is to determine the clinical course and effectiveness of endoscopic closure in addition to the clinicopathologic features related to perforation. METHODS: A total of 935 lesions in 900 consecutive patients between February 1998 and February 2013 underwent ESD for colorectal tumors at our institution. We studied the clinical course and histologic features of perforation through a matched case-control study that included 24 patients with intraprocedural perforation and 240 matched patients without perforation as a control group. Endoscopic closure by using through-the-scope endoclips was attempted in all cases of intraprocedural perforations immediately after perforation was recognized during the procedure. RESULTS: Perforation occurred in 25 cases (2.7%), including 24 intraprocedural perforation and 1 delayed perforation. All but 1 patient with intraprocedural perforation was conservatively managed by endoscopic closure. One patient with unsuccessful endoscopic closure required emergency surgery. Analysis of clinical courses revealed statistically significant differences (P < .01) between the patients with perforation and the case-controlled, nonperforation patients in total procedure time, white blood cell count, and level of serum C-reactive protein on the day after the procedure, admission period, and fasting period. Both location (P = .027) and submucosal fibrosis (P = .04) of the lesion were significantly associated with perforation. Multivariate analysis revealed that fibrosis was a significant risk factor associated with perforation (odds ratio 2.86; 95% confidence interval, 1.03-7.90). CONCLUSIONS: Endoscopic closure allows effective nonsurgical management in cases of intraprocedural perforation during ESD. PMID- 26774355 TI - A novel BAP1 mutation is associated with melanocytic neoplasms and thyroid cancer. AB - Germline mutations in the tumor suppressor gene, BRCA-1 associated protein (BAP1), underlie a tumor predisposition syndrome characterized by increased risk for numerous cancers including uveal melanoma, melanocytic tumors and mesothelioma, among others. In the present study we report the identification of a novel germline BAP1 mutation, c.1777C>T, which produces a truncated BAP1 protein product and segregates with cancer. Family members with this mutation demonstrated a primary clinical phenotype of autosomal dominant, early-onset melanocytic neoplasms with immunohistochemistry (IHC) of these tumors demonstrating lack of BAP1 protein expression. In addition, family members harboring the BAP1 c.1777C>T germline mutation developed other neoplastic disease including thyroid cancer. IHC analysis of the thyroid cancer, as well, demonstrated loss of BAP1 protein expression. Our investigation identifies a new BAP1 mutation, further highlights the relevance of BAP1 as a clinically important tumor suppressor gene, and broadens the range of cancers associated with BAP1 inactivation. Further study will be required to understand the full scope of BAP1 associated neoplastic disease. PMID- 26774357 TI - Scrotal reconstruction with modified pudendal thigh flaps. AB - Scrotal skin loss can occur following trauma, Fournier's gangrene, post tumour excision, burns, etc. There are many techniques described in the literature including residual scrotal skin mobilization, skin grafts, pedicled and free flaps. The management is complex and challenging shown by the multiplicity of flaps and techniques described in the literature. We used a modified pudendal thigh flap to reconstruct scrotal defects in five patients. This study describes the vascularity of the flap, technique of elevation and the inset of the flap. The elevation and particularly the insetting make it different from other flaps raised on this vascular network for scrotal reconstruction. This pedicled flap is robust, reliable, resilient and produces a neo-scrotum that looks natural in appearance, offers good-quality skin cover and cushion to the testes as well as protective sensation. PMID- 26774358 TI - Salvage of a complex first metatarso-phalangeal joint injury and synchronous reconstruction of medial collateral ligament and soft tissue with a distally based medial plantar artery flap. PMID- 26774360 TI - Unilateral sagittal split mandibular ramus osteotomy: indications and geometry. AB - Small mandibular asymmetries may be corrected by unilateral sagittal split ramus osteotomy (USSO). This study had two objectives: first to define the geometric changes in the mandibular condyle and the lower incisor teeth that result from the rotation of the major segment (n=26), and secondly to examine in a clinical study the temporomandibular joints (TMJ) of 23 patients after correction of mandibular asymmetry by USSO to find out if there were any long-term adverse effects. Small mandibular asymmetries (<5mm) can be corrected by USSO. Secondary anteroposterior changes as a result of setback or advancement on the operated side should be taken into account during the planning of treatment. The small rotational changes of the condyle did not adversely affect the TMJ. PMID- 26774359 TI - [Cholesterol and atherosclerosis. Historical considerations and treatment]. AB - Cholesterol is a precursor of steroid hormones and an essential component of the cell membrane, however, altered regulation of the synthesis, absorption and excretion of cholesterol predispose to cardiovascular diseases of atherosclerotic origin. Despite, the recognition of historical events for 200 years, starting with Michel Chevreul naming "cholesterol"; later on, Lobstein coining the term atherosclerosis and Marchand introducing it, Anichkov identifying cholesterol in atheromatous plaque, and Brown and Goldstein discovering LDL receptor; as well as the emerging of different drugs, such as fibrates, statins and cetrapibs this decade, promising to increase HDL and the most recent ezetimibe and anti-PCSK9 to inhibit the degradation of LDL receptor, however morbidity has not been reduced in cardiovascular disease. PMID- 26774356 TI - Circulating fibrocytes correlate with the asthma control test score. AB - BACKGROUND: Bronchial asthma is characterised by airway inflammation and remodelling with a decline of lung function. Fibrocytes are bone marrow-derived mesenchymal progenitor cells that play important roles in the pathogenesis of airway remodelling. Several clinical parameters are currently being used in routine clinical practice to assess outcome of therapy in asthma including frequency of rescue with short-acting beta2-agonist and the asthma control test. In this study, we hypothesised that asthma control test is associated with circulating levels of fibrocytes in bronchial asthma. METHODS: There were 20 patients with asthma and seven healthy controls. The number of CD45(+)Collagen I(+) circulating fibrocytes was assessed in the peripheral blood by flow cytometry. RESULTS: The number of circulating fibrocytes was significantly increased in asthma patients with moderate and severe disease compared to controls, and it was inversely correlated with % forced expiratory volume in one second and % forced vital capacity (%FVC). The frequency of inhalation of short acting beta2 agonist and the asthma control test score was significantly and inversely correlated with the number of circulating fibrocytes. CONCLUSION: The results of this study showed that the number of circulating fibrocytes is inversely correlated with clinical asthma control parameters, further supporting the relevance of measuring circulating fibrocytes as a marker of clinical control in bronchial asthma. PMID- 26774361 TI - Detecting internet search activity for mouth cancer in Ireland. AB - Mouth Cancer Awareness Day in Ireland was launched in September 2010 by survivors of the disease to promote public awareness of suspicious signs of oral cancer and to provide free dental examinations. To find out whether its introduction had increased public interest in the disease, we used Google Trends to find out how often users in Ireland had searched for "oral cancer" and "mouth cancer" across all Google domains between January 2005 and December 2013. The number of internet searches for these cancers has increased significantly (p <0.001) and has peaked each September since the awareness day was launched in 2010. More people searched for "mouth cancer" than for "oral cancer". These findings may have valuable clinical implications, as an increase in public awareness of mouth cancer could result in earlier presentation and better prognosis. PMID- 26774362 TI - Hepato-peritoneal tuberculosis with negative interferon gamma assay (QuantiferonTM) in an immunocompetent patient: A case report. PMID- 26774364 TI - Pre-invasive intraductal papillary neoplasm of the pancreatobiliary system. PMID- 26774363 TI - Aminopeptidase N (APN/CD13) as a target molecule for scirrhous gastric cancer. AB - BACKGROUND: Scirrhous gastric cancer is associated with peritoneal dissemination and advanced lymph node metastasis from an early stage, and the prognosis is still poor. In this study, we aimed to analyze candidate molecules for targeted therapy of scirrhous gastric cancer. We searched for molecules/metabolic activity that might be predominantly expressed in a subpopulation of scirrhous gastric cancer cells and might function as cancer stem cell markers. RESULTS: For this purpose, we investigated the expression of various cell surface markers and of aldehyde dehydrogenase (ALDH) activity. These analyses showed that the scirrhous gastric cancer cell lines HSC-58 and HSC-44PE heterogeneously expressed CD13, while CD44, CDCP1, EpCAM and ABCG2 were expressed uniformly. Moreover, 10% of the total HSC-58 cell population expressed ALDH enzyme activity. A subpopulation of cells strongly positive for ALDH also expressed high levels of CD13, both of which are known as cancer stem cell markers. HSC-58 cells expressing high levels of CD13 showed lower sensitivity to a cancer drug cisplatin than cells with low levels of CD13. In contrast, CD13(-high) subpopulation of HSC-58 was more sensitive to an aminopeptidase N inhibitor bestatin. In terms of antibody-drug therapy, anti-CD13-immunotoxin was highly cytotoxic towards HSC-58 cells and was more cytotoxic than anti-EpCAM-immunotoxin. CONCLUSION: These data suggest that CD13 is a suitable cell surface candidate for targeted antibody-drug therapy of scirrhous gastric cancer. PMID- 26774365 TI - A Prospective Cohort Study to Examine the Association Between Dietary Patterns and Sarcopenia in Chinese Community-Dwelling Older People in Hong Kong. AB - OBJECTIVES: Dietary pattern analysis has recently emerged as an alternative approach to investigate the association between diet and sarcopenia. This study examined the association of dietary patterns with sarcopenia in Chinese community dwelling older people. METHODS: Chinese men and women aged 65 years or older participating in a cohort study examining the risk factors for osteoporosis completed a validated food frequency questionnaire at baseline between 2001 and 2003. Adherence to a priori dietary patterns, namely the Diet Quality Index International (DQI-I) and the Mediterranean Diet Score (MDS) was assessed. Factor analysis identified 3 a posterior dietary patterns: "vegetables-fruits," "snacks drinks-milk products," and "meat-fish." Sarcopenia was defined using the Asian Working Group for Sarcopenia algorithm. Multiple logistic regression was used for cross-sectional analysis (n = 3957) to assess the associations between dietary patterns and prevalent sarcopenia, and for longitudinal analysis (n = 2948) on their associations with 4-year incident sarcopenia with adjustment for sociodemographic and lifestyle factors. RESULTS: There were 290 (7.3%) (185 men, 105 women) sarcopenic cases at baseline and 264 (9.0%) (160 men, 104 women) incident sarcopenic cases at the 4-year follow-up. At baseline, men in the highest quartile of DQI-I had reduced odds of sarcopenia (Adjusted OR 0.50, 95% CI 0.31-0.81, Ptrend = .004) compared with men in the lowest quartile. Men in the highest quartile of "vegetables-fruits" pattern score (Adjusted OR 0.60, 95% CI 0.36-0.99, Ptrend = .034) showed lower likelihood of sarcopenia compared with men in the lowest quartile. Higher quartile of "snacks-drinks-milk products" pattern score was associated with lower odds of sarcopenia in men (Adjusted OR 0.41, 95% CI 0.24-0.70, Ptrend < .001). There was no association between dietary patterns and prevalent sarcopenia in women. None of the dietary patterns was associated with incident sarcopenia at 4-year in both sexes. CONCLUSIONS: Higher DQI-I, higher "vegetables-fruits" dietary pattern score, and higher "snacks-drinks-milk products" dietary pattern score were associated with lower odds of prevalent sarcopenia in Chinese older men. PMID- 26774366 TI - The NRAMP1, VDR, TNF-alpha, ICAM1, TLR2 and TLR4 gene polymorphisms in Iranian patients with pulmonary tuberculosis: A case-control study. AB - The innate immune response drives early events in Mycobacterium tuberculosis infection. Since human genetic variation is an important determinant in the outcome of infection with M. tuberculosis, we typed polymorphisms in the innate immune molecules, such as natural-resistance-associated macrophage protein 1 (NRAMP1), Vitamin D receptor (VDR), Tumor necrosis factor alpha (TNF-alpha), intercellular adhesion molecule1 (ICAM-1), Toll-like receptor 2 (TLR2) and Toll like receptor 4 (TLR4) in a case-control study of pulmonary tuberculosis in Iranian population. We conducted an association study and included 96 patients and 122 matched healthy individuals. We used single ARMS-PCR technique to simultaneously genotype fourteen polymorphisms in this survey. Among all fourteen polymorphisms that were examined, three polymorphisms were significantly different between case and control groups. The TNF -308A polymorphism showed significant increase in allele and genotype frequencies among patients compared to control individuals [-308A allele: 19.3 vs. 9.4%, GA genotype: 28.1 vs. 17.2%, AA genotype: 5.2 vs. 0.8%; Corrected P (Pc)<0.05], and the TLR4 variant allele and genotypes prevalence (D299G and T399I) were significantly higher among patients compared to controls [DG genotype: 14.6 vs. 5.7%, Pc<0.05 and I399 allele: 4.2 vs. 0.8%, TI genotype: 8.3 vs. 1.6%; Pc<0.05], respectively. In conclusion, our data suggest that TLR4 (D299G and T399I) and TNF (-308G/A) genetic polymorphisms may influence the risk of developing tuberculosis after exposure to Mycobacterium. PMID- 26774367 TI - Analysis of the miRNA expression profile in an Aedes albopictus cell line in response to bluetongue virus infection. AB - Cellular microRNAs (miRNAs) have been reported to be key regulators of virus-host interactions. Bluetongue virus (BTV) is an insect-borne virus that causes huge economic losses in the livestock industry worldwide. Aedes albopictus cell lines have become powerful and convenient tools for studying BTV-vector interactions. However, the role of miRNAs in A. albopictus cells during BTV infection is not well understood. In this study, we performed a deep sequencing analysis of small RNA libraries of BTV-infected and mock-infected A. albopictus cells, and a total of 11,206,854 and 12,125,274 clean reads were identified, respectively. A differential expression analysis showed that 140 miRNAs, including 15 known and 125 novel miRNAs, were significantly dysregulated after infection, and a total of 414 and 2307 target genes were annotated, respectively. Real-time quantitative reverse transcription-polymerase chain reaction validated the expression patterns of 11 selected miRNAs and their mRNA targets. Functional annotation of the target genes suggested that these target genes were mainly involved in metabolic pathways, oxidative phosphorylation, endocytosis, RNA transport, as well as the FoxO, Hippo, Jak-STAT, and MAPK signaling pathways. This is the first systematic study on the effect of BTV infection on miRNA expression in A. albopictus cells. This investigation provides information concerning the cellular miRNA expression profile in response to BTV infection, and it offers clues for identifying potential candidates for vector-based antiviral strategies. PMID- 26774368 TI - Interplay of autophagy and apoptosis during PRRSV infection of Marc145 cell. AB - Autophagy and apoptosis play essential roles 'in virus infection. Our study was performed to investigate the interplay between autophagy and apoptosis in PRRSV replication. In our present study, autophagy and apoptosis were induced by PRRSV infection. Viral replication was dampened/attenuated by autophagy deficient and potentiated by apoptosis inhibition. Furthermore, PRRSV replication was restored by apoptosis inhibition in autophagy deficient cells. Taken together, our findings unveil the functional relationship between autophagy and apoptosis during PRRSV replication. PMID- 26774369 TI - Endovascular treatment for Angio-Seal-related complications: long-term outcome. PMID- 26774371 TI - Re: comparison of clinically suspected injuries with injuries detected at whole body CT in suspected multi-trauma victims. A reply. PMID- 26774372 TI - Validation of 3 T MRI including diffusion-weighted imaging for nodal staging of newly diagnosed intermediate- and high-risk prostate cancer. AB - AIM: To prospectively validate 3 T magnetic resonance imaging (MRI) including diffusion-weighted imaging (DWI) for preoperative lymph node (LN) staging in a clinical setting, in intermediate- and high-risk prostate cancer (PCa) patients using laparoscopic extended LN dissection (ePLND) as the reference standard. MATERIALS AND METHODS: Between August 2011 and May 2013, 40 newly diagnosed intermediate and high-risk PCa patients underwent preoperative LN staging with 3 T MRI DWI using histopathology of ePLND as the reference standard. The sensitivity, specificity, and accuracy of MRI DWI were calculated. A subgroup analysis of proven LN-positive patients was made to investigate differences in PSA, Gleason score, number, and size of LN metastases, estimated risk of LN involvement, and if curative treatment was indicated, between the true-positive and the false-negative groups. RESULTS: A total of 728 LN were harvested from six anatomical regions per patient (external, obturator, internal) with a mean number of 18 LNs per patient (range 11-40). Twenty patients had histologically proven LN positive disease. MRI DWI was true positive in 11 patients, false negative in nine patients, false positive in two patients, and true negative in 18 patients, resulting in 90% specificity, 55% sensitivity, and 72.5% accuracy. The true positive patients had significantly more involved LNs (mean 6.9 versus 2.7, p=0.017), with larger diameter (mean 12.3 versus 5.2 mm, p=0.048) and fewer were treated with curative intent (six versus nine, p=0.03), compared with the false negative group. CONCLUSION: MRI DWI LN staging has a low sensitivity but high specificity. The true-positive patients have a considerably higher burden of LN metastases compared to false-negative patients. PMID- 26774370 TI - Three-dimensional isotropic T2-weighted fast spin-echo (VISTA) ankle MRI versus two-dimensional fast spin-echo T2-weighted sequences for the evaluation of anterior talofibular ligament injury. AB - AIM: To compare the performance of axial images of the ankle joint on three dimensional (3D) volume isotropic turbo spin echo acquisition (VISTA) with that of two-dimensional (2D) fast spin echo (FSE) T2-weighted images for the diagnosis of anterior talofibular ligament (ATFL) injury. MATERIALS AND METHODS: This retrospective study included 101 patients who underwent both 2D FSE T2-weighted and 3D VISTA magnetic resonance imaging (MRI) of the ankle. The signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) of both sequences were measured. The anatomical identification score and diagnostic performances of both sequences were evaluated by two radiologists. The diagnostic performances of 3D VISTA and 2D FSE images were analysed in terms of sensitivity, specificity, and accuracy for diagnosing ATFL injury. Surgically or clinically confirmed diagnoses were used as reference standards. RESULTS: The margin sharpness scores on 3D VISTA were significantly inferior to those of 2D FSE (p<0.001). Other scores (entire length, entire width) were not significantly different between the two imaging methods. The SNRs and CNRs of 3D VISTA were significantly higher than those of 2D FSE (p<0.001). When diagnoses were classified as normal and abnormal, the specificity of the 3D VISTA images for the diagnosis of ATFL injury was 95.7%, significantly superior to 2D FSE (84.3-85.7%). There were no significant differences between 3D VISTA and 2D FSE images in sensitivity or accuracy for diagnosis (p=0.227-1.000), with the exception of accuracy by reader 1 (p=0.039). CONCLUSION: 3D VISTA imaging has a diagnostic performance comparable to that of 2D FSE for the diagnosis of ATFL injury, although 3D VISTA is inferior to 2D FSE for the evaluation of margin sharpness. Replacing axial and coronal images with 3D VISTA can save imaging time without negatively impacting the diagnostic ability for ATFL injury. PMID- 26774373 TI - Pelvic-perineal reconstruction with the combined transverse upper gracilis and profunda artery perforator (TUG-PAP) flap. PMID- 26774374 TI - Galactosylated alginate-curcumin micelles for enhanced delivery of curcumin to hepatocytes. AB - Galactosylated alginate-curcumin conjugate (LANH2-Alg Ald-Cur) is synthesized for targeted delivery of curcumin to hepatocytes exploiting asialoglycoprotein receptor (ASGPR) on hepatocytes. The synthetic procedure includes oxidation of alginate (Alg), modification of lactobionic acid (LA), grafting of targeting group (modified lactobinic acid, LANH2) and conjugation of curcumin to alginate. Alginate-curcumin conjugate (Alg-Cur) without targeting group is also prepared for the comparison of properties. LANH2-Alg Ald-Cur self assembles to micelle with diameter of 235 +/- 5 nm and zeta potential of -29 mV in water. Cytotoxicity analysis demonstrates enhanced toxicity of LANH2-Alg Ald-Cur over Alg-Cur on HepG2 cells. Cellular uptake studies confirm that LANH2-Alg Ald-Cur can selectively recognize HepG2 cells and shows higher internalization than Alg-Cur conjugate. Results indicate that LANH2-Alg Ald-Cur conjugate micelles are suitable candidates for targeted delivery of curcumin to HepG2 cells. PMID- 26774375 TI - Purification and characterization of polysaccharides degradases produced by Alteromonas sp. A321. AB - Two different degradases from Alteromonas sp. A321 for polysaccharides from Enteromorpha prolifera (DPE-L and DPE-P) were purified to homogeneity. The molecular weights of purified DPE-L and DPE-P were 75.2 and 102.5 kDa, respectively, and their internal sequences were analysed by LC-MS-MS. The enzymes exhibited an optimum temperature of 30-40 degrees C (DPE-L) and 35-45 degrees C (DPE-P), an optimum pH of 7.0 (DPE-L) and 6.0 (DPE-P). DPE-P was highly stable in the presence of EDTA and 1,10-phenanthroline while DPE-L was inhibited by 1,10 phenanthroline. The Km values of DPE-L and DPE-P were 2.93 mg/ml and 0.31 mg/ml and the Vmax values were 6.11 MUmol/min/ml and 2.88 MUmol/min/ml, respectively. Results of HPLC and ESI-MS analyses showed that enzymatic products were: Rha1(SO3H)1, Rha1(SO3H)1Gluc1, Rha2(SO3H)2Gluc1, and Rha3(SO3H)3Gluc1Xyl1 by DPE L, and Glu2, Glu3, plus Glu4 by DPE-P, respectively. Thus DPE-L and DPE-P can be used to produce oligosaccharides which potentially revealed more of structure of polysaccharides from E. prolifera. PMID- 26774377 TI - Structure and preventive effects against ethanol-induced gastric ulcer of an expolysaccharide from Lachnum sp. AB - An extracellular polysaccharide of Lachnum sp. (LEP) was purified by DEAE cellulose 52 column chromatography and Sepharose CL-6B column chromatography. LEP 2a was identified to be a homogeneous component with an average molecular weight of 3.22 * 10(4)Da. The structure of LEP-2a was characterized by chemical and spectroscopic methods, including methylation analysis, periodate oxidation-smith degradation, infrared spectroscopy and NMR analysis. Results indicated that LEP 2a was a (1->3)-,(1->6)-beta-D-Glcp, whose branch chain was consist of two d glucopyranosyl residues linked by beta-1,3-glycosidic linkage, which was linked at C6 of the backbone chain by beta-1,6-glycosidic linkage. To study the protective effects of LEP-2a on the ethanol-induced gastric ulcer in mice, LEP-2a (100, 200 and 400mg/kg/d) was given to mice by gavage for 2 weeks. Results showed that LEP-2a significantly decreased the ulcer bleeding areas, pepsin activity, gastric juice volume, gastric juice total acidity and the malondialdehyde (MDA) content in serum. Meanwhile, the superoxide dismutase (SOD) increased significantly. The above findings suggested that LEP-2a had a significant preventive effect against the ethanol-induced gastric ulcer. PMID- 26774378 TI - Promoting gross motor skills and physical activity in childcare: A translational randomized controlled trial. AB - OBJECTIVES: Educator-led programs for physical activity and motor skill development show potential but few have been implemented and evaluated using a randomized controlled design. Furthermore, few educator-led programs have evaluated both gross motor skills and physical activity. Therefore, the aim of this study was to evaluate a gross motor skill and physical activity program for preschool children which was facilitated solely by childcare educators. DESIGN: A six-month 2-arm randomized controlled trial was implemented between April and September 2012 in four early childhood centers in Tasmania, Australia. METHODS: Educators participated in ongoing professional development sessions and children participated in structured physical activity lessons and unstructured physical activity sessions. RESULTS: In total, 150 children were recruited from four centers which were randomized to intervention or wait-list control group. Six early childhood educators from the intervention centers were trained to deliver the intervention. Gross motor skills were assessed using the Test of Gross Motor Development (2nd edition) and physical activity was measured objectively using GT3X+ Actigraph accelerometers. No statistically significant differences were identified. However, small to medium effect sizes, in favor of the intervention group, were evident for four of the five gross motor skills and the total gross motor skill score and small to medium effect sizes were reported for all physical activity outcomes. CONCLUSIONS: This study highlights the potential of educator led physical activity interventions and supports the need for further translational trials within the early childhood sector. PMID- 26774379 TI - Concurrent fungus ball and squamous cell carcinoma of the maxillary sinus. PMID- 26774376 TI - Development of ecofriendly bionanocomposite: Whey protein isolate/pullulan films with nano-SiO2. AB - During the past decade, the limitation of petroleum based polymers, the high price of oil, and the environmental concern were attracted the attention of researchers to develop biobased polymers. The composition of different biopolymers and the reinforcement with nano filler are common methods to improve the drawbacks of biopolymers. In this study whey protein isolate/pullulan (WPI/PUL) films contain 1%, 3%, and 5% (w/w) nano-SiO2 (NS) were prepared by a casting method. Tensile strength of nanocomposite films increased after increasing NS content, but elongation at break decreased, simultaneously. Water absorption, moisture content, solubility in water improved in the wake of increasing NS content because NS increase the cohesiveness of the polymer matrix and improved the barrier and water resistance properties of the films. water vapor permeability of film specimens decreased by increasing NS content. Uniform distribution of NS into polymer matrix was confirmed by scanning electron microscopy (SEM). XRD pattern and thermal analysis revealed increasing crystallinity and increasing Tg of film specimens with increasing NS content, respectively. According to our result WPI/PUL/NS films possess potential to be used as environment friendly packaging films to improve shelf life of food and can be used as promising alternative to petroleum based packaging films. PMID- 26774381 TI - Narrow-band ultraviolet B radiation induces the expression of beta-endorphin in human skin in vivo. AB - BACKGROUND: Ultraviolet radiation (UVR) from the sun and solaria has addictive properties that may develop into dependence. In mice, UVR addiction was connected to beta-endorphin (beta-END) formed in the skin after UVR exposure. In humans, the formation of beta-END in skin keratinocytes has not been confirmed in vivo. OBJECTIVE: To determine with immunohistochemistry if sub-erythematous narrow-band UV-B (NB-UV-B) exposures stimulate p53 mediated expression of pro opiomelanocortin (POMC), beta-END and alpha-melanocyte stimulating hormone (alpha MSH) in human skin keratinocytes in vivo. METHODS: Within 12 healthy volunteers, 7 received a single 1 standard erythema dose (SED) of NB-UV-B on their whole body, and 5 volunteers received a cumulative dose of 3 SED delivered on two subsequent days i.e., 1+2 SED. Skin biopsies were taken immediately before the first exposure and at 24h from the last UV-B exposure to assess p53, beta-END, POMC, and alpha-MSH expression. RESULTS: Nuclear p53 expression increased in all samples taken at 24h after NB-UV-B exposure. UV-B irradiation also increased epidermal beta-END expression in 11 out of 12 samples taken at 24h after UV-B exposure. The brownish staining was localized in the cytoplasm of keratinocytes and around the nuclei, being more pronounced in the basal cell layers. POMC and alpha-MSH staining showed no obvious meaningful increase since only one section of each showed any change compared with basal levels. CONCLUSIONS: Our study is the first to show that UV-B exposures increase beta-END expression in epidermal keratinocytes of human skin in vivo, which could be the link to proposed UVR addiction. PMID- 26774380 TI - Differential immunological effects of infrared irradiation and its associated heat in vivo. AB - Infrared irradiation (IR) is the most abundant fraction of sunlight reaching the earth's surface and provides heat. The fever response of an animal is known to regulate its immune responses. However, the non-thermal immune responses of IR were difficult to assess owing to its close association with heat. We hypothesized that IR irradiation induced differential immunological responses, independent of its associated heat. With an IR machine coupled with a delicate temperature control system, we investigated the non-thermal immunological effects of IR in vivo. With heating at 37 degrees C or 39 degrees C using an electric blanket or IR irradiation, we measured the skin's physiological parameters, including transepidermal water loss (TEWL), pH, skin hydration, elasticity, sebum production, and skin blood flow. We also measured the number of Langerhans cells in epidermal sheets and draining lymph nodes. Lymph node cells were activated by anti-CD3 antibody and their production of interleukin (IL)-5, 10, 13, 17, and interferon (IFN)-gamma was measured by enzyme-linked immunosorbent assay (ELISA). The result showed that compared to heating alone, IR causes an enhanced activation of epidermal Langerhans cells, both in epidermal sheets and in draining lymph nodes. The activation of draining lymph node cells by anti-CD3 antibody in vitro induces both Th2 and Th1, but not Treg immune responses. Interestingly, IL-13, a Th2 cytokine, is induced the most. In contrast, physiological parameters and barrier functions of skin were not altered after IR irradiation. The study showed that IR alone without heat modulates immune responses in vivo, indicating that IR irradiation might regulate host immunity in a heat-independent manner. PMID- 26774382 TI - Green and ecofriendly synthesis of silver nanoparticles: Characterization, biocompatibility studies and gel formulation for treatment of infections in burns. AB - The current study summarizes a unique green process for the synthesis of silver nanoparticles (AgNPs) by simple treatment of silver nitrate with aqueous extract of Ammania baccifera. Phytosynthesized AgNPs were characterized by various advanced analytical methods and studied for its use against infections associated with burns. Formation of AgNPs was observed by visual color change from colorless to dark brown and confirmed by UV-visible characteristic peak at 436 nm. Zeta potential, particle size and polydispersity index of nano-silver were found to be -33.1 +/- 1.12, 112.6 +/- 6.8 nm and 0.3 +/- 0.06 respectively. XRD spectra revealed crystalline nature of AgNPs whereas TEM confirmed the presence of mixed morphology of AgNPs. The overall approach designated in the present research investigation for the synthesis of AgNPs is based on all 12 principles of green chemistry, in which no man-made chemical other than the silver nitrate was used. Synthesized nano-silver colloidal dispersion was initially tested for minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) against a panel of organisms involved in infections associated with burns (Pseudomonas aeruginosa (PA), Staphylococcus aureus (SA) and methicillin resistant S. aureus (MRSA)). MIC and MBC were found to be in range of 0.992 to 7.93 and 7.93 to 31.75 MUg/mL respectively. MBC was used for formulation of AgNP gel and tested for its efficacy using agar well diffusion method against PA, SA and MRSA. Comparative bactericidal efficacy of formulated gel (0.03% w/w) and marked formulation SilverexTM ionic (silver nitrate gel 0.2% w/w) showed equal zone of inhibition against all pathogenic bacteria. Formulated AgNP gel consisting of 95% lesser concentration of silver compared to marketed formulation was found to be equally effective against all organisms. Hence, the formulated AgNP gel could serve as a better alternative with least toxicity towards the treatment presently available for infections in burns. PMID- 26774383 TI - Egr-1 identifies neointimal remodeling and relates to progression in human pulmonary arterial hypertension. AB - BACKGROUND: Pulmonary arterial hypertension (PAH) is hallmarked by the development of neointimal lesions. The transcription factor Egr-1 seems to play a critical role in neointimal formation in experimental PAH and was identified as a putative target for intervention. In this study we investigated whether Egr-1 is also associated with neointimal-type vascular remodeling in different forms of human PAH or pulmonary hypertension. METHODS: Using immunohistochemistry, we studied Egr-1 expression specifically in a wide morphologic spectrum of pulmonary arteries in the lung tissue of 72 patients with different forms and stages of PAH, specifically idiopathic PAH (n = 18), advanced-stage congenital heart disease-associated PAH (PAH-CHD) (n = 21), early-stage PAH-CHD (n = 19) and non neointimal hypoxic pulmonary hypertension (PH) (n = 4), and controls (n = 10). RESULTS: In PAH patients, pulmonary vascular expression of Egr-1 protein was abundant, whereas it was sporadic in non-neointimal (hypoxic) PH patients and controls. In PAH-CHD, protein expression was more pronounced in patients with advanced vascular lesions compared to those with less advanced lesions, such as medial hypertrophy. CONCLUSIONS: Pulmonary vascular Egr-1 expression is significantly increased in patients with PAH, appears specifically associated with neointimal-type vascular remodeling, and correlates with disease progression. These data translate the critical role of Egr-1 in the development of experimental PAH to human pulmonary vascular disease forms. PMID- 26774385 TI - Phagocyte function decreases after high-dose treatment with melphalan and autologous stem cell transplantation in patients with multiple myeloma. AB - High-dose melphalan with autologous hematopoietic stem cell transplantation (ASCT) is the standard of care for younger patients with newly diagnosed multiple myeloma and is aimed at achieving as deep and complete a response as possible after various combinations of induction therapy. However, it is frequently associated with infectious complications. This study investigated the effects of high-dose treatment with autologous stem cell support on patients' innate immunity, with a focus on subpopulations and functioning of recently released polymorphonuclear leukocytes (PMNs) and monocytes in peripheral blood. Flow cytometry-based analysis was used to measure the degree of PMN maturation and activation, before and after ASCT and compared with healthy controls. After high dose treatment and ASCT, a smaller proportion of patients' PMNs had the capacity for oxidative burst. Moreover, patients' PMNs, both before and after ASCT, had a reduced capacity for phagocytosis. Eosinophils, which recently have been suggested to play a role in promoting malignant plasma cell proliferation, were markedly reduced after ASCT, with slow regeneration. HLA-DR expression by monocytes was significantly depressed after ASCT, a characteristic often attributed to monocytic myeloid-derived suppressor cells. Our results suggest that several aspects of phagocytic function are impaired for at least 20 days after ASCT. PMID- 26774386 TI - ESAM is a novel human hematopoietic stem cell marker associated with a subset of human leukemias. AB - Reliable markers are essential to increase our understanding of the biological features of human hematopoietic stem cells and to facilitate the application of hematopoietic stem cells in the field of transplantation and regenerative medicine. We previously identified endothelial cell-selective adhesion molecule (ESAM) as a novel functional marker of hematopoietic stem cells in mice. Here, we found that ESAM can also be used to purify human hematopoietic stem cells from all the currently available sources (adult bone marrow, mobilized peripheral blood, and cord blood). Multipotent colony-forming units and long-term hematopoietic-reconstituting cells in immunodeficient mice were found exclusively in the ESAM(High) fraction of CD34(+)CD38(-) cells. The CD34(+)CD38(-) fraction of cord blood and collagenase-treated bone marrow contained cells exhibiting extremely high expression of ESAM; these cells are likely to be related to the endothelial lineage. Leukemia cell lines of erythroid and megakaryocyte origin, but not those of myeloid or lymphoid descent, were ESAM positive. However, high ESAM expression was observed in some primary acute myeloid leukemia cells. Furthermore, KG-1a myeloid leukemia cells switched from ESAM negative to ESAM positive with repeated leukemia reconstitution in vivo. Thus, ESAM is a useful marker for studying both human hematopoietic stem cells and leukemia cells. PMID- 26774387 TI - A retrospective analysis of morphokinetic parameters according to the implantation outcome of IVF treatment. AB - OBJECTIVE: The aim of this study was to identify candidates for a morphokinetic embryo selection model for day-3 transfer through the analysis of known implantation data. STUDY DESIGN: A diagnostic trial study was conducted. Two hundred twelve embryos from 109 patients participating in in-vitro fertilization (IVF) protocols. RESULTS: In this diagnostic trial study, we analyzed cleavage times of transferred embryos with either failed (n=102) or full implantations (n=110). The logistic regression (LR) model of the relationship between the morphokinetic parameters and the implantation rate had a sensitivity of 79.61% and specificity of 47.56%. Results also showed that morphokinetic parameters such as tPNf (the time when pronuclei disappearanced), t2 (t2 for two cells), t4 (t4 for four cells) and t4-t3 were significantly different between embryos in the two groups (p<0.037). Implantation rates of embryos within the time interval of 21.27 h< t2 < 26.725 h were higher than those of embryos outside this period (60.83% vs. 40.21%, p=0.003). Fifty-seven patients with fully implanted embryos included five patients with pregnancy loss and 52 patients with live births. Embryos that met the time interval criteria for t2 and were also within the range of 11h